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Item does not contain fulltext, INTRODUCTION: A 6-month course of cyclophosphamide (CP) and steroids is effective in primary membranous nephropathy (MN), but unappealing because of long-term side effects. We evaluated efficacy of an "antibody-guided" treatment schedule. METHODS: Patients with phospholipase A2 receptor (PLA2R)-related MN and high risk of progression were treated with CP 1.5 mg/kg/d and steroids in cycles of 8 weeks. Anti-PLA2R antibodies were measured by indirect immunofluorescence (IIFT) at 8, 16, and 24 weeks, and a negative test resulted in withdrawal of CP, and rapid tapering of prednisone. In patients with persistent anti-PLA2R antibodies at 24 weeks, CP was switched to mycophenolate mofetil. Treatment was repeated in patients with a relapse. RESULTS: Our analysis included 65 patients (48 males, 17 females), age 61 ± 12 years, estimated glomerular filtration rate (eGFR) 46 ml/min per 1.73 m(2) (35-68), urine protein-to-creatinine ratio 7.7 grams/10 mmol creatinine (5.4-11.1) and serum albumin 20 g/l (16-26). Immunologic remission rate was 71% after 8 weeks, 86% after 16 weeks, 88% after 24 weeks, and 94% after 3 years. Twenty-seven patients (42%) had persistent clinical remission after only 8 weeks of therapy. Sixteen patients needed a second course of therapy because of immunologic or clinical relapse. Follow-up was 37 (26-58) months. Overall partial remission rate was 92%. One patient developed end-stage kidney disease. Antibody-guided therapy (ABG) was as effective as the standard 6-month course, whereas providing a lower cumulative dose of CP (11.1 [8.0-18.5] vs. 18.9 [14.2-23.6] grams). CONCLUSION: ABG is effective, and allows individualized therapy, with many patients responding to 8 weeks of CP-based therapy.

Radboud University, 19 september 2022, Promotor : Wetzels, J.F.M. Co-promotor : Hofstra, J.M., Contains fulltext : 252891.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 220480.pdf (publisher's version ) (Open Access), 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 x 10(-12)) and IRF4 (rs9405192, OR = 1.29, P = 1.4 x 10(-14)), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 x 10(-103)) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 x 10(-49)), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 x 10(-93)), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 x 10(-23) and OR = 3.39, P = 5.2 x 10(-82), respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20-37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk.

Contains fulltext : 191656.pdf (publisher's version ) (Closed access)

Item does not contain fulltext, Guidelines recommend steroid plus cyclical cyclophosphamide (St-Cp) therapy for patients with idiopathic membranous nephropathy at high risk of progression to ESRD. Rituximab (Rtx) may be a safer alternative. In this retrospective, observational cohort study, we compared time to any adverse event (primary outcome); serious or nonserious events; partial and complete remission of the nephrotic syndrome; and a composite of doubling of serum creatinine, ESRD, or death between 100 Rtx-treated patients and 103 patients who received daily St-Cp We monitored patients with standardized protocols and adjusted for baseline characteristics by Cox regression. Over a median follow-up of 40 months, the Rtx group had significantly fewer adverse events than the St-Cp group (63 versus 173; P<0.001), both serious (11 versus 46; P<0.001) and nonserious (52 versus 127; P<0.001). Cumulative incidence of any first (35.5% versus 69.0%; P<0.001), serious (16.4% versus 30.2%; P=0.002), or nonserious (23.6% versus 60.8%; P<0.001) event was significantly lower with Rtx Adjusted hazard ratios (95% confidence intervals) between Rtx and St-Cp groups were 0.27 (0.16 to 0.44) for any first adverse event, 0.32 (0.15 to 0.68) for serious adverse events, and 0.23 (0.13 to 0.41) for nonserious adverse events. Although the cumulative incidence of partial remission was lower in the Rtx group, rates of complete remission and the composite renal end point did not differ significantly between groups. Because of its superior safety profile, we suggest that Rtx might replace St-Cp as first-line immunosuppressive therapy in patients with idiopathic membranous nephropathy and nephrotic syndrome.

