Kwaku Marfo

Desensitization protocols and their outcome

In the last decade, transplantation across previously incompatible barriers has increasingly become popular because of organ donor shortage, availability of better methods of detecting and characterizing anti-HLA antibodies, ease of diagnosis, better understanding of antibody-mediated rejection, and the availability of effective regimens. This review summarizes all manuscripts published since the first publication in 2000 on desensitized patients and discusses clinical outcomes including acute and chronic antibody-mediated rejection rate, the new agents available, kidney paired exchange programs, and the future directions in sensitized patients. There were 21 studies published between 2000 and 2010, involving 725 patients with donor-specific anti-HLA antibodies (DSAs) who underwent kidney transplantation with different desensitization protocols. All studies were single center and retrospective. The patient and graft survival were 95% and 86%, respectively, at a 2-year median follow-up. Despite acceptable short-term patient and graft survivals, acute rejection rate was 36% and acute antibody-mediated rejection rate was 28%, which is significantly higher than in nonsensitized patients. Recent studies with longer follow-up of those patients raised concerns about long-term success of desensitization protocols. The studies utilizing protocol biopsies in desensitized patients also reported higher subclinical and chronic antibody-mediated rejection. An association between the strength of DSAs determined by median fluorescence intensity values of Luminex single-antigen beads and risk of rejection was observed. Two new agents, bortezomib, a proteasome inhibitor, and eculizumab, an anti-complement C5 antibody, were recently introduced to desensitization protocols. An alternative intervention is kidney paired exchange, which should be considered first for sensitized patients.

Lack of effect in desensitization with intravenous immunoglobulin and rituximab in highly sensitized patients.

Background We conducted a prospective cohort study in highly sensitized kidney transplant candidates with a calculated panel reactive antibody (cPRA) greater than 50% and on the deceased-donor waiting list for more than 5 years to investigate the effects of intravenous immunoglobulin (IVIG) and rituximab treatment. Methods Desensitization protocol included two doses of IVIG (2 g/kg, max 120 g each dose) and a single dose of rituximab (375 mg/m2). Patients were followed up monthly by Luminex single antigen beads. Whole blood gene expression profiles were studied by Affymetrix Human 1.0 ST GeneChips before and after treatment. Results Forty patients were eligible for desensitization treatment. Thirteen of these patients agreed to participate, and 11 completed the treatment. After a mean follow-up of 334 ± 82 days, two desensitized patients (18%) received a kidney transplant compared with 14 patients (52%) in the nondesensitized group. Comparing with 14 patients who received transplants without any desensitization treatment, desensitized patients showed higher class I (99% vs. 80%) and class II (98% vs. 69%) cPRA levels and more unacceptable antigens (32 vs. 8). Desensitization treatment did not lead to any significant reduction in patients’ class I and II cPRA levels and any change in the mean number of unacceptable antigens or their mean fluorescence intensity values. Whole blood gene expression analysis by microarrays demonstrated down-regulation of immunoglobulin and B-cell–associated transcripts after treatment. Conclusion These results suggested that pretransplant desensitization with IVIG and rituximab was not successful in highly sensitized kidney transplant candidates with cPRA levels higher than 90%.

Pretransplant anti-HLA-Cw and anti-HLA-DP antibodies in sensitized patients.

We investigated the prevalence and the strength of anti-HLA-Cw and DP antibodies and clinical outcomes in kidney transplant recipients with isolated donor-specific anti-HLA-Cw antibodies. Patients on the waiting list were screened by Luminex single antigen beads (One Lambda). The strength of antibodies was determined by mean fluorescence intensity (MFI) values of the beads. Of the 1069 patients on the waiting list, 251 (24%) were sensitized with calculated panel reactive antibody >0%. The frequency and the median MFI values of anti-HLA antibodies to Cw (56%, 4955) and DP (35%, 2945) were lower than anti-HLA-A (79%, 10,194), B (86%, 11,235), DR (66%, 7866) and DQ (69%, 8283) (p<0.01). Among three major sensitizing events, only previous transplant was associated with development of all anti-HLA antibodies and history of pregnancy was associated only with development of anti-HLA-A antibodies. Eight patients with donor-specific anti-HLA-Cw antibodies received transplantation. During a median 6 months of follow-up (range 3-24 months), patient and graft survival was 100% without any acute rejection. In summary, the prevalence and the strength of anti-HLA-Cw and HLA-DP were lower compared to anti-HLA-A, B, DR, and DQ antibodies and previous organ transplantation was the main sensitizing event in our cohort of patients.

Pretransplant immunologic risk assessment of kidney transplant recipients with donor-specific anti-human leukocyte antigen antibodies.

