Renal hemodynamic effects differ between antidiabetic combination strategies: randomized controlled clinical trial comparing empagliflozin/linagliptin with metformin/insulin glargine - Ott, Christian; Jung, Susanne; Korn, Manuel; Kannenkeril, Dennis; Bosch, Agnes; Kolwelter, Julie; Striepe, Kristina; Bramlage, Peter; Schiffer, Mario; Schmieder, Roland (Cardiovascular Diabetology, 2021)
Background: Type 2 diabetes causes cardio-renal complications and is treated with different combination therapies. The renal hemodynamics profile of such combination therapies has not been evaluated in detail. Methods: Patients (N = 97) with type 2 diabetes were randomized to receive either empagliflozin and linagliptin (E+L group) or metformin and insulin glargine (M+I group) for 3 months. Renal hemodynamics were assessed with para-aminohippuric acid and inulin for renal plasma flow (RPF) and glomerular filtration rate (GFR). Intraglomerular hemodynamics were calculated according the Gomez´ model. Results: Treatment with E+L reduced GFR (p = 0.003), but RPF remained unchanged (p = 0.536). In contrast, M+I not only reduced GFR (p = 0.001), but also resulted in a significant reduction of RPF (p < 0.001). Renal vascular resistance (RVR) decreased with E+L treatment (p = 0.001) but increased with M+I treatment (p = 0.001). The changes in RPF and RVR were different between the two groups (both padjust < 0.001). Analysis of intraglomerular hemodynamics revealed that E+L did not change resistance of afferent arteriole (RA) (p = 0.116), but diminished resistance of efferent arterioles (RE) (p = 0.001). In M+I group RA was increased (p = 0.006) and RE remained unchanged (p = 0.538). The effects on RA (padjust < 0.05) and on RE (padjust < 0.05) differed between the groups. Conclusions: In patients with type 2 diabetes and preserved renal function treatment with M+I resulted in reduction of renal perfusion and increase in vascular resistance, in contrast to treatment with E+I that preserved renal perfusion and reduced vascular resistance. Moreover, different underlying effects on the resistance vessels have been estimated according to the Gomez model, with M+I increasing RA and E+L predominantly decreasing RE, which is in contrast to the proposed sodium-glucose cotransporter 2 inhibitor effects. Trial registration: The study was registered at www.clinicaltrials.gov (NCT02752113) on April 26, 2016
CRIS-Team Scopus Importer:2021-09-17
Keywords: Hemodynamics; Intraglomerular; Renal; Type 2 diabetes

Renal impairment and worsening of renal function in acute heart failure: can new therapies help? The potential role of serelaxin - Schmieder, Roland; Mitrovic, Veselin; Hengstenberg, Christian (Clinical Research in Cardiology, 2015)
Renal dysfunction is a frequent finding in patients with acute heart failure (AHF) and an important prognostic factor for adverse outcomes. Worsening of renal function occurs in 30-50 % of patients hospitalised for AHF, and is associated with increased mortality, prolonged hospital stay and increased risk of readmission. Likely mechanisms involved in the decrease in renal function include impaired haemodynamics and activation of neurohormonal factors, such as the renin-angiotensin-aldosterone system, the sympathetic nervous system and the arginine-vasopressin system. Additionally, many drugs currently used to treat AHF have a detrimental effect on renal function. Therefore, pharmacotherapy for AHF should carefully take into account any potential complications related to renal function. Serelaxin, currently in clinical development for the treatment of AHF is a recombinant form of human relaxin-2, identical in structure to the naturally occurring human relaxin-2 peptide hormone that mediates cardiac and renal adaptations during pregnancy. Data from both pre-clinical and clinical studies indicate a potentially beneficial effect of serelaxin on kidney function. In this review, we discuss the mechanisms and impact of impairment of renal function in AHF, and the potential benefits of new therapies, such as serelaxin, in this context.
EVALuna2:3787

Renal nerve ablation in nephritis and beyond - Rodionova, Kristina; Ditting, Tilmann; Veelken, Roland (Journal of the American Society of Nephrology, 2021)
CRIS-Team Scopus Importer:2021-10-22

Renal outcomes and blood pressure patterns in diabetic and nondiabetic individuals at high cardiovascular risk - Böhm, Michael; Schumacher, Helmut; Teo, Koon K.; Lonn, Eva M.; Mahfoud, Felix; Emrich, Insa; Mancia, Giuseppe; Redon, Josep; Schmieder, Roland; Sliwa, Karen; Lehrke, Michael; Marx, Nikolaus; et al. (Journal of Hypertension, 2021)
BACKGROUND: Diabetes and hypertension are risk factors for renal and cardiovascular outcomes. Data on the association of achieved blood pressure (BP) with renal outcomes in patients with and without diabetes are sparse. We investigated the association of achieved SBP, DBP with renal outcomes and urinary albumin excretion (UAE) in people with vascular disease. METHODS: In this pooled analysis, we assessed renal outcome data from high-risk patients aged 55 years or older with a history of cardiovascular disease, 70% of whom had hypertension, randomized to The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial and to Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease trials investigating telmisartan, ramipril and their combination with a median follow-up of 56 months. Standardized office BP was measured every 6 months, estimated glomerular filtration rate (eGFR) and UAE at baseline, 2 years and study end. Associations of mean achieved BP on treatment were investigated on major renal outcomes including end-stage renal disease (ESRD), decline of eGFR by at least 40%, doubling of creatinine and the composites thereof and on UAE. Analyses were by Cox regression analysis, analysis of variance and Chi2-test. Of 30 937 patients with complete data, 19 450 patients without and 11 487 with diabetes were enrolled between 1 December 2001 and 31 July 2003 and followed until 31 July 2008. Data were pooled as the outcomes for telmisartan 80 mg/day (n = 2903) or placebo (n = 2907) for Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease and ramipril 10 mg/day (n = 8407), telmisartan 80 mg/day (n = 8386) or the combination of both (n = 8334) were similar. RESULTS: For both those with and without diabetes, the hazard ratios for the composites ESRD or doubling of serum creatinine (707 events overall) and ESRD or 40% eGFR loss (2371 events overall) reached a nadir at achieved SBP of 120 to less than 140 mmHg, and increased with higher and lower SBP with similar relative risk with or without diabetes. For example, risk for the former composite reached a hazard ratios 3.06 (confidence interval 1.90-4.92) with a mean achieved SBP more than 160 mmHg compared with 120 to less than 130 mmHg with diabetes and hazard ratios 2.14 (1.09-4.26) without diabetes. In contrast, the development of new microalbuminuria and macroalbuminuria (3002 and 846 events overall) associated linearly over the whole range of achieved SBP (apart from a slight increase in risk at SBP less than 120 mmHg only in those without diabetes). Absolute risks for the composite and albuminuria outcomes were consistently greater in those with diabetes as compared with without diabetes with high event rates over the whole SBP spectrum. The increased renal risk at low SBP was not related to a meaningful reduction of mandated study drugs or open label renin-angiotensin-aldosterone system inhibition. CONCLUSION: In patients at high cardiovascular risk, SBP levels more than 140 mmHg and less than 120 are associated with increased risk for renal outcomes. Renal risk was greater in diabetes across the whole range of achieved SBP and DBP. These data suggest similar target BP range in patients with and without diabetes to prevent renal outcomes, a frequent complication in high-risk vascular patients. CLINICAL TRIAL REGISTRATION: Clinical Trial registration: http://clinicaltrials.gov.Unique identifier: NCT00153101.
CRIS-Team Scopus Importer:2021-04-19

Renal sympathetic nerve activity regulates cardiovascular energy expenditure in rats fed high salt - Morisawa, Norihiko; Kitada, Kento; Fujisawa, Yoshihide; Nakano, Daisuke; Yamazaki, Daisuke; Kobuchi, Shuhei; Li, Lei; Zhang, Yifan; Morikawa, Takashi; Konishi, Yoshio; Yokoo, Takashi; Luft, Friedrich C.; et al. (Hypertension Research, 2020)
We recently reported that a 4% high-salt diet + saline for drinking (HS + saline) leads to a catabolic state, reduced heart rate, and suppression of cardiovascular energy expenditure in mice. We suggested that HS + saline reduces heart rate via the suppression of the sympathetic nervous system to compensate for the high salt intake-induced catabolic state. To test this hypothesis, we directly measured renal sympathetic nerve activity (RSNA) in conscious Sprague-Dawley (SD) rats using a radiotelemetry system. We confirmed that HS + saline induced a catabolic state. HS + saline decreased heart rate, while also reducing RSNA in SD rats. In contrast, Dahl salt-sensitive (DSS) rats exhibited no change in heart rate and increased RSNA during high salt intake. Renal denervation significantly decreased heart rate and attenuated the catabolic state independent of blood pressure in DSS rats fed HS + saline, suggesting that salt-sensitive animals were unable to decrease cardiovascular energy consumption due to abnormal renal sympathetic nerve activation during high salt intake. These findings support the hypothesis that RSNA mediates heart rate during high salt intake in SD rats. However, the insensitivity of heart rate and enhanced RSNA observed in DSS rats may be additional critical diagnostic factors for salt-sensitive hypertension. Renal denervation may benefit salt-sensitive hypertension by reducing its effects on catabolism and cardiovascular energy expenditure.
CRIS-Team Scopus Importer:2020-01-31
Keywords: Heart rate; Renal sympathetic nervous system; Salt; Salt-sensitive hypertension

Renal tubular HIF-2α expression requires VHL inactivation and causes fibrosis and cysts - Schietke, Ruth E.; Hackenbeck, Thomas; Tran, Maxine; Guenther, Regina; Klanke, Bernd; Warnecke, Christina; Knaup, Karl X.; Shukla, Deepa; Rosenberger, Christian; Koesters, Robert; Bachmann, Sebastian; Betz, Peter; et al. (PLoS ONE, 2012)
The Hypoxia-inducible transcription Factor (HIF) represents an important adaptive mechanism under hypoxia, whereas sustained activation may also have deleterious effects. HIF activity is determined by the oxygen regulated α-subunits HIF-1α or HIF-2α. Both are regulated by oxygen dependent degradation, which is controlled by the tumor suppressor "von Hippel-Lindau" (VHL), the gatekeeper of renal tubular growth control. HIF appears to play a particular role for the kidney, where renal EPO production, organ preservation from ischemia-reperfusion injury and renal tumorigenesis are prominent examples. Whereas HIF-1α is inducible in physiological renal mouse, rat and human tubular epithelia, HIF-2α is never detected in these cells, in any species. In contrast, distinct early lesions of biallelic VHL inactivation in kidneys of the hereditary VHL syndrome show strong HIF-2α expression. Furthermore, knockout of VHL in the mouse tubular apparatus enables HIF-2α expression. Continuous transgenic expression of HIF-2α by the Ksp-Cadherin promotor leads to renal fibrosis and insufficiency, next to multiple renal cysts. In conclusion, VHL appears to specifically repress HIF-2α in renal epithelia. Unphysiological expression of HIF-2α in tubular epithelia has deleterious effects. Our data are compatible with dedifferentiation of renal epithelial cells by sustained HIF-2α expression. However, HIF-2α overexpression alone is insufficient to induce tumors. Thus, our data bear implications for renal tumorigenesis, epithelial differentiation and renal repair mechanisms. © 2012 Schietke et al.

Renal uptake of the antiapoptotic protein survivin is mediated by megalin at the apical membrane of the proximal tubule - Jobst-Schwan, Tilman; Knaup, Karl; Nielsen, Rikke; Hackenbeck, Thomas; Büttner-Herold, Maike; Lechler, Philipp; Kroening, Sven; Goppelt-Strübe, Margarete; Schlötzer-Schrehardt, Ursula; Fuernrohr, Barbara G.; Voll, Reinhard E.; Amann, Kerstin Ute; et al. (American Journal of Physiology-Renal Physiology, 2013)
The inhibitor of apoptosis protein survivin is a bifunctional molecule that regulates cellular division and survival. We have previously shown that survivin protein can be found at high concentrations in the adult kidney, particularly in the proximal tubules. Here, survivin is localized primarily at the apical membrane, a pattern that may indicate absorption of the protein. Several proteins in primary urine are internalized by megalin, an endocytosis receptor, which is in principle found in the same localization as survivin. Immunolabeling for survivin in different species confirmed survivin signal localizing to the apical membrane of the proximal tubule. Immunoelectron microscopy also showed apical localization of survivin in human kidneys. Furthermore, in polarized human primary tubular cells endogenous as well as external recombinant survivin is stored in the apical region of the cells. Costaining of survivin and megalin by immunohistochemistry and immunoelectron microscopy confirmed colocalization. Finally, by surface plasmon resonance we were able to demonstrate that survivin binds megalin and cubilin and that megalin knockout mice lose survivin through the urine. Survivin accumulates at the apical membrane of the renal tubule by reuptake, which is achieved by the endocytic receptor megalin, collaborating with cubilin. For this to occur, survivin will have to circulate in the blood and be filtered into the primary urine. It is not known at this stage what the functional role of tubular survivin is. However, a small number of experimental and clinical reports implicate that renal survivin is important for functional integrity of the kidney. © 2013 by the American Physiological Society.
Created from Fastlane, Scopus look-up
Keywords: Acute kidney injury; Apoptosis; Glomerular filtration; Lysosomes; Proteinuria

RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM INHIBITOR THERAPY IN PATIENTS WITH CHRONIC KIDNEY DISEASE: AN ANALYSIS FROM THE GERMAN CHRONIC KIDNEY DISEASE STUDY - Schneider, Markus; Meiselbach, Heike; Schulmann, Thierry; Cornea, Georgiana; Eckardt, Kai-Uwe (NEPHROLOGY DIALYSIS TRANSPLANTATION, 2019)
CRIS-Team WoS Importer:2019-11-26

Repeated kidney re-transplantation—the Eurotransplant experience: a retrospective multicenter outcome analysis - Assfalg, Volker; Selig, Katharina; Tolksdorf, Johanna; Van Meel, Marieke; De Vries, Erwin; Ramsoebhag, Anne-Marie; Rahmel, Axel; Renders, Lutz; Novotny, Alexander; Matevossian, Edouard; Schneeberger, Stefan; Rosenkranz, Alexander R.; et al. (Transplant International, 2020)
In Eurotransplant kidney allocation system (ETKAS), candidates can be considered unlimitedly for repeated re-transplantation. Data on outcome and benefit are indeterminate. We performed a retrospective 15-year patient and graft outcome data analysis from 1464 recipients of a third or fourth or higher sequential deceased donor renal transplantation (DDRT) from 42 transplant centers. Repeated re-DDRT recipients were younger (mean 43.0 vs. 50.2 years) compared to first DDRT recipients. They received grafts with more favorable HLA matches (89.0% vs. 84.5%) but thereby no statistically significant improvement of patient and graft outcome was found as comparatively demonstrated in 1st DDRT. In the multivariate modeling accounting for confounding factors, mortality and graft loss after 3rd and ≥4th DDRT (P < 0.001 each) and death with functioning graft (DwFG) after 3rd DDRT (P = 0.001) were higher as compared to 1st DDRT. The incidence of primary nonfunction (PNF) was also significantly higher in re-DDRT (12.7%) than in 1st DDRT (7.1%; P < 0.001). Facing organ shortage, increasing waiting time, and considerable mortality on dialysis, we question the current policy of repeated re-DDRT. The data from this survey propose better HLA matching in first DDRT and second DDRT and careful selection of candidates, especially for ≥4th DDRT.
CRIS-Team Scopus Importer:2020-02-11
Keywords: allocation; child; fourth; graft; kidney; loss; re-transplantation; repeated; survival; third

Reply - Schmieder, Roland; Mahfoud, Felix (Journal of Hypertension, 2019)
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Reply to comment on Cost of poor adherence to anti-hypertensive therapy in five European country - Mennini, F S; Marcellusi, Andrea; von der Schulenburg, J M Graf; Gray, A; Levy, P; Sciattella, P; Soro, M; Staffiero, G; Zeidler, J; Maggioni, A; Schmieder, Roland (European Journal of Health Economics, 2015)
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Reproducibility of Kidney Perfusion Measurements With Arterial Spin Labeling at 1.5 Tesla MRI Combined With Semiautomatic Segmentation for Differential Cortical and Medullary Assessment - Hammon, Matthias; Janka, Rolf Matthias; Siegl, Christian; Seuß, Hannes; Grosso, Roberto; Martirosian, Petros; Schmieder, Roland; Uder, Michael; Kistner, Iris (Medicine, 2016)
Magnetic resonance imaging with arterial spin labeling (ASL) is a noninvasive approach to measure organ perfusion. The purpose of this study was to evaluate the reproducibility of ASL kidney perfusion measurements with semiautomatic segmentation, which allows separate quantification of cortical and medullary perfusion.The right kidneys of 14 healthy volunteers were examined 6 times on 2 occasions (3 times at each occasion). There was a 10-minute pause between each examination and a 14-day interval between the 2 occasions. Cortical, medullary, and whole kidney parenchymal perfusion was determined with customized semiautomatic segmentation software. Coefficient of variances (CVs) and intraclass correlations (ICCs) were calculated.Mean whole, cortical, and medullary kidney perfusion was 307.26 ± 25.65, 337.10 ± 34.83, and 279.61 ± 26.73 mL/min/100 g, respectively. On session 1, mean perfusion for the whole kidney, cortex, and medulla was 307.08 ± 26.91, 336.79 ± 36.54, and 279.60 ± 27.81 mL/min/100 g, respectively, and on session 2, 307.45 ± 24.65, 337.41 ± 33.48, and 279.61 ± 25.94 mL/min/100 g, respectively (P > 0.05; R = 0.60/0.59/0.54). For whole, cortical, and medullary kidney perfusion, the total ICC/CV were 0.97/3.43 ± 0.86%, 0.97/4.19 ± 1.33%, and 0.96/4.12 ± 1.36%, respectively. Measurements did not differ significantly and showed a very good correlation (P > 0.05; R = 0.75/0.76/0.65).ASL kidney measurements combined with operator-independent semiautomatic segmentation revealed high correlation and low variance of cortical, medullary, and whole kidney perfusion.
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Response by Mann et al to Letter Regarding Article, "Effects of Liraglutide Versus Placebo on Cardiovascular Events in Patients With Type 2 Diabetes Mellitus and Chronic Kidney Disease: Results From the LEADER Trial" - Mann, Johannes; Fonseca, Vivian; Mosenzon, Ofri; Raz, Itamar; Goldman, Bryan; Idorn, Thomas; von Scholten, Bernt Johan; Poulter, Neil R. (Circulation, 2019)
CRIS-Team Scopus Importer:2019-06-25

Response to: Cavagna et al The importance of considering cultural and environmental elements in an interventional model of care to fight hypertension in Africa - Otieno, Harun A.; Miezah, Charles; Yonga, Gerald; Kueffer, Fred; Guy, Molly; Lang’at, Chemuttaai; Hettrick, Douglas A.; Schmieder, Roland (Journal of Clinical Hypertension, 2021)
CRIS-Team Scopus Importer:2021-04-09

Response to letter regarding article, "ambulatory blood pressure changes after renal sympathetic denervation in patients with resistant hypertension" - Mahfoud, Felix; Ukena, Christian; Schmieder, Roland; Cremers, Bodo; Rump, Lars C.; Vonend, Oliver; Weil, Joachim; Schmidt, Martin; Hoppe, Uta C.; Zeller, Thomas; Bauer, Axel; Ott, Christian; et al. (Circulation, 2014)
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Responsiveness of afferent renal nerve units in renovascular hypertension in rats - Rodionova, Kristina; Hilgers, Karl Friedrich; Rafii-Tabrizi, Salman; Doellner, Johannes; Cordasic, Nada; Linz, Peter; Karl, Annalena; Ott, Christian; Schmieder, Roland; Schiffer, Mario; Amann, Kerstin Ute; Veelken, Roland; et al. (Pflügers Archiv: European Journal of Physiology, 2021)
Previous data suggest that renal afferent nerve activity is increased in hypertension exerting sympathoexcitatory effects. Hence, we wanted to test the hypothesis that in renovascular hypertension, the activity of dorsal root ganglion (DRG) neurons with afferent projections from the kidneys is augmented depending on the degree of intrarenal inflammation. For comparison, a nonhypertensive model of mesangioproliferative nephritis was investigated. Renovascular hypertension (2-kidney, 1-clip [2K1C]) was induced by unilateral clipping of the left renal artery and mesangioproliferative glomerulonephritis (anti-Thy1.1) by IV injection of a 1.75-mg/kg BW OX-7 antibody. Neuronal labeling (dicarbocyanine dye [DiI]) in all rats allowed identification of renal afferent dorsal root ganglion (DRG) neurons. A current clamp was used to characterize neurons as tonic (sustained action potential [AP] firing) or phasic (1-4 AP) upon stimulation by current injection. All kidneys were investigated using standard morphological techniques. DRG neurons exhibited less often tonic response if in vivo axonal input from clipped kidneys was received (30.4% vs. 61.2% control, p < 0.05). However, if the nerves to the left clipped kidneys were cut 7 days prior to investigation, the number of tonic renal neurons completely recovered to well above control levels. Interestingly, electrophysiological properties of neurons that had in vivo axons from the right non-clipped kidneys were not distinguishable from controls. Renal DRG neurons from nephritic rats also showed less often tonic activity upon current injection (43.4% vs. 64.8% control, p < 0.05). Putative sympathoexcitatory and impaired sympathoinhibitory renal afferent nerve fibers probably contribute to increased sympathetic activity in 2K1C hypertension.
CRIS-Team WoS Importer:2021-07-23

Resting heart rate is associated with renal disease outcomes in patients with vascular disease: results of the ONTARGET and TRANSCEND studies - Boehm, M.; Schumacher, H.; Schmieder, Roland; Mann, J. F. E.; Teo, K.; Lonn, E.; Sleight, P.; Mancia, G.; Linz, D.; Mahfoud, F.; Ukena, C.; Sliwa, K.; et al. (Journal of Internal Medicine, 2015)
Resting heart rate (RHR) is associated with cardiovascular disease outcomes in high-risk patients. It is not known whether RHR is predictive of renal outcomes such as albuminuria, end-stage renal disease (ESRD) or doubling of creatinine. We evaluated whether RHR could predict renal endpoints in patients at a high risk of cardiovascular disease. We also tested the effects of RHR at different levels of systolic blood pressure (SBP).We analysed data from 28 757 patients in the ONTARGET and TRANSCEND trials. RHR and SBP were available for a mean of 4.9 ± 0.4 visits (range 3-5) within the first 2 years of the studies. Albuminuria was determined at baseline, at 2 years and at study end.Mean RHR was predictive of incident micro-albuminuria [hazard ratio (HR) for RHR >=80 vs. <60 beats min(-1) 1.49, 95% confidence interval (CI) 1.29-1.71, P < 0.0001], incident macro-albuminuria (HR 1.84, 95% CI 1.39-2.42, P < 0.0001), doubling of creatinine (HR 1.47, 95% CI 1.00-2.17, P = 0.050) and ESRD (HR 1.78, 95% CI 1.00-3.16, P = 0.050), and the combined renal end-point (HR 1.51, 95% CI 1.32-1.74, P < 0.0001). Associations were robust at SBPs from <120 to >=150 mmHg, with the lowest risk at a SBP of 130-140 mmHg.Resting heart rate is a potent predictor of these renal outcomes, as well as their combination, in patients with cardiovascular disease. RHR at all SBP levels should be considered as a possible renal disease risk predictor and should be investigated as a treatment target with RHR-reducing agents.
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Results of Renal Transplantation on Alloplastic Arterial Grafts - Sagban, Tolga Atilla; Regus, Susanne; Heller, Katharina; Jacobi, Johannes; Apel, Hendrik; Keck, Bastian; Richterstetter, Mario; Eckardt, Kai-Uwe; Wullich, Bernd; Lang, Werner (Urologia Internationalis, 2016)
The aim of this retrospective study was to report results of a consecutive series of kidney transplant patients in whom the renal artery was implanted on a prosthetic vascular graft (PVG).Between January 2011 and December 2014, 208 deceased donor renal transplantations (68 female, 140 male, mean age 52, SD 16 years) were performed. Medical charts and outpatient clinical records of patients who had undergone renal artery implantation on a PVG were reviewed. Extensive literature research added to our 4 patients further 170 published cases during 1989 and 2015 and was compared with regular transplanted patients. Data on patient characteristics, prior vascular procedures, postoperative and long-term outcome were collected.Patients with transplant renal artery anastomosis on a PVG were 4 years older than the control group. Function of the graft was similar in these patients compared to regular renal transplant patients. Resistance indices assessed in our clinic over the entire follow-up period showed also no significant difference between the 2 groups. Thirty-day mortality was 6% (none in our group), which occurred mostly in combination when renal transplantation and PVG replacement was performed simultaneously.Grafting of the renal artery to a PVG is feasible and yields good results, despite the technical difficulties involved.
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Retinal arterial remodeling in patients with pheochromocytoma or paraganglioma and its reversibility following surgical treatment - Gosk-Przybylek, Maria; Doroszko, Adrian; Dobrowolski, Piotr; Warchol-Celinska, Ewa; Harazny, Joanna; Binczyk, Ewelina; Szymanek, Katarzyna; Peczkowska, Mariola; Kabat, Marek; Toutounchi, Sadegh; Galazka, Zbigniew; Gornicka, Barbara; et al. (Journal of Hypertension, 2020)
OBJECTIVE: Structural abnormalities in resistance arteries are a hallmark of patients with hypertension. In hypertensive patients with pheochromocytoma or paraganglioma (PPGL), it is still a matter of debate whether structural vascular changes are because of elevated blood pressure (BP) or to toxic effects of elevated circulating catecholamines. Hence, the aim of our study was to assess whether catecholamine excess and/or elevated BP affect the structure of small retinal arteries in patients with catecholamine-producing tumors. METHODS: The study included 27 patients with PPGL and 27 hypertensive patients. All patients underwent biochemical tests for catecholamine excess, echocardiography and analyses of scanning-laser-Doppler-flowmetry (SLDF) both at baseline and 12 months following surgical resection of PPGL. RESULTS: Baseline retinal arterial diameter, arterial wall thickness and wall cross sectional area (WCSA) were higher in patients with PPGL as compared with subjects without PPGL (arterial diameter: 110 ± 16.5 vs. 99.5 ± 10.8 μm, wall thickness: 16.3 ± 6.0 vs. 13.5 ± 4.0 μm, WCSA: 4953.9 ± 2472.8 vs. 3784.1 ± 1446.3 μm, P < 0.05). Significant correlations were noted between wall thickness and WCSA and echocardiographic parameters assessing diastolic and systolic function of left ventricle. No correlations between retinal parameters, BP level and plasma concentrations of metanephrines were observed. In patients with PPGL, there were postoperative decreases in wall thickness (16.4 ± 15.8 vs. 14.8 ± 4.7 μm; P = 0.011) and WLR (0.42 ± 0.13 vs. 0.37 ± 0.10; P = 0.003) at 12 months after surgical removal of tumors. CONCLUSION: This is the first study to demonstrate that catecholamine excess is related to thickening of retinal arteries independent of BP and reversible after surgical cure. These data support a role of catecholamines in vascular remodeling in PPGL patients.
CRIS-Team Scopus Importer:2020-07-31

Retinal capillary and arteriolar changes in patients with chronic kidney disease - Bosch, Agnes; Scheppach, Johannes B.; Harazny, Joanna M.; Raff, Ulrike; Schmieder, Roland; Schneider, Markus; Eckardt, Kai-Uwe (Microvascular Research, 2018)
RATIONALE: Premature cardiovascular disease is a leading cause of death in patients with chronic kidney disease (CKD). In animal models CKD has been shown to cause renal and extrarenal vascular remodeling and capillary rarefaction, but data in humans with CKD are sparse. Retinal arteriolar wall-to-lumen ratio (WLR) is an established marker of early end-organ damage and there is evidence that arteriolar and capillary changes in the retinal circulation mirror those in the general and in particular the cerebrovascular microcirculation. OBJECTIVE: The aim of this study was to compare retinal capillary density and arteriolar structure between patients with CKD and healthy individuals. METHODS: We compared 76 patients with CKD stage 3+ or proteinuria >500 mg/g creatinine in the presence of a normal GFR from the German Chronic Kidney Disease cohort to 53 healthy control subjects, who participated in clinical trials during 2007 and 2015 in our Clinical Research Center. Retinal vascular parameters were measured non-invasively in vivo by scanning laser Doppler Flowmetry (SLDF, Heidelberg Engineering, Germany). Capillary rarefaction was assessed by intercapillary distance. RESULTS: Patients with CKD showed greater WLR (0.403 ± 0.11 vs 0.351 ± 0.11, p = 0.010) and greater wall thickness (WT) (15.1 ± 4.1 vs 13.5 ± 3.8, p = 0.026) compared to healthy individuals. Intercapillary distance (ICD) (22.4 ± 5.7 vs 20.2 ± 4.1, p = 0.008) was greater in the CKD group compared to the healthy control group. After adjustment for differences in clinical characteristics of the groups (age, gender, BMI, serum cholesterol) WLR (p = 0.046), WT (p = 0.025) and ICD (p = 0.003) remained significantly different between the two groups. There was a correlation between serum phosphate level and WLR in the CKD group (r = 0.288, p = 0.013). CONCLUSION: Patients with moderately severe CKD show retinal signs of end-organ damage indicated by an increased wall-to-lumen ratio and capillary rarefaction.
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Retinal Capillary Damage Is Already Evident in Patients With Hypertension and Prediabetes and Associated With HbA1c Levels in the Nondiabetic Range. - Kannenkeril, Dennis; Nolde, Janis M.; Kiuchi, Márcio Galindo; Carnagarin, Revathy; Lugo-Gavidia, Leslie Marisol; Chan, Justine; Joyson, Anu; Jose, Ancy; Robinson, Sandi; Matthews, Vance B.; Herat, Lakshini Y.; Azzam, Omar; et al. (Diabetes Care, 2022)
OBJECTIVE: We analyzed whether any change in capillary density in the retinal circulation could be detected in patients with hypertension in the prediabetic stage. RESEARCH DESIGN AND METHODS: In a cross-sectional analysis, we assessed capillary density in the foveal (CDF) and parafoveal retinal areas using optical coherence tomography-angiography in 62 patients with hypertension and normal glucose metabolism and 40 patients with hypertension and prediabetes. RESULTS: The CDF was lower in patients with prediabetes than in those with normal glucose metabolism. Moreover, we found a correlation between CDF and HbA1c and glucose levels for the entire cohort. In patients with HbA1c <6.5% (48 mmol/mol), CDF was lower in patients with HOMA for insulin resistance (HOMA-IR) ≥2.5 than in patients with HOMA-IR <2.5. CONCLUSIONS: Patients with hypertension and prediabetes display retinal capillary changes, and an association with markers of glucose metabolism exists, even within a nondiabetic HbA1c range.
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Retinal Capillary Rarefaction in Patients with Type 2 Diabetes Mellitus - Jumar, Agnes; Harazny, Joanna M.; Ott, Christian; Friedrich, Stefanie; Kistner, Iris; Striepe, Kristina; Schmieder, Roland (PLoS ONE, 2016)
In diabetes mellitus type 2, capillary rarefaction plays a pivotal role in the pathogenesis of end-organ damage. We investigated retinal capillary density in patients with early disease.This cross-sectional study compares retinal capillary rarefaction determined by intercapillary distance (ICD) and capillary area (CapA), measured non-invasively and in vivo by scanning laser Doppler flowmetry, in 73 patients with type 2 diabetes, 55 healthy controls and 134 individuals with hypertension stage 1 or 2.In diabetic patients, ICD was greater (23.2±5.5 vs 20.2±4.2, p = 0.013) and CapA smaller (1592±595 vs 1821±652, p = 0.019) than in healthy controls after adjustment for differences in cardiovascular risk factors between the groups. Compared to hypertensive patients, diabetic individuals showed no difference in ICD (23.1±5.8, p = 0.781) and CapA (1556±649, p = 0.768).In the early stage of diabetes type 2, patients showed capillary rarefaction compared to healthy individuals.
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Retinal capillary rarefaction in patients with untreated mild-moderate hypertension - Bosch, Agnes J.; Harazny, Joanna M.; Kistner, Iris; Friedrich, Stefanie; Wojtkiewicz, Joanna; Schmieder, Roland (Bmc Cardiovascular Disorders, 2017)
Microvascular rarefaction influences peripheral vascular resistance, perfusion and metabolism by affecting blood pressure and flow pattern. In hypertension microvascular rarefaction has been described in experimental animal studies as well as in capillaroscopy of skin and biopsies of muscle tissue in patients. Retinal circulation mirrors cerebral microcirculation and allows non-invasive investigations. We compared capillary rarefaction of retinal vessels in hypertensive versus normotensive subjects.In this study retinal capillary rarefaction in 70 patients with long time (more than 67 month of disease duration) and 64 patients with short time hypertension stage 1 or 2 has been compared to 55 healthy control subjects, who participated in clinical trials in our Clinical Research Center ( www.clinicaltrials.gov : NCT01318395, NCT00627952, NCT00152698, NCT01319344). Retinal vascular parameters have been measured non-invasively and in vivo in perfusion image by scanning laser Doppler flowmetry (Heidelberg Engineering, Germany). Capillary rarefaction was assessed by capillary area (CapA) (in pixel-number) and intercapillary distance (ICD) (in ?m). Additionally retinal capillary flow (RCF) was measured.ICD was greater in the long time hypertensive group compared to healthy individuals (24.2 ± 6.3 ?m vs 20.1 ± 4.2 ?m, p = 0.001) and compared to short time hypertensive patients (22.2 ± 5.2 ?m, p = 0.020). Long time hypertensive patients showed less CapA compared to healthy people (1462 ± 690 vs 1821 ± 652, p = 0.005). Accordingly, RCF was significantly lower in the long time hypertensive group compared to the healthy control group (282 ± 70 AU vs 314 ± 60 AU, p = 0.032). Our data indicate a lower level of retinal capillary density in hypertensive patients, especially in those with long time hypertension.Patients with hypertension stage 1 or 2 showed retinal capillary rarefaction in comparison to healthy normotensive subjects. Retinal capillary rarefaction was intensified with duration of disease.
EVALuna2:4038

Retinal microperfusion after renal denervation in treatment-resistant hypertensive patients - Ott, Christian; Harazny, Joanna M.; Schmid, Axel; Ditting, Tilmann; Veelken, Roland; Bladowski, Marek; Michelson, Georg; Uder, Michael; Schmieder, Roland (Clinical Research in Cardiology, 2015)
High pulsatile pressure and flow in the arteries causes microvascular damage, and hence increased cardio-, and cerebrovascular complications. With advanced stages of hypertensive disease, an exaggerated pulsatile retinal capillary flow (RCF) has been shown, but data about interventional effect are missing.Fifty-one patients with true treatment-resistant hypertension (TRH) underwent renal denervation (RDN) using the Symplicity Flex(TM) catheter and were followed for 12 months. RCF was assessed non-invasively using Scanning laser Doppler flowmetry (SLDF) before, 6 (6 M), and 12 (12 M) months after RDN. RCF was measured in systole and diastole and pulsed RCF (difference of RCF in systole minus diastole) was calculated. In addition, flicker light-induced vasodilation (representing vasodilatory capacity) was assessed.Systolic and diastolic office blood pressure (BP) as well as 24-h ABPM decreased significantly 6 M and 12 M after RDN, compared to baseline values (all p < 0.001). There was a significant reduction of pulsed RCF 6 M (231 ± 81 versus 208 ± 68 AU, p = 0.046) and 12 M (194 ± 72 AU, p = 0.001) after RDN, whereas the mean RCF was unchanged. Moreover, there was a significant increase of flicker light-induced vasodilation after RDN (p = 0.043).In hypertensive patients with TRH, we observed a decrease of pulsed RCF 6 M and 12 M after RDN and an increase of vasodilatory capacity, in parallel to decreases in BP and heart rate. The reduction of pulsed RCF after RDN implies a decrease of shear stress on the vascular wall by the pulsed blood flow. This and the increment of vasodilatory capacity suggest an improvement of retinal (and potentially cerebral) microcirculation.
EVALuna2:3762

