Plasma Exchange for Kidney Disease: What Is the Best Evidence? Ainslie M. Hildebrand, Shih-Han S. Huang, and William F. Clark Therapeutic plasma exchange (TPE) has been used as adjunctive therapy for various kidney diseases dating back to the 1970s. In many cases, support for TPE was on mechanistic grounds given the potential to remove unwanted large molecular-weight substances such as autoantibodies, immune complexes, myeloma light chains, and cryoglobulins. More recently, growing evidence from randomized controlled trials, meta-analyses, and prospective studies has provided insights into more rational use of this therapy. This report describes the role of TPE for the 6 most common kidney indications in the 2013 Canadian Apheresis Group (CAG) registry and the evidence that underpins current recommendations and practice. These kidney indications include thrombotic microangiopathy, antiglomerular basement membrane disease, anti-neutrophil cytoplasmic antibodyassociated vasculitis, cryoglobulinemia, recurrence of focal and segmental glomerulosclerosis in the kidney allograft, and kidney transplantation. Q 2014 by the National Kidney Foundation, Inc. All rights reserved. Key Words: Plasma exchange, Kidney disease, Thrombotic microangiopathy, Vasculitis, Kidney transplantation

Introduction

Discussion

Therapeutic plasma exchange (TPE) is an automated extracorporeal apheresis technique in which plasma and large molecular-weight substances are removed from the body through a cell separator and replaced with another blood product such as donor plasma or albumin.1 The introduction of TPE as a form of treatment for kidney disease was initially reported by Lockwood and colleagues in 1975 in a patient who suffered from Goodpasture’s syndrome.2 Treatment with TPE in combination with immunosuppressive therapy resulted in recovery from kidney failure and pulmonary hemorrhage. Since then, TPE has been used in various kidney diseases directed primarily at 2 main mechanisms: (1) removal of unwanted large molecular-weight substances, such as autoantibodies, immune complexes, myeloma light chains, and cryoglobulins; and (2) replacement of deficient substances, such as ADAMTS13 (A Disintegrin And Metalloprotease with a ThromboSpondin type 1 motif, member 13) in the case of thrombotic thrombocytopenic purpura (TTP).3 According to prospective registry data of over 60,000 patients presenting for plasma exchange over the last 6 years collected by the Canadian Apheresis Group (CAG), kidney diseases account for approximately 36% of TPE procedures each year.4 However, over the last 2 decades, the proportion and order of each of these kidney diseases has changed significantly, highlighting the growing evidence available to guide proper application of TPE in these settings.5 In this review, we will discuss the role of TPE for the 6 most commonly used kidney indications in the 2013 CAG registry and the evidence that underpins current recommendations and practice.4,6,7 These kidney indications include thrombotic microangiopathy (TMA), anti-GBM disease, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cryoglobulinemia, recurrence of focal and segmental glomerulosclerosis in the kidney allograft, and kidney transplantation (Table 1).4

TMA TMA is a pathological process characterized by microangiopathic hemolytic anemia, thrombocytopenia, and variable signs of organ injury including neurologic and/or kidney abnormalities due to endothelial damage and systemic microvascular thrombosis.8 Although TMA is a defining feature in various conditions, it is most commonly used to describe the clinical syndromes associated with TTP, hemolytic uremic syndrome (HUS), and disseminated intravascular coagulation (DIC). In children, typical HUS is easily differentiated from other TMAs by the diarrheal prodrome caused by Shiga toxin-producing Escherichia coli (most commonly subtype O157:H7), and outcomes with supportive care are considered favorable.9 In adults, the underlying etiology of TMA is often more difficult to differentiate with available testing, and prompt empiric initiation of TPE for non-DIC TMAs is considered a standard of care given high early mortality rates.8 The mechanism driving many of the non-DIC TMA cases in adults is the presence of a circulating factor that provokes endothelial injury and/or platelet aggregation and promotes microthrombi formation.10 In acquired

From Kidney Clinical Research Unit, London Health Sciences Centre, London, Ontario, Canada and Division of Nephrology, Western University, London, Ontario, Canada. Support: W.F.C. is a member of the Advisory Board of the Canadian Apheresis Group, World Apheresis Association, and Alexion Canada. He has received speaking honoraria from the American Society of Nephrology, the Canadian Society of Nephrology, Octapharma, Alexion, and Danone. Address correspondence to William F. Clark, MD, Room A2-341 London Health Sciences Centre, 800 Commissioners Road East, London, Ontario, Canada N6A 4G5. E-mail: [email protected] Ó 2014 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 http://dx.doi.org/10.1053/j.ackd.2014.01.008

