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Abstract Background The lack of adequate randomized clinical trials (RCT) has hindered identification of new therapies that are safe and effective for patients with primary focal segmental glomerulosclerosis (FSGS), especially in patients who fail to respond to corticosteroids and immunosuppressive therapies. Recent basic science advances have led to development of alternative treatments that specifically target aberrant pathways of fibrosis which are relevant to disease progression in FSGS. There is a need for a flexible Phase II study design which will test such novel antifibrotic strategies in order to identify agents suitable for phase III testing. Methods/Design The Novel Therapies for Resistant Focal Segmental Glomerulosclerosis (FONT) project is a multicenter Phase I/II RCT designed to investigate the potential efficacy of novel therapies for resistant FSGS. Adalimumab and galactose will be evaluated against conservative therapy consisting of the combination of lisinopril, losartan and atorvastatin. The sample size is defined to assure that if one of the treatments has a superior response rate compared to that of the other treatments, it will be selected with high probability for further evaluation. Comparison of primary and secondary endpoints in each study arm will enable a choice to be made of which treatments are worthy of further study in future Phase III RCT. Discussion This report highlights the key features of the FONT II RCT including the two-step outcome analysis that will expedite achievement of the study objectives. The proposed phase II study design will help to identify promising agents for further testing while excluding ineffective agents. This staged approach can help to prevent large expenditures on unworthy therapeutic agents in the management of serious but rare kidney diseases Trial Registration ClinicalTrials.gov, NCT00814255

Abstract Background Patients with resistant primary focal segmental glomerulosclerosis (FSGS) are at high risk of progression to chronic kidney disease stage V. Antifibrotic agents may slow or halt this process. We present outcomes of follow-up after a Phase I trial of adalimumab and rosiglitazone, antifibrotic drugs tested in the Novel Therapies in Resistant FSGS (FONT) study. Methods 21 patients -- 12 males and 9 females, age 16.0 ± 7.5 yr, and estimated GFR (GFRe) 121 ± 56 mL/min/1.73 m2 -- received adalimumab (n = 10), 24 mg/m2 every 14 days or rosiglitazone (n = 11), 3 mg/m2 per day for 16 weeks. The change in GFRe per month prior to entry and after completion of the Phase I trial was compared. Results 19 patients completed the 16-week FONT treatment phase. The observation period pre-FONT was 18.3 ± 10.2 months and 16.1 ± 5.7 months after the study. A similar percentage of patients, 71% and 56%, in the rosiglitazone and adalimumab cohorts, respectively, had stabilization in GFRe, defined as a reduced negative slope of the line plotting GFRe versus time without requiring renal replacement therapy after completion of the FONT treatment period (P = 0.63). Conclusion Nearly 50% of patients with resistant FSGS who receive novel antifibrotic agents may have a legacy effect with delayed deterioration in kidney function after completion of therapy. Based on this proof-of-concept preliminary study, we recommend long-term follow-up of patients enrolled in clinical trials to ascertain a more comprehensive assessment of the efficacy of experimental treatments.

Abstract Background Previous studies have examined the spectrum of diseases identified with a kidney biopsy and the complications of the procedure. However, few studies have examined the utility of the test to clarify the diagnosis and guide treatment of pediatric patients. This retrospective, single-center chart review was performed to test the hypothesis that at least 80% of native kidney biopsies provide clinically valuable information that rationally guides diagnosis and patient management. Methods 200 biopsies performed between January 1, 2000 and June 30, 2008 were reviewed. A scheme composed of six categories was devised to classify the utility of each kidney biopsy. Results 196 complete case files were available for review. Twenty-four (12.2%) biopsies did not shed light on the diagnosis and were unhelpful in patient management – 21 biopsies (10.7%) were non-diagnostic and 3 (1.5%) failed to yield enough tissue for examination. The number of unhelpful biopsies did not cluster in any specific disease entity. Conclusion Our findings provide guidance to nephrologists about the total risk of a kidney biopsy, including uninformative results, when seeking informed consent for the procedure. The results suggest an appropriate balance has been reached which maximizes the use of kidney biopsies while minimizing the risk of this invasive procedure (word count: 202).

