Focal Segmental Glomerulosclerosis

Focal segmental glomerulosclerosis accounts for approximately 20% of cases of the nephrotic syndrome in children and 40% of such cases in adults, with an estimated incidence of 7 per 1 million.(1) It is the most common primary glomerular disorder causing end-stage renal disease in the United States, with a prevalence of 4%.(2) The cardinal feature is progressive glomerular scarring. Early in the disease course, glomerulosclerosis is both focal, involving a minority of glomeruli, and segmental, affecting a portion of the glomerular globe. With progression, more widespread and global glomerulosclerosis develops. Since the first clinical-pathological studies of the disease in the 1970s,(3) there has been renewed interest because of the increasing incidence of the disease,(4) better understanding of causation, and identification of the podocyte as the major cellular target.(5) The discovery that mutations in podocyte genes are associated with genetic focal segmental glomerulosclerosis has advanced the field of podocyte biology and stimulated new approaches to diagnosis and management.(6

The Effect of a Gluten-Free Diet in Children With Difficult-to-Manage Nephrotic Syndrome

Case reports have linked childhood nephrotic syndrome to food sensitivity, including gluten. We report our experience with 8 children (6 boys, 2 girls; age at implementation of special diet 2–14 years) with difficult-to-manage nephrotic syndrome who were placed on a gluten-free diet for 3.4 ± 4.3 years (range, 0.6–14 years) and who had clinical improvement enabling reduction or discontinuation in steroid dosage

Preemptive Use of Eculizumab for Living-Donor Kidney Transplantation in a Child with Atypical Hemolytic Uremic Syndrome

Eculizumab is an anti-complement C5 monoclonal antibody that has recently been reported as an effective therapy for atypical hemolytic uremic syndrome. However, few data are available on the preemptive use of this medication in pediatric kidney transplantation. This report describes a successful preemptive use of eculizumab in combination with living unrelated kidney transplanta- tion in a 10-year-old child with end-stage renal disease secondary to atypical hemolytic uremic syndrome who has a complement factor H mutation that has not been previously reported. Further observations and clinical trials are required to address the challenges and areas of uncertainty related to preemptive eculizumab therapy for kidney transplantation in children and adults with atypical hemolytic uremic syndrome.

Renal and Cardiovascular Morbidities Associated with APOL1 Status among African-American and Non-African-American Children with Focal Segmental Glomerulosclerosis

Background and objectives: African American (AA) children with focal segmental glomerulosclerosis (FSGS) have later onset disease that progresses more rapidly than in non-AA children. It is unclear how APOL1 genotypes contribute to kidney disease risk, progression and cardiovascular morbidity in children. Design, setting, participants, & measurements: We examined the prevalence of APOL1 genotypes and associated cardiovascular phenotypes among children with FSGS in the Chronic Kidney Disease in Children (CKiD) study; an ongoing multicenter prospective cohort study of children aged 1-16 years with mild to moderate kidney disease.Results: A total of 140 AA children in the CKiD study were genotyped. HR APOL1 genotypes were present in 24% of AA children (33/140) and were associated with FSGS, p 3 mg/L (33% vs. 15%, p=0.12) and obesity (48% vs. 19%, p=0.01). There were no differences in glomerular filtration rate, hemoglobin, iPTH, or calcium-phosphate product. Conclusions: AA children with HR APOL1 genotype and FSGS have increase prevalence of obesity and LVH despite a later age of FSGS onset, while adjusting for socioeconomic status. Treatment of obesity may be an important component of CKD and LVH management in this population

Pathophysiology of focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is a major cause of idiopathic steroid-resistant nephrotic syndrome (SRNS) and end-stage kidney disease (ESKD). In recent years, animal models and studies of familial forms of nephrotic syndrome helped elucidate some mechanisms of podocyte injury and disease progression in FSGS. This article reviews some of the experimental and clinical data on the pathophysiology of FSGS

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 m 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

Growth hormone axis in chronic kidney disease

Chronic kidney disease (CKD) in children is associated with dramatic changes in the growth hormone (GH) and insulin-like growth factor (IGF-1) axis, resulting in growth retardation. Moderate-to-severe growth retardation in CKD is associated with increased morbidity and mortality. Renal failure is a state of GH resistance and not GH deficiency. Some mechanisms of GH resistance are: reduced density of GH receptors in target organs, impaired GH-activated post-receptor Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling, and reduced levels of free IGF-1 due to increased inhibitory IGF-binding proteins (IGFBPs). Treatment with recombinant human growth hormone (rhGH) has been proven to be safe and efficacious in children with CKD. Even though rhGH has been shown to improve catch-up growth and to allow the child to achieve normal adult height, the final adult height is still significantly below the genetic target. Growth retardation may persist after renal transplantation due to multiple factors, such as steroid use, decreased renal function and an abnormal GH–IGF1 axis. Those below age 6 years are the ones to benefit most from transplantation in demonstrating acceleration in linear growth. Newer treatment modalities targeting the GH resistance with recombinant human IGF-1 (rhIGF-1), recombinant human IGFBP3 (rhIGFBP3) and IGFBP displacers are under investigation and may prove to be more effective in treating growth failure in CKD