Clinical Characteristics and Outcomes of Drug-Induced Acute Kidney Injury Cases.

Introduction: Drug-induced acute kidney injury (DI-AKI) is a frequent adverse event. The identification of DI-AKI is challenged by competing etiologies, clinical heterogeneity among patients, and a lack of accurate diagnostic tools. Our research aims to describe the clinical characteristics and predictive variables of DI-AKI. Methods: We analyzed data from the Drug-Induced Renal Injury Consortium (DIRECT) study (NCT02159209), an international, multicenter, observational cohort study of enriched clinically adjudicated DI-AKI cases. Cases met the primary inclusion criteria if the patient was exposed to at least 1 nephrotoxic drug for a minimum of 24 hours prior to AKI onset. Cases were clinically adjudicated, and inter-rater reliability (IRR) was measured using Krippendorff's alpha. Variables associated with DI-AKI were identified using L1 regularized multivariable logistic regression. Model performance was assessed using the area under the receiver operating characteristic curve (ROC AUC). Results: A total of 314 AKI cases met the eligibility criteria for this analysis, and 271 (86%) cases were adjudicated as DI-AKI. The majority of the AKI cases were recruited from the United States (68%). The most frequent causal nephrotoxic drugs were vancomycin (48.7%), nonsteroidal antiinflammatory drugs (18.2%), and piperacillin/tazobactam (17.8%). The IRR for DI-AKI adjudication was 0.309. The multivariable model identified age, vascular capacity, hyperglycemia, infections, pyuria, serum creatinine (SCr) trends, and contrast media as significant predictors of DI-AKI with good performance (ROC AUC 0.86). Conclusion: The identification of DI-AKI is challenging even with comprehensive adjudication by experienced nephrologists. Our analysis identified key clinical characteristics and outcomes of DI-AKI compared to other AKI etiologies.

Assessment of fluid status in neonatal dialysis: the need for new tools.

BACKGROUND: Assessment of fluid status in neonatal dialysis has largely focused on traditional tools including clinical assessment, serial weights, and blood pressure (BP) measurements. However, in infants on kidney replacement therapy, the assessment of fluid overload is problematic due to errors in weight assessment, subtlety of physical exam findings, and inaccuracy of non-invasive BP measurements. In this presentation of a neonate with bilateral renal agenesis requiring kidney replacement therapy, the treating team assessed a number of variables in determining the ultrafiltration prescription for dialysis across 2 modalities (hemodialysis and continuous kidney replacement therapy). COMPLICATIONS: Fluid overload, cardiomegaly, and worsened respiratory status occurred when attempting to assess the neonate's fluid status by traditional markers (weights, blood pressures, physical exam findings). B-type natriuretic peptide (BNP) was obtained and was noted to correlate with the degree of fluid overload. KEY MANAGEMENT POINTS: Compared to traditional tools for assessment of fluid status in pediatric dialysis, BNP assisted the medical team in optimizing the volume status of the subject and determining optimal daily ultrafiltration goals. Due to the rapid release in response to myocardial stretch and the lack of kidney clearance of the peptide, BNP may represent an objective, timely, and reliable index of volume status in the pediatric dialysis patient.

A unique pancreatic phenotype in a child with a WDR19-related ciliopathy: A case report and literature review of pancreatic involvement in ciliopathies.

Ciliopathies are a group of genetic disorders caused by ciliary dysfunction. Thirty-five distinct multi-organ phenotypes have been recognized, with 187 genes associated. We performed a literature review of pancreatic involvement in ciliopathies and found that pancreatic disease is an uncommon phenotype described in only a handful of these genetic disorders. We present a case report of a pediatric patient with WDR19-related ciliopathy whose degree of pancreatic disease exceeds what has previously been reported in the literature for WDR19-related ciliopathies. WDR19 is one member of the nephronophthisis (NPHP)-related ciliopathy gene family and encodes an intra-flagellar transport protein (IFT144). Our patient presented with restrictive and obstructive lung disease, short rib thoracic dysplasia, end-stage renal disease (ESRD), developmental delay, hepatic fibrosis, and severe recurrent pancreatitis. Whole-exome sequencing (GeneDx) showed two likely pathogenic WDR19 variants in trans (maternally inherited: c.742G > A, p.G248S; paternally inherited: c.617 T > C, p.L206P). Among WDR19-related ciliopathies, pancreatic involvement is rarely reported and there have been no cases of severe, recurrent pancreatitis. Through this case report and literature review we hope to emphasize that pancreatic involvement is a rare yet important clinical phenotype to recognize in ciliopathies, especially in WDR19-related ciliopathies.

