Salt Intake and Reductions in Arterial Pressure and Proteinuria Is There A Direct Link?

The preponderance of Ihc medical literature supports the concept that modest or moderate dietary salt restriction enhances the blood pressure lowering responses to most antihypertensive medications and may permit either dose reduction or, in a few cases, complete drug withdrawal. Moreover, reduction in salt intake has a permissive action on the antiproteinuric responses of angiotensin converting enzyme inhibitors and nondihydmpyridine calcium channel blockers. It does not, however, affect pmteinuria in those receiving dihydropyridine calcium channel blockers. The importance of selecting out those individuals who can most benefit from dietary salt modification (the “salt sensitive” groups of hypertensive patients) is important. Prospective randomized clinical studies are needed to assess the correlation between dietary salt intake and renal endpoints, such as time dialysis. This will be particularly important in different demographic groups that may have a greater predisposition to salt sensitivity, such as elderly or obese hypertensives, hypectensives of black or Hispanic descent, and those with non-insulin-dependent diabetes mellihrs. Hypertension,


I3
igh salt intake is kr.own to worsen preexisting hypertension.' This is especially true for a subgroup of individuals who are "salt sensi&e."' _ Conversely, J. reduction in salt intake to less than 4 g/day reduces elevated arterial pressure end blunts increases in this surrogate endpoint.' .' The* observations make it likely that certain individuals have an impaired pressure-natriuresis response or a greater vdscular respor.-sivencss to salt and, hence, arc potentially at a higher risk for developin; hypertension. A better understanding of the relationship between dietary salt intake and the vascular reactivity that correlates with blood pressure changes will help investigators understand the physiologic impact of salt. To this 2nd. studies have evaluated the contribution of vasoactive hormones as wel! as both the reninangiotensin-aldosterone and sympathetic nervous systems in the context of salt intake and arterial pressure changes.' -' Additionally, recent studies have evaluated the renal hemodynamic effects of sodium in different disease states.'"-" These findings cons~stently demcnstrate that salt sensitive patients have reduced renal plasma flow and increased glomerular filtr;:tion fraction ds well as proteinuria in irspmse to increasing dietary salt. Moreover, mounting evidence supports a deleterious relationship between salt sen-sitivity and abnormalities of carbohydrate and lipid metabolism." " Microalbuminuria is assoclatcd with an increased risk of both cardiovascular and renal mortality among diabetic patients. I'-'* Sodium intake is known to affect proteinuria levels in animal models of diabetes mellitus." Moreover, sodium intake also afftyts the antiprotcinuric response of certain antihypertensive agents, such as angiotensm converting enzyme (ACE) inhibitors. and nondihydropyridine calcium channel blockers."~z" The mechanism of this effect is uncertain.
This paper will review the results of studies that evaluate the impact of salt intake on both the antihypertensive and antiproteinuric properties of various antlhypertensivr drugs. This is important, especially in light of recent data demonstrating that salt sensitivity may be a marker for cardiovascular risk clustering, particularly in blacks and diabetics." '"

SALT AND ANTIHYPERTENSIVE DRUGS
The eff& of various antihypertensive drugs varies with regard to the mechanism of blood prrssure reduction as well as their influence on pwteinwia." r These mechanistic differences may have important long-term implications regarding an individuals' risk for blood pressure related cardiovascular and renal diseases.
The relationship between dietary salt intake and the antihypertensive effect of various drugs has been explored in numerous clinical trials."" These studies have led to the long-standing belief that redo4 salt intake potentiates the hypotensive effect of most antihypertensive agents. However, the magnitude of blood pressure lowering varies across drug class and is more pronounced with certain agents at lower drug doses among "salt sensitive" individuals." y The threshold of dietary salt intake below which the hypotensive effect of antihypertensive agents is accentuated and above which an antihypertensive effect is antagonized remains to be established.
The initial mechanism of b!ood pressure reduction by thiazide diuretics was poshdated to relate solely to salt and water depletion. However, subsequent clinical studies demonstrated that dietary salt loading diminished their hypotensive response, whereas reduced dietary salt enhanced diuretic-induced slood pressure reductions."-2" Moreover, thiazide diuretics m low doses (12.5 mg/day) reduce blood pressure through their vasodilator action an effect independent of natriuresis.
