Advances in desensitization for human leukocyte antigen incompatible kidney transplantation.

PURPOSE OF REVIEW: Human leukocyte antigen (HLA) sensitization is a major barrier to kidney transplantation induced by exposure to alloantigens through pregnancy, blood product exposure and previous transplantations. Desensitization strategies are undertaken to improve the chances of finding compatible organ offers. Standard approaches to desensitization include the use of plasmapheresis/low dose intravenous immunoglobulin (IVIG) or high dose IVIG plus anti-CD20. However, current methods to reduce HLA antibodies are not always successful, especially in those with calculated panel reactive antibody 99-100%. RECENT FINDINGS: Newer desensitization strategies such as imlifidase [immunoglobulin G (IgG) endopeptidase] rapidly inactivates IgG molecules and creates an "antibody-free zone", representing an important advancement in desensitization. However, pathogenic antibodies rebound, increasing allograft injury that is not addressed by imlifidase. Here, use of anti-IL-6R (tocilizumab) or anti-interleukin-6 (clazakizumab) could offer long-term control of B-memory and plasma cell DSA responses to limit graft injury. Agents aimed at long-lived plasma cells (anti-CD38 and anti-BCMAxCD3) could reduce or eliminate HLA-producing plasma cells from marrow niches. Other agents such as complement inhibitors and novel agents inhibiting the Fc neonatal receptor (FcRn) mediated IgG recycling will likely find important roles in desensitization. SUMMARY: Use of these agents alone or in combination will likely improve the efficacy and durability of desensitization therapies, improving access to kidney transplantation for immunologically disadvantaged patients.

Importance of IL-6 inhibition in prevention and treatment of antibody-mediated rejection in kidney allografts.

Interleukin-6 (IL-6) is a cytokine critical for innate and adaptive immune responses. However, persistent expression of high levels of IL-6 are associated with a number of pathologic conditions including autoimmune diseases and capillary leak syndrome. Importantly, in kidney transplant patients, IL-6 may play a role in mediation of cell-mediated rejection (CMR) and antibody-mediated rejection (AMR). This is likely due to the importance of IL-6 in stimulating B cell responses with pathogenic donor-specific antibody (DSA) generation and stimulation of T effector cell responses while inhibiting T regulatory cells. Data from preliminary clinical trials and clinical observations show that tocilizumab (anti-IL-6R) and clazakizumab (anti-IL-6) may have promise in treatment of CMR, AMR and chronic (cAMR). This has led to a phase 3 placebo, randomized clinical trial of clazakizumab for treatment of cAMR, a condition for which there is currently no treatment. The identification of IL-6 production in vascular endothelia cells after alloimmune activation reveals another potential pathway for vasculitis as endothelia cell IL-6 may stimulate immune cell responses that are potentially inhibitable with anti-IL-6/IL-6R treatment. Importantly, anti-IL-6/IL-6R treatments have shown the ability to induce Treg and Breg cells in vivo which may have potential importance for prevention and treatment of DSA development and allograft rejection.

Evaluation of Clazakizumab (Anti-Interleukin-6) in Patients With Treatment-Resistant Chronic Active Antibody-Mediated Rejection of Kidney Allografts.

