Trastornos moleculares y genéticos en las glomerulopatías causadas por desregulación del complemento. Correlaciones genotipo-fenotipo e implicaciones terapéuticas

La glomerulopatía C3 (GC3) es una entidad clínico-patológica secundaria a una desregulación de la vía alternativa del complemento en plasma y el microentorno glomerular, distinguiéndose la glomerulonefritis C3 (GNC3) y la enfermedad por depósitos densos (EDD). La desregulación del complemento puede ser debida a alteraciones genéticas en genes del complemento y/o autoanticuerpos frente a diferentes componentes del complemento. Estudios previos han mostrado un beneficio terapéutico de la pauta de esteroides y micofenolato mofetil (MMF) en esta entidad, aunque el perfil genético-molecular de estos pacientes no fue estudiado de forma sistemática..

Role of light chain clearance in the recovery of renal function in multiple myeloma: another point of view

Lay Summary This is a retrospective multicenter study that evaluated the effectiveness of intensive haemodialysis (IHD) vs standards dialysis on renal recovery in patients with acute kidney injury (AKI) associated with myeloma multiple (MM). In this paper, we demonstrated that IHD for early light chain reduction was associated with a better renal prognosis. Another finding is the importance of maintenance diuresis as a marker of good prognosis of renal function. To our knowledge few studies have been focused in the comparison between IHD vs standard dialysis in MM patients with AKI. We consider that if we manage to recover the renal function, we achieve a great clinical impact since the patient with chronic kidney disease and especially in hemodialysis, an increased risk of mortality as well as poorer quality of life. Background Acute kidney injury (AKI) in patients with multiple myeloma (MM) requiring renal replacement treatment (RRT) is associated with high morbidity and mortality. Early reduction of serum free light chains (FLC) using both targeted therapy against MM and intensive hemodialysis (IHD) may improve renal outcomes. We evaluated the effectiveness of two different RRT techniques on renal recovery in an MM patient population: standard dialysis procedure vs IHD with either polymethylmethacrylate (PMMA) or hemodiafiltration with endogenous reinfusion (HFR). Methods This was a multicentric retrospective study with severe AKI related to MM, between 2011 and 2018. Twenty-five consecutive patients with AKI secondary to MM requiring RRT were included. Patients that underwent IHD received six dialysis sessions per week during the first 14 days (PMMA vs HFR). All patients were diagnosed with de novo MM or first relapsed MM. Primary outcome was renal recovery defined as dialysis-free at 6 months follow-up. Results A total of 25 patients were included. Seventeen patients received IHD and eight standard dialysis. All patients were treated with targeted therapy, 84% bortezomib-based. Of the 25 patients included, 14 (56%) became dialysis independent. We observed a higher proportion of patients who received IHD in the group who recovered kidney function compared with those who remained in HD (92.9% vs 36.4%, P = .007). In our study, the use of IHD to remove FLC had a statistically significant association with renal recovery compared with the standard dialysis group (P = .024). Conclusion Early reduction of FLC with IHD as an adjuvant treatment along with MM-targeted therapy may exert a positive impact on renal recovery

High exposure to tacrolimus is associated to spontaneous remission of recurrent membranous nephropathy after kidney transplantation

Introduction We aimed to characterize the incidence and clinical presentation of membranous nephropathy (MN) after kidney transplantation (KT), and to assess allograft outcomes according to proteinuria rates and immunosuppression management. Methods Multicenter retrospective cohort study including patients from six Spanish centers who received a KT between 1991-2019. Demographic, clinical, and histological data were collected from recipients with biopsy-proven MN as primary kidney disease (n = 71) or MN diagnosed de novo after KT (n = 4). Results Up to 25.4% of patients with biopsy-proven MN as primary kidney disease recurred after a median time of 18.1 months posttransplant, without a clear impact on graft survival. Proteinuria at 3-months post-KT was a predictor for MN recurrence (rMN, HR 4.28; P = 0.008). Patients who lost their grafts had higher proteinuria during follow-up [1.0 (0.5-2.5) vs 0.3 (0.1-0.5) g/24 h], but only eGFR after recurrence treatment predicted poorer graft survival (eGFR < 30 ml/min: RR = 6.8). We did not observe an association between maintenance immunosuppression and recurrence diagnosis. Spontaneous remission after rMN was associated with a higher exposure to tacrolimus before recurrence (trough concentration/dose ratio: 2.86 vs 1.18; P = 0.028). Up to 94.4% of KT recipients received one or several treatments after recurrence onset: 22.2% rituximab, 38.9% increased corticosteroid dose, and 66.7% ACEi/ARBs. Only 21 patients had proper antiPLA2R immunological monitoring. Conclusions One-fourth of patients with biopsy-proven MN as primary kidney disease recurred after KT, without a clear impact on graft survival. Spontaneous remission after rMN was associated with a higher exposure to tacrolimus before recurrence.12 página

