Impact of haemodialysis hours on outcomes in older patients.

AIM: Previous studies report an association between longer haemodialysis treatment sessions and improved survival. Worldwide, there is a trend to increasing age among prevalent patients receiving haemodialysis. This analysis aimed to determine whether the mortality benefit of longer haemodialysis treatment sessions diminishes with increasing age. METHODS: This was a retrospective cohort study of people who first commenced thrice-weekly haemodialysis aged ≥65 years, reported to the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry from 2005 to 2015, included from 90 days after dialysis start. The primary outcome was all-cause mortality. Cox regression analysis was performed with haemodialysis session duration the exposure of interest. RESULTS: Of 8224 people who commenced haemodialysis as their first treatment for kidney failure aged ≥65 years during this period, 4727 patients died. Longer dialysis hours per session was associated with a decreased risk of death in unadjusted analyses [hazard ratio, HR, for ≥5 h versus 4 to <4.5 h: 0.81 (0.75-0.88, p < .001)]. Patients having longer dialysis sessions were younger but had greater co-morbidity. In an adjusted model including age and other variables, the survival benefit of longer hours was only partially attenuated [HR for previous comparison: 0.75 (0.69-0.82, p < .001)], and no interaction between age and hours was demonstrated (p = .89). CONCLUSION: The apparent survival benefit associated with longer haemodialysis session length appears to be preserved in patients 65 years or older. In practice, the benefit of longer dialysis hours should be carefully weighed against other factors in this patient group.

Native renal biopsy: outcomes with a 4-h observation period in low-risk outpatients.

Current practice guidelines recommend that 'low-risk' outpatients undergoing percutaneous native renal biopsy (PRB) are observed for 6-8 h to identify post-biopsy complications. We performed a retrospective review of 225 PRB procedures in low-risk outpatients who were observed for a 4-h period to determine the safety with regard to complication rate and timing. PRB was performed using a standardised protocol and under ultrasound guidance with a 16- or 18-gauge needle. Bleeding complications occurred in 7% (16/225) of patients, of which 88% (14/16) were detected within a 4-h period. The two undetected complications presented more than 72 h after the procedure. This suggests that a 4-h observation period may be safe and adequate in identifying the majority of patients who will experience significant complications in the first 24 h, with a potential saving of time and resources.

Patient experiences of training and transition to home haemodialysis: A mixed-methods study.

AIM: This study aims to describe patients' perspectives on the transition to home haemodialysis. METHODS: Up to three sequential semi-structured interviews were conducted with 20 patients during the transition to home haemodialysis at an Australian renal unit. Transcripts were analysed thematically. Participants completed a satisfaction questionnaire after commencing home haemodialysis. RESULTS: We identified six themes: persevering despite trepidations (diminishing intimidation of machinery, acquiescing to fatal risks, reconciling fears of cannulation, dispelling concerns of neglect and tolerating necessary concessions); optimizing the learning pathway (practising problem solving, learning from mistakes, grasping technical complexity, minimizing cognitive overload and progressing at own pace); developing confidence (believing in own abilities, adapting to independence, depending on caregiver partnership and faith in crisis support); interrupted transition momentum (lacking individual attention, language barriers, installation delays, interfering illness and complications and acclimatizing to new conditions); noticing immediate gains (reclaiming lifestyle normality, satisfying self-sufficiency, personalizing treatment regime and thriving in a positive environment); and depleting resources and energy (exhaustion with gruelling routine, confronting medicalization of the home, draining financial reserves and imposing family burden). Fewer than 30% of respondents indicated low satisfaction with staff availability domains, staff interpersonal domains or technical domains. CONCLUSION: Home haemodialysis training fosters confidence in patients; however, many patients experience stress because of medical isolation, treatment responsibilities, family impositions and financial difficulties. Addressing patient's on-going psychosocial concerns may alleviate burdens on patients and their families during the transition to home haemodialysis.

Greater haemodialysis exposure ('quotidian haemodialysis') has different mortality associations by patient age group.

