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Introduction Glomerular diseases are characterized by variable disease activity over many years. We aimed to analyze the relationship between clinical disease activity and duration of glomerular disease. Methods Disease activity in adults with chronic minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and IgA nephropathy (IgAN; first diagnostic biopsy >5 years before enrollment; Of Longstanding Disease [OLD] cohort, n = 256) followed at Columbia University Medical Center (CUMC), was compared with disease activity of an internal and external cohort of patients with first diagnostic biopsy, Graphical abstract

IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. We performed a genome-wide association study involving 10,146 kidney biopsy-diagnosed IgAN cases and 28,751 matched controls across 17 international cohorts. We defined 30 independent genome-wide significant risk loci jointly explaining 11% of disease risk. A total of 16 loci were novel, including TNFSF4, REL, CD28, CXCL8/PF4V1, LY86, LYN, ANXA3, TNFSF8/15, REEP3, ZMIZ1, RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The SNP-based heritability of IgAN was estimated at 23%. We observed a positive genetic correlation between IgAN and total serum IgA levels, allergy, tonsillectomy, and several infections, and a negative correlation with inflammatory bowel disease. All significant non-HLA loci shared with serum IgA levels had a concordant effect on the risk of IgAN. Moreover, IgAN loci were globally enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. The explained heritability was enriched in the regulatory elements of cells from the immune and hematopoietic systems and intestinal mucosa, providing support for the pathogenic role of extra-renal tissues. The polygenic risk of IgAN was associated with early disease onset, increased lifetime risk of kidney failure, as well as hematuria and several other traits in a phenome-wide association study of 590,515 individuals. In the comprehensive functional annotation analysis of candidate causal genes across genome-wide significant loci, we observed the convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand-receptor pairs, prioritizing potential new drug targets.

Purpose of the program: This article provides guidance on optimizing the management of pediatric patients with end-stage kidney disease (ESKD) who will be or are being treated with any form of home or in-center dialysis during the COVID-19 pandemic. The goals are to provide the best possible care for pediatric patients with ESKD during the pandemic and ensure the health care team’s safety. Sources of information: The core of these rapid guidelines is derived from the Canadian Society of Nephrology (CSN) consensus recommendations for adult patients recently published in the Canadian Journal of Kidney Health and Disease ( CJKHD). We also consulted specific documents from other national and international agencies focused on pediatric kidney health. Additional information was obtained by formal review of the published academic literature relevant to pediatric home or in-center hemodialysis. Methods: The Leadership of the Canadian Association of Paediatric Nephrologists (CAPN), which is affiliated with the CSN, solicited a team of clinicians and researchers with expertise in pediatric home and in-center dialysis. The goal was to adapt the guidelines recently adopted for Canadian adult dialysis patients for pediatric-specific settings. These included specific COVID-19-related themes that apply to dialysis in a Canadian environment, as determined by a group of senior renal leaders. Expert clinicians and nurses with deep expertise in pediatric home and in-center dialysis reviewed the revised pediatric guidelines. Key findings: We identified 7 broad areas of home dialysis practice management that may be affected by the COVID-19 pandemic: (1) peritoneal dialysis catheter placement, (2) home dialysis training, (3) home dialysis management, (4) personal protective equipment, (5) product delivery, (6) minimizing direct health care providers and patient contact, and (7) caregivers support in the community. In addition, we identified 8 broad areas of in-center dialysis practice management that may be affected by the COVID-19 pandemic: (1) identification of patients with COVID-19, (2) hemodialysis of patients with confirmed COVID-19, (3) hemodialysis of patients not yet known to have COVID-19, (4) management of visitors to the dialysis unit, (5) handling COVID-19 testing of patients and staff, (6) safe practices during resuscitation procedures in a pandemic, (7) routine hemodialysis care, and (8) hemodialysis care under fixed dialysis resources. We make specific suggestions and recommendations for each of these areas. Limitations: At the time when we started this work, we knew that evidence on the topic of pediatric dialysis and COVID-19 would be severely limited, and our resources were also limited. We did not, therefore, do formal systematic review or meta-analysis. We did not evaluate our specific suggestions in the clinical environment. Thus, this article’s advice and recommendations are primarily expert opinions and subject to the biases associated with this level of evidence. To expedite the publication of this work, we created a parallel review process that may not be as robust as standard arms’ length peer-review processes. Implications: We intend these recommendations to help provide the best care possible for pediatric patients prescribed in-center or home dialysis during the COVID-19 pandemic, a time of altered priorities and reduced resources.

Objectives: This study aims to assess the feasibility of using hemofiltration for ammonia clearance in low body weight infants with an inborn error of metabolism.Design: A study of two cases.Setting: Quaternary pediatric hospital (Saint Louis Children's Hospital) NICU and PICU.Patients: Infants Interventions: Continuous renal replacement therapy (CRRT).Measurements and Main Results: We measure serum ammonia levels over time and the rate of ammonia clearance over time. Continuous renal replacement therapy was more effective than scavenger therapy alone (Ammonul™) for rapid removal of ammonia in low weight infants (as low as 2.5 kg).Conclusions: Continuous renal replacement therapy is technically feasible in low weight infants with severe hyperammonemia secondary to an inborn error of metabolism.

