Renal Manifestations of IgG4-Related Disease: A Concise Review.

IgG4-related disease (IgG4-RD) is an immune-mediated disorder marked by fibro-inflammatory masses that can infiltrate multiple organ systems. Due to its relatively recent discovery and limited understanding of its pathophysiology, IgG4-related disease may be difficult to recognize and is consequently potentially underdiagnosed. Renal involvement is becoming regarded as one of the key features of this disease. To date, the most well-recognized renal complication of IgG4-related disease is tubulointerstitial nephritis, but membranous glomerulonephritis, renal masses, and retroperitoneal fibrosis have also been reported. This concise review has two objectives. First, it will briefly encapsulate the history, epidemiology, and presentation of IgG4-related disease. Second, it will examine the reported renal manifestations of IgG4-related disease, exploring the relevant histology, imaging, clinical features, and treatment considerations. This synthesis will be highly relevant for nephrologists, rheumatologists, general internists, and renal pathologists to raise awareness and help improve early recognition of IgG4-related kidney disease (IgG4-RKD).

A case-based narrative review of pregnancy-associated atypical hemolytic uremic syndrome/complement-mediated thrombotic microangiopathy.

Atypical hemolytic uremic syndrome is a complement-mediated thrombotic microangiopathy caused by uncontrolled activation of the alternative complement pathway in the setting of autoantibodies to or rare pathogenic genetic variants in complement proteins. Pregnancy may serve as a trigger and unmask atypical hemolytic uremic syndrome/complement-mediated thrombotic microangiopathy (aHUS/CM-TMA), which has severe, life-threatening consequences. It can be difficult to diagnose aHUS/CM-TMA in pregnancy due to overlapping clinical features with other thrombotic microangiopathy syndromes including hypertensive disorders of pregnancy. However, the distinction among thrombotic microangiopathy etiologies in pregnancy is important because each syndrome has specific disease management and treatment. In this narrative review, we discuss 2 cases to illustrate the diagnostic challenges and evolving approach in the management of pregnancy-associated aHUS/CM-TMA. The first case involves a 30-year-old woman presenting in the first trimester who was diagnosed with aHUS/CM-TMA and treated with eculizumab from 19 weeks' gestation. Genetic testing revealed a likely pathogenic variant in CFI. She successfully delivered a healthy infant at 30 weeks' gestation. In the second case, a 22-year-old woman developed severe postpartum HELLP syndrome, requiring hemodialysis. Her condition improved with supportive management, yet investigations assessing for aHUS/CM-TMA remained abnormal 6 months postpartum consistent with persistent complement activation but negative genetic testing. Through detailed case discussion describing tests assessing for placental health, fetal anatomy, complement activation, autoantibodies to complement regulatory proteins, and genetic testing for aHUS/CM-TMA, we describe how these results aided in the clinical diagnosis of pregnancy-associated aHUS/CM-TMA and assisted in guiding patient management, including the use of anticomplement therapy.

Evaluation and comparison of four quantitative SARS-CoV-2 serological assays in COVID-19 patients and immunized healthy individuals, cancer patients, and patients with immunosuppressive therapy.

BACKGROUND: Semi-quantitative and quantitative immunoassays are the most commonly used methodology to evaluate immunity post immunization. OBJECTIVES: To compare four quantitative SARS-CoV-2 serological assays in COVID-19 patients and immunized healthy individuals, cancer patients, and patients with immunosuppressive therapy. STUDY DESIGN: 210 serological samples from COVID-19 infection and vaccination cohorts were used to create a serological sample repository. Serological methods from four manufacturers, namely Euroimmun, Roche, Abbott, and DiaSorin, were evaluated for quantitative, semi-quantitative, and qualitative antibody measurements. All four methods measure IgG antibodies against the SARS-CoV-2 spike receptor-binding domain and report the results in Binding Antibody Unit/mL (BAU/mL). A Total Error Allowable (TEa) of ±25% was chosen as the criteria to determine whether two methods are clinically equivalent quantitatively. Semi-quantitative results (titers) were derived using numeric antibody concentration divided by the cut-off value for each method. RESULTS: All paired quantitative comparisons demonstrated unacceptable performance. With ±25% as TEa, the best agreement was 74 (35.2% out of 210 samples) between Euroimmun and DiaSorin, whereas the lowest agreement was 11 (5.2% out of 210 samples) between Euroimmun and Roche. Antibody titers amongst all four methods were significantly different (p < 0.001). The highest titer difference from the same sample is between Roche and DiaSorin with a 1392-fold difference. On qualitative comparison, none of the paired comparison showed acceptable comparison (p < 0.001). CONCLUSIONS: Poor correlation exists between four evaluated assays, quantitatively, semi-quantitatively, and qualitatively. Further harmonization of assays is required to achieve comparable measurements.

Complement-Amplifying Conditions in Atypical Hemolytic Uremic Syndrome: A Canadian Case Series.

