Primary Sjögren’s syndrome with minimal change disease—A case report

Kaohsiung Journal of Medical Sciences (2011) 27, 190e194

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CASE REPORT

¨gren’s syndrome with minimal change Primary Sjo diseasedA case report 原發性休葛蘭症候群合併微小變化症腎炎d病例報告 Mei-Li Yang a, Mei-Chuan Kuo a,b, Tsan-Teng Ou c, Hung-Chun Chen a,b,* 楊美利 a, 郭美娟 a,b, 歐燦騰 c, 陳鴻鈞

a,b,

*

a

Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan b Department of Renal Care, Kaohsiung Medical University, Kaohsiung, Taiwan c Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan Received 15 March 2010; accepted 23 July 2010 Available online 2 April 2011

KEYWORDS Minimal change disease; Nephrotic syndrome; Sjo ¨gren’s syndrome; Thin basement membrane nephropathy

關鍵詞

微小變化症腎炎; 腎病症候群; 休葛蘭症候群; 薄基底膜病變

Abstract Glomerular involvement in patients with primary Sjo ¨gren’s syndrome (pSS) has rarely been reported. Among them, membranoproliferative glomerulonephritis and membranous nephropathy are the more common types. We report a middle-aged female presenting concurrently with nephrotic syndrome and microscopic hematuria, and her pSS was diagnosed by positive anti-Ro (SSA)/anti-La (SSB) autoantibodies, dry mouth, severely diffuse impaired function of both bilateral parotid and submandibular glands, and a positive Schirmer test. Renal pathology revealed minimal change disease and thin basement membrane nephropathy. The patient’s nephrotic syndrome resolved after treatment with corticosteroids. To our knowledge, this is the first report of minimal change disease in a patient with pSS. 摘要 過去很少有關於原發性休葛蘭症候群合併腎絲球疾病的報告。其中，又以膜性增殖性腎絲 球腎炎及膜狀腎絲球腎炎比例最多。本報告報導一位中年女性因雙下肢水腫而就醫，經診斷為腎 病症候群，又因其anti-Ro (SSA)/anti-La (SSB) 自體免疫抗體呈陽性反應，嘴巴乾燥，雙側耳下腺 及頷下腺呈彌漫性功能受損，且經Schirmer test診斷為乾眼症，其他檢驗結果顯示無其他結締組 織疾病。因此，診斷此病人罹患原發性休葛蘭症候群。腎臟切片檢查顯示其腎臟有微小變化症腎 炎及薄基底膜病變。此病人經類固醇治療後，腎病症候群之症狀已大有改善。這是首例原發性休 葛蘭症候群合併微小變化症腎炎的報告。 Copyright ª 2011, Elsevier Taiwan LLC. All rights reserved.

* Corresponding author. Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, No. 100, Tzyou 1st Road, 807 Kaohsiung, Taiwan. E-mail address: [email protected] (H.-C. Chen). 1607-551X/$36 Copyright ª 2011, Elsevier Taiwan LLC. All rights reserved. doi:10.1016/j.kjms.2010.07.003

Sjo ¨gren’s syndrome and minimal change disease

191

Introduction Sjo ¨gren’s syndrome (SS) is an autoimmune disease characterized by mononuclear cell infiltration of exocrine tissues and autoantibodies against the ribonucleoprotein particles Ro/SSA and La/SSB. Primary SS (pSS) is distinguished from secondary SS by the absence of other autoimmune diseases, such as rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus [1]. Because of the different criteria for diagnosing pSS and the small groups of patients studied for renal involvement in the previous literature, the reported prevalence of renal manifestations in pSS varies widely from 2% to 67% [2e5]. Among them, tubulointerstitial nephritis resulting in latent or overt tubular abnormalities compromised major renal involvement in pSS and may manifest as Type 1 renal tubular acidosis, nephrogenic diabetes insipidus, hypokalemia without renal tubular acidosis, or Fanconi syndrome [6e10]. However, glomerular involvement in patients with pSS has rarely been reported (Table 1) [3,11e22]. Among them, membranoproliferative glomerulonephritis and membranous nephropathy are the more common types. The small number of case reports limits our knowledge of the biochemical markers, pathogenesis, and treatment of glomerular diseases associated with pSS. In the report, we present the first case of minimal change disease (MCD) associated with pSS. The research concerning this subject is also discussed.

Case presentation A 40-year-old woman was admitted because of general edema for 3 months and intermittent attack of dry mouth.

