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Research Article
Originally Published 2 March 2020
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Prevalence of Hypokalemia and Primary Aldosteronism in 5100 Patients Referred to a Tertiary Hypertension Unit

Jacopo Burrello, Silvia Monticone, Isabel Losano, Giovanni Cavaglià, Fabrizio Buffolo, Martina Tetti, Michele Covella, Franco Rabbia, Franco Veglio, Barbara Pasini, Tracy Ann Williams, and Paolo Mulatero [email protected]Author Info & Affiliations
Hypertension
Volume 75, Number 4
https://doi.org/10.1161/HYPERTENSIONAHA.119.14063
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Graphical Abstract

Abstract

Primary aldosteronism (PA) was considered a rare disorder almost always associated with hypokalemia. The widespread screening of patients with hypertension unveiled an increased prevalence of PA with normokalemic hypertension the prevailing phenotype. Many studies have reported the prevalence of hypokalemia in patients with PA; conversely, the prevalence of PA in patients with hypokalemia is unknown. In this retrospective observational study, we define the prevalence of hypokalemia in referred patients with hypertension and the prevalence of PA in patients with hypokalemia and hypertension. Hypokalemia was present in 15.8% of 5100 patients with hypertension, whereas 76.9% were normokalemic, and 7.3% hyperkalemic. The prevalence of PA in patients with hypokalemia was 28.1% and increased with decreasing potassium concentrations up to 88.5% of patients with spontaneous hypokalemia and potassium concentrations <2.5 mmol/L. A multivariate regression analysis demonstrated the association of hypokalemia with the occurrence of cardiovascular events independent of PA diagnosis. An association of PA with the occurrence of cardiovascular events and target organ damage independent of hypokalemia was also demonstrated. In conclusion, our results confirm that PA is a frequent cause of secondary hypertension in patients with hypokalemia, and the presence of hypertension and spontaneous hypokalemia are strong indications for PA diagnosis. Finally, we show that PA and hypokalemia are associated with an increased risk of cardiovascular events.

Introduction

Potassium is the most abundant cation in human body, and the maintenance of potassium ion homeostasis across the cell membrane is of fundamental importance for cell function, particularly in excitable tissues, such as nerves, cardiac, and skeletal muscles.1 Current recommendations define the normal lower potassium limit from 3.5 to 3.8 mmol/L and the upper limit from 5.0 and 5.5 mmoL.2 Hypokalemia is a common electrolyte disorder in clinical practice.1,3 The prevalence of hypokalemia in hospitalized patients is between 6.7% and 21%.4–6 This high variability can be explained by the different cutoffs selected for diagnosis and by characteristics of enrolled cohorts. Potassium depletion is also frequent in patients with hypertension. Recent data from a nationwide registry reported a prevalence of hypokalemia of 3.8%.3 This study also demonstrated a significant reduction of survival for patients with potassium levels <3.7 mmol/L or >4.8 mmol/L.3
Diuretic-induced renal potassium loss and a diagnosis of primary aldosteronism (PA) are commonly considered as frequent causes of hypokalemia in patients with hypertension.3,7–9 The incidence of hypokalemia in patients receiving diuretics is reported between 7.2% and 56.4%.10,11 Conversely, the prevalence of diuretic-induced hypokalemia in patients with hypertension is unknown.
PA is characterized by an inappropriate secretion of aldosterone relative to suppressed plasma renin levels. The consequent activation of epithelial mineralocorticoid receptors produces inappropriate sodium retention, and deleterious effects, such as volume expansion, hypertension, and an increased risk of cardiovascular events. An early diagnosis and targeted treatment could reduce this excess risk.12,13 In particular, adrenalectomy or medical therapy at doses sufficient to increase renin levels reverts the excess risk determined by PA.13
Until the 1990s, PA was considered a rare disorder, accounting for <1% of patients with hypertension, almost always associated with spontaneous hypokalemia.14–16 The introduction of the aldosterone-to-renin ratio (ARR) and the widespread screening of patients with hypertension led to a 5- to 15-fold increase in the diagnosis of PA17 with prevalence estimates ranging from 1% to 29.8% in referral centers and from 3.2% to 12.7% in primary care practice,18 depending on different settings, patient cohorts, and diagnostic criteria. The wide use of the ARR led to an increased detection of milder forms of PA. Reflecting this change, normokalemic hypertension became the most common phenotype of PA, with a prevalence comprised between 63% and 91%.17 Indeed, hypokalemia was detected in 0% to 37.5% of patients with PA in primary care studies and 0% to 67% in referral centers.18 Prevalence of PA increases with the severity of hypertension, from 3.9% to 6.6%19,20 in stage 1, up to 20% in patients with resistant hypertension.21 The prevalence of hypokalemia also increased from 45.6% to 72% in this subgroup of patients, consistent with a more severe phenotype.21,22
A large number of studies investigated the prevalence of hypokalemia in patients with PA. Surprisingly, the prevalence of PA in patients with hypertension and hypokalemia is unknown.8 The aim of our study was to investigate the prevalence of hypokalemia in patients referred to a tertiary hypertension unit and to identify the prevalence of PA in patients with hypokalemia. In addition, considering the relevance of potassium imbalance to cardiovascular disease, we assessed the cardiovascular risk of patients with normokalemia versus patients with hypokalemia, independent of the diagnosis of PA.

