There was fibrous thickening of arterial intima in medium size arteries without arteriolar hyalinosis.

We diagnosed this case as hypocomplementaemic idiopathic tubulointerstitial nephritis, and prednisolone 1mg/kg/day (40 mg/day) was started. The patient was discharged 3 weeks after without renal function recovery. She remained on chronic haemodialysis programme and she had been followedup since discharge in the ambulatory clinic. She continued therapy with prednisone 40mg/day for 4 months, without recovery of the renal function.

However there was normalization of C3 levels (124mg/dL).

The patient was re-hospitalized, after this period, due to fever of unknown origin, associated with myalgia and tiredness. After aetiologic research, miliary tuberculosis was diagnosed. The patient began therapy with a 4-drug regimen (isoniazid, rifampin, pyrazinamide and ethambutol).

During her stay in hospital, she suffered several healthcare associated infections, after which she suffered multi-organ failure, reason why the patient was transferred to an Intensive Care Unit. Here she needed invasive mechanical ventilation and vasoactive amines, and death occurred several days later.

DISCUSSION

We present a case of a patient with renal failure, hypocomplementaemia (low C3), positive ANA, active urine sediment (blood 3+ cells/HPF) and 24h proteinuria of 1.5g. She did not have eosinophilia and anti-dsDNA, SSA and SSB were negative. The biopsy revealed tubulointerstitial immunological damage with C3 and all IgG subtypes deposition in the tubular basement membrane (TBM) and interstitium, in a granular and diffuse pattern without glomerular involvement. We diagnosed this case as hypocomplementaemic idiopathic tubulointerstitial nephritis, a very rare cause of tubulointerstitial nephritis¹.

Tubulointerstitial nephritis is related to various causative factors, including infectious, allergic, toxic, autoimmune and idiopathic conditions^2,8. Linear or granular TBM deposits may be found in systemic lupus erythematosus (SLE), Goodpasture’s syndrome, Sjogren’s syndrome (SS), and membranous glomerulopathy, and rarely, usually with linear pattern, in drug-induced nephropathy secondary to methicillin and phenytoin^1,2,4,5,9. It has also been described in urticarial vasculitis syndrome, adenovirus infection, renal allograft rejection or mixed cryoglobulinaemia⁴.

The majority of these diseases have predominantly glomerular involvement, which was not present in our case. Predominant or isolated granular tubulointerstitial deposits are usually restricted to autoimmune disorders, such as SLE, SS and IgG4-related systemic disease.

The SLE was excluded as the patient did not fulfill the American Rheumatology Association diagnostic criteria¹⁰.

Negative serology for anti-SSA/Ro and anti-SSB/La and no symptoms or signs suggestive of SS ruled out this entity¹¹.

The IgG4-related disease is a clinicopathological entity characterized by tumefactive lesions, a dense lymphoplasmocytic infiltrate rich in IgG4-positive plasma cells with fibrosis, and elevated total IgG or IgG4 in serum. In the kidney, the most dominant feature is a tubulointerstitial nephritis³. A Japanese group proposed a diagnostic algorithm for IgG4-related kidney disease (IgG4 RKD)¹². In accordance with this algorithm, IgG4 RKD should be suspected when some kidney damage is present associated to an elevated serum total IgG level, hypocomplementaemia or an elevated IgE level. Other characteristics that help in the diagnosis of this entity are serum IgG4 level (> 135mg/dL), radiologic findings like diffuse kidney enlargement, and a renal biopsy with evidence of plasma cell-rich TIN with > 10 IgG4+plasma cells/HPF fill in the most concentrated field.

Using this diagnostic algorithm for IgG4 RKD, we ruled out this hypothesis.

Only thirteen cases^1,2,4-7 of idiopathic hypocomplementaemic interstitial nephritis have been described in the literature. The largest series is that by Kambham et al. with eight cases reported².

The significant varied nature between the reported cases challenged the possibility of a common aetiology^1,4, but kidney biopsies of the reported cases always showed TBM deposits with granular and predominantly diffuse staining for IgG. Hypocomplementaemia, TBM immune complexes and glomerular sparing were consistent findings in all cases^1,2,4,5.

