Outcomes in patients with chronic kidney disease not on dialysis receiving extended dosing regimens of darbepoetin alfa: long-term results of the EXTEND observational cohort study.

BACKGROUND: Extended dosing of the erythropoiesis-stimulating agent (ESA) darbepoetin alfa (DA) once biweekly or monthly reduces anaemia treatment burden. This observational study assessed outcomes and dosing patterns in patients with chronic kidney disease not on dialysis (CKD-NoD) commencing extended dosing of DA. METHODS: Adult CKD-NoD patients starting extended dosing of DA in Europe or Australia in June 2006 or later were followed up until December 2012. Outcomes included haemoglobin (Hb) concentration, ESA dosing, mortality rates and receipt of dialysis and renal transplantation. Subgroup analyses were conducted for selected outcomes. RESULTS: Of 6035 enrolled subjects, 5723 (94.8%) met analysis criteria; 1795 (29.7%) received dialysis and 238 (3.9%) underwent renal transplantation. Mean (standard deviation) Hb concentration at commencement of extended dosing was 11.0 (1.5) g/dL. Mean [95% confidence interval (CI)] Hb 12 months after commencement of extended dosing (primary outcome) was 11.6 g/dL (11.5, 11.6) overall and was similar across countries, with no differences between subjects previously treated with an ESA versus ESA-naïve subjects, subjects with versus without prior renal transplant or diabetics versus non-diabetics. Weekly ESA dose gradually decreased following commencement of extended DA dosing and was similar across subgroups. The decrease in weekly DA dose was accompanied by an increase in the proportion of patients receiving iron therapy. Hb concentrations declined following changes in ESA labels and treatment guidelines. The mortality rate (95% CI) was 7.06 (6.68, 7.46) deaths per 100 years of follow-up. Subjects alive at study end had stable Hb concentrations in the preceding year, while those who died had lower and declining Hb concentrations in their last year. CONCLUSIONS: Long-term, extended dosing of DA maintained Hb concentrations in patients already treated with an ESA and corrected and maintained Hb in ESA-naïve patients.

High-sensitivity troponin as a predictor of cardiac events and mortality in the stable dialysis population.

BACKGROUND: High-sensitivity cardiac troponin T (hs-cTnT) is a biomarker used in diagnosing myocardial injury. The clinical utility and the variation of this biomarker over time remain unclear in hemodialysis (HD) and peritoneal dialysis (PD) patients. We sought to determine whether hs-cTnT concentrations were predictive of myocardial infarction (MI) and death and to examine hs-cTnT variability over a 1-year period. METHODS: A total of 393 nonacute HD and PD patients (70% HD and 30% PD) were followed in a prospective observational study for new MI and death. RESULTS: Median hs-cTnT was 57 ng/L (interquartile range, 36-101 ng/L) with no observed difference between HD and PD patients (P = 0.11). Incremental increases in mortality (P = 0.024) and MI (P = 0.001) were observed with increasing hs-cTnT quartiles. MI incidence increased significantly across quartiles in both HD and PD patients (P = 0.012 and P = 0.025, respectively), whereas mortality increased only in HD patients (P = 0.015). For every increase of 25 ng/L in hs-cTnT, the unadjusted hazard ratio (HR) was 1.10 for mortality in the whole group (95% CI, 1.04-1.16, P = 0.001) and 1.16 for MI (95% CI, 1.08-1.23, P < 0.001). Adjusted HR for mortality was 1.07 (95% CI, 1.01-1.15, P = 0.04) and 1.14 for MI (95% CI, 1.06-1.22, P < 0.001). Changes in hs-cTnT from baseline concentrations after 1 year were minimal (55 ng/L vs 53 ng/L, P = 0.22) even in patients who had an MI (P = 0.53). CONCLUSIONS: hs-cTnT appears to have a useful role in predicting MI and death in the dialysis population. Over a 1-year period concentrations remained stable even in patients who sustained a new cardiac event.

Is bigger better? A retrospective analysis of native renal biopsies with 16 Gauge versus 18 Gauge automatic needles.

