Nephrocalcinosis in Neonates.

Nephrocalcinosis occurs in as many as 40% of preterm neonates. Many causes and contributors predispose neonates to develop nephrocalcinosis, including metabolic, genetic, and iatrogenic factors. Because nephrocalcinosis can be a manifestation of an underlying genetic disorder, neonates with nephrocalcinosis must undergo an evaluation to identify and address contributors, to prevent further renal calcium deposition that can potentially lead to renal dysfunction. In this article, we review the epidemiology, pathogenesis, diagnosis, and evaluation of nephrocalcinosis in neonates. We also summarize the natural history of nephrocalcinosis of prematurity as well as the management of this condition.

Association between Psychiatric Disorders and Glomerular Disease.

Introduction: Patients with chronic health conditions, particularly chronic kidney disease, are at heightened risk for psychiatric disorders; yet, there are limited data on those with primary glomerular disease. Methods: This study included patients with glomerular disease enrolled in the kidney research network multisite patient registry. Registry data include encounter, diagnoses, medication, laboratory, and vital signs data extracted from participants' electronic health records. ICD-9/10 diagnosis codes were used to identify a subset of psychiatric disorders focused on anxiety, mood, and behavioral disorders. Time-varying Cox proportional hazard models were used to analyze time from the onset of kidney disease to diagnosis of psychiatric disorder. Adjusted models retained significant covariates from the full list of potential confounders, including age, sex, race, ethnicity, time-varying treatment, the estimated glomerular filtration rate, and proteinuria (urine protein-to-creatinine ratio [UPCR]). Analogous models examined diagnosis of psychiatric disorder as a predictor of time to end-stage kidney disease (ESKD). Results: Data were available for 950 participants, with a median of 58 months of follow-up. 110 (12%) participants were diagnosed with psychiatric disorder during the follow-up. The estimated rate of psychiatric diagnosis after kidney disease was 14.7 cases per 1,000 person-years and was highest among those of adolescent age at the time of kidney disease diagnosis. Adjusted analyses found adolescent age (vs. adult, hazard ratio [HR] = 3.11, 95% confidence interval [CI] 1.87-5.17) and Asian race (vs. white, HR = 0.34, 95% CI 0.16-0.71) were associated with psychiatric diagnosis. A higher UPCR per 1 log unit (HR 1.13, 95% CI 1.01-1.27) and a higher total number of oral medications were associated with psychiatric disorder (p < 0.001). Psychiatric diagnosis was also associated with progression to ESKD (HR = 2.45, 95% CI 1.53-3.92) in adjusted models. Discussion/Conclusion: Psychiatric disorders were documented in approximately one-eighth of patients with glomerular disease and correlated with clinical disease characteristics such as age, race, proteinuria, and oral medication burden. These findings suggest mental health screening is warranted in patients of all ages with glomerular disease.

Time to Initiation of Antihypertensive Therapy After Onset of Elevated Blood Pressure in Patients With Primary Proteinuric Kidney Disease.

