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Importance: Trials in patients with hypertension have demonstrated that intensive blood pressure (BP) lowering reduces the risk of cardiovascular disease and all-cause mortality but may increase the risk of chronic kidney disease (CKD) incidence and progression. Whether intensive BP lowering is associated with a mortality benefit in patients with prevalent CKD remains unknown., Objectives: To conduct a systematic review and meta-analysis of randomized clinical trials (RCTs) to investigate if more intensive compared with less intensive BP control is associated with reduced mortality risk in persons with CKD stages 3 to 5., Data Sources: Ovid MEDLINE, Cochrane Library, EMBASE, PubMed, Science Citation Index, Google Scholar, and clinicaltrials.gov electronic databases., Study Selection: All RCTs were included that compared 2 defined BP targets (either active BP treatment vs placebo or no treatment, or intensive vs less intensive BP control) and enrolled adults (≥18 years) with CKD stages 3 to 5 (estimated glomerular filtration rate <60 mL/min/1.73 m2) exclusively or that included a CKD subgroup between January 1, 1950, and June 1, 2016., Data Extraction and Synthesis: Two of us independently evaluated study quality and extracted characteristics and mortality events among persons with CKD within the intervention phase for each trial. When outcomes within the CKD group had not previously been published, trial investigators were contacted to request data within the CKD subset of their original trials., Main Outcome and Measure: All-cause mortality during the active treatment phase of each trial., Results: This study identified 30 RCTs that potentially met the inclusion criteria. The CKD subset mortality data were extracted in 18 trials, among which there were 1293 deaths in 15 924 participants with CKD. The mean (SD) baseline systolic BP (SBP) was 148 (16) mm Hg in both the more intensive and less intensive arms. The mean SBP dropped by 16 mm Hg to 132 mm Hg in the more intensive arm and by 8 mm Hg to 140 mm Hg in the less intensive arm. More intensive vs less intensive BP control resulted in 14.0% lower risk of all-cause mortality (odds ratio, 0.86; 95% CI, 0.76-0.97; P = .01), a finding that was without significant heterogeneity and appeared consistent across multiple subgroups., Conclusions and Relevance: Randomization to more intensive BP control is associated with lower mortality risk among trial participants with hypertension and CKD. Further studies are required to define absolute BP targets for maximal benefit and minimal harm.

Corticosteroids are the first-line treatment for patients with inflammatory myopathies. Myositis can be a clinical feature of scleroderma (polymyositis-scleroderma overlap syndrome), and treatment of this syndrome is a challenge for clinicians because moderate to high doses of corticosteroids are considered a risk factor for development of acute kidney injury in affected patients. We report here the case of a 56-year-old woman with scleroderma who developed polymyositis and was successfully treated with rituximab. Initial treatment of the polymyositis with prednisolone 40 mg/day was rapidly tapered to 2.5 mg/day due to development of scleroderma renal crisis, for which four weekly infusions of rituximab (500 mg; off-label) were given. She responded well to rituximab in addition to prednisolone 2.5 mg/day. Rituximab may improve inflammatory myopathies, even in cases where high-dose corticosteroids should be avoided due to complications. Rituximab should be considered as a treatment option in cases of refractory polymyositis., Competing Interests: Competing interests: KI received scholarship donations from AbbVie, Actelion, Astellas, Bristol-Myers, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Japan Blood Products Organization, Mitsubishi-Tanabe, Pfizer, Shionogi, Takeda, Teijin, and UCB. TM received scholarship donations from AbbVie, Actelion, Astellas, Bristol-Myers, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Japan Blood Products Organization, Mitsubishi-Tanabe, Pfizer, Shionogi, Takeda, Teijin, and UCB. SK received scholarship donations from AbbVie, Actelion, Astellas, Bristol-Myers, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Japan Blood Products Organization, Mitsubishi-Tanabe, Pfizer, Shionogi, Takeda, Teijin, and UCB. YM received scholarship donations from AbbVie, Actelion, Astellas, Bristol-Myers, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Japan Blood Products Organization, Mitsubishi-Tanabe, Pfizer, Shionogi, Takeda, Teijin, and UCB., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objectives: Blockade of the renin-angiotensin II (Ang II) system by AT1 blockers (ARBs) and angiotensin-converting enzyme inhibitors retards the progression of chronic kidney disease (CKD) by reducing albuminuria/proteinuria. However, many patients with CKD suffer from residual albuminuria/proteinuria, which is an independent risk factor for CKD progression. The aim of the current study is to investigate the effect of pitavastatin, one of the adjunctive agents to ARBs, on the reduction of albuminuria/proteinuria and further renoprotection mediated by telmisartan in spontaneously hypertensive rats., Methods and Results: Forty-two-week-old spontaneously hypertensive rats were grouped randomly and received 8 weeks of treatments with vehicle, telmisartan, pitavastatin or a combination of telmisartan and pitavastatin. Both albuminuria and proteinuria were inhibited significantly in the telmisartan-treated group, but an obviously residual albuminuria was maintained. The combination treatment with telmisartan and pitavastatin displayed a more effective decrease in albuminuria and proteinuria, even to the normal level. Enhanced nephroprotection was also observed in this combination group, which was independent of the cholesterol-lowering effects. Further mechanistic studies revealed that the combination therapy greatly attenuated the expression of intrarenal Ang II and AT1, thereby decreasing the activation of TGF-β-Smad and NF-κB and inhibiting fibrosis and inflammation., Conclusion: Adjunctive therapy with pitavastatin dramatically reduced residual albuminuria/proteinuria and enhanced nephroprotection, likely by downregulating the expression of intrarenal Ang II and AT1. It could be concluded that statins might be a promising adjunctive therapeutic agent to conventional ARB treatment in hypertensive renal damage.

Objective: To determine whether a clinically-utilised IL-1 receptor antagonist, anakinra, reduces renal inflammation, structural damage and blood pressure (BP) in mice with established hypertension., Methods: Hypertension was induced in male mice by uninephrectomy, deoxycorticosterone acetate (2.4mg/d,s.c.) and replacement of drinking water with saline (1K/DOCA/salt). Control mice received uninephrectomy, a placebo pellet and normal drinking water. 10days post-surgery, mice commenced treatment with anakinra (75mg/kg/d, i.p.) or vehicle (0.9% saline, i.p.) for 11days. Systolic BP was measured by tail cuff while qPCR, immunohistochemistry and flow cytometry were used to measure inflammatory markers, collagen and immune cell infiltration in the kidneys., Results: By 10days post-surgery, 1K/DOCA/salt-treated mice displayed elevated systolic BP (148.3±2.4mmHg) compared to control mice (121.7±2.7mmHg; n=18, P<0.0001). The intervention with anakinra reduced BP in 1K/DOCA/salt-treated mice by ∼20mmHg (n=16, P<0.05), but had no effect in controls. In 1K/DOCA/salt-treated mice, anakinra modestly reduced (∼30%) renal expression of some (CCL5, CCL2; n=7-8; P<0.05) but not all (ICAM-1, IL-6) inflammatory markers, and had no effect on immune cell infiltration (n=7-8, P>0.05). Anakinra reduced renal collagen content (n=6, P<0.01) but paradoxically appeared to exacerbate the renal and glomerular hypertrophy (n=8-9, P<0.001) that accompanied 1K/DOCA/salt-induced hypertension., Conclusion: Despite its anti-hypertensive and renal anti-fibrotic actions, anakinra had minimal effects on inflammation and leukocyte infiltration in mice with 1K/DOCA/salt-induced hypertension. Future studies will assess whether the anti-hypertensive actions of anakinra are mediated by protective actions in other BP-regulating or salt-handling organs such as the arteries, skin and brain., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

