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The slow transformation of new research findings into clinical guidelines is a barrier to providing evidence-based care. The Caring for Australians and New Zealanders with Kidney Impairment (CARI) guidelines are developing models to improve guideline production, one methodology involves more functional concordance between trial groups, such as the Australian Kidney Trials Network (AKTN) and CARI. The objective of this project was to rapidly produce an evidence-based guideline on urate-lowering therapy in patients with chronic kidney disease (CKD), in response to new clinical trial publications on the topic by the AKTN.To produce a guideline as rapidly as possible, an existing systematic review was utilized as the evidence base, and then updated with the inclusion of clinical trials that had been published subsequently. A Work Group was convened to review the evidence and compose an appropriate guideline using CARI/GRADE methodology. The group met 3 times over 45 days to formulate the guideline.The result was a strong recommendation against the use urate-lowering therapies in individuals with CKD (not receiving dialysis) and asymptomatic hyperuricemia. The process of identifying an appropriate existing systematic review, updating the literature search, and synthesizing the evidence, was done by 2 individuals over 15 days. The Work Group was formulated and composed the guideline over 45 days. In all, a new guideline incorporating the most up-to-date evidence was formulated in 60 days.This method of guideline development represents a potentially new way of releasing guidelines that encapsulates all available evidence in a time-efficient manner.

Background In Australia, Lupus Nephritis (LN) affects a culturally diverse population of patients. We established the Lupus Nephritis Australian Registry (LUNAR) to better understand the population of patients receiving Myfortic and other immunosuppressants, and to analyse the safety and efficacy of the treatments they received. Methods A non-interventional, multicentre, registry of patients with biopsy-proven ISN/RPS class III, IV or V LN, treated with Myfortic or other immunosuppressants, was established. We collected baseline demographic and 6-monthly follow-up data over a 5-year period (2013–2018), including clinical data, laboratory tests and safety outcomes. Results 149 patients were enrolled in LUNAR across 8 sites, with 83.7% female and a mean age of 38.8 years. Most patients were Caucasian (45.2%) – patients of Asian ethnicity (29.6%) and Aboriginal/Torres Strait Islander or Maori/Pacific Islander descent (10.4%) were significantly over-represented compared to the general population. The mean and median duration of SLE was 8.6 and 6 years, respectively (range 0–42 years), and of LN was 5.4 and 3.9 years, respectively (range 0–30 years). Most patients had class IV LN on their initial kidney biopsy (59.3%), with 21.5% having class III and 11.1% having class V LN. Immunosuppressants used prior to screening included corticosteroids (68.9%), mycophenolate mofetil ((MMF) 61.5%), Myfortic (41.5%) and cyclophosphamide (32.6%). At enrolment or during the study, most patients were treated with Myfortic (76.3%), MMF (65.2%) and/or hydroxychloroquine (67.4%). Rituximab and azathioprine were each started in 8.9% of patients during the study period. Kidney function was stable/improved for most patients over the study period and mycophenolate-based therapy was well-tolerated. Conclusions LUNAR is the first study outlining the demographics, outcomes and practice patterns in the management of patients with LN in Australia. Acknowledgements Supported by funding from Novartis Pharmaceuticals.

Advanced training programmes in nephrology should provide broad exposure to all aspects of nephrology. In Australia and New Zealand (ANZ), the Advanced Training Committee in Nephrology oversees training, and recent increases in trainee numbers have led to concern about dilution of experience. To investigate early career paths of nephrologists in ANZ and determine the adequacy of training by comparing self-determined competency and skill relevance among recently graduated nephrologists. In 2015, the Advanced Training Committee in Nephrology administered an online survey during the annual subscription for members of the Australian and New Zealand Society of Nephrology. Nephrologists who were awarded Fellowship after 2002 were invited to participate. The survey was completed by 113 Fellows with 8 respondents excluded (response rate 44.1%). Initial post-Fellowship work included full-time public hospital appointments (34.3%) or undertaking full-time higher research degrees (41.9%). The majority reported securing their desired employment. Respondents indicated adequate training in most clinical skills; however, responses of 'well trained' in home haemodialysis (41.8%), conservative care (42.9%), automated peritoneal dialysis (38.8%), and assessment of kidney transplant recipients (48%) and living kidney donors (34.7%) were less adequate. Although considered highly relevant to current practice, responses of 'well trained' were low for management and research skills, including complaint management (16.3%), private practice management (2%), health system knowledge (14.3%) and regulations (6.1%), ethics approval (23.5%), research funding (11.2%) and quality assurance (26.5%). Nephrology training in ANZ generally meets clinical needs and most secure their desired employment. Training in management and research are areas for improvement.

