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Objective: Arteriovenous fistulas created for hemodialysis often fail to become usable and are frequently abandoned. This prospective trial evaluated the efficacy of vonapanitase, a recombinant human elastase, in increasing radiocephalic fistula use for hemodialysis and secondary patency. Methods: PATENCY-2 was a randomized, double-blind, placebo-controlled trial in patients on or approaching the need for hemodialysis undergoing radiocephalic arteriovenous fistula creation. Of 696 screened, 613 were randomized, and 603 were treated (vonapanitase n = 405, placebo n = 208). The study drug solution was applied topically to the artery and vein for 10 min immediately after fistula creation. The primary endpoints were fistula use for hemodialysis and secondary patency (fistula survival without abandonment). Other efficacy endpoints included unassisted fistula use for hemodialysis, primary unassisted patency, fistula maturation and unassisted maturation by ultrasound criteria, and fistula procedure rates. Results: The proportions of patients with fistula use for hemodialysis was similar between groups, 70% vonapanitase and 65% placebo, ( p = 0.33). The Kaplan–Meier estimates of 12-month secondary patency were 78% (95% confidence interval [CI], 73–82) for vonapanitase and 76% (95% CI, 70–82) for placebo ( p = 0.93). The proportions with unassisted fistula use for hemodialysis were 46% vonapanitase and 37% placebo ( p = 0.054). The Kaplan–Meier estimates of 12-month primary unassisted patency were 50% (95% CI, 44–55) for vonapanitase and 43% (95% CI, 35–50) for placebo ( p = 0.18). There were no differences in the proportion of patients with fistula maturation or in fistula procedure rates. Adverse events were similar between groups. Vonapanitase was not immunogenic. Conclusions: Vonapanitase treatment did not achieve clinical or statistical significance to meaningfully improve radiocephalic fistula surgical outcomes. Outcome in the placebo group were better than in historical controls. Vonapanitase was well-tolerated and safe. TRIAL REGISTRATION: clinicaltrials.gov: NCT02414841 ( https://clinicaltrials.gov/ct2/show/NCT02414841 )

Background Self-titration of blood pressure (BP) medications and lifestyle modifications are effective and safe strategies to lower BP. We assessed the feasibility of implementing a pharmacist-guided, patient-driven self-titration protocol and standardized dietary counseling to improve BP in the chronic kidney disease (CKD) clinic. Methods Adult patients seen in the CKD clinic were identified via registry screening. Inclusion criteria were as follows: a diagnosis of hypertension, average of the last 3 office BP > 150/90 mmHg, and prescribed 3 or fewer BP medications. Patients with severe hypertension were excluded. BP goals were established and patients were referred to the clinical pharmacist who provided them a BP cuff, a BP medication titration plan (based on home BP monitoring), and dietary education. The following outcomes were evaluated: appeal of the program to patients identified by the registry, patient adherence to the protocol and 6-month office BP, and provider attitudes and acceptance of the protocol. Results Seventeen patients enrolled in the pilot, the majority recruited via clinic schedule screening. Eleven of the 17 patients completed a 6-month office follow-up visit. Three of the 11 patients met their pre-specified office BP goal. There was, however, significant improvement in 6-month office systolic and diastolic BP. Twelve of 17 patients were adherent to entering home BP in EMR. Provider satisfaction with the protocol was high. Conclusion Our preliminary data suggest that patient-driven self-titration of BP medications is feasible and well received by providers. Future studies are needed to validate these findings and to evaluate the safety and efficacy of this approach.

Hyperkalemia is a serious and common clinical condition associated with increased morbidity and death. The risk of hyperkalemia is increased in patients with chronic kidney disease, diabetes, conditions with impaired distal renal sodium delivery and those on renin–angiotensin–aldosterone system (RAAS) blockade. RAAS blockade has been shown to slow progression of proteinuric kidney disease and reduce mortality in patients with systolic heart failure. Yet delivery of optimum RAAS blockade is frequently limited by development of hyperkalemia. Current treatment for hyperkalemia is suboptimal and few options exist for long-term control of hyperkalemia. In this review article, we explore two new oral nonabsorbable cation exchangers, zirconium cyclosilicate (ZS-9) and patiromer that bind potassium for the treatment of hyperkalemia.

Objective Arteriovenous fistulas created in patients with chronic kidney disease often lose patency and fail to become usable. This prospective trial evaluated the efficacy of vonapanitase, a recombinant human elastase, in promoting radiocephalic fistula patency and use for hemodialysis. Methods PATENCY-1 was a double-blind, placebo-controlled trial that enrolled 349 patients on or approaching hemodialysis and being evaluated for radiocephalic arteriovenous fistula creation. Of these, 313 were randomized and 311 treated. Patients were assigned to vonapanitase (n = 210) or placebo (n = 103). The study drug solution was applied topically to the artery and vein for 10 minutes immediately after fistula creation. The primary and secondary end points were primary patency (time to first thrombosis or corrective procedure) and secondary patency (time to abandonment). Tertiary end points included use of the fistula for hemodialysis, fistula maturation by ultrasound, and procedure rates. Results The Kaplan-Meier estimates of 12-month primary patency were 42% (95% confidence interval [CI], 35-49) and 31% (95% CI, 21-42) for vonapanitase and placebo (P = .25). The Kaplan-Meier estimates of 12-month secondary patency were 74% (95% CI, 68-80) and 61% (95% CI, 51-71) for vonapanitase and placebo (P = .048). The proportions of vonapanitase and placebo patients were 39% and 25% (P = .035) with unassisted use for hemodialysis and 64% and 44% (P = .006) with unassisted plus assisted use. Conclusions Vonapanitase treatment did not significantly improve primary patency but was associated with increased secondary patency and use for hemodialysis. Further research is needed to evaluate these end points.

In 1963, Keen and Chlouverakis published a new immunoassay that detected urine albumin at low concentrations and subsequently showed that urine (micro)albumin was elevated in patients with diabetes after a glucose load ([1][1]). In the early 1980s, several small longitudinal observational studies

Timing, they say, is everything. When to swing at the baseball’s pitch, when to depart to catch an airplane, when to sell (or buy) a stock: act too early or too late and the results may be unsatisfactory. So, it seems, may be the case for placement of an arteriovenous fistula for hemodialysis.

Objective This study explored the long-term outcomes of arteriovenous fistulas treated with vonapanitase (recombinant human elastase) at the time of surgical creation. Methods This was a randomized, double-blind, placebo-controlled trial of 151 patients undergoing radiocephalic or brachiocephalic arteriovenous fistula creation who were randomized equally to placebo, vonapanitase 10 μg, or vonapanitase 30 μg. The results after 1 year of follow-up were previously reported. The current analysis occurred when the last patient treated was observed for 3 years. For the current analysis, the primary end point was primary patency; the secondary end points included secondary patency, use of the fistula for hemodialysis, and rate of procedures to restore or to maintain patency. Results There was no significant difference in the risk of primary patency loss with vonapanitase 10 μg or 30 μg vs placebo. When seven initial patency loss events related to cephalic arch and central vein balloon angioplasty were excluded, the risk of patency loss was reduced with vonapanitase overall (hazard ratio [HR], 0.63; P = .049) and 30 μg (HR, 0.51; P = .03). In patients with radiocephalic fistulas (n = 67), the risks of primary and secondary patency loss were reduced with 30 μg (HR, 0.37 [ P = .02] and 0.24 [ P = .046], respectively). The rate of procedures to restore or to maintain fistula patency was reduced with 30 μg vs placebo (0.23 vs 0.72 procedure days/patient/year; P = .03) and also reduced in patients with radiocephalic fistulas with 30 μg vs placebo (0.17 vs 0.85 procedure days/patient/year; P = .048). Conclusions In this study, vonapanitase did not significantly improve primary patency in the primary analysis but did significantly improve primary patency in an analysis that excluded patency loss due to cephalic arch and central vein balloon angioplasty. In patients with radiocephalic fistulas, 30 μg significantly improved primary and secondary patency. Vonapanitase 30 μg decreased the rate of procedures to restore or to maintain patency in the analysis that included all patients and in the subset with radiocephalic fistulas.

