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Home , Hereditary angioedema

Postgrad Med J: first published as 10.1136/pgmj.69.808.95 on 1 February 1993. Downloaded from Postgrad Med J (1993) 69, 95 - 99 ©) The Fellowship of Postgraduate Medicine, 1993

IgA nephropathy in hereditary Jayashri Srinivasan and Peter Beck Department ofMedicine, Llandough Hospital, Penarth, South Glanorgan CF6 IXX, UK

Summary: Hereditary angioedema is an autosomal dominant disorder of the in which there is a deficiency of the inhibitor of the activated first component of complement. We have previously reported on three generations of a family with classic hereditary angioedema. Three members of this family have now developed IgA nephropathy. The association of hereditary angioedema with various immunoregulatory disorders has been previously reported but this is the first report of IgA nephropathy in association with this condition.

Introduction Hereditary angioedema is an inherited disorder in report, case 1 appears at IV.2, case 2 at III.2, and which there is a quantitative or functional cases 3 and 4 at IV.3 and IV.4, respectively. deficiency of the inhibitor of the activated first Following the presentation of case 1 with component of complement, Cl inhibitor (Cl- painless haematuria in 1989, and the discovery that INH). It is characterized by recurrent attacks of this was due to IgA nephropathy, we decided to non-pitting oedema of the extremities, , larynx review the other members of the family for and abdomen including the bowel mucosa. An haematuria and to check their renal function. copyright. association of hereditary angioedema with various immunoregulatory disorders including systemic erythematosus, lupus-like disease, Sj6gren's Case reports syndrome, autoimmune thyroid disease, inflam- matory bowel disorder,' IgA deficiency,2 mesan- Case I giocapillary glomerulonephritis3 and coronary arteritis4 has been described. The use of the A 19 year old Caucasian male presented in 1973 attenuated androgen in preventing recur- with recurrent attacks of abdominal colic, facial rent attacks of angioedema in hereditary angio- and laryngeal oedema. He was diagnosed as having http://pmj.bmj.com/ was first described in 19765 and this drug is classic hereditary angioedema as his serum C1 widely used as long-term maintenance therapy in inhibitor and C4 were low and he had a positive this condition. IgA nephropathy, one of the com- family history, his grandmother and father being monest forms of nephropathy, is characterized by known to have hereditary angioedema. An attack recurrent attacks of gross or microscopic haem- of severe laryngeal oedema in 1978 required tem- aturia and is diagnosed on renal biopsy by the porary tracheotomy and ventilation. After initial presence of prominent IgA deposits in the mesan- gium by immunofluorescent techniques. We des- on October 4, 2021 by guest. Protected cribe three members of a family with hereditary angioedema on danazol prophylaxis who have developed IgA nephropathy, an association not 1m 2 previously reported. 1 2 3 I11 0 60 12 2 (64 The family 1 2 3 4 5 IV 8 36 23 2 The pedigree ofthe family is shown in 1 1 3 4 E Male Figure and V 19 O Female has been described in some detail in a family study 1 -O Affected of hereditary angio-neurotic oedema.6 In this 0+

Figure 1 Family pedigree: 'affected' refers to hereditary Correspondence: P. Beck, M.A., M.D., F.R.C.P. angioedema. Cases 1-4 are IV.2, 111.2, IV.3 and IV.4, Accepted: 21 July 1992 respectively. Postgrad Med J: first published as 10.1136/pgmj.69.808.95 on 1 February 1993. Downloaded from 96 J. SRINIVASAN & P. BECK prophylaxis with epsilon amino caproic acid, he deposition in the mesangium. He continues to have was switched to androgen therapy. He was started occasional haematuria but his plasma urea, electro- on danazol in 1982 and this resulted in a dramatic lytes and creatinine are normal and he remains improvement in his symptoms; he has had no well. documented attacks of angioedema since 1983. In 1989, at the age of 35 he presented with a 3 month Case 3 history ofintermittent painless haematuria and low back pain. Investigations included microscopic Patient 3 is the sister of the first patient and the examination of his urine which revealed 30 red daughter of the second. She was diagnosed as blood cells per high-power field, the majority of having Cl inhibitor deficiency in 1967 but only which were dysmorphic; urinary casts or white began to develop troublesome symptoms of blood cells were not seen and no organisms were angioedema in 1971 during pregnancy. She was isolated on culture. Plasma urea and electrolytes, initially started on epsilon amino caproic acid and creatinine and full blood count were normal. His once she had completed her family she was started glomerular filtration rate measured by creatinine on danazol in 1983. Apart from a few mild attacks clearance was 102 ml/min; he had proteinuria of of angioedema she has remained well. Following 4.2 g/l with a selectivity index of0. 13. Complement the diagnosis of IgA nephropathy in her family she profile revealed a low serum C4 and Cl inhibitor was investigated. She did not give a history of with a normal C3. His serum immunoglobulins haematuria but urinalysis showed microscopic including IgA were normal and auto- haematuria with no significant proteinuria; her were not detected. Renal biopsy showed glome- urea, electrolytes and creatinine, full blood count, rular mesangial proliferation and thickening with serum IgA were normal; screen was some segmental accentuation; the tubules showed negative and complement profile was consistent patchy atrophy and there was an associated mild with hereditary angioedema. Renal biopsy was focal interstitial inflammatory infiltrate. Immuno- diagnostic ofIgA nephropathy. She continues to be fluorescence showed strong mesangial staining for asymptomatic, her renal biochemistry remains nor-

