Pathogenetic mechanisms other than the quality of metabolic control may play a role in the development of diabetic nephropathy. Some cross-sectional studies have shown that elevated erythrocyte sodium-lithium countertransport (Na+/Li+ CT) activity may be linked to incipient or overt nephropathy in insulin-dependent diabetic (IDDM) patients. The aim of the present work was to ascertain if high erythrocyte Na+/Li+ CT activity anticipates the development of microalbuminuria in IDDM patients. Evaluation of this cation transport system was carried out in 159 normotensive, normoalbuminuric IDDM patients, who were divided into two groups: those with values above (Group A) and those with values below (Group B) the median level in the overall population (300 mumol/erythrocytes x h). A total of 79 patients in Group A and 80 in Group B underwent periodic examinations over a similar time period (5.2 years, range 3.3-7.4 years and 5.4 years, range 3.4-7.5 years, respectively). Median sodium-lithium countertransport activity was stable when evaluated after 2 and 4 years of follow-up. Only seven patients were excluded from the protocol because changes in their sodium-lithium countertransport activity placed them on the other side of the median value with respect to their baseline measurement. Thus, 152 patients completed the study (76 in Group A and 76 in Group B). Of the 76 patients in Group A, 17 developed persistent microalbuminuria (22.3%). The number of patients in Group B showing persistent microalbuminuria was significantly lower (4 of 76; 5.2%; p < 0.01). The sensitivity of erythrocyte Na+/Li+ CT in predicting the development of microalbuminuria was 85% and its specificity was 55%. Seven patients of Group A and five of Group B developed arterial hypertension. Subjects in Group A had significantly higher mean HbA1c values of twice yearly measurements than those in Group B (9.6 +/- 1.7 vs 8.3 +/- 1.7%, p < 0.002, mean +/- SD) despite similar daily insulin requirements. Systolic and diastolic blood pressure levels were also evaluated every 6 months and were significantly higher in the Group A than in the Group B patients, although on average within the normal range. The odds ratio for developing persistent microalbuminuria in IDDM with elevated baseline erythrocyte Na+/Li+ CT activity after adjustment for gender and baseline albumin excretion rate, and mean 6 monthly plasma creatinine, HbA1c and systolic and diastolic blood pressure levels was 4.2 (95% confidence intervals 2.0-11.1). It was also found that the percentage of offspring having both parents with Na+/Li+ CT activity above the median value was significantly higher in Group A than in Group B (Group A vs Group B: 35 vs 19%; p < 0.01). On the contrary the percentage of offspring whose erythrocyte Na+/Li+ CT was lower in both parents was lower in Group A than in Group B: 10 vs 38%, p < 0.01). Parents of Group A offspring had arterial hypertension more frequently than those of Group B. These results indicate that erythrocyte Na+/Li+ CT activity is a useful diagnostic tool in identifying normotensive, normoalbuminuric patients who may be predisposed to develop persistent microalbuminuria. This disorder in the cation transport system is associated with poor metabolic control, higher blood pressure, and male sex; it also appears to be, at least partly, genetically transmitted.