Thrombosis Research 130 (2012) 501–505

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Thrombosis Research

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Regular Article

Thromboembolic complications in membranous nephropathy patients withnephrotic syndrome-a prospective study

Shi-Jun Li a, Jing-Zhou Guo a, Ke Zuo a, Jiong Zhang a, Yang Wu a, Chang-sheng Zhou b,Guang-ming Lu b, Zhi-hong Liu a,⁎a Research Institute of Nephrology, Jinling Hospital, Nanjing University of Medicine, Nanjing, 210002, Chinab Department of Medical Imaging, Jinling Hospital, Nanjing University of Medicine, Nanjing, 210002, China

⁎ Corresponding author at: Research Institute ofNanjing University School of Medicine, Nanjing, 21002,fax: +86 25 84801992.

E-mail address: zhihong–liu@hotmail.com (Z. Liu).

0049-3848/$ – see front matter © 2012 Elsevier Ltd. Alldoi:10.1016/j.thromres.2012.04.015

a b s t r a c t

a r t i c l e i n f o

Article history:

Received 3 February 2012Received in revised form 27 March 2012Accepted 22 April 2012Available online 26 May 2012

Keywords:membranous nephropathyrenal vein thrombosispulmonary embolismcomputed tomography angiography

Background: Venous thromboembolism (VTE) is one of the most serious complications in membranous ne-phropathy (MN). We investigate the incidence of VTE in MN patients with nephrotic syndrome (NS).Methods: A total of 100 MN patients with NS were enrolled into this prospective study. The diagnosis of VTEwas based on contrast-enhanced dual source computed tomography angiography.Results: Venous thromboembolism was demonstrated in 36 patients (36%). 33 patients (33%) had renal veinthrombosis (RVT), 17 patients (17%) had pulmonary embolism (PE). Flank pain was noted in 5 patients andgross hematuria in 2 patients with RVT. Dyspnea and chest pain were present in 9 patients with PE. Thepositive predictive value for D-dimer level was 69.4%, negative predictive value for D-dimer level was96.1% in patients with MN. Of all the risk factors presented, D-dimer level, proteinuria, the ratio of proteinuriato serum albumin were independent risk factors for the development of VTE (Pb0.05), but the plasma level

of antithrombin Ш was not correlated with VTE in this study. In follow up, venous thrombosis disappearedafter anticoagulant treatment with low-molecular-weight heparins in 28 patients.Conclusion: Venous thromboembolism was confirmed in 36% of MN patients with NS. Renal vein thrombosisand pulmonary embolism are common and usually asymptomatic. Computed tomography angiography canbe used effectively to examine suspected patients. Measurement of D-dimer is helpful in VTE diagnosis.It is important that clinicians are aware that VTE should be considered as a common complication in MNpatients with NS.

© 2012 Elsevier Ltd. All rights reserved.

Introduction

Venous thromboembolism (VTE) is a complication in nephroticsyndrome (NS) patients secondary to membranous nephropathy(MN), and the consequences are often severe. Venous thromboem-bolic complications include deep venous thrombosis (DVT), pulmo-nary embolism (PE) and, in particular, renal vein thrombosis (RVT)[1,2]. The incidences of VTE, ranging from 7.2% to 60% in patientswith MN, have been reported based on different case series [2–7].However, many patients with VTE are asymptomatic, resulting inVTE being overlooked by clinical evaluation; moreover, in some re-ports, RVT was diagnosed only after a thromboembolic event, thusRVT in MN might have been underestimated in these retrospectivestudies [7]. On the other hand, renal venography has its limitationdue to its invasiveness, and the resultant complication in diagnosisof RVT [1,6]. Therefore, the incidence of VTE needs to be further

Nephrology, Jinling Hospital,China. Tel.: +86 25 80860218;

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investigated in a large cohort of MN patients by non-invasivemethods. This single-center prospective study was undertaken in anattempt to evaluate the incidence of VTE by dual source spiralcomputer tomography (CT) angiography in NS patients secondary toMN in China. The risk factors of VTE in patients with MN are alsodiscussed.