Background: Worldwide, most people requiring kidney replacement therapy receive haemodialysis (HD) three times per week. Greater HD time and/or frequency may improve survival, but implementation requires understanding potential benefits across the range of patients. Methods: Using data from the Australia and New Zealand Dialysis and Transplant Registry, we assessed whether quotidian HD (defined as >3 sessions/week and/or >5 h/session) was associated with reduced mortality in adult patients. The primary outcome of all-cause mortality was analysed by a time-varying Cox proportional hazards model with quotidian HD as the exposure of interest. Results: Of 24 138 people who received HD between 2011 and 2019, 2632 (10.9%) received quotidian HD at some stage. These patients were younger, more likely male and more likely to receive HD at home. Overall, quotidian versus standard HD was associated with a decreased risk for all-cause mortality {crude hazard ratio [HR] 0.50 [95% confidence interval (CI) 0.45-0.56]}, but an interaction between quotidian HD and age was identified (P = .005). Stratified by age groups and splitting follow-up time where proportional hazards were violated, the corresponding HR compared with standard HD was 2.43 (95% CI 1.56-3.79) for people >75 years of age in the first year of quotidian HD, 1.52 (95% CI 0.89-2.58) for 1-3 years and 0.95 (95% CI 0.51-1.78) for ≥3 years. There was no significant survival advantage in younger people. Conclusions: Although quotidian HD conferred survival benefit in crude analyses, people ≥75 years of age had greater mortality with quotidian HD than standard HD. The mortality benefit in younger people was attenuated when adjusted for known confounders.

Psychosocial factors in patients with kidney failure and role for social worker: A secondary data audit.

BACKGROUND: People with kidney failure face a multitude of psychosocial stressors that affect disease trajectory and health outcomes. OBJECTIVES: To investigate psychosocial factors affecting people with kidney failure before or at start of kidney replacement therapy (KRT) and kidney supportive and palliative care (KSPC) phases of illness and to explore role of social worker during the illness trajectory. METHODS: We conducted a secondary data audit of patients either before or at start of KRT (Phase 1) and at the KSPC (Phase 2) of illness and had psychosocial assessments between March 2012 and March 2020 in an Australian setting. RESULTS: Seventy-nine individuals, aged 70 ± 12 years, had at least two psychosocial assessments, one in each of the two phases of illness. The median time between social worker evaluations in Phase 1 and Phase 2 was 522 (116-943) days. Adjustment to illness and treatment (90%) was the most prevalent psychosocial issue identified in Phase 1, which declined to 39% in Phase 2. Need for aged care assistance (7.6%-63%; p < 0.001) and carer support (7.6%-42%; p < 0.001) increased significantly from Phase 1 to Phase 2. There was a significant increase in psychosocial interventions by the social worker in Phase 2, including supportive counselling (53%-73%; p < 0.05), provision of education and information (43%-65%; p < 0.01), and referrals (28%-62%; p < 0.01). CONCLUSION: Adults nearing or at the start of KRT experience immense psychosocial burden and adaptive demands that recognisably change during the course of illness. The positive role played by the nephrology social worker warrants further investigation.

Impact of a pharmacy-led screening and intervention in people at risk of or living with chronic kidney disease in a primary care setting: a cluster randomised trial protocol.

INTRODUCTION: Chronic kidney disease (CKD) is increasingly recognised as a growing global public health problem. Early detection and management can significantly reduce the loss of kidney function. The proposed trial aims to evaluate the impact of a community pharmacy-led intervention combining CKD screening and medication review on CKD detection and quality use of medicines (QUM) for patients with CKD. We hypothesise that the proposed intervention will enhance detection of newly diagnosed CKD cases and reduce potentially inappropriate medications use by people at risk of or living with CKD. METHODS AND ANALYSIS: This study is a multicentre, pragmatic, two-level cluster randomised controlled trial which will be conducted across different regions in Australia. Clusters of community pharmacies from geographical groups of co-located postcodes will be randomised. The project will be conducted in 122 community pharmacies distributed across metropolitan and rural areas. The trial consists of two arms: (1) Control Group: a risk assessment using the QKidney CKD risk assessment tool, and (2) Intervention Group: a risk assessment using the QKidney CKD plus Point-of-Care Testing for kidney function markers (serum creatinine and estimated glomerular filtration rate), followed by a QUM service. The primary outcomes of the study are the proportion of patients newly diagnosed with CKD at the end of the study period (12 months); and rates of changes in the number of medications considered problematic in kidney disease (number of medications prescribed at inappropriate doses based on kidney function and/or number of nephrotoxic medications) over the same period. Secondary outcomes include proportion of people on potentially inappropriate medications, types of recommendations provided by the pharmacist (and acceptance rate by general practitioners), proportion of people who were screened, referred, and took up the referral to visit their general practitioners, and economic and other patient-centred outcomes. ETHICS AND DISSEMINATION: The trial protocol has been approved by the Human Research Ethics Committee at the University of Sydney (2022/044) and the findings of the study will be presented at scientific conferences and published in peer-reviewed journal(s). TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12622000329763).

