Peripheral artery disease: Prevalence and risk factors

INTRODUCTION — Atherosclerosis is a systemic disease of the large and medium-sized arteries causing luminal narrowing (focal or diffuse) due to the accumulation of lipid and fibrous material affecting the intimal and medial layers of the vessel. Atherosclerosis of the arteries of the lower extremities is defined as peripheral artery disease (PAD). An ankle-brachial index (ABI) ≤0.9 is sensitive and specific for arterial stenosis/occlusion [1].

Although other disease processes can lead to narrowing of the limb arteries (eg, inflammation, thrombosis) and symptoms of arterial insufficiency, atherosclerosis is by far the most prevalent etiology. The lower extremity vessels are affected more commonly than the upper extremity vessels.

Ischemic symptoms result when there is an imbalance between the supply and demand for blood flow. The clinical manifestations of PAD depend upon the location and severity of arterial stenosis or occlusion and range from mild extremity pain with activity (ie, claudication) to limb-threatening ischemia. Some patients have functional symptoms without discomfort [2]. It is now recognized that most patients with PAD do not have classic signs of claudication but may still have significant limitations in function. Atypical symptoms are more common in females but also occur in males. While the risk of adverse limb events is less for asymptomatic patients compared with symptomatic patients, the risk of adverse cardiovascular events remains elevated. In addition, for those patients with PAD who continue to smoke or have diabetes or kidney function impairment, the clinical manifestations can progress rapidly and unpredictably.

The prevalence and risk factors associated with PAD are reviewed. The natural history, clinical manifestations, and management of PAD are discussed separately. (See "Asymptomatic peripheral artery disease", section on 'Disease patterns and associated vascular beds' and "Lower extremity peripheral artery disease: Clinical features and diagnosis" and "Management of claudication due to peripheral artery disease".)

An overview of upper extremity atherosclerotic disease is provided separately. (See "Upper extremity atherosclerotic disease".)

PREVALENCE — The global prevalence of PAD in 2019 was estimated at 1.52 percent, impacting 113 million people over the age of 40, but estimates vary widely even among those analyzing the same databases [3-5]. The largest cohorts (42.6 percent) were in counties with a low or middle sociodemographic index [6,7]. The prevalence of PAD has increased by about 45 percent globally, with greater increases in low- and middle-income countries (5.1 percent), although prevalence remains higher in high-income countries (7.4 percent) [8]. A systematic study found the worldwide prevalence to be 1.52 percent across all age groups, rising to 14.92 percent in those over 80, and higher in females [6].

In Europe and North America, an estimated 27 million individuals are affected with approximately 413,000 inpatient admissions annually attributed to PAD [9]. In the United States, one study estimated that 21 to 26 million people have PAD [10]; however, most others suggest the prevalence is less, at 8 to 10 million people [3].

Sociodemographic differences — The majority of individuals with PAD (70 percent) live in low-/middle-income regions of the world, including 55 million individuals in southeast Asia and 46 million in the Western Pacific Region [4]. The number of individuals with PAD increased by 29 percent in low/middle-income regions and by 13 percent in high-income regions from 2000 to 2010 compared with the preceding decade [4].

In a report from the National Health and Nutrition Examination Survey (NHANES) from the United States, in which PAD was defined as an ankle-brachial index (ABI) <0.9 in either leg, the prevalence of PAD among adults aged 40 years and over in the US was 4.3 percent [11]. PAD was more prevalent in older individuals, families with atherosclerosis, in those with risk factors for cardiovascular disease, and in those with certain ethnicities. In the NHANES study, more than 95 percent of those with PAD had one or more cardiovascular disease risk factors. An increased prevalence of PAD was reported for Black Americans (males and females), and also Hispanic American females compared with White Americans (ie, without Hispanic ethnicity) 19.2 and 19.3 percent, respectively, versus 15.6 percent [11]. The observed difference did not appear to be completely explained by differences in the prevalence of risk factors for atherosclerosis [12]. Hispanic and Black Americans had higher rates of diabetes and hypertension, whereas White Americans were more likely to have hypercholesterolemia [13]. Black and Hispanic Americans and patients with diabetes mellitus (DM) also have a higher prevalence of PAD compared with White patients, even after adjustment for other known risk factors and the excess prevalence of DM [14,15]. Reasons for these potential racial/ethnic differences in the burden of PAD among patients with diabetes are unknown.

Similarly, in the San Diego Population Study, a survey of 2343 randomly selected participants, Black Americans had a significantly higher prevalence of PAD (7.8 versus 4.9 percent) compared with White Americans [16]. In this study, PAD was defined as an ABI ≤0.9, an abnormal Doppler waveform, or prior revascularization for PAD. Although Black American individuals had significantly higher rates of diabetes, hypertension, and greater body mass index, the increased risk for PAD was maintained after adjustment for these and other variables. Hispanic and Asian Americans had somewhat lower rates of PAD compared with White Americans, but the difference was not significant.

In a multiethnic Asian (Chinese, Malay, Indian) population study from Singapore, PAD was present in 4.3 percent of the population, and a high ABI >1.4 was rare [17]. A systematic review identified 14 studies comparing the prevalence between South Asian and White European individuals. Among those at high risk for PAD, the occurrence of PAD was less in those from South Asia compared with White Europeans (with coronary artery disease: OR 0.47, 95% CI 0.39-0.56; with diabetes: OR 0.44, 95% CI 0.30-0.63) [18]. The reasons for this were unclear.

A study using the Global Burden of Disease database found that the global age-standardized mortality rate (ASMR) from PAD remained higher in areas with higher sociodemographic indexes, while the rate of death in lower sociodemographic index regions increased. The ASMR was higher in males but decreased with age [19].

A second study involving data from the Chronic Renal Insufficiency Cohort Study (CRIC) reported that, after adjusting for cardiovascular risk factors, all lower levels of annual household income were associated with increased incidence of PAD relative to a baseline annual income of >$100,000 USD [20]. Hazard ratios were 1.7 for those under $25,000 USD annual income and 1.6 for those below $100,000 USD. Educational level was not correlated with PAD.

Sex-related differences — Sex-related differences in the risk for cardiovascular disease have been described. (See "Overview of established risk factors for cardiovascular disease", section on 'Age and sex'.)

