Polymorphism of the aldosterone synthase gene is not associated with progression of diabetic nephropathy, but associated with hypertension in type 2 diabetic patients

Aim: Inhibition of aldosterone system is beneficial in diabetic nephropathy, and aldosterone synthesis is regulated at the gene-encoding aldosterone synthase (CYP11B2). Considering the role of aldosterone in diabetic nephropathy, genetic polymorphism of this gene may contribute to the development and progression of diabetic nephropathy. In this study, we investigated whether it is associated with diabetic nephropathy in type 2 diabetic patients. Methods: 197 type 2 diabetic patients and 71 healthy controls were enrolled. The study subjects were divided into four groups: healthy controls with normoalbuminuria (n = 71), normoalbuminuric diabetic group (n = 71), microalbuminuric diabetic group (n = 51) and overt proteinuria group (n = 51). Polymorphism of aldosterone synthase gene was determined using standard PCR technique. Results: Higher frequency of TT genotype and T allele in steroidogenic factor-1 (SF-1) binding site and wild type (WT) in intronic conversion (IC) in CYP11B2 was observed in diabetic patients than controls. However, there was no significant difference in SF-1 and IC genotype among diabetic patients according to the state of diabetic nephropathy. Subgroup analysis based on SF-1 polymorphism demonstrated that TT genotype is associated with higher systolic and diastolic blood pressure and higher plasma aldosterone level. In addition, WT in IC genotype showed a significantly higher urinary albumin excretion rate. Plasma aldosterone level was significantly related with systolic blood pressure. Conclusion: Our study suggests that aldosterone synthase gene polymorphism is not associated with progression of diabetic nephropathy, but it may contribute to the development of hypertension associated with increased aldosterone secretion in type 2 diabetic patients.     

Natriuretic and kaliuretic response to potassium load: modulation by sodium intake

Potassium (K) loading is followed by a rapid increase in sodium(Na) and K excretion. To evaluate the influence of Na intakeon this effect, we studied the acute natriuretic and kaliureticresponse to a single oral K load (100 mmol) in six healthy volunteersequilibrated on a 10-, 100-, and 400-mmol Na intake. Comparedto the 100-mmol Na intake, the 400-mmol Na intake greatly enhancedthe natriuretic effect of the K load; during the 10-mmol Naintake no natriuresis but even some Na retention occurred. Thekaliuretic effect was not significantly changed and occurredat similar values of plasma K. Plasma aldosterone was suppressedduring the 400-mmol Na diet and stimulated during the 10-mmolNa diet, but the relative increments after the KCI load didnot differ among the three diets. In conclusion, whereas theeffect of a K load on kaliuresis is relatively independent ofNa intake, its effect on Na excretion varies from marked natriuresisto slight Na retention. The Na retention is probably due toacute K-induced aldosterone stimulation, and the natriuresisto K-induced increase in distal Na delivery not utilized topromote K excretion. Apparently, the integration of renal Naand K handling after a K load is such that K balance is maintainedat the cost of Na balance.     

醛固酮瘤中长链非编码RNA的差异表达及功能分析

目的研究在醛间酮瘤中有差异表达的长链非编码RNA (Long non-coding RNA,lncRNA)并初步分析后者在醛同酮瘤发生发展中的作用。方法通过基因芯片筛选醛固酮瘤中瘤体相对于瘤旁有差异表达的lncRN A,通过分析得出目标lncRN A,并使用RT-qPCR对目标lncRNA的表达情况进行验证,初步分析该目标lncRNA可能具有的功能。结果经过基因芯片筛选及分析后,得出两条目标lnCRNA——NR_040090、T065445。经过RT-qPCIR验证可知二者在瘤体中表达均为上调,与基因芯片结果一致。经过lncRNA与mRNA共表达分析以及联合分析可知,NR_040090可能与醛固酮合成相关;T065445则既可参与醛固酮合成,也可能介导肾上腺细胞增生从而形成肿瘤。结论 lncRNA——NR_040090、T065445在醛固酮瘤瘤体中表达上调,前者可能与醛固酮瘤中醛固酮过量合成相关,后者可能与醛固酮合成异常及肿瘤形成相关。     

