Andre A. Kaplan

Therapeutic Plasma Exchange: Complications and Management

Therapeutic plasma exchange is a treatment modality used in a variety of disease states, some of which are characterized by renal involvement (ie, Goodpastures syndrome, multiple myeloma, cryoglobulinemia, and thrombotic thrombocytopenic purpura). To investigate the safety of this procedure we evaluated all patients receiving plasma-pheresis at the University of Connecticut from January 1988 to June 1991. Sixty-eight adverse reactions occurred in 699 treatments, resulting in an incidence of 9.7%. The most frequent complications were symptoms of hypocalcemia, hypovolemia, and anaphylactoid reactions. The incidence of hypocalcemic symptoms was lowered with the prophylactic administration of calcium. Without calcium prophylaxis the incidence of symptoms was 9.1% (six in 66 treatments), whereas with calcium prophylaxis the incidence was reduced to 1% (six in 633 treatments) (P < 0.01). Treatments in which albumin was administered as volume replacement were associated with fewer adverse reactions when compared with those using fresh-frozen plasma (1.4% v 20%). Our experience, combined with the 15,658 procedures reported in the literature, reveals that serious complications do not commonly occur. These are characterized by cardiovascular events (0.2%), respiratory events (0.2%), and anaphylactoid reactions (0.25%). Hemorrhage and infection are rare, each occurring at a rate of 0.02%. Death was reported in eight of 15,658 procedures (0.05%). We conclude that therapeutic plasma exchange is relatively safe and alterations in plasma proteins generally are well tolerated. Prophylactic calcium administration lowers the incidence of hypocalcemic symptoms. Adverse reactions are associated more commonly with the administration of fresh-frozen plasma.

Fractional Excretion of Urea as a Guide to Renal Dysfunction

The use of fractional excretion of sodium as a guide to renal perfusion is hampered by the prior use of natriuretic agents. The fractional excretion of urea (FEUr) has been shown to be affected by volume status. We, therefore, determined the value of the FEUr as a guide to renal perfusion. In 6 patients evaluated prospectively and in 87 patients evaluated retrospectively, a low FEUr (less than or equal to 35%) was found to be a sensitive index to renal perfusion, despite the prior administration of furosemide.

Toward the Rational Prescription of Therapeutic Plasma Exchange: The Kinetics of Immunoglobulin Removal

The indications for therapeutic plasma exchange continue to expand as results of well-designed randomized studies lend solid scientific support to the use of this therapeutic modality (1-4). Although the identification of targeted pathogenic substances remains unclear in some diseases such as with thrombotic thrombocytopenic purpura, the most easily comprehensible rationale for plasma exchange therapy is the removal of pathogenic autoantibodies. As such, the purpose of this review is to describe the kinetics of immunoglobulin removal as it relates to therapeutic plasma exchange. The basic tenets of immunoglobulin kinetics can be gleaned from the results of experiments in which isotopically labeled immunoglobulins have been infused into humans ( 5 , 6). These experiments have demonstrated three important concepts. The first is that immunoglobulins have relatively long half-lives, approaching 21 days for IgG and 5 days for IgM. The second is that immunoglobulins have a substantial extravascular distribution, approximately 60% for IgG and 20% for IgM, a distinction probably accounted for by the substantial differences in their molecular weights (160,000 daltons for IgG and 900,000 daltons for IgM). The third concept is that immunoglobulins exhibit an intravascular to extravascular equilibration that is approximately 1 to 2%/ hr. Animal studies, however, have demonstrated that extravascular to intravascular equilibration may be somewhat faster, governed by the rate of lymphatic flow (7). The importance of these three concepts can be simply stated. First, considering the relatively long half-life of immunoglobulins, the use of immunosuppressive agents that decrease antibody production cannot be expected to substantially lower the levels of a pathogenic autoantibody for at least several weeks, even if production is completely blocked. This is the basic rationale for their removal by extracorporeal means. Second, since extravascular to intravascular equilibration is relatively slow, the kinetics of immunoglobulin removal by plasma exchange can be calculated using first-order kinetics governing removal rates from a single compartment (i.e., the intravascular space.) Practicing nephrologists are particularly well versed in the calculations required for predicting the

Continuous Arteriovenous Hemofiltration: Improvements, Modifications, and Future Directions

In 1960, Scribner and his Seattle associates first suggested the use of continuous dialysis without the use of extracorporeal blood pumps (I). Despite their pioneering efforts, the technology was simply not available for the successful performance of this treatment. In 1977, Kramer and his co-workers described continuous arteriovenous hemofiltration (CAVH) (2). Bosh and his associates applied Kramer’s a p proach, described the operational characteristics of the system, and generally promoted this therapy in the United States (3). Geronemus and Schneider modified this technique fbrther and returned to the original Scribner concept of continuous arteriovenous hemodialysis (CAVfID) (4). Since then the scientific and manufacturing communities have improved the technology such that the continuous therapies (with or without extracorporeal blood pumps) are becoming the treatments of choice for critically ill patients with renal failure. It is the purpose of this communication to acknowledge these improvements and modifications, to describe advantageous strategies to individualize and optimize this therapy, and to suggest directions for areas of further research.

Therapeutic plasma exchange: a technical and operational review.

