Clinical Conference Essential Hypertension: A Renal Disease?

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1 380 Clinical Conference Essential Hypertension: A Renal Disease? A Review and Update of the Evidence Principal Discussant Robert G. Luke Department of Internal Medicine, University of Cincinnati, College of Medicine (Ohio) T hat essential hypertension is a primary renal disorder is not a new idea. As early as 1836, Richard Bright1 observed that "the kidney is the chief promoter of the other derangements . . . including . . . hypertrophy of the heart." Blood pressure esis has been most easily obtained from studies of African-Americans, because their hypertension is seen at an earlier age, increases more quickly with time, has a higher prevalence, is more severe, and is associated with more adverse cardiovascular and renal effects, was not yet measured then, and undoubtedly, many of excluding primarily atherosclerotic disease.6"13 Five Downloaded from by guest on June 23, 2017 Bright's cases were due to chronic glomerulonephritis, main types of supportive evidence will be discussed: but the concept that a kidney disease had systemic transplantation of hypertension or normotension with consequences involving the cardiovascular system was the kidney, prehypertensive evidence of abnormal renal clearly expressed more than 150 years ago. It is often vascular responses, epidemiological association of a overlooked that Goldblatt et al,2 in their experimental high intake of sodium chloride with hypertension, cy- animal studies in the 1930s of what turned out to be closporine-induced hypertension as a model for essen- renovascular hypertension, were trying to create a tial hypertension, and the lack of prevention to date of model of intrarenal small vessel disease that they be- end-stage renal disease (ESRD) due to hypertensive lieved to be the cause of essential hypertension: "isch- nephrosclerosis despite the widespread availability of emia limited to the kidneys may be the initial condition in antihypertensive therapy. the pathogenesis of the hypertension that is associated with nephrosclerosis." Pickering3 observed in 1973 that Exaggerated renal vasoconstriction may be due to an "renal failure represents either the effects of the malig- imbalance of endocrine, paracrine, and autocrine regu- nant phase or the progression of some primary renal lators of renal blood flow. For example, exciting recent disease unidentified in the search for a specific cause." studies in a salt-dependent model (Dahl/Rapp) of es- Thus, he even doubted the possibility that nonmalig- sential hypertension in the rat have shown that provi- nant hypertension could cause chronic renal failure sion of increased intake of the nonessential amino acid before the now extensive documentation of the phe- L-arginine prevents hypertension and nephrosclerosis nomenon, especially for African-Americans. on a high salt intake.14 L-Arginine is the substrate for Guyton and coworkers4-5 propounded the thesis that the enzyme nitric oxide synthase, which produces nitric hypertension does not occur in the presence of a normal oxide, the "endothelium-derived relaxing factor," a kidney. Provided that sensing by the kidney of systemic potent local vasodilator.15 The effect of L-arginine is hypertension was unimpaired, and sodium reabsorption specific because it is blocked by a competitive inhibitor not enhanced, natriuresis and diuresis would reduce of the synthase, and hypertension is not prevented by plasma volume and restore normotension.4-5 Essential equimolar D-arginine.14 Infusion of the synthase inhib- hypertension meant that the kidney "required" a higher itor in humans causes hypertension, suggesting that than normal blood pressure to maintain normal extra- nitric oxide functions as a physiological regulator of cellular fluid volume (Figure 1). basal vasomotor tone16; this regulation may be abnormal I wish to review the additional evidence emerging in in essential hypertension.17 Nitric oxide also inhibits the past decade that essential hypertension results from smooth muscle18 and mesangial cell mitogenesis.19 It is an inherited renal tendency toward excess vasoconstric- thus a candidate defective vasodilator and inhibitor of tion or an inability to appropriately increase renal blood smooth muscle proliferation in initiating hypertension, flow. This would be especially important in certain especially if nitric oxide is normally increased by a high environmental situations involving a high dietary intake salt intake. of sodium chloride or stress with central nervous sys- tem, sympathetic nervous system, and renal vascular Renal vasoconstriction and antinatriuresis usually consequences. Clinical evidence supporting this hypoth- accompany each other. The tendency to renal vasocon- striction and hypertension may also contribute to selec- tion of 30% of patients with type I diabetes mellitus for Dr. Luke was an invited speaker at the Cardiovascular Center, diabetic nephropathy20 and to the apparent increase in College of Medicine, University of Iowa, Iowa City, June 8, 1992. Address for correspondence: Dr. Robert G. Luke, Department the prevalence of progression of primary renal disease of Internal Medicine, University of Cincinnati, College of Medi- to ESRD in African-Americans as compared with cine, 231 Bethesda Avenue, Cincinnati, Ohio 45267-0557. Caucasians.21-22

2 Luke Essential Hypertension: A Renal Disease 381 FIGURE 1. Plot shows Guyton's5 concept of elevated arterial pressure in essential hypertension. Point A repre- sents normal steady state with balance between intake and output at normal blood pressure, which increases almost undetectably at the new steady state on a high salt intake. In contrast, with essential hypertension at all intakes, an increasingly higher blood pressure is needed to maintain balance (points C, B, and D) (from Guyton et als). 50 100 150 200 Arterial Pressure ( mm.Hg) Downloaded from by guest on June 23, 2017 Secondary causes of hypertension can readily be either before hypertension or after the to-be-trans- explained by the Guytonian nephrocentric approach. planted "hypertensive" kidney was protected by antihy- For example, aldosterone and catecholamines interfere pertensive drugs.29 Thus, hypertension is corrected or with normal sodium excretion in primary hyperaldoster- induced in rats solely by transplantation of a single onism and pheochromocytoma, respectively. Aortic co- immunologically well-tolerated kidney. arctation prevents renal sensing of systemic hyperten- Our interests in the etiology and mechanism of sion. Chronic renal failure reduces excretion of sodium postrenal transplant hypertensive syndromes allowed us chloride, and the renin-angiotensin system is inappro- to pose, and answer, the question as to whether these priately stimulated in relation to extracellular volume. A rat experiments could be reproduced in humans. Be- recent report documents a fascinating new cause of cause of the frequency and multiple causation of post- secondary hypertension due to a vascular tumor-pro- transplant hypertension in humans, it is very difficult to ducing endothelin, a very potent renal vasoconstrictor.23 show transmission of hypertension from a "hyperten- Two-kidney, one clip hypertension is similarly eluci- sive" kidney. After all, known hypertension in the donor dated by the effects of circulating angiotensin II from contraindicates use of the donor kidney. Some rather the ipsilateral kidney on the contralateral "normal" inconclusive evidence of increased hypertension in the kidney, thus preventing the "normal" kidney from cor- allograft recipient has been provided when the donor recting hypertension.24 Likewise, the native kidneys can kidney came from families with a history of hyperten- cause vasoconstriction of an apparently normally func- sion30 or after subarachnoid hemorrhage.31 The con- tioning human renal allograft. Hypertension can then be trary experiment remission of hypertension that had corrected either by native kidney nephrectomy or by caused renal failure due to nephrosclerosis after treatment with converting enzyme inhibitors.25 Second- transplantation of kidney from a normotensive donor ary causes of hypertension primarily associated with provides more convincing evidence of the primacy of the retention of sodium chloride are accompanied initially kidney. by extracellular fluid volume expansion and a normal We were able to do this in studies at a clinical peripheral resistance. How this form of hypertension research center in a large renal transplant center in makes the transition to hypertension with a normal Birmingham, Alabama, in which approximately 50% of cardiac output and an increased peripheral resistance is the transplant recipients were African-Americans. Hy- discussed later when the same pathophysiological prob- pertensive nephrosclerosis was believed to be the cause lem for essential hypertension is considered. of renal failure in about one third of these patients.32 As in most renal transplant programs in the earlier years, Transplantation of a Normotensive Kidney bilateral nephrectomy of the native kidneys was com- "Cures" Essential Hypertension monly performed before transplantation, especially if Studies to date in experimental rat models of essen- the recipient was hypertensive. We selected six patients, tial hypertension with appropriate syngeneic strains for all nephrectomized and African-American, in whom we hypertensive and normotensive controls have shown and an independent nephropathologist could be confi- that after removal of native kidneys, hypertension "fol- dent of the diagnosis of essential hypertension from the lowed" the hypertensive kidney in the normotensive clinical history and careful study of the removed kid- strain, and the normotensive kidney corrected hyperten- neys. Hypertension was in "remission" at a mean time sion in the hypertensive rat strain.26"28 Moreover, a of 5 years after transplant in all six patients. There also harmful effect of hypertension on the hypertensive had been a remarkable and documented regression in kidney before transplant as a possible cause of trans- left ventricular hypertrophy and hypertensive retinal planted hypertension was excluded by transplantation changes. An example of one of these patients follows.