Purpose To explore the safety and efficacy of PRT-201. Methods Randomized, double-blind, placebo-controlled, single-dose escalation study of PRT-201 (0.0033 to 9 mg) applied after arteriovenous fistula (AVF) creation. Participants were followed for one year. The primary outcome measure was safety. Efficacy measures were the proportion with intra-operative increases in AVF outflow vein diameter or blood flow ≥25% (primary), changes in outflow vein diameter and blood flow, AVF maturation and lumen stenosis by ultrasound criteria and AVF patency. Results The adverse events in the PRT-201 group (n=45) were similar to those in the placebo group (n=21). There were no differences in the proportion with ≥25% increase in vein diameter or blood flow, successful maturation or lumen stenosis. There was no statistically significant difference in primary patency between the dose groups (placebo n=21, Low Dose n=16, Medium Dose n=17 and High Dose n=12). In a subgroup analysis that excluded three participants with early surgical failures, the hazard ratio (HR) for primary patency loss of Low Dose compared with placebo was 0.38 (95% CI 0.10-1.41, P=0.15). In a Cox model, Low Dose (HR 0.27, 95% CI 0.04-0.79, P=0.09), white race (HR 0.17, 95% CI 0.03-0.79, P=0.02), and age Conclusions PRT-201 was not different from placebo for safety or efficacy measures. There was a suggestion for improved AVF primary patency with Low Dose PRT-201 that is now being studied in a larger clinical trial.

Extended-release dipyridamole plus low-dose aspirin (ERDP/ASA) prolongs primary unassisted graft patency of newly created hemodialysis arteriovenous grafts, but the individual contributions of each component are unknown. Here, we analyzed whether use of aspirin at baseline associated with primary unassisted graft patency among participants in a randomized trial that compared ERDP/ASA and placebo in newly created grafts. We used Cox proportional hazards regression, adjusting for prespecified baseline comorbidities and covariates. Of all participants, 43% reported use of aspirin at baseline; of these, 82% remained on nonstudy aspirin (i.e., excluding ERDP/ASA) at 1 year. After 1 year of follow-up, the incidence of primary unassisted patency among participants using aspirin at baseline was 30% (95% CI: 24 to 35%) and among those not using aspirin was 23% (95% CI: 18 to 27%). Use of aspirin at baseline associated with a dose-dependent prolongation of primary unassisted graft patency that approached statistical significance (adjusted HR, 0.83; 95% CI: 0.68 to 1.01; P = 0.06). Use of aspirin at baseline did not associate with prolongation of cumulative graft patency or participant survival. In conclusion, use of aspirin associates with a trend toward longer primary unassisted patency of newly placed hemodialysis grafts similar to that observed for ERDP/ASA.

Arteriovenous graft stenosis leading to thrombosis is a major cause of complications in patients undergoing hemodialysis. Procedural interventions may restore patency but are costly. Although there is no proven pharmacologic therapy, dipyridamole may be promising because of its known vascular antiproliferative activity.We conducted a randomized, double-blind, placebo-controlled trial of extended-release dipyridamole, at a dose of 200 mg, and aspirin, at a dose of 25 mg, given twice daily after the placement of a new arteriovenous graft until the primary outcome, loss of primary unassisted patency (i.e., patency without thrombosis or requirement for intervention), was reached. Secondary outcomes were cumulative graft failure and death. Primary and secondary outcomes were analyzed with the use of a Cox proportional-hazards regression with adjustment for prespecified covariates.At 13 centers in the United States, 649 patients were randomly assigned to receive dipyridamole plus aspirin (321 patients) or placebo (328 patients) over a period of 4.5 years, with 6 additional months of follow-up. The incidence of primary unassisted patency at 1 year was 23% (95% confidence interval [CI], 18 to 28) in the placebo group and 28% (95% CI, 23 to 34) in the dipyridamole-aspirin group, an absolute difference of 5 percentage points. Treatment with dipyridamole plus aspirin significantly prolonged the duration of primary unassisted patency (hazard ratio, 0.82; 95% CI, 0.68 to 0.98; P=0.03) and inhibited stenosis. The incidences of cumulative graft failure, death, the composite of graft failure or death, and serious adverse events (including bleeding) did not differ significantly between study groups.Treatment with dipyridamole plus aspirin had a significant but modest effect in reducing the risk of stenosis and improving the duration of primary unassisted patency of newly created grafts. (ClinicalTrials.gov number, NCT00067119.)

The arteriovenous fistula eligibility (AFE) system (Flow Forward Medical, Olathe, KS) is a small, temporary, wearable rotary blood pump system designed to rapidly dilate peripheral veins in hemodialysis patients and improve outcomes after arteriovenous fistula (AVF) creation. A benchtop pulsatile mock circulatory loop was developed to model forearm circulation and to compare the hemodynamics of the AFE system with those of a conventional radiocephalic AVF. The AFE system maintained a mean wall shear stress (mWSS) within the 2.5-7.5 Pa target range for cephalic outflow veins of 2-6 mm diameter, which when applied clinically will provide better control of mWSS during the outflow vein maturation process when compared with a conventional AVF. These results support further study to determine whether or not vein preconditioning with the AFE system under controlled levels of mWSS will promote improved AVF outcomes.

The arteriovenous graft (AVG) is most often used in hemodialysis patients when an autogenous fistula is not feasible. The optimal location (forearm or upper arm) and configuration (loop or straight) of AVGs are not known. To evaluate relationships of AVG location and configuration with patency, we conducted a secondary analysis using data from a randomized, placebo-controlled trial of dipyridamole plus aspirin for newly placed AVG.Participants of the Dialysis Access Consortium (DAC) Graft Study with newly placed upper extremity prosthetic grafts involving the brachial artery were studied. Multivariable analyses adjusting for trial treatment group, center, gender, race, body mass index, diabetes, current treatment with chronic dialysis, and prior arteriovenous vascular access or central venous catheter were performed to compare outcomes of forearm (fAVG) and upper arm (uAVG) grafts, including loss of primary unassisted patency (LPUP) and cumulative primary graft failure (CGF). Subgroup analyses of graft configuration and outflow vein used were also conducted.A total of 508 of the 649 participants (78%) enrolled in the trial had an upper extremity brachial artery graft placed, 255 with fAVG and 253 with uAVG. Participants with fAVG were less often male (33% vs 43%; P = .03), African American (62% vs 78%; P .001), and receiving dialysis at the time of surgery (62% vs 80%; P .001). Participants with fAVG had a higher mean body mass index (33 vs 29; P .001). The LPUP (fAVG 70% vs uAVG 78%; P = .07) and CGF (33% vs 36%; P = .91) were similar between fAVG and uAVG at 1-year follow-up. In multivariable analysis, AVG location (uAVG vs fAVG) was not associated with LPUP (hazard ratio, 1.21; 95% confidence interval, 0.90-1.63; P = .20) or CGF (hazard ratio, 1.36; 95% confidence interval, 0.94-1.97; P = .10). LPUP did not differ significantly between fAVG and uAVG among subgroups based on AVG configuration (P = 1.00) or outflow vein used (P = .16).Patency was comparable between fAVG and uAVG despite the larger caliber veins often encountered in the upper arm in carefully selected patients. Our findings support the traditional view that, in order to preserve a maximal number of access sites, the forearm location should be considered first before resorting to an upper arm graft.

