409-P: Arteriolar Hyalinosis Is Associated with the Rate of eGFR Decline and Predicts the Onset of Macroalbuminuria and eGFR<60 Ml/min/1.73 M2 in Patients with Type 2 Diabetes and Normo-microalbuminuria Regardless of Microalbuminuria Grade

Background and objectivesBiomarkers may improve identification of individuals at risk of eGFR decline who may benefit from intervention or dialysis planning. However, available biomarkers remain incompletely validated for risk stratification and prediction modeling.Design, setting, participants, & measurementsWe examined serum cystatin C, urinary kidney injury molecule–1 (uKIM-1), and urinary neutrophil gelatinase-associated lipocalin (UNGAL) in 5367 individuals with type 2 diabetes mellitus and recent acute coronary syndromes enrolled in the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) trial. Baseline concentrations and 6-month changes in biomarkers were also evaluated. Cox proportional regression was used to assess associations with a 50% decrease in eGFR, stage 5 CKD (eGFR<15 ml/min per 1.73 m2), or dialysis.ResultseGFR decline occurred in 98 patients (1.8%) over a median of 1.5 years. All biomarkers individually were associated with higher risk of eGFR decline (P<0.001). However, when adjusting for baseline eGFR, proteinuria, and clinical factors, only baseline cystatin C (adjusted hazard ratio per 1 SD change, 1.66; 95% confidence interval, 1.41 to 1.96; P<0.001) and 6-month change in urinary neutrophil gelatinase-associated lipocalin (adjusted hazard ratio per 1 SD change, 1.07; 95% confidence interval, 1.02 to 1.12; P=0.004) independently associated with CKD progression. A base model for predicting kidney function decline with nine standard risk factors had strong discriminative ability (C-statistic 0.93). The addition of baseline cystatin C improved discrimination (C-statistic 0.94), but it failed to reclassify risk categories of individuals with and without eGFR decline.ConclusionsThe addition of cystatin C or biomarkers of tubular injury did not meaningfully improve the prediction of eGFR decline beyond common clinical factors and routine laboratory data in a large cohort of patients with type 2 diabetes and recent acute coronary syndrome.PodcastThis article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_01_16_CJASNPodcast_18_3_G.mp3

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Hyperglycemia Regulated Circulating MicroRNAs and Their Effects on Renal Function Decline in Type 2 Diabetes

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.845 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A414-A414

Author(s):

Hiroki Kobayashi ◽

Eiichiro Satake ◽

Andrezej S Krolewski

Keyword(s):

Type 2 Diabetes ◽

Renal Function ◽

Signaling Pathway ◽

Mapk Pathway ◽

Ras Signaling ◽

Bioinformatics Analyses ◽

Renal Function Decline ◽

Function Discovery ◽

Egfr Decline

Abstract Background: It has been reported that microRNAs (miRNAs) play an important role in the pathogenesis of diabetic complications. We aimed to search for circulating miRNA that were associated with hyperglycemia in type 2 diabetes and examine their effects on renal function decline. Methods: Using the next-generation sequencing-based HTG EdgeSeq miRNA platform, a total of 2,083 miRNAswere measured in baseline plasma specimens obtained from73 subjects with type 2 diabetes (T2D) and normal renal function (discovery panel) and 136 subjects with T2D and impaired renal function (replication panel). Subjects in both panels were followed for 6–12 years to determine eGFR decline. Results: We identified 11 candidate miRNAsthat were strongly associated with elevated levels of glycated hemoglobin (HbA1c) in both screening and replication panels. Using bioinformatics analyses, we found that the candidate miRNAs targeted proteins of 6 pathways (the Ras signaling pathway, Signaling pathways regulating pluripotency of stem cells, the MAPK pathway, Glutamatergic synapse, the Rap 1 signaling pathway, and the AMPK signaling pathway). Importantly, 4 of these 11 miRNAs were significantly associated with risk of renal function decline. Conclusion: There were few previous reports about the association between circulating miRNAs, hyperglycemia, and diabetic kidney disease in T2D. The present study comprehensively examined and identified hyperglycemia-regulated miRNAs in human samples. Our finding are novel in that circulatingmiRNAsregulated by hyperglycemia are associated with risk of eGFR decline in T2D.

