IgA-dominant Postinfectious Glomerulonephritis Associated with Escherichia coli Infection Caused by Cholangitis

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1 CASE REPORT IgA-dominant Postinfectious Glomerulonephritis Associated with Escherichia coli Infection Caused by Cholangitis Hiroaki Kikuchi 1, Makoto Aoyagi 1, Kiyotaka Nagahama 2, Chisato Yamamura 1, Yohei Arai 1, Suguru Hirasawa 1, Shota Aki 1, Naoto Inaba 1, Hiroyuki Tanaka 1 and Teiichi Tamura 1 Abstract A 76-year-old man with a history of type 2 diabetes mellitus was admitted with cholangitis caused by cholangiocarcinoma. Cholangitis with Escherichia coli (E. coli) bacteremia recurred due to the unstable bile drainage. At 1 month after recurrence, rapidly progressive glomerulonephritis with nephrotic syndrome was manifested. Renal biopsy findings were consistent with immunoglobulin A (IgA)-dominant postinfectious glomerulonephritis (PIGN). After ensuring that the recurrent cholangitis was controlled by drainage and antibiotic therapy, oral prednisolone was initiated, and the patient s renal function and proteinuria subsequently gradually improved. This is the first case report of IgA-dominant PIGN associated with cholangitis caused by E. coli infection. Key words: rapidly progressive glomerulonephritis, Escherichia coli, cholangitis () () Introduction Postinfectious glomerulonephritis (PIGN) is an immunemediated glomerulonephritis caused by non-renal bacterial infection. PIGN is primarily a childhood disease that occurs following upper respiratory tract infection. In adults, PIGN is more common in immunocompromised patients, particularly diabetics and alcoholics (1). In 2011, Nasr et al. reported the pathological features of 109 cases of PIGN in patients older than 65 years of age (1). Using immunofluorescence, they showed that C3 is the dominant or co-dominant immune reactant detected in the glomeruli during typical PIGN (1). They also reported that Staphylococcus was the most common causative infectious agent, and E. coli accounted for only 5% of the total infectious agents associated with PIGN. Immunoglobulin A (IgA)-dominant postinfectious glomerulonephritis was first described by Nasr et al. in 2003 as a morphological variant of PIGN (2). This type of PIGN is pathologically different from typical PIGN in that the dominant immune reactant in the glomeruli is not C3, but IgA on immunofluorescence (2). To date, approximately 80 cases of IgA-dominant PIGN have been reported in the literature (3). The vast majority of reported cases occur in association with staphylococcal infection, as with typical PIGN. However, to the best of our knowledge, only three cases of IgA-dominant PIGN associated with E. coli infection have been reported (1, 4). We herein report a patient with IgA-dominant PIGN associated with E. coli infection caused by cholangitis. The patient was successfully treated with oral steroid therapy. Case Report A 76-year-old man with a medical history of type 2 diabetes mellitus (which was well controlled by lifestyle modification alone) and Parkinson s disease was admitted to our hospital in late August 2012 with complaint of fever and abdominal pain. Endoscopic findings showed a biliary tract obstruction caused by cholangiocarcinoma, which was clinically classified into T2N0M0. A diagnosis of acute obstructive cholangitis was established. For biliary drainage, a plastic stent was inserted into the narrow segment of his com- Department of Nephrology, Yokosuka Kyosai Hospital, Japan and Department of Pathology, Yokohama City University, School of Medicine, Japan Received for publication February 20, 2014; Accepted for publication May 2, 2014 Correspondence to Dr. Hiroaki Kikuchi, hiroaki.k1114@gmail.com 2619

