A quantitative assessment of renal function utilizing albuminuria in pediatric heart transplant recipients.

INTRODUCTION: Kidney disease is common after pediatric heart transplantation. Serum creatinine-based glomerular filtration rate is the most frequently reported measure of kidney function. Albuminuria is an additional marker of kidney dysfunction and is not well described in this population. In this study, we evaluate the prevalence and degree of albuminuria and describe clinical factors associated with albuminuria in a cohort of pediatric heart transplant recipients. METHODS: This was a cross-sectional study of pediatric heart transplant recipients. Albuminuria was assessed using spot urine albumin-to-creatinine ratio collected at the most recent annual screening cardiac catheterization through August 2019. RESULTS: In 115 patients at a median duration of 10.2 years post-transplant, 39% had albuminuria. Stage 3 or greater chronic kidney disease was present in 6%. The immunosuppressive regimen at the time of measurement contained a calcineurin inhibitor (CNI) in 88% and a proliferation signal inhibitor (PSI) in 62%. In multivariable modeling, lower eGFR, PSI use, and younger age at transplant were associated with higher levels of albuminuria, whereas CNI use was associated with lower levels of albuminuria. CONCLUSION: Albuminuria is a prevalent finding in medium-term follow up of pediatric heart transplant recipients, reflecting kidney injury, and is associated with other markers of kidney dysfunction, such as low eGFR. Younger age at transplant, lower eGFR, and PSI use were among the associations with albuminuria.

Randomized controlled trial of remote ischemic preconditioning in children having cardiac surgery.

BACKGROUND: Children undergoing cardiac surgery are at risk for acute kidney injury (AKI) and cardiac dysfunction. Opportunity exists in protecting end organ function with remote ischemic preconditioning. We hypothesize this intervention lessens kidney and myocardial injury. METHODS: We conducted a randomized, double blind, placebo controlled trial of remote ischemic preconditioning in children undergoing cardiac surgery. Pre-specified end points are change in creatinine, estimated glomerular filtration rate, development of AKI, B-type natriuretic peptide and troponin I at 6, 12, 24, 48, 72 h post separation from bypass. RESULTS: There were 45 in the treatment and 39 patients in the control group, median age of 3.5 and 3.8 years, respectively. There were no differences between groups in creatinine, cystatin C, eGFR at each time point. There was a trend for a larger rate of decrease, especially for cystatin C (p = 0.042) in the treatment group but the magnitude was small. AKI was observed in 21 (54%) of control and 16 (36%) of treatment group (p = 0.094). Adjusting for baseline creatinine, the odds ratio for AKI in treatment versus control was 0.31 (p = 0.037); adjusting for clinical characteristics, the odds ratio was 0.34 (p = 0.056). There were no differences in natriuretic peptide or troponin levels between groups. All secondary end points of clinical outcomes were not different. CONCLUSIONS: There is suggestion of RIPC delivering some kidney protection in an at-risk pediatric population. Larger, higher risk population studies will be required to determine its efficacy. Trial registration and date: Clinicaltrials.gov NCT01260259; 2021.

Association Between Urinary Biomarkers and CKD in Extremely Low Gestational Age Neonates.

