Abstract
Introduction
Thiazides are utilized in general hypertension management, however, their role in chronic kidney disease (CKD) hypertension management remains unclear. Although data support thiazide efficacy in advanced CKD, the adverse effect profile (including estimated glomerular filtration rate [eGFR] decline and electrolyte abnormalities) may lead to thiazide discontinuation. The authors assessed the thiazide discontinuation rate in Kaiser Permanente Southern California members with moderate-to-severe CKD and hypertension.
Methods
This study was a multicenter retrospective analysis evaluating Kaiser Permanente Southern California members with hypertension and CKD 3B or 4 who filled a thiazide prescription in 2021, with follow-up through 2022. The outcomes were thiazide discontinuation rate, reason for thiazide discontinuation, time to thiazide discontinuation, and discontinuing practitioner specialty. Mean changes in blood pressure and eGFR from baseline were also evaluated.
Results
Of the 401 patients followed for 1 year after thiazide initiation, 65 patients discontinued a thiazide (discontinuation rate: 16.2%, mean time to discontinuation: 7.5 months). Of the 201 patients followed for 2 years after thiazide initiation, 57 patients discontinued a thiazide (discontinuation rate: 28.4%, mean time to discontinuation: 15.5 months). The most commonly documented thiazide discontinuation reason was increased serum creatinine (30% of total reasons at 1 year and 39% of total reasons at 2 years).
Conclusion
Most patients with hypertension and CKD 3B or 4 continued on a thiazide with favorable blood pressure lowering effects and modest eGFR decline. Thiazides may be considered viable antihypertensive options with close renal function monitoring for patients with moderate-to-severe CKD.
Keywords: nephrology, hypertension, pharmacist, renal
Introduction
Hypertension is the most common comorbidity in chronic kidney disease (CKD) and remains the second cause of CKD in the United States. The reported prevalence of hypertension in CKD ranges from 67% to 92%, increasing as kidney function declines.1 The relationship between CKD and hypertension is bidirectional: 1) uncontrolled hypertension is a risk factor for CKD due to the transmission of high systemic pressures to the glomeruli, and 2) CKD may lead to hypertension via sodium dysregulation, increased sympathetic nervous system activity, or alterations in renin–angiotensin–aldosterone system activity.2 Of note, treatment-resistant hypertension is common in CKD and associated with an increased chance of adverse clinical outcomes.3 Therefore, effective hypertension control in CKD is crucial to reduce cardiovascular outcomes and prevent kidney disease progression.
Thiazides and thiazide-like diuretics (collectively referred to as “thiazides” in this review) have been important agents in general hypertension management, however, their place in therapy for the population with CKD remains unclear. The 2017 American College of Cardiology/American Heart Association (ACC/AHA) and 2021 Kidney Disease Improving Global Outcomes hypertension guidelines recommend renin–angiotensin–aldosterone system inhibitors, such as angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), for renal protective effects in CKD with albuminuria. For CKD with no albuminuria, thiazides are recommended as an option, among the usual first-line antihypertensive options of calcium channel blockers, ACE inhibitors, and ARBs.4,5
Thiazides block sodium reabsorption in the distal convoluted tubules to facilitate water and sodium excretion.6 Conventionally, thiazides have been regarded as ineffective in the treatment of the CKD population owing to relatively less reabsorption in the distal convoluted tubules compared to other parts of the nephron. The ACC/AHA hypertension guidelines reflect this in the preference for loop diuretics over thiazides in patients with moderate-to-severe CKD.5 Yet, thiazide efficacy in advanced CKD has been demonstrated in recent studies, specifically for chlorthalidone and hydrochlorothiazide (HCTZ), with cardiovascular benefits and significant systolic blood pressure (SBP) reductions.7–9
Although data support thiazide efficacy in advanced CKD, the adverse effect profile of these agents (including estimated glomerular filtration rate [eGFR] decline and electrolyte abnormalities) may present challenges for thiazide use in this population.10 Moreover, the occurrence of adverse effects may lead to thiazide discontinuation. The thiazide discontinuation rate in CKD has not been well-defined in the literature. This study aims to assess the thiazide discontinuation rate and impact on blood pressure in patients with CKD 3B or 4 who initiated a thiazide or patients who progressed to CKD 3B or 4 while on a thiazide in clinical practice at Kaiser Permanente Southern California.
