Incidence and factors of post-adrenalectomy hyperkalemia in patients with aldosterone producing adenoma

Clinica Chimica Acta 424 (2013) 114–118

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Incidence and factors of post-adrenalectomy hyperkalemia in patients with aldosterone producing adenoma Wen-Fang Chiang a,b, Chih-Jen Cheng b, Sheng-Tang Wu c, Guang-Huan Sun c, Mei-Yu Lin d, Chih-Chien Sung b, Shih-Hua Lin b,⁎ a

Department of Medicine, Armed Forces Taoyuan General Hospital, Taoyuan, Taiwan Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan Division of Urology, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan d Division of Nephrology, Department of Medicine, Cardinal Tien Hospital, Taipei, Taiwan b c

a r t i c l e

i n f o

Article history: Received 22 March 2013 Received in revised form 23 April 2013 Accepted 15 May 2013 Available online 28 May 2013 Keywords: Adrenalectomy Hyperkalemia Hypokalemia Primary aldosteronism

a b s t r a c t Background: Hyperkalemia is a potentially serious complication following adrenalectomy of aldosteroneproducing adenomas (APA). We analyzed the incidence and risk factors for hyperkalemia after adrenalectomy in patients with APA. Methods: We retrospectively analyzed the records of 55 patients who underwent adrenalectomy for APA between 2002 and 2011. Demographic features, biochemical and hormonal profiles, imaging, and relevant medications were reviewed. Results: Sixteen of 55 APA patients (29.1%) developed hyperkalemia (mean serum K+ 5.6 ± 0.3 mmol/l) after adrenalectomy and 3 had persistent hyperkalemia requiring mineralocorticoid supplementation for more than nine months. Compared with normokalemic patients, hyperkalemic patients were characterized by male predominance, older age, longer duration of hypertension (12.8 ± 9.3 vs. 6.7 ± 5.0 y, p b 0.05), lower nadir serum K+ (p b 0.05), higher preoperative serum creatinine (p b 0.01), and higher likelihood of residual hypertension. Using multivariate regression analysis, longer duration of hypertension and impaired renal function were the most important factors of post-adrenalectomy hyperkalemia. Conclusions: Post-adrenalectomy hyperkalemia in patients with APA is not rare and associated with impaired renal function and longer duration of hypertension. Serum K+ must be cautiously monitored in patients with long-term hypertension and kidney disease. © 2013 Elsevier B.V. All rights reserved.

1. Introduction Primary aldosteronism (PA), characterized by nonsuppressible hypersecretion of aldosterone, is the most common cause of secondary hypertension with a prevalence rate of 5–13% among all hypertensive patients [1–3]. Excessive aldosterone secretion enhances renal sodium (Na+) retention and potassium (K+) secretion, thus leading to chronic hypertension and potentially hypokalemia [4,5]. Idiopathic hyperaldosteronism (IHA) and aldosterone producing adenomas (APA) are the two most common etiologies of PA. IHA should be treated medically with mineralocorticoid receptor antagonists, whereas APA may be managed surgically with adrenalectomy which can effectively improve blood pressure (BP) and correct hypokalemia [3,6,7].

In patients with APA, aldosterone secretion by the lesion severely suppresses the contralateral adrenal gland [8]. After adrenalectomy, serum aldosterone level falls acutely and normalization of aldosterone secretion by the contralateral adrenal gland may be delayed from one to four months, leading to a state of hypoaldosteronism [8]. During the period of postoperative hypoaldosteronism, patients are susceptible to developing hyperkalemia, a life-threatening complication. However, post-adrenalectomy hyperkalemia has been seldom reported [9–11] and its causative factors rarely investigated. In this study, we aim to describe the incidence and associated risk factors in 55 patients with APA. 2. Materials and methods 2.1. Patients

⁎ Corresponding author at: Division of Nephrology, Department of Medicine, Tri-Service General Hospital, Number 325, Section 2, Cheng-Kung Road, Neihu 114, Taipei, Taiwan. Tel.: +886 2 87927213; fax: +886 2 87927134. E-mail address: [email protected] (S.-H. Lin). 0009-8981/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.cca.2013.05.017

The study protocol was approved by the Ethics Committee on Human Studies at Tri-Service General Hospital, Taipei, Taiwan. Patients undergoing adrenalectomy for APA at our institution between January 2002 and December 2011 were retrospectively recruited.

