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Saudi Journal of Kidney Diseases and Transplantation
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CASE REPORT  
Year : 2020  |  Volume : 31  |  Issue : 5  |  Page : 1129-1133
Two Peculiarities of the Nutcracker Syndrome: Rare Association with Multiples Thrombosis and Successful Medical Treatment (Pentoxifylline)


Department of Nephrology, Military Hospital of Tunisia, Monfleury, Tunis, Tunisia

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Date of Web Publication21-Nov-2020
 

   Abstract 


The nutcracker syndrome (NCS) is a rare condition characterized by the entrapment of the left renal vein between the superior mesenteric artery and the aorta. Clinically, it presents with hematuria, flank pain, and symptoms of pelvic venous congestion. It is more frequent in females. Conservative treatment is usually proposed children but in adults, NCS has to be treated by surgical or endovascular methods. Drug therapy is not proposed for the treatment of NCS. We report a case of a young patient who presented with recurrent gross hematuria. Our patient was treated with pentoxifylline three times daily and anti-coagulation, with a favorable outcome.

How to cite this article:
Ariba YB, Achouch S, Omrani M, Ourteni I, Labidi J. Two Peculiarities of the Nutcracker Syndrome: Rare Association with Multiples Thrombosis and Successful Medical Treatment (Pentoxifylline). Saudi J Kidney Dis Transpl 2020;31:1129-33

How to cite this URL:
Ariba YB, Achouch S, Omrani M, Ourteni I, Labidi J. Two Peculiarities of the Nutcracker Syndrome: Rare Association with Multiples Thrombosis and Successful Medical Treatment (Pentoxifylline). Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2020 Dec 1];31:1129-33. Available from: https://www.sjkdt.org/text.asp?2020/31/5/1129/301182



   Introduction Top


The nutcracker syndrome (NCS) is a vascular compression disorder that refers to compression of the left renal vein (LRV) between the superior mesenteric artery (SMA) and the aorta.[1] The exact prevalence of NCS is unknown, but may be slightly higher in females. Usually, the management of this syndrome is based on surgical or endovascular treatment.

We present a rare association between NCS and several thrombosis which had a good outcome with medical treatment (Pentoxifylline).


   Case Report Top


Written informed consent was obtained from the patient for the publication of this case.

A 27-year-old woman was referred to our department for hematuria since seven months. There was no family history of end-stage kidney disease, stones, hearing abnormalities, bleeding disorders, or sickle cell disease. She complained of macroscopic hematuria, which had occurred intermittently for months and was exacerbated by physical exercise. Hematuria was not preceded by upper respiratory tract infections. The hematuria was not accompanied by left flank or abdominal pain. Our patient also complained of shortness of breath, tiredness, and palpitations. Her body mass index was 25 kg/m2, blood pressure was 124/68 mm Hg without orthostatic hypotension and the cardiac pulse was 93 beats/min. Cardiopulmonary auscultation was unremarkable. The conjunctiva showed pallor. There was no edema of the lower limbs. The urine test was positive for hematuria, urinary protein was 0.82 g/24 h, urine sediment showed 800 red blood cells (RBCs) per high power field and urine culture was negative. There were no RBC casts. Her hemoglobin was 6.5 g/dL requiring RBC transfusions. Serum ferritin was low (2 μg/L). Her serum creatinine was normal (42 μmol/L). Coagulation profile showed normal prothrombin time (87%), activated partial thromboplastin ratio (1), fibrin level (2.34 g/L), and platelet count of 273,000/mm3. Abdominal ultrasound showed normal kidney morphology without stones and computed urography was unremarkable. Nephrological causes for hematuria were excluded. Cystoscopy did not reveal any anomalies. Bladder biopsy did not reveal any cancer cells. Computed tomography angiography (CTA) of the abdomen demonstrated mesoaortic compression of the LRV [Figure 1], and the patient was diagnosed with anterior NCS. Furthermore, the CTA showed bilateral thrombosis of the pelvic and iliac veins, extending to the right primary iliac vein associated with pulmonary embolism. Cardiac ultrasound was unremarkable. Diagnostic studies were performed to investigate this presentation of idiopathic thrombosis, especially thrombophilia studies such as protein C, S and anti-thrombin deficiency and were normal. Electrophoresis of hemoglobin was normal. There was no antiphospholipid syndrome. Anti-nuclear antibodies were negative and complement levels (C3 and C4) were normal.
Figure 1: Abdominal computed tomography angiography showing mesoaortic compression of the left renal vein.

