Publications by authors named "Jack F M Wetzels"

208 Publications

Functional tests to guide management in an adult with loss of function of type-1 angiotensin II receptor.

Pediatr Nephrol 2021 Mar 25. Epub 2021 Mar 25.

Department of Internal Medicine, Radboud University Medical Centre, Huispost 463, Geert Grooteplein 8, 6525, GA, Nijmegen, the Netherlands.

Background: Genetic loss of function of AGT (angiotensinogen), REN (renin), ACE (angiotensin-converting enzyme), or AGTR1 (type-1 angiotensin II receptor) leads to renal tubular dysgenesis (RTD). This syndrome is almost invariably lethal. Most surviving patients reach stage 5 chronic kidney disease at a young age.

Methods: Here, we report a 28-year-old male with a homozygous truncating mutation in AGTR1 (p.Arg216*), who survived the perinatal period with a mildly impaired kidney function. In contrast to classic RTD, kidney biopsy showed proximal tubules that were mostly normal. During the subsequent three decades, we observed evidence of both tubular dysfunction (hyperkalemia, metabolic acidosis, salt-wasting and a urinary concentrating defect) and glomerular dysfunction (reduced glomerular filtration rate, currently ~30 mL/min/1.73 m, accompanied by proteinuria). To investigate the recurrent and severe hyperkalemia, we performed a patient-tailored functional test and showed that high doses of fludrocortisone induced renal potassium excretion by 155%. Furthermore, fludrocortisone lowered renal sodium excretion by 39%, which would have a mitigating effect on salt-wasting. In addition, urinary pH decreased in response to fludrocortisone. Opposite effects on urinary potassium and pH occurred with administration of amiloride, further supporting the notion that a collecting duct is present and able to react to fludrocortisone.

Conclusions: This report provides living proof that even truncating loss-of-function mutations in AGTR1 are compatible with life and relatively good GFR and provides evidence for the prescription of fludrocortisone to treat hyperkalemia and salt-wasting in such patients.
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http://dx.doi.org/10.1007/s00467-021-05018-7DOI Listing
March 2021

Low plasma magnesium concentration and future abdominal aortic calcifications in moderate chronic kidney disease.

BMC Nephrol 2021 Feb 25;22(1):71. Epub 2021 Feb 25.

Department of Nephrology, Radboud Institute for Health Sciences, Radboud University Medical Center, PO box 9101, 6500, HB, Nijmegen, The Netherlands.

Background: Higher plasma magnesium concentrations are associated with reduced cardiovascular disease risk in chronic kidney disease (CKD) patients. The importance of plasma magnesium concentration for vascular calcification in earlier stages of CKD remains underexplored. This study investigated whether plasma magnesium is a determinant for the presence and severity of vascular calcification in moderate CKD.

Methods: Retrospective analysis was performed using abdominal aortic calcification (AAC) scores in 280 patients with stage 3 and 4 CKD enrolled in the MASTERPLAN trial. Lateral abdominal X-ray was used to evaluate AAC. Plasma magnesium concentration were measured over time. A zero-inflated Poisson model determined the association between plasma magnesium concentration and AAC.

Results: 79 out of 280 patients did not have AAC, and in patients with AAC the median calcification score was 3.5 (interquartile range: 0.0-8.6). The mean plasma magnesium concentration was 0.76 ± 0.10 mmol/L at baseline. A 0.1 mmol/L higher plasma magnesium concentration was associated with lower AAC of 0.07 point (95% CI -0.28 - 0.14). A 0.1 mmol/L higher plasma magnesium lowered the odds of detecting any AAC by 30% (OR = 0.63; 95% CI 0.29-1.37). After 1 year and 4 years (at time of X-ray) of follow-up this association was attenuated (OR = 0.93; 95% CI 0.61-1.43 and 0.93; 95% CI 0.60-1.45, respectively). None of these associations reached statistical significance.

Conclusions: Plasma magnesium concentration at baseline is not associated with the risk for future AAC. Interventions increasing magnesium to avoid vascular calcification may have greatest potential in early CKD stages prior to onset of vascular calcification.
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http://dx.doi.org/10.1186/s12882-021-02267-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905862PMC
February 2021

Case Report: Variable Pharmacokinetic Profile of Eculizumab in an aHUS Patient.

Front Immunol 2020 15;11:612706. Epub 2021 Jan 15.

Department of Pediatric Nephrology, Radboud Institute for Molecular Life Sciences, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, Netherlands.

Background: With the introduction of eculizumab, a C5-inhibitor, morbidity and mortality improved significantly for patients with atypical hemolytic uremic syndrome (aHUS). In view of the high costs, actual needs of the drug, and increasing evidence in literature, aHUS patients can be treated according to a restrictive eculizumab regimen. We retrospectively analyzed the pharmacokinetic and dynamic parameters of eculizumab in one patient in time, emphasizing various factors which could be taken into account during tapering of treatment.

