Indications and complications associated with centrifuge-based therapeutic plasma exchange - a retrospective review

Abstract

Background

Therapeutic Plasma Exchange (TPE) is an extracorporeal treatment modality used to manage certain conditions caused by plasma deficiencies, autoantibodies, alloantibodies, toxins, and immune complexes. We describe our experience of using TPE for various disease indications and associated complications.

Methods

This is a retrospective, single-center review of centrifuge-based TPE performed by the division of nephrology at a tertiary care academic center between July 2018 to June 2022. 1219 TPE treatments in 145 patients were included.

Results

The most common indications for TPE were Antibody-Mediated Rejection (AMR) of a kidney transplant (20%), autoimmune encephalitis (16%), and neuromyelitis optica (11%). Rare indications for TPE included Chronic Relapsing Inflammatory Optic Neuropathy (CRION), AMR of a pancreas transplant, osmotic demyelination, and belatacept removal in the setting of COVID-19. The most common complications were depletion coagulopathy (47.6%), hypocalcemia (44.1%), and hypokalemia (36.6%). Rare complications included stiff person crisis and pseudohypertriglyceridemia. 31.7% of patients received TPE for conditions managed by nephrologists.

Conclusion

TPE is an extracorporeal treatment modality for managing various renal and non-renal diseases. The study demonstrated that 18.7% of the patients at our center received TPE for conditions in which its role is not yet established, suggesting the need for further research on the use of TPE. In addition, this study supports the necessity of nephrology training program to include education on TPE as almost one-third of the indications for TPE in our center were for conditions managed by nephrologists.

Background

Therapeutic Plasma Exchange (TPE) is an extracorporeal treatment modality that involves the removal of plasma and returning the cellular components of the blood while replacing the plasma with a replacement fluid, such as albumin and/or fresh frozen plasma (FFP). Two methods to separate the plasma component from whole blood include a centrifuge-based or semipermeable membrane-based separation method [1, 2]. Initially used to treat hyperviscosity syndrome in multiple myeloma [3], TPE has become a widely available treatment option for several other conditions linked to deficiencies in plasma components, as well as those involving the circulation of autoantibodies, alloantibodies, toxins, and immune complexes [4, 5]. The American Society for Apheresis (ASFA) continuously reviews, categorizes, and grades the indications for TPE [6]. TPE is mostly overseen by hematologists, or transfusion medicine specialists in the United States. However, in 2001, the Renal Physicians Association (RPA) released a position statement, asserting that nephrologists should have expertise in extracorporeal therapies, including TPE [7, 8]. Kaplan similarly argues that nephrologists should have expertise in TPE as they belong to the only field of medicine with fellowship training in extracorporeal blood purification treatment [9]. The renal indications of plasmapheresis are outlined in Table 1, which supports the importance of nephrologists having expertise in TPE [6, 10, 11].

Table 1 Primary and secondary renal diseases managed with TPE

There are a variety of complications of TPE, such as hypotension, citrate toxicity, acid-base disequilibrium, dyselectrolytemia, depletion coagulopathy, and infections. To provide a perspective from the field of nephrology and in response to a dearth of research on the prevalence of the complications of TPE, a multi-year retrospective review of TPE treatments managed by the nephrology department at a tertiary care academic center was conducted to identify the diagnoses designated as indications for TPE as per the American Society for Apheresis (ASFA) guidelines and the complications resulting from TPE.

Methods

This is a retrospective single center review of all TPE treatments managed by the nephrology department at a tertiary care academic center between June 2018 to June 2022 with no exclusion criteria. Patient demographics, clinical and laboratory data, TPE prescription and patient outcomes were characterized after manual review of the electronic medical record. Study data were collected and managed using REDCap electronic data capture tools hosted at the University of Cincinnati. Physician and nursing notes, as well as laboratory results were utilized to identify the complications associated with TPE and their management.

