Adrenal venous sampling criteria for chemiluminescent enzyme immunoassay as a preferable alternative to radioimmunoassay in primary aldosteronism.

Plasma aldosterone concentration (PAC) was routinely measured using radioimmunoassay (RIA); however, the RIA kit was discontinued in March 2021 in Japan. This study examined PAC conversion in adrenal venous sampling (AVS) and AVS criteria when measured using chemiluminescent enzyme immunoassay (CLEIA). PAC of 415 adrenal venous blood samples from AVS (including segmental AVS) of 63 patients with primary aldosteronism was measured using RIA (Spac-S aldosterone kit; Fujirebio Inc.) and CLEIA (Lumipulse Presto Aldosterone; Fujirebio Inc.). PAC of 70 AVS samples was also measured using liquid chromatography-mass spectrometry (LC-MS/MS, ASKA Pharma Medical Co., Ltd.). PAC conversion formulas were determined for each AVS sample assay. PAC measured using CLEIA was significantly correlated with that measured using RIA (correlation coefficient = 0.971). The PAC conversion formula was PAC (CLEIA) = PAC (RIA) × 0.772 - 1,199 pg/mL. The PAC of 14,000 pg/mL in RIA was equivalent to 9,613 pg/mL in CLEIA. PAC measured using CLEIA was also correlated with that measured using LC-MS/MS, and the PAC conversion formula was PAC (CLEIA, pg/mL) = 0.97 × PAC (LC-MS/MS, pg/mL) + 211. The inter-assay coefficient of variability (CV) was 1.1-1.3% and intra-assay CV was 1.0-1.7%, measured using CLEIA. The PAC conversion formula for AVS samples was obtained using CLEIA and RIA, and the conversion formula was different from that for peripheral blood. PAC values measured by CLEIA showed preferable accuracy and high concordance with those measured by LC-MS/MS, even in AVS samples. The study outcomes are useful for interpreting AVS results using non-RIA measurement methods.

Segmental low-density area on contrast-enhanced CT is a possible clue to diagnosing branch artery fibromuscular dysplasia.

Summary: Fibromuscular dysplasia can cause renovascular hypertension. Since fibromuscular dysplasia may be underdiagnosed, precise diagnosis and management are crucial, especially for young women. A 20-year-old woman with hypertension and hypokalemia was referred to our hospital for further evaluation of secondary hypertension. At the previous hospital, her blood pressure was 160/110 mmHg and the serum potassium level was 2.9 mEq/L. The equilibrium phase on contrast-enhanced computed tomography revealed a low-density area in the upper median portion of the right kidney. On admission to our hospital, her blood pressure was 141/96 mmHg under 5 mg of amlodipine. Laboratory tests revealed plasma renin activity of 11.3 ng/mL/h and plasma aldosterone concentration of 117.1 pg/mL. Renal venous sampling of active renin concentration showed a right-to-left renin ratio of 3.13, confirming a significant increase in renin secretion from the right kidney. Selective reno-angiography detected focal stenosis with adjacent aneurysmal dilation and tortuosity in the proximal branch of the right renal artery. She was diagnosed with branch artery fibromuscular dysplasia and successfully treated with percutaneous transluminal angioplasty. After the treatment, she was free from hypertension and hypokalemia without any medications. Since branch artery fibromuscular dysplasia is sometimes difficult to diagnose, contrast-enhanced computed tomography can be a promising diagnostic tool as shown in this case. Concerning treatment, our patient was treated with percutaneous transluminal angioplasty, which should be considered for women of reproductive age because recommended antihypertensive medications can be teratogenic even in the first trimester of pregnancy. Learning points: Although branch artery fibromuscular dysplasia (FMD) is sometimes difficult to diagnose, it should be considered in patients with high-renin, high-aldosterone hypertension. Branch artery FMD can present with a low-density area of the kidney on contrast-enhanced computed tomography, as shown in this case. Percutaneous transluminal angioplasty (PTA) can be an appropriate treatment for branch artery FMD, especially in young female patients. PTA may immediately improve hypertension and hypokalemia without the need for medications.

Wnt activation disturbs cell competition and causes diffuse invasion of transformed cells through NF-κB-MMP21 pathway.

Normal epithelial cells exert their competitive advantage over RasV12-transformed cells and eliminate them into the apical lumen via cell competition. However, the internal or external factors that compromise cell competition and provoke carcinogenesis remain elusive. In this study, we examine the effect of sequential accumulation of gene mutations, mimicking multi-sequential carcinogenesis on RasV12-induced cell competition in intestinal epithelial tissues. Consequently, we find that the directionality of RasV12-cell extrusion in Wnt-activated epithelia is reversed, and transformed cells are delaminated into the basal lamina via non-cell autonomous MMP21 upregulation. Subsequently, diffusively infiltrating, transformed cells develop into highly invasive carcinomas. The elevated production of MMP21 is elicited partly through NF-κB signaling, blockage of which restores apical elimination of RasV12 cells. We further demonstrate that the NF-κB-MMP21 axis is significantly bolstered in early colorectal carcinoma in humans. Collectively, this study shows that cells with high mutational burdens exploit cell competition for their benefit by behaving as unfit cells, endowing them with an invasion advantage.

