Granulomatous interstitial nephritis: A diagnostic dilemma, case report and review of literature

INTRODUCTION

Granulomatous tubulointerstitial nephritis (TIN) is a rare histological entity detected in <1% of kidney biopsies.^[1] It is caused by diverse aetiological agents, including drugs (antibiotics: Quinolones, penicillin, cephalosporin, nitrofurantoin, etc.), infections (bacterial, viral, fungal), autoimmune diseases (Systemic lupus erythematosus [SLE], Sjogren), tuberculosis, sarcoidosis and idiopathic. In a case series of 32 cases by Mignon et al.,^[2] 9% cases of granulomatous interstitial nephritis (GIN) were associated with sarcoidosis and tuberculosis. Drug history, clinical presentation, blood biochemistry, urine analysis, kidney biopsy with special stain, serum ACE level, IGRA and MTB polymerase chain reaction (PCR) all help in arriving at the exact diagnosis and institution of appropriate treatment. Here, we discuss a case of granulomatous TIN where ACE level and MTB PCR were not contributory, but appropriate histology with special stain helped us in arriving at the correct diagnosis.

CASE REPORT

A 46-year-old lady had a history of nephrotic syndrome (minimal change disease) in 2006 and was treated with steroids. She was diagnosed with type 2 diabetes mellitus in 2011 and was started on metformin and gliptins. Later, she was shifted to insulin for the past 3 years.

In January 2021, she was evaluated elsewhere for nausea and vomiting. Evaluation revealed normal serum creatinine with hypercalcaemia. Positron emission tomography scan revealed metabolically active lesions in mediastinal, retroperitoneal, liver, spleen, kidney and vertebral column. Renal biopsy was done in January 2021 which was suggestive of granulomatous lesions with giant cells. She was started on antitubercular therapy which she stopped after 2 months. Her renal function at that time was normal (S. creatinine 0.9 mg/dL). She did not follow-up thereafter.

She was reviewed at our hospital in February 2021 and was advised serum ACE level and respiratory consultation but she did not follow-up again.

She reported again in October 2024 and this time, she was evaluated for persistent dry cough, low-grade fever and uncontrolled diabetes mellitus. Evaluation revealed hypercalcaemia (serum Ca level 12.2 mg/dL) and advanced renal dysfunction (serum creatinine 4.1 mg/dL). Other laboratory investigation revealed serum albumin 3.7 mg/dL, serum ACE level 19.6 u/L (8–68), no M band, normal K:L ratio 102/117, Vit D level 19.6 ng/mL and iPTH level 4 pg/mL. Computed tomography chest showed multiple confluent nodules in the lungs, mediastinal and bilateral hilar lymphadenopathy. Ultrasound showed normal size kidneys and fundus examination was also normal. She underwent kidney biopsy and fibro-optic bronchoscopy with transbronchial nodal aspiration. MTB GeneXpert was negative.

Native kidney biopsy [Figure 1a-e] showed the presence of multiple closely packed, non-necrotising, naked epithelioid cell granulomas with surrounding minimal lymphomononuclear cell infiltrate. These granulomas were accompanied by Langhans’ and foreign-body types of multinucleated giant cells. Ziehl–Neelsen and Periodic acid– Schiff ’s stains were negative for acid–fast bacilli and fungal profiles. The viable glomeruli showed normal histology with 3 being obsolescent out of a total of 20. Interstitial fibrosis and tubular atrophy were estimated to be 25%. Reticulin fibre-rich granuloma kidney tissue [Figure 1f] and Romanowsky stain [Figure 1g] in lung tissue showing slipper-shaped epithelioid cell granuloma suggest the diagnosis of sarcoidosis. Typical tubercular epithelioid cell granuloma with central necrosis [Figure 1h] is shown for illustration. Direct immunofluorescence was essentially negative. An opinion of granulomatous interstitial nephritis was offered. The morphology of the granulomas was suggestive of sarcoidosis.

Close

Figure 1:

(a) Hematoxylin and Eosin (H&E) (40x) stain showing marked interstitial edema (blue arrow), (b) H&E (100x) stain showing multiple naked epithelioid cell granuloma (blue arrow), (c) H&E (400x) stain showing multinucleated gaint cell (blue arrow) (d) PAS (Periodic Acid-Schiff) (100x) stain showing interstitial granulomatous inflamation (blue arrow), (e) PAS (200x) stain showing multinucleated giant cell (blue arrow), (f) Reticulin (200x) stain showing reticulin fibre rich granuloma (blue arrow), (g) Romanowsky (200x) stain from mediastinal lymph node smear showing compact slipper shaped cluster of epitheloid cells (blue arrow), (h) H&E stain (400x), tubercular granuloma with central necrosis (blue arrow, left image), Reticulin stain: devoid of reticulin fibres (right image).

Export to PPT

She was managed with steroids, with augmentation of insulin dosage. Her renal function improved to a serum creatinine of 1.5 mg/dL. Steroid tapering started after 1 month and was reduced to the lowest maintenance dose of 7.5 mg at 6 months.

DISCUSSION

Renal sarcoidosis usually presents with nephrocalcinosis or renal calculi due to hypercalciuria; granulomatous renal involvement is rare.^[3] Most patients with GIN have extrarenal manifestations.^[4]

Due to similar clinical, radiological and histological presentation and difficulty demonstrating AFB in tissue samples, it is often difficult to differentiate between tuberculosis and sarcoidosis. The diagnosis of tuberculosis in granulomatous disease is usually arrived at based on a granuloma with central necrosis, caseation, AFB stain and MTB GeneXpert in tissue sample. This case highlights the importance of histology for making a correct diagnosis when conventional testing, including stain for AFB, necrosis and caseation in granuloma and serum ACE levels for granulomatous disease, is not contributory, particularly when tuberculosis and sarcoidosis are under consideration. In a retrospective study by Hoornaert et al.^[5] consisting of 192 cases of lymph node tuberculosis and sarcoidosis, 10.4% of the sarcoidosis patients with granulomas were necrotic (n = 12) and only 74% of the sarcoidosis patients had elevated ACE levels.

In our patient, MTB PCR was negative and serum ACE levels were also normal. In such a setting, additional histology inputs such as reticulin fibre-rich granuloma and slipper-shaped epithelioid cell granuloma and negative MTB PCR suggested the diagnosis of sarcoidosis.

CONCLUSION

Histology can provide useful clues for evaluation of granulomatous interstitial nephritis when conventional testing is not contributory to differentiate between tuberculosis and sarcoidosis.