Letter to the Editor © 1990 S. Karger AG. Basel 0250-8095/90/0105-0431 $2.75/0
Am J Nephrol 1990;10:431-432
Carboplatin-Induced Acute Renal Failure Gilbert Deray. Tarek Ben-Olhman. Georges Brillet, Bertrand Baumelou. Jean Gabarre. Alain Baumelou. Jacques-Louis Binet, Claude Jacobs
The clinical usefulness of cis-diamminedichloroplatinum (cisplatin) in the treatment of a variety of neoplas tic diseases, and the development of acute and chronic nephrotoxicity associated with its use have stimulated interest in the development of analogues with either an improved therapeutic index or broader range of activi ty. Cis-diammine-dicarboxylato-1 -cyclobutane platinum (carboplatin) is a second-generation complex which was not identified as a nephrotoxic agent in various phase I and II studies [I, 2], We report reversible acute renal failure after carboplatin administration in a patient with chronic renal failure. A 50-year-old woman was admitted in May 1987 for acute renal failure. The past medical history was negative. Upon admission physical examination was unremarkable. Laboratory tests revealed a serum creatinine concentration of 650 pmol/1. Urinalysis showed a 4-g/day proteinuria. Renal biopsy revealed tubulointerstitial ne phropathy with lambda chain deposits, and a lambda multiple myeloma stage IIIB was diagnosed. The patient responded dramati cally to four cycles of MCP (melphalan, cyclophosphosphamidc. and prednisone). The renal function improved and then remained stable with serum creatinine concentration being 140 pmol/1. In April 1988 while her myeloma was in complete remission she devel oped localized immunoblastic lymphoma (cutaneous tumor). The disease progressed despite six cycles of CHOP (cyclophosphamide, adriamycin. vincristine and prednisone) and radiotherapy. Treat ment was therefore changed to a derived DHAP protocol consisting of carboplatine ( 130 mg/day for 4 days), vepeside, Aracytinc and Solumedrol. The first cycle was uneventful. Serum creatinine was 149 pmol/1 before the second cycle and on the 3rd day of the second cycle of carboplatin despite vigorous hydration scrum creatinine was found to be elevated at 260 pmol/1. Urinary sediment was nor mal with no proteinuria or infection. Blood pressure was 130/80 mm Hg. Plasma creatinine level rose up to 700 pmol/1 5 days after stopping carboplatin. Diuresis was maintained with furosemide and no hemodialysis was performed. Renal function improved gradually and 21 days after discontinuation of carboplatin serum creatinine had decreased down to 225 pmol/1.
Carboplatin is a cisplatin analogue that has been found in phase I—II investigational trials not to be neph rotoxic in patients with normal renal function [1, 2], However, there have been recent reports on renal toxic ity following high-dose carboplatin (800-1,600 mg/m2 body surface). In the study by Gore et al. [3] a fall in the glomerular filtration rate of more than 25% was noticed in 10 of 20 courses of carboplatin measured by f51CrJEDTA clearances. The change in glomerular filtration rate and effective renal plasma flow did not lead to an analogous fall in creatinine clearance. This finding may account for the fact that in phase I and II studies carbo platin was not identified as a nephrotoxic agent. The same observation was made by Smil et al. [4] and Reed and Jacob [5]. Interestingly the cumulative carboplatin dose associated with the onset of the decrease in renal function values was 800 mg/m2 in these two studies. This may explain why the first cycle of treatment was un eventful in our patient. Reversible alteration of renal function as measured by serum creatinine and/or creatinine clearance has also been reported in patients who had either an associated nephrotoxic insult concurrent with the administration of carboplatin or preexisting renal disease [6, 7], Our pa tient received carboplatin at a dose which is much lower than that described in these studies. The diagnosis of acute toxic tubulopathy is supported by low proteinuria, normal urinary sediment, absence of urinary tract ob struction, and of acute variation of arterial blood pres sure and favorable outcome within 2 weeks after discon tinuation of the drug. The intracellular presence of reac tive platinum compounds is thought to be responsible for platinum-induced nephrotoxicity. Increasing impair ment of renal function by this mode of action might be augmented by the often unavoidable use of other known
Downloaded by: Kings's College London 137.73.144.138 - 10/22/2017 8:13:42 AM
Departments of Nephrology and Hematology. Hôpital Pitié-Salpêtrière. Paris, France
432
Deray/Ben-Othman/Brillet/Baumelou/Gabarre/Baumelou/Binet/Jacobs
nephrotoxic agents in patients with preexisting de creased renal function or in patients previously treated with cisplatinum. We suggest that in patients with preexisting renal fail ure carboplatin dosage should be reduced and renal func tion carefully monitored. In our patients, further treat ment with carboplatin is now conducted with the dose determined by a formula described by Calvert et al. [8]. Moreover, whenever possible the association of other nephrotoxic drug(s) with carboplatin should be avoided. It must be stressed that whether hyperhydration during carboplatin treatment could ameliorate nephrotoxic ef fects is not yet known.