RATIONALE & OBJECTIVE: Children born before 28 weeks' gestation are at increased risk of chronic kidney disease (CKD). Urine biomarkers may shed light on mechanistic pathways and improve the ability to forecast CKD. We evaluated whether urinary biomarkers in neonates of low gestational age (GA) are associated with a reduced estimated glomerular filtration rate (eGFR) over time. STUDY DESIGN: A cohort study of neonates with an exploratory case-control study of a subset of the cohort. SETTING & PARTICIPANTS: 327 neonates born at 24-27 weeks' gestation with 2-year eGFR data from the PENUT (Preterm Erythropoietin Neuroprotection Trial) and the REPaIReD (Recombinant Erythropoietin for Prevention of Infant Renal Disease) study. EXPOSURES: 11 urinary biomarkers measured at 27, 30, and 34 weeks' postmenstrual age for the primary cohort study and 10 additional biomarkers for the exploratory case-control study. OUTCOMES: eGFR<90mL/min/1.73m2 at 2 years corrected for GA. ANALYTICAL APPROACH: Linear mixed models to assess differences in biomarker values between neonates in whom CKD did and did not develop, accounting for multiple comparisons using Bonferroni-Holm correction in the cohort study only. Cohort analyses were adjusted for sex, GA, and body mass index. Cases were matched to controls on these variables in the case-control study. RESULTS: After adjusting for weeks of GA, urinary levels of α-glutathione-S-transferase (log difference, 0.27; 95% CI, 0.12-0.43), albumin (log difference, 0.13; 95% CI, 0.02-0.25), and cystatin C (log difference, 0.19; 95% CI, 0.04-0.34) were higher in those in whom CKD developed than in those in whom it did not. Urinary albumin and cystatin C levels did not remain significantly different after Bonferroni-Holm correction. In the exploratory case-control analysis, there were no differences in any biomarkers between cases and controls. LIMITATIONS: Early deaths and a high number of subjects without eGFR at 2 years corrected for GA. CONCLUSIONS: Measurement of urinary biomarkers may assist in monitoring neonates who are at risk for CKD. Additional studies are needed to confirm these findings. FUNDING: Grants from government (National Institutes of Health). TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT01378273. PLAIN-LANGUAGE SUMMARY: Approximately 15 million neonates worldwide are born prematurely, and 2 million are born before 28 weeks' gestation. Many of these children go on to experience chronic kidney disease. Urine biomarkers may allow for early recognition of those at risk for the development of kidney disease. In this study of more than 300 children born before 28 weeks' gestational age, we found higher mean urinary levels of α-glutathione-S-transferase at 27, 30, and 34 weeks in children whose estimated glomerular filtration rate was<90mL/min/1.73m2 at 2 years compared with children whose estimated glomerular filtration rate was>90mL/min/1.73m2 at 2 years. Measurement of urinary biomarkers may assist in monitoring neonates who are at risk for chronic kidney disease. Additional studies are needed to confirm our findings.

Prospective Clinical and Biomarker Validation of the American Society for Transplantation and Cellular Therapy Consensus Definition for Transplantation-Associated Thrombotic Microangiopathy.

Transplantation-associated thrombotic microangiography (TA-TMA) is a disorder that causes severe complications after allogeneic hematopoietic cell transplantation (allo-HCT). Diagnosing TA-TMA is challenging because of the lack of standardized criteria. In this study, we aimed to evaluate the new TA-TMA consensus definition from the American Society for Transplantation and Cellular Therapy (ASTCT) panel as part of an ongoing prospective pediatric cohort study, and also to compare the impact and outcomes of using the current definition of clinical TMA (cTMA) versus the new consensus definition. We included patients age 0 to 18 years who underwent their first allo-HCT between May 2021 and January 2023 at Texas Children's Hospital. We compared the incidence, biomarkers, and outcomes of TA-TMA applying the previous and recently proposed screening algorithms and definitions. Whereas use of the classic microangiopathic hemolytic anemia (MAHA)-based cTMA definition led to an incidence of 12.7% by day 100 post-transplantation, the ASTCT-HR definition doubled the incidence to 28.5% by day 100. In contrast to patients with a concordant diagnosis (+/+), who had significantly worse post-transplantation survival, those reclassified as TA-TMA only by the new definition (-/+) had a significantly different prognosis (100% survival at day 100) despite the lack of TMA-directed therapy. Furthermore, biomarkers of the terminal and alternative complement pathways (sC5b9 and Ba, respectively) were significantly elevated compared with non-TMA patients around day 15 in the concordant group (+/+) but not in the discordant group (-/+). The recently proposed ASTCT consensus TA-TMA diagnosis is more sensitive and allows earlier recognition of manifestation that requires closer clinical monitoring but risks overdiagnosis and overtreatment. We recommend additional prospective validation.

Precision nephrology identified tumor necrosis factor activation variability in minimal change disease and focal segmental glomerulosclerosis.

