author(s): 1Naren Gupta, MD, 2Ross Milner, MD Abstract A 32-year-old woman with symptoms of pelvic venous congestion presented with a computed tomography of her abdomen that showed proximal compression of the left renal vein between the superior mesenteric artery and the aorta. In addition the patient had dilated gonadal and pelvic collaterals. A diagnosis of left renal vein entrapment (nutcracker syndrome, NCS) was supported by venography, which demonstrated proximal high-grade stenosis of the left renal vein, minimal flow of contrast into the vena cava and rapid decompression of the distal renal vein into pelvic venous collaterals, the largest of which was a dilated gonadal vein. An 18 mm x 40 mm Wallstent (Boston Scientific, Natick, Massachusetts) was deployed across the stenosis in the renal vein, with immediate improvement of venous drainage into the vena cava and diminution of flow into the gonadal vein. She was discharged the next day on aspirin and clopidogrel. The patient’s pelvic and flank pain markedly improved. After 30 days, she had abdominal imaging performed at an outside hospital. This showed a patent Wallstent and left renal vein with complete abrogation of her gonadal collaterals. Approximately forty cases of stenting for NCS have been reported in the literature, however, to our knowledge, this is the first publication of short-term radiologic results after renal vein stenting for pelvic congestion symptoms that demonstrate the rapid resolution of venous collaterals accompanying a good clinical outcome. We review the pathophysiology as well as treatment options for this uncommon disorder. Introduction Entrapment of the left renal vein between the superior mesenteric artery (SMA) and the aorta was described in standard anatomical texts in the first half of the twentieth century.1 Over the subsequent decades, scattered case reports led to a better understanding of the significance of this finding, culminating in the coining of the term “nutcracker syndrome” by de Schepper in 1972.2–4 A distinction has since been made between nutcracker phenomenon, which is a radiologic finding in an asymptomatic individual, and nutcracker syndrome (NCS).5–8 The latter is characterized by the combination of radiologic findings of meso-aortic compression of the left renal vein and dilated collateral veins with chronic left flank pain, haematuria, orthostatic proteinuria, and pelvic venous congestion. We present a case of a 32-year-old woman with NCS and imaging that documents early resolution of the venous collaterals. In addition, we review the proposed pathophysiology, indications for treatment, and therapeutic options for this uncommon condition. Case Report A 32-year woman with symptoms of pelvic venous congestion, left flank pain, and microscopic hematuria presented with computed tomography (CT) of her abdomen, which showed proximal compression of the left renal vein between the superior mesenteric artery and the aorta. In addition, the patient had dilated gonadal and pelvic venous collaterals. A diagnosis of NCS was supported by venography. This revealed a proximal high-grade stenosis of the left renal vein, minimal flow of contrast into the inferior vena cava (IVC) and rapid decompression of the distal renal vein into a dilated left gonadal vein (Figure 1, Panels A, B, and C). The renocaval pressure gradient was 1 mm Hg, likely due to the highly efficient reflux through her ovarian collaterals. A decision was made to treat the problem percutaneously. The patient was consented for an endovascular approach. We discussed with her that an open procedure may be required in the future. An initial angioplasty was performed with rapid recoil of the stenosis. An 18 mm x 40 mm Wallstent (Boston Scientific, Natick, Massachusetts) was deployed across the stenosis in the renal vein and into the inferior vena cava with immediate improvement of venous drainage into the vena cava and diminution of flow into the gonadal vein (Panel D). Intravascular ultrasound was utilized to assist with sizing. The goal was to select a size as large as possible to prevent migration of the stent into the inferior vena cava. In addition, the stent was specifically placed to allow for surgical revision, if it is needed in the future. She was discharged the next day on aspirin and clopidogrel. The patient’s pelvic and flank pain markedly improved. After 30 days she had abdominal imaging performed at an outside hospital. This showed a patent Wallstent and left renal vein with complete abrogation of her gonadal collaterals (Panels E, F). Approximately forty cases of stenting for NCS have been reported in the literature; however, to our knowledge this is the first publication of short-term radiologic results after renal vein stenting for pelvic congestion symptoms that demonstrate symptomatic improvement