Background Patients with early-stage chronic kidney disease (CKD) must make lifestyle modifications and adhere to treatment regimens to prevent their progression to end-stage kidney disease. The aim of this study was to elicit the perspectives of patients with stage 1–4 CKD about their disease, with a specific focus on their information needs in managing and living with CKD and its sequelae. Methods Patients with CKD stages 1–4 were purposively sampled from three major hospitals in Sydney, Australia to participate in focus groups. Transcripts were thematically analysed. Results From nine focus groups including 38 participants, six major themes were identified: medical attentiveness (shared decision-making, rapport, indifference and insensitivity); learning self-management (diet and nutrition, barriers to physical activity, medication safety); contextualizing comorbidities (prominence of CKD, contradictory treatment); prognostic uncertainty (hopelessness, fear of disease progression, disbelief regarding diagnosis); motivation and coping mechanisms (engage in research, pro-active management, optimism, feeling normal); and knowledge gaps (practical advice, access to information, comprehension of pathology results and CKD diagnosis, education for general practitioners). Conclusion Patients capacity to slow the progression of CKD may be limited by their lack of knowledge about the disease, its comorbidities, psychosocial influences and their ability to interact and communicate effectively with their health-care provider. Support from a multidisciplinary care team, combined with provision of comprehensive, accessible and practical educational resources may enhance patients' ability and motivation to access and adhere to therapeutic and lifestyle interventions to retard progression of CKD.

L. Amos, N. D. Toussaint, R. K. Phoon, T. J. Elias, V. Levidiotis, S. B. Campbell, A. M. Walker and C. Harrex

Background Consumer involvement in guideline development is advocated, but minimal participation, such as a nominated consumer representative on a guideline working group, can inhibit their decision-making power and contribution. Little is known about how to involve consumers more effectively in guideline development. Objective To describe a targeted approach for involving consumers actively in guideline development, by focusing on topic and outcome selection, and to discuss the impact on content and structure of the final guideline. Design Descriptive study. Setting and participants Patients and carers (n=24) from a tertiary hospital in Sydney attended three structured peer-facilitated workshops to complete group-based exercises on topic and outcome selection for guidelines for early stage chronic kidney disease. These workshops were run in parallel with the guideline-writing group. For each exercise, participants formed small groups and facilitated their own discussion, recorded their responses and presented them to the wider group. The topics and outcomes identified were fed back to the guideline writers. Results The participants actively engaged in the workshop discussions and articulated topics and outcomes they perceived should be included in clinical guidelines. Four main changes to guideline-related outputs were observed. A new guideline subtopic was introduced, guidelines were consumer-endorsed, guideline recommendations and suggestions for clinical care were augmented with consumer-focused issues, and plain English guidelines were developed. Conclusions Consumer workshops in parallel and feeding into guideline development can be a feasible and effective approach for active consumer contribution. This process can inform the development of both consumer-focused guidelines for clinicians and specific versions for consumers.

SUMMARY: Aim: Statins are widely used for their cholesterol-lowering effects and for prevention of cardiovascular disease. Evidence indicates that these drugs also have immunomodulatory and other non-lipid lowering effects, with studies suggesting benefit in some animal models of immune (particularly T helper (Th)1)-mediated inflammatory disease and their corresponding human disease counterparts. We sought to evaluate the immunomodulatory effects and therapeutic potential of atorvastatin in experimental crescentic glomerulonephritis, a Th1-predominant animal model of glomerulonephritis. Methods: Autologous phase, anti-glomerular basement membrane glomerulonephritis was induced in C57BL/6 mice by intravenous injection of sheep anti-mouse glomerular basement membrane globulin. Mice were administered atorvastatin (10 or 100 mg/kg) or control (phosphate-buffered saline) daily by oral gavage. Immune responses and renal injury were assessed after 21 days. Results: Compared with control-treated mice, treatment with atorvastatin did not alter renal injury (serum creatinine, proteinuria, glomerular crescent formation) or glomerular leukocytic infiltration (CD4+ T cells or macrophages). Atorvastatin resulted in a dose-related increase in circulating serum antibody to the disease-inducing antigen but no differences in antigen-stimulated splenocyte production of Th1/Th2 cytokines. At the higher dose, atorvastatin also led to a significant reduction in apoptosis of splenic CD4+ T lymphocytes. Conclusion: This study demonstrates that statins modulate humoral responses and alter splenic CD4+ T cell apoptosis. However, atorvastatin does not lead to significant changes in T helper cell polarization or renal injury in experimental crescentic glomerulonephritis.

