Hypertension is commonly observed in patients living with chronic kidney disease (CKD). Finding an optimal treatment regime remains challenging due to the complex bidirectional cause-and-effect relationship between hypertension and CKD. There remains variability in antihypertensive treatment practices.

To analyze data from the Salford Kidney Study database in relation to antihypertensive prescribing patterns amongst CKD patients.

The Salford Kidney Study is an ongoing prospective study that has been recruiting CKD patients since 2002. All patients are followed up annually, and their medical records including the list of medications are updated until they reach study endpoints [starting on renal replacement therapy or reaching estimated glomerular filtration rate (eGFR) expressed as mL/min/1.73 m² ≤ 10 mL/min/1.73 m², or the last follow-up date, or data lock on December 31, 2021, or death]. Data on antihypertensive prescription practices in correspondence to baseline eGFR, urine albumin-creatinine ratio, primary CKD aetiology, and cardiovascular disease were evaluated. Associations between patients who were prescribed three or more antihypertensive agents and their clinical outcomes were studied by Cox regression analysis. Kaplan-Meier analysis demonstrated differences in survival probabilities.

Three thousand two hundred and thirty non-dialysis-dependent CKD patients with data collected between October 2002 and December 2019 were included. The median age was 65 years. A greater proportion of patients were taking three or more antihypertensive agents with advancing CKD stages (53% of eGFR ≤ 15 mL/min/1.73 m² vs 26% of eGFR ≥ 60 mL/min/1.73 m², P < 0.001). An increased number of patients receiving more classes of antihypertensive agents was observed as the urine albumin-creatinine ratio category increased (category A3: 62% vs category A1: 40%, P < 0.001), with the upward trends particularly noticeable in the number of individuals prescribed renin angiotensin system blockers. The prescription of three or more antihypertensive agents was associated with all-cause mortality, independent of blood pressure control (hazard ratio: 1.15; 95% confidence interval: 1.04-1.27, P = 0.006). Kaplan-Meier analysis illustrated significant differences in survival outcomes between patients with three or more and those with less than three antihypertensive agents prescribed (log-rank, P < 0.001).

Antihypertensive prescribing patterns in the Salford Kidney Study based on CKD stage were consistent with expectations from the current United Kingdom National Institute of Health and Care Excellence guideline algorithm. Outcomes were poorer in patients with poor blood pressure control despite being on multiple antihypertensive agents. Continued research is required to bridge remaining variations in hypertension treatment practices worldwide.

Chronic kidney disease (CKD) is a progressive disease defined by the presence of structural or functional abnormalities within the kidney for 3 mo or more according to the Kidney Disease Improving Global Outcomes (KDIGO)[1]. Touted as an emerging public health issue of the 21^st century, the prevalence of CKD is exponentially growing and is projected to become the fifth-leading cause of mortality globally by 2040[2]. The aetiology of CKD is multidimensional and complex, of which there are various causes and consequences[3-5]. Other than diabetes mellitus, hypertension is a major contributor towards the progression of CKD and a leading consequence of CKD[6]. Depending on the stage of CKD, the prevalence of hypertension in CKD populations varies (ranging between 67% and 92%, according to previously published data), but the majority of patients with CKD are likely to have hypertension[7,8]. Given the potential health consequences of hypertension over time, namely its associated cardiovascular risks and risk of further kidney damage, adequate control of blood pressure (BP) in the CKD population is of vital importance to improve clinical outcomes[9,10].

It is not known to what extent clinicians adopt guideline-recommended or preferred antihypertensive treatment approaches for their CKD patients in the real-world setting[7,11]. Previous electronic health record and prospective longitudinal studies noted clinicians primarily prescribed angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) for CKD patients with hypertension, but varying combinations of antihypertensive prescription over time was noted when all antihypertensive agents are considered[12-16]. It remains largely unestablished which combination(s) of antihypertensive agents would generate the best results in terms of BP control and other clinical outcomes. Aiming to address these unknowns, our study evaluated trends and patterns relating to antihypertensive prescription over a 20-year period in patients identified with non-dialysis-dependent CKD included in the Salford Kidney Study (SKS).

In this study, we evaluated antihypertensive prescription patterns in patients from the SKS-CKD database, corresponding this to baseline eGFR, uACR, primary kidney disease aetiology and the presence of cardiovascular morbidities, and monitored prescription patterns over a 24-mo follow-up period. The number of antihypertensive agents prescribed for each patient was correlated with clinical outcomes, namely all-cause mortality and progression to ESKD.