Contains fulltext : 174782.pdf (publisher's version ) (Closed access), OBJECTIVE: An excessive release and impaired degradation of neutrophil extracellular traps (NETs) leads to the continuous exposure of NETs to the endothelium in a variety of hematologic and autoimmune disorders, including lupus nephritis. This study aims to unravel the mechanisms through which NETs jeopardize vascular integrity. APPROACH AND RESULTS: Microvascular and macrovascular endothelial cells were exposed to NETs, and subsequent effects on endothelial integrity and function were determined in vitro and in vivo. We found that endothelial cells have a limited capacity to internalize NETs via the receptor for advanced glycation endproducts. An overflow of the phagocytic capacity of endothelial cells for NETs resulted in the persistent extracellular presence of NETs, which rapidly altered endothelial cell-cell contacts and induced vascular leakage and transendothelial albumin passage through elastase-mediated proteolysis of the intercellular junction protein VE-cadherin. Furthermore, NET-associated elastase promoted the nuclear translocation of junctional beta-catenin and induced endothelial-to-mesenchymal transition in cultured endothelial cells. In vivo, NETs could be identified in kidney samples of diseased MRL/lpr mice and patients with lupus nephritis, in whom the glomerular presence of NETs correlated with the severity of proteinuria and with glomerular endothelial-to-mesenchymal transition. CONCLUSIONS: These results indicate that an excess of NETs exceeds the phagocytic capacity of endothelial cells for NETs and promotes vascular leakage and endothelial-to-mesenchymal transition through the degradation of VE-cadherin and the subsequent activation of beta-catenin signaling. Our data designate NET-associated elastase as a potential therapeutic target in the prevention of endothelial alterations in diseases characterized by aberrant NET release.

Item does not contain fulltext, BACKGROUND: Urinary excretion of alpha-1-microglobulin and beta-2-microglobulin reflects tubular damage and predicts outcome in patients with idiopathic membranous nephropathy with reasonable accuracy. Urinary kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin are novel biomarkers of tubular damage. We investigated if these markers could improve prediction of outcome in idiopathic membranous nephropathy. METHODS: We measured kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin in urine samples from patients with idiopathic membranous nephropathy, who had nephrotic proteinuria and normal renal function. Excretion of alpha-1-microglobulin and beta-2-microglobulin had been measured previously. Progression was defined as a serum creatinine rise >30%, a rise in serum creatinine to an absolute value of >/=135 micromol/L, or a clinical decision to start immunosuppressive therapy. Remission was defined as proteinuria <3.5 g/day and >50% reduction from baseline. RESULTS: Sixty-nine patients were included. Median follow-up was 35 months (interquartile range 18-63 months). Progression occurred in 30 patients (44%), and spontaneous remission in 36 (52%). Kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin excretion rates were significantly correlated with each other, and with alpha-1-microglobulin and beta-2-microglobulin. The areas under the receiver operating characteristic curves for progression were 0.75 (0.62-0.87) for kidney injury molecule-1 and 0.74 (0.62-0.87) for neutrophil gelatinase-associated lipocalin. In multivariate analysis with either alpha-1-microglobulin and beta-2-microglobulin, kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin did not independently predict outcome. CONCLUSION: Kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin excretion rates correlated with excretion rates of other tubular damage markers and predicted outcome in patients with idiopathic

Item does not contain fulltext, Patients with nephrotic syndrome are at increased risk of thrombosis. The risk of venous thrombosis is particularly high in patients with nephrotic syndrome due to primary membranous nephropathy. Recent data provide evidence that these patients also have a high absolute risk of arterial thrombotic events, which is associated with the degree of hypoalbuminemia. In this commentary we discuss whether prophylactic aspirin therapy might be indicated in this patient population.

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Contains fulltext : 152771.pdf (publisher's version ) (Open Access), TRIAL REGISTRATION: ClinicalTrials.gov NCT00694863.

