"A Privacy-protecting Environment for Child Transplants Health Related and Genomic Data Integration in the European Reference Network"

Condition(s) studied

Investigational drug(s) / intervention(s)

Whole genome sequencing: 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.

Polygenic Risk Score Calculation: 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).

Methylome and episignatures: 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.

Study summary

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).

Eligibility

Primary outcome measure(s)

• Epstein Barr Infection — From transplant until end of post-transplant follow-up period (up to 7years)
  Number of Espstein Barr infections defined as \>3500 copies in PCR in peripheral blood
• Cytomegalovirus infection — From transplant until end of post-transplant follow-up period (up to 7 years)
  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)
• BK virus infection — From transplant until end of post-transplant follow-up period (up to 7 years)
  Positive BK viremia (define cut-off level) and/or histological evidence of BK nephropathy
• Cholangitis — From transplant until end of post-transplant follow-up period
  Worsening of liver function tests accompanied by an elevation in inflammatory markers, with or without a positive blood or bile culture.
• Urinary Tract Infection — From transplant until end of post-transplant follow-up period (up to 7 years)
  Positive urine cultures AND increased inflammation marker (e.g. CRP) or fever
• Sepsis — From transplant until end of post-transplant follow-up period (up to 7 years)
  SIRS in relation to infectious cause +/- positive blood cultures
• Renal Calcineurin Inhibitors toxicity — From transplant until end of post-transplant follow-up period (up to 7 years)
  Histological evidence of kidney CNI-related kidney damage
• Mycophenolate mofetil toxicity — From transplant until end of post-transplant follow-up period (up to 7 years)
  Evidence of myelosuppression during therapy without any other proven cause and/or Clinical/histological evidence of MMF-related enteropathy
• mTOR inhibitor toxicity — From transplant until end of post-transplant follow-up period (up to 7 years)
  mTOR induced-proteinuria (occurrence of proteinuria after mTOR exposure with resolution after treatment suspension)
• Thrombotic microangiopathy — From transplant until end of post-transplant follow-up period (up to 7 years)
  Ocurrence of no non immune-mediated hemolytic anemia and/or thrombocytopenia and/or hypertension and/or proteinuria with histological evidence of kidney TMA
• Kidney rejection episode — From transplant until end of post-transplant follow-up period (up to 7 years)
  Histological evidence based on Banff criteria
• Liver rejection episode — From transplant until end of post-transplant follow-up period (up to 7 years)
  Histological evidence based on Banff criteria
• Chronic liver rejection — From transplant until end of post-transplant follow-up period (up to 7 years)
  Histological evidence based on Banff criteria
• Chronic kidney rejection — From transplant until end of post-transplant follow-up period (up to 7 years)
  Histological evidence based on Banff criteria
• Chronic renal failure after pLTx — From transplant until end of post-transplant follow up period (up to 7 years)
  Elevation of serum-creatinine for 3\>months
• Chronic liver failure (graft chirrosis and fibrosis) — From transplant until end of post-transplant follow up period (up to 7 years)
  Ocurrence of portal hypertension diagnosis both clinical (ascites, splenomegaly, varices) and analytical (thrombocytopenia) presentation.

Trial sites (4)

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