Risk factors for progression of chronic kidney disease in the EPPIC trials and the effect of AST-120.

BACKGROUND: Two randomized, double-blind, placebo-controlled trials (EPPIC-1 and EPPIC-2) investigated the efficacy and safety of AST-120, an oral spherical carbon adsorbent, in adults with chronic kidney disease (CKD). While the benefit of adding AST-120 to standard therapy was not supported by these trials, we performed a post hoc analysis to focus on CKD progression and to determine the risk factors for the primary endpoint in the EPPIC trial population. METHODS: In the EPPIC trials, patients were randomly assigned 1:1 to treatment with AST-120 or placebo. The primary endpoint was a composite of dialysis initiation, kidney transplantation, or doubling of serum creatinine. The EPPIC trial pooled population was evaluated with the same statistical methods used for analysis of the primary and secondary efficacy endpoints. The trials were registered on ClinicalTrials.gov (NCT00500682 [EPPIC-1] and NCT00501046 [EPPIC-2]). RESULTS: An analysis of the placebo population suggested baseline urinary protein to urinary creatinine ratio (UP/UCr) ≥1.0 and hematuria were independent risk factors for event occurrence and eGFR lowering. Analysis of the high risk patients revealed a difference in the primary endpoint occurrence between treatment groups, if angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers were administered (hazard ratio 0.74, 95% confidence interval 0.56-0.96). Also, the eGFR changes from baseline in the AST-120 group were smaller than that in the placebo group (P = 0.035). CONCLUSIONS: CKD progression may have an association with baseline UP/UCr and hematuria. Treatment with AST-120 may delay the time to the primary endpoint in patients with progressive CKD receiving standard therapy, thus warranting further investigation.

The effects of AST-120 on chronic kidney disease progression in the United States of America: a post hoc subgroup analysis of randomized controlled trials.

BACKGROUND: The orally administered spherical carbon adsorbent AST-120 is used on-label in Asian countries to slow renal disease progression in patients with progressive chronic kidney disease (CKD). Recently, two multinational, randomized, double-blind, placebo-controlled, phase 3 trials (Evaluating Prevention of Progression in Chronic Kidney Disease [EPPIC] trials) examined AST-120's efficacy in slowing CKD progression. This study assessed the efficacy of AST-120 in the subgroup of patients from the United States of America (USA) in the EPPIC trials. METHODS: In the EPPIC trials, 2035 patients with moderate to severe CKD were studied, of which 583 were from the USA. The patients were randomly assigned to two groups of equal size that were treated with AST-120 or placebo (9 g/day). The primary end point was a composite of dialysis initiation, kidney transplantation, or serum creatinine doubling. RESULTS: The Kaplan-Meier curve for the time to achieve the primary end point in the placebo-treated patients from the USA was similar to that projected before the study. The per protocol subgroup analysis of the population from the USA which included patients with compliance rates of ≥67 % revealed a significant difference between the treatment groups in the time to achieve the primary end point (Hazard Ratio, 0.74; 95 % Confidence Interval, 0.56-0.97). CONCLUSIONS: This post hoc subgroup analysis of EPPIC study data suggests that treatment with AST-120 might delay the time to primary end point in CKD patients from the USA. A further randomized controlled trial in progressive CKD patients in the USA is necessary to confirm the beneficial effect of adding AST-120 to standard therapy regimens. TRIAL REGISTRATION: ClinicalTrials.gov NCT00500682 ; NCT00501046 .

Ferric citrate controls phosphorus and delivers iron in patients on dialysis.

