Development and validation of a nomogram to predict kidney survival at baseline in patients with C3 glomerulopathy.

Background: C3 glomerulopathy is a rare and heterogeneous complement-driven disease. It is often challenging to accurately predict in clinical practice the individual kidney prognosis at baseline. We herein sought to develop and validate a prognostic nomogram to predict long-term kidney survival. Methods: We conducted a retrospective, multicenter observational cohort study in 35 nephrology departments belonging to the Spanish Group for the Study of Glomerular Diseases. The dataset was randomly divided into a training group (n = 87) and a validation group (n = 28). The least absolute shrinkage and selection operator (LASSO) regression was used to screen the main predictors of kidney outcome and to build the nomogram. The accuracy of the nomogram was assessed by discrimination and risk calibration in the training and validation sets. Results: The study group comprised 115 patients, of whom 46 (40%) reached kidney failure in a median follow-up of 49 months (range 24-112). No significant differences were observed in baseline estimated glomerular filtration rate (eGFR), proteinuria or total chronicity score of kidney biopsies, between patients in the training versus those in the validation set. The selected variables by LASSO were eGFR, proteinuria and total chronicity score. Based on a Cox model, a nomogram was developed for the prediction of kidney survival at 1, 2, 5 and 10 years from diagnosis. The C-index of the nomogram was 0.860 (95% confidence interval 0.834-0.887) and calibration plots showed optimal agreement between predicted and observed outcomes. Conclusions: We constructed and validated a practical nomogram with good discrimination and calibration to predict the risk of kidney failure in C3 glomerulopathy patients at 1, 2, 5 and 10 years.

Longitudinal change in proteinuria and kidney outcomes in C3 glomerulopathy.

INTRODUCTION: The association between a change in proteinuria over time and its impact on kidney prognosis has not been analysed in complement component 3 (C3) glomerulopathy. This study aims to investigate the association between the longitudinal change in proteinuria and the risk of kidney failure. METHODS: This was a retrospective, multicentre observational cohort study in 35 nephrology departments belonging to the Spanish Group for the Study of Glomerular Diseases. Patients diagnosed with C3 glomerulopathy between 1995 and 2020 were enrolled. A joint modelling of linear mixed-effects models was applied to assess the underlying trajectory of a repeatedly measured proteinuria, and a Cox model to evaluate the association of this trajectory with the risk of kidney failure. RESULTS: The study group consisted of 85 patients, 70 C3 glomerulonephritis and 15 dense deposit disease, with a median age of 26 years (range 13-41). During a median follow-up of 42 months, 25 patients reached kidney failure. The longitudinal change in proteinuria showed a strong association with the risk of this outcome, with a doubling of proteinuria levels resulting in a 2.5-fold increase of the risk. A second model showed that a ≥50% proteinuria reduction over time was significantly associated with a lower risk of kidney failure (hazard ratio 0.79; 95% confidence interval 0.56-0.97; P < 0.001). This association was also found when the ≥50% proteinuria reduction was observed within the first 6 and 12 months of follow-up. CONCLUSIONS: The longitudinal change in proteinuria is strongly associated with the risk of kidney failure. The change in proteinuria over time can provide clinicians a dynamic prediction of kidney outcomes.

C3 glomerulopathy associated with monoclonal gammopathy: impact of chronic histologic lesions and beneficial effects of clone-targeted therapies.

BACKGROUND: C3 glomerulopathy associated with monoclonal gammopathy (C3G-MIg) is a rare entity. Herein we analysed the clinical and histologic features of a cohort of C3G-MIg patients. METHODS: We conducted a retrospective, multicentre, observational study. Patients diagnosed with C3G-MIg between 1995 and 2021 were enrolled. All had genetic studies of the alternative complement pathway. The degree of disease activity and chronicity were analysed using the C3G histologic index. Descriptive statistics and propensity score matching (PSM) analysis were used to evaluate the main outcome of the study [kidney failure (KF)]. RESULTS: The study group included 23 patients with a median age 63 of years [interquartile range (IQR) 48-70], and 57% were males. Immunoglobulin G kappa was the most frequent MIg (65%). The diagnosis of C3G-MIg was made in transplanted kidneys in seven patients (30%). Five (22%) patients had C3 nephritic factor and five (22%) had anti-factor H antibodies. One patient carried a pathogenic variant in the CFH gene. During a follow-up of 40 months (IQR 14-69), nine patients (39%) reached KF and these patients had a significantly higher total chronicity score on kidney biopsy. Patients who received clone-targeted therapy had a significantly higher survival compared with other management. Those who achieved haematological response had a significantly higher kidney survival. Outcome was remarkably poor in kidney transplant recipients, with five of them (71%) reaching KF. By PSM (adjusting for age, kidney function, proteinuria and chronicity score), no significant differences were observed in kidney survival between C3G patients with/without MIg. CONCLUSIONS: The C3G histologic index can be used in patients with C3G-MIg to predict kidney prognosis, with higher chronicity scores being associated with worse outcomes. Clone-targeted therapies and the development of a haematological response are associated with better kidney prognosis.

