Publications by authors named "Tom D Blydt-Hansen"

40 Publications

Association of Urine Platinum with Acute Kidney Injury in Children Treated with Cisplatin for Cancer.

J Clin Pharmacol 2021 Feb 18. Epub 2021 Feb 18.

Western University, Schulich School of Medicine and Dentistry, Department of Physiology and Pharmacology, London, Ontario, Canada.

Cisplatin is a chemotherapeutic agent highly excreted in urine and known to cause acute kidney injury (AKI). As AKI diagnosis by serum creatinine (SCr) is usually delayed, endeavors for finding early AKI biomarkers continue. This study aims to determine if urine platinum (UP) concentration 24h after cisplatin infusion is associated with AKI, and to evaluate the association between UP and tubular damage biomarkers: neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1). Children treated with cisplatin in 12 Canadian centers (April 2013-December 2017) were included. Urine from the morning after the first cisplatin infusion of the first or second cisplatin cycle was measured for UP, NGAL and KIM-1. SCr and serum electrolytes were used to detect AKI by either SCr elevation or urinary electrolyte wasting (potassium, magnesium, phosphate). The associations of UP with AKI, NGAL and KIM-1 were assessed. One-hundred-and-fifteen participants (54% boys, median [IQR] age 8.5 [4.0-13.4] years) were included, of which 29 (25%) and 105 (91%) developed AKI defined by SCr and electrolyte criteria, respectively. Higher UP was associated with higher cisplatin dose (Spearman rho: 0.21) and with younger age (Spearman rho: -0.33). UP was not associated with post-infusion AKI. UP was not associated with KIM-1, but was weakly associated with NGAL, particularly in participants without SCr AKI (Pearson's r: 0.22). UP may be a marker of mild tubular injury but is not likely to be a useful biomarker of clinically evident AKI. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/jcph.1839DOI Listing
February 2021

Isolated diastolic high blood pressure: a distinct clinical phenotype in US children.

Pediatr Res 2021 Jan 27. Epub 2021 Jan 27.

Department of Pediatrics and Child Health, Children's Hospital Research Institute, University of Manitoba, Winnipeg, MB, Canada.

Background: Screening studies have shown that 0.7-4.5% of generally healthy children have isolated diastolic high BP. We therefore studied the characteristics of children with diastolic BP in the elevated and hypertensive ranges according to current guidelines in US children from the National Health and Nutrition Examination Survey (NHANES, 1999-2016).

Methods: We studied 17,362 children (8-18 years) with BP measured by sphygmomanometry. High BP was categorized as isolated systolic (iSH), isolated diastolic (iDH), or Mixed.

Results: Overall, 86.0% (95% CI =  85.0-87.0) of the population had normal BP, 8.7% (8.0-9.3) elevated BP, 4.9% (4.4-5.5) Stage 1, and 0.4% (0.4-0.6) Stage 2. Moreover, 11.1% (10.3-12.0) had iSH, 1.9% (1.5-2.2) iDH, and 1.0% (0.8-1.2) Mixed. Children with iDH were more likely to be female, younger, white, and leaner than those with iSH, with lower rates of overweight/obesity. iDH was generally between normals and iSH. Resting heart rate was significantly higher in iDH even after adjustment for known covariates.

Conclusions: Children with iDH may have a distinct clinical picture. A leaner habitus and higher resting heart rate may reflect differences in underlying pathophysiology. Longitudinal follow-up studies are needed to better define the pathogenesis, progression, and long-term prognosis in iDH.

Impact: Using gold-standard auscultation and 2017 guidelines, isolated diastolic high BP (iDH) is found in 1.9% (95% CI 1.5-2.2) of American children; these children are younger, leaner, more female, and have fewer cardiometabolic risks. Resting heart rate is significantly higher in iDH compared to both normals and iSH even after adjustments for known covariates. Autonomic hyperactivity in iDH may speak to both etiology and therapeutic approaches. iDH appears to be a distinct clinical phenotype characterized by differences in anthropometric measures, sex, age, and resting heart rate. Follow-up studies are clearly needed to clarify its pathogenesis, progression, and prognosis.
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http://dx.doi.org/10.1038/s41390-021-01369-xDOI Listing
January 2021

Management of Pediatric Kidney Transplant Patients During the COVID-19 Pandemic: Guidance From the Canadian Society of Transplantation Pediatric Group.

Can J Kidney Health Dis 2020 13;7:2054358120967845. Epub 2020 Nov 13.

Division of Nephrology, Alberta Children's Hospital, Calgary, Canada.

Purpose Of The Program: To provide guidance on the management of pediatric kidney transplant patients during the COVID-19 pandemic.

Sources Of Information: Program-specific documents, preexisting, and related to COVID-19; documents from provincial, national, and international kidney transplant societies/agencies and organ procurement agencies; national and international webinars, including webinars that we hosted for input and feedback; with additional information from formal and informal review of published academic literature.

Methods: Challenges in the care of pediatric kidney transplant patients during the COVID-19 pandemic were highlighted within the Canadian Society of Transplantation (CST) Pediatric Group. It identified pediatric kidney transplant nephrologists (including a pediatric nephrologist ethicist) across the country and formed a workgroup. The initial guidance document was drafted and members of the workgroup reviewed and discussed all suggestions in detail via e-mail and virtual meetings. Disagreements were resolved by consensus. The document was reviewed by the CST Kidney Transplant Working Group, by the Canadian Society of Nephrology (CSN) COVID-19 Rapid Response Team (RRT), and an infectious disease expert. The suggestions were presented at an interactive webinar sponsored by CSN in collaboration with the CST and Canadian Association of Pediatric Nephrologists (CAPN), and attended by pediatric kidney health care professionals for further peer input. Final revisions were made based on feedback received. CJKHD editors reviewed the parallel process peer review and edited the manuscript for clarity.

Key Findings: We identified 8 key areas of pediatric kidney transplant care that may be affected by the COVID-19 pandemic: (1) transplant activity, (2) outpatient clinic activity, (3) monitoring, (4) multidisciplinary care, (5) medications (immunosuppression and others), (6) patient/family education/support, (7) school and employment, and (8) management of pediatric kidney transplant patients who are COVID-19 positive. We make specific suggestions for each of these areas.

Limitations: A full systematic review of available literature was not undertaken for the sake of expediency in development of this guideline. There is a paucity of literature to support evidence-based recommendations at this time. Instead, these guidelines were formulated based on expert opinion derived from available knowledge/experience and are subject to the biases associated with this level of evidence. The parallel review process that was created to expedite the publication of this work may not be as robust as standard arms' length peer review processes.

Implications: These recommendations are meant to serve as a guide to pediatric kidney transplant directors, clinicians, and administrators for providing the best patient care in the context of limited resources while protecting patients and health care providers wherever possible by limiting exposure to COVID-19. We recognize that recommendations may not be applicable to all provincial/local health authority practices and that they may not be delivered to all patients given the time and resource constraints affecting the individual provincial/local health jurisdiction.
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http://dx.doi.org/10.1177/2054358120967845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672730PMC
November 2020

Biomarker implementation: Evaluation of the decision-making impact of CXCL10 testing in a pediatric cohort.

Pediatr Transplant 2020 Nov 6:e13908. Epub 2020 Nov 6.

British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada.

