In the era prior to the introduction of antihypertensive drugs, malignant hypertension evolved from underlying essential hypertension in more than 50% of patients.⁸ However, more recent series found a lower incidence of primary malignant hypertension, most likely reflecting prevention of malignant hypertension through effective control of blood pressure among patients with essential hypertension.⁹ In a series of patients collected between 1979 and 1985, primary malignant hypertension was found in only 20%.¹⁰ This observation may not apply to black patients, because among blacks, essential hypertension continues to represent the most common underlying etiology of malignant hypertension.¹¹,¹²,¹³ Essential hypertension appears to be a rare cause of malignant hypertension in children. Secondary causes of hypertension such as chronic pyelonephritis, chronic glomerulonephritis, and renovascular hypertension are much more common in this younger age group.¹⁴

The most common secondary cause of malignant hypertension is primary renal parenchymal disease. Chronic glomerulonephritis was reported to underlie the development of malignant hypertension in up to 20% of patients.¹⁰ Unless a history of an acute nephritic episode or long-standing hematuria or proteinuria is available, the underlying glomerulonephritis may be apparent only if a renal biopsy is performed. Underlying IgA nephropathy has been reported as a relatively common secondary cause of malignant hypertension.¹⁴,¹⁵ Vesicoureteral reflux with chronic pyelonephritis may lead to malignant hypertension in children and young adults.¹⁶ Superimposed malignant hypertension may also occur as a complication of analgesic nephropathy.²³ Malignant hypertension may develop as an early or late complication of radiation nephritis.¹⁷ Renovascular hypertension due to either fibromuscular dysplasia or atherosclerotic renal artery stenosis is a well-recognized cause of malignant hypertension. In a series of 123 patients with malignant hypertension, renovascular hypertension was found in 43% of white patients and 7% of black patients.¹⁸ Scleroderma renal crisis is the most acute and life-threatening manifestation of progressive systemic sclerosis. It is characterized by severe hypertension (sometimes malignant) with rapidly progressive renal failure. In one large series, scleroderma renal crisis occurred in 7% of white patients and 21% of black patients with progressive systemic sclerosis.¹⁹ The renal histology in scleroderma renal crisis is often virtually indistinguishable from that of primary malignant nephrosclerosis.²⁰ However, in progressive systemic sclerosis, involvement of the renal vasculature, with proliferative endarteritis involving the interlobular arteries and fibrinoid necrosis of the afferent arterioles, may be a primary event that precedes either hypertension or renal insufficiency.²⁰ The renal ischemia that results from these lesions causes hypertension through activation of the renin-angiotensin system, leading to a vicious cycle of severe hypertension and renal ischemic injury. Scleroderma renal crisis was once a uniformly fatal complication of progressive systemic sclerosis. With the introduction of angiotensinconverting enzyme (ACE) inhibitors as treatment, outcomes have improved significantly, although 39% to 50% of patients with scleroderma renal crisis continue to have poor outcomes, including ESRD and death.

Although malignant hypertension is often a complication of preexisting hypertension, the risk of its development in hypertensive patients is difficult to estimate. In early series the incidence of malignant hypertension among hypertensive patients was 1% to 7%.²¹ In the era of effective antihypertensive therapy for benign hypertension, the incidence of malignant hypertension appears to have declined to some extent. A review of death certificates in New York City between 1958 and 1974 revealed that the overall mortality due to malignant hypertension had declined by 78% from 2.25 deaths to 0.48 deaths/100,000 population/year.²² Although some of the decreased mortality was probably due to successful treatment of patients with malignant hypertension with antihypertensive drugs and dialysis, the authors speculated that the overall incidence of malignant hypertension had declined to less than 1% due to successful treatment of benign hypertension. However, despite recent advances in the treatment of essential hypertension, malignant hypertension is clearly not a disease that has vanished. In the United States, during the period from 1983 to 1992, the number of hospital admissions with malignant hypertension or accelerated hypertension as the primary diagnosis (International Classification of Diseases, ICD-9 Code 401.0) doubled from approximately 16,000 to 32,000. Moreover, the number of admissions in which one of these conditions was listed as a diagnosis tripled from approximately 23,000 to 75,000.²³ Reported experience in a multiracial population in England indicates that malignant hypertension is still common with a small proportion of hypertensive patients presenting with malignant hypertension each year.²⁴ The incidence rate of malignant hypertension for the entire population was approximately one to two cases/100,000/year. Moreover, the
incidence rate did not change over the 24-year period from 1970 to 1993. Recent studies have examined the changing demography of patients with malignant hypertension over the last 40 years.²⁵,²⁶ The incidence rate for malignant hypertension has remained relatively stable over time. In one study from the United Kingdom, 446 patients with malignant hypertension were included.²⁵ Mean age was 48 ± 12 years, 65.5% were male gender, 64.7% white European, 20.4% African-Caribbean, and 14.8% South Asian. No significant demographic differences at diagnosis were evident over the 40 years, with the exception of a significant increase in the proportion of malignant hypertension among ethnic minorities (South Asian and Afro-Caribbeans).

