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Urinary AQP5 is independently associated with eGFR decline in patients with type 2 diabetes and nephropathy.

ABSTRACT: AIMS:Intrarenal Aquaporin 5 (AQP5) is upregulated in patients with diabetic nephropathy. Here we investigate whether urinary AQP5 is independently associated with estimated glomerular filtration rate (eGFR) decline in patients with type 2 diabetes and nephropathy. METHODS:Baseline urine samples (n?=?997) from patients with type 2 diabetes and nephropathy of the sulodexide macroalbuminuria trial were measured for AQP5 through enzyme-linked immunosorbent assays. Pearson correlation and multiple linear regression between AQP5 with eGFR slope (calculated by ?3 serum creatinine during follow-up) was performed, and association with fast renal function decline, defined as eGFR slope less than 3.0?mL/min/1.73?m2/year, was determined by logistic regression. RESULTS:Follow-up eGFR data >1.4?years from n?=?700 were available for analyses. AQP5 was undetectable in 138 patients. Tertiles of AQP5 were 0.4 [0-2.2], 7.3 [5.9-9.1], and 16.0 [13.0-21.6] (ng/mL), respectively (p?

SUBMITTER: Gao C

PROVIDER: S-EPMC7509983 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Urinary AQP5 is independently associated with eGFR decline in patients with type 2 diabetes and nephropathy.

Gao Chao C Zhang Wenzheng W

Diabetes research and clinical practice 20190801

<h4>Aims</h4>Intrarenal Aquaporin 5 (AQP5) is upregulated in patients with diabetic nephropathy. Here we investigate whether urinary AQP5 is independently associated with estimated glomerular filtration rate (eGFR) decline in patients with type 2 diabetes and nephropathy.<h4>Methods</h4>Baseline urine samples (n = 997) from patients with type 2 diabetes and nephropathy of the sulodexide macroalbuminuria trial were measured for AQP5 through enzyme-linked immunosorbent assays. Pearson correlation ...[more]

PMID: 31377226

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Project description:BACKGROUND AND OBJECTIVES:Biomarkers 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, & MEASUREMENTS:We 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. RESULTS:eGFR 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. CONCLUSIONS:The 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. PODCAST:This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_01_16_CJASNPodcast_18_3_G.mp3.

Project description:BackgroundPatients with Type 1 Diabetes (T1D) are particularly vulnerable to development of Diabetic nephropathy (DN) leading to End Stage Renal Disease. Hence a better understanding of the factors affecting kidney disease progression in T1D is urgently needed. In recent years microRNAs have emerged as important post-transcriptional regulators of gene expression in many different health conditions. We hypothesized that urinary microRNA profile of patients will differ in the different stages of diabetic renal disease.Methods and findingsWe studied urine microRNA profiles with qPCR in 40 T1D with >20 year follow up 10 who never developed renal disease (N) matched against 10 patients who went on to develop overt nephropathy (DN), 10 patients with intermittent microalbuminuria (IMA) matched against 10 patients with persistent (PMA) microalbuminuria. A Bayesian procedure was used to normalize and convert raw signals to expression ratios. We applied formal statistical techniques to translate fold changes to profiles of microRNA targets which were then used to make inferences about biological pathways in the Gene Ontology and REACTOME structured vocabularies. A total of 27 microRNAs were found to be present at significantly different levels in different stages of untreated nephropathy. These microRNAs mapped to overlapping pathways pertaining to growth factor signaling and renal fibrosis known to be targeted in diabetic kidney disease.ConclusionsUrinary microRNA profiles differ across the different stages of diabetic nephropathy. Previous work using experimental, clinical chemistry or biopsy samples has demonstrated differential expression of many of these microRNAs in a variety of chronic renal conditions and diabetes. Combining expression ratios of microRNAs with formal inferences about their predicted mRNA targets and associated biological pathways may yield useful markers for early diagnosis and risk stratification of DN in T1D by inferring the alteration of renal molecular processes.

Project description:BackgroundIndividuals with type 1 diabetes (T1D) demonstrate varied trajectories of estimated glomerular filtration rate (eGFR) decline. The molecular pathways underlying rapid eGFR decline in T1D are poorly understood, and individual-level risk of rapid eGFR decline is difficult to predict.MethodsWe designed a case-control study with multiple exposure measurements nested within 4 well-characterized T1D cohorts (FinnDiane, Steno, EDC, and CACTI) to identify biomarkers associated with rapid eGFR decline. Here, we report the rationale for and design of these studies as well as results of models testing associations of clinical characteristics with rapid eGFR decline in the study population, upon which "omics" studies will be built. Cases (n = 535) and controls (n = 895) were defined as having an annual eGFR decline of ≥3 and <1 mL/min/1.73 m2, respectively. Associations of demographic and clinical variables with rapid eGFR decline were tested using logistic regression, and prediction was evaluated using area under the curve (AUC) statistics. Targeted metabolomics, lipidomics, and proteomics are being performed using high-resolution mass-spectrometry techniques.ResultsAt baseline, the mean age was 43 years, diabetes duration was 27 years, eGFR was 94 mL/min/1.73 m2, and 62% of participants were normoalbuminuric. Over 7.6-year median follow-up, the mean annual change in eGFR in cases and controls was -5.7 and 0.6 mL/min/1.73 m2, respectively. Younger age, longer diabetes duration, and higher baseline HbA1c, urine albumin-creatinine ratio, and eGFR were significantly associated with rapid eGFR decline. The cross-validated AUC for the predictive model incorporating these variables plus sex and mean arterial blood pressure was 0.74 (95% CI: 0.68-0.79; p < 0.001).ConclusionKnown risk factors provide moderate discrimination of rapid eGFR decline. Identification of blood and urine biomarkers associated with rapid eGFR decline in T1D using targeted omics strategies may provide insight into disease mechanisms and improve upon clinical predictive models using traditional risk factors.

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Urinary AQP5 is independently associated with eGFR decline in patients with type 2 diabetes and nephropathy.

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Urinary AQP5 is independently associated with eGFR decline in patients with type 2 diabetes and nephropathy.

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