The diagnosis of nephrotic syndrome relies on clinical presentation and descriptive patterns of injury on kidney biopsies, but not specific to underlying pathobiology. Consequently, there are variable rates of progression and response to therapy within diagnoses. Here, an unbiased transcriptomic-driven approach was used to identify molecular pathways which are shared by subgroups of patients with either minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS). Kidney tissue transcriptomic profile-based clustering identified three patient subgroups with shared molecular signatures across independent, North American, European, and African cohorts. One subgroup had significantly greater disease progression (Hazard Ratio 5.2) which persisted after adjusting for diagnosis and clinical measures (Hazard Ratio 3.8). Inclusion in this subgroup was retained even when clustering was limited to those with less than 25% interstitial fibrosis. The molecular profile of this subgroup was largely consistent with tumor necrosis factor (TNF) pathway activation. Two TNF pathway urine markers were identified, tissue inhibitor of metalloproteinases-1 (TIMP-1) and monocyte chemoattractant protein-1 (MCP-1), that could be used to predict an individual's TNF pathway activation score. Kidney organoids and single-nucleus RNA-sequencing of participant kidney biopsies, validated TNF-dependent increases in pathway activation score, transcript and protein levels of TIMP-1 and MCP-1, in resident kidney cells. Thus, molecular profiling identified a subgroup of patients with either MCD or FSGS who shared kidney TNF pathway activation and poor outcomes. A clinical trial testing targeted therapies in patients selected using urinary markers of TNF pathway activation is ongoing.

Kidney function outcomes in patients after complete primary repair of bladder exstrophy and penopubic epispadias: Results from the international bladder exstrophy consortium.

INTRODUCTION: Historically, repair of bladder exstrophy (BE) is associated with compromise to the upper tracts; the single stage repair of BE was considered to exacerbate risks of kidney impairment. OBJECTIVE: We aim to evaluate the risk of upper urinary tract deterioration or chronic kidney disease after the complete primary repair of exstrophy (CPRE). STUDY DESIGN: As part of the U.S.-India Multi-institutional Bladder Exstrophy Collaboration, we prospectively performed data collection on all patients managed at the Civil Hospital, Ahmedabad from 2010 to 2020. All patients who underwent primary or redo BE or primary penopubic epispadias (PE) repair using CPRE were included. Data on annual VCUG and DMSA, serum creatinine and cystatin-C, urinary albumin, and creatinine were aggregated. RESULTS: 72/104 patients who underwent CPRE at a median age of 1.7 years (IQR: 1.1-4.6) were included: 43(60%) patients with primary BE, 17(24%) with redo BE, and 12(17%) with primary PE. At a median follow-up of 4 years (IQR: 3-6), the overall median eGFR was 105 for BE, and 128 ml/min for PE. 14(19%) patients had eGFR<90, and 22(31%) had microalbuminuria. 21(30%) patients had kidney scarring in DMSA and 31(44%) had VUR. Multivariate analysis showed that neither kidney scarring nor VUR could predict the presence of eGFR<90 or microalbuminuria. Of 72 patients, 2 (3%) patients had dry intervals >3 h, 9 (13%) patients have dry intervals of 1-3 h and 44 (61%) patients had dry intervals <1 h during follow-up. We found that kidney function outcomes (i.e., eGFR and microalbuminuria) were not associated with continence status (p = 0.3). DISCUSSION: In this series, we report a 5% incidence of CKD stage 2 or above that was not impacted by continence status. Furthermore, a 40% incidence of VUR and a 30% incidence of kidney scarring during follow-up was observed within this cohort, neither of which had a significant impact on renal function deterioration (i.e, decline in eGFR), but underscores the need for close kidney surveillance in children that have undergone bladder exstrophy repair. CONCLUSIONS: Modern CPRE technique for the repair of BE may increase the risk of kidney scarring in the intermediate-term follow-up, however, this finding does not correlate with low eGFR and presence of albuminuria inpatients. Therefore, close follow-up with serial kidney function measurements is warranted and necessary after CPRE.

Psychiatric Diagnoses in Children With CKD Compared to the General Population.

