Hemodynamic Alterations and Urinary Albumin Excretion in Patients With Essential Hypertension

Hemodynamic Alterations and Urinary Albumin Excretion in Patients With Essential Hypertension Vito M. Campese, MD, Frederick Karubian, MD, and Roberto Bigazzi, MD • Salt-sensitive animals as well as patients with essential hypertension appear to have a greater propensity to develop renal disease as a consequence of hypertension. They also manifest an abnormal renal hemodynamic adaptation to changes in dietary sodium intake and blood pressure. This suggests that the two may be related. Some patients with essential hypertension manifest an increase in urinary albumin excretion (UAE). It is uncertain whether this is more common in salt-sensitive patients and whether it represents a marker for progressive renal disease. The effect of antihypertensive agents on UAE varies substantially depending on the agent used, and it is not necessarily related to the antihypertensive action. Whether antihypertensive agents that more effectively reduce UAE may also result in greater renal protective effects remains to be established. © 1993 by the National Kidney Foundation, Inc. INDEX WORDS: Essential hypertension; renal hemodynamics; albuminuria.

I

T HAS BEEN clearly demonstrated that hypertension is a common cause of end-stage renal disease in the US population. I •2 Certain groups of hypertensive patients suffer a greater and more rapid degree of progression of renal damage than others. These include persons of African descent, elderly, diabetics, and the obese. 3-7 This, in conjunction with the evidence for a high incidence of salt sensitivity among these hypertensive subgroups, suggests that the two may be related. We have postulated that differences in the renal hemodynamic adaptation to changes in dietary sodium intake and blood pressure expose the glomerulus to the ravages of increased systemic arterial pressure in salt sensitive patients. This would in turn result in a greater propensity of these patients to develop renal failure. RENAL HEMODYNAMIC CHANGES IN HYPERTENSION

Patients with established essential hypertension manifest increased renal vascular resistance and a decrease in renal blood flow (RBF). These abnormalities, however, are quantitatively and qualitatively variable. Bianchi et al 8 showed that prehypertensive subjects usually display an increase in RBF. This finding was confirmed by Hollenberg ei al 9 who observed a progressive fall in RBF with aging. The renal hemodynamic changes parallel those in the systemic circulation. In patients with borderline hypertension the rise in blood pressure is largely due to an increase in cardiac output, whereas in patients with well-established hypertension, the increase in blood pressure is largely

due to an increase in systemic vascular resistance. Messerli et al lO observed a correlation between cardiac output and RBF in patients with borderline hypertension. Thus, patients with increased cardiac output display an increase in RBF, whereas patients with established hypertension and normal or reduced cardiac output, manifest a progressive decrease in RBF. Temmar et alii observed an inverse correlation (r = 0.62, P < 0.01) between cardiac index and RBF in patients with established essential hypertension. Earlier on, the reduction in RBF can be reversed by the administration of vasodilators; with time, the decrease in RBF becomes fixed and unresponsive to the intrarenal administration of vasodilators. 12 This suggests that in early phases the increase in renal vascular resistance is functional, whereas in later stages it is largely maintained by structural and fixed anatomic changes. The decrease in RBF appears to be more pronounced in black patients with essential hypertension. 13. 14 Whether this is due to the fact that hypertension in blacks starts earlier in life and frequently folFrom the Division o.(Nephrology. Department a/Medicine, University (}(Southern California Medical Center, Los Angeles, CA. This study was supported by a National Institutes a/Health National Center/or Research Resources a/the General Clinical Rese{ffch Centers Grant No. MOl RR-43, by National Institutes (}(Health Grant No. ROI-HL 35629-03, and by a grantfrom Pfizer Laboratories Division. Address reprint requests to Vito M. Campese, MD, Division a/Nephrology, LAC/USC Medical Center, 1 Zonal Ave, Los Angeles, CA 90033. © 1993 by the National Kidney Foundation, Inc. 0272-6386/93/2105-2004$3.00/0

American Journal of Kidney Diseases, Vol 21, No 5, Suppl 2 (May), 1993: pp 15-21

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CAMPESE, KARUBIAN, AND BIGAZZI

o •

Low a HighNa

10000

Dyncslsoolcm ..

