Long-term hemodynamic and molecular effects persist after discontinued renin-angiotensin system blockade in patients with type 1 diabetes mellitus.

Animal studies suggest temporary renin-angiotensin system (RAS) blockade enhances long-term vascular protective effects; however, this is not established in humans. Here we evaluated the long-term effects of prior RAS blockade on hemodynamic function, urinary measures of inflammation, and tissue antioxidant mRNA expression in patients with type 1 diabetes mellitus (T1DM) who participated in the 5-year Renin Angiotensin System Study (RASS). At 4 years after completing the RASS and discontinuing study medication, renal hemodynamic responses to clamped hyperglycemia were significantly greater in 18 patients in the RAS blockade group compared to 9 patients of the placebo-treated group. Individuals who had received RAS blockade also exhibited higher flow-mediated vasodilatation, reduced urinary cytokine excretion in response to hyperglycemia, and increased skin mRNA expression of superoxide dismutase-1 and catalase. Thus, patients with uncomplicated T1DM who received prior RAS blockade for 5 years maintain long-term effects on renal hemodynamic and systemic vascular function, inflammatory pathways in the kidney, and antioxidant enzyme expression in skin 4 years after discontinuation of therapy. Our findings suggest that sustained long-term protective effects of finite RAS inhibition requires further study.

Using an electronic self-management tool to support patients with chronic kidney disease (CKD): a CKD clinic self-care model.

New healthcare delivery models are needed to enhance the patient experience and improve quality of care for individuals with chronic conditions such as kidney disease. One potential avenue is to implement self-management strategies. There is growing evidence that self-management interventions help optimize various aspects of chronic disease management. With the increasing use of information technology (IT) in health care, chronic disease management programs are incorporating IT solutions to support patient self-management practices. IT solutions have the ability to promote key principles of self-management, namely education, empowerment, and collaboration. Positive clinical outcomes have been demonstrated for a number of chronic conditions when IT solutions were incorporated into self-management programs. There is a paucity of evidence for self-management in chronic kidney disease (CKD) patients. Furthermore, IT strategies have not been tested in this patient population to the same extent as other chronic conditions (e.g., diabetes, hypertension). Therefore, it is currently unknown if IT strategies will promote self-management behaviors and lead to improvements in overall patient care. We designed and developed an IT solution called My KidneyCare Centre to support self-management strategies for patients with CKD. In this review, we discuss the rationale and vision of incorporating an electronic self-management tool to support the care of patients with CKD.

Age is a determinant of acute hemodynamic responses to hyperglycemia and angiotensin II in humans with uncomplicated type 1 diabetes mellitus.

Hyperglycemia is associated with hemodynamic changes in type 1 diabetes (DM), acting in part through renin-angiotensin system activation. Since aging is associated with vascular dysfunction in DM, we hypothesized that acute hemodynamic responses to clamped hyperglycemia and infused ANG II would be exaggerated in older adults compared with a group of adolescent/young adults with type 1 DM. Renal hemodynamic function, blood pressure, and arterial stiffness were assessed in adolescent/young adults (n = 34; mean age: 18 +/- 3 yr) and older adults (n = 32; mean age: 45 +/- 9 yr). Studies were performed during clamped euglycemia (4-6 mmol/l) and hyperglycemia (9-11 mmol/l). Renal and systemic hemodynamic responses to ANG II were measured during clamped euglycemia in diabetic subjects. ANG II responses were also assessed in a cohort of non-DM subjects (n = 97; mean age: 26; age range: 18-40 yr). Older DM adults exhibited higher baseline blood pressure, arterial stiffness, and renal vascular resistance, and lower glomerular filtration rate (GFR) and effective renal plasma flow, compared with adolescent/young DM adults (P < 0.05). Clamped hyperglycemia was associated with exaggerated peripheral and renal hemodynamic responses uniquely in older DM adults; only GFR increased in adolescent/young DM adults. ANG II infusion also produced exaggerated vasoconstrictive responses in older DM adults vs. adolescent/young DM adults (P < 0.05). The independent effect of age on hemodynamic responses to hyperglycemia and ANG II was confirmed using multivariate regression analysis in DM subjects (P < 0.05), and results were still significant when participants were matched for DM duration. Age-related alterations in hemodynamic function and ANG II response were not observed in healthy non-DM control subjects. Acute hemodynamic responses to clamped hyperglycemia and ANG II were exaggerated in older subjects with type 1 DM, highlighting an important interaction between age and factors that contribute to the pathogenesis of acute vascular dysfunction in DM.