RATIONALE & OBJECTIVE: The objective of the study was to estimate the prevalence of hypertension in patients with proteinuric kidney disease and evaluate blood pressure (BP) control. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Data from adults and children with proteinuric kidney disease enrolled in the multicenter Kidney Research Network Registry were used for this study. EXPOSURE: Proteinuric kidney disease. OUTCOMES: Hypertension and BP control. ANALYTICAL APPROACH: Patients with white-coat hypertension were excluded. Patients were censored at end-stage kidney disease onset. Patients were defined as hypertensive either by hypertension diagnosis code, having 2 or more encounters with elevated BPs, or treatment with antihypertensive therapy excluding renin-angiotensin-aldosterone system blockade. Elevated BP was defined as greater than 95th percentile for children and >140/90 mm Hg in adults. Sustained BP control was defined as 2 or more consecutive encounters with BPs lower than 95th percentile for children and <140/90 mm Hg for adults. Kaplan-Meier and Cox proportional hazards analyses were used to evaluate the time to initiation of antihypertensive therapy. RESULTS: 842 patients, 69% adults and 31% children, with a total observation period of 6,722 patient-years were included in the analysis. 644 (76%) had hypertension during observation. There was no difference in the prevalence of hypertension between children and adults (74% vs 78%; P = 0.3). Hypertension was most common among those of African American race compared with other races (90% vs 72%-75%; P = 0.003). 504 (78%) patients with hypertension achieved BP control but only 51% achieved control within 1 year. 140 (22%) patients with hypertension never achieved BP control during a median of 41 (IQR, 24-73) months of observation. LIMITATIONS: Differing BP control goals that may lead to overestimation of the controlled patient population. CONCLUSIONS: Hypertension affects most patients with proteinuric kidney disease regardless of age. Time to BP control exceeded 1 year in 50% of patients with hypertension and 22% did not demonstrate control. This study highlights the need to address hypertension early and completely in disease management of patients with proteinuric kidney disease.

Myelin bodies in LMX1B-associated nephropathy: potential for misdiagnosis.

BACKGROUND: Myelin figures, or zebra bodies, seen on electron microscopy were historically considered pathognomonic of Fabry disease, a rare lysosomal storage disorder caused by alpha-galactosidase A deficiency and associated with X-linked recessive mode of inheritance. More recently, iatrogenic phospholipidosis has emerged as an important alternate cause of myelin figures in the kidney. METHODS: We report two families with autosomal dominant nephropathy presenting with proteinuria and microscopic hematuria, and the kidney biopsies were notable for the presence of myelin figures and zebra bodies. RESULTS: Laboratory and genetic work-up for Fabry disease was negative. Genetic testing in both families revealed the same heterozygous missense mutation in LMX1B (C.737G>A, p.Arg246Gln). LMX1B mutations are known to cause nail-patella syndrome, featuring dysplastic nails and patella with or without nephropathy, as well as isolated LMX1B-associated nephropathy in the absence of extrarenal manifestations. CONCLUSIONS: LMX1B mutation-associated nephropathy should be considered in hereditary cases of proteinuria and/or hematuria, even in the absence of unique glomerular basement membrane changes indicative of nail-patella syndrome. In addition, LMX1B mutation should be included in the differential diagnosis of myelin figures and zebra bodies on kidney biopsy, so as to avoid a misdiagnosis.

Urinary Epidermal Growth Factor as a Marker of Disease Progression in Children With Nephrotic Syndrome.

INTRODUCTION: Childhood-onset nephrotic syndrome has a variable clinical course. Improved predictive markers of long-term outcomes in children with nephrotic syndrome are needed. This study tests the association between baseline urinary epidermal growth factor (uEGF) excretion and longitudinal kidney function in children with nephrotic syndrome. METHODS: The study evaluated 191 participants younger than 18 years enrolled in the Nephrotic Syndrome Study Network, including 118 with their first clinically indicated kidney biopsy (68 minimal change disease; 50 focal segmental glomerulosclerosis) and 73 with incident nephrotic syndrome without a biopsy. uEGF was measured at baseline for all participants and normalized by the urine creatinine (Cr) concentration. Renal epidermal growth factor (EGF) mRNA was measured in the tubular compartment microdissected from kidney biopsy cores from a subset of patients. Linear mixed models were used to test if baseline uEGF/Cr and EGF mRNA expression were associated with change in estimated glomerular filtration rate (eGFR) over time. RESULTS: Higher uEGF/Cr at baseline was associated with slower eGFR decline during follow-up (median follow-up = 30 months). Halving of uEGF/Cr was associated with a decrease in eGFR slope of 2.0 ml/min per 1.73 m2 per year (P < 0.001) adjusted for age, race, diagnosis, baseline eGFR and proteinuria, and APOL1 genotype. In the biopsied subgroup, uEGF/Cr was correlated with EGF mRNA expression (r = 0.74; P < 0.001), but uEGF/Cr was retained over mRNA expression as the stronger predictor of eGFR slope after multivariable adjustment (decrease in eGFR slope of 1.7 ml/min per 1.73 m2 per year per log2 decrease in uEGF/Cr; P < 0.001). CONCLUSION: uEGF/Cr may be a useful noninvasive biomarker that can assist in predicting the long-term course of kidney function in children with incident nephrotic syndrome.