International guidelines suggest a target culture-negative peritonitis rate of15% among patients receiving long-term peritoneal dialysis. Through a pediatric multicenter dialysis collaborative, we identified variable rates of culture-negative peritonitis among participating centers. We sought to evaluate whether specific practices are associated with the variability in culture-negative rates between low- and high-culture-negative rate centers.Thirty-two pediatric dialysis centers within the Standardizing Care to Improve Outcomes in Pediatric End Stage Renal Disease (SCOPE) collaborative contributed prospective peritonitis data between October 1, 2011 and March 30, 2017. Clinical practice and patient characteristics were compared between centers with a ≤20% rate of culture-negative peritonitis (low-rate centers) and centers with a rate20% (high-rate centers). In addition, centers completed a survey focused on center-specific peritoneal dialysis effluent culture techniques.During the 5.5 years of observation, 1113 patients had 1301 catheters placed, totaling 19,025 patient months. There were 620 episodes of peritonitis in 378 patients with 411 catheters; cultures were negative in 165 (27%) peritonitis episodes from 125 (33%) patients and 128 (31%) catheters. Low-rate centers more frequently placed catheters with a downward-facing exit site and two cuffs (Culture-negative peritonitis is a frequent complication of maintenance peritoneal dialysis in children. Despite published recommendations for dialysis effluent collection and culture methods, great variability in culture techniques and procedures exists among individual dialysis programs and respective laboratory processes.

Background: Neonates with serum creatinine (SCr) rise ≥ 0.3 mg/dL and/or 50% SCr rise are more likely to die, even when controlling for confounders. These thresholds have not been tested in newborns. We hypothesized that different gestational age (GA) groups require different SCr thresholds. Methods: Neonates in Assessment of Worldwide Acute Kidney Epidemiology in Neonates (AWAKEN) with ≥1 SCr on postnatal days 1–2 and ≥1 SCr on postnatal days 3–8 were assessed. We compared the mortality predictability of SCr absolute (≥0.3 mg/dL) vs percent (≥50%) rise. Next, we determine usefulness of combining absolute with percent rise. Finally, we determined the optimal absolute, percent, and maximum SCr thresholds that provide the highest mortality area under curve (AUC) and specificity for different GA groups. Results: The ≥0.3 mg/dL rise outperformed ≥50% SCr rise. Addition of percent rise did not improve mortality predictability. The optimal SCr thresholds to predict AUC and specificity were ≥0.3 & ≥0.6 mg/dL for ≤29 weeks GA, and ≥0.1 & ≥0.3 mg/dL for >29 week GA. The maximum SCr value provides great specificity. Conclusion: Unique SCr rise cutoffs for different GA improves outcome prediction. Percent SCr rise does not add value to the neonatal AKI definition.

A 3,250-g term infant is born via cesarean delivery to a gravida 1, para 0 woman at a community hospital. There are no complications during pregnancy. All maternal serologic test results are negative, including indirect Coombs, rubella, rapid plasma reagin, hepatitis B surface antigen, human immunodeficiency virus, Gonorrhea , Chlamydia , and group B Streptococcus . The infant is delivered via cesarean section because of a failure to progress during induction of labor. Apgar scores are 8 and 9 at 1 and 5 minutes, respectively. Growth parameters for weight, length, and orbitofrontal circumference are within the expected range for gestational age. Physical examination is notable for ambiguous genitalia with an enlarged clitoris with prepuce, enlarged labia majora bilaterally, and small labia minora bilaterally. No testicles are palpated within the inguinal canal. The infant is transferred to the NICU. Abdominal and pelvic ultrasonography reveals normal-appearing adrenal glands, a normal-appearing uterus, and an absence of intra-abdominal gonads. A congenital adrenal hyperplasia (CAH) panel reveals normal levels of androstenedione, cortisol, dehydroepiandrosterone serum, deoxycorticosterone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, testosterone, and 11-deoxycortisol. It reveals a markedly elevated level of progesterone of 261 ng/dL (830 nmol/L; normal range for our laboratory is

BACKGROUND AND OBJECTIVES: Steroid resistant nephrotic syndrome (SRNS) due to focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) is a leading cause of end stage kidney disease in children. Recurrence of primary disease following transplantation is a major cause of allograft loss. The clinical determinants of disease recurrence are not completely known. Our objectives were to determine risk factors for recurrence of FSGS/MCD following kidney transplantation, and factors that predict response to immunosuppression following recurrence. STUDY DESIGN: Multicenter study of pediatric patients with kidney transplants performed for ESKD due to SRNS between 1/2006–12/2015. Demographics, clinical course, and biopsy data were collected. Patients with primary-SRNS (PSRNS) were defined as those initially resistant to corticosteroid therapy at diagnosis, and patients with late-SRNS (LSRNS) as those initially responsive to steroids who subsequently developed steroid resistance. We performed logistic regression to determine risk factors associated with nephrotic syndrome (NS) recurrence. RESULTS: We analyzed 158 patients; 64 (41%) had recurrence of NS in their renal allograft. Disease recurrence occurred in 78% of patients with LSRNS compared to 39% of those with PSRNS. Patients with MCD on initial native kidney biopsy had a 76% recurrence rate compared with a 40% recurrence rate in those with FSGS. Multivariable analysis showed that MCD histology (OR; 95% CI: 5.6; 1.3–23.7) compared to FSGS predicted disease recurrence. CONCLUSIONS: Pediatric patients with MCD and LSRNS are at higher risk of disease recurrence following kidney transplantation. These findings may be useful for designing studies to test strategies for preventing recurrence.

