Molecular Markers of Acute Kidney Injury in Elderly Deceased Donors

Study Overview
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Brief Summary
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Scoring systems that combine donor clinical and morphological parameters to predict outcome of kidney transplantation lack enough specificity to be generally accepted. Compare to classical histology, molecular assessment of renal tissue offers unbiased and technically robust approach. In this prospective 3-months' observational study procurement biopsies in 180 brain death donors will be performed. Using microarray which detect top differently regulated genes, conventional histology, urinary AKI biomarkers, renal function and clinical variables models predicting DGF and early graft scarring (IFTA, poor graft function) in recipients will be constructed. The associations of AKI in donors with distinct fibrosis atrophy and AKI molecular signals will be found. Molecular techniques and final models may help to improve the decision-making process for the acceptance of kidneys from marginal donors but more importantly, it may help clinicians to guide less toxic immunosuppression in identified problematic grafts.

Detailed Description
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The aim is to create a prediction model of early clinical outcome (delayed graft function) based on donor and recipient clinical variables, donor eGFR, urinary AKI biomarkers, histology (glomerulosclerosis, interstitial fibrosis, vascular changes) and top differently regulated genes found in microarray of wedge procurement donor biopsy. Construct a model capable to predict early renal allograft scarring (IFTA>2), and impaired graft function (eGFR<45 mL/min), as early as at 3 months. Describe renal molecular changes associated with established AKI in brain-death deceased donor and with aging.

Official Title
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Molecular Markers of Acute Kidney Injury in Elderly Deceased Donors

Conditions
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Kidney Transplantation, Acute Kidney Injury

Intervention / Treatment
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* Diagnostic Test: Urine Biomarkers
* Diagnostic Test: Gene expression profiling of donor kidneys by microarray
* Diagnostic Test: Gene expression profiling of recipient kidneys by microarray