Rationale & Objective: Children with chronic kidney disease (CKD) are subject to physical and psychosocial challenges, which may confer greater risk of developing psychiatric disorders. We sought to examine key psychiatric diagnoses in children with CKD compared with those in the general pediatric population and assess the correlation between parent-reported diagnosis and self-reported symptoms of depression. Study Design: Cross-sectional. Setting & Participants: Children ages 2-17 years receiving current medical care who participated in the Chronic Kidney Disease in Children Study (CKiD) or the National Survey of Children's Health. Exposure: CKD. Outcomes: Parent-reported diagnoses of depression, anxiety, or attention-deficit and hyperactivity disorder (ADHD). Analytical Approach: Using Poisson regression, we determined the age, sex, and race-adjusted prevalence ratio comparing diagnoses between children with CKD and those in the general population overall and within subgroups of sex, race, maternal education status, and CKD stage. Secondarily, we examined the correlation between depression status using standardized self-reported screening instrument scores and parent-reported diagnosis. Results: Eight hundred seventy-five children with CKD and 72,699 children in the general population were included. Those with CKD had an adjusted prevalence ratio of 1.32 (95% CI, 1.01-1.73) for depression, 0.72 (95% CI, 0.52-0.99) for anxiety, and 1.03 (95% CI, 0.86-1.25) for ADHD. The results were similar across subgroups of CKD stage, sex, race, or maternal education. The correlation between parent-reported diagnosis and instrument-detected depression was weak, r = 0.13 (95% CI, 0.03-0.23). Limitations: Retrospective parent- or self-reported data were used. Conclusions: Children with CKD had a higher prevalence of parent-reported depression, equivalent prevalence of attention-deficit and hyperactivity disorder, and lower prevalence of anxiety diagnoses compared to other children. These findings are inconsistent with results of prior studies and suggest that baseline assessments used in CKiD may have limited utility in describing psychiatric disorders among children with CKD. Improved mental health assessment approaches in pediatric nephrology are needed.

Thrombotic Microangiopathy Increases the Risk of Chronic Kidney Disease but Not Overall Mortality in Long-term Transplant Survivors.

Thrombotic microangiopathy (TMA) after allogeneic hematopoietic cell transplant (HCT) is associated with acute kidney injury (AKI) and increased mortality. The impact of TMA on chronic kidney disease (CKD) and long-term mortality among HCT survivors has not been fully examined. To assess the risk of CKD and mortality in HCT survivors with and without history of TMA, we conducted a retrospective cohort study among adult allogeneic HCT recipients who survived to at least 1 year post-transplantation. We examined the association between the history of TMA within 1 year and the onset of CKD longitudinally for 5 years with generalized estimating equation (GEE) while adjusting for other key confounders. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 using the CKD-EPI formula with outpatient creatinine values collected during the annual long-term follow-up unit follow-up visits. Kaplan Meier curves landmarked at 1 year were used for survival analyses. Among 2091 adult patients who underwent allogeneic HCT, we identified 1151 patients who survived at least 1 year and had available long-term follow-up data. Among them, 57 patients developed TMA within 1 year and 1094 did not have TMA. There was no pretransplantation baseline difference in eGFR between groups. After adjusting for confounders, history of TMA was associated with an odds ratio of 2.83 (95% confidence interval 1.33-6.03) for CKD development over 5 years after transplantation. The conditional 5-year survival was 78% in the TMA survivors and 80% in the non-TMA survivors (log rank P = .122). HCT survivors with a history of TMA had increased risk of CKD development. Although TMA was associated with high risk of mortality within 1 year after transplantation, long-term survival was comparable with non-TMA survivors. Future therapeutic interventions should focus on not only short-term mortality outcomes, but also short- and long-term kidney outcomes for HCT patients with TMA.

Prognostic Biomarkers for Thrombotic Microangiopathy after Acute Graft-versus-Host Disease: A Nested Case-Control Study.

