Renal Tubular Injury and Transplant Outcomes in Cardiac Recipients Converting From IR Tacrolimus to XR Tacrolimus

Study Overview
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Brief Summary
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Immediate release (IR) tacrolimus peaks in the first two hours after administration. These peak levels are influenced by CYP3A5 expression with expressors requiring higher total daily doses with higher peak levels compared to non-expressors. Tacrolimus XR (Envarsus) is a once daily formulation with delayed absorption and lower peak levels while maintaining similar trough levels as seen with IR tacrolimus. A randomized trial of conversion from IR tacrolimus to tacrolimus XR in kidney transplant recipients have shown similar efficacy and adverse events between the two groups but no improvement in estimated GFR. However, urinary biomarkers of acute kidney injury associated with changes in tacrolimus dosing may be more sensitive then serum creatinine. The objective of this study is to assess renal tubular injury in heart transplant recipients who are converted from immediate release to tacrolimus XR. The hypothesis is that the delayed absorption and lower peak levels of tacrolimus XR will lead to less tubular injury and improved renal function without increased risk to the heart allograft.

Detailed Description
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The primary outcome is change in urinary NGAL expression with conversion from IR tacrolimus to tacrolimus XR. In aim 1, changes in urinary biomarkers of tubular injury at 4 weeks after conversion to tacrolimus XR with stable trough levels will be assessed. These changes will be assessed by CYP3A5 expressor category that will be determined by genotyping of a single gene for variants. The changes in GFR using the creatinine-cystatin C CKD-EPI equation will be assessed. In aim 2, the rate of rejection as defined as treated rejection within the last 30 days for any grade > 1R or AMR or acute graft dysfunction (LV ejection fraction drop > 10%) will be looked. The cardiac allograft vasculopathy based on coronary angiography +/- IVUS and right heart catheterization hemodynamics at baseline and 1 year post conversion will also be evaluated. In addition to changes in cardiac function, the changes in blood pressure, serum glucose, and cholesterol in the first year after conversion will be assessed.

Official Title
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Assessment of Renal Tubular Injury and Transplant Outcomes in Cardiac Recipients Converting From Immediate Release Tacrolimus to Extended Release Tacrolimus.

Conditions
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Chronic Kidney Diseases, Heart Transplant

Intervention / Treatment
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* Drug: Conversion from IR Tacrolimus to XR Tacrolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Stable, heart-only transplant recipient within 10 years of transplantation 18 -80 years old Currently taking IR Tacrolimus Baseline eGFR> 30mL/min/1.73m2 Exclusion Criteria: Multiple organ transplant recipients Less than 18 years old Greater than 80 years old Heart-only transplants recipients with active malignancy, rejection, or greater than 10 years from transplantation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Extended Release Tacrolimus<br>All participants who consent to the study will be in this group. | Drug: Conversion from IR Tacrolimus to XR Tacrolimus<br>* All participants will be consented to the study on IR Tacrolimus. After their baseline visit, they will be converted to XR Tacrolimus<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urinary neutrophil gelatinase-associated lipocalin (NGAL) | Change in Urinary NGAL level (ng/mL) | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimated Glomerular Filtration Rate (eGFR) | Change in eGRF level by the Creatinine-Cystatin C CKD-EPI equation (mL/min/1.73m2) | 4 weeks | 
| Microalbuminuria | Change in Urine albumin-creatinine ratio | 4 weeks | 
| CYP3A5 expressor category | CYP3A5 genotyping to determine expressor category | Baseline | 
| Heart transplant rejection | The rate of rejection as defined as treated rejection within the last 30 days for any grade>1R, AMR, or acute graft dysfunction (LVEF drop greater than 10%) | 1 year | 
| Cardiac allograft vasculopathy | The rate of cardiac allograft vasculopathy based on coronary angiography with or without IVUS and right heart catheterization hemodynamics | 1 year | 
| Blood pressure | Change in blood pressure (mmHg) | 1 year | 
| Serum glucose | Change in serum glucose levels (mg/dL) | 1 year | 
| LDL Cholesterol | Change in LDL cholesterol level (mg/dL) | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immediate Release Tacrolimus, Extended Release Tacrolimus, IR Tacrolimus, XR Tacrolimus, Renal Tubular Injury, Heart Transplant Recipient, Chronic Kidney Disease