T-bet is a transcription factor that is essential for T helper (Th)1 lineage commitment and optimal IFN-gamma production by CD4(+) T cells. We examined the role of T-bet in the development of experimental crescentic glomerulonephritis, which is induced by Th1-predominant, delayed-type hypersensitivity-like responses directed against a nephritogenic antigen. Anti-glomerular basement membrane (GBM) glomerulonephritis was induced in T-bet(-/-) and wild-type C57BL/6 mice. Compared with wild-type controls, renal injury was attenuated in T-bet(-/-) mice with glomerulonephritis, evidenced by less proteinuria, glomerular crescents, and tubulointerstitial inflammation. Accumulation of glomerular CD4(+) T cells and macrophages was decreased, and was associated with reduced intrarenal expression of the potent Th1 chemoattractants CCL5/RANTES and CXCL9/Mig. Supporting the pro-inflammatory nature of T-bet signaling, assessment of systemic immunity confirmed that T-bet(-/-) mice had a reduction in Th1 immunity. The kinetic profile of T-bet mRNA in wild-type mice supported the hypothesis that T-bet deficiency attenuates renal injury in part by shifting the Th1/Th2 balance away from a Th1 phenotype. Expression of renal and splenic IL-17A, characteristically expressed by the Th17 subset of effector T cells, which have been implicated in the pathogenesis of autoimmune disease, was increased in T-bet(-/-) mice. We conclude that T-bet directs Th1 responses that induce renal injury in experimental crescentic glomerulonephritis.

Objective To investigate the mechanisms underlying peripheral neuropathy and to provide insights into axonal Na + /K + pump function in patients with end-stage kidney disease (ESKD). Methods Nerve excitability was assessed in 10 ESKD patients before and after a single session of haemodialysis and in 29 age-matched control subjects. Changes in excitability were recorded at baseline and following maximal voluntary contraction (MVC) of abductor pollicis brevis (APB) for 60s. Serum concentrations of putative neurotoxins including potassium, urea, parathyroid hormone and beta-2-microglobulin were also measured. Results Baseline excitability values were consistent with axonal depolarisation prior to dialysis. Following maximal voluntary contraction (MVC), there was an increase in threshold, which was associated with reduced strength-duration time constant and increased superexcitability, consistent with axonal hyperpolarisation. These changes were quantitatively similar for patients and controls, arguing against any significant reduction in the axonal Na + /K + pump in ESKD. Following dialysis, activity-dependent changes were less in ESKD, which suggests greater Na + /K + pump activity prior to dialysis, the opposite of the changes expected with reduced Na + /K + pump function. The reduced post-contraction threshold change in post-dialysis recordings is likely to be secondary to relative hyperpolarisation of the axonal membrane following dialysis and reduction in K + concentration. Conclusions Our findings suggest that Na + /K + pump function is not impaired in patients with ESKD. Significance Pre-dialysis excitability changes in ESKD patients may be explained on the basis of hyperkalaemia. Alteration in Na + /K + pump function does not appear to be a contributing factor to the development of neuropathy in ESKD patients.

