High Plasma Renin Levels Research Articles

Systemic pseudohypoaldosteronism-1 with episodic dyslipidemia in a Sudanese child.

SummarySystemic pseudohypoaldosteronism type 1 (PHA1) is a rare genetic syndrome of tissue unresponsiveness to aldosterone caused by mutations affecting the epithelial Na channel (ENaC). The classical presentation is life-threatening neonatal/infantile salt-losing crises that mimic congenital adrenal hyperplasia (CAH). Consistently, extra-renal manifestations, including respiratory symptoms that resemble cystic fibrosis, are well reported. Clinical diagnosis is made by the presence of hyponatremia, hyperkalemia, metabolic acidosis, respiratory symptoms, evidence of high renal and extra-renal salt loss in addition to high plasma renin and aldosterone levels. We herein report a novel manifestation of PHA1: episodic dyslipidemia in a 7-month-old Sudanese boy that occurred during the salt-losing crises. Whole exome sequencing of the patient revealed one homozygous missense variant c.1636G>A p.(Asp546Asn) in the SCNN1B gene, confirming our clinical and laboratory findings that were compatible with PHA1. This report aims to highlight the possible explanation of dyslipidemia in PHA1 and its expected consequences in the long term.Learning pointsA child presenting with features that mimic salt-losing congenital adrenal hyperplasia (CAH) crises that do not respond to glucocorticoid and mineralocorticoid therapy should alert the pediatricians to the possibility of end-organ resistance to aldosterone.Pseudohypoaldosteronism type 1 (PHA1) can be diagnosed even in the absence of advanced laboratory investigations.To our knowledge, this is the first case of systemic PHA1 to have a documented episodic dyslipidemia (primarily as marked hypertriglyceridemia).

Clinical features, genetic background, and outcome in infants with urinary tract infection and type IV renal tubular acidosis.

Type IV renal tubular acidosis (RTA) is a severe complication of urinary tract infection (UTI) in infants. A detailed clinical and molecular analysis is still lacking. Infants with UTI who exhibited features of type IV RTA were prospectively enrolled. Clinical, laboratory, and image characteristics and sequencing of genes responsible for phenotype were determined with follow-up. The study cohort included 12 infants (9 males, age 1-8 months). All exhibited typical type IV RTA such as hyperkalemia with low transtubular potassium gradient, hyperchloremic metabolic acidosis with positive urine anion gap, hypovolemic hyponatremia with renal salt wasting, and high plasma renin and aldosterone levels. Seven had hyperkalemia-related arrhythmia and two of them developed life-threatening ventricular tachycardia. With prompt therapy, all clinical and biochemical abnormalities resolved within 1 week. Five had normal urinary tract anatomy, and three of them carried genetic variants on NR3C2. Three variants, c.1645T>G (S549A), c.538G>A (V180I), and c.1-2C>G, on NR3C2 were identified in four patients. During follow-up, none of them had recurrent type IV RTA, but four developed renal scaring. Genetic mutation on NR3C2 may contribute to the development of type IV RTA as a complication of UTI in infants without identifiable risk factors, such as urinary tract anomalies.

Connexin37-Dependent Mechanisms Selectively Contribute to Modulate Angiotensin II -Mediated Hypertension.

BackgroundGap junction channels made of Connexin37 (Cx37) are expressed by aortic endothelial and smooth muscle cells of hypertensive mice, as well as by the renin‐secreting cells of kidneys.Methods and ResultsTo decipher whether Cx37 has any role in hypertension, angiotensin II (Ang II) was infused in normotensive wild‐type and Cx37‐deficient mice (Cx37−/−). After 2 to 4 weeks, the resulting increase in blood pressure was lower in Cx37−/− than in wild‐type mice, suggesting an alteration in the Ang II response. To investigate this possibility, mice were submitted to a 2‐kidney, 1‐clip procedure, a renin‐dependent model of hypertension. Two weeks after this clipping, Cx37−/− mice were less hypertensive than wild‐type mice and, 2 weeks later, their blood pressure had returned to control values, in spite of abnormally high plasma renin levels. In contrast, Cx37−/− and wild‐type mice that received N‐nitro‐l‐arginine‐methyl‐ester, a renin‐independent model of hypertension, featured a similar and sustained increase in blood pressure. The data indicate that loss of Cx37 selectively altered the Ang II‐dependent pathways. Consistent with this conclusion, aortas of Cx37−/− mice featured an increased basal expression of the Ang II type 2 receptors (AT2R), and increased transcripts levels of downstream signaling proteins, such as Cnksr1 and Ptpn6 (SHP‐1). Accordingly, the response of Cx37−/− mice aortas to an ex vivo AngII exposure was altered, since phosphorylation levels of several proteins of the AngII pathway (MLC2, ERK, and AKT) remained unchanged.ConclusionsThese findings provide evidence that Cx37 selectively influences Ang II signaling, mostly via a modulation of the expression of the Ang II type 2 receptor.

