Histologic Findings in Patients Who Switched from Cyclosporine to Everolimus

Decisions regarding immunosuppression following kidney transplantation aim to ensure long-term graft survival. The survival of the graft is associated with a variety of factors that can lead to irreversible nephron loss and progressive dysfunction. Dysfunction commonly occurs relatively late, making graft function a poor marker for the severity of histological changes such as early tubulointerstitial damage from ischemic-reperfusion injury, acute and subclinical rejection, calcineurin inhibitor (CNI)-related nephrotoxicity, and viral infections. Subclinical rejection is found in 30% to 50% of patients with stable grafts up to 1 year post-transplant, and in up to 15% of patients receiving tacrolimus; it is associated with subsequent tubulointerstitial damage.

One strategy to limit pathophysiologic damage to the graft is to minimize exposure to CNI therapy. Conversion from CNI therapy to the mammalian target of rapamycin inhibitor everolimus within 6 months after kidney transplantation improves long-term graft function; however, this strategy can increase the risk of mild biopsy-proven acute cellular rejection (BPAR). Ute Eisenberger, MD, and colleagues recently conducted a post-hoc analysis of data from the ZEUS study to analyze histologic information gathered from indication and protocol biopsies up to 5 years after transplantation.

The ZEUS study randomized kidney transplant recipients at month 4.5 to switch to the everolimus or remain on cyclosporine (CsA)-based immunosuppression. Renal function in the cohort treated with everolimus was significantly improved at 5 years compared with the CsA cohort. BPAR occurred in 13.6% of patients in the everolimus cohort and 7.5% of patients in the control cohort (P=.0095). The difference in the BPAR rates was largely accounted for by grade 1 rejection. The post-hoc analysis included the presence of CNI-related toxicity, antibody-mediated rejection (AMR), and chronic/sclerosing allograft nephropathy. Results were reported online in BMC Nephrology [doi.org/10/1186/s12882-018-0950-1].

There were 300 patients in the intention-to-treat population (154 everolimus; 146 CsA). Of those, 269 (138 everolimus; 131 CsA) completed the 12-month core study; the 5-year visit was attended by 232 patients (123 everolimus; 109 CsA). With the exception of body mass index, which was higher in the everolimus group), other characteristics of recipients and donors were similar between the two treatment groups.

By year 5 post-transplant, 45.2% of patients in the everolimus group remained on everolimus in a CNI-free regimen. In the CsA group, 58.6% of patients were still receiving CsA and an additional 11 patients (7.6%) remained on CNI therapy but had switched to tacrolimus. Of patients with steroid therapy data available, 64.2% (n=79/123) of everolimus patients and 64.2% (n=70/109) of patients in the CsA group were receiving steroids at 5 years post-transplant.

At randomization, protocol biopsies were performed in 13.3% of patients (n=40; 22 everolimus; 18 CsA), and in 11.3% of patients (n=43; 17 everolimus; 17 CsA) at month 12. Prior to randomization at month 4.5, investigator-initiated biopsies were performed in 41.7% of patients (n=125) at a mean of 0.9 months post-transplant. Following randomization, a total of 178 investigator-initiated biopsies were performed (53 everolimus; 53 CsA). Of those, 67 were obtained by year 1 and 111 were obtained during years 2 to 5. In the everolimus group, the mean number of investigator-initiated biopsies between randomization and year five was 2.6, compared with 2.2 in the CsA group, at a mean of 20.2 and 19.5 months after transplantation, respectively.

There were few cases of clinically undetected mild BPAR or other lesions in either treatment group revealed in results of protocol biopsies at randomization and at month 12; however, the number of protocol biopsies was low.

Of the 125 investigator-initiated biopsies performed prior to randomization, BPAR was present in 28 cases (22.4%); the majority were grade 1A. CNI-related lesions (n=37) and acute tubular necrosis (n=36) were seen more frequently than BPAR; AMR was rare (4/125; 3.2%).

Of patients who underwent investigator-initiated biopsies between randomization and year 5, BPAR was detected in 19 patients in the everolimus group (19/154; 12.3%); 10 were grade 1A, six were grade 1B, six were grade 2A, and one was grade 3 (one missing). In the CsA-treated group, BPAR was detected in 11 patients  (11/146); 7.5%); eight episodes were grade 1A, one was grade 1B, two were grade 2A, and two were grade 3. In the everolimus group, the incidence from randomization to year 1 was 8.4% compared with 3.4% in the CsA group. Severity of BPAR between randomization and year 5 was comparable between the two groups: 22 of 24 episodes of BPAR in the everolimus group and 18 of 20 in the CsA group graded mild (grade ≤2A).

In the everolimus group, 7.1% of patients exhibited chronic/sclerosing allograft nephropathy on investigator-initiated biopsies after randomization; in the CsA group, the proportion was 8.2%. Lesions were graded mild in the majority of cases. In one patient in the everolimus group, AMR was detected post-randomization; it was categorized as acute tubular necrosis (ATN)-like and was C4d positive. In the CsA group, four patients developed AMR; two showed ATN-like changes (both C4d positive), one had arterial-v3 changes (C4d positive), and one showed capillary-marginal change/thrombosis (C4d negative). Finally, there was a higher rate of “other” lesions in the everolimus group than in the CSA group (50.5% vs 26.4%).

In conclusion, the researchers said, “This analysis of histological findings in the ZEUS study to 5 years after kidney transplantation shows no increase in antibody-mediated rejection under everolimus-based therapy with a lower rate of CNI-related toxicity compared to a conventional CsA-based regimen, and confirms the preponderance of the mild BPAR seen in the main study after the early switch to CSA-free everolimus therapy.”

Takeaway Points

  1. The ZEUS study randomized kidney transplant recipients to switch to everolimus at 4.5 months post-transplant or to remain on cyclosporine (CsA)-based immunosuppression. Researchers performed a post-hoc analysis of data from the ZEUS study to analyze histologic data up to 5 years post-transplant.
  2. In each group, at least one investigator-initiated biopsy was performed in 53 patients; mean in the everolimus group was 2.6 biopsies per patients and in the CsA group, mean was 2.2 biopsies per patient.
  3. There was no increase in antibody-mediated rejection in the everolimus group, and a lower rate of calcineurin inhibitor-related toxicity compared with the CsA group.