2 mg/dl PSL 20mg 17.5 mg 15 mg Purpura mg/dl Biopsy 8 6 Recurrence of Cre CRP g/day or g/gcre 4 U-pro Sep 2012 Oct 2012 Nov 2012 Dec 2013 Jan 2013 Feb Figure 1. Clinical course of the urine protein, serum creatinine, and C-reactive protein (CRP) levels. Cre: serum creatinine, g/gcr: urinary protein to urinary creatinine ratio, U-pro: urinary protein, PSL: prednisolone mon bile duct via endoscopy. The biopsy sample collected from this section revealed adenocarcinoma. Immediately after initiating biliary drainage and starting empirical antibiotic therapy, all symptoms described above disappeared in conjunction with the improvement of the patient s hepatobiliary enzymes as revealed by the laboratory testing. No infectious agent was detected in a blood culture on admission. However, in mid-september, purpura manifested on both of the patient s lower legs, and the hepatobiliary enzyme levels were again elevated. Four days following the skin manifestation, the patient became slightly febrile; concurrently, an evident level of proteinuria and hematuria appeared. The patient had not exhibited these abnormal urinary findings in the past. At the beginning of October, his body temperature rose to 38.3, with a blood pressure of 154/78 mmhg and pulse rate of 74 beats/min. Laboratory data revealed: white blood cell count, 10,200/μL; aspartate aminotransferase (AST) concentration, 474 U/L; alanine aminotransferase (ALT) concentration, 92 U/L; alkaline phosphatase (ALP) concentration, 1,726 U/L; γ-glutamyltransferase (γ-gtp) concentration, 398 U/L; total bilirubin (T. Bil) concentration, 3.3 mg/dl; and direct bilirubin (D. Bil) concentration, 2.3 mg/dl. Based on these findings, recurrence of cholangitis was highly suspected, and endoscopic findings showed the obstruction of the plastic stent, which was displaced by cholangiocarcinoma. At this time, in contrast to the patient s first admission, multiple blood cultures and a bile culture were positive for E. coli. Therefore, empirical antibiotic therapy was resumed, and an endoscopic nasobiliary drainage (ENBD) tube was newly inserted as a more reliable method of drainage. This immediately relieved the patient s symptoms and his laboratory results returned to the preadmission levels (Fig. 1). In late October, despite stable continuous bile drainage from the ENBD tube, the patient s renal function rapidly deteriorated with severe proteinuria (Fig. 1). Therefore, the patient was referred to the Department of Nephrology at the beginning of November. On referral, he was afebrile, his height and body weight were 162 cm and 51.6 kg, respectively, and physical findings showed marked pitting edema and purpura on both of his legs. A skin biopsy showed leukocytoclastic vasculitis. No abnormal signs were found in the abdomen. The laboratory examination revealed deteriorated renal function, decreased levels of total protein and albumin, and a slightly elevated ALP concentration. Urinalysis showed severe proteinuria and heavy hematuria with a variety of casts, which led to a diagnosis of rapidly progressive glomerulonephritis (RPGN). Antinuclear antibodies, anti- 2620

3 Table 1. Laboratory Data at Time of Referral to Department of Nephrology Blood count Serology White blood cells 7,000 IgG 1,120.5 mg/ Neutrophils 72.5 % IgA mg/ ymphocytes 16.0 % IgM 63.2 mg/ Monocytes 6.0 % IgE 79 IU/m Eosinophils 4.0 % C mg/ Basophils 1.0 % C mg/ Red blood cells CH CH50/m Hemoglobin 9.8 g/ CRP 2.56 mg/ Platelets RA <3 IU/m ANA - P-ANCA <10 EU C-ANCA <10 EU Anti-GBM antibody <10 EU Blood chemistry Cryoglobulin - Sodium 140 ASO 18 IU/m Potassium 4.1 Chloride 107 Urinalysis Urea nitrogen 44 mg/ Protein 1.97 g/day Creatinine 2.79 mg/ Occult blood (3+) Total protein 5.4 g/ Glucose (-) Albumin 2.0 g/ Sediment AST 12 RBC /HPF 7 WBC 1-4 /HPF Glucose 120 mg/ RBC casts 1-4 /HPF T. Chol 98 mg/ Granular casts 5-9 /HPF Chol 41 mg/ MG 3,180 NAG 38.7 AST: aspartate aminotransferase, A T: alanine aminotransferase, Chol: cholesterol, CH50:50% hemolytic unit of complement, CRP: C-reactive protein, RF: rheumatoid factor, ANA: anti-nuclear antibody, P-ANCA: myeloperoxidase-anti-neutrophil cytoplasmic antibody, C-ANCA: serine proteinase 3-anti-neutrophil cytoplasmic antibody, GBM: glomerular basement membrane, ASO: anti-streptolysin O antibody, RBC: