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Is Henoch-Schönlein Purpura the Systemic Form of IgA Nephropathy?
Is Henoch-Schonlein Purpura the Systemic Form of IgA Nephropathy? F. Bryson Waldo, MD • Despite different clinical features, IgA nephropathy (lgAN) and Henoch-Schonlein purpura (HSP) are indistinguishable by histopathology, leading to the suggestion that HSP is a systemic form of IgAN. This review compares and contrasts the clinical, pathologic, and experimental similarities and differences of these two disorders. Many patients with HSP have minimal extrarenal disease, while up to 30% of patients with IgAN will subsequently have systemic symptoms. Although patients with HSP are usually much younger than those with IgAN, the age distributions often overlap. Both may have recurrent macroscopic hematuria associated with pharyngitis, a similar risk of developing renal insufficiency, and recurrent disease after kidney transplantation. Although the pattern of IgA subclass and complement component deposition are similar, monocytic and T lymphocytic infiltrates have been observed only in HSP. Dermal blood vessels of many patients with IgAN have IgA immunofluorescence similar to that in HSP, supporting a systemic process in IgAN. Although the pathogenesis is not clearly understood for either disease, investigations of potential disease mechanisms have revealed striking similarities. These include an upregulated in vitro IgA immune response, circulating IgA-containing immune complexes and autoantibodies, and decreased Fc receptor-mediated immune clearance. Finally, immunogenetic studies suggest that patients with both conditions inherit a predisposition for disease. © 1988 by the National Kidney Foundation, Inc. INDEX WORDS: IgA nephropathy; Henoch-Schonlein purpura; nephritis; pathogenesis.
H
ENOCH-SCHONLEIN purpura (HSP) was first described in 1874 as a distinctive clinical syndrome of an acute systemic vasculitis of the skin, joints, gut, and kidney.! In 1968, Berger and Hinglais described IgA nephropathy (IgAN) characterized by mesangial proliferation and immunofluorescent staining for IgA in patients with mild nephritis manifested by hematuria, minimal proteinuria, and normal renal function, but without systemic symptoms. 2 Berger also noted mesangial IgA immunofluorescence in renal biopsy specimens from patients with HSP. In the subsequent years, despite their different clinical features, HSP and IgAN have remained indistinguishable by standard renal pathology. Several investigators have postulated that HSP is a systemic form of IgAN. This report will not attempt to prove or disprove that thesis, but rather will review the numerous clinical and laboratory similarities between the two conditions. Some distinctive, and potentially important, differences that may provide helpful clues in the quest to understand their pathogenesis will also be discussed.
volved. Depending on the criteria to define nephritis, renal involvement occurs in 20% to 100 % of patients. Although the systemic disease and nephritis in HSP usually occur together, the renal involvement may either precede the systemic symptoms or, conversely, appear months after the systemic signs have resolved. Similarly, although most patients with IgAN do not have systemic signs or symptoms at presentation, over 30% will develop abdominal pain, atypical rash, or arthralgia during follow-up. 3.4 Most patients with HSP present in childhood, while those with IgAN present in adolescence or early adult life. However, the age ranges in the two groups significantly overlap; patients as young as 2 years have been reported with IgAN, and 70year-old adults have developed HSP. 5 The reason for this age distribution is unclear. The IgA mucosal system is poorly developed at birth and undergoes continual antigen-driven and antigen-dependent development throughout childhood. The response of the immature immune system to an anti-
CLINICAL FEATURES
From the Department of Pediatrics, The Children's Hospital, The University of Alabama at Birmingham. Supported in part by Public Health Service Grant No. 1 R23 DK38083-02 from the National Institutes of Health. Address reprint requests to F. Bryson Waldo, MD, The University of Alabama at Birmingham, Department of Pediatrics, The Children's Hospital, 1600 7th Ave S, Birmingham, AL
The typical systemic presentation of HSP is so unique that the diagnosis is usually made on clinical criteria alone; renal biopsy is reserved for patients with severe or persistent nephritis. In contrast, the diagnosis of IgAN always requires a renal biopsy. Patients with HSP usually do not have all the major organ systems clinically in-
35233.