4 Smit EF, Sleijfer DTH, Meijer S, Mulder NH, Postmus PE: Car boplatin and renal function. Ann Intern Med 1989; 110:1034. 5 Reed E, Jacob J: Carboplatin and renal dysfunction. Ann Intern Med 1989;! 10:409. 6 Curt GA, Grygiel JJ, Corden BJ, Orols RF, Weiss RB. Collins JM: Phase 1 and pharmacokinetic study of diammine cyclobu tane dicarboxylatoplatinium (NSC 241240). Cancer Res 1983; 43:4470-4473. 7 Bahca D, Corparros B. Allen J, Walker R, Tan CTC: Cis-dianemine(-l-l-cyclobutane dicarboxylate-(2-,0,0') platinium II CBDCA; NSC 241240, in children with cancer. Proc AACR 1984;25:201. 8 Calvert AH, Newell DR, Gumbrell LA, O’Reilly S. Burnell M, Boxall FE, Siddik LH, Judson IR, Gore ME, Wiltsha W: Carbo platin dosage: Prospective evaluation of a simple formula based on renal function. J Clin Oncol 1989;7:1748-1756.
References
Received: January 19, 1990 Accepted: February 5, 1990 Gilbert Deray, MD Department of Nephrology Hôpital Pitié-Salpêtrière F-75013 Paris (France)
Downloaded by: Kings's College London 137.73.144.138 - 10/22/2017 8:13:42 AM
1 Koeller JM, Trump DL, Tutsch K.D, Earhart RM, Davis TE, Tonne CD: Phase I clinical trial and pharmacokinetics of carbo platin (NSC 24 241240) by single monthly 30 minute infusion. Cancer 1986;57:22-225. 2 Bahca DM, Caparros-Sison B, Allen JA, Walker R. Tan CTC: Phase I study of carboplatin (CBDCA) in children with cancer. Cancer Treat Rep 1986;70:865-869. 3 Gore ME, Calvert AH. Smith IE: High-dose carboplatin in the treatment of lung cancer and mesothelioma: A phase I dose escalation study. Eur J Cancer Clin Oncol 1987;23:1391-1397.
Am J Nephrol 1990;10:431-432
Carboplatin-Induced Acute Renal Failure Gilbert Deray. Tarek Ben-Olhman. Georges Brillet, Bertrand Baumelou. Jean Gabarre. Alain Baumelou. Jacques-Louis Binet, Claude Jacobs
The clinical usefulness of cis-diamminedichloroplatinum (cisplatin) in the treatment of a variety of neoplas tic diseases, and the development of acute and chronic nephrotoxicity associated with its use have stimulated interest in the development of analogues with either an improved therapeutic index or broader range of activi ty. Cis-diammine-dicarboxylato-1 -cyclobutane platinum (carboplatin) is a second-generation complex which was not identified as a nephrotoxic agent in various phase I and II studies [I, 2], We report reversible acute renal failure after carboplatin administration in a patient with chronic renal failure. A 50-year-old woman was admitted in May 1987 for acute renal failure. The past medical history was negative. Upon admission physical examination was unremarkable. Laboratory tests revealed a serum creatinine concentration of 650 pmol/1. Urinalysis showed a 4-g/day proteinuria. Renal biopsy revealed tubulointerstitial ne phropathy with lambda chain deposits, and a lambda multiple myeloma stage IIIB was diagnosed. The patient responded dramati cally to four cycles of MCP (melphalan, cyclophosphosphamidc. and prednisone). The renal function improved and then remained stable with serum creatinine concentration being 140 pmol/1. In April 1988 while her myeloma was in complete remission she devel oped localized immunoblastic lymphoma (cutaneous tumor). The disease progressed despite six cycles of CHOP (cyclophosphamide, adriamycin. vincristine and prednisone) and radiotherapy. Treat ment was therefore changed to a derived DHAP protocol consisting of carboplatine ( 130 mg/day for 4 days), vepeside, Aracytinc and Solumedrol. The first cycle was uneventful. Serum creatinine was 149 pmol/1 before the second cycle and on the 3rd day of the second cycle of carboplatin despite vigorous hydration scrum creatinine was found to be elevated at 260 pmol/1. Urinary sediment was nor mal with no proteinuria or infection. Blood pressure was 130/80 mm Hg. Plasma creatinine level rose up to 700 pmol/1 5 days after stopping carboplatin. Diuresis was maintained with furosemide and no hemodialysis was performed. Renal function improved gradually and 21 days after discontinuation of carboplatin serum creatinine had decreased down to 225 pmol/1.
