Search

Purpose: The avoidance of hospitalizations and the maintenance of in-center dialysis sessions in patients receiving dialysis for end-stage renal disease (ESRD) have obvious benefits to patients, dialysis providers and payers. Benefits include better continuity of care, better patient outcomes, improved quality of life, and reduced healthcare expenditures. The objective of this study was to quantify, from the perspective of a dialysis provider in the US, the potential impact of sevelamer versus calcium-based binders (CBBs) on hospitalization days and maintenance of in-center dialysis sessions among hyperphosphatemic dialysis patients.Methods: A Microsoft Excel-based model was developed to simulate the number of missed dialysis sessions among three hypothetical cohorts of hyperphosphatemic patients treated with either sevelamer or CBBs. The cohorts were characterized by their size to represent a small, mid-size, or large dialysis organization (75, 30,000, and 120,000 patients, respectively). In any given month, a patient in the model could receive dialysis treatments within the center, experience a hospitalization, or die. Treatment-specific monthly survival rates, hospitalization rates, length of stay, and binder dosages were derived from the Dialysis Clinical Outcomes Revisited (DCOR) study. A dialysis schedule of three treatments per week was assumed. Analyses were conducted for a 1-year time horizon.Results: For a small dialysis center, CBBs were associated with an increased number of missed in-center dialysis treatments (447) compared to sevelamer (395). Thus, sevelamer use avoided 52 missed in-center dialysis sessions during 1 year of treatment compared to CBBs. The magnitude of sevelamer's impact on maintaining in-center dialysis treatments increased with the size of the dialysis organization; for a mid-size dialysis organization sevelamer use avoided 20,571 missed in-center dialysis sessions and for a large dialysis organization sevelamer use avoided 82,286 missed in-center dialysis sessions.Conclusions: Treatment of hyperphosphatemic dialysis patients with sevelamer relative to CBBs was associated with a reduction in the number of missed in-center dialysis treatments across small, mid-size, and large dialysis organizations. This reduction could contribute to improved patient outcomes via undisrupted delivery of care within the dialysis clinic. The use of sevelamer versus CBBs could also result in an increased number of reimbursement payments to dialysis clinics and providers by avoiding missed in-center dialysis sessions due to hospitalization. [ABSTRACT FROM AUTHOR]

The dissemination of discipline-focused educational scholarship advances theory and stimulates pedagogical application. The aim of Advances in Physiology Education is to publish manuscripts that advance knowledge and inform educators in the field. This primer is tailored for individuals new to manuscript reviewing, early in their careers, or experienced in reviewing research but not educational manuscripts. Peer reviewing for basic and applied science is akin to evaluating research questions and rigor in teaching and learning studies, with differences in approach and analysis similar to those between biophysics and molecular physiology or cell and integrated physiology. Our purpose is to provide an overview of the review process and expectations. The submission and peer review process involves several steps: authors submit a manuscript and the Editor assigns an Associate Editor, who then assigns peer Reviewers. Reviewers are contacted via email and can accept or decline the invitation. Reviewers evaluate the work's strengths and weaknesses and then independently submit comments and recommendations to the Associate Editor. After review, the Associate Editor collects and weighs Reviewers' comments, sometimes garners additional reviews and input, to make a recommendation to the Editor. The Editor reviews the process, comments, and recommendations to render a final decision. Both authors and Reviewers receive an email with the decision. The editorial staff assists with communication and helps track the overall process. Peer review is integral to scientific publishing, ensuring quality and rigor, and reviewing is both a privilege and a responsibility of all in the scientific community. NEW & NOTEWORTHY This mini-review offers a comprehensive and current overview of the peer review process and the qualifications required to serve as a journal reviewer for Advances in Physiology Education . The guidelines are specifically designed for early career professionals new to manuscript reviewing, as well as seasoned research manuscript reviewers who are new to educational manuscript evaluation. Peer review is a cornerstone of scientific publishing, ensuring both quality and rigor. It is both a privilege and a responsibility for all members of the scientific community.

Incident chronic kidney disease (CKD) varies in populations with hypertension of similar severity. Proteinuria promotes CKD progression in part due to activation of plasminogen to plasmin in the podocytes, resulting in oxidative stress-mediated injury. Additional mechanisms include deficiency of renal alpha-klotho, that inhibits Wnt/beta-catenin, an up regulator of intra-renal renin angiotensin system (RAS) genes. Alpha-klotho deficiency therefore results in upregulation of the intra-renal RAS via Wnt/beta-catenin. In hypertensive, Dahl salt sensitive (DS) and spontaneously hypertensive rats (SHR), we investigated renal and vascular injury, miR-155, AT1R, alpha-klotho, and TNF-α. Hypertensive high salt DS (DS-HS), but not SHR developed proteinuria, plasminuria, and glomerulosclerosis. Compared to DS low salt (DS-LS), in hypertensive DS-HS alpha-klotho decreased 5-fold in serum and 2.6-fold in kidney, whereas serum mir-155 decreased 3.3-fold and AT1R increased 52% in kidney and 77% in aorta. AT1R, alpha-klotho, and miR-155 remained unchanged in prehypertensive and hypertensive SHR. TNF-α increased by 3-fold in serum and urine of DS-HS rats. These studies unveiled in salt sensitive DS-HS, but not in SHR, a genetically conditioned dysfunction of the intermolecular network integrated by alpha-klotho, RAS, miR-155, and TNF-α that is at the helm of their end-organ susceptibility while plasminuria may participate as a second hit., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

The kidney microcirculation is a unique structure as it is composed to 2 capillary beds in series: the glomerular and peritubular capillaries. The glomerular capillary bed is a high-pressure capillary bed, having a 60 mm Hg to 40 mm Hg pressure gradient, capable of producing an ultrafiltrate of plasma quantified as the glomerular filtration rate (GFR), thereby allowing for waste products to be removed and establishing sodium/volume homeostasis. Entering the glomerulus is the afferent arteriole, and the exiting one is the efferent arteriole. The concerted resistance of each of these arterioles is what is known as glomerular hemodynamics and is responsible for increasing or decreasing GFR and renal blood flow. Glomerular hemodynamics play an important role in how homeostasis is achieved. Minute-to-minute fluctuations in the GFR are achieved by constant sensing of distal delivery of sodium and chloride in the specialized cells called macula densa leading to upstream alternation in afferent arteriole resistance altering the pressure gradient for filtration. Specifically, 2 classes of medications (sodium glucose cotransporter-2 inhibitors and renin-angiotensin system blockers) have shown to be effective in long-term kidney health by altering glomerular hemodynamics. This review will discuss how tubuloglomerular feedback is achieved, and how different disease states and pharmacologic agents alter glomerular hemodynamics., (Copyright © 2022 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

The current heightened social awareness and anxiety triggered by escalating violence against Black Americans in the United States demands a safe space for reflection, education, and civil discourse within the academic setting. Too often there is an unmet need paired with a collective urgent desire to better understand the chronic existing structural, social, educational, and health inequities affecting disadvantaged populations, particularly Black Americans. In this perspective, the authors provide insight into a shared learning approach that provided a forum to discuss Perspectives Against Racism (PAR). Unlike existing top-down approaches, faculty, trainees, and staff were engaged in leading a series of focused discussions to examine unconscious bias, promote awareness of implicit biases, and reflect on individual and collective roles and responsibilities in working toward becoming antiracist. An existing 1-h graduate elective seminar course was dedicated to creating a space for learning, discussion, and exchange of ideas related to the experience and existence of racism (personal and institutional/systemic). A goal of each session was to go beyond didactics and identify mechanisms to implement change, at the level of the individual, department, and institution. This perspective of the shared experience may provide an adaptable framework that can be implemented in an academic setting at the departmental, center, or institutional level.

As literature indicates, historic racism and implicit bias throughout academia have been profound metrics leading to a lack of diversity, as related to people from underrepresented groups according to race and ethnicity, among biomedical sciences graduate students in U.S. universities. Recognizing such challenges, a team of biomedical scientists and inclusivity educators developed and implemented a pilot training program within an academic health sciences center as an initial step to educate faculty and staff regarding their roles in the promotion of an inclusive academic environment, receptive to all students, including underrepresented students. The 3-h workshop included didactic modules, videos, teaching modules, and active attendee participation. Faculty and staff were presented common terminology and ways to promote the development of an inclusive and diverse academic workforce. Compared with pre-workshop, post-workshop survey results indicated a statistically significant improvement in attendee knowledge of correctly identifying definitions of "implicit bias," "status leveling," "color-blind racial attitudes," "tokenism," and "failure to differentiate." Additionally, by the end of the workshop, participants had a statistically significant increase in self-perceptions regarding the importance of improving diversity and recognizing biases and stereotypes in graduate education, knowing what to say when interacting with people from different cultures, and the ability to acknowledge bias when mentoring students from groups underrepresented in the biomedical field. This preliminary initiative was successful in the introduction of faculty and staff to the importance of fostering an inclusive academic environment and thereby developing a diverse workforce.

