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.

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 pre-transplant 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:Immune-mediated acute tubulointerstitial nephritis (ICI-AIN) is the most common form of immune-mediated renal toxicity induced by immune checkpoint inhibitors (ICIs). It has an excellent response to corticosteroids, but there is no consensus on the most suitable steroid regimen. Methods:A multicentre retrospective study including 62 patients diagnosed with ICI-AIN treated with corticosteroids was conducted. Patients were categorized into two groups based on the duration of corticosteroid treatment: 'short course of steroids (SCS)' (<12 weeks) and 'long course of steroids (LCS)' (≥12 weeks). The study aims to compare the efficacy and toxicity of these two regimens. Results:Twenty-eight patients received SCS and 34 received LCS. Renal recovery was achieved in 89% of patients, with no differences between groups (P = 1). Serum creatinine levels were also similar (1.2 mg/dL, P = .71) at the end of follow-up. ICI rechallenge was attempted in 18 patients, and ICI-AIN recurred in 5 (28%). Among these, four recurrences occurred in LCS patients, 67% still receiving ≥10 mg of prednisone. Steroid-related adverse events per patient-month were lower in the SCS group (0.027 vs 0.072, 95% confidence interval 0.20-0.68; P = .001). At 12 and 18 months, progression-free survival and overall survival were significantly better in the SCS group, even after adjusting for confounders. Conclusions:SCS is an effective and safe approach for the management of ICI-AIN. It offers a comparable rate of renal recovery, fewer adverse events and possibly more favourable oncological outcomes, compared with a prolonged regimen. Future prospective studies are warranted.

Malignant hypertension with acute kidney injury or acute kidney disease is a life-threatening condition requiring urgent antihypertensive treatment and which carries a serious risk of kidney function loss. The presence of thrombotic microangiopathy (microangiopathic hemolytic anemia and thrombocytopenia) further challenges the diagnosis and treatment of these patients. As shown by recent studies, a high proportion of patients with complement-mediated thrombotic microangiopathy present with severe and malignant hypertension; however, extreme elevation of blood pressure by itself can induce vascular lesions of thrombotic microangiopathy. To resolve this conundrum, it is essential to rapidly investigate and exclude forms of secondary hypertension (in which hematologic features are rare) and secondary thrombotic microangiopathies, both of which require treatment of the specific underlying etiology. Definitive differentiation of essential hypertension and complement-mediated thrombotic microangiopathy requires complement genetic testing, the results of which usually take weeks to months. In this review, we analyze the clinical and histologic data that would support the diagnosis of complement-mediated thrombotic microangiopathy before the results of genetic tests, prompting the rapid initiation of complement blockers. However, there are numerous unmet gaps in the pathogenesis, diagnosis, and treatment of this disorder that require further research.

Recurrent C3 glomerulopathy (C3G) and primary immune complex–mediated membranoproliferative glomerulonephritis (IC-MPGN) remain major causes of kidney allograft dysfunction and loss. Their pathogenesis involves genetic susceptibility, acquired complement dysregulation, and transplant-related triggers, yet no clear validated predictors of recurrence exist. Recurrence rates after kidney transplantation frequently exceed 60% and are associated with progression to graft failure. Early detection –often achievable through protocol biopsies– offers an opportunity for timely intervention, although histologic recognition of early recurrence can be challenging. Comprehensive pre-transplant evaluation, including genetic and molecular complement testing and screening for monoclonal gammopathies, may refine risk stratification. Conventional treatments, including intensified immunosuppression, rituximab, and plasma exchange, have shown limited and inconsistent efficacy. Conversely, complement-targeted therapies have yielded promising outcomes. While eculizumab remains the most extensively studied agent, emerging proximal complement inhibitors, such as iptacopan and pegcetacoplan, have shown encouraging efficacy in both native and recurrent disease. However, optimal timing, prophylactic use, and long-term safety in transplant recipients remain uncertain. This review outlines the clinical spectrum, key diagnostic and therapeutic challenges, and emerging treatment strategies for recurrent C3G and IC-MPGN, highlighting advances that may ultimately improve graft survival and patient outcomes.

