Plasmapheresis in Rapidly Progressive Glomerulonephritis
FlWClLLA
KINCAIDSMITH,
M.D.
ANTHONY J. F. d’APICE, M.D. Victoria. Australia
Since the Hammersmith group’s report in 1975 of the successful treatment of a patient with Goodpasture’s syndrome by a combination of plasmapheresis and immunosuppression, there has been considerable interest in plasmapheresis as a method of treating patients with immunologic renal disease. However, in view of the prevailing cynicism, particularly in the U.S.A., about the value of therapy in most types of idiopathic glomerulonephritis, it is not surprising that reports of experience with this therapy in glomerulonephritis have emanated mainly from two sources [l-6]. Although lamenting the therapeutic nihilism that this fact reflects, one must agree that the initial restriction of any new and potentially hazardous therapy to a limited number of centers will increase the likelihood of its efficacy being determined quickly. This is particularly likely to be the case with rarer diseases, such as Goodpasture’s syndrome, provided all cases are referred to the regional centers, so that a large experience can be accumulated reasonably quickly. THE RATIONALE
From the Department of Nephrology, The Royal Melbourne Hospital, Victoria, Australia. Requests for reprints should be addressed to Dr. Priscilla Kincaid-Smith, Department of Nephrology, The Royal Melbourne Hospital, Victoria, 3050 Australia. Manuscript accepted June 27, 1978.
664
October
1976
FOR PLASMAPHERESIS
Abnormal immune reactants, such as antiglomerular basement membrane antibody and pathogenic immune complexes, are removed irrespective of the replacement solution, whereas depletion of mediators of the immune response, such as complement components and procoagulants, depend on the composition of the replacement fluid. Factors Influencing the Level of Primary Immunoreactants. The phenomenon of autoimmune amplification, which has recently been described in experimental antitubular basement membrane disease, may be an important mechanism in human antibasement membrane disease. Theoretically, plasmapheresis should interrupt this vicious cycle in which autoantibody provokes further autoantibody production. However, because plasmapheresis lowers antiglomerular basement membrane antibody levels, it may remove the normal feedback inhibition of immunoglobulin G (IgG) which inhibits further expansion of the relevant plasma cell population. This could result in a rebound peak of antibody production when plasmapheresis is stopped. One of the reasons for the use of concurrent immunosuppressive therapy is to prevent this rebound. There is evidence that the duration of production of antiglomerular basement membrane antibody and of immune complexes in some cases of rapidly progressive nephritis is of limited duration. The object of the therapy is to prevent irreversible damage during the period that the immune reactants are being produced and to terminate or shorten this phase.
The American Journal of Medlclne
Volume 66
PLASMAPHERESIS IN GLOMERULONEPHRITIS-KINCAID-SMITH.
On theoretic grounds, the rate of production of immune complexes is likely to be lower than that of antiglomerular basement membrane antibody. Further, antiglomerular basement membrane antibody is most commonly IgG and this has a large extravascular distribution, which is not the case with macromolecular immune complexes. More intensive plasmapheresis may, therefore, be necessary in IgG antibody-mediated disease than in soluble immune complex-mediated disease. Depletion of Mediators of Renal Injury. The importance of the coagulation and complement systems in the mediation of glomerular injury of nephrotoxic nephritis has been established. In experimental models, defibrination by ancrod has been shown to prevent crescent formation, and decomplementation by cobra venom factor prevents polymorphdependent injury. The mechanisms of glomerular injury in immune complexmediated nephritis are less well understood. Fibrinogen, despite its being an acute phase reactant, is readily depleted by intensive plasmapheresis [6]. Complement components are variably depleted. In our experience levels of the third component of complement (C3) are reduced to 10 to 30 per