Long-term Effects of Primary Aldosteronism Treatment on Patients With Primary Aldosteronism and Chronic Kidney Disease

Yujiro Nakano; Masanori Murakami; Kazunari Hara; Tatsuya Fukuda; Masato Horino; Akira Takeuchi; Yoshihiro Niitsu; Kumiko Shiba; Kazutaka Tsujimoto; Chikara Komiya; Minato Yokoyama; Kenji Ikeda; Takanobu Yoshimoto; Yasuhisa Fujii; Tetsuya Yamada

Disclosures

Clin Endocrinol. 2023;98(3):323-331.

Abstract and Introduction

Abstract

Objective: Primary aldosteronism (PA) is a major cause of secondary hypertension and is associated with chronic renal injury. The glomerular filtration rate (GFR) in PA rapidly decreases after the removal of glomerular hyperfiltration due to aldosterone excess by adrenalectomy (ADX) or mineralocorticoid receptor antagonist (MRA) treatment and is stable in the long term. However, the effects of these treatments on the long-term renal function of PA patients with chronic kidney disease (CKD) is not well understood.

Design and Patients: In this single-center, retrospective study, acute and chronic changes in the estimated GFR (eGFR) were examined in 107 patients with PA, including 49 patients with post-treatment CKD defined as eGFR < 60 ml/min/1.73 m².

Results: The reduction in eGFR observed 1 month after ADX in the CKD group (N = 31) was −20.1 ± 8.2 ml/min/1.73 m². Multivariate analysis showed that pre-treatment eGFR and plasma aldosterone concentration were independent predictive factors of the acute reduction in eGFR after ADX. The reduction of eGFR observed 1 month after MRA administration in the post-treatment CKD group (N = 18) was −9.2 ± 5.9 ml/min/1.73 m². Multivariate analysis showed that the duration of hypertension and pre-treatment eGFR were independent predictive factors of the acute reduction in eGFR after ADX administration. In 20 patients with CKD (N = 12 ADX and N = 8 MRA) followed for more than 5 years post-treatment, there was no further significant decline in eGFR over a follow-up period of 7 (6, 8) years nor any difference between the two treatment modalities.

Conclusions: Our study suggests that treatment of PA in stage 3 CKD is safe and useful in preventing renal injury.

Introduction

Primary aldosteronism (PA) is a major cause of secondary hypertension, accounting for approximately 10% of patients with hypertension.^[1,2] Previous epidemiologic studies have revealed that patients with PA have more severe cardiovascular and renal complications than age-, sex-, and blood pressure-matched patients with essential hypertension.^[3,4] Two therapeutic options are recommended for the treatment of PA: adrenalectomy (ADX) for patients with unilateral aldosterone-producing adenoma or medical treatment based on mineralocorticoid receptor antagonists (MRA) for patients with bilateral PA.^[1]

A series of clinical studies have shown that renal hemodynamic alteration due to hyperaldosteronism results in glomerular hyperfiltration,^[5,6] which is a cause of chronic renal injury.^[7] The glomerular filtration rate (GFR) in PA rapidly decreases after the removal of aldosterone excess by ADX^[5,8–10] or the blockade of aldosterone action by MRA.^[11] To prevent renal injury in the long term, complete removal of glomerular hyperfiltration by ADX or a sufficient dose of MRA is recommended for patients with PA.^[11] A previous clinical study showed that long-term chronic changes after ADX or MRA administration in patients with PA was not greater than that of essential hypertension.^[12]

Focusing on PA with chronic kidney disease (CKD), long-term changes in renal function after treatment of PA have not been fully investigated. Recently, a multicenter database in Japan showed that 19.6% of patients with PA already suffered from overt CKD^[13] that might be due to several causes: age, diabetes mellitus, and/or long-term duration of hyperaldosteronism. Previous studies have shown that masked CKD was uncovered and exacerbated by PA treatment in some patients with PA,^[14,15] and a low preoperative estimated GFR (eGFR) was suggested to be a risk factor for CKD after adrenalectomy.^[16] One case of PA with CKD required haemodialyses after MRA treatment.^[17] This led us to carefully consider ADX or MRA treatment for PA with low eGFR. Therefore, the effect of PA treatment on renal function in PA patients with CKD should be examined not only in the short term but also in the long term (i.e., more than 5 years). This study retrospectively examined the short- and long-term changes in GFR after ADX or MRA administration in patients with PA, especially those with CKD, in a single center.