Monthly access flow monitoring with increased prophylactic angioplasty did not improve fistula patency.BackgroundRegular access monitoring is recommended to detect and treat access stenosis in order to prevent access thrombosis and failure.MethodsIn 1999, we instituted monthly access blood flow monitoring using the ultrasound dilution technique (UDT). In a sequential observational trial, 222 patients were studied for the impact of UDT monitoring on patency of their first arteriovenous autogenous fistula. Group 1, the historic group (before 1999), had 146 arteriovenous fistulas (50.7% upper arm), followed for 259 access-years. Group 2, the UDT-monitored group, had 76 arteriovenous fistulas (60.5% upper arm), followed for 123 access-years. Decision to refer for angiography was based on clinical criteria for group 1, and clinical criteria plus results of UDT flow monitoring in group 2.ResultsCumulative patency was longer (P < 0.01) and the thrombosis rate was lower (P < 0.05) in group 2. However, the improvement occurred prior to initiation of UDT flow monitoring. Comparing outcomes in group 2 patients whose fistula survived to start flow monitoring with group 1 patients whose fistula survived at least 160 days (the median time to starting UDT monitoring in group 2), there was a sevenfold increase in angioplasty procedures (0.67 vs. 0.09 per access-year) but no improvement in the thrombosis rate or cumulative fistula patency.ConclusionUDT monitoring increased the rate of angioplasty procedures and thereby shortened primary unassisted patency, but did not decrease the thrombosis rate or improve cumulative fistula patency.

Background Surgically created arteriovenous (AV) grafts are the most common type of hemodialysis vascular access in the United States, but fail frequently due to the development of venous stenosis. The Dialysis Access Consortium (DAC) Aggrenox Prevention of Access Stenosis Trial tests the hypothesis that Aggrenox (containing dipyridamole and aspirin) can prevent stenosis and prolong survival of arteriovenous grafts.Methods This is a multicenter, randomized, double-blind, placebo-controlled trial that will enroll 1056 subjects over four years with one-half year follow-up. Subjects undergoing placement of a new AV graft for hemodialysis are randomized to treatment with Aggrenox or placebo immediately following access surgery. The primary outcome is primary unassisted patency defined as the time from access placement until thrombosis or an access procedure carried out to maintain or restore patency. The major secondary outcome is cumulative access patency. Monthly access flow monitoring is incorporated in the study design to enhance detection of a hemodynamically significant access stenosis before it leads to thrombosis.Results This paper describes the key issues in trial design, broadly including: 1) ethical issues surrounding the study of a clinical procedure that, although common, is no longer the clinical intervention of choice; 2) acceptable risk (bleeding) from the primary intervention; 3) inclusion of subjects already receiving a portion of the study intervention; 4) inclusion of subjects with incident rather than prevalent qualifying clinical conditions; 5) timing of the study intervention to balance safety and efficacy concerns; and 6) the selection of primary and secondary study endpoints.Conclusions This is the first, large, multicenter trial evaluating a pharmacologic approach to prevent AV graft stenosis and failure, an important and costly problem in this patient population. Numerous design issues were addressed in implementing the trial and these will form a roadmap for future trials in this area.

Background The Dialysis Access Consortium (DAC) was developed to investigate interventions to improve hemodialysis vascular access outcomes. The autogenous arteriovenous fistula created by direct connection of native artery to vein is the recommended vascular access for hemodialysis. However, it fails frequently due to clotting after surgery.Purpose The DAC Early AV Fistula Thrombosis Trial tests the hypothesis that clopidogrel can prevent early fistula failure and increase the number of fistulas that ultimately become usable for hemodialysis access. This is one of two initial and concurrent trials being performed by the DAC. The companion trial investigates pharmacologic approaches to prevent venous stenosis leading to AV graft failure.Methods This is a multicenter, randomized, double-blind, placebo-controlled trial that will enroll 1284 patients over four years. Patients undergoing creation of a new native arteriovenous (AV) fistula are randomized to treatment with clopidogrel or placebo for six weeks following fistula creation surgery. The primary outcome is fistula patency at six weeks. The major secondary outcome is fistula suitability for dialysis.Results This paper examines key aspects of this study that have broad relevance to trial design including: 1) the selection of an intermediate event as the primary outcome, 2) timing of the intervention to balance efficacy and safety concerns, 3) ethical considerations arising from required modifications of concomitant drug therapy, and 4) choosing an efficacy or effectiveness evaluation of the intervention.Conclusions This is the first, large, multicenter trial evaluating a pharmacologic approach to prevent early AV fistula failure and promote more usable fistulas for hemodialysis. The methodologic challenges identified and addressed during the development of this trial should help to inform the design of future vascular access trials, and are relevant to clinical trials addressing a wide range of questions.

The cost for providing care for patients on hemodialysis due to end stage kidney disease is high. Finding ways to improve patient outcomes and reduce the cost of dialysis is important. Dialysis care is intricate and multiple factors may influence patient survival. Over 50 parameters may be monitored on a regular basis in providing kidney dialysis treatments. Understanding the collective role of these parameters in determining outcomes for an individual patient and administering individualized treatments allowing specific interventions is a challenge. Individual patient survival may depend on a complex interrelationship between multiple demographic and clinical parameters, medications, medical interventions, and the dialysis treatment prescription. In this research, data preprocessing, data transformations, and a data mining approach are used to elicit knowledge about the interaction between many of these measured parameters and patient survival. Two different data mining algorithms were employed for extracting knowledge in the form of decision rules. These rules were used by a decision-making algorithm, which predicts survival of new unseen patients. Important parameters identified by data mining are interpreted for their medical significance. The concepts introduced in this research have been applied and tested using data collected at four dialysis sites. The computational results are reported in the paper.

Dialysis care is particularly complex and multiple factors may influence patient survival. The cost of such treatment for end stage kidney disease is high and needs attention for reducing it. Individual patient survival may depend on an intricate interrelationship between various demographic and clinical variables, medications, medical interventions and the dialysis treatment prescription. In this research, a data mining approach is used to extract knowledge regarding the interactions between the features and the outcome. There exist a complex and contradictory relationships among data mining rules that are difficult to interpret and implement. To resolve these conflicts a decision-making algorithm is developed using sixteen different classifiers. The decision-making algorithm employs simple and weighted voting schemes. Thus in this paper, a hybrid data mining enhanced decision making approach is used for predictions of an individual patient surviving beyond the median survival time. The concepts introduced in this research have been applied and tested using data collected at four dialysis sites.