An original model of nephrogenic hypertension in rats was used for histochemical mapping of NADPH diaphorase (NO synthase) in various renal segments to examine the effect of hypotensive drugs furosemide, bendazol, and clonidine on the time course of nitroxide production in the kidneys. In various nephron segments, these drugs modulated NO synthesis in different ways. Clonidine induced a stable up-regulation of NO synthesis, which can maintain active vasodilation and gradually diminish the rennin production. Bendazol also enhanced NO synthase activity in renal glomeruli and collecting tubules, but this effect was less pronounced and short lasting. During the first week after injection of bendazol, insignificant elevation of NO synthase activity was observed in the proximal nephron segments. Furosemide exerted the least effect on NO production in kidneys.

APOL1 nephropathies comprise a range of clinical and pathologic syndromes, which can be summarized as focal segmental glomerulosclerosis, in various guises, and arterionephrosclerosis, otherwise known as hypertensive kidney diseases. Current therapies for these conditions may achieve therapeutic targets, reduction in proteinuria and control of blood pressure, respectively, but often fail to halt the progressive decline in kidney function. It appears that current therapies fail to address certain underlying critical pathologic processes that are driven, particularly in podocytes and microvascular cells, by the APOL1 renal risk genetic variants. Mechanisms hypothesized to be responsible for APOL1 variant-associated cell injury can be summarized in five domains: increased APOL1 gene expression, activation of inflammasomes, activation of protein kinase R, electrolyte flux across plasma or intracellular membranes, and altered endolysosomal trafficking associated with endoplasmic reticulum stress. We briefly review the available evidence for these five mechanisms and suggest possible novel therapeutic approaches., (Published by Oxford University Press on behalf of ERA-EDTA 2017. This work is written by US Government employees and is in the public domain in the United States.)

Limited data are available on epidemiology and drug use in Chinese hypertensive patients with chronic kidney disease (CKD). We determined the prevalence; awareness, treatment, and control rates of hypertension; anti-hypertensive use, expenditure pattern; and factors associated with hypertension prevalence and control in Chinese patients with CKD. This was one of the largest cross-sectional surveys that enrolled 6079 CKD participants (mean age, 51.0 ± 16.37 years) with or without hypertension from 22 centres across China. The prevalence, awareness, and treatment rates were 71.2%, 95.4%, and 93.7%, respectively. Control rates 1 and 2 (Blood pressure, BP <140/90 and <130/80 mmHg) were 41.1% and 15.0%, respectively. Patients were treated mostly with monotherapy (37.7%) or 2-drug anti-hypertensive combination (38.7%). Factors associated with prevalence of hypertension included age; smoking; body mass index; physical exercise; family history of hypertension; hyperuricaemia; and CKD. Control rate was associated with CKD stage, BP monitoring at home, and use of drug combinations. Despite high rates of awareness and treatment, the control rates are low. CKD stages 4 and 5 adversely affect the control rate. The results suggest the immediate need of comprehensive controlling measures to improve the control of hypertension in Chinese patients with CKD.

The aim of our observation was to establish whether or not renal sympathetic denervation (RSD) may help control blood pressure (BP) levels in patients with severe hypertension refractory to pharmacological therapy. Out of a group of 12 patients, candidates for RSD, with uncontrolled hypertension and a systolic BP over 190 mm Hg on repeated measurements despite optimal medication, four patients were excluded for multiple renal arteries and one for hyperaldosteronism. Seven patients had RSD using a Symplicity device (5M, 2 F) with a mean age of 64.9 years. While all were followed up for a minimum of 6 months, follow-up duration in the majority of them was substantially longer (12-20 months). At six months post-RSD, six of the seven patients showed a decrease in systolic BP by at least 15 mm Hg while receiving the same or fewer doses of antihypertensive agents. A similar response was seen in diastolic BP. The BP decrease was maintained throughout whole follow-up. In a small group of patients with severe hypertension, we demonstrated that renal sympathetic denervation is capable of reducing blood pressure even in patients with severe hypertension.

Hypertension is one of the most common and well-known complications following kidney transplantation in children. Yet, despite numerous available therapies many pediatric kidney transplant recipients continue to have poorly controlled blood pressure, suggesting that traditional approaches to blood pressure management in this population might be inadequate. Over the last two decades, the Chronic Care Model has been developed to improve chronic illness outcomes through delivery system design and clinical information systems that support patient self-management and provider decision-making. In this educational review we discuss key elements of managing blood pressure following pediatric kidney transplantation and suggest ways that they may be reliably implemented into clinical practice using principles from the Chronic Care Model.

Hypertension management is one of the most common clinical tasks in the care of patients with chronic kidney disease (CKD). Elevated blood pressure (BP) is associated with greater risk of all-cause mortality, cardiovascular (CV) disease, and CKD progression in this population. However, it is still debated, to what target(s) BP should be lowered in patients with signs of kidney damage. The Systolic Blood Pressure Intervention Trial (SPRINT) provided new and important information about the effects of lowering systolic BP to a target of <120 mmHg, which is lower than the levels currently recommended by the most guidelines (<140/90 mmHg). The SPRINT results were not only exciting but also surprising for many clinicians because evidence from well-conducted observational studies in CKD patient showed increased mortality in patients with CKD whose office systolic BP levels were <120 mmHg, as compared with systolic BP in 120-139 mmHg range. In the present review, we will discuss whether a systolic BP goal of <120 mmHg that was found to be beneficial for CV and all-cause mortality outcomes in the SPRINT can be generalized to the entire CKD population.