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a complication of allogeneic hematopoietic cell transplantation (HCT) that often occurs following the development of acute graft-versus-host disease (aGVHD). In this study, we aimed to identify early TMA biomarkers among patients with aGVHD. We performed a nested-case-control study from a prospective cohort of allogeneic HCT recipients, matching on the timing and severity of antecedent aGVHD. We identified 13 TMA cases and 25 non-TMA controls from 208 patients in the cohort. Using multivariable conditional logistic regression, the odds ratio for TMA compared with non-TMA was 2.65 (95% confidence interval [CI], 1.00 to 7.04) for every 100 ng/mL increase in terminal complement complex sC5b9 and 2.62 (95% CI, 1.56 to 4.38) for every 1000 pg/mL increase in angiopoietin-2 (ANG2) at the onset of aGVHD. ADAMTS13 and von Willebrand factor (VWF) antigens were not appreciably associated with TMA. Using a Cox regression model incorporating sC5b9 >300 ng/mL and ANG2 >3000 pg/mL at the onset of aGVHD, the adjusted hazard ratio for mortality was 5.33 (95% CI, 1.57 to 18.03) for the high-risk group (both elevated) and 4.40 (95% CI, 1.60 to 12.07) for the intermediate-risk group (one elevated) compared with the low-risk group (neither elevated). In conclusion, we found that elevated sC5b9 and ANG2 levels at the onset of aGVHD were associated with the development of TMA and possibly mortality after accounting for the timing and severity of aGVHD. The results suggest important roles of complement activation and endothelial dysfunction in the pathogenesis of TMA. Measurement of these biomarkers at the onset of aGVHD may inform prognostic enrichment for preventive trials and improve clinical care.

COQ2 nephropathy: a treatable cause of nephrotic syndrome in children.

BACKGROUND: Nephrotic syndrome can be caused by a subgroup of mitochondrial diseases classified as primary coenzyme Q10 (CoQ10) deficiency. Pathogenic COQ2 variants are a cause of primary CoQ10 deficiency and present with phenotypes ranging from isolated nephrotic syndrome to fatal multisystem disease. CASE-DIAGNOSIS/TREATMENT: We report three pediatric patients with COQ2 variants presenting with nephrotic syndrome. Two of these patients had normal leukocyte CoQ10 levels prior to treatment. Pathologic findings varied from mesangial sclerosis to focal segmental glomerulosclerosis, with all patients having abnormal appearing mitochondria on kidney biopsy. In two of the three patients treated with CoQ10 supplementation, the nephrotic syndrome resolved; and at follow-up, both have normal renal function and stable proteinuria. CONCLUSIONS: COQ2 nephropathy should be suspected in patients presenting with nephrotic syndrome, although less common than disease due to mutations in NPHS1, NPHS2, and WT1. The index of suspicion should remain high, and we suggest that providers consider genetic evaluation even in patients with normal leukocyte CoQ10 levels, as levels may be within normal range even with significant clinical disease. Early molecular diagnosis and specific treatment are essential in the management of this severe yet treatable condition.

Prematurity and future kidney health: the growing risk of chronic kidney disease.

PURPOSE OF REVIEW: The purpose of this review is to describe the role prematurity plays in the development of chronic kidney disease (CKD) and to discuss potential reasons for this association including decreased nephron mass, as well as postnatal insults such as neonatal acute kidney injury (nAKI). RECENT FINDINGS: New observational studies in humans and experimental studies in animal models have strengthened the association between prematurity, low birth weight and CKD. Growing evidence suggests increased susceptibility to CKD is caused by decreased nephron mass at birth. Beginning with a low nephron count may cause only subtle abnormalities during childhood, however may result in CKD, hypertension and albuminuria in adolescence or adulthood. Recent studies in premature infants reveal a high incidence of nAKI, which may also contribute to ongoing CKD risk. SUMMARY: Children born at low birth weights (both due to prematurity and/or intrauterine growth restriction) show increased risk of kidney dysfunction during adulthood. A better understanding of the modulators of nephron mass in premature infants as well as the effects of the extrauterine environment is essential. Additionally, improved awareness of at-risk infants is important as is early evaluation and detection of kidney dysfunction, allowing interventions to slow the progression to CKD.

Impact of processing methods on urinary biomarkers analysis in neonates.

