January 2020, Volume XXXIII, No 10

Nephrology

Transplanting HCV-infected kidneys

A promising new source of donors

n July 26, 2019, Hennepin County Medical Center transplanted a hepatitis C (HCV)-infected kidney into a 54-year-old man with end-stage renal disease who did not have HCV. Although kidney transplants between HCV nucleic acid test positive (NAT) donors and HCV-negative recipients have been performed previously in a handful of other states, this was the first one performed in Minnesota. In this article, we will describe how this type of transplant can benefit waitlisted patients by increasing the number of kidneys available for transplant.

The deceased donor waitlist

Why would patients knowingly consent to being infected with HCV? The reason is that they likely will get transplanted sooner. Approximately 95,000 people in the U.S. are waiting for a kidney transplant, 2,155 of whom live in Minnesota. Due to a critical shortage of organ donors, wait times are long. Historically, the average wait time in Minnesota for a kidney transplant from a deceased donor with a non-high kidney donor profile index (a numerical measure that combines ten donor factors, including clinical parameters and demographics) was five years. However, wait times in Minnesota have been increasing, and currently it is not uncommon for candidates with O and B blood types to wait up to six–seven years, respectively (A and AB blood types have significantly shorter wait times).

There are several published risk prediction models that can give patients personalized estimates of their probability of being transplanted in a certain time frame at their center. Using one commonly cited model developed by Hart and colleagues at the Scientific Registry of Transplant Recipients (http://www.srtr.org), a 60-year-old Caucasian woman who is an O blood type and has co-morbidities of diabetes mellitus, hypertension, and end-stage renal disease with initiation of dialysis two months ago has only a 13% chance of being transplanted in five years in Minnesota, compared to a 45% chance of still waiting and a 42% chance of being too sick or having died on the wait list.

Candidates who agree to receive an HCV-infected kidney experience shorter wait times to transplant.

Although living donor transplant or being waitlisted in a region of the U.S. such as Florida, which has shorter wait times, would increase a patient’s chance of being transplanted, these are not viable options for most candidates, as two-thirds do not have living donors and most do not have the financial resources to travel to a center out of state.

As a result, a large number of patients on the kidney transplant wait list will end up never being transplanted.

Treatment of hepatitis C with direct acting antivirals

Until a few years ago, most kidneys from donors with HCV were either discarded or never procured, resulting in the loss of thousands of potential transplants. The reason these kidneys were underutilized was because effective HCV treatments were not available. Pegylated interferon alpha and ribavirin, which was the standard of care for HCV in that era, was associated with low cure rates of around 40% and numerous debilitating side effects. In addition, use of interferon after a kidney transplant increased the risk of acute rejection. Chronic HCV after renal transplant was associated with poor outcomes, including transplant glomerulopathy, post-transplant diabetes, and de novo glomerulonephritis. Hence, transplant of HCV-positive kidneys was limited to patients who already had chronic HCV, and even then this type of transplant was infrequently performed.

The advent of the direct acting antivirals (DAAs) fundamentally changed how HCV is treated. Telaprevir and boceprevir were the first DAAs released in 2011, but it wasn’t until ledipasvir/sofosbuvir in 2014 when cure rates were substantially better compared to interferon-based therapies. Cure of HCV is defined as achievement of a sustained virologic response 12 (SVR12), which is the absence of detectable viremia 12 weeks after completion of the DAA course. DAAs work by inhibiting key proteins (NS5A, NS5B, NS3) involved in the replication of the virus. Treatment durations are eight to 12 weeks and patients report relatively few side effects. There are currently nine Food and Drug Administration-approved DAA regimens with studies reporting SVR12 rates over 90%, even in hard-to-treat populations such as dialysis and transplant patients.

Benefits of HCV NAT-positive donor to HCV-negative recipient kidney transplant

The availability of an effective treatment for HCV led members of the transplant community to explore transplanting kidneys from HCV NAT-positive donors into HCV-negative recipients, followed by DAA treatment post-transplant. The advantages with such a strategy are several-fold:

Wait time reduction. Candidates who agree to receive an HCV-infected kidney experience shorter wait times to transplant. In their 2018 study in the Annals of Internal Medicine, Reese et al reported a median wait time of 57 days between listing for an HCV-positive kidney and transplant. The patient described above transplanted at our center after a wait of 20 days. Although wait times are expected to increase as more patients opt in for HCV-positive kidneys and “compete” for the same kidneys, it is likely that they still will experience shorter wait times compared to waiting for an HCV non-infected kidney.

High quality organs. Patients who agree to an HCV-infected kidney might end up receiving a higher quality kidney than they would with a HCV-negative kidney. According to the CDC, the opioid epidemic is responsible for the increased incidence of HCV since 2010. The majority of these new HCV cases are due to intravenous drug use in persons less than 30 years old, and this is reflective in the changing demographic of deceased donors.