地氟醚对手术病人肾素—血管紧张素—醛固酮系统及皮质醇的影响

目的 观察地氟醚在手术中对肾素-血管紧张素-醛固酮系统（RAAS）及皮质醇的影响。方法 选择30例择期在全麻下实施上腹部手术病人，随机分为地氟醚组和安氟醚组，每组15例。术中分五个时点采集静脉血，以放免法测定血浆肾素活性（PRA）、血管紧张素Ⅱ（AⅡ）、醛固酮（Al）及皮质醇（Cor）。结果 地氟醚组在切皮时即出现PRA、AⅡ、Al的升高，尤以Al显著，术中继续升高。两组Cor术中均升高，但无明显组间差异。地氟醚组中血压及心率增加明显。结论 地氟醚可早期激活RAAS，并有交感兴奋作用；但不能抑制手术刺激引起的Cor升高。     

Aldosterone breakthrough during therapy with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in proteinuric patients with immunoglobulin A nephropathy

BACKGROUND: We are investigating whether aldosterone breakthrough negatively impacts on the antiproteinuric effects of angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II receptor blockers (ARB). METHODS: We examine the role of aldosterone breakthrough in 43 normotensive, proteinuric (0.7 +/- 0.3 g/day) outpatients (aged 41.5 +/- 10.9 years) with immunoglobulin A nephropathy (IgAN) accompanied by stable renal function (creatinine clearance >50 mL/min). The patients were treated with temocapril (1 mg; n = 14), losartan (12.5 mg; n = 16), or a combination therapy (n = 13) for 12 months. We prospectively evaluated blood pressure (BP), urinary protein excretion (UPE), biochemical parameters and the renin-angiotensin-aldosterone system before and after 12 months of treatment. RESULTS: Although the overall plasma aldosterone concentrations values did not change after any of the treatments administered for 12 months, they eventually increased in 23 (temocapril, seven patients; losartan, eight patients; combination, seven patients) of the 43 patients (53.4%; aldosterone breakthrough), and fell in the remainder (46.6%). Blood pressure and renal function did not differ among the three groups at 12 months. In contrast, UPE was significantly higher in patients with, than without aldosterone breakthrough during temocapril and losartan administration. However, combination therapy induced a more remarkable reduction in UPE regardless of aldosterone breakthrough. CONCLUSIONS: A combination of ACE inhibitors and ARB in normotensive patients with IgAN produces a more profound decrease in proteinuria than either monotherapy. This additive antiproteinuric effect is not dependent on aldosterone breakthrough. Additional larger, prospective, randomized studies will be needed for general acceptance of this strategy.     

Adrenocortical Adenoma Producing 18-Hydroxycorticosterone

A 30-year-old man presented at our hospital with microscopic hematuria. Ultrasonography and computed tomography scanning revealed a right adrenal mass measuring 20 × 20mm. The tumor was asymptomatic, but there was obvious accumulation on the right side when scintigraphy was performed with radioactive iodine (¹³¹I)-labeled adosterol. Endocrinology studies showed elevation of the plasma cortisol and renin concentrations, while the plasma aldosterone level was low. Right laparoscopic adrenalectomy was done on July 4, 1994. Histologic examination showed an adrenocortical adenoma. Serum levels of adrenocortical hormones were measured before and after surgery, and the tissue content for the same hormones was determined in the resected tumor. The hormonal studies showed that the tumor produced 1 8-hydroxycorticosterone.     

