There are many difficulties and uncertainties in studying the relationship between kidney function and peripheral arterial disease, and it is important to weigh out these issues. Measures of kidney function are highly variable, and optimizing ascertainment of kidney function can be difficult due to a lack of understanding of the interactions of kidney disease, diet, and inflammation on the level of serum creatinine, creatinine clearance, and estimation of glomerular filtration rate. Also, peripheral artery disease has many clinical presentations, and those who are asymptomatic may not be captured in studies. This will cause misclassification and bias. Finally, peripheral arterial disease is a chronic condition, and the duration and timing of the disease in relation to kidney function are important to consider. Cross-sectional studies, which are easier to conduct, provide no data on whether the peripheral arterial disease preceded the kidney disease.
The number of people suffering from peripheral arterial disease has increased worldwide in recent decades. The relationship between atherosclerotic disease and kidney function has been identified in previous studies. Findings from the Cardiovascular Health Study and the Atherosclerosis Risk in Communities Study Research Group have suggested that impaired kidney function may be a risk factor for the development of atherosclerotic disease, including peripheral arterial disease. It has also been shown that progression of atherosclerosis, as measured by carotid artery intimal-medial thickness, was associated with a decline in kidney function, specifically in older adults. However, whether kidney function actually boosts the probability of developing peripheral arterial disease has not been quantified.
Understanding Peripheral Arterial Disease
The classic symptom of PAD in the legs is reproducible ischemic muscle pain, known as intermittent claudication, that is relieved by rest. However, many patients with PAD do not report leg pain. They may complain only of fatigue or cramping in the legs, or they may have difficulty walking that they assume is due to aging or arthritis. In the absence of specific questioning about walking and leg symptoms, many patients will not volunteer that they have a symptom potentially caused by PAD. On physical examination, a decreased or absent pedal pulse is the most specific finding for PAD, but it has a limited sensitivity. An abnormal ankle-brachial index (ABI) is a noninvasive means of diagnosis. ABI is calculated by dividing the higher of the two brachial pressures by the higher of the two ankle pressures. An ABI value less than 0.90 is the most reliable noninvasive measure to confirm the diagnosis of PAD. Measurement of the ABI has a 95% sensitivity and specificity for detecting angiographically confirmed PAD of 50% or greater stenosis. However, fewer than 50% of patients who have or exhibit symptoms of PAD will have the ABI measured by primary care physicians or other specialists, and this simple and reliable test is underused in clinical practice.
Peripheral arterial disease (PAD) is a common vascular problem caused by atherosclerosis and associated with a high risk of cardiovascular events and impaired functional status. It has been considered a mere consequence of atherosclerosis; however, it is associated with functional impairment. Local and systemic factors contribute to the functional impairment in PAD. An understanding of the mechanisms by which PAD leads to impaired functional status is important for identification of effective treatments.
Risk factors
This section defines the major risk factors for the development of peripheral arterial disease (PAD). The first section addresses the importance of atherosclerosis as a causative mechanism for PAD. This is in contrast to other popular explanations such as thrombo-embolism, which this review will show to be an exacerbating mechanism for preexisting PAD. The discussion leads to a review of the strong epidemiological evidence supporting diabetes mellitus and cigarette smoking as the two most important risk factors. These are then followed by an examination of the relative importance of lipid disorders and hypertension as risk factors for PAD. The aim is to show how there is a synergy between these risk factors and kidney function, which increases the risk of developing PAD and leads to exaggerated atherosclerosis in other cardiovascular territories. An understanding of the concepts laid out in this section will add weight to the hypothesis that impaired kidney function can be an important factor in increasing the severity and impact of PAD.
Symptoms
Sam: Constricted peripheral blood flow is responsible for the symptoms that most patients with PAD experience in the lower extremities. The severity of symptoms can range from mild to severe, and often the disease is asymptomatic. According to the American Heart Association, the most common symptoms of peripheral arterial disease are summarized by the “5 P’s”: Intermittent claudication or leg pain – this is the most common symptom. In fact, about 2 out of every 3 people with PAD have intermittent claudication. Claudication is leg pain that occurs with exercise and goes away with rest. The location of the pain depends on where the narrowed or blocked arteries are. It usually occurs in the calves, but it can occur in the buttocks, thighs, hips, or feet. If the site of the blockage is high in the leg or in the thigh, you may feel pain in your buttock when you walk. This may be confused with muscle pain from lack of activity or other types of back and hip pain. Limping and pain – Many people who have pain from walking say that they limp to try to avoid getting pain. Changes in your skin and nails – this is a result of reduced blood flow. The skin on the lower legs may get shiny and the toenails thickened with a yellowish hue. Cold feet or legs and color changes. This can happen in one or both legs. Even though these symptoms are specific to PAD, many patients attempt to attribute leg pain to other causes. It is very important to expose a history of said symptoms to further understand a patient’s true condition.
