Renal failure in giant cell vasculitis

Renal Failure in Giant Cell Vasculitis Tomas Lenz, MD, Ru¨diger Schmidt, MD, Ju¨rgen E. Scherberich, MD, and Hermann-Josef Gro¨ne, MD ● A 59-year-old white woman with temporal arteritis developed progressive renal failure. Renal biopsy results showed focal and segmental necrotizing glomerulonephritis; furthermore, giant cells were present in the destructed vessel walls. Immunosuppressive therapy did not prevent terminal renal failure. This case shows that renal involvement may be a feature of temporal arteritis. r 1998 by the National Kidney Foundation, Inc. INDEX WORDS: Temporal arteritis; glomerulonephritis; renal failure.

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HE KIDNEYS ARE frequently affected by systemic vasculitides, which in most cases are small vessel diseases, such as microscopic polyarteritis, Wegener’s granulomatosis, and cryoglobulinemic vasculitis.1 Giant cell (temporal) arteritis is a common vasculitic disease in elderly people that predominantly affects the external carotid arteries and their branches, leading to facial nerve palsy, ophthalmoplegia, vertigo, and anosmia. This vasculitic disorder may, however, involve any arteries of medium and large size.2 We report on a case with renal involvement in giant cell arteritis, leading to the development of rapidly progressive renal failure. CASE REPORT A 59-year-old white woman was admitted to our hospital because of remittant fever episodes (maximum temperature, 39oC) for the last 4 weeks. She had not been feeling well for the last 8 months, with complaints of fatigue and a weight loss of 3 kg. At that time, her erythrocyte sedimentation rate (ESR) was 38 mm/h and C-reactive protein level was normal. There was occult blood in her stool; the colonoscopy was without pathological findings. Three months before admission, she had experienced a progressive vision loss of her left eye with ptosis. Atrophy of the optical nerve and complete paralysis of the oculomotor nerve was diagnosed. The electroencephalogram was unremarkable, and a brain tumor was ruled out by magnetic resonance imaging. Her ESR was reportedly accelerated and there was mild leukocytosis. Temporal arteritis was suspected (no temporal biopsy was performed), and the patient was treated with oral prednisone plus

From the Medical Clinic IV, Division of Nephrology, University Hospital, Johann Wolfgang Goethe University, Frankfurt am Main; and the Department of Pathology, Division of Nephropathology, University Hospital, PhilippsUniversity, Marburg, Germany. Submitted October 17, 1996; accepted in revised form December 5, 1997. Address reprint requests to Tomas Lenz, MD, University Hospital, Medical Clinic IV, Division of Nephrology, Theodor Stern Kai 7, 60596 Frankfurt a.M, Germany.

r 1998 by the National Kidney Foundation, Inc. 0272-6386/98/3106-0021$3.00/0 1044

aspirin. No improvement of her vision was noted. Four weeks before admission, her plasma creatinine level was 0.9 mg/dL, and her urinalysis showed mild hematuria. Her temperature was elevated and a urinary tract infection was suspected; therefore, she was started on cotrimoxazole therapy (and later ampicillin) for about a week with no clinical improvement. She was then admitted to our hospital for further diagnostic work-up. At the time of admission, she was receiving ampicillin 500 mg three times daily, prednisone 5 mg daily, and aspirin 100 mg daily. Her past medical history was otherwise unremarkable, except for long-standing moderate hypertension. On admission, the patient was in a reduced state of health. Her weight was 56 kg at a height of 155 cm, blood pressure was 120/85 mm Hg, and pulse rate was 100 beats/min. Her temperature was 39oC. There was left-sided amaurosis and a slight divergent strabismus without ptosis. Temporal arteries were nontender and beating. There were no cutaneous lesions or lymphadenopathy. Heart and lungs were normal. Her abdomen was normal without a palpable mass, and the liver and spleen were not enlarged. Her kidneys were nontender, and there was no edema. Musculoskeletal and neurological systems were otherwise normal. Chest radiograph showed no abnormalities, and a renal sonogram showed normal kidneys with no obstruction.

