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NDT Advance Access originally published online on May 23, 2006
Nephrology Dialysis Transplantation 2006 21(8):2311-2314; doi:10.1093/ndt/gfl018
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Case Report

Granulomatous interstitial nephritis treated with a tumour necrosis factor-{alpha} inhibitor

Laurie Tomlinson1, Kevin Davies2, David A. Wright3 and Stephen Holt1

1 Sussex Kidney Unit, Brighton and Sussex University Hospital, Royal Sussex County Hospital Brighton, BN2 5BE, 2 Brighton and Sussex Medical School, University of Sussex, Falmer, Sussex, BN 9PX and 3 Brighton and Sussex University Hospital, Royal Sussex County Hospital Brighton, BN2 5BE, UK

Correspondence and offprint requests to: Professor Kevin Davies, Brighton and Sussex Medical School, University of Sussex, Falmer, Sussex, BN 9PX, UK. Email: Kevin.Davies{at}bsuh.nhs.uk

Keywords: interstitial nephritis; tumour necrosis factor-{alpha}



   Introduction
Top
 Introduction
Case
 Discussion
 References
 
Granulomatous interstitial nephritis (GIN) is a rare condition characterized histologically by interstitial infiltrate and the accumulation of lymphocytes and other mononuclear cells in granulomas. It has been associated with infections, drugs and autoimmune conditions and has also been reported in the absence of known aetiological factors [1]. Some series have suggested that a proportion of cases of ‘idiopathic’ GIN may be due to renal-limited sarcoidosis [2,3]. Tumour necrosis factor-{alpha} (TNF) has been implicated in the pathogenesis of sarcoidosis, particularly in granuloma formation, and agents that inhibit TNF have shown some benefit in treating sarcoidosis resistant to corticosteroid therapy [4]. Infliximab, a monoclonal antibody against TNF has been successfully used to treat complicated sarcoidosis [5–7]. Treatment of isolated sarcoid GIN has been reported in a child [8] but not in an adult. We report a case of an adult with a history of steroid-sensitive childhood nephrotic syndrome who developed renal impairment, proteinuria and microscopic haematuria in adulthood. GIN was found on renal biopsy and the subject was treated with corticosteroids. Side-effects led to the need for a different type of therapy and he was treated with infliximab with resolution of his illness.



   Case
Top
 Introduction
 Case
Discussion
 References
 
The patient was diagnosed with nephrotic syndrome at 2 years of age and was treated with oral prednisolone with complete resolution. A presumptive diagnosis of minimal change nephropathy was made. He had further episodes of nephrotic syndrome, which were all steroid responsive. The frequency of these episodes meant that he required continuous corticosteroid therapy. He received three courses of cyclophosphamide (duration and doses unknown) at the ages of 3, 5 and 13 years and had a maximum remission of 10 months. At 18 years of age, he was transferred to the adult renal services. He was suffering from a relapse of nephrotic syndrome with marked oedema, heavy proteinuria on urine dipstick testing and a serum albumin of 20 g/l. The general treatment for his illness at this stage was a maintenance dose of 10 mg prednisolone, but with relapses approximately twice a year requiring increased dosage to 60 mg daily. He was suffering from obesity, short stature and delayed puberty, attributed to the high steroid doses that he had received. His investigations were repeated with a normal renal ultrasound, normal renal function (creatinine clearance 156 ml/min), normal serum complement levels (during remission) and negative immunology for ANA and ANCA. Urine dipstick testing was negative for proteinuria and haematuria during periods of remission. The disease pattern and investigation results were felt to be consistent with the presumed diagnosis of minimal-change nephropathy and in view of his steroid dependence, treatment with cyclosporin was commenced. Subsequently, the patient had a 2 year remission, with a reduction and eventually a temporary withdrawal of steroids. However, each time the cyclosporin dose was reduced, he relapsed again (proteinuria >3 g/2 h) and steroids were again required (Figure 1). On each occasion, a high dosage of steroids resulted in the resolution of proteinuria.


