Hironobu Umakoshi

Outcomes after adrenalectomy for unilateral primary aldosteronism: an international consensus on outcome measures and analysis of remission rates in an international cohort

BACKGROUND Although unilateral primary aldosteronism is the most common surgically correctable cause of hypertension, no standard criteria exist to classify surgical outcomes. We aimed to create consensus criteria for clinical and biochemical outcomes and follow-up of adrenalectomy for unilateral primary aldosteronism and apply these criteria to an international cohort to analyse the frequency of remission and identify preoperative determinants of successful outcome. METHODS The Primary Aldosteronism Surgical Outcome (PASO) study was an international project to develop consensus criteria for outcomes and follow-up of adrenalectomy for unilateral primary aldosteronism. An international panel of 31 experts from 28 centres, including six endocrine surgeons, used the Delphi method to reach consensus. We then retrospectively analysed follow-up data from prospective cohorts for outcome assessment of patients diagnosed with unilateral primary aldosteronism by adrenal venous sampling who had undergone a total adrenalectomy, consecutively included from 12 referral centres in nine countries. On the basis of standardised criteria, we determined the proportions of patients achieving complete, partial, or absent clinical and biochemical success in accordance with the consensus. We then used logistic regression analyses to identify preoperative factors associated with clinical and biochemical outcomes. FINDINGS Consensus was reached for criteria for six outcomes (complete, partial, and absent success of clinical and biochemical outcomes) based on blood pressure, use of antihypertensive drugs, plasma potassium and aldosterone concentrations, and plasma renin concentrations or activities. Consensus was also reached for two recommendations for the timing of follow-up assessment. For the international cohort analysis, we analysed clinical data from 705 patients recruited between 1994 and 2015, of whom 699 also had biochemical data. Complete clinical success was achieved in 259 (37%) of 705 patients, with a wide variance (range 17-62), and partial clinical success in an additional 334 (47%, range 35-66); complete biochemical success was seen in 656 (94%, 83-100) of 699 patients. Female patients had a higher likelihood of complete clinical success (odds ratio [OR] 2·25, 95% CI 1·40-3·62; p=0·001) and clinical benefit (complete plus partial clinical success; OR 2·89, 1·49-5·59; p=0·002) than male patients. Younger patients had a higher likelihood of complete clinical success (OR 0·95 per extra year, 0·93-0·98; p<0·001) and clinical benefit (OR 0·95 per extra year, 0·92-0·98; p=0·004). Higher levels of preoperative medication were associated with lower levels of complete clinical success (OR 0·80 per unit increase, 0·70-0·90; p<0·001). INTERPRETATION These standardised outcome criteria are relevant for the assessment of the success of surgical treatment in individual patients and will allow the comparison of outcome data in future studies. The variable baseline clinical characteristics of our international cohort contributed to wide variation in clinical outcomes. Most patients derive clinical benefit from adrenalectomy, with younger patients and female patients more likely to have a favourable surgical outcome. Screening for primary aldosteronism should nonetheless be done in every individual fulfilling US Endocrine Society guideline criteria because biochemical success without clinical success is by itself clinically important and older women and men can also derive post-operative clinical benefit. FUNDING European Research Council; European Unions Horizon 2020; Else Kröner-Fresenius Stiftung; Netherlands Organisation for Health Research and Development-Medical Sciences; Japanese Ministry of Health, Labour and Welfare; Ministry of Health, Slovenia; US National Institutes of Health; and CONICYT-FONDECYT (Chile).

Importance of contralateral aldosterone suppression during adrenal vein sampling in the subtype evaluation of primary aldosteronism

Adrenal vein sampling (AVS) is the standard criterion for the subtype diagnosis in primary aldosteronism (PA). Although lateralized index (LI) ≥4 after cosyntropin stimulation is the commonly recommended cut‐off for unilateral aldosterone hypersecretion, many of the referral centres in the world use LI cut‐off of <4 without sufficient evidence for its diagnostic accuracy.

Chronic kidney disease score for predicting postoperative masked renal insufficiency in patients with primary aldosteronism.

Chronic kidney disease (CKD) is sometimes unmasked after unilateral adrenalectomy in patients with primary aldosteronism (PA) without expectation.

