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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

, PhD candidate and , MD.

Author Information
, PhD candidate
Molecular Otolaryngology and Renal Research Laboratories
University of Iowa
Iowa City, Iowa
, MD
Professor of Internal Medicine, Division of Nephrology
Sterba Hearing Research Professor of Otolaryngology
Director, Molecular Otolaryngology and Renal Research Laboratories
University of Iowa
Iowa City, Iowa

Initial Posting: ; Last Update: May 19, 2011.

Summary

Disease characteristics. Dense deposit disease (DDD)/membranoproliferative glomerulonephritis type II (MPGNII) is characterized by onset of hematuria and/or proteinuria, acute nephritic syndrome, or nephrotic syndrome. It most frequently affects children between ages five and 15 years. Spontaneous remissions are uncommon and about 50% of affected individuals develop end-stage renal disease (ESRD) within ten years of diagnosis. DDD/MPGNII can be associated with acquired partial lipodystrophy (APL). Drusen, whitish-yellow deposits within Bruch's membrane of the retina often develop in the second decade of life; they initially have little impact on vision, but cause vision problems from subretinal neovascular membranes, macular detachment, and central serous retinopathy in about 10% of affected individuals.

Diagnosis/testing. The definitive diagnosis of DDD/MPGNII requires electron microscopy and immunofluorescence studies of a renal biopsy. Sequence variants in the genes CFH, CFHR5, C3, and LMNA have been implicated in the pathogenesis of DDD/MPGNII, a complex genetic disease that is rarely inherited in a simple Mendelian fashion.

Management. Treatment of manifestations: Nonspecific therapies used in numerous chronic glomerular diseases are the mainstay; use of angiotensin-converting enzyme inhibitors, angiotensin II type-1 receptor blockers, and lipid-lowering agents (in particular hydroxymethylglutaryl coenzyme A reductase inhibitors) should be considered; renal allografts have a lower-than-average survival and an almost 100% risk of DDD/MPGNII recurrence.

Prevention of primary manifestations: In individuals with pathologic mutations in CFH, plasma replacement therapy can control complement activation and prevent ESRD.

Surveillance: Periodic eye examinations including funduscopic examination.

Evaluation of relatives at risk: If two CFH disease-causing mutations have been identified in an affected individual, sibs can be offered molecular genetic testing to identify those who have the same mutations in order to facilitate early diagnosis and management of renal disease.

Genetic counseling. DDD/MPGNII is a complex genetic disease that is rarely inherited in a simple Mendelian fashion. Multiple affected persons within a single nuclear family are only reported occasionally; in these instances, parental consanguinity is common. In persons with DDD/MPGNII in whom two pathologic mutations can be identified in CFH, inheritance is autosomal recessive. However, in most persons with DDD/MPGNII, two pathologic mutations cannot be identified and risks to family members are not known.

Diagnosis

Clinical Diagnosis

Dense deposit disease (DDD) (also known as membranoproliferative glomerulonephritis type II [MPGNII]) is a complex genetic disease caused by defective regulation of the alternative complement pathway in blood (as opposed to cell surface) that is rarely inherited in a simple Mendelian fashion.

DDD/MPGNII is typically diagnosed in children age five to 15 years who present with one of the following:

  • Hematuria
  • Proteinuria
  • Hematuria and proteinuria
  • Acute nephritic syndrome
  • Nephrotic syndrome

Testing

Renal biopsy. The definitive diagnosis of DDD/MPGNII requires electron microscopy and immunofluorescence studies of a renal biopsy [Walker et al 2007].

  • Light microscopy most commonly demonstrates mild mesangial cell hypercellularity (45% of cases), although membranoproliferative (25%), crescentric (18%), and acute proliferative and exudative (12%) patterns are also seen.
  • Electron microscopy should demonstrate dense transformation of the glomerular basement membrane (GBM) that occurs in a segmental, discontinuous, or diffuse pattern in the lamina densa. The precise composition of these altered areas remains unknown.
  • Immunofluorescence should be positive for C3, usually in the absence of immunoglobulin deposition.

Serum C3 nephritic factor (C3NeF). Most persons with DDD/MPGNII have detectable serum levels of C3NeF. C3NeF is an autoantibody that recognizes neoantigenic epitopes on C3bBb, the C3 convertase of the alternative pathway (AP) of the complement cascade [Schwertz et al 2001]. C3 convertases cleave C3 into C3b and C3a. In the presence of C3NeF the half-life of C3 convertase is increased, and as a consequence, serum concentrations of C3 are low and serum concentrations of C3 breakdown products such as C3d are elevated.

Note: (1) Serum concentrations of C3NeF can vary over time and C3NeF may be detected in the serum of persons without renal disease [Appel et al 2005]. (2) C3NeF is also present in up to 50% of individuals with MPGNI and MPGNIII (see Differential Diagnosis).