The angiotensin II receptor type 2 polymorphism influences haemodynamic function and circulating RAS mediators in normotensive humans.

BACKGROUND: The haemodynamic responses to angiotensin II type 1 (AT1) receptor blockade may be mediated in part by interactions between angiotensin II and the angiotensin II type 2 receptor (AT2R). An AT2R G1675A gene polymorphism has been described, but the functional effects of this polymorphism are unknown. METHODS: Haemodynamic function, circulating renin-angiotensin system mediators and norepinephrine were measured in young healthy subjects at baseline and at 2 and 4 weeks after treatment with irbesartan. Subjects were divided into two groups on the basis of the AT2R G1675A gene polymorphism: GG subjects (n = 12) and AA/GA subjects (n = 22). RESULTS: AA/AG subjects exhibited hypotensive and renal vasodilatory responses to irbesartan at 4 weeks, but GG subjects did not. In accord with haemodynamic effects, circulating aldosterone levels were suppressed in AA/AG, while circulating norepinephrine levels were augmented only in GG subjects. In contrast, increases in circulating renin, angiotensin II and plasma renin activity after irbesartan were exaggerated in AA/AG subjects. CONCLUSIONS: The AT2R G1675A polymorphism is a determinant of haemodynamic responses to AT1 receptor blockade, an effect that may be due to influences on aldosterone escape.

Endothelial nitric oxide synthase gene polymorphisms and the renal hemodynamic response to L-arginine.

Nitric oxide is generated from L-arginine by nitric oxide synthase (NOS), an enzyme that exists in several isoforms. Some studies found that a polymorphism (G894T) in the endothelial NOS gene was associated with decreased nitric oxide bioactivity and vascular complications. However, it is not known whether the enzyme had a reduced activity. Here we measured the effect of an infusion of L-arginine on renal hemodynamic function in subjects segregated by the presence or absence of the T allele. If this polymorphism represented a functional variant, subjects with the GT/TT form should exhibit a blunted renal hemodynamic response to L-arginine compared to those with a GG allele. All subjects were given a diet controlled for sodium and protein intake. GG subjects had lower mean arterial pressure and an augmented glomerular filtration rate at baseline. In response to a graded L-arginine infusion, this group had significant changes in effective renal plasma flow, glomerular filtration rate, filtration fraction, renal vascular resistance, and renal blood flow. The renal response to L-arginine in GT/TT subjects was blunted. Circulating cGMP levels and endothelial NOS mRNA expression, measured in skin biopsies by real-time PCR, did not differ between the groups. Our study shows that the G894T allele of endothelial NOS is associated with a blunted response to L-arginine, suggesting this polymorphism may be a functional variant in humans.

A Multicenter, Randomized Controlled Trial of Perioperative Palliative Care Surrounding Cancer Surgery for Patients and Their Family Members (PERIOP-PC).

