Renal granuloma as an extraintestinal manifestation in Crohn’s disease: A case report

Abstract

BACKGROUND

Crohn’s disease (CD) is a chronic inflammatory bowel disorder characterized by transmural inflammation and granuloma formation. Extraintestinal manifestations are well-recognized but renal granulomatous involvement remains exceedingly rare, with limited reports in the literature.

CASE SUMMARY

We describe an 18-year-old male with Crohn’s colitis who concurrently presented with renal impairment. Renal biopsy revealed acute interstitial nephritis with a single non-necrotizing granuloma. Initial steroid therapy led to partial improvement in gastrointestinal and renal parameters; however, relapse occurred upon tapering. Subsequent induction and maintenance therapy with infliximab resulted in sustained clinical, endoscopic, and biochemical remission, including resolution of pyuria and normalization of renal function.

CONCLUSION

This case highlights a rare presentation of Crohn’s-related renal granuloma successfully managed with infliximab monotherapy following corticosteroid induction. It underscores the importance of recognizing renal granuloma as a potential extraintestinal manifestation of CD and demonstrates that targeted Crohn’s therapy can result in both intestinal and renal recovery. Our findings add to the sparse literature supporting anti-tumor necrosis factor agents as an effective, steroid-sparing treatment in this context.

Key Words: Crohn’s disease; Renal granuloma; Interstitial nephritis; Extraintestinal manifestation; Infliximab; Case report

Core Tip: Renal granulomatous inflammation is an exceedingly rare extraintestinal manifestation of Crohn’s disease (CD) and lacks established management guidelines. We report a biopsy-confirmed case of CD-associated renal granuloma with interstitial nephritis demonstrating sustained renal and intestinal response to infliximab therapy. This case underscores the importance of considering immune-mediated renal involvement in CD and suggests that disease-targeted biologic therapy may represent an effective treatment approach for this rare manifestation.

INTRODUCTION

Crohn’s disease (CD) is a type of inflammatory bowel disease (IBD) that represents immune-mediated inflammation of the gastrointestinal tract (GIT)[1]. CD can have variable disease location across the GIT and varying phenotypes (stricturing, fistulizing, and penetrating forms), requiring multiple modalities of investigation prior to diagnosis. Skip lesions across the GIT and histological evidence of granulomas are more suggestive of CD than ulcerative colitis[2]. CD-related granulomas may manifest outside the GIT, with the most commonly reported sites being lymph nodes, mesentery, peritoneum, liver, and lungs[3,4]. Extraintestinal manifestations (EIMs) of IBD presenting as renal granulomatous disease are extremely rare, with only a few cases reported in the literature to date. Additionally, there are currently no clear guidelines for the management of CD-related renal granulomas. We present an unusual case of renal granuloma secondary to CD and provide insight into a successful treatment strategy.

CASE PRESENTATION

Chief complaints

An 18-year-old male was referred with a one-year history of abdominal pain, bloody diarrhoea, and bloating.

History of present illness

At the time of referral, he was undergoing investigation for autoimmune renal disease by a nephrologist and had been commenced on prednisone prior to gastroenterology review. His gastrointestinal symptoms were well controlled on a high dose of prednisone (50 mg), with relapse occurring during steroid tapering.

History of past illness

His medical history included previous gastrointestinal helminth infection (treated), Giardia gastroenteritis, and lactose intolerance. There was no significant non-steroidal anti-inflammatory drug use.

Personal and family history

There was no family history of CD or colorectal cancer.

Physical examination

Physical examination showed a soft abdomen with generalized abdominal tenderness but no signs of peritonism.

Laboratory examinations

Laboratory investigations revealed hemoglobin of 122 g/L, white cell count of 15.6 × 10⁹/L, erythrocyte sedimentation rate of 40 mm/hour, creatinine of 194 μmol/L, estimated glomerular filtration rate of 55 mL/minute, and albumin of 38 g/L. Fecal calprotectin was elevated at 307 μg/g. Renal biopsy was performed following negative infectious, immune, and metabolic screening and in the absence of significant nephrotoxic drug exposure. Histopathology demonstrated acute interstitial nephritis without chronic damage and a single granuloma (Figure 1). Urinalysis confirmed pyuria.

Figure 1 Renal biopsy showing features (marked with arrows and circles) of acute interstitial nephritis and a single granuloma. A: Interstitial nephritis (hematoxylin and eosin, 100 ×); B: Granuloma (hematoxylin and eosin, 200 ×); C: Tubulitis with lymphocytes infiltrating a renal tubule (hematoxylin and eosin, 400 ×); D: Interstitial inflammation with eosinophils (hematoxylin and eosin, 400 ×).

Imaging examinations

An ultrasound examination of the kidneys was performed, and the renal ultrasound showed mild vesicoureteral reflux.

