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Protect_Child_101 is an observational study to be performed in children that have undergone a liver or renal transplant.
The aim of this study is to analyse small variations in the genetic material (DNA) of transplanted children. The investigators will also study a type of chemical 'marks' called methylations, which do not change the DNA itself, but can affect how it functions. These marks can influence how certain diseases develop or how the body responds to transplantation.
Specifically, investigators seek to discover:
Within this study, data from the child's medical history will be collected. The data to be collected are demographic data (gender, age, ethnicity), clinical data, personal and family history possibly related to his/her disease, course and evolution of the disease, and complementary and laboratory examinations collected from his/her clinical history.
The only non-routine tests to be performed will be the genomic and methylomic tests. Nevertheless, these determinations will be performed on samples obtained during the child's routine care. No extra intervention is planned as part of this study.
Samples and clinical data will be collected at different time points after transplantation. Schematically, collection is planned for months 0, 1, 3, 6, 12 and 24 post-transplant. In addition to these pre-established points, comprehensive data collection will be attempted when the child suffers a relevant clinical event, e.g. infection, treatment toxicity, organ rejection (post-transplant complication).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Paediatric kidney and liver transplant that suffered a clinical event of interest after transplant | This cohort is made up of paediatric kidney and liver patients that had a clinical event after transplantation. The main clinical events of interest of this study are: viral infections, bacterial infections, drug-related toxicity and rejection. All patients will undergo genomic and methylomic tests to diagnose biological risk factors that could help determine the risk of developing the clinical event of interest. |
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| Paediatric kidney and liver transplant patients with no events after transplant | This cohort is made up of paediatric kidney and liver patients that did not develop a clinical event after transplantation. All patients will undergo genomic and methylomic tests. The genetic and methylomic results will be compared to those of the patients that developed a clinical event. The objetive is to identify biological risk factors that could help determine the risk of developing the clinical event of interest. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Whole genome sequencing | Genetic | Whole genome sequencing (WGS) is an advanced genomic technique that allows for the comprehensive analysis of an individual's entire DNA sequence, including both coding and non-coding regions. In the context of pediatric transplantation, WGS offers a powerful tool for uncovering underlying genetic disorders that may influence transplant eligibility, donor-recipient compatibility, immune response, or risk of post-transplant complications. It enables the identification of rare monogenic diseases, pharmacogenomic markers relevant to immunosuppressive therapy, and potential genetic predispositions to graft rejection or infection. Integrating WGS into transplant evaluation process enhances personalized medicine approaches, contributing to improved long-term outcomes in pediatric transplant recipients. |
| Measure | Description | Time Frame |
|---|---|---|
| Epstein Barr Infection | Number of Espstein Barr infections defined as >3500 copies in PCR in peripheral blood | From transplant until end of post-transplant follow-up period (up to 7years) |
| Cytomegalovirus infection | A) Primary CMV infection after transplant with or without CMV disease (>1000 copies/ml in peripheral blood in patients with previous negative CMV serology) B) Secondary CMV infection after transplant (any PCR with CMV disease or CMV >1000 copies/ml in asymptomatic patients) | From transplant until end of post-transplant follow-up period (up to 7 years) |
| BK virus infection | Positive BK viremia (define cut-off level) and/or histological evidence of BK nephropathy | From transplant until end of post-transplant follow-up period (up to 7 years) |
| Cholangitis | Worsening of liver function tests accompanied by an elevation in inflammatory markers, with or without a positive blood or bile culture. | From transplant until end of post-transplant follow-up period |
| Urinary Tract Infection | Positive urine cultures AND increased inflammation marker (e.g. CRP) or fever | From transplant until end of post-transplant follow-up period (up to 7 years) |
| Sepsis | SIRS in relation to infectious cause +/- positive blood cultures | From transplant until end of post-transplant follow-up period (up to 7 years) |
| Renal Calcineurin Inhibitors toxicity |
| Measure | Description | Time Frame |
|---|---|---|
| Liver Primary non-function | Requirement for immediate re-transplantation | From transplant to post-trasnplant follow-up period (up to 7 years) |
| Liver Primary non-function | Early death within the first 7 or 14 days following LT after exclusion of other identifiable causes of graft function such as vascular complications, rejection, or infection |
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Inclusion Criteria:
Both patients with de novo transplantation or in follow-up can be included in the study.
