Key words : ABMR, Focal segmental glomerulonephritis, Photopheresis, Plasmapheresis

Introduction

Therapeutic apheresis (TA) has been designated for removal of dedicated blood components with or without replacement of plasma. The process is used to treat various conditions in children. Therapeutic apheresis procedures are considered mostly as a lifesaving treatment option for pediatric patients or their allograft. Although some conditions treated with TA are rarely encountered in pediatric patients, TA is often applied to affected children, although perhaps not with the same frequency as in adults.

Although TA has been recently increasingly used in Europe and the United States, it is of low interest of use in other regions because of its cost and availability. In this review, we discussed the many aspects of TA in pediatric patients, including indications of TA and the types and procedures of TA used for pediatric patients. We will also briefly discuss problems associated with TA in pediatric transplantation.

Indications for Therapeutic Apheresis in Pediatric Renal Transplantation

Ideal substances to remove with TA should have at least 4 of these characteristics: large molecular weight (>15 kDa), prolonged half-life, rapid elimination from the plasma, higher percentage intravascular distribution of the substance, and low turnover rate.

Antibody-mediated rejection (ABMR) and de novo antibody in transplant recipients are mostly due to immunoglobulin G (IgG) or IgM. Among these antibodies, IgG is distributed 45% intravascularly; within 48 hours, plasma IgG returns to approximately 60% of pre-TA levels. These characteristics of IgG cause a rigorous regimen that involves 5 procedures of TA, along with use of immunosuppressive agents to reduce IgG levels. In contrast, because approximately 75% of IgM is intravascular, only 1 or 2 procedures are required to rapidly reduce IgM levels ¹.

Because the IgG half-life is 22 days and even if immunosuppressive therapy could immediately inhibit new antibody production, the plasma concentration would decrease by only approximately 50% within 21 days. Such a delay is not acceptable in ABMR, a catastrophic situation in which early intervention is mandatory. Another benefit of TA is unloading of the reticuloendothelial system, which can enhance endogenous removal of circulating toxins for allografts such as interleukins and complements. Another mechanism of TA is to make lymphocyte clones predisposing to cytotoxic therapy, such as antithymocyte globulin or rituximab.¹ Alterations in cellular components of the immune system following TA have been identified. After treatment with therapeutic plasma exchange (TPE), suppressor T-cell function is significantly increased compared with baseline levels in all patients (20.1% before TPE vs 39.3% after TPE).¹ Its use may modulate cellular immunity by altering the ratio of T-helper type 1 and type 2 cells in peripheral blood. T-helper type 2 cells are known to facilitate the humoral immune response by facilitating antibody production by B cells. Another possible mechanism of TA may be sensitizing of antibody-producing cells to immunosuppressive therapy.

Therapeutic apheresis may also be used for changing of drug concentrations in circulation through direct removal or via removal of metabolizing drug enzymes.² Maintenance immunosuppressive drugs used for organ transplant are generally not removed significantly by TA procedures. Therapeutic apheresis removes only 1% of prednisolone, and additional doses are not required after TPE. Cyclosporine and tacrolimus are predominantly intracellular, protein bound, and have limited volume of distribution (13%). Consequently, these agents are not affected by TPE. In contrast, immunosuppressive drugs used for induction therapy and treatment of acute rejection, such as rituximab and antithymocyte globulin, can be removed at up to 50% with an effective TPE, so a dose should be administered after a TPE session.²

Many evidence-based indications for TA have been described in pediatric renal transplant, including ABMR, recurrence of primary focal segmental glomerulosclerosis (FSGS), desensitization protocols, prevention and treatment of complement-mediated atypical hemolytic uremic syndrome (aHUS), de novo thrombotic microangiopathy (TMA), antiphospholipid syndrome, systemic lupus erythematosus, recurrent and de novo anti-glomerular basement membrane antibody (GBM) disease, and recurrence of antineutrophil cytoplasmic antibody-associated antibody (ANCA-AAV).

