Pathways for Diagnosing and Treating CKD-Associated Pruritus: A Narrative Review.

Purpose of Review: Chronic kidney disease (CKD)-associated pruritus is a common, persistent, and distressing itch experienced by patients across the CKD spectrum. Although the disorder is associated with adverse outcomes and poor health-related quality of life, it remains underdiagnosed and undertreated. The purpose of this narrative review is to offer health care providers guidance on how to effectively identify, assess, and treat patients with CKD-associated pruritus, with the goal of reducing symptom burden and improving patient-important outcomes, such as quality of life (QoL). Sources of Information: A panel of nephrologists and researchers from across Canada and the United States was assembled to develop this narrative review based on the best available data, current treatment guidelines, and their clinical experiences. Methods: A panel of nephrologists who actively care for patients with pruritus receiving dialysis from across Canada was assembled. Two researchers from the United States were also included based on their expertise in the diagnosis and management of CKD-associated pruritus. Throughout Spring 2023, the panel met to discuss key topics in the identification, assessment, and management of CKD-associated pruritus. Panel members subsequently developed summaries of the pertinent information based on the best available data, current treatment guidelines, and added information on their own clinical experiences. In all cases, approval of the article was sought and achieved through discussion. Key Findings: This narrative review provides pragmatic guidance addressing: (1) methods for screening CKD-associated pruritus, (2) assessing severity, (3) management of CKD-associated pruritus, and (4) suggested areas for future research. The panel developed a 3-pillar framework for proactive assessment and severity scoring in CKD-aP: systematic screening for CKD-associated pruritus (pillar 1), assessment of pruritus intensity (pillar 2), and understanding the impact of CKD-associated pruritus on the patient's QoL (pillar 3). Management of CKD-associated pruritus can include ensuring optimization of dialysis adequacy, achieving mineral metabolism targets (ie, calcium, phosphate, and parathyroid hormone). However, treatment of CKD-associated pruritus usually requires additional interventions. Patients, regardless of CKD-associated pruritus severity, should be counseled on adequate skin hydration and other non-pharmacological strategies to reduce pruritus. Antihistamines should be avoided in favor of evidence-based treatments, such as difelikefalin and gabapentin. Limitations: A formal systematic review (SR) of the literature was not undertaken, although published SRs were reviewed. The possibility for bias based on the experts' own clinical experiences may have occurred. Key takeaways are based on the current available evidence, of which head-to-head clinical trials are lacking. Funding: This work was funded by an arm's length grant from Otsuka Canada Pharmaceutical Inc. (the importer and distributer of difelikefalin in Canada). LiV Medical Education Agency Inc. provided logistical and editorial support.

Motif de la revue: Le prurit associé à l'insuffisance rénale chronique (IRC) est une démangeaison cutanée fréquente, persistante et invalidante que les patients de tout le specter de l'IRC peuvent ressentir. Bien que le prurit soit associé à des effets indésirables et à une mauvaise qualité de vie liée à la santé, il demeure sous-diagnostiqué et sous-traité. L'objectif de cette revue narrative est d'offrir des conseils aux professionnels de la santé sur la façon d'identifier, d'évaluer et de traiter efficacement les patients atteints de prurit associé à l'IRC; ceci dans le but de réduire la charge des symptômes et d'améliorer les résultats importants pour les patients, notamment leur qualité de vie (QdV). Sources de l'information: Un comité de néphrologues et de chercheurs de partout au Canada et des États-Unis a été constitué pour élaborer la présente revue narrative à partir des meilleures données disponibles, des lignes directrices actuelles pour le traitement et de leurs expériences cliniques. Méthodologie: Un groupe de néphrologues canadiens qui s'occupent activement de patients dialysés souffrant de prurit a été constitué. Deux chercheurs des États-Unis ont été inclus au groupe en raison de leur expertise dans le diagnostic et la prise en charge du prurit associé à l'IRC. Le comité s'est réuni tout au long du printemps 2023 pour discuter de sujets clés en lien avec l'identification, l'évaluation et la prise en charge du prurit associé à l'IRC. Les membres du comité ont par la suite rédigé des résumés des informations pertinentes en se basant sur les meilleures données disponibles et les lignes directrices actuelles pour le traitement, auxquels ils ont ajouté des informations issues de leurs propres expériences cliniques. Dans tous les cas, l'approbation du manuscrit a été sollicitée et obtenue par discussion. Principaux résultats: Cette revue narrative offre des conseils pragmatiques sur les points suivants: (1) les méthodes de dépistage du prurit associé à l'IRC; (2) l'évaluation de sa gravité; (3) sa prise en charge; et (4) les domaines suggérés pour de futures recherches. Le comité a développé un cadre à trois piliers pour l'évaluation proactive du prurit associé à l'IRC et l'établissement d'un score de gravité: le dépistage systématique du prurit associé à l'IRC (pilier 1), l'évaluation de son intensité (pilier 2) et la compréhension de son impact sur la QdV du patient (pilier 3). La prise en charge du prurit associé à l'IRC peut inclure l'optimisation de l'adéquation de la dialyse et l'atteinte des cibles du métabolisme minéral (c.-à-d. calcium, phosphate et hormone parathyroïdienne). Cependant, son traitement nécessite habituellement des interventions supplémentaires. Les patients, quelle que soit la gravité du prurit associé à l'IRC, devraient être avisés d'hydrater adéquatement leur peau et informés des autres stratégies non pharmacologiques afin de réduire le prurit. On devrait éviter les antihistaminiques et les remplacer par des traitements fondés sur des données probantes comme la difélikéfaline et la gabapentine. Limites: Aucune revue systématique de la littérature n'a été formellement entreprise, bien que les revues systématiques publiées aient été examinées. La possibilité d'un biais fondé sur les expériences cliniques des experts est envisageable. Les principales conclusions de cette étude sont fondées sur les données probantes actuellement disponibles, pour lesquelles il n'existe pas d'essais cliniques comparatifs. Financement: Ces travaux ont été financés par une subvention indépendante d'Otsuka Canada Pharmaceutical Inc. (l'importateur et distributeur de la difélikéfaline au Canada). Un soutien logistique et éditorial a été fourni par liV Medical Education Agency Inc.

