Renin Status Research Articles

Suppressed Renin Status Is a Risk Factor for Cardiocerebrovascular Events in Bilateral Primary Aldosteronism Treated With Mineralocorticoid Receptor Antagonists

ObjectiveMineralocorticoid receptor antagonists are the recommended medical therapy for bilateral primary aldosteronism (BPA). Patients with BPA have higher risk of cardiocerebrovascular disease (CCVD) than those with essential hypertension. There is no consensus on the criteria to assess the effectiveness of medical therapy for BPA. This study aimed to investigate the incidence of and risk factors for CCVD after medical therapy of BPA. MethodsWe conducted a retrospective cohort study including 240 patients with BPA treated with mineralocorticoid receptor antagonists. The posttreatment plasma renin activity (PRA) was defined as unsuppressed (PRA, ≥1 ng/mL/h); otherwise, it was defined as suppressed. We analyzed the association of posttreatment PRA status with CCVD outcomes. ResultsOf patients with BPA, 7.1% (17/240) developed CCVD at a median follow-up of 5.0 (range, 2.96-7.66) years. Moreover, 57.1% of patients had a PRA of ≥1 ng/mL/h after treatment. Patients with a PRA of <1 ng/mL/h had a higher incidence of CCVD (12.6% vs 2.9%, P < .05) and were at higher risk than those with a PRA of ≥1 ng/mL/h (hazard ratio, 4.50 [95% CI, 1.47-13.83; P < .05]; adjusted hazard ratio, 3.98 [95% CI, 1.22-13.02; P < .05]). ConclusionPatients with BPA who receive pharmacologic treatment have a high incidence of CCVD. PRA may be an indicator that mineralocorticoids are being adequately antagonized.

FRI155 Effect Of Reversal Of Renin Suppression On Renal Outcome In Medically Treated Primary Aldosteronism

Abstract Disclosure: Y. Tsurutani: None. S. Katsuragawa: None. K. Inoue: None. K. Nakai: None. J. Saito: None. T. Nishikawa: None. A. Goto: None. Background and Objective: In the strategy of medical treatment with mineralocorticoid receptor antagonist (MRA) for primary aldosteronism (PA), achieving reversal of renin suppression, which reflects effective blockade of the mineralocorticoid receptor activation, is considered a reasonable approach. However, whether this approach mitigates long-term renal impairment is still unclear. We examined whether reversal of renin suppression after initiation of MRA affects the long-term renal outcome among patients with medically treated PA. Methods: This study included 318 adults with primary aldosteronism who started MRA between 2008 to 2020. The post-treatment renin status was defined as unsuppressed (i.e., reversal of renin suppression) when individual plasma renin activity at least 6 months after the initiation of MRA (post-PRA) was 1.0 ng/mL/h or more; otherwise the post-treatment renin status was defined as suppressed. We analyzed the association of the post-treatment renin status with the change in subsequent longitudinal estimated glomerular filtration rate (eGFR) using linear mixed-effects models for repeated measurements. Results: Among 318 patients analyzed, the post-treatment renin status of 119 patients was unsuppressed (median post-PRA [interquartile range] = 1.7 [1.3-2.5] ng/mL/h) and that of 199 patients was suppressed (median post-PRA [interquantile range] = 0.5 [0.3-0.7] ng/mL/h). Through the median follow-up period of 3.1 years, the decline in eGFR was less severe among patients with the unsuppressed post-treatment renin (−0.554 [95% CI, −0.73 to -0.36] ml/min/1.73m2/year) compared to those with suppressed renin (−1.42 [95% CI, −1.56 to −1.27] ml/min/1.73m2/year; deference, 0.87 [95% CI, 0.62 to 1.12] ml/min/1.73m2/year) after adjusting for potential confounders. In subgroup analyses, the difference in annual eGFR change by the post-treatment renin status was greater among female patients (1.17 [95% CI, 0.82 to 1.53] ml/min/1.73m2/year) than male patients (0.60 [95% CI, 0.27 to 0.94] ml/min/1.73m2/year; P-for-interaction = 0.02), among overweight patients (1.14 [95% CI, 1.04 to 1.78] ml/min/1.73m2/year) than non-overweight patients (0.46 [95% CI, 0.15 to 0.77] ml/min/1.73m2/year; P-for-interaction &amp;lt; 0.01), and among patients with higher plasma renin activity at baseline (1.38 [95% CI, 0.90 to 1.86] ml/min/1.73m2/year) than those with lower plasma renin activity at baseline (0.69 [95% CI, 0.39 to 0.99] ml/min/1.73m2/year; P-for-interaction = 0.02). Conclusion: The post-treatment unsuppressed renin was associated with subsequent milder eGFR decline. Our findings indicate the importance of reversal of renin suppression with optimal MRA titration for medically treated primary aldosteronism that could mitigate the adverse renal outcome. Presentation: Friday, June 16, 2023