Background: Children are at high risk for subclinical rejection, and kidney biopsy is currently used for surveillance. Our objective was to test how novel rejection biomarkers such as urinary CXCL10 may influence clinical decision-making to indicate need for a biopsy.

Methods: A minimum dataset for standard decision-making to indicate a biopsy was established by an expert panel and used to design clinical vignettes for use in a survey. Pediatric nephrologists were recruited to review the vignettes and A) estimate rejection risk and B) decide whether to biopsy; first without and then with urinary CXCL10/Cr level. Accuracy of biopsy decisions was then tested against the biopsy results. IRA was assessed by Fleiss Kappa (κ) for binary choice and ICC for probabilities.

Results: Eleven pediatric nephrologists reviewed 15 vignettes each. ICC of probability assessment for rejection improved from poor (0.28, P < .01) to fair (0.48, P < .01) with addition of CXCL10/Cr data. It did not, however, improve the IRA for decision to biopsy (K = 0.48 and K = 0.43, for the comparison). Change in clinician estimated probability of rejection with additional CXCL10/Cr data was correlated with CXCL10/Cr level (r  = 0.7756, P < .0001). Decision accuracy went from 8/15 (53.3%) cases to 11/15 (73.3%) with CXCL10/Cr, although improvement did not achieve statistical significance. Using CXCL10/Cr alone would have been accurate in 12/15 cases (80%).

Conclusion: There is high variability in decision-making on biopsy indication. Urinary CXCL10/Cr improves probability estimates for risk of rejection. Training may be needed to assist nephrologists in better integrate biomarker information into clinical decision-making.
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http://dx.doi.org/10.1111/petr.13908DOI Listing
November 2020

Yield and utility of surveillance kidney biopsies in pediatric kidney transplant recipients at various time points post-transplant.

Pediatr Transplant 2021 Mar 19;25(2):e13869. Epub 2020 Oct 19.

Division of Nephrology, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, BC, Canada.

Background: Due to a lack of consensus on SB for pediatric kidney transplant recipients, we evaluated the yield and clinical utility of SB findings at various time points post-transplant.

Methods: Patients transplanted at a single institution between 2014 and 2020 with at least one SB at 1.5, 3, 6, 12, and 24 months post-transplant were included. Additional biopsies were done for indication (IB). TCMR was classified by Banff criteria (score ≥i1t1).

Results: Forty-seven patients had 142 biopsies (SB = 113, IB = 29); 19 (40.4%) of whom experienced at least one TCMR episode in the first-year post-transplant. The greatest SB yield of any pathologic abnormality was at 6 months (57.1%; P < .001). Six months also had the highest yield for TCMR (42.9%), compared with 3.3%, 20.8%, 15.0%, and 9.1% at 1.5, 3, 12 months, and 24 months, respectively (P = .003). SB instigated intensification of immunosuppression (28.3% cases), reduction of immunosuppression (2.7% cases), and other non-immunosuppressant changes (1.8% cases). The 6-month SB led to the greatest number of changes in management (53.6%), compared with 1.5, 3, 12, and 24 months (13.3, 20.8, 25.0, and 36.4%, respectively; P = .012). There were no major biopsy-related complications.

Conclusions: SBs identify an important burden of subclinical rejection and other pathology leading to changes in clinical management. The greatest yield was at 6 months, whereas the least utility was at the 1.5 months. Selection of SB timing may be tailored such that the optimal yield is balanced against the procedural risk.
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http://dx.doi.org/10.1111/petr.13869DOI Listing
March 2021

Low renal transplantation rates in children with end-stage kidney disease: A study of barriers in a low-resource setting.

Pediatr Transplant 2021 Mar 15;25(2):e13867. Epub 2020 Oct 15.

Department of Pediatric Nephrology, St John's Medical College, St John's National Academy of Health Sciences, Bangalore, India.

After 2 decades as a low-cost transplant centre in India, our rates of kidney transplantation are low compared to the burden of end-stage kidney disease (ESKD). We performed this study to identify possible barriers inhibiting paediatric kidney transplant and to assess the outcomes of paediatric ESKD. A retrospective chart review of ESKD patients (2013 - 2018) at a tertiary paediatric nephrology centre was conducted. Medical/non-medical barriers to transplant were noted. Patient outcomes were classified as "continued treatment," "lost to follow-up (LTFU)" or "died." Of 155 ESKD patients (monthly income 218 USD [146, 365], 94% self-pay), only 30 (19%) were transplanted (28 living donor). Sixty-five (42%) were LTFU, 19 (12%) died, and 71 (46%) continued treatment. LTFU/death was associated with greater travel distance (300 km [60, 400] vs 110 km [20, 250] km, P < .0001) and lower monthly income (145 USD [101, 290] vs 290 USD [159, 681], P < .0001). Among those who continued treatment, 41 proceeded to transplant evaluation of whom 13 had no living donor and remained waitlisted for 27 months (15, 30). The remainder (n = 30) did not proceed to transplant due to unresolved medical issues (n = 10) or a lack of parental interest in pursuing transplant (n = 20). Barriers to transplantation in low-resource setting begin in ESKD. LTFU resulted in withdrawal of care and was associated with low socioeconomic status. Among those who continued treatment, transplant rates were higher but medical challenges and negative attitudes towards transplant and organ donation occurred.
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http://dx.doi.org/10.1111/petr.13867DOI Listing
March 2021

Validity and utility of urinary CXCL10/Cr immune monitoring in pediatric kidney transplant recipients.

Am J Transplant 2020 Oct 8. Epub 2020 Oct 8.

Nephrology, University of Manitoba, Winnipeg, Manitoba, Canada.

Individualized posttransplant immunosuppression is hampered by suboptimal monitoring strategies. To validate the utility of urinary CXCL10/Cr immune monitoring in children, we conducted a multicenter prospective observational study in children <21 years with serial and biopsy-associated urine samples (n = 97). Biopsies (n = 240) were categorized as normal (NOR), rejection (>i1t1; REJ), indeterminate (IND), BKV infection, and leukocyturia (LEU). An independent pediatric cohort of 180 urines was used for external validation. Ninety-seven patients aged 11.4 ± 5.5 years showed elevated urinary CXCL10/Cr in REJ (3.1, IQR 1.1, 16.4; P < .001) and BKV nephropathy (median = 5.6, IQR 1.3, 26.9; P < .001) vs. NOR (0.8, IQR 0.4, 1.5). The AUC for REJ vs. NOR was 0.76 (95% CI 0.66-0.86). Low (0.63) and high (4.08) CXCL10/Cr levels defined high sensitivity and specificity thresholds, respectively; validated against an independent sample set (AUC = 0.76, 95% CI 0.66-0.86). Serial urines anticipated REJ up to 4 weeks prior to biopsy and declined within 1 month following treatment. Elevated mean CXCL10/Cr was correlated with first-year eGFR decline (ρ = -0.37, P ≤ .001), particularly when persistently exceeding ≥4.08 (ratio = 0.81; P < .04). Useful thresholds for urinary CXCL10/Cr levels reproducibly define the risk of rejection, immune quiescence, and decline in allograft function for use in real-time clinical monitoring in children.
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http://dx.doi.org/10.1111/ajt.16336DOI Listing
October 2020

A Canadian Survey on Adverse Symptoms Experienced by Solid Organ Transplant Recipients.