Methods
Study design
This is a multicenter retrospective analysis that evaluated Kaiser Permanente Southern California members with diagnoses of hypertension and CKD 3B (eGFR 30–44 mL/min/1.73 m2) or CKD 4 (eGFR 15–29 mL/min/1.73 m2) who filled a thiazide prescription (the first or any subsequent fill) between January 1, 2021, and December 31, 2021. The thiazide must have been initiated between January 1, 2020, and December 31, 2021. These patients were followed up to 2 years after thiazide initiation through December 31, 2022. Patients with a history of kidney transplant, dialysis, or pregnancy, concurrent use of loop diuretics, or thiazide prescriptions for as-needed use were excluded from the study (Figure 1). The study was reviewed and approved by the Kaiser Permanene Southern California/Hawaii institutional review board.
Figure 1:
Flow diagram for study population. CKD = chronic kidney disease.
Data collection and statistical analysis
The thiazide prescription fill data, vitals, and laboratory values for this study were retrieved from the Kaiser Permanente Southern California electronic health record system and CKD registry. The data included the drug name, first and last prescription fill dates, patient demographics, CKD stage at first prescription fill, prescribing practitioner specialty, and discontinuing practitioner specialty, if applicable. Values for eGFR and blood pressure were calculated as an average of a maximum of 3 values within the following prespecified time periods. The baseline eGFRs and blood pressures were extracted before or on the date of the first prescription fill. If the prescription was discontinued during the follow-up period, the eGFRs and blood pressures were extracted between the dates of the last fill and thiazide discontinuation. If the prescription was still active at the end of the follow-up period, the most recent laboratory values and blood pressures were retrieved. Chart reviews were conducted by research investigators for each unique patient to collect data on thiazide discontinuation and discontinuation reasons. Discontinuation was defined as documented discontinuation in practitioner notes or 6 or more months elapsed between last fill and study end.11
The main statistical method used for this study was descriptive. Discontinuation rates were measured by the number of events per total number of patients in the follow-up period.
Study outcomes
The objective of this study was to describe the thiazide discontinuation–related outcomes as well as the efficacy and safety of thiazides in Kaiser Permanente Southern California members with hypertension and CKD 3B or 4. The outcomes of this study were the thiazide discontinuation rate, reason for thiazide discontinuation, time to thiazide discontinuation, and discontinuing practitioner specialty. In addition, the mean changes in blood pressure and eGFR from baseline were evaluated. All study outcomes were assessed at 1 and 2 years after thiazide initiation.
Results
Patient characteristics
The final study cohort included a total of 401 patients, excluding 765 patients who initiated a thiazide prior to 2020 and 401 patients based on other exclusion criteria. Table 1 shows the study population characteristics at thiazide initiation.
