IGA NEPHROPATHY – OVERVIEW OF THE DISEASE
IgA Nephropathy (also known as Berger’s disease) was first described by Berger and Hinglais in 1968. It is a progressive auto immune disease which results in chronic inflammation of the kidneys and leads to reduced kidney function over time.
It can take a long time for the kidney function to be significantly affected (10-20 years) but up to 50% of patients with IgA Nephropathy (IgAN) may develop end-stage renal disease (“ESRD”) which requires dialysis or kidney transplant for survival. IgAN is a rare disease and as such occurs in less than 200,000 individuals in the United States and in less than 5 of 10,000 individuals in the EU, which roughly corresponds to less than 250,000 individuals in EU.
Presumed origin and disease mechanism
The kidney’s primary function is to filter the blood and remove excess fluid. According to the predominant theory on disease origin and progression, IgAN is a disease that starts in the intestine and not in the kidney itself.
IgA is an antibody produced in the lymph like nodes called Peyer’s patches located in the small intestine, and it plays a key role in the immune system by protecting the body from foreign substances such as bacteria and viruses. In patients with IgA Nephropathy these antibodies appear in the blood, instead of being restricted to the intestines, which sets off a reaction where the body attacks these as a foreign matter, creating large immune complexes. These complexes ultimately end up in the kidneys where they set off an inflammatory reaction which causes damage to the filtration mechanism. This affects both kidneys.
In order to develop the disease, the patient has to have a genetic predisposition, but this is not in itself sufficient. It is presumed that either an environmental, bacterial or dietary trigger is also needed.
Patients can have IgAN without any obvious signs or symptoms for an extended period of time. The first symptoms of IgA Nephropathy are typically proteinuria (protein in the urine) and/or hematuria (blood in the urine). This causes urine to be foamy or turn dark brown like the color of tea or cola.
The disease is primarily diagnosed either through routine health checks where protein is found in the urine, or by the patient going to a physician because of blood in the urine or frothing or foamy urine. Following elimination of various other reasons for the symptoms, patients are typically referred to a Nephrologist (kidney specialist). During the period from initial discovery until an official diagnosis, patients should expect to have physical exams, urine tests, blood tests, and a kidney biopsy. During this time patients often begin with their Primary Care Physician and can be sent to a Urologist on the way to ending up with a Nephrologist for an official diagnosis.
IgA Nephropathy normally presents in a persons’ twenties or thirties and is more common in men than in women in the western world. The progression of the disease is relatively slow. As the kidney’s function is affected, waste products accumulates in the blood and are measured by Creatinine. Creatinine levels in the blood are used to calculate eGFR, which is a measure of the kidney’s capacity to filter the blood. As the disease progresses the eGFR deteriorates. Deterioration of kidney function can in a significant part of the patients lead to end stage renal disease (ESRD). A patient with ESRD will need dialysis or a renal transplant.
ESRD – REQUIRES DIALYSIS OR TRANSPLANTATION
Dialysis removes waste, salt and extra water to prevent them from building up in the body. There are two types of dialysis – peritoneal dialysis and hemodialysis. Peritoneal dialysis is when the blood is cleaned inside your body. Hemodialysis is used on approximately 90 percent of all dialysis patients and involves pumping a patient’s blood through an external filtration system before it is pumped back into the body. A typical hemodialysis schedule is three sessions per week, for 3–5 hours per session at a medical clinic.
Kidney transplant is a treatment option when ESRD occurs. Transplanted kidneys are used from deceased or living donors. As IgA nephropathy is an autoimmune disease which originates in the intestine and does not primarily reside in the kidney, there is a significant risk , up to 50 per cent, that the disease reoccurs even after a kidney transplant.
How common is IgA nephropathy?
IgA nephropathy is a rare disease. Various sources quote different estimates for prevalence in the United States, but it is generally assumed to be a large orphan disease. Calliditas Therapeutics estimates the number of patients in the US to be less than 200,000. In Europe, the same company has carried out a prevalence study which resulted in an estimate of 4 people per 10,000 which is the equivalence of around 250,000 people.
Beyond the United States and Europe, high prevalence rates have been observed in China, Singapore, Japan, Australia and Hong Kong. In China, IgA nephropathy was for a long time the leading cause of ESRD, before being overtaken by diabetes. In Japan, lgA nephropathy is also more common and the higher prevalence in Asia is presumed to be a result of the interplay of a genetic predisposition, environmental, bacterial and dietary impact.
CURRENT TREATMENT OF IGA NEPHROPATHY
Today there are no drugs approved by European Medicines Agency (“EMA”) or the US Food and Drug Administration (”FDA”) for the treatment of IgA nephropathy. An association of kidney disease experts, Kidney Disease: Improving Global Outcomes (“KDIGO”), has however published guidelines for the treatment of IgA nephropathy in the absence of approved medications. Recommendations relate to how to attempt to reduce the proteinuria levels in patients. The only recommended treatment for reducing proteinuria levels by the KDIGO consortium is systemic blood pressure lowering agents such as either a angiotensin converting enzyme (“ACE”) inhibitors or an angiotensin II receptor blockers (“ARBs”). The reductions in blood pressure in the kidney reduces the amount of protein excreted into the urine and is generally considered symptomatic and has not been proven to address the presumed underlying cause of the disease.
This approach is helpful to some patients, but others continue to progress and some clinicians choose to employ a variety of high dose systemic off label immunosuppressive agents such as prednisone, prednisolone, and methyl prednisolone. The use of these systemic steroids is not recommended by KDIGO due to a lack of consistent supportive data and the concern around severe side effects, which recently also has been documented in a clinical trial setting (TESTING and STOPIgan). KDIGO however does not reject the use of such immunosuppressive agents but simply prefer to leave it up to the treating nephrologist.
WHAT IS A RARE OR ORPHAN DISEASE?
Orphan drug designation
To stimulate the development of therapies for patients affected by orphan diseases with unmet medical needs, regulatory authorities worldwide introduced the designation of Orphan Drug. The Orphan Drug Act of 1983 introduces several incentives for drug companies developing drugs to prevent, diagnose or treat so-called orphan diseases that affect less than 200,000 individuals in the United States. These incentives consist of seven years of market exclusivity from the grant date of market approval, assistance in clinical research study designs, tax credits for the costs of clinical research, FDA fee waiver and eligibility for FDA grants. The adopted incentives consist of ten years of market exclusivity from the grant date of market approval in the EU, access to the EU centralized procedure, protocol assistance and scientific advice, fee reductions on EMA procedural activities and eligibility for EU grants.