Renal Vein Thrombosis

Author: Aheed Siddiqi, MD, Radiology Resident, Department of Radiology, Northwestern

University Feinberg School of Medicine
Coauthor(s): Robert K Ryu, MD, Consulting Staff, Department of Radiology, Decatur
Memorial Hospital

Introduction
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.1 However, since
Rayer's timeas increased awareness and better radiographic techniques have helped physicians
gain a greater understanding of the etiology, characteristics, and treatment of RVTnephrotic
syndrome has been identified as the most frequent cause.2

CT reveals thrombus extending from the left renal vein into the inferior vena cava. Note
that the left renal vein is retroaortic.

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 conditionnephrotic syndrome and lower abdominal and flank pain in adults and renal
failure and a painful, palpable mass in infantsare only 2 extremes of RVT's clinical spectrum.3
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.4

Etiology And Incidence

Investigators have found that experimentally induced renal vein thrombosis (RVT) causes only
mild proteinuria.5 Many cases of RVT have been identified in which no associated proteinuria
occurs. In patients with unilateral RVT, proteinuria has been shown to be qualitatively and
quantitatively equal in the 2 kidneys.
Nephrotic syndromes

Serial venograms obtained in patients with nephrotic syndrome have revealed that RVT can
occur in renal veins that initially were normal.6 In patients with nephrotic syndrome, widespread
thrombosis can be found in nonrenal vessels, suggesting that the renal veins simply share
involvement in a hypercoagulable state.5 Such reports have led to the current perception that
RVT is a consequence or complication, rather than a cause, of nephrotic syndrome.

The nephropathy most commonly associated with RVT is MGN.7,8,9 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%.10

Similarly, other studies have revealed that MGN and MPGN are the renal histologic pictures of
nephrotic syndrome that are most frequently associated with RVT.8,10,11 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 renal vein thrombosis 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.12 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 pediclewhich may occur during
pregnancy or as a result of retroperitoneal fibrosis or the presence of lymphomas, tumors, or
abscessescan 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 renal vein

thrombosis.7,10,13,14 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.10

When other prospective studies7,8 are taken into account, research indicates that symptomatic or
asymptomatic RVT occurs in 16-42% of patients with nephrotic syndrome.7,8 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 Clotting

As a complication of nephrotic syndrome, renal vein thrombosis (RVT) is thought to result from
the hypercoagulable state related to nephrosis.9 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.15 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.16

Antithrombin III

Alterations in coagulation inhibitors, such as proteins C and S and antithrombin III (AT-III), also
have been observed in nephrotic syndrome.9 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.17

Researchers have demonstrated that the loss of low-molecular-weight proteins, resulting from
nephrotic syndromeassociated proteinuria, lowers AT-III serum levels; this contributes to a
hypercoagulable state, ultimately resulting in thrombosis.18 The reduction in serum levels of AT-
III has been correlated with the degree of proteinuria and the severity of hypoalbuminemia.17

Other studies have revealed that nephrotic syndrome is associated with decreased functional
activities of proteins C and S.17 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 syndromewhich gives rise to RVTis 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.9 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.9

Pathophysiology
The description of renal vein thrombosis (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.8,19

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.20 DVT and pulmonary embolism are the most common complications of
RVT and nephrotic syndrome, with pulmonary embolism being the most common fatal
thromboembolic complication.21,22

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.

Diagnosis
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.23,24,25,26

CT reveals thrombus extending from the left renal vein into the inferior vena cava. Note
that the left renal vein is retroaortic.

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.27

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.28 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.29
In one study, color Doppler US was found to be useful for diagnosis of large renal infarcts
caused by thrombosis or embolism in the main renal artery; however, small infarcts could be
missed by color Doppler US, necessitating other imaging modalities for confirmation.24

Computed tomography

Some reports indicate that CT also can detect RVT.30 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.31

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.32 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.32

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-99mdiethylenetriaminepentaacetic 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.33 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.33

Treatment
Treatment

The treatment of renal vein thrombosis (RVT) has evolved from nephrectomy to thrombectomy
to anticoagulation, which is currently the standard treatment of choice.21 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.34,35

Thrombolytic therapy

In patients with normal renal function and neither flank pain noraside 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.21,36

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.37,38 Currently, no particular thrombolytic agent appears to have an obvious advantage
over the others.39

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%.37
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.
The general consensus is that heparin should be used initially, with thrombolytics reserved for
second-line treatment if heparin therapy fails.21

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.33
Prognosis
An evaluation of 27 nephrotic patients with renal vein thrombosis (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.40

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. 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.

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.