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.

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.

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.

Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.

Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. Pseudohypoaldosteronism type II (PHAII), a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis, has revealed previously unrecognized physiology orchestrating the balance between renal salt reabsorption and K(+) and H(+) excretion. Here we used exome sequencing to identify mutations in kelch-like 3 (KLHL3) or cullin 3 (CUL3) in PHAII patients from 41 unrelated families. KLHL3 mutations are either recessive or dominant, whereas CUL3 mutations are dominant and predominantly de novo. CUL3 and BTB-domain-containing kelch proteins such as KLHL3 are components of cullin-RING E3 ligase complexes that ubiquitinate substrates bound to kelch propeller domains. Dominant KLHL3 mutations are clustered in short segments within the kelch propeller and BTB domains implicated in substrate and cullin binding, respectively. Diverse CUL3 mutations all result in skipping of exon 9, producing an in-frame deletion. Because dominant KLHL3 and CUL3 mutations both phenocopy recessive loss-of-function KLHL3 mutations, they may abrogate ubiquitination of KLHL3 substrates. Disease features are reversed by thiazide diuretics, which inhibit the Na-Cl cotransporter in the distal nephron of the kidney; KLHL3 and CUL3 are expressed in this location, suggesting a mechanistic link between KLHL3 and CUL3 mutations, increased Na-Cl reabsorption, and disease pathogenesis. These findings demonstrate the utility of exome sequencing in disease gene identification despite the combined complexities of locus heterogeneity, mixed models of transmission and frequent de novo mutation, and establish a fundamental role for KLHL3 and CUL3 in blood pressure, K(+) and pH homeostasis.

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.

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.

Canadian Society of Nephrology Commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis: management of glomerulonephritis in adults.

The KDIGO (Kidney Disease: Improving Global Outcomes) clinical practice guideline for management of glomerulonephritis was recently released. The Canadian Society of Nephrology convened a working group to review the recommendations and comment on their relevancy and applicability to the Canadian context. A subgroup of adult nephrologists reviewed the guideline statements for management of glomerular disease in adults and agreed with most of the guideline statements developed by KDIGO. This commentary highlights areas for which there is lack of evidence and areas in need of translation of evidence into clinical practice. Areas of controversy or uncertainty, including the choice of second-line agents, are discussed in more detail. Existing practice variation also is addressed. The relevance of treatment recommendations to the Canadian practitioner is discussed.

Canadian Society of Nephrology Commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis: management of nephrotic syndrome in children.

The KDIGO (Kidney Disease: Improving Global Outcomes) clinical practice guideline for management of glomerulonephritis was recently released. The Canadian Society of Nephrology convened a working group to review the recommendations and comment on their relevancy and applicability to the Canadian context. A subgroup of pediatric nephrologists reviewed the guideline statements for management of childhood nephrotic syndrome and agreed with most of the guideline statements developed by KDIGO. This commentary highlights areas in which there is lack of evidence and areas in need of translation of evidence into clinical practice. Areas of controversy or uncertainty, including the length of corticosteroid therapy for the initial presentation and relapses, definitions of steroid resistance, and choice of second-line agents, are discussed in more detail. Existing practice variation is also addressed.

Deletions in 16q24.2 are associated with autism spectrum disorder, intellectual disability and congenital renal malformation.

BACKGROUND: The contribution of copy-number variation (CNV) to disease has been highlighted with the widespread adoption of array-based comparative genomic hybridisation (aCGH) and microarray technology. Contiguous gene deletions involving ANKRD11 in 16q24.3 are associated with autism spectrum disorder (ASD) and intellectual disability (ID), while 16q24.1 deletions affecting FOXF1 are associated with congenital renal malformations, alveolar capillary dysplasia, and various other abnormalities. The disease associations of deletions in the intervening region, 16q24.2, have only been defined to a limited extent. AIM: To determine whether deletions affecting 16q24.2 are correlated with congenital anomalies. METHODS: 35 individuals, each having a deletion in 16q24.2, were characterised clinically and by aCGH and/or SNP-genotyping microarray. RESULTS: Several of the 35 16q24.2 deletions identified here closely abut or overlap the coding regions of FOXF1 and ANKRD11, two genes that have been previously associated with the disease. 25 patients were reported to have ASD/ID, and three were found to have bilateral hydronephrosis. 14 of the deletions associated with ASD/ID overlap the coding regions of FBXO31 and MAP1LC3B. These same genes and two others, C16orf95 and ZCCHC14, are also included in the area of minimal overlap of the three deletions associated with hydronephrosis. CONCLUSIONS: Our data highlight 16q24.2 as a region of interest for ASD, ID and congenital renal malformations. These conditions are associated, albeit without complete penetrance, with deletions affecting C16orf95, ZCCHC14, MAP1LC3B and FBXO31. The function of each gene in development and disease warrants further investigation.

Quality of life in children with vesicoureteral reflux.

