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Joint Bone Spine 79 (2012) 274–280

riginal article

ubclinical renal involvement in essential cryoglobulinemic vasculitis and classicolyarteritis nodosa

amer A. Gheitaa,∗, Nermeen A. Khairya, Mohamed M. Nasrallahb, Hani Husseinc

Rheumatology department, Faculty of medicine, Cairo University, Cairo, EgyptInternal medicine department, Nephrology unit, Faculty of medicine, Cairo University, Cairo, EgyptChemical pathology department, faculty of medicine, Cairo University, Cairo, Egypt

r t i c l e i n f o

rticle history:ccepted 23 June 2011vailable online 15 September 2011

eywords:enalonANCAANryoglobulinemiaasculitis

a b s t r a c t

Objective: Renal vasculitis is usually associated with anti-neutrophil cytoplasmic antibodies (ANCAs).However, non-ANCA patients constitute a rarely studied variant of renal vasculitis. The aim of the presentstudy was to demonstrate the features of renal involvement in patients with primary systemic non-ANCA associated vasculitis (NAAV) and compare essential cryoglobulinemic vasculitis (ECV) with classicpolyarteritis nodosa (PAN).Methods: The study included 30 patients with primary systemic non-ANCA associated vasculitis (NAAV).Fifteen with ECV and another 15 patients with classic PAN. The patients were recruited from theRheumatology and Internal medicine departments and outpatient clinics of Cairo University Hospi-tals. The patients had no or mild renal involvement at entry and the ANCA was negative as tested byimmunoflourescence and ELISA. Renal biopsy was performed for all the patients and histopathologicallystudied.Results: Renal biopsy abnormalities were seen in six females. One patient with PAN showed renal vasculi-tis and membranoproliferative glomerulonephritis (MPGN) and was HBV and ANA positive. The patient

had negative HCV and cryoglobulins. Five patients with ECV-associated HCV had findings; one had chronicinterstitial nephritis and was HBV positive. The other four were HBV negative with MPGN in two, focalproliferative and crescentic GN in one patient each.Conclusions: Increased understanding of the manifestations of systemic vasculitis is likely to provide thebasis for the use of more selective immunomodulatory therapies in the future. It is our hope that thisstudy will raise awareness of the non ANCA-associated vasculitic renal involvement.

ncais

© 2011 Société fra

. Introduction

The diagnosis of systemic vasculitides is challenging as the clin-cal and pathologic features are protean and overlapping. However,recise diagnostic categorization is essential for appropriate treat-ent. [1]. Systemic necrotizing vasculitis may be idiopathic or

ssociated with a variety of diseases of known etiology such asolyarteritis nodosa (PAN) [2]. In most cases, Antineutrophil cyto-lasmic antibodies (ANCA) should be an exclusion criterion for PAN3] and with more accurate criteria, there might be a low frequencyf GN and ANCA rather than a total absence [4]. Progressive renalnsufficiency can occur during the acute course of PAN due to renal

ascular involvement without GN [5].

The association between mixed cryoglobulinemia (MC) andepatitis C virus (HCV) infection has been described and the asso-

∗ Corresponding author. Tel.: +2 01 04 56 79 75; fax: +2 25 08 53 72.E-mail address: gheitamer@hotmail.com (T.A. Gheita).

297-319X/$ – see front matter © 2011 Société francaise de rhumatologie. Published by Eoi:10.1016/j.jbspin.2011.06.009

e de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.

ciated kidney involvement seems to indicate a new syndromecharacterized by immune system impairment, lack of progres-sion to kidney failure, and poor survival (HCV-risk syndrome) [6].Several renal diseases including Membranoproliferative glomeru-lonephritis (MPGN) and less frequently membranous nephropathyand crescentic glomerulonephritis (CrGN) are associated with HCVand cryoglobulinemia [7,8]. The most important extrahepatic man-ifestations of chronic HCV infection are MC and GN, which worsensthe overall prognosis [9].

