Epidemiology and pathophysiology of nephrotic syndrome-associated thromboembolic disease

Abstract

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.

Figure 1.

Thromboembolism in nephrotic syndrome is due to multifaceted pathophysiology.

Figure 2.

Nephrotic syndrome is a prothrombotic state of variable magnitude. Marked decrease (↓↓) through normal (N) to marked increase (↑↑). Numbers in parentheses are molecular masses of proteins given in kilodaltons (45,47). *Thrombophilic genetic polymorphisms (Factor V Leiden, Prothrombin G20210A, MTHFR C677T) may increase thromboembolism risk, but have not been shown to occur with higher prevalence in NS with VTE; other thrombophilic polymorphisms have not yet been studied in NS (8,44,55). ^#APL has been inadequately studied in NS, but some thromboembolism patients are positive for APL (2,46). Plt, platelet; vWF, von Willebrand factor; AT, antithrombin; α₂-AP, α₂-antiplasmin; tPA, tissue-type plasminogen activator; α₁-AT, α₁-antitrypsin; PAI, plasminogen activator inhibitor; Lp(a), lipoprotein(a); α₂-M, α₂-macroglobulin; APL, antiphospholipid antibodies; RBC, red blood cell.