Nutcracker Syndrome


Introduction

Left renal vein entrapment syndrome, or nutcracker syndrome (NCS), is characterized by extrinsic compression of the left renal vein (LRV) most commonly between the aorta (Ao) and superior mesenteric artery (SMA),[1] although anatomic differences exist.[2] This entrapment syndrome restricts flow through the left renal vein,[1] resulting in venous congestion and a host of symptoms.[3] Nutcracker syndrome describes patients with characteristic symptoms associated with nutcracker anatomical morphology, whereas the nutcracker phenomenon describes the aortomesenteric compression of the LRV while asymptomatic.[1]

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, subcardinal veins, and supracardinal 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 part, or posterior regression failure, can lead to a retroaortic 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] 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 to be a rare condition, although the exact prevalence is unknown. Cases, including ages from infancy to the seventh decade, have been reported.[8][9] 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][9] 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.[9] Studies show an earlier diagnosis in males (23.59+/-13.09) than females (29.34+/-13.93).[10]

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 retroaortic 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][11] Collateralization of venous circulation involves mainly the left gonadal vein and the communicating lumbar vein.[2][12] 

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.[10] 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][13] 

Symptoms of autonomic dysfunction may occur, although rare, including hypotension, syncope, and tachycardia.[1][14] Cases of nausea and weight loss, unexplained pelvic pain, and left flank pain with postprandial exacerbation have been described.[14][13][14][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).[9] Venography with measurement of renocaval pressure gradient is the gold-standard, although invasive and usually unnecessary for diagnosis.[8] 

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.[8] It should be noted that renocaval pressure gradients ≥ 3 mmHg can be observed in healthy individuals.[9] Additionally, reduced renocaval pressure gradients < 3 mmHg can be seen in patients with NCS and collateralization.[9] Narrowing of the LRV, collateralization, gonadal vein distention, or pelvic congestion may be demonstrated by imaging.[9][13] 

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.[9][15] IVUS has been shown to have a specificity of 90% compared to 62% with venography.[9] DUS has a sensitivity of 69 to 90% and specificity of 89 to 100% and is most commonly used.[8][11] 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.[8] Urinalysis may reveal orthostatic proteinuria or hematuria that is most often microscopic.[13] Anemia may be observed in patients with prolonged and or significant hematuria.[9][11]

Differential Diagnosis

Entrapment of the LRV can be caused by retroperitoneal tumors, retroperitoneal lymphadenopathy, or pancreatic neoplasm.[21] 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.[27][28][27][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.[13]

Prognosis

The natural history of NCS is not entirely clear.[9] It can resolve spontaneously, particularly in children, but may lead to LRV thrombosis and renal injury if left untreated.[9] Gross hematuria can occur, leading to anemia and proteinuria requiring blood transfusion and resulting complications.[9][29] Many young patients outgrow their symptoms after a benign clinical course.[11] Some cases present dramatically and are effectively managed, whereas others have a delayed diagnosis and uncertain treatment.[11]

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.[8][11] 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.[11] 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.[22] 

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.[30] 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.[25][24][31][32]

Deterrence and Patient Education

Patients should be educated on the complications, particularly renal injury if left untreated. The risk of infertility in those with pelvic congestion syndrome or varicocele should be discussed. Screening is not necessary for family members, as NCS is not a genetic condition.[1]

Enhancing Healthcare Team Outcomes

A primary care clinician or emergency medical clinician may sometimes be the first to encounter a patient presenting with symptoms of NCS. Considering the differential diagnoses, complications, and different treatment strategies, it is crucial to consult promptly with an interprofessional team of specialists to improve outcomes. This may include an adult or pediatric urologist, nephrologist, obstetrician, gynecologist, interventional cardiologist, interventional radiologist, vascular surgeon, general surgeon, or transplant surgeon. Radiologists are essential to interpreting imaging modalities, including CT or MRI, to determine the cause. Sonographers play an essential role in obtaining doppler ultrasonography images. Nurses serve as vital team members in caring for, monitoring, and educating the patients before and after treatment.

Catheterization laboratory or operating room teams are critical in ensuring safe and effective endovascular or open surgery interventions. Pharmacists are necessary to conservative management involving angiotensin-converting enzyme inhibitors and to post-intervention anticoagulation, antiplatelet therapy, and analgesics when indicated. This collaboration is especially important, as Carroll and Moll note that the potential benefit of keeping venous stents patent with antiplatelets is unknown, and guidelines related to venous stents are currently lacking because of insufficient evidence, rendering the need for clinical trials.[26] 

In recent years, de Macedo et al. and Velasquez et al. have performed systematic reviews and produced treatment approaches. (Level 1)[8][19] Further studies, including large multi-center RCTs and meta-analyses, are still needed to truly elucidate the long-term safety and efficacy of the various treatment modalities discussed and direct the development of management guidelines.


Article Details

Article Author

Dana Penfold

Article Editor:

Saran Lotfollahzadeh

Updated:

12/1/2020 9:51:14 AM

PubMed Link:

Nutcracker Syndrome

References

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