Abstract
The uremic toxins indoxyl sulfate (IS) and p-cresyl sulfate (pCS) accumulate in patients with chronic kidney disease (CKD) as a consequence of altered gut microbiota metabolism and a decline in renal excretion. Despite of solid experimental evidence for nephrotoxic effects, the impact of uremic toxins on the progression of CKD has not been investigated in representative patient cohorts. In this analysis, IS and pCS serum concentrations were measured in 604 pediatric participants (mean eGFR of 27 ± 11 ml/min/1.73m2) at enrolment into the prospective Cardiovascular Comorbidity in Children with CKD study. Associations with progression of CKD were analyzed by Kaplan-Meier analyses and Cox proportional hazard models. During a median follow up time of 2.2 years (IQR 4.3–0.8 years), the composite renal survival endpoint, defined as 50% loss of eGFR, or eGFR <10ml/min/1.73m2 or start of renal replacement therapy, was reached by 360 patients (60%). Median survival time was shorter in patients with IS and pCS levels in the highest versus lowest quartile for both IS (1.5 years, 95%CI [1.1,2.0] versus 6.0 years, 95%CI [5.0,8.4]) and pCS (1.8 years, 95%CI [1.5,2.8] versus 4.4 years, 95%CI [3.4,6.0]). Multivariable Cox regression disclosed a significant association of IS, but not pCS, with renal survival, which was independent of other risk factors including baseline eGFR, proteinuria and blood pressure. In this exploratory analysis we provide the first data showing a significant association of IS, but not pCS serum concentrations with the progression of CKD in children, independent of other known risk factors. In the absence of comorbidities, which interfere with serum levels of uremic toxins, such as diabetes, obesity and metabolic syndrome, these results highlight the important role of uremic toxins and accentuate the unmet need of effective elimination strategies to lower the uremic toxin burden and abate progression of CKD.
Highlights
Identifying modifiable risk factors for the continuous loss of renal function that characterizes chronic kidney disease (CKD) is a major challenge towards improving treatment for patients with CKD
We found a significant association of serum indoxyl sulfate (IS) concentrations with the prospective progression of CKD, independent of other known traditional risk factors, i.e. baseline estimated glomerular filtration rate (eGFR), proteinuria and blood pressure
The toxicity of IS in vitro and in animal models depends on its concentration, and this is reflected by the fact that those patients with IS levels in the 4th quartile have the highest risk for progression of CKD [22]
Summary
Identifying modifiable risk factors for the continuous loss of renal function that characterizes chronic kidney disease (CKD) is a major challenge towards improving treatment for patients with CKD. We have previously shown that the uremic toxins indoxyl sulfate (IS) and p-cresyl sulfate (pCS) are inversely correlated to the estimated glomerular filtration rate (eGFR) in children and adolescents across all stages of CKD [5]. The accumulation of these toxins in the circulation has deleterious consequences, as their plasma concentrations are associated with cardiovascular events in adult CKD patients and with surrogate markers of cardiovascular disease (CVD) in pediatric patients [5, 6]. We investigated the impact of IS and pCS on progression of CKD in a cohort of more than 600 children with CKD of the prospective Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) study
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
