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.

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.

Genetically Related (Allelic) Disorders

CFH. Mutations in CFH cause atypical hemolytic uremic syndrome (aHUS), which is characterized by hemolytic anemia, thrombocytopenia, and renal failure. The thrombotic microangiopathy of aHUS damages endothelial cells and causes detachment of the basement membrane.

Although most typical HUS is caused by Gram-negative bacteria that produce shiga toxin (Shigella dysenteriae serotype 1; Escherichia coli serotypes O-157, O-111, O-26), atypical HUS is caused by loss-of-function or gain-of-function mutations in several genes encoding regulators (CFH, CFHR1, CFI, and MCP) or activators (C3, CFB), respectively, of the alternative pathway (AP) of complement [Goodship et al 2006, Zipfel et al 2006]. The result of these mutations is impaired protection of host surfaces against complement activation [Saunders et al 2007].

The most common mutated gene is CFH, which encodes CFH, an important regulator of the AP. CFH mutations are reported in 20%-30% of individuals with aHUS. Over 40% of the identified mutations are located in a portion of CFH that encodes SCRs 19 and 20 of the factor H protein [Saunders et al 2007]. These mutations, which affect only one allele and lead to haploinsufficiency, include:

• Mutations that lead to premature stop codons;
• Mutations that affect framework cysteine residues and prevent disulfide bond formation and the adoption of the appropriate conformational structure;
• Non-framework mutations that affect protein expression, result in a defective secreted protein, or severely impair capability to bind to endothelial cell surfaces.

The normal allelic variant c.1204T>C (p.Tyr402His) of Factor H affects the risk of age-related macular degeneration (AMD): the c.1204C (His402) variant significantly increases the risk of (AMD) [Haines et al 2005].

CFHR5. A complex rearrangement of CFHR5 producing a mutant protein in which the first two short consensus repeats (SCRs) are duplicated (CFHR5^12123 9) was found in 26 individuals from Cyprus with ‘CFHR5 nephropathy’, a C3 glomerulopathy similar to DDD/MPGNII that is common in Cyprus. (See also Differential Diagnosis.)

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.

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].

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.