Objective: To investigate the roles of catestatin (CST) in 2-kidney-1 clip (2K1C)-induced renal hypertension in rats, and to explore the underlying mechanism., Methods: Thirty six male SD rats were randomly divided into Sham group ( n =15) and Model group( n =21).The model group was performed by 2K1C operation. For 2K1C operation, the left renal arteries were narrowed by cotton thread. The Sham group was treated with the same condition as the 2K1C group except the renal artery was narrowed. Tail-cuff systemic blood pressure of rats was measured before and every weeks after 2K1C operation. Six weeks after 2K1C operation, a carotid artery catheter was inserted to measure blood pressure of rats under anesthesia. Then, the model group was randomly subdivided into 2K1C group ( n =15) and 2K1C+CST group ( n =6). The rats of 2K1C+CST group were intravenous given CST (80 μ g/100 g) and the rats of Sham or 2K1C group were given normal saline. All rats were sacrificed after blood pressure was measured and blood was collected. Then, the left ventricular plus interventricular septum weight (LV+S) was weighted and the ratio of (LV+S)/body weight(BW) was calculated as the index of left ventricular hypertrophy. Norepinephrine (NE) contents in plasma were determined by high performance liquid chromatography(HPLC) and CST contents in plasma by ELISA. The nitrite/nitrate contents in the left ventricular tissue and plasma were measured by nitrate reduction method to represent nitric oxide (NO)contents.Expression levels of CST in the left ventricle, kidney, medulla oblongata and adrenal gland,as well as eNOS and iNOS, were tested by Western blot., Results: ①The 2K1C group had higher tail-artery blood pressure( P <0.01) and were more marked presence of right ventricular hypertrophy than those of sham group ( P <0.01). Compared with Sham group, plasma CST content in 2K1C group was decreased by 226% ( P <0.01), while plasma NE content in 2K1C group was increased by 246% ( P <0.01), expression levels of chromograminA(Chga) in medulla oblongata of 2K1C group were increased by 108%, in leftventricle and kidneywere decreased by 60% and 30%, respectively ( P <0.05).the content of NO in left ventricular and plasmawere increased by 46% and 24% respectively. ②The carotid arterial blood pressure of 2K1C group markedly reduced after administration of CST.③Compared with 2K1C group, the content of NO in left ventricul and plasma of 2K1C+CST group were increased by 35% and 19% respectively( P <0.05). The expression of eNOS in left ventricular of 2K1C+CST group were also obviously increased., Conclusions: The CST expression of 2K1C-induced renal hypertension rats is reduced and the effects of exogenous CST lowering their blood pressure may be related to NO/NOS system.Therefore, we speculate CST could contribute to the pathogenesis and progression of renal hypertension.

The aim of this review is to present recommendations of the currently valid Hungarian practice guidelines regarding antihypertensive therapy of the elderly and very elderly with different cardiovascular risk profiles, compare and contrast these with international guidelines, describe changes brought about by the past 15 years, and review the evidence behind. Hypertension treatment guidelines and relevant statements of the Hungarian and European Societies of Hypertension, of the Joint National Committee and American Heart Association were processed. The use of age-independent treatment threshold, goal blood pressure values, and the tendency towards more intensive control in co-morbidities conferring high cardiovascular risk were overcome by the upsurge of new evidence and the re-evaluation of previous clinical trial data. These lead to the introduction of age-specific and generally less stringent blood pressure targets in all regions compared. However, the guidelines currently in force still differ in terms of the attainable values in concomitant diabetes, chronic kidney disease or albuminuria, use of beta-blockers and the definition of elderly. Nevertheless, there is unanimous agreement that benefit from lowering of blood pressure under systolic 140 mmHg is not supported by evidence and further investigation is warranted to determine optimal treatment targets in the elderly, in the aged over 80 and specific elderly risk groups.

Pharmacological inhibition of the proximal tubular sodium-glucose linked cotransporter-2 (SGLT2) leads to glycosuria in both diabetic and non-diabetic settings. As a consequence of their ability to modulate tubuloglomerular feedback, SGLT2 inhibitors, like agents that block the renin-angiotensin system, reduce intraglomerular pressure and single nephron GFR, potentially affording renoprotection. To examine this further we administered the SGLT2 inhibitor, dapagliflozin, to 5/6 (subtotally) nephrectomised rats, a model of progressive chronic kidney disease (CKD) that like CKD in humans is characterised by single nephron hyperfiltration and intraglomerular hypertension and where angiotensin converting enzyme inhibitors and angiotensin receptor blockers are demonstrably beneficial. When compared with untreated rats, both sham surgery and 5/6 nephrectomised rats that had received dapagliflozin experienced substantial glycosuria. Nephrectomised rats developed hypertension, heavy proteinuria and declining GFR that was unaffected by the administration of dapagliflozin. Similarly, SGLT2 inhibition did not attenuate the extent of glomerulosclerosis, tubulointerstitial fibrosis or overexpression of the profibrotic cytokine, transforming growth factor-ß1 mRNA in the kidneys of 5/6 nephrectomised rats. While not precluding beneficial effects in the diabetic setting, these findings indicate that SGLT2 inhibition does not have renoprotective effects in this classical model of progressive non-diabetic CKD.

Background: Inhibition of transcription factor nuclear factor-kappa B (NFκB) is beneficial in various models of hypertension and renal disease. We hypothesized first that NFκB inhibition during renal development ameliorates hereditary hypertensive renal disease and next whether this was mediated via suppression of peroxisome proliferator-activated receptor (PPAR)γ coactivator 1α (PGC-1α)., Methods and Results: Prior to the development of renal injury in fawn-hooded hypertensive (FHH) rats, a model of hypertension, glomerular hyperfiltration, and progressive renal injury, NFkB activity, measured by nuclear protein expression of NFkB subunit p65, was enhanced twofold in 2-day-old male and female FHH kidneys as compared to normotensive Wistar-Kyoto (WKY) rats (P < 0.05). Treating FHH dams with pyrrolidine di thio carbamate (PDTC), an NFκB inhibitor, from 2 weeks before birth to 4 weeks after birth diminished NFkB activity in 2-day-FHH offspring to 2-day-WKY levels (P < 0.01). Perinatal PDTC reduced systolic blood pressure from 20 weeks onwards by on average 25 mm Hg (P < 0.001) and ameliorated proteinuria (P < 0.05) and glomerulosclerosis (P < 0.05). In kidneys of 2-day-, 2-week-, and adult offspring of PDTC-treated FHH dams, PGC-1α was induced on average by 67% (quantitative polymerase chain reaction (qPCR)) suggesting that suppression of this factor by NFkB could be involved in renal damage. Follow-up experiments with perinatal pioglitazone (Pio), a PPARγ agonist, failed to confer persistent antihypertensive or renoprotective effects., Conclusions: Perinatal inhibition of enhanced active renal NFκB in 2-day FHH had persistent antihypertensive and renoprotective effects. However, this was not the case for PPARγ stimulation. NFkB stimulation is therefore involved in renal damage in the FHH model of proteinuric renal disease by pathways other than via PPARγ., (© American Journal of Hypertension, Ltd 2015. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Context: Earlier we reported cardioprotective, antihyperlipidemic, and in vitro antioxidant activity of flax lignan concentrate (FLC) obtained from the seeds of Linum usitatissimum L. (Linaceae)., Objective: To investigate the effect of FLC in deoxycorticosterone acetate (DOCA)-salt induced experimental renal hypertension in rats., Materials and Methods: Hypertension was induced in uninephrectomized (UNTZD) male Wistar rats (230-280 g) by injecting DOCA (25 mg/kg, subcutaneously, twice weekly) and supplementing 1% NaCl in drinking water for 5 weeks. The rats were divided in six groups. Captopril (30 mg/kg, p.o.) and FLC (200, 400 and 800 mg/kg, p.o.) were administered daily to the rats of groups III-VI, respectively, for 5 weeks. Various hemodynamic and biochemical parameters were investigated as well as histology of kidney and heart were carried out., Results: In this study, the FLC (400 and 800 mg/kg) significantly (p < 0.01, p < 0.001) decreased the systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure. It also significantly (p < 0.01, p < 0.001) decreased elevated end diastolic pressure (EDP), dP/dt max and dP/dt min, organs weights (kidney and heart) and activities of hepatic, renal and cardiac marker enzymes in the serum. Furthermore, FLC (400 and 800 mg/kg) significantly (p < 0.01, p < 0.001) restored altered antioxidant status, serum electrolyte level, lipid profile values, and histological abnormalities. Captopril (30 mg/kg) showed maximum antihypertensive effect but low dose of FLC (200 mg/kg) was not enough to show the antihypertensive activity., Conclusion: FLC possessed antihypertensive effect via modulation of endogenous enzymes in DOCA-salt induced renal hypertension in rats.

