In the earliest stages, most patients are asymptomatic, and the condition is recognized only at routine examination, when injury to the vessels may already be present. Symptoms that may be recognized include headache, epistaxis, tinnitus, and dizziness, but symptoms are unusual. Excessive weight, smoking, abnormal serum lipid patterns, and diabetes mellitus are common. Repeated blood pressure readings are necessary to establish the diagnosis and to determine the appropriate therapy (77). The prevalence of hypertension is increasing in children. As in adults, these patients do not present with symptoms but are detected on routine evaluation. Hypertension in children is defined as the average of at least three determinations of systolic and/or diastolic blood pressure ≥95% for gender, age, and height (78). Kaelber and Pickett (79) have devised a table to help determine which children should undergo further evaluation following a first reading of elevated blood pressure.

As the duration of hypertension lengthens at any age, evidence for complications may become manifest. The target organs of hypertension include the heart, brain, peripheral arteries, eye, and kidney (80,81). Hypertension accelerates atherosclerosis in the systemic circulation, whereas the lowerpressure pulmonary circulation rarely develops atherosclerotic plaques even in the face of elevated serum lipids (81). The chief manifestations of hypertensive injury in the heart include concentric left ventricular hypertrophy, congestive heart failure, atrial fibrillation, and coronary artery atherosclerosis, leading to increased risk of myocardial infarction (80,81,82). Additional cardiovascular risk is seen in hypertensive patients with the metabolic syndrome (83) defined as three or more of the following conditions: abdominal obesity, triglycerides greater than 150 mg/dL, high-density lipoprotein cholesterol less than 40 mg/dL in men or 50 mg/dL in women, blood pressure greater than 130/85 mm Hg or being treated for hypertension, and a fasting glucose greater than 110 mg/dL. Hypertension is associated with cerebral hemorrhage due to lesions in the penetrating vessels in the midbrain or due to rupture of berry aneurysms. Additional cerebrovascular complications of hypertension include stroke and vascular dementia (80). Aortic aneurysms as well as claudication are well-known peripheral artery manifestations of hypertension. Hypertension may cause retinal arteriolar thickening, hemorrhage, exudates, or papilledema (77). Hypertensive injury to the kidney is manifest chiefly by the appearance of microalbuminuria and/or decline in estimated glomerular filtration rate (eGFR) (84).

The current classification of hypertension no longer uses the term malignant hypertension (1). However, this term remains in the literature. In the past, malignant hypertension was defined as severe elevation of arterial pressure in combination with funduscopic changes including retinal hemorrhages and exudates with or without papilledema (85). It is often accompanied by target organ damage. It affects less than 1% of patients with essential hypertension, and its incidence has not declined since its description (86). The clinical symptoms may include visual disturbances, headache, headache with visual disturbance, heart failure, stroke or transient ischemic attack, or dyspnea (87). Hematuria is present in as many as 21% of patients, and some patients have gross hematuria. Significant proteinuria is present in 63.4% of patients and was associated with higher serum creatinine levels (87).

Malignant hypertension may occur without any history of hypertension, or it may be preceded by a period of essential hypertension. It may also complicate secondary forms of hypertension such as renal parenchymal disease, renal artery stenosis, various endocrinologic causes of hypertension, or cocaine abuse (86,88). Lane et al. (86) studied 446 patients (64.5% were men) with malignant hypertension who had been admitted to or were referred to City Hospital, Birmingham, England, between 1964 and 2006. Of these patients, 54.3%
had a history of essential hypertension. The remaining patients had secondary hypertension caused by renal artery stenosis, renal parenchymal diseases, or other such conditions. They found an incidence of 1 to 2 cases of malignant hypertension per 100,000 per year and found no apparent decline over the 40 years of the study. An excess of black and Asian patients has been noted relative to the number expected for the population studied in several cohorts (86,89). Survival has increased with the introduction of more effective antihypertensive drugs. In particular, patient survival has increased from 33% to 90% over the past 40 years (86) with 10-year renal survival of 84% (90). Factors involved in determining survival include creatinine at presentation and successful control of blood pressure and proteinuria during follow-up (86,90).