Table 1

She denied any systemic diseases or specific medication taken previously, including analgesics and Chinese herbs. On admission, the vital signs showed blood pressure of 110/ 70 mmHg, pulse rate of 84/min, respiratory rate of 16e18/ min, and body temperature of 37.2
C. The physical examination only revealed obvious edema over the bilateral lower limbs and mild dryness over the oral mucosa. Laboratory tests revealed a serum albumin of 1.79 g/dL and a cholesterol level of 304 mg/dL. The daily urine protein loss was 6.35 g. Serum creatinine was 0.78 mg/dL (creatinine clearance 87.6 mL/min) and blood urea nitrogen was 12.8 mg/dL. Her liver function was normal. The white blood cell count was 4,600/mL and hemoglobin level was 12.3 g/ dL. Analysis of venous blood gas showed pH 7.352, HCO3 28.4 mEq/L, and pCO2 52.5 mmHg. The serum electrolyte levels were Naþ 138 mEq/L, Kþ 4.2 mEq/L, Ca2þ 4.65 mg/ dL, Mg2þ 2.33 mg/dL, and phosphate 4.2 mg/dL. Further laboratory studies showed mild elevation of immunoglobulin A level (IgA: 461 mg/dL, IgG: 905 mg/dL, IgM: 162 mg/ dL), negative antiglomerular basement membrane antibody, normal antistreptolysin O titer, negative antineutrophil cytoplasmic antibodies, normal b2-microglobulin level (350 mg/dL), and negative indicators for hepatitis B and C markers. The evaluation of serum complement showed normal C3 level (82.9 mg/dL) and slightly decreased C4 level (13 mg/dL). There was no monoclonal component or hypergammaglobulinemia shown by serum and urine immunofixation electrophoresis examination. The serum antinuclear antibody titer was 1:320 (speckled type), and anti-ds DNA was negative. Positive anti-Ro (SSA, >240 U/mL)/anti-La (SSB, 35.6 U/mL) autoantibodies were subsequently found. Urinalysis showed pH 6.0, specific

Summary of glomerulonephritis in previously reported patients with Sjo ¨gren’s syndrome

Reference Current case Chen et al. [11] Guillot et al. [12] Stefanidis et al. [13] Ren et al. [14]

Tsai et al. [15] Kau et al. [16] Watanabe et al. [17] Bossini et al. [3]

Goules et al. [7] Cortez et al. [18] Dussol et al. [19] Khan et al. [20] Siamopoulos et al. [21] Moutsopoulos et al. [22]

Glomerulonephritis

Case number

Minimal change disease and thin basement nephropathy IgA nephropathy Membranous nephropathy Membranous nephropathy Membranous nephropathy Membranoproliferative glomerulonephritis Focal segmental glomerulosclerosis Mesangioproliferative glomerulonephritis IgA nephropathy Cryoglobulinemic glomerulonephritis IgA nephropathy Membranous nephropathy Membranoproliferative glomerulonephritis Mesangioproliferative glomerulonephritis Membranoproliferative glomerulonephritis Mesangioproliferative glomerulonephritis Membranoproliferative glomerulonephritis Crescentic glomerulonephritis Membranoproliferative glomerulonephritis Membranous nephropathy Membranoproliferative glomerulonephritis Membranoproliferative glomerulonephritis Membranous nephropathy

1 2 1 1 1 2 2 3 1 1 1 1 1 1 5 4 1 1 1 1 1 2 1

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gravity of 1.015, microscopic hematuria (red blood cell 3e5/high power field), heavy proteinuria (protein 4þ), and absence of glucosuria. pSS was finally diagnosed according to positive anti-Ro/anti-La autoantibodies, dry mouth with severely diffuse impaired function of the bilateral parotid and submandibular glands revealed by salivary scintigraphy, and positive Schirmer test. Further evaluation showed no evidence of association with other connective tissue diseases or renal tubular acidosis. Renal biopsy was performed to evaluate the cause of nephrotic syndrome. The specimen contained 22 glomeruli. The immunofluorescent studies did not show reaction to any of the IgG, IgA, IgM, C3, C4, and heavy or light chains. Light microscopy revealed unremarkable changes over the glomerulus, tubules, and interstitium. Electron microscopy showed diffuse effacement of the foot processes without electron dense deposits. The glomerular capillary basement membranes were relatively thin with a thickness of 270  46 nm (Fig. 1). These findings were consistent with MCD and thin basement membrane nephropathy (TBMN). Ultimately, the patient’s nephrotic syndrome was resolved gradually after treatment with glucocorticoid.

