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A National Kidney Foundation Symposium on IgA Nephropathy: Opening Remarks
A National Kidney Foundation Symposium on IgA Nephropathy: Opening Remarks Richard J. Glassock, MD
I
HAVE BEEN asked by the organizers of this meeting, the First National Symposium on IgA Nephropathy, to welcome you on behalf of the National Kidney Foundation. The National Kidney Foundation is pleased and highly honored to be one of the sponsors of this prestigious conference. The National Kidney Foundation has invited some internationally known investigators and the patriarch of the field to discuss and debate a single topic: IgA nephropathy. Unfortunately, due to budgetary restrictions, we were unable to invite all of the world experts who participated in the recent international symposia on the same topic. We are hopeful that this meeting will educate as well as illuminate concerning the enigma of IgA nephropathy. We also express our appreciation to Dr Bruce Julian and his colleagues at the University of Alabama School of Medicine and to the Kidney, Urology, and Hematology Division of the National Institutes of Health for so diligently pursuing the notion of a conference on this subject in the United States and for organizing and supporting such an excellent meeting . I would like to reiterate the themes that have dominated the two international symposia held in Bari and Milan, Italy, on IgA nephropathy \.2 and to quote from the preface of a recently published volume edited by one of the participants of this symposium, Dr A Clarkson 3 : "IgA nephropathy in the course of only two decades has become the most common form of glomerulonephritis seen in many countries, and it is also one of the most frequent causes of end-stage renal disease." Yet, 1. Disagreement continues about whether it is a syndrome or a specific disease entity. 2. The role of IgA as the fundamental pathogenetic vector remains uncertain. 3. The etiology of the primary disease remains From the Department of Medicine. Harbor-UCLA Medical Center, Torrance, CA. and the National Kidney Foundation. Inc. Address reprint requests to Richard J. Glassock. MD, Professor and Chair. Department of M edicine . Harbor-UCLA Medical Center. 1000 W Carson St. Torrance. CA 90509. © 1988 by the National Kidney Foundation . Inc. 0272-6386/88/1205-0002$3.00/0 338
elusive in all but a vanishingly small number of patients. 4. No reliable, sensitive, and specific methods for noninvasively diagnosing the disorder have yet been developed. 5. No effective form of therapy has yet been defined and rigorously tested for safety and longterm efficacy. Despite these very serious and nagging deficiencies in our knowledge, we have learned a great deal and will hear more at this conference about the morphology, immunopathology, clinical immunology, clinical spectrum, and natural history of IgA nephropathy. Unfortunately, the sum total of this knowledge allows us only to operate primarily at a descriptive rather than a mechanistic level when approaching the disease. Advances in the treatment of this common disorder have been agonizingly slow to emerge. Indeed, apessimist might put forth that we are no better off today than we were 5 years ago at the first International Conference devoted to IgA nephropathy held in Milan, Italy, under the direction of Dr D'Amico et al. 1 Indeed, it is a great disappointment that only 30 minutes of the more than 11 hours of talks at this meeting are devoted to the treatment of IgA nephropathy. A small glimmer of tantalizing hope may be surfacing from therapeutic studies conducted in Japan and Singapore,2 but we are a very, very long way from being able to make any specific therapeutic recommendations that are rationally devised and buttressed by prospective, randomized clinical trials. However, we should not despair; at least we think we know what will not work and perhaps we can at least identify those patients who are likely to progress rapidly enough to allow for randomized controlled trials with unambiguous end-points occurring over practical periods of observation. All of us are sanguine enough to recognize that even these trials, once conducted, will have only limited general applications and will elicit further controversy and debate. In the final analysis, true progress will depend on identification of the pathogenetic processes operative in humans and establishment of the links
American Journal of Kidney Diseases, Vol XII, No 5 (November), 1988: pp 338-339
339
OPENING REMARKS
between pathogenesis, etiology, and genetic susceptibility. Only then can rationality prevail and prophylaxis emerge as a realistic possibility. Thus, fundamental observations, including those involving surrogate disease in animals (socalled models of IgA nephropathy) must continue to be performed. Even so, the true test of the meaning of the observations and proposed pathways that emerge from animal studies will have to be applied to the human disease. My own suspicion is that modeling of IgA nephropathy in animals may give as much misdirection as direction, and I would make a plea for caution in interpretation of experiments in which IgA nephrop-
athy is induced in an otherwise normal laboratory animal. What we need are methods to directly duplicate in a suitable laboratory animal the sequence of events in humans. This will require identification of the gene or genes responsible for disease susceptibility in humans, analysis of the protein products of these genes, and identification of the environmental factor(s) responsible in concert with the susceptibility gene products for induction of disease. This is a formidable task, but one that should be within our grasp. Finally, this symposium will define where we are today and may help us to make it clear what direction future inquiries should take.