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Abstract and Introduction
Materials and Methods
Results
Discussion
References

Table 1. Baseline parameters of patients with primary aldosteronism
Parameters	ADX		MRA
Parameters	non-CKD (n = 22)	CKD (n = 31)	non-CKD (n = 36)	CKD (n = 18)
Age at diagnosis	46 ± 10	54 ± 9*^,a	54 ± 9*^,b	62 ± 9*^,c,d
Sex (% male)	36	61*^,a	47	72*^,c
Duration of HT (years)	5 (2, 10)	9 (5, 20)*^,a	6 (3, 11)	17 ± 9*^,c
BMI (kg/m²)	23.2 ± 3.9	23.8 (21.1, 25.3)	25.7 ± 3.2*^,b	26.8 (25.2, 27.9)*^,d
Systolic BP (mmHg)	133 ± 18	131 (122, 140)	141 ± 18	138 ± 17
Diastolic BP (mmHg)	83 ± 12	83 ± 14	85 ± 11	83 ± 7
Cre (μmol/l)	55 ± 9	79 (70, 89)*^,a	57 (53, 75)	86 ± 19*^,c
Pre-treatment eGFR (ml/min/1.73 m²)	90.8 ± 15.1	67.0 (54.8, 73.9)*^,a	75.8 (70.0, 88.3)*^,b	60.2 ± 10.4*^,c
PRA (μg/l/hr)	0.1 (0.1, 0.4)	0.3 (0.1, 0.7)	0.3 (0.2, 0.4)	0.2 (0.1, 0.3)*^,c,d
PAC (pmol/l)	892 ± 430	1057 (715, 1833)	439 ± 202*^,b	432 (300, 628)*^,d
Potassium (mmol/l)	3.6 ± 0.6	3.6 (3.3, 3.7)	3.9 ± 0.4	3.9 ± 0.4*^,d
UAE (mg/gCre)	15.4 ± 10.4	32.3 (22.6, 91.7)*^,a	7.0 (4.1, 19.3)	10.4 (6.6, 27.2)*^,d
FPG (mmol/l)	5.00 ± 0.27	4.91 (4.66, 5.41)	5.05 ± 0.67	5.51 ± 0.72
HbA1c (%)	5.3 ± 0.3	5.5 (5.1, 5.8)	5.6 (5.3, 6.0)*^,b	5.7 ± 0.5
HbA1c (mmol/mol)	34.7 ± 4.0	36.5 (32.2, 39.8)	37.6 (34.4, 42.0)*^,b	39.3 ± 6.0
Acute changes in eGFR after ADX (ml/min/1.73 m²)	−18.2 ± 8.6	−20.1 ± 8.2	n.e.	n.e.
Acute changes in eGFR after MRA (ml/min/1.73 m²)	n.e.	n.e.	−8.0 ± 9.9	−9.2 ± 5.9
Eplerenone (mg)	n.e.	n.e.	100 (50, 100)	100 (100, 100)
Number of pre-treatment CKD	n.e.	9 (29%)	n.e.	10 (55%)
Post-treatment eGFR (ml/min/1.73 m²)	68.6 (64.4, 82.3)	44.0 ± 8.9*^,a	69.4 (65.4, 73.7)	52.4 (42.5, 58.8)*^,c