Pediatric Immunization Practices in Nephrotic Syndrome: An Assessment of Provider and Parental Knowledge.

Background: Children with nephrotic syndrome (NS) are at high risk for vaccine-preventable infections due to the immunological effects from the disease and concurrent treatment with immunosuppressive medications. Immunizations in these patients may be deferred due to their immunosuppressive treatment which may increase the risk for vaccine-preventable infections. Immunization practices in children with NS continue to vary among pediatric nephrologists. This raises the question of whether children with NS are receiving the recommended vaccinations at appropriate times. Therefore, it is critical to understand the practices and patient education provided by physicians to patients on the topic of vaccinations. Methods: After informed consent, parents/guardians of 153 pediatric patients (<18 years old) diagnosed with NS from 2005 to 2018 and 50 pediatric nephrologists from 11 participating centers completed anonymous surveys to evaluate immunization practices among pediatric nephrologists, assess the vaccine education provided to families of children with NS, assess the parental knowledge of immunization recommendations, and assess predictors of polysaccharide pneumococcal vaccine adherence. The Advisory Committee on Immunization Practices (ACIP) Immunization 2019 Guideline for those with altered immunocompetence was used to determine accuracy of vaccine knowledge and practices. Results: Forty-four percent of providers self-reported adherence to the ACIP guidelines for inactive vaccines and 22% to the guidelines for live vaccines. Thirty-two percent of parents/guardians reported knowledge that aligned with the ACIP guidelines for inactive vaccines and 1% for live vaccines. Subjects residing in the Midwest and provider recommendations for vaccines were positive predictors of vaccine adherence (p < 0.001 and p 0.02, respectively). Conclusions: Vaccine recommendation by medical providers is paramount in vaccine adherence among pediatric patients with NS. This study identifies potential educational opportunities for medical subspecialty providers and family caregivers about immunization recommendations for immunosuppressed patients.

Text Messaging for Disease Monitoring in Childhood Nephrotic Syndrome.

INTRODUCTION: There is limited information on effective disease monitoring for prompt interventions in childhood nephrotic syndrome. We examined the feasibility and effectiveness of a novel text messaging system (SMS) for disease monitoring in a multicenter, prospective study. METHODS: A total of 127 patients <19 years with incident nephrotic syndrome were enrolled in the ongoing Nephrotic Syndrome Study Network between June 2015 and March 2018. Text messages soliciting home urine protein results, symptoms, and medication adherence were sent to a designated caregiver (n = 116) or adolescent patient (n = 3). Participants responded by texting. Feasibility of SMS was assessed by SMS adoption, retention, and engagement, and concordance between participant-reported results and laboratory/clinician assessments. The number of disease relapses and time-to-remission data captured by SMS were compared with data collected by conventional visits. RESULTS: A total of 119 of 127 (94%) patients agreed to SMS monitoring. Retention rate was 94%, with a median follow-up of 360 days (interquartile range [IQR] 353-362). Overall engagement was high, with a median response rate of 87% (IQR, 68-97). Concordance between SMS-captured home urine protein results and edema status with same-day in-person study visit was excellent (kappa values 0.88 and 0.92, respectively). SMS detected a total of 108 relapse events compared with 41 events captured by scheduled visits. Median time to remission after enrollment was 22 days as captured by SMS versus 50 days as captured by scheduled visits. CONCLUSION: SMS was well accepted by caregivers and adolescent patients and reliably captured nephrotic syndrome disease activity between clinic visits. Additional studies are needed to explore the impact of SMS on disease outcomes.

