Manjula Gowrishankar

Band 3 Edmonton I, a novel mutant of the anion exchanger 1 causing spherocytosis and distal renal tubular acidosis

dRTA (distal renal tubular acidosis) and HS (hereditary spherocytosis) are two diseases that can be caused by mutations in the gene encoding the AE1 (anion exchanger 1; Band 3). dRTA is characterized by defective urinary acidification, leading to metabolic acidosis, renal stones and failure to thrive. HS results in anaemia, which may require regular blood transfusions and splenectomy. Mutations in the gene encoding AE1 rarely cause both HS and dRTA. In the present paper, we describe a novel AE1 mutation, Band 3 Edmonton I, which causes dominant HS and recessive dRTA. The patient is a compound heterozygote with the new mutation C479W and the previously described mutation G701D. Red blood cells from the patient presented a reduced amount of AE1. Expression in a kidney cell line showed that kAE1 (kidney AE1) C479W is retained intracellularly. As kAE1 is a dimer, we performed co-expression studies and found that, in kidney cells, kAE1 C479W and G701D proteins traffic independently from each other despite their ability to form heterodimers. Therefore the patient carries one kAE1 mutant that is retained in the Golgi (G701D) and another kAE1 mutant (C479W) located in the endoplasmic reticulum of kidney cells, and is thus probably unable to reabsorb bicarbonate into the blood. We conclude that the C479W mutant is a novel trafficking mutant of AE1, which causes HS due to a decreased cell-surface AE1 protein and results in dRTA due to its intracellular retention in kidney.

Weight and height changes and factors associated with greater weight and height gains after pediatric renal transplantation: A naprtcs study

Background. Obesity is a significant problem among children undergoing renal transplantation. We sought to describe changes in adiposity (reflected by percent difference from the median body mass index [BMI] for height-age and sex [BMI%]) after pediatric renal transplantation and to identify risk factors for greater gains in adiposity within 12 months of transplantation and for persistence of these gains at 48 months. The changes in height-for-age were also examined. Methods. By using the North American Pediatric Renal Trials and Collaborative Studies registry, we performed a retrospective cohort study of children (age 2–18 years.) transplanted between 1995 and 2006, and followed up to January 2007. Multivariable linear regression was used to identify risk factors for greater gains in adiposity and height. Results. BMI was recorded at baseline in 4326 children, and collected every 6 months. Median BMI% increased by 11.37 units within 6 months; no substantial changes were seen thereafter. The pattern of change in BMI% was similar regardless of BMI% at transplant. Age 6 to 12 years at transplant, more remote transplant, female sex, black race, Hispanic ethnicity, and lower baseline BMI% were associated with significantly greater gains in adiposity both within 12 months and persisting 48 months posttransplant. Compared with daily use, no corticosteroid use at 6 and 48 months were associated with smaller increases in BMI% within the first 12 months and at 48 months, respectively. Conclusions. The majority of children experienced early increases in BMI%, which persisted up to 4 years. Increases in BMI% were similar regardless of BMI% at baseline.

Management and outcome of positive urine cultures in a neonatal intensive care unit

OBJECTIVES The aim of this study was to describe the management and outcome of positive urine cultures in a neonatal intensive care unit (NICU). STUDY DESIGN A chart review was completed of infants born October 1, 2004 to December 31, 2006 and admitted to the NICU at the Royal Alexandra Hospital, Edmonton, Alberta with any growth of bacteria or fungi in urine. RESULTS Positive urine cultures were obtained in 64 of 2936 admissions (2%) and were classified as contaminated urines (n=34), possible urinary tract infection (UTI) (n=14), definite UTI (n=10), and candidal UTI (n=6). Management was inconsistent. Two children required new assisted ventilation but no other complications occurred. CONCLUSIONS The diagnosis of UTI in NICU is hampered by use of urine collection methods that are subject to contamination. Outcome is generally excellent, but there is a great need for guidelines on management of positive urine cultures in the NICU.

