Transplanting Sensitized Kidney Transplant

Patients With Equivalent Outcomes Utilizing

Stringent HLA Crossmatching

Experimental and Clinical Transplantation, 2017; 1: 47 – 55.

Santos S. Lisbon School of Health Technology.

Biomedical Engineering Master | Seminários II

Introduction
Elevated panel reactive antibody (PRA) levels have been traditionally
associated with increased time on transplant wait lists, delayed graft function
(DGF), acute rejection rate, and decreased long-term graft survival.1-4 Materials and Methods
Objective: Determine patient and allograft outcomes in sensitized kidney • Study design: Prospective, risk-stratified, randomized study to evaluate
transplant recipients with advanced HLA antibody detection and stringent the safety and efficacy of rATG versus interleukin 2 receptor antagonist
protein sequence epitope analyses. in combination with maintenance immunossupression in adult kidney
transplant recipients.
• Inclusion criteria: All patients between the ages of 18 and 75 years undergoing kidney transplant were eligible for enrollment.
• Exclusion criteria: Patients had received an organ other than a kidney, had a positive crossmatch, were recipients of HLA-identical living donors, were recipients of
an ABO-incompatible donor kidney, had received a multiorgan transplant, were themselves or received an organ from a donor known seropositive HIV, HBV or HCV.
• Clinical Analyses: Panel reactive antibody screening - FlowPRA (One Lambda); HLA antibody assays (Luminex, One Lambda); Flow cytometry crossmatch.
• Efficacy endpoints: The primary treatment efficacy was defined as the incidence of biopsy-proven acute rejection at 1 year after transplant.
• Safety endpoints: Incidence of posttransplant infection (CMV, BK virus), significant bacterial infection. Protocol biopsies if the patient experienced DGF.
• Induction therapy: rATG (Thymoglobulin) or interleukin 2 receptor antagonist (basiliximab).
• Maintenance immunosuppression: Mycophenolate mofetil (CellCept), tacrolimus (Prograf) and prednisone.

Results Luminex assays provide greater

sensitivity and specificity in detection
of antibodies. 5
Baseline characteristics
Evaluate the PRA levels according to
• No significant: Age, body mass, type 2 D.Mellitus, donor age, hypertension, hyperlipidemia, coronary disease, EBV.
donor specificity is significant to
• Significant: Female patients (P < .001), African American patients (P < .001), deceased-donors (P = .004),
reduce the possibility of rejection. 5
Cytomegalovirus (CMV) seropositivity (P = .010) and longer ischemia times (P = .002).
Bray and associates, using single
antigen beads and virtual
Immunosuppressive therapy
crossmatching, demonstrated that,
with biologic matching approach,
highly sensitized patients can be
successfully transplanted with
equivalent graft survival to patients
with low sensitization. 6
Previous studies demonstrated that
high PRA levels are associated with
increased DGF rate.7, 8
Transplant related factor remain the
most important determinants of DGF,
acute rejection and rejection. 9
Kidney paired donation avoids the
costs and complications of
desensitization therapies. 10
Figure 1 – Tacrolimus Concentrarion, Mycophenolate Mofetil and Corticosteroid Doses for the 2 cohorts during the first year after transplantt.

Table 2 – Factors affectoing acute rejection rates

Analysis of highly sensitized:

• Similar rates of acute rejection (P = 1.00) between PRA
Table 1 – Complications and Efficacy Endpoints ≤ 80% (180 patients) with PRA > 80% (20 patients).
Figure 2 – Curve for Rejection Survival based on PRA level. • In PRA > 80%, DGF was the strongest predictor of
rejection (P = .002) and immunossupressive induction
therapy had no effect on rejection episodes (P = .20).
Discussion
Traditionally, elevated PRA levels have been associated with increased risk of posttransplant DGF, acute rejection rates, and decreased long-term graft survival.1,3,4
Virtual crossmatching has enabled prediction of actual crossmatch results with a high degree of sensitivity and specificity. 6, 11 The results demonstrate similar rates of
complications between cohorts, including bacterial infections, CMV disease or syndrome, new-onset diabetes after transplant, and malignancy. The type of induction
immunossuppression was not associated with rejection episodes.
Rejection rates did not differ based on PRA level, even when analyzed in the cohort with PRA levels > 80%. Only 1 patient in this highly sensitized group experienced
rejection, secondary to CMV infection. The incidence of BK viremia and BK virus nephropathy in our study is similar to other reported studies. 12
Limitations presented are the relatively small number of patients in the highly sensitized group (PRA >80%), the large number of African American transplant
recipients known to be at higher risk of acute rejection, the study time of 1-year follow-up.
This analysis demonstrated that the use of contemporary maintenance immunosuppression with appropriate biologic matching provides very low acute rejection rates
in sensitized patients.
1.Barama A, Oza U, Panek R, et al. Effect of recipient sensitization (peak PRA) on graft outcome in haploidentical living related kidney transplants. Clin Transplant. 2000;14(3):212-217.
2.Krieger NR, Becker BN, Heisey DM, et al. Chronic allograft nephropathy uniformly affects recipients of cadaveric, nonidentical living-related, and living-unrelated grafts. Transplantation. 2003;75(10):1677-1682.

References 3.Basu A, Falcone J, Dvorchik I, et al. Outcomes of renal transplantation in recipients with peak panel reactive antibody >30% under tacrolimus-based immunosuppression. Ann Transplant. 2011;16(3):5-13.
4.Opelz G, Collaborative Transplant S. Non-HLA transplantation immunity revealed by lymphocytotoxic antibodies. Lancet. 2005;365(9470):1570-1576.
5.Inal A, Ozçelik U., et al. Analysis of Panel Reative Amtibodies in Renal Transplant Recipients Detected by Luminex: A Single-Center Experience. Experimental and Clinical Transplantation. 2016; 4: 401-404.
6.Bray RA, Nolen JD, Larsen C, et al. Transplanting the highly sensitized patient: The emory algorithm. Am J Transplant. 2006;6(10):2307-2315.
7. Arias M. Impact of the delayed graft function in hypersensitized kidney transplant patients. Transplant Proc. 2003;35(5):1655-1657.
8. Lopez-Hoyos M, Fernandez-Fresnedo G, Rodrigo E, Ruiz JC, Arias M. Effect of delayed graft function in hypersensitized kidney transplant recipients. Hum Immunol. 2005;66(4):371-377.
9.Dirk Jan A.R. Moes, et al. Exploring genetic and non-genetic risk factos for delayed graft function, acute and subclinical rejection in renal transplant recipientes. Br J Clin Pharmacol. 2016; 82: 227-237.
10. Vivek K. et al. International kidney paired donation transplantation to increase kidney transplant of O Group and highly sensitized patient: First repot from India. World J Trnasplant. 2017; 24; 7(1): 64-69.
11. Amico P, Honger G, Steiger J, Schaub S. Utility of the virtual crossmatch in solid organ transplantation. Curr Opin Organ Transplant. 2009;14(6):656-661.
12. Sood P, Senanayake S, Sujeet K, et al. Management and outcome of BK viremia in renal transplant recipients: a prospective single-center study. Transplantation. 2012;94(8):814-821.