While surveying Illinois Amaranthus tuberculatus (Moq) Sauer (tall waterhemp) half-sib populations for herbicide response variability, several were observed to segregate for resistance to atrazine. Studies were conducted on greenhouse-grown A tuberculatus plants to compare atrazine responses among populations that were segregating for resistance (SegR), uniformly sensitive (UniS) or uniformly resistant (UniR). In chlorophyll fluorescence assays, leaves of plants from the SegR and UniS populations displayed changes in fluorescence after treatment with atrazine, indicating that atrazine was inhibiting electron transport of photosystem II in chloroplasts. Sequencing of a fragment of psbA, which encodes the D1 protein, revealed that the SegR population did not contain the amino acid substitution that is typically found in triazine-resistant plants. Whole-plant herbicide dose-response experiments revealed that, relative to the UniS population, atrazine resistances in the UniR and SegR populations were >770-fold and 16-fold, respectively. The SegR population was also resistant to cyanazine (59-fold), but not to metribuzin, linuron or pyridate. Triazine resistance in the SegR population was shown to be a nuclear inherited trait, unlike maternal inheritance of site-of-action mediated triazine resistance found in the UniR population. Taken collectively, these findings confirm the existence of two distinct triazine resistance mechanisms in A tuberculatus. Copyright © 2003 Society of Chemical Industry

Achieving Dialysis Outcomes Quality Initiative guidelines for native arteriovenous fistulae using the radiocephalic forearm fistula (lower-arm fistula [LAF]) is difficult. This study reports results using the upper-arm native arteriovenous fistula (UAF). From a prospective access database (1992 to 1998), this study was based on 204 patients (322 accesses). Average patient age was 56 +/- 1 years, 63% were men, and 47% had diabetes. A native fistula was the first access in 73% of patients (36%, LAFs; 37%, UAFs) and accounted for 48% of subsequent accesses (13%, LAFs; 35%, UAFs). Younger men were more likely to receive an LAF, but there was no demographic difference between patients receiving a UAF or arteriovenous graft (AVG). Both primary unassisted and cumulative access patencies were significantly better for UAFs than either LAFs or AVGs. For first accesses, cumulative access patency rates at 1, 3, and 5 years were 71%, 57%, and 57% for UAFs; 54%, 46%, and 36% for LAFs; and 54%, 28%, and 0% for AVGs (P < 0.01). Despite shorter access survival, AVGs required more total access procedures than either UAFs or LAFs (procedures per access: 2.5, 1.0, and 0.6 for AVGs, UAFs, and LAFs, respectively). When used, catheters were required for dialysis for a longer time for UAFs (median catheter days, 36, 53, and 56 for AVGs, LAFs, and UAFs, respectively; P < 0.05). Access flow rates were greater in UAFs (1,247 mL/min; n = 48; P < 0.01) than AVGs (851 mL/min; n = 30) or LAFs (938 mL/min; n = 31). There was no evidence that UAFs were banded or ligated for steal syndromes or heart failure more often than AVGs or LAFs. These results show that the UAF is a good alternative to an AVG for achieving Dialysis Outcomes Quality Initiative guidelines.

Hyperkalemia is a commonly encountered clinical problem and has been reported in up to 10% of hospitalized patients, with 10% to 38% of those episodes associated with medications that block the renin-angiotensin-aldosterone system (RAAS).1 Mortality has been shown to be increased in patients with hyperkalemia even after accounting for other comorbidities.2 As a complication of RAASblockade, hyperkalemia limits delivery of optimal therapy tomany patients whomight otherwise benefit. RAAS blockade is recommended to slow the progression of proteinuric kidney disease and prolong survival in patients with systolic heart failure.3 However, these patients also are at increased risk for developing hyperkalemia.4RAASblockade is reportedlyunderused in the recommended populations, and many patients do not receive the targeteddose,5 inpart becauseof concerns abouthyperkalemia.Hyperkalemia of anydegreehas been reported to occur in approximately 10%ofoutpatientswithin ayear of initiatingRAASblockadeand is severe inapproximately 1%ofpatients with diabetes.1,4 The ratio of potassium across cell membranes is the major determinant of restingmembrane potential.6 Efflux of potassium, the major intracellular cation, down its concentrationgradient frominsidetooutside thecellgeneratesanegative intracellular transmembrane potential that sets the baseline activity of all other voltage sensitive processes in the cell. Extracellular potassiumconcentration is thus a critical determinantof the resting cellmembranepotential andmustbemaintained within tight limits between 3.5 to 5 mEq/L. Disorders of potassium homeostasis that alter extracellular potassium concentrationwill affectvoltage-dependentprocesses inmany tissues, but effects on the heart, including cardiac arrhythmias, asystole, and death, are most concerning. Electrocardiographic (ECG) manifestations of hyperkalemia may include peaked T waves, first-degree atrioventricular block, diminishedP-waveamplitude,andsinusarrest,whereashigher levels of hyperkalemia (particularly >9 mEq/L) may be associated with bundle-branch block, intraventricular conductiondefect, ventricular tachycardia, fibrillation, andasystole.7 However, the correlationbetweenECGchanges andserumpotassium is poor, and 50% of patients with plasma potassium levels greater than 6.5 mEq/L may lack any ECG changes.8 A balance between intake, transcellular distribution, and excretiondeterminesplasmapotassiumconcentration.6Acute increases in potassium intake are buffered by cellular uptake particularly in liver and muscle to prevent large increases in plasmapotassium.9Ultimately, however, the kidney, particularly the aldosterone-sensitivedistal nephron, secretes potassiumandmaintains homeostatic balance between intake and excretion.10Acutechanges inplasmapotassiummayoccurwith massive cell injury (eg, rhabdomyolysis); geneticdefects inpotassium-channelproteins; or alterations inplasma insulin, catecholamines, tonicity, or pH that affect thedistributionof potassium across the cell membrane. Chronic alterations in plasma potassium usually represent a defect in renal potassiumhandling.Renal potassiumhandlingdependsonglomerular filtration rateanddistalpotassiumsecretion,which is controlled by distal tubular flow rate; sodium, bicarbonate, and chloride delivery; and the hormone aldosterone. Renal dysfunction; alterations in distalwater, sodium, and aniondelivery; genetic defects in renal potassium handling; and disorders of theRAASare all factors that can affect renal potassium excretion and increase plasma potassium concentration. Currentmanagementof chronichyperkalemia includes removing exogenous potassium supplements, discontinuing otherdrugs suchasnonsteroidal anti-inflammatorydrugs that impair renal potassium excretion, instituting dietary potassium restriction, treating with diuretics to improve distal sodiumandwaterdelivery, andusingsodiumbicarbonate to treat any coexisting acidosis.4 Switching from an angiotensinconvertingenzymeinhibitor toanangiotensin-receptorblocker can help lower plasma potassium.11 For intractable cases, use of theoral sodium-potassiumexchange resin sodiumpolystyrene sulfonate (SPS), 15 to 30 g orally per day, or even initiation of dialysis in patientswith chronic kidneydisease stage 5 maybe indicated. It isno longer recommended tomixSPSwith hypertonic sorbitol becauseof occasional reports of bowel necrosis. However, the efficacy of SPS in the absence of sorbitol to lower serum potassium is uncertain and has not been established in a randomized clinical trial.12 Despite these measures, in many instances, hyperkalemia cannot be adequately controlled. For patients receiving RAAS blockade medications, thismay lead to adecrease or discontinuationof this therapy. New treatments to limit hyperkalemia in these patient populations could be potentially lifesaving. Sodium zirconium cyclosilicate is a new orally administered, nonabsorbed sodium-potassium cation exchanger.13 Comparedwith the organic SPS resin, zirconiumcyclosilicate is an inorganic crystal with highly selective potassium pores that reportedly binds 9 times asmuch potassium per gram as SPS. In vitro, zirconium cyclosilicate binds 3.5 mmoL of potassium per gram. In a phase 2 trial, acute administration of this agent to patients with chronic kidney disease was reported to be safe, well tolerated, and effective.14 In this issue of JAMA, Kosiborod and colleagues15 present the results of HARMONIZE, a phase 3, randomized, doubleRelated article page 2223 Opinion

