Association of BKV viremia and nephropathy with adverse alloimmune outcomes in kidney transplant recipients.

BACKGROUND: Immunosuppression reduction for BK polyoma virus (BKV) must be balanced against risk of adverse alloimmune outcomes. We sought to characterize risk of alloimmune events after BKV within context of HLA-DR/DQ molecular mismatch (mMM) risk score. METHODS: This single-center study evaluated 460 kidney transplant patients on tacrolimus-mycophenolate-prednisone from 2010-2021. BKV status was classified at 6-months post-transplant as "BKV" or "no BKV" in landmark analysis. Primary outcome was T-cell mediated rejection (TCMR). Secondary outcomes included all-cause graft failure (ACGF), death-censored graft failure (DCGF), de novo donor specific antibody (dnDSA), and antibody-mediated rejection (ABMR). Predictors of outcomes were assessed in Cox proportional hazards models including BKV status and alloimmune risk defined by recipient age and molecular mismatch (RAMM) groups. RESULTS: At 6-months post-transplant, 72 patients had BKV and 388 had no BKV. TCMR occurred in 86 recipients, including 27.8% with BKV and 17% with no BKV (p = .05). TCMR risk was increased in recipients with BKV (HR 1.90, (95% CI 1.14, 3.17); p = .01) and high vs. low-risk RAMM group risk (HR 2.26 (95% CI 1.02, 4.98); p = .02) in multivariable analyses; but not HLA serological MM in sensitivity analysis. Recipients with BKV experienced increased dnDSA in univariable analysis, and there was no association with ABMR, DCGF, or ACGF. CONCLUSIONS: Recipients with BKV had increased risk of TCMR independent of induction immunosuppression and conventional alloimmune risk measures. Recipients with high-risk RAMM experienced increased TCMR risk. Future studies on optimizing immunosuppression for BKV should explore nuanced risk stratification and may consider novel measures of alloimmune risk.

A rational approach to guide cost-effective de novo donor-specific antibody surveillance with tacrolimus immunosuppression.

De novo donor-specific antibody (dnDSA) after renal transplantation has been shown to correlate with antibody-mediated rejection and allograft loss. However, the lack of proven interventions and the time and cost associated with annual screening for dnDSA are difficult to justify for all recipients. We studied a well-characterized consecutive cohort (n = 949) with over 15 years of prospective dnDSA surveillance to identify risk factors that would help institute a resource-responsible surveillance strategy. Younger recipient age and HLA-DR/DQ molecular mismatch were independent predictors of dnDSA development. Combining both risk factors into recipient age molecular mismatch categories, we found that 52% of recipients could be categorized as low-risk for dnDSA development (median subclinical dnDSA-free survival at 5 and 10 years, 98% and 97%, respectively). After adjustment, multivariate correlates of dnDSA development included tacrolimus versus cyclosporin maintenance immunosuppression (hazard ratio [HR], 0.37; 95% CI, 0.2-0.6; P < .0001) and recipient age molecular mismatch category: intermediate versus low (HR, 2.48; 95% CI, 1.5-4.2; P = .0007), high versus intermediate (HR, 2.56; 95% CI, 1.6-4.2; P = .0002), and high versus low (HR, 6.36; 95% CI, 3.7-10.8; P < .00001). When combined, recipient age and HLA-DR/DQ molecular mismatch provide a novel data-driven approach to reduce testing by >50% while selecting those most likely to benefit from dnDSA surveillance.

Acute kidney injury during cisplatin therapy and associations with kidney outcomes 2 to 6 months post-cisplatin in children: a multi-centre, prospective observational study.

BACKGROUND: Few studies describe acute kidney injury (AKI) burden during paediatric cisplatin therapy and post-cisplatin kidney outcomes. We determined risk factors for and rate of (1) AKI during cisplatin therapy, (2) chronic kidney disease (CKD) and hypertension 2-6 months post-cisplatin, and (3) whether AKI is associated with 2-6-month outcomes. METHODS: This prospective cohort study enrolled children (aged < 18 years at cancer diagnosis) treated with cisplatin from twelve Canadian hospitals. AKI during cisplatin therapy (primary exposure) was defined based on Kidney Disease: Improving Global Outcomes (KDIGO) serum creatinine criteria (≥ stage one). Severe electrolyte abnormalities (secondary exposure) included ≥ grade three hypophosphatemia, hypokalemia, or hypomagnesemia (National Cancer Institute Common Terminology Criteria for Adverse Events v4.0). CKD was albuminuria or decreased kidney function for age (KDIGO guidelines). Hypertension was defined based on the 2017 American Academy of Pediatrics guidelines. RESULTS: Of 159 children (median [interquartile range [IQR]] age: 6 [2-12] years), 73/159 (46%) participants developed AKI and 55/159 (35%) experienced severe electrolyte abnormalities during cisplatin therapy. At median [IQR] 90 [76-110] days post-cisplatin, 53/119 (45%) had CKD and 18/128 (14%) developed hypertension. In multivariable analyses, AKI was not associated with 2-6-month CKD or hypertension. Severe electrolyte abnormalities during cisplatin were associated with having 2-6-month CKD or hypertension (adjusted odds ratio (AdjOR) [95% CI]: 2.65 [1.04-6.74]). Having both AKI and severe electrolyte abnormalities was associated with 2-6-month hypertension (AdjOR [95% CI]: 3.64 [1.05-12.62]). CONCLUSIONS: Severe electrolyte abnormalities were associated with kidney outcomes. Cisplatin dose optimization to reduce toxicity and clear post-cisplatin kidney follow-up guidelines are needed. A higher resolution version of the Graphical abstract is available as Supplementary information.

Mutations in CLDN2 Are Not a Common Cause of Pediatric Idiopathic Hypercalciuria in Canada.