Case Presentation: A nowadays 18-year-old male with a severe, frequently relapsing form of atypical HUS due to a hybrid CFH/CFHR1 gene in combination with the homozygous factor H haplotype, required chronic plasma therapy (PT), including periods with plasma infusion, from the age of onset at 5 months until initiation of eculizumab at the age of 11 years. A mild but stable chronic kidney disease (CKD) and 9 years of disease remission enabled prolongation of eculizumab interval. At the age of 15 years, a sudden yet multifactorial progression of chronic kidney disease (CKD) was observed, without any signs of disease recurrence. However, an acquired glomerulocystic disease, a reduced left kidney function, and abnormal abdominal venous system of unknown etiology were found. In addition, after an aHUS relapse, an unexpected increase in intra-patient variability of eculizumab concentrations was seen. Retrospective pharmacokinetic analysis revealed a change in eculizumab clearance, associated with a simultaneous increase in proteinuria.

Conclusion: High intra-patient variability of eculizumab pharmacokinetics were observed over time, emphasizing the necessity for adequate and continuous therapeutic drug monitoring in aHUS patients. Eculizumab serum trough levels together with complement activation markers (CH50) should be frequently assessed, especially during tapering of drug therapy and/or changing clinical conditions in the patient. In addition, an increase in proteinuria could result in urinary eculizumab loss, indicating that urinary monitoring of eculizumab may be important in aHUS patients with an unexplained decline in serum concentrations.
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http://dx.doi.org/10.3389/fimmu.2020.612706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843372PMC
January 2021

Novel in vitro assays to detect circulating permeability factor(s) in idiopathic focal segmental glomerulosclerosis.

Nephrol Dial Transplant 2021 01;36(2):247-256

Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

Background: Many patients with idiopathic focal segmental glomerulosclerosis (FSGS) develop recurrence of proteinuria after kidney transplantation (TX). Although several circulating permeability factors (CPFs) responsible for recurrence have been suggested, there is no consensus. To facilitate CPF identification and predict recurrence after TX, there is a need for robust methods that demonstrate the presence of CPFs.

Methods: Cultured human podocytes (hPods) and human and mouse glomerular endothelial cells (ciGEnC, mGEnC) were exposed to plasmas of FSGS patients with presumed CPFs, and of (disease) controls. A visual scoring assay and flow cytometry analysis of side scatter were used to measured changes in cellular granularity after exposure to plasma.

Results: Nine out of 13 active disease plasmas of 10 FSGS patients with presumed CPFs induced granularity in hPod in a dose- and time-dependent manner. Corresponding remission plasmas induced no or less granularity in hPod. Similar results were obtained with ciGEnC and mGEnC, although induced granularity was less compared with hPod. Notably, foetal calf serum, healthy plasma and a remission plasma partially blocked FSGS plasma-induced hPod granularity.

Conclusions: We developed a novel assay in which active disease, presumably CPF-containing, FSGS plasmas induced granularity in cultured hPod. Our results may indicate the presence of CPF inhibitor(s) in healthy and remission plasma. We suggest the presence of a delicate balance between CPF and a CPF inhibitory factor, which is disturbed in patients with active disease. Our novel assays can be applied in future research to identify CPF and CPF inhibitors, and possibly to predict recurrence after TX.
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http://dx.doi.org/10.1093/ndt/gfaa211DOI Listing
January 2021

Author's Reply to Liu et al.: "Pharmacology, Pharmacokinetics and Pharmacodynamics of Eculizumab, and Possibilities for an Individualized Approach to Eculizumab".

Clin Pharmacokinet 2020 12 28;59(12):1645-1646. Epub 2020 Oct 28.

Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands.

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http://dx.doi.org/10.1007/s40262-020-00952-5DOI Listing
December 2020

Prognostic models for chronic kidney disease: a systematic review and external validation.

Nephrol Dial Transplant 2020 Oct 14. Epub 2020 Oct 14.

Department of Nephrology, Radboud Institute of Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

Background: Accurate risk prediction is needed in order to provide personalized healthcare for chronic kidney disease (CKD) patients. An overload of prognosis studies is being published, ranging from individual biomarker studies to full prediction studies. We aim to systematically appraise published prognosis studies investigating multiple biomarkers and their role in risk predictions. Our primary objective was to investigate if the prognostic models that are reported in the literature were of sufficient quality and to externally validate them.

Methods: We undertook a systematic review and appraised the quality of studies reporting multivariable prognosis models for end-stage renal disease (ESRD), cardiovascular (CV) events and mortality in CKD patients. We subsequently externally validated these models in a randomized trial that included patients from a broad CKD population.

Results: We identified 91 papers describing 36 multivariable models for prognosis of ESRD, 50 for CV events, 46 for mortality and 17 for a composite outcome. Most studies were deemed of moderate quality. Moreover, they often adopted different definitions for the primary outcome and rarely reported full model equations (21% of the included studies). External validation was performed in the Multifactorial Approach and Superior Treatment Efficacy in Renal Patients with the Aid of Nurse Practitioners trial (n = 788, with 160 events for ESRD, 79 for CV and 102 for mortality). The 24 models that reported full model equations showed a great variability in their performance, although calibration remained fairly adequate for most models, except when predicting mortality (calibration slope >1.5).

