Current Hypertension Reports

, Volume 14, Issue 5, pp 382–387

Salt Sensitivity and Nondippers in Chronic Kidney Disease

Authors

    • Department of Cardio-Renal Medicine and HypertensionNagoya City University Graduate School of Medical Sciences
  • Genjiro Kimura
    • Department of Cardio-Renal Medicine and HypertensionNagoya City University Graduate School of Medical Sciences
Antihypertensive Therapy: Patient Selection and Special Problems (K Kario and H Rakugi, Section Editors)

DOI: 10.1007/s11906-012-0286-3

Cite this article as:
Fukuda, M. & Kimura, G. Curr Hypertens Rep (2012) 14: 382. doi:10.1007/s11906-012-0286-3

Abstract

High salt-sensitivity and nondipper blood pressure (BP) rhythm are highly associated with each other, because both are caused by impaired renal sodium excretion capability. We proposed that nocturnal hypertension and resultant pressure natriuresis could compensate for daytime sodium retention. If so, high BP may continue until sodium is sufficiently excreted at night. In fact, it takes longer for the night-time BP to fall in patients with more severe renal dysfunction. The time appears to be an essential component of the nondipper BP rhythm and, therefore, we defined the duration as the dipping time. Also, renal function was the sole determinant of a nocturnal BP dip other than age, sex, or BMI. Furthermore, we reported that diuretic therapy or dietary salt restriction, which can prevent sodium retention, restored the circadian BP rhythm into a dipper pattern. Large-scale studies are needed to explore whether these interventions can decrease the risks.

Keywords

HypertensionBlood pressureBPSalt sensitivityRenal sodium excretionSympathetic nerve activityChronic kidney diseaseCKDRenal functionCardio-renal connectionNondipperDipping timeCircadian BP rhythmNocturnal BPInterventionsDiuretic therapyDietary salt restriction

Introduction

Normally, blood pressure (BP) dips during the night by 10 %–20 % from daytime in healthy subjects (dipper type of circadian BP rhythm). In some patients with hypertension or chronic kidney disease (CKD), however, BP fails to dip during the night and they have been called “nondippers.” High salt-sensitivity and nondipper circadian rhythm of the BP are highly associated with each other, on the basis of our postulation that both are caused by impaired renal sodium excretion capability [1]. Actually, in patients, whose sodium sensitivity is high, their night-time BP is prevented from dipping regardless of the original diseases increasing sodium sensitivity [1]. Also, we proposed that renal sodium excretion is diminished by the decrease in glomerular ultrafiltration coefficient (KF) or increase in fractional tubular sodium reabsorption (FRNa) [2, 3]. Therefore, high salt-sensitivity and nondipper circadian rhythm of the BP are commonly expected in patients with CKD.

Renal Sodium Excretion and Salt Sensitivity

Dahl [4] developed two strains of rats by selective inbreeding: (1) a salt-sensitive strain (S), which exhibits hypertension under high salt ingestion, and (2) salt-resistant strain (R), which remains normotensive under the same condition. He also found that renal homograft from R-rat into S-rat (the opposite kidney was removed) made the rat salt-resistive, whereas renal homograft from S-rat into R-rat made the rat salt-sensitive [5]. These findings indicated that the subjects’ salt-sensitivity of the BP was determined by the kidney. Kawasaki [6] and Fujita [7] reported that the salt-sensitivity of BP could be separated into these two classes, salt-sensitive or salt-resistant type, even in humans. Thereafter, various definitions have been arbitrarily used for the salt-sensitive type of hypertension [811].

