Associations of non-invasive indices of liver steatosis and fibrosis with progressive kidney impairment in adults with type 2 diabetes.

AIMS: Longitudinal data linking non-alcoholic fatty liver disease to kidney dysfunction in type 2 diabetes (T2D) are limited. This study evaluated the associations of non-invasive indices of liver steatosis and liver fibrosis with kidney impairment, and the mediatory role of the pro-angiogenic factor leucine-rich α-2 glycoprotein 1 (LRG1). METHODS: T2D adults (n = 2057) were followed for a mean period of 6.1 ± 1.6 years. Baseline liver steatosis [(hepatic steatosis index (HSI) and Zhejiang University index (ZJU)] and liver fibrosis [aspartate transaminase/alanine transaminase ratio (AAR) and BARD] indices derived from composite scoring systems were calculated. Plasma LRG1 levels were quantified using immunoassay. The study outcomes were progressive kidney function decline defined as estimated glomerular filtration rate (eGFR) decline of ≥ 40% and albuminuria progression defined as an increase in albuminuria category. RESULTS: Cross-sectionally, liver steatosis and liver fibrosis indices were associated with increased albuminuria (urinary albumin/creatinine ratio ≥ 30 µg/mg) and reduced renal function (eGFR < 60 mL/min/1.73 m2) after covariate adjustment, respectively. Approximately 32% of the participants experienced progressive kidney function decline, while 38% had albuminuria worsening over time. Longitudinal analysis revealed that baseline AAR (hazard ratio: 1.56; 95% CI 1.15-2.11) and BARD (hazard ratio: 1.16, 95% CI 1.04-1.28) predicted progressive kidney function decline, partly mediated by LRG1. In contrast, liver steatosis (HSI and ZJU) but not liver fibrosis (AAR and BARD) indices were independently associated with albuminuria progression. CONCLUSIONS: Increased liver steatosis scores were associated with albuminuria deterioration. Conversely, liver fibrosis indices may be associated with progressive kidney function decline, potentially driven by increased inflammation and angiogenesis.

Plasma osteoprotegerin as a biomarker of poor glycaemic control that predicts progression of albuminuria in type 2 diabetes mellitus: A 3-year longitudinal cohort study.

AIMS: Poor glycaemic control elevates the risk for vascular complications. Biomarkers for predicting susceptibility to glycaemic worsening are lacking. This 3-year prospective analysis assessed the utility of several circulating diabetes-related biomarkers for predicting loss of glycaemic control, and their contribution to albuminuria progression in type 2 diabetes mellitus (T2DM). METHODS: T2DM subjects with adequately-controlled diabetes (HbA1c < 8%) at initial recruitment were analysed (N = 859). Baseline plasma levels of osteoprotegerin (OPG), C-reactive protein (CRP), adiponectin, intercellular-cell adhesion molecule-1, and vascular-cell adhesion molecule-1 were quantified using immunoassay. Definitions for development of uncontrolled diabetes and albuminuria progression were HbA1c ≥ 8.0% and increase in albuminuria category at follow-up, respectively. RESULTS: At follow-up, 185 subjects developed uncontrolled diabetes. Higher baseline CRP and OPG levels were observed in the high-risk individuals, and predicted increased risk for developing uncontrolled diabetes. OPG, but not CRP, was associated with albuminuria progression after multivariable adjustment. The relationship was attenuated following adjustment for development of uncontrolled diabetes, which emerged as a significant associate. Mediation analysis revealed that loss of glycaemic control explained 64.5% of the relationship between OPG and albuminuria progression. CONCLUSIONS: OPG outperformed other diabetes-related biomarkers to be a potentially useful biomarker for predicting loss of glycaemic control and its associated albuminuria deterioration.

Association of the anti-angiogenic factor secreted protein and rich in cysteine (SPARC) with vascular complications among Chinese type 2 diabetic patients in Singapore.

