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Background Calcific uraemic arteriolopathy (CUA; calciphylaxis) is a rare disease seen predominantly in patients receiving dialysis. Calciphylaxis is characterized by poorly healing or non-healing wounds, and is associated with mortality, substantial morbidity related to infection and typically severe pain. In an open-label Phase 2 clinical trial, SNF472, a selective inhibitor of vascular calcification, was well-tolerated and associated with improvement in wound healing, reduction of wound-related pain and improvement in wound-related quality of life (QoL). Those results informed the design of the CALCIPHYX trial, an ongoing, randomized, placebo-controlled, Phase 3 trial of SNF472 for treatment of calciphylaxis. Methods In CALCIPHYX, 66 patients receiving haemodialysis who have an ulcerated calciphylaxis lesion will be randomized 1:1 to double-blind SNF472 (7 mg/kg intravenously) or placebo three times weekly for 12 weeks (Part 1), then receive open-label SNF472 for 12 weeks (Part 2). All patients will receive stable background care, which may include pain medications and sodium thiosulphate, in accordance with the clinical practices of each site. A statistically significant difference between the SNF472 and placebo groups for improvement of either primary endpoint at Week 12 will demonstrate efficacy of SNF472: change in Bates-Jensen Wound Assessment Tool-CUA (a quantitative wound assessment tool for evaluating calciphylaxis lesions) or change in pain visual analogue scale score. Additional endpoints will address wound-related QoL, qualitative changes in wounds, wound size, analgesic use and safety. Conclusions This randomized, placebo-controlled Phase 3 clinical trial will examine the efficacy and safety of SNF472 in patients who have ulcerated calciphylaxis lesions. Patient recruitment is ongoing.

Background and aims Calciphylaxis is a rare condition associated with very high mortality in patients with end-stage kidney disease. Data from country-based registries have been an invaluable resource for a better understanding of the natural history and management for this condition. This study aimed to investigate the current management strategies and outcomes of patients enrolled in the United Kingdom Calciphylaxis study (UKCS). Methods The study was conducted on 89 patients registered in the UKCS since 2012. The initial analysis included a description of the baseline characteristics, management strategies and outcomes on follow-up until May 2020. Further analysis included a comparison of the mortality outcome of the UKCS patients who were receiving haemodialysis with a propensity score matched cohort of haemodialysis patients from the Chronic Renal Insufficiency Standards Implementation Study- Haemodialysis (CRISIS-HD). Results Median age of the cohort was 59 years, with a predominance of females (61%) and Caucasian (95%) ethnicity. About 54% of the patients were diabetic and 70% were receiving haemodialysis at study entry. The skin lesions were mostly distributed in the lower extremities (48%). Sodium thiosulphate and calcimimetic were the most widely used management strategies. The mortality rate was 72 deaths per hundred patient-years (50 deaths observed in 69.5 patient years). Complete wound healing was noted in 17% and bacteraemia was reported in 26% of patients. In a comparative analysis of the matched haemodialysis patients, the presence of calciphylaxis in 62 patients showed a strong association with all-cause mortality (HR 6.96; p Conclusions This UK wide study strengthens the evidence that calciphylaxis is a strong and independent risk factor associated with all-cause mortality; no significant benefit was shown with any individual treatment modality. Until further evidence becomes available, a multifaceted approach would be the appropriate treatment strategy in the management of this extremely serious condition. Graphic abstract

BACKGROUND AND AIMS ANCA-associated vasculitis (AAV) refers to a group of conditions in which the end result is systemic injury of small blood vessels, resulting in damage to distinct organ systems including the lung, kidneys, ear, nose and throat. A characteristic, although not exclusive feature, is the development of anti-neutrophil cytoplasmic antibodies (ANCA) against specific proteins within the neutrophil-leucocyte proteinase 3 (PR3) and myeloperoxidase (MPO). The incidence varies according to geographic location but is ∼20 cases/million/year. The age of onset is usually between 45–75 years old, with a male: female ratio of 1:1. Without treatment, it is life-threatening; the aim of treatment is to induce remission with a strong immunosuppressive induction regimen followed by a maintenance phase. The risk of relapse remains. Here, we assessed the epidemiology of AAV >2 decades at our centre (Salford Royal Hospital, UK) with particular reference to severity of disease at presentation, ANCA positivity and outcomes. METHOD Patients with a diagnosis of AAV (either granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) or eosinophilic granulomatosis with polyangiitis (EGPA)) were identified from our database between January 2000 and December 2021 (see Figure 1). Diagnosis was based on clinical features, ANCA result and kidney biopsy findings. A total of 47 were excluded and demographic data, co-morbidities, laboratory values (including baseline creatinine, eGFR, proteinuria, ANCA positivity), treatment given and outcomes were collected in the remaining sample. Analysis determined (i) basic demographic description of our cohort, (ii) median baseline creatinine, eGFR and proteinuria, (iii) those with an initial requirement for renal replacement therapy (RRT) at presentation, (iv) ANCA positivity rates and (v) outcomes including progression to RRT and mortality. RESULTS The evaluable cohort totalled 369 patients (see Table 1). Of these, 194 were male (52.6%), and the median age at presentation was 73 (IQR 60–82) years; 91.9% were Caucasian. Median baseline creatinine was 165 µmol/L (93–338), eGFR 33 mL/min/1.73 m2 (15–66) and proteinuria 98 g/mol (25–258). ANCA was measured in 363 (98.4%), of which c-ANCA and or PR3 positivity was seen in 142 (39.1%), and p-ANCA and or MPO positivity was seen in 148 (40.8%). In a small number, atypical ANCA was seen (1.9%) or ANCA was obscured by anti-nuclear factor (ANF) (2.8%). An immediate requirement for RRT at presentation was seen in 26 (7%). Progression to RRT at any time point over the follow up period was observed in 86 (23.3%), with the first RRT modality being haemodialysis in 64 (17.3%), peritoneal dialysis in 20 (5.4%) and transplant in 2 (0.5%). A total of 147 patients (39.8%) died over the follow-up period. A combined outcome of progression to RRT or death was seen in 191 (51.8%). CONCLUSION We show that patients present with AAV at an advanced age and with significant renal involvement (median baseline eGFR of 33 mL/min/1.73 m2 in our study). The distribution of PR3 and MPO positive vasculitis is similar, although there were a significant number of ANCA negative patients in our cohort. There were differences in concordance between c-ANCA and PR3 positivity, along with p-ANCA and MPO positivity, which may be explained by historical differences in testing. There remains a significant risk of progression to the requirement for RRT or death: 51.8% observed over our follow-up period of two decades.