Discussion Renal involvement is one of the extraglandular manifestations of pSS, although the true prevalence and types of renal diseases are unclear. Some previous studies on renal involvement did not distinguish primary from secondary SS, making it difficult to clarify whether renal involvement contributed to SS per se or to other associated disorders. Therefore, early diagnosis is important for understanding the effects of pSS on renal disorder. The present case of pSS was diagnosed based on the positive anti-Ro/anti-La autoantibodies, dry mouth, and positive findings in the salivary scintigraphy, and Schirmer test, fulfilling the European American co-criteria of 2002 [23]. Renal involvement in SS is usually limited to the tubulointerstitium, with mainly the distal renal tubular acidosis (dRTA) in a reported incidence between 5% and 70% [2e4,14]. The high percentage of patients with dRTA suggests pSS may have important contributions to tubular damages. Glomerular involvement in pSS is far less common than the tubulointerstitium, and the manifestations might be hematuria, proteinuria, or even nephrotic syndrome. In a study by Bossini et al. [3], the incidence of glomerular lesion was 5%. In 62 patients with pSS reported by Aasarød et al. [2], only one case (1.6%) of glomerular involvement was found. A higher incidence of 13.6% of glomerular involvement in pSS was also reported by Ren et al. [14]. As summarized in Table 1, common glomerular diseases associated with pSS were membranoproliferative glomerulonephritis, membranous nephropathy, and mesangioproliferative glomerulonephritis [3,7,12e14,18,20e22]. Moreover, few cases with IgA nephropathy and focal segmental glomerulosclerosis were also reported [11,14,15,17]. MCD, as in our case, was not found in the literature. Glomerular involvement in pSS was associated with older age, longer courses of renal impairment, higher occurrence of late stage of the disease, and higher morbidity and mortality [7]. Thus, the glomerular

Figure 1. Light microscopy showing unremarkable change in glomerulus and renal tubules. (A) Hematoxylin-eosin staining, magnification200. (B) Periodic acid Schiff, magnification200. Electron microscopy showing the effacement of foot processes and thin basement membrane with a thickness of 270  46 nm, without electron dense deposits. (C) Transmission electron microscopy, magnification  4,000.

Sjo ¨gren’s syndrome and minimal change disease involvement in pSS is noteworthy, although it has a much rarer incidence than tubulointerstitial involvement. In the classical manifestations of SS, renal diseases were considered to precede the onset of subjective sicca syndrome. However, Bossini et al. [3] and Tu et al. [10] reported the renal diseases antedated by months or even years of the onset of ocular, oral, or articular abnormalities. In present case, nephrotic syndrome also antedated the subjective symptom of dry mouth. The effects of this timing sequence on the disease prognosis require further evaluation. However, it is clear that serological and imaging evidence for SS should be worked out in patient with unexplained nephrotic syndrome or tubulointerstitial disease, even without subjective sicca syndrome. The pathogenesis of renal involvement in pSS remains unclear. High levels of serum b2-microglobulin, hypergammaglobulinemia, and positive anti-SSA/anti-SSB have been suggested to be associated with dRTA in SS [2,13,14,24]. Urinary b2-microglobulin, N-acetyl-b-glucosaminidase and alkaline phosphatase were also significantly higher in patients with dRTA [2]. On the other hand, deposits of circulating immune complex were thought to be the key factor for developing glomerular diseases. Mixed cryoglobulinaemia and decreased complement C4 were assumed to be significant predictors for developing glomerular diseases in pSS [2,3,7,14,25]. Additionally, Ioannidis et al. [26] showed that low C4 level was an independent predictor of lymphoproliferation, and Theander et al. [27] found that patients with low C4 levels had an increased mortality for lymphoproliferative disease as well as an increased hazard ratio for death. Our case, without lymphoproliferative disease, did not show cryoglobulinemia, but the C4 level was slightly decreased. Because of the limited case reports and the controversial results of previous studies, the associations between these serological markers and glomerular involvements or lymphoproliferative disease in pSS require more studies to be clarified. As a bridge between activated B cells and defective T cells, IgA plays a pivotal role in the pathogenesis of SS. High levels of serum and secretary IgA, IgArheumatoid factor, and IgA-containing circulating immune complexes were reported in previous studies [28]. Additionally, saliva IgA autoantibody, against M3 muscarinic acetylcholine receptor, was shown to be implicated in the pathophysiology of dry mouth in pSS [29]. However, the importance of the slightly elevated serum IgA level related to dry mouth or glomerular disease in our case needs further evaluation. Immune complexes may result in glomerular deposition and play a key role in glomerular disease. Nevertheless, SS is a multifaceted autoimmune disease with an interconnection among different effector T cells, B lymphocytes and antigen-presenting cells. Progressive lymphocyte infiltration, with the highest numbers of CD4þ T helper cells and a lesser numbers of B cells, is often seen in salivary lacrimal glands during the development of SS, especially during the early stage and the very late stage of disease [30]. Diffuse infiltration of the interstitium by lymphocytes and plasma cells were implicated in interstitial nephritis in pSS. However, it is still unclear whether T-cell abnormalities cause pSS-associated glomerular disease as MCD. In our patient with nephritic syndrome and microscopic