Antibody-mediated rejection

The present management of ABMR, based on American Society For Apheresis (ASFA), is TA and immunosuppression. Therapeutic plasma exchange is important for management of acute ABMR after transplant. Therapeutic apheresis can be based on plasma exchange, double filtration plasmapheresis (DFPP), or immunoadsorption, always in conjunction with other immunosuppressive drugs. Because a rebound of antibodies is usually seen, repeated posttransplant TA is suggested to avoid antibody rebound. Plasma exchange modality for ABMR is to have plasma exchange volume of 1 to 1.5 plasma volume on a daily or every other day basis. The replacement fluid could be albumin or fresh frozen plasma (FFP) plus intravenous immunoglobulin (IVIG) of 100 to 200 mg/kg. Duration of treatment of TA is usually daily or every other day for 5 or 6 sessions or based on clinical outcomes and demonstration of decrease in donor-specific antibody titers. Therapeutic apheresis may be effective even in subclinical ABMR.³ As shown over 2-year follow-up, DFPP and rituximab therapies may be partially effective for biopsy-proven subclinical ABMR.

Experiences of TA in pediatric renal transplant patients over 1 decade and in 389 sessions⁴ showed that TA procedures after renal transplant were effective and safe; however, because this treatment is combined with variable immunosuppressive therapies, the final clinical efficacy seems to be related to the cumulative effects of pharmacotherapy and plasma exchange, not TPE by itself. Present data have shown that TA is only indicated if ABMR is diagnosed during the first year posttransplant.⁵ Its efficacy has not been proven if ABMR occurred 1 year after renal transplant.

Whenever ABMR is treated with TA, IVIG is necessary after each session of plasma exchange, especially in children with fragile immunity. This may be an effective manner for prevention of infection. A dose of IVIG of 200 to 400 mg/kg should be considered for children with IgG 4 g after each plasma exchange session. In addition, TA stimulates production of donor-specific antibodies (DSAs) by rebound phenomena; this effect is mitigated with administration of IVIG after each TA session.⁶

Recurrent focal segmental glomerulosclerosis following kidney transplant

The etiology of recurrent FSGS following renal transplant has been postulated for anti-nephrin antibodies and toxic lipoproteins. Focal segmental glomerulosclerosis is the most common cause of graft loss in pediatric renal transplant⁷ and may recur from a few hours to 2 years posttransplant. Proteinuria is the only marker that is used to assess effects of treatment. Recurrence after renal transplant is mainly diagnosed by examination of biopsy samples. Recurrent FSGS affects up to 60% of first kidney grafts and exceeds 80% in patients who have lost their first graft due to recurrent FSGS.⁸ Despite treatment, 30% to 60% of patients experience progression to kidney failure within 3 to 7 years.

The current treatment for recurrent FSGS after kidney transplant is based on ASFA guidelines and includes a combination of steroids, rituximab, TA, and/or IVIG. The methods of TA could be plasma exchange, lipoprotein apheresis, or immunoadsorption. In the case of plasma exchange, replaced plasma volume is between 1 and 1.5 with frequency of daily or every other day. The main substitute fluid is albumin. The duration of TA is 3 consecutive days, which is followed with 6 more sessions during the next 2 weeks. Lipoprotein apheresis includes 2 sessions per week for 3 weeks followed by 6 weekly treatments.

A systematic review and meta-analysis, to estimate the remission rate after treatment with plasma exchange and to determine if remission varied with patient or treatment characteristics,⁹ showed that about 71% of patients achieved full or partial remission after treatment with plasma exchange. Patients treated within 2 weeks of recurrence appeared to have a higher likelihood of remission from proteinuria. Some cases required intensive plasmapheresis for up to several months.

Another study¹⁰ reported 17 pediatric renal transplant patients with recurrent FSGS who were treated with a standardized protocol using plasmapheresis and cyclophosphamide instead of standard immunosuppression with calcineurin inhibitors (CNIs) and steroids. Results showed that 15 children achieved a complete remission within 3 months of treatment for FSGS recurrence, without another recurrence.

