Jack F M Wetzels

Radboud University Nijmegen, Nymegen, Gelderland, Netherlands

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Publications (326)1836.79 Total impact

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    ABSTRACT: To reduce lithium-induced nephrogenic diabetes insipidus (lithium-NDI), patients with bipolar disorder are treated with thiazide and amiloride, which are thought to induce antidiuresis by a compensatory increase in prourine uptake in proximal tubules. However, thiazides induced antidiuresis and alkalinized the urine in lithium-NDI mice lacking the sodium-chloride cotransporter, suggesting that inhibition of carbonic anhydrases (CAs) confers the beneficial thiazide effect. Therefore, we tested the effect of the CA-specific blocker acetazolamide in lithium-NDI. In collecting duct (mpkCCD) cells, acetazolamide reduced the cellular lithium content and attenuated lithium-induced downregulation of aquaporin-2 through a mechanism different from that of amiloride. Treatment of lithium-NDI mice with acetazolamide or thiazide/amiloride induced similar antidiuresis and increased urine osmolality and aquaporin-2 abundance. Thiazide/amiloride-treated mice showed hyponatremia, hyperkalemia, hypercalcemia, metabolic acidosis, and increased serum lithium concentrations, adverse effects previously observed in patients but not in acetazolamide-treated mice in this study. Furthermore, acetazolamide treatment reduced inulin clearance and cortical expression of sodium/hydrogen exchanger 3 and attenuated the increased expression of urinary PGE2 observed in lithium-NDI mice. These results show that the antidiuresis with acetazolamide was partially caused by a tubular-glomerular feedback response and reduced GFR. The tubular-glomerular feedback response and/or direct effect on collecting duct principal or intercalated cells may underlie the reduced urinary PGE2 levels with acetazolamide, thereby contributing to the attenuation of lithium-NDI. In conclusion, CA activity contributes to lithium-NDI development, and acetazolamide attenuates lithium-NDI development in mice similar to thiazide/amiloride but with fewer adverse effects.
    Journal of the American Society of Nephrology 11/2015; DOI:10.1681/ASN.2015070796 · 9.34 Impact Factor
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    ABSTRACT: The bioartificial kidney (BAK) aims at improving dialysis by developing 'living membranes' for cells-aided removal of uremic metabolites. Here, unique human conditionally immortalized proximal tubule epithelial cell (ciPTEC) monolayers were cultured on biofunctionalized MicroPES (polyethersulfone) hollow fiber membranes (HFM) and functionally tested using microfluidics. Tight monolayer formation was demonstrated by abundant zonula occludens-1 (ZO-1) protein expression along the tight junctions of matured ciPTEC on HFM. A clear barrier function of the monolayer was confirmed by limited diffusion of FITC-inulin. The activity of the organic cation transporter 2 (OCT2) in ciPTEC was evaluated in real-time using a perfusion system by confocal microscopy using 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide (ASP(+)) as a fluorescent substrate. Initial ASP(+) uptake was inhibited by a cationic uremic metabolites mixture and by the histamine H2-receptor antagonist, cimetidine. In conclusion, a 'living membrane' of renal epithelial cells on MicroPES HFM with demonstrated active organic cation transport was successfully established as a first step in BAK engineering.
    Scientific Reports 11/2015; 5:16702. DOI:10.1038/srep16702 · 5.58 Impact Factor
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    ABSTRACT: Complement C5 inhibitor eculizumab treatment in atypical hemolytic uremic syndrome is effective, but associated with high costs. Complement inhibition monitoring in these patients has not been standardized. In this study we evaluated novel functional assays for application in routine follow-up. We documented that the Wieslab® complement screen assay showed a sensitivity of 1-2% of C5 activity by adding purified C5 or normal human serum to a C5 deficient serum. All the patient samples obtained during the treatment course, were completely blocked for terminal complement pathway activity for up to four weeks after the eculizumab infusion. Levels of complexes between eculizumab and C5 were inversely correlated to the complement activity (p=0.01). Moreover, titrating serum from eculizumab-treated patients into normal serum revealed that eculizumab was present in excess up to four weeks after infusion. Thus, we demonstrate sensitive, reliable and easy-performed assays which can be used to design individual eculizumab dosage regimens.
