- Email: [email protected]
Familial membranoproliferative glomerulonephritis type III
CASE REPORT
Familial Membranoproliferative Glomerulonephritis Type III John Neary, MB, MRCPI, Anthony Dorman, MB, FRCPath, Eileen Campbell, PhD, Mary Keogan, MB, FRCPath, and Peter Conlon, MB, FRCPI, FACP ● Background: Membranoproliferative glomerulonephritis (MPGN) is a relatively uncommon cause of progressive renal disease characterized by immune complex deposition resulting in mesangial proliferation and endocapillary inflammation with capillary wall thickening and double contour formation. Although a familial linkage has been reported in MPGN type II disease and less often in type I disease, a familial linkage in type III disease has not been reported previously. Methods: We identified a family in which MPGN type III developed in a living-related donor 12 years later and recurred in the renal allograft of his son, whose primary disease was MPGN type III. We screened the members of the extended family, looking for evidence of hematuria and proteinuria. Renal biopsy specimens exhibited the findings of subendothelial deposits, subepithelial deposits, and complex glomerular basement membrane changes with C3 but not IgG seen on immunofluoresence. Results: Screening identified eight affected family members (six biopsy proven) over three generations. The condition is inherited in an apparent autosomal dominant fashion. Conclusion: This is the first description of familial MPGN type III. We hope that by studying the disease in this family group, we may learn more about the pathogenesis of the condition. © 2002 by the National Kidney Foundation, Inc. INDEX WORDS: Membranoproliferative glomerulonephritis (MPGN); hereditary disease.
M
EMBRANOPROLIFERATIVE glomerulonephritis (MPGN) describes a pattern of injury characterized by mesangial proliferation and endocapillary inflammation resulting in capillary basement membrane double contour formation (types I and III) or thickening (type II). Although many cases are associated with infection (in particular, hepatitis C), malignancy, connective tissue disease, and many congenital diseases,1 most cases seem to be of primary origin and are considered to be idiopathic. MPGN is divided into three major subtypes (I, II, and III) on the basis of histologic, immunofluorescence, and electron microscopic features (Table 1). Type III MPGN is characterized by the presence of subepithelial deposits associated with extensive subendothelial deposits. Two forms have been described. The first, by Burkholder et al,2 was a mixed membranous and membranoproliferative pattern of injury. They described extensive subepithelial deposits seen in association with a typical type I membranoproliferative lesion. The second pattern of injury, described by Strife et al,3 also was characterized by extensive subepithelial and subendothelial deposits. Strife et al3 also described the presence of secondary changes in the lamina densa identifiable on silverimpregnated electron micrograph studies. These changes were characterized by thickening and expansion of the basement membrane. In this study, the family members all showed extensive
subepithelial and subendothelial deposits. Many also showed features of associated basement membrane thickening, lucency, and lamellation. We performed a literature search using the MEDLINE and OMIM (Online Mendelian Inheritance in Man) databases, using the key words Hereditary/Familial, Membranoproliferative Glomerulonephritis (⫾ type III), and Mesangiocapillary Glomerulonephritis (⫾ type III). Although familial forms of type I and II disease have been reported previously, a familial form of type III disease has not been described. We report a family in which MPGN type III is inherited in an apparent autosomal dominant fashion. CASE REPORT The index case (subject 105 [see pedigree, Fig 1]) presented to us at 51 years of age. He had donated a kidney to his son (subject 213) 12 years previously. He presented with
From the Departments of Nephrology, Renal Pathology, and Clinical Immunology, Beaumont Hospital, Dublin, Ireland. Received October 13, 2001; accepted in revised form March 4, 2002. Supported by Beaumont Foundation, Beaumont Hospital. Address reprint requests to Peter Conlon, MB, FRCPI, FACP, Department of Nephrology, Beaumont Hospital, Beaumont Road, Dublin 9, Ireland. E-mail: [email protected] © 2002 by the National Kidney Foundation, Inc. 1523-6838/02/4001-0027$35.00/0 doi:10.1053/ajkd.2002.33932
American Journal of Kidney Diseases, Vol 40, No 1 (July), 2002: E1
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NEARY ET AL Table 1.
