Steroid-resistant NS Research Articles

The Need for a Children's Oncology Group–Oriented Approach to Advance the Care of Children with Idiopathic Nephrotic Syndrome

diopathic nephrotic syndrome (INS) affects 16 per 100,000 children, making this condition one of the most common childhood kidney diseases. Because of the significant com- plications associated with INS and its treatments in children, childhood INS remains a daunting challenge for children, fam- ilies, and medical professionals. Amazingly, the approach to childhood INS today is still based on decades-old pivotal stud- ies that were impressive in scope but have limited applicability to the clinical challenges faced by pediatric nephrologists to- day. These foundational studies began with an international collaborative effort sponsored by the International Study of Kidney Disease in Children (ISKDC) (1). From 1967 to 1974, 521 children with new-onset INS underwent renal biopsies and standard prednisone treatment to demonstrate that normaliza- tion of urine protein excretion with 8 wk of corticosteroid therapy is predictive of minimal-change nephrotic syndrome (2). As a result, pediatric nephrologists began using the initial therapeutic response to glucocorticoids to guide the subsequent evaluation and therapy for children who present with INS. This sentinel work of the ISKDC was followed by a series of studies by the Arbeitsgemeinschaft fur Padiatrische Nephrologie, which together form the basis for modern practice treatment of children with INS (3-5). Of note, these landmark studies are also almost 20 yr old, but the clinical characteristics and chal- lenges of children who present with INS have clearly changed in recent decades. For example, the incidence of FSGS in chil- dren with INS has increased dramatically (6); children in the United States have a rapidly increasing prevalence of obesity and type 2 diabetes, which may be exacerbated by our standard treatments with glucocorticoids (7); and the importance of de- mographic status and treatment compliance in patient out- comes is being increasingly recognized (8). In 2008, a survey regarding treatment of childhood INS among North American pediatric nephrologists at 10 US cen- ters was performed. That survey highlighted significant dispar- ities among practitioners, including wide practice variations in even the most fundamental aspects of care, such as the man- agement of initial presentations, relapses, and steroid resistance in children with INS (9). In this context, the North American Children's Nephrotic Syndrome Consensus Conference was convened to develop updated evidence- and opinion-based recommendations for the evaluation and treatment of children with INS for North American pediatric nephrologists (10). In that consensus conference report, only a limited number of treatment recommendations could be based on class 1 evidence; recommendations related to extent of evaluation, monitoring for complications, and treatment for steroid-dependent and steroid-resistant NS almost all were based on small case series and expert opinion. Of note, despite the 344 published original investigations reviewed during this process, only three of the 86 articles cited in that consensus conference report involved 10 yr of outcome follow-up in children with INS. This sober- ing reality emphasizes the value of the study of Kyrieleis et al. (11) in this month's CJASN, which addresses the long-term outcome of frequently relapsing minimal-change nephrotic syndrome in children and focuses on the effectiveness of con- tinued immunosuppression and the complications of these agents in this population. In this report, at least 10 yr of fol- low-up is provided for all 15 patients with steroid-responsive INS that presented in childhood. All had at least one relapse after 16 yr of age, and the long follow-up offers insights into the ongoing treatment responsiveness in these children. Although this article indicates that corticosteroid responsiveness may persist for many years in some children, particularly in combi- nation with second-line agents such as calcineurin inhibitors, complications are common and the risk-benefit ratios of treat- ments are unexplored. Although this report is only observa- tional, it does reinforce the value and usefulness of detailed long-term observational studies of these children. Because the vast majority of our patients will survive to adulthood, there is a distinct need for studies of the long-term outcomes (and

Recurrence of Focal-Segmental Glomerulosclerosis in Children after Renal Transplantation: Clinical and Genetic Aspects

Focal segmental glomerulosclerosis (FSGS) is the primary renal disease in approximately one-tenth of pediatric patients receiving a renal allograft. Recurrence of proteinuria after renal transplantation is observed in approximately 30% of patients and negatively impacts graft survival. Risk factors for recurrence are a chronological age <15 years at onset of the nephrotic syndrome and a rapid progression of the disease in the native kidneys leading to end-stage renal disease in less than 3 years. Mesangial proliferation in the native kidneys is also an important negative predictive factor for disease recurrence. With rapid recurrence of FSGS and loss of the allograft, further renal transplants also carry a high likelihood of FSGS recurrence. Different pathogenic factors have been discussed for the recurrence of proteinuria/FSGS in the transplanted kidney, especially the involvement of a proteinuric circulating factor, whose production seems to follow T-cell dysfunction. In the last decade, mutations in genes encoding podocyte proteins have been identified in different forms of hereditary FSGS. Mutations of NPHS2 were detected in 26-38% of familial autosomal recessive steroid-resistant NS (SRNS), 6-19% of sporadic cases of SRNS, and in few adult patients with FSGS. Large multicenter studies demonstrated that patients with two pathogenic NPHS2 mutations have a very low risk of recurring FSGS after renal transplantation, whereas patients with only one mutation presumably have a risk comparable to non-NPHS2 FSGS patients. The management of FSGS following renal transplantation remains controversial. Following the assumption of a putative permeability factor, several studies have suggested the efficacy of plasmapheresis in inducing remission, preferably in conjunction with high-dose cyclosporine A or cyclophosphamide. Prospective studies will be necessary to better evaluate different therapeutic approaches.

Vibrio cholerae meningitis in a neonate

the delays before renal failure developed showed wide variations, and ranged from two to 16 years. 12, 13 In the present family, the two youngest patients died from nonrenal causes, so that the course of the renal disease remains unknown. Two siblings reported by Moncrieff et al ~' developed a NS at 11 months and had normal renal function 22 and 13 years later. Steroid-resistant familial nephrosis may have a protracted course, and an early pessimistic prognosis must be given with caution. The two older patients of this family had a steroidresistant NS which did not differ from sporadic steroidresistant nephrosis with minimal changes, and further development of focal segmental hyalinosis or sclerosis. Although environmental factors accounting for the familial incidence cannot be excluded, it is more likely that the disease of the three children was hereditary. This favors the hypothesis that steroid-resistant nephrosis may be caused by several primary mechanisms and is not a single entity?~, 13