Salt.Sensitive

Fig 1. Renal vascular resistance (dynes/sec/cm- 5 ) in salt-sensitive and in salt-resistant patients with essential hypertension, during a low and a high dietary sodium intake. *P < 0.01 versus low sodium intake.

lows a more severe or accelerated course has not been established. The glomerular filtration rate (GFR), on the other hand, remains normal for longer periods of time. A progressive fall in RBF not accompanied by equal changes in GFR indicates that filtration fraction progressively increases. Thus, the sclerotic changes in the afferent arterioles lead to progressive reduction in renal perfusion, and the GFR is maintained at the expense of progressive increases in efferent arteriolar tone and intraglomerular pressure. This may create a vicious cycle causing the progressive demise of glomeruli. Goldrin et al 15 showed a progressive decrease in RBF which correlated with severity of hypertension in 60 patients with essential hypertension; they also observed that the increase in resistance of the renal efferent arterioles was greater than in the afferent arterioles. Lowenstein et al,16 using measurements of renal wedge pressure to calculate renal interstitial and intraglomerular pressures, documented a rise in intraglomerular pressure despite increased tone of the afferent arterioles in patients with essential hypertension. Recent evidence indicates that dietary sodium intake may affect the hemodynamic derangements in patients with essential hypertension. 17 Thus, when salt-resistant patients were fed a diet containing a high sodium content, their GFR did not change, while renal vascular resistance decreased by 7% and the filtration fraction by 8% (Fig I). Conversely, when dietary sodium was increased in salt-sensitive patients, renal vascular

resistance increased by 37%, and filtration fraction by 19%, whereas RBF decreased by 17% and GFR did not change. The pathophysiologic importance of these findings relates to the changes in intraglomerular pressure as a result of these hemodynamic alterations. Using the Gomez formulas,1 8,19 intraglomerular pressure can be approximated. In doing so it was observed that while intraglomerular pressure decreased by 10% in salt-resistant hypertensives during high sodium compared with low sodium intake, the opposite was true in salt-sensitive hypertensives, in whom intraglomerular pressure increased by 21 % (Fig 2). This difference was largely due to different changes in the tone of the renal efferent arterioles during high dietary sodium intake: renal efferent resistance decreased by 21 % in salt-resistant hypertensives, while it increased by 52% in salt-sensitive hypertensives. This may well represent the pathophysiologic basis for the absence of a protective mechanism to shield the glomerulus from uncontrolled systemic hypertension, and may explain the greater propensity of salt-sensitive patients to develop progressive deterioration of renal function. These observations share some similarity with those of Williams and Hollenberg.20 These investigators observed that some patients with essential hypertension and normal or high plasma renin activity fail to modulate their renal blood flow and aldosterone response to angiotensin II during changes in dietary salt intake. In these "non-modulators", renal blood flow failed to 80

o •

LowNa High a

60

mmHg

40

20

o .1<----'-_ _ SaltScnsitive

Fig 2. Intra glomerular pressure determined by modified Gomez formulas in salt-sensitive and salt-resistant patients with essential hypertension, during a low and a high dietary sodium intake .•p < 0.01 versus low sodium intake. #P < 0.05 versus low sodium intake.

