Hypocomplementemic urticarial vasculitis

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1 KIDNEY BIOPSY TEACHING CASES Crescentic Glomerulonephritis Associated With Hypocomplementemic Urticarial Vasculitis Syndrome Leah Balsam, MD, 1 Mohammed Karim, MD, 1 Frederick Miller, MD, 2 and Sofia Rubinstein, MD 1 INDEX WORDS: Crescentic glomerulonephritis; hypocomplementemic urticarial vasculitis syndrome; plasmapheresis. From the 1 Division of Nephrology and Hypertension, Nassau University Medical Center, East Meadow; and 2 Department of Pathology, Stony Brook University Medical Center, Stony Brook, NY. Received January 16, Accepted in revised form July 8, Originally published online as doi: /j.ajkd on September 29, Address correspondence to Leah Balsam, MD, Division of Nephrology and Hypertension, Box 49, Nassau University Medical Center, 2201 Hempstead Tpke, East Meadow, NY lbalsam@numc.edu 2008 by the National Kidney Foundation, Inc /08/ $34.00/0 doi: /j.ajkd Hypocomplementemic urticarial vasculitis syndrome (HUVS) is a rare disorder characterized clinically by recurrent urticaria and a variety of systemic manifestations. 1 HUVS was first described by McDuffie in In 1982, Schwartz et al 2 established the diagnostic criteria (Table 1). Two major criteria (recurrent urticaria for 6 months and hypocomplementemia) and at least 2 minor criteria (venulitis on skin biopsy, arthralgias or arthritis, glomerulonephritis, ocular inflammation, abdominal pain, and positive C1q antibodies) are required for a diagnosis of HUVS. Exclusion criteria are cryoglobulinemia, high levels of antinuclear antibody, positivity of anti double-stranded DNA antibody, hepatitis B virus antigenemia, and deficiency of complement factors. 2,3 Renal involvement in HUVS occurs in up to 50% of cases; the majority manifest in a benign manner. 4 In a 1994 literature review, Kobayashi et al 5 described 78 patients with HUVS reported from 1973 to Eighteen biopsies had been performed in this group. The various histopathologic types reported by these investigators were mesangial proliferative (8 cases), focal proliferative (3 cases), membranoproliferative (3 cases), membranous (2 cases), minimal change (1 case), and severe sclerosing proliferative glomerulonephritis (1 case). In 1995, Wisnieski et al 6 reported another 18 patients with HUVS, of whom 50% had renal involvement. The investigators described renal manifestations ranging from minimal proteinuria to nephrotic syndrome with variable degrees of hematuria. Glomerular involvement included mesangial and membranoproliferative glomerulonephritis. Crescentic glomerulonephritis in patients with HUVS is very rare. Since the original description in 1973, only 2 adults and 2 pediatric patients with crescentic glomerulonephritis complicating the course of HUVS have been reported in the world literature 1,3,4,7 (Table 2). We describe a young woman with crescentic glomerulonephritis associated with HUVS who rapidly progressed to end-stage renal disease. Clinical History CASE REPORT A 23-year-old Hispanic woman was seen as an emergency department consultation. She had been well until 6 months earlier, when she developed a skin rash over her trunk and extremities soon after she changed the carpet in her apartment. The rash was diffuse, erythematous, and wheal-like; varying in size; pruritic; and painful. It resolved on its own and the patient did not seek medical attention at that time. During the next 5 months, the rash appeared intermittently, lasting for 24 to 48 hours at a time. She then saw her primary care physician, who treated her with an antihistamine and topical steroid cream for a possible urticarial allergic reaction. There was no improvement. One week later, she developed increased urinary frequency, dysuria, abdominal pain, dark orange urine, and a 5-pound weight gain. She returned to the physician, who obtained laboratory tests. Urinalysis showed 3 protein and 3 blood, and microscopy showed more than 30 red blood cells and more than 30 white blood cells/high-power field. Blood urea nitrogen level was 18 mg/dl (6.426 mmol/l), and creatinine level was 1 mg/dl (88.4 mol/l). She was treated with oral antibiotics for a presumed urinary tract infection. Three days later, the patient presented to our emergency department because of worsening skin rash, suprapubic and flank pain, arthralgias of the joints of the hands and knees, and a 20-pound weight gain with total-body swelling. The patient denied respiratory symptoms, chest pain, fever, morning 1168 American Journal of Kidney Diseases, Vol 52, No 6 (December), 2008: pp

