362
determined by genes in the HLA region common genetic factors may be involved. This is supported by the finding of a higher than normal pre-eclampsia rate in those 31 pregnancies (mainly first pregnancies) of our patients which were carried beyond the 26th gestational week. In 6 of these pregnancies the patients had pre-eclampsia. Reginald and colleagues2 have reported an increased rate of small-for-gestational-age babies in women with a history of recurrent miscarriage. There seems to be some support for the suggestion that pre-eclampsia and repeated fetal loss may share common immunogenetic markers, the expression of which may lead to at least two different clinical pictures.
Department Immunology, Aalborg Hospital, DK 9100 Aalborg, Denmark
OLE B. CHRISTIANSEN OLE MATHIESEN NIELS GRUNNET CASPER JERSILD
Department of Obstetrics and Gynaecology, Aalborg Hospital
J. GLENN LAURITSEN
of Clinical
1. Christiansen OB, Riisom K, Lauritsen JG, Grunnet N, Jersild C. Association of maternal HLA haplotypes with recurrent spontaneous abortion. Tissue Antigens 1989; 34: 190-99. 2. Reginald PW, Beard RW, Chapple J, et al. Outcome of pregnancies progressing beyond 28 weeks gestation in women with a history of recurrent miscarriage. Br J Obstet Gynaecol 1987; 94: 643-48.
Correct
of University of Wisconsin preservation solution
use
SiR,—Two European transplant centres have reported an adverse reaction after transplantation of kidneys stored in the University of Wisconsin (UW) solution. The UW solution was used to flush the kidney immediately before transplantation. This practice resulted in some cases of cardiac dysfunction which seems to be related to the infusion of the UW solution into the systemic circulation (particularly adenosine, one of the components). Adenosine is known to cause cardiac dysfunction and is a potent coronary vasodilator. The UW solution was introduced by our group for the preservation of organs and was not intended to be used to flush the kidney before transplantation. When used properly the adenosine is catabolised to hypoxanthine and inosine, agents that do not cause cardiac problems. But this catabolism takes some time at hypothermia. It seems that the pretransplant flushout is done to check for arterial injuries. A more appropriate solution would be Ringers/lactate or Ringers/lactate with dextrose (5%). This latter solution is what we use to flush the liver before transplantation to remove potassium from the organ. The added advantage of a glucose containing solution is the impermeability of glucose which can retard cell swelling. At the University of Wisconsin Hospitals we have used the UW solution in preservation of kidneys, pancreases, and livers in about 600 organ transplants, and we have not had an adverse reaction due to its use. We continue to use this solution at the time of initial organ procurement and during the subsequent preservation period. We have not advocated its use to flush organs before transplantation, a use which is a contraindication of the UW solution. Department of Surgery, University of Wisconsin, Madison, Wisconson 53792, USA
FOLKERT O. BELZER
Post-isotretinoin vasculitis SIR,-Dr Reynolds and colleagues (Nov 18, p 1216) report a new of disseminated vasculitis related to treatment with isotretinoin. However, the relation between occurrence of vasculitis and this drug is not obvious. First, the onset of the disease was 6 weeks after completion of treatment. Pharmacokinetic studies with that radiolabelled 1°C-isotretinoin showed isotretinoin, oxoisotretinoin, and other possible metabolites’ half lives were 13, 28, and 90 hours, respectively.1 In healthy subjects as well as in disease states, kinetics of isotretinoin metabolites after repetitive dosing can be predicted from single-dose data.2 We therefore case
consider that in Reynolds and colleagues’ patient isotretinoin and its metabolites were absent when vasculitis began. This assumption is supported by the fact that women are advised that it is safe to conceive one month after isotretinoin withdrawal. Moreover, in all other reports isotretinoin-associated vasculitis occurred during treatment.3 Second, the association of vasculitis with rectal bleeding, mild proteinuria, and microscopic haematuria strongly suggests Henoch Schonlein disease. However, other data such as renal histology and cutaneous immunofluorescence were not available. A diagnosis of periarteritis nodosa (PAN) could also have been applied to this patient because of the presence of myalgias, muscular angiitis, and hypertension. Pathological findings showed muscular small-vessel angiitis with fibrinoid necrosis. Since inflammatory lesions in PAN usually affect small and medium arteries segmentally this diagnosis cannot be ruled out. It is noteworthy that these two syndromes are not usually regarded as drug related. Finally, it took more than 6 months’ treatment with corticosteroids and immunosuppressive drugs to control this vasculitis. Such an outcome is unusual in drug-induced vasculitis. With one of the standard methods to identify a drug producing adverse reaction4 we found that the isotretinoin culpability score was 1 This casts doubt on the hypothesis. Isotretinoin-induced vasculitis cases are very rare and the features in some are consistent with Wegener or Henoch Scholein diseases. Therefore this relation should be proposed only with caution. Clinic for Skin Diseases, Hôpital Saint Louis, 75475 Pans Cedex 10, France
SÉLIM ARACTINGI KAÏSS LASSOUED LOUIS DUBERTRET
1. Colburn W, Vane F, Bugge C, Carter D, Bressler R, Ehmann C. Pharmacokinetics of
14C isotretinoin in healthy volunteers and volunteers with biliary T-tube drainage. Drug Metabol Disposition 1984; 13: 327-32. 2. Brazell R, Colburn W. Pharmacokinetics of the retinoids isotretinoin and etretinate. J Am Acad Dermatol 1982; 6: 643-51. 3. Dwyer JM, Kenicer K, Taylor Thompson B, et al. Vasculitis and retinoids. Lancet 1989; ii: 494-97. 4. Begaud B, Evreux JC, Jouglard J, Lagier G. Unexpected or toxic drug reaction assessment (imputation). Therapie 1985; 40: 111-18.
