EDITORIAL
Intensive Plasma Exchange in Crescentic Glomerulonephritis: Help or No Help? Richard J. Glassock, MD
I
NTENSIVE plasma exchange, or plasmapheresis as it is often called, was introduced into the nephrologic therapeutic armamentarium in 1976 by the Hammersmith Group led by Lockwood et al. I Initially used to treat various forms of rapidly progressive glomerulonephritis, this form of therapy has been extended to many other types of glomerular disease including systemic lupus erythematosus (SLE), IgA nephropathy, focal glomerulosclerosis, and membranoproliferative glomerulonephritis.2- 5 Until relatively recently, most of the data dealing with the safety and efficacy of this form of therapy were derived from limited, uncontrolled trials, or small studies involving historical noncontemporaneous controls. The vagaries of prognostication in glomerular disease have precluded the establishment of intensive plasma exchange as an appropriate therapy for many disorders. Nevertheless, the serious and often irreversible nature of crescentic glomerulonephritis continues to evoke interest in dramatic remedies such as intensive plasma exchange. We now recognize the diversity of pathogenetic mechanisms operative in crescentic glomerulonephritis and, also at least in some cases, that extensive necrotizing and crescentic glomerulonephritis are manifestations of an organ-limited form of microscopic polyarteritis. 6- 7 Anti-glomerular basement membrane (GBM) antibodymediated disease is widely held to be beneficially affected by combinations of intensive plasma exchange and immunosuppression, providing therapy is begun before dialysis is required. 8 Indeed, many believe that controlled trials of such therapy From the Department ofMedicine, Harbor-UCLA Medical Center, UCLA School ofMedicine, Torrance and Los Angeles, CA. Received May 15, 1992; accepted May 15,1992. Address reprint requests to Richard J. Glassock, MD, Chair, Department of Medicine, University of Kentucky College of Medicine, Lexington, KY 40536-0084. © 1992 by the National Kidney Foundation, Inc. 0272-6386/92/2003-0010$3.00/0 270
can no longer be ethically justified. 9 Nevertheless, it is important to point out that the only controlled trial performed in anti-GBM-mediated disease did not support any additive beneficial effect of intensive plasma exchange. 10 However, since this trial was small and many patients were referred late for therapy, many regard it as inconclusive. Much greater controversy exists as to whether intensive plasma exchange combined with immunosuppression offers any renal or patient survival advantage compared with immunosuppressive therapy alone among patients with non-anti-GBM antibody-mediated disease, including those patients with crescentic glomerulonephritis due to renal-limited forms of microscopic polyarteritis. II The recent description of small groups of patients in whom both anti-GBM antibody-mediated disease and renal limited forms of necrotizing vasculitis coexist adds further confusion to the controversy. 12 Cole et al describe a randomized, controlled trial of intensive plasma exchange and immunosuppression compared with immunosuppression alone in the therapy of crescentic glomerulonephritis in this issue of the American Journal ofKidney Diseases. 13 The conclusion of these investigators, based on 32 patients randomized to receive either therapy, was that intensive plasma exchange did not contribute in a meaningful way to the outcome of the patients when this therapy was added to a standard immunosuppressive regimen. While this study was well done and included a sufficient number of patients to detect an overall effect of intensive plasma exchange if it were present, several caveats must be raised lest we prematurely conclude that intensive plasma exchange is of no additive value to standard immunosuppressive regimens in this disease. Clearly, aggressive therapy of patients with crescentic glomerulonephritis due to non-antiGBM antibody mechanisms early in the course of disease can have a profound effect on outcome. Regimens involving high-dose intravenous methylprednisolone often combined with oral or
American Journal of Kidney Diseases, Vol XX, No 3 (September). 1992: pp 270-275
PLASMAPHERESIS IN CRESCENTIC GLOMERULONEPHRITIS
intravenous cyclophosphamide have yielded excellent short-term results assessed in terms ofimproved renal function, avoidance or discontinuance of dialysis, and partial resolution of the histologic lesion. 14-16 Indeed, 75% to 85% of patients so treated, providing therapy is instituted before the development of irreversible renal damage, experience sustained improvement of renal function, although most patients are left with some residual manifestations of renal injury such as impaired glomerular filtration rate or persistent moderate or even heavy proteinuria and progressive glomerulosclerosis. 14,16,17 There is nearly universal agreement, supported by randomized trials, including those of Cole et aI, that intensive plasma exchange has no additive beneficial effect on such predialysis patients, except for those patients with anti-GBM antibody-mediated disease. 8,18,19 Some patients will later slowly progress to renal failure, often accompanied by nephrotic-range proteinuria. This evolution may well be the consequence of the superimposition of nonimmunologic factors aiding progression. 14-17 Still other patients will eventually die of the extrarenal manifestations of their disease. This is particularly true in the subgroup with microscopic polyarteritis. 14,19 Unfortunately, delays in diagnosis, particularly the tardy application of modern serologic assessment of rapidly progressive glomerulonephritis by measurement of autoantibodies to neutrophil cytoplasmic antigens or GBM antigens, and hesitation over the performance of renal biopsy in patients with rapidly deteriorating renal function, still leads to the disease not being recognized in many patients until it has progressed to dialysis dependency. It is in this group, namely, patients with crescentic glomerulonephritis and severely impaired renal function requiring dialysis, that major controversies continue to exist regarding a possible role for intensive plasma exchange added to immunosuppression. 8,9 Current clinical wisdom would suggest that the benefit is marginal or nonexistent in those patients with anti-GBM antibody disease who have progressed to dialysisdependent renal failure. 8,18 In the largest singlecenter series of such patients reported to date, none of 58 patients with anti-GBM antibodymediated, dialysis-dependent crescentic glomerulonephritis had any improvement when intensive plasma exchange plus immunosuppression
271