Methods

The data that support the findings of this study are available from the corresponding author on reasonable request.

Patient Selection

Between 2007 and 2018, 7110 patients were referred to our tertiary hypertension unit and of these 5100 had at least 2 visits to our center, concluded the diagnostic workup for secondary hypertension, and were selected for inclusion to the study. Medical records of patients were reviewed by 3 independent reviewers, who were blinded to patients’ identification and diagnosis and evaluated clinical data and cardiovascular risk indicators. For each patient, clinical (age, sex, duration of hypertension, systolic blood pressure and diastolic blood pressure, weight, and body mass index) and biochemical parameters (sodium, potassium, creatinine, glucose, total cholesterol, HDL [high-density lipoprotein], triglycerides, plasma renin activity, and aldosterone) were assessed. We considered the lowest recorded serum potassium concentration to define hypokalemia (K+<3.7 mmol/L) and the highest to define hyperkalemia (K+>5.2 mmol/L). These cutoffs were chosen to exclude patients with spurious hyperkalemia and include those with masked hypokalemia (patients with hypokalemia but normal potassium levels due to undetected sample hemolysis or other preanalytical factors).
Subjects who were tested as hypokalemic on one occasion and hyperkalemic on another were classified as hypokalemic. In most cases (36 of 42 patients), subjects displaying both hypokalemia and hyperkalemia were patients with PA who had hypokalemia at diagnosis that subsequently developed hyperkalemia after adrenalectomy or therapy with mineralocorticoid receptor antagonists. When potassium measurements were all comprised between 3.7 and 5.2 mmol/L, patients were considered in the group with normokalemia, and the first available measurement was used in the analysis. For each patient, clinical and biochemical parameters closest to the selected potassium measurement were considered in the analysis. For patients with hypokalemia, we determined when possible, the factor(s) responsible for the reduction in potassium levels (PA, diuretic-induced hypokalemia, renovascular hypertension, Cushing syndrome, laxative use/diarrhea, licorice or grapefruit abuse, monogenic forms of low-renin hypertension).
The entire cohort was also compared with a previously described population of 1672 unselected primary care patients with hypertension.20

Cardiovascular Risk Indicators

We considered as cardiovascular events (occurring after the considered potassium measurement) sustained arrhythmias (atrial fibrillation, atrial flutter, sustained ventricular tachycardia, and ventricular fibrillation), coronary heart disease (myocardial infarction and unstable angina requiring angioplasty), heart failure requiring hospitalization, and stroke (ischemic stroke or transient ischemic attack). Other reported events were preeclampsia, aortic dissection, acute kidney injury, and hypertensive encephalopathy. Chronic kidney disease (CKD) was defined if eGFR was <60 mL/minute23; diabetes mellitus, metabolic syndrome, and dyslipidemia were defined according to guidelines.24–26 Left ventricular hypertrophy (LVH) was assessed and defined as a left ventricular mass index >115 g/m2 (men) or >95 g/m2 (women).27 Microalbuminuria was diagnosed in presence of urine albumin concentration of 30 to 300 mg/24 hour or by an albumin to creatinine ratio of 30 to 300 mg/g.27

Diagnostic Criteria

PA was diagnosed in agreement with the Endocrine Society guideline.8 An ARR >30 ng/dL/ng×mL−1×h−1 together with an aldosterone level >10 ng/dL were considered for a positive screening test; all patients with a positive screening test underwent confirmatory/exclusion testing through an intravenous saline loading test or a captopril challenge test, as previously described.20 Intravenous saline loading test was performed in recumbent position until April 2014 and in seated position thereafter. Patients with a confirmed diagnosis of PA underwent subtype differentiation through computed tomography scanning and adrenal venous sampling. Other forms of secondary hypertension associated with hypokalemia (renovascular hypertension, Cushing syndrome, Liddle syndrome) were diagnosed according to available guidelines.27,28

Statistical Analysis

IBM SPSS Statistics 22 (IBM Corp, Armonk, NY) was used for statistical analyses. Data were analyzed with the Kolmogorov-Smirnov test to determine their distributions. Normally distributed variables are expressed as mean±SD and were analyzed by ANOVA 1-way and Bonferroni post hoc tests. Non-normally distributed variables are expressed as median (interquartile range) and were analyzed by Mann-Whitney and Kruskall-Wallis. Categorical variables are expressed as absolute number and proportion (percentage, %) and were analyses by χ2 and Fisher tests. Multivariate logistic regression was used to determine odds ratios (ORs) and assess the association between hypokalemia and cardiovascular risk indicators. An OR >1 indicates an increased likelihood of the evaluated variable, whereas an OR <1 a decreased likelihood. P values of <0.05 were considered significant.

