Combined Renal Endpoint Research Articles

Treatment of diabetic kidney disease. A network meta-analysis.

Diabetic kidney disease (DKD) is a health burden of rising importance. Slowing progression to end stage kidney disease is the main goal of drug treatment. The aim of this analysis is to compare drug treatments of DKD by means of a systemic review and a network meta-analysis. We searched Medline, CENTRAL and clinicaltrials.gov for randomized, controlled studies including adults with DKD treated with the following drugs of interest: single angiotensin-converting-enzyme-inhibitor or angiotensin-receptor-blocker (single ACEi/ARB), angiotensin-converting-enzyme-inhibitor and angiotensin-receptor-blocker combination (ACEi+ARB combination), aldosterone antagonists, direct renin inhibitors, non-steroidal mineralocorticoid-receptor-antagonists (nsMRA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i). As primary endpoints, we defined: overall mortality and end-stage kidney disease, as secondary endpoints: renal composite outcome and albuminuria and as safety endpoints: acute kidney injury, hyperkalemia and hypotension. Under the use of a random effects model, we computed the overall effect estimates using the statistic program R4.1 and the corresponding package "netmeta". Risk of bias was assessed using the RoB 2 tool and the quality of evidence of each pairwise comparison was rated according to GRADE (Grading of Recommendations Assessment, Development and Evaluation). Of initial 3489 publications, 38 clinical trials were found eligible, in total including 42346 patients. Concerning the primary endpoints overall mortality and end stage kidney disease, SGLT2i on top of single ACEi/ARB compared to single ACEi/ARB was the only intervention significantly reducing the odds of mortality (OR 0.81, 95%CI 0.70-0.95) and end-stage kidney disease (OR 0.69, 95%CI 0.54-0.88). The indirect comparison of nsMRA vs SGLT2i in our composite endpoint suggests a superiority of SGLT2i (OR 0.60, 95%CI 0.47-0.76). Concerning safety endpoints, nsMRA and SGLT2i showed benefits compared to the others. As the only drug class, SGLT2i showed in our analysis beneficial effects on top of ACEi/ARB treatment regarding mortality and end stage kidney disease and by that reconfirmed its position as treatment option for diabetic kidney disease. nsMRA reduced the odds for a combined renal endpoint and did not raise any safety concerns, justifying its application.

Neuropeptide Y gene polymorphisms and chronic kidney disease progression.

Neuropeptide Y (NPY) is a neurotransmitter expressed in both the central and peripheral nervous systems, which is involved in regulating a multitude of physiological processes ranging from arterial pressure, energy balance, the immune response and inflammation and renal electrolyte transport. In a cohort of chronic kidney disease (CKD) patients, we recently showed that high plasma NPY levels predict renal disease progression independently of hypertension and other risk factors but the causal nature of this association remains unproven. In the same cohort of the previous study, we tested the relationship of NPY gene variability, as assessed by five single nucleotide polymorphisms (SNPs) that explained the whole gene variability, with the incidence rate of a predefined combined renal endpoint (dialysis/transplantation/estimated glomerular filtration rate reduction >30%) over a median follow up of 36 months (inter-quartile range 35-37 months) in 735 ethnically homogeneous patients with stage 2-5 CKD. Two variants [rs16131 (recessive model for the T risk allele: TT, n = 563; CT + CC, n = 172) and rs16140 (dominant model for the G risk allele: GG + CG, n = 413; CC, n = 322)] were coherently associated with the incidence rate of renal events [hazard ratio (HR) ranging from 1.39 to 1.57, P ≤ 0.015] and this was also true when the two SNPs were jointly introduced into the same Cox model ( P ≤ 0.043). The analysis of the biological interaction showed a significant synergism between the NPY rs16131 and rs16140 variants. Indeed, patients harboring NPY rs16131 TT and NPY rs16140 GG + CG risk genotypes had a much higher HR of renal events [HR: 1.80, 95% confidence interval (CI):1.16-2.79, P = 0.009] than that expected in the absence of biological interaction under both the additive and multiplicative models and the attributable proportion due to interaction (AP) was 25% and 38% on crude and adjusted analyses, respectively. This study, based on the Mendelian randomization approach and using NPY gene variants as instrumental variables to test the link between NPY and CKD progression, is in line with findings indicating that high plasma NPY levels predict an increased risk for renal events and lend support to the hypothesis that NPY is causally involved in renal disease progression.

Venous bicarbonate and CKD progression: a longitudinal analysis by the group-based trajectory model.

Metabolic acidosis accelerates chronic kidney disease (CKD) progression towards kidney failure in animal models. Clinical trials testing the effect of bicarbonate on kidney outcomes are underpowered and/or of suboptimal quality. On the other hand, observational studies testing the same hypothesis are generally based on bicarbonate measured at a single time point. We studied the longitudinal relationship between repeated venous bicarbonate levels and a predefined composite renal outcome (a ≥30% estimated glomerular filtration rate reduction, dialysis or transplantation) by using group-based trajectory model (GBTM) analysis. The GBTM analysis was used to classify patients based on individual bicarbonate levels over time. The relationship between trajectory groups and renal outcomes was investigated using crude and adjusted Cox regression models. A total of 528 patients with stage 2-5 CKD were included in the analysis. The GBTM analysis identified four distinct trajectories of bicarbonate levels: low, moderate, moderate-high and high. During the follow-up period, 126 patients experienced the combined renal endpoint. The hazard rate of renal events decreased dose-dependently from the lowest to the highest bicarbonate trajectory. After adjusting for potential confounders, there was a 63% risk reduction for the composite renal endpoint for patients in the high trajectory category compared with those in the low trajectory category. The study found that higher bicarbonate trajectories were associated with a lower risk of adverse renal outcomes in CKD patients. These results suggest that strategies to maintain higher bicarbonate levels may benefit patients with CKD. However, further high-quality randomised trials are needed to confirm these findings and recommend bicarbonate supplementation as a strategy to delay CKD progression.

