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THROMBOCYTOSIS AFTER CYCLOSPORIN THERAPY IN CHILD WITH NEPHROTIC SYNDROME
1018 than
two years and before HBV-DNA has integrated into the hepatocyte genome.3 This was another factor not controlled for in this trial. Loss of HBsAg per se is not necessarily of benefit unless it accompanies loss of HBeAg, as non-replicating (HBV-DNA and HBeAg negative) HBsAg carriers who do not have cirrhosis have at worst a small risk of hepatocellular carcinoma.1,4 This trial’s most interesting result was the observed loss of HBsAg in 5 of 17 HBeAg positive patients. However, rates of spontaneous seroconversion vary greatly from centre to centre and such high rates have been seen in untreated patients.5 The short follow-up period is also a problem as early spontaneous relapses are well recognised.1 Thyagarajan and colleagues rightly describe the results as tentative and until a well-designed randomised controlled trial, which includes at least one year of follow-up, has been reported, no one should be convinced that chronic hepatitis B can be treated by anything other than alpha-interferon or adenine arabinoside monophosphate.5
Department of Infectious Diseases, Royal Free Hospital at Coppetts Wood Hospital London N10 1JN
Platelet count in 5-year-old girl with steroid-resistant syndrome treated with cyclosporin.
M. G. BROOK al.
Clinical, virologic and histologic outcome following seroconversion from HBeAg to anti-HBe in chronic hepatitis type B. Hepatology 1986; 6: 167-72. 2. Alexander GJM, Brahm J, Fagan EA, et al. Loss of HBsAg with interferon therapy in chronic hepatitis B virus infection. Lancet 1987; ii: 66-69. 3. Scully LJ, Shein R, Karayiannis P, McDonald JA, Thomas HC. Lymphoblastoid interferon therapy of chronic HBV infection. J Hepatol 1987; 5: 51-58. 4. Edmann JC, Gray P, Valenzuela P, Rall LB, Rutter WJ Integration of hepatitis B virus sequences and their expression in a human hepatoma cell line. Nature 1980; 1. Fattovich
G, Rugge M, Brollo L,
et
286: 535-37.
5.
nephrotic
Hoofnagle JH. Antiviral treatment of chronic type B hepatitis. Ann Intern Med 1987; 107: 414-15.
THROMBOCYTOSIS AFTER CYCLOSPORIN THERAPY IN CHILD WITH NEPHROTIC SYNDROME
SIR,-Children with nephrotic syndrome are usually treated with corticosteroids. In most cases these treatments are effective but their side-effects, including growth failure and cataracts, limit their use. Cyclosporin has been reported to induce remission of relapsing nephrotic syndrome in children without toxicity, and was beneficial even in cases of steroid-resistant nephrotic syndrome (SRNS).2 We have observed thrombocytosis early in the course of cyclosporin in a child with SRNS. Thrombocytosis has not been
reported during cyclosporin treatment although thrombocytopenia has been. Thromboembolism is one of the most serious complications of nephrotic syndrome. Our observation suggests that cyclosporin treatment may increase the thrombotic episodes in
nephrotic syndrome. A 5-year-old Japanese girl was referred to us with SRNS. There was no evidence of systemic disease. The serum complement profile was normal. Renal biopsy revealed minor glomerular abnormalities. Full-dose prednisolone was given over 4 weeks with no response, then gradually withdrawn. Cataract, probably due to prednisolone, developed and cyclosporin was started at a dose of 5 mg/kg per day in two divided doses. Her serum albumin and 24-hour urinary protein excretion at the start of therapy were 1 ’2 g/dl and 6-0 g, respectively. Plasma fibrinogen was 7 27 g/1 (normal 2-0-4-0) and other coagulation tests were normal. The initial platelet count was 704 x 109/1; the count was 978 x 109/1 on the 1 lth day, 932 x 109/1 on the 14th day, and 840 x 109/1 on the 20th day (figure), and gradually returned to the pretreatment