Across the SKS-CKD cohort at baseline, RAS blockers were the most commonly prescribed agents for management of hypertension, followed by diuretics, dihydropyridine CCBs, and beta blockers. RAS blocker prescriptions decreased in patients with CKD stage 5 at baseline, whereas diuretics, dihydropyridine CCBs, and beta blockers were prescribed more frequently for patients with lower eGFR. Surprisingly, although it has not been widely advocated for use as an antihypertensive in current guidelines, alpha blockers were amongst the more commonly prescribed antihypertensive agents amongst patients in SKS-CKD, especially for those in the lower eGFR ranges. A major adverse effect of alpha blockers is orthostatic hypotension in patients with kidney function impairment[20-22]. The purposes of prescribing alpha blockers may not be solely for lowering of BP, as a substantial proportion of patients with benign prostatic hyperplasia are routinely initiated on them to relieve symptoms and improve urinary flow[23].

RAS blockers, diuretics, and dihydropyridine CCBs were prescribed with increasing frequency in patients with a greater degree of uACR. Ultimately, with an increase in the uACR category, a greater proportion of patients were prescribed more antihypertensive agents. RAS blockers remain the primary antihypertensive agents prescribed for patients with all forms of primary kidney disease. For CKD patients with CCF, the prescriptions of diuretics, beta blockers, and potassium sparing diuretics (spironolactone and eplerenone) were significantly higher compared to those without. This pattern was similar when comparing antihypertensive prescribing patterns between CKD patients with pre-existing cardiovascular events and those without.

Our analysis demonstrated that antihypertensive prescribing patterns at 12 mo and 24 mo had only minimally changed compared to baseline, but this was most likely because most patients had been enrolled in the renal service well before entry into the SKS. When determining associations between the number of antihypertensive agents prescribed and clinical outcomes, patients receiving a higher number of antihypertensive agents had worsened outcomes, namely increased all-cause mortality and reaching ESKD. Such associations remained following adjustment of baseline demographic factors (i.e. age, sex, ethnicity, smoking status, and alcohol intake), plus diabetes, cardiovascular comorbidities, baseline eGFR, and uACR.

Consensus recommendation to commence ACEI or angiotensin receptor ARB as a first-line antihypertensive treatment option for CKD patients, particularly for those with proteinuria and/or reduced eGFR defined by eGFR < 60 mL/min/1.73 m² has been reached across the major international societies in cardiology and nephrology such as the American College of Cardiology, the American Heart Association, and KDIGO[8,24]. The updated 2021 KDIGO clinical practice guideline for BP management in CKD continues to advocate this approach in patients with hypertension and CKD, with or without diabetes, and not receiving dialysis[24]. Where an adult patient has a transplanted kidney, commencing an ARB or dihydropyridine CCB has been recommended[24]. In the United Kingdom, the National Institute of Health and Care Excellence (NICE) guideline defines BP targets (clinic measured) for patients with CKD according to the patient’s uACR[25]. Adult CKD patients are divided into 2 groups: those with a uACR < 70 mg/mmol (618.8 mg/g); and those with a uACR > 70 mg/mmol (618.8 mg/g). In patients with a uACR < 70 mg/mmol (618.8 mg/g), the BP target is below 140/90 mmHg, whereas in patients with a uACR > 70 mg/mmol (618.8 mg/g), the BP target is below 130/80 mmHg.

An ACEI or ARB is first-line treatment for hypertension in CKD patients with uACR > 30mg/mmol (265.2 mg/g). A thiazide diuretic or CCB is to be used as second-line medications. While both dihydropyridine CCB and non-dihydropyridine CCB have been shown to have similar effects in terms of BP control, non-dihydropyridine CCBs such as verapamil and diltiazem have been shown to reduce proteinuria to a greater extent. However, prescribing non-dihydropyridine CCBs over dihydropyridine CCBs would generally appear to be less popular in actual clinical practice, mainly due to concerns of increased risk of cardiac adverse effects such as bradycardia that could be potentially life-threatening in severe cases[26]. A potassium sparing agent such as spironolactone can also be added, but due to the increased risk of hyperkalaemia, this is recommended only if there is persistent poor BP control following the addition of a thiazide diuretic. Whilst these are the main antihypertensive options as per NICE guidelines, other antihypertensive classes exist, such as alpha blockers, direct renin inhibitors, vasodilators, and centrally acting antihypertensive agents. These medications are not currently recommended under the NICE and other international guidelines for various reasons, such as the presence of adverse effects as well as the lack of evidence that they offer a strong clinical benefit for CKD patients with hypertension.