Carboplatin is a cisplatin analogue that has been found in phase I—II investigational trials not to be neph rotoxic in patients with normal renal function [1, 2], However, there have been recent reports on renal toxic ity following high-dose carboplatin (800-1,600 mg/m2 body surface). In the study by Gore et al. [3] a fall in the glomerular filtration rate of more than 25% was noticed in 10 of 20 courses of carboplatin measured by f51CrJEDTA clearances. The change in glomerular filtration rate and effective renal plasma flow did not lead to an analogous fall in creatinine clearance. This finding may account for the fact that in phase I and II studies carbo platin was not identified as a nephrotoxic agent. The same observation was made by Smil et al. [4] and Reed and Jacob [5]. Interestingly the cumulative carboplatin dose associated with the onset of the decrease in renal function values was 800 mg/m2 in these two studies. This may explain why the first cycle of treatment was un eventful in our patient. Reversible alteration of renal function as measured by serum creatinine and/or creatinine clearance has also been reported in patients who had either an associated nephrotoxic insult concurrent with the administration of carboplatin or preexisting renal disease [6, 7], Our pa tient received carboplatin at a dose which is much lower than that described in these studies. The diagnosis of acute toxic tubulopathy is supported by low proteinuria, normal urinary sediment, absence of urinary tract ob struction, and of acute variation of arterial blood pres sure and favorable outcome within 2 weeks after discon tinuation of the drug. The intracellular presence of reac tive platinum compounds is thought to be responsible for platinum-induced nephrotoxicity. Increasing impair ment of renal function by this mode of action might be augmented by the often unavoidable use of other known
Downloaded by: Kings's College London 137.73.144.138 - 10/22/2017 8:13:42 AM
Departments of Nephrology and Hematology. Hôpital Pitié-Salpêtrière. Paris, France
432
Deray/Ben-Othman/Brillet/Baumelou/Gabarre/Baumelou/Binet/Jacobs
nephrotoxic agents in patients with preexisting de creased renal function or in patients previously treated with cisplatinum. We suggest that in patients with preexisting renal fail ure carboplatin dosage should be reduced and renal func tion carefully monitored. In our patients, further treat ment with carboplatin is now conducted with the dose determined by a formula described by Calvert et al. [8]. Moreover, whenever possible the association of other nephrotoxic drug(s) with carboplatin should be avoided. It must be stressed that whether hyperhydration during carboplatin treatment could ameliorate nephrotoxic ef fects is not yet known.
4 Smit EF, Sleijfer DTH, Meijer S, Mulder NH, Postmus PE: Car boplatin and renal function. Ann Intern Med 1989; 110:1034. 5 Reed E, Jacob J: Carboplatin and renal dysfunction. Ann Intern Med 1989;! 10:409. 6 Curt GA, Grygiel JJ, Corden BJ, Orols RF, Weiss RB. Collins JM: Phase 1 and pharmacokinetic study of diammine cyclobu tane dicarboxylatoplatinium (NSC 241240). Cancer Res 1983; 43:4470-4473. 7 Bahca D, Corparros B. Allen J, Walker R, Tan CTC: Cis-dianemine(-l-l-cyclobutane dicarboxylate-(2-,0,0') platinium II CBDCA; NSC 241240, in children with cancer. Proc AACR 1984;25:201. 8 Calvert AH, Newell DR, Gumbrell LA, O’Reilly S. Burnell M, Boxall FE, Siddik LH, Judson IR, Gore ME, Wiltsha W: Carbo platin dosage: Prospective evaluation of a simple formula based on renal function. J Clin Oncol 1989;7:1748-1756.
References
Received: January 19, 1990 Accepted: February 5, 1990 Gilbert Deray, MD Department of Nephrology Hôpital Pitié-Salpêtrière F-75013 Paris (France)
Downloaded by: Kings's College London 137.73.144.138 - 10/22/2017 8:13:42 AM
1 Koeller JM, Trump DL, Tutsch K.D, Earhart RM, Davis TE, Tonne CD: Phase I clinical trial and pharmacokinetics of carbo platin (NSC 24 241240) by single monthly 30 minute infusion. Cancer 1986;57:22-225. 2 Bahca DM, Caparros-Sison B, Allen JA, Walker R. Tan CTC: Phase I study of carboplatin (CBDCA) in children with cancer. Cancer Treat Rep 1986;70:865-869. 3 Gore ME, Calvert AH. Smith IE: High-dose carboplatin in the treatment of lung cancer and mesothelioma: A phase I dose escalation study. Eur J Cancer Clin Oncol 1987;23:1391-1397.
