BACKGROUND:IgA nephropathy, the most common primary glomerulopathy worldwide, is a kidney disorder of B-cell origin characterized by mesangial accumulation of IgA-containing immune complexes. In at least 50% of patients, IgA nephropathy leads to kidney failure or death within 10 to 20 years after diagnosis. Atacicept is a native human transmembrane activator and calcium-modulator and cyclophilin-ligand interactor (TACI)-Fc fusion protein that inhibits two key immunoregulatory cytokines - B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) - that are thought to be central to the pathophysiology of IgA nephropathy. METHODS:In this ongoing, phase 3, multicenter, double-blind, randomized, placebo-controlled trial, we assigned patients with IgA nephropathy in a 1:1 ratio to receive atacicept at a dose of 150 mg once weekly, administered subcutaneously by patients at home, or matching placebo. The primary end point was the percentage change from baseline in the 24-hour urinary protein-to-creatinine ratio at week 36. Safety was also evaluated. RESULTS:A total of 203 patients were included in the prespecified interim analysis: 106 patients in the atacicept group and 97 in the placebo group. At week 36, the percentage reduction from baseline in the urinary protein-to-creatinine ratio was 45.7% in the atacicept group and 6.8% in the placebo group, with a geometric mean between-group difference of 41.8 percentage points (95% confidence interval, 28.9 to 52.3; P<0.001). Adverse events were observed in 59.3% of the patients in the atacicept group and in 50.0% in the placebo group; most were mild or moderate in severity. CONCLUSIONS:In this prespecified interim analysis, treatment with atacicept resulted in a significantly greater reduction in proteinuria than placebo at week 36 in patients with IgA nephropathy. (Funded by Vera Therapeutics; ORIGIN 3 ClinicalTrials.gov number, NCT04716231.).

Key PointsParticipants who completed a 36-week double-blind study of atacicept were eligible for a 60-week, open-label extension study.Atacicept 96-week treatment resulted in sustained reductions in galactose-deficient IgA1, hematuria, and urine protein-creatinine ratio.The slope of the eGFR was similar to that observed in the general population without kidney disease.BackgroundB-cell activating factor (BAFF) and A proliferation-inducing ligand (APRIL) play key roles in the pathogenesis of IgA nephropathy. Atacicept is a novel fully humanized fusion protein, self-administered at home by subcutaneous injection, that binds and inhibits BAFF and APRIL. By inhibiting BAFF and APRIL, atacicept targets the underlying B-cell-mediated pathogenesis driving disease progression. This study evaluated the long-term efficacy and safety of atacicept in patients with IgA nephropathy over 96 weeks.MethodsParticipants with IgA nephropathy who received atacicept (25, 75, or 150 mg) or placebo in a 36-week phase 2b, randomized, blinded trial were enrolled in an open-label extension study and received atacicept 150 mg for an additional 60 weeks. Key efficacy outcomes were changes in galactose-deficient IgA1 (Gd-IgA1), percentage of participants with hematuria, urine protein-creatinine ratio (UPCR), and eGFR over 96 weeks. Long-term safety data were also evaluated.ResultsThere were 113 participants (67 [59%] male; 46 [41%] female) who ranged in age from 18 to 67 years who received >= 1 atacicept dose. Over 96 weeks, safety data demonstrated that atacicept was generally well tolerated. There were also sustained reductions (mean +/- SEM) in Gd-IgA1 (-66%+/- 2%), percentage of participants with hematuria (-75%; 95% confidence intervals, -87 to -59; in participants with baseline hematuria), and UPCR (-52%+/- 5%). The mean annualized slope of eGFR was -0.6 +/- 0.5 ml/min per 1.73 m2 through 96 weeks.ConclusionsAtacicept was also well tolerated over the duration of the study. Atacicept treatment reduced Gd-IgA1, hematuria, and UPCR with stabilization of eGFR through 96 weeks.Clinical Trial registry name and registration number:Atacicept in Subjects with IgA Nephropathy (ORIGIN 3), NCT04716231.

Atacicept is a first-in-class, dual anti-B-cell Activation Factor-A Proliferation-Inducing Ligand fusion protein in clinical evaluation for treatment of IgA nephropathy. To compare efficacy and safety of atacicept versus placebo in patients with IgAN, this randomized, double-blind, placebo-controlled phase 2b clinical trial ORIGIN enrolled 116 individuals with biopsy-proven IgA nephropathy. Participants were randomized to atacicept 150, 75, or 25 mg versus placebo once weekly for up to 36 weeks. Primary and key secondary endpoints were changes in urine protein creatinine ratio based on 24-hour urine collection at weeks 24 and 36, respectively, in the combined atacicept 150 mg and 75 mg group versus placebo. The primary endpoint was met at week 24 as the mean urine protein creatinine ratio was reduced from baseline by 31% in the combined atacicept group versus 8% with placebo, resulting in a significant 25% reduction with atacicept versus placebo. At week 36, the key secondary endpoint was met as the mean urine protein creatinine ratio reduced from baseline by 34% in the combined atacicept group versus a 2% increase with placebo, resulting in a significant 35% reduction with atacicept versus placebo. The reduction in proteinuria was accompanied by stabilization in endpoint eGFR with atacicept compared to a decline with placebo at week 36, resulting in significant between-group geometric mean difference of 11%, approximating an absolute difference of 5.7 mL/min/1.73m2. Endpoint galactose deficient IgA1 levels significantly decreased from baseline by 60% versus placebo. The safety profile of atacicept was like placebo. Thus, our results provide evidence to support a pivotal, phase 3 study of atacicept in IgA nephropathy.

