Abstract
Objective
In primary aldosteronism (PA), renal impairment has been identified as an important comorbidity. Excess cortisol production also may lead to renal damage; thus, concomitant mild autonomous cortisol secretion (MACS) may predispose PA patients to renal disorders. However, there is limited evidence to support this claim. Therefore, this study aimed to determine whether the concurrence of MACS and PA increases the risk of renal complications.
Design
This study is a retrospective cross-sectional study.
Methods
A total of 1310 patients with PA were stratified into two groups according to 1 mg dexamethasone suppression test (DST) results (cut-off post-DST serum cortisol 1.8 µg/dL): MACS (n = 340) and non-MACS (n = 970). The prevalence of renal complications was compared between the group. We also performed multiple logistic regression analysis to determine factors that increase the risk for renal complications.
Results
The prevalence of lowered estimated glomerular filtration rate (eGFR) and proteinuria was nearly twice higher in the MACS group than in the non-MACS group. Not only plasma aldosterone concentration (PAC) but also the presence of MACS was selected as independent factors that were associated with the two renal outcomes. The risk of lower eGFR or proteinuria in patients who had MACS and higher levels PAC was several folds higher than in those who had an absence of MACS and lower levels of PAC.
Conclusions
MACS is an independent risk factor for renal complications in patients with PA, and MACS concomitant with higher aldosterone secretion in PA patients causes an increase in the risk of developing renal complications.
Introduction
Primary aldosteronism (PA) is more common than previously believed and accounts for 3–10% of all cases of hypertension (1, 2, 3). With comparable blood pressure levels, PA-induced hypertension is associated with a higher risk of cardiovascular events (CVE) than essential hypertension (4, 5). Renal impairment is also important comorbidity in PA (6, 7, 8) as elevated aldosterone levels can lead to renal perivascular fibrosis, glomerulosclerosis, and interstitial fibrosis by promoting inflammation, fibrosis, mesangial cell proliferation, and podocyte injury in the kidney (9, 10). Early stage PA is associated with glomerular hyperfiltration, and PA progression is associated with proteinuria and lower estimated glomerular filtration rates (eGFR) (11). Patients with PA showed a higher prevalence of chronic kidney diseases at diagnosis than patients with essential hypertension, and the risk of disease progression was significantly greater in PA patients (8, 12). Similar to aldosterone excess, cortisol excess, or hypercortisolism, may lead to renal damage even when the over-secretion is subtle (13). For example, two recent reports have indicated that patients with mild autonomous cortisol secretion (MACS) had a higher prevalence of renal dysfunction than in those without MACS (14, 15). In addition, numerous studies have shown that MACS is associated with increased cardiometabolic disorders (e.g. obesity, dyslipidemia, and hypertension) which are well known as risk factors for chronic renal disease (16, 17). Thus, concomitant MACS is likely to predispose patients with PA to renal disorders. Many factors such as baseline plasma aldosterone concentration (PAC), serum potassium, diabetes mellitus (DM), hypertension, and male sex have been reported as independent predictors of lower eGFR in patients with PA (8, 18, 19, 20). However, there is little evidence showing that the presence of MACS in PA patients is involved in renal dysfunction. The aim of this study was to determine whether the concurrence of MACS and PA increases the risk of renal complications.
Methods
Study design and participants
This observational study was conducted as part of the Japan Primary Aldosteronism Study (JPAS) and the Japan Rare/Intractable Adrenal Diseases Study (JRAS), which involved 41 participating centers. We obtained data on patients who were diagnosed with PA based on the clinical guidelines in Japan and underwent adrenal venous sampling (AVS) between January 2006 and March 2019 (21, 22). The PA subtype was diagnosed based on AVS with adrenocorticotropic hormone (ACTH, cosyntropin) stimulation as previously described (23). Briefly, AVS was considered successful when the selectivity index (the ratio of the cortisol concentration in the adrenal vein to that in the inferior vena cava) was >5 on ACTH stimulation. Unilateral PA was diagnosed when the lateralization index (i.e. the aldosterone-to-cortisol ratio on the dominant side divided by that on the nondominant side) (24, 25) was >4 on ACTH stimulation. System construction, data security, and maintenance of the registration data were outsourced to the EPA Corporation (Tokyo, Japan). The datasets generated and analyzed during the present study are available from the corresponding authors on request.
MACS was defined as the failure to suppress serum cortisol concentration to <1.8 µg/dL after the standard overnight 1 mg dexamethasone suppression test (DST) (26, 27). In addition, we took plasma ACTH levels before and after the DST into consideration to exclude MACS. If serum cortisol after DST was ≥1.8 µg/dL with baseline plasma ACTH level ≥ 10 pg/mL, MACS was diagnosed based on the post-DST plasma ACTH level. Patients’ MACS status was categorized as indeterminate if the post-DST serum cortisol and plasma ACTH levels were ≥1.8 µg/dL and ≥10 pg/mL, respectively, thereby minimizing the risk of false-positive results (28, 29). In this study, when plasma ACTH level at baseline was <10 pg/mL, plasma ACTH level after DST was always <10 pg/mL.
From among 3393 patients with PA in the original JPAS/JRAS database, 1903 patients who underwent a 1-mg DST were extracted. Of those 1903 subjects, the following were excluded from our study: those with incomplete data sets on cortisol and/or ACTH before and after the DST (n = 551) and those with indeterminant results on the DST (n = 42). Thus, the final study cohort comprised 1310 patients confirmed to have PA with or without MACS (Fig. 1).
Flow diagram of patient enrollment. ACTH, adrenocorticotropic hormone; DST, dexamethasone suppression test; MACS, mild autonomous cortisol secretion; n, number of patients.
Citation: European Journal of Endocrinology 186, 6; 10.1530/EJE-21-1131
Flow diagram of patient enrollment. ACTH, adrenocorticotropic hormone; DST, dexamethasone suppression test; MACS, mild autonomous cortisol secretion; n, number of patients.
Citation: European Journal of Endocrinology 186, 6; 10.1530/EJE-21-1131
Flow diagram of patient enrollment. ACTH, adrenocorticotropic hormone; DST, dexamethasone suppression test; MACS, mild autonomous cortisol secretion; n, number of patients.
Citation: European Journal of Endocrinology 186, 6; 10.1530/EJE-21-1131
Measurements
The following data were collected: patient demographics, including age, sex, BMI, systolic blood pressure (SBP), diastolic blood pressure (DBP), and duration of hypertension at the time of diagnosis; biochemical and hormonal profiles, including serum creatinine concentration, eGFR, serum potassium, PAC, plasma renin activity (PRA), aldosterone-to-renin ratio (ARR), and serum cortisol or plasma ACTH concentrations before and after the 1-mg DST; presence of cardiovascular risk factors, including obesity, DM, or dyslipidemia; AVS findings; presence of an adrenal tumor on CT scanning; and medical history, including the defined daily dose (DDD) (30) of antihypertensive drugs. Hypokalemia was thought to be present if the serum potassium levels were ≤3.5 mmol/L despite potassium supplementation. Lower eGFR was defined as an eGFR < 60 mL/min/1.73 m2. Proteinuria was graded as 1+, 2+, or 3+ on the dipstick test. Renal impairment was diagnosed based on the presence of proteinuria or lower eGFR. Thus, we assessed the influence of lower eGFR or proteinuria on MACS. An adrenal tumor was defined as a space-occupying lesion ≥1.0 cm within the adrenal gland observable on CT examination (27). The CVE prevalence was determined based on cerebral infarcts and cerebral hemorrhage, confirmed by a neurologist; myocardial infarcts or angina pectoris, confirmed by a cardiologist; heart failure requiring hospitalization; and arrhythmias (atrial fibrillation or ventricular arrhythmias).
