Case Report
Granulomatous Interstitial Nephritis as a Manifestation of Crohn Disease Robert B. Colvin, MD; Avram Z. Traum, MD; Diana Taheri, MD; Mohsen Jafari, MD; Shahaboddin Dolatkhah
Granulomatous interstitial nephritis is a rare extraintestinal manifestation of Crohn disease that has been described previously in 4 patients. We report a 23-yearold man with a history of Crohn disease since age 6 years who was admitted to the hospital for weight loss, fever, and bloody diarrhea in the midst of a recent flare up during the past 2 months. Investigations revealed anemia, high erythrocyte sedimentation rate, high C-reactive protein level, and an elevated serum creatinine level. Histopathologic examination of tissue specimens obtained at renal biopsy demonstrated granulomatous interstitial nephritis. Crohn disease needs to be in the differential diagnosis of granulomatous interstitial nephritis and can be a manifestation of drug allergy or the Crohn disease itself. (Arch Pathol Lab Med. 2014;138:125–127; doi: 10.5858/ arpa.2012-0224-CR)
R
enal complications of Crohn disease (CD) are rare and include glomerulonephritis, proximal tubular dysfunction, amyloidosis, calcium oxalate stones, tubular proteinuria with normal renal function, and tubulointerstitial nephritis (TIN). Documented cases of TIN in CD have mostly been reported in patients treated with 5-aminosalicylic acid (5-ASA), the nephrotoxicity of which has been described previously.1 Based on the literature, TIN has been reported in 19 patients with CD, of whom 9 patients were not on 5-ASA therapy. Granuloma formation was seen in 4 patients, of whom 2 were on 5-ASA (Table).1–14 We report a case of acute renal failure due to acute granulomatous interstitial nephritis in a patient with CD.
Accepted for publication March 9, 2013. From the Departments of Pathology (Drs Colvin and Taheri) and Nephrology (Dr Traum), Massachusetts General Hospital, Harvard Medical School, Boston; the Isfahan Kidney Disease Research Center, Isfahan, Iran (Dr Taheri); and the Department of Pathology, School of Medicine (Drs Taheri and Jafari), and the Faculty of Medicine (Dolatkhah), Isfahan University of Medical Sciences, Isfahan, Iran. The authors have no relevant financial interest in the products or companies described in this article. Reprints: Diana Taheri, MD, Isfahan Kidney Diseases Research Center, Department of Pathology, Isfahan University of Medical Sciences, Isfahan 8168788131, Iran (e-mail:
[email protected]. ir). Arch Pathol Lab Med—Vol 138, January 2014
REPORT OF A CASE A 23-year-old man with a history of CD since age 6 years (based on multiple biopsies—the first of which was in 1993—showing granuloma throughout his colon) presented with weight loss, fever, and bloody diarrhea in the midst of a recent flare up during the prior 2 months. Laboratory evaluation showed anemia, high erythrocyte sedimentation rate (.100), and high C-reactive protein level, but no joint symptoms, edema, headache, or rash. He had been maintained on balsalazide (5-ASA), metronidazole, adalimumab, and omeprazole. During the course of 3 months his serum creatinine level rose from 0.8 to 1.5 mg/dL (to convert to micromoles per liter, multiply by 88.4). Six weeks prior to presentation, he had a flare up of his diarrhea. The metronidazole was discontinued and ciprofloxacin was started. During the subsequent 4 weeks his creatinine level continued to rise, to 2.2 mg/dL, so his ciprofloxacin was discontinued. His creatinine level remained elevated during the next 10 days, rising to 2.3 mg/dL, at which point a renal biopsy was performed. His urine sediment showed white blood cells, white blood cell casts, and rare dysmorphic red blood cells, whereas his urine eosinophils were positive (2%). The protein to creatinine ratio was 0.38 mg/mg. The biopsy included 1 core of renal parenchyma with 15 glomeruli, of which 1 was globally sclerotic and the remaining ones were within normal limits on periodic acid–Schiff and trichrome stains. The interstitium showed a diffuse, intense mononuclear infiltrate with scattered eosinophils, neutrophils, and abundant plasma cells. Four noncaseating granulomas with multinucleated giant cells were present in the cortex, some of them disrupted tubules that showed fragmentation of the tubular basement membrane (Figure). Tubulitis was prominent, and some tubules had neutrophil casts. Small arteries showed no remarkable changes. No organisms were seen on special stains (periodic acid–Schiff, Gomori silver methenamine, Brown-Hopps, or Ziehl-Neelsen). Immunofluorescence microscopy of 4 glomeruli showed granular mesangial deposits that stained for immunoglobulin (Ig) M (1þ), C3 (2þ), C1q (1þ), kappa, and lambda (1þ). Reabsorption droplets stained for multiple reactants and casts were positive for IgA. Fibrin, albumin, and IgG were negative. There were no deposits along the tubular basement membrane. Electron microscopy of 2 glomeruli showed segmental podocyte foot process effacement. The glomerular basement membrane was normal without deposits. The mesangium contained sparse, amorphous, electron-dense deposits. Findings were compatible with granulomatous interstitial nephritis due to renal involvement by CD. The patient was treated by stopping the 5-ASA and adding prednisone (60 mg every day). During the next several months his serum creatinine level fell to 1.1 mg/dL, where it has remained 21 months later, after tapering off prednisone.