was used in therapy.8,9,18 However, occasional anecdotes of partial recovery of renal function coincident with the use of intensive plasma exchange and immunosuppression in such patients continue to appear. Such patients tend to have very fulminant renal disease, very cellular nonfibrotic crescents, and little chronic tubulointerstitial fibrosis. Perhaps the renal failure in these patients is engendered, in part, by "cytokine storm" as the local products of inflammation are produced and released locally. As discussed by Cole et aI, 13 more doubt exists regarding the role of intensive plasma exchange added to immunosuppression in the non-antiGBM antibody-induced variety of induced crescentic glomerulonephritis, including the microscopic forms of polyarteritis and in multisystem diseases, such as Wegener's granulomatosis, where exuberant segmental necrotizing glomerulonephritis and crescent formation may occur and result in rapidly progressive glomerulonephritis. 21 ,22 The nephritis that accompanies SLE is a special case. Although renal failure may ensue in lupus nephritis, it is more often associated with florid endocapillary proliferative glomerulonephritis and only seldom is due to extensive extracapillary crescentic glomerulonephritis. Randomized prospective trials have conclusively shown no additional benefits of intensive plasma exchange in severe lupus nephritis over standard immunosuppression, at least in terms of patient and renal survival in groups of patients with renal insufficiency not requiring renal dialysis? Whether intensive plasma exchange and immunosuppression have a role in the management oflupus nephritis associated with extensive crescentic disease and dialysis-dependent renal failure has not yet been definitively tested. The contemporary medical literature contains several reports relevant to the question of efficacy of intensive plasma exchange added to immunosuppression in dialysis-dependent renal failure due to necrotizing and crescentic glomerulonephritis. 23 ,24 Glockner et al reported on a multicenter randomized prospective trial of intensive plasma exchange added to immunosuppression versus immunosuppression alone.23 Twenty-six patients were randomized to receive either highdose glucocorticoids (1.5 mg/kg/d of oral methylprednisolone initially) plus cyclophosphamide (3 mg/kg/d orally, initially) and azathioprine (1.0
272
mg/kg/d orally, initially), or the same immunosuppressive regimen plus intensive plasma exchange (three sessions per week). All patients had greater than 70% crescents on renal biopsy, either segmental or circumferential, and the initial creatinine clearance was measured to be less than 0.83 mL/s (50 mL/min). After 4 weeks, nonresponders in the immunosuppressive therapy alone group were subsequently offered intensive plasma exchange; and intensive plasma exchange was discontinued after 4 weeks in the nonresponders in the immunosuppression plus intensive plasma exchange groups. Twenty-one of the 26 patients had "idiopathic" rapidly progressive glomerulonephritis, while the remaining five patients had a variety of multisystem diseases, including Wegener's granulomatosis, lupus nephritis, periarteritis nodosa, and scleroderma. At the time therapy was initiated, 12 of the 26 patients already required hemodialysis and the mean serum creatinine for all patients at entry was between 530 and 619 ~mol/L (6.0 and 7.0 mg/dL). Eight of 11 (73%) of the patients receiving immunosuppressive therapy alone and monitored for at least 8 weeks were classified as responders on the basis of improved renal function, including three of four patients initially requiring dialysis. At 6 months' follow-up, the average serum creatinine for this group had declined to 221 ~mol/L (2.5 mg/dL) from pretherapy values of 619 ~mol/L (7.0 mg/dL). On the other hand, nine of 13 (69%) of patients receiving intensive plasma exchange added to immunosuppression were judged improved at 8 weeks, including five of eight patients who were receiving hemodialysis at study entry. At 6 months' follow-up, the average serum creatinine for this group of patients had declined to 248 ~mol/L (2.8 mg/dL) from pretherapy values of 548 ~mol/L (6.2 mg/dL). While the extent of recovery was no different between the two groups, the speed of response was somewhat more rapid in the intensive plasma exchange plus immunosuppression group (33% response rate in immunosuppression alone v 50% response rate in the intensive plasma exchange plus immunosuppression group at 4 weeks). Furthermore, the extent of improvement in the hemodialysis-dependent patients receiving intensive plasma exchange plus immunosuppression was somewhat better (average serum creatinine at 6 months of 486 ~mol/L [5.5 mg/dL] in the im-
RICHARD J. GLASSOCK
munosuppressive therapy alone group v 150 [1.7 mg/dL] in the group receiving both intensive plasma exchange and immunosuppression). However, the number of patients in the dialysis-dependent category was too small (n = 12) to draw any firm conclusions. Nevertheless, this study suggested that intensive plasma exchange had no added benefit over immunosuppressive therapy alone in crescentic glomerulonephritis. It is noteworthy that two thirds to three quarters of all patients responded to immunosuppressive therapy alone. Similar or superior results have been reported by others using a variety of regimens, including high-dose intravenous methylprednisolone with or without oral or intravenous cyclophosphamide in what appears to be a comparable group of patients. 14·16 Quite different conclusions were reached by Pusey et al in another recently published controlled trial of intensive plasma exchange in crescentic glomerulonephritis inaugurated in 1978. 24 These investigators reported on a single-center, randomized study of intensive plasma exchange plus immunosuppression compared with immunosuppression alone in patients with necrotizing and/or crescentic glomerulonephritis. A total of 48 evaluable patients were randomized to receive either glucocorticoids (prednisolone 60 mg/d orally, initially) plus cyclophosphamide (3 mg/kg/d orally, initially) and azathioprine (1 mg/ kg/d orally, initially). A reduced dose of cyclophosphamide and no azathioprine was used in patients over the age of 55 at study entry. The experimental group received the same immunosuppressive regimen plus intensive plasma exchange (five exchanges per week initially). Only five patients had idiopathic rapidly progressive glomerulonephritis (according to definitions used by the authors), whereas 43 patients had either Wegener's granulomatosis or microscopic polyarteritis. All patients had evidence of segmental and necrotizing glomerulonephritis, and most but not all, had extensive extracapillary crescents. Approximately 22 of the 48 patients had predominately endocapillary necrotizing rather than extracapillary crescentic glomerulonephritis. All but two patients had increase serum creatinine levels (>124 ~mol/L [1.4 mg/dL]) at entry. Nineteen of the 48 patients were dialysis-dependent at the time therapy was begun. No significant differences between the groups were noted at en~mol/L
PLASMAPHERESIS IN CRESCENTIC GLOMERULONEPHRITIS
