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.

Identification of Novel Genetic Risk Factors for Focal Segmental Glomerulosclerosis in Children: Results From the Chronic Kidney Disease in Children (CKiD) Cohort.

RATIONALE & OBJECTIVE: Focal segmental glomerulosclerosis (FSGS) is a major cause of pediatric nephrotic syndrome, and African Americans exhibit an increased risk for developing FSGS compared with other populations. Predisposing genetic factors have previously been described in adults. Here we performed genomic screening of primary FSGS in a pediatric African American population. STUDY DESIGN: Prospective cohort with case-control genetic association study design. SETTING & PARTICIPANTS: 140 African American children with chronic kidney disease from the Chronic Kidney Disease in Children (CKiD) cohort, including 32 cases with FSGS. PREDICTORS: Over 680,000 common single-nucleotide polymorphisms (SNPs) were tested for association. We also ran a pathway enrichment analysis and a human leucocyte antigen (HLA)-focused association study. OUTCOME: Primary biopsy-proven pediatric FSGS. ANALYTICAL APPROACH: Multivariate logistic regression models. RESULTS: The genome-wide association study revealed 169 SNPs from 14 independent loci significantly associated with FSGS (false discovery rate [FDR]<5%). We observed notable signals for genetic variants within the APOL1 (P=8.6×10-7; OR, 25.8 [95% CI, 7.1-94.0]), ALMS1 (P=1.3×10-7; 13.0% in FSGS cases vs 0% in controls), and FGFR4 (P=4.3×10-6; OR, 24.8 [95% CI, 6.3-97.7]) genes, all of which had previously been associated with adult FSGS, kidney function, or chronic kidney disease. We also highlighted novel, functionally relevant genes, including GRB2 (which encodes a slit diaphragm protein promoting podocyte structure through actin polymerization) and ITGB1 (which is linked to renal injuries). Our results suggest a major role for immune responses and antigen presentation in pediatric FSGS through (1) associations with SNPs in PTPRJ (or CD148, P=3.5×10-7), which plays a role in T-cell receptor signaling, (2) HLA-DRB1∗11:01 association (P=6.1×10-3; OR, 4.5 [95% CI, 1.5-13.0]), and (3) signaling pathway enrichment (P=1.3×10-6). LIMITATIONS: Sample size and no independent replication cohort with genomic data readily available. CONCLUSIONS: Our genetic study has identified functionally relevant risk factors and the importance of immune regulation for pediatric primary FSGS, which contributes to a better description of its molecular pathophysiological mechanisms. PLAIN-LANGUAGE SUMMARY: We assessed the genetic risk factors for primary focal segmental glomerulosclerosis (FSGS) by simultaneously testing over 680,000 genetic markers spread across the genome in 140 children, including 32 with FSGS lesions. Fourteen independent genetic regions were significantly associated with pediatric FSGS, including APOL1 and ALMS1-NAT8, which were previously found to be associated with FSGS and chronic kidney diseases in adults. Novel genes with relevant biological functions were also highlighted, such as GRB2 and FGFR4, which play a role in the kidney filtration barrier and in kidney cell differentiation, respectively. Finally, we revealed the importance of immune regulation in pediatric FSGS through associations involving cell surface proteins presenting antigens to the immune system and interacting with T-cell receptors.

Reduced kidney function and hypertension in adolescents with low birth weight, NHANES 1999-2016.