RENAL HEMODYNAMICS IN HYPERTENSION

display the increase that is normally observed in response to a high dietary sodium intake. The relative increase in renal efferent arteriolar resistance in salt-sensitive compared with salt-resistant patients may be also at the root of the greater propensity of the former group to retain salt.21.22 Weinberger et al23 demonstrated that saltsensitive patients excreted a salt load more slowly and less completely than did salt-resistant patients receiving the identical sodium load. Dustan et al 24 have also shown that a salt load following a period of salt depletion was excreted more efficiently by salt-resistant patients as compared with salt-sensitive patients. We have shown that saltsensitive hypertensives manifest a rise in arterial pressure which is in direct correlation with the increase in body weight when the patients are exposed to high dietary sodium intake. 16 This disturbance in renal tubular sodium handling resulting in greater sodium retention may also explain why the renal function curve is altered in salt-sensitive hypertensives. We have demonstrated that the slope of the renal function curve (pressure-natriuresis curve) was significantly lower in salt-sensitive than in salt-resistant patients. 25 In addition to the human studies mentioned above, animal studies suggest alterations in renal hemodynamic adaptation in salt-sensitive compared with salt-resistant rats. The spontaneously hypertensive rats are an inbred strain in which the development of hypertension is independent of dietary sodium intake. After 1 year, the superficial nephrons of these animals do not develop glomerulosclerosis, largely due to an appropriate increase in afferent arteriolar resistance, which protects the glomeruli from the adverse effects of hypertension. 26·28 The juxtaglomerular nephrons of these rats, however, are more susceptible to glomerular injury and are in large part responsible for the development of proteinuria. The Dahl salt-sensitive rats, on the other hand, are an inbred strain which develop hypertension after exposure to a high dietary sodium intake. In prehypertensive or hypertensive Dahl S rats, the slope of the pressure-natriuresis relationship was significantly blunted in comparison with that measured in Dahl R rats.29 These rats are more susceptible to glomerulosclerosis and proteinuria. This is largely due to inadequate renal afferent

17

arteriolar constriction in response to the rise in blood pressure, resulting in increased intraglomerular pressure. 30 ALBUMINURIA IN ESSENTIAL HYPERTENSION

In a study of over 200 subjects, Bigazzi et al have recently shown 31 that approximately 40% of patients with mild to moderate essential hypertension manifest microalbuminuria exceeding 30 mg/24 h. Other investigators have confirmed the presence of microalbuminuria in some patients with essential hypertension. 32-35 The significance of increased urinary albumin excretion (UAE) remains to be established. Microalbuminuria is a good predictor offuture progression of renal disease in patients with diabetes 36-38 and an independent predictor of cardiovascular morbidity and mortality in patients with essential hypertension. 39-43 Whether microalbuminuria represents an initial sign of renal damage or is a prognostic indicator of progressive renal disease in patients with essential hypertension remains to be determined. To our knowledge, no study has been published correlating levels of UAE with salt sensitivity in patients with essential hypertension. One could speculate that the increase in intraglomerular pressure that occurs in these patients in response to high dietary sodium intake might lead to more UAE and greater propensity to develop renal failure. If so, UAE could represent a good renal prognostic indicator in patients with essential hypertension, as well as in diabetic patients. This possibility needs to be properly explored. Uncertainty also remains about the prognostic value of reducing UAE in patients with essential hypertension. Two short-term studies have recently shown that despite similar antihypertensive efficacy, converting enzyme inhibitors, but neither calcium channel blockers, l'1-blockers, nor diuretics, reduced microalbuminuria in patients with essential hypertension. 44,45 Other investigators have also shown that short-term treatment with amlodipine,46 nifedipine,47 or isradipine 48 caused no changes in UAE in these patients. Data regarding the long-term effects of antihypertensive agents on UAE in patients with essential hypertension and normal renal function are scanty and inconclusive. Hartfort et al 49 treated 13 patients with essential hypertension

18

with metoprolol for 7 years. The antihypertensive treatment normalized the cardiovascular parameters and reduced UAE while GFR remained constant. However, baseline values of microalbuminuria in these patients were in the normal range, and the observed decrements in microalbuminuria after 7 years were not statistically significant. De Venuto et al 50 compared the effects of 1 year of treatment with captopril or with a fJblocker on UAE in 34 patients with essential hypertension. There was a significant reduction in UAE after 3 and 6 months, but not after 12 months of treatment, only in patients treated with captopril. The investigators pointed out that the average level of microalbuminuria at 12 months returned to the initial values because of a single patient who manifested a significant rise in UAE rate. Recently, the long-term effect on UAE of enalapril, a converting enzyme inhibitor (CEI), and of nicardipine, a calcium channel blocker of the dihydropyridine group, has been prospectively evaluated in a group of patients with mild to moderate essential hypertension and normal renal function. These studies have shown that the administration of a converting enzyme inhibitor for 2 years persistently decreased UAE in patients with essential hypertension and normal renal function. On the other hand, despite similar effects on blood pressure control, monotherapy with nicardipine did not modify U AE. This was the first demonstration that long-term therapy with a CEI may result in a persistent reduction of UAE in patients with essential hypertension. Several studies have, on the other hand, evaluated the long-term effect ofCEls on proteinuria in patients with diabetic nephropathy or with other glomerular diseases. Taguma et al 51 observed that captopril reduced proteinuria in patients with advanced diabetic nephropathy. The decrease in proteinuria occurred independently of changes in blood pressure or in creatinine clearance. Hommel et al 52 observed a parallel decrease in blood pressure and albuminuria in patients with diabetic nephropathy treated with captopril. Hermans et al 53 observed a reduction of microalbuminuria after 3 years of therapy with perindopril in patients with insulin-dependent diabetes. In one study, captopril failed to decrease proteinuria in diabetic patients with renal fail-