try in terms of severity of disease or underlying diagnosis. At 4 weeks following initiation oftherapy, virtually all patients who were not dialysisdependent were improved in both the treatment groups. Among the non-dialysis-dependent patients, only one patient in the immunosuppression only group died of a subarachnoid hemorrhage and progressive renal failure at 2 months. Another patient died of lung hemorrhage at I month. On the other hand, six patients died in the intensive plasma exchange group (two of acute myocardial infarction, one of cardiac failure, one of pneumonia, and one of renal failure). The results in the dialysis-dependent group were quite different in that only three of eight patients receiving immunosuppressive therapy alone recovered sufficient renal failure to discontinue dialysis, two of whom were still alive at 3 and 5 years following discontinuance of therapy with near-normal or normal renal function. On the other hand, 10 of 11 dialysis patients treated with intensive plasma exchange plus immunosuppression recovered independent renal function. Three patients in this group died in less than 3 months (largely of infection or lung hemorrhage). Among long-term survivors, later progression to renal insufficiency was common, but no patient had to return to hemodialysis even after follow-up periods of 3 to 8 years. The prevalence of partial renal functional recovery in dialysis-dependent patients treated with intensive plasma exchange plus immunosuppressive therapy in this series is higher than that reported by Glockner et al and in other series that used pulse methylprednisolone alone. 13 ,23 However, the results of therapy of dialysis-dependent patients with immunosuppression alone are less satisfactory than those reported using similar therapy by Glockner et al. 23 The study of Cole et al 13 supports the conclusions of Glockner et al. 23 The patient population studied by Cole et al 13 resembles that studied by the latter authors, but the treatment protocols differed in that pulse methylprednisolone (10 mg/ kg/d) was used as the initial glucocorticoid therapy and azathioprine (1.5 to 3.0 mg/kg/d) was the only cytotoxic agent administered. The intensity of plasma exchange was comparable to that used by Glockner et al and Pusey et al. 23,24 Both patients with obvious systemic disease or anti-GBM antibody-mediated disease were ex-
273
cluded. It was not possible to determine in this study how many patients actually had microscopic polyarteritis versus idiopathic rapidly progressive glomerulonephritis if indeed this disorders can be distinguished. Approximately 40% of patients had only trace amounts of immunoglobulins deposited in their glomeruli and approximately 70% of those tested had anti-neutrophil cytoplasmic autoantibodies, thus indicating that a renal-limited form of microscopic polyarteritis was common among their patients. Among the 32 randomized patients, no clinical or histological differences could be distinguished at the time of entry between the group treated with intensive plasma exchange plus immunosuppression and the group treated with immunosuppression alone. Eleven of the 32 patients were on dialysis at the time of randomization versus 12 of 26 in the Glockner et al study and 19 of 48 in the Pusey et al trial. 23,24 While no differences in outcome of the non-dialysis-dependent patients could be found, confirming the results of other controlled trials,23,24 three of four patients receiving intensive plasma exchange plus immunosuppression discontinued dialysis versus two of seven patients receiving immunosuppression only. Two patients receiving intensive plasma exchange plus immunosuppression not initially receiving dialysis, eventually required dialysis for progressive renal impairment. Among the non dialyzed patients receiving immunosuppression alone, seven of nine (78%) improved, whereas among those receiving intensive plasma exchange plus immunosuppression, eight of twelve (67%) improved. Therefore, in agreement with other controlled trials,23,24 intensive plasma exchange provides no additive benefit over conventional immunosuppressive therapy (employing glucocorticoids, cyclophosphamide, and/or azathioprine) in non-dialysis-dependent patients with crescentic glomerulonephritis, the majority of whom are likely to have a form of microscopic polyarteritis. Interestingly, the improvement rate (78%) in non-dialysis-dependent patients receiving immunosuppressives alone in this study, which used intravenous pulse methylprednisolone as initial therapy, is not different from that of similar groups in the studies of Pusey et al (93%) and Glockner et al (71 %), which used oral prednisone as the glucocorticoid regimen. 23 ,24 Thus, pooling of the results in all three series, 26
274
RICHARD J. GLASSOCK
of 31 (84%) of patients without dialysis dependency responded to combinations of oral or intravenous glucocorticoids plus immunosuppressive therapy only. Among dialysis-dependent patients treated with intensive plasma exchange plus immunosuppression, 77% improved, whereas among those patients treated with immunosuppression alone, 42% improved. Although the trials mentioned above are small and probably studied a somewhat different group of patients in differing stages of a rapidly progressive disease, several generalizations can be drawn from their collective results: (1) Segmental necrotizing and/or crescentic glomerulonephritis not due to anti-GBM antibody disease and associated with progressive renal failure is a disorder, which when treated in the early stages of its evolution, is quite responsive to therapy with combinations of glucocorticoids and cytotoxic agents. Intensive plasma exchange added to this regimen contributes little or nothing to the eventual outcome, and 80% or more of patients can be expected to at least initially experience improved renal function. On the other hand, anti-GBM antibody-induced disease is clearly benefitted by early application of intensive plasma exchange added to immunosuppression. (2) High-dose methylprednisolone may not be necessary in initial management, particularly in patients with regimens incorporating cyclophosphamide. This would likely be particularly true in patients with renal-limited forms of microscopic polyarteritis as evidenced by segmental capillary necrosis and/or seropositivity for antineutrophil cytoplasmic antibody. (3) In patients with non-anti-GBM antibodyinduced disease who have already progressed to dialysis-dependent renal failure, the addition of intensive plasma exchange to a regimen of immunosuppression may have some marginal benefits, at least over the short term. Whether this marginal benefit is worthwhile can only be de-
termined on a case-by-case basis. Unfortunately, many patients will eventually later progress to renal insufficiency, perhaps reflecting nonimmunologic responses activated by very severe initial disease. Attention to these latter factors in all patients who have partially recovered renal function after an episode of crescentic glomerulonephritis is required. Long-term patient mortality will probably remain high, particularly among older patients and those with underlying multisystem disease. Anti-GBM antibody-induced nephritis that has progressed to dialysis dependency is poorly responsive, if at all, to intensive plasma exchange and immunosuppression. (4) Until further trials are conducted, it would seem appropriate to perform serologic studies (including anti-GBM, anti-neutrophil cytoplasmic antibody, and antinuclear antibody) and renal biopsy, when feasible, as quickly as possible in all patients with the syndrome of rapidly progressive glomerulonephritis so that appropriate therapy can be initiated early in the course. For the non-anti-GBM antibody-mediated disease (usually but not universally anti-neutrophil cytoplasmic autoantibody-positive), oral or intravenous glucocorticoids plus a cytotoxic agent (azathioprine and/or cyclophosphamide) would seem to be the best initial therapy. Intensive plasma exchange could be added for patients who are nonresponsive to this therapy after 1 to 2 weeks or if severe dialysis-dependent renal failure is also present. Intensive plasma exchange plus immunosuppression must be applied early in the course of anti-GBM antibody-induced disease in order to obtain maximum benefit. Although intensive plasma exchange is a valuable and effective form of therapy in certain progressive renal diseases, the degree to which it helps in fostering a favorable outcome is dependent on when it is administered in the course of disease and the type of disease being treated.
