Transplantation of Kidneys from HCV-Positive Donors: How to Best Use a Scarce Resource
Authors: David Roth, Marco Ladino
Journal: Journal of the American Society of Nephrology (2017)

After the discovery of the hepatitis C virus (HCV) in 1989 and the availability of an ELISA to detect anti-HCV antibody, reports soon appeared documenting the transmission of HCV with kidney transplantation.1,2 Accompanying the demonstration of disease transmission were data reporting the development of an aggressive form of chronic cholestatic hepatitis in some patients associated with poor outcomes. In an era in which there were no safe and effective treatments for HCV, the use of kidneys from HCV-infected donors was discouraged, and kidneys from positive donors were either not harvested or discarded. Fast forwarding 25 years brings us into the current era of the direct-acting antiviral agents (DAAs), a class of drugs that has dramatically altered the landscape of HCV infection and brought the possibility of cure within reach for most patients. Phase 3 clinical trials in the general population showing cure rates exceeding 90% have been followed by reports that focused on the treatment of HCV-infected patients with CKD or ESRD and after kidney transplantation.3 These studies unequivocally showed that DAAs are now available that are safe and effective in patients with advanced CKD or after transplantation. Caution should be exercised, however, when selecting a DAA for a patient with advanced CKD, because sofosbuvir-based regimens have been associated with worsened kidney function, increased proteinuria,4 and collapsing glomerulopathy.5 The availability of alternative DAAs that are safe and effective in patients with CKD has enabled clinicians to challenge the boundaries of what was previously considered acceptable and study the safety and outcomes of transplantation of kidneys from HCV-infected donors into HCV-positive as well as uninfected transplant candidates. Encouraging reports from studies using DAAs in HCV-infected kidney transplant recipients heightened interest in exploring the possibility of transplanting kidneys that had been harvested from HCV-infected donors. Any discussion surrounding transplanting a kidney from an HCV-infected donor must be framed within several overarching realities. The first is that the number of patients on deceased donor kidney waiting lists is steadily increasing. This has translated into waiting times that exceed 5–7 years in parts of the country, creating the stark reality that some patients will die before ever being offered the opportunity of transplantation. The second is that we are in the midst of a serious injection drug epidemic in the United States. As a direct consequence, there has been a surge in the number of anoxic brain-dead donors, many of whom are infected with HCV. A steady increase in the number of offers for kidneys from these HCV-infected donors has been occurring over the last several years. The third is the premise of primum non nocere or "first, do no harm." Any institution that develops a patient care plan that includes knowingly transmitting an infectious disease to a patient must do so with complete confidence that health care delivery systems are in place that will guarantee the patient timely access to expensive and often tightly controlled DAAs that have been conclusively shown to be highly effective, such that the risk-to-benefit ratio remains unquestionably in the patients favor. The increasing availability of kidneys from HCV-infected donors was highlighted by Reese et al.6 They emphasized that most of these kidneys either were not being harvested or were ultimately discarded and not transplanted. Their paper challenged the transplant community to develop a paradigm, whereby these kidneys could be successfully transplanted followed by treatment with DAAs in the early post-transplant period. Interestingly, this concept had been previously suggested in a paper by Morales et al.7 from the IFN era that retrospectively reviewed the Spanish experience with transplanting HCV-positive kidneys into HCV-positive recipients. They showed no difference in long-term patient survival; however, information on antiviral treatment was not available. More recently, interest has focused on transplanting kidneys from HCV-infected donors into HCV-infected patients on the waiting list followed by post-transplant DAA therapy (Table 1). Sawinski et al.8 retrospectively identified 40 HCV-positive recipients treated with DAAs post-transplant, 19 of whom had received a kidney from an HCV-positive deceased donor. A sustained viral response (SVR) was reported in 100% of the patients. In a report specifically focusing on positive to positive transplant, Bhamidimarri et al.9 reported an SVR of 96% in 25 HCV-infected patients who received a kidney from an HCV-positive donor followed by early initiation of DAA therapy post-transplant. Both studies highlighted the dramatically shortened wait time to receive a kidney from an HCV-positive donor and the need for close monitoring of calcineurin inhibitor levels as the virus is being cleared from the liver.8,9 Table 1. - Transplanting kidneys from HCV-positive donors in the DAA era Study No. of Patients HCV