Lethal Arrhythmia Induced by Severe Hypokalemia with Primary Aldosteronism: A Case Report and Literature Review.

A 26-year-old woman experienced sudden loss of consciousness with respiratory arrest while engaged in a heated conversation shortly after consuming a carbohydrate-rich meal; she was resuscitated immediately. Severe hypokalemia became evident and was deemed to have caused lethal arrhythmia. She was diagnosed with a left aldosterone-producing adenoma and achieved remission following partial adrenalectomy. Primary aldosteronism is frequently complicated by hypokalemia; however, hypokalemia-induced lethal arrhythmias are rare. Clinicians should recognize that primary aldosteronism can potentially cause sudden death in apparently healthy individuals; hence, an early diagnosis and proper treatment are critical.

Differences between left adrenal vein sampling sites revealed with segmental sampling in primary aldosteronism.

OBJECTIVES: To clarify the differences between two left sampling sites (left adrenal central vein [LCV] and common trunk [CMT], conjunction with LCV and inferior phrenic vein) and their impact on adrenal venous sampling (AVS) in primary aldosteronism by analyzing the results of segmental AVS (sAVS). METHODS: We retrospectively analyzed a final cohort of 432 patients who underwent cosyntropin-stimulated sAVS from 2017 to 2020. Hormone levels in the LCV and the CMT were compared. Subtype diagnosis was based on the lateralization index with LCV and CMT sampling (a cutoff value of 4) and sAVS after excluding patients with a selectivity index (SI) <3. RESULTS: Compared with the LCV, CMT sampling showed significantly lower aldosterone and cortisol levels and a higher proportion of cases with an SI of <3 (2.8% vs 0.5%, p = 0.025) and <5 (6.9% vs 0.5%, p < 0.001), while the aldosterone-to-cortisol ratio and the lateralization index were not significantly different. Subtyping of both sites was concordant in 94.7% (393/415) and discordant in the remainder, which included left and right aldosterone-producing adenoma and idiopathic hyperaldosteronism cases referring to the sAVS. There was no significant difference between the concordance rate of the two sampling sites based on the sAVS diagnosis. CONCLUSIONS: LCV sampling meets the SI criteria for successful AVS more frequently compared with CMT sampling, but neither was better than the other in terms of diagnosis under conditions of meeting the criteria. ADVANCES IN KNOWLEDGE: LCV sampling would decrease the number of cases judged as AVS failure.

High aldosterone levels in the renal capsular vein from the left aldosterone-producing adenoma on adrenal venous sampling.

Summary: A 42-year-old female patient was referred to our hospital with hypertension and hypokalemia and was diagnosed with primary aldosteronism. Dynamic contrast-enhanced computed tomography images revealed a 13-mm nodule on the lateral segment of the left adrenal gland and a fine venous connection between the nodule and the prominent renal capsular vein running nearby. The venograms in the left lateral tributary with a microcatheter confirmed alternative drainage to the left renal capsular vein during adrenal venous sampling, and the left renal capsular vein sampling was added. The patient was diagnosed with a left aldosterone-producing adenoma (APA) using the lateralization index (48.3) and a higher plasma aldosterone concentration (PAC) of the left lateral tributary (66 700 pg/mL) than other tributary samples after adrenocorticotropic hormone stimulation. Furthermore, markedly higher PAC (224 000 pg/mL) was observed in the left renal capsular vein blood than in the left adrenal central vein (45 000 pg/mL) and tributaries, confirming the diagnosis. Laparoscopic left partial adrenalectomy and following histopathological analysis revealed a CYP11B2-positive adrenocortical adenoma. Complete clinical and biochemical success for primary aldosteronism was achieved after 6 months. Direct evidence of APA blood venous drainage into the renal capsular vein has been demonstrated. Sampling from an alternative drainage pathway could be beneficial for APA diagnosis if such APA blood drainage is assumed. Learning points: Aldosterone-producing adenomas may drain blood into an alternative pathway but for the adrenal vein. The presence of alternative venous drainage could be assumed by contrast-enhanced computed tomography or venogram during adrenal venous sampling. Sampling in the alternative drainage veins and demonstrating elevated aldosterone levels could help in diagnosing aldosterone-producing adenoma.

Association of Reversal of Renin Suppression With Long-Term Renal Outcome in Medically Treated Primary Aldosteronism.

