The immunogenetics of early nephropathy in insulin-dependent diabetes mellitus: association between the HLA-A2 antigen and albuminuria.
One-hundred and seventy-two normotensive, insulin-dependent diabetic patients without clinical proteinuria (Albustix negative) were typed for the major histocompatibility complex class I (HLA-A, -B) and class II (HLA-DR) antigens. Urinary albumin excretion was measured as the albumin:creatinine ratio (UA/UC, mg/mmol) in an early morning sample. Patients expressing the HLA-A2 antigen had significantly higher UA/UC values than those not expressing the antigen. The observed ratio of geometric means was 1.77 (95 per cent confidence interval (CI) 1.18-2.67; p < 0.01); the relative risk of microalbuminuria (UA/UC > 3.0 mg/mmol) associated with expression of HLA-A2 was 2.52 (95 per cent CI 1.11-5.73; p < 0.05). There was no significant association between UA/UC and HLA-B8, -B15, -DR3, -DR4 or other antigens. Patients were re-studied after a mean period of 5.3 years: multiple linear regression analysis showed that the UA/UC at this time was positively related to the initial glycosylated haemoglobin level (p < 0.01) and expression of the HLA-A2 antigen (p < 0.05), but not to blood pressure or creatinine clearance. Fifteen patients developed macroalbuminuria at follow-up (UA/UC > 45.5 mg/mmol). Compared with a group matched for age, sex, duration of diabetes, and glycosylated haemoglobin who did not develop macroalbuminuria, macroalbuminuric patients had a higher frequency of HLA-A2 (p < 0.01). The odds ratio of progressing to macroalbuminuria associated with HLA-A2 had a 95 per cent CI of 1.71 to infinity. We conclude that an immunogenetic factor may play a role in the development of early diabetic nephropathy and that the risk associated with expression of the HLA-A2 antigen is independent of metabolic control and blood pressure.