Therapeutic apheresis in kidney transplantation: Emerging trends

The use of therapeutic apheresis (TA) either as stand‐alone or adjunctive treatment in kidney transplantation has increased over the years to become a leading indication. This study shows recent trends in indications for TA related to kidney transplantation, adverse events, and patient outcome in this cohort.

Therapeutic apheresis (TA) procedures target pathological elements in circulation, for example, cells, antibodies, immune complexes, and inflammatory mediators for removal through an extracorporeal system. 1,2The TA techniques widely used in transplantation medicine include therapeutic plasma exchange (TPE) and selective TA techniques such as double-filtration plasmapheresis, immunoadsorption, and extracorporeal photopheresis. 3,4he most recent special issue of the Journal of Clinical Apheresis published by the American Society for Apheresis (ASFA) lists the following kidney transplant-related indications for TA as category 1 indications; antibodymediated rejection, desensitization/prophylaxis for living donor transplants and ABO incompatible transplants, and recurrent focal segmental glomerulosclerosis (FSGS) in kidney transplants.This means that TA is accepted as first-line therapy, either as a primary stand-alone treatment or in conjunction with other modes of treatment for these disorders.For antibody-mediated rejection in the background of ABO-incompatible transplants, TA was identified as category II indication, that is, accepted as second-line therapy, either as a stand-alone treatment or in conjunction with other modes of treatment. 5A procedures are complex with some inherent risks of adverse events. 6These adverse events are predominantly low in incidence and mild in presentation among both adult and pediatric age groups. 7,8In the analysis of large series of TA, Mokrzycki and Balogun reported an overall incidence of adverse events of less than 10%. 6Similar reports of 9.7% adverse reactions occurring in 699 treatments were reported. 9Reports from the Swedish apheresis group showed mild adverse events (no intervention required) of 1.5%, moderate adverse events (intervention required, treatment completed) of 2.8%, and severe (procedure interrupted or abandoned) of 0.8%, with no fatal event (loss of life). 10he uptake of TA across the different ASFA category indications with respect to kidney transplantation is emerging.From the available literature search, there is paucity of data on the adverse effects and outcome of treatment among kidney transplant patients.Hence, the specific objectives of this study were to obtain the kidney transplant indications for TA in the study center, enumerate the adverse events associated with therapy and obtain the procedure-related mortality.