The most current versions of renal sympathetic denervation have been invented as minimally invasive approaches for the management of drug-resistant hypertension. The anatomy, physiology and pathophysiology of renal sympathetic innervation provide a strong background supporting an important role of the renal nerves in the regulation of blood pressure (BP) and volume. In addition, historical data with surgical sympathectomy and experimental data with surgical renal denervation indicate a beneficial effect on BP levels. Early clinical studies with transcatheter radiofrequency ablation demonstrated impressive BP reduction, accompanied by beneficial effects in target organ damage and other disease conditions characterized by sympathetic overactivity. However, the failure of the SYMPLICITY 3 trial to meet its primary efficacy end point raised a lot of concerns and put the field of renal denervation into hibernation. This review aims to translate basic research into clinical practice by presenting the anatomical and physiological basis for renal sympathetic denervation, critically discussing the past and present knowledge in this field, where we stand now, and also speculating about the future of the intervention and potential directions for research., (© 2016 S. Karger AG, Basel.)

Hypertension is an independent risk factor for the progression of chronic renal failure, and oxidative stress plays a critical role in hypertensive renal damage. Forkbox O1(FoxO1) signaling protects cells against oxidative stress and may be a useful target for treating oxidative stress-induced hypertension. Tongxinluo is a traditional Chinese medicine with cardioprotective and renoprotective functions. Therefore, this study aimed to determine the effects of Tongxinluo in hypertensive renal damage in spontaneously hypertensive rats(SHRs)and elucidate the possible involvement of oxidative stress and FoxO1 signaling in its molecular mechanisms. SHRs treated with Tongxinluo for 12 weeks showed a reduction in systolic blood pressure. In addition to increasing creatinine clearance, Tongxinluo decreased urinary albumin excretion, oxidative stress injury markers including malondialdehyde and protein carbonyls, and expression of nicotinamide adenine dinucleotide phosphate oxidase subunits and its activity in SHR kidneys. While decreasing phosphorylation of FoxO1, Tongxinluo also inhibited the phosphorylation of extracellular signal-regulated kinase1/2 and p38 and enhanced manganese superoxide dismutase and catalase activities in SHR kidneys. Furthermore, histology revealed attenuation of glomerulosclerosis and renal podocyte injury, while Tongxinluo decreased the expression of α-smooth muscle actin, extracellular matrixprotein, transforming growth factor β1 and small mothers against decapentaplegic homolog 3,and improved tubulointerstitial fibrosis in SHR kidneys. Finally, Tongxinluo inhibited inflammatory cell infiltration as well as expression of tumor necrosis factor-α and interleukin-6. In conclusion, Tongxinluo protected SHRs against hypertension-induced renal injury by exerting antioxidant, antifibrotic, and anti-inflammatory activities. Moreover, the underlying mechanisms of these effects may involve inhibition of oxidative stress and functional activation of FoxO1 signaling.

Loss of Klotho and activation of the renin-angiotensin system (RAS) are common pathological findings in chronic kidney diseases. However, whether these two events are intricately connected is poorly understood. We hypothesized that Klotho might protect kidneys by targeted inhibition of RAS activation in diseased kidneys. To test this hypothesis, mouse models of remnant kidney, as well as adriamycin nephropathy and unilateral ureteral obstruction, were utilized. At 6 weeks after 5/6 nephrectomy, kidney injury was evident, characterized by elevated albuminuria and serum creatinine levels, and excessive deposition of interstitial matrix proteins. These lesions were accompanied by loss of renal Klotho expression, up-regulation of RAS components, and development of hypertension. In vivo expression of exogenous Klotho through hydrodynamic-based gene delivery abolished the induction of multiple RAS proteins, including angiotensinogen, renin, angiotensin-converting enzyme, and angiotensin II type 1 receptor, and normalized blood pressure. Klotho also inhibited β-catenin activation and ameliorated renal fibrotic lesions. Similar results were obtained in mouse models of adriamycin and obstructive nephropathy. In cultured kidney tubular epithelial cells, Klotho dose-dependently blocked Wnt1-triggered RAS activation. Taken together, these results demonstrate that Klotho exerts its renal protection by targeted inhibition of RAS, a pathogenic pathway known to play a key role in the evolution and progression of hypertension and chronic kidney disorders., (Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Hypertension is highly prevalent affecting nearly one third of the US adult population. Though generally approached as an outpatient disorder, elevated blood pressure is observed in a majority of hospitalized patients. The spectrum of hypertensive disease ranges from patients with hypertensive emergency including markedly elevated blood pressure and associated end-organ damage to asymptomatic patients with minimally elevated pressures of unclear significance. It is important to note that current evidence-based hypertension guidelines do not specifically address inpatient hypertension. This narrative review focuses primarily on best practices for diagnosing and managing nonemergent hypertension in the inpatient setting. We describe examples of common hypertensive syndromes, provide suggestions for optimal post-acute management, and point to evidence-based or consensus guidelines where available. In addition, we describe a practical approach to managing asymptomatic elevated blood pressure observed in the inpatient setting. Finally, arranging effective care transitions to ensure optimal ongoing hypertension management is appropriate in all cases.