Background: Despite positive outcomes associated with specialist palliative care (PC) in diverse medical populations, little research has investigated specialist PC in surgical ones. Although cancer surgery is predominantly safe, operations can be extensive and unpredictable perioperative morbidity and mortality persist, particularly for patients with upper gastrointestinal (GI) cancers. Objectives and Hypotheses: Our objective is to complete a multicenter, randomized controlled trial comparing surgeon-PC co-management with surgeon-alone management among patients pursuing curative-intent surgery for upper GI cancers. We hypothesize that perioperative PC will improve patient postsurgical quality of life. This study and design are based on >8 years of engagement and research with patients, family members, and clinicians surrounding major cancer surgery and advance care planning/PC for surgical patients. Methods: Randomized controlled superiority trial with two study arms (surgeon-PC team co-management and surgeon-alone management) and five data collection points over six months. The principal investigator and analysts are blinded to randomization. Setting: Four, geographically diverse, academic tertiary care hospitals. Data collection began December 20, 2018 and continues to December 2020. Participants: Patients recruited from surgical oncology clinics who are undergoing curative-intent surgery for an upper GI cancer. Interventions: In the intervention arm, patients receive care from both their surgical team and a specialist PC team; the PC is provided before surgery, immediately after surgery, and at least monthly until three months postsurgery. Patients randomized to the usual care arm receive care from only the surgical team. Main Outcomes and Measures: Primary outcome: patient quality of life. Secondary outcomes: patient: symptom experience, spiritual distress, prognostic awareness, health care utilization, and mortality. Caregiver: quality of life, caregiver burden, spiritual distress, and prognostic awareness. Intent-to-treat analysis will be used. Ethics and Dissemination: This study has been approved by the institutional review boards of all study sites and is registered on clinicaltrials.gov (NCT03611309, First received: August 2, 2018).

The impact of sex in primary glomerulonephritis.

BACKGROUND: Studies comparing the impact of sex in primary glomerular disease have reported conflicting results. METHODS: We analysed 395 membranous (MGN), 370 focal and segmental glomerulosclerosis (FSGS) and 542 IgA nephropathy patients to determine the impact of the patients' sex on outcome. We assessed initial and follow-up blood pressure, proteinuria, anti-hypertensive and immunosuppressive therapy, rate of renal function decline and survival from renal failure or a 50% decrease in creatinine clearance (combined event). RESULTS: Women accounted for one-third of the cohort. At presentation they were on average 2 years younger than men, and over follow-up received no more immunosuppression or anti-hypertensive agents than their male counterpart. Their mean arterial pressure (MAP) overall was 2 mmHg lower. Proteinuria at presentation and during follow-up in women compared to men was 50% and 30% lower in MGN and FSGS, while no differences were seen in IgA nephropathy. The rate of renal function decline and outcome favoured women over men in MGN (hazard ratios of a combined event of 0.63, 95% CI 0.40-1.00, P = 0.05) and in FSGS (HR 0.67, 95% CI 0.48-0.95, P = 0.02) but not in IgA nephropathy. These differences were not independent of blood pressure and proteinuria, indicating that these sex-dependent risk factors accounted for most of the hazards seen in men. However, the quantitative effect of proteinuria on the rate of progression was distinct and modified by sex in MGN and FSGS with higher proteinuria levels having less impact on progression rate in women. This interaction was independent of blood pressure. CONCLUSIONS: Women have a better outcome than men in MGN and FSGS but not in IgA nephropathy. These benefits are mostly mediated through both lower proteinuria and blood pressure at presentation and throughout follow-up, although females did have an independent advantage at higher levels of proteinuria.

A patient and community-centered approach selecting endpoints for a randomized trial of a novel advance care planning tool.

BACKGROUND: Despite a movement toward patient-centered outcomes, best practices on how to gather and refine patients' perspectives on research endpoints are limited. Advanced care planning (ACP) is inherently patient centered and would benefit from patient prioritization of endpoints for ACP-related tools and studies. OBJECTIVE: This investigation sought to prioritize patient-centered endpoints for the content and evaluation of an ACP video being developed for patients undergoing major surgery. We also sought to highlight an approach using complementary engagement and research strategies to document priorities and preferences of patients and other stakeholders. MATERIALS AND METHODS: Endpoints identified from a previously published environmental scan were operationalized following rating by a caregiver co-investigator, refinement by a patient co-investigator, review by a stakeholder committee, and validation by patients and family members. Finalized endpoints were taken to a state fair where members of the public who indicated that they or a loved one had undergone major surgery prioritized their most relevant endpoints and provided comments. RESULTS: Of the initial 50 ACP endpoints identified from the review, 12 endpoints were selected for public prioritization. At the state fair, 359 individuals prioritized the endpoints, the highest ranking of which was having a meaningful conversation with a physician before surgery (57%). CONCLUSION: Using a novel combination of engagement and research techniques provided the opportunity to understand which endpoints were most important to patients and families and fostered framework development clarifying the differential contributions of engagement and research. Results from this study ultimately changed the content and evaluation of the ACP video.