Introduction: Interleukin-6 (IL-6) is an important mediator of inflammation and activation of T cells, B cells, and plasma cells. Excessive IL-6 production is linked to human diseases characterized by unregulated antibody production, including alloimmunity, where persistence of donor-specific antibodies (DSAs), chronic active antibody-mediated rejection (cAMR), and graft loss are noted. Here, we report our experience investigating clazakizumab, a novel IL-6 inhibitor, in treating human leukocyte antigen (HLA)-sensitized patients with cAMR. Methods: Between February 2018 and January 2019, 10 adults with biopsy-proven cAMR were enrolled in a phase 2, single-center, open-label study. Patients received clazakizumab 25 mg subcutaneously (s.c.) monthly for 12 months, with a 6-month protocol biopsy. Primary end points included patient survival, graft survival, estimated glomerular filtration rate (eGFR), and safety. Secondary end points assessed immune markers (DSAs, IgG, T-regulatory [Treg] cells). At 12 months, stable patients entered a long-term extension (LTE). Results: LTE patients received clazakizumab for >2.5 years. Mean eGFRs showed significant declines from -24 months to study initiation (0 months) (52.8 ± 14.6 to 38.11 ± 12.23 ml/min per 1.73 m2, P = 0.03). However, after initiation of clazakizumab, eGFR stabilized at (41.6 ± 14.2 and 38.1 ± 20.3 ml/min per 1.73 m2, at 12 and 24 months, respectively). Banff 2017 analysis of pre- and post-treatment biopsies showed reductions in g+ptc and C4d scores. DSA reductions were seen in most patients. Adverse events (AEs) were minimal, and 2 graft losses occurred, both in patients who discontinued clazakizumab therapy at 6 months and 12 months after study initiation. Conclusion: In this small cohort of patients with cAMR, clazakizumab treatment showed a trend toward stabilization of eGFR and reductions in DSA and graft inflammation. No significant safety issues were observed. A randomized, placebo-controlled clinical trial (IMAGINE) of clazakizumab in cAMR treatment is underway (NCT03744910).

Assessment of humoral and cellular immune responses to SARS CoV-2 vaccination (BNT162b2) in immunocompromised renal allograft recipients.

BACKGROUND: Assessing the composition of immune responses to SARS-CoV-2 vaccines is critical for our understanding of protective immunity, especially for immune compromised patients. The Pfizer (BNT162b2) vaccination showed >90% efficacy in protecting individuals from infection. However, these studies did not examine responses in immunocompromised kidney transplant patients (KT). Subsequent reports in KT have shown severe deficiencies in Spike-specific immunoglobin G (IgG) responses prompting booster vaccinations, but a broader understanding of T-cell immunity to vaccinating is lacking. METHODS: We examined SARS-CoV-2 Spike IgG and CD4+/CD8+ Spike-specific T-cell responses in 61 KT patients maintained on different immunosuppressive protocols (ISP) (Tac + mycophenolate mofetil + prednisone) versus (belatacept + MMF + prednisone) and compared to 41 healthy controls. We also examined cytomegalovirus-cytotoxic T-cell responses (CMV-Tc) in both groups to assess T-cell memory. RESULTS: Our data confirmed poor Spike IgG responses in vaccinated KT patients with both ISP (21% demonstrating Spike IgG 1M post-second dose of BNT162b2 vs. 93% in controls). However, 35% of Spike IgG (-) patients demonstrated CD4+ and/or CD8+ T-cell responses. All but one CMV-IgG+ patient demonstrated good CMV-Tc responses. No differences in T-cell immunity by ISP were seen. CONCLUSION: Immunocompromised KT recipients showed severe defects in humoral and T-cell immune response after vaccination. No differences in immune responses to SARS-CoV-2 Spike peptides were observed in KT patients by ISP post-vaccination. The detection of Spike-specific T-cell immunity in the absence of Spike IgG suggests that vaccination in immunocompromised KT patients may provide partial immunity, although not preventing infection, T-cell immunity may limit its severity.

Clazakizumab for desensitization in highly sensitized patients awaiting transplantation.

