Junlin Zhang

COL4A3 Gene Variants and Diabetic Kidney Disease in MODY

BACKGROUND AND OBJECTIVES Despite advances in identifying genetic factors of diabetic kidney disease (DKD), much of the heritability remains unexplained. Nine maturity-onset diabetes in young (MODY) probands with kidney biopsy-proven DKD were selected and included in this study. The probands had more severe DKD compared with their parents with MODY, with overt proteinuria or rapid progression to ESKD. We aimed to explore the contribution of the variants in susceptibility genes of DKD to the severity of kidney phenotype between the probands and their parents. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Whole-exome sequencing was performed to identify suspected MODY probands and their families. Known DKD susceptibility genes were reviewed. Variants reported to be associated with DKD, or those with minor allele frequency <0.05 and predicted to be pathogenic, were selected and analyzed. Immunofluorescence staining of COL4α3 was performed in kidney specimens of patients with DKD with or without R408H and M1209I of COL4A3 variants. RESULTS HNF1B-MODY, CEL-MODY, PAX4-MODY, and WFS1-MODY were diagnosed among nine families. We identified 196 selected variants of 25 DKD susceptibility genes among the participants. Analysis of phenotype between probands and parents, gene function, and protein-protein interaction networks revealed that COL4A3 variants were involved in the progression of DKD. Weak granular staining of COL4α3 was observed in the glomerular basement membrane of patients with the R408H and M1209I variants, whereas strong consecutive staining was observed in patients without these variants. Moreover, more number of DKD variants were identified in probands than in their parents with MODY. CONCLUSIONS The genetic effect of more pathogenic variants in various DKD susceptibility genes, especially variants in the COL4A3 gene, partially explained the more severe kidney phenotype in probands with kidney biopsy-proven DKD.

The clinical impact of glomerular immunoglobulin M deposition in patients with type 2 diabetic nephropathy

Background: Glomerular immunoglobulin M (IgM) deposition is common in diabetic kidney disease. The clinical implication of IgM deposition in the renal tissues of type 2 diabetes mellitus patients with biopsy‐proven diabetic nephropathy remains unclear. Materials and Methods: One hundred thirty‐two patients with type 2 diabetes and biopsy‐proven pure diabetic nephropathy were enrolled retrospectively. Clinicopathological features and renal outcomes were compared between patients with and without glomerular capillary IgM deposition. A Cox proportional hazards model was employed to identify the risk factors associated with renal survival. Results: Fifty‐two patients had positive linear glomerular capillary IgM staining. Patients with glomerular capillary IgM deposition presented with heavier proteinuria, and lower serum albumin. During 35.5 (12, 107) months of follow‐up, patients with glomerular tuft IgM deposition had shorter renal survival than those with negative IgM deposition (39 [23.74, 54.26] versus (vs.) 64 [45.82, 82.18] months, P = 0.01). Patients with glomerular complement 1q (C1q) deposition showed worse renal survival than those lacking glomerular C1q deposition (36 [23.82, 48.18] vs. 60 [50.27, 69.74] months, P = 0.001). Worse renal outcome was observed in patients with glomerular C3 deposition than in those without glomerular C3 deposition (37 [22.43, 51.56] vs. 63 [51.75, 74.25] months, P = 0.001). Multivariate Cox proportional analysis demonstrated that combined glomerular capillary IgM and C1q deposition was an independent predictor of end‐stage renal disease (hazard ratio 3.75, 95% CI[ 1.68,8.35], P = 0.001). Conclusions: Patients with diabetic nephropathy and combined glomerular capillary IgM and C1q deposition had unfavorable renal outcome, which indicates that IgM derived from B cells might be involved in diabetic kidney injury.

MicroRNA-326-3p ameliorates high glucose and ox-LDL-IC- induced fibrotic injury in renal mesangial cells by targeting FcγRIII

The aim of the present study was to identify the regulatory relationship between miR‐326‐3p and FcγRIII, and to explore the involvement of miR‐326‐3p/FcγRIII/TGF‐β/Smad signalling pathway in fibrotic injury, which was induced by the high glucose (HG) and oxidized low density lipoprotein immune complex (ox‐LDL‐IC) in mouse glomerular mesangial cells (GMCs).

Effects of neutrophil-lymphocyte ratio on renal function and histologic lesions in patients with diabetic nephropathy: NLR& Diabetic Nephropathy

Chronic low‐grade inflammation related to diabetic nephropathy (DN) may affect the serum neutrophil–lymphocyte ratio (NLR). We aimed to examine the cross‐sectional relationships of NLR with renal function and structural lesions of DN in patients with type 2 diabetes mellitus (T2DM).

