Hypertensive nephrosclerosis: pathogenesis and prevalence

Essential hypertension is an important cause of end-stage renal disease

Robert G. Luke

Department of Internal Medicine, University of Cincinnati, College of Medicine, Cincinnati, Ohio, USA

Correspondence and offprint requests to: Robert G. Luke, MD, Chairman, Department of Internal Medicine, University of Cincinnati College of Medicine, 231 Bethesda Avenue, Cincinnati, OH 45267-0557, USA.

On October 14, 1995, Professor A. Raine (St Bartholomew's Hospital, London) died at the young age of 46 years. He was a fascinating man who combined a rigorous scientific approach with clinical acumen. He excelled in the fields of hypertension research and nephrological research. He was an inspiring investigator whose untimely death is mourned by many colleagues in European nephrology.

NDT commemorates the outstanding contributions of our former subject editor in the field of hypertension by a contribution bearing on the major research topic of the late Professor Raine, i.e. the interrelation of kidney and blood pressure.

The case for a Guytonian approach to the nephrogenesis of essential hypertension is strong [13]. Hypertension is not maintained in the presence of normal kidney function untrammelled by inappropriate renal vasoconstriction or by non-physiological sodium acquisitiveness. All monogenic disorders discovered to date which cause hypertension lead to inappropriate sodium retention [4,5]. Doubts, however, continue to be expressed about the accuracy of the observation that hypertensive nephrosclerosis causes 25% of end-stage renal disease (ESRD) in the US and 8% in Europe; in this view, at the very least, the diagnosis is much over-utilized [69].

Diagnosis

The diagnosis of hypertensive nephrosclerosis is dependent on the exclusion of other primary renal diseases. A careful past history, family history, search for signs for target organ damage, such as left ventricular hypertrophy and hypertensive retinal changes, careful urine microscopy, measurement of 24-h urinary protein and performance of renal ultrasound should establish the diagnosis, with additional tests for glomerulonephritic or vasculitic diseases if indicated. Such an approach was vindicated at about the 90% specificity level by the renal biopsy study [10] performed on the pilot patients in the African-American Study on Kidney Disease and Hypertension (AASK) which is discussed further subsequently.

As in the diagnosis of diabetic glomerulosclerosis, renal biopsy for the diagnosis of hypertensive nephrosclerosis is indicated in clinical practice only when there is substantial doubt based on the clinical evidence. In my view, biopsy should be considered in patients who do not have accelerated hypertension or a long history of hypertension, whose serum creatinine is less than 2.5–3 mg/dl and in whom 24-h urine protein excretion exceeds 1.5 g/24 h. In large series of patients with non-accelerated hypertension, proteinuria has usually been less than 0.5 g/24 h [11,12]. In the AASK study 1094 patients have been enrolled in a prospective randomized, controlled comparison of a calcium channel blocker (CCB), converting enzyme inhibitor (CEI) versus beta blocker as the initial treatment for patients with essential hypertension and hypertensive nephrosclerosis with glomerular filtration rates in the range of 25–70 ml/min. Amlodipine, enalapril and atenolol are the chosen antihypertensives with a recommended sequence of additional other drugs as needed to control blood pressure. In addition a 3x2 factorial design was used to include goal mean arterial pressures of <92 mmHg and 102–107 mmHg. Median protein excretion in this group prior to randomization was 117 mg/dl; mean excretion was 0.5 g/24 h. Patients with proteinuria >2.5 g/24 h were excluded. Mean protein excretion in the Fogo biopsy study was 300 mg/24 h. Thirty-two patients with GFR's in the range 25–55 ml/min in the MDRD study had a median 24-h protein excretion of 90 mg and a mean of 0.5 g/24 h [13]. The mechanisms of progression of proteinuric disease so elegantly described recently by Remuzzi et al. [14] do not, therefore, appear to explain the progression of renal disease in most patients with primary non-accelerated hypertension. Several biopsy studies of highly selected patients in whom renal biopsy was believed to be clinically indicated—usually because of increased protein excretion or other renal indication—demonstrated that patients with non-accelerated hypertension can excrete protein in the range of 2–6 g/24 h; usually serum creatinine is then >2.5 mg/dl [1517].

