Although renal vein thrombosis (RVT) has numerous etiologies, it occurs most commonly in patients with nephrotic syndrome (ie, >3 g/day protein loss in the urine, hypoalbuminemia, hypercholesterolemia, edema).
The syndrome is responsible for a hypercoagulable state. The excessive urinary protein loss is associated with decreased antithrombin III, a relative excess of fibrinogen, and changes in other clotting factors; all lead to a propensity to clot. Numerous studies have demonstrated a direct relation between nephrotic syndrome and both arterial and venous thromboses. Why the renal vein is susceptible to thrombosis is unclear.[1]
The renal vein may also contain thrombus after invasion by renal cell cancer. Other less common causes include renal transplantation, Behçet syndrome, hypercoagulable states, and antiphospholipid antibody syndrome.
Hypercoagulability is the fundamental process involved in both arterial and venous renal thrombosis. In the setting of malignant invasion of the vein by cancer, the presence of the tumor cells elicits thrombosis of the renal vein only. It may also occur as the result of blunt trauma to the abdomen or back. In infants, RVT can be associated with dehydration.[2, 3, 4]
In patients who are nephrotic, the most common underlying nephropathy associated with RVT is membranous nephropathy. The tumor association for RVT is renal cell carcinoma (RCC). However, most cases of membranous nephropathy are idiopathic.
RVT also may be the result of nephrotic syndrome from membranoproliferative glomerulonephritis, minimal change disease, rapidly progressive glomerulonephritis, amyloid, focal sclerosis, or lupus nephritis. RVT is more common in patients with primary nephropathy than in those with secondary nephropathy.
Findings relative to the causative disease may be present (eg, systemic lupus erythematosus [SLE], antiphospholipid antibody syndrome, cancer[5] ).
Theories for the putative relation between nephrotic syndrome and RVT have evolved. Initially, nephrotic syndrome was believed to be a consequence of RVT. However, this presumed sequence was found to be incorrect, for reasons including the following:
Experimentally induced RVT causes only mild proteinuria
RVT in the absence of nephrotic syndrome has been reported in the surgical literature
Nephrotic patients with RVT who have undergone histologic evaluation show evidence of an identifiable glomerulopathy
RVT is known to occur after the onset of nephrotic syndrome; thus, nephrotic syndrome is not a direct result of RVT but, rather, leads to RVT
SLE has also been associated with RVT. In general, patients with lupus and documented RVT have membranous lupus nephritis (World Heath Organization class V). Generally, thrombophlebitis and circulating anticoagulants (anticardiolipin antibodies) are believed to be much less important than nephrotic syndrome as predisposing factors of RVT in SLE.
RVT is an uncommon but definite problem in neonates.[6, 7] A possible association exists between RVT and the factor V Leiden mutation in this age group.
Other diseases or situations that have been associated with RVT include the following:
Aside from RCC, the other associations are uncommon. Trauma, ingestion of oral contraceptive agents, dehydration (infants), and steroid administration also have been associated with RVT.
The US prevalence of RVT has been difficult to establish. Studies have shown a high degree of variability in the presence of RVT among patients with nephrotic syndrome, with reported rates of 5-62%.
Age is a factor in RVT only insofar as is the case with any age-related risk of glomerular disease. For example, membranous nephropathy, the lesion most associated with RVT, is the most common cause of nephrotic syndrome in adults, but it is rare in children. Membranous nephropathy peaks in the fourth through sixth decade, thus making RVT more likely in this specific age group. However, exact incidence or prevalence figures are not available. RVT from RCC occurs in older age groups.
No specific numbers are available for the respective frequencies of RVT in the two sexes. Theoretically, however, membranous nephropathy, the disease most commonly associated with RVT, has a male-to-female ratio of 2:1; therefore, a male preponderance may exist for RVT.
The morbidity and mortality of RVT are usually secondary to the effects of nephrotic syndrome (including arterial thrombosis), renal dysfunction or failure, or the complications resulting from thromboembolism.
If the etiology of the RVT is malignancy, morbidity and mortality are a result of either thromboembolism or the cancer itself. RVT that is secondary to cancer may signal dissemination of the malignancy. In the setting of transplantation, RVT may lead to loss of the graft. If the RVT eventuates from the other causes discussed, thromboembolism is the source of complications.
The prognosis of any glomerular disease may be worsened by superimposition of acute RVT, but it is unclear whether the slow development of chronic RVT accelerates renal functional loss.
