Fernando Caravaca-Fontán

Lupus nephritis is a major cause of morbidity and long-term kidney damage in patients with systemic lupus erythematosus. Despite therapeutic advances, complete remission rates remain modest, and progress to kidney failure still occurs in a substantial proportion of patients. Contemporary management has shifted toward early initiation of ‘triple therapy’, yet patients continue to suffer from the adverse effects of prolonged glucocorticoid exposure. Challenges persist, including treatment duration, safe tapering, and the high rates of flare following immunosuppression withdrawal, underscoring the potential role of repeat kidney biopsy in guiding decisions. Poor adherence is very common and a significant impediment in daily practice and often leads to the incorrect classification of patients as having ‘refractory disease’. Furthermore, conventional biomarkers are not ideal for flare prediction. Emerging therapies offer promising efficacy but remain inaccessible for many patients due to high costs and different reimbursement policies. Comprehensive management further requires attention to pregnancy planning, infection prophylaxis, care of chronic kidney disease, and long-term complications such as malignancy and osteoporosis. The goal should be to preserve kidney function, minimize cumulative toxicity, and restore quality of life to all patients, regardless of geography or economic status. This article provides a perspective of the Immunonephrology Working Group of the European Renal Association and discusses the key unmet needs in the management of lupus nephritis.

C3 glomerulopathy (C3G) is an ultra-rare, complement-mediated glomerular disease characterized by dysregulation of the alternative complement pathway and a high propensity for recurrence after kidney transplantation. Although kidney transplantation remains the optimal treatment for patients reaching kidney failure, post-transplant recurrence continues to be a major cause of graft dysfunction and loss. Over the past decade, improved histopathologic recognition and the increasing adoption of protocol biopsies have revealed that C3G frequently recurs early after transplantation, often in a subclinical form. At present, no validated clinical, genetic, or functional biomarkers reliably predict recurrence, and preventive strategies remain unproven. Consequently, from our standpoint, management of recurrent C3G requires a pragmatic, surveillance-driven approach rather than prophylactic intervention. In this review, we provide a practical framework for managing recurrent C3G after kidney transplantation, from transplant candidacy and pretransplant evaluation to post-transplant monitoring and therapeutic decision-making. We discuss the role of protocol biopsies, the limitations of conventional immunosuppression, and the emerging place of proximal complement inhibitors. Finally, we highlight several unmet needs that continue to limit optimal care, including persistent uncertainty about therapeutic goals, management of subclinical histologic recurrence, and interpretation of treatment response. This review reflects a transplant-centered clinical perspective aimed at supporting nephrologists in real-world decision-making.

Background: Renal sarcoidosis is a rare manifestation of systemic sarcoidosis. Evidence guiding management remains limited. We aimed to characterize clinical and histopathological features, renal outcomes, and predictors of recovery and relapse in patients with renal sarcoidosis. Methods: In this retrospective, multicenter observational study across hospitals affiliated with the Spanish Group for the Study of Glomerular Diseases, we included patients with biopsy-confirmed renal sarcoidosis and ≥6 months of follow-up. Primary outcomes were renal recovery (defined as >50% improvement in estimated glomerular filtration rate) and disease relapse (renal or extrarenal). Secondary outcomes included progression to end-stage kidney disease (ESKD) and treatment-related complications. Results: In this study, 60 patients with a mean age of 56.8 years were included. Tubulointerstitial involvement predominated (80%), with granulomatous interstitial nephritis in 56.7%, while 23.3% exhibited glomerular disease. Patients with interstitial-only patterns achieved more frequently renal recovery at 12 months compared with those with glomerular involvement (65.9% vs 20%, P = .013). Intravenous corticosteroid pulses were associated with faster renal improvement in our cohort, although it should be interpreted cautiously because of potential indication bias. Higher oral corticosteroid doses, prolonged high-dose exposure, or slower tapering strategies did not improve renal outcomes and were associated with increased complications. Over a median follow-up of 36 months, 38.3% of patients experienced relapse, and 6.7% of patients progressed to ESKD. Conclusions: Renal sarcoidosis exhibits heterogeneous presentations but substantial potential for renal recovery, particularly in patients with granulomatous interstitial nephritis. These findings may support further investigation of pathology-informed treatment strategies aimed at reducing corticosteroid exposure. Prospective studies are needed to define optimal treatment strategies.

