Chapter 13: Vascular Disease in the Elderly Nobuyuki Bill Miyawaki* and Paula E. Lester† *Division of Nephrology and †Division of Geriatrics, Winthrop University Hospital, Mineola, New York PHYSIOLOGIC EFFECTS OF AGING ON stiffening of medium and large arteries lined with BLOOD VESSEL ELASTICITY AND atheromatous plaques. The progressive accumula- COMPLIANCE tion of atherosclerotic plaque continues with aging and often remains silent until lesions reach a critical The aging process is commonly associated with in- stenotic threshold or rupture, leading to dimin- creased vascular rigidity and decreased vascular ished organ perfusion. Arterial stiffening also leads compliance. This process reflects the accumulation to an increase in pulse wave velocity and an en- of smooth muscle cells and connective tissue in the hancement in central aortic systolic pressure.3 The walls of major blood vessels. Endothelial cells and increased waveform velocity allows the backward smooth muscle cells constitute most of vessel wall reflective wave to return earlier back to the heart. cellularity and the remainder of the wall is com- The resulting increases of the left ventricular myo- posed of extracellular matrix including collagen cardial load and the loss of coronary perfusion at and elastin. Although aging has minimal effect on the onset of diastole may potentiate myocardial the muscular tunica media layer thickness, aging ischemia.3 leads to profound progressive thickening of the tu- Common ailments in the elderly including dia- nica intima layer comprised of endothelial cells and betes, dyslipidemia, hypertension, obesity, and cig- an extracellular matrix. In addition, with aging, arette smoking can accelerate the process. Although there is a thinning and separation of individual elas- the exact mechanisms have yet to be elucidated, tin lamellae, as well as an increase in the collagen multiple factors including genetics, advanced glyca- matrix.1 tion endproducts, and oxidative stress likely con- The age-related vascular rigidity and decreased ar- tribute to the pathogenesis of accelerated athero- terial compliance leads to progressive increase in sys- sclerosis. tolic BP, with 25% of patients over 75 yr of age suffer- ing from isolated systolic hypertension.2 Healthy elderly patients without hypertension also show a EFFECTS OF AGING, ATHEROSCLEROSIS, modest increase in peripheral vascular resistance and AND HYPERTENSION ON THE KIDNEYS only a modest related increase in systolic BP.2 Dilation and stiffening of the proximal aorta and its major Renal blood flow declines with aging at a magnitude branches including the brachiocephalic, carotid, and of 6 ml/min per year, with a proportionately larger subclavian arteries occur to a greater extent than the reduction in cortical blood flow than medullary peripheral arteries with aging. This also blunts the ca- flow.2 GFR also declines with aging albeit at a slower rotid baroreceptor sensitivity and increase the risk of rate of 1 ml/min per year. It is unclear if this change end organ damage to the kidneys, heart, and brain.1,2 is caused by the aging process alone or is also attrib- It is important to keep in mind that the presence of utable to hypertension and arteriosclerosis. It is es- pre-existing hypertension and accelerated atheroscle- timated that as much as 26% of all end-stage kidney rosis intensify the vascular pathology discussed to a far disease (ESKD) in the United States is related to greater extent. hypertensive arteriolar nephrosclerosis. This num- Correspondence: Nobuyuki Bill Miyawaki, MD, Winthrop Univer- EFFECTS OF ATHEROSCLEROSIS ON sity Hospital, Division of Nephrology, 200 Old Country Road, AGING Suite 135, Mineola, NY 11501. Phone: 516-663-2169; Fax: 516- 663-2179; E-mail: [email protected] Atherosclerosis is characterized by the progressive Copyright ᮊ 2009 by the American Society of Nephrology American Society of Nephrology Geriatric Nephrology Curriculum 1 ber is expected to grow as the population of the United States Intrarenal Arterioles and Interlobular Arteriolar continues to age.4 Furthermore, it is estimated that 10% of all Disease: Arterial Hyalinosis ESKD is caused by renal artery stenosis.5,6 The ESKD incidence Aging, hypertension, and arteriosclerosis all affect the arte- from renovascular disease has increased in parallel with the rioles in the kidney parenchyma causing afferent and efferent advancing age of the general population in the United States.6 arteriolar atrophy.4 Microcirculatory adaptive changes to the Numerous causes of vascular insult to the kidneys exist as glomerular mass also occur, including impaired autoregula- listed in Figure 1. When classified anatomically by arterial ves- tion with preglomerular vasodilatation. This is associated