Patients and Methods

Patients

This was a prospective observational study and the inclusion cri-teria for patients’ enrollment were as follows: (1) The histologic andimmunopathologic changes were consistent with those of MN; (2)24-h urine protein excretion was greater than 3.5 g, serum albuminlevel less than 30 g/l, and eGFR greater than 40 ml/min. The exclusioncriteria include: (1) systemic lupus erythematosus and antiphospho-lipid syndrome, hepatitis B, hepatitis C, and cancer associated withMN; (2) exposure to classic risk factors for venous thrombosis suchas major surgery, prolonged immobilization; (3) use of oral contra-ceptives or prophylactic anticoagulation . From June 2009 to October

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2010, 230 MN patients were initially screened at our hospital, and170 fit the inclusion criteria; 55 were further excluded, of whom, 34had hepatitis B infection, 2 had lung cancer, 6 used oral contracep-tives, and 13 patients had prophylactic anticoagulation treatment.Thus, a total of 115 patients were recruited into this study, but 15patients refused to receive CT angiography. The remaining 100patients completed the study. Informed consent including a detaileddescription of the CT angiography procedure (which was approvedby the institutional review board of Jinling Hospital) was obtainedfrom all patients before CT angiography.

Data Collection

Baseline information at the time of CT angiography was collectedfrom all patients, including sex, age, duration of renal diseases, hyper-tension, ultrasonography of bilateral kidneys. A detailed medicalhistory was recorded to document any past or present history ofthrombo-embolic episodes in the form of flank pain, macroscopichematuria, hemoptysis, dyspnea and pleuritic pain.

Laboratory Measurements

Laboratory measurements consisted of routine urinalysis including24-h urine protein, plasma urea, serum creatinine, albumin, lipidsand blood sugar. Coagulation detection was composed of (1) plateletcount, (2) plasma fibrinogen, (3) prothrombin time (PT), (4) activatedpartial thromboplastin time (APTT), (5) antithrombin III level (radioim-munodiffusion assay; AT-III b25mg/dlwas defined asAT-III deficiency),(6) plasma D-dimer level (enzyme-linked immunoabsorbent assay[ELISA]; D-dimer>0.5 mg/dl was defined as positive).

CT Angiography

Computed tomography pulmonary angiography (CTPA) and CTvenography (CTV) was performed within 10 days after the renal bi-opsy procedure, with the exception of studies in 9 patients in whichrenal biopsy was performed elsewhere. In these 9 patients, therewas a maximal interval of 3 months between the biopsy procedureand the CT angiography. Computed tomography angiography wasperformed with a dual source spiral CT scanner (SIEMENS definition)with a collimation of 0.75 mm, a pitch of 0.5 mm, a scan time of 0.5 s,120 kV and ref 200 mAs. Non-ionic contrast medium ultravist 300(Iopromide concentration, 300 mgI/ml) was administered with anautomatic injector through antecubital vein. A total of 80~100 ml(1.5~2 ml/kg) of contrast were injected at a rate of 4 ml/sec. Time-attenuation curves over the right pulmonary artery were generatedfrom images. The patients were instructed to hold their breath duringthe detection. Pulmonary arteries, renal vein and inferior venacava were scanned following one injection. Initial images were thenreconstructed by InSpace software for 3D image postprocessing.Lower extremity compression venous ultrasonography was done inall patients.

Renal vein thrombosis was diagnosed once either complete orpartial filling defects within renal vein were present. PE was definedwhen either complete or partial filling defects within the main, lobar,subsegmented branches were identified. The images were reviewedindependently by two experience radiologists, and achieved a consen-sus diagnosis. Lower limb DVT was detected by compression venousultrasonography.

Treatment and Follow-up

Once thrombosis was confirmed, systemic anticoagulation therapywas initiated immediately. Low-molecular-weight heparin (LMWH)preparations havemore predictable pharmacokinetic and pharmacody-namic properties, and are associated with a lower risk of side effects.