Rationale: Thrombotic microangiopathies (TMAs) are systemic disorders that often affect the kidneys and encompass a heterogeneous group of conditions, including atypical hemolytic uremic syndrome (aHUS). The complement pathway is thought to play a crucial role in the pathogenesis of aHUS, and a favorable response can be obtained through complement C5 inhibition. There is emerging evidence to suggest that the same is also true for several other forms of TMA. Objective: The purpose of this series is to report cases of aHUS in which both an innate defect of the alternative complement pathway and a complement-amplifying condition were suspected. Methods: This case series describes 8 patients who were managed in Canadian tertiary centers for aHUS and who presented initially with complement-amplifying conditions. Results: In all cases, aHUS was associated with organ dysfunction and in some, with an innate defect of the alternative complement pathway. The complement-amplifying conditions identified were diverse including immune disorders, pregnancy, and a Shiga toxin infection. Patients improved rapidly when treated with eculizumab or plasma exchange. Conclusions: These observations illustrate the seriousness of secondary aHUS. They also add to existing lines of evidence that the complement pathway is potentially involved in this condition and that it should be considered as a therapeutic target of interest under such circumstances.

Justification: Les microangiopathies thrombotiques (MAT) sont des troubles systémiques qui affectent souvent les reins et qui englobent un groupe hétérogène d'affections, notamment le syndrome hémolytique et urémique atypique (SHUa). On pense que la voie du complément joue un rôle crucial dans la pathogenèse du SHUa et qu'une réponse favorable pourrait être obtenue par inhibition du complément C5. De nouvelles preuves suggèrent qu'il en serait de même pour plusieurs autres formes de MAT. Objectif: Cette série vise à rapporter des cas de SHUa pour lesquels on soupçonnait à la fois une anomalie congénitale de la voie alterne du complément et une condition d'amplification du complément. Méthodologie: Cette série décrit les cas de huit patients qui présentaient initialement des conditions d'amplification du complément et qui ont été pris en charge pour un SHUa dans des centres tertiaires canadiens. Résultats: Dans tous les cas, le SHUa était associé à un dysfonctionnement d'organe et, dans certains cas, à une anomalie congénitale de la voie alterne du complément. Les conditions d'amplification du complément identifiées étaient diverses, notamment des troubles immunitaires, une grossesse et une infection à une shigatoxine. L'état des patients s'est rapidement amélioré après un traitement avec éculizumab ou des échanges plasmatiques. Conclusion: Ces observations illustrent la gravité du SHUa secondaire. Elles s'ajoutent aux preuves existantes qui suggèrent que la voie du complément est potentiellement impliquée dans cette pathologie et qu'elle devrait être considérée comme une cible thérapeutique d'intérêt dans de telles circonstances.

Association of Clonal Hematopoiesis of Indeterminate Potential with Worse Kidney Function and Anemia in Two Cohorts of Patients with Advanced Chronic Kidney Disease.

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) is an inflammatory premalignant disorder resulting from acquired genetic mutations in hematopoietic stem cells. This condition is common in aging populations and associated with cardiovascular morbidity and overall mortality, but its role in CKD is unknown. METHODS: We performed targeted sequencing to detect CHIP mutations in two independent cohorts of 87 and 85 adults with an eGFR<60 ml/min per 1.73m2. We also assessed kidney function, hematologic, and mineral bone disease parameters cross-sectionally at baseline, and collected creatinine measurements over the following 5-year period. RESULTS: At baseline, CHIP was detected in 18 of 87 (21%) and 25 of 85 (29%) cohort participants. Participants with CHIP were at higher risk of kidney failure, as predicted by the Kidney Failure Risk Equation (KFRE), compared with those without CHIP. Individuals with CHIP manifested a 2.2-fold increased risk of a 50% decline in eGFR or ESKD over 5 years of follow-up (hazard ratio 2.2; 95% confidence interval, 1.2 to 3.8) in a Cox proportional hazard model adjusted for age, sex, and baseline eGFR. The addition of CHIP to 2-year and 5-year calibrated KFRE risk models improved ESKD predictions. Those with CHIP also had lower hemoglobin, higher ferritin, and higher red blood cell mean corpuscular volume versus those without CHIP. CONCLUSIONS: In this exploratory analysis of individuals with preexisting CKD, CHIP was associated with higher baseline KFRE scores, greater progression of CKD, and anemia. Further research is needed to define the nature of the relationship between CHIP and kidney disease progression.

Making the Correct Diagnosis in Thrombotic Microangiopathy: A Narrative Review.