Intraperitoneal vancomycin for peritoneal dialysis-associated peritonitis in children: Evaluation of loading dose guidelines.

BACKGROUND: Current pediatric International Society for Peritoneal Dialysis guidelines for initial treatment of peritoneal dialysis (PD)-associated peritonitis suggest either monotherapy with cefepime or double therapy with first-generation cephalosporin or glycopeptide and ceftazidime or aminoglycoside. When using vancomycin, the intraperitoneal (IP) recommended pediatric loading dosage is 1000 mg/L of dialysate. This is based on adult pharmacokinetic (PK) studies and roughly translates to the adult recommendation where 30 mg/kg in 2 L is approximately 1000 mg/L. However, since the dialysate volume in pediatric patients is normalized to body surface area and not weight, the current recommended dosing can result in high vancomycin exposure in children. Vancomycin can potentially cause adverse effects. We aimed to determine if the IP vancomycin dosing of 1000 mg/L was causing elevated vancomycin levels and to offer possible dosing recommendations based on PK modeling and simulation. METHODS: Retrospective review of pediatric patients who had been treated with IP vancomycin for PD-associated peritonitis. Vancomycin levels obtained for clinical monitoring were analyzed using NONMEM to generate population and individual (empiric Bayesian) estimates of vancomycin PK parameters and estimated peak levels. Predicted vancomycin peaks were also simulated from virtual pediatrics patients 3-70 kg following various dosing strategies. RESULTS: Six episodes of peritonitis in three patients were analyzed. In the two episodes treated with 1000 mg/L, the first vancomycin levels (h post) were 95.6 ug/mL (3) and 49 (33) and following 500 mg/L were 33.2 (11), 30.2 (11), 23.6 (24), and 22.1 (11). All patients were cured of their peritonitis without the need for catheter removal. Based on our population PK model, a 1000 mg/L IP vancomycin loading dose will typically result in peak > 50 mg/L in patients weighing <35 kg and >60 mg/L in patients <15 kg. Vancomycin levels will remain above 20 mg/L for over 2 days without additional vancomycin dosing. CONCLUSION: The data suggest that a loading dose of vancomycin 1000 mg/L leads to higher than desired vancomycin levels and should be lowered. A 500 mg/L loading dosing appears more appropriate and needs further study.

Establishing core outcome domains in pediatric kidney disease: report of the Standardized Outcomes in Nephrology-Children and Adolescents (SONG-KIDS) consensus workshops.

Trials in children with chronic kidney disease do not consistently report outcomes that are critically important to patients and caregivers. This can diminish the relevance and reliability of evidence for decision making, limiting the implementation of results into practice and policy. As part of the Standardized Outcomes in Nephrology-Children and Adolescents (SONG-Kids) initiative, we convened 2 consensus workshops in San Diego, California (7 patients, 24 caregivers, 43 health professionals) and Melbourne, Australia (7 patients, 23 caregivers, 49 health professionals). This report summarizes the discussions on the identification and implementation of the SONG-Kids core outcomes set. Four themes were identified; survival and life participation are common high priority goals, capturing the whole child and family, ensuring broad relevance across the patient journey, and requiring feasible and valid measures. Stakeholders supported the inclusion of mortality, infection, life participation, and kidney function as the core outcomes domains for children with chronic kidney disease.

De novo weekly and biweekly darbepoetin alfa dosing in pediatric patients with chronic kidney disease.

BACKGROUND: Darbepoetin alfa is a commonly prescribed erythropoiesis-stimulating agent (ESA) for correcting anemia in pediatric chronic kidney disease (CKD) patients. However, little information exists on its use in ESA-naïve patients. This study evaluated the efficacy and safety of darbepoetin alfa in pediatric patients initiating ESA therapy. METHODS: One-hundred sixteen pediatric ESA-naïve subjects (aged 1-18 years) with CKD stages 3-5D and hemoglobin (Hb) <10 g/dl from 43 centers in the US, Europe, and Mexico were randomized by age (three groups) and dialysis status (yes vs. no) to receive darbepoetin alfa once weekly (QW) or every 2 weeks (Q2W) subcutaneously (not on dialysis and peritoneal dialysis subjects) and intravenously (hemodialysis subjects). The drug was titrated to achieve Hb levels of 10.0-12.0 g/dl over 25 weeks. Patient- and parent-reported health-related outcomes were measured by the Pediatric Quality of Life Inventory (PedsQL™) in children ≥2 years. RESULTS: In both groups, mean Hb concentrations increased to ≥11.0 g/dl over the first 3 months of treatment and remained stable within the 10.0-12.0 g/dl target range. The median time to achieve hemoglobin ≥10 g/dl was slightly longer for subjects <12 years (QW and Q2W, both 28 days) vs. those ≥12 years (23 and 22 days, respectively). Adverse event profiles were similar between groups, with QW, four (7%) and Q2W, five (9%). PedsQL™ scores showed modest increases. CONCLUSIONS: Darbepoetin alfa can be safely administered either QW or Q2W to ESA-naïve pediatric patients with CKD-related anemia to achieve Hb targets of 10.0-12.0 g/dl.

