You are in: eMedicine Specialties > Radiology > GENITOURINARY Renal Vein ThrombosisArticle Last Updated: Dec 8, 2006AUTHOR AND EDITOR INFORMATIONSection 1 of 10
  Author: Aheed Siddiqi, MD, Radiology Resident, Department of Radiology, Northwestern University Feinberg School of Medicine Aheed Siddiqi is a member of the following medical societies: American Medical Association, American Medical Student Association/Foundation, and Radiological Society of North America Coauthor(s): Robert K Ryu, MD, Consulting Staff, Department of Radiology, Decatur Memorial Hospital Editors: Bernard D Coombs, MB, ChB, PhD, Consulting Staff, Department of Specialist Rehabilitation Services, Hutt Valley District Health Board, New Zealand; Joshua A Becker, MD, Professor, Department of Radiology, New York University School of Medicine; Robert M Krasny, MD, Consulting Staff, Department of Radiology, The Angeles Clinic and Research Institute; Eugene C Lin, MD, Consulting Staff, Department of Radiology, Virginia Mason Medical Center Author and Editor Disclosure Synonyms and related keywords: RVT, renal venous thrombosis, nephrotic syndrome, membranous glomerulonephropathy, membranoproliferative glomerulonephritis INTRODUCTIONSection 2 of 10
  In 1840, Rayer first described the association between renal vein thrombosis (RVT) and nephrotic syndrome. Earlier reports, from postmortem examinations, had correctly cited infectious suppuration, malignancy, and trauma as likely causes of RVT. However, since Rayer's time—as increased awareness and better radiographic techniques have helped physicians gain a greater understanding of the etiology, characteristics, and treatment of RVT—nephrotic syndrome has been identified as the most frequent cause. On the basis of early descriptions, researchers initially believed that RVT always produced such acute symptoms as flank pain, edema, and a lumbar mass. However, the classic presentations of the condition—nephrotic syndrome and lower abdominal and flank pain in adults and renal failure and a painful, palpable mass in infants—are only 2 extremes of RVT's clinical spectrum (Harrison, 1956). Currently, most patients with RVT present with only nephrotic syndrome in the absence of other symptoms. In addition, although the incidence of RVT is relatively high, most patients remain asymptomatic for it, and spontaneous recovery occurs more frequently than is suggested clinically. ETIOLOGY AND INCIDENCESection 3 of 10
Reports before 1960 indicated that nephrotic syndrome resulted directly from thrombosis of the renal veins. However, subsequent investigations have refuted this theory.
Such reports have led to the current perception that RVT is a consequence or complication, rather than a cause, of nephrotic syndrome. Nephrotic syndromes As previously stated, the nephropathy most commonly associated with RVT is MGN (Cameron, 1987; Llach, 1980; Llach, 1984). In 1980, Llach et al found RVT in 33 of 151 patients with nephrotic syndrome; in 20 of these 33, the nephrotic syndrome was identified as MGN. Another prospective histologic investigation revealed that RVT was associated with MGN in 60% of patients, membranoproliferative glomerulonephritis (MPGN) in 40%, and focal sclerosis (FS) in 28% (Velasquez, 1988). Similarly, other studies have revealed that MGN and MPGN are the renal histologic pictures of nephrotic syndrome that are most frequently associated with RVT (Velasquez; Llach, 1980; Trew, 1978). However, other nephrotic syndromes, including amyloidosis and lipoid nephrosis, also can cause RVT, as can such primary renal diseases as glomerulonephritis, pyelonephritis, and vasculitis. Other causes Other conditions leading to RVT include alterations in renal flow secondary to fluid volume losses (as a consequence of GI fluid loss, hemorrhage, dehydration, infection) and functional states of decreased cardiac output and renal hypoperfusion (congestive heart failure, aortic insufficiency, constrictive pericarditis). RVT resulting from GI fluid loss is observed primarily in neonates, but it reportedly can occur in adults as well (Morrissey, 1997). Researchers believe that dehydration and subsequent hemoconcentration induce sludging and thrombosis in the smaller interlobular and arcuate renal veins; propagation to both larger and smaller vessels occurs. Eventually, the renal vein becomes occluded, and occasionally, the effects extend into the inferior vena cava (IVC). All of the following can predispose an individual to RVT: blunt or iatrogenic trauma; neoplasms (such as renal cell carcinoma, Wilms tumor, transitional cell carcinoma, and growths from metastatic diseases); drugs, including birth control pills and exogenous estrogens; hypercoagulable states, such as pregnancy and disseminated malignancy; septic abortion; and extension of leg or pelvic venous thrombus. In addition, extrinsic compression of the renal vascular pedicle—which may occur during pregnancy or as a result of retroperitoneal fibrosis or the presence of lymphomas, tumors, or abscesses—can precipitate thrombus formation in the renal vein or IVC. Finally, a number of systemic diseases, including