Acute Coronary Syndrome
Management of Patients With Advanced Chronic Kidney Disease and Preexisting Acute Myocardial Infarction
2021 Volume 85 Issue 10 Pages 1719-1721
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2021 Volume 85 Issue 10 Pages 1719-1721
Chronic kidney disease (CKD) is a strong and independent risk factor for cardiovascular disease (CVD) and all-cause death, and it is also associated with adverse outcomes in patients with acute myocardial infarction (AMI).1 Although CKD has been associated with adverse outcomes in patients with AMI, the underlying pathophysiological mechanism of this relationship remains unclear. Furthermore, few reports have shown the long-term prognosis of patients with AMI complicated by CKD.
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In this issue of the Journal, Hashimoto et al2 investigate the independent risk factors for in-hospital outcome, 3-year mortality, and major adverse cardiovascular events (MACE) in Japanese CKD patients who underwent modern percutaneous coronary intervention (PCI) and optimal medical therapy for AMI. The risk for MACE and all-cause death was significantly increased in both the acute and chronic phase in advanced CKD patients with AMI. At baseline, the proportion of patients with Killip classification 3 or 4 was higher in the moderate and severe CKD groups, associated with an increased risk of MACE and all-cause death in hospital. This suggested that moderate and severe CKD exacerbated the risk of CVD and death in patients with AMI. What are the mechanisms behind the interaction between the degree of CKD and the aforementioned CVD risk, and how should we manage inpatients with moderate and severe CKD with concomitant AMI?
The following mechanisms were identified as causes of this association. First, the higher incidence of acute kidney injury (AKI) may involve long-term outcomes after AMI. Second, bleeding and contrast nephropathy, as side effects of PCI, may be involved in the deleterious effect on clinical outcome. Third, the coronary lesion in AMI is located more proximally in CKD patients, leading to higher event rates. After adjusting for classical risk factors, including age, hypertension, diabetes, dyslipidemia, and smoking, CKD was the sole independent determinant of in-hospital and 3-year clinical outcomes, suggesting that novel risk factors were implicated in the deterioration of outcome. CKD-related novel risk factors, such as uremic toxins, renal anemia, and CKD-mineral and bone disorder (CKD-MBD), should be considered, as they are crucial therapeutic targets for preventing the development of CVD and death in patients presenting with AMI (Figure).
Mechanisms underlying the development of adverse outcomes and therapeutic agents in patients with CKD presenting with AMI. Classical risk factors (age, hypertension, dyslipidemia, diabetes, and smoking) and novel risk factors (TMAO, AGEs, ADMA, FGF23, renal anemia) correlate with each other and are implicated in cardiac and endothelial dysfunction and the development of vascular calcification, leading to CVD progression and death in CKD patients. AMI-related risk factors (PCI, contrast-induced nephropathy, AKI, and bleeding) exacerbate CKD-induced adverse outcomes. ADMA, asymmetric dimethylarginine; AGEs, advanced glycation endproducts; AKI, acute kidney injury; AMI, acute myocardial infarction; CVD, cardiovascular disease; ESA, erythropoiesis-stimulating agents; FGF23, fibroblast growth factor 23; HIF-PH, hypoxia-inducible factor prolyl hydroxylase; PCI, percutaneous coronary intervention; RAS, renin-angiotensin system; SGLT2, sodium-glucose transporter 2; TMAO, trimethylamine N-oxide.
Uremic toxins, such as asymmetric dimethylarginine (ADMA), advanced glycation endproducts (AGEs), and trimethylamine N-oxide (TMAO), are elevated in advanced CKD patients due to their decreased urinary output, which contributes to CVD development.3 AGEs are produced by the nonenzymatic glycation between sugar and amino residues of proteins. They exert inflammatory and profibrotic responses by binding to the receptor for AGEs on the transmembrane of endothelial cells, and activate nuclear factor kappa-B and reactive oxygen species, leading to the development of CVD. ADMA is an endogenous antagonist of L-arginine that inhibits nitric oxide production, which is an independent risk factor for vascular endothelial dysfunction. Elevated plasma ADMA levels in AMI patients indicates a poorer prognosis and angiographic impaired reperfusion.4 Trimethylamine is produced by the intestinal bacterial flora upon intake of colin and carnitine, which can be metabolized into TMAO. This promotes atheroma and thrombus formation, thereby increasing MACE.5 TMAO levels were associated with poor prognosis within 2 years for patients hospitalized due to AMI.6 AST-120, an oral charcoal adsorbent, is a common therapeutic agent that depresses circulating uremic toxins such as AGEs in patients with CKD.7 This is a possible therapeutic strategy for CVD after AMI in patients with severe CKD.
Anemia is a possible mechanism through which renal dysfunction increases the risk of death among patients with CKD presenting with AMI. Anemia is associated with the progression of left ventricular hypertrophy and cardiac dysfunction, which can progress to heart failure, arrhythmia, and death.8 Anemia frequently occurs in older CKD patients hospitalized for AMI, because they have a decreased ability to produce erythropoietin due to contrast-induced nephropathy and/or PCI-elicited bleeding, which are independent predictors of death.9 In predialysis CKD patients, the hemoglobin level should be adjusted to between 11 and 13 g/dL, as recommended by the Japanese Society of Nephrology guidelines. After excluding iron-deficiency anemia, drug-induced anemia, digestive tract hemorrhage and other causes, erythropoiesis-stimulating agents or hypoxia-inducible factor prolyl hydroxylase inhibitors should be prescribed in CKD patients with renal anemia even after AMI. However, low-dose erythropoietin did not improve left ventricular ejection fraction in patients with ST-segment elevation MI.10
CKD-MBD decreases bone density and induces vascular calcification, resulting in CVD. Suppressing 1,25-dihydroxyvitamin D activation in the kidney induces hypocalcemia and produces parathyroid hormone (PTH), causing secondary hyperparathyroidism. Fibroblast growth factor 23 (FGF23), a potent factor for phosphorus diuresis, is secreted from osteoblasts via hyperphosphatemia. It suppresses 1,25-dihydroxyvitamin D synthesis, indirectly increasing PTH secretion.11 High phosphoremia and FGF23 levels predict CVD in CKD patients. Furthermore, FGF23 directly engages with epidermal growth factor receptor and activates cell signaling in cardiomyocytes, leading to cardiac hypertrophy, development of CVD, and cardiac death. Aronson et al have reported a graded and independent association between serum phosphorus, and all-cause death and heart failure in patients after AMI. The effect of elevated phosphorus was more pronounced in patients with CKD.12 Therefore, a decrease in serum phosphorus using phosphate binders will reduce FGF23 levels and provide benefits against cardiomegaly in CKD patients presenting with AMI.
Advanced CKD is associated with adverse outcomes in patients presenting with AMI, treated with contemporary PCI and optimal medical therapy. Because CKD is an independent prognostic factor, it should be closely monitored in patients with AMI. Sodium-glucose transporter 2 inhibitors reportedly ameliorate cardiorenal adverse outcomes in diabetic13 and nondiabetic patients with CKD.14 This is a strong therapeutic strategy for these patients. Further studies to demonstrate the efficacy of the aforementioned interventions are needed to prevent CVD progression and death in CKD patients presenting with AMI.
K.F. received lecture fees from Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Bayer’s Pharmaceuticals, Astellas Pharma Inc., and Torii Pharmaceutical Co., Ltd, Japan Boehringer Ingelheim Co., Ltd., Astrazeneca Co., Ltd.
Scholarship fund was granted by Kyowa Kirin Co., Ltd. to the Kurume University School of Medicine.