Malignant hypertension tends to occurs more frequently in younger subjects. The mean age of patients with malignant hypertension ranges from 40 to 50 years, with 57% of patients between 30 and 50 years old.²¹ No difference has been found in the age at onset in men compared to women or whites compared to blacks.²¹,²⁷ The age dependency of malignant hypertension could be related to the increased frequency of secondary, more severe forms of hypertension in the young. Alternatively, it is possible that hypertension in patients destined to enter the malignant phase may be more rapidly progressive from the onset, so that the disease would be expected to occur predominantly in younger patients. Malignant hypertension is a rare development in patients beyond the age of 65.²⁸ The declining incidence of malignant hypertension in patients with essential hypertension relative to age is in marked contrast to the overall incidence of benign hypertension, which reaches a peak in the eighth decade. Patients over age 60 with malignant hypertension usually have underlying renovascular hypertension or primary renal parenchymal disease.²¹ In most series of patients with malignant hypertension, males predominate over females by as much as 2 to 1.²¹,²⁷

Blacks have an increased incidence of essential hypertension compared to whites. Moreover, several studies demonstrate that blacks with essential hypertension also have an increased risk of developing malignant hypertension. In a population in which 31% of all hypertensive patients were black, 46% of 200 patients with malignant hypertension were found to be black.²⁹ In a study of 135 pairs of black and white hypertensive patients matched for age and gender, 4.4% of the black patients had retinopathy consistent with malignant hypertension, whereas only 0.74% of the white patients had these funduscopic findings.²⁹ The increased frequency of malignant hypertension among blacks may be due to the fact that they presented later in the course of essential hypertension, that antihypertensive therapy in blacks was inadequate to prevent the development of malignant hypertension, or that essential hypertension may be more aggressive and likely to enter the malignant phase in blacks than whites.³⁰

Although there are occasional case reports in which the malignant phase appears to begin de novo, the majority of patients show evidence of a variable period of preceding benign hypertension before the onset of malignant hypertension. Among 77 patients with malignant hypertension, the documented duration of benign hypertension was 0 to 6 months in 4%, 6 months to 1 year in 10%, 1 to 2 years in 12%, 2 to 4 years in 23%, 4 to 6 years in 16%, 6 to 8 years in 17%, and 8 to 10 years in 4%. Only 14% had benign hypertension for more than 10 years prior to the onset of the malignant phase.²¹

A number of additional risk factors have been associated with hypertensive crisis. These include smoking³¹,³³ and obesity.⁴¹ However, a major under recognized risk factor for hypertensive crisis is nonadherence to therapeutic regimens. In a recent study of 89 patients at a single center, 33 potential risk factors were assessed. Nonadherence to antihypertensive medications was the most important risk identified.³⁴

The most common presenting complaints in patients with malignant hypertension are headache, blurred vision, and weight loss. Less common presenting symptoms include dyspnea, fatigue, malaise, gastrointestinal complaints (nausea, vomiting, epigastric pain), polyuria, nocturia, and gross hematuria. In many series, the onset of symptoms was noted to be remarkably sudden, such that it could often be dated precisely. In contrast, an “asymptomatic” presentation of malignant hypertension is not uncommon, especially in young black males who deny any prior symptoms when they present in the end-stage of the hypertensive process with florid failure of the brain, heart, and kidneys.

