Objective: The first changes in the diabetic kidney are glycogen deposits in the epithelial cells of the thick ascending limb of Henle, which leads to decreased production of Tamm-Horsfall protein (THP). The production of THP is also influenced by nitric oxide (NO). The aims of this study were to investigate whether low excretion of THP, a sign of distal tubular dysfunction, in patients with type 1 diabetes was associated with polymorphisms in the THP gene and the endothelial NO synthase (eNOS) gene.
Material and methods: Urine was collected from 301 patients with type 1 diabetes, 164 with normoalbuminuria, 91 with microalbuminuria and 46 with macroalbuminuria. Urinary THP concentration below median (3.12 mg/l) was defined as tubular dysfunction. Representative polymorphisms were analysed in the THP and eNOS genes.
Results: Patients with tubular dysfunction had longer diabetes duration and higher blood pressure than patients without tubular dysfunction. Tubular dysfunction was common in patients with macroalbuminuria (70% of patients) and it was associated with the AA+AT genotypes of rs12444268 in the THP gene [odds ratio (OR) 1.8, 95% confidence interval (CI) 1.1-2.8], and the GG genotype of rs1799983 in the eNOS gene (OR 1.6, 95% CI 1.03-2.6). When adjusting for other associated factors, diabetes duration, glycosylated haemoglobin (HbA(1c)), mean arterial pressure and albuminuria, the THP rs12444268 and macroalbuminuria were independently associated with tubular dysfunction.
Conclusion: Distal tubular dysfunction was associated with the THP gene and macroalbuminuria in patients with type 1 diabetes.