1 Division of Hypertension and Nephrology and 2 Division of Pathology, National Cardiovascular Center, Suita, Japan
Keywords: ANCA-related glomerulonephritis; histology; losartan; minimal-change nephropathy; prednisolone; renal biopsy
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Introduction |
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We report a patient with biopsy-documented minimal-change nephropathy associated with a high myeloperoxidase (MPO)-ANCA titre, who responded favourably to moderate doses of oral prednisolone and losartan, an angiotensin II receptor antagonist. This case suggests that the therapy of ANCA-related glomerulonephritis could be adjusted according to the activity of the disease observed on renal histology.
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Case |
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The patient's blood pressure on admission was 144/86 mmHg, and the physical examination was otherwise unremarkable. Urinalysis showed 2+ proteinuria and 3+ haematuria, with 3040 red blood cells per/high-power field and 35 granular casts per high-power field. Protein excretion over 24 h was 1.5 g. Serum creatinine was 1.5 mg/dl and creatinine clearance was 40 ml/min. C-reactive protein was 2.73 mg/dl (normal <0.3). Antinuclear antibody was at x160 (normal <40). Although microsomal antibody was elevated, x6400 (normal <100), the patient was euthyroid and had no signs of thyroid disease. MPO-ANCA was elevated at 158 EU (normal <10), and PR3-ANCA was negative. MPO-ANCA and PR3-ANCA titres were determined by enzyme-linked immunosorbent assay, using Nephroscholar. MPO-ANC and Nephroscholar.PR3-ANC kits (Nipro Corp., Osaka, Japan). Anti-DNA antibody was negative. Complement levels and antistreptolysin titres were normal. A solitary cyst was found in the right kidney by renal ultrasonography. A chest X-ray showed a small amount of pleural effusion in the right hemithorax. The cultures and cytology of the pleural fluid were negative.
A renal biopsy revealed no mesangial proliferation, but focal tubular atrophy, interstitial fibrosis and lymphocytic infiltrates were noted. Immunofluorescence demonstrated no deposits of IgA, IgG, IgM, C1q, C3, C4 or fibrinogen. Electron microscopy confirmed the absence of mesangial proliferation, thickening of basement membrane, electron-dense deposits and effacement of epithelial foot processes. Therefore the renal biopsy was highly suggestive of minimal-change nephropathy despite high MPO-ANCA titre. As no vasculitic lesions were apparent in the specimen, the likelihood that the patient had a burnt out vasculitis was minimal. Treatment with an angiotensin-converting enzyme inhibitor (enalapril maleate, 5 mg/day) was begun, but it was discontinued after 3 months because it produced a side-effect of an intolerable cough. Treatment with oral prednisolone (30 mg/day) was begun on 13 December 1999, and the dosage was tapered very gradually. An angiotensin II receptor antagonist (losartan, 25 mg/day) was begun on 21 February 2000.
During 2.5 years of follow-up, the patient's MPO-ANCA titre declined steadily to 17 EU in March 2002. The decline in the MPO-ANCA titre was accompanied by a steady decline in the 24-h urinary protein excretion (0.28 g/day in March 2002). Creatinine clearance remained at around 40 ml/min (Table 1).
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Discussion |
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We have reported here on a patient for whom a relatively mild regimen of oral prednisolone and losartan was chosen not on the basis of the MPO-ANCA titre but because of the renal histology. A favourable outcome in this case, with a significant reduction in urinary protein excretion and the maintenance of creatinine clearance counsels caution in the empiric use of cytotoxic agents to treat ANCA-associated renal disease in stable patients.
Since its description in the mid-1980s, the ANCA assay has evolved into a well-established screening test for diagnosing pauci-immune necrotizing crescentic glomerulonephritis (NCGN). There is general agreement that most patients with pauci-immune NCGN have P-ANCA (MPO-ANCA) [1]. It should be remembered, however, that P-ANCA in serum is not an absolute indicator of the presence of NCGN. Some drugs induce P-ANCA seropositivity [2], though this was not relevant in our case, as the patient had not been taking any medication. Treatment should therefore never be based solely on a positive test for P-ANCA, because the correlation of P-ANCA titres with clinical disease activity is not well established [3].
A couple of retrospective studies have demonstrated some prognostic factors in ANCA-associated renal disease. The degree of proteinuria at diagnosis influenced renal survival. Patients with a daily proteinuria of less than 2 g at diagnosis had a better long-term renal survival than those with proteinuria of more than 2 g [4]. Renal survival was inversely correlated with serum creatinine prior to the start of treatment, and with the percentage of sclerosed glomeruli, the degree of tubular atrophy and the extent of arterial sclerosis observed in renal biopsies at diagnosis [5]. The association between proteinuria and renal outcome in patients with ANCA-associated renal disease argues for strict laboratory follow-up, salt restriction, and the use of drugs such as angiotensin II-converting enzyme inhibitors and angiotensin-receptor antagonists to reduce proteinuria in order to retard the loss of renal function. The diagnosis and initiation of therapy for this disease must begin as early as possible in its course to decrease glomerular inflammation and abate renal insufficiency. Some recommend that in the presence of a nephritic urine sediment and a positive ANCA, some form of anti-inflammatory therapy be instituted during the process of evaluation while the kidney biopsy is being performed and its pathological diagnosis reported [5].
Some P-ANCA-positive patients evince a not so rapidly progressive form of glomerulonephritis that progresses to uraemia over months to years [6]. Earlier recognition and consequently earlier treatment of these patients could favourably affect renal outcome. It is difficult, however, to decide how intensive the treatment should be when the renal histology is not markedly deformed. Treatment should be tailored to the severity and extent of the disease. Cyclophosphamide-based regimens carry a high risk of side-effects such as life-threatening infection, neoplasia, infertility and haemorrhagic cystitis. It would be reasonable to reserve cyclophosphamide for severe disease with systemic involvement and use relatively milder regimens for patients with less fulminant disease.
Our case emphasizes the importance of performing renal biopsies before embarking on a full-scale immunosuppression therapy, rather than basing it upon MPO-ANCA titre alone. It should also be borne in mind, however, that due to the technical limitations of renal biopsies, glomerular and vascular lesions could escape detection. This case also emphasizes the importance of adjusting treatment to the age of the patient, the presence of other co-morbidities and to the severity and the type of organ involvement.
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Notes |
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References |
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