Remission of De Novo Membranous Nephropathy in a Kidney Allograft Recipient: a Case Report

Membranous nephropathy (MN), one of the most frequent causes of nephrotic syndrome in native kidneys, is also a common glomerular pathology in transplanted kidneys(Davison AM, Johnston PA. Allograft membranous nephropathy, Nephrol Dial Transplant, 1992;7(Suppl. 1):114–118. Specific treatment modalities have not been described for this population. However, renal transplanted patients presented with MN could have spontaneous remission as those with idiopathic MN. Here, we report a kidney allograft recipient diagnosed with de novo MN in early phases of posttransplantation period having a clinical remission over months.     

Anti-Phospholipase A2 Receptor Antibody Titer Predicts Post-Rituximab Outcome of Membranous Nephropathy

Rituximab induces nephrotic syndrome (NS) remission in two-thirds of patients with primary membranous nephropathy (MN), even after other treatments have failed. To assess the relationships among treatment effect, circulating nephritogenic anti-phospholipase A₂ receptor (anti-PLA₂R) autoantibodies and genetic polymorphisms predisposing to antibody production we serially monitored 24-hour proteinuria and antibody titer in patients with primary MN and long-lasting NS consenting to rituximab (375 mg/m²) therapy and genetic analyses. Over a median (range) follow-up of 30.8 (6.0–145.4) months, 84 of 132 rituximab-treated patients achieved complete or partial NS remission (primary end point), and 25 relapsed after remission. Outcomes of patients with or without detectable anti-PLA₂R antibodies at baseline were similar. Among the 81 patients with antibodies, lower anti-PLA₂R antibody titer at baseline (P=0.001) and full antibody depletion 6 months post-rituximab (hazard ratio [HR], 7.90; 95% confidence interval [95% CI], 2.54 to 24.60; P<0.001) strongly predicted remission. All 25 complete remissions were preceded by complete anti-PLA₂R antibody depletion. On average, 50% anti-PLA₂R titer reduction preceded equivalent proteinuria reduction by 10 months. Re-emergence of circulating antibodies predicted disease relapse (HR, 6.54; 95% CI, 1.57 to 27.40; P=0.01), whereas initial complete remission protected from the event (HR, 6.63; 95% CI, 2.37 to 18.53; P<0.001). Eighteen patients achieved persistent antibody depletion and complete remission and never relapsed. Outcome was independent of PLA2R1 and HLA-DQA1 polymorphisms and of previous immunosuppressive treatment. Therefore, assessing circulating anti-PLA₂R autoantibodies and proteinuria may help in monitoring disease activity and guiding personalized rituximab therapy in nephrotic patients with primary MN.     

In Patients with Membranous Lupus Nephritis,Exostosin-Positivity and Exostosin-Negativity Represent Two Different Phenotypes

BackgroundIn patients with secondary (autoimmune) membranous nephropathy, two novel proteins, Exostosin 1 and Exostosin 2 (EXT1/EXT2), are potential disease antigens, biomarkers, or both. In this study, we validate the EXT1/EXT2 findings in a large cohort of membranous lupus nephritis.MethodsWe conducted a retrospective cohort study of patients with membranous lupus nephritis, and performed immunohistochemistry studies on the kidney biopsy specimens against EXT1 and EXT2. Clinicopathologic features and outcomes of EXT1/EXT2-positive versus EXT1/EXT2-negative patients were compared.ResultsOur study cohort included 374 biopsy-proven membranous lupus nephritis cases, of which 122 (32.6%) were EXT1/EXT2-positive and 252 (67.4%) were EXT1/EXT2-negative. EXT1/EXT2-positive patients were significantly younger (P=0.01), had significantly lower serum creatinine levels (P=0.02), were significantly more likely to present with proteinuria ≥3.5 g/24 h (P=0.009), and had significantly less chronicity features (glomerulosclerosis, P=0.001 or interstitial fibrosis and tubular atrophy, P<0.001) on kidney biopsy. Clinical follow-up data were available for 160 patients, of which 64 (40%) biopsy results were EXT1/EXT2-positive and 96 (60%) were EXT1/EXT2-negative. The proportion of patients with class 3/4 lupus nephritis coexisting with membranous lupus nephritis was not different between the EXT1/EXT2-positive and EXT1/EXT2-negative groups (25.0% versus 32.3%; P=0.32). The patients who were EXT1/EXT2-negative evolved to ESKD faster and more frequently compared with EXT1/EXT2-positive patients (18.8% versus 3.1%; P=0.003).ConclusionsThe prevalence of EXT1/EXT2 positivity was 32.6% in our cohort of membranous lupus nephritis. Compared with EXT1/EXT2-negative membranous lupus nephritis, EXT1/EXT2-positive disease appears to represent a subgroup with favorable kidney biopsy findings with respect to chronicity indices. Cases of membranous lupus nephritis that are EXT1/EXT2-negative are more likely to progress to ESKD compared with those that are EXT1/EXT2-positive.     

