Rapidly Progressive IgA Nephropathy - MedIND

Clinical Brief

Rapidly Progressive IgA Nephropathy Naho Kobayashi1, Masashi Nishida1, Michiko Aoyama2, Kentaro Yokoi2, Tomoyo Yahata1, Tatsujiro Oka1, Koichi Sakata1, Isao Shiraishi1, Toshiyuki Itoi1 and Kenji Hamaoka1 1 Departments of Pediatric Cardiology and Nephrology and 2Pediatrics, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan.

Abstract. A 14-year-old boy presented with macroscopic hematuria and a rapid deterioration in renal function. Percutaneous renal biopsy demonstrated severe crescentic IgA nephropathy (IgAN) with extensive (88%) glomerular crescent formation. After started intravenous administration of high-dose pulse methylprednisolone, severe nausea and general malaise accompanied by a rapid increase in Blood Urea Nitrogen (BUN) and serum creatinine levels appeared, however, the renal function ameliorated rapidly and fully recovered by following oral administration of corticosteroid. The clinical presentation of our case seems to be very remarkable compared to previously reported cases of rapidly progressive IgAN. [Indian J Pediatr 2005; 72 (3) : 257-260] E-mail: [email protected]

Key words: IgA nephropathy; Rapidly progressive glomerulonephritis; Diffuse crescentic glomerulonephritis; Acute renal failure

IgA nephropathy (IgAN) was first described in 1969 by Berger and Hinglais and is now recognized as the most common form of glomerulonephritis seen clinically worldwide. While initial reports and reviews indicated that the prognosis of this disease was generally good, extended follow-up of patients showed that there may be a slow deterioration in renal function, occurring over a decade or more, in some patients even in the pediatric series of IgAN.1 However, previous reports also indicate that in rare cases IgAN may develop a rapidly progressive course. 2-4 We report a 14-year-old boy with IgAN presenting with rapidly progressive glomerulonephritis (RPGN) that, despite the high frequency of glomerular crescent formation, a rapid amelioration of renal function has been obtained following treatment mainly with oral administration of corticosteroid. CASE REPORT A 14-year-old boy was referred and admitted to our hospital because of the deterioration in renal function accompanied with general malaise and frequent vomiting. Six days prior to admission, he also developed a sore throat, low-grade fever and macroscopic hematuria. He had been pointed out microscopic hematuria at 9 years of age by school urinary screening for the first time. Laboratory studies showed normal BUN and serum creatinine levels at 9 years of age, and the follow up data of urinalysis thereafter showed persistent Correspondence and Reprint requests : Dr. Masashi Nishida, Department of Pediatric Cardiology and Nephrology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan. Fax: +81-75-251-5833.

Indian Journal of Pediatrics, Volume 72—March, 2005

microscopic hematuria without proteinuria. There was no history of cutaneous manifestations, arthralgia or melena. Family history was negative for renal diseases. Physical examination on admission was unremarkable and blood pressure was normal. Urinalysis showed proteinuria (3+) and there was a large amount of occult blood on admission. Urine protein to creatinine ratio was 2.47. Laboratory studies showed the following: WBC 7 100/µL; Hb 13.4 g/dl; platelets 299 000/µL; serum total protein 6.7 g/dL; albumin 3.3 g/dL; BUN 37 mg/dL; creatinine 2.9 mg/dL; total cholesterol 211 mg/dL; sodium 136 mEq/L; potassium 5.5 mEq/L; chloride 100 mEq/L; calcium 8.4 mg/dL; C-reactive protein 0.7 mg/dL; and fibrinogen 425 mg/dL. Immunological studies showed: IgG 666 mg/dL (normal range, 803-1 785 mg/dL); IgA 418 mg/dL (normal range, 102-411 mg/dL); IgM 40 mg/dL (normal range, 30-207 mg/dL); C3 96 mg/dL (normal range, 68138 mg/dL); C4 32 mg/dL (normal range, 12-35 mg/dL); and hemolytic complement activity 51 U/mL (normal range, 34-49 U/mL). There was no antinuclear antibody, anti-DNA antibody, circulating immune complexes (C1q and C3d), anti-neutrophil cytoplasmic antibody (cytoplasmic and perinuclear staining) or anti-glomerular basement membrane antibody detected. Renal function deteriorated rapidly and on day 4 after admission, BUN was 99 mg/dL, serum creatinine was 5.4 mg/dL and creatinine clearance (Ccr) was 11.5 ml/min/ 1.73m2. Drip infusion with heparin (3 000 U/day) was performed, and although the levels of BUN and serum creatinine gradually decreased without dialytic treatment thereafter, they remained elevated. Urinary volume was 1 500-2 500 mL/day and blood pressure was normal. Both proteinuria and hematuria persisted at the same level. Severe general malaise and nausea were persistent and 257