CAMPESE, KARUBIAN, AND BIGAZZI

ure. 54 Sauter and Bakris55 observed a paradoxical initial increase in proteinuria in five patients with membranous glomerulonephritis treated with enalapril. One reason for these discrepancies might be related to dietary sodium intake at the time of the study. Heeg et al 56 have, in fact, shown that the anti protein uric effect of angiotensin converting enzyme inhibitors was present during a restricted, but not during a liberalized dietary sodium intake. Bedogna et al 57 have shown that the anti protein uric action of CEls depends on baseline plasma renin activity; the higher the plasma renin activity (PRA) the greater the effects on proteinuria. Comparisons ofCEls with other antihypertensive agents on proteinuria have provided conflicting results. Some have shown a decrease in proteinuria with CEls but not with nifedipine. 58,59 Other investigators have observed no difference between the antiproteinuric action of CEls and nicardipine. 60 Bakris et al observed no difference between the antiproteinuric effect of lisinopril versus diltiazem 61 or verapamil 62 in small numbers of patients with diabetic nephropathy. This raises the possibility that differences might exist between classes of calcium channel blockers with respect to the antiproteinuric effects in diabetic patients. The Melbourne Diabetic Nephropathy Study Group, however, demonstrated equal effects of perindopril and nifedipine on UAE in hypertensive diabetic patients. 63 Bjorck et al 64 compared the effects of enalapril and metoprolol on UAE in hypertensives with diabetic nephropathy and observed that enalapril reduced proteinuria and slowed the progression of renal disease more effectively than metoprolol, despite similar antihypertensive action. Studies in patients with a variety of renal diseases have shown that CEls may lower proteinuria more effectively than atenolol 65 or a-I-antagonists. 66 The mechanisms for the beneficial effect of CEls on proteinuria are complex. The reduction of proteinuria cannot be exclusively attributed to a decrease in blood pressure, since agents with similar antihypertensive efficacy had no beneficial effect, and the reduction in UAE observed with CEls occurred irrespective of their hypotensive action. 67 Experimental evidence seems to indicate that improvement of intrarenal hemodynamics and decreased perm selectivity of the glomerular

RENAL HEMODYNAMICS IN HYPERTENSION

basement membranes may contribute to the antiproteinuric action of these agents. 68 -72 These pharmacologic properties may not necessarily be a feature of other antihypertensive agents.

