Valvular and perivalvular involvement in patients with chronic kidney disease

Mitral annular calcification (MAC) and aortic valve calcification (AVC) are the most common valvular and perivalvular abnormalities in patients with chronic kidney disease (CKD). Both MAC and AVC occur at a younger age in CKD patients than in the general population. AVC progresses to aortic stenosis and mild aortic stenosis progresses to severe aortic stenosis at a more rapid rate in patients with CKD than in the general population. The use of calcium-free phosphate binders in such patients may reduce the calcium burden in valvular and perivalvular structures and retard the rate of progression of aortic stenosis. Despite high rates of morbidity and mortality, the prognosis associated with valve surgery in patients with CKD is better than without valve surgery. Infective endocarditis remains an important complication of CKD, particularly in those treated with hemodialysis.     

Pericarditis in end-stage renal disease

Our approach to the clinical management of uremic and dialysis-associated pericarditis has been presented previously and is outlined in Figure 1. In hemodynamically stable patients with no effusion and in those with small to medium effusions, we recommend initial therapy with intensified dialysis. Close monitoring, perhaps every third day, with echocardiography should be carried out. If pericardial effusion progressively increases or if a large pericardial effusion fails to resolve after 7 to 10 days of intensive dialysis, the pericardial effusion may be drained by subxiphoid pericardiotomy or by pericardiectomy. Similarly, if hemodynamic evidence of cardiac pretamponade or tamponade appears, surgical drainage also should be carried out. If the echocardiogram is inadequate for interpretation but tamponade physiology is present, we recommend confirmation by cardiac catheterization before surgical drainage is attempted, recognizing that there may be circumstances such as left ventricular failure and pulmonary hypertension that may complicate the interpretation of the catheterization data. The type of invasive pericardial procedure chosen is determined by local experience. As stated, we prefer not to perform pericardiocentesis before surgery unless tamponade-induced hypotension is so severe that an adequate blood pressure cannot be maintained by means of plasma volume expansion. Under these circumstances, we prefer that pericardiocentesis be performed in the operating room immediately before the induction of anesthesia for the definitive surgical procedure. Although pericardiectomy is a definitive procedure for pericarditis with effusion in the uremic patient, the procedure has substantial morbidity. The results of subxiphoid pericardiotomy are encouraging, and it is clear that it can be carried out safely in patients who are debilitated or who are at increased risk from general anesthesia and major surgery.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiac disease in diabetic end-stage renal disease

Summary 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 < 0.00 001) 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. [Diabetologia (1997) 40: 1307–1312] Received: 25 March 1997 and in final revised form: 23 June 1997     

Inflammation and atherosclerosis in end-stage renal disease

Atherosclerosis is a multifaceted process which may be initiated by various insults to vascular endothelium. Independently of the nature of the offending factor, the endothelial dysfunction that results from the initial insult is characterized by increased adhesiveness of the endothelium to leukocytes and platelets and by the synthesis of vasoactive molecules, cytokines and procoagulant factors. This defensive response is characterized by classical inflammatory changes and may lead to plaque formation, luminal obstruction and plaque rupture. Factors involved in arterial damage in end-stage renal disease (ESRD) span from classical risk factors to disease-peculiar factors (anemia, secondary hyperparathyroidism and exposure to bioincompatible dialysis membranes and/or contaminated dialysis fluid) and to emerging and novel risk factors such as hyperhomocysteinemia, infections and accumulation of the endogenous inhibitor of NO synthase, asymmetric dimethylarginine (ADMA). There is strong and consistent evidence that acute phase reactants like C-reactive protein and cytokines like IL-beta, TNF-alpha and IL-6 are independently associated with death and atherosclerosis in ESRD patients. The experimental and epidemiological data collected thus far coherently show that endothelial dysfunction resulting from inflammation may promote abnormal vascular behavior and thrombosis in ESRD. There are several possible therapeutic approaches for reducing the risk excess associated with inflammation in ESRD. These possibilities range from drugs interfering with the angiotensin system or with adrenergic activity to anti-inflammatory and antilipid agents to vitamins, antioxidants, to the amino acid precursor of nitric oxide, L-arginine, and perhaps to antibiotics. The intellectual framework is well delineated but very few controlled trials have been performed or are underway in patients with ESRD.     