PAD is cited historically as more prevalent in males overall compared with females. However, the population-based prevalence of PAD in females has not been fully evaluated. In population studies, the prevalence of PAD in females is at least as high as that of males across all age groups but increases to a greater extent in females after age 70 compared with males of the same age [3,13,21-23].

An epidemiologic model based upon a systematic review of the prevalence of PAD around the world was used to compare predicted PAD prevalence in three high-income and five low-/middle-income World Health Organization (WHO) regions [4].

●Sex-specific prevalence increased with age (eg, for males, 5.4 percent, 45 to 49 years; 18.8 percent, 86 to 89 years).

●Prevalence in males was lower in low-/middle-income regions compared with high-income regions (eg, 2.9 versus 5.4 percent for males 45 to 49 years; 14.9 versus 18.8 percent for males 85 to 89 years).

●Prevalence was higher in females, especially at younger ages in low-/middle-income regions (6.31 versus 5.3 percent for females 45 to 49 years; 15.2 versus 18.4 percent for females 85 to 89 years).

In a review of 133,750 females and 71,996 males who underwent voluntary screening for PAD (ie, Lifeline), females were significantly more likely to have ABI ≤0.9 (4.1 versus 2.6 percent) [24]. In a large review, incident cardiovascular disease varied by type of presentation (eg, myocardial infarction, transient ischemic attack, PAD, abdominal aortic aneurysm), age, and sex [25]. The risk difference between men and females for an initial presentation of PAD was most pronounced for males aged 50 to 59, with a twofold increase compared with females.

In a population study of individuals 60 to 90 years of age in Sweden, females had a higher prevalence of PAD compared with males when ABI only was used to diagnose PAD (asymptomatic: 12.6 versus 9.4 percent). In this study, the prevalence of severe limb ischemia was higher in females compared with males (1.5 versus 0.8 percent) [26]. Similar results were found in a retrospective review of 231 consecutive patients diagnosed with PAD following referral to a vascular laboratory [23]. The prevalence of severe limb ischemia was 13.2 percent in females and 4.3 percent in males. The difference was likely related to the significantly higher incidence of hypercholesterolemia (88.2 versus 73 percent), metabolic syndrome (78 versus 43 percent), and diabetes (67.6 versus 42.9 percent) found in the female patients.

Whether there is any effect of hormone replacement therapy in postmenopausal females on the development of PAD is largely unknown. One study of 847,982 postmenopausal females found that in spite of an increased prevalence of several atherosclerotic risk factors among females who used hormone replacement therapy, they were significantly less likely to have PAD (3.3 versus 4.1 percent) [27]. The benefits and risks of hormone replacement therapy are discussed in detail elsewhere. (See "Menopausal hormone therapy: Benefits and risks".)

RISK FOR ATHEROSCLEROSIS — Risk factors that favor the development of PAD are similar to those that promote the development of coronary heart disease (CHD) [11,28-30]. (See "Overview of possible risk factors for cardiovascular disease" and "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach".)

Risk differences for PAD — Identified differences in risk factors for PAD versus CHD may indicate subtle differences in pathophysiology.

●The Scottish Heart Health Extended Cohort identified some risk factor differences for PAD compared with CHD [31]. Among over 15,000 males and females aged 30 to 75 years who were free of PAD or CHD and followed for 15 to 25 years, 19.7 percent developed CHD and 3.2 percent developed PAD. PAD and CHD shared seven of the nine of the ASSIGN risk score variables (age, sex, family history, socioeconomic status, diabetes mellitus, tobacco smoking, and systolic blood pressure), and four biomarkers (N-terminal pro b-type natriuretic peptide [NT-pro-BNP], cotinine, high-sensitivity C-reactive protein, and cystatin-C).

●For PAD, markers associated with inflammation and tobacco smoking predominated, while total cholesterol and body mass were less important. The highest ranked adjusted hazard ratios in PAD were age, high-sensitivity C-reactive protein, systolic blood pressure, expired carbon monoxide, cotinine, socioeconomic status, and lipoprotein(a). Diabetes mellitus was also an important risk factor but not the most common cause of PAD.

Biomarkers and PAD — Biomarkers are increasingly being studied to identify those at higher risk for the development of atherosclerosis. (See "Overview of possible risk factors for cardiovascular disease", section on 'Vitamins, antioxidants and homocysteine'.)

Some studies have noted differences for patients with PAD.

●In the Scottish Heart Health Extended Cohort study, NT-pro-BNP, cotinine, high-sensitivity C-reactive protein, and cystatin-C are risk factors for PAD [31]. Biomarker risk factors for PAD were not entirely consistent with those for CHD. For PAD, high-sensitivity C-reactive protein, indicative of inflammatory state, and expired carbon monoxide and cotinine, associated with tobacco abuse, as well as lipoprotein(a), were associated with higher rates of PAD development. A review of patients in an ambulatory care setting reported elevated levels of NT-pro-BNP compared to non-PAD patients in the absence of cardiac symptoms [32].

●Another study reported 11 other biomarkers as significantly elevated in patients with PAD [33]. Biomarkers included the secretoglobin family 3A member 2, osteoprotegerin, urokinase-type plasminogen activator surface receptor, serum macrophage chemokine ligand 16, matrix metalloproteinase 9, p-selectin, growth differentiation factor 15, elafin, cystatin-B, trefoil factor 3, and fatty acid-binding protein 4.

●Homocysteine was one of the earliest biomarkers to be studied in association with the development of atherosclerosis [34]. Elevated homocysteine is associated with earlier-onset atherosclerosis and is present in up to 40 percent of patients with PAD [35]. Homocysteine is thought to promote smooth muscle proliferation, increase arterial wall inflammation, and increase levels of plasminogen activator inhibitor. Homocysteine also interferes with nitric oxide released by endothelial cells. Excess homocysteine leads to vessel thickening, luminal stenosis, and thrombus formation. Although a more rapid progression of PAD in patients with increased homocysteine has been described in some studies [36,37], this finding is not uniform [38]. However, no study has shown that homocysteine-lowering therapy reduces PAD progression or improves outcomes [39].

●Tissue plasminogen activator activity appears to be associated with asymptomatic PAD. In a study of subjects previously unknown to have PAD, tissue plasminogen activator activity at baseline and at the 10-year follow-up significantly predicted the presence of sign(s) of PAD (OR 1.78, 95% CI 1.02-3.10) [40]. Age, hypertension, and HbA1c were also independent risk factors in this study for the development of PAD at 10 years.

