Hypertension in Chronic Kidney Disease: Guidelines and Therapies

Introduction

The incidence of chronic kidney disease (CKD) is steadily increasing worldwide due to multiple factors, including diabetes, hypertension, and other chronic diseases. The management of CKD requires aggressive control of predisposing risk factors. The main principle in CKD management is to stabilize kidney function and ultimately avoid and/ or delay ESKD. CKD is an important cause of morbidity, disability, and mortality. Hypertension is common among patients with CKD, and the prevalence of hypertension increases as overall kidney function deteriorates, ranging from 60 to 100% depending on the population studied.¹

Blood pressure (BP) is poorly controlled in patients with CKD, with only 10% achieving BP levels < 130/85 mmHg.² Hypertension in patients with CKD/ ESKD greatly increases the risk of cardiovascular disease (CVD), which accounts for >50% mortality in patients with CKD. In fact, patients with CKD are a high-risk group for premature and extensive CVD in the community. Most patients, unfortunately, succumb to CVD. CKD further promotes and accentuates the full spectrum of CVD. Hypertension and diabetes are contributing factors for a vast majority of patients with CKD/ESKD. Hypertension and CKD are linked to each other via common pathophysiological pathways and similar susceptibilities. An overwhelming majority of patients with CKD/ESKD have chronic and often significant hypertension. Both hypertension and CKD contribute significantly to CVD. As described below, uncontrolled hypertension leads to CKD and vice versa. Thus, as comorbidities, they are inseparable.

The complex pathophysiological mechanisms of hypertension in patients with CKD dictate the application of multiple therapeutic strategies to control hypertension in this high-risk population. In addition to hypertension, there are other factors that contribute to the progression of CKD to ESKD; these include (but are not limited to) hyperlipidemia, obesity, diabetes, tobacco use, and obstructive sleep apnea. Hence, all these predisposing factors should also be addressed in the management of patients with CKD.

Pathophysiology of Hypertension

Standardized Blood Pressure Measurement

Optimal BP measurement methodology is paramount in accurately assessing a patient who is at risk for prehypertension and hypertension. The KDIGO management of BP in CKD guideline includes a recommendation for the practice and evidence for the reasoning.²⁴ There has been great recognition of the excessive variability in the routine office setting measurement techniques causing various results. We must employ a standard procedure for office BP measurement that is easily replicable in all clinical settings around the world.

The standardized method of acquiring office BP stems from the 2017 American College of Cardiology/American Heart Association BP guidelines.²⁵ The SPRINT study was the cornerstone trial for describing how to implement the standard practice, and proof that it allowed for reliable results.²⁶ These recommendations are applicable to patients with and without CKD, and currently there is no guideline for other methods for sicker patients. In summary, a patient should be sitting in a chair with their feet supported on the ground after >5 minutes of rest. A validated and calibrated, automated or manual BP device, as per availability, should be placed around the patient’s bicep with the arm bent. The forearm must be supported. Neither the patient nor the medical personnel should speak during the measurement, to avoid anxiety or increased sympathetic stimulation. Two readings should be taken, one on each arm, and any differences should be recorded. Average the readings of at least two measurements to determine the “final” standardized office reading and record the systolic and diastolic measurements.

This procedure is important because it offers a standardized method for BP measurement in almost any clinical setting in the world. Common office blood pressure measurement is contradictory to the guideline recommended process. Many times, the patient is sitting with their feet dangling, or stand, or lie horizontally on the exam table or hospital bed. Frequently, the clinical personnel ask questions relevant to health or socializing, which can stimulate the patient. The patient may ask questions or engage in active communication with the health care professional team. Clinical practices and hospitals are frequently very busy places, and a single measurement is very common, as several other vital signs and medical history taking are needed with each encounter. All these distractions and interjections can lead to inaccurate and unreliable BP readings. The KDIGO guideline for the standardized office measurement technique hopes to correct these attributes that can lead to unreliable results. This technique closely mimics BP measurement in a patient’s home, which is usually quieter, with fewer distractions, and patients are usually sitting to take their own BP from a chair or bed. Rural clinics and those with low resources should be able to measure BP consistently following these guidelines. A standard, brachial arm, balloon-inflating manual cuff can be used when necessary in a quiet room free of distractions. Following the recommendations above will allow all health care providers (HCPs) to have as accurate results as possible, to then be able to create an accurate diagnostic plan and therapeutic intervention.

