Nutcracker Syndrome

Etiology

NCS results from compression of the LRV, associated with embryological LRV development from the aortic collar at 6-8 weeks gestation.[2] Development of the renal veins in utero is critically dependent on the aortic collar, anastomosis of the posterior cardinal veins, sub cardinal veins, and supra cardinal veins.[4] The LRV is a derivative of the anterior anastomosis, as the posterior portion normally degenerates. Abnormal degeneration of the anterior instead of the posterior segment, or posterior regression failure, can lead to a retro aortic LRV or circumaortic LRV, respectively.[4] 

The inferior vena cava (IVC) derives from this anastomosis of fetal veins, forming the final infrarenal, renal, suprarenal, and hepatic segments of the IVC at 8 weeks gestation.[4][5] Extremely rare cases involving abnormal IVC development causing a similar clinical picture have also been described.[5][6][7] The SMA, along with the inferior mesenteric artery and celiac trunk, normally derives from the midline fusion of the 10th, 13th, and 21st pair of the ventral segmental arteries, branches of the paired dorsal aortae.[4] Abnormal angulation of the SMA from the aorta is thought to contribute to the condition.[2][4]

Epidemiology

NCS is considered a rare condition, although the exact prevalence is unknown, and the incidence rates are reported to vary among different age groups[8]. Cases, including ages from infancy to the seventh decade, have been reported.[9][10] It has been described as occurring more frequently in females in the third to fourth decade, although a later study demonstrated equal prevalence between males and females.[2][10] Prevalence peaks in middle-aged adults and the second to third decade, likely due to the rapid development of the vertebral bodies during puberty, causing angle narrowing between the Ao and SMA.[10] Studies show an earlier diagnosis in males (23.59+/-13.09) than females (29.34+/-13.93).[11]

Pathophysiology

Anterior NCS is the most common type, in which the LRV is compressed between the Ao and SMA. Rarely, posterior NCS occurs and is most commonly a variant involving a retro aortic or circumaortic LRV compressed between the Ao and spinal column.[1][4] Other described variants include LRV duplication, LRV compression between the SMA and right renal artery, LRV compression by dilated left IVC, and right-sided NCS.[4] The venous compression results in outflow obstruction that causes LRV hypertension, which is the underlying mechanism of collateralization and varices.[1][12] Collateralization of venous circulation involves mainly the left gonadal vein and the communicating lumbar vein.[2][13] 

Moreover, co-occurrence of venous compression syndromes in the paralumbar area and resultant hypertensive venous collaterals might describe the association of two underdiagnosed entities of NCS and May - Thurner (MTS).

Hematuria occurs when the elevated blood pressure in the collaterals and subsequent venous sinuses near the renal calyces ruptures the thin-walled septum between the small veins and the renal collecting system.[1][4] A lack of renal symptoms may occur in patients with a well-developed collateral circulation that decreases LRV hypertension.[4] Venous congestion proximal to the LRV compression involving the left gonadal vein may cause pelvic congestion syndrome or varicocele.

History and Physical

A study of 112 cases reported a frequency of symptoms including 78.57% for hematuria, 38.39% for left flank pain, 35.71% for varicocele in males, 30.36% for proteinuria, and 13.39% for anemia.[11] Patients may also present with abdominal pain, dyspareunia, dysmenorrhea, orthostatic hypotension, fatigue, infertility, varicose veins of the abdomen, vaginal wall, buttocks, or upper thighs.[1][3][1][14] 

Symptoms of autonomic dysfunction may occur, although rare, including hypotension, syncope, and tachycardia.[1][15] Cases of nausea and weight loss, unexplained pelvic pain, and left flank pain with postprandial exacerbation have been described.[15][14][15][3] Physical examination may reveal a left testicular varicocele, vulvar and pelvic varices, or enlarged and tortuous lower extremity varicose veins.