HIGH-RISK GROUPS — The American College of Cardiology/American Heart Association (ACC/AHA) guidelines on PAD identified the risk groups that are associated with an increased prevalence of PAD and earlier onset of symptomatic PAD [41-43]. Patients in these groups should be evaluated for PAD.

●Age ≥70 years. (See 'Older age' below.)

●Age 50 to 69 years with a history of smoking or diabetes. (See 'Cigarette smoking' below and 'Diabetes' below.)

●Age 40 to 49 with diabetes and at least one other risk factor for atherosclerosis. (See 'Diabetes' below.)

●Known atherosclerosis at other sites (eg, coronary, carotid, renal artery disease). (See 'Known atherosclerosis in another vascular bed' below.)

Several large studies have evaluated the incidence and prevalence of these factors, alone or together, in patients with PAD.

●The Health Professionals Follow-up Study tracked 44,985 males in the United States without a history of cardiovascular disease at baseline for a median follow-up of 24.2 years (1986 to 2011) [44]. There were 537 cases of incident PAD (defined as limb amputation or revascularization, angiogram reporting vascular obstruction ≥50 percent, ankle-brachial index (ABI) <0.9, or physician-diagnosed PAD). Each risk factor (smoking, hypertension, hypercholesterolemia, type 2 diabetes) was significantly and independently associated with a higher risk of PAD after adjustment for the other three risk factors, and confounders. Males without any of the four risk factors had a lower risk of PAD compared with all other males in the cohort (hazard ratio [HR] 0.23, 95% CI 0.14-0.36). The age-adjusted incidence rates (cases per 100,000 person-years) were nine for no risk factors, 23 for one risk factor, 47 for two risk factors, 92 for three risk factors, and 186 for four risk factors. The population-attributable risk for PAD associated with these four risk factors was 75 percent.

●Similarly, a study evaluating data from the United States National Health and Nutrition Examination Survey (NHANES) determined the cumulative effects of known risk factors for PAD [45]. Risk factors for PAD used in the model included age, sex, race/ethnicity, hypertension, diabetes, chronic kidney disease (CKD), and smoking. The likelihood of PAD increased with each additional risk factor present. With one risk factor present relative to no risk factors, the risk for PAD was not significant (odds ratio [OR] 1.5, 95% CI 0.9-2.6). For two risk factors, the risk for PAD was nearly quadrupled (OR 3.7, 95% CI 2.3-6.1), and for three risk factors the risk was increased 10-fold (OR 10.2, 95% CI 6.4-16.3). Smoking was the single factor associated with the highest risk for PAD. Black Americans (Black only; not Hispanic) and females, who had the highest prevalence rates, were particularly sensitive to this cumulative effect.

●In the PAD Awareness, Risk, and Treatment: New Resources for Survival (PARTNERS) program study that included 6979 subjects, the prevalence of PAD in individuals at high risk for PAD (50 to 69 years of age and diabetes mellitus [DM] or >10 pack-year history of smoking, or >70 years of age) was 29 percent [28]. Of these, 13 percent had PAD only, and 16 percent had evidence of PAD and coronary artery disease.

Older age — The prevalence of PAD increases progressively with age, beginning after age 40 [11,46-51]. As a result, PAD is a growing clinical problem in the United States and other developed countries due to an aging population. (See "Overview of established risk factors for cardiovascular disease", section on 'Age and sex'.)

Individuals over 70 are at a significantly increased risk for PAD due to age alone [52], while risk for those who are younger is due to other factors, most commonly cigarette smoking [53]. However, only half of aged adults with PAD are symptomatic from lower extremity PAD, often because of other comorbidities that limit mobility, such as arthritis, cardiac disease, and pulmonary disease [54].

The relationship between PAD prevalence and age was illustrated in the NHANES study [11,53]. The prevalence of PAD was:

●0.9 percent between the ages of 40 and 49

●2.5 percent between the ages of 50 and 59

●4.7 percent between the ages of 60 and 69

●14.5 percent age 70 and older

●23.2 percent for those over 80

Traditional risk factors for ABI may be absent in patients older than 80 years, particularly those with infrapopliteal disease [55].

Cigarette smoking — Cigarette smoking correlates significantly with the development and progression of atherosclerosis. On average, a diagnosis of PAD is made approximately a decade sooner in cigarette smokers than in nonsmokers [56].

The mechanism by which cigarette smoking promotes atherosclerosis is not clearly understood, but its effects include endothelial damage, arterial smooth muscle proliferation, thrombophilia, inflammation, increased sympathetic tone, and other metabolic abnormalities [57-61]. In the NHANES study, the risk for PAD was increased in active cigarette smokers, but no association was found for other forms of tobacco exposure [53]. A systematic review that included 55 original studies performed in North America, South America, Europe, Australia, and Africa assessed the magnitude of increased risk of PAD in current smokers relative to never-smokers (OR 2.71, 95% CI 2.28-3.21), and ex-smokers relative to never-smokers (OR 1.67, 95% CI 1.43-1.81) [62]. Most studies (47 out of 55) used ABI to define PAD; the remainder used symptoms of claudication. The Erfurt Male Cohort (ERFORT) study, which followed 1160 males aged 40 to 59 years every five years, also associated smoking with an increased risk of incident intermittent claudication (HR 2.20, 95% CI 1.24-3.92) [63]. In another study, ongoing cigarette smoking was associated with the largest decline in ABI compared with other risk factors [64].

Smoking appears to be a more powerful risk factor for PAD than for coronary heart disease (CHD) [62,65,66]. In the Edinburgh Artery Study, the adjusted relative risk for PAD in heavy smokers compared with nonsmokers was 2.72 (95% CI 1.13-6.53), but lower for CHD at 1.61 (95% CI 0.91-2.85) [65,66]. A separate meta-analysis evaluating the risk of CHD in smokers identified a relative risk of 1.72 for males and 1.92 in females [67].