When introduced clinically 6 years ago, renal denervation was thought to be the solution for all patients whose blood pressure could not be controlled by medication. The initial two studies, SYMPLICITY HTN-1 and HTN-2, demonstrated great magnitudes of blood pressure reduction within 6 mo of the procedure and were based on a number of assumptions that may not have been true, including strict adherence to medication and absence of white-coat hypertension. The SYMPLICITY HTN-3 trial controlled for all possible factors believed to influence the outcome, including the addition of a sham arm, and ultimately proved the demise of the initial overly optimistic expectations. This trial yielded a much lower blood pressure reduction compared with the previous SYMPLICITY trials. Since its publication in 2014, there have been many analyses to try and understand what accounted for the differences. Of all the variables examined that could influence blood pressure outcomes, the extent of the denervation procedure was determined to be inadequate. Beyond this, the physiological mechanisms that account for the heterogeneous fall in arterial pressure following renal denervation remain unclear, and experimental studies indicate dependence on more than simply reduced renal sympathetic activity. These and other related issues are discussed in this paper. Our perspective is that renal denervation works if done properly and used in the appropriate patient population. New studies with new approaches and catheters and appropriate controls will be starting later this year to reassess the efficacy and safety of renal denervation in humans., (Copyright © 2015 the American Physiological Society.)

Background: We conducted a randomized, open-label trial to determine which of the antihypertensive drugs was most beneficial for CKD patients with hypertension in spite of treatment with an angiotensin receptor blocker (ARB)., Methods: Patients 20-75 years of age who had CKD according to the definition in the K/DOQI Guidelines and hypertension (systolic blood pressure ≥130 mmHg and/or diastolic blood pressure ≥80 mmHg) with the usual dose of an ARB were randomly assigned to receive losartan 50 mg plus 5 mg of the calcium channel blocker amlodipine (CCB group, n = 37), 5 mg of the angiotensin-converting enzyme inhibitor enalapril (ACEI group, n = 36), or 12.5 mg of the thiazide diuretic hydrochlorothiazide (HCTZ group, n = 36). The primary endpoints were changes in blood pressure (BP), ratio of urinary excretion of protein to creatinine (UPCR), tolerability, and eGFR during the 12-month treatment period compared with control period., Results: There were no significant differences in BP and tolerability between the three groups. The percentage changes in UPCR at 12 months after start of the combination therapy were significantly different in the HCTZ group (-26.3 ± 11.1 %, mean ± SE) and CCB group (+46.7 ± 33.6 %, p < 0.05), while eGFR was significantly lower in the HCTZ group than in the ACEI group or CCB group at 4 months but not at 12 months., Conclusion: Addition of diuretics, CCB, or ACEI to ARB was equally effective for the control of hypertension in CKD, while, in terms of urinary excretion of protein, diuretics may be better than CCB.

Medication compliance among individuals with hypertension symbolizes a growing concern within the medical community. It is said that roughly 50% of hypertensive patients in the United States do not comply with their medication regimen. Uncontrolled hypertension in turn can lead to kidney failure and other complications. Because compliance to medication regimens is complex and difficult to ascertain, solutions to this problem must be multifactorial.

In recent years, a number of studies have investigated complementary medical approaches to the treatment of hypertension using dietary supplements. Rice bran protein hydrolysates extracted from rice is a rich source of bioactive peptides. The present study aimed to investigate the vasorelaxation and antihypertensive effects of peptides-derived from rice bran protein hydrolysates (RBP) in a rat model of two kidney-one clip (2K-1C) renovascular hypertension. 2K-1C hypertension was induced in male Sprague-Dawley rats by placing a silver clip around the left renal artery, whereas sham-operated rats were served as controls. 2K-1C and sham-operated rats were intragastrically administered with RBP (50 mg kg(-1) or 100 mg kg(-1)) or distilled water continuously for six weeks. We observed that RBP augmented endothelium-dependent vasorelaxation in all animals. Administration of RBP to 2K-1C rats significantly reduced blood pressure and decreased peripheral vascular resistance compared to the sham operated controls (p < 0.05). Restoration of normal endothelial function and blood pressure was associated with reduced plasma angiotensin converting enzyme (ACE), decreased superoxide formation, reduced plasma malondialdehyde and increased plasma nitrate/nitrite (p < 0.05). Up-regulation of eNOS protein and down-regulation of p47phox protein were found in 2K-1C hypertensive rats-treated with RBP. Our results suggest that RBP possesses antihypertensive properties which are mainly due to the inhibition of ACE, and its vasodilatory and antioxidant activity.

The gene SLC4A5 encodes the Na(+)-HCO3 (-) cotransporter electrogenic 2, which is located in the distal nephron. Genetically deleting Na(+)-HCO3 (-) cotransporter electrogenic 2 (knockout) causes Na(+)-retention and hypertension, a phenotype that is diminished with alkali loading. We performed experiments with acid-loaded mice and determined whether overactive epithelial Na(+) channels (ENaC) or the Na(+)-Cl(-) cotransporter causes the Na(+) retention and hypertension in knockout. In untreated mice, the mean arterial pressure was higher in knockout, compared with wild-type (WT); however, treatment with amiloride, a blocker of ENaC, abolished this difference. In contrast, hydrochlorothiazide, an inhibitor of Na(+)-Cl(-) cotransporter, decreased mean arterial pressure in WT, but not knockout. Western blots showed that quantity of plasmalemmal full-length ENaC-α was significantly higher in knockout than in WT. Amiloride treatment caused a 2-fold greater increase in Na(+) excretion in knockout, compared with WT. In knockout, but not WT, amiloride treatment decreased plasma [Na(+)] and urinary K(+) excretion, but increased hematocrit and plasma [K(+)] significantly. Micropuncture with microelectrodes showed that the [K(+)] was significantly higher and the transepithelial potential (Vte) was significantly lower in the late distal tubule of the knockout compared with WT. The reduced Vte in knockout was amiloride sensitive and therefore revealed an upregulation of electrogenic ENaC-mediated Na(+) reabsorption in this segment. These results show that, in the absence of Na(+)-HCO3 (-) cotransporter electrogenic 2 in the late distal tubule, acid-loaded mice exhibit disinhibition of ENaC-mediated Na(+) reabsorption, which results in Na(+) retention, K(+) wasting, and hypertension., (© 2015 American Heart Association, Inc.)

Background: Peritoneal dialysis (PD) or conventional hemodialysis (HD) are considered to be equally efficient dialysis methods in children and adolescents. The aim of our study was to analyze whether an intensified, nocturnal HD program (NHD) is superior to PD in an adolescent cohort., Methods: Thirteen patients were prospectively enrolled in a NHD program. We measured uremia-associated parameters, parameters for nutrition, medication and blood pressure and analyzed the data. These data were compared to those of 13 PD controls, matched for gender, age and weight at the beginning the respective dialysis program and after 6 months of treatment., Results: Serum phosphate levels decreased significantly in the NHD group and remained unchanged in the PD group. Arterial blood pressure in the NHD was significantly lower despite the reduction of antihypertensive treatment, whereas blood pressure levels remained unchanged in the PD controls. Preexisting left ventricular hypertrophy resolved and albumin levels improved with NHD. Dietary restrictions could be lifted for those on NHD, whereas they remained in place for the patients on PD treatment. Residual diuresis remained unchanged after 6 months of either NHD or PD. NHD patients experienced fewer days of hospitalization than the PD controls., Conclusions: Based on our results, NHD results in significantly improved parameters of uremia and nutrition. If individually and logistically possible, NHD should be the treatment modality of preference for older children and adolescents.

