Pathophysiology of cyclosporine-induced nephrotoxicity in humans: a role for nitric oxide?

BACKGROUND: The causes for the nephrotoxicity of cyclosporine A (CsA) have not been fully elucidated. Intrarenal vasoconstriction induced by several different mediators, both in humans and experimental animals, have been proposed. METHODS: We studied prostaglandin metabolites, endothelin and nitric oxide in kidney transplant patients receiving their first CsA dose. Prostaglandin metabolites in the urine and endothelin and nitric oxide (NO2/NO3 in urine and plasma were measured in 14 patients before and 3 and 6 h after oral ingestion of CsA (10 mg/kg b.w.). Clearances for inulin and p-aminohippuric acid (PAH) were measured before and in two separate 3-hour periods after CsA. Blood pressure, heart rate, and CsA blood levels were also determined. RESULTS: Clearances of inulin and PAH decreased progressively after CsA dosage while renal vascular resistance increased. Nitric oxide plasma levels decreased in nearly all patients from 21.0 +/- 2.8 to 19.1 +/- 2.6 (p = 0.003) and then rose slightly to 19.5 +/- 2.5 micromol/l (p = 0.1) 3 and 6 h after CsA ingestion, respectively. Urinary excretion of NO2/NO3 decreased nonsignificantly from 269 +/- 38.8 to 259 +/- 27.7 and 254 +/- 41.6 micromol/min (p = 0.5 and 0.5). At the same time, urinary prostaglandin E2 and 6-keto-prostaglandin F(1 alpha) excretion rate declined significantly [from 1,187 +/- 254 to 1,186 +/- 351 and 730 +/- 148 pg/min (p = 0.27 and 0.02) and from 697 +/- 115 to 645 +/- 134 and 508 +/- 58.2 pg/min (p = 0.34 and 0.05)]. Urinary thromboxane B2 and plasma and urinary endothelin first increased and then decreased nonsignificantly. Mean arterial pressure rose from 107 +/- 2.5 to 110 +/- 2.6 and 114 +/- 3.4 mm Hg (p = 0.1 and 0.05). CONCLUSION: The pathophysiology of CsA-induced acute renal vasoconstriction involves several different mechanisms including a decrease of the vasodilating prostaglandins E2 and 6-keto-prostaglandin F(1 alpha) and possibly nitric oxide.

Blood pressure control in essential hypertension and impairment of renal function with age.

Hypertension has been recognized to be an important cause for the development of end-stage renal disease (ESRD). We assessed the quality of blood pressure control in 103 patients with essential hypertension and correlated renal function and age. Patients were stratified into three subgroups by their blood pressure level under current medication. Group 1 were hypertensive patients with normalized blood pressure (<140/90 mmHg, n = 25), group 2 patients with mild hypertension (140-159/90-99 mmHg, n = 43) and group 3 patients with moderate to severe hypertension (> 160/100 mmHg, n = 35). A negative correlation between age and creatinine clearance (Ccr) could be confirmed for patients of group 1 (correlation coefficient r1 = -0.56; p, < 0.01) and group 2 (r2 = -0.55; P2 < 0.001). Furthermore the regression coefficient (m) of decline in C(Cr) versus age was higher in group 2 patients (m2 = -1.83) than in group 1 (m1 = -1.30). In group 3 we found no correlation of renal function with age, indicating that age may not be the leading variable. Patients in group 1 were all within normal limits of age adjusted Ccr, but 12% in group 2 and 23% in group 3 had impaired C(Cr). Furthermore proteinuria was found to be 20% (group 1), 26% (group 2) and 31% (group 3). This analysis provides further evidence of the importance of blood pressure control in essential hypertension to preserve renal function.

Characterization of the mononuclear cell infiltrate in the glomerulus of rats with glomerulonephritis.

Bone marrow-derived inflammatory cells contribute to glomerular damage in experimental glomerulonephritis. The time sequential appearance and the pattern of inflammatory cells in the diseased glomerulus is, however, unclear. We therefore characterized the inflammatory cell infiltrate in a model of unilateral in situ immune complex glomerulonephritis. The cellular infiltrate was specific for the diseased kidney and independent of changes in peripheral blood or spleen. We found an influx of leukocyte common antigen (LCa)-positive and ED1-positive (monocytes/macrophages) cells in isolated glomeruli as early as 24 h after induction of the disease. Lymphocytes of the CD4-, CD8- and CD20-positive phenotypes were present in diseased glomeruli at Day 10. Complement depletion prevented the influx of monocytes/macrophages at 24 h in the glomerulus, which indicates that complement activation is important for the glomerular cell infiltrate at this early time point. The results demonstrate that the inflammatory cell infiltrate is regulated in situ at the glomerular level and not accompanied by similar changes in peripheral blood and spleen cells.