Psychosocial factors affecting patients with end-stage kidney disease and the impact of the social worker.

BACKGROUND: End-stage kidney disease (ESKD) incidence has been increasing over time, contributing significantly to morbidity and mortality. However, there is limited data examining the psychosocial factors affecting people with ESKD and how the social worker fits within the multidisciplinary CKD care. This integrative systematic review aims to summarise the existing evidence on psychosocial determinants of outcomes in ESKD and the role of the social worker in nephrology care. METHOD: The literature search was conducted using PubMed and MEDLINE, targeting articles published from database inception until May 2021. This systematic review was performed in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The Joanna Briggs Institute tools were employed to assess the quality of included studies. RESULTS: Of the 397 citations, 13 studies applicable to 1465 patients met the inclusion criteria. The studies were of cross-sectional, experimental, and exploratory qualitative design in nature. The findings of the studies were summarised into three major themes-psychosocial factors, role of the renal social worker, and impact of the renal social worker. The studies demonstrated that concerns related to adjustment, death and dying, family and social functioning, and loss were common amongst participants of the included studies indicating the need for a social worker. Three studies explored the impact of social workers in ESKD, revealing that people who received support from social workers had an improved quality of life, lower depression scores, and reduced hospitalisations and emergency room visits. CONCLUSION: This review summarizes the multitude of physical and psychological stressors that patients with ESRD face, and highlights the positive role social workers can play in improving the psychosocial stressors in this patient group, and the need for large-scale randomised trials to understand the role of social workers as part of a multidisciplinary nephrology care.

Predictive Models for Recurrent Membranous Nephropathy After Kidney Transplantation.

Recurrent membranous nephropathy (MN) posttransplantation affects 35% to 50% of kidney transplant recipients (KTRs) and accounts for 50% allograft loss 5 y after diagnosis. Predictive factors for recurrent MN may include HLA-D risk alleles, but other factors have not been explored with certainty. Methods: The Australian and New Zealand Dialysis and Transplant registry was used to develop 3 prediction models for recurrent MN (Group Least Absolute Shrinkage and Selection Operator [LASSO], penalized Cox regression, and random forest), which were tuned using tenfold cross-validation in a derivation cohort with complete HLA data. KTRs with MN but incomplete HLA data formed the validation cohort. Model performance was evaluated using area under the receiver operating characteristic curve (AUC-ROC). Results: One hundred ninety-nine KTRs with MN were included, and 25 (13%) had recurrent MN (median follow-up 5.9 y). The AUC-ROCs for Group LASSO, penalized Cox regression, and random forest models were 0.85 (95% confidence interval, 0.76-0.94), 0.91 (0.85-0.96), and 0.62 (0.57-0.69), respectively, in the derivation cohort, with moderate agreement in selected variables between the models (55%-70%). In their validation cohorts, the AUC-ROCs for Group LASSO and penalized Cox regression were 0.60 (0.49-0.70) and 0.73 (0.59-0.86), respectively. Variables of importance chosen by all models included recipient HLA-A2, donor HLA-DR12, donor-recipient HLA-B65, and HLA-DR12 match. Conclusions: A penalized Cox regression performed reasonably for predicting recurrent MN and was superior to Group LASSO and random forest models. These models highlighted the importance of donor-recipient HLA characteristics to recurrent MN, although validation in larger datasets is required.

Membranous nephropathy: Clearer pathology and mechanisms identify potential strategies for treatment.

Primary membranous nephropathy (PMN) is one of the common causes of adult-onset nephrotic syndrome and is characterized by autoantibodies against podocyte antigens causing in situ immune complex deposition. Much of our understanding of the disease mechanisms underpinning this kidney-limited autoimmune disease originally came from studies of Heymann nephritis, a rat model of PMN, where autoantibodies against megalin produced a similar disease phenotype though megalin is not implicated in human disease. In PMN, the major target antigen was identified to be M-type phospholipase A2 receptor 1 (PLA2R) in 2009. Further utilization of mass spectrometry on immunoprecipitated glomerular extracts and laser micro dissected glomeruli has allowed the rapid discovery of other antigens (thrombospondin type-1 domain-containing protein 7A, neural epidermal growth factor-like 1 protein, semaphorin 3B, protocadherin 7, high temperature requirement A serine peptidase 1, netrin G1) targeted by autoantibodies in PMN. Despite these major advances in our understanding of the pathophysiology of PMN, treatments remain non-specific, often ineffective, or toxic. In this review, we summarize our current understanding of the immune mechanisms driving PMN from animal models and clinical studies, and the implications on the development of future targeted therapeutic strategies.