Recurrent C3 glomerulopathy (C3G) and primary immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) remain major causes of kidney allograft dysfunction and loss. Their pathogenesis involves genetic susceptibility, acquired complement dysregulation, and transplant-related triggers, yet no clear validated predictors of recurrence exist. Recurrence rates after kidney transplantation frequently exceed 60% and are associated with progression to graft failure. Early detection, often achievable through protocol biopsies, offers an opportunity for timely intervention, although histologic recognition of early recurrence can be challenging. Comprehensive pretransplant evaluation, including genetic and molecular complement testing and screening for monoclonal gammopathies, may refine risk stratification. Conventional treatments, including intensified immunosuppression, rituximab, and plasma exchange, have shown limited and inconsistent efficacy. Conversely, complement-targeted therapies have yielded promising outcomes. Although eculizumab remains the most extensively studied agent, emerging proximal complement inhibitors such as iptacopan and pegcetacoplan have shown encouraging efficacy in both native and recurrent disease. However, optimal timing, prophylactic use, and long-term safety in transplant recipients remain uncertain. In this review, we outline the clinical spectrum, key diagnostic and therapeutic challenges, and emerging treatment strategies for recurrent C3G and IC-MPGN, highlighting advances that may ultimately improve graft survival and patient outcomes.

Monkeypox (mpox) is an orthopoxviral zoonotic disease with a similar but less severe clinical presentation as smallpox. However, immunocompromised patients such as solid organ transplant recipients are at higher risk of developing severe forms of the disease. Herein, we describe the case of a 43-year-old female kidney transplant recipient that manifested severe skin ulcers alongside nodular lung opacities and pleural effusion attributed directly to the monkeypox virus. Notwithstanding the initiation of early treatment with tecovirimat, a satisfactory response was not achieved until a reduction in immunosuppression to everolimus monotherapy, coupled with the transition to cidofovir for antiviral treatment. In conclusion, mpox has the potential to produce a severe form of systemic infection in individuals who have undergone solid organ transplantation, demanding a meticulous approach involving sequential antiviral treatment and modifications to immunosuppressive regimens in order to achieve complete healing.

IntroductionPersistent chronic hypotension affects 5-10% of dialysis patients. It seems to be reversible after receiving a functioning graft, but data regarding its influence on transplant outcomes are scarce. We analyse the evolution of patients with chronic hypotension in dialysis who undergo kidney transplantation at our center.MethodsA retrospective observational study was conducted. Sixty-six patients with chronic hypotension (defined as systolic blood pressure ≤ 100 mmHg at the time of transplantation) were identified. A control group of 66 non-hypotensive patients was assigned and matched for organ source and age. The evolution of both groups was compared.ResultsHypotensive patients had higher rates of primary non-function (18.2% vs 6.1%, p= 0.03) mainly due to venous thrombosis of the allograft (15.2% vs 3%, p= 0.015), worse renal function at the end of follow-up (eGFR of 35mL/min/1.73m2 vs 48mL/min/1.73m2, p= 0.001) but there was no statistical difference in graft survival after censoring for primary non-function. After multivariable adjustment, chronic hypotension remained an independent predictor factor for kidney graft failure (adjusted HR of 2.85; 95% CI: 1.24-6.57; p= 0.014). Use of vasoactive drugs and anticoagulation in hypotensive patients was associated with 7.1% of venous graft thrombosis compared to 17.3% in those with no intervention (p= 0.68). Receiving a functioning graft implied blood pressure normalization in patients with chronic hypotension.ConclusionsChronic hypotension in dialysis has a negative impact on short-term kidney transplant outcomes but a lower impact on long-term results. It is reversible after receiving a functioning graft. Identifying this subgroup of patients seems crucial to implement measures aimed at improving transplant results.