FINAL DIAGNOSIS

CD was diagnosed on colonoscopy, which demonstrated pancolitis, and histopathology revealed mild chronic colitis with non-necrotizing granulomas (Figure 2A). Further investigations showed negative antinuclear antibody, antineutrophil cytoplasmic antibody, complement levels (C3 and C4), hepatitis B and hepatitis C serology, human immunodeficiency virus testing, and QuantiFERON-TB Gold assay. Chest X-ray was normal. The patient was diagnosed with CD-associated renal granuloma with interstitial nephritis.

Figure 2 Serial colonoscopy investigations. A: Index colonoscopy with normal terminal ileum, erythematous and featureless colon in all segments with rectal sparing; B: Healed colon one-year post infliximab therapy.

TREATMENT

Steroid tapering was undertaken, followed by intravenous infliximab induction and subsequent maintenance therapy with subcutaneous infliximab administered every two weeks. Both renal function and gastrointestinal symptoms improved on infliximab monotherapy. Seven months post-induction, dose escalation to weekly subcutaneous infliximab was required due to secondary loss of response.

OUTCOME AND FOLLOW-UP

Colonoscopy performed one year after diagnosis demonstrated endoscopic remission (Figure 2B), accompanied by ongoing improvement in renal function and resolution of pyuria (Figure 3).

Figure 3 Improvement in estimated glomerular filtration rate and creatinine post infliximab induction and on maintenance therapy. Note that at 18 months there was a decline in renal function (estimated glomerular filtration rate 66 mL/minute, creatinine 132 μmol/L) - this corresponded to an increase in bowel frequency (without per rectal bleeding and urgency) and coincided with planned de-escalation in infliximab to fortnightly from weekly treatment. Subsequent escalation to weekly infliximab led to resolution of gastrointestinal symptoms and improved renal function. eGFR: Estimated glomerular filtration rate.

DISCUSSION

We describe an exceptionally rare EIM of CD: Biopsy-confirmed renal granulomatous inflammation consistent with CD, which has been rarely reported in the literature. Following standard induction with corticosteroids, the patient demonstrated marked improvement in renal function after initiation of infliximab therapy. To the best of our knowledge, we report the first instance of renal granulomatous disease successfully treated with subcutaneous infliximab monotherapy, providing novel insight into a potentially effective therapeutic approach for this rare manifestation. In the following sections, we review published cases to date that have reported renal granulomatous disease secondary to CD, comment on known pathogenesis of renal manifestations in CD and discuss a very limited case series that proposed successful treatment options, noting that evidence-based treatment recommendations are overall lacking. All previously reported cases studies are summarized in Table 1[5-14].

Table 1 Summary of previously reported case studies of renal granulomatosis in Crohn’s disease.

Ref.	Age (years)	Treatment	Renal impairment	Resolution of renal impairment	Follow up
Archimandritis and Weetch[5], 1993	22	Sulfasalazine, prednisolone	BUN 10 mmol to 19.9 mmol, CrCl reduced to 14-15 mL/minute2	Yes	Followed up in 4 years: Remission
Baumer et al[6], 1999	21		Elevated serum Cr 394 μmol/L	NA	Followed up in 4 years: ESRD
Unal et al[7], 2008	43	Prednisolone	Elevated serum Cr 256 μmol/L and CrCl 32.6 mL/minute2	Mild improvement	Followed up in 2 months and 4 months post diagnosis of granuloma on biopsy
Marcus et al[8], 2008	16	Steroids, infliximab	Elevated serum 221 μmol/L to 186 μmol/L, CrCl 35 mL/minute2	No	Followed up in 6 months: No improvement in renal function
Marcus et al[8], 2008	11	Prednisolone, 6MP, infliximab, 5-ASA	Elevated serum Cr 168 μmol/L at diagnosis	No	Follow up at time of writing: No improvement in renal function despite improving intestinal symptoms
Semjén et al[9], 2011	50	Nephrectomy	Elevated serum Cr	NA	Nil follows up
Polci et al[10], 2012	56	Steroid, anti-TNF	Serum Cr 97 μmol/L to 256 μmol/L, BUN 79 mg/dL, eGFR 24 mL/minute2	No	Follow-up in 1 year: Worsening renal function
Colvin et al[11], 2014	23	5-ASA ceased, prednisolone	Serum Cr 71-133 μmol/L to 203 μmol/L in 2 months	Mild improvement	Follow-up in 21 months: Improved renal function
Saha et al[12], 2014	17	Prednisone, azathioprine, infliximab	Serum Cr 398 μmol/L (reference 0.7-1.2 mg/dL), eGFR 18 mL/minute2	Mild improvement	26 months post renal biopsy: Referred for renal transplant
Timmermans et al[13], 2016	19	Prednisone, + tacrolimus	Elevated serum Cr 177 μmol/L, eGFR 43 mL/minute2	Mild improvement	Follow up renal function: Serum Cr 133 μmol/L, eGFR 60 mL/minute/1.73 m2
Timmermans et al[13], 2016	22	Prednisone, mycophenolate mofetil, ciclosporine	Serum Cr increased from 101 μmol/L to 160 μmol/L, eGFR 37 mL/minute2	No	Follow up: ESRD
Han et al[14], 2022	19	Prednisolone, infliximab	Elevated serum Cr 237 μmol/L	Yes	Follow up in 11 months: Improved Cr 2.12 μmol/L