ANCA are strongly associated with a spectrum of vasculitis thatincludes CrGN but not with cryoglobulinemia [10]. The ANCA ishighly specific for small vessel systemic vasculitides with renalinvolvement. Patients with HCV and positive ANCA showed signifi-cantly higher incidence of ANA [11]. Despite important therapeuticimprovements, permanent organ failure may develop and affect the

heart, the lungs, and especially the kidneys. In ANCA-associatedsystemic vasculitides, end-stage renal failure develops in 20% ofcases [12] and rapidly progressive necrotizing GN occurs [13].In a substantial proportion of patients with CrGN, ANCAs with

lsevier Masson SAS. All rights reserved.

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pecificity for myeloperoxidase (MPO-ANCA) are detected [14].ecause patients with ANCA associated vasculitis have either anti-PO with pANCA or anti-PR3 with cANCA, and rarely both, a

ombined ANCA testing system including cANCA and pANCA isecommended to optimize the diagnostic performance [15]. ELISAroved to be more sensitive in the detection of ANCA than IFT16].

Systemic vasculitis, although rare, is often diagnosed late andong after the onset of symptoms. The small vessel vasculitides areecognized clinically by their multisystem presentation, markersf inflammation and evidence for an acute GN. Routine labora-ory tests are usually non-specific in systemic vasculitis but these of ANCAs can aid diagnosis, treatment and monitoring deci-ions. The presence or absence of ANCA does not confirm or excludehe diagnosis of systemic vasculitis but negative and positive pre-ictive values will be strongly influenced by clinical presentation.he reappearance of ANCA in a patient who was rendered ANCAegative following treatment is more likely to indicate relapse [17].

Pauci-immune renal vasculitis with focal glomerular necrosisnd crescent formation is usually associated with ANCAs. How-ver, ANCA’s are absent in up to 10% of cases, which constitutesrarely studied variant of renal vasculitis [18]. Majority of patientsith ANCA negative pauci-immune GN have multi-system involve-ent. Renal biopsy is characterized by focal proliferative lesionsith crescents and significant chronic interstitial fibrosis [19]. Theathogenesis of different types of systemic vasculitis negative forNCA and involving small or medium-sized vessels is not very wellocumented. In PAN related to HBV, and in cryoglobulinemic vas-ulitides, associated with HCV, histological lesions may result fromhe deposition of immune complexes responsible for the activa-ion of the classic complement pathway and for recruitment ofolymorphonuclear neutrophils [20].

. Methods

The study included 30 patients with primary systemicon-ANCA associated vasculitis (NAAV). Fifteen with essentialryoglobulinemic vasculitis (ECV) and another 15 patients withlassic PAN. The patients were recruited from the Rheumatologynd Internal medicine departments and outpatient clinics of Caironiversity Hospitals. They were further assessed in the Nephrol-gy department for renal biopsy. The PAN patients fulfilled the990 ACR criteria for classification of PAN [21]. Cryoglobulinsere isolated from sera of patients at 37 ◦C. Full history taking,

horough clinical examination, laboratory and radiological investi-ations were performed for all the patients and their current drugherapy was also reported. Relevant clinical and laboratory inves-igations were performed to exclude the possibility of secondaryasculitis. The CBC, ESR, liver and kidney function test, lipid profile,alcium, phosphorus, sodium and potassium, in addition to C3 and4 were measured. The RF, ANA, anti-ds DNA and anticardiolipinntibodies (ACL) IgG and IgM were determined. Furthermore, ANCAanti-PR3 and anti-MPO) were determined by combining the resultsf indirect immunofluorescence tests for cytoplasmic (c-ANCA) anderinuclear (p-ANCA) patterns with those of ELISA directed to mea-ure antigen. Only those negative to both methods of measurementere recruited. Abdominal ultrasonography (US) and detailed renalS examination were performed.

Disease activity was assessed using the Vasculitis Activity IndexVAI) [22] as well as the Birmingham Vasculitis Activity ScoreBVAS) [23]. Renal biopsy was performed to all patients and their

onsent taken. The tissues were histopathologically studied. Thetudy was approved by the local ethics committee and it conformso the standards currently applied in Cairo University Teachingospitals.

ine 79 (2012) 274–280 275

The aim of the present study was to detect subclinical renalinvolvement in patients with primary systemic NAAV and to com-pare those with ECV and classic PAN.

