Novel Antigens and Clinical Updates in Membranous Nephropathy.

Membranous nephropathy (MN), an autoimmune kidney disease and leading cause of nephrotic syndrome, leads to kidney failure in up to one-third of affected individuals. Most MN cases are due to an autoimmune reaction against the phospholipase A2 receptor (PLA2R) located on kidney podocytes. Serum PLA2R antibody quantification is now part of routine clinical practice because antibody titers correlate with disease activity and treatment response. Recent advances in target antigen detection have led to the discovery of more than 20 other podocyte antigens, yet the clinical impact of additional antigen detection remains unknown and is under active investigation. Here we review recent findings and hypothesize how current research will inform future care of patients with MN.

Ectodomain shedding of PLA2R1 is mediated by the metalloproteases ADAM10 and ADAM17.

Phospholipase A2 receptor 1 (PLA2R1) is a 180-kDa transmembrane protein that plays a role in inflammation and cancer and is the major autoantigen in membranous nephropathy, a rare but severe autoimmune kidney disease. A soluble form of PLA2R1 has been detected in mouse and human serum. It is likely produced by proteolytic shedding of membrane-bound PLA2R1 but the mechanism is unknown. Here, we show that human PLA2R1 is cleaved by A Disintegrin And Metalloprotease 10 (ADAM10) and ADAM17 in HEK293 cells, mouse embryonic fibroblasts, and human podocytes. By combining site-directed mutagenesis and sequencing, we determined the exact cleavage site within the extracellular juxtamembrane stalk of human PLA2R1. Orthologs and paralogs of PLA2R1 are also shed. By using pharmacological inhibitors and genetic approaches with RNA interference and knock-out cellular models, we identified a major role of ADAM10 in the constitutive shedding of PLA2R1 and a dual role of ADAM10 and ADAM17 in the stimulated shedding. We did not observe evidence for cleavage by ß- or γ-secretase, suggesting that PLA2R1 may not be a substrate for regulated intramembrane proteolysis. PLA2R1 shedding occurs constitutively and can be triggered by the calcium ionophore ionomycin, the protein kinase C activator PMA, cytokines, and lipopolysaccharides, in vitro and in vivo. Altogether, our results show that PLA2R1 is a novel substrate for ADAM10 and ADAM17, producing a soluble form that is increased in inflammatory conditions and likely exerts various functions in physiological and pathophysiological conditions including inflammation, cancer, and membranous nephropathy.

Effectiveness of a novel rat model of off-target PLA2R1 knockout to renal impairment.

Phospholipase A2 receptor 1 (PLA2R1) plays a crucial role in various diseases, including membranous nephropathy. However, the precise implications of PLA2R1 deficiency remain poorly understood. In this study, we created PLA2R1 knockout rats to explore potential consequences resulting from the loss of the PLA2R1 gene. Unexpectedly, our PLA2R1 knockout rats exhibited symptoms resembling those of chronic kidney disease after an 8-week observation period. Notably, several rats developed persistent proteinuria, a hallmark of renal dysfunction. Immunohistochemical and immunofluorescence analyses revealed insignificant glomerular fibrosis, reduced podocyte count, and augmented glomerular expression of complement C3 (C3) compared to immunoglobin A (IgA) and immunoglobin G(IgG) in the rat model. These findings suggest that the loss of PLA2R1 may contribute to the pathogenesis of membranous nephropathy and related conditions. Our knockout rat model provides a valuable tool for investigating the underlying pathology of PLA2R1-associated diseases, and may facilitate the development of targeted therapies for membranous nephropathy and other related disorders.

miR-664a-5p promotes experimental membranous nephropathy progression through HIPK2/Calpain1/GSα-mediated autophagy inhibition.