3 382 Hypertension Vol 21, No 3 March 1993 The patient was a 33-year-old black man who was first these inclusion criteria were normotensive. This is very told he had hypertension in 1966 during a physician close to the prevalence of hypertension we had ob- examination for the armed forces. He did not receive served in patients with primary parenchymal renal therapy for his hypertension until 1976, when he was disease who met these same criteria.33 This suggests that seen in a local emergency room for a laceration on his hypertension associated with hypertensive nephroscle- arm and was again found to be hypertensive. For 6 rosis, like primary renal disease, remits after successful months, his blood pressure was controlled with antihy- transplantation of an allograft in the absence of, for pertensive medications, but headaches developed and instance, allograft chronic rejection, renal artery steno- he was seen at a local emergency room with a blood sis, or native kidney hypertension. This contrasts with pressure of 188/120 mm Hg. He was admitted to that the recurrence of another common "secondary" cause hospital and found to have left ventricular hypertrophy of ESRD, diabetic nephropathy, despite successful re- by chest radiography and electrocardiography; arterio- nal transplantation. Dr. Curtis (personal communica- lar narrowing and exudates were seen on funduscopic tion) confirms that normotension continues for the long examination. His serum potassium level was 4 mmol/L, term after transplantation in these patients, provided his blood urea nitrogen level was 35 mg/dL (12 mmol/ renal function is maintained. Of course, the problem is L), and urinalysis was negative for protein. His blood now compounded by the almost universal use of the pressure was better controlled with increases in his hypertensinogenic drug cyclosporine after renal trans- antihypertensive medications, and he was referred to plantation. Cyclosporine probably has reduced the Vanderbilt University Hospital for evaluation of the prevalence of chronic rejection and its associated hyper- cause of his hypertension. At Vanderbilt, he underwent tension but has decreased the prevalence of normoten- intravenous pyelography and renal arteriography, the sion due to normal allograft function. Downloaded from by guest on June 23, 2017 results of both of which were normal. Urinalysis re- Our studies of the transplant patients whose hyper- vealed trace protein, and the 24-hour urinary protein tension and hypertensive disease had remitted after excretion level was 500 mg. The 24-hour urinary excre- successful renal transplantation also demonstrated nor- tion of catecholamines was also normal. The blood urea mal renal handling of sodium and normal changes in nitrogen level was 29 mg/dL (14 mmol/L), and the plasma renin activity in response to a normal, low, and patient was seen in consultation with members of the high salt intake. nephrology service, who thought his long-standing hy- We postulate that essential hypertension begins with pertension, low level of proteinuria, and normal-sized a functional defect in sodium chloride excretion that is kidneys were consistent with nephrosclerosis and rec- associated with renal vasoconstriction. Renal vasocon- ommended that he not undergo renal biopsy. The strictors such as angiotensin II and endothelin also patient's mother and father were both hypertensive and appear to cause arteriolar smooth muscle proliferation, required medication. One sister (aged 30 years) was also which could cause both heightened responses to ago- taking antihypertensive medications, and a brother nists and, eventually, nephrosclerosis. In this construct, (aged 23 years) had been told he was hypertensive and hypertension might initially be prevented or, at least in given prescriptions for medications. the very early stages, reversed by manipulation of renal The patient's antihypertensive medications were blood flow, dietary intake, or both. Later irreversible adjusted at Vanderbilt, and he was discharged in 1976 structural renal changes might require nephrectomy for with a diagnosis of essential hypertension to be followed cure of hypertension. The analogy of the progression in by his local physician. In 1978 he saw his physician essential hypertension from a reversible, functional again, admitted he had not taken his medications, and vascular defect to an irreversible, structural vascular was noted to have a blood urea nitrogen level of 129 renal lesion with experience in patients on cyclosporine mg/dL (46.1 mmol/L) and a creatinine level of 19 mg/dL will be discussed. The diagnosis of hypertensive neph- (1,700 Aimol/L). His blood pressure was 200/130 rosclerosis is one of exclusion, and knowledge of the mm Hg, and he was started on hemodialysis therapy. A sequence of onset of hypertension, renal insufficiency bilateral nephrectomy was performed because his blood and proteinuria, family history of hypertension, and pressure could not be adequately controlled on dialysis. renal histology is often unavailable but invaluable for One month after nephrectomy, blood pressure control establishing the diagnosis of primary hypertension. We was improved. Mean arterial pressure was 1133 had to screen approximately 80 patients to obtain our mm Hg on long-term dialysis. One year later (1979), the six patients with a firm diagnosis, as in the patient patient received a cadaver renal transplant and did well. described. Furthermore, our studies clearly would not Three years later he was admitted to the clinical re- have been feasible if cyclosporine had been in routine search center for studies. His blood pressure was 125/80 use at the time. mm Hg (mean arterial pressure, 95 mm Hg) without antihypertensive medications. Prehypertensive Changes in Renal Blood Flow Because we had made great efforts to ensure primary Studies of normotensive relatives of patients with hypertension as a diagnosis, the question as to whether essential hypertension have shown increased renal va- these results were representative of other posttrans- soconstriction in response to mental stress and postural plant patients arises. One female Caucasian patient met changes.34"36 Interactions between stress, renal blood our clinical requirements for inclusion and was nor- flow, and sodium chloride retention have also been motensive but was excluded mainly for epidemiological seen.37-38 Failure of renal blood flow to increase in reasons. When we included all patients who had been response to a high salt intake has also been seen in nephrectomized, were at least 1 year posttransplant, similar subjects by the investigators who have described and had stable renal function with a serum creatinine "nonmodulating hypertension."39 An important recent level less than 2 mg/dL, 76% of the 33 patients meeting European study of normotensive children of parents

