Tobacco exposure in adults and children with proteinuric glomerulopathies: a NEPTUNE cohort study.

BACKGROUND: Tobacco exposure has been recognized as a risk factor for cardiovascular disease (CVD) and progression of kidney disease. Patients with proteinuric glomerulopathies are at increased risk for cardiovascular morbidity and mortality. Multiple studies have linked tobacco exposure to CVD and chronic kidney disease, but the relationships between smoking and proteinuric glomerulopathies in adults and children have not been previously explored. METHODS: Data from the Nephrotic Syndrome Study Network (NEPTUNE), a multi-center prospective observational study of participants with proteinuric glomerulopathies, was analyzed. 371 adults and 192 children enrolled in NEPTUNE were included in the analysis. Self-reported tobacco exposure was classified as non-smoker, active smoker, former smoker, or exclusive passive smoker. Baseline serum cotinine levels were measured in a sub-cohort of 178 participants. RESULTS: The prevalence of active smokers, former smokers and exclusive passive smoking among adults at baseline was 14.6%, 29.1% and 4.9%, respectively. Passive smoke exposure was 16.7% among children. Active smoking (reference non-smoking) was significantly associated with greater total cholesterol among adults (ß 17.91 95% CI 0.06, 35.76, p = 0.049) while passive smoking (reference non-smoking) was significantly associated with greater proteinuria over time among children (ß 1.23 95% CI 0.13, 2.33, p = 0.03). Higher cotinine levels were associated with higher baseline eGFR (r = 0.17, p = 0.03). CONCLUSION: Tobacco exposure is associated with greater risk for CVD and worse kidney disease outcomes in adults and children with proteinuric glomerulopathies. Preventive strategies to reduce tobacco exposure may help protect against future cardiovascular and kidney morbidity and mortality in patients with proteinuric glomerulopathies.

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.

Comparing Kidney Health Outcomes in Children, Adolescents, and Adults With Focal Segmental Glomerulosclerosis.

Importance: Focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage kidney disease (ESKD) across the lifespan. While 10% to 15% of children and 3% of adults who develop ESKD have FSGS, it remains uncertain whether the natural history differs in pediatric vs adult patients, and this uncertainty contributes to the exclusion of children and adolescents in clinical trials. Objective: To examine whether there are differences in the kidney health outcomes among children, adolescents, and adults with FSGS. Design, Setting, and Participants: This cohort study used pooled and parallel analyses, completed July 5, 2022, from 3 complimentary data sources: (1) Nephrotic Syndrome Rare Disease Clinical Research Network (NEPTUNE); (2) FSGS clinical trial (FSGS-CT); and (3) Kidney Research Network (KRN). NEPTUNE is a multicenter US/Canada cohort study; FSGS-CT is a multicenter US/Canada clinical trial; and KRN is a multicenter US electronic health record-based registry from academic and community nephrology practices. NEPTUNE included 166 patients with incident FSGS enrolled at first kidney biopsy; FSGS-CT included 132 patients with steroid-resistant FSGS randomized to cyclosporine vs dexamethasone with mycophenolate; and KRN included 184 patients with prevalent FSGS. Data were collected from November 2004 to October 2019 and analyzed from October 2020 to July 2022. Exposures: Age: children (age <13 years) vs adolescents (13-17 years) vs adults (≥18 years). Covariates of interest included sex, disease duration, APOL1 genotype, urine protein-to-creatinine ratio, estimated glomerular filtration rate (eGFR), edema, serum albumin, and immunosuppressive therapy. Main Outcomes and Measures: ESKD, composite outcome of ESKD or 40% decline in eGFR, and complete and/or partial remission of proteinuria. Results: The study included 127 (26%) children, 102 (21%) adolescents, and 253 (52%) adults, including 215 (45%) female participants and 138 (29%) who identified as Black, 98 (20%) who identified as Hispanic, and 275 (57%) who identified as White. Overall, the median time to ESKD was 11.9 years (IQR, 5.2-19.1 years). There was no difference in ESKD risk among children vs adults (hazard ratio [HR], 0.67; 95% CI, 0.43-1.03) or adolescents vs adults (HR, 0.85; 95% CI, 0.52-1.36). The median time to the composite end point was 5.7 years (IQR 1.6-15.2 years), with hazard ratio estimates for children vs adults of 1.12 (95% CI, 0.83-1.52) and adolescents vs adults of 1.06 (95% CI, 0.75-1.50). Conclusions and Relevance: In this study, the association of FSGS with kidney survival and functional outcomes was comparable at all ages.