Conclusions: This review shows that there is an abundance of multivariable prognosis models for the CKD population. Most studies were considered of moderate quality, and they were reported and analysed in such a manner that their results cannot directly be used in follow-up research or in clinical practice.
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http://dx.doi.org/10.1093/ndt/gfaa155DOI Listing
October 2020

Treatment-resistant nephrotic syndrome in dense deposit disease: complement-mediated glomerular capillary wall injury?

Pediatr Nephrol 2020 09 23;35(9):1791-1795. Epub 2020 May 23.

Department of Nephrology, Radboud University Medical Center, PO BOX 9101, 6500 HB, Nijmegen, Netherlands.

Background: The C3 glomerulopathies (C3G) are recently defined glomerular diseases, attributed to abnormal complement regulation. Dense deposit disease (DDD) is part of the spectrum of C3G, characterized by electron-dense deposits in the lamina densa of the glomerular basement membrane. Patients with DDD present with hematuria, variable degrees of proteinuria, and kidney dysfunction. Kidney biopsies typically disclose proliferative and inflammatory patterns of injury. Treatment with glucocorticoids and mycophenolate mofetil has been shown to achieve remission of proteinuria in a significant proportion of C3G patients.

Case-diagnosis/treatment: We report two patients with persistent nephrotic syndrome while on immunosuppressive therapy. Repeat kidney biopsies disclosed massive C3 deposits with foot process effacement in the absence of proliferative or inflammatory lesions on light microscopy.

Conclusion: These cases, coupled with data from animal models of disease and the variable response to eculizumab in C3G patients, illustrate that two different pathways might be involved in the development of kidney injury in C3G: a C5-independent pathway leading to glomerular capillary wall injury and the development of proteinuria versus a C5-dependent pathway that causes proliferative glomerulonephritis and kidney dysfunction.
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http://dx.doi.org/10.1007/s00467-020-04600-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384995PMC
September 2020

Inhibition of mTOR delayed but could not prevent experimental collapsing focal segmental glomerulosclerosis.

Sci Rep 2020 05 22;10(1):8580. Epub 2020 May 22.

Department of pathology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands.

Anti-Thy1.1 transgenic mice develop glomerular lesions that mimic collapsing focal segmental glomerulosclerosis (FSGS) in humans with collapse of the glomerular tuft and marked hyperplasia of the parietal epithelial cells (PECs). Immunostaining of phosphor-S6 ribosomal protein (pS6RP) revealed high mTOR activity in PECs of the FSGS lesions of these mice. In this study we questioned whether the mTOR inhibitor rapamycin (sirolimus) could attenuate the development and progression of glomerulosclerotic lesions in the anti-Thy1.1 transgenic mice. We observed reduced mTOR signalling and proliferation in human parietal epithelial cells after rapamycin treatment. Experiments with anti-Thy1.1. mice showed that early treatment with sirolimus reduced the development of glomerular lesions and glomerular cell proliferation at day 4. Levels of albuminuria, podocyte injury and podocyte number were similar in the sirolimus and vehicle treated groups. The initial beneficial effects of sirolimus treatment were not observed at day 7. Late sirolimus treatment did not reduce albuminuria or the progression of glomerulosclerosis. Taken together, rapamycin attenuated PEC proliferation and the formation of early FSGS lesions in experimental FSGS and reduced human PEC proliferation in vitro. However, the initial inhibition of PEC proliferation did not translate into a decline of albuminuria nor in a sustained reduction in sclerotic lesions.
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http://dx.doi.org/10.1038/s41598-020-65352-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244565PMC
May 2020

The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis.