Factor H autoantibodies have been reported in the serum of one woman who developed a renal disease consistent with DDD/MPGNII and MPGN type I [Jokiranta et al 1999]. One individual with DDD and a diagnosis of monoclonal gammopathy of undetermined significance (MGUS) had low levels of factor H autoantibodies [Sethi et al 2010].

Factor B auto-antibodies (FBAA) were identified in a person with DDD without serum C3NeF. FBAA bind to and stabilize C3 convertase, enhancing the consumption of C3. C5 convertase formation from C3 convertase is prevented, thus interfering with activation of the terminal complement cascade (TCC) [Strobel et al 2010].

Complement activity. Hemolytic assays using sheep erythrocytes are used to measure the activity of the alternative pathway (AP) of complement [Joiner et al 1983]. In DDD serum complement-mediated lysis of sheep erythrocytes is observed.

Molecular Genetic Testing

Genes

Other possible genes. Mutation of C3 and LMNA has been reported in one family each. To more completely define the genetics of DDD/MPGNII, molecular genetic testing of multiple complement genes is currently under investigation on a research basis.

  • LMNA. Owen et al [2004] reported one individual with a mutation in LMNA who had both familial partial lipodystrophy type 2 (characterized by fat loss from the face and upper body) and DDD/MPGNII.
  • C3. A heterozygous mutation in C3 (the gene encoding complement component 3) resulting in a ΔDG923 protein (a C3 protein that cannot be cleaved by C3 convertase) was reported in one familial case of DDD/MPGNII [Martinez-Barricarte et al 2010].

Table 1. Summary of Molecular Genetic Testing Used in DDD/MPGNII

Gene SymbolProportion of Inherited DDD/MGNPII Attributed to Pathologic Mutations in This GeneTest MethodMutations Detected
CFH ~10% 1Sequence analysis Sequence variants 2
CFHR5 Unknown 3Sequence analysisNone reported 3

1. About 10% of persons with DDD/MPGNII have variants that are likely pathologic; these are detected by sequence analysis of CFH [Licht et al 2006, Zipfel et al 2006, Abrera-Abeleda et al 2011]. 85% of persons with DDD/MPGNII have at least one copy of the His402 variant of CFH [Abrera-Abeleda et al 2006]. (See Molecular Genetics.)

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. Pathologic mutations have not yet been reported in CFHR5. However, 7% of persons with DDD/MPGNII have at least one copy of the p.Pro46Ser (see Molecular Genetics, CFHR5) variant of CFHR5 [Abrera-Abeleda et al 2006].

Testing Strategy

To confirm/establish the diagnosis in a proband

  • The diagnosis of DDD/MPGNII must be made by renal biopsy, using electron microscopy to demonstrate dense deposits in the GBM.
    • As a histologically defined disease, DDD/MPGNII lacks unequivocal diagnostic serologic markers of disease activity, although nearly 90% of individuals have C3NeF detectable in serum. (A subgroup of individuals with MPGNI also have C3NeF detectable in serum.)
    • In addition, nearly 80% of individuals with DDD/MPGNII have evidence of activation of the alternative pathway of complement as reflected in the serum by low concentrations of C3 and high concentrations of C3 degradation products, including C3d [Appel et al 2005].
  • In persons with a histologic diagnosis of DDD/MPGNII, molecular genetic testing of CFH to detect pathologic mutations is appropriate, because identification of such a mutation helps to direct treatment. Most treatments for DDD/MPGNII are ineffective, but in individuals with pathologic mutations in CFH, plasma replacement therapy to replace factor H can control complement activation and prevent end-stage renal disease (ESRD) [Licht et al 2006].
  • At this time, the presence of the His402 variant of CFH (see Molecular Genetics, CFH) or of the p.Pro46Ser normal variant in CFHR5 (see Molecular Genetics, CFHR5) cannot be used to direct therapy in individuals with DDD/MPGNII. However, molecular genetic testing of CFH may be useful (a) in determining whether there is a genetic basis for the diagnosis, and if so, (b) in directing genetic counseling as well as carrier and prenatal testing for at-risk family members.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Renal disease. Individuals with dense deposit disease/membranoproliferative glomerulonephritis type II (DDD/MPGNII) typically present with one of the five following findings:

  • Hematuria
  • Proteinuria
  • Hematuria and proteinuria
  • Acute nephritic syndrome
  • Nephrotic syndrome

DDD/MPGNII affects females slightly more frequently than males. The DDD Database, a registry that currently contains information on 56 individuals with DDD/MPGNII, reports a 3:2 female:male bias [Lu et al 2007].