Retinal neurodegeneration in patients with end-stage renal disease assessed by spectral-domain optical coherence tomography - Jung, Susanne; Bosch, Agnes; Ott, Christian; Kannenkeril, Dennis; Dienemann, Thomas; Harazny, Joanna M.; Michelson, Georg; Schmieder, Roland (Scientific Reports, 2020)
Spectral-domain optical coherence tomography (SD-OCT) represents a reliable tool for retinal layer volume and thickness measurement. The aim of this study was to evaluate retinal changes indicating neurodegenerative processes in patients with end-stage renal disease (ESRD) compared to healthy controls. This was a cross-sectional, single-center study comprising 32 ESRD patients and 38 controls. Sectoral retinal nerve fiber layer (RNFL) thickness and retinal layer volumes were obtained by SD-OCT. Age- and gender-adjusted retinal layer volumes such as total retinal volume (p = 0.037), ganglion cell layer volume (GCL, p = 0.003), ganglion cell layer – inner plexiform layer volume (GCL-IPL, p = 0.005) and inner retinal layer volume (IRL, p = 0.042) of the right eye were lower in ESRD patients. Inner plexiform layer volume of both eyes (IPL, right eye: p = 0.017; left eye: 0.044) was reduced, as was RNFL thickness in the temporal superior sector (right eye: p = 0.016). A subgroup analysis excluding patients with diabetes revealed that GCL (p = 0.014) and GCL-IPL volume of the right eye (p = 0.024) and temporal superior sector of the RNFL scan (p = 0.021) in ESRD patients were still significantly thinner. We observed a decrease in several retinal layer volumes and temporal RNFL thickness indicative of retinal neurodegenerative processes in patients with ESRD.
CRIS-Team Scopus Importer:2020-04-03

Retinal vascular resistance in arterial hypertension - Kannenkeril, Dennis; Harazny, Joanna M.; Bosch, Agnes; Ott, Christian; Michelson, Georg; Schmieder, Roland; Friedrich, Stefanie (Blood Pressure, 2017)
Retinal microcirculation represents an easily accessible, non-invasive, in-vivo possibility to assess early microvascular changes. In addition to the assessment of functional (e.g. retinal capillary flow, RCF) and retinal arteriolar structural parameters (e.g. wall-to-lumen-ratio, WLR) we now suggest a new parameter reflecting the resistance in small retinal arterioles (RVR).In 45 normotensive (NT) subjects and 123 patients with hypertension stage 1 (HT) we assessed RCF, WLR, arteriolar diameter, lumen diameter and wall cross section area in the retinal circulation by using scanning laser Doppler flowmetry (SLDF). Mean arterial pressure (MAP) was measured immediately before the SLDF measurement and retinal vascular resistance was calculated (RVR = MAP/RCF). In a separate study the test-retest reliability was determined in 6 volunteers from our clinical staff by assessing RVR three times within six weeks.The analysis of the volunteers revealed a coefficient of variation for RVR of 7.75 ± 2.11% and Cronbach´s alpha was 0.90. WLR, a marker of vascular remodeling did not differ between NT and HT. In contrast, RCF and inner diameter of the retinal arterioles (ID) were significantly lower (RCF: p = .045 and ID: p = .001) in the HT group than in the NT group and RVR was significantly higher in the HT group than in the NT group (p < .001). In both groups we found no correlation of RVR with age, but a significant correlation of RVR with WLR (NT: r = 0.34, p = .006; HT: r = 0.25, p = .01), indicating that the RVR reflects vascular remodeling in the retinal circulation.Our data showed an increased retinal vascular resistance in hypertensive patients compared to non-hypertensive patients prior to the occurrence of structural retinal vascular remodeling. The correlation between RVR and WLR indicates that RVR is a reliable, non-invasive and early-sensitive marker of vascular remodeling in early hypertension.
EVALuna2:4030

Risk-based individualisation of target haemoglobin in haemodialysis patients with renal anaemia in the post-TREAT era: theoretical attitudes versus actual practice patterns (MONITOR-CKD5 study) - Gesualdo, Loreto; Combe, Christian; Covic, Adrian; Dellanna, Frank; Goldsmith, David; London, Gerard; Mann, Johannes; Zaoui, Philippe; Turner, Matthew; Muenzberg, Mike; Macdonald, Karen; Abraham, Ivo (International Urology and Nephrology, 2015)
Data from an ongoing European pharmacoepidemiological study (MONITOR-CKD5) were used to examine congruence between physician-reported risk-based individualisation of target haemoglobin (Hb) and the actual Hb targets set by these physicians for their patients, as well as actual Hb levels in their patients.Physician investigators participating in the study completed a questionnaire about their anaemia practice patterns and attitudes post-TREAT at the start of the study (T1) and in summer 2013 (T2). These data were compared with the Hb targets identified at baseline for actual patients (n = 1197) enrolled in the study. Risk groups included presence/absence of hypertension, diabetes, cardiovascular complications, history of stroke, history of cancer, and age/activity level (elderly/inactive or young/active).At each time point, more than three quarters of physicians responded that results from the TREAT study, in patients not on dialysis, have influenced their use of erythropoiesis-stimulating agents in patients on haemodialysis. At T1, there was a clear difference in physician-reported (theoretical) target Hb levels for patients across the different risk groups, but there was no difference in patients' actual Hb levels across the risk groups. A similar disparity was noted at T2.Physicians' theoretical attitudes to anaemia management in patients on haemodialysis appear to have been influenced by the results of the TREAT study, which involved patients not on dialysis. Physicians claim to use risk-based target Hb levels to guide renal anaemia care. However, there is discrepancy between these declared risk-based target Hb levels and actual target Hb levels for patients with variable risk factors.
EVALuna2:3879

Risk Prediction for Early CKD in Type 2 Diabetes - Dunkler, Daniela; Gao, Peggy; Lee, Shun Fu; Heinze, Georg; Clase, Catherine M.; Tobe, Sheldon; Teo, Koon K.; Gerstein, Hertzel; Mann, Johannes; Oberbauer, Rainer (Clinical Journal of the American Society of Nephrology, 2015)
Quantitative data for prediction of incidence and progression of early CKD are scarce in individuals with type 2 diabetes. Therefore, two risk prediction models were developed for incidence and progression of CKD after 5.5 years and the relative effect of predictors were ascertained.Baseline and prospective follow-up data of two randomized clinical trials, ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and Outcome Reduction with Initial Glargine Intervention (ORIGIN), were used as development and independent validation cohorts, respectively. Individuals aged >=55 years with type 2 diabetes and normo- or microalbuminuria at baseline were included. Incidence or progression of CKD after 5.5 years was defined as new micro- or macroalbuminuria, doubling of creatinine, or ESRD. The competing risk of death was considered as an additional outcome state in the multinomial logistic models.Of the 6766 ONTARGET participants with diabetes, 1079 (15.9%) experienced incidence or progression of CKD, and 1032 (15.3%) died. The well calibrated, parsimonious laboratory prediction model incorporating only baseline albuminuria, eGFR, sex, and age exhibited an externally validated c-statistic of 0.68 and an R(2) value of 10.6%. Albuminuria, modeled to depict the difference between baseline urinary albumin/creatinine ratio and the threshold for micro- or macroalbuminuria, was mostly responsible for the predictive performance. Inclusion of clinical predictors, such as glucose control, diabetes duration, number of prescribed antihypertensive drugs, previous vascular events, or vascular comorbidities, increased the externally validated c-statistic and R(2) value only to 0.69 and 12.1%, respectively. Explained variation was largely driven by renal and not clinical predictors.Albuminuria and eGFR were the most important factors to predict onset and progression of early CKD in individuals with type 2 diabetes. However, their predictive ability is modest. Inclusion of demographic, clinical, and other laboratory predictors barely improved predictive performance.
EVALuna2:3873

RNA sequencing reveals induction of specific renal inflammatory pathways in a rat model of malignant hypertension - Menendez-Castro, Carlos; Cordasic, Nada; Fahlbusch, Fabian; Ekici, Arif Bülent; Kirchner, Philipp; Daniel, Christoph; Amann, Kerstin Ute; Velkeen, Roland; Wölfle, Joachim; Schiffer, Mario; Hartner, Andrea; Hilgers, Karl Friedrich (Journal of Molecular Medicine, 2021)
Abstract: In malignant hypertension, far more severe kidney injury occurs than in the “benign” form of the disease. The role of high blood pressure and the renin–angiotensin–aldosterone system is well recognized, but the pathogenesis of the renal injury of malignant hypertension (MH) remains incompletely understood. Using the rat model of two-kidney, one-clip renovascular hypertension in which some but not all animals develop MH, we performed a transcriptomic analysis of gene expression by RNA sequencing to identify transcriptional changes in the kidney cortex specific for MH. Differential gene expression was assessed in three groups: MH, non-malignant hypertension (NMH), and normotensive, sham-operated controls. To distinguish MH from NMH, we considered two factors: weight loss and typical renovascular lesions. Mean blood pressure measured intraarterially was elevated in MH (220 ± 6.5 mmHg) as well as in NMH (192 ± 6.4 mmHg), compared to controls (119 ± 1.7 mmHg, p < 0.05). Eight hundred eighty-six genes were exclusively regulated in MH only. Principal component analysis revealed a separated clustering of the three groups. The data pointed to an upregulation of many inflammatory mechanisms in MH including pathways which previously attracted relatively little attention in the setting of hypertensive kidney injury: Transcripts from all three complement activation pathways were upregulated in MH compared to NMH but not in NMH compared with controls; immunohistochemistry confirmed complement deposition in MH exclusively. The expression of chemokines attracting neutrophil granulocytes (CXCL6) and infiltration of myeloperoxidase-positive cells were increased only in MH rats. The data suggest that these pathways, especially complement deposition, may contribute to kidney injury under MH. Key messages: The most severe hypertension-induced kidney injury occurs in malignant hypertension.In a rat model of malignant hypertension, we assessed transcriptional responses in the kidney exposed to high blood pressure. A broad stimulation of inflammatory mechanisms was observed, but a few specific pathways were activated only in the malignant form of the disease, notably activation of the complement cascades.Complement inhibitors may alleviate the thrombotic microangiopathy of malignant hypertension even in the absence of primary complement abnormalities.
CRIS-Team Scopus Importer:2021-09-24
Keywords: Complement activation; Inflammation; Kidney injury; Malignant hypertension; RNA-Seq; Two-kidney one-clip renovascular hypertension (2K1C)

Role of endothelial microRNA 155 on capillary leakage in systemic inflammation - Etzrodt, Valerie; Idowu, Temitayo O.; Schenk, Heiko; Seeliger, Benjamin; Prasse, Antje; Thamm, Kristina; Pape, Thorben; Müller-Deile, Janina; van Meurs, Matijs; Thum, Thomas; Garg, Ankita; Geffers, Robert; et al. (Critical Care, 2021)
Background: Capillary leakage is a key contributor to the pathological host response to infections. The underlying mechanisms remain incompletely understood, and the role of microRNAs (MIR) has not been investigated in detail. We hypothesized that specific MIRs might be regulated directly in the endothelium thereby contributing to vascular leakage. Methods: SmallRNA sequencing of endotoxemic murine pulmonary endothelial cells (ECs) was done to detect regulated vascular MIRs. In vivo models: transgenic zebrafish (flk1:mCherry/l-fabp:eGFP-DPB), knockout/wildtype mouse (B6.Cg-Mir155tm1.1Rsky/J); disease models: LPS 17.5 mg/kgBW and cecal ligation and puncture (CLP); in vitro models: stimulated human umbilical vein EC (HUVECs), transendothelial electrical resistance. Results: Endothelial MIR155 was identified as a promising candidate in endotoxemic murine pulmonary ECs (25 × upregulation). Experimental overexpression in a transgenic zebrafish line and in HUVECs was sufficient to induce spontaneous vascular leakage. To the contrary, genetic MIR155 reduction protects against permeability both in vitro and in endotoxemia in vivo in MIR155 heterozygote knockout mice thereby improving survival by 40%. A tight junction protein, Claudin-1, was down-regulated both in endotoxemia and by experimental MIR155 overexpression. Translationally, MIR155 was detectable at high levels in bronchoalveolar fluid of patients with ARDS compared to healthy human subjects. Conclusions: We found that MIR155 is upregulated in the endothelium in mouse and men as part of a systemic inflammatory response and might contribute to the pathophysiology of vascular leakage in a Claudin-1-dependent manner. Future studies have to clarify whether MIR155 could be a potential therapeutic target. [Figure not available: see fulltext.]
CRIS-Team Scopus Importer:2021-03-05
Keywords: Endothelium; MicroRNAs; Respiratory distress syndrome; Sepsis; Tight junctions

Role of Microparticles in Cardiovascular Disease Implications for Endothelial Dysfunction, Thrombosis, and Inflammation - Lugo-Gavidia, Leslie Marisol; Burger, Dylan; Matthews, Vance B.; Nolde, Janis M.; Galindo Kiuchi, Marcio; Carnagarin, Revathy; Kannenkeril, Dennis; Chan, Justine; Joyson, Anu; Herat, Lakshini Y.; Azzam, Omar; Schlaich, Markus P. (Hypertension, 2021)
Microparticles are small cell vesicles that are derived from the cell membrane in response to different biological processes. There is growing evidence supporting the association between microparticles and cardiovascular disease, as their pathophysiology commonly includes endothelial damage and chronic inflammation which also promote a prothrombotic state. The direct causal link between the release of the different subtypes of microparticles and their implications on physiological and pathological conditions is still not completely elucidated. However, evidence suggests microparticles released from platelets, leukocytes, and endothelium may help to evaluate vascular health as they have a relevant role in inflammation, endothelial function, and thrombosis. This review aims to provide a short overview of the biogenesis, characteristics, and detection methodology of microparticles with a special focus on their possible implication in cardiovascular settings.
CRIS-Team WoS Importer:2021-06-11

Role of oxygen and the HIF-pathway in polycystic kidney disease - Buchholz, Björn; Eckardt, Kai-Uwe (Cellular Signalling, 2020)
Kidney cyst growth in ADPKD is associated with regional hypoxia, presumably due to a mismatch between enlarged cysts and the peritubular capillary blood supply and compression of peritubular capillaries in cyst walls. Regional hypoxia leads to activation of hypoxia-inducible transcription factors, with the two main HIF isoforms, HIF-1 and HIF-2 expressed in cyst epithelia and pericystic interstitial cells, respectively. While HIF-2 activation is linked to EPO production, mitigating the anemia that normally accompanies chronic kidney disease, HIF-1 promotes cyst growth. HIF-dependent cyst growth is primarily due to an increase in chloride-dependent fluid secretion into the cyst lumen. However, given the broad spectrum of HIF-target genes, additional HIF-mediated pathways may also contribute to cyst progression. Furthermore, hypoxia can influence cyst growth through the generation of reactive oxygen species. Since cyst expansion aggravates regional hypoxia, a feedforward loop is established that accelerates cyst expansion and disease progression. Inhibiting the HIF pathway and/or HIF target genes that are of particular relevance for HIF-dependent cyst fluid secretion may therefore represent novel therapeutic approaches to retard the progression of APDKD.
CRIS-Team Scopus Importer:2020-01-21
Keywords: Autosomal dominant polycystic kidney disease; ADPKD; Hypoxia; Hypoxia-inducible factor; HIF; Polycystic kidney disease; PKD

Role of TMEM16 proteins in polycystic kidney disease - Cabrita, I.; Buchholz, Björn; Ousingsawat, J.; Kunzelmann, K.; Schreiber, R. (Acta Physiologica, 2019)

Role of TMEM16 proteins in polycystic kidney disease - Cabrita, I.; Buchholz, B.; Ousingsawat, J.; Kunzelmann, K.; Schreiber, R. (ACTA PHYSIOLOGICA, 2019)
CRIS-Team WoS Importer:2019-11-12

Roscovitine blocks collecting duct cyst growth in Cep164-deficient kidneys - Airik, Rannar; Airik, Merlin; Schüler, Markus; Bates, Carlton M.; Hildebrandt, Friedhelm (Kidney International, 2019)
Nephronophthisis is an autosomal recessive kidney disease with high genetic heterogeneity. Understanding the functions of the individual genes contributing to this disease is critical for delineating the pathomechanisms of this disorder. Here, we investigated kidney function of a novel gene associated with nephronophthisis, CEP164, coding a centriolar distal appendage protein, using a Cep164 knockout mouse model. Collecting duct-specific deletion of Cep164 abolished primary cilia from the collecting duct epithelium and led to rapid postnatal cyst growth in the kidneys. Cell cycle and biochemical studies revealed that tubular hyperproliferation is the primary mechanism that drives cystogenesis in the kidneys of these mice. Administration of roscovitine, a cell cycle inhibitor, blocked cyst growth in the cortical collecting ducts and preserved kidney parenchyma in Cep164 knockout mice. Thus, our findings provide evidence that therapeutic modulation of cell cycle activity can be an effective approach to prevent cyst progression in the kidney.
CRIS-Team Scopus Importer:2019-07-02
Keywords: centrosome; CEP164; cilia; nephronophthisis; polycystic kidney disease

Rundumversorgung Nierentransplantation – Optimierung der interdisziplinären Betreuung vor und nach Nierentransplantation - Krusemark, Helge; Schiffer, Mario (Die Urologie, 2024)
Due to the divergence between the number of potential organ recipients and organ availability, transplant survival is of particular importance. In order to create the best possible conditions, it is not only important to address the risk factors for loss of organ functionality after transplantation, but also to focus on the time before transplantation. During this period, which lasts several years on average, the patient can create the conditions for risk reduction before and after transplantation with support. The optimization of physical health plays an important role here in order to maintain transplantability, on the one hand, and to counteract the general loss of physical performance due to dialysis, on the other. Therefore, the focus must be placed on “exercise” and “nutrition”, which represent an increased risk of declining physical health in dialysis patients. After transplantation, the focus should again be on physical health. Through support, patients learn how to improve their cardiovascular risk profile and increase their physical performance. Psychosocial support is also important to combat psychological comorbidities and prevent risks such as nonadherence. In addition to improved physical and mental health, the focus here is also on the long-term survival of the patient and the transplant.
CRIS-Team Scopus Importer:2024-03-08
Keywords: Cardiovascular risk factors; Dialysis; Frailty; Physical performance; Treatment adherence and compliance

S2k guidelines for the diagnosis and treatment of type B aortic dissection - Torsello, G.; Czerny, M.; Grundmann, R. T.; Krankenberg, H.; Nikol, S.; Puls, R.; Raddatz, A.; Schelzig, H.; Schmieder, Roland; Zahn, R. (Gefässchirurgie, 2019)
Type B aortic dissection is a relatively rare clinical picture that involves many fields of medicine and requires a multidisciplinary approach. In this report, the disciplines involved constitute the most important aspects of the new S2k guidelines for the diagnosis and treatment of type B aortic dissection. More specifically, the definition and epidemiology, the clinical and technical diagnostic methods, in addition to the imaging methods, are presented, and recommendations for the individual topics based on scientific studies and expert opinion are given. In the guidelines, the various procedures related to the main conservative and surgical treatment regimes in the acute, subacute, and chronic phases of the condition are dealt with.
CRIS-Team WoS Importer:2019-02-27

Safety and effectiveness of a fixed-dose combination of olmesartan, amlodipine, and hydrochlorothiazide in clinical practice - Bramlage, Peter; Fronk, Eva Maria; Wolf, Wolf Peter; Smolnik, RüDiger; Sutton, Gemma; Schmieder, Roland (Vascular Health and Risk Management, 2015)
Clinical trials indicate that the use of fixed-dose combinations (FDCs) is associated with a higher level of treatment adherence and prolonged blood pressure (BP) control. The aim of this study was to document the safety and effectiveness of the FDC olmesartan/amlodipine/hydrochlorothiazide in patients with essential hypertension in clinical practice.This multicenter, prospective, 24-week, noninterventional study enrolled 5,831 patients from primary care offices in Germany and Austria. Inclusion criteria were a diagnosis of essential hypertension and newly initiated treatment with the FDC.The mean age of patients was 63.5 years, almost 50% of patients had a time since diagnosis of essential hypertension of over 5 years, and approximately 70% of patients had at least one cardiovascular risk factor, including 29.4% of patients with diabetes mellitus. Following approximately 24 weeks of treatment, the mean reduction in systolic/diastolic BP was 29.0/14.0 mmHg, a BP response was observed by 94.2% of patients, and a target BP of <140/90 mmHg was attained in 67.5% of patients. At least one adverse drug reaction (ADR) was experienced by 1.2% of patients, with the most common being peripheral edema. Subanalyses demonstrated that the following factors did not have a significant influence on the ADR rate: age (<65 years versus >=65 years), diabetes mellitus (no/yes), cardiovascular risk (low/high), and concomitant medication (no/yes).This study demonstrates that in clinical practice, treatment with the three-drug combination as an FDC tablet resulted in a very high proportion of patients with a BP response and control, accompanied by a very low rate of ADRs.
EVALuna2:3750

Safety of intravenous ferric carboxymaltose versus oral iron in patients with nondialysis-dependent CKD: an analysis of the 1-year FIND-CKD trial - Roger, Simon D.; Gaillard, Carlo A.; Bock, Andreas H.; Carrera, Fernando; Eckardt, Kai-Uwe; Van Wyck, David B.; Cronin, Maureen; Meier, Yvonne; Larroque, Sylvain; Macdougall, Iain C. (Nephrology Dialysis Transplantation, 2017)
The evidence base regarding the safety of intravenous (IV) iron therapy in patients with chronic kidney disease (CKD) is incomplete and largely based on small studies of relatively short duration.FIND-CKD (ClinicalTrials.gov number NCT00994318) was a 1-year, open-label, multicenter, prospective study of patients with nondialysis-dependent CKD, anemia and iron deficiency randomized (1:1:2) to IV ferric carboxymaltose (FCM), targeting higher (400-600 µg/L) or lower (100-200 µg/L) ferritin, or oral iron. A post hoc analysis of adverse event rates per 100 patient-years was performed to assess the safety of FCM versus oral iron over an extended period.The safety population included 616 patients. The incidence of one or more adverse events was 91.0, 100.0 and 105.0 per 100 patient-years in the high ferritin FCM, low ferritin FCM and oral iron groups, respectively. The incidence of adverse events with a suspected relation to study drug was 15.9, 17.8 and 36.7 per 100 patient-years in the three groups; for serious adverse events, the incidence was 28.2, 27.9 and 24.3 per 100 patient-years. The incidence of cardiac disorders and infections was similar between groups. At least one ferritin level >=800 µg/L occurred in 26.6% of high ferritin FCM patients, with no associated increase in adverse events. No patient with ferritin >=800 µg/L discontinued the study drug due to adverse events. Estimated glomerular filtration rate remained the stable in all groups.These results further support the conclusion that correction of iron deficiency anemia with IV FCM is safe in patients with nondialysis-dependent CKD.
EVALuna:34009

Safety of Liraglutide in Type 2 Diabetes and Chronic Kidney Disease - Mann, Johannes; Fonseca, Vivian A.; Poulter, Neil R.; Raz, Itamar; Idorn, Thomas; Rasmussen, Søren; von Scholten, Bernt Johan; Mosenzon, Ofri (Clinical Journal of the American Society of Nephrology, 2020)
BACKGROUND AND OBJECTIVES: The glucagon-like peptide-1 receptor agonist liraglutide demonstrated cardiovascular and kidney benefits in the LEADER trial, particularly in participants with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This post hoc analysis evaluated the safety of liraglutide treatment in patients with CKD in LEADER. Overall, 9340 patients were randomized to liraglutide or placebo, both in addition to standard of care. Of those, 2158 patients had CKD versus 7182 without CKD (defined as eGFR <60 versus ≥60 ml/min per 1.73 m2, respectively); 966 patients had macroalbuminuria and 2456 had microalbuminuria (urine albumin-creatinine ratio >300 mg/g and ≥30 to ≤300 mg/g, respectively). At baseline, the mean eGFR in patients with CKD was 46±11 ml/min per 1.73 m2 versus 91±22 ml/min per 1.73 m2 in those without CKD. Time to first event within event groups was analyzed using Cox regression with treatment group, baseline eGFR group, or baseline albuminuria group as fixed factors. RESULTS: Overall, serious adverse events were more frequently recorded in patients with CKD compared with those without CKD (59% versus 50%; interaction P=0.11); however, they occurred to the same extent in those on liraglutide versus placebo. Similarly, no interaction of adverse events with randomized therapy was observed in patients with micro- or macro- versus normoalbuminuria (interaction P=0.11). Risk of severe hypoglycemia was significantly reduced with liraglutide versus placebo in patients with CKD or with micro- or macroalbuminuria (hazard ratio, 0.63 [95% CI, 0.43 to 0.91] and 0.57 [95% CI, 0.40 to 0.82], respectively). CONCLUSIONS: In LEADER, the use of liraglutide in those with CKD was safe, with no difference between patients with and without CKD. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: ClinicalTrials.gov; NCT01179048 (https://clinicaltrials.gov/ct2/show/NCT01179048).
CRIS-Team Scopus Importer:2020-04-17
Keywords: albumins; chronic kidney disease; chronic renal insufficiency; confidence intervals; creatinine; GFR; glucagon-like peptide-1 receptor; humans; hypoglycemia; kidney; liraglutide; microalbuminuria; standard of care; type 2 diabetes mellitus

Salt intake determines retinal arteriolar structure in treatment resistant hypertension independent of blood pressure - Raff, Ulrike; Harazny, Joanna M.; Titze, Stephanie I.; Schmidt, Bernhard Magnus Wilhelm; Michelson, Georg; Schmieder, Roland (Atherosclerosis, 2012)
Patients with treatment resistant hypertension are at increased risk of developing cardiovascular end organ damage. The role of sodium in end organ damage is gaining interest and an independent association of sodium and cardiovascular morbidity and mortality has been described.In an observational study including 40 patients with treatment resistant hypertension, we analysed retinal arteriolar structure in vivo as a determinant of remodelling of small resistant vessels (wall/lumen ratio, wall thickness, wall cross section area) using scanning laser Doppler flowmetry and automatic full-field perfusion imaging analysis. Urinary sodium excretion was determined by 24h urine sample and, in parallel 24h ambulatory blood pressure was measured. We analysed the association of the retinal arterial structure with urinary sodium excretion and blood pressure.Wall to lumen ratio, wall thickness and wall cross section area were strongly associated with urinary sodium excretion but not with 24h blood pressure. In a multiple regression analysis including urinary sodium excretion, BMI, age and 24h blood pressure, urinary sodium excretion emerged as the only independent determinant of wall thickness (?=0.432, p=0.01), and wall cross section area (?=0.439, p=0.008).Our results clearly demonstrate that salt intake influences the structure of retinal arterioles independent of blood pressure in treatment resistant hypertension. Considering the morphologic relation of retinal arteriolar and cerebral vascular structure these results might prove to have important implications on risk stratification in patients with treatment resistant hypertension.
EVALuna2:3574

Salt Sensitivity of Angiogenesis Inhibition-Induced Blood Pressure Rise: Role of Interstitial Sodium Accumulation? - Lankhorst, Stephanie; Severs, David; Marko, Lajos; Rakova, Natalia; Titze, Jens; Mueller, Dominik N.; Danser, A. H. Jan; Van Den Meiracker, Anton H. (Hypertension, 2017)
In response to salt loading, Na+ and Cl- accumulate in the skin in excess of water, stimulating skin lymphangiogenesis via activation of the mononuclear phagocyte system cell-derived vascular endothelial growth factor-C-vascular endothelial growth factor type 3 receptor signaling pathway. Inhibition of this pathway results in salt-sensitive hypertension. Sunitinib is an antiangiogenic, anticancer agent that blocks all 3 vascular endothelial growth factor receptors and increases blood pressure. We explored the salt dependency of sunitinib-induced hypertension and whether impairment of skin lymphangiogenesis is an underlying mechanism. Normotensive Wistar-Kyoto rats were exposed to a normal or high salt with or without sunitinib administration. Sunitinib induced a 15 mm Hg rise in telemetrically measured blood pressure, which was aggravated by a high-salt diet (HSD), resulting in a decline of the slope of the pressure-natriuresis curve. Without affecting body weight, plasma Na+ concentration or renal function, Na+ and Cl- skin content increased by 31% and 32% with the high salt and by 49% and 50% with the HSD plus sunitinib, whereas skin water increased by 17% and 24%, respectively. Skin mononuclear phagocyte system cell density increased both during sunitinib and a HSD, but no further increment was seen when HSD and sunitinib were combined. HSD increased skin lymphangiogenesis, while sunitinib tended to decrease lymphangiogenesis, both during a normal-salt diet and HSD. We conclude that sunitinib induces hypertension that is aggravated by high salt intake and not accompanied by impaired skin lymphangiogenesis.
EVALuna2:35438

Scanned versus Fused-Reconstructed Oblique MR-Images for Assessment of the Tibiofibular Syndesmosis-Diagnostic PerFormance and Reader Agreement - Seuß, Hannes; Hammon, Matthias; Roemer, Frank; Heiß, Rafael; Janka, Rolf Matthias; Uder, Michael; Dankerl, Peter (Diagnostics, 2021)
To evaluate the diagnostic performance and reader agreement of a novel MRI image fusion method enabling the reconstruction of oblique images for the assessment of the tibiofibular syndesmosis. We evaluated 40 magnetic resonance imaging examinations of patients with ankle sprains (16 with ruptures and 24 without) for the presence of anteroinferior tibiofibular ligament rupture. For all patients, we performed a fusion of standard two-dimensional transversal and coronal 3 mm PDw TSE images into an oblique-fusion reconstruction (OFR) and compared these against conventionally scanned oblique sequence for the evaluation of the tibiofibular syndesmosis. To evaluate diagnostic performance, two expert readers independently read the OFR images twice. We analyzed sensitivity, specificity, negative and positive predictive values, accuracy, and agreement. Reader 1 misinterpreted one OFR as a false negative, demonstrating a sensitivity of 0.94 and specificity of 1.00, reader 2 demonstrated perfect accuracy. Intrareader agreement was almost perfect for reader 1 (alpha = 0.95) and was perfect for reader 2 (alpha = 1.00). Additionally, interreader agreement between all fusion sequence reads was almost perfect (alpha = 0.97). The proposed OFR enables reliable detection of anteroinferior tibiofibular ligament rupture with excellent inter- and intrareader agreement, making conventional scanning of oblique images redundant and supplies a method to retroactively create oblique images, e.g., from external examinations.
CRIS-Team WoS Importer:2021-03-19

Scientific Data and Transparency of Conflict of Interest Are Important, Not Biased Editorial Without Facts - Schmieder, Roland; Neuzil, Petr (Jacc-Cardiovascular Interventions, 2016)
EVALuna2:3909

Secreted frizzled-related protein 4 predicts progression of autosomal dominant polycystic kidney disease - Zschiedrich, Stefan; Budde, Klemens; Nürnberger, Jens; Wanner, Christoph; Sommerer, Claudia; Kunzendorf, Ulrich; Banas, Bernhard; Hoerl, Walter H.; Obermüller, Nicholas; Arns, Wolfgang; Pavenstädt, Hermann; Gaedeke, Jens; et al. (Nephrology Dialysis Transplantation, 2015)
Autosomal dominant polycystic kidney disease (ADPKD) is a common autosomal dominant condition associated with renal cysts and development of renal failure. With the availability of potential therapies, one major obstacle remains the lack of readily available parameters that identify patients at risk for disease progression and/or determine the efficacy of therapeutic interventions within short observation periods. Increased total kidney volume (TKV) correlates with disease progression, but it remains unknown how accurate this parameter can predict disease progression at early stages.To identify additional parameters that help to stratify ADPKD patients, we measured secreted frizzled-related protein 4 (sFRP4) serum concentrations at baseline and over the course of 18 months in 429 ADPKD patients.Serum creatinine and sFRP4 as well as TKV increased over time, and were significantly different from baseline values within 1 year.Elevated sFRP4 levels at baseline predicted a more rapid decline of renal function at 2, 3 and 5 years suggesting that sFRP4 serum levels may provide additional information to identify ADPKD patients at risk for rapid disease progression.
EVALuna2:3777

Secretory Capacity of Pancreatic Beta-Cells Is Enhanced 6 Months After Renal Denervation in Hypertensive Patients - Ott, Christian; Schmid, Axel; Mahfoud, Felix; Akarca, Ertan; Kistner, Iris; Ditting, Tilmann; Veelken, Roland; Boehm, Michael; Uder, Michael; Schmieder, Roland (Journal of the American College of Cardiology, 2018)
EVALuna2:35226

Selective stabilization of HIF-1α in renal tubular cells by 2-oxoglutarate analogues - Schley, Gunnar; Klanke, Bernd; Schoedel, Johannes; Kroening, Sven; Türkoglu, Gazi; Beyer, Andreas; Hagos, Yohannes; Amann, Kerstin Ute; Burckhardt, Birgitta C.; Burzlaff, Nicolai; Eckardt, Kai-Uwe; Willam, Carsten (American Journal of Pathology, 2012)
The role of proximal versus distal tubular injury in the pathogenesis of acute kidney injury (AKI) is debatable. Inhibition of prolyl hydroxylases that regulate the degradation of hypoxia-inducible transcription factors (HIFs) is a promising therapeutic approach to optimize energy preservation under hypoxia and has successfully been applied to protect kidney structure and function in AKI models. Presently used prolyl hydroxylase inhibitors are lipophilic 2-oxoglutarate analogues (2OGAs) that are widely taken up in cells of most organs. Given the selective expression of organic anion transporters (OATs) in renal proximal tubular cells, we hypothesized that hydrophilic 2OGAs can specifically target proximal tubular cells. We found that cellular hydrophilic 2OGAs uptake depended on OATs and largely confined to the kidney, where it resulted in activation of HIF target genes only in proximal tubular cells. When applied in ischemia-reperfusion experiments, systemically active 2OGA preserved kidney structure and function, but OAT1-transported 2OGA was not protective, suggesting that HIF stabilization in distal tubular rather than proximal tubular cells and/or nontubular cells mediates protective effects. This study provides proof of concept for selective drug targeting of proximal tubular cells on the basis of specific transporters, gives insights into the role of different nephron segments in AKI pathophysiology, and may offer options for long-term HIF stabilization in proximal tubules without confounding effects of erythropoietin induction in peritubular cells and unwarranted extrarenal effects. © 2012 American Society for Investigative Pathology.