Authors:
Jingyuan Xie Lili Liu Nikol Mladkova Yifu Li Hong Ren Weiming Wang Zhao Cui Li Lin Xiaofan Hu Xialian Yu Jing Xu Gang Liu Yasar Caliskan Carlo Sidore Olivia Balderes Raphael J Rosen Monica Bodria Francesca Zanoni Jun Y Zhang Priya Krithivasan Karla Mehl Maddalena Marasa Atlas Khan Fatih Ozay Pietro A Canetta Andrew S Bomback Gerald B Appel Simone Sanna-Cherchi Matthew G Sampson Laura H Mariani Agnieszka Perkowska-Ptasinska Magdalena Durlik Krzysztof Mucha Barbara Moszczuk Bartosz Foroncewicz Leszek Pączek Ireneusz Habura Elisabet Ars Jose Ballarin Laila-Yasmin Mani Bruno Vogt Savas Ozturk Abdülmecit Yildiz Nurhan Seyahi Hakki Arikan Mehmet Koc Taner Basturk Gonca Karahan Sebahat Usta Akgul Mehmet Sukru Sever Dan Zhang Domenico Santoro Mario Bonomini Francesco Londrino Loreto Gesualdo Jana Reiterova Vladimir Tesar Claudia Izzi Silvana Savoldi Donatella Spotti Carmelita Marcantoni Piergiorgio Messa Marco Galliani Dario Roccatello Simona Granata Gianluigi Zaza Francesca Lugani GianMarco Ghiggeri Isabella Pisani Landino Allegri Ben Sprangers Jin-Ho Park BeLong Cho Yon Su Kim Dong Ki Kim Hitoshi Suzuki Antonio Amoroso Daniel C Cattran Fernando C Fervenza Antonello Pani Patrick Hamilton Shelly Harris Sanjana Gupta Chris Cheshire Stephanie Dufek Naomi Issler Ruth J Pepper John Connolly Stephen Powis Detlef Bockenhauer Horia C Stanescu Neil Ashman Ruth J F Loos Eimear E Kenny Matthias Wuttke Kai-Uwe Eckardt Anna Köttgen Julia M Hofstra Marieke J H Coenen Lambertus A Kiemeney Shreeram Akilesh Matthias Kretzler Lawrence H Beck Benedicte Stengel Hanna Debiec Pierre Ronco Jack F M Wetzels Magdalena Zoledziewska Francesco Cucca Iuliana Ionita-Laza Hajeong Lee Elion Hoxha Rolf A K Stahl Paul Brenchley Francesco Scolari Ming-Hui Zhao Ali G Gharavi Robert Kleta Nan Chen Krzysztof Kiryluk

Nat Commun 2020 03 30;11(1):1600. Epub 2020 Mar 30.

Department of Medicine, Division of Nephrology, Columbia University, College of Physicians & Surgeons, New York, USA.

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) and IRF4 (rs9405192, OR = 1.29, P = 1.4 × 10), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 × 10) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 × 10), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 × 10), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 × 10 and OR = 3.39, P = 5.2 × 10, 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.
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http://dx.doi.org/10.1038/s41467-020-15383-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105485PMC
March 2020

The multifaceted role of iron in renal health and disease.

Nat Rev Nephrol 2020 02 25;16(2):77-98. Epub 2019 Sep 25.

Department of Laboratory Medicine, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands.

Iron is an essential element that is indispensable for life. The delicate physiological body iron balance is maintained by both systemic and cellular regulatory mechanisms. The iron-regulatory hormone hepcidin assures maintenance of adequate systemic iron levels and is regulated by circulating and stored iron levels, inflammation and erythropoiesis. The kidney has an important role in preventing iron loss from the body by means of reabsorption. Cellular iron levels are dependent on iron import, storage, utilization and export, which are mainly regulated by the iron response element-iron regulatory protein (IRE-IRP) system. In the kidney, iron transport mechanisms independent of the IRE-IRP system have been identified, suggesting additional mechanisms for iron handling in this organ. Yet, knowledge gaps on renal iron handling remain in terms of redundancy in transport mechanisms, the roles of the different tubular segments and related regulatory processes. Disturbances in cellular and systemic iron balance are recognized as causes and consequences of kidney injury. Consequently, iron metabolism has become a focus for novel therapeutic interventions for acute kidney injury and chronic kidney disease, which has fuelled interest in the molecular mechanisms of renal iron handling and renal injury, as well as the complex dynamics between systemic and local cellular iron regulation.
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http://dx.doi.org/10.1038/s41581-019-0197-5DOI Listing
February 2020

Complement inhibitors are not useful in secondary hemolytic uremic syndromes.

Kidney Int 2019 10;96(4):829-833

Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands.

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http://dx.doi.org/10.1016/j.kint.2019.08.001DOI Listing
October 2019

Evaluating Glomerular Filtration Rate Slope as a Surrogate End Point for ESKD in Clinical Trials: An Individual Participant Meta-Analysis of Observational Data.

J Am Soc Nephrol 2019 09 10;30(9):1746-1755. Epub 2019 Jul 10.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland;

Background: Decline in eGFR is a biologically plausible surrogate end point for the progression of CKD in clinical trials. However, it must first be tested to ensure strong associations with clinical outcomes in diverse populations, including patients with higher eGFR.

Methods: To investigate the association between 1-, 2-, and 3-year changes in eGFR (slope) with clinical outcomes over the long term, we conducted a random effects meta-analysis of 3,758,551 participants with baseline eGFR≥60 ml/min per 1.73 m and 122,664 participants with eGFR<60 ml/min per 1.73 m from 14 cohorts followed for an average of 4.2 years.

