934 Table 48 6 (continued) LDL apheresis Familial hypercholesterolemia (homozygous) 1A Erythrocytapheresis/RBC exchange Hereditary hemochromatosis 1B Polycythemia vera 1B Sickle cell disease Acute str[.]
C Taylan and S M Sutherland 934 Table 48.7 (continued) Table 48.6 (continued) LDL apheresis Familial hypercholesterolemia (homozygous) Erythrocytapheresis/RBC exchange Hereditary hemochromatosis Polycythemia vera Sickle cell disease Acute stroke Stroke prophylaxis/iron overload prevention Immunoadsorption Acute inflammatory demyelinating polyradiculoneuropathy/Guillain-Barre syndrome 1A 1B 1B 1C 1A 1B Adapted from Padmanabhan et al [17] Table 48.7 Category II apheresis indications Therapeutic plasma exchange Disease Acute disseminated encephalomyelitis Age-related macular degeneration, dry (high risk) Autoimmune hemolytic anemia (severe cold agglutinin disease) Cardiac transplantation, desensitization Cryoglobulinemia, symptomatic/severe Familial hypercholesterolemia (homozygous/heterozygous) Hematopoietic stem cell transplant (ABO incompatible) Major HPC, marrow Major HPC, apheresis Lambert-Eaton myasthenic syndrome Multiple sclerosis, acute attack, or relapse Mushroom poisoning Myasthenia gravis, long-term treatment (+/− immunoadsorption) Myeloma cast nephropathy Neuromyelitis optica spectrum disorders, acute attack, or relapse Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection, Sydenham’s chorea Phytanic acid storage disease (Refsum’s disease, +/− immunoabsorption) Polyarteritis nodosa, hepatitis B virus associated Renal transplantation, ABO incompatible, antibody mediated rejection (+/− immunoabsorption) Grade 2C 2B 2C 1C 2A 1B 1B 2B 2C 1A 2C 2B 2B 1B 1B 2C 2C 1B Steroid-responsive encephalopathy associated with autoimmune thyroiditis (Hashimoto’s encephalopathy) Systemic lupus erythematosus, severe complications Thyroid storm Voltage-gated potassium channel antibodies (+/− immunoabsorption) Leukapheresis Hyperleukocytosis, symptomatic Behcet’s disease (adsorption granulocytapheresis) Immunoadsorption Cryoglobulinemia, symptomatic/severe Dialysis related amyloidosis (β2 microglobulin column) Dilated cardiomyopathy, idiopathic Multiple sclerosis, acute attack, or relapse Neuromyelitis optica spectrum disorders, acute attack or relapse Photopheresis Cardiac transplantation Cellular/recurrent rejection Rejection prophylaxis Graft versus host disease Acute Chronic Lung transplantation, bronchiolitis obliterans syndrome LDL apheresis Familial hypercholesterolemia (heterozygous) Focal segmental glomerulosclerosis, recurrence in renal transplant OR steroid resistance disease in native kidney Lipoprotein (a) hyperlipoproteinemia with progressive atherosclerotic cardiovascular disease Peripheral vascular disease Phytanic acid storage disease (Refsum’s disease) Erythrocytapheresis/RBC exchange Babsiosis Sickle cell disease, acute (severe acute chest syndrome) Sickle cell disease, non-acute Pregnancy Recurrent vaso-occlusive pain crisis Platletpheresis Thrombocytosis, symptomatic Adapted from Padmanabhan et al [17] 2C 2C 2C 1B 2B 1C 2B 2B 1B 1B 1C 1B 2A 1C 1B 1C 1A 2C 1B 1B 2C 2C 1C 2B 2B 2C 48 Therapeutic Apheresis in Children ANCA-associated disease cases, in patients who have severe renal involvement, the use of plasma exchange improves outcomes The largest study to date, MEPEX (Methylprednisone versus Plasma Exchange), demonstrated that in patients who have severe renal dysfunction, the use of plasma exchange improved the rate of renal recovery and reduced progression to end-stage renal disease at year [78] The regimen utilized was seven plasmapheresis sessions delivered over 14 days; our practice (SMS) is to perform 1–1.5x volume exchanges on alternate days for a total of treatments In most cases, 5% albumin can be used as the replacement fluid However, patients who are at high risk for bleeding and those who have undergone or will undergo a procedure (i.e., kidney biopsy) should receive at least partial replacement with fresh frozen plasma Plasma exchange is also recommended in patients with ANCA-associated disease who have concurrent anti-glomerular basement membrane (GBM) antibodies regardless of the severity of renal involvement; this recommendation is extrapolated from the data showing a benefit in the setting of isolated anti-GBM disease [79] Finally, although not universally recommended, plasma exchange is commonly used in ANCA patients who have evidence of pulmonary hemorrhage independent of the severity of renal involvement [80, 81] No randomized controlled trials to date have examined this; however, the recommendation is based upon observational studies and the demonstrated benefit in anti- GBM associated pulmonary hemorrhage The regimens employed in the two aforementioned situations mirror that used to treat severe ANCA-associated renal disease described above Thrombotic Microangiopathies Thrombotic microangiopathy (TMA) is a general term for conditions which are characterized by thrombocytopenia, microangiopathic hemolytic anemia, and end organ damage [82] Although 935 TMA can be secondarily associated with certain diseases (i.e., systemic lupus erythematosis, or stem cell transplantation) and medications (i.e., calcinurin inhibitors), the most archetypal TMAs are thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) [82] TTP is particularly common in adults and, in addition to thrombocytopenia and microangiopthic hemolytic anemia, patients with TTP often develop fever, mental status change, and acute kidney injury TTP has been associated with severe ADAMSTS13 (a disintegrin and metalloproteinase with thrombospondin type motif, member 13) deficiency; indeed the hallmark of TTP is an ADAMSTS13 activity level of 150 × 109/L and lactate dehydrogenase (or other markers of hemolysis) levels begin to normalize [17] It is important to note that the replacement fluid in this particular indication needs to be FFP since one of the main goals of the therapy is to restore normal levels of ADAMSTS13 Plasma exchange alone is rarely adequately effective, and comprehensive management strategies include the use of immunosuppressive agents (i.e., steroids and rituximab) [17, 87, 88] Although TTP is common in adults, it is relatively rare in children and pediatric practitioners are far more likely to manage HUS which tends to be further subdivided into diarrheal-associated HUS (D+ HUS) and atypical HUS (aHUS) [88] D+ HUS is classically caused by shiga-toxin producing Escherichia coli (STEC) and tends to be managed conservatively Currently there is no official indication for plasma exchange in D+ HUS unless there is underlying evidence of complement activation (i.e., STEC or diarrheal illness triggers a presentation of atypical HUS) [89, 90] However, it is often employed 936 in children with D+ HUS when there is evidence of severe neurologic involvement given the clinical overlap with TTP. Atypical HUS, on the other hand, was historically managed with plasma exchange Atypical disease is commonly due to mutations affecting the alternative complement pathway (i.e., Factor H, Factor I, MCP, CFHR1 thrombomodulin, complement factor B (CFB), and C3) [91] Plasma exchange is effective and was utilized due to its ability to remove defective mutant complement proteins or autoantibodies as well as its ability to replace these defective/ deficient proteins with fully functional versions [92] However, plasma exchange has been largely replaced by complement blockade agents One such agent, eculizumab, is a monoclonal antibody against C5 which prevents formation of the membrane attack complex (MAC), thereby blocking activation of the terminal component of the complement cascade [93] Although plasma exchange can still be used to treat aHUS, it should be considered second-line therapy in the vast majority of cases C Taylan and S M Sutherland conventional teaching is that FSGS recurrence is due to a circulating permeability factor which can be removed by plasmapheresis [99] Plasmapheresis is usually provided in conjunction with augmented immunosuppression and seems to be more effective if initiated early in the course of the recurrence [100–102] Although several regimens have been described, our practice (SMS) is to perform daily plasma exchange until some semblance of response is seen (i.e., reduction in spot urinary protein/creatinine ratio, higher serum albumin levels, improved renal allograft function, less severe hypertension) Following this, plasmapheresis is weaned serially to determine the minimum effective therapeutic frequency; patients may often require plasmapheresis one to two times per week indefinitely While we believe aggressive, early daily apheresis carries the highest likelihood of success; it is time and resource intensive and often necessitates the use of FFP as a replacement fluid Alternate-day regimens or short daily courses followed by early transition to alternate-day therapy may be equally effective Many centers also perform plasmapheresis immediately prior