James S. Kaufman

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.

Age Affects Outcomes in Chronic Kidney Disease

Chronic kidney disease (CKD) is common among the elderly. However, little is known about how the clinical implications of CKD vary with age. We examined the age-specific incidence of death, treated end-stage renal disease (ESRD), and change in estimated glomerular filtration rate (eGFR) among 209,622 US veterans with CKD stages 3 to 5 followed for a mean of 3.2 years. Patients aged 75 years or older at baseline comprised 47% of the overall cohort and accounted for 28% of the 9227 cases of ESRD that occurred during follow-up. Among patients of all ages, rates of both death and ESRD were inversely related to eGFR at baseline. However, among those with comparable levels of eGFR, older patients had higher rates of death and lower rates of ESRD than younger patients. Consequently, the level of eGFR below which the risk of ESRD exceeded the risk of death varied by age, ranging from 45 ml/min per 1.73 m(2) for 18 to 44 year old patients to 15 ml/min per 1.73 m(2) for 65 to 84 year old patients. Among those 85 years or older, the risk of death always exceeded the risk of ESRD in this cohort. Among patients with eGFR levels <45 ml/min per 1.73 m(2) at baseline, older patients were less likely than their younger counterparts to experience an annual decline in eGFR of >3 ml/min per 1.73 m(2). In conclusion, age is a major effect modifier among patients with an eGFR of <60 ml/min per 1.73 m(2), challenging us to move beyond a uniform stage-based approach to managing CKD.

FGF-23 Associates with Death, Cardiovascular Events, and Initiation of Chronic Dialysis

Concentrations of the phosphate-regulating hormone fibroblast growth factor-23 (FGF-23) are elevated in patients with chronic kidney disease (CKD), but whether higher plasma FGF-23 concentrations associate with all-cause mortality, cardiovascular events, or initiation of chronic dialysis is not completely understood. Here, we measured FGF-23 concentration in stored plasma samples from 1099 patients with advanced CKD who participated in The Homocysteine in Kidney and End Stage Renal Disease study. Mean serum phosphorus concentration was 4.3 mg/dl, median FGF-23 concentration was 392 RU/ml, and mean GFR was 18 ml/min/1.73 m(2). During a median follow-up of 2.9 yr, 453 (41%) patients died from any cause, 215 (20%) had a cardiovascular event, and 615 (56%) initiated chronic dialysis. Compared with the lowest quartile of FGF-23, each subsequent quartile associated with a progressively higher risk for death, adjusted for confounders (HR [95% CI] of 1.24 [0.91 to 1.69], 1.76 [1.28 to 2.44], and 2.17 [1.56 to 3.08] for the second through fourth quartiles, respectively). In addition, compared with the lowest quartile, the two highest quartiles of FGF-23 also associated with a significantly elevated risk for cardiovascular events and initiation of chronic dialysis. In conclusion, in advanced CKD, FGF-23 strongly and independently associates with all-cause mortality, cardiovascular events, and initiation of chronic dialysis.

Subcutaneous Compared with Intravenous Epoetin in Patients Receiving Hemodialysis

BACKGROUND Several studies have suggested that if recombinant human erythropoietin (epoetin) is administered subcutaneously rather than intravenously, a lower dose may be sufficient to maintain the hematocrit at a given level. METHODS In a randomized, unblinded trial conducted at 24 hemodialysis units at Veterans Affairs medical centers, we assigned 208 patients who were receiving long-term hemodialysis and epoetin therapy to treatment with either subcutaneous or intravenous epoetin. The dose was initially reduced until the hematocrit was below 30 percent and then was gradually increased to a level that would maintain the hematocrit in the range of 30 to 33 percent for 26 weeks. We compared the average doses in the 26-week maintenance phase and the discomfort associated with the two routes of administration. RESULTS For the 107 patients treated by the subcutaneous route, the average weekly dose of epoetin during the maintenance phase was 32 percent less than that for the 101 patients treated by the intravenous route (mean [+/-SD], 95.1+/-75.0 vs. 140.3+/-88.5 U per kilogram of body weight per week; P<0.001). Only one patient in the subcutaneous-therapy group withdrew from the study because of pain at the injection site, and 86 percent rated the pain associated with subcutaneous administration as ranging from absent to mild. CONCLUSIONS In patients receiving hemodialysis, subcutaneous administration of epoetin can maintain the hematocrit in a desired target range, with an average weekly dose of epoetin that is lower than with intravenous administration.

