Burckart, GJ

Caritis, SN

Koneru, B

Paul Wang, CC

Starzl, TE

Venkataramanan, R

English

PubMed

Wang, CP

Name not available

Cyclosporine and its metabolites in mother and baby

RAMAN VENKATARAMANAN

BABURAO KONERU

CHUNG-CHIEE PAUL WANG

GILBERT J. BURCKART

STELEANOS N. CARITIS

THOMAS E. STARZL

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CYCLOSPORINE AND ITS METABOLITES IN MOTHER AND BABY

D-Scholarship@Pitt

468 TRANSPLANTATION Vol. 46, No.3 become useful as a provocative and predictive test for early renal abnormalities. In summary, our data indicate that exercise microalbumi-nuria is not detected in most kidney donors and support the notion that the uninephrectomized state does not result in a progressive hyperfiltration nephropathy. In addition, longitu-dinal studies could reveal whether. a particular subset of donors with abnormal exercise albuminuria represent an early phase of overt proteinuria and kidney damage. SUSANA GERTRUDIS RODRIGUEZ ESTEBAN LUCAS SIGA CESAR BOGADO RODOLFO SANTIAGO MARTINI MARCOS ROZENBERG ELVIRA E. ARRIZURIETA Instituto de Investigaciones Medicas Alfredo Lanari Facultad de Ciencias Medicas Universidad de Buenos Aires Argentina 1 Address correspondence to: Rodolfo S. Martin, M.D., Instituto de Investigaciones Medicas, Donato Alvarez 3150, 1427 Buenos Aires, Argentina. REFERENCES 1. Hostetter TH, Olson JL, Rennke HG, Venkatachalam MA, Bren-ner BM. Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation. Am J Physiol198I; 241: F85. 2. Tapson J, Marshall S, Wilkinson R. Exercise-induced microalbu-minuria in kidney donors: a cause for concern? [Abstract]. 10th International Congress of Nephrology, London, 1987. 3. Bertolatus JA, Friedlander MA, Scheidt C, Hunsicker LG. Urinary albumin excretion after donor nephrectomy [Abstract]. Kidney Int 1984; 25:340. 4. Vicenti F, Amend WJC Jr, Kaysen G, et a1. Long-term renal function in kidney donors. Transplantation 1983; 36: 626. 5. McCrary RP, Pitts TO, PU8chett JB. Diabetic nephropathy: nat-ural course, survivorship and therapy. Am J Nephrol 1981; 1: 206. 6. Mogensen CE, Vittinghus, Solling K. Abnormal albumin excretion after two provocative renal tests in diabetes: physical examina-tion and lysine injection. Kidney lnt 1979; XI6: 385. 7. Hakim RM, Goldszer RC, Brenner BM. Hypertension and protein-uria: long-term sequelae of uninephrectomy in humans. Kidney lnt 1984; 25: 930. 8. Mogensen CEo Microalbuminuria as a predictor of clinical diabetic nephropathy. Kidney Int 1987; 31: 673. 9. Viberti G, Keen H. The patterns of proteinuria in diabetes mellitus: relevance to pathogenesis and prevention of diabetic nephropa-thy. Diabetes 1984; 33: 686. 10. Olsen JL, Hostetter TH, Rennke HG, Brenner BM, Venkatach-alam MA. Altered glomerular permselectivity and progressive sclerosis following extreme ablation of renal mass. Kidney Int 1982; 2: 112. 11. Kanwar YS, Rosenzweig LJ, Linker A, Jakubewski ML. Decreased de novo synthesis of glomerular proteoglycans in diabetes: bio-chemical and autoradiographic evidence. Proc Nat! Acad Sci USA 1983; 80: 2272. Received 19 November 1987. Accepted 22 February 1988. CYCLOSPORINE AND ITS METABOLITES IN MOTHER AND BABY Cyclosporine (CsA) is a potent immunosuppressive agent that has significantly improved allograft survival in recipients of human organ transplants (1, 2). Recently there have been a few cases of successful pregnancies in transplant patients re-ceiving CsA alone or in combination with steroids (3, 4). A general concern regarding pregnancy in transplant patients is the potential harmful effect of chronic maternal immuno-- suppression on the fetus. It is essential to determine the extent of exposure of the fetus to the immunosuppressive drug and its metabolites. We recently studied the concentrations of CsA and several of its metabolites in maternal and cord blood, placenta, and the umbilical cord in two patients receiving chronic CsA therapy. The first patient was a 26-year-old woman with primary biliary cirrhosis secondary to common bile duct obstruction who received a successful liver transplantation in November 1985. Immunosuppression was achieved with CsA and steroids. During the second