Cardiovascular Disease Independently Increases Risk for Chronic Kidney Disease
News Author: Steve Stiles
CME Author: Laurie Barclay, MD
Release Date: June 18, 2007; Valid for credit through June 18, 2008 Credits Available
Physicians - maximum of 0.25 AMA PRA Category 1 Credit? for physicians;
Family Physicians - up to 0.25 AAFP Prescribed credit for physicians
from Heartwire — a professional news service of WebMD
June 18, 2007 — The vast pathophysiologic overlap between atherosclerotic cardiovascular (CV) disease and chronic kidney disease (CKD) may be increasingly appreciated but it remains less thoroughly studied than either condition alone. Two reports released this week do their parts toward changing that. One demonstrates strong independent relationships between CV disease and multiple measures of renal dysfunction among volunteer participants in a screening program for people with kidney-disease risk factors. The other portrays CV disease itself as a major independent risk factor for future renal functional decline and for CKD in a community-based population.
Together the studies highlight the intimate relationship between two broad disorders that, in some ways, are separated less by clinical and therapeutic issues than by the different hospital departments responsible for them.
An editorial on the 2 studies, published with them online June 11, 2007, by the Archives of Internal Medicine, casts CKD as both "cause and consequence" of CV disease and, in particular, asserts that "the presence of atherosclerotic CV disease should now be recognized as an independent risk factor for the development and progression of kidney disease."
The editorialists, nephrologists Drs Barry I Freedman and Thomas D DuBose Jr (Wake Forest University, Winston-Salem, NC), observe that the two disorders share risk factors and pathophysiology and note, for example, that "urinalysis provides a window into the systemic vasculature, since relatively small increases in urinary protein excretion appear to be surrogate markers for endothelial dysfunction and are an independent risk factor for systemic atherosclerosis. Reduced [glomerular filtration rate (GFR)] appears to pose a similar risk for cardiovascular disease."
Dr Daniel E Weiner (Tufts–New England Medical Center, Boston, MA), a coauthor of the report
highlighting the increased risk of renal dysfunction and CKD when there is known CV disease —
lauds both studies for calling attention to the links between the two disorders. "When you think of one, you should probably think of the other," he said to heartwire.
"In people with cardiovascular disease, we should screen for kidney disease. And when we find it, we should treat it," Weiner said. "If you stay on top of it, you can manage the progression of kidney disease fairly well, and for a lot of people who live long enough, you can really make a difference by slowing it down."
Screening could consist merely of serum-creatinine measurement to estimate GFR, "and you want to check the urine periodically to see if there's protein in it," Weiner said. Therapy would largely take after some forms of CV pharmacotherapy except, for example, "maybe you focus more on ACE inhibitors or angiotensin receptor blockers for blood pressure control," because those drugs can be renoprotective.
"As Good as We're Going to Get"
In his group's analysis, which Weiner called "probably about as good as we're going to get" to evidence that CV disease actually promotes CKD, 13,826 participants pooled from the Atherosclerosis Risk in Communities (ARIC) study and Cardiovascular Health Study (CHS) were followed for a mean of 9.3 years. The increased renal risks associated with CV disease persisted "after adjusting for demographic and clinical characteristics and remained robust in multiple analyses using serum creatinine level and estimated GFR to assess kidney function," report the authors, led by Dr Essam F Elsayed (Tufts–New England Medical Center).
The pooled population, they write, represented patients from both longitudinal, community-based studies for whom long-term data were available, including complete demographics and both entry and final measurements of serum creatinine, and who didn't show evidence of imminent kidney failure.
About 13% of the participants had baseline CV disease, defined as a history of stroke, angina, claudication, TIA, PCI or CABG, or symptomatic or silent MI. The rate of kidney-function decline, defined as a serum creatinine increase of at least 0.4 mg/dL, for patients with or without CV disease was 7.2% and 3.3%, respectively (P < 0.001). When renal functional decline was defined as a drop in estimated GFR of at least 15 mL/min per 1.73 m2, the rates were nonsignificantly different at 34% and 32.5%, respectively. Outright CKD developed during follow-up in 2.3% of the population according to serum-creatinine criteria and 5.6% using a GFR-based definition.