We previously found that miR-664a-5p is specifically expressed in urinary exosomes of idiopathic membranous nephropathy (IMN) patients. Homeodomain-interacting protein kinase 2 (HIPK2), a nuclear serine/threonine kinase, plays an important role in nephropathy. But the function of these factors and their connection in MN are unclear. To investigate the function and mechanism of miR-664a-5p in MN, the miR-664a-5p expression in HK-2 cells, exosomes, podocytes and renal tissues were studied, as well as cell growth and apoptosis of these cells, the binding of miR-664a-5p to HIPK2 mRNA, the levels of relative proteins and autophagy. The MN progression in MN mice model was also studied. Albumin increased the miR-664a-5p content and apoptosis of HK-2 cells, which was blocked by miR-664a-5p antagomir. miR-664a-5p bound to the 3' UTR of HIPK2 mRNA, resulting in the up-regulation of Calpain1, GSα shear and the inhibition of autophagy level. Autophagy inhibitor CQ blocked the protective effect of miR-664a-5p antagomir, HIPK2 overexpression, Calpain inhibitor SJA6017 on albumin-mediated injury. MiR-664a-5p from albumin-treated HK-2 cells could be horizontally transported to podocytes through exosomes. Exosomes from albumin-treated HK-2 cells promoted progression of MN mice, AAV-Anti-miR-664-5p (mouse homology miRNA) could improve them. Albumin increases the miR-664a-5p level and causes changes of HIPK2/Calpain1/GSα pathway, which leads to autophagy inhibition and apoptosis up-regulation of renal tubular epithelial cells. miR-664a-5p can horizontally enter podocytes through exosomes resulting in podocytes injury. Targeted inhibition of miR-664a-5p can reduce the apoptosis of renal tubule cells and podocytes, and may improve the MN progression.

A reliable clinical test for detection of membranous nephropathy antigens using laser microdissection and mass spectrometry.

Membranous nephropathy (MN) results from accumulation of antigen-antibody immune complexes along the subepithelial region of the glomerular basement membranes. Over the last years, 13 target antigens have been discovered and include PLA2R, THSD7A, EXT1 and EXT2, NELL1, SEMA3B, NCAM1, CNTN1, HTRA1, FAT1, PCDH7, NTNG1, PCSK6 and NDNF, accounting for 80-90% of MN antigens. MN associated with many of these antigens have distinctive clinicopathologic findings. It is important to accurately identify the antigen in MN. Immunohistochemical (IHC) and/or immunofluorescence (IF) methods are currently used to detect PLA2R, THSD7A, NELL1, SEMA3B and EXT1/EXT2. However, for the remaining antigens, IHC/IF methods do not exist and are not practical for detection. Here, we developed laser microdissection-based mass spectrometry methodology (LMD/MS) as a one-stop clinical test for the detection of MN antigens using paraffin-embedded kidney biopsy tissue. The LMD/MS test was validated in two steps. LMD/MS was used to detect the antigen in 75 cases of MN with known antigens and correctly identified the antigen in all these cases. Next, LMD/MS was used to identify the antigen in 61 MN cases where the antigen was unknown and identified one of the known antigens in 40 of 61 cases including many of the less common antigens. This lower-than-expected detection rate is explained by intentional enrichment of the cohort with PLA2R-negative MN. Overall, PLA2R was identified in 16.4%, one of the other antigens detected in 49.1%, and in the remaining 34.5% of cases, none of the above antigens was detected. Thus, LMD/MS is an extremely useful and reliable method for the detection of known MN antigens and possibly indicating an unknown MN antigen for eventual discovery.

Complement activation and effector pathways in membranous nephropathy.

Complement activation has long been recognized as a central feature of membranous nephropathy (MN). Evidence for its role has been derived from the detection of complement products in biopsy tissue and urine from patients with MN and from mechanistic studies primarily based on the passive Heymann nephritis model. Only recently, more detailed insights into the exact mechanisms of complement activation and effector pathways have been gained from patient data, animal models, and in vitro models based on specific target antigens relevant to the human disease. These data are of clinical relevance, as they parallel the recent development of numerous specific complement therapeutics for clinical use. Despite efficient B-cell depletion, many patients with MN achieve only partial remission of proteinuria, which may be explained by the persistence of subepithelial immune complexes and ongoing complement-mediated podocyte injury. Targeting complement, therefore, represents an attractive adjunct treatment for MN, but it will need to be tailored to the specific complement pathways relevant to MN. This review summarizes the different lines of evidence for a central role of complement in MN and for the relevance of distinct complement activation and effector pathways, with a focus on recent developments.

A Neanderthal haplotype introgressed into the human genome confers protection against membranous nephropathy.