Altered renin and aldosterone excretion in patients treated for metastatic germ cell tumours

Twenty-four patients with metastatic germ cell tumours were studied for abnormalities in the renin-aldosterone axis and for persistent abnormalities of renal function 9+ to 54+ months following completion of cisplatin based chemotherapy. Increased plasma renin activity and aldosterone were identified in fourteen of nineteen (79%) patients. The mean serum magnesium was subnormal. Statistically lower serum phosphorus levels, and higher urea and creatinine levels were also observed. No patients was hypertensive or on diuretics at the time of study. Since vascular toxicity has been reported after cisplatin based chemotherapy and hypomagnesaemia and increased plasma renin activity have been linked to cardiovascular events, these data imply that germ cell tumour patients treated with cisplatin based chemotherapy should be carefully observed for delayed cardiovascular toxicity.     

Aldosterone resistance in kidney transplantation is in part induced by a down-regulation of mineralocorticoid receptor expression

BACKGROUND: After renal transplantation immunosuppressive drugs-like cyclosporin A (CsA) and FK506 induce either hypoaldosteronism or pseudo-hypoaldosteronism presenting with hyperkalemia and metabolic acidosis. We investigated the relationship between renal allograft function under CsA therapy and plasma aldosterone concentration, potassium- and water homeostasis and mineralocorticoid receptor (MR) expression level in peripheral leukocytes. METHODS: We studied 21 renal transplant patients under CsA therapy and 12 healthy controls. Transplant recipients were studied before and under fludrocortisone treatment. Using quantitative reverse-phase polymerase chain reaction (RT-PCR) specific for the MR, we analyzed the level of expression of MR in peripheral leukocytes. RESULTS: In acidotic transplant recipients (HCO(3) 18.5 +/- 1.2 mM) renal function was only slightly impaired with 2.0 +/- 0.2 mg creatinine/dL when compared with 1.8 +/- 0.3 mg/dL (ns) in non-acidotic patients (HCO(3) 23.0 +/- 2.8 mM). Mean plasma aldosterone levels in renal transplant recipients did not differ from control levels (150 +/- 33 pg/mL vs. 148 +/- 33 pg/mL, ns). In contrast, the expression level of MR in peripheral leukocytes of renal transplant recipients treated with CsA was significantly decreased when compared with healthy controls without renal disease (120 +/- 78 vs. 423 +/- 73 RNA molecules/0.5 microg total RNA, p < 0.01). The level of expression of MR in renal transplant recipients did not differ between acidotic patients and non-acidotic patients (ns). The application of fludrocortisone reversed hyperkalemia and metabolic acidosis without significant effect on MR expression. CONCLUSIONS: The present data demonstrate that hyperkalemia and metabolic acidosis following CsA treatment in kidney transplantation might be associated with a down-regulation of MR expression on peripheral leukocytes. Electrolyte imbalance is reversible on application of fludrocortisone. This observation supports fludrocortisone treatment in transplant patients with severe electrolyte disturbances.     

Hypothesis: a simple algorithm to distinguish between hypoaldosteronism and renal aldosterone resistance in patients with persistent hyperkalemia

Aim: Many patients with hyperkalemia have a readily identifiable cause, which leads to appropriate management. In others, particularly those with a reduced glomerular filtration rate, differentiating between (relative) hypoaldosteronism (HA) and renal aldosterone resistance (RAR) can be problematic. The aim of this study was to see if a plasma aldosterone to potassium algorithm could be defined which would help identify patients with hyperkalemia owing to suboptimal levels of aldosterone, thereby validating treatment with 9-alpha-fluhydrocortisone, instead of cation exchange resins, if more conservative treatment fails. Methods: A literature search for, and analysis of, studies providing details of plasma aldosterone and plasma potassium in normals (made hyperkalemic)and patients with a plasma potassium >5.3 mmol/L, and a contemporaneous plasma aldosterone. Results: One study was found in which normals were made significantly hyperkalemic (to 6.3 mmol/L). These subjects, while on a high sodium, low potassium (western) diet (n = 5), provided an arbitrary definition of a simple aldosterone to potassium algorithm for diagnosis (factored aldosterone (FAldo) = plasma aldosterone/(plasma K – 4.2)). The limit for FAldo is set at 280(pmol/L) or 10(ng/dL): results below the limit suggest HA; above the limit, RAR. This algorithm was then tested against, and, when plasma potassium was greater than 5.3, found to be consistent with, reported patients with confirmed HA (n = 33) and pseudohypoaldosteronism (n = 23). The ratios in reported patients with renal failure (n = 43) were consistent with either HA (n = 30) or RAR(n = 13). Hypothesis: In hyperkalemic patients a plasma aldosterone to potassium algorithm may help distinguish HA from RAR, thereby guiding therapy.     