4 Luke Essential Hypertension: A Renal Disease 383 both of whom had well-established essential hyperten- Renal Vasoconstriction sion in comparison with children with matched nor- motensive parents showed reduced renal blood flow in the children of the hypertensive parents.40 Reduced renal blood flow and enhanced responsiveness to angio- Nephrosclerosis : Hypertension tensin II41 have also been shown in prehypertensive rat ("Vicious Circle") models. In established hypertension, renal blood flow has long been known to be reduced, with a relative FIGURE 2. Diagram shows proposed primary role of vaso- preservation of glomerular filtration rate (GFR). 4243 constriction in genesis of both nephrosclerosis and hyperten- sion. See text for details. The Role of Sodium Chloride Intake We postulate, along with others, that enhanced ability If a high sodium chloride intake is an important to conserve salt by renal mechanisms in a high-tempera- environmental factor in the genesis of essential hyper- ture, very low salt environment (estimated intake of 9 tension, reduction in sodium chloride intake might meq/day of sodium) conveyed a Darwinian advantage to, reduce hypertension. In an extensive meta-analysis, Law especially, our African ancestors. Renal conservation of et al54 have summarized that evidence. Their review of sodium occurs by multiple mechanisms, including renal 78 studies in humans clearly shows a very significant vasoconstriction, neurohumoral changes, enhanced sym- effect of sodium chloride intake, provided that subjects pathetic and renin-angiotensin-aldosterone activity, and are observed on the reduced intake for at least 5 weeks. decreased formation of renal bradykinin, dopamine, and It would not be surprising if the mechanisms described Downloaded from by guest on June 23, 2017 possibly nitric oxide. Enhancement of renal salt conserva- that can account for enhanced peripheral resistance tion might well involve multiple separate mechanisms in might require some time to reverse. Patients with individuals, and, if this hypothesis is correct, a single gene chronic renal failure also have evidence for a circulating defect is unlikely. Enhanced renal salt conservation on a natriuretic, ouabainlike substance and require several low salt intake might well be associated with decreased weeks on a low salt diet to develop normal sodium ability to excrete a salt load. In African-Americans, a salt conservation.55 Perhaps a similar delay is needed to load is less efficiently excreted than in Caucasians as a reverse the process leading to an enhanced arteriolar group.44 Likewise, bradykinin and dopamine responses to cytosolic calcium concentration in essential hyperten- salt loading are diminished.4546 sion when dietary sodium is reduced. Subtle salt retention on a high salt intake would lead Only approximately 50% of all patients with essential initially to hypertension with a high extracellular fluid volume, high cardiac output, and normal peripheral hypertension show a reduction in blood pressure on a resistance. Essential hypertension is usually associated, lowered sodium chloride intake even though group however, with a normal cardiac output and enhanced means fall significantly. This may relate to the stage of peripheral resistance. Three mechanisms of transition hypertension (e.g., patients with irreversible vascular from the former to the latter hemodynamic state are changes would be less likely to respond) or to different postulated: reflex vasoconstriction in response to high pathophysiological mechanisms for hypertension, in- organ flow4-5; brain release of a ouabainlike inhibitor of cluding the renin-angiotensin system. Na+ ,K+-ATPase, the purpose of which is restoration of Not considered in this discussion is an important extracellular fluid volume via natriuresis but a second- effect of dietary potassium on both hypertension and ary consequence of which leads to increased cytosolic cardiovascular and renal vascular disease.56 Primitive calcium and arteriolar vasoconstriction47; and structural diets were probably very high in potassium by contem- changes in arterial and arteriolar walls.48 porary standards, as well as being low in sodium. Arteriolosclerotic changes in hypertensive patients Cyclosporine-Induced Hypertension as a Model are most severe in the kidney,49 which would be consis- tent with primary renal vasoconstriction. From exten- for Essential Hypertension sive studies of renal histology obtained at the time of To test the hypothesis that primary renal vasocon- bilateral sympathectomy for treatment of essential hy- striction causes essential hypertension, one might plan pertension, Castleman and Smithwick50 believed that an experiment in which blood pressure is observed arteriolonephrosclerosis was secondary to, and usually during the long-term administration and subsequent was not seen until after 5 years of, hypertension. In withdrawal of an agent that produced reversible renal contrast, recent careful morphometric studies of renal vasoconstriction. The opportunity to do this has been vessels obtained from autopsies of young adult (aged provided by the widespread therapeutic use of cyclo- 15-24 years) victims of accidents in various countries sporine, initially for organ transplantation, but now for showed that increased intimal renal arteriolar narrow- a wide variety of systemic and localized (e.g., psoriasis) ing correlated with increased hypertension in these immunological diseases. Cyclosporine even in small societies,51 raising the possibility of primary renal vas- doses reproducibly causes renal vasoconstriction after cular changes in hypertension. Primary renal vasocon- every oral administration of the drug.57 GFR is rela- striction may lead to both hypertension on a high salt tively well maintained at least in the initial reversible intake and nephrosclerosis (Figure 2). It should be stage of renal vasoconstriction, but nephrosclerosis can remembered that nephrosclerosis has been observed in eventually occur with a fall in filtration rate due to normotensive states with prolonged vasoconstriction, irreversible glomerular sclerosis.58 such as in Bartter's syndrome52 and in chloridiarrhea,53 Initially, the Medicare program did not pay for cyclo- which are associated with renal wasting of sodium sporine after renal transplantation, and we observed 14 chloride. patients with excellent renal function at approximately

5 384 Hypertension Vol 21, No 3 March 1993 TABLE 1. Effect of Conversion From Cyclosporine to Acute Kciiiil KHecls Azathioprine at 102 Months Cyclo- Azathi- Measurement sporine oprine "EKDOTHELIAL" Mean arterial pressure (mm Hg) 10815 9810* VASOCONSTRICTORS Cytnsol Effective renal plasma flow (mL/min) 23660 32280*

6 Luke Essential Hypertension: A Renal Disease 385 TABLE 2. Comparison of Essential and Cyclosporine-Induced STRESS HIGH SALT INTAKE Hypertension Essential Cyclosporine induced Usually mild to moderate. Rare malignant phase in Rare hemolytic-uremic which microangiopathic syndrome. hemolytic anemia is common. CYCLO "Salt-dependent." Associated with initial prehypertensive renal vasoconstriction and, in established phase, with a high filtration fraction. SODIUM CHLORIDE RETENTION Associated later with nephrosclerosis. Can cause hypertension of chronic renal failure and end-stage renal disease. Develops over Develops in weeks to "OUABAIN" ECF VOLUME AND 10-20 years. months in most cases. CARDIAC OUTPUT More severe in African-Americans. ? INCREASED ARTERIOLAR CA++ I ORGAN FLOW f Reversible or preventable Reversible if if renal blood normalized cyclosporine Downloaded from by guest on June 23, 2017 REFLEX SYSTEMIC and/or low salt intake? discontinued early. VASOCONSTRICTION transplantation within 2 weeks, a time at which any SUSTAINED HYPERTENSION renal reinnervation is very unlikely. Cyclosporine is WITH NORMAL CARDIAC OUTPUT clearly a new and important iatrogenic form of hyper- tension in humans. The comparison with essential hy- pertension is very interesting (Table 2). In both, renal vasoconstriction precedes hypertension and nephroscle- rosis. Myers and Newton58 estimate a 10% prevalence of ESRD at 10 years after cardiac transplantation and FIGURE 5. Diagram shows proposed short-circuiting effect maintained cyclosporine therapy. Whether or not cy- of cyclosporine (CYCLO) on development of "salt-depen- closporine-induced hypertension is more severe in Af- dent" hypertension; the key accelerating influence is that of rican-Americans is not yet established, but I predict that direct systemic