Exclusion Criteria:
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This study will enroll paediatric patients that have underdone a renal i liver transplant
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Paula Valle Simon, PhD | Contact | 914975485 | pvalle@salud.madrid.org |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University Medical Center Hamburg-Eppendorf (UKE), | Hamburg | 20251 | Germany |
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Blood samples will be retained for extraction of DNA.
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| Polygenic Risk Score Calculation | Genetic | A polygenic risk score (PRS) calculation will be performed to quantitatively estimate the an individual's genetic predisposition to the original disease that led to transplantation. These scores are calculated by aggregating the weighted sum of risk alleles-most commonly single nucleotide polymorphisms (SNPs)-each of which contributes a small effect size as determined by genome-wide association studies (GWAS). |
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| Methylome and episignatures | Diagnostic Test | Methylomic analysis in paediatric transplantation refers to the comprehensive profiling and study of DNA methylation patterns across the genome to understand epigenetic modifications associated with transplant-related outcomes. This epigenetic approach enables the identification of differentially methylated regions (DMRs) that may correlate with clinical phenotypes, such as graft acceptance or rejection, infectious complications, or immune dysregulation. The studies withjin the Protect_Child_101 project will be aimed at: 1) Refinement of episignatures, to increase specificity, sensitivity and robustness of those episignatures that already exist and 2) Discovery and validation of new disease, gene or variant specific mDNA signatures. |
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Histological evidence of kidney CNI-related kidney damage |
| From transplant until end of post-transplant follow-up period (up to 7 years) |
| Mycophenolate mofetil toxicity | Evidence of myelosuppression during therapy without any other proven cause and/or Clinical/histological evidence of MMF-related enteropathy | From transplant until end of post-transplant follow-up period (up to 7 years) |
| mTOR inhibitor toxicity | mTOR induced-proteinuria (occurrence of proteinuria after mTOR exposure with resolution after treatment suspension) | From transplant until end of post-transplant follow-up period (up to 7 years) |
| Thrombotic microangiopathy | Ocurrence of no non immune-mediated hemolytic anemia and/or thrombocytopenia and/or hypertension and/or proteinuria with histological evidence of kidney TMA | From transplant until end of post-transplant follow-up period (up to 7 years) |
| Kidney rejection episode | Histological evidence based on Banff criteria | From transplant until end of post-transplant follow-up period (up to 7 years) |
| Liver rejection episode | Histological evidence based on Banff criteria | From transplant until end of post-transplant follow-up period (up to 7 years) |
| Chronic liver rejection | Histological evidence based on Banff criteria | From transplant until end of post-transplant follow-up period (up to 7 years) |
| Chronic kidney rejection | Histological evidence based on Banff criteria | From transplant until end of post-transplant follow-up period (up to 7 years) |
| Chronic renal failure after pLTx | Elevation of serum-creatinine for 3>months | From transplant until end of post-transplant follow up period (up to 7 years) |
| Chronic liver failure (graft chirrosis and fibrosis) | Ocurrence of portal hypertension diagnosis both clinical (ascites, splenomegaly, varices) and analytical (thrombocytopenia) presentation. | From transplant until end of post-transplant follow up period (up to 7 years) |
| From transplant to post-transplant follow-up period (up to 7 years) |
| Liver Primary non-function | Ocurrence of at least 2 of the following within 7 days post-transplant:
| From transplant to post-trasnplant follow-up period (up to 7 years) |