Results

Hypokalemia: Prevalence, Etiology, and Associated Cardiovascular Events

Using 3.7 and 5.2 mmol/L as potassium cutoff levels to discriminate patients with hypokalemia and hyperkalemia, respectively, after exclusion of patients with hyperkalemia (n=374), the final cohort was composed of 4726 patients, including 3922 patients who are normokalemic and 804 patients with hypokalemia (Figure 1). Demographic and clinical features of patients included in the analysis are summarized in Table 1. Overall, the mean age was 50±13 years, 53.4% were men. The prevalence of hypokalemia was 15.8% (804 of 5100 patients) considering the lowest potassium measurement recorded for each patient. The prevalence decreases to 10.5% considering potassium levels assessed at the first visit (P<0.001) and to 8.1% using a stricter cutoff to define hypokalemia (<3.5 mmol/L; P<0.001; Table S1 in the online-only Data Supplement).
Table 1. Patients Characteristics
VariableTotal CohortPatients With NormokalemiaPatients With HypokalemiaP Value
Clinical characteristics
 Age, y50±13.149±13.152±12.8<0.001
 Sex, male; %2522 (53.4)2087 (53.2)435 (54.2)0.635
 Duration of HTN, y7.0 (3.0–14.0)7.0 (3.0–13.0)10.0 (4.0–19.0)<0.001
 SBP, mm Hg155±22.2154±21.6158±25.0<0.001
 DBP, mm Hg95±11.995±11.895±12.90.125
 BMI, kg/m226.4±4.426.3±4.426.5±4.40.280
Biochemical characteristics
 K+, mmol/L4.1±0.54.3±0.33.3±0.3<0.001
 Creatinine, mg/dL0.9±0.30.9±0.30.9±0.30.772
 Glucose, mg/dL97±21.997±21.9100±21.6<0.001
 Cholesterol tot, mg/dL214±40.9214±40.6214±43.00.868
 HDL, mg/dL54±15.254±15.252±15.20.003
 Triglycerides, mg/dL128±79.9127±79.4137±82.50.017
 PRA, ng/(mL·h)1.2 (0.4–3.3)1.3 (0.5–3.3)0.9 (0.3–2.9)<0.001
 Aldosterone, ng/dL18.4 (11.8–27.5)17.6 (11.4–26.4)22.0 (14.3–33.4)<0.001
Cardiovascular profile
 CV event, %332 (7.0)246 (6.3)86 (10.7)<0.001
 Age at event, y56.3±13.955.8±14.157.5±13.30.223
 Arrhythmias, %99 (2.1)72 (1.8)27 (3.4)0.006
 CAD, %64 (1.4)50 (1.3)14 (1.8)0.290
 Heart failure, %24 (0.5)16 (0.4)8 (1.0)0.032
 Stroke, %71 (1.5)45 (1.1)26 (3.3)<0.001
 Other events, %74 (1.6)63 (1.6)11 (1.4)0.627
 CKD, %193 (4.1)124 (3.2)69 (8.6)<0.001
 Diabetes mellitus, %376 (8.4)293 (7.9)83 (10.4)0.025
 Metabolic syndrome, %1438 (34.6)1070 (31.9)368 (46.0)<0.001
 Dyslipidemia, %3314 (74.8)2721 (74.9)593 (74.1)0.649
 LVH at echo, %1832 (55.8)1437 (54.3)395 (61.9)0.001
 Microalbuminuria, %445 (16.3)329 (15.3)116 (20.1)0.005
Clinical and biochemical parameters of patients included in the analysis (N=4726). The table reports data recorded in the visit closest to the considered potassium value (see Methods), cardiovascular profile (events and target organ damage), and the comparison between patients with normokalemia (N=3922) or hypokalemia (N=804). Differences were considered significant for P values <0.05. BMI indicates body mass index; CAD, coronary artery disease; CKD, chronic kidney disease; CV, cardiovascular; DBP, diastolic blood pressure; HDL, high-density lipoprotein; HTN, hypertension; LVH, left ventricular hypertrophy; PRA, plasma renin activity; and SBP, systolic blood pressure.
Figure 1. Study flow chart. From 7110 patients referred to a tertiary hypertension unit, we selected 5100 patients for the analysis: 374 patients with hyperkalemia (7.3%), 3922 patients with normokalemia (76.9%), and 804 patients with hypokalemia (15.8%).
The main causes of hypokalemia were diuretic therapy or a diagnosis of PA (Table 2). The prevalence of PA was 28.1% (226 of 804 patients); 8.3% had an aldosterone-producing adenoma (APA) 15.3% were diagnosed as bilateral PA, whereas we were unable to determine the subtype for 36 patients (4.4%). Diuretic-induced hypokalemia was detected in 357 patients (44.4%): 40.9% of patients used thiazide diuretics and 4.3% loop diuretics. The other considered causes were renovascular hypertension, Cushing syndrome, Liddle syndrome, laxatives/diarrhea, licorice or grapefruit abuse, which together accounted for 7.3% of hypokalemia cases. Finally, we could not identify the cause of hypokalemia in 248 patients (30.8%). Compared with normokalemic patients, patients with hypokalemia were older (52±12.8 versus 49±13.1 years; P<0.001), with a longer known duration of hypertension (10 [4–19] versus 7 [3–13] years; P<0.001) and higher systolic blood pressure (158±25 versus 154±21.6 years; P<0.001). In keeping with the higher prevalence of PA, aldosterone values were higher, and potassium and plasma renin activity levels were lower in patients with hypokalemia. In addition, glucose and triglycerides were significantly higher, whereas HDL levels were lower in patients with hypokalemia (P<0.001 for all comparisons; Table 1).
Table 2. Causes of Hypokalemia
EtiologyN (%)
Primary aldosteronism, %226 (28.1)
 Aldosterone-producing adenoma67 (8.3)
 Bilateral primary aldosteronism123 (15.3)
 Undetermined36 (4.4)
Diuretic-induced hypokalemia, %357 (44.4)
 Thiazide diuretics329 (40.9)
 Loop diuretics34 (4.3)
Other causes, %59 (7.3)