vasoconstriction. ECF, extracellular fluid. this will be observed. Renal transplant rejection has been more common in blacks, and this has made it more difficult to examine the frequency of cyclosporine-in- yearly incidence of ESRD due to hypertensive nephro- duced hypertension. This should be feasible, however, sclerosis despite the availability of antihypertensive in cardiac transplant patients and other groups of therapy since the 1950s. Hypertensive nephrosclerosis patients treated with cyclosporine and merits attention. accounts for 40% of ESRD in African-Americans and In this construct, then, cyclosporine offers a com- approximately 25% of ESRD in U.S. whites, the latter pressed-in-time model for essential hypertension (Fig- being mainly in patients older than 65 years.72 The ure 5). The weakest link and most difficult aspect to black:white ratio is 20:1 for the group from 25 to 45 study, because of the long observation period required, years of age, and there has also been no reduction in is the mechanism of proposed transition from high this age group. All of this younger group are highly cardiac output to high peripheral resistance essential unlikely to have been excluded from consideration for hypertension. Cyclosporine short-circuits this period by ESRD therapy since the introduction of renal Medicare causing early systemic vasoconstriction, albeit less se- in 1972. However, it is possible that some of the increase vere than the renal vascular vasoconstrictive response. in hypertensive ESRD in the elderly is due to increased Careful studies of the effect of a diminished dietary salt selection of, and acceptability for, elderly patients for intake plus maintained renal blood flow (perhaps by ESRD treatment. We have recently shown a change in calcium channel blockers) on the prevalence of cyclo- the peak incidence by age of hypertensive nephroscle- sporine-induced hypertension in patients on cyclospor- rosis but an overall total increase for all ages between ine for a nonsystemic renal disease such as psoriasis 1978 and 1988 in Jefferson County, Alabama.80 We might be enlightening. interpreted this as a possible delay in the development of ESRD due to primary hypertension because of Lack of Prevention of End-Stage Renal Disease antihypertensive therapy; however, there is, as yet, no Due to Primary Hypertension evidence of prevention of development of ESRD. If hypertension has a nonrenal cause, then effective The studies establishing the efficacy of antihyperten- antihypertensive therapy should prevent secondary re- sive therapy in lowering morbidity and mortality contain nal effects. It has certainly been easy to demonstrate only a few renal events with no evidence of reduction in effective reduction in cardiovascular secondary effects their frequency.81-83 Cardiovascular events, of course, such as stroke and cardiac failure.79 We now have are much more common than renal failure probably by excellent data on the yearly incidence of ESRD in the a factor of at least 100:1 if ESRD is the renal event United States.72 There continues to be an increase in considered; approximately 10,000 patients per year de-

7 386 Hypertension Vol 21, No 3 March 1993 velop ESRD due to hypertension. There is absolutely no suggests that the effects of remaining intact nephron doubt, however, that in some patients with malignant adaptation and hypertrophy lead to often slowly but hypertension, antihypertensive treatment can lead to inexorably progressive chronic renal failure once GFR eventual improvement in renal function. is less than approximately 25-30 mL/min; this progres- Long-term prospective studies of renal function in sion can be slowed but not stabilized or reversed. treated hypertensive patients are scanty and obviously Indeed, for primary renal disease, blood pressure con- not yet available for more recently available classes of trol remains the best documented method for slowing drugs such as converting enzyme inhibitors or calcium progression. channel blockers. This is especially true if one considers Increasing emphasis is being placed on the effects of serial measurement of true GFR. In a Scandinavian different antihypertensive drugs on individual organ follow-up of 8 years, Ljungman et al84 showed a fall in responses to lowering of blood pressure, e.g., left ven- GFR in comparison with age-matched controls. In tricular hypertrophy for the heart. In the kidney, control contrast, in a study over several years but with patient of intraglomerular pressure may be important in pre- groups partially separated into two levels of target blood serving renal function.92 It is possible that, if systemic pressure, GFR was apparently maintained by therapy blood pressure is not lowered enough, a predominantly that included minoxidil.85 Several retrospective studies afferent arteriolar effect of an antihypertensive agent have shown no evidence of renal protection by appar- would actually increase intraglomerular pressure. Nev- ently effective antihypertensive treatment, especially in ertheless, ischemic wrinkling collapse of the glomerular African-Americans.86"89 In an important analysis of the tuft is a much more commonly seen lesion in hyperten- Multiple Risk Factor Intervention Trial (MRFIT), ad- sive nephrosclerosis than is focal glomerulosclerosis, the mittedly using reciprocal serum creatinine measure- hallmark lesion of the adapted hyperperfused nephron. Downloaded from by guest on June 23, 2017 ments but over 8 years and with well-documented good It is also possible that our conventional target blood control of blood pressure (to 132/87 mm Hg in the pressure is too high at 140/90 mm Hg for patients at "usual care" group and 121/82 mm Hg in the "special renal risk. intervention" group), Walker and coworkers89 demon- The diagnosis of hypertensive nephrosclerosis is one of strated protection of renal function in white but not in exclusion and can be quite difficult without histological black subjects. Mean blood pressure at entry was 143/97 corroboration, as noted previously. Overdiagnosis in Afri- mm Hg and age ranged from 35 to 57 years (mean, 47 can-Americans is certainly possible. Occult primary renal years); projection of the data on reciprocal creatinine disease and, especially in the elderly, renovascular renal suggested that approximately 3-5% of such hyperten- failure or atheroembolic renal disease can be overlooked. sive African-Americans would go on to ESRD in later Nevertheless, two recent studies as to the accuracy of life. These calculations, if correct, clearly show that even causes of ESRD in the U.S. renal registry have shown moderate primary essential hypertension can lead to approximately 90% diagnostic accuracy for the original ESRD and can explain the continuing high annual diagnosis including hypertensive nephrosclerosis.22'93 incidence of ESRD due to hypertension, especially in Before antihypertensive drugs were available, approx- blacks. Long-term studies in spontaneously hyperten- imately two thirds of patients with "benign" hyperten- sive rats90 using triple therapy with reserpine, hydral- sion died within 20 years; uremia accounted for approx- azine, and thiazide controlled blood pressure well and imately 10% of these deaths, with most of the remainder prevented left ventricular hypertrophy and strokes, but being due to stroke and heart failure.94-95 Since heart renal arterial lesions and renal failure developed and failure and stroke have been much reduced by lowering progressed, again suggesting lack of renal protection by of blood pressure, more of these patients may now be at least these antihypertensive agents. surviving to develop renal failure, but even if this is true, How can we explain the failure to