Urinary Biomarkers in Paediatric Kidney Transplantation (pKTx)

Study Overview
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Brief Summary
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This study aims to test and validate the panel of study urinary biomarker to assess whether (1) reference values differ between paediatric renal transplant patients, patients with chronic kidney disease stage IV and V (CKD IV-V) and children without any disease, (2) characteristic changes in concentration profile may be observed after event-specific injury, (3) differences between paediatric renal transplant patients with AR and other causes of AKI can be detected, and (4) stratification of renal transplant patients to different histological types of AR is possible.

Detailed Description
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Despite advances in kidney transplantation, acute rejection (AR) is one of the primary risk factors for allograft kidney injury and function deterioration, and may have a significant impact on long-term graft survival, particularly in paediatric renal transplant patients. Against the background of the limited availability of kidney donor organs, the early recognition of AR is of particular interest to improve long-term allograft survival. Renal allograft biopsy remains the current gold standard for the diagnosis of kidney transplant rejection. However, it is an invasive procedure associated with the risk of bleeding, infection of the renal allograft, arterio-venous fistula, introducing sampling error, and a large inter-observer variation. Therefore, urinary biomarkers from minimally invasive compartments would be helpful for the early detection of clinical rejection before graft functional decline occurs. The current standard monitoring of the renal transplant function includes measurements of serum-creatinine (SCr) levels, estimatedglomerular filtration rate (eGFR), and proteinuria. These markers exhibit a lack of sensitivity and specificity and are late indicators for molecular and cellular events following AR. Furthermore, conditions other than AR (viral and bacterial infection, calcineurin nephrotoxicity, acute ischemic injury) resemble similar morphological features within the renal allograft challenging detection and differentiation of the underlying process. Early treatment of AR could lead to diminished histological injury and improved functional outcome. An intensified immunosuppression management represents the main strategy to counteract the uncontrolled attack of the recipient´s immune system against the renal allograft. Not surprisingly, many attempts have been made to develop new biomarkers to improve the precision and accuracy in detecting AR for optimizing immunosuppression management. Because allograft reactive cells can gain access to the urinary space, urine represents an appropriate biospecimen to investigate allograft injury. The study urinary biomarkers have been partially discovered and characterized in the past for detection of acute kidney injury (AKI), rarely in renal transplant patients. This study aims to test and validate the panel of study urinary biomarker to assess whether (1) reference values differ between paediatric renal transplant patients, patients with chronic kidney disease stage IV and V (CKD IV-V) and children without any disease, (2) characteristic changes in concentration profile may be observed after event-specific injury, (3) differences between paediatric renal transplant patients with AR and other causes of AKI can be detected, and (4) stratification of renal transplant patients to different histological types of AR is possible.

Official Title
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Estimation of Kidney Function Through a Combination of Renal Urinary Biomarkers in Paediatric Renal Transplant Patients - A Multi-centre Prospective Observational Study

Conditions
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Renal Transplantation, Chronic Kidney Insufficiency, Healthy Controls

Intervention / Treatment
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* Diagnostic Test: Biomarker test


