Efficacy of Single Dose Anti-thymocyte Globulin in the Modulation of T Lymphocytes in Kidney Transplantation

Immunosuppression Clinical Trial

Official title:

Study of the Efficacy of Single Dose Anti-thymocyte Globulin in the Modulation of T Lymphocytes in Kidney Transplant Outcomes

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04835948
• Other study ID #: 38361620.0.0000.5327
• Status: Completed
• Start date: October 20, 2018
• Est. completion date: April 13, 2021

Study information

• Verified date: March 2021
• Source: Hospital de Clinicas de Porto Alegre
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The use of polyclonal anti-T cell antibodies (ATG) has benefits in kidney transplantation, however, its use is associated mainly with hematological, infectious, and neoplastic complications. Monitoring T cells in patients receiving ATG was first proposed in 1975 to improve efficacy in preventing acute rejection and avoiding excessive immunosuppression. The dose regimen is guided by a daily count of TCD3+ lymphocytes. Monitoring the dose of thymoglobulin through its biological effects on T cells is a rational and safe method of titrating the dose of that antibody. This way, it is possible to reduce the total amount of drug administered to the patient and, consequently, reduce undesirable complications, as well as the cost of treatment, without losing effect on the benefit of immunosuppression. Currently, the usual cumulative dose of ATG for induction in kidney transplant patients is 6mg/kg, in divided doses. However, the ideal dose and duration of therapy are still the subject of studies, with protocols between centers varying from total doses of 3 to 6 mg/kg, either fractionated or single, to achieve the lowest dose with fewer undesirable effects, and with reduced length of inpatient stay. The use of ATG in a single dose of 3 mg/kg was successfully assessed for risks of infection and rejection in patients with low immunological risk. This study proposes evaluating the efficacy and safety of a single 3mg/kg dose of ATG for patients with low and standard immune risk, with TCD3+ lymphocyte monitoring, to assess the duration of the TCD3+ cells in the peripheral blood.

Description:

Kidney transplantation is one of the major advances in medicine in the past 60 years. Currently, is considered the best treatment for terminal chronic kidney disease in the medium and long term, and the least costly. To obtain these successful outcomes, the immune response to the graft must be properly controlled and monitored since its implantation. T and B lymphocytes are crucial in the alloimmune response by mediating cellular and antibody-mediated rejections, respectively, and along with anti-HLA antibodies are the main effectors of acute and chronic rejections. Anti-thymocyte globulin (ATG) has a key role in the immunosuppressive induction regimens used in kidney transplants as well as in the treatment of acute rejections. It is a purified solution that contains a variety of T cell-specific immunoglobulins, including CD2, CD3, CD4, CD8, CD11a, CD18, CD25, HLA-DR, and class I HLA (human leukocyte antigen). This solution is produced by immunizing rabbits with human thymocytes. The use of these agents is particularly important in inducing patients who are more predisposed to the nephrotoxic effects of calcineurin inhibitors (CI), allowing the delayed introduction of the CI. Induction with antibodies is also of great value in patients with higher immunological risk, such as pediatric, Afro-descendants, re-transplanted, and previously sensitized to HLA antigens recipients. Polyclonal antibodies have definite benefits in kidney transplantation, but their use is associated with hematological, infectious, and neoplastic complications. The use of reduced doses of ATG has been the subject of recent studies, but still with inconclusive results. The concept of monitoring T cells in patients receiving ATG was first proposed in 1975 to improve efficacy in preventing acute rejection and avoiding excessive immunosuppression. The dose regimen is guided by a daily count of peripheral blood TCD3+ lymphocytes. Monitoring the dose of thymoglobulin through its biological effects on T cells is a rational and safe method of titrating the dose of that antibody. This way, it is possible to reduce the total amount of drug administered to the patient and, consequently, reduce undesirable complications, as well as the cost of treatment, hopefully without losing effect on the benefit of immunosuppression. A 60% reduction in the total dose of ATG and 58% reduction in therapy cost was observed in patients who were monitored using TCD3+ cell counts. Currently, the usual total dose of ATG for induction in kidney transplant patients is 6mg/kg, divided into 4 doses, which can be administered from day zero until day 14 (maximum) of transplantation. However, the ideal dose and duration of therapy are still the subject of investigation, with protocols between centers varying from total doses of 3 to 6 mg/kg, fractionated or single, to attempt to achieve the lowest dose with fewer undesirable effects, and with reduced length of inpatient stay. The use of ATG in a single dose of 3 mg/kg was successfully assessed for risks of infection and rejection in patients with low immunological risk. Considering that the adverse effects associated with the use of ATG are relevant in the clinical context of kidney transplantation, the use of a lower dose, keeping its immunomodulatory effect, with a safer profile, is desirable. The study evaluates the efficacy and safety of a single dose of 3mg/kg ATG for patients with low and standard immune risk, with TCD3+ lymphocyte monitoring, to assess the clinical efficacy and the modulation of the T cell response.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 200
• Est. completion date: April 13, 2021
• Est. primary completion date: March 31, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

Inclusion Criteria:

• Kidney transplant patients from Hospital de Clínicas de Porto Alegre (HCPA) between October 2018 to March 2020 who received a single 3 mg/kg ATG dose at the immediate postoperative period. Recipients of standard and low immunological risk (PRA - panel reactive antibodies <50% and without donor-specific antibodies), regardless of the time of cold ischemia and the presence of kidney failure in the donor.
• Control group consisting of patients from the same and previous period, who received fractionated ATG dosing up to 6 mg/kg total dose.

