Diseases of the renal veins, as with other diseases of the venous system, tend to be forgotten in the study of both renal disease and peripheral vascular disease. The full functional impact of renal venous disease remains to be established; however, adequate experience with anatomic derangements in the renal venous system has led to some appreciation of the importance of the “passive” side of renal circulation. As a part of the deep venous system, the renal veins may suffer from thrombosis in a similar fashion as other manifestations of venothromboembolic disease. Renal venous thrombosis, however, is the predominant primary disease of the renal veins. The other syndromes—renal venous tumors, renal vein entrapment, and renal arteriovenous malformations (AVMs)—result more from the anatomic environment the renal veins are surrounded by (i.e., in these disease processes, the renal veins tend to be injured as bystanders in local pathology). Finally, increasing interest is developing on functional disease of the renal venous system, primarily in the form of renal venous congestion.

As with all deep veins, the renal venous system is at risk for the formation of luminal thrombus, the syndrome known as renal vein thrombosis (RVT) (Table 25-1). Although similar to deep venous thrombosis (DVT) in other circulatory beds with regard to risk factors, pathophysiology, diagnosis, and, even treatment, unique aspects of RVT are present. The renal vein’s intrinsic connection to a vital organ subject to specific injuries related to hemodynamic, immunologic, and physiologic derangements, makes RVT is distinct from other DVTs in certain aspects. Specifically, RVT carries a higher risk in selected patient populations with underlying disease states, requires a higher index of suspicion given the absence of physical examination clues to its presence, and requires specific treatment at underlying risk factors for its development to not only preserve vital organ function but also to prevent extension of existing thrombosis and recurrence of thrombotic events.

The development of RVT requires the pathologic environment shared by all sites of DVT; one or more elements of Virchow’s triad—low blood flow (stasis), hypercoagulable state and/or vascular injury. Although occasionally only a single risk factor is identifiable, many instances of RVT manifest with more than one or all of the underlying risk factors for DVT.¹ Examining the different populations that develop RVT offers insight into how each of the risk factors can contribute to the development of RVT.

Low Blood Flow (Stasis)

Stasis in the renal venous system is perhaps the least significant contributor for the development of RVT. However, the occurrence of the disease in certain patient populations suggests it plays a role.

RVT is the most common venous thrombosis that occurs in neonates.² The unique features of the neonatal circulation and the stress of the birthing process create an environment at risk for RVT. RVT begins in the smaller caliber veins before involving the larger renal vein. Veins such as the arcuate and interlobular veins have slower flow at baseline than higher pressure venous sites. The addition of low blood volume from neonatal asphyxiation, hyperosmolar dehydration from maternal diabetes mellitus, or dehydration (from another cause) further decrease flow, creating an environment suitable for venous thrombosis.³

Although the combination of local sluggish flow and volume depletion was previously thought to be the most significant predisposing factor in the development of RVT, more recent data suggest that the addition of an inherited hypercoagulable state may play a more significant role in perinatal venous thrombosis than previously thought.³

Furthermore, although the sluggish blood flow and state of relative venous stasis theoretically play a role in causing RVT in adults, the exact role of stasis exclusive of local vascular injury and hypercoagulability remains unclear, and it is likely that more than one of Virchow’s triad is present when RVT occurs.⁴

Vascular Injury

The cause of vascular injury leading to RVT is varied. Conventionally, in the deep vein systems of the lower extremities, direct trauma (either accidental or iatrogenic) predisposes to thrombus formation.⁴ The location of the renal venous system makes direct trauma, although not extraordinarily rare, less common. Instrumentation, especially via umbilical vein catheterization in neonates, may cause macrovascular injury, predisposing to RVT. In adults, although direct trauma leading to RVT has been reported, the more important method of vascular injury appears to be microvascular via immune complex or alternative endogenous proteins that cause endothelial injury. Vasculitis from systemic autoimmune disease (e.g., systemic lupus erythematosus [SLE] and Behçet’s disease) has been associated with RVT. However, to separate the ultimate cause of thrombosis between the nephrotic syndrome associated with vasculitides leading to a hypercoagulable milieu versus direct vascular injury remains difficult.^5,6,7 Nevertheless, local inflammation from infection or noninfectious tissue injury has been associated with vascular injury leading to RVT. Before the widespread use of antibiotics, acute pyelonephritis was associated with RVT. Cases reported more recently are those associated with more severe infections or with an alternative hypercoagulable state.^8,9 Local inflammation adjacent to the renal circulation has also been associated with the development of RVT. Specifically, reports of RVT and inferior vena cava (IVC) thrombosis have been reported in cases of severe pancreatitis.¹⁰ Finally, hyperhomocystinuria, itself or in combination with another inflammatory condition, has been associated with endothelial injury leading to RVT.¹¹ Although potentially also caused by the development of a local hypercoagulable state, the most direct nontraumatic vascular injury associated with RVT occurs as result of tumors of the renal parenchyma extending into the renal vein or tumors involving the renal vein and IVC leading to thrombosis. Leiomyosarcomas and renal cell carcinomas (RCCs) are the neoplasms most commonly associated with RVT.

The vascular injury portion of Virchow’s triad does appear to contribute to the development of RVT. However, as with stasis, more than one predisposing factor most often appears to be necessary for the development of DVT.

Hypercoagulable State

Perhaps the most important risk factor for the development of RVT is an acquired or inherited condition creating an environment prone for clotting and thrombosis. In approaching the hypercoagulable states that predispose to RVT, one can divide them into states intrinsic to the kidney and systemic hypercoagulable states. Although overlap exists, this division provides a simplified classification.