Low-density lipoprotein-apheresis is another modality for treatment of posttransplant recurrent FSGS in pediatric patients.¹¹ Lipoprotein apheresis treatment for recurrent FSGS after transplant in 7 patients was successful for treatment of posttransplant FSGS and substantially decreased proteinuria.

Desensitization protocol

Desensitization protocols by TA are usually used for the following recipients: (1) for desensitization in ABO-incompatible kidney transplant, (2) for desensitization in patients with pre-preformed HLA antibodies, (3) for desensitization of deceased donor kidney transplant recipients, and (4) for desensitization of living donor kidney transplant recipients. Patients with high immunological risk wait for an immunologically compatible donor. Renal graft outcomes in patients with high immunological risk after an adequate desensitization protocol were similar to those observed in nonsensitized patients, at least during the first year posttransplant.¹²

Living donor transplant after desensitization showed a significant survival benefit for patients with HLA sensitization, compared with waiting for a compatible organ.¹³ The patient survival advantage more than doubled in long-term follow-up. These data provided evidence that desensitization protocols may help overcome incompatibility barriers in living donor renal transplant.

Apheresis tools available to desensitize HLA-incompatible kidney transplant candidates include plasmapheresis, DFPP, and immunoadsorption modalities.¹⁴ The best method for deciding to select each form of TA is based on DSA by Luminex. It is generally considered that DSA is negative when mean fluorescence intensity (MFI) is lower than 1000. In cases with DSA lower than 3000, a desensitization program is not recommended by each modality of TA. Selection of plasmapheresis is inexpensive and efficient if DSA MFI <9000, many repeated sessions are mandatory, and depletion of immunoglobulin or clotting factors is problematic. In the case of double-filtration plasmapheresis, it is relatively inexpensive and more efficient if DSA MFI <12 000, many repeated sessions are mandatory, and depletion of immunoglobulin/clotting factors are problematic. Semi-specific immunoadsorption is more expensive, the columns adsorb only Ig, many repeated sessions are mandatory, it has reusable columns, is more efficient if DSA MFI <15 000, and it depletes only specific antibodies.

Desensitization in patients with pre-preformed HLA antibodies is divided as desensitization of deceased donor kidney transplant recipients and desensitization of living donor kidney transplant recipients. Deceased donor kidney transplant candidates could be desensitized perioperatively.¹⁵ This effective modality of TA (mainly based on immunoadsorption) is conducted pretransplant, with continuation of TA posttransplant until DSAs become negative. A general accepted desensitization protocol for living donor kidney transplant recipients is a combination of alternate-day plasma exchange followed by low-dose IVIG (100-150 mg/kg) pretransplant with initiation of tacrolimus and mycophenolate mofetil up to 2 weeks pretransplant.

To date, there is no firm evidence for superiority of one technique over another apheresis technique to HLA desensitization. In a study that assessed the efficacy, safety, and tolerance of each apheresis technique in the setting of desensitization,¹⁶ desensitization with apheresis was effective at removing HLA antibodies and allowed access to HLA-incompatible kidneys for sensitized patients. Immunoadsorption and plasma exchange were more effective to remove IgG and anti-HLA antibodies, especially for class II DSAs, and were better tolerated than DFPP. In a cohort of 10 desensitized living donor kidney transplant recipients with a median follow-up of 19 months, desensitization of recipients allowed rapid and lifelong elimination of DSAs by repeated pre- and posttransplant immunoadsorption.¹⁷ The combination of peritransplant apheresis with potent immunosuppression and anti-CD20 therapy prevented re-emergence of antibodies and de novo antibody production in most patients. Side effects were negligible, and short- to medium-term graft outcomes were acceptable.

