Bilateral or Unilateral Aldosterone Hypersecretion and Responsiveness to Therapy are Associated with Differences in Calcium/Phosphate Homeostasis in Patients with Primary Aldosteronism.

Introduction Primary aldosteronism is characterized by the autonomous excretion of aldosterone, which may induce bone mineral disorders. Patients and methods A total of 96 patients with primary aldosteronism were analyzed to identify differences in the regulation of serum calcium/phosphate balance between patients with unilateral and bilateral aldosterone hypersecretion and to determine whether or not adrenalectomy or mineralocorticoid receptor blockers affected such differences. Results Serum phosphate concentrations were significantly lower in patients with unilateral aldosterone hypersecretion than in patients with bilateral aldosterone hypersecretion (2.96±0.45 vs. 3.36±0.55 mg/dL, P<0.05), and recovered after adrenalectomy (2.96±0.45 vs. 3.49±0.32 mg/dL, P<0.01). In patients with bilateral aldosterone hypersecretion, the baseline serum phosphate levels were significantly lower in responders to mineralocorticoid receptor blocker treatment, defined as post-treatment plasma renin activity ≥1 ng/mL/h, than in non-responders. In responders, these levels tended to recover after treatment. A weak negative correlation between the plasma aldosterone concentration (PAC) and serum phosphate was observed, but there were no associations between the PAC and serum calcium concentration or between the aldosterone renin ratio and serum calcium and phosphate concentrations. Conclusions The effects on calcium/phosphate homeostasis may differ according to the primary aldosteronism subtype.

A Case of Hypokalemia Caused by Left Native Renal Artery Stenosis in a Kidney Transplant Recipient.

A 39-year-old woman with end-stage renal failure of unknown origin was on peritoneal dialysis for 10 years. One year ago, she underwent ABO-incompatible living-donor kidney transplantation from her husband. After the kidney transplantation, her serum creatinine level remained around 0.7 mg/dL, but her serum potassium level remained low at around 3.5 mEq/L despite potassium supplementation and spironolactone. The patient's plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were markedly elevated (20 ng/mL/h and 868 pg/mL, respectively). A CT angiogram of the abdomen performed 1 year previously suggested stenosis of the left native renal artery, which was considered responsible for the hypokalemia. Renal venous sampling was done on both the native kidneys and the transplanted kidney. Since renin secretion from the left native kidney was significantly elevated, a laparoscopic left nephrectomy was performed. Postoperatively, the renin-angiotensin-aldosterone system was markedly improved (PRA: 6.4 ng/mL/h, PAC: 147.3 pg/mL), and the serum potassium levels also improved. Pathological examination of the removed kidney showed many atubular glomeruli and hyperplasia of the juxtaglomerular apparatus (JGA) in residual glomeruli. In addition, renin staining showed strong positivity in the JGA of these glomeruli. Here, we report a case of hypokalemia caused by left native renal artery stenosis in a kidney transplant recipient. This valuable case study provides histological confirmation of maintained renin secretion in an abandoned native kidney after kidney transplantation.

Antihypertensive Drugs and Cancer Risk.

Hypertension is the most prevalent comorbidity in cancer patients. Consequently, many cancer patients are prescribed antihypertensive drugs before cancer diagnosis or during cancer treatment. However, whether antihypertensive drugs affect the incidence, treatment efficacy, or prognosis of cancer remains unanswered. For instance, renin-angiotensin and ß-adrenergic signaling may be involved not only in blood pressure elevation but also in cell proliferation, angiogenesis, and tissue invasion. Therefore, the inhibition of these pathways may have beneficial effects on cancer prevention or treatment. In this article, we reviewed several studies regarding antihypertensive drugs and cancer. In particular, we focused on the results of clinical trials to evaluate whether the use of antihypertensive drugs affects future cancer risk and prognosis. Unfortunately, the results are somewhat inconsistent, and evidence demonstrating the effect of antihypertensive drugs remains limited. We indicate that the heterogeneity in the study designs makes it difficult to clarify the causal relationship between antihypertensive drugs and cancer. We also propose that additional experimental studies, including research with induced pluripotent cells derived from cancer patients, single-cell analyses of cancer cell clusters, and clinical studies using artificial intelligence electronic health record systems, might be helpful to reveal the precise association between antihypertensive drugs and cancer risk.