Time-Averaged Hematuria as a Prognostic Indicator of Renal Outcome in Patients with IgA Nephropathy.

We aim to investigate the association of time-averaged hematuria (TA-hematuria) with the progression of IgA nephropathy (IgAN). Based on TA-hematuria during follow-up, 152 patients with IgAN were divided into a hematuria remission group (≤28 red blood cells [RBCs]/μL) and a persistent hematuria group (>28 RBCs/μL). The persistent hematuria group had a higher percentage of patients with macroscopic hematuria, lower levels of hemoglobin and TA-serum albumin, and more severe renal pathologic lesions. The composite endpoint is defined as a doubling of the baseline SCr level (D-SCr), or the presence of ESRD. During the mean follow-up of 58.08 ± 23.51 months, 15 patients (9.9%) reached the primary outcome of ESRD and 19 patients (12.5%) reached the combined renal endpoint. Kaplan-Meier analysis showed that the persistent hematuria group had a lower renal survival rate. The persistent hematuria patients who were incorporated with proteinuria (≥1.0 g/day) and low TA-serum albumin (<40 g/L) had the worst renal outcomes. Multivariate Cox regression indicated that TA-hematuria (hazard ratio [HR] = 0.004, 95% CI: 0.001, 0.008; p = 0.010) was independently associated with the progression of IgAN. Receiver operating characteristic analysis indicated the optimal TA-hematuria cutoff value for predicting the progression of IgAN was 201.21 RBCs/μL in females and 37.25 RBCs/μL in males.

CKD-MBD biomarkers and CKD progression: an analysis by the joint model.

Biomarkers of chronic kidney disease-mineral and bone disorder (CKD-MBD) have been implicated in CKD progression in follow-up studies focusing on single measurements of individual biomarkers made at baseline only. The simultaneous relationship between the time trend of these biomarkers over the course of CKD and renal outcomes has never been tested. We applied the joint model (JM) to investigate the longitudinal relationship between repeated measurements of CKD-MBD biomarkers and a combined renal endpoint (estimated glomerular filtration rate reduction>30%, dialysis or transplantation) in 729 stage 2-5 CKD patients over a 36-month follow-up. In the survival submodel of the JM, the longitudinal series of parathyroid hormone (PTH) values was directly and independently related to the risk of renal events [hazard ratio (HR) (1 ln increase in parathyroid hormone (PTH) 2.0 (range 1.5-2.8), P<.001)] and this was also true for repeated measurements of serum phosphate [HR (1mg/dl) 1.3924 (range 1.1459-1.6918), P=.001], serum calcium [HR (1mg/dl) 0.7487 (range 0.5843-0.9593), P=.022], baseline fibroblast growth factor 23 [HR (1 pg/ml) 1.001 (range 1.00-1.002), P=.045] and 1,25-dihydroxyvitamin D [HR (1 pg/ml) 0.9796 (range 0.9652-0.9942), P=.006]. Repeated measurements of serum PTH, calcium and phosphate as well as baseline FGF23 and 1,25-dihydroxyvitamin D are independently related with the progression to kidney failure in a cohort of stage 2-5 CKD patients. This longitudinal study generates the hypothesis that interventions at multiple levels on MBD biomarkers can mitigate renal function loss in this population.

The Significance of Crescents on the Clinical Features and Outcomes of Primary Immunoglobin A Nephropathy