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Efficacy and Safety of Dapagliflozin by Baseline Glycemic Status: A Prespecified Analysis From the DAPA-CKD Trial

10.2337/figshare.14465844.v1 ◽

2021 ◽

Author(s):

Frederik Persson ◽

Peter Rossing ◽

Priya Vart ◽

Glenn M. Chertow ◽

Fan Fan Hou ◽

...

Keyword(s):

Type 2 Diabetes ◽

Kidney Disease ◽

Primary Outcome ◽

Composite Endpoint ◽

Cardiovascular Death ◽

Glycemic Status ◽

End Stage ◽

Design And Methods ◽

Egfr Decline

Objective DAPA-CKD demonstrated risk reduction for kidney and cardiovascular outcomes with dapagliflozin versus placebo in participants with chronic kidney disease (CKD) with and without diabetes. We compared outcomes according to baseline glycemic status. Research Design and Methods We enrolled participants with CKD, estimated glomerular filtration rate (eGFR) 25–75ml/min/1.73m2 and urinary albumin-to-creatinine ratio 200–5000mg/g. The primary composite endpoint was sustained eGFR decline ≥50%, end-stage kidney disease, or kidney or cardiovascular death. Results Of 4304 participants, 738 had normoglycemia, 660 pre-diabetes, and 2906 type 2 diabetes. The effect of dapagliflozin on the primary outcome was consistent (p-interaction=0.19) in normoglycemia (HR [95%CI] 0.62 [0.39–1.01]), pre-diabetes (HR 0.37 [0.21–0.66]) and type 2 diabetes (HR 0.64 [0.52–0.79]). We found no evidence for effect modification on any outcome. Adverse events were similar, with no major hypoglycemia or ketoacidosis in participants with normoglycemia or pre-diabetes. Conclusions Dapagliflozin safely reduced kidney and cardiovascular events independent of baseline glycemic status.

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Validation of Plasma Biomarker Candidates for the Prediction of eGFR Decline in Patients With Type 2 Diabetes

Diabetes Care ◽

10.2337/dc18-0532 ◽

2018 ◽

Vol 41 (9) ◽

pp. 1947-1954 ◽

Cited By ~ 18

Author(s):

Andreas Heinzel ◽

Michael Kammer ◽

Gert Mayer ◽

Roman Reindl-Schwaighofer ◽

Karin Hu ◽

...

Keyword(s):

Type 2 Diabetes ◽

Plasma Biomarker ◽

Egfr Decline

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Rate of Decline in Kidney Function and Age-of-Onset or Duration of Type 2 Diabetes

10.21203/rs.3.rs-289704/v1 ◽

2021 ◽

Author(s):

Oyunchimeg Buyadaa ◽

Agus Salim ◽

Jedidiah I Morton ◽

Dianna J Magliano ◽

Jonathan E Shaw

Keyword(s):

Type 2 Diabetes ◽

Kidney Function ◽

Estimated Glomerular Filtration Rate ◽

Middle Age ◽

Age Of Onset ◽

Duration Of Diabetes ◽

Rate Of Decline ◽

Kidney Function Decline ◽

Egfr Decline

Abstract The association between rate of kidney function decline and age-of-onset or duration of type 2 diabetes has not been well investigated. We aimed to examine whether rates of estimated glomerular filtration rate (eGFR) decline differ by age-of-onset or duration in people with type 2 diabetes. Using the Action to Control Cardiovascular Risk in Diabetes study dataset rates of eGFR decline were calculated using a joint-longitudinal-survival model and were compared among groups defined by the age-of-onset (0–39, 40–49, 50–59, 60–69 and > 70 years) and 5-year diabetes duration intervals. Changes in renal function were evaluated using median of 6 (interquartile range: 3–10) eGFR measurements per person. eGFR decline was the slowest in those with an age-at-diagnosis of 50 − 59 years or those with duration of diabetes < 5 years. The rates of eGFR decline were significantly greater in those with an age-of-onset < 40 years or those with duration of diabetes > 20 years compared to those diagnosed at 50 − 59 or those with duration of diabetes < 5 years (-1.98 vs -1.61 ml/min/year; -1.82 vs -1.52 ml/min/year; respectively (p < 0.001). Those with youngest age-of-onset or longest duration of type 2 diabetes had more rapid declines in eGFR compared to those diagnosed at middle age or those with shorter duration of diabetes.

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Abstract P274: Kidney Filtration Markers and the Risk of Clinical Outcomes in Individuals With Type 2 Diabetes in the Advance Trial

Circulation ◽

10.1161/circ.141.suppl_1.p274 ◽

2020 ◽

Vol 141 (Suppl_1) ◽

Author(s):

Hyunju Kim ◽

Dan Wang ◽

John Chalmers ◽

Mark Woodward ◽

Elizabeth Selvin ◽

...