Prog Transplant 2020 09 29;30(3):254-264. Epub 2020 Jun 29.

College of Pharmacy and Nutrition, 70398University of Saskatchewan, Saskatoon, Saskatchewan, Canada.

Introduction: Adverse symptoms experienced by solid organ transplant recipients remain largely unexplored despite their purported frequency.

Objective: To characterize patient perspectives on adverse symptoms, identifying the most problematic symptoms and the perceived cause and treatability, and to evaluate their impact on quality of life (QoL) and medication adherence.

Methods: An electronic survey was distributed to members of the Canadian Transplant Association, to characterize perceptions on symptom experience (Modified Transplant Symptom Occurrence and Distress Scale), and QoL (Short Form-12), medication adherence (Basel Assessment of Adherence to Immunosuppressive Medications Scale), demographics, and clinical situation.

Results: The questionnaire was distributed to 249 solid organ transplant recipients and achieved a 51% response rate (N = 127). Respondents reported a mean of 25 (standard deviation 10) adverse symptoms each. In women, the most prevalent and distressing symptoms were tiredness, lack of energy, sleep difficulties, difficulty concentrating or memory problems, diarrhea, joint pain, and depression. In men, they were tiredness, flatulence, lack of energy, sleep difficulties, and erectile problems. With the exception of flatulence, these symptoms were more often perceived to be caused by medical conditions rather than by immunosuppressants or other medications. Quality of life was similar to the general public, with mean physical and mental component scores of 47.4 (9.9) and 52.1 (8.2), respectively (relative to a US average of 50 [10]). However, QoL scores inversely correlated to the number of symptoms reported and were higher in patients who perceived all symptoms to be treatable.

Conclusion: Adverse symptoms may impact patient well-being. Perceived cause and treatability should be further explored.
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http://dx.doi.org/10.1177/1526924820933821DOI Listing
September 2020

To accompany Banas et al., Time for a Paradigm Shift.

EBioMedicine 2019 Nov 1;49:19-20. Epub 2019 Nov 1.

Department of Pediatrics, University of British Columbia, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.ebiom.2019.10.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945202PMC
November 2019

Valganciclovir prophylaxis delays onset of EBV viremia in high-risk pediatric solid organ transplant recipients.

Pediatr Res 2020 04 4;87(5):892-896. Epub 2019 Aug 4.

Department of Pediatrics, University of British Columbia, BC Children's Hospital, Vancouver, BC, Canada.

Background: The role of antiviral prophylaxis to prevent Epstein-Barr virus (EBV) viremia or posttransplant lymphoproliferative disorder in pediatric solid organ transplant recipients is controversial. We examined whether valganciclovir (VAL) prophylaxis for cytomegalovirus infection was associated with EBV viremia following transplantation in EBV-naive children.

Methods: A single-center, retrospective study was conducted of EBV-naive pediatric heart and renal transplant recipients with an EBV-positive donor from January 1996 to April 2017. VAL was tested for association with EBV viremia-free survival in the first 6 months posttransplantation when immunosuppressant exposure is the highest. Survival models evaluated VAL duration, with adjustment for other baseline confounders.

Results: Among the cohort (n = 44), 3 (6.8%) were heart transplants, 25 (56.8%) received VAL, and 22 (50%) developed EBV viremia in the first-year posttransplantation. Mean time-to-viremia was 143 vs. 90 days for the VAL and no-VAL groups, respectively (p = 0.008), in the first 6 months. Only two patients developed viremia while on VAL. Each additional day of VAL was associated with 1.4% increase in viremia-free survival (p < 0.001). Multivariable modeling of VAL with other baseline risk factors did not identify other independent risk factors.

Conclusion: VAL is independently associated with delayed onset of EBV viremia, with prolongation of delay with each additional day of antiviral prophylaxis.
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http://dx.doi.org/10.1038/s41390-019-0523-4DOI Listing
April 2020

Acute Shoshin beriberi syndrome immediately post-kidney transplant with rapid recovery after thiamine administration.

Pediatr Transplant 2019 08 24;23(5):e13493. Epub 2019 May 24.

Multi Organ Transplant Program, BC Children's Hospital, Vancouver, British Columbia, Canada.

Pediatric kidney transplant surgery is usually well tolerated, despite suboptimal physical conditioning that may result from uremia and nutritional deficiencies that accompany end-stage kidney failure. Nutritional supplementation is used to overcome such deficiencies, especially for children needing dialysis. Thiamine, a water-soluble vitamin also known as vitamin B1, is a critical cofactor in energy metabolism and may be competitively inhibited by the antimetabolite oxythiamine, a uremic toxin that accumulates in kidney failure. We report a case of a thiamine deficiency syndrome leading to overwhelming cardiac dysfunction, metabolic instability, and hemodynamic compromise, after otherwise uneventful kidney transplant surgery. Prior to transplant, this 14-year-old boy was treated with peritoneal dialysis and received thiamine supplementation. Post-transplant, the patient first developed hyperglycemia, then lactic acidosis, and subsequently hemodynamic instability despite escalating treatment with volume resuscitation and inotropic medication. He made a rapid and complete recovery after administration of IV thiamine. This is the first reported case of Shoshin beriberi syndrome in a pediatric kidney transplant recipient. Inadequate dialysis may have been a key factor, with toxin accumulation and thiamine transporter downregulation contributing to his status. Functional thiamine deficiency should be considered as a potential treatable cause of early post-transplant hemodynamic instability.
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http://dx.doi.org/10.1111/petr.13493DOI Listing
August 2019

A Holistic Approach to Risk for Early Kidney Injury in Indigenous Youth With Type 2 Diabetes: A Proof of Concept Paper From the iCARE Cohort.

Can J Kidney Health Dis 2019 21;6:2054358119838836. Epub 2019 Apr 21.

Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Canada.

Background: Indigenous youth with type 2 diabetes (T2D) are disproportionately affected by early onset albuminuria and are at high risk of kidney failure in early adulthood. Traditional biological approaches have failed to fully explain the renal morbidity seen in this population. The mproving renal omplications in dolescents with type 2 diabetes through search cohort (iCARE) study was therefore designed in collaboration with patients, to more holistically evaluate risk factors for renal morbidity. We hypothesize that both biological factors and mental health influence renal outcomes, mediated via inflammatory pathways.

Objective: The objective of this study was to evaluate the iCARE analytic framework which evaluates relationships between biological factors, mental health, inflammation, and albuminuria utilizing a structural equation modeling (SEM) approach.

Methods: The first 187 youth with T2D (10-25 years) from the Manitoba iCARE cohort are presented here to evaluate our theoretical and analytic framework. An SEM was chosen to evaluate the statistical significance of proposed associations. The primary outcome was a nonorthostatic urine albumin:creatinine ratio ≥2 mg/mmol. Main exposures (ie, latent factors) included psychological health (distress, perceived stress, positive mental health and resilience), hypertension (24 hour monitored), and inflammatory markers (C-reactive protein [CRP], erythrocyte sedimentation rate [ESR], fibrinogen). Hemoglobin A1c (HbA1c) and duration of diabetes were covariates.