Statistical analysis, Statistical Package for Social Science (SPSS)program version 15 was used for analysis of data. Data was pre-sented as mean ± SD. Mann-Whitney test was used for analysisof two quantitative data. One-way ANOVA was used to comparemore than two quantitative data. Pearson’s correlation was usedfor detection of the relation between two variables. P-value wasconsidered significant if < 0.05.

3. Results

Thirty patients with primary systemic NAAV were included;15 patients with ECV and another 15 with classic PAN. None ofthe patients had nephrotic syndrome or renal failure. The demo-graphic features, clinical manifestations and disease activity ofthe patients are shown in Table 1 and their laboratory investi-gations in Table 2. All patients were receiving oral prednisolone,pulse cyclophosphamide, oral calcium preparation and periph-eral vasodilators. Pulse methylprednisolone was occasionally used.Antihypertensives where received by hypertensive cases. Only onepatient was further given azathioprine and mycophenolate mofitiltablets.

The differential WBC count was comparable in both groups.Thrombocytosis was found in three and polycythemia vera in onePAN patient. Urine analysis revealed mild proteinuria in sevenpatients; one with PAN and six (20%) ECV. Granular casts werepresent in one with PAN pyuria in three patients (1 PAN and 2ECV) and none had hematuria. The BUN and creatinine were ele-vated above normal in two patients with PAN and four with ECV.All patients with a positive RF had a negative Anti-CCP test. Twopatients with PAN had positive HCV and cryoglobulins.

Echocardiography was normal except in four patients of whichonly one was symptomatic. Two of the patients had PAN; one withdilated cardiomyopathy of the left atrium and ventricle, mitral andtricuspid regurge with ejection fraction (EF) 25%, diastolic dys-function and septal hypertrophy while the other had findings ofhypertensive heart disease. The other two ECV patients showedmild impairment of overall systolic function, impaired left ventricu-lar relaxation and sclerodegenerative changes in the aortic valve inone and the other had mildly dilated LA and LV with mild hypertro-phy, EF 52%, impaired left ventricular relaxation (grade II), diastolicdysfunction and trivial aortic regurge.

Skin biopsy was performed from all the skin lesions. From thepurpuric eruptions, leukocytoclastic vasculitis of the small ves-sels of the dermis was revealed with thrombosis and fibrinoidnecrosis. In PAN patients, the arterial wall revealed PMN leuco-cytes and some inflammatory cells consistent with its classification.Fundus examination revealed bilateral attenuated vessels in onePAN patient and abnormalities were present in four (26.67%) withECV. The findings were as follows: the first patient had bilateralflame hemorrhage along the lower temporal border with hyperten-sive retinopathy, the second showed bilateral age related maculardegeneration with left subfoveal scar, the third had attenuatedblood vessels (atherosclerosis) while the fourth had angioid streaksand macular scar in one eye. None of the patients had any signif-icant abdominal pain and, accordingly, visceral arteriography wasnot performed.

Color doppler ultrasonography of the vessels of the lower limbsrevealed arterial system abnormality in four patients with PAN

showing narrowing and occlusion of the tibial arteries and refillingof the collaterals with mural irregularities with microcirculationimpairment. Additionally, diffuse atherosclerosis was present inthe elderly two. However, the arterial system of all the other

276 T.A. Gheita et al. / Joint Bone Spine 79 (2012) 274–280

Table 1Demographic, Clinical manifestations and disease activity of non-ANCA associated vasculitis (NAAV) patients including polyarteritis nodosa (PAN) and essential cryoglobu-linemic vasculitis (ECV) patients.