Results: Slower eGFR decline by 0.75 ml/min per 1.73 m per year over 2 years was associated with lower risk of ESKD in participants with baseline eGFR≥60 ml/min per 1.73 m (adjusted hazard ratio, 0.70; 95% CI, 0.68 to 0.72) and eGFR<60 ml/min per 1.73 m (0.71; 95% CI, 0.68 to 0.74). The relationship was stronger with 3-year slope. For a rapidly progressing population with predicted 5-year risk of ESKD of 8.3%, an intervention that reduced eGFR decline by 0.75 ml/min per 1.73 m per year over 2 years would reduce the ESKD risk by 1.6%. For a hypothetical low-risk population with a predicted 5-year ESKD risk of 0.58%, the same intervention would reduce the risk by only 0.13%.

Conclusions: Slower decline in eGFR was associated with lower risk of subsequent ESKD, even in participants with eGFR≥60 ml/min per 1.73 m, but those with the highest risk would be expected to benefit the most.
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http://dx.doi.org/10.1681/ASN.2019010008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727262PMC
September 2019

Performance of GFR Slope as a Surrogate End Point for Kidney Disease Progression in Clinical Trials: A Statistical Simulation.

J Am Soc Nephrol 2019 09 10;30(9):1756-1769. Epub 2019 Jul 10.

Division of Nephrology, Tufts Medical Center, Boston, Massachusetts;

Background: Randomized trials of CKD treatments traditionally use clinical events late in CKD progression as end points. This requires costly studies with large sample sizes and long follow-up. Surrogate end points like GFR slope may speed up the evaluation of new therapies by enabling smaller studies with shorter follow-up.

Methods: We used statistical simulations to identify trial situations where GFR slope provides increased statistical power compared with the clinical end point of doubling of serum creatinine or kidney failure. We simulated GFR trajectories based on data from 47 randomized treatment comparisons. We evaluated the sample size required for adequate statistical power based on GFR slopes calculated from baseline and from 3 months follow-up.

Results: In most scenarios where the treatment has no acute effect, analyses of GFR slope provided similar or improved statistical power compared with the clinical end point, often allowing investigators to shorten follow-up by at least half while simultaneously reducing sample size. When patients' GFRs are higher, the power advantages of GFR slope increase. However, acute treatment effects within several months of randomization can increase the risk of false conclusions about therapies based on GFR slope. Care is needed in study design and analysis to avoid such false conclusions.

Conclusions: Use of GFR slope can substantially increase statistical power compared with the clinical end point, particularly when baseline GFR is high and there is no acute effect. The optimum GFR-based end point depends on multiple factors including the rate of GFR decline, type of treatment effect and study design.
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http://dx.doi.org/10.1681/ASN.2019010009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727266PMC
September 2019

Placental passage of eculizumab and complement blockade in a newborn.

Kidney Int 2019 04;95(4):996

Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands.

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http://dx.doi.org/10.1016/j.kint.2019.01.012DOI Listing
April 2019

Novel ELISA for thrombospondin type 1 domain-containing 7A autoantibodies in membranous nephropathy.

Kidney Int 2019 03;95(3):666-679

Université Côte d'Azur, Centre National de la Recherche Scientifique, Institut de Pharmacologie Moléculaire et Cellulaire, UMR7275 Valbonne Sophia Antipolis, France. Electronic address:

Autoantibodies against phospholipase A2 receptor 1 (PLA2R1) and thrombospondin type 1 domain-containing 7A (THSD7A) are emerging as biomarkers to classify membranous nephropathy (MN) and to predict outcome or response to treatment. Anti-THSD7A autoantibodies are detected by Western blot and indirect immunofluorescence test (IIFT). Here, we developed a sensitive enzyme-linked immunosorbent assay (ELISA) optimized for quantitative detection of anti-THSD7A autoantibodies. Among 1012 biopsy-proven MN patients from 6 cohorts, 28 THSD7A-positive patients were identified by ELISA, indicating a prevalence of 2.8%. By screening additional patients, mostly referred because of PLA2R1-unrelated MN, we identified 21 more cases, establishing a cohort of 49 THSD7A-positive patients. Twenty-eight patients (57%) were male, and male patients were older than female patients (67 versus 49 years). Eight patients had a history of malignancy, but only 3 were diagnosed with malignancy within 2 years of MN diagnosis. We compared the results of ELISA, IIFT, Western blot, and biopsy staining, and found a significant correlation between ELISA and IIFT titers. Anti-THSD7A autoantibodies were predominantly IgG4 in all patients. Eight patients were double positive for THSD7A and PLA2R1. Levels of anti-THSD7A autoantibodies correlated with disease activity and with response to treatment. Patients with high titer at baseline had poor clinical outcome. In a subgroup of patients with serial titers, persistently elevated anti-THSD7A autoantibodies were observed in patients who did not respond to treatment or did not achieve remission. We conclude that the novel anti-THSD7A ELISA can be used to identify patients with THSD7A-associated MN and to monitor autoantibody titers during treatment.
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http://dx.doi.org/10.1016/j.kint.2018.10.024DOI Listing
March 2019

Pharmacology, Pharmacokinetics and Pharmacodynamics of Eculizumab, and Possibilities for an Individualized Approach to Eculizumab.