Class 2 HLA and PLA2R1 alleles are exceptionally strong genetic risk factors for membranous nephropathy (MN), leading, through an unknown mechanism, to a targeted autoimmune response. Introgressed archaic haplotypes (introduced from an archaic human genome into the modern human genome) might influence phenotypes through gene dysregulation. Here, we investigated the genomic region surrounding the PLA2R1 gene. We reconstructed the phylogeny of Neanderthal and modern haplotypes in this region and calculated the probability of the observed clustering being the result of introgression or common descent. We imputed variants for the participants in our previous genome-wide association study and we compared the distribution of Neanderthal variants between MN cases and controls. The region associated with the lead MN risk locus in the PLA2R1 gene was confirmed and showed that, within a 507 kb region enriched in introgressed sequence, a stringently defined 105 kb haplotype, intersecting the coding regions for PLA2R1 and ITGB6, is inherited from Neanderthals. Thus, introgressed Neanderthal haplotypes overlapping PLA2R1 are differentially represented in MN cases and controls, with enrichment In controls suggesting a protective effect.

Targeting APRIL in the treatment of glomerular diseases.

A proliferation-inducing ligand (APRIL) is a key member of the tumor necrosis factor superfamily of cytokines and plays a central role in B-cell survival, proliferation, and Ig class switching. Recently, there has been increasing interest in the role of APRIL and the related cytokine B-cell activating factor in several glomerular diseases, because of their importance in the above processes. The therapeutic inhibition of APRIL represents a potentially attractive immunomodulatory approach that may abrogate deleterious host immune responses in autoimmune diseases while leaving other important functions of humoral immunity intact, such as memory B-cell function and responses to vaccination, in contrast to B-cell-depleting strategies. In this review, we describe the physiological roles of APRIL in B-cell development and their relevance to glomerular diseases, and outline emerging clinical trial data studying APRIL inhibition, with a focus on IgA nephropathy where the clinical development of APRIL inhibitors is in its most advanced stage.

Donor-derived membranous nephropathy in the allograft kidney: A rare but probably underestimated complication.

Transmitted donor-derived glomerular diseases in the allograft kidney are rare, especially when encountered in an allograft from a living donor. To date, only individual reports of donor-derived membranous nephropathy (MN) have been described. In this report, we present a case of MN discovered in a postreperfusion biopsy of a living-donor allograft. A follow-up biopsy 3 weeks later demonstrated persistent deposits. Thirteen months posttransplant, the recipient showed mildly worsening proteinuria but stable kidney function. To further our understanding of this exceedingly rare complication, we share our experience with 7 additional in-house cases together with 6 cases described in the literature to date. A minority of the donors were living. Most donors did not exhibit significant proteinuria illustrating how predonation screening could potentially miss donor-derived MN. Reactivity for phospholipase A2 receptor and thrombospondin type 1 domain containing 7A were negative in all stained cases. On follow-up, recipients variably exhibited slow resolution of the immune deposits, variable degrees of proteinuria (mainly subnephrotic), and no significant impairment of kidney function. Donor-derived MN is rare, phospholipase A2 receptor-negative, and can still be encountered in living donors despite rigorous screening. This report provides a brief examination of the pathology, clinical, and laboratory features of such patients involved.

De novo membranous nephropathy in a pig-to-baboon kidney xenograft: A new xenograft glomerulopathy.

De novo membranous nephropathy (dnMN) is an uncommon immune complex-mediated late complication of human kidney allografts that causes proteinuria. We report here the first case of dnMN in a pig-to-baboon kidney xenograft. The donor was a double knockout (GGTA1 and ß4GalNT1) genetically engineered pig with a knockout of the growth hormone receptor and addition of 6 human transgenes (hCD46, hCD55, hTBM, hEPCR, hHO1, and hCD47). The recipient developed proteinuria at 42 days posttransplant, which progressively rose to the nephrotic-range at 106 days, associated with an increase in serum antidonor IgG. Kidney biopsies showed antibody-mediated rejection (AMR) with C4d and thrombotic microangiopathy that eventually led to graft failure at 120 days. In addition to AMR, the xenograft had diffuse, global granular deposition of C4d and IgG along the glomerular basement membrane on days 111 and 120. Electron microscopy showed extensive amorphous subepithelial electron-dense deposits with intervening spikes along the glomerular basement membrane. These findings, in analogy to human renal allografts, are interpreted as dnMN in the xenograft superimposed on AMR. The target was not identified but is hypothesized to be a pig xenoantigen expressed on podocytes. Whether dnMN will be a significant problem in other longer-term xenokidneys remains to be determined.

The compositional and functional imbalance of the gut microbiota in CKD linked to disease patterns.