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All DBD (donation after brain death) donors whose kidneys will be procured by transplant team of Institute for Clinical and Experimental Medicine (IKEM) in donor hospital. All DBD (donation after brain death) donors whose kidneys will be procured by transplant team of Institute for Clinical and Experimental Medicine (IKEM) at IKEM. Exclusion Criteria: Donors with circulatory death Donors with machine perfusion Donors with multiorgan transplantation.
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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Acute kidney injury (AKI)<br>Donors with AKI (acute kidney injury) defined based on the results of creatinine increase and diuresis decrease before organ harvest. | Diagnostic Test: Urine Biomarkers<br>* Biomarkers of kidney damage in donors, such as neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-beta-D-glucosaminidase (NAG), beta2-microglobulin, alpha1-microglobulin, alpha2-macroglobulin and transferrin will be measured by ELISA.<br>Diagnostic Test: Gene expression profiling of donor kidneys by microarray<br>* Gene expression profiling of donor kidney biopsies using Affymetrix microarray platform (PrimeView Human Gene Expression Array).<br>Diagnostic Test: Gene expression profiling of recipient kidneys by microarray<br>* Gene expression profiling of donor kidney biopsies using Affymetrix microarray platform (PrimeView Human Gene Expression Array).<br>|
| no-AKI<br>Donors without AKI (acute kidney injury) defined based on the results of creatinine increase and diuresis decrease before organ harvest. | Diagnostic Test: Urine Biomarkers<br>* Biomarkers of kidney damage in donors, such as neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-beta-D-glucosaminidase (NAG), beta2-microglobulin, alpha1-microglobulin, alpha2-macroglobulin and transferrin will be measured by ELISA.<br>Diagnostic Test: Gene expression profiling of donor kidneys by microarray<br>* Gene expression profiling of donor kidney biopsies using Affymetrix microarray platform (PrimeView Human Gene Expression Array).<br>Diagnostic Test: Gene expression profiling of recipient kidneys by microarray<br>* Gene expression profiling of donor kidney biopsies using Affymetrix microarray platform (PrimeView Human Gene Expression Array).<br>|
| delayed graft function (DGF)<br>Donors and the paired recipients in whom the organ was transplanted in IKEM (Institute for Clinical and Experimental Medicine) who developed delayed graft function (DGF) defined as dialysis in the 1st week after transplantation. | Diagnostic Test: Urine Biomarkers<br>* Biomarkers of kidney damage in donors, such as neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-beta-D-glucosaminidase (NAG), beta2-microglobulin, alpha1-microglobulin, alpha2-macroglobulin and transferrin will be measured by ELISA.<br>Diagnostic Test: Gene expression profiling of donor kidneys by microarray<br>* Gene expression profiling of donor kidney biopsies using Affymetrix microarray platform (PrimeView Human Gene Expression Array).<br>Diagnostic Test: Gene expression profiling of recipient kidneys by microarray<br>* Gene expression profiling of donor kidney biopsies using Affymetrix microarray platform (PrimeView Human Gene Expression Array).<br>|
| no-DGF<br>Donors and the paired recipients in whom the organ was transplanted in IKEM (Institute for Clinical and Experimental Medicine) with immediate graft function (no-DGF). | Diagnostic Test: Urine Biomarkers<br>* Biomarkers of kidney damage in donors, such as neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-beta-D-glucosaminidase (NAG), beta2-microglobulin, alpha1-microglobulin, alpha2-macroglobulin and transferrin will be measured by ELISA.<br>Diagnostic Test: Gene expression profiling of donor kidneys by microarray<br>* Gene expression profiling of donor kidney biopsies using Affymetrix microarray platform (PrimeView Human Gene Expression Array).<br>Diagnostic Test: Gene expression profiling of recipient kidneys by microarray<br>* Gene expression profiling of donor kidney biopsies using Affymetrix microarray platform (PrimeView Human Gene Expression Array).<br>|
| Recipient IFTA<br>Donors and the paired recipients in whom the organ was transplanted in IKEM with 3-month protocol biopsy histology finding of IFTA≥2. | Diagnostic Test: Gene expression profiling of donor kidneys by microarray<br>* Gene expression profiling of donor kidney biopsies using Affymetrix microarray platform (PrimeView Human Gene Expression Array).<br>Diagnostic Test: Gene expression profiling of recipient kidneys by microarray<br>* Gene expression profiling of donor kidney biopsies using Affymetrix microarray platform (PrimeView Human Gene Expression Array).<br>|
| Recipient no-IFTA<br>Donors and the paired recipients in whom the was transplanted in IKEM with 3-month protocol biopsy histology finding of IFTA<2. | Diagnostic Test: Gene expression profiling of donor kidneys by microarray<br>* Gene expression profiling of donor kidney biopsies using Affymetrix microarray platform (PrimeView Human Gene Expression Array).<br>Diagnostic Test: Gene expression profiling of recipient kidneys by microarray<br>* Gene expression profiling of donor kidney biopsies using Affymetrix microarray platform (PrimeView Human Gene Expression Array).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kidney graft function at month 3 | Kidney graft function is measured as estimated glomerular filtration in ml/s/1.73m2. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kidney graft survival | Measured as numbers of patients with graft loss censored to death. | 1 year | 
| Delayed graft function | The need of dialysis in the 1st week after transplantation. Measured as numbers of patients. | 1 week | 
| Fibrosis grade at month 3 | Histologic result of interstitial fibrosis and atrophy at protocol biopsy. Min 0, Max 3, higher means worse | 3 months | 
| Gene expression in Donor kidney | Whole transcriptome microarray profiling of wedge biopsy taken immediately after organ procurement. | 3 months | 
| Gene expression in 3-month protocol biopsy of recipient | Whole transcriptome microarray profiling of 3-months protocol biopsies of recipients . | 3 months | 
| Urinary biomarkers of AKI in donors before organ taking | NGAL, Neutrophil gelatinase-associated lipocalin, ng/ml. | 3 months | 
| Urinary biomarkers of AKI in donors before organ taking (NAG) | NAG, N-acetyl-beta-D-glucosamine, in IU/l | 3 months | 
| Urinary biomarkers of AKI in donors before organ taking (beta 2 microglobulin) | beta 2 microglobulin, in mg/l | 3 months | 
| Urinary biomarkers of AKI in donors before organ taking (alfa1 microglobulin) | alfa1 microglobulin, in mg/l | 3 months | 
| Urinary biomarkers of AKI in donors before organ taking (alfa2 macroglobulin) | alfa2 macroglobulin, in mg/l | 3 months | 
| Urinary biomarkers of AKI in donors before organ taking (transferrin) | transferrin, in mg/l | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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kidney transplantation, donor kidney, microarray