BackgroundIt is still controversial whether the proportion of crescents below 50% can be an independent predictive risk factor for poor prognosis in IgAN patients. We reported the significance of different proportions of crescents on the clinical features and the cut-off value of crescents in predicting the occurrence of end-stage kidney disease (ESKD) in patients with IgAN.MethodsWe retrospectively analyzed biopsy-proven primary IgAN patients in Sichuan Provincial People’s Hospital from 2007 to 2019. The patients were divided into 5 groups on the basis of crescent proportion as follows: 0 (n = 647), < 10% (n = 221), 10 to 24% (n = 272), 25 to 49% (n = 80), and ≥50% (n = 22). The primary endpoint was defined as ESKD, and the secondary endpoint was the combined renal endpoint (≥50% reduction in eGFR or ESKD). A validation cohort of 346 patients were enrolled from Affiliated Hospital of Southwest Medical University. Cox regression model and Kaplan-Meier survival analysis were performed.ResultsA total of 1242 eligible patients with biopsy-proven IgAN were recorded in the database, compared with the non-crescent group, patients in the crescent group had lower levels of hemoglobin (Hb) and albumin (Alb), higher levels of blood urea nitrogen (BUN), 24h urinary protein and hematuria, a higher proportion of mesangial hypercellularity (M1), endocapillary hypercellularity (E1), segmental glomerulosclerosis (S1), and tubular atrophy/interstitial fibrosis (T1/T2) (p < 0.05). A higher crescent proportion was associated with lower levels of Hb, ALB, eGFR and serum IgG (p < 0.05), higher levels of SCr, BUN, increasing amounts of 24 h urinary protein, increasing proportion of M1 and E1, and increasing severity of interstitial inflammatory infiltration. During the median follow-up of 43 months (range 6-151), 63 individuals (7.0%) reached the primary outcome of ESKD and 99 patients (11.1%) reached the combined renal endpoint. 34(7.5%), 21 (13.3%), 24(12.2%), 14(21.5%) and 6(31.6%) patients reached the combined renal endpoint in the above five groups in crescents 0, <10%, 10∼24%, 25∼49% and ≥50%, respectively. A total of 274(62.6%) cases in the crescent group and 254 (55.7%) cases in the non-crescent group received immunosuppressive therapy. Multivariate Cox regression showed that crescents ≥50% was an independent risk factor for the progression of ESKD (p = 0.003) and crescents ≥25% was an independent risk factor for the combined renal endpoint(p < 0.001). The receiver operating characteristic curve showed that IgAN patients with crescents ≥43.7% had a higher risk of ESKD, even with immunosuppressants (Sensitivity = 75.7%,specificity = 89.6%,p < 0.001). This discovery cohort and the validation cohort further confirmed that patients with crescents <43.7% had better renal prognosis than those with crescents ≥43.7% in the whole group and those with immunosuppressants (p < 0.001).ConclusionIgAN patients with crescents had more severe clinicopathological features and poorer prognosis. Crescents ≥50% was an independent risk factor for the progression of ESKD and crescents ≥25% was an independent risk factor for ≥50% reduction in eGFR or ESKD in treated and untreated IgAN patients. Crescents ≥43.7% was an independent risk factor for ESKD in those with immunosuppressants.

Gliflozins for the Treatment of Congestive Heart Failure and Renal Failure in Type 2 Diabetes.

Gliflozins are effective drugs for the treatment of type 2 diabetes. They inhibit sodium glucose cotransporter 2 in the proximal renal tubule, leading to increased glucose excretion. On the basis of findings from relevant studies, gliflozins are also increasingly used in clinical practice to treat congestive heart failure and renal failure. This review is based on pertinent publications retrieved from a selective literature search in PubMed and GoogleScholar. Cardiovascular safety studies revealed early on that gliflozins can lower the hospitalization rate of patients suffering from congestive heart failure with a reduced leftventricular ejection fraction (HFrEF). They also showed favorable effects on multiple renal endpoints. In recent years, studies such as DAPA-HF and CREDENCE have further documented the benefit of gliflozins in the treatment of congestive heart failure and renal failure in patients with type 2 diabetes, and gliflozins have accordingly been incorporated into the pertinent guidelines. In the recently published EMPEROR-Reduced trial, empagliflozin was found to significantly lower the frequency of a combined cardiovascular endpoint in patients with HFrEF (19.4 % versus 24.7%; hazard ratio [HR] 0.75; 95% confidence interval [0.65; 0.86]; number needed to treat [NNT] 19, p <0.001). In the DAPA-CKD trial, which was also recently published, dapagliflozin was found to significantly lower the frequency of a combined renal endpoint (9.2% versus 14.5%; HR 0.61 [0.51; 0.72]; NNT 19; p <0.001). On the basis of findings from specific studies, gliflozins will henceforth be a major class of drug for the treatment of HFrEF and renal failure, independently of the presence of type 2 diabetes.

Copeptin and renal function decline, cardiovascular events and mortality in type 1 diabetes.

Plasma copeptin is a surrogate of arginine vasopressin (AVP) secretion and is associated with a risk of renal and cardiovascular disease. We investigated associations between copeptin and renal events, cardiovascular events and mortality in type 1 diabetes (T1D). We conducted a prospective cohort study on 658 individuals with T1D from Steno Diabetes Center Copenhagen. Plasma copeptin concentrations and conventional risk factors were assessed at baseline. The five endpoints were traced through national registries and electronic laboratory records. Baseline mean age was 55 ± 13 years and estimated glomerular filtration rate (eGFR) was 81 ± 26 mL/min/1.73 m2. The median follow-up was 6.2 years (interquartile range 5.8-6.7); 123 participants reached a combined renal endpoint [decline in eGFR ≥30%, end-stage kidney disease (ESKD) or all-cause mortality], 93 had a decrease in eGFR ≥30%, 21 developed ESKD, 94 experienced a combined cardiovascular endpoint and 58 died from all causes. Higher copeptin was associated with all endpoints in unadjusted Cox regression analyses. Upon adjustment for baseline eGFR, the associations were attenuated and remained significant only for the combined renal endpoint and decrease in eGFR ≥30%. Results were similar upon further adjustment for other risk factors, after which hazard ratios for the two renal endpoints were 2.27 (95% confidence interval 1.08-4.74) and 4.49 (1.77-11.4), respectively, for the highest versus the lowest quartile of copeptin. Higher copeptin was an independent risk marker for a combined renal endpoint and decline in renal function. AVP may be a marker of renal damage or a factor whose contribution to renal and cardiovascular risk is partially mediated by renal damage.