Steroid-Associated Side Effects in Patients With Primary Proteinuric Kidney Disease.

INTRODUCTION: The goal of this study was to assess the occurrence of steroid-associated adverse events (SAAE) in patients with primary proteinuric kidney disease. METHODS: The Kidney Research Network Registry consists of children and adults with primary proteinuric kidney disease. SAAEs of interest were hypertension, hyperglycemia and diabetes, overweight and obesity, short stature, ophthalmologic complications, bone disorders, infections, and psychosis. Events were identified using International Classification of Diseases, Ninth Revision/Tenth Revision codes, blood pressures, growth parameters, laboratory values, and medications. Poisson generalized estimating equations tested the association between steroid onset and dose on SAAE risk. RESULTS: A total of 884 participants were included in the analysis; 534 (60%) were treated with steroids. Of these, 62% had at least one SAAE. The frequency of any SAAE after initiation of steroids was 293 per 1000 person-years. The most common SAAEs were hypertension (173.7 per 1000 person-years), diabetes (78.7 per 1000 person-years), obesity (66.8 per 1000 person-years), and infections (46.1 per 1000 person-years). After adjustment for demographics, duration of kidney disease, estimated glomerular filtration rate (eGFR), proteinuria, and other therapies, steroid exposure was associated with a 40% increase in risk of any SAAE (Relative risk [RR]: 1.4; 95% confidence interval [CI]: 1.3-1.6). A 1-mg/kg per day increase in steroid dose was associated with a 2.5-fold increase in risk of any SAAE. CONCLUSION: Most patients with primary proteinuric kidney disease treated with steroids experienced at least one SAAE. Steroid therapy increased risk of hypertension, diabetes, weight gain, short stature, fractures, and infections after adjusting for disease-related factors. This study highlights the importance of surveillance and management of SAAE and provides rationale for the development of steroid minimization protocols.

NephCure Accelerating Cures Institute: A Multidisciplinary Consortium to Improve Care for Nephrotic Syndrome.

INTRODUCTION: NephCure Accelerating Cures Institute (NACI) is a collaborative organization sponsored by NephCure Kidney International and the University of Michigan. The Institute is composed of 7 cores designed to improve treatment options and outcomes for patients with glomerular disease: Clinical Trials Network, Data Warehouse, Patient-Reported Outcomes (PRO) and Endpoints Consortium, Clinical Trials Consulting Team, Quality Initiatives, Education and Engagement, and Data Coordinating Center. METHODS: The Trials Network includes 22 community- and hospital-based nephrology practices, 14 of which are trial-only sites. Eight sites participate in the NACI Registry, and as of October 2017, 1054 patients are enrolled with diagnoses including but not limited to focal segmental glomerulosclerosis, minimal change disease, membranous nephropathy, IgA nephropathy, and childhood-onset nephrotic syndrome. By using electronic health record data extraction, robust and efficient clinical data are captured while minimizing the burden to site-based network staff. RESULTS: The Data Warehouse includes her-extracted data from registry patients, PRO development data, and data from completed observational studies and clinical trials. The Clinical Trial Consulting Team provides support for trial design in rare diseases leveraging these data. The PRO and Endpoints Consortium develops shorter-term endpoints while capturing the patient-reported significance of interventions under study. The Quality Initiatives and Education/Engagement cores elevate the level of care for patients. The Data Coordinating Center manages the analysis and operations of the Institute. CONCLUSION: By engaging with patients, academia, industry, and patient advocate community representatives, including our Patient Advisory Board, NACI strives for better outcomes and treatments using evidence-based support for clinical trial design.

An Outcomes-Based Definition of Proteinuria Remission in Focal Segmental Glomerulosclerosis.

