Original ArticlesTransplantation

Three-Year Outcomes of a Randomized, Double-Blind, Placebo-Controlled Study Assessing Safety and Efficacy of C1 Esterase Inhibitor for Prevention of Delayed Graft Function in Deceased Donor Kidney Transplant Recipients

Edmund Huang, Ashley Vo, Jua Choi, Noriko Ammerman, Kathlyn Lim, Supreet Sethi, Irene Kim, Sanjeev Kumar, Reiad Najjar, Alice Peng and Stanley C. Jordan
CJASN January 2020, 15 (1) 109-116; DOI: https://doi.org/10.2215/CJN.04840419

Abstract

Background and objectives Delayed graft function is related to ischemia-reperfusion injury and may be complement dependent. We previously reported from a randomized, placebo-controlled trial that treatment with C1 esterase inhibitor was associated with a shorter duration of delayed graft function and higher eGFR at 1 year. Here, we report longer-term outcomes from this trial.

Design, setting, participants, & measurements This is a post hoc analysis of a phase 1/2, randomized, controlled trial enrolling 70 recipients of deceased donor kidney transplants at risk for delayed graft function (NCT02134314). Subjects were randomized to receive C1 esterase inhibitor 50 U/kg (n=35) or placebo (n=35) intraoperatively and at 24 hours. The cumulative incidence functions method was used to compare graft failure and death over 3.5 years. eGFR slopes were compared using a linear mixed effects model.

Results Three deaths occurred among C1 esterase inhibitor–treated patients compared with none receiving placebo. Seven graft failures developed in the placebo group compared with one among C1 esterase inhibitor–treated recipients; the cumulative incidence of graft failure was lower over 3.5 years among C1 esterase inhibitor–treated recipients compared with placebo (P=0.03). Although no difference in eGFR slopes was observed between groups (P for group-time interaction =0.12), eGFR declined in placebo-treated recipients (−4 ml/min per 1.73 m2 per year; 95% confidence interval, −8 to −0.1) but was stable in C1 esterase inhibitor–treated patients (eGFR slope: 0.5 ml/min per 1.73 m2 per year; 95% confidence interval, −4 to 5). At 3.5 years, eGFR was 56 ml/min per 1.73 m2 (95% confidence interval, 42 to 70) in the C1 esterase inhibitor group versus 35 ml/min per 1.73 m2 (95% confidence interval, 21 to 48) in the placebo group, with an estimated mean eGFR difference of 21 ml/min per 1.73 m2 (95% confidence interval, 2 to 41 ml/min per 1.73 m2).

Conclusions Treatment of patients at risk for ischemia-reperfusion injury and delayed graft function with C1 esterase inhibitor was associated with a lower incidence of graft failure.

Introduction

Delayed graft function (DGF), defined as the need for dialysis in the first week after kidney transplant, is estimated to occur in >20% of deceased donor kidney transplants (1). Its development is associated with an increased risk of rejection, poorer long-term kidney allograft function, and lower patient and graft survival (2,3). This association is modified by the severity of DGF as indicated by the duration of dialysis dependence after transplant, where longer periods of dialysis dependence are associated with progressively higher hazards of rejection and graft failure (4). Not surprisingly, kidneys at higher risk for DGF are more likely to be discarded in the United States, despite the well-documented shortage in donor organ supply (5,6).