Although multiple toxins have been implicated in the development of uraemic neuropathy, no causative agent has been identified. In the present study, the excitability properties of lower limb motor nerves in patients with end-stage kidney disease treated with haemodialysis were measured before, during and after a standard 5 h haemodialysis session, in an attempt to explore the pathophysiology of uraemic neuropathy. Compound muscle action potentials were recorded from tibialis anterior and extensor digitorum brevis, following stimulation of the common peroneal nerve in 14 patients. Measures of excitability were assessed in relation to changes in serum levels of potential neurotoxins, including potassium, calcium, urea, uric acid, parathyroid hormone and beta-2-microglobulin. Before dialysis, measures of nerve excitability were significantly abnormal in the patient group for axons innervating tibialis anterior and extensor digitorum brevis, consistent with axonal depolarization: refractoriness was increased and superexcitability and depolarizing threshold electrotonus were reduced. Pre-dialysis excitability abnormalities were strongly correlated with serum K+. Correlation was also noted between the severity of symptoms and excitability abnormalities. Haemodialysis normalized the majority of nerve excitability parameters. In conclusion, lower limb motor axons in uraemic patients are depolarized before dialysis. The correlation between serum K+ and excitability measures indicates that hyperkalaemia is primarily responsible for uraemic depolarization, and a likely contributing factor to the development of neuropathy.

Summary Experimental crescentic glomerulonephritis is driven by systemic cellular immune responses. A pathogenic role for T helper type 1 (Th1) and Th17 cells is well established. T-bet, a key transcription factor required for Th1 lineage commitment, and retinoic acid-related orphan receptor-γt (Rorγt), a key Th17 transcription factor, are required for full expression of disease. Similarly, several Th1- and Th17-associated cytokines have been implicated in disease augmentation. The role of Th2 cells in the disease is less clear, although Th2-associated cytokines, interleukin (IL)-4 and IL-10, are protective. We sought to determine the role of signal transducer and activation of transcription 6 (STAT6), a key regulator of Th2 responses, in experimental crescentic glomerulonephritis. Compared to wild-type mice, histological and functional renal injury was enhanced significantly in STAT6–/– mice 21 days after administration of sheep anti-mouse glomerular basement membrane globulin. Consistent with the enhanced renal injury, both Th1 and Th17 nephritogenic immune responses were increased in STAT6–/– mice. Conversely, production of IL-5, a key Th2-associated cytokine, was decreased significantly in STAT6–/– mice. Early in the disease process systemic mRNA expression of T-bet and Rorγ was increased in STAT6–/– mice. We conclude that STAT6 is required for attenuation of Th1 and Th17 nephritogenic immune responses and protection from crescentic glomerulonephritis.

A 62-year-old woman presented with acute renal failure, hematuria, proteinuria, and increased C-reactive protein level. She was positive for antineutrophil cytoplasmic antibodies (ANCAs) directed against myeloperoxidase (MPO) and negative for anti–glomerular basement membrane antibody. Kidney biopsy confirmed a diagnosis of pauci-immune crescentic glomerulonephritis with no immunoglobulin G staining. Remission was induced with prednisolone and intravenous cyclophosphamide, followed by maintenance therapy with azathioprine, during which MPO-ANCA results became negative. Nine months after the initial presentation, kidney function rapidly deteriorated again in association with hematuria, proteinuria, and increased C-reactive protein level. A second kidney biopsy again showed crescentic glomerulonephritis; however, on this occasion, direct immunofluorescence showed prominent linear staining of the glomerular basement membrane with immunoglobulin G. Test results were strongly positive for glomerular basement membrane antibody, but remained negative for MPO-ANCA. HLA-DR typing showed HLA-DRB1*15011, an allele strongly associated with anti–glomerular basement membrane disease. To our knowledge, this is the only reported case of 2 distinct forms of crescentic glomerulonephritis characterized by separate autoantibody profiles developing sequentially in a patient with proved HLA susceptibility. We speculate that glomerular damage caused by the initial renal insult resulted in a subsequent autoimmune response to autoantigen presented on the HLA-DR susceptibility allele.