PURPOSE OF REVIEW: Thrombotic microangiopathy (TMA) is suspected in patients presenting with thrombocytopenia and evidence of a microangiopathic hemolytic anemia. Patients with TMA can be critically ill, so rapid and accurate identification of the underlying etiology is essential. Due to better insights into pathophysiology and causes of TMA, we can now categorize TMAs as thrombotic thrombocytopenic purpura, postinfectious (mainly Shiga toxin-producing Escherichia coli-induced) hemolytic uremic syndrome (HUS), TMA associated with a coexisting condition, or atypical HUS (aHUS). We recognized an unmet need in the medical community to guide the timely and accurate identification of TMA, the selection of tests to clarify its etiology, and the sequence of steps to initiate treatment. SOURCES OF INFORMATION: Key published studies relevant to the identification, classification, and treatment of TMAs in children or adults. These studies were obtained through literature searches conducted with PubMed or based on the prior knowledge of the authors. METHODS: This review is the result of a consultation process that reflects the consensus of experts from Canada, the United States, and the United Arab Emirates. The members represent individuals who are clinicians, researchers, and teachers in pediatric and adult medicine from the fields of hematology, nephrology, and laboratory medicine. Authors, through an iterative review process identified and synthesized information from relevant published studies. KEY FINDINGS: Thrombotic thrombocytopenic purpura occurs in the setting of insufficient activity of the von Willebrand factor protease known as ADAMTS13. Shiga toxin-producing Escherichia coli-induced hemolytic uremic syndrome, also known as "typical" HUS, is caused by gastrointestinal infections with bacteria that produce Shiga toxin (initially called verocytotoxin). A variety of clinical conditions or drug exposures can trigger TMA. Finally, aHUS occurs in the setting of inherited or acquired abnormalities in the alternative complement pathway leading to dysregulated complement activation, often following a triggering event such as an infection. It is possible to break the process of etiological diagnosis of TMA into 2 distinct steps. The first covers the initial presentation and diagnostic workup, including the processes of identifying the presence of TMA, appropriate initial tests and referrals, and empiric treatments when appropriate. The second step involves confirming the etiological diagnosis and moving to definitive treatment. For many forms of TMA, the ultimate response to therapies and the outcome of the patient depends on the rapid and accurate identification of the presence of TMA and then a standardized approach to seeking the etiological diagnosis. We present a structured approach to identifying the presence of TMA and steps to identifying the etiology including standardized lab panels. We emphasize the importance of early consultation with appropriate specialists in hematology and nephrology, as well as identification of whether the patient requires plasma exchange. Clinicians should consider appropriate empiric therapies while following the steps we have recommended toward definitive etiologic diagnosis and management of the TMA. LIMITATIONS: The evidence base for our recommendations consists of small clinical studies, case reports, and case series. They are generally not controlled or randomized and do not lend themselves to a stricter guideline-based methodology or a Grading of Recommendations Assessment, Development and Evaluation (GRADE)-based approach.

JUSTIFICATION: La microangiopathie thrombotique (MAT) est suspectée chez les patients présentant une thrombocytopénie et la preuve d'une anémie hémolytique microangiopathique (AHMA). Les patients atteints de MAT peuvent être gravement malades, il est donc essentiel de déterminer rapidement et précisément l'étiologie sous-jacente. Grâce à une meilleure connaissance de la physiopathologie et des causes de la MAT, nous pouvons désormais classer les MAT par catégorie: purpura thrombocytopénique thrombotique (PTT), syndrome hémolytique urémique post-infectieux (SHU) principalement induit par STEC (Escherichia coli produisant la toxine Shiga), ou MAT associée à une affection coexistante ou à un SHU atypique (SHUa). Nous avons constaté un besoin dans la communauté médicale pour guider à la fois la détection rapide et précise de la MAT, la sélection des tests pour clarifier son étiologie et la séquence des étapes menant à l'initiation du traitement. SOURCES: Des recherches documentaires sur PubMed et les connaissances antérieures des auteurs ont permis de colliger les principales études publiées portant sur la détection, la classification et le traitement de la MAT chez les enfants ou les adultes. MÉTHODOLOGIE: Cet examen est le résultat d'un processus de consultation qui reflète le consensus des experts du Canada, des États-Unis et des Émirats arabes Unis. Les membres représentent des cliniciens, des chercheurs et des enseignants en médecine pédiatrique et adulte dans les domaines de l'hématologie, de la néphrologie et de la médecine de laboratoire. Les auteurs, par le biais d'un processus d'examen itératif, ont colligé et synthétisé l'information provenant des études publiées jugées pertinentes. PRINCIPAUX RÉSULTATS: Le PTT survient lors d'une activité insuffisante de la protéase du facteur Willebrand connue sous le nom d'ADAMTS13. Le SHU-STEC, aussi appelé SHU « typique ¼, est causé par des infections gastro-intestinales dues à des bactéries produisant la toxine Shiga (initialement appelée vérocytotoxine). Plusieurs états pathologiques ou expositions à des médicaments peuvent déclencher la MAT. Quant au SHU atypique (SHUa), il survient en présence d'anomalies héréditaires ou acquises de la voie du complément alternatif qui mènent à un dérèglement de l'activation du complément, souvent à la suite d'un événement déclencheur comme une infection. On peut diviser le processus de diagnostic étiologique de la MAT en deux étapes distinctes. La première couvre la présentation initiale et le diagnostic, y compris les processus de détection de la MAT, les tests initiaux et aiguillages appropriés, ainsi que les traitements empiriques si nécessaire. La deuxième étape consiste à confirmer le diagnostic étiologique et à procéder au traitement définitif. Pour de nombreuses formes de MAT, la réponse ultime aux traitements et le résultat du patient dépendent de la détection rapide et précise de la MAT et ensuite, d'une approche standardisée pour la recherche du diagnostic étiologique. Nous présentons une approche structurée pour détecter la présence de MAT ainsi qu'une démarche pour rechercher l'étiologie, y compris des tableaux de laboratoire normalisés. Nous soulignons l'importance d'une consultation précoce avec les spécialistes appropriés en hématologie et en néphrologie, et de la détermination d'un éventuel besoin d'échange de plasma (PLEX) pour le patient. Les cliniciens devraient envisager les traitements empiriques appropriés tout en suivant la démarche que nous recommandons pour le diagnostic étiologique définitif et la gestion de la MAT. LIMITES: La base factuelle de nos recommandations est constituée de petites études cliniques, de rapports de cas et de séries de cas. Ces études ne sont généralement pas contrôlées ou randomisées et ne se prêtent pas à une méthodologie plus stricte basée sur des lignes directrices ni à une approche fondée sur le GRADE (Grading of Recommendations Assessment, Development and Evaluation).