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

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. 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. 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). 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.

Abstract MP46: Mutagenesis Of PRR Cleavage Site In Mice Attenuates Angiotensin II-induced Hypertension And Suppresses Renin Expression

It is well demonstrated that activation of renal (pro)renin receptor (PRR) contributes to AngII-induced hypertension. Relatively, less is known about involvement of soluble PRR (sPRR), the extracellular domain of PRR, primarily generated by site-1 protease(S1P) and furin. Moreover, the relationship between PRR/sPRR and the renin-angiotensin system (RAS) has been debated. In the present study, we used CRISPR/Cas9 strategy to generate mice with mutagenesis of the overlapping cleavage site for both proteases in PRR (termed as PRR R279V/L282V ) to examine the phenotype during angiotensin II (AngII) infusion with particular emphasis on circulating and intrarenal renin status. PRR R279V/L282V mice exhibited a reduction of sPRR level in plasma by ~53% and in the kidney by ~82%, were fertile, and had no gross developmental abnormalities. At basal condition, PRR R279V/L282V mice had drastically suppressed renin levels from plasma (plasma total prorenin/renin content [ng/ml]: 9.3 ± 0.7 in PRR R279V/L282V mice vs. 12.8 ± 0.9 in WT mice, n = 5, p &lt; 0.05), urine (urinary total prorenin/renin excretion [ng/24h]: 0.54 ± 0.11 in PRR R279V/L282V mice vs. 1.05 ± 0.15 in WT mice, n = 5, p &lt; 0.05), and the kidney as compared to wild-type controls (WT). By telemetry, the hypertensive response of PRR R279V/L282V to AngII infusion (300 ng/min/kg) was blunted (MAP [mmHg] in Day 10: 125.9 ± 4.6 in PRR R279V/L282V mice vs. 138.5 ± 2.8 in WT mice, n = 8 for each group, p &lt; 0.05) in parallel with attenuated response of intrarenal renin and renal medullary α-ENaC expression. We further examined the direct role of sPRR in renin regulation in As4.1 cells, a renin-expressing cell line isolated from mouse renal tumor and M-1 cells, a mouse cell line derived from the collecting duct. The exposure to sPRR-His in both cell types consistently elevated renin activity, and renin expression at both protein and mRNA levels, all of which were sensitive to inhibition by ICG-001, a β-catenin signaling inhibitor. Together, these results represent strong evidence favoring sPRR as a mediator of AngII-induced hypertension and a master regulator of renin expression at systemic and local levels. Therefore, PRR should be considered as an integrative member of the RAS.

Mutagenesis of the Cleavage Site of Pro Renin Receptor Abrogates Angiotensin II-Induced Hypertension in Mice.

[Figure: see text].

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.