Results: Within the initial cohort (median age = 15 years, duration of diabetes = 2.3 years, 66.8% female), 30.5% (n = 57) had nonorthostatic albuminuria (ALB), and the majority of ALB was persistent (confirmed in 2/3 samples over a 6-month period; n = 47). Youth with ALB had higher HbA1c (10.9% vs 8.9%; < .001), more hypertension (94.2% vs 78·2%; = .02), longer duration of diabetes (3.4 vs 2.4 years; = .01), higher distress (9.2 vs 7.3; = .02), and stress scores (28.7 vs 26.4; = .03), and elevated inflammatory markers (CRP: 4.9 vs 3.1 mg/L; = .01, fibrinogen: 3.7 vs 3.3 µmol/L; = .02). Factors directly associated with ALB in the SEM were hypertension (0.28; = .001), inflammation (0.41; < .001), and HbA1c (0.50; < .001). Psychological health was independently associated with inflammation (-0.20; < .001) but not directly associated with ALB.

Conclusions: Albuminuria is highly prevalent in Indigenous youth with T2D. This preliminary analysis supports a theoretical framework linking glycemic control, hypertension, and inflammation, potentially mediated by psychological factors with albuminuria. These data support the need for more holistic models of evaluation and care for youth with T2D and multifactorial interventions to prevent complications.
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http://dx.doi.org/10.1177/2054358119838836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6477761PMC
April 2019

Identifying Important Outcomes for Young People With CKD and Their Caregivers: A Nominal Group Technique Study.

Am J Kidney Dis 2019 07 15;74(1):82-94. Epub 2019 Mar 15.

Sydney School of Public Health, The University of Sydney, Sydney, Australia; Centre for Kidney Research, The Children's Hospital at Westmead, Sydney, Australia.

Rationale & Objective: Chronic kidney disease (CKD) has wide-ranging and long-term consequences for young people and their families. The omission of outcomes that are important to young people with CKD and their caregivers limits knowledge to guide shared decision making. We aimed to identify the outcomes that are important to young people with CKD and their caregivers.

Study Design: We used the nominal group technique whereby participants identified and ranked outcomes and explained their priorities.

Settings & Participants: Young people with CKD (stages 1-5, dialysis, or transplantation) and their caregivers were purposively sampled from 6 centers across Australia, the United States, and Canada.

Analytical Approach: Importance scores were calculated (scale of 0-1), and qualitative data were analyzed thematically.

Results: 34 patients (aged 8-21 years) and 62 caregivers participated in 16 groups and identified 48 outcomes. The 5 highest ranked outcomes for patients were survival (importance score, 0.25), physical activity (0.24), fatigue (0.20), lifestyle restrictions (0.20), and growth (0.20); and for caregivers, kidney function (0.53), survival (0.28), infection (0.22), anemia (0.20), and growth (0.17). 12 themes were identified reflecting their immediate and current priorities (wanting to feel normal, strengthening resilience, minimizing intrusion into daily life, imminent threats to life, devastating family burdens, and seeking control over health) and considerations regarding future impacts (protecting health/development, remaining hopeful, concern for limited opportunities, prognostic uncertainty, dreading painful and invasive procedures, and managing expectations).

Limitations: Only English-speaking participants were recruited.

Conclusions: Kidney function, infection, survival, and growth were the highest priorities for patients with CKD and their caregivers. Young people with CKD also prioritized highly the outcomes that directly affected their lifestyle and sense of normality, while caregiver's highest priorities concerned the long-term health of their child, current health problems, and the financial and family burdens of caring for a child with CKD.
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http://dx.doi.org/10.1053/j.ajkd.2018.12.040DOI Listing
July 2019

Non-invasive differentiation of non-rejection kidney injury from acute rejection in pediatric renal transplant recipients.

Pediatr Transplant 2019 05 4;23(3):e13364. Epub 2019 Feb 4.

Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.

Acute kidney injury (AKI) is a major concern in pediatric kidney transplant recipients, where non-alloimmune causes must be distinguished from rejection. We sought to identify a urinary metabolite signature associated with non-rejection kidney injury (NRKI) in pediatric kidney transplant recipients. Urine samples (n = 396) from 60 pediatric transplant participants were obtained at time of kidney biopsy and quantitatively assayed for 133 metabolites by mass spectrometry. Metabolite profiles were analyzed via projection on latent structures discriminant analysis. Mixed-effects regression identified laboratory and clinical predictors of NRKI and distinguished NRKI from T cell-mediated rejection (CMR), antibody-mediated rejection (AMR), and mixed CMR/AMR. Urine samples (n = 199) without rejection were split into NRKI (n = 26; ΔSCr ≥25%), pre-NRKI (n = 35; ΔSCr ≥10% and <25%), and no NRKI (n = 138; ΔSCr <10%) groups. The NRKI discriminant score (dscore) distinguished between NRKI and no NRKI (AUC = 0.86; 95% CI = 0.79-0.94), confirmed by leave-one-out cross-validation (AUC = 0.79; 95% CI = 0.68-0.89). The NRKI dscore also distinguished between NRKI and pre-NRKI (AUC = 0.82; 95% CI = 0.71-0.93). In a linear mixed-effects regression model to account for repeated measures, the NRKI dscore was independent of concurrent rejection, but there was a non-statistical trend for higher dscores with rejection severity. A second exploratory classifier developed to distinguish NRKI from clinical rejection had similar test characteristics (AUC = 0.81, 95% CI = 0.70-0.92, confirmed by LOOCV). This study demonstrates the potential of a urine metabolite classifier to detect NRKI in pediatric kidney transplant patients and non-invasively discriminate NRKI from rejection.
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http://dx.doi.org/10.1111/petr.13364DOI Listing
May 2019

Non-invasive staging of chronic kidney allograft damage using urine metabolomic profiling.

Pediatr Transplant 2018 08 31;22(5):e13226. Epub 2018 May 31.

Department of Pediatrics, University of British Columbia, BC Children's Hospital, Vancouver, BC, Canada.

Chronic kidney allograft damage is characterized by IFTA and GS. We sought to identify urinary metabolite signatures associated with severity of IFTA and GS in pediatric kidney transplant recipients. Urine samples (n = 396) from 60 pediatric transplant recipients were obtained at the time of kidney biopsy and assayed for 133 metabolites by mass spectrometry. Metabolite profiles were quantified via PLS-DA. We used mixed-effects regression to identify laboratory and clinical predictors of histopathology. Urine samples (n = 174) without rejection or AKI were divided into training/validation sets (75:25%). Metabolite classifiers trained on IFTA severity and %GS showed strong statistical correlation (r = .73, P < .001 and r = .72; P < .001, respectively) and remained significant on the validation sets. Regression analysis identified additional clinical features that improved prediction: months post-transplant (GS, IFTA); and proteinuria, GFR, and age (GS only). Addition of clinical variables improved performance of the %GS classifier (AUC = 0.9; 95% CI = 0.85-0.96) but not for IFTA (AUC = 0.82; 95% CI = 0.71-0.92). Despite the presence of potentially confounding phenotypes, these findings were further validated in samples withheld for rejection or AKI. We identify urine metabolite classifiers for IFTA and GS, which may prove useful for non-invasive assessment of histopathological damage.
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http://dx.doi.org/10.1111/petr.13226DOI Listing
August 2018

The prognostic value of urinary chemokines at 6 months after pediatric kidney transplantation.

Pediatr Transplant 2018 08 7;22(5):e13205. Epub 2018 May 7.

Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.

Pediatric kidney transplantation is lifesaving, but long-term allograft survival is still limited by injury processes mediated by alloimmune inflammation that may otherwise be clinically silent. Chemokines associated with alloimmune inflammation may offer prognostic value early post-transplant by identifying patients at increased risk of poor graft outcomes. We conducted a single-center prospective cohort study of consecutive pediatric kidney transplant recipients (<19 years). Urinary CCL2 and CXCL10 measured at 6 months post-transplant were evaluated for association with long-term eGFR decline, allograft survival, and concomitant acute cellular rejection histology. Thirty-eight patients with a mean age of 12.4 ± 4.6 years were evaluated. Urinary CCL2 was associated with eGFR decline until 6 months (ρ -0.43; P < .01), but not at later time points. Urinary CXCL10 was associated with eGFR decline at 36 months (ρ -0.49; P < .01), risk of 50% eGFR decline (HR = 1.04; P = .02), risk of allograft loss (HR = 1.05; P = .01), borderline rejection or rejection episodes 6-12 months post-transplant (r .41; P = .02), and Banff i + t score (r .47, P < .01). CCL2 and CXCL10 were also correlated with one another (ρ 0.54; P < .01). CCL2 and CXCL10 provide differing, but complementary, information that may be useful for early non-invasive prognostic testing in pediatric kidney transplant recipients.
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http://dx.doi.org/10.1111/petr.13205DOI Listing
August 2018

Evolution of renal function and urinary biomarker indicators of inflammation on serial kidney biopsies in pediatric kidney transplant recipients with and without rejection.

Pediatr Transplant 2018 08 25;22(5):e13202. Epub 2018 Apr 25.

Department of Pediatrics, University of British Columbia, BC Children's Hospital, Vancouver, BC, Canada.

Urinary CXCL10 and metabolites are biomarkers independently associated with TCMR. We sought to test whether these biomarkers fluctuate in association with histological severity of TCMR over short time frames. Forty-nine pairs of renal biopsies obtained 1-3 months apart from 40 pediatric renal transplant recipients were each scored for TCMR acuity score (i + t; Banff criteria). Urinary CXCL10:Cr and TCMR MDS were obtained at each biopsy and were tested for association with changes between biopsies in acuity, estimated GFR (ΔeGFR), and 12-month ΔeGFR. Sequential biopsies were obtained 1.8 ± 0.8 months apart. Biopsy 1 was usually obtained under protocol (75%), and 62% percent had evidence of TCMR. Using each biopsy pair for comparison, ΔeGFR did not predict change in acuity. By contrast, change in acuity was significantly correlated with change in urinary CXCL10:Cr (ρ 0.45, P = .003) and MDS (ρ 0.29, P = .04) between biopsies. The 12-month ΔeGFR was not predicted by TCMR acuity or CXCL10:Cr at Biopsy 2; however, an inverse correlation was seen with urinary MDS (ρ -0.35; P = .02). Changes in eGFR correlate poorly with evolving TCMR acuity on histology. Urinary biomarkers may be superior for non-invasive monitoring of rejection, including histological response to therapy, and may be prognostic for medium-term function.
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http://dx.doi.org/10.1111/petr.13202DOI Listing
August 2018

Albuminuria, Proteinuria, and Renal Disease Progression in Children with CKD.

Clin J Am Soc Nephrol 2017 Jun 25;12(6):912-920. Epub 2017 May 25.

Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.

Background And Objectives: The role of albuminuria as an indicator of progression has not been investigated in children with CKD in the absence of diabetes.

Design, Setting, Participants, & Measurements: Children were enrolled from 49 centers of the CKD in Children study between January of 2005 and March of 2014. Cross-sectional multivariable linear regression (=647) was used to examine the relationship between urine protein-to-creatinine (UP/C [milligrams per milligram]) and albumin-to-creatinine (ACR [milligrams per gram]) with eGFR (milliliters per minute per 1.73 m). Parametric time-to-event analysis (=751) was used to assess the association of UP/C, ACR, and urine nonalbumin-to-creatinine (Unon-alb/cr [milligrams per gram]) on the time to the composite endpoint of initiation of RRT or 50% decline in eGFR.

Results: The median follow-up time was 3.4 years and 202 individuals experienced the event. Participants with a UP/C≥0.2 mg/mg and ACR≥30 mg/g had a mean eGFR that was 16 ml/min per 1.73 m lower than those with a UP/C<0.2 mg/mg and ACR<30 mg/g. Individuals with ACR<30 mg/g, but a UP/C≥0.2 mg/mg, had a mean eGFR that was 9.3 ml/min per 1.73 m lower than those with a UP/C<0.2 mg/mg and ACR<30 mg/g. When categories of ACR and Unon-alb/cr were created on the basis of clinically meaningful cutoff values of UP/C with the same sample sizes for comparison, the relative times (RTs) to the composite end-point were almost identical when comparing the middle (RT=0.31 for UP/C [0.2-2.0 mg/mg], RT=0.38 for ACR [56-1333 mg/g], RT=0.31 for Unon-alb/cr [118-715 mg/g]) and the highest (RT=0.08 for UP/C [>2.0 mg/mg], RT=0.09 for ACR [>1333 mg/g], RT=0.07 for Unon-alb/cr [>715 mg/g]) levels to the lowest levels. A similar trend was seen when categories were created on the basis of clinically meaningful cutoff values of ACR (<30, 30-300, >300 mg/g).

Conclusions: In children with CKD without diabetes, the utility of an initial UP/C, ACR, and Unon-alb/cr for characterizing progression is similar.
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http://dx.doi.org/10.2215/CJN.11971116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5460717PMC
June 2017

Urinary Metabolomics for Noninvasive Detection of Antibody-Mediated Rejection in Children After Kidney Transplantation.

Transplantation 2017 10;101(10):2553-2561

1 Department of Pediatrics, University of British Columbia, BC Children's Hospital Vancouver, BC, Canada. 2 Department of Pediatrics and Child Health, University of Manitoba, Children's Hospital at Health Sciences Center, Winnipeg, MB, Canada. 3 Department of Pathology, University of Manitoba, Health Sciences Center, Winnipeg, MB, Canada. 4 The Metabolomics Innovation Center, University of Alberta, Edmonton, AB, Canada. 5 Section of Nephrology, Department of Internal Medicine, University of Manitoba, Health Sciences Center, Winnipeg, MB, Canada. 6 Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada. 7 Manitoba Center for Proteomics and Systems Biology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.

Background: Biomarkers are needed that identify patients with antibody-mediated rejection (AMR). The goal of this study was to evaluate the utility of urinary metabolomics for early noninvasive detection of AMR in pediatric kidney transplant recipients.

Methods: Urine samples (n = 396) from a prospective, observational cohort of 59 renal transplant patients with surveillance or indication biopsies were assayed for 133 unique metabolites by quantitative mass spectrometry. Samples were classified according to Banff criteria for AMR and partial least squares discriminant analysis was used to identify associated changes in metabolite patterns by creating a composite index based on all 133 metabolites.