Chymase released from mast cells produces pro-fibrotic, inflammatory, and vasoconstrictor agents. Studies were performed to test the hypothesis that chronic chymase inhibition provides a renal protective effect in type 2 diabetes. Diabetic (db/db) and control mice (db/m) were chronically infused with a chymase-specific inhibitor or vehicle for 8 weeks. Baseline urinary albumin excretion (UalbV) averaged 42 ± 3 and 442 ± 32 microg/d in control (n = 22) and diabetic mice (n = 27), respectively (p < .05). After administration of chymase inhibitor to diabetic mice, the change in UalbV was significantly lower (459 ± 57 microg/d) than in vehicle-treated diabetic mice (645 ± 108 microg/d). U NGAL V was not different at baseline between diabetic mice that would receive the chymase inhibitor (349 ± 56 ng/d, n = 6) and vehicle (373 ± 99 ng/d, n = 6) infusions, but increased significantly only in the vehicle-treated diabetic mice (p < .05). Glomeruli of diabetic kidneys treated chronically with chymase inhibition demonstrated reduced mesangial matrix expansion compared to glomeruli from untreated diabetic mice. Plasma angiotensin II levels were not altered by chymase inhibitor treatment. In summary, chronic chymase inhibition slowed the progression of urinary albumin excretion in diabetic mice. In conclusion, renal chymase may contribute to the progression of albuminuria in type 2 diabetes renal disease., (© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

The primary purpose of conducting two interprofessional education (IPE) experiences during a multidisciplinary physiology graduate-level course was to provide basic science, physical therapy, and physician assistant graduate students opportunities to work as a team in the diagnosis, treatment, and collaborative care when presented with a patient case focused on acute kidney injury (first case) and female athlete triad (second case). The secondary purpose was to apply basic physiology principles to patient case presentations of pathophysiology. The overall purpose was to assess the longitudinal effects and the value of IPE integrated within a basic science course. The following Interprofessional Education Collaborative subcompetencies were targeted: roles/responsibilities (RR1, RR4). Students were given a pre- and postsurvey to assess their IPE perceptions and knowledge of professional roles. There were statistically significant increases from the presurvey renal IPE experience to the presurvey endocrine IPE experience for two perception questions regarding the ability to explain the roles and responsibilities of a physical therapist (PT) and physician assistant using a Likert scale. In addition, student knowledge of the role of a PT increased significantly when comparing the renal IPE presurvey to the endocrine IPE presurvey results to open-ended questions. Students' perceptions of their knowledge as well as their ability to express, in writing, their newly learned knowledge of the role of a PT was sustained over time. Incorporating multiple IPE experiences into multidisciplinary health science courses represents an appropriate venue to have students learn and apply interprofessional competencies.

We have previously reported significant increases in neuronal nitric oxide synthase (NOS) immunostaining in renal arterioles of angiotensin type 1A receptor (AT1A) knockout mice, and in arterioles and macula densa cells of AT1A/AT1B knockout mice. The contribution of nitric oxide derived from endothelial and macula densa cells in the maintenance of afferent arteriolar tone and acetylcholine-induced vasodilation was functionally determined in kidneys of wild-type, AT1A, and AT1A/AT1B knockout mice. Acetylcholine-induced changes in arteriolar diameters of in vitro blood-perfused juxtamedullary nephrons were measured during control conditions, in the presence of the nonspecific NOS inhibitor, N ω -nitro-l-arginine methyl ester (NLA), or the highly selective neuronal NOS inhibitor, N 5 -(1-imino-3-butenyl)-l-ornithine (VNIO). Acetylcholine (0.1 mM) produced a significant vasoconstriction in afferent arterioles of AT1A/AT1B mice (-10.9 ± 5.1%) and no changes in afferent arteriolar diameters of AT1A knockout mice. NLA (0.01-1 mM) or VNIO (0.01-1 μM) induced significant dose-dependent vasoconstrictions (-19.8 ± 4.0% 1 mM NLA; -7.8 ± 3.5% 1 μM VNIO) in afferent arterioles of kidneys of wild-type mice. VNIO had no effect on afferent arteriole diameters of AT1A knockout or AT1A/AT1B knockout mice, suggesting nonfunctional neuronal nitric oxide synthase. These data indicate that acetylcholine produces a significant renal afferent arteriole vasodilation independently of nitric oxide synthases in wild-type mice. AT1A receptors are essential for the manifestation of renal afferent arteriole responses to neuronal nitric oxide synthase-mediated nitric oxide release.

Background/objectives: Expanding visceral adiposity is associated with increased inflammation and increased risk for developing obesity-related comorbidities. The goal of this study was to examine high fat diet (HFD)-induced differences in adipocyte size and cytokine/chemokine expression in visceral and subcutaneous adipose depots in obesity-prone (OP) and obesity-resistant (OR) rats., Methods: OP and OR rats were fed either a low fat diet (LFD, 10% kilocalories from fat) or HFD (60% kilocalories from fat) for 7 weeks. Adipocyte size and the presence of crown-like structures in epididymal and inguinal adipose tissue were determined. A multiplex cytokine/chemokine panel was used to assess the expression of inflammatory markers in epididymal and inguinal adipose tissues., Results: A higher percentage of large adipocytes (>5000 μm 2 ) was detected in the epididymal and inguinal adipose tissues of OP rats and a higher percentage of small adipocytes (<4000 μm 2 ) was detected in the epididymal and inguinal adipose tissues of OR rats. More crown-like structures were identified in epididymal adipose tissue of OP rats fed a LFD, compared to OR rats. Consumption of a HFD increased the number of crown-like structures in OR, but not OP rats. Epididymal expression of pro-inflammatory cytokines (IL-1β and TNF-α) was higher in OP rats, compared to OR rats fed LFD. HFD consumption increased epididymal expression of GM-CSF, IL-1α, IL-1β, IL-6, MIP-2 and TNF-α in OP and OR rats. Inguinal expression of pro-inflammatory cytokines (IL-1α, IL-1β and TNF-α) was higher in OP rats, compared to OR rats., Conclusions: Overall, these data suggest that a higher susceptibility to developing obesity is characterized by large adipocytes and increased visceral adipose inflammation. Interestingly, in OR rats, the detrimental effects of HFD consumption on visceral adipose inflammation are evident with only small increases in weight and adiposity, suggesting that HFD also increases the risk for obesity-related comorbidities in OR rats.

The primary purpose of conducting an interprofessional education (IPE) experience during the renal physiology block of a graduate-level course was to provide basic science, physical therapy, and physician assistant graduate students with an opportunity to work as a team in the diagnosis, treatment, and collaborative care of a patient with acute kidney injury. The secondary purpose was to enhance the understanding of basic renal physiology principles with a patient case presentation of renal pathophysiology. The overall purpose was to assess the value of IPE integration within a basic science course by examining student perceptions and program evaluation. Graduate-level students operated in interprofessional teams while working through an acute kidney injury patient case. The following Interprofessional Education Collaborative subcompetencies were targeted: Roles/Responsibilities (RR) Behavioral Expectations (RR1, RR4) and Interprofessional Communication (CC) Behavioral Expectations (CC4). Clinical and IPE stimulus questions were discussed both within and between teams with assistance provided by faculty facilitators. Students were given a pre- and postsurvey to determine their knowledge of IPE. There were statistically significant increases from pre- to postsurvey scores for all six IPE questions for all students. Physical therapy and physician assistant students had a statistically significant increase in pre- to postsurvey scores, indicating a more favorable perception of their interprofessional competence for RR1, RR4, and CC4. No changes were noted in pre- to postsurvey scores for basic science graduate students. Incorporating planned IPE experiences into multidisciplinary health science courses represents an appropriate venue to have students learn and apply interprofessional competencies., (Copyright © 2017 the American Physiological Society.)