来氟米特与环磷酰胺治疗膜性肾病的疗效比较

目的：评价来氟米特（LEF）与环磷酰胺（CTX）分别联合泼尼松（PED）治疗成年人特发性膜性肾病（IMN）的疗效及安全性。方法：80例原发性肾病综合征患者经肾活检确诊为IMN,在诊断上排除了继发性膜性肾病,随机分两组：LEF组40例采用LEF＋PED治疗,CTX组40例采用CTX＋PED治疗。治疗期间及治疗前后,监测血常规、尿常规、24h尿蛋白定量、血白蛋白、血脂、肝肾功能,6个月后行疗效和安全性的评价。结果：（1）LEF组40例中失访1例,完成6个月治疗39例。CTX组40例中因不耐受药物不良反应中途退出7例,完成6个月治疗33例;（2）治疗3个月后LEF组的完全缓解率显著低于CTX组（χ2=4.3516,P〈0.05）,LEF组的未缓解显著高于CTX组（χ2=4.9059,P〈0.05）;治疗6个月后两组的完全缓解率、未缓解率差异无统计学意义（P均〉0.05）;（3）治疗6个月后,两组患者的24hUpro、Alb、TC、TG均较治疗前显著改善（LEF组：t=7.0841,9.0998,8.4412,7.7942;CTX组：t=8.7823,9.2826,7.1252,6.9731,P均〈0.01）,CTX组的改善略微优于LEF组（t=1.8112,1.6780,0.9881,1.6778,P均〉0.05）,但差异均无统计学意义;（4）CTX组中因不良反应中途退出的比率（7/40）显著高于LEF组（0/40）,（χ2=5.6360,P〈0.05）;LEF组不良反应发生率（5/39）显著低于CTX组（13/40）,（χ2=4.3468,P〈0.05）,差异均有统计学意义。结论：来氟米特治疗膜性肾病,与环磷酰胺的临床疗效相似,不良反应较少,但起效稍慢。     

Mechanisms of Renal Control of Potassium Homeostasis in Complete Aldosterone Deficiency

