Granulomatous interstitial nephritis: a rare diagnosis with an overlooked culprit

Abstract

Granulomatous interstitial nephritis (GIN) is a rare entity identified in <1% of native kidney biopsies. The most frequent aetiology is drug-related, followed by systemic granulomatous conditions. Among drugs implicated in GIN, antibiotics and non-steroidal anti-inflammatory drugs (NSAIDs) are the most frequent. We report the case of a 45-year-old white man referred to a nephrology consult due to chronic kidney disease. He had a history of arterial hypertension with 10 years of evolution, hyperuricaemia, medicated with allopurinol and NSAID abuse for at least 20 years. Urine sediment was blunt, without proteinuria. Renal ultrasound was normal. A kidney biopsy revealed well-defined epithelioid granulomas with glomerular wrinkling and collapse. Infectious and systemic conditions were excluded, favouring the hypothesis of drug-induced GIN, probably related to NSAIDs. Kidney biopsy remains the gold standard for the diagnosis of GIN. Facing a patient with renal failure without significant proteinuria or active sediment, one should look for causes of tubulointerstitial injury.

Background

The term acute interstitial nephritis (AIN) was introduced in 1898.¹ Ever since, tubulointerstitial nephritis (TIN) has been widely studied and encompasses two clinical presentations: acute TIN, characterised by a sudden onset and prompt decline in renal function, and chronic TIN, with a protracted and slower course, being characterised by interstitial fibrosis with tubular atrophy and irregular inflammation.² Scarring can begin within a week to 10 days from initiation of the acute injury.³ Renal biopsy remains the gold standard for diagnosis and is essential to delineate the extent of inflammation, fibrosis and eosinophilic infiltration. Untreated acute TIN may result in irreversible renal injury.²

Within TIN, granulomatous type is rare, occurring in 0.5%–0.9% of native kidney biopsies and 0.6% of renal transplant biopsies.^{4 5}

Granulomatous interstitial nephritis (GIN) affects both genders equally and can present at any age, more frequently between the fifth and sixth decades.⁴ Data on possible aetiologies are dependent on published case reports and case series.^6–9 In most reports, the chief aetiology of GIN is drug-related, followed by systemic granulomatous conditions, such as sarcoidosis, tuberculosis and granulomatosis with polyangiitis. Among drugs implicated, some antibiotics and non-steroidal anti-inflammatory drugs (NSAIDs) are the most frequent. Allopurinol, proton pump inhibitors and immunotherapy drugs have also been described.^{3 10} Idiopathic form accounts for 10% of cases.

Case presentation

We report the case of a 45-year-old white man, plumber, referred to a nephrology consult in 2016 due to chronic kidney disease (CKD) stage 3b (serum creatinine (sCr) 1.87 mg/dL, estimated glomerular filtration rate (eGFR) 42 mL/min/1.73 m²). The patient reported no respiratory, gastrointestinal or urinary symptoms, had no visual or hearing deficits and denied skin lesions. He had a history of arterial hypertension with 10 years of evolution, controlled with rilmenidin 1 mg qd, and persistent hyperuricaemia, with past gout crisis, medicated irregularly with allopurinol 100 mg qd for the last decade. He also had a history of NSAID abuse for at least 20 years. He had neither smoking nor drinking habits and had no known allergies. His maternal grandmother had end-stage renal disease (ESRD) of undetermined aetiology, having started renal replacement therapy at the age of 80 years old.

On physical examination, he presented normal facies and musculature, normal heart rate and blood pressure, no oedema, no skin lesions and no swollen lymph nodes. Neurologic, auditory and ophthalmologic examinations were normal.

Investigations

His blood tests showed elevated sCr and blood urea nitrogen (1.68 mg/dL and 33.2 mg/dL, respectively), without other relevant alterations, except for hyperuricaemia (8.4 mg/dL). Consulting his medical file, we found a value of sCr from 2010 of 1.43 mg/dL (eGFR 59.1 mL/min/1.73 m²), indicating that his kidney disease had at least 6 years of evolution. Table 1 summarises laboratory data on admission and during follow-up.

Table 1.