Guyton and colleagues figured out that the pressure-natriuresis relationship must contribute to the genesis of hypertension [12, 13]. At the steady state, the amount of the urinary sodium excretion (UNaV) is equal to that of the dietary intake. Therefore, assuming the pressure-natriuresis curve as a linear relationship and plotting the mean arterial pressure (MAP, x-axis) and urinary sodium excretion (UNaV, y-axis) during the low- and high-salt intake, we [2] demonstrated that UNaV could be represented as a first-order function of MAP, where A and B corresponded the extrapolated x-intercept and the slope, respectively:
$$ {{\text{U}}_{\text{Na}}}{\text{V}} = {\text{B}} \times \left( {{\text{MAP}} - {\text{A}}} \right) $$
(1)
We defined the sodium sensitivity index (SI) as the reciprocal of the slope (B), and we also interpreted that the (MAP–A) is equal to the net effective filtration pressure gradient across the glomerular capillary walls (ΔPF) [2]. Therefore, the net effective filtration pressure is proportionally related to the sodium sensitivity:
$$ {\text{MAP}}--{\text{A}} = \Delta {\text{PF}} = {\text{SI}} \times {{\text{U}}_{\text{Na}}}{\text{V}} $$
(2)
This equation indicates that, in the individuals with high salt sensitivity, the effective filtration pressure gradient (ie, glomerular capillary hydraulic pressure) is elevated, especially under high sodium intake. In fact, in experimental models for salt sensitive type of hypertension, which may be caused by reduced KF or enhanced FRNa, glomerular capillary hydraulic pressure is elevated (Table 1) [1421]. Accordingly, in patients with high salt-sensitivity, glomerular hypertension is of concern (Table 2) [13].
Table 1

Experimental models for salt-sensitive type of hypertension

Cause of salt sensitivity

Expected mechanism

Models

PGC

Kf

1. Reduced whole kidney KF

Reduced single glomerular Kf

Dahl-S rats[14]

Glomerulonephritis [15]

Reduced number of nephrons

Milan hypertensive rats [16]

NA

Uninephrectomy [17]

Extensive renal ablation [18]

2. Enhanced FRNa

Epithelial sodium channel

DOCA-salt rats [19]

Sodium-glucose co-transport

Experimental DM [20]

Hyperinsulinemia

Obese Zucker rats [21]

↑ (NS)

KF whole kidney ultrafiltration coefficient, Kf single glomerulus ultrafiltration coefficient; NA, not available, FRNa, fractional tubular sodium reabsorption DOCA deoxycorticosterone acetate, DM, diabetes mellitus, NS, not significant.

Table 2

Classification of hypertension based on the salt sensitivity

Salt sensitivity

Cause of high BP

Circadian rhythm

Original disease

PGC

Proteinuria

Therapeutic strategies

Non-sensitive

Increase in vascular resistance

Dipper

Essential hypertension (EHT)

→ ~ ↓

→*

Conventional therapy

Renovascular hypertension

Ischemic nephropathy

Benign nephrosclerosis

Polycystic kidney disease

Tubulo-interstitial diseases

Sensitive

Reduced KF

Nondipper

Glomerulonephritis

Glomerular preload and afterload reduction

Salt-sensitive type of EHT (hypertension in African-American)

Enhanced FRNa

Nondipper

Primary Aldosteronism

Glomerular preload and afterload reduction

Diabetes mellitus

Obesity

Metabolic syndrome

* Daily urinary protein excretion seldom exceed 1.0 g/day.

† The goal of blood pressure is <130/80 mmHg, and particular classes of antihypertensive agents are not recommended. Moreover, the possibility of the presence of ischemic nephropathy should be consider if renin-angiotensin system inhibitor were chosen.

‡ The therapeutic strategies to reduce the glomerular capillary hydraulic pressure: glomerular preload reduction includes dietary protein restriction, whereas afterload reduction includes renin-angiotensin system inhibitor (angiotensin-converting enzyme inhibitors, and angiotensin II type 1 receptor blocker), and diuretics. In this strategy, goal of blood pressure lowering is <130/80 mm Hg and even lower (such as <125/75 mm Hg) if proteinuria is >1 g/day.

BP blood pressure, PGC, glomerular capillary hydraulic pressure.