Value of serum cystatin C in estimating renal function in children with non‐renal solid organ transplantation

Children with non‐renal solid organ transplants are surviving longer, but outcome is complicated by CKD. Accurate and frequent renal function monitoring is imperative to recognize and institute measures early to reverse, prevent, or arrest progression. This study of 59 children determined the accuracy (P30), bias, sensitivity and specificity between measured renal function by NM‐GFR, and estimated GFR by three formulas: Filler (serum cystatin C), mSchwartz (serum creatinine), and CKiD (serum cystatin C, creatinine, urea, and height). Mean GFR by all formulas differed significantly from NM‐GFR. Filler and mSchwartz formulas significantly increased the proportion of patients with GFR ≥ 90 mL/min/1.73 m2 (CKD stage 1) while decreasing those with GFR 60–89 mL/min/1.73 m2 (CKD stage 2). All formulas overestimated GFR. CKiD showed the highest P30 and lowest bias (79.7%; 6.9 mL/min/1.73 m2) followed by Filler (67.7%; 19.9 mL/min/1.73 m2) and Schwartz (57.6%; 26.8 mL/min/1.73 m2) for all GFR values. All formulas performed best with GFR ≥ 90 mL/min/1.73 m2, but CKiD was the only formula to achieve 91.1% accuracy. All formulas showed high sensitivities, but low specificities at NM‐GFR cutoff at 90. Thus, GFR estimated by CKiD followed by Filler formula is an adequate method to monitor renal function closely and frequently in these children.

Multifaceted Support for a New Medical School in Nepal Devoted to Rural Health by a Canadian Faculty of Medicine and Dentistry

Nepal and Alberta are literally a world apart. Yet they share a common problem of restricted access to health services in remote and rural areas. In Nepal, urban-rural disparities were one of the main issues in the recent civil war, which ended in 2006. In response to the need for improved health equity in Nepal a dedicated group of Nepali physicians began planning the Patan Academy of Health Sciences (PAHS), a new health sciences university dedicated to the education of rural health providers in the early 2000s. Beginning with a medical school the Patan Academy of Health Sciences uses international help to plan, deliver and assess its curriculum. PAHS developed an International Advisory Board (IAB) attracting international help using a model of broad, intentional recruitment and then on individuals’ natural attraction to a clear mission of peace-making through health equity. Such a model provides for flexible recruitment of globally diverse experts, though it risks a lack of coordination. Until recently, the PAHS IAB has not enjoyed significant or formal support from any single international institution. However, an increasing number of the international consultants recruited by PAHS to its International Advisory Board are from the University of Alberta in Edmonton, Alberta, Canada (UAlberta). The number of UAlberta Faculty of Medicine and Dentistry members involved in the project has risen to fifteen, providing a critical mass for a coordinated effort to leverage institutional support for this partnership. This paper describes the organic growth of the UAlberta group supporting PAHS, and the ways in which it supports a sister institution in a developing nation.

Hyperkalemia in the Early Post Renal Transplant Period

Introduction Hyperkalemia is a recognized and potentially life threatening complication post renal transplantation. Aside from delayed graft function, the most frequent culprit identified is pharmacotherapy. Many of the medications routinely used in the post-transplant period alter renal potassium handling or impair potassium movement into cells. These include calcineurin inhibitors, sulfa based antibiotics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and beta blockers. Episodic hyperkalemia develops in 44 to 73 percent of transplant recipients on calcineurin inhibitors [1] and is associated with patient morbidity as well as increased health care costs. The aim of this chart review is to assess the prevalence of hyperkalemia in our renal transplant program, and identify any predictive factors to design preventative and therapeutic algorithms in this high risk population. Materials and Methods Retrospective cohort identified all adult renal transplant recipients between July 2011 and August 2017 within the University of Alberta Northern Alberta Renal Program who developed hyperkalemia (defined as serum potassium >5.0 mmol/L) within the first 6 months post-transplant. Patients with abnormal allograft function or delayed graft function were excluded (creatinine >200 umol/L). Patient characteristics, diagnoses, medications, laboratory values and outcomes were extracted from the electronic medical record. A descriptive analysis was undertaken. Results and Discussion Of the 505 renal transplant patients transplanted during the study period, 48 developed at least one episode of hyperkalemia. These episodes were not associated with metabolic acidosis. Most patients had a period of persistent values in the hyperkalemic range. The majority of patients were on the combination of tacrolimus and trimethoprim-sulfamethoxazole, and approximately half of the patients were on a total of 3 or more medications that could contribute to abnormal potassium handling. Elevated tacrolimus levels were only present in 10% of hyperkalemic episodes. Conclusions The prevalence of hyperkalemia among renal transplant recipient in our centre was lower than expected based on published data. Our findings suggest that hyperkalemia in the early post-transplant period is largely related to the additive effects of multiple therapeutic medications altering potassium homeostasis, and does not seem associated with shift due to metabolic acidosis or as a direct effect from supratherapeutic tacrolimus levels. Our recommendation is to consider alternative agents for blood pressure management and PJP prophylaxis in those patients where hyperkalemia is a recurrent issue. Further investigation into which other factors may best predict those post renal transplant patients at risk for hyperkalemia is warranted.