Journal of Clinical Apheresis 25:250–264 (2010)
Clinical Applications of Therapeutic Apheresis Rasheed A. Balogun,1* Andre Kaplan,2 David M. Ward,3 Chidi Okafor,1 Ted M. Burns,4 A. Sergio Torloni,5 B. Gail Macik,6 and Emaad M. Abdel-Rahman1 1
Department of Medicine, Division of Nephrology, University of Virginia Health System, Charlottesville, Virginia 2 Department of Medicine, University of Connecticut Health Center, Farmington, Connecticut 3 Department of Medicine, University of California, San Diego, California 4 Department of Neurology, University of Virginia, Charlottesville, Virginia 5 Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Arizona 6 Division of Hematology, Department of Medicine, University of Virginia, Charlottesville, Virginia
THERAPEUTIC APHERESIS FOR RENAL DISORDERS
The vast majority of the renal indications for plasma exchange are related to immunoglobulin removal. Immunoglobulins, especially IgG, have a relatively long half-life. Thus in antibody-mediated disease, there could be persistence of significant amounts of antibody in the circulation despite cessation of antibody production. The aim of plasma exchange is to significantly reduce circulating antibodies. Removal of the circulating antibodies constitutes the rationale for using plasmapheresis to treat antibody-associated glomerulonephritis (GN). Although small molecular weight substances are removed by plasma exchange, their large volume of distribution and short half-lives make plasma exchange an inefficient means of extracorporeal removal of these substances. For instance, some complement proteins have a half-life of 2 days. If the goal were to be to deplete plasma complement levels, virtually daily plasma exchanges would be needed. Discontinuation of daily plasma exchange would be followed by rapid resurgence to normal complement titers. Hence the shorter the half-life of the molecule being removed, the more aggressive has to be the apheresis schedule. Plasma volume can be estimated using the following formula:
24–48 h to allow for extravascular to intravascular equilibration. Apheresis has been used to treat several renal conditions including primary renal diseases as well as renal manifestations of systemic conditions (Table I). PRIMARY RENAL DISEASES Antiglomerular Basement Membrane Antibody Disease/Goodpasture's Syndrome
Glomerular basement membrane (GBM) antibodies are pathogenic antibodies capable of causing alveolar hemorrhage and rapidly progressive glomerulonephritis (RPGN). There is only one randomized, controlled trial [1] that showed that plasmapheresis results in rapid lowering of anti-GBM antibody, lower post-treatment creatinine, and reduced incidence of end-stage renal disease (ESRD). Thus, plasmapheresis is now accepted as one of the therapeutic modalities used to treat antiGBM disease. IgA Nephropathy
Although the vast majority of patients with IgA nephropathy run a benign renal course, IgA nephropathy is sometimes associated with RPGN. Removal of circulating IgA-containing immune complexes may prevent worsening of renal function in such patients with IgA
EPV ¼ 0:065 3 TBW 3 ½1 Hct where EPV is the estimated plasma volume, TBW is the total body water, and Hct is hematocrit. The removal of large molecular weight substances from the plasma compartment follows first-order kinetics. Repetitive treatments should be spaced every C 2010 Wiley-Liss, Inc. V
*Correspondence to: Rasheed A. Balogun, Division of Nephrology, University of Virginia Health System, Box 800133, Charlottesville, VA 22908. E-mail:
[email protected] Received 12 May 2010; Accepted 23 May 2010 Published online 30 August 2010 in Wiley Onlinelibrary (wileyonlinelibrary.com). DOI: 10.1002/jca.20249
Clinical Applications of Therapeutic Apheresis TABLE I. Renal Indications for Plasmapheresis Primary renal disease 1. Anti-GBM nephritis/ Goodpasture’s disease 2. IgA nephritis/ Henoch–Scho¨nlein purpura 3. Pauci-immune rapidly progressive glomerulonephritis 4. Focal segmental glomerulosclerosis
TABLE II. Controlled Trials of TPE for Severe RPGN
Secondary renal disease 1. Systemic lupus erythematosus 2. Antiphospholipid antibody syndrome