Demographic feature (mean ± SD) All NAAV (30) PAN (15) ECV (15) P valueAge (Years) 46.83 ± 13.72 49.8 ± 14.55 43.87 ± 12.63Disease duration (Years) 3.65 ± 5.6 3.32 ± 4.09 3.98 ± 6.93BMI 26.36 ± 3.49 26.8 ± 3.85 25.92 ± 3.18Male: Female 11:19 8:07 3:12

Clinical manifestation Number (%)General

Malaise 1 (3.33) 1 (6.67) 0 0Myalgias 12 (40) 12 (80) 0 0Arthralgia 11 (36.67) 6 (40) 5 (33.33)Fever 4 (13.33) 1 (6.67) 3 (20)Weight loss > 4 kg 7 (23.33) 7 (46.67) 0 0

CutaneousInfarction 2 (6.67) 2 (13.33) 0 0Purpura 11 (36.67) 3 (20) 8 (53.33)Ulcer 1 (3.33) 1 (6.67) 0 0Gangrene of digits 15 (50) 9 (60) 6 (40)Livido reticularis 6 (20) 6 (40) 0 0Lichen planus 1 (3.33) 0 0 1 (6.67)

RenalHypertension 13 (43.33) 7 (46.67) 6 (20)Proteinuria 7 (23.33) 1 (6.67) 6 (20)Hematuria 0 0 0 0 0 0Increased creatinine 6 (20) 2 (13.33) 4 (26.67)

Nervous systemStroke 1 (3.33) 1 (6.67) 0 0Peripheral neuropathy 15 (50) 9 (60) 6 (40)Polyneuropathy 10 (33.33) 6 (40) 4 (26.67)Mononeuritis Multiplex 4 (13.33) 1 (6.67) 3 (20)

CardiovascularCongestive heart failure 1 (3.33) 1 (6.67) 0 (0)DVT 1 (3.33) 1 (6.67) 0 (0)

OthersSinus involvement 1 (3.33) 0 (0) 1 (6.67)Dyspnea/wheeze 2 (6.67) 1 (6.67) 1 (6.67)Testicular pain 2 (6.67) 3 (20) 0 (0)

Vasculitis Activity (mean ± SD)VAI 4.53 ± 1.77 5.17 ± 2.04 4.01 ± 1.38 0.11

11.33 ± 5.35 6.6 ± 3.04 0.006

B Activity Score. Bold values are significantly different at P < 0.05

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BVAS 8.97 ± 4.91

MI: Body mass Index, VAI: vasculitis activity index, BVAS: Birmingham Vasculitis

atients revealed normal caliber flow and triphasic pattern ofaveform with patent arterial flow. Venous system was normal

n all patients except two with PAN and chronic DVT of femoralnd poplitial veins with recanalization.

Renal biopsy was performed in all patients and only sixemales showed abnormalities. One patient with PAN showedenal vasculitis and membranoproliferative (mesangiocapillary)lomerulonephritis (MPGN) and was HBV and ANA positive. Theatient had negative HCV and cryoglobulins (Fig. 1). Five patientsith ECV-associated HCV had findings; one had chronic intersti-

ial nephritis and was HBV positive. The other four were HBVegative with MPGN in two, focal proliferative and crescentic GN

n one patient each (Fig. 2). On comparing the renal parametersetween those with histological abnormalities and those without,he 24 h urinary protein was significantly higher (0.33 ± 0.16 vs.08 ± 0.08 g/24 h, respectively) and the C4 level was more con-umed (0.1 ± 0.06 vs 0.18 ± 0.12 g/l, respectively).

Abdominal and renal Ultrasonographic findings in the patientsre presented in Table 3 and correlations in Table 4. There was aignificant correlation between the age of the patients and the cre-tinine, urea as well as the BVAS (r = 0.45, 0.37, 0.41 and P = 0.01,

.047 and 0.02 respectively). Similarly, a correlation between the4 h urinary protein and the disease duration was present (r = 0.37,= 0.046). The BVAS significantly correlated with the uric acid

evel (r = 0.49, P = 0.008) and the ACL IgG (r = 0.41, P = 0.03). The VAIFig. 1. Mesangiocapillary (Membranoproliferative) glomerulonephritis (MPGN) ina polyarteritis nodosa (PAN) patient.

T.A. Gheita et al. / Joint Bone Spine 79 (2012) 274–280 277

Table 2The laboratory investigations of the non-ANCA associated vasculitis (NAAV) patients including polyarteritis nodosa (PAN) and essential cryoglobulinemic vasculitis (ECV)patients.