The eGFR was calculated using the equation established for the Japanese population by the Japanese Society of Nephrology: eGFR (mL/min/1.73 m2) = 194 × serum creatinine−1.094 × age−0.287 (× 0.739 for female patients) (31). Obesity was defined as BMI > 25 kg/m2as specified by the Japan Society for the Study of Obesity (32). DM was defined as the need for antihyperglycemic medications or a DM diagnosis according to the Japan Diabetes Association guidelines (33). Dyslipidemia was defined as low-density lipoprotein cholesterol levels ≥3.6 mmol/L or high-density lipoprotein cholesterol levels <1.0 mmol/L; triglyceride levels ≥ 1.7 mmol/L; or current antilipemic pharmacotherapy (34).
Assay methods
The assay methods in this study are available in the Supplementary data of this article (see section on supplementary materials given at the end of this article).
Statistical analysis
The statistical analysis in this study is available in the Supplementary data of this article.
Ethics
The ethical approval for this study is available in the Supplementary data of this article.
Results
Study population and baseline clinical characteristics
A total of 1310 eligible PA patients with DST results were included in this study and stratified into two groups based on the presence or absence of MACS: a MACS group (n = 340, 26.0%) and a non-MACS group (n = 970, 74.0%) (Fig. 1). Compared with the non-MACS group, the MACS group included more older patients with longer durations of hypertension and a higher prevalence of DM and dyslipidemia. The prevalence of obesity in the MACS group was lower than that in the non-MACS group (Table 1). Furthermore, there were significant intergroup differences in ARR, PAC, and prevalence of hypokalemia, adrenal tumor, and unilateral subtype. The tumor diameter in the MACS group was larger than that in the non-MACS group (18.0 (14.0, 23.0) vs 14.0 (11.0, 18.0), P < 0.001). As expected, in the MACS group, the pre- and post-DST serum cortisol concentrations were higher, and the baseline plasma ACTH concentrations were lower in the MACS group than in the non-MACS group. Blood pressure did not differ significantly between the two groups, although the DDD of antihypertensive drugs in the MACS group was higher than that in the non-MACS group. The overall prevalence of CVE did not significantly differ between the two groups.
Clinical and biochemical characteristics of primary aldosteronism patients with and without MACS. Values are presented as n (%) or as median (IQR).
| Characteristics | MACS | Non-MACS | P value | ||
|---|---|---|---|---|---|
| n | Values | n | Values | ||
| n (%) | 340 (26) | 970 (74.0) | |||
| Age (years) | 340 | 58.0 (46.0, 65.0) | 969 | 52.0 (44.0, 62.0) | <0.001 |
| Sex, female (%) | 340 | 186 (54.7) | 970 | 495 (51.0) | 0.256 |
| BMI (kg/m2) | 339 | 23.6 (21.1, 26.8) | 967 | 24.7 (22.2, 27.6) | <0.001 |
| Duration of hypertension (years) | 319 | 10.0 (3.0, 17.0) | 901 | 5.0 (1.5, 12.0) | <0.001 |
| SBP (mmHg) | 338 | 138.0 (127.8, 151.3) | 962 | 138.0 (128.0, 150.0) | 0.894 |
| DBP (mmHg) | 338 | 85.0 (78.8, 93.0) | 962 | 86.5 (78.8, 96.0) | 0.211 |
| DDD of antihypertensive drugs | 338 | 1.5 (1.0, 2.5) | 964 | 1.3 (0.7, 2.0) | <0.001 |
| Creatinine (mg/dL) | 340 | 0.7 (0.6, 0.9) | 965 | 0.7 (0.6, 0.9) | 0.100 |
| eGFR (mL/min/1.73 m2) | 340 | 75.9 (62.1, 87.6) | 966 | 78.4 (67.1, 91.6) | 0.001 |
| Serum potassium (mEq/L) | 340 | 3.7 (3.3, 4.1) | 967 | 3.8 (3.4, 4.0) | 0.259 |
| Hypokalemia (%) | 340 | 167 (49.1) | 967 | 398 (41.2) | 0.013 |
| Cortisol (μg/dL) | 340 | 12.5 (9.3, 16.6) | 970 | 10.9 (7.9, 14.3) | <0.001 |
| Cortisol post-1-mg DST (μg/dL) | 340 | 2.5 (2.0, 3.9) | 970 | 1.0 (0.8, 1.3) | <0.001 |
| ACTH (pg/mL) | 340 | 16.3 (9.4, 27.8) | 970 | 21.0 (13.3, 32.2) | <0.001 |
| ARR (ng/dL/ng/mL/h) | 339 | 60.0 (37.3, 134.7) | 966 | 56.0 (31.2, 113.9) | 0.031 |
| PAC (ng/dL) | 339 | 21.3 (14.4, 37.3) | 967 | 19.1 (13.4, 30.0) | <0.001 |
| PRA (ng/mL/h) | 306 | 0.3 (0.2, 0.5) | 924 | 0.3 (0.2, 0.5) | 0.997 |
| Unilateral hyperaldosteronism (%) | 302 | 127 (42.1) | 904 | 285 (31.5) | 0.001 |
| Adrenal tumor (%) | 335 | (243 (72.5) | 961 | 475 (49.4) | <0.001 |
| Diameter of adrenal tumor | 243 | 18.0 (14.0, 23.0) | 475 | 14.0 (11.0, 18.0) | <0.001 |
| Cardiovascular events (%) | 340 | 39 (11.5) | 970 | 81 (8.4) | 0.087 |
| Diabetes mellitus (%) | 340 | 68 (20.0) | 970 | 142 (14.6) | 0.025 |
| Dyslipidemia (%) | 340 | 113 (33.2) | 970 | 257 (26.5) | 0.021 |
| Obesity (%) | 339 | 130 (38.3) | 967 | 461 (47.7) | 0.004 |
Regarding renal complications, lower eGFR was reported in 201 (15.4%) of 1306 subjects, and proteinuria was reported in 159 (13.0%) of 1227 subjects (Table 2). The prevalence of the two renal outcomes in the MACS group was nearly two times higher than those in the non-MACS group (lower eGFR: OR: 2.040, 95% CI: 1.488–2.798, P < 0.001; proteinuria: OR: 1.881, 95% CI: 1.324–2.672, P < 0.001)).
Comparison of renal complications between the MACS and non-MACS groups.
| Complications | Total patients | MACS | Non-MACS | Odds ratio | 95% CI | P value |
|---|---|---|---|---|---|---|
| n (%) | 1310 | 340 (26.0) | 970 (74.0) | |||
| Lower eGFR (%) | 15.4 (201/1306) | 22.9 (78/340) | 12.7 (123/966) | 2.040 | 1.488–2.798 | <0.001 |
| Proteinuria (%) | 13.0 (159/1227) | 18.8 (59/314) | 11.0 (100/913) | 1.881 | 1.324–2.672 | <0.001 |
Factors associated with the prevalence of lower eGFR
Table 3 shows the differences between PA patients in the lower eGFR and the non-lower eGFR groups. Compared with the non-lower eGFR group, the lower eGFR group included more older men who had a longer duration of hypertension; received more intensive antihypertensive treatments; and had a higher prevalence of proteinuria, hypokalemia, adrenal tumor, DM, dyslipidemia, and CVE. SBP and DBP were similar between the two groups. The serum cortisol concentration before and after a DST and the prevalence of MACS were significantly higher in patients with lower eGFR than in those without lower eGFR. Plasma ACTH levels at baseline in the lower eGFR group tended to be higher than the levels in the non-lower eGFR group, but the difference was not significant. PA-related indicators (i.e. ARR, PRA, and PA subtype; except PAC) and BMI were comparable between the two groups.