Alloantibodies are a significant barrier to successful transplantation. While desensitization has emerged, efficacy is limited. Interleukin-6 (IL-6) is an important mediator of inflammation and immune cell activation. Persistent IL-6 production increases the risk for alloantibody production. Here we report our experience with clazakizumab (anti-IL-6) for desensitization of highly HLA-sensitized patients (HS). From March 2018 to September 2020, 20 HS patients were enrolled in an open label pilot study to assess safety and limited efficacy of clazakizumab desensitization. Patients received PLEX, IVIg, and clazakizumab 25 mg monthly X6. If transplanted, graft function, pathology, HLA antibodies and regulatory immune cells were monitored. Transplanted patients received standard immunosuppression and clazakizumab 25 mg monthly posttransplant. Clazakizumab was well tolerated and associated with significant reductions in class I and class II antibodies allowing 18 of 20 patients to receive transplants with no DSA rebound in most. Significant increases in Treg and Breg cells were seen posttransplant. Antibody-mediated rejection occurred in three patients. The mean estimated glomerular filtration rate at 12 months was 58 ± 29 ml/min/1.73 m2 . Clazakizumab was generally safe and associated with significant reductions in HLA alloantibodies and high transplant rates for highly-sensitized patients. However, confirmation of efficacy for desensitization requires assessment in randomized controlled trials.

Approach to Highly Sensitized Kidney Transplant Candidates and a Positive Crossmatch.

Human leukocyte antigen (HLA)-incompatible kidney transplantation offers survival benefit compared with ongoing dialysis. There have been considerable advances in the last decade to allow for increased access to transplant for the HLA-sensitized kidney transplant candidates. These include increased priority in the kidney allocation system, kidney paired donation, and novel desensitization strategies. A better understanding of the role of B cells, plasma cells, and complement and inflammatory cytokines in the pathophysiology of HLA antibody-mediated allograft injury has led to the use of novel therapeutics for desensitization and treatment of antibody-mediated rejection. Here we discuss current approaches to kidney transplantation in HLA-sensitized kidney transplant candidates.

Donor-derived Cell-free DNA Combined With Histology Improves Prediction of Estimated Glomerular Filtration Rate Over Time in Kidney Transplant Recipients Compared With Histology Alone.

Higher Banff inflammation and chronicity scores on kidney transplant biopsies are associated with poorer graft survival, although histology alone has limitations in predicting outcomes. We investigated if integrating donor-derived cell-free DNA (dd-cfDNA, Allosure; CareDx, Inc.) with Banff biopsy scores into a predictive model for estimated glomerular filtration rate over time can improve prognostic assessment versus histology alone. METHODS: We identified 180 kidney transplant patients with dd-cfDNA assessed within 1 mo of biopsy. Using linear mixed-effects models, a prediction model of Banff histology scores and dd-cfDNA on estimated glomerular filtration rate over time was derived. Nested models were compared using the likelihood-ratio test, Akaike Information Criterion, and Bayesian Information Criterion to assess if inclusion of dd-cfDNA into a model consisting of Banff biopsy scores would improve model fit. RESULTS: Univariate models identified significant covariate-by-time interactions for cg = 3 versus <3 (coefficient: -1.3 mL/min/1.73 m2/mo; 95% confidence interval [CI], -2.4 to -0.2; P = 0.02) and ci + ct ≥ 3 versus <3 (coefficient: -0.7 mL/min/1.73 m2/mo; 95% CI, -1.3 to -0.1; P = 0.03) and a trend toward significant covariate-by-time interaction for dd-cfDNA (coefficient: -0.5 mL/min/1.73 m2/mo; 95% CI, -1.0 to 0.1; P = 0.08). Addition of acute inflammation (i, t, and v), microvascular inflammation (g and ptc), and inflammation in area of interstitial fibrosis and tubular atrophy scores to chronicity scores (cg ≥ 3 and ci + ct ≥ 3) did not improve model fit. However, a model including dd-cfDNA with cg and ci + ct with covariate-by-time interactions had a better model fit compared with cg and ci + ct alone (likelihood-ratio test statistic = 21.1; df = 2; P < 0.001). CONCLUSIONS: Addition of dd-cfDNA to Banff biopsy scores provided better prognostic assessment over biopsy characteristics alone.

Compassionate Use of Tocilizumab for Treatment of SARS-CoV-2 Pneumonia.

