Renal vein thrombosis

 Patients with the nephrotic syndrome are at increased risk of developing venous and arterial thromboembolism, particularly RVT  The mechanism of thromboembolism in nephrotic syndrome and optimal diagnostic and anticoagulant management strategies remain controversial

Prevalence of renal vein thrombosis according to underlying disease in nephrotic syndrome StudyMembranous GNMPGNMCDFSGSOtherOverall Llach, et al. Am J Med (69)22.2 (27)20.0 (10)25.0 (4)9.8 (41)21.9 (151) Chugh, et al. Postgrad Med J (7)20.0 (5)26.3 (19)0 (5)25.0 (8)25.0 (44) Velasquez, et al. Am J Nephrol (5)40.0 (10)0 (0)28.6 (7)50.0 (4)42.3 (26) Wagoner, et al. Kidney Int (27)0 (0) 51.9 (27) Bennett, et al. Ann Intern Med 1975–––––28.6 (21) Overall37.0 (108)26.2 (42)24.1 (29)18.8 (16)15.1 (53)27.9 (269) Singhal et al, Thrombosis Research (2006) 118, 397—407

 A retrospective study involving 298 patients with mean follow up of 10 years showed annual incidences of VTE and ATE of 1.02% and 1.48% respectively  Risks of both VTE and ATE were particularly high within the first 6 months of NS (annual incidences 9.85% and 5.52% respectively) Mahmoodi et. Al Circulation Jan 15;117(2):224-30

Clinical features  RVT may be unilateral or bilateral and may extend into the inferior vena cava  RVT most often has an insidious onset and produces no symptoms referable to the kidney

 Acute RVT is usually due to trauma, severe dehydration or a generalized hypercoagulable state  It typically presents with symptoms of renal infarction, including flank pain, microscopic or gross hematuria, a marked elevation in serum lactate dehydrogenase, and an increase in renal size on radiographic study  Bilateral RVT may present with acute renal failure

Pathogenesis

Increased platelet aggregation  Thrombocytosis, decreased red blood cell deformability, and increased von Willebrand factor levels in NS favor platelet transport towards the vessel wall and increase platelet adhesion  Hypoalbuminemia results in increased availability of normally albumin-bound arachidonic acid, leading to increased formation of thromboxane A2 in platelets, a stimulus for platelet aggregation  Elevated levels of LDL cholesterol may increase platelet aggregation

Activation of the coagulation system  Patients with nephrotic syndrome demonstrate urinary loss of plasma proteins that include factors IX, X, and XII, prothrombin, antithrombin, and α2- antiplasmin  In contrast, proteins of higher molecular weight, including factor V, factor VIII, von Willebrand factor, fibrinogen, and α2- macroglobulin accumulate, presumably because of increased synthesis

 Factor VIII levels are typically increased as much as 2- to 3-fold compared to controls and increased factor VIII may be a risk factor for venous thromboembolism  There is an inverse correlation between serum albumin and fibrinogen levels in nephrotic syndrome  Hyperfibrinogenemia may contribute to the procoagulant state by providing more substrate for fibrin formation and by promoting platelet hyperaggregability, increased blood viscosity, and red blood cell aggregation

Decreased endogenous anticoagulants  Antithrombin deficiency occurs in 40% to 80% of patients with NS  Plasma levels of antithrombin correlate negatively with proteinuria and positively with serum albumin level, presumably due to urinary loss of this factor  The association between antithrombin deficiency and venous thromboemolism is inconsistent among different studies

Additional factors predisposing to thromboembolism in NS  Intravascular volume depletion and exposure to steroids  Loss of fluid across the glomerulus causing hemoconcentration in the postglomerular circulation which is worsened by diuretic therapy  Clotting activation and thrombin formation might occur in the diseased kidney  The nature of immunologic injury itself

Factors reported to be associated with RVT in the absence of nephrotic syndrome  Trauma (including kidney biopsy)  Oral contraceptives  Hypovolemia  Inherited procoagulant defects

Screening Routine screening for RVT is not recommended in patients with nephrotic syndrome  No proven benefit to diagnosing occult disease  A patient with a negative study may develop RVT at a later time

It is also not useful to evaluate for RVT in a patient who experiences an overt embolic event such as PE  It cannot be proven that the pulmonary embolus originated in the renal veins  In situ pulmonary thrombosis may occur  Patients will be treated with anticoagulants whether or not RVT is present