Patients on dialysis require phosphorus binders to prevent hyperphosphatemia and are iron deficient. We studied ferric citrate as a phosphorus binder and iron source. In this sequential, randomized trial, 441 subjects on dialysis were randomized to ferric citrate or active control in a 52-week active control period followed by a 4-week placebo control period, in which subjects on ferric citrate who completed the active control period were rerandomized to ferric citrate or placebo. The primary analysis compared the mean change in phosphorus between ferric citrate and placebo during the placebo control period. A sequential gatekeeping strategy controlled study-wise type 1 error for serum ferritin, transferrin saturation, and intravenous iron and erythropoietin-stimulating agent usage as prespecified secondary outcomes in the active control period. Ferric citrate controlled phosphorus compared with placebo, with a mean treatment difference of -2.2±0.2 mg/dl (mean±SEM) (P<0.001). Active control period phosphorus was similar between ferric citrate and active control, with comparable safety profiles. Subjects on ferric citrate achieved higher mean iron parameters (ferritin=899±488 ng/ml [mean±SD]; transferrin saturation=39%±17%) versus subjects on active control (ferritin=628±367 ng/ml [mean±SD]; transferrin saturation=30%±12%; P<0.001 for both). Subjects on ferric citrate received less intravenous elemental iron (median=12.95 mg/wk ferric citrate; 26.88 mg/wk active control; P<0.001) and less erythropoietin-stimulating agent (median epoetin-equivalent units per week: 5306 units/wk ferric citrate; 6951 units/wk active control; P=0.04). Hemoglobin levels were statistically higher on ferric citrate. Thus, ferric citrate is an efficacious and safe phosphate binder that increases iron stores and reduces intravenous iron and erythropoietin-stimulating agent use while maintaining hemoglobin.

Randomized Placebo-Controlled EPPIC Trials of AST-120 in CKD.

Reduced GFR in patients with CKD causes systemic accumulation of uremic toxins, which has been correlated with disease progression and increased morbidity. The orally administered spherical carbon adsorbent AST-120 reduces systemic toxin absorption through gastrointestinal sequestration, which may slow disease progression in these patients. The multinational, randomized, double-blind, placebo-controlled Evaluating Prevention of Progression in CKD (EPPIC)-1 and EPPIC-2 trials evaluated the effects of AST-120 on the progression of CKD when added to standard therapy. We randomly assigned 2035 adults with moderate to severe disease (serum creatinine at screening, 2.0-5.0 mg/dl for men and 1.5-5.0 mg/dl for women) to receive either placebo or AST-120 (9 g/d). The primary end point was a composite of dialysis initiation, kidney transplantation, and serum creatinine doubling. Each trial continued until accrual of 291 primary end points. The time to primary end point was similar between the AST-120 and the placebo groups in both trials (EPPIC-1: hazard ratio, 1.03; 95% confidence interval, 0.84 to 1.27; P=0.78) (EPPIC-2: hazard ratio, 0.91; 95% confidence interval, 0.74 to 1.12; P=0.37); a pooled analysis of both trials showed similar results. The estimated median time to primary end points for the placebo groups was 124 weeks for power calculations, but actual times were 189.0 and 170.3 weeks for EPPIC-1 and EPPIC-2, respectively. Thus, disease progression was more gradual than expected in the trial populations. In conclusion, the benefit of adding AST-120 to standard therapy in patients with moderate to severe CKD is not supported by these data.

AST-120 for the management of progression of chronic kidney disease.

Uremic toxins such as indoxyl sulfate contribute to the pathogenesis of chronic kidney disease (CKD) by promoting glomerulosclerosis and interstitial fibrosis with loss of nephrons and vascular damage. AST-120, an orally administered intestinal sorbent, adsorbs indole, a precursor of indoxyl sulfate, thereby reducing serum and urinary concentrations of indoxyl sulfate. AST-120 has been available in Japan since 1991, and subsequently Korea (2005), and the Philippines (2010) as an agent to prolong the time to initiation of hemodialysis and for improvement of uremic symptoms in patients with CKD. A Medline search was performed to identify data supporting clinical experience with AST-120 for managing CKD. Prospective open-label and double-blind trials as well as retrospective analyses were included. In prospective trials and retrospective analyses, AST-120 has been shown to prolong the time to initiation of hemodialysis, and slow decline in glomerular filtration rate and the increase serum creatinine. In an initial randomized, double-blind, placebo-controlled trial in the United States, AST-120 was associated with a significant dose-dependent reduction in serum indoxyl sulfate levels and a decrease in uremia-related malaise. The Evaluating Prevention of Progression in CKD (EPPIC) trials, two double-blind, placebo-controlled trials undertaken in North America/Latin America and Europe, are evaluating the efficacy of AST-120 for preventing the progression of CKD. The results of the EPPIC trials will further define the role of AST-120 in this debilitating condition.