Expanding the phenotypic spectrum of Mendelian connective tissue disorders to include prominent kidney phenotypes.

Heritable connective tissue disorders are a group of diseases, each rare, characterized by various combinations of skin, joint, musculoskeletal, organ, and vascular involvement. Although kidney abnormalities have been reported in some connective tissue disorders, they are rarely a presenting feature. Here we present three patients with prominent kidney phenotypes who were found by whole exome sequencing to have variants in established connective tissue genes associated with Loeys-Dietz syndrome and congenital contractural arachnodactyly. These cases highlight the importance of considering connective tissue disease in children presenting with structural kidney disease and also serves to expand the phenotype of Loeys-Dietz syndrome and possibly congenital contractural arachnodactyly to include cystic kidney disease and cystic kidney dysplasia, respectively.

Hypertension in Children and Adolescents with Turner Syndrome (TS), Neurofibromatosis 1 (NF1), and Williams Syndrome (WS).

PURPOSE OF REVIEW: Turner syndrome (TS), neurofibromatosis type 1(NF1), and William Syndrome (WS) are 3 genetic conditions that are all associated with a substantial increase in risk of hypertension. In this review, we focus on factors leading to hypertension and on clinical manifestations and management of hypertension in children and adolescents with these genetic conditions RECENT FINDINGS: In most instances, hypertension is secondary. There is a high prevalence of masked hypertension in TS; however, the extent to which control of the BP helps reduce the risk of aortic dissection/aneurysm in TS is not yet fully elucidated. Vasculopathies are the least emphasized but most important manifestation of NF1. Of note, routine screening for pheochromocytoma in NFI is not recommended as it is not cost-effective. Cardiovascular complications are the major cause of death in patients with WBS. ABPM identifies patients without overt aortic or renovascular narrowing. Antihypertensive agents such as ARBs that have direct vascular wall effects and agents that inhibit oxidative stress (minoxidil) should be considered, even in those who do not exhibit overt hypertension. Elevated blood pressure in children and adolescence manifests early with end-organ changes and when left untreated, increases risk for premature onset of cardiovascular disease. Vigilant monitoring of the blood pressure is recommended. Accurate early diagnosis and management of hypertension will delay or prevent target organ damage and ensure a healthier transition to adulthood among children afflicted with these conditions.

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.

Ciliopathies: Coloring outside of the lines.

Ciliopathy syndromes are a diverse spectrum of disease characterized by a combination of cystic kidney disease, hepatobiliary disease, retinopathy, skeletal dysplasia, developmental delay, and brain malformations. Though generally divided into distinct disease categories based on the pattern of system involvement, ciliopathy syndromes are known to display certain phenotypic overlap. We performed next-generation sequencing panel testing, clinical exome sequencing, and research-based exome sequencing reanalysis on patients with suspected ciliopathy syndromes with additional features. We identified biallelic pathogenic variants in BBS1 in a child with features of cranioectodermal dysplasia, and biallelic variants in BBS12 in a child with the clinical stigmata of Bardet-Biedl syndrome, but also with anal atresia. We additionally identified biallelic pathogenic variants in WDR35 and DYNC2H1 in children with predominant liver disease and ductal plate malformation without skeletal dysplasia. Our study highlights the phenotypic and genetic diversity of ciliopathy syndromes, the importance of considering ciliopathy syndromes as a disease-spectrum and screening for all associated complications in all patients, and describes exclusive extra-skeletal manifestations in two classical skeletal dysplasia syndromes.