cent or normal whereas levels of the fourth component (C4) are barely reduced below the limits of the normal range [6]. METHODOLOGIC ASPECTS The introduction of continuous and semicontinuous plasmapheresis machinery has made the widespread and repeated application of plasmapheresis possible because a 4 liter exchange can be performed in about 2 hours. Vascular access is usually obtained using arteriovenous shunts. Artificial plasma expanders are not satisfactory for replacement during intensive plasmapheresis. The most commonly used solutions are human albumin-based solutions, usually prepared by differential salt precipitation and closely resembling Cohn fraction V in composition. Four liter exchanges have been used by us and by the Hammersmith group. Our practice has been to use plasmapheresis daily for four or five days and then to reduce the frequency to every second or third day. Plasmapheresis should not be commenced within 24 hours of renal biopsy because of the risk of hemorrhage resulting from depletion of fibrinogen and other procoagulants. At present, the duration of treatment is judged by the clinical response obtained. We usually continue treatment for one or two weeks after renal function has stabilized. Several patients have failed to show a marked improvement in renal function for up to two weeks after the start of plasmapheresis, emphasizing the need to continue treatment for a period even
D’APICE
in the absence of improving renal function [6]. The presence of anuria indicates that recovery is extremely unlikely [I], however, we have seen recovery with return of serum creatinine to normal levels in patients with profound oliguria [6]. Folate iron and B group vitamins should be administered to avoid deficiencies of these substances. The removal of antibody combined with the effects of cyclophosphamide and steroids render the patients highly susceptible to infection. Patients should be warned of this risk and told to report any sign of infection, particularly fever. Infection at arteriovenous shunt sites may be a particular problem and must be managed with full aseptic technic, and urgent and detailed microbiologic investigation at the earliest sign of infection. Antibiotics should be chosen to give a broad bactericidal cover until the infecting agent and its sensitivities are known. It is, of course, necessary to administer all drug therapy at the end of plasmapheresis and not in accord with the usual ward routine. If infection does not respond rapidly to therapy, all immunosuppression, including plasmapheresis, should be terminated. CLINICAL EXPERIENCE Goodpasture’s Syndrome. The mortality of patients with Goodpasture’s syndrome, either with or without immunosuppressive therapy, exceeds 90 per cent if one includes in this figure patients who require maintenance dialysis. The Hammersmith group have reported death or terminal renal failure in four of seven patients treated with plasmapheresis [l] and have achieved similar results in a series of 26 patients [5]. We have been able to preserve renal function in five of 10 patients, thus the mortality rate has been reduced by about 50 per cent by the introduction of this form of therapy. Examination of the failures in our group of patients indicates that much better results could have been achieved. Two patients referred late presented with anuria and did not recover renal function, both patients died subsequently, one of pulmonary hemorrhage due to plasmapheresis-induced anticoagulation. In one other patient severe pulmonary hemorrhage developed after initial control of bleeding, but hemorrhage ceased when concommitant heparin therapy was discontinued. Two patients responded to therapy but had a relapse when plasmapheresis was stopped and did not respond adequately when it was reinstituted. One patient died of influenza1 pneumonia contracted during the period of plasmapheresis and immunosuppression. There is also an indication that clinical experience with the treatment of this disease is all important in its success: four of our failures occurred in the first five patients treated. Peters [5] recently emphasized that pulmonary hemorrhage can be precipitated by fluid overload and the administration of anticoagulants.