| MATERIALS AND METHODS
Ethical approval for this study was obtained from the Human Investigations Committee of the University of Virginia, Charlottesville.Waiver of informed consent for the study was also approved for the study.
The study was carried out in the Division of Nephrology of the University of Virginia Health, USA.The hospital has a transplant program that includes kidney, liver, lung, heart, and stem cell transplantation.There is an inpatient TA unit that uses centrifuge-based apheresis hardware, the Spectra Optia (Terumo BCT).The replacement fluid is 5% albumin with rate of administration preset at the apheresis machine; and fresh frozen plasma for select indications like thrombotic thrombocytopenic pupura.Citrate dextrose (ACD-A) is the circuit anticoagulant (AC) of choice.It contains 3% citrate (112 mmol/L of citrate or 21.3 mg/mL) by concentration.Calcium gluconate supplementation is given prophylactically to all patients in the course of each treatment.The standard operating protocol for calcium supplementation in TA in the institution is prophylactic continuous infusion of intravenous calcium gluconate 2 g in 100 mL of 0.9% saline given at an infusion rate dependent on the level of ionized calcium.The plasma volume is calculated using standard online apheresis calculators with the input of indications, hematocrit, height, and weight of the patients.Treated volume is usually 1.2-1.5 times patient's plasma volume.The therapy is administered at intervals stated by ASFA guidelines for each indication. 5The prescription is done by the Medical Doctors who also supervise the procedure as delivered by trained nurses.
The study was a retrospective cohort study involving adults, aged 18 years and above who underwent TA before or after kidney transplantation at the University of Virginia Health over a 6-year period, between January 1, 2017, and December 31, 2022.Patients were selected if they started apheresis between the study durations and had, at least, one session of apheresis.Patients with simultaneous kidney-pancreas transplant, kidney transplant in addition to heart or lung transplants were excluded.
Data extracted from the medical records included age, sex, weight, height, and blood pressure.Others included procedure data such as indication for TA, serum ionized calcium at start, mid, and end of the procedure, vascular access, replacement fluid, and replacement volume.The kidney function (serum creatinine) immediately before the first procedure, and at the time the graft function was lost, patient died or lost to follow-up was documented.The date of kidney transplantation, commencement of apheresis, graft loss, return to dialysis, and death were recorded.In-patients charts for the day after procedure were reviewed.Other definitions used for the purpose of this study include the following: • Hypocalcemia: This was defined as serum-ionized calcium less than 4.5 mg/dL in the mid-or end-procedure laboratory test for serum-ionized calcium. 11 • Hypotension: This was defined as either a decrease in systolic blood pressure by 20 mmHg or more of the initial blood pressure, or a systolic blood pressure less than 100 mmHg at any time during therapy.• Hypertension: An increase in systolic blood pressure by >10 mmHg or mean arterial pressure (MAP) ≥15 mmHg from pre-and post-TPE procedure. 12A rise in blood pressure to 150 mmHg or more, necessitating administration of anti-hypertensives during the procedure was also regarded as hypertension.• Diagnosis of other adverse events was as documented in the procedure note by the supervising physician or nurse.• Procedure-related mortality was defined as death on machine or within 24 h of performance of apheresis while case mortality was defined as death of any patient undergoing TA related to primary disease during the study period.
Data obtained was stored on the excel sheet and analyzed using the statistical package for social sciences (SPSS-version 2020 IBM Inc, USA).Mean (±SD) was used to describe continuous variables while proportions were used to describe categorical variables.Tables, bar chart, and line graph were used to describe data where appropriate.

| RESULTS
Data were available for all 131 patients.Table 1 shows some of the basic demographic details of the patients.There were more males than females with a male:female ratio of 1.5:1.The mean age of the patients was 48.8 ± 14.8.There was no statistical significant difference between the mean age of the males (49.2 ± 14.1) and that of the females (48.5 ± 14.9), P = 0.841.
A total of 860 sessions of TA for transplant indication was recorded within the study period giving an average of seven sessions per patient.There was a progressive increase in the number of patients undergoing TA over the last 3 years of the study in parallel with the increase in a number of adult kidney transplants performed in the center.The majority of the patients were of 40-59 years age bracket, and the leading cause of end-stage renal disease is hypertension.
Table 2 shows some of the procedure characteristics.Tunneled internal jugular catheter was used for therapy in the majority of patients (50.4%) while arterio-venous fistula was accessed in 31.3% of patients.The replacement fluid was albumin in the majority of the first prescriptions (44.3%) while albumin plus fresh frozen plasma was the replacement fluid of choice in 38.9%.
The transplant indications for TA are shown in Figure 1.Antibody-mediated rejection is the leading indication for TA in the study center, constituting 69% of all indications for TA.Other indications include recurrent FSGS (15%), desensitization for ABO blood group incompatibility (4.5%) or for human leukocyte antigen (HLA) incompatibility (4.5%), thrombotic microangiopathy (5%), and recurrent IgA nephropathy (1%).
Figure 2 shows the percentage distribution of therapy sessions over time (in years).It reveals that antibody- mediated rejection is the leading indication in each of the 6-year period of the study.TA for HLA incompatibility and ABO blood group incompatibility constituted less than 10% of the procedures in each of the year across the study duration.Adverse events were recorded for the 860 sessions of apheresis (Table 3).The number of sessions with adverse events was 144 (16.7%).Among these, hypocalcemia was the leading complication and was found in 7% of the procedures.Mild-to-moderate adverse events recorded include hypotension (1.2%), nausea and vomiting (1.4%), chest pain (0.1%) mild itching (0.4%), fever (0.2%), and shortness of breath (0.2%).Others are as shown in Table 3. Severe adverse events included vascular access blockage leading to interruption of procedure and depletion coagulopathy.
Among patients with depletion coagulopathy (0.6%), two cases (0.2%) occurred during procedure with mild oozing of blood from the vascular access entry site, and two episodes (0.2%) occurred in the immediate postapheresis period leading to prolonged time of compression of the A-V fistula while one of the episodes led to reexploration of the vascular access (internal jugular access) to control bleeding.Arrhythmias (0.5%) documented were tachycardia (0.2%), bradycardia (0.2%), and self-limiting atrial fibrillation (0.1%).The study recorded one episode of cardiac arrest from arrhythmia leading to the death of patient while undergoing apheresis.This gives us a procedure mortality rate of 1.2 per 1000 procedures.
Out of the 131 patients who underwent TA, 96 (73.3%) patients remained dialysis free after the initial therapy sessions with TA and with their GFR persistently above 20 mL/min/1.73m 2 ; 29 (22.1%)returned back to repeated dialysis or retransplantation while 6 (4.6%) were lost to follow up or transferred to another center.Eleven patients were recorded dead, giving a case mortality of 8.4% over the 6-year period.There was one death recorded on machine during TA resulting in a proceduremortality rate of 0.12%.

