Glomerular Filtration Rate Slope Research Articles

Nephroplex: a kidney-focused NGS panel highlights the challenges of PKD1 sequencing and identifies a founder BBS4 mutation

BackgroundGenetic testing of patients with inherited kidney diseases has emerged as a tool of clinical utility by improving the patients’ diagnosis, prognosis, surveillance and therapy.MethodsThe present study applied a Next Generation Sequencing (NGS)-based panel, named NephroPlex, testing 115 genes causing renal diseases, to 119 individuals, including 107 probands and 12 relatives. Thirty-five (poly)cystic and 72 non (poly)cystic individuals were enrolled. The latter subgroup of patients included Bardet-Biedl syndrome (BBS) patients, as major components.ResultsDisease-causing mutations were identified in 51.5 and 40% of polycystic and non-polycystic individuals, respectively. Autosomal dominant polycystic kidney disease (ADPKD) patients with truncating PKD1 variants showed a trend towards a greater slope of the age-estimated glomerular filtration rate (eGFR) regression line than patients with (i) missense variants, (ii) any PKD2 mutations and (iii) no detected mutations, according to previous findings. The analysis of BBS individuals showed a similar frequency of BBS4,9,10 and 12 mutations. Of note, all BBS4-mutated patients harbored the novel c.332+1G>GTT variant, which was absent in public databases, however, in our internal database, an additional heterozygote carrier was found. All BBS4-mutated individuals originated from the same geographical area encompassing the coastal provinces of Naples.DiscussionIn conclusion, these findings indicate the potential for a genetic panel to provide useful information at both clinical and epidemiological levels.Graphic abstract

Association of Treatment Effects on Early Change in Urine Protein and Treatment Effects on GFR Slope in IgA Nephropathy: An Individual Participant Meta-analysis

An early change in proteinuria is considered a reasonably likely surrogate end point in immunoglobulin A nephropathy (IgAN) and can be used as a basis for accelerated approval of therapies, with verification in a postmarketing confirmatory trial. Glomerular filtration rate (GFR) slope is a recently validated surrogate end point for chronic kidney disease progression and may be considered as the end point used for verification. We undertook a meta-analysis of clinical trials in IgAN to compare treatment effects on change in proteinuria versus change in estimated GFR (eGFR) slope. Individual patient-level meta-analysis. Individual data of 1,037 patients from 12 randomized trials. Randomized trials of IgAN with proteinuria measurements at baseline and 6 (range, 2.5-14) months and at least a further 1 year of follow-up for the clinical outcome. For each trial, we estimated the treatment effects on proteinuria and on the eGFR slope, computed as the total slope starting at baseline or the chronic slope starting 3 months after randomization. We used a Bayesian mixed-effects analysis to relate the treatment effects on proteinuria to effects on GFR slope across these studies and developed a prediction model for the treatment effect on the GFR slope based on the effect on proteinuria. Across all studies, treatment effects on proteinuria accurately predicted treatment effects on the total slope at 3 years (median R2= 0.88; 95% Bayesian credible interval [BCI], 0.06-1) and on the chronic slope (R2= 0.98; 95% BCI, 0.29-1). For future trials, an observed treatment effect of approximately 30% reduction in proteinuria would confer probabilities of at least 90% for nonzero treatment benefits on the total and chronic slopes of eGFR. We obtained similar results for proteinuria at 9 and 12 months and total slope at 2 years. Study population restricted to 12 trials of small sample size, leading to wide BCIs. There was heterogeneity among trials with respect to study design and interventions. These results provide new evidence supporting that early reduction in proteinuria can be used as a surrogate end point for studies of chronic kidney disease progression in IgAN.

Assessing Risk of Rapid Progression in Autosomal Dominant Polycystic Kidney Disease and Special Considerations for Disease-Modifying Therapy

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of kidney failure, accounting for 5%-10% of cases. Predicting which patients with ADPKD will progress rapidly to kidney failure is critical to assess the risk-benefit ratio of any intervention and to consider early initiation of long-term kidney protective measures that will maximize the cumulative benefit of slowing disease progression. Surrogate prognostic biomarkers are required to predict future decline in kidney function. Clinical, genetic, environmental, epigenetic, and radiologic factors have been studied as predictors of progression to kidney failure in ADPKD. A complex interaction of these prognostic factors determines the number of kidney cysts and their growth rates, which affect total kidney volume (TKV). Age-adjusted TKV, represented by the Mayo imaging classification, estimates each patient's unique rate of kidney growth and provides the most individualized approach available clinically so far. Tolvaptan has been approved to slow disease progression in patients at risk of rapidly progressive disease. Several other disease-modifying treatments are being studied in clinical trials. Selection criteria for patients at risk of rapid progression vary widely among countries and are based on a combination of age, baseline glomerular filtration rate (GFR), GFR slope, baseline TKV, and TKV rate of growth. This review details the approach in assessing the risk of disease progression in ADPKD and identifying patients who would benefit from long-term therapy with disease-modifying agents.

