Molecular Markers of Acute Kidney Injury in Elderly Deceased Donors (MoliDon)

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.

Study Overview

• Status: Completed
• Conditions: Kidney Transplantation; Acute Kidney Injury
• Intervention / Treatment: Diagnostic test: Urine Biomarkers; Diagnostic test: Gene expression profiling of donor kidneys by microarray; Diagnostic test: Gene expression profiling of recipient kidneys by microarray

Detailed Description

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.

• Study Type: Observational
• Enrollment (Actual): 200

Contacts and Locations

Study Locations

• Czechia
  • Prague, Czechia, 140 21
    • Institute for Clinical and Experimental Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

All DBD donors whose kidneys will be procured by IKEM transplant team either in donor hospital or at IKEM. Corresponding recipients, transplanted at IKEM will be further monitored. Patients will receive standard immunosuppression based on tacrolimus, mycophenolate mofetil and steroids along with induction (basiliximab in low risk and rATG in high-risk) according to center protocol. All procedures in transplant recipients will be routine ones, included for cause biopsies and 3M protocol biopsy (standard of care in the center).

Description

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.

Study Plan

How is the study designed?

Number of groups / cohorts

6

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Acute kidney injury (AKI); Donors with AKI (acute kidney injury) defined based on the results of creatinine increase and diuresis decrease before organ harvest.	Diagnostic test: Urine Biomarkers; 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.; Diagnostic test: Gene expression profiling of donor kidneys by microarray; Gene expression profiling of donor kidney biopsies using Affymetrix microarray platform (PrimeView Human Gene Expression Array).; Diagnostic test: Gene expression profiling of recipient kidneys by microarray; Gene expression profiling of donor kidney biopsies using Affymetrix microarray platform (PrimeView Human Gene Expression Array).
no-AKI; Donors without AKI (acute kidney injury) defined based on the results of creatinine increase and diuresis decrease before organ harvest.	Diagnostic test: Urine Biomarkers; 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.; Diagnostic test: Gene expression profiling of donor kidneys by microarray; Gene expression profiling of donor kidney biopsies using Affymetrix microarray platform (PrimeView Human Gene Expression Array).; Diagnostic test: Gene expression profiling of recipient kidneys by microarray; Gene expression profiling of donor kidney biopsies using Affymetrix microarray platform (PrimeView Human Gene Expression Array).
delayed graft function (DGF); 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; 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.; Diagnostic test: Gene expression profiling of donor kidneys by microarray; Gene expression profiling of donor kidney biopsies using Affymetrix microarray platform (PrimeView Human Gene Expression Array).; Diagnostic test: Gene expression profiling of recipient kidneys by microarray; Gene expression profiling of donor kidney biopsies using Affymetrix microarray platform (PrimeView Human Gene Expression Array).
no-DGF; 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; 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.; Diagnostic test: Gene expression profiling of donor kidneys by microarray; Gene expression profiling of donor kidney biopsies using Affymetrix microarray platform (PrimeView Human Gene Expression Array).; Diagnostic test: Gene expression profiling of recipient kidneys by microarray; Gene expression profiling of donor kidney biopsies using Affymetrix microarray platform (PrimeView Human Gene Expression Array).
Recipient IFTA; 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; Gene expression profiling of donor kidney biopsies using Affymetrix microarray platform (PrimeView Human Gene Expression Array).; Diagnostic test: Gene expression profiling of recipient kidneys by microarray; Gene expression profiling of donor kidney biopsies using Affymetrix microarray platform (PrimeView Human Gene Expression Array).
Recipient no-IFTA; 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; Gene expression profiling of donor kidney biopsies using Affymetrix microarray platform (PrimeView Human Gene Expression Array).; Diagnostic test: Gene expression profiling of recipient kidneys by microarray; Gene expression profiling of donor kidney biopsies using Affymetrix microarray platform (PrimeView Human Gene Expression Array).

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Institute for Clinical and Experimental Medicine
• Investigators: Principal Investigator: Ondrej Viklicky, Prof., Institute for Clinical and Experimental Medicine

Study record dates

Study Major Dates

• Study Start (Actual): June 11, 2021
• Primary Completion (Actual): December 1, 2022
• Study Completion (Actual): October 31, 2023

Study Registration Dates

• First Submitted: November 28, 2023
• First Submitted That Met QC Criteria: December 12, 2023
• First Posted (Actual): December 14, 2023

Study Record Updates

• Last Update Posted (Actual): December 14, 2023
• Last Update Submitted That Met QC Criteria: December 12, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: kidney transplantation; microarray; donor kidney
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Wounds and Injuries; Acute Kidney Injury
• Other Study ID Numbers: G339-2021

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No