Pregnancy, tacrolimus, and renal transplantation: survival of a 358-g ...

Nephrol Dial Transplant (2000) 15: 2065

combined with prednisolone is superior to the frequently used combination of azathioprine and prednisolone. We present a case of pHUS that developed shortly after renal transplantation, and in which CsA was withdrawn. Subsequently the patient was maintained on an MMF and prednisolone combination. Case. A 10-year-old male child received a kidney from his mother in November 1998. The child had bilaterally shrunken (probably congenital hypoplastic) kidneys with the right kidney being in ectopic location. The patient was maintained on intermittent peritoneal dialysis for a month prior to transplantation. During the transplant surgery, while dissecting the donor artery, there was an accidental division of one of the branches that had to be repaired, and that led to a slightly prolonged cold ischaemia time. The patient was put on a three-drug protocol of wysolone 20 mg/day, azathioprine 1.5 mg/kg/day, and CsA 10 mg/kg/day. Postoperative urine output was about 2 litres over the next 24 h, which was much less than expected. The patient also developed a high-grade fever, but no clinical focus of infection was detected. Until the culture results were available the patient was put on broad-spectrum antibiotics. Surprisingly, the laboratory results also revealed a significant drop in haemoglobin (from 11 g to 6 g%). However, no evidence of blood loss was detected and intravascular haemolysis was suspected. A remote possibility of pHUS was also entertained, but haematological investigations did not reveal any evidence of haemolysis, nor was there any thromocytopenia. Direct and indirect Coombs’ tests were also negative. Meanwhile urine and blood cultures were negative and chest X-ray was normal. The patient also became afebrile. On the 2nd postoperative day a graft biopsy was performed that revealed acute tubular necrosis and did not show any evidence of thrombotic microangiopathy (TMA). Blood transfusions were given for severe anaemia, leading to an increase in haemoglobin to 11 g%. Over the next 2 weeks the patient’s urine output increased and serum creatinine decreased and stabilized at 2.3 mg/dl. However, the haemoglobin decreased and finally after a period of 3 weeks repeat haematological investigations revealed evidence of haemolysis. The reticulocyte count increased to 5% and plenty of crenated red blood cells were seen on peripheral film, but there was no significant thrombocytopenia. Serum lactate dehydrogenase was markedly elevated (LDH 2027 units/litre, normal 85–300) again indicating haemolysis. A repeat graft biopsy was performed that revealed evidence of TMA, thus establishing diagnosis of pHUS. CsA was finally withdrawn and the patient was put on antithymocyte globulin prophylaxis, which was continued for the next 2 weeks until MMF was available. During this period renal function improved markedly and MMF was started at dose of 750 mg/day in two divided doses (34 mg/kg/day), along with prednisolone and azathioprine. After about a week, azathioprine was withdrawn and the patient was maintained on a combination of prednisolone and MMF. Seven months post-transplant the patient is doing well with adequate graft function (serum creatinine 0.9 mg/dl ). Comment. Although pHUS is an infrequent complication after kidney transplant, early recognition and elimination of identifiable risk factors is critical in its management and may prevent consequent graft loss. One of the factors implicated in the pathogenesis of pHUS is immunosuppressive therapy, particularly with CsA. Substitution of FK506 for CsA has been shown to have a beneficial effect. However, recurrence

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of pHUS occurs even in patients on FK506, more so when pHUS was the primary renal disease [3]. Gerder et al. [4] reported a case in 1997 in which a 52-year-old woman with pHUS was successfully maintained on MMF and prednisolone. A similar case was reported by McGregor et al. in 1998 [5]. In the present case, it was essential to save the graft as a second transplant would not have been possible due to family financial constraints. As soon as the diagnosis of pHUS was established CsA was withdrawn and MMF was started. Since recurrence of pHUS has been reported with FK506, we decided to avoid this drug. Although the safety and efficacy of MMF in the paediatric population is not very well established, this child tolerated the drug well and after 7 months is doing well, without any side-effects. In conclusion, an MMF and prednisolone combination may be a safe and effective alternative to CsA patients with pHUS, even in the paediatric age group. Departments of 1Nephrology 2Urology and 3Pathology Sanjay Gandhi Post Graduate Institute of Medical Sciences Lucknow India