Obesity, though not commonly reported as a cause of fistula failure, may influence fistula survival by making it difficult to cannulate the vein and possibly by releasing adipokines, such as interleukin-6, tumor necrosis factor-alpha, plasminogen activator inhibitor-1, or adiponectin, that modulate the development of neointimal hyperplasia and thrombosis leading to fistula failure.

Recent evidence suggests that bradykinin (BK) plays a role in regulating neointimal formation after vascular injury. The present study examined the mechanism whereby BK regulates platelet-derived growth factor (PDGF) AB-induced mitogenesis in smooth muscle cells from rat mesenteric artery. BK, but not other activators of phosphoinositidase C (e.g., angiotensin II), inhibited PDGF-stimulated mitogenesis. The B1 receptor agonist des-Arg9-BK (DABK) was more potent than the B2 agonist BK; smaller BK fragments had no activity. In studies in which the B2 receptor antagonist HOE-140 inverted question markD-Arg0[Hyp3,beta-(2-thienyl)-Ala5,D-Tic7,Oic 8]BK inverted question mark and the B1 receptor antagonist DHOE [[D-Arg0,Hyp3,beta-(2-thienyl)-Ala5,D-Tic7,Oi c8,des-Arg9]BK] were used, both receptors independently mediated inhibition of PDGF-induced mitogenesis. There was no evidence for metabolism of BK to DABK. The rank potency for activating phosphoinositidase C and increasing intracellular Ca2+ (BK > DABK) was opposite that for inhibiting mitogenesis (DABK > BK). Inhibition of cyclooxygenase did not prevent the kinin-mediated inhibition. Kinetic analysis of the cell cycle effects of kinins on PDGF-stimulated mitogenesis revealed that continuous exposure to DABK or BK was inhibitory even when added shortly before the cells initiated DNA synthesis (S phase). However, short-term exposure (5-60 min) to DABK or BK was inhibitory only when added after exposure to PDGF. These data suggest that the B1 and B2 receptors potently inhibited PDGF-stimulated mitogenesis and proliferation by activating an alternative signal transduction cascade not involving phosphoinositidase C or prostaglandins. The inhibition occurred at a point late in progression of the cell cycle from G1 to S and was dependent on the presence of kinins after exposure to PDGF.

MORE THAN 600 000 PATIENTS IN THE UNITED States have end-stage kidney disease, with the majority—nearly 400 000 patients— requiring long-term maintenance hemodialysis. Ready access to the bloodstream is essential for hemodialysis and may be provided by a surgically created arteriovenous fistula, arteriovenous graft, or central venous catheter. An arteriovenous fistula is preferred because of its lower risk of thrombosis and lower overall cost. However, delayed maturation and failure rates of 20% to 60% for new fistulas result in greater reliance on catheters, the least desirable type of hemodialysis access. Compared with a new fistula, an arteriovenous graft is easier to cannulate and can be used within a few weeks of surgical creation. Yet grafts are associated with a higher rate of thrombosis, with attendant increased morbidity and cost. Grafts were once the most common type of hemodialysis access in the United States. However, through the efforts of the Fistula First Initiative, the End-Stage Renal Disease Networks, and the medical community, the prevalence of grafts in the United States has recently declined to less than 25%. Given the challenges of fistula maturation, grafts remain an appealing option, if the problem of thrombosis can be solved. The underlying cause of thrombosis in grafts and fistulas is neointimal hyperplasia leading to stenosis, typically at the vein-graft or vein-artery anastomosis. Fish oil has measurable anti-inflammatory, antiproliferative, and antithrombotic effects as well as a salutary effect on endothelial function that could slow the development of neointimal hyperplasia and graft thrombosis. Fish oil has been shown to reduce distal occlusion in coronary vein grafts and is associated with lower overall cardiovascular disease mortality. In a small, randomized, placebo-controlled trial of 24 patients, supplementation with 4 g of fish oil daily (1 g/capsule, 4 capsules/d) decreased hemodialysis graft thrombosis from 75.6% to 14.9% at 1 year. In this issue of JAMA, Lok and colleagues report the results of a randomized placebo-controlled trial evaluating the effect of fish oil supplementation on patency of newly created hemodialysis grafts. Patients were randomized 7 days after graft surgery to receive either four 1-g capsules daily of fish oil (containing 400 mg of eicosapentaenoic acid and 200 mg of docosahexaenoic acid per capsule) or matching placebo capsules taken for 12 months. The primary outcome was the proportion of patients with loss of primary unassisted graft patency, defined as the first graft thrombosis or a surgical or radiological intervention on the graft. Because of slow recruitment, the study was terminated early before reaching its target goal of 232 patients. A total of 201 patients were randomized; 5 dropped out before receiving treatment, 2 in the fish oil group and 3 in the placebo group. A total 196 patients were ultimately treated, 99 with fish oil and 97 with placebo. The analysis was based on patients who completed the study rather than those randomized. At 12 months, loss of primary unassisted graft patency occurred in 48% of patients who received fish oil and 62% who received placebo, for a relative risk reduction of 22%, a difference that did not reach statistical significance. However, predefined secondary outcomes that measured the rate of occurrence of events, including the number of primary events per 1000 access-days (incidence rate ratio) and the loss of primary unassisted patency by the Kaplan-Meier method (hazard ratio), revealed reductions of 42% and 32%, respectively, both of which were statistically significant. Although other predefined secondary graft outcomes including the rate of thrombosis and rate of radiological or surgical interventions were also significantly reduced, cumulative graft patency was not prolonged. As is consistent with other trials of fish oil, Lok et al reported a statistically significant reduction in systolic and diastolic blood pressure and a reduction in the cardiovascular event rate among patients who received fish oil. However, the latter finding should be interpreted with caution, given the small sample size and overall small number of events. Nonetheless, given the high mortality from cardiovascular disease in the hemodialysis population, this latter observation should stimulate an appropriately powered trial evaluating the effect of fish oil for prolonging patient survival. In the study by Lok et al, there was no between-group difference in triglyceride levels, which has usually been a re

