Correspondence *Division of Nephrology, Hospital for Sick Children, Department of Paediatrics, University of Toronto, 555 University Avenue, Toronto, ON M5G 1X8, Canada

Email aoife.waters@sickkids.ca

The case

A previously healthy 12-year-old boy presented to hospital with a 6-month history of crampy pre-defecation abdominal pain, non-bloody diarrhea, anorexia and weight loss. There was no family medical history of note and the patient was not receiving any medication. Physical examination revealed generalized pallor. His weight was 31 kg (below the third percentile for his age) and his height was 142 cm (on the 25^th percentile). The patient was normotensive (blood pressure 92/60 mmHg) and other findings were unremarkable. Investigations revealed hypochromic microcytic anemia (hemoglobin 88 g/l), a low serum iron level (0.39 mol/l), a low serum ferritin level (99.8 pmol/l) and an elevated serum creatinine level (159 mol/l). Serum albumin and electrolyte levels were normal. The patient's 24 h urinary protein excretion was 0.32 g/day and his urine metabolic screen was normal. Histopathological examination of tissue specimens obtained at esophagogastroduodenoscopy and colonoscopy revealed cryptitis, crypt abscesses with chronic non-necrotizing granulomatous inflammation consistent with Crohn's disease.

Further laboratory tests detected no antinuclear antibodies, anti-double-stranded DNA antibodies, antineutrophil cytoplasmic antibodies nor any anti-liver–kidney–microsomal antibodies. Renal ultrasonography with Doppler demonstrated normal-sized kidneys with no evidence of obstruction, no structural abnormalities and no renovascular anomalies. Bilateral diffuse increased echogenicity of the renal parenchyma was evident. A dimercaptosuccinic acid scan showed reduced cortical function with bilateral loss of renal volume and equivalent differential kidney function. Renal diethylene triamine pentaacetic acid clearance was 42 ml/min/1.73 m² (normal 120 ml/min/1.73 m²). Histopathological examination of a percutaneous renal biopsy specimen demonstrated moderate interstitial fibrosis with mild tubular atrophy (Figure 1A). A diffuse interstitial inflammatory infiltrate consisting mostly of lymphocytes was observed, with several foci of tubulitis. No foci of granulomatous inflammation nor any intratubular neutrophils were reported. The glomeruli appeared slightly ischemic with an increase in mesangial matrix; one glomerulus was globally sclerosed. Immunofluorescence was negative and electron microscopy findings were normal. The overall findings were consistent with a diagnosis of tubulointerstitial nephritis (TIN).

Figure 1 Renal biopsy findings from two patients with tubulointerstitial nephritis secondary to Crohn's disease.

(A) Histopathological examination of the renal biopsy specimen from the main case revealed tubulointerstitial inflammation and interstitial fibrosis surrounding the tubules (t). The glomeruli appeared slightly ischemic with a slight increase in mesangial matrix but no increase in cellularity. Inset: the interstitial inflammatory infiltrate shows activated lymphocytes with a paucity of eosinophils. Magnification 40. (B) Histopathological examination of the renal biopsy specimen from the patient presented in Box 1 revealed tubulointerstitial inflammation consisting of mononuclear cells and a well-formed non-necrotizing granuloma (g). Tubulitis (t) was present in the tubule not affected by the granuloma. Magnification 100.

Full figure and legend (145K)Figures & Tables indexDownload Power Point slide (263K)

Oral prednisone 60 mg daily was commenced with improvement of intestinal symptoms. Over the following 3 months, the prednisone was tapered and an improvement in the patient's serum creatinine level was noted (106 mol/l) but it remained elevated and the patient had persistent tubular proteinuria (58 mg protein per day; 17 mg microalbumin per day). Eight months later, during an intestinal relapse of Crohn's disease, the patient's serum creatinine level was further elevated (168 mol/l). Prednisone 60 mg daily was recommenced and tapered over the following month with the introduction of azathioprine therapy (75 mg daily) and subsequent improvement of intestinal symptoms. Thirty months after initial presentation, the patient has persistent chronic renal impairment (serum creatinine level 168 mol/l, estimated glomerular filtration rate 50 ml/min/1.73 m²). A second example of tubulointerstitial nephritis occurring in a patient with Crohn's disease is presented in Box 1.

Discussion of diagnosis

Crohn's disease is a chronic relapsing inflammatory disease characterized by mucosal ulcerations of the digestive tract. The disease results from a genetic predisposition to abnormal interactions between intestinal epithelial cells and luminal bacteria. Mutations within the caspase recruitment domain 15 (CARD15), toll-like receptor (TLR), ATP-binding cassette (ABCB1) transporter and discs large homolog 5 (DLG5) genes have all been implicated in the pathogenesis of Crohn's disease.¹ Extraintestinal manifestations occur in up to 25–35% of pediatric patients and usually precede the onset of gastrointestinal symptoms, which are often colonic in nature and are influenced by disease activity.² The organs most commonly involved include the biliary tract, joints, skin and eyes.²

Renal manifestations are rare in Crohn's disease, but examples include calcium oxalate stones, amyloidosis, glomerulonephritis, proximal tubular dysfunction, tubular proteinuria with normal renal function, and TIN.³ The etiology of TIN is heterogeneous and there are reports of TIN occurring with other autoimmune disorders such as primary biliary cirrhosis,⁴ Sjögren's syndrome,⁵ autoimmune pancreatitis⁶ and systemic lupus erythematosus;⁷ however, such cases are rare. TIN can result from a direct cytotoxic response to an injurious agent such as a nephrotoxin, which is dependent on both dose and duration of exposure.