Management of Patients With Glomerulonephritis During the COVID-19 Pandemic: Recommendations From the Canadian Society of Nephrology COVID-19 Rapid Response Team.

PURPOSE OF PROGRAM: This article will provide guidance on how to best manage patients with glomerulonephritis (GN) during the COVID-19 pandemic. SOURCES OF INFORMATION: We reviewed relevant published literature, program-specific documents, and guidance documents from international societies. An informal survey of Canadian nephrologists was conducted to identify practice patterns and expert opinions. We hosted a national webinar with invited input and feedback after webinar. METHODS: The Canadian Society of Nephrology (CSN) Board of Directors invited physicians with expertise in GN to contribute. Specific COVID-19-related themes in GN were identified, and consensus-based recommendations were made by this group of nephrologists. The recommendations received further peer input and review by Canadian nephrologists via a CSN-sponsored webinar. This was attended by 150 kidney health care professionals. The final consensus recommendations also incorporated review by Editors of the Canadian Journal of Kidney Health and Disease. KEY FINDINGS: We identified 9 areas of GN management that may be affected by the COVID-19 pandemic: (1) clinic visit scheduling, (2) clinic visit type, (3) provision of multidisciplinary care, (4) blood and urine testing, (5) home-based monitoring essentials, (6) immunosuppression, (7) other medications, (8) patient education and support, and (9) employment. LIMITATIONS: These recommendations are expert opinion, and are subject to the biases associated with this level of evidence. To expedite the publication of this work, a parallel review process was created that may not be as robust as standard arm's length peer review processes. IMPLICATIONS: These recommendations are intended to provide optimal care during the COVID-19 pandemic. Our recommendations may change based on the evolving evidence.

Drug-induced Thrombotic Microangiopathy with Concurrent Proteasome Inhibitor Use in the Treatment of Multiple Myeloma: A Case Series and Review of the Literature.

Thrombotic microangiopathy (TMA) is a life-threatening clinical syndrome characterized by hemolytic anemia, thrombocytopenia, and microvascular thrombosis, resulting in ischemia and organ damage. Multiple myeloma (MM) is a neoplasm arising from clonal plasma cells within the bone marrow. The treatment frequently includes multi-agent immunochemotherapy, often with the use of proteasome inhibitors (PIs) such as bortezomib, carfilzomib, or ixazomib. There are increasing reports of TMA in association with PI exposure. This review summarizes the epidemiology, pathogenesis, and diagnosis of PI-related drug-induced TMA. We will outline the definition and diagnosis of TMA and explore an important cause of hemolysis in patients with MM: drug-induced TMA after PI exposure, an increasingly recognized therapeutic complication. This will be emphasized through the description of 3 novel cases of TMA. These illustrative cases occurred after treatment with high-dose weekly carfilzomib, cyclophosphamide, and dexamethasone as part of the MCRN003/MYX1 phase II clinical trial (NCT02597062) in relapsed MM.

Relationship of coronary artery calcification with renal function decline and mortality in predialysis chronic kidney disease patients.