October 1976
The American Journal of Medicine
Volume 65
565
PLASMAPHERESIS IN GLOMERULONEPHRITIS-KINCAID-SMITH,D’APICE
Furthermore, intercurrent bacterial infection can cause rapid deterioration of renal function and the development of lung hemorrhage, despite continued plasmapheresis and low antiglomerular basement membrane antibody levels [5]. Goodpasture’s syndrome may be an exception to the rule that the anticoagulant effect of plasmapheresis does not usually result in hemorrhage. In three patients, we observed severe renal or pulmonary hemorrhage, which developed during a period of intensive plasmapheresis and responded to cessation of plasmapheresis in one and to the use of fresh frozen plasma during replacement in another. We have not observed this complication in over 50 patients who received intensive plasmapheresis for other indications. Experience, therefore, indicates that plasmapheresis with combined immunosuppression is the treatment of choice in Goodpasture’s syndrome but that success of therapy is critically dependent on early diagnosis and immediate therapy, preferably by an experienced unit. It cannot be overemphasized that treatment should be commenced as soon as possible after diagnosis, as exsanguinating pulmonary hemorrhage causes sudden unexpected deaths. The glomerular lesion also progresses with alarming rapidity and an early focal and segmental lesion may destroy all glomeruli in one to two weeks. The diagnosis of Goodpasture’s syndrome can be made on clinical grounds in the vast majority of cases. The presentation with anemia, dyspnea, pulmonary hemorrhage and the accompanying fulminating glomerulonephritis is very characteristic. The delay in commencing plasmapheresis occasioned by diagnostic renal biopsy can be avoided in the first instance by reliance on clinical diagnosis, and confirmatory biopsy can be used after clinical response to plasmapheresis to confirm the characteristic linear immunoglobulin deposition which persists for months. Plasmapheresis in Goodpasture’s syndrome should be intensive commencing with daily treatment and continuing for at least one week after maximal improvement in renal function or complete cessation of pulmonary hemorrhage. Anticoagulant drugs should not be used and partial
plasma replacement with fresh frozen plasma, given at the end of each exchange, may be necessary in patients with severe pulmonary hemorrhage. Venous pressure should be carefully monitored to avoid circulatory overload. Meticulous aseptic management of arteriovenous shunts is essential to avoid infection. For optimal management, patients should be referred to regional centers. This also permits accumulation of valuable experience with this rare disease. Serial measurement of the corrected gas transfer factor (kC0) has recently been shown to be a more sensitive index of pulmonary hemorrhage than other indices such as hemoptysis, x-ray evidence of pulmonary infiltrates or increasing anemia. Immune Complex-Mediated Glomerulonephritis. Despite the fact that rapidly progressive (crescentic) glomerulonephritis represents only a fraction of the spectrum of immune complex-mediated glomerulonephritis, its fulminant nature, poor prognosis and histologic similarity to the nephritis of Goodpasture’s syndrome caused Peter’s group [3] and our own [4] to study the effects of treatment by plasmapheresis. The patients treated have had a variety of etiologies and associated clinical syndromes, such as polyarteritis nodosa, Wegener’s granulomatosus and systemic lupus erythematosus. The results have been impressive [3,4,6]: in 16 of 22 patients improved renal function was attributable to the therapy. There is little doubt that these results represent a marked improvement over the natural history of the disease in patients with diffuse crescents and a rapidly progressive course. However, although plasmapheresis appears to be an effective form of treatment, other forms of therapy, particularly combinations of heparin and immunosuppressive agents, have also been found to be effective and are much less expensive. Ideally, a controlled trial is desirable to establish the relative merits of these alternative therapies, however, the rarity of the condition may make this impractical. The incidence of serious complications of therapy in this group has been very low compared with that in Goodpasture’s syndrome.
REFERENCES 1.
2.
3.
4.
566
Lockwood CM, Rees AJ, Pearson TA, et al.: Immunosuppression and plasma-exchange in the treatment of Goodpasture’s syndrome. Lancet 1: 711, 1976. Walker RG, d’Apice AJF, Kincaid-Smith P, et al.: Plasmapheresis in Goodpasture’s syndrome with renal failure. Med J Aust 1: 875, 1977. Lockwood CM, et al.: Plasma-exchange and immunosuppression in the treatment of fulminating immune complex crescentic nephritis. Lancet 1: 63, 1977. Becker 61, d’Apice AJF, Walker GJ, et al.: Plasmapheresis in
October 1976
The American Journal of Medlclne
5.
6.
Volume 65
the treatment of glomerulonephritis. Med J Aust 2: 693, 1977. Peters DK: Anti-glomerular basement membrane antibody disease, chap 18. Progress in Glomerulonephritis, (Kinraid-Smith P, d’Apice AJF, Atkins RC. eds) New York, John Wiley 8 Sons, (in press). d’Apice AJF, Kincaid-Smith P: Treatment of glomerulonephritis by plasma exchange, chap 19. Progress in Glomerulonephritis, (Kincaid-Smith P, d’Apice AJF, Atkins RC, ed), New York, John Wiley & Sons, (in press).