Clin Pharmacokinet 2019 07;58(7):859-874

Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands.

Eculizumab is the first drug approved for the treatment of complement-mediated diseases, and current dosage schedules result in large interindividual drug concentrations. This review provides insight into the pharmacokinetic and pharmacodynamic properties of eculizumab, both for reported on-label (paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, generalized myasthenia gravis) and off-label (hematopoietic stem cell transplantation-associated thrombotic microangiopathy) indications. Furthermore, we discuss the potential of therapeutic drug monitoring to individualize treatment and reduce costs.
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http://dx.doi.org/10.1007/s40262-019-00742-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6584251PMC
July 2019

NMR and MS urinary metabolic phenotyping in kidney diseases is fit-for-purpose in the presence of a protease inhibitor.

Mol Omics 2019 02;15(1):39-49

Metabometrix Ltd, Sir Alexander Fleming Building, South Kensington, London SW7 2AZ, UK.

Nephrotic syndrome with idiopathic membranous nephropathy as a major contributor, is characterized by proteinuria, hypoalbuminemia and oedema. Diagnosis is based on renal biopsy and the condition is treated using immunosuppressive drugs; however nephrotic syndrome treatment efficacy varies among patients. Multi-omic urine analyses can discover new markers of nephrotic syndrome that can be used to develop personalized treatments. For proteomics, a protease inhibitor (PI) is sometimes added at sample collection to conserve proteins but its impact on urine metabolic phenotyping needs to be evaluated. Urine from controls (n = 4) and idiopathic membranous nephropathy (iMN) patients (n = 6) were collected with and without PI addition and analysed using 1H NMR spectroscopy and UPLC-MS. PI-related data features were observed in the 1H NMR spectra but their removal followed by a median fold change normalisation, eliminated the PI contribution. PI-related metabolites in UPLC-MS data had limited effect on metabolic patterns specific to iMN. When using an appropriate data processing pipeline, PI-containing urine samples are appropriate for 1H NMR and MS metabolic profiling of patients with nephrotic syndrome.
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http://dx.doi.org/10.1039/c8mo00190aDOI Listing
February 2019

Management and treatment of glomerular diseases (part 1): conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Kidney Int 2019 02;95(2):268-280

Division of Nephrology, The Ohio State University, Wexner Medical Center, Columbus, Ohio, USA. Electronic address:

The Kidney Disease: Improving Global Outcomes (KDIGO) initiative organized a Controversies Conference on glomerular diseases in November 2017. The conference focused on the 2012 KDIGO guideline with the aim of identifying new insights into nomenclature, pathogenesis, diagnostic work-up, and, in particular, therapy of glomerular diseases since the guideline's publication. It was the consensus of the group that most guideline recommendations, in particular those dealing with therapy, will need to be revisited by the guideline-updating Work Group. This report covers general management of glomerular disease, IgA nephropathy, and membranous nephropathy.
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http://dx.doi.org/10.1016/j.kint.2018.10.018DOI Listing
February 2019

Correction to: Eculizumab in atypical hemolytic uremic syndrome: strategies toward restrictive use.

Pediatr Nephrol 2019 Apr;34(4):741-742

Radboud Institute for Molecular Life Sciences, Amalia Children's Hospital, Department of Pediatric Nephrology, Radboud University Medical Center, P.O. Box 9101, 6500, HB, Nijmegen, The Netherlands.

The original version of this article unfortunately contained two mistakes. The presentation of Table 1 and Fig. 1 was incorrect. The corrected versions are given below.
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http://dx.doi.org/10.1007/s00467-018-4186-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394660PMC
April 2019

Change in albuminuria and subsequent risk of end-stage kidney disease: an individual participant-level consortium meta-analysis of observational studies.

Lancet Diabetes Endocrinol 2019 02 8;7(2):115-127. Epub 2019 Jan 8.

Department of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.

Background: Change in albuminuria as a surrogate endpoint for progression of chronic kidney disease is strongly supported by biological plausibility, but empirical evidence to support its validity in epidemiological studies is lacking. We aimed to assess the consistency of the association between change in albuminuria and risk of end-stage kidney disease in a large individual participant-level meta-analysis of observational studies.

Methods: In this meta-analysis, we collected individual-level data from eligible cohorts in the Chronic Kidney Disease Prognosis Consortium (CKD-PC) with data on serum creatinine and change in albuminuria and more than 50 events on outcomes of interest. Cohort data were eligible if participants were aged 18 years or older, they had a repeated measure of albuminuria during an elapsed period of 8 months to 4 years, subsequent end-stage kidney disease or mortality follow-up data, and the cohort was active during this consortium phase. We extracted participant-level data and quantified percentage change in albuminuria, measured as change in urine albumin-to-creatinine ratio (ACR) or urine protein-to-creatinine ratio (PCR), during baseline periods of 1, 2, and 3 years. Our primary outcome of interest was development of end-stage kidney disease after a baseline period of 2 years. We defined an end-stage kidney disease event as initiation of kidney replacement therapy. We quantified associations of percentage change in albuminuria with subsequent end-stage kidney disease using Cox regression in each cohort, followed by random-effects meta-analysis. We further adjusted for regression dilution to account for imprecision in the estimation of albuminuria at the participant level. We did multiple subgroup analyses, and also repeated our analyses using participant-level data from 14 clinical trials, including nine clinical trials not in CKD-PC.