Naho Kobayashi et al anemia also appeared (Fig. 1). Percutaneous renal biopsy performed on day 23 after admission, when the general state was improved, demonstrated cellular or fibrocellular crescents in 16 of 18 glomeruli (88%) with collapsed remnants of capillary tuft, and most of the crescents were large and widespread (Fig. 2a,b). Diffuse mild proliferation of glomerular mesangial cells and focal infiltration of mononuclear cells in the interstitium were also noted. On immunofluorescence, mesangial deposits of IgA (++), C3 (++) and IgG (+) were present while IgM

Fig. 1. Course of treatment administered, symptoms appeared, BUN and serum creatinine levels in patient with IgA nephropathy. Thick arrows indicate when methylprednisolone pulse therapy (MPT) was administered.

and fibrinogen were weak or negative (Fig. 2c). Electron microscopic examination demonstrated electron dense deposits seen elsewhere in the mesangial area, and also focal thinning and discontinuities in the glomerular basement membrane as well as extensive fusion of the epithelial foot processes (Fig. 2d). Intravenous administration of high-dose pulse methylprednisolone (1 g/day) with heparin (5 000 U/ day) was started after the first renal biopsy. On the day that methylprednisolone pulse therapy (MPT) was started, laboratory studies showed the following: Serum total protein 5.4 g/dL; albumin 2.7 g/dL; BUN 56 mg/dL; creatinine 4.8 mg/dL. However, severe nausea, general malaise and chills accompanied by a rapid increase in BUN and serum creatinine levels reappeared shortly after starting MPT. Urinary volume decreased to 1 000 mL/ day and facial edema with the weight increase of up to 2 kg appeared. Intravenous administration of pulse methylprednisolone was discontinued in two days and oral administration of prednisolone (60 mg/day), dipyridamole (300 mg/day) and warfarin (2 mg/day) was started. Renal function ameliorated rapidly thereafter and on day 71 after admission, BUN and serum creatinine levels had improved to 19 mg/dL and 0.9 mg/dL, respectively, and Ccr was 97.3 ml/min/1.73m 2 (Fig. 1). Along with the improvement of renal function, urinary protein excretion increased and he developed nephrotic syndrome accompanied by hypertension. However, these

Fig. 2(a). Light microscopy of the first renal biopsy specimen. Large cellular or fibrocellular crescents, mild diffuse mesangial proliferation and focal interstitial mononuclear cell infiltration (Periodic acid-Schiff [PAS] stain, × 200). (b) Light microscopy of the first renal biopsy specimen (PAS stain, ×400). (c) Immunofluorescence of the first renal biopsy specimen. IgA deposition in the mesangial area (× 400). (d) Electron microscopy of the first renal biopsy specimen. Electron dense deposits in the mesangial area, extensive foot process fusion and focal thinning and discontinuity (arrow) in the glomerular basement membrane (×16,000).