BACKGROUND: Preliminary data from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia patients indicate that a cytokine storm may increase morbidity and mortality. Tocilizumab (anti-IL-6R) is approved by the Food and Drug Administration for treatment of cytokine storm associated with chimeric antigen receptor T-cell therapy. Here we examined compassionate use of tocilizumab in patients with SARS-CoV-2 pneumonia. METHODS: We report on a single-center study of tocilizumab in hospitalized patients with SARS-CoV-2 pneumonia. All patients had confirmed SARS-CoV-2 pneumonia and oxygen saturations <90% on oxygen support with most intubated. We examined clinical and laboratory parameters including oxygen and vasopressor requirements, cytokine profiles, and C-reactive protein (CRP) levels pre- and post-tocilizumab treatment. RESULTS: Twenty-seven SARS-CoV-2 pneumonia patients received one 400 mg dose of tocilizumab. Interleukin (IL)-6 was the predominant cytokine detected at tocilizumab treatment. Significant reductions in temperature and CRP were seen post-tocilizumab. However, 4 patients did not show rapid CRP declines, of whom 3 had poorer outcomes. Oxygen and vasopressor requirements diminished over the first week post-tocilizumab. Twenty-two patients required mechanical ventilation; at last follow-up, 16 were extubated. Adverse events and serious adverse events were minimal, but 2 deaths (7.4%) occurred that were felt unrelated to tocilizumab. CONCLUSIONS: Compared to published reports on the morbidity and mortality associated with SARS-CoV-2, tocilizumab appears to offer benefits in reducing inflammation, oxygen requirements, vasopressor support, and mortality. The rationale for tocilizumab treatment is supported by detection of IL-6 in pathogenic levels in all patients. Additional doses of tocilizumab may be needed for those showing slow declines in CRP. Proof of efficacy awaits randomized, placebo-controlled clinical trials.

The role of novel therapeutic approaches for prevention of allosensitization and antibody-mediated rejection.

Modification of pathogenic antibodies and their effector functions in autoimmune diseases or use of B cell/plasma cell-directed anticancer therapies have illuminated the biologic relevance of B cells, plasma cells (PCs), and pathogenic antibodies and complement in alloimmunity. They have also rejuvenated interest in how B cells mediate multiple effector functions that include antibody production, antigen presentation to T cells, costimulation, and the production of immune stimulating and immune modulatory cytokines that drive dysfunctional immune responses. Current methods to reduce alloantibodies are only modestly successful. Rituximab is used for desensitization and antibody-mediated rejection (AMR) treatment by targeting CD20 found on B-lymphocytes. However, PCs do not express CD20, likely explaining the limited success of this approach. Intravenous immunoglobulin and plasmapheresis (PLEX) have limited success due to antibody rebound. Despite attempts to develop tolerable therapeutics for management of AMR, none, to date, have been universally accepted or obtained Food and Drug Administration approval. Lack of approved therapeutics often results in patients having a much shorter graft survival due to AMR. Repurposing drugs from autoimmunity and cancer immunotherapy has rapidly yielded important advancements in the care of AMR patients. Here we discuss emerging therapeutics aimed at prevention and treatment of AMR.

