After infections, thromboembolism is considered by many experts to be the most significant life-threatening complication of nephrotic syndrome. The purpose of this review is to summarize the epidemiology, clinical and molecular pathophysiology, and management of this complication. Children (2.8%) are less likely than adults (26.7%) with nephrotic syndrome to develop thromboembolism. However, infants and children aged >12 years are at much greater risk. Membranous histologic changes increase thromboembolic risk at all ages; in particular, adults with membranous nephropathy have the highest reported risk (37.0%) and children with membranous histology have a rate (25%) that approaches the overall adult rate. There are striking, but variable, pathologic alterations of molecular hemostasis associated with nephrotic syndrome. No clear molecular therapeutic targets have been identified, but most studies show that the major pathologic changes involve antithrombin, fibrinogen, and factors V and VIII. There is inadequate evidence to support routine prophylactic therapy. Therapy includes anticoagulation in all cases, with thrombolysis reserved for those with the most severe thromboembolic disease. Future hemostatic research in nephrotic syndrome should focus on identifying cohorts at highest risk for thrombosis through the use of clinical markers and biomarkers as well as searching for molecular targets to correct the prothrombotic pathophysiology of this disease.

Membranoproliferative glomerulonephritis type II (MPGN II)

The therapeutic approach to childhood nephrotic syndrome is based on a series of studies that began with an international collaborative effort sponsored by the International Study of Kidney Disease in Children in 1967. The characteristics of children presenting with nephrotic syndrome have changed over recent decades with greater frequency of the challenging condition focal segmental glomerulosclerosis and a greater prevalence of obesity and diabetes mellitus, which may be resistant to glucocorticoids in the former and exacerbated by long-term glucocorticoid therapy in the latter 2 conditions. The Children's Nephrotic Syndrome Consensus Conference was formed to systematically review the published literature and generate a children's primary nephrotic syndrome guideline for use in educational, therapeutic, and research venues.

Nephrotic syndrome is a highly prevalent disease that is associated with high morbidity despite notable advances in its treatment. Many of the complications of nephrotic syndrome, including the increased risk of atherosclerosis and thromboembolism, can be linked to dysregulated lipid metabolism and dyslipidaemia. These abnormalities include elevated plasma levels of cholesterol, triglycerides and the apolipoprotein B containing lipoproteins VLDL and IDL; decreased lipoprotein lipase activity in the endothelium, muscle and adipose tissues; decreased hepatic lipase activity; and increased levels of the enzyme PCSK9. In addition, there is an increase in the plasma levels of immature HDL particles and reduced cholesterol efflux. Studies from the past few years have markedly improved our understanding of the molecular pathogenesis of nephrotic syndrome associated dyslipidaemia, and also heightened our awareness of the associated exacerbated risks of cardiovascular complications, progressive kidney disease and thromboembolism. Despite the absence of clear guidelines regarding treatment, various strategies are being increasingly utilized, including statins, bile acid sequestrants, fibrates, nicotinic acid and ezetimibe, as well as lipid apheresis, which seem to also induce partial or complete clinical remission of nephrotic syndrome in a substantial percentage of patients. Future potential treatments will likely also include inhibition of PCSK9 using recently developed anti PCSK9 monoclonal antibodies and small inhibitory RNAs, as well as targeting newly identified molecular regulators of lipid metabolism that are dysregulated in nephrotic syndrome.

Idiopathic nephrotic syndrome newly affects 1-3 per 100,000 children per year. Approximately 85% of cases show complete remission of proteinuria following glucocorticoid treatment. Patients who do not achieve complete remission within 4-6 weeks of glucocorticoid treatment have steroid-resistant nephrotic syndrome (SRNS). In 10-30% of steroid-resistant patients, mutations in podocyte-associated genes can be detected, whereas an undefined circulating factor of immune origin is assumed in the remaining ones. Diagnosis and management of SRNS is a great challenge due to its heterogeneous etiology, frequent lack of remission by further immunosuppressive treatment, and severe complications including the development of end-stage kidney disease and recurrence after renal transplantation. A team of experts including pediatric nephrologists and renal geneticists from the International Pediatric Nephrology Association (IPNA), a renal pathologist, and an adult nephrologist have now developed comprehensive clinical practice recommendations on the diagnosis and management of SRNS in children. The team performed a systematic literature review on 9 clinically relevant PICO (Patient or Population covered, Intervention, Comparator, Outcome) questions, formulated recommendations and formally graded them at a consensus meeting, with input from patient representatives and a dietician acting as external advisors and a voting panel of pediatric nephrologists. Research recommendations are also given.

Objectives To identify clinical variables predictive of the risk of thromboembolism (TE), and to confirm the incidence of TE in primary and secondary childhood nephrotic syndrome (NS). Study design A comprehensive chart review identified 326 children with NS from any cause evaluated between 1999 and 2006. These patients had a total of 1472.8 patient-years of follow-up. Comparison statistics, survival analysis, and logistic regression were used to define TE epidemiology and clinical risk factors. Results We found that 9.2% of our cohort had experienced at least 1 TE. The overall incidence was 20.4 patients with TEs/1000 patient-years. The median time to the first TE was 70.5 days after diagnosis of NS. Deep venous thrombosis was the most common TE (76%) and was frequently associated with the use of a central venous catheter (45%). Significant independent predictors of TE included age ≥ 12 years at onset of NS (P < .0001), severity of proteinuria (P < .0001), and history of TE preceding diagnosis of NS (P < .0001). Life- or limb-threatening TEs represented 23.7% of the events. Conclusions Children with NS should be carefully followed for TE, particularly those who are age 12 years or older, have severe proteinuria, or have a previous history of TE.

These data suggest that, contrary to the current therapeutic paradigm, the beneficial effects of glucocorticoids in nephrotic syndrome may result, at least in part, from direct effects on podocytes leading to enhanced actin filament stability.

Nephrotic syndrome is a common kidney disease seen in both children and adults. The clinical syndrome includes massive proteinuria, hypoalbuminemia, edema, and usually hypercholesterolemia. Development of these clinical changes is closely correlated with profound structural changes in glomerular epithelial cells, or podocytes, which together with the glomerular basement membrane and endothelium comprise the kidney's blood filtration barrier. Although relatively little is known about the cellular or molecular changes which occur within podocytes during the development of nephrotic syndrome, cytoskeletal proteins very likely play a central role in these changes since they are primarily responsible for the maintenance of cell structure in almost all cells. This review focuses on: (a) the structure and function of podocytes in both the normal state and during nephrotic syndrome and (b) the potential roles of several cytoskeleton-associated proteins identified in podocytes in the development of and/or recovery from the pathophysiological cytoskeletal changes which occur in podocytes during nephrotic syndrome.