Kidney Outcomes and Hypertension in Survivors of Wilms Tumor: A Prospective Cohort Study.

OBJECTIVE: To assess the prevalence of therapy-related kidney outcomes in survivors of Wilms tumor (WT). STUDY DESIGN: This prospective cohort study included survivors of WT who were ≥5 years old and ≥1 year from completing therapy, excluding those with preexisting hypertension, prior dialysis, or kidney transplant. Participants completed 24-hour ambulatory blood pressure monitoring (ABPM). Abnormal blood pressure (BP) was defined as ≥90th percentile. Masked hypertension was defined as having normal office BP and abnormal ABPM findings. Urine was analyzed for kidney injury molecule-1, interleukin-18, epidermal growth factor, albumin, and creatinine. The estimated glomerular filtration rate (eGFR) was calculated using the bedside chronic kidney disease in children equation. Recent kidney ultrasound examinations and echocardiograms were reviewed for contralateral kidney size and left ventricular hypertrophy, respectively. Clinical follow-up data were collected for approximately 2 years after study enrollment. RESULTS: Thirty-two participants (median age, 13.6 years [IQR, 10.5-16.3 years]; 75% stage 3 or higher WT) were evaluated at a median of 8.7 years (IQR, 6.5-10.8 years) after therapy; 29 participants underwent unilateral radical nephrectomy, 2 bilateral partial nephrectomy, and 1 radical and contralateral partial nephrectomy. In this cohort, 72% received kidney radiotherapy and 75% received doxorubicin. Recent median eGFR was 95.6 mL/min/1.73 m2 (IQR, 84.6-114.0; 11 [34%] had an eGFR of <90 mL/min/1.73 m2). Abnormal ABPM results were found in 22 of 29 participants (76%), masked hypertension in 10 of 29 (34%), and microalbuminuria in 2 of 32 (6%). Of the 32 participants, 22 (69%) had abnormal epidermal growth factor; few had abnormal kidney injury molecule-1 or interleukin-18. Seven participants with previous unilateral nephrectomy lacked compensatory contralateral kidney hypertrophy. None had left ventricular hypertrophy. CONCLUSIONS: In survivors of WT, adverse kidney outcomes were common and should be closely monitored.

Restoration of nocturnal blood pressure dip and reduction of nocturnal blood pressure with evening anti-hypertensive medication administration in pediatric kidney transplant recipients: A pilot randomized clinical trial.

Non-dipping and nocturnal hypertension are commonly found during ABPM in pediatric kidney transplant recipients. These entities are independently associated with increased cardiovascular disease risk in adults. Kidney transplant recipients aged 5-21 years with eGFR > 30 mL/min/1.73 m2 and ABPM demonstrating non-dipping status and normal daytime BP were randomized to intervention (short acting BP medication added in the evening) or control (no medication change) in this pilot, randomized, open-label, blinded end-point clinical trial. ABPM, echocardiography, and PWV were performed at baseline, 3 months, and 6 months. The trial included 17 intervention and 16 control participants. Conversion to dipper status occurred in 53.3% vs 7.7% (P = .01) at 6 months for intervention and controls, respectively. Systolic dip was greater in the intervention group compared to controls (10.9 ± 4.5 vs 4.2 ± 4.6, P = .001), and average systolic nighttime BP was significantly lower in the intervention group (106 ± 8.3 vs 114.9 ± 9.5 mm Hg, P = .01) at 6 months. There were no significant differences in LVMI, PWV, or eGFR between groups. Within-group changes in the intervention group demonstrated improvements in non-dippers, dipping, systolic nighttime BP and nighttime BP load. Restoration of nocturnal dip and improvement in nocturnal BP were observed in the population following chronotherapy. Future studies are needed with larger sample sizes over a longer period of time to delineate the long-term effect of improved nocturnal dip on target organ damage.

