Renal artery stenosis: causes and pathogenesis

Causes of stenosis of the renal arteries

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

As the main non-modifiable risk factor for atherosclerotic stenosis of the renal arteries, an elderly age is considered in which the probability of stenosing atherosclerotic lesions of the visceral aorta branches, including the renal arteries, increases manifold.

Atherosclerotic stenosis of the renal arteries is somewhat more common in men, but the difference with women is not sufficiently expressed in order to consider male gender an independent risk factor for atherosclerotic stenosis of the renal arteries.

Disorders of lipoprotein metabolism are typical for the majority of patients with atherosclerotic Renovascular hypertension. Along with hypercholesterolemia, an increase in LDL and a decrease in HDL, hypertriglyceridemia is typical, often increasing as the disturbances in the filtration function of the kidneys worsen.

Essential arterial hypertension often precedes atherosclerotic stenosis of the renal arteries; with the acquisition of hemodynamic significance, they almost always observe a further increase in blood pressure. A particularly clear relationship is established between ischemic kidney disease and an increase in systolic blood pressure.

Diabetes mellitus type 2 is one of the main risk factors for atherosclerotic stenosis of the renal arteries, which often develops ahead of diabetic kidney damage.

Like other variants of atherosclerotic lesion 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, as a risk factor for atherosclerotic stenosis of the renal arteries, is almost unquestionable.

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

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

The principal difference of atherosclerotic stenosis of renal arteries from other clinical forms lies in the fact that as renal failure progresses along with general population cardiovascular risk factors, these patients develop so-called uremic risk factors (anemia, phosphorus-calcium metabolism abnormalities) contributing to further maladaptive remodeling of the cardiovascular system, including the growth of atherosclerotic lesions of the renal arteries.

[1], [2], [3], [4], [5], [6]

Risk factors for renal artery stenosis

Groups	Options
Unmodified	Elderly age Carrying out the D-allele of the ACE gene and Asp at the locus of the 298th gene of endothelial NO synthase 1 Disorders of lipoprotein metabolism (hypercholesterolemia, increased LDL level, decreased level of HDL, hypertriglyceridemia) Essential arterial hypertension (especially an increase in systolic blood pressure) Diabetes mellitus type 2
Modifiable	Smoking Abdominal obesity Obesity Hyperhomocysteinemia 2 Uremic factors (abnormalities in phosphorus-calcium metabolism, anemia)

• ¹ Communication is not definitively established, the clinical significance is currently controversial due to the inaccessibility of screening.
• ² Can be considered in a group of factors associated with renal insufficiency ("uremic").

Pathogenesis of stenosis of the renal arteries

The formation and progression of atherosclerotic stenosis of the renal arteries is determined by the increasing global hypoperfusion of renal tissue. Intensification of the synthesis of renin (hyperenenemia is particularly noticeable in the measurement of the renal vein, whose artery is most narrowed) is supplemented by activation of the local renal pool of angiotensin II. The latter, supporting the tonus of the bringing and delivering arterioles, the glomerulus, for a certain time, promotes the maintenance of GFR and adequate blood supply to the structures of renal tubulointerstitium, including proximal and distal tubules. The hyperactivation of RAAS causes the formation or increase of systemic arterial hypertension.

Hemodynamically significant is believed stenosis of the renal artery, resulting in a decrease in its lumen by 50% or more. At the same time, factors that aggravate kidney tissue hypoperfusion due to a decrease in BCC, dilatation of the glomerulus and arthritis-bearing glomerulus, and embolism of the intrarenal vessels, can contribute to a significant reduction in GFR, especially tubular ischemia with the development of their dysfunction (the most threatening manifestation of this is hyperkalaemia) and with 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 a rapidly progressive impairment of renal function is characteristic of the cholesterol embolism of the intrarenal arteries. The source of the emboli is the lipid core of the atherosclerotic plaque localized in the abdominal aorta or, more rarely, directly in the renal arteries. The release of cholesterol detritus with its entry into the bloodstream and further blockage by separate particles of small intracellular arteries and arterioles occurs when the integrity of the fibrous plaque of the atherosclerotic plaque is disrupted during the catheterization of the aorta and its large branches, as well as in the destabilization of its (especially superficial thrombus) by anticoagulants in inadequately large doses. Provoke cholesterol embolism of the internal arteries can also injuries (especially when falling and striking the stomach). Directly in contact with the renal tissue, cholesterol causes the activation of the C5a fraction of the complement that attracts eosinophils. Later, 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, ESR acceleration, increase in serum C-reactive protein concentration, hyperfibrinogenemia). The consumption of complement in the loci of inflammation of the renal tissue may reflect hypocompletenemia.

