Successful reduction of immunosuppression in older renal transplant recipients who exhibit donor-specific regulation

Abstract

Background: We hypothesized that T-regulatory cells specific for donor alloantigens would protect a renal transplant during partial withdrawal of immunosuppression.

Methods: To test this hypothesis, 32 renal transplant recipients aged 55 years and older with excellent renal function were tested for donor-specific regulation (DSR) by trans-vivo delayed type hypersensitivity assay at the time of enrollment (T=0) and 6 months later (T=6). Twenty-two patients had prednisone withdrawn during a 3-month period, whereas 10 controls were maintained on triple therapy (prednisone, cyclosporine, and mycophenolate).

Results: Of 22 patients in the steroid withdrawal group, 10 were DSR+ and 12 were DSR- at the time of enrollment (T=0). None of the DSR+ patients experienced acute rejection, nor did any have donor-specific human leukocyte antigen (HLA) antibody during or after withdrawal. Of 12 DSR- patients, three developed acute rejection, which were reversed with bolus steroid treatment, and four were donor-specific antibody+ at T=0 or T=6. Two years later, 80% (8 of 10) of DSR+ patients in the withdrawal group remain steroid free while maintaining excellent renal function, as compared with only 58% (7 of 12) DSR- patients. Patient survival at 4 years was similar for DSR+ (9 of 10) and DSR- (11 of 12) patients in the withdrawal group. Patients maintained on triple therapy remained rejection free during the 4-year follow-up regardless of initial DSR status, with patient survival rate of 70% (7 of 10).

Conclusions: DSR before steroid withdrawal may identify a subset of transplant patients who could benefit from reduction of immunosuppression without elevated risk of rejection or deteriorating renal function.

Figure 1

TV-DTH assay results from two selected patients exemplifying the DSR+ (A) and DSR- (B) phenotypes. TV-DTH testing was performed at T=0 and T=6 mo. For TV-DTH assay 7×10⁶ PBMCs from each patient were mixed in different combination with dAg or EBV, or combination of both and injected into the footpads of SCID mice. Net swelling response was measured after 24 hours. Background swelling (PBMC+PBS) varied from 10–30×10⁻⁴ in. and was subtracted from raw values to calculate the net swelling response to each antigen or antigen combination; % inhibition values were determined as described in Methods. Bars indicate mean ± SEM for duplicate assays. Diagram below each figure shows the time course of IS drug therapy in each patient. Dashed arrow indicates T=0 the beginning of steroid withdrawal process. (↓, A0–2) indicates biopsy time point and score.

Figure 2

Kaplan-Meier plot showing incidence and timing of acute rejection episodes in the withdrawal group [n=22 pts]. Log rank p value comparing DSR+ and DSR- pts is shown.

Figure 3. Serum creatinine values over a 4-year period

A: Withdrawal group. Patients with initial DSR + status are shown at left; those with initial DSR- status at time T =0 [0 time point on x-axis] are shown at right. Dashed lines indicate patients in withdrawal group who had an acute rejection episode and were returned to triple drug IS.*Two patients died with functioning grafts: DSR+ patient DD 12 due to unknown causes at 33 mos., after excessive alcohol abuse and non-compliance with all medication at 24 mos.; and DSR- pt DD10 as a result of renal complications from an angiography procedure. B: Control group. Patients with initial DSR score ≥ 50% ( DSR+) are shown at left; those with initial DSR score < 50% (DSR- ) at time T =0 [0 time point on x-axis] are shown at right. (*)Indicates patients who died with functioning grafts: DSR+ patient DD 4 due to malignant disease, DSR+ LURD 8 due to myocardial infarction, and DSR-patient DD 7 who died in an car accident.