Steroid Withdrawal and Donor-specific Anti-HLA Antibodies in Renal Transplant Patients

Renal Transplant Rejection Clinical Trial

Official title:

Steroid Withdrawal and Novo Donor-specific Anti-HLA Antibodies in Renal Transplant Patients: a Prospective, Randomized and Controlled Study in Parallel Groups

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02284464
• Other study ID #: EVITAESTEROIDE-12
• Status: Completed
• Phase: Phase 4
• Start date: February 2015
• Est. completion date: December 2019

Study information

• Verified date: December 2019
• Source: Fundación Pública Andaluza para la Investigación de Málaga en Biomedicina y Salud
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Steroids are one of the pillars of immunosuppression for kidney transplant patients but their use is associated with a high rate of complications. Withdrawal of steroids reduces some metabolic and cardiovascular complications, but it may increase the risk of acute rejection. However, little is known about whether steroid withdrawal is associated with the generation of anti-HLA donor-specific antibodies (DSA) and the relation between DSA and clinical and histological data. The aim of this study is to compare the incidence of de novo anti-HLA DSA in stable kidney transplant patients after withdrawing the steroids 3 months after the transplantation as compared with patients who continue with steroids. The hypothesis is that steroid withdrawal will increase the presence of de novo anti-HLA DSA in stable kidney transplant patients

Recruitment information / eligibility

• Status: Completed
• Enrollment: 230
• Est. completion date: December 2019
• Est. primary completion date: July 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Male and female patients aged over 18 years with no immunological risk (PRA <25% and no DSA) who are receiving their first cadaveric or living kidney transplant.

2. Patients who, three months after the transplantation, are receiving tacrolimus in combination with mycophenolic acid (MPA) or mycophenolate mofetil (MMF) plus steroids, with stable plasma levels of tacrolimus.

3. No clinical or histological immunological dysfunction before randomization

4. No de novo anti-HLA DSA at the time of randomization.

5. Patients who wish to and are able to give written informed consent to participate in the study.

6. For women, agreeing to use efficient contraception during the study.

Exclusion Criteria:

1. Patients who receive a multiorgan transplant.

2. Retransplants.

3. Presence of DSA before the transplant or at the time of randomization.

4. Cold ischemia time >30 hours

5. Patients with serum creatinine >2 mg/dL or proteinuria >1g/day at the time of randomization

6. Prior episode of severe rejection (II-B-III in the Banff/13 classification) prior to randomization.

7. Presence of subclinical rejection on the protocol biopsy prior to randomization

8. Patients with BK-polyomavirus nephropathy at the time of randomization.

9. Patients with recurrent or de novo glomerulonephritis.

10. Patients who are being treated with immunosuppressive drugs other than those in the randomized clinical trial in question.

11. Patients who are positive for the human immunodeficiency virus (HIV) or those who have a severe systemic infection that, in the investigator's judgment, will require continued treatment.

12. Patients with any present or prior (during the previous 5 years) malignant disease, except basal or squamous cell carcinoma that has been excised.

Related Conditions & MeSH terms

• Other Complication of Kidney Transplant
• Renal Transplant Rejection

Intervention

Drug:
• Prednisone withdrawal
Withdrawal of steroids
• Prednisone continuation
Continuation of steroids

Locations

Country	Name	City	State
Spain	Bellvitge Hospital	Barcelona
Spain	Vall d Hebron Hospital	Barcelona
Spain	Carlos Haya Hospital	Malaga
Spain	Canarias University Hospital	Tenerife
Spain	Dr. Peset Hospital	Valencia

Sponsors (2)

Lead Sponsor	Collaborator
Fundación Pública Andaluza para la Investigación de Málaga en Biomedicina y Salud	Sociedad Andaluza de Trasplantes de Organos y Tejidos

Country where clinical trial is conducted

Spain, 

References & Publications (19)