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Rapidly Progressive IgA Nephropathy symptoms improved gradually with combined administration of enalapril (an angiotensin converting enzyme inhibitor) (5 mg/day) and candesartan (an angiotensin receptor blocker) (4 mg/day). The second renal biopsy performed three months after the first renal biopsy demonstrated fibrocellular or fibrous crescents in 26 of 33 glomeruli (78%) and 4 glomeruli (12%) showed global sclerosis with the presence of focal tubular atrophy (Fig. 3). At present, eighteen months after onset, urinalysis shows proteinuria (1+) and occult blood (10-20 red blood cells per high power field in urinary sediments), serum creatinine is within the normal range (0.7-0.8 mg/dL), and blood pressure and blood hemoglobin levels are also normal. The patient is now under combination therapy consisting of prednisolone (15 mg/day), mizoribine (100 mg/day), dipyridamole (300 mg/day), warfarin (1.5 mg/ day), enalapril (5 mg/day) and candesartan (4 mg/day).

Fig. 3. Light microscopy of the second renal biopsy specimen. Fibrocellular crescents and sclerotic region in glomeruli (PAS stain, × 200).

DISCUSSION In the present case, histological examinations and the lack of Henoch-Schönlein purpura indicated IgAN complicated by a diffuse crescentic RPGN. Although there is no specific therapeutic strategy of proven benefit in IgAN presenting diffuse crescentic RPGN, the use of high-dose pulse methylprednisolone intravenous administration is recommended in severe glomerulonephritis including crescentic immune-complex mediated glomerulonephritis. 5-8 In previous reports, however, even intensive treatments including intravenous MPT and immunosuppressive agents were not effective to halt the deterioration in renal function in severe crescentic IgAN with extensive (more than 80 percent) glomerular crescent formation.2,3,9 In our case, although a deterioration of renal function along with the exacerbation of symptoms such as general malaise and nausea was observed after MPT, a rapid improvement in renal Indian Journal of Pediatrics, Volume 72—March, 2005

function was obtained by subsequent treatment with oral corticosteroid despite extensive glomerular crescent formation. In this perspective, the clinical presentation of this case seems to be very remarkable. Previous reports also described transient and reversible renal failure after MPT as seen in this patient. 10, 11 Increased sodium and water retention caused by a mineralcorticoid’s effect on the renal tubules is considered to be responsible for this MPT-associated transient renal failure, probably by triggering the same mechanisms of acute renal failure as seen in nephrotic patients. Also in this patient, hypoalbuminemia was present before starting MPT and a decrease in urinary volume with water retention was observed during MPT. These observations were consistent with the previously reported mechanisms for this type of renal failure. Careful consideration seems to be required before the MPT administration to children with RPGN. This patient showed a rapid amelioration of renal function following treatment consisting mainly of oral corticosteroids. However, the second renal biopsy performed three months after the first renal biopsy, when the renal function had fully recovered, still showed a high frequency of glomerular crescent formation as well as some sclerotic glomeruli. Thus, a rapid improvement in renal function in the present case seems not to be the result of a dramatic decrease in glomerular crescent formation. Although the pathophysiology of acute crescentic RPGN has not been fully understood, total collapse of the glomerular capillary lumens by compression of capillary tufts with large swollen crescents in the acute stage is considered closely related to the rapid deterioration of renal function. Also in the present case, it is possible that improvement in the swelling of crescents and relaxation of the compressed capillary tufts led to the recovery of blood flow to the capillary lumens, resulting in a rapid improvement in renal function. Furthermore, focal infiltration of mononuclear cells to the interstitium was observed in the first renal biopsy specimen. Thus, the coexisting acute interstitial nephritis may have some relationship with the initial acute deterioration of renal function, and an amelioration of interstitial nephritis may have been related to an improvement of renal function. Nevertheless, because the histological improvement was not evident in glomerular crescent formation in the second renal biopsy of the present case, a careful follow up of renal function seems to be necessary. For treatment of RPGN, because of the heterogeneity in the etiology and underlying diseases as well as the differences in disease status among patients, it would be difficult to choose a single most appropriate therapeutic strategy for all settings. Further studies in the management of diffuse crescentic RPGN are considered necessary. Attention should also be paid to RPGN complicating the management of IgA nephropathy. Conflict of interest statement None declared. 259

Naho Kobayashi et al Acknowledgments There was no funding source for this study.

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