2 Crescentic GN in HUVS 1169 Table 1. Diagnostic Criteria for Hypocomplementemic Urticarial Vasculitis Syndrome Criteria Manifestations Required for Diagnosis Major Recurrent urticaria for 6 mo The patient must have both major criteria Hypocomplementemia Minor Venulitis of the dermis (established by means of biopsy) The patient must have at least 2 minor criteria Arthralgia or arthritis Glomerulonephritis Ocular inflammation (uveitis or episcleritis) Recurrent abdominal pain Positive C1q precipitin test result by immunodiffusion with an associated suppressed C1q level joint stiffness, hair loss, photosensitivity, facial rash, or ocular symptoms. The patient denied a significant medical and surgical history. There was no history of food, drug, or dust allergy. She denied using any medicine, including over-the-counter or herbal remedies, other than those prescribed by her physician. She denied a family history of autoimmune or kidney diseases. She did not smoke, drink alcohol, or use recreational drugs. The patient was married and had a monogamous relationship with her husband. She worked as a house cleaner. Physical examination showed a young woman in no distress. Blood pressure was 140/93 mm Hg, with a regular heart rate of 74 beats/min. She was febrile and had urticarial lesions all over her body, except for her face, and anasarca was noted. No oral ulcers were seen. The rest of the physical examination findings were unremarkable. Laboratory tests showed the following values. Urinalysis showed 3 protein and 3 blood, and microscopy showed 50 to 100 red blood cells/high-power field, 2 to 5 white blood cells/high-power field, and a few granular casts. Twenty-four hour urine protein was 3.9 g. The patient had mild normocytic anemia with a hemoglobin level of 10.1 mg/dl (101 g/l), hematocrit of 29.1%, erythrocyte sedimentation rate of 102 mm/h, albumin level of 2.3 g/dl (23 g/l), total cholesterol level of 247 mg/dl (6.39 mmol/l), lowdensity lipoprotein cholesterol level of 170 mg/dl (4.40 mmol/l), blood urea nitrogen level of 43 mg/dl, and creatinine level of 2.3 mg/dl. Complement analysis showed hypocomplementemia with low total hemolytic component (CH50) less than 10 U/mL (normal range, 31 to 66 U/mL) and low complement C3 fraction (C3) of 41.8 mg/dl (0.42 g/l; normal range, 86.3 to mg/dl [0.86 to 1.84 g/l]), low complement C4 fraction (C4) of 10.4 mg/dl (0.10 g/l; normal range, 19.7 to 57.0 mg/dl [0.20 to 0.57 g/l]), undetectable complement C1q fraction (C1q), increased C1q immune complex of g/dl (normal range, 4.4 g/dl), and increased anti-c1q antibody (C1q precipitin) level of 115.8% (normal range, 1.1% to 7.7% of standard deviation). Complement C2 fraction (C2) and complement C1 (C1) esterase inhibitor levels were normal. Antinuclear antibody, anti-dna (double-stranded) antibody, anti-smith antibody, anti SS-A/SS-B, lupus anticoagulant, rheumatoid factor, antistreptolysin O titer, anti glomerular basement membrane antibody, and cytoplasmic antineutrophil cytoplasmic antibody (proteinease-3) were negative. Perinuclear antineutrophil cytoplasmic antibody (myeloperoxidase) was weakly positive at 8 U/mL (normal reference range, 6 U/mL). Test results for immunoglobulin, cryoglobulins, hepatitis C, hepatitis B, syphilis, and HIV were normal or negative. Kidney Biopsy Prior to the kidney biopsy, a skin biopsy had been performed. As shown in Fig 1, an urticarial lesion was sampled and showed interstitial edema with acute venulitis. The kidney biopsy specimen is shown in Fig 2. Light microscopy showed 19 glomeruli, all of which showed crescents (Fig 2A and B). Extensive tubular loss and interstitial inflammation were of note, and fibrosis was present even at the early stage of the patient s course. Immunofluorescent studies showed a heavy granular epimembranous staining strongly positive with antisera directed against immunoglobulin G, immunoglobulin A, immunoglobulin