[Downloaded free from http://www.sjmms.net on Wednesday, February 24, 2016, IP: 41.45.223.130]

Case Report

Non-Lupus Glomerulonephritis in a Patient with Systemic Lupus Erythematosus

Emad Abdallah, Bassam Al-Helal1, Reem Asad1, Faisal Shehab2, Abdulrahman Al-Rashidi3 Department of Nephrology, Theodor Bilharz Research Institute, Cairo, Egypt, 1Department of Internal Medicine, Nephrology Unit, Al-Adan Hospital, Kuwait, 3Department of Internal Medicine, Rheumatology Unit, Al-Adan Hospital, Kuwait, 2Department of Internal Medicine, Al-Adan Hospital, Kuwait Correspondence: Dr. Emad Abdallah, Department of Nephrology, Theodor Bilharz Research Institute, Cairo, Egypt. E-mail: [email protected].

ABSTRACT Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can affect almost any organ system. Lupus nephritis (LN) is one of the most serious manifestations of SLE. The occurrence of nonlupus glomerulopathies has been rarely reported in patients with SLE. Here, we report a case of male Kuwaiti patient suffering from SLE with microscopic hematuria and nonnephrotic-range proteinuia. The renal biopsy findings showed IgA nephropathy. Although the incidence of IgA nephropathy is high in Kuwait, we believe that this is the first report of a Kuwaiti patient in whom SLE presented with IgA nephropathy rather than LN.

Key words: IgA nephropahy, lupus nephritis, systemic lupus erythematosus

ملخص البحث : مرض الذئبة الحمراء هو احد أمراض المناعة الذاتية المزمنة الذي قد يؤثر على معظم أعضاء الجسم. ويعتبر التهاب الكلية المناعي من أهم المضاعفات لدى مرضى الذئبة الحمراء, كما يندر حدوث التهاب الكلى المناعي غير المصاحب لمرضى الذئبة الحمراء. يناقش الباحثون حالة مريض يعاني من مرض الذئبة الحمراء مع وجود دم وزالل في البول. بينت نتائج الخزعة من الكلية اعتالال يدعى IgA nephropathy وليس بسبب الذئبة الحمراء.

INTRODUCTION classification criteria in 2012, they classified a person as having SLE in the presence of biopsy-proven lupus Systemic lupus erythematosus (SLE) is a chronic nephritis (LN) with antinuclear antibody (ANA) or anti- autoimmune disease that can affect almost any organ dsDNA antibodies or if four of the diagnostic criteria, system; thus, its presentation and course are highly including at least one clinical and one immunologic variable, ranging from indolent to fulminant. criterion, have been satisfied.[3]

The diagnosis of SLE is based on a combination of clinical Lupus nephritis is one of the most serious manifestations findings and laboratory evidence. The presence of 4 of the of SLE and histologically evident in most patients with 11 American College of Rheumatology (ACR) criteria yields SLE, even those without clinical manifestations of renal [1,2] a sensitivity of 85% and a specificity of 95% for SLE. disease.[4] When the Systemic Lupus International Collaborating CASE REPORT Clinics group revised and validated the ACR SLE A 43-year-old male Kuwaiti patient presented to our renal Access this article online clinic because of persistent microscopic hematuria and Quick Response Code: Website: proteinuria. There was arthralgia, but no skin rash. His www.sjmms.net past history was unremarkable with no history of recent upper respiratory infection or gastroenteritis, and physical

DOI: examination was normal. White blood count was 6.56 × 7 10.4103/1658-631X.162040 10 /L, hemoglobin 132.00 mmol/L, hematocrit 0.37 L/L, platelet 340.00 × 107/L. Erythrocyte sedimentation rate

Saudi Journal of Medicine & Medical Sciences | Vol. 3 | Issue 3 | September 2015 | 241-244 241 [Downloaded free from http://www.sjmms.net on Wednesday, February 24, 2016, IP: 41.45.223.130]

