Clinical trial NCT05208788: Urinary Biomarkers in Paediatric Kidney Transplantation (pKTx)
Official title: Estimation of Kidney Function Through a Combination of Renal Urinary Biomarkers in Paediatric Renal Transplant Patients - A Multi-centre Prospective Observational Study
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Renal Transplantation
Chronic Kidney Insufficiency
Healthy Controls
Keywords: renal transplantation
biomarkers
Lead sponsor: University Hospital Tuebingen
Sponsor class: OTHER
Collaborators: name: Natural and Medical Sciences Institute (NMI)
name: Cooperative European Paediatric Renal Transplant Initiative (CERTAIN)
First posted: 2022-01-26
Enrollment: 186
Sex: ALL
Minimum age (years): 0
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: children \< 18 years

Brief summary: 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: 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.

Eligibility criteria: 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).

Primary outcomes:
measure: Change of serum creatinine level [mg/dl]
timeFrame: from Baseline up to 18 months
measure: Change of serum urea level [mg/dl]
timeFrame: from Baseline up to 18 months
measure: Change of serum Cystatin C level [mg/l]
timeFrame: from Baseline up to 18 months
measure: Measurement of urine creatinine level [g/l]
timeFrame: from Baseline up to 18 months
measure: Change of urine alpha-1-Microglobulin (A1M)
timeFrame: from Baseline up to 18 months
measure: Change of urine Aquaporin 2 (AQP2) [ng/ml]
timeFrame: from Baseline up to 18 months
measure: Change of urine Caldesmon [ng/ml]
timeFrame: from Baseline up to 18 months
measure: Change of urine Clusterin [ng/ml]
timeFrame: from Baseline up to 18 months
measure: Change of urine Cystatin C [ng/ml]
timeFrame: from Baseline up to 18 months
measure: Change of urine Interleukin 9 (IL-9) [ng/ml]
timeFrame: from Baseline up to 18 months
measure: Change of urine Kidney injury molecule 1 (Kim-1) [ng/ml]
timeFrame: from Baseline up to 18 months
measure: Change of urine Nephrin [ng/ml]
timeFrame: from Baseline up to 18 months
measure: Change of urine Neutrophil gelatinase-associated lipocalin (NGAL) [ng/ml]
timeFrame: from Baseline up to 18 months
measure: Change of urine Osteopontin (OPN) [ng/ml]
timeFrame: from Baseline up to 18 months
measure: Change of urine P-selectin (SELP) [ng/ml]
timeFrame: from Baseline up to 18 months
measure: Change of urine Podocin [ng/ml]
timeFrame: from Baseline up to 18 months
measure: Change of urine Retinol-binding protein 4 (RBP4) [ng/ml]
timeFrame: from Baseline up to 18 months
measure: Change of urine Smoothelin [ng/ml]
timeFrame: from Baseline up to 18 months
measure: Change of urine Synaptopodin [ng/ml]
timeFrame: from Baseline up to 18 months
measure: Change of urine tumour necrosis factor alpha (TNF-α) [ng/ml]
timeFrame: from Baseline up to 18 months
measure: Change of urine vascular cell adhesion molecule-1 (VCAM-1)
timeFrame: from Baseline up to 18 months
Secondary outcomes:
Other outcomes:
Locations:
city: Tuebingen
country: Germany
facility: University Children's Hospital Tuebingen
Study officials:
affiliation: University Children's Hospital Tuebingen
name: Marcus Weitz, PD Dr. med.
role: PRINCIPAL_INVESTIGATOR
References: