Table 3.
Observational studies of the effects of UTs on cardiovascular complications.
| First Author, Year | Models | UT(s) Studied | Main Findings |
|---|---|---|---|
| Atheromatous CVDs | |||
| Arinze [50], 2022 | 20 HD patients and 15 | IS | Elevated plasma levels of IS, kynurenine, and KA in |
| controls | Kynurenine | HD patients showed a significant decrease in ECs | |
| KA | proliferation and migration, compared with the control group. | ||
| Arinze [50], 2022 | PAD patients: 35 without | IS | Elevated plasma levels of IS, kynurenine, KA, with |
| adverse limb event and | Kynurenine | suppressed Wnt activity in ECs were associated with | |
| 28 with | KA | an increased risk of future adverse limb events. | |
| Shafi et al. [153], 2015 | 394 incident HD patients | IS | Elevated serum levels of IS, PCS, PAG and HA were |
| PCS | associated with greater risk of fatal or nonfatal | ||
| PAG | atherosclerotic cardiovascular events in incident HD | ||
| HA | patients. | ||
| Hsu [154], 2013 | 191 mild-to-moderate CKD patients | IS | Elevated serum IS levels were associated with coronary atherosclerosis and correlated with the severity of the disease. |
| Melamed [167], 2013 | 521 incident HD patients | IS | IS and PCS were not associated with atherosclerotic |
| PCS | cardiovascular death. | ||
| Lin [155], 2012 | 70 pre-dialysis patients (CKD stage 3 to 5) | IS | Serum IS levels were positively correlated with atherosclerotic cardiovascular events. |
| Lin [152], 2012 | 100 stable HD patients | IS | Elevated serum levels of IS and PCS were associated |
| PCS | with PAD and arteriosclerosis markers. | ||
| Lin [157], 2010 | 100 HD patients | IS | Only elevated serum PCS levels were significantly |
| PCS | associated with fatal or nonfatal atherosclerotic cardiovascular events. | ||
| Taki [156], 2007 | 224 HD patients | IS | Plasma IS levels were significantly and negatively correlated with HDL cholesterol and were positively associated with atherosclerotic lesions. |
| Poesen [158], 2016 | 488 patients (all CKD | PCS | A lower serum PCS:PCG ratio and a higher |
| stages) | PCG | total PCS + PCG level were associated with fatal or nonfatal atherosclerotic CVDs. | |
| Wang [160], 2010 | 202 patients with stable angina and early-stage kidney failure | PCS | Elevated plasma PCS levels were associated with coronary artery disease and correlated with the severity of the disease. |
| Poesen [159], 2016 | 488 patients with CKD stages 1–5 | PAG | An elevated serum PAG level was a powerful, independent risk factor for major CVD (such as MI and stroke). |
| Merhi [162], 2017 | 3138 CKD patients | Phosphate | Hyperphosphatemia was associated with atherosclerotic CVD. |
| Eddington [163], 2010 | 1203 nondialyzed CKD patients | Phosphate | Hyperphosphatemia increased the risk of cardiovascular death from atheromatous CVD. |
| Kestenbaum [164], 2005 | 3490 CKD patients | Phosphate | Hyperphosphatemia was associated with MI. |
| Nakamura [161], 2002 | 525 HD patients | Phosphate | Hyperphosphatemia was associated with atherosclerotic diseases. |
| Stubbs [165], 2016 | 104 CKD patients | TMAO | Elevated TMAO concentrations were correlated with coronary atherosclerosis. |
| Kim [166], 2016 | 2529 patients (stages 3b and 4 CKD) | TMAO | Elevated serum TMAO levels were associated with ischemic cardiovascular events. |
| Non-atheromatous CVDs | |||
| Chinnappa [168], 2018 | 56 male patients with | IS | These serum UT levels showed significant negative |
| stage 2–5 CKD, nondia- | IAA | correlation with peak cardiac power and subclinical | |
| lyzed and free of heart | PCS | cardiac dysfunction, but no correlation with left ven- | |
| disease | PCG | tricular mass index was found. | |
| HA | |||
| Cao [169], 2015 | 258 HD patients | IS | Elevated plasma IS was associated with heart failure. |
| Sato [171], 2013 | 204 CKD patients with preserved left ventricular function | IS | Elevated plasma IS levels were associated with an increased risk of left ventricular diastolic dysfunction. |
| Shimazu [170], 2013 | 76 patients with mild-to-moderate CKD and dilated cardiomyopathy | IS | Elevated serum IS levels were associated with hospitalization for heart failure and cardiac death. |
| Barreto [172], 2009 | 139 patients with CKD from stage 2 to dialysis | IS | Being in the highest serum IS tertile was directly associated with pulse wave velocity, aortic calcification, and higher cardiovascular mortality. |
| Zapolski [173], 2020 | 100 CKD patients with persistent atrial fibrillation | KA | Serum KA levels were positively correlated with aortic stiffness and indices of diastolic dysfunction of left atrium and left ventricle. |
| Pawlak [174], 2010 | 106 CKD patients | KA | Elevated plasma kynurenine and KA levels were as- |
| Kynurenine | sociated with intima-media thickness. | ||
| Liabeuf [175], 2010 | 139 CKD patients | PCS | Elevated total and free serum PCS levels were significantly associated with vascular calcification, and free PCS was shown to be a predictor of cardiovascular death. |
| Yu [176], 2018 | 80 HD patients | HA | Elevated HA levels were significantly associated with left ventricular hypertrophy. |
| Petchey [177], 2012 | 120 CKD pre-dialysis patients | Phosphate | Serum phosphate was positively correlated with aortic pulse wave velocity, arterial stiffness, and the presence of vascular calcification. |
| Adeney [178], 2009 | 6814 patients with CKD aged 45–84 | Phosphate | Hyperphosphatemia was associated with vascular and valvular calcification. |
| Ix [180], 2009 | 440 patients with moderate CKD | Phosphate | Hyperphosphatemia was strongly associated with peripheral arterial stiffness. |
| Ketteler [179], 2003 | 312 HD patients | Phosphate | Hyperphosphatemia was associated with vascular calcification and cardiovascular mortality. |
| Drechsler [181], 2015 | 1255 HD patients | Urea | Higher blood urea levels were associated with higher tertile serum carbamylated albumin levels, which in turn were positively correlated with heart failure and arrhythmia. |
| Atheromatous and non-atheromatous CVDs | |||
| Chen [147], 2021 | 3407 participants with | IS | Lower 24-h kidney clearance of IS, KA, and PCS |
| CKD, excluding those | KA | was not found to be associated with heart failure and | |
| with a GFR < 20 mL/min/1.73 m2 | PCS | MI after adjustment for GFR. | |
| Fan [135], 2019 | 147 patients with CKD stage 1–5 | IS | Elevated plasma IS levels were associated with major adverse cardiovascular events, independently of GFR and nutritional status. |
| Shafi [148], 2017 | 1273 HD patients | IS | Overall, elevated serum IS, PCS, PAG and HA levels |
| PCS | were not associated with any cardiovascular event. | ||
| PAG | However, high IS levels were predictive of cardiac | ||
| HA | and sudden cardiac death in patients with low albumin levels. | ||
| Konje [136], 2021 | 92 CKD patients with a history of CVD, 46 with no history of CVD, and 46 with incident CVD | Kynurenine | Elevated serum kynurenine levels were associated with incident atheromatous and non-atheromatous CVDs. |
| Wu [137], 2012 | 112 HD patients aged from 65 to 90 | PCS | Elevated free PCS serum levels were associated with cardiovascular mortality. |
| Liabeuf [138], 2013 | 139 CKD patients | PCG | Elevated free and total serum PCG levels were correlated with cardiovascular mortality independently of survival predictors. |
| Luce [149], 2018 | 270 HD patients | CMPF | Elevated serum CMPF was not associated with any CVD. |
| McGovern [139], 2013 | 13,292 CKD patients at stages 3–5 | Phosphate | Hyperphosphatemia was correlated with increased CVDs. |
| Kimata [140], 2007 | 3973 HD patients | Phosphate | Hyperphosphatemia was significantly associated with cardiovascular mortality. |
