Hypertension and the kidney: culprit and victim

Nephrol Dial Transplant (1996) 11: 1961-1966

Nephrology Dialysis Transplantation

Tony Raine Memorial Lecture

Hypertension and the kidney: culprit and victim Hein A. Koomans, Jaap A. Joles and Ton J. Rabelink Department of Nephrology and Hypertension, University Hospital Utrecht, The Netherlands On October 14, 1995, Professor A. Raine (St Bartholomew's Hospital, London) died at the voung 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.

was not the angle from which hypertension researchers have classically looked at the problem, one may wonder whether that was in fact what Bright's discovery was about: the vicious circle of the kidney as culprit and victim of hypertension. We should remember Volhard, who already concluded at the beginning of this century that vascular changes in the kidney are the primary event leading to hypertension and nephrosclerosis [10].

Kidney: culprit of hypertension

Direct evidence for the kidney as primary cause of hypertension comes from the classical kidney transplantation experiments in rats showing that hypertenThis short overview is dedicated to the memory of sion follows the kidney [11,12]. Rare but precious is Tony Raine, who, within his wide field of interest, the documentation of normotension following implantcontributed so much to the understanding of pathogen- ation of 'normotensive kidneys' into hypertensive esis and consequences of hypertension [1]. As life nephrosclerotic patients [13]. Recent data, less direct merges with death, our reflections will cover past, but definitely in this line, show increased renal vascular present and future. resistance in normotensive offspring of hypertensive parents [14]: the kidney is first. The two mechanisms leading to the elevated blood Introduction pressure are disturbed volume excretion on the one hand, and imbalance between intrarenal vasoconstricAlthough Bright already made the first link between tive and dilatory factors on the other. Thus, resetting abnormal renal function and hypertension in 1831, it of the pressure-natriuresis curve has long been recogwas more than a century before the key role of the nized as dominant hypertensive mechanism [15,16], kidney was fully recognized. Crucial experiments were whereas abnormal renal vasoconstriction also is an performed by Goldblatt, who found systemic hyperten- early, well-established characteristic of the hypertensive sion after placing clips around the renal arteries of state [17,18]. Clearly, these two conditions should not dogs [2], and by Guy ton and coworkers, who in a be seen as separate items, but rather as interdependent large series of experiments explored the crucial role of players that always need each other to raise blood the renal sodium excretion capacity in long-term blood pressure. Interestingly, the past decades showed differpressure regulation [3,4]. Meanwhile, it is clear that ent descriptions for this interplay. Apparent differences essential hypertension is a multifactorial disease, in however, concerned the frame rather than the picture. which polygenic factors [5-7], affecting neurohumoral Recognition of the increased filtration fraction early mechanisms and the renal sodium excretion capacity, in hypertension [17,19], led in the mid-seventies to the as well as environmental factors, particularly sodium concept of increased tubular sodium reabsorption by intake [8,9], take part. peritubular physical factors, thus linking increased Somewhere along the way of these explorations, we intrarenal vasoconstriction to impaired sodium excrebegan to see the kidney not only as the source, but tion [18]. As part of this concept, an important role also as possible victim of hypertension. Although this was attributed to the renin-angiotensin system, known to cause preferential efferent arteriolar constriction and Correspondence and offprint requests to: Prof. Dr Hein A. Koomans, to raise filtration fraction and tubular reabsorption Dept. of Nephrology and Hypertension, University Hospital Utrecht, [20,21]. At approximately the same time, the nonP.O. Box 85500, 3508 GA Utrecht, The Netherlands. E. Ritz