Dose-response and efficacy of ferric citrate to treat hyperphosphatemia in hemodialysis patients: a short-term randomized trial.

BACKGROUND: Most dialysis patients require phosphate binders to control hyperphosphatemia. Ferric citrate has been tested in phase 2 trials as a phosphate binder. This trial was designed as a dose-response and efficacy trial. STUDY DESIGN: Prospective, phase 3, multicenter, open-label, randomized clinical trial. SETTING & PARTICIPANTS: 151 participants with hyperphosphatemia on maintenance hemodialysis therapy. INTERVENTION: Fixed dose of ferric citrate taken orally as a phosphate binder for up to 28 days (1, 6, or 8 g/d in 51, 52, and 48 participants, respectively). OUTCOMES: Primary outcome is dose-response of ferric citrate on serum phosphorus level; secondary outcomes are safety and tolerability. MEASUREMENTS: Serum chemistry tests including phosphorus, safety data. RESULTS: 151 participants received at least one dose of ferric citrate. Mean baseline phosphorus levels were 7.3 ± 1.7 (SD) mg/dL in the 1-g/d group, 7.6 ± 1.7 mg/dL in the 6-g/d group, and 7.5 ± 1.6 mg/dL in the 8-g/d group. Phosphorus levels decreased in a dose-dependent manner (mean change at end of treatment, -0.1 ± 1.3 mg/dL in the 1-g/d group, -1.9 ± 1.7 mg/dL in the 6-g/d group, and -2.1 ± 2.0 mg/dL in the 8-g/d group). The mean difference in reduction in phosphorus levels between the 6- and 1-g/d groups was 1.3 mg/dL (95% CI, 0.69 to 1.9; P < 0.001), between the 8- and 1-g/d groups was 1.5 mg/dL (95% CI, 0.86 to 2.1; P < 0.001), and between the 8- and 6-g/d groups was 0.21 mg/dL (95% CI, -0.39 to 0.81; P = 0.5). The most common adverse event was stool discoloration. LIMITATIONS: Sample size and duration confirm efficacy, but limit our ability to confirm safety. CONCLUSIONS: Ferric citrate is efficacious as a phosphate binder in a dose-dependent manner. A phase 3 trial is ongoing to confirm safety and efficacy.

In-center thrombolysis for clotted AV access: a cohort review.

Thrombosis is the leading cause of arteriovenous (AV) access failure for hemodialysis patients requiring frequent interventions. We describe a novel approach to the lyse-and-wait technique in thrombosed AV access using nurse-administered thrombolytics in a hospital-based hemodialysis unit. All patients at a single-center, large, urban, tertiary care hospital, who underwent in-center thrombolysis via alteplase instilled directly into a thrombosed AV access by inpatient hemodialysis unit staff between January 1, 2003 and December 31, 2007, were eligible. Included subjects were at least 18 years old and did not have known or suspected infection or trauma to the AV access site. Primary outcome measure was successful thrombolysis defined as hemodialysis performed immediately or after the interventional radiology (IR) procedure. Adverse events related to the procedure were collected. A total of 321 procedures, performed on 145 subjects (77 (53%) male, 68 (47%) female) remained for analysis. Successful instillation occurred in 317 of 321 procedures (98.8%). Successful thrombolysis occurred in 237 of 321 procedures (73.8%). Adverse events (8 major and 10 minor) occurred in 18 procedures, yielding a complication rate of 5.6%. In-center thrombolysis with alteplase administration by hemodialysis unit nursing staff under physician supervision is safe and effective with an adverse outcome rate similar to the literature. Thus, this modified lyse-and-wait protocol can be adopted with appropriate IR and surgical backup in place.