level. Blood cyclosporin trough levels (radioimmunoassay), which should be between 250 and 600 ng/ml, were 430 ng/ml on the 5th day, 520 ng/ml on the 13th day, and 550 ng/ml on the 20th day. Platelet aggregation with adenosine 5’-diphosphate (ADP) on the 19th day was normal. The serum albumin and 24-hour urinary protein excretion on the last day of observation were 28 g/dl and 10 g, respectively. It is well known that nephrotic patients may have a thrombotic diathesis. Many causes have been proposed, including alterations in the concentrations of almost every coagulation factor and clotting as well as defects in platelets and the fibrinolytic system. Several
studies have demonstrated platelet hyperactivity. The platelet often increased and platelet adhesiveness and aggregation is exaggerated. Platelets may have a key role in the genesis of the coagulopathy of the nephrotic syndromealthough the data are confusing and complicated. Cyclosporin is reported to be toxic to the bone marrow, causing anaemia, leucopenia, and thrombocytopenia. In our case mild thrombocytosis appeared before the start of cyclosporin therapy. However, the platelet count increased to 978 x 109/1 on the 10th day after the beginning of cyclosporin, then gradually decreased. It took about 3 weeks to reach the pretreatment level. No other causes of secondary thrombocytosis were found. Vanerenterghem et al5 observed in cadaveric kidney allograft recipients that cyclosporin enhanced ADP-induced platelet aggregation and increased the incidence of thromboembolism which mainly occurred during the first week after surgery. Cohen et al6 also reported that cyclosporin-treated renal allograft recipients had chronic platelet hyperactivity. We had already administered dipyridamole to inhibit platelet adhesiveness and aggregation when mild thrombocytosis occurred. We did not study platelets systematically but platelet aggregation on the 19th day was normal. Such treatment might prevent thromboembolism. Because of the risk of thromboembolism in children, which is as frequent as in adults,8 we agree with Meyrier et al2 that we should monitor the platelet count and/or prescribe platelet anti-aggregants in the early course of cyclosporin in children with nephrotic syndrome, although further study is necessary. count is
Department of Pediatrics Hokkaido University School of Medicine, Sapporo, 060 Japan We thank Sandoz for
NORITOMO ITAMI YASUSHI AKUTSU KOHICHI YASOSHIMA
providing cyclosporin and Prof S. Matsumoto for
helpful advice. Tejani A, Butt K, Traman H, et al. Cyclosporin-induced remission of relapsing nephrotic syndrome in children.J Pediatr 1987; 111: 1056-62. 2. Meyrier A, Simon P, Perret G, et al. Remission of idiopathic nephronc syndrome after treatment with cyclosporin A. Br Med J 1986, 292: 789-92. 3. Bernard DB. Extrarenal complications of the nephrotic syndrome. Kidney Int 1988, 1.
33: 1184-202.
Schapner WH, Robson AM. Nephrotic syndrome: minimal change disease, focal glomerulosclerosis and related disorders. In: Schrier WB, Gottschak CW, eds. Diseases of the kidney. 4th ed. Boston: Little Brown, 1988: 1949-2004. 5. Vanrenterghem Y, Roels L, Lerut T, et al. Thromboembolic complications and haemostatic changes in cyclosporin-treated cadaveric kidney allograft recipients. 4.
Lancet 1985; i: 999-1002. 6. Cohen N, Neild GH, Patel R, et al. Evidence for chronic platelet hyperaggregability and in vivo activation in cyclosporin-treated renal allografts. Thombo Res 1988; 49: 91-101. 7. Rajah SM, Crow MJ, Penny AF, Ahmad R, Watson DA. The effect of dipyndamole on platelet function: correlation with blood levels in man Br J Clin Pharmacol 1977; 4: 129-33. 8. Hoyer PF, Gonda S, Barthels M, Krohn HP, Brodehl J. Thromboembolic complications in children with nephrotic syndrome. Acta Paediatr Scand 1986; 75: 804-810.