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Hildebrand et al

TTP, this circulating factor has been identified as an Despite differences in currently available plasma inhibitory autoantibody to ADAMTS13, an enzyme that product composition, the theoretical benefits of 1 plasma works to minimize microvascular thrombosis by cleaving product over another have not been substantiated in complexes formed by ultralarge multimers of von Willecontrolled studies.20 However, several reports using large brand factor that serve as a platform for platelets to attach volume exchanges for more severe cases of TTP have and form microthrombi. Without treatment, this systemic been encouraging, including the initial study showing microthrombosis results in progressive neurologic deterithe superiority of TPE to plasma infusion by Rock and oration, irreversible kidney failure, cardiac ischemia, colleagues in which the TPE group received 3 times and death in 90% of cases.11,12 TPE reverses the process more plasma volume than those in the infusion-alone group (21.5 6 7.8 L vs 6.7 6 3.3 L).15 A subsequent case of TTP by removal of the circulating autoantibody to ADAMTS13 and replacement of plasma with normal report by Clark and colleagues described a patient with plasma containing the ADAMTS13 protease.13 However, severe TTP who dramatically responded to a 48-hour continuous 69-L plasma exchange,21 although in a larger only 1/3 of patients with TTP that present for TPE actu14 ally have low ADAMTS13 activity or severe deficiency. retrospective study of patients with TTP treated with TPE, the correlation between survival and higher volIn a recent systematic review, there were only 2 trials that umes of TPE (additional 10-15 mL/kg per day, received specifically address the efficacy of TPE relative to any by patients with more severe disease) was not statistically intervention in the treatment of TTP (Table 2).15-17 The significant.19 The only study to specifically address the largest of these trials was reported by Rock and 15 colleagues in 1991. They demonstrated a higher disease role of twice-daily TPE in TTP was by Nguyen and colleagues.22 Among patients who failed to respond to response rate with TPE compared with plasma infusion (47% vs 25%, P ¼ .025) and a lower mortality rate (22% initial daily TPE or experienced an exacerbation of vs 37%, P ¼ .035) at symptoms, twice-daily TPE 6 months.15 Although they resulted in a definite CLINICAL SUMMARY response in 3 of 31 episodes excluded patients with seof TTP and a possible vere kidney failure at the  The use of plasma exchange for kidney disease by the CAG response in 27 of the 31 epidiscretion of the physician correlates with published evidence. sodes.22 However, the small because of concerns of vol Early introduction of plasma exchange appears to be ume overload in the plasma sample size, lack of control effective for various immunologic kidney diseases. infusion group, the average group, and presence of coHowever, plasma exchange primarily serves as an adjunct to other immunosuppressive therapies and is often serum creatinine level interventions make it diffiexpected to offer only a small, incremental benefit. at presentation was 160 cult to draw conclusions mmol/L.15 This success of from these data alone.  The strongest evidence for plasma exchange is for thrombotic microangiopathy, in which it serves as the Although further research TPE, coupled with almost single most important therapy in most cases. is necessary to establish the certain mortality in the best plasma product compoabsence of treatment, sition and the role of large prompted the sense of urvolume or twice-daily TPE in the optimal treatment of gency for diagnosis and a decrease in the stringency of TTP, these data do weakly support the common practice criteria required for initiation of treatment despite the of increasing volume or frequency of TPE for patients lack of randomized controlled trials to support the who do not respond to initial therapy.8 routine delivery of TPE in diarrheal-associated HUS 18 and many other secondary forms of TMA. Current recIt is important to recognize at least 3 other distinct ommendations now support empiric initiation of daily groups of patients when considering the role of plasma exTPE (1-1.5 plasma volumes replaced with plasma prodchange for TMA. These include (1) TMA due to another uct) for cases of unexplained thrombocytopenia and miknown or suspected precipitant (secondary TMA), (2) croangiopathic hemolytic anemia with a normal diarrheal-associated HUS due to enterohemorrhagic E. international normalized ratio and partial thrombocoli, and (3) atypical HUS due to complement dysregulaplastin time.6,8 In the absence of the identification of an tion. Secondary causes account for approximately 50% to 60% of non-DIC TMA cases.19,23 Although direct underlying cause, TPE should be continued until a response is achieved, defined by a sustained platelet endothelial injury associated with normal or only count of greater than 150,000/mL.6,8 This has resulted in moderately reduced ADAMTS13 appears to be the case in most secondary forms of TMA, most cases have been almost complete disappearance of the diagnostic reported to respond to TPE.14 A possible explanation could pentad of thrombocytopenia, hemolytic anemia, kidney failure, neurologic signs, and fever previously be secondary inhibition of ADAMTS13 protease resulting described by Amorosi and Ultmann in 1966 and a in increasing von Willebrand factor multimers, although reduction in the mortality from uniformly fatal to less this is likely only responsible in the minority of cases. than 20%.12,19 The secondary causes of TMA are highlighted in Table 3

219

Mean Cr 278 mmol/L TPE (20) vs PI (19) Henon et al,16 1992

Rock et al,

Abbreviations: Cr, creatinine; FFP, fresh frozen plasma; NR, not reported; PI, plasma infusion; PV, plasma volume; TPE, therapeutic plasma exchange. *Statistically significant difference between groups (P , .05).