Estimated GFR Slope in Kidney Transplant Patients: When the Error Is Random.

The evaluation of renal function changes over time is crucial in day-to-day renal transplant care, and the slope of renal function is a major outcome in clinical trials. Little is known about the reliability of estimated glomerular filtration rate (eGFR) in reflecting real glomerular filtration rate (GFR) changes. We analyzed the variability of eGFR slope by 63 equations in estimating measured GFR (mGFR) changes in 110 renal transplant patients. The agreement between eGFR and mGFR slopes was evaluated by the concordance correlation coefficient and the limits of agreement. Patients were grouped based on mGFR slope in rapid GFR loss: faster than -3 mL/min/y; stable renal function: -3 to +3 mL/min/y; and improvement in GFR: higher than +3 mL/min/y. Concordance correlation coefficient averaged 0.36 and limits of agreement ±10 mL/min/y, indicating very poor agreement between eGFR and mGFR slopes. The eGFR slope classified patients into the same group of mGFR slope only in 25% of the cases. In about two-thirds of patients, the eGFR slope was either markedly faster or slower than the mGFR slope. In half of these cases, the discrepancy between mGFR and eGFR slopes was ≥50%. Formulas are neither accurate nor precise in reflecting real GFR decline in renal transplant patients, making them unreliable for clinical practice and trials.

Plasma total adiponectin and changes in renal function in a cohort from the community: the prospective Data from an Epidemiological Study on the Insulin Resistance Syndrome study.

High adiponectin levels are associated with diabetic nephropathy. Nevertheless, it is not known whether plasma adiponectin is associated with renal function decline in the general population. We evaluated whether adiponectin concentrations were associated with changes in renal function in a community cohort, the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study. Plasma adiponectin concentrations were measured in a random sample of 3284 people from the DESIR study, a 9-year prospective cohort from the general population. Data were analysed for three endpoints during follow-up: incidence of Stage 3 chronic kidney disease (CKD); the Kidney Disease: Improving Global Outcomes (KDIGO) criterion 'certain drop in eGFR' and rapid kidney function decline [estimated glomerular filtration rate (eGFR) slope steeper than -3 mL/min/1.73 m2/year]. After exclusion of participants with an eGFR <60 mL/min/1.73 m2 at baseline and those with type 2 diabetes or impaired fasting glycaemia at any time during follow-up (remaining n = 2174), there was a 113% higher risk for a rapid decline in kidney function in participants with adiponectin above the third tertile (T3) versus below the first tertile (T1) (Ptrend = 0.004) and a 53% higher risk for kidney function decline as defined by the KDIGO criterion (Ptrend = 0.04). In a cross-sectional analysis, adiponectin was positively associated with urinary albumin:creatinine ratio at baseline (P = 0.009). In a healthy cohort from the general population, higher levels of plasma adiponectin were associated with decreased renal function at baseline and at follow-up. This result is similar to what is observed in people with diabetic nephropathy, in contrast with animal models of nephropathy.

Urinary excretion of epidermal growth factor and rapid loss of kidney function.

Lower urinary excretion of the kidney tubule-specific biomarker epidermal growth factor (uEGF) is associated with increased risk of renal function [glomerular filtration rate (GFR)] loss in diabetes and in patients with established chronic kidney disease (CKD). We investigated whether uEGF is associated with rapid GFR decline or incident CKD in the general population. Subjects without CKD or diabetes were recruited from the general population in Tromso, Norway [Renal Iohexol Clearance Survey (RENIS); N = 1249] and Groningen, the Netherlands [Prevention of REnal and Vascular END-stage disease (PREVEND); N = 4534], with a median follow-up of 5.6 and 7.4 years, respectively. GFR was measured by iohexol clearance in the RENIS and estimated using the CKD Epidemiology Collaboration creatinine-cystatin C equation in the PREVEND study. Rapid GFR decline was defined as an annual GFR loss >3.0 mL/min/1.73 m2 and in sensitivity analyses as subjects with the 10% steepest GFR slope within each cohort. Lower baseline uEGF excretion was associated with rapid GFR loss in both cohorts {RENIS, odds ratio [OR] per 1 μg/mmol lower uEGF 1.42 [95% confidence interval (CI) 1.06-1.91], P = 0.02; PREVEND, OR 1.29 [95% CI 1.10-1.53], P < 0.01}, adjusted for baseline GFR, albumin:creatinine ratio and conventional CKD risk factors. Similar results were obtained using the outcome of the 10% steepest GFR slope in each cohort. Lower uEGF levels were associated with incident CKD in the combined analysis of both cohorts. Lower uEGF levels are associated with increased risk of rapid GFR loss and incident CKD in the general population. This finding, together with previous findings in CKD and high-risk populations, supports that uEGF may serve as a broadly applicable biomarker representing the tubular component of the current glomerulus-centric clinical risk assessment system.