Blood Pressure Targets

A question that many clinicians answer incorrectly is “What is the appropriate BP for patients with CKD?” This is not their fault, as recommendations have gone through much change and controversy over the last decade, specifically from the JNC 8 publication. Currently, most guideline authorities recommend a systolic BP <120 mmHg, as determined by the standard office BP measurement stated above. This is mainly based on the widely accepted results of the SPRINT trial showing improved cardioprotective benefits and decreased mortality, that the previous recommendations of <130 mmHg. Each patient must still have individualized consideration in their tolerability of a systolic <120 mmHg, specifically as it relates to potential risk for falls, mental status, and decreased kidney perfusion resulting in CKD progression and electrolyte abnormalities. While this is currently the broad guideline for CKD, clinical judgment and patient-reported outcomes (PROs) must be factored into medication titration and class selection.

Our current and even historic data from the general population and patients with CKD demonstrate that reductions in dietary salt intake result in minimal short-term reductions in BP. If a patient is on a low salt diet, the need for BP medications also reduces. The KDIGO work group recommends that patients with CKD and hypertension consume <2 g (or <90 mmol) of sodium per day.²⁴ The evidence for the general population is stronger than in those with CKD, with future study needed specifically in CKD patients not on dialysis. Additionally, we know there is moderate evidence that lowering salt intake reduces cardiovascular events in the general population, but data are also lacking in those with CKD. While this recommendation is aspirational and does lower cardiovascular events, many trials show that patients have a very difficult time adhering to <2 g of sodium daily over the long term.²⁴ Many foods that are packaged or preserved contain salt or salt derivatives that may be hidden and not completely obvious to the consumer. And from a practical standpoint, food that has salt in it is generally preferable from a taste perspective in almost all populations.

One way to coach and counsel patients to limit their salt is to recommend the Dietary Approaches to Stop Hypertension (DASH) diet.²⁴ DASH recommends high fruit and vegetable intake, with a low intake of processed meats and cheeses (hidden sources of sodium). Patients with advanced CKD or a history of hyperkalemia must be cautious because many foods on the DASH diet are high in potassium. This is good for patients with kidney capacity to eliminate potassium through appropriate kaliuresis, but many patients with advancing eGFR struggle with this issue.

Previous intervention studies in patients with and without CKD show that regular physical activity lowers BP, improves physical strength, promotes weight loss, and lowers the risk of diabetes. Evidence in the CKD population is lacking more than in the general population, but even low-quality studies have been comparable in showing improvements in BP, weight loss, and improved quality of life.²⁴ The most recent KDIGO recommendations are for patients with CKD to undertake moderate-intensity physical activity for at least 150 minutes per week, or to a level of physical tolerance. This is also recommended in KDIGO guidelines for patients with CKD and Diabetes Mellitus. As some patients have advanced CKD due to disease or older age, frailty and personal capabilities should be factored into appropriate counseling of physical activity.

Pharmacotherapy

Timing and choice of classic antihypertensive medication

When initiating pharmacotherapy for hypertension, the choice of agent should maximize cardiovascular and nephroprotective benefit, while being efficacious and tolerable. Assessing the patient’s cardiovascular risk and considering the cause of CKD is important in guiding this decision. Fortunately, there is significant overlap between cardioprotective medications and nephroprotective medications, and rarely are the two considerations at odds.

This reasoning drives the recommendations of both the KDIGO 2021 workgroup²⁴ and the recently released 2025 guideline from the American Heart Association (AHA) and other cardiology societies.²⁷ The classes of antihypertensives that have been shown to improve cardiovascular outcomes are non-dihydropyridine calcium channel blockers, angiotensin converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB), and thiazide-type diuretics. Of these, only ACE/ARB have been shown to reduce progression of CKD as demonstrated in the RENAAL²⁸ and IDNT.²⁹ For this reason, ACEi or ARB are recommended for all patients with hypertension and CKD of any etiology by both guidelines.

It should be noted that the effect of ACEi and ARB in slowing the progression of nonproteinuric and nondiabetic CKD is less well-established. A small Italian trial of nondiabetic patients with <1 g proteinuria per day found that lisinopril reduced progression of CKD over around 2 years compared to equivalent BP control with alternate agents.³⁰ Though the data supporting nephroprotective benefit in these patients is less robust, ACEi and ARBs are sufficiently well-tolerated and inexpensive that their first-line use in patients with CKD of any cause is supported by expert opinion.