Laboratory investigationsMean (± SD) PAN (15) ECV (15) Sig. P All non-ANCA (30)

CBCHb 11.71 ± 2.09 12.38 ± 1.41 0.23 12.04 ± 1.78WBC 12.97 ± 6.47 7.85 ± 2.69 0.019 10.41 ± 5.52Platelets 361.13 ± 193.04 193 ± 78.96 0.001 277.07 ± 168.26ESR 66.33 ± 43.43 42.2 ± 26.89 0.14 54.27 ± 37.56

KFTCreatinine 0.76 ± 0.31 0.98 ± 0.34 0.06 0.87 ± 0.34Urea 32.73 ± 12.34 57.93 ± 31.02 0.01 45.33 ± 26.524 hr urine protein 0.07 ± 0.06 0.2 ± 0.17 0.01 0.13 ± 0.14Serum uric acid 5.57 ± 2.34 5.37 ± 1.21 0.81 5.47 ± 1.81

MineralsCalcium 9.16 ± 0.62 8.8 ± 0.39 0.11 8.97 ± 0.53Phosphorus 4.38 ± 0.78 4.59 ± 1.6 0.76 4.49 ± 1.27

LFTAST (U/L) 39.4 ± 27.02 59.8 ± 59.92 0.19 49.6 ± 46.83ALT (U/L) 36.13 ± 35.52 58.87 ± 69.53 0.16 47.5 ± 55.47Alkaline phosphatase 229.47 ± 89.13 197.6 ± 104.59 0.22 213.53 ± 96.84Albumin 3.53 ± 0.79 3.77 ± 0.44 0.53 3.65 ± 0.64

Lipid profileTriglycerides 122.08 ± 9.34 116.13 ± 16.47 0.08 118.78 ± 13.85Cholesterol 172.08 ± 25.66 188.33 ± 43.75 0.54 181.11 ± 37.11Fasting blood sugar 135.33 ± 70.97 121.6 ± 49.31 0.85 128.47 ± 60.45

Immune profileACLIgG 13.08 ± 13.49 13.11 ± 4.76 0.12 13.09 ± 9.45ACLIgM 9.68 ± 6.25 8.29 ± 3.9 0.84 8.91 ± 5.02Complement factor C3 1.15 ± 0.26 0.87 ± 0.35 0.019 1.01 ± 0.33C4 0.24 ± 0.11 0.086 ± 0.046 0.000 0.16 ± 0.11

Number (%)

HCV positivity 2 (13.33) 15 (100) 17 (56.67)HBV positivity 6 (40) 5 (33.33) 11 (36.67)Cryoglobulins 3 (20) 15 (100) 20 (66.67)ANA 6 (40) 5 (33.33) 11 (36.67)Anti-dsDNA 1 (6.67) 0 (0) 1 (3.33)Rheumatoid factor 1 (6.67) 6 (40) 7 (23.33)

CBC: Complete Blood Count, Hb: hemoglobin, WBC: white blood cells, ESR: erythrocyte sedimentation rate, KFT: Kidney function tests, LFT: Liver function tests, AST: aspartatet ent, Hd

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ransaminase, ALT: alanine transaminase, ACL: anticardiolipin, C3 and C4: Complemouble stranded DNA, bold values are significantly different at P < 0.05

howed a negative correlation with the hemoglobin level (r = −0.44,= 0.02). In the PAN cases, there was a positive significant correla-

ion between the serum creatinine and ACL IgG (r = 0.646, P = 0.023).

. Discussion

The vasculitides may involve the kidneys with variable frequen-ies. The manifestations and prognosis of renal vasculitis range

able 3bdominal and renal ultrasonography of the non-ANCA associated vasculitis (NAAV)atients including polyarteritis nodosa (PAN) and essential cryoglobulinemic vas-ulitis (ECV) patients.

