Association between serum hepcidin-25 and primary resistance to erythropoiesis-stimulating agents in chronic kidney disease: a secondary analysis of the HERO trial.

BACKGROUND: Pentoxifylline has been shown to increase haemoglobin levels in patients with chronic kidney disease (CKD) and erythropoietin-stimulating agent (ESA)-hyporesponsive anaemia in the Handling Erythropoietin Resistance with Oxpentifylline multicentre double-blind, randomized controlled trial. The present sub-study evaluated the effects of pentoxifylline on the iron-regulatory hormone hepcidin in patients with ESA-hyporesponsive CKD. METHODS: This sub-study included 13 patients in the pentoxifylline arm (400 mg daily) and 13 in the matched placebo arm. Hepcidin-25 was measured by ultra performance liquid chromatography/quadrupole time-of-flight mass spectrometry following isolation from patient serum. Serum hepcidin-25, serum iron biomarkers, haemoglobin and ESA dosage were compared within and between the two groups. RESULTS: Hepcidin-25 concentration at 4 months adjusted for baseline did not differ significantly in pentoxifylline versus placebo treated patients (adjusted mean difference (MD) -7.9 nmol, P = 0.114), although the difference between the groups mean translated into a >25% reduction of circulating hepcidin-25 due to pentoxifylline compared with the placebo baseline. In paired analysis, serum hepcidin-25 levels were significantly decreased at 4 months compared with baseline in the pentoxifylline group (-5.47 ± 2.27 nmol/l, P < 0.05) but not in the placebo group (2.82 ± 4.29 nmol/l, P = 0.24). Pentoxifylline did not significantly alter serum ferritin (MD 55.4 mcg/l), transferrin saturation (MD 4.04%), the dosage of ESA (MD -9.93 U/kg per week) or haemoglobin concentration (MD 5.75 g/l). CONCLUSION: The reduction of circulating hepcidin-25 due to pentoxifylline did not reach statistical significance; however, the magnitude of the difference suggests that pentoxifylline may be a clinically and biologically meaningful modulator of hepcidin-25 in dialysis of patients with ESA-hyporesponsive anaemia.

Representativeness of Honeypot Trial Participants to Australasian PD Patients.

BACKGROUND: The HONEYPOT trial failed to establish the superiority of exit-site application of Medihoney compared with nasal mupirocin prophylaxis for the prevention of peritonitis in peritoneal dialysis (PD) patients. This study aimed to assess the representativeness of the patients in the HONEYPOT trial to the Australian and New Zealand PD population. METHODS: This study compared baseline characteristics of the 371 PD patients in the HONEYPOT trial with those of 6,085 PD patients recorded on the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry. RESULTS: Compared with the PD population, the HONEYPOT sample was older (standardized difference [d] = 0.19, p = 0.003), more likely to be treated with automated PD (d = 0.58, p < 0.001), had higher residual renal function (d = 0.26, p < 0.001) and a higher proportion of participants with end-stage kidney disease due to polycystic kidney disease (d = 0.17) and lower proportion due to diabetes (d = -0.17) and glomerulonephritis (d = -0.18) (p < 0.001), and lower proportions of indigenous people (d = -0.17, p < 0.001), current smokers (d = -0.10, p < 0.001), and people with prior histories of hemodialysis (d = -0.16, p < 0.001), diabetes mellitus (d = -0.18, p < 0.001), and coronary artery disease (d = -0.15, p < 0.001). CONCLUSIONS: HONEYPOT trial participants tended to be healthier than the Australian and New Zealand PD patient population. Although the differences between the groups were generally modest, it is possible that their cumulative effect may have had some impact on external generalizability, which is not an uncommon occurrence in clinical trials.

The effect of pentoxifylline on oxidative stress in chronic kidney disease patients with erythropoiesis-stimulating agent hyporesponsiveness: Sub-study of the HERO trial.

OBJECTIVE: Pentoxifylline has previously been shown to increase haemoglobin levels in patients with chronic kidney disease (CKD) and erythropoietin-stimulating agent (ESA)-hyporesponsive anaemia in the HERO multi-centre double-blind, randomized controlled trial. The present study evaluated the effects of pentoxifylline on oxidative stress in ESA-hyporesponsive CKD patients. METHODS: This sub-study of the HERO trial compared 15 patients in the pentoxifylline arm (400 mg daily) and 17 in the matched placebo arm on oxidative stress markers: plasma total F2-isoprostanes, protein carbonyls, glutathione peroxidase (GPX), and superoxide dismutase (SOD) activities. RESULTS: Pentoxifylline did not significantly alter total F2-isoprostanes (adjusted mean difference (MD) 35.01 pg/ml, P = 0.11), SOD activity (MD 0.82 U/ml, P = 0.07), GPX activity (MD -6.06 U/l, P = 0.09), or protein carbonyls (MD -0.04 nmol/mg, P = 0.52). Replicating results from the main study, pentoxifylline significantly increased haemoglobin concentration compared with controls (MD 7.2 g/l, P = 0.04). CONCLUSIONS: Pentoxifylline did not alter oxidative stress biomarkers, suggesting that alternative mechanisms may be responsible for the agent's ability to augment haemoglobin levels in CKD patients with ESA-hyporesponsive anaemia.