The effects of bradykinin (BK) and angiotensin II (ANG II) were compared in cultured rat mesenteric arterial smooth muscle cells. BK and ANG II activated a phosphoinositide-specific phospholipase C, leading to the rapid release of [3H]inositol phosphates, an increase in intracellular calcium, and formation of sn-1,2-diacylglycerol (DAG). DAG formation was biphasic with a transient peak at 5 s followed by a sustained increase from 60 to 600 s. The BK-mediated increases in inositol triphosphate and DAG were dose dependent with half-maximal increases at concentrations of 5 and 2 nM, respectively. Both hormones were found to activate protein kinase C (PKC) as assessed by phosphorylation of the 68- to 72-kDa intracellular PKC substrate myristoylated alanine-rich C kinase substrate. However, despite similar phosphorylation of this substrate, only ANG II produced a significant increase in membrane-bound PKC activity. The mechanism accounting for the inability of BK to increase membrane-bound PKC activity is unclear. Our studies excluded differential translocation of PKC to the nuclear membrane, production of an inhibitor of membrane-bound PKC activity, and expression of BK and ANG II receptors on different cells as the mechanism. Vascular smooth muscle cells were found to express at least four different PKC isozymes: alpha, delta, zeta, and a faint band for epsilon. All of the isozymes except zeta-PKC were translocated by treatment with the phorbol ester 4 beta-phorbol 12-myristate 13-acetate. However, neither ANG II nor BK produced significant translocation of any measured isozyme; therefore, we could not exclude the possibility that ANG II and BK activate different isozymes of PKC. Both hormones were found to have a similar small and inconsistent effect in stimulating [3H]thymidine incorporation. These observations demonstrate that BK and ANG II have similar biochemical effects on vascular smooth muscle cells and imply that, in selected vessels, the vasodilatory effects of BK mediated by the endothelium may be partially counterbalanced by a vasoconstrictor effect on the underlying vascular smooth muscle cells.

The role of neurohumoral factors in the sodium retention of nephrotic syndrome is controversial. We report a case with abrupt onset of severe nephrotic-range proteinuria and hypoalbuminemia due to membranous glomerulonephritis that was associated with renal salt wasting and hypovolemia without edema. Further evaluation showed hypoaldosteronism, hyporeninemia, and primary autonomic failure principally affecting the sympathetic nervous system, determined by the Valsalva maneuver. Administration of exogenous mineralocorticoid and oral salt caused edema and accelerated hypertension. The severe hypoaldosteronism likely was due to use of the angiotensin-converting enzyme inhibitor lisinopril, and it improved after this drug treatment was discontinued. The nephrotic proteinuria resolved after treatment with cyclosporine and prednisone, but the primary autonomic failure with hyporeninemic hypoaldosteronism persisted. The case shows that intratubular factors activated by nephrotic proteinuria are not sufficient to produce sodium retention in the absence of aldosterone and an intact sympathetic nervous system.

Hepatic membrane subfractions prepared from control rats demonstrated forskolin (FSK)-stimulated adenylate cyclase activity in the basolateral (sinusoidal) but not apical (canalicular) plasma membrane. After bile duct ligation (BDL) for 12 or 24 h, there was an increase in FSK-stimulated adenylate cyclase activity in the apical membrane (54.2 +/- 3.9 pmol.mg-1 x min-1). The mechanism for this increase was explored further. ATP hydrolysis was found to be much higher in the apical than the basolateral membrane. Increasing the ATP levels in the assay enhanced apical membrane adenylate cyclase activity (10.5 +/- 0.2 pmol.mg-l.min-1); however, total adenosinetriphosphatase (ATPase) activity was not altered after BDL. Extraction of the apical membrane with bile acids or other detergents resulted in a two- to threefold increase in adenylate cyclase activity (30.6 +/- 3.6 pmol.mg-1 x min-1; detergent C12E8) This suggested that bile duct ligation was acting via the detergent-like action of bile acids to uncover latent adenylate cyclase activity on apical membranes. Further studies demonstrated that both BDL and detergent extraction also enhanced toxin-directed ADP-ribosylation of Gs alpha (cholera toxin) and Gi alpha (pertussis toxin) in the apical but not the basolateral membrane. After BDL, Gi alpha was found to be twofold greater in the apical membrane than the basolateral membrane. Immunoblotting using specific G protein antibodies further confirmed that apical membranes from control rats had a higher concentration of Gi1, 2 alpha and beta and slightly elevated levels of Gi3 alpha and Gs alpha compared with the basolateral membrane. The results demonstrate that adenylate cyclase and heterotrimeric GTP-binding proteins are present on the apical membrane, but measurement of their functional activity requires detergent permeabilization of apical membrane vesicles and is limited by the presence of high ATPase activity.

Context The arteriovenous fistula is the preferred type of vascular access for hemodialysis because of lower thrombosis and infection rates and lower health care expenditures compared with synthetic grafts or central venous catheters. Early failure of fistulas due to thrombosis or inadequate maturation is a barrier to increasing the prevalence of fistulas among patients treated with hemodialysis. Small, inconclusive trials have suggested that antiplatelet agents may reduce thrombosis of new fistulas. Objective To determine whether clopidogrel reduces early failure of hemodialysis fistulas. Design, Setting, and Participants Randomized, double-blind, placebo-controlled trial conducted at 9 US centers composed of academic and community nephrology practices in 2003-2007. Eight hundred seventy-seven participants with end-stage renal disease or advanced chronic kidney disease were followed up until 150 to 180 days after fistula creation or 30 days after initiation of dialysis, whichever occurred later. Intervention Participants were randomly assigned to receive clopidogrel (300-mg loading dose followed by daily dose of 75 mg; n = 441) or placebo (n = 436) for 6 weeks starting within 1 day after fistula creation. Main Outcome Measures The primary outcome was fistula thrombosis, determined by physical examination at 6 weeks. The secondary outcome was failure of the fistula to become suitable for dialysis. Suitability was defined as use of the fistula at a dialysis machine blood pump rate of 300 mL/min or more during 8 of 12 dialysis sessions. Results Enrollment was stopped after 877 participants were randomized based on a stopping rule for intervention efficacy. Fistula thrombosis occurred in 53 (12.2%) participants assigned to clopidogrel compared with 84 (19.5%) participants assigned to placebo (relative risk, 0.63; 95% confidence interval, 0.46-0.97; P = .018). Failure to attain suitability for dialysis did not differ between the clopidogrel and placebo groups (61.8% vs 59.5%, respectively; relative risk, 1.05; 95% confidence interval, 0.94-1.17; P = .40). Conclusion Clopidogrel reduces the frequency of early thrombosis of new arteriovenous fistulas but does not increase the proportion of fistulas that become suitable for dialysis. Trial Registration clinicaltrials.gov Identifier: NCT00067119

Fistula maturation requires a compliant and responsive vasculature capable of dilating in response to the increased velocity of blood flowing into the newly created low-resistance circuit. Successful maturation to a high volume flow circuit capable of sustaining hemodialysis typically occurs within the first few weeks after creation. Failure to achieve maturation within 4–8 weeks should prompt a search for reversible etiologies; however, an accepted definition of maturation, particularly for patients not yet on dialysis remains elusive. The most commonly identified etiology is neointimal hyperplasia typically occurring in the juxta-anastomotic vein. However, failed maturation has also been reported secondary to impaired arterial and venous dilation and accessory veins. The exact frequency of each of these etiologies is unclear. Understanding the etiologies of impaired fistula maturation will focus future studies of targeted interventions to improve the rate of fistula maturation and increase the number of dialysis patients with a functioning autogenous fistula.

