Gerjan Navis

University of Groningen, Groningen, Groningen, Netherlands

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Publications (486)3234.2 Total impact

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    ABSTRACT: Formerly preeclamptic women have an increased risk for developing end stage renal disease, that has been attributed to altered renal hemodynamics and abnormalities in the renin-angiotensin aldosterone system. Whether this is due to preeclampsia itself or to co-morbid conditions is unknown. Renal hemodynamics and responsiveness to angiotensin II during low sodium (7 days 50 mmol Na+/24h) and high sodium intake (HS; 7 days 200 mmol Na+/24h) were studied in 18 healthy normotensive formerly early-onset preeclamptic women (fPE-women) and 18 healthy controls (fHP-women), all selected for absence of co-morbidity. At the end of each diet, renal hemodynamics and blood pressure were measured before and during graded angiotensin II infusion. Both HS intake and former preeclampsia increased filtration fraction (FF) without an interaction between the two. FF was highest during HS in fPE-women (0.31 ± 0.12 vs fHP-women: 0.29 ± 0.11, GEE analysis BMI corrected, p=0.03). Renal response to angiotensin II infusion was not different between groups. In conclusion, fPE-women have a higher FF compared to fHP-women. As this was observed in the absence of co-morbidity, preeclampsia itself might exert long-term effects on renal hemodynamics. However, we cannot exclude the presence of pre-pregnancy alterations in renal function which in itself lead to an increased risk for preeclampsia. In experimental studies, an elevated FF has been shown to play a pathogenic role in the development of hypertension and renal damage. Future studies, however, should evaluate whether the subtle differences in renal hemodynamics after preeclampsia contribute to the increased long-term renal risk after preeclampsia. Copyright © 2014, American Journal of Physiology - Renal Physiology.
    American journal of physiology. Renal physiology 02/2015; · 3.30 Impact Factor
  • Transplantation 01/2015; 99(1):e5-e6. · 3.78 Impact Factor
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    ABSTRACT: The administration of loop diuretics to achieve decongestion is the cornerstone of therapy for acute heart failure. Unfortunately, impaired response to diuretics is common in these patients and associated with adverse outcomes. Diuretic resistance is thought to result from a complex interplay between cardiac and renal dysfunction, and specific renal adaptation and escape mechanisms, such as neurohormonal activation and the braking phenomenon. However, our understanding of diuretic response in patients with acute heart failure is still limited and a uniform definition is lacking. Three objective methods to evaluate diuretic response have been introduced, which all suggest that diuretic response should be determined based on the effect of diuretic dose administered. Several strategies have been proposed to overcome diuretic resistance, including combination therapy and ultrafiltration, but prospective studies in patients who are truly unresponsive to diuretics are lacking. An enhanced understanding of diuretic response should ultimately lead to an improved, individualized approach to treating patients with acute heart failure.
    Nature Reviews Cardiology 01/2015; · 10.40 Impact Factor
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    ABSTRACT: -The renin-angiotensin-aldosterone-system (RAAS) is critical for regulation of blood pressure and fluid balance and influences cardiovascular remodeling. Dysregulation of the RAAS contributes to cardiovascular and renal morbidity. The genetic architecture of circulating RAAS components is incompletely understood. -We meta-analyzed genome-wide association data for plasma renin activity (n=5,275), plasma renin concentrations (n=8,014) and circulating aldosterone (n=13,289) from up to four population-based cohorts of European and European-American ancestry, and assessed replication of the top results in an independent sample (n=6,487). Single nucleotide polymorphisms (SNPs) in two independent loci displayed associations with plasma renin activity at genome-wide significance (p<5x10(-8)). A third locus was close to this threshold (rs4253311 in kallikrein B [KLKB1], p=5.5x10(-8)). Two of these loci replicated in an independent sample for both plasma renin and aldosterone concentrations (SNP rs5030062 in kininogen 1 [KNG1]: p=0.001 for plasma renin, p=0.024 for plasma aldosterone concentration; rs4253311 with p<0.001 for both plasma renin and aldosterone concentration). SNPs in the NEBL gene reached genome-wide significance for plasma renin concentration in the discovery sample (top SNP rs3915911, p=8.81x10(-9)), but did not replicate (p=0.81). No locus reached genome-wide significance for aldosterone. SNPs rs5030062 and rs4253311 were not related to blood pressure or renal traits; in a companion study, variants in the kallikrein B locus were associated with B-type natriuretic peptide concentrations in African-Americans. -We identified two genetic loci (kininogen 1 and kallikrein B) influencing key components of the RAAS, consistent with the close interrelation between the kallikrein-kinin system and the RAAS.