Aim People with chronic kidney disease experience high rates of cardiovascular disease. Cholesterol-lowering therapy is a mainstay in the management but there is uncertainty in the treatment effects on patient-important outcomes, such as fatigue and rhabdomyolysis. Here, we summarise the updated CARI Australian and New Zealand Living Guidelines on cholesterol-lowering therapy in chronic kidney disease. Methods We updated a Cochrane review and monitored newly published studies weekly to inform guideline development according to international standards. The Working Group included expertise from nephrology, cardiology, Indigenous Health, guideline development and people with lived experience of chronic kidney disease. Results The guideline recommends people with chronic kidney disease (eGFR >= 15 mL/min/1.73 m(2)) and an absolute cardiovascular risk of 10% or higher should receive statin therapy (with or without ezetimibe) to reduce the risk of cardiovascular events and death (strong recommendation, moderate certainty evidence). The guidelines also recommends a lower absolute cardiovascular risk threshold (>= 5%) for Aboriginal and Torres Strait Islander Peoples and M & amacr;ori with chronic kidney disease to receive statin therapy (with or without ezetimibe) (strong recommendation, low certainty evidence). The evidence was actively surveyed from 2020-2023 and updated as required. No changes to guideline recommendations were made, with no new data on the balance and benefits of harms. Conclusions The development of living guidelines was feasible and provided the opportunity to update recommendations to improve clinical decision-making in real-time. Living guidelines provide the opportunity to transform chronic kidney disease guidelines.

Chronic kidney disease (CKD) is a major cause of morbidity and mortality, contributing to approximately 20 000 deaths in 2021 in Australia. Importantly, progression of CKD can be substantially reduced if it is detected and treated early. Here we present the perspectives of a general practitioner (primary care physician), a nephrologist and a patient advocate on how the diagnosis and management of CKD in primary care could be improved. Early detection and treatment of CKD are impeded by limited patient awareness and knowledge, communication challenges between patients and doctors, and psychosocial issues, with these factors also interacting with, and exacerbating, each other. We make the following recommendations to help improve outcomes in patients with CKD: (1) identifying people at increased risk of CKD and ensuring they have a complete kidney health check (including estimated glomerular filtration rate, urine albumin-creatinine ratio and a blood pressure check) every 1−2 years; (2) using simple, nonconfrontational language and supportive resources to communicate with patients about kidney health; (3) implementing early treatment to slow the progression of CKD and avoid adverse cardiovascular disease outcomes; and (4) asking patient-orientated questions to support shared decision-making and empower patients to be active partners in their healthcare. We acknowledge that limited time is a major barrier to implementing these recommendations in primary care. Utilizing the expertise of the whole practice team, and adopting supportive technology to introduce efficiencies, are likely to be of benefit. By adopting these recommendations, we believe general practitioners have the opportunity to drive improved outcomes and quality of life for people living with CKD in Australia.

Introduction: 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 publica-tions on the topic by the AKTN.Methods: 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.Results: 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.Conclusion: This method of guideline development represents a potentially new way of releasing guide-lines 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.

A nephrologist should have the generic skills of a consultant general physician, plus theoretical knowledge, and skills in nephrology. Moving on from a purely apprenticeship model, in the last 40 years several countries have listed the desirable knowledge and skills content for a specialist nephrologist in their jurisdiction. Some of these lists are exhaustive. Assessments of competence often include a written test of knowledge, and workplace based assessment or reports on specific skills or overall performance. We list some of the common generic headings used to define these areas of competence, and point to some curricula for specialist nephrologists. We also summarize methods of learning and point to resources which are available internationally, particularly online. The majority of the numerical need for additional nephrologists globally is in regions with fewer physicians, and fewer resources for their education. The ISN has proposed a global curriculum and identified how this might be tailored to regional needs. We might all help with producing support learning internationally, and we point to some good sources below. How to best support the development of nephrologists in these regions without unintentionally attracting them away from places of greatest need is an important question.