All TPE treatments included in the study utilized the centrifuge-based method of plasma separation from whole blood. The form of citrate used for anticoagulation at our center was Acid Citrate Dextrose Solution A (ACD-A), and patients received either calcium gluconate or calcium chloride to replete calcium. 98% of treatments were performed via a central line while 2% of treatments were performed via a peripheral line. 5% albumin was used as the replacement fluid in most cases, with three exceptions in which 100% FFP was used for catabolic antiphospholipid syndrome, TMA secondary to SLE, and diffuse alveolar hemorrhage secondary to ANCA vasculitis. The fluid balance was 100% in all cases. The volume of plasma exchange was 1.5 in 70% of cases and 1.0 in 30% of cases.

Laboratory values were obtained the morning after TPE in the inpatient setting or prior to the patient’s next TPE session in the outpatient setting. For the purposes of the review, hypocalcemia was defined as a serum calcium value less than 8.0 mg/dL, hypokalemia was defined as a serum potassium value less than 3.5 mEq/L, and hypomagnesemia was defined as a serum magnesium less than 1.5 mg/dL. Metabolic alkalosis was defined as an arterial blood gas pH greater than 7.45 and/or a serum bicarbonate greater than 28 mEq/L. Depletion coagulopathy was defined in the patients who required fresh frozen plasma based on low fibrinogen levels (less than 150 mg/dL) with or without evidence of bleeding.

Results

Patient characteristics

Overall, 1219 TPE treatments were performed on 145 patients for a total of 23 indications, as outlined in Table 3. The median age of the patients in this study was 49 years (range 20–78 years), 42.7% were men, 56.6% women, and one non-binary patient. The majority were Caucasians 69%, 24.1% were Black, 1.4% were LHS+, 4.1% were Asian and 1.4% identified as “Other”. 54% of patients received TPE in inpatient setting and the rest 46% were managed as outpatient treatments. Central line was the most common choice for vascular access in 98% of the patients.

The breakdown of TPE procedures performed by ASFA category is outlined in Table 2. Most patients received TPE for a Category I or II indication. However, 18.7% of patients received TPE for conditions in which the role of TPE is not yet established (ASFA Category III or ASFA Category Unknown).

Table 2 TPE procedures performed per ASFA category

Indication of TPE (Table 3)

The most common indications for TPE included antibody-mediated rejection (AMR) in kidney transplant patients (20%), autoimmune encephalitis (16%), and neuromyelitis optica (11%).

Table 3 Indications for TPE

Complications of TPE

In total, 28 (19.3%) patients have died since the start date of the study. However, none of the patients died as a direct result of TPE. Complications of TPE are outlined in Fig. 1. The most common complications identified by our study were depletion coagulopathy followed by electrolytes imbalances, namely hypocalcemia, hypokalemia and hypomagnesemia.

Fig. 1

Complications of TPE

Depletion coagulopathy occurs when using albumin as a replacement fluid, which was the most common replacement fluid used in our study. Our study showed that depletion coagulopathy was higher in patients who were prescribed anticoagulants (53%) prior to the administration of TPE compared to those who were not on any anticoagulation (47.0%).

Chest discomfort, dizziness and hypotension were the most common symptoms or signs in patients with hypocalcemia. The average serum calcium for all 145 patients in the study was 9.0 mg/dL. Notably, one patient with history of seizures experienced an active seizure with normal serum calcium levels. Of the patients who experienced muscle spasms during the TPE procedure, two were being treated for autoimmune encephalitis and two for neuromyelitis optica.

Of the 8 patients who were documented to have metabolic alkalosis in our study, only 3 had concomitant hypokalemia.

Hypotension is usually caused by fluid shifts during the TPE procedure. Among the patients who experienced hypotension during the administration of TPE, two patients were administered IV fluids, TPE was halted in one patient who received only three treatments out of the five prescribed, and one treatment had their dose of losartan temporarily halted until the remaining treatments were performed.

In our study, six patients (4.1%) developed catheter related infections, most of whom received TPE for an extended duration of time. Blood cultures grew Staphylococcus epidermidis in two patients, Pseudomonas aeruginosa in one patient, and 3 patients were empirically treated for culture-negative infection. In addition to IV antibiotics, catheters were exchanged in two patients.

