Therapeutic Plasma Exchange in Renal Disorders

Introduction

Therapeutic plasma exchange (TPE) interchangeably termed as plasmapheresis is a process involving extracorporeal removal of plasma from other components of blood, discarding and replacing plasma with physiological fluids.[1] TPE targets removal of a single or allied group of high molecular weight (MW) substances (>15 kD) compared to hemodialysis and hemofiltration and reduces the concentration of target molecule(s), thereby providing a therapeutic window for drugs to act.[2] TPE is an appropriate choice if the pathogenic substance(s) that cannot be removed by conventional therapy, requires rapid removal and/or has a relatively long half-life, slow re-synthesis rate and has intravascular distribution.[3] Since its introduction in 1952, TPE has been used in many disorders either alone or in combination with other therapies, with improved safety and efficacy.[45] This review focus on the role of TPE in renal disorders. Cytapheresis, the selective removal of cellular elements, and hemoperfusion is not discussed.

Procedure

TPE is performed either using centrifugation (cTPE) devices that separate the plasma from cellular components based on density or membrane apheresis, based on molecular size (mTPE).[6] Both technologies are comparable in safety and efficacy.[7] The former removes target substances at a higher plasma extraction ratio but at a lower blood flow rate, while the latter, though with a lower plasma extraction ratio, compensates with a higher blood pump speed.[7] Nephrologists largely favor mTPE, an adaptation of technology on the dialysis machine, while others use cTPE when feasible. Details on prescription for plasmapheresis are outlined in Table 1.

Centrifugal Separation

Modern-day centrifugal separation devices operating on continuous flow technology utilize gravitational forces to separate plasma and cellular components of blood. Blood is collected from the patient; anticoagulant, usually citrate, is added before centrifugation, pumped through centrifuge bowl (spinning container) through the inlet port, and spun at 2000–2500 rpm, separating components [Figure 1a]. During this process, red blood cells move to the outer rim of the bowl, plasma near the axis of rotation far from the bowl, and white blood cells and platelets between the red cell and plasma layers. These fractionated components are collected in separate collection bags and reinfused.

Close

Figure 1

Therapeutic plasma exchange – Modalities. (a) Centrifugal TPE. (b) Double Membrane -Filtration. (c) Immunoadsorption

Export to PPT

Membrane Separation

In this system, plasma is filtered from cellular components of the blood by filtration through a highly permeable membrane filter.[7] Blood passes through the filter having large pores that allow plasma only to pass through but retain the large cellular constituents. Membrane filtration is nonselective in removing plasma with dissolved “toxins” and useful components. The concept is similar to hemofiltration where microporous membrane sieves a number of solutes. The membranes used in this system have larger pores compared to hemofilters but <0.6 μ, thereby rejecting the cellular components. This procedure can be performed using a hemodialysis machine in isolated ultrafiltration-dialysis bypass mode or with continuous renal replacement therapy machines.[2] Efficiency depends on filter characteristics, filtration rates, formed element deposition, clotting of fibers, and protein adsorption. This technology is simple, cost-effective, and reliable with no loss of cellular constituents of blood compared to centrifugation technique.

Mechanisms of Action of Therapeutic Plasma Exchange

The principal factors influencing the removal of the target substance in plasma are the relative distribution of the substance in intravascular and extravascular compartments, transfer rates of the substance across compartments, plasma half-life, regeneration of the substance, and ratio of plasma volume removed.[6] These features are applicable to the removal of immunoglobulins (Ig) IgM, IgG and immune complexes. Antibodies with a prolonged half-life will remain for longer duration even when endogenous production has stopped.[8] IgG molecules have MW of 150 kD, prolonge half-life for 21 days, 60% extravascular distribution, and a slow redistribution across vascular compartments.[9] A number of autoimmune disorders are mediated by IgG requiring several TPE sessions. IgM, MW 970 kD, has a plasma half-life of 5 days and 80% intravascular distribution that allows for early clearance once production ceases, necessitating fewer exchanges.[10] The removal of immune complexes resulted in better monocyte/macrophage functions in an in vitro study.[11] Certain autoimmune disorders treated with TPE show increasing T-suppressor cell function and the Th1/Th2 ratio shifting to a predominance of Th1 subsets.[12] Cytokines and soluble adhesion molecules in the plasma are removed by TPE but counteracted by their persistent production on contact of blood with the membrane.[13]