Reversible cyclosporin myopathy SIR,-Cyclosporin has been suggested as a possible but infrequent of myopathy.12 One patient with Graves’ ophthalmopathy and three who had heart transplants, all receiving less than 10 mg/kg daily cyclosporin, have been described. Two of these patients were noticeably affected by a myopathic process, presenting with muscle pain, cramps, weakness, and rhabdomyolysis, the other two were symptomless. Muscle pathology revealed type-2 fibre atrophy, segmentary necrosis, and occasional glycogen deposition. Z-line streaming, disruption of myofibrils, and abnormal mitochondria were seen electromicroscopically in some cases. Chassagne et aP were not convinced about evidence of myopathy due to cyclosporin because of the possibility of an association with other drugs. We report a patient with clinical and histological reversible cyclosporin myopathy, who received high doses of cyclosporin after kidney transplantation, and in whom no other drug could be implicated in the toxicity. A 57-year-old man with chronic renal failure from polycystic kidney disease, on haemodialysis since February, 1979, had a cadaveric kidney transplantation in April, 1989. Cyclosporin (12 mg/kg daily) was given as an immunosuppressive. Doses were adjusted to keep blood concentrations between 200 and 300 ng/mt (specific monoclonal radioimmunoassay). Norfloxacin 400 mg daily as prophylaxis for urinary tract infection was also given. The post-transplant period was uneventful. The patient was discharged after 18 days, with a serum creatinine of 2-2 mg/dl and serum cyclosporin concentration of 504 ng/ml. The cyclosporin dose was reduced to 10 mg/kg daily. Two months after engraftment gingival hypertrophy developed. Serum creatinine was 1-6 mg/dl and cyclosporin concentration 375 ng/ml. Cyclosporin was reduced to 8 mg/kg daily. Three months later the patient gradually noticed severe pain and weakness of proximal limb muscles. He had some proximal limb muscle cause
determined by genes in the HLA region common genetic factors may be involved. This is supported by the finding of a higher than normal pre-eclampsia rate in those 31 pregnancies (mainly first pregnancies) of our patients which were carried beyond the 26th gestational week. In 6 of these pregnancies the patients had pre-eclampsia. Reginald and colleagues2 have reported an increased rate of small-for-gestational-age babies in women with a history of recurrent miscarriage. There seems to be some support for the suggestion that pre-eclampsia and repeated fetal loss may share common immunogenetic markers, the expression of which may lead to at least two different clinical pictures.
Department Immunology, Aalborg Hospital, DK 9100 Aalborg, Denmark
OLE B. CHRISTIANSEN OLE MATHIESEN NIELS GRUNNET CASPER JERSILD
Department of Obstetrics and Gynaecology, Aalborg Hospital
J. GLENN LAURITSEN
of Clinical
1. Christiansen OB, Riisom K, Lauritsen JG, Grunnet N, Jersild C. Association of maternal HLA haplotypes with recurrent spontaneous abortion. Tissue Antigens 1989; 34: 190-99. 2. Reginald PW, Beard RW, Chapple J, et al. Outcome of pregnancies progressing beyond 28 weeks gestation in women with a history of recurrent miscarriage. Br J Obstet Gynaecol 1987; 94: 643-48.