REFERENCES I. Lockwood CM, Rees AJ, Pearson TA, et al: Immunosuppression and plasma exchange in the treatment of Goodpasture's syndrome. Lancet 1:711·715, 1976 2. Lewis E, Lachin J: Primary outcomes in the controlled trial of plasmapheresis therapy in severe lupus nephritis. Kidney Int 31 :208, 1987 3. Coppo R, Basolo P, Grachino 0, et al: Plasmapheresis in a patient with rapidly progressive idiopathic IgA nephrop-
athy: Removal of IgA containing immune complexes and clinical recovery. Nephron 40:488-490, 1985 4. Zimmerman SW: Plasmapheresis and dipyridamole for recurrent focal glomerular sclerosis. Nephron 40:241-245, 1985 5. D'Apice AJF: Plasmapheresis for the management of renal diseases, in Massry S, Glassock RJ (eds): Textbook of Nephrology (ed 2). Baltimore, MD, Williams & Wilkins, 1989, pp 1571-1576
PLASMAPHERESIS IN CRESCENTIC GLOMERULONEPHRITIS
6. Couser WG: Rapidly progressive glomerulonephritis: Classification, pathogenetic mechanism and therapy. Am 1 Kidney Dis 6:449-464, 1988 7. Falk R, lennettel: Antineutrophil cytoplasmic antibodies with specificity for myeloperoxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic nephritis. N Engll Med 318:1651-1657,1988 8. Pusey CD, Lockwood CM: Plasma exchange for glomerular disease, in Robinson DR (ed): Nephrology. New York, NY, Springer-Verlag, 1984, pp 1474-1485 9. Rees Al, Lockwood CM: Anti-glomerular basement membrane antibody mediated nephritis, in Schrier RW, Gottshalk C (eds): Disease of the Kidney. Boston, MA, Little Brown, 1988, pp 2091-2126 10. 10hnson 1, Moore 1, Austin HH, et al: Therapy of antiglomerular basement membrane antibody disease: Analysis of prognostic significance of clinical, pathologic and treatment factors. Medicine (Baltimore) 64:21911. Crocker B, Lee T, Gunnells 1: Clinical and pathologic features of polyarteritis nodosa and its renal-limited variant: Primary crescentic and necrotizing glomerulonephritis. Hum Pathol 18:38-44, 1987 12. layne DRW, Marshall PD, Jones SJ, et al: Antibodies to GBM and neutrophil cytoplasm in rapidly progressive glomerulonephritis. Kidney Int 37:965-970, 1990 13. Cole E, Cattran D, Magil A, et al: A prospective randomized trial of plasma exchange as additive therapy in idiopathic crescentic glomerulonephritis. Am J Kidney Dis 20: 261-269, 1992 14. Bruns FJ, Adler S, Fraley RS, et al: Long-term followup of aggressively treated idiopathic rapidly progressive glomerulonephritis. Am J Med 86:400-406, 1989
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15. Bolton WK, Sturgill BC: Methylprednisolone therapy for acute, crescentic rapidly progressive glomerulonephritis. Am J NephroI9:368-375, 1989 16. Kunis CL, Kiss B, Williams G, et al: Intravenous "pulse" cyclophosphamide therapy of crescentic glomerulonephritis. Clin NephroI37:1-7, 1992 17. Leaker B, Neild GH: Effect of enalapril on proteinuria and renal function in patients with healed severe crescentic glomerulonephritis. Nephrol Dial Transplant 6:936-938, 1991 18. Savage COS, Pusey CD, Bowman C, et al: Antiglomerular basement membrane antibody mediated disease in the British Isles, 1980-1984. Br Med J 292:301-304, 1986 19. Lockwood CM, Pinching AJ, Seveny P, et al: Plasma exchange and immunosuppression in the treatment of fulminating immune complex crescentic nephritis. Lancet 1:6367, 1977 20. Hind CRK, Paraskevekow H, Lockwood CM, et al: The prognosis after immunosuppression in patients with crescentic nephritis needing dialysis. Lancet 1:98- iO 1, 1983 21. Savage COS, Winearls CG, Evans DJ, et al: Microscopic polyarteritis: Presentation, pathology and prognosis. Q J Med 56:467-483, 1985 22. Pinching AJ, Lockwood CM, Prussell BA, et al: Wegener's granulomatosis: Observation in 18 patients with severe renal disease. Q J Med 52:435-460, 1983 23. Glockner WM, Siebierth HG, Wichmann H, et al: Plasma exchange and immunosuppression in rapidly progressive glomerulonephritis: A controlled, multicenter study. Clin NephroI29:1-8, 1988 24. Pusey CD, Rees AJ, Evans DJ, et al: Plasma exchange in focal necrotizing glomerulonephritis without anti-GBM antibodies. Kidney Int 40:757-763, 1991
Intensive Plasma Exchange in Crescentic Glomerulonephritis: Help or No Help? Richard J. Glassock, MD
I
NTENSIVE plasma exchange, or plasmapheresis as it is often called, was introduced into the nephrologic therapeutic armamentarium in 1976 by the Hammersmith Group led by Lockwood et al. I Initially used to treat various forms of rapidly progressive glomerulonephritis, this form of therapy has been extended to many other types of glomerular disease including systemic lupus erythematosus (SLE), IgA nephropathy, focal glomerulosclerosis, and membranoproliferative glomerulonephritis.2- 5 Until relatively recently, most of the data dealing with the safety and efficacy of this form of therapy were derived from limited, uncontrolled trials, or small studies involving historical noncontemporaneous controls. The vagaries of prognostication in glomerular disease have precluded the establishment of intensive plasma exchange as an appropriate therapy for many disorders. Nevertheless, the serious and often irreversible nature of crescentic glomerulonephritis continues to evoke interest in dramatic remedies such as intensive plasma exchange. We now recognize the diversity of pathogenetic mechanisms operative in crescentic glomerulonephritis and, also at least in some cases, that extensive necrotizing and crescentic glomerulonephritis are manifestations of an organ-limited form of microscopic polyarteritis. 6- 7 Anti-glomerular basement membrane (GBM) antibodymediated disease is widely held to be beneficially affected by combinations of intensive plasma exchange and immunosuppression, providing therapy is begun before dialysis is required. 8 Indeed, many believe that controlled trials of such therapy From the Department ofMedicine, Harbor-UCLA Medical Center, UCLA School ofMedicine, Torrance and Los Angeles, CA. Received May 15, 1992; accepted May 15,1992. Address reprint requests to Richard J. Glassock, MD, Chair, Department of Medicine, University of Kentucky College of Medicine, Lexington, KY 40536-0084. © 1992 by the National Kidney Foundation, Inc. 0272-6386/92/2003-0010$3.00/0 270