Literature Cited

1. Abrera-Abeleda MA, Nishimura C, Frees K, Jones M, Maga T, Katz LM, Zhang Y, Smith RJH. Allele variants of complement genes associated with dense deposit disease. J Am Soc Nephrol. 2011;22:1551–9. [PMC free article: PMC3148710] [PubMed: 21784901]
2. Abrera-Abeleda MA, Nishimura C, Smith JL, Sethi S, McRae JL, Murphy BF, Silvestri G, Skerka C, Józsi M, Zipfel PF, Hageman GS, Smith RJ. Variations in the complement regulatory genes factor H (CFH) and factor H related 5 (CFHR5) are associated with membranoproliferative glomerulonephritis type II (dense deposit disease). J Med Genet. 2006;43:582–9. [PMC free article: PMC2564553] [PubMed: 16299065]
3. Angelo JR, Bell CS, Braun MC. Allograft failure in kidney transplant recipients with membranoproliferative glomerulonephritis. Am J Kidney Dis. 2011;57:291–9. [PubMed: 21215503]
4. Appel GB, Cook HT, Hageman G, Jennette JC, Kashgarian M, Kirschfink M, Lambris JD, Lanning L, Lutz HU, Meri S, Rose NR, Salant DJ, Sethi S, Smith RJ, Smoyer W, Tully HF, Tully SP, Walker P, Welsh M, Wurzner R, Zipfel PF. Membranoproliferative glomerulonephritis type II (dense deposit disease): an update. J Am Soc Nephrol. 2005;16:1392–403. [PubMed: 15800116]
5. Ault BH, Schmidt BZ, Fowler NL, Kashtan CE, Ahmed AE, Vogt BA, Colten HR. Human factor H deficiency. Mutations in framework cysteine residues and block in H protein secretion and intracellular catabolism. J Biol Chem. 1997;272:25168–75. [PubMed: 9312129]
6. Barbiano di Belgiojoso G, Baroni M, Pagliari B, Lavagni MG, Porri MT, Banfi G, Colasanti G, Confalonieri R. Is membranoproliferative glomerulonephritis really decreasing? A multicentre study of 1,548 cases of primary glomerulonephritis. Nephron. 1985;40:380–1. [PubMed: 4010856]
7. Bennett WM, Fassett RG, Walker RG, Fairley KF, d'Apice AJ, Kincaid-Smith P. Mesangiocapillary glomerulonephritis type II (dense-deposit disease): clinical features of progressive disease. Am J Kidney Dis. 1989;13:469–76. [PubMed: 2658560]
8. Braun MC, Stablein DM, Hamiwka LA, Bell L, Bartosh SM, Strife CF. Recurrence of membranoproliferative glomerulonephritis type II in renal allografts: The North American Pediatric Renal Transplant Cooperative Study experience. J Am Soc Nephrol. 2005;16:2225–33. [PubMed: 15888559]
9. Braun MC, West CD, Strife CF. Differences between membranoproliferative glomerulonephritis types I and III in long-term response to an alternate-day prednisone regimen. Am J Kidney Dis. 1999;34:1022–32. [PubMed: 10585311]
10. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861–9. [PubMed: 11565518]
11. Cameron JS, Turner DR, Heaton J, Williams DG, Ogg CS, Chantler C, Haycock GB, Hicks J. Idiopathic mesangiocapillary glomerulonephritis. Comparison of types I and II in children and adults and long-term prognosis. Am J Med. 1983;74:175–92. [PubMed: 6337487]
12. Colville D, Guymer R, Sinclair RA, Savige J. Visual impairment caused by retinal abnormalities in mesangiocapillary (membranoproliferative) glomerulonephritis type II ("dense deposit disease"). Am J Kidney Dis. 2003;42:E2–5. [PubMed: 12900843]
13. Davis AE, Schneeberger EE, Grupe WE, McCluskey RT. Membranoproliferative glomerulonephritis (MPGN type I) and dense deposit disease (DDD) in children. Clin Nephrol. 1978;9:184–93. [PubMed: 657595]
14. di Belgiojoso B, Tarantino A, Colasanti G, Bazzi C, Guerra L, Durante A. The prognostic value of some clinical and histological parameters in membranoproliferative glomerulonephritis (MPGN): report of 112 cases. Nephron. 1977;19:250–8. [PubMed: 917174]
15. Donadio JV Jr, Offord KP. Reassessment of treatment results in membranoproliferative glomerulonephritis, with emphasis on life-table analysis. Am J Kidney Dis. 1989;14:445–51. [PubMed: 2596471]
16. Dragon-Durey MA, Fremeaux-Bacchi V, Loirat C, Blouin J, Niaudet P, Deschenes G, Coppo P, Herman Fridman W, Weiss L. Heterozygous and homozygous factor h deficiencies associated with hemolytic uremic syndrome or membranoproliferative glomerulonephritis: report and genetic analysis of 16 cases. J Am Soc Nephrol. 2004;15:787–95. [PubMed: 14978182]
