Variation in estimated glomerular filtration rate at dialysis initiation in children.

BACKGROUND: Data guiding the timing of dialysis initiation in children are limited. We sought to determine current practice and secular trends in Canada with respect to the timing of dialysis initiation in children based on estimated glomerular filtration rate (eGFR). METHODS: This observational study included incident chronic dialysis patients aged ≤21 years identified from the Canadian Organ Replacement Register who started dialysis in Canada between January 2001 and December 2010 at any of the nine participating Canadian centers (n = 583). Youth were categorized utilizing CKiD Schwartz eGFR into ≥10.5 (higher) or <10.5 ml/min/1.73 m2 (lower) eGFR groups. Differences at dialysis initiation by facility and region were examined, and secular trends were determined. RESULTS: Median eGFR at dialysis initiation was 8.1 (interquartile range 5.4-11.0) ml/min/1.73 m2. Overall, 29 % of the patients started dialysis with an eGFR of ≥10.5 ml/min/1.73 m2. The proportion of children starting with higher eGFR increased from 27.3 % in 2001 to 35.4 % in 2010 (p = 0.04) and differed by treatment facility (12-70 %; p = 0.0001). Factors associated with higher eGFR at dialysis initiation in the adjusted regression model were female sex [odds ratio (OR) 1.48; 95 % confidence interval (CI) 1.02-2.14], genetic cause of end-stage kidney disease (OR 2.77; 95 % CI 1.37-5.58) and living ≥50 km from treatment facility (OR 1.47; 95 % CI 1.01-2.14). CONCLUSIONS: One-third of the children were found to have initiated dialysis with an eGFR ≥10.5 ml/min/1.73 m2, however significant practice variation exists with respect to timing of dialysis initiation by treatment facility. More data is required to evaluate the clinical implications of this practice variation.

Structures, Organization, and Delivery of Kidney Care to Children Living in Low-Resource Settings.

Introduction: There is a disparity in the availability of health care for children in resource-constrained countries. The International Pediatric Nephrology Association (IPNA) commissioned an initiative exploring the challenges in the care of children with kidney disease in low- or middle-income countries (LMICs) with a focus on human, diagnostic, and therapeutic resources. Methods: A survey was sent by e-mail to all members of IPNA and its affiliated regional or national societies residing in LMICs. Data were extracted from individual responses after merging duplicate data. Descriptive analysis was done using Microsoft Excel. Results: Responses were obtained from 245 centers across 62 countries representing 88% of the LMIC pediatric population. Regional disparity in the availability of basic diagnostic and therapeutic resources was noted. Even when resources were available, they were not accessible or affordable in 15% to 20% of centers. Acute and chronic dialysis were available in 85% and 75% of centers respectively. Lack of trained nurses, pediatric-specific supplies, and high costs were barriers to providing dialysis in these regions. Kidney transplantation was available in 32% of centers, with the cost of transplantation and lack of surgical expertise reported as barriers. About 65% of centers reported that families with chronic disease opted to discontinue care, with financial burden as the most common reason cited. Conclusion: The survey highlights the existing gaps in workforce, diagnostic, and therapeutic resources for pediatric kidney care in resource-constrained regions. We need to strengthen the health care workforce, address disparities in health care resources and funding, and advocate for equitable access to medications, and kidney replacement therapy (KRT).

Access to and Health Outcomes of Pediatric Solid Organ Transplantation for Indigenous Children in 4 Settler-colonial Countries: A Scoping Review.

Solid organ transplantation (SOT) is considered the optimal treatment for children with end-stage organ failure; however, increased efforts are needed to understand the gap surrounding equitable access to and health outcomes of SOT for Indigenous children. This scoping review summarizes the literature on the characteristics of access to and health outcomes of pediatric SOT among Indigenous children in the settler-colonial states of Canada, Aotearoa New Zealand, Australia, and the United States. A search was performed on MEDLINE, EMBASE, PsycINFO, and CINAHL for studies matching preestablished eligibility criteria from inception to November 2021. A preliminary gray literature search was also conducted. Twenty-four studies published between 1996 and 2021 were included. Studies addressed Indigenous pediatric populations within the United States (n = 7), Canada (n = 6), Aotearoa New Zealand (n = 5), Australia (n = 5), and Aotearoa New Zealand and Australia combined (n = 1). Findings showed that Indigenous children experienced longer time on dialysis, lower rates of preemptive and living donor kidney transplantation, and disparities in patient and graft outcomes after kidney transplantation. There were mixed findings about access to liver transplantation for Indigenous children and comparable findings for graft and patient outcomes after liver transplantation. Social determinants of health, such as geographic remoteness, lack of living donors, and traditional spiritual beliefs, may affect SOT access and outcomes for Indigenous children. Evidence gaps emphasize the need for action-based initiatives within SOT that prioritize research with and for Indigenous pediatric populations. Future research should include community-engaged methodologies, situated within local community contexts, to inform culturally safe care for Indigenous children.