    Circulation Cardiovascular Genetics 12/2014; · 6.73 Impact Factor
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    ABSTRACT: Background and Aims A high circulating fibroblast growth factor 23 (FGF23) level is an independent risk factor for cardiovascular mortality in renal transplant recipients and the general population. N-3 fatty acids eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) may contribute to cardiovascular risk reduction. We investigated whether fish and EPA-DHA intake are related to FGF23 levels in renal transplant recipients. Methods and results We performed a cross-sectional analysis in 619 stable renal transplant recipients (mean age 53 years, 57% male, estimated glomerular filtration rate [eGFR] 53±20 mL/min/1.73m2). Dietary intake was assessed by a 177-item food frequency questionnaire. Serum intact FGF23 was measured by ELISA. We examined differences in FGF23 levels across categories of fish and EPA-DHA intake using analysis of variance models adjusted for age, sex, dietary and lifestyle factors and key determinants of FGF23. Patients consumed on average 15 g of fish and 139 mg EPA-DHA/day. Median FGF23 was 62 pg/mL (IQR 43-98 pg/mL). Higher dietary EPA-DHA and fish intake were associated with lower serum FGF23 levels. Subgroup analyses revealed that particularly in patients with reduced renal function (eGFR <60mL/min/1.73m2), adjusted FGF23 levels (114, 79, 75 pg/mL, P=0.0001) were inversely associated with tertiles of EPA-DHA intake. Similarly, we observed an inverse association between fish consumption and serum FGF23 levels in adjusted analyses. Conclusion A higher intake of fish and dietary n-3 fatty acids (EPA-DHA) is related to lower circulating FGF23 levels in renal transplant recipients. Further research is needed to assess the causality of this association and the clinical implications.
    Nutrition Metabolism and Cardiovascular Diseases 12/2014; · 3.88 Impact Factor
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    ABSTRACT: The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.
    Nature Genetics 12/2014; · 29.65 Impact Factor
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    ABSTRACT: Please cite this article in press as: Boersema, M., CD16+ monocytes with smooth muscle cell characteristics are reduced in human renal chronic transplant dysfunction. Immunobiology (2014),
    Immunobiology 11/2014; 171(14):236. · 2.81 Impact Factor
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    ABSTRACT: Vitamin K modulates calcification by activating calcification inhibitors such as matrix Gla protein (MGP). In kidney transplant recipients, vitamin K insufficiency is common, but implications for long-term outcomes are unclear. Single-center observational study with a longitudinal design. 518 stable kidney transplant recipients; 56% men; mean age, 51±12 (SD) years; and a median of 6 (IQR, 3-12) years after kidney transplantation. Plasma desphosphorylated-uncarboxylated MGP (dp-ucMGP) levels, reflecting vitamin K status. All-cause mortality and transplant failure. At inclusion, median dp-ucMGP level was 1,038 (IQR, 733-1,536) pmol/L, with 473 (91%) patients having vitamin K insufficiency (defined as dp-ucMGP>500pmol/L). During a median follow-up of 9.8 (IQR, 8.5-10.2) years, 152 (29%) patients died and 54 (10%) developed transplant failure. Patients in the highest quartile of dp-ucMGP were at considerably higher mortality risk compared with patients in the lowest quartile (HR, 3.10; 95% CI, 1.87-5.12; P for trend<0.001; P for quartile 1 [Q1] vs Q4<0.001). After adjustment for potential confounders, including kidney function and exclusion of patients treated with a vitamin K antagonist, this association remained significant. Patients in the highest quartile also were at higher risk of developing transplant failure (HR, 2.61; 95% CI, 1.22-5.57; P for trend=0.004; P for Q1 vs Q4=0.01), but this association was lost after adjustment for baseline kidney function (HR, 1.20; 95% CI, 0.52-2.75; P for trend=0.6; P for Q1 vs Q4=0.7). Although MGP exists as various species, only dp-ucMGP was measured. No data were available for vascular calcification as an intermediate end point. Vitamin K insufficiency, that is, a high circulating level of dp-ucMGP, is highly prevalent in stable kidney transplant recipients and is associated independently with increased risk of mortality. Future studies should address whether vitamin K supplementation may lead to improved outcomes after kidney transplantation. Copyright © 2014 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.