Add-On Therapy with DPP-4 Inhibitors May Improve Renal Function Decline in α-Glucosidase Inhibitor and Metformin Users: A Retrospective Observational Study.

PurposeWe retrospectively evaluated the long-term effect of dipeptidyl peptidase (DPP)-4 inhibitors on estimated glomerular filtration rate (eGFR) slopes, and then evaluated the beneficial interaction between DPP-4 inhibitor initiation and baseline use of α-glucosidase inhibitor and/or metformin in patients with diabetic kidney disease.Patients and MethodsAltogether, 1512 patients with type 2 diabetes were receiving DPP-4 inhibitor therapy over 1 year and were followed up for a maximum of 2 years before and after 7 years of treatment. The decline in renal function was estimated as the slope of the individual linear regression line of eGFR over 2-year follow-up. Prescription data on medications before and after DPP-4 inhibitor treatment were examined.ResultsThe mean length of DPP-4 inhibitor treatment was 5.3 ± 2.6 years. The baseline mean eGFR slope (mL/min/1.73m2/year) was −2.24 ± 6.05. After DPP-4 inhibitor treatment, mean eGFR slope was significantly improved (−1.53 ± 6.36, P < 0.01) in patients with type 2 diabetes. This effect appeared more pronounced for baseline use of α-glucosidase inhibitor and/or metformin in patients with diabetic kidney disease. These non-users showed a trend towards attenuation or no effects.ConclusionIn the present study, patients treated with DPP-4 inhibitors had a significantly slower annual loss of kidney function. The benefit appears pronounced in α-glucosidase inhibitor and metformin users with advanced renal dysfunction. These results suggest that the beneficial effects of DPP-4 inhibitors on kidney function may have occurred in the presence of an α-glucosidase inhibitor and/or metformin.

Effect of sacubitril/valsartan on renal function: a systematic review and meta-analysis of randomized controlled trials.

A worsening renal function is prevalent among patients with cardiovascular disease, especially heart failure (HF). Sacubitril/valsartan appears to prevent worsening of renal function and progression of chronic kidney disease (CKD) as compared with renin–angiotensin system (RAS) inhibitors alone in HF patients. It is unclear whether these advantages are present in HF patients only, or can be extended to other categories of patients, in which this drug was studied. We performed a systematic review and meta‐analysis to assess the consistency of effect size regarding renal outcome across randomized controlled trials (RCTs) that compared sacubitril/valsartan with RAS inhibitors in patients with or without HF. We searched Medline (PubMed), Scopus, and Thomson Reuters Web of Science databases until June 2020. We took into account RCTs that compared sacubitril/valsartan with a RAS inhibitor and reported data regarding renal function. We used random‐effects models to obtain summary odds ratio (OR) with 95% confidence interval (CI). We extracted hazard ratios for renal outcomes, glomerular filtration rate slopes or rates of renal adverse events. Sensitivity analyses were performed by moderator analysis and random‐effects meta‐regression. The search revealed 10 RCTs (published between 2012 and 2019) on 16 456 subjects. Sacubitril/valsartan resulted in a lower risk of renal dysfunction as compared with RAS inhibitors alone [k = 10; pooled OR = 0.70 (95% CI 0.57–0.85); P < 0.001], with a moderate inconsistency between studies [Q(9) = 15.18; P = 0.086; I 2 = 40.73%]. A stronger association was found in studies including older patients (k = 10; β = −0.047730; P = 0.020) or HF patients with preserved ejection fraction [pooled OR = 0.53 (0.41–0.68) vs. 0.76 (0.57–1.01) for studies on HF patients with reduced ejection fraction; P for comparison = 0.065]. The effect size did not change with different comparators (angiotensin‐converting enzyme inhibitors vs. angiotensin II type 1 receptor blockers, P = 0.279). No significant association was found when the analysis was restricted to studies on non‐HF patients [k = 3; pooled OR = 0.86 (0.61–1.22); P = 0.403] and studies with high risk of bias [k = 3; pooled OR = 0.34 (0.08–1.44); P = 0.143]. Our findings support the role of sacubitril/valsartan on preservation of renal function, especially in older patients and HF patients with preserved ejection fraction. However, evidence is currently limited to HF patients, while the renal outcome of sacubitril/valsartan therapy outside the HF setting needs to be further investigated.

Effect of once-weekly exenatide on estimated glomerular filtration rate slope depends on baseline renal risk: A post hoc analysis of the EXSCEL trial.