Characterizing Cluster-Based Frailty Phenotypes in a Multicenter Prospective Cohort of Kidney Transplant Candidates.

Frailty is associated with a higher risk of death among kidney transplant candidates. Currently available frailty indices are often based on clinical impression, physical exam or an accumulation of deficits across domains of health. In this paper we investigate a clustering based approach that partitions the data based on similarities between individuals to generate phenotypes of kidney transplant candidates. We analyzed a multicenter cohort that included several features typically used to determine an individual's level of frailty. We present a clustering based phenotyping approach, where we investigated two clustering approaches-i.e. neural network based Self-Organizing Maps (SOM) with hierarchical clustering, and KAMILA (KAy-means for MIxed LArge data sets). Our clustering results partition the individuals across 3 distinct clusters. Clusters were used to generate and study feature-level phenotypes of each group.

Focused Jurisdictional Scan of Glomerulonephritis Medication Access in Canada: A Program Report.

Purpose of Program: Glomerulonephritis (GN) is a group of rare kidney diseases that is increasingly being managed with higher cost immunosuppressive (IS) agents in Canada. Ontario Health's Ontario Renal Network (ORN) oversees the management and delivery of GN services in the province. Stakeholder surveys previously conducted by ORN identified that both clinicians and patients do not perceive access to GN medications as comprehensive or timely. The program conducted a focused jurisdictional scan among 7 provinces to inform ORN initiatives to improve access to GN medications. Specifically, the program examined clinician experience with GN access, public drug coverage criteria, and timelines for public coverage for select IS agents (ie, tacrolimus, cyclosporine, mycophenolate mofetil [MMF], mycophenolate sodium, rituximab, and eculizumab) used to manage GN in adults who live in Canada. Methods: For the selected IS agents, a focused jurisdictional scan on medication access was conducted by ORN in 2018 and updated in July 2022. Information was obtained by searching the gray literature and/or credible online sources for public funding policies and eligibility criteria. Findings were supplemented by personal communications with provincial drug programs and consulting GN clinical experts from 7 provinces (ie, Alberta, British Columbia, Saskatchewan, Manitoba, Ontario, Nova Scotia, and Quebec). Key Findings: Clinicians from different provinces prescribe IS agents similarly for GN indications, despite distinctions in public drug funding policies. While patients can obtain public funding for many IS agents, for GN, most provinces rely on case-by-case review processes. In addition, provinces can vary in their funding criteria and which IS agents are listed on the public formulary. For IS agents that require prior authorization or case-by-case review, timelines vary by province with decisions taking a few days to weeks. British Columbia, with a GN-specific drug formulary, had the most integrated and efficient system for patients and prescribers. Limitations: This scan primarily relied on publicly available information for drug coverage criteria and clinician experience with access in their province. Since this scan was conducted, public drug coverage criteria and/or application processes may have changed. Implications: While patients in most provinces have similar needs and nephrologists similar prescribing patterns, gaps still exist for publicly funded GN medications. Interprovincial differences in the drugs funded, funding criteria, and application process may affect timely and equitable access to GN medications across Canada. Given the rarity of GN, a pan-Canadian funding approach may be warranted to improve the current state.

Objectif du programme: Les glomérulonéphrites (GN) sont un groupe de néphropathies rares qui sont de plus en plus fréquemment traitées avec les agents immunosuppresseurs (IS) coûteux au Canada. Le Réseau rénal de l'Ontario (ORN­Ontario Renal Network) de Santé Ontario supervise la gestion et la prestation des services liés à la GN dans cette province. Des enquêtes menées précédemment par l'ORN auprès des parties prenantes ont révélé que tant les cliniciens que les patients ne percevaient pas l'accès aux médicaments pour traiter la GN comme complet ou opportun. Le programme a mené une analyse ciblée des territoires de compétences dans sept provinces afin d'orienter les initiatives de l'ORN ayant pour objectif d'améliorer l'accès aux médicaments pour traiter la GN. Plus précisément, le programme a examiné l'expérience des cliniciens en matière d'accès aux médicaments pour traiter la GN, les critères d'admissibilité au régime public d'assurance-médicaments et les délais de couverture publique de certains agents IS (p. ex., tacrolimus, cyclosporine, mycophénolate mofétil [MMF], mycophénolate sodique, Rituximab, éculizumab) utilisés pour traiter la GN chez les adultes canadiens. Méthodologie: Une analyse ciblée des territoires de compétences quant à l'accès aux médicaments a été réalisée par l'ORN en 2018 et mise à jour en juillet 2022. L'information quant aux politiques de financement public et aux critères d'admissibilité a été obtenue en effectuant une recherche dans la littérature grise et des sources crédibles en ligne. Les résultats ont été complétés par des communications directes avec les régimes provinciaux d'assurance-médicaments et des experts cliniques de la GN de sept provinces (Alberta, Colombie-Britannique, Saskatchewan, Manitoba, Ontario, Nouvelle-Écosse et Québec). Principaux résultats: Les cliniciens des différentes provinces prescrivent des agents IS de façon similaire pour les indications liées à la GN, malgré des distinctions dans les politiques publiques de financement des médicaments. Bien que les patients bénéficient d'une couverture publique pour de nombreux agents IS, pour le traitement de la GN, la plupart des provinces s'appuient sur des processus d'examen au cas par cas. De plus, il peut exister des différences entre les provinces en ce qui concerne les critères de financement et les agents IS qui figurent sur leur formulaire public. Dans le cas des agents IS nécessitant une autorisation au préalable ou un examen au cas par cas, les délais varient d'une province à l'autre; les décisions pouvant prendre de quelques jours à quelques semaines. La Colombie-Britannique, qui dispose d'un formulaire de médicaments pour traiter spécifiquement la GN, présente le système le plus intégré et le plus efficace pour les patients et les prescripteurs. Limites: Cette analyse s'est principalement appuyée sur des renseignements accessibles au public en ce qui concerne les critères de couverture des médicaments et l'expérience des cliniciens en matière d'accès dans leur province. Les critères de couverture des médicaments publics et les processus de demande pourraient avoir changé depuis que cette analyse a été effectuée. Conclusion: Bien que les patients de la plupart des provinces aient des besoins similaires et que les néphrologues aient des habitudes de prescription similaires, des lacunes subsistent en ce qui concerne le financement public des médicaments pour traiter la GN. Les différences interprovinciales entre les médicaments financés, les critères de financement et le processus de demande peuvent avoir une incidence sur l'accès opportun et équitable aux médicaments pour traiter la GN à travers le Canada. Étant donné la rareté de cette maladie, une approche de financement pancanadienne pourrait être justifiée afin d'améliorer l'état actuel.

