Plasma or Urine Neutrophil Gelatinase-Associated Lipocalin (NGAL): Which Is Better at Detecting Chronic Kidney Damage in Type 2 Diabetes?

Abstract

Background and study aims—Albuminuria, defined as an enhanced urine albumin/creatinine ratio (ACR) on a spot sample, is a validated biomarker of glomerular damage. However, it cannot always detect early renal failures in patients with type 2 diabetes (T2D), thus prompting the search for more sensitive and specific parameters. Herein, we investigated the differential role of plasma and urine neutrophil-gelatinase-associated lipocalin (NGALp,—NGALu) for the detection of diabetic kidney disease (DKD). Methods—Traditional glomerular (serum creatinine, cystatin C, ACR) damage biomarkers were evaluated in 84 patients with T2D and in 21 metabolically healthy controls. Diabetic patients were stratified into four groups based on T2D duration (less or more than 5 years) and presence and severity of DKD (early- or advanced-stage), as defined by the ACR and estimated glomerular filtration rate (eGFR). NGALp and NGALu were determined by ELISA methodology and compared among groups. Results—There was no difference in NGALp and NGALu levels between the metabolically healthy individuals and the age-matched, newly diagnosed diabetic patients in the absence of DKD. However, in contrast to NGALu, NGALp was found to be substantially increased in patients with long-standing diabetes without biochemical evidence of DKD, closely mirroring the modest, but still accelerated, decline in the eGFR typical of this chronic dysmetabolic condition, and remained overexpressed throughout the stages of DKD progression. Increased NGALu levels were, instead, rather specific in patients with biochemical evidence of DKD (i.e., marked by increased albuminuria), regardless of T2D duration. Spearman’s correlation and regression analyses showed that patient age and T2D duration could exert a strong positive impact exclusively on NGALp concentrations (ρ = 0.419, p < 0.001 for age; ρ = 0.581, p < 0.001 for T2D), and none on NGALu. Furthermore, receiver operating characteristic (ROC) analysis showed the best performance of NGALp compared to NGALu for the detection of DKD (AUC = 0.817 for NGALp, AUC = 0.711 for NGALu). Conclusions—Our data suggest a different pathophysiological and predictive role for urine and plasma NGAL in the context of T2D and DKD.

From Euglycemia to Recent Onset of Type 2 Diabetes Mellitus: A Proof-of-Concept Study on Circulating microRNA Profiling Reveals Distinct, and Early microRNA Signatures

“…A further concern is the considerable diversity in algorithms employed for normalizing miRNAs in the context of disease association studies, encompassing methods such as spike-in normalization, small nucleolar RNA normalization and mean-centric normalization. In light of this, the Global Ct mean normalization has recently undergone validation as the most effective normalization method in highthroughput miRNA profiling studies where the process of miRNA biomarker identification is initiated [31]. The use of diverse normalization techniques in high-throughput miRNA profiling studies may explain the lack of prior reports indicating an association between T2D and the increased expression of circulating hsa-miR-1225-3p [62].…”

“…Inflammation (C-Reactive Protein (CRP) > 6 mg/L; Erythrocyte Sedimentation rate (ESR) > 30 mm/h), obesity (BMI > 30 kg/m 2 ), poor glycemic control (glycated hemoglobin, HbA1c > 8%, 64 mmol/mol), smoking, alcohol and drug use, including antidiabetic pharmacological medications with possible impact on miRNAs (i.e., metformin [29]), as well as intercurrent illnesses and moderate-to-severe hypertriglyceridemia (triglycerides > 175 mg/dL, 2.0 mmol/L) were assumed as exclusion criteria. Additionally, in consideration of the possible alterations in miRNA expression throughout the various stages of chronic kidney disease [18,30], to mitigate any potential bias in the detection of circulating miRNAs that are specifically linked to the progression from prediabetes to T2D, individuals with indications of renal impairment (such as an estimated glomerular filtration rate < 60 mL/min/1.73 m 2 or the presence of microalbuminuria), regardless of whether it was related to diabetic nephropathy [31], were excluded from the study.…”

Association between Circulating Ectodysplasin A and Diabetic Kidney Disease

“…In addition to hyperglycemia and insulin resistance, hypertension, dyslipidemia, smoking, drinking history, and other factors will lead to progressive renal dysfunction and microcirculatory disorder, which will aggravate the occurrence and development of diabetic nephropathy [ 16 ]. Cui et al found that the circulating EDA level of NAFLD patients was significantly higher than that of healthy subjects [ 11 ], which was further confirmed by Bayliss et al [ 12 ].…”

Fecal and Urinary Adipokines as Disease Biomarkers

“…An increase in urinary lipocalin-2 amounts was noticed in diabetic patients with clinical signs of renal diseases. In the cohort of diabetic patients, urinary lipocalin-2 levels positively correlated with serum creatinine, cystatin C, hemoglobin A1c (HbA1c) and albuminuria [ 111 ].…”