Catherine Morgan

Kidney stones and kidney function loss: a cohort study

Objective To investigate whether the presence of kidney stones increase the risk of end stage renal disease (ESRD) or other adverse renal outcomes. Design A registry cohort study using validated algorithms based on claims and facility utilisation data. Median follow-up of 11 years. Setting Alberta, Canada, between 1997 and 2009. Participants 3 089 194 adult patients without ESRD at baseline or a history of pyelonephritis. Of these, 1 954 836 had outpatient serum creatinine measurements and were included in analyses of chronic kidney disease and doubling of serum creatinine level. Exposure One or more kidney stones during follow-up. Main outcome measures Incident ESRD, development of stage 3b–5 chronic kidney disease (estimated glomerular filtration rate <45 mL/min/1.73 m2), and sustained doubling of serum creatinine concentration from baseline. Results 23 706 (0.8%) patients had at least one kidney stone, 5333 (0.2%) developed ESRD, 68 525 (4%) developed stage 3b–5 chronic kidney disease, and 6581 (0.3%) experienced sustained doubling of serum creatinine. Overall, one or more stone episodes during follow-up was associated with increased risk of ESRD (adjusted hazard ratio 2.16 (95% CI 1.79 to 2.62)), new stage 3b–5 chronic kidney disease (hazard ratio 1.74 (1.61 to 1.88)), and doubling of serum creatinine (hazard ratio 1.94 (1.56 to 2.43)), all compared with those without kidney stones during follow-up. The excess risk of adverse outcomes associated with at least one episode of stones seemed greater in women than in men, and in people aged <50 years than in those aged ≥50. However, the risks of all three adverse outcomes in those with at least one episode of stones were significantly higher than in those without stones in both sexes and age strata. The absolute increase in the rate of adverse renal outcomes associated with stones was small: the unadjusted rate of ESRD was 2.48 per million person days in people with one or more episodes of stones versus 0.52 per million person days in people without stones. Conclusion Even a single kidney stone episode during follow-up was associated with a significant increase in the likelihood of adverse renal outcomes including ESRD. However, the increases were small in absolute terms.

Statin prophylaxis and inflammatory mediators following cardiopulmonary bypass: a systematic review

IntroductionInduction of an inflammatory response is thought to have a significant role in the complications that follow cardiopulmonary bypass (CPB). The statin drugs are increasingly being recognized as having potent anti-inflammatory effects and hence have potential to influence an important mechanism of injury in CPB, although there is no current confirmation that this is indeed the case. Our objective was to systematically review if pre-operative prophylactic statin therapy, compared with placebo or standard of care, can decrease the inflammatory response in people undergoing heart surgery with CPB.MethodsWe performed a systematic and comprehensive literature search for all randomized controlled trials (RCTs) of open heart surgery with CPB in adults or children who received prophylactic statin treatment prior to CPB, with reported outcomes which included markers of inflammation. Two authors independently identified eligible studies, extracted data, and assessed study quality using standardized instruments. Weighted mean difference (WMD) was the primary summary statistic with data pooled using a random effects model. Descriptive analysis was used when data could not be pooled.ResultsEight RCTs were included in the review, with the number of trials for each inflammatory outcome being even more limited. Pooled data demonstrated benefit with the use of statin to attenuate the post-CPB increase in interleukins 6 and 8 (IL-6, IL-8), peak high sensitivity C-reactive protein (hsCRP), and tumor necrosis factor-alpha (TNF-α) post-CPB (WMD [95% confidence interval (CI)] -23.5 pg/ml [-36.6 to -10.5]; -23.4 pg/ml [-35.8 to -11.0]; -15.3 mg/L [CI -26.9 to -3.7]; -2.10 pg/ml [-3.83 to -0.37] respectively). Very limited RCT evidence suggests that prophylactic statin therapy may also decrease adhesion molecules following CPB including neutrophil CD11b and soluble P (sP)-selectin.ConclusionsAlthough the RCT evidence may suggest a reduction in post-CPB inflammation by statin therapy, the evidence is not definitive due to significant limitations. Several of the trials were not methodologically rigorous and statin intervention was highly variable in this small number of studies. This systematic review demonstrates that there is a significant gap that exists in the current literature in regards to the potential anti-inflammatory effect of statin therapy prior to CPB.

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 (Spearmans 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.

Acute Kidney Injury Is Common in Pediatric Severe Malaria and Is Associated With Increased Mortality

Acute kidney injury is common in severe malaria and associated with short- and long-term mortality developing in 50% of cases after admission. Cystatin C and BUN are associated with the severity of AKI, are elevated at admission and predict mortality.

Strategies to improve the understanding of long-term renal consequences after neonatal acute kidney injury.