Replacement Fluids

Human serum albumin (HSA) is the common replacement fluid though, in certain clinical conditions, plasma is preferred for replacing missing plasma components. In thrombotic thrombocytopenic purpura (TTP), there is a deficiency in activity of A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13). TPE improves the survival of patients suffering from TTP with the removal of autoantibodies against ADAMTS13 and replacement of ADAMTS13 with plasma infusion.[14] Concomitant immunosuppressive therapy reduces rebound autoantibody production.[15]

The replacement fluid often is 5% HSA. Some centers prefer replacement of initial one-third the volume with saline followed by albumin substitution.[16] This is economical as significant proportion of infused albumin is lost during TPE. There are complications associated with the use of HSA and also with fresh frozen plasma (FFP) that is occasionally used as a replacement fluid during TPE [Table 2].[2171819] FFP is a sole replacement fluid in patients with TTP as this provides a therapeutic replacement of missing ADAMTS13.

Vascular Access

Central venous catheters either temporary or tunneled are preferred to antecubital veins when multiple exchanges are planned. Permanent arteriovenous fistula or a graft is ideal if multiple TPE sessions are required as in postrenal transplant recurrence of focal segmental glomerulosclerosis. Antecubital veins can be used for low flow treatment and for short duration.

Renal Indications for Therapeutic Plasma Exchange

The recent American Society for Apheresis recommendations classifies the considered disorders into four categories and grades recommendations [Table 3].[5] The KDIGO guidelines discuss the status of TPE for various glomerulonephritis (GN).[20]

Antiglomerular Basement Membrane Disease

Antiglomerular basement membrane (anti-GBM) disease is an autoimmune disorder mediated by anti-GBM antibody binding to the “good pasture autoantigen” – the noncollagenous domain of α3 chain of type 4 collagen of GBM in isolation or frequently with alveolar basement membrane binding.[21] This results in rapidly progressive GN (RPGN) and diffuse alveolar hemorrhage (DAH). Majority present with renal disease, about a half will have simultaneous DAH, and a minority present with isolated DAH.[21] Pathogenic antibodies are present in almost in all patients, usually of IgG (IgG1, IgG3), though IgA and IgG4 can occur.[21]

Nonrandomized case–control studies and a single small randomized control study (RCT) have shown that adjunct TPE in addition to steroids and cyclophosphamide provides rapid clearance of anti-GBM antibodies, resulting in quicker resolution of DAH, improved patient, and renal survival.[2223] A prospective study from North India found that most patients presented with dialysis-dependent renal failure with poor prognosis.[24] A Chinese center found that serum level of anti-GBM antibodies was an independent factor associated with mortality.[25] Early implementation of TPE targeting undetectable levels of anti-GBM antibodies is the goal of the therapy. A follow-up study involving 71 patients from Hammersmith Hospital has shown renal dysfunction at presentation and crescent score correlating with renal and patient survival. Patients who were dialysis dependent and having 100% crescents did not recover renal function despite therapy.[24] However, even in patients presenting with renal failure requiring dialysis, it is appropriate to initiate adjunct TPE. Renal biopsy done at the earliest opportunity showing 100% crescents (regardless of cellularity – personal opinion) indicates that renal recovery is unlikely and disease-modifying treatment including TPE can be withdrawn.[20] Patients presenting with both anti-GBM antibodies and antineutrophil cytoplasmic antibodies (ANCAs) will require aggressive early treatment as for anti-GBM disease including TPE and in addition long-term maintenance immunosuppression for ANCA-associated GN.[26]