 Renovascular hypertension13 (1.6)
 Cushing syndrome6 (0.8)
 Liddle syndrome1 (0.1)
 Laxative/diarrhea9 (1.1)
 Licorice/grapefruit17 (2.2)
No identified causes248 (30.8)
Causes and prevalence of hypokalemia in our cohort. The table reports number of patients and percentages referred to the cohort with hypokalemia (N=804).
For all patients included in the analysis, we evaluated the occurrence of cardiovascular events, target organ damage and the diagnosis of CKD, diabetes mellitus, metabolic syndrome, and dyslipidemia (Table 1). Comparing patients with hypokalemia versus normokalemia, we demonstrated a higher prevalence of cardiovascular events (10.7% versus 6.3%; P<0.001). In detail, patients with hypokalemia displayed more frequently arrhythmias (3.4% versus 1.8%; P=0.006), heart failure (1.0% versus 0.4%; P=0.032), and stroke (3.3% versus 1.1%; P<0.001). There was no difference regarding the age of patients at the event (58±13.3 versus 56±14.1 years; P=0.223). Moreover, patients with hypokalemia displayed a significantly higher prevalence of CKD (8.6% versus 3.2%; P<0.001), diabetes mellitus (10.4% versus 7.9%; P=0.025), metabolic syndrome (46.0% versus 31.9%; P<0.001), LVH (61.9% versus 54.3%; P=0.001), and microalbuminuria (20.1% versus 15.3%; P=0.005).
To further characterize the cardiovascular risk of these patients, we performed a multivariate logistic regression analysis, evaluating associations between hypokalemia, and cardiovascular events, CKD, diabetes mellitus, metabolic syndrome, LVH, or microalbuminuria; we considered sex, age, duration of hypertension, systolic blood pressure, and a diagnosis of PA, as possible confounding factors (Table 3). We confirmed the association of hypokalemia with cardiovascular events (OR, 1.37 [95% CI, 1.06–1.77]; P=0.017), CKD (OR, 1.75 [95% CI, 1.22–2.52]; P=0.003), and metabolic syndrome (OR, 1.59 [95% CI, 1.32–1.90]; P<0.001). Of note, the same analysis demonstrated the association between PA and cardiovascular events (OR, 1.53 [95% CI, 1.12–2.10]; P=0.007), CKD (OR, 1.80 [95% CI, 1.18–2.75]; P=0.007), diabetes mellitus (OR, 1.68 [95% CI, 1.19–2.39]; P=0.003), metabolic syndrome (OR, 1.78 [95% CI, 1.31–2.34]; P<0.001), LVH (OR, 1.32 [95% CI, 1.01–1.74]; P=0.034), and microalbuminuria (OR, 1.66 [95% CI, 1.19–2.34]; P=0.003), independent of serum potassium concentrations and the other considered confounding factors.
Table 3. Associations of Hypokalemia and Primary Aldosteronism With Cardiovascular and Metabolic Complications and Organ Damage
VariablesSex, Ref. MaleAge, yDuration of HTN, ySystolic BP, mm HgPA Diagnosis, Ref. PresentHypokalemia, Ref. Present
Cardiovascular events1.15*1.04*1.01*1.01*1.53*1.37*
(0.93–1.43)(1.03–1.05)(0.99–1.02)(0.99–1.01)(1.12–2.10)(1.06–1.77)
0.189†<0.001†0.131†0.254†0.007†0.017†
Chronic kidney disease1.31*1.06*1.01*1.01*1.80*1.75*
(0.95–1.81)(1.04–1.08)(0.99–1.02)(1.01–1.02)(1.18–2.75)(1.22–2.52)
0.097†<0.001†0.578†0.001†0.007†0.003†
Diabetes mellitus1.07*1.04*1.01*1.01*1.68*0.96*
(0.84–1.35)(1.02–1.05)(0.99–1.02)(1.01–1.02)(1.19–2.39)(0.71–1.30)
0.595†<0.001†0.268†<0.001†0.003†0.796†
Metabolic syndrome1.48*1.02*1.01*1.01*1.78*1.59*
(1.28–1.72)(1.02–1.03)(1.01–1.03)(1.01–1.01)(1.31–1.44)(1.32–1.90)
<0.001†<0.001†0.001†<0.001†<0.001†<0.001†
Left ventricular hypertrophy2.42*1.04*1.01*1.02*1.32*1.15*
(2.05–2.87)(1.03–1.04)(0.99–1.02)(1.01–1.02)(1.01–1.74)(0.93–1.43)
<0.001†<0.001†0.236†<0.001†0.034†0.197†
Microalbuminuria1.48*0.99*1.01*1.01*1.66*1.21*
(1.17–1.88)(0.98–1.00)(0.99–1.02)(1.01–1.02)(1.19–2.34)(0.91–1.61)
0.001†0.171†0.315†<0.001†0.003†0.188†
Multivariate logistic regression analysis: association between PA (primary aldosteronism) and hypokalemia with cardiovascular events, CKD (chronic kidney disease), diabetes mellitus, metabolic syndrome, LVH (left ventricular hypertrophy) at echocardiography, and microalbuminuria. Sex, age, duration of HTN (hypertension), and systolic BP (blood pressure) were considered as possible confounding factors. The table reports the 95% CI (in brackets). Differences were considered significant for P<0.05.
*
Odds ratio.
†
P value.
Finally, we compared patients with spontaneous hypokalemia with those with diuretic-induced hypokalemia (Table S2). Patients receiving diuretics were older (57±11.8 versus 49±12.5 years; P<0.001), with a longer known duration of hypertension (10 [5–19] versus 5 [1–11] years; P<0.001), higher systolic blood pressure (160±25.6 versus 156±24.3 years; P=0.019), and higher body mass index (27.3±4.5 versus 25.9±4.2 years; P<0.001). Moreover, they displayed a higher prevalence of metabolic syndrome (56% versus 37.6%; P<0.001), dyslipidemia (81.5% versus 67.6%; P<0.001), and LVH (57.1% versus 42.7%; P=0.007). After correction for possible confounders, we confirmed a significant association between the use of diuretics and the presence of metabolic syndrome in patients with hypokalemia (OR, 1.49 [95% CI, 1.09–2.04]; P=0.014; Table S3).