IgA with associated C3 extending into the glome- mal and she has noticed no macroscopiccopyright. rular basement membrane, diagnostic of IgA haematuria. nephropathy. His renal function has remained stable over the last year and apart from occasional Case 4 haematuria he has remained asymptomatic. Patient 4 is another sister ofthe first patient and the daughter of the second. She had mild cutaneous Case 2 oedema at the age of 24 during her first pregnancy in 1990 and serum complement analysis confirmed Patient 2, who is the father of patient 1, had the diagnosis of C1 inhibitor deficiency and recurrent symptoms of , laryngeal hereditary angioedema. Her symptoms are mild http://pmj.bmj.com/ and cutaneous oedema since the age of 5 and he and she is not on any prophylactic therapy. She was diagnosed as having hereditary angioedema in does not give a history of haematuria and her 1969 when aged 41. He had recurrent symptoms urinalysis was normal. Her serum urea and electro- from his angioedema until he was commenced on lytes, creatinine, full blood count and serum IgA danazol in 1982 and he has had no serious attacks were normal and autoantibody screen was of angioedema since. He initially noticed haem- negative. In the absence of signs or symptoms of aturia in 1981 and had been under the care of a nephropathy she was not offered a renal biopsy. on October 4, 2021 by guest. Protected urologist and various investigations including Although there is no evidence oflinkage between intravenous urography and cystoscopy revealed no hereditary angioedema and HLA phenotypes,7 abnormality. He continued to have episodic occasional HLA associations with IgA nephro- haematuria but remained quite well. Following pathy have been reported.8'9 The HLA phenotypes the diagnosis of IgA nephropathy in his son, of this family were therefore examined and the further investigations were undertaken; his plasma results are given here: urea and electrolytes, creatinine and full blood count were normal; urinalysis showed microscopic Case 1 (IV.2) HLA-A2, 1 1;B51 ,W60;Cw3,X; haematuria but no significant proteinuria. Immune- DRl,W13;DQwl electrophoresis including serum IgA was normal; Case 2 (111.2) HLA-A2,X;B5 1 ,W50;Cw6,X; autoantibody screen was negative and complement DRl,7;DQwl,2 profile showed reduced Cl esterase inhibitor, Case 3 (IV.3) HLA-A2,29;B5 1 ,44;CwX; C4 and C2. Renal biopsy showed immuno- DRl ,7;DQwl ,2 fluorescence features consistent with IgA nephro- Case 4 (IV.4) HLA-A2,29;B51 ,44;CwX; pathy, that is, focal IgA with C3 and fibrinogen DRl ,7;DQwl ,2 Postgrad Med J: first published as 10.1136/pgmj.69.808.95 on 1 February 1993. Downloaded from IgA NEPHROPATHY ANGIOEDEMA 97

