In Press, 1995, Transplantation Proceedings copyright by Appleton and Lange.

Effect of Subclinical Rejection on Renal Allograft Histology and Function at 6 Months

D. Rush*, J. Jeffery*, K. Trpkov, K. Solez and J. Gough*

Universities of Manitoba* and of Alberta, Canada

Kidney Transplant Biopsy Cyclosporine Rejection




We have reported that renal transplant patients with stable graft function have a 30% prevalence of acute rejection (Banff criteria) in protocol biopsies done in the first three months post-transplant [1]. Although the significance of these "subclinical" rejection episodes is unknown, we have found an association between the cumulative inflammation sustained by the graft, as documented in sequential biopsies over 1 year, and graft function [2]. The aim of the present study is to determine whether treatment of subclinical rejections in the first three months post-transplant has a beneficial effect on graft histology and/or function at 6 months.



    Patients. Sixty nine patients have been entered into the study, and a final number of 75 is targeted for. Six-antigen match patients were excluded. Cadaveric and 1 haplotype match recipients of living-donor kidneys were stratified by kidney source, and were randomized to a biopsy at 1, 2, 3 and 6 months post-transplant (Group A) or to a 6 month biopsy only (Group B). Baseline characteristics were similar for the study groups after randomization (not shown). A preliminary report on 58 patients who have completed the study is presented. A follow-up biopsy at one year is planned, and has been done in 40 patients.


    Biopsies. We have used the Biopsy instrument under ultrasound guidance.


    Histology. Pathologic changes were interpreted using the Banff schema [3], by two independent groups of renal pathologists blinded to the clinical data.


    Immunosuppressive Protocol. CsA 3 mg/kg/day IV for 3-5 days, then oral CsA. Target levels were 250-350 µg/L in the first three months and 150-200 ug/L thereafter. CsA levels were measured in whole blood at 12 hours after dosing using the monoclonal TDx system. Azathioprine was given at 1-2 mg/kg/day and prednisone was given at 1 mg/kg/day with taper. All patients received SR Diltiazem 60 to 90 mg po bid.


    Definitions. Clinical rejection episode was defined as rise in serum creatinine by >10% from baseline in the absence of another cause. In some cases rejection episodes were confirmed histologically if they occurred at the time of a protocol biopsy. Protocol biopsies also enabled a diagnosis of subclinical rejection episodes when histologically diagnosed rejection was not accompanied by an increase in the serum creatinine >10%. All rejections were treated with a course of high dose corticosteroids.



Biopsies. 111/116 (96%) protocol biopsies were done in Group A, and 29/29 (100%) in Group B. Twenty-one non-protocol biopsies were done; 9 in Group A and 12 in Group B; 19 biopsies were done prior to randomization. Three patients required transfusions (1 for hematuria, 1 for an AV fistula needing embolization and 1 for abdominal pain and a drop in hemoglobin).


Cyclosporine levels. CsA levels (ug/L; mean + SD) were 322 + 67, 302 + 88, 271+ 55 and 260 + 42 for Group A and 332 + 77, 284 + 55, 290 + 63 and 259 + 52 for Group B at one, two, three and six months, respectively (p=NS at all time points).


Renal function. Serum creatinines (µmol/L; mean + SD) were 131.6 + 39.9, 124.1 + 37.0, 125.6 + 49.7 and 137.1 + 68.9 for Group A and 144.3 + 57.4, 135.2 + 48.6, 140.8 + 53.0 and 139.1 + 48.2 for Group B at one, two, three and six months, respectively (p=NS at all time points).


Renal histology. The prevalence of subclinical rejection was 35% in months 1-3 post-renal transplant. At 6 months subclinical acute rejection was present in 24% of Group A and in 40% of Group B patients. Biopsy scores at 6 months are shown in [Table 1].



Treatment of subclinical rejections at 1, 2 and 3 months did not result in improved renal function (serum creatinine) at 6 months. Renal histology at 6 months was not significantly improved after treatment of subclinical rejection although chronic changes may be less severe. The alarming prevalence of subclinical rejection suggests that current "triple therapy" protocols with cyclosporine, azathioprine and prednisone may not provide adequate immunosuppression.

The definitive result from this study will come from the one year results on the full cohort of patients. The suggestive differences in chronic rejection changes shown in [Table 1], if confirmed in the full study, will provide a strong impetus to incorporate protocol biopsies into standard clinical practice.



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Table 1:
Histology Scores at 6 months

Group A 1.98 ±1.7 0.58 ±0.8 2.57 ±1.9
Group B 2.32 ±1.9 1.07 ±1.9 3.39 ±3.2

The histology scores were obtained by adding the score of individual acute (e.g. "tubulitis", "endothelialitis") and chronic (e.g. interstitial fibrosis, fibrous intimal thickening) lesions, scored 0-3 according to the Banff schema (3); p= NS for all comparisons.



  1. Rush DN, Henry SF, Jeffery JR et al. Histological findings in early routine biopsies of stable renal allograft recipients. Transplantation 1994; 57:208.


  2. Rush DN, Jeffery JR, Gough J. Sequential protocol biopsies in renal transplant patients. Clinico-pathological correlation using the Banff schema. Transplantation 1995; 59:511.


  3. Solez K, Axelsen RA, Beneditksson H et al. International standardization of criteria for the histologic diagnosis of renal allograft rejection: The Banff working classification of kidney transplant pathology. Kidney International 1993; 44:411.



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