© 1988 by the National Kidney Foundation, Inc. 0272-6386/88/1205-0010$3.00/0
American Journal of Kidney Diseases, Vol XII, No 5 (November), 1988: pp 373-377
373
374
genic challenge may more frequently produce circulating immune complexes that deposit in tissue. Alternatively, differences in antigen exposure, handling of immune complexes, or other unknowns in children may favor development of systemic disease. A systemic infection commonly precedes the onset of HSP in children, while in many patients with IgAN, macroscopic hematuria is often noted first concomitant with an infection, leading to diagnosis. Because of the insidious nature of IgAN, the date of the true onset of the disease may not be discernible. Many patients may develop the initial immunologic renal lesion of IgAN months, or even years, before the disease is clinically manifest. Therefore, some patients with IgAN may develop their initial renal lesion following an infection , as do patients with HSP. During follow-up, 10% to 30% of patients with either condition experience recurrent bouts of macroscopic hematuria associated with upper respiratory tract infections. 4 .6.7 The long-term clinical course of both HSP and IgAN are quite variable and thus difficult to compare. Few series of unselected patients with HSP are available, and prognostic data are drawn from groups of patients with significant renal involvement. Most patients with HSP with or without renal disease resolve their initial systemic symptoms within 3 months of onset. Many have one or more relapses of purpura and systemic symptoms, which may include nephritis , in the first 12 months after presentation, but most will ultimately remit. Similarly, patients with IgAN presenting with macroscopic hematuria frequently have recurrent episodes associated with upper respiratory tract infections during the first 2 years after diagnosis. As with HSP, these episodes usually become less frequent or cease during extended observation. Approximately one third of patients with IgAN will progress to end-stage renal disease (ESRD) . In an unselected series of patients with HSp, only 5 % progressed to ESRD. However, in patients with HSP referred for renal disease and followed for six to 21 years, one third developed renal insufficiency.8 A few patients with HSP presenting with a severe necrotizing, crescentic glomerulonephritis progress to ESRD. Most patients with HSP show persistent glomerular deposits of IgAcontaining immune complexes indistinguishable from those in patients with IgAN.
F. BRYSON WALDO
The renal transplant experience in patients with IgAN has been very instructive. Thirty percent to 40 % of patients develop recurrent IgA deposits in their allografts, suggesting that IgAN is a systemic disease. In contrast, recurrence of the extrarenal manifestations of HSP after renal transplantation is rare. However, one third of patients with HSP with a renal allograft had recurrent IgA deposits in the kidney, although none had systemic symptoms or allograft dysfunction .9 In both HSP and IgAN, recurrent disease rarely causes loss of the allograft. 9 The reasons for this are unclear. The use of immunosuppressive drugs during the potential initiation period of disease (ie, immediately posttransplant) is one possibility; a "burn out" effect as described with systemic lupus erythematosus is another. PATHOLOGY
As noted above, the similar pathology of IgAN and HSP initially suggested that they represented a spectrum of a single disorder. By light microscopy, both diseases have mesangial proliferation and sometimes focal sclerosis or necrosis and crescent formation. 4.6. 10 Both exhibit electron-dense deposits containing IgA in the mesangium. The IgA is accompanied by C3 and IgG or IgM, or both, in 80 % of patients . Complement components C 1q and C4 are usually absent, but properdin, C5, and the membrane attack complex are detected. Furthermore, deposits may al so occasionally occur in subendothelial and, less commonly, subepithelial locations. Patients with deposits in the capillary loops more often have necrotic lesions and crescent formation. Crescentic disease was initially described more commonly in patients with HSp, but larger series have shown this pathologic finding in a comparable number of patients with IgAN .4 Much debate has focused on the subclass of IgA deposited in either disease. Initial data indicated that IgA2 predominated, II while many subsequent reports using several different monoclonal antibodies found predominantly IgAl.12 Although some authors expressed concern about possible nonreactivity of the monoclonal antibodies with tissue-bound immunoglobulin, no study found a different predominant IgA subclass in IgAN compared with HSP. The hypercellularity in HSP and IgAN has traditionally been attributed to mesangial cells. A re-
375
IS HSP THE SYSTEMIC FORM OF IGAN?