RATIONALE & OBJECTIVE: The KDIGO (Kidney Disease: Improving Global Outcomes) guideline on CKD presented an international classification system that ranks patients' risk for CKD progression. Few data on children informed guideline development STUDY DESIGN: Observational cohort study SETTINGS AND PARTICIPANTS: Children aged 1-18 years enrolled in the North American Chronic Kidney Disease in Children (CKiD) cohort study and the European Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of CRF in Pediatric Patients (ESCAPE) trial. PREDICTOR: Level of estimated glomerular filtration rate (eGFR) and proteinuria (urine protein-creatinine ratio (mg/mg)) at study entry OUTCOME: A composite event of renal replacement therapy, 50% reduction of estimated GFR (eGFR), or eGFR 2.0 at study entry. Six ordered stages with varying combinations of eGFR categories (60-89, 45-59, 30-44 and 15-29 ml/min/1.73m(2)) and UPCR categories (2.0) described the risk continuum. Median times to event ranged from >10 years for eGFR 45-90 and UPCR 2. Children with glomerular disease were estimated to have a 43% shorter time to event than children with nonglomerular disease. Cross-validation demonstrated risk patterns that were consistent across the ten subsample validation models. LIMITATIONS: Observational study, utilized cross validation rather than external validation CONCLUSION: CKD staged by level of eGFR and proteinuria characterizes the timeline of progression and can guide management strategies in children.

There is scant literature describing the effect of glomerular disease on health-related quality of life (HRQOL). The Cure Glomerulonephropathy study (CureGN) is an international longitudinal cohort study of children and adults with four primary glomerular diseases (minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and IgA nephropathy). HRQOL is systematically assessed using items from the Patient-Reported Outcomes Measurement Informative System (PROMIS). We assessed the relationship between HRQOL and demographic and clinical variables in 478 children and 1115 adults at the time of enrollment into CureGN. Domains measured by PROMIS items included global assessments of health, mobility, anxiety, fatigue, and sleep impairment, as well as a derived composite measure incorporating all measured domains. Multivariable models were created that explained 7 to 32% of variance in HRQOL. Patient-reported edema consistently had the strongest and most robust association with each measured domain of HRQOL in multivariable analysis (adjusted β [95% CI] for composite PROMIS score in children, -5.2 [-7.1 to -3.4]; for composite PROMIS score in adults, -6.1 [-7.4 to -4.9]). Female sex, weight (particularly obesity), and estimated glomerular filtration rate were also associated with some, but not all, domains of HRQOL. Primary diagnosis, disease duration, and exposure to immunosuppression were not associated with HRQOL after adjustment. Sensitivity analyses and interaction testing demonstrated no significant association between disease duration or immunosuppression and any measured domain of HRQOL. Thus, patient-reported edema has a consistent negative association with HRQOL in patients with primary glomerular diseases, with substantially greater impact than other demographic and clinical variables.

We describe the successful treatment of a pediatric transplant patient with simultaneous intermittent hemodialysis and therapeutic plasma exchange (TPE). The patient presented with kidney graft failure. He had life threatening electrolyte disturbances and fluid overload due to antibody-mediated rejection. Therefore, he was in need of both emergent kidney replacement therapy and TPE. Both extracorporeal circuits were set up, established, and maintained safely and effectively without difficulty or alarms. Running intermittent hemodialysis and TPE simultaneously significantly reduced therapy time, allowed both needed therapies priority, and provided a superior pediatric patient experience in an acute situation.

Posaconazole is an antifungal therapy reported to cause incident hypertension. Hypokalemia is also a known side effect. The combination of hypertension and hypokalemia suggests mineralocorticoid excess. We present the case of a 15-year-old adolescent male with hypertensive urgency while on prophylactic posaconazole therapy for a combined immunodeficiency. We identify the mechanism of posaconazole-induced hypertension to be inhibition of the 11β-hydroxylase enzyme, resulting in elevated levels of the mineralocorticoid receptor activator deoxycorticosterone. Loss of function of the 11β-hydroxylase enzyme is responsible for a rare form of congenital adrenal hyperplasia and can be associated with life-threatening adrenal crisis.

Rationale & Objectives Glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and immunoglobulin A (IgA) nephropathy, share clinical presentations, yet result from multiple biological mechanisms. Challenges to identifying underlying mechanisms, biomarkers, and new therapies include the rarity of each diagnosis and slow progression, often requiring decades to measure the effectiveness of interventions to prevent end-stage kidney disease (ESKD) or death. Study Design Multicenter prospective cohort study. Setting & Participants Cure Glomerulonephropathy (CureGN) will enroll 2,400 children and adults with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy (including IgA vasculitis) and a first diagnostic kidney biopsy within 5 years. Patients with ESKD and those with secondary causes of glomerular disease are excluded. Exposures Clinical data, including medical history, medications, family history, and patient-reported outcomes, are obtained, along with a digital archive of kidney biopsy images and blood and urine specimens at study visits aligned with clinical care 1 to 4 times per year. Outcomes Patients are followed up for changes in estimated glomerular filtration rate, disease activity, ESKD, and death and for nonrenal complications of disease and treatment, including infection, malignancy, cardiovascular, and thromboembolic events. Analytical Approach The study design supports multiple longitudinal analyses leveraging the diverse data domains of CureGN and its ancillary program. At 2,400 patients and an average of 2 years' initial follow-up, CureGN has 80% power to detect an HR of 1.4 to 1.9 for proteinuria remission and a mean difference of 2.1 to 3.0mL/min/1.73m2 in estimated glomerular filtration rate per year. Limitations Current follow-up can only detect large differences in ESKD and death outcomes. Conclusions Study infrastructure will support a broad range of scientific approaches to identify mechanistically distinct subgroups, identify accurate biomarkers of disease activity and progression, delineate disease-specific treatment targets, and inform future therapeutic trials. CureGN is expected to be among the largest prospective studies of children and adults with glomerular disease, with a broad goal to lessen disease burden and improve outcomes.

