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.
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).
nsurprisingly, 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.
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