O 1996 European Renal Association-European Dialysis and Transplant Association

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modulator concept was put forward by Williams and Hollenberg [22]. This concept was based on the observation that patients with essential hypertension often have decreased ability to suppress the concentrations of angiotensin II in accordance with their sodium intake. As a result, renal vasodilation is impaired, and aldosterone inappropriately elevated. Angiotensin converting enzyme inhibitors normalized both disturbances [23], stressing the central role of the reninangiotensin system in the link between renal vasoconstriction and impaired sodium excretion. Almost a decade ago, Sealey et al. proposed nephron heterogeneity, that is existence of a subpopulation of ischaemic nephrons which is responsible for elevated intrarenal angiotensin II levels, as basis for impaired sodium excretion and hypertension [24]. This hypothesis linked renal vasoconstriction and impaired sodium excretion to inappropriate (local) intrarenal angiotensin levels, and at the same time provided an explanation for the often normal renin-angiotensin levels in peripheral blood. Clearly, whichever hypothesis one prefers (or where one wants to put the emphasis), renal vasoconstriction and impaired sodium excretion together form the central paradigm of the renal disturbance in hypertension, and inappropriate activity of the renin-angiotensin system is a possible link between the two. Pathophysiology provides many examples of the validity this principle. Most instructive is the comparison between unilateral renal artery clip and unilateral nephrectomy. In the former case, the clipped kidney is exposed to a low perfusion pressure and retains sodium, while the non-clipped kidney cannot restore sodium balance (at least not at a normal blood pressure) as it cannot escape from the vasoconstrictive and sodium retaining action of the elevated circulating angiotensin II [25]. On the contrary, no such thing happens after uninephrectomy: although an even more flagrant insult to the nitration surface and ability of sodium excretion, the simultaneous strong renal vasodilatation in the remaining kidney precludes net sodium retention and hypertension [26]. Renal vasoconstriction and impaired sodium excretion are the hallmark of virtually every form of hypertension. Pregnancy-induced hypertension [27], and hypertension associated with hyperparathyroidism [28], sinoaortic denervation [29], use of cyclosporine [30], erythropoietin [31], and contraceptive pills [32], and with rare experiments of nature such as pheochromocytoma [33], can all be explained in that way, albeit that the mechanisms leading to renal vasoconstriction and sodium excretion impairment will be different. In renal parenchymal hypertension [34,35] and renal transplant hypertension [36,37], one has to assume that vasoconstriction is added to the loss of functioning nephrons. One may have some difficulties with hypertension due to primary hyperaldosteronism (which is incorrectly judged as a rare condition, if one follows the newly defined diagnostic criteria [38]) and related conditions: in these cases hormone-induced sodium retention is generally associated with unchanged or

H. A. Koomans, J. A. Joles and T. J. Rabelink

increased renal plasma flow [39,40]. However, even then one can propose that the renal vascular resistance is too high for the body fluid volumes, as in the case of non-modulating essential hypertension (perhaps due to whole-body autoregulation). If renal vasoconstriction and sodium retention can explain all forms of hypertension, what news can we expect from 'new hypertensive mechanisms'? In fact very much, if we look at the consequences for the kidney. Obviously, inappropriate renin stimulation as the sole link between renal vasoconstriction and sodium retention is not the whole story. In fact, renal vascular tone is determined by an intricate balance between many vasodilating and constricting systems, such as sympathetic neural tone, vasoconstricting and vasodilatory eicosanoids, bradykinine, and adenosine. Any disturbance in this balance associated with renal vasoconstriction causes hypertension. For example, in unilateral renal artery stenosis not only increased angiotensin II but also sympathetic tone plays a role in sodium retention and vasoconstriction of the contralateral kidney [41,42]. Recently, endotheliumderived factors have been implicated in the renal vasoconstriction of hypertension. The endothelium has been recognized as an important modulator of vascular tone by simultaneous localized production of strong vasoconstrictor substances, such as thromboxane and endothelin, and vasodilator substances, such as prostacyclin and nitric oxide [43,44], An imbalance between these factors can induce profound renal vasoconstriction, as found, for example, during infusion of even modest amounts of endothelin or nitric oxide synthase blockers in humans (see below). Animal models for essential hypertension corroborate a role of endothelium dysfunction in the pathogenesis of hypertension. Salt-sensitive hypertension in Dahl rats can be prevented by administration of L-arginine, suggesting that insufficient endogenous nitric oxide production is involved [45]. In the salt-insensitive spontaneously hypertensive rat, however, the nitric oxide production is probably normal, but in stead constrictor eicosanoids seem to be increased [46,47]. An extensive discussion of the many possible options is beyond the scope of this overview. However, we have to realize that little is known about the exact basis of renal vasoconstriction imbalance underlying the essential hypertension and secondary hypertension in humans. Conceivably, the relevance of this pertains to the renal damage that may follow the hypertension.