Weight loss is a very common symptom early in the course of malignant hypertension, and often occurs before the onset of anorexia or uremia.²¹ In many patients, at least a portion of the weight loss can be attributed to volume depletion resulting from a spontaneous natriuresis with the onset of malignant hypertension.¹⁷,²¹

There is apparently no absolute level of blood pressure above which malignant hypertension invariably occurs. In most series of patients with malignant hypertension, the average diastolic blood pressure is higher than 120 to 130 mm Hg.²¹ However, two series found considerable overlap of blood pressure levels in patients with benign and malignant hypertension.²¹,⁴⁰

Examination of the ocular fundus is of great importance in the assessment of patients with severe hypertension, especially with regard to prognosis.⁴¹,⁴²,⁴³,⁴⁴

Although the original classification of hypertensive retinopathy by Keith⁴⁵ has proven useful, a number of authorities have recommended abandonment of the Keith and Wagener classification in favor of the hypertensive retinopathy classification initially proposed by Fishberg and Oppenheimer.⁴² This classification draws a distinction between retinal arteriosclerosis with arteriosclerotic retinopathy, which is characteristic of benign hypertension, and hypertensive neuroretinopathy, which defines the presence of malignant hypertension (Table 44.3). In essence, two different types of retinal disease occur in patients with hypertension: one that reflects changes induced by arteriolar narrowing (retinal arteriosclerosis) and one that represents acute retinal vascular injury induced by severe hypertension (hypertensive neuroretinopathy).

Retinal arteriosclerosis with or without arteriosclerotic retinopathy is seen in patients with long-standing benign hypertension from either primary or secondary causes. Retinal arteriosclerosis (arteriolosclerosis) is characterized histologically by the accumulation of hyaline material in arterioles. Funduscopic changes reflecting retinal arteriosclerosis include irregularity of the lumen and focal narrowing, arteriovenous crossing changes, broadening of the light reflex, copper or silver wiring, perivasculitis (parallel white lines around blood column), and generalized arteriolar narrowing. Arteriosclerotic retinopathy, which results from this arteriosclerotic process, is manifested by the presence of hemorrhages and hard exudates. The hemorrhages are usually solitary, round, or oval and confined to the
periphery of the fundus. They are caused by venous or arterial occlusion.⁴³ Hard exudates may appear as multiple small white dots that give a powdery appearance to the retina, or they may appear as large glistening spots that are sharply defined from the adjacent retina. Arteriosclerotic retinopathy can also cause localized areas of retinal edema and hemorrhage due to occlusion of small branch veins. However, the principal findings of hypertensive neuroretinopathy, namely, striate hemorrhages, cotton-wool spots, and papilledema, are absent (Table 44.3). The finding of retinal arteriosclerosis in hypertensive patients usually does not imply a poor prognosis.

The lack of clinical significance of retinal arteriosclerosis in hypertensive patients contrasts markedly with the importance and prognostic significance of the finding of hypertensive neuroretinopathy. The appearance of striate hemorrhages and cotton-wool spots with or without papilledema closely parallels the development of severe arteriolar damage (fibrinoid necrosis and proliferative endarteritis) in the circulation of other organs including the brain and kidneys. Hypertensive neuroretinopathy is the clinical sine qua non of malignant hypertension and therefore signifies a far more ominous prognosis than does the finding of retinal arteriosclerosis in benign hypertension.

The appearance of small striate (so-called flame-shaped) hemorrhages is often the first sign that malignant hypertension has developed (Fig. 44.1).

Cotton-wool spots are the most characteristic feature of malignant hypertension and are the result of ischemic infarction of nerve fiber bundles caused by arteriolar occlusion. They usually surround the optic disc and most commonly occur within three disc diameters of the optic disc (Figs. 44.2,44.3,44.4). Cotton-wool spots begin as grayishwhite discoloration of the retina, but within 24 hours they become shiny white with fluffy margins. Red dots may be seen in the bed of the exudate (microaneurysms). Cotton-wool spots are not specific for hypertensive neuroretinopathy and can also be seen with diabetic retinopathy, retinal emboli, and central and branch retinal vein occlusion. However, differentiation of these disorders from malignant hypertension is usually not difficult.

Papilledema can occur in patients with hypertensive neuroretinopathy, but it is not invariably present. In malignant
hypertension, papilledema is usually accompanied by striate hemorrhages and cotton-wool spots (Figs. 44.3 and 44.4). When papilledema occurs alone, the possibility of a primary intracranial process such as a tumor or cerebrovascular accident should be considered.