Evaluation

A diagnosis of exclusion of other causes is employed and confirmed with imaging. A stepwise approach includes history and physical examination, doppler ultrasonography (DUS), computed tomography angiography (CTA), magnetic resonance imaging (MRI), venography, and intravascular ultrasound (IVUS).[10] Venography with measurement of renocaval pressure gradient is the gold-standard, although invasive and usually unnecessary for diagnosis.[9] 

Diagnostic imaging criteria include: a renocaval pullback gradient ≥ 3 mmHg, a maximum flow velocity five times increased in the LRV passing the SMA compared to the renal hilum, or an angle less than 45º between the Ao and SMA on CTA or MRA.[9] It should be noted that renocaval pressure gradients ≥ 3 mmHg can be observed in healthy individuals.[10] Additionally, reduced renocaval pressure gradients < 3 mmHg can be seen in patients with NCS and collateralization.[10] Narrowing of the LRV, collateralization, gonadal vein distention, or pelvic congestion may be demonstrated by imaging.[10][14] 

CT has been recommended more recently because of its accuracy and ability to investigate abdominal findings. Of the CT parameters, the most accurate is the "beak sign" and LRV diameter ratio (hilar-aortomesenteric) of ≥4.9.[10][16] IVUS has been shown to have a specificity of 90% compared to 62% with venography.[10] DUS has a sensitivity of 69 to 90% and specificity of 89 to 100% and is most commonly used.[9][12] The decision to use DUS or CT should be based on consideration of individual characteristics, including urgency, radiation exposure, cost and accessibility, contrast allergy, and other abdominal diagnostic possibilities.[9] Urinalysis may reveal orthostatic proteinuria or hematuria that is most often microscopic.[14] Anemia may be observed in patients with prolonged and or significant hematuria.[10][12]

Treatment / Management

There is currently a lack of established treatment guidelines because of limited data. Management is controversial, ranging from conservative treatment to nephrectomy, and depends on symptom severity with interventions typically reserved for those who are symptomatic.[9] De Macedo et al. proposed a treatment algorithm in which conservative treatment is recommended first for patients with mild symptoms and discrete hematuria for 6 months for adults and 24 months for patients under the age of 18 years.[9] 

Prolonged conservative treatment in the pediatric population is highly recommended due to the possibility of spontaneous resolution following adipose tissue development, and multiple venous collateralizations. Medical treatments, including low dose aspirin and angiotensin-converting enzyme inhibitors, specifically, alacepril, have been assumed to improve orthostatic proteinuria.[10][12][17] Elastic compression stockings can alleviate pelvic or flank pain.[18][19] Thin patients may benefit from weight gain.[18] (B3)

Endovascular treatment or open surgery is indicated if symptoms persist following conservative treatment, or for those with significant hematuria, severe pain, or renal dysfunction.[9][19] If unsuccessful, open surgery is indicated. If stent complications arise following endovascular treatment, proceed with endovascular repair or repair with open surgery. The point at which treatment or repair is successful and symptoms resolve, regular follow-up should take place.[9]

A review of literature from October 1982 to July 2017 reported 47% of articles described the open surgical approach (most commonly LRV transposition followed by renal autotransplantation), 41.1% described endovascular stenting (EVS), and 11.7% described the minimally invasive extravascular stenting.[20] Although LRV transposition has been the mainstay of treatment formerly, EVS has appeared more recently as a less invasive option, although with insufficient evidence to support it previously.[21] More data is accumulating, which demonstrates the success of EVS, and it is increasingly becoming the preferred approach in centers with both EVS and open surgery experience.[10] Neste first described the use of balloon dilation and endovascular stent placement as a treatment for NCS in 1996.[22] (A1)