BackgroundSecondary atypical hemolytic uremic syndrome (secondary aHUS) is a heterogeneous group of thrombotic microangiopathies (TMA) associated with various underlying conditions. Unlike primary aHUS, there is still no hard evidence on the efficacy of complement blockade in secondary aHUS, since the two main series that investigated this subject showed discrepant results. Our work aims to reassess the efficacy of eculizumab in treating secondary aHUS.MethodsObservational, retrospective, single-center study, in which we analyzed the hematological and renal evolution of 23 patients diagnosed with secondary aHUS who received treatment with eculizumab and compared them with a control cohort of 14 patients. Complete renal response was defined as the recovery of renal function before the event, partial renal response as a recovery of 50% of lost glomerular filtration rate, and hematological response as normalization of hemoglobin and platelets.ResultsWe found no statistically significant differences in baseline characteristics or disease severity between both groups. After a median of 5 doses of eculizumab, the group of patients who received complement blockade presented a significant difference in renal response (complete in 52.3% of patients and partial in 23.8%) compared to the control cohort (complete response 14.3% and partial of 14.3%). Rates of hematological remission were similar in both groups (90.9% in the eculizumab cohort and 85.7% in the control cohort).ConclusionEarly and short-term use of eculizumab in patients with secondary aHUS could be an effective and safe therapeutic option, assuring better renal recovery compared to patients who do not receive complement blockade.

Activation of the alternative pathway (AP) of complement is involved in the pathogenesis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), although the underlying molecular mechanisms are unclear. To gain insight into the role of the AP, common gene variants in CFH/CFHR1-5, CFB, C3 and MCP, and longitudinal determinations of plasma C3, C4, FH, FHR-1, FHR-2, FHR-5, FB, properdin and sC5b-9 levels were analyzed in a Spanish AAV cohort consisting of 102 patients; 54 with active AAV (active cohort) and 48 in remission not receiving immunosuppressants or dialysis therapy (remission cohort). The validation cohort consisted of 100 patients with ANCA-associated glomerulonephritis. Here, we demonstrated that common genetic variants in complement components of the AP are associated with disease susceptibility (CFB32Q/W) or severity of kidney damage in AAV (CFH-H1, CFH1H2 and DCFHR3/1). Plasma levels of complement components were significantly different between active and remission cohorts. In longitudinal observations, a high degree of AP activation at diagnosis was associated with worse disease outcome, while high basal FHR-1 levels and lower FH/FHR-1 ratios determined severe forms of kidney associated AAV. These genetic and plasmatic findings were confirmed in the validation cohort. Additionally, autoantibodies against FH and C3 convertase were identified in one and five active patients, respectively. Thus, our study identified key genetic and plasma components of the AP that determine disease susceptibility, prognosis, and severity in AAV. Our data also suggests that balance between FH and FHR-1 is critical and supports FHR-1 as a novel AP -specific therapeutic target in AAV. Kidney International (2024) 105, 177-188; https://doi.org/10.1016/ j.kint.2023.10.013

BackgroundThrombotic microangiopathy (TMA) is a rare complication after lung transplantation (LT) that has seldom been characterized in detail. Recent evidence has linked TMA other than primary atypical hemolytic uremic syndrome (aHUS) with hyperactivation of the complement alternative pathway. The focus of this investigation was to analyze the treatment response with eculizumab in TMA after LT.MethodsCase series where we have studied 11 patients with TMA after LT from 2 Spanish tertiary healthcare centers. Clinical data and response rates to eculizumab are provided.ResultsThe main indication for lung transplant was chronic obstructive pulmonary disease (COPD) (36%) and most cases (82%) received bilateral LT. The median time to TMA diagnosis was 11.6 months (4.7-28.9) and the TMA trigger in the majority of cases (73%) was immunosuppressive drugs. Platelet and hemoglobin nadir were 58 x 103/mu L (24-108) and 7.7 g/dL (7.1-7.9), respectively. All cases presented acute kidney injury (AKI) with a median creatinine of 4 mg/dL (3.2-4.8) and 54.5% required acute dialysis. Eculizumab was started after a median time of 8 days (6-14) with a median duration of 3 weeks (2-8). Complete TMA response was observed in 7 (63.6%) cases and hematologic response in 10 (90.9%). The time to hematologic and renal response was 23 days (13-29) and 28 days (14-46), respectively.ConclusionsTMA after LT is infrequent but potentially devastating. Our findings suggest that short cycles of eculizumab may be effective for severe TMA after LT.