| Kidney primary non-function | Persistence of dialysis status or eGFR <15 ml/min/1.7 m2 | From transplant until end of post-transplant follow-up period (up to 7 years) |
| Liver early allograft dysfunction | One of the following laboratory criteria within the 7 first days post transplant:
Or, for 5 consecutive days after day 7:
| From transplant until end of post-transplant follow-up period (up to 7 years) |
| Delayed kidney Graft Function | Need for dialysis within the first 7 days after kidney transplantation | From transplant until end of post-transplant follow-up period (up to 7 years) |
| Vascular Complications | Hepatic artery thrombosis (HAT) or portal vein stenosis (may lead to ischemic injury and chronic dysfunction) | From transplant until end of post-transplant follow-up period (Up to 7 years) |
| Biliary Complications | Biliary structures, leaks, or ischemic cholangiopathy due to vascular insufficiency can cause chronic dysfunction. | From transplant until end of post-transplant follow-up period (up to 7 years) |
| Urological complications | Need of re-intervention due to post-surgical events | From transplant until end of post-transplant follow-up period (up to 7 years) |
| Post-transplant lymphoproliferative disease | Histological diagnosis of PTLD: histology, immunohistochemistry, EBV detection (EBER in situ hybridization), and clonality studies, classified according to WHO PTLD categories. | From transplant until end of post-transplant follow-up period (up to 7 years) |
| Post-transplant lymphoproliferative disease | Radiological diagnosis of PTLD: heterogeneous extranodal masses, allograft involvement, and CNS or visceral lesions. | From transplant until end of post-transplant follow-up period (up to 7 years) |
| Diabetes | The diagnosis is confirmed when one of the following criteria is met on two separate occasions: Fasting plasma glucose (FPG): ≥126 mg/dL (7.0 mmol/L) after at least 8 hours fasting. Oral glucose tolerance test (OGTT): 2-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) after a 75 g oral glucose load. Hemoglobin A1c (HbA1c): ≥6.5%, using a standardized assay. Random plasma glucose: ≥200 mg/dL (11.1 mmol/L) in the presence of classic symptoms of hyperglycemia (polyuria, polydipsia, weight loss). | From transplant until end of post-transplant follow-up period (up to 7 years) |
| Posterior reversible encelopathy (PRES) | Ocurrence of acute neurologic symptoms (headache, seizures, altered consciousness or visual disturbances) with typical neuroimaging (CT, MRI) findings (bilateral areas of white matter edema in the posterior cerebral hemispheres). | From transplant until end of post-transplant follow-up period (up to 7 years) |
| Mortality | Death by any cause | From transplant until end of post-transplant follow-up period (up to 7 years) |
| Relapse of primary immune mediated disease | Ocurrence of nephrotic range proteinuria after kidney transplant (excluding other causes) | From transplant until end of post-transplant follow-up period (up to 7 years) |
| Relapse of primary immune mediated disease | histological findings of Focal segmental glomerulosclerosis (FSGS) in kidney biopsy in a patient with primary FSGS | From transplant until end of post-transplant follow-up period (up to 7 years) |
| Graft survival | Time from transplant to the need for dialysis or entry onto the re- transplant list. | From transplant until end of post-transplant follow-up period (up 7 years) |
| Mediterranean Institute for Transplantation (ISMETT) | Palermo | Sicily | 90127 | Italy |
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| University Hospital Padova | Padova | 35128 | Italy |
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| Hospital Universitario La Paz | Madrid | Madrid | 28046 | Spain |
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| ID | Term |
|---|---|
| D000073336 | Whole Genome Sequencing |
| D000081122 | Epigenome |
| ID | Term |
|---|---|
| D017422 | Sequence Analysis, DNA |
| D017421 | Sequence Analysis |
| D005821 | Genetic Techniques |
| D008919 | Investigative Techniques |
| D016678 | Genome |
| D040342 | Genetic Structures |
| D055614 | Genetic Phenomena |
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