Thyroid hormones and diabetic nephropathy: an essential relationship to recognize: Thyroid hormones and diabetic nephropathy

Although abnormal thyroid hormone metabolism is common in patients with type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN), the relationship between thyroid hormones and DN is unclear and has been ignored during clinical practice. This study aimed to investigate the relationship between thyroid hormones and clinicopathologic changes in biopsy‐proven DN patients.

Serum fibrinogen predicts diabetic ESRD in patients with type 2 diabetes mellitus

AIMS Although increased serum fibrinogen level was often observed in patients with diabetic nephropathy (DN), its association with DN severity and progression remains unclear. The aim of this study was to investigate the relationship between the serum fibrinogen levels and clinicopathological features and renal prognosis in Chinese patients with type 2 diabetes mellitus (T2DM) and DN. METHODS A total of 174 patients with T2DM and biopsy-proven DN were enrolled. Patients were stratified by the quartiles of serum fibrinogen levels; Q1: <3.30 g/L; Q2: between 3.30 and 4.00 g/L; Q3: between 4.00 and 4.74 g/L; Q4:≥4.74 g/L. The renal outcomes were defined by reaching end stage renal disease (ESRD). The influence of serum fibrinogen levels on renal outcomes was evaluated using Cox regression analysis. RESULTS The factors associated with higher level of fibrinogen (Q3 and Q4) were diabetic retinopathy, low e-GFR, high proteinuria and severe glomerular and tubulointerstitial lesions. Importantly, in adjusted analysis, higher levels of fibrinogen were independently related with a greater risk of reaching ESRD with a hazard ratio (HR) of 1.64 per standard deviation (SD) of the natural log-transformed fibrinogen concentration (95%CI, 1.22-2.20; p = 0.001). In reference to the Q1, the risk of renal failure increased by quartiles of the serum fibrinogen level: the HRs were 7.12 for the Q2 (95%CI, 2.29-22.16; p = 0.001), 5.77 for Q3 (95%CI, 1.99-16.75; p = 0.001), and 8.81 for Q4 (95%CI, 2.79-27.80; p < 0.001). CONCLUSIONS These findings suggested that the elevated serum levels of fibrinogen were associated with diabetic ESRD in patients with T2DM.

The relationship between increased ratio of visceral-to-subcutaneous fat area and renal outcome in Chinese adult with type 2 diabetes and diabetic kidney disease

OBJECTIVE Abdominal obesity is a risk factor of diabetes and hypertension. The aim of this study was to investigate the association between excessive abdominal fat and renal outcomes in patients with type 2 diabetes and diabetic kidney disease. METHODS Thirty-five patients with type 2 diabetes and diabetic kidney disease who were followed up on for at least 1 year were enrolled. Visceral fat area and subcutaneous fat area were assessed by computed tomography to evaluate the degree of abdominal fat. Patients were divided into 2 groups. Patients in group 1 had a ratio of visceral fat area to subcutaneous fat area (V/S ratio) <0.70 (n=16), and those in group 2 had a V/S ratio ≥0.70 (n=19) according to the second quartile. Renal outcome was defined as end-stage renal disease and initiation of renal replacement therapy. RESULTS At baseline, patients with a high V/S ratio had higher levels of triglycerides (p=0.060) and C-reactive protein (p=0.028), but lower high-density lipoprotein cholesterol levels (p=0.006). Strong correlations between V/S ratio and C-reactive protein (r=0.521, p=0.015) and high-density lipoprotein cholesterol (r=-0.576, p<0.001) were observed. Univariate Cox regression indicated the higher the V/S ratio, the greater the risk for a poor renal outcome (hazard ratio, 3.536; 95% confidence interval, 1.140 to 10.960; p=0.029). However, multivariate Cox analysis demonstrated that a higher V/S ratio was not an independent risk factor for progression to end-stage renal disease (hazard ratio, 2.212; 95% confidence interval, 0.543 to 9.005; p=0.268) when adjustments were made for important clinical variables. CONCLUSION The V/S ratio was positively correlated with C-reactive protein and high-density lipoprotein cholesterol. The higher V/S ratio was associated with a greater risk for progression to end-stage renal disease, although it did not emerge as an independent predictor of diabetic kidney disease progression.