Abstract Background and Aims Immune checkpoint inhibitors (ICPi) have been a revolution in oncology. Due to their mechanism of action they can produce inflammatory adverse events, called “immune related adverse events” (IrAEs). Immune-mediated renal toxicity appears to be infrequent (2.2-5%), with acute tubulointerstitial nephritis being the most common form, clinically manifested as acute kidney injury (AKI). Corticosteroids are a highly effective treatment. However, the most suitable regimen has not been established. Method Retrospective multicenter study to evaluate the efficacy and safety of a short course of steroids (Group A) versus a long course (Group B) in patients with a clinical or histologic diagnosis of ICPi-associated acute kidney injury (ICPi-AKI). Short-duration regimen was considered to be that with a duration ≤3 months. Renal response was assessed 3 months after initiation of steroid therapy. Partial and complete renal response rates were compared in both groups, as well as relapses of ICPi-AKI with the lowering or suspension of steroid treatment. The development of adverse effects attributable to corticosteroids and the evolution of the oncologic disease were also evaluated. Results Sixty-three patients were included, 30 (48%) of whom received a short course of corticosteroids. Type of malignancy and oncologic treatment were similar in both groups. Baseline serum creatinine (1.1 mg/dL Group A and 0.9 mg/dL Group B; p = 0.53) and at ICPi-AKI diagnosis (3.0 mg/dL in Group A and 2.8 mg/dL in Group B; p = 0.43) were comparable. As shown in the table below, cumulative prednisone dose was lower in Group A than in Group B (1654 mg vs 4030 mg; p = 0.001). The overall renal response was 92% (87% Group A and 97% Group B; p = 0.2). There were no differences in complete response (40% Group A and 40% Group B; p = 1) or partial response (47% Group A and 57% Group B; p = 0.4). There were no recurrences of AKI after rechallenge of ICPi treatment. Adverse events related to corticosteroids were similar. There was a trend towards greater progression of oncologic disease in group B (64% versus 40%; p = 0.08). Conclusion A short course of steroids (< 3 months) is equally effective as a treatment for ICPi-AKI as longer courses, both in terms of renal response and relapse rate of ICPi-AKI. Adverse events related to steroid treatment were comparable in both groups. There appeared to be greater oncologic progression in the prolonged steroid treatment group.

BackgroundThe current definition of chronic kidney disease applied to patients over the age of 80 has increased the number of referrals to Nephrology. However not all of these patients may benefit from its assessment. This study aims to analyze the evolution of ≥80 years old patients referred to Nephrology.MethodsSingle-center study including patients ≥80 years old with eGFR <60 mL/min/1,73m2 who were referred to Nephrology consultation for the first time. Clinical and analytical parameters were collected retrospectively 12 months before the visit, and prospectively at baseline, and 12 and 24 months after the initial visit. We divided patients into two groups based on annual eGFR loss: progressors (>5 mL/min/1.73m2) and non-progressors (≤5 mL/min/1,73m2).ResultsA total of 318 patients were included, mean age was 84,9 ± 4 (80-97) years. Baseline serum creatinine was 1,65 ± 0,62 mg/dL, eGRF 35 (28-42) mL/min/1,73, and albumin/creatinine ratio 36 (7-229) mg/g. 55,7% of the patients met the definition of progressor at baseline (initial-progressors), 26,3% were progressors after a 12-month follow-up and 13,4% after 24 months. 21,2% and 11,4% of initial-progressors met this definition at 12 and 24 month follow up. The main risk factor for progression was albuminuria. No relationship was found between the nephrologist intervention and the evolution of renal function among initial non-progressors.ConclusionElderly patients who have stable renal function at the time of referral will continue to have stable renal function over the subsequent 24 months and thus may not need to be referred to a nephrologist.

Background: C3 glomerulopathy (C3G) is a rare kidney disease, which makes it difficult to collect large cohorts of patients to better understand its variability. The aims of this study were to describe the clinical profiles and patterns of progression of kidney disease. Methods: Retrospective, observational cohort study. Patients diagnosed with C3G between 1995–2020 were enrolled. Study population was divided into clinical profiles by combining the following predictors: eGFR under/above 30 ml/min/1.73m 2 fn2, proteinuria under/above 3.5 g/day, histologic chronicity score under/above 4. The change in eGFR and proteinuria over time was evaluated in a subgroup with consecutive measurements of eGFR and proteinuria. Results: 115 patients with a median age of 30 years (IQR 19–50) were included. Patients were divided into 8 clinical profiles. Kidney survival was significantly higher in patients with a chronicity score <4 and proteinuria <3.5g/day, both in those presenting with an eGFR under/above 30 ml/min/1.73m 2 . Median eGFR slope of patients who reached kidney failure was -6.5 ml/min/1.73m 2 /per year (IQR -1.6; -17). Patients who showed a reduction in proteinuria over time did not reach kidney failure. Based on the rate of eGFR decline patients were classified as faster eGFR decline (≥5 ml/min/1.73m 2 /year), slower (<5 ml/min/1.73m 2 /year), and those without decline. A faster eGFR decline was associated with higher probability of kidney failure. Conclusions: Kidney survival is significantly higher in patients with a chronicity score <4 and proteinuria <3.5 g/day regardless of baseline eGFR, and a faster rate of decline in eGFR is associated with higher probability of kidney failure.