Community-acquired acute renal failure

Acute renal failure usually occurs during hospitalization, but may also be present on admission to the hospital. To define the causes and outcomes of community-acquired acute renal failure, we undertook a prospective study of patients admitted to the hospital with acute elevations in serum creatinine concentrations. Over a 17-month period, all admission serum creatinine determinations were screened for patients with values greater than 177 mumol/L (2 mg/dL). These values were compared with baseline creatinines to select patients with an acute elevation in serum creatinine occurring outside the hospital. One hundred patients were entered into the study, with an overall incidence of 1% of hospital admissions. Seventy percent of the patients had prerenal azotemia, 11% had intrinsic acute renal failure, 17% had obstruction, and 2% could not be classified. Mean peak serum creatinine (318 +/- 18 mumol/L [3.6 +/- 0.2 mg/dL]) and mortality (7%) was lowest in the group with prerenal azotemia. In this group, volume contraction due to vomiting, decreased fluid intake, diarrhea, fever, glucosuria, or diuretics was the most common underlying cause. The group with intrinsic acute renal failure had the most severe renal failure and the highest mortality (55%). Although ischemic acute tubular necrosis is the most common cause of hospital-acquired intrinsic acute renal failure, this etiology was seen in only one patient. Drug-induced nephrotoxicity and infection-related causes were the most common underlying etiologies of intrinsic acute renal failure. Obstructive renal failure had a mortality of 24% and was most commonly due to benign prostatic hypertrophy.(ABSTRACT TRUNCATED AT 250 WORDS)

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.)

Randomized Controlled Trial of Clopidogrel plus Aspirin to Prevent Hemodialysis Access Graft Thrombosis

Thrombosis of hemodialysis vascular access grafts represents a major medical and economic burden. Experimental and clinical models suggest a role for antiplatelet agents in the prevention of thrombosis. The study was designed to determine the efficacy of the combination of aspirin and clopidogrel in the prevention of graft thrombosis. The study was a randomized, double-blind trial conducted at 30 hemodialysis units at Veterans Affairs medical centers. Participants undergoing hemodialysis with a polytetrafluoroethylene graft in the arm were randomized to receive either double placebos or aspirin (325 mg) and clopidogrel (75 mg) daily. Participants were to be monitored while receiving study medications for a minimum of 2 yr. The study was stopped after randomization of 200 participants, as recommended by the Data Safety and Monitoring Board because of a significantly increased risk of bleeding among the participants receiving aspirin and clopidogrel therapy. The cumulative incidence of bleeding events was significantly greater for those participants, compared with participants receiving placebos [hazard ratio, 1.98; 95% confidence interval (CI), 1.19 to 3.28; P = 0.007]. Twenty-three participants in the placebo group and 44 participants in the active treatment group experienced a bleeding event (P = 0.006). There was no significant benefit of active treatment in the prevention of thrombosis (hazard ratio, 0.81; 95% CI, 0.47 to 1.40; P = 0.45), although there was a trend toward a benefit among participants who had not experienced previous graft thrombosis (hazard ratio, 0.52; 95% CI, 0.22 to 1.26; P = 0.14). In the hemodialysis population, therapy with aspirin and clopidogrel was associated with a significantly increased risk of bleeding and probably would not result in a reduced frequency of graft thrombosis.

Mortality patterns among adult Hispanics: findings from the NHIS, 1986 to 1990.

OBJECTIVES The purpose of this study was to assess the mortality pattern of the adult Hispanic population in the United States. METHODS This was a cohort study using data from the National Health Interview Survey from 1986 through 1990. Deaths were ascertained by matching the National Death Index through 1991. RESULTS This representative national sample included 297,640 non-Hispanic Whites, 53,552 Blacks, and 27,239 Hispanics, all aged 18 years or older at baseline. Different matching criteria resulted in modest differential estimates of the number of deaths by ethnic groups; these differences were quantitatively more important for Hispanics. Overall age-standardized mortality was lower among Hispanics. A prominent age by race interaction was apparent. The Hispanic: White mortality ratio was 1.33, 0.92, and 0.76 among men aged 18 through 44, 45 through 64, and 65 and older, respectively. Among women in the same age groups the Hispanic: White mortality ratio was 1.22, 0.75, and 0.70, respectively. CONCLUSIONS Longitudinal cohorts provide an important source of health status information on Hispanics. These results suggest that overall mortality is lower among Hispanics than among non-Hispanic Whites, especially in the oldest age group. Among younger and middle-aged persons, the mortality of Hispanics is similar to or even higher than that of Whites.

