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Year : 1999  |  Volume : 10  |  Issue : 3  |  Page : 267-274
Hypertensive Nephrosclerosis Pathogenesis, Diagnosis and Management

Service de Nephrologie and INSERM U 430, University Hopital Broussais, Paris, France

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Nephrovasculopathies are an increasing cause of end-stage renal failure. Hypertensive nephroscierosis is an old concept. In fact, the renal vascular lesions corresponding to this term can result from aging or a host of parenchymal renal diseases in the absence of elevated blood pressure. Nephrosclerosis is overdiagnosed. The diagnosis should rest only on renal biopsy, which is not usually done in an elderly patient with chronic renal insufficiency, hypertension and atrophic kidneys. Atherosclerotic renal disease and renal cholesterol crystal embolism are often misdiagnosed for nephro-sclerosis. The classical picture of nephrosclerosis is the patient with primary hypertension accompanied by arterio-and arteriolonephrosclerosis, focal and segmental glomerulo­sclerosis leading to glomerular obsolescence, interstitial fibrosis and inflammatory infiltrates. However, similar lesions can be observed in animal models as well as in some humans, especially blacks, in the absence of, or preceding the onset of hypertension. This suggests that nephrosclerosis might stem from a genetic defect in the renal vascular bed, a defect closely associated with the hypertensive trait. Recent data regarding the link between low birthweight and hypertension of early onset might have bearing on future developments in understanding the pathogenesis of nephrosclerosis. Treatment pursues two goals: normalizing blood pressure according to international recommendations and retarding sclerosis with a regimen essentially based on angiotensin II antagonists.

Keywords: Nephrosclerosis, Nephrovasculopathies, Hypertension, Atherosclerotic renal disease, Cholesterol crystal embolism, Black race, Genetics, Angiotensin converting enzyme gene I/D polymorphism, Renal fibrosis, Antihypertensive therapy.

How to cite this article:
Meyrier A. Hypertensive Nephrosclerosis Pathogenesis, Diagnosis and Management. Saudi J Kidney Dis Transpl 1999;10:267-74

How to cite this URL:
Meyrier A. Hypertensive Nephrosclerosis Pathogenesis, Diagnosis and Management. Saudi J Kidney Dis Transpl [serial online] 1999 [cited 2023 Jan 27];10:267-74. Available from: https://www.sjkdt.org/text.asp?1999/10/3/267/37233

   Introduction Top

Both the term and the description of nephrosclerosis date back to the beginning of the century when Fahr and Volhard described a variety of renal fibrosis with "hardening" of the kidney, which they considered a cause of renal vasulopathyand hypertension. [1] In fact, over the second half of the 19th century, when measurement of blood pressure became available, it was observed that hypertension is accompanied by generalized changes in blood vessels, and especially in the kidney. Whether such changes were the cause or the consequence of high blood pressure was an unsettled issue. [2] Apparently the German authors chose the first explanation. Since then, it has been accepted that nephrosclerosis, more adequately termed nephroangio­sclcrosis in the European literature, is the consequence of aging and of primary hypertension. There is no doubt that protracted hypertension is deleterious to renal as well as other vessels. However, renal lesions similar to those observed in the hypertensive patient can occur in a variety of renal diseases that are not accompanied by substantial increase in blood pressure. [3] Moreover, the notion that primary hypertension is a common cause of chronic renal failure has been established in certain ethnic groups, especially in blacks, but epidemiologic studies have shown that this is not true in the white. [4] In fact, and this is also true in the white European, genetic factors controlling the renin angiotensin system play a significant role in the propensity of the hypertensives to develop lesions of nephroangiosclerosis. [5]