Hypertensive neuroretinopathy almost always precedes clinically apparent damage in other end organs but there are occasional reports of malignant nephrosclerosis appearing before the onset of hypertensive neuroretinopathy.⁴⁶ It should also be noted that the findings of striate hemorrhages, cotton-wool spots, and papilledema are not specific for malignant hypertension. Funduscopic findings that are indistinguishable from those of hypertensive neuroretinopathy can occur with severe anemia, subacute bacterial endocarditis, systemic lupus erythematosus, polyarteritis, temporal arteritis, and scleroderma. In these disorders the retinopathy may develop even in the absence of hypertension. Central retinal vein occlusion can also mimic hypertensive neuroretinopathy but is usually unilateral, whereas hypertensive neuroretinopathy is almost always bilateral.

Severe hypertension can also affect the choroidal as well as the retinal circulation. Hypertensive choroidopathy can occur with malignant hypertension and is manifested by lesions known as acute Elschnig spots, which are white areas of retinal pigment epithelial necrosis with overlying localized serous detachments of the retina (Fig. 44.5).⁴⁷ The serous retinal detachments may vary from one-third to six disc diameters. Fluorescein angiography reveals staining of the damaged pigment epithelium and leakage into the subretinal space.⁴⁷ Although most patients with this hypertensive choroidopathy also have typical changes of hypertensive neuroretinopathy with striate hemorrhages and cotton-wool spots, if the elevation of blood pressure is relatively sudden, the changes of hypertensive choroidopathy may predominate.⁴⁷

It is important to note that papilledema should not be regarded as an essential requirement for the diagnosis of malignant hypertension. By life table analysis, the 10-year survival rate for hypertensive patients was 46% in patients with hemorrhages and exudates and 48% when papilledema was also present.⁴⁸ The lack of association between papilledema and the length of survival was confirmed using the Cox’s proportional hazards model, which revealed associations between survival and age, smoking habit, initial serum creatinine concentration, and the level of blood pressure control achieved with therapy. No association was found with papilledema. When controlled for these covariates, no association was found between the presence of papilledema and survival (Fig. 44.6). There is no evidence to indicate that the apparent severity of hypertensive neuroretinopathy is predictive of a more severe hypertensive vasculopathy or more advanced end-organ destruction. Papilledema is not always present even when there is severe malignant nephrosclerosis presenting as oliguric acute renal failure. In four series with a total of 25 patients presenting with malignant hypertension and acute renal failure, only 14 patients had papilledema. The other 11 patients had hemorrhages and cotton-wool spots
but no papilledema.⁴⁹,⁵⁰,⁵¹,⁵² This lack of a difference in prognosis for patients with hypertensive neuroretinopathy whether or not it is accompanied by papilledema may be explained by the fact that cotton-wool spots and papilledema share a similar pathogenesis (see later discussion).⁵³,⁵⁴

Malignant hypertension is a progressive systemic vasculopathy in which renal involvement is a secondary and relatively late development. Patients with malignant hypertension may present with a spectrum of renal involvement ranging from minimal albuminuria with normal renal function to ESRD indistinguishable from that seen in patients with primary renal parenchymal disease.²¹,²⁷

The first sign of renal involvement in malignant hypertension is often the abrupt appearance of proteinuria. About 20% of patients also have painless gross hematuria, while 50% have microhematuria.²¹ Quantitation of 24-hour protein excretion in patients with malignant hypertension has revealed less than 2 g in one third, between 2 and 4 g in one third, and more than 4 g in one third of patients.²⁶ The level of protein excretion is of little value in the differentiation of primary (essential) malignant hypertension from malignant hypertension due to secondary causes.²¹,²⁷

Renal size is variable and depends on the duration of prior benign hypertension. In patients with primary (essential) malignant hypertension, the size of the kidneys may be normal to only slightly reduced. In fact, there may be little reduction in renal size even when patients develop terminal renal failure.²¹