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: i) Group 1 (patients < 18 years of age)- obtaining reference values without any of the pre-defined events renal transplant patients with stable renal function parameters (mean SCr (or cystatin C) or mean eGFR based on creatinine and / or cystatin C defined as changes ≤ ±15 % for at least three consecutive ambulatory controls). patients with CKD IV-V (and maintained urine output, without renal replacement therapy and without pre-defined events). healthy controls. Study patients from group 1 may be assigned to the group 2 in the following conditions: ii) Group 2 (patients < 18 years of age)- obtaining biomarker-specific characteristic in the presence of any of the pre-defined events renal transplant recipients with living or deceased kidney transplantation. patients with CKD IV-V (and maintained urine output without renal replacement therapy). healthy controls. Exclusion Criteria: i) Healthy controls any comorbidity / medication which may have an impact on urinary biomarker profile (e.g. primary kidney or liver disease, metabolic disease, vasculitis or other immunological disease other than the pre-defined events). for group 1: presence of any of the pre-defined event. ii) CKD IV-V any comorbidity / medication which may have an impact on urinary biomarker profile (e.g. liver disease, metabolic disease, vasculitis or other immunological disease other than the pre-defined events). for group 1: presence of any of the pre-defined event. iii) Renal transplant patients for group 1: presence of any of the pre-defined event. Primary non-function of the renal transplant organ. Blood group (AB0) incompatible. Detection of donor specific antibody (DSA) positive (panel-reactive antibodies) at time of enrolment. any comorbidity / medication which may have an impact on urinary biomarker profile (e.g. liver disease, metabolic disease, vasculitis or other immunological disease) other than the pre-defined events. Presence of other transplanted organs or co-transplanted organs. Intention to not use a standard maintenance immunosuppression regimen consisting of calcineurin inhibitor (CNI), antimetabolite (mycophenolate or azathioprine), inhibitor of mechanistic target of rapamycin (mTOR) (Sirolimus / Everolimus) with/without corticosteroids. Any condition that, in the opinion of the investigator, would pose risk to the subject's safe participation, or interfere with their ability to comply with the study requirements, or may impact the quality of the interpretation of the data (e.g. detection of malignancy). Failure to collect urine samples or incomplete additional CERTAIN dataset (for collecting information about pre-defined events).