Clinical and biochemical characteristics of primary aldosteronism patients with and without lower eGFR. Values are presented as n (%)or as median (IQR).
| Characteristics | Lower eGFR | Non-Lower eGFR | P value | ||
|---|---|---|---|---|---|
| n | Values | n | Values | ||
| n (%) | 201 (15.4) | 1105 (84.6) | |||
| Age (years) | 201 | 62.0 (54.0, 67.0) | 1105 | 52.0 (44.0, 61.0) | <0.001 |
| Sex, female (%) | 201 | 77 (38.3) | 1105 | 602 (54.5) | <0.001 |
| Body mass index (kg/m2) | 201 | 24.7 (22.2, 27.4) | 1101 | 24.4 (21.8, 27.3) | 0.313 |
| Duration of hypertension (years) | 188 | 11.0 (5.0, 21.8) | 1028 | 5.0 (1.4, 11.0) | <0.001 |
| SBP (mmHg) | 199 | 140.0 (127.0, 154.0) | 1098 | 138.0 (128.0, 150.0) | 0.557 |
| DBP (mmHg) | 199 | 85.0 (76.0, 94.0) | 1098 | 87.0 (79.0, 95.0) | 0.059 |
| DDD of antihypertensive drugs | 199 | 2.0 (1.0, 2.7) | 1099 | 1.3 (0.7, 2.0) | <0.001 |
| Creatinine (mg/dL) | 200 | 1.1 (0.9, 1.2) | 1105 | 0.7 (0.6, 0.8) | <0.001 |
| eGFR (mL/min/1.73 m2) | 201 | 53.0 (47.3, 57.0) | 1105 | 80.6 (71.6, 92.7) | <0.001 |
| Proteinuria (%) | 192 | 47(24.5) | 1034 | 112 (10.8) | <0.001 |
| Serum potassium (mEq/L) | 201 | 3.7 (3.3, 4.1) | 1104 | 3.8 (3.4, 4.0) | 0.817 |
| Hypokalemia (%) | 201 | 100 (49.8) | 1104 | 463 (41.9) | 0.044 |
| Cortisol (μg/dL) | 201 | 11.8 (9.4, 15.3) | 1105 | 11.1 (8.0, 14.7) | 0.010 |
| Cortisol post-1-mg DST (μg/dL) | 201 | 1.5 (1.0, 2.2) | 1105 | 1.1 (0.8, 1.7) | <0.001 |
| ACTH (pg/mL) | 201 | 21.9 (13.1, 34.6) | 1105 | 19.5 (12.0, 30.2) | 0.052 |
| MACS | 201 | 78 (38.8%) | 1105 | 262 (23.7%) | <0.001 |
| ARR (ng/dL/ng/mL/h) | 201 | 63.2 (33.0, 163.5) | 1101 | 56.0 (32.5, 115.5) | 0.060 |
| PAC (ng/dL) | 201 | 21.8 (14.7, 39.5) | 1102 | 19.2 (13.4, 31.3) | 0.010 |
| PRA (ng/mL/h) | 184 | 0.3 (0.2, 0.5) | 1043 | 0.3 (0.2, 0.5) | 0.344 |
| Unilateral hyperaldosteronism (%) | 182 | 72 (39.6) | 1020 | 339 (33.2) | 0.107 |
| Adrenal tumor (%) | 199 | 127 (63.8) | 1093 | 590 (54.0) | 0.011 |
| Cardiovascular events (%) | 201 | 40 (19.9) | 1105 | 80 (7.2) | <0.001 |
| Diabetes mellitus (%) | 201 | 49 (24.4) | 1105 | 160 (14.5) | 0.001 |
| Dyslipidemia (%) | 201 | 72 (35.8) | 1105 | 298 (27.0) | 0.013 |
| Obesity (%) | 201 | 96(47.8) | 1101 | 493 (44.8) | 0.442 |
We next determined factors associated with the prevalence of lower eGFR using a multiple logistic regression analysis with a backward stepwise selection procedure (Table 4). Age, sex, CVE, log PAC, and the presence of MACS (Model 1) or log cortisol after a DST (Model 2) linearly influenced the odds of developing lower eGFR.
Factors associated with the prevalence of lower estimated glomerular filtration.
| Factors | Model 1 | Model 2 | ||
|---|---|---|---|---|
| OR (95% CI) | P value | OR (95% CI) | P value | |
| Age | 1.075 (1.057–1.094) | <0.001 | 1.074 (1.056–1.092) | <0.001 |
| Female | 0.506 (0.359–0.714) | <0.001 | 0.505 (0.358–0.713) | <0.001 |
| Log PAC | 1.709 (1.322–2.210) | <0.001 | 1.701 (1.318–2.196) | <0.001 |
| Cardiovascular events | 2.123 (1.340–3.364) | 0.001 | 2.145 (1.354–3.397) | 0.001 |
| MACS | 1.537 (1.075–2.197) | 0.018 | ||
| Log post-1-mg DST cortisol | 1.464 (1.131–1.896) | 0.004 | ||
Factors associated with the prevalence of proteinuria
Table 5 presents the differences between PA patients in the proteinuria group and non-proteinuria group. Substantial differences were observed between the two groups with respect to the proportion of women; BMI; duration of hypertension; blood pressure; DDDs of antihypertensive drugs; serum creatine and eGFR levels; serum potassium levels; and the prevalence of hypokalemia, DM, obesity, CVE, unilateral PA, and adrenal tumor. Age, the prevalence of dyslipidemia, baseline serum cortisol concentration, plasma ACTH level, and PRA did not differ between the two groups. However, serum cortisol concentrations after a DST and the prevalence of MACS, PAC, and ARR in the proteinuria group were significantly higher than those in the non-proteinuria group.