Comparison of Natriuretic Peptides as Risk Markers for All-Cause Mortality and Cardiovascular and Renal Complications in Individuals With Type 1 Diabetes.

Few studies have compared midregional proatrial natriuretic peptide (MR-proANP) and N-terminal probrain natriuretic peptide (NT-proBNP). We compared their value as risk markers for all-cause mortality and cardiovascular (CV) and renal complications in individuals with type 1 diabetes. MR-proANP and NT-proBNP were measured in 664 individuals. Hazard ratios (HRs) were assessed per doubling of NT-proBNP or MR-proANP for risk of a composite of ischemic events, heart failure (HF), a combined renal end point of end-stage kidney disease (ESKD), decline in estimated glomerular filtration rate (eGFR) ≥30%, and all-cause mortality or individual end points. Adjustments included CV risk factors and addition of MR-proANP or NT-proBNP. Median follow-up was 5.1-6.2 years. MR-proANP was associated with higher risk of all-cause mortality (n = 57; HR 1.7, 95% CI 1.1-2.7), combined CV end point (n = 94; 1.6, 1.1-2.2), HF (n = 27; 2.8, 1.5-5.2), combined renal end point (n = 123; 1.6, 1.2-2.1), and ESKD (n = 21; 3.1, 1.2-7.8) independent of CV risk factors (P ≤ 0.02). After addition of NT-proBNP, significance for all end points was lost. A doubling of NT-proBNP was associated with higher risk of all-cause mortality (HR 1.5, 95% CI 1.2-1.8), the combined CV end point (1.3, 1.1-1.5), HF (1.7, 1.3-2.1), and the combined renal end point (1.3, 1.1-1.4) independent of CV risk factors (model 2 [P < 0.001]) and MR-proANP (model 3 [P ≤ 0.03]). There was no association with decline in eGFR ≥30% (n = 93). Higher NT-proBNP was independently associated with all-cause mortality, CV disease, HF, and the combined renal end point. MR-proANP was associated with all end points but decline in eGFR, although not independent of NT-proBNP. MR-proANP may contribute to the predictive value of NT-proBNP for risk stratification in type 1 diabetes.

P0831HIGH SERUM ALKALINE PHOSPHATASE PREDICTS THE RISK OF CKD PROGRESSION: EFFECT NODIFICATION BY THE GFR

Abstract Background and Aims In the post-hoc analyses of the SUSTAIN and ASSURE trials (Kidney Blood Press Res. 2018;43:449-457), Apabetalone, an epigenetic modulator which lowers serum alkaline phosphatase (AlkPhos), stabilized the GFR in patients with cardiovascular disease and a GFR &amp;lt;60/ml/min/1.73m2. Analyzing the relationship between AlkPhos and renal outcomes in patients with established CKD is useful to preliminarily explore the biological hypothesis that AlkPhos is implicated in CKD progression. Method We investigated the relationship between AlkPhos and the risk for a combined renal end-point (30% GFR loss or dialysis/renal transplantation) in a cohort of 609 stage 3-5 CKD patients with an average GFR of 34.8±12.1ml/min/1.73 m2. Results Median AlkPhos levels were 91 IU/L (Interquartile range 71-117 IU/L) and in the vast majority of patients had values below 147 IU/L (the upper limit of the normal range). Over a median follow up of 3 years, two-hundred patients had the combined renal end-point. In an unadjusted analysis 1 ln increase in AlkPhos entailed a 49% risk excess for the renal end-point (HR: 1.49, 95% CI 1.11-2.01, P=0.008). Adjusting for traditional (age, gender, smoking, diabetes, total cholesterol, BMI, systolic BP, CV comorbidities) and CKD specific risk factors (hemoglobin, albumin, phosphate, and hs-CRP) did not modify the strength of this association (HR:1.48, 95% CI 1.08-2.02, P=0.016). Furthermore, In a fully adjusted analysis testing the GFR as an effect modifier of the AlkPhos - combined renal end point relationship showed a strong GFR- AlkPhos interaction (Figure). Indeed the risk for the combined renal end-point was gradually more pronounced at progressively more severe degrees of renal dysfunction, the HR being 0.94 (CI95% 0.60-1.47) at a GFR of 40 ml/min/m2 and 2.71 (CI95% 1.49-4.93) at 10 ml/min/1.73m2. Conclusion In patients with stage 3-5 CKD alkaline phosphatase within the normal range is associated with the risk for progression to ESRD and the GFR is an effect modifier of this relationship. Findings in this study are compatible with the hypothesis that within the normal range of this biomarker, the risk for CKD progression by alkaline phosphatase is amplified by the severity of CKD. These data are in keeping with post-hoc analyses of the SUSTAIN and ASSURE trials and provide circumstantial support to the hypothesis that interventions lowering serum alkaline phosphatase may mitigate CKD progression.