can no longer be ethically justified. 9 Nevertheless, it is important to point out that the only controlled trial performed in anti-GBM-mediated disease did not support any additive beneficial effect of intensive plasma exchange. 10 However, since this trial was small and many patients were referred late for therapy, many regard it as inconclusive. Much greater controversy exists as to whether intensive plasma exchange combined with immunosuppression offers any renal or patient survival advantage compared with immunosuppressive therapy alone among patients with non-anti-GBM antibody-mediated disease, including those patients with crescentic glomerulonephritis due to renal-limited forms of microscopic polyarteritis. II The recent description of small groups of patients in whom both anti-GBM antibody-mediated disease and renal limited forms of necrotizing vasculitis coexist adds further confusion to the controversy. 12 Cole et al describe a randomized, controlled trial of intensive plasma exchange and immunosuppression compared with immunosuppression alone in the therapy of crescentic glomerulonephritis in this issue of the American Journal ofKidney Diseases. 13 The conclusion of these investigators, based on 32 patients randomized to receive either therapy, was that intensive plasma exchange did not contribute in a meaningful way to the outcome of the patients when this therapy was added to a standard immunosuppressive regimen. While this study was well done and included a sufficient number of patients to detect an overall effect of intensive plasma exchange if it were present, several caveats must be raised lest we prematurely conclude that intensive plasma exchange is of no additive value to standard immunosuppressive regimens in this disease. Clearly, aggressive therapy of patients with crescentic glomerulonephritis due to non-antiGBM antibody mechanisms early in the course of disease can have a profound effect on outcome. Regimens involving high-dose intravenous methylprednisolone often combined with oral or
American Journal of Kidney Diseases, Vol XX, No 3 (September). 1992: pp 270-275
PLASMAPHERESIS IN CRESCENTIC GLOMERULONEPHRITIS
intravenous cyclophosphamide have yielded excellent short-term results assessed in terms ofimproved renal function, avoidance or discontinuance of dialysis, and partial resolution of the histologic lesion. 14-16 Indeed, 75% to 85% of patients so treated, providing therapy is instituted before the development of irreversible renal damage, experience sustained improvement of renal function, although most patients are left with some residual manifestations of renal injury such as impaired glomerular filtration rate or persistent moderate or even heavy proteinuria and progressive glomerulosclerosis. 14,16,17 There is nearly universal agreement, supported by randomized trials, including those of Cole et aI, that intensive plasma exchange has no additive beneficial effect on such predialysis patients, except for those patients with anti-GBM antibody-mediated disease. 8,18,19 Some patients will later slowly progress to renal failure, often accompanied by nephrotic-range proteinuria. This evolution may well be the consequence of the superimposition of nonimmunologic factors aiding progression. 14-17 Still other patients will eventually die of the extrarenal manifestations of their disease. This is particularly true in the subgroup with microscopic polyarteritis. 14,19 Unfortunately, delays in diagnosis, particularly the tardy application of modern serologic assessment of rapidly progressive glomerulonephritis by measurement of autoantibodies to neutrophil cytoplasmic antigens or GBM antigens, and hesitation over the performance of renal biopsy in patients with rapidly deteriorating renal function, still leads to the disease not being recognized in many patients until it has progressed to dialysis dependency. It is in this group, namely, patients with crescentic glomerulonephritis and severely impaired renal function requiring dialysis, that major controversies continue to exist regarding a possible role for intensive plasma exchange added to immunosuppression. 8,9 Current clinical wisdom would suggest that the benefit is marginal or nonexistent in those patients with anti-GBM antibody disease who have progressed to dialysisdependent renal failure. 8,18 In the largest singlecenter series of such patients reported to date, none of 58 patients with anti-GBM antibodymediated, dialysis-dependent crescentic glomerulonephritis had any improvement when intensive plasma exchange plus immunosuppression
271
was used in therapy.8,9,18 However, occasional anecdotes of partial recovery of renal function coincident with the use of intensive plasma exchange and immunosuppression in such patients continue to appear. Such patients tend to have very fulminant renal disease, very cellular nonfibrotic crescents, and little chronic tubulointerstitial fibrosis. Perhaps the renal failure in these patients is engendered, in part, by "cytokine storm" as the local products of inflammation are produced and released locally. As discussed by Cole et aI, 13 more doubt exists regarding the role of intensive plasma exchange added to immunosuppression in the non-antiGBM antibody-induced variety of induced crescentic glomerulonephritis, including the microscopic forms of polyarteritis and in multisystem diseases, such as Wegener's granulomatosis, where exuberant segmental necrotizing glomerulonephritis and crescent formation may occur and result in rapidly progressive glomerulonephritis. 21 ,22 The nephritis that accompanies SLE is a special case. Although renal failure may ensue in lupus nephritis, it is more often associated with florid endocapillary proliferative glomerulonephritis and only seldom is due to extensive extracapillary crescentic glomerulonephritis. Randomized prospective trials have conclusively shown no additional benefits of intensive plasma exchange in severe lupus nephritis over standard immunosuppression, at least in terms of patient and renal survival in groups of patients with renal insufficiency not requiring renal dialysis? Whether intensive plasma exchange and immunosuppression have a role in the management oflupus nephritis associated with extensive crescentic disease and dialysis-dependent renal failure has not yet been definitively tested. The contemporary medical literature contains several reports relevant to the question of efficacy of intensive plasma exchange added to immunosuppression in dialysis-dependent renal failure due to necrotizing and crescentic glomerulonephritis. 23 ,24 Glockner et al reported on a multicenter randomized prospective trial of intensive plasma exchange added to immunosuppression versus immunosuppression alone.23 Twenty-six patients were randomized to receive either highdose glucocorticoids (1.5 mg/kg/d of oral methylprednisolone initially) plus cyclophosphamide (3 mg/kg/d orally, initially) and azathioprine (1.0
272