A significant relationship between cigarette dose and risk for PAD has been reported [28,30,68]. In the PARTNERS program study discussed above, patients aged 50 to 69 years of age with a history of cigarette smoking more than 10 pack-years or a history of diabetes had an incidence of PAD similar to those ≥70 years of age [28]. The Framingham Heart Study found that the risk for developing claudication was directly related to the number of cigarettes smoked, with a 1.4-fold risk increase for every 10 cigarettes smoked per day [30]. In another study, the HR for PAD was 2.52 (95% CI 1.49-4.25) for 10 pack-years, 6.75 (95% CI 4.33-10.52) for 10 to 29 pack-years, and 11.09 (95% CI 6.94-17.72) for ≥30 pack-years [68]. A greater number of pack-years of smoking is also associated with increasing disease severity, negative effects on the patency of vascular reconstruction, and an increased risk of amputation and cardiovascular mortality following revascularization [56]. Passive exposure to smoke appears to increase vascular endothelial inflammation and may increase the risk for atherosclerotic plaque development in children and adults [69]. (See "Secondhand smoke exposure: Effects in adults", section on 'Cardiovascular disease and stroke' and "Secondhand smoke exposure: Effects in children", section on 'Atherogenesis'.)

Although smoking cessation decreases morbidity related to PAD, the risk of progression of PAD is significantly greater in former smokers compared with never smokers [68,70,71]. The Edinburgh Arterial Study found a decreased risk of claudication for patients who stopped smoking compared with those who continued to smoke [72]. Smoking cessation is also associated with a decreased risk of graft failure following lower extremity bypass surgery [73]. These effects are limited if the patient reduces cigarette consumption rather than eliminating smoking altogether [74]. Because the effect of smoking cessation on quality of life and survival is not immediately evident, patients require a high level of support to initiate and maintain smoking cessation [75,76]. (See "Overview of smoking cessation management in adults".)

Diabetes — DM is characterized by hyperglycemia, dyslipidemia, and insulin resistance. DM is a powerful risk factor for PAD and is second only to cigarette smoking in contributing to the magnitude of increased risk [4]. Among the more than 10 million people in the United States with PAD, approximately one-third have diabetes mellitus (DM) [15,77-79].

Compared with the general population, the prevalence of DM is higher, but PAD prevalence may still be underestimated in patients in diabetes due to the asymptomatic nature of less severe PAD and often concomitant diabetic neuropathy [15,80-82]. The prevalence of PAD is approximately doubled or more in those with diabetes compared with those without diabetes [4,83]. In a large, multinational meta-analysis, the presence of DM among participants in high-income countries was associated with nearly a twofold increased odds for PAD (OR 1.88, 95% CI 1.66-2.14) [4]. The NHANES study reported an increased risk for PAD in patients with diabetes (OR 2.71, 95% CI 1.03-7.12), a level of risk exceeded only by smokers (OR 4.46, 95% CI 2.25-8.84) [11]. A prospective cohort study with more than 20 years follow-up found an increased risk of death (HR 2.9, 95% CI 1.3-4.0) for patients with diabetes and PAD, compared with those without diabetes [84].

The prevalence of DM increases with age, as does the prevalence of PAD in those with, as well as those without, DM. Among individuals with DM older than 70 years of age attending outpatient medical or vascular surgery clinics in Spain, PAD was detected by screening (ABI <0.90) in more than 70 percent [85]. In addition, among patients with PAD undergoing lower extremity revascularization, approximately 50 percent have concomitant DM [86].

DM may be a more significant risk factor for females for the development of claudication, though data are limited [87]. In a review of the Framingham study cohort, DM in the presence of glycosuria increased the risk of claudication nearly ninefold in females versus 3.5-fold in males [88]. No confidence interval or test for heterogeneity by sex was reported.

While alcohol use has typically been associated with a protective effect, one review found that heavy alcohol use in patients with type 2 diabetes was associated with an increased risk for lower extremity PAD (OR 6.25, 95% CI 1.78-22.65) [89]. The increased risk remained after adjusting for all other factors, including smoking, body mass index, and sex. A dose-response relationship was also found between prolonged alcohol consumption and PAD.

Mechanisms of increased risk — The pathogenesis of atherosclerosis is similar for those with and without diabetes [15]; however, the underlying metabolic abnormalities associated with diabetes enhance this risk and impact the development of PAD [90]. (See "Pathogenesis of atherosclerosis".)

●Increased inflammation — Inflammation as measured by elevated levels of C-reactive protein and high-sensitivity C-reactive protein is an established risk factor for systemic cardiovascular disease, including PAD [91,92]. DM is a hyperinflammatory state, with elevated levels of C-reactive protein and other markers of systemic inflammation [93]. Some of these inflammatory markers may also be important in PAD pathogenesis. As an example, C-reactive protein has procoagulant effects related to its enhancement of tissue factor expression [94]. Hyperglycemia from DM also leads to overproduction of mitochondrial reactive oxygen species (ROS) via the protein kinase C (PKC) pathway, which in turn serves as a causal link between elevated glucose and major adverse vascular outcomes [95]. Once activated, PKC leads to structural and functional changes in the vasculature, including changes in cellular permeability, inflammation, angiogenesis, cell growth, extracellular matrix expansion, and apoptosis [96].

●Endothelial dysfunction — Endothelial dysfunction is extremely common among patients with comorbid DM and PAD. In healthy blood vessels, endothelial cells synthesize nitric oxide (NO), which is a potent vasodilator that inhibits platelet activation and vascular smooth muscle cell migration [15]. Diabetic hyperglycemia induces an imbalance between NO bioavailability and accumulation of ROS, leading to impaired vascular health [95,97-99]. Endothelial dysfunction in diabetes is also a result of increased synthesis of vasoconstrictors and prostanoids [98]. Mitochondrial ROS production also enhances advanced glycation end product (AGE) and AGE receptor signaling [95,100], in turn activating ROS-sensitive biochemical pathways that further induce endothelial dysfunction and vascular homeostasis [100,101].

●Enhanced vasoconstriction — PKC activity also leads to increased production of endothelin-1 (ET-1), leading to enhanced vasoconstriction and platelet aggregation [96]. Notably, endogenous ET-1 has enhanced vascular activity among patients with type 2 DM [102]. In the setting of diabetic hyperglycemia, increased PKC activity alters NO signaling and enhances vasoconstriction [95], two processes important in the pathogenesis of PAD [103].