Abdallah, et al.: Non-Lupus GN in SLE

was 60 mm/h. Chemistry values showed serum creatinine Kidney biopsy findings 119 μmol/L, blood urea nitrogen 31.1 mmol/L, serum potassium 5.5 mmol/L, serum sodium 131 mmol/L and Light microscopy sections showed 20 glomeruli, 25% albumin 32 g/L. Total Ca 2.25 mmol/L, phosphorous out of which showed increased cellularity [Figure 1]. 1.39 mmol/L. Total cholesterol 7.4 mmol/L, high density Two glomeruli showed global sclerosis and one with lipoprotein-cholesterol 2.05 mmol/L and triglycerides segmental sclerosis are also seen. Interstitial inflammation 2.38 mmol/L. Liver enzymes were normal. The serological and fibrosis (30%) with areas of tubular atrophy (20%) examination revealed circulating IgG 12.80 g/L were also seen. By immunohistochemistry, the glomeruli (normal range: 7-16 g/L); IgM 0.94 g/L (normal revealed granular deposits of IgA in the glomerular range: 0.56-3.52 g/L); IgA 5.21 g/L (normal range: basement membrane and mesangium [Figure 2]. The 0.7-3.12 g/L). Serum complement levels were within normal range. ANA was positive (1/640 IU/mL), anti- dsDNA antibodies were positive (48.2 IU/mL). IgG and IgM anticardiolipin antibodies were negative. Hepatitis B surface antigen and hepatitis C antibodies were negative. The urine sediment contained 40-50 red blood cells and 2-3 white blood cell/hpf and 24 urinary protein was 2405 mg/day [Table 1]. Abdominal ultrasound revealed normal both kidneys in position, size and echotecture with normal corticomedullary differentiation. Chest X-ray, electrocardiography and echocardiography were normal. The clinical manifestations in combination with ANA, anti-dsDNA antibodies were diagnostic for SLE. Renal

biopsy was performed in order to establish the diagnosis Figure 1: Light microscopy of a glomerulus from a patient with IgA and adequate therapy. nephropathy showing increased mesangial matrix and cellularity.

Table 1: Time course of laboratory characteristics of our patient Variable At admission 70 days later 100 days later 158 days later Serum creatinine (60-106 μmol/l) 119 80 76 90 Blood urea (2.14-7.14 mmol/l) 131 5.2 6.07 5.7 Serum glucose (mmol/l) 5.4 7.33 4.7 5.4 Total cholesterol (3.63-5.19 mmol/l) 7.46 6.46 4.55 4.89 HDL-C (0.83-1.89 mmol/l) 2.05 2.31 1.75 1.83 LDL-C (mmol/l) 4.31 3.08 2.01 2.24 TGs (0.7-2.2 mmol/l) 2.38 2.33 1.72 1.79 Urine analysis (RBCs) (per hpf) 40-50 12-15 10-12 10–12 24 h urinary protein (10-150 mg/day) 2405 1140 350 420.65 ANA screen +ve +ve ANA pattern Speckeled Speckeled ANA titre 1/640 1/160 Anti-ds-DNA (0-20 IU/ml) 48.2 23.5 ANCA −ve −ve ACL IgM, IgG −ve −ve C3 (0.83-1.77 g/l) 1.51 1.43 C4 (0.15-0.45 g/l) 0.33 0.4 IgA (0.7-3.12 g/l) 5.21 4.82 Serum IgG (7-16 g/l) 12.8 12.3 Serum IgM (0.56-3.52 g/l) 0.94 0.87 HBsAg −ve HCV ab −ve HDL-C – High density lipoprotein-cholesterol; LDL-C – Low density lipoprotein-cholesterol; TGs – Triglycerides; RBCs – Red blood cells; ANA – Antinuclear antibody; ANCA – Anti-neutrophil cytoplasnic antibody; ACL – Anticardiolipin; HBsAg – Hepatitis B surface antigen; HCV – Hepatitis C virus

242 Saudi Journal of Medicine & Medical Sciences | Vol. 3 | Issue 3 | September 2015 [Downloaded free from http://www.sjmms.net on Wednesday, February 24, 2016, IP: 41.45.223.130]

Abdallah, et al.: Non-Lupus GN in SLE

There are six classes of LN according to the classification of LN revised by the International Society of Nephrology and the Renal Pathology Society in 2003 and is based on light microscopy, immunofluorescence, and electron microscopy findings from renal biopsy specimens.[8]

These typical LN classes are characterized by staining positively for IgG, IgM, C3, C4 and C1q in the glomerular capillary basement membrane under immunofluorescent microscopy.[9]