M, C1q, C3, C4, and and light chains, with particularly heavy deposition of C1q (Fig 2C). Electron microscopy showed abundant subendothelial deposits (Fig 2D). The pattern of renal changes was indistinguishable from that of severe lupus nephritis, except for the absence of tubuloreticular inclusions. A repeated biopsy 6 weeks later showed a decrease in both inflammation and immune deposits; however, all 11 glomeruli were almost totally sclerotic with extensive tubular loss and interstitial fibrosis. Diagnosis Our patient fulfilled the diagnostic criteria for HUVS. 2 She had 2 major criteria (recurrent urticaria for 6 months and hypocomplementemia) and 5 minor criteria (venulitis on skin biopsy, positive anti-c1q antibody, arthralgias, abdominal pain, and glomerulonephritis). The other possible causes of crescentic glomerulonephritis were excluded. Clinical Follow-up Three daily doses of methylprednisolone (each 500 mg) and 1 dose of 1 g of intravenous cyclophosphamide followed by oral prednisone, 1 mg/kg/d, were administered. The skin lesions resolved; however, proteinuria and hematuria persisted, with progressive worsening of kidney function and peak creatinine level of 4.7 mg/dl. Plasmapheresis was initiated 1 week after the first dose of intravenous steroids

3 1170 Balsam et al Table 2. Summary of All Reported Cases of Cresescentic Glomerulonephritis and Hypocomplementemic Urticarial Vasculitis Syndrome Reference Patient Age (y)/sex Clinical Presentation Kidney Biopsy Treatment Clinical Follow-up Martini et al 7 12/Boy Renal: hypertension, renal failure, microscopic hematuria, proteinuria Extrarenal: urticaria, arthralgia, conjunctival hyperemia Renard et al 1 13/Boy Renal: renal failure, gross hematuria, nephrotic syndrome Extrarenal: urticaria, angioedema, arthritis, conjunctivitis, abdominal pain Messiaen et al 4 27/Woman Renal: renal failure, gross hematuria, proteinuria Extrarenal: urticaria, arthritis, episcleritis, hemoptysis with intrapulmonary hemorrhage Enriquez et al 3 39/Woman Renal: renal failure, hypertension, microscopic hematuria, nephrotic syndrome Extrarenal: urticaria, arthralgias, xerophthalmia Present study 23/Woman Renal: gross hematuria, nephrotic syndrome, acute renal failure Extrarenal: urticaria, arthralgias, abdominal pain LM: mesangial proliferation with complete sclerosis and crescents in 50% of glomeruli IF: C3, C1q, C4, IgG, IgM EM: not available LM: extra and intracapillary proliferation with mesangial hypercellularity and crescents IF & EM: not available LM: membranoproliferative with crescents IF: C3, C1q (mesangium), IgM (vessel walls) EM: subepithelial and subendothelial deposits LM: mesangial proliferation, membranoproliferative with crescents IF: C3, C4, C1q, IgG, IgM (capillary walls) EM: not available LM: crescents with extensive tubular loss and interstitial inflammation IF: heavy granular epimembranous staining strongly positive with antisera directed against IgG, IgA, IgM, C1q, C3, C4, and light chains with particularly heavy deposition of C1q EM: subendothelial deposits CS, CyC CS, Aza, CyA CS, CyC CS, CyC, MMF CS, CyC, PPH Maintenance hemodialysis initiated 5 mo after diagnosis Recovery of renal function with mild proteinuria Maintenance hemodialysis initiated 3 y after diagnosis, subsequently received renal transplant Mild renal insufficiency and nephrotic syndrome 42 mo after diagnosis Maintenance hemodialysis initiated 3 wk after diagnosis Abbreviations: Aza, azathioprine; CS, corticosteroids; CyA, cyclosporine; CyC, cyclophosphamide; EM, electron microscopy; IF, immunofluorescence; IgG, immunoglobulin G; LM, light microscopy; MMF, mycophenolate mofetil; PPH, plasmapheresis. was administered. It was given every other day as 1 plasma exchange with albumin replacement. After 2 plasmapheresis treatments, creatinine level decreased to 3.4 mg/dl. However, 2 days later, the patient was transferred to the intensive care unit with gram-negative sepsis, pneumonia, and respiratory failure. Kidney function also deteriorated. The patient was treated with broad-spectrum antibiotics and respiratory support with mechanical ventilation. Cyclophosphamide and plasmapheresis therapy were discontinued. Hemodialysis therapy was initiated to treat volume overload and uremic