Results: Urine samples of patients with (n = 40) and without AMR (n = 278) were analyzed and a classifier for AMR was identified (area under receiver operating characteristic curve = 0.84; 95% confidence interval, 0.77-0.91; P = 0.006). Application of the classifier to "indeterminate" samples (samples that partially fulfilled Banff criteria for AMR; n = 65) yielded an AMR score of 0.19 ± 0.15, intermediate between scores for AMR and No AMR (0.28 ± 0.14 and 0.10 ± 0.13 respectively, P ≤ 0.001). The AMR score was associated with the presence of donor-specific antibodies, biopsy indication, Banff ct, t, ah and cg scores, and retained accuracy when applied to subclinical cases (creatinine, <25% increase from baseline) or had minimal or no transplant glomerulopathy (Banff cg0-1). Exploratory classifiers that segregated samples based on concurrent T cell-mediated rejection (TCMR) identified overlapping metabolite signatures between AMR and TCMR, suggesting similar pathophysiology of tissue injury.

Conclusions: These preliminary findings identify a urine metabolic classifier for AMR. Independent validation is needed to verify its utility for accurate, noninvasive AMR detection.
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http://dx.doi.org/10.1097/TP.0000000000001662DOI Listing
October 2017

Canadian Forum on Combined Organ Transplantation.

Transplantation 2016 06;100(6):1339-48

1 Division of Nephrology, Department of Medicine, Multi-Organ Transplant Program, McGill University Health Center, Montréal, Québec, Canada. 2 Division of Pediatric Nephrology, University of British Columbia, Vancouver, British Columbia, Canada. 3 Division of Nephrology, Department of Medicine, St. Paul's Hospital, Vancouver, British Columbia, Canada. 4 Division of Nephrology, Department of Medicine, Multi-Organ Transplant Program, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada. 5 Canadian Blood Services Donation and Transplantation, Edmonton, Alberta, Canada. 6 Division of Surgery, Multi-Organ-Transplant Program, Queen Elisabeth II, Health Sciences Centre, Dalhousie University, Halifax, Nova Scotia, Canada. 7 Division of Gastroenterology, Department of Medicine, Liver Transplant Program, University of Alberta Hospital, Edmonton, Alberta, Canada. 8 Department of Paediatrics, Labatt Family Heart Centre, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. 9 Division of Cardiology, Department of Medicine, Multi-Organ Transplant Program, Alberta Health Services, Calgary, Alberta, Canada. 10 Division of Pulmonary Medicine, Department of Medicine, Lung Transplant Program, University of Alberta Hospital, Edmonton, Alberta, Canada. 11 Division of Nephrology, Department of Medicine, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada l2 Division of Nephrology, Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.

The Canadian Society of Transplantation and Canadian Blood Services conducted a consensus forum on combined renal/nonrenal transplants, as they are not part of Canadian organ-specific allocation models at present. The purpose of this initiative was to make recommendations, develop eligibility criteria, and a decision-making model on listing and allocation. Forty-two participants with expertise in combined transplantation participated in the consensus forum. The United States and Canadian data were reviewed. The consensus forum made recommendations regarding the following: (1) investigation of etiology, severity, duration, and level of renal dysfunction; (2) documentation of degree of nonreversible kidney injury; (3) eligibility for combined (either simultaneous or staged) transplantation; (4) research. Key recommendations were: (1) patients with end-stage nonrenal disease with estimated glomerular filtration rate less than 30 mL/min per 1.73 m for longer than 1 month or on dialysis less than 3 months, who fulfill criteria for nonreversibility of renal dysfunction (by level and duration of renal dysfunction, imaging, and pathology findings), would be eligible for combined renal/nonrenal transplantation; (2) patients on dialysis longer than 3 months would be eligible for combined renal/nonrenal transplantation; (3) staged renal after nonrenal transplantation with subsequent prioritized allocation of renal transplant was endorsed in selected cases. The validation and impact of these recommendations on allocation will require further studies.
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http://dx.doi.org/10.1097/TP.0000000000000963DOI Listing
June 2016

Genetic loci associated with renal function measures and chronic kidney disease in children: the Pediatric Investigation for Genetic Factors Linked with Renal Progression Consortium.

Nephrol Dial Transplant 2016 Feb 28;31(2):262-9. Epub 2015 Sep 28.

Renal Division, Department of Internal Medicine, Medical Center, University of Freiburg, Freiburg im Breisgau, Germany Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

Background: Chronic kidney disease (CKD) in children is characterized by rapid progression and a high incidence of end-stage renal disease and therefore constitutes an important health problem. While unbiased genetic screens have identified common risk variants influencing renal function and CKD in adults, the presence and identity of such variants in pediatric CKD are unknown.

Methods: The international Pediatric Investigation for Genetic Factors Linked with Renal Progression (PediGFR) Consortium comprises three pediatric CKD cohorts: Chronic Kidney Disease in Children (CKiD), Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of CRF in Pediatric Patients (ESCAPE) and Cardiovascular Comorbidity in Children with CKD (4C). Clean genotype data from > 10 million genotyped or imputed single-nucleotide polymorphisms (SNPs) were available for 1136 patients with measurements of serum creatinine at study enrollment. Genome-wide association studies were conducted to relate the SNPs to creatinine-based estimated glomerular filtration rate (eGFR crea) and proteinuria (urinary albumin- or protein-to-creatinine ratio ≥ 300 and ≥ 500 mg/g, respectively). In addition, European-ancestry PediGFR patients (cases) were compared with 1347 European-ancestry children without kidney disease (controls) to identify genetic variants associated with the presence of CKD.

Results: SNPs with suggestive association P-values < 1 × 10(-5) were identified in 10 regions for eGFR crea, four regions for proteinuria and six regions for CKD including some plausible biological candidates. No SNP was associated at genome-wide significance (P < 5 × 10(-8)). Investigation of the candidate genes for proteinuria in adults from the general population provided support for a region on chromosome 15 near RSL24D1/UNC13C/RAB27A. Conversely, targeted investigation of genes harboring GFR-associated variants in adults from the general population did not reveal significantly associated SNPs in children with CKD.

Conclusions: Our findings suggest that larger collaborative efforts will be needed to draw reliable conclusions about the presence and identity of common variants associated with eGFR, proteinuria and CKD in pediatric populations.
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http://dx.doi.org/10.1093/ndt/gfv342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4829056PMC
February 2016

Progression of pediatric CKD of nonglomerular origin in the CKiD cohort.

Clin J Am Soc Nephrol 2015 Apr 29;10(4):571-7. Epub 2015 Jan 29.

Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.

Background And Objectives: Congenital anomalies of the kidney and urinary tract and genetic disorders cause most cases of CKD in children. This study evaluated the relationships between baseline proteinuria and BP and longitudinal changes in GFR in children with these nonglomerular causes of CKD.

Design, Setting, Participants, & Measurements: Urine protein-to-creatinine ratio, casual systolic and diastolic BP (normalized for age, sex, and height), and GFR decline were assessed in the prospective CKD in Children cohort study.

