Gregory Braden

Effect of clopidogrel on early failure of arteriovenous fistulas for hemodialysis: a randomized controlled trial.

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.

Tenofovir-associated acute and chronic kidney disease: A case of multiple drug interactions.

Tenofovir therapy in patients with human immunodeficiency virus (HIV) infection has been associated with acute renal failure (ARF) and Fanconi syndrome. In the past 2 years, we diagnosed tenofovir-associated ARF in 5 HIV-infected patients who were receiving tenofovir therapy and who had classic findings of acute tubular necrosis, and we compared findings for our patients with data on 22 patients described in the literature. The mean serum creatinine level increased from 0.9 to 3.9 mg/dL, and it decreased to 1.2 mg/dL during recovery. ARF resolved in 22 of 27 patients after discontinuation of tenofovir therapy. The most common drugs given with tenofovir were ritonavir or lopinavir-ritonavir (21 of 27 patients), atazanavir (5 of 27 patients), and didanosine (9 of 27 patients). Tenofovir-associated ARF manifests as acute tubular necrosis that may not resolve with tenofovir withdrawal. Tenofovir is associated with multiple drug interactions, leading to an increased risk of ARF. Frequent monitoring of renal function is warranted for any patient receiving these combinations.

Effect of Dipyridamole plus Aspirin on Hemodialysis Graft Patency

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.)

Changing incidence of glomerular diseases in adults

Studies performed at large metropolitan medical centers have reported an increasing incidence of idiopathic focal segmental glomerulosclerosis (FSGS) in adults. To determine whether a similar trend occurs in small urban and rural communities and to determine the role of race in these observations, we reviewed the patient records of all adults who underwent renal biopsies at our institution over the 20-year period from 1974 to 1994. The patients were grouped for analysis in 5-year intervals, 1975 to 1979, 1980 to 1984, 1985 to 1989, and 1990 to 1994, for the following diagnoses: FSGS, membranous nephropathy (MN), minimal change nephropathy (MCN), membranoproliferative glomerulonephritis (MPGN), immunoglobulin A (IgA) nephropathy, chronic glomerulonephritis, diabetic nephropathy, hypertensive nephrosclerosis, and chronic interstitial nephritis. Patients with secondary causes for these lesions were excluded. The relative frequency of FSGS increased from 13.7% during 1975 to 1979 to 25% during 1990 to 1994 (P < 0.05). The relative frequency of MN decreased from 38.3% during 1975 to 1979 to 14.5% during 1990 to 1994 (P < 0.01). There were no changes in the frequencies of MCN, MPGN, IgA nephropathy, chronic glomerulonephritis, diabetic nephropathy, hypertensive nephrosclerosis, or chronic interstitial nephritis over the 20-year period. However, there was a significant increase in the percentage of blacks with FSGS, from 0% in 1975 to 1979 to 22.6% in 1990 to 1994, and an increased percentage of Hispanics with FSGS, from 0% in 1975 to 1979 to 21.3% in 1990 to 1994 (P < 0.05). The modest increase in whites with FSGS did not reach statistical significance. The incidence of MN in blacks and whites decreased over the 20-year period. In the last 5 years, 15 patients per year had FSGS compared with 7 patients per year with MN (P < 0.05). No changes in age or sex between groups or over time accounted for these results. We conclude that FSGS is now diagnosed twice as often as MN and is the most common idiopathic glomerular disease at our hospital. Reasons for this increase include the emergence of FSGS in both Hispanics and blacks, with a modest increase of FSGS in whites. The increase in FSGS in the three most common races in our community suggests that factors other than genetic, perhaps environmental, have a role in the pathogenesis of FSGS.

Emergence of gentamicin-resistant bacteremia in hemodialysis patients receiving gentamicin lock catheter prophylaxis.