Update in the clinical management of low renin hypertension

The renin-angiotensin-aldosterone system modulates volume, sodium and potassium homeostasis. In the setting of a high sodium diet, up to 30% of patients with hypertension have a low or suppressed renin and increased volume. This phenotype of low renin hypertension (LRH) is multifactorial and includes infrequent inherited genetic syndromes, milder phenotypes of classic diseases and environmental exposures. All these conditions have in common a higher cardiovascular risk mediated by the over activation of the mineralocorticoid receptor (MR), present not only in the kidney, but also in vasculature, myocardium and adipocytes. Consequently, the aim of LRH treatment goes beyond the control of blood pressure and requires antagonizing MR with specific pharmacologic agents, pursuing normalization of renin as a clinical objective. Due to the unusual evaluation of renin status by non-endocrinologists and lack of disease awareness, only a minority of hypertensive patients receive this pathophysiologically-driven treatment that should reduce cardiovascular outcomes.

Diagnostic approach to low-renin hypertension.

Renin-angiotensin-aldosterone system (RAAS) plays a crucial role in maintaining water and electrolytes homoeostasis, and its deregulation contributes to the development of arterial hypertension. Since the historical description of the "classical" RAAS, a dramatic increase in our understanding of the molecular mechanisms underlying the development of both essential and secondary hypertension has occurred. Approximatively 25% of the patients affected by arterial hypertension display low-renin levels, a definition that is largely arbitrary and depends on the investigated population and the specific characteristics of the assay. Most often, low-renin levels are expression of a physiological response to sodium-volume overload, but also a significant number of secondary hereditary or acquired conditions falls within this category. In a context of suppressed renin status, the concomitant examination of plasma aldosterone levels (which can be inappropriately elevated, within the normal range or suppressed) and plasma potassium are essential to formulate a differential diagnosis. To distinguish between the different forms of low-renin hypertension is of fundamental importance to address the patient to the proper clinical management, as each subtype requires a specific and targeted therapy. The present review will discuss the differential diagnosis of the most common medical conditions manifesting with a clinical phenotype of low-renin hypertension, enlightening the novelties in genetics of the familial forms.

Norepinephrine-secreting paraganglioma: a clinical case

Among the rare causes of secondary hypertension pheochromocytoma is traditionally considered. It represents a chromaffin tumor of the adrenal glands. Paraganglioma is an extra-adrenal chromaffinoma. High blood pressure due to the neurohormonal excess accelerates target organ damage. Variable manifestations of pheochromocytoma/paragangliomaclinical make more difficult timely diagnosis and dictate the need of multidisciplinary approach. We present a clinical case of norepinephrine-secreting retroperitoneal paraganglioma in a middle-aged female. An integrated approach to the diagnosis and the assessment of target organ damage is suggested. The features of renin status are highlighted. The case also demonstrates appropriate dynamics of the cardiovascular parameters, neurohormonal regulation of blood circulation, and carbohydrate metabolism after successful surgical treatment of chromaffin tumor.

НIGH-RENIN HYPERTENSIONS: FROM SYMPTOM TO dIAGNOSIS

The article highlights the current understanding of renin-angiotensin-aldosterone system function- ing, as well as mechanisms for blood pressure raising depending on its activity. Authors presented data on the prevalence and characteristics of arterial hypertension with high levels of renin. Along with high-renin essential hypertension authors considered secondary arterial hypertensions accompanied by high-renin status increasing the diagnostic value of this hormone determination and explains the fea- tures of pathophysiological processes occurring in patients’ organism. Authors proved the importance of renin status diagnostic studies allowing defining a successful strategy of antihypertensive therapy.

Endothelial function but not in intima-media thickness relates to renin status in a multi-ethnic group of young healthy adults

Endothelial function but not in intima-media thickness relates to renin status in a multi-ethnic group of young healthy adults

Should We Be Recommending Vitamin D Supplementation for Hypertension and Cardiovascular Disease Prevention?

Should We Be Recommending Vitamin D Supplementation for Hypertension and Cardiovascular Disease Prevention?