    Clinical Immunology 09/2015; 160(2):237-243. DOI:10.1016/j.clim.2015.05.018 · 3.67 Impact Factor
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    ABSTRACT: New options recently became available for treatment of uncontrolled blood pressure. Information on the prevalence of therapy-resistant hypertension (TRH) in patients with chronic kidney disease and its consequences is relevant to balance risks and benefits of potential new therapies. Data of 788 patients with chronic kidney disease came from a multicenter study investigating the effect on outcome of an integrated multifactorial approach delivered by nurse practitioners added to usual care versus usual care alone. Blood pressure was measured at the office and during 30 minutes using an automated oscillometric device. Apparent TRH (aTRH) was defined as a blood pressure ≥130/80 mm Hg despite treatment with ≥3 antihypertensive drugs, including a diuretic or treatment with ≥4 antihypertensive drugs. Participants were followed up for the occurrence of myocardial infarction, stroke or cardiovascular mortality (composite cardiovascular end point) and end-stage renal disease. aTRH was present in 34% (office blood pressure) and in 32% (automated measurements). During 5.3 years of follow-up, 17% of patients with aTRH reached a cardiovascular end point and 27% reached end-stage renal disease. aTRH lead to a 1.5-fold higher risk (95% confidence interval, 0.8-3.0) of a cardiovascular end point compared with controlled hypertensives in multivariable-adjusted analysis. aTRH increased end-stage renal disease risk 2.3-fold (95% confidence interval, 1.4-3.7). During 4 years of follow-up, the prevalence of aTRH did not decline in either treatment group. The prevalence of aTRH is high in patients with chronic kidney disease even after optimization of nephrologist care. The presence of TRH is related to a substantially increased risk of renal and cardiovascular outcomes.
    Hypertension 09/2015; 66(5). DOI:10.1161/HYPERTENSIONAHA.115.05694 · 6.48 Impact Factor
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    ABSTRACT: Dermatan sulfate (DS), also known as chondroitin sulfate (CS)-B, is a member of the linear polysaccharides called glycosaminoglycans (GAGs). The expression of CS/DS and DS proteoglycans is increased in several fibrotic renal diseases, including interstitial fibrosis, diabetic nephropathy, mesangial sclerosis and nephrosclerosis. Little, however, is known about structural alterations in DS in renal diseases. The aim of this study was to evaluate the renal expression of two different DS domains in renal transplant rejection and glomerular pathologies. DS expression was evaluated in normal renal tissue and in kidney biopsies obtained from patients with acute interstitial or vascular renal allograft rejection, patients with interstitial fibrosis and tubular atrophy (IF/TA), and from patients with focal segmental glomerulosclerosis (FSGS), membranous glomerulopathy (MGP) or systemic lupus erythematosus (SLE), using our unique specific anti-DS antibodies LKN1 and GD3A12. Expression of the 4/2,4-di-O-sulfated DS domain recognized by antibody LKN1 was decreased in the interstitium of transplant kidneys with IF/TA, which was accompanied by an increased expression of type I collagen, decorin and transforming growth factor beta (TGF-β), while its expression was increased in the interstitium in FSGS, MGP and SLE. Importantly, all patients showed glomerular LKN1 staining in contrast to the controls. Expression of the IdoA-Gal-NAc4SDS domain recognized by GD3A12 was similar in controls and patients. Our data suggest a role for the DS domain recognized by antibody LKN1 in renal diseases with early fibrosis. Further research is required to delineate the exact role of different DS domains in renal fibrosis.
    PLoS ONE 08/2015; 10(8):e0134946. DOI:10.1371/journal.pone.0134946 · 3.23 Impact Factor
  • Jacobien C Verhave · Anneke P Bech · Jack F M Wetzels · Tom Nijenhuis ·
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    ABSTRACT: Hepatocyte nuclear factor 1β (HNF1β)-associated disease is a recently recognized clinical entity with a variable multisystem phenotype. Early reports described an association between HNF1B mutations and maturity-onset diabetes of the young. These patients often presented with renal cysts and renal function decline that preceded the diabetes, hence it was initially referred to as renal cysts and diabetes syndrome. However, it is now evident that many more symptoms occur, and diabetes and renal cysts are not always present. The multisystem phenotype is probably attributable to functional promiscuity of the HNF1β transcription factor, involved in the development of the kidney, urogenital tract, pancreas, liver, brain, and parathyroid gland. Nephrologists might diagnose HNF1β-associated kidney disease in patients referred with a suspected diagnosis of autosomal dominant polycystic kidney disease, medullary cystic kidney disease, diabetic nephropathy, or CKD of unknown cause. Associated renal or extrarenal symptoms should alert the nephrologist to HNF1β-associated kidney disease. A considerable proportion of these patients display hypomagnesemia, which sometimes mimics Gitelman syndrome. Other signs include early onset diabetes, gout and hyperparathyroidism, elevated liver enzymes, and congenital anomalies of the urogenital tract. Because many cases of this disease are probably undiagnosed, this review emphasizes the clinical manifestations of HNF1β-associated disease for the nephrologist. Copyright © 2015 by the American Society of Nephrology.