Introduction: Kidney involvement is frequent in AL amyloidosis and significantly impacts prognosis. Although hematologic response is the recommended marker for monitoring treatment efficacy, organ-specific responses are frequently evaluated in clinical practice. In this context, the significance and optimal timing of kidney-specific response remain poorly defined in the literature. Methods: We conducted a retrospective study of patients with renal AL amyloidosis treated with or without anti-clonal therapy (ACT). Kidney response rates and their timing were analyzed. Patients were stratified by time to kidney response: very early (0–6 months), early (6–12 months), and late (>12 months). Baseline characteristics, treatments, and outcomes were compared across groups. Results: Seventy-six patients were included; 58 received ACT. Among them, 59% achieved hematologic response and 52% achieved kidney response. Kidney response was associated with improved kidney survival. Median time to hematologic response was 4.58 (1–9.38) months, whereas median time to partial and complete kidney response were 9 (6–18) and 16.5 (9–25) months (P = .03). Kidney outcomes were similar regardless of response timing. Patients with late kidney response had longer time to hematologic response (9.75 vs. 3 months, P = .02), longer treatment duration (24.5 vs. 9 months, P = .02), and received more ACT lines, particularly among those with very early hematologic response. Conclusion: Kidney response in AL amyloidosis occurs later than hematologic response but is associated with favorable kidney outcomes. In our study, delayed kidney response was associated with longer treatment duration despite hematologic response. Prospective studies are needed to determine whether treatment decisions based on kidney response alone improve or worsen patient outcomes.

Complement 3 glomerulopathy (C3G) and primary immune complex–mediated membranoproliferative glomerulonephritis (IC-MPGN) are ultra-rare glomerular diseases driven by dysregulation of the complement system, most commonly involving the alternative pathway. Recent advances in the understanding of disease pathogenesis have enabled the development of targeted complement therapies. The publication of pivotal phase 3 trials evaluating proximal complement inhibitors –iptacopan, a selective factor B inhibitor, and pegcetacoplan, a C3 inhibitor– marks a turning point in the management of C3G and IC-MPGN. Both agents demonstrated clinically meaningful reductions in proteinuria and stabilization of kidney function, establishing proof of efficacy. Despite these advances, important uncertainties remain. Key unresolved issues include optimal patient selection, timing and duration of therapy, treatment sequencing, monitoring strategies, and long-term kidney outcomes. Conventional immunosuppressive approaches provide inconsistent benefit and do not directly address complement dysregulation, while validated biomarkers to guide complement blockade are lacking. Additional challenges relate to treatment discontinuation, management of special populations, and health-system implementation. This review critically appraises the evidence from recent pivotal trials, highlighting both their transformative impact and the questions they raise. We emphasize the need for long-term outcome studies, precision-based therapeutic strategies, and pragmatic real-world data. Ultimately, the challenge ahead is not whether complement inhibition is effective but how best to deploy these therapies to maximize durable benefit, minimize risk, and ensure equitable access.

Background: C3 glomerulopathy (C3G) and primary immune complex–mediated membranoproliferative glomerulonephritis (IC-MPGN) frequently recur after kidney transplantation and represent leading causes of graft loss. However, the natural history of recurrent disease and the prognostic value of longitudinal kidney biomarkers remain poorly defined. Methods: We conducted a multinational, retrospective cohort study of adults and children with biopsy-proven recurrent C3G or primary IC-MPGN in the kidney allograft (2001–2023). Patients were enrolled from 48 centers across 11 countries and required ≥4 serial measurements of estimated glomerular filtration rate (eGFR) and proteinuria after recurrence. Longitudinal trajectories of eGFR and proteinuria and their association with graft failure were evaluated using linear mixed-effects and Bayesian joint longitudinal–survival models. Complement genetic and autoantibody testing was performed in a subset of patients. Results: Of 332 eligible transplant recipients, 134 developed biopsy-proven recurrence (C3GN 60%, DDD 12%, IC-MPGN 28%). Median time to recurrence was 16 months, and 58% progressed to graft failure after a median follow-up of 62 months. Earlier recurrence, lower serum albumin, and higher histologic chronicity independently predicted failure. Joint models demonstrated that lower eGFR and higher proteinuria were dynamically associated with higher graft failure risk. Time-averaged proteinuria >1 g/day and eGFR lowering steeper than –5 mL/min/1.73 m ² /year identified high-risk trajectories. Among 71 tested patients, 34% carried pathogenic complement variants and 23% had complement-directed autoantibodies; autoantibody-positive patients experienced earlier graft failure despite similar overall failure rates. Conclusions: Recurrent C3G and primary IC-MPGN after transplantation are associated with poor long-term outcomes, substantial histologic injury, and marked biological heterogeneity. Longitudinal eGFR and proteinuria provide powerful prognostic information, and clinically meaningful thresholds (>1 g/day time-averaged proteinuria; eGFR slope steeper than –5 mL/min/1.73 m ² /year) refine risk stratification. Dynamic biomarkers may serve as surrogate endpoints, underscoring the need for prospective validation with emerging proximal complement therapies.

