Predictors of outcome in a Spanish cohort of patients with Fabry disease on enzyme replacement therapy

Fabry disease may be treated by enzyme replacement therapy (ERT), but the impact of chronic kidney disease (CKD) on the response to therapy remains unclear. The aim of the present study was to analyse the incidence and predictors of clinical events in patients on ERT. Study design: Multicentre retrospective observational analysis of patients diagnosed and treated with ERT for Fabry disease. The primary outcome was the first renal, neurological or cardiological events or death during a follow-up of 60 months (24-120). Results: In 69 patients (42 males, 27 females, mean age 44.6±13.7 years), at the end of follow-up, eGFR and the left ventricular septum thickness remained stable and the urinary albumin: creatinine ratio tended to decrease, but this decrease only approached significance in patients on agalsidase-beta (242-128mg/g (p=0.05). At the end of follow-up, 21 (30%) patients had suffered an incident clinical event: 6 renal, 2 neurological and 13 cardiological (including 3 deaths). Events were more frequent in patients with baseline eGFR≤60ml/min/1.73m2 (log Rank 12.423, p=0.001), and this remained significant even after excluding incident renal events (log Rank 4.086, p=0.043) and in males and in females. Lower baseline eGFR was associated with a 3- to 7-fold increase the risk of clinical events in different Cox models. Conclusions: GFR at the initiation of ERT is the main predictor of clinical events, both in males and in females, suggesting that start of ERT prior to the development of CKD is associated with better outcomes

Longitudinal change in proteinuria and kidney outcomes in C3 glomerulopathy

11 p.-4 fig.-4 tab.Introduction: The association between a change in proteinuria over time and its impact in kidney prognosis has not been analyzed in C3 glomerulopathy. This study aims to investigate the association between the longitudinal change in proteinuria and the risk of kidney failure.Methods: Retrospective, multicenter observational cohort study in 35 nephrology departments belonging to the Spanish Group for the Study of Glomerular Diseases (GLOSEN). Patients diagnosed with C3 glomerulopathy between 1995 and 2020 were enrolled. A joint modeling 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 (HR: 0.79; 95% CI : 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.Conclusion: 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.This study was supported by the Instituto de Salud Carlos III/Fondo Europeo de Desarrollo Regional (ISCIII/FEDER) grant PI16/01685 and PI19/1624, and Red de Investigación Renal (RedInRen) (RD12/0021/0029) (to M.P.), the Autonomous Region of Madrid (S2017/BMD-3673) (to M.P.); E.G.d.J. was supported by the Spanish ‘Ministerio de Ciencia, Innovación y Universidades’ (RYC-2013-13395 and RTI2018-095955-B-100); S.R.d.C. was supported by Ministerio de Economía y Competitividad/FEDER grant SAF2015-66287R and Autonomous Region of Madrid grant S2017/BMD3673.Peer reviewe

Recurrent acute interstitial nephritis: what lies beneath

Background: Acute interstitial nephritis (AIN) is an emerging cause of acute kidney disease. While this disease usually follows an acute course, it may occasionally recur, representing a major challenge for the clinician. Methods: We performed a retrospective, observational cohort study in 13 nephrology departments belonging to the Spanish Group for the Study of Glomerular Diseases. Patients with biopsy-proven AIN between 1996 and 2018 were included. Results: The study group consisted of 205 patients with AIN, 22 of which developed recurrent AIN (RAIN) after a median of 111 days from diagnosis. RAIN was due to a surreptitious reintroduction of a previously known implicated drug or toxic in six patients (27%), sarcoidosis in two (9%), Sjögren's syndrome in three (14%), light-chain-mediated AIN in two (9%) and tubulointerstitial nephritis and uveitis syndrome in two (9%), while in the rest of cases (32%), no precise cause could be identified. Microscopic haematuria was more frequent in patients with underlying systemic diseases. The first RAIN episode was treated with a repeated course of corticosteroids in 21 patients (95%). In six cases (27%), azathioprine and mycophenolate mofetil were added as corticosteroid-sparing agents. During a median follow-up of 30 months, 50 patients (27%) with no recurrences and 12 patients (55%) with RAIN reached Stages 4 and 5 chronic kidney disease (CKD). By multivariable logistic regression analysis, RAIN was independently associated with the risk of reaching Stages 4 and 5 CKD, even after adjusting for potential covariables. Conclusions: RAIN is infrequent but is associated with poor kidney survival. RAIN should prompt clinicians to search for an underlying aetiology other than drug induced. However, in a large percentage of cases, no precise cause can be identified

Anti-glomerular Basement Membrane Glomerulonephritis: A Study in Real Life.