The nephrotic syndrome is the primary intrinsic renal pathology that leads to a hypercoagulable state. Conventionally, the hypercoagulability of the nephrotic syndrome has been attributed to, simply, the loss of anticoagulant proteins in the nonselective proteinuria occurring as a result of glomerular injury. Although the resulting deficiency of endogenous anticoagulant proteins certainly contributes, there appear to be local factors that predispose to RVT rather than other DVT. The exact mechanisms remain yet to be determined; however, current findings suggest the presence of a thrombotic milieu in the renal circulation of patients with nephrotic syndrome. Intrarenal thrombin formation may occur, leading to glomerular fibrin deposition. Elevated fibrinogen levels in renal venous blood correlate with the presence of fibrin deposition. Furthermore, the inflammatory cells associated with glomerular injury may activate the coagulation cascade within the renal circulation, predisposing to local thrombosis.^12,13,14,15

Although any of the forms of the nephrotic syndrome can be associated with RVT, membranous nephropathy appears to be the primary glomerular disease with the highest risk association. Focal segmental glomerulosclerosis (FSGS) and membranoproliferative glomerulonephritis (MPGN) are the next most commonly associated underlying renal pathologies.¹⁶ In addition to the type of underlying disease, the degree of proteinuria, caused by the accelerated loss of anticoagulant proteins and increased local viscosity, also appears to contribute to the risk of venous thrombosis in patients with nephrotic syndrome.

Given the presence of extrarenal DVT, local environmental alterations do not appear to be adequate to fully explain the hypercoagulable state associated with the development of thrombosis in the nephrotic syndrome. The systemic hypercoagulability resulting from loss of endogenous anticoagulants, relative increase in larger-size procoagulant proteins, and platelet activation lead to a hypercoagulable state predisposing to DVT of any site.¹⁶ Hypoalbuminemia resulting from severe proteinuria may also lead to alteration in hepatic synthesis of procoagulant proteins such as fibrinogen.¹⁶ Specifically, loss of antithrombin, protein C, protein S, and tissue factor pathway inhibitor have been identified as potential contributors to the risk of thrombosis. However, protein C, protein S, and tissue factor pathway inhibitor plasma levels have inconsistently correlated with risk of thrombosis or degree of proteinuria. In contrast, the degree of antithrombin deficiency has correlated with the severity of proteinuria, hypoalbuminemia, and risk of thrombosis. Finally, some procoagulant proteins, such as von Willebrand factor, factor V, and factor VIII, have higher than normal concentrations because of increased production despite losses¹⁶. In combination with local alterations in hemostasis outlined above, the alterations in procoagulant and anticoagulant protein concentrations lead to the development of RVT in the setting of the nephrotic syndrome.

Although not encountered as commonly, other systemic hypercoagulable states have been associated with RVT. Specifically, the antiphospholipid antibody syndrome (APS) has been associated with RVT. Both primary APS and the APS associated with SLE have been associated with RVT. The mechanism of RVT in patients with APS is similar to the development of DVT in any other vascular bed—endothelial activation, induction of tissue factor, or inhibition of endogenous anticoagulants. The frequency of RVT as a manifestation of APS compared with other vascular thrombosis is unclear, but it appears to be a common cause of RVT in those without intrinsic renal disease or systemic connective tissue disease.^17,18

Alternative systemic hypercoagulable conditions have also been linked to RVT, including protein C or protein S deficiency, antithrombin III deficiency, factor V Leiden mutation, and so on. However, their relative frequencies are not well known.¹

RVT appears to manifest in individuals with intrinsic renal pathology and alterations in systemic coagulation independent of renal disease. Ultimately, those at greatest risk appear to be individuals with some combination of alterations in blood flow, vascular injury, and local hypercoagulability.

The onset of flank pain and hematuria in a patient with risk factors for RVT should raise suspicion for its presence. Alternatively, the same symptoms in an otherwise healthy patient in whom more common diagnoses such as nephrolithiasis or pyelonephritis have been excluded should also raise suspicion. Although the triad of flank pain, hematuria, and palpable flank mass had been described as a “classic” triad, the sensitivity and specificity of these symptoms individually or together have not been noted to have adequate diagnostic utility. Ultimately, the presenting signs and symptoms can be quite variable (Figure 25-2). Acute and chronic variants of RVT have been described, each yielding different, yet overlapping clinical syndromes. Incidentally noted RVT has also been reported; however, its clinical significance remains in question. Ultimately, the suspicion of RVT in the appropriate clinical context with the manifestations outlined above requires further investigation.

Both unilateral and bilateral RVT have been described, and posttransplant kidneys appear to particularly vulnerable to RVT. RVT may be the only manifestation of a thrombophilic state or may be associated with thrombosis in other vascular beds, including the IVC, gonadal veins, DVT of the lower extremities, or even, pulmonary emboli (Figure 25-3).

Once suspected, the diagnosis of RVT can also pose significant difficulty. Given the relative infrequency of RVT, the various imaging modalities have not been well studied; nevertheless, certain conclusions have been made.

Direct IVC venography remains the gold standard of diagnosis. However, given its invasive nature and the potential risk of both direct renovascular injury via catheterization and nephrotoxicity caused by contrast administration, it is not used a primary diagnostic tool.¹⁹

The noninvasive options for diagnosis of RVT include duplex ultrasonography, computed tomography (CT) angiography, and magnetic resonance angiography (MRA) (Figure 25-4).