Abdominal US finding No. (%) PAN (15) ECV (15) All NAAV (30)

Hepatomegaly 5 (33.33) 10 (66.67) 15 (50)Cirrhosis 2 (13.33) 4 (26.67) 6 (20)Dilated portal vein 1 (6.67) 1 (6.67) 2 (6.67)Ascitis 0 (0) 3 (20) 3 (10)Splenomegaly 1 (6.67) 6 (40) 7 (23.33)Gall bladder stones 4 (26.67) 2 (13.33) 6 (20)Cholecystitis 2 (13.33) 2 13.33) 4 (13.33)

Renal findingsParenchymal nephropathy 2 (13.33) 1 (6.67) 3 (10)Stones 3 (20) 1 (6.67) 4 (13.33)Hydronephrosis 2 (13.33) 0 (0) 2 (6.67)Renal cyst 0 (0) 1 (6.67) 1 (3.33)

CV: hepatitis C virus, HBV: hepatitis B virus, ANA: antinuclear antibodies, dsDNA:

widely and dictates the need for early and prompt immunosup-pressive therapy [24]. In the present study, all patients were ANCAnegative and renal vasculitis was present in one PAN and five ECVpatients. Because of the segmentary and dynamic nature of vasculi-tis, it is often difficult in clinical practice to obtain a representativebiopsy specimen [25]. In the absence of immune complex deposi-tion, the role of the ANCA is particularly intriguing [26]. The p-ANCAand c-ANCA are negative in 98% of patients with HCV-related cryo-globulinemia while two new ANCA target antigens (BPI-ANCA andCG-ANCA) were identified in a higher percent of cases (5–8%) [16].All patients with cryoglobulinemia complicating HCV had MPGN[7].

In the present study complement was consumed more in thosewith ECV and RF was present in six with a negative Anti-CCPand two ECV patients had MPGN. In agreement was anotherstudy that found positive RF and a reduced complement in ECVpatients and the renal biopsy finding is typically MPGN. Mixedessential cryoglobulinaemia is due to HCV infection in over 80%of cases. Clinical features include palpable purpura, arthralgia,distal necrosis, peripheral neuropathy, abdominal pain and GN[27].

There is ample evidence suggesting that HCV plays a role ina broad spectrum of autoimmune diseases, which are usuallyoverlooked. A case initially reported to have HCV-associated cryo-globulinemic GN may lead to a common dilemma and an inevitable

278 T.A. Gheita et al. / Joint Bone Spine 79 (2012) 274–280

Table 4Correlation of the renal laboratory investigations with other tests and activity indeces in All non-ANCA associated vasculitis (NAAV) patients.

Correlation Creatinine Urea 24 h Protein

r P r P r P

Liver function testsAST 0.13 0.51 −0.06 0.77 0.51 0.004ALT 0.04 0.82 −0.08 0.69 0.48 0.008Alkaline phosphatase 0.31 0.10 0.36 0.05 0.04 0.84Albumin −0.30 0.11 −0.35 0.07 −0.23 0.24

MineralsCalcium −0.01 0.97 −0.08 0.70 −0.13 0.52Phosphorus 0.04 0.84 0.05 0.82 −0.16 0.41

Complete blood pictureHb −0.4 0.03 −0.31 0.10 −0.09 0.65WBC 0.27 0.15 0.41 0.02 0.30 0.11Platelets 0.12 0.53 0.34 0.06 −0.31 0.10ESR 0.44 0.02 0.44 0.02 −0.11 0.55

Immunological profileACL IgG 0.37 0.06 0.32 0.10 −0.49 0.81ACL IgM 0.26 0.19 0.23 0.25 −0.22 0.26C3 0.16 0.41 0.29 0.12 −0.09 0.66C4 0.11 0.57 0.24 0.21 −0.41 0.02

Disease activityVAI 0.34 0.08 0.49 0.01 −0.04 0.84BVAS 0.58 0.001 0.54 0.002 −0.03 0.89

AST: aspartate transaminase, ALT: alanine transaminase, Hb: hemoglobin, WBC: white blood cells, ESR: erythrocyte sedimentation rate, ACL: anticardiolipin, C3 and C4:Complement, VAI: vasculitis activity index, BVAS: Birmingham Vasculitis Activity Score. Bold values are significantly different at P < 0.05