with the rapid resolution of venous collaterals. Discussion Nutcracker phenomenon, or the extrinsic compression of the proximal left renal vein between the superior mesenteric artery and the aorta, is often seen as an incidental finding on abdominal imaging for unrelated disease in both pediatric and adult populations.9,10 NCS should be suspected when radiologic evidence of obstructed left renal vein outflow and collateral drainage through dilated gonadal, peri-renal, and peri-ureteral vessels is accompanied by chronic complaints of left flank pain, gross, or microscopic haematuria, orthostatic proteinuria, left lower extremity varicose veins, left varicocele or pelvic venous congestion (chronic pelvic pain, dysparuenia, dysuria, dysmennhorea, vulvar varices).5,6 Incidence and Patient Profile Nutcracker phenomenon is present in as many as 72% of abdominal CT scans and shows no preference for gender.9 Though the exact incidence of NCS is unknown, it may be more common in women in the 3rd and 4th decades.11 Typically, they are relatively asthenic and have had previous pregnancies.12 In a large series of women with pelvic venous congestion, more than 13% were due to NCS.13,14 In the pediatric population, NCS has been associated with pediatric chronic fatigue syndrome.15,16 Etiology/Pathophysiology The normal course of the proximal SMA has been described as an inverted J shape, with an initial perpendicular origin off the aorta followed by a steep descent. The left renal vein fits into this groove without compression. However, if the SMA takeoff is more acute, then the space is converted into a slit, and can cause extrinsic compression.17,18 This is the anterior nutcracker phenomenon. An aortomesenteric angle less than 35˚ (normal being greater than 45˚) is also consistent with this phenomenon.19 Early radiologic studies suggested that if the distance between the SMA and the aorta at the level of the left renal vein crossover was less than 15 mm, distal renal vein distension was always present, though this is probably a normal anatomic variant since none of the patients were symptomatic.9 Posterior nutcracker occurs when a retro-aortic renal vein is compressed between the aorta and the spine.19 A combination of both has also been described where duplication or bifurcation of the left renal vein anterior and posterior to the aorta is accompanied by compression of both tributaries.12 Anatomic variants of the takeoff of the left gonadal artery from the left renal artery or even an aberrant right renal artery may also cause a nutcracker effect on an underlying left renal vein.20, 21 Another proposed anatomic contributor to nutcracker phenomenon is an asthenic body habitus that may cause excessive posterior ptosis of the left kidney with resultant stretching of the left renal vein over the aorta.11,22,23 A ring of excessive fibrous tissue compressing the renal vein in the vicinity of the aortomesenteric angle has also been implicated.7,8,24 Surgeons who cite the ability to ligate the left renal vein during trauma or open abdominal aortic aneurysm repair with no appreciable ill effect have challenged renal vein entrapment by mesoaortic compression as an etiology for pelvic venous hypertension. Investigators in the field counter that the two patient populations are very different. One group consists of predominantly multiparous females who have chronic renal venous outflow obstruction superimposed on the effects of hormones and a 60-fold increased venous return during pregnancy.25 The other population consists of predominantly male patients who have their left renal vein acutely ligated.26 However, there are also a wide variety of clinical and radiologic findings within a homogenous patient population with the nutcracker phenomenon. While some may have dilated collateral drainage with or without symptoms of venous hypertension, others have neither radiologic nor clinical sequelae. This suggests that, as in other venous beds, the manner in which the pelvic venous bed responds to outflow obstruction and venous hypertension is highly individualized, and perhaps affected as much by the presence and pattern of competent venous valves and venous anatomic variants as by a genetic predisposition.27 Diagnosis/Investigations Nutcracker syndrome is a clinical diagnosis that lacks a clear set of defining criteria, and is, in no small part, a diagnosis of exclusion. In the patient with chronic left flank and pelvic pain, transabdominal doppler ultrasonography is a useful non-invasive screening test.28,29 This modality can be used in the pediatric population as well. A ratio greater than 4.16 between the diameters of the aortomesenteric and hilar segments of the renal vein combined with a peak velocity ratio greater than 3.98 is suggestive of the NCS.30 Unfortunately, neither the direction of