The cause of the switch from benign to malignant hypertension is not yet fully understood. Many authors have suggested that the renin-angiotensin axis may be paradoxically stimulated by an ischemic renovascular bed stemming from microvascular damage due to increased blood pressure (91,92). This theory has been supported by a transgenic model of malignant hypertension that has been developed by the insertion of the mouse Ren-2 renin gene into Sprague-Dawley rats (93). The affected rats had increased blood pressure and typical renal changes of malignant hypertension and died at 50 to 90 days of age. Heterozygotes showed target organ damage in the heart and kidney but no other characteristics of malignant hypertension. This model has been further refined by inserting the Ren-2 renin gene fused to the cytochrome P450 1a1 (Cyp1a1) promoter (94) that allows controlled inducible angiotensin II-dependent hypertension. Study of this model shows the expected pathologic findings of malignant hypertension and allows therapeutic manipulation. For example, administration of aliskiren, which directly inhibits renin, normalizes blood pressure in these rats (95). Patients with malignant hypertension have elevated plasma renin activity and aldosterone. These levels correlate to markers for intravascular hemolysis and renal function in patients with malignant hypertension (92).

The glomeruli may be normal or may simply show age-related changes (110). A few globally sclerosed glomeruli are seen in all adults despite the absence of increased blood pressure. Sclerosed glomeruli may disappear and sometimes one may find such “disappearing glomeruli” that appear to merge into the surrounding renal parenchyma (Fig. 20.2). In hypertensive nephropathy two additional types of glomerular changes are seen: ischemic glomeruli and solidified ones (111). The earliest change is that of collapse of the capillary loops with apparent thickening of their walls on hematoxylin and eosin
(H&E)-stained sections. Periodic acid-Schiff (PAS) reaction or silver stain, however, shows that the apparent thickening is chiefly due to wrinkling of the capillary basement membrane (Fig. 20.3). With time, the entire glomerular tuft shrinks and retracts to the vascular pole. This is accompanied by the filling in of the Bowman space by a faintly eosinophilic material. H&E-stained sections of such glomeruli reveal only pink, nondescript balls (Fig. 20.4). However, PAS staining demonstrates the shrunken tuft as well as mild thickening of the Bowman capsule (Fig. 20.5). Furthermore, the material filling the Bowman space is PAS negative, a characteristic staining pattern for collagen. This change may begin in the hilar portion of the tuft, but it soon fills the entire space emptied by the shrinking glomerulus (112) until it becomes obsolescent.

The solidified glomerulus is characterized by an increase in the mesangial matrix, which results in either segmental or global solidification (sclerosis) of the glomerular tuft (Fig. 20.6), extending to the Bowman capsule without collagenization of the Bowman space. Such glomeruli frequently contain hyalinosis lesions and represent “decompensated benign nephrosclerosis” (DBN) (113,114). This term is used by Bohle et al. to describe those cases of benign nephrosclerosis in which many glomeruli show prominent hyalinosis accompanied by mesangial widening. In a study of hypertensive patients, these authors found that 775 kidneys showed the obsolescent glomeruli described above accompanied by hyaline arteriolosclerosis. An additional 251 patients had the solidified glomeruli of DBN (114). These latter patients developed chronic renal failure within a few years and had higher levels of blood pressure, proteinuria, and higher
serum creatinine than patients with solely ischemic lesions. Solidified glomeruli are readily distinguished from obsolescent glomeruli by use of the PAS staining technique. Marcantoni et al. (74) recognized these solidified glomeruli of DBN in a higher proportion of African American hypertensive patients than in Caucasians. They also reported a higher frequency of segmental sclerosis in the patients with DBN. Thus, this alteration may represent a secondary form of focal segmental glomerulosclerosis (FSGS). Kincaid-Smith (115) has suggested that the increase in segmental glomerular lesions may be related to the increase in the association between the metabolic syndrome (chiefly obesity and insulin resistance) and hypertension. She posits that these factors are producing the segmental glomerular sclerosis rather than the hypertension. Kidneys with hypertensive nephrosclerosis also may contain a population of hypertrophied glomeruli (116). Hill et al. (116,117) have described pathologic differences in the afferent arterioles supplying these different types of glomeruli. This is addressed below in the discussion of the pathogenesis of these changes.

