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Nephrol Dial Transplant (1999) 14: 2210-2215
© 1999 European Renal Association-European Dialysis and Transplant Association

Case Reports

Acute interstitial nephritis with immune complex deposition and MHC class II antigen presentation along the tubular basement membrane

Masanori Tokumoto1, Kyoichi Fukuda1, Michiya Shinozaki1, Minoru Kashiwagi1, Ritsuko Katafuchi2, Tetsuhiko Yoshida1, Taihei Yanagida1, Hidetoshi Kanai1, Hideki Hirakata1, Kiyoshi Tamaki3, Seiya Okuda3 and Masatoshi Fujishima1

1 Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, 2 Kidney Center, Division of Internal Medicine, Fukuoka Red Cross Hospital Fukuoka City and 3 Third Department of Internal Medicine, Faculty of Medicine, Kurume University, Kurume City, Japan

Correspondence and offprint requests to: Masanori Tokumoto MD, The Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Maidashi 3-1-1, Higashi-Ku, Fukuoka City, 812-8582 Japan.

Keywords: acute renal failure; interstitial nephritis; MHC class II antigen; tubular basement membrane immune deposition



   Introduction
Top
 Introduction
Case
 Discussion
 References
 
Renal tubulointerstitium has been recognized to be a common site of immune-complexes deposition leading to tissue destruction [1–3]. However, cases of interstitial nephritis in which interstitial immune complex deposition play a major role are not commonly reported [4–14]. Most reported cases have been finally diagnosed as either collagen disease or adenovirus-type 11 infection.

Here we present a case of acute interstitial nephritis with tubular immune complex depositions and MHC class II antigen expression defined on the proximal tubular cells.



   Case
Top
 Introduction
 Case
Discussion
 References
 
A 66-year-old Japanese man was admitted to our hospital because of renal functional deterioration on September 19, 1995. He was well until June 1995, when he had had flu-like symptoms with low-grade fever and general malaise. He visited his primary physician in August, and trace proteinuria and increased serum creatinine were noted. Laboratory tests are listed in Table 1Go. Blood pressure was 144/86 mmHg. He had no skin eruption or peripheral oedema. Urinary sediment was not specific. Mild anaemia (erythrocytes of 419x104/µl and haemoglobin of 12.4 g/dl), and elevated serum total protein, together with a slight decrease in serum albumin was noted. Serum creatinine was 3.6 mg/dl and blood urea nitrogen was 53 mg/dl. Serum chloride was slightly increased (112 mmol/l). The endogenous creatinine clearance was 21.6 ml/min/ 1.73 m2. Serological tests showed hypocomplementaemia (C3 of 24 mg/dl, C4 of 3 mg/dl), a low titre of antinuclear antibody (x40, speckled type), but other autoantibodies such as ds-DNA Ab, SS-A Ab, and SS-B Ab were negative. His serum creatinine rose progressively to 4.7 mg/dl and he was started on corticosteroids (prednisolone 40 mg/day).


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  		Table 1. Laboratory data at primary physician visit
 
On 19 September the patient was transferred to our hospital for renal histological examination. Upon admission, serum creatinine had decreased to 1.7 mg/dl and hypocomplementaemia improved (C3 of 42 mg/dl and C4 of 18 mg/dl). Renal biopsy was performed and 32 glomeruli were obtained. It revealed a marked cellular infiltration with some scattered fibrosis in the interstitium, but the glomeruli did not show any change (Figure 1A,BGo). Immunofluorescence examination revealed coarse granular depositions of IgG, C3, and C1q along the tubular and Bowman's capsular basement membrane (TBM) but not in the glomerular area (Figure 2A–CGo). By electronmicroscopy, electron-dense deposits were found within the TBM, but a feature indicating viral particles was not detected (Figure 3Go). In order to clarify the immune pathogenesis, MHC class II antigen expression was examined and anti-MHC class II monoclonal antibody (Dakopatts A/S, Denmark) was applied. It yielded positive staining of intact proximal tubular cells, some clusters of infiltrating mononuclear cells and interstitial fibroblasts (Figure 4 A,BGo). A normal human kidney specimen, obtained from a kidney removed for clear-cell carcinoma, was stained with serially diluted patient serum, followed by FITC-conjugated rabbit anti-human IgG and IgM antibody. It was found to bind to the nuclei of tubular cells, but not TBM and the nuclei of other cells of the kidney (Figure 5 A,BGo). In contrast, the healthy control serum did not show any positive staining of either the nuclei of renal cells or TBM. Using normal human liver specimen the same tests revealed no positive staining in the nuclei of hepatic cells. Prednisolone was tapered and discontinued on 5 November 1995. Urinary protein excretion decreased to below 0.4 g/day and his serum creatinine was 1.3 mg/dl and he was discharged. One month later, however, hypocomplementaemia developed gradually without any symptoms.