An advance care plan decision support video before major surgery: a patient- and family-centred approach.

OBJECTIVE: Video-based advanc care planning (ACP) tools have been studied in varied medical contexts; however, none have been developed for patients undergoing major surgery. Using a patient- and family-centredness approach, our objective was to implement human-centred design (HCD) to develop an ACP decision support video for patients and their family members when preparing for major surgery. DESIGN AND METHODS: The study investigators partnered with surgical patients and their family members, surgeons and other health professionals to design an ACP decision support video using key HCD principles. Adapting Maguire's HCD stages from computer science to the surgical context, while also incorporating Elwyn et al's specifications for patient-oriented decision support tool development, we used a six-stage HCD process to develop the video: (1) plan HCD process; (2) specify where video will be used; (3) specify user and organisational requirements; (4) produce and test prototypes; (5) carry out user-based assessment; (6) field test with end users. RESULTS: Over 450 stakeholders were engaged in the development process contributing to setting objectives, applying for funding, providing feedback on the storyboard and iterations of the decision tool video. Throughout the HCD process, stakeholders' opinions were compiled and conflicting approaches negotiated resulting in a tool that addressed stakeholders' concerns. CONCLUSIONS: Our patient- and family-centred approach using HCD facilitated discussion and the ability to elicit and balance sometimes competing viewpoints. The early engagement of users and stakeholders throughout the development process may help to ensure tools address the stated needs of these individuals. TRIAL REGISTRATION NUMBER: NCT02489799.

Integrating a Smartphone-Based Self-Management System into Usual Care of Advanced CKD.

BACKGROUND AND OBJECTIVES: Patient self-management has been shown to improve health outcomes. We developed a smartphone-based system to boost self-care by patients with CKD and integrated its use into usual CKD care. We determined its acceptability and examined changes in several clinical parameters. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We recruited patients with stage 4 or 5 CKD attending outpatient renal clinics who responded to a general information newsletter about this 6-month proof-of-principle study. The smartphone application targeted four behavioral elements: monitoring BP, medication management, symptom assessment, and tracking laboratory results. Prebuilt customizable algorithms provided real-time personalized patient feedback and alerts to providers when predefined treatment thresholds were crossed or critical changes occurred. Those who died or started RRT within the first 2 months were replaced. Only participants followed for 6 months after recruitment were included in assessing changes in clinical measures. RESULTS: In total, 47 patients (26 men; mean age =59 years old; 33% were ≥65 years old) were enrolled; 60% had never used a smartphone. User adherence was high (>80% performed ≥80% of recommended assessments) and sustained. The mean reductions in home BP readings between baseline and exit were statistically significant (systolic BP, -3.4 mmHg; 95% confidence interval, -5.0 to -1.8 and diastolic BP, -2.1 mmHg; 95% confidence interval, -2.9 to -1.2); 27% with normal clinic BP readings had newly identified masked hypertension. One hundred twenty-seven medication discrepancies were identified; 59% were medication errors that required an intervention to prevent harm. In exit interviews, patients indicated feeling more confident and in control of their condition; clinicians perceived patients to be better informed and more engaged. CONCLUSIONS: Integrating a smartphone-based self-management system into usual care of patients with advanced CKD proved feasible and acceptable, and it appeared to be clinically useful. The results provide a strong rationale for a randomized, controlled trial.

Relationship between diurnal blood pressure, renal hemodynamic function, and the renin-angiotensin system in type 1 diabetes.

