Crohn’s Disease With Progressive Renal Impairment

Abstract

Question: The patient was diagnosed with Crohn’s disease of the colon at the age of 39 years and had a chronic active disease course with rapid response to infliximab. Biopsies from the colon showed extensive inflammation with granulomas. The patient had secondary loss of response to infliximab due to formation of antidrug antibodies (ADA). She did not tolerate azathioprine or 6-mercaptopurine owing to pancreatitis and had severe hair loss when treated with methotrexate. Owing to previous good response to anti-TNF treatment, the patient was given adalimumab and subsequently certolizumab pegol, both with good initial responses, but unfortunately with subsequent loss of response caused by ADA formation. The patient also had significant extraintestinal manifestations (iridocyclitis, sacroiliitis, and peripheral arthropathies) that tended to respond to biologics. At the age of 45, the patient was switched to golimumab with good symptomatic control of the disease and extraintestinal manifestations, but fluctuating C-reactive protein levels between 0.5 and 2.5 mg/dL. At the age of 48, her estimated glomerular filtration rate decreased to <60 mL/min with more rapid decreases in periods with elevated inflammatory markers (Figure A). Urinalysis revealed proteinuria and no occult blood. Urinary excretion of protein was between 0.2 and 0.6 g/d. An initial ultrasound examination of the kidneys and urinary tracts was normal and a Tc-99-MAG3 renography showed bilateral decreased kidney function. A kidney biopsy was performed (Figure B). What is the diagnosis and treatment? Look on page 59 for the answer and see the Gastroenterology website (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and images in GI. The kidney biopsy showed normal glomeruli and well-preserved tubuli without atrophy. However, granulomatous inflammation was found in the interstitial tissue. No crystal casts, amyloid deposits, or vasculitis were found. The diagnosis is granulomatous interstitial nephritis. The patient was in her childhood treated for suspected tuberculosis, but polymerase chain reaction for tuberculosis was negative, as was immunohistochemistry for Epstein–Barr virus and cytomegalovirus. There was no sign of fungal infection. Other etiologies associated with granulomatous disease, especially sarcoidosis, were also ruled out. Granulomatous interstitial nephritis is generally a rare condition and is typically secondary to exposure to drugs including antibiotics and nonsteroidal anti-inflammatory drugs.1Shah S. Carter-Monroe N. Atta M.G. Granulomatous interstitial nephritis.Clin Kidney J. 2015; 8: 516-523Crossref PubMed Scopus (51) Google Scholar The patient had been sporadically exposed to ciprofloxacin. Both adalimumab and infliximab (but not golimumab or certolizumab) have been associated with autoimmune nephritis, but not specifically to granulomatous interstitial nephritis.2Piga M. Chessa E. Ibba V. et al.Biologics-induced autoimmune renal disorders in chronic inflammatory rheumatic diseases: systematic literature review and analysis of a monocentric cohort.Autoimmun Rev. 2014; 13: 873-879Crossref PubMed Scopus (61) Google Scholar In fact, anti-tumor necrosis factor agents have been used to alleviate granulomatous interstitial nephritis in patients with Crohn’s disease.3Timmermans S.A. Christiaans M.H. Abdul-Hamid M.A. et al.Granulomatous interstitial nephritis and Crohn's disease.Clin Kidney J. 2016; 9: 556-559Crossref PubMed Scopus (9) Google Scholar First-line treatment is glucocorticoids, and the patient was kept on golimumab and had 50 mg prednisolone. The treatment was ceased after 4 weeks owing to intolerance to side effects, and lack of improvements on estimated glomerular filtration rate levels. Ileocolonoscopy and gastroscopy were without signs of active inflammation. Renal function plateaued at around 37 mL/min for some months, but a subsequent decrease to <30 mL/min required reevaluation of the condition. Owing to the patient’s tendency to form granulomas, we considered the granulomatous interstitial nephritis to be an extraintestinal manifestation-like condition to Crohn’s disease. Alternatively, the granulomatous inflammation could be a direct drug reaction to golimumab exposure. Despite the lack of activity in the intestine, a switch of treatment was considered in the face of decreasing kidney function and ongoing systemic inflammation. Because a systemic effect of the new drug was considered important and the inflammation was not driven by intestinal activity, ustekinumab was preferred over vedolizumab. The change from golimumab to ustekinumab resulted in remarkably better control of systemic inflammation with continued undetectable C-reactive protein for the first time in the disease course and was accompanied by an almost complete regain of renal function within 8 months (Figure C). Interestingly, a correlation was found between C-reactive protein levels and the speed of renal function loss (ie, the derived function of estimated glomerular filtration rate; R2 = 0.42; P < .02), suggesting that the granulomatous inflammation in the kidneys were the main driver of the systemic inflammatory response during the observed period.