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APA was suspected based on clinical presentation of hypertension in young people (b40 years), therapy-resistant hypertension or the coexistence of hypertension and hypokalemia. Therapy-resistant hypertension was defined as systolic BP > 140 or diastolic BP > 90 mmHg despite treatment with at least 3 hypertensive drugs [2]. Two weeks before hormone profile workup, angiotensin converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB), β-blocker, and diuretics were discontinued, and patients were treated with calcium channel blocker (CCB) and/or α-blocker. The diagnosis of APA was confirmed by the following criteria: (1) increased aldosterone to renin ratio (ARR) with non-suppressible hyperaldosteronism by intravenous saline load or captopril challenge tests; (2) lateralized aldosterone excess at adrenal vein sampling or [I-131]6-beta-iodomethylnorcholesterol (NP-59) scintigraphy; (3) identification of adrenal adenoma at surgery and/or pathology; and (4) demonstration of correction of the hyperaldosteronism and cure, or marked improvement of the hypertension after adrenalectomy [2,12]. Eighteen patients received adrenal vein sampling and 9 received NP-59 scintigraphy. Laparoscopic adrenalectomy was performed in all patients by an experienced surgeon. After the operation, all patients received acetaminophen or intravenous fentanyl for pain management. The final diagnosis was confirmed by the pathology of the excised tumors. Medical records including patient characteristics, clinical presentations, laboratory values, hormone profiles, imaging findings, and use of antihypertensive drugs were reviewed. 2.2. Methods The following clinical data were analyzed: gender, age, tumor size and location, systolic and diastolic blood pressure, duration of hypertension, comorbidities, clinical features, and categories and numbers of antihypertensive medications prescribed pre- and postoperatively. Specific attention was paid to compare the pre- and postoperative laboratory data including renal function [serum creatinine, blood urea nitrogen (BUN)], electrolytes (Na+, K+, chloride), and hormone profiles [plasma aldosterone concentration (PAC), plasma renin activity (PRA)]. Estimated glomerular filtration rate (eGFR) was calculated using the abbreviated Modification of Diet in Renal Disease Study Group (MDRD) equation: eGFR = 186 × Creatinine−1.154 × Age−0.203 (×1 if male, ×0.742 if female) [13]. Pre- and postoperative eGFRs were computed based on stable serum creatinines before and after adrenalectomy, respectively. Patients were usually instructed to measure BP in a sitting position twice daily post-adrenalectomy. The follow-up visit was scheduled weekly in the first month, monthly in the following 3 months, and every 3 months thereafter. The described BP was the average of each values recorded at home and office in the first month. Postoperative residual hypertension was defined as systolic BP > 140 or diastolic BP > 90 mmHg requiring antihypertensive treatment. 2.3. Definitions Nadir serum K+ was defined as the serum K+ level when APA was first diagnosed. Hyperkalemia was defined as serum K+ > 5.0 mmol/l and the exclusion of pseudohyperkalemia. Hyperkalemia that resolved during the first 3 months after adrenalectomy was defined as “transient”; those lasting more than three months requiring mineralocorticoid supplementation were defined as “persistent”. 2.4. Statistical analysis Results are expressed as mean ± SD. Data before and after adrenalectomy were compared using the paired t-test. The Mann–Whitney U test was used to analyze the differences in parameters between normokalemic and hyperkalemic groups. The distribution of categorical variables was assessed by the χ2 or Fisher exact test. Multivariate logistic regression was used to identify independently significant risk factors

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for the development of post-adrenalectomy hyperkalemia. Statistical significance was defined as a p b 0.05.