Adrenal Venous Sampling in Patients With Positive Screening but Negative Confirmatory Testing for Primary Aldosteronism

Adrenal venous sampling is considered to be the most reliable diagnostic procedure to lateralize aldosterone excess in primary aldosteronism (PA). However, normative criteria have not been established partially because of a lack of data in non-PA hypertensive patients. The aim of the study was to investigate aldosterone concentration and its gradient in the adrenal vein of non-PA hypertensive patients. We retrospectively studied the results of cosyntropin-stimulated adrenal venous sampling in 40 hypertensive patients who showed positive screening testing but negative results in 2 confirmatory tests/captopril challenge test and saline infusion test. Plasma aldosterone concentration, aldosterone/cortisol ratio, its higher/lower ratio (lateralization index) in the adrenal vein with cosyntropin stimulation were measured. Median plasma aldosterone concentration in the adrenal vein was 25 819 pg/mL (range, 5154–69 920) in the higher side and 12 953 (range, 1866–36 190) pg/mL in the lower side (P<0.001). There was a significant gradient in aldosterone/cortisol ratio between the higher and the lower sides (27.2 [5.4–66.0] versus 17.3 [4.0–59.0] pg/mL per &mgr;g/dL; P<0.001) with lateralization index ranging from 1.01 to 3.87. The aldosterone lateralization gradient was between 1 to 2 in 32 patients and 2 to 4 in 8 patients. None of the patients showed lateralization index ≥4. The present study demonstrated that plasma aldosterone concentration in the adrenal veins showed significant variation and lateralization gradient even in non-PA hypertensive patients. Adrenal venous sampling aldosterone lateralization gradients between 2 and 4 should be interpreted with caution in patients with PA because these gradients can be found even in patients with negative confirmatory testing for PA.

Optimum position of left adrenal vein sampling for subtype diagnosis in primary aldosteronism

Although adrenal vein sampling (AVS) is the standard method for subtype diagnosis in primary aldosteronism (PA), protocol details including the sampling position in the adrenal vein are not standardized.

Accuracy of adrenal computed tomography in predicting the unilateral subtype in young patients with hypokalaemia and elevation of aldosterone in primary aldosteronism

The current Endocrine Society Guideline suggests that patients aged <35 years with marked primary aldosteronism (PA) and unilateral adrenal lesions on adrenal computed tomography (CT) scan may not need adrenal vein sampling (AVS) before proceeding to unilateral adrenalectomy. This suggestion is, however, based on the data from only one report in the literature.

Prevalence of Cardiovascular Disease and Its Risk Factors in Primary AldosteronismNovelty and Significance: A Multicenter Study in Japan

There have been several clinical studies examining the factors associated with cardiovascular disease (CVD) in patients with primary aldosteronism (PA); however, their results have left it unclear whether CVD is affected by the plasma aldosterone concentration or hypokalemia. We assessed the PA database established by the multicenter JPAS (Japan Primary Aldosteronism Study) and compared the prevalence of CVD among patients with PA with that among age-, sex-, and blood pressure-matched essential hypertension patients and participants with hypertension in a general population cohort. We also performed binary logistic regression analysis to determine which parameters significantly increased the odds ratio for CVD. Of the 2582 patients with PA studied, the prevalence of CVD, including stroke (cerebral infarction, cerebral hemorrhage, or subarachnoid hemorrhage), ischemic heart disease (myocardial infarction or angina pectoris), and heart failure, was 9.4% (stroke, 7.4%; ischemic heart disease, 2.1%; and heart failure, 0.6%). The prevalence of CVD, especially stroke, was higher among the patients with PA than those with essential hypertension/hypertension. Hypokalemia (K+ ⩽3.5 mEq/L) and the unilateral subtype significantly increased adjusted odds ratios for CVD. Although aldosterone levels were not linearly related to the adjusted odds ratio for CVD, patients with plasma aldosterone concentrations ≥125 pg/mL had significantly higher adjusted odds ratios for CVD than those with plasma aldosterone concentrations <125 pg/mL. Thus, patients with PA seem to be at a higher risk of developing CVD than patients with essential hypertension. Moreover, patients with PA presenting with hypokalemia, the unilateral subtype, or plasma aldosterone concentration ≥125 pg/mL are at a greater risk of CVD and have a greater need for PA-specific treatments than others.