In IgA nephropathy, pathologically, a spectrum of glomerular lesions can be seen, but mesangial Figure 2: Immunofluorescence microscopy demonstrating large hypercellularity with prominent IgA deposition is mesangial IgA deposits diagnostic of IgA nephropathy. observed in almost all biopsies.[6,7]

glomeruli were negative for IgG, IgM, C3 and C1q. In our case, immunohistochemistry of the kidney biopsy, The diagnosis was IgA nephropathy; Class 111 (focal the glomeruli showed granular deposits of IgA in the proliferative glomerulonephitis). glomerular basement membrane and mesangium. The glomeruli are negative for IgG, IgM, C3 and C1q.These Our patient was treated with prednisolone 30 mg daily for 2 features of IgA nephopathy (IgAN) do not match with months and then tapered to 20 mg daily, lisinopril 20 mg the typical LN. daily, Omega 3 plus twice a day and atorvastatin 20 mg daily and with follow-up, the proteinuria decreased from 2405 mg/ Therefore, pathologiclly this nonlupus form of day to 420 mg/day and still on close follow-up [Table 1]. glomerulonephrtis should be considered as IgA DISCUSSION nephropathy in the patient with SLE rather than LN, because the prominent IgA deposits in the mesagium IgA nephropathy is the most common cause of dominated the histological picture, and significant glomerulonephritis (GN) in the world.[5-7] Clinical features proliferation was absent. However, according to the [10] range from asymptomatic hematuria to rapidly progressive recommendations of Churg et al. Class IV LN is GN. Pathologically, a spectrum of glomerular lesions can defined by diffuse distribution of subendothelial deposits be seen, but mesangial proliferation with prominent IgA regardless of the pattern of proliferation and the presence deposition is observed in almost all biopsies. of large subendothelial depositions of immunoglobulins without activation of the complement system and Although IgA nephropathy is a limited nonsystemic proliferation is exceptional and although C1q, C3, C4, renal disease, many systemic diseases are sporadically and IgG depositions are more common in typical LN, associated with mesangial IgA deposition. Henoch– IgA deposition can also be seen.[9] Thus, our case with Schönlein purpura, systemic illness, has been closely predominant mesangial IgA deposits may be proposed to linked to IgA nephropathy. Other systemic diseases in be a special subtype of LN. which mesangial deposits of IgA are regularly observed include SLE, hepatitis, dermatitis herpetiformis, and Serum IgA levels are elevated in approximately half ankylosing spondylitis. of patients with IgA nephropathy, but that increase is unlikely to play a role in the pathogenesis of the disease, The occurrence of nonlupus glomerulopathies has been as markedly elevated IgA levels are observed in patients rarely reported in patients with SLE. Here, we report a case with AIDS who do not have IgA nephropathy. However, of male Kuwaii patient suffering from SLE with microscopic IgA is probably accumulated and deposited because of a hematuria and nonnephrotic-range proteinuria. The renal systemic abnormality rather than a defect intrinsic to the biopsy findings showed IgA nephropathy. kidney.[11]

The pathological distinction between IgA nephropathy In our case, IgA was measured in the serum of our and LN should be straightforward because it determines patient and was abnormally high. Serum complement C3 the mode of treatment and the renal prognosis. and C4 levels were within normal range. As stated above,

Saudi Journal of Medicine & Medical Sciences | Vol. 3 | Issue 3 | September 2015 243 [Downloaded free from http://www.sjmms.net on Wednesday, February 24, 2016, IP: 41.45.223.130]

