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Nephrotoxic medication (NTMx) exposure is a common cause of acute kidney injury (AKI) in hospitalized children. The Nephrotoxic Injury Negated by Just-in time Action (NINJA) program decreased NTMx associated AKI (NTMx-AKI) by 62% at one center. To further test the program, we incorporated NINJA across nine centers with the goal of reducing NTMx exposure and, consequently, AKI rates across these centers. NINJA screens all non-critically ill hospitalized patients for high NTMx exposure (over three medications on the same day or an intravenous aminoglycoside over three consecutive days), and then recommends obtaining a daily serum creatinine level in exposed patients for the duration of, and two days after, exposure ending. Additionally, substitution of equally efficacious but less nephrotoxic medications for exposed patients starting the day of exposure was recommended when possible. The main outcome was AKI as defined by the Kidney Disease Improving Global Outcomes (KDIGO) serum creatinine criteria (increase of 50% or 0.3 mg/dl over baseline). The primary outcome measure was AKI episodes per 1000 patient-days. Improvement was defined by statistical process control methodology and confirmed by Autoregressive Integrated Moving Average (ARIMA) modeling. Eight consecutive bi-weekly measure rates in the same direction from the established baseline qualified as special cause change for special process control. We observed a significant and sustained 23.8% decrease in NTMx-AKI rates by statistical process control analysis and by ARIMA modeling; similar to those of the pilot single center. Thus, we have successfully applied the NINJA program to multiple pediatric institutions yielding decreased AKI rates.

Background:Cardiac surgery-associated acute kidney injury is common. In order to improve our understanding of acute kidney injury, we formed the multi-centre Neonatal and Pediatric Heart and Renal Outcomes Network. Our main goals are to describe neonatal kidney injury epidemiology, evaluate variability in diagnosis and management, identify risk factors, investigate the impact of fluid overload, and explore associations with outcomes.Methods:The Neonatal and Pediatric Heart and Renal Outcomes Network collaborative includes representatives from paediatric cardiac critical care, cardiology, nephrology, and cardiac surgery. The collaborative sites and infrastructure are part of the Pediatric Cardiac Critical Care Consortium. An acute kidney injury module was developed and merged into the existing infrastructure. A total of twenty-two participating centres provided data on 100–150 consecutive neonates who underwent cardiac surgery within the first 30 post-natal days. Additional acute kidney injury variables were abstracted by chart review and merged with the corresponding record in the quality improvement database. Exclusion criteria included >1 operation in the 7-day study period, pre-operative renal replacement therapy, pre-operative serum creatinine >1.5 mg/dl, and need for extracorporeal support in the operating room or within 24 hours after the index operation.Results:A total of 2240 neonatal patients were enrolled across 22 centres. The incidence of acute kidney injury was 54% (stage 1 = 31%, stage 2 = 13%, and stage 3 = 9%).Conclusions:Neonatal and Pediatric Heart and Renal Outcomes Network represents the largest multi-centre study of neonatal kidney injury. This new network will enhance our understanding of kidney injury and its complications.

This study seeks to evaluate the association between acute kidney injury (AKI), fluid overload (FO), and mortality in children supported with extracorporeal membrane oxygenation (ECMO) for refractory respiratory failure. This retrospective observational cohort study was performed at six tertiary care children's hospital intensive care units, studying 424 patients < 18 years of age supported with ECMO for ≥ 24 hours for a respiratory indication from January 1, 2007, to December 31, 2011. In a multivariate analysis, FO level at ECMO initiation was not associated with hospital mortality, whereas peak FO level during ECMO was associated with hospital mortality. For every 10% increase in peak FO during ECMO, the odds of hospital mortality were approximately 1.2 times higher. Every 10% increase in peak FO during ECMO resulted in a significant relative change in the duration of ECMO hours by a factor of 1.08. For hospital survivors, every 10% increase in peak FO level during ECMO resulted in a significant relative change in the duration of mechanical ventilation hours by a factor of 1.13. In this patient population, AKI and FO are associated with increased mortality and should be considered targets for medical interventions including judicious fluid management, diuretic use, and renal replacement therapy.

OBJECTIVE(S): To test if acute kidney injury (AKI) is preventable in patients in the neonatal intensive care unit and if infants at high-risk of nephrotoxic medication-induced AKI can be identified using a systematic surveillance program previously used in the pediatric nonintensive care unit setting. STUDY DESIGN: Quality improvement project that occurred between March 2015 and September 2017 in a single center, level IV neonatal intensive care unit. Infants were screened for high-risk nephrotoxic medication exposure (≥3 nephrotoxic medication within 24 hours or ≥4 calendar days of an intravenous [IV] aminoglycoside). If infants met criteria, a daily serum creatinine (SCr) was obtained until 2 days after end of exposure or end of AKI, whichever occurred last. The study was divided into 3 eras: pre-Nephrotoxic Injury Negated by Just-in-time Action (NINJA), initiation, and sustainability. Differences for 5 metrics across 3 eras were compared: SCr surveillance, high nephrotoxic medication exposure rate (per 1000 patient-days), AKI rate (per 1000 patient-days), nephrotoxin-AKI percentage, and AKI intensity (number of AKI days per 100 susceptible patient-days). RESULTS: Comparing the initiation with sustainability era, there was a reduction in high nephrotoxic medication exposures from 16.4 to 9.6 per 1000 patient-days (P = .03), reduction in percentage of nephrotoxic medication-AKI from 30.9% to 11.0% (P < .001), and reduction in AKI intensity from 9.1 to 2.9 per 100 susceptible patient-days (P < .001) while maintaining a high SCr surveillance rate. This prevented 100 AKI episodes during the 18-month sustainability era. CONCLUSION(S): A systematic surveillance program to identify high-risk infants can prevent nephrotoxic-induced AKI and has the potential to prevent short and long-term consequences of AKI in critically ill infants.