Complex regional pain syndrome (CRPS) is a chronic, debilitating, neuropathic pain condition which is often misdiagnosed, difficult to manage, and lacks proven methods for remission. Most available methods provide some relief to a small percentage of patients. Recent FDA approval and superiority of the Nevro Senza 10-kHz high frequency (HF10) spinal cord stimulation (SCS) therapy over traditional low-frequency spinal cord stimulation for treatment of chronic back and leg pain may provide a new interventional therapeutic option for patients suffering from CRPS. We provide a case report of a 53-year-old Caucasian woman who suffered with CRPS in the right knee and thigh for over 7 years. Implantation of the HF10 device provided over 75% relief of pain, erythema, heat, swelling, and tissue necrosis to the entire region within 1 month of treatment. Because the HP10 therapy provides pain relief without paresthesia typical of traditional low-frequency, this system may provide relief for patients suffering from chronic pain.Key words: Complex regional pain syndrome, spinal cord stimulation, Nevro Senza HF10, erythema, knee, thigh.

Background and Objectives: People with CKD stages 3-5 and on dialysis (5D) have dramatically increased mortality, which has been associated with hyperphosphatemia in many studies. Oral phosphate binders are commonly prescribed to lower serum phosphate. We conducted an updated meta-analysis of the noncalcium-based binder (non-CBB) sevelamer versus CBBs in CKD stages 3-5D., Design, Setting, Participants, & Measurements: Randomized, controlled trials comparing sevelamer with CBBs were identified through MEDLINE and the Cochrane Central Register of Controlled Trials. Patient-level outcomes included all-cause mortality, cardiovascular events and mortality, hospitalization, and adverse effects. Intermediate outcomes included vascular calcification and bone changes. Biochemical outcomes included serum phosphate, calcium, parathyroid hormone, lipids, and hypercalcemia. We conducted and reported this review according to Cochrane guidelines., Results: We included 25 studies to March 31, 2015 with 4770 participants (88% on hemodialysis). Patients receiving sevelamer had lower all-cause mortality (risk ratio [RR], 0.54; 95% confidence interval [95% CI], 0.32 to 0.93), no statistically significant difference in cardiovascular mortality (n=2712; RR, 0.33; 95% CI, 0.07 to 1.64), and an increase in combined gastrointestinal events of borderline statistical significance (n=384; RR, 1.42; 95% CI, 0.97 to 2.08). For biochemical outcomes, patients receiving sevelamer had lower total serum cholesterol (mean difference [MD], -20.2 mg/dl; 95% CI, -25.9 to -14.5 mg/dl), LDL-cholesterol (MD, -21.6 mg/dl; 95% CI, -27.9 to -15.4 mg/dl), and calcium (MD, -0.4 mg/dl; 95% CI, -0.6 to -0.2 mg/dl) and a reduced risk of hypercalcemia (RR, 0.30; 95% CI, 0.19 to 0.48). End of treatment intact parathyroid hormone was significantly higher for sevelamer (MD, 32.9 pg/ml; 95% CI, 0.1 to 65.7 pg/ml). Serum phosphate values showed no significant differences., Conclusions: Patients with CKD stages 3-5D using sevelamer have lower all-cause mortality compared with those using CBBs. Because of a lack of placebo-controlled studies, questions remain regarding phosphate binder benefits for patients with CKD stages 3-5 and not on dialysis., (Copyright © 2016 by the American Society of Nephrology.)

Objective: In patients with significant mitral regurgitation (MR) at high risk of mortality and morbidity from mitral valve surgery, transcatheter mitral valve repair with the MitraClip System is associated with a reduction in MR and improved quality-of-life and functional status compared with baseline. The objective was to evaluate the cost-effectiveness of MitraClip therapy compared with standard of care in patients with significant MR at high risk for mitral valve surgery from a Canadian payer perspective., Methods: A decision analytic model was developed to estimate the lifetime costs, life years, quality-adjusted life years (QALYs), and incremental cost per life year and QALY gained for patients receiving MitraClip therapy compared with standard of care. Treatment-specific overall survival, risk of clinical events, quality-of-life, and resource utilization were obtained from the Endovascular Valve Edge-to-Edge REpair High Risk Study (EVEREST II HRS). Health utility and unit costs (CAD $2013) were taken from the published literature. Sensitivity analyses were conducted to explore the impact of alternative assumptions and parameter uncertainty on results., Results: The base case incremental cost per QALY gained was $23,433. RESULTS were most sensitive to alternative assumptions regarding overall survival, time horizon, and risk of hospitalization for congestive heart failure (CHF). Probabilistic sensitivity analysis showed MitraClip therapy to have a 92% chance of being cost-effective compared with standard of care at a willingness-to-pay threshold of $50,000 per QALY gained., Study Limitations: Key limitations include the small number of patients included in the EVEREST II HRS which informed the analysis, the limited data available to inform clinical events and disease progression in the concurrent comparator group, and the lack of a comparator group from a randomized control trial., Conclusion: MitraClip therapy is likely a cost-effective option for the treatment of patients at high risk for mitral valve surgery with significant MR.

Chemotherapy plus G-CSF (C+G) and G-CSF alone are two of the most common methods used to mobilize CD34(+) cells for autologous hematopoietic SCT (AHSCT). In order to compare and determine the real-world outcomes and costs of these strategies, we performed a retrospective study of 226 consecutive patients at 11 medical centers (64 lymphoma, 162 multiple myeloma), of whom 55% of lymphoma patients and 66% of myeloma patients received C+G. Patients with C+G yielded more CD34(+) cells/day than those with G-CSF alone (lymphoma: average 5.51 × 10(6) cells/kg on day 1 vs 2.92 × 10(6) cells/kg, P=0.0231; myeloma: 4.16 × 10(6) vs 3.69 × 10(6) cells/kg, P<0.00001) and required fewer days of apheresis (lymphoma: average 2.11 vs 2.96 days, P=0.012; myeloma: 2.02 vs 2.83 days, P=0.0015), although nearly all patients ultimately reached the goal of 2 × 10(6) cells/kg. With the exception of higher rates of febrile neutropenia in myeloma patients with C+G (17% vs 2%, P<0.05), toxicities and other outcomes were similar. Mobilization with C+G cost significantly more (lymphoma: median $10,300 vs $7300, P<0.0001; myeloma: $8800 vs $5600, P<0.0001), although re-mobilization adds $6700 for drugs alone. Our results suggest that although both C+G and G-CSF alone are effective mobilization strategies, C+G may be more cost-effective for patients at high risk of insufficient mobilization.

Background: Diabetic nephropathy (DN) is associated with enhanced renal, plasma, and urinary endothelin (ET)-1 levels. Chymase cleaves Big ET-1 (1-38) to ET-1 (1-31), which is further cleaved by neutral endopeptidase to ET-1 (1-21). The current study tested the hypothesis that afferent arterioles (AA) of diabetic kidneys exhibit enhanced vasoconstrictor responses to chymase-dependent intrarenal ET formation compared to control kidneys., Methods: In situ juxtamedullary AA vasoconstrictor responses to the intrarenal conversion of Big ET-1 (1-38) to ET-1 (1-21) were performed in the absence and presence of chymase inhibition in type 2 diabetic db/db and control db/m mice studied under in vitro experimental conditions., Results: AA vasoconstrictor responses to Big ET-1 (1-38) were significantly enhanced in diabetic compared to control kidneys. In the presence of chymase inhibition (JNJ-18054478), AA vasoconstrictor responses of diabetic kidneys to Big ET-1 (1-38) were significantly less than the responses of control kidneys. AA diameters decreased similarly to ET-1 (1-21) in diabetic and control kidneys., Conclusions: AA responses to the intrarenal conversion of Big ET-1 (1-38) to ET-1 in the absence of chymase enzymatic activity were significantly reduced in kidneys of diabetic compared to control mice, while the magnitude of the vasoconstriction to ET-1 (1-21) was not different. These data suggest that AA vasoconstriction produced by the chymase-dependent pathway is significantly greater in diabetic compared to control kidneys. We propose that intrarenal chymase-dependent ET-1 production contributes to the decline in function and progression to end-stage renal disease in patients with type 2 diabetes.

Diabetes mellitus is one of the most prevalent diseases and is associated with increased incidence of structural and functional derangements in the kidneys, eventually leading to end-stage renal disease in a significant fraction of afflicted individuals. The renoprotective effects of renin-angiotensin system (RAS) blockade have been established; however, the mechanistic pathways have not been fully elucidated. In this review article, the cardinal role of an activated RAS in the pathogenesis of diabetic nephropathy (DN) is discussed with a focus on 4 themes: (1) introduction to RAS cascade, (2) intrarenal RAS in diabetes, (3) clinical outcomes of RAS blockade in DN, and (4) potential of urinary angiotensinogen as an early biomarker of intrarenal RAS status in DN. This review article provides a mechanistic rational supporting the hypothesis that an activated intrarenal RAS contributes to the pathogenesis of DN and that urinary angiotensinogen levels provide an index of intrarenal RAS activity.