Note: PRA and PAC were assayed using radioimmunoassay. The data are presented as mean ± standard deviation for parameters of normal distribution or median (interquartile range) for parameters of skewed distribution. An unpaired t-test for parametric analysis or a Mann–Whitney U test for nonparametric analysis was performed.
Abbreviations: ADX, adrenalectomy; BMI, body mass index; BP, blood pressure; CKD, chronic kidney disease; Cre, creatinine; eGFR, estimated glomerular filtration rate; FPG, fasting plasma glucose; HT, hypertension; MRA, mineralocorticoid receptor antagonist; n.e., not examined; PAC, plasma aldosterone concentration; PRA, plasma renin activity; UAE, urinary albumin excretion.
^aBetween non-CKD and CKD patients in the ADX group.
^bBetween ADX and MRA in the non-CKD group.
^cBetween the non-CKD and CKD groups in the MRA group.
^dBetween ADX and MRA in the CKD group.
*p < .05.

Table 2. Correlations between the acute decline in eGFR and each baseline parameter
Parameters	ADX						MRA
	All		non-CKD		CKD		All		non-CKD		CKD
	r	p	r	p	r	p	r	p	r	p	r	p
Age at diagnosis	0.04	0.73	0.45*	0.03*	−0.79	0.67	−0.10	0.47	−0.06	0.70	−0.07	0.77
Duration of HT (years)	−0.05	0.70	0.05	0.81	0.26	0.89	−0.21	0.13	0.01	0.91	−0.41	0.08
BMI (kg/m²)	0.31*	0.02*	−0.05	0.82	0.61*	<0.01*	0.15	0.25	0.25	0.13	0.28	0.25
Systolic BP (mmHg)	−0.25	0.07	−0.31	0.14	−0.04	0.82	0.18	0.18	0.15	0.37	0.19	0.42
Cre (μmol/l)	0.21	0.13	0.38	0.07	0.46*	0.01*	0.36*	<0.01*	0.42*	0.01*	0.54*	0.01*
eGFR (ml/min/1.73 m²)	−0.33*	0.01*	−0.57*	<0.01*	−0.56*	<0.01*	−0.54*	<0.01*	−0.73*	<0.01*	−0.71*	<0.01*
PRA (μg/l/hr)	0.03	0.81	<0.01	0.97	0.11	0.54	<0.01	0.95	−0.07	0.65	−0.06	0.79
PAC (pmol/l)	−0.35*	0.01*	−0.37	0.09	−0.42*	0.01*	<0.01	0.95	−0.08	0.64	−0.27	0.91
Potassium (mmol/l)	0.45*	0.04*	0.55	0.11	0.42*	0.01*	0.11	0.46	0.26	0.13	−0.61*	0.04*
UAE (mg/gCre)	−0.34*	0.04*	−0.21	0.46	−0.24	0.28	−0.15	0.33	−0.02	0.89	−0.32	0.23

Note: Pearson's correlation coefficient for parametric analysis or Spearman's rank correlation coefficient for nonparametric analysis was calculated.
Abbreviations: ADX, adrenalectomy; BMI, body mass index; BP, blood pressure; CKD, chronic kidney disease; Cre, creatinine; eGFR, estimated glomerular filtration rate; HT, hypertension; MRA, mineralocorticoid receptor antagonist; p, p value; PAC, plasma aldosterone concentration; PRA, plasma renin activity; r, correlation coefficient; UAE, urinary albumin excretion.
*p < .05.

Table 3. Multivariate analysis of acute decline in eGFR
Parameters	Acute changes in eGFR after ADX		Acute changes in eGFR after MRA
Parameters	Standardized β	p	Standardized β	p
Duration of HT	−0.114	0.33	−0.441	<0.01*
BMI	0.182	0.14	0.092	0.36
Systolic BP	0.019	0.87	0.094	0.33
Pre-treatment eGFR	−0.457	<0.01*	−0.704	<0.01*
PAC	−0.507	<0.01*	−0.159	0.11

Note: Multivariate linear regression analysis with a forced entry procedure was performed. Adjusted R ² = 0.379 and 0.596 in ADX group and MRA group, respectively.
Abbreviations: ADX, adrenalectomy; BMI, body mass index; BP, blood pressure; eGFR, estimated glomerular filtration rate; HT, hypertension; MRA, mineralocorticoid receptor antagonist; p, p value; PAC, plasma aldosterone concentration.
*p < .05.

