Protocol biopsy‐driven interventions after pediatric renal transplantation

The clinical significance of subclinical rejection detected by protocol biopsies is controversial. Several studies report progression to interstitial fibrosis and poor graft survival rates in patients with subclinical rejection (1–3), while others did not find this to be a precursor to graft failure (4– 6). Scholten et al. (6) provided evidence that untreated subclinical rejection did not lead to interstitial fibrosis or loss of graft function. In contrast, Nickerson et al. (7) found that treatment of early subclinical rejection reduced the risk for having late clinical rejection episodes and led to improved graft outcomes at two yr posttransplant. There are few pediatric studies that address the assumption that without protocol biopsies, subclinical rejection would go undetected and result in inferior graft outcomes. In support of this hypothesis, Seikku et al. (8) retrospectively compared pediatric recipients receiving protocol biopsies to a historical control group. Subclinical rejection at three months was detected and treated in 39%. The biopsy group experienced fewer acute rejection episodes, and GFR was significantly higher at 18 months compared to controls (87 vs. 68 mL/min/1.73 m). However, these findings are suspect because of retrospective nature of this study and its failure to control for differences in immunosuppression and HLA mismatches among protocol biopsy patients and the control group. In the recent issue of Pediatric Transplantation, Kanzelmeyer et al. (9) prospectively compared 57 pediatric transplant recipients who underwent protocol biopsies at six months to a control group of 51 patients without protocol biopsies. The study was not randomized but unlike the previous study (8), both groups were transplanted during the same period, and HLA mismatches, cold ischemic times and donor age were also similar in both groups. Patients with subclinical rejection (15%) were treated with increased immunosuppression. GFR was similar at 1.5 and 2.5 yr, but by 3.5 yr the protocol biopsy group demonstrated better renal function than the control group. This longer period of review suggests that extended periods are needed to detect the benefits of early subclinical rejection. However, it is uncertain why a single protocol biopsy at six months would not show benefits until 3.5 yr after transplantation and not earlier. Alternatively, the use of lower doses of calcineurin inhibitors in the protocol biopsy group may account for this observation. Additionally, the incidence of subclinical rejection (15%) was relatively low when compared to other pediatric studies (6, 10, 11) which further casts doubts on the conclusion that allograft renal function at 3.5 yr was influenced by intervention for early subclinical rejection. Kanzelmeyer et al. should be given credit for performing a prospective study and comparing two groups that are similar for HLA mismatches, cold ischemic times and donor age. However, their findings that appear to justify the use of early protocol biopsies are problematic because of the reasons stated above. As Kanzelmeyer et al. concluded, future randomized prospective studies are need to address significance of early subclinical rejection and therapeutic interventions. Clearly, implementing the same immunosuppression regimen in both the protocol biopsy and control groups is also required in such studies.