2.3 Diagnosis
Pulse volume recordings (PVR). This test uses inflatable cuffs and a Doppler ultrasonic device to measure the blood pressure in the arms and legs at several different points. A Duplex ultrasound. This is a combination of a traditional ultrasound and the Doppler ultrasound and is used to generate images of the blood vessels. Computerised tomography (CT) or magnetic resonance angiography (MRA). These are types of medical imaging which create visualisations of the inside of the body. Angiography. In this test a special dye is injected into the blood vessels and then X-ray images are captured. This is an invasive test and is usually only performed if a surgical angioplasty or bypass is being considered.
The most important test for diagnosing PAD is the ankle brachial index (ABI). This is a simple and reliable test which measures the blood pressure in the arms and the legs by inflating and then deflating a blood pressure cuff placed around both the arm and the ankle, and comparing the two readings. The test is painless and takes only a few minutes. A Doppler ultrasound is often used in conjunction with the ABI to gauge the severity and exact location of the blockage. If an ABI test is inconclusive or suggestive of PAD but the patient does not exhibit symptoms, an exercise ABI may be performed. This is similar to the ABI test but the readings are taken before and after a short session of exercise, usually walking on a treadmill. If the ABI is still inconclusive then one of the following tests may be employed:
Kidney Function and its Importance
The kidneys, a pair of vital organs, are located at the base of the rib cage in the human body. Their function is to filter waste from the blood, converting the waste to urine. Every day, the kidneys filter over 200 liters of blood and remove about 2 liters of water and waste products. The waste and extra water become urine. This is amongst the most crucial functions of the kidneys and without this process, waste would build up in the blood and damage the body. The kidneys keep the composition of the body’s internal environment stable and this is more clear when it is realized that all the blood in the body is filtered 40 times a day by the kidneys. This stability is at the expense of the kidneys’ own health as they can also become damaged by the toxic substances mentioned above. This is why testing the urine is so often a test of the state of the body and its various organs. Hormones which help to regulate blood pressure, make blood cells and keep bones strong are produced by the kidneys as well. This shows the kidneys also play a very important role in homeostasis by manipulation of the volume and pressure of blood. The final crucial function of the kidneys is the excretion of waste products that are a result of metabolism. There are many diseases which can affect the kidneys, often seriously impairing the kidneys’ ability to filter the blood and sometimes leading to the damage of the other functions. One such disease is diabetes. High levels of blood sugar can damage the blood vessels in the kidneys so it is important for diabetics to monitor blood sugar level. High blood pressure can also lead to many kidney diseases so, like diabetes, it is crucial that this condition is monitored closely. Inflammation of the kidneys and inherited diseases can also be problematic, sometimes leading to the need for a kidney transplant. However, the most common kidney problem is the formation of kidney stones from the build-up of calcium oxalate. A decrease in kidney function can be very detrimental to health and can cause a number of health problems. Kidney impairment and risks that cause it are both independently and strongly associated with increased prevalence of peripheral arterial disease (PAD). The close association between PAD and impaired renal function should alert physicians to consider the coexistence of these conditions and act appropriately to evaluate for both. Due to the immense importance of kidneys as an organ and the extent to which they affect several systems, it is crucial that kidney function is kept at a healthy level by good diet and regular exercise to reduce the risk of diseases, many of which cause irreversible damage.
Role of the kidneys
In terms of cardiovascular health, the kidneys play an integral role in regulating blood pressure. A special type of cell in the kidney called a baroreceptor detects drops in blood pressure and, in turn, causes the release of an enzyme called renin into the blood. This renin converts angiotensinogen from the liver into angiotensin I, which is then converted to angiotensin II in the lungs by an enzyme called angiotensin-converting enzyme (ACE). Angiotensin II has various effects, the main of which are to constrict arterioles and increase the reabsorption of sodium and water into the blood, in turn increasing blood volume and therefore blood pressure. Angiotensin II also stimulates the release of the hormone aldosterone from the adrenal glands, which also causes an increase in blood volume and pressure. High blood pressure can cause damage to the blood vessels in the kidney, and if left untreated, can lead to kidney disease.
Kidneys are essential organs that filter waste and extra fluid from the bloodstream, which is then expelled in the urine. The kidneys are part of the renal system, which also includes the ureters, bladder, and urethra. The kidneys are located in the back of the abdomen, one on each side of the spine. Good kidney function is imperative for the body and the individual to maintain homeostasis. If the kidneys were to fail, waste products and excess fluid would build up in the body, which would cause the individual to feel weak and nauseated and would eventually lead to death.