venous flow nor the presence or absence of renal vein hypertension, renal vein distension and gonadal collaterals, or any combination of the above, is conclusively pathognomic or exclusionary of the diagnosis. There can be normal renal flow in distended veins as well as abnormal flow in non-distended veins.31 An abdominal computerized tomographic angiography (CTA) or magnetic resonance venography (MRV) and urine exam should be ordered. NCS is suspected when these studies demonstrate the nutcracker phenomenon, together with evidence of pelvic venous collateralization and hematuria. A narrow aortomesenteric angle on CTA or MRA is also suggestive of NCS.19 Early filling of the main left renal vein collateral, the ipsilateral gonadal vein, as well as peri-renal and bilateral pelvic collaterals is strong evidence of venous hypertension. It is also important to remember that other etiologies of hematuria and proteinuria may co-exist with the nutcracker phenomenon, so occasionally a renal biopsy is warranted.6,32 In these situations, intravenous pyelography and cystoscopy can rule out other etiologies. Cystoscopy, in particular, can be very suggestive of NCS if it provides visual confirmation of hematuria arising from the left ureter.8,33,34 Venography is the single most useful, though invasive, diagnostic test. Venography can demonstrate renal vein outflow obstruction, early filling of dilated collaterals, and elevated intravenous pressures. Intravenous pressure measurements during renocaval pullback should demonstrate a gradient greater than or equal to 3 mm Hg in NCS.13,35 Normally this gradient should be less than 1 mm Hg.36,37 However, there is considerable overlap between normal and elevated renal vein pressures and the degree with which the collateral drainage has compensated for renal venous outflow obstruction can impact the magnitude of detectable renal venous hypertension.31 Treatment In 1974, Pastershank first documented the surgical management of NCS with a venolysis procedure.24 Since that report, there have been a variety of reported management options for NCS. These were comprehensively reviewed by Ahmed et al in 2006.11 This review included 19 publications with a total of 57 patients who underwent conservative management, left renal vein (LRV) transposition, renal autotransplantation, external stent, internal stent, gonadocaval bypass, venolysis, or SMA transposition, amongst others. Since this review, an additional 3 series with a total of 66 patients have been published.7,8,26 Here we present treatment options focused on the new data from these three large, recent series. Conservative Management The decision to treat NCS is based on the severity of symptoms. In mild or atypical disease, conservative management and continued surveillance for worsening symptoms or manifestations of another etiology for the symptoms like endometriosis, renal stones, IgA nephropathy, or thin basement membrane disease is indicated. In the pediatric or adolescent patient, growth or weight gain will often cause the symptoms to abate, so observation alone is supported here as well.11,23 In two recent series, 28 out of 43 (65%) patients who had mild or atypical symptoms were treated conservatively and followed for a mean of 26 and 41.2 months.8,26 Clinical improvement or stabilization of tolerable symptoms occurred in up to 68% in one of the series.8 One patient with an atypical constellation of symptoms had a laparoscopic procedure for endometriosis and was found to be negative. Two others patients with atypical symptoms sought and received surgical therapy at other facilities and had significant postoperative complications leading to non-resolution of symptoms in one and a nephrectomy, with resolution of symptoms in the other. At least 8 patients received non-steroidal pain medication and 2 others were treated with medroxyprogesterone with undocumented results. No decrease in renal function was documented in the patients who did not undergo an operation. Surgical Management In patients with long-standing and severe symptoms, open surgery is an option. Transposition of the SMA to an aortic site caudad to the crossing renal vein was performed in 3 patients in one series.7 Of these, one (33%) suffered from post-operative ileus and a retroperitoneal hematoma that required re-operation, which was successful. The symptoms of all three improved on followup (mean followup for that study was 24 months, range 6 months (mo.) to 6 years), though microscopic hematuria was still present in 2 patients who had preoperative gross hematuria. This approach should be weighed carefully in light of the risk of bowel infarction or ischemia, and most would shy away from involving an important intestinal arterial bed to relieve a venous obstruction of unclear significance in another organ system. Twenty