Chronic kidney disease (CKD) is associated with increased risk of cardiovascular (CV) events, and the disease burden is rising rapidly. An important contributor to CV events and CKD progression is high blood pressure (BP). The main mechanisms of hypertension in early and advanced CKD are renin-angiotensin system activation and volume overload, respectively. Sodium retention is well known as a factor for high BP in CKD. However, a BP increase in response to total body sodium or volume overload can be limited by neurohormonal modulation. Recent clinical trial data favoring intensive BP lowering in CKD imply that the balance between volume and neurohormonal control could be revisited with respect to the safety and efficacy of strict volume control when using antihypertensive medications. In hemodialysis patients, the role of more liberal use of antihypertensive medications with the concept of functional dry weight for intensive BP control must be studied.
In chronic kidney disease (CKD), cardiovascular (CV) risk is increased linearly by 7% per 10 mL/min/1.73 m2 decrease in glomerular filtration rate (GFR) [
CKD is defined as persistently elevated urine albumin excretion (≥30 mg/g [3 mg/mmoL] creatinine [Cr]), persistently reduced estimated GFR (eGFR < 60 mL/min per 1.73 m2), or both for greater than 3 months, in accordance with current Kidney Disease: Improving Global Outcomes (KDIGO) guidelines [
Approximately one-third of CKD stage 3 and less than one-half of CKD stage 4 patients have albuminuria [
The differences in the rationale or approach between prevention of renal progression and CVD are frequently discussed among cardiologists, hypertension specialists, and nephrologists. This article will review recent updates in BP control in CKD with a major focus on CVD prevention in addition to renal outcomes with viewpoints of salt retention or volume status control and the use of diuretics and non-diuretics as antihypertensive medications (AHMs) for intensive BP control. This review will not cover specific target BPs according to specific disease populations of CKD.
In addition to classic pressure natriuresis relationships, recent views highlighted that sodium balance is largely dependent on neurohormonal modulation [
However, a recent study by Rossitto G et al. [
Hypertonic or nonosmolar sodium accumulation in tissue compartments can be denied when sodium in tissues is isotonic and a reflection of ECF volume [
In CKD, a diverse level of skin or tissue sodium was reported, which now could be interpreted as silent edema or volume expansion by high salt intake. In a prospective observational study performed in a CKD population, high salt intake measured by 24-hour urine sodium excretion was significantly correlated with CKD progression and CVD events [
There is also ample, recent evidence to indicate that physical factors are clearly the subordinates of the neurohumoral mechanisms. Essentially, the question is then whether the normal physiological situation is best described as (i) neurohumoral modulation of the pressure natriuresis mechanism, or (ii) neurohumoral control occasionally modulated by pressure natriuresis. The latter possibility appears attractive [
Slight changes in osmolarity by salt intake, inducing immediate movement of water from the intracellular to the extracellular compartments, thirst, and secretion of antidiuretic hormones resulted in increasing and maintaining ECF volumes almost without apparent changes in sodium concentration [
When a bout of dietary salt is loaded in a normal subject, approximately half is excreted on day 1. With thirst and renal water resorption, body weight and ECF volume increases are associated with a variable degree of BP changes according to individual salt sensitivity [
The sodium excretion rate appears to be reduced by aging and CKD, and the mechanisms of decreased sodium excretion are a mixture of reduced glomerular filtration of sodium and increased tubular reabsorption of sodium independently, or both situations in combination. CKD is an important contributor to salt sensitivity. In a small study for male CKD patients on sequential low salt and high salt diets, the salt sensitivity index was calculated by the increase in mean arterial pressure in mmHg divided by the increase in 24-hour sodium excretion in mEq/day, which is the inversed slope of the classic pressure natriuresis relationship [
In an insightful and comprehensive study by Essig et al. [
In general, the prevalence of masked hypertension (MH) is higher in CKD compared to the general population and is related to low eGFR and proteinuria [
The association of MH and lower eGFR was observed only in patients with increased nighttime BP even though the mechanisms of increased MH in CKD are multifactorial [
