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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
REVIEW ARTICLE  
Year : 2019  |  Volume : 30  |  Issue : 2  |  Page : 291-298
Therapeutic plasma exchange for children with kidney disorders: Definitions, prescription, indications, and complications


Department of Pediatrics, College of Medicine, King Saud University, King Khalid University Hospital, Riyadh, Saudi Arabia

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Date of Submission26-Sep-2018
Date of Acceptance27-Sep-2018
Date of Web Publication23-Apr-2019
 

   Abstract 


Therapeutic plasma exchange (TPE) is a procedure that involves the removal of a large volume of plasma that is replaced with a replacement fluid, which is usually 5% albumin or fresh-frozen plasma. This therapeutic modality presents several technical challenges in children but has become increasingly used in pediatric nephrology. Owing to advances in technology, scientists have gained substantial knowledge of the molecular pathogenesis underlying many pediatric renal diseases, supporting the use of TPE in treating these disorders. This review presents a synopsis of the literature as it relates to the accepted indications for TPE in children, the technical aspects of the procedure, and the associated complications. Increased collaboration between pediatric nephrologists will hopefully allow scientists to obtain more data in children to assess the benefits of TPE in various renal disorders and improve the quality of care provided in children with renal disorders.

How to cite this article:
Alhasan KA. Therapeutic plasma exchange for children with kidney disorders: Definitions, prescription, indications, and complications. Saudi J Kidney Dis Transpl 2019;30:291-8

How to cite this URL:
Alhasan KA. Therapeutic plasma exchange for children with kidney disorders: Definitions, prescription, indications, and complications. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2019 Sep 22];30:291-8. Available from: http://www.sjkdt.org/text.asp?2019/30/2/291/256835



   Introduction Top


Plasmapheresis is a medical procedure that broadly refers to the extracorporeal separation of blood components, resulting in a filtered plasma product.[1] Manual plasmapheresis was first used in 1952 to manage hyperviscosity in patients with multiple myeloma.[2] A decade later, therapeutic plasma exchange (TPE) was facilitated with the emergence of the automated cell separator and was successfully applied to various kidney-related disorders such as Goodpasture syndrome.[3],[4] Subsequently, plasma exchange (PLEX) was used in the clinical management of several kidney disorders to remove unwanted macromolecules from the blood. The purpose of this review is to provide an overview of TPE and highlight its complications and indications in children with renal diseases and how to prescribe it, especially in young children.


   Terminology Top


Therapeutic apheresis (TA) is a general term that includes all TA-based procedures.

Plasmapheresisis a procedure that involves the separation and removal of plasma from blood without replacing the removed volume.[5]

TPE or PLEX involves the removal of a large volume of plasma that is replaced with a replacement fluid, which is usually 5% albumin or fresh-frozen plasma (FFP).[5]

Immunoadsorption is a procedure by which the patient’s plasma, after separation from the blood, is passed through a medical device that removes immunoglobulins by binding them to the active component (for example, staphylococcal protein A) of the device.[1]


   Mechanism of Action of Therapeutic Plasma Exchange Top


TPE effectively removes large-molecular-weight pathological substances from the plasma, including pathological antibodies, immune complexes, complement components, and coagulation cascade factors. The clearance of different circulating substances depends not only on their size but also on their distribution between intravascular and extravascular compartments. For instance, IgM is removed more effectively than IgG because it is largely intra-vascular[6]. Evidence suggests that TPE may have a different mechanism of action through an immunomodulatory effect by different mechanisms.[7],[8]


   Plasmapheresis Techniques Top


Currently, two basically different technological approaches to plasma separation are available, namely filtration by centrifugal cell separation and filtration by hollow fiber plasma filters.[9] Centrifugal TPE (cTPE) is the most preferred plasma treatment in Saudi Arabia and North America, whereas other countries, including Japan and Germany, prefer membrane TPE (mTPE).[10]

Centrifugal therapeutic plasma exchange system

This technique employs the use of machines that separate plasma from cellular components by density-gradient centrifugation. It is the most commonly performed plasmapheresis technique. Centrifugation makes use of the distinct specific gravities of blood components, including red blood cells (RBCs), white blood cells, platelets, and plasma.[5],[11] In cTPE, plasma is filtered and discarded, and RBCs, along with replacement fluid (donor plasma or albumin), are reinfused into the patient.