BACKGROUND AND OBJECTIVES: Proteinuria is used as an indicator of FSGS disease activity, but its use as a clinical trial end point is not universally accepted. The goal of this study was to refine proteinuria definitions associated with long-term kidney survival. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data on 466 patients with primary FSGS with proteinuria (urine protein-to-creatinine ratio >1 g/g) were analyzed from five independent cohorts. Proteinuria by months 1, 4, and 8 after study baseline was categorized by conventional definitions of complete (<0.3 g/g) and partial remission (<3.5 g/g and 50% reduction in proteinuria). Novel remission definitions were explored using receiver operating curves. Kaplan-Meier methods were used to estimate the associations of proteinuria with progression to ESRD or a 50% loss in kidney function. Propensity score-adjusted Cox proportional hazards models were used to adjust for baseline proteinuria, eGFR, and therapy. RESULTS: In the initial derivation cohort, conventional partial remission was not associated with kidney survival. A novel definition of partial remission (40% proteinuria reduction and proteinuria<1.5 g/g) on the basis of receiver operating curve analyses of 89 patients was identified (Sensitivity=0.70; Specificity=0.77). In the validation cohort analyses, complete remission was associated with better prognosis (6 out of 41 patients progressed to kidney failure; 6.6 per 100 patient-years) as was the novel partial remission (13 out of 71 progressed; 8.5 per 100 patient-years), compared with those with no response (51 out of 116 progressed; 20.1 per 100 patient-years). Conventional partial remission at month 8, but not month 4, was also associated with better response (19 out of 85 patients progressed; risk=10.4 per 100 patient-years). Propensity score-adjusted analyses showed the novel partial remission was associated with less progression at months 4 and 8 (month 4: hazard ratio, 0.50; P=0.01; month 8: hazard ratio, 0.30; P=0.002). CONCLUSIONS: Reaching either a complete or partial remission using a novel or conventional definition was associated with better long-term outcomes in patients with FSGS. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_02_20_CJASNPodcast_18_3_T.mp3.

Expanding the phenotype of hawkinsinuria: new insights from response to N-acetyl-L-cysteine.

Hawkinsinuria is a rare disorder of tyrosine metabolism that can manifest with metabolic acidosis and growth arrest around the time of weaning off breast milk, typically followed by spontaneous resolution of symptoms around 1 year of age. The urinary metabolites hawkinsin, quinolacetic acid, and pyroglutamic acid can aid in identifying this condition, although their relationship to the clinical manifestations is not known. Herein we describe clinical and laboratory findings in two fraternal twins with hawkinsinuria who presented with failure to thrive and metabolic acidosis. Close clinical follow-up and laboratory testing revealed previously unrecognized hypoglycemia, hypophosphatemia, combined hyperlipidemia, and anemia, along with the characteristic urinary metabolites, including massive pyroglutamic aciduria. Treatment with N-acetyl-L-cysteine (NAC) restored normal growth and normalized or improved most biochemical parameters. The dramatic response to NAC therapy supports the idea that glutathione depletion plays a key role in the pathogenesis of hawkinsinuria.

Perioperative fluid management and postoperative hyponatremia in children.

Intravenous (IV) fluids are used ubiquitously when children undergo surgical procedures. Until recently, Holliday and Segar's guidelines for calculating maintenance fluids dictated fluid management strategies in postoperative pediatric patients. An increased recognition of hospital-acquired hyponatremia and its associated morbidity has led to a critical re-examination of IV fluid management in this population. Postsurgical patients are at high risk of developing hyponatremia due to the presence of non-osmotic stimuli for antidiuretic hormone release. Recent studies have established that, as they are administered in current practice, hypotonic maintenance fluids are associated with increased rates of hyponatremia. The best available data demonstrate that administration of isotonic fluid reduces hyponatremic risk. In this review, we discuss the collective data available on the subject and offer guidelines for fluid management and therapeutic monitoring.

Whole-body single-frequency bioimpedance analysis in pediatric hemodialysis patients.