Chronic Kidney Disease Associated With Environmental Toxins and Exposures

People are exposed to various potentially toxic agents and conditions in their natural and occupational environments. These agents may be physical or chemical, may enter the human body through oral, inhalational, or transdermal routes, and may exert effects on all organ systems. Several well-known as well as lesser known associations exist between chronic kidney disease (CKD) and both environmental agents and conditions, such as heavy metals, industrial chemicals, elevated ambient temperatures, and infections. The effects of these agents may be modulated by genetic susceptibility and other comorbid conditions and may lead to the development of acute and CKD. In this article, we present environmental factors that are associated with CKD.

Current Guidelines for Using Angiotensin-Converting Enzyme Inhibitors and Angiotensin II–Receptor Antagonists in Chronic Kidney Disease: Is the Evidence Base Relevant to Older Adults?

Key Summary Points Almost one half of adults in the general population who meet criteria for chronic kidney disease are older than 70 years. Persons older than 70 years are underrepresented in most trials underpinning major U.S. practice guidelines for the use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin IIreceptor blockers (ARBs) in chronic kidney disease. More than 85% of persons older than 70 years who meet criteria for chronic kidney disease do not have proteinuria. The relevance of guideline trials to this group may be limited because most favored inclusion of participants with proteinuria. Differences between guidelines in criteria for the use of ACE inhibitors and ARBs in chronic kidney disease lead to considerable variation across guidelines in the proportion of older adults targeted. Practice guidelines specifically recommend the use of ACE inhibitors and ARBs in patients with chronic kidney disease because these agents are renoprotective. However, slowing progression of kidney disease may not be the most patient-centric goal of therapy in many older adults with this condition. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin IIreceptor blockers (ARBs) are widely recommended in clinical practice guidelines for patients with chronic kidney disease. Such recommendations are based on the results of randomized, controlled trials (RCTs) demonstrating that these agents slow progression of kidney disease. The unique renoprotective properties of ACE inhibitors and ARBs are generally attributed to their ability to reduce proteinuria (1, 2). Proteinuria is a major risk factor for end-stage renal disease (3, 4) and may play a direct pathogenic role in progression of chronic kidney disease (2). In RCTs, both ACE inhibitors and ARBs are more likely to slow progression of kidney disease in participants with greater degrees of proteinuria (57). In patients without diabetes excreting less than 500 mg/d of protein, ACE inhibitors may be no more renoprotective than other antihypertensive agents (7). Use of these agents in patients with chronic kidney disease mandates close monitoring for acute renal failure and hyperkalemia, may require dietary modification or long-term administration of an ion-exchange resin, and may limit the use of other medications that also increase serum potassium level (8). More than one third of adults in the general population age 70 years or older have chronic kidney disease (9). Whether evidence supporting current guidelines for the use of ACE inhibitors and ARBs in chronic kidney disease can be extrapolated to this large group is unknown. To address this question, we first examined the representation of older adults in RCTs used to formulate contemporary guidelines from the Kidney Disease Outcomes Quality Initiative (KDOQI); the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7); and the American Diabetes Association (Table 1) (8, 1012). We also examined the representation of older adults in relevant major trials whose results were published after guideline preparation. Second, we compared the characteristics of participants in guideline trials with those of a representative sample of older adults with chronic kidney disease from the general population enrolled in the National Health and Nutrition Examination Survey (NHANES) 19992006. Table 1. Summary of Guidelines Were Older Adults Well Represented in Trials Underpinning Major U.S. Practice Guidelines for the Use of ACE Inhibitors and ARBs in Chronic Kidney Disease? Two coauthors screened all articles referenced in the aforementioned guidelines (Table 1). When the primary article cited in the relevant guideline did not provide all prespecified data elements, we performed directed searches to identify additional publications from that study that might include this information. We restricted these searches to English-language articles published before or during the evidence review period for the most recent guideline in which the primary study was cited (Table 1). We performed these directed searches by using MEDLINE and by hand-searching the reference lists of primary articles. When we could not identify all data elements from published sources, we requested needed information from corresponding authors. For inclusion in our review, the study was required to be an RCT in which at least 1 group was treated with an ACE inhibitor or ARB and was compared with a control