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The kidney and heart have essential roles in maintaining blood volume homeostasis and in the regulation of systemic blood pressure. Acute or chronic dysfunction in either the heart or kidneys can induce dysfunction in the other organ, resulting in the so-called cardiorenal syndromes, which are classified into five different types. Abrupt worsening of cardiac function predisposes an individual to acute kidney injury from renal hypoperfusion or renal congestion. Progressive, sometimes permanent, chronic kidney impairment can result from chronic renal hypoperfusion or congestion. Heart failure is common in patients with acute kidney injury. Chronic kidney disease predisposes individuals to atherosclerotic, arteriosclerotic and cardiomyopathic disease. Finally, both cardiac and renal disease can also occur secondary to systemic conditions, such as diabetes or autoimmune disease. This Review examines the mechanisms presiding over the first four types of cardiorenal syndromes. These mechanisms provide a template that accounts for the heart-kidney interactions that occur in patients whose concomitant cardiac and renal conditions result from a third cause.

Little is known about the epidemiology of cardiac disease in diabetic end-stage renal disease. We therefore prospectively followed a cohort of 433 patients who survived 6 months after the inception of dialysis therapy for an average of 41 months. Clinical and echocardiographic data were collected yearly. At baseline, diabetic patients (n = 116) had more echocardiographic concentric left ventricular hypertrophy (50 vs 38%, p = 0.04), clinically diagnosed ischaemic heart disease (32 vs 18%, p = 0.003) and cardiac failure (48 vs 24%, p < 0.00001) than non-diabetic patients (n = 317). After adjusting for age and sex, diabetic patients had similar rates of progression of echocardiographic disorders, and de novo cardiac failure, but higher rates of de novo clinically diagnosed ischaemic heart disease (RR 3.2, p = 0.0002), overall mortality (RR 2.3, p < 0.0001) and cardiovascular mortality (RR 2.6, p < 0.0001) than non-diabetic patients. Mortality was higher in diabetic patients following admission for clinically diagnosed ischaemic heart disease (RR 1.7, p = 0.05) and cardiac failure (RR 2.2, p = 0.0003). Among diabetic patients older age, left ventricular hypertrophy, smoking, clinically diagnosed ischaemic heart disease, cardiac failure and hypoalbuminaemia were independently associated with mortality. The excessive cardiac morbidity and mortality of diabetic patients seem to be mediated via ischaemic disease, rather than progression of cardiomyopathy while on dialysis therapy. Potentially remediable risk factors include smoking, left ventricular hypertrophy, and hypoalbuminaemia.

Cardiomyopathy in chronic uremia results from pressure and volume overload. The former causes concentric left ventricular [LV] hypertrophy, results from hypertension and aortic stenosis, and is also associated with diabetes mellitus and anemia. Volume overload causes LV dilatation, results from arteriovenous shunting, salt and water overload, and anemia, and is also associated with ischemic heart disease, hypertension, and hypoalbuminemia. Decreased major arterial compliance and an early return of arterial wave reflections are also associated with the extent of LV hypertrophy. Cardiomyopathy predisposes to diastolic and systolic dysfunction. The latter results from myocyte death, and predisposing factors include ischemic heart disease and the uremic environment. Ischemic heart disease may be atherosclerotic or nonatherosclerotic in origin. Multiple factors contribute to the vascular pathology of chronic uremia, including injury to the vessel wall, dyslipidemia, prothrombotic factors, increased oxidant stress, and hyperhomocysteinemia. Ischemic risk factors include hypertension, LV hypertrophy, hypoalbuminemia, and perhaps hyperparathyroidism. The clinical consequences of cardiomyopathy include heart failure, ischemic heart disease, dialysis hypotension, and arrhythmias. The adverse impact of ischemic heart disease is probably mediated through the development of cardiac failure.