Aldosterone-independent mechanisms may contribute to K⁺ homeostasis. We studied aldosterone synthase knockout (AS^−/−) mice to define renal control mechanisms of K⁺ homeostasis in complete aldosterone deficiency. AS^−/− mice were normokalemic and tolerated a physiologic dietary K⁺ load (2% K⁺, 2 days) without signs of illness, except some degree of polyuria. With supraphysiologic K⁺ intake (5% K⁺), AS^−/− mice decompensated and became hyperkalemic. High-K⁺ diets induced upregulation of the renal outer medullary K⁺ channel in AS^−/− mice, whereas upregulation of the epithelial sodium channel (ENaC) sufficient to increase the electrochemical driving force for K⁺ excretion was detected only with a 2% K⁺ diet. Phosphorylation of the thiazide-sensitive NaCl cotransporter was consistently lower in AS^−/− mice than in AS^+/+ mice and was downregulated in mice of both genotypes in response to increased K⁺ intake. Inhibition of the angiotensin II type 1 receptor reduced renal creatinine clearance and apical ENaC localization, and caused severe hyperkalemia in AS^−/− mice. In contrast with the kidney, the distal colon of AS^−/− mice did not respond to dietary K⁺ loading, as indicated by Ussing-type chamber experiments. Thus, renal adaptation to a physiologic, but not supraphysiologic, K⁺ load can be achieved in aldosterone deficiency by aldosterone-independent activation of the renal outer medullary K⁺ channel and ENaC, to which angiotensin II may contribute. Enhanced urinary flow and reduced activity of the thiazide-sensitive NaCl cotransporter may support renal adaptation by activation of flow-dependent K⁺ secretion and increased intratubular availability of Na⁺ that can be reabsorbed in exchange for K⁺ secreted.     

Nephrotic syndrome as a result of membranous nephropathy caused by renal cell carcinoma

A 77‐year‐old woman was admitted for a renal biopsy to evaluate a case of nephrotic syndrome. In the course of the examination, a right renal tumor was incidentally found. We performed a right radical nephrectomy in advance of the renal biopsy. Histologically, the tumor was diagnosed as a renal cell carcinoma (clear cell carcinoma) and the non‐neoplastic renal cell tissue showed membranous nephropathy (MN). After surgery, the nephrotic syndrome remitted without any further medical treatment and the MN was considered to be a malignancy associated syndrome. There have been few case reports in the literature regarding this association and we wish to describe another case.     

False positivity for PLA2R1 antibody measured by ELISA in a nephrotic patient with no membranous nephropathy

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New ‘Antigens’ in Membranous Nephropathy

Membranous nephropathy (MN) occurs due to deposition of immune complexes along the subepithelial region of glomerular basement membrane. Two previously identified target antigens for the immune complexes, PLA2R (identified in 2009) and THSD7A (in 2014), account for approximately 60% of all MN, both primary and secondary. In the remaining MN, target antigens were unknown. Use of laser microdissection and mass spectrometry enabled identification of new “antigens.” This approach led to the identification of four novel types of MN: exotosin 1 (EXT1)– and exotosin 2 (EXT2)–associated MN, NELL1-associated MN, Sema3B-associated MN, and PCDH7-associated MN. Each of these represents a distinct disease entity, with different clinical and pathologic findings. In this review, the structure of the proteins and the clinical and pathologic findings of the new types of MN are discussed. The role of mass spectrometry for accurate diagnosis of MN cannot be overemphasized. Finally, any classification of MN should be made on the basis of the antigens that are detected. Further studies are required to understand the pathophysiology, response to treatment, and outcomes of these new MNs.     

Identification of the Immunodominant Epitope Region in Phospholipase A2 Receptor-Mediating Autoantibody Binding in Idiopathic Membranous Nephropathy

Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. Recent clinical studies established that >70% of patients with idiopathic (also called primary) MN (IMN) possess circulating autoantibodies targeting the M-type phospholipase A₂ receptor-1 (PLA₂R) on the surface of glomerular visceral epithelial cells (podocytes). In situ, these autoantibodies trigger the formation of immune complexes, which are hypothesized to cause enhanced glomerular permeability to plasma proteins. Indeed, the level of autoantibody in circulation correlates with the severity of proteinuria in patients. The autoantibody only recognizes the nonreduced form of PLA₂R, suggesting that disulfide bonds determine the antigenic epitope conformation. Here, we identified the immunodominant epitope region in PLA₂R by probing isolated truncated PLA₂R extracellular domains with sera from patients with IMN that contain anti-PLA₂R autoantibodies. Patient sera specifically recognized a protein complex consisting of the cysteine-rich (CysR), fibronectin-like type II (FnII), and C-type lectin-like domain 1 (CTLD1) domains of PLA₂R only under nonreducing conditions. Moreover, absence of either the CysR or CTLD1 domain prevented autoantibody recognition of the remaining domains. Additional analysis suggested that this three-domain complex contains at least one disulfide bond required for conformational configuration and autoantibody binding. Notably, the three-domain complex completely blocked the reactivity of autoantibodies from patient sera with the full-length PLA₂R, and the reactivity of patient sera with the three-domain complex on immunoblots equaled the reactivity with full-length PLA₂R. These results indicate that the immunodominant epitope in PLA₂R is exclusively located in the CysR-FnII-CTLD1 region.     