    Journal of the American Society of Nephrology 08/2015; DOI:10.1681/ASN.2015050544 · 9.34 Impact Factor
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    ABSTRACT: The uremic solutes p-cresyl sulfate (pCS) and p-cresyl glucuronide (pCG) accumulate in patients with chronic kidney disease (CKD), and might contribute to disease progression. Moreover, retention of these solutes may directly be related to renal tubular function. Here, we investigated the role of the efflux transporters Multidrug Resistance Protein 4 (MRP4) and Breast Cancer Resistance Protein (BCRP) in pCS and pCG excretion, and studied the impact of both solutes on the phenotype of human conditionally immortalized renal proximal tubule epithelial cells (ciPTEC). Our results show that p-cresol metabolites accumulate during CKD, with a shift from sulfation to glucuronidation upon progression. Moreover, pCS inhibited the activity of MRP4 by 40% and BCRP by 25%, whereas pCG only reduced MRP4 activity by 75%. Moreover, BCRP-mediated transport of both solutes was demonstrated. Exposure of ciPTEC to pCG caused epithelial-to-mesenchymal transition, indicated by increased expression of vimentin and Bcl-2, and diminished E-cadherin. This was associated with altered expression of key tubular transporters. In conclusion, BCRP is likely involved in the renal excretion of both solutes, and pCG promotes phenotypical changes in ciPTEC, supporting the notion that uremic toxins may be involved in CKD progression by negatively affecting renal tubule cell phenotype and functionality.
    Toxicology in Vitro 08/2015; 29(7):1868-77. DOI:10.1016/j.tiv.2015.07.020 · 2.90 Impact Factor
  • H P E Peters · J A J van den Brand · S P Berger · J F M Wetzels ·
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    ABSTRACT: Background: There is limited evidence to support cytotoxic therapy in patients with IgA nephropathy and renal insufficiency. We studied the effect of cytotoxic therapy in patients with IgA nephropathy and renal insufficiency, and evaluated possible predictors of response. Methods: Retrospective analysis of patients with IgA nephropathy who received immunosuppressive therapy. The primary outcome measure was progression of renal disease, defined as an increase in serum creatinine levels of ≥ 50% or development of end-stage renal disease. Results: From 1996 to 2008, 19 patients with biopsy-proven IgA nephropathy were treated with cytotoxic agents and prednisone because of renal insufficiency and÷ or severe proteinuria. Characteristics of patients at the start of therapy: age 42±11 years, serum creatinine 208 (96-490) μmol÷l, estimated glomerular filtration rate (eGFR) 33 (12-65) ml÷min÷1.73 m2, and protein- creatinine ratio 3.8 (0.6-18.2) g÷10 mmol. Follow-up after initiation of therapy was 35 (7-133) months. Ten patients had progressive renal disease, whereas eGFR was stable in nine. Serum creatinine levels and proteinuria at the start of treatment were not significantly different between responders and non- responders. Proteinuria response at six months after start of therapy proved a good predictor: proteinuria decreased by ≥ 50% and÷or reached levels below 1 g÷day in 8÷9 responders. In contrast, proteinuria decreased by more than 50% and reached levels < 1 g÷day in only 3÷10 non-responders (p < 0.01). Conclusion: Prolonged immunosuppressive therapy with cytotoxic agents and prednisone may benefit a subgroup of patients with progressive IgA nephropathy. A reduction of proteinuria ≥ 50% to levels below 1 g÷day within six months predicts a favourable long-term response.