Basic Research Protocol: Exome Sequencing in Adults With Loin Pain Hematuria Syndrome: A Pilot Study.

Background: Loin pain hematuria syndrome (LPHS) is a poorly understood clinical syndrome characterized by hematuria and either unilateral or bilateral severe kidney pain in the absence of identifiable urological disease. Loin pain hematuria syndrome imposes a significant health and economic impact with a loss of productivity and quality of life in a young population. Owing to an incomplete understanding of its pathophysiology, treatment has been limited to nonspecific pain management. Nearly 60 years after its initial description, we are no further ahead in understanding the molecular pathways involved in LPHS. Objective: To outline the study design for exome sequencing in adults with LPHS and their families. Methods: In this single-center case series, 24 patients with LPHS and 2 additional first-degree family members per participant will be recruited. DNA extracted from venous blood samples will undergo exome sequencing on the Illumina NovaSeq 6000 System at 100× depth and will be assessed for pathogenic variants in genes associated with hematuria (number of genes in: glomerular endothelium [n = 10] and basement membrane [n = 8]), and pain pathways (number of genes in: pain transduction [n = 17], conduction [n = 8], synaptic transmission [n = 37], and modulation [n = 27]). We will further examine identified potentially pathogenic variants that co-segregate with LPHS features among affected families. Conclusions: This pilot study may identify new directions for an investigation into the molecular mechanisms underlying LPHS.

Contexte: Le syndrome de lombalgie-hématurie est un syndrome clinique encore mal compris qui se caractérise par une hématurie et une forte douleur rénale unilatérale ou bilatérale en l'absence d'une maladie urologique identifiable. Le syndrome de lombalgie-hématurie a une incidence importante sur la santé et l'économie en entraînant une perte de productivité et de qualité de vie dans une population jeune. La compréhension de la physiopathologie de ce syndrome étant incomplète, le traitement a été limité à la gestion non spécifique de la douleur. Près de soixante ans après sa description initiale, nous en sommes au même point dans la compréhension des voies moléculaires impliquées dans le syndrome de lombalgie-hématurie. Objectif: Décrire le plan de l'étude pour le séquençage de l'exome chez les adultes atteints du syndrome de lombalgie-hématurie et des membres de leur famille. Méthodologie: Pour cette série de cas menée dans un seul center, nous recruterons 24 patients atteints du syndrome de lombalgie-hématurie et deux membres au premier degré de leur famille. L'ADN extrait d'échantillons de sang veineux sera soumis à un séquençage de l'exome sur le système Ilumina NovaSeq 6000 réglé à 100X de profondeur. Il sera également analysé pour la présence de variants pathogènes dans les gènes associés à l'hématurie (nombre de gènes dans l'endothélium glomérulaire [n = 10] et la membrane basale [n = 8]), et aux voies de transmission de la douleur (nombre de gènes dans la transduction [n = 17], la conduction [n = 8], la transmission synaptique [n = 37] et la modulation [n = 27] de la douleur). Nous poursuivrons l'examen des variants potentiellement pathogènes identifiés qui co-ségrègent avec les caractéristiques du syndrome de lombalgie-hématurie parmi les familles touchées. Conclusion: Cette étude pilote pourrait révéler de nouveaux axes de recherche sur les mécanismes moléculaires qui sous-tendent le syndrome de lombalgie-hématurie.

Kidney Biopsy and Type IV Collagen Gene Sequencing Fail to Explain Hematuria in Loin Pain Hematuria Syndrome.

Introduction: Loin pain hematuria syndrome (LPHS) is a rare clinical syndrome with a reported prevalence of 1 in 10,000. The syndrome is characterized by severe pain localized to the kidney in the absence of identifiable urinary tract disease. Because of an inadequate understanding of the pathophysiology of the disease, the goal of management has been limited to symptomatic pain management. Through detailed phenotype and genotype assessment we sought to identify possible underlying etiologies. Methods: We completed a chart review, ultrasound imaging, kidney biopsy, and type IV collagen (COL4A3, COL4A4, and COL4A5) gene sequencing in 14 patients with loin pain hematuria recruited from a single center. Results: Red blood cells and red cell casts were observed within the tubules in 10 of 14 patients. The glomerular basement membrane (GBM) was normal in 11 patients and thickened in 1 patient. Staining for IgA kappa was present in 1 patient. C3 deposition without any inflammation was present in 7 patients. Arteriolar hyalinosis was present in 4 patients and endothelial cell injury was present in 6 patients. No pathogenic COL4A3, COL4A4, or COL4A5 variants were identified. Conclusion: Conventional histopathology and genetic testing for type IV collagen variants failed to identify the cause of hematuria in 14 patients with LPHS.

CENtral blood pressure Targeting: a pragmatic RAndomized triaL in advanced Chronic Kidney Disease (CENTRAL-CKD): A Clinical Research Protocol.