Anti-glomerular basement membrane (anti-GBM) disease is a severe entity with few therapeutic options including plasma exchange and immunosuppressive agents. The aim of this study was to analyze the clinical and pathological features that predict the evolution of end-stage kidney disease (ESKD) and the kidney survival in a cohort of patients with anti-GBM disease with renal involvement in real life. A retrospective multicentre observational study including 72 patients from 18 nephrology departments with biopsy-proven anti-GBM disease from 1999 to 2019 was performed. Progression to ESKD in relation to clinical and histological variables was evaluated. Creatinine at admission was 8.6 (± 4) mg/dL and 61 patients (84.7%) required dialysis. Sixty-five patients (90.3%) underwent plasma exchange. Twenty-two patients (30.6%) presented pulmonary hemorrhage. Kidney survival was worse in patients with creatinine levels > 4.7 mg/dL (3 vs. 44% p 4.7 mg/dL (3 vs. 44% p 50% crescents (6 vs. 49%; p = 0.03). Dialysis dependence at admission and creatinine levels > 4.7 mg/dL remained independent significant predictors of ESKD in the multivariable analysis [HR (hazard ratio) 3.13 (1.25-7.84); HR 3 (1.01-9.14); p 4.7 mg/dL remained independent significant predictors of ESKD in the multivariable analysis [HR (hazard ratio) 3.13 (1.25-7.84); HR 3 (1.01-9.14); p 4.7 mg/dL and 50.5% crescents had an area under the curve (AUC) of 0.9 (95% CI 0.82-0.97; p In real life, patients with severe anti-GBM disease (creatinine > 4.7 mg/dL and > 50% crescents) remained with devastating renal prognosis despite plasma exchange and immunosuppressive treatment. New therapies for the treatment of this rare renal disease are urgently needed

Antimyeloperoxidase and proteinase 3 antibodies for nephritis flare prediction in ANCA-associated-vasculitis

Data de publicació electrònica: 03-02-2021Background: The value of myeloperoxidase and proteinase 3 antibodies titers in the assessment of renal disease activity and flare prediction in patients with ANCA-associated-vasculitis (AAV) is not well-known. Methods: Retrospective study including 113 AVV patients with a renal biopsy-proven pauci-immune necrotizing glomerulonephritis from seven Spanish hospitals. The main inclusion criteria were assessment of MPO antibodies (MPOab) using multiplex flow immunoassay and PR3 antibodies (PR3ab) measurements using immunoassay chemiluminescence with an identical range of values for all participating centers. Results: Serum MPOab, 3 ± 1.2 months before relapse, was higher in patients who relapsed (19.2 ± 12.2 vs 3.2 ± 5.1 AI, p < 0.001). The discrimination value of MPOab 3 months before renal relapse had an AUC of 0.82 (95%CI 0.73-0.92; p < 0.001). ΔMPOab (change in antibodies titration 6 months before relapse) was higher in patients who relapsed [8.3 ± 12 vs 0.9 ± 3.1 AI, p = 0.001) (AI; antibody index unit). The discrimination value of ΔMPO had an AUC of 0.76 (95%CI 0.63-0.88; p < 0.001). The positive predictive value of renal relapse in PR3 patients is 100% and the negative predictive value of renal relapse in patients with PR3 positive titers is 57.1%. Serum PR3ab was higher in patients who relapsed 2.8 ± 1.4 months before relapse (58.6 ± 24.6 vs 2.0 ± 0.6 AI, p < 0.001). Conclusions: MPO antibody level monitorization using multiplex flow immunoassay and PR3 measurements using immunoassay chemiluminescence are useful and sensitive tools for the prediction of renal relapse in the follow-up of AAV patients with renal disease, and relevant surrogate markers of renal disease activity

IgA Nephropathy in Elderly Patients.

