Ryuichi Kikkawa

Pathogenesis of diabetic nephropathy

Diabetic nephropathy is one of the most serious complications among patients with long-standing diabetes mellitus. In recent years, nearly one third of the patients newly admitted to dialysis therapy in Japan suffer from diabetic nephropathy. Hyperglycemia appears to play a major role in the pathogenesis of this disease, probably via glomerular hemodynamic changes, as well as via metabolic alterations in glomerular cells, although both pathways may interact with each other. Recently, an activation of protein kinase C has been advocated to be a critical mediator between hyperglycemia and diabetic nephropathy. Protein kinase C is known to induce the production of various extracellular matrix proteins, which may cause the expansion of glomerular mesangium. Administration of a specific inhibitor of the β isoform of protein kinase C corrected glomerular hyperfiltration in diabetic rats. In addition, genetic factors may be involved in the progression of diabetic nephropathy, since various clinical studies have indicated the familial clustering of this complication in diabetes mellitus. Although the association with gene polymorphism of angiotensin-converting enzyme has been extensively studied by several individual research groups, a decisive conclusion has not been obtained. Further research using multicenter studies enrolling large numbers of patients may be needed to detect nephropathic gene(s).

Risk Factor for Progression of Microalbuminuria in Relatively Young NIDDM-Patients

Microalbuminuria, which is defined as a minute increase in urinary albumin excretion rate in patients whose urine is Albustix-negative, is reported the most reliable predictor for the development of clinical diabetic nephropathy in IDDM [1,2]. Similarly to findings in IDDM, the pioneering work by Mogensen has clearly showed that, in NIDDM, the incidence of macroalbuminuria or of clinical proteinuria of a 9-year period is higher in those with microalbuminuria (22%) than in those with normoalbuminuria (5%) [3], although the predictive power of microalbuminuria appeared to be lower in patients with NIDDM. Since microalbuminuria can reportedly predict the risk of early mortality as well as of clinical proteinuria in subjects with NIDDM [3], it is important to identify the factor(s) responsible for the development and progression of microalbuminuria. Although it may be worthwhile to investigate the progression of microalbuminuria in relatively young subjects with NIDDM, who would be expected to live long enough to show the outcome of microalbuminuria perhaps by minimizing the influence of age-related cardiovascular diseases, the mean age of such subjects studied is in the late 50s. In this chapter, we will summarize the data obtained in such patients with NIDDM.