Finally, it should be recalled that the diagnosis of nephroangiosclerosis is not a clinical but a histological one and that it is just too easy to attach this label to an aging patient with progressive renal failure following years of hypertension before other causes of renal insufficiency have been ruled out; especially atherosclerotic ischemic renal disease. These considerations are relatively recent, [6] owing to the fact that hypertension has been acknowledged as a major public health issue and is diagnosed by wide scale screening, in addition to the fact that effective antihypertensive therapy is relatively recent. This is illustrated by a remarkable publication by Perera in 1955, [7] at a time when virtually no medication was available to treat hypertension. This author personally followed 500 hypertensive patients until death. It is more than probable that many of them were misdiagnoscd as "primary" hypertension. Despite this reservation, it is worth noting that 42% had proteinuria, that 10% died of malignant hypertension and that 18% suffered from chronic renal failure. In contrast, recent publications have clearly shown that when hypertension is treated, even only partially, the percentage of patients developing chronic renal failure is now extremely low, in the order of 2%.[8],[9]

   Description of Nephroangiosclerosis Top

The conventional description of nephro­angiosclerosis is clinical and histological. It should be stressed, however, that progressive renal insufficiency in a middle-aged or elderly patient with protracted hypertension, slight albuminuria or microalbuminuria and normal urinary sediment cannot be attributed solely to nephroangiosclerosis. Zucchelli and Zuccala investigated 136 patients diagnosed clinically as having "benign nephroangiosclerosis". [10] The diagnostic work up included renal biopsy. The final diagnosis was renovascular atherosclerotic disease in 26.5%, renal cholesterol crystal emboli in 29.4% and true nephroangio­sclerosis in only 44.1%. In the United States, a country where renal specialists are more reluctant to carry out renal biopsy than in Europe, Schlessinger et al [11] reached similar conclusions concerning the propensity to wrongly label patients as suffering from "nephrosclerosis" in the absence of renal biopsy. These remarks must be kept in mind when interpreting the favorable results of a particular antihypertensive treatment on the anticipated slowing of hypertensive renovasculopathy in series of patients in whom the diagnosis of nephroangio­sclerosis was based only on the presence of microalbuminuria.

The renal lesions of nephroangiosclerosis involve not only the renal vasculature but also all the structures of the renal tissue. [1] Their appearance is remarkably similar to that observed in the rat after long-term infusion of angiotensin II at slightly pressive dosage, according to the protocol described by Johnson et al. [12],[13] The arcuate and interlobular arteries show myointimal hypertrophy, replication of the internal elastic lamina and some atrophy of the media. The smooth muscle cells focally disappear and are replaced by fibrous tissue. Hyaline eosinophilic deposits are found in the arterial wall. The vascular lumen is not always narrowed. Glomeruli are usually ischemic with ' thickened and folded capillary walls. Typical lesions of focal segmental glomerulosclerosis (FSGS) are common. Other glomeruli are globally obsolescent. The most striking changes affect the tubulointerstitium. The renal tubules are atrophic and microcystic. Many contain proteinaceous casts with the appearance of pseudothyroid areas. Finally, the interstitium is extensively fibrotic and contains abundant inflammatory cells. Overall, the picture resembles chronic interstitial nephritis.

These changes are common in the elderly. Tracy et al, [14] by careful histological analysis, showed that subtle differences distinguish two variants of nephrosclerosis, separately related to age and to blood pressure. Nevertheless, it is difficult to determine whether lesions of nephroangiosclerosis are purely the consequence of aging,[15],[16] of longstanding hypertension, or proceed from another mechanism. In fact, studies conducted in black patients, in whom hypertension and nephrosclerosis occur early in life and follow a particularly rapid course, seem to indicate that renal vascular lesions typical of nephrosclerosis may occur before significant elevation of blood pressure.[17],[18],[19],[20],[21] Conversely, a number of nephropathies are characterized histological by severe vascular lesions in the absence of hypertension. Chronic interstitial nephritis, in which a salt-losing tendency partly explains the absence of hypertension, is accompanied by severe nephrosclerosis. Among glomerular diseases, FSGS, IgA nephropathy, diabetic nephropathy and membranous glomerulopathy are commonly associated with severe vascular lesions before significant hypertension develops. [3]

The foregoing observations raise two issues. The first is the precise role of primary hypertension in eliciting the renal lesions of nephrosclerosis. The second is the provocative hypothesis that renal vascular lesions and primary hypertension are two separate entities, closely related genetically, including the possibility that hypertension may follow rather than cause the elevation in blood pressure readings. [21]

   Pathogenesis Top

The pathophysiology of nephroangio­sclerosis is not simple. It is clear that arterial hypertension, whether primary or secondary to glomerular disease, is detrimental to the renal vasculature. [6] The brunt of high systolic pressure in the preglomerular arteries induces stretch injury of the intima, the elastic laminae and the myocytes. [22],[23] Normally, the glomerular circulation is protected from the consequences of systemic hypertension by contraction of the afferent arteriole. Incidentally, antihypertensive drugs that impair this afferent vasoconstriction, such as dihydropyridine calcium channel blockers, are not recommended for preventing the glomerular consequences of high blood pressure.