Results: A total of 522 children, median age 10 years (interquartile range, 7, 14 years) with nonglomerular CKD were followed for a median of 4.4 years. The mean baseline GFR in the cohort was 52 ml/min per 1.73 m(2) (95% confidence interval [95% CI], 50 to 54) and declined 1.3 ml/min per 1.73 m(2) per year on average (95%CI, 1.6 to 1.1). A 2-fold higher baseline urine protein-to-creatinine ratio was associated with an accelerated GFR decline of 0.3 ml/min per 1.73 m(2) per year (95% CI, 0.4 to 0.1). A 1-unit higher baseline systolic BP z-score was associated with an additional GFR decline of 0.4 ml/min per 1.73 m(2) per year (95% CI, 0.7 to 0.1). Among normotensive children, larger GFR declines were associated with larger baseline urine protein-to-creatinine ratios; eGFR declines of 0.8 and 1.8 ml/min per 1.73 m(2) per year were associated with urine protein-to-creatinine ratio <0.5 and ≥0.5 mg/mg, respectively. Among children with elevated BP, average GFR declines were evident but were not larger in children with higher levels of proteinuria.

Conclusions: Baseline proteinuria and systolic BP levels are independently associated with CKD progression in children with nonglomerular CKD.
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http://dx.doi.org/10.2215/CJN.07480714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4386256PMC
April 2015

Effect of sirolimus on malignancy and survival after kidney transplantation: systematic review and meta-analysis of individual patient data.

BMJ 2014 Nov 24;349:g6679. Epub 2014 Nov 24.

Ottawa Hospital Research Institute, Ottawa, ON, Canada University of Ottawa, Ottawa, ON, Canada.

Objective: To examine risk of malignancy and death in patients with kidney transplant who receive the immunosuppressive drug sirolimus.

Design: Systematic review and meta-analysis of individual patient data.

Data Sources: Medline, Embase, and the Cochrane Central Register of Controlled Trials from inception to March 2013.

Eligibility: Randomized controlled trials comparing immunosuppressive regimens with and without sirolimus in recipients of kidney or combined pancreatic and renal transplant for which the author was willing to provide individual patient level data. Two reviewers independently screened titles/abstracts and full text reports of potentially eligible trials to identify studies for inclusion. All eligible trials reported data on malignancy or survival.

Results: The search yielded 2365 unique citations. Patient level data were available from 5876 patients from 21 randomized trials. Sirolimus was associated with a 40% reduction in the risk of malignancy (adjusted hazard ratio 0.60, 95% confidence interval 0.39 to 0.93) and a 56% reduction in the risk of non-melanoma skin cancer (0.44, 0.30 to 0.63) compared with controls. The most pronounced effect was seen in patients who converted to sirolimus from an established immunosuppressive regimen, resulting in a reduction in risk of malignancy (0.34, 0.28 to 0.41), non-melanoma skin cancer (0.32, 0.24 to 0.42), and other cancers (0.52, 0.38 to 0.69). Sirolimus was associated with an increased risk of death (1.43, 1.21 to 1.71) compared with controls.

Conclusions: Sirolimus was associated with a reduction in the risk of malignancy and non-melanoma skin cancer in transplant recipients. The benefit was most pronounced in patients who converted from an established immunosuppressive regimen to sirolimus. Given the risk of mortality, however, the use of this drug does not seem warranted for most patients with kidney transplant. Further research is needed to determine if different populations, such as those at high risk of cancer, might benefit from sirolimus.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4241732PMC
http://dx.doi.org/10.1136/bmj.g6679DOI Listing
November 2014

The Improving Renal Complications in Adolescents With Type 2 Diabetes Through the REsearch (iCARE) Cohort Study: rationale and Protocol.

Can J Diabetes 2014 Oct;38(5):349-55

Manitoba Institute of Child Health, Winnipeg, Manitoba, Canada.

Background: Youth-onset type 2 diabetes is associated with a high burden of renal complications, culminating with end stage kidney disease in early adulthood. The establishment of relevant bioclinical determinants of albuminuria and ultimately progression of chronic kidney disease in youth is critically important to facilitate patient risk stratification and aid in the development of treatment targets and tailored prevention strategies. In response to the important gaps in knowledge, we created a prospective cohort study of youth with type 2 diabetes titled the Improving Renal Complications in Adolescents with Type 2 Diabetes through the REsearch (iCARE) Study.

Methods: iCARE is a prospective observational cohort study of individuals with type 2 diabetes diagnosed prior to 18 years of age; the recruitment target was 400 patients. Phase 1 entailed a detailed phenotypic assessment of youth, including anthropometrics, biochemistry, 24-hour ambulatory blood pressure monitoring, overnight urine collections for albumin excretion, renal ultrasound and iohexol-derived glomerular filtration rate. Phase 2 of the study is an evaluation of psychological factors, including hair-derived cortisol; validated questionnaires for perceived stress, distress and resiliency; and a detailed evaluation of systemic and urine inflammatory biomarkers. Annual follow up is planned to assess temporal associations between clinical risk factors and renal outcomes, including progression of albuminuria.

Conclusion: This study will provide novel insight into the risk factors for albuminuria and progression of chronic kidney disease in youth with type 2 diabetes. New knowledge generated by this study will inform clinical care, and the infrastructure developed will provide a framework for future intervention studies.
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http://dx.doi.org/10.1016/j.jcjd.2014.07.224DOI Listing
October 2014

How should we identify early chronic kidney disease risk in non-kidney transplant recipients?

Pediatr Transplant 2014 Nov;18(7):661-2

Department of Pediatrics and Child Health (Nephrology), University of Manitoba, Winnipeg, Manitoba, Canada.

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http://dx.doi.org/10.1111/petr.12356DOI Listing
November 2014

Elevated urinary CXCL10-to-creatinine ratio is associated with subclinical and clinical rejection in pediatric renal transplantation.

Transplantation 2015 Apr;99(4):797-804

1Department of Pediatrics and Child Health (Nephrology), University of Manitoba, Children's Hospital at Health Sciences Center, Winnipeg, MB, Canada. 2Department of Pathology, University of Manitoba, Health Sciences Center, Winnipeg, MB, Canada. 3Manitoba Center for Proteomics and Systems Biology, Winnipeg, MB, Canada. 4Department of Community Health Sciences, University of Manitoba, George and Fay Yee Center for Healthcare Innovation, Winnipeg, MB, Canada. 5Manitoba Center for Proteomics and Systems Biology, and Department of Internal Medicine (Nephrology), University of Manitoba, Health Sciences Center, Winnipeg, MB, Canada.

Background: Subclinical and clinical T cell-mediated rejection (TCMR) has significant prognostic implications in pediatric renal transplantation. The goal of this study was to independently validate urinary CXCL10 as a noninvasive biomarker for detecting acute rejection in children and to extend these findings to subclinical rejection.

Methods: Urines (n = 140) from 51 patients with surveillance or indication biopsies were assayed for urinary CXCL10 using enzyme-linked immunosorbent assay and corrected with urinary creatinine.

Results: Median urinary CXCL10-to-creatinine (Cr) ratio (ng/mmol) was significantly elevated in subclinical TCMR (4.4 [2.6, 25.4], P < 0.001, n = 17); clinical TCMR (24.3 [11.2, 44.8], P < 0.001, n = 9); and antibody-mediated rejection (6.0 [3.3, 13.7], P = 0.002, n = 9) compared to noninflamed histology (1.4 [0.4, 4.2], normal and interstitial fibrosis and tubular atrophy, n = 52), and borderline tubulitis (3.3, [1.3, 4.9], n = 36). Elevated urinary CXCL10:Cr was independently associated with t scores (P < 0.001) and g scores (P = 0.006) on multivariate analysis. The area under receiver operating curve for subclinical and clinical TCMR was 0.81 (P = 0.045) and 0.88 (P = 0.019), respectively. This corresponded to a sensitivity-specificity of 0.59-0.67 and 0.77-0.60 for subclinical and clinical TCMR at cutoffs of 4.82 and 4.72 ng/mmol, respectively.