polyarteritis nodosa, diabetic glomerulosclerosis, sickle cell anemia, and systemic lupus erythematosus, also may be associated with RVT. Incidence of RVT A variety of conditions, particularly nephrotic syndrome, can lead to RVT (Llach, 1977; Llach, 1975; Velasquez; Cameron). However, the exact incidence of RVT is not well known, because many patients remain asymptomatic. A prospective study by Velasquez et al investigated the incidence of asymptomatic RVT in 26 patients with idiopathic nephrotic syndrome. Using inferior venacavography with selective catheterization of the renal veins, the researchers found RVT in 42% of the patients. When other prospective studies (Cameron; Llach, 1980) are taken into account, research indicates that symptomatic or asymptomatic RVT occurs in 16-42% of patients with nephrotic syndrome (Velasquez; Cameron; Llach, 1980). In each of the investigations cited, patients with nephrotic syndrome underwent venography regardless of whether or not they had symptoms of RVT. NEPHROTIC SYNDROME AND CLOTTINGSection 4 of 10
As a complication of nephrotic syndrome, RVT is thought to result from the hypercoagulable state related to nephrosis (Llach, 1984). Many studies have revealed that clotting factor abnormalities, such as increased levels of factors II, V, VII, VIII, and X, occur in the presence of nephrotic syndrome, as do heightened levels of alpha2-antiplasmin and increased platelet counts (Thompson, 1974). Researchers believe that these changes are a response to proteinuria, which stimulates the liver to augment increased synthesis of these proteins. In addition, a rise in plasma fibrinogen levels, again due to increased hepatic synthesis, raises blood viscosity and produces a hypercoagulable state. Finally, defective fibrinolysis, a decreased plasma plasminogen concentration, thrombocytosis, and increased platelet aggregation also characterize nephrotic syndrome (Kuhlmann, 1981). Antithrombin III Alterations in coagulation inhibitors, such as proteins C and S and antithrombin III (AT-III), also have been observed in nephrotic syndrome (Llach, 1984). Of these, AT-III, a protease inhibitor synthesized in the liver, has been studied the most. A low-molecular-weight protein, it is the main inhibitor of thrombin, factors IX -XII, and plasmin and allows heparin to exert its anticoagulant activity (Kauffmann). Researchers have demonstrated that the loss of low-molecular-weight proteins, resulting from nephrotic syndrome–associated proteinuria, lowers AT-III serum levels; this contributes to a hypercoagulable state, ultimately resulting in thrombosis (Du, 1985). The reduction in serum levels of AT-III has been correlated with the degree of proteinuria and the severity of hypoalbuminemia (Kauffmann). Other studies have revealed that nephrotic syndrome is associated with decreased functional activities of proteins C and S (Kaufmann, 1976). Thus, the hypercoagulable milieu created by the nephrotic syndrome is enhanced by proteinuria and the resultant depressed serum levels of AT-III. Summary The hypercoagulable state present in nephrotic syndrome—which gives rise to RVT—is marked by alterations in zymogens and cofactors, increased plasma fibrinogen levels, decreased levels of AT-III and functional proteins C and S, thrombocytosis, increased platelet aggregation, and higher levels of beta-thromboglobulin (Llach, 1984). Beta-thromboglobulin may be a reliable marker of platelet aggregation. The diuretic therapy and reduced plasma volume associated with nephrotic syndrome lead to decreased renal venous flow, further encouraging the development of RVT. The generalized hypercoagulable state resulting from nephrotic syndrome produces, in addition to RVT, thromboses in the axillary and subclavian veins, as well as in the pulmonary, femoral, coronary, and mesenteric arteries (Llach, 1984). PATHOPHYSIOLOGYSection 5 of 10
The description of RVT in earlier literature included flank pain with tenderness, appearance of a lumbar mass, and macroscopic hematuria. The clinical presentation of RVT largely depends on the rate and degree of renal vein occlusion, the extension of the thrombosis, and the subsequent development of collaterals. Often, RVT produces few or no clinical manifestations; it frequently goes undiagnosed until a patient with nephrotic syndrome has developed a pulmonary embolism or deep vein thrombosis (DVT) or has suffered an abrupt decline in renal function. In general, patients with RVT have 2 primary modes of clinical presentation: acute and chronic (Llach, 1980). Acute RVT Acute RVT is characterized by abrupt onset of flank pain, nausea, vomiting, and gross or microscopic hematuria. Physical findings may include a palpable kidney (RVT results in an enlarged kidney that is tense, swollen, and cyanotic) and hypertension. On occasion, acute RVT may be bilateral, leading to oliguric acute renal failure and flank pain. Bilateral acute renal vein thrombosis may be lethal if left untreated. A characteristic, although rare, radiographic finding is notching of the ureter, which usually occurs when collateral veins in close relation to