The predominant mechanism of DGF is ischemia-reperfusion injury. This is marked by an alloantigen-independent inflammatory response characterized by an influx of proinflammatory cells early after ischemic injury (7). Additionally, the complement cascade can be activated in response to ischemia-induced membrane changes (8). Although the alternative pathway has historically been thought to play the major role in ischemia-reperfusion injury, evidence suggests that the classical and mannose binding lectin (MBL) pathways are also important (9,10). Damage-associated molecular patterns, polysaccharides, and intracellular antigens exposed during ischemic injury can activate both the classical and MBL pathways (11). C4-deficient mice, which cannot activate the classical pathway C3 convertase (C2aC4b), were less susceptible to ischemia-induced injury compared with wild-type mice, and antibodies against mannan binding lectin-associated serine protease 2 (MASP-2) were protective against ischemia-reperfusion injury in the murine gastrointestinal tract and myocardium (11,12). Recent data from an animal model of heart transplant ischemia-reperfusion injury demonstrated that ischemia-reperfusion injury was largely prevented in animals that were genetic knockouts for the MBL collectin-11 but not for Factor B (alternative pathway) knockouts (10). In addition, wild-type mice treated with C1 esterase inhibitor were protected from ischemia-reperfusion injury, similar to collectin-11 (−/−). Thus, mounting experimental evidence suggests that blockade of the classical and MBL complement pathways is a potentially attractive approach for prevention or mitigation of DGF caused by ischemia-reperfusion injury.

C1 esterase inhibitor was approved by the US Food and Drug Administration in 2009 for the treatment of hereditary angioedema. C1 esterase inhibitor is a serine protease inhibitor targeting C1s and C1r in the classical pathway and MASP-1 and MASP-2 in the MBL complement pathway, and it is, therefore, a relevant intervention to test the effect of complement inhibition on short- and long-term kidney function among allografts with ischemia-reperfusion injury. Our group recently reported 12-month outcomes of a double-blind, randomized, placebo-controlled study investigating the safety and efficacy of C1 esterase inhibitor among deceased donor kidney transplant recipients at high risk for DGF (13). Salient findings from this study were a shorter duration of DGF and higher eGFR at 12 months among patients treated with C1 esterase inhibitor compared with placebo. Here, we report a follow-up study of outcomes up to 3.5 years from the original randomized, controlled trial of C1 esterase inhibitor versus placebo among patients at high risk for DGF.

Materials and Methods

The clinical and research activities being reported are consistent with the Principles of the Declaration of Istanbul as outlined in the “Declaration of Istanbul on Organ Trafficking and Transplant Tourism.” This study was approved by the Cedars-Sinai Institutional Review Board, and the conduct of the study adhered to the principles of the Declaration of Helsinki. A detailed description of study procedures was reported previously, and the full study protocol is available in Supplemental Material (13). Briefly, the original study, performed at Cedars-Sinai Medical Center in Los Angeles, California, was a phase 1/2, double-blind, randomized, placebo-controlled trial investigating the safety and efficacy of C1 esterase inhibitor for prevention of DGF after deceased donor kidney transplantation (NCT02134314; date of registration May 9, 2014). All enrolled subjects provided written consent for participation in the trial. Eligibility criteria included patients aged 18–70 years old with ESKD requiring maintenance dialysis awaiting kidney transplantation. Patients were considered to be at high risk for DGF if they met the following eligibility criteria: (1) recipient of an allograft from an expanded criteria donor or donor with a kidney donor profile index (KDPI) ≥85%, (2) recipient of an allograft from a donor classified as “donor after cardiac death,” or (3) recipient of an allograft with a risk index of three to eight for DGF (Table 1). This index was on the basis of traditional risk factors for DGF and a previously published nomogram by Irish et al. (14).

View this table:
Table 1.

Risk factors for delayed graft function

Study Design and Treatment

From November 25, 2014 to December 29, 2016, a total of 70 patients with ESKD on dialysis were randomized 1:1 to receive C1 esterase inhibitor 50 U/kg (n=35) or placebo (normal saline; n=35) given in the operating room before reperfusion of the kidney allograft and repeated 24 hours later. The study treatment was prepared according to a pharmacist-supplied randomization code that was blinded from all other study personnel. Per study protocol, patients underwent a preimplantation allograft biopsy before administration of study medication.