Laboratory data (the values outside the normal range are presented in bold)

Variable	June 2016	January 2017	June 2018 (emergency room)	July 2018	August 2018
Haemoglobin (g/L)	141	138	131	118	118
White blood cells (x109/L)	6.0	6.3	6.9	4.9	6.3
Platelets (x109/L)	205	202	109	202	209
INR (international normalized ratio)	1.01	–	–	–	0.91
Serum creatinine (mg/dL)	1.68	1.77	3.60	2.80	2.95
Estimated glomerular filtration rate (mL/min/1.73 m2)	49	46	19.2	26.1	24.5
Blood urea nitrogen (mg/dL)	33.2	35	40	50	42
Na+/K+ (mmol/L)	142/4.8	142/4.6	134/3.9	139/4.4	139/4.2
Ca2+/${\displaystyle \mathrm{P}{\mathrm{O}}_4^{-}}$ (mg/dL)	9.3/3.5	9.3/3.0	9.1/–	9.6/3.1	9.9/–
Glucose (mg/dL)	99	100	–	–	–
Uric acid (mg/dL)	8.4	–	–	–	6.3
Total protein/albumin (g/dL)	7.2/4.5	7.6/4.3	–/–	–/–	7.6/4.5
C reactive protein (mg/dL)	0.11	0.22	27	0.14	0.15
Total/HDL chol. (mg/dL)	194/45	–/–	–/–	–/–	187/33
Triglycerides (mg/dL)	146	–	–	–	224
Parathormone (pg/mL)	–	107	114	114	–

On more extensive study, and aside from positive anti-nuclear antibodies, with a title 1:160, his immune tests were normal, with negative anti-neutrophil cytoplasmic antibodies (ANCAs), normal range immunoglobulins and kappa and lambda light chains, normal serum electrophoresis and immunofixation, C3 and C4 complement fragments within normal range. Thyroid study was normal. Hepatitis B and C and HIV serologies were negative. Urine analysis showed inactive sediment and a protein/creatinine ratio of 125 mg/g. Renal ultrasound revealed normal sized kidneys, without structural alterations or signs of obstruction.

Subsequent analysis revealed steady function (table 1).

He was advised to avoid NSAIDs. Two years after the first consult, his nephrologist proposed a kidney biopsy on which the patient asked to ponder. Meanwhile, he presented to the emergency room (ER) with fever, myalgia, prostration and headache, denying other symptoms. He had already started auto-medication with ibuprofen. He was febrile (38.4°C), normotensive and not hypoxic, had a grossly normal heart, lungs and neurologic examinations. Laboratory tests showed aggravated renal function (sCr 3.6 mg/dL) and elevated C reactive protein (27 mg/dL). Urine test strip was positive for ketones (++) and blood (+). Thoracic radiography was normal. The patient was medicated with cefuroxime and discharged from the ER.

Two weeks later, as febrile syndrome resolved but aggravated renal function subsisted, the patient was admitted to the nephrology ward and was submitted to a kidney biopsy (figure 1).

Figure 1.

(A) H&E stain at ×100 magnification showing a glomerulus surrounded by tubular atrophy, interstitial inflammatory infiltrate and interstitial fibrosis. (B) Periodic acid–Schiff stain at ×100 magnification and (C) Silver stain at ×100 magnification revealing well-defined epithelioid granuloma completely involving a glomerulus with wrinkling and collapse of the capillary tuff. (D) CD68 stain marking macrophagic cells. (E) Transmission electron microscopy 4000× showing focal fusion of pedicels and increased mesangial matrix and sclerosis.

Light microscopy revealed eight glomeruli, one of which enclosed by a well-defined epithelioid granuloma and presenting retraction of the capillary tuff (figure 1B,C). There were other small granulomas with macrophagic and multinucleated giant cells, neutrophils and eosinophils. Five glomeruli were sclerotic and the remaining showed no thrombi, double contours or spicules. Surrounding the glomeruli and the tubules was a chronic interstitial inflammatory process, with lymphocytes, plasma cells and macrophages (figure 1D). Moderate tubular atrophy was observed in 30%–40% of the cortical tubules, accompanied by mild to moderate interstitial fibrosis and foci of AIN (figure 1A). There were no sclerotic areas, as confirmed by the trichrome and reticulin stains. Mild atherosclerosis was observed. No acid-alcohol resistant fungi or bacilli were identified by the Grocott and Ziehl-Neelsen techniques, neither were spirochetes observed by the Warthin–Starry stain. Characteristic signs of cytomegalovirus infection were absent. On immunofluorescence, four glomeruli were observed, which were IgA, IgG, C3, kappa and lambda chains negative; fibrinogen 1+; C1q+/− and IgM+/− mesangial focal and segmental. These histomorphological aspects were consistent with a non-necrotising GIN. Electronic microscopy revealed a glomerular basement membrane with normal thickness. There was increased matrix and mesangial sclerosis but no immune-type deposits or fibrils (figure 1E).