Desensitization in ABO-incompatible kidney transplant is an effective way to partially overcome organ shortages. A desensitization protocol can lead to long-term graft and patient survival for ABO-incompatible renal transplant recipients, with outcomes acceptable to those with ABO-compatible kidney transplant.¹⁸ Among 12 ABO-incompatible renal transplants,¹⁹ long-term outcomes of ABO-incompatible/HLA-incompatible kidney transplant patients who were desensitized pretransplant by rituximab, IVIG, and immunoadsorption were acceptable and accompanied by reduced or eliminated donor-specific alloantibodies and by good clinical outcomes.

ABO-incompatible kidney transplant was also shown to be safe and effective, with excellent graft (96.6%) and patient survival (98.3%).²⁰ The incidences of acute rejection and posttransplant infections were comparable to standard data. The strategy of avoiding posttransplant plasma exchange appears feasible and allows cost reduction and shortening of hospitalization without affecting outcomes.

Increasing evidence has shown good short-term and medium-term outcomes of ABO-incompatible and HLA-incompatible kidney transplant with pretransplant positive cross-matches in pediatric practice, similar to adults. Long-term follow-up on all ABO-incompatible and HLA-incompatible pediatric kidney transplant recipients in the United Kingdom²¹ showed that, in 13 pediatric nephrology centers with 711 pediatric living donor kidney transplants, 23 were ABO-incompatible. Patient survival was 87%, and long-term follow-up showed that ABO incompatibility is feasible for pediatric kidney transplant where no compatible donors are available, with desensitization minimized where possible. An algorithm suggested for TA in the cases of ABO-incompatible transplantation is shown in Table 1.

Atypical hemolytic uremic syndrome

Atypical hemolytic uremic syndrome is another evidence-based indication for TA in children. Complement-mediated TMA, also known as aHUS, is caused by overactivation of the alternative complement pathway. Patients present with thrombocytopenia, microangiopathic hemolytic anemia, acute kidney injury, present or absent neurologic disorder, and fever. Complement cascade overactivation is secondary to genetic mutations, which cause impaired function of the alternative inhibitors pathway (factor H, membrane cofactor protein, and factor I) or overexpression of complement activators (ie, factor B and complement component C3). The recurrence rate after transplant can reach 75% and predicts poorer graft survival. Up to 90% of these grafts may be lost within the first year after transplant. Complement-mediated TMA can be treated with daily plasma exchange plus immunosuppression, with substitution fluid of choice being FFP. Eculizumab, a terminal complement inhibitor, is presently the best treatment, and the role of PE per se or in combination with eculizumab is not superior to eculizumab alone.²²

Thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) after kidney transplant has similar clinical and laboratory findings as complement-mediated TMA. However, TTP is more common in adults than in children, presents with more profound thrombocytopenia, usually presents with more severe neurological impairment, and demonstrates varying degrees of renal failure. The common causes of this disorder are drug-induced TMA due to CNIs and mammalian target of rapamycin inhibitors, ischemia-reperfusion injury, ABMR, and viral infection. The crucial role of treatment is correction of immunosuppressive treatment and treatment of the underlying condition. Therapeutic apheresis can be used as adjunctive therapy, although its role has not been confirmed. Eculizumab has been proved to be effective in the resistant cases of ABMR-associated TMA, although it is usually treated with TA + IVIG and rituximab.²³ Based on ASFA guidelines, TA should be performed daily with plasma exchange of 1 to 1.5 volume each. The replacement fluid should be FFP or FFP and albumin. The duration of treatment should be continued until adequate clinical response or until antibody titer is reduced to less than clinical threshold (similar to immune TTP).

Antiphospholipid syndrome

Catastrophic antiphospholipid syndrome (cAPS) is an acute life-threatening disorder associated with diffuse thromboses in at least 3 systems within a few days. It is secondary to existence of antiphospholipid antibodies (primary or secondary to systemic lupus erythematosus). Graft thrombosis takes place in 40% of the APS population despite anticoagulant therapy. Presence of cAPS is an indication for early TA. The procedure should be performed in combination with steroids ± IVIG and anticoagulants. This triple therapy has been proven to be effective in cAPS. Other new drugs have also been effective for the disorder, such as cyclophosphamide, eculizumab, and rituximab. Plasma exchange in cAPS is performed daily or every other day, and substitution fluid is usually FFP or FFP and albumin. The role of eculizumab to prevent posttransplant cAPS has been shown in the presence of antiphospholipid antibody.²⁴²⁵