193 hematuria, the histological diagnosis was made of MCD associated with TBMN. TBMN, an autosomal dominant disease with excellent prognosis, is characterized by hematuria, minimal proteinuria, normal renal function, and another family member with hematuria. Nogueira et al. [31] described adults with TBMN having microscopic hematuria with heavy proteinuria or nephritic syndrome and concluded that nephritic syndrome might be caused by an associated MCD in some patients with TBMN. This finding is in accordance with the current case. We speculate, therefore, that the nephrotic-range proteinuria in our case is not because of TBMN but rather the manifestation of MCD. However, her family history of benign hematuria for TBMN should be evaluated. Additionally, more accumulated cases are necessary to elucidate whether MCD-superimposed TBMN is just a mere coincidence in the case or there is causal relationship between pSS and kidney disease. In summary, we present the first case of MCD associated with thin basement membrane nephropathy in patient with pSS, and her renal disease anteceded the onset of subjective sicca syndrome.

References [1] Manthorpe R, Asmussen K, Oxholm P. Primary Sjogren’s syndrome: diagnostic criteria, clinical features and disease activity. J Rheumatol 1997;24(Suppl 50):8e11. [2] Aasarød K, Haga HJ, Berg KJ, Hammerstrøm J, Jørstad S. Renal involvement in primary Sjogren’s syndrome. QJM 2000; 93:297e304. [3] Bossini N, Savoldi S, Franceschini F, Mombelloni S, Baronio M, Cavazzana I, et al. Clinical and morphological features of kidney involvement in primary Sjogren’s syndrome. Nephrol Dial Transplant 2001;16:2328e36. [4] Eriksson P, Denneberg T, Larsson L, Lindstro ¨m F. Biochemical markers of renal disease in primary Sjo ¨gren’s syndrome. Scand J Urol Nephrol 1995;29:383e92. [5] Vitali C, Tavoni A, Sciuto M, Maccheroni M, Moriconi L, Bombardieri S. Renal involvement in primary Sjogren’s syndrome: a retrospective-prospective study. Scand J Rheumatol 1991;20:132e6. [6] Cohen EP, Bastani B, Cohen MR, Kolner S, Hemken P, Gluck SL. Absence of Hþ-ATPase in cortical collecting tubules of a patient with Sjogren’s syndrome and distal renal tubular acidosis. J Am Soc Nephrol 1992;3:264e71. [7] Goules A, Masouridi S, Tzioufas AG, Ioannidis JP, Skopouli FN, Moutsopoulos HM. Clinically significant and biopsy-documented renal involvement in primary Sjogren syndrome. Medicine (Baltimore) 2000;79:241e9. [8] Kobayashi T, Muto S, Nemoto J, Miyata Y, Ishiharajima S, Hironaka M, et al. Fanconi’s syndrome and distal (type 1) renal tubular acidosis in a patient with primary Sjo ¨gren’s syndrome with monoclonal gammopathy of undetermined significance. Clin Nephrol 2006;65:427e32. [9] Shearn MA, Tu WH. Nephrogenic diabetes insipidus and other defects of renal tubular function in Sjo ¨gren’s syndrome. Am J Med 1965;39:312e8. [10] Tu WH, Shearn MA, Lee JC, Hopper J. Interstitial nephritis in Sjo ¨gren’s syndrome. Ann Intern Med 1968;69:1163e70. [11] Chen Y, Zhao X, Tang D, Xu C, Sun L, Sun L, et al. IgA nephropathy in two patients with Sjo ¨gren’s syndrome: one with concomitant autoimmune hepatitis. Intern Med 2010;49: 37e43.