Spontaneous remissions of DDD/MPGNII are uncommon [Habib et al 1975, Cameron et al 1983, Marks & Rees 2000]. Although the disease can remain stable for years despite persistent proteinuria, in some individuals rapid fluctuations in proteinuria occur, with episodes of acute renal deterioration in the absence of obvious triggering events.

About half of affected individuals develop ESRD within ten years of diagnosis [di Belgiojoso et al 1977, Droz et al 1982, Swainson et al 1983, McEnery 1990, Lu et al 2007], occasionally with the late comorbidity of impaired visual acuity [Colville et al 2003]. Consistent with these studies, the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) database reports that of the 119 children registered with DDD/MPGNII, 81 have progressed to ESRD [William Harmon, personal communication]. Progression to ESRD develops rapidly, usually within four years of diagnosis, and is the more likely outcome in individuals age ten years or younger than in older persons (p=0.006) [Smith et al 2007]. Girls may have a more aggressive disease course than boys (p=0.16).

Acquired partial lipodystrophy (APL). DDD/MPGNII can be associated with APL [Eisinger et al 1972]. In persons with APL the loss of subcutaneous fat in the upper half of the body usually precedes the onset of kidney disease by several years.

Misra et al [2004] reported that approximately 83% of individuals with APL have low serum concentrations of C3 and polyclonal C3NeF, and that about 20% develop DDD/MPGNII approximately eight years after the onset of lipodystrophy. Individuals who develop DDD/MPGNII have an earlier age of onset of lipodystrophy (12.6 ± 10.3 yrs vs. 7.7 ± 4.4 yrs, respectively; p<0.001) and a higher prevalence of C3 hypocomplementemia (78% vs. 95%, respectively; p=0.02), suggesting that the disease is more virulent in these individuals [Misra et al 2004].

Owen et al [2004] described DDD/MPGNII in a person with Dunnigan-Kobberling syndrome, a form of partial lipodystrophy characterized by sparing of the face.

The association between partial lipodystrophy and DDD/MPGNII appears to be related to the effects of dysregulation of the AP of complement on both kidneys and adipose tissue [Mathieson & Peters 1997]. The deposition of activated components of complement in adipose tissue results in the destruction of adipocytes in areas in which factor D (fD, adipsin) is high.

Eye findings. Individuals with DDD/MPGNII develop drusen, often in the second decade of life. These whitish-yellow deposits lie within Bruch's membrane beneath the retinal pigment epithelium (RPE) of the retina. The distribution of drusen in individuals with DDD/MPGNII is variable [Duvall-Young et al 1989, Colville et al 2003, Holz et al 2004] and initially has little impact on visual acuity or visual fields.

Over time, however, tests of retinal function such as dark adaptation, electroretinography, and electro-oculography can become abnormal, and vision can deteriorate as subretinal neovascular membranes, macular detachment, and central serous retinopathy develop [Colville et al 2003]. The long-term risk of visual problems in individuals with DDD/MPGNII is approximately 10%.

Drusen are deposits similar in composition and structure to the deposits observed in the kidney [D’Souza et al 2009], reflecting similarities between the choriocapillaris-Bruch's membrane-retinal pigment epithelial interface and the capillary tuft-GBM-glomerular epithelial interface.

No correlation exists between disease severity in the kidney and the eye.

Autoimmune diseases. Other autoimmune diseases including diabetes mellitus type 1 and celiac disease have been observed in families with DDD/MPGNII [Sacks et al 1987, Ludvigsson et al 2006].

Pathophysiology. Fluid-phase dysregulation of the AP of the complement cascade is the triggering pathophysiologic event in DDD/MPGNII, and dysregulation of the C3 convertase alone is necessary and sufficient to result in DDD/MPGNII [Martinez-Barricarte et al 2010]. However, during disease progression, activation of downstream complement proteins in the solid phase, in particular cleavage of C5 to C5a and C5b, can contribute to tissue injury [Appel et al 2005, Smith et al 2007].

C3NeF persists in serum throughout the disease course [Schwertz et al 2001]. Its presence is nearly always associated with evidence of complement activation such as reduction in serum concentration of CH50, decrease in serum concentration of C3, and increase in serum concentration of C3 degradation products such as C3d. However, the relationship between C3NeF, C3, and prognosis is not clear. Some investigators have reported no correlation between C3 serum concentrations and clinical course [Eisinger et al 1972, di Belgiojoso et al 1977, Davis et al 1978, Bennett et al 1989], while others found that persistent hypocomplementemia indicates a poor prognosis [Klein et al 1983, Kashtan et al 1990].

The observed differences may be reconciled by noting that not all C3NeFs are the same, the methods for detecting the presence of C3NeFs vary, and many studies do not report titers. There is good evidence that the triggering epitopes can differ and even change over time.

