Nephrology

Abstract Genetic susceptibility probably plays a role in
the development and/or progression of diabetic kidney
disease. Small ubiquitin-related modifier 4 (SUMO4)
mRNA is expressed in human kidney. Substitution of
methionine with valine at codon 55 (M55V) of SUMO4
gene induces higher nuclear factor-kB activity, which is
known to mediate the development of kidney disease in
individuals with diabetes. We investigated the association
between the SUMO4 M55V (rs237025, c.163 G[A) and
kidney disease in north Indian subjects with diabetes. A
case–control analysis was performed using genomic DNA
samples from 216 diabetic patients without nephropathy
(DM) and 201 diabetic with nephropathy (DN). The
SUMO4 c.163 G[A polymorphism was genotyped using
polymerase chain reaction amplification followed by
restriction digestion. The duration of diabetes was significantly
greater in DN. The genotypic and allelic frequencies
were different in DM and DN groups: GG genotype was
significantly more frequent in DN as compared to DM
(p = 0.018, OR 1.72, 95 % CI 1.1–2.7). Similarly the G
allele was more frequent in DN compared to DM
(p = 0.017, OR 1.4, 95 % CI 1.1–1.8). This study suggests
that SUMO4 c.163 G[A polymorphism is associated with
the susceptibility to diabetic nephropathy in north Indian
subjects with type 2 diabetes.

Background: The rate and factors that influence progression of chronic kidney disease (CKD) in developing countries like India are unknown. A pan-country prospective, observational cohort study is needed to address these knowledge gaps.
Methods: The Indian Chronic Kidney Disease (ICKD) study will be a cohort study of approximately 5000 patients with mild to moderate CKD presenting to centers that represent different geographical regions in India. Time to 50% decline in baseline estimated glomerular filtration rate, need of renal replacement therapy or any new cardiovascular disease (CVD) event or death from CVD are the primary end points.
Value of Study: This study will provide the opportunity to determine risk factors for CKD progression and development of CVD in Indian subjects and perform international comparisons to determine ethnic and geographical differences. A bio-repository will provide a chance to discover biomarkers and explore genetic risk factors.

This study aims to determine risk factors for CKD progression and CVD development in Indian people through the international comparisons to determine ethnic and geographical differences. Authors also apply the bio-repository to discover biomarkers and explore genetic risk factors in this study. ABSTRACT: Aim: The rate and factors that influence progression of chronic kidney disease

Vitamin D deficiency associates with mortality in patients with CKD, and vitamin D supplementation might mitigate cardiovascular disease risk in CKD. In this randomized, double-blind, placebo-controlled trial, we investigated the effect of cholecalciferol supplementation on vascular function in 120 patients of either sex, aged 18–70 years, with nondiabetic CKD stage 3–4 and vitamin D deficiency (serum 25-hydroxyvitamin D #20 ng/ml). We randomized patients using a 1:1 ratio to receive either two directly observed oral doses of cholecalciferol (300,000 IU) or matching placebo at baseline and 8 weeks. The primary outcome was change in endothelium-dependent brachial artery flow-mediated dilation at 16 weeks. Secondary outcome measures included changes in pulse wave velocity and circulating biomarkers. Cholecalciferol supplementation significantly increased endothelium-dependent brachial artery flow-mediated dilation at 16 weeks, whereas placebo did not (between-group difference in mean change: 5.49%; 95% confidence interval, 4.34% to 6.64%; P,0.001). Intervention also led to significant favorable changes in pulse wave velocity and circulating IL-6 levels. Thus, in nondiabetic patients with stage 3–4 CKD and vitamin D deficiency, vitamin D supplementation may improve vascular function. This study is registered with the Clinical Trials Registry of India (no.: CTRI/2013/05/003648).

Use of active forms of vitamin D is advocated in patients with chronic kidney disease (CKD) for treatment of mineral bone disease because of the presumption that native forms of vitamin D would not undergo significant activation to calcitriol, the most active biological form of vitamin D. We present secondary analysis looking at bone turnover in subjects who completed the randomized, double blind, placebo-controlled trial investigating the effect of cholecalciferol supplementation on vascular function in nondiabetic CKD stage G3G4 and vitamin D 20 ng/mL (Clinical Trials Registry of India: CTRI/2013/05/003648). Patients were randomized (1:1) to receive either two directly observed oral doses of 300,000 IU of cholecalciferol or matching placebo at baseline and 8 weeks. Of the 120 subjects enrolled, 58 in the cholecalciferol group and 59 in the placebo group completed the study. At 16 weeks, the serum 25(OH)D and 1,25(OH) 2 D levels increased in the cholecalciferol group but not in the placebo group (between-group difference in mean change: 23.40 ng/mL; 95% CI, 19.76 to 27.06; p < 0.001, and 14.98 pg/mL; 95% CI, 4.48 to 27.18; p ¼ 0.007, respectively). Intact parathyroid hormone (iPTH) decreased in the cholecalciferol group (between-group difference in mean change –100.73 pg/mL (95% CI, –150.50 to –50.95; p < 0.001). Serum total and bone-specific alkaline phosphatase (SAP, BAP) and serum C-terminal cross-linked collagen type I telopeptides (CTX-1) were significantly reduced in cholecalciferol group (between group difference for change in mean: –20.25 U/L; 95% CI, –35.14 to –5.38 U/L; p ¼ 0.008 for SAP; –12.54 U/L; 95% CI, –22.09 to –2.98 U/L; p ¼ 0.013 for BAP; and –0.21 ng/mL; 95% CI, –0.38 to –0.05 ng/mL; p ¼ 0.05 for CTX-1). Correlation analysis showed significant correlation of D25(OH)D with DiPTH (r ¼ –0.409, p < 0.0001), D1,25(OH) 2 D (r ¼ 0.305, p ¼ 0.001), DSAP (r ¼ –0.301, p ¼ 0.002), DBAP (r ¼ –0.264, p ¼ 0.004), and DCTX-1 (r ¼ –0.210, p ¼ 0.0230). Cholecalciferol supplementation corrects vitamin D deficiency and is effective in lowering serum intact parathyroid hormone and bone turnover markers in early stages of CKD.

Vitamin D deficiency is common and associated with mortality in chronic kidney disease (CKD) patients. Cardiovascular disease (CVD) is the commonest cause of mortality in CKD patients. In a randomized, double blind, placebo controlled trial, we have recently reported favorable effects of vitamin D supplementation on vascular & endothelial function and inflammatory biomarkers in vitamin D deficient patients with non-diabetic stage 3–4 CKD (J Am Soc Nephrol 28: 3100–3108, 2017). Subjects in the placebo group who had still not received vitamin D after completion of the trial received two oral doses 300,000 IU of oral cholecalciferol at 8 weeks interval followed by flow mediated dilatation (FMD), pulse wave velocity (PWV), circulating endothelial and inflammatory markers (E-Selectin, vWF, hsCRP and IL-6), 125 (OH) 2 D, iPTH and iFGF-23 assessment at 16 weeks. 31 subjects completed this phase of the study. Last values recorded in the preceding clinical trial were taken as baseline values. Serum 25(OH)D and 1,25(OH) 2 D increased and FMD significantly improved after cholecalciferol supplementation [mean change in FMD%: 5.8% (95% CI: 4.0–7.5%, p < 0.001]. Endothelium independent nitroglycerine mediated dilatation, PWV, iPTH, iFGF-23 and IL-6 also showed favorable changes. The data further cement the findings of beneficial effects of correction of vitamin D deficiency on vascular function.