BACKGROUND: In neonates, the validation of urinary biomarkers to diagnose acute kidney injury is a rapidly evolving field. The neonatal population poses unique challenges when assessing the collection, storage, and processing of urinary samples for biomarker analysis. Given this, establishing optimal and consistent sample processing in this population for meaningful use in ongoing clinical trials is important. METHODS: Urine from a cohort of 19 hospitalized neonatal intensive care unit patients enrolled in the Preterm Erythropoietin Neuroprotection Trial (Clinical Trial NCT01378273) was collected for biomarker analysis by indirect techniques using Fisher-brand cotton balls placed in the diapers. Fourteen urinary biomarkers were measured using commercially available kits via electrochemiluminescence on multiarray plates and compared between paired samples processed with centrifugation prior to storage versus prior to analysis. RESULTS: None of the biomarker concentrations differed between samples undergoing centrifugation prior to storage versus prior to analysis. The difference between samples was within 2% of the estimated concentration for the protein in 12 of 14 biomarkers (86%), and all paired biomarker concentrations were within 4%. The percentage error analysis did not show a difference between paired samples, with biomarker percentage errors smaller than the stated immunoassay coefficient of variance. CONCLUSIONS: The urinary concentrations of biomarkers were comparable between paired samples, demonstrating that indirectly collected neonatal urine samples do not require centrifugation after collection and before storage. The ability to use routine urine collection and storage methods to obtain samples for subsequent quantitative immunoassay analysis should facilitate studies of newborns and young children.

Complete Remission in the Nephrotic Syndrome Study Network.

BACKGROUND AND OBJECTIVES: This analysis from the Nephrotic Syndrome Study Network (NEPTUNE) assessed the phenotypic and pathology characteristics of proteinuric patients undergoing kidney biopsy and defined the frequency and factors associated with complete proteinuria remission (CRever). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We enrolled adults and children with proteinuria ≥0.5 g/d at the time of first clinically indicated renal biopsy at 21 sites in North America from April 2010 to June 2014 into a prospective cohort study. NEPTUNE central pathologists assigned participants to minimal-change disease (MCD), FSGS, membranous nephropathy, or other glomerulopathy cohorts. Outcome measures for this analysis were (1) CRever with urine protein-to-creatinine ratio (UPC) <0.3 g/g with preserved native kidney function and (2) ESRD. Continuous variables are reported as median and interquartile range (IQR; 25th, 75th percentile). Cox proportional hazards modeling was used to assess factors associated with CRever. RESULTS: We enrolled 441 patients: 116 (27%) had MCD, 142 (32%) had FSGS, 66 (15%) had membranous nephropathy, and 117 (27%) had other glomerulopathy. The baseline UPC was 4.1 g/g (IQR, 1.9, 7.7) and the eGFR was 81 ml/min per 1.73 m(2) (IQR, 50, 105). Median duration of observation was 19 months (IQR, 11, 30). CRever occurred in 46% of patients, and 4.6% progressed to ESRD. Multivariate analysis demonstrated that higher prebiopsy proteinuria (hazard ratio, 0.3; 95% confidence interval, 0.2 to 0.5) and pathology diagnosis (FSGS versus MCD; hazard ratio, 0.2; 95% confidence interval, 0.1 to 0.5) were inversely associated with CRever. The effect of immunosuppressive therapy on remission varied by pathology diagnosis. CONCLUSIONS: In NEPTUNE, the high frequency of other pathology in proteinuric patients affirms the value of the diagnostic kidney biopsy. Clinical factors, including level of proteinuria before biopsy, pathology diagnosis, and immunosuppression, are associated with complete remission.

Transient renal enlargement in pediatric hematopoietic cell transplant recipients.

Age-dependent renal length tables are routinely used when interpreting pediatric ultrasound. Standard renal length tables may not be accurate for HCT patients due to treatment effects on kidney size. The purpose of this study was to determine whether renal size changes from expected lengths based on age after HCT in the absence of other markers of renal disease. Four hundred and fifty renal measurements were made on 101 patients who underwent HCT between 2006 and 2010. Renal length was measured at 1-90 days pre-HCT and at 0-30, 31-90, 91-180, and 181+ days post-HCT. Values were compared with normal renal length tables. Average post-HCT renal lengths were greater than established normative renal length data within every age group. Age-adjusted average renal lengths measured at 0-30 and 31-90 days post-transplantation were significantly larger than pre-HCT renal lengths, with relative increases of 6.9% (4.5, 9.4; p < 0.001) and 3.9% (1.4, 6.4; p = 0.003), respectively. Average renal length did not differ significantly after 90 days post-transplantation. HCT patients may have larger kidneys in the absence of renal disease. Awareness of the potential phenomenon of transient renal enlargement following HCT can prevent misdiagnosis and eliminate unnecessary diagnostic evaluations, interventions, anxiety, resource allocation, and financial costs.