Further examinations were requested based on the diagnostic hypothesis. Toxoplasma, Brucella and Epstein-Barr virus serologies were negative, and so was the interferon-gamma release assay (quantiFERON test) and tuberculin skin test. The serum angiotensin-converting enzyme (SACE) value was normal (58 U/L). Thoracic CT revealed no pulmonary lesions.

Given the most likely hypothesis of drug-induced GIN related to NSAIDs, this medication was discontinued, and the patient was started on corticoid therapy with prednisolone 1 mg/kg/day in an attempt to resolve the acute interstitial lesions.

Differential diagnosis

In our patient, it is important to consider drug-induced GIN. He had a history of NSAID abuse for at least 20 years. His renal ultrasound showed normal kidneys, which is a typical feature in this condition.² The presence of lymphocytes and macrophages on light microscopy and the paucity of immune deposits on immunofluorescence support this diagnosis.⁴ He was also taking allopurinol, described as one of the potential causative agents. However, looking back to the patient’s records we found that he already had some degree of renal insufficiency before being started with this drug.

Regarding infectious causes, tuberculosis must be excluded. QuantiFERON and tuberculin skin tests were negative, and no acid-alcohol resistant fungi or bacilli were identified on light microscopy. Also, our patient had no history of contact with the mycobacteria and did not have any respiratory symptoms or pulmonary or mediastinal lesions on CT. Moreover, infections are usually associated with necrotising granulomas,⁴ which was not the case of our patient.

Other infectious agents have been implicated in GIN and our patient was tested for most of them, but neither the blood tests nor the histology revealed alterations suggestive of such aetiology.

It is also important to consider inflammatory causes, such as sarcoidosis. Our patient denied extrarenal manifestations, such as pulmonary, cutaneous or ocular. He had normal serum calcium concentration and normal SACE levels. Thoracic CT revealed no pulmonary lesions. Although there were some reported cases of sarcoid GIN without extrarenal involvement, it does not seem like our patient’s case. Granulomatosis with polyangiitis seems unlikely, as our patient reported no respiratory symptoms, had an inactive urine sediment and irrelevant proteinuria, and his ANCAs were negative.

Treatment

Our patient stopped both NSAIDs and allopurinol. Even though the lesions were mostly chronic, there were some foci of AIN and therefore, given the young age and good general condition, we decided to start him on prednisone 1 mg/kg/day, in an attempt to resolve the acute lesions and improve his kidney function.

Outcome and follow-up

One month after the beginning of corticoid therapy, our patient’s sCr improved to 2.5 mg/dL. He is currently still on treatment with progressive weaning. Our poor response is perhaps justified by the predominance of chronic lesions found on his biopsy.

So far, no side effects were reported.

Discussion

Our patient’s kidney biopsy revealed a GIN. The diagnosis in these situations can be challenging and imposes a review on the main causes. These are summarised in table 2.

Table 2.

Causes of granulomatous interstitial nephritis

Drug-related	Antimicrobials	Sulfonamides; penicillins; cephalosporins; fluoroquinolones; vancomycin; gentamicim; nitrofurantoin; erytromycin; rifampicin; acyclovir; clotrimazole; doxycycline
	Analgesics	Non-steroidal anti-inflammatory drugs; paracetamol; dihydrocodeine
	Other drugs	Allopurinol; omeprazole; furosemide; hydrochlorothiazide; chlorothiazide; lamotrigine; alendronate; diphenylhydantoin; carbamazepine; triamterene; amiloride; captopril; levetiracetam; phenytoin; sulfasalazine
Infectious	Mycobacterial	Mycobacterium tuberculosis; M. leprae; M. kansasii
	Fungal	Histoplasmosis; Candidiasis; Tricosporon laibachii; Cryptococcus neoformans
	Parasites	Toxoplasmosis
	Bacterial	Escherichia coli
	Viral	Epstein-Barr virus
Inflammatory/rheumatologic	Sarcoidosis; tubulointerstitial nephritis and uveitis syndrome; intestinal bypass; heroin; oxalosis; Crohn’s disease; granulomatosis with polyangiitis; eosinophilic granulomatosis with polyangiitis; BCG therapy
Idiopathic