Abstract Background Idiopathic membranous nephropathy (IMN) is one of the most common causes of primary nephrotic syndrome in adults. However, it is a relatively rare entity in the pediatric population and there is a paucity of data about the incidence, prognosis, and optimal treatment of IMN in children and adolescents. We conducted this study to evaluate pediatric patients with IMN in order to clarify the presentation, response to therapy, and clinical outcome. Methods A retrospective chart review was performed on patients identified with biopsy-proven IMN between 1988–2005. Patients with systemic lupus erythematosus or hepatitis-related lesions were excluded. The following data were tabulated: age, gender, ethnicity, presenting clinical and laboratory findings, proteinuria in a first morning urine specimen, estimated glomerular filtration rate (GFRe), histopathology, type and duration of treatment, and clinical status at final evaluation. Results 13 cases of IMN were identified out of 460 renal biopsies performed for evaluation of primary kidney disease during the study interval. Mean age was 9.6 ± 4.6, gender 6 M:7 F, ethnicity 8 W:2 B:3 H. At the initial visit hematuria was present in 9 patients, edema in 5, nephrotic-range proteinuria in 5, and hypertension in 3. Mean urinary protein:creatinine ratio 3.3 ± 2.5 and all patients had a normal GFRe. Classic glomerular findings of IMN were seen in all renal specimens, with concomitant interstitial changes in 2 cases. Treatment included an angiotensin converting enzyme inhibitor or angiotensin receptor blocker in 11 cases. Most patients were also given immunosuppressive medications – prednisone in 10, a calcineurin inhibitor in 5, and mycophenolate mofetil or azathioprine in 3 patients. At the last follow-up, 42 ± 35 months after the diagnostic biopsy, 7 children were hypertensive and the urine protein:creatinine ratio was 2.3 ± 3.1. The mean GFRe was 127 ± 57 mL/min/m2. Three patients had Chronic Kidney Disease Stage 3, all of whom were also hypertensive. Conclusion IMN is a rare but serious glomerulopathy in pediatrics. We estimate that it accounts for approximately 3% of renal biopsies. Long-term prognosis is guarded because approximately 50% of patients may have evidence of progressive kidney disease.

Author(s): Melanie H. Jacobson 1,*, Yinxiang Wu 2, Mengling Liu 2,3, Teresa M. Attina 1, Mrudula Naidu 1, Rajendiran Karthikraj 4,5, Kurunthachalam Kannan 1,4,5, Bradley A. Warady 6, Susan Furth [...], Background Exposure to environmental chemicals may be a modifiable risk factor for progression of chronic kidney disease (CKD). The purpose of this study was to examine the impact of serially assessed exposure to bisphenol A (BPA) and phthalates on measures of kidney function, tubular injury, and oxidative stress over time in a cohort of children with CKD. Methods and findings Samples were collected between 2005 and 2015 from 618 children and adolescents enrolled in the Chronic Kidney Disease in Children study, an observational cohort study of pediatric CKD patients from the US and Canada. Most study participants were male (63.8%) and white (58.3%), and participants had a median age of 11.0 years (interquartile range 7.6 to 14.6) at the baseline visit. In urine samples collected serially over an average of 3.0 years (standard deviation [SD] 1.6), concentrations of BPA, phthalic acid (PA), and phthalate metabolites were measured as well as biomarkers of tubular injury (kidney injury molecule-1 [KIM-1] and neutrophil gelatinase-associated lipocalin [NGAL]) and oxidative stress (8-hydroxy-2&apos;-deoxyguanosine [8-OHdG] and F.sub.2 -isoprostane). Clinical renal function measures included estimated glomerular filtration rate (eGFR), proteinuria, and blood pressure. Linear mixed models were fit to estimate the associations between urinary concentrations of 6 chemical exposure measures (i.e., BPA, PA, and 4 phthalate metabolite groups) and clinical renal outcomes and urinary concentrations of KIM-1, NGAL, 8-OHdG, and F.sub.2 -isoprostane controlling for sex, age, race/ethnicity, glomerular status, birth weight, premature birth, angiotensin-converting enzyme inhibitor use, angiotensin receptor blocker use, BMI z-score for age and sex, and urinary creatinine. Urinary concentrations of BPA, PA, and phthalate metabolites were positively associated with urinary KIM-1, NGAL, 8-OHdG, and F.sub.2 -isoprostane levels over time. For example, a 1-SD increase in [summation]di-n-octyl phthalate metabolites was associated with increases in NGAL ([beta] = 0.13 [95% CI: 0.05, 0.21], p = 0.001), KIM-1 ([beta] = 0.30 [95% CI: 0.21, 0.40], p < 0.001), 8-OHdG ([beta] = 0.10 [95% CI: 0.06, 0.13], p < 0.001), and F.sub.2 -isoprostane ([beta] = 0.13 [95% CI: 0.01, 0.25], p = 0.04) over time. BPA and phthalate metabolites were not associated with eGFR, proteinuria, or blood pressure, but PA was associated with lower eGFR over time. For a 1-SD increase in ln-transformed PA, there was an average decrease in eGFR of 0.38 ml/min/1.73 m.sup.2 (95% CI: -0.75, -0.01; p = 0.04). Limitations of this study included utilization of spot urine samples for exposure assessment of non-persistent compounds and lack of specific information on potential sources of exposure. Conclusions Although BPA and phthalate metabolites were not associated with clinical renal endpoints such as eGFR or proteinuria, there was a consistent pattern of increased tubular injury and oxidative stress over time, which have been shown to affect renal function in the long term. This raises concerns about the potential for clinically significant changes in renal function in relation to exposure to common environmental toxicants at current levels.