One patient who had restlessness was prescribed pramipexole to relieve symptoms. Finally, one patient with CIDP received iron infusions and another patient with FSGS received recombinant erythropoietin to treat the anemia.

Discussion

Expertise in extracorporeal blood purification is mandatory for nephrology trainees [9]. However, only 40% of nephrology fellowship programs offer trainees the opportunity to perform TPE [12]. A 2023 American Society of Nephrology survey of nephrology fellows showed that only 24% of graduating fellows listed managing apheresis as part of their responsibilities in their first position [13].

At our institution, 30% of patients received TPE for management of renal diseases, with AMR of kidney transplant as the most common indication. Electrolytes imbalances after depletion coagulopathy were the most common complication after TPE. Our study therefore highlights the utility of including TPE training during nephrology fellowship.

A few of the cases in which TPE was utilized to manage conditions for which the role of TPE is not yet established by the ASFA are outlined below.

The patient with osmotic pontine myelinolysis had a history of chronic alcoholism who presented to the emergency room with worsening gait ataxia, confusion, and seizures and was found to have a serum sodium of 109 mmol/L. Osmotic stress may cause the release of myelin toxins that contribute to the demyelination process, which can be eliminated through TPE [14]. Although the use of TPE in the management of osmotic pontine myelinolysis is not established in the 2023 ASFA guidelines, several case reports have demonstrated at least partial reversal of symptoms after treatment with TPE, supporting the use of this modality in the management of osmotic pontine myelinolysis [14,15,16,17].

One living kidney donor recipient on maintenance belatacept for immunosuppression was admitted to ICU with acute respiratory failure secondary to COVID-19 infection. Belatacept is a cytotoxic T-lymphocyte‐associated protein 4 (CTLA‐4) fusion protein used as an immunosuppression therapy in kidney transplant recipients. One case report postulated that belatacept interferes with the cytokine storm and led to a milder course of COVID-19 in a patient who had received a kidney transplant [18]. However, another case report demonstrated improvement in a patient with a severe COVID-19 infection after mycophenolate mofetil and belatacept were held. The authors hypothesized that belatacept may interfere with immune responses to viruses and recommended the avoidance of belatacept until viral clearance could be achieved [19].

Two patients in our study received TPE for the indication of intentional polysubstance overdose. TPE is most effective in removing drugs that are > 80% protein-bound in the plasma with a small volume of distribution. TPE is also more effective with decreased time between drug administration and TPE start-time and when used to remove drugs that have a longer half-life [20].

One patient was suspected to have overdosed on carvedilol. Carvedilol is 95–98% protein-bound but has a large volume of distribution, so while TPE is useful in the treatment of carvedilol, prompt treatment is required [21]. Another patient presented with hypotension and metabolic alkalosis after overdosing on quetiapine and an unknown amount of amlodipine. Quetiapine is 83% protein-bound and has a large volume of distribution [22]. Amlodipine is 98% protein-bound and also has a large volume of distribution [23].

CRION is a syndrome that is thought to be at least partially immune-mediated with features including recurrent painful vision loss that responds to early treatment with steroids. A 2019 case report by Yassa and Bakbak [24]. reported a patient who also had severe impairment in color vision. The management of CRION is IV methylprednisolone pulses, although plasmapheresis has been used in patients who do not respond to this treatment option [25].

For the most part, TPE is a relatively safe procedure with positive patient outcomes and few complications requiring treatment. However, there are a few complications of TPE to note including citrate toxicity. Citrate is an anticoagulant used to prevent clotting in the extracorporeal circuit. The most common complication of citrate toxicity is hypocalcemia and hypomagnesemia, as citrate binds to calcium and magnesium in the plasma [26]. Severe symptoms of hypocalcemia include seizures and prolonged QT interval and patients with underlying cardiac arrythmias, and neuromuscular disorders are particularly vulnerable to these side effects [26].