BACKGROUND: Chronic kidney disease (CKD) is a major health problem, and the risk of CKD and hypertension in children born low birth weight (LBW) is under-recognized. We hypothesized that children born with LBW would have a higher prevalence of reduced kidney function and hypertension. METHODS: Using the National Health and Nutrition Examination Survey (NHANES), we conducted a cross-sectional study to evaluate whether LBW (< 2500 g), very low birth weight (VLBW < 1500 g), and large birth weight (BW) (> 4000 g) were associated with kidney disease using 4 different estimating equations. We used the Counahan-Barratt, updated Schwartz, CKiD-U25, and full age spectrum creatinine-based GFR estimating equations to evaluate associations between a history of LBW/VLBW/large BW and reduced kidney function (eGFR < 90 mL/min/1.73 m2) in children. We also assessed blood pressure (BP) using the old and new pediatric hypertension guidelines. RESULTS: Our analysis included 6336 children (age 12-15 years) in NHANES representing over 13 million US individuals. Using the updated Schwartz, the prevalence of reduced kidney function was 30.1% (25.2-35.6) for children born with LBW compared to 22.4% (20.5-24.3) in children with normal BW. Equations yielded different estimates of prevalence of reduced kidney function in LBW from 21.5% for Counahan-Barratt to 35.4% for CKiD-U25. Compared to those with normal BW, participants with LBW and VLBW had a 7.2 and 10.3% higher prevalence of elevated BP and a 2.4 and 14.6% higher prevalence of hypertension, respectively. CONCLUSIONS: Children born with LBW are at higher risk of reduced kidney function and hypertension than previously described. A higher resolution version of the Graphical abstract is available as Supplementary information.

A review of ferric citrate clinical studies, and the rationale and design of the Ferric Citrate and Chronic Kidney Disease in Children (FIT4KiD) trial.

Pediatric chronic kidney disease (CKD) is characterized by many co-morbidities, including impaired growth and development, CKD-mineral and bone disorder, anemia, dysregulated iron metabolism, and cardiovascular disease. In pediatric CKD cohorts, higher circulating concentrations of fibroblast growth factor 23 (FGF23) are associated with some of these adverse clinical outcomes, including CKD progression and left ventricular hypertrophy. It is hypothesized that lowering FGF23 levels will reduce the risk of these events and improve clinical outcomes. Reducing FGF23 levels in CKD may be accomplished by targeting two key stimuli of FGF23 production-dietary phosphate absorption and iron deficiency. Ferric citrate is approved for use as an enteral phosphate binder and iron replacement product in adults with CKD. Clinical trials in adult CKD cohorts have also demonstrated that ferric citrate decreases circulating FGF23 concentrations. This review outlines the possible deleterious effects of excess FGF23 in CKD, summarizes data from the adult CKD clinical trials of ferric citrate, and presents the Ferric Citrate and Chronic Kidney Disease in Children (FIT4KiD) study, a randomized, placebo-controlled trial to evaluate the effects of ferric citrate on FGF23 in pediatric patients with CKD stages 3-4 (ClinicalTrials.gov Identifier NCT04741646).

Fetal-Not Maternal-APOL1 Genotype Associated with Risk for Preeclampsia in Those with African Ancestry.

Black Americans are at increased risk for preeclampsia. Genetic variants in apolipoprotein L1 (APOL1) account for much of the increased risk for kidney disease in blacks. APOL1 is expressed in human placenta and transgenic mice expressing APOL1 develop preeclampsia. We evaluated the role of APOL1 variants in human preeclampsia. We determined maternal and fetal APOL1 genotypes in black women with preeclampsia in two populations. At Einstein Montefiore Center (EMC) Affiliated Hospitals, we studied 121 pregnancies in black women with preeclampsia. At University of Tennessee Health Science Center (UTHSC), we studied 93 pregnancies in black women with preeclampsia and 793 pregnancies without preeclampsia. We measured serum markers of preeclampsia soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF), and soluble endoglin (sEng). Fetal APOL1 high-risk (HR) genotype was associated with preeclampsia, with odds ratios at EMC and UTHSC of 1.84 (95% CI 1.11, 2.93) and 1.92 (95% CI 1.05, 3.49), respectively. Maternal APOL1 HR genotype was not associated with preeclampsia. Mothers with the fetal APOL1 HR genotype had more cerebral or visual disturbances (63% versus 37%, p = 0.04). In addition, fetal APOL1 HR genotype was associated with a higher sFLT-1/PlGF ratio at birth (p = 0.04). Fetal APOL1 high-risk genotype increases the risk for preeclampsia, likely by adversely affecting placental function. Further research is needed to assess whether APOL1 genetic testing can predict preeclampsia and improve pregnancy outcomes.