Adapted from Jennette et al,² Shah et al ⁴ and Joss et al.⁵

Drug-induced AIN is thought to be linked to a cell-mediated immune response to an antigen originated or deposited in the kidney. It can recur once patients are re-introduced to the same agent, and the response is usually not dose dependent.⁴ Antibiotics, specifically sulfonamides, were the first drug-class to be implicated in GIN, in 1946.¹¹ Since then, penicillins, cephalosporins and fluoroquinolones, and others, have also been implicated. Usually, in these cases, granulomas display a wide interstitial inflammation and the cortex is more often involved than the medulla. The latency period between antibiotic use and diagnosis of GIN is shorter than that seen with other medications.¹ Differently, with NSAIDs, the latency period tends to be longer, averaging 6 months and GIN may present with proteinuria, usually in the subnephrotic range, and can lead to ESRD.^{1 12} The typical presentation of NSAIDs nephrotoxicity is acute kidney injury. However, it can also manifest as a subclinical renal failure which correlates with the cumulative intake of the drug, in cases of prolonged use.¹³ Another potential causative agent is allopurinol, usually associated with the presence of granulomatous hepatitis.¹⁴

Within infectious causes, mycobacteria and fungi are the chief aetiologic agents and seem to be the main causative factor in renal transplant patients.⁵ As a sole condition, tuberculosis is the most common. The first description of GIN as a manifestation of tuberculosis was in 1981.¹⁵ The majority of cases were described in Asian Indian and African patients, likely reflecting the high incidence of this condition in these populations. Even though its prevalence in Portugal has been decreasing, we remain among the countries with the highest incidence rates (15.6/100 000 inhabitants in 2017).¹⁶

Inflammatory conditions are also an important cause. Sarcoidosis is a systemic disease characterised by chronic non-caseating granulomatous inflammation with tissue destruction.¹⁷ Most patients with sarcoidosis-associated GIN present with extrarenal manifestations, such as pulmonary, cutaneous or ocular. Hypercalcaemia is also a frequent characteristic in this condition.⁴

GIN may also be the histologic manifestation of granulomatosis with polyangiitis in 5%–16% of the cases.⁴ Most patients present with pulmonary symptoms, haematuria and proteinuria, besides renal failure.

Tubulointerstitial nephritis and uveitis syndrome is an idiopathic condition that manifests with renal and bone marrow granulomas.¹⁸ It generally affects adolescent girls. Sometimes its diagnosis is delayed since renal disease may precede the appearance of uveitis. It may be linked to other conditions such as rheumatoid arthritis, infections, antibiotics, Chinese herbs or NSAIDs.⁴

Finally, it is also important to consider other rare entities such as xanthogranulomatous pyelonephritis, malakoplakia, and megalocytic interstitial nephritis.¹⁹ Kidney biopsy typically reveals foam cells, Michaelis–Gutmann bodies and von Hansemann cells.

Treatment of GIN depends on its aetiology. In drug-related GIN, treatment includes withdrawal of the offending agent and corticoid therapy.⁴ Although no prospective clinical trials have been conducted to prove its efficacy, a retrospective study including 61 patients showed improvement in renal function with pulses of methylprednisolone, followed by per os prednisone 1 mg/kg/day tapered over 8–12 weeks.²⁰

Our patient’s chronic exposure to NSAIDs led to a CKD with an infrequent histologic pattern. Other case reports of NSAIDs-induced GIN have been published with good results following drug discontinuation and corticoid therapy.^{21 22} Cases of GIN induced by other classes of drugs have also been described, with good results following the same line of treatment.^23–25

GIN is an unusual condition and the kidney biopsy remains the gold standard for its diagnosis, being of uttermost importance in delineating the extent of inflammation and fibrosis, helping to predict the response to treatment. When granulomatous inflammation is present in the biopsy, a careful search for infectious, pharmacologic, or other causes of GIN must be undertaken and for this matter a global approach with clinical-pathologic correlation is essential in order to identify the underlying condition.

Learning points.

• Granulomatous interstitial nephritis is a rare entity identified in <1% of native kidney biopsies.

• The chief aetiology is drug-related, followed by systemic granulomatous conditions.

• Kidney biopsy remains the gold standard for its diagnosis.

• In the presence of acute interstitial nephritis, steroid treatment may reduce the severity of the inflammation and, in particular, lessen accompanying oedema.