The effects of glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) on renal outcomes in patients with type 2 diabetes at high cardiovascular risk are modest or neutral. However, GLP‐1RAs may confer clinical benefits in those at high risk of progressive renal function loss. We examined the effects of once‐weekly exenatide (EQW) on estimated glomerular filtration rate (eGFR) slope and urinary albumin:creatinine ratio (UACR) as a function of baseline UACR in 3503 EXSCEL participants (23.7%) with eGFR data available and 2828 participants (19.2%) with UACR change data available. EQW improved eGFR slope assessed via mixed model repeated measures, compared with placebo, in participants with baseline UACR >100 mg/g (0.79 mL/min/1.73 m2/year [95% confidence interval {CI} 0.24–1.34]) and UACR >200 mg/g (1.32 mL/min/1.73 m2/year [95% CI 0.57–2.06]), but not at lower UACR thresholds. EQW reduced UACR, compared with placebo, assessed via analysis of covariance, consistently across subgroups with baseline UACR >30 mg/g (28.2% reduction), baseline UACR >100 mg (22.5% reduction) and baseline UACR >200 mg (34.5% reduction). This post hoc EXSCEL analysis suggests that EQW reduces UACR, with improvement in eGFR slope specifically in participants with elevated baseline UACR.

GFR slope as a surrogate endpoint for CKD progression in clinical trials.

There is a paucity of therapies for chronic kidney disease (CKD), in part because of the slow nature of the disease which poses challenges in selection of endpoints in randomized controlled trials (RCT). There is increasing evidence for the use of glomerular filtration rate (GFR)-based endpoints either as percentage decline using time-to-event analyses, or as difference in slope between treatment arms. We reviewed the rationale for using surrogate endpoints and optimal methods for their evaluation prior to their use and evidence for GFR-based endpoints and particularly GFR slope as validated surrogate endpoints and considerations for their use in RCTs. In an individual patient meta-analysis of 47 studies (60 620 participants), treatment effects on the clinical endpoint were accurately predicted from treatment effects on 3-year total slope [median R = 0.97 (95% Bayesian confidence interval (BCI), 0.78-1.00] and on the chronic slope [R = 0.96 (95% BCI, 0.63-1.00)]. In a simulation study, GFR slope substantially reduced the required sample size and duration of follow-up compared to the clinical endpoint given high baseline GFR and absence of acute treatment effect. In the presence of acute effect, results were more complicated. GFR decline is accepted, and GFR slope is being considered, by regulatory authorities as a validated surrogate endpoint for CKD RCTs.

Novel Risk Factors for Progression of Diabetic and Nondiabetic CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study

Identification of novel risk factors for chronic kidney disease (CKD) progression may inform mechanistic investigations and improve identification of high-risk subgroups. The current study aimed to characterize CKD progression across levels of numerous risk factors and identify independent risk factors for CKD progression among those with and without diabetes. The Chronic Renal Insufficiency Cohort (CRIC) Study is a prospective cohort study of adults with CKD conducted at 7 US clinical centers. Participants (N=3,379) had up to 12.3 years of follow-up; 47% had diabetes. 30 risk factors for CKD progression across sociodemographic, behavioral, clinical, and biochemical domains at baseline. Study outcomes were estimated glomerular filtration rate (eGFR) slope and the composite of halving of eGFR or initiation of kidney replacement therapy. Stepwise selection of independent risk factors was performed stratified by diabetes status using linear mixed-effects and Cox proportional hazards models. Among those without and with diabetes, respectively, mean eGFR slope was-1.4±3.3 and-2.7±4.7mL/min/1.73m2 per year. Among participants with diabetes, multivariable-adjusted hazard of the composite outcome was approximately 2-fold or greater with higher levels of the inflammatory chemokine CXCL12, the cardiac marker N-terminal pro-B-type natriuretic peptide (NT-proBNP), and the kidney injury marker urinary neutrophil gelatinase-associated lipocalin (NGAL). Among those without diabetes, low serum bicarbonate and higher high-sensitivity troponin T, NT-proBNP, and urinary NGAL levels were all significantly associated with a 1.5-fold or greater rate of the composite outcome. The observational study design precludes causal inference. Strong associations for cardiac markers, plasma CXCL12, and urinary NGAL are comparable to that of systolic blood pressure≥140mm Hg, a well-established risk factor for CKD progression. This warrants further investigation into the potential mechanisms that these markers indicate and opportunities to use them to improve risk stratification.

Health-Related Quality of Life, Depressive Symptoms, and Kidney Transplant Access in Advanced CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study