Overview of Classification of Membranoproliferative Glomerulonephritis Type I
Light microscopy Electron microscopy
Immunofluorescence
Serum complement levels
Mesangial cell proliferation Thickened capillary walls Subendothelial deposits (rarely subepithelial also) Subendothelial and mesangial granular C3 and IgG (⫾IgM, C1q, C4, factor B) C3—low in 68% C4—normal/low
Type II
Type III
As type I ⫹ dense deposits in GBM Osmophilic amorphous dense deposits in basement membrane ⫾ subepithelial deposits C3 staining but not in dense deposits
As type I
C3—low in 82% C4—normal
C3—low in 84% C4—normal
hypertension, nephrotic-range proteinuria, hematuria, and renal function impairment (serum creatinine, 1.5 mg/dL). He was healthy before donation with no evidence of proteinuria or hypertension. At presentation, 24-hour urine protein was 3.1 g/L, and his serum albumin was 33 g/L. Complement profile was normal. A biopsy specimen of the remaining kidney was obtained and submitted for light, fluorescence, and electron microscopy. On light microscopy, all 18 of the 25 nonsclerosed glomeruli showed typical features of MPGN. There was mesangial proliferation, capillary wall thickening with double contour formation, and proteinaceous deposit–like structures evident on trichrome stains in a predominantly subendothelial location. On immunofluorescence, there was strong granular positivity for C3 only along the capillary loop basement membranes. On electron microscopy, large numbers of electron densities were evident in the mesangium and in the capillary loops in a subendothelial, intramembranous, and subepithelial location. These deposits were associated with thickening of the lamina densa associated with lamellation and lucent areas (Fig 2). These features were believed to be typical of MPGN type III. The patient currently has moderate renal dysfunction (serum creatinine, 2.7 mg/dL) despite treatment with steroids and pulsed cyclophosphamide. The pathology of his son’s biopsy material (renal transplant recipient, subject 213) was reviewed immediately. At 4 years of age, he had presented with steroid-unresponsive
Subendothelial, mesangial, and subepithelial deposits C3 and rarely IgG but not in same area
nephrotic syndrome and hypocomplementemia. A 24-hour urine protein was 5.0 g, and urine microscopy revealed numerous red cells with no casts. Serum albumin was 21 g/L. C3 was reduced at 450 mg/mL (range, 750 to 1,650 mg/mL) and C4 was in the low normal range, 198 mg/mL (range, 180 to 400 mg/mL). Antinuclear factor was negative. The renal biopsy specimen, which was obtained in 1978 and reported in a different institution, was described as showing lobulation of glomeruli with mesangial proliferation. Basement membrane thickening was pronounced, and polymorphonuclear leukocytes were present in glomerular tufts. Immunofluorescence was done with positivity for C3 described in the glomeruli, but no IgG, IgM, and IgA were identified. On electron microscopy (pictures available for review), deposit-like structures were present in the peripheral capillary loops in a subendothelial, intramembranous, and subepithelial location. They also were associated with thickening and lucency of the basement membrane. This patient progressed to end-stage renal disease and was 10 years old when he received a living-related transplant from his father. At day 14 post-transplant, a biopsy specimen showed the presence of capillary loop C3, and electron microscopy showed deposit-like densities in the mesangium and in the capillary walls in a subepithelial and a subendothelial location. At 2 years post-transplant, a repeat biopsy was done because of a combined nephrotic/nephritic clinical presentation. This biopsy specimen showed strong capillary loop C3 positivity and on electron microscopy extensive
Fig 1. Pedigree of family. Classification of disease status as follows: Affected, biopsy-proven disease; Probable affected, significant proteinuria (>300 mg/24 h or >3ⴙ protein on dipstick on two occcasions) or significant hematuria (>3ⴙ on two occasions); Unaffected, insignificant proteinuria/hematuria or normal.
FAMILIAL MPGN TYPE III
Fig 2. Subject 105. Electron micrograph shows subendothelial deposits (➡); subepithelial deposits, one with glomerular basement membrane (GBM) spiky projections (2); and a deposit that is now intramembranous (22). There is also focal thickening and lamellation of the GBM (). (Original magnification ⴛ 12,000.)
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Fig 4. Subject 212. Glomerulus shows global deposit-like structures in capillary loops associated with thickening of the basement membrane. (Masson trichrome, original magnification ⴛ 400.)
deposition in the mesangium and in capillary walls with subendothelial, subepithelial, and intramembranous deposits (Fig 3). The features were those of a deposition disease with a type III membranoproliferative pattern. In view of the initial native biopsy report and clinical picture, this was believed to represent recurrence of primary disease in the allograft. The subject went on to develop graft failure at 6 years post-transplant. He subsequently received a second graft that is functioning well but with evidence of persistent moderate proteinuria. Subsequently a son (subject 212) (Figs 4 and 5) and daughter (subject 214) of the index case also were investigated for nephrotic-range proteinuria, hypoalbuminuria, and hypertension (Table 2). Renal biopsy specimens of both showed light, fluorescence, and electron microscopic fea-
tures of type III MPGN. Renal function and complement levels were normal. Another paternal aunt (subject 103) developed end-stage renal disease at age 51. Examination of her original biopsy specimen, obtained when she was 26 years old, revealed a pattern consistent with MPGN. No tissue was available for electron microscopic studies to confirm whether subendothelial and subepithelial deposits were present. She was normocomplementemic. She subsequently received a renal transplant at age 54, which is functioning well, although she has persistent moderate proteinuria. The daughter (subject 207) of this subject also has presented with moderate proteinuria and is awaiting further investigation. Another aunt (subject 107) and cousin (subject 223) were noted to have persistent hematuria and mild proteinuria during screening. Subject 223 subsequently underwent a renal biopsy, which showed an MPGN type III pattern (Fig
Fig 3. Subject 213—recurrence of MPGN type III in allograft. Electron micrograph shows subendothelial deposits (➡); subepithelial deposits, some with associated adjacent glomerular basement membrane (GBM) spiky projections (2); and lucencies and lamellation () of the GBM. (Original magnification ⴛ 12,000.)
Fig 5. Subject 212. Electron micrograph shows large subendothelial deposits (➡) with glomerular basement membrane (GBM) double contours enclosing them, a subepithelial deposit (2), intramembranous deposits (22), and GBM lamellations (). (Original magnification ⴛ 12,000.)