Rationale and study design of a three-period, 58-week trial of ferric citrate as a phosphate binder in patients with ESRD on dialysis.

Chronic kidney disease associated mineral and bone disorders arise as a result of aberrant bone mineral metabolism in patients with advancing levels of renal dysfunction and end-stage renal disease. One of the cornerstones of treatment is the use of phosphate-binding agents. We describe the rationale and study design for a clinical trial to assess the safety and efficacy of ferric citrate as a phosphate binder. This trial is a three-period, international, multicenter, randomized, controlled clinical trial to assess the safety and efficacy of ferric citrate as a phosphate binder, consisting of a 2-week washout period, a 52-week safety assessment period in which subjects are randomized to ferric citrate or active control, and a 4-week efficacy assessment period in which subjects randomized to ferric citrate in the safety assessment period are randomized to ferric citrate or placebo. Eligible subjects include end-stage renal disease patients who have been treated with thrice-weekly hemodialysis or peritoneal dialysis for at least 3 months in dialysis clinics in the United States and Israel. Primary outcome measure will be the effect of ferric citrate vs. placebo on the change in serum phosphorus. Safety assessments will be performed by monitoring adverse events, concomitant medication use, and sequential blood chemistries (including iron parameters, phosphorus, and calcium). This three-period trial will assess the efficacy of ferric citrate as a phosphate binder. If proven safe and efficacious, ferric citrate will likely provide an additional phosphate binder to treat chronic kidney disease associated mineral and bone disorders.

Effects of frequent hemodialysis on measures of CKD mineral and bone disorder.

More frequent hemodialysis sessions and longer session lengths may offer improved phosphorus control. We analyzed data from the Frequent Hemodialysis Network Daily and Nocturnal Trials to examine the effects of treatment assignment on predialysis serum phosphorus and on prescribed dose of phosphorus binder, expressed relative to calcium carbonate on a weight basis. In the Daily Trial, with prescribed session lengths of 1.5-2.75 hours six times per week, assignment to frequent hemodialysis associated with both a 0.46 mg/dl decrease (95% confidence interval [95% CI], 0.13-0.78 mg/dl) in mean serum phosphorus and a 1.35 g/d reduction (95% CI, 0.20-2.50 g/d) in equivalent phosphorus binder dose at month 12 compared with assignment to conventional hemodialysis. In the Nocturnal Trial, with prescribed session lengths of 6-8 hours six times per week, assignment to frequent hemodialysis associated with a 1.24 mg/dl decrease (95% CI, 0.68-1.79 mg/dl) in mean serum phosphorus compared with assignment to conventional hemodialysis. Among patients assigned to the group receiving six sessions per week, 73% did not require phosphorus binders at month 12 compared with only 8% of patients assigned to sessions three times per week (P<0.001). At month 12, 42% of patients on nocturnal hemodialysis required the addition of phosphorus into the dialysate to prevent hypophosphatemia. Frequent hemodialysis did not have major effects on calcium or parathyroid hormone concentrations in either trial. In conclusion, frequent hemodialysis facilitates control of hyperphosphatemia and extended session lengths could allow more liberal diets and freedom from phosphorus binders.

Novel dialysis modalities: do we need new metrics to optimize treatment?

Delivered dose of hemodialysis has long been an important predictor of mortality. The limitations of conventional hemodialysis treatments have led to a renewed interest in more frequent and longer hemodialysis treatments. As alternative hemodialysis schedules have become more prevalent, a need for modified metrics to measure adequacy has emerged. In addition, there is an interest in finding measures of hemodialysis adequacy that are more reliable in certain subgroups of patients, such as women, ethnic minority groups, or people with small body size. Finally, extended hemodialysis schedules suggest a need for metrics that can measure the clearance of solutes other than urea, such as middle-size molecules, and solutes for which clearance depends on intercompartmental transport across membranes. New metrics to quantify clearance in extended and alternate hemodialysis schedules are needed. As new metrics are developed, it is anticipated that they will also contribute to more accurate assessments of associations between clinical outcomes and delivered dose of dialysis in more intensive, nontraditional hemodialysis schedules. This review provides a historical prospective of dialysis dose and adequacy and describes the need for new metrics from both solute type and dialysis dose prospective as alternative hemodialysis schedules have emerged and become more prevalent.

