An organ transplant entails the surgical transfer of a donor organ to a recipient whose own organ has become impaired and is typically performed to address conditions that do not readily respond to other therapies. In 2020, the Organ Procurement and Transplantation Network reported more than 39,000 total organ transplants performed in the United States, of which kidney transplants comprised close to 60 percent (OPTN, 2023).
Matching blood type has long been recognized as greatly diminishing the risk of immune-mediated rejection and has consequently formed a critical consideration in organ transplantation (Mohamed et al., 2021). Rejection refers to the process wherein the recipient’s immune system recognizes the transplanted organ as foreign and launches a destructive response. Often, rejection can result in a range of complications, including graft failure and reduced patient survival (Naik & Shawar, 2022). Transplantation across incompatible blood types has been known to result in hyperacute rejection, which is caused by antibodies in the recipient’s blood that attack the transplanted organ’s blood vessels. In modern organ transplantation, the use of ABO typing—a method used to determine a person’s blood type based on the presence of antigens and antibodies in their blood—has significantly reduced the likelihood of hyperacute rejection (Mohamed et al., 2021).
Similarly, human leukocyte antigen (HLA) mismatching has historically been considered one of the most important factors in kidney transplantation (Gilks et al., 1987). HLA molecules are proteins found on the surface of cells that play a role in enabling the immune system to distinguish between self and non-self. HLA molecules are highly polymorphic, meaning they vary greatly between individuals, and their variation has been associated with an increased risk of organ rejection after transplantation (Alelign et al., 2018; Lim et al., 2016). To mitigate the risk of rejection, transplant centers typically aim to optimize the HLA match between the donor and recipient (Zachary & Leffell, 2016). Likewise, the Organ Procurement and Transplantation Network has developed a renal allocation calculator that heavily considers HLA mismatches in assigning scores for transplant candidates, citing an aim to reduce the risk of rejection and “increase the efficiency of organ allocation” by screening for compatible donors (CPRA Calculator – OPTN, 2023).
However, with advancements in immunosuppressive medications—which can reduce the risk of rejection in the absence of a perfect HLA match—HLA matching is no longer considered the sole determinant of transplant success (Su et al., 2004). Other factors, such as organ size and quality, recipient age, and donor health, have been found to be equally, if not more, critical in determining the success of a kidney transplant. One study found that the size match between the donor and recipient more significantly influenced graft status than did HLA mismatches, noting that 0 HLA mismatches and a suboptimal size match correlated with “poor patient and graft survival,” while an optimal size match “mitigated the risk of graft loss seen with 6 HLA MM” (Vinson et al., 2019). Another study observed that time spent on dialysis more effectively predicted graft survival than the number of HLA mismatches, noting that included “recipients of matched kidneys spent a significantly shorter average time on dialysis,” which resulted in a “survival benefit … independent of [HLA] matching status” (Gramlick et al., 2022).
Upon examining data regarding kidney transplants performed in 1998, a study also found that the risk of graft failure was comparable across recipients with 0-5 HLA mismatches and only significantly increased for those with 6 mismatches. This study also established a strong association between factors such as donor age and prolonged cold ischemia time with an increased risk for graft failure (Su et al., 2004). Cold ischemia time refers to the period of time during which an organ, such as a kidney, is kept cold and without blood flow before transplantation; this time begins when the organ is removed from the donor and placed in cold preservation solution and ends when the organ is transplanted into the recipient. The detrimental effect of prolonged cold ischemia time on graft survival in spite of few HLA mismatches was corroborated in a later study (Vinson et al., 2020).
Though additional studies have observed that HLA matching helps to diminish the risk of rejection, there exists a growing trend towards reduced emphasis on strict matching in recent years. HLA matching, once a cornerstone of the kidney transplant, has lessened in significance with the advancement of medicine and the emergence of other relevant factors. Developments in immunosuppressive medications have made it possible to expand the pool of potential donors and provide more patients with life-saving transplants, and other variables have been identified as being more significant to graft survival than HLA mismatches. Furthermore, several of these variables, such as prolonged cold ischemia time, have the potential to be mitigated appropriately, which signals a promising future for kidney transplantation unaccompanied by the restrictive considerations of stringent HLA matching.