SO091URINE-TO-PLASMA UREA RATIO, AS SURROGATE MARKER FOR URINE CONCENTRATING CAPACITY, IS ASSOCIATED WITH DISEASE PROGRESSION IN ADPKD

Abstract Introduction Predicting disease progression in autosomal dominant polycystic kidney disease (ADPKD) patients poses a challenge, especially in early stage disease when renal function is not yet affected. The ongoing formation and growth of cysts causes the urine concentrating capacity to decrease from early on in the disease. We therefore hypothesized that the easy and inexpensive to measure urine-to-plasma urea ratio (UPU ratio), which is assumed to be surrogate for maximal urine concentrating capacity, can be used as marker to predict disease progression in ADPKD. Methods The UPU ratio was calculated by dividing urea concentration in a fasting morning spot urine sample by plasma urea concentration adjusted for plasma creatinine concentration. First, we validated the UPU ratio in 30 ADPKD patients who underwent a prolonged water deprivation test to measure the maximal urine concentrating capacity. Thereafter, the association of the UPU ratio with renal outcome was evaluated in 583 ADPKD patients participating in the DIPAK observational cohort (inclusion criteria: age&amp;gt;18 years, eGFR &amp;gt;15 mL/min/1.73m2, no concomitant diseases affecting eGFR, without V2 receptor antagonist prescription). Kidney function was assessed as eGFR by the creatinine based CKD-EPI formula, height adjusted total kidney volume (htTKV) by MRI and copeptin (surrogate for vasopressin) by ELISA. Results In the water deprivation test participants (n=30), the UPU ratio was strongly correlated with maximal urine concentrating capacity (R = 0.67, p&amp;lt;0.001). This association remained significant after correcting for sex, age, htTKV and eGFR (st. β = 0.53, p = 0.007). In these subjects maximal urine concentrating capacity as well as UPU ratio were associated with the rate of eGFR decline during a median follow-up of 6.3 yr (12 eGFR assessments per patient) assessed using linear mixed modeling, also when corrected for sex, baseline age and eGFR (β = 0.009, p = 0.04, and β = 5.56, p&amp;lt;0.001, resp.). We subsequently corroborated in the larger DIPAK observational cohort (n=583, 58% female, mean age 47 yr median eGFR 60 mL/min/1.73m2 and htTKV 898 ml/m), that the UPU ratio was significantly associated with rate of eGFR decline during a median follow-up of 4.0 yr (6 eGFR assessments per patient): β = 0.23, p = 0.005. This association remained significant when corrected for sex, baseline age and eGFR (β = 0.32, p&amp;lt;0.001) and even when additionally corrected for Mayo class, PDK mutation and copeptin (β = 0.40, p &amp;lt;0.001). Stepwise backward multivariate regression analysis resulted in a final model including the UPU ratio, PKD mutation, Mayo Class and copeptin. Cox survival analysis showed that a lower baseline UPU ratio (indicating less urine concentrating capacity) was significantly associated with a higher risk to develop the combined renal endpoint of incidence of start of kidney replacement therapy, eGFR &amp;lt;15 mL/min/1.73m2 or eGFR decrease &amp;gt;40% during follow-up (adjusted Hazard Ratio per SD = 1.39, p = 0.007). Limiting the aforementioned analyses to the subgroup of patients with relative early stage disease (n=122, age &amp;lt;40 yr and eGFR &amp;gt;60 mL/min/1.73m2) rendered essentially similar results, with an adjusted β for UPU ratio in the final model of 0.33 (p = 0.04). In this subgroup with a limited number of events (n=10), Cox survival analysis did not reach formal significance (adjusted HR per SD: 2.67, p = 0.055). Conclusion The UPU ratio, which is calculated from routine laboratory measurements, predicts renal prognosis in ADPKD in addition to other, more laborious to measure and expensive risk markers. Notably, this marker of urine concentrating capacity also shows promise in early-stage disease.

Metabolomic Assessment Reveals Alteration in Polyols and Branched Chain Amino Acids Associated With Present and Future Renal Impairment in a Discovery Cohort of 637 Persons With Type 1 Diabetes.

Background: Improved understanding of the pathophysiology causing diabetic kidney disease (DKD) is imperative. The aim of this study was to uncover associations between serum metabolites and renal outcomes.Methods: Non-targeted serum metabolomics analyses were performed in samples from 637 persons with type 1 diabetes using two-dimensional gas chromatography coupled to time-of-flight mass-spectrometry. Longitudinal data at follow-up (median 5.5 years) on renal events were obtained from national Danish health registries. A composite renal endpoint (n = 123) consisted of estimated glomerular filtration rate (eGFR) decline from baseline (≥30%), progression to end-stage renal disease and all-cause mortality. Metabolites with significant associations (p < 0.05) in any of the cross-sectional analyses with eGFR and albuminuria were analyzed for specific and composite endpoints. Adjustments included traditional cardiovascular risk factors and correction for multiple testing.Results: A data-driven partial correlation analysis revealed a dense fabric of co-regulated metabolites and clinical variables dominated by eGFR. Ribonic acid and myo-inositol were inversely associated with eGFR, positively associated with macroalbuminuria (p < 0.02) and longitudinally associated with higher risk of eGFR decline ≥30% (HR 2.2–2.7, CI [1.3–4.3], p < 0.001). Ribonic acid was associated with a combined renal endpoint (HR 1.8, CI [1.3–2.3], p = 0.001). The hydroxy butyrate 3,4-dihydroxybutanoic acid was cross-sectionally associated with micro- and macroalbuminuria, urinary albumin excretion rate and inversely associated with eGFR (p < 0.04) while branched chain amino acids were associated with eGFR and lower risk of the combined renal endpoint (p < 0.02).Conclusions: Alterations in serum metabolites, particularly polyols and amino acids, were associated with renal endpoints in type 1 diabetes highlighting molecular pathways associated with progression of kidney disease. External validation is needed to further assess their roles and potentials as future therapeutic targets.

