Trimethylamine N-Oxide as a Novel Therapeutic Target in CKD

Tang, W.H. Wilson

doi:10.1681/asn.2015050576

Cited by 14 publications

(14 citation statements)

References 21 publications

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“…Recent studies found that the enterogenous toxin TMAO is closely associated with the occurrence and development of cardiovascular events in patients with uremia [19][20][21][22]. In recent years, TMAO was found to be possibly cytotoxic to mammals.…”

Section: Discussionmentioning

confidence: 99%

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Trimethylamine- N -oxide is an independent risk factor for hospitalization events in patients receiving maintenance hemodialysis

Yin

Tang

et al. 2020

Renal Failure

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Background: Hospitalization is a significant outcome measurement for maintenance hemodialysis pantients. Trimethylamine-N-oxide (TMAO), created by gut microflora from dietary L-carnitine and choline, cleared by the kidney, has been implicated in the causation of cardiovascular diseases in patients with chronic kidney disease. However, whether it associates with hospitalization risk for these patients is unclear. Methods: In this study, 69 patients undergoing outpatient dialysis were enrolled. Enzyme-linked immunosorbent assay was used to quantitate the baseline plasma TMAO levels in patients. The patients were divided into a high TMAO level group (TMAO ! 15 lmol/L) and a low TMAO level group (TMAO < 15 lmol/L). During the 1-year follow-up, 1-year dialysis-related data and all-cause hospitalization events were recorded. Results: The incidence of hospitalization events was significantly higher in the high TMAO level group than in the low TMAO level group (91 per 100 patient-year vs. 32 per 100 patient-year). The Kaplain-Meier survaial analysis showed that the incidence of hospitalization events in the high TMAO level group was significantly higher than that in the low TMAO level group (log-rank p ¼ 0.0004). After adjustment age, sex, CK-MB and albumin, the results of multivariate Cox proportional hazard analysis showed that high TMAO level was an independent risk factor for hospitalization in maintenance hemodialysis patients. Conclusion: TMAO is an independent risk factor for hospitalization events in patients receiving maintenance hemodialysis. It may be a new therapeutic target for improving the outcomes of these patients.

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Section: Discussionmentioning

confidence: 99%

“…TMAO is a potential marker for the clinical assessment of outcomes in these patients. At present, some researchers believe that TMAO is a new therapeutic target for improving the outcomes of patients with uremia [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

Trimethylamine- N -oxide is an independent risk factor for hospitalization events in patients receiving maintenance hemodialysis

Yin

Tang

et al. 2020

Renal Failure

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“…63 Kidney vascular AT1 receptors contribute to the pathogenesis of AngII-induced hypertension by reducing renal blood flow which also enhances sodium retention. 64 Thus, the long-term effects of AngII on BP and salt-sensitivity are closely coupled to renal tubular and hemodynamic actions that cause salt/water retention.…”

Section: Acquired Kidney Disorders That Cause Salt-sensitive Hypertenmentioning

confidence: 99%

Renal Dysfunction, Rather Than Nonrenal Vascular Dysfunction, Mediates Salt-Induced Hypertension

2016

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Chronic excess salt intake increases the risk for hypertension and moderation of salt intake is an important strategy for prevention of cardiovascular and kidney disease, especially in salt-sensitive subjects. Although short-term blood pressure (BP) responses to high salt intake over several days are highly variable, chronic high salt intake worsens BP salt-sensitivity. Aging, diabetes, hypertension, and various acquired and genetic kidney disorders also exacerbate salt-sensitivity of BP. Kidney dysfunction, characterized by impaired pressure natriuresis, has been demonstrated in all forms of experimental and human genetic or acquired salt-sensitive hypertension studied thus far. Abnormalities of kidney function that directly or indirectly increase NaCl reabsorption, decrease glomerular capillary filtration coefficient, or cause nephron injury/loss exacerbate BP salt-sensitivity. In most cases, salt-sensitive hypertension is effectively treated with drugs that increase glomerular filtration rate or reduce renal NaCl reabsorption (e.g. diuretics, renin-angiotensin-aldosterone system blockers). Increased vascular resistance may occur concomitantly or secondarily to kidney dysfunction and increased BP in salt-sensitive hypertension. However, primary increases in non-renal vascular resistance have not been shown to cause salt-sensitive hypertension or long-term changes in BP in the absence of impaired renal-pressure natriuresis. The mechanisms responsible for increased total peripheral resistance (TPR) during high salt intake in salt-sensitive subjects are not fully understood but likely involve pressure-dependent and/or flow-dependent autoregulation in peripheral tissues as well as neurohormonal factors that occur concomitantly with kidney dysfunction. Physiological studies have demonstrated that increased BP almost invariably initiates secondary pressure-dependent functional and structural vascular changes that increase TPR.