Substantial practice variation exists in the management of childhood nephrotic syndrome.

BACKGROUND: Practice variation is common for nephrotic syndrome (NS) treatment. METHODS: A cross-sectional, web-based survey on NS treatment was administered to 58 Canadian pediatric nephrologists with the aim to document existing practice variation and compare practice with the recommendations of the Kidney Disease Improving Global Outcomes Clinical Practice Guideline for NS. RESULTS: Of the 58 nephrologists asked to participate in the survey, 40 (69 %) responded. Among these, 62 % prescribed initial daily glucocorticoid (GC) therapy for 6 weeks, 26 % for 4 weeks by 26 %, and 10 % prescribed 'other'. Alternate-day GC was continued for 6 weeks by 63 % of respondents and for >6 and <6 weeks by 32 and 6 %, respectively. For biopsy-confirmed minimal change disease, 65 and 46 % of respondents chose oral cyclophosphamide for frequently relapsing and steroid-dependent phenotypes, respectively; calcineurin inhibitors or mycophenolate were the second most popular choices. Kidney biopsy was 'always' performed by 16, 39, and 97 % of respondents for frequently relapsing, steroid-dependent, and steroid-resistant patients, respectively. Rituximab had been administered by 60 % of respondents; 22, 56, and 72 % reported that they would consider rituximab for frequently relapsing, steroid-dependent, and steroid-resistant patients, respectively. Most notable differences between practice and Guideline recommendations were first presentation GC duration, GC-sparing agent choices in frequently relapsing and steroid-dependent patients, and biopsy practices. CONCLUSIONS: There is substantial Canadian practice variation in NS treatment. Assessment of factors driving variation and strategies to implement Guideline recommendations are needed.

Congenital Anomalies of the Kidney and Urinary Tract (CAKUT): An Emerging Relationship With Pregestational Diabetes Mellitus Among First Nations and Non-First Nations People in Saskatchewan-Results From the DIP: ORRIIGENSS Project.

OBJECTIVES: Because congenital anomalies of the kidneys and urinary tract (CAKUT) represent a frequent cause of end stage renal disease (ESRD) in the young, we explored the epidemiology of CAKUT and the role of diabetes in pregnancy. METHODS: This was a retrospective cohort study of CAKUT, by maternal diabetes status, from among all 1980‒2009 births in Saskatchewan First Nations (FN) and non-First Nations (non-FN) people. We determined frequencies, predictors and complications of CAKUT, as well as cumulative survival (to 2014) of affected persons until ESRD and death. RESULTS: Of the 411,055 babies (204,167 mothers) in the Saskatchewan maternal-infant database, 2,540 had CAKUT (391 FN and 2,149 non-FN). Overall annual CAKUT incidence was 0.63% for non-FN and 0.57% for FN (p=0.082), but 5-year CAKUT incidence only increased among FN (0.40% in 1980‒1984 and 0.76% in 2005‒2009, p<0.0001) and was highest among offspring of FN mothers with pregestational diabetes (pre-G/DM) (0% before 1995, 2.51% in 2000‒2004 and 1.66% in 2005-2009). Pre-G/DM, but not gestational diabetes mellitus (GDM), was an independent predictor of CAKUT in non-FN (odds ratio, 1.79; 95% confidence interval, 1.20 to 2.69), and in FN interacting with maternal history of stillbirth (odds ratio, 7.90; 95% confidence interval, 1.14 to 54.6). ESRD was >100-fold more likely among offspring with CAKUT compared with all other offspring and was responsible for 40% of ESRD cases in young FN and non-FN people. CONCLUSIONS: In Saskatchewan, pre-G/DM is an emerging cause of CAKUT, accounting for 40% of ESRD cases in FN/non-FN children and young adults. Because pre-G/DM‒related CAKUT is potentially preventable with optimal glycemic management, increased recognition of this serious complication is required.

Microarray analyses during adipogenesis: understanding the effects of Wnt signaling on adipogenesis and the roles of liver X receptor alpha in adipocyte metabolism.