Nephrolithiasis in pediatric hematopoietic cell transplantation with up to 40 years of follow-up.

BACKGROUND: Kidney stones have been reported to occur after childhood cancer, but little is known about kidney stones in children following hematopoietic cell transplantation (HCT). The objective of this retrospective study was to determine risk factors for the development of kidney stones and to describe the prevalence among survivors. PROCEDURE: The study included 1,343 childhood HCT patients. Mean follow-up was 15.8 (1.0-40.0) years. Patients were treated with total body irradiation (TBI) (n = 948) or non-TBI regimens. Methotrexate (MTX) for acute graft-versus-host disease (GVHD) prophylaxis was given as long-course (n = 360), short-course (n = 626), or none (n = 357). Prednisone for chronic GVHD therapy was received by 525 patients. Multivariate Cox regression models were used to estimate the hazard ratio (HR) of risk factors associated with kidney stones. RESULTS: Kidney stones developed in 51 patients, a median of 9.9 (0.2-29.4) years after first HCT, with a 30-year cumulative incidence of 7.4%. Risk factors associated with kidney stones were TBI (HR = 2.2; P = 0.03), age at HCT (12-18 vs. <6 years, HR = 2.7; P = 0.01), MTX (long vs. none, HR = 3.6; P = 0.02), and prednisone (HR = 2.2; P = 0.008). Among 868 survivors, the prevalence of a history of kidney stones was 4.7%. CONCLUSIONS: Survivors of childhood HCT have an increased risk of developing kidney stones.

Acute kidney injury and its association with in-hospital mortality among children with acute infections.

BACKGROUND: We investigated prevalence of acute kidney injury (AKI) at hospitalization and its association with in-hospital mortality among Ugandan children hospitalized with common acute infections, and predictors of mortality among AKI children. METHODS: We enrolled 2,055 children hospitalized with primary diagnoses of acute gastroenteritis, malaria, or pneumonia. Serum creatinine, albumin, electrolytes, hemoglobin, and urine protein were obtained on admission. Participants were assessed for AKI based on serum creatinine levels. Demographic and clinical data were obtained using a primary care provider survey and medical chart review. Logistic regression was used to determine predictors of in-hospital mortality. RESULTS: A total of 278 (13.5%) of children had AKI on admission; for 76.2%, AKI was stage 2 (98/278) or stage 3 (114/278) defined as serum creatinine >2- or 3-fold above normal upper limit for age, respectively. AKI prevalence was particularly high in gastroenteritis (28.6%) and underweight children (20.7%). Twenty-five percent of children with AKI died during hospitalization, compared to 9.9% with no AKI (adjusted odds ratio (aOR) 3.5 (95% CI, 2.2-5.5)). In-hospital mortality risk did not differ by AKI stage. Predictors of in-hospital mortality among AKI children included primary diagnosis of pneumonia, aOR 4.5 (95% CI, 1.8-11.2); proteinuria, aOR = 2.1 (95% CI, 1.0-4.9) and positive human immunodeficiency virus (HIV) status, aOR 5.0 (95% CI, 2.0-12.9). CONCLUSIONS: Among children hospitalized with gastroenteritis, malaria, or pneumonia, AKI at admission was common and associated with high in-hospital mortality.

Design of the Nephrotic Syndrome Study Network (NEPTUNE) to evaluate primary glomerular nephropathy by a multidisciplinary approach.

The Nephrotic Syndrome Study Network (NEPTUNE) is a North American multicenter collaborative consortium established to develop a translational research infrastructure for nephrotic syndrome. This includes a longitudinal observational cohort study, a pilot and ancillary study program, a training program, and a patient contact registry. NEPTUNE will enroll 450 adults and children with minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy for detailed clinical, histopathological, and molecular phenotyping at the time of clinically indicated renal biopsy. Initial visits will include an extensive clinical history, physical examination, collection of urine, blood and renal tissue samples, and assessments of quality of life and patient-reported outcomes. Follow-up history, physical measures, urine and blood samples, and questionnaires will be obtained every 4 months in the first year and biannually, thereafter. Molecular profiles and gene expression data will be linked to phenotypic, genetic, and digitalized histological data for comprehensive analyses using systems biology approaches. Analytical strategies were designed to transform descriptive information to mechanistic disease classification for nephrotic syndrome and to identify clinical, histological, and genomic disease predictors. Thus, understanding the complexity of the disease pathogenesis will guide further investigation for targeted therapeutic strategies.