From culprit to victim It is widely accepted that chronic exposure to elevated blood pressure is bad for the kidney. Recent studies described correlations between renal lesions such as arteriolar hyalinization and parenchymal fibrosis with blood pressure and atherosclerotic lesions in other organs [48,49]. Yet, one may doubt whether loss of kidney function as a direct effect of intrarenal hypertension should be regarded as a significant danger in

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Hypertension and the kidney

patients with essential hypertension. It is estimated that the yearly incidence of terminal renal failure due to hypertension is about 30 per million in white subjects [50,51 ]> which is not much if one considers a prevalence of hypertension of 15%. Moreover this incidence, about one-fourth of the total population entering dialysis, is probably due to renovascular disease rather than to nephrosclerosis (see below). The prevalence of nephrosclerosis is higher in blacks [52-54] but, rather than taking this as counter argument, one could consider that more than hypertension alone is required to destroy a relevant number of functioning nephrons. The spontaneously hypertensive rat is characterized by advanced development of proteinuria, but this may not be related to the hypertensive state [55]. On the other hand, nephrosclerosis with renal failure develops earlier in the Dahl salt sensitive hypertensive rat [56], again indicating that factors other than hypertension play an important role. In combination with metabolic or additional hemodynamic burden (such as uninephrectomy) the hypertension may be a decisive factor in renal parenchymal damage in these animals [57,58]. Hypertension also has been proven to be a factor of substance in accelerating kidney damage in renal disease due to primary causes or systemic disease in humans [59-61]. Thus, despite the fact that renal vasoconstriction is a generalized phenomenon in essential hypertension, there appears to be a large individual variability in the susceptibility to develop renal injury. We would like to submit the hypothesis that individual differences in pathogenesis of the renal vasoconstriction may be decisive. For example, enhanced sympathetic tone as the primary constricting factor would mainly cause afferent arteriolar constriction, and prevent transmission of the high systemic arterial pressure to the glomerular tuft. If this is the primary mechanism of essential hypertension (which is not unlikely, since muscle sympathetic nerve activity is also increased in offspring of hypertensive subjects [62]), one may not expect major renal damage, as long as there is no other noxious factor. By contrast, if endothelial dysfunction contributes to the renal vasoconstriction, renal injury is much more likely to follow. The endothelium derived factors not only modulate vascular tone, but also processes such as inflammation, intima-media proliferation, and vascular restructuring [43,44,63]. In this process, which counts numerous positive and negative feedback loops, each of the known endotheliumderived vasoactive factors plays its own part, vasodilators generally acting as decelerators, and vasoconstrictive factors as accelerators at multiple levels of the process [43,44,63].

rats [64,65] and humans [66] in acute experiments, can cause development of severe renal failure when administered for only a few weeks in the rat [67,68]. Morphological changes include arteriolar hypertrophy, with afferent arteriolar endothelitis and obliteration, and glomerular thrombosis [69,70]. Impaired nitric oxide availability probably underlies the renal vasoconstriction, endothelitis, and quickly progressive renal dysfunction in conditions such as hemolytic uremic syndrome and preeclampsia [70,71 ]. The other example concerns vasoconstriction induced by the chronic use of cyclosporin, also known to lead to renal dysfunction in apparent disproportion to the elevation of arterial pressure. Cyclosporin induces increased plasma levels and renal expression of endothelin [72], and impaired nitric oxide-dependent vasodilation [73]. Infusion of endothelin at a rate to obtain similarly elevated plasma levels in humans causes strong vasoconstriction, predominantly in the kidneys [74]. Taking these observations back to the clinic of essential hypertension, we know that impaired nitric oxide activity (measured impaired nitric oxide dependent vasodilation) is found in hyperlipidemia and and diabetes [75-78], which in fact are the risk factors for the development of renal failure in hypertension [79-81]. Whereas these and other secondary risk factors can be readily acknowledged in individual patients, the present pursuit focuses on recognition of patients which have an increased intrinsicrisk.Plasma markers such as platelet adhesion molecules, perhaps reflecting endothelial injury, are associated with an increased incidence of organ damage [82,83], but will not be specific for renal endothelial conditions. With the exception of one single study, fore-arm plethysmography studies show impaired endothelium-dependent vasodilation in essential hypertension [84]. Without denying the possible importance of such dysfunction, the wide prevalence of such dysfunction precludes its use as predictor of renal risk. Preferably, we should develop quantitative methods to measure endothelium function in the renal circulation in humans. Microalbuminuria, of which the incidence is increased in essential hypertension [85] but still low [86], may prove to be a good indicator of endothelium (dys-) function, but confirmation also awaits development of tests of endothelium-dependent vasomotor function of the human kidney. Need for such techniques is also emphasized by the new pharmacological options that have been developed not merely to decrease blood pressure, but also to improve endothelium function.

