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CHRONIC AND MALIGNANT HYPERTENSION


CHRONIC AND MALIGNANT HYPERTENSION
Chronic hypertension, defined as a baseline blood pressure greater than 140/90 mm Hg, is cited as a leading cause of end-stage renal disease (ESRD), especially among African Americans. The diagnosis of hypertensive kidney disease, or hypertensive nephrosclerosis, is typically made on a clinical basis in those patients who have long-standing hypertension and evidence of renal dysfunction. In most cases, the hypertension is considered essential, meaning known causes (such as renal artery stenosis [see Plate 4-36]) are considered unlikely or have been ruled out.

Although there is firm evidence that uncontrolled hypertension can lead to more rapid progression of existing kidney disease, there is increasing doubt as to whether chronic hypertension is itself a primary cause of kidney disease. Indeed, there is increasing evidence that many individuals diagnosed with hypertensive kidney disease actually have another intrinsic kidney disease, such as focal segmental glomerulosclerosis, that causes hypertension as a secondary effect.

In contrast to the debate regarding chronic hypertension, there is clear evidence that marked and/or sudden increases in blood pressure, known as malignant or accelerated hypertension, can cause renal failure, as discussed in detail at the end of this section.
Chronic Hypertension. Chronic elevations in blood pressure have been associated with numerous microvascular changes in multiple organ systems. In the kidney, these changes are prominent in both the preglomerular and glomerular vasculature.
The arcuate and interlobular arteries appear narrowed secondary to fibroplasia of the intima layer, which results from increased deposition of collagen and elastin, as well as migration of myofibroblasts from the media layer. The afferent arterioles, meanwhile, exhibit a lesion known as hyalinosis, which results from insudation of plasma proteins into the vessel wall, where they accumulate as glassy, acellular deposits.
The glomerular capillaries may exhibit several different patterns of involvement. Some tufts appear normal, whereas others appear either segmentally or globally sclerotic. The pattern of global sclerosis may be further characterized as “obsolescence” or “solidification.” In obsolescence, there is wrinkling of the glomerular basement membrane followed by collapse of the entire glomerular tuft toward the vascular pole. The collapsed tuft becomes sclerotic, whereas the enlarged Bowman space is filled in with collagenous material. Meanwhile, in solidification, the glomerular tuft undergoes hypertrophy and then becomes globally sclerotic without collapse.
Even though hypertension is known to be associated with these histopathologic changes, an ongoing question has been whether mild to moderate hypertension induces a degree of glomerulosclerosis that results in a clinically significant loss of renal function.
Recent evidence suggests that the severity of the glomerular abnormalities seen in the kidneys do not correlate well with the degree of hypertension or the severity of the preglomerular disease. Moreover, it has been noted that in biopsies of patients with the clinical diagnosis of hypertensive kidney disease, “solidified” glomeruli are more common in African Americans compared with Caucasians, and that they are associated with the presence of segmentally sclerotic glomeruli. In contrast, both groups exhibit a comparable number of obsolescent glomeruli.

These findings raise the possibility that hypertension may be occurring in concert with, or as the result of, a primary glomerular disease, especially in African Americans. Indeed, there is emerging evidence that in many African Americans who receive the diagnosis of “hypertensive kidney disease,” hypertension is actually the result of a primary renal disease, rather than its cause. Recent analysis of the APOL1 gene, which encodes apolipoprotein L1, has lent further support to this claim. In large groups of African Americans, the presence of two variant APOL1 alleles was associated with a substantial increase in the risk of biopsy-proven focal segmental glomerulosclerosis and the clinical diagnosis of hypertensive kidney disease. Although the role of apolipoprotein L1 in the kidney is not known, these data suggest that many patients with hypertensive kidney disease actually have focal segmental glomerulosclerosis. Interestingly, the same APOL1 variant that causes renal disease has also been shown to protect against infection with Trypanosoma parasites, which would explain its wide distribution throughout part of the African population.
Thus it appears possible that certain APOL1 alleles confer a survival advantage to heterozygotes but increase the risk of renal disease among homozygotes. This situation would be akin to the wide distribution of certain hemoglobin mutations that confer protection from malarial parasites to heterozygotes but cause sickle cell disease among homozygotes.
Although these findings do not eliminate the possibility that hypertension is a primary cause of renal disease, they do suggest that it could account for a smaller number of ESRD cases than currently estimated.
Numerous studies have shown that treating hypertension can slow the progression of chronic kidney disease. ACE inhibitors and ARBs exert an additional benefit by reducing proteinuria, which further retards progressive glomerulosclerosis and tubular injury.
Importantly, however, the African American Study of Kidney Disease and Hypertension Trial (AASK) demonstrated that in patients with hypertension and renal insufficiency, intensive blood pressure control (target MAP of 92 mm Hg) offers no additional benefit over standard control (target MAP of 102 to 107 mm Hg).
Malignant Hypertension. Although the connection between chronic hypertension and renal disease remains controversial, there is less ambiguity concerning the effects of severe elevations in blood pressure, which can cause the rapid development of microvascular disease. Such disease may manifest as neurologic changes (head-ache, seizures, coma), ocular changes (retinal hemorrhage or exudates, papilledema), and renal disease (acute kidney injury, hematuria, proteinuria).
Although there is no strict definition of malignant hypertension, it is generally considered to occur when diastolic pressure exceeds 110 to 120 mm Hg and there is evidence of associated end-organ damage that includes papilledema. If papilledema is absent but other end-organ damage is seen, “accelerated hypertension” is the preferred term. If there is no evidence of end- organ damage despite a very elevated pressure, “hypertensive urgency” is the preferred term.
In untreated malignant hypertension, the kidney grossly shows subcapsular and cortical hemorrhages, sometimes accompanied by small infarcts. At a microscopic level, the major vascular lesion of afferent arterioles is known as “fibrinoid necrosis,” in which an acellular, eosinophilic mixture of material that stains like fibrin (“fibrinoid”) is deposited into the intima and media. These deposits appear granular, in contrast to the glassy appearance of hyaline deposits. Hemorrhage, thrombosis, and mesangiolysis are often seen. These changes may extend into the glomeruli, usually in a segmental pattern. In the interlobular arterioles, there is often concentric thickening of the intima with mucoid matrix and myointimal cells, which may assume an “onion skin” appearance and occlude the lumen if advanced.
Malignant or accelerated hypertension is a life threatening emergency, and careful lowering of blood pressure (by no more than 25% of the presenting value) should occur over the course of several hours to prevent organ ischemia from impaired autoregulation. Although fibrinoid necrosis heals with improved blood pressure control, the interlobular arteries may remain narrow, producing glomerular ischemia and collapse.

CHRONIC AND MALIGNANT HYPERTENSION

SUMMARY
Based on the above, patients with hypertension and renal disease can be divided into several groups: those with true “essential hypertension” that may result in renal disease; those with a primary renal disease that causes secondary hypertension but is mislabeled as “hypertensive kidney disease”; and those with malignant hypertension in whom renal failure presents acutely.
No matter the cause of the renal disease, it is clear that uncontrolled hypertension leads to progression of renal failure and should thus be treated aggressively. The optimal blood pressure targets, however, remain unknown.