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.ACKNOWLEDGEMENTS: Work on this study was supported by the Instituto de Salud Carlos III / Fondo Europeo de Desarrollo Regional (ISCIII/FEDER; grants PI16/01685 and PI19/1624) and Red de Investigación Renal (RD12/0021/0029; to M.P.) and the Autonomous Region of Madrid (S2017/BMD-3673; to M.P.). S.R.d.C. is supported by the Ministerio de Economia y Competitividad (grant PID2019-104912RB-I00) and the Autonomous Region of Madrid (grant S2017/BMD-3673). None of the funders had any role in the study design, data collection, analyses, reporting or decision to submit for publication

Evaluation of Variation in the Performance of GFR Slope as a Surrogate End Point for Kidney Failure in Clinical Trials that Differ by Severity of CKD

BACKGROUND: The GFR slope has been evaluated as a surrogate end point for kidney failure in meta-analyses on a broad collection of randomized controlled trials (RCTs) in CKD. These analyses evaluate how accurately a treatment effect on GFR slope predicts a treatment effect on kidney failure. We sought to determine whether severity of CKD in the patient population modifies the performance of GFR slope. METHODS: We performed Bayesian meta-regression analyses on 66 CKD RCTs to evaluate associations between effects on GFR slope (the chronic slope and the total slope over 3 years, expressed as mean differences in ml/min per 1.73 m2/yr) and those of the clinical end point (doubling of serum creatinine, GFR &lt;15 ml/min per 1.73 m2, or kidney failure, expressed as a log-hazard ratio), where models allow interaction with variables defining disease severity. We evaluated three measures (baseline GFR in 10 ml/min per 1.73 m2, baseline urine albumin-to-creatinine ratio [UACR] per doubling in mg/g, and CKD progression rate defined as the control arm chronic slope, in ml/min per 1.73 m2/yr) and defined strong evidence for modification when 95% posterior credible intervals for interaction terms excluded zero. RESULTS: There was no evidence for modification by disease severity when evaluating 3-year total slope (95% credible intervals for the interaction slope: baseline GFR [-0.05 to 0.03]; baseline UACR [-0.02 to 0.04]; CKD progression rate [-0.07 to 0.02]). There was strong evidence for modification in evaluations of chronic slope (95% credible intervals: baseline GFR [0.02 to 0.11]; baseline UACR [-0.11 to -0.02]; CKD progression rate [0.01 to 0.15]). CONCLUSIONS: These analyses indicate consistency of the performance of total slope over 3 years, which provides further evidence for its validity as a surrogate end point in RCTs representing varied CKD populations.</p

Factor H-related protein 1 drives disease susceptibility and prognosis in C3 glomerulopathy

17 p.-8 fig.Background: C3 glomerulopathy (C3G) is a heterogeneous group of chronic renal diseases characterized predominantly by glomerular C3 deposition and complement dysregulation. Mutations in factor H-related (FHR) proteins resulting in duplicated dimerization domains are prototypical of C3G, although the underlying pathogenic mechanism is unclear.Methods: Using in vitro and in vivo assays, we performed extensive characterization of an FHR-1 mutant with a duplicated dimerization domain. To assess the FHR-1 mutant's association with disease susceptibility and renal prognosis, we also analyzed CFHR1 copy number variations and FHR-1 plasma levels in two Spanish C3G cohorts and in a control population.Results: Duplication of the dimerization domain conferred FHR-1 with an increased capacity to interact with C3-opsonized surfaces, which resulted in an excessive activation of the alternative pathway. This activation does not involve C3b binding competition with factor H. These findings support a scenario in which mutant FHR-1 binds to C3-activated fragments and recruits native C3 and C3b; this leads to formation of alternative pathway C3 convertases, which increases deposition of C3b molecules, overcoming FH regulation. This suggests that a balanced FHR-1/FH ratio is crucial to control complement amplification on opsonized surfaces. Consistent with this conceptual framework, we show that the genetic deficiency of FHR-1 or decreased FHR-1 in plasma confers protection against developing C3G and associates with better renal outcome.Conclusions: Our findings explain how FHR-1 mutants with duplicated dimerization domains result in predisposition to C3G. They also provide a pathogenic mechanism that may be shared by other diseases, such as IgA nephropathy or age-related macular degeneration, and identify FHR-1 as a potential novel therapeutic target in C3G.E. Goicoechea de Jorge is supported by Ministerio de Ciencia e Innovación grant RTI2018-095955-B-100 and the European Union’s Horizon 2020 Framework Programme grant 899163. J. Gutiérrez-Tenorio is supported by Ministerio de Ciencia e Innovación grant BES-2015-073833. L. Lucientes Continente is supported by the Autonomous Region of Madrid grant S2017/BMD-3673. G. Fernández-Juarez, P. Sánchez-Corral, B. Márquez-Tirado, and M. Praga are supported by the Instituto de Salud Carlos III and the European Union’s European Regional Development Fund grants PI19/01695, PI19/00970, and PI19/01624, respectively. M.C. Pickering is a Wellcome Trust Senior Fellow in Clinical Science (212252/Z/18/Z). S. Rodríguez de Córdoba is supported by the Ministerio de Economía y Competitividad grant PID2019-104912RB-100 and Autonomous Region of Madrid grant S2017/BMD-3673.Peer reviewe