the ureter become tortuous and dilated. If swelling continues to increase, arterial perfusion can be compromised and the kidney may undergo hemorrhagic infarction and atrophy. Acute RVT is most commonly observed in infants and neonates secondary to dehydration. Chronic RVT The chronic presentation of RVT is observed more frequently than the acute form. Patients with chronic RVT generally present with few or no accompanying symptoms and, aside from albuminaria, no sign of abnormal renal function, making the true prevalence of chronic RVT difficult to determine. However, gradual worsening is seen in patients with nephrotic syndrome and resultant chronic edema. Many patients with RVT develop DVT. They can initially present with pulmonary thromboembolism (Llach, 1985). DVT and pulmonary embolism are the most common complications of RVT and nephrotic syndrome, with pulmonary embolism being the most common fatal thromboembolic complication (Pasquariello, 1992; Markowitz, 1995). In chronic RVT, regardless of the degree of thrombosis, the collateral circulation always evolves. Occasionally, evidence of venous collateralization in the form of a varicocele or retrograde flow in dilated superficial epigastric veins is observed. The presence of a varicocele should prompt careful imaging of the kidney to assess for bland or malignant RVT. In general, patients with chronic RVT are older than those with the acute form and have a greater incidence of other thromboembolic phenomena. DIAGNOSISSection 6 of 10
Because the classic presentation of hematuria, flank pain, and a lumbar mass is rarely seen in RVT, a high index of suspicion is essential for the condition's diagnosis. Ultrasonography (US), computed tomography (CT) scanning, and magnetic resonance imaging (MRI) have varying levels of sensitivity and specificity. Ultrasonography Currently, US is the initial study of choice to exclude the presence of RVT. In an acute setting, US may reveal an edematous and enlarged kidney with decreased echogenicity caused by diffuse edema, as well as focal or diffuse disruption of parenchymal architecture and/or thrombus in the renal veins (Avasthi, 1983). Duplex Doppler US demonstrates peaked, abruptly decreasing systolic-frequency shifts and retrograde plateau-like shifts during diastole at the level of the main renal artery and its proximal branches, with an absent venous signal (Reuther, 1989). Doppler US may reveal increased blood velocity and turbulence in narrowed sections of the renal vein or cessation of blood flow if the lumen is completely obstructed. Power Doppler US has increased confidence in the diagnosis of RVT and in the assessment of caval tumor thrombus (Helenon, 1998). Computed tomography Some reports indicate that CT also can detect RVT (Gatewood, 1986). CT findings include decreased nephrographic attenuation, loss of corticomedullary differentiation, a low-attenuating thrombus in the renal vein, renal enlargement with persistent parenchymal opacification, and renal vein enlargement. In the acute stage of RVT, capsular venous collaterals, thickening of the Gerota fascia, and pericapsular whiskering also are often observed (Glazer, 1984). Magnetic resonance angiography Recent observations suggest that when US findings are equivocal, magnetic resonance angiography (MRA) is a useful and accurate alternative test for RVT before venography (Kangasundaram, 1998). MRA provides high contrast between flowing blood, vascular walls, and surrounding tissues. Other advantages include the avoidance of contrast material, noninvasiveness, and the ability to image both the arterial and venous phases. Preliminary observations indicate that MRI and/or MRA may be the diagnostic procedures of choice for RVT detection (Kangasundaram, 1998). Renal venography and renal arteriography Currently, renal venography remains the diagnostic criterion standard. Assessing the venous phase of renal arteriography also aids in diagnosis. However, both are invasive procedures and, unlike US and MRA, require the use of potentially nephrotoxic contrast agents even in patients with existing renal compromise. Radionuclide renography Radionuclide renography using technetium-99m–diethylenetriaminepentaacetic acid also has proven to be useful in the assessment of renal perfusion. Organ damage in acute RVT results primarily from arterial compromise caused by venous pressure elevations (Keating, 1985). In such cases, scintigraphy reveals delayed or absent perfusion to the kidney. When a scan indicates perfusion arrest, an aggressive therapeutic approach may be warranted (Keating). TREATMENTSection 7 of 10