Background: Emerging data favor central blood pressure (BP) over brachial cuff BP to predict cardiovascular and kidney events, as central BP more closely relates to the true aortic BP. Considering that patients with advanced chronic kidney disease (CKD) are at high cardiovascular risk and can have unreliable brachial cuff BP measurements (due to high arterial stiffness), this population could benefit the most from hypertension management using central BP measurements. Objective: To assess the feasibility and efficacy of targeting central BP as opposed to brachial BP in patients with CKD G4-5. Design: Pragmatic multicentre double-blinded randomized controlled pilot trial. Setting: Seven large academic advanced kidney care clinics across Canada. Patients: A total of 116 adults with CKD G4-5 (estimated glomerular filtration rate [eGFR] < 30 mL/min) and brachial cuff systolic BP between 120 and 160 mm Hg. The key exclusion criteria are 1) ≥ 5 BP drugs, 2) recent acute kidney injury, myocardial infarction, stroke, heart failure or injurious fall, 3) previous kidney replacement therapy. Methods: Double-blind randomization to a central or a brachial cuff systolic BP target (both < 130 mm Hg) as measured by a validated central BP device. The study duration is 12 months with follow-up visits every 2 to 4 months, based on local practice. All other aspects of CKD management are at the discretion of the attending nephrologist. Outcomes: Primary Feasibility: Feasibility of a large-scale trial based on predefined components. Primary Efficacy: Carotid-femoral pulse wave velocity at 12 months. Others: Efficacy (eGFR decline, albuminuria, BP drugs, and quality of life); Events (major adverse cardiovascular events, CKD progression, hospitalization, mortality); Safety (low BP events and acute kidney injury). Limitations: May be challenging to distinguish whether central BP is truly different from brachial BP to the point of significantly influencing treatment decisions. Therapeutic inertia may be a barrier to successfully completing a randomized trial in a population of CKD G4-5. These 2 aspects will be evaluated in the feasibility assessment of the trial. Conclusion: This is the first trial to evaluate the feasibility and efficacy of using central BP to manage hypertension in advanced CKD, paving the way to a future large-scale trial. Trial registration: clinicaltrials.gov (NCT05163158).

Contexte: Des données émergentes favorisent la mesure de la pression artérielle (PA) centrale plutôt que brachiale pour prédire les événements cardiovasculaires et rénaux, car la PA centrale est plus proche de la véritable PA aortique. Les patients souffrant d'insuffisance rénale chronique (IRC) de stade avancé présentent un risque cardiovasculaire élevé, et les mesures de la pression artérielle avec brassard brachial ne sont pas toujours fiables (en raison d'une rigidité artérielle élevée). La prise en charge de l'hypertension à l'aide de mesures centrales de la pression artérielle pourrait donc bénéficier à cette population de patients. Objectif: Évaluer la faisabilité et l'efficacité d'un ciblage de la PA par mesure centrale plutôt que brachiale chez les patients atteints d'IRC de stade G4-5. Conception: Essai pilote pragmatique, contrôlé et randomisé, mené en double aveugle dans plusieurs centers. Cadre: Sept grandes cliniques universitaires de soins rénaux avancés de partout au Canada. Sujets: 116 adultes atteints d'IRC de stade G4-5 (DFGe < 30 ml/min) avec une mesure de PA systolique mesurée par brassard brachial entre 120 et 160 mm Hg. Les principaux critères d'exclusion sont 1) la prise d'au moins 5 médicaments associés à la PA; 2) un épisode récent d'insuffisance rénale aiguë, d'infarctus du myocarde, d'accident vasculaire cérébral, d'insuffisance cardiaque ou une chute avec blessure; et 3) des antécédents de thérapie de remplacement rénal. Méthodologie: Randomization en double aveugle vers une cible de PA systolique centrale ou brachiale (toutes deux à < 130 mm Hg) mesurée par un appareil validé de mesure de la PA centrale. La durée de l'étude est de 12 mois avec visites de suivi tous les 2 à 4 mois, selon la pratique locale. Tous les autres aspects de la gestion de l'IRC sont à la discrétion du néphrologue traitant. Résultats: Faisabilité principale: faisabilité d'un essai à grande échelle fondé sur des paramètres prédéfinis. Efficacité principale: vitesse de l'onde de pouls carotido-fémorale à 12 mois. Autres: efficacité (déclin du DFGe, albuminurie, médicaments pour la PA, qualité de vie); événements (événements cardiovasculaires indésirables majeurs, progression de l'IRC, hospitalization, mortalité); innocuité (faible nombre d'événements liés à la PA, insuffisance rénale aiguë). Limites: Il peut être difficile de déterminer si la mesure de la PA centrale est vraiment différente de celle de la PA brachiale, et ce, au point d'influencer de manière significative les décisions de traitement. L'inertie thérapeutique peut constituer un obstacle à la réussite d'un essai randomisé dans une population de patients atteints d'IRC de stade G4-5. Ces deux aspects seront évalués dans la portion évaluant la faisabilité de l'essai. Conclusion: Il s'agit du premier essai visant à évaluer la faisabilité et l'efficacité de l'utilization de la PA centrale pour la prise en charge de l'hypertension chez les patients atteints d'IRC de stade avancé, ce qui ouvre la voie à un futur essai à grande échelle. Enregistrement de l'essai: ClinicalTrials.gov (NCT05163158).

Deep learning architectures for Parkinson's disease detection by using multi-modal features.

BACKGROUND: The use of multi-modal features for improving the diagnosing accuracy of Parkinson's disease (PD) is still under consideration. METHOD: Early diagnosis of PD is very crucial for better management and treatment planning of PD, as the delay in the diagnosis may even lead to death of the patient. Two frameworks, feature-level and modal-level, both of which are based on deep learning, are presented to classify the given subjects into PD and healthy by using neuroimaging (T1 weighted MRI scans and SPECT) and biological (CSF) features as the dataset. In the feature-level framework, all these features are integrated to form a heterogeneous dataset which is then supplied to two deep learning models to diagnose PD. In the modal-level framework, the number of features from T1 weighted MRI scans is reduced first, by using the filter feature selection method ReliefF. Those reduced number of features from the MRI scans are integrated with SPECT and CSF features to form another heterogeneous dataset, which is then fed to a deep learning model. RESULTS: Due to imbalanced nature of the dataset (consists of 73 PD and 59 healthy subjects), F1-score, geometric-mean, sensitivity, and specificity are measured, in addition to measuring the accuracy, to evaluate the performance of the developed models. A maximum accuracy of 93.33% and 92.38% is observed, for CNN, in the feature-level framework and modal-level framework, respectively. CONCLUSIONS: Though the complexity of the approach based on multi-modal features is high as compared to an approach that uses only one type of feature, i.e., either neuroimaging or biological; the results prove that the approach based on multi-modal features is useful for classifying the given subjects into PD and healthy and can help the clinicians in accurately diagnosing the PD.

