Management of hypertension in specific populations: a review

Abstract

Hypertension is a widespread global health issue that disproportionately affects certain populations, including self-identified Blacks, the older persons, patients with chronic kidney disease (CKD), and kidney transplant recipients. Hypertension disproportionately affects self-identified Black individuals, with a prevalence of 57.1% compared to 43.6% in non-Hispanic White individuals. This disparity is linked to social determinants of health. Furthermore, APOL1 genetic variants found in self-identified Black individuals increase their susceptibility to kidney injury and CKD, which can subsequently contribute to hypertension. Although in the past thiazide diuretics and calcium channel blockers (CCBs) were suggested to be more effective in Black adults, combination therapy is now generally required, with comparable efficacy across populations. In the older persons, hypertension affects approximately 70% of individuals over the age of 65 years, often manifesting as isolated systolic hypertension (ISH). Trials like the SPRINT study (Systolic Blood Pressure Intervention Trial) have demonstrated the benefits of lowering systolic blood pressure (SBP) to less than 120 mmHg; however, treatment must take into account factors like orthostatic hypotension and frailty. Patients with CKD have a hypertension prevalence of 80–85%. The KDIGO (Kidney Disease: Improving Global Outcomes) 2021 guidelines recommend maintaining an SBP of less than 120 mmHg based on the SPRINT trial, although this goal may increase the risk of acute kidney injury (AKI). Renin-angiotensin-aldosterone system (RAAS) blockers are typically preferred for those with proteinuric CKD. Kidney transplant recipients also experience high rates of hypertension, with approximately 85% affected. The KDIGO 2021 guidelines suggest a blood pressure (BP) target of less than 130/80 mmHg in kidney transplant patients, with a focus on promoting graft survival. Dihydropyridine CCBs and angiotensin receptor blockers are commonly preferred treatments in kidney transplant patients, especially for patients with proteinuric kidney disease. This review synthesizes current evidence regarding the unique challenges and management strategies for hypertension in these specific groups. It examines the prevalence, underlying mechanisms, and treatment considerations while emphasizing the importance of individualized care to achieve optimal BP control and reduce cardiovascular risk.

Introduction

The World Health Organization (WHO) estimates that 1.28 billion adults aged 30 to 79 years worldwide have hypertension [based on a blood pressure (BP) cutoff of ≥140/90 mmHg] (1). While the fundamental principles of BP management are generally applicable, specific considerations are necessary for certain groups. These special populations, which include older adults, patients with chronic kidney disease (CKD), and those who have undergone kidney transplantation, as well as racial and ethnic populations, often face disparities in hypertension prevalence, treatment response, and outcomes. Understanding the unique challenges associated with hypertension in these groups is essential for optimizing care and reducing cardiovascular risk. This review will delve into the distinct challenges and management strategies for hypertension in these populations, highlighting the importance of personalized approaches to achieve optimal BP control and enhance long-term health.

Hypertension in self-identified Black adults

Prevalence and disparities

Non-Hispanic Black (NHB) individuals experience higher rates of hypertension compared to other populations in the United States (2). The 2020 National Health and Nutrition Examination Survey reported that NHB individuals had a higher age-adjusted prevalence of hypertension (57.1%) compared to non-Hispanic Whites (43.6%) and Hispanic adults (43.7%) (3). A complex interplay of social determinants of health drives this increased risk of hypertension among NHB patients. Factors contributing to this disparity include socioeconomic and educational inequalities, the stress associated with concentrated neighborhood poverty (which can lead to accelerated aging), limited access to affordable and healthy food, and the adoption of less healthy dietary patterns, such as high-sodium and low-potassium diets (4,5). In multiracial societies like the United States and South Africa, populations of African descent with lower social status experience a higher prevalence of hypertension than would be expected based on standard anthropometric and socioeconomic risk factors (6).

Disparities in BP control are evident among NHB individuals compared to other populations, as demonstrated in various studies and analyses (7,8). One study conducted in the United States found that NHB adults were less likely to have controlled BP than non-Hispanic White adults, with rates of 41.5% and 48.2%, respectively (9). A population-based study in Europe also reported poorer control of hypertension among Black individuals compared to Whites (10).

In the United States, NHB individuals face a disproportionately higher burden of complications related to hypertension than other racial groups (11). This disparity is reflected in several critical health outcomes. For instance, Black Americans have a two-fold greater risk of experiencing a first-ever stroke, and this disparity persists even when taking stroke severity into account (12). Additionally, heart failure (HF) is another devastating consequence, with NHB individuals showing higher rates of HF, both with preserved and reduced ejection fraction (13). CKD and end-stage renal disease (ESRD) are also significantly more prevalent in the NHB population, often linked to uncontrolled hypertension (14).