    The Netherlands Journal of Medicine 08/2015; 73(6):284-9. · 1.97 Impact Factor
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    ABSTRACT: In autosomal dominant polycystic kidney disease (ADPKD), obtaining measured total kidney volume (mTKV) by magnetic resonance (MR) imaging and manual tracing is time consuming. Two alternative MR imaging methods have recently been proposed to estimate TKV (eTKVellipsoid and eTKVPANK), which require less time. Cross-sectional and longitudinal diagnostic test study. Patients with ADPKD with a wide range of kidney function and an approved T2-weighted MR image obtained at the University Medical Centers of Groningen, Leiden, Nijmegen, and Rotterdam, the Netherlands, in 2007 to 2014. Test set for assessing reproducibility, n=10; cohort for cross-sectional analyses, n=220; and cohort for longitudinal analyses, n=48. Average times for eTKVellipsoid and eTKVPANK were 5 and 15 minutes, respectively. Bias is defined as (mTKV - eTKV)/mTKV × 100%; precision, as one standard deviation of bias. mTKV using manual tracing to calculate the area within kidney boundaries times slice thickness. Average time for mTKV was 55 minutes. In the test set, intra- and intercoefficients of variation for mTKV, eTKVellipsoid, and eTKVPANK were 1.8% and 2.3%, 3.9% and 6.3%, and 3.0% and 3.4%, respectively. In cross-sectional analysis, baseline mTKV, eTKVellipsoid, and eTKVPANK were 1.96 (IQR, 1.28-2.82), 1.93 (IQR, 1.25-2.82), and 1.81 (IQR, 1.17-2.62) L, respectively. In cross-sectional analysis, bias was 0.02% ± 3.2%, 1.4% ± 9.2%, and 4.6% ± 7.6% for repeat mTKV, eTKVellipsoid, and eTKVPANK, respectively. In longitudinal analysis, no significant differences were observed between percentage change in mTKV (16.7% ± 17.1%) and percentage change in eTKVellipsoid (19.3% ± 16.1%) and eTKVPANK (17.8% ± 16.1%) over 3 years. Results for follow-up data should be interpreted with caution because of the limited number of patients. Both methods for eTKV perform relatively well compared to mTKV and can detect change in TKV over time. Because eTKVellipsoid requires less time than eTKVPANK, we suggest that this method may be preferable in clinical care. Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.
    American Journal of Kidney Diseases 07/2015; DOI:10.1053/j.ajkd.2015.06.017 · 5.90 Impact Factor
  • M. A. G. J. ten Dam · J. F. M. Wetzels ·

    The Netherlands Journal of Medicine 07/2015; 73(1):45-45. · 1.97 Impact Factor
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    ABSTRACT: Connective tissue growth factor (CTGF; CCN2) plays a role in the development of diabetic nephropathy (DN). Urinary CTGF (uCTGF) is elevated in DN patients and has been proposed as a biomarker for disease progression, but it is unknown which pathophysiological factors contribute to elevated uCTGF. We studied renal handling of CTGF by infusion of recombinant CTGF in diabetic mice. In addition, uCTGF was measured in type 1 DN patients and compared with glomerular and tubular dysfunction and damage markers. In diabetic mice, uCTGF was increased and fractional excretion (FE) of recombinant CTGF was substantially elevated indicating reduced tubular reabsorption. FE of recombinant CTGF correlated with excretion of endogenous CTGF. CTGF mRNA was mainly localized in glomeruli and medullary tubules. Comparison of FE of endogenous and recombinant CTGF indicated that 60% of uCTGF had a direct renal source, while 40% originated from plasma CTGF. In DN patients, uCTGF was independently associated with markers of proximal and distal tubular dysfunction and damage. In conclusion, uCTGF in DN is elevated as a result of both increased local production and reduced reabsorption due to tubular dysfunction. We submit that uCTGF is a biomarker reflecting both glomerular and tubulointerstitial hallmarks of diabetic kidney disease.
    Journal of Diabetes Research 07/2015; 2015:539787. DOI:10.1155/2015/539787 · 2.16 Impact Factor
  • Anne-Els van de Logt · Julia M Hofstra · Jack F M Wetzels ·
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    ABSTRACT: Kidney International aims to inform the renal researcher and practicing nephrologists on all aspects of renal research. Clinical and basic renal research, commentaries, The Renal Consult, Nephrology sans Frontieres, minireviews, reviews, Nephrology Images, Journal Club. Published weekly online and twice a month in print.