Urinary Epidermal Growth Factor as a Marker of Disease Progression in Children With Nephrotic Syndrome.

INTRODUCTION: Childhood-onset nephrotic syndrome has a variable clinical course. Improved predictive markers of long-term outcomes in children with nephrotic syndrome are needed. This study tests the association between baseline urinary epidermal growth factor (uEGF) excretion and longitudinal kidney function in children with nephrotic syndrome. METHODS: The study evaluated 191 participants younger than 18 years enrolled in the Nephrotic Syndrome Study Network, including 118 with their first clinically indicated kidney biopsy (68 minimal change disease; 50 focal segmental glomerulosclerosis) and 73 with incident nephrotic syndrome without a biopsy. uEGF was measured at baseline for all participants and normalized by the urine creatinine (Cr) concentration. Renal epidermal growth factor (EGF) mRNA was measured in the tubular compartment microdissected from kidney biopsy cores from a subset of patients. Linear mixed models were used to test if baseline uEGF/Cr and EGF mRNA expression were associated with change in estimated glomerular filtration rate (eGFR) over time. RESULTS: Higher uEGF/Cr at baseline was associated with slower eGFR decline during follow-up (median follow-up = 30 months). Halving of uEGF/Cr was associated with a decrease in eGFR slope of 2.0 ml/min per 1.73 m2 per year (P < 0.001) adjusted for age, race, diagnosis, baseline eGFR and proteinuria, and APOL1 genotype. In the biopsied subgroup, uEGF/Cr was correlated with EGF mRNA expression (r = 0.74; P < 0.001), but uEGF/Cr was retained over mRNA expression as the stronger predictor of eGFR slope after multivariable adjustment (decrease in eGFR slope of 1.7 ml/min per 1.73 m2 per year per log2 decrease in uEGF/Cr; P < 0.001). CONCLUSION: uEGF/Cr may be a useful noninvasive biomarker that can assist in predicting the long-term course of kidney function in children with incident nephrotic syndrome.

Clinical Innovation: A Multidisciplinary Program for the Diagnosis and Treatment of Systemic Hypertension in Children and Adolescents.

Pediatric systemic hypertension (HTN) is underdiagnosed and undertreated. The Divisions of Cardiology and Nephrology at our institution developed a comprehensive outpatient HTN program to (1) screen children at risk for HTN, (2) assess cardiovascular health, and (3) optimize medical management. We report our findings during all initial visits (n = 304) from December 2011 to September 2018. Of the cohort, 38% were obese and 36% reported little to no exercise. More than half of patients ≥11 years old did not have recommended lipid screening. When evaluating ambulatory blood pressure monitoring results, clinic blood pressure did not accurately diagnose patients with or without HTN and many patients on antihypertensive medications were inadequately treated. Visit recommendations included addition of or changes to antihypertensive medication in 35% of patients. A multidisciplinary program dedicated to pediatric HTN helps screen patients who are at risk. Ambulatory blood pressure monitoring identifies HTN in patients with normal clinic blood pressure and those on antihypertensive medication.

DUET: A Phase 2 Study Evaluating the Efficacy and Safety of Sparsentan in Patients with FSGS.

