Robert N. Foley

The impact of anemia on cardiomyopathy, morbidity, and mortality in end- stage renal disease

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.

Cardiac disease in diabetic end-stage renal disease

SummaryLittle 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.

Long-term changes in left ventricular hypertrophy after renal transplantation.

Background. Concentric and eccentric left ventricular hypertrophy are common progressive disorders in dialysis patients and are associated with cardiac failure and death. Although partial regression of these abnormalities is known to occur during the first posttransplant year, their long-term evolution is unknown. Methods. A total of 143 of 433 dialysis patients participating in a long-term prospective cohort study received renal transplants. Laboratory parameters were assessed monthly. Echocardiography was performed annually. Left ventricular mass index (LVMI) and cavity volume index were calculated according to standard formulae. Multiple linear regression was used to model change in LVMI as a function of baseline clinical and laboratory variables. Results. LVMI fell from 161 g/m2 at 1 year to 146 g/m2 (P =0.009) g/m2 after 2 years. No further regression was seen in years 3 and 4. Left ventricular volume index showed similar trends, with a decline from year 1 to year 2 (P =0.05) followed by stabilization in years 3 and 4. Older age, long duration of hypertension, need for more than one antihypertensive, high pulse pressure in normal-size hearts, and low pulse pressure in dilated hearts were significantly associated with failure of regression of LVMI between the first and second years (MLR, P <0.000001, r2=0.57). Conclusions. Regression of left ventricular hypertrophy continues beyond the first year after renal transplantation, reaching a nadir at 2 years and persisting into the third and fourth posttransplant years. Failure to regress was associated with older age, hypertension, high pulse pressure in normal-size hearts and low pulse pressure in dilated hearts.

Hypocalcemia, Morbidity, and Mortality in End-Stage Renal Disease

BACKGROUNDnHypocalcemia and hyperphosphatemia with secondary hyper-parathyroidism are characteristic of end-stage renal disease (ESRD). Although calcium levels critically affect almost all cellular processes, the impact of chronic hypocalcemia and other abnormalities of calcium-phosphate homeostasis on the prognosis of ESRD patients is unknown.nnnMETHODSnAn inception cohort of 433 patients starting ESRD therapy was followed prospectively for an average of 41 months. Serum calcium and other parameters were measured monthly. The mean calcium levels were 9.4 +/- 0.7 mg/dl. 23% of the patients had mean calcium levels < 8.8 mg/dl. After adjusting for baseline age, diabetes mellitus, ischemic heart disease, smoking and cholesterol levels, as well as serial albumin, hemoglobin, mean arterial blood pressure, phosphate and alkaline phosphatase levels, chronic hypocalcemia was strongly associated with mortality (RR 2.10, p = 0.006 for a mean calcium level < 8.8 mg/dl). The association with mortality was similar in hemodialysis (RR 2.10, p = 0.006) and peritoneal dialysis patients (2.67, p = 0.034). Using similar covariate adjustment, chronic hypocalcemia was associated with de novo ischemic heart disease (RR 5.23, p < 0.001), recurrent ischemic heart disease (RR 2.46, p = 0.006), de novo cardiac failure (RR 2.64, p < 0.001), and recurrent cardiac failure (RR 3.30, p < 0.001). Hypocalcemia retained its independent impact on morbidity and mortality when analyzed as a time-dependent covariate.nnnCONCLUSIONSnChronic hypocalcemia, a very common, reversible feature of chronic uremia, is independently associated with morbidity and mortality in ESRD patients.

Advance Prediction of Early Death in Patients Starting Maintenance Dialysis

Accurate information on short-term prognosis is needed to help patients, their doctors, and society to make appropriate decisions concerning starting dialysis. We sought to develop a clinically applicable prognostic scoring system to aid in the prediction of death within 6 months of starting maintenance dialysis. Factors potentially predictive of early death were examined retrospectively in an inception cohort of all 325 patients starting dialysis for irreversible renal failure between 1980 and 1991 at a single tertiary care center. The overall mortality rate was 22% at 6 months. Age, cardiac failure, ischemic heart disease, dysrhythmia requiring therapy, severe peripheral vascular disease, advanced neoplasia, ventilator dependency, coma, systemic sepsis, and hepatic failure were independent, significant, prognostic indicators for early death. Multivariate models were used to suggest weights for these variables in a simplified scoring system. Patients with scores < or = 4 (N = 201) had a 6-month mortality rate of 4%, whereas those with a score higher than 9 (N = 21) had a 6-month mortality rate of 100%. Thus, when age and multiple comorbid illnesses were taken into account, it was possible to identify with 100% accuracy 29% of the patients who died within 6 months of starting maintenance dialysis therapy, accounting for 6.5% of the cohort studied. A larger prospective study is warranted to validate this scoring system.