Serine Protease HTRA1 as a Novel Target Antigen in Primary Membranous Nephropathy

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Rituximab or Cyclophosphamide in the Treatment of Membranous Nephropathy: The RI-CYCLO Randomized Trial

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Fludarabine in Chronic Lymphocytic Leukemia with Membranous Nephropathy

Chronic lymphocytic leukemia (CLL) is the most frequent form of leukemia in Western countries. Despite its relative frequency, the association of glomerular disease is extremely rare. We present a case of membranous nephropathy (MN) during CLL treated with fludarabine. A 74-year-old man was admitted to our hospital because of the onset of nephrotic syndrome (proteinuria was 7 g/24 h). Six years before, he had been diagnosed with CLL. Biochemical analysis showed the following results: creatinine was 1.7 mg/dL (creatinine clearance was 39 mL/min), urea was 64 mg/dL, hemoglobin was 8.6 g/dL, and white blood cells was 16,580/mm³ (60% lymphocytes). The urine sediment revealed 7–8 red blood cells and many hyaline and granular casts. No monoclonal peak was demonstrated in either serum or urine electrophoresis. Bence-Jones proteinuria was negative. The patient underwent renal biopsy that showed MN with an extensive lymphocyte perivascular infiltration; immunohistochemistry on renal biopsy specimen showed that infiltrating lymphocytes were CD20+. Moreover, DNA from tissue fractions was analyzed by qualitative polymerase chain reaction-based detection of clonal gene rearrangements of the immunoglobulin heavy chain gene, confirming the monoclonality of the infiltrating lymphocytes. The patient was started on fludarabine as monotherapy, with complete remission of proteinuria and recovery of renal function (creatinine clearance was 75 mL/min) after 1 year of follow-up.     

成人特发性膜性肾病遗传易感性与中医证型的关联性研究

目的:探讨特发性膜性肾病(IMN)的足细胞裂隙隔膜相关蛋白基因NPHS1、NPHS2与中医辨证分型的关联。方法:收集原发性肾病综合征患者200例,其中实验组(IMN)38例,对照组(非IMN)162例,两组病人外周血淋巴细胞中获得基因组DNA进行序列分析、测定,分析NPHS1基因G349A位点、NPHS2基因G686A,C695T位点的多态性及其与中医证型关联。结果:(1)两组年龄分布差异有统计学意义(P<0.05);(2)两组NPHS1基因G349A位点基因型频率分布差异有统计学意义(P<0.05)。实验组纯合突变AA基因型频率明显高于对照组;杂合突变GA基因型频率明显低于对照组;(3)两组NPHS2基因G686A,C695T位点未发现多态性改变;(4)两组中医证型本虚证中气(阳)虚证、阴虚证差异有统计学意义(P<0.05);两组标实证中湿热证和血瘀证差异有统计学意义(P<0.05)。(5)未发现候选基因多态性与中医辨证分型的明显相关性。结论:在PNS患者中IMN患者年龄偏大。NPHS1基因G349A位点基因型AA与IMN发病有相关性。IMN中医证型气(阳)虚证、血瘀证明显多于非IMN患者,阴虚证、湿热证明显少于非IMN患者。未发现候选基因多态性与中医辨证分型的明显相关性。