6-MP: 6-mercaptopurine; 5-ASA: 5-aminosalicylic acid; TNF: Tumor necrosis factor; BUN: Blood urea nitrogen; CrCl: Creatinine clearance; Cr: Creatinine; eGFR: Estimated glomerular filtration rate; NA: Not available; ESRD: End-stage renal disease.

The first case of renal granuloma was described by Archimandritis and Weetch[5] in 1993, where they reported a severe case of Crohn’s colitis associated with renal impairment. Renal biopsies revealed chronic interstitial nephritis with local periglomerulofibrosis and granuloma formation. More recently, in 2011, a case of biopsy-proven renal granuloma with tumor-like radiological appearance was reported in a patient with long-standing CD without any evidence of diffuse renal disease or renal impairment[9]. There are well-established renal complications secondary to CD, and these are considered EIMs. These include glomerulonephritis, tubulointerstitial nephritis (TIN), nephrolithiasis, and amyloidosis[15].

The pathogenesis of CD-related renal interstitial disease remains poorly understood. During a CD flare, highly activated T cells against gastrointestinal antigens circulate in the peripheral circulation. These primed T cells are thought to simultaneously undergo cross-reactivity against renal interstitial antigens. This subsequently stimulates differentiation into effector cell populations, including cytotoxic T cells, which cause direct cellular toxicity in the renal interstitium[13]. Timmermans et al[13] also report that levels of soluble interleukin-2 receptor, a marker of T-cell activation, correlate with disease activity in cases of granulomatous interstitial nephritis (GIN) in CD. Thus, interleukin-2 signaling may also play a role in disease pathogenesis[13].

GIN is an uncommon histopathological diagnosis, found in less than 1% of native kidney biopsies[13,16]. Reported causes of GIN include drug hypersensitivity reactions, chronic inflammatory diseases including renal sarcoidosis, and infections, including Mycobacterium tuberculosis[16-18].

In a case series of 38 patients with GIN, 44.7% of cases were drug-induced, of which non-steroidal anti-inflammatory drugs and antibiotics were most commonly associated[17]. In the wider literature, antibiotics including clarithromycin, ciprofloxacin, and vancomycin; anticonvulsants including phenytoin; and allopurinol, alendronate, and immunotherapy agents have all been identified as potential culprit agents[16,17,19].

Five-aminosalicylate (5-ASA) medications, commonly used in the treatment of mild-to-moderate severity IBD, are also known to cause nephrotoxicity[20]. 5-ASA-related renal disease is typically characterized by chronic TIN, as described in a multicenter study of 151 cases of 5-ASA medication-related nephrotoxicity in IBD patients. However, the same study also identified four 5-ASA-treated patients with a histopathological diagnosis of non-necrotizing GIN[20]. Colvin et al[11] also report an isolated case of GIN in CD with concomitant 5-ASA use. Determining whether GIN is a result of the disease process itself or 5-ASA nephrotoxicity in these cases is challenging[11,20]. Thus, it may be appropriate to withdraw 5-ASA therapy and monitor for improvement in renal function before making an alternate diagnosis or undergoing further treatment.

Renal sarcoidosis is one of the most common causes of GIN[13,17,19]. Bijol et al[17] reported that 28.9% of cases were secondary to renal sarcoidosis in their case series, of which many patients had an established history of sarcoidosis and the presence of granulomas in other organs. This is similar to another case series by Joss et al[19], describing 27.8% of GIN cases due to renal sarcoidosis. Of note, GIN caused by sarcoidosis frequently responds to steroid therapy[18]. Thus, a lack of response in renal function to steroids alone favors a diagnosis of CD over sarcoidosis in our case. GIN associated with granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, and TIN with uveitis syndrome have also been described[18,19].

Excluding infections is an essential step in the work-up of GIN. Tuberculosis is the most common infectious cause and is particularly prevalent in India. Rarely, GIN may also be caused by fungal infections, toxoplasmosis, Epstein-Barr virus, and Escherichia coli. Of note, poor response to steroid therapy may indicate an infectious cause for GIN and should prompt infectious screening if not previously completed[18].