Proteinuria Reduction and Kidney Survival in Focal Segmental Glomerulosclerosis.

RATIONALE & OBJECTIVE: Remission of proteinuria has been shown to be associated with lower rates of kidney disease progression among people with focal segmental glomerulosclerosis (FSGS). The goal of this study was to evaluate whether reductions in proteinuria after treatment are associated with greater kidney survival. STUDY DESIGN: Cohort analysis of clinical trial participants. SETTING & PARTICIPANTS: Patients with steroid-resistant FSGS enrolled in a randomized treatment trial that compared cyclosporine with mycophenolate mofetil plus dexamethasone. PREDICTORS: Reduction in proteinuria measured during 26 weeks after initiating treatment. OUTCOMES: Repeated assessments of estimated glomerular filtration rate (eGFR) and time to a composite outcome of kidney failure or death assessed between 26 weeks and 54 months after randomization. ANALYTICAL APPROACH: Multivariable linear mixed-effects models with participant-specific slope and intercept to estimate the association of change in proteinuria over 26 weeks while receiving treatment with the subsequent slope of change in eGFR. Multivariable time-varying Cox proportional hazards models were used to estimate the association of changes in proteinuria with time to the composite outcome. RESULTS: 138 of 192 trial participants were included. Changes in proteinuria over 26 weeks were significantly related to eGFR slope. A 1-unit reduction in log-transformed urinary protein-creatinine ratio was associated with a 3.90mL/min/1.73m2 per year increase in eGFR (95% CI, 2.01-5.79). This difference remained significant after adjusting for complete remission. There was an analogous relationship between time-varying proteinuria and time to the composite outcome: the HR per 1-unit reduction in log-transformed urinary protein-creatinine ratio was 0.23 (95% CI, 0.12-0.44). LIMITATIONS: Limited to individuals with steroid-resistant FSGS followed up for a maximum of 5 years. CONCLUSIONS: These findings provide evidence for the benefit of urinary protein reduction in FSGS. Reductions in proteinuria warrant further evaluation as a potential surrogate for preservation of kidney function that may inform the design of future clinical trials.

Patterns of recombinant growth hormone therapy use and growth responses among children with chronic kidney disease.

BACKGROUND: Recombinant growth hormone (rGH) is an efficacious therapy for growth failure in children with chronic kidney disease (CKD). We described rGH use and estimated its relationship with growth and kidney function in the Chronic Kidney Disease in Children (CKiD) cohort. METHODS: Participants included those with growth failure, prevalent rGH users, and rGH initiators who did not meet growth failure criteria. Among those with growth failure, height z scores and GFR were compared between rGH initiators and non-initiators across 42 months. Inverse probability weights accounted for differences in baseline variables in weighted linear regressions. RESULTS: Among 148 children with growth failure and no previous rGH therapy, 42 (28%) initiated rGH therapy. Of the initiators, average age was 8.9 years, height z score was 2.50 standard deviations (SDs) (0.6th percentile), and GFR was 44 ml/min/1.73m2. They were compared to 106 children with growth failure who never initiated therapy (8.8 years, -2.33 SDs, and 51 ml/min/1.73m2). At 30 and 42 months after rGH, height increased +0.26 (95%CI: -0.11, +0.62) and +0.35 (95%CI: -0.17, +0.87) SDs, respectively, relative to those who did not initiate rGH. rGH was not associated with GFR. CONCLUSIONS: Participants with growth failure receiving rGH experienced significant growth, although this was attenuated relative to RCTs, and were more likely to have higher household income and lower GFR. A substantial number of participants, predominantly boys, without diagnosed growth failure received rGH and had the highest achieved height relative to mid-parental height. Since rGH was not associated with accelerated GFR decline, increasing rGH use in this population is warranted.

Longitudinal outcomes of body mass index in overweight and obese children with chronic kidney disease.