Our previous work supports a major role for angiotensin-converting enzyme (ACE)-independent intrarenal angiotensin (ANG) II formation on microvascular function in type 2 diabetes mellitus. We tested the hypothesis that there is a switch from renal vascular ACE-dependent to chymase-dependent ANGII formation in diabetes mellitus. The in vitro juxtamedullary afferent arteriole (AA) contractile responses to the intrarenal conversion of the ACE-specific, chymase-resistant ANGI peptide ([Pro(10)]ANGI) to ANGII were significantly reduced in kidneys of diabetic (db/db) compared with control (db/m) mice. AA responses to the intrarenal conversion of the chymase-specific, ACE-resistant ANGI peptide ([Pro(11), D-Ala(12)]ANGI) to ANGII were significantly enhanced in kidneys of diabetic compared with control mice. AA diameters were significantly reduced by 9 ± 2, 15 ± 3, and 24 ± 3% of baseline in diabetic kidneys in response to 10, 100, and 1000 nmol/L [Pro(11), D-Ala(12)]ANGI, respectively, and the responses were significantly attenuated by angiotensin type 1 receptor or chymase-specific (JNJ-18054478) inhibition. [Pro(11), D-Ala(12)]ANGI did not produce a significant AA vasoconstriction in control kidneys. Chymase inhibition significantly attenuated ANGI-induced AA vasoconstriction in diabetic, but not control kidneys. Renal vascular mouse mast cell protease-4 or chymase/β-actin mRNA expression was significantly augmented by 5.1 ± 1.4 fold; while ACE/β-actin mRNA expression was significantly attenuated by 0.42 ± 0.08 fold in diabetic compared with control tissues. In summary, intrarenal formation of ANGII occurs primarily via ACE in the control, but via chymase in the diabetic vasculature. In conclusion, chymase-dependent mechanisms may contribute to the progression of diabetic kidney disease.

Historically, tools to assess renal function have been developed to investigate the physiology of the kidney in an experimental setting, and certain of these techniques have utility in evaluating renal function in the clinical setting. The following work will survey a spectrum of these tools, their applications and limitations in four general sections. The first is clearance, including evaluation of exogenous and endogenous markers for determining glomerular filtration rate, the adaptation of estimated glomerular filtration rate in the clinical arena, and additional clearance techniques to assess various other parameters of renal function. The second section deals with in vivo and in vitro approaches to the study of the renal microvasculature. This section surveys a number of experimental techniques including corticotomy, the hydronephrotic kidney, vascular casting, intravital charge coupled device videomicroscopy, multiphoton fluorescent microscopy, synchrotron-based angiography, laser speckle contrast imaging, isolated renal microvessels, and the perfused juxtamedullary nephron microvasculature. The third section addresses in vivo and in vitro approaches to the study of renal blood flow. These include ultrasonic flowmetry, laser-Doppler flowmetry, magnetic resonance imaging (MRI), phase contrast MRI, cine phase contrast MRI, dynamic contrast-enhanced MRI, blood oxygen level dependent MRI, arterial spin labeling MRI, x-ray computed tomography, and positron emission tomography. The final section addresses the methodologies of metabolic balance studies. These are described for humans, large experimental animals as well as for rodents. Overall, the various in vitro and in vivo topics and applications to evaluate renal function should provide a guide for the investigator or physician to understand and to implement the techniques in the laboratory or clinic setting.

The angiotensin II type 1 receptor (AT(1)R) mediates most hypertensive actions of angiotensin II. To understand the molecular regulation of the AT(1)R in normal physiology and pathophysiology, methods for sensitive and specific detection of AT(1)R protein are required. Here, we examined the specificity of a panel of putative AT(1)R antibodies that are commonly used by investigators in the field. For these studies, we carried out Western blotting and immunohistochemistry with kidney tissue from wild-type mice and genetically modified mice lacking the major murine AT(1)R isoform, AT(1A) (AT(1A)KO), or with combined deficiency of both the AT(1A) and AT(1B) isoforms (AT(1AB)KO). For the 3 antibodies tested, Western blots of protein homogenates from wild-type kidneys yielded distinct bands with the expected size range for AT(1)R. In addition, these bands appeared identical in samples from mice lacking 1 or both murine AT(1)R isoforms. Additionally, the pattern of immunohistochemical staining in kidneys, liver, and adrenal glands of wild-type mice was very similar to that of AT(1AB)KO mice completely lacking all AT(1)R. We verified the absence of AT(1)R subtypes in each mouse line by the following: (1) quantitative polymerase chain reaction documenting the absence of mRNA species, and (2) functionally by assessing angiotensin II-dependent vasoconstriction, which was substantially blunted in both AT(1A)KOs and AT(1AB)KOs. Finally, these antibodies failed to detect epitope-tagged AT(1A)R protein overexpressed in human embryonic kidney cells. We conclude that anti-AT(1)R antibodies available from commercial sources and commonly used in published studies exhibit nonspecific binding in mouse tissue that may lead to erroneous results.

In many jurisdictions, cost-effectiveness analysis (CEA) plays an important role in determining drug coverage and reimbursement and, therefore, has the potential to impact patient access. Health economic guidelines recommend the inclusion of future costs related to the intervention of interest within CEAs but provide little guidance regarding the definition of 'related'. In the case of CEAs of therapies that extend the lives of patients with chronic kidney disease (CKD) on dialysis but do not impact the need for or the intensity of dialysis, the determination of the relatedness of future dialysis costs to the therapy of interest is particularly ambiguous. The uncertainty as to whether dialysis costs are related or unrelated in these circumstances has led to inconsistencies in the conduct of CEAs for such products, with dialysis costs included in some analyses while excluded in others. Due to the magnitude of the cost of dialysis, whether or not dialysis costs are included in CEAs of such therapies has substantial implications for the results of such analyses, often meaning the difference between a therapy being deemed cost effective (in instances where dialysis costs are excluded) or not cost effective (in instances where dialysis costs are included). This paper explores the issues and implications surrounding the inclusion of dialysis costs in CEAs of therapies that extend the lives of dialysis patients but do not impact the need for dialysis. Relevant case studies clearly demonstrate that, regardless of the clinical benefits of a life-extending intervention for dialysis patients, and due to the high cost of dialysis, the inclusion of dialysis costs in the analysis essentially eliminates the possibility of obtaining a favourable cost-effectiveness ratio. This raises the significant risk that dialysis patients may be denied access to interventions that are cost effective in other populations due solely to the high background cost of dialysis itself. Finally, the paper presents a case for excluding dialysis costs in CEAs of therapies that extend the lives of patients receiving dialysis but do not impact the need for dialysis. The argument is founded on the following: (i) health economic guidelines imply that dialysis costs are unrelated to such therapies and therefore should not be included in CEAs of such therapies; (ii) the high cost and cost-effectiveness ratio associated with dialysis place an unreasonable and insurmountable barrier to demonstrating the cost effectiveness of such therapies, particularly since the decision to fund dialysis has already been made; and (iii) current clinical and reimbursement practices include the use of such therapies for patients with CKD receiving dialysis. We conclude that the exclusion of dialysis costs in such cases is methodologically correct given current health economic guidelines and is consistent with current practices regarding the treatment of dialysis patients.

Atrial natriuretic peptide (ANP) exerts an inhibitory effect on juxtaglomerular (JG) renin synthesis and release by activating guanylyl cyclase/ natriuretic peptide receptor-A (GC-A/NPRA). Renin has also been localized in connecting tubule cells; however, the effect of ANP/NPRA signaling on tubular renin has not been determined. In the present study, we determined the role of NPRA in regulating both JG and tubular renin using Npr1 (coding for NPRA) gene-disrupted mice, which exhibit a hypertensive phenotype. Renin-positive immunoreactivity in Npr1(-/-) homozygous null mutant mice was significantly reduced compared with Npr1(+/+) wild-type mice (23% vs 69% renin-positive glomeruli). However, after chronic diuretic treatment, Npr1(-/-) mice showed an increment of JG renin immunoreactivity compared with Npr1(+/+) mice (70% vs 81% renin-positive glomeruli). There were no significant differences in the distal tubule renin between Npr1(+/+) and Npr1(-/-) mice. However, after diuretic treatment, Npr1(-/-) mice showed a significant decrease in renin immunoreactivity in principal cells of cortical collecting ducts (p<0.05). The increased JG renin immunoreactivity after reduction in blood pressure in diuretic-treated Npr1(-/-) mice, demonstrates an inhibitory action of ANP/NPRA system on JG renin; however, a decreased expression of distal tubular renin suggests a differential effect of ANP/NPRA signaling on JG and distal tubular renin.

