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NORD is very grateful to 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.
Dense deposit disease (DDD) is a rare kidney disease that stops the kidneys from correctly filtering waste from the blood. The name is descriptive of the electron-dense changes that transform the middle layer (lamina densa) of the glomerular basement membrane (GBM) in a segmental, discontinuous or diffuse pattern. The glomeruli are the filtering units of the kidney. Blood flows through very small capillaries in each glomerulus where it is filtered through the GBM to form urine. When DDD is present, deposits in the GBM lead to disruption of kidney function. Because damage to glomeruli is progressive, about half of all persons with DDD experience kidney failure after living with their disease for 10 years. The development of kidney failure means that dialysis or transplantation must be started.
In addition to dense deposits in the GBM, persons with DDD can develop deposits in their eyes along an interface called the choriocapillaris-Bruch's membrane-retinal pigment epithelium. This region is very similar to the capillary-GBM interface in the kidney. The eye deposits are called drusen.
The signs and symptoms of DDD (and also MPGN1 and MPGN3) are similar. They include: blood in the urine (hematuria), dark foamy urine (proteinuria) and cloudiness of the urine as a result of the presence of white blood cells; swelling (water retention or edema) of almost any part of the body; high blood pressure; decreased urine output; and decreased alertness.
The kidney deposits stain for a specific complement protein called C3 using a technique called immunofluorescence microscopy. Recently, the precise composition of the dense deposits has been determined. In addition to C3, DDD glomeruli contain other complement proteins belonging to the alternative pathway (AP) and terminal pathway of the complement cascade. This finding is consistent with our understanding of the disease process.
The former name for DDD was membranoproliferative glomerulonephritis type II (MPGN2). MPGN2 was felt to be an inadequate name primarily because it implied a relationship to two other types of MPGN called MPGN1 and MPGN3. By immunofluorescence microscopy, MPGN2 is clearly different from MPGN1 and MPGN3, suggesting that there may not necessarily be a relationship amongst these diseases. The major difference is that MPGN1 and MPGN3 stain for immuno-complexes (antibodies), while DDD does not. In addition, although dense deposits are seen with all three diseases, their location differs for each type of MPGN.
As would be expected if complement proteins become deposited in the kidneys of persons with DDD, the levels of these proteins in their blood stream are correspondingly reduced. In particular, persons with DDD can have exceedingly low levels of C3, a condition referred to as hypocomplementemia.
While damage to glomeruli is progressive, it is not possible to predict if a person with DDD will develop kidney failure. However studies of persons with DDD have shown that five years after the diagnosis, about 40% of persons will have no kidney function. By 10 years, 50% of persons with DDD are on dialysis. When end-stage renal failure develops, dialysis or transplantation is required.
Recently, another type of kidney pathology has been recognized, which is called C3GN (C3 glomerulonephritis). Like DDD, in C3GN there is positive staining for C3 but negative staining for immunoglobulins, but UNLIKE DDD, the electron-dense deposits are NOT as dense and tend to be paramesangial and sub-epithelial in location rather than only in the middle layer of the glomerular basement membrane. Both DDD and C3GN are now classified under the heading of C3Gs (C3 glomerulopathies).
The immediate cause of the symptoms of DDD (and other MPGN disorders) 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 circulation is albumin. As albumin passes into the urine and is lost from the blood stream, hypoalbuminemia (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. Because of gravity and hydrostatic pressure (water pressure), the effects of fluid leakage are most apparent in the feet and ankles, which can become swollen or edematous. As kidney function deteriorates further and urine output decreases, sodium and water are retained and the swelling becomes magnified. In addition, high blood pressure often develops.
The specific cause of DDD is lack of regulation (dysregulation) of the complement cascade. The factors that lead to dysregulation include specific antibodies known as C3 nephritic factors (C3NeFs) that are present in about 80% of persons with DDD. C3NeFs binds to a specific enzyme called C3 convertase to cause the enzyme to remain turned on. When C3 convertase stays turned on, C3 is consumed and its concentration in the blood decreases markedly. A low concentration of C3 in the blood is a key sign of DDD.
Other causes of DDD are mutations or duplications in the complement proteins in about 15% of persons with DDD. Like C3NeFs, these changes also lead to dysregulation of the complement cascade.
DDD affects persons of all ages although it seems to be more aggressive in younger persons, especially younger girls. The incidence of DDD is estimated at 2-3 per 1,000,000 people. Racial data suggest that whites may be preferentially affected.
The disorder most closely related to DDD is C3GN. Scientists believe that the difference in the two diseases is caused by different degrees of dysregulation of two key complement enzymes, C3 convertase and C5 convertase. The symptoms of DDD and C3GN are virtually identical. In addition symptoms of the following disorders can be similar to those of DDD. Comparisons may be useful for a differential diagnosis:
Acute glomerulonephritis is the result of inflammation of the glomeruli often caused by an immune response triggered by infection of some kind. Among children, acute glomerulonephritis may be caused by such diseases as IgA nephropathy, Henoch-Schonlein purpura, hemolytic uremic syndrome and post-streptococcal glomerulonephritis. Among adults, the list of disorders that may trigger the onset of acute glomerulonephritis is longer and more varied. Included are Goodpasture's syndrome; viral diseases such as mononucleosis, measles, or mumps; infective endocarditis; and sexually transmitted diseases.