SELF-REPORTED MEDICATION USE AND URINARY DRUG METABOLITES IN THE GERMAN CHRONIC KIDNEY DISEASE (GCKD) STUDY: A PHARMACOMETABOLOMIC APPROACH - Kotsis, Fruzsina Kinga; Schultheiss, Ulla T.; Wuttke, Matthias; Schlosser, Pascal; Oefner, Peter; Mohney, Robert P.; Eckardt, Kai-Uwe; Mielke, Johanna; Becker, Michael; Sekula, Peggy; Koellgen, Anna (NEPHROLOGY DIALYSIS TRANSPLANTATION, 2021)
CRIS-Team WoS Importer:2021-12-03

Self-Reported Medication Use and Urinary Drug Metabolites in the German Chronic Kidney Disease (GCKD) Study - Kotsis, Fruzsina; Schultheiss, Ulla T.; Wuttke, Matthias; Schlosser, Pascal; Mielke, Johanna; Becker, Michael S.; Oefner, Peter J.; Karoly, Edward D.; Mohney, Robert P.; Eckardt, Kai-Uwe; Sekula, Peggy; Köttgen, Anna (Journal of the American Society of Nephrology, 2021)
Background Polypharmacy is common among patients with CKD, but little is known about the urinary excretion of many drugs and their metabolites among patients with CKD. Methods Toevaluate self-reportedmedicationuse in relation tourine drugmetabolite levels in a largecohort of patients with CKD, the German Chronic Kidney Disease study, we ascertained self-reported use of 158 substances and41medication groups, andcodedactive ingredients accordingto theAnatomicalTherapeutic Chemical Classification System. We used a nontargeted mass spectrometry-based approach to quantify metabolites in urine; calculated specificity, sensitivity, and accuracy of medication use and corresponding metabolite measurements; and used multivariable regression models to evaluate associations and prescription patterns. Results Among 4885 participants, therewere 108medication-drugmetabolite pairs on the basis of reported medication use and 78 drug metabolites. Accuracy was excellent for measurements of 36 individual substances inwhich the unchanged drugwasmeasured in urine (median, 98.5%; range, 61.1%-100%). For 66 pairs of substances andtheir relateddrugmetabolites,medianmeasurement-basedspecificity and sensitivity were 99.2% (range, 84.0%-100%) and 71.7% (range, 1.2%-100%), respectively. Commonly prescribed medications for hypertension and cardiovascular risk reduction-including angiotensin II receptor blockers, calcium channel blockers, and metoprolol-showed high sensitivity and specificity. Although self-reported use of prescribed analgesics (acetaminophen, ibuprofen) was <3% each, drug metabolite levels indicated higher usage (acetaminophen, 10%-26%; ibuprofen, 10%-18%). Conclusions This comprehensive screen of associations between urine drug metabolite levels and selfreported medication use supports the use of pharmacometabolomics to assess medication adherence and prescription patterns in persons with CKD, and indicates under-reported use of medications available over the counter, such as analgesics.
CRIS-Team Scopus Importer:2021-09-17

SEMI-AUTOMATIC MEASUREMENT OF INTIMA-MEDIA THICKNESS OF BRACHIAL ARTERY IN PATIENTS WITH CONGESTIVE HEART FAILURE - Kannenkeril, Dennis; Kolwelter, Julie; Pietschner, Robert; Striepe, Kristina; Bosch, Agnes; Achenbach, Stephan; Schmieder, Roland (JOURNAL OF HYPERTENSION, 2022)
CRIS-Team WoS Importer:2023-02-17

SEMI-AUTOMATIC MEASUREMENT OF INTIMA-MEDIA THICKNESS OF BRACHIAL ARTERY IN PATIENTS WITH CONGESTIVE HEART FAILURE - Kannenkeril, Dennis; Kolwelter, Julie; Pietschner, Robert; Striepe, Kristina; Bosch, Agnes; Achenbach, Stephan; Schmieder, Roland (Journal of Hypertension, 2022)
OBJECTIVE: Cardiovascular diseases are associated with an increase in intima-media thickness (IMT). However, the techniques used to measure IMT have limitations. A semi-automatic device called UNEX has been developed, which overcomes the limitation of classic systems (in particular the investigator-dependency of conventional, "hand-held'' measurements). The purpose of this study was to measure the intima-media thickness of the brachial artery (bIMT) with the UNEX device in patients with and without congestive heart failure. DESIGN AND METHOD: The UNEX device is comprised of a 7.5-MHz, H-shaped linear array transducer and a novel stereotactic probe-holding device (UNEX EF 18G; UNEX Co., Nagoya, Japan). Another advantage of this device is the continuous recording of B-mode images and A-mode waves of the brachial artery. Measurement of bIMT was automatically performed on A-mode images of the far wall of the brachial artery. The analysis system automatically detects the measurement point where an image was clearly obtained. The average of mean measurement values obtained from 10 cardiac cycles was defined as bIMT. In a first set of clinical studies, we measured bIMT in patients with reduced left ventricular ejection fraction (HFrEF) and in patients without heart failure. RESULTS: Patients with HFrEF (n = 85, ejection fraction: 38.3 ± 8.4 %, NT-pro-BNP: 713 ± 714.7 pg/ml) compared to patients without heart failure (n = 63) were older (66.4 ± 9.2 vs. 53.8 ± 12.6 years, p < 0.001), with more male subjects (67 vs. 40, p = 0.039). bIMT was higher in patients with HFrEF compared to the other group (0.295 ± 0.083 vs. 0.249 ± 0.083 mm, p < 0.001). After adjustment for age, gender and other cardiovascular risk factors, the result remained significant (p = 0.032). CONCLUSIONS: Our study demonstrate that IMT of large muscular arteries can be automatically (investigator independently) measured. Our data indicate an increased vascular remodeling in patients with HFrEF independent of other confounders.
CRIS-Team Scopus Importer:2022-09-16

Serum levels of the Th1 chemoattractant interferon-gamma-inducible protein (IP) 10 are elevated in patients with essential hypertension - Stumpf, Christian; Auer, Claudia; Yilmaz, Atilla; Lewczuk, Piotr; Klinghammer, Lutz; Schneider, Markus; Daniel, Werner; Schmieder, Roland; Garlichs, Christoph (Hypertension Research, 2011)
Growing evidence shows that inflammation has a pivotal role in the pathophysiology of essential hypertension (EH). Although it has been acknowledged that target organ damage involves an inflammatory response, most work has focused on the role of macrophages, but T lymphocytes have recently become the center of interest. The goal of our study was to evaluate the role of T-cell-specific cytokines in the pathogenesis of EH. The study examined 39 patients with EH (57.7±6.8 years, systolic blood pressure (SBP) 157.5±11.8 mm Hg, diastolic blood pressure 92.2±12.9 mm Hg, mean arterial pressure 113.9±12.6 mm Hg) and 30 healthy, normotensive controls (55.2±4.9 years). Blood was drawn from a peripheral vein, and serum levels of interferon-inducible protein (IP)-10 and interleukins (IL)-4,-7 and-13 were measured by a multiplexing assay. Hypertensive patients had significantly higher levels of IP-10, IL-4, IL-7 and IL-13 than control subjects. When the patients were classified into tertiles according to their serum IP-10 levels (T1: 41.2-9±4.1 pg ml-1; T2: 103.4-1±62.5 pg ml 1; T3: 171.7-443.5 pgml 1), the patients classified into the highest tertile also had the highest blood pressure. In a correlation analysis, plasma IP-10 concentration was significantly associated with SBP (r0.59, P<0.001). Furthermore, hypertensives with microalbuminuria, an early sign of hypertensive target organ damage, had the highest IP-10 levels. A stepwise multivariate regression analysis revealed IP-10 as the strongest independent predictor of SBP (P<0.01). In conclusion, our study provides new insights into the pathophysiological mechanisms in EH linking inflammation and IP-10. However, these preliminary results need to be confirmed in larger trials. © 2011 The Japanese Society of Hypertension All rights reserved.
CRIS-Team Scopus Importer:2023-07-10
Keywords: cytokines; inflammation; IP-10; microalbuminuria; T-cells

Serum markers of fibrosis, cardiovascular and all-cause mortality in hemodialysis patients: the AURORA trial - Salib, Madonna; Girerd, Sophie; Girerd, Nicolas; Marz, Winfried; Scharnagl, Hubert; Massy, Ziad A.; Leroy, Celine; Duarte, Kevin; Holdaas, Hallvard; Jardine, Alan G.; Schmieder, Roland; Fellstrom, Bengt; et al. (Clinical Research in Cardiology, 2021)
Background Biomarkers of fibrosis are associated with outcome in several cardiovascular diseases. However, their relevance to chronic kidney disease and dialysis is uncertain, as it remains unclear how the kidneys and the dialysis procedure itself affect their elimination and degradation. We aimed to investigate the relationship of the blood levels of two markers associated with fibrosis: procollagen type I C-terminal pro-peptide (PICP) and galectin-3 (Gal-3) with mortality in dialysis patients.
CRIS-Team WoS Importer:2021-07-09

Severe neurological outcomes after very early bilateral nephrectomies in patients with autosomal recessive polycystic kidney disease (ARPKD) - Burgmaier, Kathrin; Ariceta, Gema; Bald, Martin; Buescher, Anja Katrin; Burgmaier, Mathias; Erger, Florian; Gessner, Michaela; Gokce, Ibrahim; König, Jens; Kowalewska, Claudia; Massella, Laura; Mastrangelo, Antonio; et al. (Scientific Reports, 2020)
To test the association between bilateral nephrectomies in patients with autosomal recessive polycystic kidney disease (ARPKD) and long-term clinical outcome and to identify risk factors for severe outcomes, a dataset comprising 504 patients from the international registry study ARegPKD was analyzed for characteristics and complications of patients with very early (≤ 3 months; VEBNE) and early (4–15 months; EBNE) bilateral nephrectomies. Patients with very early dialysis (VED, onset ≤ 3 months) without bilateral nephrectomies and patients with total kidney volumes (TKV) comparable to VEBNE infants served as additional control groups. We identified 19 children with VEBNE, 9 with EBNE, 12 with VED and 11 in the TKV control group. VEBNE patients suffered more frequently from severe neurological complications in comparison to all control patients. Very early bilateral nephrectomies and documentation of severe hypotensive episodes were independent risk factors for severe neurological complications. Bilateral nephrectomies within the first 3 months of life are associated with a risk of severe neurological complications later in life. Our data support a very cautious indication of very early bilateral nephrectomies in ARPKD, especially in patients with residual kidney function, and emphasize the importance of avoiding severe hypotensive episodes in this at-risk cohort.
CRIS-Team Scopus Importer:2020-10-16

Sex and the risk of acute reduction in kidney function after renin-angiotensin blockade: Parallel analyses of a primary care cohort and two randomised trials - Wong, Angel; Gao, Peggy; Mansfield, Kathryn; Bhaskaran, Krishnan; Carrero, Juan Jesus; Sinnott, Sarah-Jo; Nitsch, Dorothea; Smeeth, Liam; Mann, Johannes; Clase, Catherine; Tomlinson, Laurie (PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, 2020)
CRIS-Team WoS Importer:2020-11-13

Sex Differences in Blood Pressure and Potential Implications for Cardiovascular Risk Management - Picone, Dean S.; Stoneman, Elif; Cremer, Antoine; Schultz, Martin G.; Otahal, Petr; Hughes, Alun D.; Black, J. Andrew; Bos, Willem Jan; Chen, Chen Huan; Cheng, Hao Min; Dwyer, Nathan; Lacy, Peter; et al. (Hypertension, 2023)
BACKGROUND: Accurate blood pressure (BP) measurement is critical for optimal cardiovascular risk management. Age-related trajectories for cuff-measured BP accelerate faster in women compared with men, but whether cuff BP represents the intraarterial (invasive) aortic BP is unknown. This study aimed to determine the sex differences between cuff BP, invasive aortic BP, and the difference between the 2 measurements. METHODS: Upper-arm cuff BP and invasive aortic BP were measured during coronary angiography in 1615 subjects from the Invasive Blood Pressure Consortium Database. This analysis comprised 22 different cuff BP devices from 28 studies. RESULTS: Subjects were 64±11 years (range 40-89) and 32% women. For the same cuff systolic BP (SBP), invasive aortic SBP was 4.4 mm Hg higher in women compared with men. Cuff and invasive aortic SBP were higher in women compared with men, but the sex difference was more pronounced from invasive aortic SBP, was the lowest in younger ages, and the highest in older ages. Cuff diastolic blood pressure overestimated invasive diastolic blood pressure in both sexes. For cuff and invasive diastolic blood pressure separately, there were sex*age interactions in which diastolic blood pressure was higher in younger men and lower in older men, compared with women. Cuff pulse pressure underestimated invasive aortic pulse pressure in excess of 10 mm Hg for both sexes in older age. CONCLUSIONS: For the same cuff SBP, invasive aortic SBP was higher in women compared with men. How this translates to cardiovascular risk prediction needs to be determined, but women may be at higher BP-related risk than estimated by cuff measurements.
CRIS-Team Scopus Importer:2023-01-27
Keywords: diagnostic equipment; hypertension; physiology; pulse wave analysis; sex factors

Sex differences in long-term kidney fibrosis following neonatal nephron loss during ongoing nephrogenesis - Menendez-Castro, Carlos; Cordasic, Nada; Fahlbusch, Fabian; Wölfle, Joachim; Hilgers, Karl Friedrich; Hartner, Andrea (Molecular and Cellular Pediatrics, 2023)
Background: Clinical studies suggest that female sex plays a protective role in the development and progression of kidney disease. Recent experimental studies indicate that in male rats early nephron loss under ongoing nephrogenesis is accompanied by severe long-term sequelae. In humans, nephron formation occurs mainly in the third trimester, ceasing with 36 weeks of gestation. Due to perinatal complications, preterm infants delivered during this vulnerable period may undergo acute nephron loss. In rats nephrogenesis persists until postnatal day 10, reflecting the situation of human preterms with persisting nephrogenesis. In our animal model of neonatal uninephrectomy, female and male rats were uninephrectomized at day 1 of life. Hypothesizing sex-dependent differences, long-term renal outcome was assessed after 1 year. Results: In both sexes, neonatal uninephrectomy was not followed by arterial hypertension at 1 year of age. Compensatory weight gain and glomerular hypertrophy of the remaining kidney occurred in uninephrectomized female and male animals. Selected markers of interstitial inflammation and fibrosis were regulated sex-dependently. The expression of monocyte chemoattractant protein-1 was increased in females, while tubulointerstitial infiltration by M1 macrophages was significantly higher in males after neonatal uninephrectomy. Neonatally uninephrectomized male rats had more glomerulosclerosis and podocyte damage compared to females, which was assessed by a semiquantitative score and desmin staining. RT-PCR revealed that after neonatal uninephrectomy in the remaining contralateral kidney of female rats the expression of candidate genes of renal development and function, i.e., wt-1, nephrin, synaptopodin, gdnf, and itga8 was higher than in males. Conclusions: Based on these observations we conclude that female sex is protective in the long-term response of the kidney to acute nephron loss under active nephrogenesis.
CRIS-Team Scopus Importer:2023-09-08
Keywords: Kidney fibrosis; Neonatal nephron loss; Neonatal uninephrectomy; Nephrogenesis; Sex differences

Sex differences in the development of vascular and renal lesions in mice with a simultaneous deficiency of Apoe and the integrin chain Itga8 - Marek, Ines; Canu, Maurizio; Cordasic, Nada; Rauh, Manfred; Volkert, Gudrun; Fahlbusch, Fabian B.; Rascher, Wolfgang; Hilgers, Karl Friedrich; Hartner, Andrea; Menendez-Castro, Carlos (Biology of Sex Differences, 2017)
BACKGROUND: Apoe-deficient (Apoe-/-) mice develop progressive atherosclerotic lesions with age but no severe renal pathology in the absence of additional challenges. We recently described accelerated atherosclerosis as well as marked renal injury in Apoe-/- mice deficient in the mesenchymal integrin chain Itga8 (Itga8-/-). Here, we used this Apoe-/-, Itga8-/- mouse model to investigate the sex differences in the development of atherosclerosis and concomitant renal injury. We hypothesized that aging female mice are protected from vascular and renal damage in this mouse model. METHODS: Apoe-/- mice were backcrossed with Itga8-/- mice. Mice were kept on a normal diet. At the age of 12 months, the aortae and kidneys of male and female Apoe-/-Itga8+/+ mice or Apoe-/-Itga8-/- mice were studied. En face preparations of the aorta were stained with Sudan IV (lipid deposition) or von Kossa (calcification). In kidney tissue, immunostaining for collagen IV, CD3, F4/80, and PCNA and real-time PCR analyses for Il6, Vegfa, Col1a1 (collagen I), and Ssp1 (secreted phosphoprotein 1, synonym osteopontin) as well as ER stress markers were performed. RESULTS: When compared to male mice, Apoe-/-Itga8+/+ female mice had a lower body weight, equal serum cholesterol levels, and lower triglyceride levels. However, female mice had increased aortic lipid deposition and more aortic calcifications than males. Male Apoe-/- mice with the additional deficiency of Itga8 developed increased serum urea, glomerulosclerosis, renal immune cell infiltration, and reduced glomerular cell proliferation. In females of the same genotype, these renal changes were less pronounced and were accompanied by lower expression of interleukin-6 and collagen I, while osteopontin expression was higher and markers of ER stress were not different. CONCLUSIONS: In this model of atherosclerosis, the female sex is a risk factor to develop more severe atherosclerotic lesions, even though serum fat levels are higher in males. In contrast, female mice are protected from renal damage, which is accompanied by attenuated inflammation and matrix deposition. Thus, sex affects vascular and renal injury in a differential manner.
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Sex-specific differences and long-term outcome of patients with coronary artery disease and chronic kidney disease: the Coronary Artery Disease and Renal Failure (CAD-REF) Registry - Engelbertz, Christiane; Pinnschmidt, Hans O.; Freisinger, Eva; Reinecke, Holger; Schmitz, Boris; Fobker, Manfred; Schmieder, Roland; Wegscheider, Karl; Breithardt, Günter; Pavenstädt, Hermann; Brand, Eva (Clinical Research in Cardiology, 2021)
Background: Cardiovascular morbidity and mortality are closely linked to chronic kidney disease (CKD). Sex-specific long-term outcome data of patients with coronary artery disease (CAD) and CKD are scarce. Methods: In the prospective observational multicenter Coronary Artery Disease and REnal F﻿ailure (CAD-REF) Registry, 773 (23.1%) women and 2,579 (76.9%) men with angiographically documented CAD and different stages of CKD were consecutively enrolled and followed for up to 8 years. Long-term outcome was evaluated using survival analysis and multivariable Cox-regression models. Results: At enrollment, women were significantly older than men, and suffered from more comorbidities like CKD, hypertension, diabetes mellitus, and multivessel coronary disease. Regarding long-term mortality, no sex-specific differences were observed (Kaplan–Meier survival estimates: 69% in women vs. 69% in men, plog-rank = 0.7). Survival rates decreased from 89% for patients without CKD at enrollment to 72% for patients with CKD stages 1–2 at enrollment and 49% for patients with CKD stages 3–5 at enrollment (plog-rank < 0.001). Cox-regression analysis revealed that sex or multivessel coronary disease were no independent predictors of long-term mortality, while age, CKD stages 3–5, albumin/creatinine ratio, diabetes, valvular heart disease, peripheral artery disease, and left-ventricular ejection fraction were predictors of long-term mortality. Conclusions: Sex differences in CAD patients mainly exist in the cardiovascular risk profile and the extent of CAD. Long-term mortality was not depended on sex or multivessel disease. More attention should be given to treatment of comorbidities such as CKD and peripheral artery disease being independent predictors of death. Clinical Trail Registration ClinicalTrials.gov Identifier: NCT00679419 Graphic abstract: [Figure not available: see fulltext.]
CRIS-Team Scopus Importer:2021-06-04
Keywords: Chronic kidney disease; Coronary artery disease; Long-term mortality; Sex; Treatment

SGLT-2-inhibition with dapagliflozin reduces tissue sodium content: a randomised controlled trial - Karg, Margarete; Bosch, A.; Kannenkeril, D.; Striepe, Kristina; Ott, Christian; Schneider, M. P.; Boemke-Zelch, Franziska; Linz, Peter; Nagel, Armin Michael; Titze, Jens; Uder, Michael; Schmieder, Roland (Cardiovascular Diabetology, 2018)
Sodium tissue content by 23Na magnetic resonance imaging (Na-MRI) has been validated in experimental and human studies. SGLT-2 inhibition blocks the reabsorption of glucose and of sodium in the proximal tubular cells in a 1:1 fashion. We hypothesized that SGLT-2 inhibition in patients with type 2 diabetes characterized by sodium retention leads to decreased tissue sodium content due to its pharmacological action.In a prospective double blind, placebo controlled, cross-over trial 59 patients (61 ± 7.6 years) with type 2 diabetes were randomized to either dapagliflozin 10 mg or placebo once daily for 6 weeks each. In addition to metabolic parameters and ambulatory blood pressure (BP) we analysed the sodium content in the skin and muscles of the lower leg by Na-MRI.Compared to baseline 6 weeks treatment with the SGLT-2 inhibitor dapagliflozin decreased fasting (132 ± 28 vs. 114 ± 19 mg/dl, p < 0.001), postprandial blood glucose (178 ± 66 mg/dl vs. 153 ± 46 mg/dl, p < 0.001), body weight (87.6 vs. 86.6 kg, p < 0.001) and systolic (129 ± 12 vs. 126 ± 11 mmHg, p = 0.010), and diastolic (77.4 ± 9 vs. 75.6 ± 8 mmHg, p = 0.024), 24-h ambulatory BP. Tissue sodium content in the skin was reduced after 6 weeks treatment with dapagliflozin compared to baseline [24.1 ± 6.6 vs. 22.7 ± 6.4 A.U.(arbitrary unit) p = 0.013]. No significant reduction of tissue sodium content was observed in the muscle (M. triceps surae: 20.5 ± 3.5 vs. 20.4 ± 3.7 A.U. p = 0.801). No clear significant difference in tissue water content of muscle and skin was observed after 6 weeks of treatment with dapagliflozin, compared to baseline.SGLT-2 inhibition with dapagliflozin resulted in a significant decrease in tissue sodium content of the skin after 6 weeks. This observation point to a decrease of total sodium content in patients with type 2 diabetes prone to cardiovascular complications, that might be mitigated by SGLT-2 inhibition. Trial registration The study was registered at http://www.clinicaltrials.gov (NCT02383238) retrospectively registered.
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Significance of Glomerular Immune Reactivity in Time Zero Biopsies for Allograft Survival Beyond IgA - Vonbrunn, Eva; Serikova, Sofya; Daniel, Christoph; Amann, Kerstin Ute; Schödel, Johannes; Buchholz, Björn; Ferrazzi, Fulvia; Heller, Katharina M.; Apel, Hendrik; Büttner-Herold, Maike (Frontiers in Medicine, 2021)
The quality of a renal transplant can influence the clinical course after transplantation. Glomerular immune reactivity in renal transplants has previously been described, focusing particularly on IgA, and has been shown to disappear in most cases without affecting the outcome. Here, we describe a cohort of time zero biopsies with regard to glomerular immune reactivity and implications for histomorphology and follow-up. 204 Time zero biopsies were analyzed by immunohistochemistry for glomerular immune reactivity. Time zero and 1-year biopsies were evaluated for histomorphological changes, which, together with clinical and follow-up data, were assessed for associations with glomerular immune profiles. Nearly half of the analyzed time zero biopsies showed glomerular immune reactivity with mesangial C3 being the most common (32.9%), followed by IgA (13.7%) and fullhouse patterns (6.9%). Strong C3 deposits (C3high) were only observed in deceased transplants. In the majority of cases immune reactivity was undetectable in follow-up biopsies and had no adverse effect on transplant function in follow-up of 5 years. In kidney pairs transplanted to different recipients a strong concordance of immune profiles in both kidneys was observed. Moreover, an association of male donor sex and deceased donor transplantation with the presence of immune reactivity was observed. In conclusion, glomerular immune reactivity is a very frequent finding in time zero biopsies, which seems to be determined by donor parameters including male sex and deceased donor transplants. It had no adverse impact on transplant function in 5-year follow-up. Glomerular immune reactivity in time zero biopsies, therefore, does not appear to indicate an inferior quality of the transplant.
CRIS-Team WoS Importer:2021-04-30
Keywords: complement; renal tranplantation; time zero biopsy; transplant quality; immune reactivity

Similar Impact of Psoriatic Arthritis and Rheumatoid Arthritis on Objective and Subjective Parameters of Hand Function - Liphardt, Anna-Maria; Manger, Eva; Liehr, Sonja; Bieniek, Lisa Maria; Kleyer, Arnd; Simon, David; Tascilar, Koray; Sticherling, Michael; Rech, Jürgen; Schett, Georg; Hueber, Axel (ACR Open Rheumatology, 2020)
ObjectiveThe objective of this study was to compare the impact of psoriatic disease (psoriatic arthritis [PsA] and psoriasis) and rheumatoid arthritis (RA) on objective and subjective parameters of hand function.
CRIS-Team WoS Importer:2021-07-16

Similar Impact of Psoriatic Arthritis and Rheumatoid Arthritis on Objective and Subjective Parameters of Hand Function - Liphardt, Anna-Maria; Manger, Eva; Liehr, Sonja; Bieniek, Lisa; Kleyer, Arnd; Simon, David; Tascilar, Koray; Sticherling, Michael; Rech, Jürgen; Schett, Georg; Hueber, Axel (ARTHRITIS & RHEUMATOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

Simultaneously measured interarm blood pressure difference is not associated with pulse wave velocity in a clinical dataset of at-risk hypertensive patients - Nolde, J.; Lugo-Gavidia, L. M.; Kannenkeril, Dennis; Chan, J.; Robinson, Sandi; Jose, A.; Joyson, A.; Schlaich, L.; Carnagarin, Revathy; Azzam, O.; Kiuchi, M.; Schlaich, Markus (European Heart Journal, 2021)
Abstract Background/Introduction Recent analysis of systolic inter-arm differences in blood pressure from the INTERPRESS-IPD Collaboration suggest an association with increased all-cause mortality, cardiovascular mortality and cardiovascular events, previous studies have demonstrated associations with other risk parameters. Purpose We aimed to reproduce these associations in a cohort of 199 treated, at-risk, hypertensive patients with pulse wave velocity (PWV) as a surrogate marker of cardiovascular (CV) damage. Methods Simultaneously measured Inter-arm blood pressure differences, 24 hour ambulatory BP and PWV were measured in 199 treated patients of a tertiary hospital hypertension outpatient clinic. Associations between systolic inter-arm BP difference and PWV were analyzed with uni- and multivariate regression models. Results Out of 199 participants, 90 showed an Inter-arm blood pressure difference of more than 5 mmHg. The Inter-arm difference was not associated with PWV. Furthermore, neither observed single blood pressure measurements nor 24 hour ambulatory blood pressure was associated with Inter-arm blood pressure differences. Conclusion In our clinical patient cohort we failed to observe an association between inter-arm BP differences and PWV. Mode of assessment, study design or the sample characteristics of this treated, hypertensive cohort may explain the negative results. The limited sample size of the study poses a challenge to the detection of smaller effects in our study.
CRIS-Team WoS Importer:2021-12-10
Keywords: Target Organ Damage; Left Ventricular Hypertrophy

Simultaneously measured inter-arm blood pressure difference is not associated with pulse wave velocity in a clinical dataset of at-risk hypertensive patients - Nolde, Janis M.; Lugo-Gavidia, Leslie Marisol; Kannenkeril, Dennis; Chan, Justine; Robinson, Sandi; Jose, Ancy; Joyson, Anu; Schlaich, Luca; Carnagarin, Revathy; Azzam, Omar; Kiuchi, Márcio Galindo; Schlaich, Markus P. (Journal of Human Hypertension, 2021)
Recent analysis of systolic inter-arm differences in blood pressure from the INTERPRESS-IPD Collaboration suggest an association with increased all-cause mortality, cardiovascular mortality and cardiovascular events. Previous studies have demonstrated associations with other risk parameters. We aimed to reproduce these associations in a cohort of 199 treated, at-risk hypertensive patients with pulse wave velocity (PWV) as a surrogate marker of cardiovascular (CV) damage. Simultaneously measured inter-arm blood pressure (BP) differences, 24 hour ambulatory BP and PWV were measured in 199 treated patients from a tertiary hospital hypertension outpatient clinic. Associations between systolic inter-arm BP difference and PWV were analyzed with uni- and multi-variate regression models. Out of 199 participants, 90 showed an inter-arm BP difference of more than 5 mmHg. The inter-arm difference was not associated with PWV. Furthermore, neither observed single BP measurements nor 24 hour ambulatory BP was associated with inter-arm BP differences. In our clinical patient cohort we failed to observe an association between inter-arm BP differences and PWV. Mode of assessment, study design and the sample characteristics of this treated, hypertensive cohort may have contributed to the negative findings. The limited sample size of the study poses a challenge to the detection of smaller effects in our study.
CRIS-Team Scopus Importer:2021-08-13

Single molecule real time sequencing in ADTKD-MUC1 allows complete assembly of the VNTR and exact positioning of causative mutations - Wenzel, Andrea; Altmueller, Janine; Ekici, Arif Bülent; Popp, Bernt; Stueber, Kurt; Thiele, Holger; Pannes, Alois; Staubach, Simon; Salido, Eduardo; Nuernberg, Peter; Reinhardt, Richard; Reis, André; et al. (Scientific Reports, 2018)
Recently, the Mucin-1 (MUC1) gene has been identified as a causal gene of autosomal dominant tubulointerstitial kidney disease (ADTKD). Most causative mutations are buried within a GC-rich 60 basepair variable number of tandem repeat (VNTR), which escapes identification by massive parallel sequencing methods due to the complexity of the VNTR. We established long read single molecule real time sequencing (SMRT) targeted to the MUC1-VNTR as an alternative strategy to the snapshot assay. Our approach allows complete VNTR assembly, thereby enabling the detection of all variants residing within the VNTR and simultaneous determination of VNTR length. We present high resolution data on the VNTR architecture for a cohort of snapshot positive (n = 9) and negative (n = 7) ADTKD families. By SMRT sequencing we could confirm the diagnosis in all previously tested cases, reconstruct both VNTR alleles and determine the exact position of the causative variant in eight of nine families. This study demonstrates that precise positioning of the causative mutation(s) and identification of other coding and noncoding sequence variants in ADTKD-MUC1 is feasible. SMRT sequencing could provide a powerful tool to uncover potential factors encoded within the VNTR that associate with intra- and interfamilial phenotype variability of MUC1 related kidney disease.
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Single pill regimen improves persistence and leads lo better clinical outcome compared to identical multi pill combination. Results of START, a German claims data analysis - Predel, H. G.; Weisser, B.; Schmieder, Roland; Wassmann, S.; Blettenberg, J.; Gillessen, A.; Fournier,; Noetel, A.; Randerath, O.; Boehm, M. (EUROPEAN HEART JOURNAL, 2020)
CRIS-Team WoS Importer:2021-02-12

Single pill treatment in daily practice is associated with improved clinical outcomes and all-cause mortality in cardiovascular diseases: results from the START project - Weisser, B.; Wilke, T.; Predel, H. G.; Schmieder, Roland; Wassmann, S.; Gillessen, A.; Blettenberg, J.; Maywald, U.; Randerath, O.; Mevius, A.; Boehm, M. (EUROPEAN HEART JOURNAL, 2022)
CRIS-Team WoS Importer:2023-03-03

Sirolimus in renal transplant recipients with malignancies in Germany - Naik, Marcel G.; Arns, Wolfgang; Budde, Klemens; Diekmann, Fritz; Eitner, Frank; Gwinner, Wilfried; Heyne, Nils; Jurgensen, Jan Steffen; Morath, Christian; Riester, Udo; Heller, Katharina M.; Fischereder, Michael (Clinical Kidney Journal, 2021)
Background. Renal transplant recipients have an increased cancer risk. The mammalian target of rapamycin inhibitor sirolimus (SRL) has immunosuppressive and antitumour activities but knowledge about its use in recipients with cancer is limited.
CRIS-Team WoS Importer:2021-10-01

Six-Month Results of Treatment-Blinded Medication Titration for Hypertension Control Following Randomization to Endovascular Ultrasound Renal Denervation or a Sham Procedure in the RADIANCE-HTN SOLO Trial - Azizi, Michel; Schmieder, Roland; Mahfoud, Felix; Weber, Michael A.; Daemen, Joost; Lobo, Melvin D.; Sharp, Andrew S. P.; Bloch, Michael J.; Basile, Jan; Wang, Yale; Saxena, Manish; Lurz, Philipp; et al. (Circulation, 2019)
BACKGROUND: The multicenter, international, randomized, blinded, sham-controlled RADIANCE-HTN SOLO trial demonstrated a 6.3 mmHg greater reduction in daytime ambulatory systolic blood pressure (BP) at 2 months by endovascular ultrasound renal denervation (RDN) compared with a sham procedure among patients not treated with antihypertensive medications. We report 6-month results following the addition of a recommended standardized stepped-care antihypertensive treatment (SSAHT) to the randomized endovascular procedure under continued blinding to initial treatment. METHODS: Patients with a daytime ambulatory BP greater ≥135/85 mmHg and <170/105 mmHg after a 4-week discontinuation of up to 2 antihypertensive medications and a suitable renal artery anatomy, were randomized to RDN (n=74) or sham (n=72). Patients were to remain off antihypertensive medications throughout the first 2 months of follow-up unless safety BP criteria were exceeded. Between 2 and 5 months, if monthly measured home BP was ≥135/85 mmHg, a SSAHT was recommended consisting of the sequential addition of amlodipine 5 mg/day, a standard dose of an angiotensin converting enzyme inhibitor/angiotensin receptor blocker, and hydrochlorothiazide 12.5 mg/day, followed by the sequential uptitration of hydrochlorothiazide (25 mg/day) and amlodipine (10 mg/day). Outcomes included the 6-month (i) change in daytime ambulatory systolic BP adjusted for medications and baseline SBP, (ii) medication burden, and (iii) safety. RESULTS: A total of 69/74 RDN patients and 71/72 sham patients completed the 6-month ambulatory BP measurement. At 6 months, 65.2% of patients in the RDN group were treated with the SSAHT vs. 84.5% in the sham group (p=0.008) and the average number of antihypertensive medications and defined daily dose were less in the RDN group than in the sham group (0.9±0.9 vs. 1.3±0.9, p=0.010 and 1.4±1.5 vs. 2.0±1.8, p=0.018; respectively). Despite less intensive SSAHT, RDN reduced daytime ambulatory systolic BP to a greater extent than sham (-18.1±12.2 vs. -15.6±13.2 mmHg, respectively; difference adjusted for baseline BP and number of medications: -4.3 mmHg, 95% confidence interval, -7.9 to -0.6, p=0.024). There were no major adverse events in either group through 6 months. CONCLUSIONS: The BP lowering effect of endovascular ultrasound RDN was maintained at 6 months with less prescribed antihypertensive medications compared with a sham control. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02649426.
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Skin Sodium Accumulates in Psoriasis and Reflects Disease Severity - Maifeld, András; Wild, Johannes; Karlsen, Tine V.; Rakova, Natalia; Wistorf, Elisa; Linz, Peter; Jung, Rebecca; Birukov, Anna; Gimenez-Rivera, Vladimir Andrey; Wilck, Nicola; Bartolomaeus, Theda; Dechend, Ralf; et al. (Journal of Investigative Dermatology, 2021)
Sodium can accumulate in the skin at concentrations exceeding serum levels. A high sodium environment can lead to pathogenic T helper 17 cell expansion. Psoriasis is a chronic inflammatory skin disease in which IL-17‒producing T helper 17 cells play a crucial role. In an observational study, we measured skin sodium content in patients with psoriasis and in age-matched healthy controls by Sodium-23 magnetic resonance imaging. Patients with PASI > 5 showed significantly higher sodium and water content in the skin but not in other tissues than those with lower PASI or healthy controls. Skin sodium concentrations measured by Sodium-23 spectroscopy or by atomic absorption spectrometry in ashed-skin biopsies verified the findings with Sodium-23 magnetic resonance imaging. In vitro T helper 17 cell differentiation of naive CD4+ cells from patients with psoriasis markedly induced IL-17A expression under increased sodium chloride concentrations. The imiquimod-induced psoriasis mouse model replicated the human findings. Extracellular tracer Chromium-51–EDTA measurements in imiquimod- and sham-treated skin showed similar extracellular volumes, rendering excessive water of intracellular origin. Chronic genetic IL-17A‒driven psoriasis mouse models underlined the role of IL-17A in dermal sodium accumulation and inflammation. Our data describe skin sodium as a pathophysiological feature of psoriasis, which could open new avenues for its treatment.
CRIS-Team Scopus Importer:2021-08-13