Item does not contain fulltext, In addition to disturbed apoptosis and insufficient clearance of apoptotic cells, there is recent evidence for a role of neutrophils in the aetiopathogenesis of systemic lupus erythematosus (SLE). In response to various stimuli, neutrophils can rapidly release DNA fibres decorated with citrullinated histones and anti-microbial peptides. These structures are referred to as neutrophil extracellular traps (NETs). In addition to apoptotic cell-derived microparticles, these NETs may comprise a further source of autoantigens, able to drive the autoimmune response in SLE. Our group recently identified specific histone modifications occurring during apoptosis that play an important role in the autoimmune response in SLE. In the current study, we evaluated the presence and immunostimulatory potential of these previously identified histone modifications in NETs. Compared to NETs from healthy donors, the histones present in NETs formed by SLE-derived neutrophils contain increased amounts of acetylated and methylated residues, which we previously observed to be associated with apoptosis and SLE. Treatment of neutrophils with histone deacetylase (HDAC) inhibitor Trichostatin A (TSA), prior to induction of NETosis, induced NETs containing hyperacetylated histones, endowed with an increased capacity to activate macrophages. This implies that specific histone modifications, in particular acetylation, might enhance the immunostimulatory potential of NETs in SLE.

Radboud Universiteit Nijmegen, 22 januari 2015, Promotor : Wetzels, J.F.M. Co-promotor : Hofstra, J.M., Contains fulltext : 134481.pdf (publisher's version ) (Open Access)

Contains fulltext : 136913.pdf (publisher's version ) (Open Access), 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.

Item does not contain fulltext, BACKGROUND AND OBJECTIVES: Cyclophosphamide treatment improves renal survival in patients with idiopathic membranous nephropathy. However, use of cyclophosphamide is associated with cancer. The incidence of malignancies in patients with idiopathic membranous nephropathy was evaluated, and the cancer risk associated with cyclophosphamide use was estimated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients who attended the clinic were included prospectively from 1995 on. A crude incidence ratio for the occurrence of malignancy was calculated. Incidence ratios were subsequently standardized to potential confounders. Latency between cyclophosphamide therapy and the occurrence of cancer was estimated by stratifying for time since the start of treatment. Finally, Poisson regression was used to obtain a multiple adjusted incidence ratio and investigate the dose-response relationship between cyclophosphamide and cancer. Results : Data were available for 272 patients; the mean age was 51 years, and 70% of the patients were men. Median follow-up was 6.0 years (interquartile range=3.6-9.5), and 127 patients were treated with cyclophosphamide. Cancer incidence was 21.2 per 1000 person-years in treated patients compared with 4.6 per 1000 person-years in patients who did not receive cyclophosphamide, resulting in crude and adjusted incidence ratios of 4.6 (95% confidence interval, 1.5 to 18.8) and 3.2 (95% confidence interval, 1.0 to 9.5), respectively. CONCLUSION: Cyclophosphamide therapy in idiopathic membranous nephropathy gives a threefold increase in cancer risk. For the average patient, this finding translates into an increase in annual risk from approximately 0.3% to 1.0%. The increased risk of malignancy must be balanced against the improved renal survival.

Item does not contain fulltext, Recently published Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend limiting the use of immunosuppressive drugs in idiopathic membranous nephropathy to patients at the highest risk of kidney failure. However, recommendations are based on natural history rather than direct assessment of a restrictive treatment strategy. Here, we describe the long-term outcomes of treating a large cohort of patients with idiopathic membranous nephropathy according to a restrictive treatment policy. We analyzed data for 254 patients who visited our outpatient clinic between 1995 and 2009. All patients were treated with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers. Immunosuppressive therapy was recommended in cases of deteriorating renal function or untreatable nephrotic syndrome. Primary outcomes for the present study were renal replacement therapy and death. Secondary outcomes included adverse events during follow-up and remission of proteinuria. In total, 124 patients (49%) received immunosuppressive therapy, which predominantly consisted of cyclophosphamide combined with steroids. Ten-year cumulative incidence rates were 3% for renal replacement therapy and 10% for death. Partial remission rates were 39%, 70%, and 83% after 1, 3, and 5 years, respectively; complete remission rates were 5%, 24%, and 38% at 1, 3, and 5 years, respectively. A serious adverse event occurred in 23% of all patients. The most notable complications were infections (17%), leukopenia (18%), cardiovascular events (13%), and malignancies (8%). In conclusion, the use of a restrictive treatment strategy in this cohort of patients with idiopathic membranous nephropathy yielded favorable outcomes while limiting the number of patients exposed to toxic drugs. These results support current KDIGO guidelines.

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Item does not contain fulltext, 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.