Pancreatic-type hyperamylasemia in end-stage renal disease

Pancreatic-type isoamylase (P-type) and salivary-type isoamylase (S-type) activities were determined by the wheat protein inhibitor method in 29 patients with end-stage renal disease and in 38 healthy volunteers. Serum levels of total amylase (322±43 units/liter) and P-type (212±39 units/liter) in ESRD were significantly higher than those of controls (total: 142±7 units/liter,P<0.01; P-type: 52±4 units/liter,P<0.01). There was no significant difference between S-type activities in ESRD (110±16 units/liter) and in controls (90±6 units/liter). The ratios of amylase clearance to creatinine clearance (C_am/C_cr) and S-type clearance to creatinine clearance (C_s-amy/C_cr) rose significantly in ESRD(C_am/C_cr: 5.7±0.6%; C_s-amy/C_cr: 4.3±0.55%) compared to controls (C_am/C_cr: 3.2±0.24%,P<0.01; C_s-amy/C_cr: 2.1±0.17%,P<0.01). The ratio of P-type clearance to creatinine clearance (C_p-amy/C_cr) revealed no significant difference between ESRD (5.5±0.54%) and controls (5.6±0.42%). The renal excretion of P-type appeared to be more impaired than that of S-type in ESRD.     

Coronary revascularization in end-stage renal disease

Advanced coronary artery disease and acute cardiac events are the most common causes of death in patients with end-stage renal disease. Because of their heightened risk, end-stage renal disease patients are frequently referred for coronary revascularization. However, these patients are almost always excluded from trials examining various innovations in medical and revascularization interventions for cardiovascular conditions. Extrapolation of trial conclusions regarding dialysis patients can be misleading because the risk-benefit ratios of various interventions in this patient population can be markedly different. Thus, clinical decisions regarding the need for (and type of) coronary revascularization are based on retrospective outcome analyses from various databases. This article reviews the data available in the literature on the morbidity, mortality, and outcomes of dialysis patients undergoing surgical or percutaneous revascularization, particularly with the addition of drug-eluting stents to the available therapeutic options.     

The thyroid in end-stage renal disease

Previous studies of patients with end-stage renal disease (ESRD) indicate that the prevalence of goiter varies from 0 to 58% while that of hypothyroidism ranges from 0 to 9.5%. In addition, altered serum thyroid hormone levels are present in euthyroid patients with ESRD and may be related to nonthyroidal disorders including malnutrition. To examine these issues further, 306 patients with ESRD were compared to 139 hospitalized patients without renal disease (control population). Goiter was present in 43% with ESRD compared to 6.7% of controls (P less than 0.001). Goiter frequency was greater (49.6%, P = 0.047) and serum parathyroid hormone levels higher (mean: 238.6 microlitersEq/ml, P less than 0.001; normal: less than 15 microlitersEq/ml) in 115 patients dialyzed for longer than 1 year than in 191 dialyzed for less than 1 year or not at all (38.7%, and 61.5 microlitersEq/ml, respectively). In addition, goiter was more common in females (50.0%) than in males (35.1%, P = 0.008) with ESRD. No significant relationships were observed between goiter frequency and age, race, diabetes mellitus, or elevated antimicrosomal antibody titers. The prevalence of primary hypothyroidism was higher in ESRD (2.6%) than in 2122 in- and out-patients (1.1%) (P = 0.024). Compared to the total group of ESRD patients, the hypothyroid patients were predominantly female (88% vs. 50%) and had a higher frequency of positive antimicrosomal antibody titers (50% vs. 6.7%, P = 0.029). The frequency of hyperthyroidism was not significantly different, being 1.0% in ESRD compared to 0.3% in the general population (P = 0.057). There was a higher frequency of reduced free T4 index values in the 287 euthyroid patients with ESRD (12.9%) than in controls (3.6%) (P = 0.002). Similarly, free T3 index values were reduced below 100 in 65.5% with ESRD compared to 33.8% of controls (P less than 0.001). In addition, serum albumin levels were lower in euthyroid patients with ESRD (3.5 g/dl, P less than 0.001) than in controls (3.8 g/dl). Serum T3 levels correlated directly with both serum albumin (r = 0.57, P less than 0.001) and transferrin (r = 0.54, P less than 0.001) levels in ESRD as well as in controls (r = 0.74, P less than 0.001, and r = 0.69, P less than 0.001, respectively).(ABSTRACT TRUNCATED AT 400 WORDS)     

