Faculty Bibliography

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hemolytic anemia caused by somatic mutations in the phosphatidylinositol glycan-complementation class A gene and the resulting absence of a key complement regulatory protein, CD59. Affected red blood cells in patients with PNH undergo intravascular complement-mediated lysis with resulting anemia, hemoglobinuria, and venous thromboses. Hepatic venous outflow thrombosis [Budd-Chiari syndrome (BCS)] is especially common in PNH patients and often fatal. The few case reports of outcomes in patients undergoing liver transplant for BCS secondary to PNH detail instances of recurrent BCS as well as early thrombotic portal vein occlusion and hepatic artery thrombosis requiring retransplantation. PNH is therefore generally considered a contraindication to liver transplantation. Here we present the first report of a patient with PNH and BCS undergoing successful liver transplantation while receiving eculizumab, a humanized monoclonal antibody that blocks the activation of the terminal complement at C5.

Single-center studies have reported equivalent outcomes of kidney allografts recovered with histidine-tryptophan-ketoglutarate (HTK) or University of Wisconsin (UW) solution. However, these studies were likely underpowered and often unadjusted, and multicenter studies have suggested HTK preservation might increase delayed graft function (DGF) and reduce graft survival of renal allografts. To further inform clinical practice, we analyzed the United Network for Organ Sharing (UNOS) database of deceased donor kidney transplants performed from July 2004 to February 2008 to determine if HTK (n = 5728) versus UW (n = 15 898) preservation impacted DGF or death-censored graft survival. On adjusted analyses, HTK preservation had no effect on DGF (odds ratio [OR] 0.99, p = 0.7) but was associated with an increased risk of death-censored graft loss (hazard ratio [HR] 1.20, p = 0.008). The detrimental effect of HTK was a relatively late one, with a strong association between HTK and subsequent graft loss in those surviving beyond 12 months (HR 1.43, p = 0.007). Interestingly, a much stronger effect was seen in African-American recipients (HR 1.55, p = 0.024) than in Caucasian recipients (HR 1.18, p = 0.5). Given recent studies that also demonstrate that HTK preservation reduces liver and pancreas allograft survival, we suggest that the use of HTK for abdominal organ recovery should be reconsidered.

Outcomes after heart and lung transplants have improved, and many recipients survive long enough to develop secondary renal failure, yet remain healthy enough to undergo kidney transplantation. We used national data reported to United Network for Organ Sharing (UNOS) to evaluate outcomes of 568 kidney after heart (KAH) and 210 kidney after lung (KAL) transplants performed between 1995 and 2008. Median time to kidney transplant was 100.3 months after heart, and 90.2 months after lung transplant. Renal failure was attributed to calcineurin inhibitor toxicity in most patients. Outcomes were compared with primary kidney recipients using matched controls (MC) to account for donor, recipient and graft characteristics. Although 5-year renal graft survival was lower than primary kidney recipients (61% KAH vs. 73.8% MC, p < 0.001; 62.6% KAL vs. 82.9% MC, p < 0.001), death-censored graft survival was comparable (84.9% KAH vs. 88.2% MC, p = 0.1; 87.6% KAL vs. 91.8% MC, p = 0.6). Furthermore, renal transplantation reduced the risk of death compared with dialysis by 43% for KAH and 54% for KAL recipients. Our findings that renal grafts function well and provide survival benefit in KAH and KAL recipients, but are limited in longevity by the general life expectancy of these recipients, might help inform clinical decision-making and allocation in this population.

We present four cases of renal transplant recipients who were treated with bortezomib for four different indications, each of whom had circulating anti-HLA antibodies that were followed serially throughout their courses of bortezomib therapy. It is important to note that each patient was administered bortezomib in conjunction with other agents and therapies traditionally used for desensitization or the treatment of AMR. The results have been mixed. In some cases substantial decreases in HLA-antibody were temporally related to bortezomib therapy. In the one case of recalcitrant AMR there has been no reduction in DSA after 2 cycles of the drug. Bortezomib has been well tolerated. One patient developed reversible peripheral neuropathic pain while another experienced line sepsis, a urinary tract infection, and an invasive fungal skin infection. Again, this patient had also received protracted courses of plasmapheresis combined with T-cell and B-cell depleting agents. The use of these other drugs precludes the ability to rigorously evaluate the efficacy of bortezomib in isolation and points towards a need for large-scale, controlled trials to determine whether the drug's promising mechanism of action is applicable in the setting of solid organ transplantation.