NR

Remission* TPE group: 78% Controls: 49% Remission TPE group: 80% Controls: 52% Mean: 16 (range 3-36) Replacement: FFP Volume: 1.0-1.5 3 PV Mean: NR (range 3-35) Replacement: FFP Volume: 15 mL/kg FFP in 45 mL/kg 5% albumin 1991

TPE (51) vs PI (20)

Mean Cr 138 mmol/L

NR

Mortality Remission Kidney Plasma Exchange Prescription

along with the expected response to TPE.14,24 In a large prospective registry of patients with TMA, TPE appears to be effective in cases associated with drug hypersensitivity, autoimmune disease, infection, pregnancy or postpartum, and pancreatitis; however, there is no demonstrated therapeutic effect of TPE in cases associated with mitamycin C, malignancy, hematopoietic stem cell transplantation, or malignant hypertension.14 The role of TPE in adult-onset diarrheal-associated HUS is less certain. Multiple small underpowered studies have demonstrated no significant effect; however, in a large meta-analysis of nearly 3500 cases of diarrhealassociated HUS in children, dialysis-free survival and kidney protection were 8% and 28% better, respectively, among those who received TPE.25 Further, in a recent report of the latest outbreak of diarrheal-associated HUS among adults in Germany in 2011, in which nearly all patients with progressive disease were treated with TPE, mortality was strikingly low; mortality in the TPE group was 3.2% compared with 8.5% among those not treated with TPE. However, the benefit of TPE for mortality was not statistically significant (odds ratio 0.27, 95% confidence interval 0.32-2.30).26 Although this evidence is inconclusive, in the absence of randomized control data to guide therapy, many centers do provide TPE for cases of diarrheal-associated HUS complicated by neurologic deterioration. Major progress has been made during the last decade in understanding the role of alternative complement pathway dysregulation in the pathophysiology of TMA, with these cases now referred to as ‘‘atypical HUS.’’27 Although there are no randomized controlled trials comparing TPE to other therapies in atypical HUS, it is widely accepted as the first-line therapy on mechanistic grounds.28,29 TPE removes complement factor H autoantibodies and defective variants of complement regulatory factors, including complement factor H, complement factor I, complement factor B, and C3 convertase, while replacing defective components with normal functioning complement

Kidney Function at Presentation

5.2 5.0

Treatment Comparison (n)

6.0

15

61.9 12.0 6.8

Study, Year

Thrombotic microangiopathy Kidney transplantation Anti-neutrophil cytoplasmic antibodyassociated vasculitis Antiglomerular basement membrane disease Cryoglobulinemia Post-transplant recurrence of focal segmental glomerulosclerosis

Outcomes

Kidney Indication (N ¼ 21,698)

Proportion of Plasma Exchange Delivery for Kidney Indications (%)

Table 2. Randomized Controlled Trials Assessing the Efficacy of Plasma Exchange vs Other Therapies in the Treatment of Thrombotic Thrombocytopenic Purpura

Table 1. Six Most Common Kidney Indications for Plasma Exchange (Canadian Apheresis Registry 2013)

Mortality* TPE group: 22% Controls: 37% Mortality TPE group: 15% Controls: 43%

Plasma Exchange for Kidney Disease

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Table 3. Thrombotic Microangiopathy and Response to Plasma Exchange Etiology of Thrombotic Microangiopathy Thrombotic thrombocytopenic purpura Primary (33-40%) Acquired or idiopathic Hereditary or congenital (UpshawSchulman) Secondary (45-55%) Drugs* Autoimmune disease Infection† Pregnancy or postpartum Pancreatitis Hematopoietic stem cell transplantation Malignancy Malignant hypertension Hemolytic uremic syndrome Primary (,5%) Complement dysregulation‡ Secondary (.5%) Diarrheal-associated (preserved ADAMTS13 activity)

Expected Response to Plasma Exchange (%)

80-90 80-90

80-90 50-70 50-70 50-70 50-70 0 0 0

30-70

Inconclusive

ADAMTS13, A Disintegrin And Metalloprotease with a ThromboSpondin type 1 motif, member 13. *Includes ticlodipine, clopidogrel, quinine, valacyclovir, oral contraceptives, chemotherapy, cyclosporine, tacrolimus, and sirolimus. No response demonstrated for mitamycin C. †Including but not limited to infection with enterohemorrhagic Escherichia coli, human immunodeficiency virus, and Streptococcus pneumoniae. No response demonstrated for E. coli O157:H7, except in cases with severe neurologic involvement. ‡Including abnormalities in regulation of complement factor H, complement factor H receptor 1/3, complement factor I, complement factor B, C3 convertase, and thrombomodulin. No response demonstrated for abnormalities in membrane cofactor protein.