Risk factors for cardiac morbidity and mortality in dialysis 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.

Left Ventricular Hypertrophy in Dialysis Patients

The many common clinical manifestations of cardiac disease and advanced renal disease often lead to difficulties in diagnostic and therapeutic decision making. For example, dyspnea, with the associated clinical findings of peripheral edema, elevated jugular venous pressure, and bibasalar rales could as easily be induced by excessive fluid ingestion, as caused by myocardial disease. Chronic fatigue, associated with hypotension, could as easily be due to anemia, uremia, or autonomic neuropathy as to cardiac dysfunction. Echocardiography can often help greatly in resolving these dilemmas by providing useful information about cardiac cavity and wall dimensions; in particular, we can learn whether left ventricular hypertrophy (LVH) is present. From population-based studies we have known for some time that LVH (by electrocardiographic criteria) independently confers a risk of mortality of about 30% over 5 years (1). In dialysis patients LVH is a very common finding and is also an independent risk factor for death. This paper will review the diagnosis, incidence, etiology and consequences of LVH in end-stage renal disease (ESRD).

Temporal trends in the burden of chronic kidney disease in the United States

Purpose of reviewThe public health importance of chronic kidney disease (CKD) has only recently come to be appreciated and careful examination of temporal trends is warranted. The purpose of the present review was to examine existing research on temporal trends for CKD and treated end-stage renal disease (ESRD) in the United States. Recent findingsWhen the broadly representative National Health and Nutrition Examination Survey (NHANES) datasets were compared in 1988–1994 and 1999–2002, a pronounced increase in the prevalence of abnormally low glomerular filtration rate was observed when serum creatinine was used to estimate glomerular filtration rate. In contrast, glomerular filtration rate findings were almost identical when cystatin C levels were examined. Thus, although the community-wide burden of CKD is already high, uncertainty exists as to the growth rate of this problem. For treated ESRD a dramatic increase in incidence rate occurred in the 1980s and 1990s. Changing burdens of standard risk factors for CKD do not readily explain increased rates of treated ESRD, suggesting that selection criteria for dialysis and transplant programs may underlie these secular trends. If the hypothesis that nonbiological factors are major determinants of rates of treated ESRD is valid, the latter may be a poor surrogate for true ESRD and for understanding its causes and rates of progression. SummaryGiven its prevalence and prognostic implications, it makes intuitive sense to monitor the burden of CKD over time; the validity of the tools used to generate an answer, however, is at least as important as the direction of the answer.

Anemia as a Risk Factor for Cardiac Disease in Dialysis Patients

In otherwise healthy experimental animals, it has long been known that anemia proceeds to the following sequence of events: tissue hypoxia leading to systemic vasodilatation, leading to increased venous return, leading to lengthening of cardiac fibrils and ventricular dilatation–increased cardiac output. In the short term, this can be seen as a physiologic adaptation. It is known that left ventricular dilatation leads to increased wall tension, in accordance with Laplace’s law, and to increased energy consumption. In this scheme, the price for increased tissue oxygen delivery is cardiac enlargement and increased myocardial energy consumption. Over the short term, provided tissue oxygen delivery is adequate, anemia should not lead to enhanced cardiac risk. Until relatively recently, this physiologic approach was the rationale for our treatment of anemia in uremic patients. Treatment of anemia was viewed as a reactive process, aimed only at improved tissue oxygen delivery. This approach, however, ignores the possibility that reaction to the primary stimulus of anemia might have adverse consequences if the anemia is sustained longterm. In the long run, it is conceivable that the cardiac response to sustained anemia is maladaptive, leading to quicker-than-normal cardiac myocyte loss (1), especially in the highly myocyte-unfriendly environment seen in end-stage renal disease (ESRD) patients. (The roles of “uremia,” hypertension, and other hemodynamic stresses, which are ubiquitous in these patients, are discussed elsewhere in this issue.)

Risk Factors for Cardiac Dysfunction in Dialysis Patients: Implications for Patient Care

Cardiac disease exerts a major influence on the morbidity and mortality of dialysis patients, as demonstrated by the frequent occurrence of heart failure and ischemic heart disease (1), very high mortality rates (2), and high proportion of cardiac deaths (2). These adverse events can usually be attributed to disorders of cardiac muscle structure and function and/or disorders of perfusion (Fig. 1) (3).