Tubulointerstitial injury can also result from an indirect response through the induction of systemic inflammatory or immunological reactions. Both animal and human studies support the role of immune-mediated mechanisms in TIN. In some instances, immune complexes may form against components of the tubular basement membrane. In other cases, immune complexes are more specific to the structures of the tubulointerstitium and involve antibodies to cell surface antigens or antigens that are processed and presented by tubular epithelial or interstitial dendritic cells, resulting in cell-mediated reactions. Some studies have suggested that the colon and the extracolonic organs share similar epitopes and that immunopathogenetic autoantibodies formed against organ-specific cellular antigens might play a role in the pathogenesis of extraintestinal manifestations in Crohn's disease.⁸

Most reported cases of TIN in Crohn's disease have occurred in patients treated with 5-aminosalicylic acid (5-ASA) derivatives, which have known nephrotoxic effects (Table 1). Serious renal impairment is reported to occur in 1 in 500 patients treated with 5-ASA derivatives.⁹ TIN has been reported in only six adults and two children with Crohn's disease who were not on 5-ASA therapy, and these cases occurred during exacerbation of the bowel disease.^{2, 10} The main patient presented in this Case Study had no prior exposure to any known nephrotoxin. The predominant diffuse lymphocytic infiltrate and the paucity of significant eosinophilic infiltrate on renal biopsy failed to support a drug-induced etiology. Despite the initial improvement of renal function after initiation of steroid therapy, further deterioration was noted during relapse of colonic symptoms when therapy was discontinued.

Table 1 Reports in the literature of tubulointerstitial nephritis in Crohn's disease.

Full tableFigures & Tables indexDownload Power Point slide (226K)

In the patient presented in Box 1, it is possible that the initial renal impairment observed was related to previous 5-ASA or ciprofloxacin therapy; however, this could not be confirmed as no prior creatinine values were available for comparison. The patient's serum creatinine level improved (from 141 mol/l to 133 mol/l) despite ongoing ciprofloxacin therapy and 3 days of NSAID treatment, however, which indicates that the TIN did not progress in the presence of either ciprofloxacin or NSAIDs. Furthermore, 7 weeks after discontinuation of ciprofloxacin, the patient's serum creatinine level had increased to 203 mol/l. Interestingly, this increase followed a suspected episode of colonic exacerbation, which led the physicians to suspect a renal exacerbation of Crohn's disease. Of note, the only medication the patient was taking at that time was azathioprine. TIN has been reported to occur in association with azathioprine therapy and most commonly occurs in the context of a hypersensitivity reaction towards the drug. It is highly improbable that azathioprine was the etiological factor in the patient presented in Box 1, however, given the paucity of eosinophilic infiltration on biopsy. The presence of a predominant lymphocytic infiltrate with non-necrotizing granulomata on renal biopsy further supported a diagnosis of TIN secondary to Crohn's disease and is in keeping with findings from other cases of primary TIN reported in Crohn's disease (Table 1).

Treatment and management

TIN has a variable prognosis depending on the underlying cause of disease. TIN that is associated with treatment of 5-ASA derivatives depends on the duration of exposure to the drug; early discontinuation of such derivatives results in the resolution of renal impairment in 78% of patients.⁹ A systematic review of 5-ASA derivatives and nephrotoxicity in patients with inflammatory bowel disease was recently published.¹³ The review analyzed data from 2,671 patients who received 5-ASA treatment during a total of 3,070 years of follow-up. The mean overall risk of nephrotoxicity calculated from the studies was 0.3%, with an annual nephrotoxicity rate of 0.26%. Previous reports of TIN secondary to Crohn's disease suggest that renal insufficiency persists despite an initial response to steroid therapy. Other therapies such as anti-tumor necrosis factor alpha and infliximab do not seem to alter the course of renal insufficiency in such patients.² While reports are rare and there are few studies with long-term follow-up, all idiopathic cases reported to date have chronic renal failure with 30% of patients having reached end-stage renal disease at 3 years (Table 1). One patient with TIN secondary to Crohn's disease underwent renal transplantation.¹¹ That patient experienced deterioration in renal function during a post-transplantation relapse of Crohn's disease, which suggests that the kidney might be an extraintestinal target in Crohn's disease.