Whole Exome Sequencing of Patients with Steroid-Resistant Nephrotic Syndrome.

BACKGROUND AND OBJECTIVES: Steroid-resistant nephrotic syndrome overwhelmingly progresses to ESRD. More than 30 monogenic genes have been identified to cause steroid-resistant nephrotic syndrome. We previously detected causative mutations using targeted panel sequencing in 30% of patients with steroid-resistant nephrotic syndrome. Panel sequencing has a number of limitations when compared with whole exome sequencing. We employed whole exome sequencing to detect monogenic causes of steroid-resistant nephrotic syndrome in an international cohort of 300 families. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Three hundred thirty-five individuals with steroid-resistant nephrotic syndrome from 300 families were recruited from April of 1998 to June of 2016. Age of onset was restricted to <25 years of age. Exome data were evaluated for 33 known monogenic steroid-resistant nephrotic syndrome genes. RESULTS: In 74 of 300 families (25%), we identified a causative mutation in one of 20 genes known to cause steroid-resistant nephrotic syndrome. In 11 families (3.7%), we detected a mutation in a gene that causes a phenocopy of steroid-resistant nephrotic syndrome. This is consistent with our previously published identification of mutations using a panel approach. We detected a causative mutation in a known steroid-resistant nephrotic syndrome gene in 38% of consanguineous families and in 13% of nonconsanguineous families, and 48% of children with congenital nephrotic syndrome. A total of 68 different mutations were detected in 20 of 33 steroid-resistant nephrotic syndrome genes. Fifteen of these mutations were novel. NPHS1, PLCE1, NPHS2, and SMARCAL1 were the most common genes in which we detected a mutation. In another 28% of families, we detected mutations in one or more candidate genes for steroid-resistant nephrotic syndrome. CONCLUSIONS: Whole exome sequencing is a sensitive approach toward diagnosis of monogenic causes of steroid-resistant nephrotic syndrome. A molecular genetic diagnosis of steroid-resistant nephrotic syndrome may have important consequences for the management of treatment and kidney transplantation in steroid-resistant nephrotic syndrome.

Therapeutic plasma exchange for the treatment of pediatric renal diseases in 2013.

Therapeutic plasma exchange is an extracorporeal treatment modality that removes systemic circulating pathologic factors or replaces absent plasma components and plays a role in many nephrologic conditions. It presents a number of technical challenges in the pediatric population but has become an increasingly common practice in pediatric nephrology over the past several decades. While prospective evidence is often lacking, our increased understanding of the molecular pathogenesis underlying many pediatric renal diseases provides sound reasoning for the use of plasma exchange in treating these conditions. This review will present the currently accepted indications for plasma exchange in children, the technical aspects of the procedure and its potential complications.

Association between common iron store markers and hemoglobin in children with chronic kidney disease.

BACKGROUND: Serum ferritin and transferrin saturation (TSAT) are used to assess iron status in children with chronic kidney disease (CKD), but their sensitivity in identifying those at risk of lower hemoglobin (HGB) values is unclear. METHODS: We assessed the association of iron status markers (ferritin, TSAT, and serum iron) with age- and gender-related HGB percentile in mild-to-moderate CKD in 304 children in the Chronic Kidney Disease in Children (CKiD) Study. Standardized HGB percentile values were examined by KDOQI-recommended ferritin (≥ 100 ng/ml) and TSAT (≥ 20 %) thresholds. Regression tree methods were used to identify iron status markers and clinical characteristics most associated with lower HGB percentiles. RESULTS: The cohort was 62 % male, 23 % African American, and 12 % Hispanic, median age 12 years, and median HGB 12.9 g/dl. 34 % had low TSAT and 93 % low ferritin as defined by KDOQI. Distribution of HGB percentile values was lower in those with ferritin ≥ 100 ng/ml, while TSAT ≥ 20 % was associated with only modest increase in HGB percentile. In regression tree analysis, lower glomerular filtration rate (GFR), serum iron <50 µg/dl and ferritin ≥ 100 ng/ml were most strongly associated with lower HGB percentile. CONCLUSIONS: The level of GFR was significantly associated with HGB. Higher serum ferritin was associated with lower HGB in this cohort. Low serum iron in the context of normal/increased ferritin and low HGB may be a useful indicator of iron-restricted erythropoiesis.