Association between serum alkaline phosphatase and primary resistance to erythropoiesis stimulating agents in chronic kidney disease: a secondary analysis of the HERO trial.

BACKGROUND: Erythropoiesis stimulating agent (ESA)-resistant anemia is common in chronic kidney disease (CKD). OBJECTIVES: To evaluate the determinants of severity of ESA resistance in patients with CKD and primary ESA-resistance. DESIGN: Secondary analysis of a randomized controlled trial (the Handling Erythropoietin Resistance with Oxpentifylline, HERO). SETTING AND PATIENTS: 53 adult patients with CKD stage 4 or 5 and primary ESA-resistant anemia (hemoglobin ≤120 g/L, ESA resistance index [ERI] ≥1.0 IU/kg/week/gHb for erythropoietin or ≥0.005 µg/kg/week/gHb for darbepoeitin, no cause for ESA-resistance identified). MEASUREMENTS: Iron studies, parathyroid hormone, albumin, liver enzymes, phosphate or markers of oxidative stress and inflammation. METHODS: Participants were divided into tertiles of ERI. Multinomial logistic regression was used to analyse the determinants of ERI tertiles. RESULTS: All patients, except one, were receiving dialysis for end-stage kidney disease. The mean ± SD ERI values in the low (n = 18), medium (n = 18) and high (n = 17) ERI tertiles were 1.4 ± 0.3, 2.3 ± 0.2 and 3.5 ± 0.8 IU/kg/week/gHb, respectively (P < 0.001). There were no significant differences observed in age, gender, ethnicity, cause of kidney disease, diabetes, iron studies, parathyroid hormone, albumin, liver enzymes, phosphate or markers of oxidative stress and inflammation between the ERI tertiles. The median [inter-quartile range] serum alkaline phosphatase concentrations in the low, medium and high ERI tertiles were 89 [64,121], 99 [76,134 and 148 [87,175] U/L, respectively (P = 0.054). There was a weak but statistically significant association between ERI and serum alkaline phosphatase (R(2) = 0.06, P = 0.03). Using multinomial logistic regression, the risk of being in the high ERI tertile relative to the low ERI tertile increased with increasing serum alkaline phosphatase levels (P = 0.02). No other variables were significantly associated with ERI. LIMITATIONS: Small sample size; bone-specific alkaline phosphatase, other markers of bone turnover and bone biopsies not evaluated. CONCLUSIONS: Serum alkaline phosphatase was associated with severity of ESA resistance in ESA-resistant patients with CKD. Large prospective studies are required to confirm this association. ( TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry 12608000199314).

CONTEXTE: L'anémie résistante à l'agent stimulant l'érythropoïèse (ASE) est courante chez les patients atteints d'insuffisance rénale chronique (IRC). OBJECTIFS: Évaluer les déterminants de la gravité de la résistance à l'ASE chez les patients atteints d'IRC et de la résistance primaire à l'ASE. TYPE D'ÉTUDE: Analyse secondaire d'un essai clinique randomisé (le Handling Erythropoietin Resistance with Oxpentifylline, HERO). CONTEXTE ET PARTICIPANTS: 53 patients adultes atteints d'IRC de stade 4 ou 5, de même que d'anémie résistante à l'ASE (hémoglobine ≤120 g/L, indice de résistance à l'ASE [IRA] ≥1,0 IU/kg/semaine/gHb pour l'érythropoïétine ou ≥0,005 µg/kg/semaine/gHb pour la darbépoétine, aucune cause justifiant la résistance à l'ASE). MESURES: Mesure des taux de fer, de la parathormone, de l'albumine, de l'enzyme hépatique, du phosphate ou des marqueurs de stress oxydatif et d'inflammation. MÉTHODES: Les participants étaient divisés en tertiels d'IRA. La méthode de régression logistique multinominale a été utilisée pour analyser les déterminants des tertiels d'IRA. RÉSULTATS: Tous les patients, sauf un, recevaient une dialyse pour l'IRT. La moyenne ± ÉT des valeurs d'IRA des tertiels inférieur (n = 18), intermédiaire (n = 18) et supérieur (n = 17) étaient respectivement de 1,4 ± 0,3, de 2,3 ± 0,2 et de 3,5 ± 0,8 IU/kg/semaine/gHb (P < 0,001). On n'a observé aucune différence importante en fonction de l'âge, du sexe, de l'ethnicité, de la cause de l'insuffisance rénale, du diabète, des taux de fer, de la parathormone, de l'albumine, de l'enzyme hépatique, du phosphate ou des marqueurs de stress oxydatif et d'inflammation entre les tertiels d'IRA. La médiane [écart interquartile] des concentrations de phosphatase alcaline sérique des tertiels d'IRA inférieur, intermédiaire et supérieur étaient respectivement de 89 [64,121], de 99 [76,134] et de 148 [87,175] U/L (P = 0,054). Bien que statistiquement significative, la relation était plutôt faible entre l'IRA et la phosphatase alcaline sérique (R2 = 0,06; P = 0,03). Selon la méthode de régression logistique multinominale, les chances de se retrouver dans le tertiel d'IRA supérieur, par opposition au tertiel d'IRA inférieur, augmentait avec des taux élevés de phosphatase alcaline sérique (P = 0,02). On n'a observé aucune association forte entre une autre variable et l'IRA. CONCLUSION: La phosphatase alcaline sérique a été associée à une forte résistance à l'ASE chez les patients résistants à l'ASE atteints d'IRC. Des études prospectives à grande échelle sont nécessaires afin de confirmer cette association. (Enregistrement de l'essai clinique: Australian New Zealand Clinical Trials Registry 12608000199314).

