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Lupus Nephritis Classes I and II

Classes I and II lupus nephritis refer to pure mesangial glomerulopathy. These patients present clinically with mild hematuria, or proteinuria, or

Candidatus Phytoplasma Australiense
Figure 8.1. Lupus nephritis ISN/RPS class II (mesangial) with granular mesangial immunoglobulin G (IgG) (immunofluorescence).

both. In general they have a good prognosis with respect to their renal function, and the histologic alterations remain stable in the majority of cases. However, functional deterioration and progression of glomerular lesions to more active or generalized proliferative forms occurs in about 20% of cases. In the past decades the availability of better supportive therapy and more selective use of immunosuppressive agents has led to improved survival of patients with mild forms of lupus glomerulonephritis, while new forms of immunosuppressive therapy are being developed (5,6).

Class I or minimal mesangial lupus glomerulonephritis refers to biopsies showing normal glomeruli by light microscopy, but mesangial immune deposits by immunofluorescence or electron microscopy. Class II contains mesangial proliferative lesions characterized by purely mesangial hyper-cellularity of any degree or mesangial matrix expansion by light microscopy with immune deposits, predominantly mesangial with none or few isolated subepithelial or subendothelial deposits by immunfluorescence or electron microscopy but not visible by light microscopy (Fig. 8.1).

Lupus Nephritis Class III

Class III lupus nephritis entails focal (involving less than half of the glomeruli available for inspection) and segmental (involving mostly a small part or a segment of the cut surface of the affected glomeruli) or global (involving the majority of the cut surface of the involved glomeruli) proliferative, necrotizing, or sclerosing lesions. The involvement of the glomeruli may occur in different combinations. A subdivision is made according to the predominance of active versus sclerotic lesions as indicated in Table 8.1.

In the pathology report, the proportion of glomeruli with active and with sclerotic lesions and the proportion of glomeruli with fibrinoid necrosis or cellular crescents should be indicated. The lesions may be superimposed on a diffuse mesangial expansion, as seen in class II lupus nephritis. Narrowing and obliteration of the capillary lumina is often present with segmental intracapillary and extracapillary proliferation and adhesions of visceral and parietal epithelial cells (Figs. 8.2 and 8.3). In addition, nuclear debris is seen as well as influx of inflammatory cells, which has been ascribed to altered expression of adhesion molecules in the diseased vessel walls (7,8). The inflammatory process may also lead to disruption of the glomerular basement membrane and fibrinoid necrosis. Amorphous eosin-ophilic material staining bright red in trichrome staining and present most often in the context of an extracapillary proliferative lesion is regarded as fibrinoid necrosis. However, little is known about the pathogenesis, specificity, and molecular content of fibrinoid necrosis, although splice variants of fibronectin seem to be present in the lesion (9-11). In the affected glomerular areas, endothelial damage may allow direct contact between serum proteins and collagen present in the subendothelial basement membrane, leading to activation of the coagulation cascade. Thus, necrotizing lesions may contain fibrin or microthrombi. Segmental sclerotic scars with capsule adhesions can develop from focal crescents with necrotic lesions. Focal tubular and interstitial signs of nephron deterioration can be seen. The validity of the cutoff point between classes III and IV of 50% involved glomeruli has been disputed recently, but is currently retained in the 2003 revision of the lupus nephritis classification system (4,12).

Figure 8.2. Lupus nephritis ISN/RPS class III, focal proliferative: early necrotizing lesion with rupture of glomerular basement membrane (Jones silver stain).
Figure 8.3. Lupus nephritis ISN/RPS class III, focal proliferative: segmental proliferative lesion ("crescent") (Jones silver stain).

Immunofluorescence investigations show the presence of immunoglobulin G (IgG), IgM, and IgA immunoglobulins, complement factors C3 and C1q ("full-house" immunofluorescence) in granular and globular depositions along the glomerular capillary walls and in the mesangium (Fig. 8.4). Although the light microscopic changes are focal, the immunofluorescence

Figure 8.4. Lupus nephritis ISN/RPS class III, focal proliferative: diffuse, chunky granular pattern for IgG (immunofluorescence).

