Zakharova EV1,2*, Makarova TA1 and Stolyarevich ES2
1Nephrology Unit, City Clinical Hospital n.a. S.P. Botkin, Moscow, Russian Federation
2Nephrology Chair, State University of Medicine and Dentistry, Moscow, Russian Federation
Received: 23 September, 2016;Accepted: 11 November, 2016; Published: 12 November, 2016
Elena Zakharova, Head of Nephrology Unit, City Clinical Hospital n.a. SP Botkin, Moscow, Russian Federation, Tel: +7 967 134 6936; E-mail:
Zakharova EV, Makarova TA, Stolyarevich ES (2016) ANCA-Associated Vasculitis in Patient with CREST-Syndrome - Case Report. Arch Clin Nephrol 2(1): 049-052.
© 2016 Zakharova EV, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Scleroderma; Systemic sclerosis; Vasculitis; Kidney biopsy; Chronic kidney disease
AAV, ANCA: Associated Vasculitis; AH: Arterial Hypertension; ANCA: Antineutrophil Cytoplasmic Antibody; CAPD: Continuous Ambulatory Peritoneal Dialysis; CKD: Chronic Kidney Disease; CREST: Calcinosis, Raynaud Phenomenon, Esophageal Dysmotility, Sclerodactyly, and Telangiectasias; EGPA: Eosinophilic Granulomatosis With Polyangiitis; ESRD: End Stage of Renal Disease; GPA: Granulomatosis with Polyangiitis; MPA: Microscopic Polyangiitis; MPO-ANCA: Anti-Myeloperoxidase ANCA; RNA: Ribonucleic Acid; PR3-ANCA: Anti-Proteinase3 ANCA; RRT: Renal Replacement Therapy; SS: Systemic Sclerosis; SVV: Small Vessel Vasculitis; UTI: Urinary Tract Infection
Background: ANCA-associated vasculitis is a small vessel necrotizing vasculitis with few or no immune deposits, necrotizing glomerulonephritis is very common in the microscopic poliangiitis subset. Systemic scleroderma renal involvement is included neither in the current classification criteria, nor in the definition of CREST-syndrome. The presence of ANCA in patients with SS was first described in 1996, and since that has been reported to be rare and not presenting clinical significance. However during next decade about 50 cases with association of SS and AAV were described, and more recently, additional cases were reported and the clinical features of such association were recognized.
Results: We present here a case, illustrating association of systemic sclerosis and ANCA-associated vasculitis, proven by kidney biopsy findings of sclerosing and necrotizing glomerulonephritris with11% of crescents.
Conclusions: Patients with systemic sclerosis in general, and CREST-syndrome in particular, demonstrating unexplained deterioration of kidney function, should be tested for ANCA and undergo kidney biopsy in search for association with AAV. Immunosuppressive treatment, especially in cases with advanced sclerotic changes by kidney pathology evaluation, should be performed with caution to ensure patient’s survival even in cases of progression to ESRD.
According to the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a small vessel vasculitis (SVV), distinguished from immune complex SVV. AAV is necrotizing vasculitis with few or no immune deposits, predominantly affecting small vessels, associated with MPO-ANCA or PR3-ANCA. AAV is subdivided into microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA/Wegener’s), and eosinophilic granulomatosis with polyangiitis (EGPA/Churg-Strauss). MPA in particular is SVV necrotizing vasculitis with few or no immune deposits; necrotizing arteritis involving small and medium arteries may be present, necrotizing glomerulonephritis is very common .
Revised classification of systemic sclerosis (SS) published by the joint committee of the American College of Rheumatology and the European League Against Rheumatism in 2013, defined the following classification criteria: skin thickening of the fingers of both hands extending proximally to the metacarpophalangeal joints; skin thickening of the fingers; fingertip lesions; telangiectasia; abnormal nailfold capillaries; pulmonary arterial hypertension and/or interstitial lung disease; Raynaud phenomenon; and systemic sclerosis–related autoantibodies (anticentromere, anti–topoisomerase I and anti–RNA polymerase III). Renal involvement, though it is not rare and might be life-threatening, was not included into the list of classification criteria . CREST syndrome (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias), although not all are needed for the disorder to be called CREST, is an older term used to describe this subset of limited systemic sclerosis, formerly named scleroderma .
The presence of ANCA in patients with SS was first described in 1996  and since that has been reported to be rare and not presenting clinical significance. However since 1996 to 2006 about 50 cases with association of SS and AAV were described, and more recently additional cases were reported, and the clinical features of such association were recognized [5-10].
We present here a case, illustrating association of SS and AAV, diagnosed on the basis of kidney involvement characteristics.