to Focal Segmental Glomerulosclerosis kidney transplantation in children with FSGS in (Recurrent) an attempt to prevent or reduce the risk of recurrence Preventative use of plasmapheresis has not Focal segmental glomerulosclerosis (FSGS) is a been universally effective; however, given the descriptive, histologic term which encompasses ramifications of disease recurrence its use is fairly several genetic and non-genetic conditions which common [98, 103] Recently, post- transplant are associated with nephrotic syndrome [94] In FSGS recurrence has been treated successfully children, approximately 10% of nephrotic syn- with immunoadsorption [104] Compared with drome cases will exhibit steroid resistance and plasmapheresis, immunoadsorption offers simiFSGS accounts for the majority of these cases lar efficacy but eliminates the risks related to for[95] Immunosuppression and renin-angiotensin- eign plasma exposure such as allergic reactions aldosterone system (RAAS) blockade are the and sensitization Immunoadsorption can be percornerstones of therapy; however, these inter- formed weekly or bi-weekly with 200% plasma ventions are often only partially effective and a exchange volume Monitoring should consist of, significant number of children with FSGS prog- at a minimum, plasma fibrinogen levels (safety ress to end-stage renal disease (ESRD) In these and factor depletion) and proteinuria (efficacy) children transplantation is offered; however, recurrence of FSGS is quite common with rates between 20–40% [96] Although not necessarily Solid Organ Transplantation effective for primary FSGS, therapeutic apheresis is effective in the treatment of FSGS recur- Therapeutic apheresis can be used before and/or rence following renal transplantation [97–99] after solid organ transplantation in a variety of Although the physiology is not fully understood, circumstances The primary transplant-associated 48 Therapeutic Apheresis in Children indications are the mitigation of sensitization, the treatment of antibody-mediated rejection (AMR), and ABO-incompatible transplantation Across all organs, sensitization is becoming more common; sensitization refers to the presence of pre- formed HLA antibodies [105, 106] Sensitization occurs most commonly due to prior transplantation, blood product administration, pregnancy (rare in children but common in adults), and immunizations [107] Regardless of the cause, the presence of pre-formed anti-HLA antibodies makes transplantation more difficult and puts allograft recipients at greater immunological risk for rejection [105, 107] Desensitization strategies aim to mitigate or eliminate the anti-HLA antibody burden, thereby allowing transplantation to proceed and reducing future risk of antibody mediated rejection Anti-HLA desensitization has been performed most commonly for kidney, heart, and lung allograft recipients; potential interventions include intravenous immunoglobulin (IVIG), rituximab, bortezomib, and plasma exchange [105–112] A complete discussion of desensitization is beyond the scope of this chapter; however, it will be useful to highlight some of the apheresis-related concepts Plasma exchange is rarely used in isolation as without some additional antibody control mechanism, rebound can occur; as a result, it is used most commonly with IVIG at a minimum and, at times, in conjunction with rituximab or bortezomib [113–116] Since plasma exchange non-selectively removes antibody-sized proteins, it is imperative that immunologic agents such as these are administered after apheresis Additionally, once administered, apheresis should not be performed again until the agent has had adequate time to achieve its desired effect The one exception is IVIG as small doses of IVIG are often given after each apheresis episode in many desensitization protocols [113] When employed, therapeutic plasma exchange if often performed daily or on an alternate-day basis with single or 1.5x volume exchanges Replacement can consist of either 5% albumin or FFP depending on proximity to a surgical procedure, bleeding risk, and intensity of the exchange regimen Plasma exchange is far more effective in the setting of living donation as antibody strength 937 can be monitored and serial cross matches can be performed This is only an option for renal transplantation; however, apheresis prior to living donation often results in complete elimination of a previously positive cross match The use of plasmapheresis in the setting of antibody-mediated