protect the kidney it at least means that a diminished protective effect is in primary hypertension? The following possible expla- being seen for the kidney. nations are by no means mutually exclusive. Finally, antihypertensive drugs may be treating the Potential contributory causes include lack of compli- effect of the underlying problem (the hypertension) and ance with therapy for financial reasons or intolerance of not the cause (the renal abnormality); this may apply side effects; lack of access to medical care; or, even in especially to African-Americans. At the very least, those adequately insured, lack of detection of hyperten- present therapy appears inadequate for renal protec- sion or inadequate attention to mild hypertension. Re- tion, especially in that group. We need, as in type I cently, however, we were able to examine ESRD due to diabetes mellitus, predictors of renal risk and new hypertension together with socioeconomic status in treatments that use additional or different drugs to blacks in New York State but could see no correlation. control blood pressure to, perhaps, lower levels. A trial This was also observed in Maryland.91 These findings that will address these issues and, it is hoped, will use argue against access or compliance as an important cause renal biopsy for diagnostic and prognostic purposes, is for the increased prevalence in African-Americans. currently being organized by the National Institutes of In some patients at least, treatment may begin too Health. The major question addressed will be whether, late, so intrinsic renal damage, especially arterioneph- in moderate hypertension especially in African-Ameri- rosclerosis, is already present and conventional renal cans, GFR can be maintained or improved by various hypertension then exists. An elevated serum creatinine drug regimens. level is probably a very insensitive test for nephroscle- Purposes of proposed inclusion of renal biopsy for at rosis or for a reduction in GFR, although little correl- least some of the subjects in this trial include the ative data exists because renal biopsies are currently so exclusion of otherwise missed primary renal disease, seldom performed in patients with modest hypertension assessment of the degree of vascular and glomerular with minimal or no proteinuria. Much evidence now damage, and determination of histological indicators for

8 Luke Essential Hypertension: A Renal Disease 387 patients at risk for progressive renal damage. Similar I have tried to discuss the reasons why some patients arguments have been made for renal biopsy in trials with essential hypertension, especially African-Ameri- attempting to prevent diabetic glomerulosclerosis.96 It is cans, appear to have effective reduction in cardiovascu- hoped that careful correlation of histology with clinical lar disease in response to antihypertensive therapy but features and noninvasive measurements such as mi- not in progressive renal disease. A lower target blood croalbuminuria, proteinuria, retinal fundal changes, left pressure in the earlier, milder phases of essential hy- ventricular hypertrophy, and GFR will allow subsequent pertension seems a reasonable goal that should be avoidance of renal biopsy for actual clinical practice. tested in any prospective study if it is feasible. From the In no way do I wish my position to be interpreted as renal viewpoint, provided one keeps within the autoreg- therapeutic nihilism. Obviously, even if hypertensive ulatory blood pressure range, GFR seems to be well therapy does not fully protect the kidney, vigorous and maintained with most currently used antihypertensive effective blood pressure control is indicated from the drugs, with the possible exception of some j3-blockers, cardiovascular viewpoint. In addition to controlling hy- although this is somewhat controversial. With severe pertension, current evidence suggests that attempts to nephrosclerosis, as with renovascular hypertension, an normalize renal blood flow and restrict salt intake in abrupt drop in GFR can be seen with converting younger hypertensive patients and especially in African- enzyme inhibitors, even when blood pressure is still Americans with a family history of hypertensive renal within the autoregulatory range. This presumably is due to efferent dilatation in a situation in which efferent disease are reasonable. It would also seem prudent to constriction is maintaining glomerular capillary pres- advocate a low dietary salt intake from childhood in all sure. In accelerated or malignant hypertension, auto- close relatives of especially black patients with hyper- regulation of GFR may be defective, and renal function Downloaded from by guest on June 23, 2017 tensive renal disease. An increase in dietary potassium may deteriorate when blood pressure is controlled. This intake would also be rational in such patients. Even can be minimized by gradual rather than abrupt return normotensive live, related donors under the age of 40 of blood pressure toward the normal range. Renal years should probably not be used for transplantation of function usually subsequently improves over weeks or patients with hypertensive renal disease, because loss of months. Indeed, it is not uncommon to see such patients one kidney might contribute to the development of come off dialytic treatment if such has been required. hypertension in the donor. Dr. Allyn L. Mark (University of Iowa, Iowa City): An In summary, I have provided evidence that, at least interesting observation with cyclosporine-induced hy- for some members of our society, facile renal vasocon- pertension is that both the frequency and severity of the striction and conservation of sodium chloride, previ- hypertension are greater after cardiac transplantation ously an evolutionary advantage, can now initiate a than in patients with myasthenia gravis. Do you have an mechanism leading to essential hypertension. explanation for this? How does it fit with your hypoth- esis about the primary role of the kidney in cyclospor- Questions and Answers ine-induced hypertension? Dr. Michael Shasby (University of Iowa, Iowa City): Dr. Luke: I must admit I am not aware of specific data What is the microvascular pressure in the glomerulus? on cyclosporine treatment in myasthenia gravis. In most In the lung, pressures of 45-50 mm Hg will disrupt the long-term follow-up studies lasting more than a year, microvascular wall. with doses of cyclosporine of 5 mg/kg or more, the Dr. Luke: The normal glomerular capillary pressure prevalence of hypertension approaches 80-90%. In solid in humans is believed to be around 50 mm Hg. In organ transplantation, most agree that the prevalence of essential hypertension, afferent arteriolar or at least hypertension is greater with cardiac transplantation than preglomerular restriction is believed to protect the in renal transplantation. This may be due, at least in part, glomerular capillaries from substantial rises in intra- to maintained renal sympathetic innervation in cardiac glomerular pressure. Certainly, the characteristic lesion transplantation, in contrast to renal transplantation. of hypertensive nephrosclerosis is ischemic glomerular Sympathetic stimulation clearly plays a role in cyclospo- "wrinkling collapse." In malignant hypertension when rine-induced hypertension. Nevertheless, it is not essen- fibrinoid necrosis of the preglomerular resistance ves- tial because hypertension that appears to relate to cyclo- sels occurs, severe glomerular disruption and damage sporine can be seen within 2 weeks of live donor then ensues. Focal glomerulosclerosis, the hallmark of transplantation at a time when there is certainly no the adapted nephron syndrome, is not