Chronic Kidney Disease Clinical Trial
Official title:
Part 2 of: 'Conceptualisation and Validation of a Paradigm Based on Uraemic Toxins for Management of Chronic Kidney Disease in Paediatric Patients (UToPaed)'
Children with chronic kidney disease (CKD) suffer from one of the most devastating diseases
in childhood resulting in a lifelong need for health care, and a 3 times decreased life
expectancy. In addition, they have important comorbidities that negatively impact on their
quality of life and integration in society, jeopardizing their future even after a potential
transplantation. Retention of uraemic toxins is accepted to play a major role in the
pathogenesis of the comorbid conditions, but studies in children are lacking. Furthermore,
there are currently no good tools to evaluate severity and monitor adequacy of treatment,
resulting in suboptimal management.
The overall scientific objective of this four years UToPaed IWT-TBM project is to provide the
clinician with new diagnostic and therapeutic tools for the management of children with CKD,
based on the improved understanding of uraemic toxicity.
In the first part of UToPaed, the investigators will associate concentrations of a wide
variety of uraemic toxins with different comorbidities in CKD children. In this second part,
a kinetic analysis will be performed to unravel the distribution and transport of the
different studied uraemic toxins in the body of the patient. The toxins of which
concentrations are best correlated with comorbidities during the progress of CKD (UToPaed -
part 1: observational study) and have representative kinetics will be selected as markers.
These markers will be, together with the comorbidities, further tracked after interventions,
i.e. starting on dialysis, transplantation, changes in dialysis strategy (UToPaed - part 3 -
intervention study) in order to validate the different kinetic models.
From the validated kinetic models (UToPaed - part 2 and 3), an open access user-friendly
prediction simulator (PAEDSIM) based on patient characteristics and marker concentrations
will be developed to optimise and individualise the dialysis therapy.
By providing clinicians with more advanced and appropriate tools to improve management of all
children with CKD, i.e. better assessment of the degree of renal dysfunction, better
determination of the ideal time to start renal replacement therapy, and more accurate
monitoring of dialysis adequacy, the investigators aim to improve neurocognitive and
psychosocial functioning (short term), growth, maturation into puberty, and social
integration (median term) and survival (long term).
This is an observational multicenter study in 20 children (≤ 18 years) with chronic kidney
disease (CKD) stage 5D treated with haemodialysis.
Distribution and transport of uraemic toxins inside the body is derived from a
cross-sectional study. During a midweek haemodialysis session, blood is sampled from the
dialyser inlet line at different time points (e.g. at 0, 15, 30, 60, 120, 240min) during the
session to obtain the evolution of intradialytic concentrations as is needed for the kinetic
analysis. To calculate dialyser clearance, blood is sampled simultaneously at the dialyser
inlet and outlet in the first part of the session (e.g. at 30min). Total solute removal is
measured by partial dialysate collection during the entire dialysis duration, using a
validated sampling system. For each uraemic toxin under study, a kinetic model is calibrated
simulating distribution and mass transport inside the patient's body. The body is
characterised by a total distribution volume V (per toxin), consisting of one or more
distinct compartments. In e.g. a 2-compartment model, one can distinguish a plasmatic or
peripheral compartment, which is directly cleared by haemodialysis (i.e. dialyser clearance)
or by renal or extrarenal clearances, and extraplasmatic compartment(s). Each compartment is
assumed to be characterised by a homogeneous uraemic toxin concentration with variable inputs
and outputs. The solute transport between two compartments is considered to be driven by
concentration gradients (diffusion), and/or pressure gradients (convection) and is
characterised by an intercompartment clearance.
Presuming that removal and generation are in equilibrium in stable HD patients, solute
generation rate in the interdialytic period is assumed equal to the total solute removal
during the dialysis session. The patient-specific ultrafiltration rate is taken into account
to change total distribution volume over time.
The time variation of the compartment concentration is, for a particular toxin, determined by
solving the mass balance equation for each compartment. The kinetic model iteratively solves
these equations for the complete dialysis session time. Herewith, plasmatic volume, total
distribution volume, as well as intercompartment clearance are calculated from fitting the
solution to the measured patient's plasma concentrations. Such kinetic analyses result in the
knowledge of all kinetic parameters for each studied toxin.
These calibrated kinetic models for paediatrics are further used to simulate different
dialysis strategies and, with it, look for the most optimal one, with the experience the
investigators have from kinetic studies in adults. Herewith, per solute, inter- and
intradialytic evolutions in concentration are calculated according to the mass balance
equations per compartment using the derived kinetic parameters. In the interdialytic period,
dialyser clearance is kept at zero, while solute generation is maintained constant, and the
interdialytic volume gain is set equal to the intradialytic applied ultrafiltration rate.
Starting from the intra- and interdialytic concentrations in steady state with a 3x4 hours
dialysis schedule, intra- and interdialytic concentrations are calculated after
mathematically altering several key characteristics of the dialysis regime. This is done for
the individual paediatric patient data as well as for the average paediatric patient within
its age category with data emanating out of our primary kinetic analysis. Possible strategies
are: longer and/or more frequent dialysis with or without adapting blood and/or dialysate
flow rates, increasing convection, haemodiafiltration (pre, post, or mixed dilution), or a
combination accounting for different parameters. For each strategy, consecutive sessions are
simulated until a new steady state of predialysis solute concentrations is reached (deviation
between 2 consecutive sessions <1%), paralleling the real in vivo effect of altering dialysis
strategy.
The different strategies are evaluated mathematically by comparing the calculated total
solute removal during the first week with the new strategy, and the steady state time
averaged as well as predialysis concentrations in the plasmatic volume.
The calibrated kinetic modelling parameters and the results of the different dialysis
strategies are compared for the different studied uraemic toxins. Accounting for the
correlations with comorbidities (UToPaed-part 1), one (or more) uraemic toxin marker(s) are
chosen.
The kinetic models are further validated by quantifying uraemic toxin marker concentrations
and comorbidities in individual patients after switching to different strategies as well as
to the individualised optimal dialysis strategy based on the model (UToPaed- part 3).
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