Item does not contain fulltext, Membranous nephropathy, focal segmental glomerulosclerosis (FSGS), and minimal change disease (MCD) are the most common causes of idiopathic nephrotic syndrome. For many years prednisone, alkylating agents, and calcineurin inhibitors have been the standard of therapy for these patients. More effective or better tolerated treatment modalities are needed. B cell targeted therapy was recently introduced in clinical practice. In this review, we briefly summarize the current standard therapy and discuss the efficacy of B cell targeted therapy in primary glomerular diseases. Observational, short-term studies suggest that rituximab is effective and comparable to standard therapy in maintaining remissions in patients with frequently relapsing or steroid-dependent MCD or FSGS. In contrast, response is limited in patients with steroid-resistant nephrotic syndrome. Rituximab also induces remissions in patients with membranous nephropathy. Controlled clinical trials on kidney endpoints are urgently needed to position B cell targeted therapy in clinical practice.

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.

Contains fulltext : 118864.pdf (publisher's version ) (Closed access), BackgroundFocal segmental glomerulosclerosis (FSGS) is a leading cause of steroid-resistant nephrotic syndrome. Hereditary FSGS is frequently caused by mutations in important structural podocyte proteins, including the slit diaphragm-associated transient receptor potential channel C6 (TRPC6).MethodsIn five patients with biopsy-proven autosomal-dominant FSGS from five different Dutch families, all 13 exons of TRPC6 were sequenced. Upon identification of a novel TRPC6 sequence variant, the resultant amino acid change was introduced in the wild-type TRPC6 protein and functionally tested using patch-clamp analyses and cell-surface biotinylation experiments.ResultsNone of the previously described TRPC6 mutations were found in our cohort. In one family, we identified a novel c.524G>A sequence variant resulting in a p.Arg175Gln (R175Q) substitution in the TRPC6 protein. This sequence variant was absent in 449 control subjects and from public SNP databases. The mutation was located in the third ankyrin repeat domain (ANK3) in the cytoplasmic N-tail of TRPC6, important for protein-protein interaction and regulation of ion channel activity. Patch-clamp analyses of the mutant channel indeed showed an increased TRPC6 channel-mediated current. However, cell-surface expression of the mutant channel was not increased.ConclusionsWe identified a novel TRPC6 p.Arg175Gln gain-of-function mutation that shows increased TRPC6-mediated current, which is not due to altered cell-surface expression. This is the first mutation identified in ANK3 of the TRPC6 N-tail and is most likely responsible for the late-onset autosomal dominant FSGS in this family.

Item does not contain fulltext, BACKGROUND: Autoantibodies against the M-type phospholipase A2 receptor (PLA2R1) are specific markers for primary membranous nephropathy (pMN) and anti-PLA2R1 serum levels may be useful to monitor disease activity. So far, a recombinant cell-based indirect immunofluorescence assay (RC-IFA) using recombinant PLA2R1 as a substrate has been widely available but lacks a finely graduated assessment of antibody concentrations. METHODS: In order to setup a standardized ELISA, the extracellular domain of human PLA2R1 was expressed in HEK293. The purified protein was used to form the solid-phase in an ELISA which was then employed to analyze sera from 200 patients with primary MN, 27 patients with secondary MN, 230 patients with other glomerular diseases, 316 patients with systemic autoimmune diseases, and from 291 healthy blood donors. RESULTS: At a set specificity of 99.9% the sensitivity of the anti-PLA2R1 IgG ELISA was found to be 96.5%. A similar sensitivity (98.5%) was obtained when binding of only subclass IgG4 was analyzed. The calibrated assay showed a good class correlation with the results of the RC-IFA, was robust and could be stored for several months without any loss of quality. CONCLUSION: The results demonstrate that the new test system is qualified for routine use and that it has an almost perfect agreement with both, the clinical characterization of the patients and the results generated with RC-IFA.