Prevalence of Primary Aldosteronism

The prevalence of PA in the entire cohort was 7.8% (396 of 5100 patients) compared with 28.1% in patients with hypokalemia (226 of 804) and 4.3% in patients with normal potassium levels (170 of 3922). In patients with diuretic-induced or spontaneous hypokalemia, the prevalence was 16.5% (59 of 357 patients) and 37.4% (167 of 447 patients), respectively (Figure 2A; Table S4). The prevalence of PA progressively increased from 0.8%, with potassium of 5.0 to 5.2 mmol/L, up to 76.7% in patients with potassium concentrations <2.5 mmol/L (Figure 2B). Considering only patients with spontaneous hypokalemia, the prevalence of PA increased from 21.8% in patients with potassium of 3.5 to 3.6 mmol/L up to 88.5% in patients with potassium concentrations <2.5 mmol/L. In patients with PA, 42.9% were normokalemic and 57.1% hypokalemic. Thus, hypokalemic hypertension was the more common phenotype in our cohort, using <3.7 mmol/L as cutoff to define hypokalemia.
Figure 2. Prevalence of primary aldosteronism. Prevalence of primary aldosteronism (PA) in different cohorts. Black bars represent all patients included in the analysis (N=4726), gray bars represent the Primary Aldosteronism in Torino study cohort (N=1672). A, Comparison of PA prevalence in patients with hypokalemia and normokalemia. B, Prevalence of PA stratified for the lowest recorded serum potassium concentrations. Differences were considered significant for P values <0.05. *P<0.05.
The prevalence of PA was not significantly different in patients with hypokalemia considering potassium levels assessed at the first visit compared with the lowest potassium level recorded for each patient (26.0% versus 28.1%; P=0.403) but was higher using a stricter cutoff (<3.5 mmol/L) to define hypokalemia (28.1%–35%; P=0.006; Table S1).
Moreover, we evaluated the number of positive screening tests in hypokalemic and normokalemic patients using a different cutoff for ARR (Table S5). This showed that the number of patients screened positive for PA increased with a more permissive cutoff (ARR>20 [ng/dL]/[ng/mL per hour]); 74 patients (9.2%) were hypokalemic and displayed an ARR ranging between 20 and 30, of which only 19 were hypokalemic of unknown cause.
The percentage of patients diagnosed with PA increased from 6.3% to 12% after the introduction of seated saline loading testing.29 The prevalence of PA was significantly increased among both patients who are hypokalemic and normokalemic from 24.9% to 32.0%, respectively, and from 3.0% to 6.8%, before and after the introduction of seated testing. The percentage of patients with a positive intravenous saline loading test increased from 20.1% to 38.6% (P<0.001; Table S5). Of note, the respective distribution of hypokalemic and normokalemic PA did not change after the introduction of seated confirmatory testing (59.4% and 40.6% versus 55.0% and 45.0%; P=0.383).
Essential hypertension was the main cause of hypertension in patients with normokalemia (94.7%; 3669 of 3922) and hypokalemia (69.8%; 605 of 804). Considering only patients with essential hypertension, 86.9% displayed normokalemia and 13.1% hypokalemia. In addition, normal serum potassium concentrations were the most frequent findings also in patients with Cushing syndrome, pheochromocytoma, and renovascular hypertension (75.0%, 72.7%, and 67.6% of patients with normokalemia, respectively; Table S6 and Figure S1).
Finally, to evaluate if selection bias might have influenced the data of our referred cohhort, we compared patient data from this study with that from the 1672 unselected primary care patients with hypertension from the PATO (Primary Aldosteronism in Torino Study) cohort (Tables S4 and S7).20 Compared with our selected cohort, patients from the PATO study were younger (46±9 years; P<0.001), with a shorter known duration of hypertension (3 [1–7] years; P<0.001) and lower BP values (147±15/94±8 mm Hg; P<0.01). The prevalence of diabetes mellitus and LVH was lower (4.0%, P<0.001 and 33.3%, P<0.001; respectively) and patients displayed significantly higher levels of HDL and lower levels of glucose, total cholesterol, and triglycerides (P<0.01 for all comparisons).
The overall prevalence of PA was lower in the PATO study compared with the present cohort (5.9% versus 7.8% patients; P=0.011; Figure 2A), whereas no differences were found in PA prevalence in patients who are normokalemic (4.5% versus 4.3%; P=0.764), and patients who are hypokalemic (27.4% versus 28.1%; P=0.862), or in patients with diuretic-induced (19.1% versus 16.5%; P=0.655), or spontaneous hypokalemia (33.9% versus 37.4%; P=0.603), thus excluding a significant effect of referral bias in the findings of the present study. Finally, stratification of patients for potassium levels demonstrated a similar distribution of patients with a diagnosis of PA in the PATO study to our cohort (P>0.05 for all comparisons; Figure 2B).