Discussion thought to be physiologically important.'3 The mechanism of the production of angi- Angioneurotic oedema (as it was then called) was oedema in the presence ofC1 inhibitor deficiency is first described in 1881 by Quincke and its familial still something of an enigma. Various theories exist incidence was reported by Sir William Osler in involving the cleavage of the Cl complex, either 1888.10 A deficiency of C1 inhibitor was recognized spontaneously or via Factor XII activation (which to be the pathological basis ofthe disorder in 1963" later can activate Cl directly or via plasmin) and an acquired form was described in 1972.12 leading to generation of -like peptides, pos- Hereditary angioedema (HAE) is inherited as an sibly derived from, and certainly requiring C2; or autosomal co-dominant trait with equal sex and via the production ofbradykinin via and racial distribution. Major advances in under- high molecular weight .'3 16-18 standing the molecular and genetic basis of the Various immunoregulatory disorders have been disease have been made in recent years and are well associated with hereditary angioedema including summarized in a recent review by Oltvai and system , thyroiditis, Sjogren's colleagues.'3 The C1 inhibitor gene has been syndrome, inflammatory bowel disease, IgA localized to chromosome 11 (qi I-q13) and the deficiency,2 coronary arteritis4 and with mesan- underlying molecular pathology relates to changes giocapillary nephritis.3 The increased incidence of in the DNA sequence of one allele, with a predis- these diseases in patients with hereditary angi- position of the gene to deletions and insertions oedema remains unexplained. Complement is being proposed. involved in immune clearance, immunoregulation, Two types of hereditary angioedema have been viral lysis and immune complex solubilization.'9 described;'4 the common Type I, which affects The latter is thought to be an important function of approximately 85% ofpatients, is characterized by the complement system and failure of solubiliza- a quantitative deficiency of structurally and func- tion of immune complexes could result in their tionally normal Cl inhibitor and the variant Type deposition in tissues and lead to such immuno- II, affecting 15%, has a quantitative defect of regulatory disorders. Hereditary angioedema is not inhibitor function, although the actual circulating HLA linked7 and it has been reported that the copyright. levels may be normal or even slightly elevated. In patients with hereditary angioedema who develop- the Type I disorder the deficiency appears to be due ed autoimmune diseases did not share one partic- to an apparent lack of function of the one Cl ular HLA or DR type but rather developed the inhibitor allele in the genome. Restriction fragment autoimmune disease known to be associated with length polymorphism (RFLP) analysis has shown their particular haplotype.' Therefore it appears that this co-segregates with the disease in those that additional predisposing factors such as HLA families in whom it is detected but an abnormal haplotype were required for the development of RFLP is found in only 15-12% of Type I patients autoimmune diseases in patients with hereditary and partial deletions or insertions within the Cl angioedema. inhibitor gene have been found in most of them. In The role of androgen therapy in reducing the http://pmj.bmj.com/ the Type II cases, various point mutations affecting frequency and the severity of acute attacks in the active binding site of the enzyme have been hereditary angioedema is well established and described."3 attenuated androgens such as danazol form the As well as angioedema due to inherited Cl mainstay of prophylaxis in hereditary angio- inhibitor deficiency, a similar clinical syndrome edema.5 Danazol increases the serum levels of Cl occurring in older patients, with no family history, inhibitor in all phenotypes of this condition has been described.'5 Subsequent studies have presumably because the androgen increases the on October 4, 2021 by guest. Protected shown that there are also two types ofthe acquired synthesis of the deficient or defective protein. disorder, the more common being found in patients Long-term danazol has been shown to be with lympho-proliferative disorders where associated with various adverse effects including antibodies to Cl inhibitor appear to arise through neuromusclular dysfunction, headaches, transient molecular mimicry with anti-idiotype antibodies elevation of hepatic enzymes, menstrual while, rarely, directed against an irregularities in women and of particular relevance epitope very adjacent to the active binding site of to this case, microscopic haematuria. 12 In this the protein have been described with no associated study, 13% ofpatients with hereditary angioedema lympho-proliferative disorder.'3 on long-term therapy with danazol developed The Cl inhibitor protein is a member of the haematuria without impairment of renal function. serine inhibitors ('') whose main target Haemorrhagic cystitis was found to be present in proteases are the Clr and Cls subunits of the Cl some of these and in two patients renal biopsy complex and, although inhibition of plasmin, kal- revealed mild mesangial proliferation. The likrein, factor XI and factor XII occurs, only haematuria resolved with reduction of the dose of inhibition of C1, Factor XII and kallikrein are danazol. Postgrad Med J: first published as 10.1136/pgmj.69.808.95 on 1 February 1993. Downloaded from 98 J. SRINIVASAN & P. BECK