FlWClLLA
KINCAIDSMITH,
M.D.
ANTHONY J. F. d’APICE, M.D. Victoria. Australia
Since the Hammersmith group’s report in 1975 of the successful treatment of a patient with Goodpasture’s syndrome by a combination of plasmapheresis and immunosuppression, there has been considerable interest in plasmapheresis as a method of treating patients with immunologic renal disease. However, in view of the prevailing cynicism, particularly in the U.S.A., about the value of therapy in most types of idiopathic glomerulonephritis, it is not surprising that reports of experience with this therapy in glomerulonephritis have emanated mainly from two sources [l-6]. Although lamenting the therapeutic nihilism that this fact reflects, one must agree that the initial restriction of any new and potentially hazardous therapy to a limited number of centers will increase the likelihood of its efficacy being determined quickly. This is particularly likely to be the case with rarer diseases, such as Goodpasture’s syndrome, provided all cases are referred to the regional centers, so that a large experience can be accumulated reasonably quickly. THE RATIONALE
From the Department of Nephrology, The Royal Melbourne Hospital, Victoria, Australia. Requests for reprints should be addressed to Dr. Priscilla Kincaid-Smith, Department of Nephrology, The Royal Melbourne Hospital, Victoria, 3050 Australia. Manuscript accepted June 27, 1978.
664
October
1976
FOR PLASMAPHERESIS
Abnormal immune reactants, such as antiglomerular basement membrane antibody and pathogenic immune complexes, are removed irrespective of the replacement solution, whereas depletion of mediators of the immune response, such as complement components and procoagulants, depend on the composition of the replacement fluid. Factors Influencing the Level of Primary Immunoreactants. The phenomenon of autoimmune amplification, which has recently been described in experimental antitubular basement membrane disease, may be an important mechanism in human antibasement membrane disease. Theoretically, plasmapheresis should interrupt this vicious cycle in which autoantibody provokes further autoantibody production. However, because plasmapheresis lowers antiglomerular basement membrane antibody levels, it may remove the normal feedback inhibition of immunoglobulin G (IgG) which inhibits further expansion of the relevant plasma cell population. This could result in a rebound peak of antibody production when plasmapheresis is stopped. One of the reasons for the use of concurrent immunosuppressive therapy is to prevent this rebound. There is evidence that the duration of production of antiglomerular basement membrane antibody and of immune complexes in some cases of rapidly progressive nephritis is of limited duration. The object of the therapy is to prevent irreversible damage during the period that the immune reactants are being produced and to terminate or shorten this phase.
The American Journal of Medlclne
Volume 66
PLASMAPHERESIS IN GLOMERULONEPHRITIS-KINCAID-SMITH.
On theoretic grounds, the rate of production of immune complexes is likely to be lower than that of antiglomerular basement membrane antibody. Further, antiglomerular basement membrane antibody is most commonly IgG and this has a large extravascular distribution, which is not the case with macromolecular immune complexes. More intensive plasmapheresis may, therefore, be necessary in IgG antibody-mediated disease than in soluble immune complex-mediated disease. Depletion of Mediators of Renal Injury. The importance of the coagulation and complement systems in the mediation of glomerular injury of nephrotoxic nephritis has been established. In experimental models, defibrination by ancrod has been shown to prevent crescent formation, and decomplementation by cobra venom factor prevents polymorphdependent injury. The mechanisms of glomerular injury in immune complexmediated nephritis are less well understood. Fibrinogen, despite its being an acute phase reactant, is readily depleted by intensive plasmapheresis [6]. Complement components are variably depleted. In our experience levels of the third component of complement (C3) are reduced to 10 to 30 per cent or normal whereas levels