Association between polymorphism at IGF-1 rs35767 gene locus and long-term decline in renal function: a Japanese retrospective longitudinal cohort study.

BACKGROUND: Insulin-like growth factor-1 (IGF-1) acts on glucose and protein metabolism and human growth and also influences blood pressure and renal function. This study investigated whether the single-nucleotide polymorphism of IGF-1, rs35767, plays a role in metabolic syndrome indicators, including blood pressure, glucose metabolism, uric acid levels, and renal function. METHODS: In this retrospective longitudinal cohort study, blood samples from 1506 Japanese individuals were collected and used for genotyping for variant rs35767: T > C in the IGF-1 upstream promoter. Data were analyzed to identify associations between IGF-1 genotypes and patient biochemical parameters, including the components of metabolic syndrome and the long-term change in renal function. RESULTS: The cohort rs35767 genotypes included 650 CC carriers (43.2%), 687 TC carriers (45.6%), and 169 TT carriers (11.2%). Multiple regression analysis revealed no association between IGF-1 genotype and blood pressure, glycated hemoglobin level, and serum uric acid level. However, in females, blood pressure was negatively correlated with the TT genotype. Longitudinal observation revealed that the decline in eGFR over 10 years was greater in TT (- 18.51 ± 1.04 mL/min/1.73m2) than in CC carriers (- 16.38 ± 0.52 mL/min/1.73m2; P < 0.05). CONCLUSION: The present study suggests that renal function declines faster in individuals with the TT genotype at the IGF-1 rs35767 locus than in those with the CC genotype, suggesting that the TT genotype is associated with the long-term chronological decline in renal function.

Effect of uric acid levels on mortality in Japanese peritoneal dialysis patients.

BACKGROUND: Unlike the situation in the general population, most studies of patients receiving hemodialysis have reported lower uric acid (UA) as associated with higher mortality. However, the relationship between UA level and mortality remains unclear among patients receiving peritoneal dialysis (PD). METHODS: We collected baseline data for 4742 prevalent PD patients (age, 63 ± 14 years; male, 61.5%; diabetes, 29.1%; median dialysis duration, 28 months) from a nationwide dialysis registry in Japan at the end of 2012. One-year all-cause and cardiovascular (CV) mortality and mortality caused by infectious disease were assessed using Cox regression analysis and competing-risks regression analysis, respectively. We used multiple imputation to deal with missing covariate data. RESULTS: Within 1 year, 379 patients (8.0%) died, including 129 patients (2.7%) from CV causes and 95 patients (2.0%) from infectious disease. In multivariate analysis, serum UA, treated as a continuous variable, was not associated with any outcome. Conversely, both lower (<297 µmol/L) and higher (≥476 µmol/L) UA levels were independently associated with higher all-cause mortality compared to the reference group (416 to <446 µmol/L) in analyses where serum UA was treated as a categorical variable. Body mass index (BMI) affected the association between serum UA and all-cause mortality (interaction p = 0.049). CONCLUSIONS: A U-shaped relationship appears to exist between UA levels and all-cause mortality among Japanese PD patients. Additionally, lower BMI significantly enhanced the effect of UA levels on mortality.

New Concept of Onco-Hypertension and Future Perspectives.

Owing to aging populations, the prevalence of hypertension and associated cardiovascular events has been increasing worldwide. The morbidity and mortality due to cancer have also been increasing with aging populations. Several small-molecule inhibitors have been used in cancer therapy, which have a positive impact on the prognosis and survival of patients with cancer. Consequently, the number of cancer survivors with hypertension has been rapidly increasing. Anticancer therapy, including vascular endothelial growth factor inhibitors, increases blood pressure. However, both clinical and laboratory evidence are lacking regarding optimal blood pressure control in patients with hypertension with cancer. Here, we propose the concept of onco-hypertension, which is an evolving subspecialty focused on the complex pathophysiology of hypertension and cancer. In this review, we highlight blood pressure changes in cancer, hypertension induced by anticancer therapy, and optimal blood pressure management in patients with hypertension with cancer. In addition, we discuss needed studies to further establish this new onco-hypertension concept.