BACKGROUND AND AIMS Membranous nephropathy (MN) commonly presents with nephrotic syndrome and carries significant risk of progression to end-stage kidney disease (ESKD) (33% without treatment, 10%–20% with). Patients may spontaneously remit (up to 40%), but are also at risk of relapse. A total of 80% of cases are primary (kidney-specific) and the majority of these are associated with antibodies to the M-type phospholipase A2 receptor (anti-PLA2R) or thrombospondin type 1 domain containing 7A antibodies (THS7DA). Treatment ranges from supportive care with renin–angiotensin system (RAS) blockade through to immunosuppression. Here we assessed the epidemiology of MN over 20 years at our centre (Salford Royal Hospital, UK) with particular reference to treatment administered and key clinical outcomes. METHOD A total of 238 patients with kidney biopsy-proven MN were identified from the local database between January 2000 and December 2020. Twenty-one were excluded (see Fig. 1) resulting in a total of 217 patients in whom demographic data, co-morbidities, remission and relapse rates, baseline laboratory values, treatment given, and outcomes were collected. Analyses compared effects of (i) immunosuppressed versus non-immunosuppressed, (ii) effect of modified Ponticelli versus other forms of immunosuppression and (iii) rates of remission. Univariate and multivariate cox regression determined factors that were associated with increased risk of renal replacement therapy (RRT) or death. RESULTS A total of 63.6% of the cohort were male, 88% Caucasian, 10.1% diabetic, 50.2% hypertensive and 15.2% had coexisting cardiovascular disease (Table 1). A total of 82.0% had primary MN. Median baseline eGFR was 72.7 mL/min/1.73 m2 and median baseline uPCR was 664 g/mol. A total of 157 patients (72.4%) went into remission (either spontaneous—75 (47.8%) or with treatment—85 (52.2%)), and of these 41.4% subsequently relapsed. A total of 89.4% received RAS blockade and 48.8% received immunosuppression. The median follow-up period was 56 months; 9.7% progressed to ESKD and 32.3% died. Patients who received immunosuppression had significantly more proteinuria than those who did not (765 g/mol versus 514 g/mol, P ≤ 0.001), were more likely to relapse (53.7% versus 28.0%, p ≤0.001) and were more likely to require RRT (15.1% versus 4.9%, P = .028). Those who received modified Ponticelli were less likely to relapse than those who received other forms of immunosuppression (34% versus 46%, P = .019), less likely to require RRT (3% versus 22%, P = .018) and less likely to die (11% versus 38%). Multivariate cox regression showed that pre-existing cardiovascular disease was a risk factor for death (HR 2.47, P < .001) and higher baseline eGFR and use of RAS blockade was associated with reduced risk of death (HR 0.98, P < .001 and HR 0.34, P = .012, respectively). CONCLUSION Despite advances in knowledge of underlying pathogenesis and increased treatment options, MN continues to pose a significant risk of progression to ESKD and death. This real-world study suggests that immunosuppression with modified Ponticelli is associated with lower rates of progressive CKD compared with MMF and calcineurin-inhibitor based therapy. Whilst many patients respond to treatment and can achieve remission, a significant proportion of these subsequently relapse. Identifying these patients early with judicial use of appropriate immunosuppression is key.

Purpose of review Vascular calcification (VC) is associated with increased cardiovascular event rates, particularly in patients with end-stage kidney disease (ESKD). Dysregulated mineral metabolism and inflammation have been shown to promote VC, however, treatment options targeting VC specifically are not available. This review outlines the pathophysiological mechanisms contributing to VC in ESKD and describes recent studies evaluating the effects of the first-in-class inhibitor of VC, SNF472. Recent findings SNF472 directly inhibits calcium phosphate crystal formation and aggregation. SNF472 has completed early phase clinical trials with a favourable safety profile and Phase 2 clinical trial data have shown attenuation of coronary artery and aortic valve calcification in patients receiving hemodialysis. Summary Therapeutic agents that directly target VC may prevent the multiple complications associated with dystrophic calcification in patients with ESKD.

Background and Aims IgA nephropathy is the most common glomerulonephritis worldwide. The clinical course is heterogeneous and not always easy to predict. As such, determining which patients to treat with immunosuppression has been the cause of much debate. Over recent years there has been a focus on risk prediction to help with treatment decisions (such as the widely validated International IgA Risk Prediction Tool). Here, we present a 20 year retrospective study from a single centre with the following aims: to describe the epidemiology of our cohort, to assess outcomes (such as progression to ESKD requiring RRT, mortality), and to determine if treatment choices have changed over time. Method We collected all cases of IgA nephropathy from our biopsy database between January 2020 and December 2019. This totalled 525 biopsies. Of these, a number were excluded from analysis, including transplant biopsies and repeat biopsies in the same patient. After exclusion, the original 525 biopsies were narrowed down to 452 patients for analysis. We collected demographic data for each patient, along with creatinine and proteinuria values over time, MEST-C scores, progression to ESKD, mortality, use of RAAS blockade and immunosuppressants. Initial analysis was performed using Excel. We plan to perform further multivariate Cox regression analysis to determine if there are associations with progression to ESKD such as degree of proteinuria, MEST-C scores and immunosuppression treatment. Results We identified 452 patients with biopsy confirmed IgA nephropathy at our centre between January 2000 and December 2019. 138 (30.5%) were female and 314 (69.4%) were male. The average age at time of biopsy was 45.7 years. Mortality over this period was 19.2% (87 patients). 126 (27.9%) progressed to ESKD requiring RRT, 6 (1.3%) required temporary dialysis whilst 313 (69.2%) did not require RRT. With regards to treatment, 329 (72.8%) were treated with RAAS blockade in comparison to 85 (18.8%) who were not (in 38 patients this was unclear). No immunosuppression was used in 349 (77.2%), whilst a combination of prednisolone; IV cyclophosphamide and prednisolone; and MMF and prednisolone was used in 97 (21.5%). Conclusion We present here a large single centre dataset of IgA nephropathy patients over a 20 year period. We show that there remains a significant risk of progression to ESKD over time. It is important to identify those patients most at risk of progression early on in their disease course so that optimal treatment can be initiated. Further analysis of this dataset will allow us to assess whether treatment strategies in recent years has had a beneficial effect on outcomes, and also to assess the correlation between MEST-C scores and treatment decisions.