The clinical spectrum of renal involvement in malignant hypertension is variable. Four clinical renal syndromes have been described. Progressive subacute deterioration of renal function leading to ESRD occurs in some patients. In patients presenting with malignant hypertension and initially normal renal function, in the absence of adequate treatment, it is common to observe deterioration of renal function with progression to ESRD over a period of weeks to months. The second clinical renal syndrome observed in malignant hypertension is transient deterioration of renal function following the initial control of blood pressure. This well-described entity occurs in patients presenting with mild to moderate renal impairment. In the third clinical renal syndrome, patients with malignant hypertension present with established renal failure. The close similarity between the terminal stage of primary malignant nephrosclerosis and chronic kidney disease with superimposed malignant hypertension has long been recognized. In this regard, it may not be possible to ascertain whether a patient presenting with severe hypertension, hypertensive neuroretinopathy, and renal failure has primary or secondary malignant hypertension. In the fourth clinical renal syndrome, patients with malignant hypertension present with oliguric acute renal failure. Cases of malignant hypertension have been described that were characterized by diastolic blood pressure higher than 130 mm Hg; advanced hypertensive neuroretinopathy; marked weight loss; and with an active urine sediment with proteinuria, hematuria, and red blood cell casts.⁵¹,⁵² Renal size was normal. There was often evidence of microangiopathic hemolytic anemia. Although the initial blood urea nitrogen (BUN) concentration was less than 60 mg per dL, in each case oliguric renal failure occurred and necessitated the initiation of dialysis within a few days of hospitalization. Despite dialytic therapy, the blood pressure was extremely difficult to control and each patient died. Renal histology revealed malignant nephrosclerosis with fibrinoid necrosis
and proliferative endarteritis. The glomeruli were normal except for ischemic changes. Multifocal tubular necrosis was present and presumed to be secondary to ischemia. In most of these patients, the diagnosis of malignant hypertension was delayed because the patients were initially considered to have rapidly progressive glomerulonephritis or systemic vasculitis, which was treated with high-dose steroids. The diagnosis of malignant hypertension was not suspected until autopsy revealed malignant nephrosclerosis.

Clarke and Murphy⁵⁵ detail the neurologic findings among 190 patients with malignant hypertension. CNS involvement was present at some time during the course in 42% of patients. Of the 65 patients for whom a cause of death could be ascertained, 33 had a fatal neurologic event. Of the total deaths, 20% were due to a neurologic cause. Intracerebral hemorrhage occurred in 23 patients. Episodes of focal brain ischemia, presumed due to cerebral thrombosis, occurred in 35 patients. Generalized seizures occurred in 11 patients and focal seizures in 8. Bell’s palsy occurred in seven patients. Primary subarachnoid hemorrhage occurred in four patients. In this series, hypertensive encephalopathy was found in only 1% of patients; however, other series reported a higher incidence.⁵⁶ The clinical presentation, pathophysiology, and treatment of hypertensive encephalopathy are discussed in detail later in this chapter within Hypertensive Encephalopathy.

The most common gastrointestinal (GI) manifestations of malignant hypertension are nonspecific symptoms including nausea, vomiting, and epigastric pain. However, acute pancreatitis has been reported as a rare complication. In a series of 42 patients with malignant hypertension, severe acute pancreatitis that could not be attributed to gallstones or alcohol abuse developed in seven patients.⁵⁷

Patients with malignant hypertension can present with an acute abdomen.⁵⁸ Abdominal exploration revealed necrotic bowel with involvement of the distal ileum and ascending colon. Moreover, malignant hypertension may increase the risk of subsequent development of mesenteric ischemia in patients on chronic hemodialysis.⁵⁹ GI hemorrhage can occur in patients with malignant hypertension due to hypertension-induced necrotizing mesenteric arteriolitis.⁶⁰

A variety of hematologic findings have been observed in patients with malignant hypertension. The hemoglobin concentration at the time of presentation may correlate with the etiology of the malignant phase. A hemoglobin concentration higher than 12.5 g per dL is more often associated with primary malignant hypertension, whereas a lower value is more often associated with chronic glomerulonephritis or pyelonephritis.²¹

There are numerous reports of microangiopathic hemolytic anemia in association with malignant hypertension. In one series of 24 patients with malignant hypertension, 16 were found to have evidence of microangiopathic hemolysis.⁶¹ Other significant abnormalities reported with malignant hypertension include thrombocytopenia, increased fibrin degradation products, increased factor VIII levels, increased fibrinogen, and increased urokinase sensitivity consistent with decreased fibrinolysis.⁶²

Congestive heart failure can be a presenting feature of malignant hypertension. Moreover, heart failure, alone or in combination with uremia, was a common cause of death prior to the advent of effective antihypertensive drugs. Heart failure in patients with malignant hypertension is predominantly left-sided with pulmonary congestion resulting in orthopnea, paroxysmal nocturnal dyspnea, cardiac asthma, and recurrent episodes of acute pulmonary edema. Peripheral venous congestion with dependent edema or hepatic congestion may be minimal or absent even when death results from congestive heart failure.