Discussion

In this retrospective analysis of 5100 referred patients with hypertension, we report the prevalence, clinical, and biochemical characteristics of subjects with hypokalemia. For the first time, we establish the prevalence of PA in patients who are hypokalemic with hypertension and demonstrate the association of hypokalemia and PA with an unfavorable cardiovascular outcome.
The prevalence of hypokalemia in the cohort with hypertension reported herein was 15.8%. To date, a single study screened a large cohort of 44 799 hospitalized patients with hypertension from a national registry, reporting a prevalence of 3.8%.3 Differences in strategy for patient selection and the definition of hypokalemia (<3.7 versus <3.5 mmol/L) may explain variance between our study and previous reports. In this regard, using 3.5 mmol/L as cutoff, we observed a prevalence of hypokalemia of 8.1%, whereas considering the potassium measurement at the first visit instead of the lowest potassium recorded for each patient, the prevalence was 10.5%.
In our cohort, the main causes of hypokalemia were the use of diuretics or PA. A total of 7.2% of the chlorthalidone-treated patients with hypertension in the Systolic Hypertension in the Elderly Program were hypokalemic,11 compared with 8.5% of patients treated with chlorthalidone for 4 years in the ALLHAT trial (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack)30 and with 56.4% of 447 referred patients receiving hydrochlorothiazide.10 The incidence of hypokalemia in patients with hypertension receiving diuretics is well described,7 but the prevalence of diuretic-induced hypokalemia has never been systematically investigated. In our study, diuretics were the putative cause of potassium depletion in 44.4% of patients with hypokalemia receiving thiazide diuretics (40.9%) and loop diuretics (4.3%).
PA was the second cause of hypokalemia in our cohort. The prevalence of PA was 28.1% in patients with hypokalemia increasing to 37.4% in cases of spontaneous hypokalemia. The detection rate of PA gradually increased with decreasing serum potassium concentrations, with a maximum prevalence of 88.5% for patients with spontaneous hypokalemia and serum potassium <2.5 mmol/L.
After the introduction of seated intravenous saline loading testing, the prevalence of PA increased from 6.3% to 12% in the entire cohort and from 24.9% to 32% in patients with hypokalemia, in accordance with the higher reported sensitivity of seated versus recumbent testing.29 This is probably only partly due to the increased percentage of positive confirmatory tests using the seated saline load test because of the concomitant increased referral of patients with suspect PA to our center. The distribution of PA diagnoses in patients with hypokalemia and normokalemia was similar using seated versus recumbent confirmatory testing, thus excluding a significant effect determined by the type of confirmatory test on the findings of the present study.
Although spontaneous or diuretic-induced hypokalemia were originally considered prerequisite for screening patients for PA,31 several studies have since demonstrated that hypertension with normokalemia is common in patients with PA (reviewed in Käyser et al18 and Buffolo et al16). This has been demonstrated both in patients in primary care, where the mean prevalence of hypokalemia is 20.9%,18,20,32,33 and in patients referred to specialized centers where the mean prevalence is 43.4%.17–19,22,34,35 In our study, 57.1% of PA patients displayed hypokalemia, consistent with estimates in referred patients and in agreement with a more florid phenotype and with our definition of hypokalemia.
A possible cause of selection bias for patients with a more florid PA was the ARR cutoff used in our study for PA diagnosis. In contrast, selection for a less severe phenotype was favored by the definition of hypokalemia and using the lowest potassium value reported for each patient. The selection of 3.5 mmol/L as cutoff for hypokalemia (instead of 3.7 mmol/L) caused a decrease of the prevalence of hypokalemia, whereas the prevalence of PA in hypokalemic patients increased, as expected. However, the use of potassium measurement at the first visit instead of the lowest potassium recorded did not change the prevalence of PA in hypokalemic patients. Finally, using an ARR cutoff of 20 instead of 30 ([ng/dL]/[ng/(mL·h)]) for screening increased the number of positive screening tests in the entire cohort (to a similar degree for patients who are hypokalemic and normokalemic), with a relatively low number of potentially missed patients with PA.
In the overall cohort, the prevalence of PA was higher compared with the unselected primary care patients with hypertension of the PATO study (7.8 versus 5.9%), whereas no differences were found between the 2 populations with hypertension after stratification for potassium levels.20 Of note, only 6.3% of the PATO cohort displayed hypokalemia (around half that of the present study). These findings show a higher number of PA diagnoses in the referred patients compared with patients from the primary care setting but rule out a significant bias on the prevalence of PA in patients who are hypokalemic and support the recommendation of screening for PA in most patients with hypertension, independent of serum potassium concentrations.18,20