Antibody induction consisted of alemtuzumab 30 mg by subcutaneous injection postoperatively (for highly sensitized recipients defined as having calculated panel reactive antibodies ≥30% or recipient of a prior transplant) or antithymocyte globulin 1.5 mg/kg daily for four doses. Maintenance immunosuppression consisted of tacrolimus or cyclosporin, mycophenolate mofetil, and corticosteroids per center protocol. In addition to standard antimicrobial prophylaxis against Pneumocystis jirovecii, cytomegalovirus, and fungal infections given according to local institutional guidelines, all patients were given meningococcal vaccination before transplantation and received antibiotic prophylaxis directed against Neisseria meningitides for 1 month post-transplant.

The primary outcome of the original study was the proportion of patients with DGF defined as the need for dialysis in the first week after transplant excluding dialysis in the first 24 hours for hyperkalemia or volume overload. Exploratory outcomes of the original study included patient and graft survival at 12 months and eGFR at 12 months.

Statistical Analyses

This study was a post hoc analysis investigating outcomes up to 3.5 years among the original cohort of trial participants from the randomized trial. Exploratory outcomes were the cumulative incidence of graft failure and death, time to rejection, and change in eGFR over time. The cumulative incidence functions method was used to assess time to graft failure and death using the Gray test for statistical comparison. Graft failure was defined as return to dialysis, and the date of return to dialysis was considered as the date of graft failure. The Kaplan–Meier product-limit method was used to compare time to rejection between the two groups. Patients were censored at the end of the study period, with last follow-up date on November 21, 2018.

For comparison of eGFR, a linear mixed effects model was used with random slopes and intercepts and an unstructured covariance matrix to compare the slope difference in eGFR between C1 esterase inhibitor– and placebo-treated recipients. eGFR was estimated using the Chronic Kidney Disease Epidemiology Collaboration creatinine equation (15). The fixed effect represents the average change in eGFR by treatment group, whereas the random effect accounts for subject-specific correlation between repeated measures of eGFR within an individual. The intent of this analysis was to compare long-term changes in eGFR between the two groups. Given that early allograft dysfunction in the setting of DGF could erroneously affect the modeled slope, only eGFR values obtained >1 month post-transplant were used for the analysis. All eGFR values up to the date of graft failure or death were included in the model, and no eGFR values were imputed.

P values were two tailed, and a P<0.05 was considered statistically significant. All analyses were performed using Stata version 14.2 (College Station, TX) and R version 3.5.1. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Results

Between November 25, 2014 and December 29, 2016, a total of 70 deceased donor kidney transplant recipients were enrolled in the study, with 35 recipients randomized to receive C1 esterase inhibitor and 35 randomized to receive placebo (Figure 1). The median follow-up time of participants was 2.5 years (interquartile range [IQR], 2.0–3.0 years). Baseline characteristics are shown in Table 2. The groups were well matched with regard to recipient, donor, and immunologic characteristics. Specifically, the number of donor after cardiac death, mean KDPI, and the number of donors with KDPI≥85% were similar among C1 esterase inhibitor– and placebo-treated recipients. Additionally, the groups were similar in the degree of HLA allosensitization and donor-recipient crossmatching. A comparison of baseline preimplantation allograft biopsies was reported previously and was not different between C1 esterase inhibitor– and placebo-treated recipients in histologic scoring for glomerulosclerosis, interstitial fibrosis/tubular atrophy, arteriosclerosis, and arteriolar hyalinosis (13). There was no difference in the original trial’s primary outcome of DGF between the two groups, defined as the need for dialysis in the first post-transplant week (C1 esterase inhibitor 44% versus placebo 60%, P=0.23), and there was no difference in the mean number of dialysis sessions required (C1 esterase inhibitor 1±1 versus placebo 2±2, P=0.12) (13). However, exploratory analyses revealed that the duration of DGF was shorter in C1 esterase inhibitor–treated patients, and all patients in the C1 esterase inhibitor group discontinued dialysis by 2 weeks post-transplant, whereas five (14%) patients in the placebo arm remained dialysis dependent beyond 2 weeks (P=0.02) (13).

Figure 1.
Figure 1.

Study flowchart. There were a total of 70 patients randomized, 35 each to the C1 esterase inhibitor and placebo groups. No patients were excluded from the analysis.