Figure 1
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  		Fig. 1. This patient suffered a steroid responsive nephrotic illness since the age of 2. From the age of 18 (0 days) he was commenced on cyclosporin but still suffered relapses requiring high-dose steroids (shaded arrows). After more than 10 years of treatment he developed renal impairment, hypertension, microscopic haematuria and persistent proteinuria. There was concern about cyclosporin toxicity, so the drug was withdrawn, but he suffered relapses of nephrotic syndrome and renal function worsened. A renal biopsy showed GIN and high-dose steroids were instituted, but as these were reduced proteinuria worsened again. Infliximab infusions were commenced which led to cessation of proteinuria and normalization of renal function and blood pressure to 18 months of follow-up.

 
At 30 years of age, the patient developed mild renal impairment with hypertension, persistent low-grade proteinuria (<0.5 g/24 h) and microscopic haematuria. These changes were persistent, and concern about cyclosporin nephrotoxicity prompted a renal biopsy which took place at the age of 32 years (Figure 2).


Figure 2
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  		Fig. 2. Light microscopy of the kidney. Several well-formed granulomata were present within the interstitium with a predominantly lymphocytic inflammatory infiltrate, but with a component of eosinophils and neutrophils. Special stains for fungi and mycobacteria were negative. There was no deposition of immune reactants and electron microscopy revealed preserved podocyte foot processes with no electron dense deposits (not shown). Eight of 19 glomeruli were globally sclerosed but the remainder were normally sized, normocellular and without segmental sclerosing lesions. In addition, focal lymphocytic and neutrophilic infiltration of non-atrophied tubules was seen with infrequent neutrophil casts. There was patchy atrophy, in a vaguely striped distribution, of approximately 20% of tubules, with accompanying interstitial fibrosis. Very occasional foci of tubular microcalcification were present and there was mild arteriolosclerosis.

 
The biopsy showed a granulomatous interstitial nephritis. Review of the drug history did not suggest exposure to a drug or infection known to cause GIN. Chest radiograph, lung-function tests, serum calcium, serum ACE level and gallium scan were all normal. Three midstream urine samples showed no evidence of Mycobacterium tuberculosis on extended culture.

High dose steroids were again instituted and the renal function improved with resolution of haematuria and proteinuria. However, side effects meant that a better long-term treatment was needed. The patient had developed GIN on treatment with cyclosporin and low dose steroids, making further therapeutic options limited. The patient declined treatment with thalidomide. Treatment with infliximab was therefore commenced, after informed consent was given for experimental therapy. The patient received monthly infusions of infliximab 5mg/kg for 6 months. He suffered no side effects during or after infusion, and cyclosporin and steroid treatment were withdrawn. He had no further proteinuria and blood pressure, and his renal function remained normal. After six monthly infusions of infliximab therapy he was commenced on tacrolimus, which was chosen as the GIN had developed while on treatment with cyclosporin. At 18 months, since commencing anti-TNF treatment the patient remains in remission without steroid use.



   Discussion
Top
 Introduction
 Case
 Discussion
References
 
We have described the case of a patient with idiopathic GIN, which resolved on treatment with a TNF inhibitor. The patient had a previous history of nephrotic syndrome from early childhood and a change in the nature of his disease with renal impairment, persistent proteinuria and microscopic haematuria led to a renal biopsy being performed, which demonstrated GIN. None of the infections, drugs or autoimmune diseases known to be associated with GIN could be implicated in the patient and there were no features of sarcoidosis.

The exact underlying renal pathology in this patient is unclear. The history is suggestive of two overlapping renal diseases; a relapsing nephrotic illness, which may have been a minimal change disease, and a subsequent evolution into GIN. Only evidence of the second process was present on the renal biopsy. GIN has not been reported as causing a relapsing nephrotic illness, although it has been reported in association with membranous nephropathy [9,10] and mesangiocapillary glomerulonephritis [11] in the context of sarcoidosis with multi-organ involvement. There are two case reports of sarcoidosis in association with minimal change disease in adults [12,13], but in both these cases the minimal change nephropathy developed at the same time as the diagnosis of sarcoidosis or subsequently. Idiopathic GIN has not, to the knowledge of the authors, been associated with minimal change disease. It is interesting to note that the patient had been on long-term cyclosporin. Sarcoidosis is known to be associated with subtle abnormalities of T cell function including an increased frequency of common variable immunodeficiency [14], and it is possible that long-term immunosuppressive therapy could have played a role in the development of GIN.