Several other glomerular alterations have been noted in the kidneys from hypertensive patients. First, the podocyte number is decreased in hypertensive nephrosclerosis accompanied by increased urinary podocin, nephrin, and synaptopodin as compared to healthy controls (118). Reduced podocyte numbers have been described in a number of renal diseases with glomerulosclerosis. Hoy et al. (119) have demonstrated lower glomerular number in hypertensive American whites and Australian Aborigines. However, there was no difference in nephron number in hypertensive blacks from the United States as compared to nonhypertensive blacks. However, the mean glomerular volume was greater in hypertensive blacks as compared to nonhypertensive controls (119). Finally, the juxtaglomerular apparatus (JGA) is slightly enlarged with respect to numbers of cells in patients with benign hypertension compared with normotensive controls (120).

The glomerular changes in accelerated (malignant) hypertension may be acute or chronic (121,122,123). They are identical to those seen in secondary forms of malignant hypertension in association with a preexisting renal parenchymal disease; the alterations described here are superimposed on the changes of the respective condition. The acute changes are focal; most glomeruli appear unchanged. The most obvious change is that of fibrinoid necrosis, which is usually segmental (Fig. 20.7). This lesion is eosinophilic, but it is most easily seen with a silver stain, which demonstrates interruption of the glomerular basement membrane (GBM). Furthermore, the intense eosinophilia of the area of necrosis stands in sharp contrast to the black staining of the GBM and mesangial matrix (Fig. 20.8). The mesangial matrix may also show loosening, so-called mesangiolysis. The fibrinoid necrosis may extend from the afferent arteriole, or it may be peripheral and associated with a crescent. Fibrin, which accounts for the eosinophilia of the lesion, may also be seen in other capillary lumina within the glomerular tuft or may accumulate under endothelial cells. Endothelial cells of arterioles and capillaries may become swollen and obscure the lumen. Fibrin platelet thrombi with red blood cell fragments may also be seen (Fig. 20.9). In other glomeruli, the predominant alteration is one of intense congestion with dilation of the capillary lumina (Fig. 20.10). The final acute alteration is that of thickening of capillary walls in open capillary lumina. Silver stain demonstrates double contours indicative of subendothelial widening and new basement membrane formation (Fig. 20.11) (see also Chapter 18)

The chronic changes are of two different types. The first is similar to that seen in benign hypertension, in that there is collapse of the tuft with wrinkling of the GBM accompanied by collagenization of the Bowman space. This change may occur with or without a preceding period of benign hypertension, although it is much more prominent in patients with a history of hypertension. In the second type, glomeruli are also collapsed, but seem almost acellular and, on silver stain, show the subendothelial widening described earlier in the preceding paragraph. Thus, the collapsed glomeruli have evolved from those that showed subendothelial widening.

The tubules in either benign or malignant hypertension may be atrophic and sometimes contain hyaline casts. The epithelial cells are flattened and surrounded by a thickened tubular basement membrane, which may be wrinkled. Such atrophic areas often alternate with zones of tubules with dilated lumina and tall hypertrophied epithelial cells (Fig. 20.12). Such zones form the granularity seen on the capsular surface of gross specimens. The size of the scars, or fields of atrophic tubules, depends on the diameter of the narrowed vessel supplying the area, thus determining the number of nephrons affected. Although such atrophic tubules are frequently near an obsolescent glomerulus, this is not always the case, a finding that may reflect the greater susceptibility of tubules to ischemia. Actual loss of tubules may also occur suggested by glomerular crowding. If the patient has proteinuria, protein reabsorption droplets may be present in the tubular epithelial cells. In patients with sudden onset of malignant hypertension, patchy necrosis of tubules may be evident, and there may be cortical infarcts. Such areas are more common in scleroderma-associated TMA than in that associated with malignant hypertension (see also Chapter 18.)