    American Journal of Kidney Diseases 11/2014; · 5.76 Impact Factor
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    ABSTRACT: Little is known about optimal protein intake after transplantation. The aim of this study was to prospectively investigate associations of urinary urea excretion, a marker for protein intake, with graft failure and mortality in renal transplant recipients (RTR) and potential effect modification by body mass index (BMI) and estimated glomerular filtration rate (eGFR).
    Transplantation 11/2014; · 3.78 Impact Factor
  • Martin H de Borst, Gerjan Navis
    Nature Reviews Nephrology 11/2014; · 7.94 Impact Factor
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    ABSTRACT: Circulating bilirubin, a natural antioxidant, is associated with decreased risk of type 2 diabetes (T2D), but the nature of the relationship remains unknown. We performed Mendelian randomization in a prospective cohort of 3,381 participants free of diabetes at baseline (aged 28-75 years; women, 52.6%). We used rs6742078 located in UDP-glucuronosyltransferase (UGT1A1) locus as instrumental variable (IV) to study a potential causal effect of serum total bilirubin on T2D risk. A total of 210 (6.2%) participants developed T2D during a median follow-up of 7.8 years. In adjusted analyses, rs6742078, which explained 19.5% of bilirubin variation, was strongly associated with total bilirubin (a 0.68-SD increase in bilirubin levels per T allele; P<1×10(-122)) and was also associated with T2D risk (OR 0.69 [95%CI, 0.54-0.90]; P=0.006). Per 1-SD increase in log-transformed bilirubin levels, we observed a 25% (OR 0.75 [95%CI, 0.62-0.92]; P=0.004) lower risk of T2D. In Mendelian randomization analysis, the causal risk reduction for T2D was estimated to be 42% (causal ORIVestimation per 1-SD increase in log-transformed bilirubin 0.58 [95%CI, 0.39-0.84]; P=0.005), which was comparable to the observational estimate (Durbin-Wu-Hausman chi-square test Pfor difference =0.19). These novel results provide evidence that elevated bilirubin is causally associated with risk of T2D and support its role as a protective determinant.
