ANCA-Associated Glomerulonephritis: Diagnosis and Therapy Proceedings of the Henry Shavelle Lectureship

Abstract

Background: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) frequently affects the kidney. Glomerulonephritis (GN) in AAV, ANCA-GN, not only dictates therapeutic decisions but is also of relevance for overall survival influencing the risk of cardiovascular disease and serious infections.

Summary: A diagnosis of ANCA-GN includes laboratory investigations including urinalysis and a thorough assessment of potential organ involvement. A kidney biopsy can be performed to ascertain the diagnosis but has an additional prognostic relevance and tools have been established to predict long-term kidney survival. Experimental biomarkers indicating kidney inflammation include urinary soluble CD163 and the presence of urinary T cells. Therapeutic options are refined and some of these therapies, such as the added value of performing plasma exchange, are the matter of controversial discussions. Safe reduction of cumulative exposure to glucocorticoids and eventually the use of avacopan to substantially reduce glucocorticoid exposure has been implemented in most centers. In the remission of maintenance, the optimal duration of therapy is still unclear, but extended use of rituximab as maintenance agent has shown long-term remission rates, thus limiting the damage accrued by relapsing disease and thus also reducing the risk of end-stage kidney disease (ESKD). Avacopan has been the first agent with a glomerular filtration rate-sparing effect, likely due to more rapid control of kidney inflammation. Those reaching ESKD should be evaluated for kidney transplantation and the risk of remaining on dialysis must be balanced against the risk of recurrence of disease following transplantation.

Key messages: The advent of a magnitude of landmark studies in ANCA-GN has refined diagnostic approaches, implemented tools to predict kidney outcome, and eventually led to the approval of newer therapies with avacopan, the latest addition to the armamentarium. Once ESKD is present, patients should be considered for kidney transplantation as remaining on dialysis portends poor overall prognosis.

Keywords: Anti-neutrophil cytoplasmic antibody; Diagnosis; Glomerulonephritis; Prognosis; Treatment.

Fig. 1.

Established and experimental biomarkers in anti-neutrophil cytoplasmic antibody (ANCA)-GN. Established biomarkers include blood and urine measurements of parameters established in most laboratories, while analysis of the experimental biomarkers is often restricted to special laboratories. ANCA, anti-neutrophil cytoplasmic antibody; eGFR, estimated glomerular filtration rate; MCP-1, monocyte chemoattractant protein-1; MPO, myeloperoxidase; PR3, proteinase 3; sCD163, soluble cluster of differentiation 163.

Fig. 2.

Anti-neutrophil cytoplasmic antibody (ANCA)-GN may affect a variable number of glomeruli in a kidney biopsy. In many instances, it is a focal GN meaning that more than half of glomeruli in a biopsy are normal, with “focal” referring the minority of glomeruli that are affected. Giving a definition of a normal glomerulus is more challenging than defining any particular glomerular lesion. It may be difficult to determine to what extent slight alterations, e.g., as a result of ischemia, are allowed before excluding a glomerulus from the “normal” category and this decision will rely heavily on the pathologist’s experience. Normal and virtually normal glomeruli: a Glomerulus without histomorphological lesions. b Slight mesangial matrix increase. c Minimal hypercellularity due to a small amount of inflammatory cells in capillary loops. d Ischemic changes characterized by enlarged Bowman’s space.

Fig. 3.

Extracapillary proliferation or crescent formation is characterized by the presence of cells in Bowman’s space, usually a combination of cells from epithelial origin and inflammatory cells. In ANCA-GN, it is the vasculitis of glomerular capillary loops responsible for crescent formation. With rupture of the GBM in areas of fibrinoid necrosis, signifying the vasculitis process, inflammatory mediators enter Bowman’s space and initiate the proliferation of the visceral and parietal epithelium. Crescents are categorized according to the percentage of cells in relation to collagen fibers as cellular, fibrocellular, or fibrous. Crescents may either be segmental or circumferential depending on the extensiveness of the lesion in more or less than 50% of the circumference of the glomerulus. In order to determine crescentic class in the Berden classification, only cellular crescents should be taken into account. Crescents in various appearances: a Segmental cellular crescent. b Circumferential cellular crescent. c Segmental fibrous crescent. d Circumferential fibrous crescent. Fibrocellular crescent in e with a distribution pattern that suggests that new cellular proliferation occurs superimposed on an old crescent that turned fibrous. Rupture of the GBM caused by small vessel vasculitis in f with consequent leakage of inflammatory mediators in Bowman’s space leading to extracapillary proliferation.

Fig. 4.

Global glomerulosclerosis is an end stage in which the glomerulus has lost all of its former anatomical structures and is non-functioning. Global glomerulosclerosis may have a variable appearance, and it has been tried to determine the cause of global glomerulosclerosis from the histopathological features as it may be relevant to know whether glomerulosclerosis is caused by disease progression or another cause, e.g., hypertension. Specific features are not well described in the literature, which makes this an area of great uncertainty. A variety of globally sclerotic glomeruli: a Pre-existent capillary loops still discernable. In b, glomerulus seems to become destructed whereas in c, it shrinks. Appearance in d could be suggestive of global sclerosis caused by crescentic GN but example is from a biopsy not affected by ANCA-GN.

Fig. 5.

An overview over clinical trials informing about strategies to maintain remission of ANCA-associated vasculitis, with a particular focus on renal outcomes. Most clinical trials neither had kidney-related inclusion or exclusion criteria nor assessed renal outcomes separately. ANCA, anti-neutrophil cytoplasmic antibody; AZA, azathioprine; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; MMF, mycophenolate mofetil; NA, not applicable; R group, rituximab group.