Table 1:
Patient characteristics of Kaiser Permanente Southern California study population at thiazide initiation
| Variable | Value (N = 401) |
|---|---|
| Age, y, mean ± SD | 70.1 ± 11.3 |
| Sex, n (%) | |
| Male | 170 (42.4) |
| Race, n (%) | |
| White | 158 (39.4) |
| Hispanic/Latino | 120 (29.9) |
| Other | 46 (11.5) |
| Black | 39 (9.7) |
| Asian | 38 (9.5) |
| BMI, kg/m2, mean ± SD | 29.8 ± 6.6 |
| Smoking status, n (%) | |
| Never smoker | 252 (62.8) |
| Former smoker | 128 (31.9) |
| Current smoker | 21 (5.2) |
| Thiazide initiation, n (%) | |
| In 2020 | 201 (50.1) |
| In 2021 | 200 (49.9) |
| Comorbidities, n (%) | |
| Hyperlipidemia | 341 (85.0) |
| Diabetes | 228 (56.9) |
| Coronary artery disease | 67 (16.7) |
| History of stroke | 46 (11.5) |
| Heart failure | 26 (6.5) |
| Blood pressure, mmHg, mean ± SD | |
| Systolic blood pressure | 143.9 ± 17.3 |
| Diastolic blood pressure | 74.6 ± 13.5 |
| eGFR, mL/min/1.73 m2, mean ± SD | 43.0 ± 11.6 |
| CKD stage, n (%)a | |
| Stage 1 | 2 (0.5) |
| Stage 2 | 24 (6.0) |
| Stage 3A | 82 (20.4) |
| Stage 3B | 137 (34.2) |
| Stage 3 (unspecified)b | 62 (15.5) |
| Stage 4 | 9 (2.2) |
| Unknownc | 85 (21.2) |
| ACR, mg/g, mean ± SDd | 746.1 ± 1546 |
| A1 ( < 30), n (%) | 67 (16.7) |
| A2 (30–299), n (%) | 68 (17.0) |
| A3 ( ≥ 300), n (%) | 66 (16.5) |
| Unknown, n (%) | 200 (49.9) |
| Thiazide type, n (%) | |
| Hydrochlorothiazide | 362 (90.3) |
| Dose, mg, mean ± SD | 18.8 ± 8.8 |
| Chlorthalidone | 39 (9.7) |
| Dose, mg, mean ± SD | 19.9 ± 8.0 |
| Concurrent BP medications, n (%) | |
| ACE inhibitor | 209 (52.1) |
| Calcium channel blocker | 167 (41.6) |
| Beta blocker | 166 (41.4) |
| ARB | 147 (36.7) |
| Vasodilator | 30 (7.5) |
| Potassium-sparing diuretic | 25 (6.2) |
| Central-acting agent | 8 (2.0) |
| Alpha antagonist | 2 (0.5) |
| Concurrent SGLT2 inhibitor, n (%) | 33 (8.2) |
CKD staging based on Kaiser Permanente CKD Registry criteria.
Stage 3 (unspecified) is defined as patients with 1) 1 eGFR classified as stage 3 with no eGFR 90 d later OR 2) last and 3-mo-ago eGFRs classified as stage 3 without elevated ACR, CKD diagnosis, or diabetes diagnosis.
Unknown is defined as patients not captured by Kaiser Permanente CKD registry likely due to missing labs.
Value is the mean ACR, calculated with albumin measured in mg and creatinine measured in g.
ACE, angiotensin converting enzyme; ACR, albumin-to-creatinine ratio; ARB, angiotensin II receptor blocker; BMI, body mass index; BP, blood pressure; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; SD, standard deviation; SGLT2, sodium-glucose cotransporter-2.
At thiazide initiation, the mean patient age was 70 years old, 42% were male, and 39% were White. The mean SBP was 144 mmHg and the mean diastolic blood pressure (DBP) was 75 mmHg. The mean eGFR was 43 mL/min/1.73 m2 and the mean ACR was 746 mg/g, with approximately 70% of the study population with CKD 3. It was noted that 48.1% of patients had CKD stage 1 to 3A or unknown CKD stage at thiazide initiation and progressed to CKD 3B/4 during the study period, meeting inclusion criteria. A total of 90.3% of patients were on HCTZ (mean initial dose: 18.8 mg, most commonly 12.5 mg) and 9.7% were on chlorthalidone (mean initial dose: 19.9 mg, most commonly 25 mg), both medications on the Kaiser Permanente formulary with HCTZ as the preferred agent. Approximately half (50.1%) of the study population initiated a thiazide in 2020 and the remaining patients initiated a thiazide in 2021.
In terms of concurrent medications, approximately half (52.1%) of patients were on an ACE inhibitor and 8.2% of patients were on a sodium-glucose cotransporter-2 inhibitor.
Discontinuation outcomes
Of the 401 patients followed for 1 year after thiazide initiation, 65 patients discontinued a thiazide. The resulting discontinuation rate was 16.2%, with a mean time to discontinuation of 7.5 months. Of the 201 patients followed for 2 years after thiazide initiation, 57 patients discontinued a thiazide. The resulting discontinuation rate was 28.4% with a mean time to discontinuation of 15.5 months (Table 2). Figure 2A and B display the time to thiazide discontinuation for patients followed for 1 and 2 years after thiazide initiation.