Currently, different machines using this technique with different extracorporeal volumes are available in the market, such as Cobe Optia (185 mL; Terumo BCT, Lakewood, CO, USA) and Cobe Spectra (170 mL; Terumo BCT).[12]

Membrane plasma filtration-based system

In this system, machines are used to separate plasma from cellular components based on size by using membrane filters. Membrane plasma filtration exploits differences in particle size to separate plasma from blood, and filtration can be performed using a flat plate or hollow fiber design.[11] In practice, mTPE is nonselective and involves the removal of all plasma components. However, undesired macromolecules can be selectively filtered by secondary membrane plasma fractionation. The filtered plasma is then reinfused into the patient instead of administering donor plasma or albumin.[13] The main differences between mTPE and cTPE, and their benefits and downsides are summarized in [Table 1].
Table 1: Differences between centrifugal therapeutic plasma exchange and membrane therapeutic plasma exchange.

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   Prescription of Therapeutic Plasma Exchange Top


Access

A wide range of vascular access options can be used for TPE, including central venous catheters (CVCs), peripheral venous access, arteriovenous fistula (AVF), arteriovenous graft (AV graft), and CVC ports. The physician should select the most suitable vascular access option for each patient. For instance, a CVC Portis not suitable for a patient who requires urgent TPE because it cannot be used immediately after its placement; however, it would be the best option for a patient who needs long-term TPE.[14]

  1. CVCs: Double-lumen CVCs with the appropriate size according to the age of the child [Table 2] are the most commonly used intravascular devices for TPE
  2. Peripheral venous access: Peripheral access with a large-size intravenous cannula can be used in older children (weight >30 kg). Although it is small-sized, it can be used because the prescribed blood flow is usually low. In cases where a single-lumen peripheral venous access catheter is used, therapy is discontinuous because blood is withdrawn, processed, and then reinfused. Continuous therapy can be administered with peripheral access, but two access ports are required [Figure 1].
  3. AVF/AV graft: This type of access can also be used successfully and is usually used for patients who already have an AVF or AF graft for his/her hemodialysis [Figure 2]. Unfortunately, in comparison with an AV fistula, an AV graft is more prone to thrombosis and infections.
  4. CVC ports: These ports are tunneled devices that are implanted below the skin. They are typically placed in the subcutaneous tissue of the anterior chest wall with their distal tip reaching the junction of the superior vena cava and right atrium. This type of vascular access should be considered in any patient planned for longterm TPE procedures.
Table 2: Appropriate catheter size in children based on body weight.

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Figure 1: Peripheral venous access at both arms.

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Figure 2: Arteriovenous fistula at a patient's left arm.

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One of the advantages of a CVC port is that it is associated with low rates of infection. In addition, patients have reported feeling comfortable with the device and are even able to participate in many types of physical activities, including swimming.[14],[15] Many types of ports with the tubing are made of silicone or polyurethane, and the chamber can be funnel-shaped or cylindrical. In the United States, Power Flow is the only port approved by the US Food and Drug Administration for use in apheresis. In Saudi Arabia, no port has been approved by the Saudi Food and Drug Authority until now.

Dose of TPE

The standard practice is 1.0–1.5 plasma volume (PV) exchanged per session. PV is equal to the total blood volume (TBV) × (1-Hct/100). To calculate the TBV, several formulas can be used [Table 3].[16]
Table 3: Proposed formulas to estimate blood volume based on gender and body weight and age.