BACKGROUND: The prevalence of chronic kidney disease (CKD) is on the rise, posing a significant public health challenge. Although gut microbiome dysbiosis has been implicated in the impairment of kidney functions, the existence of pathological subtypes-linked differences remains largely unknown. We aimed to characterize the intestinal microbiota in patients with membranous nephropathy (MN), IgA nephropathy (IgAN), minimal change disease (MCD), and ischemic renal injury (IRI) in order to investigate the intricate relationship between intestinal microbiota and CKD across different subtypes. METHODS: We conducted a cross-sectional study involving 94 patients with various pathological patterns of CKD and 54 healthy controls (HCs). The clinical parameters were collected, and stool samples were obtained from each participant. Gut microbial features were analyzed using 16S rRNA sequencing and taxon annotation to compare the HC, CKD, MN, IgAN, MCD, and IRI groups. RESULTS: The CKD subjects exhibited significantly reduced alpha diversity, modified community structures, and disrupted microbial composition and potential functions compared to the control group. The opportunistic pathogen Klebsiella exhibited a significant enrichment in patients with CKD, whereas Akkermansia showed higher abundance in HCs. The study further revealed the presence of heterogeneity in intestinal microbial signatures across diverse CKD pathological types, including MN, IgAN, MCD, and IRI. The depression of the family Lachnospiraceae and the genus Bilophila was prominently observed exclusively in patients with MN, while suppressed Streptococcus was detected only in individuals with MCD, and a remarkable expansion of the genus Escherichia was uniquely found in cases of IRI. The study also encompassed the development of classifiers employing gut microbial diagnostic markers to accurately discriminate between distinct subtypes of CKD. CONCLUSIONS: The dysregulation of gut microbiome was strongly correlated with CKD, exhibiting further specificity towards distinct pathological patterns. Our study emphasizes the significance of considering disease subtypes when assessing the impact of intestinal microbiota on the development, diagnosis, and treatment of CKD.

Ofatumumab in Rituximab-Resistant and Rituximab-Intolerant Patients With Primary Membranous Nephropathy: A Case Series.

RATIONALE & OBJECTIVE: Rituximab is the first-choice therapy for patients with primary membranous nephropathy (MN) and nephrotic syndrome. However, approximately 30% of patients are treatment-resistant or become treatment-intolerant with hypersensitivity reactions upon repeated drug exposures. We aimed to assess whether ofatumumab, a fully human second-generation anti-CD20 antibody, could be a valuable alternative to rituximab in this population. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: 7 rituximab-intolerant and 10 rituximab-resistant patients with MN who consented to receive ofatumumab (50-300mg, single intravenous infusion) and were followed at the nephrology unit of Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII (Bergamo, Italy) between September 2015 and January 2019. FINDINGS: Over a median (IQR) follow-up of 5.0 (3.0-9.8) months, all 7 rituximab-intolerant and 3 of the 10 rituximab-resistant patients exhibited complete (proteinuria<0.3g/d) or partial (proteinuria<3.5g/d with≥50% reduction vs baseline) remission of nephrotic syndrome. Circulating B cells were similarly depleted in all patients by 1 week, and serum anti-phospholipase A2 receptor antibody concentrations decreased to<2.7 relative units/mL in 3 of 4 rituximab-intolerant and 4 of 8 rituximab-resistant patients with phospholipase A2 receptor-related disease. Ofatumumab significantly reduced 24-hour urinary protein and immunoglobulin G excretion and increased serum albumin and immunoglobulin G levels. These effects were greater in rituximab-intolerant than in rituximab-resistant patients. Measured glomerular filtration rate significantly increased by an average of 13.4% at 24 months compared with baseline (P=0.036) among all patients in the series. There were 14 nonserious infusion-related adverse events in 9 patients that recovered with temporary infusion interruption. LIMITATIONS: Retrospective design, limited number of patients. CONCLUSIONS: Ofatumumab may represent an effective and safe treatment for rituximab-intolerant cases of MN. Larger prospective studies will be needed to validate these preliminary findings and explore the effectiveness of other second-generation anti-CD20 antibodies in this clinical setting. PLAIN-LANGUAGE SUMMARY: Primary membranous nephropathy (MN) is one of the most frequent causes of nephrotic syndrome (NS) in adults. In this case series, we explored the efficacy of ofatumumab, a fully human second-generation anti-CD20 antibody, in 17 patients with MN and NS who were intolerant or unresponsive to rituximab. All 7 rituximab-intolerant patients exhibited complete or partial clinical remission, compared with only 3 of the 10 rituximab-resistant patients. Autoantibody levels decreased in all patients with phospholipase A2 receptor-related disease. Ofatumumab achieved a significant reduction in urinary protein and immunoglobulin G excretion while increasing serum albumin and immunoglobulin G levels. Ofatumumab may be a promising option for patients with MN who are rituximab-intolerant. Further investigations are warranted to validate these preliminary findings.

