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3d illustration of a constricted and narrowed artery

dnDSA and African American ethnicity linked with thickening of blood vessels after kidney transplant

3d illustration of a constricted and narrowed artery

Emerging evidence links dnDSA with increased risk of accelerated systemic hardening of the arteries (arteriosclerosis) and major cardiac events in adult organ transplant recipients. However, this phenomenon has not been studied extensively in children who receive kidney transplants.

Children who developed anti-human leukocyte antibodies against their donor kidney, known as de novo donor-specific antibodies (dnDSA), after kidney transplant were more likely to experience carotid intima-media thickening (CIMT) than those without these antibodies, according to preliminary research presented May 7, 2019, during the 10th Congress of the International Pediatric Transplant Association.

dnDSA play a key role in the survival of a transplanted organ. While human leukocyte antibodies protect the body from infection, dnDSA are a major cause of allograft loss. CIMT measures the thickness of the intima and media layers of the carotid artery and can serve as an early marker of cardiac disease.

Emerging evidence links dnDSA with increased risk of accelerated systemic hardening of the arteries (arteriosclerosis) and major cardiac events in adult organ transplant recipients. However, this phenomenon has not been studied extensively in children who receive kidney transplants.

To investigate the issue, Children’s researchers enrolled 38 children who had received kidney transplants and matched them by race with 20 healthy children. They measured their CIMT, blood pressure and lipids 18 months and 30 months after their kidney transplants. They monitored dnDSA at 18 months and 30 months after kidney transplant. The transplant recipients’ median age was 11.3 years, 50 percent were African American, and 21% developed dnDSA.

“In this prospective controlled cohort study, we compared outcomes among patients who developed dnDSA with transplant recipients who did not develop dnDSA and with race-matched healthy kids,” says Kristen Sgambat, Ph.D., a pediatric renal dietitian at Children’s National who was the study’s lead author.  “Children with dnDSA after transplant had 5.5% thicker CIMT than those who did not have dnDSA. Being African American was also independently associated with a 9.2% increase in CIMT among transplant recipients.”

Additional studies will need to be conducted in larger numbers of pediatric kidney transplant recipients to verify this preliminary association, Sgambat adds.

10th Congress of the International Pediatric Transplant Association presentation:

  • “Circulating de novo donor-specific antibodies and carotid intima-media thickness in pediatric kidney transplant recipients.”

Kristen Sgambat, Ph.D., pediatric renal dietitian and study lead author; Sarah Clauss, M.D., cardiologist and study co-author; and Asha Moudgil, M.D., Medical Director, Transplant and senior study author, all of Children’s National.

antibodies-illustration

Detecting and treating dnDSA early preserves allograft function

antibodies-illustration

Monitoring and treating de novo donor-specific antibodies (dnDSA) before they could cause graft damage helped to decrease dnDSA in a majority of pediatric kidney transplant recipients at Children National Health System and prevented graft failure in the first few years.

Development of de novo donor-specific antibodies (dnDSA) is known to cause graft failure. Therefore, a protocol aimed at prospective monitoring and treating dnDSA – before they can cause graft damage – was developed for kidney transplant recipients at Children National Health System. This helped to decrease dnDSA in 76 percent of pediatric patients and prevented graft failure in the first few years, indicates a longitudinal cohort study published online Jan. 22, 2018, in Pediatric Transplantation. However, the benefit of preserving function of transplanted kidneys came at a price: Heightened hospitalization rates for infection.

An estimated 20 percent to 30 percent of children develop dnDSA and many of these patients go on to develop allograft failure after three to six years, write the study authors.

Clinical signs of graft failure due to antibodies appear too late to safeguard long-term graft survival. According to the study authors, developing earlier methods to detect dnDSA offers the opportunity to intervene before irreversible graft injury occurs.

“Children’s National Health System instituted a routine protocol that standardizes monitoring and treatment of dnDSA,” says Asha Moudgil, M.D., FASN, associate chief of the Division of Nephrology at Children’s National and the study’s senior author. “We followed this protocol as we monitored and treated all children younger than 19 who received a kidney transplant at Children’s National from Jan. 1, 2008, to Dec. 31, 2013.”

After transplant, these children were monitored for development of dnDSA at six months and then yearly. Upon detection of DSA, these children underwent kidney biopsy to assess for acute rejection. Additionally, monitoring was intensified to every two months.

“Our patients did not have a statistically significant increase in graft loss or dysfunction, suggesting that early and targeted treatment of dnDSA may benefit patients,” says Asha Moudgil, M.D., FASN.

Sixty-seven of the 72 children who received kidney transplants during that six-year period were included in this retrospective analysis. Their mean age was 14.1 years. Acute cellular rejection was treated according to a prespecified protocol.

  • The team treated de novo DSA with high-dose intravenous immunoglobulin (IVIG) if antibody titers were low and added two doses of rituximab to that treatment regimen if antibody titers were high.
  • If either C1q binding of immunodominant DSA was present or C4d+ were seen on biopsy, six sessions of plasma exchange were added to the above protocol.
  • Kids who were resistant to such treatment approaches received an additional four doses of IVIG monthly.

Nearly 39 percent of the children developed dnDSA within a median of 1.36 years. Ten of these 26 children had increased creatinine, 12 had new onset proteinuria and six had newly diagnosed hypertension at the time the dnDSA was detected. The multivariate analysis found that the coefficient of variance of tacrolimus, which measures adherence to immunosuppressive drugs, was the only statistically significant predictor for developing dnDSA.

DSA-positive patients had a higher rate of admissions (1.23 hospital admissions for infectious- or immunosuppressive-related side effects per patient, compared with 0.59 hospital admissions for the DSA-negative patients), which the study team attributes to aggressive treatment of dnDSA.

“Our patients did not have a statistically significant increase in graft loss or dysfunction, suggesting that early and targeted treatment of dnDSA may benefit patients,” Dr. Moudgil adds. “There was a higher risk of treatment-related complications, however, and this risk must be balanced against the short-term benefit of prolonging allograft function.”

Study co-authors include Olga Charnaya, M.D., a Children’s fellow when the study was designed and the article was drafted, now at Johns Hopkins; and Children’s Nephrologist, Shamir Tuchman, M.D.