cent study of infiltration of leukocytes in several forms of glomerulonephritis found significant numbers of monocytes and T cells in the glomeruli of patients with HSP but not with IgAN.n All renal biopsies of the patients with HSP were performed early in the disease course (13 ± 1.4 weeks), compared with those of patients with IgAN (158 ± 18.5 weeks). This time difference may explain a temporal difference in immunopathology or, alternatively, it may suggest a basic difference in the mechanism of glomerular injury. Further studies will be needed to clarify this issue. In patients with HSP, immune complexes containing IgA and C3 are not only deposited in the kidney but also in blood vessels of the gut, joints, and skin. Immunofluorescence staining of purpuric and normal skin in patients with HSP reveals perivascular deposits of IgA. Although most patients with IgAN have no rash, many have perivascular deposits of IgA in clinically normal skin. This dermatologic finding suggests that the absence of purpura in patients with IgAN may represent a quantitative rather than qualitative difference in immunopathology. DEMOGRAPHICS
Worldwide, IgAN is the most common primary inflammatory glomerular disease 7 ,14; however, its prevalence and incidence are not evenly distributed. It is very common in the Orient, Australia, and southern Europe, but less common in northern Europe and the United States. Within the United States, some regions have a particularly high prevalence. The actual prevalence in a given area is difficult to determine because of the varied indications for renal biopsy. In the southern United States, IgAN and HSP are common in whites, although rare in blacks. 15 In Nigeria, the African origin of many blacks in the southern United States, neither IgAN nor HSP is seen (personal communication, Professor 0.0. Akinkugbe, Ibadan, Nigeria, 1987). The data on the geographic and racial distribution of HSP are limited. HSP is common in western Europe, the United States, and Japan, areas where IgAN is also seen. No population has yet been described in which only HSP or IgAN is commonly seen. PATHOGENESIS
First, the pathogenesis of neither HSP nor IgAN is understood. However, several general lines of
active investigation have produced a variety of stimulating results. 10,16,17 Whether these data point to causal mechanisms or epiphenomena is unclear. Nevertheless, the similarities between HSP and IgAN have been striking and will be briefly reviewed. Immune Complex Deposition It has been hypothesized that mesangial deposition of circulating immune complexes containing IgA occur in IgAN and HSP. Circulating immune complexes that bind to anti-C3 antibody or conglutinin (a C3bi ligand) and contain IgA are easily detected in both conditions. These complexes may also contain IgG and IgM. Although no large series from a single center has compared the characteristics of circulating immune complexes in IgAN and HSp, no obvious or significant differences are apparent from small studies. The relationship between disease activity and circulating immune complex levels in either disease is unclear. Despite a few reports in which the two correlated, most investigators agree that a correlation exists at best in only selected patients. The possible role of autoimmunity in both diseases has generated recent interest. IgA rheumatoid factor (anti-IgG Fc) has been found in patients with either disease. One report revealed crossreactive antibodies eluted from kidney sections of patients with HSP and IgAN. 18 These antibodies did not bind to sections of normal kidney but did bind to diseased renal tissue. IgA antibody against the Fab portion of normal IgG has recently been reported in patients with IgAN. Similar studies have not been done in patients with HSP.
