Childhood Nephrotic Syndrome (NS) is clinically and genetically heterogeneous entity characterized by either relapsing, and/or chronic course with significant morbidity and mortality resulting from complications of the disease itself, and/or its therapy. Globally, NS is a very significant medical problem responsible for up to 20% of kidney failures in children. The economic costs and psychosocial impact of this condition on the pediatric patient and the family are tremendous. Constellation of proteinuria, dyslipidemia, hypoalbuminemia, and gravity dependent edema constitute hallmarks of this syndrome. Much of the clinical knowledge of the natural history of NS, including the response to therapy came from the NIH sponsored International Study of Kidney Disease in Childhood (ISKDC). The study thought is that minimal change disease is the most common cause of NS during childhood, and that over 90% of children with minimal change disease will have a remission of NS when treated with glucocorticosteroids. This also led to a generally accepted practice of deferring a kidney biopsy until steroids have failed. Steroid resistance is often the first clinical sign of Focal Segmental Glomerulosclerosis (FSGS), and is an indication for a change in therapy. Classically, steroid-resistant NS has been associated with activation of the pro-fibrotic TGF-ß pathway and progression to chronic kidney disease, while steroid-sensitive NS has been associated with activation of T-cells and favorable outcome. We now know that a subset of children who do not respond to treatment have genetic causes of NS. Understanding the genetics of FSGS begun over couple of decades ago with appreciating the molecular composition of the glomerular filtration barrier comprised of podocytes, basement membrane, and the fenestrated endothelium. However, it is still not understood why the FSGS lesions are focal (only some glomeruli are affected) and segmental (only part of the glomerulus has the anatomic lesion). In addition, we observe that the incidence of steroid-resistant disease is much higher now as oppose to the ISKDC report. Steroid-resistant disease is especially common in African Americans. There is strong evidence that polymorphisms in the non-muscle myosin heavy chain 9 gene (MYH9) and APOL1 are important risk factors for kidney disease in African-Americans, but it is still unclear how those mutations contribute to NS. In addition, increased proportion of FSGS is observed in Caucasian patients. We currently have no information on the yield of genetic screening in children with NS in the United States. Despite that over the last decade several new therapeutic options for treating children with NS have only become available, recent NIH-sponsored clinical trials demonstrated no clear therapeutic “favorite”. We offer more vaccines to children with NS than ever before, but it is unclear how different immunosuppressive medications are modulating vaccines effects. We are beginning to understand several factors that contribute to the changing phenotypes and outcome of NS, such as genetic background, socioeconomic status, diet, or environmental factors. We propose a comprehensive state-of-the-art review of NS and the most up-to-date evidence based guidelines on the management of NS.
Childhood Nephrotic Syndrome (NS) is clinically and genetically heterogeneous entity characterized by either relapsing, and/or chronic course with significant morbidity and mortality resulting from complications of the disease itself, and/or its therapy. Globally, NS is a very significant medical problem responsible for up to 20% of kidney failures in children. The economic costs and psychosocial impact of this condition on the pediatric patient and the family are tremendous. Constellation of proteinuria, dyslipidemia, hypoalbuminemia, and gravity dependent edema constitute hallmarks of this syndrome. Much of the clinical knowledge of the natural history of NS, including the response to therapy came from the NIH sponsored International Study of Kidney Disease in Childhood (ISKDC). The study thought is that minimal change disease is the most common cause of NS during childhood, and that over 90% of children with minimal change disease will have a remission of NS when treated with glucocorticosteroids. This also led to a generally accepted practice of deferring a kidney biopsy until steroids have failed. Steroid resistance is often the first clinical sign of Focal Segmental Glomerulosclerosis (FSGS), and is an indication for a change in therapy. Classically, steroid-resistant NS has been associated with activation of the pro-fibrotic TGF-ß pathway and progression to chronic kidney disease, while steroid-sensitive NS has been associated with activation of T-cells and favorable outcome. We now know that a subset of children who do not respond to treatment have genetic causes of NS. Understanding the genetics of FSGS begun over couple of decades ago with appreciating the molecular composition of the glomerular filtration barrier comprised of podocytes, basement membrane, and the fenestrated endothelium. However, it is still not understood why the FSGS lesions are focal (only some glomeruli are affected) and segmental (only part of the glomerulus has the anatomic lesion). In addition, we observe that the incidence of steroid-resistant disease is much higher now as oppose to the ISKDC report. Steroid-resistant disease is especially common in African Americans. There is strong evidence that polymorphisms in the non-muscle myosin heavy chain 9 gene (MYH9) and APOL1 are important risk factors for kidney disease in African-Americans, but it is still unclear how those mutations contribute to NS. In addition, increased proportion of FSGS is observed in Caucasian patients. We currently have no information on the yield of genetic screening in children with NS in the United States. Despite that over the last decade several new therapeutic options for treating children with NS have only become available, recent NIH-sponsored clinical trials demonstrated no clear therapeutic “favorite”. We offer more vaccines to children with NS than ever before, but it is unclear how different immunosuppressive medications are modulating vaccines effects. We are beginning to understand several factors that contribute to the changing phenotypes and outcome of NS, such as genetic background, socioeconomic status, diet, or environmental factors. We propose a comprehensive state-of-the-art review of NS and the most up-to-date evidence based guidelines on the management of NS.