3. Results 3.1. Patients' characteristics Fifty-five patients underwent adrenalectomy for APA during the 9-year retrospective review (Table 1). There were 29 females and 26 males with a mean age of 49 ± 11 (24–76) years. The known duration of hypertension before adrenalectomy ranged from 0.1 to 30 years (mean 8.5 ± 7.0 years, median 8 years). Major comorbidities included diabetes mellitus (9/55, 16%), stage III–V chronic kidney disease (9/55, 16%), and coronary artery disease (4/55, 7%). Therapy-resistant hypertension (69%) was the most common presentation. Other clinical features included muscle weakness (31%), hypokalemic paralysis (25%), hypertensive crisis (5%), and intracerebral hemorrhage (4%). The most commonly used antihypertensive drugs were CCB (93%) and ACEI/ARB (65%). Three-drug regimens were the most commonly used therapies (42%) for hypertension. The mean number of antihypertensive drugs per patient was 2.3 ± 0.8. Among laboratory findings, mean PAC and PRA were 49 ± 31 ng/dl and 1.2 ± 2.5 ng/ml/h, respectively. Fifty-two patients (95%) had PACs above the normal range while the remaining 3 patients had normal PACs with severe hypokalemia (mean serum K+ level 1.8 mmol/l) at presentation. The ARR was b20 in six patients (11%) but these patients had either ACEI/ARB onboard or a history of chronic kidney disease. Nadir serum K+ b3 mmol/l and b3.5 mmol/l was documented in 80% and 93% of the APA patients, respectively. Ten patients (18%) were receiving thiazide diuretics initially. All patients were treated with spironolactone, at a mean dose of 72 ± 13 mg daily, after diagnosis of APA until the day of surgery. Hypokalemic patients were given K+ supplementation (median 124 mmol) until they were normokalemic. The mean serum K+ level was 3.8 ± 0.3 mmol/l before adrenalectomy. The mean size of excised adrenal tumors was 1.8 ± 0.5 cm. Thirty patients (55%) had their adenoma in the left adrenal gland.

Table 1 Baseline data of the study population (n = 55). Parameters

Data

Characteristics Gender (male/female) Age (years) Duration of hypertension (years) Systolic/diastolic BP (mmHg) Tumor size (cm) Diabetes mellitus Coronary artery disease Chronic kidney disease, stages III–V

26/29 49 ± 11 8.5 ± 7.0 155 ± 24/91 ± 16 1.8 ± 0.5 9 (16%) 4 (7%) 9 (16%)

Clinical presentations Resistant hypertension Muscle weakness/paralysis Hypertensive crisis/intracranial hemorrhage

38 (69%) 31 (56%) 5 (9%)

Laboratory data Nadir serum K+ (mmol/l) (3.5–5.0) BUN (mg/dl) (6–20) Serum creatinine (mg/dl) (0.5–1.0) eGFR (ml/min/1.73 m2) PAC (ng/dl) (1.2–15) PRA (ng/ml/h) (0.15–2.33) ARR

2.6 ± 0.6 17 ± 10 1.0 ± 0.9 93 ± 30 49 ± 31 1.2 ± 2.5 208 ± 234

ARR, aldosterone to renin ratio; BP, blood pressure; BUN, blood urea nitrogen; eGFR, estimated glomerular filtration rate; K+, potassium; PAC, plasma aldosterone concentration; PRA, plasma renin activity.

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3.2. Effect of adrenalectomy After adrenalectomy, serum aldosterone levels decreased and renin increased significantly. Improvements in systolic and diastolic BP were observed in all patients with mean reduction in systolic BP of 20 ± 18 mmHg (p b 0.001) and diastolic BP of 9.4 ± 15 mmHg (p b 0.001). The mean decrease in the number of antihypertensive drugs was 1.7 ± 1.1 and hypertension was cured in 35 patients (64%). Only 20 patients (36%) had residual hypertension. Serum K+ and creatinine levels increased by 0.9 ± 0.6 mmol/l (p b 0.001) and 0.2 ± 0.2 mg/dl (p b 0.05), respectively. The average decline of eGFR right after adrenalectomy was 14 ± 19 ml/min/1.73 m2 (p b 0.05). 3.3. Patients with hyperkalemia after adrenalectomy Sixteen of the 55 patients (29%) developed hyperkalemia after adrenalectomy, 11 male and 5 female. Their mean age was 56.4 ± 11.8 years. Four patients (25%) had diabetes mellitus, 1 patient (6%) coronary artery disease, and 6 patients (38%) stage III–V chronic kidney disease. The average duration of hypertension was 12.8 ± 9.3 years. The most commonly used antihypertensive drugs were CCB (94%) and ACEI/ARB (69%). The mean nadir serum K+ level was 2.3 ± 0.5 mmol/l. After adrenalectomy, average serum K+ level was 5.6 ± 0.3 mmol/l, with a range of 5.3–6.2 mmol/l (Table 2). The time to onset of post-adrenalectomy hyperkalemia ranged from one to three weeks. Among these 16 patients, 13 had transient hyperkalemia lasting from 7 days to 2 months, which was controlled by avoidance of high K+ foods, replacement of ACEI/ARB or β-blockers with CCB, and administration of calcium polystyrene sulfonate. As shown in Table 3, three patients (5.5%) had persistent hyperkalemia for > 9 months requiring fludrocortisone 0.1 μg daily to treat severe hypoaldosteronism. Of note, these patients were all male, had hypokalemia at presentation, and had duration of hypertension for > 10 years. Patients 2 and 3 had impaired renal function Table 2 Comparison in patients with APA undergoing adrenalectomy. Parameters