Anti-neutrophil Cytoplasmic Antibody-associated Glomerulonephritis

Granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) presents as pauci-immune complex GN and has elevated cytoplasmic ANCA/proteinase 3 in GPA and perinuclear ANCA/myeloperoxidase in MPA. Approximately 70% of the patients presenting with RPGN in India have pauci-immune complex GN.[27] ANCAs being IgG can be rapidly reduced with TPE, improving outcome. A randomized trial of TPE or methyl prednisolone in severe renal vasculitis (MEPEX trial; n = 137) demonstrated that TPE increased the rate of renal recovery.[28] A substudy of MEPEX showed that TPE improved renal survival despite disquieting renal histological findings.[29] A meta-analysis of nine RCTs, including the MEPEX trial comprising 387 patients with ANCA-associated vasculitis or idiopathic RPGN, showed that with TPE there was a 20% relative risk reduction in the composite outcome of end-stage renal disease or death.[30] At 3.95 years, however, the MEPEX study participants did not sustain the earlier renal benefits of TPE.[31] There was a nonsignificant increase in infection-related deaths in patients randomized to the TPE arm raising concerns that TPE could cause harm. This could be a major detriment in the tropics. The role of TPE in DAH in these patients is based on observational data from a case series. Mortality in patients with DAH is mainly due to infection and TPE may further increase the risk of infection as Igs are removed. The ongoing PEXIVAS study with an open-label randomization of TPE is designed to address these questions.[32] Replacement with plasma is indicated in patients with DAH to avoid dilutional coagulopathy.[5] In patients with DAH and severe pulmonary compromise, the risk of an allergic reaction may be reduced with solvent detergent-treated plasma.[33]

Catastrophic Antiphospholipid Antibody Syndrome

The antiphospholipid antibody syndrome (APS), an acquired hypercoagulable condition, is characterized by arterial or venous thrombosis with the presence of persistent antiphospholipid antibodies (APLAs), lupus anticoagulant, anticardiolipin, and or anti-β2-glycoprotein 1. Catastrophic APS is a life-threatening presentation with the presence of APL and acute thrombosis of at least three organs over a period of days to a few weeks. Kidneys, lungs, brain, skin, and other sites may be involved. TPE removes APLA, cytokines, and complement components. TPE in conjunction with steroids, anticoagulants, and intravenous Ig (IVIG) improve survival. Case series have shown that TPE is useful in managing these patients though the mechanism is unclear[34] and APLA titers may be monitored to assess response to treatment.

Cryoglobulinemic Renal Disorders

Cryoglobulinemic disorders are mediated by circulating cryoglobulins. TPE can remove these molecules but has no effect on their production or on the underlying primary disease. There are case series to support the use of TPE in cryoglobulinemic vasculitis in conjunction with antiviral and immunosuppressive therapy.[35] TPE is indicated in catastrophic hepatitis C virus cryoglobulinemic vasculitis presenting with RPGN, gastrointestinal (GI) system, central nervous system, and/or pulmonary involvement.[36]

Idiopathic Immune-Complex Rapidly Progressive Glomerulonephritis

RPGN with crescent formation can occur occasionally in IgA nephropathy, membranoproliferative GN, postinfectious GN, and GN associated with infective endocarditis. TPE has no evidence of benefit.[37]

IgA Vasculitis and IgA Nephropathy

IgA nephropathy and IgA vasculitis (Henoch-Schonlein purpura) are mediated by IgA containing immune complexes which TPE can remove. TPE can be used in IgA vasculitis with RPGN, severe GI or cerebral manifestations based on anecdotal reports and a case series.[3839]