Objectives: Renal manifestations are the second most significant cause of morbidity and mortality in patients with tuberous sclerosis complex (TSC), and include renal cysts, angiomyolipomas, fat-poor lesions, and malignant tumors. These lesions begin in childhood and often lead to chronic kidney disease (CKD). Little is known on the incidence of early modifiable risk factors of CKD, such as proteinuria and hypertension, or subtle decreases in glomerular filtration rate that correspond to the early stages of CKD in children with TSC. The impact of genotype on these early manifestations of CKD has not been investigated. Design: Retrospective chart review of 84 children and young adults with TSC. Measurements: This study assessed the prevalence of hypertension, renal impairment, and proteinuria, as well as the genotype-phenotype correlations. Results: Children and young adults with TSC2 mutations had a significantly higher rate of renal lesions, hypertension (36% vs 14%), and decreased renal function than those with TSC1 mutations. Conclusion: On the basis of estimated glomerular filtration rate and blood pressure, our findings are consistent with the hypothesis that TSC2 mutations are associated with more severe early renal involvement in children. There is a compelling need for close collaboration of nephrologists and neurologists to provide care to pediatric patients with TSC to improve screening and management of early manifestations of renal disease. [ABSTRACT FROM AUTHOR]

Background: Patients with resistant focal segmental glomerulosclerosis (FSGS) who are unresponsive to corticosteroids and other immunosuppressive agents are at very high risk of progression to end stage kidney disease. In the absence of curative treatment, current therapy centers on renoprotective interventions that reduce proteinuria and fibrosis. The FONT (Novel Therapies for Resistant FSGS) Phase II clinical trial (NCT00814255, Registration date December 22, 2008) was designed to assess the efficacy of adalimumab and galactose compared to standard medical therapy which was comprised of lisinopril, losartan, and atorvastatin. Methods: Key eligibility criteria were biopsy confirmed primary FSGS or documentation of a causative genetic mutation, urine protein:creatinine ratio >1.0 g/g, and estimated glomerular filtration rate (eGFR) >40 ml/min/1.73 m². The experimental treatments - adalimumab, galactose, standard medical therapy-- were administered for 26 weeks. The primary endpoint was a 50 % reduction in proteinuria with stable eGFR. Results: Thirty-two subjects were screened and 21 were assigned to one of the three study arms. While none of the adalimumab-treated subjects achieved the primary outcome, 2 subjects in the galactose and 2 in the standard medical therapy arm had a 50 % reduction in proteinuria without a decline in eGFR. The proteinuria response did not correlate with serial changes in the serum glomerular permeability activity measured by the Palb assay or soluble urokinase plasminogen activator receptor (suPAR). There were no serious adverse effects related to treatments in the study. Conclusions: Recruitment into this trial that addressed patients with resistant FSGS fell short of the enrollment goal. Our findings suggest that future studies of novel therapies for rare glomerular diseases such as FSGS may benefit from enrollment of patients earlier in the course of their disease. In addition, better identification of patients who are likely to respond to a new treatment based on biomarkers suggesting involvement of the disease pathway targeted by the experimental agent may reduce the required sample size and increase the likelihood of a favorable outcome. [ABSTRACT FROM AUTHOR]

Background. Failure to thrive (FTT) poses a diagnostic dilemma for pediatricians. The kidney disorder that is considered most often is renal tubular acidosis (RTA). However, the prevalence of RTA may be overestimated, leading to unnecessary referrals for subspecialty evaluation. Moreover, preliminary data suggest that venous blood gas (VBG) testing may provide a more accurate measurement of the serum bicarbonate concentration than routine biochemical testing. Objective. 1) To compare the results of bicarbonate measurements by using VBG and routine clinical biochemistry methods under a variety of in vitro conditions; 2) to determine the frequency of RTA as a cause of FTT; and 3) to assess the utility of VBG measurement of serum bicarbonate in the clinical assessment of RTA. Experimental Design and Methods. In blood samples collected from healthy volunteers, bicarbonate was measured by using a VBG apparatus and a clinical biochemistry analyzer under a variety of in vitro conditions including variation in time until sample processing (0-4 hours), variations in temperature (room temperature versus on ice), addition of sodium fluoride, or addition of heparin. A retrospective chart review was also performed of all children referred to the renal clinic for evaluation of FTT during the 5-year period of 1997 to 2002. The following data were collected for each case: demographic and clinical information and laboratory testing including serum bicarbonate determined by both routine biochemical testing and VBG analysis. Data are reported as mean [+ or -] standard deviation. Results. In the in vitro studies, VBG determination of bicarbonate concentration consistently yielded a value that was 3 to 6 mmol/L higher than routine biochemical analysis regardless of whether the sample was processed immediately or up to 4 hours later, maintained at room temperature or on ice until the measurement was performed, or the sample tube contained sodium fluoride or heparin. Thirty-six children were referred to exclude a renal etiology of FTT with a presumptive diagnosis of RTA in all cases. The patient group was comprised of 16 males and 20 females whose ages ranged from 4 to 156 months (mean: 27 [+ or -] 33 months). The serum bicarbonate concentration determined by biochemical testing was 18 [+ or -] 4 mmol/L, whereas the bicarbonate level by VBG was 24 [+ or -] 3 mmol/L. The mean difference between the bicarbonate by VBG and bicarbonate by routine biochemistry measurements was 5.6 [+ or -] 4.4. Only 1 child (2.8%) was confirmed to have RTA. Conclusions. RTA is a rare renal cause of FTT in children. VBG determination of serum bicarbonate yielded a significantly higher value than the result obtained by routine biochemical testing under both in vitro and in vivo conditions. These data suggest that reliance on routine biochemical testing results in an overestimation of the importance of RTA as a cause of FTT. We recommend the use of a VBG determination of serum bicarbonate concentration for the evaluation of a child with FTT who is thought to have a metabolic acidosis. Adoption of this practice will reduce the number of children suspected of having RTA and decrease the need for referral to a nephrologist for further evaluation. Pediatrics 2003;112:e463-e466. URL: http://www.pediatrics. org/cgi/content/full/112/6/e463; failure to thrive, renal tubular acidosis, bicarbonate, venous blood gas.