Objectives: Recent results of the U.S. Oncology Adjuvant Trial 9735 demonstrated significant disease-free survival and overall survival benefits for docetaxel and cyclophosphamide (tc) compared with doxorubicin and cyclophosphamide (ac) in the adjuvant treatment of operable invasive breast cancer. Based on clinical data from the 9735 study, we evaluated the lifetime cost-effectiveness of tc compared with ac from the perspective of the Canadian publicly funded health care system., Methods: A Markov model was developed to estimate the incremental cost per quality-adjusted life-year gained and per life-year gained. Monthly survival and risk of disease recurrence up to 7 years were obtained directly from the overall survival and disease-free survival curves in the 9735 study; life-years beyond 7 years were estimated using the average life expectancy of age-matched women in the general Canadian population. Canadian-specific resource utilization and unit costs (in 2008 Canadian dollars) were applied to estimate costs for chemotherapy administration, chemotherapy-related toxicities, recurrence, and adverse events. Health-utility scores and decrements used in the calculation of quality-adjusted life-years were derived from the literature., Results: The lifetime cost per quality-adjusted life-year gained was $8,251 for tc compared with ac, and the cost per life-year gained was $6,842. The results were robust across a range of sensitivity analyses., Conclusions: Cost-effectiveness, combined with efficacy and an acceptable safety profile, support the adoption of tc as an alternative to ac in Canadian clinical practice for the adjuvant treatment of operable early breast cancer.

Diabetic nephropathy is a major cause of end-stage renal disease worldwide. The current studies were performed to determine the later stages of the progression of renal disease in type II diabetic mice (BKS; db/db). Methodology was developed for determining glomerular filtration rate (GFR) in conscious, chronically instrumented mice using continuous intravenous infusion of FITC-labeled inulin to achieve a steady-state plasma inulin concentration. Obese diabetic mice exhibited increased GFR compared with control mice. GFR averaged 0.313 ± 0.018 and 0.278 ± 0.007 ml/min in 18-wk-old obese diabetic (n = 11) and control (n = 13) mice, respectively (P < 0.05). In 28-wk-old obese diabetic (n = 10) and control (n = 15) mice, GFR averaged 0.348 ± 0.030 and 0.279 ± 0.009 ml/min, respectively (P < 0.05). GFR expressed per gram BW was significantly reduced in 18- and 28-wk-old obese diabetic compared with control mice (5.9 ± 0.3 vs. 9.0 ± 0.3; 6.6 ± 0.6 vs. 7.8 ± 0.3 μl·min(-1)·g body wt(-1)), respectively (P < 0.05). However, older nonobese type II diabetic mice had significantly reduced GFR (0.179 ± 0.023 ml/min; n = 6) and elevated urinary albumin excretion (811 ± 127 μg/day) compared with obese diabetic and control mice (514 ± 54, 171 ± 18 μg/day), which are consistent with the advanced stages of renal disease. These studies suggest that hyperfiltration contributes to the progression of renal disease in type II diabetic mice.

Objective: The cost-effectiveness of oxaliplatin in combination with 5-fluorouracil/leucovorin (5FU/LV)-the FOLFOX regimen-was compared with that of 5FU/LV alone as adjuvant therapy for patients with stage III colon cancer, from the perspective of the Cancer Care Ontario New Drug Funding Program. In the mosaic (Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer) trial, the FOLFOX regimen significantly improved disease-free survival. The mosaic trial formed the basis of the present analysis., Methodology: Extrapolated patient-level data from the mosaic trial were used to model patient outcomes from treatment until death. Utilities were obtained from the literature. Resource utilization data were derived from the mosaic trial and supplemented with data from the literature. Unit costs were obtained from the Ontario Ministry of Health and Long-Term Care, the London Health Sciences Centre, and the literature., Results: Lifetime incremental cost-effectiveness ratios for FOLFOX compared with 5fu/lv were CA$14,266 per disease-free year, CA$23,598 per life-year saved, and CA$24,104 per quality adjusted life-year (QALY) gained, discounting costs and outcomes at 5% per annum. These results were stable for a wide range of inputs; only utility values associated with relapse seemed to influence the cost-effectiveness ratios observed., Conclusions: With an incremental cost of CA$24,104 per QALY gained, FOLFOX is a cost-effective adjuvant treatment for stage iii colon cancer. Compared with 5fu/lv alone, this regimen offers better clinical outcomes and provides good value for money.

Combination therapy of angiotensin-converting enzyme (ACE) inhibition and AT(1) receptor blockade has been shown to provide greater renoprotection than ACE inhibitor alone in human diabetic nephropathy, suggesting that ACE-independent pathways for ANG II formation are of major significance in disease progression. Studies were performed to determine the magnitude of intrarenal ACE-independent formation of ANG II in type II diabetes. Although renal cortical ACE protein activity [2.1 +/- 0.8 vs. 9.2 +/- 2.1 arbitrary fluorescence units (AFU) x mg(-1) x min(-1)] and intensity of immunohistochemical staining were significantly reduced and ACE2 protein activity (16.7 +/- 3.2 vs. 7.2 +/- 2.4 AFU x mg(-1) x min(-1)) and intensity elevated, kidney ANG I (113 +/- 24 vs. 110 +/- 45 fmol/g) and ANG II (1,017 +/- 165 vs. 788 +/- 99 fmol/g) levels were not different between diabetic and control mice. Afferent arteriole vasoconstriction due to conversion of ANG I to ANG II was similar in magnitude in kidneys of diabetic (-28 +/- 3% at 1 microM) and control (-23 +/- 3% at 1 microM) mice; a response completely inhibited by AT(1) receptor blockade. In control kidneys, afferent arteriole vasoconstriction produced by ANG I was significantly attenuated by ACE inhibition, but not by serine protease inhibition. In contrast, afferent arteriole vasoconstriction produced by intrarenal conversion of ANG I to ANG II was significantly attenuated by serine protease inhibition, but not by ACE inhibition in diabetic kidneys. In conclusion, there is a switch from ACE-dependent to serine protease-dependent ANG II formation in the type II diabetic kidney. Pharmacological targeting of these serine protease-dependent pathways may provide further protection from diabetic renal vascular disease.

The renin-angiotensin system (RAS) is a critical regulator of sodium balance, extracellular fluid volume, vascular resistance, and, ultimately, arterial blood pressure. In the kidney, angiotensin II exerts its effects to conserve salt and water through a combination of the hemodynamic control of renal blood flow and glomerular filtration rate and tubular epithelial cell sodium chloride and water transport mechanisms. Pharmacological inhibition of the actions of the RAS are widely used in the treatment of patients with hypertension, congestive heart failure, left ventricular dysfunction, pulmonary and systemic edema, diabetic nephropathy, cirrhosis of the liver, scleroderma, and migraines. Therefore, a thorough understanding of the influences of the RAS on normal renal physiology is of major importance for first-year medical students.

The db/db mouse is a genetic model of type 2 diabetes that exhibits progressive renal disease. Obesity, hyperglycemia, and albuminuria (822 +/- 365 vs. 28 +/- 8 microg/day) are evident in 18-wk-old db/db compared with db/m (lean littermate control) mice. Our goal was to determine the blood pressure (BP) phenotype of the db/db mouse. Mean arterial BP measured in conscious mice by radiotelemetry was not different between db/db (n = 9) and db/m (n = 12) mice, averaging 113 +/- 3 and 112 +/- 2 mmHg, respectively. The circadian BP profile of db/db mice was shifted to the left and exhibited a significant reduction in amplitude compared with db/m mice. Heart rate (487 +/- 9 vs. 542 +/- 7 beats/min; P < 0.05) and locomotor activity were significantly reduced in db/db compared with db/m mice. We tested the hypothesis that intact afferent arteriole (AA) responsiveness to increases in renal artery pressure (RAP) and angiotensin (ANG) II sensitivity contributes to normal BP in this diabetic model. AA diameters of in vitro blood-perfused juxtamedullary nephrons of db/db mice (15.7 +/- 0.5 microm; n = 38) were significantly larger than those of db/m mice (12.5 +/- 0.4 microm; n = 37). AA responses to increases in RAP and ANG II were not different between kidneys of db/db and db/m mice. Significant AA vasoconstriction to 1 nM ANG II was observed in kidneys of db/db mice (-11 +/- 4%), while 10 nM ANG II decreased AA diameter in both groups [db/db, -20 +/- 4%, (n = 12); db/m, -26 +/- 4% (n = 12)]. In summary, AA responses to increases in renal perfusion pressure and ANG II remain intact in db/db mice. Diabetic renal disease occurs in db/db mice independently of elevated BP.