AIM: Percutaneous renal biopsy (PRB) remains the gold standard for the diagnosis of renal disease; however, the tissue yield which relates to the optimal needle size used for native-kidney biopsies has not been clearly established. Our study compares the sample adequacy and complication rates using 16 gauge (G) and 18 gauge (G) automatic needles on native kidney PRB. METHODS: A retrospective analysis was performed of native-kidney biopsies at two centres, one exclusively using 16G and the other exclusively using 18G needles. All samples were assessed by a single centralized pathology service. We compared patient characteristics, indications, diagnoses, adequacy of tissue samples, and complications. RESULTS: A total of 934 native-kidney biopsies were performed with real time ultrasound guidance: 753 with Bard Max Core 16G × 16 cm needles, and 181 with Bard Magnum 18G × 20 cm needles. The median (range) of total glomeruli count per biopsy was higher in the 16G group compared with the 18G group (19 (0-66) vs. 12 (0-35), P < 0.001), despite having fewer cores per biopsy (2 (0-4) vs. 3 (1-4), P < 0.001). The 16G group provided a greater proportion of adequate biopsy samples (94.7% vs. 89.4%, P = 0.001). There was no significant difference in the frequency of total complications between the 16G and 18G groups (3.7% vs. 2.2%, P = 0.49). CONCLUSION: This retrospective study demonstrates 16G needles provide more glomeruli, more diagnostically adequate renal tissue, with fewer cores without a significant increase in complications compared with 18G needles. Based on these observations, 16G needles should be considered as the first line option in native-kidney PRB.

An observational cohort study of extended dosing (once every 2 weeks or once monthly) regimens with darbepoetin alfa in patients with chronic kidney disease not on dialysis: the EXTEND study.

BACKGROUND: Darbepoetin alfa (DA) has been shown to be an effective treatment of anaemia in patients with chronic kidney disease (CKD) not on dialysis (NoD). EXTEND is an observational study assessing the effectiveness of DA administered once biweekly (Q2W) or monthly (QM) in a general CKD-NoD population. METHODS: Adult CKD-NoD patients starting DA Q2W/QM treatment in June 2006 or later were eligible. Retrospective and/or prospective data including haemoglobin levels and erythropoiesis-stimulating agent (ESA) dosing were collected for 6 months before and 12 months after DA initiation. Mean Hb levels were calculated every 3 months, and ESA dose was converted to a geometric mean weekly DA equivalent dose and summarized monthly. RESULTS: Data from 4278 patients showed that patients receiving ESA treatment before DA Q2W/QM initiation had a mean (95% confidence interval) Hb level of 11.9 g/dL (11.8-12.0 g/dL) at initiation and 11.6 g/dL (11.6-11.7 g/dL) at Months 10-12, with mean ESA dose of 22 µg/week (21-23 µg/week) prior to initiation, 16 µg/week (15-16 µg/week) at initiation and 16 µg/week (15-16 µg/week) at Month 12. In ESA-naive patients, Hb levels increased from 10.3 g/dL (10.2-10.3 g/dL) at initiation to 11.7 g/dL at Months 4-6 and were maintained at a mean level of 11.7 g/dL (11.7-11.8 g/dL) at Months 10-12, with mean ESA dose of 16 µg/week (16-17 µg/week) at initiation and 16 µg/week (16-17 µg/week) at Month 12. In the 85% of patients receiving DA at extended intervals (Q2W or less frequently) at Month 12, 12 patients (0.3%) experienced DA-related adverse reactions. CONCLUSION: DA Q2W/QM was an effective treatment of anaemia in the general CKD-NoD patient population and a dose increase was not required in patients switching from a previous ESA regimen.

The effect of low glucose degradation product, neutral pH versus standard peritoneal dialysis solutions on peritoneal membrane function: the balANZ trial.

