*Purpose: Kidney transplantation remains limited by the chronic toxicities associated with calcineurin inhibitors (CNIs) and steroids. The objective of this clinical trial was to determine whether CNIs and steroids could be avoided in a costimulation-based regimen.

*Methods: We enrolled recipients of live (n=30) and deceased (n=10) donor kidneys in an IRB approved trial using intraoperative alemtuzumab induction followed by maintenance therapy with monthly belatacept and daily sirolimus. The trial was designed to offer patients the option to reduce immunosuppressive therapy in years 2 and 3 and wean to monotherapy belatacept. All patients (median 47 years, range 20-69; 27M:13F, 24C/15AA/1Asian) have been followed for over 48 months. Phenotypic lymphocyte analysis was performed longitudinally for 36 months posttransplantation.

*Results: All patients tolerated belatacept; 28 patients tolerated sirolimus, with 6 patients converted to MMF permanently, and 6 patients requiring transient conversion to MMF. There was no patient death or kidney allograft loss within 48 months. Two patients have experienced graft loss to light chain disease and recurrent hypertensive nephropathy respectively at 5 years. At 6, 12, 24, and 36 months, the mean serum creatinine was 1.3±0.4, 1.2±0.6, and 1.4±0.8 and the mean eGFR was 83±19, 85±21, 82±22, and 80±22, respectively. There was no clinical rejection in the first year, though subclinical rejection (Banff 1A or greater) was detected by protocol biopsy in 2 patients at 6 months and 3 patients at 1 year. 19 patients attempted weaning to belatacept monotherapy and 12 patients were successfully maintained with belatacept monotherapy. Biopsies showed Banff 1A to 2B in 3 patients after weaning sirolimus that responded to bolus methylprednisolone and return to protocol therapy. Patients who weaned or attempted to wean to belatacept monotherapy did not develop DSA. DSA was detected in 5 patients, three with sirolimus intolerance, 1 removed from belatacept, and 1 removed from trial therapy for pregnancy. One patient developed histoplasmosis and one patient develop cutaneous Kaposi’s sarcoma; both were cured with therapy. CMV and EBV reactivation was not seen, though transient BK nephritis was detected in 4 patients. Phenotypic lymphocyte analysis demonstrated that alemtuzumab produced profound lymphocyte depletion followed by slow T cell repopulation and more rapid B cell reconstitution with a repertoire deviated toward naïve T and B cells. A significant increase of CD4⁺CD25⁺Foxp3⁺ regulatory T cells and regulatory/transitional B cells was evident in the first year.

*Conclusions: Our data suggest the efficacy and limitations of a novel belatacept-based regimen. The regimen effectively prevents belatacept resistant rejection, enriches the immune repertoire for naïve cells and regulatory cells, and is permissive for control of rejection with belatacept monotherapy in selected patients.

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