These disparities in health complications highlight the complex interplay of factors contributing to the disproportionate burden of hypertension and its consequences in NHB individuals. These factors include genetics, socioeconomic status, access to healthcare, and the pervasive impact of systemic racism (15).

Socioeconomic disparities, such as limited educational opportunities and lower income, significantly contribute to this disparity by restricting access to quality healthcare, safe environments for physical activity, and healthy food options (7). In addition, the chronic stress associated with living in disadvantaged neighborhoods, which are often characterized by limited resources and concentrated poverty, can result in sustained elevations in BP. Experiences of discrimination and systemic racism, a unique stressor faced by NHB individuals, further exacerbate these disparities through pathways involving both physiological dysregulation and psychological stress (16).

Dietary factors also play a role in these disparities. For example, one study found that a higher prevalence of hypertension in Black individuals is related to a relatively low intake of potassium (17). Additionally, self-identified Blacks are noted to have a higher salt sensitivity (18), which is postulated to be due to upward resetting of the tubuloglomerular feedback that leads to progressive renal injury. Salt sensitivity is more pronounced in NHB individuals than White individuals when dietary potassium is low but is reversed when potassium intake is increased (19).

NHBs have higher rates of nocturnal non-dipping BP, which is linked to psychosocial and environmental factors like lower socioeconomic status and neighborhood violence (20). One study found that experiences of everyday discrimination are associated with less nocturnal BP dipping, even after considering known covariates (21).

Suboptimal hypertension control in NHB is partly due to medication nonadherence, which is caused by social determinants. Barriers to medication adherence include side effects, mistrust in the medical system, and discomfort with taking medication (22). Additionally, missed doctor’s appointments often result from various barriers to care, including limited access to healthcare resources, knowledge gaps, and potentially negative attitudes about healthcare (23). While therapeutic inertia impedes BP control, its role in disparities among NHB patients is debated. In standardized care settings, such as the SPRINT trial (Systolic Blood Pressure Intervention Trial), therapeutic inertia rates were similar or even lower in NHB patients, suggesting that it may not disproportionately affect them when care is consistent (24).

While social determinants of health exert a greater influence on hypertension and its complications, studies show a link between APOLIPOPROTEIN A1 (APOL1) gene renal risk variants and hypertension in NHB individuals. The APOL1 G1 and G2 variants are strongly associated with glomerular diseases like focal segmental glomerulosclerosis (FSGS) and hypertensive nephrosclerosis, which in turn lead to consequent hypertension. Evidence indicates that the primary effect of APOL1 risk alleles is on podocyte injury and glomerular dysfunction, leading to proteinuria and progressive CKD. Hypertension then emerges as a consequence of this renal damage, rather than a direct, primary effect of the APOL1 variants themselves (25-27). Some epidemiological studies show that individuals with two APOL1 risk alleles may develop hypertension earlier. However, these observations are best explained by subclinical or early kidney injury preceding a significant decline in glomerular filtration rate (GFR), rather than a direct hypertension-inducing effect of APOL1 when kidney disease is absent (28).

Treatment strategies in NHBs with hypertension

The African American Study of Kidney Disease and Hypertension (AASK) trial (29) was a significant study involving 1,094 NHB adults with hypertensive kidney disease, specifically those with a GFR of 20–65 mL/min per 1.73 m², excluding diabetic patients and proteinuric patients with urine protein-to-creatinine ratio (UPCR) >2.5 g/g. The AASK trial used a 3×2 factorial design to compare ramipril, metoprolol, and amlodipine, and two BP targets (MAP ≤92 mmHg vs. MAP 102–107 mmHg). Primary outcome: GFR decline rate; secondary outcomes: ≥50% GFR reduction, ESRD, or death. Key findings were that angiotensin-converting enzyme inhibitors (ACEi)-based therapy (ramipril) was superior to both beta-blocker and calcium channel blocker (CCB) regimens in slowing the progression of kidney disease, particularly in those with proteinuria. However, more intensive BP lowering did not confer additional renal benefit compared to the usual BP target.

The SPRINT (30) also provided valuable insights. It demonstrated that reducing systolic blood pressure (SBP) to 120 mmHg or less, compared to 140 mmHg or less, yielded similar BP control and comparable benefits and risks across all racial and ethnic groups examined. However, on average, NHB participants required about 0.3 additional medications to achieve the lower target (31).

The American Heart Association (AHA) 2017 guidelines recommend using CCBs or thiazide-type diuretics as preferred agents (see Table 1 for different classes of antihypertensives) for managing hypertension in NHBs. For most patients, particularly NHBs with stage 2 hypertension (≥140/90 mmHg), two or more medications are typically required (33). The Jackson Heart Study further confirmed the efficacy of thiazide diuretics in this population. It also showed that while CCBs were effective, patients using CCB monotherapy were significantly less likely to reach target BP than those on thiazide monotherapy.

