Lack of evidence does not justify neglect. how can we address unmet medical needs in calciphylaxis

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 medicin

Understanding the implementation of 'sick day guidance' to prevent acute kidney injury across a primary care setting in England: a qualitative evaluation

ObjectivesThe study sought to examine the implementation of sick day guidance cards designed to prevent acute kidney injury (AKI), in primary care settings.DesignQualitative semistructured interviews were conducted and comparative analysis informed by normalisation process theory was undertaken to understand sense-making, implementation and appraisal of the cards and associated guidance.SettingA single primary care health setting in the North of England.Participants29 participants took part in the qualitative evaluation: seven general practitioners, five practice nurses, five community pharmacists, four practice pharmacists, two administrators, one healthcare assistant and five patients.InterventionThe sick day guidance intervention was rolled out (2015–2016) in general practices (n=48) and community pharmacies (n=60). The materials consisted of a ‘medicine sick day guidance’ card, provided to patients who were taking the listed drugs. The card provided advice about medicines management during episodes of acute illness. An information leaflet was provided to healthcare practitioners and administrators suggesting how to use and give the cards.ResultsImplementation of sick day guidance cards to prevent AKI entailed a new set of working practises across primary care. A tension existed between ensuring reach in administration of the cards to at risk populations while being confident to ensure patient understanding of their purpose and use. Communicating the concept of temporary cessation of medicines was a particular challenge and limited their administration to patient populations at higher risk of AKI, particularly those with less capacity to self-manage.ConclusionsSick day guidance cards that focus solely on medicines management may be of limited patient benefit without adequate resourcing or if delivered as a standalone intervention. Development and evaluation of primary care interventions is urgently warranted to tackle the harm associated with AKI.</jats:sec

The role of iron in calciphylaxis—a current review

Calcific uraemic arteriolopathy (CUA), also known as calciphylaxis, is a rare and often fatal condition, frequently diagnosed in end-stage renal disease (ESRD) patients. Although exact pathogenesis remains unclear, iron supplementation is suggested as a potential risk factor. Iron and erythropoietin are the main stay of treatment for anaemia in ESRD patients. Few observational studies support the role of iron in the pathogenesis of calciphylaxis although data from the pivotal trial was not strongly supportive of this argument, i.e., no difference in incidence of calciphylaxis between the low-dose and high-dose iron treatment arms. Elevated levels of vascular cell adhesion molecules in association with iron excess were postulated to the pathogenesis of CUA by causing inflammation and calcification within the microvasculature. In-addition, oxidative stress generated because of iron deposition in cases of systemic inflammation, such as those seen in ESRD, may play a role in vascular calcification. Despite these arguments, a direct correlation between cumulative iron exposure with CUA incidence is not clearly demonstrated in the literature. Consequently, we do not have evidence to recommend iron reduction or cessation in ESRD patients that develop CUA

Effects of SNF472, a Novel Inhibitor of Hydroxyapatite Crystallization in Patients Receiving Hemodialysis - Subgroup Analyses of the CALIPSO Trial

Coronary artery calcium (CAC) is highly prevalent and linked with poor outcomes in patients receiving maintenance hemodialysis, and its reduction may improve patient prognosis. SNF472, a selective inhibitor of hydroxyapatite crystallization, slows CAC progression in patients receiving maintenance hemodialysis. In this analysis, we assessed the efficacy of SNF472 in prespecified patient subgroups. In a randomized clinical trial SNF472 300 mg, SNF472 600 mg, or placebo were infused thrice weekly in 91, 92, and 91 patients receiving maintenance hemodialysis and with CAC at baseline, respectively. In prespecified subanalyses, the percent change in CAC volume score (CACvs) from baseline to week 52 in modified intention-to-treat (mITT) and per-protocol (PP) populations was calculated in the following subgroups: age, sex, diabetes mellitus, dialysis vintage, prior atherosclerotic cardiovascular disease, baseline use of non-calcium and calcium-based phosphate binders, calcimimetics, activated vitamin D, warfarin, and statins. In the main trial, SNF472 significantly reduced CACvs progression compared with placebo (11% versus 20% mITT analyses; P = 0.016; 8% vs. 24% PP analyses; P < 0.001). Treatment differences for CACvs progression were similar across all subgroups, and all interaction P values were non-significant in mITT and PP analyses. SNF472 treatment for 52 weeks reduced CACvs progression compared with placebo in a broad range of patients receiving maintenance hemodialysis. Future studies will determine the impact of SNF472 on cardiovascular events in this population