Rationale & ObjectiveAmong individuals with chronic kidney disease (CKD), poor self-reported health is associated with adverse outcomes including hospitalization and death. We sought to examine the association between health-related quality-of-life (HRQoL) and depressive symptoms in advanced CKD and subsequent access to the kidney transplant waiting list.Study DesignProspective cohort study.Setting & Population1,676 Chronic Renal Insufficiency Cohort (CRIC) study participants with estimated glomerular filtration rates ≤ 30 mL/min/1.73 m2 at study entry or during follow-up.ExposuresHRQoL ascertained by 5 scales of the Kidney Disease Quality of Life-36 Survey (Physical Component Summary [PCS], Mental Component Summary, Symptoms, Burdens, and Effects), with higher scores indicating better HRQoL, and depressive symptoms ascertained using the Beck Depression Inventory.OutcomesTime to kidney transplant wait-listing and time to pre-emptive wait-listing.Analytic ApproachTime-to-event analysis using Cox proportional hazards regression.ResultsDuring a median follow-up of 5.1 years, 652 (39%) participants were wait-listed, of whom 304 were preemptively wait-listed. Adjusted for demographics, comorbid conditions, estimated glomerular filtration rate slope, and cognitive function, participants with the highest scores on the Burden and Effects scales, respectively, had lower rates of wait-listing than those with the lowest scores on the Burden (wait-listing adjusted hazard ratio [aHR], 0.70; 95% CI, 0.57-0.85; P < 0.001) and Effects scales (wait-listing aHR, 0.74; 95% CI, 0.59-0.92; P = 0.007). Participants with fewer depressive symptoms (ie, Beck Depression Inventory score < 14) had lower wait-listing rates than those with more depressive symptoms (aHR, 0.81; 95% CI, 0.66-0.99; P = 0.04). Participants with lower Burden and Effects scale scores and those with higher Symptoms and PCS scores had higher pre-emptive wait-listing rates (aHR in highest tertile of PCS relative to lowest tertile, 1.58; 95% CI, 1.12-2.23; P = 0.01).LimitationsUnmeasured confounders.ConclusionsSelf-reported health in late-stage CKD may influence the timing of kidney transplantation.

Impact of CKD Progression on Cardiovascular Disease Risk in a Contemporary UK Cohort of Individuals With Diabetes

IntroductionIt remains unclear whether an increased progression rate of chronic kidney disease (CKD) adds predictive information regarding cardiovascular disease (CVD) risk. The aim of this study was to evaluate the association between CKD progression, based on estimated glomerular filtration rate (eGFR) slope estimates and the risk for CVD.MethodsWe compared the updated eGFR slope calculated over multiple overlapping 2-year periods and the updated mean eGFR. Incident CKD subjects were selected from a prevalent population with diabetes (T2DM). Subjects from the UK Clinical Practice Research Data Link GOLD (CPRD) were followed from CKD diagnosis (n = 30,222) until heart failure (HF), myocardial infarction (MI), ischemic stroke (IS), or a composite end point including all 3 event types (MACE plus), mortality, database dropout, or end of study follow-up.ResultsBoth the updated eGFR slope and updated mean eGFR were associated with MACE plus and HF. Updated eGFR slope decline of > –3 ml/min/1.73 m2 increased the risk for MACE plus (adjusted hazard ratio [HR] = 1.45; 95% confidence interval [CI], 1.26–1.67), HF (HR = 1.50; 95% CI, 1.27–1.76), and MI (HR = 1.39; 95% CI, 1.01–1.91).ConclusionsThis study strongly supports current evidence that CKD is an independent risk factor for CVD. From a clinical perspective, both rate of progression and cumulative status of CKD describe distinct aspects of the cardiorenal risk among persons with diabetes. This evidence is essential to enable more timely and improved use of treatments in this population.

A profile of multiple circulating tumor necrosis factor receptors associated with early progressive kidney decline in Type 1 Diabetes is similar to profiles in autoimmune disorders

This study comprehensively evaluated the association between known circulating tumor necrosis factor (TNF) superfamily ligands and receptors and the development of early progressive kidney decline (PKD) leading to end-stage kidney disease (ESKD) in Type 1 diabetes. Participants for the study were from the Macro-Albuminuria Study (198 individuals), and the Micro-Albuminuria Study (148 individuals) of the Joslin Kidney Study. All individuals initially had normal kidney function and were followed for seven-fifteen years to determine the slope of the estimate glomerular filtration rate and to ascertain onset of ESKD. Plasma concentrations of 25 TNF superfamily proteins were measured using proximity extension assay applied in the OLINK proteomics platform. In the both studies risk of early PKD, determined as estimated glomerular filtration rate loss greater than or equal to three ml/min/1.73m2/year, was associated with elevated circulating levels of 13 of 19 TNF receptors examined. In the Macro-Albuminuria Study, we obtained similar findings for risk of progression to ESKD. These receptors comprised: TNF-R1A, -R1B, -R3, -R4, -R6, -R6B, -R7, -R10A, -R10B, -R11A, -R14, -R21, and -R27. Serial measurements showed that circulating levels of these TNF receptors had increased before the onset of PKD. In contrast, none of the six measured TNF ligands showed association with risk of early PKD. Of significance, the disease process that underlies PKD leading to ESKD in Type 1 diabetes has a profile also seen in autoimmune disorders. The mechanisms of this enrichment may be causally related to the development of PKD in Type 1 diabetes and must be investigated further. Thus, some of these receptors may be used as new risk predictors of ESKD.