proteins.30 One exception to this may be in patients with abnormal CD46, a noncirculating membrane cofactor protein, who exhibit higher spontaneous remission rates but do not seem to respond to TPE.31 Anecdotal reports of response rates to plasma exchange have been highly variable (30-70%; Table 3),14 but the role of eculizumab, a recombinant humanized monoclonal immunoglobulin G2/4 antibody and a C5 inhibitor, for complement inhibition is much more promising, inducing remission in 80% of patients. Unfortunately, first-line use of this therapy is still costly.32

Anti-GBM Disease Anti-GBM disease is a disorder in which circulating antibodies are directed against the noncollagenous domain of the a3 chain of type IV collagen, a major component of

glomerular, alveolar, and other specialized basement membranes.33,34 These autoantibodies correlate with disease activity and are directly pathogenic, resulting in acute or rapidly progressive glomerulonephritis (typically associated with crescent formation) and pulmonary hemorrhage.35 Left untreated, this disease has an almost universally poor outcome with death resulting from kidney failure or pulmonary hemorrhage in over 90% of cases.36 The therapeutic approach for anti-GBM disease is based on targeting this pathogenic antibody by removal with TPE and suppression of production using immunosuppressive therapies. Despite this being the first kidney disease for which TPE was delivered, there is only 1 randomized controlled trial supporting its use. In this trial, Johnson and colleagues compared the effect of therapy with cyclophosphamide and prednisone alone or with TPE on the clinical course and rate of disappearance of antibody in 17 patients with anti-GBM antibody-induced kidney disease.37 After the end of treatment, the mean serum creatinine in the TPE group was 389 (standard error 53) mmol/ L, compared with the immunosuppression-alone group, in which the mean serum creatinine was 840 (standard error 62) mmol/L (P , .05); fewer patients became dependent on dialysis in the TPE group (25% vs 56%, P , .05). The rate of disappearance of anti-GBM antibodies was also 2.5 times greater in the TPE group compared with the immunosuppression-alone group. Percent crescents on the initial biopsy and entry serum creatinine correlated with outcomes to a greater degree than treatment regimen; patients with less than 30% crescents and more preserved kidney function (serum creatinine , 265 mmol/L) did well whereas those with greater than 70% crescents and more severe kidney dysfunction did worse with either treatment.37 This trial was severely underpowered, making it impossible to compare treatments in equally affected individuals, and kidney biopsies of patients in the immunosuppression-alone group at presentation showed a higher percentage of glomerular crescents compared with those in the TPE group. Additional evidence has come from a retrospective review in which 71 patients were treated for anti-GBM disease with prednisone, oral cyclophosphamide, and TPE over 25 years and followed for survival and dialysis independence (kidney survival).38 In this study, 50 mL/kg (to a maximum of 4 L) of plasma was exchanged daily for at least 14 days or until anti-GBM titers were undetectable. Among patients who presented with a serum creatinine of less than 500 mmol/L, patient and kidney survival at 1 year were 100% and 95% respectively, and 84% and 74% at last follow-up (median 7.5, range 1-24 years), respectively. Among patients who presented with a serum creatinine of greater than 500 mmol/L but did not require immediate dialysis, patient and kidney survival at 1 year were 83% and 82%, respectively, and 62% and 69% at last follow-up, respectively. Among patients who presented

Plasma Exchange for Kidney Disease

with dialysis-dependent kidney failure, patient and kidney survival at 1 year were 65% and 8%, respectively, and 36% and 5% at last follow-up, respectively.38 These results compare favorably with historical controls before 1975 in which TPE was not delivered.36 All patients who required immediate dialysis and had 100% crescents on biopsy remained dependent on dialysis despite adequate suppression of anti-GBM antibody titers.38 Although median time to death was shorter in patients with pulmonary hemorrhage, TPE resulted in resolution of hemoptysis in 90% of patients in this series.38 On the basis of the results of these studies and the mechanistic biological plausibility, TPE is widely accepted as the standard of care for all patients with anti-GBM disease in addition to immunosuppressive therapy. Current recommendations from the Kidney Disease Improving Global Outcomes (KDIGO) foundation suggest initiation of TPE in all patients with anti-GBM disease except for those who are dependent on dialysis at presentation and have 100% crescents in an adequate biopsy sample and do not have pulmonary hemorrhage.7 TPE should be delivered as one 4-L exchange with 5% albumin daily for 14 days or until anti-GBM antibodies are undetectable.6,7 Replacement with 2 units of fresh, frozen plasma at the end of TPE should be considered for replacement of clotting factors in cases of ongoing daily TPE or diffuse alveolar hemorrhage.6

