Emerging Minimal-change Nephrotic Syndrome in a Patient with Chronic Mesangial Proliferative Lupus Nephritis

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1 CASE REPORT Emerging Minimal-change Nephrotic Syndrome in a Patient with Chronic Mesangial Proliferative Lupus Nephritis Naoko Deji, Toshiro Sugimoto, Masami Kanasaki, Masahiro Aoyama, Yuki Tanaka, Masayoshi Sakaguchi, Yoshihiko Nishio, Takashi Uzu and Atsunori Kashiwagi Abstract A 41-year-old Japanese woman with a 25-year history of systemic lupus erythematosus was admitted because of abrupt onset of nephrotic syndrome and acute renal failure. Renal biopsy specimen showed only mild mesangial proliferative glomerulonephritis associated with mesangial deposition of immunoglobulins/ complements. No significant immune deposits were found in the glomerular capillary walls, but mild foot process effacement was observed on electron microscopy. Further, two-month corticosteroid therapy improved her massive proteinuria and renal dysfunction, indicating that this patient showed minimal-change nephropathy superimposed on mesangial proliferative lupus nephritis. Key words: mesangial proliferative lupus nephritis, minimal-change nephropathy, nephrotic syndrome, systemic lupus erythematosus (DOI: /internalmedicine ) Introduction Systemic lupus erythematosus (SLE) commonly involves the kidney, which is known as lupus nephritis (1, 2). The various forms of lupus nephritis are classified following the recommendations of the World Health Organization (WHO, 1,2) and the International Society of Nephrology (ISN, 3), and the clinical manifestations of lupus nephritis vary from no or mild urinary abnormalities to severe renal insufficiency (1, 2). Nephrotic syndrome is thought usually to occur in SLE patients in association with immune aggregate deposition in the glomerular capillary wall, frequently accompanied by endocapillary proliferation or necrosis [e.g., ISN, Class III/IV or Class V, (1, 2, 4)]. Here, we describe a patient with chronic SLE who suddenly developed acute renal failure with nephrotic-range proteinuria, although the kidney biopsy showed only mild mesangial proliferative lupus nephritis (ISN, Class II) on light microscopy. Case Report A 41-year-old Japanese woman with a 25-year history of SLE was admitted because of sudden development of systemic edema. At the age of 17, she developed facial erythema and arthritis with high titers of anti-nuclear antibodies and anti-double-stranded DNA antibodies, and was diagnosed as having SLE, and was started on corticosteroid therapy. Although she did not show any remarkable urinary abnormalities, renal biopsy, performed when she was 18, revealed mild mesangial proliferative lupus nephritis (ISN, class II). Right breast cancer was surgically removed two years prior to admission, and she had been treated with an estrogen antagonist, tamoxifen. Two months prior to admission, severe back pain developed and marked sacroiliitis was identified with bone scintigraphy; thus, the dose of prednisolone was increased, from 10 mg/day to 20 mg/day. She had never been noted to have marked proteinuria, hypertension, or renal dysfunction, but she had noticed the sudden development of leg edema several days before admission. On admission, the patient was in mild distress and her blood pressure was 116/80 mmhg. No new skin lesions were found. No remarkable physical abnormalities were identified except for marked systemic pitting edema. The results of laboratory examination revealed the following findings: the urine was 4+ positive for protein with daily excretion at 12 g (selectivity index: CIgG/C transferrin, 0.104), and the urinary sediments contained no red blood cells, Department of Internal Medicine, Shiga University of Medical Science, Otsu Received for publication January 18, 2007; Accepted for publication March 11, 2007 Correspondence to Dr. Toshiro Sugimoto, toshiro@belle.shiga-med.ac.jp 991

2 Figure1. Renalbiopsyshowstheslightwideningoftheinterstitialspacewithedema(A,Hematoxylinandeosinstain;magnification, 100)andmildmesangialhypercelularity(B,Hematoxylin andeosinstain, 400;C,PeriodicacidSchifstain, 400;D,Silver-methenaminestain, 400). Figure2. Immunofluorescencestudyshowsmesangialdepositionofimmunoglobulinsandcom plementsintheglomeruli(a,igg;b,c3;magnification, 400). white blood cells, or granular casts; hematocrit was 44.7%; hemoglobin, 14.1 g/dl; white blood cells, 6,900/μl; and platelets, 251,000/μl. Peripheral blood smear and coagulation screen were normal. Total protein was 4.2 g/dl; albumin, 1.8 g/dl; alanine aminotransferase, 12 IU/l; aspartate aminotransferase, 16 IU/l; lactate dehydrogenase, 201 IU/l; alkaline phosphatase, 156 IU/l; total bilirubin, 0.38 mg/dl; and creatine kinase, 31 IU/l. Blood urea nitrogen was 28 mg/dl; creatinine, 1.03 mg/dl; Na, 139 