Lipidomic analysis reveals sphingomyelin and phosphatidylcholine species associated with renal impairment and all-cause mortality in type 1 diabetes

There is an urgent need for a better molecular understanding of the pathophysiology underlying development and progression of diabetic nephropathy. The aim of the current study was to identify novel associations between serum lipidomics and diabetic nephropathy. Non-targeted serum lipidomic analyses were performed with mass spectrometry in 669 individuals with type 1 diabetes. Cross-sectional associations of lipid species with estimated glomerular filtration rate (eGFR) and urinary albumin excretion were assessed. Moreover, associations with register-based longitudinal follow-up for progression to a combined renal endpoint including ≥30% decline in eGFR, ESRD and all-cause mortality were evaluated. Median follow-up time was 5.0–6.4 years. Adjustments included traditional risk factors and multiple testing correction. In total, 106 lipid species were identified. Primarily, alkyl-acyl phosphatidylcholines, triglycerides and sphingomyelins demonstrated cross-sectional associations with eGFR and macroalbuminuria. In longitudinal analyses, thirteen lipid species were associated with the slope of eGFR or albuminuria. Of these lipids, phosphatidylcholine and sphingomyelin species, PC(O-34:2), PC(O-34:3), SM(d18:1/24:0), SM(d40:1) and SM(d41:1), were associated with lower risk of the combined renal endpoint. PC(O-34:3), SM(d40:1) and SM(d41:1) were associated with lower risk of all-cause mortality while an SM(d18:1/24:0) was associated with lower risk of albuminuria group progression. We report distinct associations between lipid species and risk of renal outcomes in type 1 diabetes, independent of traditional markers of kidney function.

522-P: Long-Term Renal Outcomes in Young Onset Type 2 Diabetes

Young adult onset type 2 diabetes (YT2DM) is an aggressive disease. Cross-sectional studies have shown a higher prevalence of albuminuria in YT2DM compared to age-matched young adults with T1DM (YT1DM). Whether this translates to poorer long-term renal outcomes has not been widely studied. We aimed (i) to examine progression to renal replacement therapy (RRT) and renal-related death (RRD) in our young adult population, and (ii) to examine survival on RRT for those individuals who reached end stage renal disease. We performed probabilistic linkage of prospectively collected data from the RPA Diabetes Centre eMR to the Australian National Death Index and the Australian and New Zealand Dialysis and Transplant Registry up to 31/12/2015. In our patient cohort diagnosed between the ages of 15 and 35 years, 1,248 had YT1DM and 1,534 had YT2DM. After a median (IQR) observation of 13.6 (6.9-20.7) years, 56 (4.5%) of YT1DM vs. 98 (6.4%) of YT2DM reached the combined renal end-point of RRT/RRD. Analysis of Kaplan-Meier survival curves demonstrated a greater rate of progression of renal disease in YT2DM (Log-rank p=0.003). Cox proportional hazard modelling of RRT/RRD with adjustment for gender, ethnicity and duration of diabetes exposure was undertaken. The HR (95% CI) for an adverse renal outcome in YT2DM relative to YT1DM was 2.0 (1.4-2.9), p&amp;lt;0.001. This HR was attenuated when further adjustments were made for HbA1c, blood pressure, BMI and cholesterol. Similar results were obtained after multiple imputation for missing data. For the 80 young adults who commenced RRT, there were 19 deaths (70%) in the YT1DM subgroup and 26 deaths (49%) in the YT2DM subgroup after a median (IQR) observation time of 4.2 (2.2-9.1) years. KM survival analysis demonstrated equally poor survival in YT1DM and YT2DM. Cox regression with transplant as a time-varying covariate also showed non-significance. These data highlight the more rapidly progressive renal disease seen in YT2DM compared to YT1DM; however, survival on RRT appears to be equally poor for both diabetes types. Disclosure T. Middleton: Other Relationship; Self; AstraZeneca. S. Chadban: None. L.M. Molyneaux: None. M.I. D'Souza: None. M.I. Constantino: None. D. Yue: None. M. McGill: None. T. Wu: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk A/S, Sanofi. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S, Sanofi. S.M. Twigg: Advisory Panel; Self; Abbott, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi-Aventis. Board Member; Self; AstraZeneca. Research Support; Self; Abbott. Speaker's Bureau; Self; Abbott, AstraZeneca, Merck Sharp &amp; Dohme Corp., Novo Nordisk Inc., Sanofi-Aventis. J. Wong: Advisory Panel; Self; Sanofi. Speaker's Bureau; Self; AstraZeneca, Lilly Diabetes.