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  		Fig. 1. Light micrograph of the first renal biopsy specimen. Note remarkable diffuse infiltration of mononuclear cells into the interstitium (A, PASx100, B, PAS,x400).

 


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  		Fig. 2. Immunofluorescence micrographs of renal biopsy specimen. Granular deposits of IgG (A), C3 (B), and C1q (C), which are present along both the tubular basement membranes and Bowman's capsules but not in the glomeruli (x200).

 


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  		Fig. 3. Electron micrograph (x6000) of a proximal tubule. Electron-dense deposits are found within the tubular basement membrane.

 


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  		Fig. 4. MHC class II antigen is expressed on the proximal tubular epithelial cells, infiltrating mononuclear cells and interstitial fibroblasts of the patient's kidney: Immunohistochemical examination (A, x100; B, x400).

 


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  		Fig. 5. A normal kidney was stained by patient serum and FITC-conjugated rabbit anti-human IgG and IgM antibody (x200). Binding of patient IgG(A) and IgM(B) are observed in the nuclei of tubular epithelial cells. They are absent in the other part of the kidney, including the glomeruli and the tubular basement membrane.

 
The patient was re-admitted on 1 December, 1995. Physical examination was unremarkable, and laboratory data were similar to those at the first admission except for a high level of IgG. Serum creatinine remained at 1.4 mg/dl, but anaemia was more severe (haemoglobin of 11.1 g/dl). The endogenous creatinine clearance was 52.5 ml/min/1.73 m2. Serum IgG, IgA, IgM and complement components (C3 and C4) were 3271, 334, 213, 33, and 2 mg/dl respectively. Antinuclear antibody was positive (x40). Circulating immune complex tests for C1q and C3d were 28.2, 14.8 µg/ml respectively. Anti-C1q antibody was detected by immunoprecipitation. A second percutaneous renal biopsy was performed and 10 glomeruli were obtained. Light-microscopy examination showed mild mesangial widening of all glomeruli, and severely advanced interstitial damage; the infiltrating cells were mainly plasma cells. Tubular atrophy and epithelial destruction with collagenous fibrosis were marked. Granular depositions of IgG, C3 and C1q were also found along the TBM. Electromicroscopy findings were similar as those seen in the first biopsy. A gallium scintigram using [67Ga] citrate revealed isotope accumulation in both kidneys. Since serum creatinine had risen to 2.5 mg/dl, corticosteroid treatment was reintroduced, i.e. 60 mg prednisolone per day. After starting the treatment, serum C4 was restored gradually to 19 mg/dl, and serum creatinine decreased to 1.4 mg/dl. Renal retention of [67Ga]citrate was no longer demonstrable. The patient was discharged on 18 April 1996. On 15 March 1998, he had no subjective symptoms. Serum C4 and creatinine were stable at 18 mg/dl and 1.3 mg/dl respectively, with administration of prednisolone 5 mg every other day.



   Discussion
Top
 Introduction
 Case
 Discussion
References
 
The present case was characterized by hypocomplementaemia before full manifestation of acute renal failure. Renal biopsy findings were compatible with acute tubulointerstitial nephritis. Positive granular immunostaining with IgG, C3 and C1q along TBM alone was remarkable. Electron-dense deposits were also demonstrated along the TBM, but glomeruli remained almost intact throughout the course. This constellation suggested that the primary site of the inflammation was the tubular cell. Immunological mechanisms underlying some forms of experimental interstitial nephritis such as chronic serum sickness of rabbits [15–17] and Heyman nephritis of rats [18,19] have also been reported in humans [1–14,20]. Interstitial nephritis is most frequently associated with systemic lupus erythematosus (SLE) [1–3], where positive immune deposits are often detected only along the TBM [4–9,11,12]. Although the present case had hypocomplementaemia, renal failure, and a low titre of antinuclear antibody constantly, the clinical profiles did not meet the criteria of American Rheumatic Association for SLE. In patients with SLE, the extent of the depositions has been reported to correlate closely with both the amount of the membrane attack complex (MAC) C5b-9 formation, the end-product of complement cascade process, and the severity of tubulointerstitial damage [21,22]. Thus, activation of complement system may be a major pathogenic factor for this form of tubulointerstitial injuries. In the present case, the tubular deposits were positive for C1q and C3, and therefore MAC might have participated in tissue injury. Autoantibodies noted in our case included antinuclear antibody and anti-C1q antibody, consistent with the hypothesis that autoimmune mechanisms were the primary abnormality.

