An atypical form of renal failure: granulomatous interstitial nephritis

A 42-year-old man developed AKI during his recent hospitalization due to presumed sepsis. He was started on vancomycin and levofloxacin as empirical therapy. When renal was consulted 7 days after admission, creatinine level had peaked at 4.39 mg/dl and WBC 33K with eosinophilia. Urinalysis was associated with 2+ proteinuria and 2+ leukocyte esterase with some granular casts, though no cellular casts were visualized. On examination, he had generalized erythematous rash associated with diffuse body edema.

The initial diagnosis by the team was thought to be ATN associated with sepsis, though the presence of rash and eosinophilia raised the concern for superimposed drug-induced acute interstitial nephritis (AIN).

A renal biopsy was performed and the histopathologic findings revealed an AIN with granulomatous features (figure on the top left - Courtesy of Dr Rennke/Dr Bijol).

AIN is a common finding in kidney biopsies of patients with acute renal failure in the hospital. However, granulomatous interstitial nephritis (GIN) occurs in only about 1% of biopsies. GIN is a histologic form of interstitial nephritis characterized by the presence of necrotizing or non-necrotizing granulomas in renal biopsy. Its pathogenesis is not well defined. Some immunologic mechanisms were proposed as culprits such as T-cell-mediated delayed hypersensitivity, anti-tubular basement membrane antibodies and autoimmune antibody response.

Potential etiologies include:

 - Drug-induced processes [[most common]] (Antibiotics, NSAIDs, Diuretics (thiazide), Allopurinol, Anticonvulsant (lamotrigine), Omeprazole, Bisphosphonate, All-trans retinoic acid, Heroin abuse)
- Infections (xanthogranulomatous pyelonephritis, tuberculosis and other mycobacterial infections; Histoplasmosis and other fungal infections; adenovirus)
- Systemic inflammatory conditions (Sarcoidosis, Wegener granulomatosis, TINU, Crohn’s disease)

In about 15% of cases, an exact etiology for GIN is not found.

Further work-up on the case above did not reveal any systemic inflammatory process or infections, though a high suspicion for antibiotic-induced GIN was raised. In particular, there has been case reports of levofloxacin-associated GIN.

The treatment of GIN depend on the underlying associated factor. For example, in drug-induced processes, the removal the offending agent will play a central role in the treatment; while in infection-related cases, the underlying infection must be controlled.

In the case presented, antibiotics were changed and an empirical trial of steroids was administered. Patient’s creatinine slowly trended down in the subsequent weeks but plateau at 1.5 mg/dl. Though there has been no randomized trials, most GIN cases deserve a trial of steroids once infectious etiologies are excluded, in particular based on the intense inflammation observed on the biopsies.

Anthony Gueratto Klepp

Eduardo Kaiser Ururahy Nunes Fonseca

Leonardo V. Riella

Kidney Biopsy Case: AKI

A 54 year old man was referred to the Nephrology service due to AKI after presenting with lethargy and severe thirst. He had a long history of pulmonary and hepatic sarcoidosis which had been quiescent for some time. He likely had some baseline mild CKD with a serum creatinine of 1.3 mg/dl and 0.5 g/day proteinuria. His medications were unremarkable except for a calcium and vitamin D preparation which he had been taking for several months. His creatinine was 4.0 mg/dL and calcium was 13.5 mg/dl on presentation. He was volume resuscitated, treated for his hypercalcemia and proceeded to renal biopsy. Low power light microscopy is below which reveals an interstitial infiltrate with moderate fibrosis and some sclerosed glomeruli.

Higher power demonstrates multiple non-caseating granulomas. The granulomas consist of amorphous reddish material as well as multi-nucleated giant cells (below; top left and right of center).

Another example below of a granuloma (on the left of the panel) in a sick looking tubulo-interstitium.

The diagnosis was sarcoidosis-related granulomatous interstitial nephritis. He was commenced on high dose oral steroids and his renal function settled back down to normal over several weeks. Sarcoidosis does uncommonly affect the kidneys and is a major differential for granulomatous interstitial nephritis (see previous post). A teaching point for this case is not to presume the hypercalcemia is all iatrogenic. The high calcium points to sarcoid activity which was demonstrated nicely on the biopsy.

Differential Diagnosis of Granulomatous Kidney Disease

Although it's not common (somewhere between 0.5 - 0.9% of all native kidney biopsies according to published case series), one of the fellows produced an interesting case of granulomatous interstitial nephritis in Renal Grand Rounds today.

The case, in a nutshell: a middle-aged individual with ESRD of unknown etiology who is now on a 2nd cadaveric kidney transplant which was transplanted about a decade ago, presented to the Transplant Clinic with a creatinine that bumped from its baseline of 1.8 mg/dL to 2.4 mg/dL and a urinalysis which was largely unremarkable with the exception of a few WBC casts. The patient was being treated with sirolimus 1mg po daily, MMF 500mg po bid, and prednisone 2.5mg po daily which had not been changed recently. A renal allograft ultrasound was unremarkable, as were tests for circulating donor-specific antibodies. The patient underwent an allograft biopsy, which surprisingly showed multiple granulomas in the renal parenchyma along with significant interstitital nephritis.

What's the underlying etiology of the granulomatous renal disease? To be fair, we don't yet know. Granulomas are essentially an organized collection of macrophages--they are often recognized by the presence of multinucleated giant cells, which are multiple macrophages which fuse together, and they can be broadly categorized as being either caseating (that is, containing a necrotizing core) or non-caseating granulomas. The following is a differential diagnosis of the most likely culprits:

1. Tuberculosis: TB is a classic cause of non-caseating granulomas. This patient worked in the health care industry and therefore had annual PPD tests, all of which were negative.

2. Fungal infection: Histoplasmosis and Cryptococcus are some of the more common granuloma-inducing fungal infections.

3. Other infections: Cat-scratch fever (caused by Bartonella henselae) and chronic pyelonephritis can sometimes cause granulomas to be seen on kidney biopsy, and in these instances the interstitial infiltrate is usually more neutrophil-rich.

4. Sarcoidosis: Although sarcoid most often manifests as pulmonary issues, it can really affect almost any site, including the kidney.

5. Wegener's granulomatosis: Evidence of pulmonary-renal syndrome and glomerulonephritis can raise suspicion for Wegener's. It's important to realize however that granulomas in the kidney are much more rare than granulomas in the upper respiratory tract.

6. Drugs: there are several reported instances of AIN producing granulomatous disease in the kidney. Somebody at RGR also suggested that perhaps sirolimus (known to result in other inflammatory complications such as pneumonitis and oral ulcers, for instance) should be considered as a culprit.

7. Idiopathic.

Due to the rarity of the condition, there is little consensus on how the condition should be managed. This case series by Joss et al in a 2007 issue of CJASN suggests that low- to moderate-dose steroids, after successfully ruling out infectious etiologies, can be beneficial.