Anil Kumar MS, Irfan Saeed M, Ranganna K, Malat G, Sustento-Reodica N, Kumar AM, Meyers WC. Comparison of four different immunosuppression protocols without long-term steroid therapy in kidney recipients monitored by surveillance biopsy: five-year outcomes. Transpl Immunol. 2008 Nov;20(1-2):32-42. doi: 10.1016/j.trim.2008.08.005. Epub 2008 Sep 4. — View Citation

Arnol M, de Mattos AM, Chung JS, Prather JC, Mittalhenkle A, Norman DJ. Late steroid withdrawal and cardiovascular events in kidney transplant recipients. Transplantation. 2008 Dec 27;86(12):1844-8. doi: 10.1097/TP.0b013e31818ffec0. — View Citation

Cantarovich D, De Amicis S, Akl A, Devys A, Vistoli F, Karam G, Soulillou JP. Posttransplant donor-specific anti-HLA antibodies negatively impact pancreas transplantation outcome. Am J Transplant. 2011 Dec;11(12):2737-46. doi: 10.1111/j.1600-6143.2011.03729.x. Epub 2011 Sep 11. — View Citation

Gill JS, Landsberg D, Johnston O, Shapiro RJ, Magil AB, Wu V, Tinckam K, Keown P. Screening for de novo anti-human leukocyte antigen antibodies in nonsensitized kidney transplant recipients does not predict acute rejection. Transplantation. 2010 Jan 27;89(2):178-84. doi: 10.1097/TP.0b013e3181c3503e. — View Citation

Gonzalez-Molina M, Gentil MA, Burgos D, Cabello M, Cobelo C, Bustamante J, Errasti P, Franco A, Hernández D. Effect of long-term steroid withdrawal in renal transplant recipients: a retrospective cohort study. NDT Plus. 2010 Jun;3(Suppl_2):ii32-ii36. — View Citation

Hoshino J, Kaneku H, Everly MJ, Greenland S, Terasaki PI. Using donor-specific antibodies to monitor the need for immunosuppression. Transplantation. 2012 Jun 15;93(11):1173-8. doi: 10.1097/TP.0b013e31824f3d7c. — View Citation

Kasiske BL, Chakkera HA, Louis TA, Ma JZ. A meta-analysis of immunosuppression withdrawal trials in renal transplantation. J Am Soc Nephrol. 2000 Oct;11(10):1910-7. — View Citation

Mao Q, Terasaki PI, Cai J, Briley K, Catrou P, Haisch C, Rebellato L. Extremely high association between appearance of HLA antibodies and failure of kidney grafts in a five-year longitudinal study. Am J Transplant. 2007 Apr;7(4):864-71. — View Citation

Marcén R. Immunosuppressive drugs in kidney transplantation: impact on patient survival, and incidence of cardiovascular disease, malignancy and infection. Drugs. 2009 Nov 12;69(16):2227-43. doi: 10.2165/11319260-000000000-00000. Review. — View Citation

Miller LW. Cardiovascular toxicities of immunosuppressive agents. Am J Transplant. 2002 Oct;2(9):807-18. Review. — View Citation

Moreso F, Ibernon M, Gomà M, Carrera M, Fulladosa X, Hueso M, Gil-Vernet S, Cruzado JM, Torras J, Grinyó JM, Serón D. Subclinical rejection associated with chronic allograft nephropathy in protocol biopsies as a risk factor for late graft loss. Am J Transplant. 2006 Apr;6(4):747-52. — View Citation

Opelz G, Döhler B, Laux G; Collaborative Transplant Study. Long-term prospective study of steroid withdrawal in kidney and heart transplant recipients. Am J Transplant. 2005 Apr;5(4 Pt 1):720-8. — View Citation

Opelz G, Döhler B. Association between steroid dosage and death with a functioning graft after kidney transplantation. Am J Transplant. 2013 Aug;13(8):2096-105. doi: 10.1111/ajt.12313. Epub 2013 Jun 10. — View Citation