View this table:
Table 2.

Baseline characteristics

Figure 2 shows the cumulative incidence of death and graft failure with corresponding event-free survival in the placebo and C1 esterase inhibitor groups. The cumulative incidence of death was not statistically different between the two groups over the study period (P value by Gray test =0.09). There were three deaths, all within the C1 esterase inhibitor group, each occurring >1.5 years after transplant. Given the time interval post-transplant, these deaths were considered to be unrelated to C1 esterase inhibitor. Death was due to a bacterial infection in two patients, one of whom had received intensified immunosuppression as treatment for antibody-mediated rejection. The third patient was also treated for antibody-mediated rejection and died due to an unknown cause. All three patients had a functioning allograft at the time of death.

Figure 2.
Figure 2.

Cumulative incidence of graft failure and death among placebo-treated and C1 esterase inhibitor–treated patients. There was a higher incidence of graft failure and no difference in the incidence of death over 3.5 years in the placebo group compared to the C1 esterase inhibitor group. Event-free survival was not different between the groups.

There were seven graft failures observed in the placebo group compared with one in the C1 esterase inhibitor group, all occurring within the first 2 years post-transplant. The cumulative incidence of graft failure was significantly higher over 3.5 years among placebo-treated patients compared with C1 esterase inhibitor–treated recipients (P value by Gray test =0.03; unadjusted hazard ratio [HR], 0.14; 95% confidence interval [95% CI], 0.02 to 1.15). At 3.5 years, the cumulative incidence of graft failure was 21% among placebo-treated patients and 3% among C1 esterase inhibitor–treated patients.

When death and graft loss were considered together, there was no association between treatment group (C1 esterase inhibitor versus placebo) and event-free survival over the study period (unadjusted HR, 0.53; 95% CI, 0.16 to 1.82).

There was no difference in rejection-free survival between the C1 esterase inhibitor and placebo groups over the study period (Figure 3) (log rank P=0.95; unadjusted HR, 0.96; 95% CI, 0.28 to 3.33). At 3.5 years, rejection-free survival was 82% in the C1 esterase inhibitor group and 86% in the placebo group. Five patients with rejection were observed in each group. The distribution of rejection types was similar in both groups. Among C1 esterase inhibitor–treated recipients, there were two cases of isolated cell-mediated rejection in patients, two cases of chronic active antibody-mediated rejection that developed in recipients who were HLA sensitized, and one case with mixed cell-mediated and chronic active antibody-mediated rejection in a recipient of a prior organ transplant. Within the placebo group, there were two cases of isolated cell-mediated rejection in patients, one case of isolated antibody-mediated rejection that developed in a recipient of an HLA-incompatible kidney transplant, and two cases of mixed cell-mediated and antibody-mediated rejection. De novo donor-specific antibodies developed in eight (23%) placebo-treated and three (9%) C1 esterase inhibitor–treated recipients (P=0.10). There was no difference in time to de novo donor-specific antibodies between the two groups (median months; placebo: 14 [IQR, 9–15]; C1 esterase inhibitor: 19 [IQR, 2–27]; P=0.68).

Figure 3.
Figure 3.

Kaplan–Meier curve for rejection-free survival comparing C1 esterase inhibitor–treated and placebo-treated patients. There was no difference in rejection-free survival over 3.5 years between the C1 esterase inhibitor and placebo groups.