Clinical and biochemical characteristics of primary aldosteronism patients with and without proteinuria.
| Characteristics | Proteinuria | Non-Proteinuria | P value | ||
|---|---|---|---|---|---|
| n | Values | n | Values | ||
| n (%) | 159 (13.0) | 1068 (87.0) | |||
| Age (years) | 159 | 55.0 (47.0, 64.0) | 1068 | 53.0 (45.0, 63.0) | 0.097 |
| Sex, female (%) | 159 | 52 (32.7) | 1068 | 580 (54.3) | <0.001 |
| BMI (kg/m2) | 159 | 25.9 (22.5, 29.0) | 1065 | 24.3 (21.8, 27.2) | <0.001 |
| Duration of hypertension (years) | 151 | 10.0 (6.0, 20.0) | 993 | 5.0 (1.8, 12.0) | <0.001 |
| SBP (mmHg) | 158 | 142.0 (134.0, 156.0) | 1060 | 138.0 (127.0, 149.0) | <0.001 |
| DBP (mmHg) | 158 | 90.0 (80.0, 98.0) | 1060 | 86.0 (78.0, 94.8) | 0.001 |
| DDD of antihypertensive drugs | 156 | 2.0 (1.3, 3.0) | 1064 | 1.3 (0.7, 2.0) | <0.001 |
| Creatinine (mg/dL) | 159 | 0.9 (0.6, 1.0) | 1066 | 0.7 (0.6, 0.8) | <0.001 |
| eGFR (mL/min/1.73 m2) | 159 | 70.0 (56.8, 85.0) | 1067 | 78.3 (67.1, 91.6) | <0.001 |
| Serum potassium (mEq/L) | 159 | 3.5 (3.1, 3.8) | 1067 | 3.8 (3.4, 4.1) | <0.001 |
| Hypokalemia (%) | 159 | 111 (69.8) | 1067 | 424 (39.7) | <0.001 |
| Cortisol (μg/dL) | 159 | 11.7 (8.8, 14.7) | 1068 | 11.2 (8.2, 15) | 0.273 |
| Cortisol post-1-mg DST (μg/dL) | 159 | 1.4 (1.0, 2.0) | 1068 | 1.1 (0.8, 1.7) | <0.001 |
| ACTH (pg/mL) | 159 | 20.5 (13.4, 33.1) | 1068 | 20.0 (12.0, 30.5) | 0.229 |
| MACS (%) | 159 | 59 (37.1) | 1068 | 255 (23.9) | 0.001 |
| ARR (ng/dL/ng/mL/h) | 159 | 88.7 (45.0, 196.0) | 1064 | 53.6 (31.4, 112.6) | <0.001 |
| PAC (ng/dL) | 159 | 29.6 (19.6, 48.8) | 1065 | 18.8 (13.1, 29.9) | <0.001 |
| PRA (ng/mL/h) | 144 | 0.3 (0.2, 0.5) | 1009 | 0.3 (0.2, 0.5) | 0.895 |
| Unilateral hyperaldosteronism (%) | 151 | 88 (58.3) | 978 | 302 (30.9) | <0.001 |
| Adrenal tumor (%) | 158 | 111 (70.3) | 1057 | 563 (53.3) | <0.001 |
| Cardiovascular events (%) | 159 | 26 (16.4) | 1068 | 87 (8.1) | 0.002 |
| Diabetes mellitus (%) | 159 | 51 (32.1) | 1068 | 151 (14.1) | <0.001 |
| Dyslipidemia (%) | 159 | 56 (35.2) | 1068 | 296 (27.7) | 0.060 |
| Obesity (%) | 159 | 94 (59.1) | 1065 | 462 (43.4) | <0.001 |
A multiple logistic regression analysis with a backward stepwise selection procedure was performed to determine the factors associated with proteinuria (Table 6). Female sex, BMI, duration of hypertension, SBP, log PAC, the presence of hypokalemia and DM, and the presence of MACS (Model 1) or log cortisol after a DST (Model 2) were selected a significant factor that increased the odds of developing proteinuria.
Factors associated with the prevalence of proteinuria.
| Factors | Model 1 | Model 2 | ||
|---|---|---|---|---|
| OR (95% CI) | P value | OR (95% CI) | P value | |
| Female | 0.557 (0.371–0.836) | 0.005 | 0.560 (0.373–0.840) | 0.005 |
| BMI | 1.102 (1.052–1.154) | <0.001 | 1.101 (1.051–1.154) | <0.001 |
| Duration of hypertension | 1.029 (1.011–1.048) | 0.002 | 1.029 (1.01–1.047) | 0.002 |
| Systolic blood pressure | 1.015 (1.004–1.026) | 0.007 | 1.015 (1.004–1.026) | 0.007 |
| Hypokalemia | 2.121 (1.347–3.342) | 0.001 | 2.099 (1.332–3.305) | 0.001 |
| Log PAC | 2.366 (1.701–3.292) | <0.001 | 2.391 (1.722–3.321) | <0.001 |
| Diabetes mellitus | 2.152 (1.374–3.370) | 0.001 | 2.167 (1.385–3.392) | 0.001 |
| MACS | 1.555 (1.028–2.351) | 0.036 | ||
| Log post-1-mg DST cortisol | 1.361 (1.011–1.831) | 0.042 | ||
The effects of cortisol secretion on renal complications in patients with PA
To further evaluate the effects of cortisol secretion on renal complications in patients with PA, the participants were reclassified into four groups based on quartiles of the serum cortisol concentrations after a DST. The rates of prevalence of both lower eGFR and proteinuria increased with increases in post-DST serum cortisol levels (P < 0.001 in both cases; Fig. 2).
Prevalence of lower estimated glomerular filtration rate (eGFR) (left) and proteinuria (right) in patients with primary aldosteronism (PA) grouped according to quartiles of the serum cortisol concentration after the 1 mg dexamethasone suppression test. P < 0.05 was considered significant (the linear-by-linear association test was used to assess trends). DST, dexamethasone suppression test; n, number of patients.
Citation: European Journal of Endocrinology 186, 6; 10.1530/EJE-21-1131
Prevalence of lower estimated glomerular filtration rate (eGFR) (left) and proteinuria (right) in patients with primary aldosteronism (PA) grouped according to quartiles of the serum cortisol concentration after the 1 mg dexamethasone suppression test. P < 0.05 was considered significant (the linear-by-linear association test was used to assess trends). DST, dexamethasone suppression test; n, number of patients.
Citation: European Journal of Endocrinology 186, 6; 10.1530/EJE-21-1131
Prevalence of lower estimated glomerular filtration rate (eGFR) (left) and proteinuria (right) in patients with primary aldosteronism (PA) grouped according to quartiles of the serum cortisol concentration after the 1 mg dexamethasone suppression test. P < 0.05 was considered significant (the linear-by-linear association test was used to assess trends). DST, dexamethasone suppression test; n, number of patients.
Citation: European Journal of Endocrinology 186, 6; 10.1530/EJE-21-1131
Because the presence of MACS as well as plasma aldosterone levels was likely to affect renal outcomes, patients were stratified into four groups according to the presence or absence of MACS and the median PAC (19.6 ng/dL). The results are shown in Fig. 3. The risk of lower eGFR (left) and proteinuria (right) in patients who had MACS and higher levels of PAC was nearly three-fold (OR: 2.764, 95% CI: 1.826–4.185, P < 0.001) and six-fold (OR: 5.655, 95% CI: 3.472–9.211, P < 0.001) higher than those who had an absence of MACS and lower levels of PAC, respectively.
Changes in the prevalence of lower estimated glomerular filtration rate (eGFR) (left) and proteinuria (right) in patients with primary aldosteronism (PA) stratified into four groups according to the presence or absence of mild autonomous cortisol secretion (MACS) and the median plasma aldosterone concentration (PAC, 19.6 ng/dL). The risk of lower eGFR in patients who had MACS and higher levels of PAC was increased nearly three-fold (OR: 2.764, 95% CI: 1.826–4.185, P < 0.001). The risk of proteinuria in patients who had MACS and higher levels of PAC was approximately six-fold (OR: 5.655, 95% CI: 3.472–9.211, P < 0.001) higher than in those who had an absence of MACS and lower levels of PAC. MACS, mild autonomous cortisol secretion; n, number of patients; PAC, plasma aldosterone concentration.