Tony Raine, in a consideration of the issue being discussed, concluded that `the extent to which "benign" hypertension truly leads to significant renal impairment will only be known if appropriately controlled prospective studies are performed in hypertensive patients initially free of any renal involvement, and in whom histology is obtained if any evidence of renal dysfunction develops' [18]. Certainly the sequence of hypertension occurring for years before renal insufficiency or fixed proteinuria develops, in the absence of any other primary renal disease, is supportive of a diagnosis of hypertensive nephrosclerosis. Longitudinal cohort studies are needed. These however, will be difficult and prolonged because of the slow progress of the disease in Caucasian patients with mild-to-moderate hypertension, especially if the latter is treated [19]. The peak annual incidence of ESRD due to hypertensive nephrosclerosis in US Caucasians is at the age of over 65 years (as compared to 45–64 years in African-Americans).

As compared to Caucasians, hypertension in African-Americans occurs earlier, is more severe, and more often causes ESRD even after adjustment for severity of hypertension [20]. Some pathologists believed that malignant hypertension causes different renal histological changes in blacks as compared to white patients; in particular fibrinoid necrosis was less common [21]. The histological changes in `benign' nephrosclerosis, however, do not seem to differ. Because of the older age at which hypertension and hypertensive renal disease develops, however, atherosclerotic renal vascular disease and atheroembolic renal disease are more common and make the differential diagnosis more complex in whites [9,22]. In my view, hypertensive nephrosclerosis is, except for demographic factors, age of onset, rate of development, prevalence and severity, a very similar disease in blacks and whites. Tracey et al. [23] have emphasized the fibrolastic intimal lesion in small renal arteries and its earlier occurrence in African-Americans; they believe that it precedes the development of hypertension, based on population studies. Yet blood pressures of black children are higher than those of whites [24]. Whatsoever the relationship, the lesions differ only in severity and time of onset and show that subtle structural microvascular involvement is a very early renal change in, or even before, the development of essential hypertension.

Epidemiology

The `essential challenge' in determining the answer to the question, as to if or how mild-to-moderate primary hypertension causes ESRD, is due to the low incidence and long gestation of the disease, even in African-Americans. In the US 42 million people [25] have primary hypertension (defined as SBP of 140 mmHg or greater, DBP of 90 mmHg or greater, or taking antihypertensive therapy). The annual incidence of cardiovascular events is 1.5 million and most of these are in hypertensive patients. The present US annual incidence of ESRD due to primary hypertension is very much less at 19 000 (1 in 2200 hypertensives). Raine concluded in 1994 that the comparable figureGo in Europe was 1 in 6000 at a time when primary hypertension was regarded as a cause of 7% of ESRD [18]. The classical prospective controlled studies which establish the efficacy of anti-hypertensive therapy in essential hypertension revealed a paucity of renal events, however defined; these therefore could not be utilized for any statistical analysis as to the efficacy of anti-hypertensive treatment in prevention of renal disease [20]. We were able to show postponement but not reduction in the development of ESRD due to hypertension in sequential studies [26] in Jefferson County, Alabama, a site at which the highly increased incidence of hypertensive nephrosclerosis as a cause of ESRD in African-Americans was early demonstrated [27]. The most recent rate of increase of ESRD due to primary hypertension may be somewhat less than before in the US Renal Disease Registry (3% for 1991–1996). Nevertheless, the evidence to date that we are effectively preventing progression of renal disease due to primary hypertension is sparse [28]. This may be attributed, at least in part, to the failure to reduce blood pressure below 140/90 mmHg in 75% of US hypertensive patients [29] and to continuing less-than-optimal therapy both in the US [30] and in Europe [31,32]. However, there has been a very significant reduction of about 50% in strokes and myocardial infarctions [25]. It is possible that protection of the kidney requires, at least in some at-risk patients (see below), normotension.



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Professor Antony Raine 21.7.49–14.10.95.

 
Additional support for the causation of ESRD by moderate-to-severe hypertension is provided by the demonstration that in follow up studies of hypertensive patients, a small percentage [12,33,35] do show progressive elevation of the serum creatinine, even when treated. In a 16-year follow-up of a random sample of 330 000 males who were screened for the MRFIT study [36], there was a strong association between both elevated systolic and diastolic blood pressures and development of ESRD. In a smaller number of patients in the same study with initial negative urinalysis and normal serum creatinines the same correlation held. Eight hundred and fourteen of these 330 000 patients (about 1 in 400) developed ESRD in that 16-year follow-up period; only about 6% of the patients were African-Americans.