Background and objectives In the CaLIPSO study, intravenous administration of SNF472 (300 or 600 mg) during hemodialysis significantly attenuated progression of coronary artery and aortic valve calcification. SNF472 selectively inhibits formation of hydroxyapatite, the final step in cardiovascular calcification. Because bone mineral is predominantly hydroxyapatite, we assessed changes in bone mineral density in CaLIPSO. Design, setting, participants, & measurements Patients with coronary artery calcification at screening (Agatston score of 100–3500 U) were randomized 1:1:1 to receive placebo, 300 mg SNF472, or 600 mg SNF472 as an intravenous infusion during hemodialysis three times weekly for 52 weeks. Dual-energy x-ray absorptiometry (DXA) scans were obtained at baseline (screening) and end of treatment, and between-group changes from baseline were compared using analysis of covariance. Results Among 274 randomized patients, 202 had evaluable DXA scans at baseline and postrandomization (the DXA-modified intention-to-treat population). Mean (95% confidence interval) changes in total-hip bone mineral density from baseline to week 52 were −1.5% (−2.7% to −0.3%), −1.5% (−2.7% to −0.4%), and −2.5% (−3.8% to −1.2%) in the placebo, 300 mg SNF472, and 600 mg SNF472 groups, respectively. Mean (95% confidence interval) changes in femoral-neck bone mineral density from baseline to week 52 were −0.3% (−1.6% to 1.0%), −1.0% (−2.3% to 0.2%), and −2.6% (−4.0% to −1.3%), respectively. Regression analyses showed no correlation between change in coronary artery calcium volume and change in bone mineral density at either location. Changes in serum alkaline phosphatase, calcium, magnesium, phosphate, and intact parathyroid hormone levels were similar across treatment groups. Clinical fracture events were reported for four of 90, three of 92, and six of 91 patients in the placebo, 300 mg SNF472, and 600 mg SNF472 groups, respectively. Conclusions Bone mineral density decreased modestly in all groups over 1 year. In the 600 mg SNF472 group, the reduction appeared more pronounced. Reported fractures were infrequent in all groups. Clinical Trial registry name and registration number: Effect of SNF472 on Progression of Cardiovascular Calcification in End-Stage-Renal-Disease (ESRD) Patients on Hemodialysis (HD), NCT02966028

Background Calciphylaxis is a rare condition usually seen in patients with end-stage renal disease. Pain is a hallmark of this condition and can be extremely difficult to control. Anecdotal data suggests that pain management in calciphylaxis is challenging with variable approaches across the United Kingdom (UK) and internationally. A knowledge and practice survey was conducted to establish current practice in the management of pain in patients with calciphylaxis, in the UK. Based on the results and clinical experience the authors suggest a clinical practice guideline. Methods An online questionnaire was circulated among physicians (renal and palliative care) involved in the management of pain in calciphylaxis. The questionnaire included a mix of open-ended questions and questions with drop down options. Results One hundred and six clinicians responded to the survey of which 60 (57%) respondents were from palliative medicine; the remaining 46 (43%) were from renal medicine. 31 (30%) respondents across both specialties had not encountered any patients with a diagnosis of calciphylaxis (renal-2, palliative care-29). A referral to the palliative care team was undertaken by 18% of renal physicians, 32% referred to the pain team and 50% referred to both. Only 3% of the palliative medicine respondents indicated that they had received a referral from the renal team at the time of diagnosis. Opioids were the preferred initial drug of choice for the management of all types of pain. Paracetamol was universally selected as the preferred first-choice adjuvant agent for management of all types of pain. The importance of advance care planning was highlighted with 72% undertaking advanced care planning discussions often or most of the time. Conclusion There was wide variation in the current practice of pain management in patients with calciphylaxis, with variation between renal specialists and palliative care specialists. Referral to specialists in pain management is not universal despite the severe nature of the pain experienced by patients with calciphylaxis. The data generated has facilitated the development of a clinical practice guideline to support complex pain management in a group of patients with multiple comorbidities.

Background and Aims Calciphylaxis is a rare disease usually seen in patients with end-stage renal disease. Pain is a hallmark of this disease and can be extremely difficult to control. Anecdotal data suggests that pain management in calciphylaxis is unsatisfactory with differing practice, variable across the United Kingdom (UK) and also around the world. This knowledge, attitude and practice (KAP) survey aims to gather information on the current practice in the management of pain in patients with calciphylaxis. Method A pre-tested online questionnaire was circulated among physicians (renal and palliative care) involved in the management of pain in calciphylaxis. (https://www.gmann.co.uk/ website/calciphylaxis-pain-management-survey.cfm). The questionnaire included a mix of open-ended questions and questions with drop down options. Results One hundred and six clinicians responded to the survey of which 60 (57%) respondents were from palliative medicine and the remainder 46 (43%) were from renal medicine. There were 31 (30%) respondents, across both specialties who had not encountered any patients with a diagnosis of calciphylaxis (renal-2, palliative care-29). 18% of renal physicians refer patients to palliative care team, 32% refer to pain team and 50% refer to both. Only 3% of the palliative medicine respondents indicated that they’d received a referral from the renal team at the time of diagnosis. Opioids were the preferred initial drug of choice for the management of all types of pain although the preferred drug varied with the specialities (Fig–1). Paracetamol was universally selected as the preferred first-choice adjuvant agent for management of all types of pain. Additional procedures to aid pain management (epidural analgesia and nerve blocks) were used by 6.6% of respondents. A majority (83%) felt the presence of infection impacts on the effectiveness of pain control. The importance of advanced care planning was also highlighted with 72% undertaking advanced care planning discussions often or most of the times. Conclusion In conclusion, there was wide variation in the current practice of management of pain in calciphylaxis, with variation between renal specialists and palliative care specialists. Referral to pain specialists is not universal despite the severe nature of the pain experienced by patients with calciphylaxis. The data generated will enable to us to develop practice guidelines to support complex pain management in a group of patients with multiple comorbidities.