a frequent find- sympathetic reinnervation of the allograft. ing in hypertensive nephrosclerosis. Dr. Annette Fitz (University of Iowa, Iowa City): Is Dr. Gerald F. DiBona (University of Iowa, Iowa City): there a difference between endothelial function in Would concern about the J point effect limit the target blacks versus whites? level of blood pressure control and subsequent benefi- Dr. Luke: I do not think that this has been studied as cial effect on the kidney? yet in a definitive fashion, but it is a very good question Dr. Luke: Certainly, in older patients with known or and should be addressed in humans. Endothelium- suspected coronary artery disease, it would be reason- derived constricting and relaxing factors such as endo- able to have a target goal for diastolic blood pressure of thelin and nitric oxide are clearly important in the 85 mm Hg. In younger patients, I favor aiming at a regulation of renal blood flow and may be important in blood pressure within the normal range if the patient the normal excretion of an increased intake of sodium tolerates it. There is good evidence for patients with chloride. The kallikrein-bradykinin and dopamine vaso- underlying primary renal disease that excellent blood dilator systems do seem to be less effective in blacks. It pressure control is the best documented method of is important to remember that all primary renal diseases slowing progression. appear to go more frequently to end stage in blacks as

9 388 Hypertension Vol 21, No 3 March 1993 compared with whites, and the answer to this problem ously, there is a very good correlation between malig- may also lie in different endothelial and vascular re- nant or accelerated hypertension, and grade III or grade sponses to injury. Of course, changes in endothelial IV fundi, but in the earlier stages of hypertension, I do function could result from, as well as cause, hyperten- not know of any definitive studies on the correlation sion. Dietary potassium in African-Americans tends to between retinal vascular changes and hypertensive be less than in whites, and Tobian has thoroughly nephrosclerosis. This would be a useful part of any documented, at least in animal models, the beneficial prospective controlled multicenter study. effects of a high potassium intake on the microvascula- ture in brain and kidney. Some of the differences References between blacks and whites in prevalence of hyperten- 1. Bright R: Tabular view of morbid appearance in 100 cases con- sion and in the vascular response to hypertension may nected with albuminous urine. Guys Hosp Rev 1836;l:380410 relate at least partly to dietary influences. 2. Goldblatt H, Lynch J, Hanzal RF, Summerville WW: Studies on experimental hypertension: 1. Production of persistent elevation of Dr. Gerald F. DiBona (University of Iowa, Iowa City): systolic blood pressure by means of renal ischemia. J Exp Med Based on your pathogenesis scheme, would you favor the 1934;59:347-379 use of antihypertensive agents that are renal vasodilators? 3. Pickering G: Hypertension, definitions, natural histories, and con- sequences in Laragh JH (ed): Hypertension Manual: Mechanisms, Dr. Luke: Both calcium channel blockers and convert- Methods, Management. New York, Yorke Medical Books, 1973 ing enzyme inhibitors appear to be able to increase 4. Guyton AC, Coleman TG, Cowley AW Jr, Scheel KW, Manning renal blood flow in essential hypertension for periods of RD, Norman RA: Arterial pressure regulation: Overriding domi- a year or so. The long-term effects in terms of prevent- nance of the kidneys in long-term regulation and in hypertension. ing target-organ damage in the cardiovascular system or Am J Med 1972;52:584-594 5. Guyton AD, Manning RD Jr, Hall JE, Norman R, Young DB, Pan Downloaded from by guest on June 23, 2017 in the kidney remain to be proved. If a pathological YJ: The pathogenic role of the kidney. J Cardiovasc Pharmacol increase in glomerular capillary pressure is important in 1984;6:S151-S161 producing glomerular damage, then the principal site of 6. Campese VM, Parise M, Karubian F, Bigazzi R: Abnormal renal vasodilation in the renal resistance levels, and in partic- hemodynamics in black salt-sensitive patients with hypertension. Hypertension 1991;18:805-812 ular whether these are preglomerular or postglomeru- 7. Entwisle G, Apostolides AY, Hebel JR, Henderson MM: Target lar, may be important. There do appear to be differ- organ damage in black hypertensives. Circulation 1977;55:792-796 ences in responses to various hypertensive drugs in 8. Freis ED: Age, race, sex and other indices of risk in hypertension. terms of effects on proteinuria, but this may or may not Am J Med 1973;55:275-280 relate to long-term preservation of renal function. We 9. Levy SG, Talner LB, Coel MN, Holle R, Stone RA: Renal vascu- lature in essential hypertension: Racial differences. Ann Intern Med seldom use direct-acting vasodilators such as minoxidil 1978;88:12-16 or hydralazine without the concomitant use of /3-block- 10. Light KC, Obrist PA, Sherwood AJ: Effect of race and marginally ers and often diuretics. Some animal studies suggest elevated blood pressure on responses to stress. Hypertension 1987; that, even at the same blood pressure level, direct 10:555-563 11. Manatunga AK, Jones JJ, Pratt JH: A racial difference in the rate vasodilators are less protective for glomerular and renal of blood pressure change with age. (abstract) Clin Res 1992;40: function than are, for example, converting enzyme 426A inhibitors. However, as yet we have no such evidence in 12. National Health Survey: Hypertension and Hypertensive Heart Dis- humans on any long-term basis. It should be remem- ease in Adults: U.S. 1960-62. US Dept of Health, Education, and Welfare, Vital and Health Statistics Series 11, No. 13. Washington, bered that Pettinger's studies on preservation of renal DC, US Government Printing Office, 1966 function in hypertensive nephrosclerosis included the 13. Eknoyan G, Suki WN: Renal consequences of antihypertensive use of minoxidil. therapy. Semin Nephrol 1991;11:129-137 I think the most important therapeutic issue is to 14. Chen PY, Sanders PW: L-Arginine abrogates salt-sensitive hyper- tension in Dahl/Rapp rats. 7 Clin Invest 1992;88:1559-1567 control blood pressure by any means acceptable to, and 15. Moncada S, Palmer RMJ, Higgs EA: Nitric oxide: Physiology, affordable by, the patient. Given a choice, in terms of pathophysiology, and pharmacology. Pharmacol Rev 1991;43: prevention of hypertensive nephrosclerosis, I would 109-142 favor a combination of calcium channel blockers and 16. Rees DD, Palmer RMJ, Moncada S: Role of endothelium-derived nitric oxide in the regulation of blood pressure. Proc NatlAcad Set converting enzyme inhibitors if hypertension is moder- USA 1989;86:3375-3378 ate to severe, and the use of monotherapy if it is mild. 17. Panza JA, Quyyumi AA, Brush JE, Epstein SE: Abnormal endo- Clinical proof of increased efficacy of one antihyperten- thelium-dependent vascular relaxation in patients with essential sive drug over another in humans in terms of hyperten- hypertension. N EnglJ Med 1990;323:22-27 18. Garg UC, Hassid A: Nitric oxide-generating vasodilators and sive nephrosclerosis will probably take a long time to be 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and developed. proliferation of cultures of rat vascular smooth muscle cells. J Clin Dr. John B. Stokes, III (University of Iowa, Iowa City): Invest 1989;83:1774-1777 You indicated that some transplanted patients with 19. Garg UC, Hassid A: Inhibition of rat mesangial cell mitogenesis by nitric oxide-generating vasodilators. Am J Physiol 1989;257(/?ena/ hypertension as a cause of renal failure had correction