Pathogenesis

My conviction as to the reality of hypertensive nephrosclerosis as a cause of ESRD perhaps relates, in part, to my varied geographical clinical investigative experiences, initially in Scotland then in Birmingham, Alabama. In Scotland I was engaged in a search for renovascular hypertension in Caucasian hypertensives [37]. There, hypertensive nephrosclerosis as a cause of progressive renal disease in patients under 45 years is rare. A very different experience awaited me some years later in Birmingham where I was involved in a very large renal transplant programme in which half of the patients were African-Americans. The prevalence of hypertensive nephrosclerosis was impressive, even in patients under 35 years old, and this experience [2] left me convinced about the potentially deleterious effects of sustained non-accelerated hypertension when the genetic background was appropriate.

The histological lesion of hypertensive nephrosclerosis is well recognized; myointimal hyperplasia of interlobular and afferent arteriolar vessels, hyaline arteriolosclerosis especially of the latter, `wrinkling collapse' of the glomerular tuft and, commonly, global glomerulosclerosis [20,38]. These changes are believed to result from `glomerular ischaemia' due to afferent arteriolar narrowing. In response to increased afferent arteriolar flow secondary to hypertension there is a myogenic contractile response [39], supplemented by tubuloglomerular feedback from the macula densa signal, in the late segments of the preglomerular vessels which leads to autoregulation of glomerular capillary pressure and flow.

In an experimental rat model of hypertension in which this afferent constrictive response is defective [40], the fawn-hooded rat, focal glomerulosclerosis and progressive renal disease occur even in the presence of modest hypertension. A gene contributing to renal susceptibility but not to hypertension has been identified [41]. Further support for the importance of the genetic susceptibility genes in the fawn-hooded rat is provided by hypertensive renal damage produced by L-NAME at levels of blood pressure causing much less damage in heterozygote controls [42]. This introduces the concept of renal susceptibility genes, which determine whether, and how much, hypertension-induced progressive renal damage occurs. When the kidney of the normotensive Brown–Norway (BN) rat is transplanted to replace one kidney of another congenic spontaneous hypertensive rat (SHR) strain which develops hypertension but not renal disease, the BN kidney develops progressive glomerulosclerosis in response to DOC-salt induced hypertension even though the remaining ipselateral native (SHR) kidney remains unaffected by the hypertension [43]. Indeed, even the modest spontaneous hypertension in the SHR's caused more glomerular damage in BN rats. Thus, equal exposure to the same level of hypertension in the same host produced very different renal responses in these congenic rat strains. SHRs which maintain a normal GCP via appropriate afferent and efferent arteriolar adjustments of tone do not develop hypertensive renal damage until very late in their life [44]. Five-sixths renal ablation, however, led to afferent dilatation, autoregulatory failure and the changes of malignant hypertension in the renal microvasculature despite levels of hypertension no different from non-ablated rats.

I propose that the afferent arteriolar changes, the wrinkling collapse of the basement membrane and global sclerosis occur when afferent constriction is excessive with a marked reduction in glomerular blood flow and pressure (Figure 1Go). Increasing evidence suggests that endothelial cells require a normal physiological level of shear stress secondary to blood flow to avoid release of vasoconstrictors such as angiotensin II and endothelin and to maintain adequate production of nitric oxide as a vasodilator autocoid; low shear stress may sensitize endothelial cells to injury, prevent apoptosis and diminish response to cytokines [4548]. This concept has been mainly applied to anti-atherogenesis until now [49,50]. Concomitant activation of the intrarenal renin–angiotensin system by diminished late afferent blood flow is known to stimulate the cytokine TGF-ß, which sets the fibrotic cascade in motion [51]. Harriet Dustan noted several years ago that the fibroblasts from keloid scars of African-Americans produce excess TGF-ß and suggested that this may be relevant to the renal hypertensive response to injury in these patients [52]. Cyclosporin a potent vasoconstrictor of the afferent arteriole—likely in part via endothelin release [53]—causes renal changes in the transplanted kidney very similar to hypertensive nephrosclerosis with global sclerosis.



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Fig. 1. Autoregulatory response to hypertension. If inadequate, systemic blood pressure is transmitted to glomerular capillaries (hyperglycaemia, malignant hypertension, reduced nephron mass); if excessive, glomerular ischaemia results and leads to a fibrosis cascade both in the affected glomeruli and in the related tubulointerstitial tissue supplied by that post-glomerular circulation. GCP, glomerular capillary pressure; GBF, glomerular blood flow; Gs, glomerulosclerosis.