An Unusual Case of Anti-Glomerular Basement Membrane Disease and Phospholipase A2 Receptor-Associated Membranous Nephropathy After Exposure to Hydrocarbons.

We present a rare case of a patient with toluene exposure manifesting as anti-glomerular basement membrane (GBM) disease on a background of phospholipase A2 receptor (PLA2R)-associated membranous nephropathy. A 23-year-old man presented to the emergency department with hypertension, headache, hemoptysis, anemia, acute kidney injury, glomerular hematuria, and proteinuria. He endorsed repeated exposure to toluene-containing products while repairing dirt bikes. Serologies were positive for anti-GBM antibodies. Kidney biopsy showed crescentic glomerulonephritis with linear immunoglobulin G and granular PLA2R staining by immunofluorescence. He was initially treated with high-dose steroids, plasmapheresis, and hemodialysis for pulmonary-renal syndrome followed by oral cyclophosphamide and prednisone, which were discontinued after 3 months when follow-up biopsies confirmed little chance for renal recovery. He remained on dialysis 1 year later. This case exhibits a unique presentation of anti-GBM syndrome and underlying membranous nephropathy following repeated hydrocarbon exposure. Inhaled toxins promote recurrent localized inflammation, unmasking previously hidden epitopes. Early diagnosis and appropriate use of immunosuppressive and extracorporeal therapies are necessary to prevent morbidity and to improve survival in this rare condition.

Anti-Phospholipase A2 Receptor 1 and Anti-Cysteine Rich Antibodies, Domain Recognition and Rituximab Efficacy in Membranous Nephropathy: A Prospective Cohort Study.

RATIONALE & OBJECTIVE: Proteinuria and anti-phospholipase A2 receptor 1 (anti-PLA2R1) antibody titers are associated with primary membranous nephropathy (MN) outcomes. We evaluated the association of antibodies against the cysteine-rich (CysR) and C-type lectin 1, 7, and 8 (CTLD1, CTLD7, and CTLD8) domains of PLA2R1 with MN outcomes. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: One-hundred-thirteen consecutive, consenting patients referred to the Nephology Unit of the Azienda-Socio-Sanitaria-Territoriale (ASST) Papa Giovanni XXIII (Bergamo, Italy) with PLA2R1-related, biopsy-proven MN whose persistent nephrotic syndrome (NS) was managed conservatively for>6 months and were monitored with serial evaluations of proteinuria, autoantibodies (by enzyme-linked immunosorbent assay), and clinical outcomes. EXPOSURE: Rituximab. OUTCOME: Complete (proteinuria<0.3g/24h) or partial (proteinuria≥0.3g/24h and<3.0g/24h with>50% reduction vs basal) NS remission. ANALYTICAL APPROACH: Univariable and multivariable Cox regression analyses. RESULTS: All patients had anti-CysR antibodies; 62 (54.9%) were multidomain recognizers. Anti-PLA2R1 and anti-CysR antibody titers were strongly correlated at baseline (P<0.001, r=0.934), 6 months (P<0.001, r=0.964), and 12 months (P<0.001, r=0.944). During a median follow-up of 37.1 (IQR, 20.3-56.9) months, 71 patients (62.8%) achieved either complete or partial remission of their NS. Lower baseline anti-PLA2R1 (HR, 0.997 [95% CI, 0.996-0.999], P=0.002) and anti-CysR [HR, 0.996 [95% CI, 0.993-0.998], P=0.001) titers were associated with a higher probability of remission, along with female sex, lower proteinuria, and lower serum creatinine levels (P<0.05 for all comparisons). Anti-CTLD antibodies were not associated with outcomes. At 6 and 12 months, compared to baseline, anti-PLA2R1 and anti-CysR antibody titers decreased more in patients progressing to partial or complete remission than in those without remission (P<0.05 for all comparisons). LIMITATIONS: Observational design. CONCLUSIONS: In PLA2R1-related MN, anti-PLA2R1 and anti-CysR antibodies similarly predict rituximab efficacy independent of PLA2R1 domain recognition. The choice between these tests should be dictated by feasibility and costs. Evaluating anti-CTLD antibodies appears unnecessary. PLAIN-LANGUAGE SUMMARY: Primary membranous nephropathy (MN), a leading cause of nephrotic syndrome (NS) in adults, is an autoimmune disease caused by autoantibodies binding to the podocyte antigen phospholipase A2 receptor 1 (PLA2R1). We assessed whether the effects of anti-CD20 cytolytic therapy with the monoclonal antibody rituximab are associated with detection rates and levels of anti-PLA2R1 antibodies and antibodies against PLA2R1 domains such as cysteine-rich (CysR), and C-type lectin 1, 7, and 8 (CTLD1, 7, and 8), in patients with PLA2R1-related MN and persistent NS. The probability of rituximab-induced complete or partial NS remission was associated with baseline anti-PLA2R1 and anti-CysR antibody titers, but not with anti-CTLD1, 7 and 8 antibodies or multidomain recognition. Integrated evaluation of anti-PLA2R1 or anti-CysR antibodies with proteinuria and kidney function may play a role in monitoring the effects of rituximab in patients with PLA2R1-related NS and MN.