meq/l; K, 4.3 meq/l; Cl, 103 meq/l; Ca, 7.2 mg/dl; phosphorus, 4.6 mg/dl; and uric acids, 7.7 mg/dl. Twenty-four-hour creatinine clearance was 42 ml/min. Neither marked inflammatory signs (Creactive protein was 0.09 mg/dl) nor hypocomplementemia (C3 was 86 mg/dl, and C4 18 mg/dl) were identified. The serum was positive for anti-nuclear antibody (1 320) and anti-double-stranded DNA antibody (47.4 IU/ml, normal value <20), but was negative for anti-cardiolipin antibodies and anti-neutrophil cytoplasmic antibodies. A chest X-ray film revealed bilateral pleural effusion, and an echocardiogram showed normal cardiac function. Neither kidney atrophy nor obstruction of the urinary tracts was found on an abdominal echogram. Percutaneous renal biopsy was performed on day 5. On light microscopy of a specimen of renal tissue consisting of 21 glomeruli, all glomeruli showed mild hypercellularity in the mesangium (Fig. 1). No endocapillary proliferation, segmental tuft necrosis, or fibrous/cellular crescents was observed in any of the glomeruli. The interstitial space was slightly widened with edema, and slight interstitial cell infiltration/interstitial fibrosis were also observed. Immunofluorescence microscopic examination disclosed the mesangial deposition of immunoglobulins (IgG, IgM, and IgA) and complements (C3, C4 and C1q) but revealed no marked immune deposits in the capillary walls (Fig. 2). Under electron microscopy, electron-dense deposits were found mainly in the mesangial areas, not in the peripheral capillary walls, and mild foot process effacement was observed (Fig. 3). As our patient showed nephrotic syndrome with renal dysfunction, oral corticosteroids, prednisolone at 50 mg/day, was started on day 6. Her renal function, however, deteriorated, serum creatinine levels were elevated, and oliguria also developed with low urinary sodium concentrations (less 992

3 Figure3. Electronmicroscopicstudyshowselectron-densedeposits(arrows)mainlyinthemesangialareas(A),andnotintheperipheralcapilarywals(B),andmildfootprocesefacement (arrowheads)inthevisceralepithelialcels (originalmagnification, 2500). Figure4. Clinicalcourseofpresentcase.S-Cr,serum creatinine;u-na,urinarysodium concentration,fena,fractionalexcretionofsodium. than 10 meq/l); fractional urinary excretion of sodium (FENa) was less than 0.50% (Fig. 4). Therefore, intravenous diuretics and albumin were started. On day 31, urinary volume started to increase and renal function gradually improved. Further, daily urinary protein excretion also decreased. Eight weeks after admission, her renal function was completely improved and her urinary protein excretion was reduced to below 0.5 g/day, and she was discharged. Discussion We encountered a SLE patient presenting with sudden onset of nephrotic syndrome. Her renal biopsy had shown mesangial proliferative lupus nephritis (ISN, Class II) at the onset of SLE; thus, we initially suspected that the transformation of lupus nephritis might have occurred, from Class II to Class III/IV or Class V in the ISN classification. However, renal biopsy on this admission revealed that her nephrotic syndrome might be caused by minimal-change nephropathy superimposed on chronic mesangial lupus nephritis, for several reasons. First, the increasing titers of anti-dna antibodies and hypocomplementemia, which usually precede active lupus nephritis, were not found. Second, her renal biopsy specimen showed only mild mesangial hy- 993

4 percellularity with mesangial immune deposits, which is consistent with mesangial proliferative lupus nephritis (ISN, Class II), in spite of massive proteinuria and acute renal failure. Third, no significant capillary wall immune complex was found, but mild foot process effacement was observed with electron microscopy. Fourth, the two-month corticosteroid therapy did improve her renal function and completely reduce her urinary protein excretion. Finally, she had no known causes of minimal-change nephropathy [e.g., nonsteroidal anti-inflammatory drugs and hematological malignancies (5)]. The present patient presented with acute renal failure in association with nephrotic syndrome. Acute renal failure commonly occurs in patients with minimal-change nephropathy and this renal impairment might be caused by ischemic tubular injury, interstitial edema, plasma volume depletion, or reduced glomerular permeability (6). She showed marked hypoalbuminemia (less than 2.0 g/dl), low levels of FENa, and the minor renal tubular/interstitial lesions; indicating that a diminished effective circulating plasma volume might have been the primary cause of her reversible renal failure. Recently, there are increasing numbers of reports of the occurrence of nephrotic syndrome due to minimal-change nephropathy or focal segmental glomerulosclerosis in patients with SLE, particularly