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Immunomodulating treatment in primary glomerulonephritides
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Pharmacological Research, Vol. 26, Supplement 2, 1992 IMMUNOMODULATING TREATMENT IN PRIMARY GLOMERULONEPHRITIDES G . Piccoli, F. Quarello, B . Basolo, D. Roccatello, C. Rollino, G . Beltrame, G .B . Piccoli. Nephro-Urology Institute (Prof. A . Vercellone) . University of Turin. Italy. Key words: Glomerulonephritis, pathogenesis, treatment, immunomodulation .
Pathogenesis of primary glomerulonephritides (GN) is still debated : complex interactions between host and exogenic/endogenic antigens, environmental factors and genetic conditioning represent the major causes for difficulties in interpretation . However, host immune system seems to play a major role . Many experimental evidences (even if not always concordant) have demonstrated the involvement of immunologic abnormalities in the pathogenesis of GN, then offering a rational basis to therapeutic approaches . Immunomodulating treatment has proven effective, even if it is most often "broad spectrum", acting aspecifically on the immunologic system . Lymphocytes functional abnormalities have been documented in some GN. Unbalanced T lymphocytes subpopulation (decrease in T helper or increase in T suppressor lymphocytes) and production of lymphokines increasing glomerular basement membrane permeability (with secondary proteinuria) have been observed in minimal change GN and in some focal and segmental glomeruloscleroses . In these GN, therapeutic approach is based on the observation that in 85% of patients (pts) corticosteroids induce the disappearance of proteinuria after 4-8 weeks . Only 4% of pts respond after 12 weeks. Ten to 70% of pts relapse (40% behave as "frequent relapser") . In relapsing or corticoresistant cases cyclophosphamide or chlorambucil for 6-8 weeks often allow remission. Levamisole has been proposed in corticodependent pts : it would reduce the number of relapses . In case of steroid-resistant or -dependent pts, cyclosporine A has proven effective ; however, a decrease in glomerular filtration rate, reversible at discontinuation, is possible and dependence on the drug is frequent (1). An important role was formerly attributed to IgG-circulating immune complexes (CIC). At present, their pathogenetic involvement is still accepted in membranous GN ("in situ" formation of the complexes) and in acute post-infectious GN ; it is suspected in type I membrano-proliferative GN and in rapidly progressive (RP) GN with granular immunofluorescence (IF). The association of steroid pulses, cyclophosphamide and plasma exchanges has modified the prognosis mainly of RPGN . Side effects of this treatment are important (above all infectious) . However, its use is justified by the poor prognosis accounted for by these GN before its introduction. The positive results now obtained are rapidly occurring, so that the risk of long-term administration of dangerous and ineffective drugs can be avoided . Membranous GN is the most frequent cause of nephrotic syndrome in adults . Progression towards renal failure is generally slow. Kidney survival is 50-80% at 10 years, but the disease can be highly disabling because of nephrotic syndrome complications . Steroids have been shown to be effective on proteinuria, with a great frequency of short-term clinical remissions and stabilization of glomerular function. Every other day prednisone given for 8 weeks (2) or 6 alternate-month steroids and chlorambucil courses (3) are employed . Cyclosporine A is still unsatisfactory because of the frequent dependence on the drug, documented also in other GN . High dose immunoglobulin pulses have recently been proposed. They could transform soluble CIC into insoluble complexes which are more easily cleared by the monocyte-macrophage system; they could stimulate an
1043-6618/92/26110112-02/$03 .00/0
© 1992 The Italian Pharmacological Society
Pharmacological Research, Vol . 26, Supplement 2, 1992 anti-idiotypic reaction and reduce the OKT4/OKT8 ratio . For the time being, results are only anecdotal . RPGN with linear IF has an autoimmune etiology, probably induced by environmental and genetic factors, and due to formation of anti-GBM antibodies . In the forms of RPGN with negative IF, cellular immunity involvement has been advocated and in some of these cases anti-neutrophil cytoplasm antibodies (ANCA) have been found (4) . Aggressive therapies, similar to those used in RPGN with granular IF, can slow down their progression . Primary IgAGN (Berger GN) is the most diffuse GN in our country . It is due to the mainly mesangial deposition of IgA-CIC . A huge series of studies allowed to propose an etio-pathogenetic schema in which bacterial, viral or dietary antigens would favour IgA-CIC formation and persistence : hyperreactivity of the mucous immune system with increased production of IgA, increased intestinal permeability to antigens because of chronic, subchronic infections or dietary factors (lectins), dysfunction of the immune material clearance mechanisms and defective CIC solubilization by complement (5) . This situation would favour