  • Ohi et al [1992] provided evidence that triggering epitopes can differ. Their report of six individuals with detectable serum concentration of C3NeF in the absence of hypocomplementemia showed that in these individuals serum C3NeF did not interfere with factor H (fH)-induced inactivation of C3bBb.
  • Spitzer & Stitzel [1996] documented that triggering epitopes can change over time. Serum concentration of C3 in three affected persons eventually normalized despite continued C3NeF production. C3NeF isolated from these individuals and added to normal sera mediated consumption of C3, as did the addition of normal factor B (fB) to their sera, consistent with a change in the fB autoantigen in these individuals.

Genotype-Phenotype Correlations

To date, no correlations have been reported for the DDD/MPGNII phenotype as a function of genotype. Too few cases have had pathogenic mutations of CFH to explore phenotype-genotype relationships. It is also possible that pathogenic heterogeneity exists with a final common pathway.

Nomenclature

The designation 'dense deposit disease' (DDD)/MPGNII refers to the electron-dense transformation of the glomerular basement membrane.

Dense deposit disease is a more accurate name than membranoproliferative glomerulonephritis type II (MPGNII) because (1) only a minority of persons with DDD has a membranoproliferative pattern of histology; and (2) MPGNII implies a relationship to MPGNI and MPGNIII, which is not correct [Smith et al 2007, Walker et al 2007, Pickering & Cook 2008].

Prevalence

The prevalence of DDD/MPGNII is estimated to be 2-3:1,000,000 population.

Epidemiologic data from the past 30 years indicate that the incidence of the membranoproliferative glomerulonephritides, in general, is declining in developed countries [Jungers 1982, Simon 1984, Barbiano di Belgiojoso et al 1985, Jungers 1985, Gonzalo et al 1986, Simon et al 1987, Study Group of the Spanish Society of Nephrology 1989, Study Group of the Spanish Society of Nephrology 1990, Simon et al 1994]; most, if not all, of this change can be attributed to a decrease in the incidence of MPGNI. The prevalence of DDD/MPGNII appears to be stable.

Differential Diagnosis

The membranoproliferative glomerulonephritides are diseases of diverse and often obscure etiology and pathogenetic mechanisms; they account for approximately 4% and 7% of primary renal causes of nephrotic syndrome in children and adults, respectively [Orth & Ritz 1998].

Based on immunopathology and ultrastructure analysis of the kidney, and of the glomerulus in particular, three subtypes of membranoproliferative glomerulonephritides are recognized.

  • Membranoproliferative glomerulonephritis types I and III (MPGNI, MPGNIII) are variants of immune complex-mediated disease. MPGNI is characterized by the presence of subendothelial deposits and MPGNIII by the concomitant presence of subendothelial and subepithelial deposits, suggesting that MPGNIII is possibly a morphologic variant of MPGNI, given their clinical, immunologic, and immunohistologic similarities [Ferrario & Rastaldi 2004]. Of note, however, treatment outcomes following alternate-day prednisone therapy are better for those with MPGNI than for those with MPGNIII [Braun et al 1999].
  • DDD/MPGNII has no known association with immune complexes. In DDD/MPGNII, pathognomonic dense intramembranous deposits cause capillary wall thickening. Although the list of diseases associated with an MPGN-like pattern and capillary wall thickening is constantly growing, the differences in histology and immunology are sufficient to consider DDD/MPGNII an entity separate and discrete from either MPGNI or III. DDD/MPGNII accounts for fewer than 20% of children with MPGN and fewer than 1% of adults with MPGN [Habib et al 1975].

Other types of glomerulonephritis with deposition of C3 are:

  • Glomerulonephritis C3 (GN-C3), characterized by the presence of isolated mesangial C3 deposits. The main difference between DDD/MPGNII and GN-C3 is the absence of intramembranous deposits within the GBM in the latter [Servais et al 2007]. Based on renal biopsy findings, GN-C3 can be divided in two types: GN-C3 with MPGN (mesangial proliferation and subendothelial C3 deposits); and GN-C3 without MPGN (no mesangial proliferation and subendothelial C3 deposits) [Servais et al 2007].
  • CFHR5 nephropathy, a nephropathy found in Cypriots characterized by isolated microscopic hematuria that can rapidly progress to renal failure and macroscopic hematuria following an upper respiratory tract infection. Inheritance is autosomal dominant. The cause is partial duplication of CFHR5 (CFHR512123 9) that generates a hybrid protein with two additional short consensus repeats (SCRs). The hybrid CFHR5 protein binds weakly to complement deposited in the glomerulus [Gale et al 2010]. (See Genetically Related Disorders.)

