—  SPECIALTY CONFERENCE  —

Renal Pathology

Case 4 - Crescentic Glomerulonephritis Due to Anti-GBM Antibodies Occurring on a Background of Pre-existing Membranous Glomerulonephritis

Terence Cook
Hammersmith Hospital
London, U.K.


Click on each slide thumbnail image for an enlarged view
Clinical History
The patient is a 74 year old Caucasian male. He first presented in January 2004 having noticed increasing ankle oedema over the previous 2 months. On examination weight was 78Kg, BP 142/90 mmHg. Chest, abdomen, nervous system exam showed no abnormalities. There was marked pedal and pre-tibial oedema. Urinalysis showed 4+ prot, +rbc's no wbc's no casts; 24 hour urine protein was 5.5g, serum albumin 22g/l, serum creatinine 80mmol/l (0.9 mg/dl), ANA negative, anti-DNA negative, HBSAg , HCV, ASLO, ANCA all negative, SPEP-UPEP no monoclonal spike, complement normal.

The patient was treated conservatively with diuretics.

Eight months later he re-presented complaining of nausea and vomiting. He had been anuric for 48 hours. BP was 180/110 mmHg, serum albumin 18g/l, and serum creatinine 1400 mmol/l (15.8mg/dl).

A renal biopsy was performed.


Case 4 - Figure 1 -
Low power view of the renal cortex. The glomeruli are difficult to make out but do not appear normal. There is mild focal tubular dilatation (H&E)
Case 4 - Figure 2 -
Low power view of renal cortex. In this silver stain it is clear that all the glomeruli are involved by cellular crescents (Methenamine silver)
Case 4 - Figure 3 -
Medium power view showing two glomeruli with cellular crescents. At this power the tubules are seen to be dilated with flattened epithelium (H&E)



Case 4 - Figure 4 -
Medium power view showing four glomeruli with cellular crescents. All the crescents appear to be of a similar age (Methenamine silver)
Case 4 - Figure 5 -
Two glomeruli with cellular crescents. Where the glomerular capillary walls can be made out they appear slightly thickened. (H&E)
Case 4 - Figure 6 -
Three glomeruli with cellular crescents. In one there is extensive destruction of Bowman's capsule (Methenamine silver)



Case 4 - Figure 7 -
The glomerulus shows a circumferential cellular crescent (Methenamine silver)
Case 4 - Figure 8 -
The glomerulus shows extensive fibrinoid necrosis, a circumferential cellular crescent and rupture of Bowman's capsule (Methenamine sliver)
Case 4 - Figure 9 -
At high power the glomerular capillary wall is seen to be thickened with an irregular outer aspect with segmental spike formation (Methenamine silver)



Case 4 - Figure 10 -
At high power the glomerular capillary wall is seen to be thickened with an irregular outer aspect with segmental spike formation (Methenamine silver)
Case 4 - Figure 11 -
IgG shows a granular pattern of localisation along the capillary wall (IgG immunofluorescence)
Case 4 - Figure 12 -
C3 shows a similar pattern to IgG with predominantly granular capillary wall staining (C3 immunofluorescence)


Pathology
The biopsy contained 12 glomeruli all of which showed circumferential cellular crescents. In some there was fibrinoid necrosis. All the crescents appeared of a similar age. In some glomeruli there was rupture of Bowman's capsule. The silver stain revealed that the glomerular capillary walls were thickened and irregular on the subepithelial aspect with spikes in some areas. Tubules showed dilatation and epithelial flattening. Immunofluorescence showed capillary wall localisation of IgG and C3 with a granular pattern. Electron microscopy revealed multiple large subepithelial electron dense deposits with spikes of basement membrane material between.

When the patient had originally presented with nephrotic syndrome 8 months previously a renal biopsy had been performed. This showed 14 glomeruli all with slight capillary wall thickening. There was granular capillary wall IgG and C3 on immunofluorescence and multiple subepithelial electron dense deposits by EM. A diagnosis of membranous glomerulonephritis was made. At that time a routine test for anti-GBM antibodies was negative but by the time of the second biopsy the circulating anti-GBM antibody ELISA was 64% (normal < 15%).

