In Press, 1995, Transplantation Proceedings copyright by Appleton and Lange.
Effect of Subclinical Rejection on Renal Allograft Histology and Function at
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 . 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 .
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.
MATERIALS AND METHODS
- 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
- Histology. Pathologic changes were interpreted using the
Banff schema , 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
- 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
- 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
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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Histology Scores at 6 months
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.
- Rush DN, Henry SF, Jeffery JR et al. Histological
findings in early routine biopsies of stable renal allograft recipients.
Transplantation 1994; 57:208.
- Rush DN, Jeffery JR, Gough J. Sequential protocol
biopsies in renal transplant patients. Clinico-pathological correlation
using the Banff schema. Transplantation 1995; 59:511.
- 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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Last Modified: April 03, 1996 1:23:36 PM