17. Droz D, Noel LH, Barbanel C, Grünfeld JP. Long-term evolution of membranoproliferative glomerulonephritis in adults : spontaneous clinical remission in 13 cases with proven regression of glomerular lesions in 5 cases (author's transl). Nephrologie. 1982;3:6–11. [PubMed: 7088263]
18. D'Souza YB, Jones CJ, Short CD, Roberts IS, Bonshek RE. Oligosaccharide composition is similar in drusen and dense deposits in membranoproliferative glomerulonephritis type II. Kidney Int. 2009;75:824–7. [PubMed: 19177159]
19. Duvall-Young J, Short CD, Raines MF, Gokal R, Lawler W. Fundus changes in mesangiocapillary glomerulonephritis type II: clinical and fluorescein angiographic findings. Br J Ophthalmol. 1989;73:900–6. [PMC free article: PMC1041923] [PubMed: 2605144]
20. Eisinger AJ, Shortland JR, Moorhead PJ. Renal disease in partial lipodystrophy. Q J Med. 1972;41:343–54. [PubMed: 4561162]
21. Farah SE, Fazelat A, Frei G. Treatment of subretinal neovascular membrane in a patient with membranoproliferative glomerulonephritis type II. Ophthalmic Surg Lasers Imaging. 2009;40:416–8. [PubMed: 19634750]
22. Ferrario F, Rastaldi MP. Histopathological atlas of renal diseases. Membranoproliferative glomerulonephritis. J Nephrol. 2004;17:483–6. [PubMed: 15372408]
23. Fremeaux-Bacchi V, Weiss L, Brun P, Kazatchkine MD. Selective disappearance of C3NeF IgG autoantibody in the plasma of a patient with membranoproliferative glomerulonephritis following renal transplantation. Nephrol Dial Transplant. 1994;9:811–4. [PubMed: 7970124]
24. Gale DP, de Jorge EG, Cook HT, Martinez-Barricarte R, Hadjisavvas A, McLean AG, Pusey CD, Pierides A, Kyriacou K, Athanasiou Y, Voskarides K, Deltas C, Palmer A, Frémeaux-Bacchi V, de Cordoba SR, Maxwell PH, Pickering MC. Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis. Lancet. 2010;376:794–801. [PMC free article: PMC2935536] [PubMed: 20800271]
25. Gonzalo A, Matesanz R, Teruel JL. Incidence of membranoproliferative glomerulonephritis in a Spanish population. Clinical Nephrology. 1986;26:161. [PubMed: 3769232]
26. Goodship THJ, Fremeaux-Bacchi V, Atkinson JP. Genetic testing in atypical HUS and the role of membrane cofactor protein (MCP; CD46) and factor I. In: Zipfel PF, ed. Complement and Kidney Disease. Berlin: Springer; 2006:111-27.
27. Habib R, Gubler MC, Loirat C, Maiz HB, Levy M. Dense deposit disease: a variant of membranoproliferative glomerulonephritis. Kidney Int. 1975;7:204–15. [PubMed: 1095806]
28. Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, Hardisty LI, Hageman JL, Stockman HA, Borchardt JD, Gehrs KM, Smith RJ, Silvestri G, Russell SR, Klaver CC, Barbazetto I, Chang S, Yannuzzi LA, Barile GR, Merriam JC, Smith RT, Olsh AK, Bergeron J, Zernant J, Merriam JE, Gold B, Dean M, Allikmets R. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A. 2005;102:7227–32. [PMC free article: PMC1088171] [PubMed: 15870199]
29. Haines JL, Hauser MA, Schmidt S, Scott WK, Olson LM, Gallins P, Spencer KL, Kwan SY, Noureddine M, Gilbert JR, Schnetz-Boutaud N, Agarwal A, Postel EA, Pericak-Vance MA. Complement factor H variant increases the risk of age-related macular degeneration. Science. 2005;308:419–21. [PubMed: 15761120]
30. Herbert AP, Deakin JA, Schmidt CQ, Blaum BS, Egan C, Ferreira VP, Pangburn MK, Lyon M, Uhrin D, Barlow PN. Structure Shows That a Glycosaminoglycan and Protein Recognition Site in Factor H Is Perturbed by Age-related Macular Degeneration-linked Single Nucleotide Polymorphism. J Biol Chem. 2007;282:18960–8. [PubMed: 17360715]
31. Holz FG, Pauleikhoff D, Klein R, Bird AC. Pathogenesis of lesions in late age-related macular disease. Am J Ophthalmol. 2004;137:504–10. [PubMed: 15013875]
32. Joiner KA, Hawiger A, Gelfand JA. A study of optimal reaction conditions for an assay of the human alternative complement pathway. Am J Clin Pathol. 1983;79:65–72. [PubMed: 6849295]
33. Jokiranta TS, Solomon A, Pangburn MK, Zipfel PF, Meri S. Nephritogenic lambda light chain dimer: a unique human miniautoantibody against complement factor H. J Immunol. 1999;163:4590–6. [PubMed: 10510403]