AIMS: This study evaluated the association of the anti-angiogenic SPARC with known angiogenesis-associated factors and diabetes-related micro- and macro-vascular complications in a Singapore Chinese cohort with type 2 diabetes (T2DM). METHODS: Plasma SPARC was measured by immunoassay in 438 T2DM adults (mean age:58±11years). RESULTS: Higher SPARC levels in subjects stratified by SPARC tertiles displayed decreased pro-angiogenic adiponectin, osteopontin, vascular cell adhesion molecule (VCAM)-1 and matrix metalloproteinase (MMP)-2 concentrations (all p<0.05). The anti-angiogenic pigment epithelium-derived factor (PEDF) level was not statistically different among the SPARC tertiles. Age-adjusted partial correlation revealed significant associations of SPARC with adiponectin, osteopontin, VCAM-1, MMP-2, and PEDF (all p<0.05). Lower SPARC was accompanied by less favorable estimated glomerular filtration rate (eGFR) and carotid-femoral pulse wave velocity (PWV) readings (all p<0.05). Conversely, ankle-brachial index (ABI) reduced with increasing SPARC (p=0.048). The eGFR (B=0.834, p=0.019), PWV (B=-7.925, p=0.009), and ABI (B=-142.160, p=0.010) remained as determinants of SPARC after confounder adjustment. Moreover, individuals in the lowest SPARC tertile had increased odds of aortic stiffness (OR=1.900, 95% CI=1.103-3.274) but reduced odds of peripheral arterial disease (OR=0.400, 95% CI=0.175-0.919). However, SPARC was not independently associated with chronic kidney disease. CONCLUSIONS: The anti-angiogenic SPARC may be associated with the pathophysiology of diabetes-related macrovascular complications.

Genetic variants in the receptor for advanced glycation end products (RAGE) gene were associated with circulating soluble RAGE level but not with renal function among Asians with type 2 diabetes: a genome-wide association study.

BACKGROUND: The soluble receptor for advanced glycation end products (sRAGE) has been shown to play an important role in diabetic complications. We conducted genome-wide association study (GWAS) of sRAGE in Asian type 2 diabetes mellitus (T2DM) patient and validated the association in an independent cohort of T2DM. METHODS: GWAS for sRAGE was performed in 2058 T2DM patients. Associations between single-nucleotide polymorphisms (SNPs) and plasma sRAGE level were analyzed in an additive model using a linear mixed model. To validate the associations, we performed de novo genotyping in an independent cohort (n = 1984). We selected the top SNP for assessment with diabetic kidney disease (DKD). RESULTS: The strongest SNP, rs2070600C>T (P = 1.21 × 10-52), was a genotyped, missense SNP located on chromosome 6, corresponding to the RAGE (AGER) gene locus, the gene encoding RAGE. Conditioning analysis on rs2070600 revealed that rs2071288C>T was the top genotyped independent SNP (P = 8.36 × 10-10). Both SNPs were strongly and dose-dependently correlated with sRAGE level (TT = 399.6 pg/mL, CT = 737.0 pg/mL and CC = 967.0 pg/mL, P < 0.001 for rs2070600; TT = 687.9 pg/mL, CT = 737.6 pg/mL and CC = 904.7 pg/mL, P < 0.001 for rs2072188). Both SNPs were robustly replicated in the independent cohort, especially among Chinese patients (P = 9.02 × 10-72 for rs2070600; P = 1.13 × 10-9 for rs2071288). Log-transformed sRAGE was associated with DKD after adjustment for age, gender and ethnicity in pooled cohorts [odds ratio 2.536 (95% confidence interval 1.864-3.450), P < 0.001]. However, we did not observe any significant association between rs2070600 and DKD. CONCLUSIONS: Common variants in RAGE are strongly associated with plasma sRAGE level, which is associated with DKD. However, we did not find a causal link between sRAGE and renal function by Mendelian randomization.