The Effect of Exit-Site Antibacterial Honey Versus Nasal Mupirocin Prophylaxis on the Microbiology and Outcomes of Peritoneal Dialysis-Associated Peritonitis and Exit-Site Infections: A Sub-Study of the Honeypot Trial.

UNLABELLED: ♦ BACKGROUND: The HONEYPOT study recently reported that daily exit-site application of antibacterial honey was not superior to nasal mupirocin prophylaxis for preventing overall peritoneal dialysis (PD)-related infection. This paper reports a secondary outcome analysis of the HONEYPOT study with respect to exit-site infection (ESI) and peritonitis microbiology, infectious hospitalization and technique failure. ♦ METHODS: A total of 371 PD patients were randomized to daily exit-site application of antibacterial honey plus usual exit-site care (N = 186) or intranasal mupirocin prophylaxis (in nasal Staphylococcus aureus carriers only) plus usual exit-site care (control, N = 185). Groups were compared on rates of organism-specific ESI and peritonitis, peritonitis- and infection-associated hospitalization, and technique failure (PD withdrawal). ♦ RESULTS: The mean peritonitis rates in the honey and control groups were 0.41 (95% confidence interval [CI] 0.32 - 0.50) and 0.41 (95% CI 0.33 - 0.49) episodes per patient-year, respectively (incidence rate ratio [IRR] 1.01, 95% CI 0.75 - 1.35). When specific causative organisms were examined, no differences were observed between the groups for gram-positive (IRR 0.99, 95% CI 0.66 - 1.49), gram-negative (IRR 0.71, 95% CI 0.39 - 1.29), culture-negative (IRR 2.01, 95% CI 0.91 - 4.42), or polymicrobial peritonitis (IRR 1.08, 95% CI 0.36 - 3.20). Exit-site infection rates were 0.37 (95% CI 0.28 - 0.45) and 0.33 (95% CI 0.26 - 0.40) episodes per patient-year for the honey and control groups, respectively (IRR 1.12, 95% CI 0.81 - 1.53). No significant differences were observed between the groups for gram-positive (IRR 1.10, 95% CI 0.70 - 1.72), gram-negative (IRR: 0.85, 95% CI 0.46 - 1.58), culture-negative (IRR 1.88, 95% CI 0.67 - 5.29), or polymicrobial ESI (IRR 1.00, 95% CI 0.40 - 2.54). Times to first peritonitis-associated and first infection-associated hospitalization were similar in the honey and control groups. The rates of technique failure (PD withdrawal) due to PD-related infection were not significantly different between the groups. ♦ CONCLUSION: Compared with standard nasal mupirocin prophylaxis, daily topical exit-site application of antibacterial honey resulted in comparable rates of organism-specific peritonitis and ESI, infection-associated hospitalization, and infection-associated technique failure in PD patients.

A randomized, placebo-controlled trial of pentoxifylline on erythropoiesis-stimulating agent hyporesponsiveness in anemic patients with CKD: the Handling Erythropoietin Resistance With Oxpentifylline (HERO) trial.