In other clinical entities, such as Sjögren's syndrome [14], urticarial vasculitis syndrome [10], adenovirus-type 11 infection [13], renal allograft rejection [20], and mixed cryoglobulinaemia [2], immune depositions along the TBM have also been reported, but these possibilities were excluded by serological and histological examinations in our patient. Table 2Go lists the previously reported cases of tubulointerstitial immune complex nephritis without significant glomerular involvement [4–14]. Only in 1 of 13 cases, was the final clinical diagnosis idiopathic interstitial nephritis. Our patient did not show any glomerular injury in the first biopsy specimen, but mild mesangial widening and positive IgG staining were observed in the second biopsy. Possibly these changes were non-specific, however.


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  		Table 2. Characteristics of tubulointerstitial immune complex nephritis without significant glomerular involvement in the reported 13 cases. Abbreviations: M,F, male,female; IITD, idiopathic interstitial and tubular disease; SLE, systemic lupus erythematosus; SS, Sjögren's syndrome; HCCV, hypocomplementaemic cutaneous vasculitis syndrome; ND, not determined
 
Experimentally, Brentjens et al. [16] demonstrated that after administration of high dose of bovine serum albumin rabbits developed acute interstitial nephritis secondary to in situ formation of immune complexes. Serum sickness is also known to cause acute tubulointerstitial nephritis [15–17]. The histological findings in these experimental models were similar to those in our case except for small-vessel vasculitis in the experimental studies. Heyman nephritis is another candidate resembling our case [18,19]. In this condition the causative nephritogenic antigen is megalin/gp330 which is derived from the brush borders of the proximal tubular cells [23].

Our case is a very rare observation of acute interstitial nephritis, in which immunological damage to the tubules was the primary feature. It was of interest that the proximal tubular cells presented MHC class II antigen, indicative of cellular transformation resulting in the presentation of unknown antigen(s). Recent studies have provided evidence for a role of renal tubular epithelial cells in antigen processing and presentation in the pathogenesis of tubulointerstitial nephritis [24–27]. Abbate et al. demonstrated that the most common mechanism for tubular upregulation of class II molecules is proteinuria via activated complement [28]. When serially diluted serum of the patient was applied to a nephrectomy specimen and followed by FITC-conjugated rabbit anti-human IgG and IgM, the nuclei of proximal tubular cells were positively stained, but the nuclei of other cells of the kidney and TBM were not. And also, when same tests were performed on normal human liver specimens the nuclei of hepatic cells were not stained. These findings strongly suggest that the patient had autoantibodies to the nucleus of the proximal tubular cell, which in turn could transform the cells to present MHC class II antigen. He had antinuclear antibody without anti-DNA antibody, suggesting that he had a tissue-specific autoantibody similar to the anti-glomerular basement membrane antibody in Goodpasture's disease. Thus, our patient resembles SLE, to some extent.

Corticosteroid treatment of 60 mg/day, i.e. a relatively small dose, was effective in the present case. The patient had a relapse after discontinuation, suggesting that corticosteroids should be continued with a lower maintenance dose, even after clinical improvement.



   Acknowledgments
 
We are grateful to Jiro Uozumi MD, Department of Urology, Kyushu University, and Mitsuo Shimada MD, Department of Surgery II, Kyushu University, for their kind provision of normal human kidney and liver specimens. Normal kidney specimen was the normal part of kidney removed because of clear cell carcinoma, and normal liver specimen was the normal part of liver removed for hepatocellular carcinoma.



   References
Top
 Introduction
 Case
 Discussion
 References
 

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Received for publication: 11. 1.99
Accepted in revised form: 30. 4.99


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