C3 Glomerulopathy

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Synonyms

C3 Glomerulonephritis, DDD, C3GN, C3G, Dense Deposit Disease,

Overview

C3 glomerulopathy (also known as Dense Deposit Disease, C3 Glomerulonephritis,DDD, C3GN, and C3G) refers to a group of related rare conditions that cause the kidneys to malfunction. The prevalence of C3G is estimated to be 2-3 per 1,000,000 people. There are two major forms of C3G and they are recognised as dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). These rare kidney conditions are characterized on a renal biopsy test called ‘immunofluorescence’ by an abundance of a protein called Complement 3 (C3) in the renal glomeruli. In DDD, extremely dense ‘sausage-like’ deposits are observed in the glomerular basement membrane (GBM) using electron microscopy. Whereas in C3GN, the deposits are lighter in color and are more widespread in location, but on immunofluorescence, as with DDD there is an abundance of C3 in the renal glomeruli.   Both forms are known to cause similar kidney problems, however the features of dense deposit disease tend to appear earlier than those of C3 glomerulonephritis, usually in adolescence. The signs and symptoms of either disease may not fully develop until adulthood. C3G is known to affect persons of all age. The major features of C3G include high levels of protein in the urine (proteinuria), blood in the urine (hematuria), reduced amounts of urine, low levels of protein in the blood, and swelling in many areas of the body. Affected individuals may have particularly low levels of a protein called complement component 3 (or C3) in the blood.

Symptoms

The signs and symptoms of dense deposit disease and C3 glomerulonephritis are similar. These are:

  • Blood in the urine
  • Dark foamy urine
  • Cloudiness of the urine
  • Oedema
  • High blood pressure
  • Decreased urine output
  • Decreased alertness

Please note that dense deposit disease can also be associated with other conditions unrelated to kidney function. For example, people with dense deposit disease may have acquired partial lipodystrophy, a condition characterized by a lack of fatty (adipose) tissue under the skin in the upper part of the body. Additionally, some people with dense deposit disease develop a buildup of yellowish deposits called drusen in the light-sensitive tissue at the back of the eye (the retina). These deposits usually appear in childhood or adolescence and can cause vision problems later in life.

Causes

The direct cause of the symptoms of C3G is the dysregulation of the complement filtering mechanism in the kidney. The damaged glomeruli (the filters) permits protein (albumin) and red and white blood cells to pass into the urine-containing space. Albumin, the most abundant protein in the blood stream, passes into the urine and is lost from the blood stream. Hence, hypoalbuminemia or ‘low albumin in the blood stream’ develops and consequently water leaks out of the circulation and accumulates in the surrounding tissues (oedema). This is most apparent in the feet and ankles, which becomes swollen. As kidney function further deteriorates and urine output decreases, sodium and water are retained and the swelling worsens. High blood pressure also develops. Furthermore, the causes of dysregulation of the complement filtering mechanism can be divided into genetic and acquired factors. Amongst the former are changes in many of the complement genes, and amongst the latter are specific antibodies called C3 nephritic factors or C3Nefs that impair normal regulation of the complement system.

Diagnosis

C3G can only be diagnosed by a kidney biopsy. The kidney deposits stain for the complement protein C3 and when examined under an electron microscope, dense deposits are present. Studies are currently being done to measure the levels of many different complement proteins in persons with DDD and C3GN and to compare these levels to persons without any kidney disease to determine whether the ‘profile’ for DDD and C3GN is unique by using the ‘complement biomarker profiling’ technique. Because the treatment of C3G is difficult, it is hoped that this type of information may provide clinicians with insight into what is happening at the level of the complement system in their patients with DDD and C3GN. Moreover, complement biomarker profiling may also help drive treatment decisions.

Prognosis

Renal prognosis is poor, with a 30% risk of end stage renal disease at 2-years. The risk of recurrence in the transplanted kidney is over 70%, with more than a 50% chance of graft loss.

Treatment

There is currently no specific therapy for C3G, however a number of non-specific treatments are appropriate.
This may include:

  • ACE inhibitors and ARBs: The first-line drugs used in C3G are both angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type-1 receptor blockers (ARBs), to decrease spillage of protein into the urine and to improve kidney hemodynamics. These treatments aim to slow the progression of the C3 glomerulopathy through aggressive blood pressure control and reduction of proteinuria. These drugs may also limit the infiltration of white blood cells into the kidney. If hyperlipidemia (increased lipid in the blood stream) is present, lipid-lowering drugs can be used to reduce long-term atherosclerotic risks.
  • Eculizimab: Eculizumab, is a humanized monoclonal antibody against C5 that blocks activity of the terminal pathway of complement. It is widely avaialbe. Studies that have looked at the effect of Eculizimab in patients with C3G, have reported that Eculizumab is effective in decreasing proteinuria and the rate of progression of kidney disease in some but not all patients.
  • Mycophenolate mofetil (MMF):  It is known to be beneficial in patients with C3GN and can decrease the rate of progression to end-stage kidney failure. MMF inhibits inosine monophosphate dehydrogenase, the enzyme that controls the rate of synthesis of guanine monophosphate. Studies have not shown a similar effect for DDD.
  • Dialysis/Kidney transplant: Patients with C3G who progress to end-stage kidney failure must receive dialysis – either peritoneal dialysis or hemodialysis – or a kidney transplantation. Transplantation is associated with a high rate of disease recurrence in the allograft and about half of transplants ultimately fail.
  • Investigational therapies: A drug called CDX-1135 (also known as soluble CR1) is being investigated and is open for recruitment. And another trial using a small molecule anti-C3 agent may soon start, however additional therapies for C3G are needed. Please discuss the benefits and risks of clinical trial with your medical practitioner.

Resources

NORD; GHR; NICE