Synthetic ACTH for Treatment of Glomerular Diseases: A Case Series.

RATIONALE: Synthetic adrenocorticotropic hormone (Tetracosactide) has been used in the treatment of refractory glomerular diseases. Literature surrounding the use of this medication is limited to small case series and there is conflicting data on the rate of adverse events associated with this medication. PRESENTING CONCERNS OF THE PATIENT: Glomerulonephritis not in remission after at least 6 months of treatment with conservative care. Stable doses of concurrent immunosuppression were permitted. DIAGNOSES: Membranous nephropathy, IgA nephropathy, minimal change disease, and focal and segmental glomerulosclerosis. INTERVENTION: Intramuscular synthetic adrenocorticotropic hormone (Tetracosactide, Synacthen Depot) with doses of either 1 mg weekly or 1 mg twice weekly. OUTCOMES: Five of 12 patients had at least a partial remission with Tetracosactide. Median time to response was 6 months for responders. Five of the 12 patients had adverse events documented, 2 of which led to treatment discontinuation. No patients with focal and segmental glomerulosclerosis responded to treatment. LESSONS LEARNED: Higher rate of adverse events than previously reported with synthetic adrenocorticotropic hormone and uncertain treatment efficacy.

JUSTIFICATION: L'hormone adrénocorticotrope synthétique (tétracosactide) a été utilisée pour le traitement des maladies glomérulaires réfractaires. La littérature portant sur l'utilisation de ce médicament est limitée à de petites séries de cas et les données sur le taux d'événements indésirables associés à ce médicament sont contradictoires. PRÉSENTATION DES CAS: Glomérulonéphrites qui ne sont pas en rémission après un minimum de six mois de traitement conservateur. Des doses stables de traitement immunosuppresseur concomitant étaient autorisées. DIAGNOSTICS: Néphropathie membraneuse, néphropathie à IgA, néphropathie à lésion glomérulaire minime, hyalinose segmentaire et focale. INTERVENTIONS: Des doses soit de 1 mg par semaine soit de 1 mg deux fois par semaine d'hormone adrénocorticotrope synthétique (Tetracosactide, Synacthen Depot) administrées par voie intramusculaire. RÉSULTATS: Cinq patients sur douze ont connu au moins une rémission partielle avec le tétracosactide. Le délai de réponse médian était de six mois pour les patients qui répondaient au traitement. Cinq des douze patients ont eu des réactions indésirables documentées, dont deux ont entraîné l'arrêt du traitement. Aucun des patients présentant une hyalinose segmentaire et focale n'a répondu au traitement. ENSEIGNEMENTS TIRÉS: Un taux de réactions indésirables plus élevé que celui rapporté précédemment avec l'hormone adrénocorticotrope synthétique et une efficacité incertaine du traitement.

Kidney Failure Risk Equation and Cost of Care in Patients with Chronic Kidney Disease.

BACKGROUND AND OBJECTIVES: Patients with CKD exhibit heterogeneity in their rates of progression to kidney failure. The kidney failure risk equation (KFRE) has been shown to accurately estimate progression to kidney failure in adults with CKD. Our objective was to determine health care utilization patterns of patients on the basis of their risk of progression. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a retrospective cohort study of adults with CKD and eGFR of 15-59 ml/min per 1.73 m2 enrolled in multidisciplinary CKD clinics in the province of Saskatchewan, Canada. Data were collected from January 1, 2004 to December 31, 2012 and followed for 5 years (December 31, 2017). We stratified patients by eGFR and risk of progression and compared the number and cost of hospital admissions, physician visits, and prescription drugs. RESULTS: In total, 1003 adults were included in the study. Within the eGFR of 15-29 ml/min per 1.73 m2 group, the costs of hospital admissions, physician visits, and drug dispensations over the 5-year study period comparing high-risk patients with low-risk patients were (Canadian dollars) $89,265 versus $48,374 (P=0.008), $23,423 versus $11,231 (P<0.001), and $21,853 versus $16,757 (P=0.01), respectively. Within the eGFR of 30-59 ml/min per 1.73 m2 group, the costs of hospital admissions, physician visits, and prescription drugs were $55,944 versus $36,740 (P=0.10), $13,414 versus $10,370 (P=0.08), and $20,394 versus $14,902 (P=0.02) in high-risk patients in comparison with low-risk patients, respectively, for progression to kidney failure. CONCLUSIONS: In patients with CKD and eGFR of 15-59 ml/min per 1.73 m2 followed in multidisciplinary clinics, the costs of hospital admissions, physician visits, and drugs were higher for patients at higher risk of progression to kidney failure by the KFRE compared with patients in the low-risk category. The high-risk group of patients with CKD and eGFR of 15-29 ml/min per 1.73 m2 had stronger association with hospitalizations costs, physician visits, and drug utilizations.

Global Estimates of Capacity for Kidney Transplantation in World Countries and Regions.