Normokalemia (n = 39)

Hyperkalemia (n = 16)

p

Serum K+ (mmol/l) Gender (male/female) Age (years) Duration of hypertension (years) Tumor size (cm) Chronic kidney disease, stages III–V

4.4 ± 0.3 15/24 46.5 ± 10.0 6.7 ± 5.0

5.6 ± 0.3 11/5 56.4 ± 11.8 12.8 ± 9.3

b0.001 0.041 0.002 0.013

1.8 ± 0.6 3 (8%)

1.8 ± 0.4 6 (38%)

NS 0.013

Preoperative Systolic/diastolic BP (mmHg) Nadir serum K+ (mmol/l) BUN (mg/dl) Serum creatinine (mg/dl) PAC (ng/dl) PRA (ng/ml/h) ARR Postoperative Systolic/diastolic BP (mmHg) Residual hypertension BUN (mg/dl) Serum creatinine (mg/dl) PAC (ng/dl) PRA (ng/ml/h) ARR

153 ± 19/90 ± 13 158 ± 33/92 ± 22 0.956/0.816 2.7 ± 0.6 15 ± 5 0.8 ± 0.2 51 ± 30 1.4 ± 2.9 191 ± 215

2.3 ± 0.5 23 ± 16 1.5 ± 1.6 45 ± 32 0.5 ± 0.8 250 ± 278

0.038 0.021 0.002 ND NS NS

133 ± 10/81 ± 10 137 ± 17/81 ± 13 0.597/0.993 10 (26%) 18 ± 6 0.9 ± 0.3 17 ± 11 3.1 ± 4.6 21 ± 28

10 (63%) 31 ± 21 1.7 ± 1.7 14 ± 7 2.7 ± 5.7 36 ± 56

0.01 0.007 0.004 NS NS NS

APA, aldosterone-producing adenoma; ARR, aldosterone to renin ratio; BP, blood pressure; BUN, blood urea nitrogen; eGFR, estimated glomerular filtration rate; K+, potassium; PAC, plasma aldosterone concentration; PRA, plasma renin activity.