Ages Eligible for Study
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Minimum Age: 0 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Renal transplant patients - group 1<br>Renal transplant patients with stable renal function parameters (mean SCr (or cystatin C) or mean eGFR based on creatinine and / or cystatin C defined as changes ≤ ±15 % for at least three consecutive ambulatory controls). | Diagnostic Test: Biomarker test<br>* collection of 500µl to 1 ml of a spot urine sample<br>|
| renal transplant patients - group 2<br>Renal transplant recipients with stable renal function at inclusion, facing a pre-defined event during the course of the study. Pre-defined events are Acute Rejection (AR), viral transplant-associated infection (e.g. BKV), bacterial infection (febrile urinary tract infection (fUTI)), calcineurin-inhibitor (CNI) toxicity, and acute tubular necrosis (ATN). | Diagnostic Test: Biomarker test<br>* collection of 500µl to 1 ml of a spot urine sample<br>|
| Patients with Chronic Kidney Disease Stage IV and V (CKD IV-V) - group 3<br>Patients with CKD IV-V (and maintained urine output, without renal replacement therapy and without pre-defined events). | Diagnostic Test: Biomarker test<br>* collection of 500µl to 1 ml of a spot urine sample<br>|
| Healthy controls<br>Healthy children serve as control group | Diagnostic Test: Biomarker test<br>* collection of 500µl to 1 ml of a spot urine sample<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of serum creatinine level [mg/dl] | Standard surveillance parameter of kidney function / renal allograft | from Baseline up to 18 months | 
| Change of serum urea level [mg/dl] | Standard surveillance parameter of kidney function / renal allograft | from Baseline up to 18 months | 
| Change of serum Cystatin C level [mg/l] | Standard surveillance parameter of kidney function / renal allograft | from Baseline up to 18 months | 
| Measurement of urine creatinine level [g/l] | Standard surveillance parameter of renal function / renal allograft. All urinary study biomarkers (see below) will be correlated to urine creatinine level [ng/mg Creatinine] and compared with standard surveillance parameters of kidney function / renal allograft (see Outcome 1-3). | from Baseline up to 18 months | 
| Change of urine alpha-1-Microglobulin (A1M) | Urinary study biomarker. The performance (sensitivity, specificity, positive predictive value and negative predictive value) for detection of kidney / graft deterioration will be calculated using receiver operator characteristics (ROC) curves. | from Baseline up to 18 months | 
| Change of urine Aquaporin 2 (AQP2) [ng/ml] | Urinary study biomarker. The performance (sensitivity, specificity, positive predictive value and negative predictive value) for detection of kidney / graft deterioration will be calculated using receiver operator characteristics (ROC) curves. | from Baseline up to 18 months | 
| Change of urine Caldesmon [ng/ml] | Urinary study biomarker. The performance (sensitivity, specificity, positive predictive value and negative predictive value) for detection of kidney / graft deterioration will be calculated using receiver operator characteristics (ROC) curves. | from Baseline up to 18 months | 
| Change of urine Clusterin [ng/ml] | Urinary study biomarker. The performance (sensitivity, specificity, positive predictive value and negative predictive value) for detection of kidney / graft deterioration will be calculated using receiver operator characteristics (ROC) curves. | from Baseline up to 18 months | 
| Change of urine Cystatin C [ng/ml] | Urinary study biomarker. The performance (sensitivity, specificity, positive predictive value and negative predictive value) for detection of kidney / graft deterioration will be calculated using receiver operator characteristics (ROC) curves. | from Baseline up to 18 months | 
| Change of urine Interleukin 9 (IL-9) [ng/ml] | Urinary study biomarker. The performance (sensitivity, specificity, positive predictive value and negative predictive value) for detection of kidney / graft deterioration will be calculated using receiver operator characteristics (ROC) curves. | from Baseline up to 18 months | 
| Change of urine Kidney injury molecule 1 (Kim-1) [ng/ml] | Urinary study biomarker. The performance (sensitivity, specificity, positive predictive value and negative predictive value) for detection of kidney / graft deterioration will be calculated using receiver operator characteristics (ROC) curves. | from Baseline up to 18 months | 
| Change of urine Nephrin [ng/ml] | Urinary study biomarker. The performance (sensitivity, specificity, positive predictive value and negative predictive value) for detection of kidney / graft deterioration will be calculated using receiver operator characteristics (ROC) curves. | from Baseline up to 18 months | 
| Change of urine Neutrophil gelatinase-associated lipocalin (NGAL) [ng/ml] | Urinary study biomarker. The performance (sensitivity, specificity, positive predictive value and negative predictive value) for detection of kidney / graft deterioration will be calculated using receiver operator characteristics (ROC) curves. | from Baseline up to 18 months | 
| Change of urine Osteopontin (OPN) [ng/ml] | Urinary study biomarker. The performance (sensitivity, specificity, positive predictive value and negative predictive value) for detection of kidney / graft deterioration will be calculated using receiver operator characteristics (ROC) curves. | from Baseline up to 18 months | 
| Change of urine P-selectin (SELP) [ng/ml] | Urinary study biomarker. The performance (sensitivity, specificity, positive predictive value and negative predictive value) for detection of kidney / graft deterioration will be calculated using receiver operator characteristics (ROC) curves. | from Baseline up to 18 months | 
| Change of urine Podocin [ng/ml] | Urinary study biomarker. The performance (sensitivity, specificity, positive predictive value and negative predictive value) for detection of kidney / graft deterioration will be calculated using receiver operator characteristics (ROC) curves. | from Baseline up to 18 months | 
| Change of urine Retinol-binding protein 4 (RBP4) [ng/ml] | Urinary study biomarker. The performance (sensitivity, specificity, positive predictive value and negative predictive value) for detection of kidney / graft deterioration will be calculated using receiver operator characteristics (ROC) curves. | from Baseline up to 18 months | 
| Change of urine Smoothelin [ng/ml] | Urinary study biomarker. The performance (sensitivity, specificity, positive predictive value and negative predictive value) for detection of kidney / graft deterioration will be calculated using receiver operator characteristics (ROC) curves. | from Baseline up to 18 months | 
| Change of urine Synaptopodin [ng/ml] | Urinary study biomarker. The performance (sensitivity, specificity, positive predictive value and negative predictive value) for detection of kidney / graft deterioration will be calculated using receiver operator characteristics (ROC) curves. | from Baseline up to 18 months | 
| Change of urine tumour necrosis factor alpha (TNF-α) [ng/ml] | Urinary study biomarker. The performance (sensitivity, specificity, positive predictive value and negative predictive value) for detection of kidney / graft deterioration will be calculated using receiver operator characteristics (ROC) curves. | from Baseline up to 18 months | 
| Change of urine vascular cell adhesion molecule-1 (VCAM-1) | Urinary study biomarker. The performance (sensitivity, specificity, positive predictive value and negative predictive value) for detection of kidney / graft deterioration will be calculated using receiver operator characteristics (ROC) curves. | from Baseline up to 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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renal transplantation, biomarkers