Pascual J, Quereda C, Zamora J, Hernández D; Spanish Group for Evidence-Based Medicine in Renal Transplantation. Steroid withdrawal in renal transplant patients on triple therapy with a calcineurin inhibitor and mycophenolate mofetil: a meta-analysis of randomized, controlled trials. Transplantation. 2004 Nov 27;78(10):1548-56. — View Citation

Terasaki PI, Ozawa M. Predicting kidney graft failure by HLA antibodies: a prospective trial. Am J Transplant. 2004 Mar;4(3):438-43. — View Citation

Vincenti F, Schena FP, Paraskevas S, Hauser IA, Walker RG, Grinyo J; FREEDOM Study Group. A randomized, multicenter study of steroid avoidance, early steroid withdrawal or standard steroid therapy in kidney transplant recipients. Am J Transplant. 2008 Feb;8(2):307-16. doi: 10.1111/j.1600-6143.2007.02057.x. Erratum in: Am J Transplant.2008 May;8(5):1080. — View Citation

Wiebe C, Gibson IW, Blydt-Hansen TD, Karpinski M, Ho J, Storsley LJ, Goldberg A, Birk PE, Rush DN, Nickerson PW. Evolution and clinical pathologic correlations of de novo donor-specific HLA antibody post kidney transplant. Am J Transplant. 2012 May;12(5):1157-67. doi: 10.1111/j.1600-6143.2012.04013.x. Epub 2012 Mar 19. — View Citation

Woodle ES, First MR, Pirsch J, Shihab F, Gaber AO, Van Veldhuisen P; Astellas Corticosteroid Withdrawal Study Group. A prospective, randomized, double-blind, placebo-controlled multicenter trial comparing early (7 day) corticosteroid cessation versus long-term, low-dose corticosteroid therapy. Ann Surg. 2008 Oct;248(4):564-77. doi: 10.1097/SLA.0b013e318187d1da. — View Citation

Worthington JE, Martin S, Al-Husseini DM, Dyer PA, Johnson RW. Posttransplantation production of donor HLA-specific antibodies as a predictor of renal transplant outcome. Transplantation. 2003 Apr 15;75(7):1034-40. — View Citation

* Note: There are 19 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cases of Kidney Transplant Patients With DSA	Measurements of DSA at baseline, and at 3, 6, 12, 18 and 24 months	24 months
Secondary	Mean Score on the Protocol Biopsies in the Two Treatment Groups	Measurement at 24 months according to the Banff classification. The Banff Classification of Allograft Pathology is an international consensus classification for the reporting of biopsies from solid organ transplant. The scale ranges from 0 to 3, 3 being the worst.	24 months
Secondary	Number of Participants With Acute Rejection Lesions	Patients with acute rejection lesions (including subclinical rejection) at 24 months according to Banff classification	24 months
Secondary	Incidence of Diabetes Mellitus	Incidence of diabetes mellitus after kidney transplant in both groups at 1, 2, 3, 4, 6, 9, 12, 18 and 24 months	24 months
Secondary	Lipid Profile	Lipid profile after kidney transplant in both groups at 24 months	24 months
Secondary	Blood Pressure	Blood pressure after kidney transplant in both groups at 24 months	24 months
Secondary	Renal Function	Renal function after kidney transplant in both groups at 24 months measured according to the creatinine (mg/dL) concentrations	24 months
Secondary	Assess the Adherence to Immunosuppressive Therapy in the Two Treatment Groups	The Basle scale was used to assess adherence (BAASIS questionnaire) to immunosuppressive therapy.	At 24 months
Secondary	Patient Survival	Patient survival after kidney transplant in both groups	24 months
Secondary	Graft Survival	Graft survival after kidney transplant in both groups	24 months
Secondary	Renal Function	Renal function after kidney transplant in both groups at 24 months measured according to the proteinuria (mg/24 h) concentrations	24 months