194 [12] Guillot X, Solau-Gervais E, Coulon A, Debiais F. Sjo ¨gren’s syndrome with ANCA-associated crescentic extramembranous glomerulonephritis. Joint Bone Spine 2009;76:188e9. [13] Stefanidis I, Giannopoulou M, Liakopoulos V, Dovas S, Karasavvidou F, Zachou K. A case of membranous nephropathy associated with Sjo ¨gren’s syndrome, polymyositis and autoimmune hepatitis. Clin Nephrol 2008;70:245e50. [14] Ren H, Wang WM, Chen XN, Zhang W, Pan XX, Wang XL, et al. Renal involvement and followup of 130 patients with primary Sjo ¨gren’s syndrome. J Rheumatol 2008;35:278e84. [15] Tsai TC, Chen CY, Lin WT, Lee WJ, Chen HC. Sjogren’s syndrome complicated with IgA nephropathy and leukocytoclastic vasculitis. Ren Fail 2008;30:755e8. [16] Kau CK, Hu JC, Lu LY, Tseng JC, Wang JS, Cheng HH. Primary Sjo ¨gren’s syndrome complicated with cryoglobulinemic glomerulonephritis, myocarditis, and multi-organ involvement. J Formos Med Assoc 2004;103:707e10. [17] Watanabe M, Fujimoto T, Iwano M, Shiiki H, Nakamura S. Report of a patient of primary Sjo ¨gren’s syndrome, IgA nephropathy and chronic idiopathic thrombocytopenic purpura. Nihon Rinsho Meneki Gakkai Kaishi 2002;25:191e8. [18] Cortez MS, Sturgill BC, Bolton WK. Membranoproliferative glomerulonephritis with primary Sjo ¨gren’s syndrome. Am J Kidney Dis 1995;25:632e6. [19] Dussol B, Tsimaratos M, Bolla G, Harle ´ JR, Brunet P, Casanova P, et al. Crescentic glomerulonephritis and primary Gougerot-Sjo ¨gren syndrome. Nephrologie 1994;15:295e8. [20] Khan MA, Akhtar M, Taher SM. Membranoproliferative glomerulonephritis in a patient with primary Sjo ¨gren’s syndrome. Report of a case with review of the literature. Am J Nephrol 1988;8:235e9. [21] Siamopoulos KC, Mavridis AK, Elisaf M, Drosos AA, Moutsopoulos HM. Kidney involvement in primary Sjo ¨gren syndrome. Scand J Rheumatol Suppl 1986;61:156e60.

M.-L. Yang et al. [22] Moutsopoulos HM, Balow JE, Lawley TJ, Stahl NI, Antonovych TT, Chused TM. Immune complex glomerulonephritis in sicca syndrome. Am J Med 1978;64:955e60. [23] Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carson SE, et al. The European Study Group on Classification Criteria for Sjo ¨gren’s Syndrome. Classification criteria for Sjo ¨gren’s syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 2002;61:554e8. [24] Pertovaara M, Korpela M, Pasternack A. Factors predictive of renal involvement in patients with primary Sjo ¨gren’s syndrome. Clin Nephrol 2001;56:10e8. [25] Skopouli FN, Dafni U, Ioannidis JP, Moutsopoulos HM. Clinical evolution and morbidity and mortality of primary Sjo ¨gren’s syndrome. Semin Arthritis Rheum 2000;29:296e304. [26] Ioannidis JP, Vassiliou VA, Moutsopoulos HM. Long-term risk of mortality and lymphoproliferative disease and predictive classification of primary Sjogren’s syndrome. Arthritis Rheum 2002;46:741e7. [27] Theander E, Manthorpe R, Jacobsson LT. Mortality and causes of death in primary Sjogren’s syndrome: a prospective cohort study. Arthritis Rheum 2004;50:1262e9. [28] Levy Y, Dueymes M, Pennec YL, Shoenfeld Y, Youinou P. IgA in Sjo ¨gren’s syndrome. Clin Exp Rheumatol 1994;12:543e51. [29] Alejandro B, Leonor SB, Sandra B, Borda E. Role of salivary IgA in the pathogenesis of Sjo ¨gren’s syndrome. Clin Immunol 2002;104:49e57. [30] Lee BH, Tudares MA, Nguyen CQ. Sjo ¨gren’s syndrome: An old tale with a new twist. Arch Immunol Ther Exp 2009;57: 57e66. [31] Nogueira M, Cartwright Jr J, Horn K, Doe N, Shappell S, Barrios R, et al. Thin basement membrane disease with heavy proteinuria or nephrotic syndrome at presentation. Am J Kidney Dis 2000;35:E15.