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Replacement fluid

FFP and 5% albumin can be used as replacement fluid. Fresh-frozen plasma should be used in cases of derangements in coagulation factors or complements (as in atypical hemolyticuremic syndrome) or ADAMTS-13 (as in thrombotic thrombocytopenic purpura). The fibrinogen level should be monitored in cases where 5% of albumin is used as the only replacement fluid. If the patient’s fibrinogen level is <1.25 g/L, FFP should be used alone or should constitute at least part of the replacement solution.

Priming

Priming is usually done using normal saline or 5% albumin, but in cases where the extra-corporeal volume is >10% of the TBV, priming should be performed using packed RBCs. Packed RBC should be diluted with normal saline or FFP to reach a hematocrit level of 35%. By priming the circuit with packed RBC, TPE can be used in infants weighing up to 3.2 kg.[17] The aim of diluting the packed RBC is to prevent clotting and polycythemia.[12]

Anticoagulation

In cTPE, usually regional anticoagulation or citrate based-anticoagulation, the risk of bleeding is low, especially in cases where the risk of bleeding is from the primary disease. The rate of anticoagulation is, by default, set by the manufacturer as blood flow as follows: anticoagulation ratio = 10–14:1.[18] Calcium should be administered to avoid hypocalcemic tetany. Usually, the calcium drip can either be given through peripheral intravenous access or as a part into a return line as calcium gluconate (20 mg/mL) at an infusion rate of 1 mL/kg/h.[19] The rate of the calcium infusion is adjusted as necessary for symptoms and/or low ionized calcium (<1.00 mEq/L). In cases where mTPE is utilized, heparin is typically administered as an anticoagulant.

Frequency

The efficiency of the removal of pathogenic substances from plasma is greatest early in the procedure, and it decreases progressively during the same exchange session. This explains why the routine practice is to exchange only 1–1.5 PV during each session. Approximately 60%–70% of the antibodies and substances present in plasma is removed during each 1–1.5 PV exchanged. Sustained reduction in antibody levels is usually achieved after about five exchanges.[20] The frequency of PTE is usually tapered off in cases of improved laboratory or clinical evidence of disease activity. The duration of therapy is sometimes prolonged in certain diseases such as recurrent focal segmental sclerosis postkidney transplantation.


   Complications of Therapeutic Plasma Exchange Top


Michon et al reported that in contrast to adults in whom complications are relatively uncommon (<6%) and usually minor,[21] children have a much higher incidence of complications, with the rate reaching up to 55%.[22] Hypotension was the most common complication (14%), but only <5% of the patients who developed hypotension required fluid bolus. Other common complications include symptomatic hypocalcemia (9.7%) and allergic reactions (4.4%). Cases of anemia, access-related thrombosis, and infection have been reported in rates ranging from 1.7% to 2.5%. Hypocalcemia is mostly observed when FFP is used as a replacement fluid with citrate as an anticoagulant.


   Indications for Therapeutic Plasma Exchange in Children with Kidney Disease Top


During the past 10 years, TPE has been increasingly used as a first-line, often the life-saving treatment for different conditions in both the adult and pediatric populations. The American Society for Apheresis (ASFA) is responsible for reviewing and categorizing indications for TA through an evidence-based approach.[23] However, for the most part, the recommendations of the ASFA are based on evidence from studies conducted on adults, and these studies do not differentiate childhood from adult-onset disease.

Since the first human treatment with TPE was performed in the 1960s,[24] improvements in plasmapheresis technology and advancements in our comprehension of disease processes have made plasmapheresis an essential and safe treatment modality for pediatric kidney diseases and other immune-mediated conditions. During the past four decades, scientists have investigated the efficiency of TPE in a wide range of diseases, and the number of conditions for which TPE is indicated is growing as the mechanisms underlying the developmental origins of disease are determined and more clinical trials are performed. In addition, it is plausible that TPE may no longer be firstline therapy for some of these conditions owing to the discovery of new immunological agents.

Recently, the ASFA published its seventh issue, including a growing list of disease processes for which TPE is indicated.[1] Unfortunately, no specific guidelines are available to address the diseases for which TPE is indicated in children, especially kidney diseases.