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Paroxysmal nocturnal hemoglobinuria was suspected in view of hematuria, anemia, and thrombosis, but there were no signs of hemolysis (reticulocytes, lactate dehydrogenase, biluribin, and haptoglobin levels were normal). Flow cytometric analysis did not identify GPI-AP deficiency in the peripheral blood cells.

The pressure gradient at the level of the LRV on either side of the mesoaortic angle was not significant (20 mm Hg). Hence, the surgical team did not indicate interventional treatment.

The patient was treated with intravenous iron therapy, pentoxifylline 1200 mg and for thrombosis she was treated with acenocoumarol. Macroscopic hematuria completely disappeared after nine weeks of medical treatment.

After six months, abdominal CTA was performed and showed the absence of thrombosis and the persistence of a discrete dilation of the LRV measuring 8.7 mm. Acenocoumarol was discontinued and our patient was maintained on pentoxifylline 1200 mg without recurrence of hematuria after 15 months of follow-up. At the time of reporting, our patient is clinically well and asymptomatic.


   Discussion Top


The NCS is a rare syndrome resulting from LRV impingement between the proximal SMA and abdominal aorta. Its prevalence is unknown.[2]

White and Comerota reported 99 consecutive CT angiograms for potential renal transplant donors and found that the overall prevalence of compression of the LRV by the SMA is approximately 27%.[3]

Grant, who found the anatomy analogous to a nut in a nutcracker, first described LRV compression in 1944 and the first veinographic description of NCS was reported in 1972 by Schepper.[3],[4] The predisposing factors include: nephroptosis, lumbar hyperlordosis, and reduced peri-renal fat.[5]

Several theories have been proposed concerning the underlying etiology for the anatomic predisposition for the development of NCS, typically implicating either the LRV or superior mesenteric anatomy. An acute caudal angulation of the central SMA can cause extrinsic compression on the LRV against the aorta. This morphologic confirmation is the most common version of NCS and is also termed anterior NCS. Posterior NCS can occur when the LRV courses behind the aorta and is compressed between the aorta and vertebral bodies.[3]

Other mechanisms described include abnormal branching or origin of the SMA from the aorta. Another reported mechanism is entrapment of the LRV by pre-aortic fibrous tissue.[6]

Published data, till recently, include case reports or small case series involving affected individuals ranging from children and adolescents to middle-aged and older people in their 70s. Most of the patients, however, are in their third or fourth decade, with a predilection for women.[6] In our case, this is a young women in the third decade.

Clinically, this condition can be silent. Hematuria is the most commonly reported finding. It results from hypertension in the LRV with formation of collateral thin-walled venous pathways, which cause small venous ruptures into the collecting system.[1],[2]

The hematuria is usually more intense during orthostasis and exercise.

Other possible symptoms include left-sided varicocele, left flank/abdominal pain, orthostatic proteinuria, pelvic congestion, and chronic fatigue.[3]

Pain is the next most common symptom. Pain is characterized by flank or lower abdominal pain and is exacerbated by sitting, standing, walking, or riding in a vibrating vehicle.[4]

Orthostatic proteinuria is also reported in NCS although the exact mechanism is not known; increased hemodynamic response and subclinical immune injury are the suspected mechanisms.[7]

Males can present with left-sided varicocele. In women, pelvic congestion syndrome may manifest as dysmenorrhea, dysuria, dyspareunia, and pelvic pain secondary to gonadal vein reflux. Associated ovarian vein reflux can result in superficial vulvar, gluteal, and extremity varicosities.[4]

Our patient presented with recurrent gross hematuria that is more intense during exercise and was associated with a low level of proteinuria without abdominal pain or gynecological manifestations.