Background: Hypercalciuria is the most common risk factor for kidney stone formation, including in pediatric patients. However, the etiology is often unknown and children are frequently diagnosed with idiopathic hypercalciuria. Nearly 50% of children with hypercalciuria have a first-degree relative with kidney stones, suggesting a strong genetic basis for this disease. A failure of calcium reabsorption from the proximal nephron is implicated in the pathogenesis of hypercalciuria. Claudin-2 is a tight junction protein abundantly expressed in the proximal tubule. It confers paracellular permeability to calcium that is essential for transport across the proximal tubule where the majority of filtered calcium is reabsorbed. Objective: Our objective was to examine the frequency of coding variations in CLDN2 in a cohort of children with idiopathic hypercalciuria. Design: Mixed method including retrospective chart review and patient interview, followed by genetic sequencing. Setting: Three tertiary care centers in Canada. Patients: Children (age 1-18 years) with idiopathic hypercalciuria. Patients with other causes of hypercalciuria were excluded. Methods: Data were collected from 40 patients with idiopathic hypercalciuria. Informed consent to collect DNA was obtained from 13 patients, and the final and only coding exon of CLDN2 was sequenced. Results: The majority of patients were male, white, and had a positive family history of kidney stones. Parathyroid hormone levels were significantly lower than the reference range (P < .001). The levels of 1,25-dihydroxyvitamin D were also significantly higher in our patient cohort, relative to the reference range (P < .001). Sequence analysis of CLDN2 did not identify any coding variations. Limitations: Sequencing analysis was limited to the final coding exon and small sample size. Conclusions: CLDN2 coding variations are not a common cause of idiopathic hypercalciuria in Canadian children. Further study is needed to determine the causes of hypercalciuria in pediatric patients and develop targeted therapies.

Contexte: L'hypercalciurie est le facteur de risque le plus courant pour la formation de calculs rénaux, y compris chez les patients pédiatriques. Son étiologie est cependant souvent inconnue et les enfants sont fréquemment diagnostiqués avec une hypercalciurie idiopathique. Près de 50 % des enfants atteints d'hypercalciurie ont un parent de premier degré souffrant de calculs rénaux, ce qui suggère une importante contribution génétique à cette maladie. Une atteinte de la réabsorption du calcium au niveau du néphron proximal est impliquée dans la pathogenèse de l'hypercalciurie. La claudine-2, une protéine de jonction abondamment exprimée dans le tubule proximal, confère une perméabilité paracellulaire au calcium, laquelle est essentielle pour le transport à travers le tubule proximal, où la majorité du calcium filtré est réabsorbée. Objectif: Étudier la fréquence des variations dans le codage de CLDN2 dans une cohorte d'enfants atteints d'hypercalciurie idiopathique. Conception de l'étude: Une méthode mixte, comprenant un examen rétrospectif des dossiers médicaux et un entretien avec les patients, suivie d'un séquençage génétique. Cadre: Trois centres de soins tertiaires au Canada. Sujets: Des enfants (1 à 18 ans) atteints d'hypercalciurie idiopathique. Les patients dont l'hypercalciurie avait une autre cause ont été exclus. Méthodologie: Les données proviennent de 40 patients atteints d'hypercalciurie idiopathique. Le consentement éclairé à la collecte d'ADN a été obtenu pour treize patients. L'exon final et le seul exon codant pour CLDN2, a été séquencé. Résultats: La majorité des sujets étaient des garçons d'origine caucasienne et avaient des antécédents familiaux de calculs rénaux. Les taux d'hormone parathyroïdienne étaient significativement plus faibles que les valeurs de référence (p < 0,001). Les taux de 1,25 dihydroxyvitamine D étaient significativement plus élevés dans notre cohorte de patients, par rapport à l'intervalle de référence (p < 0,001). Le séquençage de CLDN2 n'a pas révélé de variations dans le codage. Limites: L'étude porte sur un faible échantillon de patients et le séquençage s'est limité à l'exon final du gène. Conclusion: Les mutations du gène CLDN2 ne sont pas une cause fréquente d'hypercalciurie idiopathique chez les enfants canadiens. D'autres études sont nécessaires pour préciser la ou les causes de l'hypercalciurie chez les patients pédiatriques et développer des traitements ciblés.

Urine Neutrophil Gelatinase-Associated Lipocalin and Kidney Injury Molecule-1 to Detect Pediatric Cisplatin-Associated Acute Kidney Injury.

Background: Few studies have described associations between the AKI biomarkers urinary neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) with AKI in cisplatin-treated children. We aimed to describe excretion patterns of urine NGAL and KIM-1 and associations with AKI in children receiving cisplatin. Methods: Participants (n=159) were enrolled between 2013 and 2017 in a prospective cohort study conducted in 12 Canadian pediatric hospitals. Participants were evaluated at early cisplatin infusions (at first or second cisplatin cycle) and late cisplatin infusions (last or second-to-last cycle). Urine NGAL and KIM-1 were measured (1) pre-cisplatin infusion, (2) post-infusion (morning after), and (3) at hospital discharge at early and late cisplatin infusions. Primary outcome: AKI defined by serum creatinine rise within 10 days post-cisplatin, on the basis of Kidney Disease Improving Global Outcomes guidelines criteria (stage 1 or higher). Results: Of 159 children, 156 (median [interquartile range (IQR)] age: 5.8 [2.4-12.0] years; 78 [50%] female) had biomarker data available at early cisplatin infusions and 127 had data at late infusions. Forty six of the 156 (29%) and 22 of the 127 (17%) children developed AKI within 10 days of cisplatin administration after early and late infusions, respectively. Urine NGAL and KIM-1 concentrations were significantly higher in patients with versus without AKI (near hospital discharge of late cisplatin infusion, median [IQR] NGAL levels were 76.1 [10.0-232.7] versus 14.9 [5.4-29.7] ng/mg creatinine; KIM-1 levels were 4415 [2083-9077] versus 1049 [358-3326] pg/mg creatinine; P<0.01). These markers modestly discriminated for AKI (area under receiver operating characteristic curve [AUC-ROC] range: NGAL, 0.56-0.72; KIM-1, 0.48-0.75). Biomarker concentrations were higher and better discriminated for AKI at late cisplatin infusions (AUC-ROC range, 0.54-0.75) versus early infusions (AUC-ROC range, 0.48-0.65). Conclusions: Urine NGAL and KIM-1 were modest at discriminating for cisplatin-associated AKI. Further research is needed to determine clinical utility and applicability of these markers and associations with late kidney outcomes.

CYP24A1 and SLC34A1 Pathogenic Variants Are Uncommon in a Canadian Cohort of Children with Hypercalcemia or Hypercalciuria.