Trial design and baseline characteristics of CaLIPSO : a randomized, double-blind placebo-controlled trial of SNF472 in patients receiving haemodialysis with cardiovascular calcification

The objective of CaLIPSO, a Phase 2b, randomized, double-blind, placebo-controlled clinical trial, is to test the hypothesis that myo-inositol hexaphosphate (SNF472) attenuates the progression of cardiovascular calcification in patients receiving maintenance haemodialysis. Here we report the trial design and baseline characteristics of trial participants. Adult patients on maintenance haemodialysis (≥6 months) with an Agatston coronary artery calcium score, as measured by a multidetector computed tomography scanner, of 100-3500 U were enrolled. Patients were stratified by Agatston score (100-1000 U) and randomized in a 1:1:1 ratio to receive placebo, SNF472 300 mg or SNF472 600 mg administered intravenously three times weekly during each haemodialysis session. Overall, 274 patients were randomized. The mean age of trial participants was 63.6 (standard deviation 8.9) years and 39% were women. The coronary artery, aorta and aortic valve median (25th-75th percentile) Agatston scores at baseline were 730 U (315-1435), 1728 U (625-4978) and 103 U (31-262), respectively, and the median (25th-75th percentile) calcium volume scores at baseline were 666 (310-1234), 1418 (536-4052) and 107 (38-278), respectively. Older age and diabetes mellitus were associated with higher calcium scores at baseline. The CaLIPSO trial enrolled patients on haemodialysis with pre-existent cardiovascular calcification to test the hypothesis that SNF472 attenuates its progression in the coronary arteries, aorta and aortic valve

Presentation of laboratory test results in patient portals: influence of interface design on risk interpretation and visual search behaviour

Abstract Background Patient portals are considered valuable instruments for self-management of long term conditions, however, there are concerns over how patients might interpret and act on the clinical information they access. We hypothesized that visual cues improve patients’ abilities to correctly interpret laboratory test results presented through patient portals. We also assessed, by applying eye-tracking methods, the relationship between risk interpretation and visual search behaviour. Methods We conducted a controlled study with 20 kidney transplant patients. Participants viewed three different graphical presentations in each of low, medium, and high risk clinical scenarios composed of results for 28 laboratory tests. After viewing each clinical scenario, patients were asked how they would have acted in real life if the results were their own, as a proxy of their risk interpretation. They could choose between: 1) Calling their doctor immediately (high interpreted risk); 2) Trying to arrange an appointment within the next 4 weeks (medium interpreted risk); 3) Waiting for the next appointment in 3 months (low interpreted risk). For each presentation, we assessed accuracy of patients’ risk interpretation, and employed eye tracking to assess and compare visual search behaviour. Results Misinterpretation of risk was common, with 65% of participants underestimating the need for action across all presentations at least once. Participants found it particularly difficult to interpret medium risk clinical scenarios. Participants who consistently understood when action was needed showed a higher visual search efficiency, suggesting a better strategy to cope with information overload that helped them to focus on the laboratory tests most relevant to their condition. Conclusions This study confirms patients’ difficulties in interpreting laboratories test results, with many patients underestimating the need for action, even when abnormal values were highlighted or grouped together. Our findings raise patient safety concerns and may limit the potential of patient portals to actively involve patients in their own healthcare

The investigative burden of Membranous Nephropathy in the United Kingdom

BackgroundMembranous 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.MethodsPatients 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.ResultsIn 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.ConclusionsSince 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

Chronic kidney disease-mineral and bone disorder: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference

In 2017, Kidney Disease: Improving Global Outcomes (KDIGO) published a Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Since then, new lines of evidence have been published related to evaluating disordered mineral metabolism and bone quality and turnover, identifying and inhibiting vascular calcification, targeting vitamin D levels, and regulating parathyroid hormone. For an in-depth consideration of the new insights, in October 2023, KDIGO held a Controversies Conference on CKD-MBD: Progress and Knowledge Gaps Toward Personalizing Care. Participants concluded that the recommendations in the 2017 CKD-MBD guideline remained largely consistent with the available evidence. However, the framework of the 2017 Guideline, with 3 major sections-biochemical abnormalities in mineral metabolism; bone disease; and vascular calcification-may no longer best reflect currently available evidence related to diagnosis and treatment. Instead, future guideline efforts could consider mineral homeostasis and deranged endocrine systems in adults within a context of 2 clinical syndromes: CKD-associated osteoporosis, encompassing increased fracture risk in patients with CKD; and CKD-associated cardiovascular disease, including vascular calcification and structural abnormalities, such as valvular calcification and left ventricular hypertrophy. Participants emphasized that the complexity of bone and cardiovascular manifestations of CKD-MBD necessitates personalized approaches to management.</p

Use of surrogate endpoints in health technology assessment and reimbursement of treatments for the management of chronic kidney disease

The judicious use of surrogate endpoints as substitutes for patient relevant target outcomes can substantially reduce the size and duration of clinical trials, thereby driving down research and development costs and driving faster patient access to innovative therapies. Whilst increasingly used by regulators over the last two decades, health technology assessment (HTA) agencies and payers have been more sceptical in acceptance of surrogates in their reimbursement decisions. Central to acceptance is scientific validation and demonstration of the association in the treatment effect on the surrogate endpoint and target outcome. This review summarises the validity and utility of glomerular filtration rate (GFR) slope as a ‘first in class’ surrogate with robust evidence of a strong treatment effect association (i.e., R2 trial of 97%) with clinically meaningful kidney target outcomes including dialysis and kidney transplantation. Given the likely continued challenges in the use of surrogate endpoints in future healthcare policy making, we conclude this review with the opportunities for stakeholders–healthcare industry, regulators and payers, clinicians and trialists, and patients and the public–to leverage the future appropriate use of surrogates

Comparative clinical and cost effectiveness of non-ST elevation myocardial infarction management strategies in patients living with kidney impairment during the COVID-19 pandemic: protocol for a target trial emulation using English routinely collected health data

Introduction: Recent national and international guidelines recommend an invasive cardiac investigation and treatment strategy for people at high risk of cardiovascular events, regardless of kidney function status. These guidelines are based on observational evidence suggesting that the benefits of invasive cardiac investigation and treatment versus conservative management for non-ST elevated myocardial infarction (NSTEMI) outweigh the risks for people with kidney impairment. Despite this, among people with kidney impairment there is substantial variation in the proportions who have early invasive versus conservative NSTEMI management across hospitals in England. The impact of the COVID-19 pandemic on this variation is unknown. This protocol describes a study to investigate this variation and any changes during the COVID-19 pandemic, and how this variation will be used to evaluate the comparative clinical and cost-effectiveness of alternative NSTEMI treatment strategies among people with reduced kidney function. Methods and analysis: The CVD-COVID-UK/COVID-IMPACT British Heart Foundation (BHF) Data Science Centre Secure Data Environment, which contains nationally representative linked data on over 50 million people living in the United Kingdom, will be used to define a cohort of people hospitalised for NSTEMI. We will use linked secondary care data (Hospital Episode Statistics and National Institute for Cardiovascular Outcomes Research Audit) for cases with recent evidence of kidney impairment in primary care data (General Practice Extraction Service Data for pandemic planning and research) between 2019 and 2024. First, we will describe variation in early invasive versus conservative NSTEMI management at the hospital-level before and during the COVID-19 pandemic. Second, we will emulate a hypothetical trial using the target trial emulation framework to evaluate the comparative and cost-effectiveness of early invasive versus conservative NSTEMI management among people with reduced kidney function. We will use advanced analytical methods (clone-censor-weighting and instrumental variable analyses) to minimise the risk of bias due to immortal time and confounding by indication. Ethics and dissemination: This study was reviewed and approved by the BHF Data Science Centre Scientific and Public Panels. Results will be published in peer-reviewed journals, presented at conferences, and shared at patient and public panels. Analysis code will be shared in line with the BHF Data Science Centre’s code-sharing procedures