Citation: European Journal of Endocrinology 186, 6; 10.1530/EJE-21-1131
Changes in the prevalence of lower estimated glomerular filtration rate (eGFR) (left) and proteinuria (right) in patients with primary aldosteronism (PA) stratified into four groups according to the presence or absence of mild autonomous cortisol secretion (MACS) and the median plasma aldosterone concentration (PAC, 19.6 ng/dL). The risk of lower eGFR in patients who had MACS and higher levels of PAC was increased nearly three-fold (OR: 2.764, 95% CI: 1.826–4.185, P < 0.001). The risk of proteinuria in patients who had MACS and higher levels of PAC was approximately six-fold (OR: 5.655, 95% CI: 3.472–9.211, P < 0.001) higher than in those who had an absence of MACS and lower levels of PAC. MACS, mild autonomous cortisol secretion; n, number of patients; PAC, plasma aldosterone concentration.
Citation: European Journal of Endocrinology 186, 6; 10.1530/EJE-21-1131
Changes in the prevalence of lower estimated glomerular filtration rate (eGFR) (left) and proteinuria (right) in patients with primary aldosteronism (PA) stratified into four groups according to the presence or absence of mild autonomous cortisol secretion (MACS) and the median plasma aldosterone concentration (PAC, 19.6 ng/dL). The risk of lower eGFR in patients who had MACS and higher levels of PAC was increased nearly three-fold (OR: 2.764, 95% CI: 1.826–4.185, P < 0.001). The risk of proteinuria in patients who had MACS and higher levels of PAC was approximately six-fold (OR: 5.655, 95% CI: 3.472–9.211, P < 0.001) higher than in those who had an absence of MACS and lower levels of PAC. MACS, mild autonomous cortisol secretion; n, number of patients; PAC, plasma aldosterone concentration.
Citation: European Journal of Endocrinology 186, 6; 10.1530/EJE-21-1131
The effect of age on renal complications in patients with PA
Age in the MACS group differed significantly from that in the non-MACS group. eGFR is directly related to age. Thus, we performed age-matched comparison of clinical and biochemical characteristics between the MACS (n = 331) and non-MACS groups (n = 331) (Supplementary Table 1). Median age in both groups was 58.0 (46.0, 65.0) years old. No differences in eGFR, serum cortisol levels at baseline and the rate of unilateral PA, dyslipidemia, and obesity were noted between the two groups after age matching. However, differences in the risk of lower eGFR and proteinuria between the two groups remained after matching for age (lower eGFR, OR: 1.539, 95% CI: 1.039–2.281, P = 0.032; proteinuria, OR: 2.763, 95% CI: 1.680–4.545, P < 0.001)] (Table 7).
Comparison of renal complications between the MACS and non-MACS groups after age matching.
| Complications | Total patients | MACS | Non-MACS | Odds ratio | 95% CI | P value |
|---|---|---|---|---|---|---|
| Patients, n | 662 | 331 | 331 | |||
| Lower eGFR, % | 19.1 (126/661) | 22.4 (74/331) | 15.8 (52/330) | 1.539 | 1.039–2.281 | 0.032 |
| Proteinuria, % | 13.6 (84/618) | 19.3 (59/305) | 8.0 (25/313) | 2.763 | 1.680–4.545 | <0.001 |
Discussion
In the present study, we examined whether the concurrence of MACS and PA increases the risk of renal complications. We have demonstrated that the prevalence of renal impairment in PA patients with MACS is nearly double that found in those without MACS. Furthermore, we have clearly demonstrated that MACS itself is an independent risk factor for renal complications in patients with PA and increased PAC and further increased the risk of developing renal injuries.
Chronic exposure to aldosterone excess is well established to cause a deterioration in renal function (35). Early stage PA is associated with glomerular hyperfiltration, and disease progression is associated with proteinuria and/or lower eGFR (11). Similar to aldosterone, cortisol excess may lead to renal complications. A decreased eGFR, glomerular sclerosis, and proteinuria were observed in some patients with overt Cushing’s syndrome (36, 37). Recently, Kjellbom et al. investigated the prevalence of lower eGFR in 1048 patients with adrenal incidentaloma. The frequency of lower eGFR in patients with or without MACS was 21.7% (103/473) and 8.0% (46/575), respectively (15). Singh et al. also have shown that patients with MACS (n = 168) had a higher prevalence of chronic kidney disease than patients with non-functioning adrenal tumor (n = 275) (25.3% vs 16.9%, respectively) (14). According to these results, PA concomitant with MACS may worsen renal outcomes. However, more investigation is necessary to confirm this finding.
To the best of our knowledge, this is the first report to evaluate the impact of MACS on renal impairment in patients with PA. In this study, the prevalence of lower eGFR and proteinuria was nearly two times higher in the MACS group than in the non-MACS group (Table 2). In addition, the prevalence of MACS was higher in the lower eGFR group than in the non-lower eGFR group (Table 3). Similar results were obtained from the comparison between the proteinuria group and the non-proteinuria group (Table 5). Moreover, we found that the prevalence of the two renal complications rose with increases in cortisol secretion (Fig. 2). Thus, MACS in PA patients appears to have an additional harmful impact on renal function.
Many factors such as hypertension, DM, aging, and male sex may contribute to the development of renal complications in PA (38, 39, 40). Several reports (8, 18, 19) including our study (20) previously showed that renal impairment in PA patients without MACS was associated with PAC. In the current study, not only PAC but also the presence of MACS and the serum cortisol levels after a DST were selected as independent significant variables that were associated with the prevalence of lower eGFR or proteinuria (Table 3). Furthermore, the risks of lower eGFR or proteinuria in patients who had MACS and higher PAC were several times higher than in those who had lower PAC and an absence of MACS (Fig. 3). Therefore, subtle hypercortisolism in the presence of higher aldosterone secretion could further negatively impact the renal function in PA. Recently, Nakamura et al. longitudinally examined pre- and post-adrenalectomy renal function in patients with adrenal Cushing’s syndrome and found a persistent but not progressive fall in eGFR after adrenalectomy (13). Because the postoperative trends in eGFR were similar in patients with PA, they suggested that the mineralocorticoid actions of cortisol may influence renal function in Cushing’s syndrome. Similarly, subtle hypercortisolism may lead to further activation of mineralocorticoid receptors in patients with PA and MACS.
Another possible explanation for these results is that MACS may indirectly lead to the worsening of eGFR and/or proteinuria via hypertension, DM, obesity, and CVE, which are well established as frequent comorbidities in MACS (16, 41, 42). In addition, age, male sex, and longstanding hypertension, which are well known as risk factors for chronic kidney disease (43), also exacerbate renal injuries. In this study, differences in the risk of renal outcomes between the MACS and non-MACS groups remained after matching for age (Table 7). However, the duration of hypertension in the MACS group remained 3 years longer than in the non-MACS group (Supplementary Table 1). As expected, longstanding hypertension was an important independent relevant factor that worsened renal complications in PA patients with MACS.