Another study,' looking into the clinical reported;8'9 as reported above, none of our patients immunoregulatory diseases associated with her- showed these HLA haplotypes. editary angioedema, found that in the majority any This is the first report of IgA nephropathy urinary abnormality - haematuria, active urinary occurring in association with hereditary angi- sediment and proteinuria - developed before start- oedema. In this family with hereditary angioedema ing danazol therapy. This study also reported on and IgA nephropathy it is possible that the comple- five patients with renal disease associated with ment deficiency predisposed to the development of hereditary angioedema; four of these patients this disease. IgA nephropathy has been reported in developed the urinary abnormality before danazol three patients with a familial partial deficiency of a therapy was instituted. Renal biopsy showed mem- single complement protein - C2, properdin or H.25 braneoproliferative glomerulonephritis in two and An increased frequency ofthe homozygous C4 null mild mesangial disease in the other three but in no phenotype has been described in some patients with case was IgA nephropathy found. Danazol therapy IgA nephropathy.'3 Complement is involved has been definitively associated with haematuria, in various immunological processes including but not with IgA nephropathy. On the contrary immunoregulation, immune clearance and immune danazol has been used in the treatment of IgA complex solubilization and it has been suggested nephropathy and one study has shown that that these partial complement deficiencies inhibit danazol may increase the solubilization of the clearance of normally innocuous IgA- glomerular immune complexes and reduce pro- containing immune complexes from the circulation teinuria in IgA nephropathy.20 or the glomerular mesangium.'5 The deficiency of IgA nephropathy was first described by Berger the early components of the classical complement and Hinglais in 196821 and it is now thought to be pathway that occurs in hereditary angioedema has one of the commonest forms of glomerulo- been associated with various autoimmune diseases, nephritis.22 The diagnostic immunopathologic pat- although the mechanisms of this association is tern is the presence of mesangial deposits of IgA poorly defined. Although the complement activa- with C3 and properdin and sometimes other tion in IgA nephropathy is thought to be

immunoglobulins, IgM and IgG. The pathogenesis predominantly via the alternative pathway, there iscopyright. of IgA nephropathy is not known but IgA contain- some evidence that classical pathway activation ing immune complexes of IgA aggregates are may not be uncommon.23 The occurrence of IgA thought to be involved. Their deposition in the nephropathy in this family with hereditary renal mesangium followed by complement activa- angioedema may therefore imply a greater role for tion and release of other mediators including classical complement pathway activation in the proteases and prostaglandins are postulated to pathogenesis of this nephropathy. mediate the glomerular injury.23 There is con- We think that the occurrence of IgA nephro- siderable evidence for the role ofcomplement in the pathy in this family with hereditary angioedema is pathogenesis of IgA nephropathy. The finding of unlikely to be a coincidence. In our opinion it is the alternative pathway component properdin with likely that the underlying http://pmj.bmj.com/ C3 and membrane attack complex (C5b-9), with predisposed to its occurrence and we suggest that the relative absence of the classical pathway com- IgA nephropathy be added to the list of ponents Clq and C4, has been suggested as immunoregulatory disorders associated with her- evidence for the importance ofalternative pathway editary angioedema. activation in the pathogenesis of IgA nephro- pathy.23 A genetic predisposition of IgA nephro-

pathy has been suggested by the familial clustering on October 4, 2021 by guest. Protected of the disease noticed by some studies.24 No HLA Acknowledgements haplotype has consistently been associated with We are grateful to Dr David Fisher of Cardiff Royal IgA nephropathy, although in some countries, Infirmary for performing the renal biopsies and to Dr primarily Japan and France, an association with David Griffiths, Cardiff Royal Infirmary, for the HLA DR4 and B35, respectively, has been pathology reports.

References 1. Brickman, C.M., Tsokos, G.C., Balow, J.E. et al. 3. Plaza, J., Malasit, P. & Kerr, D.N.S. Hereditary angioedema Immunoregulatory disorders associated with hereditary with mesangiocapillary glomerulonephritis. Postgrad Med J angioedema. 1. Clinical manifestations of autoimmune 1977, 53: 627-630. disease. J Allergy Clin Immunol 1986, 77: 749-757. 4. Harrington, T.M., Torretti, D., Pytko, V.F. & Plotkin, G.R. 2. Bond, W.R., Herrod, H.G. & Duberstein, L.E. Hereditary Hereditary angioedema and coronary arteritis. Am J MedSci angioedema: association with IgA deficiency and otolaryn- 1984, 287: 50-52. gologic disorders. Laryngoscope 1981, 91: 417-421. Postgrad Med J: first published as 10.1136/pgmj.69.808.95 on 1 February 1993. Downloaded from IgA NEPHROPATHY ANGIOEDEMA 99