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20 33. Losito A, Fortunati F, Zampi I, Del Favero A: Impaired functional reserve and albuminuria in essential hypertension. Br Med 1 296: 1562-1564, 1988 34. Giaconi S, Levanti C, Fommei E, Innocenti F, Seghieri G, Palla L, Palombo C, Ghione S: Microalbuminuria and casual and ambulatory blood pressure monitoring in normotensives and in patients with borderline and mild essential hypertension. Am 1 Hypertens 2:259-261, 1989 35. Pedersen EB, Mogensen CE: Effect of antihypertensive treatment on urinary albumin excretion, glomerular filtration rate and renal plasma flow in patients with essential hypertension. Scand 1 Clin Lab Invest 36:231-237, 1976 36. Parving HH, Oxenboll B, Svendsen PA, Christiansen lS, Anderson AR: Early detection of patients at risk of developing diabetic nephropathy: A longitudinal study of urinary albumin excretion. Acta Endocrinol 100:550-555, 1982 37. Viberti GC, Hill RD, larret RD, Argyropoulos A, Mahmud U, Keen H: Microalbuminuria as a predictor of clinical nephropathy in insulin-dependent diabetes mellitus. Lancet 1:1430-1432,1982 38. Mogensen CE: Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N Engll Med 310:356-360, 1986 39. Lewin A, Blaufox D, Castle H, Entwisle G, Langford R: Apparent prevalence of curable hypertension in the Hypertension Detection and Follow-up Program. Arch Intern Med 145:424-427, 1985 40. Samuelsson 0, Wilhelmsen L, Elmfeldt D, Pennert K, Wedel H, Wikstrand 1, Berglund G: Predictors of cardiovascular morbidity in treated hypertension results from the primary preventive trial in Goteborg, Sweden. 1 Hypertens 3: 167-176,1985 41. Bulpitt Cl, Beevers DG, Butler A, Coles EC, Hunt D, Munro-Faurr AD, Newson RB, Dollery CT: The survival of treated hypertensive patients and their causes of death: A report from the DHSS Hypertensive Care Computing Project (DHCCP). 1 Hypertens 4:93-99, 1986 42. Kannel WB, Stampfer Ml, Castelli WP, Verter 1: The prognostic significance of proteinuria: The Framingham Study. Am Heart 1 108:1347-1352, 1984 43. Yudkin lS, Forrest RD, lackson CA: Microalbuminuria as predictor of vascular disease in non-diabetic subjects. Lancet 3:530-533, 1898 44. Bianchi S, Bigazzi R, Baldari G, Campese VM: Microalbuminuria in patients with essential hypertension: Effect of an angiotensin converting enzyme inhibitor and of a calcium channel blocker. Am 1 Hypertens 4:291-296, 1991 45. Bianchi S, Bigazzi R, Baldari G, Campese VM: Microalbuminuria in patients with essential hypertension: Effect of several antihypertensive drugs. Am 1 Med 93:525-528, 1992 46. Reams GP, Lau A, Hamory A, Bauer lH: Amlodipine therapy corrects renal abnormalities encountered in the hypertensive state. Am 1 Kidney Dis 10:446-451, 1987 47. Reams GP, Hamory A, Lau A, Bauer lH: Effect of nifedipine on renal function in patients with esst;ntial hypertension. Hypertension 11:452-456, 1988 48. Persson B, Anderson OK, Wysocki M, Hedner T, Karlberg B: Calcium antagonists in essential hypertension: Effect on renal haemodynamics and microalbuminuria. 1 Intern Med 231:247-252, 1992