    Diabetes 11/2014; · 7.90 Impact Factor
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    ABSTRACT: Context: Vitamin D deficiency is common in renal transplant recipients (RTR). The long-term implications of vitamin D deficiency in RTR remain unclear. Objective: We investigated whether 25(OH) or 1,25(OH)2 levels are associated with mortality, renal function decline, and graft failure in stable RTR. Design: Observational study with longitudinal design; follow-up of 7.0 [6.2-7.5] years. Setting: Single-center outpatient clinic. Participants: 435 stable RTR, 51% men, mean age 52±12 years, included at a median of 6 [3-12] years after kidney transplantation. Main Outcome Measures: All-cause mortality, annual change of renal function (eGFR), graft failure. Results: Mean 25(OH)D and 1,25(OH)2D were 21.6±9.1 ng/mL and 45.2±19.0 pg/mL, respectively. During follow-up, 99 patients died (22.8%) and 44 patients developed graft failure (10.1%). In univariate analysis, both 25(OH)D and 1,25(OH)2D were significantly associated with mortality (HR 0.64 [95%CI 0.51-0.81], P<0.001 and 0.69 [0.55-0.87], P=0.002 per SD increase, respectively). The inverse association of 25(OH)D with mortality remained significant after adjustment for potential confounders (HR 0.68 [0.52-0.89], P=0.004 per SD increase). The associations of 1,25(OH)2D with mortality and graft failure lost significance after adjustment for renal function. Severe vitamin D deficiency (25[OH]D <12 ng/mL) was independently associated with stronger annual eGFR decline . Conclusions: Low 25(OH)D is independently associated with an increased risk of all-cause mortality and 25(OH)D <12 ng/mL with a rapid eGFR decline in stable RTR. The association of low 1,25(OH)2D with mortality or graft failure depends on renal function. These results should encourage RCTs evaluating the effect of vitamin D supplementation after kidney transplantation..
    Journal of Clinical Endocrinology &amp Metabolism 10/2014; · 6.31 Impact Factor
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    ABSTRACT: Hypertension and proteinuria are important mediators of renal damage. Despite therapeutic interventions, the number of patients with end stage renal disease steadily increases. Hydrogen sulfide (H2S) is an endogenously produced gasotransmitter with vasodilatory, anti-inflammatory and antioxidant properties. These beneficial characteristics make H2S an attractive candidate for pharmacological use in hypertensive renal disease. We investigated the protective properties of H2S in angiotensin II (Ang II)-induced hypertensive renal disease in rats. Treatment with the H2S donor NaHS and major H2S metabolite sodium thiosulfate (STS) during three weeks of Ang II infusion reduced hypertension, proteinuria, oxidative stress and renal functional and structural deterioration. In an ex vivo isolated perfused kidney setup NaHS, but not STS, reduced intrarenal pressure. The effect of NaHS could partially be explained by its activation of the ATP-sensitive potassium channels. In conclusion, treatment with H2S attenuates Ang II-associated functional and structural renal deterioration, suggesting that intervention in H2S production pathways has potential therapeutic benefit and might be a valuable addition to the already existing antihypertensive and renoprotective therapies.
    Nitric Oxide. 10/2014;
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    International Journal of Behavioral Medicine 10/2014; · 2.63 Impact Factor
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    ABSTRACT: -Serelaxin is a promising therapy for acute heart failure. The renal hemodynamic effects of serelaxin in patients with chronic heart failure (CHF) are unknown.
    Circulation Heart Failure 10/2014; · 6.68 Impact Factor
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    ABSTRACT: Background Residual proteinuria during renin-angiotensin-aldosterone system (RAAS) blockade is a major renal and cardiovascular risk factor in chronic kidney disease. Dietary sodium restriction potentiates the antiproteinuric effect of RAAS blockade, but residual proteinuria remains in many patients. Previous studies linked high fibroblast growth factor 23 (FGF-23) levels with volume overload; others linked higher serum phosphate levels with impaired RAAS-blockade efficacy. We hypothesized that FGF-23 reduces the capacity of dietary sodium restriction to potentiate RAAS blockade, impairing the antiproteinuric effect. Study Design Post hoc analysis of cohort data from a randomized crossover trial with two 6-week study periods comparing proteinuria after a regular-sodium diet with proteinuria after a low-sodium diet, both during background angiotensin-converting enzyme inhibition. Setting & Participants 47 nondiabetic patients with CKD with residual proteinuria (median protein excretion, 1.9 [IQR, 0.8-3.1] g/d; mean age, 50 ± 13 [SD] years; creatinine clearance, 69 [IQR, 50-110] mL/min). Predictor Plasma carboxy-terminal FGF-23 levels. Outcomes Difference in residual proteinuria at the end of the regular-sodium versus low-sodium study period. Residual