Furthermore, glomerular filtration rate (GFR) is the product of the whole kidney ultrafiltration coefficient (KF) and ΔPF:
$$ {\text{GFR}} = {{{\text{K}}}_{{\text{F}}}} \times \Delta {\text{PF}} $$
(3)
Meanwhile, UNaV is the difference between the filtered sodium load (SNa x GFR) and tubular sodium reabsorption (tNa):
$$ {{\text{U}}_{\text{Na}}}{\text{V}} = {{\text{S}}_{\text{Na}}} \times {\text{GFR}}--{{\text{t}}_{\text{Na}}} $$
(4)
Finally, solving the equations 1–4, the slope (B) can be represented as:
$$ {\text{B}} = {{\text{S}}_{\text{Na}}} \times \;{{\text{K}}_{\text{F}}} \times \left[ {1--{{\text{t}}_{\text{Na}}}/\left( {{{\text{S}}_{\text{Na}}} \times {\text{GFR}}} \right)} \right] = {{\text{S}}_{\text{Na}}} \times { }{{\text{K}}_{\text{F}}} \times \left( {1--{\text{F}}{{\text{R}}_{\text{Na}}}} \right) $$

Here, FRNa is the fractional tubular sodium reabsorption [= tNa/(SNa × GFR)] [13]. As mentioned above, SI is the reciprocal of the slope (B). Therefore, the salt sensitivity is enhanced by two mechanisms: (1) diminished KF; (2) increased FRNa (Table 2) [13]. This means that impaired renal sodium excretion capability can increment the salt sensitivity, because these two mechanisms attenuate the renal sodium excretion, as can be seen in equation 4.

In summary, salt sensitivity is enhanced by diminished renal sodium excretion capability resulting from reduced KF or enhanced FRNa, both of which are accompanied by the elevated glomerular capillary pressure (ie, glomerular hypertension).

Salt Sensitivity and Circadian BP Rhythm

As mentioned above, salt sensitivity is enhanced by diminished renal sodium excretion capability that can be caused by reduced KF or enhanced FRNa. We have illustrated the example of the former condition. In biopsy proven glomerular disease, an inverse relationship was found between GFR and the night/day ratios of both MAP and UNaV [22]. On the basis of the findings, we postulated that patients with the diminished renal sodium excretion (ie, high salt sensitivity) can incur sodium retention during the day, which prevents night-time BP dip; that is the nondipper circadian BP rhythm. We speculated that the night-time high BP and resultant night-time pressure natriuresis could compensate for the daytime sodium retention. This speculation can be supported by our previous studies. If the nocturnal pressure natriuresis compensates for reduced daytime renal sodium excretion, night-time BP may remain high to exert pressure-natriuresis until sufficient sodium is eliminated. Thus, in patients with more severe renal dysfunction, longer duration is needed. To confirm the theory, when the nighttime MAP reached and remained < 90 % of the daytime average continuously for ≥1 hour, this was defined as “nocturnal BP dip.” The duration, from the time when subjects went to bed until the time when nocturnal BP dip first occurred, was defined as dipping time (DT). In fact, the DT was prolonged as renal function deteriorated [23••]. However, regression analysis alone would be insufficient to evaluate the relationships between DT and the renal function because among the 65 study subjects, 24 individuals exhibited no nocturnal BP dip during the night. Therefore, we adopted life table analysis to compare the cumulative incidence rate of the nocturnal BP dip across tertiles with different levels of creatinine clearance (Ccr). In the first tertile with preserved renal function, BP reached to <90 % of daytime averages soon after the initiation of sleep, and hardly exceeded the level again. In the third tertile with deteriorated renal function, BP almost continued elevated throughout the night above the daytime averages and hardly fell to <90 % of the daytime averages. BPs in the second tertile behaved as their intermediates between the first and third tertiles. This is evident that as renal function deteriorated, the cumulative incidence rate of the nocturnal BP dip was significantly reduced. Hazard ratios of nocturnal BP dip adjusted for age, gender, and body mass index were 0.37 (95 % CI: 0.17–0.79; P = 0.01) for the second tertile (Ccr: 50–90 mL/min) and 0.20 (95 % CI: 0.08–0.55; P = 0.002) for the third tertile (Ccr: 5–41 mL/min) compared with the first tertile (Ccr: 91–164 mL/min). Moreover, renal function was the sole determinant of a nocturnal BP dip (hazard ratio: 1.017; 95 % CI: 1.008–1.026; P = 0.0002), with a higher Ccr being associated with a higher incidence of nocturnal BP dip. Age, sex, and body mass index did not influence the nocturnal BP dip. We believe that these results indicate that nocturnal BP dip is manipulated mainly by renal dysfunction. These findings are consistent with Dahl’s study that the salt-sensitivity is determined by the kidney [5]. The DT appears to be an essential component and a more quantitative index of circadian BP rhythm. Furthermore, we reported that treatment with a diuretic, hydrochlorothiazide (HCTZ), which is known to decrease FRNa, restored the nondipper pattern of circadian BP rhythm into a dipper pattern in patients with essential hypertension [24], and IgA nephropathy [25]. These also support the above postulation that nondipper BP rhythm is the compensatory mechanism for reduced daytime renal sodium excretion.

