Ask the Experts - Renal Transplant Recipient With Microangiopathic...
A 25-year-old male developed atypical adult-type hemolytic uremic syndrome and was treated with multiple plasmaphereses (60+) and other supportive measures. However, in spite of this, he developed end-stage renal disease requiring continuous ambulatory peritoneal dialysis followed by living-related renal transplantation. The patient developed recurrence of microangiopathic hemolytic anemia (MAHA) in the immediate postoperative period, requiring reinstitution of plasmapheresis. In spite of over 30 total plasma exchange treatments and over 10 units of packed cell transfusions over the past 2 months, the MAHA is not responding to treatment. Antirejection therapy with prednisone, Rapamune, and CellCept resulted in leukopenia (total white blood cell count of 2.7), requiring discontinuation of CellCept temporarily, which resulted in a mild episode of rejection that was successfully treated with OKT3. Resumption of CellCept over several weeks is beginning to cause bone marrow suppression. Neoral was not considered because of the MAHA. Any suggestions regarding treatment of MAHA and antirejection therapy would be appreciated.

Jeet R. Mehta, MD, FRCS(C), FACS

Therapeutic options in this particular patient with recurrent MAHA are limited. However, it is not certain that adding a calcineurin blocker will make his MAHA worse, though the risk definitely exists. The patient apparently cannot tolerate both Cellcept and Rapamune due to leukopenia, and Rapamune monotherapy has been unsuccessful in this case. We suggest adding low-dose Prograf (trough target levels of 4-6 ng/mL) in addition to usual-dose Rapamune for prophylaxis against rejection. If MAHA recurs on this regimen, we would switch to low-dose Neoral. We believe the risk of rejection with rapamycin and prednisone is greater than the risk for exacerbation of MAHA with the initiation of a calcinuerin blocker. We instituted a similar regimen at New York Hospital-Cornell Medical Center for a patient with recurrent MAHA. We used Prograf and CellCept and maintained prednisone at 15 mg daily long term, along with several plasmapheresis treatments. It has worked thus far.

Hemolytic uremic syndrome (HUS) is characterized by renal failure, microangiopathic hemolytic anemia, and thrombocytopenia. There are 2 distinct forms: typical or endemic, and atypical. The typical form occurs most commonly in children after a diarrheal illness associated with verotoxin-producing Escherichia coli 0515:H7 or endotoxin-producing Shigella dysenteriae type 1. The atypical type can be triggered by viral infections (ie, entervovirus, HIV), drugs (cyclosporine [CSA], mitomycin C, tacrolimus, oral contraceptives, and monoclonal antibody preparations), pregnancy, malignant hypertension, systemic scleroderma, systemic lupus erythematosis, and acute renal transplant rejection. Hereditary forms have also been described.

Pathogenesis of HUS is multifactorial. It involves abnormalities of the vascular endothelium, altered prostaglandin production (decreased PGI2/prostacyclin), excessive amounts of von Willebrand's multimers, platelet hyperaggregability, increased TPA inhibitor type 1, neutrophil activation, oxygen free radical production, decreased nitric oxide production, and excessive endothelin production (a known procoagulant mitogenic peptide), leading to platelet aggregation, fibrin production, thrombosis, mesangiolysis, endothelial swelling, and subsequent glomerular ischemia and sclerosis.

With the advent of more efficacious immunosuppressive agents, there was an overall improvement in renal allograft survival, but the incidence of recurrent renal disease remained at 10% to 20%, leading to 2% to 4% of all allograft loss. Among the recurrent glomerulopathies, HUS has been reported to recur in 13% to 41% of cases, with subsequent graft loss of 10% to 77%, mostly from the atypical or familial forms of the disease. Renal transplant recipients may develop both recurrent and de novo disease.

CSA as well as Prograf and monoclonal antibody preparations such as OKT3 and antilymphocyte globulin have been shown to increase the incidence of de novo and recurrent HUS (CSA usually within the first 8 weeks, although some reports are conflicting as to its culpability). Increased incidence has also been reported in posttransplant patients with a panel reactive antibody (PRA) level greater than 85% along with CSA or OKT3 use. Other inciting factors include cytomegalovirus and influenza A infections, retransplants (sensitized patients), and non-heart-beating donor grafts. Not only can acute vascular rejection give rise to HUS, it also can be difficult to differentiate the 2 entities on histologic examination, thus warranting close attention to clinical presentation and laboratory parameters in order to establish the correct diagnosis and treatment.

In a review of 157 posttransplant patients with HUS, 50% regained graft function, 42% lost their graft, and 8% died. In CSA-induced cases, there was 60% graft survival and 5% mortality. Recurrent HUS was associated with 13% graft survival and 8% mortality. Rejection-associated HUS led to a 35% graft survival rate with 24% mortality, which, with the use of CSA, improved to 50% and 0% graft survival and mortality, respectively.