BACKGROUND: Patients with chronic kidney disease (CKD) have higher levels of coronary artery calcification (CAC) compared with the general population. The role of CAC in renal function decline is not well understood. METHODS: In this prospective cohort study of Stages 3-5 CKD patients with CAC scores kidney function decline, development of end-stage kidney disease (ESKD) and all-cause mortality were determined at 5 and 10 years. Baseline variables included markers of CKD and chronic kidney disease mineral and bone disorder (CKD-MBD), demographics and comorbidities. Multivariable analyses identified predictors of outcomes, and survival curves demonstrated the association of CAC score with ESKD and mortality. RESULTS: One hundred and seventy-eight patients were enrolled between 2005 and 2007. Independent predictors of ESKD at 5 years were estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR); at 10 years, eGFR was no longer a predictor, but CAC was now significant. Those who developed ESKD at the fastest rate either had the highest CAC score (≥400 AU) or were youngest and had the lowest calcidiol, and highest serum phosphate, UACR and percentage change in CAC per year. Predictors of eGFR decline over 5 years were UACR, parathyroid hormone and CAC score. Predictors of mortality at 5 years were age, diabetes and eGFR and at 10 years also included CAC score. CONCLUSIONS: In Stages 3-5 CKD patients, CAC is an independent predictor of both ESKD and mortality at 10 years. Those who developed ESKD at the fastest rate either had the highest CAC score or the worst CKD-MBD derangements.

De novo antineutrophil cytoplasmic antibody-associated vasculitis in pregnancy: a systematic review on maternal, pregnancy and fetal outcomes.

BACKGROUND: De novo antineutrophil cytoplasmic antibody-associated vasculitis typically arises in post-reproductive years, but can occur during pregnancy. Concerns of treatment-related teratogenicity persist, while efficacy and safety of new therapies including intravenous immunoglobulin (IVIG) and rituximab are uncertain. There remains a paucity of maternal, fetal and pregnancy outcome data in these women, and therefore a lack of guidance on safe treatment for clinicians. METHODS: We conducted a systematic review of the literature and a local, retrospective chart review of women with de novo antibody-associated vasculitis (AAV) in pregnancy. Cochrane, Embase and PubMed databases and relevant conference abstracts were searched. Patient demographics, clinical presentation, management and outcomes (maternal, fetal and pregnancy-related) were analyzed. RESULTS: Twenty-seven cases of de novo AAV in pregnancy were included. Women presented were from 5 to 39 weeks' gestation, of which a majority were in the second trimester (median 20 weeks). The median gravida of women was 2 and the median parity was 1. Women were treated with steroids (89%), cyclophosphamide (CYC) (37%), other immunosuppressive agents [azathioprine (AZA), IVIG, plasma exchange (PLEX)] or no therapy (11%). High rates of serious complications, including preeclampsia (29%) and maternal death (7%), were reported; however, most pregnancies resulted in live birth (73%). Prematurity was common; 73% of live births occurred prior to 37 weeks' gestation and 40% prior to 34 weeks' gestation. The majority of infants were born in the third trimester (median 34.5 weeks). Rates of pregnancy termination were high (23%) and only one intrauterine death was reported, shortly after initiation of therapy (4%). Congenital abnormalities were rare, with one infant having a solitary, pelvic kidney (6%) after maternal treatment with steroids, CYC and PLEX. Use of PLEX, IVIG and AZA increased after 2005, whereas CYC use decreased. Remission often occurred postpartum (60%). CONCLUSIONS: De novo AAV in pregnancy can result in uncomplicated pregnancies; however, serious maternal risks exist. Further data on potentially pregnancy compatible therapies such as IVIG and rituximab are needed in this population.

The WISHED Trial: implementation of an interactive health communication application for patients with chronic kidney disease.

BACKGROUND: Despite many advantages over facility-based therapies, less than 25 % of prevalent dialysis patients in Ontario are on a home therapy. Interactive health communication applications, web-based packages for patients, have been shown to have a beneficial effect on knowledge, social support, self-efficacy, and behavioral and clinical outcomes but have not been evaluated in patients with chronic kidney disease (CKD). Web-based tools designed for patients with CKD exist but to our knowledge have not been assessed in their ability to influence dialysis modality decision-making. OBJECTIVE: To determine if a web-based tool increases utilization of a home-based therapy in patients with CKD starting dialysis. DESIGN: This is a multi-centered randomized controlled study. SETTING: Participants will be recruited from sites in Canada. PARTICIPANTS: Two hundred and sixty-four consenting patients with an estimated glomerular filtration rate (eGFR) less than 20 ml/min/1.73 m(2) who have received modality education will be enrolled in the study. MEASUREMENTS: The primary outcome will be the proportion of participants who are on dialysis using a home-based therapy within 3 months of dialysis initiation. Secondary outcomes will include the proportion of patients intending to perform a home-based modality and measures of dialysis knowledge, decision conflict, and social support. METHODS: The between-group differences in frequencies will be expressed as either absolute risk differences and/or by calculating the odds ratio and its associated 95 % confidence interval. CONCLUSIONS: This study will assess whether access to a website dedicated to supporting and promoting home-based dialysis therapies will increase the proportion of patients with CKD who initiate a home-based dialysis therapy. TRIAL REGISTRATION: ClinicalTrials.gov #NCT01403454, registration date: July 21, 2011.