Conclusion: This study demonstrates that urinary CXCL10:Cr corresponds with microvascular inflammation and is a sensitive and specific biomarker for subclinical and clinical TCMR in children. This may provide a noninvasive monitoring tool for posttransplant immune surveillance for pediatric renal transplant recipients.
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http://dx.doi.org/10.1097/TP.0000000000000419DOI Listing
April 2015

Antibody-mediated rejection: analyzing the risk, proposing solutions.

Transplantation 2014 Aug;98 Suppl 3:S3-21

1 Nephrology Department, Hospital Universitario Marqués de Valdecilla, Universidad de Cantabria, Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain. 2 Instituto Carlos III, Red de Investigació en Enfermedades Renales (REDinREN), Madrid, Spain. 3 Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada. 4 Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada. 5 Department of Pathology, University of Manitoba, Winnipeg, Manitoba, Canada. 6 Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada. 7 Nephrology Department, Hospital Universitari Vall D ´Hebron, Barcelona, Spain. 8 Immunology Department, Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain. 9 Heart Transplant Program, Cardiology Department, Complejo Universitario de A Coruña, Spain. 10 Pneumology Department, Hospital Universitari Vall D ´Hebron, Barcelona, Spain. 11 Department of Nephrology, Hospital Universitari Vall D ´Hebron, Universidad Autónoma de Barcelona, Barcelona, Spain. 12 Nephrology and Dialysis Division, Medical University Vienna, Austria. 13 Address correspondence to: Manuel Arias, M.D., Nephrology Department, Edificio 2 de Noviembre, planta 1a, Hospital Universitario Marqués de Valdecilla, 39008 Santander, Spain.

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http://dx.doi.org/10.1097/TP.0000000000000218DOI Listing
August 2014

Canadian Society of Nephrology commentary on the 2012 KDIGO clinical practice guideline for the management of blood pressure in CKD.

Am J Kidney Dis 2014 Jun 12;63(6):869-87. Epub 2014 Apr 12.

Division of Nephrology, University of Ottawa, Ottawa, Ontario.

The KDIGO (Kidney Disease: Improving Global Outcomes) 2012 clinical practice guideline for the management of blood pressure (BP) in chronic kidney disease (CKD) provides the structural and evidence base for the Canadian Society of Nephrology (CSN) commentary on this guideline's relevancy and application to the Canadian health care system. While in general agreement, we provide commentary on 13 of the 21 KDIGO guideline statements. Specifically, we agreed that nonpharmacological interventions should play a significant role in the management of hypertension in patients with CKD. We also agreed that the approach to the management of hypertension in elderly patients with CKD should be individualized and take into account comorbid conditions to avoid adverse outcomes from excessive BP lowering. In contrast to KDIGO, the CSN Work Group believes there is insufficient evidence to target a lower BP for nondiabetic CKD patients based on the presence and severity of albuminuria. The CSN Work Group concurs with the Canadian Hypertension Education Program (CHEP) recommendation of a target BP for all non-dialysis-dependent CKD patients without diabetes of ≤140 mm Hg systolic and ≤90 mm Hg diastolic. Similarly, it is our position that in diabetic patients with CKD and normal urinary albumin excretion, raising the threshold for treatment from <130 mm Hg systolic BP to <140 mm Hg systolic BP could increase stroke risk and the risk of worsening kidney disease. The CSN Work Group concurs with the CHEP and the Canadian Diabetic Association recommendation for diabetic patients with CKD with or without albuminuria to continue to be treated to a BP target similar to that of the overall diabetes population, aiming for BP levels < 130/80 mm Hg. Consistent with this, the CSN Work Group endorses a BP target of <130/80 mm Hg for diabetic patients with a kidney transplant. Finally, in the absence of evidence for a lower BP target, the CSN Work Group concurs with the CHEP recommendation to target BP<140/90 mm Hg for nondiabetic patients with a kidney transplant.
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http://dx.doi.org/10.1053/j.ajkd.2014.03.003DOI Listing
June 2014

Medication treatment complexity and adherence in children with CKD.

Clin J Am Soc Nephrol 2014 Feb 21;9(2):247-54. Epub 2013 Nov 21.

Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.

Background And Objectives: The complexity of CKD management in children is increased by the number of comorbid conditions. This study assessed the prevalence of comorbidities in pediatric CKD and the frequency with which multiple comorbidities present together by assessing prevalent medication use by CKD stage and diagnosis and their association with clinical or sociodemographic factors. The association between number and frequency of dosing of medications prescribed and self-report of nonadherence was also assessed.

Design, Setting, Participants, & Measurements: In this cross-sectional analysis of the Chronic Kidney Disease in Children study, medication use at study entry grouped by indication was examined by CKD stage, diagnosis, age, race, ethnicity, income, and CKD duration. Multivariate adjusted predictors of medication use and clustering were examined. Nonadherence was assessed by self-report of missed medications in the past 7 days.

Results: The 558 eligible participants had a median age of 11 years and median GFR of 44 ml/min per 1.73 m(2); 62% of participants were male and 78% had nonglomerular kidney disease. The number of medications for treatment of CKD comorbidities increased with advanced CKD stage (2.5-fold for stages IV versus II; P<0.001) and glomerular disease (1.4-fold versus nonglomerular; P<0.001). Three distinct medication clusters were identified that corresponded to treatment of glomerular disease, advanced renal tubular dysfunction, and proteinuric complications, respectively. Nonadherence was associated with increased medication dosing frequency (administration >2 times/d; P<0.001) but not the number of medications.

Conclusions: Medical therapy for children with CKD is complex and is affected by glomerular diagnosis, CKD stage, and medication frequency. The need for CKD-related medication treatment cannot be easily predicted by CKD staging alone. Poorer adherence was associated with increased medication frequency, but not with the number of medical problems needing treatment. Consolidating medical treatment and reducing medication frequency may improve adherence rates in children with CKD.
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http://dx.doi.org/10.2215/CJN.05750513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3913241PMC
February 2014

Pediatric kidney transplant practice patterns and outcome benchmarks, 1987-2010: a report of the North American Pediatric Renal Trials and Collaborative Studies.

Pediatr Transplant 2013 Mar 2;17(2):149-57. Epub 2013 Jan 2.

Department of Pediatrics, University of Washington, Seattle, WA 98105, USA.

The NAPRTCS transplant registry has collected clinical information on children undergoing kidney transplantation since 1987 and now includes information on 11 603 kidney transplants in 10 632 patients. Since the first data analysis in 1989, NAPRTCS reports have documented marked improvements in outcome after kidney transplantation in addition to identifying factors associated with both favorable and poor outcomes. Patient demographics have changed over the course of the registry with a decrease in the percentage of white recipients from a high of 72% in 1987 to less than 43% in 2007. The percentage of living donors decreased to its lowest point in 2007 at 37%. Acute rejection rates continue to decline with improvements in short- and long-term graft survival. Recently, NAPRTCS data have been used as a source of benchmark data for pediatric kidney transplant centers.
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http://dx.doi.org/10.1111/petr.12034DOI Listing
March 2013