symptoms. One month after hospitalization, repeated laboratory tests showed normal complement levels, but kidney function never improved. Repeated renal biopsy performed 6 weeks after the first biopsy showed sclerosis of all glomeruli. Oral steroid therapy was discontinued. Currently, the patient is on maintenance hemodialysis therapy. DISCUSSION This case illustrates several important points. First, although many may consider HUVS as a subset of lupus, the absence of classic serological test results and a different skin picture have led this to be regarded as a separate entity. Second, the case illustrates the importance of measuring C1q and anti-c1q antibodies in a patient with suspected HUVS. Third, it emphasizes the importance of complement as a prognostic indicator in patients with this disease. The low complement levels in patients with this syndrome herald a poor prognosis, and the diminution or absence of

4 Crescentic GN in HUVS 1171 Figure 1. Punch biopsy specimen of an urticarial lesion (hematoxylin and eosin stain; original magnification 400). There is acute venulitis. Neutrophils in this area are conspicuous and show leukocytoclastic changes, but in other regions, the findings are more subtle. Separation of collagen bundles is consistent with edema. C1, C2, and C4 tend to favor the development of autoimmune disease. Fourth, the case is important in illuminating a pathogenetic mechanism. C1q antibody can be detected in 100% of patients with HUVS. 8 However, only approximately half the patients with HUVS develop renal manifestations; severe renal involvement is uncommon. 4 Animal studies have shown that injection of anti-c1q antibodies, either monoclonal or polyclonal, did not result in overt renal disease, although glomerular deposition of C1q and anti-c1q antibodies, as well as a significant influx of leukocytes, could be observed. 9 Anti- C1q autoantibodies were pathogenic only in combination with glomerular C1q-containing immune complexes. 10 The investigators concluded that anti-c1q autoantibodies by themselves do not seem to be able to induce overt renal inflammatory disease. However, in the presence of immune complex deposition that is recognized by C1q, C1q and subsequently C1q antibodies bind to the immune complexes. This results in full activation of the classical pathway of the complement system, leading to tissue injury mediated by the membrane attack complex and the influx of inflammatory cells. 11 This mechanism may explain why certain patients with HUVS (those with immune complex deposition) develop renal disease, whereas others are spared, although all patients have detectable C1q antibody. Finally, the case highlights the prognosis and treatment of patients with HUVS and crescentic glomerulonephritis; the potential for rapid deterioration in kidney function and a possible role for plasmapheresis. The 4 known patients with HUVS and crescentic glomerulonephritis were treated with combinations of immunosuppressive therapy, including steroids, cyclophosphamide, cyclosporine A, azathioprine, and mycophenolate mofetil, but not plasmapheresis. Enriquez et al 3 described a 39-year-old woman with crescentic membranoproliferative glomerulonephritis in the setting of HUVS who was treated with pulse doses of steroids and cyclophosphamide, with improvement in kidney function in a 42-month follow-up period. Messiaen et al 4 described a 27-year-old woman with a clinical course complicated by crescentic glomerulonephritis 6 years after the initial diagnosis of HUVS, with partial response to steroids and cyclophosphamide initially. However, the patient eventually developed end-stage renal disease requiring hemodialysis therapy 3 years after the diagnosis of glomerulonephritis. Martini et al 7 and Renard et al 1 described 2 pediatric patients with crescentic glomerulonephritis associated with HUVS. One responded to steroid and immunosuppressive therapy with normalization of kidney function, but persistent mild proteinuria, and the other did not respond and developed end-stage renal disease within 5 months after diagnosis. The kidney function of our patient did not respond to steroid and cyclophosphamide therapy, but may have had some improvement with plasmapheresis. Unfortunately, because of sepsis, treatment could not be continued and she developed end-stage renal disease within 3 weeks after the diagnosis of HUVS. In conclusion, hypocomplementemic urticarial vasculitis is a separate disease from lupus, based on the absence of classic serological test results and different skin lesions and pathologi-

