Summary
The chronic nephrotoxic effects of cyclosporine (CsA) include proximal tubular atrophy and vacuolization. This study investigated the effect of CsA on renal hemodynamics and segmental electrolyte transport in CsA-treated patients. The clearance of inulin (CIn) and PAH para-amino-hippuric acid (CPAH) was determined; proximal tubular function was studied using a lithium clearance method and calculating tubular phosphate reabsorption per milliliter of glomerular filtrate (TP/CIn). Twenty patients without renal disease were investigated: ten treated with CsA because of nonrenal grafting (group 1) and ten healthy volunteers (group 2). The results obtained were compared with those from 20 renal allograft recipients, of whom ten were treated with CsA and methylprednisolone (group 3) and ten with azathioprine and methylprednisolone (group 4). CIn and CPAH were significantly impaired in patients treated with CsA. No significant impairment of lithium clearance as induced by CsA was observed. The fractional excretion of lithium was slightly increased in patients treated with CsA compared to their respective controls. TP/CIn was lower in graft recipients compared to controls; no impairment of phosphate reabsorption as induced by CsA was found. The fractional tubular excretion of lithium was slightly increased compared to controls, rising evidence that proximal tubular reabsorption of lithium was decreased. Tubular reabsorption of phosphate was not impaired. The decrease in glomerular filtration and renal perfusion during chronic treatment with CsA was accompanied by a reduced proximal reabsorptive capacity, as was shown by lithium clearance. Our data do not support the hypothesis that functional parameters of the proximal tubular system can be used as indicators of CsA-induced nephrotoxicity.
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Abbreviations
- CIn :
-
inulin clearance
- CLi :
-
lithium clearance
- CPAH:
-
clearance of para-aminohippuric acid
- CPO4 :
-
phosphate clearance
- Aza:
-
azathioprine
- CsA:
-
cyclosporine A
- GFR:
-
glomerular filtration rate
- MP:
-
methylprednisolone
- TmP:
-
threshold phosphate concentration
- TP/CIn :
-
tubular phosphate reabsorption/ml inulin clearance
- TP/GFR:
-
tubular phosphate reabsorption/ml glomerular filtration rate
References
Berg KJ, Holdaas H, Enfresen L, Fauchald P, Hartmann A, Pran T, Solbu T (1991) Effects of isradipin on renal function in cyclosporin treated renal transplanted patients. Nephrol Dial Transplant 6:725–730
Brodehl J, Offner G, Wegener G (1980) Renal handling of phosphate in children with various stages of renal insufficieny. Abstracts of Pediatric Research 14:988
Brodehl J, Gelissen K, Weber HP (1982) Postnatal development of tubular phosphate reabsorption. Clin Nephrol 17:163–171
Dieperink H, Leyssac PP, Kemp E, Starklint H, Frandsen NE, Tvede N, Moller J, Büchler P, Fredrikson P, Rossing N (1987) The nephrotoxicity of cyclosporin A in humans. Eur J Clin Invest 17:493–496
Heering P, Grabensee B (1991) The influence of cyclosporine A on renal tubular function after kidney transplantation. Nephron 59:66–70
Heering P, Grabensee B (1992) Die Inulin- und PAH Clearance in der Diagnostik chronischer Nierenerkrankungen. Zeitschrift für Nieren- und Hochdruckkrankheiten 21:165–171
Heering P, Kutkuhn B, Kreuzpaintner G, Sundmacher R, Grabensee B (1991) Untersuchung zur Nierenfunktion nierengesunder Patienten unter Ciclosporin. Klin Wochenschr 69:880–886
Hilbrands LB, Artz M, Wetzels JFM, Koene RAP (1991) Cimetidin improves the reliability of creatinine as a marker of glomerular filtration. Kidney Int 40:1171–1176
Hoyer P (1987) Cyclosporin A Therapie bei Kindern nach Nierentransplantation. Dosierung and Nierenfunktion. Thesis, University of Hannover
Hoyer P, Lee I, Oemar BS, Krohn HP, Offner G, Brodehl J (1988) Renal handling of uric acid with cyclosporin A treatment. Pediatr Nephrol 2:18–21
Jones M, Mackay J, Whiting P, Power D, Propper D, Edwards N, Catto DR (1987) Proximal tubular dysfunction in cyclosporine treated renal allograft recipients. Nephrology Dialysis Transplantation 2:63
Koomans HA, Boer WH, Mees EJD (1989) Evaluation of lithium clearance as a marker of proximal tubule sodium handling. Kidney Int 36:2–12
Myers BD, Newton L (1991) Cyclosporine induced chronic nephropathy. An obliterative microvascular renal injury. J Am Soc Nephrol 2:S45-S52
Myers BD, Newton L, Boskos C, Makoviak JA, Frist WH, Derby GC, Perlroth MG, Sibley RK (1988) Chronic injury of human renal microvessels with low dose cyclosporine therapy. Transplantation 46:694–703
Sacks H, Chalmers TC, Smith H (1992) Randomized versus historical controls for clinical trials. Am J Med 72:233–323
Schnurr E, Lahme W, Küppers H (1980) Measurement of renal clearance of inulin and PAH in the steady state without urine collection. Clin Nephrol 13:26–29
Stark H, Eisenstein B, Tieder M, Rachmel A, Alpert G (1986) Direct measurement of TP/GFR: a simple and reliable parameter of renal phosphate handling. Nephron 44:125–128
Thomsen K (1984) Lithium clearance: a new method for determing proximal and distal tubular reabsorption of sodium and water. Nephron 37:217–223
Tomlanovich S, Golbetz H, Perlroth M, Stinson E, Myers BD (1986) Limitations of creatinine in quantifying the severity of cyclosporine A induced nephrotoxicity. Am J Kidney Dis 8:332–337
Versluis DJ, Wenting GJ, Jeekel J, Weimar W (1988) The influence of cyclosporine A on proximal tubular function in renal allografts. Transplant Proc 20 [Suppl 3]:686–690
Vincent HH, Wenting GJ, Versluis DJ, Weimar W, Schalekamp MADH (1988) Impaired fractional excretion of lithium. An early marker of cyclosporine induced changes in renal hemodynamics. Transplant Proc 20[Suppl 3]:681–685
Walton RJ, Bijvoet O (1975) Nomogram for derivation of renal threshold phosphate concentration. Lancet 11:309–310
Whiting PH, Propper DJ, Simpson JG, MaKay J, Jones MC, Catto GRD (1988) The use of lithium clearance measurements to assess renal tubular function in experimental and clinical cyclosporin nephrotoxicity. Transplant Proc 20[Suppl 3]:675–680
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Supported by a grant from the A. Krupp von Bohlen und Halbach Foundation, D-45133 Essen, Germany
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Heering, P., Schadewaldt, P., Bach, D. et al. Nephrotoxicity of cyclosporine in humans: effect of cyclosporine on glomerular filtration and proximal tubular reabsorption. Clin Investig 71, 1010–1015 (1993). https://doi.org/10.1007/BF00180033
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DOI: https://doi.org/10.1007/BF00180033