Indoxyl sulfate in uremia: an old idea with updated concepts

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Abstract

Patients with end-stage kidney disease (ESKD) have increased vascular disease. While protein-bound molecules that escape hemodialysis may contribute to uremic toxicity, specific contributing toxins remain ambiguous. In this issue of the JCI, Arinze et al. explore the role of tryptophan metabolites in chronic kidney disease–associated (CKD-associated) peripheral arterial disease. The authors used mouse and zebrafish models to show that circulating indoxyl sulfate (IS) blocked endothelial Wnt signaling, which impaired angiogenesis. Plasma levels of IS and other tryptophan metabolites correlated with adverse peripheral vascular disease events in humans. These findings suggest that lowering IS may benefit individuals with CKD and ESKD.

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FGF23 induces left ventricular hypertrophy.

Christian Faul, Ansel P Amaral, Behzad Oskouei … (2011)

Chronic kidney disease (CKD) is a public health epidemic that increases risk of death due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiovascular disease in individuals with CKD. Elevated levels of FGF23 have been linked to greater risks of LVH and mortality in patients with CKD, but whether these risks represent causal effects of FGF23 is unknown. Here, we report that elevated FGF23 levels are independently associated with LVH in a large, racially diverse CKD cohort. FGF23 caused pathological hypertrophy of isolated rat cardiomyocytes via FGF receptor-dependent activation of the calcineurin-NFAT signaling pathway, but this effect was independent of klotho, the coreceptor for FGF23 in the kidney and parathyroid glands. Intramyocardial or intravenous injection of FGF23 in wild-type mice resulted in LVH, and klotho-deficient mice demonstrated elevated FGF23 levels and LVH. In an established animal model of CKD, treatment with an FGF-receptor blocker attenuated LVH, although no change in blood pressure was observed. These results unveil a klotho-independent, causal role for FGF23 in the pathogenesis of LVH and suggest that chronically elevated FGF23 levels contribute directly to high rates of LVH and mortality in individuals with CKD.

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Normal and pathologic concentrations of uremic toxins.

Flore Duranton, Gerald Cohen, Rita De Smet … (2013)

An updated review of the existing knowledge regarding uremic toxins facilitates the design of experimental studies. We performed a literature search and found 621 articles about uremic toxicity published after a 2003 review of this topic. Eighty-seven records provided serum or blood measurements of one or more solutes in patients with CKD. These records described 32 previously known uremic toxins and 56 newly reported solutes. The articles most frequently reported concentrations of β2-microglobulin, indoxyl sulfate, homocysteine, uric acid, and parathyroid hormone. We found most solutes (59%) in only one report. Compared with previous results, more recent articles reported higher uremic concentrations of many solutes, including carboxymethyllysine, cystatin C, and parathyroid hormone. However, five solutes had uremic concentrations less than 10% of the originally reported values. Furthermore, the uremic concentrations of four solutes did not exceed their respective normal concentrations, although they had been previously described as uremic retention solutes. In summary, this review extends the classification of uremic retention solutes and their normal and uremic concentrations, and it should aid the design of experiments to study the biologic effects of these solutes in CKD.

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The current and future landscape of dialysis

Jonathan Himmelfarb, Raymond Vanholder, Rajnish Mehrotra … (2020)

The development of dialysis by early pioneers such as Willem Kolff and Belding Scribner set in motion several dramatic changes in the epidemiology, economics and ethical frameworks for the treatment of kidney failure. However, despite a rapid expansion in the provision of dialysis — particularly haemodialysis and most notably in high-income countries (HICs) — the rate of true patient-centred innovation has slowed. Current trends are particularly concerning from a global perspective: current costs are not sustainable, even for HICs, and globally, most people who develop kidney failure forego treatment, resulting in millions of deaths every year. Thus, there is an urgent need to develop new approaches and dialysis modalities that are cost-effective, accessible and offer improved patient outcomes. Nephrology researchers are increasingly engaging with patients to determine their priorities for meaningful outcomes that should be used to measure progress. The overarching message from this engagement is that while patients value longevity, reducing symptom burden and achieving maximal functional and social rehabilitation are prioritized more highly. In response, patients, payors, regulators and health-care systems are increasingly demanding improved value, which can only come about through true patient-centred innovation that supports high-quality, high-value care. Substantial efforts are now underway to support requisite transformative changes. These efforts need to be catalysed, promoted and fostered through international collaboration and harmonization.

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Contributors

Anders H. Berg

Sanjeev Kumar

S. Ananth Karumanchi:

ORCID: http://orcid.org/0000-0002-2281-6831

Journal

Journal ID (nlm-ta): J Clin Invest

Journal ID (iso-abbrev): J Clin Invest

Journal ID (publisher-id): J Clin Invest

Title: The Journal of Clinical Investigation

Publisher: American Society for Clinical Investigation

ISSN (Print): 0021-9738

ISSN (Electronic): 1558-8238

Publication date (Electronic, pub): 4 January 2022

Publication date (Electronic, collection): 4 January 2022

Publication date (Print, pub): 4 January 2022

Publication date PMC-release: 4 January 2022

Volume: 132

Issue: 1

Electronic Location Identifier: e155860

Affiliations

[1 ]Department of Pathology and

[2 ]Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.

[3 ]Deparment of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.

Author notes

Address correspondence to: S. Ananth Karumanchi, Cedars-Sinai Medical Center, AHSP 8110A, 8700 Beverly Blvd., Los Angeles, California, USA. Phone: 310.423.7608; Email: SAnanth.Karumanchi@ 123456csmc.edu .

Author information

S. Ananth Karumanchi http://orcid.org/0000-0002-2281-6831

Article

Publisher ID: 155860

DOI: 10.1172/JCI155860

PMC ID: 8718144

PubMed ID: 34981787

SO-VID: 8885f44a-e24b-4940-99fc-a2eed5c82876

License:

This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Indoxyl sulfate in uremia: an old idea with updated concepts

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Most cited references 20

FGF23 induces left ventricular hypertrophy.

Normal and pathologic concentrations of uremic toxins.

The current and future landscape of dialysis

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