In concurrence with our results, several reports have shown a higher prevalence of CVE in PA patients with associated subclinical hypercortisolism (44, 45, 46). Cardiovascular diseases can aggravate eGFR decline (47). Hypertension, glucose intolerance, and overweight, which are common features in subtle hypercortisolism, are major contributors to the global burden of chronic kidney disease (43). Thus, it is easy to assume that an increase in complication rates of these disorders due to MACS would precipitate further renal dysfunction in PA. Unexpectedly, BMI and prevalence of obesity were lower in the MACS group than in the non-MACS group in our study. It is well known that overweight or obesity is more prevalent in patients with bilateral PA than in those with unilateral PA (48, 49, 50). Compared with the MACS group, the bilateral PA subtype was more frequently observed in the non-MACS group (57.9% vs 68.5%, P = 0.001). Furthermore, when patients were reclassified according to the PA subtype and BMI, the prevalence of obesity in patients with bilateral PA was higher than in those with unilateral PA (BMI: 24.7 (22.2, 27.8) kg/m2 vs 24.0 (21.5, 26.7) kg/m2, P = 0.001; obesity 48.8% vs 40.6%, P = 0.007). The higher rate of the bilateral PA subtype in the non-MACS group might explain the unexpected findings.
Finally, in agreement with previous reports (51, 52, 53), we demonstrated that MACS in PA patients was more common than expected (occurring in nearly a quarter of patients) and may cause increased renal and cardiovascular complications in PA patients. PAC, ARR, and the prevalence of adrenal tumors in the MACS group were higher than those in the non-MACS group. In addition, MACS concomitant with higher PAC in PA patients increased the risk of renal injuries. Furthermore, the tumor diameter in the MACS group was larger than that in the non-MACS group (Table 1). There was a significant but weak correlation between visible tumor diameter and serum cortisol levels after DST (n = 718, r = 0.317, P < 0.001). Given these findings, a DST should be recommended in patients with confirmed PA, particularly in those with higher aldosterone secretion or larger adrenal mass on imaging procedures.
It is important to note the following limitations of our study, most of which are attributable to its retrospective design. The first is the possibility of selection bias related to differences in patient referral practices and data handling among participating centers. In addition, there was an imbalance in the number of patients in the MACS group and the non-MACS group. Moreover, there is no predefined protocol for the diagnosis of MACS, which may have led to inconsistencies in diagnoses. The wide variability in the assays used is another limitation of this study. Furthermore, our study took place only in Japan and was conducted according to Japanese PA clinical guidelines.
However, one major strength of the current study is that it involved multiple centers and larger sample size than what has been previously reported.
In conclusion, this is the first report to show that MACS is an independent risk factor for renal complications in patients with PA. Notably, we have shown that MACS concomitant with higher aldosterone secretion in PA patients causes an increase in the risk of developing renal injuries. Careful examination for the presence of MACS may be needed in all patients with PA. Because subtle hypercortisolism is likely to lead to further activation of mineralocorticoid receptors in patients with PA and MACS, effort should be made to suppress receptor overactivation via adrenalectomy (for unilateral PA), sufficient dose of mineralocorticoid receptor antagonists, and strict salt restriction. In addition, more intensive management of each renal risk factor, such as plasma glucose, blood pressure, and body weight, is required for these patients.
Supplementary materials
This is linked to the online version of the paper at https://doi.org/10.1530/EJE-21-1131.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this study.
Funding
This study was conducted as a part of the Japan Primary Aldosteronism Study (JPAS) and Japan Rare/Intractable Adrenal Diseases Study (JRAS) and was supported by the Japan Agency for Medical Research and Development (AMED; grant numbers: JP17ek0109122 and JP19ek0109352) and the National Center for Global Health and Medicine, Japan (grant number: 27-1402, 30-1008). This work was also supported by the Ministry of Health, Labour and Welfare of Japan (grant number Nanbyo-Ippan-20FC1020).
Acknowledgement
The acknowledgement list of JPAS and JRAS groups is available in the supplementary data of this article.
References
- 1↑
Käyser SC, Dekkers T, Groenewoud HJ, van der Wilt GJ, Carel Bakx J, van der Wel MC, Hermus AR, Lenders JW, Deinum J. Study heterogeneity and estimation of prevalence of primary aldosteronism: a systematic review and meta-regression analysis. Journal of Clinical Endocrinology and Metabolism 2016 101 2826–2835. (https://doi.org/10.1210/jc.2016-1472)
- 2↑
Monticone S, Burrello J, Tizzani D, Bertello C, Viola A, Buffolo F, Gabetti L, Mengozzi G, Williams TA & Rabbia F et al.Prevalence and clinical manifestations of primary aldosteronism encountered in primary care practice. Journal of the American College of Cardiology 2017 69 1811–1820. (https://doi.org/10.1016/j.jacc.2017.01.052)
- 3↑
Vaidya A, Mulatero P, Baudrand R, Adler GK. The expanding spectrum of primary aldosteronism: implications for diagnosis, pathogenesis, and treatment. Endocrine Reviews 2018 39 1057–1088. (https://doi.org/10.1210/er.2018-00139)
- 4↑
Ohno Y, Sone M, Inagaki N, Yamasaki T, Ogawa O, Takeda Y, Kurihara I, Itoh H, Umakoshi H & Tsuiki M et al.Prevalence of cardiovascular disease and its risk factors in primary aldosteronism: a multicenter study in Japan. Hypertension 2018 71 530–537. (https://doi.org/10.1161/HYPERTENSIONAHA.117.10263)
- 5↑
Reincke M, Fischer E, Gerum S, Merkle K, Schulz S, Pallauf A, Quinkler M, Hanslik G, Lang K & Hahner S et al.Observational study mortality in treated primary aldosteronism: the German Conn’s registry. Hypertension 2012 60 618–624. (https://doi.org/10.1161/HYPERTENSIONAHA.112.197111)
- 6↑
Rossi GP, Bernini G, Desideri G, Fabris B, Ferri C, Giacchetti G, Letizia C, Maccario M, Mannelli M & Matterello MJ et al.Renal damage in primary aldosteronism: results of the PAPY Study. Hypertension 2006 48 232–238. (https://doi.org/10.1161/01.HYP.0000230444.01215.6a)
- 7↑