Angina and acute myocardial infarction, although common with long-standing benign hypertension, are uncommon with malignant hypertension.²¹ Aortic dissection is also rare in patients with malignant hypertension.²²

Evidence of activation of the renin-angiotensin-aldosterone axis is present in many, but not all, patients with malignant hypertension.⁶³ Among 53 patients with malignant hypertension not secondary to renal artery stenosis, 55% had increased plasma renin activity (PRA).⁶⁴ Among 25 patients with malignant hypertension secondary to renal artery stenosis, PRA was consistently elevated.⁶⁴

Aldosterone secretion rate has been studied in patients with malignant hypertension.⁶⁵ There was a marked increase in secretion rate in seven of eight patients with malignant hypertension (papilledema present), and in five of eight patients with accelerated hypertension (retinal hemorrhages without papilledema). The aldosterone secretion rate in these patients was often higher than that seen in patients with aldosterone-producing adenoma.

Hypokalemic metabolic alkalosis was found in up to 50% of patients with malignant hypertension, presumably reflecting a state of hyperreninemia and secondary hyperaldosteronism.⁶⁵ After effective therapy, aldosterone hypersecretion can persist long after volume depletion is corrected and renin levels have returned to normal. Thus, the findings of hypokalemia, increased urinary potassium losses, and aldosterone hypersecretion with suppressed PRA may mimic the findings of primary hyperaldosteronism.⁶³

Hyponatremia is not uncommon in patients with malignant hypertension, particularly when sodium restriction is instituted. Patients with malignant hypertension due to renal artery stenosis occasionally present with the striking hyponatremic hypertensive syndrome.⁶⁶,⁶⁷ The characteristic features of this syndrome include severe hypertension, hypertensive neuroretinopathy, polyuria, polydipsia, weight loss, and salt craving. Biochemical changes include hyponatremia, hypokalemia, and low total exchangeable sodium and potassium, with markedly elevated PRA, angiotensin II, aldosterone, and arginine vasopressin (AVP) levels. This syndrome may result from a vicious cycle of volume depletion with further activation of the renin-angiotensin-aldosterone axis as a result of a pressure-induced natriuresis from the contralateral kidney.

With malignant nephrosclerosis, small pinpoint petechial hemorrhages may be present on the cortical surface, giving the kidney a peculiar flea-bitten appearance. The renal size varies depending on the duration of preexisting benign hypertension or the presence of underlying primary renal parenchymal disease. When terminal renal failure occurs in patients with primary malignant hypertension, the kidneys may be normal in size.³⁷ However, when secondary malignant hypertension is superimposed on primary renal disease, the kidneys may be small.

Fibrinoid necrosis of the afferent arterioles has traditionally been regarded as the hallmark of malignant nephrosclerosis (Fig. 44.7).²¹ The characteristic finding is the deposition in the arteriolar wall of a granular material that appears bright pink with hematoxylin and eosin stain. On trichrome staining, this granular material is deep red. This fibrinoid material is usually found in the media, but it may also be present in the intima. Histochemical and immunofluorescent techniques have identified this material as fibrin. Within the media, muscle fibers cannot be identified and cell nuclei are lost or fragmented. Whole or fragmented erythrocytes may be extravasated into the arteriolar wall. The hemorrhages that occur may account for the petechiae observed on the cortical surface. The arteriolar lumen may be reduced in size as a result of wall thickening and intraluminal fibrin thrombi. Infrequently, polymorphonuclear leukocytes and monocytes may infiltrate the arterioles, giving the appearance of necrotizing arteriolitis.

The interlobular arteries reveal characteristic lesions variously referred to as proliferative endarteritis, productive endarteritis, endarteritis fibrosa, or the onionskin lesion. The typical finding is intimal thickening that causes moderate to severe luminal narrowing. In severely affected vessels, the luminal diameter may be reduced to the size of a single red blood cell. Occasionally, there is complete obliteration of the lumen by a fibrin thrombus.