Other diseases to consider in the differential diagnosis of the renal manifestations of DDD/MPGNII:

  • Juvenile acute non-proliferative glomerulonephritis (JANG), a disease exclusively of the young (no affected individual exceeded age 12 years in the report by West et al [2000]). JANG is characterized by rapid crescent formation but no mesangial cell proliferation. Large subepithelial deposits that contain C3 and C5 but no IgG develop on the paramesangial portion of the GBM. JANG can be distinguished from DDD/MPGNII on clinical grounds as the latter is typically associated with C3NeF-induced hypocomplementemia, often with nephrotic syndrome and hypertension, while in JANG, serum concentrations of C3 remain at the lower limits of normal [West et al 2000].
  • Familial lecithin-cholesterol acyltransferase (LCAT) deficiency, an autosomal recessive disorder characterized by corneal opacities, normochromic normocytic anemia, and renal dysfunction that can progress to ESRD. High serum concentrations of an abnormal lipoprotein (lipoprotein X) cause glomerular capillary endothelial damage and glomerular deposition of membrane-like, cross-striated structures and vacuole structures. One individual with LCAT deficiency showed glomerular histologic lesions and an immunofluorescent glomerular pattern typical of DDD/MPGNII [Sessa et al 2001].
  • Partial lipodystrophy (PLD) can be associated with DDD/MPGNII [Eisinger et al 1972]. In persons with PLD, the loss of subcutaneous fat in the upper half of the body usually precedes the onset of kidney disease by several years. The relationship between the two diseases reflects the effects of dysregulation of the AP of the complement cascade on kidney and adipose tissue [Mathieson & Peters 1997]. The deposition of activated components of complement in adipose tissue results in the destruction of adipocytes in areas high in content of factor D (fD, adipsin).

The retinal abnormalities of DDD/MPGNII are similar to those seen in the following:

  • Age-related macular degeneration (AMD), the most common cause of visual loss in the US in persons over age 50 years. AMD is characterized by the development of whitish-yellow deposits within Bruch's membrane beneath the RPE. In DDD/MPGNII, drusen develop at an early age and are often detectable in the second decade of life. Both AMD and DDD/MPGNII are associated with common 'at-risk' alleles of CFH [Hageman et al 2005].
  • Malattia leventinese and Doyne honeycomb retinal dystrophy, two autosomal dominant disorders in which drusen accumulate beneath the RPE. The two disorders are phenotypically similar to AMD [Stone et al 1999].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

After the diagnosis of dense deposit disease/membranoproliferative glomerulonephritis type II (DDD/MPGNII) has been made, the following evaluations are recommended:

  • Evaluate the complement system by measuring serum concentration of CH50, APH50, C3, C3d, C4, factor H and sMAC. (For a list of laboratories providing these tests, contact Richard Smith. See Author Notes.)
    • Complement protein measures in DDD/MPGNII are distinctive, with most patients having only low serum concentrations of C3, while serum concentrations of properdin, C5, and other terminal proteins are within the normal range.
    • Factor H serum concentrations can be low, as has been reported with missense mutations in the CFH coding sequence that block protein secretion from the endoplasmic reticulum [Ault et al 1997, Dragon-Durey et al 2004].
  • Measure autoantibodies including C3NeF, Factor H autoantibodies (FHAA) and Factor B autoantibodies (FBAA).
  • Screen CFH for mutations using bidirectional sequencing.
  • Establish the extent of renal disease by measuring serum creatinine concentration, and monitor creatinine clearance, proteinuria and hematuria.
  • Obtain a baseline ophthalmologic examination [McAvoy et al 2004].

Treatment of Manifestations

Nonspecific therapies have been shown to be effective in numerous chronic glomerular diseases and should be initiated. The judicious use of these agents, along with optimal blood pressure control, may be of benefit in individuals with DDD/MPGNII.

  • Angiotensin-converting enzyme inhibitors and angiotensin II type-1 receptor blockers decrease proteinuria in many glomerular diseases and slow the progression to renal failure [Ruggenenti et al 1999, Brenner et al 2001]. A retrospective study found that the combination of angiotensin blockers and immunosuppressants (steroids) is more effective than each therapy alone in preventing the development of renal failure [Nasr et al 2009].
  • Lipid-lowering agents, and in particular hydroxymethylglutaryl coenzyme A reductase inhibitors, may delay progression of renal disease as well as correct endothelial cell dysfunction and alter long-term atherosclerotic risks in the presence of hyperlipidemia [Nickolas et al 2003, Maisch & Pezzillo 2004]. These agents are not widely used in children.

Renal allografts. Fewer than 200 individuals with DDD/MPGNII have undergone transplantation [Braun et al 2005]. Five-year allograft survival approximates 50%, which is significantly worse than for the NAPRTCS database as a whole (p=0.001). Living-related donor grafts fare better than deceased donor grafts (p<0.005). Allograft survival appears to be age-dependent in DDD; the survival of pediatric DDD transplant recipients is significantly worse than the rest of the pediatric transplant population [Angelo et al 2011].