Unsuccessfully Treated Hypertension: A Major Public Health Problem With a Potential Solution.

About one-half of all hypertensive adults do not have their blood pressure controlled. They are often prescribed medications that conform to national guidelines but they continue to have elevated blood pressure. This public health problem might be improved by applying plasma renin guided therapy. A contributor to the public health problem of unsuccessfully treated hypertension is that the circulating renin-angiotensin system (RAS) is not recognized in treatment guidelines as clinically relevant for the treatment of hypertension or as important as the body salt status for determining blood pressure levels. Another contributor to the problem is the lack of specificity in the package inserts for antihypertensive drugs. They do not specifically state under the heading "Indications" that RAS blockers are primarily most effective in hypertensive subjects with medium and high plasma renin levels; by contrast, natriuretic drugs are most effective in those with low plasma renin levels. Literature review. To address the problem of unsuccessfully treated hypertension, we recommend that the "Indications" section of package inserts for antihypertensive drugs be more specific. The primary indication for RAS blockers ought to be hypertension with medium and high plasma renin levels, and natriuretic agents for those with low plasma renin levels. Similar language ought to be added to treatment guidelines. Additionally, 3 other reasons for lack of blood pressure control also need to be addressed-failure to prescribe antihypertensive drugs to hypertensive subjects, failure of patients to fill prescriptions, and low drug adherence.

Clinical features and molecular basis of pseudohypoaldosteronism type 1.

.Pseudohypoaldosteronism (PHA) type 1 is a disease showing mineralocorticoid resistance in the kidney and/or other mineralocorticoid target tissues. Patients with PHA1 present very high plasma aldosterone and renin levels, but they develop excessive salt wasting. There are three types of PHA1. The systemic form of PHA1 is inherited in an autosomal recessive manner and causes severe life-long salt loss in multiple target tissues, such as sweat glands, salivary glands, the colonic epithelium, and the lung. In the systemic form of PHA1, life-long salt supplementation is necessary. The second type is the renal form, where aldosterone resistance is shown only in the kidney, and its inheritance is autosomal dominant. In the renal form of PHA1, salt supplementation generally becomes unnecessary by 1–3 yr of age. The third type is the secondary PHA1, which is strongly associated with urinary tract infections and/or urinary tract malformations. This review summarizes the clinical features and molecular basis of PHA1. Understanding of its pathogenesis can be helpful for the early diagnosis and clinical care of affected children with PHA1.

A novel NR3C2 mutation in a Japanese patient with the renal form of pseudohypoaldosteronism type 1.

Pseudohypoaldosteronism type 1 (PHA1) is a rare disease characterized by congenital resistance to the action of aldosterone on epithelial tissue; PHA1 results in excessive salt wasting despite very high plasma aldosterone and renin levels (1,2,3). There are 3 types of PHA1. The systemic form of PHA1 is inherited in an autosomal recessive manner and manifests as severe life-long salt wasting caused by mineralocorticoid resistance in multiple target tissues (e.g., sweat glands, salivary glands, colonic epithelium, and lung). The renal form of PHA1 (adPHA1) is inherited in an autosomal dominant manner. In this form, mineralocorticoid resistance exists only in the kidney; moreover, salt wasting and other symptoms improve around 1–3 yr of age (1,2,3). The third type of PHA1 is the transient form, which is commonly seen in patients with urinary tract infection or obstructive uropathy. In the transient form, clinical symptoms disappear after treatment. adPHA1 is caused by a heterozygous mutation in NR3C2, which encodes the mineralocorticoid receptor (MR). Herein, we report the case of a young girl with adPHA1, a novel mutation in NR3C2, hyponatremia, and failure to thrive associated with urinary tract infection. We also describe a genetic analysis of her family.