Successful Treatment of Severe COVID-19 Pneumonia With Clazakizumab in a Heart Transplant Recipient: A Case Report.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is characterized by an overwhelming cytokine response. Various treatment strategies have been attempted. METHODS AND RESULTS: A 61-year-old man with heart transplantation in 2017 presented with fever, cough, and dyspnea, and was confirmed positive for coronavirus disease 2019 (COVID-19). Laboratory tests showed significant elevations in C-reactive protein and interleukin-6 (IL-6). Echocardiogram showed left ventricular ejection fraction 58% (with ejection fraction 57% 6 months prior). Given the lack of clear management guidelines, the patient was initially managed symptomatically. However, the patient subsequently had a rapid respiratory deterioration with worsening inflammatory markers on day 5 of admission. Tocilizumab (anti-IL-6R) was in low supply in the hospital. The patient was offered clazakizumab (anti-IL-6) for compassionate use. Patient received 25 mg intravenously × 1 dose. Within 24 hours, he showed significant improvement in symptoms, oxygen requirements, radiological findings, and inflammatory markers. There was a transient leukopenia that improved in 4 days. He was discharged home on day 11, with negative nasopharyngeal SARS-CoV-2 PCR as an outpatient on day 35, development of positive serum COVID-19 IgG antibody, and he continued to do well on day 60, with no heart-related symptoms. CONCLUSION: Clazakizumab is a monoclonal antibody against human IL-6, which may be helpful in inhibiting the cytokine response to SARS-CoV-2 in COVID-19. Although not yet FDA approved, it is being investigated for treatment of renal antibody-mediated rejection. Clinical trials of clazakizumab for treatment of COVID-19 are underway worldwide.

Intravenous immunoglobulin significantly reduces exposure of concomitantly administered anti-C5 monoclonal antibody tesidolumab.

Awareness of drug-drug interactions is critical in organ transplant recipient management. However, biologic agents interfering with monoclonal antibodies is not widely considered. We report the effect of high-dose intravenous immunoglobulin (IVIg) on safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of the human anti-C5 monoclonal antibody tesidolumab (LFG316) in end-stage renal disease patients awaiting kidney transplant. In this single-center, phase 1, open-label, parallel-group study, 8 patients were assigned to receive either single-dose tesidolumab + IVIg or tesidolumab alone, with 56-day follow-up. Within-group PK parameters were consistent. Mean tesidolumab exposure decreased 34%, clearance increased 63%, and half-life decreased 41% comparing tesidolumab + IVIg to tesidolumab alone. IVIg influence on tesidolumab elimination was most evident in the first 3 weeks. Complete suppression of both total and alternative complement activities was maintained for 4 weeks in the tesidolumab alone group and for 2 weeks in the tesidolumab + IVIg group. Tesidolumab was well tolerated. IVIg infused before tesidolumab affected tesidolumab PK and PD, resulting in a shortened period of full complement activity inhibition. These findings suggest a clinically relevant impact of IVIg on monoclonal antibody clearance and indirectly hint at an IVIg mechanism of action in treating autoimmune diseases and allosensitization by accelerating pathogenic IgG antibody degradation. Trial registration number: NCT02878616.

Interleukin-6: An Important Mediator of Allograft Injury.

Interleukin-6 (IL-6) is a cytokine with critical innate and adaptive immunity functions. Its diverse immunological and physiological actions include direction of immune cell differentiation, initial response to invading pathogens and ischemic injury, sustained plasma cell growth, and immunoglobulin production. IL-6 transcriptional dysregulation is commonly seen in patients with autoimmune or inflammatory disorders. Emerging information suggests that IL-6 transcription is upregulated in patients with kidney and heart transplant rejection and may account for perpetuation of inflammatory responses in the allograft, leading to allograft rejection and vasculopathy. IL-6-directed therapeutics include monoclonal antibodies directed at IL-6, the IL-6 receptor (IL-6R), and Janus kinase inhibitors. IL-6-mediated signaling to cell targets is unique, involving classic signaling (IL-6->IL-6R) cell membrane receptors, transsignaling (IL-6->soluble IL-6R->gp130) which activates any cell, and the recently discovered IL-6/IL-6R transpresentation in which antigen-presenting cells synthesize and express IL-6/IL-6R complexes, which are transported through the cell membrane subsequently interacting with gp130 to costimulate T cells. Currently, there are new trials in autoimmunity and heart and kidney transplantation to determine effectiveness of inhibiting IL-6/IL-6R to ameliorate chronic allograft rejection and coronary allograft vasculopathy. Therapeutic trials aimed at prevention of ischemia/reperfusion injury to allografts based on animal data should be considered.