Is there long-term value of pathology scoring in immunoglobulin A nephropathy? A validation study of the Oxford Classification for IgA Nephropathy (VALIGA) update

It is unknown whether renal pathology lesions in immunoglobulin A nephropathy (IgAN) correlate with renal outcomes over decades of follow-up. In 1130 patients of the original Validation Study of the Oxford Classification for IgA Nephropathy (VALIGA) cohort, we studied the relationship between the MEST score (mesangial hypercellularity, M; endocapillary hypercellularity, E; segmental glomerulosclerosis, S; tubular atrophy/interstitial fibrosis, T), crescents (C) and other histological lesions with both a combined renal endpoint [50% estimated glomerular filtration rate (eGFR) loss or kidney failure] and the rate of eGFR decline over a follow-up period extending to 35 years [median 7 years (interquartile range 4.1-10.8)]. In this extended analysis, M1, S1 and T1-T2 lesions as well as the whole MEST score were independently related with the combined endpoint (P < 0.01), and there was no effect modification by age for these associations, suggesting that they may be valid in children and in adults as well. Only T lesions were associated with the rate of eGFR loss in the whole cohort, whereas C showed this association only in patients not treated with immunosuppression. In separate prognostic analyses, the whole set of pathology lesions provided a gain in discrimination power over the clinical variables alone, which was similar at 5 years (+2.0%) and for the whole follow-up (+1.8%). A similar benefit was observed for risk reclassification analyses (+2.7% and +2.4%). Long-term follow-up analyses of the VALIGA cohort showed that the independent relationship between kidney biopsy findings and the risk of progression towards kidney failure in IgAN remains unchanged across all age groups and decades after the renal biopsy.

A comparison of the effectiveness of cyclophosphamide, leflunomide, corticosteroids, or conservative management alone in patients with IgA nephropathy: a retrospective observational study

To compare the long-term efficacy of corticosteroids (P) alone or in combination with cyclophosphamide (CTX), leflunomide (LEF), or Angiotensin-convertase inhibitors or angiotensin II receptor blockers (ACEI/ARB) in treatment for IgA nephropathy (IgAN), 311 patients with IgAN were identified. Therapeutic effectiveness (including progression, partial remission, complete remission) and combined renal endpoint (defined as 30% reduction in eGFR or ESRD) were compared based on different therapies. After immunosuppressive and ACEI/ARB treatment, the levels of eGFR, proteinuria and albumin were significantly improved at the last follow-up, the extent of improvement of eGFR, proteinuria, and albumin was more notable in P + CTX group and P + LEF group. 41%, 52.2%, 55.3% and 55.2% in P + CTX, P + LEF, P and ACEI/ARB group achieved complete remission, respectively. Multivariate regression analysis indicated that only proteinuria (Relative risk (RR) 0.82(0.72–0.94), P = 0.004) and tubular atrophy/interstitial fibrosis (RR 0.26(0.13–0.57), P = 0.001) were predictors for complete remission. The optimal cutoffs of eGFR was 47.085 ml/min/1.73 m2 predicting renal function recovery in P + CTX therapy. In conclusion, tubular atrophy/interstitial fibrosis and massive proteinuria were poor predictors for complete remission in IgAN, it appears as though patients may have benefited from immunosuppressive treatment but that comparison to a well-matched contemporary control group or, ideally, a randomized controlled clinical trial, would be required to show this.

Neuropeptide Y and chronic kidney disease progression: a cohort study.

Neuropeptide Y (NPY) is a sympathetic neurotransmitter that has been implicated in various disorders including obesity, gastrointestinal and cardiovascular diseases. We investigated the relationship between circulating NPY and the progression of the glomerular filtration rate (GFR) and proteinuria and the risk for a combined renal endpoint (>30% GFR loss, dialysis/transplantation) in two European chronic kidney disease (CKD) cohorts including follow-up of 753 and 576 patients for 36 and 57 months, respectively. Average plasma NPY was 104 ± 32pmol/L in the first CKD cohort and 119 ± 41pmol/L in the second one. In separate analyses of the two cohorts, NPY associated with the progression of the estimated GFR (eGFR) and proteinuria over time in both unadjusted and adjusted {eGFR: -3.60 mL/min/1.73m2 [95% confidence interval (CI): -4.46 to - 2.74] P < 0.001 and -0.83 mL/min/1.73m2 (-1.41 to - 0.25, P = 0.005); proteinuria: 0.18 g/24 h (0.11-0.25) P < 0.001 and 0.07 g/24 h (0.005-0.14) P = 0.033} analyses by the mixed linear model. Accordingly, in a combined analysis of the two cohorts accounting for the competitive risk of death (Fine and Gray model), NPY predicted (P = 0.005) the renal endpoint [sub-distribution hazard ratio (SHR): 1.09; 95% CI: 1.03-1.16; P = 0.005] and the SHR in the first cohort (1.14, 95% CI: 1.04-1.25) did not differ (P = 0.25) from that in the second cohort (1.06, 95% CI: 0.98-1.15). NPY associates with proteinuria and faster CKD progression as well as with a higher risk of kidney failure. These findings suggest that the sympathetic system and/or properties intrinsic to the NPY molecule may play a role in CKD progression.

Office, standardized and 24-h ambulatory blood pressure and renal function loss in renal transplant patients.

