The primary purpose of this study is to provide a preliminary evaluation of the safety and potential efficacy of carfilzomib in reducing HLA antibody levels in highly sensitized kidney transplant candidates.

This study is a non-randomized, open label, iterative pilot study. The duration of study will include a 16 month enrollment period and 5 to 6 months of follow-up. A total of 32 patients, male and female, between the ages 18 to 65 will be enrolled.

Inclusion Criteria:

1. Patient is between 18 and 65 years of age, inclusive.
2. Voluntary written informed consent.
3. Female subject is either postmenopausal for at least 1 year prior to initiation of study treatment, is surgically sterilized, or if of childbearing potential, agrees to practice 2 effective methods of contraception through 3 months after the last dose of carfilzomib.
4. Male subjects, even if surgically sterilized (i.e. status post-vasectomy) must agree to 1 effective contraception.
5. Patient with eligible living donor will have: 1) positive cytotoxic crossmatch, or 2) moderate to strongly positive T or B cell flow cytometry crossmatch (with confirmed donor-specific antibodies (DSAs) on solid-phase assay at screening, or 3) > 2 low to moderate level DSAs (DSA value from 1500 - 8000 MFI).
6. LVEF ≥ 45% within 3 months of evaluation.
7. Patient that is on the kidney transplant waiting list awaiting a deceased donor transplant and has a current or peak cytotoxic or calculated panel reactive antibody (PRA) > 30%.
8. Patient must have no known contraindications to treatment with carfilzomib or rituximab.
9. Review of pre-transplant medical clearance by the patient's dialysis nephrologist or transplant nephrologist or treating physician to assure the patient is medically acceptable for study entry.
10. Patient must be vaccinated against hepatitis B virus.

Exclusion Criteria:

1. Patient has significant neuropathy (Grades 3 - 4, or Grade 2 with pain) by CTCAE criteria within 14 days before enrollment.
2. Myocardial infarction within 6 months prior to enrollment or has ADQI Heart Failure in ESRD Classification System Class 2NR or greater (Appendix B), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.
3. Patient has received other investigational drugs within 14 days prior to initiation of study treatment.
4. Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
5. Diagnosed or treated for another malignancy within 2 years of enrollment, with the exception of: 1) complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, 2) an in situ malignancy, 3) low-risk prostate cancer after curative therapy, or 4) any cancer with a cure rate ≥ 99%.
6. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies.
7. Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib)
8. Patients with a hemoglobin count <8 g/dL (80 g/L) (subjects may be receiving red blood cell [RBC] transfusions in accordance with institutional guidelines), absolute neutrophil count < 1,000/mm3 or platelet count < 75,000/mm3 within 14 days of consent.
9. Patients who are anti-HIV-positive, or HBsAg-positive, or anti-HCV positive with a detectable HCV viral load on testing performed within one year of consent.
10. Patients with current or recent severe systemic infections requiring treatment (systemic antibiotics, antivirals, or antifungals) within the 2 weeks prior to initiation of study treatment.
11. Receipt of a live vaccine within 4 weeks prior to initiation of study treatment.
12. Evidence of severe liver disease by medical history or physical exam with abnormal liver profile (aspartate aminotransferase [AST], alanine aminotransferase [ALT] or total bilirubin > 1.5 times upper limit of normal [ULN]) on testing performed within 30 days of consent.
13. Female subject is pregnant or breast-feeding.
14. Any other clinically significant medical disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent.
15. Patient is not yet on dialysis.