Cystatin C and Urine Albumin to Creatinine Ratio Predict 5-Year Mortality and Cardiovascular Events in People Living With HIV.

Identifying people with HIV (PWH) at risk for chronic kidney disease, cardiovascular events, and death is crucial. We evaluated biomarkers to predict all-cause mortality and cardiovascular events, and measured glomerular filtration rate (mGFR) slope. Biomarkers were measured at enrollment. Baseline and 5-year mGFR were measured by plasma iohexol clearance. Outcomes were a composite criterion of all-cause mortality and/or cardiovascular events, and mGFR slope. Of 168 subjects, 146 (87.4%) had undetectable HIV load. Median follow-up was 59.1 months (interquartile range, 56.2-62.1). At baseline, mean age was 49.5 years (± 9.8) and mean mGFR 98.9 mL/min/1.73m2 (± 20.6). Seventeen deaths and 10 cardiovascular events occurred during 5-year follow-up. Baseline mGFR was not associated with mortality/cardiovascular events. In multivariable analysis, cystatin C (hazard ratio [HR], 5.978; 95% confidence interval [CI], 2.774-12.88; P < .0001) and urine albumin to creatinine ratio (uACR) at inclusion (HR, 1.002; 95% CI, 1.001-1.004; P < .001) were associated with mortality/cardiovascular events. Area under receiver operating curve of cystatin C was 0.67 (95% CI, .55-.79) for mortality/cardiovascular event prediction. Biomarkers were not associated with GFR slope. uACR and cystatin C predict all-cause mortality and/or cardiovascular events in PWH independently of mGFR.

Clinical impact of urinary CD11b and CD163 on the renal outcomes of anti-neutrophil cytoplasmic antibody-associated glomerulonephritis.

The detection of leukocyte-derived CD11b (α subunit of integrin Mac-1) and CD163 (scavenger receptor) in urine may reflect renal inflammation in antineutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA-GN). The objective of this study was to evaluate the clinical significance of urinary CD11b (U-CD11b) and CD163 (U-CD163) in ANCA-GN. U-CD11b and U-CD163 were examined using enzyme-linked immunosorbent assay in ANCA-GN urine samples from our institutional cohort (n = 88) and a nationwide cohort (n = 138), and their association with renal histology was subsequently analyzed. Logistic regression analyses were performed on a nationwide ANCA cohort to determine the associations of the two urinary molecules with renal remission failure at 6 months or with yearly estimated glomerular filtration rate (eGFR) slope over a 24-month observation period. U-CD11b and U-CD163 were significantly associated with cellular crescent formation and leukocyte accumulation in glomerular crescents. With regard to interstitial inflammation, both levels of U-CD11b and U-CD163 at diagnosis remarkably increased in ANCA-GN compared with the levels observed in nonglomerular kidney disorders including nephrosclerosis, immunoglobulin G4-relateddisease and tubulointerstitial nephritis; however, the presence of U-CD11b alone was significantly correlated with tubulointerstitial leukocyte infiltrates. Although neither U-CD11b nor U-CD163 at diagnosis was associated with remission failure at 6 months, multivariate analysis demonstrated that the baseline U-CD11b levels were significantly associated with the increase in eGFR following immunosuppressive therapy. Although both U-CD11b and U-CD163 reflect renal leukocyte accumulation, U-CD11b at diagnosis provides additional clinical value by predicting the recovery rate after the treatment of ANCA-GN.

Liraglutide Improves Estimated Glomerular Filtration Rate Slopes in Patients with Chronic Kidney Disease and Type 2 Diabetes: A 7-Year Retrospective Analysis.

Background: Liraglutide was administered to patients with type 2 diabetes, and its effects on estimated glomerular filtration rate (eGFR) slopes and albuminuria were retrospectively evaluated. Methods: This study included 568 patients with type 2 diabetes who received liraglutide therapy (up to 0.9 mg/day) >1 year and were followed-up for a maximum of 2 years before and 7 years after treatment. The decline in renal function was estimated as the slope of the individual linear regression line of eGFR over the follow-up time. Spot urine samples were collected to measure albuminuria, which were calculated using creatinine levels. In addition, HbA1c, body weight, blood pressure, and heart rate were monitored. Results: The mean liraglutide treatment period was 3.1 ± 2.0 years. The mean baseline eGFR slope [mL/(min ·1.73 m2·year)] was -2.75 ± 6.04. After liraglutide treatment, the mean eGFR slope significantly improved (-1.42 ± 4.30, P < 0.01). This effect appeared more pronounced for baseline eGFRs <45 mL/(min ·1.73 m2). Albuminuria, HbA1c, body weight, and systolic blood pressure levels were significantly reduced after treatment with liraglutide for 1 year, whereas diastolic blood pressure and heart rates were increased. Conclusions: Patients treated with liraglutide experienced a significantly slower annual decline in kidney function. The benefit appeared more pronounced in patients with the development and progression of diabetic kidney disease. These results suggest that the benefits of liraglutide on kidney function identified in clinical trials appear to be well generalizable to clinical practice.

