Impact of Immunosuppressive Regimens on Polyomavirus-related Transplant Nephropathy

Study Overview
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Brief Summary
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The aim of this study is to characterize and evaluate risk factors of polyomavirus nephropathy (PVN) including the impact of three immunosuppressive regimens.

Detailed Description
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Polyomavirus nephropathy (PVN) is an emerging cause of renal transplant loss. Until now the risk factors of PVN are poorly understood. Tacrolimus (Tacr) and mycophenolate mofetil (MMF) are thought to be associated with a higher risk of developing PVN. However, the way in which Tacr or MMF might enhance the susceptibility for PVN remains largely unknown. In this prospective study we will analyze whether differences in immune-reactivity patterns (Th1, Th2, B cell and monocyte responses, sCD30, immunoregulatory antibodies) of renal transplant patients induced by different immunosuppressive regimens (cyclosporine A [CsA]/MMF, Tacr/MMF, Tacr/MMF with conversion to Tacr/Everolimus [ERL]) or by cytokine promoter gene polymorphisms may account for the different risks of developing PVN. Comparison(s): renal transplant recipients stratified according to their relative immunological risk (group 1: low risk (primary recipients without pre-immunization [PRA < 5%]); group 2: moderate risk (group 2a: primary recipients with low pre-immunization [PRA 6-20%]; group 2b: re-transplanted patients); group 3: very high risk (re-transplanted patients with a history of vascular rejection or recipients of a first graft with high pre-immunization [PRA > 20%]) randomized to be treated with one of three immunosuppressive regimens (CsA/MMF, Tacr/MMF, Tacr/MMF with subsequent conversion to Tacr/ERL).

Official Title
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Prospective Randomized Study to Characterize Risk Factors of Polyomavirus-related Transplant Nephropathy and the Impact of Three Immunosuppressive Regimens on Nephropathy Incidence

Conditions
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Polyomavirus Infections

Intervention / Treatment
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* Drug: Ciclosporin and Mycophenolate-mofetil
* Drug: Tacrolimus and Mycophenolate-mofetil
* Drug: Tacrolimus and Mycophenolate-mofetil with change from Mycophenolate-mofetil to Everolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Cadaver kidney and living donor kidney transplant recipients Primary, secondary, and tertiary transplant recipients Pre-immunized and not pre-immunized transplant recipients Age > 18 years Exclusion Criteria: Contraindications against administration of one of the four study drugs History of severe gastrointestinal morbidity Age < 18 years Pregnant or breast feeding women Rejection of effective contraceptive methods with young women Combined kidney and islet cell transplantation

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>Immunosuppression with Ciclosporin and Mycophenolate-mofetil; Ciclosporin treatment being started at the latest at day 4 after transplantation with 7 mg/kg body weight daily administered every 8 hours until the target trough level of 300 µg/l was reached. Then it was administered twice daily with daily monitoring of trough levels. The target trough level was lowered to 200 µg/l 1 month after transplantation. Thereafter dosage and target trough levels were adjusted at the investigators discretion. Mycophenolate-mofetil was started previous to transplantation procedure with a starting dosage of 3 g/day administered twice daily. Once ciclosporin was entered into the therapy-scheme Mycophenolate-mofetil dosage was reduced to 2 g/daily. The therapy was controlled by measuring of trough levels with a target trough level exceeding 1 µg/ml. The dosage was adjusted at the investigators discretion. | Drug: Ciclosporin and Mycophenolate-mofetil<br>* according to the Giessen protocol<br>|
| Active Comparator: 2<br>Immunosuppression with Tacrolimus and Mycophenolate-mofetil Mycophenolate-mofetil was started previous to transplantation procedure with a starting dosage of 3 g/day administered twice daily. Once tacrolimus was entered into the therapy-scheme Mycophenolate-mofetil dosage was reduced to 2 g/daily. The therapy was controlled by measuring of trough levels with a target trough level exceeding 1 µg/ml. The dosage was adjusted to clinical signs of overimmunosuppression (infections) or intolerance (mainly gastrointestinal side effects) or rejections. | Drug: Tacrolimus and Mycophenolate-mofetil<br>* according to Giessen protocol<br>|
| Active Comparator: 3<br>Immunosuppression with Tacrolimus and Mycophenolate-mofetil with change from Mycophenolate-mofetil to Everolimus after completion of posttransplant wound healing | Drug: Tacrolimus and Mycophenolate-mofetil with change from Mycophenolate-mofetil to Everolimus<br>* according to Giessen protocol<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| incidence of polyomavirus associated transplant nephropathy (PVN) |  | 2 years posttransplant | 
| incidence of polyoma viremia |  | 2 years posttransplant | 
| urine polyomavirus concentration within the first two years post-transplant |  | 2 years posttransplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| patients' and grafts' survival |  | 2 years posttransplant | 
| incidence of acute rejections |  | 2 years posttransplant | 
| transplant function 1 and 2 years post-transplant |  | 2 years posttransplant | 
| comparison of urine cytology and polymerase chain reaction (PCR) quantitative data regarding diagnosis of PVN |  | 2 years posttransplant | 
| predictive value of immune parameters prognostically relevant for acute or chronic rejection |  | 2 years posttransplant | 
| side effects of immunosuppressive drugs |  | 2 years posttransplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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kidney transplantation, polyoma virus associated transplant nephropathy, tacrolimus, mycophenolate mofetil, everolimus, cyclosporin A, BK virus PCR, viruria screening, BK polyomavirus, immunosuppression