Table 1. Classes of anti-hypertensive medications (32).

Class	Thiazide diuretics	Loop diuretics	Potassium-sparing diuretics	ACEi	ARBs	Beta-blockers	CCBs	Direct vasodilators	Alpha-blockers	Central alpha-2 agonists	Direct renin inhibitors
Mechanism	Inhibit Na+/Cl− cotransporter in the distal convoluted tubule, increasing Na+ and water excretion. Reduces plasma volume and subsequently lowers blood pressure. May also have a direct vasodilatory effect	Inhibit the Na+/K+/2Cl− cotransporter in the loop of Henle, leading to significant Na+ and water excretion—more potent diuretics than thiazides	Spironolactone & eplerenone: block the MR, inhibiting the effects of aldosterone. Amiloride & triamterene: block the epithelial ENaC. All reduce sodium reabsorption & potassium excretion	Inhibit the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor. Also inhibit the breakdown of bradykinin, which contributes to vasodilation	Block the angiotensin II receptor (AT1), preventing angiotensin II from binding and exerting its effects	Block beta-adrenergic receptors, reducing heart rate and contractility, and decreasing renin release. Carvedilol and labetalol have alpha and beta blocking properties and are better antihypertensives than cardioselective beta-blockers (metoprolol)	Dihydropyridines: primarily act on vascular smooth muscle, causing vasodilation. Non-dihydropyridines: affect vascular smooth muscle and cardiac muscle, reducing heart rate and contractility	Relax vascular smooth muscle, causing vasodilation and BP control. Hydralazine: a direct vasodilator that primarily affects arterioles. It is often used in combination with other antihypertensive medications. Hydralazine, in combination with isosorbide dinitrate, is particularly beneficial in African-Americans in mortality outcomes in patients with heart failure with reduced ejection fraction in patients who are intolerant of ACEi, ARB, ARNI. Minoxidil: a potent vasodilator that is reserved for severe or resistant hypertension	Block alpha-adrenergic receptors, causing vasodilation	Stimulate alpha-2 adrenergic receptors in the brainstem, reducing sympathetic outflow to the heart and blood vessels	Inhibit renin, the enzyme that initiates the RAAS
Side effects	Hypokalemia, hyponatremia, hyperuricemia, hyperglycemia, hypercalcemia, orthostatic hypotension, dizziness, photosensitivity	Hypokalemia, hyponatremia, hypomagnesemia, hypocalcemia, metabolic alkalosis, orthostatic hypotension, dizziness, tinnitus	Hyperkalemia, gynecomastia (spironolactone), metabolic acidosis (amiloride & triamterene), dizziness	Dry cough, hypotension, hyperkalemia, angioedema (rare but serious), dizziness, fatigue, renal impairment	Hypotension, hyperkalemia (less common than with ACEi), dizziness, fatigue, renal impairment, angioedema (less common than with ACEi)	Bradycardia, hypotension, fatigue, dizziness, bronchospasm, erectile dysfunction, masking hypoglycemia symptoms	Dihydropyridines: peripheral edema, headache, flushing, dizziness. Non-dihydropyridines: bradycardia, constipation (verapamil), dizziness, headache	Hydralazine: headache, flushing, tachycardia. Minoxidil: hypertrichosis, pericardial effusion, reflex tachycardia	Orthostatic hypotension, dizziness, headache, nasal congestion	Sedation, dry mouth, dizziness, bradycardia, rebound hypertension (with abrupt discontinuation of clonidine)	Hypotension, hyperkalemia, dizziness, diarrhea, angioedema (rare)
Considerations	Monitor electrolytes. Can exacerbate gout. Chlorthalidone has a longer half-life than hydrochlorothiazide. Chlorthalidone can be effective even if eGFR <30 mL/min	Monitor electrolytes closely. Higher risk of dehydration and volume depletion and electrolyte imbalances compared to thiazides. Used more commonly in patients with edema or heart failure. Loop diuretics cause more hypernatremia than hyponatremia. Used in advanced CKD for volume and hypertension control	Monitor potassium. Contraindicated in hyperkalemia or severe renal impairment. Eplerenone is more selective for MR than spironolactone and has a lower risk of gynecomastia. Spironolactone is used as a 3rd or 4th line agent in resistant hypertension. Amiloride can be used to block ENaC channels in nephrotic syndrome patients	Monitor renal function and potassium. Contraindicated in pregnancy. Cough may resolve with ARB switch. Have kidney protective effects in diabetic and non-diabetic CKD	Monitor renal function and potassium. Contraindicated in pregnancy. Have kidney protective effects in diabetic and non-diabetic CKD. ARBs can be used in ACE inhibitor-induced angioedema. Do not combine ARB with ACEi or direct renin inhibitor	Use with caution in patients with asthma or COPD. Can worsen bradycardia or heart block. Taper off gradually. Cardioselective beta-blockers primarily block β1 receptors and are not potent antihypertensives	Verapamil and diltiazem can interact with other drugs affecting cardiac conduction. Amlodipine is commonly used for hypertension. Non-Dihydropyridine CCBs block cytochrome CYP3A4 and raise the blood levels of calcineurin inhibitors	Hydralazine is often not used as a first-line agent due to dosing frequency. Hydralazine can cause drug-induced lupus and ANCA vasculitis. Minoxidil can cause fluid retention and reflex tachycardia, so it is commonly used with a diuretic and beta-blocker	Often used to treat hypertension in patients with BPH	Methyldopa is safe for use in pregnancy. Clonidine is sometimes used for resistant hypertension and is available in patch form to improve patient compliance	Monitor renal function and potassium. Contraindicated in pregnancy. Do not combine ARB with ACEi or direct renin inhibitor