    Kidney International 06/2015; 87(6):1263-1264. DOI:10.1038/ki.2015.34 · 8.56 Impact Factor
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    ABSTRACT: The Modification of Diet in Renal Disease (MDRD) formula is widely used in clinical practice to assess the correct drug dose. This formula is based on serum creatinine levels which might be influenced by chronic diseases itself or the effects of the chronic diseases. We conducted a systematic review to determine the validity of the MDRD formula in specific patient populations with renal impairment: elderly, hospitalized and obese patients, patients with cardiovascular disease, cancer, chronic respiratory diseases, diabetes mellitus, liver cirrhosis and human immunodeficiency virus. We searched for articles in Pubmed published from January 1999 through January 2014. Selection criteria were (1) patients with a glomerular filtration rate (GFR) < 60 ml/min (/1.73m2), (2) MDRD formula compared with a gold standard and (3) statistical analysis focused on bias, precision and/or accuracy. Data extraction was done by the first author and checked by a second author. A bias of 20% or less, a precision of 30% or less and an accuracy expressed as P30% of 80% or higher were indicators of the validity of the MDRD formula. In total we included 27 studies. The number of patients included ranged from 8 to 1831. The gold standard and measurement method used varied across the studies. For none of the specific patient populations the studies provided sufficient evidence of validity of the MDRD formula regarding the three parameters. For patients with diabetes mellitus and liver cirrhosis, hospitalized patients and elderly with moderate to severe renal impairment we concluded that the MDRD formula is not valid. Limitations of the review are the lack of considering the method of measuring serum creatinine levels and the type of gold standard used. In several specific patient populations with renal impairment the use of the MDRD formula is not valid or has uncertain validity.
    PLoS ONE 03/2015; 10(3):e0116403. DOI:10.1371/journal.pone.0116403 · 3.23 Impact Factor
  • Jack F.M. Wetzels · Nicole C.A.J. van de Kar ·

    American Journal of Kidney Diseases 02/2015; 65(2). DOI:10.1053/j.ajkd.2014.04.039 · 5.90 Impact Factor
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    ABSTRACT: Cardiovascular risk is increased in patients with chronic kidney disease (CKD). Fibroblast growth factor 23 (FGF23) has emerged as an important, independent predictor of outcome in CKD patients. High FGF23 may, however, be a reflection of renal tissue resistance to its actions, reflected by low fractional excretion of phosphate (FePi). We evaluated the modifying effect of FePi on the association between FGF23 and outcome in patients with CKD stage 3-4. An analysis was performed in a subset of 166 adult patients of two participating centers of the MASTERPLAN trial of whom urine samples at baseline were available to calculate FePi. Outcome was defined as a composite of death, renal failure (defined as need for renal replacement therapy or doubling of serum creatinine) and cardiovascular events (myocardial infarction, cerebrovascular accident, percutaneous transluminal coronary angioplasty or coronary artery bypass graft. Patients were categorized by FGF23 and FePi. A product term was added to Cox regression and RERIs were calculated. Patients had a median estimated glomerular filtration rate (eGFR) of 36 ml/min/1.73 m(2) [interquartile range (IQR) 27-44], serum phosphate 1.04 mmol/l (IQR 0.92-1.20), FGF23 140 RU/ml (IQR 81-236) and FePi 0.32 (IQR 0.25-0.44). A total of 96 events occurred during 5 years of follow up. LnFGF23 was a significant, independent predictor for the composite outcome [hazard ratio (HR) 2.13, 95 % confidence interval (CI) 1.53-2.95]. FePi did not modify the relation between FGF23 and outcome in these patients with CKD. Our study shows that FGF23 itself, but not its renal tissue resistance as reflected by FePi, is an important risk factor for clinical events in subjects with CKD stage 3-4.