The presentation of renal vein thrombosis (RVT) is variable, and patients may be asymptomatic. When RVT occurs as a result of malignancy, the signs of the renal malignancy (eg, hematuria, weight loss) predominate.
The more common chronic form of RVT is generally covert. The less frequent acute form usually occurs in younger patients, with flank pain and macroscopic hematuria, which can be severe in the acute onset of thrombosis. Patients may present with thrombosis, pulmonary embolism, or both.
The patient should be observed for signs of nephrotic syndrome (edema or anasarca).
No specific laboratory studies are indicated for renal vein thrombosis (RVT) except those specific for nephrotic syndrome or other associated factors such as trauma or coexisting hypercoagulable state. Studies that may be helpful include the following:
Cholesterol levels for hypercholesterolemia
Albumin levels for hypoalbuminemia
Serum complement levels
Urine protein and loss renal function studies, including serum creatinine and blood urea nitrogen (BUN); these are necessary because RVT may present as unexplained acute renal failure or a sudden increase in proteinuria
In RVT, intravenous pyelography (IVP) with an abdominal plain film may reveal an enlarged kidney. If the renal pelvis is observed, it is usually distorted. An infrequent but characteristic finding of RVT is notching of the ureter, which occurs when collateral veins near the ureters become tortuous. IVP seldom is used to help make the diagnosis.
Inferior vena cavography may help provide a diagnosis of RVT. Occasionally, it is not diagnostic, in which case selective renal vein catheterization can be performed.
Renal arteriography may be useful in situations where RVT is secondary to trauma or tumor, in which case renal artery involvement is common.
Renal ultrasonography (US) is a safe noninvasive technique. With underlying RVT, the kidneys swell and become echogenic, with prominent echo-poor medullary pyramids. Color Doppler scanning may also provide information. However, US usually is not sensitive enough to assist in making the diagnosis,[12] though it is possible that contrast-enhanced US may yield better results.[13]
Computed tomography (CT) is the procedure of choice for diagnosing RVT noninvasively (see the image below). Intravenous (IV) infusion of contrast material assists in visualizing the renal veins. CT also demonstrates the presence of renal cell cancer.
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CT scan shows renal vein thrombosis secondary to renal cell cancer. Arrow is pointed at thrombosed renal vein.
At some point, magnetic resonance imaging (MRI) may become the procedure of choice for the diagnosis of RVT (see the image below). MRI produces high-contrast images between flowing blood, vascular walls, and surrounding tissue. Its major benefit is the avoidance of radiation and IV contrast material. MRI also may help detect RVT and the presence of tumor.
View Image
MRI is from patient with renal cell cancer and renal vein thrombosis. Arrow is on thrombosed renal vein.
In a study comparing the diagnostic accuracy of three-dimensional contrast-enhanced magnetic resonance venography (3D-CE-MRV) with that of multidetector CT venography (as the reference standard) for detecting RVT, Zhang et al found that the sensitivities and specificities of 3D-CE-MRV relative to CT venography were 94.1% and 100% on a per-patient basis and 95.5% and 100% on a per-vessel basis.[14] They concluded that 3D-CE-MRV would be an optimal alternative imaging modality for detecting RVT.
Renal biopsy plays an essential role in the evaluation of patients who are nephrotic and who have RVT. Renal histologic features of these patients reflect the responsible primary renal disease. Membranous nephropathy is the most common finding (see the image below).
View Image
Renal biopsy shows membranous nephropathy. Light (hematoxylin and eosin) stain shows thickened capillary loops via electron microscopy, with subepithe....
Measures employed to treat nephrotic syndrome may include steroids and immunosuppressive therapy. Treatment of underlying renal cell carcinoma (RCC) includes surgery for early-stage disease.
Symptomatic treatment includes diuretics and angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) to decrease proteinuria from nephrotic syndrome. Urinary protein is injurious to the renal tubules. ACEIs and ARBs decrease urine protein through an effect on efferent arteriolar pressure. Titrate to as high a dose as tolerated. If a combination of ACEIs and ARBs lowers protein excretion more than either does alone, the two types of medication should be used together. Decreasing protein loss in the urine decreases hypercoagulability.