BACKGROUND: We hypothesized that the percent change in resistance (%RΔ) from bioimpedance analysis (BIA) measurements during hemodialysis (HD) can provide information on pediatric HD patients' hydration status. METHODS: Whole-body single-frequency BIA measurements were obtained before HD, each hour on HD, and after HD during two HD sessions. Pre-and post-HD weights, blood pressures, Crit-Line® measurements, and intradialytic symptoms were collected on the day of the BIA measurements. RESULTS: One hundred and thirty BIA measurements were obtained from 14 HD patients. The group was 43 % girls, and the mean age was 13.2 ± 4.4 years. Percent change in resistance was 13.5 ± 10.8 % at the end of HD; %RΔ correlated with percent body weight change (%BWΔ) following HD (r = -0.83, P < 0.01), as well as with percent blood volume change (%BVΔ) (r = -0.79, P < 0.01). The %RΔ was similar between patients with and without hypertension immediately before HD and was greater in those with intradialytic symptoms (19.1 ± 7.7 %) than in those without (9.9 ± 11.2 %) (P = 0.02). Patients with left ventricular hypertrophy (LVH) had lower %RΔ (7.2 ± 9.7 %) than those without (19.5 ± 7.7 %) (P = 0.03). Left ventricular mass index (LVMI) also correlated strongly with %RΔ (r = -0.79, P = 0.004) and %BWΔ (r = 0.82, P = 0.002). CONCLUSIONS: Our study showed that %RΔ strongly correlates with %BWΔ and %BVΔ and that %RΔ also correlated with intradialytic symptoms and LVMI.

Characteristics of children with sporadic hemolytic uremic syndrome in a single Northern California center.

PURPOSE: Hemolytic uremic syndrome (HUS) is a frequent cause of acute kidney injury in children. The aim of this study is to describe our experience at a Northern California center. METHODS: Medical records of children suffered from HUS (08/99 to 03/09) at University of California Davis Medical Center were reviewed. RESULTS: Forty-six children (70% girls) were studied, and their median age was 3.5 years. Diarrhea was a presenting symptom in 42 subjects (91%), and hematochezia was present in 31 children (67%). Escherichia coli 0157:H7 was isolated in 20 patients (44%). Thirteen subjects (28%) underwent dialysis for a median of 7 days during their hospitalization. Follow-up was achieved in 36 patients (78.3%) for a median of 16 months. One patient required angiotensin-converting enzyme (ACE) inhibitor for proteinuria but none was on dialysis. CONCLUSIONS: In our cohort in children with HUS in a single Californian center, long-term complications were uncommon during a median follow-up time of 16 months.

Heterogeneity within the Asian American community.

BACKGROUND: Educational interventions are grounded on scientific data and assumptions about the community to be served. While the Pan Asian community is composed of multiple, ethnic subgroups, it is often treated as a single group for which one health promotion program will be applicable for all of its cultural subgroups. Compounding this stereotypical view of the Pan Asian community, there is sparse data about the cultural subgroups' similarities and dissimilarities. The Asian Grocery Store based cancer education program evaluation data provided an opportunity to compare data collected under identical circumstances from members of six Asian American cultural groups. METHODS: A convenience sample of 1,202 Asian American women evaluated the cultural alignment of a cancer education program, completing baseline and follow-up surveys that included questions about their breast cancer knowledge, attitudes, and screening behaviors. Participants took part in a brief education program that facilitated adherence to recommended screening guidelines. RESULTS: Unique recruitment methods were needed to attract participants from each ethnic group. Impressions gained from the aggregate data revealed different insights than the disaggregate data. Statistically significant variations existed among the subgroups' breast cancer knowledge, attitudes, and screening behaviors that could contribute to health disparities among the subgroups and within the aggregate Pan Asian community. CONCLUSION: Health promotion efforts of providers, educators, and policy makers can be enhanced if cultural differences are identified and taken into account when developing strategies to reduce health disparities and promote health equity.