Salt Sensitivity and Sympathetic Nerve Activity

High BP related to CKD includes sodium retention (ie, salt sensitivity), inappropriate enhancement of renin-angiotensin-aldosterone system, and sympathetic hyperactivity. Recently, Fujita’s group [26•] has proposed the linkage between salt sensitivity and sympathetic nerve activity. They found that in rat model of salt-sensitive hypertension with sympathetic over-activity, salt-induced renal sympathetic over-activity (β2-adrenergic receptor) down-regulated renal WNK4 expression, activated the Na+-Cl co-transporter, and induced sodium retention leading to salt-sensitive hypertension, whereas high-salt diet increased the expression in normal mice. They speculated that the paradoxical response of the renal sympathetic activity to salt loading was attributed to either genetic predisposition or acquired factors. In humans, single-nucleotide polymorphism (SNP) was also studied: GRK4 gene variants are reported to be associated with salt-sensitive and low-renin hypertension [27]. Further studies, including Genome-wide association study (GWAS), are needed to clarify the genetic contribution to the link between sympathetic activity and salt-sensitivity.

Cardio-Renal Connection and CKD Progression

Since impaired renal sodium excretion capacity causes sodium retention leading to pressure overload on the systemic circulation, it makes individuals with salt-sensitive hypertension and nondipper circadian BP rhythm susceptible to stroke or heart failure rather than ischemic coronary disease. Actually, it was reported that there was a clinically significant association between nondipper BP rhythm [2836] or sodium-sensitive hypertension [3742], and the incidence of stroke and congestive heart failure. Weinberger et al. also found that normotensive salt-sensitive subjects had a cumulative mortality similar to that of hypertensive subjects, whereas salt-resistant normotensive subjects exhibited better survival rate [43]. Moreover, in Japanese and African American populations, both of which are known to have high salt sensitivity, most of the cardiovascular event is stroke rather than ischemic heart disease, indicating the relevancy between salt sensitivity and stroke [4447].