Finally, we demonstrated a higher prevalence of cardiovascular events, CKD, diabetes mellitus, metabolic syndrome, LVH, and microalbuminuria in patients with hypokalemia. Considering the high prevalence of PA in these patients, we hypothesize that hypokalemia could explain part of the excess risk of cardiovascular events associated with PA.12,36 In the multivariate analysis, after correction for possible confounders, such as sex, age, duration of hypertension, and BP levels, hypokalemia was associated with cardiovascular events, CKD, and metabolic syndrome independent of a diagnosis PA, whereas PA was associated with cardiovascular events, CKD, diabetes mellitus, metabolic syndrome, LVH, and microalbuminuria independent of hypokalemia.
Several observational studies have demonstrated the association of abnormal potassium concentrations with increased mortality, major cardiovascular events, and hospitalization rates in different selected cohorts.9,37–39 In all cases, studies observed a high risk of adverse outcomes in patients with hypokalemia.1,9,39
Few studies have focused on patients with hypertension, reporting similar associations between serum potassium concentrations and outcomes.2,3 Of note, serum potassium <3.5 mmol/L is associated with a 2.1-fold increased risk of all-cause mortality in patients with hypertension.3 In accordance with these findings, in our cohort, hypokalemia was associated with cardiovascular events independent of sex, age, duration of HTN, systolic BP, and diagnosis of PA. Patients with PA displayed an increase of cardiovascular events and target organ damage, in agreement with previous reports.12,20,36,40,41 In patients with PA, the association between hypokalemia and cardiovascular risk is not entirely dependent on a more severe blood pressure phenotype; indeed, the multivariate analysis showed that PA and hypokalemia were independently associated with the occurrence of cardiovascular events.
Diuretics may worsen metabolic parameters.42 Accordingly, we found a higher prevalence of metabolic syndrome, dyslipidemia, and LVH in patients with hypokalemia receiving diuretics. Diuretic-induced hypokalemia was associated with metabolic syndrome even after correction for possible confounding factors. Therefore, a worsening of the metabolic profile might have contributed together with the higher prevalence of PA, to determine the higher risk of cardiovascular events in patients with hypokalemia.
The main strength of our study is the systematical assessment of hypokalemia in a large cohort of patients with hypertension. Medical records were independently reviewed by 3 investigators who were blind to patients’ diagnosis, thus excluding any adjudication bias. Moreover, this is the first study reporting the prevalence of PA in patients with hypokalemia.
A first limitation is the retrospective observational design resulting in the exclusion of 2010 of 7110 patients because the diagnostic workup was not concluded. In addition, all patients included in the analysis were referred to a single specialized center, which could potentially limit the generalizability of our results. The use of a permissive cutoff for potassium levels to maximize the number of patients with hypokalemia might have influenced our results, but this choice allowed us to include patients with potentially masked hypokalemia.43 We also used a relatively high cutoff for ARR, which may have determined a selection of patients with a relatively more florid PA phenotype and the potential loss of some patients with a mild phenotype. Furthermore, we could not investigate the prevalence and relevance of hypomagnesemia, especially in association with arrhythmias as this parameter is not routinely measured in our patients with hypertension. Finally, we cannot determine if the association of increased cardiovascular events with hypokalemia and PA diagnosis is caused by decreased potassium concentrations or is simply a marker of associated pathologies.
In conclusion, arterial hypertension is frequently associated with PA and hypokalemia; PA is particularly frequent among hypokalemic hypertensive patients and its prevalence gradually increases with the decrease of potassium levels; indeed, 1 of 3 patients with hypokalemia was diagnosed as PA in our study. Finally, PA and hypokalemia are independently associated with the occurrence of cardiovascular events.

Perspectives

Normokalemia does not exclude the diagnosis of PA; nevertheless, the presence of hypokalemia and hypertension strongly suggests this condition and is associated with a worse cardiovascular risk profile. Clinicians and general practitioners should focus attention on risks of hypokalemia in patients with a diagnosis of essential hypertension and PA. The reported prevalence of PA in patients with hypokalemia should be confirmed in large prospective multicenter cohorts. Future studies may elucidate further the association between hypokalemia and PA with increased cardiovascular risk and target organ damage.

Novelty and Significance

What Is New?