Background and Aims In the CaLIPSO study, SNF472 significantly attenuated progression of coronary artery calcium (CAC) volume score compared with placebo. This pre-specified analysis examined the effect of SNF472 on CAC progression in key subgroups of patients in CaLIPSO. Method Patients with a CAC Agatston score of 100 to 3500 at baseline were randomized to SNF472 300 mg (n=92), SNF472 600 mg (n=91), or placebo (n=91), infused during hemodialysis (HD) thrice weekly for 52 weeks. Patients received standard of care therapy, including phosphate binders and calcimimetics as determined by investigator. The primary endpoint (change in log CAC volume score from baseline to week 52 in the combined dose groups vs placebo) was analyzed for patients who received SNF472 or placebo and had an evaluable CT scan post-randomization (modified ITT population). Sensitivity analysis was also performed for the per protocol population of patients that met entry criteria, received 80% of scheduled treatment, completed the study procedures, and had both a baseline and week 52 evaluable CT scan. The analysis plan pre-specified key subgroups: age, sex, diabetes, dialysis vintage, and arteriosclerotic cardiovascular disease (ASCVD), as well as baseline use of non-calcium phosphate binders, calcium-based phosphate binders, calcimimetics, activated vitamin D, warfarin, or statins. Results Demographics and disease characteristics were similar across the treatment groups. Age (mean±SD) at baseline was 63.6±8.9 years and 39% of the patients were female; 62% had diabetes and 41% had prior ASCVD. Median dialysis vintage was 42.4 months; 33% had received hemodialysis for ≥5 years. Concomitant medications at baseline were: non-calcium phosphate binders, 62%; calcium-based phosphate binders, 28%; calcimimetics, 31%; activated vitamin D, 51%; warfarin, 8%; and statins, 64%. CAC volume progression was 11% for the combined dose groups and 20% for placebo (p=0.016). Treatment differences for CAC volume score progression from baseline to week 52 were similar across the subgroups (FIGURE). All interaction p-values were non-significant, and comparisons favored SNF472 vs placebo in each subgroup for both the modified ITT and per protocol population. Conclusion SNF472 treatment for 52 weeks attenuated CAC progression compared with placebo in all subgroups of the CaLIPSO study. These results support the potential benefit of SNF472 across a broad population of patients with cardiovascular calcification. Future studies are needed to determine the effects of SNF472 on cardiovascular events in patients receiving HD.

Background and aims Hypocalcaemia is a common post-parathyroidectomy complication in renal patients with secondary hyperparathyroidism. This is due to reduced parathormone (PTH) mediated calcium absorption in the kidneys and increased influx of calcium to bones. Our initial study in January 2015 showed preloading patients with one alfacalcidol 2 microgram once a day for 5 days preoperatively was ineffective in reducing hypocalcaemia related complications. We re-investigated the outcomes in patients following a change in practice to use one alfacalcidol 5 microgram once a day for 5 days preoperatively. Method All patients with pre-existing chronic kidney disease (CKD) who underwent parathyroidectomy by a single surgeon in our centre between March 2016 and October 2017 were included (12 patients). The outcomes (length of hospital stay and hypocalcaemia requiring IV calcium replacements) were compared with a previous study on patients operated on by the same surgeon between April 2008 and September 2014 (24 patients). Statistical analysis was conducted using Microsoft excel and SPSS version-22. Results Twelve patients were included in this study; 5 were females. Mean age at surgery was 54 (range 45-61) years. Eight patients were on long-term haemodialysis, 3 had a functioning renal transplant and 1 had CKD stage 5. Eight patients had been receiving cinacalcet for more than one month preoperatively. Mean length of stay (LoS) was 5.3 days (range 3-10), half (n=6) were discharged four days post-op. Ten had a total parathyroidectomy, of which half (n=5) were discharged after post-op day 4. Four patients were not preloaded with 5mcg as per protocol; reasons for non-adherence to the protocol included regular prescription of alfacalcidol and physician discretion to utilise a lower dose. Patients with lower pre-op corrected calcium levels (2.4-2.6 mg/dL) stayed for a mean of 6.74 days after surgery. This was a longer LoS compared to other calcium ranges. No hypercalcemia related complications were recorded. The need for post-operative intravenous calcium use decreased from 10/24 to 2/12. Despite more patients having total parathyroidectomy and being on dialysis, a smaller proportion required IV calcium in the post-operative phase, although this was not statistically significant due to the small sample size (p=0.26). Conclusion Our study highlights that the current practice of preloading one alphacalcidol 5 mcg once a day for 5 days preoperatively in renal patients undergoing parathyroidectomy appears to be a safe and effective approach. Ongoing monitoring and further studies on a larger cohort of patients is needed to strengthen these observations.