ECF volume overload was reported as a group in early CKD, but routine assessments on an individual patient level are not practical [
There is insufficient data on the role of diuretics as the first-line therapy for the management of hypertension in CKD populations, and several guidelines on hypertension have shown different opinions and views on the use of diuretics [
Despite an increase in ECF volume in CKD, most guidelines prefer an RASB as the first-line therapy as long as BP is well controlled. The ACC/AHA (American College of the Cardiology/American Heart Association) 2017 guidelines recommend an angiotensin-converting enzyme (ACE) inhibitor for CKD and emphasize initial combination therapy and a target BP of <130/80 mmHg [
For additional use of diuretics in CKD, there was a recent observational study showing the benefit of spironolactone in CVD and renal outcomes in CKD stages 3 and 4 [
As the elderly population rapidly increases, there are more and more cardiorenal syndrome patients with CKD. From the randomized controlled trial (RCT) for heart failure in which volume control by diuretics is an essential component in standard drug therapy, two interesting drugs potentially related to volume control or sodium excretion are more and more frequently indicated in heart failure with CKD. First, the sodium glucose co-transporter 2 inhibitor (SGLT2I) has several mechanisms to protect the heart and kidneys. Among them, sodium excretion in the proximal tubule followed by increased sodium delivery to the macula densa and tubuloglomerular feedback results in a short-term increase in the excretion of renal sodium [
KDOQI guidelines underscore the purpose of antihypertensive therapy for prevention of both CKD progression and CVD [
Practically, in general, CKD stage 3 and 4 patients are very concerned about GFR decline in terms of fear of dialysis. First of all, it is very difficult for a patient to understand that higher GFR associated with higher BP could indicate a poor prognosis and that hyperfiltration or glomerular stretch at the level of the nephron is harmful. The acute decline of GFR especially by RASB, a functional side effect, could be uncomfortable for patients. Clearly informing patients of this potential issue and warning that 10% to 20% of the initial Cr increase is normal and reversible seems to be essential for patient adherence [
The initial decline in GFR has become a greater challenge for physicians because intensive BP lowering is increasingly considered for better CVD outcomes. After all, recommendations not to retry RASB in cases of an initial Cr increase of >30% and in cases of failure to return to baseline after dosage reduction or cessation do not seem to have a solid scientific basis. Avoidance of an initial Cr increase more than >30% could be regarded as a consistent application of the “
Strict volume control for intensive BP control could have increased risk of hypovolemia. Hypovolemia and/or hypotension are the most common factors for acute kidney injury (AKI). The nonrecovery of kidney function following an episode of AKI is a major contributing factor for the prevalence of CKD and the progression of CKD to an advanced stage [
There are several types of BP variabilities (BPV) such as visit-to-visit BPV in clinics, day-to-day BPV with home BP monitoring (HBPM), and short-term BPV with ABPM. The mechanisms for increased BPV in CKD are largely unknown, but impaired baroreceptor sensitivity, altered sympathetic nervous system activity, oxidative stress, inflammation, and increased arterial stiffness were suggested [
The Spanish ABPM registry showed that BPV increases as CKD progresses from stage 1 to 5 [
For clinic BP, among 114,900 patients with CKD, BPV was associated with all-cause mortality, hemorrhagic stroke, ESKD, and heart failure [
However, few studies have reported on the therapeutic implications of BPV in CKD. CCB was reported to be associated with lower BPV in CKD compared to beta-blockers or RASB [
There could also be a marked reduction in GFR when starting RASB in CKD despite the slight BP reduction. Diuretics or RASB and diuretics in combination are more commonly associated with side effects and a worse BPV profile than CCB in CKD [
BPV can affect variability in GFR because volume changes and impaired GFR autoregulation can be common in CKD, and variability in GFR can predict CV outcomes [
This review confined to BP control under a standard reimbursement protocol with a thrice a week hemodialysis (HD) protocol spanning about 4 hours seems to be limited for adopting various dialysis protocols for better BP control.
