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
从两项纵向基于社区有限访问的研究中(ARIC and CHS)收集了每位患者的资料。在总共20993
研究终点包括通过血清肌酐最终值是否超过以下水平来确定肾功能降低及肾脏疾病的进展情况，前者由血清中肌酐水平增高0.4 mg/dL或以上(? 35.4 µmol/L)进行确认，后者由血清中肌酐水平由血清肌酐基线值增高0.4 mg/dL或以上(? 35.4 µmol/L)来确定，血清肌酐基线值男性低于1.4 mg/dL (< 123.8 µmol/L)，女性低于1.2 mg/dL (< 106.1 µmol/L)。
肾功能降低通过GFR估计值下降15 mL/minute/1.73 m2或以上进行再次确认。
当最终的GFR估计值低于以下水平时，肾脏疾病进展情况的再次确认通过GFR估计值与GFR估计值的基线值，即60 mL/minute/1.73 m2(或以上)相比下降15 mL/minute/1.73 m2(或以上)。通过多元回归分析确定CVD和疾病结局间是否有相关性。
GFR was 89.8 ? 20.1 mL/minute/1.73 m2. Mean follow-up was 9.3 ? 0.9 years.
在包括13826名患者的研究人群中，平均年龄为57.6 ? 9.1岁，血清肌酐基线值平均水平为0.9 ? 0.2 mg/dL (79.6 ? 17.7 µmol/L),平均GFR估计值为89.8 ? 20.1 mL/minute/1.73 m2。平均随访期为9.3 ? 0.9年。
在1787名具有底线型CVD患者中，有128人(7.2%)肾功能降低。在12039名无底线型CVD的患者中，有392人(3.3%)肾功能降低(P < .001)。那些肾功能降低的患者血清肌酐基线水平明显更高，这些患者的年龄更大，多患有糖尿病，而且多为非洲裔美国人。
在1787名具有底线型CVD患者中，经GFR估计值确认有607人(34.0%)肾功能降低，而在12039名无底线型CVD的患者中，经GFR估计值确认有3909人(32.5%)肾功能降低(P = .22)。在729名(5.6%)肾脏疾病有所进展的患者中，155人(21.3%)具有底线型CVD。在12342名(94.4%)肾脏疾病无进展的患者中，1452人(11.8%)具有CVD(P < .001)。
底线型CVD见于1787名(12.9%)患者，并与疾病风险的增高有关(比值比[OR], 1.70; 95%可信区间[CI], 1.36 - 2.13),血清肌酐水平的OR值为1.75(95% CI, 1.32 - 2.32)，基于GFR估计值判断的肾功能降低的OR值为1.28(95% CI, 1.13 - 1.45)，基于GFR估计值判断的肾脏疾病是否有所进展的OR值为1.54(95% CI, 1.26 - 1.89)。
2007.6.18(动脉粥样硬化性和慢性肾病之间的广泛的病理生理联系日益明确，但是比起这两种疾病的单独研究，这还有待于进一步透彻的研究。本周有两篇报道改变了这种现状，一个报道揭示动脉粥样硬化与肾衰竭三个指标独立相关，而这三个指标是从对志愿者进行筛分以获得肾脏疾病危险因素研究中所确立的。另一个把心血管疾病看作日后肾功能下降和社区人群慢性肾病的一个主要独立危险因素。这些研究都强调了这两个大系统病变之间的密切联系，在一定程度上两者在临床和治疗上，比起医院设置专门科室来处理他们，联系更紧密。关于这两个研究的社论在2007年6月11号的内科档案上与他们一起在线发表，社论认为慢性肾病可以引起心血管疾病同时也是心血管疾病的结果，并特别指出有动脉粥样硬化的心脏疾病应该作为慢性肾病发生和发展的独立危险因子。肾病学专家Barry I Freedman和Thomas D DuBose Jr医生谈论道，这两种疾病享有共同的危险因子和病理生理变化，并举例说明；尿检是分析全身脉管系统的一个窗口，因为尿蛋白相对细微的升高就意味着内皮功能不全，同时也是全身动脉粥样硬化的独立危险因子。肾小球滤过率下降也被认为是心血管疾病的危险因素。Daniel E Weiner，揭示已经患有心血管疾病会增加肾脏功能和慢性肾病风险的报道的共同执笔者，称赞这两个研究引起了人们对这两种疾病之间的联系的关注。他对heartwire说；―你想起一个机能紊乱，就会想起另一个。‖Weiner 说对于心血管病人，我们要注意检查他们的肾功能。一旦发现应该立即治疗。如果你能够纵观全局，你就能够控制好肾病的发展，而且对于许多可以长寿的人，你可以减慢疾病的发展。接着他补充说，只要检测血清肌酸酐来估计肾小球滤过率，另外需要定期查尿，看是否有尿蛋白。治疗方法在很大程度上与心血管药物治疗的一些方案类似，要不例如侧重于选择ACE抑制剂和血管紧张素受体阻滞剂来控制血压，因为这些药物有肾保护作用。
Weiner所领导的小组对从粥状动脉硬化高风险社区(ARIC)研究和心血管健康研究(CHS)参与者中抽出的13,826名成员进行了长达9.3年的跟踪研究,这个被Weiner称为―和我们预计的一样好‖的研究证明了心血管疾病确实可以引发慢性肾病.与心血管疾病相关的肾病高风险在继续, ―调整了人口统计学和临床统计学差异之后,在多宗通过血浆肌氨酸酐水平和肾小球滤过率估计值来评价肾功能的分析中这种关联仍然十分明显‖ Essam F Elsayed博士 (Tufts–New England Medical
大约13%的参与者有基本的心血管疾病，指的是曾经有抽搐、绞痛、跛行、TIA、PCI或CABG、或隐性或显性MI症状。有心血管疾病和没有心血管疾病的患者，其肾功能衰退，指的是血浆肌氨酸酐增加了至少0.4 mg/dL！的比例分别为7.2%和3.3%(P < 0.001)。当用肾小球滤过率下降至少15 mL/min每 1.73 m2这一指标来定义肾功能衰退时，它们的比例没有明显区别，分别为34%和32.5%。用血浆肌氨酸酐指标来衡量时，参与者中2.3%的成员在随后的过程中发展成为慢性肾病，而用肾小球滤过率指标来定义时，这一比例为5.6%。
结果 --------------------定义为血浆肌氨酸酐 ------定义为肾小球滤过率估计值
肾功能衰退 ----------1.70 (1.36 - 2.13) ----------------1.28 (1.13 - 1.45)
发展为慢性肾病-------------1.75 (1.32 - 2.32) ----------------1.54 (1.26 - 1.89)
所有的优势比均为P < .001。所有数据均调整了年龄、性别、种族、教育水平、研究起源、糖尿病、吸烟、饮酒、高血压、体重、收缩期血压、血球容积计、白蛋白、总胆固醇和高密度脂蛋白胆固醇水平及基础肾功能的因素差异。CV指心血管疾病，ARIC指粥状动脉硬化高风险社区，CHS指心血管健康研究，OR指优势比，CI指置信区间，GFR指肾小球滤过率，CKD指慢性肾病。
来源；Arch Intern Med. 2007;167:1130-1136.