Immune Response
An upregulated IgA immune response has also been hypothesized to occur in both diseases. About one third to one half of patients with either condition had increased serum IgA concentrations. The in vitro production of IgA by cultured lymphocytes from patients with IgAN and HSP has been investigated. 16,17 Whole mononuclear cells or B cells from patients with HSP spontaneously produced increased amounts of IgA in culture without mitogen stimulation. Pokeweed mitogen stimulation of whole mononuclear cells decreased IgA production, presumably by activating T suppressor cells; a similar response was shown for patients with systemic lupus erythematosus. Some
376
studies of IgAN found similarly increased IgA production by unstimulated cells. However, other investigators have shown IgA production by cells from patients with IgAN was increased only after pokeweed mitogen stimulation. Thus, the IgA immune response in patients with either HSP or IgAN may be upregulated, although the responsible cellular mechanisms may differ. Two of the studies that showed increased spontaneous production of IgA by lymphocytes from patients with IgAN (similar to that in HSP) used cells from children. Age-related variations in the IgA immune response, as noted earlier, may be important in the apparent differences between HSP and IgAN. Immune Clearance
Defective clearance of IgA-containing immune complexes has been hypothesized for both conditions. Fc-mediated clearance is abnormal in patients with IgAN or active HSp, but not in those with inactive HSP.19.20 The etiology and significance of the reduced clearance is unclear. In primates, soluble immune complexes containing C3b, such as those in the circulation of these patients, bind to erythrocyte complement receptor (CRl) and are transported to the liver for clearance. No data on the clearance of soluble immune complexes are currently available for either HSP or IgAN. Data from baboons suggest that immune complexes containing only IgA and no C3 are not cleared normally and deposit in the kidney and other tissue. This delayed clearance may also be true in IgAN. If abnormal immune complex clearance is indeed important in the pathogenesis of IgAN, it will be important to determine if this abnormality is also present in HSP. Genetics
Neither IgAN nor HSP is usually considered a genetic disorder. However, increasing evidence suggests that individuals inherit a predisposition to develop IgAN, and probably also HSp'21 Scattered case reports describe families with more than one member with IgAN. Several families include one member with IgAN and another with HSP. One remarkable family had twins, one with HSP the other with IgAN. In addition to these families, I am aware of two others with one brother with IgAN and the other with HSP. Brothers from one family were HLA typed and found to be HLA-
F. BRYSON WALDO
identical (All,31; B51,w62; DR 1,4). The fourth component of complement is encoded by two loci on chromosome 6 within the major histocompatibility complex. Null genes (genes producing a nonfunctional gene product) occur at one of the two loci on both chromosomes (homozygous nUll) in < 10% of normal individuals. The frequency of homozygous null C4 genes at either locus is significantly increased in patients with IgAN or HSP. Whether this genetic finding relates to gene linkages within the major histocompatibility complex or to a functional difference in the complement system is unclear. An increased frequency of an unusual restriction fragment length polymorphism allele of the immunoglobulin heavy chain switch region on chromosome 14 was recently described in patients with IgAN but not HSP. 22 The patients with HSP in this study were unselected. Might this allele be more common in the subgroup of patients with HSP with a chronic course of renal involvement, similar to patients with IgAN?
REFERENCES 1. Henoch EH: Ueber eine eigenthumliche Form von Purpura. Berl Klin Wochenschr 11:641-643 , 1874 2. Berger J, Hinglais N: Les depots intercapillaires d'IgAIgG. J Urol Nephrol 74 :694-695, 1968 3. Levy M, Beaufils H, Gubler MC, et al: Idiopathic recurrent haematuria and mesangial IgA-IgG deposits in children. Clin Nephrol 1:63-69, 1973 4. Nakamoto Y, Yoshihiro A, Dohi K, et al: Primary IgA glomerulonephritis and Schonlein-Henoch purpura nephritis: Clinicopathological and immunohistological characteristics. Q J Med 188:495-516, 1978 5. Roth DA, Wilz DR, Theil GB: Schonlein-Henoch syndrome in adults. Q J Med 55: 145-152, 1985 6. Levy M, Broyer M, Arsan A, et ai: Anaphylactoid purpura nephritis in childhood: Natural history and immunopathology, Adv Nephrol 6: 183-228, 1976 7. D'Amico G, Imbasciati E, Barbiano di Belgioiso G, et al: Idiopathic IgA mesangial nephropathy. Medicine 64:49-60, 1985 8. Counahan R, Winterborn MH, White RHR, et al: Prognosis of Henoch-Schonlein nephritis in children. Br Med J 2:11-14,1977 9. Habib R, Antignac C, Hinglais N, et al: Glomerular lesions in the transplanted kidney in children. Am J Kidney Dis 10: 198-207, 1987 10. Emancipator SN, Gallo GR, Lamm ME: IgA nephropathy: Perspectives on pathogenesis and classification. Clin Nephrol 24: 161-179, 1985 II. Andre C, Berthoux FC, Andre F, et al: Prevalence of IgA2 deposits in IgA nephropathies: Aclue to their pathogenesis. N Engl 1 Med 303:1343-1346, 1980 12. Lomax-Smith 1D, Zabrowarny LA, Howarth GS, et al :
IS HSP THE SYSTEMIC FORM OF IGAN?