Co-infection with SARS-CoV-2 Omicron and Delta variants revealed by genomic surveillance.

Co-infections with different variants of SARS-CoV-2 are a key precursor to recombination events that are likely to drive SARS-CoV-2 evolution. Rapid identification of such co-infections is required to determine their frequency in the community, particularly in populations at-risk of severe COVID-19, which have already been identified as incubators for punctuated evolutionary events. However, limited data and tools are currently available to detect and characterise the SARS-CoV-2 co-infections associated with recognised variants of concern. Here we describe co-infection with the SARS-CoV-2 variants of concern Omicron and Delta in two epidemiologically unrelated adult patients with chronic kidney disease requiring maintenance haemodialysis. Both variants were co-circulating in the community at the time of detection. Genomic surveillance based on amplicon- and probe-based sequencing using short- and long-read technologies identified and quantified subpopulations of Delta and Omicron viruses in respiratory samples. These findings highlight the importance of integrated genomic surveillance in vulnerable populations and provide diagnostic pathways to recognise SARS-CoV-2 co-infection using genomic data.

Defining a significant stenosis in an autologous radio-cephalic arteriovenous fistula for hemodialysis.

The current definition of a significant stenosis in an autologous arteriovenous fistula (aAVF), the percentage narrowing compared with the adjacent "normal" vessel, is inaccurate. We believe a significant stenosis in the aAVF is an absolute minimal luminal diameter determined by the requirements of the hemodialysis pump. To determine what absolute diameter constitutes a hemodynamically significant stenosis in a radio-cephalic autologous arteriovenous fistula (RC aAVF), the minimal luminal diameter of dysfunctional RC aAVF was compared to that of functional RC aAVF using grayscale and color ultrasound. There were 93 fistulas in study group and 77 in control group. The mean minimum luminal diameter in study group was significantly lower than in control group (2.19 vs. 4.71 mm, p 0.001). With a cutoff value of 2.7 mm, there was 90% sensitivity and 80% specificity in distinguishing functional fistula from dysfunctional fistula. The area under the receiver-operator curve was 90% (CI 84-94%), indicating that a 2.7 mm diameter is accurate in discriminating functional from dysfunctional fistulas. An absolute minimal luminal diameter of 2.7 mm, as determined with grayscale and color ultrasound, is a useful cutoff for defining significant stenosis in a RC aAVF.

The CD40-CD154 co-stimulation pathway mediates innate immune injury in adriamycin nephrosis.

BACKGROUND: Blockade of CD40-CD40 ligand (CD154) interactions protects against renal injury in adriamycin nephropathy (AN) in immunocompetent mice. To investigate whether this protection relied on adaptive or cognate immunity, we tested the effect of CD40-CD154 blockade in severe combined immunodeficient (SCID) mice. METHODS: SCID mice were divided into three groups: normal, AN + hamster IgG (ADR+IgG group) and AN + anti-CD154 antibody (MR1) (ADR+MR1 group). AN was induced by tail vein injection of 5.2 mg/kg of adriamycin (ADR). Hamster IgG (control Ab) or MR1 was administered intraperitoneally on days 5, 7, 9 and 11 after ADR injection. Histological and functional data were collected 4 weeks after ADR injection. In vitro experiments tested the effect of soluble and cell-bound CD154 co-cultured with CD40-expressing cells [macrophages, mesangial cells and renal tubular epithelial cells (RTEC)]. RESULTS: All experimental animals developed nephropathy. Compared to the ADR+IgG group, ADR+MR1 animals had significantly less histological injury (glomerulosclerosis and tubular atrophy) and functional injury (creatinine clearance). Kidneys of ADR+MR1 animals had significantly less macrophage infiltration than those of ADR+IgG animals. Interestingly, expression of CD40 and CD41 (a platelet-specific marker) was significantly less in ADR+MR1 animals compared to ADR+IgG animals. In vitro, CD154 blockade significantly attenuated upregulation of CCL2 gene expression by RTEC stimulated by activated macrophage-conditioned medium. In contrast, platelet-induced upregulation of macrophage and mesangial cell proinflammatory cytokine gene expression were not CD154-dependent. CONCLUSION: CD40-CD154 blockade has a significant innate renoprotective effect in ADR nephrosis. This is potentially due to inhibition of macrophage-derived soluble CD154.