Recurrence of focal segmental glomerulosclerosis (FSGS) after renal transplantation is a complication that often leads to graft loss. There is no consensus on the optimal treatment of recurrent FSGS. Rituximab, a monoclonal antibody to CD20, may be a useful treatment of this complication. Methods. We report four pediatric cases of recurrent FSGS treated with rituximab and plasmapheresis. Results. Four children (2M/2F), age 15.3 ± 2.6, with recurrent FSGS posttransplant were identified. Four doses of rituximab were administered 171 ± 180 days posttransplant and 114 ± 169 days after the start of plasmapheresis. Three children responded with complete remission, one of whom relapsed after four months. One child had a partial response with a decrease in proteinuria that was not sustained. No adverse side effects were reported during treatment or followup (mean 22.5 months). Conclusions. Rituximab is a safe and well-tolerated ancillary treatment for recurrent FSGS in pediatric patients in conjunction with 2]: plasmapheresis. [ABSTRACT FROM AUTHOR]

Background: The lack of adequate randomized clinical trials (RCT) has hindered identification of new therapies that are safe and effective for patients with primary focal segmental glomerulosclerosis (FSGS), especially in patients who fail to respond to corticosteroids and immunosuppressive therapies. Recent basic science advances have led to development of alternative treatments that specifically target aberrant pathways of fibrosis which are relevant to disease progression in FSGS. There is a need for a flexible Phase II study design which will test such novel antifibrotic strategies in order to identify agents suitable for phase III testing. Methods/Design: The Novel Therapies for Resistant Focal Segmental Glomerulosclerosis (FONT) project is a multicenter Phase I/II RCT designed to investigate the potential efficacy of novel therapies for resistant FSGS. Adalimumab and galactose will be evaluated against conservative therapy consisting of the combination of lisinopril, losartan and atorvastatin. The sample size is defined to assure that if one of the treatments has a superior response rate compared to that of the other treatments, it will be selected with high probability for further evaluation. Comparison of primary and secondary endpoints in each study arm will enable a choice to be made of which treatments are worthy of further study in future Phase III RCT. Discussion: This report highlights the key features of the FONT II RCT including the two-step outcome analysis that will expedite achievement of the study objectives. The proposed phase II study design will help to identify promising agents for further testing while excluding ineffective agents. This staged approach can help to prevent large expenditures on unworthy therapeutic agents in the management of serious but rare kidney diseases Trial Registration: ClinicalTrials.gov, NCT00814255 [ABSTRACT FROM AUTHOR]

The normal range for the BUN:creatinine ratio (BCR) has not been determined for infants and children. The objectives of this study were to: i) test the hypothesis that the BCR is higher in young children, and ii) establish normal BCR ranges for children of various ages. In this retrospective single-center review, 482 patients evaluated in an ambulatory setting were studied. The mean BCR declined significantly with age (P<0.0001). There was an inverse relationship between BCR and age, body mass index (BMI), and serum creatinine and a direct relationship with BUN and estimated glomerular filtration rate. Based on our findings, we concluded that BCR values in adult patients are inapplic - able to children below 10 years of age. We suggest that BCR greater than 60 in children 10 years of age or younger, and greater than 30 in children older than 10 years be considered abnormal. Application of age-specific pediatric criteria will ensure the proper application of the BCR in evaluating acutely ill children. [ABSTRACT FROM AUTHOR]