The immunochemical characterization of mesangial IgA deposits . Am J Pathol 113:359-364 1983 13. Nolasco FEB, Cameron JS, Hartley B, et al: Intraglomerular T cells and monocytes in nephritis: Study with monoclonal antibodies. Kidney Int 31: 1160-1166, 1987 14. Clarkson AR: IgA nephropathy: History, classification and geographic distribution, in Clarkson AR (ed): IgA Nephropathy. Boston, Martinus Nijhoff, 1986, pp 1-8 15. Galla JH, Kohaut EC, Alexander RC, et al: Racial differences in the prevalence of IgA-associated nephropathies. Lancet 2:522 , 1984 (letter) 16. Clarkson AR , Woodroffe AJ , Bannister KM , et al: The syndrome ofIgA nephropathy. Clin Nephrol 21 :7-14, 1984 17. Egido J, Sancho J, Blasco R, et al: Imrnunopathogenetic aspects ofIgA nephropathy. Adv Nephrol 12:103-137,1983 18. Tornino Y, Sakai H, Endoh M, et al: Cross-reactivity of
377
eluted antibodies from renal tissues of patients with HenochSchonlein purpura nephritis and IgA nephropathy. Am J Nephrol 3:315-318, 1983 19. Lawrence S, Pussell BA, Charlesworth JA : Mesangial IgA nephropathy: Detection of defective reticulophagocytic function in vivo. Clin Nephrol 16:280-283, 1983 20. Bannister KM, Hay J, Clarkson AR, et al: Fc-specific reticuloendothelial clearance in systemic lupus erythematosus and glomerulonephritis. Am J Kidney Dis 3:287-292, 1984 21. Julian BA, Wyatt RJ, Quiggins PA: The immunogenetics of IgA nephropathy. Plasm Ther Transfus Technol 6:689-704, 1985 22. Demaine AG, Rambausek M, Knight JF, et al: Relation of mesangial IgA glomerulonephritis to polymorphism of immunoglobulin heavy chain switch region. J Clin Invest 81:611614, 1988
H
ENOCH-SCHONLEIN purpura (HSP) was first described in 1874 as a distinctive clinical syndrome of an acute systemic vasculitis of the skin, joints, gut, and kidney.! In 1968, Berger and Hinglais described IgA nephropathy (IgAN) characterized by mesangial proliferation and immunofluorescent staining for IgA in patients with mild nephritis manifested by hematuria, minimal proteinuria, and normal renal function, but without systemic symptoms. 2 Berger also noted mesangial IgA immunofluorescence in renal biopsy specimens from patients with HSP. In the subsequent years, despite their different clinical features, HSP and IgAN have remained indistinguishable by standard renal pathology. Several investigators have postulated that HSP is a systemic form of IgAN. This report will not attempt to prove or disprove that thesis, but rather will review the numerous clinical and laboratory similarities between the two conditions. Some distinctive, and potentially important, differences that may provide helpful clues in the quest to understand their pathogenesis will also be discussed.
volved. Depending on the criteria to define nephritis, renal involvement occurs in 20% to 100 % of patients. Although the systemic disease and nephritis in HSP usually occur together, the renal involvement may either precede the systemic symptoms or, conversely, appear months after the systemic signs have resolved. Similarly, although most patients with IgAN do not have systemic signs or symptoms at presentation, over 30% will develop abdominal pain, atypical rash, or arthralgia during follow-up. 3.4 Most patients with HSP present in childhood, while those with IgAN present in adolescence or early adult life. However, the age ranges in the two groups significantly overlap; patients as young as 2 years have been reported with IgAN, and 70year-old adults have developed HSP. 5 The reason for this age distribution is unclear. The IgA mucosal system is poorly developed at birth and undergoes continual antigen-driven and antigen-dependent development throughout childhood. The response of the immature immune system to an anti-
CLINICAL FEATURES
From the Department of Pediatrics, The Children's Hospital, The University of Alabama at Birmingham. Supported in part by Public Health Service Grant No. 1 R23 DK38083-02 from the National Institutes of Health. Address reprint requests to F. Bryson Waldo, MD, The University of Alabama at Birmingham, Department of Pediatrics, The Children's Hospital, 1600 7th Ave S, Birmingham, AL
The typical systemic presentation of HSP is so unique that the diagnosis is usually made on clinical criteria alone; renal biopsy is reserved for patients with severe or persistent nephritis. In contrast, the diagnosis of IgAN always requires a renal biopsy. Patients with HSP usually do not have all the major organ systems clinically in-
35233.