Lupus Nephritis Immunofluorescence
Figure 8.5. Subendothelial and subepithelial electron-dense deposits along the glomerular basement membrane (GBM) with irregular thickenings of GBM and pseudovillous transformation of visceral epithelial cells in lupus nephritis ISN/ RPS class III lupus nephritis (electron microscopy).

is in most cases positive in all glomeruli. Electron microscopy typically demonstrates deposits in the mesangium and in about half of the cases also subendothelially or subepithelially along the glomerular basement membranes (Fig. 8.5) (13).

Patients with lupus nephritis class III present almost invariably with proteinuria, and in the majority of cases with nephrotic syndrome. The lesions can progress to diffuse proliferative (class IV) or membranous lupus glomerulonephritis. Progression is possibly predicted by the presence of subendothelial and subepithelial deposits.

Lupus Nephritis Class IV

Class IV, the most common and severe form of lupus nephritis, refers to diffuse segmental (IV-S) or global (IV-G) proliferative forms of glomerulonephritis, characterized by diffuse hypercellularity in more than 50% of the glomeruli. The lesions may be either active or inactive, have a segmental or global distribution, and may manifest endo- or extracapillary glomerulonephritis with diffuse subendothelial immune deposits, with or without mesangial alterations. Some investigators revealed the poor outcome of diffuse segmental necrotizing glomerulonephritis involving over 50% of glomeruli (which these investigators consider a severe form of class III), as compared to other forms of class IV lupus nephritis (14). Class IV, therefore, is divided into diffuse segmental (IV-S) when >50% of the involved glomeruli have segmental lesions, and diffuse global (IV-G) when >50% of the involved glomeruli have global lesions (Fig. 8.6) (4). Furthermore, a subdivision is made according to the presence of active versus chronic lesions as was indicated for class III lesions (Table 8.1).

Figure 8.6. Circumferential ("global") extracapillary proliferation ("crescent") in ISN/RPS class IV diffuse proliferative lupus nephritis (Jones silver stain).

As in class III, in the pathology report the proportion of glomeruli with active and with sclerotic lesions and the proportion of glomeruli with fibrinoid necrosis or cellular crescents should be indicated. Between the proliferating cells focal fibrinoid necrosis is often seen with capillary mural thrombi or perforation of the glomerular capillary walls. In addition, hematoxylin bodies may be seen, representing nuclei altered by antinuclear antibodies. "Wire-loop" lesions, that is, local periodic acid-Schiff (PAS)-positive thickenings of the glomerular capillary walls, are characteristic of this form of lupus nephritis (Fig. 8.7). This thickening of the capillary walls is related to the presence of large, mostly subendothelial electron dense deposits. Glomerular lesions run the gamut from diffuse hypercellularity

Periodic Acid Schiff Lupus Kidney
Figure 8.7. Glomerulus in ISN/RPS class IV diffuse proliferative lupus nephritis: sclerosing lesion and "wire loops" [periodic acid-Schiff (PAS) stain].

to severe necrotizing "crescentic" glomerulonephritis or, in chronic cases, diffuse global glomerulosclerosis with loss of renal function. Formation of "spikes" along the glomerular basement membrane can be seen, as well as lobular accentuation of the glomerular architecture and "interpositioning" of mesangial cells along the glomerular capillary walls, giving rise to the picture of membranoproliferative glomerulonephritis. In these cases proliferating mesangial cells extend along the inner side of the glomerular capillary wall, depositing new extracellular matrix on the lumenal side, leading to double contours of the basement membrane. Whether lobular or membranoproliferative lupus glomerulonephritis should be regarded as a separate entity is unclear, but intermediate forms of lobular and diffuse proliferative glomerular lesions may occur. Tubular and interstitial signs of nephron deterioration are more extensive in class IV than in class III lupus nephritis. The predictive value of these lesions with respect to renal function, however, is disputed (15,16). The tubular epithelium shows cyto-plasmic hyaline droplets, hydropic degeneration, cytoplasmic vacuoliza-tion, hyalin protein cylinders, and, in more advanced, glomerulosclerotic stages of the disease tubular atrophy and interstitial fibrosis. Arteries and arterioles usually show no pathologic changes.

