|Year : 2019 | Volume
| Issue : 3 | Page : 156-159
Granulomatous interstitial nephritis in native kidneys and renal allografts
Praveen Kumar Etta
Department of Nephrology and Renal Transplantation, Asian Institute of Nephrology and Urology, Hyderabad, Telangana, India
|Date of Submission||23-Jan-2019|
|Date of Decision||06-Jun-2019|
|Date of Acceptance||12-Aug-2019|
|Date of Web Publication||17-Sep-2019|
Dr. Praveen Kumar Etta
Department of Nephrology and Renal Transplantation, Asian Institute of Nephrology and Urology, Hyderabad - 500 082, Telangana
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Etta PK. Granulomatous interstitial nephritis in native kidneys and renal allografts. Indian J Transplant 2019;13:156-9
Granulomatous interstitial nephritis (GIN) is a rare entity detected in <1% of native renal biopsies and much rarely reported in renal allograft recipients (RAR). It accounts for up to 6% of all cases of tubulointerstitial nephritis (TIN). The etiology of GIN varies based on geographic location and population studied. The common causes of GIN are listed in [Table 1]. In native kidneys, the most cases of GIN reported from the west were due to drugs and systemic disorders like sarcoidosis; in significant number of cases, etiology could not be identified were grouped as idiopathic variety. Drug-induced GIN (D-GIN) is the most common variety contributed up to 36% of reported cases in native kidneys. Although there is a paucity of literature from India, most of the reported cases of GIN were due to tuberculosis. The three large case series published from India concluded the same [Table 2].
|Table 2: Published case series of granulomatous interstitial nephritis in native kidneys|
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GIN can occur even in an immune deficiency state, i.e., granuloma formation may occur in the absence of adaptive immunity by innate immune mechanisms. With respect to postrenal transplant GIN, the proportion of various etiologies may vary from that of native kidney GIN. Infections (especially tuberculosis and fungal infections) are probably the most common underlying cause due to their immunocompromised status. This was identified both from the Western and Indian literature, though the literature on GIN affecting renal allografts is sparse with most of the published work was limited to individual case reports and small case series [Table 3]. GIN may occur as a de novo event in the allograft from any of the etiologic agents that cause GIN in native kidneys. Systemic diseases such as sarcoidosis, vasculitis, or TIN with uveitis (TINU) syndrome can cause either de novo or recurrent disease. Although acute rejection is a common cause of TIN in an allograft, it is not associated with granuloma formation.
|Table 3: Published case series of granulomatous interstitial nephritis in renal allografts|
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Infection is the most common reported cause of allograft GIN, accounting for 63.9% of reported cases. Mycobacterium tuberculosis is the single most commonly reported agent associated with allograft GIN contributing up to 39% of reported cases. Till date, only up to 70 cases of GIN affecting renal allografts have been reported in the literature. Important case series of GIN in renal allografts are presented in [Table 3]. The largest series of renal allograft GIN published by Farris et al. in 2017 also showed infections as the most common cause of GIN in RAR. GIN was reported in 23 specimens from 22 RAR; it was due to viral, bacterial, and fungal infections in 12 (54.5%), D-GIN in 5 cases (22.7%), one had recurrent granulomatosis with polyangiitis (GPA) (GPA, formerly called Wegener's granulomatosis) and four were idiopathic. As the Indian literature related to GIN in renal allografts is scarce, reported etiologies may not reflect true incidence of various diseases [Table 3].
Renal manifestations typically occur within 3–10 weeks after starting offending drug in the majority of cases of D-GIN. Among drugs causing GIN, latency period is shorter with antibiotic-induced GIN. Nonsteroidal anti-inflammatory drugs (NSAIDs)-induced acute interstitial nephritis (AIN) with or without granulomas often occur several months after exposure, can have nephrotic range proteinuria and less eosinophilia. GIN has been attributed to a delayed-type hypersensitivity reaction and is not dose-dependent; it can be associated with extrarenal signs of hypersensitivity such as arthralgia, fever, rash, and eosinophilia. Certain drugs such as NSAIDs and proton pump inhibitors (PPIs) are less commonly associated with systemic features in contrast to other agents like antibiotics. The development of drug-induced TIN is not dose-dependent, and recurrence or exacerbation can occur with a second exposure to the same or a related drug. Drug withdrawal leading to resolution and recovery of the renal function indicates the etiological association in most cases of D-GIN.