Introduction The Cure Glomerulonephropathy Network (CureGN) is a 66-center longitudinal observational study of patients with biopsy-confirmed minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy (IgAN), including IgA vasculitis (IgAV). This study describes the clinical characteristics and treatment patterns in the IgA cohort, including comparisons between IgAN versus IgAV and adult versus pediatric patients. Methods Patients with a diagnostic kidney biopsy within 5 years of screening were eligible to join CureGN. This is a descriptive analysis of clinical and treatment data collected at the time of enrollment. Results A total of 667 patients (506 IgAN, 161 IgAV) constitute the IgAN/IgAV cohort (382 adults, 285 children). At biopsy, those with IgAV were younger (13.0 years vs. 29.6 years, P < 0.001), more frequently white (89.7% vs. 78.9%, P = 0.003), had a higher estimated glomerular filtration rate (103.5 vs. 70.6 ml/min per 1.73 m2, P < 0.001), and lower serum albumin (3.4 vs. 3.8 g/dl, P < 0.001) than those with IgAN. Adult and pediatric individuals with IgAV were more likely than those with IgAN to have been treated with immunosuppressive therapy at or prior to enrollment (79.5% vs. 54.0%, P < 0.001). Conclusion This report highlights clinical differences between IgAV and IgAN and between children and adults with these diagnoses. We identified differences in treatment with immunosuppressive therapies by disease type. This description of baseline characteristics will serve as a foundation for future CureGN studies.

A 5-day-old female infant born at 351/7 weeks is transferred to our neonatal intensive care unit (NICU) for evaluation and management of systemic hypertension. She is twin A of a monochorionic diamniotic pregnancy complicated by twin-to-twin transfusion syndrome in which she is the donor twin. On fetal ultrasonography performed before delivery, twin B has polyhydramnios and a pericardial effusion, and twin A has reversed end-diastolic umbilical artery blood flow. The twins are born by emergency caesarean delivery due to concern for fetal status. Her Apgar scores are 4 and 8 at 1 and 5 minutes, respectively. Her birth weight is 1,990 g. In the NICU, blood pressures are noted to be elevated with recordings consistently above 120/100 mm Hg by an oscillometric device. Echocardiography reveals left ventricular hypertrophy with mild tricuspid and mitral regurgitation. On arrival at our NICU, her weight is 1,830 g, and blood pressure is 124/97 mm Hg. Four quadrant blood pressures do not identify a gradient between the upper and lower extremities. Physical examination is unrevealing: cardiac auscultation reveals a regular rate and rhythm with no murmurs, symmetric and palpable femoral and brachial pulses, and no abdominal masses or renal artery bruits. Serum electrolytes are remarkable for mild hyponatremia (sodium, 130 mEq/L [130 mmol/L]; potassium, 6.3 mEq/L [6.3 mmol/L]; chloride, 101 mEq/L [101 mmol/L]; bicarbonate, 17 mEq/L [17 mmol/L]; blood urea nitrogen, 10 mg/dL [3.6 mmol/L]; and creatinine, 0.7 mg/dL [53 μmol/L]). Renin level is elevated at 270 ng/mL/h (expected for age, 1.4–7.8 ng/mL/h), and aldosterone level is also …

Summary Background Acute kidney injury occurs in one in four children admitted to an intensive care unit (ICU) and its severity is independently associated with increased patient morbidity and mortality. Early prediction of acute kidney injury has the potential to improve outcomes. In smaller, single-centre trial populations, we have previously derived and validated the performance of a renal angina index, a context-driven risk stratification system, to predict severe acute kidney injury in children and adolescents. Here, we tested the predictive accuracy of this index for severe acute kidney injury in a large heterogeneous population. Methods We did a prospective, observational study (AWARE) that recruited patients in the ICUs of 32 hospitals in nine countries across Asia, Australia, Europe, and North America. All patients aged between 3 months and 25 years who were admitted to an ICU at least 48 h previously were eligible. Exclusion criteria were a history of stage 5 chronic kidney disease (ie, estimated glomerular filtration rate 2 or on maintenance dialysis) or kidney transplantation in the preceding 90 days. Patients' medical records were reviewed to collect data up to 3 months before (serum creatinine only), daily during the first 7 days, and on day 28 after ICU admission. For the assessment of the renal angina index, we included patients from the AWARE study who had full data from the day of ICU admission, day 3, and day 28, including serum creatinine concentrations and urine output measurements. The primary outcome was the presence of severe acute kidney injury (stage 2–3 acute kidney injury, according to Kidney Disease Improving Global Outcomes [KDIGO] guidelines) on the third day after ICU admission. We compared the performance of the renal angina index with changes in serum creatinine relative to baseline for prediction of the primary outcome. A score of eight points or more on the renal angina index defined fulfilment of renal angina; serum creatinine concentration relative to baseline was calculated using maximum serum creatinine concentration in the first 12 h of ICU admission). This trial is registered with ClinicalTrials.gov, number NCT01987921. Findings Between Jan 1 and Dec 31, 2014, we obtained data for 1590 patients. 286 patients (18%) had fulfilment of renal angina. At day 3, severe acute kidney injury occurred in 121 (42%) patients positive for renal angina and 247 (19%) patients negative for renal angina (relative risk [RR] 2·23, 95% CI 1·87–2.66, p vs 18 [2%], p vs 53 [4%], p=0·01). Fulfilment of renal angina showed better prediction for severe acute kidney injury than serum creatinine greater than baseline (RR 1.61, 95% CI 1·33–1·93; p vs serum creatinine greater than baseline 0·68, 0·49–4·94). Interpretation Earlier and better prediction of severe acute kidney injury has the potential to improve patient outcomes associated with acute kidney injury. Compared with isolated, context-free changes in serum creatinine, renal angina risk assessment improved accuracy for prediction of severe acute kidney injury in critically ill children and young people. Funding US National Institutes of Health.