© 1988 by the National Kidney Foundation, Inc. 0272-6386/88/1205-0010$3.00/0
American Journal of Kidney Diseases, Vol XII, No 5 (November), 1988: pp 373-377
373
374
genic challenge may more frequently produce circulating immune complexes that deposit in tissue. Alternatively, differences in antigen exposure, handling of immune complexes, or other unknowns in children may favor development of systemic disease. A systemic infection commonly precedes the onset of HSP in children, while in many patients with IgAN, macroscopic hematuria is often noted first concomitant with an infection, leading to diagnosis. Because of the insidious nature of IgAN, the date of the true onset of the disease may not be discernible. Many patients may develop the initial immunologic renal lesion of IgAN months, or even years, before the disease is clinically manifest. Therefore, some patients with IgAN may develop their initial renal lesion following an infection , as do patients with HSP. During follow-up, 10% to 30% of patients with either condition experience recurrent bouts of macroscopic hematuria associated with upper respiratory tract infections. 4 .6.7 The long-term clinical course of both HSP and IgAN are quite variable and thus difficult to compare. Few series of unselected patients with HSP are available, and prognostic data are drawn from groups of patients with significant renal involvement. Most patients with HSP with or without renal disease resolve their initial systemic symptoms within 3 months of onset. Many have one or more relapses of purpura and systemic symptoms, which may include nephritis , in the first 12 months after presentation, but most will ultimately remit. Similarly, patients with IgAN presenting with macroscopic hematuria frequently have recurrent episodes associated with upper respiratory tract infections during the first 2 years after diagnosis. As with HSP, these episodes usually become less frequent or cease during extended observation. Approximately one third of patients with IgAN will progress to end-stage renal disease (ESRD) . In an unselected series of patients with HSp, only 5 % progressed to ESRD. However, in patients with HSP referred for renal disease and followed for six to 21 years, one third developed renal insufficiency.8 A few patients with HSP presenting with a severe necrotizing, crescentic glomerulonephritis progress to ESRD. Most patients with HSP show persistent glomerular deposits of IgAcontaining immune complexes indistinguishable from those in patients with IgAN.
F. BRYSON WALDO
The renal transplant experience in patients with IgAN has been very instructive. Thirty percent to 40 % of patients develop recurrent IgA deposits in their allografts, suggesting that IgAN is a systemic disease. In contrast, recurrence of the extrarenal manifestations of HSP after renal transplantation is rare. However, one third of patients with HSP with a renal allograft had recurrent IgA deposits in the kidney, although none had systemic symptoms or allograft dysfunction .9 In both HSP and IgAN, recurrent disease rarely causes loss of the allograft. 9 The reasons for this are unclear. The use of immunosuppressive drugs during the potential initiation period of disease (ie, immediately posttransplant) is one possibility; a "burn out" effect as described with systemic lupus erythematosus is another. PATHOLOGY
As noted above, the similar pathology of IgAN and HSP initially suggested that they represented a spectrum of a single disorder. By light microscopy, both diseases have mesangial proliferation and sometimes focal sclerosis or necrosis and crescent formation. 4.6. 10 Both exhibit electron-dense deposits containing IgA in the mesangium. The IgA is accompanied by C3 and IgG or IgM, or both, in 80 % of patients . Complement components C 1q and C4 are usually absent, but properdin, C5, and the membrane attack complex are detected. Furthermore, deposits may al so occasionally occur in subendothelial and, less commonly, subepithelial locations. Patients with deposits in the capillary loops more often have necrotic lesions and crescent formation. Crescentic disease was initially described more commonly in patients with HSp, but larger series have shown this pathologic finding in a comparable number of patients with IgAN .4 Much debate has focused on the subclass of IgA deposited in either disease. Initial data indicated that IgA2 predominated, II while many subsequent reports using several different monoclonal antibodies found predominantly IgAl.12 Although some authors expressed concern about possible nonreactivity of the monoclonal antibodies with tissue-bound immunoglobulin, no study found a different predominant IgA subclass in IgAN compared with HSP. The hypercellularity in HSP and IgAN has traditionally been attributed to mesangial cells. A re-
375
IS HSP THE SYSTEMIC FORM OF IGAN?