Hypertension is a risk factor for renal function loss in kidney transplant patients but there are still no longitudinal studies focusing on the relationship between ambulatory blood pressure (BP) monitoring (ABPM) and the glomerular filtration rate (GFR) evolution over time in these patients. In a cohort of 260 renal transplant patients, we investigated the longitudinal relationship between repeated office BP measurements and simultaneous GFR measurements (on average 35 paired measurements per patient) and the relationship between baseline ABPM with the same outcome measure (by linear mixed models). Furthermore, we tested the prediction power of baseline ABPM and standardized BP measurements for a combined renal end point (GFR loss >30%, end-stage kidney disease or death) over a 3.7 years follow-up. Longitudinal office BP measurements were inversely related with simultaneous GFR measurements and the same was true both for baseline daytime and night-time BP. (all P < 0.001). Baseline 24-h ABPM [hazard ratio (5 mmHg):1.11; 95% confidence interval 1.03-1.19] and night-time SBP [hazard ratio (5 mmHg):1.10; 95% confidence interval 1.03-1.17] predicted the combined renal end point and the predictive model based on night-time SBP provided a data-fit superior than that by daytime SBP. In renal transplant patients, daytime and night-time SBP predict the risk of GFR loss overtime, and among the various BP metrics, night-time BP is the strongest indicator of the risk of renal function loss. Optimization of BP control and interventions targeting night-time BP may afford renal benefits in transplant patients, a hypothesis that remains to be tested in a clinical trial.

Vascular calcification in patients with nondialysis CKD over 3 years.

Vascular calcification (VC) is common in CKD, but little is known about its prognostic effect on patients with nondialysis CKD. The prevalence of VC and its ability to predict death, time to hospitalization, and renal progression were assessed. The Study of Mineral and Bone Disorders in CKD in Spain is a prospective, observational, 3-year follow-up study of 742 patients with nondialysis CKD stages 3-5 from 39 centers in Spain from April to May 2009. VC was assessed using Adragao (AS; x-ray pelvis and hands) and Kauppila (KS; x-ray lateral lumbar spine) scores from 572 and 568 patients, respectively. The primary end point was death. Secondary outcomes were hospital admissions and appearance of a combined renal end point (beginning of dialysis or drop >30% in eGFR). Factors related to VC were assessed by logistic regression analysis. Survival analysis was assessed by Cox proportional models. VC was present in 79% of patients and prominent in 47% (AS≥3 or KS>6). Age (odds ratio [OR], 1.05; 95% confidence interval [95% CI], 1.02 to 1.07; P<0.001), phosphorous (OR, 1.68; 95% CI, 1.28 to 2.20; P<0.001), and diabetes (OR, 2.11; 95% CI, 1.32 to 3.35; P=0.002) were independently related to AS≥3. After a median follow-up of 35 months (interquartile range=17-36), there were 70 deaths (10%). After multivariate adjustment for age, smoking, diabetes, comorbidity, renal function, and level of phosphorous, AS≥3 but not KS>6 was independently associated with all-cause (hazard ratio [HR], 2.07; 95% CI, 1.07 to 4.01; P=0.03) and cardiovascular (HR, 3.46; 95% CI, 1.27 to 9.45; P=0.02) mortality as well as a shorter hospitalization event-free period (HR, 1.14; 95% CI, 1.06 to 1.22; P<0.001). VC did not predict renal progression. VC is highly prevalent in patients with CKD. VC assessment using AS independently predicts death and time to hospitalization. Therefore, it could be a useful index to identify patients with CKD at high risk of death and morbidity as previously reported in patients on dialysis.

Resting heart rate is associated with renal disease outcomes in patients with vascular disease: results of the ONTARGET and TRANSCEND studies.

Resting heart rate (RHR) is associated with cardiovascular disease outcomes in high-risk patients. It is not known whether RHR is predictive of renal outcomes such as albuminuria, end-stage renal disease (ESRD) or doubling of creatinine. We evaluated whether RHR could predict renal endpoints in patients at a high risk of cardiovascular disease. We also tested the effects of RHR at different levels of systolic blood pressure (SBP). We analysed data from 28 757 patients in the ONTARGET and TRANSCEND trials. RHR and SBP were available for a mean of 4.9 ± 0.4 visits (range 3-5) within the first 2 years of the studies. Albuminuria was determined at baseline, at 2 years and at study end. Mean RHR was predictive of incident micro-albuminuria [hazard ratio (HR) for RHR ≥80 vs. <60 beats min(-1) 1.49, 95% confidence interval (CI) 1.29-1.71, P < 0.0001], incident macro-albuminuria (HR 1.84, 95% CI 1.39-2.42, P < 0.0001), doubling of creatinine (HR 1.47, 95% CI 1.00-2.17, P = 0.050) and ESRD (HR 1.78, 95% CI 1.00-3.16, P = 0.050), and the combined renal end-point (HR 1.51, 95% CI 1.32-1.74, P < 0.0001). Associations were robust at SBPs from <120 to ≥150 mmHg, with the lowest risk at a SBP of 130-140 mmHg. Resting heart rate is a potent predictor of these renal outcomes, as well as their combination, in patients with cardiovascular disease. RHR at all SBP levels should be considered as a possible renal disease risk predictor and should be investigated as a treatment target with RHR-reducing agents.