ANCA-Associated Vasculitis ANCA-associated vasculitis includes granulomatosis with polyangiits (previously known as Wegener’s granulomatosis), microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (previously known as Churg-Strauss syndrome). These diseases are characterized by a focal necrotizing pauci-immune glomerulonephritis, and in up to 90% of cases, the presence of circulating ANCA directed against myeloperoxidase or proteinase 3 present within the azurophilic granules of neutrophils and peroxidase-positive lysosomes of monocytes.39 Mortality has markedly diminished with the introduction of initial therapy with cyclophosphamide and steroids, and recent studies have shown similar outcomes with the use of rituximab.40-43 Although small studies suggest that there may be additional benefit to adjunctive TPE (Table 4), particularly when patients are dependent on dialysis, most of the published experience with TPE combines all forms of rapidly progressive glomerulonephritis (excluding those with anti-GBM antibodies confirmed), which complicates interpretation and application of these results.44-52 The largest of these studies was the Methylprednisolone versus Plasma Exchange (MEPEX) study, a multicenter randomized controlled trial of patients with ANCA-associated vasculitis presenting with a serum creatinine above 500 mmol/L that compared intravenous

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methylprednisolone (1000 mg/day for 3 consecutive days) to TPE (7 treatments of 60 mL/kg during the first 14 days after diagnosis).47 Both groups in this study received standard therapy with oral cyclophosphamide and oral prednisone followed by azathioprine for maintenance therapy. TPE was associated with a higher likelihood of dialysis independence at 3 months compared with intravenous methylprednisolone (69% vs 49%, P ¼ .02) and a 24% reduction (from 43% in the methylprednisolone group to 19% in the TPE group) in the risk of progression to ESRD at 1 year (95% confidence interval 6.1-41%). However, patient survival at 1 year was similar in both groups (73% vs 76%, P ¼ .68), and data from the long-term follow-up study suggest that although the initial benefit of kidney recovery was sustained (33% with ESRD at 4 years in the TPE group vs 49% in the methylprednisolone group, P ¼ .08), this did not translate into improved long-term survival (51% mortality in both groups, P ¼ .75).47,53 The TPE group did not receive pulse steroids at the onset of therapy in this study. This, and the use of oral instead of intravenous cyclophosphamide, may have accounted for the unexpectedly high 1-year mortality in the study population.54 A large randomized controlled trial is currently underway to compare the effects of adjunctive therapy with TPE on the risk of ESRD and mortality in ANCA-associated vasculitis (ClinicalTrials.gov: NCT00987389).55 With larger samples and longer follow-up, results of this trial could provide more conclusive evidence on whether the reduced risk of ESRD with TPE translates into a reduced risk of death. Until then, the current recommendations from the KDIGO Clinical Practice Guidelines for glomerulonephritis support TPE (7 treatments over 14 days, 60 mL/kg replaced with 5% albumin) for patients who present with diffuse alveolar hemorrhage or severe kidney failure, but the role of TPE for less severe nephritis, lung hemorrhage, and other severe organ manifestations remains unproven.7

Cryoglobulinemia Cryoglobulinemia is an immune-complex-mediated systemic vasculitis involving small-to-medium-sized vessels in which high levels of cryoglobulin are found in the blood. Cryoglobulins are a group of abnormal immunoglobulins that precipitate or form a gel if exposed to cold temperatures (4 C) and usually resolubilize at body temperature (37 C). Three types of cryoglobulinemia have been described based on clonality of the cryoglobulin and rheumatoid factor binding activity; manifestations range from mild symptoms such as purpura, arthralgia, and sensory neuropathy to more severe manifestations including glomerulonephritis and systemic vasculitis, depending on the location of precipitation of these

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Table 4. Randomized Controlled Trials Assessing the Efficacy of Plasma Exchange vs Other Therapies in the Treatment of Idiopathic and Pauci-Immune Rapidly Progressive Glomerulonephritis (Excluding anti-GBM Disease)

Study, Year

Treatment Comparison (n)

Kidney Function at Presentation 79% HD dependent

Mauri,49 1985

Steroids/CYC 1 TPE (12) vs steroids/CYC (10)

50% HD dependent

€ ckner et al,44 1988 Glo

Steroids/CYC/AZA 1 TPE (16) vs steroids/CYC/AZA (15)

46% HD dependent

Pusey et al,45 1991

Steroids/CYC/AZA 1 TPE (25) vs steroids/CYC/AZA (23)

39% HD dependent

Cole et al,46 1992

Steroids/AZA 1 TPE (16) vs steroids/AZA (16)

34% HD dependent

Guillevin,50 1997

Steroids 1/- CYC 1 TPE (19) vs steroids 1/- CYC (13)