Common kidney diseases
Kidney disease is a term used to describe any abnormality in kidney structure and/or function and can affect anyone, with prevalence rising worldwide. Chronic kidney disease (CKD) is a global health problem with increasing incidence and prevalence accompanied by poor outcomes and high cost. The prevalence ranges from 11% in Australasia to 23% in the United States, and it is likely that these numbers will continue to rise. CKD is defined as abnormalities of kidney structure or function, present for >3 months, with implications for health. It is associated with an increased risk of cardiovascular disease. It can be a progressive disease leading to end-stage renal failure and also has many adverse secondary health issues associated with it. A classic example of the negative impact of kidney disease on health is end-stage renal failure, with cardiovascular disease accounting for around 50% of deaths in people with this diagnosis and being 10 to 20 times higher in these patients compared to the general population. This shows that kidney disease can actually have an indirect adverse effect on the cardiovascular system, which is contradictory to its original association with the risk of damage to the kidneys from other cardiovascular diseases.
The kidney is a remarkable organ with the ability to sustain life and contribute to a multitude of physiological processes in the human body. Once thought of as a simple waste excretory system, we now know that the kidneys are instrumental in blood pressure regulation through actions on sodium and water balance, erythropoiesis through the production of erythropoietin (a hormone which brings about the formation of red blood cells (RBC)), calcium metabolism through affecting how much calcium is absorbed and excreted from the body, and taking part in immune system function and in situ tissue repair. This is in addition to their regulatory functions in fluid balance and electrolyte composition, all of which are vital for homeostasis maintenance in the body. Therefore, when kidney function starts to decline, the loss of these regulatory mechanisms can negatively impact other body systems and lead to a variety of health issues.
Impact of kidney function on overall health
A recent study has highlighted the potential mechanisms between PAD and decreased kidney function. In an analysis of data from the Cardiovascular Health Study, an elderly community-based population, a cohort of 5888 participants were followed over a mean of 6.2 years for a decline in kidney function. Ankle brachial pressure index (ABPI) and walking speed, a correlate of lower extremity performance and functional status, were measured to assess their relationship with decreased kidney function. Lower ABPI and slower walking speed were independently associated with a decline in kidney function. The study has provided evidence of an association of PAD with a decline in kidney function, and continued research in this area is pivotal to fully understand the causal relationships.
Kidney function has a crucial role in maintaining a delicate balance of bodily chemicals and fluids to preserve health. Changes in kidney function can lead to a series of events leading to kidney failure, which in turn could potentially contribute to an increased risk of cerebrovascular disease and peripheral arterial disease through inflammatory molecules and cytokine release. This process does not occur overnight, and there may be several opportunities for preventive intervention to slow the decline in kidney function and reduce the associated morbidity and mortality from cardiovascular events. Furthermore, the additional impact of PAD on functional status may further limit an individual’s ability to exercise, and regular exercise can often have a positive impact on kidney function. So, there is a lot of cross-talk between PAD and kidney function.
Exploring the Connection between Peripheral Arterial Disease and Kidney Function
4.2 Mechanisms linking the two conditions The mechanism of renal failure in patients with PVD has not been fully delineated. It is likely to be multifactorial and related to the cause of the PVD. For example, in patients with atherosclerosis of the renal arteries, renal failure may occur due to reduced blood flow from plaque formation. Data from the Cardiovascular Health Study showed that PVD was independently associated with a more rapid decline in renal function and a greater incidence of microalbuminuria over follow-up. This suggests that there is a direct detrimental effect of peripheral atherosclerosis on the renal parenchyma. In patients with critical limb ischemia, the mechanism of renal failure may be more straightforward, due to the ischemic muscle damaging kidney function through skeletal muscle myopathy of the diaphragm causing respiratory muscle dysfunction and subsequent hypoxia of the renal parenchyma. This is known as type II muscle fiber atrophy. In connective tissue diseases, acute renal failure and medium vessel vasculitis can occur as a result of PVD.
Given the strong association between PVD and CKD, there is a surprisingly small amount of literature regarding the link between the two conditions. One possible reason for this is the high prevalence of the diagnosis of diabetes mellitus in patients with renal failure due to other causes. Thus, studies looking at the association between PVD and renal failure, whether resulting from diabetes mellitus or not, are difficult to interpret. Shared risk factors between the two conditions include age, smoking status, diabetes mellitus, and hypertension. Diabetic nephropathy is the leading cause of renal failure in the western world and is increasingly being recognized as a major risk factor for cardiovascular disease.
Shared risk factors
With increased understanding of the pathophysiology of atherosclerosis in chronic kidney disease and peripheral arterial disease, consideration of specific risk factor interactions may aid in the identification of a high-risk group for targeted therapy.