MISE EN CONTEXTE: L'administration de traitements d'hémodialyse à domicile présente plusieurs avantages par rapport aux traitements offerts en centre hospitalier. Pourtant, moins de 25 % des patients Ontariens suivent leurs traitements de dialyse à domicile. Bien que l'accès à des outils interactifs de communication en santé (OICS) ait des effets bénéfiques sur le niveau de connaissances, le soutien social, le niveau d'autonomie ainsi que sur les résultats cliniques et comportementaux des patients qui les utilisent, ces outils n'ont jamais fait l'objet d'études chez les patients atteints d'insuffisance rénale chronique (IRC). Des OICS existent pour cette population, mais on ne connaît pas leur part d'influence au moment où le patient doit faire le choix d'une technique de dialyse. OBJECTIFS DE L'ÉTUDE: Par cette étude, on entend vérifier si l'accès à des outils sur le web augmentera le nombre de patients atteints d'IRC en amorce d'une dialyse qui choisiront d'effectuer leurs traitements à domicile. CADRE ET TYPE D'ÉTUDE: Il s'agit d'un essai contrôlé, randomisé, qui se tiendra dans plusieurs centres hospitaliers à travers le Canada. PARTICIPANTS: La cohorte sera constituée de 264 patients atteints d'IRC dont le taux de filtration glomérulaire se situe à moins de 20 ml/min/1, 73 m2. Les participants auront suivi une séance d'orientation pour les aider à naviguer dans les différents outils mis à leur disposition sur le web. MESURES: À titre de résultat principal, on établira la proportion de patients qui auront adhéré à la technique de dialyse à domicile au cours des trois mois suivant l'initiation du traitement. On cherchera ensuite à connaître la proportion de patients ayant l'intention de le faire au courant de la première année de traitement. De plus, on procèdera à l'évaluation des connaissances et de la capacité des patients de prendre des décisions concernant leur traitement, ainsi que du soutien social qu'ils reçoivent. MÉTHODOLOGIE: Les différences entre les groupes d'étude seront exprimées soit sur le plan du risque absolu ou en calculant les rapports de cotes et les intervalles de confiance à 95 % correspondants. CONCLUSION: Cette étude évaluera si l'accès à un site web consacré au soutien social des patients et à la promotion des traitements de dialyse à domicile augmentera la proportion de patients souffrant d'IRC qui choisiront cette option pour l'amorce de leur traitement.

Elevated body mass index as a risk factor for chronic kidney disease: current perspectives.

Chronic kidney disease (CKD) is defined by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative as the presence of reduced kidney function or kidney damage for a period of 3 months or greater. Obesity is considered a risk factor for CKD development, but its precise role in contributing to CKD and end stage kidney disease is not fully elucidated. In this narrative review, the objectives are to describe the pathogenesis of CKD in obesity, including the impact of altered adipokine secretion in obesity and CKD, and to provide an overview of the clinical studies assessing the risk of obesity and CKD development.

Sequence variation in vitamin K epoxide reductase gene is associated with survival and progressive coronary calcification in chronic kidney disease.

OBJECTIVE: Sequence variations in the gene(s) encoding vitamin K epoxide reductase complex subunit 1 (VKORC1), the enzyme target of warfarin, have been associated with increased cardiovascular disease in the general population. Coronary artery calcification (CAC) is a prevalent form of cardiovascular disease in chronic kidney disease. We tested the hypothesis that the VKORC1 rs8050894 CC genotype would be associated with mortality and progression of CAC ≤ 4 years. APPROACH AND RESULTS: This study is an observational, prospective study of 167 individuals with stages 3 to 5 chronic kidney disease. Survival ≤ 4 years was assessed in all participants, and CAC progression was measured in a subset of 86 patients. Participants with the CG/GG genotype of VKORC1 had higher baseline CAC scores (median score, 112 versus 299; P=0.036). Of those 86 patients who had a 4-year CAC score, those with the CG/GG genotype had an increased risk of progressive CAC (adjusted for age, diabetes mellitus, estimated glomerular filtration rate, and hypertension) compared with those with the CC genotype. Four-year mortality risk was 4 times higher for individuals with the CG/GG genotypes compared with individuals with the CC genotype (odds ratio, 3.8; 95% confidence interval, 1.2-12.5; P=0.02), adjusted for age, sex, diabetes mellitus, estimated glomerular filtration rate, baseline CAC, and hypertension. CONCLUSIONS: Patients with the CG/GG genotype of VKORC1 had a higher risk of CAC progression and a poorer survival. These data provide new perspectives on the potential extrahepatic role of VKORC1 in individuals with chronic kidney disease.

Insulin resistance is associated with Fibroblast Growth Factor-23 in stage 3-5 chronic kidney disease patients.