DDD/MPGNII recurs in nearly all grafts and is the predominant cause of graft failure in 15%-50% of transplant recipients [Appel et al 2005, Angelo et al 2011]. There are little data to suggest that any therapeutic interventions have an effect on reversing this course, although isolated reports have described the use of plasmapheresis, which appears to be of equivocal benefit [Fremeaux-Bacchi et al 1994, Kurtz & Schlueter 2002].

Prevention of Primary Manifestations

Although most treatment for DDD/MPGNII is ineffective, plasma replacement therapy in patients with pathologic mutations in CFH can control complement activation and prevent ESRD [Licht et al 2006].

Surveillance

Periodic funduscopic assessment is appropriate [McAvoy et al 2004].

Evaluation of Relatives at Risk

If disease-causing mutations in CFH have been identified in an affected individual, sibs can be offered molecular genetic testing to identify those who have the same mutation(s) in order to facilitate early diagnosis and management of renal disease. Penetrance rates, however, are not known.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

A clinical study using eculizumab in persons with DDD/MPGN2 or C3 glomerulonephritis who are age 18 years and older is ongoing but is not recruiting new patients (ClinicalTrials.gov).

A clinical study using sulodexide in persons with DDD/MPGNII who are under age 21 years was put on inactive status as no beneficial effect was noted in patients with diabetic nephropathy (ClinicalTrials.gov).

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

The impact of genotype on graft survival has not yet been explored.

Experience with intravenous immunoglobulin (IVIg) and B cell suppression is limited.

The following treatment modalities are of unproven value:

Plasmapheresis to remove or suppress serum C3NeF activity:

  • In one study, one of three adults with DDD/MPGNII experienced improvement in serum creatinine during plasmapheresis [McGinley et al 1985].
  • Another study reported success using plasmapheresis to treat a five-year-old boy with recurrent DDD/MPGNII after transplantation. Twelve phereses were performed over 24 days, and the child continued to have improved renal function one year later [Oberkircher et al 1988].
  • In another report, a 15-year-old girl with rapidly progressive recurrent DDD/MPGNII in her allograft underwent 73 phereses over 63 weeks, stabilizing her creatinine and improving her creatinine clearance. Serial biopsies during this time demonstrated persistent DDD/MPGNII without development of tubular atrophy. During the course of therapy, serum C3NeF activity decreased and C3NeF activity was detected in the removed plasma. Because of the morbidity associated with repeated phereses, treatment was discontinued and graft failure ensued [Kurtz & Schlueter 2002].
  • In another report, two patients with a pathologic mutation in CFH were successfully treated with fresh frozen plasma [Licht et al 2006].

Prednisone. Although long-term controlled studies of prednisone therapy have suggested a possible benefit as measured by a decrease in proteinuria and prolonged renal survival in children with MPGN type I-III [West 1986, McEnery 1990], a randomized placebo-controlled study found that while evidence showed an overall benefit in individuals with MPGNI, II, and III combined, children with DDD/MPGNII had no better response to prednisone than to lactose, with treatment failure defined as a creatinine greater than 350 mmol/L (4 mg/dL) in 55.6% (5/9) and 60% (3/5) of individuals, respectively [Tarshish et al 1992].

Available data on steroid therapy in adults with DDD/MPGNII suggest a similar lack of efficacy [Donadio & Offord 1989].

Note: The use of steroid therapy is extremely effective in JANG, which can be confused with DDD/MPGNII. The two diseases can be distinguished clinically, as DDD/MPGNII is typically associated with C3NeF-induced hypocomplementemia, often with nephrotic syndrome and hypertension, while in JANG, C3 levels remain at the lower limit of normal [West et al 2000].

Calcineurin inhibitors. When evaluated in small numbers of individuals, the calcineurin inhibitors do not improve renal survival in DDD/MPGNII. Furthermore, in vitro studies with two calcineurin inhibitors, cyclosporin and tacrolimus, have shown that at therapeutic concentrations neither drug suppresses C3 transcription [Sacks & Zhou 2003]. Given the evidence that uncontrolled activation of the AP of the complement cascade is the basis of MPGNII/DDD, it is not surprising that these drugs are clinically ineffective immunomodulatory treatment modalities.

Combined therapy with immunosuppression (IS) and renin aingotensin system (RAS) blockade. In a retrospective study, the combined use of IS (steroids) and RAS blockade (angiotensin-converting enzyme inhibitor and/or angiotensin II receptor blocker) was protective against developing end-stage renal disease (ESRD). The IS/RAS blockade therapy was superior to the use of either agent alone. These findings need to be confirmed by a prospective control study [Nasr et al 2009].