•
We reported for the first time the prevalence of primary aldosteronism (PA) in a cohort of referred patients with hypertension and hypokalemia.
•
PA and hypokalemia are independently associated with an increased risk of cardiovascular events.

What Is Relevant?

•
The prevalence of hypokalemia is 15.8% among referred patients with hypertension.
•
Main causes of hypokalemia are diuretic therapy (44.4%) or a diagnosis of PA (28.1%).
•
The prevalence of PA gradually increases with decreasing of potassium levels, up to 88.5% in patients with spontaneous hypokalemia and serum potassium <2.5 mmol/L.

Summary

Hypokalemia is frequent in patients with hypertension. The presence of hypertension and spontaneous/diuretic-induced hypokalemia strongly suggests a diagnosis of PA, which is associated with an increased cardiovascular risk independent of potassium levels.

Supplemental Material

File (hyp_hype201914063_supp2.pdf)

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Hypertension
Volume 75 • Number 4 • April 2020
Pages: 1025 - 1033
PubMed: 32114853

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© 2020 American Heart Association, Inc.

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History

Received: 20 September 2019
Revision received: 30 September 2019
Accepted: 9 January 2020
Published online: 2 March 2020
Published in print: April 2020

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Keywords

  1. hypertension
  2. hypokalemia
  3. phenotype
  4. potassium
  5. regression analysis

Subjects

  1. Cardiovascular Disease
  2. Hypertension

Authors

Affiliations

Jacopo Burrello
From the Division of Internal Medicine and Hypertension (J.B., S.M., I.L., G.C., F.B., M.T., M.C., F.R., F.V., T.A.W., P.M.), Department of Medical Sciences, University of Turin, Italy
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Silvia Monticone
From the Division of Internal Medicine and Hypertension (J.B., S.M., I.L., G.C., F.B., M.T., M.C., F.R., F.V., T.A.W., P.M.), Department of Medical Sciences, University of Turin, Italy
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Isabel Losano
From the Division of Internal Medicine and Hypertension (J.B., S.M., I.L., G.C., F.B., M.T., M.C., F.R., F.V., T.A.W., P.M.), Department of Medical Sciences, University of Turin, Italy
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Giovanni Cavaglià
From the Division of Internal Medicine and Hypertension (J.B., S.M., I.L., G.C., F.B., M.T., M.C., F.R., F.V., T.A.W., P.M.), Department of Medical Sciences, University of Turin, Italy
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Fabrizio Buffolo
From the Division of Internal Medicine and Hypertension (J.B., S.M., I.L., G.C., F.B., M.T., M.C., F.R., F.V., T.A.W., P.M.), Department of Medical Sciences, University of Turin, Italy
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Martina Tetti
From the Division of Internal Medicine and Hypertension (J.B., S.M., I.L., G.C., F.B., M.T., M.C., F.R., F.V., T.A.W., P.M.), Department of Medical Sciences, University of Turin, Italy
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Michele Covella
From the Division of Internal Medicine and Hypertension (J.B., S.M., I.L., G.C., F.B., M.T., M.C., F.R., F.V., T.A.W., P.M.), Department of Medical Sciences, University of Turin, Italy
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Franco Rabbia
From the Division of Internal Medicine and Hypertension (J.B., S.M., I.L., G.C., F.B., M.T., M.C., F.R., F.V., T.A.W., P.M.), Department of Medical Sciences, University of Turin, Italy
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Franco Veglio
From the Division of Internal Medicine and Hypertension (J.B., S.M., I.L., G.C., F.B., M.T., M.C., F.R., F.V., T.A.W., P.M.), Department of Medical Sciences, University of Turin, Italy
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Barbara Pasini
Medical Genetics Unit (B.P.), Department of Medical Sciences, University of Turin, Italy
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Tracy Ann Williams
From the Division of Internal Medicine and Hypertension (J.B., S.M., I.L., G.C., F.B., M.T., M.C., F.R., F.V., T.A.W., P.M.), Department of Medical Sciences, University of Turin, Italy
Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, Germany (T.A.W.).
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Paolo Mulatero [email protected]
From the Division of Internal Medicine and Hypertension (J.B., S.M., I.L., G.C., F.B., M.T., M.C., F.R., F.V., T.A.W., P.M.), Department of Medical Sciences, University of Turin, Italy
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Notes

The online-only Data Supplement is available with this article at Supplemental Material.
Correspondence to Paolo Mulatero, Division of Internal Medicine and Hypertension Unit, Department of Medical Sciences, University of Torino, Città della Salute e della Scienza di Torino, Via Genova 3, 10126 Torino, Italy. Email [email protected]

Disclosures

None.

Sources of Funding

The project was supported by a grant from the Ministero dell’Istruzione, dell’ Università e della Ricerca, RiLo ex-60% 2018 to T.A. Williams, B. Pasini, and P. Mulatero. T.A. Williams is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) Projektnummer: 314061271-TRR 205.

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    Abstract
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Prevalence of Hypokalemia and Primary Aldosteronism in 5100 Patients Referred to a Tertiary Hypertension Unit
Hypertension
  • Vol. 75
  • No. 4

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Hypertension
  • Vol. 75
  • No. 4
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