two years and before HBV-DNA has integrated into the hepatocyte genome.3 This was another factor not controlled for in this trial. Loss of HBsAg per se is not necessarily of benefit unless it accompanies loss of HBeAg, as non-replicating (HBV-DNA and HBeAg negative) HBsAg carriers who do not have cirrhosis have at worst a small risk of hepatocellular carcinoma.1,4 This trial’s most interesting result was the observed loss of HBsAg in 5 of 17 HBeAg positive patients. However, rates of spontaneous seroconversion vary greatly from centre to centre and such high rates have been seen in untreated patients.5 The short follow-up period is also a problem as early spontaneous relapses are well recognised.1 Thyagarajan and colleagues rightly describe the results as tentative and until a well-designed randomised controlled trial, which includes at least one year of follow-up, has been reported, no one should be convinced that chronic hepatitis B can be treated by anything other than alpha-interferon or adenine arabinoside monophosphate.5
Department of Infectious Diseases, Royal Free Hospital at Coppetts Wood Hospital London N10 1JN
Platelet count in 5-year-old girl with steroid-resistant syndrome treated with cyclosporin.
M. G. BROOK al.
Clinical, virologic and histologic outcome following seroconversion from HBeAg to anti-HBe in chronic hepatitis type B. Hepatology 1986; 6: 167-72. 2. Alexander GJM, Brahm J, Fagan EA, et al. Loss of HBsAg with interferon therapy in chronic hepatitis B virus infection. Lancet 1987; ii: 66-69. 3. Scully LJ, Shein R, Karayiannis P, McDonald JA, Thomas HC. Lymphoblastoid interferon therapy of chronic HBV infection. J Hepatol 1987; 5: 51-58. 4. Edmann JC, Gray P, Valenzuela P, Rall LB, Rutter WJ Integration of hepatitis B virus sequences and their expression in a human hepatoma cell line. Nature 1980; 1. Fattovich
G, Rugge M, Brollo L,
et
286: 535-37.
5.
nephrotic
Hoofnagle JH. Antiviral treatment of chronic type B hepatitis. Ann Intern Med 1987; 107: 414-15.
THROMBOCYTOSIS AFTER CYCLOSPORIN THERAPY IN CHILD WITH NEPHROTIC SYNDROME
SIR,-Children with nephrotic syndrome are usually treated with corticosteroids. In most cases these treatments are effective but their side-effects, including growth failure and cataracts, limit their use. Cyclosporin has been reported to induce remission of relapsing nephrotic syndrome in children without toxicity, and was beneficial even in cases of steroid-resistant nephrotic syndrome (SRNS).2 We have observed thrombocytosis early in the course of cyclosporin in a child with SRNS. Thrombocytosis has not been
reported during cyclosporin treatment although thrombocytopenia has been. Thromboembolism is one of the most serious complications of nephrotic syndrome. Our observation suggests that cyclosporin treatment may increase the thrombotic episodes in
nephrotic syndrome. A 5-year-old Japanese girl was referred to us with SRNS. There was no evidence of systemic disease. The serum complement profile was normal. Renal biopsy revealed minor glomerular abnormalities. Full-dose prednisolone was given over 4 weeks with no response, then gradually withdrawn. Cataract, probably due to prednisolone, developed and cyclosporin was started at a dose of 5 mg/kg per day in two divided doses. Her serum albumin and 24-hour urinary protein excretion at the start of therapy were 1 ’2 g/dl and 6-0 g, respectively. Plasma fibrinogen was 7 27 g/1 (normal 2-0-4-0) and other coagulation tests were normal. The initial platelet count was 704 x 109/1; the count was 978 x 109/1 on the 1 lth day, 932 x 109/1 on the 14th day, and 840 x 109/1 on the 20th day (figure), and gradually returned to the pretreatment level. Blood cyclosporin trough levels (radioimmunoassay), which should