Monoclonal Immunoglobulin Crystalline Membranous Nephropathy.

Monoclonal immunoglobulin (MIg) crystalline nephropathies are rare lesions resulting from precipitation of MIgs in the kidney as intracellular or extracellular crystals. We describe a patient with multiple myeloma (IgGλ) and diabetes who presented with nephrotic range proteinuria. Kidney biopsy revealed membranous nephropathy superimposed on diabetic glomerulosclerosis. Glomeruli were negative for PLA2R, THSD7A, and NELL-1. Ultrastructurally, the subepithelial deposits were composed of crystals (ranging from rhomboid to rod to needle shaped), which failed to stain for immunoglobulins by routine immunofluorescence but stained for IgG+λ by paraffin immunofluorescence after pronase digestion. RNA-based immunoglobulin repertoire sequencing performed on bone marrow aspirate identified an IgGλ (γ1) clone, which was highly atypical, combining an extensively mutated (23.6%) Ig heavy chain derived from the IGHV1-24 with low pI and unusual mutations and a light chain derived from an extremely rare germline gene (IGLV10-54). This report expands the pathologic spectrum of MIg crystalline nephropathies by describing a unique case of crystalline nephropathy with IgGλ deposits manifesting as membranous nephropathy.

Anti-Neuron-Derived Neurotrophic Factor Antibodies in Secondary Membranous Nephropathy Caused by Syphilis: A Case Report.

We present the case of a 61-year-old man who developed nephrotic syndrome as a result of syphilis-associated secondary membranous nephropathy (MN). The patient showed nephrotic syndrome remission following antibiotic treatment for syphilis alone. Pathologically, the target antigen of immune complexes accumulated on glomerular basement membranes (GBM) in secondary MN caused by syphilis has been reported to be neuron-derived neurotrophic factor (NDNF). His renal histopathology was consistent with secondary MN caused by syphilis, with a full-house pattern on immunofluorescence microscopy, in addition to NDNF deposits that colocalized with IgG deposits granularly on the GBM. However, to date, there is no serological evidence for the involvement of NDNF in the GBM. In the present study, we found that anti-NDNF autoantibodies in the acute-phase serum disappeared in the convalescent-phase serum of a patient who recovered from syphilis and nephrotic syndrome after antibiotic therapy alone. This result supports the hypothesis that treatment of syphilis with antibiotics suppresses NDNF's antigenicity. In summary, we found new serological evidence emphasizing that NDNF is an etiological antigen in secondary MN caused by syphilis.

Association of Obesity With Kidney and Cardiac Outcomes Among Patients With Glomerular Disease: Findings From the Cure Glomerulonephropathy Network.

