Renovascular diseases Doç. Dr. Işın Doğan Ekici

DISEASES INVOLVING BLOOD VESSELS Nearly all diseases of the kidney involve the renal blood vessels secondarily. Systemic vascular diseases, such as various forms of arteritis, also involve renal blood vessels, and often the effects on the kidney are clinically important. The kidney is intimately involved in the pathogenesis of both essential and secondary hypertension. Here we will cover the renal lesions associated with benign and malignant hypertension.

Benign Nephrosclerosis The term used for the renal changes in benign hypertension, is always associated with hyaline arteriolosclerosis. Some degree of benign nephrosclerosis, albeit mild, is present at autopsy in many persons older than 60 years of age. The frequency and severity of the lesions are increased at any age when hypertension or diabetes mellitus are present.

Pathogenesis It should be remembered that many renal diseases cause hypertension, which in turn is associated with benign nephrosclerosis. Whether hypertension causes the nephrosclerosis, or a subtle primary microvascular renal injury causes the hypertension, which in turn accelerates the sclerosis, is not known. Thus, this renal lesion is often seen superimposed on other primary kidney diseases. Similar changes in arteries and arterioles are seen in individuals with chronic thrombotic microangiopathies.

Grossly, the kidneys are symmetrically atrophic, each weighing 110 to 130 gm, with a surface of diffuse, fine granularity that resembles grain leather. Microscopically, the basic anatomic change is hyaline thickening of the walls of the small arteries and arterioles, known as hyaline arteriolosclerosis. This appears as a homogeneous, pink hyaline thickening, at the expense of the vessel lumina, with loss of underlying cellular detail. The narrowing of the lumen results in markedly decreased blood flow through the affected vessels and thus produces ischemia in the organ served.

All structures of the kidney show ischemic atrophy. In advanced cases of benign nephrosclerosis the glomerular tufts may become globally sclerosed. Diffuse tubular atrophy and interstitial fibrosis are present. Often there is a scant interstitial lymphocytic infiltrate. The larger blood vessels (interlobar and arcuate arteries) show reduplication of internal elastic lamina along with fibrous thickening of the media (fibroelastic hyperplasia) and the subintima

Clinical Course This renal lesion alone rarely causes severe damage to the kidney except in susceptible populations, such as African Americans, where it may lead to uremia and death. However, all persons with this lesion usually show some functional impairment, such as loss of concentrating ability or a variably diminished GFR. A mild degree of proteinuria is a frequent finding.

Malignant Hypertension and Malignant Nephrosclerosis Malignant hypertension is far less common in the United States than benign hypertension and occurs in only about 5% of persons with elevated blood pressure. It may arise de novo (i.e., without preexisting hypertension), or it may appear suddenly in a person who had mild hypertension. In less developed countries, it occurs more commonly.

Pathogenesis The basis for this turn for the worse in hypertensive subjects is unclear, but the following sequence of events is suggested: The initial event seems to be some form of vascular damage to the kidneys. This most commonly results from long-standing benign hypertension, with eventual injury to the arteriolar walls. The result is increased permeability of the small vessels to fibrinogen and other plasma proteins, endothelial injury, and platelet deposition. This leads to the appearance of fibrinoid necrosis of arterioles and small arteries and intravascular thrombosis.

Mitogenic factors from platelets (e.g., platelet- derived growth factor) and plasma cause intimal smooth hyperplasia of vessels, resulting in the hyperplastic arteriolosclerosis typical of malignant hypertension and of morphologically similar thrombotic microangiopathies (see below) and further narrowing of the lumina. The kidneys become markedly ischemic. With severe involvement of the renal afferent arterioles, the renin-angiotensin system receives a powerful stimulus, and indeed persons with malignant hypertension have markedly elevated levels of plasma renin.

This then sets up a self-perpetuating cycle in which angiotensin II causes intrarenal vasoconstriction, and the attendant renal ischemia perpetuates renin secretion. Aldosterone levels are also elevated, and salt retention undoubtedly contributes to the elevation of blood pressure. The consequences of the markedly elevated blood pressure on the blood vessels throughout the body are known as malignant arteriolosclerosis, and the renal disorder is referred to as malignant nephrosclerosis.

Morphology The kidney may be essentially normal in size or slightly shrunken, depending on the duration and severity of the hypertensive disease. Small, pinpoint petechial hemorrhages may appear on the cortical surface from rupture of arterioles or glomerular capillaries, giving the kidney a peculiar, flea-bitten appearance. The microscopic changes reflect the pathogenetic events described earlier. Damage to the small vessels is manifested as fibrinoid necrosis of the arterioles.

The vessel walls show a homogeneous, granular eosinophilic appearance masking underlying detail. In the interlobular arteries and larger arterioles, proliferation of intimal cells produces an onion-skin appearance. This name is derived from the concentric arrangement of cells whose origin is believed to be intimal smooth muscle, although this issue is not finally settled. This lesion, called hyperplastic arteriolosclerosis, causes marked narrowing of arterioles and small arteries, to the point of total obliteration.