BACKGROUND AND OBJECTIVES: Neonatal AKI is associated with poor short- and long-term outcomes. The objective of this study was to describe the risk factors and outcomes of neonatal AKI in the first postnatal week. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The international retrospective observational cohort study, Assessment of Worldwide AKI Epidemiology in Neonates (AWAKEN), included neonates admitted to a neonatal intensive care unit who received at least 48 hours of intravenous fluids. Early AKI was defined by an increase in serum creatinine >0.3 mg/dl or urine output

Background In patients with diabetes mellitus, hyperfiltration precedes the development of albuminuria. Pediatric sickle cell anemia (SCA) patients have a high prevalence of hyperfiltration and albuminuria during early childhood and adolescence. We tested the hypothesis that hyperfiltration precedes the development of albuminuria in a longitudinal pediatric SCA cohort. Methods We identified 91 participants with HbSS or SB0 thalassemia 5-21 years of age enrolled in a longitudinal sickle cell nephropathy cohort study who had a cystatin C measured during early childhood (4-10 years of age). Early hyperfiltration was defined as a mean eGFR >180 mL/min/1.73m2 using cystatin C obtained from 4 to 10 years of age. Persistent albuminuria was defined as an albumin to creatinine ratio > 30 mg/g on two of three untimed urine specimens. Time to event analysis estimated survival curves for participants with and without hyperfiltration using Kaplan-Meier curves and used logrank test for categorical variables to assess the association with time to development of the first episode persistent albuminuria. Results Persistent albuminuria occurred more often and at an earlier age in participants with early hyperfiltration compared to those without early hyperfiltration (log-rank, P = .004). Participants who developed albuminuria have a significant increase in their eGFR during childhood (P = .003) as compared to participants who have not yet progressed to albuminuria (P = .26). For every 1 g/dL increase in hemoglobin, the hazard ratio for developing persistent proteinuria decreased by 0.56 (95% CI: 0.3, 1.06, P = .07). Conclusion Hyperfiltration precedes the development of persistent proteinuria in pediatric SCA patients. Intervention strategies should target lowering eGFR during early childhood.

Serum creatinine (SCr)-based AKI definitions have important limitations, particularly in very low-birth-weight (VLBW) neonates. Urine biomarkers may improve our ability to detect kidney damage. We assessed the association between 14 different urine biomarkers and AKI in VLBW infants.We performed a prospective cohort study on 113 VLBW infants (weight ≤1200 g or31 weeks' gestation) admitted to a regional neonatal intensive care unit at the University of Alabama at Birmingham between February 2012 and June 2013. SCr was measured on postnatal days 1, 2, 3, and 4 and was combined with clinically measured SCr to determine AKI according to Kidney Disease Improving Global Outcomes AKI definition (increase in SCr ≥0.3 mg/dl or ≥50% increase from previous lowest value). Urine was collected on the first 4 days (average number of urine collections, 3; range, 1-4). The maximum urine biomarkers and urine biomarker/creatinine levels were calculated for 12 urine biomarkers, and the minimum urine biomarker and biomarker/creatinine levels were assessed for two urine biomarkers. We compared these values between infants with and those without AKI. Ideal cutoffs, area under the receiver-operating characteristic curve , and area under the curve adjusted for gestational age were calculated.Cumulative incidence of AKI during the first 2 postnatal weeks was 28 of 113 (25%). Infants with AKI had higher maximum levels of urine cystatin C, neutrophil gelatinase-associated lipocalin, osteopontin, clusterin, and α glutathione S-transferase (2.0, 1.8, 1.7, 1.7, and 3.7 times higher, respectively) than infants without AKI. In addition, infants with AKI had lower minimum levels of epithelial growth factor and uromodulin than those without AKI (1.4 and 1.6 times lower, respectively). Most but not all participants had their maximum (or minimum) biomarker values preceding AKI. These associations remained after adjustment for gestational age.Urine biomarkers measured in the first 4 days of life are associated with AKI during the first postnatal weeks. Further evaluations are necessary to determine whether these biomarkers can predict important clinical outcomes. In addition, intervention studies that use biomarkers to stratify enrollment groups are needed before bedside evaluations can be incorporated into care.

Acute kidney injury (AKI) occurs commonly in neonates and is associated with increased mortality. Recent advances in neonatal intensive care have resulted in improved patient survival, but this had not been paralleled by improved outcomes for neonates with AKI. Management of AKI remains supportive with no effective pharmacologic therapy to hasten the recovery process. Emphasis is placed on the prevention and minimization of further renal insults once AKI is established. Routine, regular assessments of renal function with identification of high risk patients and those with incipient AKI are essential so prevention strategies can be promptly initiated. Effective prevention strategies include prompt restoration/preservation of organ perfusion with fluid resuscitation to ensure an adequate effective circulating volume and inotropic support as needed to maintain hemodynamic stability while also avoiding/minimizing nephrotoxin exposure. In established AKI, efforts are focused on maintaining organ perfusion while closely monitoring cumulative fluid balance from admission and remaining cognizant of the need to minimize the degree of fluid overload as this has also been associated with poor outcomes. Continuous renal replacement therapy (CRRT) has become the preferred therapy for managing fluid overload and metabolic disturbances in critically ill children and adults but is still considered by many to be a heroic intervention for neonates due in large part to numerous technical challenges. The recent development of two miniaturized machines specifically designed to deliver CRRT and hemodialysis (HD) to neonates will hopefully change this paradigm making it easier for nephrologists and intensivists to safely offer and provide this therapy to neonates. Prospective studies are needed to assess whether early initiation of RRT with correction of fluid imbalance results in improved patient survival and renal recovery.

Despite extensive research, no therapeutic interventions have been shown to prevent AKI, accelerate recovery of AKI, or reduce progression of AKI to CKD in patients. This failure in translation has led investigators to speculate that the animal models being used do not predict therapeutic responses in humans. Although this issue continues to be debated, an important concern that has not been addressed is whether improvements in preclinical study design can be identified that might also increase the likelihood of translating basic AKI research into clinical practice using the current models. In this review, we have taken an evidence-based approach to identify common weaknesses in study design and reporting in preclinical AKI research that may contribute to the poor translatability of the findings. We focused on use of N-acetylcysteine or sodium bicarbonate for the prevention of contrast-induced AKI and use of erythropoietin for the prevention of AKI, two therapeutic approaches that have been extensively studied in clinical trials. On the basis of our findings, we identified five areas for improvement in preclinical study design and reporting. These suggested and preliminary guidelines may help improve the quality of preclinical research for AKI drug development.