Index of severity Mauri et al. [9] Initial creatinine (number of patients) Creatinine after 3 years Glockner et al. [10]
3. Cryoglobulinemia
4. Multiple myeloma 5. Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome 6. Transplantation
nephropathy [2,3]. Several studies showed that plasmapheresis can result in successful treatment of IgA nephropathy, even without immunosuppression [4,5]. € nlein Purpura HenochScho
Plasmapheresis has been used as the sole therapy for RPGN in Henoch–Scho¨nlein purpura [6]. Hattori et al. examined nine children with RPGN secondary to HSP with a mean urine protein of 4.9 g/m2/day and glomerular filtration rate (GFR) of 46.5 mL/min. Renal biopsy showed crescents in >56% of glomeruli. Therapeutic plasma exchange (TPE) was used as the sole therapy for these patients with TPE done thrice weekly for 2 weeks then weekly for 6 weeks. At the end of therapy, there was improvement in renal function, purpuric rash, and abdominal pain. On comparing the renal long-term survival in this study to previous studies, 87% showed long-term renal survival (9.6 years) versus less than 33% in previous studies. Idiopathic Rapidly Progressive Glomerulonephritis
TPE has been suggested to play a role in idiopathic RPGN. Although a randomized controlled study has shown that TPE has no additional therapeutic benefit in patients with idiopathic RPGN [7], the implication of antineutrophil cytoplasmic antibody (ANCA) in the pathogenesis of idiopathic RPGN may give credence to the possibility that TPE may have a beneficial role in treatment of RPGN which were formerly considered idiopathic [8] (Table II). Several studies have implicated ANCA as being pathogenic [12]. In vitro data showed that ANCA is capable of activating leukocytes [13,14], while animal studies have shown that antimyeloperoxidase antibodies can induce necrotizing GN and vasculitis [15,16]. In humans, a case of transplacental transfer of ANCA resulting in vasculitis in newborn infant was reported
251
Initial creatinine (number of patients) Creatinine after 6 months Pusey et al. [11] Initial number of patients on dialysis Patients off dialysis at 12 months Cole et al. [7] Initial number of patients on dialysis Patients off dialysis at 12 months
TPE
No TPE
13.5 (6)
13.1 (5)
Creatinine >9 8.7
13.4
7.4 (8)
9.2 (4)
1.7
5.5
Dialysis dependent
Dialysis dependent 11
8
10
3
4
7
3
2
Dialysis dependent
[17]. Thus, several randomized trials using plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis were done. Jayne et al. [18] studied 137 patients with a new diagnosis of ANCA-associated systemic vasculitis with serum creatinine >5.8 mg/dL. Patients were randomly assigned to receive either TPE (seven plasma exchanges) or intravenous methylprednisolone (3,000 mg of IV methylprednisolone). Both groups received oral cyclophosphamide and oral prednisolone. At 3 months, 69% of the patients who received TPE were alive and independent of dialysis versus 49% of the patients who received IV methylprednisolone (95% CI: 18–35; P 5 0.02). The risk of ESRD decreased in patients who received TPE, with only 19% of patients receiving TPE developing ESRD after 1 year of therapy versus 43% after IV methylprednisolone (95% CI: 6.1–41). Both patient survival and severe adverse event rates were similar in both groups. They concluded that TPE increased the rate of renal recovery in ANCAassociated systemic vasculitis that presented with renal failure when compared with IV methylprednisolone. Another indication of plasma exchange is for ANCA-associated pulmonary hemorrhage. Klemmer et al. [19] showed a 100% survival in those patients with alveolar hemorrhage who received prompt treatment with plasma exchange versus 50% mortality of historical controls with diffuse alveolar hemorrhage. Focal Segmental Glomerulosclerosis
Approximately 15–55% of patients with ESRD due to focal segmental glomerulosclerosis (FSGS) will have recurrence of proteinuria after renal transplantation. Journal of Clinical Apheresis DOI 10.1002/jca
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Balogun et al.