REFERENCES I. D' Amico G, Minetti L, Ponticelli C (eds): IgA mesangial
nephropathy. Contrib NephroI40: 1-301, 1984 2. Emancipator S, Schena FP (eds): Immunoglobulin A nephropathy. Semin Nephrol 7:275-424, 1987
3. Clarkson AR: IgA nephropathy, in Andreucci VE (ed) : Topics in Renal Medicine. Boston, Martinus Nijhoff, 1987, pp 1-257
I
HAVE BEEN asked by the organizers of this meeting, the First National Symposium on IgA Nephropathy, to welcome you on behalf of the National Kidney Foundation. The National Kidney Foundation is pleased and highly honored to be one of the sponsors of this prestigious conference. The National Kidney Foundation has invited some internationally known investigators and the patriarch of the field to discuss and debate a single topic: IgA nephropathy. Unfortunately, due to budgetary restrictions, we were unable to invite all of the world experts who participated in the recent international symposia on the same topic. We are hopeful that this meeting will educate as well as illuminate concerning the enigma of IgA nephropathy. We also express our appreciation to Dr Bruce Julian and his colleagues at the University of Alabama School of Medicine and to the Kidney, Urology, and Hematology Division of the National Institutes of Health for so diligently pursuing the notion of a conference on this subject in the United States and for organizing and supporting such an excellent meeting . I would like to reiterate the themes that have dominated the two international symposia held in Bari and Milan, Italy, on IgA nephropathy \.2 and to quote from the preface of a recently published volume edited by one of the participants of this symposium, Dr A Clarkson 3 : "IgA nephropathy in the course of only two decades has become the most common form of glomerulonephritis seen in many countries, and it is also one of the most frequent causes of end-stage renal disease." Yet, 1. Disagreement continues about whether it is a syndrome or a specific disease entity. 2. The role of IgA as the fundamental pathogenetic vector remains uncertain. 3. The etiology of the primary disease remains From the Department of Medicine. Harbor-UCLA Medical Center, Torrance, CA. and the National Kidney Foundation. Inc. Address reprint requests to Richard J. Glassock. MD, Professor and Chair. Department of M edicine . Harbor-UCLA Medical Center. 1000 W Carson St. Torrance. CA 90509. © 1988 by the National Kidney Foundation . Inc. 0272-6386/88/1205-0002$3.00/0 338
elusive in all but a vanishingly small number of patients. 4. No reliable, sensitive, and specific methods for noninvasively diagnosing the disorder have yet been developed. 5. No effective form of therapy has yet been defined and rigorously tested for safety and longterm efficacy. Despite these very serious and nagging deficiencies in our knowledge, we have learned a great deal and will hear more at this conference about the morphology, immunopathology, clinical immunology, clinical spectrum, and natural history of IgA nephropathy. Unfortunately, the sum total of this knowledge allows us only to operate primarily at a descriptive rather than a mechanistic level when approaching the disease. Advances in the treatment of this common disorder have been agonizingly slow to emerge. Indeed, apessimist might put forth that we are no better off today than we were 5 years ago at the first International Conference devoted to IgA nephropathy held in Milan, Italy, under the direction of Dr D'Amico et al. 1 Indeed, it is a great disappointment that only 30 minutes of the more than 11 hours of talks at this meeting are devoted to the treatment of IgA nephropathy. A small glimmer of tantalizing hope may be surfacing from therapeutic studies conducted in Japan and Singapore,2 but we are a very, very long way from being able to make any specific therapeutic recommendations that are rationally devised and buttressed by prospective, randomized clinical trials. However, we should not despair; at least we think we know what will not work and perhaps we can at least identify those patients who are likely to progress rapidly enough to allow for randomized controlled trials with unambiguous end-points occurring over practical periods of observation. All of us are sanguine enough to recognize that even these trials, once conducted, will have only limited general applications and will elicit further controversy and debate. In the final analysis, true progress will depend on identification of the pathogenetic processes operative in humans and establishment of the links
American Journal of Kidney Diseases, Vol XII, No 5 (November), 1988: pp 338-339
339
OPENING REMARKS
between pathogenesis, etiology, and genetic susceptibility. Only then can rationality prevail and prophylaxis emerge as a realistic possibility. Thus, fundamental observations, including those involving surrogate disease in animals (socalled models of IgA nephropathy) must continue to be performed. Even so, the true test of the meaning of the observations and proposed pathways that emerge from animal studies will have to be applied to the human disease. My own suspicion is that modeling of IgA nephropathy in animals may give as much misdirection as direction, and I would make a plea for caution in interpretation of experiments in which IgA nephrop-
athy is induced in an otherwise normal laboratory animal. What we need are methods to directly duplicate in a suitable laboratory animal the sequence of events in humans. This will require identification of the gene or genes responsible for disease susceptibility in humans, analysis of the protein products of these genes, and identification of the environmental factor(s) responsible in concert with the susceptibility gene products for induction of disease. This is a formidable task, but one that should be within our grasp. Finally, this symposium will define where we are today and may help us to make it clear what direction future inquiries should take.
REFERENCES I. D' Amico G, Minetti L, Ponticelli C (eds): IgA mesangial
nephropathy. Contrib NephroI40: 1-301, 1984 2. Emancipator S, Schena FP (eds): Immunoglobulin A nephropathy. Semin Nephrol 7:275-424, 1987
3. Clarkson AR: IgA nephropathy, in Andreucci VE (ed) : Topics in Renal Medicine. Boston, Martinus Nijhoff, 1987, pp 1-257