Diagnosis: Crescentic glomerulonephritis due to anti-GBM antibodies occurring on a background of pre-existing membranous glomerulonephritis

Discussion
The case raises a number of points for discussion: 1) the differential diagnosis of crescents in membranous glomerulonephritis; 2) the association of anti-GBM disease with other renal lesions; and 3) the possible role of other lesions in predisposing to anti-GBM disease
  1. Crescents in membranous glomerulonephritis . The development of crescents in membranous glomerulonephritis is rare. Because a membranous pattern of injury and crescents can be seen in SLE this should always be excluded. Many of the remaining cases will be associated with anti-GBM antibodies. The combination of anti-GBM disease and membranous glomerulonephritis was first reported by Klassen et al. in 1974 [1] and since then there have been at least another 16 cases reported. In about half of these membranous glomerulonephritis preceded the development of anti-GBM disease as in the present case [1, 2, 3, 4, 5], while in most of the other reports the two conditions were diagnosed at the same time [6, 7, 8, 9, 10, 11, 12]. Development of membranous glomerulonephritis following a remission of anti-GBM disease has also been reported [13]. In several cases crescent glomerulonephritis has been reported in association with membranous glomerulonephritis without detectable circulating anti-GBM antibodies [14, 15, 16, 17]. In one of these [17] there was also recurrence of the combined pattern of disease following renal transplantation. It is possible that some of these cases without anti-GBM antibodies may have been ANCA- associated, however it is important to recognise that crescentic glomerulonephritis due to anti-GBM antibody may occur in the absence of circulating anti-GBM antibodies as detected by standard techniques. Thus we have recently reported three cases of Goodpasture's disease in which no circulating anti-GBM antibodies were detectable in serum by either ELISA or Western blotting [18]. Antibodies could be detected using a highly sensitive biosensor system in the sera from the two patients tested.

  2. The association of anti-GBM disease with other renal lesions. There are many isolated case reports of Goodpasture's disease in association with other diseases and there are several recurrent associations which suggest possible pathogenetic mechanisms. The commonest association is that of anti-GBM antibodies with ANCA. The incidence of double positivity varies in different studies. Short et al [19] reported that ANCA were present in the serum of 21% of patients with anti-GBM antibodies and that in 73% the ANCA specificity was for MPO. Only 2.5% of patients with ANCA had anti-GBM antibodies. Some reports suggest that double positive patients are more likely to have recoverable renal function despite oliguria or severe renal impairment at presentation, features usually associated with a poor outcome in anti-GBM disease. Other associations with anti-GBM disease apart from membranous glomerulonephritis include occasional reports of anti-GBM disease occurring on a background of established diabetic nephropathy [20, 21] and, interestingly, occurring within weeks to months after lithotripsy [22, 23, 24]. There are also, of course, many reports of anti-GBM disease occurring after renal transplantation in patients with Alport's syndrome.

  3. The role of other lesions in predisposing to anti-GBM disease. It is tempting to speculate that these associated conditions such as membranous glomerulonephritis, diabetic glomerulopathy or preceding lithotripsy may actually predispose to the development of anti-GBM antibodies but proof for this is lacking. The target antigen in Goodpasture's disease has been precisely identified as the 230 amino acid, non-collagenous, carboxy-terminal NC1 domain of the α3 chain of type IV collagen [25]. Type IV collagen molecules are trimeric and associate into multimolecular networks. The α3/ α4/ α5 network is one of the three types of type IV collagen network and is found only in certain specialized basement membranes including those in the glomerulus, distal convoluted tubules, lung, eye and ear. It is remarkable that only this particular domain is the target of spontaneous autoimmunity even though multiple other tissue specific molecules can be found in GBM including the homologous a 4 chain. Hypotheses to explain why α3(IV)NC1 is targeted fall into four categories:
    1. differences in the distribution of the various type IV collagen chains results in less effective tolerance to α3(IV)NC1 than the other NC1 domains;

    2. α3(IV)NC1 possesses additional functional properties that influence the immune response

    3. unique molecular mimicry between α3(IV)NC1 and a microorganism initiates the immune response

    4. processing of a 3(IV)NC1 by antigen presenting cells results in generation of peptides that favour the development of autoimmunity rather than tolerance.
    There is no direct evidence to support any of these hypotheses. Evidence from our group suggests that maintenance of tolerance to the Goodpasture antigen may depend both on deletion of autoreactive T cells by exposure to the α3 chain of type IV collagen in the thymus [26] and on the presence of T regulatory cells [27]. It is tempting to speculate that changes to the glomerular basement membrane in membranous glomerulonephritis, or damage to membranes caused by lithotripsy may allow cryptic antigenic epitopes to be processed in a way which tips the balance from tolerance to autoimmunity. With regard to this there is a fascinating recent report suggesting that in a rat model an initial T cell mediated glomerular injury can trigger the release of autoantigens from the GBM with activation of anti-GBM antibody synthesis by B cells in the renal draining lymph nodes [28]
Follow up
The renal prognosis in patients with anti-GBM disease with oliguria at presentation is extremely poor and there is a case for not giving potentially dangerous treatment in the absence of lung haemorrhage. However, there are occasional reports of recovery despite renal failure requiring dialysis and in this case the patient was offered treatment. However he declined and is now on long-term dialysis.

References

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  28. Robertson J, Wu J, Arends J, Zhou C, McMahon J, Torres L, Lou YH: Activation of glomerular basement membrane-specific B cells in the renal draining lymph node after T cell-mediated glomerular injury. J Am Soc Nephrol 2005;16:3256-3263.