Achieving Transplant Excellence through Personalized Medicine

INNOVATION DESIGNED TO IMPROVE OUTCOMES

According to the Scientific Registry of Transplant Recipients (SRTR), the number of pediatric kidney transplants performed annually in the U.S. has remained fairly consistent over the past few years, with programs performing approximately 750 transplants annually.¹ Most important is the achievement of long-term graft function for those children with end-stage kidney disease (ESKD) who are recipients of a transplanted kidney.

Children’s Mercy Kansas City is recognized as one of the top 10 nephrology programs in the nation by U.S. News & World Report, and the kidney transplant program has incorporated a number of innovative practices into their management plan that are designed to enhance patient outcomes.

The program’s personalized approach to meeting each patient’s unique needs — including repeated surveillance biopsies, epitope matching and pharmacokinetic assessment of immunosuppressive medication — has contributed to a 100% three-year patient and graft survival rate for the past six years.

RESEARCH FINDS SURVEILLANCE BIOPSY DETECTS SUBCLINICAL REJECTION

Rejection is responsible for just under 50% of graft loss in the pediatric kidney transplant population. It is well recognized that early identification and treatment of allograft injury may improve survival.

The Children’s Mercy Pediatric Kidney Transplant team, led by Bradley Warady, MD, Division Director, recently published the largest pediatric experience in North America on surveillance biopsies in kidney transplant recipients. As noted in their Pediatric Nephrology publication, the results of the investigation were derived from a practice that was initiated at Children’s Mercy more than a decade ago based on the team’s hypothesis that a protocol surveillance biopsy offers the earliest opportunity for targeted interventions to address potentially modifiable histologic changes in pediatric kidney transplant patients.²

A retrospective review was conducted of 215 kidney surveillance biopsies obtained from 2008 to 2016 in 97 pediatric kidney transplant recipients. Surveillance biopsies were obtained at 6, 12 and 24 months post-transplant as part of the program’s standard of care.

Potentially modifiable histologic findings were seen in 38.1% of all surveillance biopsies. Subclinical rejection was found with increasing frequency across all time points, with an estimated 49% increase in the odds of a subclinical rejection finding per additional six months post-transplantation (aOR 1.49, 95% CI 1.06–2.09, p = 0.022). Among follow-up biopsies in patients who underwent treatment for subclinical rejection, 50% had no subsequent subclinical rejection and 18.8% showed histologic improvement. The complication rate associated with the biopsies was minimal.

The team concluded that surveillance biopsies are safe and offer the opportunity to identify and treat modifiable histologic changes in the pediatric kidney transplant population up to two years after transplantation. Long-term follow-up of these patients will provide valuable data on the impact of this intervention on patient and graft outcome.

THE ROLE OF EPITOPE MATCHING IN TRANSPLANT GRAFT SURVIVAL

Traditional HLA-DR antigen matching historically has been an important criterion when deciding whether or not to accept a particular kidney for transplantation. An HLA-DR mismatch with the first kidney transplant can be associated with less favorable long-term patient outcomes.

To improve donor/recipient compatibility, Children’s Mercy, in collaboration with the Midwest Transplant Network, has implemented a paradigm shift in its pediatric kidney transplant program for donor selection, incorporating HLA class II epitope matching.

In a study published in Pediatric Transplantation, Children’s Mercy reported how this practice potentially lowers the risk of donor-specific antibody development, in addition to providing enhanced personalized guidance regarding exposure to immunosuppressive medications.³

Further, this data helps guide living-related donor matching, allowing for recommendations for the best match possible when multiple donors (e.g., both parents) are viable candidates.

REDUCING TOXICITY WITH THERAPEUTIC DRUG MONITORING

Though therapeutic drug monitoring is not routine for most pediatric transplant programs, it is at Children’s Mercy. Since July 2010, all pediatric kidney transplant recipients have undergone therapeutic drug monitoring as the standard of care for the anti-rejection drug mycophenolate mofetil.

The patient’s blood samples are collected during the same inpatient visit as when the surveillance biopsies are performed at 6, 12 and 24 months post-transplant. Results provide the transplant team with individualized data, helping them optimize therapy to improve graft and patient survival.

In fact, the team has concluded that a fixed dosing regimen for mycophenolate mofetil results in unpredictable systemic exposure, while individualized dosing based on therapeutic drug monitoring targets drug exposure, helping effectively balance the risks of rejection versus toxicity in pediatric kidney transplant patients. Publication of the Children’s Mercy experience is forthcoming.

PERSONALIZED MEDICINE IMPACTS PATIENT OUTCOMES

Children’s Mercy has been performing kidney transplants for more than 30 years with outcomes that exceed national averages. One- and three-year allograft survival rates are 100%. In fact, the program’s graft and patient survival rates have been 100% since 2014.

Another SRTR metric, which complements the graft survival rate, is the hazard ratio — the relative risk of a program losing an organ within three years as compared to other programs across the country. This year, the hazard ratio places Children’s Mercy as one of the top two programs in the country.

Dr. Warady and the transplant team believe the level of personalized medicine the Children’s Mercy program has implemented as the standard of care has impacted these results, providing insights into steps that other programs could take to achieve similar patient outcomes.

REFERENCES

1 Scientific Registry of Transplant Recipients. OPTN/SRTR 2018 Annual Data Report: Kidney. Website accessed 9/3/2020: https://srtr.transplant.hrsa.gov/annual_reports/2018/Kidney.aspx.

2 Odum JD, Kats A, VanSickle JS, et al. Characterizing the Frequency of Modifiable Histological Changes Observed on Surveillance Biopsies in Pediatric Kidney Allograft Recipients. Pediatr Nephrol (2020).https://doi.org/10.1007/s00467-020-04624-1.

3 Bryan CF, Chadha V, Warady BA. Donor Selection in Pediatric Kidney Transplantation Using DR and DQ Eplet Mismatching: A New Histocompatibility Paradigm. Pediatr Transplant, 20: 926–930. DOI:10.1111/petr.12762.

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