Understanding the individual unmet needs of highly sensitized patients awaiting kidney transplant

A person is considered highly sensitized when they have donor-specific antibodies (DSAs) with a broad reactivity against ‘human leukocyte antigens’ (HLAs), found in non-self tissues such as a donor organ. The presence of these antibodies can increase the risk that a transplanted donor organ will trigger an immune response and be rejected. The immune status of highly sensitized patients makes it harder to find an immunologically suitable donor, and they tend to spend a significantly longer time on organ waiting lists having a lower chance of ever receiving a potentially lifesaving kidney transplant.

However, each person in this group is unique, and faces different challenges on their path to transplant. Vincenza Nigro, Hansa Biopharma’s Transplant Franchise Lead, helps us better understand the bigger picture of what it means to be highly sensitized.

Vincenza, why do highly sensitized patients face so many challenges when finding a donor kidney?

Highly sensitized patients can be described as the most immunologically complex individuals on the transplant waiting list, due to their preformed antibodies. These antibodies are the result of previous exposure to HLAs most commonly through pregnancy, transfusions, or previous transplants. Access to transplants for these patients is more limited than for others considered high-risk. Although allocation systems and prioritization programs have improved access to transplantation for highly sensitized kidney patients, many are still disadvantaged and in urgent need of more options.

Donor kidneys, either from living or deceased donors, are never enough to meet the demand, and kidney transplant wait-list management is complex and dynamic. Patients on the kidney waitlist often have multiple risk factors, further complicating organ allocation decisions that weigh both immunologic and nonimmunologic risk factors that can impact outcomes.

So even though highly sensitized patients “climb” the waiting list, they often see donor kidneys being offered to other patients with a less complex immune status?

Exactly. Allocation systems are optimized to balance fairness, equity and utility, to ensure the best possible organ offer. But for those candidates with a broad reactivity against HLAs, the challenges in finding a compatible donor are nearly insurmountable. I’ll put this in numbers. The measure of sensitization used in many countries is called calculated panel reactive antibody (cPRA) and is shown in percentages. The lower the percentage, the lower the sensitization. People with a cPRA of 99.9% (considered ‘very highly sensitized’) have a 1 in 3,000 chance of finding a compatible donor; people with cPRA of 99.99% have a 1 in 30,000 chance, and so forth. In the US, there are thousands of candidates on the waitlist whose transplant rates will remain markedly lower despite national priority. They are disadvantaged because the chances of finding a suitable kidney are almost nonexistent. Equity in access to kidney transplantation is still lacking. We have to offer these patients more options to access kidney transplantation.

Even within the class of those classified as sensitized or highly sensitized, there are significant differences that impact their chances for transplant, right?

Highly sensitized patients can be broadly sensitized against HLA antigens, but it is highly individualized. Some complicating factors can be, for example, ethnicity and gender, which in some cases can further reduce the potential donor pool. Even after the implementation of the new US KAS (Kidney Allocation System), Blacks continue to have limited access to kidney transplantation. In general, Blacks make up ~30% of the candidate waitlist and 50% of those with a cPRA of 99.9%. Likewise, women comprise ~40% of the waitlist and 55% of highly sensitized candidates with a cPRA of 99.9%+.

Even more strikingly, approximately 40% of the candidates with a cPRA of 99.9%+ must wait for over 5 years for a suitable donor, in which time their risk of developing co-morbidities steadily rises.

The highly sensitized (HS) patient population is not a homogeneous group and therefore more personalized and innovative options for these patients are needed.

So, while acknowledging the challenges of highly sensitized patients as a group, we should not forget the bigger picture.

It’s important to raise awareness around the highly sensitized because they form a growing patient group. As of 2022, 10-15% of all of kidney patients on waiting lists in the US and Europe are considered highly sensitized.

But the truth is that every patient is unique, with their own story. Each person’s background is different biologically, medically, and societally, and each experiences their own personal challenges. We must keep striving for complete equity by improving the existing systems and finding new solutions that can help address the medical needs of all, including highly sensitized kidney patients, no matter the challenges.

 

^{Jackson KR, et al. The national landscape of deceased donor kidney transplantation for the highly sensitized: Transplant rates, waitlist mortality, and posttransplant survival under KAS. Am J Transplant. 2019;19:1129-1138.}

^{Schinstock CA, et al. Managing highly sensitized renal transplant candidates in the era of kidney paired donation and the new kidney allocation system: Is there still a role for desensitization? Clin Transplant. 2019;33:e13751.}

^{Maldonado A, et al. Beyond CPRA: Identifying Sensitized Kidney Candidates with Markedly Low Access to Deceased Donor Transplantation by Granular CPRA and Blood Type. OBM Transplantation 2021, Volume 5, Issue 2.}

^{Kulkarni S, et al. Association of Racial Disparities With Access to Kidney Transplant After the Implementation of the New Kidney Allocation System. JAMA Surg. 2019 Jul 1;154(7):618-625.}

^{Ahearn P, et al. Sex Disparity in Deceased-Donor Kidney Transplant Access by Cause of Kidney Disease. Clin J Am Soc Nephrol. 2021 Feb 8;16(2):241-250}

^{Jordan SC, et al. Imlifidase Desensitization in Crossmatch-positive, Highly Sensitized Kidney Transplant Recipients: Results of an International Phase 2 Trial (Highdes). Transplantation. 2021 Aug 1;105(8):1808-1817}