Laboratory Results On admission, the following laboratory results were obtained. Hemogram: ESR, 120 mm/h; white blood cell count, 16.7/nL (differential: one metamyelocyte, four myelocytes, two bands, 84 segments, one eosinophil, four monocytes, five lymphocytes); hemoglobin level, 8.9 mg/dL; platelet count, 299/nL; no red cell fragmentation. Clinical chemistry: C-reactive protein, 16.6 mg/dL; creatinine level, 2.2 mg/dL; urea nitrogen level, 62 mg/dL; lactate dehydrogenase level, 262 U/L; albumin level, 2.5 g/dL, prothrombin time, 75% of control; partial thromboplastin time, 30 seconds; fibrinogen level, 1,000 mg/dL; antithrombin III, 87% of control. Normal values were obtained for potassium, sodium, aspartate and alanine aminotransferase, creatine phosphokinase, amylase, alkaline phosphatase, bilirubin, haptoglobin, and thyroid function. Urinalysis: microhematuria (10 to 12 red cells/field); no dysmorphic erythrocytes; no leukocyturia; no casts; immunoglobulin G (IgG), 52 mg/L (normal ⬍ 12 mg/L); albumin, 219 mg/L; alpha-1-microglobulin, 124 mg/L (normal ⬍ 12mg/L). Immunological parameters: normal plasma immunoglobulins (IgG, 1,427 mg/dL; IgA, 313 mg/dL; IgM, 170 mg/dL), C3 complement, 77.4 mg/dL; C4 complement, 28.7 mg/dL; rheumatoid fac-

American Journal of Kidney Diseases, Vol 31, No 6 (June), 1998: pp 1044-1047

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tor was positive (1:640); tests for antineutrophilic cytoplasmatic (ANCA), antinuclear, and antiglomerular basement antibodies were negative. Microbiology/virology: repeated blood and urine cultures were negative; serological tests for chlamydia, mycoplasma, salmonella, legionella, and treponema pallidum were negative. Virus titers were also negative with the exception of Epstein-Barr virus (EBV) (1:1280), which later decreased to 1:320; there were no clinical signs of EBV infection.

Clinical Course During the first week after admission, renal function progressively deteriorated until oliguric renal failure was present. The patient became markedly hypertensive, requiring antihypertensive medication. Her plasma creatinine level had increased to 7.7 mg/dL and hemodialysis was commenced. Rapidly progressive glomerular disease was suspected, and the patient was started on prednisone pulse therapy (500 mg daily for 3 consecutive days, followed by 100 mg daily for another 4 weeks). At the same time, an intravenous bolus of 1.3 g (750 mg/m2 of body surface area) of cyclophosphamide was administered (Fig 1). Before the onset of immunosuppression therapy, a renal biopsy was performed. Altogether, 20 glomeruli were found in the specimen, of which 10 showed segmental necrosis and extracapillary proliferation. Light microscopy is shown in Figs 2-5 with giant cell arteritis, focal and segmental necrotizing glomerulonephritis, as well as focal tubular atrophy and interstitial fibrosis. An immunohistologic study was negative for IgA (Fig 6), IgG, C1q, and C3 (Fig 7) in the glomeruli; moderate staining for IgM in the mesangium of some of the glomeruli was present. Fibrin/fibrinogen was found in thrombotic material and glomerular necrosis. Electron microscopy did show a glomerulus with segmental necrosis; no osmiophilic deposits were present in the mesangium or in peripheral basement membranes (Fig 8). Despite immunosuppression therapy, renal function did not recover and the patient remained oliguric. Four weeks after admission, an arteriovenous fistula was inserted, and the patient has been on maintenance hemodialysis since. Immunosuppression therapy was tapered off.