34. Jungers P. Is membranoproliferative glomerulonephritis disappearing in France? Kidney Int. 1982;21:899.
35. Jungers P. Rarefaction of membranoproliferative glomerulonephritis (MPGN) in France. Kidney Int. 1985;28:264.
36. Kashtan CE, Burke B, Burch G, Gustav Fisker S, Kim Y. Dense intramembranous deposit disease: a clinical comparison of histological subtypes. Clin Nephrol. 1990;33:1–6. [PubMed: 2302866]
37. Klein M, Poucell S, Arbus GS, McGraw M, Rance CP, Yoon SJ, Baumal R. Characteristics of a benign subtype of dense deposit disease: comparison with the progressive form of this disease. Clin Nephrol. 1983;20:163–71. [PubMed: 6556977]
38. Kurtz KA, Schlueter AJ. Management of membranoproliferative glomerulonephritis type II with plasmapheresis. J Clin Apher. 2002;17:135–7. [PubMed: 12378549]
39. Laine M, Jarva H, Seitsonen S, Haapasalo K, Lehtinen MJ, Lindeman N, Anderson DH, Johnson PT, Jarvela I, Jokiranta TS, Hageman GS, Immonen I, Meri S. Y402H polymorphism of complement factor H affects binding affinity to C-reactive protein. J Immunol. 2007;178:3831–6. [PubMed: 17339482]
40. Licht C, Heinen S, Jozsi M, Loschmann I, Saunders RE, Perkins SJ, Skerka C, Kirschfink M, Hoppe B, Zipfel PF. Deletion of Lys224 in regulatory domain 4 of factor H reveals a novel pathomechanism for dense deposit disease (MPGNII). Kidney Int. 2006;70:42–50. [PubMed: 16612335]
41. Lu DF, McCarthy AM, Lanning LD, Delaney C, Porter C. A descriptive study of individuals with membranoproliferative glomerulonephritis. J Nephrol Nurs. 2007;34:295–302. [PubMed: 17644874]
42. Ludvigsson JF, Montgomery SM, Olen O, Ekbom A, Ludvigsson J, Fored M. Coeliac disease and risk of renal disease-a general population cohort study. Nephrol Dial Transplant. 2006;21:1809–15. [PubMed: 16574681]
43. Maisch NM, Pezzillo KK. HMG-CoA reductase inhibitors for the prevention of nephropathy. Ann Pharmacother. 2004;38:342–5. [PubMed: 14742776]
44. Marks SD, Rees L. Spontaneous clinical improvement in dense deposit disease. Pediatr Nephrol. 2000;14:322–4. [PubMed: 10775078]
45. Martínez-Barricarte R, Heurich M, Valdes-Cañedo F, Vazquez-Martul E, Torreira E, Montes T, Tortajada A, Pinto S, Lopez-Trascasa M, Morgan BP, Llorca O, Harris CL, Rodríguez de Córdoba S. Human C3 mutation reveals a mechanism of dense deposit disease pathogenesis and provides insights into complement activation and regulation. J Clin Invest. 2010;120:3702–12. [PMC free article: PMC2947238] [PubMed: 20852386]
46. Mathieson PW, Peters DK. Lipodystrophy in MCGN type II: the clue to links between the adipocyte and the complement system. Nephrol Dial Transplant. 1997;12:1804–6. [PubMed: 9306323]
47. McAvoy CE, Best J, Sharkey JA. Extensive peripapillary exudation secondary to cat-scratch disease. Eye. 2004;18:331–2. [PubMed: 15004593]
48. McEnery PT. Membranoproliferative glomerulonephritis: the Cincinnati experience cumulative renal survival from 1957 to 1989. J Pediatr. 1990;116:S109–14. [PubMed: 2329412]
49. McGinley E, Watkins R, McLay A, Boulton-Jones JM. Plasma exchange in the treatment of mesangiocapillary glomerulonephritis. Nephron. 1985;40:385–90. [PubMed: 4022205]
50. McRae JL, Cowan PJ, Power DA, Mitchelhill KI, Kemp BE, Morgan BP, Murphy BF. Human factor H-related protein 5 (FHR-5). A new complement-associated protein. J Biol Chem. 2001;276:6747–54. [PubMed: 11058592]
51. McRae JL, Duthy TG, Griggs KM, Ormsby RJ, Cowan PJ, Cromer BA, McKinstry WJ, Parker MW, Murphy BF, Gordon DL. Human factor H-related protein 5 has cofactor activity, inhibits C3 convertase activity, binds heparin and C-reactive protein, and associates with lipoprotein. J Immunol. 2005;174:6250–6. [PubMed: 15879123]
52. Misra A, Peethambaram A, Garg A. Clinical features and metabolic and autoimmune derangements in acquired partial lipodystrophy: report of 35 cases and review of the literature. Medicine (Baltimore). 2004;83:18–34. [PubMed: 14747765]