Effects of proactive iron and erythropoiesis-stimulating agent protocol implementation on achieving clinical guideline targets for anaemia in a satellite haemodialysis patient cohort.

AIM: Anaemia management with erythropoiesis-stimulating agents (ESA) and i.v. iron replacement in haemodialysis patients poses several clinical challenges, including maintaining stable haemoglobin (Hb) levels within target ranges while achieving lowest effective ESA dose. This manuscript describes the effect of implementing proactive protocol-driven adjustments for iron and ESA in maintenance haemodialysis patients. METHODS: This was a cohort study of 46 satellite haemodialysis patients examined from 2004 to 2006 with protocol implementation in 2005. Baseline haemoglobin, transferrin saturations (TSAT), ferritin values and ESA administration were obtained during 2004. Follow-up data was collected in 2006 and compared to baseline values in reference to specified targets in the 2004 Caring for Australasians with Renal Impairment (CARI) guidelines. RESULTS: Fifty-four percent of patients achieved haemoglobin targets during follow up versus 43% patients during baseline. Seventy-nine percent of patients achieved TSAT targets during follow up versus 67% patients during baseline. Ninety percent of patients achieved ferritin targets during follow up versus 75% patients during baseline. Odds ratios for values falling within target ranges during follow up compared to baseline were 1.63 (Hb: P = 0.037; 95% confidence interval (CI), 1.03-2.57), 1.90 (TSAT: P = 0.006; 95% CI, 1.20-3.01) and 3.72 (ferritin: P = 0.003; 95% CI, 1.57-8.83). There was a trend toward lower average ESA dose (P = 0.07). CONCLUSION: This study demonstrates the successful implementation and efficacy of a proactive protocol for iron and ESA treatment in haemodialysis patients. Benefits include increased concordance with historical guideline targets and decreased haemoglobin variability. Improved iron status and optimizing ESA response allows for lower ESA doses, limiting both potential side-effects of ESA (hypertension) and the burgeoning costs of anaemia management.

Danaparoid use for haemodialysis in a morbidly obese patient with heparin-induced thrombocytopenia - Need for a higher than recommended weight-based dosing.

WHAT IS KNOWN AND OBJECTIVE: Heparin is widely used to prevent clotting of the extracorporeal circuit during haemodialysis (HD). Heparin-induced thrombocytopenia (HIT) is a potentially devastating immune mediated adverse drug reaction caused by the emergence of antibodies that activate platelets in the presence of heparin, leading to a pro-thrombotic state. Danaparoid is an alternative anticoagulant used in patients on HD with HIT but its dosing recommendations in obese patients on HD are relatively scarce. CASE SUMMARY: We report a case of a 48-year-old morbidly obese patient who received weight-based dosing of danaparoid for HD with monitoring of anti-Xa activity. However, despite the patient's anti-Xa level being within the therapeutic range at various time points, the circuit lines kept clotting during HD. WHAT IS NEW AND CONCLUSION: The report provides evidence that the manufacturer's recommendations on dosing danaparoid based on body weight may lead to sub-optimal therapeutic benefit and highlight the need for higher than recommended weight-based dosing in obese individuals on dialysis.

Multicentre, randomised, blinded, control trial of drug-eluting balloon vs Sham in recurrent native dialysis fistula stenoses.