IgA-CIC persistence in the circulation and hence increased renal uptake . Kidney survival in this nephropathy is more than 90% at 10 years, >75% at 20 years ; only 10-15% of the cases evolve unfavourably in few years . In the majority of primary IgAGN no treatment is required . Infectious foci bonification can be useful in some pts . Steroids and immunosuppressive drugs can be employed only in subjects with rapidly progressive course, sometimes in association with plasma exchanges . The pathogenesis of type II membrano-proliferative GN is still unknown. Empiric treatments (analogous to those used in type I membrano-proliferative GN) with prednisone for one year, associated with cyclophosphamide, dipyridamole and anticoagulant drugs or only aspirin and dipyridamole association have shown some positive results . In these slowly progressing GN, a glomerular function stabilization has sometimes been obtained with indomethacine, used also in other GN as an anti-proteinuric drug (6). Recent experimental data have open new approaches to the treatment of GN (monoclonal antibodies, FK 506, El prostaglandins, proteases, anti-betal TGF, etc .) . They all aim at selective immunomodulation, with the slightest side effects . Only future studies will permit to set up the optimal doses and to further evaluate the results, which are up to now only preliminary . References 1 Cyclosporin A (Sandimmun) in nephrotic syndrome . Clin . Nephrol . 1991 ; 35, suppL 1 : S 3- 62 . 2 Collaborative study of the adult idiopathic nephrotic syndrome. A controlled study of short- term prednisone treatment in adults with membranous nephropathy . N Engl J Med 1979; 301 : 1301-1305 . 3 Ponticelli C, Zucchelli P, Passerini P, Cagnoli L, Cesana B, Pozzi C, Pasquali S, Imbasciati E, Grassi C . A randomized trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy. N Eng J Med 1989; 320: 8-13. 4 Rollino C, Roccatello D, Coppo R, Menegatti E, Basolo B, Giraudo G, Martin G, Piccoli G . Experience on antineutrophil cytoplams and antimyeloperoxidase antibodies in rapidly progressive glomerulonephritis . Contr Nephrol 1991 ; 94 : 101-106. 5 Roccatello D, Picciotto G, Coppo R, Piccoli G, Molino A, Cacace G, Amore A, Quattroccio G, Ropolo R, Mosso R, Amoroso A, Sena LM . The fate of aggregated immunoglobulin A Injected in IgA Nephropathy patients and healthy controls . Am J of Kidney Diseases 18 : 20-25,1991 6 Piccoli G, Coppo R, Stratta P, Messina M, Roccatello D, Bosticardo GM, Quarello F, Alloatti S . Corticosteroid therapy in idiopathic glomerulonephritis . In : Advances in Nephrourology . Ed . Plenum Press, New York, 1981, p. 159-181 .
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Pharmacological Research, Vol. 26, Supplement 2, 1992 IMMUNOMODULATING TREATMENT IN PRIMARY GLOMERULONEPHRITIDES G . Piccoli, F. Quarello, B . Basolo, D. Roccatello, C. Rollino, G . Beltrame, G .B . Piccoli. Nephro-Urology Institute (Prof. A . Vercellone) . University of Turin. Italy. Key words: Glomerulonephritis, pathogenesis, treatment, immunomodulation .
Pathogenesis of primary glomerulonephritides (GN) is still debated : complex interactions between host and exogenic/endogenic antigens, environmental factors and genetic conditioning represent the major causes for difficulties in interpretation . However, host immune system seems to play a major role . Many experimental evidences (even if not always concordant) have demonstrated the involvement of immunologic abnormalities in the pathogenesis of GN, then offering a rational basis to therapeutic approaches . Immunomodulating treatment has proven effective, even if it is most often "broad spectrum", acting aspecifically on the immunologic system . Lymphocytes functional abnormalities have been documented in some GN. Unbalanced T lymphocytes subpopulation (decrease in T helper or increase in T suppressor lymphocytes) and production of lymphokines increasing glomerular basement membrane permeability (with secondary proteinuria) have been observed in minimal change GN and in some focal and segmental glomeruloscleroses . In these GN, therapeutic approach is based on the observation that in 85% of patients (pts) corticosteroids induce the disappearance of proteinuria after 4-8 weeks . Only 4% of pts respond after 12 weeks. Ten to 70% of pts relapse (40% behave as "frequent relapser") . In relapsing or corticoresistant cases cyclophosphamide or chlorambucil for 6-8 weeks often allow remission. Levamisole has been proposed in corticodependent pts : it would reduce the number of relapses . In case of steroid-resistant or -dependent pts, cyclosporine A has proven effective ; however, a decrease in glomerular filtration rate, reversible at discontinuation, is possible and dependence on the drug is frequent (1). An important role was formerly attributed to IgG-circulating immune complexes (CIC). At present, their pathogenetic involvement is still accepted in membranous GN ("in situ" formation of the complexes) and in acute post-infectious GN ; it is suspected in type I membrano-proliferative GN and in rapidly progressive (RP) GN with granular immunofluorescence (IF). The association of steroid pulses, cyclophosphamide and plasma exchanges