Not every study, however, has demonstrated this impact on blood pressure reduction with salt restriction in the presenr~ of diuretic therapy." -" Reasons for this discrepancy include the fact that cornLining salt restriction and diuretic therapy could enhance a person's ap petite for salt thrrugh activation of the renin-angioten-sin system and thereby paradoxicaily increase a neuro_ humoral system known to increase arterial pre.,s;re and thirst. This proposal, however. ie not supported by the data of Bing et al who tol~owed 32 diuretic-treated patients for 2 years and noted no increase in 24-h urinary sodium excretion (a reflection of dieiary salt intake), and no tendency for blood pressure to increase." However, sinw these patients were not profiled in terms of their blood pressure responses to dietary salt, interpretation of these data is difficult. Achievement of good blood pressure reductions in other studies employed more stringent dietary salt restriction, ~50 mEq /day; this is an unrealistically low level of intake for most ambulatory hypertensive patients' Blood prcwure reduction employing a combination cf salt restriction and a &blocker has also demonstrated confhcting results. Ewrteman et al performed a double blind cross-over study to examine the interaction be. tween a low salt diet and a B-blocker on blood pressure reduction." This group provided evidence that the combination of a low salt diet and P-blockade reduced blood pressure more than the drug with a high salt diet (-2M.5 mm Hg with low salt diet versus -21.3 mm Hg with high salt diet; P < .05). However, this observation was not confinned by Kimura and colleagues who failed to show a potentiation of blood pressure reduction with a low salt diet added to tire fl-blockade.2g Unfortunately, since different types of patients were examined in these two studies, no firm corxlusions may be reached.
Short-term studies demonstrate that angiotensin converting enzyme (ACE) inhibitors, like o-blockers, are cffwtive in reducing blood pressure among patients with high plasma renin levels.Y~~Y~"~'i" However, there are no long-term studies that demonstrate a relationship behveen pretreahnent renin levels and antihypertensivc response of ACE inhibitors. Moreover, recent data suggests that pretreatment plasma renin levels do not predict the antihypertensive mpome to the ACE inhibitor trandolapnl m either black or white hypertensives." Thus, these agents have effects on blood pressure that may have more to do with their effects on other factors than rcnin, such as bradykinin. Neverthe less, sodium reshiction potent&es theantihypertensive effects of ACE inhibitors." Clinical trials, although limited in number, further support this :ontention. They demonstrate consistent additive a&hypertensive cffectr of reduced salt diet in combinatiorti wth ACE inhibitors.",'" Additionally, one study demonstrated that when salt was added hark to the diet the antihypertenswe effect of the ACE inhibitors were markedly blunted." There is want published data assessing the antihypertensive activity of sympatholytic agents, nonspecific vasodilators, such as hydralazme, or minoxidil, a-blockers, or angiotensin II receptor antagonists in relation to dietary salt intake. However, there is inform.ltion assessing the utility of dietary salt restriction with c.11cium channel blocker therapy. Paradoxically. some of this clinical data suggest that greater dietary salt intake potentiates the antihyper:ensive properties o! calcium channel blockers.". N Nicholson rt al demonstrated that, with the same dose of verapamd, patients recciving a high dietary salt intake had rrlativcly greater rcductions in blood pressurr compared to those on a low tilt diet." This could be explained, hoxvevcr, by thka fact that the baseline blood pressure was higher with greater dietary salt; thus, the absolute fall in blood prcssure reduction observed was larger than on the lower dietary salt intake. Momover, the absolute Icvcl of blood pressure reached was lower on a reduced salt intake.
