Preoperative Renin Status Indicate the Clinical Outcome of Aldosterone-Producing Adenoma

Primary aldosteronism is widely recognized as renin-independent hypersecretion of aldosterone and aldosterone-producing adenoma(APA) represents the typical clinical subtype. Plasma renin below detection levels was considered as an important indicator for PA, and the suppressed renin level after confirmatory tests was considered to be a prerequisite when interpreting the results of confirmatory tests, before making the diagnosis of PA. Strictly, there is no specific definition of suppressed renin level in patients with PA. Clinically, the renin level of patients with APA varied greatly within the low to normal range. However, the clinical characteristics and outcomes in patients with APA having different renin status remain unclear. This retrospective study included 274 patients with APA who underwent unilateral laparoscopic adrenalectomy with at least a 12-month follow-up postoperatively. Patients were classified into the following 2 groups: low renin and non-low renin groups measured at 8.2 mU/L, according to the widely used criteria(defined as plasma renin activity<1ng/ml/h≈PRC 8.2 mU/L). Only patients with two consecutive PRC less than 8.2 mU/L could be classified into the low renin group. For the screening test and the confirmatory tests, antihypertensive medication was withheld or changed according to the guideline. Chemiluminescence immunoassays showed the range of the plasma renin concentration as 0.4–41.5mU/L. Non-low renin APA patients (n=26) had higher presurgical SBP(p=0.028), DBP(p=0.001) and PRC post confirmatory tests(p<0.001), compared with low renin APA patients(n=248). There was no significant difference in baseline PAC(p=0.507) and serum potassium(p=0.348) between the two groups. Intriguingly, non-low renin APA patients had higher PAC(p<0.001) and PRC(p<0.001) and lower serum potassium(p<0.001) at follow-up. For non-low renin APA patients, the rate of complete clinical success after surgery was 42.3%, 25% lower than that of low renin APA patients. APA patients with PRC<0.5mU/L had the highest rate of complete clinical success(75%), followed by PRC 0.5~8.2 mU/L(65%) and 8.2~20 mU/L(50%), with the lowest rate in patients with PRC>20 mU/L(33%). Multivariable logistic regression showed that the presence of baseline PRC>8.2 mU/L was a strong independent predictor for the lack of complete clinical success[OR 3.7(1.5–8.9),p=0.004]. Plasma renin concentration is closely related to the clinical outcome of APA patients postoperatively. APA patients with higher baseline renin status are at high likelihood of persistent hypertension after surgery, in whom strengthened monitoring of blood pressure is necessary.

Abstract P002: Soluble (pro)renin Receptor Contributes To Angiotensin II-Induced Hypertension In Mice

Activation of (pro)renin receptor (PRR) contributes to enhancement of intrarenal RAS and renal medullary α-ENaC and thus elevated blood pressure during angiotensin II (AngII) infusion. Soluble PRR (sPRR), the extracellular domain of PRR, is generated by multiple proteases including furin or ADAM19, and recently site-1 protease (S1P). The goal of the present study was to test the role of S1P-derived sPRR mediated AngII-induced hypertension. F1 B6129SF1/J mice were infused for 6 days with control (CTR) or AngII at 300 ng/kg/day alone or in combination with S1P inhibitor PF-429242 (PF) and blood pressure was monitored by radiotelemetry. S1P inhibition significantly attenuated AngII-induced hypertension accompanied with suppressed urinary and renal medullary renin levels and expression of renal medullary but not renal cortical α-ENaC expression. The effects of S1P inhibition were all reversed by supplement with histadine-tagged sPRR termed as sPRR-His. Mutagenesis of overlapping recognition site for S1P and furin in PRR for was generated in mice by CRISPR strategy (termed as mutant mice). Mutant mice were fertile and developed normally with a 50% reduction plasma sPRR. These mice exhibited blunted hypertensive response to AngII infusion accompanied with suppressed intrarenal renin levels. Ussing chamber technique was performed to determine amiloride-sensitive short-circuit current, an index of ENaC activity in confluent mpkCCD cells exposed for 24 h to AngII, AngII + PF, or AngII + PF + sPRR-His. AngII-induced ENaC activity was blocked by PF, which was reversed by sPRR-His. Together, these results support that sPRR derived from S1P or in combination with furin mediates AngII-induced hypertension through enhancement of intrarenal renin level and activation of ENaC.