Item does not contain fulltext, Immunosuppressive treatment of patients with idiopathic membranous nephropathy (iMN) is heavily debated. The controversy is mainly related to the toxicity of the therapy and the variable natural course of the disease-spontaneous remission occurs in 40-50% of patients. The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Glomerulonephritis provides guidance for the treatment of iMN. The guideline suggests that immunosuppressive therapy should be restricted to patients with nephrotic syndrome and persistent proteinuria, deteriorating renal function or severe symptoms. Alkylating agents are the preferred therapy because of their proven efficacy in preventing end-stage renal disease. Calcineurin inhibitors can be used as an alternative although efficacy data on hard renal end points are limited. In this Review, we summarize the KDIGO guideline and address remaining areas of uncertainty. Better risk prediction is needed to identify patients who will benefit from immunosuppressive therapy, and the optimal timing and duration of this therapy is unknown because most of the randomized controlled trials were performed in low-risk or medium-risk patients. Alternative therapies, directed at B cells, are under study. The discovery of anti-M type phospholipase A2 receptor-antibodies is a major breakthrough and we envisage that in the near future, antibody-driven therapy will enable more individualized treatment of patients with iMN.

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1 augustus 2012, Item does not contain fulltext, BACKGROUND AND OBJECTIVES: Accurate prediction of prognosis may improve management of patients with idiopathic membranous nephropathy. This study compared the Toronto Risk Score and urinary low-molecular weight proteins. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: One hundred four patients with biopsy-proven idiopathic membranous nephropathy who presented between 1995 and 2008 with a well-preserved kidney function and nephrotic range proteinuria were included. Urinary beta2-microglobulin and alpha1-microglobulin measurements were obtained by timed standardized measurements, and the Toronto Risk Score was calculated using data obtained from medical records. The endpoint was progression, which was defined as an increase in serum creatinine>50% or >25% with a concentration>135 mumol/L. RESULTS: Forty-nine patients showed progression. The area under the receiver-operating characteristics curve was 0.78 (95% confidence interval=0.69-0.88) for the risk score versus 0.80 (0.71-0.89) and 0.79 (0.71-0.88) for urinary beta2- and alpha1-microglobulin, respectively. Differences were not significant. Persistent proteinuria did not add accuracy to the Toronto Risk Score. Conversely, its accuracy was not reduced when data from the first 6 months of follow-up were used. Furthermore, a score based on GFR estimated with the six-variable Modification of Diet in Renal Disease equation, calculated in the first 6 months of follow-up, gave an area under the receiver-operating characteristics curve of 0.83 (0.74-0.92), which was not statistically different from other markers. CONCLUSIONS: The prognostic accuracies of the Toronto Risk Score and urinary low-molecular weight proteins were not significantly different. The risk score can be calculated within 6 months of diagnosis, and a simplified risk score using estimated GFR-Modification of Diet in Renal Disease may be sufficient.

Item does not contain fulltext, The phospholipase A(2) receptor (PLA(2)R) is the major target antigen in idiopathic membranous nephropathy. The technique for measuring antibodies against PLA(2)R and the relationship between antibody titer and clinical characteristics are not well established. Here, we measured anti-PLA(2)R (aPLA(2)R) antibody titer and subclass in a well defined cohort of 117 Caucasian patients with idiopathic membranous nephropathy and nephrotic-range proteinuria using both indirect immunofluorescence testing (IIFT) and ELISA. We assessed agreement between tests and correlated antibody titer with clinical baseline parameters and outcome. In this cohort, aPLA(2)R antibodies were positive in 74% and 72% of patients using IIFT and ELISA, respectively. Concordance between both tests was excellent (94% agreement, kappa=0.85). Among 82 aPLA(2)R-positive patients, antibody titer significantly correlated with baseline proteinuria (P=0.02). Spontaneous remissions occurred significantly less frequently among patients with high antibody titers (38% versus 4% in the lowest and highest tertiles, respectively; P<0.01). IgG4 was the dominant subclass in the majority of patients. Titers of IgG4, but not IgG1 or IgG3, significantly correlated with the occurrence of spontaneous remission (P=0.03). In summary, these data show high agreement between IIFT and ELISA assessments of aPLA(2)R antibody titer and highlight the pathogenetic role of these antibodies, especially the IgG4 subclass, given the observed relationships between aPLA(2)R titer, baseline proteinuria, and outcome.

