Dietary Salt Intake and Hypertension in Chronic Kidney Disease

Abstract

There is a high prevalence of hypertension, which is both a cause and consequence of kidney function decline, among patients with chronic kidney disease (CKD). Impaired sodium excretion and the activation of the renin-angiotensin-aldosterone system (RAAS) are central mechanisms underlying this relationship. In early CKD, compensatory increases in fractional sodium excretion help maintain the balance of sodium in the body; however, as kidney function deteriorates, this compensatory mechanism is overwhelmed, resulting in sodium retention, extracellular volume expansion, and predominantly volume-dependent hypertension. Furthermore, CKD is characterized by heightened salt sensitivity, owing to which blood pressure (BP) responds disproportionately to changes in dietary salt intake. Emerging evidence suggests that non-osmotic sodium storage in tissues, such as alterations in glycosaminoglycan networks, impaired lymphatic clearance, and endothelial glycocalyx dysfunction, further contributes to salt-sensitive hypertension. Together with RAAS activation, these mechanisms promote vascular dysfunction, BP variability, and adverse cardiovascular outcomes. Dietary salt intake is a key modifiable factor in the management of CKD and hypertension. Randomized controlled trials have shown that decreased salt intake lowers BP, reduces proteinuria, and enhances the efficacy of RAAS inhibitors, thereby slowing the progression of CKD and reducing cardiovascular risk. Conversely, increased salt intake is associated with resistant hypertension, increased BP variability, and higher mortality; therefore, current guidelines recommend limiting salt intake to 5 g/day. The role of dietary potassium is increasingly recognized; however, caution is required in patients with advanced CKD due to the risk of hyperkalemia.

INTRODUCTION

The prevalence of hypertension, a common comorbidity in patients with chronic kidney disease (CKD), increases with declining kidney function, with hypertension observed in over 90% of patients with end-stage kidney disease (ESKD) [1,2]. Hypertension is the second leading cause of CKD, while impaired kidney function simultaneously causes and exacerbates hypertension through impaired sodium excretion and activation of the renin-angiotensin-aldosterone system (RAAS), affirming the close relationship between hypertension and CKD [3,4,5]. Hypertension accelerates the decrease in estimated glomerular filtration rate (eGFR) and leads to increased proteinuria in patients with CKD, resulting in progression of the disease, subsequently increasing the incidence of cardiovascular disease (CVD) and mortality [6,7].

Decreased eGFR restricts sodium excretion in CKD, leading to increased sodium retention and elevated blood pressure (BP). Additionally, owing to RAAS hyperactivity, even a small increase in dietary salt intake can cause a rapid rise in BP. Thus, patients with CKD exhibit a salt-sensitive phenotype, in which BP responds more acutely to dietary salt intake than among individuals in the general population [3,8,9]. Dietary salt intake is a modifiable factor, the reduction of which is an important goal not only to lower BP but also slow the progression of CKD and prevent CVD.

We discuss herein the effects and management of sodium in CKD, the mechanisms of salt-sensitive hypertension, the clinical significance of dietary salt intake in CKD and hypertension, and considerations for ensuring appropriate dietary salt intake.

SODIUM MANAGEMENT IN CKD

As CKD progresses, the number of functional nephrons decreases. In the early stages of the disease, the remaining functional nephrons maintain homeostasis by increasing the fraction excretion of sodium (FENa); however, when eGFR drops below approximately 30 mL/min/1.73 m², the compensatory mechanism reaches its limit, leading to sodium retention, increased BP, and worsening proteinuria [10,11,12,13].

In early-to-moderate CKD (stage G1-3), some nephrons are damaged, resulting in decreased eGFR. Consequently, the remaining functional nephrons compensate by inhibiting sodium reabsorption and increasing sodium excretion, leading to an increased FENa. Sodium reabsorption in the proximal tubule is reduced by the release of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) owing to slightly increased fluid volume and increased peritubular hydrostatic pressure. The increased release of nitric oxide and prostaglandins to maintain renal blood flow and eGFR inhibits sodium reabsorption in the loop of Henle. Additionally, increased ANP/BNP levels inhibit the epithelial sodium channel (ENaC) in the distal tubules, thereby promoting natriuresis (Table 1).

Table 1. Sodium management according to CKD stage.

Variables	Early CKD	Advanced CKD
FENa	Increased	Maximized
Total sodium excretion	Maintained (≈ intake)	Decreased
Main handling site	Proximal tubule	Distal tubule, collecting duct
Mechanism	Hyperfiltration, ANP/BNP	RAAS activation, fibrosis
Clinical outcome	Salt sensitivity	Volume overload
Pharmacological consideration	Sodium restriction may enhance the efficacy of RAASi therapy	Monitoring of hyperkalemia and kidney function during RAASi therapy; consider diuretics for volume control

ANP, atrial natriuretic peptide; BNP, B-type natriuretic peptide; FENa, fraction excretion of sodium; RAAS, renin-angiotensin-aldosterone system; RAASi, renin-angiotensin-aldosterone inhibitor.

