The Impact of Non-Donor-Specific HLA Antibodies on Antibody-Mediated Rejection in Pediatric Kidney Transplant Recipients

Abstract

While the pathogenic role of donor-specific anti-HLA antibodies (DSAs) in long-term immune-mediated injury after kidney transplantation is well established, the clinical relevance of non-donor-specific antibodies (nDSAs), also detected in transplant recipients, remains a subject of debate. This retrospective study evaluated the prognostic value of nDSAs in 92 pediatric kidney transplant recipients (89.1%, 9.8%, and 1.1% for first, second, and third transplants, respectively) at the University Hospital of Padua between January 2015 and December 2022, investigating the association between antibody development and clinical outcomes, including graft function, rejection episodes, and viral infections. Clinical, immunological, virological, and histopathological data were collected at 6, 12, and 24 months post-transplant. Antibody prevalence increased over time, with nDSAs being more frequent than DSAs at all timepoints. The combined presence of DSAs and nDSAs significantly increased the risk of ABMR (HR = 45.10; p < 0.001). Isolated nDSAs and DSAs were also associated with an increased risk of ABMR (HR = 6.43 and 12.10, respectively), suggesting a synergistic alloimmune effect. Viral infections also emerged as relevant cofactors in humoral alloimmunity. EBV viremia and intrarenal Parvovirus B19 (PVB19) infection were significantly associated with ABMR, with PVB19 also correlating with nDSA formation. In conclusion, integrated immunological and virological monitoring may support risk stratification and guide individualized post-transplant management. Larger multicenter studies are warranted to define the long-term impact of nDSAs in pediatric kidney transplantation.

Keywords: antibody-mediated rejection; mean fluorescence intensity; non-donor-specific antibodies; pediatric kidney transplantation; viral infections.

Figure 1

Trends in kidney function and proteinuria after pediatric kidney transplantation. Median estimated glomerular filtration rate (eGFR, blue line) and proteinuria (red line) at 6, 12, and 24 months post-transplant. Error bars represent interquartile ranges. While eGFR remained stable over time (p = 0.963), proteinuria significantly increased (p = 0.013).

Figure 2

(A) Distribution of estimated glomerular filtration rate (eGFR) at 6 months and (B) proteinuria at 24 months post-transplantation, stratified by ABMR status. Boxplots show median, interquartile range, and individual values. Blue = ABMR negative; red = ABMR positive.

Figure 3

Bar chart showing the prevalence of non-donor specific antibodies (nDSAs), donor-specific antibodies (DSAs), and combined positivity at baseline, 6, and 24 months post-transplant among 92 patients with available antibody testing. Values are reported as percentages.

Figure 4

Boxplots showing the maximum mean fluorescence intensity (MFI) values for non-donor specific anti-HLA antibodies (nDSAs, left) and donor-specific antibodies (DSAs, right), stratified by the presence of antibody-mediated rejection (ABMR). Higher MFI levels were observed in ABMR-positive patients, suggesting a potential association between antibody strength and the risk of humoral rejection.

Figure 5

Distribution of Banff categories at 6, 12, and 24 months post-transplantation. The figure illustrates the temporal evolution of biopsy findings according to the Banff classification system.

Figure 6

Forest plot in logarithmic scale for ABMR predictors.