BACKGROUND: Renin suppression in primary aldosteronism indicates mineralocorticoid receptor activation via excessive aldosterone secretion, inducing renal damage. We investigated whether the reversal of renin suppression after the initiation of mineralocorticoid receptor antagonist therapy was associated with long-term renal outcomes in medically treated patients with primary aldosteronism. METHODS: This retrospective cohort study included 318 patients with primary aldosteronism treated with mineralocorticoid receptor antagonist between 2008 and 2020 at the Yokohama Rosai Hospital in Japan. The posttreatment renin status was defined as unsuppressed (ie, reversal of renin suppression) when individual plasma renin activity after the initiation of mineralocorticoid receptor antagonist (post-plasma renin activity) was ≥1.0 ng/mL per hour; otherwise, it was defined as suppressed. We analyzed the association of posttreatment renin status with subsequent longitudinal estimated glomerular filtration rate changes using linear mixed-effects models for repeated measurements, adjusting for potential confounders. RESULTS: The posttreatment renin status of 119 patients was unsuppressed (median post-plasma renin activity, 1.7 ng/mL per hour) and that of 199 patients was suppressed (median post-PRA, 0.5 ng/mL per hour). Through the median follow-up period of 3.1 years, the decline in estimated glomerular filtration rate was milder among patients with the unsuppressed posttreatment renin (-0.46 [95% CI, -0.63 to -0.28] mL/min per 1.73 m2 per year) than those with suppressed posttreatment renin (-1.41 [95% CI, -1.56 to -1.27] mL/min per 1.73 m2 per year; difference, 0.96 [95% CI, 0.72-1.20] mL/min per 1.73 m2 per year). CONCLUSIONS: Our findings may highlight the importance of reversing renin suppression with optimal mineralocorticoid receptor antagonist titration in medically treated primary aldosteronism, which could mitigate adverse renal outcomes.

Feasibility of single-port laparoscopic partial adrenalectomy with selective adrenal venous sampling and high-resolution ultrasound for unilateral aldosterone-producing adenomas.

BACKGROUND: The surgical and endocrinological outcomes of single-port laparoscopic partial adrenalectomy for patients with aldosterone-producing adenomas are unknown. Precise diagnosis of intra-adrenal aldosterone activity and a precise surgical procedure may improve outcomes. In this study, we aimed to determine the surgical and endocrinological outcomes of single-port laparoscopic partial adrenalectomy with preoperative segmental selective adrenal venous sampling and intraoperative high-resolution laparoscopic ultrasound in patients with unilateral aldosterone-producing adenomas. We identified 53 patients with partial adrenalectomy and 29 patients with laparoscopic total adrenalectomy. Single-port surgery was performed for 37 and 19 patients, respectively. METHODS: A single-center, retrospective cohort study. All patients with unilateral aldosterone-producing adenomas diagnosed by selective adrenal venous sampling and treated surgically between January 2012 and February 2015 were included. Follow-up with biochemical and clinical assessments was set at 1 year after surgery for short-term outcomes and was performed every 3 months after surgery. RESULTS: We identified 53 patients with partial adrenalectomy and 29 patients with laparoscopic total adrenalectomy. Single-port surgery was performed for 37 and 19 patients, respectively. Single-port surgery was associated with shorter operative and laparoscopic times (odds ratio, 0.14; 95% confidence interval, 0.039-0.49; P = .002 and odds ratio, 0.13; 95% confidence interval, 0.032-0.57; P = .006, respectively). All single-port and multi-port partial adrenalectomy cases showed complete short-term (median 1 year) biochemical success, and 92.9% (26 of 28 patients) who underwent single-port partial adrenalectomy and 100% (13 of 13 patients) who underwent multi-port partial adrenalectomy showed complete long-term (median 5.5 years) biochemical success. No complications were observed with single-port adrenalectomy. CONCLUSION: Single-port partial adrenalectomy is feasible after selective adrenal venous sampling for unilateral aldosterone-producing adenomas, with shorter operative and laparoscopic times and a high rate of complete biochemical success.

Node-by-node diagnosis for multiple ipsilateral nodules by segmental adrenal venous sampling in primary aldosteronism.

OBJECTIVES: In patients with primary aldosteronism (PA), multiple adrenocortical nodules may be present on the surgical side. The aim of this study was to clarify the pathological diagnosis and the node-by-node diagnostic capability of segmental adrenal venous sampling (sAVS). DESIGN: Retrospective study. PATIENTS: A total of 162 patients who underwent adrenalectomy following sAVS were studied. MEASUREMENTS: Multiple nodules on the surgical side were extracted while referring to contrast-enhanced computed tomography images. We also performed a detailed histopathological analysis of the resected specimens from patients undergoing sAVS, which included immunohistochemistry for CYP11B2. RESULTS: In 11 (6.8%) patients, two to three nodules were detected on the surgical side. All patients were diagnosed by sAVS with at least one aldosterone-producing adenoma (APA) for localized aldosterone elevation in tributaries. Seven patients showed a lateralization index value of ≥4 after ACTH stimulation. Histopathologically and clinically, two patients had two or three CYP11B2-positive APAs, and the other nine patients both APAs and non-APAs. The positive predictive value of the most suspected APA, that is, the drainer that showed the highest aldosterone level by sAVS, was 11/11 (100%, 95% confidence interval [CI]: 71.5%-100%), while that for the second and third suspected APA was 3/7 (42.9%, 95% CI: 9.9%-81.6%), and they were significantly different (p = .01). Further, the positive predictive value of non-APA was 4/4 (100%, 95% CI: 39.8%-100%). CONCLUSIONS: The sAVS could correctly diagnose the aldosterone production in multiple ipsilateral adrenal nodules.