Bevacizumab. In one study, a 29-year-old woman with DDD/MPGNII and subretinal neovascular membranes was treated with monthly intravitreal injections of bevacizumab. An improvement in vision was noted; renal function remained unaltered [Farah et al 2009].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Dense deposit disease/membranoproliferative glomerulonephritis type II (DDD/MPGNII) is a complex genetic disorder that is rarely inherited in a simple Mendelian fashion. In most persons with DDD/MPGNII, the inheritance is complex and incompletely understood. For these reasons, recurrence risk to family members is not known but likely very low.

  • Multiple affected persons within a single nuclear family are only reported occasionally; in these instances, parental consanguinity is common [Licht et al 2006].
  • In persons with DDD/MPGNII in whom two pathologic mutations can be identified in CFH inheritance is autosomal recessive.

Risk to Family Members — Autosomal Recessive DDD/MPGNII

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with DDD/MPGNII are obligate heterozygotes (carriers) for a disease-causing mutation in CFH.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible if two CFH mutations have been identified in an affected family member.

Risk to Family Members — Other Etiologies

Parents, sibs, and offspring of a proband. The risk to the family members of a proband who does not have CFH mutations, the CFHR5 common variant, or a family history consistent with autosomal recessive or dominant inheritance is low.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

DDD/MPGNII can be seen in families in which other members have other complex autoimmune diseases, such as diabetes mellitus type 1 and celiac disease [Smith et al 2007].

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutations have been identified in an affected family member, prenatal testing for at-risk pregnancies is possible through laboratories offering either prenatal testing for the gene of interest or custom testing.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Kidneeds
    Dedicated to the study of Dense Deposit Disease
    IA
    Email: kidneedsMPGN@yahoo.com
  • Kidney Foundation of Canada
    1599 Hurontario Street
    Suite 201
    Mississauga Ontario L5G 4S1
    Canada
    Phone: 800-387-4474 (toll-free); 905-278-3003
    Fax: 905-271-4990
    Email: kidney@kidney.on.ca
  • Medline Plus
  • National Kidney Foundation (NKF)
    30 East 33rd Street
    New York NY 10016
    Phone: 800-622-9010 (toll-free); 212-889-2210
    Fax: 212-689-9261
    Email: info@kidney.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II (View All in OMIM)

134370COMPLEMENT FACTOR H; CFH
608593COMPLEMENT FACTOR H-RELATED 5; CFHR5
609814COMPLEMENT FACTOR H DEFICIENCY; CFHD

CFH

Normal allelic variants. CFH comprises 23 exons that encode complement factor H, a protein of 1234 amino acids. Of the several alleles of CFH, the one that encodes a His at residue 402 is of particular interest because of the association of this amino acid substitution with DDD/MPGNII and AMD [Hageman et al 2005, Abrera-Abeleda et al 2006]. The c.1204T>C (p.Tyr402His) normal allelic variant is in SCR(short consensus repeat)7, one of at least three glycosaminoglycan (GAG) recognition sites in factor H. SCR7 participates in binding to C-reactive protein (CRP) and to a number of pathogens that sequester factor H as protection from complement-mediated destruction. Structural studies have shown that p.Tyr402His lies toward the center of SCR7, away from its boundaries with SCR8 and SCR9. The 3D structures of both the His402 and Tyr402 protein variants are otherwise identical [Herbert et al 2007]. In spite of this similarity, binding studies indicate that the p.Tyr402His change alters the specific types of GAGs that are recognized by SCR7. For example, binding to both human umbilical vein endothelial cells and to C-reactive protein is reduced for the His402 protein variant as compared to the Tyr402 protein variant [Laine et al 2007, Skerka et al 2007].

Pathologic allelic variants. CFH has been implicated in DDD/MPGNII by the following:

  • A report of two sisters with DDD/MPGNII who were homozygous for the c.670_672delAAG (p.Lys224del) mutation of CFH [Licht et al 2006, Zipfel et al 2006]. As a result of this amino acid deletion in factor H, the N-terminal activities of the mutant protein (C3b binding and complement regulation) were defective, indicating that dysfunctional factor H protein is associated with the development of DDD/MPGNII [Licht et al 2006].
  • Studies of skin fibroblasts from a factor H-deficient child with chronic hypocomplementemic renal disease. Normal amounts of 4.3- and 1.8-kb messages were observed, but secretion of the 155-kd protein was blocked; the 45-kd protein was secreted with normal kinetics. Consistent with this finding, the affected individual's plasma lacked the 155-kd factor H protein but contained the smaller factor H-like 1 protein. The 155-kd factor H protein was retained in the endoplasmic reticulum and was not degraded even after 12 hours. Mutation screening of CFH revealed a c.1607G>A substitution on one allele and a 2949G>A substitution on the other, predicting a p.Cys536Arg change in short consensus repeat SCR9 and a p.Cys959Tyr change in SCR16, respectively. Both mutations affect conserved cysteine residues characteristic of the SCR modules of factor H and therefore predict profound changes in the higher-order structure of the 155-kd protein [Ault et al 1997].
  • Mutation screening results in two brothers with MPGN who were homozygous for a p.Arg127Leu amino acid change in CFH [Dragon-Durey et al 2004]