D. K. Agarwal1 S. Gulati1 A. Mehta1 A. Kumar2 R. K. Sharma1 B. Mehta3 A. Gupta1 R. K. Gupta3

1. Candinas D, Keusch G, Schlumpf R, Burger HR, Gmur J, Largiader F. Hemolytic uremic syndrome following kidney transplantation: prognostic factors. Schweiz Med Wochenschr 1994; 124: 1789–1799 2. Singh N, Gayowski T, Marino IR. Hemolytic uremic syndrome in solid-organ transplant recipients. Transplant Int 1996; 9: 68–75 3. Franz M, Regele H, Schmaldienst S, Stummvoll HK, Horl WH, Pohanka E. Posttransplant hemolytic uremic syndrome in adult retransplanted kidney graft recipients: advantage of FK506 therapy? Transplantation 1998; 66: 1258–1262 4. Van Gelder T, Klaassen RJ, Van Riemsdijk Van Overbeeke I, Ijzermans JN, Weimar W. Mycophenolate mofetil and prednisolone as maintenance treatment after kidney transplantation. Transplantation 1997; 63: 1530–1531 5. McGregor DO, Robson RA, Lynn KL. Hemolytic uramic syndrome in a renal transplant recipient treated by conversion to mycophenolate mofetil. Nephron 1998; 80: 365–366

Pregnancy, tacrolimus, and renal transplantation: survival of a 358-g baby Sir, One in 50 female renal transplant recipients of child-bearing age becomes pregnant. However, there are only a few reports of pregnancies in transplant patients taking tacrolimus. We report such a pregnancy marked by severe intra-uterine growth retardation (IUGR) and the delivery at 28 weeks gestation of an infant weighing only 358 g but surviving at 15 months of age. Case. A 26-year-old woman received a cadaveric renal transplant 2 years after commencing haemodialysis. Early rejection was treated with steroids and antithymocyte globulin and immunosuppression was maintained with prednisolone, cyclosporin, and azathioprine. The best serum creatinine of 155 mmol/l was reached after 4 months. Three years after transplantation, borderline cellular rejection was treated with pulsed prednisolone. After 5 years cyclosporin was replaced with tacrolimus (0.12 mg/kg/day) because the serum creatinine had risen to 255 mmol/l and a further biopsy showed

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ongoing cellular rejection. At this time the patient became pregnant (despite medical advice against this) when her serum creatinine was 282 mmol/l. Her last menstrual period began 13 days before starting tacrolimus. During pregnancy, tacrolimus trough blood levels were 8–12 ng/ml. The maternal creatinine remained stable apart from a transient rise following delivery and was 284 mmol/l 2 weeks after delivery, but deteriorated to 393 mmol/l 12 months later. However there was marked IUGR and a Caesarian section (CS) was performed at 28 weeks. The female infant weighed only 358 g and required respiratory support. She was slow to wean from ventilation, developed bronchopulmonary dysplasia, and still required overnight oxygen when discharged, aged 6 months. Other problems included neonatal hepatitis, coagulopathy, nephrogenic diabetes insipidus, and excessive urinary salt loss. Metabolic bone disease resulted in several long bone and rib fractures. She weighed only 2.11 kg (3rd centile 4.35 kg) at discharge. Comment. This case is exceptional in the maintenance of a pregnancy in a patient with a poorly functioning renal allograft and treated with tacrolimus and also in the survival of the extremely low-birth-weight infant. We discuss the influence of renal failure and drug treatments on the pregnancy and the resulting infant. In patients with renal disease but near-normal renal function, pregnancy is usually uncomplicated provided blood pressure remains well controlled. However, in patients with severe renal failure (creatinine >230 mmol/l ) only 2/3 of pregnancies succeed and there is a very high incidence of IUGR and preterm delivery. In renal transplant recipients, 93% of gestations that continue beyond the 20th week end successfully, but the incidence of IUGR (40%) and preterm delivery (50%) is high [1]. Experience of pregnancy in renal transplant patients treated with tacrolimus is limited to a few cases. One woman with a serum creatinine at conception of 124 mmol/l underwent a CS at 33.4 weeks because of IUGR and the infant weighed 1312 g [2]. Another report describes two pregnancies with maternal creatinines at conception of 140 and 120 mmol/l. Healthy infants weighing 3410 and 2400 g were delivered by CS at 38 and 36 weeks respectively [3]. In a further case the initial serum creatinine was 118 mmol/l and fetal growth was normal but a CS was performed at 31 weeks because of pre-eclampsia. The infant weighed 1140 g [4]. There is wider experience with tacrolimus in pregnancy in liver transplant recipients in whom preterm deliveries are common, but prenatal growth for gestational age and postnatal infant growth are normal [5]. Survival of a 358-g neonate is very unusual. This weight is on 3rd centile for a 23-week gestation fetus and well below that expected at 28 weeks gestation (3rd centile 800 g, 50th centile 1100 g). Survival at 28 weeks gestation is approxi-

