NORD gratefully acknowledges Richard JH Smith, MD, Director of the Iowa Institute of Human Genetics and the Molecular Otolaryngology and Renal Research Laboratories at the University of Iowa, for assistance in the preparation of this report.
Over the past decade, important advances in our understanding of complement-mediated renal diseases have led to the adoption of new names or ‘disease categories’ to more precisely group diseases that appear to share a similar cause. Consider, for example, dense deposit disease (DDD), a very rare kidney disease characterized on a renal biopsy test called ‘immunofluorescence’ by an abundance of a protein called C3 in the renal glomeruli, and named for the extremely dense ‘sausage-like’ deposits that are seen in the glomerular basement membrane (GBM) using electron microscopy. In 2013, as a result of a consensus meeting, scientists recommended that DDD be sub-grouped under a new heading – C3 Glomerulopathy, abbreviated C3G. The adoption of this new term was driven by the recognition that there is another group of patients with glomerular disease whose kidney biopsy is reminiscent of DDD. On electron microscopy, the deposits in these patients are lighter in color and more widespread in location, but on immunofluorescence, as with DDD there is an abundance of C3 in the renal glomeruli. These patients are said to have C3 glomerulonephritis or C3GN. In recognition of shared similarities, both DDD and C3GN are now classified as sub-types of C3G.
What happens in C3G? Recall that the glomeruli are the filtering units of the kidney, where blood gets filtered under pressure through the GBM into another space, called Bowman’s space, as urine. About half a million glomeruli in each kidney do the filtering, creating a filtrate of water, sodium, potassium, chloride, glucose and small proteins. In both DDD and C3GN, deposits of C3 and other proteins in the GBM disrupt kidney function. Progressive damage to the glomeruli occurs and after about 10 years, enough damage has occurred so that about half of all persons with C3G have kidney failure. When kidney failure occurs, dialysis must be started or transplantation must be performed. The rate of progression to end-stage kidney failure and dialysis appears to be similar for both DDD and C3GN.
In addition to dense deposits in the kidney, persons with DDD can develop deposits in their eyes in an area called Bruch’s membrane. This occurs because the ‘choriocapillaris-Bruch’s membrane-retinal pigment epithelium’ interface in the eye is very similar to the capillary-GBM interface in the kidney. The eye deposits are called drusen. Whether they occur more or less frequently in patients with C3GN is not clear.
The signs and symptoms of DDD and C3GN are similar.They include: blood in the urine, which is called hematuria; dark foamy urine, which signifies the presence of protein or ‘proteinuria’; cloudiness of the urine, reflecting the presence of white blood cells; swelling or ‘edema’, initially of the legs although any part of the body can be affected; high blood pressure; decreased urine output; and decreased alertness.
As mentioned earlier, when a kidney biopsy is done in a person with the above signs and symptoms if C3G (either DDD or C3GN) is suspected, the immunofluorescence analysis should show abundant C3 in the glomerular capillaries. This finding is a requirement and in its absence, the diagnosis of C3G can be excluded. Sophisticated studies have been done to determine the precise composition of the electron-dense deposits in DDD and C3GN, and in addition to C3 the glomeruli contain many other proteins that belong to a system called the complement system. Proteins from both the alternative pathway of complement and the terminal pathway of the complement are found. This finding is in agreement with our understanding of the pathophysiology of DDD and C3GN.
As might be expected, since complement proteins are typically in the blood stream, if they become trapped in the kidneys, blood stream levels will often be correspondingly reduced; and in fact, in persons with both DDD and C3GN several complement proteins in the blood stream circulate at lower than expected levels. The most notable is the decrease in C3, which tends to be reduced to a greater extent in persons with DDD as compared to C3GN. 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. This technique is called ‘complement biomarker profiling’. 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. One day, complement biomarker profiling may also help drive treatment decisions.
The immediate cause of the symptoms of C3G is the change in the filtering mechanism of the kidney. The damaged glomeruli (the filters) permit protein and red and white blood cells to pass into the urine-containing space.
The most abundant protein in the blood stream is albumin. As albumin passes into the urine and is lost from the blood stream, hypoalbuminemia or ‘low albumin in the blood stream’ develops. One consequence of hypoalbuminemia is that water leaks out of the circulation and accumulates in the surrounding tissues. This process leads to edema. Because of gravity and hydrostatic pressure (water pressure), the effects of fluid leakage are most apparent in the feet and ankles, which become swollen. As kidney function further deteriorates and urine output decreases, sodium and water are retained and the swelling becomes magnified. High blood pressure also develops.
The specific cause of C3G is lack of regulation of the complement system. The causes of complement dysregulation 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. It appears that patients with DDD are more likely to have C3Nefs, while patients with C3GN are more likely to have abnormalities in a group of proteins called the ‘Complement Factor H Related’ proteins, although more research needs to be done in this area.
C3G affects persons of all ages, although the mean age appears to be lower in DDD patients as compared to C3GN patients. The prevalence of C3G is estimated at 2-3 per 1,000,000 people.
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.
There is currently no specific therapy for C3G, however a number of non-specific treatments are appropriate. These treatments slow progression of chronic glomerular diseases through aggressive blood pressure control and reduction of proteinuria. Both angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type-1 receptor blockers (ARBs) are first-line drugs to decrease spillage of protein into the urine and to improve kidney hemodynamics. 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. These drugs may also delay progression of kidney disease.
Although widely used at one point, steroid therapy is not effective in C3G. However it is effective in a form of glomerulonephritis called juvenile acute non-proliferative glomerulonephritis (JANG), which can be confused with DDD. JANG can be distinguished from DDD because: 1) DDD is associated with low C3 levels; and, 2) persons with DDD often have nephrotic syndrome (greater than 3.5 gm of protein in the urine over 24 hours; hypoalbuminemia; edema). In JANG, C3 levels remain at the lower limit of normal.
Recent studies suggest that mycophenolate mofetil (MMF) is 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.
One anti-complement drug is widely available. Called Eculizumab, it is a humanized monoclonal antibody against C5 that blocks activity of the terminal pathway of complement. In a small number of studies that have looked at the effect of Eculizumab in patients with C3G, it appears that Eculizumab is effective in decreasing proteinuria and the rate of progression of kidney disease in some but not all patients. Identifying those patients who are likely to respond to Eculizumab is difficult, but it appears that elevated levels of soluble C5b-9 may be indicative of a good response. Soluble C5b-9 is one of the biomarkers of complement activity that is regularly measured when complement biomarker profiling is done, as was mentioned earlier.
Persons 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.
A number of investigation anti-complement therapies are in development. In the USA, all clinical trials receiving U.S. Government funding and some trials supported by private industry are posted on www.clinicaltrials.gov.
Currently, two trials, one by ChemoCentryx and the other by Achillion, are registered. The ChemoCentryx trial is a randomized, double blind, placebo controlled study to evaluate the safety and efficacy of avacopan in C3G patients. Avacopan (formerly CCX168) must be taken orally twice daily during the 26-week treatment period. It inhibits the complement 5a receptor to reduce the complement-triggered inflammatory response. The Achillion trial is a proof-of-concept study to evaluate the efficacy and safety of ACH-0144471 in C3G patients. Participants are randomized 1:1 to receive either study drug ACH-0144471 or placebo for a period of 6 months. The drug is taken orally three times daily and inhibits the formation of the C3 convertase by blocking a protein called factor D to reduce or prevent activation of the alternative complement pathway.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Contact for additional information about this condition:
Richard JH Smith, MD
Director of the Iowa Institute of Human Genetics and the Molecular Otolaryngology and Renal Research Laboratories
University of Iowa
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