Membranous glomerulonephritis (MGN) is a leading cause of nephrotic syndrome worldwide. It is characterised by formation of subepithelial deposits of immunoglobulins and complement resulting in alteration to the glomerular basement membrane, leading to proteinuria.1Glassock R.J. Adler S.G. Ward H.J. Cohen A.H. Brenner B.M. Rector F.C. The Kidney. Saunders, Philadelphia1986: 929-1013Google Scholar Approximately 75% of MGN are primary or idiopathic and the remainder secondary causes include systemic lupus erythematosus (SLE), infections such as hepatitis B or C virus, malignancy and use of certain drugs. Antineutrophil cytoplasmic antibodies (ANCA)-associated glomerulonephritis (GN) typically presents with rapidly progressive glomerulonephritis (RPGN) characterised by necrotising and crescentic glomerulonephritis (NCGN) with a paucity of immune complex deposition, which is also generally classified as pauci-immune crescentic and necrotising glomerulonephritis (PCNGN).2Kaldas A. Warraich I. Prabhakar S. ANCA associated glomerulonephritis – an in depth review.J Nephrol Ther. 2013; 4: 147Google Scholar Concurrent MGN with ANCA-associated NCGN in the same patient is an unusual combination, rarely cited in the literature.3Nasr S.H. Said S.M. Valeri A.M. et al.Membranous glomerulonephritis with ANCA-associated necrotizing and crescentic glomerulonephritis.Clin J Am Soc Nephrol. 2009; 4: 299-308Crossref PubMed Scopus (73) Google Scholar, 4Kanahara K. Yorioka N. Nakamura C. et al.Myeloperoxidase antineutrophil cytoplasmic antibody-associated glomerulonephritis with membranous nephropathy in remission.Intern Med. 1997; 36: 841-846Crossref PubMed Scopus (23) Google Scholar, 5Tse W.Y. Howie A.J. Adu D. et al.Association of vasculitis glomerulonephritis with membranous nephropathy. A report of 10 cases.Nephrol Dial Transplant. 1997; 12: 1017-1027Crossref PubMed Scopus (69) Google Scholar, 6Hanamura K. Tojo A. Kinugasa S. et al.Detection of myeloperoxidase in membranous nephropathy-like deposits in patients with anti-neutrophil cytoplasmic antibody-associated glomerulonephritis.Hum Pathol. 2011; 42: 649-658Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar We present a case of membranous GN with myeloperoxidase (MPO) positive ANCA-associated NCGN in a patient with RPGN. A 55-year-old Asian male patient was referred by his local medical officer (LMO) and admitted to hospital for investigation for acute deterioration in renal function. His creatinine was 673 μmol/L [reference range (RR) 60–110] on admission, peaking at 732 μmol/L during admission. A few months earlier, his baseline creatinine had been 75 μmol/L. His background medical history included interstitial lung disease, type 2 diabetes, hypertension, hypercholesterolaemia and benign prostatic hypertrophy. Prior to admission, he was being investigated by his LMO for nocturia, frequency and dysuria that had been ongoing for a few months. He also experienced unintentional weight loss (2 kg) but was otherwise well, barring a persistent dry cough which was attributed to pre-existing interstitial lung disease. On physical examination, he was afebrile, normotensive, euvolaemic with no pitting oedema. His chest was clear and there were no palpable abdominal masses. Other laboratory values at time of referral showed mild microcytic anaemia (HGB 103 g/L, MCV 79 fL, MCH 27 pg, Hct 0.31 L/L), decreased eGFR 14 mL/min/1.73m2, elevated urea 29.4 mmol/L (RR 3–7.5), elevated WCC 14×109/L (RR 3.7–9.5), normal platelet count 350×109/L, total serum protein 75 g/L (RR 63–84); low serum albumin 16 g/L (RR 35–50), elevated random glucose 17.3 mmol/L (RR 3.0–7.7), serum sodium 133 mmol/L (RR 135–145) and normal LFTs. Further laboratory testing showed normal levels of ANA and double stranded (DS) DNA antibodies, slightly increased C3 1.73 g/L (RR 0.74–1.57) and C4 0.55 g/L (RR 0.13–0.41). Other immunological tests showed elevated MPO antibodies >100 U/mL (RR <10), normal ANCA PR3 antibodies 2 U/mL (RR <5), elevated ESR 116 mm/hr H (RR 1–20) and CRP 170 mg/L (RR <3). Urine analysis showed 2.57 g/day proteinuria, microhaematuria, urine white cell count 10–100×106/L (RR <10) and occasional hyaline casts. Urine immunoelectrophoresis showed elevated kappa light chains 629.21 mg/L (RR 3.3–19.4) and lambda light chains 277.58 mg/L (RR 5.71–26.30) with a kappa/lambda ratio of 2.27 (RR 0.26–1.65). Other screening tests for hepatitis B, hepatitis C, human immunodeficiency virus, herpes simplex virus, anti-glomerular basement membrane, and tuberculosis were negative. Renal ultrasound showed normal-sized bilateral kidneys with no obstructive lesions. Initial chest X-ray showed coarse interstitial opacities diffusely in both lungs, consistent with pre-existing interstitial lung disease. Blood and urine cultures were negative. A renal biopsy was subsequently performed. On microscopic examination, a total of 19 glomerular profiles were identified, none of which were sclerosed. Up to 12 glomeruli per section showed crescent formation of cellular type. Up to 12 glomeruli showed fibrinoid necrosis, eight of which were associated with crescent formation (Fig. 1A). Elsewhere, the capillary loops unaffected by crescents or fibrinoid necrosis show thickened walls. Spike formation was identified with silver stain. The tubules showed mild to moderate tubular atrophy. Acute tubular injury was also seen. The interstitium showed mild to moderate interstitial fibrosis with patchy foci of inflammation. One small muscular artery showed vasculitis featuring segmental fibrinoid necrosis (Fig. 1B). Immunofluorescence studies (IF) showed fine diffuse capillary loop staining for IgG (2+) (Fig. 2), IgA (2+), IgM (3+), C3 (1+). C1q staining was negative. Electron microscopy showed mainly stage 3 MGN with many subepithelial electron deposits incorporated within the GBM (Fig. 3A). This was associated with evolution to stage 4 MGN with occasional incorporated deposits showing dissolution (Fig. 3B). Based on the above findings with the exclusion of systemic lupus erythematosus and anti-GBM nephritis, a diagnosis of MPO positive ANCA-associated crescentic and necrotising GN with