BACKGROUND: The balANZ trial recently reported that neutral pH, low glucose degradation product (biocompatible) peritoneal dialysis (PD) solutions significantly delayed anuria and reduced peritonitis rates compared with conventional solutions. This article reports a secondary outcome analysis of the balANZ trial with respect to peritoneal membrane function. METHODS: Adult, incident PD patients with residual renal function were randomized to receive either biocompatible or conventional (control) PD solutions for 2 years. Peritoneal equilibration tests were performed at 1, 6, 12, 18 and 24 months. Peritoneal small solute clearances and ultra-filtration (UF) were measured at 3, 6, 9, 12, 18 and 24 months. RESULTS: Of the 185 patients recruited into the trial, 85 patients in the Balance group and 82 patients in the control group had peritoneal membrane function evaluated. Mean 4-h dialysate:plasma creatinine ratios (D:P Cr 4h) at 1 month were significantly higher in the Balance group compared with controls (0.67 ± 0.10 versus 0.62 ± 0.10, P = 0.002). Over the 2-year study period, mean D:P Cr 4 h measurements remained stable in the Balance group but increased significantly in controls [difference -0.004 per month, 95% confidence interval (95% CI) -0.005 to -0.002, P < 0.001]. Similar results were obtained for dialysate glucose ratios (D/D0 glucose). Peritoneal UF was significantly lower in the Balance group than in controls at 3 and 6 months. Over the 2-year study period, peritoneal UF increased significantly in the Balance group but remained stable in controls (difference 24 mL/day/month, 95% CI 9-39, P = 0.002). No differences in peritoneal small solute clearances, prescribed dialysate fill volumes or peritoneal glucose exposure were observed between the two groups. CONCLUSIONS: Biocompatible and conventional PD solutions exert differential effects on peritoneal small solute transport rate and UF over time. Adequately powered trials assessing the impact of these differential membrane effects on PD technique and patient survival rates are warranted.

Barriers to timely arteriovenous fistula creation: a study of providers and patients.

BACKGROUND: Current clinical practice guidelines recommend a native arteriovenous fistula (AVF) as the vascular access of first choice. Despite this, most patients in western countries start hemodialysis therapy using a catheter. Little is known regarding specific physician and system characteristics that may be responsible for delays in permanent access creation. STUDY DESIGN: Multicenter cohort study using mixed methods; qualitative and quantitative analysis. SETTING & PARTICIPANTS: 9 nephrology centers in Australia and New Zealand, including 319 adult incident hemodialysis patients. PREDICTOR: Identification of barriers and enablers to AVF placement. OUTCOMES: Type of vascular access used at the start of hemodialysis therapy. MEASUREMENTS: Prospective data collection included data concerning predialysis education, interviews of center staff, referral times, and estimated glomerular filtration rate (eGFR) at AVF creation and dialysis therapy start. RESULTS: 319 patients started hemodialysis therapy during the 6-month period, 39% with an AVF and 59% with a catheter. Perceived barriers to access creation included lack of formal policies for patient referral, long wait times for surgical review and access placement, and lack of a patient database for management purposes. eGFR thresholds at referral for and creation of vascular accesses were considerably lower than appreciated (in both cases, median eGFR of 7 mL/min/1.73 m(2)), with median wait times for access creation of only 3.7 weeks. First assessment by a nephrologist less than 12 months before dialysis therapy start was an independent predictor of catheter use (OR, 8.71; P < 0.001). Characteristics of the best performing centers included the presence of a formalized predialysis pathway with a centralized patient database and low nephrologist and surgeon to patient ratios. LIMITATIONS: A limited number of patient-based barriers was assessed. Cross-sectional data only. CONCLUSIONS: A formalized predialysis pathway including patient education and eGFR thresholds for access placement is associated with improved permanent vascular access placement.

Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis.

BACKGROUND: Treatment of secondary hyperparathyroidism with vitamin D and calcium in patients receiving dialysis is often complicated by hypercalcemia and hyperphosphatemia, which may contribute to cardiovascular disease and adverse clinical outcomes. Calcimimetics target the calcium-sensing receptor and lower parathyroid hormone levels without increasing calcium and phosphorus levels. We report the results of two identical randomized, double-blind, placebo-controlled trials evaluating the safety and effectiveness of the calcimimetic agent cinacalcet hydrochloride. METHODS: Patients who were receiving hemodialysis and who had inadequately controlled secondary hyperparathyroidism despite standard treatment were randomly assigned to receive cinacalcet (371 patients) or placebo (370 patients) for 26 weeks. Once-daily doses were increased from 30 mg to 180 mg to achieve intact parathyroid hormone levels of 250 pg per milliliter or less. The primary end point was the percentage of patients with values in this range during a 14-week efficacy-assessment phase. RESULTS: Forty-three percent of the cinacalcet group reached the primary end point, as compared with 5 percent of the placebo group (P<0.001). Overall, mean parathyroid hormone values decreased 43 percent in those receiving cinacalcet but increased 9 percent in the placebo group (P<0.001). The serum calcium-phosphorus product declined by 15 percent in the cinacalcet group and remained unchanged in the placebo group (P<0.001). Cinacalcet effectively reduced parathyroid hormone levels independently of disease severity or changes in vitamin D sterol dose. CONCLUSIONS: Cinacalcet lowers parathyroid hormone levels and improves calcium-phosphorus homeostasis in patients receiving hemodialysis who have uncontrolled secondary hyperparathyroidism.