with sel size, the vascular diseases can be subdivided to those affect- structural and functional hypertrophy of the intact nephrons ing (1) the microscopic vessels in the kidney, (2) arterioles, and leading to glomerular hypertension, albuminuria, and further (3) the main renal arteries. We will focus here on the predom- glomerular sclerosis.4 The histologic changes include hyper- inant forms of vascular insult to the kidneys seen with aging: plastic elastic arteriosclerosis present in the interlobular arter- hypertensive nephrosclerosis, arteriolar hyalinosis, and ath- ies, intimal thickening, reduplication of the lamina elastica in- erosclerotic renal artery stenosis. terna, and mild hyalinization.4 The development of hyperplastic elastic and/or hyaline arteriolosclerosis leads to a Microscopic Vascular Disease in the Kidney With reduction in renal blood flow along with progressive ischemic Aging: Nephrosclerosis changes observed in the cortical glomeruli and renal tubules.4 As systemic hypertension worsens, an increase in renal vascu- lar resistance and a progressive decrease in effective renal Main Renal Artery Disease: Atherosclerotic Renal plasma flow are observed. Although the GFR is relatively main- Artery Stenosis tained, serious renal impairment may occur in as many as 20% Renal artery stenosis (RAS) may be defined as the presence of of essential hypertensive patients. cross-sectional arterial luminal narrowing, which may or may With aging, the total number of functioning glomeruli de- not have any significant hemodynamic effects. Atherosclerotic crease by 30 to 50% as the percentage of sclerotic or abnormal renal artery stenosis leads to an occlusion at the ostium and the glomeruli increases.4 Under ischemic insult from vascular dis- proximal third of the renal arteries. Variability in criteria used ease, the glomeruli in renal cortex show wrinkling of the cap- to define RAS based on anatomical luminal narrowing exist illary basement membrane followed by thickening, collapse, but atherosclerotic RAS often becomes clinically significant and global sclerosis. The initial ischemic changes are reversible. only when the arterial cross-sectional luminal diameter is re- However, with the appearance of hyaline in the capsular space, duced by 70%.6 Hemodynamically significant stenosis leads to the process proceeds to complete glomerular obsolescence. In parenchymal ischemia, atrophy, and loss of kidney function. the deeper juxtamedullary areas, direct channels between af- The exact prevalence of atherosclerotic RAS is unclear, but ferent and efferent arterioles are formed that leads to the for- it has been consistently shown that the risk increases with older mation of aglomerular arterioles. These vascular lesions are age. Based on autopsy series estimates, when renal artery ste- usually distributed in a focal, irregular fashion throughout the nosis is defined as a 50% or greater reduction in luminal diam- renal cortex and result in ischemic changes that follow a similar eter, it is present in 27% of patients in their sixties and 62% of pattern of distribution. However, if the vascular lesions are patients 70 years of age and older.6 The presence of aortic and severe and generalized, the entire kidney may undergo isch- peripheral arterial disease increases the chance of coexisting emic atrophy. atherosclerotic renal arteries. There are several histologic changes seen with aging. Sec- This ischemic insult leads to histologic changes in mul- ondary tubular atrophy, thickening of tubular basement mem- tiple levels. Patchy tubular necrosis and tubular atrophy are branes, and interstitial fibrosis occur. Renal tubules decrease in prominently seen, in addition to focal areas of collagenous number. Additionally, the proximal tubules decrease in vol- filling of Bowman’s space and patchy peritubular leukocyte ume and length, whereas the distal tubules form diverticula and mononuclear infiltrates. Glomerular atrophy with because of alterations in intrarenal vasculature. wrinkling of glomerular capillary tuft and thickening and duplication of Bowman’s capsule is also found. Of note, the Vascular Insult to Kidneys often concurrent extension of atherosclerotic disease into Hypertensive nephrosclerosis the major branches of intrarenal arterioles can lead to the Atherosclerotic renal artery stenosis ischemic glomerular and tubular changes noted above even Fibromuscular dysplasia induced renal artery stenosis in the absence of hemodynamically significant main renal Renal artery thrombosis artery stenosis. Polyarteritis nodosa In response to the chronic vascular ischemic change, corti- Microscopic polyangiitis cal blood flow is redistributed to the deeper corticomedullary Microangiopathic hemolytic anemia circulation