Background and Aims Percutaneous renal biopsy is the mainstay of renal pathological diagnosis. Not only does it secure an accurate diagnosis, but also lends itself to guiding the prognosis of a myriad of renal disorders. An important diagnostic modality for nephrologists, they have contributed greatly to the field of nephrology, both in terms of the classification of diseases and assisting in understanding their pathogenesis. Adequacy of the tissue samples of at least ten to fifteen glomeruli is generally preferred. The aim of our retrospective study was to review the renal biopsies done in one large UK renal centre, namely Salford Royal Foundation Trust, over the last twenty years. This Trust covers a catchment area that serves approximately 1.5 million people. Method A list of all renal biopsies performed at Salford Royal Foundation Trust between January 2000 to January 2020 was generated by our pathology department. Following this, each individual biopsy report was reviewed. In addition to this, certain information was collated from individual patient records; namely patient demographics, the indication for biopsy, tissue type (native or transplant), histological diagnosis and outcomes. Our centre has an excellent electronic patient record (EPR). This enabled us to analyse full clinical data retrospectively for each case. Results Between January 2000 and January 2020 a total of 3555 renal biopsies were performed at Salford Royal Foundation Trust. These biopsies were performed solely by nephrology specialists and supervised trainees, under ultrasound guidance. 177.5 biopsies were performed on average, per year, ranging between 140 – 203. 90% of biopsies were performed on native kidneys, with 10% being performed on transplanted kidneys. 10% of biopsies had normal histology morphologically when reviewed by light microscopy. There diagnoses of these included entities minimal change disease and thin basement membrane disease most commonly. IgA nephropathy was the most common glomerular pathology identified, in keeping with the wealth of published literature. There were over 525 biopsies done confirming IgAN as the primary pathology. 7% of biopsies had a crescentic glomerular pathology when examined histologically. The main causes included crescentic IgA nephropathy and anca-associated vasculitis. Conclusion Kidney biopsies have long been regarded as safe, minimally invasive procedures are of paramount importance to our diagnostic armamentarium. Our data echoes that of already published pathology series, IgAN being the most common glomerular pathology in our series. We further plan to analyse the various conditions and their outcomes in further detail.

Background It is unknown whether patients recruited to renal cardiac imaging studies are fully representative of the investigated population and whether there are differences in characteristics and survival between participants and non-participants (excluded or declined consent). Subjects and Methods Four hundred thirty-five maintenance haemodialysis patients were screened in an observational, prospective study. Baseline demographics, laboratory results, social deprivation scores and survival data were collected from patient records. All patients were followed-up until death, renal transplantation or 16 November 2015. Results Forty-four patients were excluded (16 language barrier, 10 mental incapacity, 9 severe co-morbid illness and 9 because of immobility), 172 patients declined consent (84% due to reluctance to attend for an extra visit) and 219 patients were recruited. Excluded patients had a lower mean haemoglobin (10.2 g/dL vs 10.7 g/dL), phosphate (4.15 mg/dL vs 4.74 mg/dL), albumin (3.6 g/dL vs 3.8 g/dL) and higher C-reactive protein (3.2 mg/dL vs 1.6 mg/dL) compared with recruited patients. No difference was identified between groups for Charleston comorbidity index (P = 0.115) or social deprivation scores. After a median follow-up of 29.7 (25th–75th percentile, 21.1–34.3) months, there were 141 deaths. In a multivariable Cox regression model adjusting for BMI, age, Charleston comorbidity index, haemoglobin, albumin, smoking status and diabetes mellitus, patients who declined consent had an adjusted HR of 1.70, 95% CI 1.10–2.52, and excluded patients had an adjusted HR of 1.30, 95% CI 0.75–2.25, for all-cause mortality compared with recruited patients. Conclusions Patients recruited to the study had longer survival compared with non-participants. Research studies should document phenotypes of non-participants to aid interpretation and generalizability of results.

AIMS The prevalence of hyponatraemia in the outpatient setting has not been thoroughly explored, and little is known about the prognostic implication of dysnatraemia in chronic kidney disease (CKD) patients, in particular accommodating the effect of concurrent medications. METHODS This is a prospective observational study of non-dialysis-dependent CKD patients managed in a nephrology clinic. Patients enrolled between 2002 and 2012 in the Chronic Renal Insufficiency Standards Implementation Study were assessed. Survival analyses were performed using baseline sodium and 12-month time-averaged sodium, with adjustment for co-morbid diseases, laboratory findings and concurrent medications. RESULTS At baseline (n = 2093), mean estimated glomerular filtration rate was 32.8 ± 15.9 ml/min per 1.73 m(2) , median age was 67 (interquartile range 56-75) years and median serum sodium concentration was 140 (138-142) mmol/l. After a follow up of 41 (18-67) months, there were 684 deaths, 174 from cardiovascular causes; 1925 time-averaged sodium values were analysed. In the Cox multivariate adjusted regression, baseline hyponatraemia, but not hypernatraemia, was independently associated with all-cause mortality (hazard ratio (HR) 1.35, 95% confidence interval (CI) 1.02-1.78, P = 0.04, and HR 1.15, 95% CI 0.84-1.57, P = 0.39, respectively). This was similarly the case for time-averaged hyponatraemia and hypernatraemia (HR 2.15, 95% CI 1.59-2.91, P

Background Membranous nephropathy (MN) represents two distinct disease entities. Primary MN is now recognized as an autoimmune condition associated with the anti-PLA2R antibody and secondary MN occurs in tandem with malignancy, infection, drug therapy and other autoimmune conditions. Prior to the development of accessible enzyme-linked immunosorbent assays, the diagnosis of MN was one of exclusion. We studied whether the introduction of serum anti-PLA2R antibody testing leads to a reduction in the frequency of investigations in MN patients. Methods Patients from three UK centres with a diagnosis of MN between 2009 and 2014 were identified. We compared patients who had a positive anti-PLA2R test within 6 months of biopsy with those who had no test or a negative test. Records were reviewed for investigations that took place 6 months prior to and 6 months following the biopsy date to see if these were normal or identified a secondary cause of MN. Results In total, 184 patients were included: 80 had no test, 66 had a negative anti-PLA2R test and 38 had a positive test within 6 months of diagnosis. In 2012, 46.5% of patients had an anti-PLA2R test, increasing to 93.3% in 2014. From 2012 to 2014 the number of screening tests dropped from 10.03 to 4.29 and the costs from £497.92 to £132.94. Conclusions Since its introduction, a progressively higher proportion of patients diagnosed with MN had an anti-PLA2R test. This has led to a reduction in the number of screening tests and in the cost of investigations carried out. The anti-PLA2R test has the potential to reduce this burden as its use becomes more widespread.

