Renal tubular peptide catabolism in chronic vascular rejection

Chronic vascular rejection (CR) is the commonest cause of renal transplant loss, with few clues to etiology, but proteinuria is a common feature. In d iseased native kidneys, proteinuria and progression to failure are linked. We proposed a pathogenic role for this excess protein at a tubular level in kidney diseases of dissimilar origin. We demonstrated in both nephrotic pa tients with normal function and in those with failing kidneys increased ren al tubular catabolism and turnover rates of a peptide marker, Aprotinin (Ap r), linked to increased ammonia excretion and tubular injury. These potenti ally injurious processes were suppressed by reducing proteinuria with Lisin opril. Do similar mechanisms of renal injury and such a linkage also occur in proteinuric transplanted patients with CR, and if so, is Lisinopril then of beneficial value? We now examine these aspects in 11 patients with mode rate/severe renal impairment ((51)CrEDTA clearance 26.2 +/- 3.3 mL/min/1.73 m(2)), proteinuria (6.1 +/- 1.5 g/24 h) and biopsy proven CR. Lisinopril ( 10-40 mg) was given daily for 2 months in 7 patients. Four others were give n oral sodium bicarbonate (Na HCO3) for 2 months before adding Lisinopril. Renal tubular catabolism of intravenous Tc-99m-Apr (Apr* 0.5 mg, 80 MBq), w as measured before and after Lisinopril by gamma -ray renal imaging and uri nary radioactivity of the free radiolabel over 26 h. Fractional degradation was calculated from these data. Total 24 h urinary N-acetyl-beta -glucoami nidase (NAG) and ammonia excretion in fresh timed urine collections were al so measured every two weeks from two months before treatment. After Lisinop ril proteinuria fell significantly (from 7.8 +/- 2.2 to 3.4 +/- 1.9 g/24 h, p < 0.05). This was associated with a reduction in metabolism of Apr* over 26 h (from 0.5 +/- 0.05 to 0.3 +/- 0.005% dose/h, p < 0.02), and in fracti onal degradation (from 0.04 +/- 0.009 to 0.02 +/- 0.005/h, p < 0.01). Urina ry ammonia fell, but surprisingly not significantly and this was explained by the increased clinical acidosis after Lisinopril, (plasma bicarbonate fe ll from 19.1 +/- 0.7 to 17.4 +/- 0.8 mmol/L, p < 0.01), an original observa tion. Total urinary NAG did fall significantly from a median of 2108 (range 1044-3816) to 1008 (76-2147) mu mol/L, p < 0.05. There was no significant change in blood pressure or in measurements of glomerular hemodynamics. In the 4 patients who were given Na HCO3 before adding Lisinopril, both acidos is (and hyperkalemia) were reversed and neither recurred after adding Lisin opril. These observations in proteinuric transplanted patients after Lisino pril treatment have not been previously described.