Hypertension in long-term survivors of pediatric hematopoietic cell transplantation.

A retrospective study was conducted to determine risk factors for the development of hypertension (HTN) and to describe the prevalence among long-term survivors of pediatric hematopoietic cell transplant (HCT). Records of 689 pediatric patients who survived 5 years or more after HCT, from 1969 to 2004, were reviewed for development of HTN. In children, HTN was defined as either a systolic or diastolic pressure > or =95th percentile according to age, sex, and height. In adults, HTN was defined as systolic pressures > or =140 mmHg and/or diastolic pressures > or =90 mmHg in nondiabetic adults and systolic pressures > or =130 and/or diastolic pressures > or =80 in diabetic adults. Multivariate Cox regression models were used to estimate the hazard ratio (HR) of risk factors associated with HTN. All patients included were off immunosuppressive therapy. Patients had been treated with total body irradiation (TBI) (n = 482, 70%) or non-TBI regimens (n = 207, 30%) followed by autologous (n = 87), related (n = 484), or unrelated donor HCT (n = 118). Median follow-up was 16 (range: 5-36) years. HTN developed in 120 patients with a 30-year cumulative incidence of 36%. Risk factors associated with HTN were acute kidney injury (AKI; doubling of baseline creatinine by day 100 after HCT) (HR = 2.5; 95% confidence interval (CI) 1.7-3.7, P < .0001), TBI in the preparative regimen (HR = 2.1; 95% CI 1.3-3.3, P = .001), donor type (autologous HR = 2.4; 95% CI 1.3-4.4 and unrelated donor HR = 1.8; 95% CI 1.0-3.2, P = .01), obesity (HR = 4.0; 95% CI 2.3-6.8, P < .0001), diabetes (HR = 6.7; 95% CI 3.9-11.0, P < 0.0001), and history of growth hormone therapy (HR = 1.6; 95% CI 1.0-2.5, P = .05). Patients with a positive history of hepatitis C infection were less likely to develop HTN (HR = 0.5; 95% CI 0.3-0.9, P = .009). Prevalence of HTN was 15% overall and among survivors 11-17 years and 18-39 years old, the prevalence was 10% and 14% or triple and double that of the general U.S. population, respectively. Pediatric HCT survivors are more likely to develop HTN than the general population and should be monitored for HTN throughout adulthood.

Renal thrombotic microangiopathy after hematopoietic cell transplant: role of GVHD in pathogenesis.

BACKGROUND AND OBJECTIVES: Thrombotic microangiopathy (TMA) is a known complication of hematopoietic cell transplantation (HCT). The etiology and diagnosis of TMA in this patient population is often difficult because thrombocytopenia, microangiopathic hemolytic anemia, and kidney injury occur frequently in HCT recipients, and are the result of a variety of insults. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS: The authors reviewed renal pathology and clinical data from HCT patients to determine the prevalence of TMA and to identify correlative factors for developing TMA in the kidney. Kidney tissue was evaluated from 314 consecutive autopsies on patients who died after their first HCT (received between 1992 and 1999). Renal pathology was classified into three groups: (1) no renal thrombus (65%), (2) TMA (20%), and (3) isolated thrombosis (15%). Logistic regression models estimated the associations between each histologic category and clinical parameters: donor and recipient gender, patient age, human leukocyte antigen (HLA) matching of the donor and recipient, total body irradiation (TBI), acute graft versus host disease (GVHD), acute kidney injury, medications, and viral infections. RESULTS: In a multivariate analysis, TMA correlated with acute GVHD grades II to IV, followed by female recipient/male donor, TBI > 1200 cGy, and adenovirus infection. Grades II to IV acute GVHD and female gender were associated with isolated renal thrombus. CONCLUSIONS: TMA in HCT recipients is associated with acute GVHD grades II to IV, recipient/donor mismatch, TBI > 1200 cGy, and adenovirus infection.