Wnt signaling maintains preadipocytes in an undifferentiated state. When Wnt signaling is enforced, 3T3-L1 preadipocytes no longer undergo adipocyte conversion in response to adipogenic medium. Here we used microarray analyses to identify subsets of genes whose expression is aberrant when differentiation is blocked through enforced Wnt signaling. Furthermore, we used the microarray data to identify potentially important adipocyte genes and chose one of these, the liver X receptor alpha (LXR alpha), for further analyses. Our studies indicate that enforced Wnt signaling blunts the changes in gene expression that correspond to mitotic clonal expansion, suggesting that Wnt signaling inhibits adipogenesis in part through dysregulation of the cell cycle. Experiments designed to uncover the potential role of LXR alpha in adipogenesis revealed that this transcription factor, unlike CCAAT/enhancer binding protein alpha and peroxisome proliferator-activated receptor gamma, is not adipogenic but rather inhibits adipogenesis if inappropriately expressed and activated. However, LXR alpha has several important roles in adipocyte function. Our studies show that this nuclear receptor increases basal glucose uptake and glycogen synthesis in 3T3-L1 adipocytes. In addition, LXR alpha increases cholesterol synthesis and release of nonesterified fatty acids. Finally, treatment of mice with an LXR alpha agonist results in increased serum levels of glycerol and nonesterified fatty acids, consistent with increased lipolysis within adipose tissue. These findings demonstrate new metabolic roles for LXR alpha and increase our understanding of adipogenesis.

Perceptions of pediatric nephrologists regarding timing of dialysis initiation in children in Canada.

BACKGROUND: Significant practice variation exists in Canada with respect to timing of dialysis initiation in children. In the absence of evidence to guide practice, physicians' perceptions may significantly influence decision-making. OBJECTIVE: The objectives of this study are to (1) evaluate Canadian pediatric nephrologists' perceptions regarding dialysis initiation in children with chronic kidney disease (CKD) and (2) determine the factors guiding practice that may contribute to practice variation across Canada. DESIGN: This study was a cross-sectional online survey. SETTING: This study was done in academic pediatric nephrology centers in Canada. PARTICIPANTS: The participants of this study are pediatric nephrologists. MEASUREMENTS AND METHODS: An anonymous web-based survey was administered to pediatric nephrologists in Canada to evaluate perspectives and practice patterns regarding timing of dialysis initiation. We also explored the importance of estimated glomerular filtration rate (eGFR) vs. symptoms and the role of patient and provider factors influencing decisions. RESULTS: Thirty-five nephrologists (59 %) completed the survey. Most respondents care for advanced CKD patients in a multidisciplinary clinic (86 %) and no centers have a formal policy on timing of dialysis initiation. Seventy-five percent of centers follow <20 stage 4-5 CKD patients, and 9 % follow >30 patients. Discussions about dialysis initiation are generally informal (75 %) and the decision to start is made by the nephrologist (37 %) or a team (57 %). Fifty percent agreed GFR was important when deciding when to initiate dialysis, 41 % were neutral, and 9 % disagreed. Variability exists in the threshold that nephrologists considered early (vs. late) dialysis initiation: >20 (21 %), >15 (38 %), >12 (26 %), and >10 ml/min/1.73 m(2) (12 %). Practitioners however typically start dialysis in asymptomatic patients at eGFRs of 7-9 (9 %), 10-11 (41 %), 12-14 (38 %), and 15-19 (6 %) ml/min/1.73 m(2). Patient factors important in the decision to start dialysis for >90 % of nephrologists were fatigue, >10 % weight loss, nausea, increasing missed school, and awaiting a pre-emptive transplant. Age was only a factor for 56 %. LIMITATIONS: This study has a 59 % response rate. CONCLUSIONS: Variability exists in Canada regarding the importance and threshold of eGFR guiding the decision as to when to start dialysis in children, whereas patient symptoms are almost universally important to pediatric nephrologists' decision-making. Additional studies evaluating outcomes of children starting dialysis earlier vs. later are needed to standardize decision-making and care for children with kidney failure.