The present study was performed to determine the influence of absence of angiotensin type 1A (AT(1A)) and/or AT(1B) receptor feedback regulation of kidney neuronal nitric oxide synthase (nNOS) and renin protein expression. Kidneys were harvested from wild-type (WT), AT(1A)(-/-), AT(1B)(-/-), and AT(1A)(-/-)AT(1B)(-/-) mice and immunostained for nNOS and renin protein localization. AT(1A)(-/-) and AT(1A)(-/-)AT(1B)(-/-) kidneys demonstrated an increase in the percentage of glomeruli with nNOS-positive afferent and interlobular arterioles compared with WT mice. Density of vascular nNOS immunostaining was 20-fold higher in kidneys of AT(1A)(-/-) and AT(1A)(-/-)AT(1B)(-/-) compared with WT mice. Density of macula densa nNOS immunostaining was 7-fold higher in AT(1A)(-/-)AT(1B)(-/-) than in WT mice. Percent of glomeruli positive for juxtaglomerular (JG) cell renin was 3-fold higher, whereas the density of JG cell renin immunostaining was 15-fold higher in kidneys of AT(1A)(-/-) and AT(1A)(-/-)AT(1B)(-/-) compared with WT mice. Kidneys of AT(1A)(-/-) and AT(1A)(-/-)AT(1B)(-/-) mice displayed recruitment of renin protein expression along afferent and interlobular arterioles. Absence of AT(1) receptor signaling resulted in enhanced nNOS protein expression in both microvascular and tubular structures. Enhanced NO generation may contribute to the reduced renal vascular tone and blood pressure observed with blockade of the renin-angiotensin system.

Angiotensin type 1A (AT(1A)) and 1B (AT(1B)) receptor deletion (AT1DKO) results in renal microvascular disease, tubulointerstitial injury, and reduced blood pressure. To test the hypothesis that renal preglomerular responses to angiotensin (ANG) II are mediated by AT(1A) and AT(1B) receptors, experiments were performed in AT1DKO mice using the in vitro blood perfused juxtamedullary nephron technique. Kidneys were harvested from AT1DKO and wild-type (WT) mice and bathed with ANG II (1-100 nM), norepinephrine (NE; 100-1,000 nM), or acetylcholine (ACh; 10 microM). Baseline diameters of afferent (19.5 +/- 0.7 and 13.9 +/- 0.7 microm, n = 17 and 16) and efferent (15.5 +/- 2.1 and 10.8 +/- 1.0 microm, n = 4 and 7) arterioles of AT1DKO were significantly larger than WT. Afferent and efferent arteriolar responses to ANG II, 100, and 300 nM NE were absent in AT1DKO; although significant constriction to 1 microM NE was observed (-17 +/- 5 and -23 +/- 6%, respectively). Afferent arterioles of WT mice dilated significantly in response to ACh (15.1 +/- 0.6 to 17.0 +/- 1.2 microm, n = 6); however, arterioles from AT1DKO tended to contract (19.9 +/- 1.2 to 17.8 +/- 1.6 microm; n = 6, P = 0.06). In summary, loss of ANG II-induced contraction, reduced vasoconstriction to NE, and endothelial cell dysfunction contribute to the renal vascular phenotype of AT1DKO mice. We conclude that ANG II signaling via the AT(1) receptor plays a pivotal role in basal renal microvascular tone and effectiveness to respond to vasoconstrictor and vasodilator agonists.

Cross-talk between G protein-coupled receptors (GPCR) is known to occur at multiple levels, including receptor heterodimerization and intracellular signaling. This study tested the hypothesis that GPCR cross-talk occurs at the transcriptional level. It was demonstrated that the bradykinin B2 receptor gene (BdkrB2) is a direct transcriptional target of the angiotensin II (AngII) type 1 receptor (AT(1)R) in collecting duct cells. AngII induced BdkrB2 mRNA expression in mouse inner medullary collecting duct cells, and this effect was abrogated by AT(1)R blockade; in contrast, AT(2)R blockade was ineffective. Actinomycin D, an inhibitor of gene transcription, abrogated AngII-stimulated BdkrB2 expression. In addition, AngII produced dosage- and time-dependent increases in B2 receptor protein levels (2.9 +/- 0.4 fold; P < 0.05). AngII stimulated phosphorylation of cAMP response element binding protein (CREB) on Ser-133 and assembly of p-CREB on the BdkrB2 promoter in vivo. Moreover, AngII induced hyperacetylation of BdkrB2 promoter-associated H4 histones, a chromatin modification that is associated with gene activation. Mutations of the CRE abrogated AngII-induced activation of the BdkrB2 promoter. AngII-treated inner medullary collecting duct cells exhibited augmented intracellular calcium signaling in response to bradykinin, confirming the functional relevance of AT(1)-B2 receptor signaling. Finally, studies that were conducted in angiotensin type 1 receptor (Agtr1)-null mice revealed that BdkrB2 mRNA levels were significantly lower in the renal medulla of Agtr1(A)(-/-) and Agtr1(A/B)(-/-) than in Agtr1(+/+) and Agtr1(B)(-/-) mice. It is concluded that BdkrB2 is a downstream target of the AT(1)R-CREB signaling pathway. Transcriptional regulation represents a novel form of cross-talk between GPCR that link the renin-angiotensin and kallikrein-kinin systems.

Background: Rodents express two isoforms of the angiotensin II type 1 (AT(1)) receptor: AT(1A) and AT(1B). It is unclear which receptor subtype mediates contraction in response to angiotensin II in various arteries. We tested the hypothesis that the AT(1B) receptor is the predominant receptor that mediates contraction in the abdominal aorta in response to angiotensin II., Methods: Isometric tension responses to angiotensin II were determined in abdominal aortic rings obtained from male wild-type and AT(1B) receptor knockout mice. The rings were suspended in an organ bath of a wire myograph and contractions to angiotensin II and other vasoconstrictors were determined., Results: Angiotensin II contracted aortic segments from wild-type mice; however, this response was virtually absent in rings obtained from AT(1B) receptor knockout mice. Contractions in response to K(+) and U46619 (thromboxane A(2) mimetic) were not different between rings obtained from wild-type and AT(1B) receptor knockout mice., Conclusions: Reduced angiotensin II contraction is not related to a generalized decrease in smooth muscle function, rather it is specifically due to genetic ablation of the AT(1B) receptor. Our data support the concept that AT(1B) receptors couple to contraction in the mouse abdominal aorta, a function that parallels the single known AT(1) receptor in human vascular smooth muscle.

Purpose: To facilitate future glaucoma model development and to provide guidance for decision-makers evaluating them, we provide an overview of an innovative glaucoma model and highlight important modeling considerations., Considerations: The considerations that were addressed include: disease outcome that is both relevant and meaningful to current clinical practice; diversity in treatment options and practices; incorporation of therapy discontinuation; and consideration of the variability in patient response to treatment., Model Scope: A state-transition, Monte Carlo simulation model was developed to simulate the management and treatment of patients with glaucoma and/or ocular hypertension. The model examines strategies involving sequential use of up to 6 pharmacologic interventions. Transitions are based on the monthly probability that a patient is no longer "successfully maintained" on therapy, which can be a consequence of lack of intraocular pressure control, adverse events, lack of compliance, or lack of persistence. Outputs of the model include months on each treatment, frequency of therapy switches, days of intraocular pressure control, frequency of ophthalmologist visits, frequency of surgery, and glaucoma-related costs. The model allows the user to specify country-specific treatment strategies, survival on therapy, surgical rates, practice patterns, and costs., Concept Application: The model presented offers insights into accommodating patient and clinician variability through the use of persistence distributions. It will facilitate future glaucoma model development and provide insight for decision-makers who must evaluate model-based analyses of the economic value of glaucoma interventions.