of the fourth component (C4) are barely reduced below the limits of the normal range [6]. METHODOLOGIC ASPECTS The introduction of continuous and semicontinuous plasmapheresis machinery has made the widespread and repeated application of plasmapheresis possible because a 4 liter exchange can be performed in about 2 hours. Vascular access is usually obtained using arteriovenous shunts. Artificial plasma expanders are not satisfactory for replacement during intensive plasmapheresis. The most commonly used solutions are human albumin-based solutions, usually prepared by differential salt precipitation and closely resembling Cohn fraction V in composition. Four liter exchanges have been used by us and by the Hammersmith group. Our practice has been to use plasmapheresis daily for four or five days and then to reduce the frequency to every second or third day. Plasmapheresis should not be commenced within 24 hours of renal biopsy because of the risk of hemorrhage resulting from depletion of fibrinogen and other procoagulants. At present, the duration of treatment is judged by the clinical response obtained. We usually continue treatment for one or two weeks after renal function has stabilized. Several patients have failed to show a marked improvement in renal function for up to two weeks after the start of plasmapheresis, emphasizing the need to continue treatment for a period even
D’APICE
in the absence of improving renal function [6]. The presence of anuria indicates that recovery is extremely unlikely [I], however, we have seen recovery with return of serum creatinine to normal levels in patients with profound oliguria [6]. Folate iron and B group vitamins should be administered to avoid deficiencies of these substances. The removal of antibody combined with the effects of cyclophosphamide and steroids render the patients highly susceptible to infection. Patients should be warned of this risk and told to report any sign of infection, particularly fever. Infection at arteriovenous shunt sites may be a particular problem and must be managed with full aseptic technic, and urgent and detailed microbiologic investigation at the earliest sign of infection. Antibiotics should be chosen to give a broad bactericidal cover until the infecting agent and its sensitivities are known. It is, of course, necessary to administer all drug therapy at the end of plasmapheresis and not in accord with the usual ward routine. If infection does not respond rapidly to therapy, all immunosuppression, including plasmapheresis, should be terminated. CLINICAL EXPERIENCE Goodpasture’s Syndrome. The mortality of patients with Goodpasture’s syndrome, either with or without immunosuppressive therapy, exceeds 90 per cent if one includes in this figure patients who require maintenance dialysis. The Hammersmith group have reported death or terminal renal failure in four of seven patients treated with plasmapheresis [l] and have achieved similar results in a series of 26 patients [5]. We have been able to preserve renal function in five of 10 patients, thus the mortality rate has been reduced by about 50 per cent by the introduction of this form of therapy. Examination of the failures in our group of patients indicates that much better results could have been achieved. Two patients referred late presented with anuria and did not recover renal function, both patients died subsequently, one of pulmonary hemorrhage due to plasmapheresis-induced anticoagulation. In one other patient severe pulmonary hemorrhage developed after initial control of bleeding, but hemorrhage ceased when concommitant heparin therapy was discontinued. Two patients responded to therapy but had a relapse when plasmapheresis was stopped and did not respond adequately when it was reinstituted. One patient died of influenza1 pneumonia contracted during the period of plasmapheresis and immunosuppression. There is also an indication that clinical experience with the treatment of this disease is all important in its success: four of our failures occurred in the first five patients treated. Peters [5] recently emphasized that pulmonary hemorrhage can be precipitated by fluid overload and the administration of anticoagulants.