In terms of the technique, most of the evidence came from trials using the cTPE technique.[1] The ASFA grades indications into four categories based on systematic reviews and evidence-based strategies. They recommend the first-line apheresis for category I disorders, either as a primary stand-alone treatment or in conjunction with other modes of treatment, and second-line apheresis, either as a primary stand-alone treatment or in conjunction with other modes of treatment.

For category II disorders, the ASFA recommends tailoring the treatment to the patient because of a lack of evidence supporting the optimum role of apheresis in patients with these disorders. They recommend tailoring the treatment to the patient for category III disorders owing to the lack of evidence supporting the optimum role of apheresis in patients with these disorders. Finally, category IV includes disorders for which evidence shows or suggests that apheresis is not beneficial or harmful and should only be offered after obtaining approval from an Institutional Review Board.[25] A list of ASFA indications for plasmapheresis for pediatric renal disease is provided in [Table 4] for categories I–III.
Table 4: American Society for Apheresis indications for plasmapheresis in pediatric renal disease.*

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   Medication Clearance by Therapeutic Plasma Exchange Top


The removal of medications by apheresis depends on the volume of distribution of the medication and its protein-bound state. Medications that are highly protein bound and have a low distribution volume will likely be removed by TPE. Immunoglobulins, basiliximab, and rituximab are greatly removed by TPE. Calcineurin inhibitors (cyclosporine and tacrolimus) and corticosteroids are minimally removed by TPE. It is of note that although cyclophosphamide and azathioprine are poorly protein bound, most researchers recommend giving a dose after TPE.[26]


   Conclusion Top


In this review, we present a synopsis of the literature as it relates to the accepted indications for TPE in children, the technical aspects of the procedure, and associated complications. The procedure is safe and effective in children with various renal diseases but requires specialized care and clinicians experienced in managing the pediatric renal disease to meet the patients’ specialized needs. Increased collaboration between pediatric nephrologists will hopefully allow scientists to obtain more data in children to assess the benefit of TPE in various renal disorders and improve the quality of care provided in treating renal diseases in these cases.

Conflict of interest: None declared.



 
   References Top

1.
Schwartz J, Padmanabhan A, Aqui N, et al. Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the writing committee of the American Society for Apheresis: The seventh special issue. J Clin Apher 2016;31:149-62.  Back to cited text no. 1
    
2.
Adams WS, Blahd WH, Bassett SH. A method of human plasmapheresis. Proc Soc Exp Biol Med 1952;80:377-9.  Back to cited text no. 2
    
3.
Jones JV, Cumming RH, Bucknall RC, Asplin CM. Plasmapheresis in the management of acute systemic lupus erythematosus? Lancet 1976;1:709-11.  Back to cited text no. 3
    
4.
Bukowski RM, King JW, Hewlett JS. Plasmapheresis in the treatment of thrombotic thrombocytopenic purpura. Blood 1977;50:413-7.  Back to cited text no. 4
    
5.
Winters JL. Plasma exchange: Concepts, mechanisms, and an overview of the American Society for Apheresis guidelines. Hematology Am Soc Hematol Educ Program 2012;2012:7-12.  Back to cited text no. 5
    
6.
Pusey CD, Levy JB. Plasmapheresis in immunologic renal disease. Blood Purif 2012;33: 190-8.  Back to cited text no. 6
    
7.
Shariatmadar S, Nassiri M, Vincek V. Effect of plasma exchange on cytokines measured by multianalyte bead array in thrombotic thrombocytopenic purpura. Am J Hematol 2005;79: 83-8.  Back to cited text no. 7
    
8.
Goto H, Matsuo H, Nakane S, et al. Plasmapheresis affects T helper type-1/T helper type-2 balance of circulating peripheral lymphocytes. Ther Apher 2001;5:494-6.  Back to cited text no. 8
    
9.
Johnson RJ, Feehally J, Floege J, editors. Comprehensive Clinical Nephrology. 5. Philadelphia: Elsevier; 2014. p. 1323.  Back to cited text no. 9
    