Thiazide diuretics (e.g., HCTZ, chlorthalidone); loop diuretics (e.g., furosemide, bumetanide); potassium-sparing diuretics (e.g., spironolactone, eplerenone, amiloride, triamterene); ACEi (e.g., lisinopril, enalapril, ramipril); ARBs (e.g., valsartan, losartan, irbesartan); beta-blockers (e.g., carvedilol, labetalol, metoprolol); direct vasodilators (hydralazine, minoxidil); alpha-blockers (e.g., prazosin, terazosin, doxazosin); central alpha-2 agonists (e.g., clonidine, methyldopa); direct renin inhibitors (e.g., aliskiren). ACE, angiotensin-converting enzyme; ACEi, angiotensin-converting enzyme inhibitor; ANCA, antineutrophil cytoplasmic antibodies; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor-neprilysin inhibitor; BP, blood pressure; BPH, benign prostatic hyperplasia; CCB, calcium channel blocker; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; eGFR, estimated glomerular filtration rate; ENaC, epithelial sodium channel; MR, mineralocorticoid receptor; RAAS, renin-angiotensin-aldosterone system.

Furthermore, hypertensive NHBs face a higher risk of adverse cardiovascular outcomes when using ACEi, which is why these are not advised as monotherapy (34,35). This conflicts with the AASK study, which supports using ACEi in patients with CKD and proteinuria, regardless of race or ethnicity. However, ACEi or angiotensin receptor blockers (ARBs) may be utilized as initial or add-on therapy for better renal outcomes in NHB patients with hypertension and diabetic nephropathy.

NHBs with hypertension tend to have low plasma renin levels, which may explain their poor response to renin-angiotensin-aldosterone system (RAAS) inhibition (36). For those with stage 2 hypertension, it is recommended to start treatment with two BP-lowering agents immediately after diagnosis. The choice of medications should be based on specific indications. A combination of a CCB with a RAAS blocker or a CCB with a diuretic (in edematous patients) is often a reasonable approach. Patients with hypertension resistant to a two-drug combination may have plasma volume expansion; thus, adding a diuretic or substituting a more potent diuretic in the combination may be necessary (37).

Hypertension in the older persons

Hypertension affects 70% of Americans over 65 years (38). Age-related vascular changes cause increased BP, especially SBP (due to arterial stiffness), resulting in isolated systolic hypertension (ISH). ISH increases the risk of HF, stroke, kidney failure, and myocardial infarction (MI) (39,40).

Managing hypertension in older adults involves lifestyle changes such as dietary sodium restriction (41) and weight loss for obese patients. However, excessive weight loss should be avoided to prevent frailty and impaired daily activities due to sarcopenia.

Landmark trials demonstrate the cardiovascular benefits of lowering BP in the older persons. The Syst-Eur trial (mean age 70 years) showed significant stroke reduction and cardiac effects with nitrendipine (with enalapril and hydrochlorothiazide if needed) vs. placebo (7.9 vs. 13.7 total endpoints per 1,000 patient years for stroke) (42). Also, it had a beneficial effect on the onset of dementia. Another significant study was the Systolic Hypertension in the Elderly Program (SHEP) trial, which included 4,376 older adult patients with a mean BP of 170/77 mmHg at baseline. Participants were randomly assigned to receive either chlorthalidone or a placebo. Over 5 years, the incidence of total stroke was 5.2 per 100 participants in the active treatment group compared to 8.2 per 100 in the placebo group. Additionally, the more recent SPRINT trial demonstrated favorable cardiovascular and survival outcomes in individuals over 75 years with intensive BP lowering.