Immunofluorescence in lupus nephritis class IV shows irregular deposits of immunoglobulins and complement along the glomerular capillary walls and in the mesangium (Fig. 8.8). Ultrastructurally, electron dense deposits are seen in the mesangium and subendothelially along the capillary walls, in larger quantities than in the other classes. Proliferating mesangial cells extending along the inner side of peripheral capillary walls and incorporation of subendothelial deposits can be seen by electron microscopy as well. Deposits are usually also present intramembranously and subepithelially, with obliteration of epithelial foot processes. In addition, epithelial cells

Lupus Electron Microscopy
Figure 8.8. Lupus nephritis ISN/RPS class IV diffuse proliferative: large confluent predominantly subendothelial IgG deposits along GBM (immunofluorescence).

may be enlarged and show pseudovillous transformation with increase of cytoplasmic organelles. Microtubular myxovirus-likeparticles or tubulore-ticular inclusions (TRIs) can be found in the cytoplasm of endothelial cells or lymphocytes, localized in dilated segments of rough and smooth endoplasmic reticulum. These TRIs are not specific for SLE but are often seen in patients with AIDS and other viral infections, probably reflecting local or systemic a-interferon production. Large and often confluent subendothelial deposits represent the ultrastructural analogue of the "wire-loop" lesions seen light microscopically. Subepithelial deposits can be large, as in acute proliferative glomerulonephritis. Penetration of the subepithelial deposits in the underlying basement membrane and partial embracement of the deposits by the spike-like basement membrane thickenings are often present. As in the other classes of lupus nephritis, the electron dense deposits can show a typical fingerprint-like crystalline pattern, considered pathognomonic for lupus nephritis and possibly representing the presence of cryoglobulins.

Patients with class IV lupus nephritis may show a rapidly progressive renal failure with high proteinuria and, without treatment, a poor prognosis with respect to renal function.

Lupus Nephritis Class V

Class V lupus nephritis is characterized by diffuse membranous glomeru-lonephritis. Among patients with lupus nephritis the incidence of membranous glomerulonephritis varies between 8% and 27%. The prognosis of patients with membranous lupus nephritis is relatively favorable, with a reported 10-year kidney survival of 91% (17). Still, one third of patients with membranous lupus nephritis progress to proliferative lupus nephritis (18). Characteristically patients present with high proteinuria at an early stage. By light microscopy, some mesangial expansion is seen with diffuse thickening of the glomerular capillary walls in hematoxylin and eosin (H&E) and PAS stains. With silver-methenamine staining, argyrophilic spike-like formations often can be seen in subepithelial locations along the glomerular basement membrane. The spikes correspond to thickenings of the basement membrane between and around the subepithelially localized immune deposits, as can be seen by electron microscopy. Altered basement membrane homeostasis probably underlies the spike formation (13). By immunofluorescence, granular deposits of immunoglobulins and complement are usually present in the mesangium and peripherally along the glomerular capillary walls, corresponding to the presence of subepithelial electron dense deposits. In addition to IgG and C3, the presence of IgA and C1q in the deposits is regarded as a marker for lupus membranous glomerulonephritis (19), although the presence of Ig A and C1q has also been noted in idiopathic membranous glomerulopathy. The deposits in membranous lupus nephritis are usually regularly distributed and uniform in size. This in contrast to proliferative lupus nephritis, in which the deposits are irregularly distributed and of differing size. Epithelial cells show extensive obliteration of foot processes. Although similar stages of development can be seen in class V lupus nephritis as in idiopathic membranous glomerulopathy, in lupus nephritis mesangial deposits are more often present.

Class V lupus nephritis may occur in combination with classes III or IV in which case both are diagnosed. The presence of subendothelial deposits or necrosis is probably of more prognostic value than a coinciding membranous pattern: patients with pure membranous lupus nephritis experience a relatively benign course, whereas in those with mixed membranous and diffuse proliferative lesions, the survival rates are similar to those of patients with diffuse lupus nephritis alone. Likewise, in a study of membranous lupus nephritis, patients with a major endocapillary proliferative component had higher serum creatinine levels at entry and were more likely to experience a decline in renal function than those without proliferation (20).

Lupus Nephritis Class VI

This class refers to a late stage, resembling morphologically any late or end stage in chronic glomerulonephritis with global sclerosis of >90% of glom-eruli without residual activity. Alternatively or in addition, secondary focal and segmental glomerulosclerosis with its different subtypes may develop (21). Specific features for lupus nephritis are usually lacking. However, in patients with lupus nephritis such chronic end-stage glomerulosclerotic lesions are seldom seen. Patients with lupus nephritis who have been treated for longer periods may show chronic glomerular lesions at autopsy. These may be morphologically similar to other late stages of glomerulonephritis and of focal global sclerotic lesions that occur invariably at an older age (22).

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