BACKGROUND AND OBJECTIVES Antibiotic locks in catheter-dependent chronic hemodialysis patients reduce the rate of catheter-related blood stream infections (CRIs), but there are no data regarding the long-term consequences of this practice. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Over a 4-year period, from October 1, 2002, to September 30, 2006, we initiated a gentamicin and heparin lock (GHL) protocol in 1410 chronic hemodialysis patients receiving dialysis through a tunneled catheter in eight outpatient units. RESULTS Within the first year of the GHL protocol, our CRI rate decreased from 17 to 0.83 events per 1000 catheter-days. Beginning 6 months after initiation of the GHL protocol, febrile episodes occurred in 13 patients with coagulase-negative Staphylococcus bacteremia resistant to gentamicin. Over the 4 years of GHL use, an additional 10 patients developed 11 episodes of gentamicin-resistant CRI (including 7 with Enterococcus faecalis), in which there were 4 deaths, 2 cases of septic shock requiring intensive care unit admission, and 4 cases of endocarditis. Because of these events, the GHL protocol was discontinued at the end of 2006. CONCLUSIONS Although the use of GHL effectively lowered the CRI rate in our dialysis population, gentamicin-resistant CRIs emerged within 6 months. Gentamicin-resistant infections are a serious complication of the long-term use of GHLs. Alternative nonantibiotic catheter locks may be preferable to decrease the incidence of CRIs without inducing resistant pathogens.

Trough serum vancomycin levels predict the relapse of gram-positive peritonitis in peritoneal dialysis patients.

We reviewed 31 episodes of gram-positive peritonitis that occurred in our peritoneal dialysis population between 1990 and 1993 in an attempt to identify the risk factor(s) for peritonitis relapse. All patients were treated with 4 weekly doses of intravenous vancomycin. Vancomycin doses no. 1 and 2 were based on body weight (15 mg/kg with a 1-g minimum); vancomycin doses no. 3 and 4 were adjusted in an attempt to maintain the trough serum vancomycin level at greater than 12 mg/L. Nine peritonitis episodes complicated by a relapse were identified. Peritonitis episodes preceding a relapse were similar to relapse-free episodes with respect to patient age, diabetes, peritoneal dialysis modality, duration of peritoneal dialysis treatment, residual urea clearance, peritoneal fluid cell count, causative organism, and weekly vancomycin dose. However, cumulative 4-week mean trough vancomycin levels were consistently lower during peritonitis episodes preceding a relapse (7.8 +/- 0.6 mg/L during relapse-prone episodes v 13.7 +/- 0.9 mg/L during relapse-free episodes; P = 0.0004). Furthermore, relapses developed during nine of 14 peritonitis episodes demonstrating a 4-week mean trough vancomycin level less than 12 mg/L compared with zero of 17 episodes with a 4-week trough level greater than 12 mg/L (P < 0.05). The detection of a low initial 7-day trough vancomycin level also was a useful marker for subsequent peritonitis relapse. In 13 peritonitis episodes associated with an initial trough level less than 9 mg/L, nine were complicated by a relapse.(ABSTRACT TRUNCATED AT 250 WORDS)

The safety and efficacy of the StarClose Vascular Closure System: the ultrasound substudy of the CLIP study.