Table 2:
Thiazide discontinuation rate and time to discontinuation at 1 and 2 years after thiazide initiation
| Parameter | At 1 y (N = 401) | At 2 y (N = 201) |
|---|---|---|
| Discontinuation rate, n (%) | 65 (16.2) | 57 (28.4) |
| Time to discontinuation, mo, mean ± SD | 7.5 ± 2.7 | 15.5 ± 4.9 |
SD, standard deviation.
Figure 2:
Time to thiazide discontinuation at (A) 1 year follow-up and (B) 2 year follow-up.
Table 3 shows the discontinuation reasons at 1 and 2 years after thiazide initiation. The most common discontinuation reason was increased serum creatinine based on practitioners’ documentation (30% and 39% of total reasons at 1 and 2 years, respectively), followed by side effects (21% and 24% of total reasons at 1 and 2 years, respectively).
Table 3:
Reason for thiazide discontinuation at 1 and 2 years after thiazide initiation
| Reason for discontinuation, N (%) | At 1 y (N = 66)a | At 2 y (N = 59)b |
|---|---|---|
| Increase in serum creatinine | 20 (30) | 23 (39) |
| Side effect | 14 (21) | 14 (24) |
| Dehydration/dizziness | 3 (21) | 2 (14) |
| Hyponatremiac | 3 (21) | 3 (21) |
| Urinary frequency | 3 (21) | 2 (14) |
| Cough | 2 (14) | 1 (7) |
| Other | 2 (14) | 1 (7) |
| Gout | 1 (7) | 1 (7) |
| Hypercalcemia | – | 2 (14) |
| Hypokalemia | – | 2 (14) |
| Unknown | 11 (17) | 7 (12) |
| Low blood pressure | 8 (12) | 2 (3) |
| Patient reported not taking | 7 (11) | 1 (2) |
| Not filledd | 6 (9) | 12 (20) |
One patient experienced increased serum creatinine and low blood pressure.
One patient experienced 2 side effects (hypokalemia and hypercalcemia) and increased serum creatinine.
Defined as sodium level < 135 mEq/L (milliequivalents per liter).
Defined as 6 or more mo elapsed between last fill and study end.
Adult primary care practitioners accounted for 80% and 63% of thiazide prescribing and discontinuing practitioners, respectively. Nephrology made up 11% and 29% of thiazide prescribing and discontinuing practitioners, respectively (Figure 3).
Figure 3:
Prescriber and discontinuing practitioner specialty. UC = urgent care; ED = emergency department.
Efficacy outcomes
Figure 4 shows the mean changes in blood pressures from baseline to 1 and 2 years after thiazide initiation. At 1 year, the mean SBP reduction was 7.9 mmHg and mean DBP reduction was 5.1 mmHg (data available for 265/401 patients). At 2 years, the mean SBP reduction was 10.4 mmHg and mean DBP reduction was 6.6 mmHg (data available for 121/201 patients). Of note, limited albuminuria data collected for patients demonstrated a 29.8% decrease in ACR at 1 year and a 33.8% decrease in ACR at 2 years after thiazide initiation.
Figure 4:
Mean changes in systolic and diastolic BP. BP = blood pressure.
Safety outcomes
Figure 5 shows the mean changes in eGFR from baseline to 1 and 2 years after thiazide initiation. The mean eGFR reductions were 8.9 (data available for 268/401 patients) and 12.7 (data available for 117/201 patients) mL/min/1.73 m2 at 1 and 2 years, respectively.
Figure 5:
Mean changes in eGFR. eGFR = estimated glomerular filtration rate.
Patient characteristics and thiazide discontinuation
Table 4 summarizes thiazide discontinuation data in relation to patient characteristics at thiazide initiation. Similar discontinuation rates were observed based on sex, approximately 16% at 1 year and 30% at 2 years after thiazide initiation for both males and females. Patients < 65 years old and those ≥ 65 years old had similar discontinuation rates (16%) at 1 year; the former group had higher rates of discontinuation at 2 years. Thiazide discontinuation appeared highest for Black patients (20.5%) at 1 year after thiazide initiation and for Hispanic/Latino patients (34.8%) at 2 years after thiazide initiation.