Recurrent and de novo anti-glomerular basement membrane antibody disease

Anti-glomerular basement membrane antibody disease is an autoimmune disorder in which IgG antibodies directed against the ?3 chain of type IV collagen result in glomerulonephritis and/or alveolar hemorrhage. Although it is a rare disorder in the pediatric population, it often rapidly progresses to kidney failure in approximately 55% of patients despite treatment. The histological recurrence of anti-GBM may be as high as 50% in patients who receive a transplant while circulating anti-GBM antibodies persist. Therapeutic apheresis should be used promptly to remove the causative antibody plus glucocorticoids and cyclophosphamide to inhibit further autoantibody production. Therapeutic apheresis should be performed daily or every other day. Anti-GBM antibody titers should be monitored, and the procedure should be performed until the autoantibodies are undetectable (average of 10-14 sessions). The KDIGO guidelines recommend TA except in dialysis patients with generalized glomerular crescents or those in which more than half the glomeruli have glomerulosclerosis without pulmonary hemorrhage.²⁶

Recurrence of ANCA-AAV

The last part of this discussion is related to the patients with recurrent ANCA-associated vasculitis after renal transplant, which is a rare event after pediatric transplant. The disease is a necrotizing small-vessel vasculitis in which few or no immune deposits are apparent in kidney biopsy specimens. De novo kidneys are involved in 70% of cases and the lungs in more than 50% of cases. The most common kidney manifestation is glomerular crescent formation with vasculitis.²⁷ Transplant should be delayed until a complete extrarenal remission for at least 12 months is achieved. ANCA-positive patients with extrarenal remission can be transplanted. Therapeutic apheresis is indicated for deteriorating kidney function and diffuse alveolar hemorrhage. Therapeutic apheresis is recommended, in conjunction with glucocorticoids and either cyclophosphamide or rituximab, in the setting of relapse manifesting as alveolar hemorrhage, severe segmental necrotizing glomerulonephritis with serum creatinine above 4.0 mg/dL, or concurrent anti-GBM disease.

Types and Procedures of Therapeutic Apheresis Used for Pediatric Renal Transplant Recipients

Therapeutic apheresis modalities used in renal transplant are generally divided into 4 modalities: TPE, DFPP, immunoadsorption, and extracorporeal photopheresis (ECP).

Therapeutic plasma exchange

Therapeutic plasma exchange is an extracorporeal therapy performed by using centrifugation type or membrane filtration type. Notably, the ideal characteristics of a substance to be removed by TPE include, among others, large molecular weight, distribution in the intravascular space, and prolonged half-life. Two modalities are available for the removal of plasma and its pathogenic substances. In membrane filtration, TPE can only separate plasma, whereas, in centrifugation-type filtration, TPE can fractionate any of the blood components and is performed when specific blood fractions are targeted. Both modalities are almost effective for removing plasma proteins, and each needs the amount of replacement fluid that has been removed. The efficacy of membrane-based plasma filtration is almost half of the centrifugal modality of plasmapheresis during treatment. Because lower blood flow rate is sufficient for centrifugation method, peripheral vein access may be sufficient for TPE. Importantly, TPE should not be used as an ultrafiltration procedure by intentionally replacing less than the exchanged volume. In patients on hemodialysis for kidney failure, alkalemia may result from repeated apheresis treatments when FFP is the primary replacement fluid. Therefore, if TPE and dialysis are required on the same day, TPE should be performed first to allow subsequent dialysis to correct the blood pH or hypervolemia resulting from TPE.