Exclusion Criteria:

• Patients who used other induction strategies that did not include ATG in a single dose of 3 mg/kg or the fractionated dose of 6 mg/kg.
• Patients who died within 24 hours after transplantation.
• Patients who had a transplant nephrectomy within 24 hours after transplantation.
• Pediatric recipients (< 14 years old).
• Recipients with incomplete data.

Related Conditions & MeSH terms

• Immunosuppression
• Kidney Transplant; Complications

Intervention

Drug:
• single dose of Anti-thymocyte globulin
Used anti-thymocyte globulin (ATG) in a single dose of 3 mg/kg for immunosuppression induction in the immediate postoperative period

Locations

Country	Name	City	State
Brazil	Hospital de Clínicas de Porto Alegre	Porto Alegre	RS

Sponsors (1)

Lead Sponsor	Collaborator
Hospital de Clinicas de Porto Alegre

Country where clinical trial is conducted

Brazil, 

References & Publications (21)

Abouna GM, al-Abdullah IH, Kelly-Sullivan D, Kumar MS, Loose J, Phillips K, Yost S, Seirka D. Randomized clinical trial of antithymocyte globulin induction in renal transplantation comparing a fixed daily dose with dose adjustment according to T cell monitoring. Transplantation. 1995 Jun 15;59(11):1564-8. — View Citation

Alangaden GJ, Thyagarajan R, Gruber SA, Morawski K, Garnick J, El-Amm JM, West MS, Sillix DH, Chandrasekar PH, Haririan A. Infectious complications after kidney transplantation: current epidemiology and associated risk factors. Clin Transplant. 2006 Jul-Aug;20(4):401-9. — View Citation

Bauer AC, Franco RF, Manfro RC. Immunosuppression in Kidney Transplantation: State of the Art and Current Protocols. Curr Pharm Des. 2020;26(28):3440-3450. doi: 10.2174/1381612826666200521142448. Review. — View Citation

Bishop G, Cosimi AB, Voynow NK, Whelchel JD, Wortis HH. Effect of immunosuppressive therapy for renal allografts on the number of circulating sheep red blood cells rosetting cells. Transplantation. 1975 Aug;20(2):123-9. — View Citation

Clesca P, Dirlando M, Park SI, García R, Ferraz E, Pinheiro-Machado PG, Kushnaroff L, Tedesco-Silva H Jr, Medina-Pestana JO. Thymoglobulin and rate of infectious complications after transplantation. Transplant Proc. 2007 Mar;39(2):463-4. — View Citation

Djamali A, Turc-Baron C, Portales P, Leverson G, Chong G, Clot J, Mourad G. Low dose antithymocyte globulins in renal transplantation: daily versus intermittent administration based on T-cell monitoring. Transplantation. 2000 Mar 15;69(5):799-805. — View Citation

First MR. Immunologically high-risk recipient strategies. Transplant Proc. 1999 Feb-Mar;31(1-2):243-6. Review. — View Citation

Gaber AO, Knight RJ, Patel S, Gaber LW. A review of the evidence for use of thymoglobulin induction in renal transplantation. Transplant Proc. 2010 Jun;42(5):1395-400. doi: 10.1016/j.transproceed.2010.04.019. Review. — View Citation

Grandtnerovà B, Mocikovà H, Kohutovà M. CD2+, CD3+, and CD19+ depletion after a course of antithymocyte globulin for a steroid-resistant rejection. Transplant Proc. 1997 Nov;29(7):2958-9. — View Citation

Kho MM, Bouvy AP, Cadogan M, Kraaijeveld R, Baan CC, Weimar W. The effect of low and ultra-low dosages Thymoglobulin on peripheral T, B and NK cells in kidney transplant recipients. Transpl Immunol. 2012 Jun;26(4):186-90. doi: 10.1016/j.trim.2012.02.003. Epub 2012 Mar 5. — View Citation

Krasinskas AM, Kreisel D, Acker MA, Bavaria JE, Pochettino A, Kotloff RM, Arcasoy S, Blumenthal N, Kamoun M, Moore JS, Rosengard BR. CD3 monitoring of antithymocyte globulin therapy in thoracic organ transplantation. Transplantation. 2002 Apr 27;73(8):1339-41. — View Citation