MacGregor et al hypothesized that greater dietary salt intake may boost intracrilular calcium concentration, thus enhancing the vasorelaxmg propertic? of calcium channel blockersM Some invesbgaton bavc dcmonstrated a reduced efficacy of calcium channel blockers in lowering blood prcssurc in salt restricted patients or even elevation of blood pressure in others."'" Ilowever, these clinical studies have not addressed the salt sensitivity status of the patients in making these obscrvations. In a separate study, patients who werr found to be more salt sensitive had a greater hypotensive rcsponse to calcium channel blocker therapy compared to salt resistant patients." In the Treatment of Mild Hypertension Study (TOMHS), the antihypertensive properties of five different drug classes in black participants wcrc rvaluatedd.'2," They observed significant differences in antihypertensive efficacy between different classes of drugs depending on salt intake. The black participants, presumably salt sensitive as suggested by thr work of Luft and Weinberger,' responded most effcutivrly to thrrapy with either a diuretic, calcium channel bhrkcr, or a P-blccker with intrinsic sympathomimetic activity, as compared to therapy with an ACE inhibitor or an (Iblorker.".'r However, these studies did not address whether higher doses of these drugs might result in greater efficacy of blood pressure reductmn in the presence of different sodium intakes. Both black and white patients who ingested less salt experienced a potentiation of the antihypertensive effect of most drugs used in the study. These dat3 suggest that reduced dietary salt intake potentiates the antihypertensive effect of most antihypertensive drugs in patients with stage I hypertension. Thus, modest sait restriction facilit.+tes blood pressure reduction in most hypertensive populations, particularly those who are salt sensitive (eg, older, obese, and black populabons).
Nevertheless, the !ink between the blood pressure lowering efficacy of salt restriction during antihypertensive therapy with any drug class has not been established. Lastly, calcium channel b1ockts.s may poswsn more robust antlhypertenslve propertics m the tace ot high salt intake compxcd to other drugs.
Clinical trials have also studied whether or not dietary ult restriction facilita:cs reduced antihypertensi.tie m&cation rtyuirements.Y'~n For the most part, climcal research has demonstrated improved withdrawal from z number of different antihypertensive !herapics with mcdebt dietary ralt restriction. However, this has been particula:ly apparent in p;.tirnts who arc ovenveiqht and presumably more salt sensitive." Moreover, other studic?; have demonctratcd that mod-& dlrtary salt restriction (urinary sodium excretmn < RI1 m&j/day) can be helpful m reducing the amount of antihypertensive mediration ingested by the patlcnt.".*' This observation 1s further supported by a recent studv that demonstrated that .I modest reduction in dietary -salt intake (utinary sodium excretion re-duc~J from I66 to 106 mEq /day) resulted in a marked improvement in contmllrd blood pressurt> without returning to medication compared to patient.; not rrducmg their diet:r/ salt."

DIETARY SALT AND ANTIPROTEINURIC RESPONSE TO ANTIHYPERTENSIVE DRUGS
The kidneys avidly conserve serum proteins. Ten to fifteen kilograms of serum proteins pass through the renal microcirculation daily, ye1 <151l mg appears in the urine." The glomerular capillary endothelial barrier is relatively impcrvlous to most proteins because of Its size, negative electrical charge, and the rigidity of individual proteins. However, an increase in urinary protein excretion can occur if there is damage to the glomerular capillary hltering barrier, an increase in glomerular capillary pressure, or increased plasma concentration of proteins.'2,F' Further, decreased tubular reabsorption of filtered proteins or increased renal tubular secretion of proteins into the urine may also cause clinically detectable proteintiria." Increased urinary protein excretion has been shown to be an independent predictor of cardiovascular morbidlty and mortality in patients with 8-3sential hyper-tensux3-% Moreover, proteinuria has prognostic implications for progressive loss of renal function, particularly among patients with diabetes mellitus.'h.'".C7 It is clear in clinical trials that there are differing effects of antihypertensive drugs on urinary albumin excretion in hypertensive patients with and without kidney disease." z'.w-N' A large intake of dietary salt raises urme protein excretion not only through its influence cn systemic blood pres.sure but also through effects on glomerular hemodynamics and possibly through structural changes of the glomerulus.".'"~2'~~z The ACE inhibitors and angiotensin II receptor antagonists are the antihypertensive agents that most consistently reduce proteinuria regardless of their response to the higher salt diet occurred in the absence of any blood pressure differences. In this study of patients with macroproteinuria (mean value of 6.4 -r 2.4 g/day) and hyprrtension (mean arterial pressure 104 I 11 mm Hg), those who received the ACE inhibItor showed d 3% ? 38 reduction in blood pressure (89 ) 8 mm Hg to 87 z 8 mm Hg) when going from a high salt to a i.xv salt diet. However, there was a 52% ? 14% reduction in proteinuria during the transition from the high salt to low salt diet. Consequently, the effect of dietary salt on the antiproteinuric effect of ACE inhibitors cannot be ascribed solely to changes in systemic blood pressure. Accordingly, it is also well known that both the antihypertensive and antiproleinurir effects of ACE inhibitw, are enhanced by sodium drpletion.""x.","' Thus, It can be postulated that the speciiic beneficial renal effects with ACE inhibitors might be greatest in the presence of a relatively low salt diet. Since the majority of patients consume approximatrly 160 mEq/day of sodium in their dirt,' an effort to encourage dietary salt restriction should be made when one uses an ACE inhibitor, both to reduce proteinuria as well as to augment the blocd pressure lowering effect.