Providing renal support for small children is very challenging using the machinery currently available in the United States. As the extracorporeal volume (ECV) relative to blood volume increases and the state of critical illness worsens, the chance for instability during continuous renal replacement therapy (CRRT) initiation also increases. CRRT machines with smaller ECV could reduce the risks and improve outcomes. We present a case series of small children (n = 12) who received continuous venovenous hemofiltration (CVVH) via an Aquadex™ machine (ECV = 33 ml) with 30 ml/kg/h of prereplacement fluids at Children’s of Alabama between December 2013 and April 2015. We assessed in vitro fluid precision using the adapted continuous veno-venous hemofiltration (CVVH) system. We used 101 circuits over 261 days to provide CVVH for 12 children (median age 30 days; median weight 3.4 kg). Median CVVH duration was 14.5 days [interquartile range (IQR) = 10; 22.8 days]. Most circuits were routinely changed after 72 h. Five of 101 (5 %) initiations were associated with mild transient change in vital signs. Complications were infrequent (three transient cases of hypothermia, three puncture-site bleedings, one systemic bleed, and one right atrial thrombus). Most patients (7/12, 58 %) were discharged from the intensive care unit; six of them (50 %) were discharged home. CRRT machines with low ECV can enable clinicians to provide adequate, timely, safe, and efficient renal support to small, critically ill infants.

During the first postnatal weeks, infants have abrupt changes in fluid weight that alter serum creatinine (SCr) concentration, and possibly, the evaluation for acute kidney injury (AKI). We performed a prospective study on 122 premature infants to determine how fluid adjustment (FA) to SCr alters the incidence of AKI, demographics, outcomes, and performance of candidate urine biomarkers. FA-SCr values were estimated using changes in total body water (TBW) from birth; FA-SCR = SCr × [TBW + (current wt. – BW)]/ TBW; where TBW = 0.8 × wt in kg). SCr-AKI and FA-SCr AKI were defined if values increased by ≥ 0.3 mg/dl from previous lowest value. AKI incidence was lower using the FA-SCr vs. SCr definition [(23/122 (18.8 %) vs. (34/122 (27.9 %); p

Acute kidney injury in the neonate is due to a myriad of causes, often resulting in death from ultimate renal failure. Outcomes for the infant are dependent on underlying cause, degree of injury, and response to treatment. Improved outcomes can be seen with prompt recognition and appropriate treatment of the neonate who develops acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) is common in neonatal encephalopathy (NE) and is associated with worse outcomes. Our objectives were to determine the incidence, risk factors, and outcomes of AKI in infants with NE. METHODS: We performed a retrospective analysis of infants ≥ 34 weeks’ gestational age with a diagnosis of NE from the AWAKEN (Analysis of Worldwide Acute Kidney injury Epidemiology in Neonates) database. AKI was defined using the modified Kidney Disease Improving Global Outcomes criteria. Perinatal and postnatal factors were evaluated. Multivariate logistic and linear regression were performed. RESULTS: 113 patients with NE were included. 41.6% (47) developed AKI. Being born outside the admitting institution (OR 4.3; 95% CI:1.2 – 14.8; p = 0.02), intrauterine growth restriction (OR: 10.3, 95% CI:1.1 – 100.5; p = 0.04) and meconium at delivery (OR: 2.8, 95% CI:1.04 – 7.7; p = 0.04) conferred increased odds of AKI. After controlling for confounders, infants with AKI stayed in the hospital an average of 8.5 days longer than infants without AKI (95% CI: 0.79 – 16.2 days; p = 0.03). CONCLUSIONS: In this multi-national analysis, several important perinatal factors were associated with AKI and infants with both NE and AKI had longer length of stay than NE alone. Future research aimed at early AKI detection, renoprotective management strategies, and understanding the long-term renal consequences are warranted in this high-risk group of patients.

Acute kidney injury (AKI) occurs commonly in preterm neonates and is associated with increased morbidity and mortality.To examine the association between caffeine citrate administration and AKI in preterm neonates in the first 7 days after birth and to test the hypothesis that caffeine administration would be associated with reduced incidence and severity of AKI.This study was a secondary analysis of the Assessment of Worldwide Acute Kidney Injury Epidemiology in Neonates (AWAKEN) study, a retrospective observational cohort that enrolled neonates born from January 1 to March 31, 2014. The dates of analysis were October 2016 to December 2017. The setting was an international, multicenter cohort study of neonates admitted to 24 participating level III or IV neonatal intensive care units. Participants met the original inclusion and exclusion criteria of the AWAKEN study. Additional exclusion criteria for this study included participants greater than or equal to 33 weeks' gestation at birth, admission after age 7 days, use of theophylline in the neonatal intensive care unit, or lack of data to define AKI. There were 675 preterm neonates available for analysis.Administration of caffeine in the first 7 days after birth.The primary outcome was the incidence of AKI (based on the modified neonatal Kidney Disease: Improving Global Outcomes [KDIGO] definition) in the first 7 days after birth. The hypothesis that caffeine administration would be associated with reduced AKI incidence was formulated before data analysis.The study cohort (n = 675) was 55.4% (n = 374) male, with a mean (SD) gestational age of 28.9 (2.8) weeks and a mean (SD) birth weight of 1285 (477) g. Acute kidney injury occurred in 122 neonates (18.1%) in the first 7 days after birth. Acute kidney injury occurred less frequently among neonates who received caffeine than among those who did not (50 of 447 [11.2%] vs 72 of 228 [31.6%], P .01). After multivariable adjustment, administration of caffeine remained associated with reduced odds of developing AKI (adjusted odds ratio, 0.20; 95% CI, 0.11-0.34), indicating that for every 4.3 neonates exposed to caffeine one case of AKI was prevented. Among neonates with early AKI, those receiving caffeine were less likely to develop stage 2 or 3 AKI (adjusted odds ratio, 0.20; 95% CI, 0.12-0.34).Caffeine administration in preterm neonates is associated with reduced incidence and severity of AKI. Further studies should focus on the timing and dosage of caffeine to optimize the prevention of AKI.

Extraordinary advancements in neonatal care have markedly reduced mortality of infants hospitalized in Neonatal Intensive Care Unit (NICU). Over the last decade, studies show that neonatal acute kidney injury (AKI) is common and those with AKI have higher mortality and prolonged length of stay. The most common accepted definition of the neonatal AKI is based on a rise in serum creatinine and/or decrease in urine output. Premature infants are born with low nephron numbers which predisposes them to AKI and chronic kidney disease (CKD). Despite recent insights that substantiate the impact of poor kidney health on outcomes in sick neonates, significant critical gaps in our understanding of the antenatal and postnatal factors exist. The global burden of AKI and CKD in NICU graduates need to be better understood. Fortunately, progress is being made as investigators are performing large observational studies, and randomized clinical trials that evaluate risk factors, outcomes, and interventions. Peritoneal dialysis is a method of choice for kidney function replacement in newborns. In addition, novel machines, with smaller extracorporeal volume, designed to provide renal support for neonates have been designed and are currently in use in a few centers around the world.