Renal granuloma is a distinct histopathological finding seen within the interstitial inflammatory infiltrate in GIN. Granulomas can be further classified as necrotizing or non-necrotizing, which may help differentiate the cause. Renal sarcoidosis, CD-related GIN, and drug-induced GIN typically present with non-necrotizing granulomas. Necrotizing granulomas are more commonly seen in GIN secondary to tuberculosis, fungal infections, and granulomatosis with polyangiitis[18].

Evidence regarding the use of anti-tumor necrosis factor (TNF)-α agents in CD-related renal disease is limited. Only isolated case reports exist detailing the use of infliximab for TIN secondary to CD[8,21]. Saha et al[12] describe a case of granulomatous TIN as the initial presentation of CD treated with infliximab 5 mg/kg, with subsequent improvement in renal function, stabilization of creatinine, and improvement in gastrointestinal symptoms. A break in infliximab therapy for seven months caused rapid deterioration in renal function, which later improved following treatment re-initiation[12]. Stanton et al[21] report a case of non-granulomatous TIN and progression to chronic kidney disease as an initial EIM of CD. In this case, infliximab 5 mg/kg was successful in stabilizing creatinine levels and maintaining gastrointestinal symptom-free remission. On the other hand, Marcus et al[8] describe two pediatric cases with suboptimal responses to infliximab. In a case of granulomatous TIN in CD, there was improvement in gastrointestinal symptoms with infliximab; however, elevated serum creatinine persisted. In the second case of non-granulomatous TIN in CD, there was an initial gastrointestinal and renal response to infliximab; however, relapse of gastrointestinal symptoms was mirrored by new elevation in creatinine[8].

The mechanism of action of infliximab in the treatment of CD-related renal disease is not well elucidated. Stanton et al[21] postulate that in granulomatous TIN, infliximab acts to reduce TNF-α in the renal tubules directly, mirroring its effect on granulomatous disease elsewhere in the body. Rather, in non-granulomatous TIN, it is suggested that treatment of CD itself subsequently alleviates renal disease. Of note, renal function response to infliximab may also be impacted by the severity of interstitial fibrosis and tubular atrophy and progression to chronic kidney disease, as well as the degree of pre-renal insults secondary to exacerbated intestinal losses in CD[12].

Our case report illustrates that a treatment regimen directed towards CD, vs traditional therapy for acute interstitial nephritis, was successful in improving renal impairment, particularly with steroid weaning as per Crohn’s colitis protocol and introduction of a steroid-sparing agent with an anti-TNF inhibitor, infliximab. We additionally show that subcutaneous infliximab continued to be effective for both this patient’s Crohn’s colitis and Crohn’s-related interstitial nephritis. Additionally, this case demonstrates that disease monitoring can be performed satisfactorily with endoscopic and histological assessment, eliminating the need for more invasive tests such as serial renal biopsies.

Limitations

This report has several important limitations. Firstly, as a single-patient case study, the ability to generalize our proposed treatment efficacy - particularly the use of subcutaneous infliximab - is inherently limited. Secondly, the rarity of Crohn’s-related renal granulomatous disease restricts meaningful comparison with pre-existing cases and therefore potential for establishing a relationship between other therapies and clinical improvement. Thirdly, while alternative causes of GIN were extensively investigated, the possibility of multifactorial or overlapping etiologies, including prior medication exposure, cannot be fully excluded. Fourthly, our team did not have evidence from longitudinal or serial renal histopathological assessments to determine response or remission to treatment; therefore, we relied on biochemical and clinical improvement as surrogate markers. Finally, ongoing longer-term follow-up is required to determine the durability of response to subcutaneous infliximab and assess potential relapse or progression to chronic kidney disease.

Future directions

Given the extreme rarity of this presentation and the reliance on isolated case reports, further work is needed to better characterize the clinical behavior, immunopathological mechanisms, and optimal treatment strategies for Crohn’s-related renal granulomatous disease. Establishing collaborative case series would allow for more robust assessment of therapeutic responses and long-term renal outcomes. Mechanistic studies investigating T-cell activation pathways, cytokine profiles, and the role of TNF-α in renal granulomatous inflammation may also help identify patients most likely to benefit from targeted biologic therapy. Finally, as our case highlighted the potential utility of subcutaneous infliximab, future comparative studies evaluating intravenous vs subcutaneous dosing could provide valuable guidance for personalized treatment of these rare renal manifestations.

CONCLUSION

In summary, we describe a highly uncommon EIM of CD - a case of biopsy-proven renal granulomatous inflammation, a condition for which evidence-based management strategies remain undefined. Our case demonstrates that treatment directed at controlling CD itself - specifically steroid induction followed by infliximab therapy - can lead to significant renal function improvement. Notably, this is, to our knowledge, the first reported case showing successful and sustained clinical response with subcutaneous infliximab monotherapy, highlighting its potential role as an effective steroid-sparing treatment option in Crohn’s-related GIN.