BACKGROUND: Kidney transplantation (KT) is the optimal treatment for kidney failure and is associated with better quality of life and survival relative to dialysis. However, knowledge of the current capacity of countries to deliver KT is limited. This study reports on findings from the 2018 International Society of Nephrology Global Kidney Health Atlas survey, specifically addressing the availability, accessibility, and quality of KT across countries and regions. METHODS: Data were collected from published online sources, and a survey was administered online to key stakeholders. All country-level data were analyzed by International Society of Nephrology region and World Bank income classification. RESULTS: Data were collected via a survey in 182 countries, of which 155 answered questions pertaining to KT. Of these, 74% stated that KT was available, with a median incidence of 14 per million population (range: 0.04-70) and median prevalence of 255 per million population (range: 3-693). Accessibility of KT varied widely; even within high-income countries, it was disproportionately lower for ethnic minorities. Universal health coverage of all KT treatment costs was available in 31%, and 57% had a KT registry. CONCLUSIONS: There are substantial variations in KT incidence, prevalence, availability, accessibility, and quality worldwide, with the lowest rates evident in low- and lower-middle income countries. Understanding these disparities will inform efforts to increase awareness and the adoption of practices that will ensure high-quality KT care is provided around the world.

Change in Physical Activity and Function in Patients with Baseline Advanced Nondialysis CKD.

BACKGROUND AND OBJECTIVES: Although progressive decline in physical activity and function are common in individuals with worsening CKD, little is known about the effect of dialysis initiation on physical activity. We assessed for any association of progression to dialysis in people with advanced CKD with temporal rates of change in physical activity and function. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Canadian Frailty Observation and Interventions Trial (CanFIT) participants with an eGFR of <30 ml/min per 1.73 m2 were included. Outcomes included change in physical activity level, measured using the Physical Activity Scale for the Elderly, and physical function, measured using the chair stand, 4-m gait speed, and grip strength tests. Generalized linear regression models were conducted to determine whether dialysis initiation was associated with greater decline in physical activity or function. RESULTS: Of 386 individuals, 162 progressed to dialysis. Both assessments were completed by 98% of individuals for the Physical Activity Scale for the Elderly, 86% for the chair stand test, 84% for the gait speed test, and 91% for the grip strength test. Median (interquartile range) interassessment follow-up was 427 (357-578) days for the "stable advanced CKD" group and 606 (428-1000) days for the "progressed to dialysis" group. Self-reported physical activity and gait speed significantly declined in both groups. Mean (SD) chair stand time increased from 20.8 (17.1) to 24.0 (21.0) seconds among patients with stable advanced CKD, and from 18.5 (15.4) to 27.4 (22.2) seconds among those who progressed to dialysis (adjusted difference in change, 5.2 seconds; 95% confidence interval, 0.8 to 9.7 seconds; P=0.02). CONCLUSIONS: Patients with advanced CKD experience progressive declines in physical activity and function. Transition to dialysis is associated with accelerated decline in physical function, as measured by the chair stand test.

T Scores, FRAX, Frailty Phenotype, Falls, and Its Relationship to Fractures in Patients on Maintenance Hemodialysis.

BACKGROUND: Despite the magnitude of fracture and the consequences in patients receiving hemodialysis, optimal risk assessment tools in this population are not well explored. Frailty and falls-known risk factors for fracture in chronic kidney disease (CKD) and non-CKD populations-are common in patients receiving hemodialysis (HD) therapy. While the relationship between T scores in relation to fractures in patients receiving HD is recognized, there is a paucity of data to the additional contributions of fracture assessment tool (FRAX), frailty status, and falls in its relationship with fracture. OBJECTIVES: To evaluate the clinical utility of adding FRAX, frailty status, and falls to T scores at the femoral neck to determine whether it enhances fracture discrimination in patients on maintenance HD. DESIGN: A cross-sectional observational study. SETTING: Two main dialysis units in Regina, Saskatchewan, Canada. PATIENTS: A total of 109 patients on maintenance HD at two dialysis units from January 1, 2017, to December 31, 2018, were included in the study. MEASUREMENTS: Fracture (the main outcome) was documented based on the review of medical charts, self-recall, and additionally vertebral fractures were identified by an x-ray. Areal bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). FRAX score was calculated using an online algorithm based on 11 clinical risk factors. We calculated the FRAX score for hip fracture and major osteoprotoic fracture with and without the inclusion of BMD. Frailty was assessed using the Fried criteria, which included assessments of unintentional weight loss, weakness (handgrip strength), slowness (walking speed), and questionnaires for physical activity and self-perceived exhaustion. Patients were enquired about the history and frequency of falls. METHODS: A total of 131 patients underwent frailty assessments at the two dialysis units during the dialysis treatment. Following frailty assessments, they were referred for DXA scans and upon receipt of the results undertook FRAX questionnaires. They were additionally sent for lumbar x-rays and contacted for a history of falls. Association between the BMD-T score, FRAX, frailty status, falls, with fracture were examined with sequential multivariable logistic regression models. Differences were considered statistically significant at P values <.05. RESULTS: A total of 109 patients were included in the data analysis. The composite of fracture occurred in 37.6% of patients. About 59.3% were identified as frail, and 29% of the participants had at least one fall in the last year. On multivariate regression analysis, each lower standard deviation (SD) in femoral neck T score was associated with 48% higher odds of fracture (odds ratio [OR] = 1.48; 95% confidence interval [CI] 1.20-1.68, P = .005). With the inclusion for FRAX scores (hip), the OR for fracture remained significant at 1.38 (OR = 1.38, 95% CI 1.04-1.63, P = .043). The addition of frailty status and history of falls did not further improve the model. Low T score and FRAX were both independent risk factors in patients on HD therapy. LIMITATIONS: This is a single-center study with a small sample size which limits the generalizability of the findings. Due to the cross-sectional study, associations identified may be difficult to interpret. CONCLUSIONS: Both BMD measurements by DXA and FRAX are useful tools to assess fracture in patients receiving HD. The addition of frailty status and history of falls is not associated with fractures in this population. Larger prospective studies are needed to determine whether the inclusion of frailty and falls to the conventional models will improve fracture assessment in the population receiving HD. TRIAL REGISTRATION: The study was not registered on a publicly accessible registry as it did not involve health care intervention on human participants.

