Diabetic nephropathy is limited to a subset of patients with long-standing poorly controlled diabetes and an apparent hereditary predisposition [1, 2]. To depict the subset of patients prone to renal damage, several markers, e. g. urinary excretion of very small amounts of albumin (microalbuminuria) [3] and elevation of arterial pressure [4], have been proposed. However, these symptoms appear when the renal damage is already impending [5].Enhanced sodium-lithium countertransport and sodium-hydrogen exchange (NHE) found in blood cells and skin fibroblasts of diabetic patients prone to nephropathy [6±10] represent a very early (if not congenital) sign. Its accuracy in predicting diabetic nephropathy has not been established. In this study we have followed-up non-microalbuminuric patients with IDDM of at least a 10-year duration for 8 years after their first NHE evaluation. Subjects and methodsStudy group. We followed-up 156 patients (98 women, 58 men) aged 33 ± 8 years, with juvenile onset of insulin-dependent diabetes mellitus (diabetes duration prior to enrollment 15 ± 4 years) for 8 years (total diabetes duration 23 ± 3 years). The criteria for the patients' enrollment in the study were: duration of insulin treatment of at least 10 years and up to 25 years, absence of proteinuria/microalbuminuria, normal arterial blood pressure, normal serum urea, creatinine and electrolyte levels, and absence of clinically evident retinopathy at the time of enrollment. Anamnestic or clinical evidence of recurrent or chronic urinary infection was the single exclusion criterion both on enrollment and during the follow-up. Any Diabetologia (1998) Summary Diabetic nephropathy develops in a subset of patients with an apparently hereditary predisposition. Microalbuminuria and elevated arterial pressure have been proposed as predictors of nephropathy but both appear when renal damage is impending. Enhanced sodium-hydrogen exchange in the cell membranes of diabetic patients is an early marker of diabetic nephropathy but its predictive value has not been assessed. In this study, sodium-hydrogen exchange was measured in erythrocytes as an initial velocity of amiloride-inhibited H + efflux (pH 6.35± 6.45) into a Na + -containing medium (pH 7.95±8.05) in 156 non-microalbuminuric insulin-treated diabetic patients (98 women, 58 men, age 33 ± 8 years, diabetes duration prior to enrollment 15 ± 4 years) during 8 years of follow-up. Enhanced erythrocyte sodiumhydrogen exchange predicted diabetic nephropathy alone and in association with a familial tendency to hypertension/nephropathy with 86 and 96 % sensitivity, and 80 % specificity. Thus, sodium-hydrogen exchange appears to detect a subset of diabetic patients prone to develop renal damage, in whom a more intensive treatment modality might be considered.[ Diabetologia (1998) 41: 201±205]

Microangiopathy disables thousands of diabetic patients throughout the world. Aggressive treatment modalities, such as combined therapy with antihyperglycaemic drugs and insulin, appear to decrease the extent of microvascular damage, but are associated with increased incidence of hypoglycaemic events and weight gain [1]. Their risk-to-benefit ratio is high also because less than one third of diabetic patients develop nephropathy [2].Attempts have been made to find a marker that can predict micro-angiopathy in diabetes, and identify a group of patients for whom aggressive treatment is indicated despite its possible adverse effects. Urinary excretion of very small amounts of albumin (microalbuminuria) and elevation of arterial pressure [3] have been proposed for this purpose, but both appear when renal damage is already impending [4].Enhanced permeability of extracellular membranes to sodium (defined as sodium-lithium and sodium-hydrogen antiports) found in blood cells and skin fibroblasts of diabetic patients prone to renal damage [5][6][7] is, however, a very early (if not congenital) sign. To assess the reliability of Na + /H + exchange (NHE) study in predicting diabetic nephropathy, we followed initially non-microalbuminuric patients with non-insulin-dependent diabetes mellitus (NIDDM) of at least 10 years' duration for 8 years after NHE evaluation was first made. Diabetologia (1997) Summary Intensive treatment of non-insulin-dependent diabetes mellitus (NIDDM) decreases the rate of microvascular complications, but is associated with increased incidence of cardiovascular morbidity. Enhanced permeability of plasma membranes for sodium (e. g. sodium-hydrogen exchange, NHE) may predict the subset of diabetic patients for whom intensive modalities of treatment are indicated despite their potential risk. However, the accuracy of NHE as a marker of microangiopathy has not been assessed. In this study NHE as initial velocity of amiloride-inhibited H + efflux from erythrocytes (pH i 6.35-6.45) into an Na + -containing medium (pH o 7.95-8.05), was estimated during 8 years of follow-up in 138 non-microalbuminuric diabetic patients (74 women, 64 men, age 52 ± 4 years) treated with antihyperglycaemic drugs for 14 ± 2 years. Appearance of microalbuminuria, overt proteinuria, azotaemia and retinopathy was assessed annually. Enhanced erythrocyte NHE predicted diabetic nephropathy alone and in association with a family history of hypertension and/or nephropathy with a sensitivity of 86 and 93 %, respectively. No association was found between NHE and retinopathy in NIDDM. It is concluded that assessment of erythrocyte NHE can identify a subset of patients likely to develop renal damage, for whom an aggressive treatment approach might be considered. [Diabetologia (1997) 40: 302-306] Keywords Na + /H + exchange, NIDDM, diabetic nephropathy, diabetic retinopathy, erythrocytes.Received: 14 June 1996 and in final revised form: 8 November 1996Corresponding author: W. Koren, M. D., Department of Medicine C, Chaim Sheba Medical ...

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