The Effect of Niacinamide Supplementation on Phosphate Concentrations in Dutch Dialysis Patients: A Randomized Crossover Trial.

OBJECTIVE: Hyperphosphatemia is a common complication in patients with kidney failure, despite the use of phosphate binders. Vitamin B3, either in the form of niacin or niacinamide (NAM), shows potential as "add-on" treatment to reduce serum phosphate concentrations in this population. NAM seems to lack many of the side effects that are observed with niacin. The aim of this study was to investigate whether NAM is an effective and acceptable treatment in reducing serum phosphate concentrations in patients with kidney failure. METHODS: DiaNia was a double-blind placebo-controlled randomized crossover trial, comparing NAM (250-500 mg/day) to placebo as "add-on" treatment to an individual treatment with approved phosphate binders for 12 weeks in patients receiving hemodialysis. The primary outcome was serum phosphate concentrations, and the secondary outcomes were platelet counts as well as drop-outs due to side effects. Data were analyzed using both per-protocol and intention-to-treat analyses. RESULTS: Mean age of the per-protocol population (n = 26) was 63.6 ± 17.2 years and 53.8% were men. NAM treatment significantly reduced serum phosphate with 0.59 mg/dL (p = .03). Linear mixed-effects models demonstrated superiority of 12 weeks NAM over 12 weeks placebo with a between-treatment difference of 0.77 mg/dL (95% CI 0.010, 1.43; P = .03). Similar results, although not significant, were found in the intention-to-treat population. We found no between-treatment differences in platelet counts and during the NAM treatment we observed 3 drop-outs due to side effects (8.6%). CONCLUSION: NAM is effective in reducing serum phosphate concentrations in patients with kidney failure receiving hemodialysis. In addition, NAM is well-tolerated and seems not to increase the risk of thrombocytopenia. Thus, NAM can be valuable as "add-on" treatment to combat hyperphosphatemia in patients with kidney failure. However, more research in larger populations is needed to confirm this.

Neutrophil Extracellular Traps Drive Endothelial-to-Mesenchymal Transition.

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 ß-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 ß-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.

Safety of Rituximab Compared with Steroids and Cyclophosphamide for Idiopathic Membranous Nephropathy.

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.

Should aspirin be used for primary prevention of thrombotic events in patients with membranous nephropathy?

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.

Long-term outcomes in idiopathic membranous nephropathy using a restrictive treatment strategy.

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.

Risk HLA-DQA1 and PLA(2)R1 alleles in idiopathic membranous nephropathy.

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=8.6×10(-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=8.0×10(-93)). The association with HLA-DQA1 was significant in all three populations (P=1.8×10(-9), P=5.6×10(-27), and P=5.2×10(-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 is regulated by HLA.

Phospholipase A2 receptor (PLA2R1) sequence variants in idiopathic membranous nephropathy.

The M-type receptor for phospholipase A2 (PLA2R1) is the major target antigen in idiopathic membranous nephropathy (iMN). Our recent genome-wide association study showed that genetic variants in an HLA-DQA1 and phospholipase A2 receptor (PLA2R1) allele associate most significantly with biopsy-proven iMN, suggesting that rare genetic variants within the coding region of the PLA2R1 gene may contribute to antibody formation. Here, we sequenced PLA2R1 in a cohort of 95 white patients with biopsy-proven iMN and assessed all 30 exons of PLA2R1, including canonical (GT-AG) splice sites, by Sanger sequencing. Sixty patients had anti-PLA2R1 in serum or detectable PLA2R1 antigen in kidney tissue. We identified 18 sequence variants, comprising 2 not previously described, 7 reported as rare variants (<1%) in the Single Nucleotide Polymorphism Database or the 1000 Genomes project, and 9 known to be common polymorphisms. Although we confirmed significant associations among 6 of the identified common variants and iMN, only 9 patients had the private or rare variants, and only 4 of these patients were among the 60 who were PLA2R positive. In conclusion, rare variants in the coding sequence of PLA2R1, including splice sites, are unlikely to explain the pathogenesis of iMN.

New TRPC6 gain-of-function mutation in a non-consanguineous Dutch family with late-onset focal segmental glomerulosclerosis.

BACKGROUND: Focal 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). METHODS: In 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. RESULTS: None 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. CONCLUSIONS: We 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.

Antiphospholipase A2 receptor antibody titer and subclass in idiopathic membranous nephropathy.

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, κ=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.

Antibody-Guided Therapy in Phospholipase A2 Receptor-Associated Membranous Nephropathy.

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 m2 (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.

Estimated glomerular filtration rate in the nephrotic syndrome.

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 (ß2m) as markers of GFR. RESULTS: The final analysis included 142 patients (93 M/49 F), median age 48 years (±15), plasma creatinine 101 µmol/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), ß2m 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 ß2m and CysC. In multivariable analysis, plasma albumin concentration proved to be the most important predictor of the relationship between eGFR and both CysC and ß2m. In the presence of hypoalbuminaemia, eGFR was ~ 30-40% higher at equal levels of plasma CysC or ß2m. 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 ß2m. 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.

Early versus late start of immunosuppressive therapy in idiopathic membranous nephropathy: a randomized controlled trial.

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.

Introduction of a cyclophosphamide-based treatment strategy and the risk of ESRD in patients with idiopathic membranous nephropathy: a nationwide survey in the Netherlands.

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.

Beta-2-microglobulin is superior to N-acetyl-beta-glucosaminidase in predicting prognosis in idiopathic membranous nephropathy.

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 unnecessary immunosuppressive therapy. We therefore conclude that U beta 2m is superior to U beta-NAG in predicting prognosis in patients with iMN.

Urinary excretion of fatty acid-binding proteins in idiopathic membranous nephropathy.

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 research tools; however, they are not superior to more conventional marker proteins.

Pharmacological treatment of primary membranous nephropathy in 2016.

INTRODUCTION: Therapy in patients with primary membranous nephropathy is debated. The discovery of anti-PLA2R antibodies provides opportunities for new treatment strategies. Areas covered: The PubMed database and Cochrane library were searched for full-text articles published in English before March 2016. The search terms included 'Glomerulonephritis, Membranous' [MESH], 'membranous glomerulonephritis' [tiab] and, 'idiopathic membranous nephropathy' [tiab] and 'membranous nephropathy' [tiab], in combination with 'Therapeutics' [MESH], 'therapeutic*'[tiab], 'immunosuppression' [MESH] and 'immunosuppression' [tiab]. All randomized trials were included, cohort trials were included dependent of study design and sufficient number of patients. Expert commentary: With the current available immunosuppressive therapies less than 10% of patients will progress to end stage renal disease. Various treatment options are available and can be used adapted to the clinical characteristics of the patient. Treatment in patients with membranous nephropathy can be individualized using measurement of anti-PLA2R antibodies.

Kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin as prognostic markers in idiopathic membranous nephropathy.

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 µmol/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 membranous nephropathy. They did not add prognostic value compared to measurement of either alpha-1-microglobulin or beta-2-microglobulin.