5 1172 Balsam et al Figure 2. (A) Renal biopsy specimen (hematoxylin and eosin stain; original magnification 40). Three glomeruli show crescents that are cellular. The interstitium is severely inflamed, and there is obvious tubular loss and fibrosis. (B) A glomerulus (hematoxylin and eosin stain; original magnification 400) shows a typical lesion. There is proliferation of all elements with relatively little acute inflammation. (C) Glomeruli (immunofluorescence with anti-c1q; original magnification 400) all showed staining for immunoglobulin G (IgG), IgA, IgM, C1q, C3, C4,,, and fibrin. The pattern was granular and subendothelial. (D) Electron microscopy shows many large subendothelial electron-dense deposits. No tubuloreticular inclusions are seen. cal states. Low C1q levels in serum caused by circulating anti-c1q are crucial to making the diagnosis. Because of the limited number of cases, it is difficult to determine the effect of immunosuppressive therapy on patients with severe kidney disease associated with HUVS. However, it was suggested that steroids and cyclophosphamide are the drugs of choice. 12 Cyclosporine A, azathioprine, mycophenolate mofetil, and plasmapheresis could be other valuable alternatives. 3,13,14 Our case together with the 4 other reported cases of crescentic glomerulonephritis associated with HUVS support that this disease is potentially aggressive and should be considered in the differential diagnosis of small-vessel vasculitis with renal involvement. ACKNOWLEDGEMENTS Support: None. Financial Disclosure: None. REFERENCES 1. Renard M, Wouters C, Proesmans W: Rapidly progressive glomerulonephritis in a boy with hypocomplementaemic urticarial vasculitis. Eur J Pediatr 157: , Schwartz HR, McDuffie FC, Black LF, Schroeter AL, Conn DL: Hypocomplementemic urticarial vasculitis. Association with chronic obstructive pulmonary disease. Mayo Clin Proc 57: , Enriquez R, Sirvent AE, Amoros F, Perez M, Matarredona J, Reyes A: Crescentic membranoproliferative glomerulonephritis and hypocomplementemic urticarial vasculitis. J Nephrol 18: , Messiaen T, Van Damme B, Kuypers D, Maes B, Vanrenterghem Y: Crescentic glomerulonephritis complicat-

6 Crescentic GN in HUVS 1173 ing the course of a hypocomplementemic urticarial vasculitis. Clin Nephrol 54: , Kobayashi S, Nagase M, Hidaka S, et al: Membranous nephropathy associated with hypocomplementemic urticarial vasculitis. Report of two cases and a review of the literature. Nephron 66:1-7, Wisnieski JJ, Baer AN, Christensen J, et al: Hypocomplementemic urticarial vasculitis syndrome. Clinical and serological findings in 18 patients. Medicine 74:24-41, Martini A, Ravelli A, Albani S, De Benedetti F, Massa M, Wisnieski JJ: Hypocomplementemic urticarial vasculitis syndrome with severe systemic manifestations. J Pediatr 124: , Horvath L, Czirjak L, Fekete B, et al: Levels of antibodies against C1q and 60 kda family of heat shock proteins in the sera of patients with various autoimmune diseases. Immunol Lett 75: , Trouw LA, Duijs JM, vankooten C, Daha MR: Immune deposition of C1q and anti-c1q antibodies in the kidney is dependent on the presence of glomerular IgG. Mol Immunol 40: , Trouw LA, Groeneveld TW, Seelen MA, et al: Anti- C1q autoantibodies deposit in glomeruli but are only pathogenic in combination with glomerular C1q-containing immune complexes. J Clin Invest 114: , Flierman R, Daha MR: Pathogenic role of anti-c1q autoantibodies in the development of lupus nephritis A hypothesis. Mol Immunol 44: , Grimbert P, Schulte K, Buisson C, et al: Renal transplantation in patients with hypocomplementemic urticarial vasculitis syndrome: Am J Kidney Dis 37: , Ramirez G, Saba SR, Espinoza L: Hypocomplementemic vasculitis and renal involvement. Nephron 45: , Soma S, Sato H, Ito S, Saito S: Nephrotic syndrome associated with hypocomplementaemic urticarial vasculitis syndrome: Successful treatment with cyclosporine A. Nephrol Dial Transplant 14: , 1999