Vesicoureteral reflux (VUR) is commonly diagnosed in children presenting with urinary tract infections. Antibiotic prophylaxis and ureteric surgery are standard treatments for these children. Our aim was to investigate whether health-related quality of life (HRQOL) was altered in children treated for VUR. Children aged 1-5 years with grade III or higher VUR were identified through electronic records at the Stollery Children's Hospital. Parents of these children were mailed the TNO-AZL Netherlands Organisation for Applied Scientific Research Academic Medical Centre Quality of Life (TAPQOL) questionnaire. QOL scores for this group were compared with normative controls from the instrument's creators using the Mann-Whitney U test. Thirty-two of the 96 (33%) mailed surveys were returned. Eight children had surgery, and 19 were treated with antibiotic prophylaxis. When comparing the VUR group with the control group, we found that anxiety and social functioning scores were significantly better in patients with VUR (p < 0.01). The VUR group had worse scores in problem behavior, stomach complaints ,and communication (p < 0.01). This study reveals that children with VUR have a reasonable QOL when compared with controls. However, the diagnosis of VUR and its management does have an impact on gastrointestinal complaints, behavior, and communication, which may occur as a result of chronic medical intervention.

Pseudohyperphosphatemia associated with high-dose liposomal and lipid complex amphotericin B when tested with Synchron LX 20 (Beckman/Coulter) phosphorous assay.

Although case reports of hyperphosphatemia have been previously described in patients receiving liposomal amphotericin B, this has not been reported in patients receiving the lipid complex formulation. We report a case of hyperphosphatemia that persisted despite switching from liposomal to lipid complex amphotericin B in a child with invasive zygomycosis. This case suggests that in the context of acute renal dysfunction, hyperphosphatemia may also be observed with lipid complex amphotericin B. This case highlights the importance of differentiating between pseudohyperphosphatemia and hyperphosphatemia to prevent complications.

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.

Renal interstitial fibrosis in children treated with FK506 for nephrotic syndrome.

BACKGROUND: Steroid-dependent, steroid-resistant or frequently relapsing nephrotic syndrome carries a poor prognosis, including progression to renal failure. There are a number of studies confirming the efficacy of FK506 in steroid-resistant or steroid-dependent nephrotic syndrome. Although the use of this medication is becoming more common, we know very little about the potential nephrotoxicity when used in nephrotic syndrome. METHOD: We retrospectively reviewed the characteristics and biopsy findings of 11 children with steroid-dependent or frequently relapsing nephrotic syndrome treated with FK506. Two sequential biopsies were evaluated for the change in interstitial fibrosis, measured by a quantitative stereological method, and the change in arteriolar hyaline thickening, tubular atrophy and interstitial fibrosis, graded according to Banff criteria. RESULTS: There was an increase in interstitial fibrosis (P = 0.005), with a median absolute change in the per cent volume density between initial and follow-up biopsies of 1.8% [interquartile range (IQR) 3.9%]. Median percentage change in volume density of interstitial fibrosis, relative to volume density of interstitial fibrosis prior to initiating FK506, was 93% (IQR 138%). Banff scores for interstitial fibrosis and tubular atrophy also increased following tacrolimus therapy (P = 0.04 for both). Average FK506 trough level over the treatment period was significantly associated with change in fibrosis (Spearman's rho = 0.67 and P = 0.02). CONCLUSIONS: This is some of the first histological data concerning tacrolimus nephrotoxicity in childhood nephrotic syndrome. Although the role of the natural progression of the underlying disease in the observed change is not definitively clear, the changes seen are in keeping with the known nephrotoxic effects of FK506 demonstrated in renal transplant. This increase is small when presented as a median change. However, there were a number of children who had a larger change in fibrosis. The factors predictive of interstitial fibrosis while on FK506 are not well defined; the findings from this study suggest that FK506 level may be a factor. Given the observations and limitations of the few published studies, there is an obvious need for further study in a large multicenter prospective trial.

Novel therapies for resistant focal segmental glomerulosclerosis (FONT) phase II clinical trial: study design.

BACKGROUND: The lack of adequate randomized clinical trials (RCT) has hindered identification of new therapies that are safe and effective for patients with primary focal segmental glomerulosclerosis (FSGS), especially in patients who fail to respond to corticosteroids and immunosuppressive therapies. Recent basic science advances have led to development of alternative treatments that specifically target aberrant pathways of fibrosis which are relevant to disease progression in FSGS. There is a need for a flexible Phase II study design which will test such novel antifibrotic strategies in order to identify agents suitable for phase III testing. METHODS/DESIGN: The Novel Therapies for Resistant Focal Segmental Glomerulosclerosis (FONT) project is a multicenter Phase I/II RCT designed to investigate the potential efficacy of novel therapies for resistant FSGS. Adalimumab and galactose will be evaluated against conservative therapy consisting of the combination of lisinopril, losartan and atorvastatin. The sample size is defined to assure that if one of the treatments has a superior response rate compared to that of the other treatments, it will be selected with high probability for further evaluation. Comparison of primary and secondary endpoints in each study arm will enable a choice to be made of which treatments are worthy of further study in future Phase III RCT. DISCUSSION: This report highlights the key features of the FONT II RCT including the two-step outcome analysis that will expedite achievement of the study objectives. The proposed phase II study design will help to identify promising agents for further testing while excluding ineffective agents. This staged approach can help to prevent large expenditures on unworthy therapeutic agents in the management of serious but rare kidney diseases.

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.