35% HD dependent

Szpirt,51 1999

Steroids/CYC 1 TPE (16) vs steroids/CYC (16)

19% HD dependent

€uner,94 2002 Za

Steroids/CYC 1 TPE (21) vs steroids/CYC (18)

28% HD dependent

Jayne et al,47 2007

PO steroids/CYC 1 TPE (70) vs PO steroids/CYC 1 IV steroids (67)

69% HD dependent

Rifle,

1981

Plasma Exchange Prescription Mean: 19 (range 10-30) Replacement: 5% albumin Volume 1.5 PV Mean: 6 (range 6-6) Replacement: FFP and 3.5% albumin Volume: 3.5 L Mean: 11 (range 7-18) Replacement: 3-5% albumin Volume: 50 mL/kg Mean: 9 (range 5-25) Replacement: 5% albumin Volume: 4 L Mean: $10 Replacement: 5% albumin Volume: 1 PV Mean: NR (range 9-12) Replacement: 4% albumin Volume: 60 mL/kg Mean: NR (range 6-12) Replacement: NR Volume: 4 L Mean: 6 (range 3-12) Replacement: FFP Volume: 40 mL/kg Mean: 7 (range 7-7) Replacement: 5% albumin Volume: 60 mL/kg

Kidney

Mortality

ESRD* TPE group: 33% Controls: 88% ESRD† TPE group: 50% Controls: 70%

Mortality TPE group: 17% Controls: 0% Mortality TPE group: 8% Controls: 0%

ESRD TPE group: 19% Controls: 17% ESRD TPE group: 29% Controls: 39% ESRD TPE group: 21% Controls: 31% ESRD TPE group: 16% Controls: 8% ESRD TPE group: 13% Controls: 44% ESRD TPE group: 47% Controls: 38% ESRD‡ TPE group: 20% IV steroid group: 43%

Mortality TPE group: 6% Controls: 2% Mortality TPE group: 48% Control: 35% Mortality TPE group: 13% Controls: 0% Mortality TPE group: 21% Controls: 54% Mortality TPE group: 25% Controls: 38% Mortality TPE group: 10% Controls: 11% Mortality TPE group: 27% IV steroid group: 24%

Abbreviations: AZA, azathioprine; CYC, cyclophosphamide; ESRD, End-stage renal disease defined by dialysis dependence or the receipt of a kidney transplant; GBM, glomerular basement membrane; HD, hemodialysis; IV, intravenous; NR, not reported; PO, oral; PV, plasma volume; TPE, therapeutic plasma exchange. *Statistically significant difference between groups for HD-dependent subgroup (P , .05). †Statistically significant difference between groups for creatinine . 800 mmol/L subgroup (P , .05). ‡Statistically significant difference between groups (P , .05).

Hildebrand et al

Steroids/CYC 1 TPE (6) vs steroids/CYC (8)

48

Outcomes

Plasma Exchange for Kidney Disease

cryoglobulins.56 Kidney involvement is apparent at presentation in approximately 20% of cases, but it occurs in follow-up in up 50% of patients.57 Many of these cases are mixed cryoglobulinemia associated with hepatitis C and present with a membranoproliferative glomerulonephritis.58 TPE is typically regarded as adjunctive therapy for life- or organ-threatening cases of cryoglobulinemia because the primary goal of therapy is treatment of the underlying disease with immunosuppression or, in the case of hepatitis C, antiviral therapy.59 In theory, TPE transiently removes circulating cryoglobulins limiting deposition in tissues; however, the therapeutic benefit has not been proven. In a recent descriptive analysis, Rockx and colleagues identified 11 studies that describe the role of TPE for cryoglobulinemia. This literature was limited to small case reports and case series, many without a clear report of the apheresis procedure delivered or clearly defined quantitative outcomes.60 Although the results of these studies do weakly support the use of TPE for improvement of acute kidney injury and treatment of neuritis and ulcers, this evidence is far from definitive.60 Despite the lack of data from randomized controlled trials, which arguably would be difficult to obtain in this rare condition, current recommendations support the use of TPE in cases of life- or organ-threatening complications (including rapidly progressive glomerulonephritis) and symptomatic hyperviscosity syndrome on the basis of mechanistic grounds.6,61 The optimal frequency, dose, and replacement fluid has not been studied; however, it is reasonable to start exchanging at least 1 plasma volume 3 times per week for 2 to 3 weeks using the clinical response to guide subsequent therapy. Plasma should be replaced with 5% albumin, and the room, lines, and replacement fluid should be warmed to prevent precipitation of circulating cryoglobulins.6,62

Post-Transplant Recurrence of Primary Focal Segmental Glomerulosclerosis Among patients with kidney failure due to primary (idiopathic) focal segmental glomerulosclerosis (FSGS), the risk of recurrence in the first transplant is between 20% and 50%.63 Recurrence typically occurs within the first month after transplantation and is manifested by heavy proteinuria, hypertension, and graft dysfunction, ultimately leading to graft failure in 13% to 20% of patients at 10 years.63 As in native kidneys, FSGS in the kidney allograft may be primary or related to other known causes such as infection, toxins, genetic mutation, obesity, or hyperfiltration injury. These conditions may be difficult to differentiate because they often present with similar clinical and histologic features. However, distinct differences in pathogenesis between them dictate important differences in the management and the potential efficacy of TPE.