Bilateral aldosterone suppression and its resolution in adrenal vein sampling of patients with primary aldosteronism: analysis of data from the WAVES-J study

In adrenal vein sampling (AVS) for patients with primary aldosteronism, the contralateral ratio of aldosterone/cortisol (A/C) between the nondominant adrenal vein and the inferior vena cava is one of the best criteria for determining lateralized aldosterone secretion. Despite successful cannulation in some patients, the A/C ratios in the adrenal veins are bilaterally lower than that in the inferior vena cava (bilateral aldosterone suppression; BAS).

Shortened saline infusion test for subtype prediction in primary aldosteronism

Primary aldosteronism (PA) is a common cause of endocrine hypertension [1, 2]. Since hyperaldosteronism induces various complications [3–5], early diagnosis and treatment is important in clinical practice. Aldosteroneproducing adenoma (APA) and idiopathic hyperaldosteronism (IHA) are the major subtypes of PA [6]. Since APA is surgically curable and IHA is not subjected to adrenal surgery but to medical treatment, subtype classification is essential in selecting the type of treatment for PA. Several guidelines have been proposed for the clinical practice of PA [2, 7, 8]. Adrenal vein sampling (AVS) is considered as the reference test to distinguish between unilateral and bilateral hypersecretion of aldosterone. However, it is relatively invasive, costly, and scarcely available even in developed countries. Moreover, its true diagnostic value is unknown and has been called into question. More convenient means to make subtype diagnoses are awaited. Saline infusion test (SIT) is one of the most commonly used and inexpensive confirmatory tests. It was also demonstrated to be useful for predicting PA subtypes [9]. It can be of great help in abbreviating the diagnostic procedure if the confirmatory test is also useful for subtype diagnosis. However, there is still little evidence to support the significance of SIT for subtype classification. In addition, the test requires 2 l of saline loading over 4 h, which is a physical burden to patients and can cause potential adverse effects on cardiovascular function. Another adverse effect of the SIT is that it lowers serum potassium and is therefore dangerous for patients with uncorrected hypokalemia. Considering the limited availability of AVS compared to the high prevalence of PA, it would be helpful if we could gain additional information from routine clinical practice to select patients who should undergo AVS before surgery. The aim of the present study was to assess the value of the standard SIT and a shortened version thereof in predicting unilateral aldosterone hypersecretion in patients with PA.

Significance of Computed Tomography and Serum Potassium in Predicting Subtype Diagnosis of Primary Aldosteronism.

Context The number of centers with established adrenal venous sampling (AVS) programs for the subtype diagnosis of primary aldosteronism (PA) is limited. Objective Aim was to develop an algorithm for AVS based on subtype prediction by computed tomography (CT) and serum potassium. Design A multi-institutional retrospective cohort study in Japan. Patients A total of 1591 patients with PA were classified into four groups according to CT findings and potassium status. Subtype diagnosis of PA was determined by AVS. Main Outcome Measure Prediction value of the combination of CT findings and potassium status for subtype diagnosis. Results The percentages of unilateral hyperaldosteronism on AVS were higher in patients with unilateral disease on CT than those with bilateral normal results on CT (50.8% vs 14.6%, P < 0.01), and these percentages were higher in those with hypokalemia than those with normokalemia (58.4% vs 11.5%, P < 0.01). The prevalence and odds ratio for unilateral hyperaldosteronism on AVS were as follows: bilateral normal on CT with normokalemia, 6.2% (reference); unilateral disease on CT with normokalemia, 23.8% and 4.8 [95% confidence interval (CI), 3.1 to 7.2]; bilateral normal on CT with hypokalemia, 38.1% and 9.4 (95% CI, 6.2 to 14.1), and unilateral disease on CT with hypokalemia, 70.6% and 36.4 (95% CI, 24.7 to 53.5). Conclusions Patients with PA with bilateral normal results on CT and normokalemia likely have a low prior probability of a lateralized form of AVS and could be treated medically, whereas those with unilateral disease on CT and hypokalemia have a high probability of a lateralized form of AVS.