Clinical Course The full-blown syndrome of malignant hypertension is characterized by: diastolic pressures greater than 120 mm Hg, papilledema, encephalopathy, cardiovascular abnormalities, and renal failure. Most often, the early symptoms are related to increased intracranial pressure and include headache, nausea, vomiting, and visual impairment, particularly the development of scotomas, or spots before the eyes.

At the onset of rapidly mounting blood pressure there is marked proteinuria and microscopic, or sometimes macroscopic, hematuria but no significant alteration in renal function. Soon, however, renal failure makes its appearance. The syndrome is a true medical emergency that requires prompt and aggressive antihypertensive therapy before irreversible renal lesions develop. About 50% of patients survive at least 5 years, and further progress is still being made. Ninety percent of deaths are caused by uremia and the other 10% by cerebral hemorrhage or cardiac failure.

Thrombotic Microangiopathies As described in, this term describes lesions seen in various clinical syndromes, characterized morphologically by widespread thrombosis in the microcirculation and clinically by microangiopathic hemolytic anemia, thrombocytopenia, and, in certain instances, renal failure. Common diseases that cause lesions of thrombotic microangiopathy include: (1) childhood hemolytic uremic syndrome (HUS), (2) various forms of adult HUS, and (3) thrombotic thrombocytopenic purpura (TTP).

Pathogenesis Although clinically overlapping, HUS and TTP are pathogenetically distinct. Central to the pathogenesis of HUS is endothelial injury and activation, with resultant intravascular thrombosis. TTP is now known to be caused by an acquired defect in proteolytic cleavage of von Willebrand factor (vWF) multimers, or more rarely, an inherited defect as seen in familial TTP. The defect involves a von Willebrand factor protease referred to as ADAMTS 13 (a disintegrin and metalloprotease with thrombospondin-like motifs).

Childhood HUS is the best characterized of the renal syndromes. As many as 75% of cases follow intestinal infection with Shiga toxin-producing E. coli, such as occurs in epidemics caused by ingestion of infected ground meat (e.g., hamburgers) and infections with Shigella dysenteriae type I.

The pathogenesis of this syndrome is related to the effects of Shiga toxin, which is carried by neutrophils in the circulation. Renal glomerular endothelial cells are targets of this toxin because the cells express the membrane receptor for the toxin. The toxin has multiple effects on the endothelium, including increased adhesion of leukocytes, increased endothelin production, and loss of endothelial nitric oxide (both favoring vasoconstriction), and (in the presence of cytokines, such as tumor necrosis factor) endothelial damage. The toxin also gains entry to the cells and directly causes cell death. The resultant endothelial damage leads to thrombosis, which is most prominent in glomerular capillaries, afferent arterioles, and interlobular arteries, as well as vasoconstriction, resulting in the characteristic thrombotic microangiopathy

Approximately 10% of the cases of HUS in children are not preceded by diarrhea caused by Shiga toxin-producing bacteria. In a subset of these patients there is mutational inactivation of complement regulatory proteins (e.g. factor H), which allows uncontrolled complement activation following minor vascular injuries. This then promotes the formation of thrombi.

Morphology In childhood HUS, there are lesions of classic thrombotic microangiopathy with fibrin thrombi predominantly involving glomeruli, and extending into arterioles and larger arteries in severe cases. Cortical necrosis may be present. Morphologic changes in glomeruli resulting from endothelial injury include widening of the subendothelial space in glomerular capillaries, duplication or splitting of GBMs, and lysis of mesangial cells with mesangial disintegration. Chronically, scarring of glomeruli may develop.

Clinical Course Typically, childhood HUS is characterized by the sudden onset, usually after a gastrointestinal or flulike prodromal episode, of bleeding manifestations (especially hematemesis and melena), severe oliguria, hematuria, microangiopathic hemolytic anemia, and (in some persons) prominent neurologic changes. This disease is one of the main causes of acute renal failure in children. If the renal failure is managed properly with dialysis, most patients recover in a matter of weeks. The long-term (15- to 25-year) prognosis, however, is not uniformly favorable, because about 25% of children eventually develop renal insufficiency due to the secondary scarring.

Summary; Vascular Diseases of the Kidney Benign nephrosclerosis: Progressive, chronic renal damage associated with benign hypertension; characterized by hyaline arteriolosclerosis and narrowing of vascular lumens with resultant cortical atrophy. Malignant nephrosclerosis: Acute renal injury associated with malignant hypertension; arteries and arterioles show fibrinoid necrosis and hyperplasia of smooth muscle cells; petechial hemorrhages on the cortical surface; often culminates in acute renal failure. Thrombotic microangiopathies: Disorders characterized by fibrin thrombi in glomeruli and small vessels resulting in acute renal failure; childhood hemolytic uremic syndrome is caused by endothelial injury by an E. coli toxin; thrombotic thrombocytopenic purpura is caused by defects in von Willebrand factor leading to excessive thrombosis, with platelet consumption.