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

In recent years, there have been significant advancements in our understanding of acute kidney injury (AKI) and its impact on outcomes across medicine. Research based on single-center cohorts suggests that neonatal AKI is very common and associated with poor outcomes. In this state-of-the-art review on neonatal AKI, we highlight the unique aspects of neonatal renal physiology, definition, risk factors, epidemiology, outcomes, evaluation, and management of AKI in neonates. The changes in renal function with gestational and chronologic age are described. We put forth and describe the neonatal modified Kidney Diseases: Improving Global Outcomes AKI criteria and provide the rationale for its use as the standardized definition of neonatal AKI. We discuss risk factors for neonatal AKI and suggest which patient populations may warrant closer surveillance, including neonates

Aminoglycoside (AG) therapy is a common cause of acute kidney injury (AKI) in cystic fibrosis (CF) patients. The aim of this study was to identify factors associated with AKI during intravenous AG courses in this population. This was a matched case–control study utilizing two independent cohorts of hospitalized CF patients receiving ≥3 days of intravenous AG at Cincinnati Children’s Hospital Medical Center and Children’s of Alabama. All admissions with AKI (cases, N = 82) were matched to two randomly selected admissions without AKI (controls, N = 164) by center, gender, and age ±3 years of the case. AKI was defined as a 1.5-fold increase in the baseline serum creatinine (SCr) level or by an increase in SCr level of 0.3 mg/dL within 48 h. Admissions with AKI before day 4 or without at least weekly SCr monitoring were excluded from the analysis. Factors were compared between cases and controls using simple and multiple conditional logistic regression. Multivariable analysis identified receipt of an AG within 90 days prior to admission, longer duration of AG therapy, low serum albumin, and receipt of trimethoprim/sulfamethoxazole as independent risk factors for developing AKI. Infection with Staphylococcus aureus diminished the odds of developing AKI. This study identifies risk factors contributing to AG-associated AKI in CF patients. These findings can be used to anticipate high-risk scenarios and limit AKI in CF patients under clinical care.

Background Heme Oxygenase 1 (HO1) catalyzes heme degradation, and offers protection for several organs, including the kidney. Genetic polymorphisms of HO-1 are associated with poor clinical outcomes in several populations. Methods Population: We prospectively enrolled 117 premature infants (birth weight ≤1200 gm. or post gestational age ≤31 weeks) and evaluated 2 DNA genetic variants proximal to the promoter region of HO-1 (GT(n) repeats, and–413T>A SNP). We evaluated how these polymorphisms affect 2 clinical outcomes i) AKI - rise in serum creatinine (SCr) ≥ 0.3 mg/dl or ≥ 150–200% from lowest previous value, ii) bronchopulmonary dysplasia (BPD) defined as receipt of oxygen at 36 weeks post menstrual age (PMA) / mortality. Results AKI occurred in 34/117 (29%) of neonates; 12/117 (10%) died; 29/105 (28%) survivors had BPD. Neonates with TT genotype at – 413T>A before the HO-1 promoter) had higher rates of AKI (pA genetic alteration had lower incidence of AKI. Further studies using larger cohorts are needed to better understand these relationships.

OBJECTIVE To characterize the epidemiology of fluid overload and its association with mortality and duration of extracorporeal membrane oxygenation in children treated with extracorporeal membrane oxygenation. DESIGN Retrospective cohort study. SETTING Six tertiary children's hospital ICUs. PATIENTS Seven hundred fifty-six children younger than 18 years old treated with extracorporeal membrane oxygenation for greater than or equal to 24 hours from January 1, 2007, to December 31, 2011. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Overall survival to extracorporeal membrane oxygenation decannulation and hospital discharge was 74.9% (n = 566) and 57.7% (n = 436), respectively. Median fluid overload at extracorporeal membrane oxygenation initiation was 8.8% (interquartile range, 0.3-19.2), and it differed between hospital survivors and non survival, though not between extracorporeal membrane oxygenation survivors and non survivors. Median peak fluid overload on extracorporeal membrane oxygenation was 30.9% (interquartile range, 15.4-54.8). During extracorporeal membrane oxygenation, 84.8% had a peak fluid overload greater than or equal to 10%; 67.2% of patients had a peak fluid overload of greater than or equal to 20% and 29% of patients had a peak fluid overload of greater than or equal to 50%. The median peak fluid overload was lower in patients who survived on extracorporeal membrane oxygenation (27.2% vs 44.4%; p < 0.0001) and survived to hospital discharge (24.8% vs 43.3%; p < 0.0001). After adjusting for acute kidney injury, pH at extracorporeal membrane oxygenation initiation, nonrenal complications, extracorporeal membrane oxygenation mode, support type, center and patient age, the degree of fluid overload at extracorporeal membrane oxygenation initiation (p = 0.05), and the peak fluid overload on extracorporeal membrane oxygenation (p < 0.0001) predicted duration of extracorporeal membrane oxygenation in survivors. Multivariable analysis showed that peak fluid overload on extracorporeal membrane oxygenation (adjusted odds ratio, 1.09; 95% CI, 1.04-1.15) predicted mortality on extracorporeal membrane oxygenation; fluid overload at extracorporeal membrane oxygenation initiation (adjusted odds ratio, 1.13; 95% CI, 1.05-1.22) and peak fluid overload (adjusted odds ratio, 1.18; 95% CI, 1.12-1.24) both predicted hospital morality. CONCLUSIONS Fluid overload occurs commonly and is independently associated with adverse outcomes including increased mortality and increased duration of extracorporeal membrane oxygenation in a broad pediatric extracorporeal membrane oxygenation population. These results suggest that fluid overload is a potential target for intervention to improve outcomes in children on extracorporeal membrane oxygenation.