Traditionally, three patterns of intimal thickening in malignant nephrosclerosis have been described.⁶⁸ The onionskin pattern consists of pale layers of elongated, concentrically arranged, myointimal cells. Delicate connective tissue fibrils give rise to a lamellated appearance (Fig. 44.8). The media often appears as an attenuated layer stretched around the expanded intima. Mucinous intimal thickening consists of a scarcely cellular lesion containing a lucent, faintly basophilic-staining
amorphous material (Fig. 44.9). In fibrous intimal thickening, there are hyaline deposits, reduplicated bands of elastica, and coarse layers of pale connective tissue with the staining properties of collagen (Fig. 44.10). In rare cases, fibrinoid necrosis may also be apparent in the interlobular arteries.⁶⁸

The renal histology in blacks with malignant hypertension may be somewhat different.⁶⁹,⁷⁰ Although fibrinoid necrosis of the afferent arterioles is not found, there is instead a marked degree of arteriolar hyalinization. In addition, there is a prominent and characteristic finding in the larger arterioles and interlobular arteries known as musculomucoid intimal hyperplasia (Fig. 44.11).⁶⁹,⁷⁰,⁷¹ The arterial walls are thickened due to the presence of hyperplastic smooth muscle cells. A small amount of myxoid material, which stains light blue with hematoxylin and eosin, is observed between the cells. With periodic acid-Schiff staining this material resembles basement membrane. Staining for acid mucopolysaccharide suggests the presence of chondroitin sulfate and possibly hyaluronic acid.

By electron microscopy, in each of the above-mentioned types of intimal thickening, the most abundant cellular element is a modified smooth muscle cell called a myointimal cell. In these cells there are smooth musclelike ultrastructural features including cytoplasmic myofilaments and abundant rough endoplasmic reticulum.⁶⁸,⁷² In the pure onionskin variant, the intercellular space is occupied by multiple strands of nonperiodic fibrils with the ultrastructural features of basement membrane.⁶⁸ In the mucinous variant, broad electron-lucent zones with scattered finely granular material are found in the intercellular space.⁷² With the fibrous variant, numerous bundles of collagen, recognizable by characteristic banding, are dispersed between the myointimal cells.⁷²

In patients who have received antihypertensive therapy, as well as blacks with treated or untreated malignant hypertension, the most characteristic glomerular lesion in malignant nephrosclerosis is accelerated glomerular obsolescence secondary to the intense ischemia produced by the obliterative arterial lesions.⁷⁰,⁷³ The earliest glomerular changes consist of thickening and wrinkling of the basement membrane (Fig. 44.12).⁷⁵,⁷⁸ Later, there is shrinkage of the tuft such that it does not fill Bowman’s space. There is laminar reduplication of Bowman’s capsule around the shrunken glomerulus.⁶⁸ The end stage is the obsolescent glomerulus, which is an avascular, wrinkled glomerular tuft surrounded by a collagenous scar that fills Bowman’s space (Fig. 44.13). Focal segmental glomerulosclerosis may occur in primary malignant hypertension either as the result of glomerular hyperfiltration or fibrinoid necrosis, and may contribute to renal dysfunction. In an autopsy series of 38 black South Africans with primary malignant hypertension, mucoid intimal hyperplasia was present in all sections whereas fibrinoid necrosis was seen in 76%. Glomerulosclerosis was present in 38 cases, and was axially distributed in 18%, segmental in 58%, and global in 24% of sections. Cases with segmental sclerosis tended to have the highest proteinuria, whereas those with global glomerulosclerosis had the highest serum creatinine levels.⁷⁴

By electron microscopy, the lamina densa of the glomerular capillary basement membrane is thickened and wrinkled (Fig. 44.14).⁷³ Eventually, the entire basement membrane becomes thickened. These glomerular changes are not specific for malignant nephrosclerosis as they also can occur in scleroderma renal crisis, hemolytic-uremic syndrome, and even severe benign nephrosclerosis. However, the glomerular changes in malignant nephrosclerosis differ from the simple ischemic
obsolescence observed in benign hypertension. In addition to the wrinkled basement membrane observed in benign nephrosclerosis, there is constriction of the glomerular vascular bed in malignant nephrosclerosis due to the deposition of a new subendothelial layer of basement membrane material inside the original basement membrane (Fig. 44.15).⁷³ The new capillary lumen formed by this process is smaller, resulting in decreased blood volume in the ischemic glomerulus.