STEP trial (Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients) (43) investigated optimal SBP targets in older adults (aged 60–80 years) with hypertension. The trial randomized 8,511 Chinese patients to either an intensive SBP target of 110 to <130 mmHg or a standard target of 130 to <150 mmHg. Over a median follow-up of 3.34 years, the intensive group had a significantly lower incidence of major cardiovascular events [3.5% vs. 4.6%; hazard ratio (HR) 0.74; 95% confidence interval (CI): 0.60–0.92; P=0.007], including reductions in stroke, acute coronary syndrome, and HF. However, the risk of death from any cause did not differ significantly between groups. Hypotension was more frequent in the intensive group, but other adverse events (dizziness, syncope, fracture, renal outcomes) were similar between groups. Only Han Chinese patients were included and the study excluded adults with a history of stroke(s).

ESPRIT trial (Effects of intensive Systolic blood Pressure lowering treatment in reducing RIsk of vascular evenTs) (44) was conducted across 116 Chinese hospitals and communities, followed high-cardiovascular-risk participants [mean age 64.6 years, including those with diabetes (38.8%) or stroke history (27%)] for 3.4 years. The intensive treatment group (targeting SBP <120 mmHg) had a primary composite outcome (MI, revascularization, HF hospitalization, stroke, or cardiovascular death) in 9.7% of participants, vs. 11.1% in the standard group (targeting SBP <140 mmHg) (HR 0.88, 95% CI: 0.78–0.99; P=0.03). Effects were consistent regardless of diabetes status or history of stroke. Syncope was more prevalent in the intensive group (0.4% vs. 0.1%; HR 3.00; 95% CI: 1.35–6.68).

While ISH linearly correlates with adverse outcomes in the older persons, diastolic BP has a J-shaped relationship with mortality. Reduced coronary perfusion with diastolic BP below 60 mmHg necessitates avoiding aggressive BP lowering in this population (45).

The 2017 AHA guidelines recommend an SBP goal of 130 mmHg or less for noninstitutionalized hypertensive adults over 65 years, with an individualized approach for those with comorbidities and limited life expectancy (33).

Orthostatic hypotension is a concern, as worsening with antihypertensive medications can lead to falls and fractures. Supine and standing BP should be checked before treatment. Frailty is another consideration, as major trials lacked significant frail patient representation.

Comorbidities, cost, and tolerability should guide antihypertensive choice in older adults. Thiazide diuretics or CCBs can be used initially, combined if needed, and supplemented with ACEi or ARB, and then spironolactone if BP remains uncontrolled (46). The HyVET (Hypertension in the Very Elderly Trial) (47) specifically showed the benefits of lowering mortality from stroke, death from any cause, and HF from indapamide with or without perindopril in octogenarians; 8.3% of the patients in this trial had orthostatic hypotension at baseline.

Hypertension in CKD (not on dialysis)

Hypertension is present in approximately 80 to 85 percent of patients with CKD (48). The KDIGO (Kidney Disease: Improving Global Outcomes) guidelines, updated in 2021 and reaffirmed in 2024, recommend a target SBP of <120 mmHg, if tolerated (2B recommendation) (49). This recommendation, which updates the 2017 guidelines, is supported by evidence demonstrating that intensive BP lowering can reduce cardiovascular risk, although it does not necessarily reduce the risk of kidney failure (based on SPRINT trial). The guidelines stress the importance of individualized targets, particularly for older adults or those with frailty, a high risk of falls, limited life expectancy, or symptomatic postural hypotension, where less aggressive targets may be more suitable.

Interestingly a 2024 meta-analysis of six randomized controlled trials (RCTs) (50) (7,348 participants) on CKD and hypertension found that lower BP targets (≤130/80 mmHg) showed little to no significant benefit over standard targets (140–160/90–100 mmHg) for mortality (RR 0.90, 95% CI: 0.76 to 1.06), adverse events (RR 1.01, 95% CI: 0.94 to 1.08), total cardiovascular events (RR 1.00, 95% CI: 0.87 to 1.15), or ESRD progression (RR 0.94, 95% CI: 0.80 to 1.11), despite greater BP reduction. Evidence certainty was moderate to low.

Subsequent systematic review and meta-analysis of nine RCTs (51) investigated optimal BP targets in CKD patients. Intensive BP control (<130/80 mmHg) tended to reduce all-cause mortality (RR 0.81; 95% CI: 0.65–1.00; P=0.051) and cardiovascular events (RR 0.89; 95% CI: 0.77–1.03; P=0.13), without increasing serious renal events [50% estimated glomerular filtration rate (eGFR)/GFR reduction: RR 0.95; 95% CI: 0.74–1.22; P=0.69; ESKD progression: RR 0.92; 95% CI: 0.75–1.14; P=0.45]. These findings suggest intensive BP control may reduce mortality and cardiovascular events in CKD patients without increasing renal risk.