LMWHs can be administered without coagulation monitoring inpatients without severe renal insufficiency (creatinine clearance,CrClb30 mL/min). Therefore, all patients found to have VTE weregiven LMWH for a month, followed by oral warfarin for a minimum ofsixmonths. The dose ofwarfarinwas adjusted based on the internation-al normalized ratio (INR) of 2~3. A second CT scan was performed onemonth later after anticoagulation therapy. Patients were reassessed pe-riodically for changes in renal function and degree of proteinuria andclinical evidence suggestive of thromboembolic events in follow-up.All patients were given corticosteroids and immunosuppressive regi-mens that were deemed to be adequate on the basis of current interna-tional consensus guidelines (cyclophosphamide, or tacrolimus withsteroids) [8]. Complete remission (CR) was defined as ≤0.3 g/dayproteinuria plus stable renal function, partial remission (PR) as a 50%reduction of initial proteinuria, and less than 3.5 g/day with stablerenal function.

Statistical Analysis

Statistical analyses were performed using the software SPSS ver-sion 13.0 (SPSS Inc. Chicago, IL, USA). Quantitative variables wereexpressed as the mean±SD or medians (ranges) for data with abnor-mal distribution, while categorical variables were expressed as thefrequency or percentage. Comparisons between two groups involvedStudent's t test, Mann–Whitney U test for data with abnormal distri-bution and the X2 test for categorical data. The potential risk factorsfor VTE in patients with MN were evaluated in the entire cohortwith the use of univariate logistic regression analysis. All variableswith a univariate level of significance of less than 0.1 were included ina backward, stepwise multivariate logistic regression model. P valuesless than 0.05 were regarded as significant.

Results

Findings on CT Angiography

Out of the100 patients (80 males and 20 females, age range:18~73 years) with MN, Venous thromboembolism was detected in36 patients (36%). Among them, 33 (33%) had RVT with 15 accompa-nied with PE; one had inferior vena cava thrombosis, one had lowerlimb DVT and PE, and the remaining one had PE alone.

Out of 33 patients with RVT, 9 had bilateral RVT(Fig. 1A), 18 hadleft RVT(Fig. 1B) , and 6 had right RVT. Renal venous thrombosis ex-tends beyond the renal vein to involve the inferior vena cava in 18 pa-tients, and extending to the iliac vein in 2 patients. Vena genitalisthrombosis was observed in 5 patients with left main RVT(Table 1).Pulmonary embolism was detectable in 17 (17%) patients, of whom9 had bilateral inferior pulmonary artery embolism (Fig. 1C), and8 had subsegmented PE (Fig. 1D).

In this study, dual source spiral CT provided adequate enhance-ment of pulmonary arteries, renal vein and inferior vena cava. Therewere no serious complications associated with the contrast medium.None of patients had 25% increases in serum creatinine concentra-tions in the week after the CT angiography.

Clinical Findings

The characteristic clinical symptoms of RVT were presented in 7(21.2%) patients, including gross hematuria in 2 patients (beforerenal biopsy) and flank pain in 5 patients. Acute renal injury wasfound in only 1 patient out of the 33 with RVT. Dyspnea and chestpain were present in 9 (52.9%) patients with PE, of whom 4 were ac-companied with hemoptysis and hypoxemia. None of these 9 patientspresented with shock or hypotension. Computed tomography pulmo-nary angiography showed bilateral inferior pulmonary artery embo-lism in these patients with clinical symptom (Fig. 1C). The remaining

C

A B

D

Fig. 1. Localization of RVT and PE in MN patient with NS. A: Curved reformatted image from CT venography shows bilateral renal vein thrombosis (RVT) extending into theinferior vena cava (arrow). B: Contrast-enhanced CT image shows left renal vein thrombosis (arrowhead). C: Coronal reformatted CT image showed bilateral inferior pulmonaryartery embolism (arrow). D: Contrast-enhanced CT image shows left lower pulmonary artery branch embolism (arrow).