proteinuria during the low-sodium diet period adjusted for proteinuria during the regular-sodium diet period. Results Higher baseline FGF-23 level was associated with reduced antiproteinuric response to dietary sodium restriction (standardized β = −0.46; P = 0.001; model R2 = 0.71). For every 100-RU/mL increase in FGF-23 level, the antiproteinuric response to dietary sodium restriction was reduced by 10.6%. Higher baseline FGF-23 level was a determinant of more residual proteinuria during the low-sodium diet (standardized β = 0.27; P = 0.003) in linear regression analysis adjusted for baseline proteinuria (model R2 = 0.71). There was no interaction with creatinine clearance (P interaction = 0.5). Baseline FGF-23 level did not predict changes in systolic or diastolic blood pressure upon intensified antiproteinuric treatment. Limitations Observational study, limited sample size. Conclusions FGF-23 levels are associated independently with impaired antiproteinuric response to sodium restriction in addition to RAAS blockade. Future studies should address whether FGF-23−lowering strategies may further optimize proteinuria reduction by RAAS blockade combined with dietary sodium restriction.
    American Journal of Kidney Diseases 09/2014; · 5.76 Impact Factor
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    Jelmer K Humalda, Gerjan Navis
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    ABSTRACT: Restriction of dietary sodium is recommended at a population level as well as for groups at high cardiovascular risk, and chronic kidney disease (CKD). This review addresses recent evidence for the protective effect of dietary sodium restriction in CKD patients specifically.
    Current opinion in nephrology and hypertension. 09/2014;
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    ABSTRACT: Collagen type XV and XVIII are proteoglycans found in the basement membrane zones of endothelial and epithelial cells, and known for their cryptic anti-angiogenic domains named restin and endostatin, respectively. Mutations or deletions of these collagens are associated with eye, muscle and microvessel phenotypes. We now describe a novel role for these collagens, namely a supportive role in leukocyte recruitment. We subjected mice deficient in collagen XV or collagen XVIII, and their compound mutant, as well as the wild-type control mice to bilateral renal ischemia/reperfusion, and evaluated renal function, tubular injury, and neutrophil and macrophage influx at different time points after ischemia/reperfusion. Five days after ischemia/reperfusion, the collagen XV, collagen XVIII and the compound mutant mice showed diminished serum urea levels compared to wild-type mice (all p<0.05). Histology showed reduced tubular damage, and decreased inflammatory cell influx in all mutant mice, which were more pronounced in the compound mutant despite increased expression of MCP-1 and TNF-α in double mutant mice compared to wildtype mice. Both type XV and type XVIII collagen bear glycosaminoglycan side chains and an in vitro approach with recombinant collagen XVIII fragments with variable glycanation indicated a role for these side chains in leukocyte migration. Thus, basement membrane zone collagen/proteoglycan hybrids facilitate leukocyte influx and tubular damage after renal ischemia/reperfusion and might be potential intervention targets for the reduction of inflammation in this condition.
    PLoS ONE 09/2014; 9(9):e106732. · 3.53 Impact Factor
    This article is viewable in ResearchGate's enriched format
  • Grigory Sidorenkov, Gerjan Navis
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    ABSTRACT: Introduction: ACE inhibitors are first-line therapy in patients with chronic kidney disease (CKD). The main adverse effects of ACE inhibitors are hypotension, renal function impairment and hyperkalemia. Areas covered: This paper reviews evidence from clinical studies regarding adverse effects of ACE inhibitors in patients with CKD. The safety aspects of ACE inhibitors are discussed in relation to their pharmacological action, drug-drug interactions, drug-diet interaction, precautions needed in certain clinical conditions and other adverse effects. Expert opinion: The main adverse effects of ACE inhibitors follow from their interaction with renin-angiotensin-aldosterone system (RAAS)-activity and volume depletion. This interaction can be turned into clinical benefit and increase efficacy of ACE inhibitors by reduction in dietary sodium or adding diuretics. Dual RAAS-blockade is no longer advocated in patients with CKD because of the safety issues, and combination of ACE inhibitors with moderate reduction in dietary sodium intake is a better alternative. The intensified treatment regimens based on ACE inhibitors can potentially improve renoprotection, but increase the risk of adverse effects. Better strategies to address safety concerns are needed. Introduction of clinical rules and safety indicators may help clinicians to identify hazardous co-prescriptions and adverse dietary habits and can decrease the frequency of adverse effects.