According to a 2017 study by Levitsky et al in the American Journal of Transplantation, the median age of deceased donors with HCV has been decreasing since 2012 and was 36 compared to 41 for HCV-negative donors in 2016. Given that HCV-infected donors are younger, they are likely to have fewer co-morbid conditions such as hypertension and diabetes mellitus that may adversely affect kidney function. Kidneys transplanted from these patients may last longer.

High SVR12 rates. Two studies published in 2018 in the Annals of Internal Medicine demonstrated that this type of transplant was safe and efficacious. In the EXPANDER study, 100% SVR12 rate was seen in 10 HCV-negative recipients who received HCV-infected kidneys and were treated empirically with grazoprevir/elbasvir post-transplant. The THINKER-2 study also reported a 100% SVR12 mark in 20 HCV-noninfected patients transplanted with HCV-positive kidneys receiving grazoprevir/elbasvir upon HCV seroconversion.

Cost effective. Dialysis is an expensive treatment, costing about $95,000 a year per patient. Transplanting a patient sooner with an HCV-infected kidney can decrease societal end-stage renal disease health costs by reducing the time spent on dialysis. Gupta et al, in a 2018 American Journal of Transplantation study, reported that HCV-positive donor to negative recipient kidney transplantation followed by DAA treatment was less expensive than remaining on dialysis waiting for a HCV-negative donor, provided the wait time for an HCV-infected kidney was less than 2.5 years.

With all of these potential benefits, it is not surprising that the number of kidney transplants between HCV-infected donors and HCV-noninfected recipients has been increasing from 43 among U.S. transplant centers in 2016 to 338 in 2018.

Given that HCV-infected donors are younger, they are likely to have fewer co-morbid conditions.

Preoperative evaluation and perioperative management

Although there is no universal eligibility criteria among transplant programs for patients to receive an HCV-positive kidney, interested patients typically undergo additional testing beyond what is normally required to be placed on a waitlist. At our transplant center, the pretransplant workup entails a comprehensive hepatic evaluation, including blood work and liver elastography. Patients who are found to have cirrhosis or other chronic liver disease are ruled out. Similarly, patients with human immunodeficiency virus or hepatitis B are not eligible.

Evaluation by a transplant pharmacist is essential, as there are numerous drug-drug interactions between DAAs and commonly prescribed medications. For example, DAAs can significantly increase the levels of various statins, placing an individual at risk for rhabdomyolysis, and may require switching to an alternative agent or a dose reduction before they can be used concurrently. Finally, a prior authorization is submitted to the candidate’s insurance carrier. Although prices are decreasing, the cost of a DAA course still can range between $25,000–$50,000, which most patients cannot afford out of pocket.

In the operating room

The surgical procedure to implant a kidney from a donor with hepatitis C is unchanged from a standard deceased donor kidney transplant. The kidney is placed in the right or left iliac fossa in the retroperitoneal position with anastomoses between the donor renal artery to recipient external iliac artery, donor renal vein to recipient external iliac vein, and donor ureter to recipient bladder. Either basiliximab or anti-thymocyte globulin is used for induction.

Maintenance immunosuppression is identical to kidney transplants from donors without HCV, with the notable exception that cyclosporine is contraindicated with some DAAs. The timing of DAA initiation post-transplant to treat the HCV is variable. Some transplant programs start empirically prior to the transplant, while others start once the recipient has detectable HCV viremia, and some wait until a few months post-transplant. Given that there have been case reports of severe transaminitis from fibrosing cholestatic hepatitis in kidney transplant recipients receiving an HCV-infected kidney with delayed DAA initiation, we recommend starting DAAs as soon as possible post-transplant. Treatment durations are 12 weeks with frequent monitoring of transaminases and HCV viral loads.

Conclusion

Kidney transplantation is the gold standard treatment for end-stage renal disease. However, wait times are long and a significant proportion of waitlisted patients will never undergo a transplant due to a shortage of donors. Transplanting kidneys from HCV-infected donors into HCV-negative recipients followed by treatment with DAAs with intent to cure is a novel strategy that can, potentially, significantly shorten a candidate’s wait time to transplant and allow more patients to receive a transplant by reducing the organ discard rate. Although the collective experience with this type of kidney transplant is brief, short-term allograft outcomes appear good and should be considered in select transplant candidates.

Jeffrey H. Wang, MD, is a staff nephrologist with Hennepin Healthcare. He completed his nephrology fellowship at the University of Michigan and practices at the Transplant Center at Hennepin County Medical Center in Minneapolis.

Paul A. Stahler, MD, FACS, is a transplant surgeon at Hennepin Healthcare. He graduated from the University of Minnesota Medical School and completed his general surgery residency at Hennepin Healthcare. He completed his transplant surgery fellowship at the University of Wisconsin-Madison. 

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Paul A. Stahler, MD, FACS, is a transplant surgeon at Hennepin Healthcare. He graduated from the University of Minnesota Medical School and completed his general surgery residency at Hennepin Healthcare. He completed his transplant surgery fellowship at the University of Wisconsin-Madison.