has modified the prognosis mainly of RPGN . Side effects of this treatment are important (above all infectious) . However, its use is justified by the poor prognosis accounted for by these GN before its introduction. The positive results now obtained are rapidly occurring, so that the risk of long-term administration of dangerous and ineffective drugs can be avoided . Membranous GN is the most frequent cause of nephrotic syndrome in adults . Progression towards renal failure is generally slow. Kidney survival is 50-80% at 10 years, but the disease can be highly disabling because of nephrotic syndrome complications . Steroids have been shown to be effective on proteinuria, with a great frequency of short-term clinical remissions and stabilization of glomerular function. Every other day prednisone given for 8 weeks (2) or 6 alternate-month steroids and chlorambucil courses (3) are employed . Cyclosporine A is still unsatisfactory because of the frequent dependence on the drug, documented also in other GN . High dose immunoglobulin pulses have recently been proposed. They could transform soluble CIC into insoluble complexes which are more easily cleared by the monocyte-macrophage system; they could stimulate an
1043-6618/92/26110112-02/$03 .00/0
© 1992 The Italian Pharmacological Society
Pharmacological Research, Vol . 26, Supplement 2, 1992 anti-idiotypic reaction and reduce the OKT4/OKT8 ratio . For the time being, results are only anecdotal . RPGN with linear IF has an autoimmune etiology, probably induced by environmental and genetic factors, and due to formation of anti-GBM antibodies . In the forms of RPGN with negative IF, cellular immunity involvement has been advocated and in some of these cases anti-neutrophil cytoplasm antibodies (ANCA) have been found (4) . Aggressive therapies, similar to those used in RPGN with granular IF, can slow down their progression . Primary IgAGN (Berger GN) is the most diffuse GN in our country . It is due to the mainly mesangial deposition of IgA-CIC . A huge series of studies allowed to propose an etio-pathogenetic schema in which bacterial, viral or dietary antigens would favour IgA-CIC formation and persistence : hyperreactivity of the mucous immune system with increased production of IgA, increased intestinal permeability to antigens because of chronic, subchronic infections or dietary factors (lectins), dysfunction of the immune material clearance mechanisms and defective CIC solubilization by complement (5) . This situation would favour IgA-CIC persistence in the circulation and hence increased renal uptake . Kidney survival in this nephropathy is more than 90% at 10 years, >75% at 20 years ; only 10-15% of the cases evolve unfavourably in few years . In the majority of primary IgAGN no treatment is required . Infectious foci bonification can be useful in some pts . Steroids and immunosuppressive drugs can be employed only in subjects with rapidly progressive course, sometimes in association with plasma exchanges . The pathogenesis of type II membrano-proliferative GN is still unknown. Empiric treatments (analogous to those used in type I membrano-proliferative GN) with prednisone for one year, associated with cyclophosphamide, dipyridamole and anticoagulant drugs or only aspirin and dipyridamole association have shown some positive results . In these slowly progressing GN, a glomerular function stabilization has sometimes been obtained with indomethacine, used also in other GN as an anti-proteinuric drug (6). Recent experimental data have open new approaches to the treatment of GN (monoclonal antibodies, FK 506, El prostaglandins, proteases, anti-betal TGF, etc .) . They all aim at selective immunomodulation, with the slightest side effects . Only future studies will permit to set up the optimal doses and to further evaluate the results, which are up to now only preliminary . References 1 Cyclosporin A (Sandimmun) in nephrotic syndrome . Clin . Nephrol . 1991 ; 35, suppL 1 : S 3- 62 . 2 Collaborative study of the adult idiopathic nephrotic syndrome. A controlled study of short- term prednisone treatment in adults with membranous nephropathy . N Engl J Med 1979; 301 : 1301-1305 . 3 Ponticelli C, Zucchelli P, Passerini P, Cagnoli L, Cesana B, Pozzi C, Pasquali S, Imbasciati E, Grassi C . A randomized trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy. N Eng J Med 1989; 320: 8-13. 4 Rollino C, Roccatello D, Coppo R, Menegatti E, Basolo B, Giraudo G, Martin G, Piccoli G . Experience on antineutrophil cytoplams and antimyeloperoxidase antibodies in rapidly progressive glomerulonephritis . Contr Nephrol 1991 ; 94 : 101-106. 5 Roccatello D, Picciotto G, Coppo R, Piccoli G, Molino A, Cacace G, Amore A, Quattroccio G, Ropolo R, Mosso R, Amoroso A, Sena LM . The fate of aggregated immunoglobulin A Injected in IgA Nephropathy patients and healthy controls . Am J of Kidney Diseases 18 : 20-25,1991 6 Piccoli G, Coppo R, Stratta P, Messina M, Roccatello D, Bosticardo GM, Quarello F, Alloatti S . Corticosteroid therapy in idiopathic glomerulonephritis . In : Advances in Nephrourology . Ed . Plenum Press, New York, 1981, p. 159-181 .
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