This same group of Dutch investigators provides evidence that the addition of diuretic therapy facilitates the antiprotrinuric effects of ACE inhibitohs even in the presence of a high salt diet.*' Moreover, this potrntiating effect was not related to further reductions in blood pressure. This study also supports previous findings that the addition of a diuretic to an ACE inhibitor provides substan!ial reductions in blood pressure that, over the long term, should confer renal protection.
Unfortunately, there is on!y one study that documents this association. Moreover, the zlifferences in blood pressure between the high salt .Iiuretic and nondiuretic groups were statistically different. Thus, further studies are needed to solidify this association.
With recent evidence that ACE inhibitors markedly slow progression of nephopathy in the patient with diabetes :nellitus, it becomes more important for clinicians to focus on the optimal clinical use of ACE mhib-Itors. Some of the heterogeneity in the literature regarding differing antiproteinuric responses of the ACE inhibitws may be directly related to differing dietary salt intake. It may also be possible that those patlents who derive optnnal benefit from ACE inhibitors may ingest the least amount of dietary salt.
Nondihydropyridine caicium channel blockers (diltlurm and verapamll) may also have utility 111 reducing urinary protein excretion in hypertensive patients with kidney discase."~"' M Since the original reports were Fublished over 7 years ago demonstrating that these agents reduce protrinurra to a similar extent as ACE Inhibitors, other investigators have confirmed thesr findings."."'.'" One clmical study has also demonstrated that the addition of an ACE Inhibitor to a nondihydropyridine calcium channel blocker provides even greater antiprotemuric effect than either drug given aione."' This occurred despite comparable reductiuns II systemic blood pressure with the individual mono'hrrapies.
As with ACE inhibitors, salt intake aftects the antiproteinuric effects of nondihydropyridine calcium channel blockers. A prospective cross-over study of non-insulin-dependent diabetic subjects with nephropathy, given either nifedipine GlTS (gastrointestinal system) or diltiazem CD for blood pressure control and random&d to either a high (250 mEq /day) or low sodium (5G mEq/day) diet, showed divergent antiprotrinuric effects. " Sodium intake did not affect proteinuria if a dihydropyridine calcium channel blocker, uch as nifedipine GITS was used. Conversely, the nondihydropyridine diltiazem reduced proteinuria in the presence of a low salt diet, but this response was significnatly blunted in the presence of a high salt diet. Moreover, this response was independent of the change in blood pressure reduction.
Cunsrqurntly, it appears that the ablity df ACE inhibltors and nondihydmpyridinc calcium blockers to reduce proteinuria may, in part, rely on a permissive action of reduced dietary salt intake. Interestingly, drhydropyridine calcium channel blockers do not appear to reduce proteinwin independently of their ability to reduce systemic arterial pressure."."" This is primarily related to the inability of these agents to alter glomerular membrane permeability."'~"' Potential mechanisms by which ACE inhibitors and nondihydropyridine calcium channel blockers moy interact with salt on glomcrular permeability are summanzrd in Table 1. &cent evidence from micropuncture and clinical studies documents that low salt diets aloile do not significantly alter renal function or increase intra$omerular pressure or efferent arteriolar resistancr.~"~" Moreover, recent studies in normotensive individuals demonstrates that salt restriction