Table 2Laboratory findings of MN patients with or without thrombosis.

Thrombus group(n=36)

No Thrombus group(n=64)

Age. (yr) 35.1±15.0 40.8±18.1

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8 patients of PE had no clinical signs of PE, but regardless of the pulmo-nary artery branch embolism as revealed by CTPA (Fig. 1D).

The clinical characteristics of patients with and without veinthrombosis at the time when CT angiography performed are shownin Table 2. Patients with thrombosis appeared younger than thosewithout thrombosis, but there was no significant difference. Thetime between NS onset and when thrombosis was identified byscreening CT angiography was within 3 months in 18 patients. The24-h urine protein in patients with thromboembolic complicationswas higher than that in those without thrombosis. No significantdifferences were found in the serumalbumin, serum creatinine, choles-terol, triglycerides, and hematuria between patients with and without

Table 1Localization of vein thrombosis and symptomatic patients with MN.

Thrombus Location n (%) Symptomatic event (%)

Renal vein 33 (33%) 7 (21.2%)Bilateral renal vein 9 (9%)Left renal vein 18 (18%)Right renal vein 6(6%)Inferior vena cava 19(19%)Vena genitalis 5(5%)Iliac vein 2(2%)Popliteal vein 2(2%)Pulmonary embolism 17(17%) 9 (52.9%)

thrombosis. The renal size was bigger in RVT patients but there wasno significant difference. Renal pathological examination showed noobvious differences between patients with and without RVT.

Course of disease (month) 3.5(0.3, 30) 4(0.2, 36)Left kidney (mm) 115.5±10.9 112±9.1Right kidney (mm) 111.7±9.1 109.8±7.4Proteinuria (g/d) 7.98±3.93 6.39±2.52*Serum albumin(g/l) 22.6±3.1 23.7±2.8Serum Creatinine (umol/l) 77.8 (27.4, 212) 75.1 (42.4, 118)Total cholesterol (mmol/l) 10.1±2.5 9.2±2.8Total triglyceride (mmol/l) 3.0 (1.3, 12.4) 2.6 (0.7, 11.5)Hematuria n (%) 17(47.2%) 36 (56.3%)NAG (u/g.cr) 51.2±43.21 59.6±37.5RBP (mg/l) 0.8 (0.1, 39.5) 0.9 (0.1, 48.5)Follow-up month 11.2±3.89(n=33) 10.5±3.92(n=57)Complete Remission(n) 5 12Partial Remission(n) 9 20No Response(n) 19 25

NAG: N-acetyl-pD glucosaminidase enzyme. RBP: retinol-binding protein* Pb0.05

Table 3Findings in coagulation test in MN patients.

Thrombus group(n=36)

No Thrombus group(n=64)

Hb (g/l) 123±19.7 128±21.0Blood platelet count (109/l) 194±75.6 251±90.8*PT (s) 10.4 (9.4,15.8) 10.4 (8.5,13.1)APTT (s) 25.4±7.0 25.8±5.2Fibrinogen level (mg/l) 406±103 441±75.5D-dimer positive n (%) 34 (94.4%) 15 (23.4%)#

ATIII deficiency n(%)(b25 mg/dl) 22(61.1%) 35(54.7%)

* Pb0.05 , # Pb0.01

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Coagulation Findings

Plasma D-dimer positive was present in 34 out of 36 patients withthrombosis; but negative in 2 patients with RVT. D-dimer levelwas positive in 15 patients without thrombosis. The positive rate ofD-dimer was significantly higher in patients with thrombus thanthat in those without thrombus (Pb0.01). The positive predictivevalue (PPV) for D-dimer level was 69.4%; negative predictive value(NPV) for D-dimer level was 96.1% in patients with MN. The bloodplatelet count was significantly lowered in patients with thrombosis(Table 3). Decreased antithrombin III level was noted in 61.1% ofpatients with thrombosis and 54.7% of patients without thrombosis.However, there was no difference between patients with and withoutthrombosis. PT and APTT remained unchanged in all patients.