●Enhanced thrombosis — Among patients with DM, insulin resistance and hyperglycemia contribute to a prothrombotic state, characterized by increased platelet activation and coagulation [104,105]. Insulin resistance increases levels of plasminogen activator inhibitor-1 (PAI-1) and fibrinogen. Patients with DM and poor glycemic control have high levels of PAI-1, and some studies have suggested that treatment with glucose-lowering agents such as glipizide and metformin decrease levels of PAI-1 [106]. In addition, hyperinsulinemia and hyperglycemia can act synergistically to increase monocyte expression of tissue factor, increasing procoagulant activity and thrombin generation [107,108].

Microparticles, which are vesicles released in the circulation from various cell types in response to apoptosis or activation, are increased in patients with DM and independently predict cardiovascular events in patients with stable CHD [109]. Microparticles also increase coagulant activity in the endothelial cells of patients with DM and promote thrombus formation at sites of injury [110]. Increased platelet-derived microparticles are also associated with PAD and may represent a pathway of shared pathogenesis for PAD risk among patients with DM [111].

Finally, platelet hyperreactivity likely has major relevance for macrovascular disease and PAD in those with DM. A number of mechanisms contribute to platelet dysfunction and hyperreactivity in DM [95], many of which may also play a role in the pathogenesis of PAD [111]. Hyperglycemia alters platelet-calcium homeostasis and increases secretion of factors that increase platelet aggregability [112]. Upregulation of glycoproteins Ib and IIb/IIIa among patients with DM interacts with von Willebrand factor and fibrin to trigger thrombogenesis [95].

Diabetes-specific risk factors — PAD often occurs at a younger age in patients with diabetes. Several other factors specifically influence the occurrence of PAD in patients with diabetes, including diabetes duration, diabetes severity, sex, and race/ethnicity, are briefly reviewed below. PAD risk is also associated with peripheral neuropathy, a burning or painful discomfort of the feet or thighs, which often leads to delayed PAD diagnosis [78].

●Duration of diabetes – The duration of diabetes correlates with the incidence and extent of PAD [113,114]. This was shown clearly among 3834 participants in the United Kingdom Prospective Diabetes Study (UKPDS 59), which showed a higher prevalence of PAD among participants with longer durations of DM [115].

●Diabetes severity – Poor glycemic control incrementally increases the risk of atherosclerosis [115,116]. A systematic review identified 13 studies evaluating hyperglycemia and cardiovascular risk reported a 26 percent increase in risk for every 1 percent increase in HbA1c [116]. Even before reaching a diagnostic threshold for DM, 20 percent of patients with dysglycemia alone have an abnormal ABI compared with only 7 percent of patients with normal glucose homeostasis [117]. Other measures of DM severity, such as insulin use, may also be associated with prevalent PAD [118].

●Diabetes-associated vascular calcification – DM is frequently associated with medial arterial calcification, a process distinct from atherosclerosis, and characterized by precipitation of calcium phosphate within the medial layer [119]. Medial artery calcification is strongly associated with diabetes. Further, the combined presence of DM and chronic kidney disease is associated with even higher rates of medial artery calcification. The presence of medial calcification increases the risk for major adverse limb events in those undergoing intervention [120]. Interestingly, the use of metformin is associated with a reduction in the medial artery calcification seen in patients with diabetes [121,122].

Patients with diabetes have more advanced arterial disease at initial diagnosis, increased rates of progression, and are at risk for worse outcomes compared with those without diabetes [113,123]. In addition to poor outcomes, patients with DM are more likely to have arterial disease distal to the knee compared with those without DM [113,124]. (See "Asymptomatic peripheral artery disease", section on 'High-risk for progression' and "Management of chronic limb-threatening ischemia".)

Known atherosclerosis in another vascular bed — Atherosclerosis is systemic disease. Patients with atherosclerotic disease in one vascular bed (eg, coronary, carotid, renal, mesenteric, peripheral) often have disease in other vascular bed. Data from the REduction of Atherothrombosis for Continued Health (REACH) registry indicated that 18 to 35 percent of patients with coronary artery disease and 46 to 68 percent of patients with PAD had atherosclerotic disease in one or more vascular beds [125]. Individuals identified with atherosclerotic disease in any vascular bed have an increased risk for future cardiovascular morbidity and mortality. Disease in more than one arterial bed is associated with a worse prognosis compared with disease confined to a single vascular bed [126]. For many patients with symptomatic atherosclerotic disease elsewhere, PAD is frequently asymptomatic. (See "Asymptomatic peripheral artery disease", section on 'Disease patterns and associated vascular beds'.)

Other subgroups

Chronic kidney disease — Many guidelines do not specifically identify CKD as a risk factor for PAD [9,42,43,127]. Older epidemiologic studies of cardiovascular disease did not report subgroup analyses among patients with CKD [30,49,72,128-134]. However, an association between PAD and CKD is being recognized and reported with increasing frequency. While an increased risk has generally been recognized for patients with severely reduced kidney function (table 1), a growing number of studies have suggested an increased risk for even mild to moderately reduced kidney function [135-137]. As such, CKD is now considered a CHD risk equivalent. (See "Overview of established risk factors for cardiovascular disease", section on 'Chronic kidney disease' and "Chronic kidney disease and coronary heart disease".)

Associated risk factors for PAD among those with CKD are similar to the general population and include smoking, hypertension, and diabetes [138-144]. Among dialysis patients, some traditional risk factors do not appear to be as important. In the HEMO study, hypercholesterolemia, male sex, and hypertension did not correlate with PAD in chronic hemodialysis patients [144]. Similarly, in the United States Renal Data System (USRDS) Dialysis Morbidity and Mortality Study (DMMS), high serum cholesterol and triglycerides were also not significantly associated [138]. Some studies have reported associations supporting a role for nontraditional risk factors (eg, hyperphosphatemia, hyperparathyroidism) in the development of PAD in dialysis patients [138,145,146]. Soft tissue and vascular calcification is reportedly associated with hyperphosphatemia, use of calcium-containing binders, hypervitaminosis D, and dialysis vintage. However, the nature of the relationship between PAD and such vascular calcification has not been clearly established.