Table 1. Risk of Two Renal Outcomes in Patients With Baseline CV Disease in the Pooled ARIC and CHS Studies, OR (95% CI)*
Outcome-------------------- Defined by Serum Creatinine ------Defined by Estimated GFR Kidney function decline ----------1.70 (1.36 - 2.13) ----------------1.28 (1.13 - 1.45)
Development of CKD -------------1.75 (1.32 - 2.32) ----------------1.54 (1.26 - 1.89)
*P < .001 for all increased odds ratios. Adjusted for age, sex, race, educational level, study of origin, diabetes, smoking, alcohol use, hypertension, body mass index, systolic blood pressure, hematocrit, albumin, total and high-density lipoprotein cholesterol levels, and baseline kidney function. CV indicates cardiovascular; ARIC, Atherosclerosis Risk in Communities; CHS, Cardiovascular Healthy Study; OR odds ratio; CI, confidence interval; GFR, glomerular filtration rate; and CKD, chronic kidney disease.
Source: Arch Intern Med. 2007;167:1130-1136.
"Although several studies have evaluated epidemiological risk factors for progression of kidney disease, to our knowledge, this is the first community-based study that has demonstrated that CV disease is independently associated with kidney function decline and with development of kidney disease," according to the group.
"This well-executed study conclusively demonstrates that CV disease per se is independently associated with subsequent development of kidney disease and renal functional decline," write Freedman and DuBose in their editorial. "The effect of prevalent CV disease on the development and progression of kidney disease was heretofore unknown."
Three Markers of Renal Function and CV Risk
In the other analysis, based on the ongoing Kidney Early Evaluation Program (KEEP) of the National Kidney Foundation, a presence of CV disease was independently associated with its traditional risk markers but also with low hemoglobin levels, microalbuminuria (defined as > 30 mg/L) and CKD (estimated GFR < 60 mL/min per 1.73 m2). A combination of the kidney-related markers compounded the risk of CV disease and also predicted mortality.
The screened population consisted of 37,153 adult volunteers with diabetes, hypertension, or a family history of either or of kidney disease. About 8% had CV disease, defined as a self-reported history of "heart attack" or stroke, according to the authors, led by Dr Peter A McCullough (William Beaumont Hospital Royal Oak, MI).
Table 2. Significant Risk Factors for CV Disease in KEEP*
Parameter ----------------------------------------------------------OR (95% CI) ----------P Microalbuminuria, > 30 mg/L vs ? 10 mg/L -----------------1.28 (1.06 - 1.55) ------.01
Estimated GFR, 30 - 59 vs > 90 mL/min/1.73 m2 -----------1.37 (1.13 - 1.67)----- .001 Hb ? 12.8 g/dL (1st quartile) vs > 14.6 g/dL (4th quartile) --1.45 (1.20 - 1.75) ---< .001
Hb 12.9 - 13.6 g/dL (2nd quartile) vs > 14.6 g/dL (4th quartile) --1.17 (1.00 - 1.35) .04
*Adjusted for demographics, including race/ethnicity and education; smoking status; health insurance coverage; family history of diabetes mellitus, hypertension, and kidney disease; and estimated GFR, anemia, microalbuminuria. CV indicates cardiovascular; KEEP, Kidney Early Evaluation Program; OR, odds ratio; CI, confidence interval; GFR, glomerular filtration rate; and Hb, hemoglobin.
Source: Arch Intern Med. 2007;167:1122-1129.
Unsurprisingly, current smoking (P < 0.001), diabetes (P < 0.001), higher body-mass index (P = 0.03), and hypertension (P < 0.001) were also significantly predictive of CV disease. But having at least a high-school education and being African American were significantly protective (P < 0.001 for both).
Compared to an absence of both CKD and CV disease, current CKD without CV disease about doubled the age-adjusted mortality risk (P = 0.05), CV disease without CKD tripled it (P = 0.003), and a presence of both disorders nearly quadrupled the risk, with a hazard ratio of 3.8 (P < 0.001).
Given that more than one-fourth of those in the study who had all three kidney-related risk factors also had CV disease, write McCullough et al, the findings "suggest that screening for CV disease would be of high yield among patients with these risk markers but who do not report any history of CV disease symptoms."
According to Freedman and DuBose, "When caring for individuals with preexisting CV disease and multiple CV-disease risk factors, primary care physicians and cardiologists should be vigilant in checking for the development and progression of CKD. Moreover, attention should be directed to the potential complications of kidney disease that may require consultation by a nephrologist." There is evidence, they write, that diabetes and hypertension often do not prompt primary-care physicians to screen for CKD. "It is reasonable to encourage screening for most patients in such high-risk groups."
Elsayed et al coauthor Dr Tobias Kurth (Brigham and Women's Hospital, Boston, MA) "has received research funding from... 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." In the same study, partial financial support for the creation of the pooled database came from Amgen. Freedman reports that he is a consultant for and has received honoraria from Pfizer.
