This is a single center, Phase I/II, open label single-arm exploratory study. The trial will primarily examine the safety and tolerability of clazakizumab given after consented and eligible patients begin desensitization therapy to achieve HLAi renal transplantation at Cedars-Sinai Medical Center. 20 subjects (ages 15 to 75) who are highly-HLA sensitized (HS) as determined by the cPRA ≥50% and are eligible for desensitization will be evaluated. All patients will be accrued from the renal transplant program at Cedars-Sinai Medical Center. Once desensitization begins, anti-HLA antibodies will be assessed which are associated with ABMR and/or graft loss. HLA antibodies will be detected using solid phase assay systems currently utilized at the Cedars-Sinai Medical Center HLA Laboratory. These anti-HLA antibodies may result naturally or from previous pregnancy, transfusions, or prior transplants. Patients treated with clazakizumab x 6 doses for desensitization will have blood sampling for HLA antibodies, and other monitoring blood samples as well as immunologic studies as outlined. If patients receive an HLAi transplant during the study, participants will receive the standard post-transplant immunosuppressive protocol, and clazakizumab 25 mg SC Q4W X 6 doses with immune monitoring as indicated.

Immune monitoring in blood samples for Treg, Tfh, Th17 and B-cell subsets as well as IL-6 and CRP monitoring will be carried out at the Cedars-Sinai Transplant Immunology Laboratory.

Patients identified as study participants will be HS and listed for HLAi renal transplantation at Cedars-Sinai Medical Center. Cedars-Sinai is a major U.S. desensitization center and performs \~80 HLAi renal transplants per-year. \~ 100 new HS patients are referred to Cedars-Sinai each year as potential candidates for desensitization. Eligible patients entering the study will initially receive PLEX (5-7 sessions) + IVIG and receive clazakizumab 25 mg SC one week post-IVIG. If no safety/tolerability/efficacy issues are observed after the initial dose, patients will receive 5 additional injections Q4W. If patients receive an HLAi transplant, clazakizumab will be continued for 6M post- transplant at 25mg SC Q4W for 6 doses (starting at Day 5 post-transplant). A protocol biopsy will be performed at 6M post-transplant to assess the allograft for evidence of ABMR, including C4d staining and TG using Banff 2015 criteria. Patients will continue another 6 doses over 6 months if improvements are seen after the 6th dose of clazakizumab. Patients who develop evidence of persistent allograft dysfunction may have non-protocol biopsies for cause. Patients who receive 12 doses of clazakizumab post-transplant will receive a 12M protocol biopsy. In the event a patient does not show improvement after receiving 6 doses of clazakizumab, no further treatment will be given and the patient will return at Day 365 for a final study visit. All subjects will be evaluated on an intent-to-treat basis. The subject accrual rate will be limited to no more than 1-2 subjects per month in the initial three months to assure safety to all subjects. Repeat laboratories will be performed at the completion of clazakizumab therapy to determine effect on levels and correlation with any potential events.

The subjects will be followed to determine if the use of clazakizumab for desensitization in this high risk transplant population is safe and without infectious risks. In addition, the investigators will determine the effects of clazakizumab treatment on HLA antibodies in efforts to improve access to HLAi transplants for these individuals. The investigators have previously reported acceptance criteria for HLAi kidney transplants. Renal biopsy assessments will be performed at 6M (per protocol) and 12M (for those who received 12 doses of therapy). The investigators will assess the transplanted patients to determine the number who sustain a viable and functioning kidney allograft as well. All subjects will be evaluated on an intent-to-treat basis. The subject accrual rate will be limited to no more than 1-2 subjects per month in the initial three months to assure safety to all subjects.