Non-traditional risk factors shared between peripheral arterial disease and chronic kidney disease also play an important role in the progression of atherosclerotic disease. High inflammation and oxidative stress, as seen in chronic kidney disease, are independent predictors of cardiovascular events and are highly prevalent in peripheral arterial disease. Anemia, a known risk factor for cardiovascular disease and present in its severe form in many with renal impairment, is also highly prevalent in peripheral arterial disease, increasing susceptibility to tissue ischemia.
Older age, male gender and diabetes have been shown to be independently associated with peripheral arterial disease in the general population. The high prevalence of tobacco use, with its known dose-related association with atherosclerotic vascular disease, is also highly prevalent in chronic kidney disease. In the Strong Heart Study, diabetic patients with impaired renal function were four times more likely to have peripheral arterial disease than non-diabetic patients with normal renal function. The very same traditional atherosclerotic risk factors are also highly prevalent in peripheral arterial disease, undoubtedly contributory to the high cardiovascular mortality in these patients.
As we can see from the literature reviewed in previous chapters, the high prevalence of cardiovascular disease in patients with chronic kidney disease parallels that in patients with diabetes. Indeed, the very same traditional atherosclerotic risk factors – older age, male gender, tobacco use, dyslipidaemia, hypertension and diabetes – commonly identified in patients with established cardiovascular disease, have been shown to be highly prevalent in patients with chronic kidney disease, even in its early stages and in those with diabetes but without diagnosed renal impairment. Such shared risk factors, although not exclusive to those with renal impairment, are of increased prevalence in these patients and, combined with non-traditional risk factors to be discussed, provide a substrate for the high cardiovascular disease burden in kidney disease.
Mechanisms linking the two conditions
In one study, it was found that patients with increased serum creatinine had a significant increase in plasma concentration of soluble vascular cell adhesion molecule-1, and this finding had an independent association with increased prevalence of lower extremity PAD. It has also been shown that in uremia there is increased expression of CAMs and increased adhesion of leukocytes to endothelial cells even without inflammatory stimulus. This suggests that there is a basal level of increased atherosclerotic activity in patients with renal impairment.
An early event in atherogenesis is the adhesion of leukocytes to the endothelial cells of the arterial wall and their migration into the intima. The leukocytes release various growth factors and cytokines which lead to alteration of the endothelial cells and expression of adhesion molecules. Cell adhesion molecules (CAMs) are responsible for the firm adhesion and transmigration of leukocytes. This process is increased in patients with renal impairment and it has been suggested to explain a part of the increased cardiovascular process.
Patients with PAD and renal impairment tend to have a systemic atherosclerotic state. Atherosclerosis is a chronic inflammatory condition considered to be a disease of the arterial wall, initiated by retention of atherogenic lipoproteins within the wall which initiate an inflammatory response. Activation and subsequent recruitment of leukocytes to the area promote oxidation of these lipoproteins and other injurious stimuli leading to uncontrolled growth of vascular smooth muscle cells and stenosis of the artery.
Clinical implications and management strategies
A shared decision-making approach is recommended for CLI patients with renal insufficiency. The risks and benefits of each treatment option must be carefully weighed against the patient’s preferences and values. This is particularly an area where more patient-oriented research is needed to understand the outcomes that are most important to CLI patients with renal insufficiency.
Primary amputation may be a more attractive option to CLI patients with severe renal insufficiency who are poor surgical candidates. However, data suggests that amputation is associated with high mortality and rapid functional decline in patients with renal insufficiency. Therefore, the utility of primary amputation as a strategy to improve quality of life and long-term outcomes in this population is uncertain.
CLI patients with renal insufficiency are faced with a difficult management decision as to whether to undergo revascularization procedures or proceed with primary amputation. Revascularization procedures in patients with renal insufficiency have been associated with higher risks of contrast-induced nephropathy and long-term worsening of renal function. However, data from the PREVENT III trial demonstrated that the long-term survival benefit of aortoiliac revascularization compared to conservative therapy is seen in both patients with and without renal insufficiency. Although the sample size was small, there was no significant difference in the 6-month outcomes of patients with renal insufficiency in the surgical and endovascular revascularization arms in the BEST-CLI trial. However, patients with renal insufficiency have been historically underrepresented in clinical trials and more data is needed to determine the impact of revascularization procedures on both short and long-term kidney function in this population.
Patients with PAD experience a progressive decline in kidney function, with an associated increase in cardiovascular events and death. Even a slight decline in kidney function can lead to increased mortality and cardiovascular events in patients with PAD. Thus, the presence of renal insufficiency in patients with PAD must be considered a high-risk condition.