Skin Sodium Concentration Correlates with Left Ventricular Hypertrophy in CKD - Schneider, Markus P.; Raff, Ulrike; Kopp, Christoph; Scheppach, Johannes B.; Toncar, Sebastian; Wanner, Christoph; Schlieper, Georg; Saritas, Turgay; Floege, Juergen; Schmid, Matthias; Birukov, Anna; Dahlmann, Anke; et al. (Journal of the American Society of Nephrology, 2017)
The pathogenesis of left ventricular hypertrophy in patients with CKD is incompletely understood. Sodium intake, which is usually assessed by measuring urinary sodium excretion, has been inconsistently linked with left ventricular hypertrophy. However, tissues such as skin and muscle may store sodium. Using (23)sodium-magnetic resonance imaging, a technique recently developed for the assessment of tissue sodium content in humans, we determined skin sodium content at the level of the calf in 99 patients with mild to moderate CKD (42 women; median [range] age, 65 [23-78] years). We also assessed total body overhydration (bioimpedance spectroscopy), 24-hour BP, and left ventricular mass (cardiac magnetic resonance imaging). Skin sodium content, but not total body overhydration, correlated with systolic BP (r=0.33, P=0.002). Moreover, skin sodium content correlated more strongly than total body overhydration did with left ventricular mass (r=0.56, P<0.001 versus r=0.35, P<0.001; P<0.01 between the two correlations). Linear regression analysis demonstrated that skin sodium content is a strong explanatory variable for left ventricular mass, unaffected by BP and total body overhydration. In conclusion, we found skin sodium content to be closely linked to left ventricular mass in patients with CKD. Interventions that reduce skin sodium content might improve cardiovascular outcomes in these patients.
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Skin sodium content as a predictor of blood pressure response to renal denervation - Günes-Altan, Merve; Schmid, Axel; Kannenkeril, Dennis; Linz, Peter; Ott, Christian; Bosch, Agnes; Schiffer, Mario; Uder, Michael; Schmieder, Roland (Hypertension Research, 2023)
Patients with treatment resistant hypertension (TRH) are known to have elevated sodium (Na) content in muscle and skin. Renal denervation (RDN) emerged as an adjacent therapeutic option in this group of patients. This analysis aimed at evaluating whether tissue Na content predicts blood pressure (BP) response after RDN in patients with TRH. Radiofrequency-device based RDN was performed in 58 patients with uncontrolled TRH. Office and 24-h ambulatory BP were measured at baseline and after 6 months. To assess tissue Na content Na magnetic resonance imaging (Na-MRI) was performed at baseline prior to RDN. We splitted the study cohort into responders and non-responders based on the median of systolic 24-h ambulatory blood pressure (ABP) reduction after 6 months and evaluated the association between BP response to RDN and tissue Na content in skin and muscle. The study was registered at http://www.clinicaltrials.gov (NCT01687725). Six months after RDN 24-h ABP decreased by −8.6/−4.7 mmHg. BP-Responders were characterized by the following parameters: low tissue sodium content in the skin (p = 0.040), female gender (p = 0.027), intake of aldosterone antagonists (p = 0.032), high baseline 24-h night-time heart rate (p = 0.045) and high LDL cholesterol (p < 0.001). These results remained significant after adjustment for baseline 24-h systolic BP. Similar results were obtained when the median of day-time and night-time ABP reduction after 6 months were used as cut-off criteria for defining BP response to RDN. We conclude that in addition to clinical factors including baseline 24-h ABP Na-MRI may assist to select patients with uncontrolled TRH for RDN treatment. [Figure not available: see fulltext.].
CRIS-Team Scopus Importer:2023-11-03
Keywords: Renal denervation; Sodium MRI; Tissue sodium

Skin sodium is increased in male patients with multiple sclerosis and related animal models - Huhn, Konstantin; Linz, Peter; Pemsel, Franziska; Michalke, Bernhard; Seyferth, Stefan; Kopp, Christoph; Chaudri, Mohammad Anwar; Rothhammer, Veit; Dörfler, Arnd; Uder, Michael; Nagel, Armin M.; Müller, Dominik N.; et al. (Proceedings of the National Academy of Sciences of the United States of America, 2021)
Novel MRI techniques allow a noninvasive quantification of tissue sodium and reveal the skin as a prominent compartment of sodium storage in health and disease. Since multiple sclerosis (MS) immunopathology is initiated in the periphery and increased sodium concentrations induce proinflammatory immune cells, the skin represents a promising compartment linking high sodium concentrations and MS immunopathology. We used a 7-T sodium MRI (23Na-MRI) and inductively coupled plasma mass spectrometry to investigate the skin sodium content in two mouse models of MS. We additionally performed 3-T 23Na-MRI of calf skin and muscles in 29 male relapsing-remitting MS (RRMS) patients and 29 matched healthy controls. Demographic and clinical information was collected from interviews, and disease activity was assessed by expanded disability status scale scoring. 23Na-MRI and chemical analysis demonstrated a significantly increased sodium content in the skin during experimental autoimmune encephalomyelitis independent of active immunization. In male patients with RRMS, 23Na-MRI demonstrated a higher sodium signal in the area of the skin compared to age- and biological sex-matched healthy controls with higher sodium, predicting future disease activity in cranial MRI. In both studies, the sodium enrichment was specific to the skin, as we found no alterations of sodium signals in the muscle or other tissues. Our data add to the recently identified importance of the skin as a storage compartment of sodium and may further represent an important organ for future investigations on salt as a proinflammatory agent driving autoimmune neuroinflammation such as that in MS.
CRIS-Team Scopus Importer:2021-07-30
Keywords: Experimental autoimmune encephalomyelitis; Multiple sclerosis; Skin; Sodium magnetic resonance imaging

Skin sodium measured with ²³Na MRI at 7.0 T - Linz, Peter; Santoro, Davide; Renz, Wolfgang; Rieger, Jan; Ruehle, Anjuli; Ruff, Jan; Deimling, Michael; Rakova, Natalia; Muller, Dominik N.; Luft, Friedrich C.; Titze, Jens; Niendorf, Thoralf (NMR in Biomedicine, 2015)
Skin sodium (Na(+) ) storage, as a physiologically important regulatory mechanism for blood pressure, volume regulation and, indeed, survival, has recently been rediscovered. This has prompted the development of MRI methods to assess Na(+) storage in humans ((23) Na MRI) at 3.0 T. This work examines the feasibility of high in-plane spatial resolution (23) Na MRI in skin at 7.0 T. A two-channel transceiver radiofrequency (RF) coil array tailored for skin MRI at 7.0 T (f = 78.5 MHz) is proposed. Specific absorption rate (SAR) simulations and a thorough assessment of RF power deposition were performed to meet the safety requirements. Human skin was examined in an in vivo feasibility study using two-dimensional gradient echo imaging. Normal male adult volunteers (n = 17; mean ± standard deviation, 46 ± 18 years; range, 20-79 years) were investigated. Transverse slices of the calf were imaged with (23) Na MRI using a high in-plane resolution of 0.9 × 0.9 mm(2) . Skin Na(+) content was determined using external agarose standards covering a physiological range of Na(+) concentrations. To assess the intra-subject reproducibility, each volunteer was examined three to five times with each session including a 5-min walk and repositioning/preparation of the subject. The age dependence of skin Na(+) content was investigated. The (23) Na RF coil provides improved sensitivity within a range of 1 cm from its surface versus a volume RF coil which facilitates high in-plane spatial resolution imaging of human skin. Intra-subject variability of human skin Na(+) content in the volunteer population was <10.3%. An age-dependent increase in skin Na(+) content was observed (r = 0.78). The assignment of Na(+) stores with (23) Na MRI techniques could be improved at 7.0 T compared with current 3.0 T technology. The benefits of such improvements may have the potential to aid basic research and clinical applications designed to unlock questions regarding the Na(+) balance and Na(+) storage function of skin.
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Sodium and water handling during hemodialysis: new pathophysiologic insights and management approaches for improving outcomes in end-stage kidney disease - Canaud, Bernard; Kooman, Jeroen; Selby, Nicholas M.; Taal, Maarten; Francis, Susan; Kopperschmidt, Pascal; Maierhofer, Andreas; Kotanko, Peter; Titze, Jens (Kidney International, 2019)
Space medicine and new technology such as magnetic resonance imaging of tissue sodium stores ((NaMRI)-Na-23) have changed our understanding of human sodium homeostasis and pathophysiology. It has become evident that body sodium comprises 3 main components. Two compartments have been traditionally recognized, namely one that is circulating and systemically active via its osmotic action, and one slowly exchangeable pool located in the bones. The third, recently described pool represents sodium stored in skin and muscle interstitium, and it is implicated in cell and biologic activities via local hypertonicity and sodium clearance mechanisms. This in-depth review provides a comprehensive view on the pathophysiology and existing knowledge gaps of systemic hemodynamic and tissue sodium accumulation in dialysis patients. Furthermore, we discuss how the combination of novel technologies to quantitate tissue salt accumulation (e.g., (NaMRI)-Na-23) with devices to facilitate the precise attainment of a prescribed hemodialytic sodium mass balance (e.g., sodium and water balancing modules) will improve our therapeutic approach to sodium management in dialysis patients. While prospective studies are required, we think that these new diagnostic and sodium balancing tools will enhance our ability to pursue more personalized therapeutic interventions on sodium and water management, with the eventual goal of improving dialysis patient outcomes.
CRIS-Team WoS Importer:2020-02-21

Sodium balance is not just a renal affair - Titze, Jens (Current Opinion in Nephrology and Hypertension, 2014)
The equilibration theory of extracellular body fluids is tightly linked to sodium (Na) metabolism. It is accepted that with changes in salt intake, renal sodium elimination will prevent any change in interstitial Na content and concentration. This review summarizes recent anomalous findings regarding salt and water homeostasis that are inconsistent with current assumptions.Recent findings from chemical analysis studies of laboratory animals, as well as noninvasive quantitative Na MRI (Na-MRI) studies in patients, have shown that remarkable amounts of Na are stored in muscle and in skin without commensurate water retention. Furthermore, an ultra-long Na balance study in humans suggests the presence of endogenous clocks that generate weekly and monthly infradian rhythmicity of Na storage independent of salt intake. Animal experiments suggest that fluids in the skin interstitium are hypertonic compared with plasma, and that interstitial osmotic stress induces local extrarenal immune cell and lymph-capillary driven mechanisms for electrolyte clearance and maintenance of the internal environment.Recent quantitative evidence challenges current ideas on salt and water homeostasis, and suggests that Na homeostasis cannot be maintained without additional previously unappreciated extrarenal regulatory mechanisms.
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Sodium Handling and Interaction in Numerous Organs - Minegishi, Shintaro; Luft, Friedrich C.; Titze, Jens; Kitada, Kento (American Journal of Hypertension, 2020)
Salt (NaCl) is a prerequisite for life. Excessive intake of salt, however, is said to increase disease risk, including hypertension, arteriosclerosis, heart failure, renal disease, stroke, and cancer. Therefore, considerable research has been expended on the mechanism of sodium handling based on the current concepts of sodium balance. The studies have necessarily relied on relatively short-term experiments and focused on extremes of salt intake in humans. Ultra-long-term salt balance has received far less attention. We performed long-term salt balance studies at intakes of 6, 9, and 12 g/day and found that although the kidney remains the long-term excretory gate, tissue and plasma sodium concentrations are not necessarily the same and that urinary salt excretion does not necessarily reflect total-body salt content. We found that to excrete salt, the body makes a great effort to conserve water, resulting in a natriuretic-ureotelic principle of salt excretion. Of note, renal sodium handling is characterized by osmolyte excretion with anti-parallel water reabsorption, a state-of-affairs that is achieved through the interaction of multiple organs. In this review, we discuss novel sodium and water balance concepts in reference to our ultra-long-term study. An important key to understanding body sodium metabolism is to focus on water conservation, a biological principle to protect from dehydration, since excess dietary salt excretion into the urine predisposes to renal water loss because of natriuresis. We believe that our research direction is relevant not only to salt balance but also to cardiovascular regulatory mechanisms.
CRIS-Team Scopus Importer:2020-08-14
Keywords: blood pressure; body fluid; energy metabolism; estivation; hypertension; osmolyte; salt; urea

Soluble DPP4 originates in part from bone marrow cells and not from the kidney - Wang, Zhendi; Grigo, Christina; Steinbeck, Julia; von Hörsten, Stephan; Amann, Kerstin Ute; Daniel, Christoph (Peptides, 2014)
Dipeptidyl peptidase 4 (DPP4) is known to inactivate incretins as well as important chemokines and neuropeptides. DPP4 is expressed as a transmembrane protein but also occurs as a soluble enzyme circulating in the blood. However, the origin of the soluble DPP4 (sDPP4) is still unknown. In this study, DPP4 activity was quantified in plasma and extracted from different rat organs. Then, in order to see if the kidney or the bone marrow was the source of sDPP4, kidney or bone marrow transplantation was performed between wildtype (wt) Dark Agouti (DA) and DPP4 deficient congenic rats (n=6-9). Kidney was verified to have the highest DPP4 activity, followed by spleen and lung. In the following three weeks after successful kidney transplantation only transient trace plasma DPP4 activity was detected in DPP4 deficient rats receiving wt kidneys. In addition, DPP4 activity was not diminished in DA wt rats receiving DPP4 deficient kidneys. Both findings indicated that sDPP4 did not originate from the kidney. In contrast, 43±14% (compared to wt) sDPP4 activity was detected in the plasma of DPP4 deficient DA rats that were reconstituted with wt bone marrow cells. Not only leukocyte but also macrophage subpopulations express DPP4 in bone marrow as well as in blood as assessed by flow cytometry. Thus, bone marrow derived cells but not the kidney represent at least one source of sDPP4. And leukocyte or macrophage subpopulations could be potential candidates.
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Soluble Urokinase Receptor and Acute Kidney Injury - Schley, Gunnar; Rosen, Seymour; Heyman, Samuel N. (New England Journal of Medicine, 2020)
CRIS-Team Scopus Importer:2020-06-05

Specific Aldosterone Synthase Inhibition: A Potential Improvement Over Mineralocorticoid Receptor Antagonism? - Schneider, Markus P.; Hilgers, Karl Friedrich (Hypertension, 2017)
EVALuna2:3928

Spectrum and dosing of urate-lowering drugs in a large cohort of chronic kidney disease patients and their effect on serum urate levels: a cross-sectional analysis from the German Chronic Kidney Disease study - Kielstein, Jan T.; Heisterkamp, Markus; Jing, Jiaojiao; Nadal, Jennifer; Schmid, Matthias; Kronenberg, Florian; Busch, Martin; Sommerer, Claudia; Lorenzen, Johan M.; Eckardt, Kai-Uwe; Koettgen, Anna (Clinical Kidney Journal, 2021)
Background: Despite a plethora of studies on the effect of urate-lowering therapy (ULT) in patients with chronic kidney disease (CKD), current guidelines on the treatment of hyperuricaemia and gout vary, especially concerning the need for dose adjustment of allopurinol, whose main metabolite is accumulating with declining renal function. Data on allopurinol dosing and its relationship to renal function, co-medication and sex and the resulting urate level in large cohorts are missing.
CRIS-Team WoS Importer:2021-05-21

Spooky sodium balance - Titze, Jens; Dahlmann, Anke; Lerchl, Kathrin; Kopp, Christoph; Rakova, Natalia; Schröder, Agnes; Luft, Friedrich C. (Kidney International, 2014)
Current teaching states that when sodium intake is increased from low to high levels, total-body sodium (TBNa) and water increase until daily sodium excretion again equals intake. When sodium intake is reduced, sodium excretion briefly exceeds intake until the excess TBNa and water are eliminated, at which point sodium excretion again equals intake. However, careful balance studies oftentimes conflict with this view and long-term studies suggest that TBNa fluctuates independent of intake or body weight. We recently performed the opposite experiment in that we fixed sodium intake for several weeks at three levels of sodium intake and collected all urine made. We found weekly (circaseptan) patterns in sodium excretion that were inversely related to aldosterone and directly to cortisol. TBNa was not dependent on sodium intake but instead exhibited far longer (>= monthly) infradian rhythms independent of extracellular water, body weight, or blood pressure. The findings are consistent with our ideas on tissue sodium storage and its regulation that we developed on the basis of animal research. We are implementing (23)Na-magnetic resonance imaging (MRI) to pursue open questions on sodium balance in patients. Our findings could be relevant to therapeutic strategies for hypertension and target-organ damage.
EVALuna2:3656

Status of periodontal health in German patients suffering from chronic kidney disease—Data from the GCKD study - Dannewitz, Bettina; Sommerer, Claudia; Stoelzel, Peggy; Baid-Agrawal, Seema; Nadal, Jennifer; Bärthlein, Barbara; Wanner, Christoph; Eckardt, Kai-Uwe; Zeier, Martin; Schlagenhauf, Ulrich; Krane, Vera; Jockel-Schneider, Yvonne (Journal of Clinical Periodontology, 2019)
Aim: To assess the prevalence and severity of periodontitis in patients with moderate chronic kidney disease (CKD) and comparing the results with the self-reported periodontitis awareness of the study subjects. Material and methods: The periodontal status of 270 patients with moderate CKD randomly selected from a cohort of 5,217 subjects participating in the prospective observational German Chronic Kidney Disease (GCKD) project was analysed by recording bleeding on probing (BOP), probing pocket depth (PPD) and clinical attachment level (CAL). Furthermore, the awareness of the study subjects of their periodontal conditions was evaluated by a self-reported questionnaire. Results: 24.4% of the CKD study patients showed no or only mild signs of periodontal disease, 47.6% displayed moderate and 27% severe periodontitis. Questionnaire data revealed that 62.3% of the study subjects with severe periodontitis were not aware of the presence of the disease, 44.4% denied having received any systematic periodontal therapy so far, although 50% of them indicated to visit their dentist regularly for professional tooth cleanings. Conclusion: While the clinical study data confirm an increased prevalence of periodontitis in CKD patients, their self-reported awareness of periodontitis was low.
CRIS-Team Scopus Importer:2019-11-19
Keywords: chronic kidney disease; observational cohort study; periodontitis; risk factors

Strikingly conserved gene expression changes of polyamine regulating enzymes among various forms of acute and chronic kidney injury - Sieckmann, Tobias; Schley, Gunnar; Ögel, Neslihan; Kelterborn, Simon; Boivin, Felix J.; Fähling, Michael; Ashraf, Muhammad I.; Reichel, Martin; Vigolo, Emilia; Hartner, Andrea; Lichtenberger, Falk Bach; Breiderhoff, Tilman; et al. (Kidney International, 2023)
The polyamines spermidine and spermine and their common precursor molecule putrescine are involved in tissue injury and repair. Here, we test the hypothesis that impaired polyamine homeostasis contributes to various kidney pathologies in mice during experimental models of ischemia-reperfusion, transplantation, rhabdomyolysis, cyclosporine treatment, arterial hypertension, diabetes, unilateral ureteral obstruction, high oxalate feeding, and adenine-induced injuries. We found a remarkably similar pattern in most kidney pathologies with reduced expression of enzymes involved in polyamine synthesis together with increased expression of polyamine degrading enzymes. Transcript levels of amine oxidase copper-containing 1 (Aoc1), an enzyme which catalyzes the breakdown of putrescine, were barely detectable by in situ mRNA hybridization in healthy kidneys. Aoc1 was highly expressed upon various experimental kidney injuries resulting in a significant reduction of kidney putrescine content. Kidney levels of spermine were also significantly reduced, whereas spermidine was increased in response to ischemia-reperfusion injury. Increased Aoc1 expression in injured kidneys was mainly accounted for by an Aoc1 isoform that harbors 22 additional amino acids at its N-terminus and shows increased secretion. Mice with germline deletion of Aoc1 and injured kidneys showed no decrease of kidney putrescine content; although they displayed no overt phenotype, they had fewer tubular casts upon ischemia-reperfusion injury. Hyperosmotic stress stimulated AOC1 expression at the transcriptional and post-transcription levels in metanephric explants and kidney cell lines. AOC1 expression was also significantly enhanced after kidney transplantation in humans. These data demonstrate that the kidneys respond to various forms of injury with down-regulation of polyamine synthesis and activation of the polyamine breakdown pathway. Thus, an imbalance in kidney polyamines may contribute to various etiologies of kidney injury.
CRIS-Team Scopus Importer:2023-05-26
Keywords: Aoc1; kidney injury; mRNA in situ hybridization; osmotic stress; polyamines; putrescine

STRONG ASSOCIATION BETWEEN SERUM PCSK9 AND CARDIOVASCULAR DISEASE IN PATIENTS WITH MODERATE CHRONIC KIDNEY DISEASES THE GCKD STUDY - Kheirkhah, A.; Lamina, C.; Kollerits, B.; Schachtl-Riess, J. F.; Schultheiss, U. T.; Forer, L.; Sekula, P.; Ottgen, F. Kotsis A. K.; Eckardt, Kai-Uwe; Kronenberg, F. (ATHEROSCLEROSIS, 2021)
CRIS-Team WoS Importer:2021-09-24

SUBGROUP ANALYSIS IN THE GLOBAL SYMPLICITY REGISTRY: 3-YEAR SAFETY AND EFFICACY - Mahfoud, F.; Mancia, G.; Schmieder, Roland; Narkiewicz, K.; Ruilope, L.; Schlaich, M.; Williams, B.; Fahy, M.; Boehm, M. (JOURNAL OF HYPERTENSION, 2019)
CRIS-Team WoS Importer:2019-09-20

Successful treatment of COVID-19 infection with convalescent plasma in B-cell-depleted patients may promote cellular immunity - Kremer, Andreas E.; Kremer, Anita; Willam, Carsten; Völkl, Simon; Verhagen, Johan; Achenbach, Susanne; van der Meijden, Edith; Lang, Vanessa; Aigner, Michael; Maier, Clara; Tenbusch, Matthias; Korn, Klaus; et al. (European Journal of Immunology, 2021)
Treatment with convalescent plasma has been shown to be safe in coronavirus disease in 2019 (COVID-19) infection, although efficacy reported in immunocompetent patients varies. Nevertheless, neutralizing antibodies are a key requisite in the fight against viral infections. Patients depleted of antibody-producing B cells, such as those treated with rituximab (anti-CD20) for hematological malignancies, lack a fundamental part of their adaptive immunity. Treatment with convalescent plasma appears to be of general benefit in this particularly vulnerable cohort. We analyzed clinical course and inflammation markers of three B-cell-depleted patients suffering from COVID-19 who were treated with convalescent plasma. In addition, we measured serum antibody levels as well as peripheral blood CD38/HLA-DR-positive T-cells ex vivo and CD137-positive T-cells after in vitro stimulation with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-derived peptides in these patients. We observed that therapy with convalescent plasma was effective in all three patients and analysis of CD137-positive T-cells after stimulation with SARS-CoV-2 peptides showed an increase in peptide-specific T-cells after application of convalescent plasma. In conclusion, we here demonstrate efficacy of convalescent plasma therapy in three B-cell-depleted patients and present data that suggest that while application of convalescent plasma elevates systemic antibody levels only transiently, it may also boost specific T-cell responses.
CRIS-Team Scopus Importer:2021-09-17
Keywords: B-cell deficiency; convalescent plasma; COVID-19; SARS-CoV-2; T-cell immunity

Successful treatment of COVID-19 with convalescent plasma in B-cell depleted patients may promote cellular immunity - Kremer, Andreas; Kremer, Anita; Willam, Carsten; Verhagen, Johan; Achenbach, Susanne; Van Der Meiden, E.; Lang, Vanessa; Aigner, M.; Maier, Clara; Tenbusch, Matthias; Korn, Klaus; Lutzny-Geier, Gloria; et al. (ONCOLOGY RESEARCH AND TREATMENT, 2021)
CRIS-Team WoS Importer:2022-03-25

Supine blood pressure—A clinically relevant determinant of vascular target organ damage in hypertensive patients - Nolde, Janis M.; Kiuchi, Márcio Galindo; Carnagarin, Revathy; Frost, Shaun; Kannenkeril, Dennis; Lugo-Gavidia, Leslie Marisol; Chan, Justine; Joyson, Anu; Matthews, Vance B.; Herat, Lakshini Y.; Azzam, Omar; Schlaich, Markus P. (Journal of Clinical Hypertension, 2020)
Night-time blood pressure (BP) is an important predictor of cardiovascular outcomes. Its assessment, however, remains challenging due to limited accessibility to ambulatory BP devices in many settings, costs, and other factors. We hypothesized that BP measured in a supine position during daytime may perform similarly to night-time BP when modeling their association with vascular hypertension-mediated organ damage (HMOD). Data from 165 hypertensive patients were used who as part of their routine clinic workup had a series of standardized BP measurements including seated attended office, seated and supine unattended office, and ambulatory BP monitoring. HMOD was determined by assessment of kidney function and pulse wave velocity. Correlation analysis was carried out, and univariate and multivariate models were fitted to assess the extent of shared variance between the BP modalities and their individual and shared contribution to HMOD variables. Of all standard non-24-hour systolic BP assessments, supine systolic BP shared the highest degree of variance with systolic night-time BP. In univariate analysis, both systolic supine and night-time BP were strong determinants of HMOD variables. In multivariate models, supine BP outperformed night-time BP as the most significant determinant of HMOD. These findings indicate that supine BP may not only be a clinically useful surrogate for night-time BP when ambulatory BP monitoring is not available, but also highlights the possibility that unattended supine BP may be more closely related to HMOD than other BP measurement modalities, a proposition that requires further investigations in prospective studies.
CRIS-Team Scopus Importer:2020-12-11
Keywords: hypertension-mediated organ damage; kidney function; nocturnal blood pressure; pulse wave velocity; supine blood pressure

Suppression of neutrophils by sodium exacerbates oxidative stress and arthritis - Zlatar, Leticija; Mahajan, Aparna; Munoz Becerra, Marco; Weidner, Daniela; Bila, Galyna; Bilyy, Rostyslav; Titze, Jens; Hoffmann, Markus H.; Schett, Georg; Herrmann, Martin; Steffen, Ulrike; Muñoz, Luis E.; et al. (Frontiers in Immunology, 2023)
Introduction: Typical Western diet, rich in salt, contributes to autoimmune disease development. However, conflicting reports exist about the effect of salt on neutrophil effector functions, also in the context of arthritis. Methods: We investigated the effect of sodium chloride (NaCl) on neutrophil viability and functions in vitro, and in vivo employing the murine K/BxN-serum transfer arthritis (STA) model. Results and discussion: The effects of NaCl and external reactive oxygen species (H2O2) were further examined on osteoclasts in vitro. Hypertonic sodium-rich media caused primary/secondary cell necrosis, altered the nuclear morphology, inhibited phagocytosis, degranulation, myeloperoxidase (MPO) peroxidation activity and neutrophil extracellular trap (NET) formation, while increasing total ROS production, mitochondrial ROS production, and neutrophil elastase (NE) activity. High salt diet (HSD) aggravated arthritis by increasing inflammation, bone erosion, and osteoclast differentiation, accompanied by increased NE expression and activity. Osteoclast differentiation was decreased with 25 mM NaCl or 100 nM H2O2 addition to isotonic media. In contrast to NaCl, external H2O2 had pro-resorptive effects in vitro. We postulate that in arthritis under HSD, increased bone erosion can be attributed to an enhanced oxidative milieu maintained by infiltrating neutrophils, rather than a direct effect of NaCl.
CRIS-Team Scopus Importer:2023-09-01
Keywords: K/BxN serum transfer arthritis; neutrophil extracellular traps (NETs); neutrophils; osteoclasts; reactive oxygen species; sodium chloride

Suspected colonic cancer turns out to be disseminated tuberculosis in a kidney transplant recipient: A case report - Schmidt-Lauber, Christian; Jacobi, Johannes; Polifka, Iris; Hilgers, Karl Friedrich; Wiesener, Michael S. (Medicine, 2019)
Rationale: Active tuberculosis constitutes a relevant risk for kidney transplant recipients. In contrast to immunocompetent hosts, kidney transplant recipients often show atypical presentation and course of the disease impeding diagnosis. Especially extrapulmonary or disseminated infection is more frequent and can resemble malignant processes. However, reactivation of tuberculosis mostly develops within the early post-transplant course, whereas malignancies are predominantly long-term complications. We report a case of disseminated abdominal tuberculosis developing 10 years after kidney transplantation and review the underlying literature. Patient concerns and diagnoses: A 51-year-old lady presented with epigastric pain, diarrhea, weight loss and night sweats 10 years after deceased-donor kidney transplantation. An epigastric as well as multiple peritoneal masses were found suspicious of a cancer of unknown primary. Colonoscopy revealed a colon tumor with the biopsy showing no dysplasia but histiocytic and granulomatous infiltration with acid-fast bacilli. Mycobacterium tuberculosis was detected in the biopsy and stool and disseminated abdominal tuberculosi was diagnosed. Interventions and outcomes: With anti-tuberculosis therapy, the masses regressed, and all cultures became sterile, sparing graft function. Lessons: This case emphasizes how variable and unspecific the presentation of tuberculosis in kidney transplant recipients may be and that tuberculosis constitutes a relevant risk also in the long-term post-transplant course.
CRIS-Team Scopus Importer:2019-09-17
Keywords: abdominal masses; colon tumor; kidney transplantation; peritoneal carcinomatosis; tuberculosis

Synergistic induction of CTGF by cytochalasin D and TGF?-1 in primary human renal epithelial cells: Role of transcriptional regulators MKL1, YAP/TAZ and Smad2/3 - Muehlich, Susanne; Rehm, Margot; Ebenau, Astrid; Goppelt-Strübe, Margarete (Cellular Signalling, 2017)
Changes in cell morphology that involve alterations of the actin cytoskeleton are a hallmark of diseased renal tubular epithelial cells. While the impact of actin remodeling on gene expression has been analyzed in many model systems based on cell lines, this study investigated human primary tubular epithelial cells isolated from healthy parts of tumor nephrectomies. Latrunculin B (LatB) and cytochalasin D (CytoD) were used to modulate G-actin levels in a receptor-independent manner. Both compounds (at 0.5?M) profoundly altered F-actin structures in a Rho kinase-dependent manner, but only CytoD strongly induced the pro-fibrotic factor CTGF (connective tissue growth factor). CTGF induction was dependent on YAP as shown by transient downregulation experiments. However, CytoD did not alter the nuclear localization of either YAP or TAZ, whereas LatB reduced nuclear levels particularly of TAZ. CytoD modified MKL1, a coactivator of serum response factor (SRF) regulating CTGF induction, and promoted its nuclear localization. TGF?-1 is one of the major factors involved in tubulointerstitial disease and an inducer of CTGF. Preincubation with CytoD but not LatB synergistically enhanced the TGF?-1-stimulated synthesis of CTGF, both in cells cultured on plastic dishes as well as in polarized epithelial cells. CytoD had no direct effect on the phosphorylation of Smad2/3, but facilitated their phosphorylation and thus activation by TGF?-1. Our present findings provide evidence that morphological alterations have a strong impact on cellular signaling of one of the major pro-fibrotic factors, TGF?-1. However, our data also indicate that changes in cell morphology per se cannot predict those interactions which are critically dependent on molecular fine tuning of actin reorganization.
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Systolic blood pressure variation and mean heart rate is associated with cognitive dysfunction in patients with high cardiovascular risk - Boehm, Michael; Schumacher, Helmut; Leong, Darryl; Mancia, Giuseppe; Unger, Thomas; Schmieder, Roland; Custodis, Florian; Diener, Hans-Christoph; Laufs, Ulrich; Lonn, Eva; Sliwa, Karen; Teo, Koon; et al. (Hypertension, 2015)
Elevated systolic blood pressure (SBP) correlates to cognitive decline and incident dementia. The effects of heart rate (HR), visit to visit HR variation, and visit to visit SBP variation are less well established. Patients without preexisting cognitive dysfunction (N=24 593) were evaluated according to mean SBP, SBP visit to visit variation (coefficient of variation [standard deviation/mean×100%], CV), mean HR, and visit to visit HR variation (HR-CV) in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial and the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease. Cognitive function was assessed with mini mental state examination. Cognitive dysfunction (fall in mini mental state examination <=24 points), important cognitive decline (drop of >=5 points), and cognitive deterioration (drop of >1 point per year or decline to <24 points) were assessed. SBP and HR were measured over 10.7±2.2 (mean±SD) visits. Mean SBP, mean HR, and SBP-CV were associated with cognitive decline, dysfunction, and deterioration (all P<0.01, unadjusted). After adjustment, only SBP-CV (P=0.0030) and mean HR (P=0.0008) remained predictors for cognitive dysfunction (odds ratios [95% confidence intervals], 1.32 [1.10-1.58] for 5th versus 1st quintile of SBP-CV and 1.40 [1.18-1.66] for 5th versus 1st quintile of mean HR). Similar effects were observed for cognitive decline and deterioration. SBP-CV and mean HR showed additive effects. In conclusion, SBP-CV and mean HR are independent predictors of cognitive decline and cognitive dysfunction in patients at high CV risk.http://www.clinicaltrials.gov. Unique identifier: NCT 00153101.
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Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels - Tin, Adrienne; Marten, Jonathan; Kuhns, Victoria L. Halperin; Li, Yong; Wuttke, Matthias; Kirsten, Holger; Sieber, Karsten B.; Qiu, Chengxiang; Gorski, Mathias; Yu, Zhi; Giri, Ayush; Sveinbjornsson, Gardar; et al. (Nature Genetics, 2019)
Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.
CRIS-Team WoS Importer:2019-10-25

Telomere length screening in young patients with head and neck squamous cell carcinoma is suitable to detect underlying inherited telomere biology disorders - Tometten, M.; Rolles, B.; Klein, M.; Ooms, M.; Winnand, P.; Simons, E.; Bourgeois, M.; Spanier, G.; Laban, S.; Weber, Manfred; Goetz, C.; Birkenfeld, F.; et al. (ONCOLOGY RESEARCH AND TREATMENT, 2021)
CRIS-Team WoS Importer:2022-03-25

The authors reply - Ott, Christian; Schmieder, Roland (Kidney International, 2022)
CRIS-Team Scopus Importer:2022-04-01