P0786CLINICAL SIGNIFICANCE AND RELATED FACTORS OF GFR SLOPE IN A LARGE MULTICENTER OBSERVATIONAL STUDY IN JAPAN

Abstract Background and Aims Recently, glomerular filtration rate (GFR) slope has attracted attention as an important surrogate marker for the prognosis of chronic kidney disease (CKD), with a reduction in slope of eGFR decline by 0.75 mL/min/1.73 m2 per year reportedly having clinical significance. As few large clinical studies on Japanese CKD patients exist, this investigation addresses the clinical significance of GFR slope and its related factors. Method To evaluate the clinical impact of GFR slope, we conducted a prognostic investigation of CKD patients in Japan by means of a large, multicenter, retrospective, observational study. Patients with CKD who were seen at among 15 general hospitals between January and March 2014 were surveyed using medical records. The selection criteria were age ≥20 years, estimated GFR (eGFR) &amp;lt;60 mL/min/1.73 m2, and receiving medical treatment for CKD. Baseline patient characteristics, eGFR changes, and hard endpoints (death or end-stage kidney disease requiring renal replacement therapy) during observation were analysed. We calculated GFR slope using GFR data of 2 years following the observation start point by 2 calculation methods, the linear mixed model and least squares linear regression, and examined the relationship of GFR slope with the hazard ratio of the composite hard endpoints. The factors related to GFR slope were also assessed by multiple regression analysis. Results Among a total of 11233 collected patients, we analyzed the data of 7490 CKD G3 and G4 patients whose GFR data during 2 years could be obtained (60% male, mean age: 71 years, CKD G3a: 55%, G3b: 30%, G4: 15%, mean eGFR: 44.1 mL/min/1.73 m2, urine protein positive: 51%, diabetes mellitus: 49%, use of RAS inhibitors: 57%). The mean observation period was 1040 days. Hard endpoints after the GFR slope measurement period occurred in 301 subjects. The GFR slope of the cohort was -0.948 mL/min/1.73 m2 per year (95% confidence interval [CI] -1.016, -0.880) in the linear mixed model and -0.982 mL/min/1.73 m2 per year (95% CI -1.075, -0.889) according to least squares linear regression. Both calculated GFR slopes were significantly related to the hazard ratio of the composite hard endpoints. Hazard ratio decreased by 0.85 (linear mixed model) and 0.9 (least squares linear regression) times in case of a reduction in slope of eGFR decline by 0.75 mL/min/1.73 m2 per year. Multiple regression analysis revealed strongly significant associations for GFR slope with urine protein and CKD stage and undetectable relationships for GFR slope with diabetes and age. Conclusion This study demonstrated the clinical significance of GFR slope as a surrogate marker for renal prognosis in Japanese CKD patients. In order to reduce slope of eGFR decline, active intervention for proteinuria before the progression to an advanced CKD stage appears to be effective.

P0711CHRONIC KIDNEY DISEASE STAGES 3-5 PROGRESSION: PATTERNS AND OUTCOMES

Abstract Background and Aims We evaluated the natural history of chronic kidney disease with regard to progression to renal replacement therapy or death in a prospective cohort of patient. Few studies are published concerning patterns of kidney function decline before initiation of dialysis while decreasing glomerular filtration rate (GFR) trajectories can influence the outcomes of the following treatment. Method The analysis of Saint-Petersburg City nephrology center data among 5935 patients with GFR below 60 ml/min/1.73m with five and more follow-up visits. The outcomes data were collected from clinical and administrative databases. Results The most common causes of end stage renal failure were chronic glomerulonephritis (19%, decreasing over time 2009-2019), diabetes (16.9 %, stable), and hypertension (13.8 %, increasing). In 18.9% cases diagnosis was not established. 49% of patients show the rate in range 0-5 ml/min/1.73m per year; 33% had the rate more than 5 ml/min/1.73m per year; 17% of pts revealed slow but stable improvement of kidney function. Overall mean of the GFR change rates were -3.86±0.21 and -3.19±0.23 ml/min/1.73m per year for men and women; being significantly different for CKD stages: -1.23 (-1.93 ÷ - 0.61); -2.69 (-3.17 ÷ - 2.14); -4.91 (-5.55 ÷ - 4.47) and -6.42 (-7.52 ÷ - 5.63) for CKD 3A, 3B, 4 and 5. CKD progression rates differed between patients with various diagnoses and were associated with phosphate, calcium, anemia and iron deficiency, serum albumin and proteinuria levels. In women, total cholesterol levels out of normal range were linked with higher progression rates. In the multiple regression male gender was linked with higher GRF slope by 1.01 ml/min/1.73m per year. The reduced baseline GFR by 10 ml/min/1.73m per year; the reduced albumin - by 2 g/l, Hb - by 5 g/l, elevated phosphate - by 0.1 mmol/l, uric acid - by 0.2 mmol/l and proteinuria by 0.33 g/d were associated with similar increase of GFR slope (by about 10%). We found three different trajectories for GFR slope during three-year period before dialysis initiation: slow progression (-2.53, 95%CI -5.02÷-0.69 mL/min/1.73m per year) from CKD3B-CKD4 – 74% of patients, faster progression (-7.96, 95%CI -11.32÷-5.89) from CKD3 – 21% of patients, initially no progression (+0.24, 95%CI -1.54÷-2.05) with following acceleration of GFR slope (-19.2, 95%CI -29.7÷-10.8) from CKD3 – 5% of patients. Dialysis was started at eGFR 7±3 ml/min/1.73m in “slow” group (31% - urgent start), 6±4 ml/min/1.73m in “fast” group (58% - urgent start) and 5±4 ml/min/1.73m in “accelerated” group (61% - urgent start).The rate of renal replacement therapy initiation over the 5-year observation period was 0.9%, 2.1%, 12.9% and 46.3%, respectively, for CKD stages 2, 3, 4, 5 while the mortality rate was 20.1%, 30.2%, 51.9 and 41.3% mainly for cardiovascular reasons. Thus, death was far more common than dialysis at all stages but CKD5, where it was comparable. Conclusion The identifying of the modifiable factors linked to CKD progression gives the opportunity to improve comprehensive renoprotective therapy. The efforts to decrease mortality in CKD3-4 cohort should be focused on prevention and treatment of coronary artery disease, congestive heart failure, diabetes mellitus, phosphatemia and anemia.