Cardiovascular Consequences of Genetic Variation at −6/235 in Human Angiotensinogen Using “Humanized” Gene-Targeted Mice

Genetic and functional data support a role for angiotensinogen in blood pressure control, and many population studies have suggested that polymorphisms in the angiotensinogen gene contribute to hypertension. Two common haplotypes of the human angiotensinogen gene are -6A/235T and -6G/235M. To study their contributions to blood pressure regulation in a controlled model system, we developed triple-transgenic mice expressing either -6A/235T or -6G/235M human angiotensinogen, expressing either an overexpressed and poorly regulated (REN9) or a tightly regulated (PAC160) human renin, and all carrying a null mutation in the endogenous murine angiotensinogen gene. These humanized mice were then examined for blood pressure differences at baseline and after a high-salt diet, changes in cardiovascular organ weight, and differences in angiotensinogen and renin gene expression. Mice expressing the -6G/235M haplotype on the PAC160 background exhibited increased blood pressure and cardiac hypertrophy at baseline. In contrast, all of the mice with the REN9 background had equivalent baseline blood pressures. On the REN9 background, there was a greater increase in blood pressure in -6A/235T in response to a high-salt diet, providing evidence it may be a susceptibility allele. There were no differences in angiotensinogen expression between haplotypes on either background strain. The data suggest that the impact of angiotensinogen haplotypes on cardiovascular end points may be dependent on renin status and environmental influences, such as dietary sodium. These insights may help explain the discrepancies among observational studies that have examined roles for the -6A/235T and -6G/235M angiotensinogen haplotypes in varied human populations.

Gender hormones and the progression of experimental polycystic kidney disease

Male gender is a risk factor for progression of autosomal-dominant polycystic kidney disease (ADPKD), clinically and in the Han:SPRD rat model. Orchiectomy limits progression, but mechanisms of the detrimental effect of androgen, and/or beneficial effects of estrogen, are not known. This protocol tested the hypothesis that male gender (intact androgen status) promotes progression, while female gender (intact estrogen status) is protective; and that these disease-modifying effects are due to changes in expression of known fibrotic mediators. Studies were performed in male and female noncystic control (+/+) and cystic (+/-) rats subjected to orchiectomy, ovariectomy, or sham operation. At 12 weeks of age, renal function was measured. Blood and kidneys were taken for measurement of plasma and renal renin, endothelin (ET-1), endothelial nitric oxide synthase (eNOS), and vascular endothelial growth factor (VEGF), using biochemical, protein expression, and immunohistochemical methods. Cystic male rats exhibited significantly reduced glomerular filtration (GFR) and effective renal plasma flow (ERPF) rates, with suppression of plasma and renal renin, up-regulation of renal ET-1 and eNOS, and down-regulation of renal VEGF expression. Orchiectomy attenuated the fall in GFR and ERPF, while numerically limiting changes in eNOS and VEGF. Female rats exhibited less cystic growth, with normal renin status, lesser elevation of renal ET-1, and proportionately lesser changes in VEGF and eNOS. Ovariectomy led to higher blood pressure and reduced GFR and ERPF, with a trend toward upregulation of ET-1, and significant down-regulation of VEGF and eNOS. Female gender is protective, but ovariectomy attenuates the protective effect of female gender, in association with changes in renal expression of ET-1, VEGF, and eNOS. The accelerated disease in male rats can be attenuated by orchiectomy and consequent changes in expression of disease mediators.

Low-Renin Hypertension With Relative Aldosterone Excess Is Associated With Impaired NO-Mediated Vasodilation