BACKGROUND: Longitudinal changes in body mass index (BMI) among overweight and obese children with chronic kidney disease (CKD) are not well characterized. We studied longitudinal trajectories and correlates of these trajectories, as results may identify opportunities to optimize health outcomes. METHODS: Longitudinal changes in age-sex-specific BMI z-scores over 1851 person-years of follow-up were assessed in 524 participants of the Chronic Kidney Disease in Children Study. A total of 353 participants were categorized as normal (BMI > 5th to < 85th percentile), 56 overweight (BMI ≥ 85th to 95th percentile) and 115 obese (BMI ≥ 95th percentile) based on the average of three BMI measurements during the first year of follow-up. Studied covariates included age, sex, race, CKD etiology, corticosteroid usage, household income, and maternal education. RESULTS: In unadjusted analysis, BMI z-scores decreased over time in elevated BMI groups (overweight: mean = - 0.06 standard deviations (SD) per year, 95% CI: - 0.11, - 0.01; obese: mean = - 0.04 SD per year, 95% CI: - 0.07, - 0.01). Among obese children, only age was associated with change in BMI z-score; children < 6 years had a mean decrease of 0.19 SD during follow-up (95% CI: - 0.30, - 0.09). Socioeconomic factors were not associated with change in BMI. CONCLUSION: Overweight and obese children with CKD demonstrated a significant annual decline in BMI, though the absolute change was modest. Among obese children, only age < 6 years was associated with significant decline in BMI. Persistence of elevated BMI in older children and adolescents with CKD underscores the need for early prevention and effective intervention.

APOL1 genotype-associated morphologic changes among patients with focal segmental glomerulosclerosis.

BACKGROUND: The G1 and G2 alleles of apolipoprotein L1 (APOL1) are common in the Black population and associated with increased risk of focal segmental glomerulosclerosis (FSGS). The molecular mechanisms linking APOL1 risk variants with FSGS are not clearly understood, and APOL1's natural absence in laboratory animals makes studying its pathobiology challenging. METHODS: In a cohort of 90 Black patients with either FSGS or minimal change disease (MCD) enrolled in the Nephrotic Syndrome Study Network (58% pediatric onset), we used kidney biopsy traits as an intermediate outcome to help illuminate tissue-based consequences of APOL1 risk variants and expression. We tested associations between APOL1 risk alleles or glomerular APOL1 mRNA expression and 83 light- or electron-microscopy traits measuring structural and cellular kidney changes. RESULTS: Under both recessive and dominant models in the FSGS patient subgroup (61%), APOL1 risk variants were significantly correlated (defined as FDR <0.1) with decreased global mesangial hypercellularity, decreased condensation of cytoskeleton, and increased tubular microcysts. No significant correlations were detected in MCD cohort. Independent of risk alleles, glomerular APOL1 expression in FSGS patients was not correlated with morphologic features. CONCLUSIONS: While APOL1-associated FSGS is associated with two risk alleles, both one and two risk alleles are associated with cellular/tissue changes in this study of FSGS patients. Our lack of discovery of a large group of tissue differences in FSGS and no significant difference in MCD may be due to the lack of power but also supports investigating whether machine learning methods may more sensitively detect APOL1-associated changes.

Grip strength in children with chronic kidney disease.

BACKGROUND: The relationship between muscle strength and chronic kidney disease (CKD) in children is unknown. This study aims to quantify the association between grip strength (GS) and kidney function and to explore factors associated with grip strength in children and adolescents with CKD. METHODS: We included 411 children (699 GS assessments) of the Chronic Kidney Disease in Children (CKiD) study. They were matched by age, sex, and height to a healthy control from the National Health and Nutrition Examination Survey to quantify the relationship between GS and CKD. Linear mixed models were used to identify factors associated with GS among CKD patients. RESULTS: Median GS z-score was - 0.72 (IQR - 1.39, 0.11) among CKD patients with CKD stages 2 through 5 having significantly lower GS than CKD stage 1. Compared with healthy controls, CKiD participants had a decreased GS z-score (- 0.53 SD lower, 95% CI - 0.67 to - 0.39) independent of race/ethnicity and body mass index. Factors associated with reduced GS included longer duration of CKD, pre-pubertal status, delayed puberty, neuropsychiatric comorbidities, need of feeding support, need for alkali therapy, and hemoglobin level. Decreased GS was also associated with both a lower frequency and intensity of physical activity. CONCLUSIONS: CKD is associated with impaired muscle strength in children independent of growth retardation and BMI. Exposure to CKD for a prolonged time is associated with impaired muscle strength. Potential mediators of the impact of CKD on muscle strength include growth retardation, acidosis, poor nutritional status, and low physical activity. Additional studies are needed to assess the efficacy of interventions targeted at these risk factors.