Table 4:
Patient characteristics at thiazide initiation and thiazide discontinuation at 1 and 2 years after thiazide initiation
| Baseline characteristics | At 1 y | At 2 y | ||
|---|---|---|---|---|
| Total, N | Discontinued, n (%) | Total, N | Discontinued, n (%) | |
| Sex | ||||
| Male | 231 | 37 (16.0) | 122 | 33 (27.0) |
| Female | 170 | 28 (16.5) | 79 | 24 (30.4) |
| Age, y | ||||
| < 65 | 110 | 18 (16.4) | 57 | 20 (35.1) |
| ≥ 65 | 291 | 47 (16.2) | 144 | 37 (25.7) |
| Race | ||||
| Black | 39 | 8 (20.5) | 23 | 8 (34.8) |
| White | 158 | 30 (19.0) | 74 | 14 (18.9) |
| Other | 46 | 7 (15.2) | 23 | 8 (34.8) |
| Hispanic/Latino | 120 | 17 (14.2) | 65 | 24 (36.9) |
| Asian | 38 | 3 (7.9) | 16 | 3 (18.8) |
Note: Percentages calculated as number of patients who discontinued thiazide (n) divided by total number of patients (N) for each patient characteristic at thiazide initiation.
Discussion
This is the first study to evaluate thiazide discontinuation–related outcomes, including thiazide discontinuation rates and discontinuation reasons, in advanced CKD hypertension management. This multicenter retrospective study demonstrated that the majority of patients with hypertension and CKD 3B or 4 continued on a thiazide: 83.8% and 71.6% of patients continued at 1 and 2 years after thiazide initiation, respectively. Although direct comparisons of antihypertensive discontinuation rates in CKD remain to be evaluated, the observed thiazide discontinuation rates (16.2% at 1 year and 28.4% at 2 years) are notably lower than the ACE inhibitor/ARB discontinuation rate reported for this population ( > 40% at 2 years).12 Although increased likelihood of thiazide-related adverse events with decreasing kidney function may potentially lead to thiazide discontinuation, the discontinuation rates in this study show continued thiazide utilization in clinical practice for the majority of patients in the advanced CKD population.10 This warrants further investigation to assess the risks and benefits of thiazides in advanced CKD hypertension management.
More than half of thiazide discontinuations were due to increased serum creatinine or occurrence of side effects. The most common documented thiazide discontinuation reason was increased serum creatinine, making up 30% and 39% of the total discontinuation reasons at 1 and 2 years, respectively. Other documented discontinuation reasons included side effects, low blood pressure, patient reported not taking, or prescription not filled. The most frequently reported side effects at 1 year after thiazide initiation were dehydration/dizziness, hyponatremia, and urinary frequency. The most frequently reported side effect at 2 years after thiazide initiation was hyponatremia. The incidence of hyponatremia observed was slightly higher than that reported in patients with CKD 4 on chlorthalidone, which may be attributed to longer follow-up in this study.7 Overall, the possible occurrence of these side effects, along with eGFR reduction, require close monitoring for patients with advanced CKD on thiazides.
Thiazides were primarily managed by practitioners in adult primary care, followed by nephrology. Nephrology involvement increased from 11% of prescribing practitioners to 29% of discontinuing practitioners, likely as patients needed more specialized care and CKD progression necessitated thiazide discontinuation. Other practitioner specialties included pharmacy, urgent care, emergency department, or other (cardiology or nurse practitioner).