be between 250 and 600 ng/ml, were 430 ng/ml on the 5th day, 520 ng/ml on the 13th day, and 550 ng/ml on the 20th day. Platelet aggregation with adenosine 5’-diphosphate (ADP) on the 19th day was normal. The serum albumin and 24-hour urinary protein excretion on the last day of observation were 28 g/dl and 10 g, respectively. It is well known that nephrotic patients may have a thrombotic diathesis. Many causes have been proposed, including alterations in the concentrations of almost every coagulation factor and clotting as well as defects in platelets and the fibrinolytic system. Several
studies have demonstrated platelet hyperactivity. The platelet often increased and platelet adhesiveness and aggregation is exaggerated. Platelets may have a key role in the genesis of the coagulopathy of the nephrotic syndromealthough the data are confusing and complicated. Cyclosporin is reported to be toxic to the bone marrow, causing anaemia, leucopenia, and thrombocytopenia. In our case mild thrombocytosis appeared before the start of cyclosporin therapy. However, the platelet count increased to 978 x 109/1 on the 10th day after the beginning of cyclosporin, then gradually decreased. It took about 3 weeks to reach the pretreatment level. No other causes of secondary thrombocytosis were found. Vanerenterghem et al5 observed in cadaveric kidney allograft recipients that cyclosporin enhanced ADP-induced platelet aggregation and increased the incidence of thromboembolism which mainly occurred during the first week after surgery. Cohen et al6 also reported that cyclosporin-treated renal allograft recipients had chronic platelet hyperactivity. We had already administered dipyridamole to inhibit platelet adhesiveness and aggregation when mild thrombocytosis occurred. We did not study platelets systematically but platelet aggregation on the 19th day was normal. Such treatment might prevent thromboembolism. Because of the risk of thromboembolism in children, which is as frequent as in adults,8 we agree with Meyrier et al2 that we should monitor the platelet count and/or prescribe platelet anti-aggregants in the early course of cyclosporin in children with nephrotic syndrome, although further study is necessary. count is
Department of Pediatrics Hokkaido University School of Medicine, Sapporo, 060 Japan We thank Sandoz for
NORITOMO ITAMI YASUSHI AKUTSU KOHICHI YASOSHIMA
providing cyclosporin and Prof S. Matsumoto for
helpful advice. Tejani A, Butt K, Traman H, et al. Cyclosporin-induced remission of relapsing nephrotic syndrome in children.J Pediatr 1987; 111: 1056-62. 2. Meyrier A, Simon P, Perret G, et al. Remission of idiopathic nephronc syndrome after treatment with cyclosporin A. Br Med J 1986, 292: 789-92. 3. Bernard DB. Extrarenal complications of the nephrotic syndrome. Kidney Int 1988, 1.
33: 1184-202.
Schapner WH, Robson AM. Nephrotic syndrome: minimal change disease, focal glomerulosclerosis and related disorders. In: Schrier WB, Gottschak CW, eds. Diseases of the kidney. 4th ed. Boston: Little Brown, 1988: 1949-2004. 5. Vanrenterghem Y, Roels L, Lerut T, et al. Thromboembolic complications and haemostatic changes in cyclosporin-treated cadaveric kidney allograft recipients. 4.
Lancet 1985; i: 999-1002. 6. Cohen N, Neild GH, Patel R, et al. Evidence for chronic platelet hyperaggregability and in vivo activation in cyclosporin-treated renal allografts. Thombo Res 1988; 49: 91-101. 7. Rajah SM, Crow MJ, Penny AF, Ahmad R, Watson DA. The effect of dipyndamole on platelet function: correlation with blood levels in man Br J Clin Pharmacol 1977; 4: 129-33. 8. Hoyer PF, Gonda S, Barthels M, Krohn HP, Brodehl J. Thromboembolic complications in children with nephrotic syndrome. Acta Paediatr Scand 1986; 75: 804-810.