Figure 4 compares the model-based predicted eGFR over time between C1 esterase inhibitor– and placebo-treated recipients. At 1 month post-transplant, the eGFR was 49 ml/min per 1.73 m2 (95% CI, 44 to 54 ml/min per 1.73 m2) in the placebo group, which was not statistically different than the C1 esterase inhibitor group (54 ml/min per 1.73 m2; 95% CI, 49 to 59 ml/min per 1.73 m2; P=0.15). A significant difference in eGFR slope was not observed between the C1 esterase inhibitor and placebo groups (coefficient for treatment group × time interaction: 5 ml/min per 1.73 m2 per year; 95% CI, −1 to 10 ml/min per 1.73 m2 per year; P=0.12). However, within each treatment group, eGFR slopes were statistically meaningful. In the C1 esterase inhibitor group, the estimated mean eGFR did not change over the study period (eGFR slope =0.5 ml/min per 1.73 m2 per year; 95% CI, −4 to 5 ml/min per 1.73 m2 per year), whereas the estimated mean eGFR decreased in the placebo group (eGFR slope =−4 ml/min per 1.73 m2 per year; 95% CI, −8 to −0.1 ml/min per 1.73 m2 per year). At 3.5 years, the estimated mean eGFR was higher among C1 esterase inhibitor–treated recipients (56 ml/min per 1.73 m2; 95% CI, 42 to 70 ml/min per 1.73 m2) compared with placebo (35 ml/min per 1.73 m2; 95% CI, 21 to 48 ml/min per 1.73 m2), with a mean eGFR difference between the two groups of 21 ml/min per 1.73 m2 (95% CI, 2 to 41 ml/min per 1.73 m2).

Figure 4.
Figure 4.

Comparison of eGFR over time among C1 esterase inhibitor–treated and placebo-treated patients. The eGFR slope was stable in the C1 esterase inhibitor group but declined in the placebo group over the study period. At 3.5 years, eGFR was higher among C1 esterase inhibitor-treated recipients compared to placebo-treated patients.

Discussion

In this follow-up study of a phase 1/2, randomized, controlled trial of C1 esterase inhibitor versus placebo for the prevention of DGF, fewer graft losses developed in C1 esterase inhibitor–treated patients, and eGFR was higher in the C1 esterase inhibitor group at 3.5 years compared with placebo. Data from this study suggest that amelioration of ischemia-reperfusion injury with C1 esterase inhibitor may lead to better long-term allograft outcomes and should be validated in larger clinical trials.

In the original report of this randomized, controlled trial, there was no difference in graft survival at 1 year between C1 esterase inhibitor– and placebo-treated patients (13). However, with longer-term follow-up, a difference in graft failure between the two groups was observed beginning after year 1. At 3.5 years, the cumulative incidence of graft failure was 21% among placebo-treated recipients, which is similar to graft failure statistics for KDPI>85% donor allografts reported nationally (16). This indicates that outcomes of placebo-treated recipients in this study were as expected for recipients of similar types of donors. In contrast, only one case of graft failure was observed among C1 esterase inhibitor–treated recipients, despite no differences in baseline donor characteristics or chronicity scores on preimplantation biopsies.

Recent animal data suggest that both MBL and classical complement pathways have a prominent role in kidney ischemia-reperfusion injury, and blockade of both pathways with C1 esterase inhibitor in swine and mice led to reduced expression of the proinflammatory cytokines and chemokines IL-6, MCP-1, and CXCL1; limited infiltration of macrophages and neutrophils to kidney tissue; reduced tubular injury; and attenuated expression of fibrotic markers, such as α-smooth muscle actin, desmin, and collagen (17,18). Additionally, administration of C1 esterase inhibitor in conjunction with autotransplantation of swine kidneys was associated with earlier recovery of kidney function after ischemia-reperfusion injury, improved long-term kidney function, and limited development of interstitial fibrosis and tubular atrophy compared with vehicle-treated swine (19). Liu et al. (20) reported on transcriptional factors associated with progression from AKI to CKD. These investigators described the early appearance of interstitial fibrosis/tubular atrophy and chronic fibrosis after a single ischemic insult that progresses to ESKD by 6 to 12 months (20). They also identified early transcription of complement-related genes after an ischemic insult that likely contributes to CKD progression and could represent potentially valuable targets for prevention or amelioration of ESKD.

