Surveillance biopsies are superior to functional studies for the diagnosis of acute and chronic renal allograft pathology in children

Abstract

In this report of our 3-yr protocol biopsy program, we describe the evolution of acute rejection (AR) and chronic renal allograft nephropathy (CAN) in a cohort of 21 children treated with antibody induction, tacrolimus, mycophenolate mofetil, and prednisone. The aims of this study were to compare the pathogenicity of clinical acute rejection (CAR) and subclinical acute rejection (SAR), and to determine whether functional studies accurately represent acute and chronic renal allograft pathology in pediatric recipients with disproportionately large grafts. Using concurrent biopsies, we evaluated: (i) the utility of changes in the baseline sCr (DeltasCr) to predict both the onset of AR and the response to immunosuppressive therapy; and (ii) the relationship of the calculated creatinine clearance and the presence of pathologic proteinuria to the severity of CAN. We performed 112 biopsies: 11 donor, 73 protocol, 16 acute graft dysfunction and 12 1-month follow-up AR therapy. CAR and SAR were similar in incidence, timing and histologic severity. Progression of CAN was associated with the first episode of CAR (p < 0.02) and the cumulative number of episodes of CAR (p < 0.01), SAR (p < 0.05), CAR plus SAR (p < 0.002) and borderline SAR (B-SAR) (p < 0.006). One-month post-treatment DeltasCrs could not distinguish 1-month follow-up biopsies with histologically confirmed worsened or unchanged AR from those with improved histology (35.2 +/- 74.8% vs. 23.8 +/- 24.9%, p = NS). These findings led to the addition of anti-lymphocyte antibody therapy in five of 10 (50%) cases. Despite 100% 3-yr actuarial graft survival and excellent function (GFR = 111 +/- 36 mL/min/1.73 m(2)), 18 of 21 (86%) patients had grade I CAN or greater chronic histology at a mean +/- sd follow-up period of 18.2 +/- 13.1 months. Thirteen of 21 (62%) patients progressed to grade I CAN at 5.2 +/- 3.6 months and five (38%) of these patients progressed to grade II CAN at 17.8 +/- 11.3 months. Schwartz GFR did not differ between patients with or without CAN (108 +/- 38 mL/min/1.73 m(2) vs. 127 +/- 8 mL/min/1.73 m(2), p = NS). In biopsies with CAN and no associated AR, neither the Banff chronic tubulointerstitial (Banff ci) score nor the Banff chronic grade correlated with the GFR. Proteinuria was not associated with CAN. Clinical AR and SAR are similar histologic lesions with a capacity for CAN progression. In pediatric renal transplant recipients, longitudinal protocol biopsies are superior to functional studies for the diagnosis and post-therapeutic monitoring of AR and for the surveillance of CAN.

Protocol Transplant Biopsies

“…Our current definition of subclinical rejection requires that the serum creatinine be increased by Ͻ10% 2 wk before the protocol biopsy and that the histologic Banff score is "ai2at2" (type IA acute rejection) or greater. Numerous groups since have confirmed the occurrence of subclinical rejection as defined above, in both adults (7)(8)(9)(10)(11)(12)(13)(14) and children (15,16). Some investigators include "borderline" rejection (Banff score Ͻai2at2) in the subclinical rejection category (7,9 -11,14).…”

The Significance of Subclinical Rejection and the Value of Protocol Biopsies

“…There is substantial variation in the reported frequency of SCR between studies, which is likely to be related to differences in patient-recipient immunological risk, ethnicity, baseline immunosuppression and era and by biopsy timing. The averaged prevalence of acute SCR (Banff 1a or above) at 1-2 weeks is 17% (range 13-25%), at 1-2 months is 29% (range 11-43%), at 2-3 months is 17% (range 3-31%) and 1 year is 18% (range 4-50%); whereas the averaged prevalence of borderline SCR at 1-2 weeks is 24% (range 12-38%), at 1-2 months is 23% (range 21-27%), at 2-3 months is 23% (range 11-41%) and 1 year is 17% (range 7-44%) from selected studies (2,5,13,14,(19)(20)(21)(22)(23)(24)(25)(26)(27).…”

“…Beyond 1 year, early intermittent or low-level lymphocytic interstitial inflammation has been followed by later tubulointerstitial damage, progressive CAN, reduced creatinine clearance and shorter graft survival (2,14,26). In pediatric kidney transplantation, SCR (borderline and acute) was associated with progression of CAN in 3-year protocol biopsies, despite comparable Schwartz calculated GFR (20). In adult kidney transplantation, borderline or acute SCR was followed by increased 3-month Banff differential scores for chronic interstitial fibrosis and tubular atrophy, compared with no rejection (2).…”

Chronic allograft nephropathy in paediatric renal transplantation

“…Protocol biopsies have provided an overall view of chronic renal injury. The best of the prospectively collected surveillance studies have defined the natural history and progression of CAN [1,2]. Additional aetiological clues come from histology of deteriorating kidneys or indication-driven biopsy findings [3].…”