OBJECTIVES: Biallelic pathogenic variants in CYPA24A1 and SLC34A1 are causes of idiopathic infantile hypercalcemia. Pathogenic variants in both may also give rise to hypercalciuria with nephrocalcinosis or nephrolithiasis without previous hypercalcemia (renal group). Our objective was to examine the frequency of CYP24A1 or SLC34A1 variants in children with early hypercalcemia or late-onset hypercalciuria. METHOD: Forty-one children from 7 centers across Canada were recruited. Local investigations were undertaken. The serum was evaluated by liquid chromatography tandem-mass spectrometry for the ratio of 25-hydroxyvitamin D3 to 24,25-dihydroxyvitamin D3, (25-OH-D3:24,25-(OH)2D3), an elevation pathognomonic for the loss of function of the CYP24A1 enzyme. Mutational analyses were undertaken. Family cascade screening was performed if pathogenic variants were detected in probands. RESULTS: Twenty-nine children had early-onset hypercalcemia; none had elevated 25-OH-D3:24,25-(OH)2D3 or variants. Interestingly, 2 of 12 in the renal group had elevated 25-OH-D3:24,25-(OH)2D3 and presented as preadolescents. In case 1, cascade testing revealed a sibling and parent with asymptomatic pathogenic variants in CYP24A1. Four CYP24A1 pathogenic variants were identified in these 2 probands: 3 have been described in European populations, and 1 is a rare variant in exon 7 (c931delC) that is likely pathogenic. No SLC34A1 pathogenic variants were detected. CONCLUSION: In Canada, pathogenic variants in CYP24A1 appear to manifest with late-onset hypercalciuria and its sequelae. The 25-OH-D3:24,25-(OH)2D3 ratio is an excellent tool for screening for biallelic pathogenic variants in CYP24A1. We confirm that cascade testing is important for these variants.

Defining the Scope of Knowledge Translation Within a National, Patient-Oriented Kidney Research Network.

PURPOSE OF PROGRAM: Integrated knowledge translation (IKT) is a collaborative approach whereby knowledge created through health research is utilized in ways that are relevant to the needs of all stakeholders. However, research teams have limited capacity and know-how for achieving IKT, resulting in a disconnect between the generation and application of knowledge. The goal of this report is to describe how IKT research was achieved across a large-scale, patient-oriented research network, Canadians Seeking Solutions and Innovations to Overcome Chronic Kidney Disease (Can-SOLVE CKD). SOURCES OF INFORMATION: Resources to facilitate knowledge translation (KT) planning across the network were developed by the Can-SOLVE CKD Knowledge User/Knowledge Translation Committee with reference to established Canadian KT and patient engagement tools and frameworks, review of the published and gray literature, and expertise of committee members. METHODS: The Can-SOLVE CKD Knowledge User/Knowledge Translation Committee consisting of patient partners, health care providers, policymakers, and researchers provided oversight of the development and implementation of the network's IKT initiatives. Guided by its strategic framework, the committee developed KT planning templates and review checklists to assist network projects with preparing for dissemination, implementation, and scale and spread of their interventions. The committee has acted in a consultative capacity to facilitate IKT across network initiatives and has supported capacity building through KT activities aimed at network membership and knowledge users more broadly. KEY FINDINGS: The Can-SOLVE CKD Knowledge User/Knowledge Translation Committee established a nation-wide strategy for KT infrastructure and capacity building. Acting as a knowledge intermediary, the committee has connected research teams with knowledge users across Canada to support practices and policies informed by evidence generated by the network. The committee has developed KT initiatives, including a Community of Practice, whereby participants across different regions and disciplines convene regularly to share health research knowledge and communications strategies relevant to the network. Critically, patients are engaged and contribute throughout the research process. Examples of IKT activities from select projects are provided, as well as ways for sustaining the network's KT platform. LIMITATIONS: The KT resources developed by the committee were adapted from other established resources to meet the needs of the network and have not undergone formal evaluation in this context. Given the broad scope of the network, resources to facilitate implementation and knowledge user engagement may not meet the needs of all initiatives and must be tailored accordingly. Knowledge barriers, including a lack of information and skills related to conceptual and practical aspects of KT, among network members provided a rationale for various KT capacity-building initiatives. IMPLICATIONS: The approach described here offers a practical method for achieving IKT, including how to plan, implement, and sustain initiatives across large-scale health research networks. Within the context of Can-SOLVE CKD, these efforts will shorten knowledge-practice gaps through producing and applying relevant research to improve the lives of people living with kidney disease.

OBJECTIF DU PROGRAMME: L'application intégrée des connaissances (AIC) est une approche collaborative à répondre aux besoins de tous les intervenants. Les équipes de recherche ont cependant une capacité et un savoir-faire limités pour réaliser l'AIC, ce qui entraîne un décalage entre la production et l'application des connaissances. L'objectif de cet article est de décrire comment la recherche sur l'AIC a été réalisée dans le cadre d'un vaste réseau de recherche axée sur le patient, le réseau CAN-SOLVE CKD (Canadians Seeking Solutions and Innovations to Overcome Chronic Kidney Disease). SOURCES: Les ressources visant à faciliter la planification de l'application des connaissances (AC) dans l'ensemble du réseau ont été élaborées par le Comité des utilisateurs/de l'application des connaissances (Knowledge User/Knowledge Translation Committee) de Can-SOLVE CKD en se référant à des outils et des cadres d'AC et de participation des patients établis au Canada, à l'examen de la documentation publiée et de la littérature grise et à l'expertise des membres du comité. MÉTHODOLOGIE: Le Comité des utilisateurs/de l'application des connaissances de CAN-SOLVE, constitué de partenaires patients, de fournisseurs de soins, de décideurs et de chercheurs, a supervisé le développement et la mise en œuvre des initiatives d'AIC du réseau. Guidé par son cadre stratégique, le comité a élaboré des modèles de planification pour l'AC et des listes de vérification pour aider les projets du réseau à se préparer à la diffusion et à la mise en œuvre de leurs interventions, de même qu'à leur élargissement et leur diffusion. Le comité a agi à titre consultatif pour faciliter l'AIC dans l'ensemble des initiatives du réseau, et a appuyé le renforcement des capacités par le biais d'activités d'AC destinées aux membres du réseau et, plus largement, aux utilisateurs des connaissances. PRINCIPAUX RÉSULTATS: Le Comité des utilisateurs/de l'application des connaissances de CAN-SOLVE a établi une stratégie nationale pour l'infrastructure et le renforcement des capacités en matière d'AC. En tant qu'intermédiaire, le comité a mis en relation des équipes de recherche et des utilisateurs des connaissances partout au Canada afin d'appuyer les pratiques et les politiques fondées sur les données probantes produites par le réseau. Le comité a élaboré des initiatives d'AC, notamment une communauté de pratique où les participants des différentes régions et disciplines se réunissent sur une base régulière pour partager les connaissances générées en recherche et les stratégies de communication pertinentes pour le réseau. Il est essentiel que les patients s'engagent et contribuent tout au long du processus de recherche. Des exemples d'activités d'AIC tirés de projets sélectionnés sont fournis, de même que des moyens de maintenir la plateforme d'AC du réseau. LIMITES: Les ressources d'AC développées par le comité ont été adaptées à partir de ressources établies pour répondre aux besoins du réseau et, dans ce contexte, n'ont pas fait l'objet d'une évaluation officielle. Compte tenu de la vaste portée du réseau, les ressources destinées à faciliter la mise en œuvre et la participation des utilisateurs des connaissances pourraient ne pas répondre aux besoins de toutes les initiatives et devraient être adaptées en conséquence. Les freins à la connaissance parmi les membres du réseau, notamment le manque d'information et de compétences liées aux aspects conceptuels et pratiques de l'AC, ont servi de justification à diverses initiatives de renforcement des capacités en matière d'AC. CONCLUSION: L'approche décrite offre une méthode pratique pour parvenir à l'AIC, notamment dans la façon de planifier, de mettre en œuvre et d'appuyer des initiatives dans les réseaux de recherche d'envergure. Dans le contexte de CAN-SOLVE CKD, ces efforts permettront de réduire les écarts entre les connaissances et les pratiques, en produisant et en appliquant des recherches visant l'amélioration de la vie des personnes atteintes de néphropathies.