In patients with diabetes, altered diurnal blood pressure (BP) regulation (high night-to-day [N/D] ratio, or "nondipping") is associated with increases in albumin excretion and a decline in the glomerular filtration rate (GFR) by an unknown mechanism. Because it is known that renin angiotensin system (RAS) activation and defective glucose control contribute to adverse renal outcomes, we examined renal responses to high glucose and to manipulation of the RAS in adolescents (mean age 14 +/- 2 years) with uncomplicated type 1 diabetes, segregated into two groups on the basis of the presence or absence of normal N/D BP ratio. In the first experiment, renal hemodynamic comparisons were made during euglycemia (4-6 mmol/l) and hyperglycemia (9-11 mmol/l), maintained by modified clamp techniques. The induction of hyperglycemia resulted in a significant increase in GFR and filtration fraction (FF) in the high N/D ratio group. In the second experiment, we examined the renal response to graded angiotensin II (Ang II) infusion while subjects were euglycemic and salt replete. High N/D ratio was associated with an enhanced FF response to Ang II. In the third experiment, the N/D ratio and GFR were assessed after 3 weeks of ACE inhibition. This maneuver corrected the high N/D ratio, but it had no effect on glomerular hyperfiltration. These results suggest that RAS activation does not explain the hyperfiltration state, nor can it explain the poor outcomes, at least in this population. However, the observed deleterious hemodynamic responses to high glucose and Ang II and the insensitivity to ACE inhibition may, taken together, provide an explanation for the adverse renal outcomes in patients with type 1 diabetes and high N/D ratio.

Promoting perioperative advance care planning: a systematic review of advance care planning decision aids.

This systematic review identifies possible decision aids that promote perioperative advance care planning (ACP) and synthesizes the available evidence regarding their use. Using PubMed, EMBASE, Cochrane, SCOPUS, Web of Science, CINAHL, PsycINFO and Sociological Abstracts, researchers identified and screened articles for eligibility. Data were abstracted and risk of bias assessed for included articles. Thirty-nine of 5327 articles satisfied the eligibility criteria. Primarily completed in outpatient ambulatory populations, studies evaluated a variety of ACP decision aids. None were evaluated in a perioperative population. Fifty unique outcomes were reported with no head-to-head comparisons conducted. Findings are likely generalizable to a perioperative population and can inform development of a perioperative ACP decision aid. Future studies should compare the effectiveness of ACP decision aids.

Living donor nephrectomy: follow-up renal function, blood pressure, and urine protein excretion.

PURPOSE: To assess the effect of donor nephrectomy on blood pressure, 24-hour urine protein excretion, and renal function. MATERIALS AND METHODS: Of the 198 individuals who donated a kidney between 1991-1996, 101 had their blood pressure, 24-hour urine protein excretion, and serum creatinine concentration levels measured. The mean duration of follow-up was 3.2 +/- 1.6 years (range: 8.5 months to 6.5 years). RESULTS: Serum creatinine concentration was significantly higher (p<.001) at follow-up (107 +/- 20 umol/L) compared to before donation (86 +/- 18 umol/L). When follow-up serum creatinine concentrations were expressed as percentages of their pre-operative values, a gradual decline was observed with time (R= -.380). Diastolic blood pressures (p<.05) and 24-hour urine protein levels (p<.001) were significantly higher at follow-up, however, neither increased with time. The prevalence of hypertension and proteinuria in our donors was no different from that of the general population. CONCLUSIONS: Donor nephrectomy does not impair renal function or result in a progressive rise in blood pressure or urine protein excretion up to 6.5 years after nephrectomy.

Effect of direct renin inhibition on renal hemodynamic function, arterial stiffness, and endothelial function in humans with uncomplicated type 1 diabetes: a pilot study.