Radboud Universiteit Nijmegen, 12 januari 2012, Promotor : Wetzels, J.F.M., Contains fulltext : 91451.pdf (publisher's version ) (Open Access)

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Item does not contain fulltext, BACKGROUND: Plasma creatinine concentration and creatinine-based equations are most commonly used as markers of glomerular filtration rate (GFR). The abbreviated MDRD formula is considered the best available formula. Altered renal handling of creatinine, which may occur in the nephrotic syndrome, will invalidate creatinine-based formulas. We have evaluated the abbreviated MDRD formula in a large cohort of patients with proteinuria. METHODS: Data on a cohort of patients with glomerular diseases were available from a large database. We have studied the relationship between estimated GFR (MDRD formula), and plasma cystatin C (CysC) and plasma beta-2-microglobulin (beta2m) as markers of GFR. RESULTS: The final analysis included 142 patients (93 M/49 F), median age 48 years (+/-15), plasma creatinine 101 mumol/L (42-368), plasma albumin 28.0 g/L (10.0-47.0), proteinuria 6.4 g/day (0.03-37.9), eGFR-MDRD4 64 mL/min/1.73 m2 (15-165), beta2m 3.43 mg/L (0.7-13.8) and CysC 1.14 mg/mL (0.56-4.00). As expected, we observed a hyperbolic relationship between eGFR and both beta2m and CysC. In multivariable analysis, plasma albumin concentration proved to be the most important predictor of the relationship between eGFR and both CysC and beta2m. In the presence of hypoalbuminaemia, eGFR was ~ 30-40% higher at equal levels of plasma CysC or beta2m. Conclusions were similar when using the recently developed CKD-EPI formula. Plasma albumin concentration did not effect the relationship between eGFR estimated by the six-variable original MDRD formula and beta2m. CONCLUSIONS: Our data point to discrepancies between eGFR using the six-variable MDRD formula and eGFR using the abbreviated MDRD formula as well as the CKD-EPI formula in patients with hypoalbuminaemia. One should be aware of possible limitations of creatinine-based eGFR formulas in patients with a nephrotic syndrome.

Contains fulltext : 97321.pdf (publisher's version ) (Open Access), BACKGROUND: Idiopathic membranous nephropathy is a major cause of the nephrotic syndrome in adults, but its etiologic basis is not fully understood. We investigated the genetic basis of biopsy-proven cases of idiopathic membranous nephropathy in a white population. METHODS: We performed independent genomewide association studies of single-nucleotide polymorphisms (SNPs) in patients with idiopathic membranous nephropathy from three populations of white ancestry (75 French, 146 Dutch, and 335 British patients). The patients were compared with racially matched control subjects; population stratification and quality controls were carried out according to standard criteria. Associations were calculated by means of a chi-square basic allele test; the threshold for significance was adjusted for multiple comparisons (with the Bonferroni method). RESULTS: In a joint analysis of data from the 556 patients studied (398 men), we identified significant alleles at two genomic loci associated with idiopathic membranous nephropathy. Chromosome 2q24 contains the gene encoding M-type phospholipase A(2) receptor (PLA(2)R1) (SNP rs4664308, P=8.6x10(-29)), previously shown to be the target of an autoimmune response. Chromosome 6p21 contains the gene encoding HLA complex class II HLA-DQ alpha chain 1 (HLA-DQA1) (SNP rs2187668, P=8.0x10(-93)). The association with HLA-DQA1 was significant in all three populations (P=1.8x10(-9), P=5.6x10(-27), and P=5.2x10(-36) in the French, Dutch, and British groups, respectively). The odds ratio for idiopathic membranous nephropathy with homozygosity for both risk alleles was 78.5 (95% confidence interval, 34.6 to 178.2). CONCLUSIONS: An HLA-DQA1 allele on chromosome 6p21 is most closely associated with idiopathic membranous nephropathy in persons of white ancestry. This allele may facilitate an autoimmune response against targets such as variants of PLA2R1. Our findings suggest a basis for understanding this disease and illuminate how adaptive immunity