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NEARY ET AL Table 2.
Pedigree No. (Fig 1)
Age at Diagnosis (y)
213 105 212 214 103 223
4 51 28 21 25 16
ESRD
Yes No No No Yes No
Clinical Details of Affected Subjects
24-h Urine Protein (g/24 h)
Serum Albumin (g/L)
C3
C4
5.0 3.06 3.77 3.13 ⬎3 0.3
21 34 26 28 30 40
Low Normal Normal Normal Normal Normal
Low normal Normal Normal Normal Normal Normal
6) She has normal renal function and complement studies and is being followed at our clinic.
DISCUSSION
MPGN type III is a rare form of primary glomerulonephritis accounting for 1% of native renal biopsies in our center and a similar percentage in registry data. Although familial cases of MPGN types I and II have been reported,4 a familial form of MPGN type III has not yet been reported. Two cases of siblings have been reported in which one sibling was found to have MPGN type I and the other MPGN type III.5,6 Some observers used these cases to argue that type III disease is probably a variant of type I disease. Strife et al7 pointed out that MPGN type III is a distinct disease entity that does not progress to either MPGN type I or membranous glomerulonephropathy, as witnessed on serial
Fig 6. Subject 223. Electron micrograph shows mesangial deposits, paramesangial subendothelial deposits (➡), and subepithelial deposits with spiky projections (2). There is also some glomerular basement membrane lamellation (). Biopsy tissue recovered from wax before electron microscopy processing. (Original magnification ⴛ 12,000.)
HLA Typing
Blood Pressure at Presentation
Biopsy
A 2, 11, B 27, 70, DR 5, 6 A 1, 11, B 12, 70, DR 6, 7 — A 2, 11, B 27, 70, DR 5, 6 A 1, 11, B 12, 70, DR 6, 7 —
High High High Normal High Normal
MPGN III MPGN III MPGN III MPGN III MPGN MPGN III
biopsy specimens. It also differs in immunohistochemical and complement patterns (Table 1). In particular, on immunofluorescence, MPGN is seen to have prominent deposits of C3 but absent or minimal deposits of C4 and IgG. IgG is not seen to correspond with C3 deposition, in contrast to type I disease. Strife et al7 also described the presence on silver-impregnated electron microscopy studies of complex lamina densa changes associated with subepithelial and subendothelial deposits (the type III lesion). West and McAdams8 pointed out that early MPGN type III sometimes may be mistaken for type I disease because type III lesions often are not present until a later stage. In our biopsied cases, these changes appeared to be most striking in family members with clinically more advanced disease. The index case (subject 105), his son’s transplanted kidney (subject 214), and his other son (subject 212) and daughter (subject 214) all had biopsy specimens showing extensive subepithelial and subendothelial deposits with complex basement membrane changes and exhibiting the characteristic immunofluoresence findings of C3 in the absence of IgG. A cousin with hematuria and mild proteinuria (subject 223) showed fewer deposits and absence of complex basement membrane changes on renal biopsy. The molecular pathogenesis of MPGN type III is unknown, but cases that occur in children or young adults often are associated with complement abnormalities suggestive of overactivity of the alternative pathway of complement.9,10 A nephritic factor, NFt, has been identified in some patients with MPGN type III,11 and its activity seems to correlate with the presence of subepithelial deposits,8 but the exact role of NFt in the pathogenesis of the condition is uncertain. In this
FAMILIAL MPGN TYPE III
family, although the index case presented with hypocomplementemia, the remaining family members all had normal complement profiles, including CH100 screens (Table 2). Complement levels in patients have been shown to return to normal as the disease goes into remission,12 and as complement returns to normal, deposits also disappear, starting with subendothelial deposits.8 In this family, low complement levels may have indicated the more severe form of disease manifest in subject 213, whereas other family members had normal complement levels in keeping with partial resolution of disease. HLA linkage also has been proposed as proof for genetic linkage with the extended haplotype HLA0B8, DR3, SCO1, and GLO2 being found in 13% of patients with type I and III MPGN compared with only 1% of controls.13 This family did not exhibit this particular HLA profile (Table 2). Other groups have pointed to a high frequency of HLA A2 in familial MPGN (type I),6,14 but because HLA A2 is one of the more common class 1 alleles, it is difficult to draw any conclusions from this. Another possible genetic link has been described, with a membranoproliferative pattern being seen in patients with deficiencies of factor H.15 The disease seen with factor H deficiency or dysfunction is typically mild, however, and although paramesangial deposits are seen, the subepithelial loop lesions seen with this family are rare. Factor H dysfunction also is associated with atypical type II MPGN,16 familial hemolytic-uremic syndrome,17 and collagen III glomerulopathy.18 An animal model of type II disease in the Yorkshire pig is due to abnormal factor H production,19 but although the dense deposits that characterize type II disease are seen in the animal model, there is also evidence of deposition of terminal components of complement, which is more in keeping with type III disease. An interesting point is made in the study of this family. The father (subject 105), who donated a kidney, developed MPGN type III 12 years later. At the time of donation, he showed no evidence of disease. His son (subject 213) went on to develop recurrent MPGN type III in the allograft, ultimately causing graft failure. If the recurrence was due to a circulating nephritic factor, we might expect a similar course to occur in his second allograft. Although the son does