High prevalence of cardiovascular risk factors in children and adolescents with Williams-Beuren syndrome.

BackgroundA high incidence of cardiovascular (CV) risk factors has been reported in adults with Williams-Beuren syndrome (WS). However, the prevalence of these factors in children and adolescents with WS is unknown. Therefore, the purpose of this study was to evaluate the prevalence of CV risk factors in these patients.MethodsThirty-two WS patients aged <18 years were enrolled in the study. Oxidized low-density lipoprotein levels (n = 32), oral glucose tolerance test results (n = 20), plasma renin and aldosterone levels (n = 31), 24-h ambulatory blood pressure (ABP; n = 24), carotid artery intima-media thickness (IMT; n = 15), and brachial artery flow-mediated dilatation (FMD; n = 15) were measured and analyzed.ResultsThe lipid profile revealed hypercholesterolemia in 22 % and elevated oxidized low-density lipoprotein levels in 94 % of the patients. Glucose metabolism abnormalities were found in 70 % of the patients. Insulin resistance was observed in 40 % of the patients. High plasma renin and aldosterone levels were detected in 45 and 39 % of the patients, respectively. A mean systolic blood pressure above the 90th percentile was noted in 29 % of patients. High IMT (>0.65 mm) and low FMD (<9 %) were detected in 80 and 73 % of patients, respectively.ConclusionIn patients with WS, CV risk factors are frequently present from childhood. In children with WS, screening tests for the early detection of CV risk factors and long-term follow-up are required to determine whether long-term exposure to these factors increases the risk for CV events in adulthood.

A challenging case of renovascular hypertension

vmj.sagepub.com Moderate arterial hypertension was incidentally diagnosed in an asymptomatic 14-year-old girl with an otherwise unremarkable medical history and physical examination. Serum creatinine, acute phase reactants and echocardiography were normal, whilst ocular fundus examination revealed mild retinal vascular tortuosity. High plasma renin and aldosterone levels suggested renovascular hypertension. Three-dimensional volume-rendering computed tomographic (CT) angiography (Panel A) and catheter-based digital subtraction angiography (DSA) (Panel B) showed an absence of flow in both ostial and proximal segments of the left renal artery with a normal appearance of the aortic wall (arrow). A complex collateral arterial network, originating from a hypertrophic left lumbar artery (chevron), bypassed these segments and merged with a normal-sized middle tract of the left renal artery, causing a delayed parenchimography of the ipsilateral kidney in comparison with the contralateral (Panel B). All other aortic branches including right renal artery, as well as aorta and supra-aortic arteries, appeared normal on DSA. Left and right kidney size were comparable on CT. Surgical exploration could not find any vascular structure or remnant connecting the aortic wall to the residual segment of the left renal artery. Histological examination of a sample of aortic wall and periaortic tissue was unremarkable: the former showed a normal arterial wall, the latter revealed the presence of adipose tissue. Normalization of blood pressure was achieved after surgical reconstruction with aortorenal bypass.

Renin-Angiotensin System Blockers May Create More Risk Than Reward for Sodium-Depleted Cardiovascular Patients With High Plasma Renin Levels