The betaboost package-a software tool for modelling bounded outcome variables in potentially high-dimensional epidemiological data - Mayr, Andreas; Weinhold, Leonie; Hofner, Benjamin; Titze, Stephanie; Gefeller, Olaf; Schmid, Matthias (International Journal of Epidemiology, 2018)
Motivation: To provide an integrated software environment for model fitting and variable selection in regression models with a bounded outcome variable. Implementation: The proposed modelling framework is implemented in the add-on package betaboost of the statistical software environment R. General features: The betaboost methodology is based on beta-regression, which is a state-of-the-art method for modelling bounded outcome variables. By combining traditional model fitting techniques with recent advances in statistical learning and distributional regression, betaboost allows users to carry out data-driven variable and/or confounder selection in potentially high-dimensional epidemiological data. The software package implements a flexible routine to incorporate linear and non-linear predictor effects in both the mean and the precision parameter (relating inversely to the variance) of a beta-regression model. Availability: The software is hosted publicly at [http://github.com/boost-R/betaboost] and has been published under General Public License (GPL) version 3 or newer.
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The Cardiovascular Literature-Based Risk Algorithm (CALIBRA): Predicting Cardiovascular Events in Patients With Non-Dialysis Dependent Chronic Kidney Disease - Neri, Luca; Lonati, Caterina; Titapiccolo, Jasmine Ion; Nadal, Jennifer; Meiselbach, Heike; Schmid, Matthias; Baerthlein, Barbara; Tschulena, Ulrich; Schneider, Markus; Schultheiß, Ulla T.; Barbieri, Carlo; Moore, Christopher; et al. (Frontiers in Nephrology, 2022)
BACKGROUND AND OBJECTIVES: Cardiovascular (CV) disease is the main cause of morbidity and mortality in patients suffering from chronic kidney disease (CKD). Although it is widely recognized that CV risk assessment represents an essential prerequisite for clinical management, existing prognostic models appear not to be entirely adequate for CKD patients. We derived a literature-based, naïve-bayes model predicting the yearly risk of CV hospitalizations among patients suffering from CKD, referred as the CArdiovascular, LIterature-Based, Risk Algorithm (CALIBRA). METHODS: CALIBRA incorporates 31 variables including traditional and CKD-specific risk factors. It was validated in two independent CKD populations: the FMC NephroCare cohort (European Clinical Database, EuCliD®) and the German Chronic Kidney Disease (GCKD) study prospective cohort. CALIBRA performance was evaluated by c-statistics and calibration charts. In addition, CALIBRA discrimination was compared with that of three validated tools currently used for CV prediction in CKD, namely the Framingham Heart Study (FHS) risk score, the atherosclerotic cardiovascular disease risk score (ASCVD), and the Individual Data Analysis of Antihypertensive Intervention Trials (INDANA) calculator. Superiority was defined as a ΔAUC>0.05. RESULTS: CALIBRA showed good discrimination in both the EuCliD® medical registry (AUC 0.79, 95%CI 0.76-0.81) and the GCKD cohort (AUC 0.73, 95%CI 0.70-0.76). CALIBRA demonstrated improved accuracy compared to the benchmark models in EuCliD® (FHS: ΔAUC=-0.22, p<0.001; ASCVD: ΔAUC=-0.17, p<0.001; INDANA: ΔAUC=-0.14, p<0.001) and GCKD (FHS: ΔAUC=-0.16, p<0.001; ASCVD: ΔAUC=-0.12, p<0.001; INDANA: ΔAUC=-0.04, p<0.001) populations. Accuracy of the CALIBRA score was stable also for patients showing missing variables. CONCLUSION: CALIBRA provides accurate and robust stratification of CKD patients according to CV risk and allows score calculations with improved accuracy compared to established CV risk scores also in real-world clinical cohorts with considerable missingness rates. Our results support the generalizability of CALIBRA across different CKD populations and clinical settings.
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The chloride channel CFTR is not required for cyst growth in an ADPKD mouse model - Talbi, Khaoula; Cabrita, Inês; Kraus, Andre; Hofmann, Sascha; Skoczynski, Kathrin; Kunzelmann, Karl; Buchholz, Björn; Schreiber, Rainer (The FASEB Journal, 2021)
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the development of bilateral renal cysts which enlarge continuously, leading to compression of adjacent intact nephrons. The growing cysts lead to a progressive decline in renal function. Cyst growth is driven by enhanced cell proliferation and chloride secretion into the cyst lumen. Chloride secretion is believed to occur mainly by the cAMP-activated cystic fibrosis transmembrane conductance regulator (CFTR), with some contribution by the calcium-activated chloride channel TMEM16A. However, our previous work suggested TMEM16A as a major factor for renal cyst formation. The contribution of CFTR to cyst formation has never been demonstrated in an adult ADPKD mouse model. We used mice with an inducible tubule-specific Pkd1 knockout, which consistently develop polycystic kidneys upon deletion of Pkd1. Cellular properties, ion currents, and cyst development in these mice were compared with that of mice carrying a co-deletion of Pkd1 and Cftr. Knockout of Cftr did not reveal any significant impact on cyst formation in the ADPKD mouse model. Furthermore, knockout of Cftr did not attenuate the largely augmented cell proliferation observed in Pkd1 knockout kidneys. Patch clamp analysis on primary renal epithelial cells lacking expression of Pkd1 indicated an only marginal contribution of CFTR to whole cell Cl− currents, which were clearly dominated by calcium-activated TMEM16A currents. In conclusion, CFTR does not essentially contribute to renal cyst formation in mice caused by deletion of Pkd1. Enhanced cell proliferation and chloride secretion is caused primarily by upregulation of the calcium-activated chloride channel TMEM16A.
CRIS-Team Scopus Importer:2021-10-08
Keywords: ADPKD; CFTR; cyst growth; proliferation; TMEM16A

The Contribution of Plasma Urea to Total Osmolality During Iatrogenic Fluid Reduction in Critically Ill Patients - Nihlen, Sandra; Frithiof, Robert; Titze, Jens; Kawati, Rafael; Rasmusson, Johan; Rylander, Christian; Pikwer, Andreas; Castegren, Markus; Belin, Anton; Hultstrom, Michael; Lipcsey, Miklos (Function, 2021)
Hyperosmolality is common in critically ill patients during body fluid volume reduction. It is unknown whether this is only a result of decreased total body water or an active osmole-producing mechanism similar to that found in aestivating animals, where muscle degradation increases urea levels to preserve water. We hypothesized that fluid volume reduction in critically ill patients contributes to a shift from ionic to organic osmolytes similar to mechanisms of aestivation. We performed a post-hoc analysis on data from a multicenter observational study in adult intensive care unit (ICU) patients in the postresuscitative phase. Fluid, electrolyte, energy and nitrogen intake, fluid loss, estimated glomerular filtration rate (eGFR), and estimated plasma osmolality (eOSM) were registered. Contributions of osmolytes Na+, K+, urea, and glucose to eOSM expressed as proportions of eOSM were calculated. A total of 241 patients were included. eOSM increased (median change 7.4 mOsm/kg [IQR-1.9-18]) during the study. Sodium's and potassium's proportions of eOSM decreased (P P < .01, respectively), whereas urea's proportion increased (P < .001). The urea's proportion of eOSM was higher in patients with negative vs. positive fluid balance. Urea's proportion of eOSM increased with eOSM (r = 0.63; adjusted for eGFR r = 0.80), but not nitrogen intake. In patients without furosemide and/or renal replacement therapy (n = 17), urea's proportion of eOSM and eOSM correlated strongly (r = 0.92). Urea's proportion of eOSM was higher in patients not surviving up to 90 d. In stabilized ICU patients, the contribution of urea to plasma osmolality increased during body water volume reduction, statistically independently of nitrogen administration and eGFR. The shift from ionic osmolytes to urea during body fluid volume reduction is similar to that seen in aestivating animals.
CRIS-Team WoS Importer:2022-04-01

The effect of ramipril and telmisartan on serum potassium and its association with cardiovascular and renal events: Results from the ONTARGET trial - Heerspink, Hiddo J. Lambers; Gao, Peggy; De Zeeuw, Dick; Clase, Catherine; Dagenais, Gilles R.; Sleight, Peter; Lonn, Eva; Teo, Koon T.; Yusuf, Salim; Mann, Johannes (European Journal of Preventive Cardiology, 2014)
In the Ongoing Telmisartan Alone and in Combination with Ramipril Trial (ONTARGET), dual agent renin-angiotensin-aldosterone system (RAAS) blockade with angiotensin-converting-enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) did not reduce the risk of renal and cardiovascular outcomes compared with the single use of either agent. Dual therapy however increased the incidence of hyperkalemia. We examined risk factors for hyper- and hyokalemia and hypothesized that both would be associated with worse cardiovascular and renal outcomes.A post-hoc analysis of the ONTARGET trial comparing dual therapy (ramipril and telmisartan) vs monotherapy (ramipril or telmisartan) was performed. The association between serum potassium at week 6 on cardiovascular and renal outcomes during the 56 months follow-up was assessed by multivariate Cox analysis. The main cardiovascular outcome was the composite of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure. The renal outcome was defined as the composite of a doubling of serum creatinine or chronic dialysis.Six weeks after randomization, hyperkalemia developed in 210 (2.7%) patients on dual therapy vs 264 (1.6%) patients on monotherapy (p < 0.001 vs dual therapy). Hypokalemia developed in 87 (1.1%) patients on dual therapy vs 200 (1.2%)patients on monotherapy. Serum potassium was nonlinearly associated with cardiovascular and renal events with a nadir between 4.0-5.0 mmol/l for cardiovascular and 4.0-4.5 mmol/l for renal events such that subjects above or below these values exhibited higher risks. This association was independent of age, gender, diabetes, estimated glomerular filtration rate, systolic blood pressure and diuretic use.With the precautions stipulated by the protocol of the ONTARGET trial, hypokalemia and hyperkalemia were infrequent events. Nevertheless, both high and low serum potassium were associated with an increased risk of cardiovascular and renal disease.
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The effect of renal denervation in moderate treatment-resistant hypertension with confirmed medication adherence - Ott, Christian; Mahfoud, Felix; Schmid, Andrea; Ewen, Sebastian; Toennes, Stefan W.; Meyer, Markus R.; Helfer, Andreas G.; Maurer, Hans H.; Ditting, Tilmann; Veelken, Roland; Zivanovic, Ina; Uder, Michael; et al. (Journal of Hypertension, 2016)
Data on the blood pressure (BP)-lowering effect of renal denervation (RDN) in moderate treatment-resistant hypertension (TRH) are limited. Moreover, change of adherence to medication, as one potential confounder of BP response, has never been analyzed rigorously in this group of patients. We analyzed the effect of RDN on BP in patients with moderate TRH who were retrospectively found to be completely adherent to their antihypertensive medication.Our study cohort comprised 40 patients with moderate TRH [office BP >= 140/90 but <160/100 mmHg and 24-h ambulatory BP monitoring (ABPM) >=130/80 mmHg] who underwent catheter-based RDN. Further major inclusion criterion was complete adherence to their medication (>=80% intake of their prescribed antihypertensive drugs) at baseline (assessed by retrospective toxicological analysis).Six months after RDN, office BP was reduced by -10/-6 mmHg (SBP: 149 ± 6 vs. 139 ± 15 mmHg; DBP: 81 ± 12 vs. 75 ± 10 mmHg; both P < 0.001) and 24-h ABPM by -7/-4 mmHg (SBP: 150 ± 14 vs. 143 ± 16 mmHg, P = 0.005; DBP: 82 ± 10 vs. 78 ± 9 mmHg, P = 0.009). Number of prescribed antihypertensive medication [6.0 (5.0-6.0) vs. 5.5 (5.0-6.0), P = 0.013] and adherence rate (95.2 ± 7.6 vs. 91.7 ± 13.9%, P = 0.065) was slightly reduced 6 months after RDN, both likely to underestimate the true BP reduction.Thus, our data indicate that even after given full respect to drug adherence as potential confounder of BP response after RDN, both office and 24-h ABPM were substantially reduced in patients with moderate TRH.
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The Effect of Resting Heart Rate on the New Onset of Microalbuminuria in Patients With Type 2 Diabetes: A Subanalysis of the ROADMAP Study - Schmieder, Roland; Bramlage, Peter; Haller, Hermann; Ruilope, Luis M.; Boehm, Michael (Medicine, 2016)
The association between resting heart rate and new-onset microalbuminuria in patients with type 2 diabetes is not clear. The objective of the current analysis was to assess the relationship between heart rate and incidence of microalbuminuria in patients with type 2 diabetes.Data from the Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study were retrospectively analyzed. New-onset microalbuminuria was documented and related to heart rate as recorded at baseline and last assessment, and the mean of the measurements taken during the double-blind part of the ROADMAP trial.Patients (n = 4299) had a mean age of 57.8 ± 8.7 years and 46.3% were male. Characteristics were not different between the olmesartan and the placebo groups, except for a higher systolic blood pressure (136.7 vs 135.7 mm Hg; P = 0.04) and albumin creatinine ratio (5.9 vs 5.5; P = 0.03).Increased risk of microalbuminuria was found with increasing heart rate, independent of whether baseline [highest vs lowest quartile odds ratio (OR) 1.39; 95% confidence interval (95% CI) 1.03-1.87; P = 0.032], last assessment (OR 1.71; 95% CI 1.26-2.31; P = 0.001), or mean heart rate was considered (OR: 1.77; 95% CI: 1.30-2.41; P = 0.0003). The greater risk of new-onset microalbuminuria with a high baseline heart rate was also found when data were adjusted for mean systolic blood pressure (OR: 1.35; 95% CI: 1.00-1.82; P = 0.0496; interaction P < 0.0001). Although there was no risk increase with baseline heart rate in the placebo group (P = 0.8253 for trend), microalbuminuria was less frequent in patients receiving olmesartan in the low heart rate quartiles (P = 0.002 for trend).A low heart rate reduces the risk of patients with type 2 diabetes developing microalbuminuria, independent of blood pressure. The data demonstrate potential benefits of reducing the heart rate of type 2 diabetes patients, and indicate that olmesartan could, in particular, reduce the risk of microalbuminuria in patients with low heart rate.
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The effect of sacubitril/valsartan compared to olmesartan on cardiovascular remodelling in subjects with essential hypertension: the results of a randomized, double-blind, active-controlled study - Schmieder, Roland; Wagner, Frank; Mayr, Michael; Delles, Christian; Ott, Christian; Keicher, Christian; Hrabak-Paar, Maja; Heye, Tobias; Aichner, Solveig; Khder, Yasser; Yates, Denise; Albrecht, Diego; et al. (European Heart Journal, 2017)
Progressive aortic stiffening eventually leads to left ventricular (LV) hypertrophy and heart failure if left untreated. Anti-hypertensive agents have been shown to reverse this to some extent. The effects of sacubitril/valsartan (LCZ696), a dual-action angiotensin receptor blocker (ARB), and neprilysin inhibitor, on arterial stiffness and LV remodelling have not been investigated.This was a randomized, multi-centre, double-blind, double-dummy, active-controlled, parallel group, study to compare the effects on cardiovascular remodelling of sacubitril/valsartan with those of olmesartan in patients with hypertension and elevated pulse pressure. Magnetic resonance imaging scans were used to assess LV mass and local aortic distensibility, at baseline and at 12 and 52 weeks after initiation of treatment. Central pulse and systolic pressure were determined using a SphymoCor® XCEL device at each time point. A total of 114 patients were included, with 57 in each treatment group. The mean age was 59.8 years, and 67.5% were male. Demographic characteristics did not vary between the two sets of patients. Left ventricular mass index decreased to a greater extent in the sacubitril/valsartan group compared to the olmesartan group from baseline to 12 weeks (-6.36 vs. -2.32 g/m2; P = 0.039) and from baseline to 52 weeks (-6.83 vs. -3.55 g/m2; P = 0.029). These differences remained significant after adjustment for systolic blood pressure (SBP) at follow-up (P = 0.036 and 0.019 at 12 and 52 weeks, respectively) and similar signals (though formally non-significant) were observed after adjusting for changes in SBP (P = 0.0612 and P = 0.0529, respectively). There were no significant differences in local distensibility changes from baseline to 12 or 52 weeks between the two groups; however, there was a larger reduction in central pulse pressure for the sacubitril/valsartan group compared to the olmesartan group (P = 0.010).Since LV mass change correlates with cardiovascular prognosis, the greater reductions in LV mass indicate valuable advantages of sacubitril/valsartan compared to olmesartan. The finding that LV mass index decrease might be to some extent independent of SBP suggests that the effect of the dual-acting agent may go beyond those due to its BP-lowering ability.
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The epidemiology of MRI-detected pelvic injuries in athletes in the Rio de Janeiro 2016 Summer Olympics - Heiß, Rafael; Guermazi, Ali; Jarraya, Mohamed; Engebretsen, Lars; Roemer, Frank (European Journal of Radiology, 2018)
OBJECTIVE: To describe the prevalence, severity and location of pelvic injuries, including hip, muscle and tendon pathologies, as assessed on MRI in athletes participating in the Rio de Janeiro 2016 Summer Olympic Games. METHODS: We analyzed all pelvic MRIs that were acquired for suspected injury as reported by the National Olympic Committee (NOC) medical teams and the Organizing Committee medical staff during the Rio 2016 Summer Olympics. Diagnostic imaging was performed through the Olympic Village Polyclinic, using 3 T and 1.5 T MR scanners. Images were interpreted retrospectively according to standardized criteria. RESULTS: A total of 11,274 athletes participated in the Games, of which 40 (0,4%) were referred for a pelvic MRI. Thirty-seven of the 40 (92%) had at least one abnormal finding, and some had as many as 17, for an average of 4.1 pathologies per examination. Almost half of all abnormal findings were assessed as pre-existing (46%). The majority of acute/subacute injuries were observed in track and field athletes (44%), whereas the highest number of pre-existing findings was seen in ball-sports athletes (39%). Forty-seven per cent of all acute/subacute injuries were muscle injuries with the gluteus maximus muscle the most commonly affected. In contrast, most pre-existing findings were detected at the symphysis (59%). CONCLUSION: Our study demonstrated a high prevalence of both acute/subacute injuries and chronic changes in Olympic athletes undergoing pelvic MRI. Muscle injuries were the most common acute injuries, found mainly in track and field athletes. Most chronic changes were identified at the symphysis region in ball-sports athletes.
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The FIND-CKD study–a randomized controlled trial of intravenous iron versus oral iron in non-dialysis chronic kidney disease patients: background and rationale - Macdougall, Iain C.; Bock, Andreas; Carrera, Fernando; Eckardt, Kai-Uwe; Gaillard, Carlo; Van Wyck, David; Roubert, Bernard; Cushway, Timothy; Roger, Simon D. (Nephrology Dialysis Transplantation, 2014)
Rigorous data are sparse concerning the optimal route of administration and dosing strategy for iron therapy with or without concomitant erythropoiesis-stimulating agent (ESA) therapy for the management of iron deficiency anaemia in patients with non-dialysis dependent chronic kidney disease (ND-CKD).FIND-CKD was a 56-week, open-label, multicentre, prospective, randomized three-arm study (NCT00994318) of 626 patients with ND-CKD and iron deficiency anaemia randomized to (i) intravenous (IV) ferric carboxymaltose (FCM) at an initial dose of 1000 mg iron with subsequent dosing as necessary to target a serum ferritin level of 400-600 µg/L (ii) IV FCM at an initial dose of 200 mg with subsequent dosing as necessary to target serum ferritin 100-200 µg/L or (iii) oral ferrous sulphate 200 mg iron/day. The primary end point was time to initiation of other anaemia management (ESA therapy, iron therapy other than study drug or blood transfusion) or a haemoglobin (Hb) trigger (two consecutive Hb values <10 g/dL without an increase of >= 0.5 g/dL).The background, rationale and study design of the trial are presented here. The study has been completed and results are expected in late 2013.FIND-CKD was the longest randomized trial of IV iron therapy to date. Its findings will address several unanswered questions regarding iron therapy to treat iron deficiency anaemia in patients with ND-CKD. It was also the first randomized trial to utilize both a high and low serum ferritin target range to adjust IV iron dosing, and the first not to employ Hb response as its primary end point.
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The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis - Xie, Jingyuan; Liu, Lili; Mladkova, Nikol; Li, Yifu; Ren, Hong; Wang, Weiming; Cui, Zhao; Lin, Li; Hu, Xiaofan; Yu, Xialian; Xu, Jing; Liu, Gang; et al. (Nature Communications, 2020)
Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (﻿rs230540, OR = 1.25, P = 3.4 × 10−12) and IRF4 (﻿rs9405192, OR = 1.29, P = ﻿1.4 × 10−14), fine-map the PLA2R1 locus (﻿rs17831251, OR = 2.25, P = 4.7 × 10−103) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 × 10−49), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 × 10−93), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 × 10−23 and OR = 3.39, P = 5.2 × 10−82, respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20–37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk.
CRIS-Team Scopus Importer:2020-04-07

The haemochromatosis gene Hfe and Kupffer cells control LDL cholesterol homeostasis and impact on atherosclerosis development - Demetz, Egon; Tymoszuk, Piotr; Hilbe, Richard; Volani, Chiara; Haschka, David; Heim, Christiane; Auer, Kristina; Lener, Daniela; Zeiger, Lucas B.; Pfeifhofer-Obermair, Christa; Boehm, Anna; Obermair, Gerald J.; et al. (European Heart Journal, 2020)
AIMS: Imbalances of iron metabolism have been linked to the development of atherosclerosis. However, subjects with hereditary haemochromatosis have a lower prevalence of cardiovascular disease. The aim of our study was to understand the underlying mechanisms by combining data from genome-wide association study analyses in humans, CRISPR/Cas9 genome editing, and loss-of-function studies in mice. METHODS AND RESULTS: Our analysis of the Global Lipids Genetics Consortium (GLGC) dataset revealed that single nucleotide polymorphisms (SNPs) in the haemochromatosis gene HFE associate with reduced low-density lipoprotein cholesterol (LDL-C) in human plasma. The LDL-C lowering effect could be phenocopied in dyslipidaemic ApoE-/- mice lacking Hfe, which translated into reduced atherosclerosis burden. Mechanistically, we identified HFE as a negative regulator of LDL receptor expression in hepatocytes. Moreover, we uncovered liver-resident Kupffer cells (KCs) as central players in cholesterol homeostasis as they were found to acquire and transfer LDL-derived cholesterol to hepatocytes in an Abca1-dependent fashion, which is controlled by iron availability. CONCLUSION: Our results disentangle novel regulatory interactions between iron metabolism, KC biology and cholesterol homeostasis which are promising targets for treating dyslipidaemia but also provide a mechanistic explanation for reduced cardiovascular morbidity in subjects with haemochromatosis.
CRIS-Team Scopus Importer:2020-12-18
Keywords: ABCA1; Atherosclerosis; Haemochromatosis; Kupffer cells; LDL receptor

The hypoxia-inducible factor renders cancer cells more sensitive to vitamin C-induced toxicity - Tian, Weihua; Wang, Yu; Xu, Yan; Guo, Xiangpeng; Wang, Bo; Sun, Li; Liu, Longqi; Cui, Fenggong; Zhuang, Qiang; Bao, Xichen; Schley, Gunnar; Chung, Tung-Liang; et al. (Journal of Biological Chemistry, 2014)
Megadose vitamin C (Vc) is one of the most enduring alternative treatments for diverse human diseases and is deeply engrafted in popular culture. Preliminary studies in the 1970s described potent effects of Vc on prolonging the survival of patients with terminal cancer, but these claims were later criticized. An improved knowledge of the pharmacokinetics of Vc and recent reports using cancer cell lines have renewed the interest in this subject. Despite these findings, using Vc as an adjuvant for anticancer therapy remains questionable, among other things because there is no proper mechanistic understanding. Here, we show that a Warburg effect triggered by activation of the hypoxia-inducible factor (HIF) pathway greatly enhances Vc-induced toxicity in multiple cancer cell lines, including von Hippel-Lindau (VHL)-defective renal cancer cells. HIF increases the intracellular uptake of oxidized Vc through its transcriptional target glucose transporter 1 (GLUT1), synergizing with the uptake of its reduced form through sodium-dependent Vc transporters. The resulting high levels of intracellular Vc induce oxidative stress and massive DNA damage, which then causes metabolic exhaustion by depleting cellular ATP reserves. HIF-positive cells are particularly sensitive to Vc-induced ATP reduction because they mostly rely on the rather inefficient glycolytic pathway for energy production. Thus, our experiments link Vc-induced toxicity and cancer metabolism, providing a new explanation for the preferential effect of Vc on cancer cells.
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The impact of age on the benefits and risks of aliskiren treatment: analyses of the 3A registry - Friedrich, S.; Zeymer, U.; Dechend, R.; Hagedorn, I.; Riemer, T.; Zemmrich, C.; Bramlage, P.; Pittrow, D.; Senges, J.; Schmieder, Roland (Journal of Human Hypertension, 2015)
We aimed to analyze benefits and risks of aliskiren treatment in older adults (?65 years) in clinical practice. Patients (n=14 986) were assigned to either aliskiren (ALIS), an angiotensin-converting-enzyme inhibitor or angiotensin receptor blocker (ACEi/ARB), or an agent not blocking the renin-angiotensin system (non-RAS). Older adults (n=7396) had a longer history of hypertension (8.7 vs 4.7 years; P<0.0001), lower mean diastolic blood pressure (DBP; 87.7±11.0 vs 92.1±11.0 mm Hg) and more renal (12.0 vs 5.6%; P<0.0001) or cardiovascular disease (44.0 vs 18.9%; P<0.0001); 4548 received aliskiren (68.8%), 1215 ACEi/ARBs (18.4%) and 850 non-RAS treatments (12.9%). Office BP at 1 year was reduced by 18.4±21.5/7.2±12.0 mm Hg. BP reductions were greater (19.5±21.7/7.6±12.1 mm Hg) in the aliskiren group than in the ACEi/ARB (15.6±20.9/6.4±11.9) and non-RAS groups (16.1±20.7/6.5±11.7 mm Hg), respectively (P<0.0001 for systolic BP (SBP) and <0.01 for DBP). After multivariable adjustment, differences in SBP reductions were clinically irrelevant and no differences were noted for DBP. Adverse effects were higher in older adults with no differences between treatment groups. In conclusion, the present analysis of a large, unselected cohort of patients in clinical practice from the 3A study, offers real-life evidence of the effectiveness and safety of aliskiren for the treatment of hypertension in older adults.
EVALuna2:3737

The impact of chloride secretion on the progression of polycystic kidney disease - Kraus, Andre; Faria, D.; Schley, Gunnar; Schödel, Johannes; Grampp, S.; Peters, D. J.; Schreiber, R.; Kunzelmann, K.; Eckardt, Kai-Uwe; Buchholz, Björn (Acta Physiologica, 2019)

The impact of chloride secretion on the progression of polycystic kidney disease - Kraus, Andre; Faria, D.; Schley, Gunnar; Schoedel, J.; Grampp, S.; Peters, D. J.; Schreiber, R.; Kunzelmann, K.; Eckardt, K. -U.; Buchholz, B. (ACTA PHYSIOLOGICA, 2019)
CRIS-Team WoS Importer:2019-11-12

The Impact of Hyperosmolality on Activation and Differentiation of B Lymphoid Cells - Cvetkovic, Ljiljana; Perisic, Stojan; Titze, Jens; Jäck, Hans-Martin; Schuh, Wolfgang (Frontiers in Immunology, 2019)
B lymphocytes, as a central part of adaptive immune responses, have the ability to fight against an almost unlimited numbers of pathogens. Impairment of B cell development, activation and differentiation to antibody secreting plasma cells can lead to malignancy, allergy, autoimmunity and immunodeficiency. However, the impact of environmental factors, such as hyperosmolality or osmotic stress caused by varying salt concentrations in different lymphoid organs, on these processes is not well-understood. Here, we report that B cells respond to osmotic stress in a biphasic manner. Initially, increased osmolality boosted B cell activation and differentiation as shown by an untimely downregulation of Pax5 as well as upregulation of CD138. However, in the second phase, we observed an increase in cell death and impaired plasmablast differentiation. Osmotic stress resulted in impaired class switch to IgG1, inhibition of phosphorylation of p38 mitogen-activated kinase and a delayed NFAT5 response. Overall, these findings demonstrate the importance of microenvironmental hyperosmolality and osmotic stress caused by NaCl for B cell activation and differentiation.
CRIS-Team WoS Importer:2019-04-30

The impact of hypoxia on nephrogenesis - Buchholz, Björn; Schley, Gunnar; Eckardt, Kai-Uwe (Current Opinion in Nephrology and Hypertension, 2016)
Purpose of reviewKidney development depends on outgrowth of the ureteric bud into the metanephric mesenchyme. The number of ureteric bud branching events determines the final number of nephrons, which correlates inversely with the risk for development of chronic kidney disease and arterial hypertension during lifetime. The purpose of this review is to highlight the influence of oxygen on nephrogenesis and to describe cellular mechanisms by which hypoxia can impair nephron formation.Recent findingsAlthough kidney development normally takes place under hypoxic conditions, nephrogenesis is impaired when oxygen availability falls below the usual range. Hypoxia-inducible factors (HIF) play an important role in linking low oxygen concentrations to the biology of nephron formation, but their effect appears to be cell type dependent. In ureteric bud cells, HIF stimulates tubulogenesis, whereas HIF stabilization in cells of the metanephric mesenchyme results in secretion of growth factors, including vascular endothelial growth factor A, which in aggregate inhibit ureteric bud branching. The balance between pro and antibranching effects may be altered in various ways, but the inhibitory effect usually seems to predominate under reduced oxygen concentrations, explaining how intrauterine hypoxia can lead to low nephron numbers.SummaryOxygen availability has a complex influence on nephrogenesis. Oxygen concentrations outside an optimal low range may affect nephron endowment. Associations between placental insufficiency and increased risk for chronic kidney disease and arterial hypertension during later life may to a large extent be due to direct effects of reduced oxygen supply to the metanephric mesenchyme and mediated through the HIF pathway.
Keywords: chronic kidney disease; hypoxia; hypoxia-inducible factor-1 alpha; kidney development; nephron number

The impact of hypoxia on nephrogenesis - Buchholz, Björn; Schley, Gunnar; Eckardt, Kai-Uwe (Current Opinion in Nephrology and Hypertension, 2016)
Kidney development depends on outgrowth of the ureteric bud into the metanephric mesenchyme. The number of ureteric bud branching events determines the final number of nephrons, which correlates inversely with the risk for development of chronic kidney disease and arterial hypertension during lifetime. The purpose of this review is to highlight the influence of oxygen on nephrogenesis and to describe cellular mechanisms by which hypoxia can impair nephron formation.Although kidney development normally takes place under hypoxic conditions, nephrogenesis is impaired when oxygen availability falls below the usual range. Hypoxia-inducible factors (HIF) play an important role in linking low oxygen concentrations to the biology of nephron formation, but their effect appears to be cell type dependent. In ureteric bud cells, HIF stimulates tubulogenesis, whereas HIF stabilization in cells of the metanephric mesenchyme results in secretion of growth factors, including vascular endothelial growth factor A, which in aggregate inhibit ureteric bud branching. The balance between pro and antibranching effects may be altered in various ways, but the inhibitory effect usually seems to predominate under reduced oxygen concentrations, explaining how intrauterine hypoxia can lead to low nephron numbers.Oxygen availability has a complex influence on nephrogenesis. Oxygen concentrations outside an optimal low range may affect nephron endowment. Associations between placental insufficiency and increased risk for chronic kidney disease and arterial hypertension during later life may to a large extent be due to direct effects of reduced oxygen supply to the metanephric mesenchyme and mediated through the HIF pathway.
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The importance of the NFAT5/TonEBP-Inediated osmotic stress response in B cells - Rokvic, Ljiljana; Titze, Jens; Schuh, Wolfgang; Jäck, Hans-Martin (2017)
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The influence of aircraft noise exposure on the systemic and renal haemodynamics - Bosch, Agnes; Kannenkeril, Dennis; Jung, Susanne; Striepe, Kristina; Karg, Marina V.; Ott, Christian; Schmieder, Roland (European Journal of Preventive Cardiology, 2022)
Aims: Epidemiological studies found a link between aircraft noise exposure and increased incidence of arterial hypertension and cardiovascular disease, but the underlying pathophysiological mechanisms are not fully understood. Clinical studies have shown that mental stress affects the systemic and renal haemodynamic, but no such study was performed with noise exposure as stress factor. We analysed systemic and renal effects of 25 min standardized aircraft noise in a sham controlled clinical study including 80 healthy men and 34 male patients with hypertension. Methods and results: Systemic haemodynamic parameters were measured using electrocardiography and impedance cardiography. The renal haemodynamic was assessed using steady state input clearance with infusion of para-aminohippuric acid and inulin for glomerular filtration rate and renal plasma flow, respectively. In the systemic circulation of hypertensive patients, there was an increase in total peripheral resistance (TPR) (1420 ± 387 vs. 1640 ± 516 dyn·s·cm-5, P = 0.001) and a decrease in cardiac index (CI) (2.9 ± 0.8 vs. 2.6 ± 0.8 L/(min·m2, P < 0.001) 25 min after the start of noise exposure, which was not present during sham procedure (P = 0.10, P = 0.86). In healthy individuals a procedure induced increase in TPR and decrease in CI was present after noise (TPR: 995 ± 239 vs. 1106 ± 308 dyn·s·cm-5, P = 0.001, CI: 3.6 ± 0.7 vs. 3.3 ± 0.9 L/(min·m2, P < 0.001) and sham application (TPR: P = 0.002, CI: P < 0.001). However, in healthy individuals changes in TPR (P = 0.450) and CI (P = 0.605) from baseline until 25 min after the start of the intervention did not differ between noise and sham exposure. In the renal circulation of hypertensive patients and healthy individuals the response did not differ between noise and sham procedure. Conclusions: In hypertensive but not healthy men we observed a systemic vasoconstrictive response after aircraft noise exposure accompanied by a decrease in CI. No significant changes were observed in the renal circulation. Our results suggest that male hypertensive patients are more susceptible for noise-induced changes of vascular resistance in the systemic circulation.
CRIS-Team Scopus Importer:2022-03-25
Keywords: Aircraft noise; Clearance; Hypertension; Renal haemodynamic; Systemic haemodynamic

THE INFLUENCE OF ANNOYANCE DUE TO AIRCRAFT NOISE ON RENAL HEMODYNAMIC - Bosch, Agnes; Kannenkeril, D.; Ott, Christian; Harazny, J. M.; Striepe, Kristina; Karg, M. V.; Jung, Susan; Schmieder, Roland (JOURNAL OF HYPERTENSION, 2019)
CRIS-Team WoS Importer:2019-09-20