Pain is a common problem in children with chronic kidney disease (CKD); however, limited data exist regarding its management. Although most pain is managed pharmacologically, in some instances non-pharmacologic management can aid in safely ameliorating discomfort. Because of the accumulation of toxic metabolites, many common pain medications have adverse effects on kidney function or altered pharmacokinetics in the setting of CKD. Decreased clearance impacts safe dosing of analgesics. The pain management of patients on renal replacement therapy requires an understanding of drug clearance due to the different modalities of dialysis. This educational review highlights pain medications that are safe, albeit often with adjusted dosing, as well as drugs best avoided in the management of pediatric kidney disease. Acetaminophen should be used as a first-line therapy for pain management in children with CKD. Opioids may be added to control moderate to severe pain. Although data are currently lacking, buprenorphine holds promise as a potentially useful drug for the treatment of pain in pediatric patients with CKD. The addition of adjuvant pain medications and non-pharmacologic therapies maybe also be helpful. Despite these options, pain often remains difficult to treat in children with CKD.

1. Alexandra Charron, MD* 2. Laura Hesemann, MD† 3. Joseph P. Gaut, MD, PhD‡ 4. T. Keefe Davis, MD† 1. *Pediatrics, Saint Louis Children’s Hospital, St Louis, MO 2. †Division of Pediatric Nephrology and 3. ‡Division of Anatomic and Molecular Pathology, Washington University School of Medicine, St Louis, MO A previously healthy 14-year-old girl presents with 2 weeks of malaise and abnormal laboratory results. She presented to her pediatrician 1 week ago with fever and fatigue and received amoxicillin for culture-positive streptococcal pharyngitis. However, she had no improvement and began having daily episodes of nonbloody, nonbilious emesis. One day ago she noted decreased urine output, facial puffiness, and mild abdominal distention. Currently, she reports no headaches, epistaxis, sinusitis, or respiratory symptoms. On physical examination, she is afebrile, with a heart rate of 78 beats/min and blood pressure of 149/85 mm Hg. She appears well, with normal physical findings except mild facial and lower extremity edema and mild abdominal distention. Initial laboratory results are: Electrocardiography reveals normal sinus rhythm without peaked T waves. Kidney ultrasonography shows enlarged, slightly echogenic kidneys. ### Differential Diagnosis The constellation of symptoms and initial laboratory findings were concerning for glomerulonephritis (GN). Acute GN has a broad differential diagnosis, with acute poststreptococcal GN occurring most commonly in children. Other possibilities include immune complex–mediated GN, including immunoglobulin (Ig)A nephropathy and lupus nephritis, as well as pauci-immune forms of rapidly progressive GN (RPGN), such as granulomatosis with …

Toxicology studies identified AB-FUBINACA, a fifth generation synthetic cannabinoid (SC), in the urine (450 ng/mL) and serum (52 ng/mL). Acute kidney injury (AKI) secondary to SCs was brought to international attention in a report from the U.S. Centers for Disease Control and Prevention in February 2013 [1] which detailed 16 cases of AKI after SC use in six states. A case series of four patients from Alabama, all from the same county, also implicated SCs as a cause of AKI [2]. An additional case has since been reported [3]. This is the first report of a fifth generation SC associated with AKI. SCs, commonly referred to as “Spice,” are designed to bind to the same cannabinoid receptors (designated CB1 and CB2) as the active compound in marijuana, delta-9 tetrahydrocannabinol (THC). Many SCs demonstrate a high affinity for CB1 and CB2 despite having markedly different chemical structures from THC; consequently, these compounds are also referred to as “synthetic marijuana” or cannabimimetics. SCs are designed and synthesized in clandestine laboratories. Plant material/inactive vegetable matter is soaked in solvent containing the dissolved SC or the SC is sprayed directly onto the matter [1, 4]. This material is then dried and smoked. The U.S Drug Enforcement Administration (DEA) has placed multiple SCs into Schedule I of the Controlled Substance Act (CSA), including AB-FUBINACA [5–7]. However, illicit use continues as new drugs are constantly being designed, and many of the older compounds remain commercially available under the guise of herbal incense, bath additives, or air fresheners with the label “not for human consumption.” The illegal use is further encouraged by affordability, expectation of an intense high, and avoidance of detection by commonly used urine drug tests. The synthetic drug industry is a growing market. In the high school age group, 8–11 % of seniors have reported use [8]. There are countless street and commercial names for SCcontaining products (Table 1)—with these names having no correlation with the presence of a particular SC. These drugs are made in laboratories with no quality or safety controls, and thus there is great variability amongst these products in terms of ingredients, potentially toxic preservatives, adulterants, and concentration of active SC [4]. There is no assurance that This article refers to the article that can be found at http://dx.doi.org/10. 1007/s00467-014-2978-1.