Fluid Electrolyte Physiol 26):F60-F66 of their hypertension. You also indicated that these 20. Krolewski AS, Canessa M, Warram JH, Laffel L, Christleib AR, patients had reversal of their retinopathy. Does the Knowles WC, Rand LI: Predisposition to hypertension and sus- retinal lesion provide a clue to the renal lesion? ceptibility to renal disease in insulin-dependent diabetes mellitus. Dr. Luke: I do not think that this has been as well N EnglJ Med 1988;318:140-145 21. Rostand SG, Kirk KA, Rutsky EA, Pate BA: Racial differences in studied in essential hypertension as it has been in the incidence of treatment for end-stage renal disease. N Engl J diabetes, where there is a fairly good correlation be- Med 1982;306:1276-1282 tween diabetic retinal vasculature disease and diabetic 22. Excerpts from United States Renal Data System 1991 annual glomerular sclerosis. We certainly need clinical risk report: Am J Kidney Dis 1991;18(suppl 5):l-93 23. Yokokawa K, Tahara H, Kohno M, Murakawa K, Yasunari K, factors, other than race and blood pressure level, for Nakagawa K, Hamada T, Otani S, Yanagisawa M, Takeda T: predicting the risks of progressive hypertensive nephro- Hypertension associated with endothelin-secreting malignant sclerosis in patients with essential hypertension. Obvi- hemangioendothelioma. Ann Intern Med 1991;114:213215

10 Luke Essential Hypertension: A Renal Disease 389 24. Ploth DW: Angiotensin-dependent renal mechanisms in 2-kidney 50. Castleman B, Smithwick RH: The relation of vascular disease to 1-clip renal vascular hypertension. Am J Physio! 1983;245(flena/ the hypertensive state: II. The adequacy of the renal biopsy as Fluid Electrolyte Physiology 14):F131-F141 determined from a study of 500 patients. N Engl J Med 1948;239: 25. Curtis JJ, Luke RG, Diethelm AG, Whelchel JD, Jones P: Benefits 729-736 of removal of native kidneys in hypertension after renal transplan- 51. Tracy RE, Malcom GR, Oalmann MC, Qureshi U, Ishii T, Velez- tation. Lancet 1985;2:739-742 Duran M: Renal microvascular features of hypertension in Japan, 26. Dahl LK, Heine N: Primary role of renal homographs in setting Guatamala, and the United States. Arch Pathol Lab Med 1992;116: chronic blood pressure levels in rats. Ore Res 1975;36:692-696 50-55 27. Kawabe K, Watanabe TX, Shiono K, Sokabe H: Influence on 52. Cannon PJ, Leeming JM, Sommers SC, Winters RW, Laragh JH: blood pressure of renal isografts between spontaneously hyperten- Juxtaglomerular cell hyperplasia and secondary hyperaldoste- sive and normotensive rate utilizing the Fl hybrids. Jpn Heart J ronism (Bartter's syndrome): A re-evaluation of the pathophysiol- 1978;19:886-894 ogy. Medicine 1968;47:107-131 28. Bianchi G, Fox U, DiFrancesco GF, Giovanetti AM, Pagetti D: 53. Pasternak A, Perheentupa J: Hypertensive angiopathy in familial Blood pressure changes by kidney cross-transplantation between chloride diarrhoea. Lancet 1966;2:1047-1049 spontaneously hypertensive rats and normotensive rats. Clin Sci 54. Law MR, Frost CD, Wald NJ: Analysis of data from trials of salt Mol Med 1974;47:435-448 reduction. Br Med J 1991;302:819-824 29. Rettig R, Folberth C, Stauss H, Kopf D, Waldherr R, Unger T: 55. Danovitch GM, Bourgoignie JJ, Bricker NS: Reversibility of the Role of the kidney in primary hypertension: A renal transplanta- "salt-losing" tendency of chronic renal failure. N Engl J Med 1977; tion study in rats. Am J Physiol 1990;258:F606-F611 296:15-19 30. Guidi E, Bianchi G, Dallosta V, Cantaluppi V, Mandelli V, Vallino 56. Tobian L: Potassium and sodium in hypertension. J Hypertens F, Polli E: Influence of familial hypertension of the donor on the 1988;6(suppl 4):S12-S24 blood pressure and antihypertensive therapy of kidney graft recip- 57. Ruggenenti P, Gaspari F, Mosconi L, Benigni A, Amuchastegur ients. Nephron 1982;30:318-323 CS, Gasparini F, Remuzzi G, Penco N: Daily renal hypoperfusion 31. Strandgaard S, Hansen U: Hypertension in renal allograft recipi- induced by cyclosporine (CsA) in renal transplant patients, ents may be conveyed by cadaveric kidneys from donors with (abstract) J Am Soc Nephrol 1991;2:815 Downloaded from by guest on June 23, 2017 subarachnoid haemorrhage. Br Med J 1986;292:1041-1044 58. Myers BD, Newton L: Cyclosporine-induced chronic nephropathy: 32. Curtis JJ, Luke RG, Dustan HP: Remission of essential hyperten- An obliterative micovascular renal injury. J Am Soc Nephrol 1991; sion after renal transplantation. N Engl J Med 1983;309:1009-1015 2:S45-S52 33. Curtis JJ, Galla JH, Kotchen TA, Lucas B, McRoberts JW, Luke 59. Curtis JJ, Luke RG, Dubovsky E, Whelchel JD, Luke RG, RG: Prevalence of hypertension in a renal transplant population Diethelm AG, Jones P: Cyclosporine in therapeutic doses on alternate-day steroid therapy. Clin Nephrol 1976;5:123-127 increases renal allograft vascular resistance. Lancet 1986;2: 34. Hollenberg NK, Williams GH, Adams DF: Essential hypertension: 477-479 Abnormal renal vascular and endocrine responses to a mild psy- 60. Curtis JJ, Luke RG, Jones P, Diethelm AG, Whelchel JD: Hyper- chological stimulus. Hypertension 1981;3:11-17 tension after successful renal transplantation. Am J Med 1985;79: 35. Hollenberg NK: The kidney in the pathogenesis of hypertension: A 193-200 prologue. Am J Kidney Dis 1985;5:A2-A4 61. Curtis JJ, Luke RG, Jones P, Diethelm AG: Hypertension in 36. Lawton WJ, Sinkey CA, Fitz AE, Mark AL: Dietary salt produces cyclosporine-treated renal transplant recipients is sodium depen- abnormal renal vasoconstrictor responses to upright posture in dent. Am J Med 1988;85:134-138 borderline hypertensive subjects. Hypertension 1988;11:529-536 62. Curtis JJ, Laskow DA, Jones P, Julian B, Deierhoi M, Barber H, 37. Light KC, Koepke JP, Obrist PA, Willis PW: Psychological stress Gaston R, Diethelm AG: Absence of hypertension in diabetic induces sodium and fluid retention in men at high risk for hyper- recipients of kidney/pancreas allografts. (abstract) J Am Soc Neph- tension. Science 1983;220:429-431 rol 1990; 1:755 38. Koepke JP, DiBona GF: High sodium intake enhances renal nerve 63. Conte G, Dal Canton A, Sabbatini M, Napodano P, DeNicola L, and antinatriuretic responses to stress in spontaneously hyperten- Testa A, Esposito C, Russo D, Andreucci VE: Acute cyclosporine sive rats. Hypertension 1985;7:357-363 renal dysfunction reversed by dopamine infusion in healthy sub- 39. Williams GH, Hollenberg NK: "Sodium-sensitive" essential hyper- jects. Kidney lnt 1989;36:1086-1092 tension: Emerging insights into pathogenesis and therapeutic 64. Laskow DA, Curtis JJ, Luke RG, Julian VA, Jones P, Deierhoi implications. Contemp Nephrol 1985;3:303-331 MH, Barber WH, Diethelm AG: Cyclosporine-induced changes in 40. Van Hooft IM, Grabbee DE, Derkx FHM, deLeeuw PW, glomerular filtration rate and urea excretion. Am J Med 1990;88: Schalekamp MADG, Hofman A: Renal hemodynamics and the 497-502 renin-angiotensin-aldosterone system in normotensive subjects 65. Lin HY, Rocher LL, McQuillan MA, Schmaltz S, Palella TD, Fox with hypertensive and normotensive parents. N Engl J Med 1991; IH: Cyclosporine-induced hyperuricemia and gout. N Engl J Med 324:1305-1311 1989;321:287-292 41. Arendshorst WJ, Chatziantoniou C, Daniels F: Role of angiotensin 66. English J, Evan A, Houghton DC, Bennett WM: Cyclosporine- in the renal vasoconstriction observed during the development of induced renal dysfunction in the rat: Evidence for arteriolar vaso- genetic hypertension. Kidney lnt 1990;38(suppl 30):S92-S96 constriction with preservation of tubular function. Transplantation 42. Goldring W, Chasis H, Ranges HA, Smith HW: Effective renal 1987;44:135-141 blood flow in subjects with essential hypertension. J Clin Invest 67. Mihatsch MJ, Thiel