OBJECTIVE: Blockade of the renin-angiotensin system (RAS) plays an important role in preventing end-organ injury associated with diabetes. The recent development of direct renin inhibitors (DRIs) provides a new approach to block the RAS, but the effects of DRIs on renal and systemic vascular function in uncomplicated type 1 diabetes have not been elucidated. RESEARCH DESIGN AND METHODS: Renal hemodynamic function (inulin and paraaminohippurate clearance), augmentation index and pulse wave velocity, endothelial dependent vasodilatation (flow-mediated dilation [FMD]), and endothelial independent vasodilatation (response to sublingual nitroglycerin) were evaluated before and after administration of aliskiren (300 mg daily for 30 days) in 10 adult subjects with uncomplicated type 1 diabetes during clamped euglycemia (4-6 mmol/l) and hyperglycemia (9-11 mmol/l). RESULTS: In response to the DRI, plasma renin activity decreased (from 0.40 to 0.13 ng . ml(-1) . h(-1), P < 0.05) and plasma renin increased (from 5.2 to 75.0 ng/l, P < 0.05). Peripheral and central blood pressures decreased, and effective renal plasma flow and glomerular filtration rate increased during clamped euglycemia and hyperglycemia (P < 0.05). The carotid augmentation index during clamped euglycemia decreased (from 26 +/- 6 to 20 +/- 5%, P < 0.05) as did pulse wave velocity during clamped hyperglycemia (from 7.8 +/- 0.6 to 6.8 +/- 0.5 m/s, P < 0.05). In response to the DRI, FMD increased during both clamped euglycemia (from 1.92 +/- 1.13 to 5.55 +/- 0.81%) and hyperglycemia (from 1.86 +/- 0.98 to 5.63 +/- 0.62) as did the vasodilatory response to sublingual nitroglycerin. CONCLUSIONS: DRIs exert a renal vasodilatory effect and improve parameters of systemic vascular function, suggesting that blockade of the RAS with this new class of agents has important functional effects in subjects with uncomplicated type 1 diabetes.

Renal hyperfiltration is a determinant of endothelial function responses to cyclooxygenase 2 inhibition in type 1 diabetes.

OBJECTIVE: Our aim was to examine the effect of cyclooxygenase 2 (COX2) inhibition on endothelial function in subjects with type 1 diabetes analyzed on the basis of renal filtration status. RESEARCH DESIGN AND METHODS: Flow-mediated dilation (FMD) was determined in type 1 diabetic subjects and hyperfiltration (glomerular filtration rate >or=135 ml/min/1.73 m(2), n = 13) or normofiltration (glomerular filtration rate >or=135 ml/min/1.73 m(2), n = 11). Studies were performed before and after celecoxib (200 mg daily for 14 days) during euglycemia and hyperglycemia. RESULTS: Baseline parameters were similar in the two groups. Pretreatment, FMD was augmented in normofiltering versus hyperfiltering subjects during clamped euglycemia (10.2 +/- 5.3% vs. 5.9 +/- 2.3%, P = 0.003). COX2 inhibition suppressed FMD in normofiltering (10.2 +/- 5.3% to 5.8 +/- 3.4%, P = 0.006) versus hyperfiltering subjects (ANOVA interaction, P = 0.003). CONCLUSIONS: Systemic hemodynamic function, including the response to COX2 inhibition, is related to filtration status in diabetic subjects and may reflect general endothelial dysfunction.

Effect of protein kinase Cbeta inhibition on renal hemodynamic function and urinary biomarkers in humans with type 1 diabetes: a pilot study.

OBJECTIVE: The aim of this study was to examine the effect of protein kinase Cbeta inhibition with ruboxistaurin on renal hemodynamic function and urinary biomarkers (monocyte chemoattractant protein-1 [MCP-1] and epidermal growth factor) in renin angiotensin system blockade-treated type 1 diabetic subjects. RESEARCH DESIGN AND METHODS: Albuminuric subjects were randomized (2:1) to ruboxistaurin (32 mg daily; n = 13) or placebo (n = 7) for 8 weeks. Renal hemodynamic function was measured during clamped euglycemia or hyperglycemia and before and after ruboxistaurin or placebo. RESULTS: Ruboxistaurin was not associated with between-group differences during clamped euglycemia or hyperglycemia. In a post hoc analysis comparing hyperfilterers with normofilterers during euglycemia, glomerular filtration rate and MCP-1 decreased, whereas the epidermal growth factor-to-MCP-1 ratio increased in hyperfilterers versus normofilterers (all P < 0.05). CONCLUSIONS: The effect of ruboxistaurin is modest and dependent, at least in part, on the level of ambient glycemia and baseline glomerular filtration rate.

Insights into the regulation of renal hemodynamic function in diabetic mellitus.