Background Vascular calcification is associated with increased cardiovascular morbidity and mortality in patients with atherosclerosis, diabetes and chronic kidney disease. However, no viable treatments for this condition have been identified. This study aimed to determine whether farnesyl transferase inhibitors (FTIs) can reduce vascular calcification and the mechanism by which this reduction occurs. Results We demonstrate that FTI-277 significantly inhibits phosphate-induced mineral deposition by vascular smooth muscle cells (VSMC) in vitro, prevents VSMC osteogenic differentiation, and increases mRNA expression of matrix Gla protein (MGP), an inhibitor of mineralization. FTI-277 increases Akt signaling in VSMC in short-term serum-stimulation assays and in long-term mineralization assays. In contrast, manumycin A has no effect on Akt signaling or mineralization. Co-incubation of VSMC with FTI-277 and SH6 (an Akt inhibitor) significantly reduces the inhibitory effect of FTI-277 on mineralization, demonstrating that FTI-277 inhibits calcification by activating Akt signaling. Over-expression of the constitutively active p110 sub-unit of PI3K in VSMC using adenovirus activates Akt, inhibits mineralization, suppresses VSMC differentiation and significantly enhances MGP mRNA expression. FTI-277 also inhibits phosphate-induced activation of caspase 3 and apoptosis of VSMC, and these effects are negated by co-incubation with SH6. Finally, using an ex vivo model of vascular calcification, we demonstrate that FTI-277 inhibits high phosphate-induced mineralization in aortic rings derived from rats with end-stage renal failure. Conclusions Together, these results demonstrate that FTI-277 inhibits VSMC mineral deposition by up-regulating PI3K/Akt signaling and preventing apoptosis, suggesting that targeting farnesylation, or Akt specifically, may have therapeutic potential for the prevention of vascular calcification.

AIM Patients with atherosclerotic renovascular disease (ARVD) have an increased risk for death and likelihood of initiating renal replacement therapy (RRT) compared with the general population. No data exist to describe prognosis in ARVD compared with other causes of chronic kidney disease (CKD). We compare patient outcomes between ARVD and other causes of CKD. METHODS Patients were selected from two prospective observational cohort studies of outcome in ARVD and CKD. Multivariate Cox regression was used to compare risk for RRT and death (both prior to and following initiation of RRT) between patients with ARVD and other causes of CKD. RESULTS Of 1472 patients (563 (38%) ARVD, 909 (62%) non-ARVD), 242 (16%) progressed to RRT and 640 (44%) died over a median follow-up period of 4.1 (2.4-5.6) years. Patients with ARVD had an increased risk for death (HR 1.5 (1.2-1.8), P

Patients with chronic kidney disease have a high risk of developing cardiovascular disease but diagnosis of cardiovascular dysfunction in this population is complicated. In this Review, the authors describe cardiac imaging techniques that can be used to detect gross cardiac structure and function, coronary calcification, wall motion abnormalities and coronary artery disease, and discuss the benefits and difficulties in using these techniques in patients with chronic kidney disease. Patients with chronic kidney disease (CKD) carry a high cardiovascular risk. In this patient group, cardiac structure and function are frequently abnormal and 74% of patients with CKD stage 5 have left ventricular hypertrophy (LVH) at the initiation of renal replacement therapy. Cardiac changes, such as LVH and impaired left ventricular systolic function, have been associated with an unfavourable prognosis. Despite the prevalence of underlying cardiac abnormalities, symptoms may not manifest in many patients. Fortunately, a range of available and emerging cardiac imaging tools may assist with diagnosing and stratifying the risk and severity of heart disease in patients with CKD. Moreover, many of these techniques provide a better understanding of the pathophysiology of cardiac abnormalities in patients with renal disease. Knowledge of the currently available cardiac imaging modalities might help nephrologists to choose the most appropriate investigative tool based on individual patient circumstances. This Review describes established and emerging cardiac imaging modalities in this context, and compares their use in CKD patients with their use in the general population.

Sudden cardiac death (SCD) is the most common cause of death in haemodialysis patients, accounting for 25% of all-cause mortality. There are many potential pathological precipitants as most patients with end-stage renal disease have structurally or functionally abnormal hearts. For example, at initiation of dialysis, 74% of patients have left ventricular hypertrophy. The pathophysiological and metabolic milieu of patients with end-stage renal disease, allied to the regular stresses of dialysis, may provide the trigger to a fatal cardiac event. Prevention of SCD can be seen as a legitimate target to improve survival in this patient group. In the general population, this is most effective by reducing the burden of ischaemic heart disease. However, the aetiology of SCD in haemodialysis patients appears to be different, with myocardial fibrosis, vascular calcification and autonomic dysfunction implicated as possible causes. Thus, the range of therapies is different to the general population. There are potential preventative measures emerging as our understanding of the underlying mechanisms progresses. This article aims to review the evidence for therapies to prevent SCD effective in the general population when applied to dialysis patients, as well as promising new treatments specific to this population group.

Background/Aims: Measures of functional status are used in the general population to aid prognostication but their use has not been explored in pre-dialysis chronic kidney disease (CKD). This analysis considers the association between the Karnofsky performance score (KPS) and all-cause mortality in a CKD stage 3-5 cohort. Methods: Patients were selected from the Chronic Renal Insufficiency Standards Implementation Study (CRISIS), a prospective observational study of outcome in CKD. Risk for death was assessed using multivariate Cox regression, and differences in progression of biochemical parameters were considered in a mixed-effects model. Results: A total of 1,515 patients with a median follow-up time of 2.9 (1.5-4.8) years were considered. Baseline age was 60 ± 11 years and eGFR was 30 ± 12 ml/min/1.73 m2. Patients with a reduced KPS had an increased risk for death. The hazard ratio (HR) for death was: KPS 90 group, HR 1.2 (95% CI 0.9-1.5), p = 0.1; KPS ≤80 group, HR 1.8 (95% CI 1.4-2.4), p < 0.001. In the mixed-effects model, the average annual loss of eGFR was greater in patients with a KPS ≤80 versus patients with a KPS >80 (5 vs. 3%, p = 0.008). Conclusion: A reduced KPS is independently associated with risk for mortality in patients with CKD stages 3-5. This may relate to a more rapid loss of eGFR.