Imatinib therapy for non-infection-related type II cryoglobulinemia with membranoproliferative glomerulonephritis.

Cryoglobulinemia is a systemic immune complex-mediated vasculitis that can have significant morbidity and mortality. The current treatment for cryoglobulinemia, including chlorambucil, steroids, plasmapheresis, and rituximab, is lacking in terms of efficacy, safety, and relapse rates. Imatinib, a tyrosine kinase inhibitor, has been shown to ameliorate the phenotype and kidney injury in a thymic stromal lymphopoietin transgenic mouse model of cryoglobulinemia. We present a case of type II cryoglobulinemia with severe kidney involvement treated with 400 mg of imatinib administered orally daily, plasmapheresis, and steroids, initially with resolution of symptoms, normalization of creatinine level, and marked improvement in proteinuria and cryocrit. Furthermore, on withdrawal of imatinib therapy, proteinuria, creatinine level, and cryocrit worsened until reinstitution of therapy. After treatment resumption, creatinine level, cryocrit, proteinuria, and symptoms dramatically improved and have remained stable for more than 22 months.

A nexus of progression of chronic kidney disease: tryptophan, profibrotic cytokines, and charcoal.

Fibrosis plays a major role in the pathogenesis of progressive chronic kidney disease (CKD). The inhibition of the renin-angiotensin system, which promotes fibrosis, has become the standard of care in the treatment of patients with CKD. The use of alternative agents capable of blocking the actions of profibrotic cytokines such as transforming growth factor-beta (TGF-ß) is also an important strategy that is in its early stages of development. An example of such a drug is AST-120, a charcoal compound that ultimately inhibits the synthesis of TGF-ß in the kidney. The inhibition is mediated by blocking the intestinal absorption of tryptophan-derived indole by AST-120. This reduces the hepatic conversion of indole to indoxyl sulfate (IS). IS stimulates the production of TGF-ß in the renal parenchyma, and lowering the level of IS with AST-120 appears to slow progression of CKD. The status of recent trials examining the safety and efficacy of AST-120 has been described, including a multicenter, randomized, placebo-controlled, phase III trial of approximately 2,000 subjects being conducted to gain approval of this drug by the U.S. Food and Drug Administration.

Baseline physical performance, health, and functioning of participants in the Frequent Hemodialysis Network (FHN) trial.

BACKGROUND: Self-reported physical health and functioning and direct measures of physical performance are decreased in hemodialysis patients and are associated with mortality and hospitalization. STUDY DESIGN: We determined baseline cross-sectional associations of physical performance, health, and functioning with demographics, clinical characteristics, nutritional indexes, laboratory benchmarks, and measures of body composition in participants in the Frequent Hemodialysis Network (FHN) trial. SETTING & PARTICIPANTS: 375 persons enrolled in the FHN with data for physical performance, health, and functioning. PREDICTORS: Explanatory variables were categorized into fixed factors of age, race, comorbid conditions (diabetes mellitus, heart failure, and peripheral arterial disease) and potentially modifiable factors of dialysis dose, phosphorus level, hemoglobin level, equilibrated normalized protein catabolic rate (enPCR), body composition, body mass index, phase angle, and ratio of intracellular water volume to body weight (calculated from bioelectrical impedance). OUTCOMES: Scores on tests of physical performance, health, and functioning. MEASUREMENTS: Physical performance measured using the Short Physical Performance Battery, self-reported physical health and functioning using the 36-Item Short Form Health Survey (SF-36). Body composition (body mass index and bioimpedance analysis) and laboratory data were obtained from affiliated dialysis providers. RESULTS: Relative to population norms, scores for all 3 physicality metrics were low. Poorer scores on all 3 metrics were associated with diabetes mellitus and peripheral arterial disease. Poorer scores on the SF-36 Physical Functioning subscale and Short Physical Performance Battery also were associated with age, lower ratio of intracellular water volume to body weight, and lower enPCR. Black race was associated with poorer scores on the Short Physical Performance Battery. LIMITATIONS: This was a cross-sectional study of individuals agreeing to participate in the FHN study and may not be generalizable to the general dialysis population. CONCLUSIONS: Hemodialysis patients show markedly impaired physical performance, health, and functioning relative to population norms. Although some factors associated with these impairments are not modifiable, others may change with improvement in nutritional status or body composition.