Atorvastatin may be helpful. A study by Bianchi suggested that atorvastatin decreases the rate of progression of kidney disease, proteinuria, and hypercholesterolemia.[15]
Cyclosporine has demonstrated benefit in early trials for treatment of membranous nephropathy. Cure of the underlying nephropathy reverses nephrotic syndrome and renal vein thrombosis (RVT).
Anticoagulation with warfarin has been recommended in some studies for prophylaxis against pulmonary embolism (PE). PE from RVT should be diagnosed and treated exactly as it is when it results from other sources (ie, heparin, warfarin). If RVT is associated with PE, anticoagulation must be continued as long as nephrotic syndrome is present.
The indicators for thrombolysis in the setting of RVT are unclear. No data are available comparing thrombolytic therapy with anticoagulation.[16] In pulmonary embolic disease from other causes, thrombolytics are indicated in the setting of pulmonary hypertension (as found during examination or discovered by echocardiography). Catheter-based techniques for rapid delivery of thrombolytics in the setting of acute or refractory RVT have been described.[17, 18, 19]
For thrombolytic therapy or interventional radiology, transfer patients, especially if a vena caval filter is necessary in the event of failure of medical therapy for recurrent thromboembolism. The vena cava filter in these cases must be placed above the level of the renal veins (ie, suprarenally). This requirement is unique because in all other forms of deep vein thrombosis (DVT) and PE, the filters are placed in the infrarenal segment of the inferior vena cava (IVC). Either the interventional radiologist or the vascular surgeon can place the filter.
Hypercholesterolemia should be treated according to accepted national guidelines (ie, by using appropriate low-density lipoprotein targets for primary or secondary prevention).
Surgical treatment of RVT is rarely indicated today. It has been used if bilateral RVT is present or if pulmonary emboli have occurred and anticoagulation is contraindicated.[20] IVC filters may be used in this instance.[21] Surgery may be necessary for RVT of RCC, particularly for cure of malignancy.
Hypernephroma or RCC is unique in that intraluminal tumor extends into the renal vein and IVC and sometimes extends into the right atrium. In such cases, radical nephrectomy and removal of the tumor from the IVC and right atrium affords the chance of cure. This is not distant metastasis; rather, it is tumor extension within the renal vein and IVC.
Many nephrologists recommend normal protein intake for patients with nephrotic syndrome. Protein restriction may be used with benefit in patients who are nephrotic who do not spill massive amounts of protein (~10 g or more over 24 hours) or in those who have chronic renal failure.[22]
Consult a nephrologist and an interventional radiologist (only when medical therapy does not prevent pulmonary emboli).
A surgeon (urologist) can assist in the staging and potential surgery for RCC (early-stage disease). A combined team that consists of a urologist, a vascular surgeon, a cardiac surgeon, a transplant surgeon, or a combination thereof works together in complex cases of RCC with extension into the renal vein, IVC, and right atrium.
Reduction in proteinuria is essential in the treatment of renal vein thrombosis (RVT) in patients who are nephrotic. The current standard is to use angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs). Pulmonary emboli from RVT should be diagnosed and treated exactly as they are when resulting from other sources (ie, heparin, warfarin). If RVT is associated with pulmonary emboli, anticoagulation must be continued as long as nephrotic syndrome is present.
The indicators for thrombolysis in the setting of RVT are unclear. No data are available comparing thrombolytic therapy with anticoagulation. In pulmonary embolic disease from other causes, thrombolytics are indicated in the setting of pulmonary hypertension (as found during examination or discovered by echocardiography).
Warfarin, ARBs, and ACEIs are unsafe in pregnancy. Pregnant patients with RVT are best treated with heparin alone.
Clinical Context:
Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor. This increases levels of plasma renin and reduces aldosterone secretion. In kidney, the drug decreases glomerular hydraulic pressure, thereby decreasing filtration of protein.
Clinical Context:
Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor. This increases levels of plasma renin and reduces aldosterone secretion. In kidney, the drug decreases glomerular hydraulic pressure, thereby decreasing filtration of protein.
Clinical Context:
Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor. This increases levels of plasma renin and reduces aldosterone secretion. In kidney, the drug decreases glomerular hydraulic pressure, thereby decreasing filtration of protein.
Clinical Context:
Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor. This increases levels of plasma renin and reduces aldosterone secretion. In kidney, the drug decreases glomerular hydraulic pressure, thereby decreasing filtration of protein.
Clinical Context:
Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor. This increases levels of plasma renin and reduces aldosterone secretion. In kidney, the drug decreases glomerular hydraulic pressure, thereby decreasing filtration of protein.