Background: Patients with resistant primary focal segmental glomerulosclerosis (FSGS) are at high risk of progression to chronic kidney disease stage V. Antifibrotic agents may slow or halt this process. We present outcomes of follow-up after a Phase I trial of adalimumab and rosiglitazone, antifibrotic drugs tested in the Novel Therapies in Resistant FSGS (FONT) study. Methods: 21 patients -- 12 males and 9 females, age 16.0 ± 7.5 yr, and estimated GFR (GFRe) 121 ± 56 mL/min/ 1.73 m² -- received adalimumab (n = 10), 24 mg/m² every 14 days or rosiglitazone (n = 11), 3 mg/m² per day for 16 weeks. The change in GFRe per month prior to entry and after completion of the Phase I trial was compared. Results: 19 patients completed the 16-week FONT treatment phase. The observation period pre-FONT was 18.3 ± 10.2 months and 16.1 ± 5.7 months after the study. A similar percentage of patients, 71% and 56%, in the rosiglitazone and adalimumab cohorts, respectively, had stabilization in GFRe, defined as a reduced negative slope of the line plotting GFRe versus time without requiring renal replacement therapy after completion of the FONT treatment period (P = 0.63). Conclusion: Nearly 50% of patients with resistant FSGS who receive novel antifibrotic agents may have a legacy effect with delayed deterioration in kidney function after completion of therapy. Based on this proof-of-concept preliminary study, we recommend long-term follow-up of patients enrolled in clinical trials to ascertain a more comprehensive assessment of the efficacy of experimental treatments. [ABSTRACT FROM AUTHOR]

Background: Infants with neonatal hydronephrosis and a normal voiding cystourethrogram (VCUG) are presumed to have ureteropelvic junction obstruction (UPJO). There is little current information about the natural history of children with hydronephrosis or clinical factors that predict resolution of the radiological abnormality. Objective: To determine the time course until spontaneous resolution of neonatal hydronephrosis and define risk factors for persistence of the abnormality. Methods: This retrospective single center review examined infants and children <5 years of age with hydronephrosis who were followed for at least 12 months. Results: 136 children were identified (96 male:40 female). The mean age at diagnosis of hydronephrosis was 3.3 ± 9.7 months and 76% of the patients were diagnosed at birth. The hydronephrosis was unilateral in 98 (72%) of cases, and hydronephrosis was at least moderate in severity in 22% of affected kidneys. At last follow-up at 30 ± 10 months, the abnormality had resolved in 77 out of 115 (67%) available patients, 30 (26%) had been referred to urology, and 12 (10%) had persistent hydronephrosis. Severity of hydronephrosis was the only clinical feature that predicted persistence of the abnormality (P < 0.001). There was an association between detection at birth and lack of resolution of hydronephrosis. Conclusions: Children with hydronephrosis and presumed UPJO and normal kidney parenchyma can be followed for at least 2 years to allow for spontaneous resolution before referral to urology. Serial sonography can be performed at 6 month intervals in uncomplicated cases. More severe hydronephrosis and presence of the lesion at birth may predict infants and children requiring closer observation and referral for possible surgical correction of the hydronephrosis. [ABSTRACT FROM AUTHOR]

IgA nephropathy (IgAN) is a common glomerular disease whose etiology is unknown. Previous studies have described the clinical and laboratory features but none have specifically compared patients during different time periods. This 20 year retrospective study was performed to assess trends in the severity of IgAN from 1989-2008. We reviewed 57 patient charts that contained a confirmed biopsy diagnosis of IgAN and recorded data at the time of diagnosis and the final follow-up appointment. Clinical data included physical examination, urine, and blood tests. Patients were separated into two cohorts, Cohort 1 1989-1998 and Cohort 2 1999-2008. An increase in severity was noted in Cohort 2 based on a significantly higher Up/c and lower serum albumin level. Other prognostic indicators including GFRe, hematocrit, and glomerular injury score also demonstrated a trend towards more severe disease over the past 20 years. The patients in both Cohorts received similar treatments and had comparable renal function at the last follow-up visit. Based on our findings, we suggest that although a kidney biopsy is required to diagnose IgAN, the procedure may not be necessary in patients clinically suspected of having the disease but who have normal kidney function and minimal urine abnormalities. [ABSTRACT FROM AUTHOR]

Background: Previous studies have examined the spectrum of diseases identified with a kidney biopsy and the complications of the procedure. However, few studies have examined the utility of the test to clarify the diagnosis and guide treatment of pediatric patients. This retrospective, singlecenter chart review was performed to test the hypothesis that at least 80% of native kidney biopsies provide clinically valuable information that rationally guides diagnosis and patient management. Methods: 200 biopsies performed between January 1, 2000 and June 30, 2008 were reviewed. A scheme composed of six categories was devised to classify the utility of each kidney biopsy. Results: 196 complete case files were available for review. Twenty-four (12.2%) biopsies did not shed light on the diagnosis and were unhelpful in patient management - 21 biopsies (10.7%) were non-diagnostic and 3 (1.5%) failed to yield enough tissue for examination. The number of unhelpful biopsies did not cluster in any specific disease entity. Conclusion: Our findings provide guidance to nephrologists about the total risk of a kidney biopsy, including uninformative results, when seeking informed consent for the procedure. The results suggest an appropriate balance has been reached which maximizes the use of kidney biopsies while minimizing the risk of this invasive procedure (word count: 202). [ABSTRACT FROM AUTHOR]