The effects of biocompatible compared with standard peritoneal dialysis solutions on peritonitis microbiology, treatment, and outcomes: the balANZ trial.

BACKGROUND: A multicenter, multi-country randomized controlled trial (the balANZ study) recently reported that peritonitis rates significantly improved with the use of neutral-pH peritoneal dialysis (PD) solutions low in glucose degradation products ("biocompatible") compared with standard solutions. The present paper reports a secondary outcome analysis of the balANZ trial with respect to peritonitis microbiology, treatment, and outcomes. METHODS: Adult incident PD patients with residual renal function were randomized to receive either biocompatible or conventional (control) PD solutions for 2 years. RESULTS: The safety population analysis for peritonitis included 91 patients in each group. The unadjusted geometric mean peritonitis rates in those groups were 0.30 [95% confidence interval (CI): 0.22 to 0.41] episodes per patient-year for the biocompatible group and 0.49 (95% CI: 0.39 to 0.62) episodes per patient-year for the control group [incidence rate ratio (IRR): 0.61; 95% CI: 0.41 to 0.90; p = 0.01]. When specific causative organisms were examined, the rates of culture-negative, gram-positive, gram-negative, and polymicrobial peritonitis episodes were not significantly different between the biocompatible and control groups, although the biocompatible group did experience a significantly lower rate of non-pseudomonal gram-negative peritonitis (IRR: 0.41; 95% CI: 0.18 to 0.92; p = 0.03). Initial empiric antibiotic regimens were comparable between the groups. Biocompatible fluid use did not significantly reduce the risk of peritonitis-associated hospitalization (adjusted odds ratio: 0.80; 95% CI: 0.48 to 1.34), but did result in a shorter median duration of peritonitis-associated hospitalization (6 days vs 11 days, p = 0.05). Peritonitis severity was more likely to be rated as mild in the biocompatible group (37% vs 10%, p = 0.001). Overall peritonitis-associated technique failures and peritonitis-related deaths were comparable in the two groups. CONCLUSIONS: Biocompatible PD fluid use was associated with a broad reduction in gram-positive, gram-negative, and culture-negative peritonitis that reached statistical significance for non-pseudomonal gram-negative organisms. Peritonitis hospitalization duration was shorter, and peritonitis severity was more commonly rated as mild in patients receiving biocompatible PD fluids, although other peritonitis outcomes were comparable between the groups.

A randomised, cross-over study comparing injection site pain with subcutaneous epoetin beta and subcutaneous darbepoetin alfa in patients with chronic kidney disease.

OBJECTIVE: To compare injection site pain of subcutaneous (sc) epoetin beta and darbepoetin alfa in adult patients with chronic kidney disease. RESEARCH DESIGN AND METHODS: This was a multi-centre, randomised, two-arm, single-blind, cross-over study. Patients were randomised to receive weekly sc darbepoetin alfa 30 mug or weekly sc epoetin beta 6000 IU for 2 weeks and were then crossed over to the alternative treatment for 2 weeks. Injection site pain was assessed using a 10 cm ungraduated visual analogue scale (0 = no pain, 10 = worst pain) and a six-point verbal rating scale. Patient preference for treatment was also assessed. TRIAL REGISTRATION: http://clinicaltrials. gov/(NCT00377481). RESULTS: All randomised patients (N = 48) completed the study. The sample comprised 29 chronic kidney disease patients (Stage 3 or Stage 4), 11 peritoneal dialysis patients and 8 renal transplant patients. Patients perceived significantly less pain with epoetin beta than darbepoetin alfa, using the visual analogue scale (relative pain score = 2.75, darbepoetin alfa:epoetin beta, 95% CI: 1.85, 4.07; p < 0.0001) and the verbal rating scale (median: 0.5, 95% CI: 0.5, 1.0 vs. median: 1.5, 95% CI: 1.0, 2.0; p < 0.0001). Epoetin beta was preferred by significantly more patients (65%) than darbepoetin alfa (10%) (p < 0.001); 25% of patients reported no preference. CONCLUSIONS: Limitations included lack of an epoetin alfa comparator and limited blinding (patients were blinded to treatment, however, an unblinded nurse administered treatment). We show that sc injection of epoetin beta is significantly less painful than darbepoetin alfa and patient preference for epoetin beta confirms that the difference is clinically meaningful.