Diabetes mellitus (DM) is characterized by renal hemodynamic changes which have been purported to contribute to the development of nephropathy. In this review we have focused on the major renal hemodynamic factors that may be associated with glomerular hyperfiltration. Recent animal and human studies have demonstrated that renal hemodynamic alterations occur very early in the natural history of DM. Most of the literature related to renal hemodynamic functional changes in type 1 DM has focused on major neurohormonal influences, such as the renin angiotensin system, cyclooxygenase-related pathways, the nitric oxide system, the autonomic nervous system and hyperglycemia. In addition, gender may have important modulatory effects on some of these putative pathways that have been implicated in the development of alterations in renal hemodynamic function related to DM.

Renal hemodynamic effect of cyclooxygenase 2 inhibition in young men and women with uncomplicated type 1 diabetes mellitus.

In experimental studies, cyclooxygenase 2 (COX2)-derived vasodilatory prostaglandins play a more prominent role in arterial vasoregulation in females. The gender-dependent effect of COX2 modulation in humans with type 1 diabetes mellitus (DM) is unknown. Accordingly, we examined the renal hemodynamic role of prostaglandins by assessing the response to COX2 inhibition in young men and women with type 1 DM. We also used a graded ANG II infusion to determine whether gender-based differences were mediated by effects of COX2 inhibition on the renin angiotensin system (RAS). We hypothesized that COX2 inhibition would be associated with preferential vasoconstriction in women and would augment their response to ANG II. Baseline renal function and the response to an ANG II infusion were assessed during clamped euglycemia, and again after COX2 inhibition (200 mg celecoxib daily for 14 days) in 12 men and 9 women after 1 wk on a controlled protein and sodium diet. COX2 inhibition was associated with increases in filtration fraction (P = 0.045) and renal vascular resistance and a decline in renal blood flow (P = 0.04) in women compared with men. Before COX2 inhibition, women exhibited a decline in glomerular filtration rate in response to ANG II. COX2 inhibition abolished this effect, whereas the response was not altered in men. In summary, COX2 inhibition was associated with hemodynamic effects that differed based on gender. The ANG II response suggests that with uncomplicated type 1 DM, prostaglandins may contribute to RAS-mediated gender differences. Our results are consistent with experimental data suggesting augmented female prostanoid dependence.

The effect of cyclooxygenase-2 inhibition on renal hemodynamic function in humans with type 1 diabetes.

OBJECTIVE: Studies in animal models suggest that cyclooxygenase-2 (COX2) plays a role in the regulation of the renal microcirculation in diabetes. Accordingly, we examined the role of COX2 in the control of renal hemodynamic function and in the renal response to hyperglycemia in humans with uncomplicated type 1 diabetes. We hypothesized that COX2 inhibition would alleviate the hyperfiltration state and would abrogate the hyperglycemia-mediated rise in glomerular filtration rate (GFR). RESEARCH DESIGN AND METHODS; Renal function was assessed during clamped euglycemia and hyperglycemia on 2 consecutive days before and then again after 14 days of COX2 inhibition using 200 mg celecoxib once daily by mouth. For analysis, the cohort was then divided into two groups based on the baseline GFR: 9 subjects exhibited hyperfiltration (GFR >or=135 ml/min per 1.73 m(2)), and 12 subjects exhibited normofiltration (GFR <135 ml/min per 1.73 m(2)). RESULTS: Under euglycemic conditions, COX2 inhibition resulted in a significant decline in GFR in the hyperfiltration group (150 +/- 5 to 139 +/- 5 ml/min per 1.73 m(2)) but increased GFR in the normofiltration group (118 +/- 5 to 138 +/- 5 ml/min per 1.73 m(2)). COX2 inhibition did not blunt the hyperglycemia-associated rise in GFR in the normofiltration group and was instead associated with an augmented rise in GFR. CONCLUSIONS: In summary, our results support the hypothesis that COX2 is an important determinant of renal hemodynamic function in subjects with type 1 diabetes. The renal response to COX2 inhibition emphasizes that hyperfiltration and normofiltration are distinct physiological states.