Uraemic solutes as therapeutic targets in CKD-associated cardiovascular disease

Ravid, Jonathan D.; Kamel, Mohamed Hassan; Chitalia, Vipul C.

doi:10.1038/s41581-021-00408-4

Cited by 61 publications

(53 citation statements)

References 214 publications

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“…These observations along with other examples ( 12 , 13 , 23 , 24 , 30 ) support a “group” effect of a set of uremic toxins. This phenomenon can be explained by the mediation of their effect through AHR and creates an opportunity to target AHR to suppress the effects of several toxins simultaneously ( 34 ). Endothelial dysfunction is universal in CKD patients and is known to be mediated in part by uremic solutes such as IS ( 11 ).…”

Section: Discussionmentioning

confidence: 99%

Tryptophan metabolites suppress the Wnt pathway and promote adverse limb events in chronic kidney disease

Arinze¹,

Yin²,

Lotfollahzadeh³

et al. 2022

Journal of Clinical Investigation

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Chronic kidney disease (CKD) imposes a strong and independent risk for peripheral artery disease (PAD). While solutes retained in CKD patients (uremic solutes) inflict vascular damage, their role in PAD remains elusive. Here, we show that the dietary tryptophan-derived uremic solutes including indoxyl sulfate (IS) and kynurenine (Kyn) at concentrations corresponding to those in CKD patients suppress β-catenin in several cell types, including microvascular endothelial cells (ECs), inhibiting Wnt activity and proangiogenic Wnt targets in ECs. Mechanistic probing revealed that these uremic solutes downregulated β-catenin in a manner dependent on serine 33 in its degron motif and through the aryl hydrocarbon receptor (AHR). Hindlimb ischemia in adenine-induced CKD and IS solute–specific mouse models showed diminished β-catenin and VEGF-A in the capillaries and reduced capillary density, which correlated inversely with blood levels of IS and Kyn and AHR activity in ECs. An AHR inhibitor treatment normalized postischemic angiogenic response in CKD mice to a non-CKD level. In a prospective cohort of PAD patients, plasma levels of tryptophan metabolites and plasma’s AHR-inducing activity in ECs significantly increased the risk of future adverse limb events. This work uncovers the tryptophan metabolite/AHR/β-catenin axis as a mediator of microvascular rarefaction in CKD patients and demonstrates its targetability for PAD in CKD models.

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Section: Discussionmentioning

confidence: 99%

Tryptophan metabolites suppress the Wnt pathway and promote adverse limb events in chronic kidney disease

Arinze¹,

Yin²,

Lotfollahzadeh³

et al. 2022

Journal of Clinical Investigation

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“…Alternatively, between-patient differences in the gut microbiome and putative modulatory effects of micronutrients may have a role 77,78 . As an example, alterations in the metabolism of tryptophan -an essential amino acid that is derived from dietary sources and contributes to the synthesis and regulation of neurotransmittersmight contribute to symptoms relating to sleep, mood and pain 58,79,80 , as well as the increased risk of cardiovascular disease 81 among patients with CKD. Tryptophan is the precursor of a number of signalling molecules, including the neurotransmitter serotonin, the hormone melatonin and vitamin B3 (niacin), all of which have important roles in the regulation of depression and sleep 79 .…”

Section: Pathophysiology Of Ckd Symptomsmentioning

confidence: 99%

“…Accelerated tryptophan metabolism is a feature of several clinical conditions including inflammation, infection and malignant disease, and malnutrition associated with alterations in the composition of symbiotic microbiota in the gut. Similarly, patients with CKD demonstrate alterations in tryptophan metabolism as a consequence of inflammatory processes and alterations in enzyme activity 81 .…”

Section: Pathophysiology Of Ckd Symptomsmentioning

confidence: 99%

Patient-centred approaches for the management of unpleasant symptoms in kidney disease

et al. 2022

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Patients with chronic kidney disease (CKD) frequently experience unpleasant symptoms. These can be gastrointestinal (constipation, nausea, vomiting and diarrhoea), psychological (anxiety and sadness), neurological (lightheadedness, headache and numbness), cardiopulmonary (shortness of breath and oedema), dermatological (pruritus and dry skin), painful (muscle cramps, chest pain and abdominal pain) or involve sexual dysfunction, sleep disorders and fatigue. These symptoms often occur in clusters, with one of them as the lead symptom and others as secondary symptoms. Uraemic toxins (also called uremic toxins) are often considered to be the main cause of CKD-associated symptom burden, but treatment of uraemia by dialysis often fails to resolve them and can engender additional symptoms. Indeed, symptoms can be exacerbated by comorbid conditions, pharmacotherapies, lifestyle and dietary regimens, kidney replacement therapy and ageing. Patients with kidney disease, including those who depend on dialysis or transplantation, should feel actively supported in their symptom management through the identification and targeting of unpleasant symptoms via a tailored palliative care approach. Such an approach may help minimize the burden and consequences of kidney disease, and lead to improved patient outcomes including health-related quality of life and better life participation.

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“…SCFAs participate in the maintenance of intestinal mucosal integrity, improve glucose and lipid metabolism, increase the secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), and regulate the immune system and inflammatory responses, as such, they confer protection against cardiometabolic and kidney disease [ 30 ]. Conversely, phenols and indoles released in the systemic circulation portend cardiometabolic and renal risks, as demonstrated in many experimental and clinical studies [ 19 , 31 , 32 , 33 , 34 , 35 , 36 ]. The toxic systemic effects of phenols and indoles are mediated at least in part by increased intracellular oxidative stress.…”

Section: The Gut–cardio–renal Axismentioning

confidence: 99%

Effects of an SGLT Inhibitor on the Production, Toxicity, and Elimination of Gut-Derived Uremic Toxins: A Call for Additional Evidence

Evenepoel

Meijers

Masereeuw

et al. 2022

Toxins

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Sodium–glucose cotransporter (SGLT) inhibitors are a class of oral hypoglycemic agents, which, in recent years, have been shown to improve renal and cardiovascular outcomes in patients with diabetic and non-diabetic chronic kidney disease. There remains considerable debate regarding the potential glucose-independent mechanisms by which these benefits are conferred. SGLT inhibitors, to a variable extent, impair small intestinal glucose absorption, facilitating the delivery of glucose into the colon. This suppresses protein fermentation, and thus the generation of uremic toxins such as phenols and indoles. It is acknowledged that such a shift in gut microbial metabolism yields health benefits for the host. SGLT inhibition, in addition, may be hypothesized to foster the renal clearance of protein-bound uremic toxins. Altered generation and elimination of uremic toxins may be in the causal pathway between SGLT inhibition and improved cardiometabolic health. Present review calls for additional research.

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Uraemic solutes as therapeutic targets in CKD-associated cardiovascular disease

Cited by 61 publications

References 214 publications

Tryptophan metabolites suppress the Wnt pathway and promote adverse limb events in chronic kidney disease

Tryptophan metabolites suppress the Wnt pathway and promote adverse limb events in chronic kidney disease

Patient-centred approaches for the management of unpleasant symptoms in kidney disease

Effects of an SGLT Inhibitor on the Production, Toxicity, and Elimination of Gut-Derived Uremic Toxins: A Call for Additional Evidence

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