Indicators of humoral regulation of the circulatory system in obese patients

Objectives - to study the indicators of humoral regulation of circulatory system in obese patients as the predictors of CHF development. Materials and methods. Two groups of 40 patients were formed: the first group consisted of patients with I or II grades obesity with BMI of up to 40 kg/m2, the second group included patients with grade III obesity with BMI of over 40 kg/m2. None of the selected patients had a history of cardiovascular events. The concentration value of renin-angiotensin-aldosterone system components and level of N-terminal pro B-type natriuretic peptide (NT-pro-BNP) was determined. Results. Aldosterone level in grade I-II obese patients was close to normal upper border: 58.9 [54.9; 73.8] pg/ml (normal range is 10-60 pg/ml), while in patients with grade III obesity it was 79.5 [64.5; 90.1], which is 25.9% higher than in patients of the first group and 24.5% higher above the normal level (p < 0.05). These two groups was significantly different not only in average plasma aldosterone level, but in absolute number of patients with hyperaldosteronism, whose number accounted for 46.2% in grades I or II obese patients and 85.7% among patients with grade III obesity. Plasma renin level and angiotensin II levels in both groups was within the normal range. NT-proBNP level in the first group was 23.7 [10.6; 23.6] pg/ml, in the second group - 138.0 [121.5; 145.9] pg/ml, which is 5.8 times higher (p = 0.001). In both groups of patients, the correlation analysis showed that aldosterone and NT-proBNP levels are closely related (r = 0.74, p < 0.05). Conclusion. This study suggests that aldosterone level can be used as a predictor of HF.

Serum Renin Levels in Sudden Sensorineural Hearing Loss

Objective: The aim of this study was to investigate the serum renin levels of patients with idiopathic sudden sensorineural hearing loss (ISSNHL). Material and Methods: Twenty-four patients with ISSNHL and 24 asymptomatic healthy volunteers were included in the study. Subjects underwent pure-tone audiometry and serum renin levels were measured. Results: There were 14 women (mean age:42.35 ± 9.53) and 10 men (mean age:43.8 ± 6.87) in the patient group. There were 14 women (mean age:42.4 ± 4.7) and 10 men (mean age:41.4 ± 4.59) in the control group. ISSNHL was detected on the right side in 13 patients and on the left side in 11 patients. Serum renin levels of the patients and controls were 788.01 ± 327.8 and 282.37 ± 107.73 pg/mL, respectively. The serum renin levels were found to be significantly higher in the patient group compared to the control group ( P ≤ .001). There was a statistically significant strong positive correlation between serum renin level and the severity of hearing loss ( r = 0.77; P = .001). Conclusion: Serum renin levels of patients with ISSNHL were higher than controls. There was a statistically significant strong positive correlation between serum renin level and the severity of hearing loss.

SUN-184 Pseudohypoaldosteronism Presenting with Salt Wasting Crisis

Pseudohypoaldosteronism (PHA) is due to end organ resistance to mineralocorticoids. It is usually inherited in an autosomal recessive or autosomal dominant pattern, and rarely can a result of the mutation de novo. Zennaro MC, Hubert EL, Fernandes-Rosa FL. Aldosterone resistance: structural and functional considerations and new perspectives. Mol Cell Endocrinol. 2012;350:206-15.10.1016/j.mce.2011.04.023[Crossref], [PubMed], [Web of Science ®] It can be sub-classified into two forms PHA type 1 A involving the kidneys or PHA-1 B which effects multiple organs. PHA type 2 (Gordon syndrome) presents with hyperkalemia and hypertension. Case: Our patient is a 5 week old male who admitted for significant electrolyte abnormalities. He was followed by PCP for failure to thrive. The child was referred to ED with increased difficulty in feeding, lethargy and episodes of emesis. In the ED, the child was in a compensated shock and had a low normal BP: 76/35, HR: 169/min and fast breathing R/R: 80/minute and afebrile. P.E: showed signs of dehydration. Lab work showed: Na: 110 mEq/L, K: 9.3 mEq/L, low Chloride and Ca: 11.1 mEq/L. Endocrinology recommended IVF supplementation with 2 x NS bolus followed by IVF’s at 1.5 times maintenance (D5 + NS), along with administration of Florinef 0.2 mg suspecting CAH. Renin, 17-OHP, random cortisol level and thyroid hormone levels were ordered. Results showed: TSH of 5.30 mcIU/mL and Free T4 of 2.2 ng/dL. Cortisol: 20.5 mcg/dL. He was subsequently admitted to PICU. Septic work-up was negative. He became hemodynamically stable after hydration and did not require the stress dose of hydrocortisone. Repeat Na: 133 mEq/L, K: 4.7 mEq/L, Cl: 102 mEq/L and Glucose: 90 mg/dL. ACTH stimulation test for CAH evaluation was performed, stimulated 17OHP: 88 ng/dl, cortisol: 27.1 mcg/d and normal DOC. Elevated Aldosterone: 632 ng/dl (5-80) and renin level: 351 (6.5-86). A diagnosis of PHA was made and florinef was stopped and the child was started on NaCl supplementation which normalized the electrolytes. Genetic testing was negative for NR3C2, CUL3, KLHL3, SCNN1A, SCNN1B, SCNN1G, WNK4 and showed that the patient is a heterozygous for a variant of unknown significance, c.6276T&gt;A (p.Ser2092Arg) in the WNK1 gene. However, the patient did not have hypertension and urine electrolytes were also normal did not show signs of PHA 2. Conclusion: PHA can present with severe salt wasting crisis. It can be diagnosed clinically. The relationship of mutation and phenotype can be elusive. Course was uncomplicated and he was discharged from the PICU in 6 days. Sodium doses were titrated based on serum levels with eventual dose of 22.5mEq/kg/day and sodium level was 139 mEq/L.