Asymptomatic dilatation of LRV is not an infrequent finding on ultrasound or computed tomography. On the other hand, the NCS can exist even in nondilated veins; therefore, the diagnosis of this condition should be made only when compatible radiological findings are associated to clinical symptoms.[8]

Duplex ultrasound may be employed as the initial diagnostic test and should follow initial ultrasound investigation; it brings excellent diagnostic yield despite the disadvantage of radiation exposure. MRA is a radiation-free alternative to CT angiography in the diagnostic work-up of the NS.[8]

Venography with adjunctive pullback pressures is an important anatomical and physiologic patient evaluation. The LRV pressures are measured and the extrinsic compression of the LRV results in outflow obstruction, which leads to LRV hypertension, and a renocaval pressure gradient is recorded.

Normally, there is 1 mm Hg or less pressure gradient between the peripheral renal vein and inferior vena cave. A renocaval pullback pressure gradient of >2 mm Hg is highly suggestive of a significant renal vein stenosis. Retrograde venography with renocaval pressure gradient determination is accepted as the gold standard diagnostic study to confirm the diagnosis.[3]

The association between NCS and thrombosis is rarely reported in literature. Yoshida et al presented the first case of extensive DVT of the left lower extremity and the left limb of the duplicated vena cava associated with extrinsic compression of the LRV by SMA.[9]

The therapeutic decision in NCS patients is controversial. Expectation management is appropriate in the great majority of cases. Conservative treatment was described, especially in children. The degree and stage of NCS and the possibility of spontaneous reduction of LRV compression during childhood should be considered before surgical treatment. Spontaneous remission of persistent severe hematuria in an adolescent with NCS as the consequence of increase height was also observed. Furthermore, the development of visceral fat changes the anatomical relation between vascular structures and may increase compression of LRV.[10]

Interventions are warranted exclusively in patients presenting with severe and long-lasting symptoms (esp., in cases where hematuria causes anemia). The management has evolved from surgical correction of the anatomy, namely, transposition of the renal vein distally into the vena cava, to percutaneous endovascular stenting of the LRV.[11]

Typical open approaches, such as LRV transposition, mesoaortic transposition, nephropexy, renal decapsulation, and renal autotransplantation are effective but invasive. Less traumatic alternative interventions should be considered such as transluminal balloon angioplasty, gonadocaval bypass, laparoscopic LRV transposition, and endovascular stenting of the LRV.

The last one, despite its low invasiveness and potential to become a gold standard, may produce such complications as venous thrombosis, stent migration, stent protrusion into inferior vena cava, and in-stent re-stenosis. The outcomes of laparoscopic procedures reported in the literature are comparable with those of open procedures. However, surgery should be considered for gross hematuria (especially if recurrent) or for severe symptoms including anemia, left flank, or abdominal pain, impairment of renal function including persistent orthostatic proteinuria and varicocele formation, and for ineffective conservative measures after 24 months in patients aged less than 18 years and after six months in adults.[10]

In our case, a pressure gradient on either sides of the compressed part of the LRV was measured and not between the peripheral renal vain and the inferior vena cave. This pressure was judged not significant by our surgical team and surgical treatment was not indicated.

The peculiarity of our case was a complete remission after two months of using pentoxifylline with disappearance of hematuria, absence of pain and normalization of hemoglobin levels. Pentoxifylline is a hemostatic agent frequently used in the management of peripheral vascular and cerebrovascular disorders especially in the elderly patients.