Calcific uraemic arteriolopathy (CUA), or calciphylaxis, is a rare disease predominantly occurring in comorbidity with dialysis. Due to the very low frequency of CUA, prospective studies on its management are lacking and even anecdotal reports on treatment remain scarce. Therefore, calciphylaxis is still a challenging disease with dismal prognosis urgently requiring adequate strategies for diagnosis and treatment.In an attempt to fill some of the current gaps in evidence on various, highly debated and controversial aspects of dialysis-associated calciphylaxis, 13 international experts joined the 1st Consensus Conference on CUA, held in Leuven, Belgium on 21 September 2015. The conference was supported by the European Calciphylaxis Network (EuCalNet), which is a task force of the ERA-EDTA scientific working group on Chronic Kidney Disease-Mineral and Bone Disorders (CKD-MBD). After an intense discussion, a 9-point Likert scale questionnaire regarding 20 items on calciphylaxis was anonymously answered by each participant. These 20 items addressed unsolved issues in terms of diagnosis and management of calciphylaxis. On the one hand, the analysis of the expert opinions identified areas of general consensus, which might be a valuable aid for physicians treating such a disease with less experience in the field. On the other hand, some topics such as the pertinence of skin biopsy and administration of certain treatments revealed divergent opinions. The aim of the present summary report is to provide some guidance for clinicians who face patients with calciphylaxis in the current setting of absence of evidence-based medicine.? The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Background: Cardiovascular mortality is high in haemodialysis (HD) patients. Arterial stiffness and global longitudinal strain (GLS) are important non-atheromatous cardiovascular risk predictors. No study has encompassed both parameters in a combined model for prediction of outcomes in HD patients. This is important because left ventricular (LV) dysfunction can result from fibrotic remodelling secondary to increased arterial stiffness. Methods: Two hundred and nineteen HD patients had pulse wave velocity (PWV) and echocardiography (including GLS) assessments. Patients were followed-up until death, transplantation or November 16, 2015, whichever happened first. Pearson's correlation coefficient was used to determine factors associated with PWV and GLS. A multivariable Cox regression model investigated factors associated with all-cause, cardiac death and events. Results: One hundred and ninety eight HD patients had full datasets (median age 64.2, 68.7% males) with a mean LV ejection fraction (LVEF) of 61.7 ± 10.1% and GLS -13.5 ± 3.3%; 51% had LV hypertrophy. Forty eight deaths (15 cardiac) and 44 major cardiac events occurred during a median follow-up of 27.6 (25th-75th percentile, 17.3-32.7) months. In separate survival models, PWV and GLS were independently associated with all-cause mortality; however, in a combined model, LV mass indexed to height2.7 (LVMI/HT2.7; adjusted hazard ratio (HR) 1.02, 95% CI 1.00-1.04) and PWV (adjusted HR 1.23, 95% CI 1.03-1.47) were significant. PWV was neither associated with cardiac death nor associated with related cardiac events. However, GLS was associated with cardiac death (adjusted HR 1.24, 95% CI 1.00-1.54) and cardiac events (adjusted HR 1.13, 95% CI 1.03-1.25). Conclusions: PWV and LVMI/HT2.7 were superior to GLS in prediction of all-cause mortality. However, GLS was associated with cardiac death and events even when accounting for LVEF and LVMI/HT2.7.

Background and objectives: Higher phosphate is associated with mortality in dialysis patients but few prospective studies assess this in nondialysis patients managed in an outpatient nephrology clinic. This prospective longitudinal study examined whether phosphate level was associated with death in a referred population. Design, setting, participants & measurements: Patients (1203) of nondialysis chronic kidney disease (CKD) in the Chronic Renal Insufficiency Standards Implementation Study were assessed. Survival analyses were performed for quartiles of baseline phosphate relative to GFR, 12-month time-averaged phosphate, and baseline phosphate according to published phosphate targets. Results: Mean (SD) eGFR was 32 (15) ml/min per 1.73 m 2 , age 64 (14) years, and phosphate 1.2 (0.30) mmol/L. Cox multivariate adjusted regression in CKD stages 3 to 4 patients showed an increased risk of all-cause and cardiovascular mortality in the highest quartile compared with that in the lowest quartile of phosphate. No association was found in CKD stage 5 patients. Patients who had values above recommended targets for phosphate control had increased risk of all-cause and cardiovascular death compared with patients below target. The highest quartile compared with the lowest quartile of 12-month time-averaged phosphate was associated with an increased risk of mortality. Conclusions: In CKD stages 3 to 4 patients, higher phosphate was associated with a stepwise increase in mortality. As phosphate levels below published targets (as opposed to within them) are associated with better survival, guidelines for phosphate in nondialysis CKD patients should be re-examined. Intervention trials are required to determine whether lowering phosphate will improve survival.

Background Low-molecular-weight iron dextran (CosmoFer) is the only form of parenteral iron that can be administered as a total dose infusion (TDI) in the United Kingdom (UK). This study aimed to evaluate the safety and efficacy of TDI CosmoFer in comparison to intravenous iron sucrose infusion (Venofer) in patients with chronic kidney disease (CKD). Methods and results A retrospective study of outpatients with CKD undergoing intravenous TDI CosmoFer or Venofer infusion was conducted at Salford Royal Hospital and Sunderland Royal Hospital. A total of 979 doses of CosmoFer and 504 doses of Venofer were administered. There were three minor adverse events in patients receiving CosmoFer compared with one minor event in a Venofer treated patient. There were no anaphylactoid-type reactions in either group. Serum haemoglobin, ferritin and transferrin saturation (TSAT) improved significantly 4-6 months postinfusion in both treatment groups. Conclusion TDI CosmoFer is an efficacious method of replenishing iron stores in CKD patients in an outpatient setting. Furthermore, TDI CosmoFer is safe and not associated with an increase in adverse events compared to Venofer.