Background: Idiopathic membranous nephropathy (IMN) is one of the most common causes of primary nephrotic syndrome in adults. However, it is a relatively rare entity in the pediatric population and there is a paucity of data about the incidence, prognosis, and optimal treatment of IMN in children and adolescents. We conducted this study to evaluate pediatric patients with IMN in order to clarify the presentation, response to therapy, and clinical outcome. Methods: A retrospective chart review was performed on patients identified with biopsy-proven IMN between 1988-2005. Patients with systemic lupus erythematosus or hepatitis-related lesions were excluded. The following data were tabulated: age, gender, ethnicity, presenting clinical and laboratory findings, proteinuria in a first morning urine specimen, estimated glomerular filtration rate (GFRe), histopathology, type and duration of treatment, and clinical status at final evaluation. Results: 13 cases of IMN were identified out of 460 renal biopsies performe for evaluation of primary kidney disease during the study interval. Mean age was 9.6 ± 4.6, gender 6 M:7 F, ethnicity 8 W:2 B:3 H. At the initial visit hematuria was present in 9 patients, edema in 5, nephrotic-range proteinuria in 5, and hypertension in 3. Mean urinary protein:creatinine ratio 3.3 ± 2.5 and all patients had a normal GFRe. Classic glomerular findings of IMN were seen in all renal specimens, with concomitant interstitial changes in 2 cases. Treatment included anangiotensin converting enzyme inhibitor or angiotensin receptor blocker in 11 cases. Most patients were also given immunosuppressive medications - prednisone in 10, a calcineurin inhibitor in 5, and mycophenolate mofetil or azathioprine in 3 patients. At the last follow-up, 42 ± 35 months after the diagnostic biopsy, 7 children were hypertensive and the urine protein:creatinine ratio was 2.3 ± 3.1. The mean GFRe was 127 ± 57 mL/min/m2. Three patients had Chronic Kidney Disease Stage 3, all of whom were also hypertensive. Conclusion: IMN is a rare but serious glomerulopathy in pediatrics. We estimate that it accounts for approximately 3% of renal biopsies. Long-term prognosis is guarded because approximately 50% of patients may have evidence of progressive kidney disease. [ABSTRACT FROM AUTHOR]

Introduction: Edema is a common manifestation of proteinuric kidney diseases, but there is no consensus approach for reliably evaluating edema. The objective of this study was to develop an edema clinician-reported outcome measure for use in patients with nephrotic syndrome., Methods: A literature review was conducted to assess existing clinician-rated measures of edema. Clinical experts were recruited from internal medicine, nephrology, and pediatric nephrology practices to participate in concept elicitation using semi-structured interviews and cognitive debriefing. Qualitative analysis methods were used to collate expert input and inform measurement development. In addition, training and assessment modules were developed using an iterative process that also utilized expert input and cognitive debriefing to ensure interrater reliability., Results: While several clinician-rated measures of edema have been proposed, our literature review did not identify any studies to support the reliability or validity of these measures. Fourteen clinician experts participated in the concept elicitation interviews, and twelve participated in cognitive debriefing. A clinician-reported outcome measure for edema was developed. The measure assesses edema severity in multiple individual body parts. An online training module and assessment tool were generated and refined using additional clinician input and investigative team expertise., Conclusion: The Edema ClinRO (V1) measure is developed specifically to measure edema in nephrotic syndrome. The tool assesses edema across multiple body parts, and it includes a training module to ensure standardized administration across raters. Future examination of this measure is ongoing to establish its reliability and validity., Competing Interests: Joshua Thurman receives royalties from Alexion Pharmaceuticals, Inc. He is a consultant for, will receive royalty income from, and holds stock in Q32 Bio Inc. He is also on the data review team for Goldfinch Bio. Michelle O’Shaughnessy is a consultant for Chinook Pharmaceuticals. Noelle Carlozzi, through the University of Michigan, received research funding for the design and conduct of this study. Laura Mariani, through the University of Michigan, has received research funding from the NIH, DOD, Nephcure Kidney International, and Boehringer Ingelheim unrelated to this work. She also receives personal consulting fees from Reata Pharmaceuticals, Calliditas Therapeutics, and Travere Therapeutics. Howard Trachtman is a consultant to Travere, Goldfinch Bio, Roche, and Walden and receives research funding from the NIH, DOD, and Natera. He is also Chair of DMC for pediatric studies conducted by Otsuka and is on the editorial board of Scientific Reports, Glomerular Diseases, Pediatric Nephrology, and Kidney360. Debbie Gipson, through the University of Michigan, received research funding for the design and conduct of this study from Goldfinch Bio and, through the University of Michigan, receives funding for research or consulting from Goldfinch Bio, Genentech, Roche, Boehringer Ingelheim, Travere, AstraZeneca, Novartis, Pfizer, Vertex, Reata, NIH, CDC, and FDA. Youssef Farag is a past employee of Goldfinch Bio. Liron Walsh is a past employee of Goldfinch Bio. All other authors report no conflicts of interest., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Objective: We conducted this study to test the hypothesis that plasma zonulin levels are elevated in pediatric patients with nephrotic syndrome compared to healthy controls. Study Design: Plasma zonulin levels were measured by ELISA in 114 children enrolled in the NEPTUNE study. Clinical and laboratory data were retrieved from the NEPTUNE database. Results: The median age of the patients was 10 (IQR = 5 to 14) years, 59 were male, 64 had minimal change disease, 47 focal segmental glomerulosclerosis, median eGFR was 96 (IQR = 80 to 114) ml/min/1.73 m 2 , and median urine protein:creatinine ratio was 0.5 (IQR = 0.1 to 3.4) (g:g). The plasma zonulin level was 14.2 ± 5.0 vs. 10.2 ± 2.5 ng/ml in healthy adults in a report using the same assay kit, P = 0.0025. These findings were confirmed in an independent cohort of children with nephrotic syndrome compared to healthy age-matched controls, P = 0.01. Zonulin concentrations did not differ in children with minimal change disease vs. focal segmental glomerulosclerosis, frequently relapsing vs. steroid-dependent vs. steroid-resistant clinical course, and were not influenced by the immunosuppressive treatment regimen. There was no relationship between plasma zonulin levels and the absolute or percentage change in proteinuria from enrollment until the time of the zonulin assay. Conclusion: Plasma zonulin levels are elevated in childhood nephrotic syndrome regardless of level of proteinuria or specific treatment. The cause of the high plasma zonulin levels and whether zonulin contributes to glomerular injury requires further study.