RATIONALE & OBJECTIVE: The influence of obesity on cardiorenal outcomes in individuals with glomerular disease is incompletely known. This study examined the association between obesity and kidney and cardiovascular outcomes in children and adults with glomerular kidney disease. STUDY DESIGN: Prospective, multicenter, observational study. SETTING & PARTICIPANTS: Participants in the Cure Glomerulonephropathy Network (CureGN) who were≥5 years of age at enrollment. EXPOSURE: Adult body mass index (BMI) groups: 20-24 (healthy) versus 25-34 (overweight/class 1 obesity) versus≥35 (class 2-3 obesity); and pediatric BMI percentiles: 5th-84th (healthy) versus 85th-94th (overweight) versus≥95th (obese). OUTCOME: A composite kidney outcome (40% estimated glomerular filtration rate [eGFR] decline or kidney failure) and a composite cardiovascular outcome (myocardial infarction, stroke, heart failure, or death). ANALYTICAL APPROACH: Time to composite primary outcomes by BMI strata were estimated using Kaplan-Meier analysis. The adjusted associations between BMI and outcomes were estimated using Cox proportional hazards analysis. RESULTS: The study included 2,301 participants (1,548 adults and 753 children). The incidence of the primary kidney end point was 90.8 per 1,000 person-years in adults with class 2-3 obesity, compared with 58.0 in normal weight comparators. In the univariable analysis, class 2-3 obesity was associated with the primary kidney outcome only in adults (HR, 1.6 [95% CI, 1.1-2.2], P=0.006) compared with the healthy weight groups. In the multivariable adjusted analysis, class 2-3 obesity did not remain significant among adults when controlling for baseline eGFR and proteinuria. Adults with class 2-3 obesity had an incidence of 19.7 cardiovascular events per 1,000 person-years and greater cardiovascular risk (HR, 3.9 [95% CI, 1.4-10.7], P=0.009) in the fully adjusted model. LIMITATIONS: BMI is an imperfect indicator of adiposity. Residual confounding may exist from socioeconomic factors. CONCLUSIONS: Among adult patients in CureGN, class 2-3 obesity is associated with cardiovascular but not kidney outcomes when adjusted for potential confounding factors. PLAIN-LANGUAGE SUMMARY: Obesity is a risk factor for adverse heart and kidney outcomes in patients with chronic kidney disease, but whether it is associated with these outcomes in patients with glomerulonephropathy is not known. This study used existing data from a large sample of adults and children with glomerular diseases to address this question. The findings suggest that obesity increases the risk of cardiovascular but not kidney disease events in adult patients with glomerular disease.

Association of COVID-19 Versus COVID-19 Vaccination With Kidney Function and Disease Activity in Primary Glomerular Disease: A Report of the Cure Glomerulonephropathy Study.

RATIONALE & OBJECTIVE: Patients with glomerular disease (GN) may be at increased risk of severe COVID-19, yet concerns over vaccines causing disease relapse may lead to vaccine hesitancy. We examined the associations of COVID-19 with longitudinal kidney function and proteinuria and compared these with similar associations with COVID-19 vaccination. STUDY DESIGN: Observational cohort study from July 1, 2021, to January 1, 2023. SETTING & PARTICIPANTS: A prospective observational study network of 71 centers from North America and Europe (CureGN) with children and adults with primary minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy. EXPOSURE: COVID-19 and COVID-19 vaccination. OUTCOME: Repeated measure of estimated glomerular filtration rate (eGFR); recurrent time-to-event outcome of GN disease worsening as defined by doubling of the urinary protein-creatinine ratio (UPCR) to at least 1.5g/g or increase in dipstick urine protein by 2 ordinal levels to 3+(300mg/dL) or above. ANALYTICAL APPROACH: Interrupted time series analysis for eGFR. Prognostic matched sequential stratification recurrent event analysis for GN disease worsening. RESULTS: Among 2,055 participants, 722 (35%) reported COVID-19 infection; of these, 92 (13%) were hospitalized, and 3 died (<1%). The eGFR slope before COVID-19 infection was-1.40mL/min/1.73m2 (± 0.29 SD); within 6 months after COVID-19 infection, the eGFR slope was-4.26mL/min/1.73m2 (± 3.02 SD), which was not significantly different (P=0.34). COVID-19 was associated with increased risk of worsening GN disease activity (HR, 1.35 [95% CI, 1.01-1.80]). Vaccination was not associated with a change in eGFR (-1.34mL/min/1.73m2±0.15 SD vs-2.16mL/min/1.73m2±1.74 SD; P=0.6) or subsequent GN disease worsening (HR 1.02 [95% CI, 0.79-1.33]) in this cohort. LIMITATIONS: Infrequent or short follow-up. CONCLUSIONS: Among patients with primary GN, COVID-19 infection was severe for 1 in 8 cases and was associated with subsequent worsening of GN disease activity, as defined by proteinuria. By contrast, vaccination against COVID-19 was not associated with change in disease activity or kidney function decline. These results support COVID-19 vaccination for patients with GN. PLAIN-LANGUAGE SUMMARY: In this cohort study of 2,055 patients with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy, COVID-19 resulted in hospitalization or death for 1 in 8 cases and was associated with a 35% increase in risk for worsening proteinuria. By contrast, vaccination did not appear to adversely affect kidney function or proteinuria. Our data support vaccination for COVID-19 in patients with glomerular disease.

