The pathogenesis of IgA nephropathy and implications for treatment

Abstract

IgA nephropathy (IgAN) is a common form of primary glomerulonephritis and represents an important cause of chronic kidney disease globally, with observational studies indicating that most patients are at risk of developing kidney failure within their lifetime. Several research advances have provided insights into the underlying disease pathogenesis, framed by a multi-hit model whereby an increase in circulating IgA1 that lacks galactose from its hinge region - probably derived from the mucosal immune system - is followed by binding of specific IgG and IgA antibodies, generating immune complexes that deposit within the glomeruli, which triggers inflammation, complement activation and kidney damage. Although treatment options are currently limited, new therapies are rapidly emerging that target different pathways, cells and mediators involved in the disease pathogenesis, including B cell priming in the gut mucosa, the cytokines APRIL and BAFF, plasma cells, complement activation and endothelin pathway activation. As more treatments become available, there is a realistic possibility of transforming the long-term outlook for many individuals with IgAN.

Fig. 1 |. Geographical variation in the prevalence of IgA nephropathy.

Percentages represent the estimated proportion of cases of IgA nephropathy compared with all native kidney biopsies performed. Reprinted from ref. 190, Springer Nature Limited.

Fig. 2 |. Long-term outcomes in IgA nephropathy.

Data from the UK National Registry of Rare Kidney Diseases. Patients with biopsy-proven IgA nephropathy and proteinuria >0.5 g/day or estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m²) were enrolled; 2,299 adults and 140 children were included in the analysis. This study demonstrates that most patients are at risk of kidney failure within their lifetime and shows a strong relationship between time-averaged proteinuria and the risk of kidney failure or death. a, Kaplan−Meier survival curves of time to kidney failure or death event in adults and paediatric patients. b, Kaplan−Meier survival curves of time to kidney failure or death event, according to total follow-up time-averaged proteinuria (g/g). Reprinted with permission from ref. , Wolters Kluwer.

Fig. 3 |. Pathogenesis of IgAN.

a, Priming of B cells takes place in mucosa-associated lymphoid tissue (1); the gut is illustrated here as an example. In IgA nephropathy (IgAN), a combination of genetic and environmental factors — including infections, food antigens, alterations in the microbiota and aberrant mucosal immune responses — prime B cells to express poorly galactosylated IgA1 (termed galactose-deficient IgA1 (Gd-IgA1)); the cytokines BAFF and APRIL promote IgA class switching. (2) Patients with IgAN have an increased circulating level of Gd-IgA1, either due to mis-trafficking of mucosa-derived Gd-IgA1⁺ B cells to the bone marrow or overspill of Gd-IgA1 from mucosal sites into the circulation. b, In the circulation, Gd-IgA1 is recognized by IgG and IgA1 antibodies specific to the Gd-IgA1 hinge region, which could be autoantibodies or cross-reactive antimicrobial antibodies. c, This recognition results in the formation of Gd-IgA1-containing immune complexes (3). d, In the kidney, Gd-IgA1-containing immune complexes deposit within the glomerular mesangium (4), leading to mesangial cell activation, proliferation, production of inflammatory mediators and extracellular matrix components, and complement activation, with resultant glomerular and tubulo-interstitial injury. Several therapeutics have been developed for treatment in IgAN that target different steps in the disease pathogenesis, depicted in the blue boxes.

Fig. 4 |. IgA1 structure and glycosylation.

a, The IgA1 molecule includes a hinge region between the CH1 and CH2 domains of the α1 heavy chain that contains serine (Ser) and threonine (Thr) residues, and these can be variably glycosylated. Initially, N-acetylgalactosamine (GalNAc) is added to serine or threonine, which can be further extended with galactose (Gal) or sialic acid (N-acetylneuraminic acid). GalNAc−Gal can be further extended with sialic acid in α2,3-linkage with Gal. b, IgA nephropathy (IgAN) is characterized by increased serum levels of IgA1 that lacks terminal galactose (that is, poorly galactosylated IgA1 glycoforms), which are termed galactose-deficient IgA1 (Gd-IgA1). IgG antibodies can recognize the exposed GalNAc and bind to form IgA1 immune complexes.

Fig. 5 |. Pathological consequences of IgA immune complex deposition in IgAN.

Following the deposition of IgA1-containing immune complexes in the glomerular mesangium, an inflammatory reaction ensues with the release of pro-inflammatory and pro-fibrotic mediators. These mediators induce several histological changes that are characteristic of IgA nephropathy (IgAN) and inform the Oxford classification of IgAN — mesangial hypercellularity (M), inflammatory cell recruitment into glomeruli (endocapillary hypercellularity, or E), and an uncontrolled inflammatory response that can lead to crescent formation (C). Release of mesangial cell-derived cytokines leads to podocyte injury (glomerular−podocyte crosstalk), podocyte loss and segmental sclerosis (S). Moreover, disruption of the glomerular filtration barrier leads to haematuria, proteinuria and increased filtration of IgA1-containing immune complexes. Filtration of these complexes, coupled with mesangial cell-derived cytokines (glomerular−tubular crosstalk), subsequently lead to tubular atrophy and interstitial fibrosis (T), and ultimately nephron loss. Activation of the complement system has an important role in accelerating each of these processes.