red blood cells, WBC: white blood cells, MG: beta-2-microglobulin, NAG: N-acetyl- lucosaminidase Figure 2. Light microscopy (LM) of a glomerulus showing endocapillary proliferation with mild mesangial proliferation and cellular crescent formation (periodic acid-schiff stain, original magnification 200 ) neutrophil cytoplasmic antibodies, and rheumatoid factor were negative (Table 1). A renal biopsy was performed one week following the patient s referral to the Department of Nephrology. The biopsy specimens contained 16 glomeruli. Light microscopy (LM) showed 2 sclerotic glomeruli, 6 glomeruli with cellular crescents, and 10 glomeruli with endocapillary proliferation (Fig. 2). The severity of the endocapillary proliferation varied with each glomerulus, and tuft necrosis was apparent within most of these glomeruli. Diabetic changes were not evident in the patient. In the interstitium, moderate mononuclear cell infiltration was observed. On immunofluorescence (IF), intense deposits of IgA and weak deposits of C3 were positive in the mesangium and segmentally along the capillary walls (Fig. 3). The glomerular staining for immunoglobulin G (IgG), immunoglobulin M (IgM), C4, or C1q was negative. On electron microscopy (EM), hump-shaped subepithelial electron-dense deposits were present (Fig. 4). Due to the patient s recent history of biliary infection preceding the onset of RPGN, we diagnosed him with IgAdominant postinfectious glomerulonephritis. Because the bile drainage was definitively performed, and the patient had no physical signs of recurrence of infection, we determined that the active infection caused by the bile obstruction was completely eradicated. Although EM of the biopsy result was not available at this point, to prevent further deterioration of the patient s kidney function, prednisolone (20 mg/day) therapy was started soon after obtaining the LM and IF results. Thereafter, the patient s RPGN gradually improved 2621

4 IgA IgG IgM C3 C4 Figure 3. Immunofluorescence microscopy shows tight granular deposits of IgA and weak deposits of C3 in the mesangium and along the glomerular capillary walls (original magnification 200 ). Figure 4. Electron microscopy shows hump-shaped subepithelial deposits (original magnification 20,000 ). (Fig. 1). At the end of December, the patient s serum creatinine level was 1.25 mg/dl, and in February 2013, his 24- hour urinary protein level was 0.33 g. The oral prednisolone was gradually tapered while the patient was in an outpatient clinic. At follow-up on August 2013, the patient was being treated with 12.5 mg/day of prednisolone, and his serum creatinine level was 1.00 mg/dl. The patient s proteinuria and hematuria completely disappeared. Discussion In adults, PIGN is more common in immunocompromised patients, particularly diabetics and alcoholics (1, 5). The major site of infection is the skin, followed by the lungs (pneumonia) and the urinary tract (1). In terms of causative agents, Staphylococcus is the most common cause in elderly people, followed by Streptococcus. Gram-negative bacteria, including E. coli, are responsible for up to 10% of cases of adult PIGN (5, 6) and 5% of cases in the elderly (1). For a diagnosis of PIGN, Nasr et al. reported that at least three of the following five criteria must be satisfied (1): 1) clinical or laboratory evidence of an infection preceding the onset of glomerulonephritis (GN); 2) decreased serum complement levels; 3) endocapillary proliferative and exudative GN on LM; 4) C3-dominant or co-dominant glomerular staining on IF; and 5) hump-shaped subepithelial deposits on EM. In the present case, 4 of the 5 criteria (including the episode of cholangitis and pathological findings on LM, IF, and EM) were met. Furthermore, dominant deposition of IgA on IF led us to suspect a diagnosis of IgA-dominant PIGN caused by cholangitis. IgA-dominant PIGN is an increasingly recognized morphological variant of PIGN that typically occurs in the elderly (7). In contrast to typical PIGN, in which deposition of IgG and C3 or C3 alone is evident, IgA is the sole or dominant immunoglobulin in IgA-dominant PIGN. Because of these histopathological features, IgA-dominant PIGN should be distinguished from IgA nephropathy (IgAN) and Henoch- Schönlein purpura nephritis (HSPN). It is unlikely that our patient s renal manifestations represented an exacerbation of pre-existing primary IgAN. The pattern of onset, which was 2622

