Urinary IgG4 and Smad1 Are Specific Biomarkers for Renal Structural and Functional Changes in Early Stages of Diabetic Nephropathy

Abstract

Diabetic nephropathy (DN) is the major cause of end-stage kidney disease, but early biomarkers of DN risk are limited. Herein we examine urinary IgG4 and Smad1 as additional early DN biomarkers. We recruited 815 patients with type 2 diabetes; 554 patients fulfilled the criteria of an estimated glomerular filtration rate (eGFR) >60 mL/min and no macroalbuminuria at baseline, with follow-up for 5 years. Patients without macroalbuminuria were also recruited for renal biopsies. Urinary IgG4 and Smad1 were determined by enzyme-linked immunoassays using specific antibodies. The specificity, sensitivity, and reproducibility were confirmed for each assay. Increased urinary IgG4 was significantly associated with lower eGFR. The level of urinary IgG4 also significantly correlated with surface density of peripheral glomerular basement membrane (Sv PGBM/Glom), whereas Smad1 was associated with the degree of mesangial expansion-both classic pathological findings in DN. Baseline eGFR did not differ between any groups; however, increases in both urinary IgG4 and Smad1 levels at baseline significantly predicted later development of eGFR decline in patients without macroalbuminuria. These data suggest that urinary IgG4 and Smad1 at relatively early stages of DN reflect underlying DN lesions and are relevant to later clinical outcomes.

NGAL and SMAD1 gene expression in the early detection of diabetic nephropathy by liquid biopsy

“…Our results suggest alterations in SMAD1 gene expression without reduction in GFR, data confirmed by Doi et al (2018), who speculated that the presence of SMAD1 in urine precedes the decline of GFR in diabetics 35…”

“…Doi et al (2018) investigated the presence of this protein in the urine of patients with DM2 and reported that SMAD1 is directly associated with mesangial matrix expansion, a classic feature of DN. In addition, increased urinary levels of SMAD1 have been found to precede the decline of GFR and of macroalbuminuria 35. SMAD1 protein expression had already been identified as a marker of mesangial matrix expansion in rats in the early phase of DN 36.…”

Glycogen synthase kinase 3β hyperactivity in urinary exfoliated cells predicts progression of diabetic kidney disease

“…In the past decade, a number of novel molecules have been tested. [14][15][16] Among these, glycogen synthase kinase 3 (GSK3) has emerged as an attractive candidate.…”

Identification of candidate biomarkers and pathways associated with type 1 diabetes mellitus using bioinformatics analysis

“…STAR (steroidogenic acute regulatory protein) [153], IL1RN [154], AQP5 [155], EGR1 [156], SFTPD (surfactant protein D) [157], KLF10 [158], PODXL (podocalyxin like) [159], FOXN3 [160], IL6R [161], PBX1 [162], APOD (apolipoprotein D) [163], ACVR2B [164], CD34 [165], INSR (insulin receptor) [166], APOA5 [167], STAR (steroidogenic acute regulatory protein) [168], PDK4 [169], GLS (glutaminase) [170], FKBP5 [171], SLC6A15 [172], MT2A [173], SLC38A4 [174], AQP7 [175], ABHD15 [176], ABCA1 [177], ZNRF1 [178], PPP1R3B [179], MAOA (monoamine oxidase A) [180], UBE2E2 [181], RNASEK (ribonuclease K) [182], PREX1 [183], DGKG (diacylglycerol kinase gamma) [184], POSTN (periostin) [185], COMP (cartilage oligomeric matrix protein) [186], GAP43 [187], P2RY12 [188], SELL (selectin L) [189] and DLG2 [190] have been revealed to be associated with type 2 diabetes mellitus, but these genes might be novel target for T1DM. Expression of ERRFI1 [191], ALOX12 [192], SOCS5 [193], DDIT4 [194], DUSP4 [195], IL6ST [196], DUSP1 [197], SMAD1 [198], NCL (nucleolin) [199], METTL14 [200], FMOD (fibromodulin) [201], CYGB (cytoglobin) [202], UNC5A [203] and TAAR9 [204] are associated with prognosis in patients with diabetic nephropathy, but these genes might be novel target for T1DM. A previous study reported that FAP (fibroblast activation protein alpha) [205], EYA4 [206], BCL9 [207], IRF2BP2 [208], EGR3 [209], GADD45B [210], DMD (dystrophin) [211], LSR (lipolysis stimulated lipoprotein receptor) [212], DLL4 [213], SUN2 [214], SOS1 [215], PIK3CA [216], GAMT (guanidinoacetate N-methyltransferase) [217], RBM47 […”