October 1976
The American Journal of Medicine
Volume 65
565
PLASMAPHERESIS IN GLOMERULONEPHRITIS-KINCAID-SMITH,D’APICE
Furthermore, intercurrent bacterial infection can cause rapid deterioration of renal function and the development of lung hemorrhage, despite continued plasmapheresis and low antiglomerular basement membrane antibody levels [5]. Goodpasture’s syndrome may be an exception to the rule that the anticoagulant effect of plasmapheresis does not usually result in hemorrhage. In three patients, we observed severe renal or pulmonary hemorrhage, which developed during a period of intensive plasmapheresis and responded to cessation of plasmapheresis in one and to the use of fresh frozen plasma during replacement in another. We have not observed this complication in over 50 patients who received intensive plasmapheresis for other indications. Experience, therefore, indicates that plasmapheresis with combined immunosuppression is the treatment of choice in Goodpasture’s syndrome but that success of therapy is critically dependent on early diagnosis and immediate therapy, preferably by an experienced unit. It cannot be overemphasized that treatment should be commenced as soon as possible after diagnosis, as exsanguinating pulmonary hemorrhage causes sudden unexpected deaths. The glomerular lesion also progresses with alarming rapidity and an early focal and segmental lesion may destroy all glomeruli in one to two weeks. The diagnosis of Goodpasture’s syndrome can be made on clinical grounds in the vast majority of cases. The presentation with anemia, dyspnea, pulmonary hemorrhage and the accompanying fulminating glomerulonephritis is very characteristic. The delay in commencing plasmapheresis occasioned by diagnostic renal biopsy can be avoided in the first instance by reliance on clinical diagnosis, and confirmatory biopsy can be used after clinical response to plasmapheresis to confirm the characteristic linear immunoglobulin deposition which persists for months. Plasmapheresis in Goodpasture’s syndrome should be intensive commencing with daily treatment and continuing for at least one week after maximal improvement in renal function or complete cessation of pulmonary hemorrhage. Anticoagulant drugs should not be used and partial
plasma replacement with fresh frozen plasma, given at the end of each exchange, may be necessary in patients with severe pulmonary hemorrhage. Venous pressure should be carefully monitored to avoid circulatory overload. Meticulous aseptic management of arteriovenous shunts is essential to avoid infection. For optimal management, patients should be referred to regional centers. This also permits accumulation of valuable experience with this rare disease. Serial measurement of the corrected gas transfer factor (kC0) has recently been shown to be a more sensitive index of pulmonary hemorrhage than other indices such as hemoptysis, x-ray evidence of pulmonary infiltrates or increasing anemia. Immune Complex-Mediated Glomerulonephritis. Despite the fact that rapidly progressive (crescentic) glomerulonephritis represents only a fraction of the spectrum of immune complex-mediated glomerulonephritis, its fulminant nature, poor prognosis and histologic similarity to the nephritis of Goodpasture’s syndrome caused Peter’s group [3] and our own [4] to study the effects of treatment by plasmapheresis. The patients treated have had a variety of etiologies and associated clinical syndromes, such as polyarteritis nodosa, Wegener’s granulomatosus and systemic lupus erythematosus. The results have been impressive [3,4,6]: in 16 of 22 patients improved renal function was attributable to the therapy. There is little doubt that these results represent a marked improvement over the natural history of the disease in patients with diffuse crescents and a rapidly progressive course. However, although plasmapheresis appears to be an effective form of treatment, other forms of therapy, particularly combinations of heparin and immunosuppressive agents, have also been found to be effective and are much less expensive. Ideally, a controlled trial is desirable to establish the relative merits of these alternative therapies, however, the rarity of the condition may make this impractical. The incidence of serious complications of therapy in this group has been very low compared with that in Goodpasture’s syndrome.
REFERENCES 1.
2.
3.
4.
566
Lockwood CM, Rees AJ, Pearson TA, et al.: Immunosuppression and plasma-exchange in the treatment of Goodpasture’s syndrome. Lancet 1: 711, 1976. Walker RG, d’Apice AJF, Kincaid-Smith P, et al.: Plasmapheresis in Goodpasture’s syndrome with renal failure. Med J Aust 1: 875, 1977. Lockwood CM, et al.: Plasma-exchange and immunosuppression in the treatment of fulminating immune complex crescentic nephritis. Lancet 1: 63, 1977. Becker 61, d’Apice AJF, Walker GJ, et al.: Plasmapheresis in
October 1976
The American Journal of Medlclne
5.
6.
Volume 65
the treatment of glomerulonephritis. Med J Aust 2: 693, 1977. Peters DK: Anti-glomerular basement membrane antibody disease, chap 18. Progress in Glomerulonephritis, (Kinraid-Smith P, d’Apice AJF, Atkins RC. eds) New York, John Wiley 8 Sons, (in press). d’Apice AJF, Kincaid-Smith P: Treatment of glomerulonephritis by plasma exchange, chap 19. Progress in Glomerulonephritis, (Kincaid-Smith P, d’Apice AJF, Atkins RC, ed), New York, John Wiley & Sons, (in press).