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The theoretical role of TPE in recurrent primary FSGS in the kidney allograft is based on the removal of a circulating factor. Proposed molecules are cardiotrophic-like cytokine-1, hemopexin, and vascular endothelial growth factor.64 Recently, there are studies suggesting the role of serum soluble urokinase receptor (suPAR) as the permeability factor in native and recurrent FSGS.65 This circulating permeability factor has been shown to be elevated in approximately 2/3 of patients with primary FSGS (but not in other glomerular diseases) and appears to correlate with an increased risk for recurrence of FSGS after transplantation.65 By contrast, a recent study by Bock and colleagues did not find the correlation between circulating suPAR levels in pediatric patients with FSGS and non-FSGS glomerular disease.66 Case series and small retrospective cohort studies suggest that removal of a circulating permeability factor in patients with recurrent FSGS after kidney transplant with TPE may be responsible for substantial reductions in proteinuria and in some cases achievement of partial or complete remission.67,68 Long-term graft survival may also be better with TPE; in 1 study of patients with early recurrence of FSGS after kidney transplant (within 4 weeks), 5-year graft survival was 85% in the TPE group, compared with 30% in historical controls who did not receive TPE.69 However, other reports have not shown these associations, and the identity of this circulating permeability factor is not known for certain.66 Further research is necessary to confirm if suPAR is the ‘‘permeability factor’’ responsible for FSGS, to elucidate the exact mechanism of recurrence of FSGS in the kidney allograft, and to determine the optimal timing and duration of TPE. Despite the paucity of data in this area, current recommendations from the KDIGO Clinical Practice Guidelines for the care of kidney transplant recipients support early initiation of TPE for cases of suspected primary FSGS in the kidney allograft.70 A typical starting regimen is 1 to 1.5 plasma volume exchanges with 5% albumin for 3 consecutive days and then every other day for a total of 2 weeks with subsequent treatment guided by clinical response.6

Kidney Transplantation A successful kidney transplant can improve the quality of life and reduce the mortality risk for patients with ESRD.71 However, organ shortage and increasing numbers of sensitized candidates have resulted in the frequent use of immunologically incompatible kidneys, posing additional risks for allograft rejection. Approximately 15% of patients currently on the waitlist are highly presensitized, defined by more than 80% panelreactive antibodies to human leukocyte antigens (HLAs).72 These antibodies may be acquired through blood transfusions, pregnancy, or prior transplantation and may be specific to a prospective donor HLA type

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Table 5. Dose and Timing Considerations for Immunosuppressive Drugs Commonly Prescribed for Treatment of Kidney Diseases in the Setting of Plasma Exchange

Drug

Plasma Protein Binding/Volume of Distribution

Removal by Plasma Exchange

90-95% PB Vd 0.6-0.7 L/kg 12% PB Vd 0.8 L/kg PB NR Vd 0.06 L/kg

No; ,1% removal

Intravenous immunoglobulin 99

41-57% PB Vd 0.05-0.13 L/kg

Yes; expect substantial removal (% NR)

Thymoglobulin 100

PB NR Vd 0.12 L/kg

Yes; expect substantial removal (% NR)

Eculizumab 101

PB NR Vd 0.11 L/kg

Yes; expect substantial removal (% NR)

Prednisone/prednisolone 95,96 Cyclophosphamide 96 Rituximab 97,98

No; expect minimal removal (% NR) Yes; 65% removal

Suggested Dose and Timing Adjustments No supplemental dose required. Administer dose post-TPE. No supplemental dose required. Administer dose post-TPE. No supplemental dose required. Administer dose post-TPE. Delay in subsequent TPE may be required. No supplemental dose required. Administer dose post-TPE. Delay in subsequent TPE may be required. No supplemental dose required. Administer dose post-TPE. Delay in subsequent TPE may be required. Supplemental dose recommended by manufacturer. Administer dose post-TPE. Delay in subsequent TPE may be required.

Abbreviations: NR, not reported; PB, protein binding; TPE, therapeutic plasma exchange; Vd, volume of distribution.