The interstitium is widened in areas with atrophic tubules. Increased collagen is noted. Chronic inflammatory cells, usually small lymphocytes, may be widely dispersed in the areas of scarring; however, larger aggregates of lymphocytes may be present in the scars in subcapsular zones. Mast cells are increased in the interstitium early in hypertensive nephropathy (124). Morphometric studies by Grund et al. (125) have shown a correlation between the amount of interstitium and the serum creatinine level. These authors hypothesized that the renal intertubular capillaries had diminished cross-sectional area resulting from interstitial fibrosis and that this change may have contributed to the decrease in the GFR. They did not determine whether the fibrosis preceded the loss of capillaries or vice versa. The chronic hypoxia hypothesis as a model for the progression of renal disease was first suggested by Fine et al. (126). One of the mechanisms for this is damage to the tubules due to reduced blood flow through the peritubular capillaries (111). The mechanisms are further discussed below. The changes in accelerated hypertension are similar to those seen in benign nephrosclerosis.

The changes vary with the size of the vessel involved and also differ among individual patients. Arcuate and larger arteries show the alterations typical of atherosclerosis, as manifest by fibrous intimal thickening that results in reduction of the vessel lumen. The internal elastic lamina may show splitting, which is best seen with either a silver or elastic stain. This change is different from the abrupt breaks seen in vasculitis. Lipidcontaining macrophages are not usually evident except in the intima of the main renal artery or its branches. In cases in which malignant hypertension is primary, and not secondary to a period of lower levels of hypertension, the larger arteries may not show any alteration. Otherwise, the arteries are similar in appearance to those seen with any level of hypertension.

Interlobular arteries show fibroelastic intimal thickening with reduplication of the internal elastic lamina (Fig. 20.13). The degree of intimal thickening in arteries is closely linked to this change in arterioles (127). The media may be thickened in small arteries and/or arterioles (Fig. 20.14), reflecting hypertrophy, hyperplasia, or remodeling. In any case, lumen size is decreased, and this decrease may be the result of remodeling, alterations in stiffness or compliance, and functional abnormalities. Remodeling and functional changes are discussed below. Stiffness may be dependent on alterations in the amount and type of collagen, the collagen-elastin ratio, and the presence of proteoglycans (128). The latter has been described in humans. An abnormal interaction among these elements may also lead to increased stiffness (128). In patients with accelerated hypertension, the smaller of the interlobular arteries may also show fibrinoid necrosis, which is a segmental change causing localized destruction of a vessel (Fig. 20.15). However, thickening of the intima with mucoid matrix and widely spaced, concentrically arranged cells are more typical changes (Figs. 20.16). The matrix has sparse collagen in a basophilic edematous-appearing
matrix. This thickened intima may also show lipid-containing macrophages as well as reduplication of the elastic lamina (Fig. 20.17). Elastic reduplication is particularly prominent in those patients who had a prolonged period of benign hypertension before the onset of malignant hypertension. In these cases, the intimal thickening is luminal to the elastic reduplication. The intimal thickening extends along most of the length of the vessels and causes marked narrowing of the lumen that results in the devastating ischemic alterations that can cause renal failure. The most common terms used to describe this lesion are onionskin thickening, endarteritis fibrosa, and musculomucoid intimal thickening. These alterations in the kidney in malignant hypertension, including the findings of fibrinoid necrosis of the afferent arteriole, glomerulitis, and onionskin thickening of small arteries, were first described by Volhard and Fahr (129).