While there were movements to increase tubular sodium excretion in early CKD, movements to inhibit sodium excretion also began. When the glomerulus recognizes that perfusion pressure is insufficient to compensate for the decrease in eGFR, it initiates renin secretion from the juxtaglomerular apparatus. Angiotensin II constricts the efferent arteriole much more strongly than the afferent arteriole, raising intraglomerular pressure in an attempt to maintain eGFR through compensatory glomerular hyperfiltration. Intrarenal RAAS activation promotes sodium retention and inhibits sodium excretion, contributing to increased fluid volume and salt-sensitive hypertension.

When eGFR drops < 45 mL/min/1.73 m² (CKD stage G3b), the capacity for tubular sodium excretion rapidly declines, leading to increased fluid volume and pronounced systemic RAAS activation. From this stage onwards, ENaC is upregulated by aldosterone, increasing sodium reabsorption in the collecting duct. As CKD progresses to advanced stages (stages G4 and 5), increased Na+/H+ exchanger type 3 (NHE3) activity is present in the proximal tubule owing to RAAS activation; however, the decrease in NHE3 activity caused by renal tissue fibrosis and tubular atrophy is greater, resulting in reduced sodium reabsorption in the proximal tubule. RAAS activation triggers sodium chloride (NaCl) cotransporter activity in the distal tubule and ENaC activation in the collecting duct, thereby increasing sodium reabsorption (Table 1). This leads to chronic volume expansion, followed by predominantly volume-dependent hypertension, which is often difficult to treat.

From a clinical perspective, pharmacological treatment strategies should be considered alongside dietary sodium restriction. In patients with early CKD, sodium restriction may enhance the antihypertensive and antiproteinuric effects of RAAS inhibitor (RAASi) therapy, including angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), and steroidal and nonsteroidal mineralocorticoid receptor antagonists (MRAs), by reducing extracellular volume expansion and mitigating compensatory RAAS activation. ACEi and ARBs remain the cornerstone of antihypertensive therapy in CKD and are recommended as first-line agents because they provide both kidney and cardiovascular (CV) protection beyond BP lowering [3,14]. While evidence supporting non-steroidal MRAs has largely been derived from trials involving patients with diabetic CKD, recent findings from the FIND-CKD trial suggest potential renoprotective benefits of finerenone in patients with albuminuric non-diabetic CKD [1,15]. In advanced CKD, however, pharmacological management requires a more individualized approach because impaired sodium excretion is often accompanied by volume overload and an increased risk of hyperkalemia. Loop diuretics may facilitate sodium removal and volume control, whereas careful monitoring of serum potassium and kidney function is necessary when RAASi therapy is used (Table 1) [1].

SALT-SENSITIVE HYPERTENSION IN CKD

Salt sensitivity is a condition in which BP changes significantly in response to variations in salt intake, typically assessed by a difference in mean arterial pressure of > 10% or 5–10 mmHg or more between a high-salt and a low-salt diet [16,17]. Salt-sensitive hypertension is a condition in which BP rises in response to increased salt intake. The kidneys play a significant role in the development of salt-sensitive hypertension, which is highly prevalent in patients with CKD [18,19], owing to the aforementioned impaired sodium handling by the kidneys, and, to a degree, an imbalance in the non-osmotic sodium storage system. Although sodium draws water into the plasma to maintain osmotic pressure and increase fluid volume, recent studies suggest that a significant amount of sodium is stored non-osmotically by binding to the glycosaminoglycan network in the dermal interstitium, without water retention [20,21].

Sodium homeostasis changes at the tissue level in patients with CKD, extending beyond simple fluid regulation. The structural modifications and reduced sulfation of dermal interstitial glycosaminoglycans impair their sodium-binding capacity, causing sodium to accumulate abnormally within the interstitial layer [20]. Normally, this sodium accumulation stimulates macrophages to secrete vascular endothelial growth factor C and promote lymphangiogenesis, thereby removing excess sodium [22]. However, in the advanced stages of CKD, this immune-lymphatic regulatory mechanism fails to function adequately, limiting the removal of sodium from the tissues. This accumulated sodium contributes to vascular dysfunction and salt-sensitive hypertension [23]. The glycocalyx in the vascular endothelium is also integral in regulating sodium [24]; however, in CKD, chronic inflammation and oxidative stress damage the glycocalyx, leading to a decrease in sodium buffering capacity at the vascular level [25,26,27]. These changes further exacerbate the increase in vascular resistance and associated rise in BP upon salt intake.

Furthermore, genetic factors are known to be involved in salt-sensitive hypertension. Monogenic disorders associated with salt-sensitive hypertension, including apparent mineralocorticoid excess and Liddle syndrome, provide strong evidence for the role of the kidney in BP regulation. Hypertension in these disorders has been shown to improve after kidney transplantation, further supporting the concept that the kidney is a key determinant of salt-sensitive hypertension [18,28].