PAD appears to be more prevalent among patients with CKD than in the general population. To some extent, this may reflect older age and higher prevalence of known risk factors for PAD among those with CKD. However, even after adjustment for potential confounders, CKD is independently associated with an increased prevalence of PAD, and with the future risk for developing clinically significant PAD [135-137]. There is a higher prevalence of abnormal ABI (≤0.9, >1.3) among patients with a low estimated glomerular filtration rate (eGFR) and in those with albuminuria [147-154]. The highest prevalence of PAD is among those with both a low eGFR and albuminuria [147-154]. However, it is unclear from the existing literature to what extent these associations differ in patients with and without coexistent diabetes.

Even mild-to-moderate CKD increases the risk of incident PAD, with a strong association between albuminuria and amputation. In a large review of over 800,000 individuals in the Chronic Kidney Disease Prognosis Consortium without a known history of PAD, 18,261 of 817,084 cases of incident PAD were recorded during a median follow-up of 7.4 years [155].

Using a baseline eGFR of 95 mL/min per 1.73 m², the risk of incident PAD was:

●For eGFR of 45 mL/min per 1.73 m², HR 1.22 (95% CI 1.14-1.30)

●For eGFR of 15 mL/min per 1.73 m², HR 2.06 (95% CI 1.70-2.48)

Using a baseline albumin-to-creatinine ratio (ACR) of 5 mg/g, the risk of incident PAD was:

●For ACR of 30 mg/g, HR 1.50 (95% CI 1.41-1.59)

●For ACR of 300 mg/g, HR 2.28 (95% CI 2.12-2.44)

Moreover, patients with end-stage renal disease are at increased risk for vascular calcification, which independently increases the risk of cardiovascular morbidity and mortality [156,157]. Calcification is an active cell-mediated process involving key regulatory proteins typically involved in bone formation and structure that become expressed in arterial tissue and lead to ossification of the vasculature. (See "Vascular calcification in chronic kidney disease".)

The prevalence of PAD among patients on dialysis ranges from 15 to 25 percent [138,139,158-160]. Estimates vary in part according to the specific population studied. The diagnosis of PAD in many of the studies is made by chart review or patient questionnaire rather than by diagnostic testing. Therefore, these data probably underestimate the true prevalence of PAD in dialysis patients. A few small studies have measured prevalence in patients using the ABI. The prevalence of abnormal ABI measurements ranged from 4 to 38 percent depending upon the population studied [45,135,147,148,161-165]. Higher estimates are obtained when measures of toe (rather than lower leg) perfusion are used [162]. The prevalence of PAD appears to be particularly high in older dialysis populations. As an example, the North Thames Dialysis study of patients over the age of 70 reported PAD prevalences of 28 and 46 percent among chronic dialysis patients and incident patients, respectively [166]. Patients receiving peritoneal dialysis may have a lower risk of developing PAD compared with those receiving hemodialysis (12.4 versus 20.7 per 1000 person-years) in one Taiwanese study [167].

Patients with CKD are more likely to present with chronic limb-threatening ischemia due to more diffuse and distal disease compared with those who have typical kidney function, possibly reflecting the high prevalence of coexistent diabetes in this population [168]. In a study of 5787 male veterans with chronic limb-threatening ischemia, patients with CKD had more severe disease at presentation [169]. Among those with an eGFR 30 to 59 and <30 mL/min per 1.73 m², more patients presented with ischemic ulceration or gangrene rather than rest pain compared with those with eGFR ≥60 mL/min per 1.73 m² (77 and 87 percent, respectively, versus 70 percent).

One clinical presentation of PAD that is unique to dialysis patients is the interaction between PAD and hemodialysis access. While lower extremity dialysis access is overall uncommon, clinical manifestations of pre-existing PAD may worsen after the creation of permanent hemodialysis access in the lower extremity [170,171]. (See "Hemodialysis access-induced distal ischemia".)

Early-onset disease — Early-onset or premature atherosclerosis is defined as PAD presenting with symptoms prior to 50 years of age. Early-onset atherosclerosis is a subgroup distinct from patients with familial hypercholesterolemia [172,173]. Patients with early-onset atherosclerosis are more frequently male, are active smokers, have diabetes, and more often present with chronic limb-threatening ischemia [174-177]. Outcomes are overall poor in this subset of PAD patients [36,177,178].

Little information exists as to the mechanisms for early-onset atherosclerosis that is not associated with diabetes or chronic kidney disease. A defect in coagulation or fibrinolysis is identified in up to 75 percent of patients [179-181]. In one study, 30 percent had hypercoagulable states, and 47 percent had platelet aggregation defects [179]. In addition, Lp(a) lipoprotein level has been identified as an independent, discriminating risk factor in white males; conventional lipid profiles were similar to controls without premature atherosclerosis, but total oxidative potential was significantly elevated in those with premature disease [182] . (See "Asymptomatic peripheral artery disease", section on 'High-risk for progression'.)

HIV-related disease — The mechanisms by which human immunodeficiency virus (HIV) might increase atherogenesis are unclear but may be related to endothelial dysfunction, platelet activation, and increased inflammation. (See "Cardiac and vascular disease in patients with HIV" and "Asymptomatic peripheral artery disease", section on 'High-risk for progression'.)

Among over 90,000 participants in the Veterans Aging Cohort Study, the rate of incident PAD events per 1000 person-years was significantly higher among HIV-positive compared with HIV-negative veterans (11.9 versus 9.9 percent). The risk was highest among those with time-updated HIV viral load >500 copies/mL and CD4 cell counts <200 cells/mm³ [183]. It is important to note that incident PAD events were defined based upon the reported diagnosis codes, rather than based upon ABIs. Also, since this study was almost exclusively males, it is not possible to determine whether HIV in females confers the same risk.

In a review of patients with an established diagnosis of PAD who have undergone a lower extremity procedure, symptomatic patients with HIV were more likely to present with chronic limb-threatening ischemia compared with those who are asymptomatic (66.2 versus 43.6 percent) [184]. Both asymptomatic and symptomatic patients were also at greater risk for minor and major amputation compared with uninfected controls (minor: 7.5 and 6.7 versus 2.6 percent, respectively; major: 12.9 and 27.4 versus 7 percent, respectively).

OTHER FACTORS AND PAD RISK

Hypertension — Hypertension is strongly associated with the development of atherosclerosis. (See "Overview of established risk factors for cardiovascular disease", section on 'Hypertension'.)

Hypertension together with smoking is a major factor for progression of PAD in patients with diabetes mellitus, but there is no evidence that adequate control of hypertension impacts disease progression [185]. (See 'Diabetes' above.)