    Journal of nephrology 02/2015; 28(4). DOI:10.1007/s40620-015-0178-0 · 1.45 Impact Factor
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    ABSTRACT: Since the beginning of living donor kidney transplantation, physicians have expressed concern about the possibility that unilateral nephrectomy can be harmful to a healthy individual. To investigate if the elevated intra-abdominal pressure (IAP) during laparoscopic donor nephrectomy causes early damage to the remaining kidney we evaluated urine biomarkers after laparoscopic donor nephrectomy. We measured albumin and alpha-1-microglobulin (α-1-MGB) in urine samples collected during and after open and laparoscopic donor nephrectomy and laparoscopic cholecystectomy and colectomy. Additionally, kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) were measured in urine samples collected during and after laparoscopic donor nephrectomy and colectomy. The same biomarkers were studied in patients randomly assigned to standard or low IAP during laparoscopic donor nephrectomy. We observed a peak in urinary albumin excretion during all procedures. Urine α-1-MGB rose in the post-operative period with a peak on the third postoperative day after donor nephrectomy. Urine α-1-MGB did not increase after laparoscopic cholecystectomy and colectomy. After laparoscopic nephrectomy we observed slight increases in urine KIM 1 during surgery and in urine NGAL at day 2-3 after the procedure. After laparoscopic colectomy both KIM-1, and NGAL were increased in the postoperative period. There were no differences between the high and low pressure procedure. Elevated urinary α-1-MGB suggests kidney damage after donor nephrectomy, occurring irrespective of IAP during the laparoscopic procedure. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Transplant International 01/2015; 28(5). DOI:10.1111/tri.12523 · 2.60 Impact Factor
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    ABSTRACT: Background & AimSeveral trials have demonstrated that somatostatin analogues decrease liver volume in mixed populations of patients with autosomal dominant polycystic kidney disease (ADPKD) and isolated polycystic liver disease. Chronic renal dysfunction in ADPKD may affect treatment efficacy of lanreotide and possibly enhances risk for adverse events. The aim of this open-label clinical trial (RESOLVE trial) was to assess efficacy of 6 months lanreotide treatment 120 mg subcutaneously every 4 weeks in ADPKD patients with symptomatic polycystic liver disease.Methods Primary outcome was change in liver volume after 6 months, secondary outcomes were changes in kidney volume, eGFR, symptom relief and health-related quality of life (Euro-Qol5D). We excluded patients with an estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73m2. We used the Wilcoxon signed-rank test or paired two-sided t-test to analyze within-group differences.ResultsWe included 43 ADPKD patients with polycystic liver disease (84% female, median age 50 years, mean eGFR 63 ml/min/1.73m2). Median liver volume decreased from 4,859 ml to 4,595 ml (-3.1%;p<0.001), and median kidney volume decreased from 1,023 ml to 1,012 ml (-1.7%;p=0.006). eGFR declined 3.5% after the first injection, remained stable up to study end, to decline again after lanreotide withdrawal. Lanreotide significantly relieved postprandial fullness, shortness of breath and abdominal distension. Three participants had a suspected episode of hepatic or renal cyst infection during the study.Conclusion Lanreotide reduced polycystic liver and kidney volumes and decreases symptoms in ADPKD patients. Moreover, eGFR decreased acutely after starting lanreotide, stabilized thereafter and declined again after withdrawal.This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 11/2014; 35(5). DOI:10.1111/liv.12726 · 4.85 Impact Factor
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    Jacobien C Verhave · Jack F M Wetzels · Nicole C A J van de Kar ·
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    ABSTRACT: The haemolytic uraemic syndrome (HUS) is part of a spectrum of thrombotic microangiopathies. The most common etiologies of HUS are the ones seen in childhood caused by an infection of Shiga toxin-producing Escherichia coli, HUS caused by an infection with Streptococcus pneumoniae and HUS due to abnormalities in the alternative pathway of the complement system. In the past decade, enormous progress has been made in understanding the pathogenesis in the latter group of patients. The analysis of genes that encode for complement regulatory proteins and the development of assays for measuring the activity of ADAMTS13 and the detection of antibodies against factor H contributed significantly to the diagnostic tools in patients with HUS. These assays have made it possible to clearly differentiate between thrombotic thrombocytopenic purpura and various forms of HUS. With the introduction of eculizumab, a monoclonal anti-C5 inhibitor, in the clinical arena as effective treatment of most complement-mediated forms of HUS, a new era of treatment in HUS has begun. We review the recent advances in HUS, with the focus on treatment. We discuss unsolved questions, which should be addressed in future studies.