AIM: To determine the associations between insulin resistance, fibroblast growth factor 23 (FGF-23), and coronary artery calcification (CAC) in chronic kidney disease (CKD) patients. INTRODUCTION: FGF-23 is associated with atherosclerosis and cardiovascular disease, but its association with insulin resistance in CKD has not been explored. SUBJECTS: Cross sectional study of 72 stage 3-5 CKD patients receiving care in Ontario, Canada. MATERIALS AND METHODS: Insulin resistance was measured by the homeostasis model assessment of insulin resistance (HOMA-IR), FGF-23 was measured by carboxyl terminal enzyme linked immunoassay (ctFGF-23) and CAC was measured by multi-slice computed tomography. RESULTS: Median HOMA-IR was 2.19µU/ml (interquartile range 1.19 to 3.94). Patients with HOMA-IR>2.2 had greater ctFGF-23 (179.7 vs 109.6; P=0.03), and 40% higher log CAC scores (2.09±0.87 vs 1.58±1.26; P=0.049). Multivariable linear regression adjusted for 1,25 dihydroxyvitamin D, kidney function, and parathyroid hormone revealed insulin resistance was a risk factor for greater log ctFGF-23 levels (log HOMA IR ß=0.37; 95% confidence interval 0.14 to 0.59; P=0.002). CONCLUSIONS: Insulin resistant CKD patients demonstrated higher FGF-23 levels, and increased CAC, while PO4 levels remained normal, suggesting a potential link between insulin resistance and PO4 homeostasis in CKD.

Associations of epicardial fat with coronary calcification, insulin resistance, inflammation, and fibroblast growth factor-23 in stage 3-5 chronic kidney disease.

BACKGROUND: Epicardial fat, quantified in a single multi-slice computed tomography (MSCT) slice, is a reliable estimate of total epicardial fat volume (EFV). We sought to determine risk factors for EFV detected in a single-slice MSCT measurement (ssEFV) in pre-dialysis chronic kidney disease (CKD) patients. Our primary objective was to determine the association between ssEFV and coronary artery calcification (CAC). METHODS: 94 pre-dialysis stage 3-5 CKD patients underwent MSCT to measure ssEFV and CAC. ssEFV was quantified at the level of the left main coronary artery. Measures of inflammation, traditional and kidney-related cardiovascular disease risk factors were collected. RESULTS: Mean age: 63.7 ± 14 years, 56% male, 39% had diabetes, and mean eGFR: 25.1 ± 11.9 mL/min/1.73 m2. Mean ssEFV was 5.03 ± 2.4 cm3. By univariate analysis, body mass index (BMI) (r = 0.53; P = <0.0001), abdominal obesity (r = 0.51; P < 0.0001), high density lipoprotein (HDL) cholesterol (r = - 0.39; P = <0.0001), insulin resistance (log homeostasis model assessment of insulin resistance (log HOMA-IR)) (r = 0.38, P = 0.001), log interleukin-6 (IL-6) (r = 0.34; P = 0.001), and log urinary albumin to creatinine ratio (UACR) (r = 0.30, P = 0.004) demonstrated the strongest associations with ssEFV. Log coronary artery calcification (log CAC score) (r = 0.28, P = 0.006), and log fibroblast growth factor-23 (log FGF-23) (r = 0.23, P = 0.03) were also correlated with ssEFV. By linear regression, log CAC score (beta =0.40; 95% confidence interval (CI), 0.01-0.80; P = 0.045), increasing levels of IL-6 (beta = 0.99; 95% CI, 0.38 - 1.61; P = 0.002), abdominal obesity (beta = 1.86; 95% CI, 0.94 - 2.8; P < 0.0001), lower HDL cholesterol (beta = -2.30; 95% CI, - 3.68 to -0.83; P = 0.002) and albuminuria (log UACR, beta = 0.81; 95% CI, 0.2 to 1.4; P = 0.01) were risk factors for increased ssEFV. CONCLUSIONS: In stage 3-5 CKD, coronary calcification and IL-6 and were predictors of ssEFV. Further studies are needed to clarify the mechanism by which epicardial fat may contribute to the pathogenesis of coronary disease, particularly in the CKD population.

Body mass index, coronary artery calcification, and kidney function decline in stage 3 to 5 chronic kidney disease patients.

OBJECTIVE: To determine whether body mass index (BMI) and coronary artery calcification (CAC) are risk factors for kidney function decline in predialysis chronic kidney disease (CKD) patients. DESIGN: Prospective cohort study of 125 stage 3 to 5 predialysis CKD patients. SUBJECTS AND SETTING: CKD patients receiving care in Kingston, Ontario, Canada. METHODS: BMI, CAC, and kidney function were measured at baseline. CAC was measured by multislice computed tomography scan. Kidney function was determined by the 4-variable reexpressed Modification of Diet in Renal Disease Study equation. At study end, kidney function decline among patients was compared according to baseline BMI and CAC. MAIN OUTCOME: Kidney function decline was defined as a 1-year decline in estimated glomerular filtration rate (eGFR) of ≥ 5%. RESULTS: Individuals with a decline in eGFR of ≥ 5% at 1 year had higher baseline BMI (33.5 ± 8.3 vs. 28.4 ± 4.9 kg/m(2); P = .0001) and higher baseline median CAC scores (239 vs. 25 Agatston units; P = .01) compared with subjects without such a decline. BMI (r = 0.35; P < .0001) and logarithmically transformed CAC score (r = 0.22; P = .01) correlated with an eGFR decline of ≥ 5%. Both crude and adjusted logistic regression analyses showed escalating CAC (with CAC reported in quintiles and CAC score = 0 Agatston unit as the reference group) was associated with an increased risk of eGFR decline of ≥ 5%. CONCLUSIONS: CAC and BMI were associated with kidney function decline over 1 year. The risk of kidney function decline was greater in those with increasing burden of CAC, which remained robust in the adjusted analysis accounting for the risk factors for CKD progression. Larger studies will be required for independent validation of the associations of BMI, CAC, and kidney function decline, and to investigate whether obesity and CAC treatment strategies are efficacious in attenuating kidney function decline in predialysis CKD patients.