mg/kg/d orally, initially), or the same immunosuppressive regimen plus intensive plasma exchange (three sessions per week). All patients had greater than 70% crescents on renal biopsy, either segmental or circumferential, and the initial creatinine clearance was measured to be less than 0.83 mL/s (50 mL/min). After 4 weeks, nonresponders in the immunosuppressive therapy alone group were subsequently offered intensive plasma exchange; and intensive plasma exchange was discontinued after 4 weeks in the nonresponders in the immunosuppression plus intensive plasma exchange groups. Twenty-one of the 26 patients had "idiopathic" rapidly progressive glomerulonephritis, while the remaining five patients had a variety of multisystem diseases, including Wegener's granulomatosis, lupus nephritis, periarteritis nodosa, and scleroderma. At the time therapy was initiated, 12 of the 26 patients already required hemodialysis and the mean serum creatinine for all patients at entry was between 530 and 619 ~mol/L (6.0 and 7.0 mg/dL). Eight of 11 (73%) of the patients receiving immunosuppressive therapy alone and monitored for at least 8 weeks were classified as responders on the basis of improved renal function, including three of four patients initially requiring dialysis. At 6 months' follow-up, the average serum creatinine for this group had declined to 221 ~mol/L (2.5 mg/dL) from pretherapy values of 619 ~mol/L (7.0 mg/dL). On the other hand, nine of 13 (69%) of patients receiving intensive plasma exchange added to immunosuppression were judged improved at 8 weeks, including five of eight patients who were receiving hemodialysis at study entry. At 6 months' follow-up, the average serum creatinine for this group of patients had declined to 248 ~mol/L (2.8 mg/dL) from pretherapy values of 548 ~mol/L (6.2 mg/dL). While the extent of recovery was no different between the two groups, the speed of response was somewhat more rapid in the intensive plasma exchange plus immunosuppression group (33% response rate in immunosuppression alone v 50% response rate in the intensive plasma exchange plus immunosuppression group at 4 weeks). Furthermore, the extent of improvement in the hemodialysis-dependent patients receiving intensive plasma exchange plus immunosuppression was somewhat better (average serum creatinine at 6 months of 486 ~mol/L [5.5 mg/dL] in the im-
RICHARD J. GLASSOCK
munosuppressive therapy alone group v 150 [1.7 mg/dL] in the group receiving both intensive plasma exchange and immunosuppression). However, the number of patients in the dialysis-dependent category was too small (n = 12) to draw any firm conclusions. Nevertheless, this study suggested that intensive plasma exchange had no added benefit over immunosuppressive therapy alone in crescentic glomerulonephritis. It is noteworthy that two thirds to three quarters of all patients responded to immunosuppressive therapy alone. Similar or superior results have been reported by others using a variety of regimens, including high-dose intravenous methylprednisolone with or without oral or intravenous cyclophosphamide in what appears to be a comparable group of patients. 14·16 Quite different conclusions were reached by Pusey et al in another recently published controlled trial of intensive plasma exchange in crescentic glomerulonephritis inaugurated in 1978. 24 These investigators reported on a single-center, randomized study of intensive plasma exchange plus immunosuppression compared with immunosuppression alone in patients with necrotizing and/or crescentic glomerulonephritis. A total of 48 evaluable patients were randomized to receive either glucocorticoids (prednisolone 60 mg/d orally, initially) plus cyclophosphamide (3 mg/kg/d orally, initially) and azathioprine (1 mg/ kg/d orally, initially). A reduced dose of cyclophosphamide and no azathioprine was used in patients over the age of 55 at study entry. The experimental group received the same immunosuppressive regimen plus intensive plasma exchange (five exchanges per week initially). Only five patients had idiopathic rapidly progressive glomerulonephritis (according to definitions used by the authors), whereas 43 patients had either Wegener's granulomatosis or microscopic polyarteritis. All patients had evidence of segmental and necrotizing glomerulonephritis, and most but not all, had extensive extracapillary crescents. Approximately 22 of the 48 patients had predominately endocapillary necrotizing rather than extracapillary crescentic glomerulonephritis. All but two patients had increase serum creatinine levels (>124 ~mol/L [1.4 mg/dL]) at entry. Nineteen of the 48 patients were dialysis-dependent at the time therapy was begun. No significant differences between the groups were noted at en~mol/L
PLASMAPHERESIS IN CRESCENTIC GLOMERULONEPHRITIS
try in terms of severity of disease or underlying diagnosis. At 4 weeks following initiation oftherapy, virtually all patients who were not dialysisdependent were improved in both the treatment groups. Among the non-dialysis-dependent patients, only one patient in the immunosuppression only group died of a subarachnoid hemorrhage and progressive renal failure at 2 months. Another patient died of lung hemorrhage at I month. On the other hand, six patients died in the intensive plasma exchange group (two of acute myocardial infarction, one of cardiac failure, one of pneumonia, and one of renal failure). The results in the dialysis-dependent group were quite different in that only three of eight patients receiving immunosuppressive therapy alone recovered sufficient renal failure to discontinue dialysis, two of whom were still alive at 3 and 5 years following discontinuance of therapy with near-normal or normal renal function. On the other hand, 10 of 11 dialysis patients treated with intensive plasma exchange plus immunosuppression recovered independent renal function. Three patients in this group died in less than 3 months (largely of infection or lung hemorrhage). Among long-term survivors, later progression to renal insufficiency was common, but no patient had to return to hemodialysis even after follow-up periods of 3 to 8 years. The prevalence of partial renal functional recovery in dialysis-dependent patients treated with intensive plasma exchange plus immunosuppressive therapy in this series is higher than that reported by Glockner et al and in other series that used pulse methylprednisolone alone. 13 ,23 However, the results of therapy of dialysis-dependent patients with immunosuppression alone are less satisfactory than those reported using similar therapy by Glockner et al. 23 The study of Cole et al 13 supports the conclusions of Glockner et al. 23 The patient population studied by Cole et al 13 resembles that studied by the latter authors, but the treatment protocols differed in that pulse methylprednisolone (10 mg/ kg/d) was used as the initial glucocorticoid therapy and azathioprine (1.5 to 3.0 mg/kg/d) was the only cytotoxic agent administered. The intensity of plasma exchange was comparable to that used by Glockner et al and Pusey et al. 23,24 Both patients with obvious systemic disease or anti-GBM antibody-mediated disease were ex-