BACKGROUND: Endovascular treatment of autogenous arteriovenous haemodialysis fistula stenosis has high reintervention rates. We investigate the effect of drug-eluting balloons in the treatment of recurrent haemodialysis fistula stenosis. METHODS: This is a randomised, controlled, investigator-initiated and run, prospective, blinded, multicentre trial. Patients with recurrent autogenous arteriovenous haemodialysis fistula stenosis received standard endovascular treatment plus drug-eluting balloon or standard endovascular treatment plus uncoated balloon (Sham). Primary endpoint was late lumen loss in trial area on ultrasound at 6 weeks, 3, 6 and 12 months. Secondary endpoints were freedom from reintervention to the Index Trial Area and decline in fistula flow (Qa). Interim analysis was performed at 6 months (unblinded due to timeliness). RESULTS: Patients with 132 recurrent stenoses (48% in bare Nitinol stents) were randomised with 70 receiving drug-eluting balloon and 62 Sham. At 6 months, decline in late lumen loss was 0.23 ± 0.03 mm/month for Sham and 0.045 ± 0.03 mm/month for drug-eluting balloon arm, a significant difference (0.18 mm, p = 0.0002). At 12 months, this difference persisted at 0.12 mm (p = 0.0003). At 6 months, significant difference in late lumen loss for instent restenoses (p = 0.0004) was observed, with non-significant difference for unstented restenoses (p = 0.065). Mean time for freedom from reintervention was 10.14 months for Sham versus 42.39 months for drug-eluting balloon (p = 0.001). The same was shown for instent (p = 0.014) and unstented (p = 0.029) restenoses. Qa decline rate at 6 months was 36.89 mL/min/month (Sham) and 0.41 mL/min (drug-eluting balloon). The difference was significant (36.48 mL/min; p = 0.02) and persisted to 12 months (p = 0.44). CONCLUSION: Paclitaxel drug-eluting balloon significantly delays restenosis after angioplasty for recurrent autogenous arteriovenous haemodialysis fistula stenosis, persisting to 12 months. Drug-eluting balloon significantly increases freedom from reintervention at 12 months with these effects true in stented and unstented fistulas.

Protein Z is reduced in chronic kidney disease and not elevated in patients on haemodialysis.

Protein Z (PZ) is a vitamin K dependent serine protease inhibitor, which along with its cofactor Protein Z-dependant protease inhibitor (ZPI) has anti-Xa activity. PZ has previously been reported to be elevated in patients with end-stage chronic kidney disease (CKD) on haemodialysis but not in non-dialysed CKD patients raising the possibility that PZ may have a role in the bleeding diathesis of patients on haemodyalisis. PZ was measured in controls (n = 18), CKD on haemodialysis (n = 23) and CKD not on dialysis (n = 23). Patients on vitamin K antagonists, with acute inflammatory conditions (as measured by CRP) or liver dysfunction were excluded PZ levels were reduced in CKD patients when compared to levels in the control group (1.35 mug/mL vs 1.80 respectively, p = 0.022). Subgroup analysis revealed a trend toward reduction in mean PZ in the CKD subgroups (non-dialysed CKD group 1.37 (p = 0.08); haemodialysis 1.33 (p = 0.12)). There were no significant differences in the PZ levels for different stages of non-dialysed CKD patients when stratified by the level of glomerular filtration rate (GFR). These data show that PZ levels were reduced in patients with CKD, and not elevated in patients on haemodialysis, arguing against a role for PZ in the bleeding diathesis of renal failure. This finding is in contradiction to a previous report which found PZ to be elevated in patients on haemodialysis.

Diameter of inflow as a predictor of radiocephalic fistula flow.

INTRODUCTION:: The optimal method for vascular access surveillance is largely unknown. A previous case-control study suggested a simplified anatomical measure obtained by Doppler ultrasound-the narrowest segment of the circuit or "minimal luminal diameter" may identify patients with a dysfunctional radiocephalic arteriovenous fistula. The relationship between minimal luminal diameter and access flow (Qa) in the radiocephalic arteriovenous fistula has not previously been studied. METHODS:: Patients undergoing Doppler ultrasound of a radiocephalic arteriovenous fistula over an 8-month period were identified retrospectively. Minimal luminal diameter was identified and demographic and clinical data were collected. Qa was estimated by Doppler estimation of brachial artery flow. The relationship between minimal luminal diameter and Qa was examined by correlation and using different levels of minimal luminal diameter as a simplified measure to detect or exclude low Qa (<600 mL/min). RESULTS:: A total of 81 Doppler ultrasound scans were performed. In all, 26 scans demonstrated brachial artery flow <600 mL/min. Simple logistic regression indicated a weak statistical relationship between the minimal luminal diameter and Qa (R2 = 0.27, p < 0.01). Minimal luminal diameter performed poorly as a marker of low Qa with low specificity, however, showed high negative predictive value for ruling out low Qa at a minimal luminal diameter of 3.2 mm or higher (94%). Qa estimated by brachial artery flow correlated well with Qa estimated by indicator dilution (R2 = 0.83, p < 0.01) without significant mean difference or proportional bias. CONCLUSION:: Minimal luminal diameter correlates weakly with Qa. Low minimal luminal diameter values should not be used in isolation to determine low Qa for a radiocephalic arteriovenous fistula. Conversely, minimal luminal diameter >3.2 mm largely excludes a low-flow radiocephalic arteriovenous fistula in this cohort. Brachial artery flow is a reasonable measure of Qa in comparison with indicator dilution.