10.
Hafer C, Golla P, Gericke M, et al. Membrane versus centrifuge-based therapeutic plasma exchange: A randomized prospective crossover study. Int Urol Nephrol 2016;48:133-8.  Back to cited text no. 10
    
11.
Williams ME, Balogun RA. Principles of separation: Indications and therapeutic targets for plasma exchange. Clin J Am Soc Nephrol 2014;9:181-90.  Back to cited text no. 11
    
12.
Carter CE, Benador NM. Therapeutic plasma exchange for the treatment of pediatric renal diseases in 2013. Pediatr Nephrol 2014;29:35-50.  Back to cited text no. 12
    
13.
Hirano R, Namazuda K, Suemitsu J, Harashima T, Hirata N. Plasma separation using a membrane. Transfus Apher Sci 2017;56:649-53.  Back to cited text no. 13
    
14.
Ipe TS, Marques MB. Vascular access for therapeutic plasma exchange. Transfusion 2018;58 Suppl 1:580-9.  Back to cited text no. 14
    
15.
Walser EM. Venous access ports: Indications, implantation technique, follow-up, and complications. Cardiovasc Intervent Radiol 2012;35: 751-64.  Back to cited text no. 15
    
16.
Diem K, Lentner C. editors. Documenta Geigy Scientific Tables. AbeBooks. Available from: https://www.abebooks.co.uk/book-search/title/documenta-geigy-scientific-tables/author/diem-k-lentner-c/. [Last accessed on 2018 Sep 15].  Back to cited text no. 16
    
17.
Jung S, Kang ES, Ki CS, Kim DW, Paik KH, Chang YS. Successful therapeutic plasma exchange in a 3.2-kg body weight neonate with atypical hemolytic uremic syndrome. J Clin Apher 2011;26:162-5. '  Back to cited text no. 17
    
18.
Lee G, Arepally GM. Anticoagulation techniques in apheresis: From heparin to citrate and beyond. J Clin Apher 2012;27:117-25.  Back to cited text no. 18
    
19.
Wong EC, Balogun RA. Therapeutic apheresis in pediatrics: Technique adjustments, indications and nonindications, a plasma exchange focus. J Clin Apher 2012;27:132-7.  Back to cited text no. 19
    
20.
Derksen RH, Schuurman HJ, Meyling FH, Struyvenberg A, Kater L. The efficacy of plasma exchange in the removal of plasma components. J Lab Clin Med 1984;104:346-54.  Back to cited text no. 20
    
21.
Norda R, Stegmayr BG, Swedish Apheresis Group. Therapeutic apheresis in Sweden: Update of epidemiology and adverse events. Transfus Apher Sci 2003;29:159-66.  Back to cited text no. 21
    
22.
Michon B, Duval M, Winikoff R, Champagne MA. Complications of pediatric apheresis. Blood 2004;104:3645.  Back to cited text no. 22
    
23.
Shaz BH, Schwartz J, Winters JL. How we developed and use the American Society for Apheresis guidelines for therapeutic apheresis procedures. Transfusion 2014;54:17-25.  Back to cited text no. 23
    
24.
Schwab PJ, Fahey JL. Treatment of waldenstram’s macroglobulinemia by plasmapheresis. N Engl J Med 1960;263:574-9.  Back to cited text no. 24
    
25.
Szczepiorkowski ZM, Winters JL, Bandarenko N, et al. Guidelines on the use of therapeutic apheresis in clinical practice – Evidence-based approach from the apheresis applications committee of the American Society for Apheresis. J Clin Apher 2010;25:83-177.  Back to cited text no. 25
    
26.
Ibrahim RB, Liu C, Cronin SM, et al. Drug removal by plasmapheresis: An evidence-based review. Pharmacotherapy 2007;27:1529- 49.  Back to cited text no. 26
    

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Correspondence Address:
Khalid A Alhasan
Department of Pediatrics, College of Medicine, King Khalid University Hospital, King Saud University, Riyadh
Saudi Arabia
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DOI: 10.4103/1319-2442.256835

PMID: 31031364

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