Developing a neonatal acute kidney injury research definition: a report from the NIDDK neonatal AKI workshop

An expert panel was convened to provide specific, expert consensus guidelines for the use of glucarpidase in patients who develop high‐dose methotrexate (HDMTX)‐induced nephrotoxicity and delayed methotrexate excretion. This guideline provides recommendations to identify the population of patients who would benefit from glucarpidase rescue by more precisely defining the absolute methotrexate concentrations associated with risk for severe or life‐threatening toxicity at several time points after the start of a HDMTX infusion., Acute kidney injury due to high‐dose methotrexate (HDMTX) is a serious, life‐threatening toxicity that can occur in pediatric and adult patients. Glucarpidase is a treatment approved by the Food and Drug Administration for high methotrexate concentrations in the context of kidney dysfunction, but the guidelines for when to use it are unclear. An expert panel was convened to provide specific, expert consensus guidelines for the use of glucarpidase in patients who develop HDMTX‐induced nephrotoxicity and delayed methotrexate excretion. The guideline provides recommendations to identify the population of patients who would benefit from glucarpidase rescue by more precisely defining the absolute methotrexate concentrations associated with risk for severe or life‐threatening toxicity at several time points after the start of an HDMTX infusion. For an HDMTX infusion ≤24 hours, if the 36‐hour concentration is above 30 µM, 42‐hour concentration is above 10 µM, or 48‐hour concentration is above 5 µM and the serum creatinine is significantly elevated relative to the baseline measurement (indicative of HDMTX‐induced acute kidney injury), glucarpidase may be indicated. After a 36‐ to 42‐hour HDMTX infusion, glucarpidase may be indicated when the 48‐hour methotrexate concentration is above 5 µM. Administration of glucarpidase should optimally occur within 48–60 hours from the start of the HDMTX infusion, because life‐threatening toxicities may not be preventable beyond this time point. Implications for Practice. Glucarpidase is a rarely used medication that is less effective when given after more than 60 hours of exposure to high‐dose methotrexate, so predicting early which patients will need it is imperative. There are no currently available consensus guidelines for the use of this medication. The indication on the label does not give specific methotrexate concentrations above which it should be used. An international group of experts was convened to develop a consensus guideline that was specific and evidence‐based to identify the population of patients who would benefit from glucarpidase.

Patients who develop sickle cell disease (SCD) nephropathy are at a high risk for mortality. The pathophysiology of vaso-occlusive pain crisis may contribute to acute kidney injury (AKI). Non-steroidal anti-inflammatory drugs, known inducers of AKI, are used to treat pain crises. Multiple gaps exist in the knowledge about the impact of AKI in SCD. We conducted a 2-year retrospective review of AKI events in patients admitted for vaso-occlusive crisis. AKI was defined by an increase of ≥0.3 mg/dL or 50% in serum creatinine from baseline. Laboratory values and ketorolac administration by days and dose (mg/kg) were identified from hospital records. A generalized mixed effects model for binary outcomes evaluated AKI based on laboratory variables and ketorolac administration. A generalized mixed Poisson effects model analyzed the association of AKI with hospital length of stay. Thirty-three out of 197 admissions for vaso-occlusive pain crisis (17%) were associated with AKI. Fifty-two percent of the cases presented to the Emergency Room (ER) with AKI. Every one unit decrease in hemoglobin from baseline to admission increased the risk of AKI by 49%. Among patients who received ketorolac for pain, both total days and doses of ketorolac were associated with AKI. Finally, patients with pain and AKI required longer periods of hospitalization than patients without AKI. Acute kidney injury during sickle cell pain crisis is common and may be an important modifiable risk factor for developing chronic kidney disease (CKD). Further studies are needed to determine the impact of nephrotoxic medications on progressive SCD nephropathy.

This chapter presents the case of a premature (31-week gestation) infant whose birth weight was 1.4 kg and who did well for the first 49 days of life. On day of life 50, the infant developed signs of sepsis and was found to have intestinal volvulus with perforation that quickly progressed to multiple organ failure, including acute kidney injury (AKI) with fluid overload. The chapter reviews the current diagnostic criteria for neonatal AKI while addressing the decision to launch renal replacement therapy. The choice of continuous renal replacement therapy (CRRT) as the RRT modality of choice for this infant is examined, followed by an in-depth discussion of the major technical issues encountered when providing CRRT for any neonate, including vascular access, blood vs. saline circuit prime, and anticoagulation modality. The details of the CRRT prescription chosen for this infant are reviewed. The chapter concludes with a summary of the infant’s course on CRRT and a series of clinical pearls illustrated by the case.

Hypothesis Acute kidney injury (AKI) is a common cause of morbidity and mortality worldwide, with a pediatric incidence ranging from 19.3% to 24.1%. Treatment of pediatric AKI is a source of debate in varying geographical regions. Currently CRRT is the treatment for pediatric AKI, but limitations due to cost and accessibility force use of adult equipment and other therapeutic options such as peritoneal dialysis (PD) and hemodialysis (HD). It was hypothesized that more cost-effective measures would likely be used in developing countries due to lesser resource availability. Methods A 26-question internet-based survey was distributed to 650 pediatric Nephrologists. There was a response rate of 34.3% (223 responses). The survey was distributed via pedneph and pcrrt email servers, inquiring about demographics, technology, resources, pediatric-specific supplies, and preference in renal replacement therapy (RRT) in pediatric AKI. The main method of analysis was to compare responses about treatments between nephrologists in developed countries and nephrologists in developing countries using difference-of-proportions tests. Results PD was available in all centers surveyed, while HD was available in 85.1% and 54.1% (p = 0.00), CRRT was available in 60% and 33.3% (p = 0.001), and SLED was available in 20% and 25% (p = 0.45) centers of developed and developing world respectively. In developing countries, 68.5% (p = 0.000) of physicians preferred PD to costlier therapies, while in developed countries it was found that physicians favored HD (72%, p = 0.00) or CRRT (24%, p = 0.041) in infants. Conclusions Lack of availability of resources, trained physicians and funds often preclude standards of care in developing countries, and there is much development needed in terms of meeting higher global standards for treating pediatric AKI patients. PD remains the main modality of choice for treatment of AKI in infants in developing world.

Critically ill neonates are at risk for acute kidney injury (AKI). AKI has been associated with increased risk of morbidity and mortality in adult and pediatric patients, and increasing evidence suggests a similar association in the neonatal population. This article describes the current AKI definitions (including their limitations), work on novel biomarkers to define AKI, diagnosis and management strategies, long-term outcomes after AKI, and future directions for much-needed research in this important area.