    Expert Opinion on Drug Safety 08/2014; · 2.74 Impact Factor
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    ABSTRACT: Syndecan-1 is a transmembrane heparan sulfate (HS) proteoglycan present on hepatocytes and involved in uptake of triglyceride-rich lipoproteins via its HS polysaccharide side chains. We hypothesized that altered hepatic syndecan-1 metabolism could be involved in dyslipidemia related to renal transplantation. In a rat renal transplantation model elevated plasma triglycerides were associated with fivefold increased expression of hepatic syndecan-1 mRNA (p < 0.01), but not protein. Expression of syndecan-1 sheddases (ADAM17, MMP9) and heparanase was significantly up-regulated after renal transplantation (all p < 0.05). Profiling of HS side chains revealed loss of hepatic HS upon renal transplantation accompanied by significant decreased functional capacity for VLDL binding (p = 0.02). In a human renal transplantation cohort (n = 510), plasma levels of shed syndecan-1 were measured. Multivariate analysis showed plasma syndecan-1 to be independently associated with triglycerides (p < 0.0001) and inversely with HDL cholesterol (p < 0.0001). Last, we show a physical association of syndecan-1 to HDL from renal transplant recipients (RTRs), but not to HDL from healthy controls. Our data suggest that after renal transplantation loss of hepatic HS together with increased syndecan-1 shedding hampers lipoprotein binding and uptake by the liver contributing to dyslipidemia. Our data open perspectives toward improvement of lipid profiles by targeted inhibition of syndecan-1 catabolism in renal transplantation.
    American Journal of Transplantation 08/2014; · 6.19 Impact Factor

Publication Stats

9k Citations
3,234.20 Total Impact Points


  • 1994–2015
    • University of Groningen
      • • Department of Nephrology
      • • Department of Cardiology
      • • Department of Internal Medicine
      Groningen, Groningen, Netherlands
  • 1984–2014
    • Universitair Medisch Centrum Groningen
      • • Department of Internal Medicine
      • • Department of Cardiology
      Groningen, Groningen, Netherlands
  • 2013
    • The Jackson Laboratory
      Bar Harbor, Maine, United States
    • Uppsala University
      Uppsala, Uppsala, Sweden
  • 2012
    • University of Rochester
      • Department of Pathology and Laboratory Medicine
      Rochester, NY, United States
    • VU University Medical Center
      • Department of Molecular Cell Biology and Immunology
      Amsterdam, North Holland, Netherlands
  • 2011
    • Medizinische Universität Innsbruck
      • Sektion für Genetische Epidemiologie
      Innsbruck, Tyrol, Austria
  • 2010
    • University of California, San Diego
      • Department of Medicine
      San Diego, CA, United States
    • University of Amsterdam
      • Faculty of Medicine AMC
      Amsterdam, North Holland, Netherlands
  • 2005
    • Charité Universitätsmedizin Berlin
      • Institute of Clinical Pharmacology and Toxicology
      Berlin, Land Berlin, Germany
  • 1996–2004
    • Mahatma Gandhi Kashi Vidyapith, Varanasi
      Varangaon, Mahārāshtra, India
  • 1996–2002
    • The Ohio State University
      • • Division of Nephrology
      • • Department of Internal Medicine
      • • Division of Hospital Medicine
      Columbus, OH, United States