In malignant nephrosclerosis, the tubules may be atrophied and focally destroyed in areas supplied by severely narrowed arteries. Occasional tubules may be dilated and filled with eosinophilic cast material.⁷⁵ In the interstitium in these areas, there may be a fine reticular fibrosis and chronic inflammatory cells. In malignant hypertension, as in primary renal parenchymal diseases, renal insufficiency appears to correlate best with the degree of tubular atrophy.⁷⁰

Immunofluorescence microscopy in patients with malignant nephrosclerosis has demonstrated deposition of gamma globulin, fibrinogen, albumin, and sometimes complement components in the walls of arterioles demonstrating fibrinoid necrosis by light microscopy.⁸¹ Some of the glomeruli, especially those with focal necrosis, may contain immunoglobulin, albumin, and complement. Fibrinogen may be found diffusely along capillary basement membranes. Fibrinogen may also be found in the intima of interlobular arteries that by light microscopy show cellular or mucinous thickening.⁷⁶

Striking juxtaglomerular hyperplasia has been reported in patients with malignant hypertension.⁷⁷ This ultrastructural finding is consistent with the hyperreninemic state often noted clinically.

Effective antihypertensive therapy may alter the pathology of malignant nephrosclerosis.⁷⁸,⁷⁹,⁸⁰ Within days, there may be resolution of fibrinoid necrosis, which leaves behind residual hyaline deposits in the arteriolar wall. In contrast to benign nephrosclerosis in which arteriolar hyaline change is often subendothelial, in treated malignant hypertension the hyaline material may be present throughout the entire vessel wall. Fibrosis of the arterioles with collagen replacement of the arteriolar muscle and elastica may also occur. Within several weeks after initiation of therapy, segmental fibrinoid necrosis in the glomeruli may also resolve, leaving behind an area of hyaline deposition that can mimic focal segmental glomerulosclerosis (FSGS). Furthermore, with treatment, in the intima of the interlobular arteries there may be an evolution from cellular hyperplasia to a more fibrous form of intimal thickening. A newly formed internal elastic lamina often separates this new collagen from the narrowed lumen. Heptinstall has postulated that the cellular lesion is an early finding implying active disease, whereas the acellular fibrotic lesion is a later process often reflecting a response to treatment.⁷⁵ These modifications in the interlobular arteries that occur following treatment may not be accompanied by any increase in the caliber of the lumen. Severely narrowed interlobular arteries often do not improve and the renal parenchyma distal to these arteries undergoes severe ischemic atrophy and scarring.⁷⁹ However, the nephrons supplied by interlobular arteries of normal caliber may undergo substantial hypertrophy following treatment of malignant hypertension. These histologic changes may explain the improvement in renal function that sometimes occurs in some patients following institution of antihypertensive therapy with resolution of malignant hypertension.

In summary, although fibrinoid necrosis was the hallmark of malignant nephrosclerosis in untreated patients at autopsy, it is now rarely observed. In treated patients with malignant hypertension or blacks with untreated malignant hypertension, closed renal biopsy most often reveals marked intimal hyperplasia of the interlobular arteries in association with accelerated glomerular obsolescence.⁷⁰,⁷³

The funduscopic changes associated with hypertensive neuroretinopathy are reversible with control of blood pressure.¹¹⁰ Striate hemorrhages cease to form as soon as the blood pressure is controlled. Clearance of existing hemorrhages takes 2 to 8 weeks. Cotton-wool spots may continue to form for several days after the blood pressure is controlled. The cellular (axonal) debris that comprises the cotton-wool spots is cleared away within 2 to 12 weeks. Hard exudates clear more slowly. A macular star may require more than a year to resolve completely. Papilledema often continues to increase during the first few days of treatment. However, in the majority of patients, it resolves slowly over several weeks. In contrast, the changes reflecting retinal arteriolosclerosis such as arteriolar narrowing, arteriovenous crossing defects, and changes in the light reflexes usually persist despite adequate blood pressure control.¹¹⁰