Vascular calcification, which is associated with arterial stiffness, is now known to be an important predictor of cardiovascular and all-cause mortality in patients with renal disease. This calcification starts developing in the early stages of chronic kidney disease (CKD) and is present in over 50% of patients at the time of dialysis commencement. Once calcification is present it continues to progress, though some medications have been shown to slow this progression. Vascular calcification and bone abnormalities are now both encompassed by the term of CKD-mineral bone disorder and are thought to be part of the same disease process in CKD. Vascular calcification and arterial stiffness have been extensively researched in the renal population and many factors are known to be associated with their presence and progression. This calcification is an important factor to be considered in the management of the renal patient but there are different methods available for its measurement. These details will be discussed further in this review along with evidence available for management of this important complication of renal disease.

Thilini Abeygunaratne, Ariane Herrick, Hector Chinoy, Evin Sowden, Jamil Choudhury and Smeeta Sinha Vascular Research Group, Manchester Academic Health Science Centre, Salford Royal NHS Foundation Trust, Salford, UK; Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Salford Royal NHS Foundation Trust, Salford, UK; Wrightington, Wigan and Leigh NHS Foundation Trust, Royal Albert Edward Infirmary, Wigan, UK; and Department of Histopathology, Salford Royal NHS Foundation Trust, Salford, UK

Patients with end-stage renal disease undergoing hemodialysis have high rates of morbidity and mortality. Cardiovascular disease accounts for almost half of this mortality, with the single most common cause being sudden cardiac death. Early detection of abnormalities in cardiac structure and function may be important to allow timely and appropriate cardiac interventions. Echocardiography is noninvasive cardiac imaging that is widely available and provides invaluable information on cardiac morphology and function. However, it has limitations. Echocardiography is operator dependent, and image quality can vary depending on the operator‘s experience and the patient's acoustic window. Hemodialysis patients undergo regular hemodynamic changes that also may affect echocardiographic findings. An understanding of the prognostic significance and interpretation of echocardiographic results in this setting is important for patient care. There are some emerging techniques in echocardiographic imaging that can provide more detailed and accurate information compared with conventional 2-dimensional echocardiography. Use of these novel tools may further our understanding of the pathophysiology of cardiac disease in patients with end-stage renal disease undergoing hemodialysis.

Calciphylaxis [calcific uraemic arteriolopathy (CUA)] is a rare disease at the interface of nephrology, dermatology and cardiology. CUA most often occurs in adult dialysis patients. It is only rarely seen in patients without relevant chronic kidney disease, and only anecdotal reports about childhood calciphylaxis have been published. Clinically, CUA is characterized by a typical cascade, starting with severe pain in initially often inconspicuous skin areas, followed by progressive cutaneous lesions that may develop into deep tissue ulcerations. The typical picture is a mixture of large retiform ulceration with thick eschar surrounded by violaceous, indurated, tender plaques. The histopathological picture reveals arteriolar, often circumferential, calcification and extensive matrix remodelling of the subcutis. These findings explain the macroscopic correlation between skin induration and ulceration. The prognosis in CUA patients is limited due to underlying comorbidities such as uraemic cardiovascular disease and infectious complications. The etiology of CUA is multifactorial, and imbalances between pro- and anti-calcification factors, especially in the setting of end-stage renal disease play an outstanding role. Oral anticoagulant treatment with vitamin K antagonists is a predominant CUA trigger factor. It is speculative as to why children and adolescents only develop calciphylaxis in exceptional cases, although a seldom usage of vitamin K antagonists and the preserved mineral buffering capacity of the growing skeleton may be protective.

Patients with chronic kidney disease have increased cardiovascular mortality from a combination of increased atherosclerotic disease, left ventricular hypertrophy and increased prevalence of vascular calcification (VC). Previously VC was thought to be a passive process which involved the deposition of calcium and phosphate into the vessel wall. However, recent studies have shown that VC is a highly regulated, cell-mediated process similar to bone formation, in that it is associated with expression of bone-related proteins, such as type I collagen and alkaline phosphatase. Animal and in vitro models of VC have shown that a multitude of factors including phosphate, matrix gla protein (MGP) and fetuin are involved in regulating VC. Certain factors induce calcification whereas others inhibit the process. Despite these insights, it is still not fully known how VC is regulated and a treatment for VC remains elusive. Ongoing research will hopefully elucidate these mechanisms and thereby produce targets for future therapeutic intervention. This review will highlight some of the scientific models of VC and how they have increased the understanding of this complex process.

Background: Vascular stiffness is associated with increased cardiovascular risk. This study aimed to identify factors associated with vascular stiffness in a cohort of chronic kidney disease (CKD) patients. Methods: The Chronic Renal Insufficiency Standards Implementation Study is a prospective epidemiological study of CKD patients not on dialysis, who are managed in a clinic setting. Phenotypic parameters were collected annually, and vascular stiffness was assessed using augmentation index (AI). Cross-sectional analysis was performed across quintiles of AI to evaluate factors associated with vascular stiffness. Results: Mean patient age was 66.1 ± 14.1 years and estimated glomerular filtration rate (eGFR) was 31.2 ± 5.7 ml/min. Corrected calcium was 2.26 ± 0.2 SD mmol/l, phosphate 1.2 ± 0.4 SD mmol/l and intact parathyroid hormone 94 ± 96 SD pg/ml; 18.3% of patients had cardiovascular disease. Increased age and systolic blood pressure were associated with increased AI (all p < 0.001). No statistical association was present between AI and eGFR, intact parathyroid hormone, phosphate or protein excretion. Conclusion: This study identified blood pressure as a potentially modifiable risk factor associated with AI, whereas eGFR was not associated with increased AI in a population of CKD stage 3–5 patients. Further knowledge of factors which influence progression of vascular stiffness will be important in risk quantification and management.

Sir, Low-molecular-weight iron dextran (cosmoFer® (marketed as INFed® in the USA), Pharmacosmos, Denmark) is available as a total dose infusion (TDI) in the United Kingdom (UK). The use of TDI regimen enables patients to receive their iron dose in one visit as opposed to numerous visits required with other preparations. However, the TDI can take up to 8 h and it would be preferable if the infusion could be safely administered over a shorter duration. The aim of this audit was to evaluate the safety of adopting an accelerated regimen of administering TDI low-molecular-weight iron dextran in comparison to standard rate infusion of the same product.