Conclusions

This Case Study highlights that tubulointerstitial nephritis is a significant and under-recognized complication of extraintestinal Crohn's disease. Physician awareness of this important comorbid condition will lead to earlier detection of renal impairment to enable avoidance and dose reduction of potential nephrotoxins. Further reporting of cases with long-term follow-up are needed to define the course of this rare but serious complication of Crohn's disease.

Acknowledgments

Charles P Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

References

1. Riis L et al. (2007) The prevalence of genetic and serologic markers in an unselected European population-based cohort of IBD patients. Inflamm Bowel Dis 13: 24–32 | Article | PubMed |
2. Marcus SB et al. (2008) Tubulointerstitial nephritis: an extraintestinal manifestation of Crohn disease in children. J Pediatr Gastroenterol Nutr 46: 338–341 | PubMed |
3. Pardi DS et al. (1998) Renal and urologic complications of inflammatory bowel disease. Am J Gastroenterol 93: 504–514 | Article | PubMed | ChemPort |
4. Lino M et al. (2005) Tubulointerstitial nephritis and Fanconi syndrome in primary biliary cirrhosis. Am J Kidney Dis 46: e41–e46 | Article | PubMed |
5. Hu DC et al. (2004) Polymorphoneutrophilic infiltration in acute interstitial nephritis of Sjögren syndrome. Am J Med Sci 327: 278–280 | Article | PubMed |
6. Takeda S et al. (2004) IgG4-associated idiopathic tubulointerstitial nephritis complicating autoimmune pancreatitis. Nephrol Dial Transplant 19: 474–476 | Article | PubMed |
7. Omokawa A et al. (2008) Predominant tubulointerstitial nephritis in a patient with systemic lupus erythematosus: phenotype of infiltrating cells. Clin Nephrol 69: 436–444 | PubMed | ChemPort |
8. Das KM (1999) Relationship of extraintestinal involvements in inflammatory bowel disease: new insights into autoimmune pathogenesis. Dig Dis Sci 44: 1–13 | Article | PubMed | ChemPort |
9. Arend LJ and Springate JE (2004) Interstitial nephritis from mesalazine: case report and literature review. Pediatr Nephrol 19: 550–553 | Article | PubMed |
10. Izzedine H et al. (2002) Primary chronic interstitial nephritis in Crohn's disease. Gastroenterology 123: 1436–1440 | Article | PubMed |
11. Archimandritis AJ and Weetch MS (1993) Kidney granuloma in Crohn's disease. BMJ 307: 540–541 | PubMed | ChemPort |
12. Tovbin D et al. (2000) Severe interstitial nephritis in a patient with renal amyloidosis and exacerbation of Crohn's disease. Clin Nephrol 53: 147–151 | PubMed | ChemPort |
13. Gisbert JP et al. (2007) 5-Aminosalicylates and renal function in inflammatory bowel disease: a systematic review. Inflamm Bowel Dis 13: 629–638 | Article | PubMed |
14. Larchet M et al. (1988) Crohn's enteritis and chronic tubulo-interstitial nephropathy in an adolescent [French]. Arch Fr Pediatr 45: 649–651 | PubMed | ChemPort |
15. Benador N et al. (2000) Interstitial nephritis in children with Crohn's disease. Clin Pediatr (Phila) 39: 253–254 | PubMed | ChemPort |
16. Behrens R and Ruder H (1992) Chronic inflammatory intestinal disease and nephritis [German]. Klin Padiatr 204: 61–64 | Article | PubMed | ChemPort |
17. Witte T et al. (1994) Interstitial nephritis associated with 5-aminosalicylic acid. Nephron 67: 481–482 | PubMed | ChemPort |
18. Wilcox GM et al. (1996) Nephrotoxicity associated with olsalazine. Am J Med 100: 238–240 | Article | PubMed | ChemPort |
19. World MJ et al. (1996) Mesalazine-associated interstitial nephritis. Nephrol Dial Transplant 11: 614–621 | PubMed | ChemPort |
20. Hamling J et al. (1997) 5-Aminosalicylic acid-associated renal tubular acidosis with decreased renal function in Crohn's disease. Digestion 58: 304–307 | PubMed | ChemPort |
21. Calvino J et al. (1998) Mesalazine-associated tubulo-interstitial nephritis in inflammatory bowel disease. Clin Nephrol 49: 265–267 | PubMed | ChemPort |
22. Baumer P et al. (1999) Severe chronic interstitial nephritis associated with Crohn's disease, but not with mesalazine? [French]. Gastroenterol Clin Biol 23: 1400–1402 | PubMed | ChemPort |
23. Margetts PJ et al. (2001) Interstitial nephritis in patients with inflammatory bowel disease treated with mesalamine. J Clin Gastroenterol 32: 176–178 | Article | PubMed | ChemPort |
24. Unal A et al. (2008) Crohn's disease complicated by granulomatous interstitial nephritis, choroidal neovascularization, and central retinal vein occlusion. Intern Med 47: 103–107 | Article | PubMed |

Contact the journal about this article or read the Article Responses associated with this article.

Subject areas under which this article appears: Interstitial nephritis | Pathology