Cardio-Renal-Metabolic Syndrome in Patients with Chronic Kidney Disease: Relevance of the Problem; Pathogenetic Mechanisms; Diagnostics; Risk Factors; Prognosis; Research and Treatment Perspectives (Literature Review; Clinical Case Description)

Aims: The relationship between parathyroid hormone (PTH) and the cardiorenal metabolic syndrome was examined among non-diabetic persons with chronic kidney disease (CKD). Methods: In a cross-sectional analysis, the relationship between PTH levels and the cardiorenal metabolic syndrome was investigated in 3,215 non-diabetic participants in the National Kidney Foundation-Kidney Early Evaluation Program (KEEP 2.0) found to have CKD (eGFR <60 ml/min/1.73 m²). Results: In unadjusted analyses, the prevalence of the cardiorenal metabolic syndrome increased along increasing PTH quartiles (31.7, 33.8, 37.3, and 48.7%, respectively, p for trend <0.0001). After multivariate adjustment, as compared to the first PTH quartile, odds of the cardiorenal metabolic syndrome were 16% (p = 0.18), 35% (p = 0.006), and 80% (p < 0.0001) higher for the second, third, and fourth quartiles, respectively. When taken as a continuous predictor, each standard deviation increase of natural log transformed PTH was associated with 26% (p < 0.0001) higher odds of the cardiorenal metabolic syndrome. The association of PTH with the cardiorenal metabolic syndrome was not modified by age or gender (p for interaction was not significant for both modifiers). Conclusions: Among an outpatient non-diabetic population with CKD, higher PTH levels were associated with a higher prevalence of the cardiorenal metabolic syndrome.

Chapter 9 - The Role of Insulin Resistance in the Cardiorenal Syndrome

Cardio-renal metabolic syndrome (CRMS), also termed cardiovascular-kidney-metabolic (CKM) syndrome, represents the convergence of metabolic risk factors, chronic kidney disease (CKD), and cardiovascular disease (CVD), underpinned by insulin resistance (IR), neurohormonal activation, oxidative stress, and chronic inflammation. This narrative review synthesizes current evidence on the epidemiology, pathophysiology, diagnostic approaches, prevention, and management of CRMS. Globally, CRMS prevalence continues to rise, driven by aging populations, urbanization, obesity, and diabetes, with disproportionate effects in low- and middle-income countries. The syndrome is associated with substantially increased morbidity and premature mortality, reflecting the synergistic effects of overlapping conditions. Advances in diagnostic evaluation, including novel biomarkers and imaging modalities, have improved early detection, but significant gaps remain. Preventive strategies emphasize lifestyle modification, dietary change, weight reduction, and smoking cessation, complemented by pharmacological therapies such as sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, mineralocorticoid receptor antagonists (MRAs), and renin-angiotensin-aldosterone system (RAAS) blockade, all of which demonstrate cardio-renal protection. Non-pharmacological approaches, including bariatric surgery and renal replacement therapies (RRTs), add to the therapeutic armamentarium. Looking ahead, precision medicine, artificial intelligence (AI)-driven prognostic tools, and emerging biomarkers offer opportunities to refine risk stratification and treatment. An integrated, multidisciplinary framework is essential to reduce the escalating global burden and improve patient-centered outcomes in CRMS.

Ischemic heart disease (IHD) remains the leading cause of mortality and disability due to cardiovascular diseases. IHD often manifests itself as stenosing atherosclerosis of the coronary arteries, which can be treated surgically or interventionally. However, chronic coronary syndromes with intact coronary vessels are a serious problem for modern medicine. Coronary microvascular dysfunction is accompanied by impaired coronary blood flow reserve, which leads to myocardial ischemia and angina pectoris, despite the absence of significant coronary artery stenosis. The objective: to study the mechanisms of myocardial ischemia in patients with coronary artery disease and cardiorenal metabolic (CRM) syndrome and to analyze the effectiveness of different treatment approaches depending on the identified mechanisms. Materials and methods. The study included 104 patients with CRM syndrome who underwent examination at the State Institution “The Scientific and Practical Medical Center of Pediatric Cardiology and Cardiac Surgery of the Ministry of Health of Ukraine” during 2023. Various forms of CHD were detected in the patients. Exercise stress tests were used to diagnose myocardial ischemia. Patients with confirmed stenosing atherosclerosis by percutaneous coronary angiography received appropriate interventional treatment. Microvascular angina was suspected in 21 patients without significant coronary artery lesions. The coronary blood flow reserve index was determined by echocardiography with intravenous administration of dipyridamole. Results. It was determined that of 21 patients with microvascular angina who received a comprehensive treatment including nicorandil, 20 (95.2%) persons were free of ischemic symptoms after 4 weeks. One patient had a decrease in complaints, but discomfort during exercise continued, which was successfully corrected after increasing the dose of nicorandil. Of 83 participants with CRM syndrome, CHD, and stenosing atherosclerosis who underwent coronary angiography, 74 (89.1%) patients had no ischemic symptoms and negative exercise test results after 28 days. In 9 cases ischemia persisted and a positive/doubtful exercise stress test was found. These patients were additionally prescribed nicorandil at a dose of 10 mg 2 times a day, which led to the disappearance of symptoms of angina pectoris and negative results of the exercise test at an additional re-examination after 7 days. Conclusions. In patients with CRM syndrome, the causes of ischemic heart disease were stenosing atherosclerosis (71.2%), microvascular angina (20.2%) and their combination (8.6%). Interventional treatment and nicorandil are effective in the treatment of coronary artery disease with different mechanisms, especially in cases of their combination.