In the United States, the prevalence of hypertension in adults is approximately 30 percent [186]. However, among those with an abnormal ankle-brachial index (ABI), the prevalence of hypertension in the Rotterdam Study was 60 percent [187]. The risk of developing symptoms of PAD, such as intermittent claudication, in those with hypertension was twice that of those without hypertension in the Framingham study [30,88]. The United States National Health and Nutrition Examination Survey (NHANES) study found that hypertensive patients also have an even higher prevalence of asymptomatic PAD [11] and, further, that patients with PAD were less likely to have antihypertensive treatment compared with those who have other forms of cardiovascular disease [188]. The association between hypertension and PAD among patients older than 60 years of age was particularly strong in those with untreated and poorly controlled hypertension [46].

In a cohort of over 1.25 million patients aged 30 years or older without baseline cardiovascular disease, including 20 percent with baseline treated hypertension, the associations of several cardiovascular diseases, including PAD with systolic hypertension, diastolic hypertension, or both, were studied [189]. PAD had the strongest association of all cardiovascular diseases with pulse pressure (hazard ratio [HR] 1.23, 95% CI 1.20-1.27). In another large database review that included over 4.2 million individuals, a 20 mmHg higher than usual systolic blood pressure was associated with a 63 percent higher risk of PAD (OR 1.62, 95% CI 1.59-1.66) [190].

Hyperlipidemia — Patients with certain lipid and lipoprotein abnormalities [eg, total cholesterol, low-density lipoprotein cholesterol, triglycerides, lipoprotein(a)] have an increased risk for cardiovascular disease, and adverse long-term cardiovascular outcomes. (See "Overview of established risk factors for cardiovascular disease", section on 'Lipids and lipoproteins' and "Lipoprotein(a)".)

Patients with PAD are more likely to have increased levels of triglycerides and/or cholesterol, lipoprotein(a), apolipoprotein B, and very low density lipoprotein compared with patients without PAD [191-193]. Conversely, the levels of high-density lipoprotein cholesterol and apolipoprotein A-I and A-II levels, the "protective" lipoproteins, are lower in these patients [194].

Lipoprotein(a) is a significant independent risk factor for PAD. Lipoprotein(a) is genetically determined and controlled by a single gene locus. In the Québec Cardiovascular Study, the risk of intermittent claudication was doubled in males with higher concentrations of plasma lipoprotein(a) [195-197]. Patients with premature PAD have lipoprotein(a) levels that are fourfold higher than controls [182]. Lipoprotein(a) levels vary between ethnic populations, with otherwise healthy Black Americans having levels that are almost twice those of White Americans [198].

In the Framingham study, a fasting cholesterol level >7 mmol/L (270 mg/dL) was associated with a doubling of the incidence of intermittent claudication relative to a lower fasting cholesterol level; for each 40 mg/dL increase in total serum cholesterol, the odds of developing symptomatic PAD increased by 1.2 [30]. In the Physicians Health Study, the ratio of total to high-density lipoprotein cholesterol was the best independent predictor of occurrence of PAD [134]. Another study reported a correlation between triglyceride glucose (TyG) index and chronic limb-threatening ischemia [199]. A TyG index of 9.13 was 70.8 percent sensitive and 65.2 percent specific in identifying the risk for chronic limb-threatening ischemia (OR 5.8).

Treatment of hyperlipidemia may decrease the risk of progression of PAD and the incidence of intermittent claudication. In the Heart Protection Study, the cholesterol-lowering agent simvastatin decreased overall mortality by 12 percent, and vascular mortality by 17 percent [200].

Family history and genetic factors — Atherosclerotic disease likely results from the interaction of numerous genes and the environment [201]. Patients with a family history of cardiovascular disease appear to be at increased risk, although the relative contributions of genetics and environmental factors are not fully elucidated but continue to be an active area of investigation. (See "Overview of established risk factors for cardiovascular disease", section on 'Family history' and "Overview of possible risk factors for cardiovascular disease", section on 'Genetic markers'.)

Studies that have investigated heritable factors in the development of PAD include family and twin studies, ABI variance analysis, and gene studies [36,172,173,202-208]. The risk of PAD is increased in families identified with early-onset or premature atherosclerosis, but no single genetic marker has been identified for PAD in this population [36]. (See 'Early-onset disease' above.)

A case control study that compared 2296 patients with PAD with 4390 controls found that a family history of PAD was present significantly more often in patients with PAD than in controls, even after adjusting for conventional risk factors (OR 1.97, 95% CI 1.60-2.42) [209]. The association was stronger in younger subjects (age <68 years), and a greater number of affected relatives with PAD was also more strongly associated with PAD. Several studies have reported that 20 to 50 percent of the variance in ABI can be explained by genetic factors [202-204]. However, in spite of finding such correlations, investigators of the National Heart, Lung, and Blood Institute Twin study found no significant difference in the prevalence of PAD for identical (monozygotic) compared with fraternal (dizygotic) twins (33 versus 31 percent) [202]. In contrast, a study using data from the Swedish Twin Registry and the national patient discharge registry found that traditional cardiovascular risk factors were significantly more prevalent in twins with PAD compared with those without PAD [205]. Concordances and correlations were higher in monozygotic compared with dizygotic twins, suggesting genetic influences in PAD. The risk of PAD for persons whose twin had PAD was significantly increased compared with persons whose twin did not have PAD (OR 17.7, 95% CI 11.7-26.6 for monozygotic twins; OR 5.7, 95% CI 4.1-7.9 for dizygotic twins). Genetic effects accounted for 58 percent of the phenotypic variance among the twins, and nonshared environmental effects accounted for approximately 42 percent.

The chromosome 9p21 (Chr9p21) locus, identified in 2007, was first associated with coronary artery disease and myocardial infarction, but it may have a more general role in vascular pathology [210]. Additional associations have been demonstrated for carotid artery plaque and plaque progression, PAD, and aneurysmal disease. A meta-analysis of possible genetic susceptibility to PAD found no strong supportive evidence for most genetic polymorphisms but did identify three genes that may be important variants (IL6-174 G/C, ICAM1 1462 A/G, and CHRNA3 831C/T) [206]. In one genotyping study, a discovery meta-analysis found a strong association between rs10757269 on chromosome 9 near CDKN2B and ABI [211]. The Million Veteran Program identified similarities and differences among various vascular beds [212]. This genome-wide association study involving over 30,000 individuals identified 19 PAD loci, 11 of which were associated with disease of the coronary, cerebral, and peripheral vascular beds. However, variants in the RP11-359M6.3, HLA-B, CHRNA3, and F5 loci appeared to be specific for PAD and were related to hemostatic mechanisms, potentially highlighting a pathogenic role for thrombosis (figure 1).