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have persistent moderate proteinuria, the second graft seems to be functioning well. This situation raises the possibility that the living-related allograft may have had some intrinsic intrarenal complement defect causing a rapid recurrence in combination with a circulating factor. An increasing number of cases of primary glomerular disease developing in the donor of a living-related transplant have been reported in the literature.20,21 As understanding of the genetic basis of these diseases improves, it is becoming obvious that living-related transplantation is relatively contraindicated in patients with certain forms of primary glomerulonephritis. In conclusion, we have reported a family who would seem to show MPGN type III being inherited in an autosomal dominant fashion. Genetic screening of this family may allow us to perform linkage analysis and develop further understanding of the disease. The family appears to be large enough to yield sufficient information in genetic studies, with a maximum predicted Lod score of 4.9. A candidate gene search is currently under way. POSTSCRIPT
We are developing an international collaborative effort to study familial MPGN and would be interested to hear from other physicians with patients with type I, II, or III MPGN. Contact Dr. Peter Conlon at the address supplied. REFERENCES 1. Rennke HG: Secondary membranoproliferative glomerulonephritis. Kidney Int 47:643-656, 1995 2. Burkholder PM, Hyman LR, Kreuger RP: Characterisation of mixed membranous and proliferative glomerulonephritis: Recognition of three varieties, in Kincaid-Smith P, Matthew TH, Becker EL (eds): Glomerulonephritis: Morphology, Natural History and Treatment. Proceedings of an International Symposium. NewYork, NY, Wiley, 1973, pp 557-589 3. Strife CF, McEnerny PT, McAdams AJ, West CD: Membranoproliferative glomerulonephritis with disruption of the glomerular basement membrane. Clin Nephrol 7:6572, 1997 4. Bakkalogu A, Soylemezoglu O, Tinaztepe K, Saatci U, Soylemezoglu F: Familial membranoproliferative glomerulonephritis. Nephrol Dial Transplant 10:21-24, 1996 5. Berry PL, McEnerny PT, McAdams AJ, West CD: Membranoproliferative glomerulonephritis in two sibships. Clin Nephrol 16:101-106, 1981 6. Bogdanovich RM, Dimitrjevic JZ, Nikolic VN, Ognjanovic MV, Rodic BD, Slavkovic BV: Familial membrano-
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proliferative glomerulonephritis. Pediatr Nephrol 14:400405, 2000 7. Strife CF, Jackson EC, McAdams AJ: Type III membranoproliferative glomerulonephritis: Long-term clinical and morphological evaluation. Clin Nephrol 21:323-334, 1984 8. West CD, McAdams AJ: Membranoproliferative glomerulonephritis type III: Association of glomerular deposits with circulating nephritic factor-stabilized convertase. Am J Kidney Dis 32:56-63, 1998 9. Coleman TH, Forristal J, Kosaka T, West CD: Inherited complement deficiencies in membranoproliferative glomerulonephritis. Kidney Int 24:681-690, 1983 10. West CD: Idiopathic membranoproliferative glomerulonephritis in childhood. Pediatr Nephrol 6:96-103, 1992 11. Clardy CW, Forristal J, Strife CF, West CD: A properdin dependent nephritic factor activating C3, C5 and C9 in membranoproliferative glomerulonephritis types I and III. Clin Immunol Immunopathol 50:333-357, 1989 12. Cameron JS: Idiopathic MCGN: Comparison of types I and II in children and adults and long term prognosis. Am J Med 74:175-192, 1983 13. Welch TR, Beischel L, Balakrishan K, Quinlan M, West CD: Major histocompatibility complex extended haplotypes in membranoproliferative glomerulonephritis. N Engl J Med 314:1476-1481, 1986
NEARY ET AL
14. Rashid HU, Papiha SS, Agroyamis B, et al: The associations of HLA and other genetic markers with glomerulonephritis. Hum Genet 63:38-44, 1983 15. West CD, McAdams AJ: The alternative pathway C3 convertase and glomerular deposits. Pediatr Nephrol 13:448453, 1999 16. Levy M, Halbwachs-Mecarelli L, Gubler M, et al: H deficiency in two brothers with atypical dense intramembranous deposit disease. Kidney Int 30:949-956, 1986 17. Waricker P, Donne RL, Goodship T: Familial relapsing haemolytic uraemic syndrome and complement factor H deficiency. Nephrol Dial Transplant 14:1229-1233, 1999 18. Vogt BA, Wyatt RJ, Burke BA, Simonton SC, Kashtan CE: Inherited factor H deficiency and collagen III glomerulopathy. Pediatr Nephrol 9:11-15, 1995 19. Jansen JH, Hogasen K, Mollnes T: Extensive complement activation in hereditary porcine membranoproliferative glomerulonephritis type II. Am J Pathol 143:1356-1365, 1993 20. Said R, Soyanno M: Renal failure in a living related kidney donor: Case report and review of the literature. Am J Nephrol 16:334-338, 1996 21. Winn MP, Alkhazunaizi AM, Howell DN, Butterly DW, Conlon PJ: Focal and segmental glomerulosclerosis: A need for caution in live-related renal transplantation. Am J Kidney Dis 33:970-974, 1999
Familial Membranoproliferative Glomerulonephritis Type III John Neary, MB, MRCPI, Anthony Dorman, MB, FRCPath, Eileen Campbell, PhD, Mary Keogan, MB, FRCPath, and Peter Conlon, MB, FRCPI, FACP ● Background: Membranoproliferative glomerulonephritis (MPGN) is a relatively uncommon cause of progressive renal disease characterized by immune complex deposition resulting in mesangial proliferation and endocapillary inflammation with capillary wall thickening and double contour formation. Although a familial linkage has been reported in MPGN type II disease and less often in type I disease, a familial linkage in type III disease has not been reported previously. Methods: We identified a family in which MPGN type III developed in a living-related donor 12 years later and recurred in the renal allograft of his son, whose primary disease was MPGN type III. We screened the members of the extended family, looking for evidence of hematuria and proteinuria. Renal biopsy specimens exhibited the findings of subendothelial deposits, subepithelial deposits, and complex glomerular basement membrane changes with C3 but not IgG seen on immunofluoresence. Results: Screening identified eight affected family members (six biopsy proven) over three generations. The condition is inherited in an apparent autosomal dominant fashion. Conclusion: This is the first description of familial MPGN type III. We hope that by studying the disease in this family group, we may learn more about the pathogenesis of the condition. © 2002 by the National Kidney Foundation, Inc. INDEX WORDS: Membranoproliferative glomerulonephritis (MPGN); hereditary disease.