Interstitial nephritis (IN) is a relatively rare entity in children and adolescents that can be caused by a range of disorders including infection, medications, inflammatory bowel disease, and sarcoid. There is no proven therapy for this condition. We present 2 cases of biopsy-proven interstitial nephritis, of which 1 case was with granulomatous features that presented with unusual sonographic findings of discrete mass lesions in the kidney parenchyma bilaterally. Although a precise cause could not be identified in either case, 1 patient progressed to end-stage kidney disease (ESKD) and the other is in the early stages of treatment. We suggest that recognition of the atypical imaging features of interstitial nephritis may enable early recognition of this condition and avoid confusion with neoplastic or infectious processes.

Background: The health effects of bisphenol A (BPA) and di-(2-ethylhexyl) phthalate (DEHP) have been studied extensively in children. The impact of other chemicals in these two classes has not been investigated as fully., Methods: We conducted a cross-sectional pilot study of 10-13 y old healthy children. We assessed descriptive, univariable, and multivariable associations of urinary metabolites of bisphenols and phthalates with oxidant stress, insulin resistance, body mass, and endothelial dysfunction. Possible associations with brachial artery distensibility, pulse wave velocity (markers of vascular stiffness), and serum endothelial cell-derived microparticle levels were also assessed., Results: We enrolled 41 participants, 12.1 ± 1.0 y, most of whom were Mexican Americans (42%) or other Hispanics (34%). Increased BPA levels were associated with increased levels of F2-isoprostane (ng/ml) (P = 0.02), with a similar trend for DEHP metabolites. Each log unit increase of high molecular weight (HMW) phthalate metabolites was associated with a 0.550 increase in Homeostatic Model Assessment of insulin resistance (HOMA-IR) units (P = 0.019) and altered circulating levels of activated endothelial cell-derived microparticles (% per ml) (P = 0.026). Bisphenol S (BPS), a replacement for BPA, was associated with increased albumin (mg):creatinine (g) ratio (P = 0.04). Metabolites of HMW phthalates were also associated with decreased brachial artery distensibility (P = 0.047)., Conclusion: Exposure to bisphenols and phthalates, including a BPA replacement, is associated with increased oxidant stress, insulin resistance, albuminuria, as well as disturbances in vascular function in healthy children.

Background. Restless legs syndrome (RLS) is a sleep disorder characterized by an urge to move or the presence of unpleasant sensations in the extremities. The prevalence of RLS is higher in children and adults with chronic kidney disease and in adults with glomerular disease. Objective. To determine the prevalence of RLS in children with nephrotic syndrome. Methods. We studied 50 children with nephrotic syndrome and 22 controls. The following surveys were administered: Pediatric Emory RLS questionnaire, Pediatric Daytime Sleepiness Scale, and Pediatric Sleep Questionnaire. Results. Children with nephrotic syndrome were 9.0 ± 4.4 years old, 27 were male, and 27 were in remission. The prevalence of RLS was similar in the nephrotic syndrome cases and controls, whether or not indeterminate cases were considered positive: 14.0% versus 13.6% including indeterminate cases, and 8.0% versus 9.1% excluding indeterminate cases. Conclusion. RLS is not more common in children with glomerular disease compared to healthy controls.