Dent disease is an X-linked recessive renal tubular disorder characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and progressive renal failure (MIM 300009). A recent case series identified four patients with CLCN5 mutations who presented with nephrotic-range proteinuria, histologic evidence of focal segmental and/or global sclerosis, and low molecular weight proteinuria. We characterize the clinical, genetic, and histopathological features of seven unrelated adolescent males with nephrotic-range proteinuria and CLCN5 mutations. Six patients underwent renal biopsy prior to assessing tubular proteinuria. All biopsied patients had either segmental sclerosis (3/6) or segmental increase in mesangial matrix (3/6). Five patients revealed some degree of foot process effacement, but only one patient biopsy revealed >50 % foot process effacement. The attenuated foot process effacement suggests the glomerulosclerosis is not due to a primary podocytopathy. These data suggest that clinicians should consider a diagnostic evaluation for Dent disease in young males presenting with high-grade proteinuria.

Background Measurement of serum creatinine (SCr) and urine creatinine (UCr) is regularly used in clinical and research settings. For small animal experiments and for studies in which sample collection is spare (i.e. neonatal cohorts), measuring SCr and UCr using tiny amounts of sample (as low as 10 mcl) would maximize exploration and minimize iatrogenic blood loss. Methods We performed an evaluation in six healthy adults to determine differences between SCr and UCr values in different methodologies and storage environments and time. Study was conducted using 20 mcl of sample. Analyses were done using two-way repeated measures of ANOVA. Results Scr values showed no significant differences between LC/MS vs. Jaffe. However, the SCr using LC/MS method was lowest when measured immediately compared to other time points (F = 7.2; P< 0.001). Similarly, Jaffe measurements showed changes in the mean differences over time; however, these were not significant. UCr values were consistently higher using LC/MS than Jaffe (F = 19; P< 0.01), and UCr changed over time (F = 8.7; P < 0.02). In addition, the interaction term for method and time was also significant (F = 5.8; P < 0.04) which reflects the stability of the Jaffe measurements over time whereas the LC/MS measurements declined; especially after being frozen for 1 year (P < 0.001). Conclusion UCr measured by Jaffe is lower than samples measured by LC/MS. UCr measurements by LC/MS vary more over time, mostly due to the sample measured after 1 year; therefore, storage of urine for more than 90 days measured by LC/MS may provide altered results.

The original version of this article unfortunately contained a mistake. The collaborators of the Neonatal Kidney Collaborative (NKC) were not named individually. The list of all collaborators is given below.

Acute kidney injury (AKI) frequently occurs in neonates and infants after cardiopulmonary bypass (CPB) and may require renal replacement therapy (RRT). Peritoneal dialysis (PD) is the RRT modality of choice in neonates with AKI after CPB, but continuous renal replacement therapy (CRRT) may be necessary if PD is ineffective or contraindicated. Vascular access is challenging in this population, in part, due to small central vein size that may preclude placement. The risk of malfunction or morbidity associated with standard dialysis catheters may be excessive in neonates with congenital heart disease. We describe a unique approach to vascular access for CRRT in six small patients with AKI.This is a retrospective review of six patients with fluid overload and AKI that received CRRT because PD was contraindicated. In all cases, CRRT was performed via two hemostasis valve sheaths placed into separate veins for dialysis access and return. The low-resistance sheaths provided excellent blood flow with normalization of metabolic derangements and significant fluid removal (median negative 167 ml/kg at 72 h). Mean circuit life before the first change was 55.2 ± 30.4 h.The use of two small single-lumen catheters in separate veins enables consistent and effective hemodiafiltration in neonates and infants with challenging vascular access.

Objective To investigate impact of prophylactic peritoneal dialysis (PD) on clinical outcomes and inflammatory cytokines in children following cardiac surgery with cardiopulmonary bypass. Design Prospective before-and-after nonrandomized cohort study. Setting Pediatric cardiovascular intensive care unit in tertiary hospital. Patients Fifty-two consecutive neonates and infants at high risk for postoperative fluid overload following cardiopulmonary bypass. All had PD catheters placed during primary cardiac surgery. Intervention Initial 27 patients were managed with passive peritoneal drainage and diuretics (controls). Following 25 patients were started on prophylactic PD in immediate postoperative period and managed per PD protocol (+PD). Outcome Measures Cumulative fluid balance, indices of disease severity, and clinical outcomes were prospectively collected. Plasma interleukin-6 and interleukin-8 were measured immediately before-and-after cardiopulmonary bypass and at 24 and 48 hours post–cardiopulmonary bypass. Results Demographics, diagnoses, and intraoperative variables were similar. Median net fluid balance was more negative in +PD at 24 hours, −24 mL/kg (interquartile range: −62, 11) vs. +18 mL/kg (interquartile range: −26, 11), P = .003, and 48 hours, −88 mL/kg (interquartile range: −132, −54) vs. −46 mL/kg (interquartile range: −84, −12), P = .004. +PD had median 55 mL/kg less fluid intake at 24 hours, P = .058. Peritoneal drain, urine, and chest tube output were comparable over first 24 hours. Mean inotrope score was lower in +PD at 24 hours. +PD had earlier sternal closure—24 hours (interquartile range: 20, 40) vs. 63 hours (interquartile range: 44, 72), P < .001—and a trend toward shorter duration of mechanical ventilation—71 hours (interquartile range: 49, 135) vs. 125 hours (interquartile range: 70, 195), P = .10. +PD experienced lower serum concentrations of interleukin-6 and interleukin-8 at 24 hours. Conclusions Prophylactic PD is associated with greater net negative fluid balance, decreased inotrope requirements, and lower serum concentrations of inflammatory cytokines in the early postoperative period.

Acute kidney injury (AKI) staging has been developed in the adult and pediatric populations, but these do not yet exist for the neonatal population. Metabolomics was utilized to uncover biomarkers of normal and AKI-associated renal function in preterm infants. The study comprised 20 preterm infants with an AKI diagnosis who were matched by gestational age and gender to 20 infants without an AKI diagnosis. Urine samples from pre-term newborn infants collected on day 2 of life were analyzed using broad-spectrum nuclear magnetic resonance (NMR) metabolomics. Multivariate analysis methods were used to identify metabolite profiles that differentiated AKI and no AKI, and to identify a metabolomics profile correlating with gestational age in infants with and without AKI. There was a clear distinction between the AKI and no-AKI profiles. Two previously identified biomarkers of AKI, hippurate and homovanillate, differentiated AKI from no-AKI profiles. Pathway analysis revealed similarities to cholinergic neurons, prenatal nicotine exposure on pancreatic β cells, and amitraz-induced inhibition of insulin secretion. Additionally, a pH difference was noted. Both pH and the metabolites were found to be associated with AKI; however, only the metabotype was a significant predictor of AKI. Pathways for the no-AKI group that correlated uniquely with gestational age included aminoacyl-t-RNA biosynthesis, whereas pathways in the AKI group yielded potential metabolite changes in pyruvate metabolism. Metabolomics was able to differentiate the urinary profiles of neonates with and without an AKI diagnosis and metabolic developmental profiles correlated with gestational age. Further studies in larger cohorts are needed to validate these results.