―这个得到很好执行的研究总结证明了心血管疾病本质上和肾病的发生及肾功能衰退的问题单独相关‖ Freedman 和DuBose在他们的评论中写道，―心血管疾病对于肾病发展的影响迄今仍然不清楚。‖
在其他研究中，如全国肾基金会正在开展得肾早期评价项目(KEEP)，心血管疾病的发生与它的传统危险因子单独相关，但也与低血红蛋白水平、微白蛋白尿，指> 30 mg/L！和慢性肾病，肾小球滤过率 < 60 mL/min per 1.73 m2！等因素有关。肾病相关的标记物的联合出现增加了心血管疾病的危险性，同时也预示着死亡。
调查的人群包括了37,153个有糖尿病、高血压、或任一种肾病家族史的成年志愿者。大约8%有心血管疾病，指自称发生过―心脏病发作‖或中风的现象，Peter A McCullough博士 (William Beaumont Hospital Royal Oak, MI)等作者称。
参数 ----------------------------------------------------------优势比 (95% 置信区间) ----------P 微白蛋白尿, > 30 mg/L vs ? 10 mg/L -----------------1.28 (1.06 - 1.55) ------.01
肾小球滤过率, 30 - 59 vs > 90 mL/min/1.73 m2 -----------1.37 (1.13 - 1.67)----- .001
血红蛋白 ? 12.8 g/dL (第一个四分位数) vs > 14.6 g/dL (第四个四分位数) --1.45 (1.20 - 1.75) ---< .001
血红蛋白 12.9 - 13.6 g/dL (第二个四分位数) vs > 14.6 g/dL (第四个四分位数) --1.17 (1.00 - 1.35) .04
所有数据均调整了人口统计学差异。包括种族和教育水平，吸烟状况，健康保险覆盖率，糖尿病、高血压和肾病家族史，肾小球滤过率估计值，贫血病，为白蛋白尿等因素。CV指心血管疾病，KEEP指早期肾评价项目，OR指优势比，CI指置信区间，GFR指肾小球滤过率，Hb指血红蛋白。 来源；Arch Intern Med. 2007;167: 1122-1129.
毫不意外的，目前吸烟(P < 0.001) 、糖尿病(P < 0.001)、高体重指数 (P = 0.03) 和高血压(P <
0.001)仍然是心血管疾病的关键预兆。但是拥有至少高中以上教育水平和作为非裔美国人可以明显预防心血管疾病 (P < 0.001 for both)。
目前，没有心血管疾病的慢性肾病患者的死亡率在排除年龄因素之后是没有心血管疾病和慢性肾病的人的两倍(P = 0.05)，有心血管疾病而无慢性肾病的患者死亡率增加到3倍(P = 0.003)，而同时有两种疾病使死亡率几乎增加到四倍，达到了危险的3.8倍 (P < 0.001)。
Freedman 和 DuBose指， ―在照顾已经有心血管疾病和有多个心血管疾病危险标记物的患者时,初级护理医生和心脏病学家应该敏锐的检查慢性肾病的发展。而且，应该关注于潜在的肾病并发症，这可能需要咨询肾病学家。 ‖有数据显示，他们写道，糖尿病和高血压通常不会促使初级护理医生检查病人是否发生慢性肾病。―鼓励在这样的高风险人群中对大多数病人进行慢性肾病筛选很合情合理。‖
Elsayed 等的共同作者Tobias Kurth 博士(Brigham and Women's Hospital, Boston, MA) ―已经从Bayer AG McNeil Consumer & Specialty Pharmaceuticals, and Wyeth Consumer Healthcare等机构取得了研究经费,他是一个i3药物安全性的顾问，曾经从Organon组织获得捐献给专家小组的酬金。‖在同一研究中，部分资金来自于Amgen关于数据库标准建立经济支持。 Freedman报告称他是Pfizer的顾问，并且从Pfizer领取酬金。
来源: Arch Intern Med. 2007;167: 1113-1115, 1122-1129, 1130-1136。