The following thiazide efficacy and safety study outcomes provide additional information, although sampling bias given paucity of data may affect validity. This study demonstrated mean SBP reductions of 7.9 and 10.4 mmHg at 1 and 2 years after thiazide initiation, respectively. The average thiazide doses at initiation were HCTZ 18.8 mg and chlorthalidone 19.9 mg. Further studies are needed to assess the long-term impact of thiazides; however, short-term trials have shown similar significant SBP reductions in patients with mean eGFR ranging between 23.2 and 38.8 mL/min/1.73 m2.7–9 Furthermore, mean SBP reductions found in this study fall within close range of those reported for patients without CKD.13 Most patients in this study were on HCTZ, providing additional data to support HCTZ efficacy in advanced CKD. Comparative studies with other antihypertensives in advanced CKD evaluating blood pressure efficacy would be valuable to determine the specific place in therapy for thiazides. Lastly, although limited data were available, this study provided further insight for the possible effects of thiazides on reducing albuminuria as seen in the CLICK trial.7
The mean eGFR reductions observed in this study (8.9 mL/min/1.73 m2 at 1 year and 12.7 mL/min/1.73 m2 at 2 years) are greater than the annual decline rate of approximately 3 mL/min/1.73 m2 defined as rapid CKD progression by other studies.14,15 Although the CLICK trial did not find an increased possibility of end-stage renal disease or death, these results still underscore the potential renal consequences of thiazides in advanced CKD, also seen by the reported acute kidney injury incidence of 41% in patients with CKD 4 on chlorthalidone in the aforementioned trial.7 In addition, these mean eGFR reductions may affect an individual’s Kidney Disease Improving Global Outcomes CKD staging, further emphasizing the importance of understanding the impact of thiazides on renal function. Evaluation of potential renal recovery after thiazide discontinuation would be beneficial in future studies.
The impact of specific population characteristics on thiazide use in CKD also remains to be studied, including the effects of sex, age, and race. This study observed higher rates of thiazide discontinuation for the Black population. In the setting of hypertension without CKD, the 2017 ACC/AHA Guidelines recommends a thiazide for Black patients.5 However, for Black patients with CKD, the knowledge of APOL1 alleles and possible increased chance of kidney dysfunction adds complexity to hypertension management and thiazide use in a frequently treatment-resistant population.16 The observed higher thiazide discontinuation rate for ages < 65 years old compared to ages ≥ 65 years old at 2 years after thiazide initiation calls for further investigation for potential explanations, although thiazide prescribing has been shown to be greater for younger patients in a previous study.17
In summary, although thiazides have been regarded as conventionally ineffective in advanced CKD, the discontinuation rates and potential demonstrated SBP reductions in this study suggest thiazides as viable antihypertensive options with close renal function monitoring for moderate-to-severe CKD.
Limitations
The findings of this study should be viewed in the context of several limitations. First, the study design did not include a comparator group, and the results were mostly reflective of HCTZ, which is a preferred antihypertensive agent on the Kaiser Permanente formulary and hypertension treatment guidelines. In addition, although rough comparisons can be drawn from several studies, there are limitations in this direct comparison resulting from differences in study design, baseline characteristics, and study duration. There were also inconsistencies in the vitals and laboratory results retrieved within the prespecified time periods with lack of data for some patients due to the nature of a retrospective real-world study. Lastly, confounding variables include natural CKD progression, concurrent antihypertensive medications, combination thiazide products, and other nephrotoxic medications; these factors were not accounted for in this study.
Future Implications
With this thiazide safety and efficacy data drawn from real-world clinical practice, health care practitioners may consider prescribing thiazides as a potential blood pressure lowering agent in advanced CKD with close renal function monitoring. The extensive involvement of adult primary care in thiazide prescribing patterns also provides opportunity for primary care practitioners and practitioner extender roles in thiazide management.
Conclusion
In conclusion, most patients with hypertension and CKD 3B or 4 continued on a thiazide with favorable blood pressure lowering effects and modest eGFR decline. Thiazides may be considered as viable antihypertensive options with close renal function monitoring for patients with advanced CKD with commonly complex blood pressure management.
Acknowledgments
The authors would like to acknowledge patient contributions to this work, including the use of data from the electronic health record.
Footnotes
Author Contributions: Kirsten Dalangin Vea, PharmD, led the study design, acquisition and analysis of data, drafting, critical review, and submission of the final manuscript. Leigh Anh Nguyen, PharmD, and Jong C Park, MD, participated in the study design, acquisition and analysis of data, and critical review of the manuscript. Kristine McGill, PharmD, BCPS, participated in the study design and critical review of the manuscript. David Selevan, PMP, conducted acquisition and extraction of data. All authors participated in final approval of the version to be published.
Conflicts of Interest: None declared
Funding: None declared
Data-Sharing Statement: Data are available upon request. Readers may contact the corresponding author to request underlying data.
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