Background Patients with pretransplantation strong donor-specific anti–human leukocyte antigen (HLA) antibodies (DSA) are at higher risk for rejection. We aimed to study the safety of kidney transplantation in patients with lower strength DSAs in a prospective cohort study. Methods Three hundred and seventy-three consecutive adult kidney transplant recipients with (DSA+; n=66) and without (DSA−; n=307) DSA were evaluated. Anti-HLA antibodies with mean fluorescence intensity values over 5,000 for HLA-A, HLA-B, and HLA-DR and more than 10,000 for HLA-DQ were reported as unacceptable antigens. Patients received transplant if flow cytometry T-cell and B-cell cross-match channel shift values were less than 150 and 250, respectively, with antithymocyte globulin and intravenous immunoglobulin induction treatment. Results Patients had a mean number of 1.6±0.8 DSAs with a mean fluorescence intensity value of 2,815±2,550. Twenty-seven percent were flow cytometry cross-match positive with T-cell and B-cell channel shift values of 129±49 and 159±52, respectively. During a median follow-up of 24 months (range, 6–50), there were no statistically significant differences in patient (99% vs. 95%) and graft survival (88% vs. 90%) rates between DSA+ and DSA− groups, respectively. Cumulative acute rejection rates of 11% in the DSA+ group and 12% in the DSA− group were similar. Two DSA+ (3%) and five DSA− (2%) patients developed chronic antibody-mediated rejection (3%). The mean serum creatinine levels were identical between the two groups (1.4±0.6 mg/dL). Conclusion Similar patient and graft survival, and acute rejection rates can be achieved in DSA+ patients compared to DSA− patients with pretransplantation immunologic risk assessment.

Genomics of BK viremia in kidney transplant recipients.

Background This study aimed to investigate global gene expression profiles of BK viremia and nephropathy (BKVN) samples using microarrays to investigate the immunologic response to BK virus. Methods Patients were monitored for BK viremia in the blood monthly for 6 months, then at 9 and 12 months after kidney transplantation. BKVN and normal transplant kidney biopsy samples, and whole blood samples of patients with and without BK viremia were analyzed by Affymetrix Human Gene 1.0 ST Arrays. Results During a mean follow-up of 917±325 days, 61 of the 289 patients (21%) developed BK viremia at a median 149 (27, 1,113) days after transplantation with a median peak PCR titers of 35,900 (1,000, 2,677,000). The only significant risk factor for development of BK viremia was induction with anti-thymocyte globulin (P=0.03). Only four patients developed BKVN (1.3%). Pathogenesis-based transcript analysis revealed a significant increased expression of interferon-gamma and rejection induced (GRIT), quantitative cytotoxic T-cell (QCAT), quantitative constitutive and alternate macrophage, B-cell and natural killer cell–associated transcripts (NKAT), indicating an active inflammatory immune response in BKVN biopsies (n=3) compared to normal transplant kidney biopsies with (n=3) and without BK viremia (n=11). The whole blood gene expression profiles of 19 BK viremia patients revealed significant increased expression of GRIT, QCAT, and NKAT compared to 14 patients without viremia. Conclusions The results showed increased activity of cytotoxic T cells and natural killer cells in BKVN and viremia samples resembling acute rejection and suggested the involvement of both adaptive and innate immunity.

Clinical and economic analysis of short-course versus standard-course antithymocyte globulin (rabbit) induction therapy in deceased-donor renal transplant recipients

PURPOSE The immunosuppressive effects of and costs associated with short-course antithymocyte globulin rabbit (ATG [rabbit]) therapy versus standard-course ATG (rabbit) therapy in deceased-donor renal transplant recipients were evaluated. METHODS The records of 84 consecutive patients who received a deceased-donor renal transplant at the Montefiore Einstein Center for Transplantation in 2008 were retrospectively reviewed. Donor and recipient characteristics, including rates of biopsy-confirmed acute rejection, serum creatinine (SCr) levels, and frequency of complications, and drug costs were collected. Patients were excluded if they had donor-specific antibodies identified before transplantation or hepatitis-C-positive serology or were under 18 years of age. RESULTS A total of 60 patients were included in the study, with 28 receiving short-course ATG (rabbit) therapy and 32 receiving standard-course ATG (rabbit) therapy. Baseline patient demographic characteristics were similar between groups. Six months after transplantation, biopsy-confirmed acute rejection episodes did not significantly differ between the short-course ATG (rabbit) and standard-course ATG (rabbit) groups (17.8% versus 12.5%, respectively), nor did SCr concentrations (1.56 mg/dL versus 1.85 mg/dL). The frequency of therapy-related leukopenia was greater in patients receiving standard-course ATG (rabbit). Patients treated with short-course ATG (rabbit) received a total mean dose of 4.6 mg/kg, compared with 7.3 mg/kg for patients in the standard-course ATG (rabbit) group, resulting in a mean cost saving of

Rabbit anti-thymocyte globulin induction in renal transplantation: review of the literature

2548 per patient. CONCLUSION After six months, there were no significant differences in biopsy- confirmed acute rejection episodes or SCr levels between deceased-donor renal transplant recipients receiving short-course versus standard-course ATG (rabbit) induction therapy. The mean cost saving associated with short-course therapy was

Clinical outcomes after conversion from brand-name tacrolimus (Prograf) to a generic formulation in renal transplant recipients: A retrospective cohort study

2548 per patient.

Pharmacoeconomic Analysis of Micafungin (Mycamine) 100 mg and 150 mg Daily In the Treatment of Candidemia.

Rabbit anti-thymocyte globulin (rATG) has proven benefit as induction therapy in renal transplant recipients, achieving reduced acute rejection rates and better short-term allograft function, with slightly higher rates of complications such as infections and malignancy. Compared with other agents, the most benefit from rATG induction has been observed in renal transplant recipients at high immunologic risk for rejection. However, in special populations, such as pediatrics, the elderly, and hepatitis C-positive and human immunodeficiency virus-positive renal transplant recipients, additional information is needed to delineate the absolute benefit of rATG induction compared with other induction agents. Selection of rATG as the choice of induction therapy in renal transplant recipients should be guided by a cost-effective approach in balancing efficacy, safety, and cost. This review summarizes the published literature on efficacy, safety, and cost of rATG induction in renal transplantation.