Short and Long-Term Outcomes of Patients with Pure Membranous Lupus Nephritis Compared to Patients with Proliferative Disease.

OBJECTIVES: Membranous lupus nephritis (MLN) is thought to have a more benign course than proliferative lupus nephritis (PLN). We aimed to determine the differences in short and long-term outcomes between patients with MLN and PLN. METHODS: We included patients with first biopsy-proven MLN and PLN. Short-term outcomes included complete proteinuria recovery (CPR), complete renal response (CRR), and primary efficacy renal response (PERR). Long-term outcomes included a sustained ≥40% reduction in baseline estimated glomerular filtration rate (eGFR), end-stage kidney disease (ESKD), cardiovascular (CV) events, ≥2 increase in SDI, and death. Univariable and multivariable Cox proportional hazard models were used to examine the effect of baseline characteristics on long-term outcomes. RESULTS: Of 215 patients, 51 had pure MLN, and 164 had PLN. We found no significant differences between the two groups in achieving CPR, CRR, and PERR at 1 and 2 years. Median time to outcomes was slightly, but insignificantly, longer in the MLN group.For long-term outcomes, PLN was associated with worse renal and non-renal outcomes, but this was not statistically significant.In the multivariable Cox proportional hazard models, ESKD was associated with the following baseline variables: younger age (HR 0.92, 95% CI 0.87-0.97), higher creatinine (HR 1.01, 95% CI 1.01-1.02), low complement (HR 4.0, 95% CI 1.04-11.10), and higher chronicity index (HR 1.28, 95% CI 1.08-1.51). CONCLUSION: The resolution of proteinuria in LN is slow. MLN is not a benign disease and may be associated with deterioration of renal function, ESKD, damage, CV events, and death.

Risk of chronic kidney disease in 260 patients with lupus nephritis-analysis of a nationwide multicentre cohort with up to 35 years of follow-up.

OBJECTIVES: To compare proliferative (PLN) and membranous (MLN) lupus nephritis (LN) regarding clinical and laboratory presentation and long-term outcomes; To investigate predictors of progression to chronic kidney disease (CKD). METHODS: Multicentre observational study, with retrospective analysis of a prospective cohort, using data from the Rheumatic Diseases Portuguese Registry-Reuma.pt. Patients with biopsy-proven PLN, MLN and mixed LN were included. Cox regression survival analysis was used to investigate predictors of CKD. RESULTS: 260 patients were included. Median follow-up was 8 years (IQR 11; minimum 1, maximum 35 years). MLN patients presented with significantly lower serum creatinine (0.70 (IQR 0.20; minimum 0.50, maximum 1.30) mg/dl vs 0.80 (IQR 0.31; minimum 0.26, maximum 2.60) in PLN, p= 0.003). Proteinuria levels did not differ between groups (p= 0.641). Levels of complement were reduced in PLN but nearly normal in MLN patients, and there were fewer patients with positive anti-dsDNA antibodies in the MLN group (p< 0.001). One year after the beginning of treatment, 62% of the patients achieved EULAR/ERA-EDTA complete response, with further 5% achieving partial response. Patients with lower proteinuria at diagnosis were more likely to achieve a complete renal response at one year, however, proteinuria at diagnosis or at one year did not predict long term CKD. Estimated glomerular filtration rate (eGFR) ≤75 mL/min/1.73 m2 at one year was the strongest predictor of progression to CKD (HR 23 [95% CI 8-62], p< 0.001). Other possible predictors included the use of azathioprine for induction of remission, older age at diagnosis and male sex. CONCLUSION: Proteinuria levels did not predict LN histologic class in our cohort. eGFR cutoff of 75 mL/min/1.73 m2 after one year of treatment was strongly predictive of progression to CKD.