Objective To provide the pediatric intensivist an in-depth understanding of citrate as regional anticoagulant during continuous renal replacement therapy. Data sources and data selection We searched the PubMed.gov database using the initial key words: citrate anticoagulation [title] AND continuous; citrate [title] AND pediatric AND continuous; prospective pediatric renal replacement AND citrate; and regional citrate anticoagulation. Additional searchers were performed using EMBASE, CINAHL, and SCOPUS with similar keywords and limits. Further articles were gathered from bibliographic references of relevant studies and reviews. Only articles published in English were reviewed. Data extraction and data synthesis In the pediatric population, there are no prospective interventional or randomized studies comparing regional versus systemic anticoagulation. However, there are 11 (retrospective and prospective observational studies) in the pediatric population using citrate anticoagulation. These studies have shown that regional citrate anticoagulation in the pediatric population can be effective, provide equivalent circuit survival, and decrease bleeding compared with heparin anticoagulation. In the adult population, there are six prospective randomized controlled trials comparing the efficacy of regional citrate anticoagulation versus heparin. Two systematic reviews with meta-analysis of these six trials have been performed. The adult data on the use of regional citrate anticoagulation during continuous renal replacement therapy show a decreased risk of bleeding and at the least equivalent circuit survival as compared to heparin. Current pediatric and adult studies support regional citrate anticoagulation as an effective alternative to systemic heparin anticoagulation in most patient populations. Conclusions Continuous renal replacement therapy is the most common modality of renal replacement in the critical care setting. Regional anticoagulation is an ideal option in a critically ill child after recent surgery or with coagulopathy. Therefore, regional citrate anticoagulation in the pediatric critical care population requiring renal replacement therapy is commonly employed. Complications of citrate anticoagulation can be avoided with a greater understanding of the properties and clearance of citrate. Continued reporting of observational data and the development of prospective multicenter trials using citrate anticoagulation are needed to ensure safe and standardized care in the pediatric population.

Hypertensive crises in children or adolescents are rare, but chronic kidney disease (CKD) is a major risk factor for occurrence. Vesicoureteral reflux nephropathy is a common cause of pediatric renal failure and is associated with hypertension. Aggressive blood pressure (BP) control has been shown to delay progression of CKD and treatment is targeted for the 50th percentile for height when compared with a target below the 90th percentile for the general pediatric hypertensive patient. We present a case of an adolescent presenting with seizures and renal failure due to a hypertensive crisis. Hypertension was thought to be secondary to CKD as she had scarred echogenic kidneys due to known reflux nephropathy. However, aggressive BP treatment improved kidney function which is inconsistent with CKD from reflux nephropathy. Secondly, aggressive BP control caused transient neurological symptoms. Further imaging identified moyamoya disease. We present this case to highlight the consideration of moyamoya as a diagnosis in the setting of renal failure and hypertensive crisis.

* Abbreviations: PUV, : posterior urethral valve VUR, : vesicoureteral reflux A male infant of estimated gestational age 36 3/7 weeks presents to our NICU immediately after birth because of rapidly enlarging kidneys in utero. The infant was born by vaginal delivery; labor was induced after noting a 5-cm enlargement of the left kidney on an ultrasound examination 1 week after a previous ultrasound. Mother received prenatal care throughout the pregnancy. At the 18-week ultrasound, the fetus was believed to have a calcium deposit in the heart, and it was recommended that the mother have an ultrasound performed by a perinatal specialist. At the follow-up ultrasound, the heart was noted to be within normal limits, but the bladder was noted to be enlarged. Thereafter, serial ultrasounds noted bilateral kidney enlargement with normal amniotic fluid levels. MRI showed a teardrop-shaped bladder. During the month before delivery, the mother had stress testing twice a week, and received steroids to facilitate fetal lung development. Family history is significant for renal disease. A paternal cousin had posterior urethral valves (PUVs). This man’s son was born with one kidney. Also, the paternal grandfather’s cousin had Bright’s disease and died at age

The original version of this article unfortunately contained a mistake. The subtitle “A Midwest Pediatric Nephrology Consortium (MWPNC) study” was missing. The correct title including subtitle is given above.

Recent advances in our understanding of the excess mortality of chronic kidney disease (CKD) due to cardiovascular complications, obtained through observational studies, demonstrate that vascular calcification and hyperphosphatemia are major cardiovascular risk factors. Mechanistic studies demonstrate that these two risk factors are related and that hyperphosphatemia directly stimulates vascular calcification. The role of hyperphosphatemia in stimulating vascular calcification in CKD is associated with a block to the skeletal reservoir function in phosphate balance due to excess bone resorption. This has led to the realization that renal osteodystrophy is linked to vascular calcification by disordered mineral homeostasis (phosphate) and that a multiorgan system fails in CKD, leading to cardiovascular mortality. In children with renal disease, the multiorgan system fails, just as in adults, but the outcomes have been less well studied, and perceptions of differences from adults are possibly incorrect. Vascular calcification and cardiovascular mortality are less prevalent among pediatric patients, but they are present. However, CKD-induced vascular disease causes stiffness of the arterial tree causing, in turn, systolic hypertension and left ventricular hypertrophy as early manifestations of the same pathology in the adult. Because of the role of the skeleton in these outcomes, renal osteodystrophy has been renamed as the CKD mineral bone disorder (CKD-MBD). This review, which focuses on the pediatric patient population, describes our current state of knowledge with regards to the pathophysiology of the CKD-MBD, including the new discoveries related to early stages of CKD. As a new necessity, cardiovascular function issues are incorporated into the CKD-MBD, and new advances in our knowledge of this critical component of the disorder will lead to improved outcomes in CKD.