Evaluation of various confirmatory tests for the diagnosis of aldosterone-producing adenoma.

INTRODUCTION: Adrenal venous sampling is useful for discriminating unilateral and bilateral hypersecretion in patients with primary aldosteronism, but it is relatively invasive. To determine the site of hypersecretion more non-invasively, we evaluated predictors of unilateral hypersecretion. MATERIALS AND METHODS: We evaluated the baseline characteristics and the results of confirmatory tests of 123 patients with primary aldosteronism who underwent adrenal venous sampling. RESULTS: Unilateral hypersecretion was identified in 22.0%. The plasma aldosterone concentration and aldosterone-renin ratio were significantly higher and serum potassium concentration and plasma renin activity were significantly lower in patients with unilateral hypersecretion. Plasma aldosterone concentrations after captopril challenge test, saline infusion test and rapid adrenocorticotropic hormone stimulation test were significantly higher among patients with unilateral hypersecretion. The plasma aldosterone concentration reduction ratio in saline infusion test and plasma aldosterone concentration elevation ratio during rapid adrenocorticotropic hormone stimulation test were significantly higher in patients with unilateral hypersecretion. However, areas under the curve for these parameters were not superior to the values after confirmatory tests. CONCLUSIONS: The plasma aldosterone concentration values after captopril challenge test, saline infusion test and rapid adrenocorticotropic hormone stimulation test were useful for identifying patients with unilateral hypersecretion. However, value changes or ratios during confirmatory tests are less useful for this aim.

The characteristics of captopril challenge test-positive patients using various criteria.

INTRODUCTION: The captopril challenge test (CCT) is the major confirmatory test for primary aldosteronism (PA), and frequently carried out because of its convenience. However, it presents false-negative results with a certain probability, and as there are many criteria for CCT, it is not concluded yet which criteria to use. MATERIALS AND METHODS: A total of 71 PA patients were evaluated. We compared CCT-positive and CCT-negative patients in the following three criteria: plasma aldosterone/renin ratio (ARR) >200 after the CCT (criterion 1); plasma aldosterone concentration (PAC) >120 pg/ml after the CCT (criterion 2); and PAC suppression <30% of PAC before CCT (criterion 3). RESULTS: The positive rate was 70.4%, 64.8% and 54.9% for criterion 1, criterion 2 and criterion 3, respectively. With criterion 1, the baseline plasma renin activity was lower, thus baseline ARR was higher in CCT-positive patients. With criterion 2, PAC was higher and estimated sodium intake and K were lower in CCT-positive patients. With criterion 3, K and PAC were lower in CCT-positive patients. Although it was not significant, in the patients with high sodium intake, the positive rate of criterion 1 was higher than that of the other criteria. CONCLUSIONS: ARR>200 is the valuable criterion for the diagnosis of PA.

Effect of hyperuricemia and treatment for hyperuricemia in Japanese hemodialysis patients: A cohort study.

Whether higher serum uric acid (UA) values comprise a risk factor for death and whether treatment for high UA is effective in patients undergoing hemodialysis (HD) are essentially unknown. To determine associations between UA and all-cause or cardiovascular (CV) mortality, interactions between UA or medication and effects on mortality, and significance of treatment for hyperuricemia in patients undergoing hemodialysis (HD). We collected the baseline data of 222,434 patients undergoing three HD sessions per week, extracted from a nationwide dialysis registry at the end of 2011 in Japan. Then we evaluated the interaction between serum uric acid level and all-cause and cardiovascular (CV) mortality by the end of 2012. Univariate and multivariate logistic regression and Cox regression analyses found higher all-cause and CV mortality rates among patients with lower, than higher UA values. Hazard ratios (HR) for all-cause and CV mortality were significantly lower in a group with, than without medication for hyperuricemia (HR, 0.837; 95% confidence interval (CI), 0.789-0.889 and HR, 0.830; 95%CI 0.758-0.909, respectively). Lower UA values remained associated with all-cause and CV mortality rates even when in patients taking medication for hyperuricemia. The chief interacting factors for higher mortality rates due to lower UA were higher BMI and diabetes mellitus. In conclusion, lower UA levels were independently associated with higher all-cause and CV mortality among Japanese patients undergoing HD. Intervention for hyperuricemia is considered to improve patient outcomes.