In-center hemodialysis six times per week versus three times per week.

BACKGROUND: In this randomized clinical trial, we aimed to determine whether increasing the frequency of in-center hemodialysis would result in beneficial changes in left ventricular mass, self-reported physical health, and other intermediate outcomes among patients undergoing maintenance hemodialysis. METHODS: Patients were randomly assigned to undergo hemodialysis six times per week (frequent hemodialysis, 125 patients) or three times per week (conventional hemodialysis, 120 patients) for 12 months. The two coprimary composite outcomes were death or change (from baseline to 12 months) in left ventricular mass, as assessed by cardiac magnetic resonance imaging, and death or change in the physical-health composite score of the RAND 36-item health survey. Secondary outcomes included cognitive performance; self-reported depression; laboratory markers of nutrition, mineral metabolism, and anemia; blood pressure; and rates of hospitalization and of interventions related to vascular access. RESULTS: Patients in the frequent-hemodialysis group averaged 5.2 sessions per week; the weekly standard Kt/V(urea) (the product of the urea clearance and the duration of the dialysis session normalized to the volume of distribution of urea) was significantly higher in the frequent-hemodialysis group than in the conventional-hemodialysis group (3.54±0.56 vs. 2.49±0.27). Frequent hemodialysis was associated with significant benefits with respect to both coprimary composite outcomes (hazard ratio for death or increase in left ventricular mass, 0.61; 95% confidence interval [CI], 0.46 to 0.82; hazard ratio for death or a decrease in the physical-health composite score, 0.70; 95% CI, 0.53 to 0.92). Patients randomly assigned to frequent hemodialysis were more likely to undergo interventions related to vascular access than were patients assigned to conventional hemodialysis (hazard ratio, 1.71; 95% CI, 1.08 to 2.73). Frequent hemodialysis was associated with improved control of hypertension and hyperphosphatemia. There were no significant effects of frequent hemodialysis on cognitive performance, self-reported depression, serum albumin concentration, or use of erythropoiesis-stimulating agents. CONCLUSIONS: Frequent hemodialysis, as compared with conventional hemodialysis, was associated with favorable results with respect to the composite outcomes of death or change in left ventricular mass and death or change in a physical-health composite score but prompted more frequent interventions related to vascular access. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov number, NCT00264758.).

Determinants of cardiac autonomic dysfunction in ESRD.

BACKGROUND AND OBJECTIVES: Cardiovascular events are common in patients with ESRD. Whether sympathetic overactivity or vagal withdrawal contribute to cardiovascular events is unclear. We determined the general prevalence and clinical correlates of heart rate variability in patients on hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We collected baseline information on demographics, clinical conditions, laboratory values, medications, physical performance, left ventricular mass (LVM), and 24-hour Holter monitoring on 239 subjects enrolled in the Frequent Hemodialysis Network Daily Trial. RESULTS: The mean R-R interval was 812 ± 217 ms. The SD of R-R intervals was 79.1 ± 40.3 ms. Spectral power analyses showed low-frequency (sympathetic modulation of heart rate) and high-frequency power (HF; vagal modulation of heart rate) to be 106.0 (interquartile range, 48.0 to 204 ms(2)) and 42.4 ms(2) (interquartile range, 29.4 to 56.3 ms(2)), respectively. LVM was inversely correlated with log HF (-0.02 [-0.0035; -0.0043]) and the R-R interval (-1.00 [-1.96; -0.032]). Physical performance was associated with mean R-R intervals (1.98 [0.09; 3.87]) and SD of R-R intervals (0.58 [0.049; 1.10]). After adjustment for age, race, ESRD vintage, diabetes, and physical performance, the relationship between log HF and LVM (per 10 g) remained significant (-0.025 [-0.042; -0.0085]). CONCLUSIONS: Holter findings in patients on hemodialysis are characterized by sympathetic overactivity and vagal withdrawal and are associated with higher LVM and impaired physical performance. Understanding the spectrum of autonomic heart rate modulation and its determinants could help to guide preventive and therapeutic strategies.