Thrombotic microangiopathy in patients with malignant hypertension

10 p.-4 fig.-4 tab.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.Work in this study was supported by the Instituto de Salud Carlos III/Fondo Europeo de Desarrollo Regional [ISCIII/FEDER;grants PI13/02502 and PICI14/00350 (to M.P.) and PI16/01685 and PI19/01624 (to M.P. and T.C.)]; the Spanish Ministerio de Economía y Competitividad/FEDER [SAF2015-66287-R and PID2019-104912RB-I00 (to S.R.d.C.)]; the Spanish ‘Ministerio de Ciencia Innovación y Universidades’ [RTI2018-095955-B-100 (to E.G.J.)]; the Autonomous Region of Madrid [S2017/BMD-3673 (to E.G.J., S.R.d.C. and M.P.)] and Red de Investigación Renal [RD12/0021/0029 (to M.P.)].Peer reviewe

Validation of a histologic scoring index for C3 glomerulopathy

12 p.-4 fig.-4 tab.Rationale & objective: A previous study that evaluated associations of kidney biopsy findings with disease progression in patients with C3 glomerulopathy (C3G) proposed a prognostic histologic index (C3G-HI) that has not yet been validated. Our objective was to validate the performance of the C3G-HI in a new patient population.Study design: Multicenter, retrospective cohort study.Setting & participants: 111 patients fulfilling diagnostic criteria of C3G between January 1995 and December 2019, from 33 nephrology departments belonging to the Spanish Group for the Study of Glomerular Diseases (GLOSEN).Predictors: Demographic, clinical parameters, C3G-HI total activity score, and the C3G-HI total chronicity score.Outcome: Time to kidney failure.Analytical approach: Intraclass correlation coefficients and κ statistic were used to summarize inter-rater reproducibility for assessment of histopathology in kidney biopsies. The nonlinear relationships of risk of kidney failure with the total activity score and total chronicity score were modeled using Cox proportional hazards analysis that incorporated cubic splines.Results: The study group included 93 patients with C3 glomerulonephritis and 18 with dense-deposit disease. Participants had an overall meanage of 35±22 (SD) years. Forty-eight patients (43%) developed kidney failure after a mean follow-up of 65±27 months. The overall inter-rater reproducibility was very good for the total activity score (intraclass correlation coefficient [ICC]=0.63) and excellent for total chronicity score (ICC=0.89). Baseline estimated glomerular filtration rate (eGFR), 24-hour proteinuria, and treatment with immunosuppression were the main determinants of kidney failure in a model with only clinical variables. Only tubular atrophy and interstitial fibrosis were identified as predictors in a model with histological variables. When the total activity score and total chronicity score were added to the model, only the latter was identified as an independent predictor of kidney failure.Limitations: Only a subset of the kidney biopsies was centrally reviewed. Residual confounding.Conclusions: We validated the performance of C3G-HI as a predictor of kidney failure in patients with C3G. The total chronicity score was the principal histologic correlate of kidney failure.Work in this study was supported by the Instituto de Salud Carlos III /Fondo Europeo de Desarrollo Regional (ISCIII/FEDER) grant PI16/01685 and Red de Investigación Renal (RedInRen) (RD12/0021/0029) (to MP), the Autonomous Region of Madrid (S2017/BMD-3673) (to MP); EGdeJ is supported by the Spanish “Ministerio de Ciencia, Innovación y Universidades" (RYC-2013-13395 and RTI2018-095955-B-100).Peer reviewe

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