Introduction: Complement 3 glomerulopathy (C3G) is a rare inflammatory kidney disease mediated by dysregulation of the alternative complement pathway. No targeted therapy exists for this aggressive glomerulonephritis. Efficacy, safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) (measured by complement biomarkers) of iptacopan were assessed in patients with C3G.Methods: In this phase 2, multicenter, open-label, single-arm, nonrandomized study, adults with biopsy-proven, native kidney C3G (native cohort) and kidney transplant recipients with C3G recurrence (recur-rent kidney transplant [KT] cohort) received iptacopan twice daily (bid) for 84 days (days 1-21: 10-100 mg; days 22-84: 200 mg). The primary end point was the urine protein-to-creatinine ratio (UPCR; native cohort) and the change in the C3 deposit score of kidney biopsy (recurrent KT cohort). The complement pathway measures included Wieslab assay, soluble C5b9, and serum C3 levels.Results: A total of 27 patients (16 native cohort and 11 recurrent KT cohort) were enrolled and all completed the study. In the native cohort, UPCR levels decreased by 45% from baseline to week 12 (P = 0.0003). In the recurrent KT cohort, the median C3 deposit score decreased by 2.50 (scale: 0-12) on day 84 versus baseline (P = 0.03). Serum C3 levels were normalized in most patients; complement hyperactivity observed pretreatment was reduced. Severe adverse events (AEs) included post-biopsy hematuria and hyperkalemia. No deaths occurred during the study.Conclusion: Iptacopan resulted in statistically significant and clinically important reductions in UPCR and normalization of serum C3 levels in the native cohort and reduced C3 deposit scores in the recurrent KT cohort with favorable safety and tolerability. (ClinicalTrials.gov identifier: NCT03832114).

Background Thrombotic microangiopathy (TMA) is a complication of malignant hypertension (mHTN) attributed to high blood pressure (BP). However, no studies have investigated in patients with mHTN of different aetiologies whether the presence of TMA is associated with specific causes of mHTN. Methods We investigated the presence of TMA (microangiopathic haemolytic anaemia and thrombocytopenia) in a large and well-characterized cohort of 199 patients with mHTN of different aetiologies [primary HTN 44%, glomerular diseases 16.6%, primary atypical haemolytic uraemic syndrome (aHUS) 13.1%, renovascular HTN 9.5%, drug-related HTN 7%, systemic diseases 5.5%, endocrine diseases 4.5%]. Outcomes of the study were kidney recovery and kidney failure. Results Patients with TMA [40 cases (20.1%)] were younger, were more likely female and had lower BP levels and worse kidney function at presentation. Their underlying diseases were primary aHUS (60%), drug-related mHTN (15%), glomerular diseases [all of them immunoglobulin A nephropathy (IgAN); 10%], systemic diseases (10%) and primary HTN (5%). The presence of TMA was 92.3% in primary aHUS, 42.9% in drug-related HTN, 36.4% in systemic diseases, 12.1% in glomerular diseases and 2.3% in primary HTN. No patient with renovascular HTN or mHTN caused by endocrine diseases developed TMA, despite BP levels as high as patients with TMA. A higher proportion of TMA patients developed kidney failure as compared with patients without TMA (56.4% versus 38.9%, respectively). Conclusions The presence of TMA in patients with mHTN should guide the diagnosis towards primary aHUS, drug-related mHTN, some systemic diseases and IgAN, while it is exceptional in other causes of mHTN.