 
Experimental renal artery stenosis is also associated with the glomerular ischaemic lesion and marked tubular-interstitial fibrosis even in the clipped kidney, which is, at least, theoretically, fully protected from systemic hypertension. Post-glomerular blood flow must be markedly reduced due to glomerular ischaemia, either when due to large vessel renal artery stenosis or to afferent arteriolar narrowing in hypertensive nephrosclerosis. Ischaemia in an experimental model due to clipping of the renal artery has been shown to cause neo-expression of tubular antigens such as vimentin with a resulting inflammatory response leading to tubulointerstitial fibrosis [54]. Unilateral nephrectomy in SHR caused arteriolonephrosclerosis, non-focal glomerulosclerosis and similar increases in interstitial fibrosis with increased inflammatory response and accumulation of extracellular matrix proteins [55]. Thus, genes determining the response by the renal interstitium and tubules to chronic ischaemia may also be relevant to the pathogenesis of hypertensive nephrosclerosis.

The concept of renal susceptibility genes is also supported in clinical studies by the strong familial occurrence of ESRD in hypertensive nephrosclerosis [56] in both African-Americans [56] and Caucasians [58].

Possible candidate gene polymorphisms for the development of hypertensive nephrosclerosis include paracrine and autocoid agents that influence the endothelial and smooth muscle responses to increased pressure and flow at the afferent arteriole and those altering response to increased salt delivery to the macula densa; kallikrein [59] nitric oxide synthase [60,61] and endothelin [62,63] are examples. Relevant also are agents (e.g. endothelin, TGF-ß [64], PDGF) enhancing glomerulosclerotic responses to reduced glomerular endothelial shear stress and to tubulointerstitial ischaemia secondary to reduction in post-glomerular blood flow. Aldosterone may also play a direct role in determining the vascular response to hypertension [65].

The microvascular changes described in hypertensive nephrosclerosis are not specific to primary hypertension and emphasize the potentially important role of other pathogenetic mechanisms than those of hypertension. Chronic intense stimulation of the renin–angiotensin system in Bartter's syndrome, chloride-diarrhea and laxative abuse causes nephroarteriolosclerosis even in younger and normotensive patients [20]. This may be secondary to prolonged vasoconstriction and/or to chronic exposure of the renal microvasculature to the effects of angiotensin II. Similar changes also occur with ageing and as a result of healing of the micro-thrombotic lesion of the haemolytic uraemic syndrome.

An overall concept of glomerular ischaemia as the primary lesion in hypertensive nephrosclerosis is outlined in Figure 2Go. Once a sufficient number of nephrons are (globally) sclerosed, adaptation of remaining nephrons with afferent dilatation causes acquired focal glomerulosclerosis in remaining intact nephrons. Such lesions could account for the occasional patients seen with heavy proteinuria in the later stages of the progression of hypertensive nephrosclerosis. Such a transition is supported by biopsy findings in the study by Harvey et al. [15] in which focal glomerulosclerosis is associated with heavier proteinuria and a higher serum creatinine; the major glomerular lesion in the other `earlier' patients is global sclerosis. Accounts of renal histology in `benign nephrosclerosis' emphasize the patchy nature of the lesion with focal areas of global sclerosis and tubular atrophy. These may in part be related to ischaemia of small arteries supplying several glomeruli. At any rate, surviving glomeruli in intervening areas would be subject to hypertrophy, hyper-perfusion and focal glomerulosclerosis.



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Fig. 2. Pathogenesis of hypertensive nephrosclerosis. The primary pathogenetic process in `benign' hypertension in the kidney is glomerular and tubular ischaemia, the response to which is determined by renal susceptibility genes (RSC). As with other renal diseases causing focal loss of nephrons, remaining intact nephrons adapt to a varying degree. The extent of this adaptation process determines severity of proteinuria via acquired focal glomerulosclerosis (Gs, glomerulosclerosis).

 
A high salt intake may be relevant not only for the pathogenesis of essential hypertension but may, independent of its hypertensinogenic effects, produce responses in the kidney that lead to renal fibrosis perhaps via increased renal production of TGF-ß [66,67]. Likewise, excess renal vasoconstriction [68,69] may not only lead to sodium retention and hence essential hypertension but also may contribute to the development of hypertensive nephrosclerosis [20].

Chronic lead toxicity can cause hypertension, renal impairment, and marked tubulointerstitial changes with low levels of proteinuria [70,71]. It seems likely that these effects could act out synergistically on some patients in causing hypertensive renal impairment. Hanta virus infection can cause endothelial damage [72]; a significant increase in viral antibodies was seen in patients on dialysis because of hypertensive nephrosclerosis in Baltimore [73]. Cocaine abuse is another possible environmental co-factor [74,75]. Socio-economic status likely contributes to progression but does not fully account for the predilection of African-Americans to develop hypertension-induced ESRD [76].