BACKGROUND: We evaluated and compared the effects of sparsentan, a dual endothelin type A (ETA) and angiotensin II type 1 receptor antagonist, with those of the angiotensin II type 1 receptor antagonist irbesartan in patients with primary FSGS. METHODS: In this phase 2, randomized, double-blind, active-control Efficacy and Safety of Sparsentan (RE-021), a Dual Endothelin Receptor and Angiotensin Receptor Blocker, in Patients with Focal Segmental Glomerulosclerosis (FSGS): A Randomized, Double-blind, Active-Control, Dose-Escalation Study (DUET), patients aged 8-75 years with biopsy-proven FSGS, eGFR>30 ml/min per 1.73 m2, and urinary protein-to-creatinine ratio (UP/C) ≥1.0 g/g received sparsentan (200, 400, or 800 mg/d) or irbesartan (300 mg/d) for 8 weeks, followed by open-label sparsentan only. End points at week 8 were reduction from baseline in UP/C (primary) and proportion of patients achieving FSGS partial remission end point (FPRE) (UP/C: ≤1.5 g/g and >40% reduction [secondary]). RESULTS: Of 109 patients randomized, 96 received study drugs and had baseline and week 8 UP/C measurements. Sparsentan-treated patients had greater reductions in UP/C than irbesartan-treated patients did when all doses (45% versus 19%; P=0.006) or the 400 and 800 mg doses (47% versus 19%; P=0.01) were pooled for analysis. The FSGS partial remission end point was achieved in 28% of sparsentan-treated and 9% of irbesartan-treated patients (P=0.04). After 8 weeks of treatment, BP was reduced with sparsentan but not irbesartan, and eGFR was stable with both treatments. Overall, the incidence of adverse events was similar between groups. Hypotension and edema were more common among sparsentan-treated patients but did not result in study withdrawals. CONCLUSIONS: Patients with FSGS achieved significantly greater reductions in proteinuria after 8 weeks of sparsentan versus irbesartan. Sparsentan was safe and well tolerated.

Imaging studies in pediatric fibromuscular dysplasia (FMD): a single-center experience.

BACKGROUND: Fibromuscular dysplasia (FMD) is a non-inflammatory vascular disease that in children unlike in adults shows no sex predilection. FMD is often underdiagnosed, and its pathophysiology is unclear. Delayed diagnosis may lead to refractory hypertension and decreases the chance of successful treatment. Doppler ultrasound (US), magnetic resonance angiography (MRA), computed tomography angiography (CTA), and catheter-based angiography (angiography) are currently used to help make a clinicoradiological diagnosis of FMD. The main aim of the study was to compare the efficacy of imaging modalities which can allow for earlier and improved detection. Furthermore, an anatomical mapping of the location of lesions can help determine the best treatment modalities. METHODS: All patients with non-syndromic non-inflammatory renovascular hypertension were recruited from the Nephrology Department at the Children's Hospital of Philadelphia (CHOP) and enrolled in the U.S. FMD Registry maintained at the University of Michigan. Clinical presentation and imaging findings on US, CT, and MRI of children diagnosed with FMD were evaluated. RESULTS: Mean age at diagnosis was 7 ± 4.9 years (4 months-17 years). Family history of hypertension (HTN) (52%), FMD (8.7%), Caucasian (60%), headache (48%), and HTN (80%) were the most prevalent symptom and sign at presentation. Bruits were 100% specific for renal artery stenosis (RAS) diagnosis but were heard in the minority of patients (3 patients, 12%). FMD was mainly unifocal within a single site (68%) or multiple sites (28%) and involved the main or first order renal branch in about 68% of children. Isolated distal lesions beyond the second order branches were found in about 25% of children. US imaging was significantly less sensitive than angiography (28%, p = 0.003). MRA had a better sensitivity (62.5%, p = 0.3) than US. Overall, CTA had the best sensitivity (84.2%, p = 0.4) compared to angiography; however, only angiography showed distal vessel disease. CONCLUSIONS: Limitations of the study include the sample size and biases-only patients diagnosed with FMD were included in this study and most patients were referred to a pediatric nephrologist for unexplained hypertension. Angiography should be performed as part of the initial work-up of any child suspected of having renovascular FMD, regardless of the findings seen on US, MRA, or CTA.

Blood Pressure and Visit-to-Visit Blood Pressure Variability Among Individuals With Primary Proteinuric Glomerulopathies.