Long-term effects of renin-angiotensin system-blocking therapy and a low blood pressure goal on progression of hypertensive chronic kidney disease in African Americans.

BACKGROUND: Antihypertensive drugs that block the renin-angiotensin system (angiotensin-converting enzyme inhibitors [ACEIs] or angiotensin receptor blockers) are recommended for patients with chronic kidney disease (CKD). A low blood pressure (BP) goal (BP, <130/80 mm Hg) is also recommended. The objective of this study was to determine the long-term effects of currently recommended BP therapy in 1094 African Americans with hypertensive CKD. METHODS: Multicenter cohort study following a randomized trial. Participants were 1094 African Americans with hypertensive renal disease (glomerular filtration rate, 20-65 mL/min/1.73 m2). Following a 3x2-factorial trial (1995-2001) that tested 3 drugs used as initial antihypertensive therapy (ACEIs, calcium channel blockers, and beta-blockers) and 2 levels of BP control (usual and low), we conducted a cohort study (2002-2007) in which participants were treated with ACEIs to a BP lower than 130/80 mm Hg. The outcome measures were a composite of doubling of the serum creatinine level, end-stage renal disease, or death. RESULTS: During each year of the cohort study, the annual use of an ACEI or an angiotensin receptor blocker ranged from 83.7% to 89.0% (vs 38.5% to 49.8% during the trial). The mean BP in the cohort study was 133/78 mm Hg (vs 136/82 mm Hg in the trial). Overall, 567 participants experienced the primary outcome; the 10-year cumulative incidence rate was 53.9%. Of 576 participants with at least 7 years of follow-up, 33.5% experienced a slow decline in kidney function (mean annual decline in the estimated glomerular filtration rate, <1 mL/min/1.73 m2). CONCLUSION: Despite the benefits of renin-angiotensin system-blocking therapy on CKD progression, most African Americans with hypertensive CKD who are treated with currently recommended BP therapy continue to progress during the long term.

Safety and efficacy of regional citrate anticoagulation during 8-hour sustained low-efficiency dialysis.

BACKGROUND AND OBJECTIVES: Patients who may benefit from sustained low-efficiency dialysis therapy are often at risk for bleeding. A safe and simple "regional" anticoagulation strategy would be beneficial. The modification of existing regional citrate anticoagulation protocols to typically performed 8-h sustained low-efficiency dialysis is necessary. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Sustained low-efficiency dialysis was performed at blood and dialysate rates of 250 and 300 ml/min, respectively. The circuit was anticoagulated with 4% sodium citrate (citrate 136, sodium 408 mmol/L) and reversed with CaCl(2). Every 2 h, electrolytes, ionized circuit, and patient calcium were monitored during the first two versions. The second version differed by an increased infusion of CaCl(2) and lower infusion of citrate, both by 10%. The third version measured only laboratory values before and after sustained low-efficiency dialysis. RESULTS: There were 41 treatments in the first iteration, 42 in the second, and 34 in the final iteration. All versions were titrated to maintain patient ionized calcium of 4.0 to 4.8 mg/dl (1.0 to 1.2 mmol/L) and the circuit ionized calcium between 0.8 and 1.6 mg/dl (0.2 and 0.4 mmol/L). The final protocol infusion was 31 mmol/h citrate and 41 mmol/h elemental calcium, which kept circuit and patient ionized calcium at targets. No unexpected metabolic complications occurred. CONCLUSIONS: Compared with continuous renal replacement therapy, one must increase the calcium infusion because of the more efficient removal of the calcium citrate complex. Safe and effective regional citrate anticoagulation can be performed in 8-h sustained low-efficiency dialysis without metabolic complications with laboratory surveillance only before and after sustained low-efficiency dialysis treatment; however, certain safeguards are mandatory.