membranous GN was made. Despite the abnormal urine immunoelectrophoresis result, our findings did not support a diagnosis of monoclonal immunoglobulin deposition disease and thus the aberrant result was disregarded. As the ANCA-associated NCGN appeared to be the disease process of main concern for the treating clinical team, aggressive therapy was commenced. He was treated with pulse methylprednisolone therapy 500 mg IV daily for 3 days, oral prednisone (50 mg initially) and one dose of cyclophosphamide (750 mg). He also required one session of dialysis. A vascath was also inserted, through which he received 2 weeks of plasmapharesis. During admission, he suffered an episode of haemoptysis and hypoxia that was attributed to pulmonary haemorrhage. The patient was discharged 3 weeks following admission on 40 mg of oral prednisone with the aim to wean further in the coming months. On discharge, his creatinine had steadily declined to 328 μmol/ L but never returned to normal baseline levels. MGN coexisting with ANCA-associated NCGN is a very rare combination, although MGN alone may rarely present with crescents and/or fibrinoid necrosis. When a crescentic and necrotising GN pattern coexists with membranous GN, there are three main plausible clinical scenarios. The first occurs in the clinical setting of SLE, corresponding to ISN/RPS lupus nephritis class III and V or IV and V.7Pasquali S. Banfi G. Zuccheli A. et al.Lupus membranous nephropathy: long term outcome.Clin Nephrol. 1993; 39: 175-182PubMed Google Scholar The other differential diagnosis includes MGN superimposed with ANCA-associated disease or anti-GBM disease. In the largest series of 14 patients reported by Nasr et al.3Nasr S.H. Said S.M. Valeri A.M. et al.Membranous glomerulonephritis with ANCA-associated necrotizing and crescentic glomerulonephritis.Clin J Am Soc Nephrol. 2009; 4: 299-308Crossref PubMed Scopus (73) Google Scholar where concurrent MGN and ANCA-associated NCGN was encountered, the patients had a clinical presentation of heavy proteinuria and acute renal failure. The degree of proteinuria in patients with MGN and ANCA-associated GN was also likely to be heavier with a mean of 6.5 g reported by Nasr et al.3Nasr S.H. Said S.M. Valeri A.M. et al.Membranous glomerulonephritis with ANCA-associated necrotizing and crescentic glomerulonephritis.Clin J Am Soc Nephrol. 2009; 4: 299-308Crossref PubMed Scopus (73) Google Scholar compared with 1.7 to 2.5 g in patients with ANCA-associated GN alone.8Chen M. Yu F. Zhang Y. Zhao M.H. Antineutrophil cytoplasmic autoantibody-associated vasculitis in older patients.Medicine. 2008; 87: 203-209Crossref PubMed Scopus (103) Google Scholar The patient in our case, however, had low level of proteinuria, possibly attributed to the relatively low GFR. In two of the larger series of 10 and 14 patients by Tse et al.5Tse W.Y. Howie A.J. Adu D. et al.Association of vasculitis glomerulonephritis with membranous nephropathy. A report of 10 cases.Nephrol Dial Transplant. 1997; 12: 1017-1027Crossref PubMed Scopus (69) Google Scholar and Nasr et al.3Nasr S.H. Said S.M. Valeri A.M. et al.Membranous glomerulonephritis with ANCA-associated necrotizing and crescentic glomerulonephritis.Clin J Am Soc Nephrol. 2009; 4: 299-308Crossref PubMed Scopus (73) Google Scholar, most of the patients were elderly with a mean age of 63.5 and 58.7 years, respectively, with a male preponderance. The mechanism of concurrent MGN with ANCA-associated glomerulonephritis is unknown as the pathogenesis of the two disease processes is distinct and there are limited samples available for study. Nasr et al.3Nasr S.H. Said S.M. Valeri A.M. et al.Membranous glomerulonephritis with ANCA-associated necrotizing and crescentic glomerulonephritis.Clin J Am Soc Nephrol. 2009; 4: 299-308Crossref PubMed Scopus (73) Google Scholar and Tse et al.5Tse W.Y. Howie A.J. Adu D. et al.Association of vasculitis glomerulonephritis with membranous nephropathy. A report of 10 cases.Nephrol Dial Transplant. 1997; 12: 1017-1027Crossref PubMed Scopus (69) Google Scholar concluded their existence was likely coincidental, as most patients with MGN and ANCA-associated GN were diagnosed simultaneously, therefore causal relationship is quite probable. This is in contrast with concurrent MGN and anti-GBM disease, where MGN preceded the development of anti-GBM disease in 50% of reported cases.9Nayak S.G. Satish R. Crescentic transformation in primary membranous glomerulopathy: association with anti-GBM antibody.Saudi J Kidney Dis Transplant. 2007; 18: 599-602Google Scholar On the other hand, this does not explain all cases when MGN and ANCA-GN were diagnosed at different time periods, as there have been few reported cases of MPO-ANCA-GN found during the remission of MGN.4Kanahara K. Yorioka N. Nakamura C. et al.Myeloperoxidase antineutrophil cytoplasmic antibody-associated glomerulonephritis with membranous nephropathy in remission.Intern Med. 1997; 36: 841-846Crossref PubMed Scopus (23) Google Scholar, 5Tse W.Y. Howie A.J. Adu D. et al.Association of vasculitis glomerulonephritis with membranous nephropathy. A report of 10 cases.Nephrol Dial Transplant. 1997; 12: 1017-1027Crossref PubMed Scopus (69) Google Scholar Hanamura et al.6Hanamura K. Tojo A. Kinugasa S. et al.Detection of myeloperoxidase in membranous nephropathy-like deposits in patients with anti-neutrophil cytoplasmic antibody-associated glomerulonephritis.Hum Pathol. 