The number of dialysis patients due to end stage kidney disease is increasing. Finding ways to improve patient outcomes and reduce the cost of dialysis is a challenging task. Dialysis care is complex and multiple factors may influence patient survival. More than 50 parameters may be monitored while providing a kidney dialysis treatment. Understanding the collective role of these parameters in determining outcomes for an individual patient and administering individualized treatments is of importance. Individual patient survival may depend on a complex interrelationship between multiple demographic and clinical variables, medications, and medical interventions. In this research, a data mining approach is used to elicit knowledge about the interaction between these variables and patient survival. Two different data mining algorithms are employed for extracting knowledge in the form of decision rules. Data mining is performed on the individual visits of the " most invariant " patients as they form " signatures " for their decision categories. The concepts introduced in this research have been applied and tested using a data collected at four dialysis sites. The computational results are reported.

To determine the benefit of preprocedural three-dimensional gadolinium (Gd)-enhanced magnetic resonance (MR) angiography before percutaneous transluminal renal artery angioplasty and stent placement (PTRA/S) in terms of procedural success, iodinated contrast material load, and procedure duration.Over an 18-month period, 39 patients underwent attempted percutaneous renal angioplasty with or without stent placement. A total of 48 renal arteries were treated (40 cases of atherosclerosis, one of stent restenosis, five of fibromuscular dysplasia, and two of transplant stenosis). Preprocedural Gd-enhanced MR angiography was available in 16 procedures (41%). Procedural outcome, complications, iodinated contrast material load, number of diagnostic angiographic runs, and total procedure duration were each compared between two subgroups: patients who had preprocedural Gd-enhanced MR angiography ("prior MR angiography group") and those who did not ("no MR angiography" group).All procedures were technically successful. The two groups were equivalent in terms of age and disease pattern. However, technical complexity of the procedure was judged to be high in five of 16 procedures in the prior MR angiography group compared to three of 23 procedures in the no MR angiography group (P =.16). Bilateral or dual interventions were performed in six of 16 procedures in the prior MR angiography group compared to three of 23 in the no MR angiography group (P =.075). Iodinated contrast material load was significantly lower in the prior MR angiography group than in the no MR angiography group (68.7 mL +/- 28.4 vs 119.1 mL +/- 49.2 mL;P.0008). The number of diagnostic angiographic runs before interventions were also significantly lower in the prior MR angiography group (1.2 +/- 0.4 vs 2.6 +/- 0.7; P.0001). Overall procedure duration was comparable between the two groups (91.9 +/- 47.8 vs 112.2 +/- 49.4;P =.2).Preprocedural planning with use of Gd-enhanced MR angiography significantly reduces the iodinated contrast material requirement during percutaneous renal artery interventions. It can also significantly shorten procedure duration.

ObjectiveThis study explored the safety and efficacy of recombinant type I pancreatic elastase (PRT-201) topically applied once to the external surface of an arteriovenous fistula.MethodsThis was a randomized, double-blind, placebo-controlled trial. Adults with kidney disease undergoing creation of a radiocephalic fistula (RCF) or brachiocephalic fistula were randomized to treatment with placebo (n = 51), PRT-201 at 10 μg (n = 51), or PRT-201 at 30 μg (n = 49). The primary efficacy measure was unassisted primary patency (PP) over 1 year. Secondary efficacy measures were secondary patency (SP), unassisted maturation by ultrasound interrogation, use for hemodialysis, and hemodynamically significant lumen stenosis.ResultsMedian PP was 224 days for placebo and >365 days for the PRT-201 groups. At 1 year, 45%, 54%, and 53% of placebo, 10-μg, and 30-μg patients retained PP. The risk of PP loss was nonsignificantly reduced for 10 μg (hazard ratio [HR], 0.69; P = .19) and 30 μg (HR, 0.67; P = .17) vs placebo. In the subset (44% of patients) with a RCF, the median PP was 125 days for placebo and >365 days for the PRT-201 groups. At 1 year, 31%, 50%, and 63% of placebo, 10-μg, and 30-μg RCFs retained PP. The risk of RCF PP loss was nonsignificantly reduced by 10 μg (HR, 0.59; P = .18) and significantly reduced by 30 μg (HR, 0.37; P = .02) vs placebo. At 1 year, 77%, 81%, and 83% of placebo, 10-μg, and 30-μg patients retained SP. The risk of SP loss was nonsignificantly reduced for 10 μg (HR, 0.79; P = .61) and 30 μg (HR, 0.76; P = .55) vs placebo. In the subset with RCFs, 65%, 82%, and 90% of placebo, 10-μg, and 30-μg patients retained SP at 1 year. The risk of RCF SP loss was nonsignificantly reduced for 10 μg (HR, 0.45; P = .19) and 30 μg (HR, 0.27; P = .08) vs placebo. At month 3, 67%, 87% (P = .03), and 92% (P < .01) of the placebo, 10-μg, and 30-μg group fistulas had unassisted maturation by ultrasound interrogation. At month 3 in the subset with an RCF, 47%, 74% (P = .17), and 93% (P < .01) of placebo, 10-μg, and 30-μg group fistulas had unassisted maturation by ultrasound interrogation. Adverse event reports were not meaningfully different between groups.ConclusionsPRT-201 appeared safe. The primary efficacy end point was not met. However, both PRT-201 doses were associated with improved unassisted maturation. The 30-μg dose was associated with increased PP in the subset with RCF.

Bradykinin and platelet-derived growth factor (PDGF) are inflammatory mediators important in the response to vascular injury. Based upon the known effect of oncogenic Ras to increase bradykinin receptor expression and the ability of PDGF to stimulate Ras, we examined whether PDGF regulates bradykinin B2 receptor expression in cultured arterial smooth muscle cells. Treatment with PDGF (AB and BB, but not AA) produced a dose- and time-dependent increase in both mRNA (6-7-fold increase at 2-4 h) and cell surface receptors (2-4-fold at 6-12 h) for the B2 receptor. There was a 60-min delay between exposure to PDGF and the initial increase in B2 receptor mRNA. Transcriptional inhibitors, actinomycin D or 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole, completely blocked the increase in B2 receptor mRNA when added up to 60 min after stimulation with PDGF. However, protein synthesis was not required, as treatment with cycloheximide did not block but rather superinduced the PDGF-induced increase in B2 receptor mRNA. Comparison with the immediate early response gene c-fos demonstrated that the increase in B2 receptor mRNA was similarly inhibited by the tyrosine kinase inhibitor, tyrphostin, as well as staurosporine. However, stimulation of c-fos was slightly more sensitive to genistein, while the B2 receptor mRNA was more sensitive to inhibition by the protein kinase C inhibitor, calphostin C. The increase in cell surface B2 receptors were functionally coupled to an increase in phosphoinositide-specific phospholipase C, and the effects of PDGF were selective as there was no increase in either angiotensin II- or arginine vasopressin-induced inositol phosphate formation or intracellular calcium release. Taken together, these results demonstrate that the B2 receptor is a delayed early response gene for PDGF in vascular smooth muscle cells.