group not receiving either agent. Because the rationale for all of the guidelines reviewed here is that ACE inhibitors and ARBs slow progression of kidney disease, we also required that at least 1 of the following renal outcomes was reported in the article cited in the relevant guideline: change in urinary protein or albumin excretion, change in serum creatinine level, creatinine clearance, measured or estimated glomerular filtration rate (GFR or eGFR, respectively), requirement for dialysis, or onset of end-stage renal disease. Two coauthors separately abstracted relevant prespecified trial characteristics, participant characteristics, and entry criteria. The guidelines referenced 37 articles describing 32 RCTs (6, 1348). We excluded 2 trials because the referenced article did not include a renal outcome measure (45, 46) and 3 trials because they lacked a comparison with a control group not receiving an ACE inhibitor or ARB (44, 47, 48) (Table 1). We included the remaining 27 trials (total participants, 15794) (Appendix Table 1). Appendix Table 1. Baseline Participant Characteristics and Entry Criteria of Guideline Trials The mean age of trial participants ranged from 29 to 71 years. The maximum age of participants could not be ascertained in 2 trials. Among the remaining trials, 19 (76%) either excluded or did not include participants older than 70 years. No trial provided information on the number and characteristics of participants older than 70 years. Although most trials did not enroll older participants, the 5662 participants in ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) (30) with an eGFR less than 60 mL/min per 1.73 m2 had a mean age of 71 years, indicating that this trial enrolled a substantial number of persons older than 70 years. With the notable exception of ALLHAT, older adults were poorly represented in most guideline trials. What Were the Other Characteristics of Participants in Guideline Trials? Most trials (70%) enrolled only participants with diabetes. Six trials were limited to those with type 1 diabetes (n= 775), 12 trials were limited to those with type 2 diabetes (n= 6840), and 1 trial included participants with either type 1 or type 2 diabetes (n= 103). Two trials included participants both with and without diabetes (n= 6245). The remaining 6 trials were conducted among participants without diabetes (n= 1831). Hypertension was an entry requirement for most trials. Female participants ranged from 23% to 70% across trials. Urinary protein excretion of at least 30 mg/d or equivalent was an entry criterion for 79% of trials in persons with diabetes. Only 1 trial that included participants without diabetes explicitly required a minimum level of proteinuria. Nevertheless, mean urinary protein excretion at baseline exceeded 500 mg/d in most trials of nondiabetic chronic kidney disease. The only trial not to ascertain urinary protein level was ALLHAT, which included participants both with and without diabetes. In summary, most guideline trials were conducted among participants with diabetes and most favored inclusion of participants with proteinuria. Are Older Adults Well Represented in Recent Trials Comparing the Effect of ACE Inhibitors or ARBs With That of Other Agents on Progression of Chronic Kidney Disease? We conducted a MEDLINE search from 1 July 2002 through 31 December 2008 to identify the results of major trials published after the most recent review dates for the 2004 KDOQI guideline (for studies of nondiabetic kidney disease) and the 2007 KDOQI guideline (for studies of diabetic kidney disease). We limited our search to English-language publications, human studies, and RCTs. One coauthor reviewed all titles, and abstracts and manuscripts as needed, to identify eligible studies. We included only RCTs that compared the effect of ACE inhibitors or ARBs with a control group not receiving either agent, enrolled more than 200 participants, and included at least 1 renal outcome measure. We excluded trials in specialized populations (for example, patients receiving dialysis, kidney transplant recipients, and patients with heart failure). Two coauthors separately abstracted prespecified baseline participant characteristics and exclusion criteria for eligible trials. We identified 380 MEDLINE citations, obtained 68 articles for further review, and identified 6 eligible trials (Appendix Table 2) (4954). Only 1 trial did not enroll participants older than 70 years. Mean participant age ranged from 45 to 63 years across trials. All but 1 trial included participants without diabetes. Only 2 trials (49, 54) included a substantial number of participants without microalbuminuria or macroalbuminuria. Dagenais and colleagues (49) randomly assigned 5269 adults age 30 years or older with glucose intolerance and without clinical proteinuria to receive ramipril or placebo. The composite renal outcome (increase in proteinuria, decrease in eGFR 30%, or dialysis or transplantation) did not differ between groups over a 3-year follow-up. Vogt and colleagues (54) randomly assigned 614 adults to receive telmisartan, hydrochlorothiazide, or placebo. Most participants did not have diabetes, and only 25% had microalbuminuria or macroalbuminuria. Over a 6-week follow-up, urinary albumin excretion decreased to the greatest extent in the group receiving telmisartan. Change in creatinine clearance did not differ across groups. Our se