2011; 42: 649-658Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar reported that myeloperoxidase might form immune complexes and develop MGN-like lesions in some cases of pauci-immune crescentic GN by demonstrating partial co-localisation of MPO and IgG within the electron deposits. Subsequent testing for anti M-type phospholipase A2 receptor antibody (PLA2R1), a marker of primary or idiopathic MGN,10Beck Jr., L.H. Bonegio R.G. Lambeau G. et al.M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy.New Engl J Med. 2009; 361: 11-21Crossref PubMed Scopus (1501) Google Scholar was not demonstrated in our case, thus primary MGN could not be confirmed. However, this test has a diagnostic sensitivity of 70–80%,10Beck Jr., L.H. Bonegio R.G. Lambeau G. et al.M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy.New Engl J Med. 2009; 361: 11-21Crossref PubMed Scopus (1501) Google Scholar and it is possible our test was a false negative result hence does not exclude primary MGN. PLA2R assessed in glomerular deposits on immunofluorescence assay is also more sensitive than serum anti-PLA2R antibodies11Debiec H. Ronco P. PLA2R autoantibodies and PLA2R glomerular deposits in membranous nephropathy.New Engl J Med. 2011; 364: 689Crossref PubMed Scopus (245) Google Scholar and would have been helpful in our case but was unavailable as a diagnostic tool. Our electron microscopy findings also showed stage 3-4 MCN, relatively old lesions of MGN indicating that the MGN had been present for some time, most likely preceding ANCA-associated CNGN, disputing the theory that MPO-ANCA-associated GN caused secondary MGN. MGN can be classified into primary and secondary forms according to IgG subclass,12Kuroki A. Shibata T. Honda H. Totsuka D. Kobayashi K. Sugisaki T. Glomerular and serum IgG subclasses in diffuse proliferative lupus nephritis, membranous lupus nephritis, and Idiopathic membranous nephropathy.Intern Med. 2002; 4: 936-942Crossref Scopus (112) Google Scholar with predominant IgG4 pattern in primary MGN; however, IgG1 may also be present. The serum subclass of MPO-ANCA consisted mainly of IgG1 and IgG4.13Segelmark M. Wieslander J. IgG subclasses of antineutrophil cytoplasm autoantibodies (ANCA).Nephrol Dial Transplant. 1993; 8: 696-702PubMed Google Scholar The overlapping IgG subclass distributions between the two entities are not supportive of a link between the two; however, analysis of the IgG subclass may be helpful to differentiate ANCA-GN coexisting with secondary MGN such as malignancy-associated MGN in which the serum IgG subclass is predominantly IgG1 and IgG2.14Ohtani H. Wakui H. Komatsuda A. et al.Distribution of glomerular IgG subclass deposits in malignant-associated membranous nephropathy.Nephrol Dial Transplant. 2004; 19: 574-579Crossref PubMed Scopus (155) Google Scholar Compared with MGN alone, which often has an insidious course with renal failure developing over many years, the clinical course of MGN with ANCA-associated NCGN is more aggressive with a worse outcome than MGN alone. Often patients present with acute renal failure, or progress to renal failure over a period of months.8Chen M. Yu F. Zhang Y. Zhao M.H. Antineutrophil cytoplasmic autoantibody-associated vasculitis in older patients.Medicine. 2008; 87: 203-209Crossref PubMed Scopus (103) Google Scholar Nasr et al.3Nasr S.H. Said S.M. Valeri A.M. et al.Membranous glomerulonephritis with ANCA-associated necrotizing and crescentic glomerulonephritis.Clin J Am Soc Nephrol. 2009; 4: 299-308Crossref PubMed Scopus (73) Google Scholar also found in their series of patients that MGN and ANCA-associated NCGN are also likely to have a worse outcome compared with ANCA-associated NCGN alone, despite similar treatments, with 50% of patients reaching endpoints of end-stage renal disease or death. In conclusion, we present a rare case of MPO-ANCA CNGN coexisting with MGN. The exact mechanism for this rare concurrent dual glomerulopathy remains unclear and further studies are required for clarification, in particular the precise onset of the diseases, testing for anti M-type phospholipase A2 receptor antibody and analysis of IgG subclass in the glomerular deposition. The authors state that there are no conflicts of interest to disclose.

AIM:Diabetes, hypertension and smoking may contribute to the development and progression of chronic kidney disease (CKD) and its complications. The aim of this study was to assess patients' awareness and beliefs about these and other risk factors associated with CKD.METHODS:Participants with CKD Stages 1-5 were purposively sampled for participation in a mixed methods study. Focus group participants completed a survey on CKD risk factors and discussed the reasons for their choices. Thematic analysis was used to analyse the qualitative data.RESULTS:Of the 38 participants, the proportion who identified hypertension, family history, diabetes and obesity as risk factors for CKD were 89%, 87%, 87% and 70% respectively. Only 54% and 38% recognized that smoking and Aboriginal or Torres Strait Islander status were risk factors. Participants considered the risks of heart attack, stroke and premature mortality to be 20-40% lower in people with CKD than those with diabetes or pre-existing cardiovascular disease. Five themes were identified: invisibility (lack of signs and symptoms of CKD), invincibility (participants did not feel they were at risk), lacking awareness (identified not knowing much about their disease), cumulative comorbidities (concerned about the increased risks of associated diseases) and inevitability of death (there is no cure for CKD).CONCLUSION:Participants had good understanding of some risk factors for CKD (hypertension and diabetes) but limited understanding of others. Awareness of comorbidities was also less than for other chronic conditions. Compared with diabetes and cardiovascular disease, CKD was perceived to pose less of a threat to life. Patient education that addresses CKD risk factors, comorbidities and outcomes may increase awareness and foster better self-management for people with CKD.

BackgroundPatients 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.MethodsPatients with CKD stages 1-4 were purposively sampled from three major hospitals in Sydney, Australia to participate in focus groups. Transcripts were thematically analysed.ResultsFrom 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).ConclusionPatients 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.Summary at a Glance This paper makes the important point that, by improving the patients' knowledge about the disease and its comorbidities, together with better communication with the health-care provider, the adherence to therapy may improve. In so doing, retardation in the progression of CKD may be better achieved. A multidisciplinary care team approach may enhance this management process.

