Citations

ABSTRACT Background Up to 20% of patients with antineutrophil cytoplasmic antibody–associated vasculitis (AAV) and kidney involvement progress to end-stage kidney disease (ESKD) despite therapy. The role of monoclonal gammopathy (MG) in disease progression in patients with AAV is not well understood. Methods We conducted a retrospective study to identify patients diagnosed with AAV and renal involvement who had undergone monoclonal protein testing between November 1999 and December 2023. A total of 167 patients were included in the renal survival analysis and were categorized into monoclonal positive (n = 34) and monoclonal negative (n = 133) groups. For the mortality analysis, we expanded the cohort to include an additional 26 patients who were dialysis-dependent at baseline and remained on dialysis throughout follow-up, resulting in a total of 193 patients. We performed multivariate Cox analysis to identify predictors of adverse renal events [>40% decline in estimated glomerular filtration rate (eGFR) or ESKD (eGFR <15 mL/min/1.73 m², need for dialysis or transplantation)] and mortality. Results Median age of the cohort was 68 (58.5–74.5) years, with 50.8% males, 65.8% MPO positive, and 64.6% receiving rituximab as induction therapy. After adjusting for baseline proteinuria, sclerotic Berden class and induction therapy, MG was associated with adverse renal events [hazard ratio (HR) 3.29 (95% confidence interval 1.12–9.68), P = .03]. MG at baseline was not associated with mortality [HR 1.65 (0.87–3.12), P = .12], however patients with persistent MG at 6 months had higher mortality compared with those without MG or those whose MG was not sustained [HR 3.95 (1.10–14.21), P = .035]. Conclusions Patients with AAV and renal involvement who have MG are at significantly increased risk of adverse renal events even after adjusting for factors such as eGFR and degree of chronicity (known predictors of poor renal outcome). The exact mechanism by which MG portends poor outcomes is poorly understood, and additional research is required.

Key Points Our study found a high prevalence of monoclonal gammopathy (MG) in patients diagnosed with ANCA-negative pauci-immune crescentic GN. Patients with MG showed a higher degree of fibrosis on kidney biopsy than those without MG with higher mortality rate. Our data suggest an association between MG and ANCA-negative pauci-immune crescentic GN, emphasizing this population's need for MG testing and monitoring. Background In a small subset of patients with pauci-immune crescentic GN (PICGN), ANCA are not identified, and patients are referred to as having ANCA-negative vasculitis. The cause of the disease in this subset of patients has remained elusive. We explored the role of monoclonal gammopathy (MG) in those with ANCA-negative PICGN. Methods We conducted a retrospective study and identified patients with PICGN who had undergone ANCA and monoclonal testing. Those positive for ANCA were excluded. Results We identified 14 patients with ANCA-negative vasculitis, of whom eight (57%) tested positive for MG with a mean age of 60.3±12.2 years, 75% were female, and with a mean serum creatinine of 4.3±1.92 mg/dl. The most common monoclonal proteins were IgG ( n =4, 50%) and kappa ( n =4, 50%). One patient had diagnosis of multiple myeloma. Most common extra-renal manifestations were skin rash (leukocytoclastic vasculitis) and neuropathy. Kidney biopsy showed a higher degree of interstitial fibrosis and tubular atrophy compared with those without MG. The median follow-up time was 3.2 years, with 50% mortality in those with MG. Conclusions More than 50% of the patients with ANCA-negative PICGN have MG, and patients present with more evidence of fibrosis on kidney biopsy, with higher mortality rate observed in our cohort. Monoclonal proteins may trigger the development of PICGN; their specific role in the pathogenesis of this disease needs further investigation.

ABSTRACT Background and hypothesis Podocytopathy associated with likely pathogenic/pathogenic variants of Transient receptor potential cation channel subfamily C member 6 (TRPC6) (TRPC6-AP) has been recognized for about 20 years. As a result of its rarity however, the spectrum of clinical phenotypes and genotype–phenotype correlation of TRPC6-AP remains poorly understood. Here, we characterized clinical, histological and genetic correlates of familial and sporadic patients with TRPC6-AP. Methods In this multicentre observational study, an online questionnaire followed by a systematic literature review was performed to create a cohort with comprehensive data on genetic and clinical outcomes [age of onset, clinical presentation, treatment response, kidney biopsy findings and progression to kidney failure (KF)]. Logistic regression, Cox proportional hazards model and Kaplan–Meier analyses investigated the associations between genetic variants and disease progression. Results Among 87 families (96 familial and 45 sporadic cases), 31 distinct missense TRPC6 variants (including 2 novel) were identified, with c.2683C>T p.(Arg895Cys) and c.523C>T p.(Arg175Trp) the commonest variants. Proteinuric kidney disease/nephrotic syndrome was the most common clinical presentation (83.7%), while focal segmental glomerulosclerosis was the most common histological finding (89.4%). By 33 (interquartile range 17–40) years, 48.9% (69/141) of patients had progressed to KF. Sporadic TRPC6-AP demonstrated an earlier progression to KF than familial cases (P = .001) and were more likely to present with nephrotic syndrome [odds ratio 4.34 (1.85–10.15); P = .001]. Gain-of-function TRPC6 variants were more frequent in familial than sporadic TRPC6-AP (70.8% vs 44.4%; P = .004). Compared with patients with other TRPC6 variants, patients with TRPC6 p.R175W and p.R895C variants progressed to KF earlier [median kidney survival of 21 years, hazard ratio 2.985 (95% confidence interval 1.40–5.79); and 38 years, hazard ratio 1.65 (95% confidence interval 1.01–2.81), respectively, log-rank P = .005]. Conclusion Our study shows unique clinical and genetic correlations of TRPC6-AP, which may enable personalized care and promising novel therapies.