Arterioles are commonly affected by hyaline arteriolosclerosis, a change that is also present in the aging kidney. Hill (111) prefers the term arteriolar hyalinosis as the hyaline deposits occur in areas of loss of smooth muscle or arteriomalacia. Burchfiel et al. (130) found that the risk of arteriolar hyalinization increased with increases in diastolic blood pressure. The severity of arteriolar hyalinization also correlates with the degree of larger artery intimal thickening (131). This lesion is characterized by the presence of homogeneous eosinophilic material, sometimes with lipid in the subendothelium of the arterioles (Fig. 20.18). It may extend into the media and is more easily seen using the PAS stain (Fig. 20.19). Use of the
term hyalin suggests that it appears glassy, to distinguish it from the more granular texture of fibrinoid necrosis, a lesion typical of the malignant phase of hypertension discussed below. In a morphometric study, Hill et al. (116) noted that arteriolar hyalinosis increased in frequency in hypertensive kidneys as compared to age-matched controls without hypertension. Furthermore, these vessels had larger luminal diameters and an increase in vascular smooth muscle and the extracellular matrix, resulting in a larger outer circumference. The afferent arterioles with hyalinosis were associated with either hypertrophied glomeruli or glomeruli with FSGS. These changes reflect the loss of autoregulation that may occur with hypertension resulting in transmission of elevated pressure through the dilated vessels and on to the glomerulus.

The characteristic lesion of severe (malignant) hypertension is fibrinoid necrosis. Eosinophilic material with a granular texture supplants the medial smooth muscle cells with loss of cell nuclei (see Fig. 20.15). This granular material must be differentiated from the glassy appearance of arteriolar hyalinosis, the more typical lesion of benign hypertension (see Fig. 20.18). Of course, arteriolar hyalinosis may also be present in patients with malignant hypertension, but the identification of true fibrinoid necrosis suggests the diagnosis of the accelerated phase. Fibrinoid necrosis also impinges on the vascular lumen. Areas of fibrinoid necrosis can be distinguished easily with the use of the PAS/Jones (silver) and the recognition of the granular texture rather than the glassy appearance of hyalin. The elastic lamina of the vessel wall as well as the interstitium between smooth muscle cells stain black from the silver. This finding is in sharp contrast to the bright pink staining of the fibrinoid material. Masson trichrome stain also delineates fibrinoid necrosis well as the fibrin stains bright red (Fig. 20.20). Thrombus formation is often superimposed on the area of necrosis, resulting in complete occlusion of the vessel. Fragmented red blood cells are frequently seen within either the thickened intima or the vessel wall, evidence of TMA (Fig. 20.21). Mixed inflammatory cells are occasionally present, but their presence is not necessary to make the diagnosis.

Hughson et al. (132) in a study of patients with malignant nephrosclerosis identified nodules in small arteries and arterioles. These nodules were composed of spindled cells with a vascular network similar to the plexiform lesion seen in pulmonary hypertension. He hypothesized that the pathogenesis was due either to arterial necrosis or organization of thrombi or to a combination of the two, with the necrosis occurring first followed by the thrombus. Hughson also suggested that the intimal hyperplasia was due to turbulent blood flow. These changes were seen most commonly in the kidneys, followed by the periadrenal fat, pancreas, intestines, gallbladder, and heart.

The term malignant nephrosclerosis was first used by Fahr (133) in a description of the renal pathologic characteristics of a patient who had an accelerated or malignant form of hypertension. Bohle et al. (134) examined the issue of malignant nephrosclerosis in great detail. They divided their patients into two groups: one with the changes of fibrinoid necrosis in glomeruli and arterioles and the other with onionskin alterations in the intima of arteries. They designated the first group with either normal blood pressure or recent onset of hypertension as primary malignant hypertension. Bohle et al. believed that in these cases, the renal vascular morphologic changes preceded the hypertension. The other group had long-standing accelerated hypertension and was considered secondary malignant hypertension. The authors believed that the vascular changes in these cases were caused by the hypertension. Patients in the primary malignant hypertension group were younger than those in the secondary group. Furthermore, women outnumbered men, and the primary group had more severe hemolytic anemia and often presented in acute renal failure. The changes are those of TMA (discussed in Chapter 18) and are the same as seen in hemolytic-uremic syndrome,
thrombotic thrombocytopenic purpura, renal involvement in systemic sclerosis (scleroderma), toxicity of certain drugs such as cyclosporine and mitomycin C, and complications of radiation and bone marrow transplantation. It is characterized by fibrinoid changes in both glomeruli and renal arterioles accompanied by fragmented erythrocytes (see Fig. 20.20). The glomeruli may also show collapse and wrinkling of the tuft. The renal arterioles and small arteries show intimal thickening, often with a mucoid appearance resulting in marked narrowing of their lumina. As suggested in the name, thrombotic occlusion of the lumen is often superimposed on this narrowing.

