Study of Vitamin D3 Supplementation in Patients With Chronic Kidney Disease

Insulin resistance, i.e., reduction in insulin responsiveness with a decrease in glucose uptake in insulin target tissues (muscle and adipose tissue) is common in end-stage renal disease (ESRD), but is also present at earlier stages of renal disease with mild-moderate renal function impairment as well as in microalbuminuria and nephrotic syndrome.

Population-based cross-sectional studies have shown that low levels of vitamin D (25(OH) vitamin D) is associated with impaired glucose tolerance in subjects with normal renal function and that reduced renal function and 25(OH) vitamin D deficiency are independently associated with insulin resistance.

Vitamin D has well-known effects on calcium metabolism and skeletal mineralisation but recent experimental studies suggest that vitamin D in addition reduces several inflammatory mediators that are of importance in the development and progression of renal disease which also associated with insulin resistance such as TNF-α and IL-6.

This is a prospective, single-blind, explorative, randomized, placebo-controlled, single-centre, two-way cross-over study with two treatment periods of 10 weeks separated by a washout period of 6 weeks. Non-diabetic patients with chronic kidney disease (CKD) stage 3 and 4 (GFR 15-60 ml/min/1.73m2) who have low serum 25-OH-vitamin D levels (< 30 ng/mL) and elevated fasting serum insulin levels (>10 IU/L) will be randomized to receive either vitamin D3 (cholecalciferol) 3200U orally (tablets) daily or placebo.

Approximately 24 patients are going to complete the study. A pre-entry wash-out period of 6 weeks is needed for patents already on vitamin D treatment. An in vivo assessment of insulin secretion and insulin sensitivity will be made by insulin-glucose clamp at the end of each treatment period.

Inclusion criteria

• Male or female, age older than 18 years
• Non-diabetic chronic kidney disease stage 3 and 4 (GFR 15-60 ml/min/1.73 m2)
• Serum 25(OH) vitamin D < 30 ng/mL (75 nmol/L)
• Fasting S-insulin > 30 IU/L
• Written informed consent before entered into study

Exclusion criteria

• Patients with current significant, major or unstable cardio-cerebrovascular, infection, respiratory, gastrointestinal or other major disease and risks according to the judgment made by the investigator
• Patients with type 1 or type 2 Diabetes
• Current severe thyrotoxicosis or other endocrine disease
• Granulomatous disease, such as sarcoidosis and tuberculosis
• Patients who are intended to receive hemodialysis (HD), peritoneal dialysis (PD) or being kidney transplanted during the course of study (9 months)
• Concomitant use of corticosteroids (except for inhalation or topical use) or other immunosuppressive medication
• Treatment with biphosphonate during last two years
• S-Calcium > 2.70 mmol/L (0.68 mg/dl)
• PTH intact < 75 ng/L (8.25 nmol/L) or > 800 ng/L (88 nmol/L)
• Proteinuria > 3.5 g/24 hours
• Alcohol or drug abuse or any condition associated with poor compliance
• Blood donors
• Women of childbearing potential, desired pregnancy, pregnancy or lactation within the study period
• Allergy or intolerance to cholecalciferol supplementation (TillVal D®) or other constituents
• Participation in a clinical trial evaluating an investigational drug in the last 12 weeks prior to inclusion to this trial
• History of kidney stones
• History of chronic hepatitis or liver enzymes (ASAT or ALAT) more than 2.5 times the upper limit of normal
• Gastrointestinal disease resulting in significant gastrointestinal dysfunction or malabsorption
• Use of medications known to interact with vitamin D metabolism such as cholestyramine, phenytoin, digitalis and antacids
• Planned vacation with "high sun exposure" during the study period