The SPRINT trial (30) demonstrated cardiovascular (1.65% per year vs. 2.19% per year; HR 0.75) and survival benefits (HR for all cause mortality 0.73) with an SBP target of <120 vs. <140 mmHg for most CKD patients, including older persons and frail individuals. However, the SPRINT MIND trial (52) found no significant difference in probable dementia rates between the two SBP targets.

The SPRINT trial subgroup analysis by Cheung et al. (53) investigated the effects of a lower SBP target (<120 mmHg) on kidney protection in patients with CKD. The primary kidney outcome was a composite of ≥50% decrease in eGFR from baseline or ESRD. Results showed no significant difference in the primary outcome between the intensive and standard treatment groups (HR 0.90; 95% CI: 0.44 to 1.83). Additionally, after 6 months, the intensive group showed a slightly higher, but statistically significant, rate of eGFR decline compared to the standard group (−0.47 vs. −0.32 mL/min per 1.73 m² per year; P<0.03).

Evidence supporting an SBP target of <120 mmHg is uncertain for specific subpopulations, including those with diabetes, advanced CKD (stages 4 & 5), significant proteinuria >1 g per day, baseline SBP of 120–129 mmHg, individuals younger than 50 or older than 90 years of age, and those with “white-coat” or severe hypertension. The guideline suggests lifestyle interventions, such as targeting a sodium intake of <2 g per day and moderate-intensity physical activity for at least 150 minutes per week. Due to limited evidence, the recommendation for a lower SBP target in CKD is considered weak, and individualized treatment is emphasized. Intensive BP lowering to SBP <120 mmHg is associated with more acute kidney injury (AKI) and electrolyte abnormalities (30).

The SPRINT trial did not include diabetics. The ACCORD trial (54), which focused on type 2 diabetes patients, found no overall cardiovascular benefit but a significant stroke reduction in the low SBP group (<120 mmHg), benefiting those with standard glucose control but not intensive control. Both SPRINT and ACCORD trials used the same SBP targets (<120 vs. <140 mmHg), but ACCORD excluded those with serum creatinine greater than 1.5 mg/dL. Thus, the cardiovascular benefits of intensive BP-lowering in patients with diabetes and CKD remain unclear, and large-scale RCTs are needed. Interestingly, in a post hoc analysis (55) of the SPRINT trial, participants with prediabetes and normoglycemia at baseline had lower cardiovascular and all-cause mortality from <120 vs. <140 mmHg SBP treatment.

The recently published Blood Pressure Control Target in Diabetes (BPROAD) trial (56) assessed the efficacy and safety of intensive BP management in patients with type 2 diabetes. This randomized trial in China included 12,821 participants with a median follow-up of 4.2 years, comparing intensive BP control (targeting <120 mmHg) to standard control (targeting <140 mmHg). Key findings revealed that intensive BP lowering significantly reduced major cardiovascular events, such as stroke and nonfatal MI, hospitalization for HF, or death from cardiovascular causes (HR 0.79; 95% CI: 0.69–0.90). There were similar rates of CKD progression (HR 1.36; 95% CI: 0.71–2.59), CKD development (HR 1.11; 95% CI: 0.92–1.34) in the intensive vs. standard group; however, incident albuminuria was lower in the intensive group (HR 0.87; 95% CI: 0.77–0.97). Even though the BPROAD trial included CKD patients, the average eGFR was 88.6 mL/min, and only 7.5% had eGFR <60 mL/min. This finding needs to be replicated across different stages of CKD in various populations. For patients with diabetic CKD, the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) suggests a BP target of <130 mmHg. This recommendation stems from concerns that more intensive BP lowering could elevate the risk of kidney failure in this population. The KDOQI commentary on the KDIGO 2021 guideline points out that major trials like SPRINT excluded diabetic patients, while ACCORD-BP, though including diabetics, excluded those with significant CKD, thus providing less robust evidence for an SBP target of <120 mmHg in this group (57).

RAAS blockers are preferred for managing CKD in diabetic and nondiabetic patients with proteinuria (58,59). A meta-analysis of 119 RCTs (60) involving 64,768 patients with CKD—both with and without diabetes and albuminuria—demonstrated the beneficial effects of ACEi and ARBs in reducing the risk of kidney failure and major cardiovascular events. However, ACEi, but not ARBs, significantly reduced the odds of all-cause death vs. active controls.