C3 glomerulopathy (C3G) is a rare complement-mediated kidney disease. Pegcetacoplan [targeted complement 3 (C3)/C3b inhibitor] and iptacopan (factor B inhibitor) target the complement system and are approved for treatment of C3G in adults and adolescents (pegcetacoplan) or adults only (iptacopan). Currently, no head-to-head randomized controlled trials (RCTs) have assessed their relative efficacy. Indirect treatment comparisons (ITCs) were conducted using the Bucher (primary analysis-preserves randomization) and matching-adjusted indirect comparison (MAIC; supportive analyses-adjusts for trial differences) methodologies and data from two similarly designed, placebo-controlled, Phase III RCTs in C3G/primary immune-complex membranoproliferative glomerulonephritis [VALIANT (NCT05067127)] and C3G only [APPEAR-C3G (NCT04817618)]. Relative efficacy was assessed at 6 months (anchored Bucher and MAIC) and 12 months (anchored Bucher/MAIC plus unanchored MAIC). At 6 months, the Bucher analysis demonstrated pegcetacoplan was associated with a significantly greater reduction in urine protein-creatinine ratio (UPCR) relative to baseline versus iptacopan [mean difference -50.90% (95% confidence interval: - 67.34, - 26.18); p < 0.001]; also a significantly greater proportion of patients achieved UPCR reduction to < 1 g/g, UPCR reduction by ≥ 50%, and the composite renal endpoint [≥ 50% reduction in UPCR and ≤ 15% reduction in estimated glomerular filtration rate (eGFR)]. The between-trial difference in mean eGFR change from baseline was not statistically different between treatments. Results from the anchored MAIC were generally consistent with the Bucher analysis. At 12 months, pegcetacoplan was associated with a significantly greater reduction in UPCR from baseline versus iptacopan but not for eGFR. These ITCs indicate that, in patients with C3G, pegcetacoplan is associated with greater reductions in proteinuria levels, and more patients achieved the composite renal endpoint compared with iptacopan. The relative efficacy benefits for pegcetacoplan observed at 6 months were sustained at 12 months. These comparative effectiveness findings may help clinicians and payers better understand the utility of new therapies to treat patients with C3G.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are systemic small-vessel necrotizing vasculitides, including microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Genetic factors, particularly human leukocyte antigen variants, contribute to disease susceptibility and define distinct myeloperoxidase- and proteinase 3-associated phenotypes. This review summarizes current understanding of organ-specific manifestations, therapeutic advances, and prognostic determinants of AAV, with particular relevance for nephrologists. Kidney involvement is common, particularly in MPA, whereas GPA and EGPA more frequently present with extrarenal manifestations. Pulmonary involvement is also frequent, ranging from alveolar haemorrhage and interstitial lung disease (ILD) in MPA to granulomatous nodules and airway disease in GPA, while asthma dominates in EGPA. Other frequent manifestations include ear, nose, and throat (ENT), peripheral nervous system, cutaneous, and constitutional manifestations, with ENT activity and non-haemorrhagic respiratory manifestations correlating with relapse risk. Current treatment emphasizes rituximab or cyclophosphamide with reduced-dose glucocorticoids for induction, avacopan for glucocorticoid-sparing strategies, and rituximab for maintenance. Avacopan has shown benefits beyond renal outcomes. Furthermore, anti-interleukin-5 therapies have recently been approved for the treatment of EGPA. Contrarily, ILD remains a therapeutic challenge, with limited evidence for antifibrotic agents. AAV patients are at high risk of infections, thromboembolism, and malignancy, influenced by both disease activity and treatment exposure. Mortality remains high, driven mainly by infections, with kidney and lung involvement serving as major prognostic determinants. For nephrologists, early recognition of extrarenal manifestations, vigilance for relapse beyond the kidney, and multidisciplinary collaboration are crucial for optimizing long-term outcomes.