Immunoglobulin A nephropathy (ORPHA:34145)
A rare glomerular disease, histologically characterized by glomerular mesangial deposits of IgA, often accompanied by IgG and complement C3 as well as mesangioproliferative changes, clinically mostly manifesting as oligosymptomatic glomerulonephritis, possibly infection-triggered macrohematuria and a variable course ranging from spontaneous remission to slow or rarely rapid progression to kidney failure.
Epidemiology
In Europe, the annual incidence of IgA nephropathy (IgAN) is approximately 1/131,578, with a point prevalence of 1/3952. Higher prevalences are observed in Asia and lower prevalences in Africa. The male to female ratio is about 2:1 in Europeans. IgAN is rare in children younger than 10-12 years.
Clinical description
IgAN typically runs an oligosymptomatic course with microscopic hematuria, variable degrees of proteinuria (but usually not the nephrotic syndrome), hypertension and slowly progressive decline of glomerular filtration rate (GFR). Consequently, the disease is often diagnosed by chance in younger adults undergoing medical work-up. Sometimes macrohematuria occurs within 1-2 days after the onset of an upper respiratory tract infection. If diagnosed very early, IgAN may spontaneously remit in up to 30% of the cases, whereas 25% slowly loose GFR. Of the patients coming to medical attention at later chronic kidney disease (CKD) stages, up to 100% progress to kidney failure over 20-30 years.
Etiology
IgAN is characterized by the deposition of IgA1 with a particular undergalactosylation pattern in the IgA1 hinge region (gd-IgA1). Deposition of gd-IgA1 with or without IgG directed at gd-IgA1 leads to complement activation, mesangial and other glomerular cell injury, followed by glomerulosclerosis and tubulointerstitial fibrosis. The origin of the B-cells producing undergalactosylated IgA1 may be the intestinal muscosa, pointing to the existence of a gut-kidney axis in IgAN, which is supported by genome-wide association studies.
Diagnostic methods
A diagnosis of IgAN can only be made by kidney biopsy. Findings include mesangial hypercellularity and matrix expansion, endocapillary proliferative changes, glomerulosclerosis and tubulointerstitial fibrosis. Glomerular crescents occur in up to 20% of all biopsies but are rarely extensive. The later very rare cases are characterized by kidney failure occurring within months to a few years.
Differential diagnosis
Secondary causes of IgAN should be excluded. These include rheumatologic, celiac, and chronic inflammatory bowel disease, and infections (hepatitis B, hepatitis C). Other associations may be coincidental since glomerular IgA deposits can be frequently detected in autopsies even in patients with no known disease.
Management and treatment
All patients should receive optimized conservative therapy, targeting blood pressure, proteinuria, and life style (stop smoking, normalize body weight, dietary sodium and protein restrictions). Use of an ACE-inhibitor or angiotensin receptor blocker with systematic uptitration to the maximum allowed or tolerated dose is mandatory in patients with a proteinuria above 0.5 g/d. Patients should also receive a sodium-glucose cotransporter-2 (SGLT2) inhibitor. The value of high dose corticosteroids tapered over 6 months is controversial with some studies (in particular in Asian patients) reporting a delay of kidney failure by about 2.5 years, whereas recent European studies noted no benefit. All randomized trials noted a significant increase in serious adverse events with high dose corticosteroids, including infection-related mortality. In 2022 an enteric coated preparation of budesonide (nefecon) was licensed for IgAN. In 2023 this was followed by sparsentan, a dual angiotensin-II receptor and endothelin receptor-A blocker. Drugs in clinical testing include selective endothelin receptor-A blockers, B-cell proliferation and differentiation inhibitors (targeting APRIL and/or BAFF) and drugs targeting the complement system.
Prognosis
The prognosis over 5-6 years can be estimated using the International IgAN Prediction Tool. Major prognostic parameters include the degree of proteinuria, GFR impairment at baseline, hypertension, nicotine consumption and obesity. However, in particular in younger adults with IgAN even low levels of proteinuria (i.e. <1 g/d) carry a high life-time risk of kidney failure.

                            Last update: 
                            December 2023


                            - Expert reviewer(s): 
                            Dr Jürgen FLOEGE | ERKNet*


                                * European Reference Network