APOL1-associated glomerular disease among African-American children: a collaboration of the Chronic Kidney Disease in Children (CKiD) and Nephrotic Syndrome Study Network (NEPTUNE) cohorts.

BACKGROUND: Individuals of African ancestry harboring two variant alleles within apolipoprotein L1 ( APOL1 ) are classified with a high-risk (HR) genotype. Adults with an HR genotype have increased risk of focal segmental glomerulosclerosis and chronic kidney disease compared with those with a low-risk (LR) genotype (0 or 1 variants). The role of APOL1 risk genotypes in children with glomerular disease is less well known. METHODS: This study characterized 104 African-American children with a glomerular disease by APOL1 genotype in two cohorts: the Chronic Kidney Disease in Children (CKiD) and Nephrotic Syndrome Study Network (NEPTUNE). RESULTS: Among these subjects, 46% had an HR genotype with a similar age at cohort enrollment. For APOL1 HR children, the median age of disease onset was older (CKiD: 4.5 versus 11.5 years for LR versus HR; NEPTUNE: 11 versus 14 years for LR versus HR, respectively) and preterm birth was more common [CKiD: 27 versus 4%; NEPTUNE: 26 versus 12%; combined odds ratio 4.6 (95% confidence interval: 1.4, 15.5)]. Within studies, HR children had lower initial estimated glomerular filtration rate (eGFR) (CKiD: 53 versus 69 mL/min/1.73 m 2 ; NEPTUNE: 74 versus 94 mL/min/1.73 m 2 ). Longitudinal eGFR decline was faster among HR children versus LR (CKiD: -18 versus -8% per year; NEPTUNE: -13 versus -3% per year). CONCLUSIONS: Children with an HR genotype in CKiD and NEPTUNE seem to have a more aggressive form of glomerular disease, in part due to a higher prevalence of focal segmental glomerulosclerosis. These consistent findings across independent cohorts suggest a common natural history for children with APOL1 -associated glomerular disease. Further study is needed to determine the generalizability of these findings.

Prevalence and correlates of 25-hydroxyvitamin D deficiency in the Chronic Kidney Disease in Children (CKiD) cohort.

BACKGROUND: Vitamin D plays an important role in the mineral and bone disorder seen in chronic kidney disease (CKD). Deficiency of 25-hydroxyvitamin D (25OHD) is highly prevalent in the adult CKD population. METHODS: The prevalence and determinants of 25OHD deficiency (defined as a level <20 ng/ml) were examined longitudinally in 506 children in the CKiD cohort. Predictors of secondary hyperparathyroidism and the determinants of 1,25-dihydroxyvitamin D (1,25(OH)2D) levels were also evaluated. RESULTS: Deficiency of 25OHD was observed in 28 % of the cohort at enrollment. Significant predictors of 25OHD deficiency were older age, non-white race, higher body mass index, assessment during winter, less often than daily milk intake, non-use of nutritional vitamin D supplement and proteinuria. Lower values of glomerular filtration rate (GFR), serum 25OHD, calcium and higher levels of FGF23 were significant determinants of secondary hyperparathyroidism. Lower GFR, low serum 25OHD, nephrotic-range proteinuria, and high FGF23 levels were significant determinants of serum 1,25(OH)2 D levels. CONCLUSIONS: Deficiency of 25OHD is prevalent in children with CKD and is associated with potentially modifiable risk factors such as milk intake, nutritional vitamin D supplement use, and proteinuria. 25OHD deficiency is a risk factor for secondary hyperparathyroidism and decreased serum 1,25(OH)2D in children with CKD.