Angiotensin (ANG) type 1A (AT(1A)) receptor-null (AT(1A)(-/-)) mice exhibit reduced afferent arteriolar (AA) constrictor responses to ANG II compared with wild-type (WT) mice, whereas efferent arteriolar (EA) responses are absent (Harrison-Bernard LM, Cook AK, Oliverio MI, and Coffman TM. Am J Physiol Renal Physiol 284: F538-F545, 2003). In the present study, the renal arteriolar constrictor responses to norepinephrine (NE) and/or ANG II were determined in blood-perfused juxtamedullary nephrons from kidneys of AT(1A)(-/-), AT(1B) receptor-null (AT(1B)(-/-)), and WT mice. Baseline AA diameter in AT(1A)(-/-) mice was not different from that in WT mice (13.1 +/- 0.9 and 12.6 +/- 0.9 microm, n = 7 and 8, respectively); however, EA diameters were significantly larger (17.3 +/- 1.4 vs. 11.7 +/- 0.4 microm, n = 10 and 8) in AT(1A)(-/-) than in WT mice. Constriction of AA (-40 +/- 8 and -51 +/- 6% at 1 microM NE) and EA (-29 +/- 6 and -38 +/- 3% at 1 microM NE) in response to 0.1-1 microM NE was similar in AT(1A)(-/-) and WT mice. Baseline diameters of AA (13.5 +/- 0.7 and 14.2 +/- 0.9 microm, n = 9 and 10) and EA (15.4 +/- 1.0 and 15.0 +/- 0.7 microm, n = 11 and 9) and ANG II (0.1-10 nM) constrictor responses of AA (-25 +/- 4 and -31 +/- 5% at 10 nM) and EA (-32 +/- 6 and -35 +/- 7% at 10 nM) were similar in AT(1B)(-/-) and WT mice, respectively. ANG II-induced constrictions were eliminated by AT(1) receptor blockade with 4 microM candesartan. Taken together, our data demonstrate that AA and EA responses to NE are unaltered in the absence of AT(1A) receptors, and ANG II responses remain intact in the absence of AT(1B) receptors. Therefore, we conclude that AT(1A) and AT(1B) receptors are functionally expressed on the AA, whereas the EA exclusively expresses the AT(1A) receptor.

Background: The purpose of this study was to characterize current patterns of treatment of glaucoma and ocular hypertension and to examine the effect of those patterns on intraocular pressure (IOP) control and persistence on therapy., Methods: A retrospective chart review was conducted at 3 ophthalmology practices in Alberta. Data were collected for patients who had begun therapy for newly diagnosed primary open-angle glaucoma or ocular hypertension between May 1, 1998, and Sept. 30, 1999 (phase 1), and for patients who had begun second-line therapy after initial therapy with a beta-blocker had failed (phase 2). Data were collected for a minimum of 24 months for phase 1 and a minimum of 18 months for phase 2., Results: We included 115 patient charts in phase 1 and 93 in phase 2. In each phase, the patients for whom latanoprost had been prescribed in unfixed combination with a beta-blocker had the greatest mean percentage reduction in IOP at month 24, and the patients for whom latanoprost had been prescribed alone or in combination with a beta-blocker were more likely to still be on initial therapy at month 24; the difference in persistence on therapy was statistically significant only in phase 1 (p = 0.001). The mean number of switches in therapy was smaller in phase 1 than in phase 2 in all therapy groups., Interpretation: Compared with other first- and second-line forms of therapy, treatment with latanoprost, alone or in combination with a beta-blocker, was associated with greater reductions in IOP, better therapeutic persistence, fewer therapy switches and fewer ophthalmologist visits over a 2-year period.

Distal nephron renin may provide a possible pathway for angiotensin (Ang) I generation from proximally delivered angiotensinogen. To examine the effects of Ang II on distal nephron renin, we compared renin protein and mRNA expression in control and Ang II-infused rats. Kidneys from sham (n=9) and Ang II-infused (80 ng/kg per minute, 13 days, n=10) Sprague-Dawley rats were processed by immunohistochemistry, Western blot, reverse transcriptase-polymerase chain reaction (RT-PCR), and quantitative real-time RT-PCR. Ang II infusion increased systolic blood pressure (181+/-4 versus 115+/-5 mm Hg) and suppressed plasma and kidney cortex renin activity. Renin immunoreactivity was suppressed in juxtaglomerular apparatus (JGA) cells in Ang II-infused rats compared with sham (0.1+/-0.1 versus 1.0+/-0.1 relative ratio) but increased in distal nephron segments (6.4+/-1.4 versus 1.0+/-0.1 cortex; 2.5+/-0.3 versus 1.0+/-0.2 medulla). Tubular renin immunostaining was apically distributed in principal cells colocalizing with aquaporin-2 in connecting tubules and cortical and medullary collecting ducts. Renin protein levels were decreased in the kidney cortex of Ang II-infused rats compared with that of sham (0.4+/-0.2 versus 1.0+/-0.4) rats but higher in the kidney medulla (1.2+/-0.4 versus 1.0+/-0.1). In kidney medulla, RT-PCR and quantitative real-time PCR showed similar levels of renin transcript in both groups. In summary, the detection of renin mRNA in the renal medulla, which is devoid of JGA, indicates local synthesis rather than an uptake of JGA renin. In contrast to the inhibitory effect of Ang II on JGA renin, Ang II infusion stimulates renin protein expression in collecting ducts and maintains renin transcriptional levels in the medulla, which may contribute to the increased intrarenal Ang II levels in Ang II-dependent hypertension.

The functional balance between angiotensin II (Ang II) and nitric oxide (NO) plays a key role in modulating salt sensitivity. Estrogen has been shown to downregulate angiotensin type 1 (AT1) receptor expression and to increase the bioavailability of endothelium-derived NO, which decreases AT1 receptor expression. The present study tests the hypothesis that in the presence of genetic salt sensitivity, deficiency of endogenous estrogens after ovariectomy (OVX) fosters an upregulation of Ang II. Female Dahl salt-resistant (DR), Dahl salt-sensitive (DS), Wistar-Kyoto (WKY), and spontaneously hypertensive (SHR) rats underwent bilateral OVX or sham surgery (SHX) and were fed a normal salt diet (0.5% NaCl) for 14 weeks. Systolic blood pressures were measured every 2 weeks and were not significantly different between OVX and SHX for DR, WKY, and SHR groups. However, at the end of 14 weeks of normal salt diet, hypertension developed in DS OVX but not SHX rats (160+/-3 versus 136+/-3 mm Hg; P<0.05). Hypertension also developed in DS OVX rats pair-fed a normal salt diet (166+/-7 mm Hg). Development of hypertension in DS OVX rats was prevented by estrogen replacement (132+/-3 mm Hg), AT1 receptor blockade (119+/-3 mm Hg), or feeding a very low salt diet (0.1% NaCl; 129+/-4 mm Hg). Renal AT1 receptor protein expression was significantly elevated 2-fold in DS OVX relative to SHX rats and was prevented by estrogen replacement. These data strongly suggest that after OVX in salt-sensitive rats there is a lower threshold for the hypertensinogenic effect of salt that is linked to an activation of Ang II.

Aberrant gene-environment interactions are implicated in the pathogenesis of congenital renal dysgenesis (CRD), a leading cause of renal failure in infants and children. We have recently developed an animal model of CRD that is caused by gestational salt stress (5% NaCl diet; HS) of bradykinin B2R null mice [B2R(-/-)CRD; El-Dahr SS, Harrison-Bernard LM, Dipp S, Yosipiv IV, and Meleg-Smith S. Physiol Genomics 3: 121-131, 2000.]. Developing B2R(-/-)CRD mice exhibit tubular and glomerular cysts, stromal expansion, and loss of corticomedullary differentiation. In addition, B2R(-/-)CRD mice exhibit transient hypertension from 2 to 4 mo of age. The present study was designed to determine the long-term consequences of CRD on renal morphology and salt sensitivity of blood pressure in B2R(-/-)CRD mice. One-year- and 18-mo-old B2R(-/-)CRD mice exhibited stunted renal growth, glomerular cystic abnormalities, and collecting duct ectasia. Moreover, tumors of mesenchymal cell origin emerged in the dysplastic kidneys of 90% of 1-yr-old and 100% of 18-mo-old B2R(-/-)CRD mice but not in age-matched B2R(-/-) or wild-type mice. When challenged with an HS diet, 18-mo-old B2R(-/-)CRD exhibited a significant rise in systolic and diastolic blood pressures and more pronounced natriuresis and diuresis compared with salt-loaded 18-mo-old wild-type mice. Kidney aquaporin-2 expression was decreased by 50%, whereas renin, ANG type 1 receptor, and Na+-K+-ATPase levels were not different in B2R(-/-)CRD mice compared with controls. In conclusion, this study demonstrates that B2R(-/-)CRD mice exhibit permanent phenotypic and functional abnormalities in renal growth and differentiation. This novel model of human disease links gene-environment interactions with renal development and blood pressure homeostasis.