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cluded. It was not possible to determine in this study how many patients actually had microscopic polyarteritis versus idiopathic rapidly progressive glomerulonephritis if indeed this disorders can be distinguished. Approximately 40% of patients had only trace amounts of immunoglobulins deposited in their glomeruli and approximately 70% of those tested had anti-neutrophil cytoplasmic autoantibodies, thus indicating that a renal-limited form of microscopic polyarteritis was common among their patients. Among the 32 randomized patients, no clinical or histological differences could be distinguished at the time of entry between the group treated with intensive plasma exchange plus immunosuppression and the group treated with immunosuppression alone. Eleven of the 32 patients were on dialysis at the time of randomization versus 12 of 26 in the Glockner et al study and 19 of 48 in the Pusey et al trial. 23,24 While no differences in outcome of the non-dialysis-dependent patients could be found, confirming the results of other controlled trials,23,24 three of four patients receiving intensive plasma exchange plus immunosuppression discontinued dialysis versus two of seven patients receiving immunosuppression only. Two patients receiving intensive plasma exchange plus immunosuppression not initially receiving dialysis, eventually required dialysis for progressive renal impairment. Among the non dialyzed patients receiving immunosuppression alone, seven of nine (78%) improved, whereas among those receiving intensive plasma exchange plus immunosuppression, eight of twelve (67%) improved. Therefore, in agreement with other controlled trials,23,24 intensive plasma exchange provides no additive benefit over conventional immunosuppressive therapy (employing glucocorticoids, cyclophosphamide, and/or azathioprine) in non-dialysis-dependent patients with crescentic glomerulonephritis, the majority of whom are likely to have a form of microscopic polyarteritis. Interestingly, the improvement rate (78%) in non-dialysis-dependent patients receiving immunosuppressives alone in this study, which used intravenous pulse methylprednisolone as initial therapy, is not different from that of similar groups in the studies of Pusey et al (93%) and Glockner et al (71 %), which used oral prednisone as the glucocorticoid regimen. 23 ,24 Thus, pooling of the results in all three series, 26
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of 31 (84%) of patients without dialysis dependency responded to combinations of oral or intravenous glucocorticoids plus immunosuppressive therapy only. Among dialysis-dependent patients treated with intensive plasma exchange plus immunosuppression, 77% improved, whereas among those patients treated with immunosuppression alone, 42% improved. Although the trials mentioned above are small and probably studied a somewhat different group of patients in differing stages of a rapidly progressive disease, several generalizations can be drawn from their collective results: (1) Segmental necrotizing and/or crescentic glomerulonephritis not due to anti-GBM antibody disease and associated with progressive renal failure is a disorder, which when treated in the early stages of its evolution, is quite responsive to therapy with combinations of glucocorticoids and cytotoxic agents. Intensive plasma exchange added to this regimen contributes little or nothing to the eventual outcome, and 80% or more of patients can be expected to at least initially experience improved renal function. On the other hand, anti-GBM antibody-induced disease is clearly benefitted by early application of intensive plasma exchange added to immunosuppression. (2) High-dose methylprednisolone may not be necessary in initial management, particularly in patients with regimens incorporating cyclophosphamide. This would likely be particularly true in patients with renal-limited forms of microscopic polyarteritis as evidenced by segmental capillary necrosis and/or seropositivity for antineutrophil cytoplasmic antibody. (3) In patients with non-anti-GBM antibodyinduced disease who have already progressed to dialysis-dependent renal failure, the addition of intensive plasma exchange to a regimen of immunosuppression may have some marginal benefits, at least over the short term. Whether this marginal benefit is worthwhile can only be de-
termined on a case-by-case basis. Unfortunately, many patients will eventually later progress to renal insufficiency, perhaps reflecting nonimmunologic responses activated by very severe initial disease. Attention to these latter factors in all patients who have partially recovered renal function after an episode of crescentic glomerulonephritis is required. Long-term patient mortality will probably remain high, particularly among older patients and those with underlying multisystem disease. Anti-GBM antibody-induced nephritis that has progressed to dialysis dependency is poorly responsive, if at all, to intensive plasma exchange and immunosuppression. (4) Until further trials are conducted, it would seem appropriate to perform serologic studies (including anti-GBM, anti-neutrophil cytoplasmic antibody, and antinuclear antibody) and renal biopsy, when feasible, as quickly as possible in all patients with the syndrome of rapidly progressive glomerulonephritis so that appropriate therapy can be initiated early in the course. For the non-anti-GBM antibody-mediated disease (usually but not universally anti-neutrophil cytoplasmic autoantibody-positive), oral or intravenous glucocorticoids plus a cytotoxic agent (azathioprine and/or cyclophosphamide) would seem to be the best initial therapy. Intensive plasma exchange could be added for patients who are nonresponsive to this therapy after 1 to 2 weeks or if severe dialysis-dependent renal failure is also present. Intensive plasma exchange plus immunosuppression must be applied early in the course of anti-GBM antibody-induced disease in order to obtain maximum benefit. Although intensive plasma exchange is a valuable and effective form of therapy in certain progressive renal diseases, the degree to which it helps in fostering a favorable outcome is dependent on when it is administered in the course of disease and the type of disease being treated.