P1639DEVELOPMENT OF SELF-LIMITED LOW-LEVEL BK VIREMIA/VIRURIA SUGGESTS IDEAL IMMUNOSUPPRESSION TO SUPPRESS T-CELL AND ANTIBODY-MEDIATED REJECTION AND PRESERVE KIDNEY ALLOGRAFT FUNCTION

Abstract Background and Aims Polyomavirus BK (BKV) viremia has been suggested as a surrogate marker of overimmunosuppression. Due to recent advances in monitoring strategies and pre-emptive therapy, progression to BKV-associated nephropathy (BKVN) has been reduced. Reduction of maintenance immunosuppression during BKVN, however, has been associated with both T-cell mediated rejection (TCMR), antibody-mediated rejection (ABMR), and inferior kidney allograft outcomes. Although the administration of intravenous immunoglobulins (IVIG) failed to treat BKVN, IVIG may have properties to reduce allosensitization. Method We studied 860 kidney transplant recipients (KTRs) predominantly under tacrolimus-based triple-drug maintenance immunosuppression from 2009 to 2018. We identified 130 KTRs (15.1%) with high-level BK viremia &amp;gt;10,000 copies/mL (presumptive BKVN), 180 KTRs (20.9%) with low-level BK viremia &amp;lt;10,000 copies/mL, 85 KTRs (9.9%) with isolated BK viruria, and 465 KTRs (54.1%) with no BK viruria/viremia. Kidney allograft outcomes with respect to TCMR, ABMR, development of de novo donor-specific antibodies (DSA), kidney allograft survival, and estimated glomerular filtration rate (eGFR) slope were analysed. Due to the increased incidence of TCMR and ABMR among KTRs with presumptive BKVN, 48 of 130 KTRs (36.9%) with high-level BK viremia starting from 2015 received IVIG (0.5 g/kg of body weight) on a biweekly basis during BKV replication. Results Very interestingly, KTRs with low-level BK viremia/viruria showed a significantly lower incidence of TCMR compared to KTRs with no BK viremia/viruria and KTRs with high-level BK viremia (p&amp;lt;0.05). In addition, KTRs with low-level BK viremia/viruria showed a significantly lower incidence of ABMR compared to KTRs with high-level BK viremia (p&amp;lt;0.05). No differences were observed with respect to the development of de novo DSA (MFI&amp;gt;5000) between KTRs with low-level BK viremia/viruria, KTRs with no BK viremia/viruria, and KTRs with high-level BK viremia (p&amp;gt;0.05). KTRs with low-level BK viremia/viruria showed superior kidney allograft survival and lower eGFR slope compared to KTRs with no BK viremia/viruria and KTRs with high-level BK viremia (p&amp;lt;0.05). The administration of IVIG during high-level BK viremia didn’t impact the development of TCMR, ABMR, development of de novo DSA, eGFR slope, and kidney allograft survival (p&amp;lt;0.05). Conclusion Our results show that low-level BK viremia/viruria is associated with suppression of TCMR and ABMR in the early period posttransplantation, and preservation of kidney allograft function in the long-term. The administration of IVIG didn’t prove beneficial to reduce allosensitization among KTRs with high-level BK viremia.