Mycophenolate mofetil as an effective alternative to cyclosporin in post-transplant haemolytic uraemic syndrome

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

1 Departments of Nephrology, 2 Urology and, 3 Pathology, Sanjay Gandhi Post Graduate, Institute of Medical Sciences, Lucknow, India

Sir,

Post-transplant haemolytic uraemic syndrome (pHUS) is an uncommon but severe complication of renal transplantation associated with poor allograft prognosis due to thrombotic microangiopathy. An incidence of 1–5% in kidney transplant was observed in the early cyclosporin A (CsA) era [1,2]. CsA-induced microangiopathy may be the major risk factor of pHUS. Early reports hypothesized that immunosuppression with FK506 (tacrolimus) would prevent the development of pHUS. However, this potentially beneficial effect remains controversial because pHUS associated with tacrolimus therapy has been reported [3].

Mycophenolate mofetil (MMF), a newer immunosuppressive drug, has been used most commonly in combination with CsA and prednisolone. It has been suggested that MMF 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We present a case of pHUS that developed shortly after renal transplantation, and in which CsA was withdrawn.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 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.

References

  1. Candinas D, Keusch G, Schlumpf R, Burger HR, Gmur J, Largiader F. Hemolytic uremic syndrome following kidney transplantation: prognostic factors. Schweiz Med Wochenschr1994; 124: 1789–1799[ISI][Medline]
  2. Singh N, Gayowski T, Marino IR. Hemolytic uremic syndrome in solid-organ transplant recipients. Transplant Int1996; 9: 68–75[ISI][Medline]
  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? Transplantation1998; 66: 1258–1262[ISI][Medline]
  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. Transplantation1997; 63: 1530–1531[ISI][Medline]
  5. McGregor DO, Robson RA, Lynn KL. Hemolytic uramic syndrome in a renal transplant recipient treated by conversion to mycophenolate mofetil. Nephron1998; 80: 365–366[ISI][Medline]




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