M
EMBRANOPROLIFERATIVE glomerulonephritis (MPGN) describes a pattern of injury characterized by mesangial proliferation and endocapillary inflammation resulting in capillary basement membrane double contour formation (types I and III) or thickening (type II). Although many cases are associated with infection (in particular, hepatitis C), malignancy, connective tissue disease, and many congenital diseases,1 most cases seem to be of primary origin and are considered to be idiopathic. MPGN is divided into three major subtypes (I, II, and III) on the basis of histologic, immunofluorescence, and electron microscopic features (Table 1). Type III MPGN is characterized by the presence of subepithelial deposits associated with extensive subendothelial deposits. Two forms have been described. The first, by Burkholder et al,2 was a mixed membranous and membranoproliferative pattern of injury. They described extensive subepithelial deposits seen in association with a typical type I membranoproliferative lesion. The second pattern of injury, described by Strife et al,3 also was characterized by extensive subepithelial and subendothelial deposits. Strife et al3 also described the presence of secondary changes in the lamina densa identifiable on silverimpregnated electron micrograph studies. These changes were characterized by thickening and expansion of the basement membrane. In this study, the family members all showed extensive
subepithelial and subendothelial deposits. Many also showed features of associated basement membrane thickening, lucency, and lamellation. We performed a literature search using the MEDLINE and OMIM (Online Mendelian Inheritance in Man) databases, using the key words Hereditary/Familial, Membranoproliferative Glomerulonephritis (⫾ type III), and Mesangiocapillary Glomerulonephritis (⫾ type III). Although familial forms of type I and II disease have been reported previously, a familial form of type III disease has not been described. We report a family in which MPGN type III is inherited in an apparent autosomal dominant fashion. CASE REPORT The index case (subject 105 [see pedigree, Fig 1]) presented to us at 51 years of age. He had donated a kidney to his son (subject 213) 12 years previously. He presented with
From the Departments of Nephrology, Renal Pathology, and Clinical Immunology, Beaumont Hospital, Dublin, Ireland. Received October 13, 2001; accepted in revised form March 4, 2002. Supported by Beaumont Foundation, Beaumont Hospital. Address reprint requests to Peter Conlon, MB, FRCPI, FACP, Department of Nephrology, Beaumont Hospital, Beaumont Road, Dublin 9, Ireland. E-mail: [email protected] © 2002 by the National Kidney Foundation, Inc. 1523-6838/02/4001-0027$35.00/0 doi:10.1053/ajkd.2002.33932
American Journal of Kidney Diseases, Vol 40, No 1 (July), 2002: E1
1
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NEARY ET AL Table 1.