Background: Cobalamin C (CblC) defects are inherited autosomal recessive disorders of vitamin B12 metabolism due to mutations in the MMACHC gene. Renal manifestations include thrombotic microangiopathy (TMA), acute or chronic renal failure, tubulointerstitial nephritis, and proximal renal tubular acidosis. However, reports about glomerular pathologies are scarce., Case Report: A 4-year-old boy presented with nephrotic syndrome, arterial hypertension, and chronic anemia but no signs of hemolysis. Renal biopsy showed TMA with ischemic glomerular collapse, foot process effacement, and tubulointerstitial fibrosis. Elevated serum levels of homocysteine suggested a cobalamin C disorder. This was confirmed by the identification of compound heterozygous mutations in the MMACHC gene. Initial therapy consisted of antihypertensive treatment including angiotensin converting enzyme inhibitor (ACEi) leading to blood pressure control and a significant reduction of proteinuria. After a definite diagnosis of CblC deficiency, hydroxocobalamin was introduced. Thereafter, homocysteine levels decreased, anemia resolved, and a further decline of proteinuria with normalization of serum protein levels was noted. Renal function remained stable., Conclusions: Although uncommon, the clinical picture of CblC defects may be ruled by nephrotic syndrome mimicking glomerulonephritis, minimal change disease, or primary focal and segmental glomerulosclerosis. Key to a correct diagnosis is elevated serum levels of homocysteine, and a definite diagnosis can be confirmed by genetic testing.

For people enrolled in Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL), we sought to examine whether variation exists in the baseline medical therapy of different geographic regions and if any variations in prescribing patterns were associated with physician specialty. Patients were grouped by location within the United States (US) and outside the US (OUS), which includes Canada, South America, Europe, South Africa, New Zealand, and Australia. When comparing US to OUS, participants in the US took fewer anti-hypertensive medications (1.9 ± 1.5 vs. 2.4 ± 1.4; P < .001) and were less likely to be treated with an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker (46% vs. 62%; P < .001), calcium channel antagonist (37% vs. 58%; P < .001), and statin (64% vs. 75%; P < .05). In CORAL, the identification of variations in baseline medical therapy suggests that substantial opportunities exist to improve the medical management of patients with atherosclerotic renal-artery stenosis., (Copyright © 2015 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Scleroderma renal crisis (SRC) is defined as the new onset of accelerated arterial hypertension and /or rapidly progressive oliguric renal failure during the course of systemic sclerosis. It is a rare but life-threatening complication. This formerly serious complication has got a considerable brighter outlook since the introduction of angiotensin converting enzyme inhibitors (ACE) however the mortality is still remaining high. We report two cases of SRC which to our knowledge are the firsts described in Dakar. They were two women aged 45 and 32 years, one of them was previously following for systemic sclerosis. Both of them had malignant hypertension associated with rapidly progressive renal failure, the other was put under corticosteroid therapy four months before SRC occurrence. The histological and laboratory finding showed thrombotic microangiopathy. The height blood pressure returned to normal value after treatment with ACE inhibitors. The final outcome was undesirable with the death of one after two months due to the hemodialysis discontinuation and persistence of renal failure in the other.

Background and Aims: Sulodexide has been reported to have antiproteinuric and nephroprotective properties. We investigated the effects of long-term low-dose Sulodexide on proteinuria and renal function in patients with chronic kidney disease (CKD) caused by diabetic nephropathy (DN), hypertensive nephropathy (HN) and primary glomerulonephritis (GN)., Material and Methods: 100 patients with CKD received low-dose Sulodexide 50 mg/day for 12 months. Treatment efficacy was evaluated as proteinuria reduction compared to baseline; response was defined as a decline in proteinuria below 0.3 g/d. Renal function evolution was assessed by eGFR variation from baseline., Results: All patients presented reduction of proteinuria, with global mean value of proteinuria decrease of 0.85 +/- 1.34 g/d (p<0.0001). Patients with HN had the highest mean percentage of proteinuria reduction (73 +/- 29%) and the lowest mean time period to achieve responder status (6.6 +/- 2.4 months), compared to patients with DN (57 +/- 29%, 8 +/- 2.9 months) and GN (63 +/- 24%, 10.7 +/- 1.2 months). Renal function as mean eGFR remained stable or improved during the study; significant increase was found only in HN group (3.41 +/- 6.38 ml/min/1.73 m2, p=0.043). Multivariate regression analysis identified that responder status was significantly associated with gender, baseline eGFR, baseline proteinuria and etiology of CKD. Concomitant administration of ACEIs or/and ARBs did not influence the response to Sulodexide therapy., Conclusions: Independently of ACEIs or/and ARBs therapy, long-term low-dose Sulodexide is efficient as antiproteinuric and renoprotective therapy in patients with CKD caused by DN, GN and HN. Better response is achieved in patients with lower degree of renal dysfunction.

Background: Qian Yang Yu Yin Granule (QYYYG), a traditional Chinese herbal medicine, has been indicated for renal damage in hypertension for decades in China, but little remains known regarding its underlying molecular mechanism. Therefore, we performed the current study in order to investigate the underlying molecular mechanism of QYYYG in the treatment of hypertensive renal damage., Methods: We hypothesize that QYYYG relieves hypertensive renal injury through an angiotensin II (Ang II)-nicotinamide adenine dinucleotide phosphate (NAPDH)-oxidase (NOX)-reactive oxygen species (ROS) pathway. In this study, we investigated the effects of QYYYG-containing serum (QYGS) in human mesangial cells (HMCs) against Ang II-induced cell proliferation, ROS production, and inflammation through the seropharmacological method., Results: We found that QYGS could inhibit cell proliferation in Ang II-treated HMCs. In addition, QYGS considerably suppressed production of ROS, decreased mRNA and protein expression of NAPDH-oxidase 4 (NOX4), p22 (phox) , and activated Ras-related C3 botulinum toxin substrate 1 (GTP-Rac1); as well as counteracted the up-regulation of inflammatory markers including tumor necrosis factor-α (TNF-α), nuclear factor-κB (NF-κB) p65, and interleukin 6 (IL-6). These effects were further confirmed in HMCs transfected with specific small interfering RNA (siRNA) targeting NOX4., Conclusions: Taken together, these results suggest that a NOX4-dependent pathway plays an important role in regulating the inhibitory effect of QYGS. Our findings provide new insights into the molecular mechanisms of QYYYG and their role in the treatment of hypertensive nephropathy.