    Nephrology Dialysis Transplantation 09/2014; 29(suppl 4):iv131-iv141. DOI:10.1093/ndt/gfu235 · 3.58 Impact Factor
  • Anneke P Bech · Julia M Hofstra · Paul E Brenchley · Jack F M Wetzels ·
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    ABSTRACT: Background: The optimal timing and duration of immunosuppressive therapy for idiopathic membranous nephropathy (iMN) have been debated. This study aimed to evaluate whether measuring the antibody against the phospholipase A2 receptor (PLA2R-ab) at start and end of therapy predicts long-term outcome and therefore may inform this debate. Design, setting, participants, & measurements: This observational study included all consecutive high-risk patients with progressive iMN observed from 1997 to 2005 and treated with oral cyclophosphamide (CP) or mycophenolate mofetil (MMF) in combination with corticosteroids for 12 months. Patients were prospectively followed, and outcome was ascertained up to 5 years after completion of immunosuppressive therapy. Serum samples were collected before and after completion of therapy. PLA2R antibodies were determined retrospectively in stored samples using ELISA. Results: In total, 48 patients (37 men) were included. The median age was 55 years (range, 34-75), and the median serum creatinine level was 1.60 mg/dl (range, 0.98-3.37 mg/dl). Twenty-two patients received MMF and 26 received CP. At baseline, PLA2R-abs were present in 34 patients (71%). Baseline characteristics and outcome did not significantly differ between patients negative or positive for PLA2R-ab. In PLA2R-ab-positive patients, treatment resulted in a rapid decrease of antibodies: median anti-PLA2R-ab, 428 U/ml (range, 41-16,260 U/ml) at baseline and 24 U/ml (range, 0-505 U/ml) after 2 months. The PLA2R-ab levels at baseline did not predict initial response, but antibody status at end of therapy predicted long-term outcome: After 5 years, 14 of 24 (58%) antibody-negative patients were in persistent remission compared with 0 of 9 (0%) antibody-positive patients (P=0.003). Conclusions: These data suggest that in PLA2R-ab-positive patients, measuring PLA2R-abs at the end of therapy predicts the subsequent course.
    Clinical Journal of the American Society of Nephrology 07/2014; 9(8). DOI:10.2215/CJN.10471013 · 4.61 Impact Factor
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    ABSTRACT: Background Activating mutations in the Transient Receptor Potential channel C6 (TRPC6) cause autosomal dominant focal segmental glomerular sclerosis (FSGS). TRPC6 expression is upregulated in renal biopsies of patients with idiopathic membranous glomerulopathy (iMN) and animal models thereof. In iMN, disease progression is characterized by glomerulosclerosis. In addition, a context-dependent TRPC6 overexpression was recently suggested in complement-mediated podocyte injury in e.g. iMN. Hence, we hypothesized that genetic variants in TRPC6 might affect susceptibility to development or progression of iMN. Methods & Results Genomic DNA was isolated from blood samples of 101 iMN patients and 292 controls. By direct sequencing of the entire TRPC6 gene, 13 single nucleotide polymorphisms (SNPs) were identified in the iMN cohort, two of which were causing an amino acid substitution (rs3802829; Pro15Ser and rs36111323, Ala404Val). No statistically significant differences in genotypes or allele frequencies between patients and controls were observed. Clinical outcome in patients was determined (remission n = 26, renal failure n = 46, persistent proteinuria n = 29, follow-up median 80 months {range 51–166}). The 13 identified SNPs showed no association with remission or renal failure. There were no differences in genotypes or allele frequencies between patients in remission and progressors. Conclusions Our data suggest that TRPC6 polymorphisms do not affect susceptibility to iMN, or clinical outcome in iMN.
    PLoS ONE 07/2014; 9(7):e102065. DOI:10.1371/journal.pone.0102065 · 3.23 Impact Factor

Publication Stats

7k Citations
1,836.79 Total Impact Points


  • 1987-2015
    • Radboud University Nijmegen
      • • Department of Nephrology
      • • Department of Physiology
      Nymegen, Gelderland, Netherlands
  • 1985-2015
    • Radboud University Medical Centre (Radboudumc)
      • Department of Human Genetics
      Nymegen, Gelderland, Netherlands
  • 2013
    • University of Zurich
      • Institute of Physiology
      Zürich, Zurich, Switzerland
    • Bridgeport Hospital
      Bridgeport, Connecticut, United States
  • 2012
    • Oxford University Hospitals NHS Trust
      • Department of Radiology
      Oxford, ENG, United Kingdom
  • 2009-2011
    • University Hospital RWTH Aachen
      • Division of Internal Medicine
      Aachen, North Rhine-Westphalia, Germany
  • 2008
    • Canisius-Wilhelmina Ziekenhuis
      Nymegen, Gelderland, Netherlands
  • 1998
    • University Hospital Essen
      Essen, North Rhine-Westphalia, Germany
  • 1992-1995
    • University of Colorado Hospital
      • Department of Medicine
      Denver, Colorado, United States
  • 1986
    • St. Joseph's Hospital
      Savannah, Georgia, United States