Cardiovascular mortality in end-stage renal disease

Cardiovascular disease accounts for more than 50% of end-stage renal disease (ESRD) deaths. The reported cardiovascular death rates in patients receiving dialysis are substantially higher than in the general population. Cardiovascular mortality in ESRD is particularly high after acute myocardial infarction, but it is also elevated in ESRD patients with other forms of atherosclerotic vascular disease (eg, chronic coronary artery disease, strokes, transient ischemic attacks, and peripheral arterial disease). Left ventricular hypertrophy and dilation are associated with increased cardiovascular mortality, as is congestive heart failure. One of the major reasons for such high cardiovascular mortality in ESRD is the large burden of cardiovascular disease present in patients with chronic artery disease before renal replacement therapy. These observations mandate not only aggressive diagnosis and treatment of cardiovascular disease in patients with ESRD, but also active screening, diagnosis, and treatment in those with chronic kidney disease before renal replacement therapy.     

Cardiac function in end-stage renal disease

To assess cardiac status in end-stage renal disease, we compared clinical, ECG, and echocardiographic data from 37 patients on maintenance hemodialysis with data from 42 patients with functioning renal transplants. Cardiovascular symptoms and abnormal cardiovascular findings were more common in dialysis-maintained patients than in those with transplants. Follow-up studies indicated that despite a high prevalence of cardiac symptoms, abnormal physical signs, and dilated left ventricles among patients with end-stage renal disease, systolic left ventricular function was generally well preserved irrespective of renal failure therapy. Compared with maintenance hemodialysis, however, successful renal transplantation is associated with an overall enhancement of cardiac status, the majority of which is probably secondary to transplant-associated improvement in hemoglobin level and control of intravascular volume.     

Aldosterone-receptor antagonism and end-stage renal disease

Blockade of aldosterone effect with either spironolactone or eplerenone is an approach that is being used more frequently in the treatment of hypertension and congestive heart failure; however, sparse information exists pertaining to efficacy or side-effects of this line of treatment for patients with chronic kidney disease and/or end-stage renal disease (ESRD). Hyperkalemia is, by far, the most worrisome complication of therapy with either of these compounds and, not surprisingly, hinders their use in moderateto-advanced renal failure. However, patients with anuric ESRD should theoretically not be at risk for hyperkalemia. To this end, pilot safety studies with aldosterone-receptor antagonists in ESRD patients have begun. These studies imply that spironolactone can be safely used in carefully selected and closely monitored patients. Eplerenone has not been studied in ESRD in a therapeutic or safety capacity. Additional studies are needed with these compounds in the ESRD population before their use can be considered safe.     

Pericardial involvement in end-stage renal disease

Pericardial involvement in end-stage renal disease (ESRD) is manifested most commonly as acute uremic or dialysis pericarditis and infrequently as chronic constrictive pericarditis. The causes of uremic and dialysis pericarditis remain uncertain. The clinical and laboratory manifestations of acute pericarditis, pericardial effusion, cardiac tamponade, and constrictive pericarditis in patients with chronic renal failure are similar to those observed in nonuremic patients with similar pericardial involvement, except that chest pain occurs less frequently in those with ESRD. Therapeutic interventions for acute uremic or dialysis pericarditis with or without pericardial effusion include intensive hemodialysis, pericardiocentesis (infrequently used), pericardiostomy with or without instillation of intrapericardial glucocorticoids, pericardial window, and pericardiectomy. Chronic constrictive pericarditis is treated with pericardiectomy.     

Cardiac performance and morphology in end-stage renal disease

Patients with end-stage renal disease (ESRD) experience a variety of hemodynamic and metabolic abnormalities that predispose to alterations in cardiac performance and morphology. High cardiac output related to renal anemia, hypertension, volume overload, and the arteriovenous fistula (in patients on hemodialysis) predispose to eccentric left ventricular (LV) hypertrophy. Hypertension, aortic stiffness, and aortic stenosis predispose to concentric LV hypertrophy. Most ESRD patients have a hybrid form of LV hypertrophy. LV hypertrophy is commonly accompanied by LV diastolic dysfunction. LV systolic dysfunction is less common. Newer dialytic techniques, excellent control of hypertension, and correction of renal anemia produce regression of LV hypertrophy. The effect of these interventions on LV systolic and diastolic function is less well established. Alterations in serum calcium, choice of dialysate base, hypoxia, and comorbid conditions may influence the effects of dialysis (particularly hemodialysis) on LV function. A variety of negative inotropic drugs may depress LV function in patients with ESRD.     

