Potential Role and Excretion Level of Urinary Transferrin, KIM-1, RBP, MCP-1 and NGAL Markers in Diabetic Nephropathy

Abstract

Background: Analyzing urinary biomarkers may provide better insight into pathophysiological mechanisms of diabetic kidney diseases. The study aimed to analyze the pattern of selected excreted urinary biomarkers and its correlation with albuminuria and estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes. Methods: A total of 185 patients with type 2 diabetes were categorized according to KDIGO guideline based on albuminuria and eGFR. The urinary markers (transferrin, KIM-1, RBP, MCP-1 and NGAL) were measured by ELISA. Results: The urinary markers were associated with eGFR (total protein/Cr, p=0.001; RBP/ Cr, p=0.007; MCP-1/Cr, p=0.023; NGAL/Cr, p=0.011) and albuminuria (total protein/Cr, p<0.001; transferrin, p<0.001; RBP/Cr, p<0.001; MCP-1/Cr, p<0.001; NGAL/Cr, p=0.002). Conclusion:The urinary marker levels (total protein, RBP, MCP-1, and NGAL) are elevated with severity of kidney damage and expressed more in progressive renal impairment.

Current Challenges and Future Perspectives of Renal Tubular Dysfunction in Diabetic Kidney Disease

“…reported that NGAL increased across the four groups from controls to normoalbuminuric, microalbuminuric, and macroalbuminuric patients ( 79 ). In several observational single-center follow-up studies, elevated urine NGAL level was shown to be associated with urinary albumin excretion ( 80 ), the rapid decline in eGFR and increased serum creatinine ( 81 ), renal progression to ESKD ( 83 ), and progressive tubular structural and functional impairment ( 84 ). Consistently, our cohort study found that the best predictive cutoff value of urinary NGAL to creatine ratio (uNCR) for DKD diagnosis was 60.685 ng/mg, and T2DM patients with the increased level of uNCR had a higher risk of nephrotic-range proteinuria and worse renal outcome ( 82 ).…”

“…found that urinary KIM-1 was elevated in the high-risk group (stratified by both ACR and eGFR) and reduced in the very high-risk group. Also, it was not found to be associated with either eGFR or albuminuria ( 84 ). The disparity of those studies may be due to the limited sample sizes and selected population.…”

“…The ACCORD trial enrolled 10,251 T2DM patients with preserved renal function and examined the association of four biomarker-to-creatinine ratio levels; only MCP-1-to-creatinine ratio concentrations were strongly associated with the sustained renal decline (13). Siddiqui et al also found that elevated urinary MCP-1 was related to the severity of kidney damage, and it was expressed more in progressive renal impairment in T2DM(84). The 2020 CRIC Study first reported an association of plasma MCP-1 concentrations and DKD progression among individuals with moderate to severe kidney disease.…”

“…elevated in T2DM with normal or mildly increased albuminuria urine (88) increased in T1DM patients who developed from macroalbuminuria to late-stage CKD urine (89) elevated in the high-risk group which was stratified by both ACR and eGFR; decreased in the very high-risk group; not associated with either eGFR or albuminuria urine(84) no predictive value for progression to ESKD independently of albumin excretion rate (AER); no prognostic benefit to conventional biomarkers (AER, eGFR); causal impact of KIM-1 on the decrease of eGFR in T1DM by Mendelian randomization analysis urine(89) no association with uKIM-1-to-creatinine ratio and eGFR decline in patients with T2DM urine (13) contains most of the predictive information for eGFR progression in T1DM urine(90) predictive value for the rapid decline of renal function in DKD urine/ serum (81, 91, 92) associated with DKD progression and yearly decline in eGFR plasma (9) the most important predictor by cross-omics technologies urine (93) YKL-40 a marker of inflammation and endothelial dysfunction; an indicator of tubular injury severity / (94, 95) associated with albuminuria in T1DM and in early stage of nephropathy in T2DM plasma not associated with eGFR decline and varying levels of baseline eGFR and albuminuria in T2DM plasma (99) a plasma marker of DKD progression plasma (9) MCP-1 upregulated and expressed in the diabetic glomerular and renal tubular epithelium urine (100) correlated with the extent of interstitial inflammatory infiltrate urine (101, 102) associated with severity of proteinuria in DKD urine (103) elevation in renal tubuli contributes to renal tubular damage in DKD tissue (103) MCP-1-to-creatinine ratio concentrations were strongly associated with sustained renal decline, severity of kidney damage in T2DM urine (13) (84) associated with an increased risk of DKD progression only among patients with baseline eGFR<45 ml/min per 1.73 m 2 plasma (9) Cubilin and megalin increased in microalbuminuria groups compared with non-albuminuric groups in T1DM urine (104) genetic association exists between a cubilin and a rare megalin variant with diabetes-associated ESKD in populations with recent African ancestry gene (105) upregulated renal megalin expression in early T2DM rats tissue (106) elevated in two models of insulin-deficient diabetes in drug-inducible megalin knockout mice tissue (107) megalin in both segment 1 and segment 2 participated in clearing the ultrafiltrate from proteins in both cortical and juxtamedullary nephrons under normal conditions tissue (108) megalin in segment 3 was inactive with regard to protein endocytosis; it was activated by the presence of proteins in the lumen of the tubule in normal physiology tissue (108) NGAL, neutrophil gelatinase-associated apolipoprotein; KIM-1, kidney injury molecule 1; YKL-40, chitinase-3-like protein 1; MCP-1, monocyte chemoattractant protein-1; T1DM/T2DM, type 1/2 diabetes mellitus; CKD, chronic kidney disease; ESKD, end-stage kidney disease; DKD, diabetic kidney disease; eGFR, estimated glomerular filtration rate; AER, albumin excretion rate; ESKD, end-stage of kidney disease; uNCR urinary NGAL to creatine ratio.…”

“…Summary of principal tubular biomarkers of DKD in clinical use.NGALincreased when acute tubular damage of various causes occurred; correlated with CKD progression urine (77, 78) associated with urinary albumin excretion, rapid decline of eGFR, and increased serum creatinine urine (79-82) associated with renal progression to ESKD, progressive tubular structural and functional impairment urine(10,(83)(84)(85) best predictive cutoff value of urinary NGAL to creatine ratio (uNCR) for T2DKD diagnosis was 60.685 ng/mg; urine (82) 7.595 times higher risk of nephrotic-range proteinuria in T2DKD patients with uNCR >60.685 vs.≤60.685 ng/mg. twofold or greater risk for CKD progression in patients with diabetes; urine (10) 1.5-fold or greater risk for CKD progression in patients without diabetes tubular cells in areas with tubulointerstitial damage induced by overload proteinuria; upregulated in proteinuric nephropathy and associated with renal fibrosis and inflammation.…”