Monitoring dialysis adequacy: history and current practice.

Dialysis adequacy for pediatric patients has largely followed the trends in adult dialysis by judging the success or adequacy of peritoneal or hemodialysis with urea kinetic modeling. While this provides a starting point to establish a dose of dialysis, it is clear that urea is only part of the picture. Many clinical parameters and interventions now have been identified that are just as impactful on mortality and morbidly as urea clearance. As such, our concept of adequacy is evolving to include non-urea parameters and assessing the impact that following an "adequate therapy" has on patient lives. As we move to a new era, we consider the impact these therapies have on patients and how it affects the quality of their lives; we must take these factors into consideration to achieve a therapy that is not just adequate, but livable.

Canadian Society of Nephrology Commentary on the Kidney Disease Improving Global Outcomes 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder.

PURPOSE OF REVIEW: (1) To provide commentary on the 2017 update to the Kidney Disease Improving Global Outcomes (KDIGO) 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD); (2) to apply the evidence-based guideline update for implementation within the Canadian health care system; (3) to provide comment on the care of children with chronic kidney disease (CKD); and (4) to identify research priorities for Canadian patients. SOURCES OF INFORMATION: The KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of CKD-MBD. METHODS: The commentary committee co-chairs selected potential members based on their knowledge of the Canadian kidney community, aiming for wide representation from relevant disciplines, academic and community centers, and different geographical regions. KEY FINDINGS: We agreed with many of the recommendations in the clinical practice guideline on the diagnosis, evaluation, prevention, and treatment of CKD-MBD. However, based on the uncommon occurrence of abnormalities in calcium and phosphate and the low likelihood of severe abnormalities in parathyroid hormone (PTH), we recommend against screening and monitoring levels of calcium, phosphate, PTH, and alkaline phosphatase in adults with CKD G3. We suggest and recommend monitoring these parameters in adults with CKD G4 and G5, respectively. In children, we agree that monitoring for CKD-MBD should begin in CKD G2, but we suggest measuring ionized calcium, rather than total calcium or calcium adjusted for albumin. With regard to vitamin D, we suggest against routine screening for vitamin D deficiency in adults with CKD G3-G5 and G1T-G5T and suggest following population health recommendations for adequate vitamin D intake. We recommend that the measurement and management of bone mineral density (BMD) be according to general population guidelines in CKD G3 and G3T, but we suggest against routine BMD testing in CKD G4-G5, CKD G4T-5T, and in children with CKD. Based on insufficient data, we also recommend against routine bone biopsy in clinical practice for adults with CKD or CKD-T, or in children with CKD, although we consider it an important research tool. LIMITATIONS: The committee relied on the evidence summaries produced by KDIGO. The CSN committee did not replicate or update the systematic reviews.

JUSTIFICATION: (1) Commenter les recommandations du KDIGO 2017 (Kidney Disease Improving Global Outcomes) sur les bonnes pratiques cliniques pour le diagnostic, l'évaluation et le traitement des troubles du métabolisme minéral osseux associés aux maladies rénales chroniques (TMO-MRC); (2) appliquer les lignes directrices actualisées et fondées sur les données probantes en vue de leur mise en œuvre dans le système de soins de santé canadien; (3) commenter les soins prodigués aux enfants atteints d'insuffisance rénale chronique (IRC) et (4) définir les priorités de recherche des patients Canadiens. SOURCES: Les recommandations du KDIGO 2017 (Kidney Disease Improving Global Outcomes) sur les bonnes pratiques cliniques pour le diagnostic, l'évaluation et le traitement des troubles du métabolisme minéral osseux associés aux maladies rénales chroniques (TMO-MRC). MÉTHODOLOGIE: Les coprésidents du comité ont sélectionné les membres potentiels sur la base de leur connaissance du secteur de la santé rénale au Canada, tout en visant une bonne représentation de toutes les disciplines concernées, des centres universitaires et communautaires et des différentes régions géographiques. PRINCIPAUX COMMENTAIRES: Nous approuvons un grand nombre des recommandations du KDIGO. Cependant, compte tenu de la rareté des anomalies du calcium et du phosphate et de la faible probabilité d'anomalies graves de la PTH (hormone parathyroïde), nous déconseillons le dépistage et la surveillance des taux de calcium, de phosphate, de PTH et de phosphatase alcaline chez les adultes atteints d'IRC de stade G3. Nous suggérons de mesurer ces paramètres chez les adultes de stade G4 et nous le recommandons pour les patients de stade G5. Chez les enfants, nous appuyons la recommandation de commencer la surveillance des TMO-MRC dès le stade G2, mais nous suggérons de mesurer le calcium ionisé plutôt que les taux de calcium total ou de calcium corrigé en fonction de l'albumine. En ce qui concerne la vitamine D, nous déconseillons le dépistage de routine des carences chez les adultes atteints d'IRC de stade G3 à G5 et G1T à G5T; nous suggérons plutôt de suivre les recommandations visant la population générale pour un apport adéquat en vitamine D. Nous recommandons que la mesure et la prise en charge de la densité minérale osseuse (DMO) se fassent en suivant les recommandations pour la population générale chez les adultes atteints d'IRC de stade G3 et G3T, mais nous déconseillons les tests de DMO de routine chez les adultes de stades G4-G5 et G4T-G5T, de même que chez les enfants atteints d'IRC. En raison de données insuffisantes, nous déconseillons également la pratique systématique d'une biopsie osseuse chez les adultes atteints d'IRC ou d'IRC-TMO, ainsi que chez les enfants atteints d'IRC, bien que nous la considérions comme un important outil de recherche. LIMITES: Le comité s'est appuyé sur le résumé des preuves rédigé par le KDIGO. Le comité de la SCN n'a pas reproduit ou mis à jour les revues systématiques.