Association of proteinuria with race, cause of chronic kidney disease, and glomerular filtration rate in the chronic kidney disease in children study.

BACKGROUND AND OBJECTIVES: Proteinuria is associated with chronic kidney disease (CKD), and heavy proteinuria predicts a rapid decline in kidney function. However, the epidemiologic distribution of this important biomarker study is not well described in the pediatric CKD population. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS: This cross-sectional study of North American children with CKD examined the association of proteinuria among the baseline clinical variables in the cohort. Urinary protein-to-creatinine ratios (Up/c) were used to measure level of proteinuria. RESULTS: Of the 419 subjects studied, the median GFR as measured by iohexol disappearance (iGFR) was 42 ml/min per 1.73 m(2), median duration of CKD was six yr, and glomerular diseases accounted for 22% of the CKD diagnoses. Twenty-four percent of children had normal range (Up/c <0.2), 62% had significant, and 14% had nephrotic-range proteinuria (Up/c >2.0). A decrease in iGFR was associated with an increase in Up/c. At any level of GFR, a higher Up/c was associated with a glomerular cause of CKD and non-Caucasian race. Among subjects with a glomerular cause of CKD, Up/c was lower in subjects reporting utilization of renin-angiotensin system (RAS) antagonists (median Up/c = 0.93) compared with those who did not (median Up/c = 3.78). CONCLUSIONS: Proteinuria is associated with level of iGFR, cause of CKD, and race. The longitudinal study design of Chronic Kidney Disease in Children (CKiD) cohort study and the large number of subjects being studied has created an opportunity to better define the association between proteinuria and CKD progression.

Nephrogenic systemic fibrosis with multiorgan involvement in a teenage male after lymphoma, Ewing's sarcoma, end-stage renal disease, and hemodialysis.

Nephrogenic systemic fibrosis (NSF) is a rare condition that always occurs after acute or chronic renal failure with or without dialysis. The vast majority of cases in the literature are adults, and postmortem findings have been reported in only 5 cases. We report a 15-year-old male who developed NSF with multiorgan involvement after successful treatment of renal lymphoma and a subsequent sacral Ewing's sarcoma, and end-stage renal disease treated with hemodialysis. At autopsy, he was found to have diffuse dural osseous metaplasia, transmural bronchiolar fibrosis, diaphragmatic central tendon fibrosis, and fibrous plaques of the mitral valve. These previously unreported findings expand the spectrum of multiorgan involvement in NSF providing additional evidence that it is an emerging systemic disorder.

Intravenous paricalcitol for treatment of secondary hyperparathyroidism in children on hemodialysis.

BACKGROUND: Secondary hyperparathyroidism is a common complication in children receiving hemodialysis. Active vitamin D is an effective therapy, but its use is often limited by hypercalcemia and increased calcium x phosphorus (Ca x P) product. Paricalcitol, a selective vitamin D receptor activator, causes less sustained hypercalcemia and increase in Ca x P product than calcitriol and has been used effectively in adult hemodialysis patients. STUDY DESIGN: Double blind, placebo-controlled. SETTING & PARTICIPANTS: Hemodialysis units and pediatric subjects receiving hemodialysis. INTERVENTION: After a washout period of 2 to 6 weeks, 29 subjects aged 5 to 19 years received either paricalcitol or placebo for up to 12 weeks (0.04 mug/kg if initial intact parathyroid hormone [iPTH] level < 500 pg/mL [ng/L]; 0.08 mug/kg if initial iPTH level > 500 pg/mL [ng/L]). The dose was increased by 0.04 mug/kg every 2 weeks until there was a 30% decrease in iPTH level from baseline or calcium level greater than 11 mg/dL (>2.74 mmol/L) or Ca x P product greater than 75 mg(2)/dL(2) (>6.04 mmol(2)/L(2)). OUTCOMES & MEASUREMENTS: Two consecutive 30% decreases from baseline in iPTH levels and safety of paricalcitol, including hypercalcemia and increase in Ca x P product. RESULTS: 60% of the paricalcitol group had 2 consecutive 30% decreases from baseline iPTH levels compared with 21% in the placebo group (P = 0.06). The paricalcitol group had a mean decrease in iPTH level of 164 pg/mL (ng/L), whereas the placebo group had a mean increase of 238 pg/mL (ng/L; P = 0.03). There was no difference from baseline to final visit in calcium, phosphorus, or Ca x P product values in either group. LIMITATIONS: Low power to detect differences in safety between groups and a short-term study. CONCLUSION: Paricalcitol decreased iPTH levels in children receiving hemodialysis with no significant changes in serum calcium, phosphorus, or Ca x P product values during the course of the study.