Overview of Classification of Membranoproliferative Glomerulonephritis Type I
Light microscopy Electron microscopy
Immunofluorescence
Serum complement levels
Mesangial cell proliferation Thickened capillary walls Subendothelial deposits (rarely subepithelial also) Subendothelial and mesangial granular C3 and IgG (⫾IgM, C1q, C4, factor B) C3—low in 68% C4—normal/low
Type II
Type III
As type I ⫹ dense deposits in GBM Osmophilic amorphous dense deposits in basement membrane ⫾ subepithelial deposits C3 staining but not in dense deposits
As type I
C3—low in 82% C4—normal
C3—low in 84% C4—normal
hypertension, nephrotic-range proteinuria, hematuria, and renal function impairment (serum creatinine, 1.5 mg/dL). He was healthy before donation with no evidence of proteinuria or hypertension. At presentation, 24-hour urine protein was 3.1 g/L, and his serum albumin was 33 g/L. Complement profile was normal. A biopsy specimen of the remaining kidney was obtained and submitted for light, fluorescence, and electron microscopy. On light microscopy, all 18 of the 25 nonsclerosed glomeruli showed typical features of MPGN. There was mesangial proliferation, capillary wall thickening with double contour formation, and proteinaceous deposit–like structures evident on trichrome stains in a predominantly subendothelial location. On immunofluorescence, there was strong granular positivity for C3 only along the capillary loop basement membranes. On electron microscopy, large numbers of electron densities were evident in the mesangium and in the capillary loops in a subendothelial, intramembranous, and subepithelial location. These deposits were associated with thickening of the lamina densa associated with lamellation and lucent areas (Fig 2). These features were believed to be typical of MPGN type III. The patient currently has moderate renal dysfunction (serum creatinine, 2.7 mg/dL) despite treatment with steroids and pulsed cyclophosphamide. The pathology of his son’s biopsy material (renal transplant recipient, subject 213) was reviewed immediately. At 4 years of age, he had presented with steroid-unresponsive
Subendothelial, mesangial, and subepithelial deposits C3 and rarely IgG but not in same area
nephrotic syndrome and hypocomplementemia. A 24-hour urine protein was 5.0 g, and urine microscopy revealed numerous red cells with no casts. Serum albumin was 21 g/L. C3 was reduced at 450 mg/mL (range, 750 to 1,650 mg/mL) and C4 was in the low normal range, 198 mg/mL (range, 180 to 400 mg/mL). Antinuclear factor was negative. The renal biopsy specimen, which was obtained in 1978 and reported in a different institution, was described as showing lobulation of glomeruli with mesangial proliferation. Basement membrane thickening was pronounced, and polymorphonuclear leukocytes were present in glomerular tufts. Immunofluorescence was done with positivity for C3 described in the glomeruli, but no IgG, IgM, and IgA were identified. On electron microscopy (pictures available for review), deposit-like structures were present in the peripheral capillary loops in a subendothelial, intramembranous, and subepithelial location. They also were associated with thickening and lucency of the basement membrane. This patient progressed to end-stage renal disease and was 10 years old when he received a living-related transplant from his father. At day 14 post-transplant, a biopsy specimen showed the presence of capillary loop C3, and electron microscopy showed deposit-like densities in the mesangium and in the capillary walls in a subepithelial and a subendothelial location. At 2 years post-transplant, a repeat biopsy was done because of a combined nephrotic/nephritic clinical presentation. This biopsy specimen showed strong capillary loop C3 positivity and on electron microscopy extensive
Fig 1. Pedigree of family. Classification of disease status as follows: Affected, biopsy-proven disease; Probable affected, significant proteinuria (>300 mg/24 h or >3ⴙ protein on dipstick on two occcasions) or significant hematuria (>3ⴙ on two occasions); Unaffected, insignificant proteinuria/hematuria or normal.
FAMILIAL MPGN TYPE III
Fig 2. Subject 105. Electron micrograph shows subendothelial deposits (➡); subepithelial deposits, one with glomerular basement membrane (GBM) spiky projections (2); and a deposit that is now intramembranous (22). There is also focal thickening and lamellation of the GBM (). (Original magnification ⴛ 12,000.)
3
Fig 4. Subject 212. Glomerulus shows global deposit-like structures in capillary loops associated with thickening of the basement membrane. (Masson trichrome, original magnification ⴛ 400.)
deposition in the mesangium and in capillary walls with subendothelial, subepithelial, and intramembranous deposits (Fig 3). The features were those of a deposition disease with a type III membranoproliferative pattern. In view of the initial native biopsy report and clinical picture, this was believed to represent recurrence of primary disease in the allograft. The subject went on to develop graft failure at 6 years post-transplant. He subsequently received a second graft that is functioning well but with evidence of persistent moderate proteinuria. Subsequently a son (subject 212) (Figs 4 and 5) and daughter (subject 214) of the index case also were investigated for nephrotic-range proteinuria, hypoalbuminuria, and hypertension (Table 2). Renal biopsy specimens of both showed light, fluorescence, and electron microscopic fea-
tures of type III MPGN. Renal function and complement levels were normal. Another paternal aunt (subject 103) developed end-stage renal disease at age 51. Examination of her original biopsy specimen, obtained when she was 26 years old, revealed a pattern consistent with MPGN. No tissue was available for electron microscopic studies to confirm whether subendothelial and subepithelial deposits were present. She was normocomplementemic. She subsequently received a renal transplant at age 54, which is functioning well, although she has persistent moderate proteinuria. The daughter (subject 207) of this subject also has presented with moderate proteinuria and is awaiting further investigation. Another aunt (subject 107) and cousin (subject 223) were noted to have persistent hematuria and mild proteinuria during screening. Subject 223 subsequently underwent a renal biopsy, which showed an MPGN type III pattern (Fig
Fig 3. Subject 213—recurrence of MPGN type III in allograft. Electron micrograph shows subendothelial deposits (➡); subepithelial deposits, some with associated adjacent glomerular basement membrane (GBM) spiky projections (2); and lucencies and lamellation () of the GBM. (Original magnification ⴛ 12,000.)
Fig 5. Subject 212. Electron micrograph shows large subendothelial deposits (➡) with glomerular basement membrane (GBM) double contours enclosing them, a subepithelial deposit (2), intramembranous deposits (22), and GBM lamellations (). (Original magnification ⴛ 12,000.)