5. Gelfand, J.A., Sherins, R.J., Alling, D.W. & Frank, M.M. 17. Schapira, M., Silver, L.D., Scott, C.F. et al. Prekallikrein Treatment of hereditary angioedema with danazol: reversal activation and high molecular weight kininogen consump- of clinical and biochemical abnormalities. N Engl J Med tion in hereditary angioedema. N Engl J Med 1983, 308: 1976, 295: 1444-1448. 1050-1053. 6. Beck, P., Wills, D., Davies, G.T., Lachmann, P.J. & Sussman, 18. Fields, T., Ghebrehiwet, B. & Kaplan, A.P. Kinin formation M. A family study of hereditary angioedema. Q J Med 1973, in hereditary angioedema plasma: evidence against kinin 166: 317-339. derivation from C2 and in support ofspontaneous formation 7. Tiwari, J.L. & Terasaki, P.I. HLA and Disease Associations. of . J Allergy Clin Immunol 1983, 72: 54-60. Springer Verlag, New York, 1985, p. 455. 19. Kijlstra, A., Van Es, L.A. & Daha, M.R. Effects ofCl on the 8. Hiki, Y., Kobayashi, Y., Tateno, S. et al. Strong association size of soluble immune aggregates and their processing by of HLA DR4 with benign IgA nephropathy. Nephron 1982, macrophages. J Immunol 1979, 123: 640-645. 32: 222-226. 20. Tomino, Y., Sakai, H., Miura, M. et al. Effect of danazol on 9. Berthoux, F.C., Genin, C., LePetit, J.C. et al. Immunogen- solubilisation of immune deposits in patients with IgA etique des glomerulonephrites a depts d'IgA. Nephrologie nephropathy. Am J Kidney Dis 1984, IV (2): 135-140. 1983, 4: 283-287. 21. Berger, J. & Hinglais, N. Les depots intracapillaries d'IgA- 10. Osler, W. Hereditary angio-neurotic oedema. Am J Med Sci IgG. J Urol Nephrol 1968, 74: 694-695. 1988, 95: 362-372. 22. D'Amico, G. The commonest glomerulonephritis in the 11. Donaldson, V.H. & Evans, R.R. A biochemical abnormality world: IgA nephropathy. Q J Med 1987, 245: 709-727. in hereditary angioedema: absence of serum inhibitor of Cl 23. Wyatt, R.J. & Julian, B.A. Activation of complement in IgA esterase. Am J Med 1963, 35: 37-44. nephropathy. Am J Kidney Dis 1988, 5: 437-442. 12. Hosea, S.W., Santaella, M.L., Brown, E.J. et al. Long term 24. Julian, B.J., Quiggins, P.A., Thompson, J.S. et al. Familial therapy of hereditary angioedema with danazol. Ann Intern IgA nephropathy. N Engl J Med 1985, 312: 202-208. Med 1980, 93: 809-812. 25. Wyatt, R.J., Julian, B.A., Bhathena, D. et al. IgA nephro- 13. Oltvai, Z.N., Wong, E.C.C., Atkinson, J.P. & Tung, K.S.K. pathy: presentation, clinical course and prognosis in children C I inhibitor deficiency: molecular and immunologic basis of and adults. Am J Kidney Dis 1984, 4: 192-200. hereditary and acquired angioedema. Lab Invest 1991, 65: 381-388. 14. Rosen, F.S., Charache, P., Pensky, J. & Donaldson, V. Hereditary angioedema: two genetic variants. Science 1965, 148: 957-958. 15. Caldwell, J.R., Ruddy, S., Schur, P.H. & Austen, K.F. Acquired C1 inhibitor deficiency in lymphosarcoma. Clin Immunol Immunopath 1972, 1: 39-42. 16. Donaldson, V.H., Ratnoff, O.D., Da Silva, W.D. & Rosen, copyright. F.S. Permeability increasing activity in hereditary angio- neurotic oedema plasma. II. Mechanism of formation of and partial characterisation. J Clin Invest 1969, 48: 642-653. http://pmj.bmj.com/ on October 4, 2021 by guest. Protected