Hypersensitivity reactions to the polysorbate contained in recombinant erythropoietin and darbepoietin.

The following case reports are of two patients who have developed hypersensitivity reactions to the red cell growth hormones, darbepoietin and erythropoietin. The subsequent skin testing and clinical course suggested that the cause of these reactions was due to the excipient polysorbate 80. This finding might have implications in the recent increase in the incidence of pure red cell aplasia.

Acute vascular access catheters for haemodialysis: complications limiting technique survival.

The use of acute vascular access catheters (AVACs) has facilitated the delivery of haemodialysis to patients lacking functioning access. A review of the experience of a tertiary Australian renal treatment centre, consisting of 205 sequential AVACs in 93 patients, was undertaken over 1 year, to identify issues limiting technique survival. Acute vascular access catheters were inserted as acute dialysis access for patients with chronic renal failure (CRF; 21%), failed grafts or fistulae (18%), acute renal failure (12%), failed chronic ambulatory peritoneal dialysis (CAPD; 8%) or failed prior AVACs (37%). The majority of AVACs were on the right (74%), and the placement site was simple jugular (69%), tunnelled jugular (15%), femoral (12%), or subclavian (4%). During follow up, 198 of 205 AVACs were removed. The mean AVAC survival was superior (P < 0.0001, Fisher's protected least significant difference (PLSD) for tunnelled jugular AVACS (62 +/- 46 (SD) days) compared with simple jugular (20 +/- 19), subclavian (18 +/- 13) and femoral (7 +/- 6). Causes for AVAC removal were: elective (47%), blockage (31%), infection (20%) or cracked catheter (1%). Routine postremoval tip cultures grew coagulase negative Staphylococcus (CNS, 46%), negative culture (33%), methicillin-resistant Staphylococcus aureus (MRSA; 9%), Staphylococcus aureus (9%), Gram-negative rods (1%), Pseudomonas (0.5%) or other uncommon organisms (2%). Blood cultures were drawn through the AVAC in the setting of suspected bacteraemia in 42 of 198 AVACs. Blood cultures were negative in 40%. Positive cultures included Staphylococcus species in 55%: including MRSA (19%), Staphylococcus aureus (29%) and CNS (34%). Rare cultures identified Escherichia coli (2%) or Serratia (2%). Infection and blockage significantly reduced AVAC survival, affecting more than 50% of cases. Approaches to minimize these complications are likely to lead to improved clinical outcomes with AVAC use.

Treatment of anemia with darbepoetin alfa administered de novo once every other week in chronic kidney disease.

BACKGROUND/AIMS: Darbepoetin alfa is an erythropoiesis-stimulating protein that works via the same mechanism and has a threefold longer serum half-life than recombinant human erythropoietin (rHuEPO). The objective of this study was to evaluate extending the dosing interval of darbepoetin alfa to once every other week administration for the treatment of anemia in patients with chronic kidney disease (CKD) not requiring dialysis who were naive to rHuEPO therapy. METHODS: This was a multi-center, open-label study. Seventy-six rHuEPO-naive patients were enrolled to receive darbepoetin alfa (0.75 microg/kg) once every other week for up to 24 weeks. Doses were titrated to achieve and maintain a hemoglobin target of 11.0 to 13.0 g/dl. RESULTS: Ninety-seven percent (95% CI: 0.92, 1.00) of patients completing 24 weeks of treatment achieved a hemoglobin response. The median time to response was 5 weeks (range 1-25 weeks). The median darbepoetin alfa dose at the time of response was 60 microg(range 30-130 microg). Darbepoetin alfa was safe and well tolerated, and no antibodies to darbepoetin alfa were detected. CONCLUSION: These results demonstrate the utility of darbepoetin alfa administered once every other week in rHuEPO-naive CKD patients. This new treatment paradigm may allow for more widespread management of anemia in patients with CKD.