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Angiotensin II receptor 1 antibodies associate with post-transplant focal segmental glomerulosclerosis and proteinuria.

ABSTRACT: BACKGROUND:Angiotensin II type 1 receptors (AT1Rs) are expressed on podocytes, endothelial and other cells, and play an essential role in the maintenance of podocyte function and vascular homeostasis. The presence of AT1R antibodies (AT1R-Abs) leads to activation of these receptors resulting in podocyte injury and endothelial cell dysfunction. We assessed the correlation between AT1R-Abs and the risk of post-transplant FSGS. METHODS:This is a retrospective study, which included all kidney transplant recipients with positive AT1R-Abs (? 9?units/ml), who were transplanted and followed at our center between 2006 and 2016. We assessed the development of biopsy proven FSGS and proteinuria by urine protein to creatinine ratio of ?1?g/g and reviewed short and long term outcomes. RESULTS:We identified 100 patients with positive AT1R-Abs at the time of kidney transplant biopsy or proteinuria. 49% recipients (FSGS group) had biopsy-proven FSGS and/or proteinuria and 51% did not (non-FSGS group). Pre-transplant hypertension was present in 89% of the FSGS group compared to 72% in the non-FSGS group, p?=?0.027. Of the FSGS group, 43% were on angiotensin converting enzyme inhibitors or angiotensin receptor blockers prior to transplantation, compared to 25.5% in the non-FSGS group, p?=?0.06. Primary idiopathic FSGS was the cause of ESRD in 20% of the FSGS group, compared to 6% in the non-FSGS group, p?=?0.03. The allograft loss was significantly higher in the FSGS group 63% compared to 39% in non-FSGS. Odds ratio and 95% confidence interval were 2.66 (1.18-5.99), p?=?0.017. CONCLUSIONS:Our data suggest a potential association between AT1R-Abs and post-transplant FSGS leading to worse allograft outcome. Therefore, AT1R-Abs may be considered biomarkers for post-transplant FSGS.

SUBMITTER: Abuzeineh M

PROVIDER: S-EPMC7331243 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Angiotensin II receptor 1 antibodies associate with post-transplant focal segmental glomerulosclerosis and proteinuria.

Abuzeineh Mohammad M Aala Amtul A Alasfar Sami S Alachkar Nada N

BMC nephrology 20200702 1

<h4>Background</h4>Angiotensin II type 1 receptors (AT1Rs) are expressed on podocytes, endothelial and other cells, and play an essential role in the maintenance of podocyte function and vascular homeostasis. The presence of AT1R antibodies (AT1R-Abs) leads to activation of these receptors resulting in podocyte injury and endothelial cell dysfunction. We assessed the correlation between AT1R-Abs and the risk of post-transplant FSGS.<h4>Methods</h4>This is a retrospective study, which included al ...[more]

PMID: 32615995

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Project description:Rationale & objectiveRemission of proteinuria has been shown to be associated with lower rates of kidney disease progression among people with focal segmental glomerulosclerosis (FSGS). The goal of this study was to evaluate whether reductions in proteinuria after treatment are associated with greater kidney survival.Study designCohort analysis of clinical trial participants.Setting & participantsPatients with steroid-resistant FSGS enrolled in a randomized treatment trial that compared cyclosporine with mycophenolate mofetil plus dexamethasone.PredictorsReduction in proteinuria measured during 26 weeks after initiating treatment.OutcomesRepeated assessments of estimated glomerular filtration rate (eGFR) and time to a composite outcome of kidney failure or death assessed between 26 weeks and 54 months after randomization.Analytical approachMultivariable linear mixed-effects models with participant-specific slope and intercept to estimate the association of change in proteinuria over 26 weeks while receiving treatment with the subsequent slope of change in eGFR. Multivariable time-varying Cox proportional hazards models were used to estimate the association of changes in proteinuria with time to the composite outcome.Results138 of 192 trial participants were included. Changes in proteinuria over 26 weeks were significantly related to eGFR slope. A 1-unit reduction in log-transformed urinary protein-creatinine ratio was associated with a 3.90mL/min/1.73m2 per year increase in eGFR (95% CI, 2.01-5.79). This difference remained significant after adjusting for complete remission. There was an analogous relationship between time-varying proteinuria and time to the composite outcome: the HR per 1-unit reduction in log-transformed urinary protein-creatinine ratio was 0.23 (95% CI, 0.12-0.44).LimitationsLimited to individuals with steroid-resistant FSGS followed up for a maximum of 5 years.ConclusionsThese findings provide evidence for the benefit of urinary protein reduction in FSGS. Reductions in proteinuria warrant further evaluation as a potential surrogate for preservation of kidney function that may inform the design of future clinical trials.