Epidemiologic Characteristics of Acute Kidney Injury During Cisplatin Infusions in Children Treated for Cancer.

Importance: Few multicenter pediatric studies have comprehensively described the epidemiologic characteristics of cisplatin-associated acute kidney injury using standardized definitions. Objective: To examine the rate of and risk factors associated with acute kidney injury among children receiving cisplatin infusions. Design, Setting, and Participants: This prospective cohort study examined children (aged <18 years) recruited from May 23, 2013, to March 31, 2017, at 12 Canadian pediatric academic health centers who were receiving 1 or more cisplatin infusion. Children whose estimated or measured glomerular filtration rate (GFR) was less than 30 mL/min/1.73 m2 or who had received a kidney transplant were excluded. Data analysis was performed from January 3, 2018, to September 20, 2019. Exposures: Cisplatin infusions. Main Outcomes and Measures: The primary outcome was acute kidney injury during cisplatin infusion, defined using a Kidney Disease: Improving Global Outcomes serum creatinine criteria-based definition (stage 1 or higher). The secondary outcome was acute kidney injury defined by electrolyte criteria from the National Cancer Institute Common Terminology Criteria for Adverse Events (grade 1 or higher). Assessments occurred at early (first or second cycle) and late (last or second to last cycle) cisplatin infusions. Results: A total of 159 children (mean [SD] age at early cisplatin infusion, 7.2 [5.3] years; 80 [50%] male) participated. The most common diagnoses were central nervous system tumors (58 [36%]), neuroblastoma (43 [27%]), and osteosarcoma (33 [21%]). Acute kidney injury (by serum creatinine level increase) occurred in 48 of 159 patients (30%) at early cisplatin infusions and 23 of 143 patients (16%) at late cisplatin infusions. Acute kidney injury (by electrolyte abnormalities) occurred in 106 of 159 patients (67%) at early cisplatin infusion and 100 of 143 patients (70%) at late cisplatin infusions. Neuroblastoma diagnosis and higher precisplatin GFR were independently associated with acute kidney injury (serum creatinine level increase) at early cisplatin infusions (adjusted odds ratio [aOR] for neuroblastoma vs other, 3.25; 95% CI, 1.18-8.95; aOR for GFR, 1.01; 95% CI, 1.00-1.03) and late cisplatin infusions (aOR for neuroblastoma vs other, 6.85; 95% CI, 1.23-38.0; aOR for GFR, 1.01; 95% CI, 1.00-1.03). Higher cisplatin infusion dose was also independently associated with acute kidney injury (serum creatinine level increase) at later cisplatin infusions (aOR, 1.05; 95% CI, 1.01-1.10). Conclusions and Relevance: The findings suggest that acute kidney injury is common among children receiving cisplatin infusions and that rate and risk factors differ at earlier vs later infusions. These results may help with risk stratification with a goal of risk reduction.

Daily Evaluation Cards Are Superior for Student Assessment Compared to Single Rater In-Training Evaluations.

INTRODUCTION: The University of Manitoba's ambulatory pediatric clerkship transitioned to daily encounter cards (DECs) from single in-training evaluation reports (ITERs). The impact of this change on quality of student assessment was unknown. Using the validated Completed Clinical Evaluation Report Rating (CCERR) scale, we compared the assessment quality of the single ITER to the DEC-based system. METHODS: Block randomization was used to select from a cohort of ITER- and DEC-based assessments during equivalent points in clerkship training. Data were transcribed and anonymized and scored by two blinded raters using the CCERR. RESULTS: Inter-rater reliability for total CCERR scores was substantive (> 0.6). Mean total CCERR score for the DEC cohort was significantly higher than for the ITER cohort (25.2 vs. 16.8, p < 0.001), as were the mean scores for each item (2.81 vs. 1.86, p < 0.05). Multivariate logistical regression supported the significant influence of assessment method on assessment quality. CONCLUSIONS: There is improvement in the average quality of student assessments associated with the transition from an ITER-based system to a DEC-based system. However, the improvement to only average CCERR scores for the DEC cohort suggests an unmet need for faculty development.

The Canadian childhood nephrotic syndrome (CHILDNEPH) study: report on mid-study feasibility, recruitment and main measures.

BACKGROUND: To assess reasons for continuing practice variation in the management of childhood nephrotic syndrome despite expert reviews and guidelines, we are conducting a longitudinal cohort study in children with glucocorticoid sensitive nephrotic syndrome. Objectives of this mid-study report are to describe patient and physician recruitment characteristics, glucocorticoid prescriptions, use of second line agents, biopsy practices, and adherence to study protocol. METHODS: Children with new onset nephrotic syndrome and providers are being recruited from all 12 pediatric nephrology centres across Canada with > 2½ years follow-up. Data collection points of observation are over a minimum 36 months. Details of prescribed glucocorticoids and of all second line agents used during treatment are being collected. All relapses are being recorded with time to urinary remission of proteinuria. RESULTS: To date, 243 patients (57.1% male) from 12 centres were included. Median number of patients per centre was 29 (range 2-45), and median age of cohort was 7.3 (IQR 4.2) at enrollment. Forty-eight physicians were recruited, median 5 (range 2-8) per site. Median number of relapses per patient year of follow-up was 2.1 (IQR 4). Cumulative dose variability of glucocorticoids prescribed per episode of proteinuria and length of treatment was observed between participating centres. CONCLUSION: The Canadian pediatric nephrology community established a longitudinal childhood nephrotic syndrome cohort study that confirms ongoing practice variability. The study will help to evaluate its impact on patient outcomes, and facilitate clinical trial implementation in nephrotic syndrome.

Examining the Transition from Child to Adult Care in Chronic Kidney Disease: An Open Exploratory Approach.

For youth with chronic kidney disease (CKD) and their families, shifting from pediatric to adult systems of renal care can be challenging. This study explored the transitional process experienced by youth with CKD and their families, including perceived facilitators and barriers to effective transition. Qualitative interviews were conducted with youth with CKD (n=28) and their parents (n=28). Ambiguity regarding healthcare provider roles within the adult system was frequently reported. Themes reflected parental challenge relinquishing care responsibility, synergistic and divergent expectations between youth and parents, tensions in youth self-care readiness, desired healthcare provider roles in transition preparedness, and system considerations in transition. A "learning stage" was recommended in which youth experienced the adult system while supported by known pediatric team members.