Perceived appetite and clinical outcomes in children with chronic kidney disease.

BACKGROUND: Children with chronic kidney disease (CKD) may have impaired caloric intake through a variety of mechanisms, with decreased appetite as a putative contributor. In adult CKD, decreased appetite has been associated with poor clinical outcomes. There is limited information about this relationship in pediatric CKD. METHODS: A total of 879 participants of the Chronic Kidney Disease in Children (CKiD) study were studied. Self-reported appetite was assessed annually and categorized as very good, good, fair, or poor/very poor. The relationship between appetite and iohexol or estimated glomerular filtration rate (ieGFR), annual changes in anthropometrics z-scores, hospitalizations, emergency room visits, and quality of life were assessed. RESULTS: An ieGFR < 30 ml/min per 1.73 m(2) was associated with a 4.46 greater odds (95 % confidence interval: 2.80, 7.09) of having a worse appetite than those with ieGFR >90. Appetite did not predict changes in height, weight, or BMI z-scores. Patients not reporting a very good appetite had more hospitalizations over the next year than those with a very good appetite. Worse appetite was significantly associated with lower parental and patient reported quality of life. CONCLUSIONS: Self-reported appetite in children with CKD worsens with lower ieGFR and is correlated with clinical outcomes, including hospitalizations and quality of life.

Clinical Features and Histology of Apolipoprotein L1-Associated Nephropathy in the FSGS Clinical Trial.

Genetic variants in apolipoprotein L1 (APOL1) confer risk for kidney disease. We sought to better define the phenotype of APOL1-associated nephropathy. The FSGS Clinical Trial involved 138 children and young adults who were randomized to cyclosporin or mycophenolate mofetil plus pulse oral dexamethasone with a primary outcome of proteinuria remission. DNA was available from 94 subjects who were genotyped for APOL1 renal risk variants, with two risk alleles comprising the risk genotype. Two APOL1 risk alleles were present in 27 subjects, of whom four subjects did not self-identify as African American, and 23 of 32 (72%) self-identified African Americans. Individuals with the APOL1 risk genotype tended to present at an older age and had significantly lower baseline eGFR, more segmental glomerulosclerosis and total glomerulosclerosis, and more tubular atrophy/interstitial fibrosis. There were differences in renal histology, particularly more collapsing variants in those with the risk genotype (P=0.02), although this association was confounded by age. APOL1 risk genotype did not affect response to either treatment regimen. Individuals with the risk genotype were more likely to progress to ESRD (P<0.01). In conclusion, APOL1 risk genotypes are common in African-American subjects with primary FSGS and may also be present in individuals who do not self-identify as African American. APOL1 risk status is associated with lower kidney function, more glomerulosclerosis and interstitial fibrosis, and greater propensity to progress to ESRD. The APOL1 risk genotype did not influence proteinuria responses to cyclosporin or mycophenolate mofetil/dexamethasone.

Validation of automated Greulich-Pyle bone age determination in children with chronic renal failure?

Growth failure is a common problem in children with chronic kidney disease (CKD). The causes are multifactorial and are associated with increased mortality and morbidity. Standard deviations of bone age versus chronological age in children with CKD have not been developed to date. Accurate and early treatment of bone age is an important component of determining the utility of GH therapy. Improvements in bone age assessments are being evaluated to optimize the understanding of growth delay in CKD.

Medication adherence in the transition of adolescent kidney transplant recipients to the adult care.