1 juni 2010, Item does not contain fulltext

1 januari 2010, Item does not contain fulltext, BACKGROUND: Immunosuppressive therapy in idiopathic membranous nephropathy (iMN) is debated. Accurate identification of patients at high risk for end-stage renal disease (ESRD) allows early start of therapy in these patients. It is unknown if early start of therapy is more effective and/or less toxic than late start (i.e. when GFR deteriorates). METHODS: We conducted a randomized open-label study in patients with iMN, a normal renal function and a high risk for ESRD (urinary beta2m >0.5 microg/min, UIgG >125 mg/day). Patients started with immunosuppressive therapy (cyclophosphamide for 12 months, and steroids) either immediately after randomization or when renal function deteriorated (DeltasCr > or =+25% and sCr >135 micromol/l or DeltasCr > or =+50%). End points were remission rates, duration of the nephrotic syndrome (NS), renal function and complications. RESULTS: The study included 26 patients (24 M/2 F), age 48 +/- 12 years; sCr 96 micromol/l (range 68-126) and median proteinuria 10.0 g/10 mmol Cr. Early treatment resulted in a more rapid onset of remission (P = 0.003) and a shorter duration of the NS (P = 0.009). However, at the end of the follow-up (72 +/- 22 m), there were no differences in overall remission rate, sCr (93 versus 105 micromol/l), proteinuria, relapse rate and adverse events. CONCLUSIONS: In high-risk patients with iMN, immunosuppressive treatment is effective in inducing a remission. Early treatment shortens the duration of the nephrotic phase, but does not result in better preservation of renal function. Our study indicates that treatment decisions must be based on risk and benefit assessment in the individual patient.

Contains fulltext : 70106.pdf (publisher's version ) (Closed access), BACKGROUND: An accurate prediction of prognosis in patients with idiopathic membranous nephropathy (iMN) would allow restriction of immunosuppressive treatment to patients who are at highest risk for end-stage renal disease (ESRD). Several markers of proximal tubular cell injury have been used as predictors of prognosis. In this study we compared the accuracy of urinary beta-2-microglobulin (U beta 2m) and N-acetyl-beta-glucosaminidase (U beta-NAG) in predicting renal insufficiency and remission rates. METHODS: Fifty-seven patients with iMN (38 M, 19 F; age 48 +/- 16 years), a nephrotic syndrome and a serum creatinine level <135 micromol/l were studied prospectively. At baseline, a standardised measurement was carried out to determine renal function and protein excretion. The end-point renal failure was defined as a serum creatinine exceeding 135 micromol/l or an increase in serum creatinine by >50%. Remission was defined as a proteinuria <2.0 g/day with stable renal function. RESULTS: The mean follow-up was 80 +/- 36 months. The mean serum creatinine concentration was 89 +/- 20 micromol/l, serum albumin 24 +/- 5.3 g/l and proteinuria 8.9 +/- 4.8 g/24 h. Thus far, 28 (49%) patients have reached the predefined end point of renal failure. Multivariate analysis identified U beta 2m as the strongest independent predictor for the development of renal insufficiency. Sensitivity and specificity were 81 and 90% respectively for U beta 2m (threshold value 54 microg/mmol cr), and 74 and 81% respectively for U beta-NAG (threshold value 2.64 U/mmol cr). The overall remission rate was 44%. A remission occurred in 78% of patients with low U beta 2m and in 14% of patients with high U beta 2m, and respectively in 71% of patients with low U beta-NAG and 21% of patients with high U beta-NAG. CONCLUSIONS: Although both U beta 2m and U beta-NAG predicted progression and remission in iMN, U beta 2m was more accurate. High specificity in predicting prognosis should be pursued to avoid un

Item does not contain fulltext, BACKGROUND: The efficacy of immunosuppressive therapy in preventing ESRD in patients with idiopathic membranous nephropathy (iMN) is debated. From 1991 onwards, we have advocated a restrictive treatment strategy in our university hospital and regional referring hospitals. We advised the use of immunosuppressive therapy, consisting of a combination of steroids and oral cyclophosphamide for 12 months, in patients with iMN at high risk for ESRD. METHODS: Primary renal diagnosis of all patients who start renal replacement therapy in the Netherlands is registered in the RENINE database. We studied the incidence of ESRD due to iMN in the Netherlands in the period 1991-2005. We mailed a questionnaire to all nephrology centres that entered a patient with ESRD and iMN in the RENINE database after 2000. RESULTS: The introduction of the cyclophosphamide-based treatment strategy in the Nijmegen region resulted in a significant 70% reduction in the incidence of ESRD in patients with iMN as compared to an unchanged incidence in other parts of the Netherlands. The response rate to the questionnaire was 65%. There were 45 patients (34 M, 11 F) with a mean age of 49 +/- 17 years at diagnosis and a median serum creatinine of 138 micromol/l (range 60-1798). Overall, only 22 patients (49%) had been treated with immunosuppressive therapy, consisting of prednisone monotherapy in 7. CONCLUSIONS: Our data suggest that the introduction of a cyclophosphamide-based restrictive treatment policy has reduced the risk of ESRD in iMN. The questionnaires reflect the differences in opinion on the optimal treatment of high-risk patients with iMN.