and patient 2 also had diabetes mellitus. All patients had an increase of serum creatinine level and a decrease of eGFR. Postoperatively, residual hypertension was documented in these three patients. Patient 3 was started on hemodialysis 10 months post-adrenalectomy. 3.4. Comparison in patients without and with post-adrenalectomy hyperkalemia There were no significant differences in preoperative BP, tumor size/location, PAC, PRA, ARR, categories/number of antihypertensive drugs, and doses of K+ supplementation/spironolactone between APA patients with and without post-adrenalectomy hyperkalemia (Tables 2, 4). However, patients with hyperkalemia were male predominant (n = 11, 69%) and older (56.4 ± 11.8 vs. 46.5 ± 10.0 years, p b 0.01). They also had longer duration of hypertension (12.8 ± 9.3 vs. 6.7 ± 5.0 years, p b 0.05), lower nadir serum K+ level (2.3 ± 0.5 vs. 2.7 ± 0.6 mmol/l, p b 0.05), lower eGFR (73 ± 30 vs. 101 ± 27 ml/min/1.73 m2, p b 0.01), and higher likelihood of residual hypertension (63% vs. 26%, p b 0.05) (Table 2). After surgery, all patients with residual hypertension received antihypertensive therapy. None of them needed spironolactone. The percentage of ACEI/ARB, β-blocker, and the combination of both prescribed for the residual hypertension in 2 groups was similar. 3.5. Factors associated with post-adrenalectomy hyperkalemia Risk factors including gender, age, duration of hypertension, nadir serum K+ level, preoperative eGFR, residual hypertension, and categories of antihypertensive drugs (ACEI/ARB, β-blocker, CCB, non-spironolactone diuretics) were further analyzed using multivariate regression. After backward elimination, the significant independent risk factors were duration of hypertension (odds ratio, 1.12; 95% CI, 1.01–1.24; p b 0.05) and eGFR (odds ratio, 0.97; 95% CI, 0.94–1.00; p b 0.05). 4. Discussion In this study, we analyzed the incidence and risk factors for post-adrenalectomy hyperkalemia in 55 patients with APA from a single academic medical center. We found that the incidence was as high as 30%. Most hyperkalemic events occurred between 1 and 3 weeks after adrenalectomy. The hyperkalemia is usually transient but sometimes persists, requiring mineralocorticoid supplementation. Longer duration of hypertension and impaired renal function were the most important risk factors for post-adrenalectomy hyperkalemia. During the disease course of APA, adenomatous aldosterone hypersecretion suppresses function of the contralateral zona glomerulosa. After sudden removal of the lesion by adrenalectomy, we found that serum aldosterone concentration was markedly decreased while PRA increased, consistent with previous reports [8]. In a recurring theme in physiology, from cortisol in Cushing's to testosterone in anabolic steroid abuse and muscle strength in space travel, prolonged disuse leads to tissue atrophy and subsequent delayed recovery [14–16]. In addition, GFR was also significantly reduced. Unlike the increased or unchanged GFR in patients with well-controlled primary hypertension [17], the attenuated renal function in APA patients following adrenalectomy is highly related to the amelioration of intraglomerular hypertension and glomerular hyperfiltration observed in PA [18–20]. In the state of relative hypoaldosteronism and reduced GFR, there is thus a potential risk of developing post-adrenalectomy hyperkalemia. Nevertheless, the incidence, causative factors, and natural course of post-adrenalectomy hyperkalemia in patients with APA have not been well investigated. Our study showed that the incidence of post-adrenalectomy hyperkalemia was approximately 30%, which is higher than the 16% in a recent retrospective report [21]. There are some reasons to account for this discrepancy. Our patients had a longer median duration of hypertension (8 vs. 6 years), implying longer suppression of

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Table 3 Clinical and laboratory findings in three APA patients with post-adrenalectomy persistent hyperkalemia. Parameters

Patient 1a

Patient 2

Patient 3

Age (years) Sex Duration of hypertension (years) Tumor size (cm) Chronic kidney disease, stages III–V Nadir serum K+ (mmol/l)

62 Male 13 1.8 No 2.3

58 Male 14 2.3 Yes 2.8

76 Male 21 2.1 Yes 2.2

Systolic/diastolic BP (mmHg) Serum K+ (mmol/l) Serum creatinine (mg/dl) PRA (ng/dl) PAC (ng/ml/h) Numbers of antihypertensive drugs Fludrocortisone dose (μg/day)

Pre

Post

Pre

Post

Pre

Post

160/90 3.9 0.8 0.2 140 2 –

146/86 5.9 0.9 8.6 8.8 1 0.1

156/96 4.1 2 0.12 21 3 –

148/92 5.9 2.8 0.13 7.7 2 0.1

236/126 4.1 7.5 0.5 47 4 –

160/88 6.2 7.8 0.9 10.8 2 0.1

APA, aldosterone-producing adenoma; BP, blood pressure; eGFR, estimated glomerular filtration rate; K+, potassium; PAC, plasma aldosterone concentration; PRA, plasma renin activity. a Reported in Reference [11].