A number of studies have been conducted reviewing antihypertensive prescribing patterns in patients with CKD. Amongst the more recent studies that have followed the introduction of updated hypertension guidelines, a study conducted by Magvanjav et al[12] utilized electronic health record data from 5658 CKD patients with hypertension to examine their antihypertensive drug prescribing patterns, BP control, and risk factors for resistant hypertension. As found in our study and in observational data stated from recent hypertension guidelines, Magvanjav et al[12] noted that 64% of patients were prescribed an ACEI or ARB. They also concluded that BP was better controlled in patients who were prescribed a combination of medications that included a diuretic and beta blocker. Another study by Alencar de Pinho et al[13] compared antihypertensive prescribing patterns in CKD patients internationally and similarly found that ACEI or ARB was the most commonly prescribed antihypertensive class. However, the investigators noted significant variations in antihypertensive medication prescribing practices globally for all antihypertensive agents across different stages of CKD. Taking ACEI or ARB for example, Alencar de Pinho et al[13] observed that the prevalence of an ACEI or ARB prescription varied between 54% and 91% across different countries. This emphasizes that significant variations remain regarding clinicians’ approaches to antihypertensive treatment prescription for their CKD patients within the real-world setting, whether they follow a guideline-recommended algorithm or basing their approach from personal clinical experiences and preferences.

Indeed there are numerous patient-specific and clinical challenges when treating hypertension in CKD, of which clinician variation in antihypertensive prescription practices is only one issue. This conundrum may be explained by the variability in national and international guideline recommendations at present. Areas where a global consensus has not been reached are the BP thresholds that determine when treatment initiation is indicated, for instance. There also remains no unified agreement on the BP targets to be achieved amongst CKD patients. More importantly, there is continuous debate and discussion on how best to optimize antihypertensive therapy for BP control and cardiorenal protection. These are avenues of research where further work is required.

There is now an increased indication for adding sodium glucose cotransport (SGLT2) inhibitors to the current portfolio of recommended medications for hypertension management in CKD, given their emergence as a therapeutic option for cardiorenal protection in people with and without diabetes[27]. Large, randomized, placebo-controlled trials have pointed to the potential of SGLT2 inhibitors as having positive effects on BP control in both office and out-of-office contexts. The SACRA, EMPA-REG BP, and CREDENCE trials were amongst the clinical trials that have made these conclusions[28-30]. The post hoc analysis of the CREDENCE trial demonstrated the BP-lowering effect of canagliflozin for patients with resistant hypertension, which is novel and encouraging[29]. Additional studies are needed to validate the role of SGLT2 inhibitors in optimizing BP control and reducing adverse cardiovascular outcomes amongst patients living with CKD and hypertension, particularly those with resistant hypertension.

Despite the main strength of our study being inclusion of an ethnically and socioeconomically diverse CKD patient group, as well as being conducted over a 20-year period, there are limitations to acknowledge. One limitation was an inability to clearly correlate details relating to the indication(s) for antihypertensive medication prescription and any adjustments during the follow-up period due to multiple clinicians being involved in a patient’s management. Furthermore, it is unclear if diuretics were prescribed as an antihypertensive agent within this context, or intended for other clinical purposes (e.g., for peripheral oedema). Understanding the indications for prescription of particular antihypertensive medication(s) would have been useful in determining the true patterns of antihypertensive prescribing practices in this study. Also, as our centre does not complete urinary antihypertensive screens routinely, there is always the confounding impact of drug non-compliance amongst patients receiving three or more antihypertensive agents. This contributes to poor BP control and its associated morbidity and mortality outcomes. Finally, there was incomplete data on determining the rate of decline in eGFR when comparing between CKD patients with three or more antihypertensive agents vs less than three antihypertensive agents prescribed due to delta eGFR data being unavailable for 162 patients (5% of entire cohort).

In summary, RAS blockers were found to be the most commonly prescribed antihypertensive agents, followed by diuretics and CCBs, which are recommended as second-line antihypertensive treatment options. Diuretics, beta blockers, and mineralocorticoid antagonists were found to be more commonly prescribed in CKD patients with cardiovascular comorbidities. Whilst our study results aligned with that of expectations from the current NICE guideline algorithm, further work determining optimal strategies in approaching antihypertensive prescription for CKD patients at both an individual and policy level is needed to reduce the variations currently observed in clinical practice. The opportunity to introduce newer and potentially more cost-effective therapies in the form of SGLT2 inhibitors for hypertension management in CKD is attractive and could be revolutionary in addressing these challenges, and continued research in this area is anticipated.

The authors would like to acknowledge the National Institute of Health Research Manchester Biomedical Research Centre for their funding support in the SKS (NIHR203308). The views expressed are those of the author(s) and not necessarily those of the National Institute of Health Research or the Department of Health and Social Care, United Kingdom.