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.

HIF-1alpha expression follows microvascular loss in advanced murine adriamycin nephrosis.

Cellular hypoxia has been proposed as a major factor in the pathogenesis of chronic renal injury, yet to date there has been no direct evidence to support its importance. Therefore, we examined cortical hypoxia in an animal model of chronic renal injury (murine adriamycin nephrosis; AN) by assessing nuclear localization of the oxygen-dependent alpha-subunit of hypoxia-inducible factor-1 (HIF-1alpha) in animals 7, 14, and 28 days after adriamycin. Results were assessed in conjunction with quantitation of the cortical microvasculature (by CD34 immunostaining) and cortical expression of VEGF. Cortical apoptosis was also examined by terminal deoxynucleotidyl transferase dUTP nick-end labeling staining. A dramatic and significant increase in nuclear localization of HIF-1alpha was seen 28 days after adriamycin in the context of severe glomerular and tubulointerstitial damage. Areas of nuclear HIF-1alpha staining did not colocalize with areas of cellular apoptosis. AN was also associated with a significant attenuation of the peritubular capillaries that was significant at 14 and 28 days after adriamycin. Cortical VEGF expression fell in a stepwise manner from day 7 until day 28 after adriamycin. In conclusion, these data are consistent with a significant increase in cellular hypoxia occurring in the advanced stages of murine AN. Increased cortical hypoxia was preceded by significant reductions in both the number of peritubular capillaries (i.e., oxygen supply) and the angiogenic cytokine VEGF. Apart from providing the first direct evidence for cellular hypoxia in a model of chronic renal disease, these results suggest that a primary dysregulation of angiogenesis may be the cause of increased hypoxia in this model.

Can murine diabetic nephropathy be separated from superimposed acute renal failure?

BACKGROUND: Streptozotocin (STZ) is commonly used to induce diabetes in experimental animal models, but not without accompanying cytotoxic effects. This study was undertaken to (1) determine an optimal dose and administration route of STZ to induce diabetic nephropathy in wild-type mice but without the concurrent acute renal injury resulting from cytotoxic effects of STZ and (2) evaluate the pattern of tubular injury and interstitial inflammation in this model. METHODS: Male Balb/c mice received either (1) STZ (225 mg/kg by intraperitoneal injection.); or (2) two doses of STZ 5 days apart (150 mg/150 mg/kg; 75 mg/150 mg/kg; 75 mg/75 mg/kg; and 100 mg/100 mg/kg by intravenous injection). Another strain of mice, C57BL/6J, also received STZ (200 mg/kg intravenously or intraperitoneally). Renal function and histology were examined at weeks 1, 2, 4, and 8 after induction of diabetes. In initial optimization studies, animals were sacrificed at week 1 or week 2 and histology examined for acute renal injury. RESULTS: Following a single intraperitoneal injection of 225 mg/kg of STZ, only two thirds of animals developed hyperglycemia, yet the model was associated with focal areas of acute tubular necrosis (ATN) at week 2. ATN was also observed in C57BL/6J mice given a single intravenous or intraperitoneal dose of STZ (200 mg/kg), at week 2 post-diabetes. At an optimal diabetogenic dose and route (75 mg/150 mg/kg by intravenous injection 5 days apart), all mice developed diabetes and no ATN was observed histologically. However, even with this regimen, glomerular filtration rate (GFR) was significantly impaired from week 2. This regimen was accompanied by progressive histologic changes, including tubular and glomerular hypertrophy, mesangial area expansion, as well as interstitial macrophage, CD4+ and CD8+ T-cell accumulation. CONCLUSION: By careful optimization of STZ dose, a stable and reproducible diabetic murine model was established. However, even in this optimized model, renal functional impairment was observed. The frequency of ATN and functional impairment casts doubt on conclusions about experimental diabetic nephropathy drawn from reports in which ATN has not been excluded rigorously.