Table 4. Parameters of primary aldosteronism who were followed long-term
Parameters	ADX		MRA
Parameters	non-CKD (n = 5)	CKD (n = 12)	non-CKD (n = 13)	CKD (n = 8)
Age at diagnosis	52 ± 11	55 ± 9	52 ± 9*^,a	70 (51, 73)*^,a
Sex (% male)	60	50	46	75*^,a
Duration of HT (years)	6 ± 5	16 ± 11*^,b	4 (2, 8)	17 ± 7*^,a
BMI (kg/m²)	26.3 ± 4.9	23.3 (21.6, 25.3)*^,d	26.1 ± 2.9*^,a	26.6 (25.6, 27.4)*^,a
Systolic BP (mmHg)	144 ± 11	132 (124, 149)	140 ± 20	142 ± 14
Diastolic BP (mmHg)	91 ± 9	85 ± 13	86 ± 10	81 ± 5
Cre (μmol/l)	57 ± 15	77 (56, 113)*^,d	55 ± 13	106 (71, 107)*^,a
Pre-treatment eGFR (ml/min/1.73 m²)	91.9 ± 16.7	62.4 ± 16.9*^,b	91.1 ± 20	54.8 ± 9.7*^,a
PRA (μg/l/hr)	0.4 (0.1, 0.4)	0.2 (0.1, 0.5)	0.3 (0.2, 0.4)	0.1 (0.1, 0.2)*^,a
PAC (pmol/l)	956 ± 596	976 (721, 1766)	395 ± 119*^,a	522 (310, 636)*^,c
potassium (mmol/l)	4.1 (3.6, 4.6)	3.5 ± 0.3	3.8 ± 0.3*^,a	3.8 ± 0.5
UAE (mg/gCre)	18.8 ± 3.7	80.0 (27.0, 297.9)*^,b	77.0 (1.4, 8.7)*^,a	17.9 (2.1, 165.6)
FPG (mmol/l)	5.33 (5.27, 5.33)	5.24 ± 1.00	5.62 ± 0.89	5.18 ± 0.74
HbA1c (%)	5.3 ± 0.2	6.1 ± 1.0	5.6 (5.2, 6.4)	5.5 ± 0.5
HbA1c (mmol/mol)	34.4 ± 3.1	43.5 ± 11.9	37.6 (33.5, 46.9)	37.4 ± 5.6
Post-treatment parameters
eGFR at 6 months after treatment (ml/min/1.73 m²)	77.6 ± 12.2	40.7 ± 10.5*^,b	75.1 ± 15.3	46.3 ± 9.0*^,a
The rate of change in the eGFR (ml/min/1.73 m²/year)	−0.9 ± 1.5	0.3 (−0.2, 1.0)	−0.4 (−0.9, 0.8)	−0.7 ± 1.2

Note: PRA and PAC were assayed using radioimmunoassay. The data are presented as mean ± standard deviation for parameters of normal distribution or median (interquartile range) for parameters of skewed distribution. An unpaired t-test for parametric analysis or a Mann–Whitney U test for nonparametric analysis was performed. Repeated measures analysis of variance followed by the Bonferroni method for post hoc test was performed to assess the rate of change in eGFR.
Abbreviations: ADX, adrenalectomy; BMI, body mass index; BP, blood pressure; CKD, chronic kidney disease; Cre, creatinine; eGFR, estimated glomerular filtration rate; FPG, fasting plasma glucose; HT, hypertension; MRA, mineralocorticoid receptor antagonist; n.e., not examined; PAC, plasma aldosterone concentration; PRA, plasma renin activity; UAE, urinary albumin excretion.
^aBetween the non-CKD and CKD groups in the MRA group.
^bBetween non-CKD and CKD patients in the ADX group.
^cBetween ADX and MRA in the CKD group.
^dPost-hoc test between patients with non-CKD and CKD in the ADX group.
*p < .05.