Arch Intern Med. 2007;167: 1113-1115, 1122-1129, 1130-1136.
Identifying risk factors for worsening kidney function is crucial to understanding and containing the epidemic of CKD in the United States. Although CKD is an independent risk factor for CVD, it is not known whether CVD is associated with kidney function decline and the development of kidney disease. Most previous studies of risk factors for kidney function decline have shown independent associations between CVD risk factors and worsening kidney function.
Because impaired kidney function may increase the risk for CVD and CVD may increase the risk
for development and progression of CKD, the objective of the current study by Elsayed and colleagues was to determine if the presence of CVD is associated with kidney function decline and development of CKD in a community-based population. A second study by McCullough and colleagues in the same issue of the Archives of Internal Medicine showed that anemia, estimated GFR, and microalbuminuria were independently associated with CVD and that, when all 3 were present, CVD was common and survival was reduced.
Individual patient data from 2 longitudinal, community-based, limited-access studies (ARIC and CHS) were pooled. Of 20,993 individuals, 350 with missing age, sex, race, or baseline serum creatinine level data and 27 individuals with baseline estimated GFR less than 15 mL/minute/1.73 m2 were excluded. Of the remaining 20,616 individuals, 6348 did not have a final serum creatinine value, yielding a final population of 13,826 individuals.
Baseline CVD was defined as (1) prior recognized or silent myocardial infarction diagnosed by self-report of a clinician-diagnosed event or by characteristic changes on the baseline electrocardiogram, (2) angina defined by the Rose questionnaire, (3) stroke and transient ischemic attack defined by CHS and ARIC consensus committees, (4) intermittent claudication based on the Rose questionnaire, and (5) prior coronary angioplasty or bypass procedures.
Study endpoints included kidney function decline, defined as an increase in serum creatinine level of 0.4 mg/dL or greater (? 35.4 µmol/L), and development of kidney disease, defined as an increase in serum creatinine level of 0.4 mg/dL or greater (? 35.4 µmol/L) from a baseline serum creatinine level of less than 1.4 mg/dL (< 123.8 µmol/L) in men and less than 1.2 mg/dL (< 106.1 µmol/L) in women, when the final serum creatinine levels exceeded these levels.
Kidney function decline was also defined secondarily by an estimated GFR reduction of 15 mL/minute/1.73 m2 or greater.
Development of kidney disease was defined secondarily by an estimated GFR reduction of 15 mL/minute/1.73 m2 or greater from a baseline estimated GFR of 60 mL/minute/1.73 m2 or greater, when the final estimated GFR was below these levels. Multivariate logistic regression analysis determined the association between CVD and outcomes.
In the study population of 13,826 individuals, mean age was 57.6 ? 9.1 years, mean baseline serum creatinine level was 0.9 ? 0.2 mg/dL (79.6 ? 17.7 µmol/L), and mean baseline estimated GFR was 89.8 ? 20.1 mL/minute/1.73 m2. Mean follow-up was 9.3 ? 0.9 years.
In serum creatinine level–based models, 520 (3.8%) individuals had kidney function decline and 314 (2.3%) individuals developed kidney disease during follow-up.
Among 1787 individuals with baseline CVD, 128 (7.2%) had a decline in kidney function. Among 12,039 individuals without baseline CVD, 392 (3.3%) had a decline in kidney function (P
< .001). Those individuals with a decline in kidney function had significantly higher baseline serum creatinine levels and were more likely to be older, have hypertension and diabetes mellitus, and be of African-American race.
Among 1787 individuals with baseline CVD, 607 (34.0%) had a decline in kidney function based on estimated GFR, whereas among 12,039 individuals without baseline CVD, 3909 (32.5%) had a decline in kidney function based on estimated GFR (P = .22). Of 729 (5.6%) individuals who developed kidney disease, 155 (21.3%) had baseline CVD. Of 12,342 (94.4%) individuals who did not develop kidney disease, 1452 (11.8%) had CVD (P < .001).
Baseline CVD, which was present in 1787 (12.9%) individuals, was associated with an increased risk for all outcomes (odds ratio [OR], 1.70; 95% confidence interval [CI], 1.36 - 2.13), an OR of 1.75 (95% CI, 1.32 - 2.32) for serum creatinine level, an OR of 1.28 (95% CI, 1.13 - 1.45) for kidney function decline based on estimated GFR, and an OR of 1.54 (95% CI, 1.26 - 1.89) for development of kidney disease based on estimated GFR.
Pearls for Practice
Cardiovascular disease is independently associated with kidney function decline. Cardiovascular disease is independently associated with development of kidney disease. 第三部分