FGF-23 is associated with cardiac troponin T and mortality in hemodialysis patients.

Fibroblast growth factor 23 (FGF-23) is elevated in patients with end-stage kidney disease and has been linked with mortality, vascular calcification, markers of bone turnover, and left ventricular hypertrophy. In this cohort study, we determined the correlates of FGF-23 (including cardiac troponin T [cTNT]) and determined its association with mortality over 3.5 years of follow-up in 103 prevalent hemodialysis patients. Mean age was 61.2 (15.5) and the mean dialysis vintage was 4.19 years (4.6). The median (interquartile range) FGF-23 was 1259 (491, 2885) RU/mL. Independent predictors (estimate standard error) of log-transformed FGF-23 concentrations included phosphorus (0.75 [0.237], P = 0.002) and cardiac troponin T (1.04 [0.41], P = 0.01). There were 57 deaths. In the fully adjusted model, the significant predictors of mortality included age and albumin. The independent association between FGF-23 and cTNT is a novel finding. Whether this relationship supports the possibility that a downstream effect of dysregulated phosphorous homeostasis may be enhanced cardiac remodeling requires further study.

Is the calcium correct? Measuring serum calcium in dialysis patients.

Abnormalities in calcium concentration are frequent in patients receiving dialysis therapy. Most cases of both hypo- and hypercalcemia are mild and asymptomatic. There is concern, however, that, on the one hand, hypocalcemia can drive hyperparathyroidism and eventually lead to gland hypertrophy and autonomous function. Hypercalcemia, on the other hand, can be associated with increased extraosseous calcium and phosphate deposition leading to vascular calcification with an attendant mortality and morbidity. Calcium exists in three main forms in the blood: the physiologically active free or ionized fraction (terms often used interchangeably), a protein bound fraction, and a fraction complexed to other anions. Although the ionized calcium can readily be measured using ion-specific electrodes, it is the total calcium that is most commonly measured because of sample handling and cost concerns. As it is the free or ionized form that is biologically active (and therefore of most relevance), a number of adjustment formulae have been derived to "correct" the total calcium for changes in albumin, protein, and complexing ion concentrations. These formulae show good statistical correlation with measured ionized calcium in populations studied as a whole, but are generally poor predictors of true ionized hypo- or hypercalcemia in individual patients. International guideline committees in nephrology recommend frequent assessment of calcium levels in dialysis patients and recommend that these levels be kept within the normal reference range. These guidelines are less clear on which measurement of calcium should be used to guide clinical decision making. This review examines the merits of making any adjustment to the total calcium measurement, and suggests when it is appropriate to measure the ionized or free calcium.

Vitamins K and D status in stages 3-5 chronic kidney disease.

BACKGROUND AND OBJECTIVES: Vitamin K, vitamin K-dependent proteins, and vitamin D may be involved in the regulation of calcification in chronic kidney disease (CKD). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Vitamin K and D status was measured as dietary intake, plasma phylloquinone, serum percent uncarboxylated osteocalcin (%ucOC), proteins induced by vitamin K absence (PIVKA-II), Vitamin K Epoxide Reductase single-nucleotide polymorphism, apolipoprotein E genotype, and plasma 25-hydroxyvitamin D (25(OH)D) in 172 subjects with stage 3 to 5 CKD. Nutritional status was determined by subjective global assessment. RESULTS: Subclinical vitamin K deficiency criteria was met by 6% (phylloquinone), 60% (%ucOC), and 97% (PIVKA-II) of subjects, whereas 58.3% and 8.6% had 25(OH)D insufficiency and deficiency, respectively. Dietary vitamin K intake was associated with higher phylloquinone and lower PIVKA-II. There were positive correlations between phylloquinone and the presence of stable weight, and the absence of subcutaneous fat loss or muscle wasting. 25(OH)D levels were positively associated with stable weight and albumin (P < 0.001). PIVKA-II levels were associated with apolipoprotein E genotype. Higher %ucOC and lower 25(OH)D were similarly associated with CKD stage, parameters of mineral metabolism, and urine albumin to creatinine ratio. CONCLUSIONS: These data indicate that a suboptimal vitamin K and D status is prevalent in patients with CKD. Sufficiency of both vitamins K and D was similarly predicted by measures of overall improved nutritional status. Proteinuria was associated with both a suboptimal vitamin D status as well as worse peripheral vitamin K status.