Association of mesangial IgM with IgM deposits in the macula densa: an indication of non-specific macromolecule transport rather than immune reactant?

E. Mary Thompson and David J. Evans

Department of Histopathology, St Mary's Hospital, Imperial College School of Medicine, London, UK



   Abstract
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. We observed IgM deposits in the macula densa of the distal convoluted tubule in some renal biopsies with mesangial IgM deposits and did a systematic study to investigate the frequency of this phenomenon. We compared the findings with those in IgA disease.

Methods. A total of 30 renal biopsies with either isolated predominantly mesangial IgM, or mesangial IgA (±IgM) deposition, were retrieved from the files and reviewed independently by both authors.

Results. Eight showed strong macula densa IgM deposits and another three showed weak deposits in the macula densa on immunoperoxidase staining. A total of 14 biopsies also showed mesangial IgA deposition but IgA was not seen in the macula densa.

Conclusions. These results confirm the association of IgM deposits in the macula densa with mesangial IgM, and suggest that mesangial IgM deposits may be a reflection of non-specific macromolecule transport rather than an immune reactant.

Keywords: IgM deposition; macromolecules; macula densa; mesangial transport



   Introduction
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Diffuse finely granular mesangial IgM deposition is a frequent finding in renal biopsies (especially when using a peroxidase technique on formalin-fixed paraffin-embedded sections). There is controversy as to its significance, and some authors have sought to categorize it as a specific disease entity when it is associated with a minimal change light microscopic appearance and heavy proteinuria [1,2]. In almost all such cases, electron microscopy fails to reveal corresponding electron dense deposits.

In patients with mesangial IgM deposits, we have sometimes observed deposits of IgM in the macula densa region of the distal tubule on immunohistochemistry. In this study, we have investigated the frequency of this association and have tried to assess its significance.



   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Thirty cases were drawn from the histopathology files at St Mary's Hospital, Paddington, London. Biopsies were chosen for review if they had been reported as showing predominantly mesangial staining with IgM (18 cases) or IgA with IgM (12 cases). Those with obvious peripheral IgG deposition were excluded. The immunostaining had been done on formalin fixed paraffin embedded sections using a standard peroxidase-antiperoxidase technique following digestion with protease 25 for 20–30 min. The immunoperoxidase slides were reviewed independently by both authors.



   Results
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 Subjects and methods
 Results
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The results are summarized in Table 1Go. There was strong staining for IgM in the macula densa in eight cases and weak staining for IgM in the same position in a further three cases. Staining with IgA in the macula densa was not seen in any of the biopsies. Of the 11 macula densa positive cases, all showed mesangial IgM and five (two strong and three weak) also showed mesangial IgA. Clinical details and histological diagnoses are given in Table 2Go. Four of the 11 were recorded as having proteinuria, two were not and five had no record. This compares with 13/19 cases with proteinuria without macula densa IgM deposition (see Tables 1Go and 2Go). There was no relationship between the heaviness of the mesangial deposits and macula densa deposition. Two of the cases of IgA disease also had small amounts of mesangial IgG but these were both negative for macula densa staining with any immunoglobulin. Eleven cases also showed IgM in blood vessels, one of which also showed arteriolar IgA, but of these only one was strongly positive and one weakly positive for macula densa IgM.


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Table 1. Immunohistochemical findings

 

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Table 2. Clinical details of the cases studied

 



   Discussion
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 Abstract
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 Subjects and methods
 Results
 Discussion
 References
 
Although the existence of a mesangial circulation has long been suspected, the fate of fluid and particulate material entering it is still uncertain. It was demonstrated in the experimental animal more than 20 years ago that macromolecules such as colloidal iron could enter the mesangium from the systemic circulation and that they subsequently entered the macula densa region of the distal tubule [3]. Another study [4] with aggregated human albumin, confirmed macromolecule circulation through the mesangium to the juxtaglomerular apparatus but suggested that as there was entry into the renal interstitium, drainage may be via lymphatics. Intravenous anionic ferritin injected into rats, confirmed the lumen of the macula densa as one of the exits for macromolecules from the mesangium, and claimed to demonstrate an ultrastructural polygonal meshwork of thin fibrils and pores in the mesangium as the morphological basis for this circulation [5]. However, these may be artefactual pores observed only after the matrix was dissolved and a more recent detailed ultrastructural study of the rat glomerulus failed to confirm this latter finding [6].

In animals, several factors are known to influence mesangial accumulation of macromolecules [7,8], including size, dysfunction of the transport mechanism [9], blood concentration [10], proteinuria [11], and administration of morphine [8].

In a study of three types of experimental proteinuria (aminoglycoside of puromycin proteinuria, Heymann nephritis and adriamycin nephropathy), mesangial uptake of aggregated immunoglobulin was increased only in the first model [12]. Further, this increase could be abolished by a continuous infusion of saralasin, a competitive inhibitor of angiotensin II. Infusion of angiotensin II increased mesangial ferritin in a separate study [13]. The conclusion was that in animals, proteinuria per se does not increase mesangial uptake, but local haemodynamic factors are also important.

Because of its size, IgM might perhaps be expected to behave similarly to other macromolecules such as ferritin; however, though it is normally present in the mesangium of the mouse it is not normally demonstrable there in the rat or man.

Mesangial IgM deposition is a common finding in renal biopsies, particularly in association with proteinuria and many renal pathologists believe it to be a non-specific finding. A 6-year follow-up study of 64 patients with nephrotic syndrome but no mesangial proliferation, showed that although 14 patients had mesangial IgM deposition, there was no difference in outcome between the two groups [2].

In the cases we report, where mesangial IgM was found immunohistologically as the only immunoglobulin, complement was absent and electron dense deposits were not seen ultrastructurally. This is consistent with the IgM being present non-specifically as a macromolecule in colloidal suspension, rather than as a specific immune reactant: we believe that the presence of IgM in the macula densa reinforces this interpretation. We do not, of course, deny that IgM may sometimes be present in the glomerulus as an immune reactant [14].

In this small study, the data for urinary protein were incomplete, but it is immediately apparent that there is no simple correlation between extent of IgM deposition and proteinuria per se. This is probably to be expected, given the possibility of confounding haemodynamic variables.

In human mesangial IgA disease we found no evidence to support movement of IgA to the macula densa of the distal tubule: this is not altogether surprising as ultrastructurally the IgA is morphologically associated with large electron dense deposits and there may be little if any in colloidal suspension. An alternative explanation might be the presence of IgA receptors on mesangial cells, trapping IgA in the mesangium.

In conclusion, we would like to make the rather obvious point that assumptions drawn about the pathological activity of a molecule such as IgM simply on the basis of its presence in the glomerulus, may not be valid. On the contrary, we believe that in this site, IgM in many cases is acting passively and non-specifically as a macromolecule, in contrast to IgA. Clearly, this study is an observational one and cannot prove such a hypothesis. Animal studies might be able to show support for such a view, but extrapolating to the human situation would not necessarily be valid.



   Notes
 
Correspondence and offprint requests to: Dr E. M. Thompson, Department of Histopathology, St Mary's Hospital, Praed Street, London W2 1NY, UK. Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 21. 7.00
Revision received 2. 5.01.



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