Endovascular stenting has been extrapolated from stenting experience that demonstrated good results in the treatment of other venous compression syndromes, including May-Thurner syndrome, and superior vena cava syndrome.[12][23] Balloon expansion can then be used if LRV stenosis remains after stent placement, as recommended by Chen et al., and otherwise avoiding balloon angioplasty.[24] A 2019 retrospective chart review of 18 patients with NCS who underwent LRV stenting (self-expanding stents with a mean diameter of 12.8 +/- 1.6 mm) showed promising results, including 72.2% reported resolved or improved symptoms at an average follow-up of 41.4 +/- 26.6 months.(B2)

No perioperative complications occurred. Three out of five patients whose symptoms remained had previously undergone LRV transposition. Stent restenosis or symptom recurrence required stent reintervention in three patients at 5.8 months, 16.8 months, and 51.7 months. No stent migration occurred.[21] Endovascular stenting with stent-assisted coil embolization and complete aneurysm resection have been employed in rare cases of left renal vein aneurysm in the setting of NCS.[25][26](B3)

Anticoagulation and antiplatelet therapy are recommended during stent endothelialization and include a regimen of 3 days on low molecular weight heparin, 30 days on clopidogrel, and 3 months on aspirin.[9][24] Although, it is unknown whether antiplatelet therapy is beneficial in keeping venous stents patent, as guidelines are very limited because of inadequate studies of venous stents in clinical trials.[27](B2)

Differential Diagnosis

Entrapment of the LRV can be caused by retroperitoneal tumors, retroperitoneal lymphadenopathy, or pancreatic neoplasm.[22] Further considerations include NCS caused by aortic dissection, coinciding with duodenal obstruction caused by SMA syndrome, or associated with Henoch-Schönlein purpura, IgA nephropathy, membranous nephropathy, and idiopathic hypercalciuria with nephrolithiasis.[28][29][28][1] A patient presenting with flank pain and hematuria should raise suspicion for nephrolithiasis, pyelonephritis, or renal cell carcinoma. A condition involving the thoracolumbar spine or lower ribs may be considered in cases of atypical left flank pain, especially if exacerbated by standing and increased lumbar lordosis.[14]

Prognosis

The natural history of NCS is not entirely clear.[10] It can resolve spontaneously, particularly in children, but may lead to LRV thrombosis and renal injury if left untreated.[10] Gross hematuria can occur, leading to anemia and proteinuria requiring blood transfusion and resulting complications.[10][30] Many young patients outgrow their symptoms after a benign clinical course.[12] Some cases present dramatically and are effectively managed, whereas others have a delayed diagnosis and uncertain treatment.[12]

Complications

Insufficient venous outflow from the left gonadal vein (LGV) can cause dilatation of the LGV walls and rupture, varicocele in men, and pelvic congestion syndrome in women.[9][12] Endovascular embolization may relieve symptoms, although coil displacement into the lung can occur rarely. Moreover, a few other complications, including massive hematuria with unknown reasons, and significant orthostatic proteinuria, were reported.[12] Infertility can result from varicocele or pelvic congestion syndrome. A 2005 review of 5 cases of endovascular stenting reported 1 case of stent migration with uneventful follow-up (mean, 14.3 months) and 2 cases of stent-dislodgement (40-mm-long stents) causing secondary recurrence of symptoms. 

Hypertensive venous collateral in the paralumbar territory might cause the uncommon association of NCS and MTS. Correction of one might aggravate unopposed hypertension, and worsen the symptom.[23] 

A 2016 retrospective evaluation of 75 patients who underwent endovascular stenting at a single center reported stent migration occurred in 5 patients (6.7%) during a mean 55 months of follow-up. The stent migrated into the left side of the LRV in one patient, IVC in two patients, right atrium in one patient, and right ventricle in one patient. They concluded that preoperative LRV measurements, stent choice, stent deployment, close follow-up, and early detection and treatment are needed to reduce the number of stent migrations, particularly into the heart.[31] Two cases of saccular aneurysm of the LRV occurring in the setting of NCS have been described, which can lead to rupture or thrombus formation and embolization to the venous circulation and pulmonary vasculature.[26][25][32][33]