The autoantigen in Goodpasture disease is the noncollagenous domain of alpha3 type IV collagen [alpha3(IV)NC1]. We previously demonstrated that IL-12p40(-/-) mice are protected from experimental autoimmune anti-glomerular basement membrane (anti-GBM) glomerulonephritis, seemingly defining a role for IL-12 in this disease; however, the recent identification of IL-23, a heterodimer composed of IL-12p40 and IL-23p19 subunits, raises the possibility that IL-23, rather than IL-12, may modulate this disease instead. We immunized wild-type, IL-12p35(-/-) (IL-12 deficient, IL-23 intact), IL-12p40(-/-) (deficient in both IL-12 and IL-23), and IL-23p19(-/-) (IL-12 intact, IL-23 deficient) mice with recombinant mouse alpha3(IV)NC1. Wild-type mice developed autoreactivity to alpha3(IV)NC1: Humoral responses, cellular responses, renal histologic abnormalities, leukocyte accumulation, autoantibody deposition, and IL-17A mRNA expression (a cytokine produced by the IL-23-maintained Th17 subset). IL-23 but not IL-12 was detected in the immune system. Regardless of the presence of IL-12, mice deficient in IL-23 were protected, but mice with IL-23 were not. Both IL-23-deficient strains exhibited lower autoantibody titers, reduced cellular reactivity, diminished cytokine production (IFN-gamma [Th1], IL-17A [Th17], TNF, and monocyte chemoattractant protein 1), and less renal disease and glomerular IgG deposition. The deficient responses in the absence of IL-23 were not due to increased regulatory T cells; IL-12p40(-/-) and IL-23p19(-/-) mice did not show increased proportions of CD4(+)CD25(+)FoxP3(+) cells or IL-10 levels early in the immune response. In conclusion, autoreactivity to the Goodpasture antigen is directed primarily by IL-23, absence of which results in hyporeactivity including but extending beyond a deficient Th17 response.

Peripheral neuropathy is present in 65% of patients with end-stage kidney disease (ESKD). No cause is yet established: nerve excitability studies have shown that axons are chronically depolarized, primarily owing to hyperkalaemia, but in vitro studies have suggested a role for axonal Na+/K+ pump dysfunction. To investigate Na+/K+ pump activity in vivo, lower limb ischaemia was induced in five ESKD patients and six healthy controls by a sphygmomanometer cuff, inflated to 200 mm Hg and maintained for 13 min. The peroneal nerve was stimulated at the fibular neck and excitability parameters were recorded from tibialis anterior (TA) and extensor digitorum brevis (EDB) before, during and after the ischaemic period. Baseline excitability studies in ESKD patients demonstrated reductions in threshold electrotonus and superexcitability and increased refractoriness, consistent with membrane depolarization. During ischaemia, threshold increased in ESKD patients [by +23.6 +/- 5.0% (TA); +32.1 +/- 7.3% (EDB)] in contrast to the persistent threshold reduction observed in normal controls [-2.4 +/- 5.2% (TA); -13.0 +/- 8.2% (EDB); P0.01]. These changes were accompanied by increased refractoriness and reduced superexcitability in both ESKD and control groups, consistent with ischaemic depolarization. Conversely, there was reduction in strength-duration time constant towards the end of ischaemia. Following release of ischaemia, the marked increase in threshold observed in normal controls was not evident in ESKD patients, but the rapid return of threshold to baseline argues against significant Na+/K+ pump dysfunction. The abnormal pattern of response to ischaemia in the ESKD patients was not fully explained by the hyperkalaemic membrane depolarization and suggests that another dialysable factor affects nerve excitability in ESKD patients, most likely H(+) ions, but that this factor only becomes evident during ischaemia. Blockade of persistent Na+ conductances by H+ would also explain the reduction in strength-duration time constant observed during ischaemia.

Background: Peripheral neuropathy is present in 65% of patients with end stage kidney disease (ESKD) starting dialysis. Studies of membrane potential and axonal ion channel function may help explain the pathophysiology. Objectives: To follow changes in median sensory axon excitability in patients with ESKD treated with haemodialysis, and correlate them with clinical rating scales and serum levels of potential neurotoxins. Methods: Sensory nerve action potentials were recorded from the second digit following stimulation of the median nerve in 12 ESKD patients. Stimulus–response behaviour using two stimulus durations, threshold electrotonus to 100 ms polarising currents, a current–threshold relation, and recovery of excitability following supramaximal stimulation were recorded before, during, and after haemodialysis. Serum concentrations of potential neurotoxins were measured. Results: Before dialysis, there were changes in nerve excitability consistent with axonal depolarisation: refractoriness was increased; superexcitability and depolarising threshold electrotonus were reduced. Following dialysis there were improvements in all indices, with correlations between excitability abnormalities and serum potassium measurements. Neuropathic symptoms correlated with excitability changes. Conclusions: Nerves are depolarised before haemodialysis in ESKD patients. The correlation of excitability abnormalities with potassium indicates that the achievement of normokalaemia should be a priority in treating such patients.