those that are superimposed on mesangial proliferative lupus nephritis (ISN, class II) (7-15). Up to 20 cases have been reported of the association between SLE and minimal change nephropathy (7-15). All these cases, like the present case, showed foot process effacement in the absence of significant peripheral capillary wall immune deposits. Hertig et al retrospectively studied 11 patients with SLE and abrupt onset of nephrotic syndrome with severe hypoalbuminemia (15). They described four cases of minimal change nephropathy and seven of focal segmental glomerulosclerosis. In these cases, glomerular immune deposits were limited to mesangial areas, which could not account for massive proteinuria. Further, these nephrotic syndromes coincided with the appearance or recurrence of SLE. Therefore, Lewis et al (16, 17) have hypothesized that these occurrences of minimal-change nephropathy/focal segmental glomerulosclerosis in SLE represent a form of lupus podocytopathy caused by the dysregulated T-cell cytokine mechanisms associated with SLE, which are toxic to the glomerular epithelial cells and promote proteinuria. The question, however, remains whether these glomerular diseases are a mere simple coincidence or a real association in patients with SLE. The present patient had suffered from chronic mesangial proliferative lupus nephritis (ISN, Class II) without any remarkable urinary abnormalities. Several months before the abrupt onset of nephrotic syndrome, she had shown a flare of SLE with sacroiliitis (18), and the dose of corticosteroid had been increased, indicating that the onset of nephrotic syndrome might be correlated with the disease activities of SLE in this case. Further, she had been treated with the estrogen antagonist, tamoxifen, for two years, when nephrotic syndrome occurred. The occurrence of steroid-responsive nephrotic syndrome has been reported in a woman receiving tamoxifen as treatment for early breast cancer (19); our patient, however, continued to take tamoxifen during this presenting episode; thus, tamoxifen might not be directly related to the development of our patient s nephrotic syndrome. Treatment with tamoxifen, however, has been reported to have beneficial effects on experimental animal SLE via the modulation of B-cell counts or cytokine receptor expression (20, 21); thus, there is a possibility that tamoxifen might be related to the atypical manifestations of lupus nephritis in our case through the alteration of immunological dysregulation of SLE. The present case indicates that physicians should be alert for the occurrence of minimal-change nephropathy/focal segmental glomerulosclerosis when abrupt onset of nephrotic syndrome is seen in patients with SLE, and that clinical and laboratory findings can not simply predict the underlying glomerular lesions; thus, renal biopsy is essential for the approach to lupus nephritis. These renal pathological changes, minimal-change nephropathy/ focal segmental glomerulosclerosis in SLE, have not been mentioned in the current classification of lupus nephritis (3); thus, the present case merits presentation because further accumulation of clinical studies including case reports is necessary to confirm the idea that lupus podocytopathy might cause nephrotic syndrome in patients with SLE. References 1. Churg J, Berstein J, Glassock RJ. Lupus nephritis. In: Renal Diseases, Classification and Atlas of Glomerular Diseases. 2nd ed. Igaku-Shoin, New York, 1995: D Agati VD. Renal disease in systemic lupus erythematosus, mixed connective tissue disease, Sjögren syndrome, and rheumatoid arthritis. In: Heptinstall s Pathology of the Kidney. 6th ed. Jennette JC, Olson JL, Schwartz MM, Silva FG, Eds. Lippincott- William & Wilkins, Philadelphia, 2007: Weening JJ, D Agati VD, Schwartz MM, et al. International Society of Nephrology Working Group on the Classification of Lupus Nephritis; Renal Pathology Society Working Group on the Classification of Lupus Nephritis. The classification of glomerulonephritis in systemic lupus erythematosus revised. Kidney Int 65: , 2004 (Erratum in Kidney Int 65:1132, 2004). 4. Baldwin DS, Gluck MC, Lowenstein J, Gallo GR. Lupus nephritis: Clinical course as related to morphological forms and their transition. Am J Med 62: 12-30, Olson JL. The nephrotic syndrome and minimal change disease. In: Heptinstall s Pathology of the Kidney. 6th ed. Jennette JC, Olson JL, Schwartz MM, Silva FG, Eds. Lippincott-William & Wilkins, Philadelphia, 2007: Rose BD. Acute renal failure minimal change disease and other forms of nephritic syndrome. In: UptoDate, CD-ROM: version Rose BD, Ed. Wellesley, MA: UptoDate; Makino H, Haramoto T, Shikata K, Ogura T, Ota Z. Minimalchange nephrotic syndrome associated with systemic lupus erythematosus. 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