Introduction of Competence by Design to Canadian Nephrology Postgraduate Training.

PURPOSE OF THE REVIEW: The Royal College of Physicians and Surgeons of Canada, with its Competence by Design initiative, is adopting the principles of competency-based medical education for residency training and continuing professional development. This initiative is being undertaken to meet the new standards of medical education in Canada, which include social accountability to meet performance-based outcomes of training. Nephrology is poised to implement Competence by Design into residency training in July 2018 and initiate a continuous quality improvement cycle to periodically renew and update the training requirements to be socially accountable and relevant in the modern age of medicine. The purpose of this review is to describe the process of entrustable professional activity and required training experience development and how they will affect subspecialty training in Canada. SOURCES OF INFORMATION: The construct of competency-based medical education was derived from existing literature searches of the medical education literature, including documentation provided by the Royal College of Physicians and Surgeons of Canada. The content for each entrustable professional activity and milestone was derived by consensus from the community expertise of the working group, existing speciality training requirements, and elements of training requirements that the Royal College has been mandated to superimpose on all training requirements to meet societal expectations. METHODS: The Royal College Specialty Committee in Nephrology participated in 2 years of preparation for this implementation, which has included the creation of a new educational design for the discipline and the elucidation of entrustable professional activities to describe the scope of nephrology practice and to guide teaching, learning, and assessment in residency, and ultimately maintenance of competence in practice. KEY FINDINGS: This article introduces the set of entrustable professional activities for adult and pediatric nephrology and describes the national consultation as part of an ongoing quality improvement of this work. LIMITATIONS: The implementation of Competence by Design will be tested by whether trainees embrace competency-based education by training to just entrustable professional activities, rather than the holistic model idealized in physician training. This is mitigated by the entrustable professional activity development incorporating multiple layers of competencies beyond a procedural skill. Time commitment for faculty will pose additional challenges in increasing the time for assessment of trainees, but is supported by electronic platforms at the Royal College to assist in data gathering and analysis. IMPLICATIONS: Competence by Design in nephrology is an outcomes-based curriculum and assessment platform that aims to train nephrologists to meet societal expectations in an ever-changing and complicated health care system. The goals are to increase safety and professional accountability to society and improve upon the already high standards of training within Canada.

CONTEXTE MOTIVANT LA REVUE: Le Collège royal des médecins et des chirurgiens du Canada, avec son initiative intitulée « La compétence par conception ¼ (CPC), adopte les principes de l'approche par compétences en formation médicale pour la formation des résidents et le perfectionnement professionnel continu. Cette initiative est entreprise pour répondre aux nouvelles normes en matière de formation médicale au Canada, qui comprennent notamment la responsabilité envers la société, pour atteindre des résultats de formation axés sur le rendement. La néphrologie fait partie des spécialités médicales qui adopteront dès juillet 2018 la CPC pour la formation de leurs résidents. La discipline amorce ainsi un cycle d'amélioration continue de la qualité qui participera à mettre à jour et à renouveler sur une base régulière les exigences de formation, de façon à demeurer pertinente et socialement responsable à l'ère de la médecine moderne. L'objectif de la présente revue est de présenter le processus régissant les activités professionnelles confiées (APC) et l'acquisition des expériences de formation exigées, et de décrire la manière dont il influencera la formation dans les sous-spécialités au Canada. SOURCES: L'élaboration de l'approche par compétences en formation médicale dérive de recherches dans la littérature existante au sujet de la formation médicale, notamment de documents fournis par le Collège royal des médecins et des chirurgiens du Canada. Le contenu de chacun des jalons et des APC a été établi par consensus à partir : i) de l'expérience communautaire des membres du groupe de travail; ii) des exigences actuelles en matière de formation spécialisée, et; iii) d'éléments d'exigences de formation que l'on a demandé au Collège royal de superposer aux précédentes, afin de répondre aux attentes de la société envers la profession. MÉTHODOLOGIE: Le comité de spécialité en néphrologie du Collège royal a participé à deux années de préparation pour la mise en œuvre du programme. Le comité devait dans un premier temps créer un nouveau modèle de formation pour la discipline. Ensuite, le comité était chargé de clarifier les APC couvrant tous les champs d'application de la pratique en néphrologie, et qui guideront l'enseignement fait aux résidents, leur apprentissage, leur évaluation et le maintien de la compétence dans la pratique. PRINCIPAUX RÉSULTATS: Cet article fait la description de l'ensemble des APC propres à la néphrologie adulte et pédiatrique, et présente la consultation nationale dans le cadre d'un processus d'amélioration continue de la qualité pour la discipline. LIMITES: Le succès de la mise en œuvre de la CPC sera mesuré selon que les stagiaires adopteront l'approche par compétences pour leur formation, soit en se concentrant uniquement sur la maîtrise des APC, plutôt que le modèle holistique idéalisé dans la formation des médecins. Cette situation est atténuée par l'élaboration d'APC intégrant de multiples niveaux de compétences qui vont au-delà des habiletés techniques. Le temps supplémentaire requis pour l'évaluation des stagiaires posera un défi au corps professoral. Les enseignants cliniques pourront toutefois compter sur les plateformes électroniques du Collège royal pour faciliter la collecte et l'analyse des données. CONCLUSION: La CPC en néphrologie consiste en un parcours axé sur les résultats et une plateforme d'évaluation des compétences. Elle aspire à former des néphrologues aptes à répondre aux attentes de la société envers la discipline, et ce, dans un système de santé complexe et en constante évolution. Ses objectifs visent à accroître la sécurité et la responsabilité professionnelle envers la société, et à renforcer les normes déjà très élevées en matière de formation médicale au Canada.

Changing Needs for Information and Support in an Online System for Parents of Children With Kidney Disease.