For the volume status description, dry weight is defined operationally as the lowest postdialysis weight with minimal signs or symptoms of hypovolemia even though the exact definition of dry weight remains uncertain or multiple definitions have been suggested [
Optimal predialysis BP for mortality risk was 130 to 160 mmHg when adjusted for confounding factors including AHM [
Volume overload and high BP are the most important contributors to LVH. In HD patients, there are other remarkable factors related to LVH such as anemia, arterial-venous dialysis accesses with high cardiac output, arterial stiffness, and bone mineral hormones [
Establishing a balance between AHMs and volume control is most challenging for treatment of severe IDH. If an effective AHM prescription during the phase of advanced CKD stage is available in a patient, the same AHM regimen with a UF amount equivalent to the role of diuretics during the CKD phase seems reasonable to be maintained during HD (
In conclusion, sodium retention can be demonstrated in both early and late CKD. The BP response to sodium retention could be modulated by neurohormones to maintain stable BP to a certain limit. RAS seems to be involved in a common pathophysiology for nephron injury in CKD with reduced renal mass. Recent clinical trial data favoring intensive BP lowering in CKD imply that the balance between volume and neurohormonal control could be shifted by using more AHMs other than diuretics than previously believed. More liberal use of AHMs could be allowed for effective BP control and CV protection even after HD is initiated with the concept of functional dry weight.
All authors have no conflicts of interest to declare.
Conceptualization: JS, CHL
Visualization: JS, CHL
Writing–original draft: JS
Writing–review & editing: CHL, JS
All authors read and approved the final manuscript.
(A) A three-compartment model with hypertonic sodium in the skin, muscle, or artery that could buffer the exchangeable sodium overload. Exact mechanisms on how sodium could be concentrated in the skin remain unknown. (B) A two-compartment model with isotonic skin sodium exhibiting distribution in the other interstitial tissues or edema. The dotted line indicates a sodium gradient across the cell membrane. The broken line means sodium distribution by Starling force. The separated bone compartment suggests different exchangeability kinetics from the other.
ECF, extracellular fluid; ICF, intracellular fluid.
All of the relationships between sodium excretion and SBP, the relationship between eGFR and sodium excretion, and the relationship between sodium excretion and eECF are not linear. Linear relationships were observed only among eGFR, eECF, and SBP. Crosses indicate projections on the two-dimensional planes from the dot points in the three-dimensional space (data from the tables in Essig et al. [
CKD, chronic kidney disease; eECF, extracellular fluid excess; eGFR, estimated glomerular filtration; SBP, systolic blood pressure.
(A) CKD, with normovolemia. (B) CKD, with permissible hypervolemia, less active use of diuretics. (C) Hemodialysis, absolute dry weight, hypovolemia with minimum use of AHM. (D) Hemodialysis, normovolemia. (E) Hemodialysis, functional dry weight or permissible hypervolemia. (F) CKD, intensive blood pressure (BP) control with permissible hypovolemia, more active use of diuretics. The achieved BP levels among A–E in the box are conventional and comparable. Relative intensity of antihypertensive therapy was depicted by the area of the rectangles. Compared to C, D–E conditions require more non-diuretics AHM to achieve the comparable level. F is the condition in need of intensive BP control to achieve the lower target BPs on the basis of permissible hypovolemia through the greater active use of diuretics or UF. The dotted line indicates the ideal status of extracellular volume or normovolemia. Each horizontal solid line represents the volume status achieved by diuretics or UF.
AHM, antihypertensive medications other than diuretics; CKD, chronic kidney disease; UF, ultrafiltration.
Each arrow represents the start of the fully dialyzable drug. (A) The blood pressure (BP) treated solely by antihypertensive drugs eliminated through the hepatic route. Since dialysis cannot reduce the drug concentration, active treatment targeting interdialytic BP could increase the risk of intradialytic hypotension. (B) It shows that BP treated by both antihypertensive drugs eliminated by the hepatic route targeting the BP in dry weight and fully dialyzable drugs targeting the BP increased during the interdialytic period and could be fully removed by dialysis without affecting the BP in dry weight. The dotted line represents the threshold for intradialytic hypotension.