Project description:Background and objectivesProteinuria is used as an indicator of FSGS disease activity, but its use as a clinical trial end point is not universally accepted. The goal of this study was to refine proteinuria definitions associated with long-term kidney survival.Design, setting, participants, & measurementsData on 466 patients with primary FSGS with proteinuria (urine protein-to-creatinine ratio >1 g/g) were analyzed from five independent cohorts. Proteinuria by months 1, 4, and 8 after study baseline was categorized by conventional definitions of complete (<0.3 g/g) and partial remission (<3.5 g/g and 50% reduction in proteinuria). Novel remission definitions were explored using receiver operating curves. Kaplan-Meier methods were used to estimate the associations of proteinuria with progression to ESRD or a 50% loss in kidney function. Propensity score-adjusted Cox proportional hazards models were used to adjust for baseline proteinuria, eGFR, and therapy.ResultsIn the initial derivation cohort, conventional partial remission was not associated with kidney survival. A novel definition of partial remission (40% proteinuria reduction and proteinuria<1.5 g/g) on the basis of receiver operating curve analyses of 89 patients was identified (Sensitivity=0.70; Specificity=0.77). In the validation cohort analyses, complete remission was associated with better prognosis (6 out of 41 patients progressed to kidney failure; 6.6 per 100 patient-years) as was the novel partial remission (13 out of 71 progressed; 8.5 per 100 patient-years), compared with those with no response (51 out of 116 progressed; 20.1 per 100 patient-years). Conventional partial remission at month 8, but not month 4, was also associated with better response (19 out of 85 patients progressed; risk=10.4 per 100 patient-years). Propensity score-adjusted analyses showed the novel partial remission was associated with less progression at months 4 and 8 (month 4: hazard ratio, 0.50; P=0.01; month 8: hazard ratio, 0.30; P=0.002).ConclusionsReaching either a complete or partial remission using a novel or conventional definition was associated with better long-term outcomes in patients with FSGS.PodcastThis article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_02_20_CJASNPodcast_18_3_T.mp3.

Project description:Focal segmental glomerulosclerosis (FSGS) is a leading cause of kidney disease worldwide. The presumed etiology of primary FSGS is a plasma factor with responsiveness to immunosuppressive therapy and a risk of recurrence after kidney transplant-important disease characteristics. In contrast, adaptive FSGS is associated with excessive nephron workload due to increased body size, reduced nephron capacity, or single glomerular hyperfiltration associated with certain diseases. Additional etiologies are now recognized as drivers of FSGS: high-penetrance genetic FSGS due to mutations in one of nearly 40 genes, virus-associated FSGS, and medication-associated FSGS. Emerging data support the identification of a sixth category: APOL1 risk allele-associated FSGS in individuals with sub-Saharan ancestry. The classification of a particular patient with FSGS relies on integration of findings from clinical history, laboratory testing, kidney biopsy, and in some patients, genetic testing. The kidney biopsy can be helpful, with clues provided by features on light microscopy (e.g, glomerular size, histologic variant of FSGS, microcystic tubular changes, and tubular hypertrophy), immunofluorescence (e.g, to rule out other primary glomerulopathies), and electron microscopy (e.g., extent of podocyte foot process effacement, podocyte microvillous transformation, and tubuloreticular inclusions). A complete assessment of renal histology is important for establishing the parenchymal setting of segmental glomerulosclerosis, distinguishing FSGS associated with one of many other glomerular diseases from the clinical-pathologic syndrome of FSGS. Genetic testing is beneficial in particular clinical settings. Identifying the etiology of FSGS guides selection of therapy and provides prognostic insight. Much progress has been made in our understanding of FSGS, but important outstanding issues remain, including the identity of the plasma factor believed to be responsible for primary FSGS, the value of routine implementation of genetic testing, and the identification of more effective and less toxic therapeutic interventions for FSGS.

Dataset Information

Angiotensin II receptor 1 antibodies associate with post-transplant focal segmental glomerulosclerosis and proteinuria.

Publications

Angiotensin II receptor 1 antibodies associate with post-transplant focal segmental glomerulosclerosis and proteinuria.

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