4
NEARY ET AL Table 2.
Pedigree No. (Fig 1)
Age at Diagnosis (y)
213 105 212 214 103 223
4 51 28 21 25 16
ESRD
Yes No No No Yes No
Clinical Details of Affected Subjects
24-h Urine Protein (g/24 h)
Serum Albumin (g/L)
C3
C4
5.0 3.06 3.77 3.13 ⬎3 0.3
21 34 26 28 30 40
Low Normal Normal Normal Normal Normal
Low normal Normal Normal Normal Normal Normal
6) She has normal renal function and complement studies and is being followed at our clinic.
DISCUSSION
MPGN type III is a rare form of primary glomerulonephritis accounting for 1% of native renal biopsies in our center and a similar percentage in registry data. Although familial cases of MPGN types I and II have been reported,4 a familial form of MPGN type III has not yet been reported. Two cases of siblings have been reported in which one sibling was found to have MPGN type I and the other MPGN type III.5,6 Some observers used these cases to argue that type III disease is probably a variant of type I disease. Strife et al7 pointed out that MPGN type III is a distinct disease entity that does not progress to either MPGN type I or membranous glomerulonephropathy, as witnessed on serial
Fig 6. Subject 223. Electron micrograph shows mesangial deposits, paramesangial subendothelial deposits (➡), and subepithelial deposits with spiky projections (2). There is also some glomerular basement membrane lamellation (). Biopsy tissue recovered from wax before electron microscopy processing. (Original magnification ⴛ 12,000.)
HLA Typing
Blood Pressure at Presentation
Biopsy
A 2, 11, B 27, 70, DR 5, 6 A 1, 11, B 12, 70, DR 6, 7 — A 2, 11, B 27, 70, DR 5, 6 A 1, 11, B 12, 70, DR 6, 7 —
High High High Normal High Normal
MPGN III MPGN III MPGN III MPGN III MPGN MPGN III
biopsy specimens. It also differs in immunohistochemical and complement patterns (Table 1). In particular, on immunofluorescence, MPGN is seen to have prominent deposits of C3 but absent or minimal deposits of C4 and IgG. IgG is not seen to correspond with C3 deposition, in contrast to type I disease. Strife et al7 also described the presence on silver-impregnated electron microscopy studies of complex lamina densa changes associated with subepithelial and subendothelial deposits (the type III lesion). West and McAdams8 pointed out that early MPGN type III sometimes may be mistaken for type I disease because type III lesions often are not present until a later stage. In our biopsied cases, these changes appeared to be most striking in family members with clinically more advanced disease. The index case (subject 105), his son’s transplanted kidney (subject 214), and his other son (subject 212) and daughter (subject 214) all had biopsy specimens showing extensive subepithelial and subendothelial deposits with complex basement membrane changes and exhibiting the characteristic immunofluoresence findings of C3 in the absence of IgG. A cousin with hematuria and mild proteinuria (subject 223) showed fewer deposits and absence of complex basement membrane changes on renal biopsy. The molecular pathogenesis of MPGN type III is unknown, but cases that occur in children or young adults often are associated with complement abnormalities suggestive of overactivity of the alternative pathway of complement.9,10 A nephritic factor, NFt, has been identified in some patients with MPGN type III,11 and its activity seems to correlate with the presence of subepithelial deposits,8 but the exact role of NFt in the pathogenesis of the condition is uncertain. In this
FAMILIAL MPGN TYPE III
family, although the index case presented with hypocomplementemia, the remaining family members all had normal complement profiles, including CH100 screens (Table 2). Complement levels in patients have been shown to return to normal as the disease goes into remission,12 and as complement returns to normal, deposits also disappear, starting with subendothelial deposits.8 In this family, low complement levels may have indicated the more severe form of disease manifest in subject 213, whereas other family members had normal complement levels in keeping with partial resolution of disease. HLA linkage also has been proposed as proof for genetic linkage with the extended haplotype HLA0B8, DR3, SCO1, and GLO2 being found in 13% of patients with type I and III MPGN compared with only 1% of controls.13 This family did not exhibit this particular HLA profile (Table 2). Other groups have pointed to a high frequency of HLA A2 in familial MPGN (type I),6,14 but because HLA A2 is one of the more common class 1 alleles, it is difficult to draw any conclusions from this. Another possible genetic link has been described, with a membranoproliferative pattern being seen in patients with deficiencies of factor H.15 The disease seen with factor H deficiency or dysfunction is typically mild, however, and although paramesangial deposits are seen, the subepithelial loop lesions seen with this family are rare. Factor H dysfunction also is associated with atypical type II MPGN,16 familial hemolytic-uremic syndrome,17 and collagen III glomerulopathy.18 An animal model of type II disease in the Yorkshire pig is due to abnormal factor H production,19 but although the dense deposits that characterize type II disease are seen in the animal model, there is also evidence of deposition of terminal components of complement, which is more in keeping with type III disease. An interesting point is made in the study of this family. The father (subject 105), who donated a kidney, developed MPGN type III 12 years later. At the time of donation, he showed no evidence of disease. His son (subject 213) went on to develop recurrent MPGN type III in the allograft, ultimately causing graft failure. If the recurrence was due to a circulating nephritic factor, we might expect a similar course to occur in his second allograft. Although the son does