Fig 1. Course of renal function and therapy in a patient with giant cell vasculitis (prednisone pulse, 500 mg daily; cyclophosphamide bolus, 1.3 g)

Fig 2. Two thrombosed vessels with destructed vessel walls, infiltrated by mononuclear cells and with focal formation of a granuloma-like lesion with multinuclear giant cells.

DISCUSSION

This case shows that renal involvement may be a feature of temporal arteritis. No temporal artery biopsy was performed; the clinical and laboratory presentation, however, is quite typical for this disorder. In particular, the markedly elevated ESR and the anemia, as well as the ischemic optic neuropathy/ophthalmoplegia and

Fig 3. Higher magnification of Fig 2, showing macrophages and multinuclear giant cells.

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Fig 4. Occluded vessel with partly organized thrombus and, in lower border of photograph, glomerulus with segmental necrosis.

her weakness were strong arguments for the presence of this disorder. The generally negative physical examination is compatible with giant cell arteritis, because abnormal findings are not always present.3 Furthermore, musculoskeletal symptoms in the sense of polymyalgia rheumatica may have been obscured by the long-term low-dose prednisone therapy; on the other hand, only approximately 50% of patients with tempo-

Fig 5. Higher magnification showing glomerulus with segmental necrosis and fibrin-like material in Bowman’s space. There is a moderately dense periglomerular mononuclear infiltrate.

LENZ ET AL

Fig 6. Immunohistologic stain for IgA (alkaline phosphatase anti-alkaline phosphatase [APAAP] method) was negative in the vessel wall and in the glomeruli.

ral arteritis develop rheumatic symptoms.4 Giant cell arteritis is often associated with tumors (mostly hematologic) and/or monoclonal gammopathy, for which there was no evidence in this patient.5,6 The presence of a pauci-immune glomerulone-

Fig 7. Immunohistologic stain for C3 complement (APAAP method) was negative in the vessel wall, except for a weak label in the glomeruli. There was positive staining in the interstitial compartment, most likely because of increased permeability of the peritubular capillaries.

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renal failure as in our case apparently is unusual.7,10 Altogether, renal disease as a systemic manifestation of temporal arteritis is a rare condition that can only be recognized by renal biopsy or postmortem examination.11 Histopathological examination may reveal diverse morphologies.7-9 In our opinion, as with other vasculitic diseases of the kidney, a therapeutic attempt with highdose corticosteroid therapy (plus cyclophosphamide) may be justified. This regimen, however, proved ineffective in our patient, possibily because of advanced sclerotic lesions. Other reports on similar cases, however, showed a more favorable outcome of immunosuppressive therapy.8,9,12 Fig 8. Mesangium without electron-dense immunodeposits. Basement membranes are regularly structured, not broadened, and are covered by partially necrotic podocytes. Part of glomerulus shown is at the rim of a necrotic focus.

phritis may also suggest other systemic vasculitis, such as microscopic polyarteritis or Wegener’s granulomatosis. These diagnoses are unlikely because ANCA was negative, and no pulmonary, ear, nose, throat, or skin involvement was clinically evident. Furthermore, in this patient, multinucleated giant cells characteristic of temporal arteritis were present in the renal arterial walls, suggesting that the kidney disease was because of this form of vasculitis.7 The vasculitis and glomerulonephritis with pronounced fibrosis led to terminal renal failure, which was unresponsive to immunosuppression therapy (high-dose corticosteroid plus cyclophosphamide therapy). Only a minority of patients with giant cell/ temporal arteritis will have renal involvement (minimal proteinuria, occasional hematuria, and red cell casts), and renal pathologic examination usually reveals no gross glomerular or larger vessel disease.1 Only a few reports exist of more severe forms of renal involvement in this disorder. The histopathological findings in these cases included the following: intrarenal giant cell vasculitis with severe fibrinoid necrosis7 similar to the findings in our patient, focal segmental necrotizing glomerulonephritis with crescents and small vessel vasculitis,8 and membranous glomerulonephritis.9 Clinically, the nephrotic syndrome appears to be the leading feature, whereas oliguric

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