cent study of infiltration of leukocytes in several forms of glomerulonephritis found significant numbers of monocytes and T cells in the glomeruli of patients with HSP but not with IgAN.n All renal biopsies of the patients with HSP were performed early in the disease course (13 ± 1.4 weeks), compared with those of patients with IgAN (158 ± 18.5 weeks). This time difference may explain a temporal difference in immunopathology or, alternatively, it may suggest a basic difference in the mechanism of glomerular injury. Further studies will be needed to clarify this issue. In patients with HSP, immune complexes containing IgA and C3 are not only deposited in the kidney but also in blood vessels of the gut, joints, and skin. Immunofluorescence staining of purpuric and normal skin in patients with HSP reveals perivascular deposits of IgA. Although most patients with IgAN have no rash, many have perivascular deposits of IgA in clinically normal skin. This dermatologic finding suggests that the absence of purpura in patients with IgAN may represent a quantitative rather than qualitative difference in immunopathology. DEMOGRAPHICS
Worldwide, IgAN is the most common primary inflammatory glomerular disease 7 ,14; however, its prevalence and incidence are not evenly distributed. It is very common in the Orient, Australia, and southern Europe, but less common in northern Europe and the United States. Within the United States, some regions have a particularly high prevalence. The actual prevalence in a given area is difficult to determine because of the varied indications for renal biopsy. In the southern United States, IgAN and HSP are common in whites, although rare in blacks. 15 In Nigeria, the African origin of many blacks in the southern United States, neither IgAN nor HSP is seen (personal communication, Professor 0.0. Akinkugbe, Ibadan, Nigeria, 1987). The data on the geographic and racial distribution of HSP are limited. HSP is common in western Europe, the United States, and Japan, areas where IgAN is also seen. No population has yet been described in which only HSP or IgAN is commonly seen. PATHOGENESIS
First, the pathogenesis of neither HSP nor IgAN is understood. However, several general lines of
active investigation have produced a variety of stimulating results. 10,16,17 Whether these data point to causal mechanisms or epiphenomena is unclear. Nevertheless, the similarities between HSP and IgAN have been striking and will be briefly reviewed. Immune Complex Deposition It has been hypothesized that mesangial deposition of circulating immune complexes containing IgA occur in IgAN and HSP. Circulating immune complexes that bind to anti-C3 antibody or conglutinin (a C3bi ligand) and contain IgA are easily detected in both conditions. These complexes may also contain IgG and IgM. Although no large series from a single center has compared the characteristics of circulating immune complexes in IgAN and HSp, no obvious or significant differences are apparent from small studies. The relationship between disease activity and circulating immune complex levels in either disease is unclear. Despite a few reports in which the two correlated, most investigators agree that a correlation exists at best in only selected patients. The possible role of autoimmunity in both diseases has generated recent interest. IgA rheumatoid factor (anti-IgG Fc) has been found in patients with either disease. One report revealed crossreactive antibodies eluted from kidney sections of patients with HSP and IgAN. 18 These antibodies did not bind to sections of normal kidney but did bind to diseased renal tissue. IgA antibody against the Fab portion of normal IgG has recently been reported in patients with IgAN. Similar studies have not been done in patients with HSP.