| DISCUSSION
The main findings of this study are that antibodymediated rejection is the leading indication for TA, hypocalcemia is the main complication in majority of the patients and the case-related and procedure-related mortality is not remarkable.
Nephrology indications for apheresis are on the increase and practice varies across the centers and with awareness of the practicing guidelines.With the global increase in the prevalence of end-stage renal disease and increase in the number of patients accessing kidney transplantations, complications such as antibody-mediated rejections are encountered in clinical practice.Our study is comparable to a retrospective study in Turkey, which similarly reported acute humoral rejection as the commonest indication among patients accessing TPE for nephrology indications. 13White et al. have demonstrated graft survival in a cohort of patients with biopsy-proven antibodymediated rejection who received plasmapheresis and intravenous immunoglobulin (IVIG). 14Similarly, Ibernom et al. have demonstrated 70% graft survival and 100% patient survival among patients with antibody-mediated rejection who received sequential TA and IVIG. 15The latter two studies analyzed acute antibody-mediated rejection treatment response with plasmapheresis.The use of TA in chronic antibody-mediated rejection is not an effective therapy and not indicated in clinical practice due to the tissue damage that has already occurred and lack of sustained antibody reduction.TA is one of the cornerstone management of acute antibody mediated rejection.
Together with IVIG and increased immunosuppression, the treatment has been considered as standard of care for patients with acute antibody-mediated rejection as it results in reduction in antibody titer and halts the rejection process and is a category 1 indication for TA in the recent ASFA guidelines. 1,5,16herapeutic plasma exchange is a safe procedure with minimal patient and procedure-related adverse events.The magnitude of adverse events reported in this study is compatible with findings from other studies. 6,17,18It, however, differs from a study in Turkey among 125 patients with 496 TA procedures, where adverse events were reported in 58% of the procedures. 19is might be explained by the heterogeneity of the patient population in the Turkish study where patients with neurological, hematological, and nephrological indications were involved.Furthermore, both TA and cytapheresis were studied in contrast with our study involving nephrology patients and TA only.This calls for more attention on adverse events of TA and factors associate that may be associated with it.Hypocalcemia is the leading adverse event in our study.This is in keeping with an earlier study that reported hypocalcemia as the most common apheresis-specific complication among 3367 apheresis procedures. 20Despite the use of intravenous calcium gluconate supplementary infusion during therapy, hypocalcemia is a notable complication of TA and can decrease to the point that symptoms develop.While this may be a reflection of different rates of body utilization of calcium or metabolism of citrate, 21 the implication is that therapy sessions need to be monitored closely for the occurrence of hypocalcemia and its consequences when severe, as life-threatening hypocalcemia during apheresis has been reported. 6,22Measures to be taken when hypocalcemia is highly likely or has occurred include increasing the rate of infusion of calcium gluconate according to the standard operation procedure, decreasing the citrate dose or the AC infusion rate, reducing the inlet pump rate or increasing the whole blood:AC ratio. 23s citrate-containing blood is returned to the circulation, there is a continuation of its pharmacological effect in the systemic circulation.As a result, citrate-related complications such as hypocalcemia, hypomagnesemia, and metabolic alkalosis can occur.Metabolic alkalosis results from accumulated bicarbonate, which is a product of citrate metabolism in the liver.Dialysis in the postapheresis period using heparin helps ameliorate the metabolic alkalosis.Other adverse events in this study, though low in prevalence should not be overlooked.Studies have shown cases of allergic reactions requiring cardiopulmonary resuscitation. 