Azilsartan causes natriuresis due to its sympatholytic action in kidney disease.

The sympathoinhibitory mechanism of azilsartan was investigated in an adenine-induced chronic renal failure model. Azilsartan exerted an antihypertensive effect, though BP elevation induced by adenine was marginal. The creatinine value was significantly lower in the azilsartan group (AZ) than in the vehicle group (VEH); furthermore, proteinuria was suppressed, and sodium excretion was augmented in the AZ group. The low frequency (LF) of systolic BP was suppressed (VEH: 4.07 ± 2.67 mmHg2 vs. AZ: 3.32 ± 1.93 mmHg2 P < 0.001), and the spontaneous baroreflex gain (sBRG) was augmented (VEH: 1.04 ± 0.62ms/mmHg vs. AZ: 1.38 ± 0.69 ms/mmHg, P < 0.001) in AZ. There were no significant differences in ACE1 and ACE2 expression between the groups, which indicated that the action of azilsartan on these components of the intrarenal renin-angiotensin-aldosterone system was comparatively small. Although NHE3, NKCC, and ENaC expression was similar between the groups, NaCl cotransporter (NCC) expression was markedly suppressed by azilsartan (P < 0.05). Thus, in a mild chronic kidney disease (CKD) model with slight BP elevation, the sympatholytic effect of ARB might be expected, and azilsartan might exert its natriuretic effect by NCC suppression achieved by sympathoinhibitory activity.

Forced expression of vascular endothelial growth factor-A in podocytes decreases mesangial cell numbers and attenuates endothelial cell differentiation in the mouse glomerulus.

BACKGROUND: Glomerular podocyte-derived vascular endothelial growth factor (VEGF) is indispensable for the migration and proliferation of glomerular endothelial cells. In contrast, podocyte-specific Vegf overexpression leads to the collapse of glomerular tufts; however, the mechanisms underlying this outcome have not yet been reported. METHODS: To further clarify the effects of elevated levels of Vegf expression on glomerular cells, we established a dual transgenic mouse line in which Vegf was exclusively and inducibly expressed in podocytes under the control of the "Tet-on system" (Podocin-rtTA/TetO-Vegf164 mice). RESULTS: Macroscopic and microscopic examination of Podocin-rtTA/TetO-Vegf164 animals following Vegf induction identified the presence of prominent red bloody spots. In addition, the endothelial cell number was increased along with enlargement of the subendothelial spaces. We also observed impaired endothelial fenestrations and aberrant plasmalemmal vesicle-associated protein-1 (PV-1) expression. In contrast, the mesangial cell number markedly decreased, resulting in a glomerular tuft intussusceptive splitting defect. Furthermore, whereas platelet-derived growth factor-B (PDGF-B) expression in the glomerular cells of Podocin-rtTA/TetO-Vegf164 mice was not decreased, phospho-PDGF receptor immunoreactivity in the mesangial cells was significantly decreased when compared to wild-type animals. CONCLUSION: Taken together, the results of this study indicated that the upregulation of podocyte VEGF decreased the number of mesangial cells, likely owing to inhibition of PDGF-B-mediated signaling.

Gender interaction of uric acid in the development of hypertension.