The question of the primacy of malignant levels of hypertension in the pathogenesis of these microangiopathic lesions is still controversial. Most of the cases I see now that have the changes I consider representative of malignant nephrosclerosis are superimposed on the kidneys with primary glomerular disease. In these patients, severe renal parenchymal disease is present, and the history is consistent with preexistence of the glomerular disease before the onset of the malignant levels of hypertension. Thus, they can be considered as cases of secondary malignant hypertension. However, I have also seen a patient with IgA nephropathy and the changes of malignant nephrosclerosis in whom glomerular disease was not severe and the tubules and interstitium showed only focal fibrosis and atrophy. Nevertheless, the arteries showed changes consistent with the malignant hypertension, which was present clinically. In that case, I believe that the malignant hypertension was separable from the renal parenchymal disease and was thus primary or essential malignant hypertension. In most cases with microangiopathic changes, malignant hypertension is prominent clinically. However, I have seen the alterations of TMA without documentation of malignant levels of hypertension. In one particularly memorable case of scleroderma renal crisis, the patient never had a recorded blood pressure exceeding 120/80 mm Hg yet had spectacular fibrinoid necrosis of both glomeruli and arterioles.

The observations of Wilson and Byrom (174) using the 2K1C rat model, in which a renal artery from one kidney is clipped to reduce blood flow to induce hypertension, form the basis of much of our understanding of the pathologic manifestations of hypertension in the kidney. In this model, the clipped kidney is protected in the short term from hypertension, while the nonclipped kidney is exposed to the elevated systemic pressure and, as a result, manifests both glomerular and vascular injury. Changes in the nonprotected glomeruli include segmental or global necrosis with adhesions and eventual total sclerosis of the tuft. Fibrinoid necrosis is present in afferent arterioles and small renal arteries. These alterations are present in human malignant hypertension. Studies in various other experimental models of hypertension have confirmed these findings (175,176,177).

Many different experimental models of hypertension have been developed and are summarized by Dornas and Silva (17). Inhibition of the synthesis of NO synthase by nitro arginine methyl ester (NAME) produced vasoconstriction (156). When NO synthesis was inhibited for 2 months, blood pressure was elevated, the GFR decreased, proteinuria occurred, and glomerular injury appeared. Addition of sodium chloride to the diet exacerbated the hypertension and the glomerular injury (178). The glomerular lesions included glomerular collapse, segmental necrosis, and segmental glomerulosclerosis. Those glomeruli that showed collapse had decreased perfusion, whereas those glomeruli with either sclerosis or necrosis had been exposed to increased pressures.