Mohty M, Bacigalupo A, Saliba F, Zuckermann A, Morelon E, Lebranchu Y. New directions for rabbit antithymocyte globulin (Thymoglobulin(®)) in solid organ transplants, stem cell transplants and autoimmunity. Drugs. 2014 Sep;74(14):1605-34. doi: 10.1007/s40265-014-0277-6. Review. Erratum in: Drugs. 2014 Dec;74(18):2217. — View Citation

Nafar M, Dalili N, Poor-Reza-Gholi F, Ahmadpoor P, Samadian F, Samavat S. The appropriate dose of thymoglobulin induction therapy in kidney transplantation. Clin Transplant. 2017 Jun;31(6). doi: 10.1111/ctr.12977. Epub 2017 Apr 18. — View Citation

Nankivell BJ, Alexander SI. Rejection of the kidney allograft. N Engl J Med. 2010 Oct 7;363(15):1451-62. doi: 10.1056/NEJMra0902927. Review. — View Citation

Peddi VR, Bryant M, Roy-Chaudhury P, Woodle ES, First MR. Safety, efficacy, and cost analysis of thymoglobulin induction therapy with intermittent dosing based on CD3+ lymphocyte counts in kidney and kidney-pancreas transplant recipients. Transplantation. 2002 May 15;73(9):1514-8. — View Citation

Taylor DO, Kfoury AG, Pisani B, Hammond EH, Renlund DG. Antilymphocyte-antibody prophylaxis: review of the adult experience in heart transplantation. Transplant Proc. 1997 Dec;29(8A):13S-15S. Review. — View Citation

Tedesco-Silva H, Felipe C, Ferreira A, Cristelli M, Oliveira N, Sandes-Freitas T, Aguiar W, Campos E, Gerbase-DeLima M, Franco M, Medina-Pestana J. Reduced Incidence of Cytomegalovirus Infection in Kidney Transplant Recipients Receiving Everolimus and Reduced Tacrolimus Doses. Am J Transplant. 2015 Oct;15(10):2655-64. doi: 10.1111/ajt.13327. Epub 2015 May 18. — View Citation

Thiyagarajan UM, Ponnuswamy A, Bagul A. Thymoglobulin and its use in renal transplantation: a review. Am J Nephrol. 2013;37(6):586-601. doi: 10.1159/000351643. Epub 2013 Jun 12. Review. — View Citation

Uber WE, Uber LA, VanBakel AB, Crumbley AJ 3rd, Pereira NL, Ikonomidis JS, Feldman DS. CD3 monitoring and thymoglobulin therapy in cardiac transplantation: clinical outcomes and pharmacoeconomic implications. Transplant Proc. 2004 Dec;36(10):3245-9. — View Citation

Wang CJ, Tuffaha A, Zhang D, Diederich DA, Wetmore JB. A CD3+ count-based thymoglobulin induction regimen permits delayed introduction of calcineurin inhibitors in kidney transplantation. Clin Transplant. 2012 Nov-Dec;26(6):900-9. doi: 10.1111/j.1399-0012.2012.01656.x. Epub 2012 Jun 4. — View Citation

Yang JW, Wang JN, Men TY, Zhang XM, Li XD, Shen B, Li GY, Chen DD. Comparison of clinical outcome of low-dose and high-dose rabbit antithymocyte globulin induction therapy in renal transplantation: a single-center experience. Ann Transplant. 2014 Jun 6;19:277-82. doi: 10.12659/AOT.890069. — View Citation

* Note: There are 21 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Occurence of infections and neoplasms	Number of patients with development of other infections and neoplasms of any etiology within one year proven by clinical features and laboratory or anatomopathological tests in the study patients.	One year
Other	Hematological effects of the drug.	Number of patients with hematological effects (laboratory analysis of anemia, leukopenia and thrombocytopenia) of ATG.	One year
Other	Time of inpatient stay (days).	Length of stay in days between groups with a single and fractionated dose of atg.	One year
Primary	Immunomodulatory effect	Immunomodulatory effect of a single dose of 3mg/kg ATG on TCD3+ lymphocytes in kidney transplant patients by comparing it with the effect of the regular fractionated dose of 6 mg/kg by counting daily the number of TCD3+ lymphocytes in peripheral blood.	one year
Secondary	Incidence of acute rejection	Number of patients with acute rejection diagnosed by renal biopsy with the single-dose ATG strategy.	one year
Secondary	Occurence of cytomegalovirus infection	Number of patients with cytomegalovirus infection (positive detection through polymerase chain reaction or active disease).	One year
Secondary	Incidence of delayed graft function	Number of patients with delayed graft function (DGF) through the number of dialysis needed in the first week after kidney transplantation.	one year
Secondary	One year survival of kidney grafts	Survival of kidney grafts at 1 year after receiving a single dose of ATG.	One year
Secondary	One year survival graft grafts	Patient survival at the end of 1 year of a single dose of ATG.	one year