Association between serum 2-microglobulin level and infectious mortality in hemodialysis patients.

BACKGROUND AND OBJECTIVES: Secondary analysis of the Hemodialysis Study showed that serum beta(2)-microglobulin levels predicted all-cause mortality and that high-flux dialysis was associated with decreased cardiac deaths in hemodialysis patients. This study examined the association of serum beta(2)-microglobulin levels and dialyzer beta(2)-microglobulin kinetics with the two most common causes of deaths: Cardiac and infectious diseases. Cox regression analyses were performed to relate cardiac or infectious deaths to cumulative mean follow-up predialysis serum beta(2)-microglobulin levels while controlling for baseline demographics, comorbidity, residual kidney function, and dialysis-related variables. RESULTS: The cohort of 1813 patients experienced 180 infectious deaths and 315 cardiac deaths. The adjusted hazard ratio for infectious death was 1.21 (95% confidence interval 1.07 to 1.37) per 10-mg/L increase in beta(2)-microglobulin. This association was independent of the prestudy years on dialysis. In contrast, the association between serum beta(2)-microglobulin level and cardiac death was not statistically significant. In similar regression models, higher cumulative mean Kt/V of beta(2)-microglobulin was not significantly associated with either infectious or cardiac mortality in the full cohort but exhibited trends suggesting an association with lower infectious mortality (relative risk 0.93; 95% confidence interval 0.86 to 1.01, for each 0.1-U increase in beta(2)-microglobulin Kt/V) and lower cardiac mortality (relative risk 0.93; 95% confidence interval 0.87 to 1.00) in the subgroup with >3.7 prestudy years of dialysis. CONCLUSIONS: These results generally support the notion that middle molecules are associated with systemic toxicity and that their accumulation predisposes dialysis patients to infectious deaths, independent of the duration of maintenance dialysis.

A randomized trial of a 6-week course of celecoxib on proteinuria in diabetic kidney disease.

BACKGROUND: Preclinical data suggest that cyclooxygenase 2 inhibitors decrease proteinuria and preserve glomerular structure in animal models of diabetic nephropathy. The objective of this study is to compare the efficacy and safety of celecoxib with placebo for decreasing proteinuria in patients with diabetic nephropathy. STUDY DESIGN: Placebo-controlled double-blinded crossover design. SETTING & PARTICIPANTS: 24 patients with type 1 or 2 diabetes mellitus, proteinuria with protein of 500 mg/d or greater, and serum creatinine level of 3.0 mg/dL or less. INTERVENTION: Patients were randomly assigned to: (1) 6 weeks of celecoxib followed by a 3-week washout period, followed by 6 weeks of placebo followed by another 3-week washout; or (2) 6 weeks of placebo followed by a 3-week washout, followed by 6 weeks of celecoxib followed by another 3-week washout period. All patients were administered quinapril, 20 to 40 mg/d, or irbesartan, 150 to 300 mg/d. All patients were administered aspirin, 81 mg/d. OUTCOMES & MEASUREMENTS: Proteinuria was assessed by means of protein-creatinine ratio. Data were analyzed using the mixed-effect statistical model. RESULTS: There was no significant difference in urinary proteinuria after 6 weeks of treatment with placebo or celecoxib (proteinuria ratio, celecoxib versus placebo, 1.041; 95% confidence interval, 0.846 to 1.282). Celecoxib had no significant effect on potassium or estimated glomerular filtration rate. Frequencies of adverse events were similar between the placebo and celecoxib treatments. LIMITATIONS: This pilot study was not designed to evaluate the safety or long-term clinical effects of celecoxib. CONCLUSIONS: Celecoxib, 200 mg/d, for 6 weeks did not alter proteinuria. Few adverse events were noted in this high-risk population.