Dr. Nancy Rodig - Pediatric Kidney Transplantation: Challenges, Advances, and Future Directions
With Dr. Nancy Rodig · hosted by Dr. Em Gootee
Chapter 1 of 10 · Fundamentals
Introduction
Introduction of Dr. Nancy Rodig
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What the experts said
Five-year patient survival for pediatric kidney transplant is greater than 94%.
Ten-year graft survival is approximately 78% for living donor kidney transplants and 57% for deceased donor transplants in pediatric recipients.
For infants and neonates who develop end-stage kidney disease and are supported with dialysis, the likelihood of reaching transplant is approximately 60%; 40% will die due to complications of dialysis.
Adolescents transplanted at ages 12-17 have outcomes only better than recipients over 65 years of age at 5 and 10-year marks, despite receiving the highest quality donor organs.
Acute rejection incidence in the first year after transplant has decreased from more than 50% in the late 1980s to approximately 10-15% in 2007-2010 and remains flat at that level currently.
The slope of late rejection (beyond one year post-transplant) has remained essentially unchanged over decades, with parallel slopes across different eras, severely impacting long-term allograft function.
In complement-mediated HUS, 30-50% of patients have identifiable mutations in complement regulation; the majority are loss-of-function mutations in liver-produced proteins (complement factor H or I).
Before availability of complement inhibitors, patients with complement-mediated HUS due to loss-of-function mutations required combined liver-kidney transplants.
Eculizumab and ravulizumab (complement C5 inhibitors) prevent development of end-stage renal disease when initiated early in complement-mediated HUS and permit kidney-only transplant without risk of recurrent disease.
Patients on complement inhibitors have increased risk for encapsulated bacteria, particularly meningococcus, requiring vaccination, indefinite prophylaxis, and immediate ER evaluation for any fever.
Primary hyperoxaluria type 1 accounts for approximately 80% of primary hyperoxaluria cases and is caused by pathologic variants in the hepatic enzyme alanine-glyoxylate aminotransferase (AGT).
When GFR falls below 30-40 mL/min in primary hyperoxaluria, oxalate builds up in blood and exceeds supersaturation threshold of 30-50 micromoles/L (normal is 1-3), causing systemic deposition in bones, heart, retina, and skin.
Children with primary hyperoxaluria require hemodialysis 6 days per week (not 3 days like typical patients) because peritoneal dialysis provides insufficient oxalate clearance; dialysis must start earlier (GFR 30-40) rather than typical threshold of GFR <10.
Primary hyperoxaluria is diagnosed after kidney transplant in approximately 4-10% of cases when nephrocalcinosis or stones develop in the transplanted kidney.
Small interfering RNA therapeutics targeting hepatocytes silence genes upstream of mutated AGT, dramatically reducing oxalate production and enabling kidney-only transplants in primary hyperoxaluria type 1.
All kidney transplants in primary hyperoxaluria require native nephrectomies because calcium oxalate stones in native kidneys will eventually pass through the transplanted kidney.
Boston Children's Hospital performed an isolated kidney transplant under siRNA therapy for primary hyperoxaluria in February 2023; patient is doing well with blood oxalate levels below detection.
Serum creatinine is an insufficient biomarker for monitoring kidney health, particularly in small children; a baby with an adult kidney transplant can have 50% reduction in GFR (creatinine rising from 0.2 to 0.4) before significant damage is detected.
Donor-derived cell-free DNA measures the fraction of donor DNA in recipient blood; rising fraction suggests allograft injury and cell breakage, but the test is expensive (thousands of dollars) and detects injury late.
Current immunosuppression regimens at Boston Children's apply essentially one package to all low immunologic risk patients, which does not meet the biological variability of recipients and donor-recipient dyads, resulting in some patients having severe rejection and others having infections and cancer from over-immunosuppression.
Class II donor-specific antibodies (directed at donor HLA) are the biggest problem; they are the critical biomarker for risk of antibody-mediated rejection.
Early rejection (within first year) is most commonly T-cell mediated and can usually be treated successfully; late rejection (after first year) is most commonly antibody-mediated and is very difficult to treat.