BACKGROUND: Pediatric chronic kidney disease is psychologically, financially, and physically demanding on parents providing care. Parents often feel isolated because of the rarity of the condition, and geographic isolation often compounds this perception in Canada. Many parents seek assistance online for both information and social support. OBJECTIVE: This study examines an online portal, titled "Ability Online," which was designed to provide support and information to a diverse group of parents using chat facilities, bulletin boards, and e-mail. Specifically, we sought to identify how the technologies offered in this system related to the support and information seeking needs for parents. Secondary aims of determining possible reasons for attrition over time were explored as well. DESIGN: Mixed methodology sequential exploratory design using the qualitative methodology of descriptive interpretation. SETTING: Telephone interviews. PATIENTS: Twenty parents of pediatric patients with chronic kidney disease from four Canadian centers who engaged in an online social support system "Ability Online." MEASUREMENTS: Interview transcripts generated from 20 taped phone conversations were reviewed from parents who engaged in the online system, and the themes derived from these transcripts served to generate semistructured interview questions that focused on their use of, and perceived benefit from, this technology for social support. Follow-up telephone interviews were then conducted with a 6-person subset of the original group in an effort to further define the impact of technology on their experience. This same smaller cohort provided data on social supports, caregiver satisfaction, and caregiver stress. RESULTS: Many parents experience a progression through which their needs for knowledge and support change over time. Specifically, parents describe a transition from pure information seeking, to seeking parental interaction, mutual support and collaboration, and ultimately to advocacy. Parents described how technology could be used to address those needs. LIMITATIONS: Our cohort was slightly more educated and representative of more urban populations than published data reflecting the population of North American pediatric patients living with kidney disease. CONCLUSIONS: Our data suggest themes of technology use influencing the goals of online support seeking. While our findings are preliminary, further study may inform Web designers to identify the changing needs of participants in designing such online support networks, and minimize the reasons that participants fail to adopt, or terminate their online experiences.

CONTEXTE: L'insuffisance rénale chronique (IRC) chez les enfants impose un fardeau physique, psychologique et financier aux parents. Ces derniers, qui doivent prodiguer des soins à leurs enfants, se sentent très souvent isolés; d'abord en raison de la rareté de cette maladie, mais également parce qu'au Canada, l'isolement géographique contribue souvent à accroître cette perception. Beaucoup de parents se tournent alors vers le Web pour s'informer ou pour obtenir du soutien. OBJECTIFS DE L'ÉTUDE: Cette étude s'est penchée sur Ability Online, un portail Web conçu pour informer et offrir du soutien au groupe hétérogène de parents d'enfants atteints d'IRC qui utilisent les forums de discussion, les différents babillards et le courriel. Concrètement, nous avons voulu savoir si les technologies offertes dans ce réseau satisfaisaient les besoins des parents en termes de recherche de soutien et d'information. L'étude visait également à explorer et à cerner les raisons pour lesquelles certains parents décidaient de s'en retirer au fil du temps. TYPE D'ÉTUDE: Un modèle exploratoire, séquentiel et à méthodologie mixte, où on a utilisé une méthodologie qualitative de l'interprétation descriptive. MÉTHODOLOGIE: L'étude a été réalisée au moyen d'entretiens téléphoniques. PARTICIPANTS: Un total de 20 parents d'enfants atteints d'IRC provenant de quatre centres urbains au Canada, et qui fréquentaient le réseau de soutien social d'Ability Online. MESURES: Les transcriptions de vingt conversations téléphoniques enregistrées lors des entretiens faits auprès de parents fréquentant le réseau ont été analysées. Les thèmes retenus dans ces transcriptions ont servi à produire un entretien semi-dirigé dont les questions mettaient l'accent sur l'usage que les parents faisaient de cet outil pour obtenir du soutien social et sur les bénéfices qu'ils en tiraient. Un entretien téléphonique subséquent a été conduit auprès d'un sous-ensemble de six personnes du groupe original, pour tenter de mieux définir l'impact de cette technologie sur leur expérience. Cette cohorte réduite a fourni des données sur le soutien reçu, de même que sur le niveau de satisfaction et le stress vécu par les aidants naturels. RÉSULTATS: Plusieurs parents ont mentionné avoir observé une progression de leurs besoins de connaissance et de soutien au fil du temps. Plus précisément, ils ont constaté la transformation de leur besoin initial d'information en une recherche d'échanges avec d'autres parents, puis en soutien mutuel et en collaboration, pour finir en mobilisation. Au cours de ces entretiens, les parents ont également précisé la manière dont cette technologie pourrait être utilisée pour répondre à ces besoins. LIMITES DE L'ÉTUDE: Notre cohorte était légèrement plus scolarisée et représentative d'une population urbaine que les données publiées précédemment sur la population d'enfants nord-américains atteints d'insuffisance rénale. CONCLUSIONS: Nos données proposent des domaines d'utilisation de la technologie qui pourraient influencer les objectifs de recherche de soutien social en ligne. Nos résultats sont préliminaires, toutefois, une étude plus approfondie servirait à guider les concepteurs de sites Web pour qu'ils soient en mesure de mieux cerner les besoins des participants et de suivre l'évolution de ceux-ci dans la conception de réseaux de soutien en ligne. De plus, on suppose que cela aiderait à réduire les irritants qui font en sorte que les participants hésitent à adopter ces sites Web ou mettent fin à leur expérience en ligne.

Factors influencing practice variation in the management of nephrotic syndrome: a qualitative study of pediatric nephrology care providers.

BACKGROUND: Treatment protocols for childhood nephrotic syndrome are highly variable between providers and care centres. We conducted a qualitative study to understand the complex multilevel processes that lead to practice variation and influence provider management of nephrotic syndrome. METHODS: Focus groups with multidisciplinary pediatric nephrology care providers (n = 67) from 10 Canadian pediatric nephrology centres that had more than 1 pediatric nephrologist were conducted between September 2013 and April 2015. Focus group discussions were guided by the Ottawa Model for Research Use. We used a semistructured interview guide to elicit participants' perspectives regarding 1) the work setting and context of the clinical environment, 2) reasons for variation at the provider level and 3) clinical practice guidelines for nephrotic syndrome. Focus group discussions were transcribed and analyzed concurrently with the use of qualitative content analysis. RESULTS: Emerging themes were grouped into 2 categories: centre-level factors and provider-level factors. At the centre level, the type of care model used, clinic structures and resources, and lack of communication and collaboration within and between Canadian centres influenced care variation. At the provider level, use of experiential knowledge versus empirical knowledge and interpretation of patient characteristics influenced provider management of nephrotic syndrome. INTERPRETATION: Centre- and provider-level factors play an important role in shaping practice differences in the management of childhood nephrotic syndrome. Further research is needed to determine whether variation in care is associated with disparities in outcomes.

Design and Methods of the Pan-Canadian Applying Biomarkers to Minimize Long-Term Effects of Childhood/Adolescent Cancer Treatment (ABLE) Nephrotoxicity Study: A Prospective Observational Cohort Study.