Although ischemia due to vasoconstriction or luminal narrowing seems likely to be important in the collapsing form of glomerular injury in hypertension, it does not adequately explain all the alterations seen. Increased glomerular pressure may occur due to increased post-glomerular pressure, leading to increased pressure within the glomerulus itself. Early evidence that the direct transmission of increased pressure to the glomerulus could induce injury came from the studies of Byrom (179), in which removal of the clip from animals with 2K1C hypertension produced acute glomerular injury. More studies have supported the concept that increased glomerular pressure, whatever its pathogenesis, can be crucially important as a mechanism for direct glomerular injury. This increased glomerular capillary pressure results from the loss of effective afferent arteriolar constriction in the face of increased systemic pressure (i.e., loss of autoregulation) confirmed by micropuncture studies in various experimental models of hypertension (180,181,182). Autoregulation refers to the ability of the kidney to maintain renal blood flow and GFR in a narrow range despite wider variation in systemic blood pressure. This is accomplished chiefly through two mechanisms, namely, a myogenic reflex in the afferent arteriole and TGF (183). During impaired autoregulation, the sensitivity of TGF is reset due to changes in NO and AII. When there is sustained delivery of NaCl to the macula densa, the neuronal type of NO synthase is increased offsetting the usual vasoconstrictive effect of TGF on the afferent arteriole. These changes are found early in the course of the development of hypertension in the spontaneously hypertensive rat, the Milan hypertensive strain, and the Dahl salt-sensitive rat (reviewed in (183)). It is thought that this mechanism may be particularly important in salt-sensitive hypertension. The vasodilation resulting from the loss of autoregulation allows the transmission of higher pressure to the glomerulus, in effect an increase in glomerular capillary pressure.. The role of loss of autoregulation as one mechanism for the hemodynamic alterations has been studied extensively by Griffin et al. in several different models (184,185,186). In the normotensive renal ablation model, the systemic pressure is slightly higher than in controls but does not attain hypertensive levels. Nevertheless, when followed for 14 to 15 weeks, these animals develop glomerular lesions that correlate to the level of their systolic pressure as well as their pulse pressure (186). The authors believe that it is the transmission of this elevated pressure to the glomerulus that results in the glomerular injury. This supposition was also
supported by the comparison of changes in autoregulation in the stroke-prone spontaneously hypertensive rat (SHRsp) and their progenitors, the stroke-resistant SHR (184). Additional evidence for the role of loss of autoregulation in glomerular injury in the setting of hypertension was provided in a comparison of four different models of hypertension (177). The two models with increased preglomerular resistance manifest less glomerular injury than the two models with decreased preglomerular resistance (177). Glomeruli throughout the cortex may be affected, with juxtamedullary glomeruli affected slightly more frequently (177). In models with vasoconstriction, the glomerular injury is much less severe and is almost restricted to juxtamedullary glomeruli (177). This finding is thought to be related to a greater loss of autoregulation in juxtamedullary as compared with superficial glomeruli in these two models.

The endothelial injury from this increased glomerular pressure may be due to shear stress, direct mechanical injury, and/or oxidative stress. The forces that bring about visceral epithelial cell injury have been studied by Kretzler et al. (187) and involve capillary loop distension with epithelial cell hypertrophy and eventual loss of attachment of the epithelial cell to the GBM. In addition, epithelial cells may show blebs and vacuoles. A possible link between mechanical strain and podocyte injury has been studied in vitro by Durvasula et al. (188). They found that increased mechanical strain was followed by increased AII production, a fivefold increase in AT1 receptor mRNA expression, and an increase in transforming growth factor-beta (TGFβ) mRNA expression. This was also accompanied by an increase in apoptosis of the epithelial cells (188). Endothelial dysfunction may precede hypertension and is associated with decreased NO levels and an increase in AII resulting in impaired vasodilation, platelet activation, and increased vascular permeability (189,190). Microalbuminuria is a marker of endothelial dysfunction. The Ren-2 transgenic rat model of hypertension has increased tissue activity of the RAS and manifests hypertension, proteinuria, and insulin resistance (191). Effacement of foot processes is noted in glomeruli of such rats accompanied by decreased cortical expression of nephrin (191). Increased levels of 3-nitrotyrosine (3-NT), a surrogate for lipid peroxidative and oxidative stress, were present in renal cortex of Ren-2 rats. Treatment with a specific renin inhibitor restored the nephrin expression and the foot processes. Concomitant decrease in 3-NT was also found (191). In previous experiments, these investigators had shown that Nebivolol, a beta blocker that increases NO synthesis by endothelial cells, abrogated the proteinuria in Ren-2 rats accompanied by decrease in ROS/NADPH oxidase production (192).