PATHOLOGIC FINDINGS Crohn disease is known as a chronic, relapsing inflammatory bowel disease with mucosal ulcerations of the GIN as a Manifestation of Crohn Disease—Colvin et al 125
Granulomatous interstitial nephritis. A, Diffuse interstitial inflammatory cell infiltration with a noncaseating granuloma (arrow). B, Noncaseating granuloma with multinucleated giant cells. C, Disrupted tubules and fragmentation of the tubular basement membrane by granuloma (hematoxylin-eosin, original magnifications 3100 [A] and 3400 [B]; periodic acid–Schiff, original magnification 3400 [C]).
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digestive tract. Extraintestinal manifestations occur in up to 25% to 35% of patients with inflammatory bowel disease that can involve almost every organ system, especially the biliary tract, joints, skin and eyes.1 Although our knowledge of the pathogenesis of inflammatory bowel disease has improved during the past 20 years, studies on the etiology of extraintestinal manifestations are limited. The main postulated mechanisms include infectious agents, T-cell–mediated hypersensitivity, circulating bacterial endotoxins, and genetic factors. Overall, the most plausible hypothesis is based on an immunologic response influenced by genetic factors. This centers on the presumption of molecular structure cross-reaction between intestinal bacterial proteins and host self antigens, which may include the interstitium of the kidney.15 Several kidney conditions have been described in CD. Some are believed to be related to the CD itself (proximal tubular dysfunction, secondary amyloidosis, calcium oxalate stones, tubular proteinuria with normal renal function, and TIN), some are related to drug complications (TIN), and some rare conditions may be coincidental (IgA nephropathy, IgM nephropathy, minimal-change glomerulonephritis, membranous glomerulonephritis, antiglomerular basement membrane glomerulonephritis, membranoproliferative glomerulonephritis, mesangiocapillary glomerulonephritis, focal segmental glomerulosclerosis, and crescentic glomerulonephritis).16 Tubulointerstitial nephritis has been reported in 19 patients with CD. Although 5-ASA is commonly imputed as a cause, 9 reported patients were not on 5-ASA therapy, and these cases mostly occurred during flare up of the bowel disease (Table).1–14 Three mechanisms of TIN in CD have been recognized: (1) direct cytotoxic response to a nephrotoxic agent, which is dependent on both dose and duration of exposure; (2) allergic drug reactions; and (3) involvement of the kidney by the Crohn inflammatory process. The role of immune-mediated mechanisms in TIN has been demonstrated in both animal and human studies.1 Often the histologic features of interstitial nephritis are relatively nonspecific, and detection of the etiology requires a combination of acquired data of the special stains, immunofluorescence and ultrastructural findings, drug history, and laboratory results. Although the presence of granulomas is an infrequent finding in renal biopsies, it may help to narrow the differential diagnosis.17 Bijol et al18 reported that drug-induced interstitial nephritides tend to have a diffuse distribution, with many eosinophils and neutrophils, as well as ill-formed granulomas, but the granulomas in our patient were well formed and have a focal distribution, with a few eosinophils and neutrophils. Granulomatous interstitial nephritis (GIN) is reported in between 0.5% and 0.9% of native renal biopsies,19 in 0.6% of renal transplant biopsies,20 and in chronic lymphocytic leukemia, and it also is seen in an idiopathic form. Drugs include antibiotics (eg, clarithromycin, ciprofloxacin, nitrofurantoin, and vancomycin), anticonvulsants (eg, phenytoin), nonsteroidal anti-inflammatory drugs, allopurinol, adalimumab, all-trans retinoic acid, bisphosphonate alendronate sodium, intravesical Bacillus Calmette-Guerin, ´ levofloxacin, and diuretics. Mycobacteria and fungi (eg, Candida, Cryptococcus, Histoplasma capsulatum, and Rhodococcus) are the main infective causes and are the main etiologic factor in cases involving renal transplants. In the study by Bijol et al18 on patients with GIN, 17 of 38 patients (44.7%) were classified as drug induced. Renal sarcoidosis was responsible GIN as a Manifestation of Crohn Disease—Colvin et al
Reports in the Literature of Tubulointerstitial Nephritis (TIN) in Crohn Disease
Age at Diagnosis, y
Source, y Marcus et al,1 2008 Izzedine et al,6 2002
Archimandritis et al,2 1993 Tovbin et al,10 2000 Larchet et al,7 1988 Behrens and Ruder,22 1992 Witte et al,13 1994 Wilcox et al,12 1996 World et al,14 1996 Hamling et al,5 1997 Calvino et al,4 1998 Baumer et al,3 1999 Margetts et al,8 2001 Unal et al,11 2008 Shahrani Muhammad et al,9 2010
16 11 24 27 21 21 22 57 11 11 22 71 31 34 22 21 48 43 14
Sex
5-ASA Therapy at Presentation
Kidney Histology
Female Female Female Male Male Male Male Male Female Male Male Male Male Female Female Female Female Male Male
No No No No No No No No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No
TIN, granuloma TIN CTIN CTIN CTIN CTIN CTIN, granuloma CTIN, amyloidosis CTIN TIN CTIN CTIN CTIN CTIN CTIN CTIN, granuloma CTIN CTIN, granuloma TIN
Abbreviations: 5-ASA, 5-aminosalicyclic acid; CTIN, chronic TIN.
for 28.9% of cases, and the remaining 15.9% of cases included Wegener granulomatosis, foreign body giant cell reaction, GIN secondary to intravesical Bacillus CalmetteGuerin ´ therapy for bladder cancer, and xanthogranulomatous pyelonephritis.18 In our center, a database of renal biopsies with 10 383 samples listed 34 cases of GIN, representing only 0.3% of all biopsies. The cause at the time was considered to be drug allergy (n ¼ 7), CD (n ¼ 3), sarcoidosis (n ¼ 3), autoimmune disorder (n ¼ 2, rheumatoid arthritis, lupus erythematosus), anti-neutrophil cytoplasmic antibody–related vasculitis with granulomas (n ¼ 2), infection (tuberculosis, adenovirus), other glomerular disease (n ¼ 2), transplant rejection (n ¼ 2), obstruction (n ¼ 1), and renal cell carcinoma (n ¼ 1). No cause was identified in 9 cases. According to the etiologies mentioned for GIN as well as our patient’s history, in our case GIN could be an extraintestinal manifestation of CD or induced by a drug, such as 5-ASA or ciprofloxacin. Therapy with 5-ASA had been used for this patient for many years in the past, and it had been accompanied by good renal function. Tubulointerstitial nephritis is most common in the first 12 months of 5-ASA therapy, although it has been reported to occur later.21 The rise in creatinine level preceded the introduction of ciprofloxacin, and the level continued to rise after metronidazole was discontinued.18 Nonetheless, we cannot exclude 5-ASA as the cause, because the patient has not resumed taking that drug and remains stable. On the basis of the previous reports of GIN in patients with CD and our findings, we propose that GIN be considered as an extraintestinal complication of CD that can cause renal failure. Previous patients as well as the present patient responded to steroid therapy. Monitoring renal function is advisable regardless of 5ASA therapy in patients with CD. References 1. Marcus SB, Brown JB, Melin-Aldana H, Strople JA. Tubulointerstitial nephritis: an extraintestinal manifestation of Crohn disease in children. J Pediatr Gastroenterol Nutr. 2008;46(3):338–341. 2. Archimandritis AJ, Weetch MS. Kidney granuloma in Crohn’s disease. BMJ. 1993;307(6903):540–541.
