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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
Study Membranous GN MPGN MCD FSGS Other Overall
Llach, et al. Am J Med 1980 29.0 (69) 22.2 (27) 20.0 (10) 25.0 (4) 9.8 (41) 21.9 (151)
Chugh, et al. Postgrad Med J 1981 42.9 (7) 20.0 (5) 26.3 (19) 0 (5) 25.0 (8) 25.0 (44)
Velasquez, et al. Am J Nephrol 1988 60.0 (5) 40.0 (10) 0 (0) 28.6 (7) 50.0 (4) 42.3 (26)
Wagoner, et al. Kidney Int 1983 51.9 (27) 0 (0) 0 (0) 0 (0) 0 (0) 51.9 (27)
Bennett, et al. Ann Intern Med 1975 – – – – – 28.6 (21)
Overall 37.0 (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. 2008 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, 18:689-699
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