The presence of a group of interactive maladaptive factors including hypertension, insulin resistance, metabolic dyslipidemia, obesity, microalbuminuria, and/or reduced renal function constitute the cardiorenal metabolic syndrome (CRS). Overweight, obesity, and chronic kidney disease (CKD) have grown to pandemic proportions in industrialized countries during the past decade. The fact that these interactive factors promote heart and renal disease has been documented in large population-based studies. Obesity seems to be the driving force behind the development of heart disease and CKD and therefore the CRS. The relationship between overweight/obesity and kidney disease begins in early childhood and appears to be related to overconsumption of high-fructose corn syrup and insufficient physical activity. Today, 13 million children are obese, and over 70% of these children are likely to become obese adults. Indeed, approximately 30% of male and 34% of female adults in the United States are obese. This lifestyle-related epidemic will be a major societal medical and economic problem that will accentuate the current epidemic of CKD in the United States and other industrialized and emerging industrialized countries. In this article, we will review the potential mechanisms by which obesity and other metabolic abnormalities interact to promote heart and progressive kidney disease.

Numerous epidemiological studies confirm that the prevalence of obesity and the cardiorenal metabolic syndrome (CRS) is extraordinarily high and that the rates have increased dramatically in the last three decades. In addition, epidemiological data demonstrate that obesity, the CRS, and diabetes are inextricably linked and are all associated with an increased incidence of a number of solid tissue cancers. The mechanisms for this association have been examined, including, but not limited to, higher levels of insulin and free levels of insulin-like growth factor and insulin resistance in obesity and the CRS. Mortality, morbidity, and the associated health care costs which are the link between obesity, the CRS, and diabetes are just beginning to be examined. In addition, we review the advantages of implementing lifestyle and surgical changes to modify obesity, lessening the development of the CRS, diabetes, and associated cancers. Epidemiological data regarding the general mechanisms of the pathogenesis of cancers associated with obesity, the CRS, and diabetes (specifically colon, pancreas, esophageal, liver, breast, prostate, thyroid, and renal carcinomas) are reviewed. The mechanisms by which obesity and other components of the CRS contribute to the pathogenesis of these cancers, such as hormone alterations and insulin- and insulin-like growth factor-dependent pathways of tumor pathogenesis, include the attending roles of inflammation and oxidative stress. Emphasis has been placed on obesity as a modifiable risk factor which, when addressed, provides a reduction in the rate of cancer deaths. In a second part to be published in the next issue of this journal, the relationship between diabetes and cancer will be reviewed in detail.

Elevated serum uric acid levels are a frequent finding in persons with obesity, hypertension, cardiovascular and kidney disease as well as in those with the cardiorenal metabolic syndrome (CRS). The increased consumption of a fructose-rich Western diet has contributed to the increasing incidence of the CRS, obesity and diabetes especially in industrialized populations. There is also increasing evidence that supports a causal role of high dietary fructose driving elevations in uric acid in association with the CRS. Animal and epidemiological studies support the notion that elevated serum uric acid levels play an important role in promoting insulin resistance and hypertension and suggest potential pathophysiological mechanisms that contribute to the development of the CRS and associated cardiovascular disease and chronic kidney disease. To this point, elevated serum levels of uric acid appear to contribute to impaired nitric oxide production/endothelial dysfunction, increased vascular stiffness, inappropriate activation of the renin-angiotensin-aldosterone system, enhanced oxidative stress, and maladaptive immune and inflammatory responses. These abnormalities, in turn, promote vascular, cardiac and renal fibrosis as well as associated functional abnormalities. Small clinical trials have suggested that uric acid-lowering therapies may be beneficial in such patients; however, a consensus on the treatment of asymptomatic hyperuricemia is lacking. Larger randomized controlled trials need to be performed in order to critically evaluate the beneficial effect of lowering serum uric acid in patients with the CRS and those with diabetes and/or hypertension.