17Hypotension is one of the adverse effects of TA and was found in 1.2% of TA procedures in this study, similar to 1.5% episodes of hypotension documented in an earlier study of 139 patients who underwent a total of 1137 sessions of plasmapheresis. 24The occurrence of hypotension in TA has been attributed to hypovolemia due to extracorporeal circulation and the vasovagal reflex.In this study, it is less likely a result of extracorporeal pooling of blood during therapy as only 141 mL of blood volume is in the extracorporeal circuit of the Spectra Optia machine used in the study center. 21,25tudies have shown that in addition to extracorporeal pooling of blood and vasovagal reflex, complements are activated during TA, and the activated complements (C3a and C5a) are strong anaphylatoxins and potent vasodilators. 24,26This phenomenon can explain the hypotension complicating some apheresis sessions in this study as centrifuge-based apheresis techniques have also been shown to activate complements. 27he predominance of internal jugular and A-V fistula as vascular access in our study is not surprising considering the patient population studied-patients with end-stage renal disease, most of whom were on regular dialysis and with a permanent vascular access prior to the therapy.In contrast to some reports, 13,16 there was hardly any transplant patient in our study who received therapy with femoral catheter or antecubital vein.These latter vascular access are characterized by frequent thrombosis, hematoma, repeated cannulation and associated patient discomfort and high rate of sepsis. 28he number of sessions of apheresis is dependent on the indication, postapheresis kidney function, and antibody level.The recent ASFA guidelines recommended five or six sessions everyday or every other day for antibody-mediated rejections, the therapy for recurrent FSGS is to begin with three daily TPE sessions followed by, at least, six more with tapering depending on the level of proteinuria.Our study reported a total of 860 sessions among 131 patients giving an average of seven sessions of TPE.This was higher than 4.5 reported by Arslan and 5.9% reported by Serine et al. 13,29 The mortality of patients undergoing apheresis has been reported by several authors including different procedures and indications. 9,30-32Mokrzycki and Kaplan reported a procedure-related mortality of 0.05% among 15 658 procedures 9 comparable to 0.12% recorded in our study.In a 2-year analysis of 96 patients who underwent a total of 720 procedures, Ersan et al. reported a case mortality rate of 16.7%, all due to primary disease. 17This is higher than 8.7% obtained in our study, and this may be due to ongoing improvement in apheresis technology and science, including uptake of indications across the different categories with improved patient outcomes.In the pretransplant period, desensitization protocols with TA as a cornerstone helps to overcome immunologic barriers posed by anti-HLA antibodies and ABO blood group incompatibility, and improve access to transplant. 33,34It also improves graft survival, especially in living donation. 35In the posttransplant phase, challenges are posed by antibody-mediated graft rejection and recurrent FSGS.

| LIMITATION
The depletion coagulopathy obtained may not be a true picture as some of the patients were on alternate-day dialysis and the effect of heparin, used as anticoagulation for dialysis, may complicate the bleeding episode.

| CONCLUSION
The use of TA across the ASFA categories indicated for kidney transplantation was found in this study with antibodymediated rejection predominating.Adverse events encountered over the study period were mild, treatable, and mainly found on laboratory evaluation.The patient outcomes are remarkable, comparable to other studies, and point to the viability of TA as a therapeutic modality in kidney transplantation.

2
Bar chart  showing the percentage distribution of therapeutic apheresis procedures by each indication over the 6-year period.T A B L E 3 Adverse events of therapeutic apheresis.
Sociodemographic and clinical characteristics of the patients.
T A B L E 1