Background: Reduction of blood pressure and proteinuria by blockade of the renin-angiotensin-aldosterone system (RAAS) has been the cornerstone of renoprotective intervention for patients with chronic kidney disease (CKD) for many years., Aims: The aims were to check the use of angiotensin converting enzyme inhibitors (ACEIs) and/or angiotensin II receptor blockers (ARBs) in CKD patients., Methods: This was a retrospective, cross-sectional study analysing data from medical records of patients who received specialist care in 1996, 2001, 2006, 2011 in the Outpatient Unit., Results: The numbers of CKD subjects included in the four independent surveys were as follows: 190, 490, 1799, 1696. The usage of RAAS blocking agents overall increased significantly in subsequent years as follows: 25, 49, 63, 74%. Patients with proteinuria and cardiovascular complications and/or diabetes were receiving RAAS blocking agents more commonly than others. The use of ACEI and/ or ARB in stage 4-5 CKD increased in subsequent years. In 2011 dual RAAS blockade was used in 10% CKD patients overall and 19% patients presented proteinuria., Conclusion: The use of RAAS blocking agents were increasing in CKD patients under specialist care between 1996-2011. The quality of the management was gradually improved., (© The Author(s) 2014.)

Previous studies have demonstrated that a natural product of celery seeds, 3‑n‑butylphthalide (NBP), has significant antihypertensive effects that are widely utilized in Chinese traditional medicine. The present study aimed to investigate the effects of NBP on hypertensive nephropathy, as well as the mechanisms underlying this disease in spontaneously hypertensive rats (SHRs). SHRs were treated orally with saline, NBP (15 or 30 mg/kg) or losartan (10 mg/kg) daily for 20 weeks, during which time blood pressure was measured every four weeks. At the end of the 20‑week treatment, blood and urine samples were collected for biochemical analysis, and kidney tissues were obtained for histopathological analysis and immunohistochemistry. Enzyme‑linked immunosorbent assays and western blotting were used to analyze the expression of transforming growth factor (TGF)‑β1 in blood and kidney tissues, respectively. The results showed that NBP effectively attenuated progression of hypertensive nephropathy by decreasing urinary albumin excretion and blood urea nitrogen levels. It significantly decreased blood pressure (although less markedly than losartan) and the incidence of glomerulosclerosis. In addition, it alleviated tubular impairment and significantly decreased oxidative stress, as well as the expression of pro‑inflammatory cytokines and TGF-‑β1 in kidney tissues. In conclusion, the results suggested that NBP may slow the progression of hypertensive nephropathy by a variety of mechanisms.

This study aimed at examining the cardioprotective effects of resveratrol in rats with simultaneous type 2 diabetes and renal hypertension. Eight groups (8-10 each) of male Sprague-Dawley rats, including a control, a diabetic, a renal hypertensive, a sham, a simultaneously hypertensive-diabetic receiving vehicle, and 3 simultaneously hypertensive-diabetic receiving resveratrol at 5, 10 or 20 mg/kg/day were used. After 4 weeks of treatment, blood pressure and glucose, and serum markers of oxidative stress were measured, and animals' hearts were used for isolated studies. Resveratrol prevented the increase of systolic blood pressure, serum malondialdehyde, fasting blood glucose, infarct size, coronary resistance, and coronary effluent creatine kinase-MB. Moreover, it prevented the decrease of serum superoxide dismutase and glutathione reductase, heart rate, left ventricular developed pressure, rate of increase of ventricular pressure, and rate of decrease of ventricular pressure. In conclusion, our findings show that resveratrol alleviates cardiac dysfunction in diabetic-hypertensive rats by virtue of antioxidant, antihypertensive, and coronary vasodilating activities.

The pathogenic role of inflammation and oxidative stress in chronic kidney disease (CKD) is well known. Anti-inflammatories and antioxidant drugs has demonstrated significant renoprotection in experimental nephropathies. Moreover, the inclusion of natural antioxidants derived from food and herbal extracts (such as polyphenols, curcumin and lycopene) as an adjuvant therapy for slowing CKD progression has been largely tested. Brazilian propolis is a honeybee product, whose anti-inflammatory, antimicrobial and antioxidant effects have been widely shown in models of sepsis, cancer, skin irritation and liver fibrosis. Furthermore, previous studies demonstrated that this compound promotes vasodilation and reduces hypertension. However, potential renoprotective effects of propolis in CKD have never been investigated. The aim of this study was to evaluate the effects of a subtype of Brazilian propolis, the Red Propolis (RP), in the 5/6 renal ablation model (Nx). Adult male Wistar rats underwent Nx and were divided into untreated (Nx) and RP-treated (Nx+RP) groups, after 30 days of surgery; when rats already exhibited marked hypertension and proteinuria. Animals were observed for 90 days from the surgery day, when Nx+RP group showed significant reduction of hypertension, proteinuria, serum creatinine retention, glomerulosclerosis, renal macrophage infiltration and oxidative stress, compared to age-matched untreated Nx rats, which worsened progressively over time. In conclusion, RP treatment attenuated hypertension and structural renal damage in Nx model. Reduction of renal inflammation and oxidative stress could be a plausible mechanism to explain this renoprotection.

Background: We often experience visit-to-visit estimated glomerular filtration rate (eGFR) variability among patients with advanced chronic kidney disease (CKD). However, the impact of eGFR variability on renal prognosis is not well understood., Methods: The Kanagawa Valsartan Trial was a multicenter, randomized, open-label trial that compared the effect of add-on treatment with angiotensin II receptor blocker, valsartan, with that of conventional treatment on the rate of CKD progression in 293 advanced CKD patients. In this post hoc analysis, we compared the effect of high eGFR variability on end-stage renal disease (ESRD). To evaluate eGFR variability, we chose participants with ≥ 5 serial measurements of eGFR during the study period and assessed the residual coefficient of variation (CV) of eGFR (residual eGFR-CV) derived from a regression line of eGFR (eGFR slope). The primary end point was the first event of ESRD., Results: Among 237 patients with ≥ 5 serial measurements of eGFR in a median follow-up of 1.47 years, there were 54 ESRD events in the higher than median residual eGFR-CV group and 36 ESRD events in the lower than median eGFR-CV group (log-rank test, p = 0.008). In multivariate Cox regression analysis, high eGFR variability was significantly associated with the primary end point as well as hypertension, high proteinuria, low baseline eGFR and steep eGFR slope (hazards ratio 2.11, 95% CI 1.33-3.33, p = 0.001)., Conclusion: High eGFR variability predicts poor renal prognosis; therefore, further attention is warranted for ambulatory patients with large eGFR fluctuations, especially those with advanced CKD., (© 2015 S. Karger AG, Basel.)

Background: Autosomal dominant polycystic kidney disease (ADPKD) causes progressive renal damage and is a leading cause of end-stage renal failure. With emerging therapies it is important to devise a method for early detection. We aimed to identify factors from routine clinical data which can be used to distinguish people with a high likelihood of having ADPKD in a primary health care setting., Method: A cross-sectional study was undertaken using data from the Quality Intervention in Chronic Kidney Disease trial extracted from 127 primary care practices in England. The health records of 255 people with ADPKD were compared to the general population. Logistic regression was used to identify clinical features which distinguish ADPKD. These clinical features were used to stratify individual risk using a risk score tool., Results: Renal impairment, proteinuria, haematuria, a diastolic blood pressure over 90 mmHg and multiple antihypertensive medications were more common in ADPKD than the general population and were used to build a regression model (area under the receiver operating characteristic curve; 0.79). Age, gender, haemoglobin and urinary tract infections were not associated with ADPKD. A risk score (range -3 to +10) of ≥0 gave a sensitivity of 70.2% and specificity 74.9% of for detection., Conclusions: Stratification of ADPKD likelihood from routine data may be possible. This approach could be a valuable component of future screening programs although further longitudinal analyses are needed.

