Angiotensin antagonists with increased specificity for the renal vasculature.

This study was designed to ascertain whether renal vascular angiotensin receptors differ from other systemic angiotensin receptors and whether, on that basis, antagonists with greater specificity for the renal vasculature can be defined. Femoral and renal blood flow and their responses to angiotensin II (AII) and its heptapeptide analogue, 1-des Asp AII (AIII), were measured with an electromagnetic flowmeter in 26 dogs. For the kidney, the threshold doses of AII and AIII were identical (2.5+/-0.27 vs. 2.3+/-0.35 pmol/100 ml renal blood flow, with similar dose-response curves. In contrast, AII had a greater pressor effect (P less than 0.001) and produced more femoral vasoconstriction (P less than 0.001) than AIII. All four antagonists studied (1-Sar, 8-Ala AII [P113]; 8-Ala AII; 1-des Asp, 8-Ala AII; 1-des Asp, 8-Ile AII) induced parallel shifts in the renal blood flow response to AII and AIII. P113 induced greater blockade than 8-Ala AII (P less than 0.001) which, in turn, was more effective than 1-des Asp, 8-Ala AII (P less than 0.001). 1-des Asp, 8-Ile AII was as effective as P113. Each analogue induced an identical inhibition of the renal vascular response to AII and AIII. In addition, AII and AIII induced cross-tachyphylaxis. All lines of evidence suggested that AII and AIII act on a single receptor in the kidney, which differs at least functionally from other systemic vascular receptors. The possibility that heptapeptide analogues represent angiotensin antagonists with greater specificity for the renal vasculature was pursued in a model in which the renin-angiotensin system is activated. Acute, partial thoracic inferior vena caval occlusion was induced in an additional 16 dogs. P113 induced progressive, dose-related hypotension and a limited increase in renal blood flow in this model. The 1-des Asp, 8-Ile AII analogue, conversely, induced a consistent, larger, dose-related renal blood flow increase, with significantly less hypotension over a wide dose range. We conclude that the renal vascular receptor differs sufficiently from systemic angiotensin receptors that heptapeptide analogues of AII will be useful in exploring angiotensin's role in states characterized by disordered renal perfusion and function.

Economic evaluation and end-stage renal disease: from basics to bedside.

Economic evaluation is the comparative analysis of alternative health care interventions in terms of their relative costs (resource use) and effectiveness (health effects). High-quality studies of economic evaluation have been increasingly published in medical journals and read by clinicians, although publication of these studies in nephrology journals has been a more recent phenomenon. This article shows how the basic principles of economics can be applied to health care through the use of economic evaluation. Different types of economic evaluation are discussed, and pitfalls common to such studies are identified. A simple framework is introduced that can be used to interpret the results of economic evaluations. Using this framework, selected therapies for patients with end-stage renal disease (ESRD) are categorized to highlight therapies that are very efficient, encourage their use, and draw attention to therapies in current use that are less effective and more expensive (ie, less efficient) than alternative therapy. Using examples pertinent to care of the patient with ESRD, we show how economic evaluation can be used to link medical outcomes, quality of life, and costs in a common index for multiple therapies with disparate outcome measures. This article highlights the need for clinical studies and economic evaluations of therapies in ESRD for which the effects of the therapy on health outcomes and/or costs are unknown.

Poor long-term survival after coronary angiography in patients with renal insufficiency.

Cardiovascular disease is common among dialysis patients, but much less is known regarding non-dialysis-dependent renal insufficiency (NDDRI) and its association with cardiac disease. We undertook a study to assess the impact of renal insufficiency on survival post-coronary angiography by comparing three groups of patients: dialysis-dependent patients, patients with NDDRI (creatinine > 2.3 mg/dL), and a reference group with creatinine levels less than 2.3 mg/dL and not on dialysis therapy. We used a prospective cohort that consisted of all patients undergoing coronary angiography in Alberta, Canada, from January 1, 1995, to December 31, 1997. Of the 16,989 patients, 196 patients (1.2%) were on dialysis therapy, 262 patients (1.5%) had NDDRI, and 16,531 patients (97.3%) formed the reference group. Mortality rates 1 year after angiography were 30.2% for patients with NDDRI, 15.8% for dialysis patients, and 4.1% for the reference group. Compared with the reference group, crude 4-year survival was significantly worse for dialysis patients and those with NDDRI, with hazard ratios of 4.05 (95% confidence interval, 3.02 to 5.42) and 7.32 (95% confidence interval, 5.97 to 8.97), respectively. Even after adjusting for clinical risk factors, survival remained worse for dialysis patients and those with NDDRI, with hazard ratios of 2.59 (95% confidence interval, 1.92 to 3.49) and 2.51 (95% confidence interval, 2.02 to 3.12), respectively. We conclude that renal insufficiency, both dialysis dependent and non-dialysis dependent, is an independent risk factor for increased mortality and poor long-term survival among patients undergoing coronary angiography.

The marital context of end-stage renal disease: illness intrusiveness and perceived changes in family environment.