Introduction Acute kidney injury (AKI) affects ~30% of hospitalized neonates. Critical to advancing our understanding of neonatal AKI is collaborative research among neonatologists and nephrologists. The Neonatal Kidney Collaborative (NKC) is an international, multidisciplinary group dedicated to investigating neonatal AKI. The AWAKEN study (Assessment of Worldwide Acute Kidney injury Epidemiology in Neonates) was designed to describe the epidemiology of neonatal AKI, validate the definition of neonatal AKI, identify primary risk factors for neonatal AKI, and investigate the contribution of fluid management to AKI events and short-term outcomes. Methods and analysis The NKC was established with at least one pediatric nephrologist and neonatologist from 24 institutions in 4 countries (USA, Canada, Australia, and India). A Steering Committee and four subcommittees were created. The database subcommittee oversaw the development of the web-based database (MediData Rave™) that captured all NICU admissions from 1/1/14 to 3/31/14. Inclusion and exclusion criteria were applied to eliminate neonates with a low likelihood of AKI. Data collection included: (1) baseline demographic information; (2) daily physiologic parameters and care received during the first week of life; (3) weekly “snapshots”; (4) discharge information including growth parameters, final diagnoses, discharge medications, and need for renal replacement therapy; and (5) all serum creatinine values. Ethics and dissemination AWAKEN was proposed as human subjects research. The study design allowed for a waiver of informed consent/parental permission. NKC investigators will disseminate data through peer-reviewed publications and educational conferences. Discussion The purpose of this publication is to describe the formation of the NKC, the establishment of the AWAKEN cohort and database, future directions, and a few “lessons learned.” The AWAKEN database includes ~325 unique variables and >4 million discrete data points. AWAKEN will be the largest, most inclusive neonatal AKI study to date. In addition to validating the neonatal AKI definition and identifying risk factors for AKI, this study will uncover variations in practice patterns related to fluid provision, renal function monitoring, and involvement of pediatric nephrologists during hospitalization. The AWAKEN study will position the NKC to achieve the long-term goal of improving the lives, health, and well-being of newborns at risk for kidney disease.

Acute kidney injury (AKI) is an independent risk factor for morbidity and mortality in critically ill neonates. Nephrotoxic medication exposure is common in neonates. Nephrotoxicity represents the most potentially avoidable cause of AKI in this population.Recent studies in critically ill children revealed the importance of recognizing AKI and potentially modifiable risk factors for the development of AKI such as nephrotoxic medication exposures. Data from critically ill children who have AKI suggest that survivors are at risk for the development of chronic kidney disease. Premature infants are born with incomplete nephrogenesis and are at risk for chronic kidney disease. The use of nephrotoxic medications in the neonatal intensive care unit is very common; yet the effects of medication nephrotoxicity on the short and long-term outcomes remains highly understudied.The neonatal kidney is predisposed to nephrotoxic AKI. Our ability to improve outcomes for this vulnerable group depends on a heightened awareness of this issue. It is important for clinicians to develop methods to minimize and prevent nephrotoxic AKI in neonates through a multidisciplinary approach aiming at earlier recognition and close monitoring of nephrotoxin-induced AKI.

Acute kidney injury (AKI) is common in neonates requiring extracorporeal membrane oxygenation (ECMO). Despite the strong association between AKI and worse outcome in patients requiring ECMO, there is considerable variation in how this morbidity is managed. We will address the pathophysiology and epidemiology of AKI in the neonatal ECMO patient. We will also discuss the indications and technical aspects of providing renal replacement therapy (RRT) for the neonate on ECMO.

Nephrotoxic medication use is common in neonates. In older children, the use of nephrotoxic medication is known to be one of the most common causes of acute kidney injury (AKI) and to be associated with increased morbidity. In critically ill neonates, AKI significantly complicates fluid and electrolyte management and may be an important risk factor for mortality. Better understanding of methods to avoid and detect the presence of nephrotoxicity may lead to more intelligent use of these medications, which could ultimately reduce the incidence of AKI and improve outcomes. In this work, we summarize why neonates are predisposed to drug nephrotoxicity, review the mechanisms and clinical picture of the most common nephrotoxic medications used in neonates (aminoglycosides, vancomycin, amphotericin B, acyclovir, nonsteroidal anti-inflammatory drugs, and radiocontrast agents), and discuss the roles of angiotensin-converting enzyme inhibitors and diuretics in nephrotoxicity. We also suggest ways to avoid and reduce the incidence and complications of neonatal nephrotoxicity.

Renal replacement therapy (RRT) is used in a wide variety of pediatric populations. In this article, we will review the advantages and disadvantages of the different RRT modalities and the technical aspects of providing pediatric RRT. In addition, we will review the use of RRT with extracorporeal membrane oxygenation, the use of continuous RRT in the critically ill child with acute kidney injury and fluid overload, and the use of RRT for the removal of toxins and treatment of inborn errors of metabolism.

Patients with sickle cell disease are at risk for developing chronic kidney disease (CKD). Acute kidney injury (AKI) has been linked to progression to CKD, but limited data exist to determine its role in acute complications of sickle cell disease. We hypothesized that AKI occurs in pediatric patients admitted for acute chest syndrome (ACS) and prolongs hospitalization.We conducted a 6-year retrospective review of pediatric patients with ACS admitted to a single medical institution.Of the 149 pediatric patients admitted for ACS during the 6-year study period, 12 (8 %) developed AKI. Comparison of patients with and without AKI revealed a significant association between AKI and a larger drop in hemoglobin value from baseline (2.7 vs. 1.4 g/dL; p = 0.003), a lower hemoglobin value at admission (6.4 vs. 7.5 g/dL; p = 0.03), and an increased white blood cell count at admission (33.1 vs. 19.8 × 10(9)/L; p 0.0001), respectively. AKI (p 0.0001) together with need for advanced respiratory support (biphasic positive airway pressure or mechanical ventilation) (p 0.0001) and need for exchange transfusion (p 0.0001) were associated with prolonged hospitalization.Clinicians should monitor pediatric patients hospitalized for ACS for the development of AKI as a potentially modifiable risk factor for prolonged hospitalization.