These pathogenetic mechanisms are being scrutinized at present, and roles of individual mediators and, in particular, their hierarchy explored. As 'magnifyingglass examples', we mention two clinical hypertensive conditions involving endothelium dysfunction, in association with renal vasoconstriction and accelerated loss of renal function. One is that nitric oxide synthase inhibitors, shown to cause strong vasoconstriction in

Suicide from a distance The true assault of hypertension on kidney integrity comes in disguise: progressive atherosclerotic narrowing of the renal arteries, causing renal hypotension rather than hypertension [87]. By causing chronic hypertension and progressive renal artery stenosis, the kidneys may commit suicide from a distance. The


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number of patients admitted to dialysis due to ischemic terminal renal failure has greatly increased over the past decade [50,88,89]. This seems somewhat paradoxical, since the frequency of other major cardiovascular complications of hypertension in the general western population is decreasing [90,91]. Relevant factors are, no doubt, increased awareness and recognition of bilateral ischemic renal disease due to better diagnostic work up, and the growing age of the patients admitted to dialysis. Recent estimations by the EDTA registry mention a frequency of 21% amoung patients over 65 years of age [51]. Estimations in individual countries were even higher: 38% in Italy [89], and 33% in the Netherlands (Renal Replacement Registry Netherlands report 1992). Prospective studies of older patients entering dialysis showed bilateral renovascular disease in 14% [92] (diagnosed by angiography) and 25% [93] (diagnosed by duplex sonography). Necropsy studies have shown a 25% prevalence of severe renal artery stenosis in subjects over 50 years of age, with bilateral disease in approximately half of these cases [94, 95]. Patients undergoing angiography for lower extremity or coronary vascular disease show severe renovascular atherosclerotic disease in, respectively, about 30-40% [96, 97] and 20% [98]. The insidously progressive character of this disease appears from observations that significant numbers of patients with established unilateral renal artery stenosis develop contralateral stenosis, a decrease in kidney length, or complete occlusion within a few years [99-101]. Until recently the main thrust of our therapeutic effort in renovascular disease was directed towards its role as source of hypertension. However, the very threat of atherosclerotic renal artery disease is probably the progressive loss of functioning nephrons due to the chronic ischaemia. Options for recanalisation are surgery, which is effective in providing primary and secondary patency, but is associated with substantial morbidity and mortality [102,103], and percutaneous transluminal angioplasty. Although the latter has a much lower morbidity, and has largely replaced surgery as primary treatment, it also knows a high primary and secondary failure rate [104-106]. This relates to the localisation of the stenosis, which is ostial in the majority of these patients [94,95]. Preliminary studies predict much better results with transluminal placement of intravascular stents [107,108], but long-term benefit and cost-effectiveness of this approach still have to be established. Given that an adequate treatment option will be found, the next and most significant task will be to design protocols for detection of patients at risk for this complication of hypertension. Clearly, we need non-invasive methods. Recent major advances in ultrasound [109] and visualising techniques [110] are very promising as for a reliable detection of anatomical lesions. However, methods to quantify the actual ischaemic threat to total kidney function will also be needed, and this has not been evaluated systematically. Once available, we will be faced with the dilemma where to begin, since so many subjects are at risk.

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