ACEi and ARBs can delay the progression of CKD through various mechanisms. These include improvements in systemic and intraglomerular hypertension, proteinuria, tubulointerstitial fibrosis, and reduced podocyte apoptosis (61). For patients with proteinuric kidney disease, it is crucial to adjust the dosage of these medications to the highest tolerable level without causing hypotension to minimize proteinuria and maintain BP below 130/80 mmHg (or below 120/80 mmHg, based on KDIGO 2021 guidelines). It is important to note that ACEi and ARBs should not be administered concurrently, especially in individuals with diabetes, due to the increased risk of AKI, hypotension, and hyperkalemia (62).

The Irbesartan Diabetic Nephropathy Trial (IDNT) (63) and the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan Study (RENAAL) (64) demonstrated that RAAS inhibition benefits patients with both diabetes and CKD with severely increased albuminuria, regardless of BP control. Irbesartan was compared with a placebo and amlodipine in the IDNT, while losartan was compared to a placebo in the RENAAL.

In contrast, a multicenter, open-label trial that randomized patients with advanced and progressive CKD (eGFR <30 mL/min) to either discontinue or continue RAAS blockade therapy found no significant difference in the rate of eGFR decline between the two groups at 3 years. The rate of decline was 12.6±0.7 in the discontinuation group vs. 13.3±0.6 mL/min/1.73 m² in the continuation group. Although there were more cardiovascular events in the discontinuation group (108 vs. 88), this difference was not statistically significant (65).

There is limited evidence on the effectiveness of specific antihypertensive agents for treating high BP in CKD beyond RAAS blockers in proteinuric CKD. Many individuals with CKD and BP levels at least 20 mmHg above the target often require combination therapy. However, no randomized trials have compared different drug combinations specifically for CKD, and treatment guidelines are primarily based on expert opinions and extrapolations from research on the general population or surrogate outcomes. In the SPRINT trial (30), patients in the intensive treatment group were started on a two- or three-drug combination of a thiazide-type diuretic and/or an ACEi or ARB (but not both) and/or a CCB. At the monthly follow-up visit, if SBP ≥120 mmHg, ongoing antihypertensives were titrated or therapy was added, which were not already in use until SBP was <120 mmHg.

CKD patients are frequently hypervolemic and may require diuretic therapy to achieve goal BP. Chlorthalidone is effective even in advanced CKD with eGFR <30 mL/min (66-68), and both loop and thiazide diuretics may be needed in advanced CKD with refractory edema (69,70).

Experimental evidence suggests that aldosterone contributes to progressive kidney disease. RAAS blockade suppresses the renin-angiotensin system but does not effectively reduce plasma aldosterone. Mineralocorticoid receptor antagonists (MRAs) can reduce glomerular hyperfiltration, improve proteinuria, help with resistant hypertension, and decrease podocyte apoptosis and tubulointerstitial fibrosis (71,72). Spironolactone has been studied in observational studies for refractory hypertension as the third or fourth line agent (73-75). Finerenone, a novel non-steroidal MRA, has been studied in the FIDELIO-DKD trial (76), showing kidney and cardiovascular benefits with modest (SBP 2–3 mmHg) BP lowering.

Hyperkalemia, a condition that can cause cardiac arrhythmias, is common in CKD and can hinder the use of RAAS blockers or MRAs. Loop diuretics and newer potassium binders can manage hyperkalemia and allow for continued use of RAAS blockers and MRAs. Older potassium binders, such as sodium polystyrene sulfonate (SPS), known as Kayexalate, can lead to intestinal necrosis and should not be used for long-term treatment (77). Newer potassium binders, including patiromer and sodium zirconium cyclosilicate, are safer alternatives for the chronic management of hyperkalemia. These newer medications allow for the continued use of RAAS blockers and MRAs, which are effective in slowing the progression of CKD (78). SGLT2 inhibitors can also reduce the risk of hyperkalemia in patients on RAAS blockers (79,80). Although low-potassium diets may be recommended for chronic hyperkalemia, potassium-rich foods have various health benefits and may help slow CKD (81,82) and cardiovascular disease progression (83-85). Naturally low in sodium, plant-based diets can also improve BP control by promoting natriuresis (86,87).

Hypertension in kidney transplant recipients

Hypertension is a prevalent issue among kidney transplant patients, affecting 85% of them, and is linked to heightened risks of kidney allograft failure, death-censored kidney allograft failure, and mortality (88). Pre-existing hypertension, high body mass index, male sex, the presence of native kidneys with an intact RAAS system, older donors with atherosclerotic disease and tubulointerstitial fibrosis, delayed or chronic allograft dysfunction, use of calcineurin inhibitors (CNIs) and glucocorticoids, acute rejection, and recurrence of the original kidney disease are all risk factors for post-kidney transplant hypertension (88,89).

