Evidence of changes in renal charge selectivity in patients with Type 1 (insulin-dependent) diabetes mellitus

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Abstract
Altered filtration of macromolecules due to decreased electrical charge of the glomerular basement membrane might be the initial step in the development of albuminuria in patients with Type 1 (insulin-dependent) diabetes mellitus. We therefore investigated the selectivity index, i. e. renal clearance of non-glycated plasma albumin/clearance of glycated plasma albumin in 38 patients with Type 1 diabetes mellitus. The two albumin molecules differed slightly in charge, non-enzymatic glycated albumin being more anionic at physiological pH compared with unmodified plasma albumin. Glycated albumin in plasma and urine was determined by a specific, sensitive and highly reproducible chromatographic procedure. In diabetic patients with normal urinary albumin excretion, the selectivity index was increased threefold compared with that of non-diabetic subjects (2p< 0.01). A significant correlation (r=0.53, 2p < 0.01) between haemoglobin A1c and selectivity index was demonstrated in these patients, indicating a change in charge-dependent renal filtration could possibly be attributed to non-enzymatic glycation of components in the glomerular basement membrane and tubuli. Diabetic patients with increased albumin excretion rate had a significantly lower selectivity index compared with patients with normal albumin excretion (2p < 0.01). A significant negative correlation (r=0.85, 2p <0.001, exponential curve fit) was seen between urinary albumin excretion and selectivity index in the diabetic patients, indicating that the capability of differentiating between macromolecules of different charges is again lost with increasing urinary albumin excretion. In conclusion, the selectivity index is significantly increased in Type 1 diabetic patients with normal urinary albumin excretion, possibly due to non-enzymatic glycation of structural glomerular proteins. The selectivity index is again reduced with increasing urinary albumin excretion, possibly due to structural changes different from non-enzymatic glycation. This observation is in accordance with the hypothesis that loss of anionic charges due to reduced heparan sulphate content in glomerular basement membranes plays an important role in the early stages of diabetic renal disease.