This indicates that the immune deposits in the TBM are capable of activating serum complement, leading to immune-mediated tubular injury¹. C3 staining in the TBM was not, however, a consistent finding among the 13 cases, as also IgM, C1q, Lambda and kappa chains^1,2,4-7. The pathogenesis of TBM deposits is unknown. The TBM antibody–antigen complex could result from either in situ immune complex formation or deposition of preformed circulating immune complexes^1,5.

Tubulointerstitial nephritis with immune deposits seems to occur predominantly in older men with underlying immunologic disorders, including sclerosing cholangitis (two cases), marginal B cell lymphoma (one case), leucocytoclastic vasculitis (one case)².

Adult onset of diabetes mellitus and coronary artery disease were also present in five and six, respectively^1,2,6,7.

However, in our case the patient was a woman and she did not present any known immunologic condition.

Although experience in treating idiopathic hypocomplementaemic tubulointerstitial nephritis is strictly limited because of the few cases, the described ones were all treated with immunosuppressant drugs^2,6,7 including, at least, prednisone. Renal function (reflected by serum creatinine) improved in 9/13 cases (significant in 6 patients)^1,2,4,5. Prednisone doses were not described in all reported cases but it seems that 1 mg/kg/day was consistent in more recent cases^1,4,5.

It is unlikely that the remission noted in these patients was related to a particular immunosuppressant, because similar regimens were used in patients in whom there was no clinical improvement.

The variability of treatment response indicates the potentially progressive nature of this disease^1,5 and could be related with the presence of irreversible lesions/different degrees of chronicity⁴, although Vaseemuddin et al support that there is no apparent correlation between biopsy findings and clinical progression¹.

Even though, so far the few reports support an early⁵ and prolonged therapy1,4 with a median of 8.5 months (3-20 months)4 that at least includes prednisone.

In the scenario of treatment failure, additional immunosuppressants could be associated^1,4. In four cases, further immunosuppressant agents were added: in two cyclophosphamide, one tacrolimus plus mycophenolate mofetil and in the last case mycophenolic acid. The patients that have done cyclophosphamide, one had a marginal B cell lymphoma, and another developed thrombotic thrombocytopenic purpura requiring plasmapheresis¹. The third patient had cirrhosis and a monoclonal interstitial infiltrate and underwent liver transplantation several weeks after the biopsy, and was thereafter maintained on tacrolimus, mycophenolate mofetil and prednisone¹.

The last patient started mycophenolic acid after hyperglycaemic development allowing prednisone withdrawl and subsequent glycaemic control4. Mycophenolate mofetil has been reported as a useful therapeutic option for steroid-resistant acute interstitial nephritis (AIN) and may be considered as potential first-line therapy in selected patients⁴.

There are no known indicators of disease progression or treatment response, but two prior cases^1,4 have revealed normalization of the complement level as renal function enhanced. Hypocomplementaemia was suggested as a marker of clinical activity⁴.

In our case, given the patient history of cancer and the presence of large interstitial fibrosis and tubular atrophy, we choose to treat her only with corticosteroids, not associating any other immunosuppressor.

We decided to extend therapy, because some similar cases with severe interstitial fibrosis and tubular atrophy have been published in which, after prolonged treatment with corticosteroids (3-9months), there was recovery of the renal function^1,2.

Despite previous publications defined IgG4-related disease as being a systemic condition described in virtually every organ system^1,4,5,9,10, Stone et al. (2012) considered that many medical conditions that have long been viewed as disorders confined to single organs are part of the spectrum of IgG4-related disease. One of these suggested conditions is idiopathic hypocomplementaemic tubulointerstitial nephritis with extensive tubulointerstitial deposits¹³.

Before Stone, Raissian et al. had already suggested that many patients diagnosed with idiopathic hypocomplementaemic tubulointerstitial nephritis likely represent IgG4-related disease, especially those cases with associated immunologic conditions3. However, some diagnostic criteria to the IgG4 related disease¹² have recently been published, which allow a higher homogeneity classifying this entity.

In summary, idiopathic hypocomplementaemic tubulointerstitial nephritis is differential diagnosis of renal failure and hypocomplementaemia, has a progressive nature and requires an early diagnosis and prolonged therapy.

References