Kidney Disease and Heart Disease Interact to No Good End

ROYAL OAK, Mich., June 12 -- Kidney disease and cardiovascular disease are intertwined risk factors, each contributing to the other, according to two studies.

Three markers of chronic kidney disease -- anemia, reduced glomerular filtration, and microalbuminuria -- were independently associated with heart disease, found Peter A. McCullough, M.D., of William Beaumont Hospital here, and colleagues,

When all three markers were present, approximately one-fourth of the patients had cardiovascular disease, they reported in the June 11 issue of the Archives of Internal Medicine.

Moreover, patients with a combination of all three markers had the lowest survival rate by the end of 30 months, about 93%, compared with any other individual marker group.

The relationship between chronic kidney disease and cardiovascular disease may be bi-directional, with impaired kidney function increasing the cardiovascular disease risk and vice versa, Dr. McCullough and colleagues wrote. However, most patients with chronic kidney disease die of complications from heart disease rather than of kidney failure, he added.

In a community-based population enrolled from 2000 to 2003, the researchers studied a cohort of 37,153 persons (mean age 52.9, 68.7% female) screened in the National Kidney Foundation's Kidney Early Evaluation Program.

A total of 1,835 (4.9%) had a self-reported history of myocardial infarction, 1,336 (3.6%) had a history of stroke, and 2,897 (7.8%) had a history of MI or stroke.

Participants, followed for a median of 16.0 months, were assessed for three markers of chronic kidney disease:

• Glomerular filtration rates (eGFR) estimated on the basis of levels of blood creatinine; 30 to 59 mL/min per 173m³ ;
• Anemia, determined by blood hemoglobin levels (12.8 g/dL or less);
• Microalbuminuria, or protein albumin in the urine (30 mg/L or more).

Of the participants followed for a maximum of 47.5 months, 5,504 (14.8%) had eGFR rates of less than 60 mL/min per 173m³, a sign of declining kidney function. In addition, 4,588 (13.1%) had anemia, and 15,959 (49.5%) had microalbuminuria.

Multivariate, analysis controlling for age found that the following were independently associated with cardiovascular disease : male sex (odds ratio [OR], 1.64; P

Another shortcoming, the researchers noted, was the use of dipstick urine for microalbuminuria detection.

"These data suggest that screening for cardiovascular disease would be of high yield among patients with these risk markers but who do not report any history of cardiovascular disease symptoms," Dr. McCullough and his colleagues concluded.

In a related study in the same journal issue, Daniel E. Weiner, M.D., of Tufts-New England Medical Center in Boston, and colleagues, reported that the presence of cardiovascular disease in almost 13 % of the patients was associated with a decline in kidney function and a more than 50% increased risk of developing kidney disease, as measured by serum creatinine levels and eGFR.

The findings came from a study of 13,826 patients pooled in two large community-based studies, the Atherosclerosis risk in Communities Study and the Cardiovascular Health Study.

During a mean follow-up of about nine years, 520 patients (3.8%) had a decline in kidney function, defined by a serum creatinine level increase of at least 0.4 mg/dL, and 314 individuals (2.3%) developed kidney disease, the researchers reported.

Baseline cardiovascular disease among 1,728 patients (12.9%) with disease was associated with an increased risk of all outcomes (odds ratio, 1.70; CI, 1.36-2.13), an OR 1.75 (CI, 1.32-2.32) for serum creatinine level, and ORs of 1.28 and 1.54 for GFR reduction for decline in kidney function and development of kidney disease, respectively.

The data were pooled from two longitudinal, community-based, limited-access studies, the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study. Patients were recruited from 1987 to 1990 and were followed-up at approximately three-year intervals for a mean 9.3 years.

Baseline cardiovascular disease was defined by stroke, angina, claudication, transient ischemic attack, coronary angioplasty or bypass, and recognized or silent MI.

Study outcomes included kidney function decline (increase in serum creatinine level of at least 0.4 mg/dL) and development of kidney disease (increase in serum creatinine level of at least 0.4 mg/dL in which the baseline serum creatinine level was less than 1.4 mg/dL in men and less than 1.2 mg/dL in women), and final serum creatinine that exceeded these levels.

Secondarily, kidney function decline was defined by a reduction in the estimated glomerular filtration rate.

Development of kidney disease was defined by an eGFR reduction of at least 15mL/min per 1.73m² in which the baseline rate was at least 60 mL/min per 1.73m² and the final GFR was below these levels.

Albuminuria was not measured in this the study.

Cardiovascular disease is independently associated with a decline in kidney function and with the development of kidney disease, Dr. Weiner and colleagues said.

Among the study's limitations the researchers noted is the fact that there is no accepted definition of kidney function decline, although the definition chosen for this study of at least 0.4 mg/dL likely exceeds the level that could be due to chance.

Furthermore, it is possible that many individuals may have been misclassified using the eGFR definition for kidney function decline, they said.

The present study, the researchers said, demonstrates that cardiovascular disease is independently associated with a decline in renal function and with the development of kidney disease.

The findings, they said, identify a population that might benefit from increased surveillance for cardiovascular risk factors and heightened awareness of the risk factors associated with kidney disease.

"Because these patients are mainly under the care of primary care physicians and cardiologists, it is important to draw attention to the increased risk of kidney disease in this population, with goals of preventing further progression, managing sequelae of kidney disease as they arise and adequately preparing individuals for kidney failure with timely nephrology referrals," the researchers concluded.

In an accompanying editorial, Barry I. Freedman, M.D., and Thomas D. DuBose Jr., M.D., of Wake Forest University in Winston-Salem, N.C., wrote that these two reports address the interactive effects of kidney disease and cardiovascular disease risk in more than 50,000 patients, "providing novel insights into the relationship between kidney disease and the vasculature."

The presence of atherosclerotic cardiovascular disease should now be recognized as an independent risk factor for developing kidney disease, and patients with both should be screened and treated accordingly, they said.

The chances for reducing the current high rates of chronic kidney disease and cardiovascular disease will be maximized when primary-care physicians, nephrologists, and cardiologists work in partnership to reduce and treat modifiable vascular disease risk factors, including those that are a consequence of kidney disease, Drs. Freedman and DuBose said.

In addition, they wrote, "the potential for achieving current treatment goals in individuals at risk for nephropathy and cardiovascular disease using a more focused approach promises greater reductions in future cardiovascular disease and end stage renal disease events."

No financial disclosures were reported by Dr. McCullough or his colleagues.

Tobias Kurth, M.D., a co-author of the Tufts study, reported research funding from the National Institutes of Health, Bayer AG, McNeil Consumer & Specialty Pharmaceuticals, and Wyeth Consumer Healthcare. He is a consultant to i3 Drug Safety and received an honorarium from Organon for contributing to an expert panel.

The Tufts study was supported by grants from the National Institutes of Health. Amgen provided partial support for the creation of the pooled database. The ARIC Study and the CHS are conducted and supported by the National Heart, Lung, and Blood Institute in collaboration with the individual study investigators.

Dr. Freedman, an editorial writer, reported that he is a paid consultant for and has received honoraria from Pfizer. Dr. Freedman's research cited in this editorial was supported in part by a Genetic Analysis of African American Hypertensive ESRD grant from the National Institutes of Diabetes, Digestive and Kidney Diseases.