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3. Baumer P, Brocard JF, Kohn W, Bedossa P, Charpentier B. Severe chronic interstitial nephritis associated with Crohn’s disease, but not with mesalazine? [in French]. Gastroenterol Clin Biol. 1999;23(12):1400–1402. 4. Calvino J, Romero R, Pintos E, et al. Mesalazine-associated tubulointerstitial nephritis in inflammatory bowel disease. Clin Nephrol. 1998;49(4): 265–267. 5. Hamling J, Raedler A, Helmchen U, Schreiber S. 5-Aminosalicylic acidassociated renal tubular acidosis with decreased renal function in Crohn’s disease. Digestion. 1997;58(3):304–307. 6. Izzedine H, Simon J, Piette AM, et al. Primary chronic interstitial nephritis in Crohn’s disease. Gastroenterology. 2002;123(5):1436–1440. 7. Larchet M, Guillot M, Mandard JC, et al. Crohn’s enteritis and chronic tubulo-interstitial nephropathy in an adolescent [in French]. Arch Fr Pediatr. 1988;45(9):649–651. 8. Margetts PJ, Churchill DN, Alexopoulou I. Interstitial nephritis in patients with inflammatory bowel disease treated with mesalamine. J Clin Gastroenterol. 2001;32(2):176–178. 9. Shahrani Muhammad HS, Peters C, Casserly LF, Dorman AM, Watts M. Relapsing tubulointerstitial nephritis in an adolescent with inflammatory bowel disease without aminosalicylate exposure. Clin Nephrol. 2010;73(3):250–252. 10. Tovbin D, Kachko L, Hilzenrat N. Severe interstitial nephritis in a patient with renal amyloidosis and exacerbation of Crohn’s disease. Clin Nephrol. 2000; 53(2):147–451. 11. Unal A, Sipahioglu MH, Akgun H, et al. Crohn’s disease complicated by granulomatous interstitial nephritis, choroidal neovascularization, and central retinal vein occlusion. Intern Med. 2008;47(2):103–107. 12. Wilcox GM, Reynolds JR, Galvanek EG. Nephrotoxicity associated with olsalazine. Am J Med. 1996;100(2):238–240. 13. Witte T, Olbricht CJ, Koch KM. Interstitial nephritis associated with 5aminosalicylic acid. Nephron. 1994;67(4):481–482. 14. World MJ, Stevens PE, Ashton MA, Rainford DJ. Mesalazine-associated interstitial nephritis. Nephrol Dial Transplant. 1996;11(4):614–621. 15. Su CG, Judge TA, Lichtenstein GR. Extraintestinal manifestations of inflammatory bowel disease. Gastroenterol Clin North Am. 2002;31(1):307–327. 16. Oikonomou K, Kapsoritakis A, Eleftheriadis T, Stefanidis I, Potamianos S. Renal manifestations and complications of inflammatory bowel disease. Inflamm Bowel Dis. 2011;17(4):1034–1045. 17. Nasr SH, Koscica J, Markowitz GS, D’Agati VD. Granulomatous interstitial nephritis. Am J Kidney Dis. 2003;41(3):714–719. 18. Bijol V, Mendez GP, Nose V, Rennke HG. Granulomatous interstitial nephritis: a clinicopathologic study of 46 cases from a single institution. Int J Surg Pathol. 2006;14(1):57–63. 19. Pasquet F, Chauffer M, Karkowski L, et al. Granulomatous interstitial nephritis: a retrospective study of 44 cases [in French]. Rev Med Interne. 2010; 31(10):670–676. 20. Meehan SM, Josephson MA, Haas M. Granulomatous tubulointerstitial nephritis in the renal allograft. Am J Kidney Dis. 2000;36(4):E27. 21. Gisbert JP, Gonzalez-Lama Y, Mate J. 5-Aminosalicylates and renal function in inflammatory bowel disease: a systematic review. Inflamm Bowel Dis. 2007;13(5):629–638. 22. Behrens R, Ruder H. Chronic inflammatory intestinal disease and nephritis [in German]. Klin Padiatr. 1992;204(1):61–64.
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