Recent studies suggest that hypertension associated with low renin status and hyperaldosteronism is associated with increased risk for end-organ damage and cardiovascular events compared with other forms of hypertension. Additionally, experimental studies have demonstrated impaired nitric oxide-mediated bioactivity in these states. To investigate the relation between renin/aldosterone status and resistance vessel function, we examined plasma renin activity, serum aldosterone level, and forearm blood flow responses to the endothelium-dependent vasodilator methacholine and the endothelium-independent vasodilators sodium nitroprusside and verapamil using venous occlusion plethysmography in 130 volunteers (43 hypertensive, 87 normotensive). Low renin status was associated with impaired responses to methacholine and nitroprusside in patients with hypertension. Peak methacholine response was 8.7+/-5.6 mL/min per dL in the lowest renin quartile (0.1 to 0.3 ng/mL per hour) versus 14.3+/-7.3 mL/min per dL in the highest 3 renin quartiles combined (0.4 to 4.6 ng/mL per hour; P<0.001). Peak nitroprusside response was 5.6+/-2.3 mL/min per dL in the lowest renin quartile versus 13.3+/-4.1 mL/min per dL in the highest 3 renin quartiles combined (P<0.001). Blood pressure and other clinical characteristics were similar in all 4 quartiles. Vasodilator responses to verapamil did not relate to renin activity. Methacholine and nitroprusside responses did not relate to renin status in normotensive controls (P=0.34). Importantly, hypertensive patients with a high aldosterone/renin ratio also had impaired responses to methacholine. This study demonstrates that low-renin hypertension is associated with marked impairment of nitric oxide-mediated vasodilation of resistance vessels in the forearm vasculature of humans. This impairment could contribute to adverse outcomes in patients with low-renin hypertension and relative aldosterone excess.

Plasma Renin Measurement in the Management of Hypertension: The V and R Hypothesis

Plasma Renin Measurement in the Management of Hypertension: The V and R Hypothesis

Effects of cyclooxygenase-2 (COX-2) inhibition on plasma and renal renin in diabetes

COX-2-derived prostaglandins (PG) have been suggested to be important modulators of renin release and expression. However, the role of COX-2 in various high-renin states is still being debated. In the present studies we explored the role of COX-2-derived PG on basal and angiotensin converting enzyme inhibitor (ACEI)-stimulated plasma and renal renin concentrations (PRC and RRC, RIA), and mRNA expression (RmRNA, RNAse protection assay) in experimental diabetes (DM). Groups of moderately hyperglycemic (n = 5, ~350 mg/dl), streptozotocin-diabetic rats (D) after 3 weeks of DM were treated with a selective COX-2 inhibitor, MF-tricyclic (MF, 5 mg/kg/day for 10 days in food), the combination of MF and the ACEI enalapril (3 mg/kg/day), enalapril alone, or vehicle (MF-free chow), for 10 days. Non-diabetic control rats, fed MF-free chow, were also studied. All groups of diabetic rats demonstrated similar glycemic control. Treatment with ACEI resulted in significant elevations in PRC, RRC and RmRNA as compared to non-ACEI treated groups of diabetic and control rats. A similar rise in these parameters was observed in the rats treated with the combination of ACEI and MF. Furthermore, in diabetic rats treated with MF alone, PRC and RRC were similar to vehicle-treated animals. Diabetic rats demonstrated higher urinary PG as compared to controls. MF-treated rats demonstrated a significant reduction in urinary PG excretion. In summary, selective COX-2 inhibition influenced neither basal renin status nor ACEI-induced renin release and expression in diabetic rats. These findings do not support a significant role for COX-2 in mediating renin status in diabetes. (J Lab Clin Med 2002;140:351-7)