Analysis of Risk Factors

D-dimer, 24 h-proteinuria, the ratio of proteinuria to serum albu-min and blood platelet count were independent risk factors for thedevelopment of VTE in patients with MN (Pb0.05, Table 4). Table 4indicates the odds ratios and 95% confidence interval of variable riskfactors for the development of VTE. Other risk factors, such as age, he-moglobin, serum albumin, cholesterol, fibrinogen level, AT III level didnot reach statistical significance as independent risk factors for VTE inpatients with MN .

Follow Up

During the follow-up, none of patients died; RVT and PE were ab-sent or almost resolved in 24 patients, partially resolved in 4 patientsby CT angiography after one month anticoagulation therapy. Six pa-tients refused to receive a second CT scan, two patients presentedwith new thromboembolic events within 1 month after discontinuinganticoagulation therapy. Ninety patients were followed-up for an av-erage of 11 months after the CT angiography, 10 patients (3 withthrombosis, 7 without thrombosis) were lost before 6 months. Therewas no different in immunosuppressive regimens between patientswith or without thrombosis during the period of observation. In pa-tients with thrombosis, 14 reached CR or PR in follow-up; 16 experi-enced no response in proteinuria; 3 experienced doubling ofbaseline creatinine and over 1.24 mg/dl. Of patients without renalvein thrombosis, 32 reached CR or PR in follow-up; 24 experiencedno response in proteinuria and 1 experienced doubling of baseline

Table 4Risk factors for predicting the development of VTE.

Risk factors Thrombus group (n=36) No Thromb

D-dimer (mg/dl) 2.23±2.12 0.46±0.70Proteinuria (g/d) 7.98±3.93 6.39±2.52Pro vs alb* 0.36±0.19 0.28±0.12Blood platelet count (109/l) 194±75.6 251±90.8

*pro vs alb: The ratio of proteinuria to serum albumin; C.I., confidence interval.

creatinine. The remission rate in patients with thrombosis was lowerthan that in those without thrombosis, but no significant differenceswere found.

Discussion

In the present study, we demonstrated that the incidence of VTEby CT angiography was 36%, and that of RVT was 33% in MN patientswith NS. Up to now, this is the first report on VTE incidence in largecohort of patients with MN by CT angiography. Renal venographywas a standard diagnostic test for RVT in previous study [3–6]. How-ever, renal venography is invasive, and has complications includingPE, inferior vena cava perforation and contrast-induced acute renalfailure [6]. Consequently, renal venography is not widely used inscreening for RVT at present; CT venography can offer a direct non-invasive tool for the visualization of the inferior vena cava and renalvein to detect the thrombus in these vessels. The sensitivity and spec-ificity of CTV for the diagnosis of covert RVT is 90 and 100%, respec-tively, using renal venous angiography as the gold standard [9–11].Coche et al. [12] indicated thin collimation multi-detector row CThad greater diagnostic accuracy and significantly higher rates of con-clusive results than V-P scintigraphy. This study demonstrated that CTcan be used to effectively examine patients with suspected RVT andPE in MN patients with NS. There were no complications associatedwith the CT angiography such as contrast-induced nephropathy dur-ing the study.

The clinical manifestations of RVT depend on the degree and loca-tion of venous occlusion. The classical clinical features such as flankpain, gross hematuria, and azotaemia are presented only in whomthe venous occlusion is abrupt and complete. In the report of Llachet al., only 4 out of 33 patients presented with acute flank pain,gross hematuria, and acute deterioration of renal function [3]. Inthis study, only few patients had acute RVT. Therefore, the absenceof such typical symptoms could not exclude the occurrence of chronicRVT in patients with MN. PE is a rare but potentially life threateningcomplication of NS. The incidence of PE in MN patients remainsunclear, because lung scanning or pulmonary angiography is doneonly in symptomatic patients with clinically suspected PE, and thusthere is potential to underestimate the incidence of PE. Llach et al.[3] reported that the incidence of PE was 12.8% of patients undergoingventilation/perfusion lung scanning, and PE was diagnosed in 32% ofpatients in other retrospective study [13]. Pulmonary angiographywas confirmed in 17 (17%) of patients, and most of them were origi-nated from RVT or inferior vena cava thrombosis in this study. It isnoteworthy that half of PE patients had no clinical symptoms. There-fore, the clinicians should be aware that PE is a common complicationin MN patients with RVT, and CTPA is recommended for patients sus-pected with PE.