postoperative week she also received the monoclonal antibody OKT 3. In February 1987, she delivered a 3208 g baby boy. At the time of delivery she was receiving esA 200 mg orally h.i.d., prednisone 10 mg, hydralazine 50 mg q.i.d., ferrous sulphate 300 t.i.d, furosemide 40 mg q.d. and multivitamin therapy. On the day of the delivery she received CsA at 10 A.M. and the baby was born at 5:45 P.M. Maternal blood was obtained at 8.5 hr after CsA administration while cord blood was obtained at 7.8 hr after CsA administration. Moternul and cord blood along with placenta and umbilical cord were annlyzed for CsA and several of its metabolites using a gradient high-pressure liquid chromatographic method devel-oped in our laboratory (5). The second patient was a 25-year-old woman who received an orthotopic liver transplant in November 1985 for cirrhosis of unknown cause. Immunosuppression was achieved with CsA and steroids. Four weeks following the transplant, the patient developed cytomegalovirus hepatitis from which she recovered with reduction in immunosuppression. She did well for 10 months and then developed biliary obstruction that was cor-rected surgically. At this time she became pregnant. Pregnancy was complicated by anemia requiring blood transfusions and preeclampsia. At gestational age 36 weeks, she had a caesarean section because of fetal distress, and a live baby boy (weight 1690 g) was delivered at 8 A.M. At the time of delivery her medications included Riopan 30 ml p.o. every 4 hr, ranitidine 150 mg orally b.i.d., ferrous sulfate 300 mg orally t.i.d., pred-nisone 15 mg orally every day and CsA 125 mg orally every 12 hr. Maternal and fetal cord blood were drawn simultaneously at the time of delivery 10 hr after the previous oral cyclosporine dose. The baby had intrauterine growth retardation, as the weight and head circumference were below the fifth percentile. The blood samples, umbilical cord, and placenta were refriger-ated at 4°C until analyzed by HPLC. Table 1 lists the concentrations of CsA and its metabolites in blood and in different tissues. The highest concentration of CsA was seen in the umbilical cord of patient 1. The placenta contained CsA concentrations nearly five to ten times greater thon the maternul llnd the fetal blood, und had the highest Q cd BRIEF COMMUNICATIONS 469 TABLE 1. Cyclosporine and its metabolites in mother and child" CyA M-17 M-21 M-l M-18 Maternal blood (ng/ml) 90, 105 134, 132 <25,0 89, 63 0, <25 Cord hlood (ng/ml) 53,55 159, 162 0,0 28, 0 0,0 Placenta (ng/g) 506, 318 481, 184 <25,0 229, 89 0,0 Umbilical cord (ng/g) 2641, <25 137,97 0,0 28,0 0,0 • The first value was observed in patient 1 and the second value was observed in patient 2. concentrations of all the metabolites measured. While small concentrations of M 21 were observed in the placenta and the maternal blood of patient 1, M 18 concentrations were below measurable levels in most of the specimens. Cyclosporine is very lipid-soluble, extensively distributed in the body, and highly metabolized. Previous studies have re-ported the presence of CsA in cord blood, placenta, amniotic fluid, and breast milk (4). In addition to CsA, we have observed high concentrations of CsA metabolites in the placenta, indi-cating the presence of CsA metabolizing enzymes in this tissue and/or accumulation of these metabolites in the placenta. Very high concentrations of CsA (nearly 30 times that of the mater-nal blood) were also observed in the umbilical cord of one patient. Some of the metabolites, particularly M 17, appear in very high concentrations in the blood and also possess signifi-cant immunosuppressive effect (6, 7). Whether the metabolites of CsA also contribute to the toxicity is not known. In this study we report for the first time the concentrations of CsA metabolites in cord blood, placenta, and umbilical cord. Of interest is the relatively high concentration of all the metabo-lites in the placenta. While no specific harmful effects attributable to CsA were observed in the baby, it is clear that the fetus is exposed not only to CsA but also to its metabolites. According to the tests conducted by Sandoz Inc. (Basel, Switzerland) CsA