Findings: Between July, 2015, and June, 2018, we transferred and analysed data from 28 cohorts in the CKD-PC, which included 693 816 individuals (557 583 [80%] with diabetes). Data for 675 904 individuals and 7461 end-stage kidney disease events were available for our primary outcome analysis. Change in ACR was consistently associated with subsequent risk of end-stage kidney disease. The adjusted hazard ratio (HR) for end-stage kidney disease after a 30% decrease in ACR during a baseline period of 2 years was 0·83 (95% CI 0·74-0·94), decreasing to 0·78 (0·66-0·92) after further adjustment for regression dilution. Adjusted HRs were fairly consistent across cohorts and subgroups (ie, estimated glomerular filtration rate, diabetes, and sex), but the association was somewhat stronger among participants with higher baseline ACR than among those with lower baseline ACR (p<0·0001). In individuals with baseline ACR of 300 mg/g or higher, a 30% decrease in ACR over 2 years was estimated to confer a more than 1% absolute reduction in 10-year risk of end-stage kidney disease, even at early stages of chronic kidney disease. Results were generally similar when we used change in PCR and when study populations from clinical trials were assessed.

Interpretation: Change in albuminuria was consistently associated with subsequent risk of end-stage kidney disease across a range of cohorts, lending support to the use of change in albuminuria as a surrogate endpoint for end-stage kidney disease in clinical trials of progression of chronic kidney disease in the setting of increased albuminuria.

Funding: US National Kidney Foundation and US National Institute of Diabetes and Digestive and Kidney Diseases.
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http://dx.doi.org/10.1016/S2213-8587(18)30313-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379893PMC
February 2019

Antibodies Against M-Type Phospholipase Receptor and Prediction of Outcome in Membranous Nephropathy: We are Not There Yet.

Authors:
Jack F M Wetzels

Am J Nephrol 2018 23;48(6):434-437. Epub 2018 Nov 23.

Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands,

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http://dx.doi.org/10.1159/000494661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381871PMC
August 2019

Is there long-term value of pathology scoring in immunoglobulin A nephropathy? A validation study of the Oxford Classification for IgA Nephropathy (VALIGA) update.

Nephrol Dial Transplant 2020 06;35(6):1002-1009

CNR-IFC, Epidemiology, Reggio Calabria, Italy.

Background: It is unknown whether renal pathology lesions in immunoglobulin A nephropathy (IgAN) correlate with renal outcomes over decades of follow-up.

Methods: In 1130 patients of the original Validation Study of the Oxford Classification for IgA Nephropathy (VALIGA) cohort, we studied the relationship between the MEST score (mesangial hypercellularity, M; endocapillary hypercellularity, E; segmental glomerulosclerosis, S; tubular atrophy/interstitial fibrosis, T), crescents (C) and other histological lesions with both a combined renal endpoint [50% estimated glomerular filtration rate (eGFR) loss or kidney failure] and the rate of eGFR decline over a follow-up period extending to 35 years [median 7 years (interquartile range 4.1-10.8)].

Results: In this extended analysis, M1, S1 and T1-T2 lesions as well as the whole MEST score were independently related with the combined endpoint (P < 0.01), and there was no effect modification by age for these associations, suggesting that they may be valid in children and in adults as well. Only T lesions were associated with the rate of eGFR loss in the whole cohort, whereas C showed this association only in patients not treated with immunosuppression. In separate prognostic analyses, the whole set of pathology lesions provided a gain in discrimination power over the clinical variables alone, which was similar at 5 years (+2.0%) and for the whole follow-up (+1.8%). A similar benefit was observed for risk reclassification analyses (+2.7% and +2.4%).

Conclusion: Long-term follow-up analyses of the VALIGA cohort showed that the independent relationship between kidney biopsy findings and the risk of progression towards kidney failure in IgAN remains unchanged across all age groups and decades after the renal biopsy.
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http://dx.doi.org/10.1093/ndt/gfy302DOI Listing
June 2020

Eculizumab in atypical hemolytic uremic syndrome: strategies toward restrictive use.

Pediatr Nephrol 2019 11 6;34(11):2261-2277. Epub 2018 Nov 6.

Radboud Institute for Molecular Life Sciences, Amalia Children's Hospital, Department of Pediatric Nephrology, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.