Cardiovascular disease (CVD), including heart disease and stroke, is the leading cause of death in the USA, regardless of self-determined race/ethnicity, and largely driven by cardiometabolic risk (CMR) and cardiorenal metabolic syndrome (CRS). The primary drivers of increased CMR include obesity, hypertension, insulin resistance, hyperglycemia, dyslipidemia, chronic kidney disease as well as associated adverse behaviors of physical inactivity, smoking, and unhealthy eating habits. Given the importance of CRS for public health, multiple stakeholders, including the National Minority Quality Forum (the Forum), the American Association of Clinical Endocrinologists (AACE), the American College of Cardiology (ACC), and the Association of Black Cardiologists (ABC), have developed this review to inform clinicians and other health professionals of the unique aspects of CMR in racial/ethnic minorities and of potential means to improve CMR factor control, to reduce CRS and CVD in diverse populations, and to provide more effective, coordinated care. This paper highlights CRS and CMR as sources of significant morbidity and mortality (particularly in racial/ethnic minorities), associated health-care costs, and an evolving index tool for cardiometabolic disease to determine geographical and environmental factors. Finally, this work provides a few examples of interventions potentially successful at reducing disparities in cardiometabolic health.

Sodium-glucose cotransporter-2 inhibitors were approved as adjunct therapy for the management of type 2 diabetes and have become a high-level recommendation for this population with cardiorenal metabolic syndrome. In addition, evidence continues to grow supporting this class of medications for people with heart failure and chronic kidney disease, regardless of diabetes status. This narrative review summarizes the sodium-glucose cotransporter inhibitors for cardiorenal metabolic syndrome.

The components of Cardiorenal Metabolic Syndrome (CRMS) include central obesity, insulin resistance, hypertension, metabolic dyslipidemia, proteinuria, and/or reduced glomerular filtration rate. Kidney biopsy is rarely performed in patients with CRMS; histopathology findings include glomerulopathy, podocytopathy, mesangial expansion and proliferation, glomerular basement thickening, global and segmental sclerosis, interstitial fibrosis and tubular atrophy, and arterial sclerosis and hyalinosis. We report a case of CRMS with slow progression during 10 years of follow-up on chronic kidney disease (CKD). The middle-aged patient had central obesity, hypertension, dyslipidemia, cardiovascular disease, type 2 diabetes mellitus, proteinuria, and CKD stage G3b-G4. Kidney biopsy, performed 3 years after the first presentation, led to the diagnosis of chronic thrombotic microangiopathy (TMA) and complement-associated glomerulopathy. This was not compatible with the medical history and the course of the disease, and previous kidney biopsy review showed metabolic nephropathy with glomerulomegaly, global and segmental glomerulosclerosis, tubular atrophy and interstitial fibrosis, arteriosclerosis, and lipid embolus in the lumen of one artery, and found neither TMA features nor C3 deposition. The reported case demonstrates the importance of an accurate and thoughtful reading and interpretation of kidney biopsy, and stresses that disregarding medical history may potentially mislead and alter the understanding of the true cause of CKD.

There is a strong relationship between the kidney and the heart, where if one of these organs fails, so does the other, in the so-called cardiorenal syndrome (CRS). Besides, there are also interactions with the rest of the body leading to a metabolic state that establishes a feedback loop that is perpetuated. The CRS is characterized by hemodynamic changes, activation of neuro-humoral systems, natriuretic peptides, and changes in mineral metabolism. In this scenario, the kidney and heart, connected by a dysfunctional endothelium, inevitably fail. In obesity, this syndrome is exacerbated due to the complications of adipose tissue dysfunction, in the so-called cardiorenal metabolic syndrome (CRMetS). Obesity promotes adipose tissue dysfunction because it exceeds lipid storage capacity and leads to a lipotoxic state, characterized by inflammation, hypertension, insulin resistance and dyslipidemia, oxidative stress, and hyperuricemia, among others, that affect different organs other than the adipose tissue. In addition, the pro-inflammatory gut microbiota present in obese patients releases uremic toxins, contributing to oxidative stress and inflammation, perpetuating and accelerating the progression of this pathology. In this article, we describe the contribution of obesity, the factors and mechanisms implicated in the development of the CRMetS. Despite the great knowledge about the CRS, more research is needed to characterize the CRMetS given the global obesity epidemic.

