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.
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.