This subtype of FSGS appears to be mediated by a circulating 30–50,000 Da protein of unknown origin that can increase glomerular permeability and cause proteinuria. Protein adsorption and plasmapheresis can lower proteinuria and maintain normal histology [20,21]. Dall’Amico et al. [22] obtained pretransplant serum from 25 children with FSGS and evaluated them for this glomerular permeability factor. They showed that 11 of 13 children with permeability factor had recurrence of FSGS, whereas only four of 12 without detectable factor had recurrence. They further showed that nine of 11 patients treated with plasmapheresis and cyclophosphamide had reversal of proteinuria, with seven of 11 having long-term remission (up to 32 months). They concluded that permeability factor can predict recurrence and that TPE and cyclophosphamide are effective in post-transplant FSGS [22]. Matalon et al. [23] studied 13 adult patients from three transplant centers who underwent plasmapheresis for recurrent FSGS between 1993 and 1999. One patient (8%) had a complete response, one (8%) had a partial response and three patients (23%) partially responded but remained plasmapheresis dependent. All five responders were started on plasmapheresis within 30 days of recurrence, whereas seven of the eight nonresponders initiated plasmapheresis after a delay of at least 42 days (P 5 0.0047). FSGS recurred within 30 days of transplantation in all five responders, whereas four of eight nonresponders had no evidence of recurrence until 42–150 days after transplantation (P 5 0.098). They concluded that plasmapheresis is less effective in adults than in children as a treatment for recurrent FSGS in the renal allograft and that predictors of response to plasmapheresis include early initiation of treatment after recurrence. Nevertheless, plasmapheresis is now a standard treatment for post-transplant recurrence of FSGS. SECONDARY RENAL DISEASES Systemic Lupus Erythrematosus
Despite early positive reports, randomized, controlled trials have been unable to document a benefit of plasmapheresis as an adjunct to standard immunosuppresive therapy in patients with systemic lupus erythrematosus (SLE) [24–26]. Antiphospholipid Antibody Syndrome
In conditions such as lupus anticoagulant and anticardiolipin antibody syndrome, which are associated with arterial and venous thrombosis, recurrent fetal loss, and renal disease, plasmapheresis has resulted in successful pregnancy and reversal of renal disease [27–29]. Another form of antiphospholipid antibody syndrome (APS) is catastrophic antiphospholipid antibody Journal of Clinical Apheresis DOI 10.1002/jca
TABLE III. Types of Cryoglobulinemia Type I
Type II
Type III
Monoclonal IgG or IgM, rarely IgA. It is associated with lymphoproliferative diseases such as multiple myeloma and Waldenstrom’s macroglobulinemia. Mixed, monoclonal IgM with rheumatoid factor activity and polyclonal IgG. It is associated with autoimmune disorders and infections, especially hepatitis C virus. Mixed, polyclonal IgM and IgG. It is associated with autoimmune disorders and infections.
syndrome (CAPS). CAPS is a rare life-threatening disease with associated mortality rate >50%. Treatment of CAPS consists of IV heparin, IV steroids, intravenous immunoglobulin (IVIG), and/or TPE. Cryoglobulinemia
The entity that was known historically as essential mixed cryoglobulinemia is now known to be due to hepatitis C in most cases. The cryoglobulinemia may cause vasculitis that can be of life-threatening severity, mainly by progressive necrosis and gangrene of the extremities. Despite the lack of randomized controlled trials, there is a general consensus that plasmapheresis, by removal of cryoglobulins, is an effective treatment of this condition. Antiviral therapy of hepatitis C infection often fails, and immunosuppression with corticosteroids, cyclophosphamide, or rituximab may be of limited or temporary benefit and can be problematic. Thus some patients are left with plasmapheresis as the only available therapeutic option or others may need plasmapheresis until these other therapies take hold. Ferri et al. [30] showed that some patients with cryoglobulinemia may respond to plasmapheresis alone (Table III). “Cast Nephropathy” in Multiple Myeloma
Light chains (Bence Jones protein) can be toxic to the tubules and result in obstruction of nephron lumen and acute renal failure. Plasmapheresis, as an adjunct to chemotherapy, results in a more rapid lowering of serum light chains and a lower post-treatment creatinine [31]. Clark et al. [32] studied 97 patients with acute renal failure at the onset of multiple myeloma. Patients were randomly assigned to conventional therapy plus five to seven plasma exchanges for 10 days or conventional therapy alone. The primary composite outcome was death, dialysis dependence, or GFR