patients underwent LRV transpositions to a site caudad on the IVC. Two of these were found intra-operatively to have organized thrombus in their renal veins. Both were treated with thrombectomy, and one received patch venoplasty in addition to LRV transposition. Both also received anticoagulation post-operatively. There were no reported intra-operative or peri-operative complications. Mean follow up for these patients from three studies were 24 months, 42.6, and 70 months.7,8,26 Three of 20 (15%) patients required re-intervention: one for chylous ascites that required ligation of lymphatics and both of the patients with thrombosed renal veins who re-thrombosed within 4 months of surgery. One required mechanical thrombolysis and stenting that stayed patent for 13 m with resolution of symptoms. The other was treated by re-implantation into the inferior vena cava. Of the 19 patients who had preoperative flank pain, 17 (89%) resolved or improved in follow up. Mild recurrent pain was reported in 3 patients; one was then treated for endometriosis with some benefit. Hematuria and proteinuria resolved in all patients in whom it was present pre-operatively. Two of three patients with preoperative varicoceles recurred post-procedure. Endovascular Options and Results Approximately 40 cases of stenting of the left renal vein have been reported in the literature, and most of these have been reviewed by Reed et al.26,38 The authors concluded that with technologic advancement, this technique would become the preferred treatment. The largest series of stents for NCS is 15 patients out of 20 in the single center series by Zhang et al,7 of which 14 patients did well over a follow up that ranged from 6 m to 6 years (mean 24 m) with documented stent patency, as well as relief of hematuria and symptoms. One stent embolized to the heart, requiring a thoracotomy to extract it. The patient was stented again with good results. With the exception of one Palmaz (Cordis, Johnson and Johnson, Miami Lakes, Florida) stent, others were self-expanding nitinol stents (Smart Control, Cordis) An earlier study by Hartung et al of 5 patients that were treated with stents provided more insight into the pitfalls of endovascular therapy for NCS.35 Based on their previous experience with treating May-Thurner syndrome, they felt that a retrievable, self-expanding metallic stent should be used. So, after initial angioplasty to 15 mm, they deployed Wallstents (Boston Scientific) of various sizes. They found that though initial technical success was 100%, recurrence of symptoms indicated the stent had migrated. The best results were with a longer stent (60 mm) that allowed enough length on either side of the SMA to stabilize across the stenosis during angioplasty. Though the authors had the most success with 16 mm diameter stents, they encourage individualization of both dimensions to suit the patient’s anatomy, with the cautionary note that some protrusion of the stent into the IVC is a desirable end point. Patients with renal vein stents do have to be on long-term anti-platelet medication. Conclusion NCS is both underdiagnosed, due to its rarity, lack of awareness, and the non-specific character of its symptoms, and over-diagnosed, due to the confusion between the radiologic finding and the clinical syndrome. Thus, a patient with chronic abdominal pain, left flank pain and hematuria has often seen several specialists, including obstetricians, nephrologists and vascular surgeons, and perhaps even been operated on unsuccessfully before the correct diagnosis is made. A patient with left sided varicocele, vulvar varices, or lower extremity varicose veins may have NCS as an undiagnosed etiology. Conversely, a surgeon may be asked to operate on an asymptomatic but concerned patient who has been told that they have the nutcracker phenomenon on abdominal imaging. In all of these, an appropriate clinical decision tailored to that individual patient should be made based on an understanding of the unique pathophysiology, anatomic variability, indications to intervene, and expected outcomes from various treatment options for NCS. This case report confirms that early symptomatic improvement after a renal vein angioplasty and stent correlates with resolution of the problematic venous collateral circulation. _____________________ From 1Emory University School of Medicine, Atlanta, Georgia and 2Loyola University Medical Center, Maywood, Illinois. Manuscript submitted June 4, 2009, provisional acceptance given August 12, 2009, accepted August 20, 2009. Correspondence: Ross Milner, MD, Loyola University Medical Center, Stritch School of Medicine, 2160 South First Avenue, EMS Building, Room 3215, Maywood, IL 60153. E-mail: firstname.lastname@example.org Disclosure: The authors report no conflict of interest regarding the content herein.