This study assessed the urinary albumin/creatinine ratio (ACR) and uric acid metabolism in 70 hypertensive patients with chronic kidney disease in whom urinary ACR had remained ≥30 mg/g under the treatment of the L-type calcium channel blocker amlodipine. Three months after switching to the N/L-type calcium channel blocker cilnidipine, blood pressure (BP) did not change; however, urinary ACR significantly decreased with cilnidipine. Serum uric acid levels showed no significant change. In cases where uric acid production had been high (urinary uric acid/creatinine ratio ≥0.5), the urinary uric acid/creatinine ratio decreased significantly after cilnidipine treatment, suggesting that cilnidipine can suppress excessive uric acid formation. These results suggest that switching from amlodipine to cilnidipine results in a significant reduction in urinary ACR as well as significant reduction in uric acid production. Thus, cilnidipine is more useful than amlodipine in improving albuminuria and uric acid metabolism in hypertensive patients with chronic kidney disease., (©2014 Wiley Periodicals, Inc.)

Rationale: Compound 21 (C-21) is a highly selective nonpeptide AT2 receptor (AT2R) agonist., Objective: To test the hypothesis that renal proximal tubule AT2Rs induce natriuresis and lower blood pressure in Sprague-Dawley rats and mice., Methods and Results: In rats, AT2R activation with intravenous C-21 increased urinary sodium excretion by 10-fold (P<0.0001); this natriuresis was abolished by direct renal interstitial infusion of specific AT2R antagonist PD-123319. C-21 increased fractional excretion of Na(+) (P<0.05) and lithium (P<0.01) without altering renal hemodynamic function. AT2R activation increased renal proximal tubule cell apical membrane AT2R protein (P<0.001) without changing total AT2R expression and internalized/inactivated Na(+)-H(+) exchanger-3 and Na(+)/K(+)ATPase. C-21-induced natriuresis was accompanied by an increase in renal interstitial cGMP (P<0.01); C-21-induced increases in urinary sodium excretion and renal interstitial cGMP were abolished by renal interstitial nitric oxide synthase inhibitor l-N(6)-nitroarginine methyl ester or bradykinin B2 receptor antagonist icatibant. Renal AT2R activation with C-21 prevented Na(+) retention and lowered blood pressure in the angiotensin II infusion model of experimental hypertension., Conclusions: AT2R activation initiates its translocation to the renal proximal tubule cell apical membrane and the internalization of Na(+)-H(+) exchanger-3 and Na(+)/K(+)ATPase, inducing natriuresis in a bradykinin-nitric oxide-cGMP-dependent manner. Intrarenal AT2R activation prevents Na(+) retention and lowers blood pressure in angiotensin II-dependent hypertension. AT2R activation holds promise as a renal proximal tubule natriuretic/diuretic target for the treatment of fluid-retaining states and hypertension., (© 2014 American Heart Association, Inc.)

Objectives: The study aimed at examining the role of oxidative stress in cadioprotective effects of oleuropein in a rat model of simultaneous type 2 diabetes and renal hypertension., Materials and Methods: Five groups of male Sprague-Dawley rats including a control group, a diabetic-hypertensive group receiving vehicle, and three diabetic-hypertensive groups receiving oleuropein at 20, 40, or 60 mg/kg/day were used. Blood pressure and glucose, serum malondialdehyde, and erythrocyte superoxide dismutase were measured, and animal's hearts with ischemia/reperfusion injuries were used using Langendorff technique., Results: Blood pressure, blood glucose, serum malondialdehyde, infarct size, coronary effluent creatine kinase-MB, and coronary resistance of diabetic-hypertensive group were significantly higher than those of the control group, while those of the oleuropein-receiving groups were significantly lower than those of the diabetic hypertensive group receiving the vehicle. Erythrocyte superoxide dismutase, left ventricular developed pressure, and rate of rise and rate of decrease of ventricular pressure of diabetic-hypertensive group were significantly lower than those of the control group. These parameters as well as heart rate of oleuropein-receiving groups were significantly higher than those of the diabetic-hypertensive group., Conclusion: The findings indicate that oleuropein offered cardioprotection, which might be partly mediated by its antioxidant properties.

Type 2 diabetes is the most common cause of CKD and ESRD in the United States and the Western world. Hypertension is prevalent in this cohort, and control of blood pressure is perhaps the most important risk factor to reduce CKD progression. The most recent blood pressure target recommended by the Kidney Disease: Improving Global Outcomes and Kidney Disease Outcomes Quality Initiative guideline committees is less than 140/90 mmHg for all patients with CKD. There is some evidence for those with 1 g or more of albuminuria, albeit weak, to support a blood pressure target of less than 130/80 mmHg. Multiple studies demonstrate that renin-angiotensin-aldosterone system (RAAS) blockers are important in reducing cardiovascular risk and progression of CKD in those with advanced proteinuric nephropathy. However, there is no evidence that they prevent nephropathy or that reduction in microalbuminuria alone is associated with slowed nephropathy progression. The purpose of this article is to review the major studies that have evaluated cardiovascular and kidney endpoints in patients with diabetes and the role of RAAS blockers in the treatment of this disease., (Copyright © 2014 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

The 6-year anniversary of the first catheter-based renal denervation procedure for resistant hypertension has passed, and the 3-year follow-up results of the Symplicity HTN-1 are now published. At the 'end of the beginning', it is timely to reflect on the observations to-date for this revolutionary therapy, and to predict the next phase in its development and clinical application in hypertension treatment. In essence, on observations to hand, the procedure is efficacious and seems safe and durable. But will the blood pressure lowering truly be permanent (or might it be cancelled out by renal sympathetic nerve regrowth)? How can patient selection for the renal denervation procedure be optimized, given that some patients do not respond with a blood pressure fall? Will blood pressure lowering with renal denervation reduce the rate of clinical cardiovascular endpoints? Will long-term safety be acceptable? Can milder hypertension be cured? And there are unresolved procedural and technical questions: how much renal denervation is optimal; is unilateral denervation, now commonly used, beneficial; will renal denervation show a 'class effect', with the different energy forms now used for renal nerve ablation producing equivalent blood pressure lowering? At the 12-year anniversary, I expect these questions will be answered, and catheter-based renal denervation will have an established clinical role in the care of patients with severe grades of hypertension. Less certain is the common prediction of its application in early, mild hypertension, in parallel with, or even before anti-hypertensive drug prescribing.