Metabolic syndrome — Metabolic syndrome (a constellation of obesity, hypertension, hypercholesterolemia, and insulin resistance) is associated with increased risk for cardiovascular disease. (See "Overview of established risk factors for cardiovascular disease", section on 'Metabolic syndrome'.)

The following studies illustrate the relationship between metabolic syndrome and PAD:

●In a cross-sectional study, 60 percent of patients with PAD also had metabolic syndrome, but the metabolic syndrome score did not significantly correlate with the extent of disease [213].

●In the Second Manifestations of Arterial Disease (SMART) study, patients with PAD and metabolic syndrome had a higher incidence of vascular events (vascular death, stroke, myocardial infarction) compared with patients with PAD and no metabolic syndrome (15 versus 8 percent) [214].

●A prospective cohort study that followed 27,111 females without baseline cardiovascular disease over an average of 13.3 years found that females with metabolic syndrome had a 62 percent increased risk for future symptomatic PAD compared with those without metabolic syndrome [215].

Heavy metal exposure — Excess exposure to heavy metals (arsenic, lead, cadmium, mercury) is associated with incident cardiovascular disease and increased cardiovascular mortality [216-219]. The risk for PAD specifically has been studied for arsenic, cadmium, and lead [220-223]. There are few data as to whether treatment of any of these heavy metal exposures alters PAD risks.

In a review using data from the NHANES, after adjusting for known risk factors, comparing the highest with lowest quartiles, the risk for PAD trended higher for cadmium (OR 2.82, 95% CI 1.36-5.85) and for lead (OR 2.88, 95% CI 0.87-9.47) [221].

In later prospective cohort studies in a Native-American population, increased exposure to arsenic or cadmium was independently associated with incident PAD [223,224]. In one of these studies, arsenic methylation increased the risk for noncompressible vessels (ABI >1.4; HR 2.04, 95% CI 1.02-3.41); however, there was no association for ABI <0.9 [224]. Urine cadmium was also significantly associated with PAD (ABI <0.9) after adjusting for cardiovascular risk factors including smoking status (HR 1.96, 1.32 to 2.81 for the highest versus lowest tertile) [223].

In a separate systematic review, high arsenic exposure was associated with PAD (pooled RR 2.17, 95% CI 1.47-3.20) and also with coronary heart disease (pooled RR 1.89, 95% CI 1.33-2.69) [225]. High arsenic levels may also increase homocysteine levels. (See 'Biomarkers and PAD' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Occlusive carotid, aortic, renal, mesenteric, and peripheral atherosclerotic disease".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Peripheral artery disease and claudication (The Basics)")

●Beyond the Basics topics (see "Patient education: Peripheral artery disease and claudication (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Risk for PAD – Risk factors for peripheral artery disease (PAD) are similar to those that promote the development of coronary atherosclerosis (ie, smoking, hypertension, hyperlipidemia, diabetes, and metabolic syndrome). Other factors include age, sex, ethnicity, family history and genetic influences, and possibly homocysteinemia. However, there are some identified differences in risk factors for PAD versus coronary heart disease (CHD), which may indicate subtle differences in pathophysiology. (See 'Risk for atherosclerosis' above.)

●Prevalence – Sex-related differences in prevalence of PAD have been documented, with PAD cited historically as more prevalent in males compared with females. However, the population-based prevalence of PAD in females has not been fully evaluated. The prevalence of PAD in females is at least as high as that of males across all age groups but increases to a greater extent in females after age 70 compared with males of the same age. (See 'Sex-related differences' above.)

●High risk groups – The American College of Cardiology/American Heart Association (ACC/AHA) guidelines on PAD identified the following at risk for lower extremity PAD. (See 'Prevalence' above.)

•Age ≥70 years

•Age 50 to 69 years with a history of smoking or diabetes

•Age 40 to 49 with diabetes and at least one other risk factor for atherosclerosis

•Known atherosclerosis at other sites (eg, coronary, carotid, renal artery disease)

●Older age – The prevalence of PAD increases progressively with age, beginning after 40 years of age. As a result, PAD is growing as a clinical problem due to the aging population in the United States and other resource-abundant countries. As such, a standard review during the examination of older patients should always include questions related to a history of walking impairment, extremity pain with ambulation, and the presence of nonhealing wounds. (See 'Introduction' above.)

●Cigarette smoking – Individuals over 70 are at a significantly increased risk for PAD due to age alone, while the risk for younger individuals is due to other factors, most commonly cigarette smoking. Early-onset atherosclerosis, or premature atherosclerosis, is defined as PAD presenting prior to 50 years of age. Patients with early-onset atherosclerosis more often present with chronic limb-threatening ischemia and have poor overall outcomes. (See 'Older age' above and 'Family history and genetic factors' above.)

●Diabetes – Approximately one-third of patients with PAD have diabetes mellitus (DM). Underlying metabolic abnormalities in DM enhance the development of atherosclerotic disease. These include increased vascular inflammation, endothelial dysfunction, vasoconstriction, platelet activation, and thrombogenesis. Diabetes-specific risk factors that influence the occurrence include duration and severity of diabetes and the presence of neuropathy. (See 'Diabetes' above.)

●Known atherosclerosis – Patients with known atherosclerotic disease in other vascular beds have an increased risk for PAD. Disease in more than one arterial bed is associated with a worse prognosis compared with disease confined to a single vascular bed.

●Other subgroups – Other subgroups of patients with a further elevated risk for PAD include those with chronic kidney disease (CKD), early onset atherosclerosis, and HIV-related disease. PAD appears to be more prevalent among patients with CKD than in the general population. While the increased risk has generally been recognized for patients with severely reduced kidney function, the risk is increased for even mild to moderately reduced kidney function. (See 'Other subgroups' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Emile R Mohler, III, MD, who contributed to an earlier version of this topic review.