Although it seems probable that renal damage would eventually be produced in all human kidneys if blood pressure became high enough, an interesting transgenic rat model, in which a high percentage of rats develop all the clinical features of the malignant hypertension syndrome in man at blood pressure levels even lower than these who do not [77], suggests again that renal susceptibility genes are important. The authors speculate that a gene influencing endothelial function may be involved.

If renal susceptibility genes allow moderate hypertension to cause ESRD, especially in African-Americans, this may at least in part, also explain the substantially higher mortality rates seen in Caucasian as compared to age- and sex-matched African-American dialysis patients [7880]. Thus, cardiovascular disease might be less in patients with renal susceptibility genes than in those in whom hypertension had to be more severe and present for a more prolonged period before ESRD occurred. This might be true for other diseases causing ESRD as well as for hypertensive nephrosclerosis because African-Americans seem to be also more susceptible to other causes of ESRD, for example in diabetes mellitus, even after controlling for blood pressure and the degree of control of glycaemia [81].

Treatment

The obvious pressing need is to be able to identify, from the large number of patients with essential hypertension, those destined to develop, or in the course of advancing, towards ESRD (hopefully at a still reversible stage). Black race, increasing age, a family history of ESRD, and microalbuminuria are all potential candidates as risk factors. Unlike in diabetes mellitus [82], it is not yet established that microalbuminuria is a harbinger of the development of renal impairment secondary to the primary disease process—in this case, hypertension, although there is some preliminary supportive evidence [83]. It is established, however, that microalbuminuria is highly associated with cardiovascular risk factors such as left ventricular hypertrophy, hyperlipidaemia, `non-dipping' nocturnal blood pressure and increased diastolic blood pressure [84,85]. Even though we cannot yet say whether microalbuminuria represents the early effects of hypertension in glomerular structure or function, the association with cardiovascular risks justifies intensification of antihypertensive therapy and normalization of blood pressure. In one study CEI but not CCB reduced the prevalence of microalbuminuria over a 2-year period [86]. Perhaps microalbuminuria, especially if increasing in an individual patient, is an indication of beginning secondary focal glomerulosclerosis.

If the concept of primary glomerular ischaemia is correct, a logical case could be made that calcium channel blockers, especially the dihydropyridines, may be the antihypertensives of choice for hypertensive nephrosclerosis, because of their ability to dilate the afferent arteriole [8789]. It would be very important to maintain normal systemic blood pressure in such circumstances to avoid transmission of elevated systemic pressure to the glomerular capillary circulation. The AASK study should answer this question and its results are awaited with great interest.

Until the AASK study results are available, a reasonable approach to patients with early hypertensive nephrosclerosis may be to employ a combination of CCB, CEI and an appropriate diuretic. While CCB functionally dilate the afferent arteriole, ACE inhibitors may more effectively prevent fibrosis and remodeling of the preglomerular microvascular [90]. Animal studies suggest possible synergistic effects for a combination of CCB and CEI [91]. CCBs may better suppress endothelin production [92] and inhibit glomerular hypertrophy [91] whereas CEI increases bradykinin levels [93,94]. More inhibition of the effects of angiotensin II may be provided by the angiotensin (AT) receptor blockers because of the continuing production of angiotensin II despite the use of ACE inhibitors [95]. A combination of a CEI and an AT receptor blocker would also prevent the effects of elevated angiotensin II levels on AT-2 receptors during the use of receptor blockers [9698].

Additional therapeutic approaches may become available in the next century. If we can identify the renal susceptibility genes or a suggestive family history of ESRD in hypertensive patients, appropriate treatment may forestall renal failure. Even now it is clear that relatives of patients with diabetic or hypertensive renal failure should avoid obesity and adopt a low or moderate salt intake. There are fascinating examples of genetic therapy in animal models. Somatic delivery of the human eNOS gene reduced blood pressure for 6 weeks in SHR [99]. Likewise, the human tissue kallikrein gene corrected Goldblatt hypertension in rats for 24 days with preservation of renal function [100]. One injection of AT1R antisense cDNA gene delivery system utilizing a retroviral vector was as effective as Losartan in treating hypertension in SHR for several weeks; plasma angiotensin II levels remained normal [101]. Whether our new and growing genetic knowledge will prove more useful in assessment of disease risk or in therapy, or in both, remains to be seen.

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