Low-renin hypertension: familial and genetic associations

Low-renin hypertension, representing roughly one quarter of all essential hypertension, is widely recognized by distinct physiologic features, including salt-sensitivity and a favorable natural history. We have reported the familial concordance for renin status, defining low-renin vigorously by plasma renin activity <0.69 ngAngI/L/sec, drawn with subjects upright after seven days on a 10 mmol sodium diet. There were twice as many low-renin sibships as expected, in sharp contrast to the normal-renin state, where the observed and expected were similar (p=0.01). To pursue the implication that genetic determinants play a large role in low-renin status, we performed association studies on 8 polymorphisms in 5 candidate genes: aldosterone synthase promoter region CYP11B2 C-344T; angiotensinogen (AGT) M235T, AGT A-20C, AGT A-6G; the angiotensin II AT1 Receptor AT1R A1166C and T573C; angiotensin-converting enzyme insertion/deletion ACE I/D; and alpha adducin G460T. Four genes belong to the renin-angiotensin system, and adducin codes for a gene whose product has been associated with renin status. Significant association was found between low-renin status and the alpha Gly460Trp polymorphism. Genotype frequencies in the hypertensive population were consistent with Hardy-Weinberg equilibrium. Genotype frequencies revealed 23% 460GG and 17% of the GT heterozygotes to be low-renin hypertensives, contrasted with 67% of the 460TT homozygotes (p=0.004). Genotype frequencies within low-renin were 39 for GG, 13 for GT, and 6 for TT; for normal renin the corresponding frequencies were 133, 62 and 3. The association was significant with whites alone; p = 0.01. The alpha-adducin G460W association was highly significant among females (p=0.003) but not among men (p=0.8). Of all the other genotypes, a trend toward significant association was seen among men only for the aldosterone synthase gene CYPC344T (p=0.08). On exploring the interaction between the two suspect genes, we observed a significant association among males (p=0.03) but not among females (p=0.2). Of 58 low-renin hypertensives genotyped at both the adducin 460 and CYP 344, 10% are homozygous at adducin 460; taking into account the heterozygotes for adducin, those who are also homozygous for the CYP344T represent an additional 30% of low-renin males. Familial determinants, probably genetic, contribute to the low-renin hypertension state.

Familial aggregation of low-renin hypertension.

Low-renin hypertension, representing roughly one quarter of all essential hypertension, is widely recognized by distinct physiological features, including salt-sensitivity, diuretic- responsiveness, and a favorable natural history. Although certain demographic features including age, ethnicity, and diabetes mellitus predispose to low-renin hypertension, these factors account for only a minority of cases. We examined familial concordance for renin status in 119 families with 257 hypertensive members. Low-renin was defined rigorously by plasma renin activity < or =0.69 ng angiotensin I/L per second, drawn when subjects had achieved balance after 5 to 7 days on a 10 mmol sodium diet and had stood upright for at least 1 hour. Given the prevalence of low-renin hypertension in our general population, low-renin hypertension was significantly more concordant among siblings than expected by chance (P=0.01). There were twice as many low-renin families as expected (10.9% versus 5.5%), in sharp contrast to the normal-renin state, in which the observed and expected were similar (61.0% versus 58.6%). These results were independent of age, race, and gender. Variance in renin status attributable to family membership was 35%. Association studies were performed on 8 polymorphisms in 5 candidate genes, and significant association was confirmed with the G460W polymorphism of the adducin gene. Familial determinants, which are probably but not definitely genetic, contribute to the low-renin hypertension state.

Interaction between sodium intake, angiotensin II, and blood pressure as a cause of cardiac hypertrophy

Cardiac hypertrophy is common in hypertension but its development is influenced by angiotensin II, sodium intake aldosterone, and the time of day blood pressure (BP) is elevated. This study examined and compared cardiac hypertrophy in the 2 kidney-1 clip (2K-1C) and 1 kidney-1 clip (1K-1C) Goldblatt models of hypertension. Blood pressure was measured by telemetry in a selected group of rats. Rats were placed on a high (4%) or reduced (0.2%) salt intake and were given captopril (75 mg/kg per day) or losartan (10 mg/kg per day). Appropriate sham-operated and untreated controls were used. Cardiac hypertrophy was greater in the 1K-1C than in the 2K-1C model. Day and sleep BP were also higher. In the 2K-1C model BP was lower on the reduced salt intake and BP decreased with captopril in both reduced and high salt groups. Cardiac weight and index decreased significantly only in the reduced salt and captopril group and was less than the size before treatment. In the 1K-1C model captopril caused all BP measures to decrease in the reduced salt group but had no significant effect in the high salt group. Cardiac weight and index were reduced only in the reduced salt + captopril group and cardiac weight was less than the pretreatment control. Losartan had a similar effect in the 1K-1C model to that achieved with captopril. The responses achieved correlated in part with renin status and dependency level. There is no prime determinant of cardiac hypertrophy. Blood pressure, sodium intake, and hormonal status are all important. It is postulated that the common pathway may be alterations in cell composition that signal the nucleus to increase cell growth.