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have persistent moderate proteinuria, the second graft seems to be functioning well. This situation raises the possibility that the living-related allograft may have had some intrinsic intrarenal complement defect causing a rapid recurrence in combination with a circulating factor. An increasing number of cases of primary glomerular disease developing in the donor of a living-related transplant have been reported in the literature.20,21 As understanding of the genetic basis of these diseases improves, it is becoming obvious that living-related transplantation is relatively contraindicated in patients with certain forms of primary glomerulonephritis. In conclusion, we have reported a family who would seem to show MPGN type III being inherited in an autosomal dominant fashion. Genetic screening of this family may allow us to perform linkage analysis and develop further understanding of the disease. The family appears to be large enough to yield sufficient information in genetic studies, with a maximum predicted Lod score of 4.9. A candidate gene search is currently under way. POSTSCRIPT
We are developing an international collaborative effort to study familial MPGN and would be interested to hear from other physicians with patients with type I, II, or III MPGN. Contact Dr. Peter Conlon at the address supplied. REFERENCES 1. Rennke HG: Secondary membranoproliferative glomerulonephritis. Kidney Int 47:643-656, 1995 2. Burkholder PM, Hyman LR, Kreuger RP: Characterisation of mixed membranous and proliferative glomerulonephritis: Recognition of three varieties, in Kincaid-Smith P, Matthew TH, Becker EL (eds): Glomerulonephritis: Morphology, Natural History and Treatment. Proceedings of an International Symposium. NewYork, NY, Wiley, 1973, pp 557-589 3. Strife CF, McEnerny PT, McAdams AJ, West CD: Membranoproliferative glomerulonephritis with disruption of the glomerular basement membrane. Clin Nephrol 7:6572, 1997 4. Bakkalogu A, Soylemezoglu O, Tinaztepe K, Saatci U, Soylemezoglu F: Familial membranoproliferative glomerulonephritis. Nephrol Dial Transplant 10:21-24, 1996 5. Berry PL, McEnerny PT, McAdams AJ, West CD: Membranoproliferative glomerulonephritis in two sibships. Clin Nephrol 16:101-106, 1981 6. Bogdanovich RM, Dimitrjevic JZ, Nikolic VN, Ognjanovic MV, Rodic BD, Slavkovic BV: Familial membrano-
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proliferative glomerulonephritis. Pediatr Nephrol 14:400405, 2000 7. Strife CF, Jackson EC, McAdams AJ: Type III membranoproliferative glomerulonephritis: Long-term clinical and morphological evaluation. Clin Nephrol 21:323-334, 1984 8. West CD, McAdams AJ: Membranoproliferative glomerulonephritis type III: Association of glomerular deposits with circulating nephritic factor-stabilized convertase. Am J Kidney Dis 32:56-63, 1998 9. Coleman TH, Forristal J, Kosaka T, West CD: Inherited complement deficiencies in membranoproliferative glomerulonephritis. Kidney Int 24:681-690, 1983 10. West CD: Idiopathic membranoproliferative glomerulonephritis in childhood. Pediatr Nephrol 6:96-103, 1992 11. Clardy CW, Forristal J, Strife CF, West CD: A properdin dependent nephritic factor activating C3, C5 and C9 in membranoproliferative glomerulonephritis types I and III. Clin Immunol Immunopathol 50:333-357, 1989 12. Cameron JS: Idiopathic MCGN: Comparison of types I and II in children and adults and long term prognosis. Am J Med 74:175-192, 1983 13. Welch TR, Beischel L, Balakrishan K, Quinlan M, West CD: Major histocompatibility complex extended haplotypes in membranoproliferative glomerulonephritis. N Engl J Med 314:1476-1481, 1986
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14. Rashid HU, Papiha SS, Agroyamis B, et al: The associations of HLA and other genetic markers with glomerulonephritis. Hum Genet 63:38-44, 1983 15. West CD, McAdams AJ: The alternative pathway C3 convertase and glomerular deposits. Pediatr Nephrol 13:448453, 1999 16. Levy M, Halbwachs-Mecarelli L, Gubler M, et al: H deficiency in two brothers with atypical dense intramembranous deposit disease. Kidney Int 30:949-956, 1986 17. Waricker P, Donne RL, Goodship T: Familial relapsing haemolytic uraemic syndrome and complement factor H deficiency. Nephrol Dial Transplant 14:1229-1233, 1999 18. Vogt BA, Wyatt RJ, Burke BA, Simonton SC, Kashtan CE: Inherited factor H deficiency and collagen III glomerulopathy. Pediatr Nephrol 9:11-15, 1995 19. Jansen JH, Hogasen K, Mollnes T: Extensive complement activation in hereditary porcine membranoproliferative glomerulonephritis type II. Am J Pathol 143:1356-1365, 1993 20. Said R, Soyanno M: Renal failure in a living related kidney donor: Case report and review of the literature. Am J Nephrol 16:334-338, 1996 21. Winn MP, Alkhazunaizi AM, Howell DN, Butterly DW, Conlon PJ: Focal and segmental glomerulosclerosis: A need for caution in live-related renal transplantation. Am J Kidney Dis 33:970-974, 1999