There is a lack of randomized trials to pinpoint the optimal BP targets for kidney transplant recipients to enhance graft survival, cardiovascular events, and mortality. Right after transplantation, hypertension often stems from volume overload and/or allograft dysfunction. Although improving allograft function with ensuing natriuresis and volume removal via diuretics or ultrafiltration can decrease BP, there is no consensus on the ideal BP targets during this phase. Some experts suggest permitting higher BP (under 160/90 mmHg) in the initial 1–2 weeks for sufficient allograft perfusion and advise against hypotension.

Antihypertensive drugs, except for RAAS blockers, are restarted after kidney transplantation in patients with preexisting hypertension. RAAS blockers can elevate serum creatinine levels, potentially masking early signs of rejection. They can also raise potassium and calcineurin target levels and impede recovery from anemia. Hence, these medications are generally avoided in the first 3–6 months.

Given the lack of data from randomized trials assessing the impacts of different BP targets on patient-relevant outcomes, target BP levels in kidney transplant recipients have traditionally been based on those for higher-risk groups, like patients with CKD, diabetes mellitus, or atherosclerotic cardiovascular disease. This approach has been adopted despite the absence of evidence to guide optimal BP in kidney transplant recipients, as the denervated transplanted kidney lacks autoregulation and is influenced by systemic hemodynamics. Kidney transplant recipients were excluded from the SPRINT trial (30), and even though SBP <120 mmHg yielded superior cardiovascular and survival benefits, they also had a slight increase in AKI and rate of eGFR loss compared to SBP <140 mmHg. Consequently, KDIGO 2021 guidelines (90) suggest a target BP of <130/80 mmHg using standardized office BP measurements for kidney transplant recipients and prioritizing graft survival.

While the target BP remains uncertain, there are RCTs using antihypertensives in kidney transplant recipients. RCTs in kidney transplant recipients indicate that dihydropyridine CCBs and ARBs are the preferred antihypertensive agents for preventing allograft loss (grade 1C recommendation). Although non-dihydropyridine CCBs (verapamil and diltiazem) can elevate the levels of CNIs and mTOR inhibitors, some clinicians use them in recipients who rapidly metabolize CNIs to limit CNI dosage and manage hypertension.

A 2009 systematic review by Cross et al. (91), which included 29 randomized trials with 2262 patients, found that dihydropyridine CCBs reduced the risk of allograft loss by 25% and increased GFR by an average of 
4.45 mL/min compared to placebo. In contrast, ACEi did not reduce GFR compared to placebo, and the results for graft loss were variable. Direct comparison between CCBs and ACEi showed that CCBs were associated with a lower risk of hyperkalemia (relative risk 3.74), decreased proteinuria (−0.28 g/24 h), and a higher GFR 
(11.48 mL/min). The data on graft loss was inconclusive when comparing CCB and ACEi (RR 7.37, 95% CI: 0.39 to 140.35).

In a study by Ibrahim et al. (92), 153 kidney transplant recipients were assigned to either losartan 100 mg or a placebo within three months of their transplant. The primary composite outcome, which was a doubling of the fraction of renal cortical volume occupied by interstitium from baseline to 5 years or ESRD from tubulointerstitial fibrosis, was 61% lower in the losartan group, but this result was not statistically significant. Additionally, there was no difference in the time to ESRD or death between the two groups. Despite this study’s lack of statistical significance, ARBs are recommended for managing proteinuric kidney disease in kidney transplant recipients. However, for pregnant women or those trying to conceive, CCBs are generally considered safe during pregnancy and lactation, whereas ARBs are contraindicated.

Conclusions

Hypertension is a complex condition that requires evidence-based, tailored management strategies for specific populations. For example, NHBs have a higher prevalence of hypertension due to socioeconomic, dietary, and genetic factors, including greater salt sensitivity. This population often responds better to thiazide-type diuretics or CCBs. Older persons have a high hypertension burden, including ISH. Their target SBP is <120 mmHg, but treatment should consider orthostatic hypotension, comorbidities, and polypharmacy from high pill burden.

Non-diabetic, non-proteinuric CKD patients should aim for SBP <120 mmHg (KDIGO 2021 guidelines); however, this may increase AKI risk without changing CKD outcomes (changes in eGFR from baseline or ESRD). The goal BP in diabetic CKD is unclear and requires further research. RAAS blockers are the first-line treatment for proteinuric CKD, with or without diabetes. Kidney transplant recipients also have a high hypertension prevalence, and KDIGO 2021 guidelines recommend <130/80 mmHg target BP, with dihydropyridine CCBs and ARBs (for proteinuric kidney disease) as first-line agents.

Effective hypertension management in these distinct populations requires an individualized approach considering specific risk factors and comorbidities.

Supplementary

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