Four recent reports revealed differences in survival rates among treated cardiovascular patients taking renin-angiotensin system-blocking drugs. Patients with higher on-treatment plasma renin activity (PRA) levels died sooner of cardiovascular mortality than those with lower levels. We investigated whether excessive sodium depletion might have induced the higher PRA levels and contributed to the greater morbidity and mortality. Using published data, ranges of PRA, blood pressures, drug usage, and biochemical parameters were compared among various groups of cardiovascular patients. We showed (i) that PRA levels are usually medium to low in treated cardiovascular patients, but are sometimes abnormally high, (ii) that excessive sodium depletion can induce such high PRA levels, (iii) that the higher PRA patients exhibited evidence of sodium depletion: lower blood pressures, more frequent natriuretic drug usage, lower N-terminal pro b-type natriuretic peptide (NT-proBNP), and higher blood urea nitrogen and uric acid levels, with similar usage of renin-angiotensin blocking drugs. We hypothesize that patients with high on-treatment PRA levels die sooner of cardiovascular events because they are excessively sodium-volume depleted. Moreover, renin-angiotensin system-blocking drugs may be harmful in such patients because they can functionally interfere with the effects of reactive rises in PRA that are triggered to prevent potentially dangerous falls in blood pressure, increases in plasma potassium, and falls in glomerular filtration rate. Careful liberalization of salt intake and subtraction of natriuretic drugs, sufficient to reduce reactive hyperreninemia without inducing unacceptable increases in blood pressure, might benefit such patients and decrease risk of adverse effects from drugs that block the renin-angiotensin system.

Two novel mutations of the CYP11B2 gene in a Japanese patient with aldosterone deficiency type 1

Isolated hypoaldosteronism is a rare and occasionally life-threatening cause of salt wasting in infancy. A 2-month-old Japanese boy of unrelated parents was examined for failure to thrive and poor weight gain. Laboratory findings were hyponatremia, hyperkalemia, high plasma renin and low aldosterone levels. Spot urine analysis by gas chromatography-mass spectrometry (GC-MS) showed that urinary excretion of corticosterone metabolites was elevated. Whereas excretion of 18-hydroxycortricosterone metabolites was within the normal range, excretion of aldosterone metabolites was undetectable. The patient was therefore suspected to have aldosterone synthase deficiency type 1. Sequence analysis of CYP11B2, the gene encoding aldosterone synthase (CYP11B2), showed that the patient was a compound heterozygote for c.168G>A, p.W56X in exon 1 and c.1149C>T, p.R384X in exon 7. p.W56X was inherited from his mother and p.R384X was from his father. Since both alleles contain nonsense mutations, a lack of CYP11B2 activity was speculated to cause his condition. To our knowledge, this is the first Japanese patient in which the molecular basis of aldosterone synthase deficiency type 1 has been clarified. This case also indicates that spot urinary steroid analysis is useful for diagnosis.

Concurrence of Thyrotoxicosis and Gitelman’s Syndrome-Associated Hypokalemia-Induced Periodic Paralysis

A 16-year-old Japanese boy with a history of truancy had been treated at a psychiatric clinic. When the patient was referred to us for hypokalemia-associated paralysis, the diagnosis of thyrotoxic hypokalemic periodic paralysis was made, common in Asian men. Subsequently, the patient was found to have persistently high plasma renin and aldos-terone levels. Thus, solute carrier family 12 member 3 gene (SLC12A3) analysis was performed. A novel missense homozygous mutation CTC->CAC at codon 858 (L858H) was found for which the patient was homozygous and his non-consanguineous parents heterozygote. These findings indicated that the patient developed hypokalemia-associated paralysis concurrently with thyrotoxicosis and Gitelman's syndrome. This case underscores the importance of careful examinations of adolescents with complaints of truancy as well as of precise determinations of the causes of hypokalemia-associated paralysis.

Common genetic variations of the renin–angiotensin–aldosterone system and response to acute angiotensin I-converting enzyme inhibition in essential hypertension