Swelling results when protein is lost from the blood stream. Acute nephritic syndrome may be associated with the development of hypertension, interstitial inflammation (inflammation of the spaces between the cells of the kidney tissue), and acute renal failure.
Lupus nephritis is a complication of the autoimmune disease, systemic lupus erythematosus (SLE). Just how lupus causes kidney damage is unknown. It is related to the autoimmune process of lupus, through which the immune system produces antibodies against body components. Complexes of these antibodies and complement accumulate in the kidneys and trigger an inflammatory response.
Lupus can cause various disorders of the kidney, including several glomerulonephritis (GN) diseases such as membranoproliferative GN, mesangial GN, membranous GN, diffuse proliferative GN, and others. It often leads to nephrotic syndrome (excessive protein excretion) and may progress rapidly to renal failure.
Post-streptococcal glomerulonephritis follows an infection at a site other than the kidneys, e.g. at a remote site such as the skin or throat, with a specific type of bacterium known as "Group A hemolytic streptococcus bacterium". As a consequence of the streptococcal infection, the glomeruli may become plugged and inflamed, leading to inefficient filtering and excreting by the kidneys. Protein and blood may be present in the urine and edema may develop throughout the body. Hypertension is generally present.
The disorder is rare because of the common use of antibiotics for infections that trigger this type of immune reaction. However post-streptococcal glomerulonephritis does still occur. It affects people of any age, but especially children 6-10 years old. The disorder develops 1-2 weeks after a throat infection and 3-4 weeks after a skin infection.
Rapidly progressive glomerulonephritis is another form of kidney disease that results from damage to the glomeruli and rapid loss of kidney function. Biopsy of the kidney(s) of a patient with this disorder shows crescent-shaped abnormalities in the glomeruli.
Rapidly progressive glomerulonephritis is a descriptive term and includes any type of glomerulonephritis in which progressive loss of kidney function occurs over weeks to months.
DDD can ONLY be diagnosed by a kidney biopsy. Tissue from the kidney is examined under an electron microscope to see if dense deposits are present. The kidney deposits stain for a specific complement protein called C3 using a technique called immunofluorescence microscopy.
There is currently no specific therapy for DDD, however a number of non-specific treatments are appropriate for DDD. 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 probably not effective in DDD. 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.
One anti-complement drug is now available. It is called Eculizumab and is a humanized monoclonal antibody against C5. A few very small studies have looked at the effect of Eculizumab in patients with DDD. It appears that Eculizumab may be effective in decreasing proteinuria and the rate of progression of kidney disease in some (about 30-40%) but NOT all patients with DDD. Those patients who do respond appear to carry elevated amounts of a protein complex called sMAC in their blood stream.
Persons with DDD who progress to end-stage renal disease must receive peritoneal dialysis or hemodialysis. Transplantation is another option however DDD will develop at the histologic level (on kidney biopsy) in virtually all transplanted kidneys, and about half of transplants will ultimately fail. There is some evidence that the likelihood of transplant failure due to recurrent DDD decreases with time.
To date, only one anti-complement drug is available for medical use (see above). Specific therapies for DDD need to be developed. One possible therapy may be a drug called CDX-1135. CDX-1135 is soluble CR1. A Phase 1 trial testing its efficacy in patients with DDD is on-going.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
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
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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Sethi S, Fervenza FC, Zhang Y, Zand L, Meyer NC, Borsa N, Nasr SH, Smith RJH. Atypical post-infectious glomerulonephritis is associated with abnormalities in the alternative pathway of complement. Kidney Inter 2012 Dec 12 [Epub ahead of print].
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Kurtz KA, Schleuter AJ. Management of membranoproliferative glomerulonephritis type II with plasmapheresis. J Clin Apheresis. 2002;17:135-37.
Kiyomasu T, Shibata M, Kurosu H, et al. Cyclosporin A treatment for membranoproliferative glomerulonephritis type II. Nephron. 2002;91:509-11.
Shimizu T, Tanabe K, Tokumoto T, et al. A case of rapid progressive glomerulonephritis with IgA deposits after renal transplantation. Clin Transplant. 2001;15 Suppl 5:11-15.
Schwertz R, Rother U, Anders D, et al. Complement analysis in children with idiopathic membranoproliferative glomerulonephritis: a long-term follow-up. Pediatr Allergy Immunol. 2001;12:166-72.
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FROM THE INTERNET
Corchado JC, Smith RJH. Dense Deposit Disease/Membranoproliferative Glomerulonephritis Type II Synonyms: DDD/MPGNII. Includes: CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II; CFHR5-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II. Last Update:May 19, 2011. Copyright, University of Washington, Seattle. 1997-2013. Available at www.genetests.org . Accessed:February 4, 2013.
Membranoproliferative Glomerulonephritis - Database Baseline Survey. https://mpgn.nursing.uiowa.edu/
Report last updated: 2013/02/07 00:00:00 GMT+0