CONTEXTE: Les outils permettant une évaluation optimale du risque de fractures chez les patients hémodialysés demeurent sous-examinés malgré le nombre de fractures et leurs conséquences dans cette population. La fragilité et les chutes ­ des facteurs de risque connus de fracture chez les patients atteints ou non d'insuffisance rénale chronique (IRC) ­ sont fréquentes chez les patients hémodialysés. Bien qu'un lien entre les scores T et les fractures soit reconnu chez les patients hémodialysés, très peu de données existent sur les contributions supplémentaires de l'outil d'évaluation des fractures (FRAX), de l'état de fragilité des patients et des antécédents de chutes dans leur lien avec les fractures. OBJECTIF: Évaluer l'utilité clinique d'ajouter le FRAX, l'état de fragilité et les chutes aux scores T du col fémoral pour déterminer s'ils améliorent la discrimination des fractures chez les patients suivant des traitements d'hémodialyse d'entretien. TYPE D'ÉTUDE: Étude transversale et observationnelle. CADRE: Les deux principales unités de dialyse de Régina (Saskatchewan) au Canada. SUJETS: Ont été inclus 109 patients suivant des traitements d'hémodialyse d'entretien dans les deux unités de dialyse entre le 1er janvier 2017 et le 31 décembre 2018. MESURES: L'auto-rappel et l'examen du dossier médical ont permis de documenter les fractures (principal résultat); les fractures vertébrales ont été confirmées par radiographie. La densité minérale osseuse (DMO) de surface a été mesurée par absorptiométrie double énergie à rayons X (DEXA). Le score FRAX a été calculé avec un algorithme en ligne selon 11 facteurs de risque cliniques. Le score FRAX pour les fractures de la hanche a été calculé avec et sans la DMO. La fragilité a été évaluée selon les critères de Fried, lesquels comprenaient l'évaluation d'une perte de poids involontaire, de la faiblesse (force de préhension) et de la lenteur (vitesse de marche), et à l'aide d'un questionnaire évaluant l'activité physique et le niveau d'épuisement perçu. Les patients ont été questionnés sur leurs antécédents de chutes et sur leur fréquence. MÉTHODOLOGIE: Au total, dans les deux unités de dialyse, 131 patients ont subi une évaluation de la fragilité pendant leurs traitements. Après l'évaluation, les patients ont été aiguillés pour un examen par DEXA et, à la réception des résultats, ont répondu à des questionnaires FRAX. Ils ont également passé une radiographie lombaire et ont été contactés pour discuter de leurs antécédents de chutes. L'association entre une fracture et le score BMD-T, le FRAX, l'état de fragilité et les chutes a été examinée à l'aide de modèles séquentiels de régression logistique multivariée. Les différences ont été considérées comme statistiquement significatives à des valeurs de P supérieures à 0,05. RÉSULTATS: L'analyse porte sur un total de 109 patients. Un critère combiné associant une fracture était présent chez 37,6 % des sujets; 59,3 % des patients ont été jugés fragiles et 29 % avaient chuté au moins une fois au cours de la dernière année. Dans l'analyse de régression multivariée, chaque valeur inférieure d'écart-type (É-T) pour le score T du col fémoral a été associée à un risque 48 % plus élevé de fracture (rapport de cote [RC] = 1,48; IC à 95 %: 1,20-1,68; P = 0,005). En incluant les scores FRAX (hanche), le rapport de cote pour la fracture est demeuré significatif à 1,38 (RC = 1,38; IC à 95 %: 1,04-1,63; P = 0,043). L'ajout de l'état de fragilité et des antécédents de chutes n'a pas amélioré le modèle. Un faible score T et un faible score FRAX se sont tous deux avérés un facteur de risque indépendant chez les patients hémodialysés. LIMITES: L'étude est monocentrique et l'échantillon est de faible taille, ce qui limite la généralisation des résultats. Les associations identifiées peuvent être difficiles à interpréter en raison de la nature transversale de l'étude. CONCLUSION: Les mesures de la DMO, qu'elles soient faites par DEXA ou par FRAX, sont des outils utiles pour évaluer les fractures chez les patients hémodialysés. L'ajout de l'état de fragilité et des antécédents de chutes n'a pas été associé aux fractures dans cette population. Des études prospectives de plus grande envergure sont nécessaires pour déterminer si l'inclusion de l'état de fragilité et des antécédents de chutes dans les modèles classiques améliorerait l'évaluation des fractures chez les patients hémodialysés. ENREGISTREMENT DE L'ESSAI: L'étude n'a pas été inscrite dans un registre accessible au public puisqu'elle n'implique aucune intervention sur les participants.

International Society of Nephrology Global Kidney Health Atlas: structures, organization, and services for the management of kidney failure in North America and the Caribbean.

The International Society of Nephrology established the Global Kidney Health Atlas project to define the global capacity for kidney replacement therapy and conservative kidney care, and this second iteration was to describe the availability, accessibility, quality, and affordability of kidney failure (KF) care worldwide. This report presents results for the International Society of Nephrology North America and the Caribbean region. Relative to other regions, the North America and Caribbean region had better infrastructure and funding for health care and more health care workers relative to the population. Various essential medicines were also more available and accessible. There was substantial variation in the prevalence of treated KF in the region, ranging from 137.4 per million population (pmp) in Jamaica to 2196 pmp in the United States. A mix of public and private funding systems cover costs for nondialysis chronic kidney disease care in 60% of countries and for dialysis in 70% of countries. Although the median number of nephrologists is 18.1 (interquartile range, 15.3-29.5) pmp, which is approximately twice the global median of 9.9 (interquartile range, 1.2-22.7) pmp, some countries reported shortages of other health care workers. Dialysis was available in all countries, but peritoneal dialysis was underutilized and unavailable in Barbados, Cayman Islands, and Turks and Caicos. Kidney transplantation was primarily available in Canada and the United States. Economic factors were the major barriers to optimal KF care in the Caribbean countries, and few countries in the region have chronic kidney disease-specific national health care policies. To address regional gaps in KF care delivery, efforts should be directed toward augmenting the workforce, improving the monitoring and reporting of kidney replacement therapy indicators, and implementing noncommunicable disease and chronic kidney disease-specific policies in all countries.

