Kidney Clearance of Secretory Solutes Is Associated with Progression of CKD: The CRIC Study

Chen, Yan; Zelnick, Leila R.; Wang, Ke; Hoofnagle, Andrew N.; Becker, Jessica O.; Hsu, Chi‐yuan; Feldman, Harold I.; Mehta, Rupal; Lash, James P.; Waikar, Sushrut S.; Shafi, Tariq; Seliger, Stephen L.; Shlipak, Michael G.; Rahman, Mahboob; Kestenbaum, Bryan

doi:10.1681/asn.2019080811

Cited by 52 publications

(67 citation statements)

References 44 publications

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“…However, almost half of the patients had diabetes, which is known to have a significant impact not only on the progression of CKD but also on the serum levels of uremic toxins [ 23 ]. Recently, it has been shown that lower kidney clearance of six endogenous solutes, including IS, but not pCS, are associated with a higher risk of CKD progression in adults participating in the CRIC study [ 24 ], which is in line with our results. In our study we provide the first results about the association of IS with progression of CKD in pediatric patients who had no other comorbidities which might interfere with renal survival.…”

Section: Discussionsupporting

confidence: 92%

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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Section: Discussionsupporting

confidence: 92%

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

et al. 2020

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“…In renal dysfunction, the tubular cells develop several disturbances of metabolism and molecular transport as well as of inflammatory reactions detectable in blood circulation that are reflected only partially by serum creatinine [ 28 , 48 ]. Accordingly, tubular clearances of secretory solutes were suggested to provide complementary information about kidney health beyond measurements of glomerular function alone [ 49 ]. Thus, the pathogenesis of renal dysfunction can be considered a complex multi-factorial series of molecular events associated with alterations of various disease pathways.…”

Section: Discussionmentioning

confidence: 99%

Serum Myo-Inositol, Dimethyl Sulfone, and Valine in Combination with Creatinine Allow Accurate Assessment of Renal Insufficiency—A Proof of Concept

et al. 2021

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Evaluation of renal dysfunction includes estimation of glomerular filtration rate (eGFR) as the initial step and subsequent laboratory testing. We hypothesized that combined analysis of serum creatinine, myo-inositol, dimethyl sulfone, and valine would allow both assessment of renal dysfunction and precise GFR estimation. Bio-banked sera were analyzed using nuclear magnetic resonance spectroscopy (NMR). The metabolites were combined into a metabolite constellation (GFRNMR) using n = 95 training samples and tested in n = 189 independent samples. Tracer-measured GFR (mGFR) served as a reference. GFRNMR was compared to eGFR based on serum creatinine (eGFRCrea and eGFREKFC), cystatin C (eGFRCys-C), and their combination (eGFRCrea-Cys-C) when available. The renal biomarkers provided insights into individual renal and metabolic dysfunction profiles in selected mGFR-matched patients with otherwise homogenous clinical etiology. GFRNMR correlated better with mGFR (Pearson correlation coefficient r = 0.84 vs. 0.79 and 0.80). Overall percentages of eGFR values within 30% of mGFR for GFRNMR matched or exceeded those for eGFRCrea and eGFREKFC (81% vs. 64% and 74%), eGFRCys-C (81% vs. 72%), and eGFRCrea-Cys-C (81% vs. 81%). GFRNMR was independent of patients’ age and sex. The metabolite-based NMR approach combined metabolic characterization of renal dysfunction with precise GFR estimation in pediatric and adult patients in a single analytical step.

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“…Serum kynurenic acid, p-cresol sulfate and indoxyl sulfate concentrations were quantified by LC-MS/MS using previously published methods (13). Samples were precipitated in organic solvent, followed by solid phase extraction (Phree phospholipid removal plate).…”

Section: Metabolite Quantificationmentioning

confidence: 99%

“…It is postulated that this endotoxemia stimulates innate immune responses and proinflammatory pathways that contribute to excess cardiovascular pathology in this population. Moreover, a variety of gut-derived bacterial metabolites with purported cardiovascular toxicity accumulate in the circulation of patients with CKD (9)(10)(11)(12)(13)(14). Pcresol sulfate, indoxyl sulfate and trimethylamine N-oxide (TMAO) are well-established examples of such metabolites (9).…”

Section: Introductionmentioning

confidence: 99%

Randomized, Placebo-Controlled Trial of Rifaximin Therapy for Lowering Gut-Derived Cardiovascular Toxins and Inflammation in CKD

et al. 2020

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BackgroundRecent evidence suggests the systemic accumulation of by-products of gut microbes contributes to cardiovascular morbidity in patients with CKD. Limiting the generation of toxic bacterial by-products by manipulating the intestinal microbiota may be a novel strategy for reducing cardiovascular disease in CKD. Rifaximin is a minimally absorbed, oral antibiotic that targets intestinal pathogens and is commonly used as chronic therapy for the prevention of encephalopathy in patients with cirrhosis.MethodsWe conducted a randomized, double-blinded, placebo-controlled trial to determine the effect of a 10-day course of oral rifaximin 550 mg BID versus placebo on circulating concentrations of gut-derived cardiovascular toxins and proinflammatory cytokines in patients with stage 3–5 CKD (n=38). The primary clinical outcome was change in serum trimethylamine N-oxide (TMAO) concentrations from baseline to study end. Secondary outcomes included change in serum concentrations of p-cresol sulfate, indoxyl sulfate, kynurenic acid, deoxycholic acid, and inflammatory cytokines (C-reactive protein, IL-6, IL-1β), and change in composition and diversity of fecal microbiota.ResultsA total of 19 patients were randomized to each of the rifaximin and placebo arms, with n=17 and n=14 completing both study visits in these respective groups. We observed no difference in serum TMAO change (post-therapy minus baseline TMAO) between the rifaximin and placebo groups (mean TMAO change −3.9±15.4 for rifaximin versus 0.5±9.5 for placebo, P=0.49). Similarly, we found no significant change in serum concentrations for p-cresol sulfate, indoxyl sulfate, kynurenic acid, deoxycholic acid, and inflammatory cytokines. We did observe differences in colonic bacterial communities, with the rifaximin group exhibiting significant decreases in bacterial richness (Chao1, P=0.02) and diversity (Shannon H, P=0.05), along with altered abundance of several bacterial genera.ConclusionsShort-term rifaximin treatment failed to reduce gut-derived cardiovascular toxins and inflammatory cytokines in patients with CKD.Clinical Trial registry name and registration number Rifaximin Therapy in Chronic Kidney Disease, NCT02342639

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Kidney Clearance of Secretory Solutes Is Associated with Progression of CKD: The CRIC Study

Cited by 52 publications

References 44 publications

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

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

Serum Myo-Inositol, Dimethyl Sulfone, and Valine in Combination with Creatinine Allow Accurate Assessment of Renal Insufficiency—A Proof of Concept

Randomized, Placebo-Controlled Trial of Rifaximin Therapy for Lowering Gut-Derived Cardiovascular Toxins and Inflammation in CKD

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