G, Basler V, Ryffel B, Landmann J, VonOver- 1941;20:637-653 beck J, Zollinger HU: Morphological patterns in cyclosporine- 43. Hollenberg NK, Boruchi LJ, Adams DF: The renal vasculature in treated renal transplant recipients. Transplant Proc 1985;17(suppl early essential hypertension: Evidence for a pathogenetic role. l):101-116 Medicine 1978;57:167-178 68. Nahman NS, Cosio FG, Kolkin S, Mendell JR, Sharma HM: Cyclo- 44. Luft FC, Grim CE, Higgins JT Jr, Weinberger MH: Differences in sporine nephrotoxicity without major organ transplantation. Ann response to sodium administration in normotensive white and Intern Med 1987;106:400-401 black subjects. J Lab Clin Med 1977;90:555-562 69. Curtis JJ, Laskow DA, Jones PA, Julian BA, Gaston RS, Luke RG: 45. Critchley JAJH, Lee MR: Salt sensitive hypertensives in West Captopril-induced fall in glomerular filtration rate in cyclosporine- Africa: An uncoupling of the renal sodium-dopamine relation, treated hypertensive patients. J Am Soc Nephrol (in press) (letter) Lancet 1986;2:460 70. Bunchman TE, Brookshire CA: Cyclosporine-induced synthesis of 46. Levy B, Lilley JJ, Frigon RP, Stone RA: Urine kallikrein and endothelin by cultured human endothelial cells. J Clin Invest 1991; plasma renin activity as determinants of renal blood flow. J Clin 88:310-314 Invest 1977;60:129-138 71. Lanese DM, Schrier RW, Conger JD: Cyclosporine (CsA) vaso- 47. Blaustein MP: Sodium ions, calcium ions, blood pressure regula- constriction mediated by endothelin in the afferent (AA) but not tion and hypertension: A reassessment and a hypothesis. Am J efferent (EA) arterioles. (abstract) J Am Soc Nephrol 1991;2:666 Physiol 1977;232:C165-C173 72. Laskow D, Curtis JJ, Luke RG, Jones P, Barber H, Deierhoi M, 48. Schiffrin EL: Reactivity of small blood vessels in hypertension: Diethelm A: Cyclosporine impairs the renal response to volume Relation with structural changes. Hypertension 1992;19(suppl II): depletion. Transplant Proc 1988;20(suppl 3):568-571 II-1-II-9 73. Kopp JB, Klotman PE: Cellular and molecular mechanisms of 49. Sommers SC, McLaughlin RJ, McAuley RL: Pathology of diastolic cyclosporine nephrotoxicity. J Am Soc Nephrol 1990;l:162179 hypertension as a generalized vascular disease. Am J Cardiol 1962; 74. Garr MD, Paller MS: Cyclosporine augments renal but not sys- 9:653-658 temic vascular reactivity. Am J Physiol 1990;258:F211-F217

11 390 Hypertension Vol 21, No 3 March 1993 75. Scherrer U, Vissing SF, Morgan BJ, Tindall RSA, Ring S, Hansen sure control in hypertensive nephrosclerosis. Hypertension 1989;13: P, Mohanty PK, Victor RG: Cyclosporine-induced sympathetic 766-772 activation and hypertension after heart transplantation. N Engl J 86. Rostand SG, Brown G, Kirk KA, Rutsky EA, Dustin HP: Renal Med 1990;323:693-700 insufficiency in treated essential hypertension. N Engl J Med 1989; 76. Moss NG, Powell SL, Falk RJ: Intravenous cyclosporine activates 320:684-688 afferent and efferent renal nerves and causes sodium retention in 87. Tierney WM, McDonald CJ, Luft FC: Renal disease in hyperten- enervated kidneys in rats. Proc Natl Acad Sci USA 1985;82: sive adults: Effect of race and type II diabetes mellitus. Am J 8222-8226 Kidney Dis 1989;13:485-493 77. Perico N, Benigni A, Zoja C, Delaini F, Remuzzi G: Functional 88. McClellan W, Tuttle E, Issa A: Racial differences in the incidence of hypertensive end-stage renal disease (ESRD) are not entirely significance of exaggerated renal thromboxane A2 synthesis explained by differences in the prevalence of hypertension. Am J induced by cyclosporin A.AmJ Physiol 1986;20:F581-F587 Kidney Dis 1988;12:285-290 78. Diederich D, Yang Z, Luscher F: Chronic cyclosporine therapy 89. Walker WG, Neaton JD, Cutler JA, Neuwirth R, Cohen JD: impairs endothelium dependent relaxation in the renal artery of Changes in serum creatinine in hypertensive participants in the the rat. J Am Soc Nephrol 1992;2:1291-1297 Multiple Risk Factor Intervention Trial (MRFIT): Evidence that 79. National High Blood Pressure Education Program (NHBPEP): lowering blood pressure protects renal function in mild to moder- Working Group Report on Hypertension and Chronic Renal Failure. ate hypertension. JAMA 1992;268:3085-3091 NIH publication No. 90-3032. Washington, DC, US Government 90. Feld LG, Van Liew JB, Brentjens JR, Baylan JW: Renal lesions Printing Office, August 1990 and proteinuria in the spontaneously hypertensive rat made nor- 80. Qualheim RE, Rostand ST, Kirk KA, Rkutsky EA, Luke RG: motensive by treatment. Kidney Int 1981;20:606-614 Changing patterns of end-stage renal disease due to hypertension. 91. Whittle J, Whelton PK, Klag MJ, Seidler AJ: Does racial variation Am J Kidney Dis 1991;18:336-343 in risk factors explain black-white differences in hypertensive end- 81. Veterans Administration Cooperative Study Group on Antihyper- stage renal disease? Arch Intern Med 1991; 151:1359-1364 tensive Agents: Effect of treatment on morbidity and mortality: 92. Anderson S, Rennke HG, Brenner BM: Therapeutic advantage of Results in patients with diastolic blood pressures averaging 115 converting enzyme inhibitors in arresting progressive renal disease through 129 mm Hg. JAMA 1967;202:1028-1034 associated with systemic hypertension in the rat. J Clin Invest Downloaded from by guest on June 23, 2017 82. Veterans Administration Cooperative Study Group on Antihyper- 1986;77:1993-2000 tensive Agents: Effects of treatment on morbidity in hypertension: 93. Byrne C, Vernon P: Validation of the cause of renal failure of Results in patients with diastolic blood pressures averaging 90 patients in the Medicare End-Stage Renal Disease Program. Am J through 114 mm Hg. JAMA 1970;213:1143-1152 Kidney Dis 1991;17:375-378 83. Hypertension Detection and Follow-up Program Cooperative 94. Bechgaard P: The natural history of benign hypertension, in Beck Group: Five-year findings of the Hypertension Detection and Fol- KD, Cottier PT (eds): Essential Hypertension: An International low-up Program: I. Reduction in mortality of persons with high Symposium. Berlin, Springer-Verlag, 1960, p 198 blood pressure, including mild hypertension. JAMA 1979;242: 95. Perera GA: Hypertensive vascular disease: Description and natu- 2562-2571 ral history. / Chronic Dis 1955;l:33-42 84. Ljungman S, Aurell M, Hartford M, Wikstrand J, Berglund G: 96. Mauer SM, Chavers BM, Steffes MW: Should there be an Renal function and renal haemodynamics before and after 7 years' expanded role for kidney biopsy in the management of patients antihypertensive treatment in men with primary hypertension. with type I diabetes? Am J Kidney Dis 1990;16:96-100 Ada Med Scand Suppl 1984;693:89-92 85. Pettinger WA, Lee WA, Reisch J, Mitchell HC: Long-term KEY WORDS vasoconstnction hypertension, essential improvement in renal function after short-term strict blood pres- kidney diseases renal circulation Presentation and publication of this Clinical Conference is supported by an educational grant from Health Sciences Service, Merck Sharp & Dohme.

12 Essential hypertension: a renal disease? A review and update of the evidence. R G Luke Hypertension. 1993;21:380-390 doi: 10.1161/01.HYP.21.3.380 Downloaded from by guest on June 23, 2017 Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright 1993 American Heart Association, Inc. All rights reserved. Print ISSN: 0194-911X. Online ISSN: 1524-4563 The online version of this article, along with updated information and services, is located on the World Wide Web at: Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Hypertension can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: Subscriptions: Information about subscribing to Hypertension is online at:

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