Intravenous calcitriol for treatment of hyperparathyroidism in children on hemodialysis.

This double-blind, placebo-controlled study evaluated the safety and efficacy of intravenous (i.v.) calcitriol (Calcijex) for treatment of secondary hyperparathyroidism (secondary HPT) in pediatric end-stage renal disease (ESRD) patients on hemodialysis (HD). After a 2 to 6-week washout period of all vitamin D compounds, patients with two consecutive PTH values > 400 pg mL(-1), calcium levels < or = 10.5 mg dL(-1) and calcium x phosphorus product values < or = 70 mg2 dL(-2) were eligible for the treatment phase. Patients received a bolus injection of calcitriol or placebo three times a week, immediately after dialysis for up to 12 weeks. Initial doses (0.5-1.5 microg) were based on the severity of secondary HPT. The dose was increased every two weeks by 0.25 microg until there was at least a 30% decrease in PTH from baseline, or Ca > 11.0 mg dL(-1), or Ca x P > 75 mg2 dL(-2). Overall, 11/21 (52%) patients in the calcitriol group had two consecutive > or = 30% decreases from baseline in serum PTH compared with 5/26 (19%) patients in the placebo group (P=0.03). The mean total alkaline phosphatase decreased from 274 to 232 IU L(-1) in the calcitriol group and increased from 547 to 669 IU L(-1) in the placebo group (P=0.002). The mean bone-specific alkaline phosphatase decreased from 72.5 to 68 microg L(-1) in the calcitriol group and increased from 105.3 to 148.5 microg L(-1) in the placebo group (P=0.03). The incidence of two consecutive occurrences of elevated calcium x phosphorus (Ca x P > 75 mg2 dL(-2)) product was higher in the calcitriol group than in the placebo group (P=0.01). Two consecutive occurrences of phosphorus > 6.5 mg dL(-1) occurred in 71% of the calcitriol group and 46% of the placebo group (P=0.14). Calcium levels > 10.5 mg dL(-1) were more common in the calcitriol group than in the placebo group (P=0.01). There was a direct relationship between serum phosphorus concentration and the percentage change in PTH from baseline in both the calcitriol group (r=0.46; P<0.0001) and the placebo group (r=0.21; P=0.0005). This study demonstrates that i.v. calcitriol, at initial doses of 0.5-1.5 microg, effectively reduces PTH levels in pediatric HD patients and that patients should be closely monitored for hyperphosphatemia and elevated Ca x P product.

Mycobacterial peritonitis in pediatric peritoneal dialysis patients.

Peritonitis is the most common complication and the leading cause of death in pediatric peritoneal dialysis (PD) patients. According to the most recent data available from the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS), approximately 25% of pediatric PD patients who die succumb to infection. There are no reported cases of Mycobacterium tuberculosis (MTB) or Mycobacterium avium-intracellulare peritonitis in the NAPRTCS registry. With an increasing incidence of MTB worldwide and the impairment of cellular immunity in chronic renal failure patients, it is not surprising that mycobacterium peritonitis can occur in PD patients. We report two pediatric PD patients with mycobacterial peritoneal infection diagnosed over an 11-year period at our institution. One patient presented with a malfunctioning Tenckhoff catheter and again 3 years later with hyponatremia and ascites. The other presented with recurrent culture-negative peritonitis. These cases illustrate the importance of more extensive evaluation of PD complications, to include evaluation for mycobacterium with special media or peritoneal biopsy, in the above clinical settings if the routine work-up is unrevealing.