In order to get insight into possible genetic determinants of antihypertensive drug action, we analysed the relations between polymorphisms of the genes of the renin-angiotensin-aldosterone system and acute effects of ACE inhibition on blood pressure as well as circulating renin and aldosterone levels in hypertensive patients. A total of 315 hypertensive patients referred for problems in drug treatment were given a single 50 mg dose of captopril. Plasma renin and aldosterone were measured before and 60 min after the drug administration. Four DNA variants, including angiotensin type I receptor (AGTR1) 1166 A/C, angiotensin-converting enzyme (ACE) I/D, angiotensinogen (AGT) M235T and AGT -217 G/A, were genotyped in the patients and normotensive men (n = 175). A replication study on the relation between AGTR1 1166 A/C and plasma renin and aldosterone levels was carried out in the 244 hypertensive men of the pharmacogenetic GENRES Study. Referred hypertensive patients with the AGTR1 CC genotype had higher aldosterone at baseline (P = 0.02) and after 60 min of captopril administration (P = 0.01) compared with the AA genotype. Replicate analysis in the GENRES patients showed a similar trend. When the two studies were combined (315 and 244 patients, respectively), plasma aldosterone level (P = 0.007) as well as aldosterone/renin ratio (P = 0.04) were significantly higher in the CC genotype (n = 13) than in the AA genotype (n = 370). Transfection studies in cultured HEK293 cells indicated that the 1166C allele was associated with higher mRNA levels than the 1166A allele. The AGTR1 1166C allele when present in homozygous form may be associated with a form of essential hypertension characterized by high plasma aldosterone and low plasma renin levels, possibly due to increased AGTR1 mRNA levels and augmented angiotensin II action.

High plasma aldosterone and low renin predict blood pressure increase and hypertension in middle-aged Caucasian populations

Plasma aldosterone and renin levels have been associated with blood pressure increase and 3-4 year incidence of hypertension in a middle-aged North American community in Framingham. To confirm these findings in a different population, a nested case-control study was performed in a national sample of 1984 French non-hypertensive volunteers aged 45-64 year and followed for 5 years. Cases and controls (individuals becoming hypertensive or remaining non-hypertensive on follow-up) were individually matched on sex, diastolic and systolic pressures at baseline. Multivariable regression models show that plasma aldosterone and renin are respectively positively and negatively associated with the increase in systolic pressure (P=0.01 and 0.001) and the risk of hypertension (22% increase and 16% decrease per s.d. increment in the log, P=0.04 and 0.07). These associations are mostly observed in the lowest tertiles of dietary sodium and potassium intakes where plasma aldosterone is positively associated with the increase in systolic pressure (P=0.01 and 0.08) and the risk of hypertension (59 and 69% increase per s.d. increment in the log, P=0.02 and 0.01), whereas plasma renin is negatively associated with the increase in systolic pressure (P=0.0004 and 0.004) and the risk of hypertension (31 and 28% decrease per s.d. increment in the log, P=0.03 and 0.05). These results reinforce the hypothesis that high plasma aldosterone and low plasma renin levels precede blood pressure increase and the occurrence of hypertension in middle-aged Caucasian populations.

Resistência aos mineralocorticóides: pseudo-hipoaldosteronismo tipo 1

Pseudohypoaldosteronism type 1 (PHA1) is a rare genetic disease characterized by neonatal renal salt wasting, vomiting, dehydration and failure to thrive. Affected patients present hyponatremia, hyperkalemia, associated with high levels of plasma renin and aldosterone resulting from a renal or systemic resistance to aldosterone. The systemic form of PHA1 results in a severe phenotype, and high doses of salt supplementation are necessary. The symptoms are life-long recurrent. This form is associated with autosomal recessive transmission. Homozygous or compound heterozygous loss of function mutations in the genes coding for the epithelial sodium channel (ENaC) subunities are responsible for this disease. The renal form of PHA1 results in a mild phenotype. Low doses of salt supplementation are required and usually the symptoms remit at the end of the first year of life. Heterozygous loss-of-function mutations in the mineralocorticoid receptor (MR) gene are associated with the renal form of PHA1 in the majority of the affected families but sporadic cases have been reported. In this review the mechanisms of aldosterone action and its effects are discussed. Additionally, clinical and molecular findings of a Brazilian family with the renal form of PHA1 caused by a nonsense mutation (R947X) in the MR gene are presented.

Liver Failure and Liver Disease

Liver Failure and Liver Disease

Troponin T as a marker of differentiation revealed by proteomic analysis in renal arterioles.