Aliskiren, Fosinopril, and Their Outcome on Renin-Angiotensin-Aldosterone System (RAAS) in Rats with Thyroid Dysfunction

Background and Objectives. Thyroid hormones have an important role in the growth and development of various tissues including the kidney, which is the major site of renin release and the consequent angiotensin and aldosterone formation. Therefore any derangement in thyroid function can result in abnormal functioning in the renin-angiotensin-aldosterone system. The current study was undertaken to find the impact of using a direct renin inhibitor (Aliskiren) and an angiotensin-converting enzyme inhibitor (Fosinopril) on the components of the renin-angiotensin-aldosterone system (RAAS) in rats with thyroid dysfunctions. Method. Forty-two male albino rats were divided into three subgroups. First group (6 rats) served as control. Second group (18 rats) served as hyperthyroid group (6 rats positive control, 6 rats given Aliskiren, and 6 rats given Fosinopril). Third group (18 rats) served as hypothyroid group (6 rats positive control, 6 rats given Aliskiren, and 6 rats given Fosinopril). Induction of hyperthyroidism and hypothyroidism was done through daily oral administration of L-Thyroxine and Propylthiouracil, respectively. On day 40 of the study, the rats were sacrificed and blood was collected for estimation of renin, angiotensin I, angiotensin II, aldosterone, TSH, T3, and T4. The collected blood samples were also used for estimation of levels blood urea, serum creatinine, liver enzymes, and serum electrolytes. Blood pressure and urine collection were done on days 1 and 40. The collected urine was used for estimation of urine flow, sodium excretion, and potassium excretion rates. Results. In hypothyroid induced rats, serum renin level dropped as expected, while the use of Aliskiren and Fosinopril on these hypothyroid rats raised renin level due to the feedback mechanism. Both angiotensin I and II were significantly (P <0.05) lower than normal levels in the hypothyroid rats, unlike the level of aldosterone, which was higher than normal level. There was nonsignificant lowering in BP (systolic, diastolic, and mean BP) in the hypothyroid rats. Treatment of these rats with Aliskiren and Fosinopril did not lower the blood pressure more than normal when compared to the hypothyroid group. The hypothyroid rats also showed a decrease in level of serum creatinine. In hyperthyroid rats, there was a rise in levels of serum renin, angiotensin II, and aldosterone; nevertheless, the increase in angiotensin I level was significant. The use of Aliskiren and Fosinopril increased the level of renin nonsignificantly (decreased angiotensin I significantly). Hyperthyroid rats showed a significant increase in systolic, diastolic, and mean blood pressure. Both Aliskiren and Fosinopril increased urine flow, Na+ excretion, and K+ excretion rates. Aliskiren was better at reducing the high blood pressure. Conclusion. Aliskiren and Fosinopril in hyperthyroid rats decreased serum angiotensin I, angiotensin II, and aldosterone. Blockade of renin and inhibition of angiotensin-converting enzyme both resulted in a rebound increase in level of renin in hypothyroid rats. Aliskiren is better at controlling blood pressure in hyperthyroid rats. Urine flow, sodium excretion, and potassium excretion rates were improved by the use of Aliskiren and Fosinopril in hyperthyroid rats.

Normal male external genitalia do not rule out CYP11A1 deficiency

Defects in the initial steps of steroidogenesis usually present with female external genitalia in both 46,XX and 46,XY. Hence, they are not often considered in the differential diagnosis of primary adrenal insufficiency children with normal male external genitalia. Here, we report a boy with normal male external genitalia who presented with hyperpigmentation since the age of 2 years but diagnosis was delayed till 11 years of age. Evaluation revealed low-serum cortisol with elevated adrenocorticotropic hormone and direct renin level confirming primary adrenal insufficiency. Clinical exome sequencing analysis revealed a homozygous c.1351C>T (p.R451W) mutation in exon 8 of the CYP11A1 gene which was confirmed on Sanger sequencing. Both parents were heterozygous for the variation. To conclude, we report the first case of CYP11A1 deficiency from India. The report reiterates the existence of non-classic CYP11A1 deficiency characterised by primary adrenal insufficiency and normal male external genitalia in 46,XY.

No effect of the angiotensin receptor blocker candesartan on cerebrovascular autoregulation in rats during very high and low sodium intake

Autoregulation of cerebral blood flow (CBF) denotes that CBF is constant despite fluctuation of blood pressure within wide limits. Inhibition of the renin–angiotensin system (RAS) is known to decrease the lower and upper limits of CBF autoregulation. We have previously shown that this includes inhibition by the angiotensin receptor blocker (ARB) candesartan. In the present study we investigated the influence of the ARB candesartan on the lower limit of CBF autoregulation in two groups of Sprague-Dawley rats, on high (4.0% Na+) and low (0.004% Na+) sodium diet, respectively. Control animals were given the same diet, but no ARB. CBF was studied with the laser Doppler method. Blood pressure was lowered by controlled bleeding. Results revealed that both high and low sodium diet with low and high renin levels respectively block the influence of candesartan on CBF autoregulation. This was expected in rats on a high salt diet with a low renin level, but unexpected in rats with a low salt intake with a high renin level.