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“…In addition, conditional gene knockout studies are generating insight into relative contributions of PHDs 1-3. Using an Epo gene-GFP mouse model to study renal EPO producing cells (R-EPs) genetic inactivation of PHD2 restored EPO expression, but resulted in polycythemia 75 . By comparison, compound deletion of PHD1 and PHD3 prevented loss of EPO expression without generating polycythemia.…”

Section: ] Targeting Hif2a To Heighten Endogenous Epo Productionmentioning

confidence: 99%

“…For the anemia of chronic kidney disease, an additional potential complication relates to renal fibrosis. Studies involving genetic or pharmacological inactivation of PHDs have demonstrated that EPO expression in EPO-low cells (which can convert to myelofibroblasts) can be reactivated 75, 150 . The extent to which this might be durably sustained (or perhaps progressively diminished) in patients with end-stage renal disease becomes one important question to address.…”

Section: ] Summary and Opinionmentioning

confidence: 99%

Targeting EPO and EPO receptor pathways in anemia and dysregulated erythropoiesis

Rainville

Jachimowicz

Wojchowski

2015

Expert Opinion on Therapeutic Targets

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Introduction Recombinant human erythropoietin (rhEPO) is a first-line therapeutic for the anemia of chronic kidney disease, cancer chemotherapy, AIDS (Zidovudine therapy) and lower-risk myelodysplastic syndrome. However, rhEPO frequently elevates hypertension, is costly and may affect cancer progression. Potential high merit therefore exists for defining new targets for anti-anemia agents within EPO, and EPO receptor (EPOR) regulatory circuits. Areas covered EPO production by renal interstitial fibroblasts is subject to modulation by several regulators of hypoxia-inducible factor 2a (HIF2a) including Iron Response Protein-1, prolyl hydroxylases and HIF2a acetylases, each with potential as anti-anemia drug targets. The cell surface receptor for EPO (EPOR) preassembles as a homodimer (together with JAK2), and novel agents that trigger EPOR complex activation also remain attractive to develop (activating antibodies, mimetics, small molecule agonists). Additionally, certain downstream transducers of EPOR/JAK2 signaling may be drugable including Erythroferrone (a hepcidin regulator), a cytoprotective Spi2a serpin, and select EPOR-associated protein tyrosine phosphatases. Expert Opinion While rhEPO (and biosimilars) presently are important mainstay erythropoiesis-stimulating agents, impetus exists for studies of novel ESAs that fortify HIF2a’s effects, act as EPOR agonists, and/or bolster select downstream EPOR pathways to erythroid cell formation. Such agents could lessen rhEPO dosing, side effects and/or costs.

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Trimethylamine N-Oxide as a Novel Therapeutic Target in CKD

Cited by 14 publications

References 21 publications

Trimethylamine- N -oxide is an independent risk factor for hospitalization events in patients receiving maintenance hemodialysis

Trimethylamine- N -oxide is an independent risk factor for hospitalization events in patients receiving maintenance hemodialysis

Renal Dysfunction, Rather Than Nonrenal Vascular Dysfunction, Mediates Salt-Induced Hypertension

Targeting EPO and EPO receptor pathways in anemia and dysregulated erythropoiesis

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