The mechanism(s) of action of pentoxifylline have not been fully resolved. It causes smooth muscle to relax. Several rheological properties have been identified which decrease blood viscosity and help improve perfusion in the impaired microcirculation. Early studies demonstrated that pentoxifylline causes an increase in the filterability of erythrocytes and neutrophils, decreased plasma fibrinogen levels and reduced platelet aggregation, but more recent studies suggest that effects on leukocytes, especially granulocytes, may be more important. The activation of leukocytes is implicated in some pathophysiological mechanisms of occlusive peripheral vascular disease. Pentoxifylline decreases neutrophil adhesive-ness to endothelial cells, enhances chemotaxis, inhibits tissue necrosis factor and blocks the activity of inflammatory cytokines, which regulate the degree of activity of vascular wall cells.[12]

To the best of our knowledge, this is the first case of successful use of pentoxifylline in symptomatic NCS. Although NCS is not a common diagnosis, it should be taken into consideration, particularly in hematuria of unknown origin. Ultrasonic Doppler flow scanning is a reliable initial diagnostic tool for these patients. Gain of weight has a positive influence on the symptoms, and expectation management is advised in the large majority of cases. Medical treatment with pentoxifylline can be proposed in cases of NCS with hematuria before interventional therapy.

Conflict of interest: None declared.



 
   References Top

1.
Copetti R, Copetti E. Renal nutcracker syndrome. Acta Medica Acad 2017;46:63-4.  Back to cited text no. 1
    
2.
Muddana N, Pai R, Nahum E, Sureshkumar KK. Quiz page october 2014: Unexplained hematuria in a thin, middle-aged man. Am J Kidney Dis 2014;64:A21-4.  Back to cited text no. 2
    
3.
White JM, Comerota AJ. Venous Compression Syndromes. Vasc Endovascular Surg 2017;51: 155-68.  Back to cited text no. 3
    
4.
Pugnet G, Doumerc N, Neveu C, et al. Fatigue and abdominal pain in a 30-year-old woman. Rev Méd Interne 2013;34:577-80.  Back to cited text no. 4
    
5.
Polaina-Rusillo M, Liébana-Carpio L, Borrego-Hinojosa J, Liébana-Cañada A. Gross haematuria in patients with nutcracker syndrome. Nefrologia 2012;32:537-8.  Back to cited text no. 5
    
6.
Venkatachalam S, Bumpus K, Kapadia SR, Gray B, Lyden S, Shishehbor MH. The nutcracker syndrome. Ann Vasc Surg 2011; 25:1154-64.  Back to cited text no. 6
    
7.
Taktak A, Hakan Demirkan T, Acar B, et al. Clinico-radiological correlation of nutcracker syndrome: A single centre experience. Arch Argent Pediatr 2017;115:165-8.  Back to cited text no. 7
    
8.
Baldi S, Rabellino M, Zander T, González G, Maynar M. Endovascular treatment of the nutcracker syndrome: Report of two cases. Minim Invasive Ther Allied Technol 2011;20: 356-9.  Back to cited text no. 8
    
9.
Yoshida R de A, Yoshida WB, Costa RF, Nacif MS, Sobreira ML, Jaldin RG. Nutcracker syndrome and deep venous thrombosis in a patient with duplicated inferior vena cava. J Vasc Surg Venous Lymphat Disord 2016;4:231-5.  Back to cited text no. 9
    
10.
Orczyk K, Łabetowicz P, Lodzinski S, Stefanczyk L, Topol M, Polguj M. The nutcracker syndrome. Morphology and clinical aspects of the important vascular variations: A systematic study of 112 cases. Int Angiol J Int Union Angiol 2016;35:71-7.  Back to cited text no. 10
    
11.
Vianello FA, Mazzoni MB, Peeters GG, et al. Micro- and macroscopic hematuria caused by renal vein entrapment: Systematic review of the literature. Pediatr Nephrol 2016;31:175-84.  Back to cited text no. 11
    
12.
Frampton JE, Brogden RN. Pentoxifylline (oxpentifylline). A review of its therapeutic efficacy in the management of peripheral vascular and cerebrovascular disorders. Drugs Aging 1995;7:480-503.  Back to cited text no. 12
    

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Correspondence Address:
Yosra Ben Ariba
Department of Nephrology, Military Hospital of Tunisia, Monfleury, Tunis
Tunisia
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DOI: 10.4103/1319-2442.301182

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