If C1 esterase inhibitor proves to be protective against the long-term effects of ischemia-reperfusion injury in humans, there may be important implications for deceased donor organ utilization. In the context of a critical donor organ shortage, approximately 20% of deceased donor kidneys that are recovered in the United States are not transplanted, and discard rates exceed 50% for KDPI>85% allografts (16,21). Although the reasons for discard may vary, donor declines are driven in large part by concern over long-term viability of the allograft. If C1 esterase inhibitor can lead to improved allograft function and long-term survival, its use could potentially result in increased utilization of higher-risk donors and provide access to deceased donor transplantation for a significant number of waitlisted patients who would not otherwise receive a kidney transplant. Given its potential effect on donor utilization, there is a strong argument for development of a large-scale clinical trial to validate the findings from this study.

The strength of this study was the randomized, double-blind, placebo-controlled trial design. The groups were well matched on recipient and donor characteristics, and there were no differences in baseline graft histology. We acknowledge that the possibility of inflated effect sizes resulting from a relatively small sample size cannot be excluded and that our findings will need to be validated in larger clinical trials. Additionally, the findings of this study would have been strengthened by a comparison of later-term histologic findings of chronic allograft injury between C1 esterase inhibitor– and placebo-treated recipients; however, post-transplant protocol biopsies were not a part of the study protocol. Nevertheless, it is well known that biopsy findings do not always correlate with allograft function.

In summary, administration of C1 esterase inhibitor immediately before reperfusion and repeated 24 hours after transplant to recipients of deceased donor kidney allografts at high risk for DGF was associated with a lower cumulative incidence of graft loss and higher eGFR at 3.5 years compared with placebo-treated recipients. These findings suggest that inhibition of the classical and MBL complement pathways in kidneys susceptible to ischemia-reperfusion injury might improve long-term allograft survival. It is possible that treatment with C1 esterase inhibitor may allow for broader utilization of higher-risk allografts, although these preliminary findings will need to be validated in larger-scale clinical trials.

Disclosures

Dr. Huang reports receiving consulting fees from CareDx, Inc. and Hansa Biopharma and grants from CareDx, Inc. and Veloxis Pharmaceuticals outside of the submitted work. Dr. Jordan reports receiving grants from CareDx, Genentech, Hansa Biopharma, and Vitaeris, Inc. and consultancy fees from Amplyx, CareDx, Hansa Biopharma, Regeneron, Inc., Viela Bio, and Vitaeris, Inc., all outside of the submitted work. Dr. Jordan also reports owning stock in CareDx. Dr. Ammerman, Dr. Choi, Dr. Kim, Dr. Kumar, Dr. Lim, and Dr. Sethi have nothing to disclose.

Funding

Dr. Jordan, Dr. Najjar, Dr. Peng, and Dr. Vo are supported by a grant from CSL Behring.

Supplemental Material

This article contains the following supplemental material online at http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN.04840419/-/DCSupplemental.

Study protocol.

Acknowledgments

We are grateful to the nurses, physicians, and research team members of the Comprehensive Transplant Center at Cedars-Sinai Medical Center for their expert and compassionate care rendered to our patients. We also recognize and thank the patients and their families who participated in this trial and CSL Behring for their support of this study.

Footnotes

  • Published online ahead of print. Publication date available at www.cjasn.org.

  • See related editorial, “Medical Therapies to Reduce Delayed Graft Function and Improve Long-Term Graft Survival: Are We Making Progress?,” on pages 13–15.

  • Received April 20, 2019.
  • Accepted October 23, 2019.

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Three-Year Outcomes of a Randomized, Double-Blind, Placebo-Controlled Study Assessing Safety and Efficacy of C1 Esterase Inhibitor for Prevention of Delayed Graft Function in Deceased Donor Kidney Transplant Recipients
Edmund Huang, Ashley Vo, Jua Choi, Noriko Ammerman, Kathlyn Lim, Supreet Sethi, Irene Kim, Sanjeev Kumar, Reiad Najjar, Alice Peng, Stanley C. Jordan
CJASN Jan 2020, 15 (1) 109-116; DOI: 10.2215/CJN.04840419
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