Renal artery stenosis - Causes and pathogenesis

Causes of renal artery stenosis

The cause of renal artery stenosis is described by the concept of risk factors, which is generally accepted for other clinical variants of atherosclerosis. It is generally accepted that atherosclerotic renal artery stenosis is formed by a combination of several cardiovascular risk factors and their severity - "aggressiveness".

Old age is considered the main non-modifiable risk factor for atherosclerotic stenosis of the renal arteries, at which the probability of stenosing atherosclerotic lesions of the visceral branches of the aorta, including the renal arteries, increases many times over.

Atherosclerotic renal artery stenosis is somewhat more common in men, but the difference with women is not pronounced enough to consider male gender as an independent risk factor for atherosclerotic renal artery stenosis.

Disturbances in lipoprotein metabolism are typical for most patients with atherosclerotic renovascular hypertension. Along with hypercholesterolemia, increased LDL levels and decreased HDL, hypertriglyceridemia is typical, often increasing as the renal filtration function impairment worsens.

Essential arterial hypertension often precedes atherosclerotic stenosis of the renal arteries; as it acquires hemodynamic significance, a further increase in arterial pressure is almost always observed. A particularly clear relationship has been established between ischemic kidney disease and an increase in systolic arterial pressure.

Type 2 diabetes mellitus is one of the main risk factors for atherosclerotic renal artery stenosis, which often develops ahead of diabetic kidney damage.

Like other types of atherosclerotic lesions of large vessels (for example, intermittent claudication syndrome), the formation of atherosclerotic stenosis of the renal arteries is also associated with smoking.

The relationship between atherosclerotic stenosis of the renal arteries and obesity has been little studied; however, the importance of obesity, especially abdominal obesity, as a risk factor for atherosclerotic stenosis of the renal arteries is practically beyond doubt.

Among the risk factors for atherosclerotic renovascular hypertension, hyperhomocysteinemia is of particular importance, occurring in these patients significantly more often than in individuals with intact renal arteries. It is obvious that an increase in the plasma homocysteine level is especially noticeable with a significant decrease in SCF.

Atherosclerotic renal artery stenosis in close relatives is usually not detected, although some probable genetic determinants of this disease have been identified. Atherosclerotic renal artery stenosis is associated with a significantly higher frequency of carriage of the D-allele of the ACE gene, including the homozygous (DD-genotype) variant. Predisposition to atherosclerotic renovascular hypertension may also be due to carriage of Asp in the locus 298 of the endothelial NO-synthase gene.

The fundamental difference between atherosclerotic stenosis of the renal arteries and other clinical forms is that as renal failure progresses, along with general population cardiovascular risk factors, these patients develop so-called uremic risk factors (anemia, phosphorus-calcium metabolism disorders), which contribute to further maladaptive remodeling of the cardiovascular system, including the growth of atherosclerotic lesions of the renal arteries.

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Risk factors for renal artery stenosis

Groups	Options
Non-modifiable	Old age Carriage of the D-allele of the ACE gene and Asp in the locus of the 298th gene of endothelial NO synthase 1 Disorders of lipoprotein metabolism (hypercholesterolemia, increased LDL levels, decreased HDL levels, hypertriglyceridemia) Essential hypertension (especially increased systolic blood pressure) Type 2 diabetes mellitus
Modifiable	Smoking Abdominal obesity Obesity Hyperhomocysteinemia 2 "Uremic" factors (disorders of phosphorus-calcium metabolism, anemia)

• ¹ The association has not been definitively established, and the clinical significance is currently controversial due to the unavailability of screening tests.
• ² Can be considered in the group of factors associated with renal failure (“uremic”).

Pathogenesis of renal artery stenosis

The development and progression of atherosclerotic stenosis of the renal arteries is determined by increasing global hypoperfusion of the renal tissue. Intensification of renin synthesis (hyperreninemia is especially noticeable when measured in the renal vein, the artery of which is most narrowed) is supplemented by activation of the local renal pool of angiotensin II. The latter, maintaining the tone of the afferent and efferent arterioles of the glomerulus, for a certain time helps to maintain the SCF and adequate blood supply to the structures of the renal tubulointerstitium, including the proximal and distal tubules. Hyperactivation of RAAS causes the formation or increase of systemic arterial hypertension.

Renal artery stenosis is considered hemodynamically significant if it reduces its lumen by 50% or more. At the same time, factors that aggravate renal tissue hypoperfusion due to a decrease in the circulating blood volume, dilation of the afferent and efferent arterioles of the glomerulus, and embolism of intrarenal vessels can contribute to a significant decrease in SCF, especially tubular ischemia with the development of their dysfunction (the most threatening manifestation of which is hyperkalemia) and with a less significant narrowing of the renal arteries (Table 20-2). In this regard, we can talk about the relativity of the hemodynamic significance of stenosis. The main role in provoking the growth of renal failure in atherosclerotic stenosis of the renal arteries is played by drugs, primarily ACE inhibitors and angiotensin II receptor blockers.