53. Monteferrante G, Brioschi S, Caprioli J, Pianetti G, Bettinaglio P, Bresin E, Remuzzi G, Noris M. Genetic analysis of the complement factor H related 5 gene in haemolytic uraemic syndrome. Mol Immunol. 2007;44:1704–8. [PubMed: 17000000]
54. Murphy B, Georgiou T, Machet D, Hill P, McRae J. Factor H-related protein-5: a novel component of human glomerular immune deposits. Am J Kidney Dis. 2002;39:24–7. [PubMed: 11774097]
55. Nasr SH, Valeri AM, Appel GB, Sherwinter J, Stokes MB, Said SM, Markowitz GS, D'Agati VD. Dense deposit disease: clinicopathologic study of 32 pediatric and adult patients. Clin J Am Soc Nephrol. 2009;4:22–32. [PMC free article: PMC2615696] [PubMed: 18971369]
56. Nickolas TL, Radhakrishnan J, Appel GB. Hyperlipidemia and thrombotic complications in patients with membranous nephropathy. Semin Nephrol. 2003;23:406–11. [PubMed: 12923730]
57. Oberkircher OR, Enama M, West JC, Campbell P, Moran J. Regression of recurrent membranoproliferative glomerulonephritis type II in a transplanted kidney after plasmapheresis therapy. Transplant Proc. 1988;20:418–23. [PubMed: 2964750]
58. Ohi H, Watanabe S, Fujita T, Yasugi T. Significance of C3 nephritic factor (C3NeF) in non-hypocomplementaemic serum with membranoproliferative glomerulonephritis (MPGN). Clin Exp Immunol. 1992;89:479–84. [PMC free article: PMC1554488] [PubMed: 1516262]
59. Orth SR, Ritz E. The nephrotic syndrome. N Engl J Med. 1998;338:1202–11. [PubMed: 9554862]
60. Owen KR, Donohoe M, Ellard S, Clarke TJ, Nicholls AJ, Hattersley AT, Bingham C. Mesangiocapillary glomerulonephritis type 2 associated with familial partial lipodystrophy (Dunnigan-Kobberling syndrome). Nephron Clin Pract. 2004;96:c35–8. [PubMed: 14988595]
61. Pangburn MK, Muller-Eberhard HJ. The C3 convertase of the alternative pathway of human complement. Enzymic properties of the bimolecular proteinase. Biochem J. 1986;235:723–30. [PMC free article: PMC1146747] [PubMed: 3638964]
62. Pickering MC, Cook HT. Translational mini-review series on complement factor H: renal diseases associated with complement factor H: novel insights from humans and animals. Clin Exp Immunol. 2008;151:210–30. [PMC free article: PMC2276951] [PubMed: 18190458]
63. Rodriguez de Cordoba S, Esparza-Gordillo J, Goicoechea de Jorge E, Lopez-Trascasa M, Sanchez-Corral P. The human complement factor H: functional roles, genetic variations and disease associations. Mol Immunol. 2004;41:355–67. [PubMed: 15163532]
64. Ruggenenti P, Perna A, Gherardi G, Garini G, Zoccali C, Salvadori M, Scolari F, Schena FP, Remuzzi G. Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet. 1999;354:359–64. [PubMed: 10437863]
65. Sacks S, Zhou W. The effect of locally synthesised complement on acute renal allograft rejection. J Mol Med. 2003;81:404–10. [PubMed: 12827269]
66. Sacks SH, Bushell A, Rust NA, Karagiannis JA, Jewell DP, Ledingham JG, Wood KJ, McMichael AJ. Functional and biochemical subtypes of the haplotype HLA-DR3 in patients with celiac disease or idiopathic membranous nephropathy. Hum Immunol. 1987;20:175–87. [PubMed: 2960642]
67. Saunders RE, Abarrategui-Garrido C, Fremeaux-Bacchi V, Goicoechea de Jorge E, Goodship TH, Lopez Trascasa M, Noris M, Ponce Castro IM, Remuzzi G, Rodriguez de Cordoba S, Sanchez-Corral P, Skerka C, Zipfel PF, Perkins SJ. The interactive Factor H-atypical hemolytic uremic syndrome mutation database and website: update and integration of membrane cofactor protein and Factor I mutations with structural models. Hum Mutat. 2007;28:222–34. [PubMed: 17089378]
68. Schwertz R, Rother U, Anders D, Gretz N, Scharer K, Kirschfink M. Complement analysis in children with idiopathic membranoproliferative glomerulonephritis: a long-term follow-up. Pediatr Allergy Immunol. 2001;12:166–72. [PubMed: 11473682]
69. Servais A, Frémeaux-Bacchi V, Lequintrec M, Salomon R, Blouin J, Knebelmann B, Grünfeld JP, Lesavre P, Noël LH, Fakhouri F. Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome. J Med Genet. 2007;44:193–9. [PMC free article: PMC2598029] [PubMed: 17018561]