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Contains fulltext : 70536.pdf (publisher's version ) (Closed access), BACKGROUND: It is suggested that proteinuria contributes to progressive renal failure by inducing tubular cell injury. The site of injury is unknown. Most studies have used markers of proximal tubular cell damage. Fatty acid-binding proteins (FABPs) are intracellular carrier proteins with different expression in the kidney. Liver-type FABP (L-FABP) is found in the cytoplasm of proximal tubules, whereas heart-type FABP (H-FABP) is localized in the distal tubules. We evaluated the urinary excretion of L-FABP and H-FABP in patients with idiopathic membranous nephropathy (iMN). METHODS: We have studied 40 patients (27 males, 13 females) with iMN. The mean age was 48 +/- 15 years, serum creatinine concentration 89 +/- 17 micromol/l and proteinuria 8.9 +/- 5.0 g/24 h. Urinary L-FABP and H-FABP were measured by ELISA. Renal failure was defined as an increase in serum creatinine >25% from baseline with a serum creatinine >135 micromol/l or an increase >50% from baseline. Urinary L-FABP excretion was detectable in all but one patient. The median (range) level was 3.29 (0.7-165.6) microg/mmol creatinine (normal <0.38 microg/mmol Cr). Urinary H-FABP was undetectable in nine patients. Median level was 1.53 (0.1-90.5) microg/mmol Cr (normal <0.1 microg/mmol Cr). Both L- and H-FABP correlated with urinary beta2-microglobulin, urinary alpha1-microglobulin and IgG. Urinary H-FABP paralleled L-FABP. RESULTS: After a mean follow-up of 75 +/- 32 months, 16 (40%) patients have reached the predefined end point of renal failure. Both urinary L-FABP and H-FABP predicted renal outcome, with the calculated sensitivity and specificity of 81 and 83% for both. CONCLUSIONS: Urinary L-FABP and urinary H-FABP are increased in patients with iMN. There was a high correlation between L-FABP and H-FABP, suggesting the concurrent development or existence of proximal and distal tubular cell injury. Both L-FABP and H-FABP predicted prognosis in patients with iMN. These markers may be of interest as rese

Item does not contain fulltext, Mean arterial pressure (MAP) is often used as an index of overall blood pressure. In recent years, the use of automated oscillometric blood pressure measurement devices is increasing. These devices directly measure and display MAP; however, MAP is often calculated from systolic blood pressure (SBP) and diastolic blood pressure (DBP) as displayed by the device. In this study we have analysed measured and calculated MAP, obtained by two different oscillometric BP measurement devices in two different patient cohorts. The first cohort included 242 healthy subjects (male 40.5%, 50+/-13 years). BP measurements were performed with a Welch Allyn 5300P device. We found a small but significant difference between measured MAP and calculated MAP (MAP(m-c:) -1.8 mmHg, range -5.7 to 12.9 mmHg, p < 0.001). MAP(m-c) showed a significant, but weak correlation with DBP and SBP. The second cohort included included 134 patients with glomerular diseases (male 63%, 50+/14 years). BP measurements were performed with a Dinamap 487210 device. In this group we also observed a small difference between measured MAP and calculated MAP (+1.7 mmHg, range -15.3 to 28.2 mmHg, p<0.001). MAP (m-c) correlated with age, all blood pressure indices and heart rate. An overall analysis showed that age, SBP, DBP, and type of device are all independently related to MAP (m-c). There is a significant difference between measured and calculated MAP. The difference is small on average; however, this MAP(m-c) can be large in the individual patient. Moreover, there are differences of reported MAP between devices. Our data suggest that calculated and measured MAP cannot be used interchangeably.

Contains fulltext : 53390.pdf (publisher's version ) (Closed access)