However, we have given reasons to believe that nephroangiosclerosis may be a genetic disorder of parenchymal renal arteries and arterioles coupled with the hypertensive trait. It has recently been shown that children with low birthweight[24] have higher than normal blood pressure readings at age seven. The hypothesis has been raised that low birth-weight is associated with fewer nephrons at birth and might bring an explanation to the etiology of essential hypertension. [25] To the best of my knowledge, there are no available studies regarding renal vascular lesions in this setting. However, this hypothesis might apply to the black race and explain the frequency of hypertensive nephrosclerosis in African Americans [26] and conceivably in other populations.

In fact, the role of genetic factors in creating or aggravating the arterial/ arteriolar lesions that have long been considered the consequence of hypertension has been documented. The severity of nephrosclerosis and hypertension is well known in the black race. Dustan [27] has raised the hypothesis of a link in blacks between the propensity to develop cheloids and to develop renovasculopathies. Fernandez-Llama et al showed that the angiotensin converting enzyme (ACE) gene I/D polymorphism seems to play a major role in the white irrespective of the degree of hypertension, [Table - 1]. Similar obser­vations have been made regarding the role of ACE I/D polymorphism in the development of various nephropathies accompanied with renal vascular lesions. [28],[29],[30],[31]

Animal experiments confirm the concept that nephrosclerosis and hypertension are not necessarily linked. The animal model closest to human primary hypertension is the spontaneously hypertensive rat (SHR). Feld et al conducted a remarkable study, in which they observed renal lesions and proteinuria in the SHR made normotensive by treatment from birth. [32] Despite normal blood pressure, the animals developed typical lesions of nephrosclerosis, FSGS and proteinuria. Similar experiments by Smeda et al [33],[34] led to the same conclusions. More recently, genetic manipulations engineered mice with zero to four functional copies of the angiotensinogen gene. The former were hypotensive, the latter hypertensive. [35] Histologically the most severe vascular lesions were observed in hypotensive mice with zero functional copies of the gene. These and other animal experiments are consistent with the hypothesis that renin, rather than angiotensin II, is vasculotoxic, at least for the fetal kidney.

   Nephroangiosclerosis Complicating Primary Nephropathies Top

In 1975, Kincaid-Smith [36] insisted on the frequency of vascular lesions associated with primary glomerulopathies and stressed that "the lesions in arteries and arterioles in patients with glomerular disease may be quite out of proportion to those which might be anticipated in relation to the patients' age and blood pressure". This statement was based on a study of 344 biopsies. Vascular lesions were found in 65% of 68 patients with minimal change disease, in 54% of 37 patients with membranous glomerulonephritis, and in 82.6% of 116 patients with FSGS.

More recently we confirmed and extended such findings in the analysis of 1450 renal biopsies performed from 1976 to 1995. There were 222 patients under 40 years of age with glomerulonephritis, of whom 75% were normotensive. Vascular lesions were found in 20.3% compared to only 6.2% in controls of similar age. In 283 patients aged 40 to 65 years, the incidence of renal vascular lesions was 60% in membranous glomerulonephritis and 50% in minimal change disease. There were 227 patients older than 65, in whom the incidence of renal vascular lesions was 80.8%. In IgA nephropathy, nephroangiosclerosis often preceded the onset of hypertension, especially in those with a family history of high blood pressure. The discrepancy between normal blood pressure and renal vascular lesions was especially striking in 266 patients with acute or chronic interstitial nephritis despite normal blood pressure in the majority. In chronic interstitial nephritis, renal vascular lesions were found in 76.5% compared with an incidence of 24.6% in 73 controls of the same age.[3],[37]