Keyword(s):

Type 2 Diabetes ◽

Clinical Outcomes ◽

Regression Models ◽

Cox Regression ◽

All Cause Mortality ◽

Baseline Levels ◽

Controlled Evaluation ◽

Egfr Decline

Introduction: Creatinine-based estimated glomerular filtration rate (eGFR) is biased in the setting of obesity and other conditions. Alternative kidney filtration markers may be particularly useful in adults with diabetes, but few studies examined the risk of clinical outcomes associated with filtration markers in adults with type 2 diabetes. Objective: We evaluated whether baseline levels and change in eGFR based on creatinine (Cr), cystatin C (Cys), and B 2 -microglobulin (B2M) were associated with the risk of clinical outcomes among individuals with type 2 diabetes. Methods: In the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, Cr, Cys, and B2M were measured in 7,217 participants at baseline and a random sample of 640 participants at the 1 year visit. We categorized baseline eGFR Cr , eGFR Cys , eGFR B2M , and the average across the 3 eGFR estimates (eGFR avg ) into quarters, and examined associations with major macrovascular and microvascular events together, and separately, and all-cause mortality using Cox regression models, adjusting for established risk factors. We also examined associations with continuous eGFR decline and increase (per 30%). Results: Over a median follow-up of 5 years, 1,313 combined major macrovascular (n=748) and microvascular events (n=637), and 743 deaths occurred. Lower levels of eGFR based on all three filtration markers individually and combined were associated with 1.5 to 2.2 times higher risk of combined major macrovascular and microvascular events, with similar patterns for other outcomes ( Table ). Per 30% decline in eGFR Cys and eGFR avg were associated with a >2-fold higher risk of all clinical outcomes, after additional adjustment of baseline eGFR. Conclusions: In adults with type 2 diabetes, baseline levels of eGFR based on alternative filtration markers and per 30% decline in eGFR Cys and eGFR avg were consistently associated with all clinical outcomes.

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Urinary complement proteins and risk of end-stage renal disease: quantitative urinary proteomics in patients with type 2 diabetes and biopsy-proven diabetic nephropathy

Journal of Endocrinological Investigation ◽

10.1007/s40618-021-01596-3 ◽

2021 ◽

Author(s):

L. Zhao ◽

Y. Zhang ◽

F. Liu ◽

H. Yang ◽

Y. Zhong ◽

...

Keyword(s):

Type 2 Diabetes ◽

Diabetic Nephropathy ◽

Renal Disease ◽

End Stage Renal Disease ◽

Renal Outcome ◽

Complement Proteins ◽

Stage Renal Disease ◽

End Stage ◽

Egfr Decline

Abstract Purpose To investigate the association between urinary complement proteins and renal outcome in biopsy-proven diabetic nephropathy (DN). Methods Untargeted proteomic and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional analyses and targeted proteomic analysis using parallel reaction-monitoring (PRM)-mass spectrometry was performed to determine the abundance of urinary complement proteins in healthy controls, type 2 diabetes mellitus (T2DM) patients, and patients with T2DM and biopsy-proven DN. The abundance of each urinary complement protein was individually included in Cox proportional hazards models for predicting progression to end-stage renal disease (ESRD). Results Untargeted proteomic and functional analysis using the KEGG showed that differentially expressed urinary proteins were primarily associated with the complement and coagulation cascades. Subsequent urinary complement proteins quantification using PRM showed that urinary abundances of C3, C9, and complement factor H (CFAH) correlated negatively with annual estimated glomerular filtration rate (eGFR) decline, while urinary abundances of C5, decay-accelerating factor (DAF), and CD59 correlated positively with annual rate of eGFR decline. Furthermore, higher urinary abundance of CFAH and lower urinary abundance of DAF were independently associated with greater risk of progression to ESRD. Urinary abundance of CFAH and DAF had a larger area under the curve (AUC) than that of eGFR, proteinuria, or any pathological parameter. Moreover, the model that included CFAH or DAF had a larger AUC than that with only clinical or pathological parameters. Conclusion Urinary abundance of complement proteins was significantly associated with ESRD in patients with T2DM and biopsy-proven DN, indicating that therapeutically targeting the complement pathway may alleviate progression of DN.

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