Provider Perception of Frailty Is Associated with Dialysis Decision Making in Patients with Advanced CKD.

BACKGROUND AND OBJECTIVES: Frailty is common in patients with CKD. Little is known about the prevalence of frailty and its effect on prognosis and decisions surrounding dialysis modalities in patients with advanced CKD (eGFR<30 ml/min per 1.73 m2). Our objective was to determine the agreement between different frailty measures and physical function and their association with dialysis modality choice (home based versus in-center) and all-cause mortality in patients with advanced CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Our study was a prospective, multicenter, cohort study. In 603 patients with advanced CKD, we collected demographics, comorbidities, and laboratory results in addition to objective (Fried frailty criteria) and subjective measures of frailty (physician and nurse impressions) and physical function (Short Physical Performance Battery). Logistic regression and Cox proportional hazards models were used to evaluate the association of frailty with dialysis modality choice and all-cause mortality, respectively. RESULTS: The prevalence of frailty varied with assessment tool used (Fried frailty criteria, 34%; Short Physical Performance Battery, 55%; physician impression, 44%; nurse impression, 36%). The agreement between all frailty and physical function measures was poor. We had 227 patients reach kidney failure and decide on a dialysis therapy, and 226 patients died during a mean follow-up of 1455 days. After adjusting for age, sex, and comorbid conditions, the Fried criteria and Short Physical Performance Battery were associated with a two-fold higher risk of all-cause mortality (hazard ratio, 1.96; 95% confidence interval, 1.47 to 2.61 and hazard ratio, 1.96; 95% confidence interval,1.42 to 2.76, respectively). Patients deemed as frail by physician and nurse frailty impressions were three to four times more likely to choose in-center dialysis (odds ratio, 3.41; 95% confidence interval, 1.56 to 7.44; odds ratio, 3.87; 95% confidence interval, 1.76 to 8.51, respectively). CONCLUSIONS: We found that the agreement between objective and subjective measures of frailty and physical function was poor. Objective measures of frailty and physical function were associated with mortality, and subjective measures of frailty were associated with dialysis modality choice.

Association of Physical Activity and Poor Health Outcomes in Patients With Advanced CKD.

RATIONALE & OBJECTIVE: Chronic kidney disease (CKD) is associated with declining physical function and activity. In the general population, lower physical activity is associated with poorer quality of life and greater all-cause mortality. The aim of this study was to assess if lower physical activity levels are associated with adverse health outcomes in patients with advanced CKD. STUDY DESIGN: A multicenter prospective cohort study. SETTING & PARTICIPANTS: 579 adult patients with CKD glomerular filtration rate categories 4 and 5 (G4-G5) treated at 4 Canadian multidisciplinary kidney health clinics between 2012 and 2018. EXPOSURE: Patient-reported measures of physical activity using the Physical Activity Scale for the Elderly (PASE) questionnaire and subsequently stratified PASE scores into tertiles. OUTCOME: All-cause mortality, progression to kidney failure, and future falls. ANALYTICAL APPROACH: Outcomes were analyzed using time-dependent proportional hazards models and logistic regression models. RESULTS: In 1,193 days of follow-up observation, 118 patients died, 204 progressed to dialysis, and 129 reported a fall. When compared with low physical activity, higher levels of physical activity were associated with a 52% lower all-cause mortality (adjusted HR, 0.48; 95% CI, 0.27-0.85) in models adjusted for age, sex, and comorbidity. No associations were detected between higher levels of physical activity and either slower progression to kidney failure or a lower rate of future falls. LIMITATIONS: Physical activity and falls were self-reported. Our population was of limited racial/ethnic diversity, which may affect generalizability. Findings were observational and do not indicate whether interventions targeting physical activity may affect adverse health outcomes. CONCLUSIONS: Higher levels of physical activity were associated with about 50% lower all-cause mortality in the advanced CKD population. These findings are consistent with a potential benefit from maintained physical activity as patients approach kidney failure.

Prevalence of Frailty in Patients Referred to the Kidney Transplant Waitlist.

Background: Comparisons between frailty assessment tools for waitlist candidates are a recognized priority area for kidney transplantation. We compared the prevalence of frailty using three established tools in a cohort of waitlist candidates. Methods: Waitlist candidates were prospectively enrolled from 2016 to 2020 across five centers. Frailty was measured using the Frailty Phenotype (FP), a 37-variable frailty index (FI), and the Clinical Frailty Scale (CFS). The FI and CFS were dichotomized using established cutoffs. Agreement was compared using κ coefficients. Area under the receiver operating characteristic (ROC) curves were generated to compare the FI and CFS (treated as continuous measures) with the FP. Unadjusted associations between each frailty measure and time to death or waitlist withdrawal were determined using an unadjusted Cox proportional hazards model. Results: Of 542 enrolled patients, 64% were male, 80% were White, and the mean age was 54±14 years. The prevalence of frailty by the FP was 16%. The mean FI score was 0.23±0.14, and the prevalence of frailty was 38% (score of ≥0.25). The median CFS score was three (IQR, 2-3), and the prevalence was 15% (score of ≥4). The κ values comparing the FP with the FI (0.44) and CFS (0.27) showed fair to moderate agreement. The area under the ROC curves for the FP and FI/CFS were 0.86 (good) and 0.69 (poor), respectively. Frailty by the CFS (HR, 2.10; 95% CI, 1.04 to 4.24) and FI (HR, 1.79; 95% CI, 1.00 to 3.21) was associated with death or permanent withdrawal. The association between frailty by the FP and death/withdrawal was not statistically significant (HR, 1.78; 95% CI, 0.79 to 3.71). Conclusion: Frailty prevalence varies by the measurement tool used, and agreement between these measurements is fair to moderate. This has implications for determining the optimal frailty screening tool for use in those being evaluated for kidney transplant.