Diagnosis  Estimated sensitivity and specificity of CT with contrast was 92.3% and 100%, respectively  Only a small number of studies have evaluated the value of MRI with or without contrast enhancement in the identification of RVT  Only one study has prospectively evaluated Doppler ultrasonography in the diagnosis of RVT and found it to be 85% sensitive and 56% specific  Intravenous pyelography was found to have a sensitivity of 34.1% and a specificity of 87.2%  Selective renal venography is the reference standard diagnostic test for RVT

Treatment

 The risks associated with asymptomatic RVT have not been compared to the risks of long term anticoagulation therefore prophylactic anticoagulation is not recommended  There are no definitive studies that have evaluated the role of anticoagulation in patients with an asymptomatic RVT, but case series report treating such patients

 Patients with a symptomatic RVT or a thromboembolic event in the absence of RVT are treated with low molecular weight heparin and then warfarin  Some patients are partially resistant to heparin therapy due to severe antithrombin deficiency  Warfarin therapy is given for a minimum of 6 to 12 months and some people recommend continuing treatment for as long as the patient remains nephrotic  Local thrombolytic therapy with or without thrombectomy in patients who have signs of acute RVT has been successfully performed in small numbers of patients

Can renal vein thrombosis cause the nephrotic syndrome?

 Animal studies in which main renal vein occlusion was produced experimentally, have failed to demonstrate the development of heavy proteinuria unless the contralateral normal kidney is removed  RVT in the absence of nephrotic syndrome has been reported in the literature  Nephrotic patients with RVT who have undergone histologic evaluation show evidence of an identifiable glomerulopathy

 In a case report of a patient with unilateral RVT and nephrotic syndrome due to membranous nephropathy, bilateral ureteral catheterization studies showed no difference in protein excretion or creatinine clearance between the two kidneys  In retrospective studies, the sequence of nephrotic syndrome leading to renal vein thrombosis was clearly established  However bilateral RVT has been reported to cause nephrotic syndrome

References  Radhakrishnan, J. Renal vein thrombosis and hypercoagulable state in nephrotic syndrome. Uptodat May 2009  Singhal, R, Brimble, KS. Thromboembolic complications in the nephrotic syndrome: Pathophysiology and clinical management. Thromb Res 2006; 118:397  F. Llach, S. Papper and S.G. Massry, The clinical spectrum of renal vein thrombosis: acute and chronic, Am J Med 69 (1980), pp. 819–827  K.S. Chugh, N. Malik, H.S. Uberoi, V.K. Gupta, M.L. Aggarwal and P.C. Singhal et al., Renal vein thrombosis in nephrotic syndrome—a prospective study and review, Postgrad Med J. 57 (1981), pp. 566–570  F.F. Velasquez, P.N. Garcia and M.N. Ruiz, Idiopathic nephrotic syndrome of the adult with asymptomatic thrombosis of the renal vein, Am J Nephrol 8 (1988), pp. 457–462  R.D. Wagoner, A.W. Stanson, K.E. Holley and C.S. Winter, Renal vein thrombosis in idiopathic membranous glomerulopathy and nephrotic syndrome: incidence and significance, Kidney Int 23 (1983), pp. 368– 374  W.M. Bennett, Renal vein thrombosis in nephrotic syndrome, Ann Intern Med 83 (1975), pp. 577–578

References  Mahmoodi, BK, ten Kate, MK, Waanders, F, et al. High absolute risks and predictors of venous and arterial thromboembolic events in patients with nephrotic syndrome: results from a large retrospective cohort study. Circulation 2008; 117:224  R.H. Kauffrnann, J.J. Veltkamp, N.H. Van Tilburg and L.A. Van Es, Acquired antithrombin III deficiency and thrombosis in the nephrotic syndrome, Am J Med 65 (1978), pp. 607–613  A. Citak, S. Emre, A. Sairin, I. Bilge and A. Nayir, Hemostatic problems and thromboembolic complications in nephrotic children, Pediatr Nephrol 14 (2000), pp. 138–142  Fisher Er, Sharkey D, Pardo V, Vuzevski V. Experimental renal vein constriction: Its relation to renal lesions observed in human renal vein thrombosis and the nephrotic syndrome. Lab Invest 1968, 18:  Wagoner, RD, Stanton, AW, Holley, KE, Winter, CS. Renal vein thrombosis in idiopathic membranous glomerulopathy and nephrotic syndrome: Incidence and significance. Kidney Int 1983; 23:368  Kauffmann, RH, de Graeff, J, de la, Riviere GB, van Es, LA. Unilateral renal vein thrombosis and nephrotic syndrome. Report of a case with protein selectivity and antithrombin III clearance studies. Am J Med 1976; 60:1048