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witch to a lupus-like GN [28]. False positive ANCA in HCV patientsoes not show any relevant clinical manifestations [11]. In thoseith ECV, positive P-ANCA was present in 2%, C-ANCA 1% and

lmost 10% for BPI- or CG-ANCA [16]. In the present study, one ofhe patients with ECV had CrGN. The incidence of ANCA-negativeauci-immune CrGN is low as almost one third of the patients

ack ANCAs [29–31]. In the present study, the age at disease onsetn ECV was 39.2 ± 14.63 years which was comparable to patients

ith ANCA negative pauci-immune CrGN (39.7 ± 17 years) beinguch younger than those with ANCA positive (57.6 ± 14 years)

30]. In PAN, virtually any organ with the exception of the lungsay be affected [32]. In PAN associated HBV, when renal involve-ent is present, so is renal vasculitis; GN is never found; ANCA

re not detected and relapses are rare [33]. The pathogenesis ofifferent types of systemic vasculitis negative for ANCA involv-

ng small or medium-sized vessels is not very well documented20]. Although renal vasculitis is more commonly considered withositive ANCA [34], NAAV may also be associated with renalroblems.

In the present study, HBV was detected in 36.67% ofases mostly PAN who showed a mild elevation of theiver enzymes. Extrahepatic manifestations of HBV includelomerulonephritis and PAN, which is the most unique, is asigh as 30%. The immunization programs may explain theresent decrease. Hepatic manifestations including ALT/AST ele-ations are mild and usually overlooked. Remarkably, nonef the HBV/PAN cases with GN showed ANCA reactivity35].

In the present study, one patient with PAN showed renal vas-ulitis and MPGN and was HBV and ANA positive while negativeor HCV and cryoglobulins. There were no cases presenting withenal failure or nephrotic syndrome. In other studies and case

eports, none of the patients with classic PAN had renal fail-re and ANCA was negative in most of the cases in spite of thessociated GN [36] HBV/PAN was associated with membranousephropathy [37] and RPGN [38]. Renal arteries are involved in

PAN [24]. Renal biopsy findings are good predictors for renal func-tion in patients with ANCA-associated GN [39]. Pauci-immunerenal vasculitis with focal glomerular necrosis and crescent for-mation is usually associated with ANCAs [40]. However, ANCA’sare absent in up to 10% of cases, which constitutes a rarely studiedvariant of renal vasculitis. The histological findings and progno-sis in ANCA-negative renal vasculitis are comparable with thoseof ANCA-positive disease [18]. In the present study, one of thepatients with PAN had positive cryoglobulinemia not linked toHCV. This could be explained by the reports on the associationof cryoglobulinemic vasculitis with CMV [41] or parvovirus [42].In a study on the clinical and immunological characterization oflife-threatening cryoglobulinemic vasculitis, renal failure due tocryoglobulinemic glomerulonephritis was present in almost 62%of the cases. This emphasizes the importance of early detectionof renal involvement before being critical [43] which is associ-ated with an increased mortality; being the most common causeof death before the availability of effective antiviral treatment[44].

In the present study, the disease activity was elevated beinghigher in those with PAN more than in ECV. The BVAS was signif-icantly different between both groups (11.33 ± 5.35 and 6.6 ± 3.04respectively, P = 0.006). Proteinuria was significantly higher in ECVcases. The BUN and creatinine were elevated above normal intwo patients with PAN and four with ECV. The BVAS was 23 inANCA negative pauci-immune GN patients with systemic involve-ment. Renal manifestations included proteinuria, hematuria andfew had renal failure and biopsy revealed focal proliferative CrGNand chronic interstitial involvement [19] proteinuria and nephroticsyndrome were higher and the renal survival poorer in ANCA-negative patients. ANCA-negative CrGN was not rare and mightrepresent an independent disease entity from ANCA-positive vas-

culitis [30].

Increased understanding of the manifestations of systemic vas-culitis is likely to provide the basis for the use of more selectiveimmunomodulatory therapies in the future. It is our hope that this

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ig. 2. Crescentic glomerulonephritis (GN) (a) and focal proliferative GN (b) inssential cryoglobulinemic vasculitis (ECV) patients.

tudy will raise awareness of the non ANCA-associated vasculiticenal involvement.

isclosure of interest

The authors declare that they have no conflicts of interest con-erning this article.

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