Therapeutic plasma exchange (TPE) is an extracorporeal blood purification technique designed for the removal of large molecular weight substances. Examples of these substances include pathogenic autoantibodies, immune complexes, cryoglobulins, myeloma light chains, endotoxin and cholesterol containing lipoproteins. The basic premise of the treatment is that removal of these substances will allow for the reversal of the pathologic processes related to their presence. This review will cover the techniques for performing TPE, the kinetics of the removal of large molecules from the plasma and the benefits and risks of the different types of replacement fluids. J. Clin. Apheresis 28:3–10, 2013.

Complications of apheresis.

In general, therapeutic apheresis is a relatively safe procedure with the most commonly seen complications caused by citrate‐induced hypocalcemia and urticarial reactions to the protein‐containing replacement fluid. Depletion coagulopathy and immunoglobulin depletion must be anticipated when albumin is used as the replacement fluid and becomes more profound as the number of treatment increases. The most serious complications are seen when there is an anaphylactoid reaction to the multiple units of fresh frozen plasma required when used as the replacement fluid. The overall incidence of death is 0.05%, but many of these deaths were in patients with severe preexisting conditions in which the apheresis procedure, itself, may not have been the precipitating cause. As with all extracorporeal treatments requiring large bore vascular access, catheter‐related trauma, clotting, infection, and bleeding may also occur.

Thrombotic Thrombocytopenic Purpura in Pregnancy: Successful Treatment with Plasma Exchange

Thrombotic thrombocytopenic purpura (TTP) is a rare syndrome which presents typically with thrombocytopenia, microangiopathic hemolytic anemia, central nervous system symptoms, fever, and renal abnormalities. The diagnosis of TTP in pregnancy previously carried a poor prognosis and a high fetal mortality when presenting early in gestation. This case report describes the earliest presentation of TTP in pregnancy (6 weeks of gestation) we could identify in the literature treated successfully with a prolonged course of plasma exchange. The differential diagnosis and the pathogenesis of TTP in pregnancy are reviewed. Therapeutic options and data regarding the removal of pregnancy-related hormones by plasma exchange are presented.

Clinical applications of therapeutic apheresis

The vast majority of the renal indications for plasmaexchange are related to immunoglobulin removal.Immunoglobulins, especially IgG, have a relativelylong half-life. Thus in antibody-mediated disease, therecould be persistence of significant amounts of antibodyin the circulation despite cessation of antibody produc-tion. The aim of plasma exchange is to significantlyreduce circulating antibodies. Removal of the circulat-ing antibodies constitutes the rationale for using plas-mapheresis to treat antibody-associated glomeruloneph-ritis (GN). Although small molecular weight substancesare removed by plasma exchange, their large volumeof distribution and short half-lives make plasmaexchange an inefficient means of extracorporeal re-moval of these substances. For instance, some comple-ment proteins have a half-life of 2 days. If the goalwere to be to deplete plasma complement levels, virtu-ally daily plasma exchanges would be needed. Discon-tinuation of daily plasma exchange would be followedby rapid resurgence to normal complement titers.Hence the shorter the half-life of the molecule beingremoved, the more aggressive has to be the apheresisschedule.Plasma volume can be estimated using the followingformula:EPV ¼ 0:065 3 TBW 3 ½1 Hctwhere EPV is the estimated plasma volume, TBW isthe total body water, and Hct is hematocrit.The removal of large molecular weight substancesfrom the plasma compartment follows first-orderkinetics. Repetitive treatments should be spaced every24–48 h to allow for extravascular to intravascularequilibration.Apheresis has been used to treat several renal condi-tions including primary renal diseases as well as renalmanifestations of systemic conditions (Table I).

Plasmapheresis Treatment in Guillain–Barré Syndrome: Potential Benefit over IVIg in Patients with Axonal Involvement

Abstract:  Response to therapeutic plasma exchange (TPE) was evaluated in patients diagnosed with Guillain–Barré Syndrome (GBS). Our aim was to assess response to TPE in patients who had failed treatment with intravenous immune globulin (IVIg). We conducted a retrospective chart review of 10 patients with the diagnosis of Guillain–Barré Syndrome who required TPE. Patients were identified by reviewing data from log books for TPE at The University of Connecticut Health Center, Farmington CT, USA. Patients who had failed IVIg treatment prior to being referred for TPE were also identified. Eight out of 10 patients treated with TPE showed improvement in their neurological exam. Four patients had axonal involvement on electromyelogram (EMG). Three patients were referred for TPE after failing IVIg treatment. All three of these had axonal involvement on EMG. Three of the four patients with axonal involvement demonstrated improvement with TPE. TPE may be a superior treatment option as compared to IVIg in patients with GBS and EMG findings of axonal involvement.

A Case Report of Therapeutic Leukapheresis in an Adult With Chronic Myelogenous Leukemia Presenting With Hyperleukocytosis and Leukostasis

Abstract:  Hyperleukocytosis (>100 × 109/L) is an uncommon presentation of chronic leukemias. It can present with a variety of symptoms secondary to leukostasis, a syndrome caused by the sludging of circulating leukemic blasts in the microvasculature. The management includes hydration, cytoreduction, prevention of tumor lysis and, rarely, leukapheresis in cases complicated by leukostasis and hyperviscosity syndrome. We present a case of severe leukocytosis complicated by leukostasis in which leukapheresis was utilized to bring about a rapid reversal of microvascular sludging.