Caucasian female 65 years old, admitted to our clinic December 17 2015.
Main complains: weakness, muscle cramps.
Previous medical history
Infiltrative tuberculosis diagnosed in 1988, successfully treated with specific therapy and followed for 10 years without recurrences, uterine fibroid, autoimmune thyroiditis, and mild arterial hypertension.
History of present illness
In 2009 she developed joint pain and weakness, outpatient work-up found sideropenic anemia, mild proteinuria, microhematuria and serum creatinine 150 µmol/L. Chest X-ray showed diffuse pneumosclerosis, kidney ultrasound was unremarkable, gasrtoscopy found erosive gastritis, urine culture revealed E. Coli contamination. She was seen by local nephrologist, diagnosed with arterial hypertension, gastroduodenitis, UTI and CKD stage 3, treated with anti-ulcer and antihypertensive medications, antibiotics, oral iron preparations and NSAIDS and improved.
In 2012 she developed skin thickening and hyperpigmentation of her left abdomen and backside area, seen by dermatologist, diagnosed with limited scleroderma and treated with penicillin and antiplatelet agents. She had positive anticentromere and anti-hystone H antibodies, her serum creatinine was the same as in 2009 (147 µmol/L), her anemia was compensated, and urinary symptoms were very mild.
July 2015 she had an episode of eye redness, successfully treated with eye drops. However, she developed progressive weakness, in November 2015 her creatinine rose to 206µmol/L, and she was referred to our clinic.
At admission: conscious, alert, oriented. Body temperature 36.8°C, RR 18 per minute, pulse regular 78 per minute, BP 140/90 mm Hg. Slightly obese (BMI 29). Skin dry, pale, pronounced thickening and hyperpigmentation of left abdomen and buttocks area, upper extremities Raynaud phenomenon, and telangiectasia’s on her chest. No edema. Eyes clear. HEENT and neck otherwise normal. Peripheral lymph nodes not felt. Joints non-painful, no swelling, movements unrestricted. No breast nodularity. Lungs clear. Heart rhythm regular, no murmur. Tongue dry, clean. Abdomen soft, non-tender, non-painful, bowel sounds normal. Liver, spleen and kidneys not felt. Urination and stools normal.
Routine labs: moderate proteinuria (1.0 g\day), microhematuria (15-20 RBC hpf), mild anemia (Hb 9.6 g/L), creatinine 226-375 µmol/L, urea 16.4-20.3 mmol/L, uric acid 492 mmol/L, CRP 12.3 mg/L (normal range <6). Other blood count and blood chemistry parameters, as well as coagulation tests, thyroid hormones, immunoglobulin’s levels, infectious screening, Diaskin test and urine culture were unremarkable.
Autoimmune screening: positive anticentromere (13.9 U/L, normal range 0-10) and antinuclear (1/640) antibodies, and MPO-ANCA >100 U\mL (normal range 0-5), other tests within normal range. Tests for anti-plasminogen and anti-tissue plasminogen activator antibodies were not available.
Electrocardiogram: Sinus rhythm, cardiac rate 65 bites per minute, left ventricular myocardial underperfusion.
Chest X-ray: no focuses or infiltration, pulmonary vascular markings.
Kidney ultrasound: lower normal kidney size, few small parenchymal cysts, no stones or urinary tract obstruction.
Echo-cardiogram: heart chambers not dilated, mild left ventricular myocardial hypertrophy. Aortic walls, aortic and mitral annulus moderate sclerosis, cusps excursion not limited. Left ventricular ejection fraction 68%. Mild mitral and tricuspid regurgitation. Left ventriclular diastolic dysfunction type 1.
Esophagogastroduodenoscopy - atrophic gastritis and esophageal dysmotility.
Kidney biopsy: Sections of formalin fixed paraffin-embedded tissue were stained with H&E, Masson’s trichrome and periodic acid-Shiff. Light microscopy found 18 glomeruli, 12 of them totally sclerosed. In 2 out of 12 sclerosed glomeruli fragments of fibrous crescents are seen. Other 2 glomeruli contain segmental cellular crescents. The rest glomeruli look enlarged and not changed. Diffuse-focal interstitial fibrosis and tubular atrophy up to 50% of parenchyma. Hypertrophy of the preserved tubules. Diffuse-focal mononuclear infiltration in the areas of sclerosis (Figures 1-4). Arteries and arterioles otherwise normal. Immunofluorescence on unfixed cryo-sections with fluorescein conjugated anti IgA, IgG, IgM, C1q, C3, fibrinogen, λ and κ light chains antibodies was negative for all immune stains.