5 Table 2. Published Cases and the Present Case of IgA-dominant PIGN Treated with Steroids Ref Year Age Sex DM Infectious agent M NR MRSA Source of infection skin abscess Clinical presentation NS Steroids half PULSE+oral PSL Renal outcome Not improved F N MSSA atopic dermatitis NS oral PSL Improved F N MSSA epidural Not RPGN NR abscess improved M N MRSA mediastinal RPGN+ abscess NS oral PSL Improved M N MSSA skin lesions RPGN NR Improved 59 M N NR bloody diarrhea RPGN NR Improved 86 M N MRSA cellulitis RPGN NR Improved 74 M Y NR diabetic Not RPGN NR foot ulcer improved The present case M Y E. coli cholangitis RPGN+ NS oral PSL Improved PIGN: postinfectious glomerulonephritis, NR: not reported, DM: diabetes, M: male, F: female, N: no, Y: yes, MRSA: methicillin-resistant S. aureus, MSSA; methicillin- sensitive S. aureus, NS: nephrotic syndrome, RPGN: rapidly progressive glomerulonephritis, PSL: prednisolone compatible with RPGN, was completely different from typical IgAN. Most patients who suffer from IgAN have slowly progressive disease with 30-50% of patients developing endstage renal disease (ESRD) over a 20-year period after diagnosis (8). Moreover, the initial renal presentation of our patient at the age of 76 years, endocapillary hypercellularity on LM, and the presence of subepithelial humps on EM excluded the possibility of an exacerbation of pre-existing primary IgAN. Patients with IgA-dominant PIGN frequently exhibit anaphylactoid purpura, which is histopathologically comparable with HSPN (9, 10). Furthermore, endocapillary hypercellularity and subepithelial deposits are not uncommon in HSPN; therefore, distinguishing HSPN from IgAdominant PIGN is challenging. However, HSPN is primarily a childhood disease, and it is generally agreed that the incidence of HSPN decreases with age. In the present case, initial skin manifestations late in the patient s life, the absence of arthritis, and abdominal pain led us to rule out the possibility of HSPN. In contrast to HSPN, IgA-dominant PIGN is most frequent in older patients (7). There is a male predominance, and underlying diabetes mellitus is common in this new entity. Sites of infection include the skin, lung, urinary tract, bone, heart, and deep-seated abscess (7). The vast majority of causative agents are Staphylococcus species, specifically methicillin-resistant Staphylococcus aureus (MRSA) (7). Therefore, earlier reports have defined this GN as MRSAassociated GN (11) or Staphylococcus infection-associated GN mimicking IgAN (12). Koyama et al. speculated that MRSA-associated GN may be induced by a staphylococcal enterotoxin, which acts as a superantigen, thus leading to massive T-cell activation and the production of cytokines (11). However, this type of GN also develops following coagulase-negative Staphylococcus infection, which does not produce an enterotoxin (7). Moreover, Wen et al. (4) recently reported that other bacteria, including Streptococcus, or, rarely, Gram-negative organisms (including Klebsiella pneumoniae and E. coli), also cause this type of GN. Thus, IgA-dominant PIGN would be the more definitive terminology for this entity. To date, approximately 80 cases of IgA-dominant PIGN have been reported (1, 2, 4, 12-22). To the best of our knowledge, only 3 cases of IgA-dominant PIGN caused by E. coli infection have been reported (4, 7). The reported causes of infection were urinary tract infection (1) and liver abscess and peritonitis (4). Therefore, this is the first reported case of IgA-dominant PIGN associated with cholangitis caused by E. coli infection. Despite