MISE EN CONTEXTE: Des différences significatives existent dans la pratique au Canada quant au moment où des traitements de dialyse devraient être entrepris chez les enfants souffrant d'insuffisance rénale. En absence de données probantes pour guider leur pratique, les différentes approches des néphrologues exerçant auprès de cette population jouent probablement un rôle majeur dans leur prise de décision. OBJECTIFS DE L'ÉTUDE: Dans un premier temps, l'étude visait à évaluer la perception des néphrologues canadiens en regard de l'amorce de traitements de dialyse chez les enfants atteints d'insuffisance rénale chronique (IRC). Ensuite, on a voulu déterminer les facteurs qui guident la pratique et qui font en sorte que des variations subsistent à cet égard dans la pratique en néphrologie pédiatrique à travers le Canada. CADRE ET TYPE D'ÉTUDE: Il s'agit d'un sondage transversal mené en ligne auprès des néphrologues pratiquant dans les unités pédiatriques des centres hospitaliers universitaires dans tout le Canada. MÉTHODOLOGIE: Un sondage accessible par le web, auquel les participants répondaient de façon anonyme, a été distribué aux spécialistes canadiens pratiquant en néphrologie pédiatrique. Ce sondage avait pour objectif d'évaluer les perceptions et les schémas de pratique relativement au moment le plus propice pour amorcer la dialyse. Le sondage explorait aussi l'importance du débit de filtration glomérulaire estimé (DFGe) par rapport aux symptômes ressentis par le patient dans la prise de décision. Finalement, nous avons tenté d'identifier les facteurs pouvant influencer le patient et son médecin traitant au moment de décider d'entreprendre des traitements de dialyse. RÉSULTATS: Tous les pédiatres-néphrologues pratiquant au Canada ont reçu le questionnaire. Toutefois, seulement 35 d'entre eux, soit un peu plus de la moitié (59 %), l'ont complété et renvoyé. La grande majorité des répondants (86 %) exerçaient au sein de cliniques multidisciplinaires, auprès de cas sévères d'IRC. Aucun des centres de soins où ces spécialistes pratiquent ne possédait de politique formelle quant au moment d'entreprendre des traitements de dialyse chez les patients suivis en néphrologie pédiatrique. Les trois quarts des centres de soins cités (75 %) suivaient moins de 20 cas d'IRC de stade 4 ou 5, alors que 9 % en suivaient plus de 30. Les répondants ont indiqué dans une proportion de 75 % que la discussion concernant l'amorce de la dialyse se déroulait de façon informelle. De plus, le sondage révèle que la décision d'amorcer la dialyse est prise par le néphrologue soignant seulement (37 % des cas) ou par une équipe (57 % des cas). La moitié des répondants (50 %) s'accordait pour dire que le DFGe était important dans leur prise de décision d'amorcer des traitements de dialyse chez leurs patients, 41 % avaient une opinion neutre à ce sujet alors que 9 % ne jugeaient pas cet élément important. Les pédiatres-néphrologues répondants sont partagés quant à la valeur seuil de DFGe qu'ils considèrent comme une amorce « hâtive ¼ de dialyse. Pour 21 % des répondants, cette valeur se situe à 20 ml/min/1,73 m2; pour 38 % elle se situe plutôt à 15 ml/min/1,73 m2; 26 % l'établissent à 12 ml/min/1,73 m2; alors que 12 % des répondants jugent l'amorce d'une dialyse dite « hâtive ¼ à un DFGe de 10 ml/min/1,73 m2. De façon générale, chez les patients asymptomatiques, la dialyse est amorcée lorsque le DFGe se situe entre 7 et 9 ml/min/1,73 m2 (9 % des cas), entre 10 et 11 ml/min/1,73 m2 (41 % des cas), entre 12 et 14 ml/min/1,73 m2 (38 % des cas) ou entre 15 et 19 ml/min/1,73 m2 (6 % des cas). Enfin, parmi les facteurs motivant les patients à entreprendre des traitements de dialyse, tels que rapportés par les répondants dans une proportion de plus de 90 %, on trouve : une sensation de fatigue, une perte de poids de plus de 10 %, des nausées, les absences répétées à l'école et l'attente d'une greffe rénale préventive. L'âge n'a été mentionné comme facteur que dans 56 % des cas. LIMITES DE L'ÉTUDE: Le taux de réponse au sondage relativement faible (59 %) limite la portée des résultats. CONCLUSIONS: En néphrologie pédiatrique, alors que les symptômes ressentis par les patients sont considérés de façon universelle dans la décision d'entreprendre une dialyse, les pédiatres-néphrologues canadiens ont des perceptions très différentes quant à la valeur seuil de DFGe qui devrait guider cette décision et à l'importance du rôle que ce paramètre devrait y jouer. Des études supplémentaires comparant les résultats chez les patients qui amorcent une dialyse dite hâtive par rapport à ceux de patients l'amorçant plus tard s'avèrent nécessaires pour établir des pratiques standardisées en matière de soins pour les enfants atteints d'insuffisance rénale.

Physical dissection of the CCAAT/enhancer-binding protein alpha in regulating the mouse amelogenin gene.

The amelogenin gene is tightly regulated at the temporal and spatial level in accord with the developmental requirement for tooth formation. Previous studies have shown that CCAAT/enhancer-binding protein alpha (C/EBPalpha) is a transactivator of the mouse X-chromosomal amelogenin gene. C/EBPalpha contains four highly conserved regions (CR) named CR1, CR2, CR3, and CR4. Transient transfection assays showed that CR2 in isolation had an exceptional capacity to enhance transcription from the 2.3 kb mouse amelogenin promoter. The remaining conserved regions of C/EBPalpha, either in isolation or in selected combinations, were less effective in amelogenin transactivation than the full length C/EBPalpha. Msx2 has previously been shown to antagonize C/EBPalpha through protein-protein interactions with C/EBPalpha, and the carboxyl-terminus of Msx2 is required for protein-protein interactions. Co-immunoprecipitation analyses identified that the carboxyl-terminal domain (residues 218-359) of C/EBPalpha is required for the C/EBPalpha-Msx2 protein-protein interactions.