Abdallah, et al.: Non-Lupus GN in SLE

the high serum IgA level and normal complement C3, C4 3. Petri M, Orbai AM, Alarcón GS, Gordon C, Merrill JT, Fortin PR, support the diagnosis of IgA nephropathy. et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012;64:2677-86. To our knowledge, there is a few description in the 4. Condon MB, Ashby D, Pepper RJ, Cook HT, Levy JB, Griffith M, literature of IgA nephropathy in patients with a well- et al. Prospective observational single-centre cohort study to established SLE in whom the renal biopsy findings evaluate the effectiveness of treating lupus nephritis with rituximab are diagnostic for IgA nephropathy have been and mycophenolate mofetil but no oral steroids. Ann Rheum Dis 2013;72:1280-6. reported.[12-17] In all these cases, the renal biopsy showed 5. Glassock RJ. IgA nephropathy: Challenges and opportunities. a mild mesangial hypercellularity with almost exclusively Cleve Clin J Med 2008;75:569-76. deposits of IgA. In these cases, the relationship between 6. Working Group of the International IgA Nephropathy Network SLE and IgAN was discussed, and the result is still and the Renal Pathology Society, Cattran DC, Coppo R, Cook HT, controversial. Most authors concluded that the reported Feehally J, Roberts IS, et al. The Oxford classification of IgA nephropathy: Rationale, clinicopathological correlations, and IgAN as a complication of SLE when the two diseases classification. Kidney Int 2009;76:534-45. [12,13,16] coexist. 7. Working Group of the International IgA Nephropathy Network and the Renal Pathology Society, Coppo R, Troyanov S, Camilla R, Some other authors assumed that IgAN may be a special Hogg RJ, Cattran DC, et al. The Oxford IgA nephropathy clinical subtype of SLE.[15,18] Horino et al.[15] have clinicopathological classification is valid for children as well as adults. Kidney Int 2010;77:921-7. reported a case of a male SLE patient whose renal biopsy 8. Weening JJ, D’Agati VD, Schwartz MM, Seshan SV, Alpers CE, was established as Class II LN. He was given the second Appel GB, et al. The classification of glomerulonephritis in systemic renal biopsy because of repeated proteinuria, and the lupus erythematosus revisited. J Am Soc Nephrol 2004;15:241-50. result suggested IgAN. The authors proposed that IgAN 9. Verma RN, Banerjee AK, Bhattacharya K. Lupus nephritis – light, may be a special clinical subtype of SLE. As there is a electron and immunofluorescent microscopy (a clinicopathological study). Indian J Pathol Microbiol 1989;32:246-51. mutual transition among the types of typical LN, typical 10. Churg J, Bernstein J, Glassock RJ. Renal Diseases, Classification LN may also convert into IgAN. and Atlas of Glomerular Diseases. New York: Igaku-Shoin; 1995. 11. Hahn WH, Suh JS, Cho BS, Kim SD. The enabled homolog gene Furthermore, Hongyan et al.[18] reported 5 cases with SLE polymorphisms are associated with susceptibility and progression in whom, renal biopsy showed that all cases had mainly of childhood IgA nephropathy. Exp Mol Med 2009;41:793-801. IgA deposits and were free of IgG, C1q, and fibrinogen- 12. Basile C, Semeraro A, Montanaro A, Giordano R, De Padova F, related antigen deposits under immunofluorescent Marangi AL, et al. IgA nephropathy in a patient with systemic lupus erythematosus. Nephrol Dial Transplant 1998;13:1891-2. microscopy, which did not match with typical LN and 13. Fujikura E, Kimura T, Otaka A, Arima S, Satoh H, Itoh S, et al. concluded that nephritis with mainly IgAN deposits, IgA nephropathy in the patient with systemic lupus erythematosus as an atypical LN, may be a special subtype of SLE. in remission. Nihon Naika Gakkai Zasshi 2002;91:3282-4. In conclusion, this patient may represent a rare case 14. Corrado A, Quarta L, Di Palma AM, Gesualdo L, Cantatore FP. of IgAN in patient with SLE. Our case highlights the IgA nephropathy in systemic lupus erythematosus. Clin Exp Rheumatol 2007;25:467-9. importance of renal biopsy in SLE patients with urinary 15. Horino T, Takao T, Terada Y. IgA nephropathy in a patient with alterations since a correct diagnosis would permit the systemic lupus erythematosus. Lupus 2010;19:650-4. most appropriate treatment to be started, thus avoiding 16. Kobak S, Hudaverdi O, Keser G, Oksel F. Coexistence of systemic unnecessary immunosuppressive treatments. The lupus erythematosus, Hashimoto’s thyroiditis and IgA nephropathy proposal that this case with predominant mesangial IgA in the same patient. Mod Rheumatol 2011;21:89-91. deposits may be a special subtype of LN needs more 17. Mac-Moune Lai F, Li EK, Tang NL, Li PK, Lui SF, Lai KN. IgA nephropathy: A rare lesion in systemic lupus erythematosus. Mod clinical observation and research. Pathol 1995;8:5-10. 18. Hongyan L, Yi Z, Bao D, Yuewu L, Juan M. A study on clinical and REFERENCES pathologic features in lupus nephritis with mainly IgA deposits and a literature review. Clin Dev Immunol 2013;2013:289316. 1. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus How to cite this article: Abdallah E, Al-Helal B, Asad R, erythematosus. Arthritis Rheum 1997;40:1725. Shehab F, Al-Rashidi A. Non-lupus glomerulonephritis in a 2. American College of Rheumatology. 1997 Update of the patient with systemic lupus erythematosus. Saudi J Med Med Sci 1982 American College of Rheumatology revised criteria for 2015;3:241-4. classification of systemic lupus erythematosus. Available from: Source of Support: Nil. Conflict of Interest: The authors http://www tinyurl.com/1997SLEcriteria. [Last accessed on declare that they have no conflict of interest. 2013 Nov 01].

244 Saudi Journal of Medicine & Medical Sciences | Vol. 3 | Issue 3 | September 2015