To prevent citrate-induced hypocalcemia, calcium gluconate, calcium chloride, or calcium carbonate are administered when performing TPE. Citrate toxicity also causes metabolic alkalosis, as its metabolism in the liver via the tricarboxylic acid cycle produces bicarbonate, particularly in patients with respiratory failure, impaired citrate metabolism in hepatic insufficiency and compromised renal excretion of bicarbonate [26,27,28]. Metabolic alkalosis also can further precipitate hypokalemia [26]. Hypokalemia and metabolic alkalosis can also be caused by the increased activation of the renin-angiotensin-aldosterone system in the setting of hypovolemia.

Infections are also common and divided into three categories: post-TPE due to immunoglobulin depletion, vascular access-related, or viral transmission from FFP.

Other known complications of TPE include hyperglycemia related to dextrose contained in the citrate solution, transfusion-related acute lung injury (TRALI), transfusion-associated circulatory overload (TACO), urticaria, and aluminum toxicity due to the presence of aluminum in 5% albumin [29, 30].

Our study highlights some of the rarer complications of TPE that have not been noted in the published literature. Stiffness crisis presenting as severe muscle spasms and pain manifested during the TPE procedure in one patient undergoing TPE for Stiff Person Syndrome.

Pseudo-hypertriglyceridemia was noted in a patient who received 5 treatments of TPE for tumefactive multiple sclerosis. The triglyceride returned to baseline following completion of TPE.

Strengths and limitations

Overall, this is one of the most comprehensive retrospective reviews of all TPE procedures performed by a nephrology department. The study includes a variety of indications for TPE, including a few indications that have been rarely reported in the literature. Our study also includes a detailed account of the complications of TPE that have been observed, including stiffness crisis and pseudo hypertriglyceridemia, which have never been reported to our knowledge.

However, our study also has several limitations. 75% of TPE procedures at our institution are performed by the nephrology division while 25% of TPE procedures are performed in an outpatient blood center, which describes the sparsity of hematologic conditions in our study. Additionally, this was a retrospective study with limited numbers that utilized physician and nursing notes, as well as laboratory values to identify the complications of TPE. Studying larger populations or a multi-center design would offer more conclusive results on rare indications and complications noted in this cohort. With the simultaneous use of multiple strategies in the treatment of underlying disease indication, it is difficult to fully ascertain the impact of each individual treatment regimen. There was some variability in how different providers documented the TPE procedure and the associated complications. An example is the inability to obtain BNP and chest radiography to diagnose TACO. In addition, aluminum levels and blood gases were not routinely measured in our lab order sets therefore aluminum toxicity and metabolic alkalosis may be underreported as complications of TPE in this study. Cardiac monitoring was also not performed as a standard procedure in patients receiving TPE, limiting our ability to identify cardiac arrhythmias that may have developed as a complication of TPE. Hyperglycemia as a complication of TPE was difficult to define due to the high incidence of Type 2 Diabetes Mellitus among patients in this study and was therefore not reported. Finally, IgG levels were not routinely assessed, which limits our ability to decipher if infections were attributed to immunoglobulin deficiency secondary to TPE.

Conclusion

Therapeutic Plasma Exchange (TPE) is an extracorporeal treatment modality for managing various renal and non-renal diseases. Nephrologists and dialysis staff with extracorporeal therapy training are uniquely positioned and well-equipped to manage TPE. This study demonstrated that 18.7% of the patients at our center received TPE for conditions in which the role of TPE is not yet established. This supports the need for further research on the use of TPE. There were some indications of TPE that were not included in the 2023 ASFA guidelines, such as CRION, antibody-mediated rejection of a pancreas transplant, central pontine myelinolysis, and belatacept removal in the setting of COVID-19. There were also a few rare complications documented in this review, including stiff person crisis and pseudohypertriglyceridemia. This study exemplifies the utility of having a systematic audit to review the practice patterns and complications of TPE and supports the inclusion of education on TPE indications and complications in nephrology training programs.