Once donor-specific antibodies develop, they are extremely difficult to eliminate; treatments include rituximab, IVIG, bortezumab, tocilizumab, and daratumumab, but once 'the cat's out of the bag,' it's out.
Tacrolimus and cyclosporine are nephrotoxic but remain cornerstones of care because they dramatically reduced acute rejection rates.
Children who lose kidney transplants to antibody-mediated rejection often become highly sensitized (>99% in some cases), making them incompatible with >99% of potential donors and requiring priority on deceased donor lists.
Adults make donor-specific antibodies less frequently than children (11% at 7 years in adults vs 30-50% at 5 years in children), likely because children have more competent immune systems.
Belatacept is a co-stimulatory blockade agent that inhibits T cell activation, proliferation, and cytokine production without the nephrotoxic effects of calcineurin inhibitors; it is used to replace tacrolimus or cyclosporine.
Belatacept is administered as a monthly IV infusion, which reduces pill burden and may improve adherence in adolescents who struggle with daily medication regimens.
Sirolimus (rapamycin) is not nephrotoxic and may have tolerogenic effects, meaning the immune system may develop tolerance to the graft when lymphocytes repopulate under sirolimus after depletion.
The ADVANTAGE trial is an NIH-sponsored randomized controlled trial led by Boston Children's Hospital (PI David Briscoe, protocol chair Eileen Chambers) enrolling across 20 sites, comparing standard care (thymoglobulin, tacrolimus, MMF, steroid-free) to investigational arm (alemtuzumab, belatacept, sirolimus) in low immunologic risk, EBV-positive pediatric kidney transplant recipients.
ADVANTAGE trial primary endpoints are incidence of de novo DSA at 1 year and decline in GFR by >7.5 mL/min/1.73m² at 2 years; secondary objectives assess safety including PTLD, infection, and rejection rates.
ADVANTAGE trial includes extensive mechanistic studies examining urinary biomarkers (to predict graft health before rejection or DSA development), intragraft transcriptomes, and immune cell phenotyping to determine if cells show regulatory or tolerance patterns.
Adolescent transplant recipients likely have worse outcomes primarily due to medication non-adherence related to developing autonomy and conflicts with parents over medication responsibility.
Dr. Joseph Murray performed the first successful long-term kidney transplantation at Peter Bent Brigham Hospital in December 1954 between identical twin brothers; recipient Richard lived 8 additional years and died of causes unrelated to kidney disease.
In 2006-2009 randomized controlled trial, steroid-free immunosuppression protocol was proven safe in low immunologic risk pediatric transplant recipients (first transplant, not sensitized).
In a Paris cohort of ~1000 adults, 7-year allograft survival was much higher in DSA-negative patients compared to DSA-positive patients; DSA-positive patients with biopsy-proven rejection had the worst outcomes.
In European pediatric cohort of ~340 recipients on standard triple immunosuppression, de novo DSA developed in >10% at 1 year and >30% at 5 years (approaching 40% when both class I and II counted); class II DSA conferred nearly 4-fold increased risk for antibody-mediated rejection.
In the adult BENEFIT trial, belatacept showed 43% reduction in risk of death or graft loss at 7 years compared to cyclosporine.
In the BENEFIT trial, estimated GFR in belatacept groups did not decline over 7 years (increased ~0.2 mL/year), while cyclosporine group declined ~2 mL/year.
De novo donor-specific antibody development at 7 years was 11.8% in cyclosporine group vs 3% in low-intensity belatacept group in the BENEFIT trial.
Belatacept in the BENEFIT trial (with MMF and steroids) had higher acute rejection in first year (17-22% vs 7% with cyclosporine) but did not meet non-inferiority criteria; however, belatacept patients who experienced rejection still maintained better GFR than cyclosporine group long-term.
BENEFIT trial showed high risk for post-transplant lymphoproliferative disorder (PTLD), particularly CNS PTLD, restricted to EBV-naive patients; this is now a black box warning, and belatacept can only be used in EBV-seropositive patients.
In Alan Kirk's adult study of alemtuzumab, belatacept, and sirolimus (106 adults), graft survival was 97% at 5 years with well-maintained GFR, acute rejection rate of 6.6% in first year, and belatacept was well-tolerated; however, sirolimus caused oral ulcers in ~30% and proteinuria in ~10%.