CAMPESE, KARUBIAN, AND BIGAZZI 49. Hartfort M, Wendelhag I, Berglund VG, Wallentin I, Ljungman S, Wikstrand R: Cardiovascular and renal effects of long-term antihypertensive treatment. lAMA 259:25532557, 1988 50. De Venuto G, Andreotti C, Matterei M, Pegoretti G: Long term captopril therapy at low doses reduces albumin excretion in patients with essential hypertension and no sign of renal impairment. 1 Hypertens 3:S 143-S 145, 1985 51. Taguma Y, Kitamoto Y, Futaki G, Ueda H, Monma H, Ishizaki M, Takahashi H, Sekino H, Sasaki Y: Effect of captopril on heavy proteinuria in azotemic diabetics. N Engl 1 Med 313:1617-1620, 1985 52. Hommel E, Parving HH, Mathiesen E, Edsberg B, Nielsen MD, Giese 1: Effect of captopril on kidney function in insulin-dependent diabetic patients with nephropathy. Br Med 1 293:467-469, 1986 53. Hermans MP, Brichard SM, Colin I, Borgies P, Ketelslegers 1M, Lambert AE: Long-term reduction of microalbuminuria after 3 years of angitensin-converting enzyme inhibition by perindopril in hypertensive insulin-treated diabetic patients. Am 1 Med 92: 102S- 108S, 1992 54. Hay U, Ludwik B, Gisinger CH, Schernthaner G: Fehlernder Effekt der ACE-inhibition auf die Makroproteinurie bei diabetischer Nephropathie - eine Langzeitstudie uber 6 Monate. Schweiz Med Wochenschr 118:165-169, 1988 55. Sauter E, Bakris GL: The effects of enalapril on urinary protein escretion in patients with idiopathic membranous nephropathy. 1 Clin Pharmacol 30:155-158, 1990 56. Heeg lE, Delong PE, van der Hem GK, de Zeeuw D: Reduction of proteinuria by converting enzyme inhibition. Kidney Int 36:272-279, 1989 57. Bedogna V, Valvo E, Casagrande P, Braggio P, Fontanarosa C, Dal Santo F, Alberti D, Valvo E: Effects of ACE inhibition in normotensive patients with incipient diabetic nephropathy. Kidney Int 38:101-107,1990 58. Insua A, Ribstein 1, Mimean A: Comparative effect of captopril and nifedipine in normotensive patients with incipient diabetic nephropathy. Postgrad Med 1 64:59-62, 1988 (suppl) 59. Ritz E, FIiser D, Keller H, Reisch C: Are newer antihypertensive agents really more effective than traditional drugs in progressive renal disease? Am 1 Kidney Dis 17:76-80, 1991 (suppl 1) 60. Baba T, Murabayashi S, Takebe K: Comparison of the renal effects of angiotensin converting enzyme inhibitor and calcium antagonist in hypertensive type 2 (noninsulin-dependent) diabetic patients with microalbuminuria: A randomized controlled trial. Diabetologia 32:4044, 1989 61. Bakris GL: Effects of diltiazem or lisinopril on massive proteinuria associated with diabetic nephropathy. Ann Intern Med 112:707-708, 1990 62. Bakris GL, Barnhill BW, Sadler R: Treatment of arterial hypertension in diabetic humans: Importance of therapeutic selection. Kidney Int 41:912-919, 1992 63. Melbourne Diabetic Nephropathy Study Group: Comparison between perindopril and nifedipine in hypertensive and normotensive diabetic patients with microalbuminuria. Br Med 1302:210-216, 1991

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64. Bjorck S, Mulec H, Johnsen SA, Norde'n G, Aurell M: Renal protective effect of enalapril in diabetic nephropathy Br Med J 304:339-343, 1992 65. Apperloo AJ, de Zeeuw D, Sluiter HE, de Jong PE: Differential effects of enalapril and atenolol on proteinuria and renal haemodynamics in non-diabetic renal disease. Br Med J 303:821-824, 1991 66. Rosenberg ME, Hostetter TH: Comparative effects of antihypertensives on proteinuria: Angiotensin-converting enzyme inhibitor versus alpha I-antagonist. Am J Kidney Dis 18:472-482,1991 67. Rudberg S, Aperia A, Freyschuss U, Persson B: Enalapril reduces microalbuminuria in young normotensive type I (insulin-dependent) diabetic patients irrespective of its hypotensive effect. Diabetologica 33:470-476, 1990 68. Anderson S, Rennke HG, Brenner BM: Therapeutic advantage of converting enzyme inhibitors in arresting pro-

21 gressive renal disease associated with systemic hypertension in the rat. J Clin Invest 77: 1993-2000, 1986 69. Zatz R, Dunn R, Meyer TW, Anderson A, Rennke HG, Brenner BM: Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension. J Clin Invest 77:1925-1930, 1986 70. Raij L, Shultz PJ, Tolins JP: Possible mechanism for the renoprotective effect of angiotensin com'erting enzyme inhibitors. J Hypertens 7:S33-S37, 1989 (suppl 7) 71. Morelli E, Loon N, Meyer T, Peters W, Myers BD: Effects of converting enzyme inhibition on barrier function in diabetic glomerulopathy. Diabetes 39:2-8, 1990 72. Remuzzi A, Schieppati A, Battaglia C, Remuzzi G: Angiotensin-converting enzyme inhibition ameliorates the defect in glomerular size selectivity in hyponatremic hypertensive syndrome. Am J Kidney Dis 14: 170-177, 1989