AIM: The present study explored the gender interaction on the risk of uric acid in the new development of hypertension. STUDY DESIGN: A longitudinal retrospective cohort. SUBJECTS & METHODS: A total of 5,807 individuals with an average age of 38 ± 7 years old were recruited. Individuals whose blood pressure rose more than 140/90mmHg or those who newly commenced antihypertensive treatment were defined as a new onset of hypertension. Cox regression analysis was employed for the analysis. RESULTS: During the 10-years follow-up, 42.8% of men and 22.2% of women had developed hypertension. Factors to predict the hypertension development were male gender, older age, higher BMI, higher uric acid, and higher mean blood pressure. An association between higher uric acid levels and higher incidence of hypertension remained statistically significant in women in a multivariate model adjusted for various clinical variables (Hazard ration (HR), 1.180; 95%CI, 1.018 to 1.369), whereas such association was not found in men (HR, 1.034; 95%CI, 0.994 to 1.075). The interaction between the two genders reached statistical significance (p for interaction = 0.007). CONCLUSION: Higher uric acid is associated with the incident hypertension in the both genders. Women are more susceptible to the development of hypertension than men.

Successful long-term effects of direct renin inhibitor aliskiren in a patient with atherosclerotic renovascular hypertension.

A 64-year-old man visited our hospital with complaints of misty vision and ophthalmalgia. On admission, his blood pressure (BP) was high at 220/135 mmHg with no past history of hypertension, and he had choked discs. He was tentatively diagnosed as having idiopathic intracranial hypertension, and was later found to have atherosclerotic unilateral renovascular hypertension (RVH) based upon the extremely high plasma renin activity together with the radiological image tests. On day 3, combined antihypertensive therapies consisting of oral angiotensin II receptor blocker (ARB) and Ca channel blocker (CCB) along with intravenous CCB induced an abrupt BP lowering which led to deterioration of his renal function, progressing into acute kidney injury (AKI). Cessation of the ARB and reduction of the CCB dose ameliorated the AKI-related decline in renal function. On day 17, as he was reluctant to receive surgical intervention, he was treated with a direct renin inhibitor, aliskiren, combined with a half-dose CCB as a maintenance antihypertensive therapy. The therapy has proven not only successful to chronically maintain his renal function but was also capable of controlling his BP in the neighborhood of 130/85 mmHg over a period of 2 years. The present case suggests that the direct renin inhibition with aliskiren can be a safe and useful antihypertensive option to control hypertension and to preserve renal function in patients with atherosclerotic unilateral RVH.

Serum uric acid and the incidence of CKD and hypertension.

BACKGROUND: Uric acid (UA) levels correlate positively with the prevalence of chronic kidney disease (CKD) and/or hypertension. We tested the hypothesis that UA may also have a link to a new incidence of CKD and hypertension. METHODS: Study design is a cohort study and the predictor is UA levels. Of the 15,470 screened cases, 8223 participants without CKD were eligible for the analysis of the incidence of CKD. Among these CKD candidates, 7569 participants were eligible for the analysis of the new development of hypertension. The observation period was 4 years. RESULTS: Relationship of UA with new cases of CKD. Higher UA levels had a closer association with the new development of CKD; 1.1 % (UA < 5 mg/dL), 1.5 % (5.0-5.9 mg/dL), 1.7 % (6.0-6.9 mg/dL), and 3.4 % (≧7 mg/dL), respectively (p < 0.001 by the Chi-square test). Cox proportional hazard analysis showed that the estimates of the CKD development were eGFR [Hazard Ratio (HR) 0.816, 95 % confidence intervals (CI) 0.791-0.840] and male gender (HR 0.562, 95 % CI 0.322-0.982). UA levels and new development of hypertension. Higher UA levels had a closer association with the new development of hypertension; 5.0 % (UA < 5 mg/dL), 8.9 % (5.0-5.9 mg/dL), 10.6 % (6.0-6.9 mg/dL), and 11.8 % (≧7 mg/dL), respectively (p < 0.001 by the Chi-square test). Cox proportional hazard analysis showed that the estimates of the hypertension development were BMI (HR 1.190, 95 % CI 1.155-1.226), age (HR 1.021, 95 % CI 1.010-1.032), HDL-cholesterol (HR 1.013, 95 % CI 1.007-1.019), male gender (HR 1.791, 95 % CI 1.338-2.395), UA level (HR 1.112, 95 % CI 1.024-1.207), and eGFR (HR 1008, 95 % CI 1.002-1.013). Furthermore, the logistic analysis showed that the odds ratio (OR) to estimate hypertension in the high UA group (UA ≧ 7 mg/dL; OR 1.33, 95 % CI 1.01-1.80) was greater than that in the low UA group (UA < 5 mg/dL). Kaplan-Meier analysis also confirmed the finding that the higher the UA levels the greater the hypertension development (p < 0.001 by the Log-rank test and Cox proportional hazard analysis). CONCLUSION: High UA levels are associated with the new development of hypertension, but not with the incidence of CKD.