is not mutagenic in the Ames test and did not produce any chromo-somal abnormalities in animals. However, since the fetus is exposed to chronic CsA and its metabolites. the immediate septic complications and the possible long-term effects on gestationally immunosuppressed children should be investi-gated. RAMAN VENKATARAMANAN BABURAO KONERU CHUNG-CHIEE PAUL WANG GILBERT J. BURCKART STELEANOS N. CARITIS THOMAS E. STARZL School of Pharmacy and School of Medicine University of Pittsburgh Pittsburgh, Pennsylvania 15261 REFERENCES 1. Starzl TE, Wei! III R, Iwatsuki S, et al. The use of cyclosporin A and prednisone in cadaver kidney transplantation. Surg Gynecol Obstet 1980; 151:17. 2. Starzl TE, Klintmalm GBG, Porter KA, Iwatsuki S, Schroter GPJ. Liver transplantation with use of cyclosporin A and prednisone. N Engl J Med 1981; 305: 266. 3. Lewis GJ, Lamont CAR, Lee HA, Slapak M. Successful pregnancy in a renal transplant recipient taking cyclosporin A. Br Med J 1982; 286: 603. 4. Flechner SM, Katz AR, Rogers AJ, Van Buren C, Kahan BD. The presence of cyclosporine in body tissues and fluids during preg-nancy. Am J Kidney Dis 1985; 1: 60. 5. Wang CP, Burckart GJ, Venkataramanan R. Separation of cyclo-sporine metabolites. Ther Drug Monit. 6. Rosano TG, Freed TG, Lempert N. In vitro immunosuppressive properties of cyclosporine metabolites. Transplantation 1986; 42: 262. 7. Zeevi A, Venkataramanan R, Burckart G, et al. Sensitivity of activated human lymphocytes to cyclosporine and its metabo-lites. Hum ImmunoI1988; 21: 143. Received 24 November 1987. Accepted 23 February 1988. MYCOTICroANEURYSM OF THE HEPATIC ARTERY ClMmifCAqfkd·~I1KfvM~ LIVER TRANSPLANTATION ~ .. I·"I;;;Ki~K , .. " __ "DDDDDDDDDD~ Reconstruction of the hepatic artery is an essential step in human hepatic transplantation. Thrombosis of the hepatic arterial anastomosis posttransplantation is the most frequent arterial complication (1, 2), particularly in small children (3). Mycotic aneurysms involving the hepatic arterial anastomosis are reported to occur much less frequently. In a series of 86 orthotopic hepatic transplantations performed (46 in children at the Cochin Hospital we have observed three cases of hepatic artery thrombosis. We have had two cases of anastomotic mycotic hepatic artery aneurysms occurring in the early post-operative period. The aim of this article is to discuss the diagnostic circumstances and therapeutic options of this serious complication, and to analyse the consequences of the resection of the aneurysm with deliberate ligation of the hepatic artery, which was the treatment used in our two patients. Case 1. An 18-year-old female patient suffering from cirrhosis due to chronic active viral hepatitis (type B) was transferred to the Cochiri Hospital on 8/18/86 for hepatic transplantation. She had previously undergone an elective distal splenorenal shunt for bleeding esophageal varices, following which hepatic function had continued to deteriorate. Clinically, she was deeply jaundiced with significant wasting. Prothrombin index was 22%. On 9/11/86, an orthotopic hepatic transplantation without extracorporeal venovenous bypass was performed using the liver of a 19-year-old man. No antibiotic was administered to the donor. Cold ischemia time was 5 hr 20 min and the anhepatic phase was 1 hr 20 min. The hepatic arterial anasto-mosis between the recipient hepatic artery proper and the donor common hepatic artery was performed with continuous 7/0 prolene. Biliary continuity was reestablished with a Roux-en-Y hepaticojejunostomy. The splenorenal anastomosis was . permeable and was not suppressed. Intraoperative transfusion was 25 units of packed cells. Routine immunosuppression with corticosteroids and cyclosporine was commenced. Mezlocillin, gentamycin and ornidazole were administered during the first 48 hr. On the 12th postoperative day the patient became febrile and suffered an intraabdominal hemorrhage. A CT scan showed a subhepatic hematoma, and angiography showed a small he-

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Cyclosporine and its metabolites in mother and baby

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