Immune Response
An upregulated IgA immune response has also been hypothesized to occur in both diseases. About one third to one half of patients with either condition had increased serum IgA concentrations. The in vitro production of IgA by cultured lymphocytes from patients with IgAN and HSP has been investigated. 16,17 Whole mononuclear cells or B cells from patients with HSP spontaneously produced increased amounts of IgA in culture without mitogen stimulation. Pokeweed mitogen stimulation of whole mononuclear cells decreased IgA production, presumably by activating T suppressor cells; a similar response was shown for patients with systemic lupus erythematosus. Some
376
studies of IgAN found similarly increased IgA production by unstimulated cells. However, other investigators have shown IgA production by cells from patients with IgAN was increased only after pokeweed mitogen stimulation. Thus, the IgA immune response in patients with either HSP or IgAN may be upregulated, although the responsible cellular mechanisms may differ. Two of the studies that showed increased spontaneous production of IgA by lymphocytes from patients with IgAN (similar to that in HSP) used cells from children. Age-related variations in the IgA immune response, as noted earlier, may be important in the apparent differences between HSP and IgAN. Immune Clearance
Defective clearance of IgA-containing immune complexes has been hypothesized for both conditions. Fc-mediated clearance is abnormal in patients with IgAN or active HSp, but not in those with inactive HSP.19.20 The etiology and significance of the reduced clearance is unclear. In primates, soluble immune complexes containing C3b, such as those in the circulation of these patients, bind to erythrocyte complement receptor (CRl) and are transported to the liver for clearance. No data on the clearance of soluble immune complexes are currently available for either HSP or IgAN. Data from baboons suggest that immune complexes containing only IgA and no C3 are not cleared normally and deposit in the kidney and other tissue. This delayed clearance may also be true in IgAN. If abnormal immune complex clearance is indeed important in the pathogenesis of IgAN, it will be important to determine if this abnormality is also present in HSP. Genetics
Neither IgAN nor HSP is usually considered a genetic disorder. However, increasing evidence suggests that individuals inherit a predisposition to develop IgAN, and probably also HSp'21 Scattered case reports describe families with more than one member with IgAN. Several families include one member with IgAN and another with HSP. One remarkable family had twins, one with HSP the other with IgAN. In addition to these families, I am aware of two others with one brother with IgAN and the other with HSP. Brothers from one family were HLA typed and found to be HLA-
F. BRYSON WALDO
identical (All,31; B51,w62; DR 1,4). The fourth component of complement is encoded by two loci on chromosome 6 within the major histocompatibility complex. Null genes (genes producing a nonfunctional gene product) occur at one of the two loci on both chromosomes (homozygous nUll) in < 10% of normal individuals. The frequency of homozygous null C4 genes at either locus is significantly increased in patients with IgAN or HSP. Whether this genetic finding relates to gene linkages within the major histocompatibility complex or to a functional difference in the complement system is unclear. An increased frequency of an unusual restriction fragment length polymorphism allele of the immunoglobulin heavy chain switch region on chromosome 14 was recently described in patients with IgAN but not HSP. 22 The patients with HSP in this study were unselected. Might this allele be more common in the subgroup of patients with HSP with a chronic course of renal involvement, similar to patients with IgAN?
REFERENCES 1. Henoch EH: Ueber eine eigenthumliche Form von Purpura. Berl Klin Wochenschr 11:641-643 , 1874 2. Berger J, Hinglais N: Les depots intercapillaires d'IgAIgG. J Urol Nephrol 74 :694-695, 1968 3. Levy M, Beaufils H, Gubler MC, et al: Idiopathic recurrent haematuria and mesangial IgA-IgG deposits in children. Clin Nephrol 1:63-69, 1973 4. Nakamoto Y, Yoshihiro A, Dohi K, et al: Primary IgA glomerulonephritis and Schonlein-Henoch purpura nephritis: Clinicopathological and immunohistological characteristics. Q J Med 188:495-516, 1978 5. Roth DA, Wilz DR, Theil GB: Schonlein-Henoch syndrome in adults. Q J Med 55: 145-152, 1985 6. Levy M, Broyer M, Arsan A, et ai: Anaphylactoid purpura nephritis in childhood: Natural history and immunopathology, Adv Nephrol 6: 183-228, 1976 7. D'Amico G, Imbasciati E, Barbiano di Belgioiso G, et al: Idiopathic IgA mesangial nephropathy. Medicine 64:49-60, 1985 8. Counahan R, Winterborn MH, White RHR, et al: Prognosis of Henoch-Schonlein nephritis in children. Br Med J 2:11-14,1977 9. Habib R, Antignac C, Hinglais N, et al: Glomerular lesions in the transplanted kidney in children. Am J Kidney Dis 10: 198-207, 1987 10. Emancipator SN, Gallo GR, Lamm ME: IgA nephropathy: Perspectives on pathogenesis and classification. Clin Nephrol 24: 161-179, 1985 II. Andre C, Berthoux FC, Andre F, et al: Prevalence of IgA2 deposits in IgA nephropathies: Aclue to their pathogenesis. N Engl 1 Med 303:1343-1346, 1980 12. Lomax-Smith 1D, Zabrowarny LA, Howarth GS, et al :
IS HSP THE SYSTEMIC FORM OF IGAN?
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