Plasma cell-rich rejection accompanied by acute antibody-mediated rejection in a patient with ABO-incompatible kidney transplantation.

We report a case of plasma cell-rich rejection accompanied by acute antibody-mediated rejection in a patient with ABO-incompatible kidney transplantation. A 33-year-old man was admitted for an episode biopsy; he had a serum creatinine (S-Cr) level of 5.7 mg/dL 1 year following primary kidney transplantation. Histological features included two distinct entities: (1) a focal, aggressive tubulointerstitial inflammatory cell (predominantly plasma cells) infiltration with moderate tubulitis; and (2) inflammatory cell infiltration (including neutrophils) in peritubular capillaries. Substantial laboratory examination showed that the patient had donor-specific antibodies for DQ4 and DQ6. Considering both the histological and laboratory findings, we diagnosed him with plasma cell-rich rejection accompanied by acute antibody-mediated rejection. We started 3 days of consecutive steroid pulse therapy three times every 2 weeks for the former and plasma exchange with intravenous immunoglobulin (IVIG) for the latter histological feature. One month after treatment, a second allograft biopsy showed excellent responses to treatment for plasma cell-rich rejection, but moderate, acute antibody-mediated rejection remained. Therefore, we added plasma exchange with IVIG again. After treatment, allograft function was stable, with an S-Cr level of 2.8 mg/dL. This case report demonstrates the difficulty of the diagnosis of, and treatment for, plasma cell-rich rejection accompanied by acute antibody-mediated rejection in a patient with ABO-incompatible kidney transplantation. We also include a review of the related literature.

Monitoring of body water composition by the simultaneous use of bioelectrical impedance analysis and Crit-Line(®) during hemodialysis.

BACKGROUND: Bioelectrical impedance analysis (BIA) is a non-invasive method to estimate total body water (TBW) and extracellular water (ECW) volume. Crit-Line(®) (CL), on the other hand, assesses intravascular water (IVW) volume. We evaluate continuous changes in body water composition during hemodialysis (HD) with concurrent use of BIA and CL. METHODS: BIA at the start and the end of the HD session was measured using a BIA device. To investigate the shifting pattern of body water composition, patients were subjected to simultaneous monitoring of BIA with CL. RESULTS: Both TBW resistance (Rt) and ECW resistance (Re) increased in response to changes in the ultrafiltration (UF) ratio. There was a positive correlation between ΔRe/Rt and the UF ratio, and the ratio of Re/Rt at the end of HD was significantly higher than that at the start of HD. Simultaneous monitoring of BIA with CL showed a parallel shift of the change in the Re (ΔRe) and the change in hematocrit (ΔHt). In one patient with increasing inflammatory response, change in ΔHt was dissociated from change in ΔRe. One hyponatremic patient showed a different pattern of changing ΔRe between the first half and the latter half of the HD session. CONCLUSION: Our study suggests that the concurrent use of BIA and CL may be a useful technique to simulate water shift patterns across the different compartments in HD.

[Relationship between serum uric acid levels and muscle strength/volume: a new insight from a large-scale survey].