Some studies suggest that the incidence of IgA nephropathy is increasing in older adults, but there is a lack of information about the epidemiology and behavior of the disease in that age group. In this retrospective multicentric study, we analyzed the incidence, forms of presentation, clinical and histologic characteristics, treatments received, and outcomes in a cohort of 151 patients ≥65 years old with biopsy-proven IgA nephropathy diagnosed between 1990 and 2015. The main outcome was a composite end point of kidney replacement therapy or death before kidney replacement therapy. We found a significant increase in the diagnosis of IgA nephropathy over time from six patients in 1990-1995 to 62 in 2011-2015 (P value for trend =0.03). After asymptomatic urinary abnormalities (84 patients; 55%), AKI was the most common form of presentation (61 patients; 40%). Within the latter, 53 (86%) patients presented with hematuria-related AKI (gross hematuria and tubular necrosis associated with erythrocyte casts as the most important lesions in kidney biopsy), and eight patients presented with crescentic IgA nephropathy. Six (4%) patients presented with nephrotic syndrome. Among hematuria-related AKI, 18 (34%) patients were receiving oral anticoagulants, and this proportion rose to 42% among the 34 patients older than 72 years old who presented with hematuria-related AKI. For the whole cohort, survival rates without the composite end point were 74%, 48%, and 26% at 1, 2, and 5 years, respectively. Age, serum creatinine at presentation, and the degree of interstitial fibrosis in kidney biopsy were risk factors significantly associated with the outcome, whereas treatment with renin-angiotensin-aldosterone blockers was associated with a lower risk. Immunosuppressive treatments were not significantly associated with the outcome. The diagnosis of IgA nephropathy among older adults in Spain has progressively increased in recent years, and anticoagulant therapy may be partially responsible for this trend. Prognosis was poor. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_07_16_CJASNPodcast_19_08_.mp3

Longitudinal change in proteinuria and kidney outcomes in C3 glomerulopathy

11 p.-4 fig.-4 tab.Introduction: The association between a change in proteinuria over time and its impact in kidney prognosis has not been analyzed in C3 glomerulopathy. This study aims to investigate the association between the longitudinal change in proteinuria and the risk of kidney failure.Methods: Retrospective, multicenter observational cohort study in 35 nephrology departments belonging to the Spanish Group for the Study of Glomerular Diseases (GLOSEN). Patients diagnosed with C3 glomerulopathy between 1995 and 2020 were enrolled. A joint modeling 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 (HR: 0.79; 95% CI : 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.Conclusion: 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.This study was supported by the Instituto de Salud Carlos III/Fondo Europeo de Desarrollo Regional (ISCIII/FEDER) grant PI16/01685 and PI19/1624, and Red de Investigación Renal (RedInRen) (RD12/0021/0029) (to M.P.), the Autonomous Region of Madrid (S2017/BMD-3673) (to M.P.); E.G.d.J. was supported by the Spanish ‘Ministerio de Ciencia, Innovación y Universidades’ (RYC-2013-13395 and RTI2018-095955-B-100); S.R.d.C. was supported by Ministerio de Economía y Competitividad/FEDER grant SAF2015-66287R and Autonomous Region of Madrid grant S2017/BMD3673.Peer reviewe

Mycophenolate Mofetil in C3 glomerulopathy and pathogenic drivers of the disease

12 p.-4 fig.-4 tab.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.Work in this study was supported by the Instituto de Salud CarlosIII/ Fondo Europeo de Desarrollo Regional (ISCIII/FEDER) grant PI16/01685 and Red de Investigación Renal (RedInRen) (RD12/0021/0029) (to M. Praga), and the Autonomous Region of Madrid (S2017/BMD-3673) (to S. Rodríguez de Córdoba and M. Praga).E. Goicoechea de Jorge is supported by the Spanish “Ministerio de Ciencia, Innovación y Universidades” (RYC-2013-13395 and RTI2018-095955-B-100). S. Rodríguez de Córdoba is supported by Ministerio de Economía y Competitividad/FEDER grant SAF2015-66287R and Autonomous Region of Madrid grant S2017/BMD3673.Peer reviewe