Indoxyl sulfate associates with cardiovascular phenotype in children with chronic kidney disease

Holle, Johannes; Querfeld, Uwe; Kirchner, Marietta; Anninos, A; Okun, Jürgen G.; Thurn‐Valsassina, Daniela; Bayazıt, Aysun Karabay; Niemirska, Anna; Canpolat, Nur; Bulut, İpek Kaplan; Düzova, Ali; Anarat, Ali; Shroff, Rukshana; Bilginer, Yelda; Çalışkan, Salim; Candan, Cengiz; Harambat, Jérôme; Özçakar, Z. Bı̇rsı̇n; Söylemezoğlu, Oğuz; Tschumi, Sibylle; Habbig, Sandra; Balat, Ayşe; Zurowska, Aleksandra; Çakar, Nilgün; Kranz, Birgitta; Ertan, Pelin; Melk, Anette; Ažukaitis, Karolis; Schaefer, Franz

doi:10.1007/s00467-019-04331-6

Cited by 30 publications

(32 citation statements)

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“…IS promotes vascular calcification [ 18 ] and inflammation [ 19 ] in vitro and in animal models of CKD [ 20 ]. Moreover, serum IS levels are associated with the surrogate markers of cardiovascular disease (intima media thickness and pulse walve velocity) in children [ 5 ] and with diminished endothelial function in adults with CKD [ 21 ]. Accordingly, 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 ].…”

Section: Discussionmentioning

confidence: 99%

“…Serum samples were available in 604 patients at the baseline visit. Total serum levels of IS and pCS were measured centrally using reverse-phase separation and fluorescence detection, as described previously [ 5 ].…”

Section: Methodsmentioning

confidence: 99%

“…Correlation of IS and pCS (log transformed) with eGFR was quantified by means of Pearson correlation coefficient. In a multivariable linear regression analysis the association of log transformed IS (pCS) with clinically relevant variables at baseline was assessed [ 5 ].…”

Section: Methodsmentioning

confidence: 99%

“…CKD leads to alterations in the gut microbiome (dysbiosis) and accumulation of gut derived uremic toxins in plasma [ 4 ]. 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 ].…”

Section: Introductionmentioning

confidence: 99%

“…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 ]. In addition, uremic toxins may affect kidney cells directly and thus promote progression of CKD.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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