Multiple Myeloma

Renal involvement in multiple myeloma can be myeloma cast nephropathy or renal amyloidosis. Cast nephropathy occurs when there are high circulating levels of free kappa or lambda light chains. TPE effectively removes culprit-free light chains, but the results are conflicting. The Mayo Clinic study (n = 40) showed that TPE improved renal survival in biopsy-proven cast nephropathy.[40] The Canadian RCT did not find a significant benefit from TPE, but only a few renal biopsies were performed.[41] TPE is likely beneficial if in conjunction with chemotherapy in patients with biopsy-proven recent-onset acute kidney injury due to cast nephropathy. Case reports suggest enhanced free light chain removal with “high cutoff” membranes compared to TPE;[42] however, this has not shown survival benefits.

Thrombotic Microangiopathies

There is deficiency in TTP, of ADAMTS13, an enzyme that normally cleaves von Willebrand factor multimers leading to prevention of microthrombosis, whereas most hemolytic-uremic syndrome (HUS) patients have normal activity of this enzyme.[43] The clinical features and rationale for the use of TPE in a spectrum of thrombotic microangiopathy are presented in Table 4.

Renal Transplantation in Human Leukocyte Antigen-sensitized Patients

Pretransplantation desensitization protocols increasingly use TPE for recipients with living donors who have an incompatible crossmatch from donor-specific human leukocyte antigen (HLA) antibodies. There is a demonstrable survival advantage with transplantation in these individuals when compared to remaining on dialysis.[45] The number of TPE sessions is influenced by the degree of sensitization and HLA mismatch. The sessions are planned daily or on alternate days till crossmatch becomes negative leaving a week's window to transplantation before antibodies rebound.

ABO-incompatible Transplantation

ABO-incompatible renal transplantation requires TPE to remove significant levels of blood group isoagglutinins and a protocol of anti-CD20 antibodies and IVIG to restrict its production.[46] The 5-year and 10-year survival rates are comparable with ABO-compatible transplantation,[47] with an increased infective risk, in some reports. Double membrane filtration (DMF) TPE is economical compared with the specific Glycosorb® columns.

Antibody-mediated Rejection

Antibody-mediated rejection of kidney allografts occurs not only in up to 60% of high-risk recipients (HLA-sensitized or ABO-incompatible) but also in about 23% of unselected low-risk recipients.[48] TPE, daily or alternate days using 5% HSA, and IVIG (a high dose 2 g/kg or a low dose of 100 mg/kg) are commonly used to clear donor-specific antibodies and suppress antibody production, respectively. Recent years has seen anti-CD20 antibody used alongside though the evidence toward safety and efficacy is weak.[49]

Focal and Segmental Glomerulosclerosis with Recurrence Post-transplantation

Among those kidney transplant recipients with primary focal segmental sclerosis, severe proteinuria recurs in 30%–55% of patients, often within hours or days of surgery due to a permeability factor of 30–50 kD.[50] DMF is unsuitable for removal of this small MW factor. A meta-analysis of uncontrolled data shows full or partial remission with early TPE.[51] There are recommendations for initial daily and later alternate day TPE to keep patients in remission. In practice, some patients require weekly to monthly TPEs long term, to sustain remission.

Other Blood Purification Techniques[452]

Drugs and Therapeutic Plasma Exchange

Drug removal during TPE depends on TPE profile and pharmacokinetics of the drugs. Less likely, the drug will be removed if the drug plasma concentration at the time of initiation of TPE is lower; lower the drug's protein binding and higher the volume of distribution. Drug removal also depends on the time between the administration of the drug and TPE initiation, duration of TPE, volume of plasma removed, and sessions in succession.[55] Intravenous cyclophosphamide, Rituximab^®, or IVIG must be administered post-TPE only.

Conclusion

TPE is a valuable tool in the treatment of renal disorders when evidence-based recommendations are weighed with risk stratification of patients. The results are not always predictable solely based on successful removal of a target substance. One must consider the likely benefits against the risks and economic impact in each instance.