KHA-CARI has been developing guidelines de novo for an Australian & New Zealand target audience since 1999. KDIGO was set up in 2002 to explore the possibility of developing international chronic kidney disease (CKD) guidelines. The science and evidence based care of those with CKD are universal and independent of geographical location/national borders. It is important to avoid duplication of effort by organizations and to efficiently use the available expertise and resources. As a consequence KHA-CARI have committed to adapting selected KDIGO guidelines to meet Australian and New Zealand circumstances and requirements rather than producing separate guidelines. This summary guideline is an adaptation of the KDIGO Clinical Practice Guideline for Acute Kidney Injury.1 The summary includes a brief description of the adaptation methodology and the adapted recommendations and suggestions for each subtopic. The complete KHA-CARI adapted guideline can be accessed at the KHA-CARI website (http://www.cari.org.au). The ultimate purpose of the adapted guideline is to provide a comprehensive listing of recommendations relevant to Australian and New Zealand practice following a detailed review and update of the KDIGO guidelines. The KDIGO Clinical Practice Guideline for Acute Kidney Injury (AKI) was published in March 2012 and contained five sections on the topics 'Introduction and Methodology', 'AKI Definition', 'Prevention and Treatment of AKI', 'Contrast-induced AKI' and 'Dialysis Interventions for Treatment of AKI'. This adapted guideline addresses issues relevant to the care of patients with acute kidney injury in Australia and New Zealand. The guideline does not address issues related to vascular access, dialyser membranes, use of bicarbonate versus lactate as a buffer in dialysate, and criteria for stopping renal replacement therapy in AKI. The section on biomarkers has been updated and the definition of AKI has been broadened. The incidence of AKI is increasing worldwide.2 While epidemiological data on AKI is sparse, an indication from Australian hospital separation data and peer reviewed articles suggest that the incidence of AKI is increasing. In Australia in 1998–1999 AKI accounted for 0.075% of total hospital separations and in 2009–2010 this figure increased to 0.094%.3 In the intensive care unit (ICU) on the day of admission between 35–40% of patients admitted to ICU fulfil the RIFLE criteria for AKI.4 Further examination of 20 ICUs in Australia over a 10 year period from 1 January 1996 to 31 December 2005 indicated that the crude incidence of AKI was increasing annually by 2.8%.5 Specific epidemiological data on AKI in New Zealand is lacking. We recommend using either iso-osmolar or low-osmolar iodinated contrast media, rather than high-osmolar iodinated contrast media, in patients at increased risk of CI-AKI. (1B) Since iohexol use as an intra-arterial injection in patients with pre-existing renal impairment is associated with an increase in CI-AKI risk when compared to iodixanol, we suggest avoiding iohexol use in this high risk setting. (1B) We recommend IV volume expansion with isotonic saline or sodium bicarbonate, rather than no IV volume expansion, in patients at increased risk for CI-AKI. (1A) We suggest that isotonic sodium bicarbonate for IV volume expansion is at least equivalent to isotonic sodium chloride in prevention of CI-AKI. (2A) Dose and delivery of dialysis We recommend the following dose of dialysis should be prescribed/delivered in AKI patients: No recommendations or suggestions possible due to lack of evidence. R.G. Langham has received honorarium and travel support from Amgen (2010–2013), consulting fees from Astra Zeneca (2013), travel support to travel to a European nephrology meeting from Novartis (2012) and honorarium for Advisory Board role from MSD (2011). R. Bellomo has received consultancy fees from Gambro Pty Ltd & Baxter Pty Ltd, for consultation regarding acute dialysis and fluid market. An Honorarium has been provided by B. Braun Pty Ltd for consultation regarding fluid management, Gambro Pty Ltd additionally paid for R. Bellomo travel to a dialysis meeting. V. D'Intini received financial support from Servier to attend the DNT Workshop in Alice Springs in March 2013. Z. Endre has received an Honorarium from Novartis Transplant Advisory Board (2012, 2013), financial support for travel from Alere (2010) and Novartis (2011) and Accommodation Amgen (2013). Research funding has been provided by Alere, Argutis, Abbot (2007–2010) for provision of assay kits. M.P. Gallagher received an honorarium from Amgen and Abbvie, Amgen also sponsor a research fellowship at The George Institute. S. McGuinness received financial support from Fresenius for CHEST study and financial support from Baxter for the SPLIT and Supplement PN studies. B.B. Hickey has no financial affiliations that would cause a conflict of interest according to the conflict of interest statement set down by KHA-CARI. R.K.S. Phoon has received consultancy fees from Baxter (2011, 2012), Janssen (2012), Novartis (2011, 2012, 2013), and Sanofi (2012). Financial support has been provided for R Phoon for travel and conference registration from Novartis (2013), Amgen (2013) and Roche (2012). Research funding has been provided to R Phoon by Amgen in 2012. K. Salamon has no financial affiliations that would cause a conflict of interest according to the conflict of interest statement set down by KHA-CARI. J. Woods has no financial affiliations that would cause a conflict of interest according to the conflict of interest statement set down by KHA-CARI. The evidence and recommendations in this KHA-CARI guideline have been evaluated and graded following the approach detailed by the GRADE working group (http://www.gradeworkinggroup.org). A description of the grades and levels assigned to recommendations is provided in Tables A1 and A2. For a full text version of the guideline, readers need to go to the KHA-CARI website (http://www.cari.org.au).

