title: Renal tubular peptide catabolism in chronic vascular rejection.
abstract: Chronic vascular rejection (CR) is the commonest cause of renal transplant loss, with few clues to etiology, but proteinuria is a common feature. In diseased 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 patients with normal function and in those with failing kidneys increased renal tubular catabolism and turnover rates of a peptide marker, Aprotinin (Apr), linked to increased ammonia excretion and tubular injury. These potentially injurious processes were suppressed by reducing proteinuria with Lisinopril. 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 moderate/severe renal impairment (51CrEDTA clearance 26.2+/-3.3 mL/min/1.73 m2), 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 given oral sodium bicarbonate (Na HCO3) for 2 months before adding Lisinopril. Renal tubular catabolism of intravenous 99mTc-Apr (Apr* 0.5 mg, 80MBq), was measured before and after Lisinopril by gamma-ray renal imaging and urinary radioactivity of the free radiolabel over 26 h. Fractional degradation was calculated from these data. Total 24 h urinary N-acetyl-beta-glucoaminidase (NAG) and ammonia excretion in fresh timed urine collections were also measured every two weeks from two months before treatment. After Lisinopril 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 fractional degradation (from 0.04+/-0.009 to 0.02+/-0.005/h, p<0.01). Urinary ammonia fell, but surprisingly not significantly and this was explained by the increased clinical acidosis after Lisinopril, (plasma bicarbonate fell from 19.1+/-0.7 to 17.4+/-0.8 mmol/L, p < 0.01), an original observation. Total urinary NAG did fall significantly from a median of 2108 (range 1044-3816) to 1008 (76-2147) micromol/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 acidosis (and hyperkalemia) were reversed and neither recurred after adding Lisinopril. These observations in proteinuric transplanted patients after Lisinopril treatment have not been previously described.
authors.affiliation: University Department of Medicine, Royal Liverpool University Hospital, UK. Rana.Rustom@liv.ac.uk
authors.forename: R
authors.initials: R
authors.lastname: Rustom
authors.forename: J S
authors.initials: JS
authors.lastname: Grime
authors.forename: R A
authors.initials: RA
authors.lastname: Sells
authors.forename: A
authors.initials: A
authors.lastname: Amara
authors.forename: M J
authors.initials: MJ
authors.lastname: Jackson
authors.forename: A
authors.initials: A
authors.lastname: Shenkin
authors.forename: P
authors.initials: P
authors.lastname: Maltby
authors.forename: L
authors.initials: L
authors.lastname: Smith
authors.forename: A
authors.initials: A
authors.lastname: Hammad
authors.forename: M
authors.initials: M
authors.lastname: Brown
authors.forename: J M
authors.initials: JM
authors.lastname: Bone
mesh_terms: D000328:Adult; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D007611:Aprotinin; D004359:Drug Therapy, Combination; D005260:Female; D006084:Graft Rejection / Q000378:metabolism* / Q000517:prevention & control*; D006801:Humans; D016030:Kidney Transplantation; D017706:Lisinopril / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011507:Proteinuria / Q000378:metabolism; D017693:Sodium Bicarbonate / Q000627:therapeutic use*; D014556:Urine / Q000737:chemistry
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D017693:Sodium Bicarbonate; D007611:Aprotinin; D017706:Lisinopril