Strategies to improve the understanding of long-term renal consequences after neonatal acute kidney injury

Association Between Fluid Balance and Outcomes in Critically Ill Children: A Systematic Review and Meta-analysis

Importance After initial resuscitation, critically ill children may accumulate fluid and develop fluid overload. Accruing evidence suggests that fluid overload contributes to greater complexity of care and worse outcomes. Objective To describe the methods to measure fluid balance, define fluid overload, and evaluate the association between fluid balance and outcomes in critically ill children. Data Sources Systematic search of MEDLINE, EMBASE, Cochrane Library, trial registries, and selected gray literature from inception to March 2017. Study Selection Studies of children admitted to pediatric intensive care units that described fluid balance or fluid overload and reported outcomes of interest were included. No language restrictions were applied. Data Extraction and Synthesis All stages were conducted independently by 2 reviewers. Data extracted included study characteristics, population, fluid metrics, and outcomes. Risk of bias was assessed using the Newcastle-Ottawa Scale. Narrative description of fluid assessment methods and fluid overload definitions was done. When feasible, pooled analyses were performed using random-effects models. Main Outcomes and Measures Mortality was the primary outcome. Secondary outcomes included treatment intensity, organ failure, and resource use. Results A total of 44 studies (7507 children) were included in this systematic review and meta-analysis. Of those, 27 (61%) were retrospective cohort studies, 13 (30%) were prospective cohort studies, 3 (7%) were case-control studies, and 1 study (2%) was a secondary analysis of a randomized trial. The proportion of children with fluid overload varied by case mix and fluid overload definition (median, 33%; range, 10%-83%). Fluid overload, however defined, was associated with increased in-hospital mortality (17 studies [n = 2853]; odds ratio [OR], 4.34 [95% CI, 3.01-6.26]; I2 = 61%). Survivors had lower percentage fluid overload than nonsurvivors (22 studies [n = 2848]; mean difference, −5.62 [95% CI, −7.28 to −3.97]; I2 = 76%). After adjustment for illness severity, there was a 6% increase in odds of mortality for every 1% increase in percentage fluid overload (11 studies [n = 3200]; adjusted OR, 1.06 [95% CI, 1.03-1.10]; I2 = 66%). Fluid overload was associated with increased risk for prolonged mechanical ventilation (>48 hours) (3 studies [n = 631]; OR, 2.14 [95% CI, 1.25-3.66]; I2 = 0%) and acute kidney injury (7 studies [n = 1833]; OR, 2.36 [95% CI, 1.27-4.38]; I2 = 78%). Conclusions and Relevance Fluid overload is common and is associated with substantial morbidity and mortality in critically ill children. Additional research should now ideally focus on interventions aimed to mitigate the potential for harm associated with fluid overload.

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.

Associations Between Fluid Balance and Outcomes in Critically Ill Children: A Protocol for a Systematic Review and Meta-analysis

Background: Fluid therapy is a mainstay during the resuscitation of critically ill children. After initial stabilization, excessive fluid accumulation may lead to complications of fluid overload, which has been independently associated with increased risk for mortality and major morbidity in critically ill children. Objectives: Perform an evidence synthesis to describe the methods used to measure fluid balance, define fluid overload, and evaluate the association between fluid balance and outcomes in critically ill children. Design: Systematic review and meta-analysis. Measurements: Fluid balance, fluid accumulation, and fluid overload as defined by authors. Methods: We will search Ovid MEDLINE, Ovid EMBASE, Cochrane Library, and ProQuest, Dissertations and Theses. In addition, we will search www.clinicaltrials.gov, World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) and the proceedings of selected key conferences for ongoing and completed studies. Search strategy will be done in consultation with a research librarian. Clinical trials and observational studies (from database inception to present) in patients (<25 years) admitted to pediatric intensive care units (PICUs) reporting fluid balance, fluid accumulation, or fluid overload, and associated outcomes will be included. Language will not be restricted. Two reviewers will independently screen studies and extract data. Primary outcome is mortality, and secondary outcomes encompass critical care resource utilization. Quality of evidence and risk of bias will be assessed using the Newcastle-Ottawa Scale (NOS). Results will be synthesized qualitatively and pooled for meta-analysis if possible. Limitations: Quality of the included studies; lack of randomized trials; high degrees of expected heterogeneity; and variations in definitions of fluid balance and fluid overload between studies. Conclusion: We will comprehensively appraise and summarize the evidence of the association between fluid balance and outcomes in critically ill children, and in doing so attempt to harmonize definitions related to fluid balance, accumulation, and overload. Systematic review registration: PROSPERO: CRD42016036209.

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.

Setting New Directions for Research in Childhood Nephrotic Syndrome: Results From a National Workshop

Background: We report on the proceedings of a national workshop held in Canada with the aims to identify priorities for research in childhood nephrotic syndrome and to develop a national strategy to address these priorities. Methods: A diverse group of participants attended the meeting, including patients, family members, researchers, and health care providers. We used small group discussions to explore priorities as perceived by patients and families and by health care providers and researchers. Results: Research evaluating glucocorticoid minimization or glucocorticoid-sparing regimens was a consistent theme in the patient and family discussion group. Families also indicated the need for precise prognostic information at diagnosis, more information to help them choose the best available therapy, and more resources for disease management. Health care providers emphasized the importance of better disease characterization including genotyping and phenotyping patients, better understanding the pathogenesis, and the need of providing targeted therapy and precise prognostic information. Conclusions: These priorities will inform the development and future directions of the Canadian Childhood Nephrotic Syndrome (CHILDNEPH) project, a national research initiative to improve care and outcomes of patients with childhood onset nephrotic syndrome.