THE INFLUENCE OF ANNOYANCE DUE TO NOISE ON RENAL HEMODYNAMIC - Bosch, Agnes; Kannenkeril, D.; Ott, C.; Harazny, J. M.; Striepe, Kristina; Karg, M.; Dienemann, T.; Jung, Susan; Schmieder, Roland (2018)
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The International Society of Hypertension and World Hypertension League call on governments, nongovernmental organizations and the food industry to work to reduce dietary sodium - Campbell, Norman R. C.; Lackland, Daniel T.; Chockalingam, Arun; Liu Lisheng,; Harrap, Stephen B.; Touyz, Rhian M.; Burrell, Louise M.; Ramirez, Agustin J.; Schmieder, Roland; Schutte, Aletta E.; Prabhakaran, Dorairaj; Schiffrin, Ernesto L. (Journal of Hypertension, 2014)
The International Society of Hypertension and the World Hypertension League have developed a policy statement calling for reducing dietary salt. The policy supports the WHO and the United Nations recommendations, which are based on a comprehensive and up-to-date review of relevant research. The policy statement calls for broad societal action to reduce dietary salt, thus reducing blood pressure and preventing hypertension and its related burden of cardiovascular disease. The hypertension organizations and experts need to become more engaged in the efforts to prevent hypertension and to advocate strongly to have dietary salt reduction policies implemented. The statement is being circulated to national hypertension organizations and to international nongovernmental health organizations for consideration of endorsement. Member organizations of the International Society of Hypertension and the World Hypertension League are urged to support this effort.
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The Isoquinolone Derived Prolyl Hydroxylase Inhibitor ICA Is a Potent Substrate of the Organic Anion Transporters 1 and 3 - Schulz, Kei; Hagos, Yohannes; Burckhardt, Gerhard; Schley, Gunnar; Burzlaff, Nicolai; Willam, Carsten; Burckhardt, Birgitta C. (Nephron, 2015)
Many cellular responses to hypoxia are mediated by the transcription factor complex hypoxia-inducible factor (HIF). HIF stability is governed by a family of dioxygenases called HIF prolyl hydroxylases (PHDs). Isoquinolone-derived PHD inhibitors, like 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate (ICA), which stabilize the intracellular HIF-? have been suggested as a potentially beneficial therapeutic strategy for the treatment of disorders associated with ischemia. To stabilize HIF-?, ICA has to be taken up into proximal tubule cells (PCTs) across the basolateral membrane by one of the organic anion transporters 1, 2 or 3 (OAT1, OAT2 or OAT3). The release into the urine across the luminal membrane may be mediated by OAT4.To demonstrate interaction of ICA with human OAT1, OAT2, OAT3 and OAT4, ICA was tested on these transporters stably transfected in HEK293 cells by using p-aminohippurate (PAH), cGMP and estrone-3-sulfate (ES) as reference substrates, respectively.Uptakes of PAH and ES in OAT1- and OAT3-transfected HEK293 cells were inhibited by ICA with half-maximal inhibition values of 0.29 ± 0.05 and 2.58 ± 0.16 µM, respectively. OAT2 was less sensitive to ICA. Efflux experiments identified ICA as an OAT1 and OAT3 substrate. Preloading OAT4-transfected HEK293 cells with ICA stimulated ES uptake by 18.3 ± 3.8%.The uptake of ICA across the basolateral membrane of PCTs occurs mainly by OAT1 and the efflux into the tubular lumen by OAT4.
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The nephrology eHealth-system of the metropolitan region of Hannover for digitalization of care, establishment of decision support systems and analysis of health care quality - Pape, L.; Schneider, N.; Schleef, T.; Junius-Walker, U.; Haller, H.; Brunkhorst, R.; Hellrung, N.; Prokosch, Hans-Ulrich; Haarbrandt, B.; Marschollek, M.; Schiffer, Mario (BMC Medical Informatics and Decision Making, 2019)
Background: Even though a high demand for sector spanning communication exists, so far no eHealth platform for nephrology is established within Germany. This leads to insufficient communication between medical providers and therefore suboptimal nephrologic care. In addition, Clinical Decision Support Systems have not been used in Nephrology until now. Methods: The aim of NEPHRO-DIGITAL is to create a eHealth platform in the Hannover region that facilitates integrated, cross-sectoral data exchange and includes teleconsultation between outpatient nephrology, primary care, pediatricians and nephrology clinics to reduce communication deficits and prevent data loss, and to enable the creation and implementation of an interoperable clinical decision support system. This system will be based on input data from multiple sources for early identification of patients with cardiovascular comorbidity and progression of renal insufficiency. Especially patients will be able to enter and access their own data. A transfer to a second nephrology center (metropolitan region of Erlangen-Nuremburg) is included in the study to prove feasibility and scalability of the approach. Discussion: A decision support system should lead to earlier therapeutic interventions and thereby improve the prognosis of patients as well as their treatment satisfaction and quality of life. The system will be integrated in the data integration centres of two large German university medicine consortia (HiGHmed (highmed.org) and MIRACUM (miracum.org)). Trial registration: ISRCTN16755335 (09.07.2019).
CRIS-Team Scopus Importer:2019-09-17
Keywords: Clinical decision support system; eHealth; Graft survival; Interoperability; Kidney transplantation; Patient survival; Quality of life

The novel MKL target gene myoferlin modulates expansion and senescence of hepatocellular carcinoma - Hermanns, C; Hampl, V; Holzer, K; Aigner, A; Penkava, J; Frank, N; Martin, D E; Maier, K C; Waldburger, N; Roessler, S; Goppelt-Strübe, Margarete; Akrap, I; et al. (Oncogene, 2017)
Megakaryoblastic Leukemia 1 and 2 (MKL1/2) are transcriptional coactivators of Serum Response Factor (SRF) with an essential role for hepatocellular carcinoma (HCC) growth and oncogene-induced senescence. In this report, we identified myoferlin as a novel MKL/SRF target gene by gene expression profiling and verification in vivo in HCC xenografts. Myoferlin was overexpressed in human and murine HCCs triggered by conditional expression of constitutively active SRF-VP16 protein in hepatocytes. Furthermore, myoferlin was required for HCC cell invasion, proliferation and anchorage-independent cell growth. We provide evidence that myoferlin is a crucial gene target of MKL1/2 mediating its effect on oncogene-induced senescence by modulating the activation state of the EGFR and downstream MAPK and p16-/Rb pathways. Depletion of myoferlin in tumour cells from SRF-VP16-derived murine HCCs induced a senescence phenotype. These findings identify MKL1/2 and myoferlin as novel therapeutic targets to treat human HCC by a senescence-inducing strategy.Oncogene advance online publication, 23 January 2017; doi:10.1038/onc.2016.496.
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The pathophysiological role of heat shock response in autoimmunity: A literature review - Androvitsanea, Ariadni; Stylianou, Kostas; Drosataki, Eleni; Petrakis, Ioannis (Cells, 2021)
Within the last two decades, there has been increasing evidence that heat-shock proteins can have a differential influence on the immune system. They can either provoke or ameliorate immune responses. This review focuses on outlining the stimulatory as well as the inhibitory effects of heat-shock proteins 27, 40, 70, 65, 60, and 90 in experimental and clinical autoimmune settings.
CRIS-Team Scopus Importer:2021-11-05
Keywords: Autoimmunity; Heat-shock proteins; Heat-shock response

The polyamine system in acute and chronic kidney injury - Sieckmann, T.; Faehling, M.; Ashraf, M. I.; Schley, Gunnar; Vigolo, E.; Rosenberger, C.; Aigner, F.; Schmidt-Ott, K.; Scholz, H.; Kirschner, K. M. (ACTA PHYSIOLOGICA, 2019)
CRIS-Team WoS Importer:2019-11-12

The prolyl hydroxylase inhibitor molidustat fails to restore erythropoietin production in the fibrotic kidney - Schley, Gunnar; Hartner, Andrea (Acta Physiologica, 2022)
CRIS-Team Scopus Importer:2022-07-15

The protective effect of prolyl-hydroxylase inhibition against renal ischaemia requires application prior to ischaemia but is superior to EPO treatment - Wang, Zhendi; Schley, Gunnar; Türkoglu, Gazi; Burzlaff, Nicolai; Amann, Kerstin Ute; Willam, Carsten; Eckardt, Kai-Uwe; Bernhardt, Wanja M. (Nephrology Dialysis Transplantation, 2012)
Background. Inhibition of the HIF regulating prolyl hydroxylation domain (PHDs) proteins prior to renal injury (preconditioning) has been shown to protect the kidney via activation of hypoxia-inducible transcription factors (HIF). Application of erythropoietin (EPO), one of the HIF target genes, has also been shown to be nephroprotective, and it remains unclear to what extent the effect of HIF induction is mediated by EPO. It is also unknown whether HIF activation after the onset of ischaemia (postconditioning) is still able to protect the kidney. Methods. Using a rat model of renal ischaemia-reperfusion injury, animals were treated with the PHD inhibitor (PHD-I) 2-(1-chloro-4- hydroxyisoquinoline-3-carboxamido) acetate (ICA), vehicle (Veh) or recombinant human EPO (300 IU/ kg) 6 h (ICA or Veh) or 30 min (EPO) prior to ischaemia (preconditioning) or with ICA prior to reperfusion (postconditioning). Renal function was assessed at baseline, 24 h and 72 h. After 72 h, kidneys were processed for histology and morphometric analysis. HIF immunohistochemistry and real-time polymerase chain reaction for HIF target genes, including EPO, were performed to evaluate ICA effects. Results. ICA treatment resulted in stabilization of HIF-1α and -2α and up-regulation of HIF target genes in a dosedependent manner. Preconditional activation of HIF by ICA significantly improved serum creatinine levels and renal morphology in comparison to Veh (P < 0.05), while postconditional ICA treatment was ineffective. EPO therapy improved tissue morphology but had no impact on the course of serum creatinine. Conclusion. These findings are in line with the concept that PHD-Is exert their protective effects through accumulation of HIF target gene products, with time requirements for increased transcription and translation of HIF-dependent genes, and suggest that their renoprotective effect is not predominately mediated by EPO. © 2011 The Author.

The quality of COPD care in German general practice—A cross-sectional study - Heinmüller, Stefan; Schaubroeck, Emmily; Frank, Luca; Höfle, Anina; Höfle, Anina; Langer, Michael; Saggau, Korbinian; Schedlbauer, Angela; Kühlein, Thomas (Chronic Respiratory Disease, 2020)
Objectives: Chronic Obstructive Pulmonary Disease (COPD) is a common health problem to be dealt with in primary care. Little is known about the quality of care provided for patients with COPD in Germany. Therefore, we wanted to assess the current quality of care delivered by a primary care network (PCN) for patients with COPD. Methods: A cross-sectional study was conducted in collaboration with a primary care network (PCN). All patients of the PCN aged 40 years and older with a diagnosis of COPD were identified through electronic health records (EHR). A set of quality indicators (QIs) developed in accordance with current COPD-guidelines were appraised through numerical data retrieved from the EHR. Results: In total, 2,568 patients with COPD were identified. Their mean age was 67 (SD±12) years, 49% were male. Thirty-five percent had a parallel diagnosis of asthma. There was no documentation of any spirometry for 54% of patients; 29% had a spirometry within the previous year. An influenza vaccination was documented for 37% within the preceding 12 months; 12% received a pneumococcal vaccination in the last 6 years. Smoking status was documented for 44% within the last year. Conclusion: The quality of care for patients with COPD in the PCN seemed suboptimal, despite the presence of a Disease Management Program (DMP). This finding is likely to apply widely to German general practice. Quality assessment through currently available EHR data was challenging due to non-standardized and insufficient documentation.
CRIS-Team Scopus Importer:2020-12-11
Keywords: chronic obstructive; documentation; general practice; practice guideline; Pulmonary disease; quality of health care

The Raf kinase inhibitor PLX5568 slows cyst proliferation in rat polycystic kidney disease but promotes renal and hepatic fibrosis - Buchholz, Björn; Klanke, Bernd; Schley, Gunnar; Bollag, Gideon; Tsai, James; Kroening, Sven; Yoshihara, Daisuke; Wallace, Darren P.; Kraenzlin, Bettina; Gretz, Norbert; Hirth, Peter; Eckardt, Kai-Uwe; et al. (Nephrology Dialysis Transplantation, 2011)
Background. Autosomal dominant polycystic kidney disease (ADPKD) is a common cause of renal failure. Aberrant epithelial cell proliferation is a major cause of progressive cyst enlargement in ADPKD. Since activation of the Ras/Raf signaling system has been detected in cyst-lining epithelia, inhibition of Raf kinase has been proposed as an approach to retard the progression of ADPKD.Methods and results. PLX5568, a novel selective small molecule inhibitor of Raf kinases, attenuated proliferation of human ADPKD cyst epithelial cells. It reduced in vitro cyst growth of Madin-Darby Canine Kidney cells and of human ADPKD cells within a collagen gel. In male cy/1 rats with polycystic kidneys, PLX5568 inhibited renal cyst growth along with a significant reduction in the number of proliferating cell nuclear antigen-and phosphorylated extracellular signal-regulated kinase-positive cyst-lining epithelial cells. Furthermore, treated animals showed increased capacity to concentrate urine. However, PLX5568 did not lead to a consistent improvement of renal function. Moreover, although relative cyst volume was decreased, total kidney-to-body weight ratio was not significantly reduced by PLX5568. Further analyses revealed a 2-fold increase of renal and hepatic fibrosis in animals treated with PLX5568.Conclusions. PLX5568 attenuated cyst enlargement in vitro and in a rat model of ADPKD without improving kidney function, presumably due to increased renal fibrosis. These data suggest that effective therapies for the treatment of ADPKD will need to target fibrosis as well as the growth of cysts.
Keywords: ERK; polycystic kidney disease; proliferation; Raf

The renal cancer risk allele at 14q24.2 activates a novel hypoxia-inducible transcription factor-binding enhancer of DPF3 expression - Protze, Johanna; Naas, Stephanie; Krüger, René; Stöhr, Christine; Kraus, Andre; Grampp, Steffen; Schiffer, Mario; Hartmann, Arndt; Wullich, Bernd; Schödel, Johannes; Wiesener, Michael (Journal of Biological Chemistry, 2022)
Evolution of clear cell renal cell carcinoma is guided by dysregulation of hypoxia-inducible transcription factor (HIF) pathways following loss of the von Hippel-Lindau tumor suppressor protein. Renal cell carcinoma (RCC)-associated polymorphisms influence HIF–DNA interactions at enhancers of important oncogenes thereby modulating the risk of developing renal cancer. A strong signal of genome-wide association with RCC was determined for the single nucleotide polymorphism (SNP) rs4903064, located on chr14q.24.2 within an intron of DPF3, encoding for Double PHD Fingers 3, a member of chromatin remodeling complexes; however, it is unclear how the risk allele operates in renal cells. In this study, we used tissue specimens and primary renal cells from a large cohort of RCC patients to examine the function of this polymorphism. In clear cell renal cell carcinoma tissue, isolated tumor cells as well as in primary renal tubular cells, in which HIF was stabilized, we determined genotype-specific increases of DPF3 mRNA levels and identified that the risk SNP resides in an active enhancer region, creating a novel HIF-binding motif. We then confirmed allele-specific HIF binding to this locus using chromatin immunoprecipitation of HIF subunits. Consequentially, HIF-mediated DPF3 regulation was dependent on the presence of the risk allele. Finally, we show that DPF3 deletion in proximal tubular cells retarded cell growth, indicating potential roles for DPF3 in cell proliferation. Our analyses suggest that the HIF pathway differentially operates on a SNP-induced hypoxia-response element at 14q24.2, thereby affecting DPF3 expression, which increases the risk of developing renal cancer.
CRIS-Team Scopus Importer:2022-03-18

The renin-angiotensin receptor blocker azilsartan medoxomil compared with the angiotensin-converting enzyme inhibitor ramipril in clinical trials versus routine practice: insights from the prospective EARLY registry - Bramlage, Peter; Schmieder, Roland; Gitt, Anselm K.; Baumgart, Peter; Mahfoud, Felix; Buhck, Hartmut; Ouarrak, Taoufik; Ehmen, Martina; Potthoff, Sebastian A. (Trials, 2015)
Patient characteristics and blood pressure-related outcomes in randomized clinical trials (RCTs) differ from clinical practice because of stringent selection criteria. The present study aimed to explore the relationship between clinical trials and clinical practice. We analyzed data from patients enrolled in the "Treatment with Azilsartan Compared to ACE-Inhibitors in Anti-Hypertensive Therapy" (EARLY) registry comparing blood pressure (BP) effects of the angiotensin receptor blocker (ARB) azilsartan medoxomil (AZL-M) with the angiotensin-converting enzyme (ACE) inhibitor ramipril between patients who met the eligibility criteria of a previous RCT and those who did not.Patients with primary arterial hypertension were consecutively enrolled from primary care offices in Germany into the EARLY registry in a 7:3 ratio for treatment with AZL-M or an ACE inhibitor, provided that they met the following criteria at baseline: 1) no antihypertensive treatment prior to inclusion or a non-renin-angiotensin system (RAS) based monotherapy; 2) initiation of treatment with either AZL-M or an ACE inhibitor alone. Analyses were performed to evaluate BP effects for patients in the EARLY registry who met the selection criteria of a prior RCT (RCT+) versus those who did not (RCT-).Out of 3,698 patients considered, 1,644 complied with the RCT criteria (RCT+) while 2,054 did not (RCT-). RCT- patients (55.5 %) displayed a higher risk profile in terms of age and comorbidities, and a wider spectrum of BP values at baseline, as highlighted by the grades of hypertension and mean BP values. The proportion of patients who achieved target blood pressure control in the RCT+ group was significantly higher for AZL-M versus ramipril (64.1 versus 56.1 %; P < 0.01), in accordance with the result of the clinical trial. In the RCT- AZL-M group, the proportion of patients who met BP targets was lower (58.1 %) than in the RCT+ AZL-M group (64.1 %), whereas the proportion of patients with target BP values in the RCT- ramipril and the RCT+ ramipril groups was similar (57.7 versus 56.1 %). Thus, in contrast to results for the RCT+ group, in the RCT- group, the target BP attainment rate for AZL-M was not significantly superior to that for ramipril. However, the tolerability profile of AZL-M and ramipril was comparable in both populations. At the 12-month follow-up, death and stroke rates were low (<=0.5 %) and adverse events did not differ between the AZL-M and ramipril groups, irrespective of RCT eligibility.These data confirm that the EARLY population comprised a broader spectrum of hypertensive patients than RCTs, and the differences in patient characteristics were accompanied by disparate rates of blood pressure goal attainment. Overall, the validity of the RCT was demonstrated and confirmed in clinical practice with a broader range of patients with various comorbidities.
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The role of ceramide in major depressive disorder - Kornhuber, Johannes; Reichel, Martin; Tripal, Philipp; Groemer, Teja W.; Henkel, Andreas W.; Mühle, Christiane; Gulbins, Erich (European archives of psychiatry and clinical neuroscience, 2009)
Major depression is a severe mood disorder with a lifetime prevalence of more than 10%. The pharmacokinetic hypothesis claims that a slow accumulation of antidepressant drugs by acid trapping mainly into lysosomes is responsible for the therapeutic latency and that a lysosomal target mediates the antidepressant effects. The lysosomal lipid metabolizing enzyme acid sphingomyelinase (ASM) cleaves sphingomyelin into ceramide and phosphorylcholine. In a pilot study, the activity of this enzyme was increased in peripheral blood cells of patients with major depressive disorder (MDD), making the ASM an interesting molecular target of antidepressant drugs. Indeed, several antidepressant drugs functionally inhibit ASM. The ASM/ceramide pathway might be a missing link unifying independent findings in neurobiology and the treatment of MDD such as therapeutic latency, oxidative stress, immune activation and increased risk of cardiovascular disease. © 2009 Springer-Verlag.
Created from Fastlane, Scopus look-up
Keywords: Acid sphingomyelinase; Amitriptyline; Ceramide; Fluoxetine; Lysosomes; Major depressive disorder; Neuroplasticity hypothesis; Pharmacokinetic hypothesis; Sphingolipids

The role of HIF-1 alpha in the pathogenesis of psoriasis - Das Mahapatra, K.; Jargosch, M.; Hillig, C.; Buchholz, Björn; Thomas, J.; Eyerich, S.; Eyerich, K.; Garzorz-Stark, N. (JOURNAL OF INVESTIGATIVE DERMATOLOGY, 2022)
CRIS-Team WoS Importer:2023-03-10

THE SGLT2 INHIBITOR EMPAGLIFLOZIN REDUCES TISSUE SODIUM CONTENT IN PATIENTS WITH CHRONIC HEART FAILURE - Kolwelter, Julie; Kannenkeril, Dennis; Linz, Peter; Jung, Susanne; Nagel, Armin Michael; Bosch, Agnes; Ott, Christian; Bramlage, Peter; Uder, Michael; Achenbach, Stephan; Schmieder, Roland (JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2021)
CRIS-Team WoS Importer:2021-06-04

The SGLT2 inhibitor empagliflozin reduces tissue sodium content in patients with chronic heart failure: results from a placebo-controlled randomised trial - Kolwelter, Julie; Kannenkeril, Dennis; Linz, Peter; Jung, Susanne; Nagel, Armin Michael; Bosch, Agnes; Ott, Christian; Bramlage, Peter; Nöh, Lisa; Schiffer, Mario; Uder, Michael; Achenbach, Stephan; et al. (Clinical Research in Cardiology, 2022)
Introduction: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have cardiovascular protective properties in addition to the metabolic effects and represent a cornerstone of treating patients with chronic heart failure (CHF). We hypothesised that empagliflozin reduces tissue sodium content in patients with CHF. Methods: In a double-blind, randomised (2:1), placebo-controlled, parallel-group, clinical trial, 74 patients with NYHA class II–III CHF and an ejection fraction of 49% or less received empagliflozin 10 mg once daily or placebo for 3 months. In each patient, tissue sodium content of the lower leg was assessed non-invasively by sodium-MRI (23Na-MRI) at baseline, after 1 and 3 months of treatment. Results: After 1 and 3 months treatment with empagliflozin (n = 48), a significant decrease in skin sodium content was observed (1 month: 22.8 ± 6.1 vs. 21.6 ± 6.0 AU, p = 0.039; 3 months: 22.9 ± 6.1 vs. 21.6 ± 6.1 AU, p = 0.013), while there was no change in muscle sodium and muscle water content. In direct comparison, the change in skin sodium content between baseline and 3 months was − 1.3 ± 3.5 AU in the empagliflozin group versus 0.6 ± 3.5 AU in the placebo group (p for between-group difference = 0.022). No significant difference regarding change in muscle sodium and in muscle water content was observed after 3 months treatment between the two groups. Conclusion: This trial showed a significant decrease in skin sodium content after 1 and 3 months of treatment with empagliflozin. The decrease in skin sodium content may reflect a decrease in subclinical micro-oedema or/and in non-osmotic bound tissue sodium, both reported to impair left ventricular function. Trial registration number: NCT03128528 (http://www.clinicaltrials.gov). Trial registration date: 25th April 2017.
CRIS-Team Scopus Importer:2022-11-04
Keywords: Chronic heart failure; Empagliflozin; Magnetic resonance imaging; SGLT2 inhibitor; Sodium; Tissue sodium content

THE SINGLE PILL CONCEPT LEADS TO IMPROVED PERSISTENCE OF MEDICATION, CLINICAL OUTCOMES AND REDUCED ALL-CAUSE MORTALITY IN HYPERTENSIVE PATIENTS - RESULTS FROM THE START PROJECT - Predel, Hans-Georg; Weisser, Burkhard; Wassmann, Sven; Gillessen, Anton; Blettenberg, Joerg; Fournier, Valerie; Noetel, Andrea; Randerath, Olaf; Boehm, Michael; Schmieder, Roland (JOURNAL OF HYPERTENSION, 2021)
CRIS-Team WoS Importer:2021-07-30

The World Hypertension League and International Society of Hypertension call on governments, nongovernmental organizations, and the food industry to work to reduce dietary sodium - Campbell, Norm; Lackland, Daniel; Chockalingam, Arun; Liu Lisheng,; Schiffrin, Ernesto L.; Harrap, Stephen; Touyz, Rhian M.; Burrell, Louise; Ramirez, Augustin; Schmieder, Roland; Aletta, Schutte; Prabhakaran, Dorairaj (Journal of Clinical Hypertension, 2014)
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The zebrafish model to understand epigenetics in renal diseases - Sopel, Nina; Müller-Deile, Janina (International Journal of Molecular Sciences, 2021)
Epigenetic modifications are able to alter gene expression and include DNA methylation, different histone variants, and post-transcriptional modifications (PTMs), such as acetylation or phosphorylation, and through short/long RNAs, respectively. In this review, we focus on current knowledge concerning epigenetic modifications in gene regulation. We describe different forms of epigenetic modifications and explain how epigenetic changes can be detected. The relevance of epigenetics in renal diseases is highlighted with multiple examples and the use of the zebrafish model to study glomerular diseases in general and epigenetics in renal diseases in particular is discussed. We end with an outlook on how to use epigenetic modifications as a therapeutic target for different diseases. Here, the zebrafish model can be employed as a high-throughput screening tool not only to discover epigenetic alterations contributing to disease, but also to test novel substances that change epigenetic signatures in vivo. Therefore, the zebrafish model harbors the opportunity to find novel pathogenic pathways allowing a pre-selection of potential targets and compounds to be tested for renal diseases.
CRIS-Team Scopus Importer:2021-09-03
Keywords: DNA methylation; Epigenetics; Histone modifications; MicroRNAs; Renal diseases; Zebrafish model

THROMBOCYTOPENIA, HAEMOLYTIC ANAEMIA, NEW ONSET HYPERTENSION AND PROTEINURIA IN A 29 WEEKS PREGNANT WOMAN WITH KIDNEY GRAFT AND ATYPICAL HAEMOLYTIC URAEMIC SYNDROME (aHUS) - CAN IT GET MORE COMPLICATED? - Ursu, R.; Schiffer, Mario; Opgenoorth, M. (TRANSPLANT INTERNATIONAL, 2019)
CRIS-Team WoS Importer:2019-10-29

Thrombospondin-2 therapy ameliorates experimental glomerulonephritis via inhibition of cell proliferation, inflammation, and TGF-β activation - Daniel, Christoph; Wagner, Andrea; Hohenstein, Bernd; Hugo, Christian (American Journal of Physiology-Renal Physiology, 2009)
We recently identified thrombospondin-2 (TSP-2) as an endogenous regulator of matrix remodelling and inflammation in experimental kidney disease by studying TSP-2-deficient mice. In this study, we asked whether systemic TSP-2 overexpression via thigh muscle transfection is able to ameliorate the time course of the anti-Thy1 glomerulonephritis model. After induction of anti-Thy1 nephritis, rats were transfected either with an overexpression plasmid for TSP-2 or lacZ as a control. Biopsies, urine, and blood samples were taken on days 1, 3, and 6 after disease induction. Muscular overexpression of TSP-2 reduced glomerular transforming growth factor (TGF)-β activation and glomerular extracellular matrix formation as determined by collagen IV and fibronectin. In addition, activation of mesangial cells to the myofibroblast-like phenotype was also significantly decreased in TSP-2-overexpressing animals. TSP-2 overexpression inhibited both glomerular endothelial and mesangial cell proliferation, resulting in a reduced glomerular cell number and glomerular tuft area. The inflammatory response, as monitored by T cells and antigen-presenting cells, was reduced significantly by TSP-2 overexpression, but influx of macrophages was unchanged. These data demonstrate TSP-2 as a potential therapeutic agent to inhibit the glomerular proliferative and inflammatory response as well as TGF-β activation and extracellular matrix accumulation in experimental mesangial proliferative glomerulonephritis. Copyright © 2009 the American Physiological Society.
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Keywords: Extracellular matrix; Glomerulonephritis; Proliferation; Thrombospondin-2; Transforming growth factor-β activation

Thyroid function, renal events and mortality in chronic kidney disease patients: the German Chronic Kidney Disease study - Schultheiss, Ulla T.; Steinbrenner, Inga; Nauck, Matthias; Schneider, Markus; Kotsis, Fruzsina; Baid-Agrawal, Seema; Schaeffner, Elke; Eckardt, Kai-Uwe; Koettgen, Anna; Sekula, Peggy (Clinical Kidney Journal, 2021)
Background. Hypothyroidism and low free triiodothyronine (FT3) syndrome [low FT3 levels with normal thyroid-stimulating hormone (TSH)] have been associated with reduced kidney function cross-sectionally in chronic kidney disease (CKD) patients with severely reduced estimated glomerular filtration rate (eGFR) or end-stage kidney disease (ESKD). Results on the prospective effects of impaired thyroid function on renal events and mortality for patients with severely reduced eGFR or from population-based cohorts are conflicting. Here we evaluated the association between thyroid and kidney function with eGFR (cross-sectionally) as well as renal events and mortality (prospectively) in a large, prospective cohort of CKD patients with mild to moderately reduced kidney function.
CRIS-Team WoS Importer:2021-05-28

Tissue sodium concentration correlates with hypertrophic vascular remodelling in type 2 diabetes - Kannenkeril, D.; Jung, Susan; Harazny, Jeremy; Striepe, Kristina; Ott, Christian; Linz, Peter; Nagel, Armin Michael; Uder, Michael; Schmieder, Roland (DIABETOLOGIA, 2019)
CRIS-Team WoS Importer:2019-10-11

Tissue sodium concentration emerged as a determinant of hypertrophic vascular remodeling in type 2 diabetes - Schmieder, Roland; Jung, Susanne; Kannenkeril, D.; Harazny, J. M.; Striepe, Kristina; Ott, Christian; Linz, Peter; Nagel, Angela; Uder, Michael (EUROPEAN HEART JOURNAL, 2019)
CRIS-Team WoS Importer:2020-02-04

Tissue sodium content correlates with hypertrophic vascular remodeling in type 2 diabetes - Kannenkeril, Dennis; Jung, Susanne; Harazny, Joanna; Striepe, Kristina; Ott, Christian; Dahlmann, Anke; Kopp, Christoph; Schiffer, Mario; Linz, Peter; Nagel, Armin Michael; Uder, Michael; Schmieder, Roland (Journal of Diabetes and Its Complications, 2021)
Background: Prospective studies describe a linkage between increased sodium intake and higher incidence of cardiovascular organ damage and end points. We analyzed whether tissue sodium content in the skin and muscles correlate with vascular hypertrophic remodeling, a risk factor for cardiovascular disease.
CRIS-Team WoS Importer:2021-12-03

Tissue sodium content in hypertension and related organ damage - Kolwelter, Julie; Uder, Michael; Schmieder, Roland (Journal of Hypertension, 2020)
Most textbooks state that sodium (Na) accumulation goes hand in hand with fluid retention to maintain the environmental isotonicity. In the last century, several studies found, however, that Na is stored in the extravascular space leading to an activation of the monocyte phagocytic system cells that work as a regulator of the interstitial electrolyte homeostasis. Na-23-MRI was developed to quantify noninvasively, accurately and reliably tissue Na content. In this review, we give an up-to-date overview of clinical studies utilizing this Na-23-MRI technique to elucidate the importance of tissue Na content in patients with cardiovascular risk factors leading to microvascular and macrovascular complications. Na storage leads ultimately to organ damage such as left ventricular hypertrophy or hypertrophic vascular remodeling of resistance vessels. Elevated Na content in muscle and skin has been detected in patients with treatment resistant hypertension, type 2 diabetes mellitus, acute and chronic heart failure, chronic kidney disease and end-stage renal failure. Pharmacological interventions have shown that a mobilization of extracellular accumulated Na is possible and may emerge as a new therapeutic approach in some diseases.
CRIS-Team WoS Importer:2021-01-01

Tissue sodium content in patients with type 2 diabetes mellitus - Kannenkeril, Dennis; Karg, Marina V.; Bosch, Agnes; Ott, Christian; Linz, Peter; Nagel, Armin Michael; Uder, Michael; Schmieder, Roland (Journal of Diabetes and Its Complications, 2019)
Background: Tissue sodium content by 23 Na magnetic resonance imaging (MRI)has been found to be increased in arterial hypertension. We analyzed whether tissue sodium content is increased in patients with type-2 diabetes (T2DM). Methods: Patients with T2DM were compared to those with primary hypertension. Patients with T2DM were off any antidiabetic and hypertensive patients off any antihypertensive therapy for at least 4 weeks. Skin and muscle sodium content was assessed non-invasively with a 3.0 T clinical MRI system (Magnetom Verio, Siemens Health Care, Erlangen, Germany)in each patient. Results: In patients with T2DM (N = 59)we observed significantly greater muscle sodium content (diabetes: 20.6 ± 3.5 vs hypertension: 16.3 ± 2.5 mmol/l, p < 0.001)and skin sodium content (diabetes: 24.5 ± 7.2 vs hypertension: 20.6 ± 5.7 mmol/l, p = 0.01)than in those with primary hypertension (N = 33). When potential confounders (age, body mass index, gender, systolic and diastolic blood pressure, estimated glomerular filtration rate)were entered in a covariance analysis, both skin sodium content (p = 0.037)and muscle sodium content (p < 0.001)were still clearly elevated. Conclusion: Patients with T2DM have greater skin and muscle sodium content. These are the first known data to demonstrate increased tissue sodium content in patients with T2DM, measured by 23 Na magnetic resonance imaging. Since tissue sodium content is related to organ damage, therapeutic intervention should aim at reducing tissue sodium content.
CRIS-Team Scopus Importer:2019-05-21
Keywords: 23Na-MRI; T2DM; Tissue sodium content; Salt; Sodium retention

TMEM16A drives renal cyst growth by augmenting Ca2+ signaling in M1 cells - Cabrita, Ines; Buchholz, Björn; Schreiber, Rainer; Kunzelmann, Karl (Journal of Molecular Medicine, 2020)
Abstract: Polycystic kidney disease (PKD) leads to continuous decline of renal function by growth of renal cysts. Enhanced proliferation and transepithelial chloride secretion through cystic fibrosis transmembrane conductance regulator (CFTR) and Ca2+-activated TMEM16A Cl− channels is thought to cause an increase in cyst volume. Recent work shows the pro-proliferative role of the Ca2+ activated Cl− channel TMEM16A (anoctamin 1), and demonstrates the essential contribution of TMEM16A to CFTR-dependent Cl− secretion. The present data demonstrate an increase in intracellular Ca2+ ([Ca2+]i) signals and Cl− secretion by TMEM16A, in renal collecting duct principle cells from dog (MDCK) and mouse (M1) as well as primary tubular epithelial cells from PKD1−/− knockout mice. M1 organoids proliferated, increased expression of TMEM16A, and secreted Cl− upon knockdown of endogenous polycystin 1 or 2 (PKD1,2), by retroviral transfection with shPKD1 and shPKD2, respectively. Knockdown of PKD1 or PKD2 increased basal intracellular Ca2+ levels and enhanced purinergic Ca2+ release from endoplasmic reticulum. In contrast, ryanodine receptors were found not to be expressed in mouse renal epithelial cells and caffeine had no effects on [Ca2+]i. Ca2+ signals, proliferation, and Cl− secretion were largely reduced by knockdown or blockade of TMEM16A. TMEM16A may be therefore important for enhanced Ca2+ release from IP3-sensitive Ca2+ stores in polycystic kidney disease. Key messages: • ADPKD leads to continuous decline of renal function by growth of renal cysts. • Knockdown of PKD1 or PKD2 increases TMEM16A expression. • TMEM16A enhanced intracellular Ca2+ signals, Cl− secretion, and proliferation. • TMEM16A contributes to cyst growth in ADPKD.
CRIS-Team Scopus Importer:2020-03-27
Keywords: ADPKD; Anoctamin 1; Ca; Renal cysts; TMEM16A

Tolvaptan induces body fluid loss and subsequent water conservation in normal rats - Kidoguchi, Satoshi; Kitada, Kento; Fujisawa, Yoshihide; Nakano, Daisuke; Yokoo, Takashi; Titze, Jens; Nishiyama, Akira (Journal of Pharmacological Sciences, 2022)
We have recently reported that the urea osmolyte-associated water conservation system is activated in fluid loss models such as high salt-induced natriuresis, renal injury-induced impaired renal concentrating ability, or skin barrier dysfunction-induced transepidermal water loss. The system consists of the interaction of multiple organs including renal urea recycling, hepato-muscular ureagenesis, and suppression of cardiovascular energy expenditure. Here, we determined the effect of pharmacological fluid loss induced by tolvaptan, a selective vasopressin V2 receptor antagonist, on water conservation. We evaluated the water conservation system in rats that consumed a control diet or a diet containing 0.1% tolvaptan. Tolvaptan increased urine volume on day 1, but this renal water loss then gradually decreased. Body water and osmolyte content were decreased by tolvaptan on day 1 but had normalized by day 7. Tolvaptan induced fluid loss on day 1, and the following restoration of body fluid on day 7 was associated with an increase in urea transporter A1-associated renal urea recycling. Tolvaptan did not affect hepato-muscular ureagenesis on day 1 and day 7, or cardiovascular energy expenditure during treatment. Thus, tolvaptan-induced fluid loss leads to activation of the water conservation system via renal urea recycling.
CRIS-Team Scopus Importer:2022-05-20
Keywords: Blood pressure; Body fluid; Cardiovascular energy expenditure; Tolvaptan; Urea

Tolvaptan treatment in an adult Fontan patient with protein-losing enteropathy: a serial 23Na-MRI investigation - Moosmann, Julia; Toka, Okan; Linz, Peter; Dahlmann, Anke; Nagel, Armin M.; Schiffer, Mario; Uder, Michael; Cesnjevar, Robert; Dittrich, Sven; Kopp, Christoph (Therapeutic Advances in Chronic Disease, 2021)
Background: Protein-losing enteropathy (PLE) is a severe complication of the univentricular Fontan circulation and associated with disturbances in salt and water homeostasis. Fontan patients with PLE have a poor prognosis, with increased morbidity and mortality. Due to limited therapeutic strategies, patients are often treated only symptomatically. Methods: We report our first experience of Tolvaptan (TLV) treatment in a Fontan patient with PLE, severe volume retention and hyponatraemia, refractory to conventional diuretic therapy. In addition to clinical parameters, we monitored drug effects including tissue sodium and volume status via serial 23Na-magnetic resonance imaging (23Na-MRI) and bioimpedance spectroscopy compared with age-matched controls. Results: 23Na-MRI identified elevated tissue sodium, which decreased under TLV treatment, as well as volume status, while serum sodium increased and the patient’s symptoms improved. During long-term treatment, we were able to differentiate between sodium and volume status in our patient, suggesting that TLV uncoupled body sodium from water. Conclusion: TLV in addition to loop diuretics improved clinical symptoms of PLE and lowered tissue sodium overload. Long-term effects should be further evaluated in Fontan patients.
CRIS-Team Scopus Importer:2021-04-30
Keywords: Congenital heart disease; Fontan; RAAS; Tolvaptan