As specified above, genetic factors pertaining to the reninangiotensin system, and especially the ACE gene I/D polymorphism, play an important role in the propensity to develop vascular lesions in the absence of hvpertension. Such lesions are commonly associated with interstitial fibrosis and this association is ominous. In fact, the best predictive factor of future development in any glomerulopathy is the severity of vascular lesions and interstitial fibrosis on first renal biopsy. [38],[39],[40],[41]

A survey of the literature confirmed that hypertension is not a prerequisite for deve­loping nephroangiosclerosis in various nephropathies. Conditions entailing high intra-renal concentrations of renin and angiotensin are commonly accompanied by severe renal vascular lesions despite normal or even low blood pressure. This is the case for Bartter's syndrome [42] and for some forms of chronic diarrhea. [43]

   Nephroangiosclerosis and Renal Fibrosis Top

The pathophysiology of the fibrotic com­ponent of nephroangiosclerosis has long remained obscure. Animal experiments have long been based on studying the consequences of Goldblatt's renovascular hypertension on the non-stenotic kidney. However, in this model the lesions are closer to those of malignant hypertension than to those of chronic, primary hypertension. Johnson et al. devised a remarkable model of experimental hypertension in the rat based on long-term infusion of slightly pressive doses of angiotensin II. [12] This protocol resulted in renal parenchymal lesions quite similar to those observed in human nephroangiosclerosis. These lesions closely resembled tubulointerstitial nephritis. The same team [13] extended their study to the mechanism of interstitial fibrosis. They showed increased osteopontin expression in the interstitial sclerotic areas. Osteopontin is a strong chemoattractant for macrophages and by immunohistochemistry the authors demonstrated co-expression of osteopontin and the EDI epitope of macrophages within the sclerotic areas.

The role of angiotensin II in eliciting interstitial matrix build up in the nephro­sclerotic kidney is paramount. In fact, interstitial fibrosis results from the interplay of angiotensin II, transforming growth factor-alpha (TGF-α), endothelin 1 and platelet-derived growth factor B (PDGF-B). [44]

These notions derived from experimental data lead directly to the issue of the thera­peutic approach to nephroangiosclerosis and especially its fibrotic component, which is the essential cause of development to end-stage renal failure.

   Management Top

We have stressed the fact that nephro­angiosclerosis is clearly overdiagnosed by lack of investigations to rule out atherosclerotic renal arterial disease, cholesterol crystal embolism to the kidneys, as well as chronic nephropathies that manifest by hypertension and slight proteinuria. It is therefore mandatory that a patient diagnosed clinically as suffering from "hypertensive nephrosclerosis" be investigated by duplex Doppler or even renal angiography to assess the patency of the main renal arteries. Similarly, any doubt regarding the possibility of cholesterol embolism or occult nephropathy of any kind should make the indication of renal biopsy more liberal than generally accepted, especially in the American literature.

Once the diagnosis of nephro­angiosclerosis has been established, management should pursue two goals.

The first goal is to obtain adequate control of blood pressure. It is beyond the scope of this review to discuss the vast question of the treatment of hypertension. Suffice, to say that the most recent recommendations that emerge from large scale international studies are currently more stringent than some years ago. The Sixth Report of the Joint National Committee on prevention, detection, evaluation and treatment of high blood pressure [45] recommends target systolic/diastolic blood pressure below 140/90 mmlig. In type II diabetics, the ideal goal blood pressure should be 120/80 ramHg.

The second goal, that is more directly relevant to nephroangiosclerosis, is to prevent the continuous build up of extracellular matrix, which leads to interstitial fibrosis as well as to glomerular lesions of FSGS. In fact, our best tools to oppose the noxious effect of angiotensin II within the kidney are converting enzyme inhibitors and angiotensin II receptor antagonists. It might well be that newer drugs such as endothelin-1 antagonists may in the future find an important place in the prevention of renal fibrosis.

   References Top

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Correspondence Address:
Alain Meyrier
Service de Nephrologie and INSERM U 430, University Hopitai Broussais, 96 Rue Didot, 75674 Paris Cedex 14
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Source of Support: None, Conflict of Interest: None

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