D-dimer is a degradation product of cross-linked fibrin. D-dimerlevels are elevated in plasma in the presence of an acute clot becauseof simultaneous activation of coagulation and fibrinolysis. Hence, a nor-mal D-dimer level renders PE unlikely [14]. The negative predictivevalue (NPV) of D-dimer is high, and the positive predictive value(PPV) of D-dimer is low in patients with MN. Therefore, D-dimershould be routinely measured in MN patients, a negative D-dimerresult may exclude RVT and PE in most of MN patients with NS,

us group (n=64) Odd ratios 95.0% C.I. P value

7.79 3.01-20.2 b0.00011.18 1.02-1.35 0.0245.8 2.31-908 0.010.90 0.85-0.97 0.003

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and routine CT angiography assessment is not considered an essentialpart of the evaluation in MN patients with D-dimer negative.

The underlying mechanism by which MN leads to VTE is poorlyunderstood. It has been shown increased platelets, elevated bloodlevels of factors V, VIII and X, and increased production of fibrinogenin the liver under the conditions of proteinuria or hypoalbuminemiahave been considered to be involved in the occurrence of hypercoa-gulable state in patients with NS [1]. Kato et al. [15] found that, ascompared to patients without proteinuria, patients with proteinuriahad a 3.4-fold increase of risk for VTE. Numerous clinical studieshave demonstrated an association between hypoalbuminemia andVTE. A study revealed that serum albumin b25 g/l was a significantrisk factor of the occurrence of VTE [16]; recent study has also dem-onstrated that hypoalbuminemia b28 g/l was the most significant in-dependent predictor of venous thrombotic risk [7]. Mahmoodi et al.[17] followed 298 consecutive patients with NS for 10 years, andresults showed that proteinuria and serum albumin levels tended tobe related to VTE, but only the predictive value of the ratio of protein-uria to serum albumin was statistically significant. In present study,the proteinuria and the ratio of proteinuria to serum albumin wereindependent risk factor for the development of VTE events in patientswith MN. Antithrombin III deficiency has been suggested as a possiblecause of thromboembolic complications [18–20], but our resultsrevealed that Antithrombin III deficiency was not related to VTEevents. Interestingly, the blood platelet count in patients withthrombus was lower than those in patients without thrombus,which may be attributed to the platelet activation and aggregationin the formation of thrombosis. Taken together, the pathogenesis ofVTE in patients with MN may be multifactor. Further studies arerequired to elucidate the role of these factors in the increase of riskfor VTE in MN patients with NS.

This study has important clinical implications in MN patients withNS. First, to the best of our knowledge, this was the largest prospectivestudy on the incidence of VTE in patients with MN. Second, this studyis noteworthy because theywere based on no-invasive CTV in RVT diag-nosis. Third, the D-dimer was confirmed as a useful marker to predictthe VTE in NS patients. However, there were still some limitations inour study. Venous thromboembolism might be underestimated in thiscross-sectional study, since patients who initially were found to haveno thrombosis may subsequently develop VTE. Additionally, the DVTin lower limbmight be underestimated comparedwith other studies [1].

In conclusion, VTE was confirmed in 36% of MN patients with NS.Renal vein thrombosis and pulmonary embolism are common andusually asymptomatic. Computed tomography angiography can beused effectively to examine patients with clinical suspected RVTand PE. The present study further demonstrates that measurementof D-dimer is helpful in VTE diagnosis. It is important that cliniciansare aware that VTE should be considered as a common complicationin MN patients with NS.

Conflict of Interest Statement

None.

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