the contralateral adrenal gland and thus slower recovery of aldosterone production. In addition, hypokalemia in APA is considered an index of disease severity [5,22]. Our patients had more severe hypokalemia at presentation. In addition, the preoperative serum K+ levels were normalized with a much higher median dose of K+ supplementation (124 vs. 40 mmol). Although the majority of post-adrenalectomy hyperkalemia was transient without severe complications, three patients (5.5%) developed persistent post-adrenalectomy hyperkalemia. The percentage is similar to a previous report [21]. All of them had severe hypokalemia at presentation and a duration of hypertension > 10 years, suggesting severe and prolonged disease with severe and prolonged stunting of the contralateral gland. Several preoperative and postoperative risk factors may be associated with post-adrenalectomy hyperkalemia. In the present study, we found that impaired pre-existing renal function and longer duration of hypertension were the two most significant independent predictors. It is well known that renal K+ secretion is usually well preserved in the early stages of kidney injury. However, patients with a late stage of chronic kidney disease (stages III–V) have the higher risk of developing hyperkalemia in the presence of post-adrenalectomy hypoaldosteronism state. Long-term exposure to hyperaldosteronism Table 4 Categories and number of antihypertensive drugs in patients with APA. Parameters

Normokalemia (n = 39)

Hyperkalemia (n = 16)

p

Preoperative ACEI/ARB β-Blocker CCB Non-spironolactone diuretics One drug Two drugs Three drugs Four drugs

25 (64%) 23 (59%) 36 (92%) 7 (18%) 7 (18%) 14 (36%) 16 (41%) 2 (5%)

11 (69%) 8 (50%) 15 (94%) 3 (19%) 2 (13%) 7 (44%) 7 (44%) 0 (0%)

NS NS NS NS NS NS NS NS

Postoperative ACEI/ARB β-Blocker CCB One drug Two drugs Three drugs Total antihypertensive therapy

7 (18%) 4 (10%) 8 (21%) 4 (10%) 3 (8%) 3 (8%) 10 (26%)

4 (25%) 5 (31%) 6 (38%) 3 (19%) 4 (25%) 1 (6%) 9 (56%)

causes endothelial dysfunction and hypertension, which lead to progressive renal vascular damage [23–25]. Chronic hypokalemia itself can cause functional and structural defects in the kidneys, such as tubular vacuolization, cyst formation, interstitial inflammation, impaired urine concentration ability, and gradual loss of renal function [26,27]. Some of the other associated risk factors for postadrenalectomy hyperkalemia, including older age and increased likelihood of residual hypertension, may be markers of pre-adrenalectomy chronic kidney disease [20,28–30]. Longer duration of hypertension is another important predictor of post-adrenalectomy hyperkalemia. It may indicate prolonged suppression of the contralateral adrenal gland and thus delayed recovery of adrenal function. It has been previously reported that plasma renin and aldosterone levels usually normalize in the first month after adrenalectomy in patients with APA [8]. Some studies have suggested that prolonged inhibition of the juxtaglomerular apparatus or reduced contralateral adrenal mass may be the underlying mechanism of prolonged postoperative hypoaldosteronism [31,32]. Sustained hypokalemia before adrenalectomy may also suppress the synthesis of aldosterone in the zona glomerulosa and prolong the duration of hypoaldosteronism [33]. There are some limitations to this study. First, the main limitation is the retrospective nature. The blood sampling for electrolytes and hormone profiles could not be standardized and the follow-up periods for patients were not the same. Second, information on dietary K+ intake, which influences serum K+ level, was not available. Third, urine tests for microalbuminuria, as an index of early renal damage, and transtubular K+ gradient (TTKG), as an indicator of renal K+ excretion, were not available. However, these are not of major clinical importance because microalbuminuria is frequently present in patients with secondary hypertension and hyperkalemia in the absence of K+ shift out of cells always indicates a renal tubular defect.

5. Conclusions NS NS NS NS NS NS 0.03

APA, aldosterone-producing adenoma; ACEI/ARB, angiotensin converting enzyme inhibitor/angiotensin receptor blocker; CCB, calcium channel blocker.

Post-adrenalectomy hyperkalemia is not rare in patients with APA. The majority of hyperkalemic patients had impaired renal function and prolonged duration of hypertension. Serum K+ must be cautiously monitored in these high risk patients after adrenalectomy to avoid potentially dangerous complications. Nevertheless, a prospective study in patients with APA is still warranted to clarify the incidence and natural course of post-adrenalectomy hyperkalemia.

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