Vascular and cardiac infections in end-stage renal disease

Patients with end-stage renal disease (ESRD) receiving hemodialysis (HD) are vulnerable to intravascular and endocardial infections. These include vascular access infections, vascular stent infections, and bacterial endocarditis. Staphylococcus aureus is the most commonly encountered microorganism in these conditions. Prolonged intravenous antibiotic therapy is often indicated in these infections. Surgical removal of the infected vascular access or stent may be required. Infective endocarditis occurs less frequently in renal transplant recipients than in patients on HD. Although bacterial endocarditis may occur, fungal endocarditis with organisms such as Aspergillus and Candida species occurs with disproportionately high frequency among renal transplant recipients because of immunosuppression. Prolonged intravenous antibiotic or antifungal therapy is indicated, and valve replacement is often necessary.     

Salt and hypertension in end-stage renal disease.

Salt and fluid overload play an important role in the pathogenesis of hypertension in patients with end-stage renal disease. However, in the individual patient, the relation between salt loading and blood pressure response is variable and appears to be influenced by various neurohumoral regulatory mechanisms. This may also have implications for the pathogenesis of structural cardiovascular abnormalities in patients with end-stage renal disease.     

Urotensin II and cardiomyopathy in end-stage renal disease

Circulating urotensin (UTN) is increased in patients with heart failure and in patients with renal diseases, and UTN antagonism is currently considered as a potential treatment for these conditions. Contrary to this contention, studies in end-stage renal disease suggest that, perhaps because of interference with sympathetic and NO systems, UTN may be cardioprotective. Therefore, we investigated the relationship between circulating UTN and echocardiographic parameters of left ventricular function (midwall fractional shortening), left atrial volume, and myocardial geometry (mean wall thickness and relative wall thickness) in 191 patients with end-stage renal disease. UTN was associated directly (r=0.39; P<0.001) with left ventricular systolic function and inversely with left atrial volume (r=-0.40; P<0.001) and the muscular component of the left ventricular (UTN versus mean wall thickness: r=-0.30, P<0.001; UTN versus relative wall thickness: r=-0.32, P<0.001). Adjustment for a series of 11 risk factors produced a relatively small change in the strength of these relationships. However, further adjustment for plasma norepinephrine or, particularly so, for the endogenous inhibitor of NO synthase asymmetrical dimethyl arginine produced a 33% to 50% decrease in the strength of such associations. Of note, there was a strong UTN-asymmetrical dimethyl arginine interaction in determining midwall fractional shortening (P=0.001) and mean wall thickness (P=0.006). These data support the hypothesis that high UTN is cardioprotective in end-stage renal disease and that interference by UTN with sympathetic activity and NO synthesis represents an intermediate mechanism mediating the favorable echocardiographic profile of patients with high UTN. Additional mechanistic insights may be needed before launching long-term clinical trials with UTN antagonists in patients with end-stage renal disease.     

Arterial structure and function in end-stage renal disease

Cardiovascular disease is a major cause of morbidity and mortality in patients with end-stage renal disease (ESRD). Macrovascular disease develops rapidly in ESRD patients and is responsible for the high incidence of left ventricular hypertrophy, ischemic heart disease, cerebrovascular accidents, and peripheral artery diseases. Occlusive lesions due to atheromatous plaques frequently cause these complications; however, atherosclerosis represents only one form of structural response to metabolic and hemodynamic alterations interfering with the “natural” process of aging. The spectrum of arterial alterations in ESRD is broader, including large artery remodeling, changes in viscoelastic properties, and stiffening of arterial walls. Nonatheromatous remodeling principally changes the dampening function of arteries, characterized by stiffening of arterial walls and with deleterious effects on the left ventricle and coronary perfusion. The origin of arterial stiffening in ESRD patients is multifactorial, with extensive arterial calcifications as an important covariate.