Bradykinin receptors are present on vascular smooth muscle cells; however, the regulation and biological function of these receptors is unclear. To address these questions the interaction between growth factors and kinins in cultured arterial smooth muscle cells has been examined. Based upon the data a hypothesis is presented that platelet-derived growth factor (PDGF) upregulates cell surface bradykinin B2 receptors on arterial smooth muscle cells. The biological effect of the increase in B2 receptors is currently unclear but under certain conditions they may enhance mitogenesis. These mitogenic effects however, are strongly opposed by the effects of bradykinin acting via a B1-type of receptor which mediates potent inhibition of growth factor-induced mitogenesis.

Anuran membrane studies suggest that the calcium-binding protein calmodulin is necessary for arginine vasopressin (AVP) to exert a hydro-osmotic effect. We therefore examined the effect of trifluoperazine and N-(6-aminohexyl)-5-chloro-1-naphtholene sulphonamide (W-7), chemically dissimilar calmodulin inhibitors, on hydraulic conductivity (Lp) response to AVP in rabbit cortical collecting tubules perfused in vitro. Trifluoperazine but not W-7 increased basal Lp in rabbit cortical collecting tubules. When cortical collecting tubules were pre-treated with either trifluoperazine or W-7, the effect of AVP to increase Lp was significantly inhibited. To determine the site of this inhibition, Lp responses to exogenous cyclic adenosine 3',5'-phosphate (AMP) were studied. Both trifluoperazine and W-7 pretreatment significantly inhibited the effect of a cyclic AMP analogue to increase rabbit cortical collecting tubule Lp. These results suggest that calmodulin may be an important mediator of the hydro-osmotic response to AVP in the mammalian cortical collecting tube by acting at a site or sites distal to cyclic AMP formation.

Membrane proteins of transporting epithelia are often distributed between apical and basolateral surfaces to produce a functionally polarized cell. The distribution of Na+,K+-ATPase [ATP phosphohydrolase (Na+/K+-transporting), EC 3.6.1.37] between apical and basolateral membranes of hepatocytes has been controversial. Because Na+,K+-ATPase activity is fluidity dependent and the physiochemical properties of the apical membrane reduces its fluidity, we investigated whether altering membrane fluidity might uncover cryptic Na+,K+-ATPase in bile canalicular (apical) surface fractions free of detectable Na+,K+-ATPase and glucagon-stimulated adenylate cyclase activities. Apical fractions exhibited higher diphenylhexatriene-fluorescence polarization values when compared with sinusoidal (basolateral) membrane fractions. When 2-(2-methoxyethoxy)ethyl 8-(cis-2-n-octylcyclopropyl)octanoate (A2C) was added to each fraction, Na+,K+-ATPase, but not glucagon-stimulated adenylate cyclase activity, was activated in the apical fraction. In contrast, further activation of both enzymes was not seen in sinusoidal fractions. The A2C-induced increase in apical Na+,K+-ATPase approached 75% of the sinusoidal level. Parallel increases in apical Na+,K+-ATPase were produced by benzyl alcohol and Triton WR-1339. All three fluidizing agents decreased the order component of membrane fluidity. Na+,K+-ATPase activity in each subfraction was identically inhibited by the monoclonal antibody 9-A5, a specific inhibitor of this enzyme. These findings suggest that hepatic Na+,K+-ATPase is distributed in both surface membranes but functions more efficiently and, perhaps, specifically in the sinusoidal membranes because of their higher bulk lipid fluidity.

The biochemical mechanisms of adenylate cyclase desensitization in arginine vasopressin-responsive epithelial cells remain unclear. Preincubation of cultured rabbit renal cortical collecting tubular cells with arginine vasopressin leads to a 30-100% decline in arginine vasopressin-stimulated adenylate cyclase activity. This loss of adenylate cyclase activity is time- and arginine vasopressin concentration-dependent. Preincubation with arginine vasopressin does not result in significant changes in basal, NaF-, forskolin-, isoproterenol- or cholera toxin-stimulated adenylate cyclase activity. Preincubation of cells with chlorophenylthio-cAMP, forskolin, and cholera toxin does not result in loss of arginine vasopressin-stimulated adenylate cyclase activity. Since products of cyclo-oxygenase inhibit arginine vasopressin action, cells were preincubated with indomethacin. Arginine vasopressin-induced adenylate cyclase desensitization is not reversed by indomethacin. By contrast, incubation with pertussis toxin prevents arginine vasopressin-induced adenylate cycle desensitization. These data demonstrate that arginine vasopressin induces homologous desensitization in membranes from cultured rabbit cortical collecting tubular cells and suggest that this desensitization is mediated, at least in part, by pertussis toxin substrate. These observations provide a unifying mechanism for desensitization of adenylate cyclase-coupled hormone receptors.

Oliguria has been considered a cardinal feature of acute renal failure. However, many recent reports indicate that acute renal failure usually occurs in the setting of well-maintained urine output. Moreover, the nonoliguric state may accompany acute renal failure due to pre- and post-renal azotemia and a variety of renal parenchymal disorders, as well as acute tubular necrosis. Most studies indicate that nonoliguric forms of acute renal failure are associated with less morbidity and mortality than oliguric acute renal failure. Uncontrolled studies also suggest that volume expansion, potent diuretic agents, and renal vasodilators can convert oliguric to nonoliguric acute tubular necrosis if administered early in the course of acute renal failure. However, prospective studies of early intervention in oliguric patients are needed.

The calcium ion has been proposed to be an important mediator of the hydroosmotic response to arginine vasopressin (AVP). We examined the effect of reducing basolateral calcium activity on hydraulic conductivity (Lp) in response to AVP in rabbit cortical collecting tubules (CCT) perfused in vitro. Each tubule served as its own control. Reducing bathing fluid calcium from 0.94 mM to 4.6 microM reduced Lp in each tubule (mean decrease from 146 +/- 13 to 106 +/- 7 cm X s-1 X atm X 10(-7), n = 11, P less than 0.025). To determine whether this inhibitory effect was due to a decrease in cellular calcium uptake, we measured the effect of adding 10(-4) M lanthanum to bathing fluid on AVP-stimulated Lp. Lanthanum decreased Lp (from 109 +/- 13 to 80 +/- 10 cm X s-1 X atm X 10(-7), P less than 0.05) in each tubule. To examine the site at which low peritubular calcium activity regulates AVP action, we measured the effect of decreasing bathing fluid calcium on 8-[p-chlorophenylthio]-adenosine 3',5'-cyclic monophosphate (ClPheS-cAMP)-stimulated Lp (n = 5). Decreasing bathing fluid calcium significantly decreases (P less than 0.025) Lp response to ClPheS-cAMP. Since these results suggest that cellular calcium uptake can exert a post-cAMP effect to modulate AVP action, we examined the effect of the calcium ionophore A23187 (10(-7) M) on AVP- and ClPheS-cAMP-stimulated Lp A23187 reversibly potentiates (25-30%, P less than 0.025) the Lp response to both AVP and ClPheS-cAMP.(ABSTRACT TRUNCATED AT 250 WORDS)