Iwakura Y, Morimoto R, Kudo M, Ono Y, Takase K, Seiji K, Arai Y, Nakamura Y, Sasano H & Ito S et al.Predictors of decreasing glomerular filtration rate and prevalence of chronic kidney disease after treatment of primary aldosteronism: renal outcome of 213 cases. Journal of Clinical Endocrinology and Metabolism 2014 99 1593–1598. (https://doi.org/10.1210/jc.2013-2180)
- 8↑
Reincke M, Rump LC, Quinkler M, Hahner S, Diederich S, Lorenz R, Seufert J, Schirpenbach C, Beuschlein F & Bidlingmaier M et al.Risk factors associated with a low glomerular filtration rate in primary aldosteronism. Journal of Clinical Endocrinology and Metabolism 2009 94 869–875. (https://doi.org/10.1210/jc.2008-1851)
- 9↑
Briet M, Schiffrin EL. Aldosterone: effects on the kidney and cardiovascular system. Nature Reviews: Nephrology 2010 6 261–273. (https://doi.org/10.1038/nrneph.2010.30)
- 10↑
Brown NJ Contribution of aldosterone to cardiovascular and renal inflammation and fibrosis. Nature Reviews: Nephrology 2013 9 459–469. (https://doi.org/10.1038/nrneph.2013.110)
- 11↑
Sechi LA, Novello M, Lapenna R, Baroselli S, Nadalini E, Colussi GL, Catena C. Long-term renal outcomes in patients with primary aldosteronism. JAMA 2006 295 2638–2645. (https://doi.org/10.1001/jama.295.22.2638)
- 12↑
Fernández-Argüeso M, Pascual-Corrales E, Bengoa Rojano N, García Cano A, Jiménez Mendiguchía L, Araujo-Castro M. Higher risk of chronic kidney disease and progressive kidney function impairment in primary aldosteronism than in essential hypertension. Case-control study. Endocrine 2021 73 439–446. (https://doi.org/10.1007/s12020-021-02704-2)
- 13↑
Nakamura Y, Yokoyama M, Yoshida S, Tanaka H, Kijima T, Ishioka J, Matsuoka Y, Saito K, Minami I & Yoshimoto T et al.Postoperative renal impairment and longitudinal change in renal function after adrenalectomy in patients with Cushing’s syndrome. International Journal of Urology 2020 27 395–400. (https://doi.org/10.1111/iju.14205)
- 14↑
Singh S, Atkinson EJ, Achenbach SJ, LeBrasseur N, Bancos I. Frailty in patients with mild autonomous cortisol secretion is higher than in patients with nonfunctioning adrenal tumors. Journal of Clinical Endocrinology and Metabolism 2020 105 105.e3307–105.e3315. (https://doi.org/10.1210/clinem/dgaa410)
- 15↑
Kjellbom A, Lindgren O, Puvaneswaralingam S, Löndahl M, Olsen H. Association between mortality and levels of autonomous cortisol secretion by adrenal incidentalomas: a cohort study. Annals of Internal Medicine 2021 174 1041–1049. (https://doi.org/10.7326/M20-7946)
- 16↑
Park J, De Luca A, Dutton H, Malcolm JC, Doyle MA. Cardiovascular outcomes in autonomous cortisol secretion and nonfunctioning adrenal adenoma: a systematic review. Journal of the Endocrine Society 2019 3 996–1008. (https://doi.org/10.1210/js.2019-00090)
- 17↑
Chen TK, Knicely DH, Grams ME. Chronic kidney disease diagnosis and management: a review. JAMA 2019 322 1294–1304. (https://doi.org/10.1001/jama.2019.14745)
- 18↑
Kramers BJ, Kramers C, Lenders JW, Deinum J. Effects of treating primary aldosteronism on renal function. Journal of Clinical Hypertension 2017 19 290–295. (https://doi.org/10.1111/jch.12914)
- 19↑
Nakamura Y, Kobayashi H, Tanaka S, Hatanaka Y, Fukuda N, Abe M. Association between plasma aldosterone and markers of tubular and glomerular damage in primary aldosteronism. Clinical Endocrinology 2021 94 920–926. (https://doi.org/10.1111/cen.14434)
- 20↑
Kawashima A, Sone M, Inagaki N, Takeda Y, Itoh H, Kurihara I, Umakoshi H, Ichijo T, Katabami T & Wada N et al.Renal impairment is closely associated with plasma aldosterone concentration in patients with primary aldosteronism. European Journal of Endocrinology 2019 181 339–350. (https://doi.org/10.1530/EJE-19-0047)
- 21↑
Umemura S, Arima H, Arima S, Asayama K, Dohi Y, Hirooka Y, Horio T, Hoshide S, Ikeda S & Ishimitsu T et al.The Japanese Society of Hypertension guidelines for the management of hypertension (JSH 2019). Hypertension Research 2019 42 1235–1481. (https://doi.org/10.1038/s41440-019-0284-9)
- 22↑
Nishikawa T, Omura M, Satoh F, Shibata H, Takahashi K, Tamura N, Tanabe A & Task Force Committee on Primary Aldosteronism , The Japan Endocrine Society. Guidelines for the diagnosis and treatment of primary aldosteronism – the Japan Endocrine Society 2009. Endocrine Journal 2011 58 711–721. (https://doi.org/10.1507/endocrj.ej11-0133)
- 23↑
Kobayashi H, Nakamura Y, Abe M, Kurihara I, Itoh H, Ichijo T, Takeda Y, Yoneda T, Katabami T & Tsuiki M et al.Effect of cosyntropin during adrenal venous sampling on subtype of primary aldosteronism: analysis of surgical outcome. European Journal of Endocrinology 2020 182 265–273. (https://doi.org/10.1530/EJE-19-0860)
- 24↑
Rossi GP, Auchus RJ, Brown M, Lenders JW, Naruse M, Plouin PF, Satoh F, Young Jr WF. An expert consensus statement on use of adrenal vein sampling for the subtyping of primary aldosteronism. Hypertension 2014 63 151–160. (https://doi.org/10.1161/HYPERTENSIONAHA.113.02097)
- 25↑
Young WF, Stanson AW, Thompson GB, Grant CS, Farley DR, Van Heerden JA. Role for adrenal venous sampling in primary aldosteronism. Surgery 2004 136 1227–1235. (https://doi.org/10.1016/j.surg.2004.06.051)
- 26↑
Yanase T, Oki Y, Katabami T, Otsuki M, Kageyama K, Tanaka T, Kawate H, Tanabe M, Doi M & Akehi Y et al.New diagnostic criteria of adrenal subclinical Cushing’s syndrome: opinion from the Japan Endocrine Society. Endocrine Journal 2018 65 383–393. (https://doi.org/10.1507/endocrj.EJ17-0456)
- 27↑
Fassnacht M, Arlt W, Bancos I, Dralle H, Newell-Price J, Sahdev A, Tabarin A, Terzolo M, Tsagarakis S, Dekkers OM. Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the study of adrenal tumors. European Journal of Endocrinology 2016 175 G1–G34. (https://doi.org/10.1530/EJE-16-0467)
- 28↑
Puvaneswaralingam S, Kjellbom A, Lindgren O, Löndahl M, Olsen H. ACTH following overnight dexamethasone suppression can be used in the verification of autonomous cortisol secretion in patients with adrenal incidentalomas. Clinical Endocrinology 2021 94 168–175. (https://doi.org/10.1111/cen.14357)
- 29↑
Sasaki Y, Katabami T, Asai S, Fukuda H, Tanaka Y. In the overnight dexamethasone suppression test, 1.0 mg loading is superior to 0.5 mg loading for diagnosing subclinical adrenal Cushing’s syndrome based on plasma dexamethasone levels determined using liquid chromatography-tandem mass spectrometry. Endocrine Journal 2017 64 833–842. (https://doi.org/10.1507/endocrj.EJ17-0083)
- 30↑
WHO Collaborating Centre for Drug Statistics Methodology. Guidelines for ATC classification and DDD assignment 2020. Oslo, Norway, 2019. (available at: https://www.whocc.no/ddd/definition_and_general_considera/)
- 31↑
Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, Yamagata K, Tomino Y, Yokoyama H & Hishida A et al.Revised equations for estimated GFR from serum creatinine in Japan. American Journal of Kidney Diseases 2009 53 982–992. (https://doi.org/10.1053/j.ajkd.2008.12.034)
