Serum indoxyl sulfate concentrations associate with progression of chronic kidney disease in children

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.

An Innovative Synbiotic Formulation Decreases Free Serum Indoxyl Sulfate, Small Intestine Permeability and Ameliorates Gastrointestinal Symptoms in a Randomized Pilot Trial in Stage IIIb-IV CKD Patients

“…It is well established that an alteration of the gut microbiota accompanies CKD and likely contributes to its progression and cardiovascular and inflammatory complications [ 1 , 2 ]. The CKD-associated dysbiosis is characterized by a prevalence of proteolytic species, with increased production and reduced clearance of uremic toxins, such as IS, PCS, TMAO and IAA [ 4 , 5 ].…”

“…The importance of gastrointestinal microbiome status in chronic kidney disease (CKD) is an emerging topic in literature, progressively recognized in the last years as both a typical feature of the disease itself and a risk factor for its progression [ 1 , 2 ]. Indeed, CKD patients display a progressive worsening of proteolytic dysbiosis of the gut microbiota, accompanying the progression of the pathology towards end-stage renal disease [ 1 , 3 ].…”

“…The increased production of uremic toxins (UTs) at the colonic level, together with their reduced renal clearance and their facilitated passage to the systemic circulation, thanks to the altered mucosal integrity, contribute to their progressive accumulation in blood as the disease progresses overall. Their documented actions in promoting inflammation, oxidative stress, insulin resistance and cardiovascular risk makes them active contributor of CKD progression [ 1 , 2 , 5 ]. Given this strict relationship between gut and kidney functionality, an active field of research is focusing on different strategies of gut microbiota modulation by nutrition and supplementation approaches, with the final aim of blunting CKD progression.…”

Thrombolome and Its Emerging Role in Chronic Kidney Diseases

“…The serum levels of IS and IAA significantly increase during the progression of CKD. Compared to healthy people, the IS concentration can increase more than 50 times as GFR decreases [ 50 , 51 , 52 ]. Due to the fact that IS and IAA are protein-bound, poorly dialyzable compounds, there are no available methods for their effective removal in ESRD.…”

Zeolite Composite Nanofiber Mesh for Indoxyl Sulfate Adsorption toward Wearable Blood Purification Devices

“…Approximately 90% of IS in serum is bound to albumin, and these large bound particles cannot pass through the dialysis membrane [7]. IS can reportedly accelerate the progression of CKD [8,9] and induce cardiovascular disease, osteoporosis, and anemia [10,11]. Therefore, the removal of IS from the blood of CKD patients is essential for effective blood purification, and a novel method for improved treatment is required.…”