Health & Medical Organ Transplants & Donation

Donor-Specific HLA Alloantibodies in Liver Transplantation

Donor-Specific HLA Alloantibodies in Liver Transplantation

DSA in Simultaneous Liver–Kidney Transplant Recipients

Recognition of the inability of the liver to afford renal allografts complete protection from preformed DSA has been described previously, but despite a 17% 6-month renal allograft survival in crossmatch-positive patients in 1994, allocation policies have not been revised to account for this risk. More specific DSA determinations with SPI led to the discovery that renal allograft protection by the liver allograft occurs when the recipient harbors isolated preformed Class I DSA in low-to-moderate amounts (Table 2). Protection is incomplete, however, in recipients with preformed Class II DSA, in which case both the kidney and liver allografts are at risk for rejection (Figure 1), especially when Class II DSA persist posttransplantation. Analyses that lack differentiation between Class I and II DSA or those without a focus on posttransplant persistence of DSA may be underpowered to find these associations. Fortunately, the risk of persistence is low and at least partly dependent on class and MFI: Class I with MFI ≥5000 = 5%, Class II with MFI 5000–9999 = 23% and Class II with MFI ≥10 000 = 33%.

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Figure 1.

The presence of Class II donor-specific HLA alloantibodies (DSA) in serum (A) did not change the risk of renal acute cellular rejection (ACR) and (B) increased the risk of renal acute antibody-mediated rejection (AMR). The increased risk (C) of liver allograft rejection was abated with (D) antibody induction, but this did not improve the overall impaired survival. (Reproduced with permission: O'Leary JG, et al American Journal of Transplantation 2013 (21).)

Importantly, antibody binding is largely stochastic and influenced by antigen and antibody density. Class I HLA is constitutively expressed on all cells within the liver, whereas Class II HLA is limited largely to subsets of resident hematolymphoid cells in normal livers. Inflammatory, infectious or ischemic injury can up-regulate Class II HLA within the liver, including the portal capillary microvascular endothelia, thereby resulting in variable antigen density. As with other organs (but more pronounced because of the liver's size), secretion of soluble HLA Class I and II antigens can neutralize DSA by forming immune complexes that are cleared by Kupffer cells, thereby augmenting antibody-mediated injury. The renal peritubular capillary bed is one-hundredth (0.21 m) that of the liver (21 m) in area, and the concentration of bound antibody within the liver allograft is therefore diluted. Although the size of the liver may mitigate the effect of preformed DSA, the impact is likely spectral.

Despite a lack of randomized controlled trials, the available literature consistently documents inferior outcomes in patients who undergo simultaneous liver–kidney transplantation (SLKT) when high MFI Class II DSA is present. Because the most effective treatment of AMR is avoidance, patients who undergo SLKT should ideally receive organs without Class II antigens against which the recipient has DSA with an MFI >10 000. However, the risks of waiting versus the risks of proceeding must always be critically evaluated in an era when the average Model for End-Stage Liver Disease score at transplantation is continually increasing. When patients must receive crossmatch-positive organs, postoperative testing to determine persistence of antibody and close follow-up with a low threshold for allograft biopsy seems prudent, although the precise testing interval and threshold for biopsy are not yet determined.

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