- 32↑
Examination Committee of Criteria & Japan Society for the Study of Obesity. New criteria for ’obesity disease’ in Japan. Circulation Journal 2002 66 987–992. (https://doi.org/10.1253/circj.66.987)
- 33↑
Committee of the Japan Diabetes Society on the Diagnostic Criteria of Diabetes Mellitus, Seino Y, Nanjo K, Tajima N, Kadowaki T, Kashiwagi A, Araki E, Ito C, Inagaki N & Iwamoto Y et al.Report of the committee on the classification and diagnostic criteria of diabetes mellitus. Journal of Diabetes Investigation 2010 1 212–228. (https://doi.org/10.1111/j.2040-1124.2010.00074.x)
- 34↑
Teramoto T, Sasaki J, Ishibashi S, Birou S, Daida H, Dohi S, Egusa G, Hiro T, Hirobe K & Iida M et al.Diagnostic criteria for dyslipidemia. Journal of Atherosclerosis and Thrombosis 2013 20 655–660. (https://doi.org/10.5551/jat.17152)
- 35↑
Monticone S, Sconfienza E, D’Ascenzo F, Buffolo F, Satoh F, Sechi LA, Veglio F, Mulatero P. Renal damage in primary aldosteronism: a systematic review and meta-analysis. Journal of Hypertension 2020 38 3–12. (https://doi.org/10.1097/HJH.0000000000002216)
- 36↑
Koh JM, Kim JY, Chung YE, Park JY, Shong YK, Hong SK, Kim GS, Lee KU. Increased urinary albumin excretion in Cushing’s syndrome: remission after correction of hypercortisolaemia. Clinical Endocrinology 2000 52 349–353. (https://doi.org/10.1046/j.1365-2265.2000.00917.x)
- 37↑
Smets P, Meyer E, Maddens B, Daminet S. Cushing’s syndrome, glucocorticoids and the kidney. General and Comparative Endocrinology 2010 169 1–10. (https://doi.org/10.1016/j.ygcen.2010.07.004)
- 38↑
Kobayashi H, Abe M, Nakamura Y, Takahashi K, Fujita M, Takeda Y, Yoneda T, Kurihara I, Itoh H & Tsuiki M et al.Association between acute fall in estimated glomerular filtration rate after treatment for primary aldosteronism and long-term decline in renal function. Hypertension 2019 74 630–638. (https://doi.org/10.1161/HYPERTENSIONAHA.119.13131)
- 39↑
Saiki A, Otsuki M, Tamada D, Kitamura T, Shimomura I, Kurihara I, Ichijo T, Takeda Y, Katabami T & Tsuiki M et al.Diabetes mellitus itself increases cardio-cerebrovascular risk and renal complications in primary aldosteronism. Journal of Clinical Endocrinology and Metabolism 2020 105 e2531–e2537. (https://doi.org/10.1210/clinem/dgaa177)
- 40↑
Wu VC, Yang SY, Lin JW, Cheng BW, Kuo CC, Tsai CT, Chu TS, Huang KH, Wang SM & Lin YH et al.Kidney impairment in primary aldosteronism. Clinica Chimica Acta: International Journal of Clinical Chemistry 2011 412 1319–1325. (https://doi.org/10.1016/j.cca.2011.02.018)
- 41↑
Elhassan YS, Alahdab F, Prete A, Delivanis DA, Khanna A, Prokop L, Murad MH, O’Reilly MW, Arlt W, Bancos I. Natural history of adrenal incidentalomas with and without mild autonomous cortisol excess: a systematic review and meta-analysis. Annals of Internal Medicine 2019 171 107–116. (https://doi.org/10.7326/M18-3630)
- 42↑
Di Dalmazi G, Vicennati V, Garelli S, Casadio E, Rinaldi E, Giampalma E, Mosconi C, Golfieri R, Paccapelo A & Pagotto U et al.Cardiovascular events and mortality in patients with adrenal incidentalomas that are either non-secreting or associated with intermediate phenotype or subclinical Cushing’s syndrome: a 15-year retrospective study. Lancet: Diabetes and Endocrinology 2014 2 396–405. (https://doi.org/10.1016/S2213-8587(1370211-0)
- 43↑
Imai E, Horio M, Watanabe T, Iseki K, Yamagata K, Hara S, Ura N, Kiyohara Y, Moriyama T & Ando Y et al.Prevalence of chronic kidney disease in the Japanese general population. Clinical and Experimental Nephrology 2009 13 621–630. (https://doi.org/10.1007/s10157-009-0199-x)
- 44↑
Nakajima Y, Yamada M, Taguchi R, Satoh T, Hashimoto K, Ozawa A, Shibusawa N, Okada S, Monden T, Mori M. Cardiovascular complications of patients with aldosteronism associated with autonomous cortisol secretion. Journal of Clinical Endocrinology and Metabolism 2011 96 2512–2518. (https://doi.org/10.1210/jc.2010-2743)
- 45↑
Adolf C, Köhler A, Franke A, Lang K, Riester A, Löw A, Heinrich DA, Bidlingmaier M, Treitl M & Ladurner R et al.Cortisol excess in patients with primary aldosteronism impacts left ventricular hypertrophy. Journal of Clinical Endocrinology and Metabolism 2018 103 4543–4552. (https://doi.org/10.1210/jc.2018-00617)
- 46↑
Araujo-Castro M, Bengoa Rojano N, Fernández Argüeso M, Pascual-Corrales E, Jiménez Mendiguchía L, García Cano AM. Cardiometabolic risk in patients with primary aldosteronism and autonomous cortisol secretion. Case-control study. Medicina Clinica 2021 157 473–479. (https://doi.org/10.1016/j.medcli.2020.07.025)
- 47↑
Yan MT, Chao CT, Lin SH. Chronic kidney disease: strategies to retard progression. International Journal of Molecular Sciences 2021 22 10084. (https://doi.org/10.3390/ijms221810084)
- 48↑
Somlóová Z, Widimský Jr J, Rosa J, Wichterle D, Strauch B, Petrák O, Zelinka T, Vlková J, Masek M & Dvoráková J et al.The prevalence of metabolic syndrome and its components in two main types of primary aldosteronism. Journal of Human Hypertension 2010 24 625–630. (https://doi.org/10.1038/jhh.2010.65)
- 49↑
Matrozova J, Steichen O, Amar L, Zacharieva S, Jeunemaitre X, Plouin PF. Fasting plasma glucose and serum lipids in patients with primary aldosteronism: a controlled cross-sectional study. Hypertension 2009 53 605–610. (https://doi.org/10.1161/HYPERTENSIONAHA.108.122002)
- 50↑
Zhang Z, Luo Q, Tuersun T, Wang G, Wu T, Zhang D, Wang M, Zhou K, Sun L & Yue N et al.Higher prevalence of metabolic disorders in patients with bilateral primary aldosteronism than unilateral primary aldosteronism. Clinical Endocrinology 2021 94 3–11. (https://doi.org/10.1111/cen.14318)
- 51↑
Gerards J, Heinrich DA, Adolf C, Meisinger C, Rathmann W, Sturm L, Nirschl N, Bidlingmaier M, Beuschlein F & Thorand B et al.Impaired glucose metabolism in primary aldosteronism is associated with cortisol cosecretion. Journal of Clinical Endocrinology and Metabolism 2019 104 3192–3202. (https://doi.org/10.1210/jc.2019-00299)
- 52↑
Arlt W, Lang K, Sitch AJ, Dietz AS, Rhayem Y, Bancos I, Feuchtinger A, Chortis V, Gilligan LC & Ludwig P et al.Steroid metabolome analysis reveals prevalent glucocorticoid excess in primary aldosteronism. JCI Insight 2017 2 e93136. (https://doi.org/10.1172/jci.insight.93136)
- 53↑
Piaditis GP, Kaltsas GA, Androulakis II, Gouli A, Makras P, Papadogias D, Dimitriou K, Ragkou D, Markou A & Vamvakidis K et al.High prevalence of autonomous cortisol and aldosterone secretion from adrenal adenomas. Clinical Endocrinology 2009 71 772–778. (https://doi.org/10.1111/j.1365-2265.2009.03551.x)