Correct
of University of Wisconsin preservation solution
use
SiR,—Two European transplant centres have reported an adverse reaction after transplantation of kidneys stored in the University of Wisconsin (UW) solution. The UW solution was used to flush the kidney immediately before transplantation. This practice resulted in some cases of cardiac dysfunction which seems to be related to the infusion of the UW solution into the systemic circulation (particularly adenosine, one of the components). Adenosine is known to cause cardiac dysfunction and is a potent coronary vasodilator. The UW solution was introduced by our group for the preservation of organs and was not intended to be used to flush the kidney before transplantation. When used properly the adenosine is catabolised to hypoxanthine and inosine, agents that do not cause cardiac problems. But this catabolism takes some time at hypothermia. It seems that the pretransplant flushout is done to check for arterial injuries. A more appropriate solution would be Ringers/lactate or Ringers/lactate with dextrose (5%). This latter solution is what we use to flush the liver before transplantation to remove potassium from the organ. The added advantage of a glucose containing solution is the impermeability of glucose which can retard cell swelling. At the University of Wisconsin Hospitals we have used the UW solution in preservation of kidneys, pancreases, and livers in about 600 organ transplants, and we have not had an adverse reaction due to its use. We continue to use this solution at the time of initial organ procurement and during the subsequent preservation period. We have not advocated its use to flush organs before transplantation, a use which is a contraindication of the UW solution. Department of Surgery, University of Wisconsin, Madison, Wisconson 53792, USA
FOLKERT O. BELZER
Post-isotretinoin vasculitis SIR,-Dr Reynolds and colleagues (Nov 18, p 1216) report a new of disseminated vasculitis related to treatment with isotretinoin. However, the relation between occurrence of vasculitis and this drug is not obvious. First, the onset of the disease was 6 weeks after completion of treatment. Pharmacokinetic studies with that radiolabelled 1°C-isotretinoin showed isotretinoin, oxoisotretinoin, and other possible metabolites’ half lives were 13, 28, and 90 hours, respectively.1 In healthy subjects as well as in disease states, kinetics of isotretinoin metabolites after repetitive dosing can be predicted from single-dose data.2 We therefore case
consider that in Reynolds and colleagues’ patient isotretinoin and its metabolites were absent when vasculitis began. This assumption is supported by the fact that women are advised that it is safe to conceive one month after isotretinoin withdrawal. Moreover, in all other reports isotretinoin-associated vasculitis occurred during treatment.3 Second, the association of vasculitis with rectal bleeding, mild proteinuria, and microscopic haematuria strongly suggests Henoch Schonlein disease. However, other data such as renal histology and cutaneous immunofluorescence were not available. A diagnosis of periarteritis nodosa (PAN) could also have been applied to this patient because of the presence of myalgias, muscular angiitis, and hypertension. Pathological findings showed muscular small-vessel angiitis with fibrinoid necrosis. Since inflammatory lesions in PAN usually affect small and medium arteries segmentally this diagnosis cannot be ruled out. It is noteworthy that these two syndromes are not usually regarded as drug related. Finally, it took more than 6 months’ treatment with corticosteroids and immunosuppressive drugs to control this vasculitis. Such an outcome is unusual in drug-induced vasculitis. With one of the standard methods to identify a drug producing adverse reaction4 we found that the isotretinoin culpability score was 1 This casts doubt on the hypothesis. Isotretinoin-induced vasculitis cases are very rare and the features in some are consistent with Wegener or Henoch Scholein diseases. Therefore this relation should be proposed only with caution. Clinic for Skin Diseases, Hôpital Saint Louis, 75475 Pans Cedex 10, France
SÉLIM ARACTINGI KAÏSS LASSOUED LOUIS DUBERTRET
1. Colburn W, Vane F, Bugge C, Carter D, Bressler R, Ehmann C. Pharmacokinetics of
14C isotretinoin in healthy volunteers and volunteers with biliary T-tube drainage. Drug Metabol Disposition 1984; 13: 327-32. 2. Brazell R, Colburn W. Pharmacokinetics of the retinoids isotretinoin and etretinate. J Am Acad Dermatol 1982; 6: 643-51. 3. Dwyer JM, Kenicer K, Taylor Thompson B, et al. Vasculitis and retinoids. Lancet 1989; ii: 494-97. 4. Begaud B, Evreux JC, Jouglard J, Lagier G. Unexpected or toxic drug reaction assessment (imputation). Therapie 1985; 40: 111-18.
Reversible cyclosporin myopathy SIR,-Cyclosporin has been suggested as a possible but infrequent of myopathy.12 One patient with Graves’ ophthalmopathy and three who had heart transplants, all receiving less than 10 mg/kg daily cyclosporin, have been described. Two of these patients were noticeably affected by a myopathic process, presenting with muscle pain, cramps, weakness, and rhabdomyolysis, the other two were symptomless. Muscle pathology revealed type-2 fibre atrophy, segmentary necrosis, and occasional glycogen deposition. Z-line streaming, disruption of myofibrils, and abnormal mitochondria were seen electromicroscopically in some cases. Chassagne et aP were not convinced about evidence of myopathy due to cyclosporin because of the possibility of an association with other drugs. We report a patient with clinical and histological reversible cyclosporin myopathy, who received high doses of cyclosporin after kidney transplantation, and in whom no other drug could be implicated in the toxicity. A 57-year-old man with chronic renal failure from polycystic kidney disease, on haemodialysis since February, 1979, had a cadaveric kidney transplantation in April, 1989. Cyclosporin (12 mg/kg daily) was given as an immunosuppressive. Doses were adjusted to keep blood concentrations between 200 and 300 ng/mt (specific monoclonal radioimmunoassay). Norfloxacin 400 mg daily as prophylaxis for urinary tract infection was also given. The post-transplant period was uneventful. The patient was discharged after 18 days, with a serum creatinine of 2-2 mg/dl and serum cyclosporin concentration of 504 ng/ml. The cyclosporin dose was reduced to 10 mg/kg daily. Two months after engraftment gingival hypertrophy developed. Serum creatinine was 1-6 mg/dl and cyclosporin concentration 375 ng/ml. Cyclosporin was reduced to 8 mg/kg daily. Three months later the patient gradually noticed severe pain and weakness of proximal limb muscles. He had some proximal limb muscle cause