Hypertension and blood pressure variability (BPV; SD and average real variability) in primary proteinuric glomerulopathies are not well described. Data were from 433 participants in the NEPTUNE (Nephrotic Syndrome Study Network). Hypertensive BP status was defined as previous history of hypertension or BP ≥140/90 mm Hg for adults/≥95th percentile for children at baseline. BPV was measured in participants with ≥3 visits in the first year. Two-hundred ninety-six adults (43 years [interquartile range, 32-57.8 years], 61.5% male) and 147 children (11 years [interquartile range, 5-14 years], 57.8% male) were evaluated. At baseline, 64.8% of adults and 46.9% of children were hypertensive. Histological diagnosis was associated with hypertensive status in adults (P=0.036). In adults, hypertensive status was associated with lower hazard of complete remission (hazard ratio, 0.36; 95% confidence interval, 0.19-0.68) and greater hazard of achieving the composite end point (end-stage renal disease or estimated glomerular filtration rate decline >40%; hazard ratio, 4.1; 95% confidence interval, 1.4-12). Greater systolic and diastolic SD and average real variability were also associated with greater hazard of reaching the composite end point in adults (all P<0.01). In children, greater BPV was an independent predictor of composite end point (determined by systolic SD and average real variability) and complete remission (determined by systolic and diastolic average real variability; all P<0.05). Hypertensive status was common among adults and children enrolled in NEPTUNE. Differences in hypertensive status prevalence, BPV, and treatment were found by age and histological diagnosis. In addition, hypertensive status and greater BPV were associated with poorer clinical outcomes.

Acquired Multiple Cysts of the Kidney in Neuroblastoma Survivors.

Cystic kidney disease includes a wide range of hereditary, developmental, and acquired conditions of the kidneys. Some of the inherited causes of cystic kidney disease include autosomal dominant polycystic kidney diseases (caused by mutations in PKD1 or PKD2), autosomal recessive polycystic kidney disease, tuberous sclerosis complex, von Hippel-Lindau disease, oral-facial-digital syndrome type I, and Hadju-Cheney syndrome. Acquired cystic kidney disease has been reported in patients receiving long-term hemodialysis or peritoneal dialysis and in children after liver transplantation. Acute kidney injury can occur in patients with neuroblastoma, usually as a result of thrombotic microangiopathy associated with bone marrow transplantation. End-stage renal disease is described in long-term survivors. However, in this case report, we provide what is to our knowledge the first description of multiple kidney cysts in long-term survivors of stage IV neuroblastoma. None of the 7 patients we describe with neuroblastoma and multiple kidney cysts had a family history of autosomal dominant polycystic kidney disease. Also, all lacked stigmata of tuberous sclerosis complex, von Hippel-Lindau disease, or Hadju-Cheney syndrome. Two patients progressed to end-stage renal disease; in addition, one of them developed an oncocytoid renal cell carcinoma.

Differences between the pediatric and adult presentation of fibromuscular dysplasia: results from the US Registry.

BACKGROUND: Fibromuscular dysplasia (FMD) is a non-inflammatory arteriopathy that causes significant morbidity in children. METHODS: The clinical features, presenting symptoms, and vascular beds involved are reviewed in the first 33 patients aged <18 years who are enrolled in the United States Registry for FMD from five registry sites and compared with 999 adult patients from 12 registry sites. RESULTS: Mean age at diagnosis was 8.4 ± 4.8 years (16 days to 17 years). Compared with adults, pediatric FMD occurs in more males (42.4 vs 6 %, p < 0.001). Children with FMD have a stronger previous history of hypertension (93.9 vs 69.9 %, p = 0.002). Hypertension (100 %), headache (55 %), and abdominal bruits (10.7 %) were the most common presenting signs and symptoms. FMD affects renal vasculature in almost all children (97 vs 69.7 %, p = 0.003). The extra-cranial carotid vessels are less commonly involved in children (23.1 vs 73.3 %, p < 0.001). The mesenteric arteries (38.9 vs 16.2 %, p = 0.02) and aorta (26.3 vs 2.4 %, p < 0.001) are more commonly involved in children. CONCLUSIONS: In the United States Registry for FMD, pediatric FMD affects children from infancy throughout childhood. All children presented with hypertension and many presented with headache and abdominal bruits. In children, FMD most commonly affects the renal vasculature, but also frequently involves the mesenteric arteries and abdominal aorta; the carotid vessels are less frequently involved.