Background: The StarClose® Vascular Closure System (Abbott Vascular, Redwood City, CA) features a nitinol clip that is designed to achieve closure of the femoral arteriotomy access site. The CLIP Study was performed to assess the safety and efficacy of StarClose when compared with standard manual compression following 5–6 French diagnostic or interventional percutaneous procedures. A substudy of this trial was designed to assess the utility of duplex ultrasonography to assess patency of the femoral artery and to determine access site complications (pseudoaneurysm, arteriovenous fistula, hematoma, deep vein thrombosis) in a multicenter prospective trial. This is the report of the duplex ultrasound (DUS) substudy of the CLIP trial. Methods: A total of 17 U.S. sites enrolled 596 subjects with 483 subjects randomized at a 2:1 ratio to receive StarClose or manual compression of the arteriotomy after a percutaneous procedure. The study included roll‐in (n = 113), diagnostic (n = 208), and interventional (n = 275) arms with a primary safety endpoint of major vascular complications through 30 days and a primary efficacy endpoint of postprocedure time to hemostasis. A substudy of the CLIP interventional arm evaluated DUS images of the closure site at five study sites, targeting 100 subjects at day 30 following hemostasis. The DUS protocol was devised and implemented by an independent vascular ultrasound core laboratory with extensive experience in vascular device trials. DUS inguinal region from 6 cm proximal to 6 cm distal to the arteriotomy puncture was performed. A qualitative examination was performed to determine the presence of iatrogenic vascular injuries: hematoma, pseudoaneurysm (PSA), arteriovenous fistula (AVF), and arterial/venous thrombosis or stenosis using 2‐dimensional gray scale, color, and focused Doppler images. Results: DUS of 96 subjects randomized to StarClose (n = 71) and compression (n = 25) were performed and evaluated. There was no evidence of hematoma, PSA, or AVF observed in the StarClose group. No StarClose subjects in the substudy had a PSA or AVF. All patients in the substudy demonstrated patency of the access site artery and vein without thrombosis or stenosis. Finally, in the entire study cohort, no clinically‐driven DUS studies demonstrated iatrogenic vascular injury or vessel thrombosis in the StarClose treated patients. Conclusion: DUS, a safe and reliable method for determining the safety and efficacy of access site closure devices, is a reliable, safe, inexpensive and accurate method of assessing vascular access site complications in multicenter trials. In this substudy of the CLIP study, DUS found no statistical difference in access site complications between the StarClose and manual compression groups. Both groups maintained vessel patency without stenosis, thrombosis, hematoma, pseudoaneurysm, or AV fistula.

Adenine phosphoribosyltransferase deficiency and renal allograft dysfunction

Adenine phosphoribosyltransferase (APRT) deficiency is a rarely diagnosed cause of renal allograft dysfunction. We report the case of a 42-year-old man who presented in 1996 with idiopathic renal failure. Native kidney biopsy showed extensive microcrystalline interstitial nephritis. The patient subsequently underwent a living-related kidney transplant with excellent early graft function. During the next year, however, he had worsening allograft function, and allograft biopsy showed recurrent interstitial nephritis. Further chemical and spectroscopic analysis showed this lesion to be an annular microcrystalline nephritis consistent with APRT deficiency. This diagnosis was confirmed on erythrocyte assay. Treatment with allopurinol and a low-purine diet led to improvement and stabilization of renal function. APRT is a rare cause of renal allograft dysfunction requiring a high index of suspicion for early diagnosis and treatment. Increased physician awareness in the United States may hasten diagnosis and limit the morbidity associated with this disease.

Use of Aspirin Associates with Longer Primary Patency of Hemodialysis Grafts

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.

Decongestive Treatment of Acute Decompensated Heart Failure: Cardiorenal Implications of Ultrafiltration and Diuretics

In patients with acute decompensated heart failure (ADHF), treatment aimed at adequate decongestion of the volume overloaded state is essential. Despite diuretic therapy, many patients remain volume overloaded and symptomatic. In addition, adverse effects related to diuretic treatment are common, including worsening kidney function and electrolyte disturbances. The development of decreased kidney function during treatment affects the response to diuretic therapy and is associated with important clinical outcomes, including mortality. The occurrence of diuretic resistance and the morbidity and mortality associated with diuretic therapy has stimulated interest to develop effective and safe treatment strategies that maximize decongestion and minimize decreased kidney function. During the last few decades, extracorporeal ultrafiltration has been used to remove fluid from diuretic-refractory hypervolemic patients. Recent clinical studies using user-friendly machines have suggested that ultrafiltration may be highly effective for decongesting patients with ADHF. Many questions remain regarding the comparative impact of diuretics and ultrafiltration on important clinical outcomes and adverse effects, including decreased kidney function. This article serves as a summary of key clinical studies addressing these points. The overall goal is to assist practicing clinicians who are contemplating the use of ultrafiltration for a patient with ADHF.