Cardiac disease is common and is the major killer in end-stage renal disease (ESRD). Cardiac failure is a highly malignant condition in ESRD patients. Cardiac failure mediates most of the adverse prognostic impact of ischemic heart disease. Left ventricular (LV) abnormalities are already present at initiation of dialysis therapy in approximately 80% of patients. These abnormalities (ie, systolic dysfunction in approximately 15%, LV dilatation with preserved systolic function in 30%, concentric LV hypertrophy [LVH] in 40%) independently predict ischemic heart disease and cardiac failure, and are the largest baseline predictor of mortality after 2 years on dialysis therapy. The associations between classical risk factors (eg, hyperlipidemia, smoking, hypertension) and cardiac outcomes in ESRD are inconsistent. "Uremic" risk factors represent a nascent, but potentially important field. In our prospective 10-year study of 433 patients starting renal replacement therapy, we identified the following as major independent risk factors for cardiac disease: (1) hypertension (concentric LVH, LV dilatation, ischemic heart disease, cardiac failure, inverse relationship with mortality); (2) anemia (LV dilatation, cardiac failure, death); and (3) hypoalbuminemia (ischemic heart disease, cardiac failure, death). Transplantation dramatically improved LV abnormalities, suggesting that a uremic environment is cardiotoxic. Multiple risk factors act in concert to produce cardiac disease in ESRD; many of these are avoidable, suggesting that the enormous burden of disease can be reduced considerably.

To determine the possible association between anemia and clinical and echocardiographic cardiac disease, a cohort of 432 end-stage renal disease patients (261 on hemodialysis and 171 on peritoneal dialysis) who started dialysis therapy between 1982 and 1991 were followed prospectively for an average of 41 months. Baseline demographic, clinical, and echocardiographic assessments were performed, as well as monthly serial clinical and laboratory tests while the patients were on dialysis therapy. The mean (+/-SD) hemoglobin level during dialysis therapy was 8.8 +/- 1.5 g/dL. After adjusting for age, diabetes, and ischemic heart disease, as well as for blood pressure and serum albumin levels measured serially, each 1 g/dL decrease in mean hemoglobin was independently associated with the presence of left ventricular dilatation on repeat echocardiogram (odds ratio, 1.46; P = 0.018) and the development of de novo (relative risk [RR] = 1.28; P = 0.018) and recurrent (RR = 1.20; P = 0.046) cardiac failure. In addition, each 1 g/dL decrease in the mean hemoglobin level was independently associated with mortality while the patients were on dialysis therapy (RR = 1.14; P = 0.024). Anemia had no independent association with the development of ischemic heart disease while the patients were on dialysis therapy. Anemia, an easily reversible feature of end-stage renal disease, is an independent risk factor for clinical and echocardiographic cardiac disease, as well as mortality in end-stage renal disease patients.

Clinical and echocardiographic manifestations of cardiac disease are frequently present in patients starting end-stage renal disease therapy. Congestive heart failure, ischemic heart disease, systolic dysfunction, concentric left ventricular hypertrophy, and left ventricular dilatation are significant, adverse prognostic indicators, independent of age, diabetes mellitus, and smoking. Risk factors related to the uremic state, which are potentially reversible, include inadequate dialysis, anemia, hypoalbuminemia and hypocalcemia. Hypertension predisposes patients to congestive heart failure, following the development of which hypotension becomes an independent predictor of mortality.

The burden of cardiac disease is high in chronic uremia. Cardiomyopathy results from a combination of cardiac disorders, particularly dilated cardiomyopathy, left ventricular hypertrophy with normal systolic function, and ischemic heart disease. The prognosis for these cardiac disorders is poor. Known potentially reversible risk factors include uremia, anemia, hypertension, smoking, coronary artery disease, hyperparathyroidism, hyperlipoproteinemia, and left ventricular hypertrophy. Randomized controlled clinical trials of interventions that may prevent or ameliorate cardiac disease in dialysis patients are required. These interventions include normalization of hematocrit with erythropoietin compared with partial correction of anemia, increased amount of dialysis compared with that provided by a dialysis prescription of KT/V of 1., control of blood pressure using angiotensin-converting enzyme inhibitors compared with other antihypertensive agents, control of hyperlipidemia, and treatment of diabetes with agents that prevent collagen cross-linking.