Implications of Fc Neonatal Receptor (FcRn) Manipulations for Transplant Immunotherapeutics.

Alloimmune injury to allografts is mediated by pathogenic donor-specific alloantibodies, usually of the IgG isotype. Currently, strategies used to reduce donor-specific alloantibodies are collectively called desensitization. Despite successes, these treatments have limited efficacy and can be associated with adverse events, infectious complications, and high cost. Fc neonatal receptor (FcRn) was originally discovered as a transport mechanism for IgG from maternal circulation to fetus. FcRn receptors are now known to be widely distributed in virtually all tissues. IgG and albumin binding to FcRn is pH-dependent, which results in a significant prolongation their half-life. Structural analysis shows FcRn is a nonclassical major histocompatibility complex Class I receptor, which is emerging as a novel target to significantly reduce the half-life of pathogenic antibodies or extend the half-life of therapeutic monoclonals. Manipulation of IgG-Fc/FcRn interactions has implications for treatment of virtually all IgG-mediated diseases. The use of monoclonals directed at the FcRn can rapidly enhance the turnover of total IgG, including pathogenic IgG. In this review, we highlight the aspects of FcRn biology responsible for development of FcRn targeted therapeutics aimed at pathogenic autoantibodies and alloantibodies. We also explore the novel modifications of therapeutic monoclonals that exploit FcRn functions to enhance therapeutic efficacy.

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.

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.

Novel Therapeutic Approaches to Allosensitization and Antibody-mediated Rejection.

Modification of pathogenic antibodies for autoimmune diseases illuminated the biologic relevance of B cells, plasma cells, and pathogenic antibodies in autoimmunity. They have also rejuvenated interest in how B cells mediate multiple effector functions that include antibody production, antigen presentation to T cells, costimulation, and the production of immune stimulating and immune modulatory cytokines. Repurposing these drugs from autoimmunity and cancer immunotherapy has yielded important advancements in the care of antibody-mediated rejection patients and novel drug development aimed at HLA desensitization have recently emerged. We now stand on an important threshold that promises many advances in the care of our allosensitized patients. We hope that these initial advances will encourage basic scientist, clinical investigators, industry, National Institutes of Health, our academic societies, and the Food and Drug Administration to continue support of these important objectives. These advances clearly have implications for sensitized patients receiving solid organ transplants and antibody-mediated rejection treatment. Modification of alloimmunity and alloantibodies will also have relevance to xenotransplantation where the xenoantibodies present a formidable obstacle to advancement of this important therapy. Working together, we can advance transplant therapeutics where biologic agents are likely to play novel and important roles. Here, we discuss novel drugs emerging in this area.

A phase I/II, 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.

Delayed graft function (DGF) is defined as need for dialysis early posttransplant. DGF is related to ischemia-reperfusion injury (IRI) that diminishes allograft function and may be complement dependent. Here, we investigate the ability of C1 esterase inhibitor (C1INH) to prevent IRI/DGF in kidney transplant recipients. Seventy patients receiving deceased donor kidney transplants at risk for DGF were randomized to receive C1INH 50 U/kg (#35) or placebo (#35) intraoperatively and at 24 hours. The primary end point was need for hemodialysis during the first week posttransplant. Assessments of glomerular filtration rate and dialysis dependence were accomplished. Complications and safety of therapy were recorded. Similar characteristics with no significant differences in cold-ischemia time or risk factors for DGF were seen. C1INH did not result in reduction of dialysis sessions at 1 week posttransplant, but significantly fewer dialysis sessions (P = .0232) were required 2 to 4 weeks posttransplant. Patients at highest risk for DGF (Kidney Donor Profile Index ≥85) benefited most from C1INH therapy. Significantly better renal function was seen at 1 year in C1INH patients (P = .006). No significant adverse events were noted with C1INH. Although the primary end point was not met, significant reductions in need for dialysis and improvements in long-term allograft function were seen with C1INH treatment.