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: * Whether there are genetic or epigenetic (methylation) alterations that may explain why some children develop serious diseases that require transplantation. * If these alterations can help us predict possible complications after transplantation, such as organ rejection, infections, organ failure, cancer development. 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).
Study Type
OBSERVATIONAL
Enrollment
200
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.
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).
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.
University Medical Center Hamburg-Eppendorf (UKE),
Hamburg, Germany
Mediterranean Institute for Transplantation (ISMETT)
Palermo, Sicily, Italy
University Hospital Padova
Padua, Italy
Hospital Universitario La Paz
Madrid, Madrid, Spain
Epstein Barr Infection
Number of Espstein Barr infections defined as \>3500 copies in PCR in peripheral blood
Time frame: 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)
Time frame: 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
Time frame: 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.
Time frame: 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
Time frame: From transplant until end of post-transplant follow-up period (up to 7 years)
Sepsis
SIRS in relation to infectious cause +/- positive blood cultures
Time frame: From transplant until end of post-transplant follow-up period (up to 7 years)
Renal Calcineurin Inhibitors toxicity
Histological evidence of kidney CNI-related kidney damage
Time frame: 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
Time frame: 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)
Time frame: 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
Time frame: From transplant until end of post-transplant follow-up period (up to 7 years)
Kidney rejection episode
Histological evidence based on Banff criteria
Time frame: From transplant until end of post-transplant follow-up period (up to 7 years)
Liver rejection episode
Histological evidence based on Banff criteria
Time frame: From transplant until end of post-transplant follow-up period (up to 7 years)
Chronic liver rejection
Histological evidence based on Banff criteria
Time frame: From transplant until end of post-transplant follow-up period (up to 7 years)
Chronic kidney rejection
Histological evidence based on Banff criteria
Time frame: 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
Time frame: 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.
Time frame: From transplant until end of post-transplant follow up period (up to 7 years)
Liver Primary non-function
Requirement for immediate re-transplantation
Time frame: 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
Time frame: 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: * Alanine aminotransferase (ALT) greater than or equal to 2,000 U/L * INR greater than or equal to 10 mg/dl * Acidosis (Defined as one of the following: a) Arterial PH less or equal to 7,30. b) Venous pH less than or equal to 7,25. c) Lactate greater than or equal to 4 mmol/L)
Time frame: 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
Time frame: 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: * Serum bilirubin ≥10 mg/dL (171 μmol/L) on day 7 * INR ≥1.6 on day 7 * AST or ALT \>2000 IU/L within the first 7 days. Or, for 5 consecutive days after day 7: * Bilirubin \> 10 mg/ dL * INR \> 1.6 * Serum Urea \> 100 mg/dL
Time frame: 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
Time frame: From transplant until end of post-transplant follow-up period (up to 7 years)
Vascular Complications
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Hepatic artery thrombosis (HAT) or portal vein stenosis (may lead to ischemic injury and chronic dysfunction)
Time frame: 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.
Time frame: 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
Time frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: 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).
Time frame: From transplant until end of post-transplant follow-up period (up to 7 years)
Mortality
Death by any cause
Time frame: 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)
Time frame: 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
Time frame: 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.
Time frame: From transplant until end of post-transplant follow-up period (up 7 years)