Mast cells were first described by Paul Ehrlich in 1879. They were initially identified and sub-typed in tissue sections according to the dye-binding characteristics of their proteoglycan-rich granules^1,2 (figure 1).

In rodents, two distinct types of mast cells are present; mucosal and connective tissue mast cells, which differ in their staining characteristics, granule contents and functions. In humans, however, no such distinct mast cell populations can be defined by traditional histochemistry. The staining of mast cell granules with dyes such as toluidine blue shows variable sensitivity to tissue fixation and most mast cells fail to stain in formalin-fixed tissues. Up to 75% of renal mast cells are formalin-sensitive and cannot be detected by traditional histochemical stains in routine paraffin sections (table 1).

More recently, immunohistochemistry (IH) for mast cell-specific enzymes tryptase and chymase has been used as a more reliable tool to identify and type human mast cells. The different functional roles of the three subsets so defined in humans (tryptase only positive, chymase only positive, tryptase and chymase positive) is currently unknown.

Mast cell precursors originate from the bone marrow and circulate within peripheral blood, although at this stage they lack granules and are thus difficult to identify^{3, 4}; the mature tissue mast cells are widespread, being present in virtually every organ in the body. The normal kidney, however, contains very few mast cells, which are mainly localised to the connective tissue around vascular bundles (figures 2 & 3). In contrast, mast cells can be seen to infiltrate the kidney in large numbers in many renal diseases (figure 4). An association between mast cells and renal disease was first noted by Pavone-Macaluso in 1960⁵, and subsequently by Colvin and co-workers in 1974⁶. After these reports, the link between mast cells and renal pathology was largely forgotten for over 20 years. In recent years, however, there has been renewed interest in the potential role of mast cells in the pathogenesis of renal failure and a number of reports have documented their presence in both primary renal disease and renal allografts.

Mast cells are seen predominantly within the interstitium (figure 5); they also infiltrate tubules (figure 6), as described by Colvin. Epithelium of infiltrated tubules often shows tryptase positivity. Mast cells are not seen in normal arteries but are present in small numbers in the fibrotic intima of intra-renal arteries in chronic allograft vasculopathy (figure 7). They are very rarely seen in glomeruli. IH for tryptase commonly reveals evidence of mast cell degranulation, with tryptase positivity seen within the extracellular matrix around mast cells (figure 8). Mast cell infiltration is associated with interstitial fibrosis of multiple aetiologies⁷. Increased numbers are observed in diabetic nephropathy⁸, chronic glomerulonephritis^{7, 9, 10, 11} and chronic pyelonephritis⁷. In IgA nephropathy, there is a close correlation between the number of renal mast cells and extent of interstitial fibrosis (figure 9).

In renal allografts, mast cells are significantly increased in chronic allograft nephropathy, whether this is immune origin (chronic rejection) or due to chronic ciclosporin toxicity^{7, 12} (table 2).

At what stage of renal disease do mast cells appear and what are the triggers and mechanisms of recruitment? To answer the first question requires the longitudinal study of patients suffering an initial acute inflammatory insult, progressing later to fibrosis. Such evidence comes from renal transplantation. In patients biopsied during acute rejection and later, during chronic rejection, it is clear that mast cell infiltration is a late event, ie mast cells are associated with the development of fibrosis, not the initial immune response (table 2)⁷. Interaction between the growth factor receptor c-kit on the surface of mast cells and its ligand, stem cell factor (SCF), bound to fibroblasts appears to be central to recruitment and leads to mast cell chemotaxis, adhesion and activation. Interestingly, serum levels of SCF increase in patients with chronic renal disease¹³ and renal expression of SCF correlates with mast cell infiltration in many primary and secondary glomerular diseases¹⁴. Many cytokines and other molecules, including PDGF, bFGF, VEGF, TNF and complement components, are chemotactic for mast cells but the most potent of all is TGF1, a cytokine that has been implicated in the development of renal fibrosis in both animal models and several human renal diseases. Increased expression of TGF1 has been demonstrated to be associated with mast cell infiltration in an animal model of progressive renal disease¹⁵.

So what is the function of renal mast cells, and what is their link to renal pathophysiology? Evidence from diseases of organs other than the kidney indicates that the answer to this question may not be straightforward. Mast cells are best known for their role in allergic conditions, in which IgE-mediated degranulation results in the release of vasoactive amines. There is evidence that the production of vasoactive molecules, including histamine, leukotrienes and prostaglandins, by renal mast cells may modulate intra-renal haemodynamics. In addition, mast cells store, or are capable of synthesising, a wide variety of pro-inflammatory cytokines and enzymes and in view of the varied activity of mast cell products and their potential biological functions these cells have been implicated in many pathological situations. There is evidence that mast cells play a role in acute inflammation¹⁶, modulation of cellular immune responses¹⁷, angiogenesis¹⁸, turnover of connective tissue and fibrosis. It is the potential fibrogenic properties of mast cells that are of most interest in terms of their association with renal disease.

Mast cells may potentiate fibrosis in a number of ways (recently reviewed by Gruber¹⁹). They are capable of synthesising several fibrogenic cytokines, including bFGF²⁰ and TGF1²¹. Mast cell proteases may also contribute to matrix remodelling and fibrosis; in vitro studies have demonstrated activation of matrix metalloproteinases by mast cell degranulation²². Mast cell tryptase, the major component of the cytoplasmic granules, can stimulate collagen synthesis by fibroblasts²³ and induce chemotaxis²⁴, possibly through interaction with protease-activated receptors. Tryptase in combination with heparin stimulates proliferation of renal interstitial fibroblasts²⁵. Human mast cell chymase is effective at releasing latent TGF1 from extracellular matrix but does not appear to convert TGF1 to the active 25kDa species²⁶. Histamine and heparin may also modulate fibroblast proliferation and stimulate collagen synthesis in vitro^{27, 28}.

There is both in vitro and in vivo evidence that mast cells may play an important role in the development of pathological fibrosis. Co-culture of mast cells and fibroblasts results in fibroblastic proliferation that is modulated by direct cell-cell contact²⁹. Mast cell granules are phagocytosed by fibroblasts in co-culture³⁰ and ultrastructural studies have confirmed an intimate association between mast cells and fibroblasts in vivo (figure 10).

In addition to chronic renal disease, mast cells have been implicated in pathological fibrosis in a number of conditions including hypertrophic scars³¹, chronic atopic dermatitis³², hepatic cirrhosis³³, fibrosing alveolitis^{34, 35} and cardiac fibrosis³⁶. Studies using mast cell deficient mice (W/Wv) have demonstrated that these animals show less collagen deposition than their normal littermates in response to fibrogenic triggers, such as bleomycin-induced lung fibrosis³⁷. Furthermore, cross breading of W/Wv mice with tight skin (TSK) mice, a strain that is genetically predisposed to developing dermal sclerosis, leads to a reduction in the level of fibrosis³⁸.

As yet, however, there is no data available using this strain of mice in a model of renal fibrosis. Renal mast cells should not be assumed to have pro-fibrotic activity without more direct in vivo evidence. In fact a recent study employing the PAN nephrosis model of chronic renal injury in a mast cell deficient rat strain (Ws/Ws) suggests that mast cells may have a protective rather than deleterious role in renal fibrosis³⁹. Further studies are urgently required to clarify the function of renal mast cells. Mast cell stabilising agents have been demonstrated to be of benefit in inhibiting cutaneous fibrosis in an animal model⁴⁰. It is possible that these compounds may provide a new approach to anti-fibrotic therapy in the management of chronic renal disease.

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