Table 2. Selected CFH Allelic Variants

Class of VariantDNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change
(Alias 1)
SCR (Domain) of the Factor H Protein 2Type of MutationReferenceReference Sequences
Normalc.1204C>Tp.His402Tyr 3SCR7NANM_000186​.3
NP_000177​.2
Pathologicc.380G>Tp.Arg127Leu 4SCR2Missense, homozygousDragon-Durey et al [2004] 5
c.670_672delAAGp.Lys224del 4
(ΔLys224)
SCR4Deletion, homozygousLicht et al [2006]
c.1606T>C
(1679T>C)
p.Cys536Arg 4
(Cys518Arg) 6
SCR9 MissenseAult et al [1997]
c.2876G>A
(2949G>A)
p.Cys959Tyr 3
(Cys991Tyr)
SCR16Missense

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. SCR = short consensus repeat

3. Although considered a normal allelic variant, the functional properties differ between proteins with the His402 and the Tyr402 amino acid residues.

4. Signal peptide included

5. This paper includes additional CFH mutations associated with other types of MPGN.

6. Signal peptide not included

Normal gene product. The normal gene product encoded by CFH is complement factor H, a plasma glycoprotein (155 kd) present in blood at concentrations ranging from approximately 500 to 800 µg/mL. It is organized in repetitive elements termed short consensus repeats (SCRs) and controls the alternative pathway (AP) of complement activation, both in fluid phase and on cellular surfaces by binding to three sites on C3b destabilizing C3bBb. In the fluid phase, this interaction results in dissociation of C3bBb into inactive fBb (ifBb) and C3bfH, which is irreversibly inactivated into iC3b by factor I [Pangburn & Muller-Eberhard 1986]. On cellular surfaces, the inactivation of bound C3b is dependent on the chemical composition of the surface to which C3b is bound [Rodriguez de Cordoba et al 2004].

Abnormal gene product. Homozygosity for the c.380G>T missense mutation is associated with absence of factor H in the serum, suggesting that this mutation results in sequestration of the protein in the endoplasmic reticulum. In contrast, the factor H with the mutation p.Lys224del is present in the serum at normal concentrations but is non-functional [Zipfel et al 2006].

CFHR5

Normal allelic variants. CFHR5 comprises ten exons that encode complement factor H related 5 (CFHR5), a protein of 551 amino acids organized into nine SCRs. Several allelic variants have been reported in the normal population, some of which are over-represented in persons with DDD/MPGNII and atypical hemolytic uremic syndrome [Abrera-Abeleda et al 2006, Monteferrante et al 2007]. One such example is the p.Pro46Ser variant (NM_030787.2:c.136C>T).

Pathologic allelic variants. No unequivocally disease-causing pathologic allelic variants have been reported in CFHR5 in association with DDD/MPGNII.

Normal gene product. The normal gene product encoded by CFHR5 is complement factor H-related protein 5 (CFHR5), a plasma protein organized like CFH in repetitive SCRs. CFHR5 has nine SCRs and is the only CFHR protein that is like CFH in its ability to inhibit C3 convertase in the fluid phase. CFHR5 also possesses complement factor I-dependent cofactor activity that leads to inactivation of C3b [McRae et al 2001, Rodriguez de Cordoba et al 2004, McRae et al 2005]. In 92 renal biopsies from patients with different glomerular diseases, CFHR5 was present in all complement-containing glomerular immune deposits [Murphy et al 2002], suggesting that CFHR5 plays an important role in protecting the glomerulus from complement activation. The role of CFHR5 in the physiopathology of DDD/MPGNII remains to be elucidated.

Abnormal gene product. No abnormal gene product of CFHR5 has been reported in association with DDD/MPGNII.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

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Chapter Notes

Author Notes

Contact Information

Richard JH Smith
Division of Nephrology
University of Iowa
200 Hawkins Drive
Iowa City, IA 52242
Telephone: 319-356-3612
Fax: 319-356-4108
E-mail: ude.awoiu@htims-drahcir

Author History

Johnny Cruz Corchado (2011-present)
Sanjeev Sethi, MD, PhD; Mayo Clinic (2007-2011)
Richard JH Smith, MD (2007-present)
Peter F Zipfel, PhD habil Prof; Hans Knöll Institute (2007-2011)

Revision History

  • 19 May 2011 (me) Comprehensive update posted live
  • 2 January 2008 (rjhs/cd) Revision: clinical testing (sequence analysis) for CFHR5 mutations
  • 20 July 2007 (me) Review posted to live Web site
  • 17 August 2005 (rjhs) Original submission
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