rejection is based upon similar pathophysiology The hallmark of AMR is the presence of circulating anti- HLA antibodies specifically directed against the HLA antigens present on the donated organ [117] Similar to desensitization, in the setting of AMR, plasmapheresis is designed to remove the offending antibodies from circulation However, plasmapheresis has not been shown to be effective in isolation It has been used with IVIG, rituximab, bortezomib, and eculizumab with varying degrees of success [110, 117–125] Most apheresis regimens are performed daily or on alternate days until there is evidence of effect; this may be manifest by a reduction in the strength or number of anti-HLA donor specific antibodies (DSA), histologic evidence of AMR mitigation, or improvement in allograft function Just as in desensitization, monitoring the strength of anti-HLA antibodies is an important facet of AMR management Whenever available, immunoadsorption is a valid alternative in patients who experience plasmapheresis-related side effects or have an inadequate response to therapy Tryptophan and Globaffin absorbers are very effective and remove IgG selectively Immunoadsorption has been used safely for extended periods of time and should be considered a viable therapeutic option in these situations Lastly, therapeutic apheresis is used in the setting of transplantation across ABO blood groups Typically, transplantation across blood groups (i.e., transplanting an allograft from a blood type B donor into a blood type A recipient) should not be performed since the recipient’s immune system will rapidly recognize and attack the foreign proteins on the transplanted allograft; without intervention, transplantation across blood groups is associated with acute antibody- mediated rejection [126–129] However, therapeutic plasma exchange has been successfully used to perform ABO-incompatible liver and kidney transplants [127, 129] The typical regi- C Taylan and S M Sutherland 938 men is to perform 1–1.5x volume exchanges both prior to and (if necessary) after transplantation [17] Regimens differ from center to center; however, the strength of the antibody titer dictates the frequency of exchange and the ultimate number of treatments will depend on the rate of antibody production and rebound, the strength of the titer, and the response to therapy [130] In Europe immunoadsorption, in combination with plasma exchange, has become first-line therapy for ABO- incompatible transplantation [131] Anti-A or anti-B columns can be used to specifically eliminate circulating ABO antibodies directed against donor cells The plasma exchange volume and number of sessions required will depend on the strength of the antibody titer, which is measured before and after every immunoadsorption session and should be lowered prior to transplantation to a target titer of ≤1:4 Although there have not been any controlled trials of plasma exchange or immunoadsorption in liver or kidney transplantation, observational studies have suggested that mid- to long-term allograft outcomes are similar to those seen in ABO compatible transplants [132–134] Summary Apheresis is an effective extracorporeal therapy for a broad swath of diseases and pathophysiologic states The technique is capable of targeted removal of cellular blood components and less-specific removal of plasma proteins and components; 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Plasma- and lymphapheresis in autoimmune diseases Z Rheumatol 1996;55(2):90–104 44 Costanzo-Nordin MR, Hubbell EA, O’Sullivan EJ, Johnson MR, Mullen GM, Heroux AL, et al Photopheresis versus corticosteroids in the therapy of heart transplant rejection Preliminary clinical report Circulation 1992;86(5 Suppl):Ii242–50 45 Meiser BM, Kur F, Reichenspurner H, Wagner F, Boos KS, Vielhauer S, et al Reduction of the incidence of rejection by adjunct immunosuppression ... described above Thrombotic Microangiopathies Thrombotic microangiopathy (TMA) is a general term for conditions which are characterized by thrombocytopenia, microangiopathic hemolytic anemia, and end... the severity of renal involvement [80, 81] No randomized controlled trials to date have examined this; however, the recommendation is based upon observational studies and the demonstrated benefit... anti-glomerular basement membrane (GBM) antibodies regardless of the severity of renal involvement; this recommendation is extrapolated from the data showing a benefit in the setting of isolated anti-GBM