Role of aldosterone in stress‐induced antinatriuresis in normotensive saline overload rats

The aim of this study was to determine aldosterone participation in the stress‐induced antinatriuresis in normotensive saline overload rats, as a probable cause of stress‐induced hypertension. Spironolactone (Sp) 6 mg/kg/day, intraperitoneal injection, as a Mineralocorticoid receptor antagonist was used. The rats were divided into four groups: basal (B), basal drug (B‐Sp), stress [Immobilization stress (IMO)] and stress‐Sp (IMO‐Sp). Urinary Na⁺ and K⁺ were measured and the K⁺/Na⁺ ratio was calculated. Aldosterone and corticosterone plasmatic levels were determined. Stressed rats showed higher aldosterone and corticosterone levels than the ones in the basal group. The antinatriuretic effect in response to acute IMO was not reverted with Sp. However, IMO‐Sp animals showed higher urinary sodium levels than IMO animals suggesting a partial inhibition of the stress response. The IMO‐Sp animals excreted 50 per cent of basal sodium while IMO animals excreted about 20 per cent of B sodium. This effect was also evidenced in the urinary K⁺/Na⁺ ratio. In conclusion, aldosterone would be a factor influencing sodium reabsorption in stressed rats. Since sodium distal handling is small with respect the proximal ones, in which the sympathetic innervation is great, the inhibition of aldosterone action is not enough to revert antinatriuretic effect. Besides, the high levels of corticosterone might exert some effect on stress‐induced antinatriuresis. These results show the importance of aldosterone in the sodium reabsorption in IMO rats as a contributing factor to explain the origin of stress‐induced hypertension in rats. Copyright © 2008 John Wiley & Sons, Ltd.     

The Effects of Spironolactone on Nephron Function in Patients with Diabetic Nephropathy

Increasing evidence suggests that circulating aldosterone per se contributes directly to renal and cardiovascular diseases. We sought to evaluate the effects of a three-month treatment with 25 mg spironolactone, an aldosterone receptor antagonist, on nephron function in 20 type II diabetic patients with persistent microalbuminuria, despite at least six months' use of an ACEi or ARB (combination group), and in eleven type II diabetic patients with persistent microalbuminuria who have never used an ACEi or an ARB (spironolactone group). In the combination group, urinary protein excretion (UPE, p = 0.015), urinary albumin excretion (UAE, p = 0.010), and the urinary albumin to creatinine ratio (ACR, p = 0.007) decreased, and serum potassium (sK⁺, p = 0.004) was significantly elevated. ACR (p = 0.016) decreased significantly in the spironolactone group. In 31 patients given spironolactone (all patients group), UPE (p = 0.019), UAE (p = 0.002), and ACR (p = 0.011) decreased, and serum creatinine (sCr, p = 0.025) and sK⁺ (p = 0.002) were significantly elevated. Changes in albuminuria showed a positive correlation with changes in GFR (p = 0.002) and a negative correlation with changes in sCr (p = 0.007), and changes in ACR showed a negative correlation with changes in sCr (p = 0.004) in all patient groups. In our study, we observed that spironolactone, both alone and in combination with ACEi/ARB treatment, was well tolerated, and that it slowed down the progression of diabetic nephropathy with a marked antialbuminuric effect. Our results showed that the antialbuminuric effect developed by the decrease of intraglomerular pressure, particularly in patients with persistent microalbuminuria despite long-term ACEi/ARB treatment; adding aldosterone blockers to treatment was beneficial.