Double filtration plasmapheresis

Double filtration plasmapheresis is a recognized treatment option for a number of conditions and can be considered as a selective TA technique. For DFPP treatment, 2 types of filters with different pore sizes are used for plasma purification, the first being a plasma separator and the second being a plasma component separator. Whole blood is separated into plasma and blood cells using a plasma separator. Thereafter, the separated plasma is fractionated into different molecular weight components by a plasma component separator. Larger molecular weight components are discarded, and smaller molecular weight components, including albumin, return to the circulation. A great advantage of DFPP, in addition to removal of selective substances, is that the volume of replacement fluid can be significantly reduced compared with conventional plasma exchange. With selection of the optimal pore size filters for the plasma component separator, DFPP can be applied to various pre- or posttransplant disorders. The clinical applications of DFPP are reviewed based on recent articles on metabolic disorders, organ transplants, rheumatic disorders, neurological disorders, and dermatologic disorders.

Approximately 70% of IgM and 60% of IgG can be removed by 1 DFPP session.²⁸ The success rate of desensitization using the pretransplant conditioning regimen has been shown to be 97% by DFPP.

A 10-year follow-up analysis reported a significant success rate (almost 74%) in 30 children (composed of AMR, chronic antibody-mediated rejection, recurrent FSGS, membranous glomerulonephritis, GN) treated with DFPP.²⁹ The analysis concluded that DFPP was a safe, well-tolerated form of apheresis that appears to have comparable outcomes to that of plasma exchange, without the routine need of replacement blood products.

Immunoadsorption

Immunoadsorption has been designed to remove immunoglobulins and immune complexes from plasma and is used for desensitization before transplant or in acute rejection after organ transplant. Mean IgG reduction is between 68% and 93% with immunoadsorption, and improvement of clinical situation has been observed in 63.0% of cases.³⁰ Overall, the treatment is well tolerated and effective in lowering immunoglobulins, with an improvement or maintenance of clinical status.

This method has 2 types of filters: the first one filters plasma and a second set of filters is composed of 2 filters of specific immunoadsorber columns. The columns can be sealed with immobilized staphylococcal protein A, which effectively clears IgG 1, 2, and 4 by binding their Fc portions. The second type of columns contains immobilized antibodies, which are specified for target immunoglobulins. The newer and more effective immunoadsorption procedure is used from immobilized antigens and synthetic epitopes on the specific column. Immunoadsorption is more tolerable, has lower likelihood of allergic reactions, and can treat larger plasma volumes with higher antibody removal than the other modalities of TA. The main limitation of this type of TA is the higher price compared with the other types. We recommend immunoadsorption when its indication is superior to the other modalities of TA.

Extracorporeal photopheresis

Extracorporeal photopheresis is a type of cell therapy used as an immunomodulatory therapy in patients with rejection after solid-organ transplant. Although the mechanism of action has not been fully elucidated, ECP entails mononuclear cell collection followed by ultraviolet A irradiation in the presence of 8-methoxypsoralen irradiated cells. After reinfusion of the exposed plasma to patients, lymphocytes become predisposed to apoptosis. Anti-inflammatory cytokines are secreted, with increases in regulatory T cells and decreases in effector T cells. Extracorporeal photopheresis is considered a safe and well-tolerated procedure in children.³¹ Extracorporeal photopheresis has been used as a part of CNI-sparing protocols to reduce drug side effects such as CNI nephrotoxicity and neurological or infectious complications of CNI. Treatment with ECP may enhance regulatory T-cell levels, with increased persistence for up to 1 year without the need for a recall ECP.³²

Administrated protocol for ECP is to perform 2 consecutive days every week during the first month (8 procedures), then taper to 2 every other week (4-8 procedures). The total number of ECP sessions can vary from 12 to 16. Each session should be for 2 to 3 hours. Standard heparin solution should be used for anticoagulation. Patients are asked to wear sunglasses and to use skin sun protection for 15 for 24 hours after the ECP session to avoid phototoxic skin reactions.