Cardiorenal metabolic syndrome (CRMS) is a health disorder arising from pathophysiological interactions among cardiovascular diseases, chronic kidney disease, diabetes, and obesity, posing a significant challenge to global healthcare systems. Insulin resistance plays a central role in the pathogenesis of CRMS. This review comprehensively explores the role of insulin resistance in CRMS, elucidating its associations with component diseases and underlying mechanisms, and aims to provide theoretical foundations for clinical management and early intervention strategies.

The cardiorenal metabolic syndrome is a collection of metabolic risk factors driven by obesity and insulin resistance that convey an increased risk for cardiovascular and kidney disease. In this context, there has been increasing interest in the impact of insulin resistance and the compensatory hyperinsulinemia on kidney disease, independent to that of the contribution of overt diabetes to the development of kidney disease. It is unknown whether there is a direct causal relationship between insulin resistance and progressive kidney disease or just the presence of known risk factors for the initiation and progression of chronic kidney disease (CKD) (i.e., hypertension and obesity), yet growing evidence supports that obesity and insulin resistance directly contribute to CKD.

Background. Patients with cardio-renal-metabolic syndrome (CRMS) have a high risk of cardiovascular mortality due to the combination of heart failure, chronic kidney disease, and endocrine diseases, as well as a high risk of coronary heart disease and complications from systemic atherosclerosis. The presence of heart failure in such patients worsens the prognosis and increases the likelihood of repeated cardiovascular events. Aim: To study the risk of major cardiovascular events or the need for repeated coronary interventions after primary percutaneous coronary intervention in patients with cardio-renal-metabolic syndrome, depending on the phenotype of heart failure. Materials and Methods. The study included 131 patients undergoing examination and percutaneous coronary intervention for CAD. The average age of the patients was 58.3±0.5 years, 81 (61.8%) of them were male. CRMS was defined as a combination of heart failure, chronic kidney disease stage ≥3A, and type 2 diabetes. Patients were divided into 4 groups depending on the presence of heart failure: clinical group 1 - patients with CRMS and heart failure with preserved ejection fraction (n=36); clinical group 2 – patients with CRMS and heart failure with mildly reduced LVEF (n=33); clinical group 3 - patients with CRMS and heart failure with reduced ejection fraction (n=32); a comparison group with type 2 diabetes, chronic kidney disease, and no signs of heart failure (stage A) (n=30). Results. Heart failure patients with reduced ejection fraction had the highest percentage of those who reached the end point during the five-year follow-up. The group of patients without heart failure showed the best results in interventional treatment. The main reason for the recurrence of coronary heart disease was restenosis in a previously implanted coronary stent or the appearance of significant stenosis in new locations. Conclusion. The phenotype of heart failure with reduced left ventricular ejection fraction in patients with cardiorenal-metabolic syndrome is associated with a worse prognosis after percutaneous coronary intervention, since the patients have a higher risk of new coronary artery stenosis.

The combination of cardiac and renal disease driven by metabolic risk factors, referred to as cardiorenal metabolic syndrome (CRMS), is increasingly recognized as a critical pathological entity. The contribution of (micro)vascular injury to CRMS is considered to be substantial. However, mechanistic studies are hampered by lack of in vivo models that mimic the natural onset of the disease. Here, we evaluated the coronary and renal microvasculature during CRMS development in obese diabetic Zucker fatty/Spontaneously hypertensive heart failure F1 hybrid (ZSF1) rats. Echocardiographic, urine, and blood evaluations were conducted in 3 groups (Wistar-Kyoto, lean ZSF1, and obese ZSF1) at 20 and 25 weeks of age. Immunohistological evaluation of renal and cardiac tissues was conducted at both time points. At 20 and 25 weeks, obese ZSF1 rats showed higher body weight, significant left ventricular hypertrophy, and impaired diastolic function compared with all other groups. Indices of systolic function did not differ between groups. Obese ZSF1 rats developed hyperproliferative vascular foci in the subendocardium, which lacked microvascular organization and were predilection sites of inflammation and fibrosis. In the kidney, obese ZSF1 animals showed regression of the peritubular and glomerular microvasculature, accompanied by tubulointerstitial damage, glomerulosclerosis, and proteinuria. The obese ZSF1 rat strain is a suitable in vivo model for CRMS, sharing characteristics with the human syndrome during the earliest onset of disease. In these rats, CRMS induces microvascular fibrotic responses in heart and kidneys, associated with functional impairment of both organs.