| Menon [150], 2005 | 840 CKD patients | Phosphate | Hyperphosphatemia was significantly associated with increased cardiovascular mortality but only before adjustment for GFR. |
| Slinin [141], 2005 | 14829 HD patients | Phosphate | Hyperphosphatemia was associated with CVDs and mortality. |
| Young [142], 2005 | 17236 dialysis patients | Phosphate | Hyperphosphatemia was significantly associated with cardiovascular mortality. |
| Block [143], 2004 | 40538 HD patients | Phosphate | Hyperphosphatemia was significantly associated with cardiovascular hospitalization and mortality. |
| Laville [27], 2022 | 2507 CKD patients before RRT | Urea | Higher serum urea levels were associated with a greater risk of CVD. |
| Berg [146], 2013 | 187 HD patients | Urea | Urea was positively correlated with carbamylation of serum albumin, which is associated with CVDs and mortality. |
| Shafi [144], 2017 | 1846 prevalent HD patients | TMAO | An elevated serum TMAO concentration was associated with cardiovascular events and death. |
| Kaysen [151], 2015 | 235 HD patients | TMAO | There was no significant association between TMAO and cardiovascular hospitalizations or death. |
| Other than ATH and non ATH CVDs | |||
| Glorieux [182], 2021 | 523 nondialyzed patients | IS | Elevated serum levels of these UTs were correlated |
| (all stages of CKD) | IAA | with markers of endothelial damage (mainly angio- | |
| PCS | poietin-2). Elevated levels of free PCS and free PCG | ||
| PCG | had the strongest association with CVD, indepen- | ||
| HA | dently of the GFR. | ||
| Wang [184], 2019 | 110 patients with stage 3–5 CKD | IS | Elevated levels of serum IS were negatively correlated with vascular reactivity index values, leading to endothelial dysfunction. |
| Kolachalama [128], 2018 | 473 participants under- | IS | Elevated serum levels of IS and kynurenine were |
| going angioplasty for dialysis access dysfunction | Kynurenine | associated with postangioplasty thrombosis of dialysis grafts. | |
| Wu [190], 2016 | 306 patients undergoing angioplasty for dialysis access dysfunction | IS | Elevated serum levels of IS were associated with postangioplasty thrombosis of dialysis grafts. |
| Jourde-Chiche [185], 2009 | 38 HD patients and 21 | IS | Elevated serum levels of IS, IAA, and PCS were asso- |
| healthy controls | IAA | ciated with low numbers of endothelial progenitor | |
| PCS | cells. | ||
| Pawlak [187], 2010 | 64 patients on peritoneal dialysis | KA | Plasma KA levels were positively associated with TF inhibitor and negatively associated with prothrombin fragment 1 + 2 levels. |
| Pawlak [188], 2009 | 48 patients with ESRD | Kynurenine | Plasma kynurenine levels were positively associated with thrombomodulin and von Willebrand factor (markers of endothelial dysfunction). |
| Pawlak [186], 2009 | 146 CKD patients with 91 | Kynurenine | Elevated serum levels of kynurenine and KA were |
| ones on dialysis | KA | associated with increased oxidative stress, inflammation, and endothelial dysfunction. | |
| Pawlak [189], 2009 | 92 patients on dialysis | Kynurenine | Elevated serum levels of kynurenine and KA were |
| KA | independently and significantly associated with hypercoagulability. | ||
| Meijers [66], 2009 | 100 HD patients | PCS | Elevated serum PCS levels were associated with the levels of circulating endothelial microparticles. |
Abbreviations: CMPF: 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid; CKD: chronic kidney disease; CVD: cardiovascular disease; EC: endothelial cell; ESRD: end-stage renal disease; GFR: glomerular filtration rate; HA: hippuric acid; HD: hemodialysis; HDL: high-density lipoprotein; IAA: indole-3-acetic acid; IS:indoxyl sulfate; KA: kynurenic acid; MI: myocardial infarction; PAD: peripheral artery disease; PAG: phenylacetylglutamine; PCS: para-cresyl sulfate; PCG: p-cresyl glucuronide; RRT: renal replacement therapy; TF: tissue factor; TMAO: trimethylamine-N-oxide; UT: uremic toxin.