Towards a Computable Data Corpus of Temporal Correlations between Drug Administration and Lab Value Changes - Newe, Axel; Wimmer, Stefan; Neubert, Antje; Becker, Linda; Prokosch, Hans-Ulrich; Beckmann, Matthias; Fietkau, Rainer; Forster, Christian; Neurath, Markus; Schett, Georg; Ganslandt, Thomas (PLoS ONE, 2015)
Background The analysis of electronic health records for an automated detection of adverse drug reactions is an approach to solve the problems that arise from traditional methods like spontaneous reporting or manual chart review. Algorithms addressing this task should be modeled on the criteria for a standardized case causality assessment defined by the World Health Organization. One of these criteria is the temporal relationship between drug intake and the occurrence of a reaction or a laboratory test abnormality. Appropriate data that would allow for developing or validating related algorithms is not publicly available, though. Methods In order to provide such data, retrospective routine data of drug administrations and temporally corresponding laboratory observations from a university clinic were extracted, transformed and evaluated by experts in terms of a reasonable time relationship between drug administration and lab value alteration. Result The result is a data corpus of 400 episodes of normalized laboratory parameter values in temporal context with drug administrations. Each episode has been manually classified whether it contains data that might indicate a temporal correlation between the drug administration and the change of the lab value course, whether such a change is not observable or whether a decision between those two options is not possible due to the data. In addition, each episode has been assigned a concordance value which indicates how difficult it is to assess. This is the first open data corpus of a computable ground truth of temporal correlations between drug administration and lab value alterations. Discussion The main purpose of this data corpus is the provision of data for further research and the provision of a ground truth which allows for comparing the outcome of other assessments of this data with the outcome of assessments made by human experts. It can serve as a contribution towards systematic, computerized ADR detection in retrospective data. With this lab value curve data as a basis, algorithms for detecting temporal relationships can be developed, and with the classification made by human experts, these algorithms can immediately be validated. Due to the normalization of the lab value data, it allows for a generic approach rather than for specific or solitary drug/lab value combination

Towards Implementation of OMOP in a German University Hospital Consortium - Maier, Carolin; Lang, L.; Storf, H.; Vormstein, P.; Bieber, R.; Bernarding, J.; Herrmann, T.; Haverkamp, C.; Horki, P.; Laufer, J.; Berger, F.; Hoening, G.; et al. (Applied Clinical Informatics, 2018)
In 2015, the German Federal Ministry of Education and Research initiated a large data integration and data sharing research initiative to improve the reuse of data from patient care and translational research. The Observational Medical Outcomes Partnership (OMOP) common data model and the Observational Health Data Sciences and Informatics (OHDSI) tools could be used as a core element in this initiative for harmonizing the terminologies used as well as facilitating the federation of research analyses across institutions. To realize an OMOP/OHDSI-based pilot implementation within a consortium of eight German university hospitals, evaluate the applicability to support data harmonization and sharing among them, and identify potential enhancement requirements. The vocabularies and terminological mapping required for importing the fact data were prepared, and the process for importing the data from the source files was designed. For eight German university hospitals, a virtual machine preconfigured with the OMOP database and the OHDSI tools as well as the jobs to import the data and conduct the analysis was provided. Last, a federated/distributed query to test the approach was executed. While the mapping of ICD-10 German Modification succeeded with a rate of 98.8% of all terms for diagnoses, the procedures could not be mapped and hence an extension to the OMOP standard terminologies had to be made.Overall, the data of 3 million inpatients with approximately 26 million conditions, 21 million procedures, and 23 million observations have been imported.A federated query to identify a cohort of colorectal cancer patients was successfully executed and yielded 16,701 patient cases visualized in a Sunburst plot. OMOP/OHDSI is a viable open source solution for data integration in a German research consortium. Once the terminology problems can be solved, researchers can build on an active community for further development.
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Transcriptional repressor ZEB2 promotes terminal differentiation of CD8+ effector and memory T cell populations during infection - Omilusik, Kyla D.; Best, J. Adam; Yu, Bingfei; Goossens, Steven; Weidemann, Alexander; Nguyen, Jessica V.; Seuntjens, Eve; Stryjewska, Agata; Zweier, Christiane; Roychoudhuri, Rahul; Gattinoni, Luca; Bird, Lynne M.; et al. (Journal of Experimental Medicine, 2015)
ZEB2 is a multi-zinc-finger transcription factor known to play a significant role in early neurogenesis and in epithelial-mesenchymal transition-dependent tumor metastasis. Although the function of ZEB2 in T lymphocytes is unknown, activity of the closely related family member ZEB1 has been implicated in lymphocyte development. Here, we find that ZEB2 expression is up-regulated by activated T cells, specifically in the KLRG1(hi) effector CD8(+) T cell subset. Loss of ZEB2 expression results in a significant loss of antigen-specific CD8(+) T cells after primary and secondary infection with a severe impairment in the generation of the KLRG1(hi) effector memory cell population. We show that ZEB2, which can bind DNA at tandem, consensus E-box sites, regulates gene expression of several E-protein targets and may directly repress Il7r and Il2 in CD8(+) T cells responding to infection. Furthermore, we find that T-bet binds to highly conserved T-box sites in the Zeb2 gene and that T-bet and ZEB2 regulate similar gene expression programs in effector T cells, suggesting that T-bet acts upstream and through regulation of ZEB2. Collectively, we place ZEB2 in a larger transcriptional network that is responsible for the balance between terminal differentiation and formation of memory CD8(+) T cells.
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Transgenic Overexpression of Alanine-glyoxylate Aminotransferase 2 in Mice Lowers Asymmetric Dimethylarginine and Improves Vasomotor Function - Rodionov, Roman N.; Burdin, Dmitri; Brilloff, Silke; Todorov, Vladimir; Jarzebska, Natalia; Martens-Lobenhoffer, Jens; Hofmann, Anja; Morawietz, Henning; Hilgers, Karl Friedrich; Cordasic, Nada; Jacobi, Johannes; Maas, Renke; et al. (2017)
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Transplant Ureteral Stenosis after Renal Transplantation: Risk Factor Analysis - Apel, Hendrik; Rother, Ulrich; Wach, Sven; Schiffer, Mario; Kunath, Frank; Wullich, Bernd; Heller, Katharina M. (Urologia Internationalis, 2021)
Introduction: The results of kidney transplants have improved dramatically in recent years, leading to reduced morbidity and mortality. Despite continuous improvements, urological complications occur at a rate of 2.6%-15%. Ureteral stenosis of graft ureters is the most common complication, with a probability of 0.5%-6.3%. This study aimed to determine the incidence of ureteral stenosis after kidney transplantation and identify risk factors that distinguish transplant patients with and without ureteral stenosis. Methods: This study retrospectively analyzed patients who had undergone kidney transplantation at the Department of Urology of the Friedrich-Alexander University Erlangen-Nuremberg between 2001 and 2015. Forty-seven patients developed ureteral stenosis during the operation. Most of the ureteral stenosis cases occurred in the first 4 months after transplantation. Kaplan-Meier analysis and the log-rank test were used to calculate the cumulative risk, and the Mann-Whitney U test was used nonparametrically. The significance level was set at p < 0.05. Results: Statistical analysis showed that residual diuresis (p = 0.008), cold ischemia time (CIT) (p = 0.040), the body mass index (p = 0.027), and donor serum creatinine value (p = 0.039) showed a significantly different distribution between recipients with or without ureteral stenosis after kidney transplantation. In multivariate Cox's regression modeling, residual diuresis and the donor serum creatinine level were identified as the only independent predictors of patients' stenosis-free survival. Conclusion: Urological complications not diagnosed and treated in time endanger the success of kidney transplantation. After evaluating the kidney transplantation data of the patients at the Transplant Center Erlangen-Nuremberg from 2001 to 2015, residual diuresis, CIT, the body mass index, and donor serum creatinine value were found to influence the development of ureteral stenosis.
CRIS-Team WoS Importer:2021-12-03

Transvenous renal transplant biopsy via a transfemoral approach - Schmid, Axel; Jacobi, Johannes; Kuefner, M. A.; Lell, Michael; Wüst, Wolfgang; Mayer-Kadner, I.; Benz, Kerstin; Schmid, Matthias; Amann, Kerstin Ute; Uder, Michael (American Journal of Transplantation, 2013)
Percutaneous renal biopsy (PRB) of kidney transplants might be prevented by an elevated risk of bleeding or limited access to the allograft. In the following, we describe our initial experience with 71 transvenous renal transplant biopsies in 53 consecutive patients with unexplained reduced graft function who were considered unsuitable candidates for PRB (4.2% of all renal transplant biopsies at our institution). Biopsies were performed via the ipsilateral femoral vein with a renal biopsy set designed for transjugular renal biopsy (TJRB) of native kidneys. Positioning of the biopsy system within the transplant vein was achievable in 58 of 71 (81.7%) procedures. The specimen contained a median of 10 glomeruli (range 0-38). Tissue was considered as adequate for diagnosis in 56 of 57 (98.2%) biopsies. With respect to BANFF 50.9% of the specimen were adequate (>10 glomeruli), 47.4% marginally adequate (1-9 glomeruli) and 1.8% inadequate (no glomeruli). After implementation of real-time assessment all specimen contained glomeruli. One of the fifty-eight (1.8%) procedure-related major complications occurred (hydronephrosis requiring nephrostomy due to gross hematuria). Transfemoral renal transplant biopsy (TFRTB) is feasible and appears to be safe compared to PRB. It offers a useful new alternative for histological evaluation of graft dysfunction in selected patients with contraindications to PRB. The authors report on an experience using transvenous renal transplant biopsy to enable histological evaluation in patients unsuitable for percutaneous transplant biopsy. © 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.
CRIS-Team Scopus Importer:2023-03-08
Keywords: Kidney transplant; percutaneous renal transplant biopsy; renal allograft; renal transplant biopsy; transjugular renal biopsy; transvenous biopsy

Treatment effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in people underrepresented from the ontarget trial: Analysis of routinely collected data using trial replication methods - Baptiste, Paris J.; Wong, Angel; Schultze, Anna; Cunnington, Marianne; Mann, Johannes; Clase, Catherine; Leyrat, Clemence; Tomlinson, Laurie; Wing, Kevin (PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, 2022)
CRIS-Team WoS Importer:2022-10-28

Treatment of Anemia With Darbepoetin Prior to Dialysis Initiation and Clinical Outcomes: Analyses From the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) - Mc Causland, Finnian R.; Claggett, Brian; Burdmann, Emmanuel A.; Chertow, Glenn M.; Cooper, Mark E.; Eckardt, Kai-Uwe; Ivanovich, Peter; Levey, Andrew S.; Lewis, Eldrin F.; Mcgill, Janet B.; Mcmurray, John J. V.; Parfrey, Patrick; et al. (American Journal of Kidney Diseases, 2019)
Rationale & Objective: Evidence from clinical trials to guide patient preparation for maintenance dialysis therapy is limited. Although anemia is associated with mortality and cardiovascular (CV) disease in individuals initiating maintenance dialysis therapy, it is not known if treatment of anemia before dialysis therapy initiation with erythropoiesis-stimulating agents alters outcomes.
CRIS-Team WoS Importer:2019-03-06

TRICHODYSPLASIA SPINULOSA WITH DISFIGURING FACIAL FEATURES AFTER KIDNEY TRANSPLANTATION IMPROVED BY mTOR-INHIBITION - Dieterle, A.; Korn, Klaus; Büttner, Maike; Schiffer, Mario; Kiesewetter, Franklin; Wiesener, M. S. (TRANSPLANT INTERNATIONAL, 2019)
CRIS-Team WoS Importer:2019-10-29

Triglyceride-glucose index, low-density lipoprotein levels, and cardiovascular outcomes in chronic stable cardiovascular disease: results from the ONTARGET and TRANSCEND trials - Haring, Bernhard; Schumacher, Helmut; Mancia, Giuseppe; Teo, Koon K.; Lonn, Eva M.; Mahfoud, Felix; Schmieder, Roland; Mann, Johannes F.E.; Sliwa, Karen; Yusuf, Salim; Böhm, Michael (European Journal of Preventive Cardiology, 2024)
Aims The triglyceride-glucose index (TyG) has been proposed as an alternative to insulin resistance and as a predictor of cardiovascular outcomes. Little is known on its role in chronic stable cardiovascular disease and its predictive power at controlled low density lipoprotein (LDL) levels. ............................................................................................................................................................................................ Methods Our study population consisted of 29 960 participants in the ONTARGET and TRANSCEND trials that enrolled patients and results with known atherosclerotic disease. Triglycerides and glucose were measured at baseline. TyG was calculated as the logarithmized product of fasting triglycerides and glucose divided by 2. The primary endpoint of both trials was a composite of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure. The secondary endpoint was all-cause death and the components of the primary endpoint. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) with extensive covariate adjustment for demographic, medical history, and lifestyle factors. During a mean follow-up of 4.3 years, 4895 primary endpoints and 3571 all-cause deaths occurred. In fully adjusted models, individuals in the highest compared to the lowest quartile of the TyG index were at higher risk for the primary endpoint (HR 1.14; 95% CI 1.05–1.25) and for myocardial infarction (HR 1.30; 95% CI 1.11–1.53). A higher TyG index did not associate with the primary endpoint in individuals with LDL levels < 100 mg/dL. ............................................................................................................................................................................................ Conclusion A higher TyG index is associated with a modestly increased cardiovascular risk in chronic stable cardiovascular disease. This association is largely attenuated when LDL levels are controlled. ............................................................................................................................................................................................ Registration www.clinicaltrials.gov: NCT00153101 - Lay summary• The association of triglyceride-glucose index (TyG) with cardiovascular disease in chronic stable cardiovascular disease and its predictive power at controlled low density lipoprotein (LDL) levels is unclear. Using a study population of 29 960 participants with chronic stable cardiovascular disease, we found that higher TyG levels were associated with a modestly increased risk for incident cardiovascular events and low LDL levels largely attenuated the association of TyG with cardiovascular risk.
CRIS-Team Scopus Importer:2024-03-01
Keywords: Cardiovascular disease; Mortality; Myocardial infarction; Triglyceride-glucose index

Tuberculous granulomatous interstitial nephritis in a renal allograft - Schmidt-Lauber, Christian; Büttner-Herold, Maike; Schiffer, Mario; Wiesener, Michael S. (Kidney International, 2019)
CRIS-Team Scopus Importer:2019-10-29

Tumor hypoxia induces nuclear paraspeckle formation through HIF-2? dependent transcriptional activation of NEAT1 leading to cancer cell survival - Choudhry, H.; Albukhari, Ashwag; Morotti, M.; Haider, S.; Moralli, D.; Smythies, J.; Schoedel, J.; Green, C. M.; Camps, C.; Buffa, Francesca; Ratcliffe, Peter; Ragoussis, J.; et al. (Oncogene, 2015)
Activation of cellular transcriptional responses, mediated by hypoxia-inducible factor (HIF), is common in many types of cancer, and generally confers a poor prognosis. Known to induce many hundreds of protein-coding genes, HIF has also recently been shown to be a key regulator of the non-coding transcriptional response. Here, we show that NEAT1 long non-coding RNA (lncRNA) is a direct transcriptional target of HIF in many breast cancer cell lines and in solid tumors. Unlike previously described lncRNAs, NEAT1 is regulated principally by HIF-2 rather than by HIF-1. NEAT1 is a nuclear lncRNA that is an essential structural component of paraspeckles and the hypoxic induction of NEAT1 induces paraspeckle formation in a manner that is dependent upon both NEAT1 and on HIF-2. Paraspeckles are multifunction nuclear structures that sequester transcriptionally active proteins as well as RNA transcripts that have been subjected to adenosine-to-inosine (A-to-I) editing. We show that the nuclear retention of one such transcript, F11R (also known as junctional adhesion molecule 1, JAM1), in hypoxia is dependent upon the hypoxic increase in NEAT1, thereby conferring a novel mechanism of HIF-dependent gene regulation. Induction of NEAT1 in hypoxia also leads to accelerated cellular proliferation, improved clonogenic survival and reduced apoptosis, all of which are hallmarks of increased tumorigenesis. Furthermore, in patients with breast cancer, high tumor NEAT1 expression correlates with poor survival. Taken together, these results indicate a new role for HIF transcriptional pathways in the regulation of nuclear structure and that this contributes to the pro-tumorigenic hypoxia-phenotype in breast cancer.
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Tumor Infiltrating Inflammatory Cells as a prognostic Factor in Glioblastoma - Schnellhardt, Sören; Zorob, Alexander; Polat, B.; Lisowski, D.; Daniel, Christoph; Monoranu, C-M; Fietkau, Rainer; Distel, Luitpold (STRAHLENTHERAPIE UND ONKOLOGIE, 2021)
CRIS-Team WoS Importer:2021-07-16

Twenty-Four-Hour Pulsatile Hemodynamics Predict Brachial Blood Pressure Response to Renal Denervation in the SPYRAL HTN-OFF MED Trial - Weber, Thomas; Wassertheurer, Siegfried; Mayer, Christopher C.; Hametner, Bernhard; Danninger, Kathrin; Townsend, Raymond R.; Mahfoud, Felix; Kario, Kazuomi; Fahy, Martin; Debruin, Vanessa; Peterson, Nicole; Negoita, Manuela; et al. (Hypertension, 2022)
Background: Renal denervation (RDN) lowers blood pressure (BP), but BP response is variable in individual patients. We investigated whether measures of pulsatile hemodynamics, obtained during 24-hour ambulatory BP monitoring, predict BP drop following RDN. Methods: From the randomized, sham-controlled SPYRAL HTN-OFF MED Pivotal trial, we performed a post hoc analysis of BP waveforms from 111 RDN patients and 111 sham controls, obtained with a brachial cuff-based sphygmomanometer. Waveforms were acquired during ambulatory BP monitoring at diastolic BP level and processed with validated ARCSolver algorithms to derive hemodynamic parameters (augmentation index; augmentation pressure; backward and forward wave amplitude; estimated aortic pulse wave velocity). We investigated the relationship between averaged 24-hour values at baseline and the change in 24-hour BP at 3 months in RDN patients, corrected for observed trends in the sham group. Results: There was a consistent inverse relationship between baseline augmentation index/augmentation pressure/backward wave amplitude/forward wave amplitude/estimated aortic pulse wave velocity and BP response to RDN: the decrease in 24-hour systolic BP/diastolic BP was 7.8/5.9 (augmentation index), 8.0/6.3 (augmentation pressure), 6.7/5.4 (backward wave amplitude), 5.7/4.7 (forward wave amplitude), and 7.8/5.2 (estimated aortic pulse wave velocity) mm Hg greater for patients below versus above the respective median value (P<0.001 for all comparisons, respectively). Taking augmentation index/augmentation pressure/backward wave amplitude/forward wave amplitude/estimated aortic pulse wave velocity into account, a favorable BP response following RDN, defined as a drop in 24-hour systolic blood pressure of >= 5 mm Hg, could be predicted with an area under the curve of 0.70/0.74/0.70/0.65/0.62 (P<0.001 for all, respectively). Conclusions: These results suggest that pulsatile hemodynamics, obtained during 24-hour ambulatory BP monitoring, may predict BP response to RDN.
CRIS-Team WoS Importer:2022-06-24

Twenty-Four Month Results in Patients With Resistant Hypertension After Endovascular Ultrasound Renal Denervation in the RADIANCE-HTN TRIO Trial - Bloch, Michael; Kirtane, Ajay; Mahfoud, Felix; Azizi, Michel; Basile, Jan; Daemen, Joost; Saxena, Manish; Gosse, Philippe; Sanghvi, Kintur; Schmieder, Roland (JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-27

Two cases of carfilzomib-induced thrombotic microangiopathy successfully treated with Eculizumab in multiple myeloma - Rassner, Michael; Waesch, Ralph; Schiffer, Mario; Schneider, Johanna; Mackensen, Andreas; Engelhardt, Monika; Baur, Rebecca (BMC Nephrology, 2021)
Background Treatment with proteasome inhibitors like carfilzomib in patients with multiple myeloma (MM) can induce thrombotic microangiopathy (TMA) characterized by neurological symptoms, acute kidney injury, hemolysis and thrombocytopenia. Successful treatment with the monoclonal antibody eculizumab was described for these patients, but reports of ideal management and definitive treatment protocols are lacking. Case Presentation The first case describes a 43-years-old IgG-kappa-MM patient that developed TMA during the first course of carfilzomib-lenalidomide-dexamethasone (KRd) consolidation after autologous stem cell transplantation (ASCT). In the second case, a 59-years-old IgG-kappa-MM patient showed late-onset TMA during the fourth and last cycle of elotuzumab-KRd consolidation within the DSMM XVII study of the German study group MM (DSMM; clinicalTrials.gov Identifier: NCT03948035). Concurrently, he suffered from influenza A/B infection. Both patients had a high TMA-index for a poor prognosis of TMA. Therapeutically, in both patients plasma exchange (TPE) was initiated as soon as TMA was diagnosed. In patient #1, dialysis became necessary. For both patients, only when the complement inhibitor eculizumab was administered, kidney function and blood values impressively improved. Conclusion In this small case series, two patients with MM developed TMA due to carfilzomib treatment (CFZ-TMA), the second patient as a late-onset form. Even though TMA could have been elicited by influenza in the second patient and occurred after ASCT in both patients, with cases of TMA post-transplantation in MM being described, a relation of TMA and carfilzomib treatment was most likely. In both patients, treatment with eculizumab over two months efficiently treated TMA without recurrence and with both patients remaining responsive months after TMA onset. Taken together, we describe two cases of TMA in MM patients on carfilzomib-combination treatment, showing similar courses of this severe adverse reaction, with good responses to two months of eculizumab treatment.
CRIS-Team WoS Importer:2021-02-12

Two cases of glomerular involvement after vaccination against COVID-19: epiphenomenon or causality? - Psyllaki, Anna; Stavrakaki, Ioanna; Androvitsanea, Ariadni; Gakiopoulou, Hariklia; Petrakis, Ioannis; Stylianou, Kostas (Clinical Kidney Journal, 2021)
CRIS-Team WoS Importer:2022-03-18

Two-year outcome and risk factors for mortality in patients with coronary artery disease and renal failure: The prospective, observational CAD-REF Registry - Engelbertz, Christiane; Reinecke, Holger; Breithardt, Günter; Schmieder, Roland; Fobker, Manfred; Fischer, Dieter; Schmitz, Boris; Pinnschmidt, Hans O.; Wegscheider, Karl; Pavenstädt, Hermann; Brand, Eva (International Journal of Cardiology, 2017)
Chronic kidney disease (CKD) and coronary artery disease (CAD) are strongly associated. CAD is the most frequent cause of cardiovascular death in patients with CKD.The prospective observational nationwide multicenter Coronary Artery Disease and REnal Failure (CAD-REF) Registry enrolled 3352 patients with angiographically documented CAD classified according to their baseline estimated glomerular filtration rate (eGFR) into 5 groups according to the K/DOQI-guidelines. Patients were followed for two years. The aim of this study was the analysis of outcome and the identification of risk factors for two-year mortality in patients with both CKD and CAD.With decreasing renal function, patients had more often diabetes mellitus, hypertension, peripheral artery disease, and previous cardiovascular events and interventions. The amount of diseased vessels increased with decreasing renal function. For the whole cohort, two-year mortality was 6.5%. Kaplan-Meier-curves showed highest mortality in patients with CKD stages 4 and 5 (22.4%). In multivariate Cox-regression analyses, significant risk factors for two-year all-cause mortality were lower eGFR, current smoking, left ventricular ejection fraction, diabetes mellitus treated with oral medication or insulin, age, and peripheral artery disease. Coronary status missed the level of statistical significance as a risk factor for mortality in multivariable regression analysis. An eGFR reduction of 10ml/min/1.73m(2) increased the risk of mortality by 19% regardless of other risk factors.Two-year morbidity and mortality increased with the degree of renal impairment. To improve survival of patients with CAD and CKD, nephroprotection is urgently needed especially for patients with atherosclerotic burden.NCT00679419, http://clinicaltrials.gov/.
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Two-Year Outcomes of Patients Treated With Aliskiren Under Clinical Practice Conditions: Non-Interventional Prospective Study - Zeymer, Uwe; Dechend, Ralf; Riemer, Thomas; Deeg, Evelin; Senges, Jochen; Pittrow, David; Schmieder, Roland (Journal of Clinical Hypertension, 2016)
The authors investigated the long-term effectiveness and safety of aliskiren (ALIS) with particular attention on its association with dual blockade of the renin-angiotensin system (RAS). The open, prospective 3A Registry (N=8723) in Germany assigned patients in a 4:1:1 ratio to ALIS, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), or non-RAS drugs. Patients taking ALIS compared with those taking ACE inhibitors/ARBs or non-RAS had more comorbidities and risk factors, were taking more antihypertensive agents, and had higher blood pressure (BP) values at entry. At 2 years, BP reduction from baseline was similar in all groups (mean, -20.5/-9.9 mm Hg). A total of 2.3% of patients died, 0.5% had myocardial infarction, 0.6% had stroke, 2.9% were hospitalized, and 5.5% had any event (not significant between groups). ALIS alone or combined with another RAS inhibitor was well tolerated and effective in lowering BP in typical unselected patients with hypertension. Given the methodical limitations of the design, the study cannot be used to confirm or refute safety concerns for dual RAS blockade as suggested by the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE) trial.
EVALuna2:3893

Tyrosine Phosphorylation of CD2AP Affects Stability of the Slit Diaphragm Complex - Tossidou, Irini; Teng, Beina; Worthmann, Kirstin; Müller-Deile, Janina; Jobst-Schwan, Tilman; Kardinal, Christian; Schroder, Patricia; Bolanos-Palmieri, Patricia; Haller, Hermann; Willerding, Jonas; Drost, Dana M.; de Jonge, Laura; et al. (Journal of the American Society of Nephrology, 2019)
BACKGROUND: CD2-associated protein (CD2AP), a slit diaphragm-associated scaffolding protein involved in survival and regulation of the cytoskeleton in podocytes, is considered a "stabilizer" of the slit diaphragm complex that connects the slit diaphragm protein nephrin to the cytoskeleton of the cell. Tyrosine phosphorylation of slit diaphragm molecules can influence their surface expression, but it is unknown whether tyrosine phosphorylation events of CD2AP are also physiologically relevant to slit diaphragm stability. METHODS: We used isoelectric focusing, western blot analysis, and immunofluorescence to investigate phosphorylation of CD2AP, and phospho-CD2AP antibodies and site-directed mutagenesis to define the specific phosphorylated tyrosine residues. We used cross-species rescue experiments in Cd2apKD zebrafish and in Drosophila cindrRNAi mutants to define the physiologic relevance of CD2AP phosphorylation of the tyrosine residues. RESULTS: We found that VEGF-A stimulation can induce a tyrosine phosphorylation response in CD2AP in podocytes, and that these phosphorylation events have an important effect on slit diaphragm protein localization and functionality in vivo. We demonstrated that tyrosine in position Y10 of the SH3-1 domain of CD2AP is indispensable for CD2AP function in vivo. We found that the binding affinity of nephrin to CD2AP is significantly enhanced in the absence of Y10; however, unexpectedly, this increased affinity leads not to stabilization but to functional impairment of the glomerular filtration barrier. CONCLUSIONS: Our findings provide insight into CD2AP and its phosphorylation in the context of slit diaphragm functionality, and indicate a fine-tuned affinity balance of CD2AP and nephrin that is influenced by receptor tyrosine kinase stimulation.
CRIS-Team Scopus Importer:2019-07-26
Keywords: CD2AP; nephrin; Phosphorylation; podocyte

Ultra-long-term human salt balance studies reveal interrelations between sodium, potassium, and chloride intake and excretion - Birukov, Anna; Rakova, Natalia; Lerchl, Kathrin; Engberink, Rik H. G. Olde; Johannes, Bernd; Wabel, Peter; Moissl, Ulrich; Rauh, Manfred; Luft, Friedrich C.; Titze, Jens (American Journal of Clinical Nutrition, 2016)
BACKGROUND: The intake of sodium, chloride, and potassium is considered important to healthy nutrition and cardiovascular disease risk. Estimating the intake of these electrolytes is difficult and usually predicated on urine collections, commonly for 24 h, which are considered the gold standard. We reported on data earlier for sodium but not for potassium or chloride. OBJECTIVE: We were able to test the value of 24-h urine collections in a unique, ultra-long-term balance study conducted during a simulated trip to Mars. DESIGN: Four healthy men were observed while ingesting 12 g salt/d, 9 g salt/d, and 6 g salt/d, while their potassium intake was maintained at 4 g/d for 105 d. Six healthy men were studied while ingesting 12 g salt/d, 9 g salt/d, and 6 g salt/d, with a re-exposure of 12 g/d, while their potassium intake was maintained at 4 g/d for 205 d. Food intake and other constituents were recorded every day for each subject. All urine output was collected daily. RESULTS: Long-term urine recovery rates for all 3 electrolytes were very high. Rather than the expected constant daily excretion related to daily intake, we observed remarkable daily variation in excretion, with a 7-d infradian rhythm at a relatively constant intake. We monitored 24-h aldosterone excretion in these studies and found that aldosterone appeared to be the regulator for all 3 electrolytes. We report Bland-Altman analyses on the value of urine collections to estimate intake. CONCLUSIONS: A single 24-h urine collection cannot predict sodium, potassium, or chloride intake; thus, multiple collections are necessary. This information is important when assessing electrolyte intake in individuals.
EVALuna2:33935

Ultrasound renal denervation for hypertension resistant to a triple medication pill (RADIANCE-HTN TRIO): a randomised, multicentre, single-blind, sham-controlled trial - Azizi, Michel; Sanghvi, Kintur; Saxena, Manish; Gosse, Philippe; Reilly, John P.; Levy, Terry; Rump, Lars C.; Persu, Alexandre; Basile, Jan; Bloch, Michael J.; Daemen, Joost; Lobo, Melvin D.; et al. (Lancet, 2021)
Background Endovascular renal denervation reduces blood pressure in patients with mild-to-moderate hypertension, but its efficacy in patients with true resistant hypertension has not been shown. We aimed to assess the efficacy and safety of endovascular ultrasound renal denervation in patients with hypertension resistant to three or more antihypertensive medications.
CRIS-Team WoS Importer:2021-07-23

Under-expression of ?8 integrin aggravates experimental atherosclerosis - Menendez-Castro, Carlos; Cordasic, Nada; Neureiter, Daniel; Amann, Kerstin Ute; Marek, Ines; Volkert, Gudrun; Stintzing, Sebastian; Jahn, Angelika; Rascher, Wolfgang; Hilgers, Karl Friedrich; Hartner, Andrea (Journal of Pathology, 2015)
Integrins play an important role in vascular biology. The ?8 integrin chain attenuates smooth muscle cell migration but its functional role in the development of atherosclerosis is unclear. Therefore, we studied the contribution of ?8 integrin to atherosclerosis and vascular remodelling. We hypothesized that ?8 integrin expression is reduced in atherosclerotic lesions, and that its under-expression leads to a more severe course of atherosclerosis. ?8 Integrin was detected by immunohistochemistry and qPCR and ?8 integrin-deficient mice were used to induce two models of atherosclerotic lesions. First, ligation of the carotid artery led to medial thickening and neointima formation, which was quantified in carotid cross-sections. Second, after crossing into ApoE-deficient mice, the formation of advanced vascular lesions with atherosclerotic plaques was quantified in aortic en face preparations stained with Sudan IV. Parameters of renal physiology and histopathology were assessed: ?8 integrin was detected in the media of human and murine vascular tissue and was down-regulated in arteries with advanced atherosclerotic lesions. In ?8 integrin-deficient mice (?8(-/-) ) as well as ?8(+/-) and ?8(+/+) littermates, carotid artery ligation increased media:lumen ratios in all genotypes, with higher values in ligated ?8(-/-) and ?8(+/-) compared to ligated ?8(+/+) animals. Carotid artery ligation increased smooth muscle cell number in the media of ?8(+/+) mice and, more prominently, of ?8(-/-) or ?8(+/-) mice. On an ApoE(-/-) background, ?8(+/-) and ?8(-/-) mice developed more atherosclerotic plaques than ?8(+/+) mice. ?8 Integrin expression was reduced in ?8(+/-) animals. Renal damage with increased serum creatinine and glomerulosclerosis was detected in ?8(-/-) mice only. Thus, under-expression of ?8 integrin aggravates vascular lesions, while a complete loss of ?8 integrin results in reduced renal mass and additional renal disease in the presence of generalized atherosclerosis. Our data support the hypothesis that integrin ?8?1 has a protective role in arterial remodelling and atherosclerosis. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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UNEXPECTED FINDING IN A RENAL ALLOGRAFT BIOPSY - Schmidt-Lauber, C.; Büttner-Herold, Maike; Schiffer, Mario; Wiesener, M. S. (TRANSPLANT INTERNATIONAL, 2019)
CRIS-Team WoS Importer:2019-10-29

Update on Nephrolithiasis: Core Curriculum 2016 - Pfau, Anja; Knauf, Felix (American Journal of Kidney Diseases, 2016)
EVALuna2:3931

Update on Treatment of Hypertension After Renal Transplantation - Chatzikyrkou, Christos; Schmieder, Roland; Schiffer, Mario (Current Hypertension Reports, 2021)
Purpose of Review: To incorporate novel findings on pathophysiology and treatment of posttransplant hypertension. Recent Findings: (1) The sodium retaining effects of CNIs are mediated by stimulation of the thiazide-sensitive sodium chloride co-transporter in the distal convoluted tubule and in this regard chlorthalidone was proven to be an effective antihypertensive drug in renal transplantation. (2) Local and not systemic activation of the renin-angiotensin-aldosterone system plays a crucial role in the pathogenesis of posttransplant hypertension. (3) Recent randomized controlled trials failed to prove the presumed superiority of renin-angiotensin blockers in kidney transplantation. (4) Steroid-free and mammalian target of rapamycin-based immunosuppressive drug combinations did not show favorable effects on blood pressure control. (5) In a recent report the risk of non-melanoma skin cancer was higher with thiazide diuretics. But the increased cancer risk in transplant recipients is mainly attributed to comorbidities, such as diabetes and hypertension and of course to the transplantation condition itself or the obligatory application of immunosuppression, and has little to do with the antihypertensive medication Summary: Actual recommendations about BP targets in adult renal transplant recipients are coming from a post hoc analysis of a large randomized trial with another primary endpoint. Unless convincing studies on treatment of hypertension after renal transplantation are available, the ESC/ESH Guidelines 2018 should apply for these patients.
CRIS-Team Scopus Importer:2021-05-21
Keywords: Antihypertensive drugs; Cardiovascular disease; Guidelines; Hypertension; Kidney transplant; Thiazide diuretics

Up to a Third of Renal Transplant Recipients Have Deficiencies in Cognitive Functioning - Stößel, Lisa; Schieber, Katharina; Jank, Sabine; Reber, Sandra Therese; Grundmann, Franziska; Lüker, Christine; Vitinius, Frank; Paslakis, Georgios; Eckardt, Kai-Uwe; Erim, Yesim (Progress in Transplantation, 2017)