End-stage renal disease (ESRD) is associated with illness-induced disruptions (i.e. illness intrusiveness) that challenge patients and their families to accommodate and adapt. We advance previous research in ESRD by examining the extent to which illness intrusiveness extends to marital, non-marital, and family life among patients and their spouses. We also investigate whether gender and mode of renal replacement therapy moderate these effects. A sample of 19 ESRD patients and their spouses completed the Illness Intrusiveness Ratings Scale and the Family Environment Scale (FES) (completed with reference to two time frames, currently and before ESRD) in structured individual interviews. As hypothesized, ESRD patients reported significantly higher illness intrusiveness than their spouses, but this discrepancy was greater in relation to aspects of non-marital as compared to marital life. Significant moderating effects were observed for gender on the FES Relationship subscale and mode of renal replacement on the FES Personal Growth subscale. Spouses reported significantly more family emphasis on norms and the regulation of family members' behavior (FES System Maintenance) than patients. A pattern of significant correlations linked patient ratings of illness intrusiveness with both premorbid and current family environment. The pattern of findings is consistent with previous clinical reports that women and spouses are more likely than their male and patient counterparts to shoulder much of the burden of adapting family environment to accommodate life with ESRD and renal replacement therapy.

Angiotensin receptors in glomeruli differ from those in renal arterioles.

Angiotensin receptors in afferent and efferent arterioles and in the glomerulus are strategically located to influence renal perfusion and glomerular function. With the size of isolated glomeruli as the index, we have demonstrated identical dose-response relationships for graded concentrations (10(-13) to 10(-3) g/liter) of angiotensin II (AII) and angiotensin III (AIII). An octapeptide analogue (saralasin 10(-6) to 10(-2) g/liter) was equally effective at blocking glomerular responses to both AII and AIII, but two heptapeptide analogues (des-asp, 8-ile AII and des-asp, 8-gly AII; 10(-6) to 10(-2) g/liter) failed to block responses to either agonist. The relative influence of octapeptide and heptapeptide analogues on GFR was examined in anesthetized dogs with partial occlusion of the thoracic inferior vena cava. In 18 dogs, caval occlusion reduced renal blood flow (35%), GFR (29%), and arterial pressure (13%). Saralasin (300 to 3000 ng/kg/min, i.v.) and des-asp, 8-ile AII (100 to 3000 ng/kg/min, i.v.) increased renal blood flow by 0.41 +/- 0.11 and 0.62 +/- 0.11 ml/g/min, respectively, but only the octapeptide induced a concomitant increase in GFR (octapeptide: delta GFR = 0.11 +/- 0.03 ml/g/min; heptapeptide: delta GFR = -0.08 +/- 0.07 ml/g/min; P less than 0.025). As octapeptide and heptapeptide analogues were equally effective on renal blood flow in this and in previous studies, but only the octapeptide was effective in isolated glomeruli and in increasing GFR in the intact animal, we conclude that renal vascular and glomerular receptors differ. Furthermore, the glomerular receptor may be the more important in modulating the glomerular functional response to angiotensin.

The Southern Alberta Renal Program database: a prototype for patient management and research initiatives.

The Southern Alberta Renal Program (SARP) database was developed to respond to an urgent need for local information on clinical outcomes, laboratory information, and health care costs, and to enable our local renal program to monitor the implementation of established clinical practice guidelines. The database captures detailed demographic, clinical, and laboratory information and is unique by also capturing comorbidity, health-related quality of life and costing information for patients with end-stage renal disease (ESRD) in southern Alberta, storing the information in one common database. By collecting information on patient comorbidity, health outcomes and costs, the SARP database has enabled many quality assurance initiatives as well as research opportunities for projects involving patients with ESRD. Due to the availability of links with other available local clinical and administrative databases, information is collected with a minimal need for manual data entry. This type of database is a method by which health programs could improve the quality of patient care. Programs caring for patients with chronic medical conditions such as ESRD should examine how computer databases could assist in clinical care and improve the efficiency with which that care is delivered to their patients.

Renal vascular response to interruption of the renin-angiotensin system in normal man.

We assessed the role of the renin-angiotensin system in the response of the renal circulation to restriction of sodium intake in 38 normal patients. Both saralasin (10 to 30 ng/kg/min), an angiotensin antagonist, and SQ 20881 (30 to 300microgram/kg), a converting enzyme inhibitor, induced a dose-related increase in renal blood flow (xenon 133 washout) only when the resin-angiotension system was activated by restriction of sodium intake to 10 MEq/day. Increasing doses of saralasin (100 to 1,000 ng/kg/min) reduced renal blood flow, presumably due to the angiotensin-like action of this partial agonist. The renal vascular response to SQ 20881 paralleled the endocrine response: An identical threshold dose (30 microgram/kg) increased renal blood flow and reduced plasma angiotensin II concentration, which fell despite a progressive rise of plasma renin activity. Plasma bradykinin concentration did not change in response to SQ 20881, which also blocks kininase II. Both agents also induced a small but consistent and statistically significant reduction in arterial blood pressure, which will be important in assessing the pathogenetic significance of a blood pressure reduction in patients with hypertension. This study indicates that angiotensin mediates the renal vascular response to restriction of salt intake in normal man and provides an approach to assessing the role played by angiotensin in the pathogenesis of functional renal disease.