Obsolete glomeruli show two different forms. In the first of these forms, the obsolescent glomeruli are characterized by wrinkling of the GBM with retraction of the tuft to one side of the Bowman capsule and collagenization of the Bowman space (see Fig. 20.5). This may be viewed as a form of collapse of the glomerular tuft. In the second form, the glomeruli are solidified or hyalinized; thus, an increase in matrix is often accompanied by remnants of hyalinosis lesions (Fig. 20.27). The obsolescent lesion is predominant in essential hypertension. The wrinkled glomerulus is likely the result of chronic ischemia. Kasiske (193) compared autopsy kidneys from patients with moderate to severe systemic atherosclerosis to those from patients of similar age with mild atherosclerosis with respect to the number of sclerotic glomeruli, the degree of vascular narrowing of arcuate and interlobular arteries, and the presence or absence of hypertension. He found that the extent of glomerular obsolescence depended on both the age of the patient and the degree of intrarenal vascular disease. Although hypertension correlated with the degree of glomerulosclerosis, it was not independent of the other two factors. The degree of narrowing of the renal artery correlated strongly with the extent of glomerular obsolescence, a finding supporting the idea that the sclerosis was due to ischemia, as represented by the vascular narrowing. It is well known that glomeruli may become sclerotic with increasing age, independent of increased blood pressure (110,194). Kaplan et al. (110) stated that 95% of the population aged ≤40 years should have fewer than 10% globally sclerotic glomeruli. Kappel and Olsen (194) countered that no more than 1% of glomeruli should be obsolete by age 40 but that as many 30% of glomeruli may become globally sclerotic by age 80.

Hypoxia has been heavily implicated in the pathogenesis of interstitial fibrosis (126,195) (see p. 870). Recent studies suggest possible mechanisms for a role in glomerulosclerosis as well. Neusser et al. (196) examined gene expression data in microdissected glomeruli from patients with hypertensive nephropathy and found an increased expression in several target genes of hypoxia-inducible factor (HIF). Furthermore, HIF-1α was identified in podocyte nuclei as a marker of transcriptional activation.

The solidified glomerulus is the alteration that Bohle described in DBN (113,114), a form associated with a more rapid course to ESRD. Marcantoni et al. (74) studied 62 hypertensive patients (19 African Americans and 43 Caucasians) with regard to the types of glomerular injury present in their renal biopsies. They found that 25% of glomeruli in the African American patients were of the solidified form as compared to 8% in Caucasians. A subgroup of patients also had segmental sclerosis, also seen more frequently in African Americans. In
addition to the segmental lesions, the African Americans in this subgroup had 38% solidified glomeruli. The higher prevalence of the solidified glomerulus in African Americans with hypertension was first associated with the more common occurrence of polymorphisms in the nonmuscle myosin heavy chain 9 (MYH9) gene in African Americans (69). Polymorphisms in MYH9 have been linked to FSGS and other renal diseases in both African Americans and Caucasians (69). More recently, this association has been found to be due to missense mutations in apolipoprotein-1, which is closely linked to MYH9 (76). Loss of autoregulation has also been suggested as a potential cause of the solidified glomerulus (111,116,197). Hill et al. (116) studied the relationship between arteriolar diameter and glomerular appearance in hypertensive individuals and found that no correlation was present in normal appearing glomeruli. However, hypertrophied glomeruli that were solidified or showed FSGS-like lesions demonstrated a correlation between arteriolar diameter and glomerular size. They suggested that this finding supported loss of autoregulation (116). Another factor in the pathogenesis of these lesions may be the presence of reduced numbers of glomeruli in some patients with hypertension (8,172,173). Brenner and Chertow (172) suggested that early gestational age or fetal growth retardation might affect nephrogenesis so that a reduced number of nephrons occur with consequent hyperfiltration of those that are present. Keller et al. (173) found a reduced number of nephrons at autopsy in patients with hypertension. Podocyte loss may also contribute to this lesion. Wang et al. (118) have demonstrated decreased podocyte number in glomeruli from hypertensive patients as compared to glomeruli from donor kidney biopsies. Podocyte loss has been recognized as a risk factor in the development of FSGS as well as other glomerular lesions (198).