As previously mentioned, increased salt sensitivity is characterized by a greater BP response to salt intake, often manifesting as a 5–10 mmHg increase in BP. Importantly, the clinical implications of this BP rise differ according to CKD stage. Patients with CKD already have a reduced capacity for sodium buffering, resulting in a larger standard deviation of systolic BP and, consequently, increased BP variability [29]. Additionally, a “pressure-natriuresis” mechanism is activated in patients with CKD to promote the excretion of sodium retained during the day, leading to nocturnal hypertension and a non-dipping pattern of BP [29]. In the early CKD (stages G1 and 2), even a modest rise in BP driven by salt intake elevates intraglomerular pressure, inducing proteinuria, inflammation, and fibrosis in the tubule and interstitium, thereby accelerating the progression of CKD [30]. In advanced CKD (stages G3-5), where sodium excretion and tissue buffering capacities are severely exhausted, this 5–10 mmHg shift serves as a critical tipping point. In these advanced stages, it directly exacerbates volume overload, precipitates resistant hypertension, and exponentially drives the risk of acute CV events, such as heart failure and stroke [31,32]. These factors—BP variability, nocturnal hypertension, and stage-specific CKD progression—are linked to an increased risk of CVD [29,33].

CLINICAL SIGNIFICANCE OF DIETARY SALT INTAKE IN HYPERTENSION AND CKD

Dietary salt intake, which plays a significant role in the progression of hypertension and CKD, is one of the major factors determining BP. Many previous randomized controlled trials (RCTs) have demonstrated the importance of dietary salt intake. For example, the Dietary Approaches to Stopping Hypertension (DASH)-sodium trial showed that in patients with hypertension, low-salt intake lowered BP in a dose-dependent manner, with the greatest reduction at the lowest intake level (≤ 1,500 mg/day) [34,35]. Furthermore, in patients with CKD, dietary salt restrictions slow the progression of CKD by reducing not only BP but also intraglomerular pressure and proteinuria [36]. RCTs conducted on patients with CKD have shown that a low-salt diet effectively reduces extracellular fluid volume and arterial stiffness, thereby lowering the risk of CVD and progression to ESKD [36,37]. Furthermore, dietary salt intake affects RAAS activation and treatment responsiveness [36]. While a high-salt diet attenuates the antiproteinuric and antihypertensive effects of RAASi therapy, dietary salt restriction significantly improved treatment responsiveness to RAASi therapy [38,39]. In a randomized crossover study of patients with CKD, reducing dietary salt intake resulted in an additional 5–10 mmHg reduction in SBP and a 30–50% reduction in proteinuria compared with the effects achieved with RAASi therapy monotherapy [40]. However, the clinical application of the DASH diet should be differentiated based on the CKD stage, particularly regarding potassium intake. While the high potassium content of the DASH diet offers significant CV benefits and BP control in the early stages of CKD, it poses a critical risk of hyperkalemia in patients with advanced CKD. Therefore, current clinical guidelines recommend regular monitoring of serum potassium levels and individualized modification of the DASH diet according to CKD stage and hyperkalemia risk [1].

Increased dietary salt intake is associated with treatment-resistant hypertension as well as increased BP variability and nocturnal hypertension, which are closely linked to worsening CVD prognoses and increased mortality. Conversely, the restriction for dietary salt improves these abnormal BP patterns and reduces the overall risk of CVD [34,41].

APPROPRIATE DIETARY SALT INTAKE

According to Kidney Disease: Improving Global Outcomes, optimal dietary salt intake is < 5 g (approximately 2,000 mg of sodium) to reduce the risk of hypertension and CVD in patients with hypertension and CKD [1,3]. While stricter dietary salt restrictions, such as ≤ 1,500 mg/day of sodium, show a more potent BP-lowering effect [42], observational studies have shown a J-shaped relationship between dietary salt intake and mortality and CV events, and very low salt intake may require caution as it can lead to inadequate nutritional intake and nutritional imbalance, particularly in elderly patients and those with advanced CKD [43].

There is a paucity of research on whether the type of dietary salt is related to clinical outcomes or on which diet should be followed. However, according to the results of the Salt Substitute and Stroke Study, replacing regular sodium chloride with potassium-fortified salt substitutes significantly lowered the risk of stroke and major CVDs compared with regular salt [44]. Furthermore, it has been reported that increased dietary potassium intake is associated with lower BP, improved vascular function, and a reduced risk of CVD [45]. In particular, the sodium-potassium ratio appears to be a more powerful predictor of hypertension and CVD outcomes than dietary salt intake alone [46]. Increased dietary potassium intake promotes sodium excretion and regulates sodium-chloride cotransporter activity in the distal tubules, thereby mitigating the hypertensive effects of sodium [47]. Therefore, even with the same dietary salt intake, a potassium-rich diet, such as the DASH diet, can help improve CV risk and metabolic parameters and control BP [1,48]. However, in patients with advanced CKD (stages G3b–G5) or RAASi therapy, caution is required when using the DASH diet or potassium-containing salt substitutes owing to the risk of hyperkalemia [3,49]. Therefore, for these high-risk patients, regular monitoring of serum potassium levels and kidney function, and individualized dietary counseling are essential to safely balance the risk of electrolyte imbalance with the benefits of salt restriction.

In conclusion, impaired sodium handling in CKD leads to salt-sensitive hypertension and adverse outcomes; therefore, appropriate dietary salt restrictions are essential, accounting for individualized consideration of disease stage and potassium balance.