Escherichia coli strains that produce Shiga toxins/verotoxins are rare, but important, causes of human disease. They are responsible for a spectrum of illnesses that range from the asymptomatic to the life-threatening hemolytic-uremic syndrome; diseases caused by E. coli belonging to serotype O157:H7 are exceptionally severe. Each illness has a fairly predictable trajectory, and good clinical practice at one phase can be inappropriate at other phases. Early recognition, rapid and definitive microbiology, and strategic selection of tests increase the likelihood of good outcomes. The best management of these infections consists of avoiding antibiotics, antimotility agents, and narcotics and implementing aggressive intravenous volume expansion, especially in the early phases of illness.

The management of Shiga toxin-producing Escherichia coli (STEC) infections is reviewed. Certain management practices optimize the likelihood of good outcomes, such as avoidance of antibiotics during the pre-hemolytic uremic syndrome phase, admission to hospital, and vigorous intravenous volume expansion using isotonic fluids. The successful management of STEC infections is based on recognition that a patient might have an STEC infection, and appropriate use of the microbiology laboratory. The timeliness of STEC identification cannot be overemphasized, because it avoids therapies prompted by inappropriate additional testing and directs the clinician to focus on effective management strategies. The opportunities during STEC infections to avert the worst outcomes are brief, and this article emphasizes practical matters relevant to making a diagnosis, anticipating the trajectory of illness, and optimizing care.

Congenital anomalies of the kidneys or lower urinary tract (CAKUT) encompass a spectrum of anomalies that result from aberrations in spatio-temporal regulation of genetic, epigenetic, environmental, and molecular signals at key stages of urinary tract development. The Rearranged in Transfection (RET) tyrosine kinase signaling system is a major pathway required for normal development of the kidneys, ureters, peripheral and enteric nervous systems. In the kidneys, RET is activated by interaction with the ligand glial cell line-derived neurotrophic factor (GDNF) and coreceptor GFRα1. This activated complex regulates a number of downstream signaling cascades (PLCγ, MAPK, and PI3K) that control proliferation, migration, renewal, and apoptosis. Disruption of these events is thought to underlie diseases arising from aberrant RET signaling. RET mutations are found in 5–30 % of CAKUT patients and a number of Ret mouse mutants show a spectrum of kidney and lower urinary tract defects reminiscent of CAKUT in humans. The remarkable similarities between mouse and human kidney development and in defects due to RET mutations has led to using RET signaling as a paradigm for determining the fundamental principles in patterning of the upper and lower urinary tract and for understanding CAKUT pathogenesis. In this review, we provide an overview of studies in vivo that delineate expression and the functional importance of RET signaling complex during different stages of development of the upper and lower urinary tracts. We discuss how RET signaling balances activating and inhibitory signals emanating from its docking tyrosines and its interaction with upstream and downstream regulators to precisely modulate different aspects of Wolffian duct patterning and branching morphogenesis. We outline the diversity of cellular mechanisms regulated by RET, disruption of which causes malformations ranging from renal agenesis to multicystic dysplastic kidneys in the upper tract and vesicoureteral reflux or ureteropelvic junction obstruction in the lower tract.

Glial cell line-derived neurotrophic factor (GDNF) binds a coreceptor GDNF family receptor α1 (GFRα1) and forms a signaling complex with the receptor tyrosine kinase RET. GDNF-GFRα1-RET signaling activates cellular pathways that are required for normal induction of the ureteric bud (UB) from the Wolffian duct (WD). Failure of UB formation results in bilateral renal agenesis and perinatal lethality. Gfrα1 is expressed in both the epithelial and mesenchymal compartments of the developing kidney while Ret expression is specific to the epithelium. The biological importance of Gfrα1’s wider tissue expression and its role in later kidney development are unclear. We discovered that conditional loss of Gfrα1 in the WD epithelium prior to UB branching is sufficient to cause renal agenesis. This finding indicates that Gfrα1 expressed in the nonepithelial structures cannot compensate for this loss. To determine Gfrα1’s role in branching morphogenesis after UB induction we used an inducible Gfrα1-specific Cre-deletor strain and deleted Gfrα1 from the majority of UB tip cells post UB induction in vivo and in explant kidney cultures. We report that Gfrα1 excision from the epithelia compartment after UB induction caused a modest reduction in branching morphogenesis. The loss of Gfrα1 from UB-tip cells resulted in reduced cell proliferation and decreased activated ERK (pERK). Further, cells without Gfrα1 expression are able to populate the branching UB tips. These findings delineate previously unclear biological roles of Gfrα1 in the urinary tract and demonstrate its cell-type and stage-specific requirements in kidney development.

To define glomerular filtration rate (GFR) decline, hypertension (HTN), and proteinuria in subjects with autosomal recessive polycystic kidney disease (ARPKD) and compare with 2 congenital kidney disease control groups in the Chronic Kidney Disease in Children cohort.GFR decline (iohexol clearance), rates of HTN (ambulatory/casual blood pressures), antihypertensive medication usage, left ventricular hypertrophy, and proteinuria were analyzed in subjects with ARPKD (n = 22) and 2 control groups: aplastic/hypoplastic/dysplastic disorders (n = 44) and obstructive uropathies (n = 44). Differences between study groups were examined with the Wilcoxon rank sum test.Annualized GFR change in subjects with ARPKD was -1.4 mL/min/1.73 m(2) (-6%), with greater decline in subjects age ≥ 10 years (-11.5%). However, overall rates of GFR decline did not differ significantly in subjects with ARPKD vs controls. There were no significant differences in rates of HTN or left ventricular hypertrophy, but subjects with ARPKD had a greater percent on ≥ 3 blood pressure medications (32% vs 0%, P.0001), more angiotensin-converting enzyme inhibitor use (82% vs 27% vs 36%, P.0005), and less proteinuria (urine protein: creatinine = 0.1 vs 0.6, P.005).This study reports rates of GFR decline, HTN, and proteinuria in a small but well-phenotyped ARPKD cohort. The relatively slow rate of GFR decline in subjects with ARPKD and absence of significant proteinuria suggest that these standard clinical measures may have limited utility in assessing therapeutic interventions and highlight the need for other ARPKD kidney disease progression biomarkers.