Ureterovesical Anastomosis Complications in Kidney Transplantation: Definition, Risk Factor Analysis, and Prediction by Quantitative Fluorescence Angiography with Indocyanine Green - Gerken, Andreas L. H.; Nowak, Kai; Meyer, Alexander; Kriegmair, Maximilian C.; Weiss, Christel; Kraemer, Bernhard K.; Glossner, Pauline; Heller, Katharina M.; Karampinis, Ioannis; Kunath, Frank; Rahbari, Nuh N.; Schwenke, Kay; et al. (Journal of Clinical Medicine, 2022)
Ureteral stenosis and urinary leakage are relevant problems after kidney transplantation. A standardized definition of ureterovesical anastomosis complications after kidney transplantation has not yet been established. This study was designed to demonstrate the predictive power of quantitative indocyanine green (ICG) fluorescence angiography. This bicentric historic cohort study, conducted between November 2015 and December 2019, included 196 kidney transplantations. The associations between quantitative perfusion parameters of near-infrared fluorescence angiography with ICG and the occurrence of different grades of ureterovesical anastomosis complications in the context of donor, recipient, periprocedural, and postoperative characteristics were evaluated. Post-transplant ureterovesical anastomosis complications occurred in 18%. Complications were defined and graded into three categories. They were associated with the time on dialysis (p = 0.0025), the type of donation (p = 0.0404), and the number of postoperative dialysis sessions (p = 0.0173). Median ICG ingress at the proximal ureteral third was 14.00 (5.00–33.00) AU in patients with and 23.50 (4.00–117.00) AU in patients without complications (p = 0.0001, cutoff: 16 AU, sensitivity 70%, specificity 70%, AUC = 0.725, p = 0.0011). The proposed definition and grading of post-transplant ureterovesical anastomosis complications is intended to enable valid comparisons between studies. ICG Fluorescence angiography allows intraoperative quantitative assessment of ureteral microperfusion during kidney transplantation and is able to predict the incidence of ureterovesical anastomosis complications. Registration number: NCT-02775838.
CRIS-Team Scopus Importer:2022-11-25
Keywords: near-infrared; NIR; perfusion assessment; renal transplantation

Urinary albumin excretion from spot urine samples predict all-cause and stroke mortality in africans - Schutte, Rudolph; Schmieder, Roland; Huisman, Hugo W.; Smith, Wayne; Van Rooyen, Johannes M.; Fourie, Carla M. T.; Kruger, Ruan; Uys, Lisa; Ware, Lisa; Mels, Catharina M. C.; Greeff, Minrie; Kruger, Iolanthe M.; et al. (American Journal of Hypertension, 2014)
Increased urinary albumin excretion reflects general vascular damage and predicts adverse cardiovascular and renal outcomes. Albuminuria can be determined from easily collected spot urine samples, especially in low-resource settings. However, no prognostic evidence exists for Africans.We followed clinical outcomes in 1,061 randomly selected non diabetic, human immunodeficiency virus (HIV)-negative Africans (mean age: 51.5 years; 62.0% women). Baseline urinary albumin-to-creatinine ratio was assessed from spot urine samples.Over a median follow-up of 4.52 years, 132 deaths occurred, of which 47 were cardiovascular related. The urinary albumin-to-creatinine ratio averaged 6.1 ?g/mg (5th to 95th percentile interval; 1.2-70.0). In multivariable-adjusted analyses, urinary albumin excretion predicted all-cause mortality (hazard ratio (HR), 1.26; 95% confidence interval (CI), 1.07-1.48; P = 0.006), and a tendency existed for cardiovascular mortality (HR, 1.26; 95% CI, 0.97-1.63; P = 0.087), which seemed to be driven by fatal stroke (HR, 1.72; 95% CI, 1.17-2.54; P = 0.006) rather than cardiac mortality (HR, 0.67; 95% CI, 0.41-1.07; P = 0.094). The predictive value remained in 528 hypertensives for both all-cause (HR, 1.38; 95% CI, 1.13-1.69; P = 0.001) and cardiovascular (HR, 1.45; 95% CI, 1.07-1.96; P = 0.017) mortality, again driven by stroke. Our findings also remained significant after we excluded participants with macroalbuminuria, those on antihypertensive treatment, as well as participants who died within 1 year after enrollment.In nondiabetic HIV-negative Africans, albuminuria predicts all-cause and stroke mortality.
EVALuna2:3675

Urine 6-Bromotryptophan: Associations with Genetic Variants and Incident End-Stage Kidney Disease - Sekula, Peggy; Tin, Adrienne; Schultheiss, Ulla T.; Baid-Agrawal, Seema; Mohney, Robert P.; Steinbrenner, Inga; Yu, Bing; Luo, Shengyuan; Boerwinkle, Eric; Eckardt, Kai-Uwe; Coresh, Josef; Grams, Morgan E.; et al. (Scientific Reports, 2020)
Higher serum 6-bromotryptophan has been associated with lower risk of chronic kidney disease (CKD) progression, implicating mechanisms beyond renal clearance. We studied genetic determinants of urine 6-bromotryptophan and its association with CKD risk factors and incident end-stage kidney disease (ESKD) in 4,843 participants of the German Chronic Kidney Disease (GCKD) study. 6-bromotryptophan was measured from urine samples using mass spectrometry. Patients with higher levels of urine 6-bromotryptophan had higher baseline estimated glomerular filtration rate (eGFR, p < 0.001). A genome-wide association study of urine 6-bromotryptophan identified two significant loci possibly related to its tubular reabsorption, SLC6A19, and its production, ERO1A, which was also associated with serum 6-bromotryptophan in an independent study. The association between urine 6-bromotryptophan and time to ESKD was assessed using Cox regression. There were 216 ESKD events after four years of follow-up. Compared with patients with undetectable levels, higher 6-bromotryptophan levels were associated with lower risk of ESKD in models unadjusted and adjusted for ESKD risk factors other than eGFR (
CRIS-Team Scopus Importer:2020-06-30

Use and preferences regarding internet-based health care delivery in patients with chronic kidney disease - Schiffer, Lena; Gertges, Raoul; Nöhre, Mariel; Schieffer, Elisabeth; Tegtbur, Uwe; Pape, Lars; de Zwaan, Martina; Schiffer, Mario (BMC Medical Informatics and Decision Making, 2021)
Background and objectives: Internet-based technologies play an increasingly important role in the management and outcome of patients with chronic kidney disease (CKD). The healthcare system is currently flooded with digital innovations and internet-based technologies as a consequence of the coronavirus disease 2019 (COVID-19) pandemic. However, information about the attitude of German CKD-patients with access to online tools towards the use of remote, internet-based interactions such as video conferencing, email, electronic medical records and apps in general and for health issues in particular, are missing. Design, setting, participants, and measurements: To address the use, habits and willingness of CKD patients in handling internet-based technologies we conducted a nationwide cross-sectional questionnaire survey in adults with CKD. Results: We used 380 questionnaires from adult CKD patients (47.6% on dialysis, 43.7% transplanted and 8.7% CKD before renal replacement therapy) for analysis. Of these 18.9% denied using the internet at all (nonusers). Nonusers were significantly older (74.4 years, SD 11.4) than users (54.5 years, SD 14.5, p < 0.001), had a lower educational level than users (≥ 12 years: 6.9% versus 47.1%, p < 0.001) and were more often on dialysis. Within the group of internet users only a minority (2.6%) was using video conferencing with their physician, only 11.7% stated that they were using email to report symptoms and 26.6% were using the internet to schedule appointments. Slightly more than one-third of internet users (35.1%) are concerned that their personal medical data are not safe when submitted via the internet. Conclusions: Within our group of German CKD-patients we found that almost one out of five patients, especially older patients and patients with a lower educational level, did not use the internet at all. The majority of internet users reported in our survey that they have not used internet-based technologies within a medical context so far, but are willing to consider it. Therefore, it seems to be important to introduce and teach motivated CKD-patients the use and benefits of simple and safe internet-based health care technologies.
CRIS-Team Scopus Importer:2021-02-12
Keywords: Chronic kidney disease (CKD); Coronavirus disease 2019 (COVID-19); eHealth; Internet-based technologies; Video conferencing

Use of an electronic medication monitoring device to estimate medication adherence in kidney transplant patients - Krause, Anna Viktoria; Bertram, Anna; Nöhre, Mariel; Bauer-Hohmann, Maximilian; Schiffer, Mario; de Zwaan, Martina (Translational Behavioral Medicine, 2021)
Electronic medication monitoring devices (EMD) have been used as a gold standard for assessing medication adherence. We used a wireless EMD (SimpleMed+), assessed its usability in patients after kidney transplantation (KTx), evaluated adherence, and analyzed concordance with other adherence measures. Fifty-five patients (53% female, mean age 46 years) at least 6 months after KTx agreed to use the EMD over a period of 8 weeks. Self-reported adherence was measured with the BAASIS, and immunosuppressant trough level variability was assessed prior to and again during the study period. Fourteen patients stopped using the EMD or were low users (<70%). These non-completers reported that using the EMD would interfere with their daily activities. Taking-adherence of the completers was high with 98.3% (±1.9) over the entire study period. Timing-adherence was somewhat lower (94.6% ± 7.9) and decreased during the second half of the study. We found statistically significant correlations between EMD results and self-reported adherence with moderate effect sizes, but no significant association with trough level variability. The low usage of the EMD supports the need to assess the practicability of an EMD before applying it in research and clinical routine. Taking- and timing-adherence of KTx patients using the EMD was satisfactory. Self-reported adherence might be a good enough estimate of medication adherence.
CRIS-Team Scopus Importer:2021-04-23
Keywords: Concordance; Electronic medication monitoring device; Kidney transplantation; Taking- and timing-adherence

Utility-Preserving Anonymization in a Real-World Scenario: Evidence from the German Chronic Kidney Disease (GCKD) Study - Pilgram, Lisa; Schäffner, Elke; Eckardt, Kai-Uwe; Prasser, Fabian (Caring is Sharing – Exploiting the Value in Data for Health and Innovation, 2023)
Data sharing provides benefits in terms of transparency and innovation. Privacy concerns in this context can be addressed by anonymization techniques. In our study, we evaluated anonymization approaches which transform structured data in a real-world scenario of a chronic kidney disease cohort study and checked for replicability of research results via 95% CI overlap in two differently anonymized datasets with different protection degrees. Calculated 95% CI overlapped in both applied anonymization approaches and visual comparison presented similar results. Thus, in our use case scenario, research results were not relevantly impacted by anonymization, which adds to the growing evidence of utility-preserving anonymization techniques.
CRIS-Team Scopus Importer:2023-06-02
Keywords: anonymization; de-identification; health data sharing; k-anonymity; privacy preserving technique

Validation of a novel predictive algorithm for kidney failure in patients suffering from chronic kidney disease: The prognostic reasoning system for chronic kidney disease (PROGRES-CKD) - Bellocchio, Francesco; Lonati, Caterina; Titapiccolo, Jasmine Ion; Nadal, Jennifer; Meiselbach, Heike; Schmid, Matthias; Baerthlein, Barbara; Tschulena, Ulrich; Schneider, Markus; Schultheiss, Ulla T.; Barbieri, Carlo; Moore, Christoph; et al. (International Journal of Environmental Research and Public Health, 2021)
Current equation-based risk stratification algorithms for kidney failure (KF) may have limited applicability in real world settings, where missing information may impede their computation for a large share of patients, hampering one from taking full advantage of the wealth of information collected in electronic health records. To overcome such limitations, we trained and validated the Prognostic Reasoning System for Chronic Kidney Disease (PROGRES-CKD), a novel algorithm predicting end-stage kidney disease (ESKD). PROGRES-CKD is a naïve Bayes classifier predicting ESKD onset within 6 and 24 months in adult, stage 3-to-5 CKD patients. PROGRES-CKD trained on 17,775 CKD patients treated in the Fresenius Medical Care (FMC) NephroCare network. The algorithm was validated in a second independent FMC cohort (n = 6760) and in the German Chronic Kidney Disease (GCKD) study cohort (n = 4058). We contrasted PROGRES-CKD accuracy against the performance of the Kidney Failure Risk Equation (KFRE). Discrimination accuracy in the validation cohorts was excellent for both short-term (stage 4–5 CKD, FMC: AUC = 0.90, 95%CI 0.88–0.91; GCKD: AUC = 0.91, 95% CI 0.86–0.97) and long-term (stage 3–5 CKD, FMC: AUC = 0.85, 95%CI 0.83–0.88; GCKD: AUC = 0.85, 95%CI 0.83–0.88) forecasting horizons. The performance of PROGRES-CKD was non-inferior to KFRE for the 24-month horizon and proved more accurate for the 6-month horizon forecast in both validation cohorts. In the real world setting captured in the FMC validation cohort, PROGRES-CKD was computable for all patients, whereas KFRE could be computed for complete cases only (i.e., 30% and 16% of the cohort in 6-and 24-month horizons). PROGRES-CKD accurately predicts KF onset among CKD patients. Contrary to equation-based scores, PROGRES-CKD extends to patients with incomplete data and allows explicit assessment of prediction robustness in case of missing values. PROGRES-CKD may efficiently assist physicians’ prognostic reasoning in real-life applications.
CRIS-Team Scopus Importer:2021-12-17
Keywords: Artificial intelligence; Chronic kidney disease (CKD); End-stage kidney disease (ESKD); Kidney replacement therapy (KRT); Machine learning; Naïve Bayes classifiers; Precision medicine; Risk prediction

Validation of semi-automated flow-mediated dilation measurement in healthy volunteers - Dobbie, Laurence J.; Mackin, Sharon T.; Hogarth, Katrina; Lonergan, Frances; Kannenkeril, Dennis; Brooksbank, Katriona; Delles, Christian (Blood Pressure Monitoring, 2020)
Background Flow-mediated dilation (FMD) is a non-invasive imaging modality used to measure endothelial function but has significant intra- and inter-observer variability. The use of semi-automated FMD devices could overcome this limitation. We assessed the reproducibility of same-day semi-automated FMD measurements by investigators who received basic training on the correct use of the device. Methods Forty-three healthy volunteers had two brachial artery FMD measurements performed 20 minutes apart using the UNEX EF 38G device, and automated outputs were produced. Images were also manually analysed using edge-detection software. The reproducibility of repeat FMD measurements within individuals was compared for automated and manual readings, and the correlation between analytical techniques was calculated. Results Twenty-five percent of scans were of non-diagnostic quality (n = 32). Automated analyses demonstrated sub-optimal reproducibility and measurement variability [intraclass correlation coefficient (ICCC) = 0.334, coefficient of variation (CV) = 45.87%]. In contrast, manually analysed scans had excellent reproducibility and low measurement variance (ICCC = 0.815, CV = 11.40%). FMD values obtained from automated and manual analysis correlated poorly (r = 0.164), whereas resting (r = 0.955) and maximal brachial artery diameters demonstrated excellent correlation (r = 0.867). Conclusion Manually evaluated serial UNEX EF readings have good reproducibility and therefore, the optimal FMD workflow involves manual analyses prior to independent automated interrogation. The high non-diagnostic scan rate is most likely the result of insufficient training and indicates that semi-automatic devices such as UNEX EF should be used by experienced investigators to achieve optimal results.
CRIS-Team Scopus Importer:2020-07-17
Keywords: cardiovascular risk; clinical research; endothelial function; flow-mediated dilation

Variability of MRI Aortic Stiffness Measurements in a Multicenter Clinical Trial Setting: Intraobserver, Interobserver, and Intracenter Variability of Pulse Wave Velocity and Aortic Strain Measurement. - Hrabak-Paar, Maja; Kircher, Achim; Sayari, Saeed Al; Kopp, Sebastien; Santini, Francesco; Schmieder, Roland; Kachenoura, Nadjia; Yates, Denise; Langenickel, Thomas; Bremerich, Jens; Heye, Tobias (Radiology: Cardiothoracic Imaging, 2020)
Purpose: To assess intraobserver, interobserver, and scan-rescan variability of MRI aortic stiffness measurements in a multicenter trial setting. Materials and Methods: This study was a retrospective analysis of prospectively collected data in a multicenter prospective clinical trial (clinicaltrials.gov ID NCT01870739). Forty-five adult patients (31 men; mean age, 58 years ± 12 [standard deviation]; 15 patients per center; three centers) with arterial hypertension underwent standardized 3-T baseline MRI assessments between June and September 2014. Aortic strain was calculated from maximum and minimum aortic area measurements repeated three times by three readers at three aortic levels on three retrospectively gated axial gradient-echo (GRE) data sets. Pulse wave velocity (PWV) was assessed three times by five readers as Δx/Δt: Δx was measured on a parasagittal GRE image of the aortic arch, and Δt was extracted from ascending and descending aortic velocity curves created on three axial phase-contrast acquisitions. Intraobserver, interobserver, and scan-rescan variability was calculated using percentage coefficient of variation (COV). Results: Aortic strain variability was lowest at the level of the distal descending aorta (DDA) with median COVs of 1.6% for intraobserver variability, 4.0% for interobserver variability, and 10.3% for scan-rescan variability. It was highest at the ascending aorta (AA) with COVs of 3.6% for intraobserver variability, 10.7% for interobserver variability, and 19.8% for scan-rescan variability. Variability of PWV was low: 0.7% for intraobserver variability, 1.5% for interobserver variability, and 8.1% for scan-rescan variability. Conclusion: Low variability can be achieved for aortic strain and PWV measurements in a multicenter trial setting using standardized MRI protocols. Although COV was lower when measuring aortic strain at DDA compared with AA, variability was acceptable at both anatomic locations.Supplemental material is available for this article.© RSNA, 2020.
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Vascular and Neurogenic Rejuvenation in Aging Mice by Modulation of ASM - Park, Min Hee; Lee, Ju Youn; Park, Kang Ho; Jung, In Kyung; Kim, Kyoung-Tae; Lee, Yong-Seok; Ryu, Hyun-Hee; Jeong, Yong; Kang, Minseok; Schwaninger, Markus; Gulbins, Erich; Reichel, Martin; et al. (Neuron, 2018)
Although many reports have revealed dysfunction of endothelial cells in aging, resulting in blood-brain barrier (BBB) breakdown, the underlying mechanism or mechanisms remain to be explored. Here, we find that acid sphingomyelinase (ASM) is a critical factor for regulating brain endothelial barrier integrity. ASM is increased in brain endothelium and/or plasma of aged humans and aged mice, leading to BBB disruption by increasing caveolae-mediated transcytosis. Genetic inhibition and endothelial-specific knockdown of ASM in mice ameliorated BBB breakdown and neurocognitive impairment during aging. Using primary mouse brain endothelial cells, we found that ASM regulated the caveolae-cytoskeleton interaction through protein phosphatase 1-mediated ezrin/radixin/moesin (ERM) dephosphorylation and apoptosis. Moreover, mice with conditional ASM overexpression in brain endothelium accelerated significant BBB impairment and neurodegenerative change. Overall, these results reveal a novel role for ASM in the control of neurovascular function in aging, suggesting that ASM may represent a new therapeutic target for anti-aging.
EVALuna2:211620

Vascular and renal hemodynamic changes after renal denervation - Ott, Christian; Janka, Rolf Matthias; Schmid, Axel; Titze, Stephanie; Ditting, Tilmann; Sobotka, Paul A.; Veelken, Roland; Uder, Michael; Schmieder, Roland (Clinical Journal of the American Society of Nephrology, 2013)
Background and objectives Renal denervation (RDN) has been shown to be effective in reducing BP in treatmentresistant hypertension. Measurement of the renal and sympathetic activity revealed a decrease in sympathetic drive to the kidney and small resistance vessels after RDN. However, the consequences on renal perfusion and renal vascular resistance (RVR), as well as central hemodynamics, are unknown. Design, setting, participants, & measurements Nineteen patients with treatment-resistant hypertension (office BP140/90mmHg, despite at least three antihypertensive drugs [including a diuretic], and diagnosis confirmed by 24-hour ambulatory BPmonitoring) underwent RDNbetween January andOctober 2011. Renal perfusion and RVR were noninvasively assessed by magnetic resonance imaging with arterial spin labeling, and renal function was assessed by estimating GFR before (day 21), after (day +1), and again after 3 months of RDN. Central hemodynamics was assessed using pulse wave analysis at day 21 and after 6 months of RDN. Results Peripheral office BP (systolic, 158±26 versus 142±23mmHg, P=0.002; diastolic, 83±13 versus 76±9mmHg, P=0.02) and mean systolic 24-hour ambulatory BP (159±17 versus 152±17 mmHg, P=0.02) were significantly reduced 6 months after RDN. Renal perfusion was not statistically different between day 21 and day +1 (256.8 [interquartile range (IQR), 241-278] versus 263.4 [IQR, 252-277] ml/min per 100 g; P=0.17) as well as after 3 months (256.8 [IQR, 241-278] versus 261.2 [IQR, 240-285] ml/min per 100 g; P=0.27) after RDN. RVR dropped (432.1 [IQR, 359-525] versus 390.6 [IQR, 338-461] AU; P=0.02), whereas renal function was not statistically different at any time point. Central systolic BP (145±31 versus 131628 mmHg; P=0.009), diastolic BP (85±18 versus 80±14 mmHg; P=0.03), and central pulse pressure (61±18 versus 52±18 mmHg; P=0.02) were significantly reduced 6 months after RDN. Central augmentation index (24±8 versus 20±8%; P=0.02) was decreased 6 months after RDN. Conclusion The data indicate that RDN significantly reduced peripheral and central BP. Despite reduced systemic BP, renal perfusion and function did not change after RDN. © 2013 by the American Society of Nephrology.
CRIS-Team Scopus Importer:2023-03-08

Vascular Calcification in Chronic Kidney Disease: The Role of Inflammation - Benz, Kerstin; Hilgers, Karl Friedrich; Daniel, Christoph; Amann, Kerstin Ute (International Journal of Nephrology, 2018)
Cardiovascular complications are extremely frequent in patients with chronic kidney disease (CKD) and death from cardiac causes is the most common cause of death in this particular population. Cardiovascular disease is approximately 3 times more frequent in patients with CKD than in other known cardiovascular risk groups and cardiovascular mortality is approximately 10-fold more frequent in patients on dialysis compared to the age- and sex-matched segments of the nonrenal population. Among other structural and functional factors advanced calcification of atherosclerotic plaques as well as of the arterial and venous media has been described as potentially relevant for this high cardiovascular morbidity and mortality. One potential explanation for this exceedingly high vascular calcification in animal models as well as in patients with CKD increased systemic and most importantly local (micro)inflammation that has been shown to favor the development of calcifying particles by multiple ways. Of note, local vascular upregulation of proinflammatory and proosteogenic molecules is already present at early stages of CKD and may thus be operative for vascular calcification. In addition, increased expression of costimulatory molecules and mast cells has also been documented in patients with CKD pointing to a more inflammatory and potentially less stable phenotype of coronary atherosclerotic plaques in CKD.
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Vascular inflammation and media calcification are already present in early stages of chronic kidney disease - Benz, Kerstin; Varga, Ildiko; Neureiter, Daniel; Campean, Valentina; Daniel, Christoph; Heim, Christian; Reimann, Albrecht; Weyand, Michael; Hilgers, Karl Friedrich; Amann, Kerstin Ute (Cardiovascular Pathology, 2017)
While patients with chronic kidney disease (CKD) have a high prevalence of classical coronary risk factors, there is increasing evidence that atherosclerosis is different in renal compared to nonrenal patients. Therefore, the present study compares changes in different vessels obtained at cardiac surgery between patients with early and advanced CKD and nonrenal control patients.Fifty patients undergoing cardiac bypass surgery were divided into three groups: (i) 24 control patients with creatinine <1.3mg/dl, (ii) 14 patients with early CKD (creatinine 1.3-2.0mg/dl), and (iii) 12 patients with advanced CKD (creatinine >2.0mg/dl). Aorta, arteria mammaria interna, and vena saphena (V. saphena) were analyzed using morphometry, Kossa stain for vascular calcification, and immunohistochemistry for markers of inflammation and proosteogenic differentiation of vascular smooth muscle cells (VSMCs). Thereby, aortic wall thickness and calcification score of aortic intima and of V. saphena were significantly higher in advanced CKD patients than in nonrenal control patients, whereas significant vascular inflammation and proosteogenic dedifferentiation of VSMC and calcification of the aortic media were already present in early CKD. Interestingly, marked calcification of the V. saphena magna was seen in advanced CKD. Of note, calcium-phosphate product correlated well with markers of inflammation, but not with calcification itself.Early stages of CKD are already associated with local up-regulation of proinflammatory and proosteogenic molecules in the vascular wall and calcification of the aortic media. These findings point to the importance of local microinflammation in CKD and may shed new light on the potentially overestimated role of the calcium-phosphate product for vessel calcification.
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VASCULAR REMODELING OF RETINAL VESSELS IN PATIENTS WITH CONGESTIVE HEART FAILURE - Jung, Susan; Kannenkeril, D.; Ott, Christian; Cifkova, R.; Harazny, J. M.; Schmieder, Roland (JOURNAL OF HYPERTENSION, 2019)
CRIS-Team WoS Importer:2019-09-20

Visit-to-visit blood pressure variability and renal outcomes: results from ONTARGET and TRANSCEND trials - Mancia, Giuseppe; Schumacher, Helmut; Böhm, Michael; Mann, Johannes; Redon, Josep; Facchetti, Rita; Schmieder, Roland; Lonn, Eva M.; Teo, Koon K.; Yusuf, Salim (Journal of Hypertension, 2020)
AIMS: There is conflicting evidence on whether in treated hypertensive patients the risk of renal outcomes is associated with visit-to-visit SBP variability. Furthermore, limited evidence is available on how important is SBP variability for prediction of renal outcomes compared with on-treatment mean SBP. We addressed these issues in 28 790 participants of the Ongoing Treatment Alone and in combination with Ramipril Global End point Trial and Telmisartan Randomized AssessmeNt Study in ACE iNtolerant Subjects with Cardiovascular Disease trials. METHODS AND RESULTS: SBP variability was expressed as the coefficient of variation of the mean with which it showed no relationship. SBP variability and mean values were obtained from five visits during the first 2 years of treatment after the end of the titration phase. Incidence of several renal outcomes (end-stage renal disease, doubling of serum creatinine, new microalbuminuria, new macroalbuminuria and their composite) was calculated from the third year of treatment onward. Patients were divided in quintiles of SBP-coefficient of variation (SBP-CV) or mean SBP, which exhibited superimposable mean blood pressure and SBP-CV values, respectively. A progressive increase of SBP-CV was not accompanied by a parallel increase in a widely adjusted (baseline and on-treatment confounders) risk of most renal outcomes (end-stage renal disease, new macroalbuminuria, new microalbuminuria and their composite) in the subsequent on-treatment years. In contrast, the adjusted risk of most renal outcomes increased progressively from the lowest to the highest quintile of on-treatment mean SBP. Progression from lowest to highest mean on-treatment SBP, but not SBP-CV, was also associated with a less frequent return to normoalbuminuria in patients with initial micro or macroalbuminuria. Renal outcome prediction was slightly improved by the combined use of SBP-CV and mean SBP quintiles. CONCLUSION: Visit-to-visit SBP variability had no major predictive value for the risk of renal outcomes, which, in contrast, was sensitively predicted by mean on-treatment SBP. A further slight increase in prediction of renal outcomes was seen by combining on-treatment mean SBP and variability.
CRIS-Team Scopus Importer:2020-09-18

Visualization of the epimysium and fascia thoracolumbalis at the lumbar spine using MRI - Adamietz, Boris; Schoenberg, Stefan O.; Reiser, Maximilian; Uder, Michael; Frank, Andreas; Strecker, Ralph; Weiss, Christel; Heiß, Rafael (Radiologe, 2021)
Background The fascia thoracolumbalis (FTL) is an important component for stabilization and motion control of the lumbar spine. It coordinates the traction forces of the autochthonous muscles of the back (AM) and connects them to the muscles of the abdominal wall, shoulder, and buttocks. Objectives The aim of our study was to describe the assessment of the normal FTL and epimysium of the AM in MRI and to identify patterns associated with pathological changes in the lumbar spine. Material and methods A total of 33 patients were retrospectively evaluated: 15 patients had no pathology at the lumbar spine; six patients had previous hemilaminectomy, three had spondylodesis, two had ventrolisthesis, and seven had scoliosis. The thickness of the FTL and EM was measured, and the adhesion of both structures was assessed. Results The fascial thickness at the levels of the lumbar vertebral bodies LVB 3 was 1.8, of LVB 4 it was 2.0, of LVB 5 it was 2.1, and at the sacral vertebra SVB 1 it was 1.8 mm. Fascial adhesions together with thickening of the EM occurred at the level of LVB 4 in 36% of the cases independently of the underlying disorder. Only thickening of the EM was seen in 48% of cases at the level of SVB 1. By contrast, adhesion of the FTL without epimysial changes occurred in 36% of cases at the level of LVB 3. Conclusion Thickening and adhesions at the EM and FTL occurred both postoperatively and in the case of scoliosis. Furthermore, lipomatous and muscular herniation could be detected in the FTL postoperatively. Epimysial and fascial alterations may be imaging manifestations of chronic myofascial back pain and should be included in radiological assessments.
CRIS-Team WoS Importer:2021-05-28

Vitamin K1 and progression of cardiovascular calcifications in hemodialysis patients: the VitaVasK randomized controlled trial - Saritas, Turgay; Reinartz, Sebastian; Krueger, Thilo; Ketteler, Markus; Liangos, Orfeas; Labriola, Laura; Stenvinkel, Peter; Kopp, Christoph; Westenfeld, Ralf; Evenepoel, Pieter; Siepmann, Robert; Wied, Stephanie; et al. (Clinical Kidney Journal, 2022)
Lay Summary Patients on chronic dialysis exhibit extensive cardiovascular calcifications and vitamin K deficiency. The vitamin K-dependent matrix Gla protein (MGP) is a potent inhibitor of vascular calcification. The multicentre, randomized, open-label, controlled VitaVasK trial showed marked attenuation of cardiovascular calcification progression in chronic haemodialysis patients treated with vitamin K1. Vitamin K1 supplementation greatly increased the serum vitamin K concentration and reduced inactive MGP levels. The treatment was safe, as no adverse advents were noted. Larger randomized controlled trials are needed to confirm vitamin K1 therapy as a safe, potent and cost-effective treatment option to reduce the progression of vascular calcification in haemodialysis patients.
CRIS-Team WoS Importer:2022-09-23

What should be the goal blood pressure in nondiabetic chronic kidney disease? - Schneider, Markus P.; Hilgers, Karl Friedrich (Current Opinion in Nephrology and Hypertension, 2014)
To summarize the available evidence on whether a lower blood pressure (BP) treatment target can ameliorate the progression of nondiabetic chronic kidney disease (CKD), and prevent cardiovascular events in CKD patients.The three prospective, randomized controlled trials which addressed the question of progression of CKD suggest that a lower BP treatment goal (<130/80 mmHg) may lead to better preservation of renal function, but only in those patients with proteinuria of more than 300 mg/day. However, the evidence is not conclusive. We are not aware of adequately powered, randomized trials that have assessed the efficacy of lower target BP levels for the prevention of cardiovascular events specifically in nondiabetic CKD patients. The available circumstantial evidence (e.g., subgroup analyses of CKD patients in cardiovascular trials) fails to reveal a clear benefit of a lower BP goal.There is currently no convincing evidence to recommend a lower than standard BP treatment target of less than 140/90 mmHg for all patients with nondiabetic CKD. A lower treatment target of less than 130/80 mmHg may delay renal disease progression but only in patients with proteinuria.
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When Mechanical Stress Matters: Generation of Polyploid Giant Cancer Cells in Tumor-Like Microcapsules - Antonelli, Yasmin; Krüger, René; Bühler, Adrian; Monavari, Mahshid; Fuentes Chandia, Miguel Angel; Colombo, Federico; Palmisano, Ralf; Boßerhoff, Anja Katrin; Kappelmann-Fenzl, Melanie; Schödel, Johannes; Boccaccini, Aldo R.; Selhuber-Unkel, Christine; et al. (Advanced Functional Materials, 2024)
Biofabrication techniques enable the performance of bioinspired three-dimensional (3D) matrices resembling primary tumors. To validate their reliability, embedded cells may express complex biophysical responses. Among others, the emergence of tumor heterogeneity and the generation of Polyploid Giant Cancer Cells (PGCC), as a result of the mechanical stress, are two of the most challenging hallmarks to resemble in vitro. Here, these phenomena are studied in cells cultured on two-dimensional (2D) flasks, in 3D spheroids, or immobilized within 3D polymer-based tumor-like microcapsules. These results show that cells cultured in 3D microcapsules exhibited an enhanced biomechanical heterogeneity, a higher number of PGCC, and an increased exertion of cell-matrix attachment forces with respect to the other two experimental conditions. Additionally, cells isolated from tumor-like microcapsules redistribute and align the cytoplasmatic protein Caveolin-1, and upregulate markers involved in cell proliferation (i.e., Ki67), metastasis (i.e., TGF-β1, TGF-β-R2), and epithelial to mesenchymal transition, to name a few. These hallmarks are barely described in the past as a result of the confinement and mechanical stress. Thus, in this work it is demonstrated that both the mechanical stress and confinement are required to stimulate cell polyploidy and biomechanical heterogeneity, which can be easily addressed by immobilizing breast cancer cells in tumor-like microcapsules.
CRIS-Team Scopus Importer:2024-02-16
Keywords: 3D cell culture; cancer biomechanics; intratumor heterogeneity; Polyploid giant cancer cells; Tumor-like microcapsules

WHEN YOUR PARTNER MAKES YOU SICK. A NEW MODEL TO INDUCE PROTEINURIA IN ZEBRAFISH USING PARABIOSIS - Müller-Deile, Janina; Schenk, Heiko; Schroder, Patricia; Schroder, Patricia; Haller, Hermann; Schiffer, Mario (2018)
EVALuna2:35235

Why in 2016 are patients with hypertension not 100% controlled? A call to action - Redon, Josep; Mourad, Jean-Jacques; Schmieder, Roland; Volpe, Massimo; Weiss, Thomas W. (Journal of Hypertension, 2016)
The objective is to consider the problem of high blood pressure (BP), a leading global risk factor, associated with substantial morbidity and mortality. Despite the availability of treatment guidelines and a wide range of therapies, BP control is suboptimal in many countries. Recent data indicate that only around 40% of patients manage to achieve an adequate level of BP control. A group of international experts in the field of hypertension met in 2008 to consider this problem. The resulting white paper delivered an urgent call to action and identified six key issues for improving BP control. In 2015, a working group of investigators spontaneously undertook an action with the primary aim of considering the current hypertension management situation in Europe, to discuss whether the situation had changed since 2008 and to determine what can be learnt from the projects in other continents, such as the Canadian Hypertension Education Program, which has shown that higher levels of BP control can be achieved across a general population. The working group identified the main challenges affecting the improvement of BP control today and suggests five key actions: identify the BP treatment target of less than 140/90 mmHg for the majority of patients, simplify treatment strategies and encourage pill reduction, decrease therapeutic inertia, improve patient empowerment, and involve healthcare systems and reduce the prevailing focus on drug costs in many healthcare systems. Implementing key actions identified by the working group may help to improve achievement of better BP control across Europe.
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Wilder's principle: pre-treatment value determines post-treatment response - Messerli, Franz H.; Bangalore, Sripal; Schmieder, Roland (European Heart Journal, 2015)
EVALuna2:3747

Will SPRINT change my practice? SPRINT: a randomised trial of intensive versus standard blood-pressure control - Ewen, Sebastian; Lobo, Melvin D.; Pathak, Atul; Schmieder, Roland; Tsioufis, Costas; Wijns, William; Mahfoud, Felix (EuroIntervention, 2016)
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