PPIs are well known to cause acute TIN in native kidneys, and are not class specific. Although rare, PPI-induced GIN has been reported in native kidneys. One such case is reported in a renal allograft and published in the earlier issue. In this case, authors have observed pantoprazole-induced GIN on graft biopsy in a 16 years old allograft after 1 month of use of drug. On drug withdrawal, graft function recovered to baseline after 2 weeks, indicating its etiological association.
GIN is an unusual feature of bacterial infection, most often described in the context of immunosuppression, and manifest usually as megalocytic interstitial nephritis or malakoplakia. Fungal infections such as Candida, Histoplasma, Coccidioides, and Cryptococcus are known to cause GIN. Among viral infections, adenovirus (AdV) is probably the most common cause of GIN in renal allografts. Severe necrotizing GIN with palisading tubulo-centric granulomas is characteristic of AdV infection. Cytomegalovirus and Epstein–Barr virus infections may also cause GIN. Granulomatous TIN is an uncommon feature of polyomavirus nephropathy, though intratubular granulomas have also been described in this setting.
Histology alone does not always give clue to the underlying cause of GIN. The clinical features, extra-renal manifestations, radiology, history of drug intake, demonstration of infective agent, and certain histological features on renal biopsy may give clue to a specific diagnosis. Infection-related allograft GIN may have microorganisms in granulomas, megalocytic inflammation, and glomerular granulomas in the setting of miliary tuberculosis, none of which were seen in noninfectious GIN. The presence of crystals and clefts, and vasculitic glomerulonephritis may also provide diagnostic clues to the underlying etiology of GIN. The granulomas can be evaluated for the presence or absence of necrosis, distinct lymphocyte cuff, well-circumscribed or noncircumscribed, calcification, and for the presence of asteroid and schumann bodies (calcium and protein inclusions inside of langhans giant cells). Nonnecrotizing granulomas are seen with D-GIN, TINU and sarcoidosis; necrotizing granulomas are common with GPA, eosinophilic GPA, tuberculosis, and fungal infections. D-GIN leads to more loose appearing aggregates of epithelioid macrophages, but granulomas in sarcoidosis tend to be rather well defined. Sarcoid granuloma is also described as “naked” with no cuff of inflammatory cells with presence of asteroid bodies and calcification. Ziehl–Neelsen staining for acid-fast Bacilli and fungal staining (chromic acid silver methenamine) may help in diagnosis. The diagnostic utility of multiplex polymerase chain reaction for tubercular DNA in renal biopsy tissue was proposed in a recent study on GIN from North India. The presence of viral inclusions may also help in etiologic diagnosis.
Treatment, prognosis, and outcome depend on the underlying etiology. The literature and experience of treating GIN is mostly limited to native kidney GIN. The removal of offending agent along with corticosteroid therapy or intensification of immunosuppression for a short period in posttransplant setting often results in recovery in cases of D-GIN. The use of corticosteroids has been supported mainly by retrospective studies on subjects with native kidney AIN with or without granulomas, but no randomized controlled trials demonstrating its efficacy exist. Steroid regimens varied between different studies, but most commonly involved pulse doses of intravenous steroids followed by oral prednisone started at 0.5–1 mg/kg/day tapered over 8–12 weeks. Longer courses of steroid therapy are required in patients with immunological disorders such as sarcoidosis and TINU. The role of steroid-sparing agents is not clear, though few studies have examined the beneficial effects of drugs such as mycophenylate mofetil, calcineurin inhibitors, azathioprine, and infliximab. Patients with infection-induced GIN are treated for their infection and steroids are generally not indicated. Noninfectious GIN portends a better outcome than infectious GIN. Higher rates of graft failure were reported in infectious GIN, especially in M. tuberculosis infection with >80% of reported cases progressed to graft loss.
In conclusion, GIN is a very rare cause of graft dysfunction in RAR, having multiple etiologies, which are mostly treatable if identified early. Allograft biopsy and evaluation of underlying cause are the key factors determining therapy and graft salvage. Infections especially tuberculosis contribute to majority of GIN in this group of patients.
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[Table 1], [Table 2], [Table 3]