A 6-year-old girl presents to the emergency room with altered mental status. She is acutely non-verbal and unable to vocalize sounds. She has bilateral nystagmus and facial twitching. She has marked hypertonia with her wrists persistently flexed and her feet and toes hyperextended. Reflexes are not elicited. She does not withdraw from painful stimuli. She is accompanied by her parents who brought her by car. You learn she has a history of an imperforated anus repair and suffers from chronic constipation with megacolon. The repair was performed at the age of 2 by pull through with reanastomosis after previous diverting colostomy. In the past, she has been managed with an aggressive bowel regime including daily polyethylene glycol 3350 (MiraLax) and two pediatric Fleets enemas administered every other day. In spite of this regime, she developed persistent fecal soiling and recent clinical evaluation identified overflow incontinence. She was instructed to increase the dose to two adult Fleets enemas every other day. On the day of presentation, she complained of abdominal pain presumed to be due to constipation. Therefore, she received two Fleets enemas. She did not evacuate her bowels so a third enema was administered for a total of three adult Fleets enemas within 12 hours.

Signaling by the glial cell line-derived neurotrophic factor (GDNF)-RET receptor tyrosine kinase and SPRY1, a RET repressor, is essential for early urinary tract development. Individual or a combination of GDNF, RET and SPRY1 mutant alleles in mice cause renal malformations reminiscent of congenital anomalies of the kidney or urinary tract (CAKUT) in humans and distinct from renal agenesis phenotype in complete GDNF or RET-null mice. We sequenced GDNF, SPRY1 and RET in 122 unrelated living CAKUT patients to discover deleterious mutations that cause CAKUT. Novel or rare deleterious mutations in GDNF or RET were found in six unrelated patients. A family with duplicated collecting system had a novel mutation, RET-R831Q, which showed markedly decreased GDNF-dependent MAPK activity. Two patients with RET-G691S polymorphism harbored additional rare non-synonymous variants GDNF-R93W and RET-R982C. The patient with double RET-G691S/R982C genotype had multiple defects including renal dysplasia, megaureters and cryptorchidism. Presence of both mutations was necessary to affect RET activity. Targeted whole-exome and next-generation sequencing revealed a novel deleterious mutation G443D in GFRα1, the co-receptor for RET, in this patient. Pedigree analysis indicated that the GFRα1 mutation was inherited from the unaffected mother and the RET mutations from the unaffected father. Our studies indicate that 5 % of living CAKUT patients harbor deleterious rare variants or novel mutations in GDNF-GFRα1-RET pathway. We provide evidence for the coexistence of deleterious rare and common variants in genes in the same pathway as a cause of CAKUT and discovered novel phenotypes associated with the RET pathway.

A 17-year-old male presented to the hospital following a TASER (TASER International, Inc., Scottsdale, AZ, USA) encounter and arrest by law enforcement. The patient exhibited agitation and aggressive behavior. He admitted to smoking “synthetic marijuana” as well as taking two tablets of combination oxycodone and acetaminophen (Percocet). He complained of retrosternal and upper abdominal pain. He recently acquired a new supply of “Brain Freeze” and smoked it multiple times in the last couple of days including the day of admission. On exam he was tachycardic (heart rate 120 beats per minute) and hypertensive (151/73 mmHg). His abdomen was soft. He had mild non-localizing tenderness. He had bilateral costovertebral angle tenderness. Laboratory evaluation was remarkable for a serum bicarbonate of 8 mmol/l with an anion gap of 29; creatinine 1.7 mg/dl; potassium 3.3 mmol/l; an elevated creatinine kinase (CK) of 2,723 U/l with myoglobinemia 3974.5 ng/ml (Table 1). Urinalysis revealed a

To assess depression in children with chronic kidney disease and to determine associations with patient characteristics, intellectual and educational levels, and health-related quality of life (HRQoL).Subjects aged 6-17 years from the Chronic Kidney Disease in Children cohort study completed the Children's Depression Inventory (CDI), Wechsler Abbreviated Scales of Intelligence, Wechsler Individual Achievement Test-II-Abbreviated, and the Pediatric Inventory of Quality of Life Core Scales 4.0. Regression analyses determined associations of CDI score and depression status with subject characteristics, intellectual and educational levels, and HRQoL. A joint linear mixed model and Weibull model were used to determine the effects of CDI score on longitudinal changes in glomerular filtration rate and time to renal replacement therapy.A total of 344 subjects completed the CDI. Eighteen (5%) had elevated depressive symptoms, and another 7 (2%) were being treated for depression. In adjusted analyses, maternal education beyond high school was associated with 5% lower CDI scores (estimate, 0.95; 95% CI, 0.92-0.99). Depression status was associated with lower IQ (99 vs 88; P = .053), lower achievement (95 vs 77.5; P.05), and lower HRQoL by parent and child reports (effect estimates, -15.48; 95% CI, -28.71 to -2.24 and -18.39; 95% CI, -27.81 to -8.96, respectively). CDI score was not related to change in glomerular filtration rate.Children with depression had lower psychoeducational skills and worse HRQoL. Identifying and treating depression should be evaluated as a means of improving the academic performance and HRQoL of children with chronic kidney disease.