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

Factor	Examples	Mechanism of action
Medicinal products Drugs	ACE inhibitors and angiotensin II receptor blockers	Dilatation of the glomerulus-bearing and inferior arterioles with decreased intraluminal pressure and GFR Exacerbation of hypoperfusion and ischemia of the renal tubules
	Non-steroidal anti-inflammatory drugs	Inhibition of the synthesis of intrarenal prostaglandins Exacerbation of hypoperfusion and ischemia of the renal tubules
	Radiopaque preparations	Provocation of glomerular endothelial dysfunction The aggravation of hypoperfusion and ischemia of the renal tubules due to the depression of the synthesis of renal prostaglandins Induction of tubulointerstitial inflammation
Hypovolemia	Diuretics	Reduction in the volume of circulating blood with an increase in its viscosity Hyponatremia Growth of global hypoperfusion of renal tissue, primarily structures of renal tubulointerstitia
	Undernutrition Syndrome 2	Hypovolemia due to insufficient fluid intake Disorders of electrolyte homeostasis (including hyponatremia) Aggravation of global hypoperfusion of kidney tissue
Thrombosis and embolism of the renal arteries	Thrombosis of the main renal arteries	Aggravation of global hypoperfusion of kidney tissue
	Thromboembolism of the intrarenal arteries	Further deterioration of the intrarenal blood flow Strengthening of renal fibrogenesis (including in the process of organization of thrombi)
	Embolism of the internal arteries and arterioles with cholesterol crystals	Further deterioration of the intrarenal blood flow Induction of migration and activation of eosinophils with the development of acute tubulointerstitial nephritis

• ¹ Inappropriately large doses.
• ² Possible in the elderly with vascular dementia, especially those living alone.

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

Many factors that contribute to vascular remodeling (LDL and VLDL, especially those subjected to peroxidation, triglycerides, excess insulin and glucose, end products of glycosylation, homocysteine, increased systemic arterial pressure transferred to the capillaries of the renal glomerulus) also participate in the formation of nephrosclerosis in atherosclerotic stenosis renal arteries; The primary target of many of them are glomerular endotheliocytes. In addition, they contribute to further disadaptive restructuring of the vascular wall and myocardium, determining a very high risk of cardiovascular complications, typical of patients with ischemic kidney disease.

Mofrology of stenosis of the renal arteries

With atherosclerotic Renovascular hypertension, the kidneys are reduced ("wrinkled"), their surface often uneven. It is characteristic of a sharp thinning of the cortical substance.

Histological examination of the kidney tissue reveals signs of generalized nephrosclerosis, which is maximally expressed in tubulointerstitia, which sometimes causes the formation of a peculiar pattern of the "atubular" glomerulus (sharp atrophy and sclerosis of tubules with comparatively preserved glomeruli). Characteristic is the hyalinosis of the intrarenal arterioles; in the lumen of their possible thrombi, including those organized.

With cholesterol embolism of the intrarenal arterioles, widespread inflammatory cell infiltrates are found in renal tubulointerstitium. When using conventional dyes (including hematoxylin-eosin), cholesterol dissolves and voids are formed at the site of the emboli. The use of dyes that have tropism for cholesterol (for example, Sudan III), confirms the cholesterol embolism of the internal arteries and arterioles.

When autopsy died patients suffering from ischemic kidney disease, they always find a severe atherosclerotic lesion of the aorta and its branches, sometimes occlusive. Blood clots are found on the surface of many atherosclerotic plaques. Typical hypertrophy of the left ventricle, as well as the expansion of its cavity. Often there is diffuse atherosclerotic atherosclerosis, in those with acute myocardial infarction - large foci of necrosis in the heart, as well as "vascular" foci in the brain, atrophy of its white matter.