Renovascular hypertension is characterized by stenosis of the renal artery and high plasma renin levels. The renal phenotype is characterized by high levels of renin in the hypoperfused kidney due to the recruitment of renin-producing cells along the afferent arterioles. This increase in myoepithelioïd cells is due mainly to the differentiation of existing smooth muscle cells with acquisition of a secretory phenotype. To understand the molecular mechanisms involved in this recruitment, we used the established rat model of renovascular hypertension known as the two-kidney, one-clip model in the Lewis rat. Renal arterioles were isolated using magnetized iron suspension. Differential proteomic analysis was performed using 2-D polyacrylamide gel electrophoresis followed by mass spectrometry. Comparative analysis of soluble proteins extracted from afferent arterioles of clipped and contralateral kidneys showed 14 proteins significantly differentially expressed by at least a factor of 2. These proteins were identified by mass spectrometry. The most striking protein revealed by proteomics is troponin T, which is down-regulated in the afferent arterioles of the clipped kidney. Confocal microscopy showed that troponin T is specific of the smooth muscle phenotype and absent in the myoepithelioïd phenotype. Our data suggest that troponin T is only present in renal smooth muscle cells.

Analyse protéomique des protéines impliquées dans le phénotype rénal en hypertension rénovasculaire

Renovascular hypertension is characterised by stenosis of the renal artery and high plasma renin levels due to the recruitment of renin-producing cells along the afferent arterioles. This increase in myoepithelioid cells is mainly a result of the differentiation of existing smooth muscle cells with acquisition of a secretory phenotype. To understand the molecular mechanisms involved in this recruitment, we used the model of renovascular hypertension known as the two-kidney, one-clip model in the Lewis rat. Renal arterioles were isolated using magnetised iron suspension. Differential proteomic analysis was performed using two-dimensional electrophoresis gel followed by mass spectrometry for identification. The most striking protein revealed by proteomics is troponin T, which is down-regulated in the afferent arterioles of the clipped kidney. Confocal microscopy showed that troponin T is specific to the smooth muscle phenotype and absent in the myoepithelioid phenotype.

Inactivating mutations of the mineralocorticoid receptor in Type I pseudohypoaldosteronism

Type I pseudohypoaldosteronism (PHA1) is a rare form of mineralocorticoid resistance characterized by neonatal renal salt wasting and failure to thrive. Typical biochemical features include high levels of plasma aldosterone and renin, hyponatremia and hyperkalemia. Different mutations of the human mineralocorticoid receptor ( hMR) gene have been identified in subjects affected by the autosomal dominant or sporadic form of the disease. Our laboratory has investigated a large number of subjects with familial and sporadic PHA1. Several different mutations have been detected, which are localized in different coding exons of the hMR gene. These mutations either create truncated proteins, either affect specific amino acids involved in receptor function. In this paper, we review hMR mutations described to date in PHA1 and their functional characterization. We discuss the absence of mutations in some kindreds and the role of precise phenotypic and biological examination of patients to allow for identification of other genes potentially involved in the disease.

Irbesartan results in more complete blockade of human renal at 1-receptor mediated effects than does candesartan cilexetil as evidenced by higher plasma renin levels

Irbesartan results in more complete blockade of human renal at 1-receptor mediated effects than does candesartan cilexetil as evidenced by higher plasma renin levels

The Renin-Angiotensin System in Essential Hypertension: Associations with Cardiovascular Risk

The importance of the renin-angiotensin system (RAS) in blood pressure regulation is well established. High RAS activity has also been implicated in connection with elevated cardiovascular risk in patients with essential hypertension. Data from epidemiological studies have related high plasma renin levels in essential hypertensive patients to cardiovascular complications. However, whether renin itself is a risk factor of cardiovascular events or just acts as a marker for other risk factors still remains to be elucidated. Several possible mechanisms that could be responsible for the association between elevated RAS activity and cardiovascular risk are reviewed. The concept of high RAS activity being a cardiovascular risk factor is strongly supported by results from large clinical studies showing the beneficial effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in congestive heart failure and hypertension. Knowing more about the exact mechanisms of the association between high RAS activity and cardiovascular complications would enable us to profile the treatment of high blood pressure more specifically to improve outcome in individuals or groups of patients.