With the introduction of the complement C5-inhibitor eculizumab, a new era was entered for patients with atypical hemolytic uremic syndrome (aHUS). Eculizumab therapy very effectively reversed thrombotic microangiopathy and reduced mortality and morbidity. Initial guidelines suggested lifelong treatment and recommended prophylactic use of eculizumab in aHUS patients receiving a kidney transplant. However, there is little evidence to support lifelong therapy or prophylactic treatment in kidney transplant recipients. Worldwide, there is an ongoing debate regarding the optimal dose and duration of treatment, particularly in view of the high costs and potential side effects of eculizumab. An increasing but still limited number of case reports and small cohort studies suggest that a restrictive treatment regimen is feasible. We review the current literature and focus on the safety and efficacy of restrictive use of eculizumab. Our current treatment protocol is based on restrictive use of eculizumab. Prospective monitoring will provide more definite proof of the feasibility of such restrictive treatment.
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http://dx.doi.org/10.1007/s00467-018-4091-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794245PMC
November 2019

The Use of N-of-1 Trials to Individualize Treatment in Patients With Renal Magnesium Wasting.

Am J Kidney Dis 2019 02 11;73(2):288-290. Epub 2018 Oct 11.

Department of Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands.

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http://dx.doi.org/10.1053/j.ajkd.2018.08.010DOI Listing
February 2019

Urine Acidification After Ammonium Chloride.

Am J Kidney Dis 2018 12 5;72(6):909-911. Epub 2018 Oct 5.

Department of Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands.

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http://dx.doi.org/10.1053/j.ajkd.2018.07.018DOI Listing
December 2018

Nephrotic Syndrome With Mutations in NPHS2: The Role of R229Q and Implications for Genetic Counseling.

Am J Kidney Dis 2019 03 18;73(3):400-403. Epub 2018 Sep 18.

Department of Nephrology, Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, the Netherlands.

Mutations in the NPHS2 gene, which encodes the podocyte slit diaphragm protein podocin, cause autosomal recessive steroid-resistant nephrotic syndrome (Online Mendelian Inheritance in Man [OMIM] #600995). Basic research and clinical studies have provided important insights about genotype-phenotype correlations. This knowledge allows personalized genetic (risk) counseling and should lead to changes in the advice given to patients. A patient who carries the R229Q variant (which has a high allele frequency of 3.7% in the European population) in combination with a pathogenic variant in exon 7 or 8 is at high risk for developing nephrotic syndrome that may not manifest before adulthood, whereas a patient with 2 pathogenic variants will develop congenital or childhood-onset nephrotic syndrome. In contrast, a patient who carries the R229Q variant in combination with a pathogenic variant in exons 1 to 6 is unlikely to develop nephrotic syndrome. In this article, we review the emerging knowledge about the NPHS2 gene and translate these findings from the bench to practical advice for the clinical bedside.
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http://dx.doi.org/10.1053/j.ajkd.2018.06.034DOI Listing
March 2019

Benefit of Eculizumab Compared to Standard of Care Still Unproven in C3 Glomerulopathy.

Am J Kidney Dis 2018 12 17;72(6):906. Epub 2018 Sep 17.

Radboud University Medical Center, Nijmegen, the Netherlands.

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http://dx.doi.org/10.1053/j.ajkd.2018.07.013DOI Listing
December 2018

What Patients with Mild-to-Moderate Kidney Disease Know, Think, and Feel about Their Disease: An In-Depth Interview Study.

J Am Board Fam Med 2018 Jul-Aug;31(4):570-577

From Radboud Institute for Health Sciences, Department of Primary and Community Care, Radboud University Medical Center, Nijmegen, the Netherlands (CvD, WdG, WA, NS, MD); Radboud Institute for Health Sciences, Department of Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands (JW).

Introduction: It is unknown what patients in primary care with mild-to-moderate chronic kidney disease (CKD) know, think, and feel about their diagnoses and how they value the information provided. The aim of the study was to explore their knowledge, thoughts, and experiences concerning their CKD and the information given to them.

Method: Qualitative interview study with patients with mild-to-moderate CKD who know their diagnoses and are treated mainly by family physicians.

Results: Four themes arose: CKD literacy, coping with anxiety, prerequisites for self-management, and reciprocity in information provision. The participants filled deficiencies in their CKD knowledge with misconceptions and half-truth about causes, symptoms, and treatment. The anxiety about CKD at the time of diagnosis versus the feeling of irrelevance later on was due to the absence of CKD symptoms and their physicians' minimization of the seriousness of CKD. Participants failed to connect lifestyle and cardiovascular disease with CKD. Not all participants were well informed about the consequences that CKD might have. CKD literacy and willingness to change were both necessary to accept lifestyle changes. Further, the participants felt that it would be helpful when information comes with empathy and is tailored to patients' personal needs.

Conclusions: Patients have various perceptions about their CKD. Exploring these perceptions could help match their needs with better-tailored information. Doctors should be aware that they can deliver inaccurate signals about CKD severity, so that patients fail to realize the potential impact of CKD. This makes them less open to lifestyle changes and improving their self-management.
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http://dx.doi.org/10.3122/jabfm.2018.04.170459DOI Listing
October 2019