(donor-specific antibodies [DSAs]). TPE is used in desensitization protocols in many centers to increase access to transplantation for patients with living donors with an incompatible crossmatch because of DSAs or patients with high PRA in need of a deceased donor.6 Desensitization regimens typically include intravenous immunoglobulin (IVIG) with or without TPE. TPE offers the theoretic advantage of antibody reduction in addition to the immunomodulatory actions of IVIG; however, there is only 1 trial comparing the efficacy of these 2 regimens.73 This study compared the efficacy of highdose IVIG with 2 different TPE-based regimens in kidney transplant recipients with high levels of DSA defined by a positive T-cell cytotoxicity crossmatch. One TPE group received TPE plus low-dose IVIG plus anti-CD20 antibody whereas the other group received TPE plus lowdose IVIG plus anti-CD20 antibody plus pretransplant thymoglobulin and post-transplant DSA monitoring. Achieving a negative crossmatch was significantly more likely with both TPE protocols (84% and 88%, respectively) when compared with high-dose IVIG (38%) (P , .01).73 Although there are significant limitations to this study, including variable co-interventions, small samples, and lack of randomization, results are in keeping with other retrospective studies using TPE-based desensitization protocols and are supported by longterm follow-up data.74-76 When compared with matched controls who remained on dialysis while waitlisted for transplantation or those who underwent either dialysis or HLA-compatible transplantation, sur-

vival in the desensitized group using a TPE-based desensitization protocol was better at 3, 5, and 8 years. At 8 years, the survival in the 3 groups, respectively, was 31% (dialysis-only group), 49% (dialysis-or-transplantation group), and 81% (desensitized group).76 When used in combination with low-dose IVIG for desensitization pretransplantation, TPE should be delivered daily or on alternate days (using 5% albumin as the replacement solution) until the crossmatch becomes negative, and it should be continued postoperatively for at least 4 procedures.6 The number of treatments required can often be estimated based on the baseline anti-HLA titer. TPE may similarly be used for ABO-incompatible desensitization pretransplant to reduce anti-A or anti-B antibody titers in the peritransplant period.6,77 Antibody-mediated rejection (AMR) in the kidney allograft is defined by the presence of DSA, histologic evidence of tissue injury, and positive C4d staining in the peritubular capillaries, and it occurs in up to 23% of unselected kidney transplant recipients and 60% of highrisk recipients (ABO-incompatible or presensitized).78,79 Therapeutic strategies typically include combinations of TPE, IVIG, and anti-CD20 antibody to clear circulating DSA and suppress antibody production; however, the optimal protocol for AMR is yet to be determined. There are no randomized controlled trials comparing the safety and efficacy of TPE-based regimens with immunosuppression alone, and it is difficult to draw conclusions on the incremental benefit of TPE from retrospective studies given the variable use of additional immunosuppressive

Plasma Exchange for Kidney Disease

agents; however, many of these studies have documented delivery of TPE for the removal of antibodies and it appears to be effective.80-85 In combination with intensification of other immunosuppressive therapies such as IVIG and anti-CD20 antibody, TPE has resulted in a 5-year graft survival of 78%.86 It appears that the transplant community has embraced this theoretical mechanism of TPE for AMR; however, the evidence is anecdotal and the approaches are formulaic, varying from center to center. Typical protocols include 5 or 6 daily or alternate-day TPE procedures using 5% albumin for replacement. Other protocols use kidney function and DSA titers to guide therapy.6

Multiple Myeloma The CAG no longer performs TPE for patients with myeloma cast nephropathy on the basis of results of a large randomized controlled trial and the lack of a theoretical benefit given the rapid turnover and large volume of distribution of monoclonal free light chains.87 Until future randomized controlled trials generate more definitive evidence, TPE is not recommended for treatment of kidney disease in multiple myeloma.

Management of Immunosuppressive Drug Therapies Although some immune-modulatory effects of TPE have been proposed, TPE does not typically treat underlying pathology (with the exception of TTP) and therefore serves as an adjunct to immunosuppressive therapies in most cases.88-90 However, some of the immunosuppressive drugs used in these settings are highly protein-bound with a low volume of distribution and are therefore easily removed by TPE.91-93 Although these properties enable drug removal in cases of overdose, unforeseen adverse effects may result from subtherapeutic drug levels if TPE is not taken into account when considering drug dosing and timing. Dose and timing considerations for medications commonly used to treat kidney diseases in the setting of TPE are presented in Table 5.

Conclusion Early introduction of TPE appears to be effective for many immunologic kidney diseases. However, TPE primarily serves as an adjunct to other immunosuppressive therapies and is often expected to offer only a small incremental benefit. Early diagnosis and treatment of the underlying condition remains important. Further research is necessary to establish the optimal dose and frequency of TPE and the appropriate replacement fluid and the plasma product composition for each condition.

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Acknowledgment A.M.H. was supported by the Clinical Investigator Program at Western University. S.-H.S.H. was supported by the Vanier Canada Graduate Scholarship.

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