La mortalidad de los pacientes en hemodiálisis está asociada con su situación clínica al comienzo del tratamiento / Mortality of hemodialysis patients is associated with their clinical situation at the start of treatment

Introducción: Estudios previos han demostrado una elevada mortalidad de los pacientes en tratamiento con hemodiálisis, aunque en pocos de ellos se analiza la supervivencia de los que reciben exclusivamente este tratamiento. Nuestro objetivo fue analizar la mortalidad de los pacientes que recibieron tratamiento con hemodiálisis. Métodos: Se analizó la cohorte de pacientes que iniciaron tratamiento sustitutivo entre los años 2010 y 2012 en la comunidad de Castilla-La Mancha y permanecieron en tratamiento con hemodiálisis. Se estudiaron las variables edad, sexo, enfermedad renal primaria, acceso vascular, hemoglobina, índice de Charlson y albúmina sérica al comienzo del tratamiento y se realizó un seguimiento hasta final de 2017. Resultados: La mortalidad fue del 63,4% a los 5 años y del 76% al final del periodo de seguimiento, sin diferencias entre varones y mujeres, y se relacionó con una mayor edad, el comienzo urgente o en aquellos con enfermedad renal reagudizada, la utilización de catéteres o una albúmina inferior a 3,5g/dl. Conclusiones: La mortalidad en los pacientes que permanecen en diálisis es muy elevada y se asocia a factores no modificables como la edad pero también a otros que podemos prevenir o tratar, como el tipo de acceso vascular o el estado de nutrición al comienzo del tratamiento. (AU)

Introduction: Previous reports have shown very high mortality among hemodialyisis patients. Our goal was to analyze the mortality of patients in the Renal Registry of Patients who remained exclusively on hemodialysis treatment. Methods: The cohort of patients who started treatment in the community of Castilla-La Mancha between 2010 and 2012 and remained on hemodialysis treatment was analysed until the end of 2017. Age, sex, primary kidney disease, vascular access, hemoglobin, Charlson index and serum albumin were included. Results: Mortality rate was 63.4% after 5 years and 76% at the end of the study, with no difference between males and females, and was linked to an older age, urgent onset or in those with acute deterioration of chronic kidney disease, the use of catheters or albumin less than 3.5g/dl. Conclusions: Mortality in patients who remain on hemodialysis is very high and is associated with non-modifiable factors such as age but also others that we can prevent or treat such as type of vascular access or nutrition status at the beginning of treatment. (AU)

Mycophenolate Mofetil in C3 Glomerulopathy and Pathogenic Drivers of the Disease.

BACKGROUND AND OBJECTIVES: C3 glomerulopathy is a complement-mediated disease arising from abnormalities in complement genes and/or antibodies against complement components. Previous studies showed that treatment with corticosteroids plus mycophenolate mofetil (MMF) was associated with improved outcomes, although the genetic profile of these patients was not systematically analyzed. This study aims to analyze the main determinants of disease progression and response to this therapeutic regimen. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a retrospective, multicenter, observational cohort study in 35 nephrology departments belonging to the Spanish Group for the Study of Glomerular Diseases. Patients diagnosed with C3 glomerulopathy (n=81) or dense deposit disease (n=16) between January 1995 and March 2018 were enrolled. Multivariable and propensity score matching analyses were used to evaluate the association of clinical and genetic factors with response to treatment with corticosteroids and MMF as measured by proportion of patients with disease remission and kidney survival (status free of kidney failure). RESULTS: The study group comprised 97 patients (84% C3 glomerulopathy, 16% dense deposit disease). Forty-two patients were treated with corticosteroids plus MMF, and this treatment was associated with a higher rate of remission and lower probability of kidney failure (79% and 14%, respectively) compared with patients treated with other immunosuppressives (24% and 59%, respectively), or ecluzimab (33% and 67%, respectively), or conservative management (18% and 65%, respectively). The therapeutic superiority of corticosteroids plus MMF was observed both in patients with complement abnormalities and with autoantibodies. However, patients with pathogenic variants in complement genes only achieved partial remission, whereas complete remissions were common among patients with autoantibody-mediated forms. The main determinant of no remission was baseline proteinuria. Relapses occurred after treatment discontinuation in 33% of the patients who had achieved remission with corticosteroids plus MMF, and a longer treatment length of MMF was associated with a lower risk of relapse. CONCLUSIONS: The beneficial response to corticosteroids plus MMF treatment in C3 glomerulopathy appears independent of the pathogenic drivers analyzed in this study.

Gemcitabine-induced hemolytic-uremic syndrome treated with eculizumab or plasmapheresis: two case reports
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BACKGROUND: Drug-induced hemolytic-uremic syndrome (HUS) has shown good response to eculizumab (ECU). We present 2 cases of patients with gemcitabine-induced HUS (GEM-HUS), one of whom was treated with ECU and the other with conventional treatment. Patient 1: A 74-year-old male with resected adenocarcinoma of the pancreas started adjuvant treatment with GEM, but after 5 months GEM was discontinued due to acute kidney injury and severe hypertension. Laboratory analyses identified microangiopathic hemolytic anemia (MHA) and thrombocytopenia. Plasmapheresis (Pph) was initiated but was stopped due to a severe adverse reaction. Treatment with ECU was initiated at the time of clinical progression requiring hemodialysis. After 7 doses of ECU, hemolysis and kidney function improved and the patient was able to stop hemodialysis. 1 month after the last dose of ECU serum creatinine (sCr) was 1.8 mg/dL. Patient 2: A 68-year-old male with resected urothelial carcinoma stopped GEM after 2 months due to hematologic toxicity. 1 month later the patient visited the emergency room due to minimal effort dyspnea, hypertension, and peripheral edema. Laboratory analyses showed decreased kidney function, MHA, and thrombocytopenia. Symptomatic treatment was started. After an initial recovery, kidney dysfunction, hemolysis, and thrombocytopenia progressed. Corticoid boluses were ineffective and hemodialysis was initiated. Eleven Pph treatments were necessary to recover hematologic data. The patient remained on hemodialysis for 2 months and evolved to stage IV chronic kidney disease. 8 months after hospital release, sCr was 3.5 mg/dL. CONCLUSION: ECU successfully improved kidney function in a patient with GEM-HUS, while conventional treatment did not.
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