This guideline addresses issues relevant to the detection, primary prevention and management of early chronic kidney disease. Chronic kidney disease (CKD) is a major public health problem in Australia and throughout the world. Based on data from the Ausdiab study,1 it is estimated that over 1.7 million Australian adults have at least moderately severe kidney failure, defined as an estimated glomerular filtration rate (eGFR) less than 60 mL/min per 1.73 m2. This pernicious condition is often not associated with significant symptoms or urinary abnormalities and is unrecognized in 80–90% of cases.1-3 CKD progresses at a rate that requires approximately 2300 individuals each year in Australia to commence either dialysis or kidney transplantation.4 Furthermore, the presence of CKD is one of the most potent known risk factors for cardiovascular disease (CVD), such that individuals with CKD have a 2- to 3-fold greater risk of cardiac death than age- and sex-matched controls without CKD.5-7 According to death certificate data, CKD directly or indirectly contributes to the deaths of approximately 10% of Australians and is one of the few diseases in which mortality rates are worsening over time.8 However, timely identification and treatment of CKD can reduce the risks of CVD and CKD progression by up to 50%.9 Early detection of CKD may therefore have value, although criteria for a screening programme to detect the disease must be met to balance the aggregate benefits with the risks and costs of the screening tests. General practitioners, in particular, play a crucial role in CKD early detection and management. All people attending their general practitioner should be assessed for CKD risk factors as part of routine primary health encounters. A number of studies10-20 have further demonstrated that early referral of patients with more serious CKD to a multidisciplinary renal unit is associated with reduced rates of kidney failure decline, decreased need for and duration of hospitalization, increased likelihood of permanent dialysis access created prior to dialysis onset, reduced initial costs of care following the commencement of dialysis, increased likelihood of kidney transplantation, and decreased patient morbidity and mortality. Nevertheless, approximately one-quarter of CKD patients in Australia are referred ‘late’ to nephrologists (i.e. within 3 months of needing to commence kidney replacement therapy).4 Such ‘late referred’ patients have markedly reduced survival rates on dialysis and are much less likely to receive a kidney transplant.21 The objective of this guideline is to identify what risk factors, present in an appreciable portion (>5%) of the community, are associated with the development of CKD and which are remediable or potentially modifiable, in order to detect early CKD and intervene at the earliest possible stage. Also, evidence regarding outcomes and complications of CKD is evaluated with particular emphasis on outcomes and symptoms that are likely to be deemed significant by people diagnosed with early stage of CKD. The role and cost-effectiveness of screening for CKD, the target population, setting and screening strategies are also addressed. Recommended screening algorithm for detection of CKD (chronic kidney disease). Sources: The Royal Australian College of General Practitioners (RACGP) ‘Red Book’ Taskforce.22 National Aboriginal Community Controlled Health Organisation (NACCHO/RACGP).23 ACR, albumin : creatinine ratio; eGFR, estimated glomerular filtration rate. *It is important to note that intra-individual variation in eGFR readings can be as high as 15–20% between consecutive eGFR measurements, such that a number of readings are required before one can be confident that a decrease in eGFR of >5 ml/min per 1.73 m2 in 6 months is real. Chronic kidney disease is associated with considerable morbidity and increased mortality risk. Biochemical evidence of CKD (reduced estimated GFR, elevated serum creatinine) usually indicates the presence of tubulointerstitial fibrosis within the kidney. Such pathology is irreversible, therefore the aim of treatment in many patients with CKD is to delay progression of disease rather than achieve a cure. In light of this it is clear that implementation of primary prevention measures to avoid development of CKD is a preferable strategy. While much information is available about risk factors for development of CKD (refer to Early CKD CARI Guideline Part I) it is less clear whether risk factor modification prevents development of CKD. In addition to primary prevention strategies, the needs of patients and their families to access CKD education and information tailored to the stage and cause of CKD, has been highlighted by some studies. White et al.25 conducted a cross sectional survey of participants of the AusDiab study to assess the level of awareness of the causes of kidney disease. The results indicated an overall low level of awareness of risk factors for kidney disease and low level of recall of kidney function testing even among subgroups of the cohort who were at greatest risk of CKD.25 A study by Ormandy et al.26 found that CKD patients had clear information needs, which changed according to their CKD stage. Moreover, Nunes et al.27 reported disparity between perceived knowledge and objective knowledge in patients with CKD. Although information is crucial to knowledgeable decision-making by patients, how it is provided is also very important. Successful contemporary educational interventions for people with a chronic disease typically incorporate psychological methods to empower patients and change behaviour.28 The aim of this guideline was to evaluate currently available clinical evidence of interventions relevant to lifestyle modification, patient education, elevated blood pressure, diabetes mellitus, referral to multidisciplinary care and the effect of pregnancy in the primary prevention of CKD. In this guideline prevention of CKD is defined as a normal serum creatinine, eGFR above 60 mL/min and absence of urinary albumin, protein or haematuria. *SI units recommended as per The International HbA1c Consensus Committee.29, 30 Patients with diabetes should be referred to other professionals specializing in diabetes (e.g. diabetologist, diabetes educator and dietician) as soon as practicable. Note: Chronic kidney disease is a significant contributor to morbidity and mortality, and represents a major expense to the healthcare system. Early intervention with appropriate medical therapies is essential to address this public health burden and may reduce the progression