BACKGROUND: Erythropoiesis-stimulating agent (ESA)-hyporesponsive anemia is common in chronic kidney disease (CKD). Pentoxifylline shows promise as a treatment for ESA-hyporesponsive anemia, but has not been rigorously evaluated. STUDY DESIGN: Multicenter, double-blind, randomized, controlled trial. SETTING & PARTICIPANTS: 53 adult patients with CKD stage 4 or 5 (including dialysis) and ESA-hyporesponsive anemia (hemoglobin≤120g/L and ESA resistance index [calculated as weight-adjusted weekly ESA dose in IU/kg/wk divided by hemoglobin concentration in g/L]≥1.0IU/kg/wk/g/L for erythropoietin-treated patients and ≥0.005µg/kg/wk/g/L for darbepoetin-treated patients). INTERVENTIONS: Pentoxifylline (400mg/d; n=26) or matching placebo (control; n=27) for 4 months. PRIMARY OUTCOME: ESA resistance index at 4 months; secondary outcomes: hemoglobin concentration, ESA dose, blood transfusion requirement, serum ferritin level and transferrin saturation, C-reactive protein level, adverse events, quality of life, and health economics. RESULTS: There was no statistically significant difference in ESA resistance index between the pentoxifylline and control groups (adjusted mean difference, -0.39 [95%CI, -0.89 to 0.10] IU/kg/wk/g/L; P=0.1). Pentoxifylline significantly increased hemoglobin concentration relative to the control group (adjusted mean difference, 7.6 [95%CI, 1.7-13.5] g/L; P=0.01). There was no difference in ESA dose between groups (-20.8 [95%CI, -67.2 to 25.7] IU/kg/wk; P=0.4). No differences in blood transfusion requirements, adverse events, or quality of life were observed between groups. Pentoxifylline cost A$88.05 (US $82.94) per person over the trial and produced mean savings in ESA cost of A$1,332 (US $1,255). The overall economic impact over the trial period was a saving of A$1,244 (US $1,172) per person for the pentoxifylline group compared with controls. LIMITATIONS: Sample size smaller than planned due to slow recruitment. CONCLUSIONS: Pentoxifylline did not significantly modify ESA hyporesponsiveness, but increased hemoglobin concentration. Further studies are warranted to determine whether pentoxifylline therapy represents a safe strategy for increasing hemoglobin levels in patients with CKD with ESA-hyporesponsive anemia.

Antibacterial honey for the prevention of peritoneal-dialysis-related infections (HONEYPOT): a randomised trial.

BACKGROUND: There is a paucity of evidence to guide the best strategy for prevention of peritoneal-dialysis-related infections. Antibacterial honey has shown promise as a novel, cheap, effective, topical prophylactic agent without inducing microbial resistance. We therefore assessed whether daily application of honey at the exit site would increase the time to peritoneal-dialysis-related infections compared with standard exit-site care plus intranasal mupirocin prophylaxis for nasal carriers of Staphylococcus aureus. METHODS: In this open-label trial undertaken in 26 centres in Australia and New Zealand, participants undergoing peritoneal dialysis were randomly assigned in a 1:1 ratio with an adaptive allocation algorithm to daily topical exit-site application of antibacterial honey plus standard exit-site care or intranasal mupirocin prophylaxis (only in carriers of nasal S aureus) plus standard exit-site care (control group). The primary endpoint was time to first infection related to peritoneal dialysis (exit-site infection, tunnel infection, or peritonitis). The trial is registered with the Australian New Zealand Clinical Trials Registry, number 12607000537459. FINDINGS: Of 371 participants, 186 were assigned to the honey group and 185 to the control group. The median peritoneal-dialysis-related infection-free survival times were not significantly different in the honey (16·0 months [IQR not estimable]) and control groups (17·7 months [not estimable]; unadjusted hazard ratio 1·12, 95% CI 0·83-1·51; p=0·47). In the subgroup analyses, honey increased the risks of both the primary endpoint (1·85, 1·05-3·24; p=0·03) and peritonitis (2·25, 1·16-4·36) in participants with diabetes. The incidences of serious adverse events (298 vs 327, respectively; p=0·1) and deaths (14 vs 18, respectively; p=0·9) were not significantly different in the honey and control groups. 11 (6%) participants in the honey group had local skin reactions. INTERPRETATION: The findings of this trial show that honey cannot be recommended routinely for the prevention of peritoneal-dialysis-related infections. FUNDING: Baxter Healthcare, Queensland Government, Comvita, and Gambro.

Establishing a clinical trials network in nephrology: experience of the Australasian Kidney Trials Network.

Chronic kidney disease is a major public health problem globally. Despite this, there are fewer high-quality, high-impact clinical trials in nephrology than other internal medicine specialties, which has led to large gaps in evidence. To address this deficiency, the Australasian Kidney Trials Network, a Collaborative Research Group, was formed in 2005. Since then, the Network has provided infrastructure and expertise to conduct patient-focused high-quality, investigator-initiated clinical trials in nephrology. The Network has not only been successful in engaging the nephrology community in Australia and New Zealand but also in forming collaborations with leading researchers from other countries. This article describes the establishment, development, and functions of the Network. The article also discusses the current and future funding strategies to ensure uninterrupted conduct of much needed clinical trials in nephrology to improve the outcomes of patients affected by kidney diseases with cost-effective interventions.