REFERENCES I. Lockwood CM, Rees AJ, Pearson TA, et al: Immunosuppression and plasma exchange in the treatment of Goodpasture's syndrome. Lancet 1:711·715, 1976 2. Lewis E, Lachin J: Primary outcomes in the controlled trial of plasmapheresis therapy in severe lupus nephritis. Kidney Int 31 :208, 1987 3. Coppo R, Basolo P, Grachino 0, et al: Plasmapheresis in a patient with rapidly progressive idiopathic IgA nephrop-
athy: Removal of IgA containing immune complexes and clinical recovery. Nephron 40:488-490, 1985 4. Zimmerman SW: Plasmapheresis and dipyridamole for recurrent focal glomerular sclerosis. Nephron 40:241-245, 1985 5. D'Apice AJF: Plasmapheresis for the management of renal diseases, in Massry S, Glassock RJ (eds): Textbook of Nephrology (ed 2). Baltimore, MD, Williams & Wilkins, 1989, pp 1571-1576
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6. Couser WG: Rapidly progressive glomerulonephritis: Classification, pathogenetic mechanism and therapy. Am 1 Kidney Dis 6:449-464, 1988 7. Falk R, lennettel: Antineutrophil cytoplasmic antibodies with specificity for myeloperoxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic nephritis. N Engll Med 318:1651-1657,1988 8. Pusey CD, Lockwood CM: Plasma exchange for glomerular disease, in Robinson DR (ed): Nephrology. New York, NY, Springer-Verlag, 1984, pp 1474-1485 9. Rees Al, Lockwood CM: Anti-glomerular basement membrane antibody mediated nephritis, in Schrier RW, Gottshalk C (eds): Disease of the Kidney. Boston, MA, Little Brown, 1988, pp 2091-2126 10. 10hnson 1, Moore 1, Austin HH, et al: Therapy of antiglomerular basement membrane antibody disease: Analysis of prognostic significance of clinical, pathologic and treatment factors. Medicine (Baltimore) 64:21911. Crocker B, Lee T, Gunnells 1: Clinical and pathologic features of polyarteritis nodosa and its renal-limited variant: Primary crescentic and necrotizing glomerulonephritis. Hum Pathol 18:38-44, 1987 12. layne DRW, Marshall PD, Jones SJ, et al: Antibodies to GBM and neutrophil cytoplasm in rapidly progressive glomerulonephritis. Kidney Int 37:965-970, 1990 13. Cole E, Cattran D, Magil A, et al: A prospective randomized trial of plasma exchange as additive therapy in idiopathic crescentic glomerulonephritis. Am J Kidney Dis 20: 261-269, 1992 14. Bruns FJ, Adler S, Fraley RS, et al: Long-term followup of aggressively treated idiopathic rapidly progressive glomerulonephritis. Am J Med 86:400-406, 1989
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15. Bolton WK, Sturgill BC: Methylprednisolone therapy for acute, crescentic rapidly progressive glomerulonephritis. Am J NephroI9:368-375, 1989 16. Kunis CL, Kiss B, Williams G, et al: Intravenous "pulse" cyclophosphamide therapy of crescentic glomerulonephritis. Clin NephroI37:1-7, 1992 17. Leaker B, Neild GH: Effect of enalapril on proteinuria and renal function in patients with healed severe crescentic glomerulonephritis. Nephrol Dial Transplant 6:936-938, 1991 18. Savage COS, Pusey CD, Bowman C, et al: Antiglomerular basement membrane antibody mediated disease in the British Isles, 1980-1984. Br Med J 292:301-304, 1986 19. Lockwood CM, Pinching AJ, Seveny P, et al: Plasma exchange and immunosuppression in the treatment of fulminating immune complex crescentic nephritis. Lancet 1:6367, 1977 20. Hind CRK, Paraskevekow H, Lockwood CM, et al: The prognosis after immunosuppression in patients with crescentic nephritis needing dialysis. Lancet 1:98- iO 1, 1983 21. Savage COS, Winearls CG, Evans DJ, et al: Microscopic polyarteritis: Presentation, pathology and prognosis. Q J Med 56:467-483, 1985 22. Pinching AJ, Lockwood CM, Prussell BA, et al: Wegener's granulomatosis: Observation in 18 patients with severe renal disease. Q J Med 52:435-460, 1983 23. Glockner WM, Siebierth HG, Wichmann H, et al: Plasma exchange and immunosuppression in rapidly progressive glomerulonephritis: A controlled, multicenter study. Clin NephroI29:1-8, 1988 24. Pusey CD, Rees AJ, Evans DJ, et al: Plasma exchange in focal necrotizing glomerulonephritis without anti-GBM antibodies. Kidney Int 40:757-763, 1991