After the addition of ACEi or ARB, thiazide-type diuretics can be added either to improve BP control or to mitigate hyperkalemia. Alternatively, calcium channel blockers can be added if further BP control is needed. Given the benefit of volume control and potassium management with thiazide diuretics, more clinical trials have been undertaken in this domain. Contrary to the longstanding belief that thiazide diuretics lose efficacy with declining GFR, the 2021 CLICK trial³¹ demonstrated an average 10 mmHg reduction in patients with CKD stage IV treated with chlorthalidone and a concurrent decrease in albuminuria. The subsequent Diuretic Comparison Project³² attempted to further refine the choice of thiazide but found no benefit of chlorthalidone over hydrochlorothiazide in either cardiovascular outcomes or kidney outcomes.³²

Whether to add thiazide diuretics before maximizing RAAS blockade remains a topic of controversy and personal preference. The 2025 AHA guidelines support combination pills for increased adherence; however, this class C recommendation is based on expert opinion rather than clinical trial data. Combination therapy may not be available to all patients, but current guidelines do suggest generic medications that are affordable and accessible in most countries. A summary of these newest guidelines has been included in Figure 1.

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Figure 1:

Top 10 Takeaways for Hypertension Management. Provided as open access from NephJC. https://www.nephjc.com.

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Finally, the addition of mineralocorticoid receptor antagonists (MRA) has become increasingly well-studied in patients with kidney disease in recent years. This class has historically had more mixed results in trials assessing cardiovascular outcomes and is not included as a recommended first-line therapy in the AHA guidelines. For example, the TOPCAT Trial³³ assigned patients with heart failure to spironolactone or placebo and found that while spironolactone increased the risk of worsening kidney function, it also improved rates of cardiovascular death. The larger FIGARO trial, however,³⁴ randomized patients with CKD to MRA or placebo and found a significant reduction in cardiovascular events without a difference in composite kidney outcomes.

The FIDELIO-DKD³⁵ investigated this benefit further and found that patients with CKD and diabetes had significantly decreased kidney failure risk when treated with finerenone compared to placebo. Patients treated with finerenone were also less likely to suffer composite cardiovascular outcomes. These combined data have spurred an increased interest by nephrologists in the beneficial effects of MRA, particularly in patients with proteinuric CKD, but are not reflected in the earlier 2021 KDIGO Hypertension guidelines. Nevertheless, MRAs have made their way to the forefront of discussion for prevention of progression of CKD (particularly diabetic kidney disease) and are a very attractive option for treating hypertension in patients with CKD and are indeed cited for this purpose in the 2023 European Hypertension Society Guidelines.³⁶

Future Hypertension Treatments

Over the last 20 years, we have not had many new medications available to treat hypertension from a different mechanism of action. For 2025 and beyond, we have many new options on the horizon. One class recently approved is dual endothelin blockers. Two types of endothelin receptors have been described, ETA and ETB, are found on vascular smooth muscle cells that mediate vasoconstriction. Aprocetentan was shown as a positive add-on agent for patients with resistant hypertension in the PRECISION trial.⁴¹ Finerenone, as mentioned earlier, has been approved for diabetic CKD and HFpEF. While the BP effects are lower than the steroidal versions, spironolactone and eplerenone, this class of medication can lower BP in some patients studied in the trials with hypertension.⁴² Other ns-MRA esaxerenone and ocedurenone are undergoing trials as well for resistant hypertension.⁴³

Aldosterone synthase inhibitors are another class currently seeing good results in trials. The suppression of aldosterone has been elusive previously, but several medications are proving that this challenge can be met. Baxdrostat is a new agent that is highly selective for inhibiting aldosterone synthase and has shown the ability to induce natriuresis in a phase II trial.⁴⁴ A recent publication of baxdrostat in the BaxHTN Phase III trial shows that primary and secondary endpoints were met and there was a significant reduction of BP when added to standard of care vs. placebo, –15.7 mm Hg (95% CI, –17.6 to –13.7) with 2-mg baxdrostat.⁴⁵ Also upcoming is another new mechanism agent targeting the NPR1 gene. This encodes the natriuretic peptide receptor, and binding results in downstream effects of lower systolic BP and salt natriuresis. An NPR1 agonist drug (REGN5381, a monoclonal antibody) is in development for its antihypertensive effects in multiple trials (Clinicaltrials.gov: NCT04506645). Other classes of medications are still in Phase I or ongoing Phase II trials, but patients should have hope that there is a continued desire to find new options to treat their disease.

Recognizing and accurately diagnosing hypertension is paramount in taking care of patients with CKD. These two pathologic conditions combine and worsen each other as the years of inadequate treatment continue. The good news for patients today is that we have more agents than ever with high quality data to control the issues and significantly lower risk for CV events, ESKD, and possible early mortality. As we learn more about these diseases, our knowledge of new pathways for treatment continues to evolve. Patients and clinicians should feel empowered as the two fields have aggressive advocates and researchers discovering new opportunities for the goal of cure.