BACKGROUND: Childhood cancer survivors experience adverse drug events leading to lifelong health issues. The Applying Biomarkers to Minimize Long-Term Effects of Childhood/Adolescent Cancer Treatment (ABLE) team was established to validate and apply biomarkers of cancer treatment effects, with a goal of identifying children at high risk of developing cancer treatment complications associated with thrombosis, graft-versus-host disease, hearing loss, and kidney damage. Cisplatin is a chemotherapy well known to cause acute and chronic nephrotoxicity. Data on biomarkers of acute kidney injury (AKI) and late renal outcomes in children treated with cisplatin are limited. OBJECTIVE: To describe the design and methods of the pan-Canadian ABLE Nephrotoxicity study, which aims to evaluate urine biomarkers (neutrophil gelatinase-associated lipocalin [NGAL] and kidney injury molecule-1 [KIM-1]) for AKI diagnosis, and determine whether they predict risk of long-term renal outcomes (chronic kidney disease [CKD], hypertension). DESIGN: This is a 3-year observational prospective cohort study. SETTING: The study includes 12 Canadian pediatric oncology centers. PATIENTS: The target recruitment goal is 150 patients aged less than 18 years receiving cisplatin. Exclusion criteria: Patients with an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 or a pre-existing renal transplantation at baseline. MEASUREMENTS: Serum creatinine (SCr), urine NGAL, and KIM-1 are measured during cisplatin infusion episodes (pre-infusion, immediate post-infusion, discharge sampling). At follow-up visits, eGFR, microalbuminuria, and blood pressure are measured and outcomes are collected. METHODS: Outcomes: AKI is defined as per SCr criteria of the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. CKD is defined as eGFR <90 mL/min/1.73m2 or albumin-to-creatinine ratio≥3mg/mmol. Hypertension is defined as per guidelines. Procedure: Patients are recruited before their first or second cisplatin cycle. Participants are evaluated during 2 cisplatin infusion episodes (AKI biomarker validation) and at 3, 12, and 36 months post-cisplatin treatment (late outcomes). LIMITATIONS: The study has a relatively moderate sample size and short follow-up duration. There is potential for variability in data collection since multiple sites are involved. CONCLUSIONS: ABLE will provide a national platform to study biomarkers of late cancer treatment complications. The Nephrotoxicity study is a novel study of AKI biomarkers in children treated with cisplatin that will greatly inform on late cisplatin renal outcomes and follow-up needs.

MISE EN CONTEXTE: Les survivants d'un cancer infantile éprouvent des effets indésirables dus à leurs traitements, ce qui leurs engendrent des problèmes de santé à vie. L'équipe The Applying Biomarkers to Minimize Long-Term Effects of Childhood/Adolescent Cancer Treatment (ABLE) vise à valider des biomarqueurs d'effets indésirables causés par les traitements contre le cancer et identifier les enfants à risque de développer des complications associées aux problèmes de coagulation, à la maladie du greffon contre l'hôte, la perte auditive et l'insuffisance rénale. La chimiothérapie cisplatine cause des dommages aux reins à court et à long terme. Relativement peu de données existent sur les biomarqueurs d'insuffisance rénale aigüe (IRA) et sur les problèmes rénaux à long terme chez les enfants traités avec le cisplatine. OBJECTIFS: Décrire les méthodologies de l'étude pancanadienne néphrotoxique ABLE qui vise à évaluer si les biomarqueurs urinaires (neutrophil gelatinase-associated lipocalin [NGAL] et kidney injury molecule-1[KIM-1]) peuvent diagnostiquer l'IRA, et s'ils peuvent prédire le risque de développer l'insuffisance rénale chronique (IRC) et l'hypertension artérielle à long terme. CADRE ET TYPE D'ÉTUDE: Étude prospective observationnelle de 3 ans dans 12 centres d'oncologie pédiatrique canadiens. PARTICIPANTS: cible de 150 patients âgés <18 ans recevant du cisplatine. Critères d'exclusion: Débit de filtration glomérulaire estimé (DFGe)<30 mL/min/1.73m2 ou avoir reçu une transplantation rénale. MESURES: Créatinine sérique, NGAL/KIM-1 sont mesurés pendant les infusions de cisplatine (échantillonnage avant l'infusion, après, et avant la sortie de l'hôpital). Visites de suivi: DFGe, microalbuminurie et tension artérielle sont mesurés; les résultats sont recueillis. MÉTHODOLOGIE: Critères d'évaluation: L'IRA est définie selon les critères de créatinine sérique de la classification Kidney Disease: Improving Global Outcomes (KDIGO). L'IRC est définie comme ayant un DFGe<90 mL/min/1.73m2 ou un ratio d'albumine/créatinine ≥3mg/mmol. L'hypertension est définie selon les lignes directrices. Procédure: Le recrutement: à lieu au premier ou deuxième cycle de cisplatine. Les patients sont évalués pendant deux infusions de cisplatine (validation des biomarqueurs d'IRA) et 3, 12 et 36 mois après le cisplatine (évaluation des problèmes rénaux à long terme). LIMITES DE L'ÉTUDE: La taille de l'échantillon est relativement modérée et la durée du suivi est moyennement courte. Il pourrait potentiellement avoir de la variabilité dans la collecte de données car plusieurs sites d'études sont impliqués. CONCLUSIONS: ABLE génèrera une plateforme nationale pour étudier les biomarqueurs de complications à long terme des traitements contre le cancer. L'étude néphrotoxique ABLE est une étude novatrice des biomarqueurs de l'IRA chez les enfants traités avec le cisplatine qui contribuera grandement à identifier les problèmes rénaux à long terme causés par le cisplatine et la nécessité de suivis cliniques.

A variant in a cis-regulatory element enhances claudin-14 expression and is associated with pediatric-onset hypercalciuria and kidney stones.

The greatest risk factor for kidney stones is hypercalciuria, the etiology of which is largely unknown. A recent genome-wide association study (GWAS) linked hypercalciuria and kidney stones to a claudin-14 (CLDN14) risk haplotype. However, the underlying molecular mechanism was not delineated. Recently, renal CLDN14 expression was found to increase in response to increased plasma calcium, thereby inducing calciuria. We hypothesized therefore that some children with hypercalciuria and kidney stones harbor a CLDN14 variant that inappropriately increases gene expression. To test this hypothesis, we sequenced the CLDN14 risk haplotype in a cohort of children with idiopathic hypercalciuria and kidney stones. An intronic SNP was more frequent in affected children. Dual luciferase and cell-based assays demonstrated increased reporter or CLDN14 expression when this polymorphism was introduced. In silico studies predicted the SNP introduced a novel insulinoma-associated 1 (INSM1) transcription factor binding site. Consistent with this, repeating the dual luciferase assay in the presence of INSM1 further increased reporter expression. Our data suggest that children with the INSM1 binding site within the CLDN14 risk haplotype have a higher likelihood of hypercalciuria and kidney stones. Enhanced CLDN14 expression may play a role in the pathophysiology of their hypercalciuria.