Venous thrombosis in the nephrotic syndrome by Lesley Catherine

The

n e w e ng l a n d j o u r na l

m e dic i n e

clinical implications of basic research The Clinical Implications of Basic Research series has focused on highlighting laboratory research that could lead to advances in clinical therapeutics. However, the path between the laboratory and the bedside runs both ways: clinical observations often pose new questions for laboratory investigations that then lead back to the clinic. One of a series of occasional articles drawing attention to the bedside-to-bench flow of information is presented here, under the Basic Implications of Clinical Observations rubric. We hope our readers will enjoy these stories of discovery, and we invite them to submit their own examples of clinical findings that have led to insights in basic science.

basic implications of clinical observations

Venous Thrombosis in the Nephrotic Syndrome Joseph Loscalzo, M.D., Ph.D. Thrombotic events complicate the nephrotic syndrome in approximately 25% of patients.1 This association was first recognized in the 19th century by W. Howship Dickinson, who pointed out that “when the kidneys themselves are the seat of chronic disease, involving the loss of albumin, . . . the blood in their vessels, as elsewhere, is rendered morbidly coagulable by the drain.”2 This observation was refined with the association between a specific renal condition (the nephrotic syndrome) and venous thrombosis, as reported by Derow and colleagues in 1939.3

Figure 1. Mechanisms of the Thrombophilic State in the Nephrotic Syndrome. Shown is a glomerulus in which several mechanisms that promote thrombo sis in patients with the nephrotic syndrome have been identified. These mech anisms include an increased urinary concentration of proteins that prevent thrombosis (including antithrombin III and possibly protein C and protein S) and increased synthesis of factors that promote thrombosis (including factors V and VIII, von Willebrand factor, α2 -plasmin inhibitor, plasminogen activator inhibitor 1, and fibrinogen).

956

Although there was considerable debate as to what was cause and what was effect, we now view the nephrotic syndrome as a thrombophilic or hypercoagulable state.4 This conclusion was based on the demonstration of elevated plasma levels of fibrinogen and other clotting factors, accelerated generation of thromboplastin, and thrombocytosis in 35 untreated patients with nephrosis who did not have either azotemia or clinical thrombosis. Soon thereafter, Kauffmann and colleagues5 suggested that the thrombophilic state of the nephrotic syndrome is a consequence of a loss of endogenous anticoagulant antithrombin III in the urine as a result of altered permselectivity of the glomerular basement membrane. The concept of size-selective permeability of the glomerular basement membrane was first proposed in 1967 with the use of an animal model of immune-mediated nephrotic syndrome.6 After that initial study, several studies addressed the determinants of molecular exclusion according to size and charge and their modification in nephrosis,7,8 including minimal change disease.9 Thus, the mechanistic basis for the permselectivity of the glomerulus was informed by observations that were made with respect to the nephrotic syndrome, and an explanation for the thrombotic state of nephrosis was derived from a detailed understanding of glomerular permselectivity. Since that time, several mechanisms that promote thrombosis in patients with nephrosis have been identified. In general, these mechanisms fall into two categories: urinary loss of proteins that prevent thrombosis and increased synthesis of factors that promote thrombosis (Fig. 1). With respect to thrombosis prevention, 40 to 80%

n engl j med 368;10 nejm.org march 7, 2013

The New England Journal of Medicine Downloaded from nejm.org at UEL on August 3, 2014. For personal use only. No other uses without permission. Copyright © 2013 Massachusetts Medical Society. All rights reserved.

Clinical Implications of Basic Research

of patients with the nephrotic syndrome were found to have reduced circulating levels of antithrombin III,10 owing to urinary loss of the anticoagulant.11 Protein C activity and protein S levels also appear to be reduced in patients with the nephrotic syndrome,12 although these findings have not been consistently observed.13 Abnormalities in factors that promote thrombosis have been shown both among procoagulant proteins and among fibrinolytic proteins. Activation of secondary coagulation in patients with the nephrotic syndrome is accompanied by increased levels of factors V and VIII, von Wille brand factor, fibrinogen, and α2-macroglobulin, probably owing to increased synthesis.13 It is thought that the increase in these higher-molecular-weight species is a reflection of increased acute-phase synthesis.13 Hyperfibrinogenemia, in particular, is a hepatic synthetic response to the hypoalbuminemia of nephrosis. This increase in fibrinogen promotes platelet aggregation, provides substrate for fibrin formation, increases blood viscosity, and promotes erythrocyte aggregation.14 Mild thrombocytosis and platelet hyperreactivity also accompany the nephrotic syndrome. Platelet hyperreactivity, which is found in approximately 70% of such patients,13 is multifactorial and can be attributed to increased levels of von Willebrand factor, hyperfibrinogenemia, hypercholesterolemia, and hypoalbuminemia.15 Hypoalbuminemia leads to increased bioavailability of arachidonic acid released by platelets, enhancing the recruitment of other platelets to the growing platelet-rich thrombus with a resulting lowered threshold for aggregation.16 Hypercholesterolemia enhances agonist-dependent sensitivity of platelets, promoting their activation,17 and cholesterol-lowering therapy with statins reduces platelet aggregation18 and lowers the risk of venous thrombosis19 in patients with nephrosis. At the level of fibrinolysis, the nephrotic syndrome is associated with a decrease in circulating plasminogen levels.20 This decrease in plasminogen is accompanied by an increase in levels of plasminogen activator inhibitor 121 and α2plasmin inhibitor,13 all of which conspire to impair fibrin clearance and promote thrombus persistence. It is important to point out that these changes in factors that contribute to a thrombophilic state in the nephrotic syndrome are glomerulocentric in origin. Changes in the permselectivity