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mately 80%, but decreases exponentially with increasing growth retardation. Predicted survival with a weight less than 500 g is less than 2%. Neonatal hepatitis has a variety of causes but the early onset in this case, the negative results of investigations, and the spontaneous recovery suggest that hepatotoxic drugs may have been involved. Renal solute loss is common in premature neonates and is probably due to nephron immaturity, which also leads to renal unresponsiveness to vasopressin, and diabetes insipidus. Metabolic bone disease of prematurity is multi-factorial in nature, but again renal loss of phosphate in particular plays a role. Poor weight gain is a recognized sequelae of IUGR, compounded here by malabsorption secondary to neonatal hepatitis, renal salt wasting, and several episodes of sepsis. The contribution of tacrolimus toxicity to the complications seen in this case cannot be precisely gauged. However, as tacrolimus crosses the placenta the similarity of these complications to adverse effects seen in adults should be noted. In adults, tacrolimus may cause a rise in plasma creatinine and hypophosphataemia, occasionally causes tubular necrosis and abnormal liver function tests and rarely causes osteoporosis and coagulopathy. However, infants born to liver transplant recipients taking tacrolimus do not generally experience these adverse effects [5]. In summary therefore it seems likely that the IUGR in this case can be attributed to a poorly functioning maternal renal allograft requiring immunosuppressive therapy rather than to a specific effect of tacrolimus. The possibility remains that some of the post-natal complications, whilst mostly due to extremely low birth weight, were exacerbated by prior maternal administration of tacrolimus. Renal Unit and Department of Paediatrics Royal Devon and Exeter Hospital Barrack Road Exeter UK

Simon Satchell John Moppett Michael Quinn Anthony Nicholls

1. Davison JM. Pregnancy in renal allograft recipients: problems, prognosis and practicalities. Baillieres Clin Obstet Gynaecol 1994; 8: 501–525 2. Yoshimura N, Oka T, Fujiwara Y, Ohmori Y, Yasumura T, Honjo H. A case report of pregnancy in renal transplant recipient treated with FK506 (tacrolimus). Transplantation 1996; 61: 1552–1553 3. Midtvedt K, Hartmann A, Brekke IB, Lyngdal PT, Bentdal Ø, Haugen G. Successful pregnancies in a combined pancreas and renal allograft recipient and in a renal graft recipient on tacrolimus treatment. Nephrol Dial Transplant 1997; 12: 2764–2765 4. Resch B, Mache CJ, Windhager T, Holzer H, Leitner G, Muller W. FK 506 and successful pregnancy in a patient after renal transplantation. Transplant Proc 1998; 30: 163–164 5. Jain A, Venkataramanan R, Fung JJ et al. Pregnancy after liver transplantation under tacrolimus. Transplantation 1997; 64: 559–565