Lyndsay A. Harshman

PAX2 in human kidney malformations and disease

Human PAX2 mutations have been associated with abnormalities in the developing and adult kidney ranging from congenital abnormalities of the kidney and urinary tract (CAKUT) to oncogenic processes. Defining the relationship of PAX2 to human renal disease requires an appreciation of its fundamental role in renal development. Given the highly conserved nature of the PAX2 gene in vertebrates, it is not surprising that much of our understanding of PAX2 involvement in renal disease has been derived from animal models. The following review will outline the current evidence supporting involvement of PAX2 in the pathologic processes involving the kidney.

Population-Based Exploration of Academic Achievement Outcomes in Pediatric Acute Lymphoblastic Leukemia Survivors

OBJECTIVE Examine academic achievement among pediatric acute lymphoblastic leukemia survivors diagnosed during the years 1993-2008. METHOD A deterministic linkage of the Iowa Cancer Registry and Iowa Testing Programs databases was performed and yielded 147 survivors. Achievement data, in the form of Iowa Percentile Rank scores, were obtained and analyzed by grade and content domain. RESULTS Children diagnosed before age 5 evidenced more underachievement than those diagnosed later (p = .05). Underachievement was noted in mathematics in grades 8 and 11 (ps < .05), in addition to a longitudinal decrease in scores from grades 4 through 11 (p = .01). No differences were found in academic achievement between males and females. CONCLUSIONS Utilization of a population-based approach with a nationally recognized, standardized instrument indicates that academic underachievement is subtle yet exists, most notably in mathematics.

Early-life course socioeconomic factors and chronic kidney disease.

Kidney failure or ESRD affects approximately 650,000 Americans, whereas the number with earlier stages of CKD is much higher. Although CKD and ESRD are usually associated with adulthood, it is likely that the initial stages of CKD begin early in life. Many of these pathways are associated with low birth weight and disadvantaged socioeconomic status (SES) in childhood, translating childhood risk into later-life CKD and kidney failure. Social factors are thought to be fundamental causes of disease. Although the relationship between adult SES and CKD has been well established, the role of early childhood SES for CKD risk remains obscure. This review provides a rationale for examining the association between early-life SES and CKD. By collecting data on early-life SES and CKD, the interaction with other periods in the life course could also be studied, allowing for examination of whether SES trajectories (eg, poverty followed by affluence) or cumulative burden (eg, poverty at multiple time points) are more relevant to lifetime CKD risk.

Peritoneal dialysis in an extremely low-birth-weight infant with acute kidney injury.

Critically ill neonates are at high risk for acute kidney injury (AKI). Renal supportive therapy (RST) can be an important tool for supporting critically ill neonates with AKI, particularly in cases of oliguria and fluid overload. There are few reports of RST for management of oligo-anuric AKI in the extremely low-birth-weight infant weighing <1000 g. We report successful provision of peritoneal dialysis (PD) to an 830-g neonate with oligo-anuric AKI through adaptation of a standard pediatric acute PD catheter.

ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients.

Congenital disorders of glycosylation (CDG) arise from pathogenic mutations in over 100 genes leading to impaired protein or lipid glycosylation. ALG1 encodes a β1,4 mannosyltransferase that catalyzes the addition of the first of nine mannose moieties to form a dolichol‐lipid linked oligosaccharide intermediate required for proper N‐linked glycosylation. ALG1 mutations cause a rare autosomal recessive disorder termed ALG1‐CDG. To date 13 mutations in 18 patients from 14 families have been described with varying degrees of clinical severity. We identified and characterized 39 previously unreported cases of ALG1‐CDG from 32 families and add 26 new mutations. Pathogenicity of each mutation was confirmed based on its inability to rescue impaired growth or hypoglycosylation of a standard biomarker in an alg1‐deficient yeast strain. Using this approach we could not establish a rank order comparison of biomarker glycosylation and patient phenotype, but we identified mutations with a lethal outcome in the first two years of life. The recently identified protein‐linked xeno‐tetrasaccharide biomarker, NeuAc‐Gal‐GlcNAc2, was seen in all 27 patients tested. Our study triples the number of known patients and expands the molecular and clinical correlates of this disorder.

Chronic Kidney Disease: A Life Course Health Development Perspective

Chronic kidney disease (CKD) reflects life events that range from maternal-fetal influences to geriatric exposures. The global direct and indirect costs of CKD are high and include maternal-neonatal hospitalization and treatment, acute kidney injury, dialysis and transplant, missed work, and medications, to name a few. The impact of poor diet, adverse childhood experiences, medication use, and failure to follow consistent public health standards are increasingly appreciated as key influences in the development of CKD. Socioeconomic factors can significantly influence the timing and phenotypic expression in people at risk for developing CKD, although more research is needed to understand these mechanisms. In general, biomedicine has been focused on treating well-established CKD morbidity. This strategy has been short sighted and costly. A more cost-effective approach would focus on early life interventions that hold the potential for mitigating CKD risk and its sequelae. This chapter applies the life course health development principles to review determinants and pathways for CKD evolution and identifies of the gaps in our knowledgebase. We also discuss several research strategies for evaluating the life course health development of CKD.

Neonatal Hyperammonemia and Continuous Renal Replacement Therapy

Abstract Neonatal hyperammonemia is a life-threatening condition that may be refractory to standard medical management with a need to use sophisticated dialysis modalities, including continuous renal replacement therapy. Use of continuous renal replacement and high-dose (high-flow) dialysate rates can provide rapid clearance of ammonia within 12 to 24 hours to reduce risk of neurologic sequelae with less potential for rebound of ammonia levels as seen with hemodialysis.

Intradialytic Hypotension: Potential Causes and Mediating Factors

Common causes of intradialytic hypotension include excessive ultrafiltration and/or use of antihypertensive medications prior to initiation of a hemodialysis treatment. An expanded differential diagnosis and evaluation may be required in cases of critically ill patients on hemodialysis – particularly those showing poor fluid responsiveness, elevation in lactate, or neurological changes. Care of the critically ill population mandates the need to be particularly aware of rare causes of intradialytic hypotension given preexistent malnutrition and accelerated clearance of water-soluble molecules as a result of renal replacement therapy.

Congenital nephrotic syndrome in an infant with ALG1-congenital disorder of glycosylation.

Congenital nephrotic syndrome (NS) in the newborn is most frequently related to mutations in genes specific for structural integrity of the glomerular basement membrane and associated filtration structures within the kidney, resulting in massive leakage of plasma proteins into the urine. Occurrence of congenital NS in a multi‐system syndrome is less common. We describe the case of an infant with deteriorating neurological status, seizures, edema, and proteinuria who was found to have a mutation in gene ALG1 and a renal biopsy consistent with congenital NS. Furthermore, we briefly review rare existing case reports documenting congenital NS in patients with mutations in ALG1, and treatment strategies, including novel use of peritoneal dialysis.

Management of Pediatric Acute Kidney Injury

Targeted management and therapy for acute kidney injury (AKI) remains challenging. Much of the care for pediatric AKI to date remains supportive in nature. Earlier detection of AKI may allow intervention with fluid management measures before AKI is fully established, thus allowing the clinician to move beyond supportive care and improve outcomes. Early identification of patients at risk to develop AKI, optimizing fluid and electrolyte status, and avoidance of nephrotoxins are key points in early goal directed management of AKI. Fluid overloaded states may develop in AKI and early renal replacement therapy intervention should be strongly considered to ameliorate and/or allow for correction of volume disturbance and metabolic derangement and permit adequate nutrition to the critically ill pediatric patient.