Clinical Context:
Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor. This increases levels of plasma renin and reduces aldosterone secretion. In kidney, the drug decreases glomerular hydraulic pressure, thereby decreasing filtration of protein.
Clinical Context:
Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor. This increases levels of plasma renin and reduces aldosterone secretion. In kidney, the drug decreases glomerular hydraulic pressure, thereby decreasing filtration of protein.
These agents reduce urine protein excretion by decreasing glomerular hydraulic pressure. Decrease efferent arteriolar constriction, thereby decreasing the pressure, resulting in the filtration of protein. The filtered protein, per se, is injurious to the kidney.
Clinical Context:
Blocks vasoconstrictor and aldosterone-secreting effects of angiotensin II. May induce more complete inhibition of renin-angiotensin system than ACEIs, does not affect response to bradykinin, and is less likely to be associated with cough and angioedema. Use in patients unable to tolerate ACEIs.
Clinical Context:
Blocks vasoconstrictor and aldosterone-secreting effects of angiotensin II. May induce more complete inhibition of renin-angiotensin system than ACEIs, does not affect response to bradykinin, and is less likely to be associated with cough and angioedema. Use in patients unable to tolerate ACEIs.
Clinical Context:
Blocks vasoconstrictor and aldosterone-secreting effects of angiotensin II. May induce more complete inhibition of renin-angiotensin system than ACEIs, does not affect response to bradykinin, and is less likely to be associated with cough and angioedema. Use in patients unable to tolerate ACEIs.
Clinical Context:
Blocks vasoconstrictor and aldosterone-secreting effects of angiotensin II. May induce more complete inhibition of renin-angiotensin system than ACEIs, does not affect response to bradykinin, and is less likely to be associated with cough and angioedema. Use in patients unable to tolerate ACEIs.
Clinical Context:
Blocks vasoconstrictor and aldosterone-secreting effects of angiotensin II. May induce more complete inhibition of renin-angiotensin system than ACEIs, does not affect response to bradykinin, and is less likely to be associated with cough and angioedema. Use in patients unable to tolerate ACEIs.
Clinical Context:
Prodrug that produces direct antagonism of angiotensin II receptors. Displaces angiotensin II from AT1 receptor and may lower blood pressure by antagonizing AT1-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic responses. May induce more complete inhibition of renin-angiotensin system than ACEIs, does not affect response to bradykinin, and is less likely to be associated with cough and angioedema. For use in patients unable to tolerate ACEIs.
Igor A Laskowski, MD, Assistant Professor of Surgery, Section of Vascular Surgery, New York Medical College, Westchester Medical Center
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Chief Editor
Vincent Lopez Rowe, MD, Professor of Surgery, Program Director, Vascular Surgery Residency, Department of Surgery, Division of Vascular Surgery, Keck School of Medicine of the University of Southern California
Disclosure: Nothing to disclose.
Additional Contributors
Richard A Santucci, MD, FACS, Specialist-in-Chief, Department of Urology, Detroit Medical Center; Chief of Urology, Detroit Receiving Hospital; Director, The Center for Urologic Reconstruction; Clinical Professor of Urology, Michigan State University College of Medicine
Disclosure: Nothing to disclose.
Acknowledgements
Sateesh C Babu, MD Professor of Clinical Surgery, New York Medical College; Chief, Vascular and Endovascular Surgery, Westchester Medical Center
Disclosure: Nothing to disclose.
Louis Schwing, MD Consulting Staff, Department of Internal Medicine, Carle Clinic Associates
Louis Schwing, MD is a member of the following medical societies: American Medical Association
CT scan shows renal vein thrombosis secondary to renal cell cancer. Arrow is pointed at thrombosed renal vein.
MRI is from patient with renal cell cancer and renal vein thrombosis. Arrow is on thrombosed renal vein.
Renal biopsy shows membranous nephropathy. Light (hematoxylin and eosin) stain shows thickened capillary loops via electron microscopy, with subepithelial deposits.
Renal biopsy shows membranous nephropathy. Light (hematoxylin and eosin) stain shows thickened capillary loops via electron microscopy, with subepithelial deposits.
CT scan shows renal vein thrombosis secondary to renal cell cancer. Arrow is pointed at thrombosed renal vein.
MRI is from patient with renal cell cancer and renal vein thrombosis. Arrow is on thrombosed renal vein.
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