of CKD and cardiovascular risk by up to 50%.9 Important risk factors for CKD include diabetes mellitus, hypertension, obesity and smoking. Modification of lifestyle habits (e.g. healthy diet, physical exercise, smoking cessation, moderate alcohol consumption and weight loss in obese people) may therefore be of value in retarding the progression of CKD. In addition, restriction of dietary protein31 and augmentation of fluid intake32 have been recommended as a treatment for retarding CKD progression for over 50 years. While the National Health and Medical Research Council (NHMRC) Dietary Guidelines for Australian Adults (http://www.nhmrc.gov.au/guidelines/publications/n29-n30-n31-n32-n33-n34) provide useful generalized, evidence-based information about healthy food choices, patients with CKD often require individualized diet prescription by an appropriately qualified dietitian. Diabetes mellitus, particularly type 2, is increasing in prevalence and associated with significant cardiovascular morbidity and mortality. It also represents the leading cause of CKD worldwide. Evidence from large, prospective trials indicates that tight glycaemic control in type 133 and, to a lesser extent, type 234, 35 diabetic patients results in clinically significant preservation of renal function. The optimal level to which glycosylated haemoglobin (HbA1c) should be targeted (<7.0%) is largely based on the Diabetes Control and Complications Trial (DCCT) and UKPDS trials33-35 but the threshold below which the benefit is lost or at which the incidence of side-effects becomes unacceptable is not clear. Chronic kidney disease is also a well-established independent cardiovascular risk factor. Evidence36, 37 for anti-platelet therapy suggests that low-dose aspirin reduces the risk of CVD by 25–33%, particularly in patients with established CVD (secondary prevention) or those at high risk (primary prevention). However, these potential benefits need to be weighed against an increased risk of bleeding in CKD.38 With regard to blood pressure management new evidence reviewed in this updated guideline has led to an upward revision of the recommended BP targets. These new targets are in line with those recommended by the NHMRC.39 There are a number of epidemiological studies40, 41 which have established that asymptomatic hyperuricaemia is associated with both CKD and ESKD. However, hyperuricaemia is a ubiquitous finding in CKD42 and could be a consequence of reduced excretion, diuretic therapy, or oxidative stress. Although it is not clear whether urate plays a causative role or is an indirect marker of kidney function, uric acid lowering therapy has emerged as a potentially novel therapeutic treatment for slowing the progression of CKD.41 In the CKD population, both vitamin D deficiency and insufficiency are common. As GFR falls, hydroxylation/activation of vitamin D is impaired leading to hyperparathyroidism and CKD mineral and bone disorder (CKD-MBD). Retention of phosphate may begin to occur when renal function falls below 80% of normal. Changes in any of these laboratory values may begin in stage CKD 3, although the presence, rate of change and severity of these abnormal parameters are highly variable among individuals. In a study of 168 consecutive new referrals of patients with stages 2–5 CKD to a CKD clinic, Ravani et al.43 observed that both 25-hydroxyvitamin D and 1,25-dihydroxyvitamin-D levels were significantly, inversely associated with eGFR. Consequently, the prevalence rates of vitamin D insufficiency and deficiency increased from 62% and 25% in stage 2 CKD to 88% and 56% in stage 5 CKD. Similarly, a cross-sectional study of 15 068 adults participating in the Third National Health and Nutrition Examination Survey (NHANES) reported a strong, inverse association between albuminuria and serum 25-hydroxyvitamin D concentrations.44 The objective of this guideline is to review currently available evidence with regards to medical therapies for the management of: hypertension, hypercholesterolaemia, diabetes mellitus, CVD, hyperuricaemia and vitamin D insufficiency and deficiency in patients with stage 1–3 CKD. Evidence for lifestyle modification and nutrition is also reviewed. *SI units recommended as per The International HbA1c Consensus.29, 30 Note: Few foods contain significant amounts of vitamin D, the major sources being fatty fish (salmon, sardine, herring and mackerel), liver, eggs and fortified foods, such as margarine and some varieties of low-fat milk. There are limited data on vitamin D content of local foods. It is exceedingly difficult to obtain sufficient vitamin D from the diet alone. Emelia Atai, Graeme Turner, Kate Wiggins, Maria Chan, Tim Usherwood, Clodagh Scott and Nigel Toussaint have no relevant financial affiliations that would cause a conflict of interest according to the conflict of interest statement set down by KHA-CARI. Richard Phoon has a level II b. conflict of interest for receiving speaker fees and honoraria from several companies related to anaemia, CKD-MBD and cardiovascular disease between 2008 and 2010. David Johnson has a level II b. conflict of interest for receiving speaker honoraria and advisor's fees from several companies related to anaemia, CKD-MBD, hypertension and cardiovascular disease between 2008 and 2012.

Background A reduction in estimated glomerular filtration rate (eGFR), and/or the presence of proteinuria, are the predominant manifestations of chronic kidney disease (CKD), which is common in the elderly population. Objective This article outlines the clinical significance of CKD in the elderly and summarises recently updated recommendations for its assessment, staging and management. Discussion Most elderly patients with CKD present asymptomatically. Despite this, it is clinically significant as it is one of the most potent risk factors for cardiovascular disease. Even modest reductions in eGFR are associated with an increased prevalence of CKD-related complications such as anaemia and hyperphosphataemia. Early detection is an important strategy and should include all three components of the kidney health check (blood pressure measurement, a blood test for serum creatinine and eGFR, and a urine test for albumin:creatinine ratio). Treatment is guided by the patient's stage of CKD, based on kidney function (eGFR) and kidney damage (degree of albuminuria), and control of blood pressure to recommended levels with appropriate medications. The majority of elderly patients with CKD will not ultimately require, or desire, renal replacement therapy and may be safely managed in general practice.