Gram-negative bacteria being responsible for approximately 10% of cases of typical adult PIGN (5, 6, 22), few previous reports have shown IgA-dominant PIGN resulting from Gram-negative bacteria. This is partly because the dominance of Staphylococcus aureus over other types of bacteria as a causative agent of this new entity may have resulted in underreporting of this condition. It is, therefore, possible that previously reported cases of PIGN caused by Gram-negative bacteria could have been categorized as IgA-dominant PIGN according to the criteria first outlined by Nasr et al. (2, 6). Because many patients, especially the elderly, are in an underlying immunocompromised state such as diabetes, immunosuppressive therapy is not recommended in most adults with PIGN (5, 6, 22). However, no randomized prospective clinical trials regarding immunosuppressive therapy in PIGN have been conducted (3). Therefore, in adults, Nasr et al. implied that steroids, with or without cyclophosphamide, may be offered to patients with diffuse crescentic and ne- 2623

6 crotizing infection-related glomerulonephritis (IRGN) (3). Unsurprisingly, no previous reports have shown the efficacy of steroids in treating IgA-dominant PIGN. Nasr et al. reported that limited available evidence does not provide any support for the use of corticosteroids in addition to antibiotic therapy (7). In the present case, considering the patient s rapid deterioration of renal function in spite of stable biliary drainage and empiric antibiotic therapy for more than 2 weeks, it seemed plausible to start immunosuppressive therapy. In 2008, Okuyama et al. reported a case of a 48- year-old Japanese man with IgA-dominant PIGN successfully treated with 20 mg/day of prednisolone (20). Referring to this report, we started the use of prednisolone at the same dose. We reviewed the previously published reports of patients with IgA-dominant PIGN who were treated with steroids (12, 18-21); the clinical features of 9 reported patients (including the present case) are shown in Table 2. Of note, steroids were used only in patients with severe renal diseases including RPGN or nephrotic syndrome. The present case was the first to achieve clinical improvement with steroids in spite of the presence of underlying type 2 diabetes mellitus. Further reports must therefore be accumulated in order to establish additional evidence supporting the use of immunosuppressive therapy in patients with IgA-dominant PIGN. In summary, to the best of our knowledge, this case report is the fourth report of IgA-dominant PIGN caused by E. coli infection. In terms of the site of infection, this is the first reported patient who suffered from cholangitis. Although the efficacy of steroids in the treatment of PIGN is unclear, the severe renal manifestations in our patient led us to administer oral steroid therapy, ensuring that the infection was under control through the use of drainage and empirical antibiotic therapy. After initiating steroids, the patient s renal function gradually recovered, and his urinary protein disappeared completely. The present case has highlighted the possibility that steroid use may be effective in the treatment of IgA-dominant PIGN with severe renal manifestations in diabetic patients. The authors state that they have no Conflict of Interest(COI). References 1. Nasr SH, Fidler ME, Valeri AM, et al. Postinfectious glomerulonephritis in the elderly. J Am Soc Nephrol 22: , Nasr SH, Markowitz GS, Whelan JD, et al. IgA-dominant acute poststaphylococcal glomerulonephritis complicating diabetic nephropathy. Hum Pathol 34: , Nasr SH, Radhakrishnan J, D Agati VD. Bacterial infectionrelated glomerulonephritis in adults. Kidney Int 83: , Wen YK, Chen ML. IgA-dominant postinfectious glomerulonephritis: not peculiar to staphylococcal infection and diabetic patients. Ren Fail 33: , Montseny JJ, Meyrier A, Kleinknecht D, Callard P. The current spectrum of infectious glomerulonephritis. 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