70. Sessa A, Battini G, Meroni M, Daidone G, Carnera I, Brambilla PL, Vigano G, Giordano F, Pallotti F, Torri Tarelli L, Calabresi L, Rolleri M, Bertolini S. Hypocomplementemic type II membranoproliferative glomerulonephritis in a male patient with familial lecithin-cholesterol acyltransferase deficiency due to two different allelic mutations. Nephron. 2001;88:268–72. [PubMed: 11423760]
71. Sethi S, Sukov WR, Zhang Y, Fervenza FC, Lager DJ, Miller DV, Cornell LD, Krishnan SG, Smith RJ. Dense deposit disease associated with monoclonal gammopathy of undetermined significance. Am J Kidney Dis. 2010;56:977–82. [PubMed: 20832153]
72. Simon P. Epidemiological data in population of 250,000 on minimal change nephrotic syndrome. IgA nephrology, idiopathic membranous, and membranoproliferative glomerulonephritis. Kidney Int. 1984;26:512.
73. Simon P, Ramee MP, Ang KS. Variations of primary glomerulonephritis incidence in a rural area of 400,000 inhabitants in the last decade. Nephron. 1987;45:171. [PubMed: 3494205]
74. Simon P, Ramee MP, Autuly V, Laruelle E, Charasse C, Cam G, Ang KS. Epidemiology of primary glomerular diseases in a French region. Variations according to period and age. Kidney Int. 1994;46:1192–8. [PubMed: 7861716]
75. Skerka C, Lauer N, Weinberger AA, Keilhamer CN, Sühnel J, Smith R, Schlötzer-Schrehardt U, Heinen S, Hartmann A, Weber BH, Zipfel PF. Defective complement control of FHL-1 and Factor H (Y402H) in age related macular degeneration. Mol Immunol. 2007;44:3398–406. [PubMed: 17399790]
76. Smith RJ, Alexander J, Barlow PN, Botto M, Cassavant TL, Cook HT, de Cordoba SR, Hageman GS, Jokiranta TS, Kimberling WJ, Lambris JD, Lanning LD, Levidiotis V, Licht C, Lutz HU, Meri S, Pickering MC, Quigg RJ, Rops AL, Salant DJ, Sethi S, Thurman JM, Tully HF, Tully SP, van der Vlag J, Walker PD, Wurzner R, Zipfel PF. New approaches to the treatment of dense deposit disease. J Am Soc Nephrol. 2007;18:2447–56. [PubMed: 17675665]
77. Spitzer RE, Stitzel AE. Loss of autoantibody activity by alteration in autoantigen. Clin Immunol Immunopathol. 1996;80:211–3. [PubMed: 8764567]
78. Stone EM, Lotery AJ, Munier FL, Heon E, Piguet B, Guymer RH, Vandenburgh K, Cousin P, Nishimura D, Swiderski RE, Silvestri G, Mackey DA, Hageman GS, Bird AC, Sheffield VC, Schorderet DF. A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy. Nat Genet. 1999;22:199–202. [PubMed: 10369267]
79. Strobel S, Zimmering M, Papp K, Prechl J, Józsi M. Anti-factor B autoantibody in dense deposit disease. Mol Immunol. 2010;47:1476–83. [PubMed: 20193965]
80. Study Group of the Spanish Society of Nephrology; Progressively decreasing incidence of membranoproliferative glomerulonephritis in Spanish adult population. Nephron. 1989;52:370–1. [PubMed: 2671766]
81. Study Group of the Spanish Society of Nephrology; Decreasing incidence of membranoproliferative GN in Spanish children. Pediatr Nephrol. 1990;4:266. [PubMed: 2400656]
82. Swainson CP, Robson JS, Thomson D, MacDonald MK. Mesangiocapillary glomerulonephritis: a long-term study of 40 cases. J Pathol. 1983;141:449–68. [PubMed: 6363655]
83. Tarshish P, Bernstein J, Tobin JN, Edelmann CM. Treatment of mesangiocapillary glomerulonephritis with alternate-day prednisone--a report of the International Study of Kidney Disease in Children. Pediatr Nephrol. 1992;6:123–30. [PubMed: 1571205]
84. Walker PD, Ferrario F, Joh K, Bonsib SM. Dense deposit disease is not a membranoproliferative glomerulonephritis. Mod Pathol. 2007;20:605–16. [PubMed: 17396142]
85. West CD. Childhood membranoproliferative glomerulonephritis: an approach to management. Kidney Int. 1986;29:1077–93. [PubMed: 3523004]
86. West CD, McAdams AJ, Witte DP. Acute non-proliferative glomerulitis: a cause of renal failure unique to children. Pediatr Nephrol. 2000;14:786–93. [PubMed: 10955928]
87. Zipfel PF, Smith RJH, Heinen ST. The role of complement in membranoproliferative glomerulonephritis. In: Zipfel PF, ed. Complement and Kidney Disease. Berlin, Germany: Springer; 2006:199-221.

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: richard-smith/at/uiowa.edu

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