AIM: Serum uric acid (UA) concentration is regulated by its production in the liver and/or intestine and its rate of excretion from the kidneys. However, little is known about skeletal muscle involvement in determining the physiological UA level. The present trial explores whether muscle strength and/or muscle volume is associated with UA levels. MATERIAL & METHODS: Muscle strength was evaluated in terms of grasping power calculated as an average of right and left hand measurements in relation to other parameters in 14,333 subjects (median age; 41.2 years), who were recruited to the study. Skeletal muscle volume was calculated based on the bioimpedance method by subtracting estimated fat volume plus estimated bone weight from the total body weight. RESULTS: 1) Multiple regression analyses to explain the association with UA levels (dependent variable) revealed that BMI, BUN, triglyceride, muscle strength, AST, age and sex are independent variables. 2) Higher UA levels (assessed as 4 UA quartiles) are associated with higher muscle volume, muscle strength, BMI, DBP, and serum creatinine (Cr) concentration. 3) Greater DBP (assessed as 2 UA categories) was associated with higher BMI, muscle strength, muscle volume, UA levels and serum Cr concentration. 4) Regression coefficient "t" for muscle strength was the largest among the other parameters including serum Cr concentration in the UA level ranging from 5.5 to 6.5 mg/dL. CONCLUSION: There was an association between muscle strength/volume and UA levels in the near physiological UA range, suggesting that the circulating UA levels can be, at least in part, controlled by its production in the skeletal muscles.

Effect of aliskiren in chronic kidney disease patients with refractory hypertension undergoing hemodialysis: a randomized controlled multicenter study.

BACKGROUND: Applying a direct renin inhibitor (DRI) to advanced stage chronic kidney disease (CKD) patients is a matter of controversy. The purpose of this study was to evaluate the effect of the DRI, aliskiren, in patients with therapy-resistant hypertension undergoing hemodialysis (HD). METHODS: The study was a prospective, randomized multicenter trial exploring the antihypertensive effect of aliskiren in comparison with amlodipine, a calcium channel blocker, in patients undergoing HD. A total of 83 participants whose blood pressure (BP) had previously been treated with more than one antihypertensive agent and not having achieved the BP goal of <140/90 mmHg were randomly assigned to either aliskiren 150 mg or amlodipine 5 mg as an add-on therapy. RESULTS: A significant decrease in pre-dialysis clinic BP and home BP was found only in the amlodipine group and not in the aliskiren group. In contrast, there was a significant decrease in atrial natriuretic peptide (ANP) in the aliskiren group but not in the amlodipine group. N-terminal pro-B-type natriuretic hormone remained unchanged in both groups. Aliskiren significantly reduced angiotensin I and II, plasma renin activity, and increased plasma renin content. However, such changes were not observed in the amlodipine group. CONCLUSION: Amlodipine, not aliskiren, effectively reduces BP in CKD patients with refractory hypertension undergoing HD. Aliskiren suppresses the renin-angiotensin system and reduces ANP. Whether the DRI is beneficial in improving cardiovascular events in patients undergoing HD remains to be elucidated in future studies.

Mechanistic view of renal protective action of calcium channel blockade.

Calcium channel blockers are one of the most useful antihypertensive agents because of their definite blood pressure lowering action. Although the antihypertensive effect of calcium channel blockers is attributed predominantly to the blockade of L-type calcium channels, recent studies demonstrate that the blockade of other subtypes of calcium channels, including T-type and N-type calcium channels, offers renal protective action because of their beneficial action on glomerular capillary pressure, renal fibrotic process, sympathetic nerve activity and aldosterone synthesis. It requires more extensive studies to clarify whether the ostensibly beneficial actions of these calcium channel blockers are available in a clinical setting.

Augmented antihypertensive effect of a fixed combination formula of candesartan and hydrochlorothiazide combined with furosemide in a patient on peritoneal dialysis.

A 38-year-old female patient on peritoneal dialysis (PD) due to type 1 diabetic nephropathy with a well-preserved residual renal function did not respond well to the conventional antihypertensive therapy consisting of candesartan, furosemide, and bunazosin. Switching candesartan for a fixed combination formula of candesartan plus hydrochlorothiazide (HCTZ) while the rest of the other two agents remained unchanged led to the remarkable reduction in both systolic and diastolic blood pressure (BP) without significant changes in the cardiothoracic ratio (CTR), body weight (BW), and residual renal function. This case suggests that when used in combination, diuretics acting on different functional segment of the nephron hold greater potential for enhanced antihypertensive effect, especially in patients on PD whose residual renal function is well preserved. A small dose of HCTZ with an angiotensin II receptor blocker (ARB) may partially explain the therapeutic benefit of this combination therapy in terms of a reliable hypotensive effect, a better adherence, and fewer side effects.