Treatment The treatment of RVT has evolved from nephrectomy to thrombectomy to anticoagulation, which is currently the standard treatment of choice (Markowitz). Anticoagulants act by preventing further propagation of the thrombus while allowing recanalization through the body's own fibrinolytic system and preventing thromboembolic phenomenon. In current standard therapy, intravenous heparin is administered to initiate systemic anticoagulation, with a subsequent switch to the oral anticoagulant warfarin. Physicians recommend that such therapy be used as long as patients have significant hypoalbuminemia (defined as a serum albumin level <2.5 g/L). For autoimmune disease (eg, lupus erythematosus), steroids and other immunosuppressive drugs are indicated. Thrombolytic therapy In patients with normal renal function and neither flank pain nor—aside from unilateral RVT—signs of thromboembolic disease, the risk-to-benefit ratio supports the use of anticoagulant therapy alone. Thrombolytic therapy is warranted in patients with bilateral RVT and acute renal failure, extension of RVT into the IVC, acute renal failure, a massive clot with high risk of acute embolic events, pulmonary emboli, or severe flank pain (Markowitz). Thrombolytic therapy should also be considered in patients whose condition fails to improve with heparin therapy. Because heparin works by enhancing the activity of AT-III, it may not be effective when, as occurs in nephrotic syndrome, AT-III levels fall. In general, several days of thrombolytic therapy may lyse more than 90% of the clots. Many investigators have demonstrated that urokinase-mediated thrombolysis can reverse acute renal failure (Vogelzang, 1988; Schwieger, 1993). Currently, no particular thrombolytic agent appears to have an obvious advantage over the others (Marder, 1988). Although thrombolytic therapy leads to a faster and more complete resolution, the treatment can potentially cause bleeding complications: Minor bleeding takes place in approximately 5% of patients, and serious bleeding events, such as intracranial hemorrhage, occur in 1% (Schwieger, 1993). Contraindications for thrombolytic therapy include a predisposition to bleeding, intracerebral cancer, recent cerebral trauma, a prior history of cerebrovascular accident, recent surgery, and gastrointestinal bleeding. The decision to dispense thrombolytic agents either systemically or locally, via venous or arterial administration, depends on risk and benefit factors. Systemic administration is noninvasive, whereas local administration allows for a lower lytic dose and shorter infusion times. Reports suggest that the systemic treatment is effective and safe if no obvious contraindications exist (Markowitz). To date, no prospective RVT studies have compared anticoagulation treatment alone with thrombolytic therapy. The general consensus is that heparin should be used initially, with thrombolytics reserved for second-line treatment if heparin therapy fails (Markowitz). Surgical thrombectomy or nephrectomy is rare and usually reserved for cases that are refractory to medical therapy. Thrombectomy is indicated when unrelenting, treatment-resistant pulmonary emboli and oliguria occur as a result of bilateral RVT or thrombosis of a solitary kidney. Nephrectomy should be considered in patients who present acutely with severe toxicity from hemorrhagic infarction of the kidney (Keating). PROGNOSISSection 8 of 10
Reports in the 1960s and 1970s suggested that RVT was associated with 64% mortality and an average survival period of 9 months after onset (Marder, 1988). Most patients died of pulmonary emboli or acute renal failure. An evaluation of 27 nephrotic patients with RVT revealed that 11 had died within 6 months after RVT's onset. Of all 27 patients, 8 had acute renal failure, and 6 of these died of hemorrhagic complications. The survivors were observed over periods ranging from 6 months to 19 years, during which time it was found that nephrotic syndrome improved or even resolved in 12 of them. Overall, the main prognostic factors in the patients were initial renal function and type of nephropathy. Compared with patients who had other nephropathies, patients with MGN had better renal function and a lower mortality. Initial renal insufficiency was associated with poor prognosis (Laville, 1988). However, the prognostic data derived before the 1990s are not indicative of current RVT prognosis. Most of the older information was based on postmortem examinations, possibly causing death rates to be overestimated. Moreover, in the past, uremia was a common cause of death in patients with acute renal failure. Dialysis therapy, however, has markedly decreased uremia-associated death. Finally, new diagnostic modalities and better use of anticoagulation therapy have contributed to earlier diagnosis and improved treatment of RVT. Pulmonary embolus is the most common and serious complication in patients with RVT. Although findings indicate that patients with RVT currently have a better prognosis than that demonstrated in Laville's report, recent prospective studies have not been performed. Most reports demonstrate that renal function often improves in patients with RVT who have been treated with anticoagulation or thrombolytic therapy. Despite recent advances, physicians must nonetheless exercise a high degree of clinical suspicion to correctly diagnose RVT in those patients with minimal or even absent symptoms. RVT still has significant associated mortality from thromboembolic phenomena. MULTIMEDIASection 9 of 10
REFERENCESSection 10 of 10
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