Under the condition when either glomerular ultrafiltration coefficient is reduced or tubular sodium reabsorption is enhanced, glomerular capillary pressure is elevated, and BP becomes salt sensitive leading to nondipper circadian BP rhythm. In addition, both salt-sensitive hypertension and nondipper BP rhythm can increase the risk for cardiovascular events. In this way, salt sensitivity and excess salt intake contribute to the cardiorenal connection. Therefore, sodium retention connects CKD and cardiovascular events, especially stroke and congestive heart failure. Emerging evidences indicated the increased cardiovascular risk in the patients with minor renal insufficiency, and the risk becomes higher in those with advanced CKD stage [4852]. Therefore, the mechanism, by which CKD is the risk for cardiovascular diseases, has been the focus of great attention. Meanwhile, nondipper circadian BP rhythm is known to have a major impact on the cardiovascular risk [2833], and we found that circadian BP rhythm turned into more nondipper pattern as a function of renal dysfunction [22]. We therefore believe that nondipper BP rhythm is the key to connect the CKD and cardiovascular diseases (cardio-renal connection). Nondipper circadian BP rhythm that originates in sodium retention can be modifiable [24, 25, 53]. Further studies are needed to explore whether the treatment that can restore the nondipper BP rhythm, such as dietary salt restriction or diuretic therapy, could sever the cardio-renal connection.

In our previous study [22], as renal function deteriorated, the night/day ratios of BP and albuminuria were both increased, indicating the night-time pressure overload to the glomerular capillaries. Nondipper circadian BP rhythm and therefore underlying high salt-sensitivity are the risk for CKD progression. In type 1 diabetes with no microalbuminuria at baseline, the nondipper BP rhythm preceded the onset of microalbuminuria [54]. An inverse relationship between albuminuria and nocturnal BP dip was also reported [55].

Other study demonstrated that the decline in GFR slope was faster in nondippers than in dippers, independent of other renal risk factors [56]. In another study, however, GFR and nocturnal BP values, but not nondipper pattern, were reported to be associated with the risk to develop ESRD [57]. However, it is not surprising that the significant effect of the nondipper pattern on the renal outcome can be disappeared if the results are adjusted for baseline GFR, because nocturnal BP dip is well-determined by GFR [23••]. In other words, the findings can indicate that non-dipping itself is the very measurement of renal function. Further studies are needed to investigate which comes first, renal dysfunction or nondipper. The association of the renal dysfunction and the nondipper BP rhythm may lead to a vicious cycle leading to the renal dysfunction.

It should be emphasized that (1) impaired renal sodium excretion (leading to nondipper BP rhythm and high salt-sensitivity) can originate in not only reduced GFR (ie, renal dysfunction) but also augmented GFR, and (2) nondipper BP rhythm can be seen in the conditions where CKD is absent.

As mentioned earlier, renal sodium excretion capability is impaired by diminished KF and increased FRNa. Increase in FRNa can be seen in patients with primary aldosteronism, diabetes, obesity, and metabolic syndrome. In these conditions, GFR is expected to be augmented due to enhanced FRNa. Indeed, it was reported that non-dipping status was related to more renal morphological changes and hyperfiltration in an early stage of type 1 diabetes [58]. In this manner, nondippers were associated with both reduced and augmented GFR.

Nondipper BP rhythm is not always related to CKD. There are number of factors affecting circadian BP rhythm other than CKD, such as levels of activity and arousal during the day and night, day-night shift workers, the depth and quality of sleep, sleep apnea, sympathetic nerve activity, and secretion rhythm of vasoactive hormones (pheochromocytoma, Cushing syndrome). Body position during the sleep also affects the 24 h-ambulatory blood pressure monitoring (ABPM) recording.

Conclusions

Diminished renal sodium excretory capability can cause the salt-sensitive hypertension and the nondipper type of circadian BP rhythm to augment pressure overload to the systemic circulation, as well as the glomeruli. In daily clinical scene, 24-hours ambulatory BP measurement is to be recommended to detect the nondipper BP rhythm especially in patients with overt proteinuria because salt-sensitive hypertension is well-associated with an elevated glomerular capillary hydraulic pressure. Both salt-sensitivity and nondipper BP rhythm are known to be the risks for cardiovascular event or CKD progression. Salt-sensitive hypertension and nondipper BP can be restored by dietary salt restriction or the treatment with diuretics. Large-scale studies are needed to explore whether these interventions can decrease the risks.

Disclosure

No potential conflicts of interest relevant to this article were reported.

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© Springer Science+Business Media, LLC 2012