Despite improvements in survival of premature infants, many have comorbid conditions. The role of the kidney in multiorgan dysfunction is unclear, particularly in regard to intraventricular hemorrhage (IVH). We hypothesized that infants diagnosed with acute kidney injury (AKI) have an increased risk of IVH independent of gestational age (GA) and other variables associated with both comorbidities. This prospective cohort study consisted of 125 infants with a birth weight ≤1,200 g and/or GA ≤31 weeks. A definition of AKI was used from KDIGO, not including urine output as nonoliguria is common in this population. IVH was based on serial head ultrasounds. Neonates with AKI had a higher trend towards having IVH compared to those without [14/35 (40%) vs. 22/83 (26.5%), p = 0.1]. Infants with AKI were more likely to have stage 2 IVH or higher than those without AKI [12/36 (33.3%) vs. 6/82 (7.3%); p < 0.01]. AKI was associated with a 3.6-fold increased risk of a grade 2 or higher IVH [hazard ratio (HR) 3.55, 95% confidence interval (CI) 1.39-9.07] and over 4-fold increase in risk of a grade 3 or higher IVH (HR 4.34, 95% CI 1.43-13.21). While there was no association between AKI and IVH overall, those with AKI had a higher hazard ratio to develop a grade 2 or higher IVH even when controlling for birth weight, antenatal steroid use, and 5-min Apgar score. Future studies are indicated to expand sample size and to control for other clinical variables that could be associated with both AKI and IVH.

Newborn screening (NBS) has rapidly changed since its origins in the 1960s. Beginning with a single condition, then a handful in the 1990 s, NBS has expanded in the past decade to allow the detection of many disorders of amino-acid, organic-acid, and fatty-acid metabolism. These conditions often present with recurrent acute attacks of metabolic acidosis, hypoglycemia, liver failure, and hyperammonemia that may be prevented with initiation of early treatment. Renal disease is an important component of these disorders and is a frequent source of morbidity. Hemodialysis is often required for hyperammonemia in the organic acidemias and urea-cycle disorders. Rhabdomyolysis with renal failure is a frequent complication in fatty-acid oxidation disorders. Newer screening methods are under investigation to detect lysosomal storage diseases, primary immunodeficiencies, and primary renal disorders. These advances will present many challenges to nephrologists and pediatricians with respect to closely monitoring and caring for children with such disorders.

Hypertension occurs in up to 3% of neonates admitted to the Neonatal Intensive Care Unit (NICU), and is a potentially under-recognized condition. The aim of this study was to examine the incidence of documented and undiagnosed hypertension from the 24-center Assessment of Worldwide Acute Kidney Injury Epidemiology in Neonates (AWAKEN) database, and to assess risk factors for hypertension according to gestational age. Diagnosed hypertension was documented if an infant had a discharge diagnosis of hypertension and/or discharged on antihypertensive medications. Undiagnosed hypertension was defined when infants did not have a diagnosis of hypertension, but >50% of the lowest mean, diastolic and systolic blood pressure recordings were >95th percentile for gestational age. Of the 2162 neonates enrolled in the study, hypertension was documented in 1.8%. An additional 3.7% were defined as having undiagnosed hypertension. There was a significant correlation with neonatal hypertension and acute kidney injury (AKI). Additional risk factors for neonatal hypertension were hyperbilirubinaemia, Caucasian race, outborn, vaginal delivery, and congenital heart disease. Protective factors were small for gestational age, multiple gestations, and steroids for fetal maturation. Neonatal hypertension may be an under-recognized condition. AKI and other risk factors predispose infants to hypertension.

The measurement properties of the newly developed Pediatric Quality of Life Inventory (PedsQL) 3.0 Transplant Module in pediatric solid organ transplant recipients were evaluated. Participants included pediatric recipients of liver, kidney, heart and small bowel transplantation who were cared for at seven medical centers across the United States and their parents. Three hundred and thirty-eight parents of children ages 2-18 and 274 children ages 5-18 completed both the PedsQL 4.0 Generic Core Scales and the Transplant Module. Findings suggest that child self-report and parent proxy-report scales on the Transplant Module demonstrated excellent reliability (total scale score for child self-report alpha= 0.93; total scale score for parent proxy-report alpha= 0.94). Transplant-specific symptoms or problems were significantly correlated with lower generic HRQOL, supporting construct validity. Children with solid organ transplants and their parents reported statistically significant lower generic HRQOL than healthy children. Parent and child reports showed moderate to good agreement across the scales. In conclusion, the PedsQL Transplant Module demonstrated excellent initial feasibility, reliability and construct validity in pediatric patients with solid organ transplants.

Outcomes in children with proliferate lupus nephritis (PLN) show 9-15% progress to end-stage renal disease (ESRD) at 5 years. Immunosuppression improves outcome, but significant side effects are possible. Clinical and laboratory analyses are poor predictors of class and progression in PLN. We describe 28 patients with systemic lupus erythematosus (SLE), between 1990 and 2005, whose initial biopsy (Bx1) showed PLN and who received nine monthly doses of intravenously administered cyclophosphamide (CYP) (500-750 mg/m(2) up to 1 g to maintain their absolute neutrophil count (ANC) > 3,000). Continued therapy with additional quarterly intravenous (i.v). administration of CYP was dictated by repeat renal biopsy (Bx2). Bx1 was done 1 +/- 1.6 years after diagnosis of SLE. Bx2 showed histological improvement by WHO classification in 20/25 children; 3/25 were unchanged, 1/25 was categorized as new class V, and 1/25 was worse. Four patients (14%) had infectious complications requiring hospitalization (one of these died). Mean follow-up (f/u) after Bx2 was 3.5 +/- 2.3 years. At last follow-up, 26 patients had normal glomerular filtration rate (GFR), with a mean of 126 +/- 42.8 ml/min per 1.73 m(2) body surface area, one non-compliant patient had ESRD, and one had chronic renal failure. At last follow-up, most patients had minimal to no proteinuria. Clinical and biopsy results greatly improved after 9 monthly intravenously administered CYP pulses in most children with class IV PLN. Those who did not improve are at risk for flares and progression of disease. The tailoring of therapies based on findings from a biopsy after induction may improve outcomes.