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.

Rapid progression to end-stage renal disease in a child with a sporadic ACTN4 mutation.

Mutations of ACTN4 cause an autosomal dominant form of focal segmental glomerulosclerosis (FSGS). Presentation usually occurs in the teenage years or later with symptoms of mild proteinuria and slowly progressive renal dysfunction leading to end-stage renal disease (ESRD). We report a 5-year-old female patient who was diagnosed with nephrotic syndrome and did not respond to 6 weeks of oral glucocorticoid therapy. Renal biopsy showed a collapsing variant of FSGS and genetic studies revealed a heterozygous disease-causing mutation in the ACTN4 gene (c.784C>T, p.Ser262Phe). No mutations were found in the NPHS2, TRPC6, and INF2 genes, nor did her parents have any mutations for FSGS. She developed ESRD 6 months after presentation. Although a disease-causing ACTN4 mutation was identified, the contribution of additional polymorphisms in other genes is not known. Such additional polymorphisms may represent yet unidentified epigenetic factors that contributed to the aggressive nature of this child's disease progression. A literature review has revealed only two similar case reports.

Fertility preservation in paediatric nephrology: results of a physician survey.

OBJECTIVE: Fertility preservation (FP) is a widespread practice in paediatric oncology when gonadotoxic medications such as cyclophosphamide (CPO) are used. FP practice outside of oncology has not been studied, although nephrologists regularly use CPO. This is the first study to explore FP practice by paediatric nephrologists when CPO is used. DESIGN: Survey study. Descriptive statistics and chi-squared analyses were employed to analyse the data. PARTICIPANTS: US paediatric nephrologists were sent a survey via email. The survey queried participants about FP practice behaviours, FP attitudes and barriers to practice. MAIN OUTCOME MEASURES: Of 579 nephrologists invited, 32% responded to the survey. RESULTS: CPO was dosed in mg/kg by 23% of physicians, g/m(2) by 40% and both by 37%. About 80% agreed that pubertal females should be offered a fertility referral, while 58% report that they actually refer. Factors negatively associated with referral include lack of training, lack of referral network and adherence to gonadotoxic dose limits. Results were similar for male patients. CONCLUSION: The survey showed that FP practice in the United States is widespread among nephrologists. Lack of referral networks is a notable barrier for nephrologists. Perceived adherence to dose limits may be problematic given the variable dosing regimens utilised. This is due to the risk of unintended overdose in large adolescents dosed in mg/kg whose cumulative dose exceeds gonadotoxic limits in g/m(2) . This paper has implications for nephrology care providers and other specialists who utilise CPO, generalists who care for these patients and oncologists with extant FP referral networks.

American Society of Nephrology clinical pathological conference.

A 13-year-old girl presented with proteinuria and acute kidney failure. She was born at full term via cesarean delivery (due to nuchal cord), but there were no other prenatal or perinatal complications. In early childhood the patient had two hospitalizations at ages 4.5 and 9 years, respectively, the latter for pneumonia. She had no history of symptoms of kidney disease. She came to the hospital at age 12 years for routine bilateral molar extractions. She was treated with oral antibiotics and discharged after the procedure without complications. At age 13 years, 10 months after the molar extraction, she was seen by a pediatrician because of puffiness and increased BP. She had had respiratory symptoms 2 weeks before presentation. The pediatrician prescribed furosemide and amlodipine. A few days later, the patient returned to the pediatrician's office because of hand, ankle, and facial swelling and malaise. The pediatrician recommended hospitalization and the patient was admitted at this time.