The patient, in this case, was found to have GIN after developing slowly progressive renal impairment, haematuria and persistent proteinuria. GIN most commonly presents with acute renal failure [2]. However, other studies report that the disease process may be insidious in a high percentage of cases [15]. In sarcoidosis, renal granulomata may be found in up to a third of patients without evidence of renal dysfunction [16].

GIN is an incompletely understood condition which appears to have an association with sarcoidosis although, debate remains as to whether GIN represents renal-limited sarcoid. Idiopathic GIN, in the absence of extrarenal sarcoid, is rare but has been described [2,3]. One study described seven cases of GIN in the absence of extrarenal sarcoid [2]. Out of these, three cases were associated with hypercalcaemia and/or raised serum ACE levels, and five responded to treatment with corticosteroids. This possible overlap between the two conditions led to infliximab, a reported treatment for steroid resistant sarcoidosis, being used to treat GIN in this case.

There is increasing evidence to show that TNF plays a critical role in promoting disease activity in sarcoidosis and granuloma formation, in particular [4]. Drugs which inhibit TNF, including pentoxifylline and thalidomide, have been used to treat resistant sarcoidosis. Infliximab is a chimeric monoclonal antibody formed by replacing the antigen-binding hypervariable portions of a human IgG1 antibody with mouse protein segments from a mouse monoclonal antibody against human TNF. The protein binds to TNF and blocks its interactions with the TNF receptor. It has been shown to be effective in Crohn's disease and rheumatoid arthritis [4]. So far, no controlled trials of the efficacy of treatment of sarcoidosis with infliximab have been completed but there are an increasing number of case reports and series suggesting benefit from its use in the treatment of patients with complicated sarcoidosis [5–7].

In the wider renal context, treatment with infliximab has been reported as being of potential benefit in antineutrophil cytoplasm antibody-associated systemic vasculitis [17], lupus nephritis [18] and renal amyloid in association with chronic inflammatory conditions [19]. However, infliximab is an immunosuppressive agent that carries an increased risk of infections, particularly reactivation of tuberculosis. Other complications include the formation of antimurine antibodies to the drug resulting in immune reactions which may limit the therapy.

In summary, we have reported the case of a patient who developed idiopathic GIN after a relapsing nephrotic steroid-sensitive illness since early childhood. Treatment with infliximab led to resolution of renal impairment, haematuria and proteinuria, and this response has been maintained till 18 months of follow-up. The patient suffered no adverse effects. The experience suggests that infliximab could be a useful potential therapy for patients with idiopathic GIN in whom high-dose steroids have unacceptable side-effects or do not control disease activity.

Conflict of interest statement. The authors confirm that there is no conflict of interest.



   References
Top
 Introduction
 Case
 Discussion
 References
 

  1. Mignon F, Mery JPH, Mougenot B. Granulomatous interstitial nephritis. Adv Nephrol 1984; 13: 219–245
  2. Robson MG, Banerjee D, Hopster D, Cairns, HS. Seven cases of granulomatous interstitial nephritis in the absence of extrarenal sarcoid. Nephrol Dial Transplant 2003; 18: 280–284[Abstract/Free Full Text]
  3. Miyoshi KI, Okura T, Manabe S, Watanabe S, Fukuoka T, Higaki J. Granulomatous interstitial nephritis due to isolated renal sarcoidosis. Clin Exp Nephrol 2004; 8: 279–282[CrossRef][Medline]
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  8. Thumfart J, Müller D, Rudolph B, Zimmering M, Querfeld U, Haffner D. Isolated sarcoid granulomatous interstitial nephritis responding to infliximab therapy. Am J Kidney Dis 2004; 45: 411–414
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  17. Mukhtyar C, Luqmani R. Current state of tumour necrosis factor {alpha} blockade in Wegener's granulomatosis. Ann Rheum Dis 2005; 64 [Suppl 4]: iv31–iv36
  18. Aringer M, Graninger WB, Steiner G, Smolen JS. Safety and efficacy of tumor necrosis factor alpha blockade in systemic lupus erythematosus: an open-label study. Arthritis Rheum 2004; 50: 3161–3169[CrossRef][Web of Science][Medline]
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Received for publication: 1. 6.05
Accepted in revised form: 15. 1.06


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