Renal Wilms' tumor-1 (WT-1) staining is used to detect podocyte loss in kidney biopsies. We aimed to determine if urinary exosomal WT-1 could serve as a noninvasive biomarker of podocyte injury. We examined WT-1 by Western blot in a human podocyte-like cell line, a mouse model of podocyte injury, and human subjects with podocyte disorders. WT-1 was detected in exosomal fraction of the conditioned media from podocytes and increased 48 h after hTGF-β1 stimulation. Cellular WT-1 decreased in podocytes following hTGF-β1 incubation. In mice with induced podocyte injury, urinary exosomal WT-1 was detected 1 wk earlier than albuminuria and also tracked the effects of angiotensin receptor blocker (ARB) treatment. In addition, urinary exosomal WT-1 levels at 1 wk post-injury correlated with the severity of glomerular injury at 3 wk later. In human subjects, urinary exosomal WT-1 was significantly increased in focal segmental glomerulosclerosis (FSGS) patients compared with healthy volunteers or steroid-sensitive nephrotic syndrome (SSNS) patients. Urinary exosomal WT-1 was also significantly decreased in patients in remission for either FSGS or SSNS or following steroid treatment in six SSNS subjects. We conclude that urinary exosomal WT-1 is a promising noninvasive biomarker with apparent podocyte specificity that can detect early progression and treatment-induced regression of podocyte injury in FSGS or SSNS. These results warrant longitudinal, prospective studies in a large cohort with a range of podocyte diseases.

Background and Objectives: Patients with primary focal segmental glomerulosclerosis (FSGS) who are resistant to standard therapy are at high risk for progressive chronic kidney disease. Prevention of renal fibrosis represents a promising strategy to slow or halt kidney function decline. This paper presents the results of a Phase I clinical trial of rosiglitazone, a thiazolidinedione, that exerts antifibrotic effects in animal models of FSGS. The primary goal was assessment of safety, tolerability, and pharmacokinetics (PK) of rosiglitazone., Design, Setting, Participants, & Measurements: Eleven patients, including eight boys/men and three girls/women, with mean age 15 +/- 6 yr and estimated GFR 131 +/- 62 ml/min/1.73 m(2), received rosiglitazone, 3 mg/m(2)/d for 16 wk. PK was assessed twice, after the initial dose and after attaining steady state, in a General Clinical Research Center., Results: There were no serious adverse events or cardiovascular complications. Rosiglitazone was well tolerated by all patients, as judged by the Treatment Satisfaction Questionnaire for Medication. The PK studies indicated that the area under the curve was decreased by 40 to 50% and oral clearance of rosiglitazone was increased by 250 to 300% in patients with resistant FSGS compared with healthy controls and patients with nonproteinuric stage 2 chronic kidney disease., Conclusions: Rosiglitazone therapy was safe and well tolerated. PK assessment of potential novel therapies for resistant FSGS is necessary to define appropriate dosing regimens. There is rationale to evaluate the efficacy of rosiglitazone as an antifibrotic agent for resistant FSGS in Phase II/III clinical trials.

Objective: Children and adolescents with newly diagnosed hypertension undergo various tests to define the cause and target organ consequences of the elevated blood pressure. We tested the hypothesis that the diagnostic yield of individual components of the currently recommended assessment does not justify performance for all patients with mild-to-moderate hypertension., Methods: A retrospective chart review was conducted of patients who were referred between July 2002 and June 2007 for mild-to-moderate hypertension, defined as maximum blood pressure at >or=95% + 20/10 mmHg. The assessment included history and physical examination, nutritional assessment, urinalysis, biochemical and fasting lipid profile, renal ultrasound, echocardiogram, and 24-hour ambulatory blood pressure monitoring., Results: A total of 249 patients were identified, and charts for 220 (88%) were available for review. There were 156 boys and 64 girls aged 13.3 +/- 4.4 years. BMI was 26.1 +/- 6.7 kg/m(2), and 143 (65%) had a BMI of >or=90%. Results of urinalysis and serum biochemical testing were clinically normal in all cases. Among those with a lipid profile, 59 (42%) had total cholesterol values of >170 mg/dL, and 26 (19%) had severe hypercholesterolemia (>200 mg/dL). Renal sonography revealed findings plausibly associated with hypertension in 14 (8%) patients; 4 (2%) had renovascular abnormalities. Yield of echocardiography was 17%. On ambulatory blood pressure monitoring, 47 (60%) children had systolic readings of >95% at least 20% of the time, and 28 (36%) had diastolic readings of >95% at least 20% of the time., Conclusions: For children and adolescents with mild-to-moderate hypertension, on the basis of a cutoff of 5% to 20% abnormal results to define a useful test, the initial evaluation can range from a serum cholesterol level and ambulatory blood pressure monitoring to a panel that consists of a fasting lipid profile, renal ultrasound, echocardiogram, and ambulatory blood pressure monitoring. Additional assessment should be guided by specific clinical features and the nature of the patient population.