of the glomerular basement membrane lead to a loss of lower-molecular-weight proteins that regulate hemostasis and thrombosis, and changes in the intraglomerular microenvironment as a consequence of the intrinsic disease process leading to nephrosis promote thrombosis. For example, inflammatory responses accompanying immune injury within the glomerulus may generate procoagulants22 and induce expression of molecules that impair fibrinolysis.23 The basic clinical observations that showed an association between thrombosis and the nephrotic syndrome have evolved considerably from those of the past century. Once viewed as a cause of nephrosis through pressure-induced injury, thrombosis that accompanies the nephrotic syndrome is now viewed as a manifestation of a thrombophilic state that is multifactorial but dependent on the urinary loss of endogenous antithrombotic factors. The evolution in the understanding of these basic thrombotic mechanisms evolved in parallel with a growth in knowledge regarding the selective mechanisms of glomerular protein loss in the nephrotic syndrome, leading to the elucidation of complex mechanisms by which normal renal function affects hemostasis. Disclosure forms provided by the author are available with the full text of this article at NEJM.org. From the Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School — both in Boston. 1. Kerlin BA, Ayoob R, Smoyer WE. Epidemiology and patho-

physiology of nephrotic syndrome-associated thromboembolic disease. Clin J Am Soc Nephrol 2012;7:513-20. 2. Dickinson WH. On renal and urinary affections. New York: William Wood & Company, 1885:32. 3. Derow HA, Schlesinger MJ, Savitz HA. Chronic progressive occlusion of the inferior vena cava and the renal and portal veins. Arch Intern Med 1939;63:626-47. 4. Kendall AG, Lohmann RC, Dossetor JB. Nephrotic syndrome: a hypercoagulable state. Arch Intern Med 1971;127:1021-7. 5. Kauffmann RH, de Graeff J, Brutel de la Riviére G, Van Es LA. Unilateral renal vein thrombosis and nephrotic syndrome. Am J Med 1976;60:1048-58. 6. Huang F, Hutton L, Kalant N. Molecular sieving by glomerular basement membrane. Nature 1967;216:87-8. 7. Venkatachalam MA, Karnovsky MJ, Cotran RS. Glomerular permeability: ultrastructural studies in experimental nephrosis using horseradish peroxidase as a tracer. J Exp Med 1969;130:381-99. 8. Brenner BM, Hostetter TH, Humes HD. Glomerular perm selectivity: barrier function based on discrimination of molecular size and charge. Am J Physiol 1978;234:F455-F460. 9. Robson AM, Giangiacomo J, Kienstra RA, Naqvi ST, Ingelfinger JR. Normal glomerular permeability and its modification by minimal change nephrotic syndrome. J Clin Invest 1974;54: 1190-9. 10. Kauffmann RH, Weltkamp JJ, Van Tilburg NH, Van Es LA. Acquired antithrombin III deficiency and thrombosis in nephrotic syndrome. Am J Med 1978;65:607-13. 11. Vaziri ND, Paule P, Toohey J, et al. Acquired deficiency and

n engl j med 368;10 nejm.org march 7, 2013

957

Clinical Implications of Basic Research urinary excretion of antithrombin III in nephrotic syndrome. Arch Intern Med 1984;144:1802-3. 12. Cosio FG, Harker C, Batard MA, Brandt JT, Griffin JH. Plasma concentrations of the natural anticoagulants protein C and protein S in patients with proteinuria. J Lab Clin Med 1985; 106:218-22. 13. Singhal R, Brimble KS. Thromboembolic complications of nephrotic syndrome: pathophysiology and clinical management. Thromb Res 2006;118:397-407. 14. Rabelink TJ, Zwaginga JJ, Koomans HA, Sixma JJ. Thrombosis and hemostasis in renal disease. Kidney Int 1994;46:287-96. 15. Machleidt C, Mettang T, Starz E, Weber J, Risler T, Kuhlmann U. Multifactorial genesis of enhanced platelet aggregability in patients with nephrotic syndrome. Kidney Int 1989;36:111924. 16. Yoshida N, Aoki N. Release of arachidonic acid from human platelets: a key role for the potentiation of platelet aggregability in normal subjects as well as in those with nephrotic syndrome. Blood 1978;52:969-77. 17. Shattil SJ, Anaya-Galindo R, Bennett J, Colman RW, Cooper RA. Platelet hypersensitivity induced by cholesterol incorporation. J Clin Invest 1975;55:636-43.

958

18. Yashiro M, Muso E, Shio H, Sasayama S. Amelioration of

hypercholesterolemia by HMG-CoA reductase inhibitor improved platelet hyperaggregability in nephrotic patients. Nephrol Dial Transplant 1994;9:1842-3. 19. Resh M, Mahmoodi BK, Navis GJ, Veeger NJ, Lijfering WM. Statin use in patients with nephrotic syndrome is associated with a lower risk of venous thromboembolism. Thromb Res 2011;127:395-9. 20. Thomson C, Forbes CD, Prentice CR, Kennedy AC. Changes in blood coagulation and fibrinolysis in the nephrotic syndrome. Q J Med 1974;43:399-407. 21. Hamano K, Iwano M, Akai Y, et al. Expression of glomerular plasminogen activator inhibitor type 1 in glomerulonephritis. Am J Kidney Dis 2002;39:695-705. 22. Sraer JD, Kanfer A, Rondeau E, Lacave R. Glomerular hemostasis in normal and pathologic conditions. Adv Nephrol Necker Hosp 1988;17:27-55. 23. Yoshida Y, Shiiki H, Iwano M, et al. Enhanced expression of plasminogen activator inhibitor 1 in patients with nephrotic syndrome. Nephron 2001;88:24-9. DOI: 10.1056/NEJMcibr1209459 Copyright © 2013 Massachusetts Medical Society.

n engl j med 368;10 nejm.org march 7, 2013