A peculiar variant of the pathogenesis of rapidly progressing deterioration of renal function is characteristic of cholesterol embolism of the intrarenal arteries. The source of emboli is the lipid core of an atherosclerotic plaque localized in the abdominal aorta or, less commonly, directly in the renal arteries. The release of cholesterol detritus with its entry into the bloodstream and subsequent blockage by individual particles of small intrarenal arteries and arterioles occurs when the integrity of the fibrous cap of the atherosclerotic plaque is compromised during catheterization of the aorta and its large branches, as well as when it is destabilized (especially a superficial thrombus) by anticoagulants in inadequately large doses. Cholesterol embolism of the intrarenal arteries can also be provoked by trauma (especially falls and blows to the abdomen). Directly contacting renal tissue, cholesterol causes activation of the C5a fraction of complement, which attracts eosinophils. Subsequently, eosinophilic tubulointerstitial nephritis develops, accompanied by further deterioration of the concentration and filtration function of the kidneys, oligo- and anuria, and a systemic inflammatory response (fever, accelerated ESR, increased serum concentration of C-reactive protein, hyperfibrinogenemia). Hypocomplementemia may reflect the consumption of complement in the inflammatory loci of renal tissue.

Factors causing the increase in renal failure in atherosclerotic stenosis of the renal arteries

Factor	Examples	Mechanism of action
Medicinal Preparations	ACE inhibitors and angiotensin II receptor blockers	Dilation of the afferent and efferent arterioles of the glomerulus with a decrease in intraglomerular pressure and SCF Worsening hypoperfusion and ischemia of renal tubules
	Nonsteroidal anti-inflammatory drugs	Inhibition of intrarenal prostaglandin synthesis Worsening hypoperfusion and ischemia of renal tubules
	Radiocontrast agents	Provocation of increasing dysfunction of the glomerular endothelium Worsening of hypoperfusion and ischemia of the renal tubules due to depression of renal prostaglandin synthesis Induction of tubulointerstitial inflammation
Hypovolemia	Diuretics	Decreased circulating blood volume with increased viscosity Hyponatremia Increased global hypoperfusion of renal tissue, primarily structures of the renal tubulointerstitium
	Malnutrition Syndrome 2	Hypovolemia due to insufficient fluid intake Disorders of electrolyte homeostasis (including hyponatremia) Worsening of global renal tissue hypoperfusion
Renal artery thrombosis and embolism	Thrombosis of the main renal arteries	Worsening of global renal tissue hypoperfusion
	Thromboembolism of intrarenal arteries	Further deterioration of intrarenal blood flow Increased renal fibrogenesis (including in the process of thrombus formation)
	Embolism of intrarenal arteries and arterioles by cholesterol crystals	Further deterioration of intrarenal blood flow Induction of eosinophil migration and activation with the development of acute tubulointerstitial nephritis

• ¹ In inappropriately large doses.
• ² Possible in elderly people with vascular dementia, especially those living alone.

Angiotensin II and other factors activated by hypoxia: TGF-beta, hypoxia-induced factors types 1 and 2, directly modulate the processes of renal fibrogenesis, which is also aggravated by powerful vasoconstrictors (endothelial-1), the hyperactivity of which is supplemented by the suppression of endogenous vasodilator systems (endothelial NO synthase, renal prostaglandins) observed under conditions of chronic hypoperfusion. Many mediators (angiotensin II, TGF-beta) also cause activation of the key factor in the expression of profibrogenic chemokines (nuclear factor kappa B). Its consequence is the intensification of nephrosclerosis processes, realized with the participation of nuclear factor kappa B-dependent chemokines, including monocyte chemotactic protein type 1. With persistent renal hypoperfusion, its expression is primarily increased by epithelial cells of the distal tubules, but subsequently it quickly becomes diffuse. The intensity of fibrogenesis is maximal in the least blood-supplied and most sensitive to ischemia renal tubulointerstitium.

Many factors that cause vascular remodeling (LDL and VLDL, especially those subjected to peroxidation, triglycerides, excess insulin and glucose, advanced glycation end products, homocysteine, elevated systemic arterial pressure transmitted to the glomerular capillaries) also participate in the formation of nephrosclerosis in atherosclerotic renal artery stenosis; the primary target of many of them is glomerular endothelial cells. Along with this, they contribute to further maladaptive remodeling of the vascular wall and myocardium, determining the very high risk of cardiovascular complications typical for patients with ischemic kidney disease.

Morphology of renal artery stenosis

In atherosclerotic renovascular hypertension, the kidneys are reduced in size ("wrinkled"), their surface is often uneven. A sharp thinning of the cortex is characteristic.

Histological examination of kidney tissue reveals signs of generalized nephrosclerosis, most pronounced in the tubulointerstitium, which sometimes causes the formation of a peculiar picture of an "atubular" glomerulus (sharp atrophy and sclerosis of the tubules with relatively intact glomeruli). Hyalinosis of the intrarenal arterioles is characteristic; thrombi, including organized ones, are possible in their lumen.

In cholesterol embolism of intrarenal arterioles, widespread inflammatory cellular infiltrates are found in the renal tubulointerstitium. When using conventional dyes (including hematoxylin-eosin), cholesterol dissolves and voids form at the site of the emboli. The use of dyes that have affinity for cholesterol (for example, Sudan III) allows confirmation of cholesterol embolism of intrarenal arteries and arterioles.

Autopsy of deceased patients suffering from ischemic kidney disease always reveals severe widespread atherosclerotic lesions of the aorta and its branches, sometimes occlusive. Thrombi are found on the surface of many atherosclerotic plaques. Pronounced hypertrophy of the left ventricle is typical, as well as expansion of its cavity. Diffuse atherosclerotic atherosclerosis is often found, in those who have had acute myocardial infarction - large foci of necrosis in the heart, as well as "vascular" foci in the brain, atrophy of its white matter.