Non-adherence is common in adolescent and young adult kidney transplant recipients, leading to adverse graft outcomes. The aim of this study was to determine whether adherence to immunosuppressant medications changes during transition from a pediatric to an adult program within the same transplant center. Adherence was assessed for a period of two yr before and two yr after the transfer. Subtherapeutic trough levels of serum tacrolimus and level variability were used as measures of adherence. Twenty-five patients were transitioned between 1996 and 2011 at the median age of 22.3 [IQR 21.6-23.0] yr. Young adults 21-25 yr of age (n = 26) and non-transitioned adolescents 17-21 yr of age (currently followed in the program, n = 24 and those that lost their grafts prior to the transfer, 22) formed the comparison groups. In the transitioned group, adherence prior to the transfer was not significantly different from the adherence after the transfer (p = 0.53). The rate of non-adherence in the group of non-transitioned adolescents who lost their grafts (68%) was significantly higher than in the transitioned group (32%, p = 0.01). In the group of young adults, adherence was not significantly different from the transitioned group (p = 0.27). Thus, transition was not associated with differences in medication adherence in this single-center study. Large-scale studies are needed to evaluate the national data on medication adherence after transfer.

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.

Late steroid resistance in childhood nephrotic syndrome: do we now know more than 40 years ago?

The formation of steroid resistance in children with nephrotic syndrome (NS) who were initially steroid responsive was described decades ago but has not been studied in sufficient depth. Except for the International Study of Kidney Disease in Children, conducted more than three decades ago, when only cyclophosphamide was available as a second-line agent in steroid-resistant NS, only a handful of small studies have addressed the problem of late steroid resistance (LSR) over the past 40 years. Epidemiology and risk factors for the formation of LSR and differences in outcomes when compared with initial steroid resistance still remain unknown. While multiple second-line treatment choices (calcineurin inhibitors, mycophenolate mofetil, rituximab) exist today, therapeutic approaches to the patients with LSR remain empirical, as no evidence-based data have become available. In the current issue of Pediatric Nephrology, Straatmann et al. report retrospective data on the treatment outcomes for 29 pediatric NS patients with LSR from eight participating centers of the Midwest Pediatric Research Consortium. The authors describe a current pattern of second-line agents used in their cohort and show that the majority of patients (66 %) achieved complete or partial remission after a period of observation for 85 ± 47 months. The authors also describe the data on renal histology. While these data represent an important step forward in our understanding of LSR, further work is needed before firm clinical recommendations can be made. Large-scale prospective studies are required to answer important questions about the epidemiology, genetics and outcomes in late steroid-resistant NS, explore the role of medication adherence and develop evidence-based practice guidelines.

Longitudinal Associations between Low Serum Bicarbonate and Linear Growth in Children with CKD.

Background: Poor linear growth is a consequence of chronic kidney disease (CKD) that has been linked to adverse outcomes. Metabolic acidosis (MA) has been identified as a risk factor for growth failure. We investigated the longitudinal relationship between MA and linear growth in children with CKD and examined whether treatment of MA modified linear growth. Methods: To describe longitudinal associations between MA and linear growth, we used serum bicarbonate levels, height measurements, and standard deviation (z scores) of children enrolled in the prospective cohort study Chronic Kidney Disease in Children. Analyses were adjusted for covariates recognized as correlating with poor growth, including demographic characteristics, glomerular filtration rate (GFR), proteinuria, calcium, phosphate, parathyroid hormone, and CKD duration. CKD diagnoses were analyzed by disease categories, nonglomerular or glomerular. Results: The study population included 1082 children with CKD: 808 with nonglomerular etiologies and 274 with glomerular etiologies. Baseline serum bicarbonate levels ≤22 mEq/L were associated with worse height z scores in all children. Longitudinally, serum bicarbonate levels ≤18 and 19-22 mEq/L were associated with worse height z scores in children with nonglomerular CKD causes, with adjusted mean values of -0.39 (95% CI, -0.58 to -0.2) and -0.17 (95% CI, -0.28 to -0.05), respectively. Children with nonglomerular disease and more severe GFR impairment had a higher risk for worse height z score. A significant association was not found in children with glomerular diseases. We also investigated the potential effect of treatment of MA on height in children with a history of alkali therapy use, finding that only persistent users had a significant positive association between their height z score and higher serum bicarbonate levels. Conclusions: We observed a longitudinal association between MA and lower height z score. Additionally, persistent alkali therapy use was associated with better height z scores. Future clinical trials of alkali therapy need to evaluate this relationship prospectively.