IgA nephropathy (IgAN) – also known as Berger’s disease – is the most common form of glomerulonephritis, a chronic inflammatory condition of the kidney, in the Western world.

IgA nephropathy is a serious autoimmune, progressive disease that leads to decreasing kidney function over the course of 10 to 20 years.

Up to 50 percent of patients diagnosed with IgAN will progress to end-stage renal disease (ESRD), a disease state requiring dialysis or kidney transplant for survival due to insufficient kidney function within 20 years. IgAN is an orphan disease, designated as an orphan indication in both the US and Europe. IgAN affects approximately 130,000–150,000 people in the US and about 250,000 people in Europe.

Today, there are no approved treatments for IgAN. Today’s standard of care treatment regimens entail primarily established, generic drugs such as blood pressure lowering agents to alleviate symptoms, complemented by off-label use of systemic corticosteroids.

End-stage renal disease (ESRD)

ESRD is characterized by an inability of the kidney to remove waste or excess fluid from the blood and is a disease state requiring dialysis or kidney transplant for survival. It is associated with significant risks of complications and quality of life deterioration as well as premature death.

Approximately 700,000 patients per year in the US and an estimated 2 million patients worldwide are affected by ESRD. Glomerulonephritis is a substantial contributor to ESRD cases on an annual basis and IgAN is the largest component of that disease category. At present, ESRD patients have two treatment options:

  1. Transplantation: live and deceased donor kidneys
  2. Dialysis: haemodialysis or peritoneal dialysis

Pathogenesis, origins and disease mechanism of IgA nephropathy

The kidney is a complex filtration organ, whose activities include production of hormones, absorption of minerals, filtration of the blood and removal of waste products. According to the most predominant theory on disease origin and progression, IgA nephropathy is a disease that starts in the intestine and not in the kidney itself, i.e. the disease’s origin is in the ileum where the Peyer’s patches are located.

IgA is an antibody that plays a key role in the immune system by protecting the body from foreign substances such as bacteria and viruses. Patients with IgA nephropathy have elevated levels of IgA molecules lacking galactose units (a type of sugar). In IgA nephropathy patients, a combination of genetic predisposition, environmental and dietary factors is presumed to lead to increased intestinal membrane permeability, which in turn leads to these IgA molecules penetrating into the blood.

The galactose-deficient spot at the hinge region of the IgA molecule is immunogenic. It therefore attracts other antibodies, forming immune complexes that become stuck in the filtrating glomerular membranes of the kidney. The trapped immune complexes initiate an inflammatory response (inflammation, cytokine release and proliferation of mesangial matrix cells) which leads to damages that ultimately may destroy the glomeruli, which is a key component of the kidney’s filtration mechanism.

The first symptoms for IgA nephropathy are appearance of protein and/or blood in the urine (proteinuria and hematuria, respectively), indicating leakage through damaged membranes in the kidney. The risk of being affected by ESRD can be predicted by the level of proteinuria. As the kidney function deteriorates, waste products, of which creatinine is a marker, accumulates in the blood. Creatinine levels in the blood are used to calculate the eGFR, which is a measure of the kidney’s capacity to filter the blood. Hence, eGFR is a measure of renal function (the lower eGFR, the less renal function remains). As the disease progresses the eGFR deteriorates and a large proportion of the patients will eventually be afflicted by ESRD. A patient with ESRD will need dialysis or a renal transplant in order to survive.