Problems Associated With Therapeutic Apheresis in Pediatric Transplant

Therapeutic apheresis procedures need specific consideration and potential modification for pediatric transplant recipients. Apheresis procedures in infants and toddlers weighing between 5.5 and 20 kg are safe and effective.³³ Attention should be given about differences in disease outcomes in pediatric compared with adult patients and also evolution of TA treatment indications. Pediatric plasmapheresis has distinct characteristics compared with adult plasmapheresis. Differences include substantial fluid shifts that occur during apheresis, potentially resulting in hemodynamic instability in children, vascular access for a sufficient flow rate is more difficult in pediatric patients, hematologic and metabolic disturbances requiring close monitoring is more important in the children, and duration of apheresis procedure often requiring sedation for agitated infants and toddlers.³⁴

In 370 articles that specifically assessed TA for treatment of a pediatric disease, adverse events were more common in children than in adults.³⁵ Complications included vascular access, patient factors (such as the volume status), replacement fluid, and technical considerations.

Machines for TA commonly need extracorporeal blood volumes of >200 mL. Therefore, in children who weigh less than 20 kg and who may have an intravascular blood volume of only 1400 to 1800 mL, these significant extracorporeal blood volumes can result in hemodynamic instability. In this situation, a priming procedure for adapting systems is necessary.³⁶ Plasmapheresis has been reported in children weighing as little as 4 kg with this adapting system.

Technical aspects of pediatric TA in kidney transplant disorders are based on priming the machine, the volume of plasma exchange, vascular access, and replacement fluid ³⁷. Effective circulatory volume greater than 15% of total blood volume for TA needs custom priming by blood or albumin. Vascular access can be used with catheters placed in separate veins or a single double lumen access placed in the smaller patient. This placement of access, or the use of peripheral access, is based on the size of the individual and the expertise of the medical team. Major complications associated with TA include access related (1%-20%); electrolyte disorders composed of hypocalcemia, hypokalemia, and alkalosis (7%-19%); thrombocytopenia (1%-5%); hypotension (0.5%-15%); and coagulopathy (<2%). Complications are more common in children. Occurrence of catheter dysfunction is related to patient age, with occurrence of catheter-related problems significantly associated with younger age.³⁷

Replacement fluids can be FFP or albumin, depending on physician decision.³⁸ Choice depends on characteristics of the disorder, the central facility, and expected complications of each solution. Advantages of albumin include no risk of hepatitis, rare events of allergic reaction, and no concern about ABO blood group. However, albumin is expensive and has no coagulation factor and immunoglobulins. Hence, coagulation testing should not be performed until 8 to 12 hours after albumin replacement. Commercially available 5% albumin solutions contain approximately 145 mmol/L sodium and <2 mmol/L potassium. This solution has lower risk than plasma of hypersensitivity reactions, transfusion-related acute lung injury, and transmission of infection. In contrast, FFP contains coagulation factors and immunoglobulins, has risk of transmission of hepatitis, has risk of allergic reactions, and must be used for ABO blood group compatible with the recipients. Because each unit of FFP has 200 to 300 mL of plasma, a single plasma volume exchange of 2.5 L will require 10 U obtained from many donors. If there is a history of hypersensitivity to FFP, pretreatment with steroids, diphenhydramine, and ephedrine is recommended. There is also risk of citrate overload. Plasma is primarily used to replenish ADAMTS13 in TTP and clotting factors in patients with bleeding. Fresh frozen plasma contains approximately 7 mmol citrate per unit, increasing the risk for citrate toxicity with large-volume infusions.

Conclusions

Multiple types of TA are used in pediatric renal transplant recipients and are based on the diseases and the facilities available at each center. When TA treatment is used, use must be accompanied by immunosuppressive drugs, such as corticosteroids, IVIGs, and antirejection medications. The common indications for plasmapheresis in pediatric renal transplant recipients are ABMR, FSGS, TMA, and desensitization protocols. Potential complications of TA include fluid and electrolyte imbalances, infection, bleeding, and vascular access changes, which are more prevalent in pediatric patients. With lower incidence of side effects and more efficacy, immunoadsorption is the preferred modality over plasma exchange in children and adolescents; however, benefit-cost ratio should be considered in these cases.

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