Status SVR,% Time DAA Initiated Donor Recipient Sawinski et al. 8 19 Positive Positive 100 Median of 1123 d post-transplant Bhamidimarri et al. 9 25 Positive Positive 96 Median of 125 d post-transplant Goldberg et al. 10 10 Positive Negative 100 When viremia was detected (approximately 3 d) Durand et al. 11 8 Positive Negative 100 Immediately pretransplant Two recently completed small trials have expanded the scope of using kidneys from HCV-infected donors by testing the feasibility and safety of transplanting a kidney from an infected donor into an HCV-negative recipient (Table 1). The Transplanting Hepatitis C Kidneys into Negative Kidney Recipients (THINKER) Trial followed ten HCV-negative patients who were transplanted with a kidney from an HCV genotype 1–infected donor.10 By protocol design, DAAs were not initiated until viremia was detected post-transplantation, which was generally around postoperative day 3. All ten recipients became viremic and went on to obtain an SVR after 12 weeks of DAA treatment. In the Exploring Renal Transplants Using Hepatitis C Infected Donors for HCV-Negative Recipients Trial, eight HCV-negative patients were transplanted with kidneys from HCV-positive donors. In contrast to the THINKER Trial, DAA treatment was initiated preoperatively on the way to the operating room. In accordance with outcomes in the THINKER Trial, all patients cleared the viremia and attained an SVR after 12 weeks of DAA therapy.11 Of interest, both of these studies confirmed that HCV is highly transmissible with kidney transplantation, which was first reported >25 years ago.1,2 These novel trials have pushed the boundaries further and set the stage for larger studies to test this hypothesis and definitively show safety. These results also raise the question as to whether different techniques of kidney preservation might be relevant when considering transplantation of a kidney from an HCV-infected donor. It was shown many years ago that pulsatile perfusion of the kidney before transplant removed substantial quantities of HCV in the perfusate and lowered viral load in tissue obtained from sequential biopsies of the kidney.12 Differences in organ preservation technique and the subsequent magnitude of the viral load accompanying the kidney were suggested as an explanation for the substantial variance in transmission rates reported by the New England Organ Bank1 and the Miami group2 that had been routinely using pulsatile perfusion. Intuitively, it would seem appropriate to lower the viral load being delivered to the recipient, and these data should be considered when designing a treatment paradigm for the transplant of kidneys from HCV-infected donors to negative recipients. Sadly, with a steady supply of kidneys from HCV-infected donors likely to continue for the foreseeable future, it is incumbent on the transplant community to determine how best to use these organs. Recent estimates are that approximately 6.2% of waitlisted patients are HCV positive.13 Intuitively, it seems most appropriate to offer priority for transplantation of kidneys from HCV-positive donors to this group of already infected patients awaiting transplantation. These patients are very likely to be treated with DAAs at some point, and by using this strategy, the patient will be transplanted sooner without incurring any additional cost of drug acquisition. If an HCV-negative patient was to receive a kidney from a positive donor, we must balance the economic and health advantages gained by removing a patient from maintenance dialysis against the high cost of the DAAs that are necessary to prevent transmission and the potential risk for iatrogenic transmission of a disease that might not respond as expected to antiviral therapy. The latter is of particular concern in the context that HCV genotype 3 is far more prevalent in injection drug users. Clinical trials have shown that this has been the genotype most difficult to treat with DAA therapy. Fortunately, several pangenotypic DAA combinations have now been approved, and therefore, this gap in therapy should be successfully closed. Until such time as the population of HCV-infected patients waiting for a kidney is nearly depleted, it would seem prudent to transplant kidneys from positive donors to positive patients. Exceptions to this premise would always be possible (for example, in a status 5 patient in urgent need of transplantation). As stated by the HCV Consensus Conference of the American Society of Transplantation, transplantation of organs from HCV-positive donors into HCV-negative recipients must be conducted under institutional review board approval with a detailed consent.14 Those of us involved in transplantation clearly recognize that the wastage of such a scarce resource must be avoided whenever possible; however, the premise of primum non nocere must also influence our clinical decision making. As is always the case, appropriate caution and reliance on solid clinical evidence will guide us as we move forward with efforts to identify additional sources of donor kidneys to meet the ever-growing need of our patients. Disclosures D.R. is on scientific advisory boards for Merck Co. and Abbvie. D.R. is a consultant for Merck Co. and Abbvie.