Purpose: To assess the cost-effectiveness of treatment strategies that utilize first-line latanoprost compared to those based on initial beta-blocker therapy in patients with open-angle glaucoma (OAG) or ocular hypertension (OH) in France., Methods: The study was based on a decision-analytic model that was populated with data from a retrospective chart review. A hypothetical cohort of patients newly diagnosed with OAG and/or OH was assessed over a period of 2 and 3 years. For each treatment strategy 10,000 patients were assumed., Results: First-line latanoprost therapy was significantly more effective than initial treatment with a beta-blocker, providing more days of intraocular pressure (IOP) control primarily due to its longer time until initial treatment failure. Latanoprost's higher acquisition cost was largely offset by reductions in costs associated with surgical procedures. The additional cost for latanoprost was estimated at approximately 41 Euro and 27 Euro over 2 and 3 years, respectively. The incremental cost per day of IOP control when latanoprost was used as first-line strategy compared to the first-line beta-blocker strategy was 0.82 Euro and 0.36 Euro over 2 and 3 years, respectively., Conclusions: These results provide compelling evidence that first-line latanoprost therapy can provide superior clinical outcomes at a small additional cost in actual clinical practice.

The relative contributions of AT(1A) and AT(1B) receptors to afferent arteriolar autoregulatory capability and afferent and efferent arteriolar responses to ANG II are not known. Experiments were conducted in kidneys from wild-type (WT) and AT(1A)-/- mice utilizing the in vitro blood-perfused juxtamedullary nephron technique. Direct measurements of afferent (AAD) and efferent arteriolar diameters (EAD) were assessed at a renal arterial pressure of 100 mmHg. AAD averaged 14.8 +/- 0.8 microm for WT and 14.9 +/- 0.8 microm for AT(1A)-/- mice. AAD significantly decreased by 7 +/- 1, 16 +/- 1, and 26 +/- 2% for WT mice and by 11 +/- 1, 20 +/- 2, and 30 +/- 3% for AT(1A)-/- mice (120, 140, 160 mmHg). AAD autoregulatory capability was not affected by the absence of AT(1A) receptors. AAD responses to 10 nM ANG II were significantly blunted for AT(1A)-/- mice compared with WT (-22 +/- 2 vs. -37 +/- 5%). ANG II (0.1-10 nM) failed to elicit any change in EAD for AT(1A)-/- mice. AAD and EAD reductions in ANG II were blocked by 1 microM candesartan. We conclude that afferent arteriole vasoconstrictor responses to ANG II are mediated by AT(1A) and AT(1B) receptors, whereas efferent arteriolar vasoconstrictor responses to ANG II are mediated by only AT(1A) receptors in the mouse kidney.

Angiotensin II (AngII) infusions augment renal angiotensinogen mRNA and protein and urinary angiotensinogen excretion (U(AGT)). Further experiments were performed in 4 groups of rats: normal salt diet with sham operation, NS+Sham, n=6; NS with AngII infusion at 40 ng/min via osmotic minipump, NS+AngII(40), n=9; NS with AngII infusion at 80 ng/min, NS+AngII(80), n=9; high-salt diet with deoxycorticosterone acetate salt pellet (100 mg), HS+DOCA, n=4. These experiments sought to determine whether enhanced U(AGT) is specifically associated with increased kidney AngII levels or is a nonspecific consequence of the hypertension. Systolic BP (SBP) was significantly increased to 131+/-2 and 162+/-2 mm Hg at day 11 in NS+AngII(40) and NS+AngII(80), respectively, compared with NS+Sham (110+/-1). Regression analysis demonstrated a positive relationship (R=0.49) between SBP and U(AGT) for NS+Sham (1.1+/-0.3 nmol AngI/d), NS+AngII(40) (2.5+/-0.9), and NS+AngII(80) (5.5+/-1.5). U(AGT) was also highly correlated (R=0.70) with kidney AngII content for NS+Sham (49+/-6 fmol/g), NS+AngII(40) (215+/-49), and NS+AngII(80) (347+/-47); but not with plasma AngII (R=0.12). HS+DOCA rats also exhibited increased SBP to 134+/-1 mm Hg, but U(AGT) (1.4+/-0.4 nmol AngI/d) and intrarenal AngII content (13+/-2 fmol/g) were not increased despite the hypertension. Infused human angiotensinogen could not be detected in urine of sham-operated or AngII-infused rats (n=4 each). These data demonstrate that U(AGT) increases in AngII-dependent hypertension in a dose- and time-dependent manner, but not in hypertension elicited by HS+DOCA. The results support the hypothesis that AngII-dependent hypertension results in elevated intrarenal AngII and angiotensinogen levels, reflected by increased U(AGT), which does not occur in an AngII-independent hypertensive model.

Experiments were performed to evaluate the hypothesis that the early stage of Type 1 diabetes mellitus (DM) increases renal angiotensin II (AngII) concentration and angiotensin type 1 (AT) receptor protein levels. Nineteen or twenty days after vehicle (Sham rats) or streptozotocin (STZ rats) treatment, plasma [AngII] was higher in STZ rats (152 +/- 23 fmol/ml) than in Sham rats (101 +/- 7 fmol/ml); however, kidney [AngII] did not differ between groups. AT1 receptor protein expression was greater in STZ kidneys than in Sham kidneys. This increase was restricted to the cortex, where AT1 protein levels were elevated by 77 +/- 26% (42 kDa) and 101 +/- 16% (58 kDa) in STZ kidneys. Immunohistochemistry revealed this effect to be most evident in distal nephron segments including the connecting tubule/cortical collecting duct. Increased renal cortical AT1 receptor protein and circulating AngII levels are consistent with an exaggerated AngII-dependent influence on renal function during the early stage of DM in the rat.

Background: In rats maintained on a high salt diet (H/S) to suppress basal renal angiotensinogen levels, angiotensin II (Ang II) infusion for 13 days increased renal angiotensinogen mRNA and protein, thus providing a mechanism for further augmentation of intrarenal Ang II levels. The present study tested the hypothesis that enhanced intrarenal angiotensinogen formation during Ang II infusion is reflected by secretion into the tubular fluid leading to increased urinary excretion of angiotensinogen (UAGT)., Methods: The effects of chronic Ang II infusion were examined on kidney and plasma Ang II levels and UAGT in male Sprague-Dawley rats maintained on an 8% salt diet for three weeks (N=10). Following one week on the H/S diet, Ang II (40 ng/min) was administered for two weeks via an osmotic minipump to one group (H/S + Ang II, N=5), while the remaining rats were sham-operated (H/S + Sham, N=5). Additionally, a control group was prepared with normal salt diet and sham-operation (N/S + Sham, N=5)., Results: H/S alone did not alter systolic blood pressure (BP) (103 +/- 2 vs. 104 +/- 2 mm Hg), while Ang II infusion to H/S rats significantly increased systolic BP from 103 +/- 2 to 154 +/- 2 after two weeks. Intrarenal Ang II content in H/S + Ang II was significantly greater than H/S + Sham (435 +/- 153 vs. 65 +/- 14 fmol/g). Ang II infusion significantly increased UAGT (4.0 +/- 0.5 vs. 1.0 +/- 0.2 nmol Ang I/day by radioimmunoassay of generated Ang I; 57 +/- 15 vs. 14 +/- 2 densitometric units by Western blotting analysis) compared to Sham. UAGT by radioimmunoassay was highly correlated with kidney Ang II content (r=0.79); but not with plasma Ang II concentration (r=0.20)., Conclusions: These data demonstrate that chronic Ang II infusion increases urinary excretion rate of angiotensinogen, and suggest that UAGT provides a specific index of intrarenal angiotensinogen production in Ang II-dependent hypertension.

Intrarenal angiotensin II (Ang II) is regulated by several complex processes involving formation from both systemically delivered and intrarenally formed substrate, as well as receptor-mediated internalization. There is substantial compartmentalization of intrarenal Ang II, with levels in the renal interstitial fluid and in proximal tubule fluid being much greater than can be explained from the circulating levels. In Ang II--dependent hypertension, elevated intrarenal Ang II levels occur even when intrarenal renin expression and content are suppressed. Studies in Ang II--infused rats have demonstrated that augmentation of intrarenal Ang II is due, in part, to uptake of circulating Ang II via an Ang II type 1 (AT(1)) receptor mechanism and also to sustained endogenous production of Ang II. Some of the internalized Ang II accumulates in the light and heavy endosomes and is therefore potentially available for intracellular actions. The enhanced intrarenal Ang II also exerts a positive feedback action to augment intrarenal levels of angiotensinogen (AGT) mRNA and protein, which contribute further to the increased intrarenal Ang II in hypertensive states. In addition, renal AT(1) receptor protein and mRNA levels are maintained, allowing increased Ang II levels to elicit progressive effects. The increased intrarenal Ang II activity and AGT production are associated with increased urinary AGT excretion rates. The urinary AGT excretion rates show a clear relationship to kidney Ang II content, suggesting that urinary AGT may serve as an index of Ang II--dependent hypertension. Collectively, the data support a powerful role for intrarenal Ang II in the pathogenesis of hypertension.