Incidence, determinants and impact of acute kidney injury in patients with diabetes mellitus and multivessel disease undergoing coronary revascularization: Results from the FREEDOM trial.

BACKGROUND: The incidence and prognostic significance of acute kidney injury (AKI) in patients with diabetes mellitus and multivessel coronary artery disease undergoing coronary revascularization is not well known. The current analysis included patients randomized to PCI vs. CABG as part of the FREEDOM trial. We sought to examine the impact of AKI and its predictors in diabetic patients with multivessel coronary artery disease undergoing PCI vs. CABG. METHODS: We conducted a pre-specified subgroup analysis of the FREEDOM trial to examine the incidence, correlates and impact of AKI according to revascularization strategy. AKI predictors were identified using multivariable logistic regression and associations between AKI and outcomes were examined using Cox regression. The primary endpoint was the composite occurrence of all-cause death, stroke or myocardial infarction at 5 years of follow-up. RESULTS: KI occurred more frequently in patients following CABG (15.6%) compared with PCI (9.1%) (p < 0.001). AKI was associated with a higher risk for major cardiovascular events (MACE) at 5 years (34.6% vs. 20.5%, p < 0.001), an effect that remained large and significant irrespective of CABG (HR = 2.18 95% CI 1.44-3.31, p ≤0.001) or PCI (HR = 2.08 95% CI 1.35-3.21, p < 0.0001). There was a non-significant interaction (p-value = 0.89) between the revascularization method and AKI, supporting that AKI is a significant risk factor in both revascularization methods. CONCLUSIONS: Although risk for AKI was higher in patients undergoing CABG, the impact of AKI on MACE was substantial irrespective of revascularization strategy. Preventive strategies to identify patients at risk for AKI are warranted to mitigate the long-term effects of this complication.

Impact of Chronic Kidney Disease on Outcomes of Myocardial Revascularization in Patients With Diabetes.

BACKGROUND: The optimal coronary revascularization strategy in patients with stable ischemic heart disease (SIHD) who have type 2 diabetes (T2DM) and chronic kidney disease (CKD) remains unclear. OBJECTIVES: This patient-level pooled analysis sought to compare outcomes of 3 large, federally-funded randomized trials in SIHD patients with T2DM and CKD (COURAGE [Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation], BARI 2D [Bypass Angioplasty Revascularization Investigation 2 Diabetes], and FREEDOM [Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multi-vessel Disease]). METHODS: The primary endpoint was the composite of major adverse cardiovascular or cerebrovascular events (MACCE) including all-cause death, myocardial infarction (MI), or stroke adjusted for trial and randomization strategy. RESULTS: Of the 4,953 patients with available estimated glomerular filtration rate (eGFR) at baseline, 1,058 had CKD (21.4%). CKD patients were more likely to be older, be female, and have a history of heart failure. CKD subjects were more likely to experience a MACCE (adjusted hazard ratio [HR]: 1.48; 95% confidence interval [CI]: 1.28 to 1.71; p = 0.0001) during a median 4.5-year follow-up. Both mild (eGFR 45 to 60 ml/min/1.73 m2) and moderate to severe (eGFR <45 ml/min/1.73 m2) CKD predicted MACCE (adjusted HRs: 1.25 and 2.26, respectively). For patients without CKD, coronary artery bypass graft (CABG) surgery combined with optimal medical therapy (OMT) was associated with lower MACCE rates compared with percutaneous coronary intervention (PCI) + OMT (adjusted HR: 0.69; 95% CI: 0.55 to 0.86; p = 0.001). For the comparison of CABG + OMT versus PCI + OMT in the CKD group, there was only a statistically significant difference in subsequent revascularization rates (HR: 0.25; 95% CI: 0.15 to 0.41; p = 0.0001) but not in MACCE rates. CONCLUSIONS: Among SIHD patients with T2DM and no CKD, CABG + OMT significantly reduced MACCE compared with PCI + OMT. In subjects with CKD, there was a nonsignificant trend toward a better MACCE outcome with CABG and a significant reduction in subsequent revascularization.

The current status of therapeutic apheresis devices in the United States.

Over the last 40 years, plasmapheresis technology and its indications for use have been continually evolving. With the growing incidence for autoimmune diseases, unsatisfactory therapeutic options, side effects of drug therapy, and economic relevance, apheresis clinicians have been leaning toward more selective plasmapheresis techniques through the use of plasma fractionators and immunoadsorption columns. Plasma fractionators are mostly used in Asia, and rarely utilized in the U.S. The majority of plasma filters approved by the Food and Drug Administration (FDA) are primary membrane plasma separators, which still require replacement fluid. The secondary plasma fractionators available in the U.S. are limited in used and mostly investigational. Immunoadsorption columns, mostly used in Europe, are gaining popularity in the U.S. Some FDA-approved immunoadsorption columns include the Prosorba protein-A silica column, Immunosorba tryptophan and phenylalanine columns, Immunosorba protein-A sepharose column, and Liposorber dextran sulfate column. In addition, the heparin-induce extracorporeal lipoprotein precipitation (HELP) system is also FDA-approved. However, there are other immunoadsorption technologies used in Europe, such as direct adsorption lipoprotein LDL-hemoperfusion, not yet available in the U.S. While each method of apheresis carries its own risks and benefits, it is the opinion of the authors that these additional apheresis techniques be available to U.S. researchers and clinicians as a therapeutic option. The authors believe that the U.S. need to aggressively investigate more specific plasmapheresis modalities and establish appropriate dialogue with regulatory and reimbursement officials for FDA-approval of these devices.

Current topics on cryofiltration technologies.

In the last 40 years, therapeutic plasmapheresis techniques have been improving considerably. These include cryofiltration technologies providing novel ways of removing large amounts of cryoproteins from plasma. The concept of cryofiltration involves exposure of plasma to below core (37 degrees C) and room temperatures (25 degrees C) without freezing. It was initially used to treat diseases such as cryoglobulinemia with systemic vasculitis, rheumatoid arthritis, systemic lupus erythematosus, and ABO-incompatible transplants. There are 2 basic types of cryofiltration. The first method removes cryoproteins, namely cryoglobulins that precipitate at 4 degrees C. Several filters have been used for this procedure like the AP06M (Asahi Medical, Tokyo, Japan) with a 0.2 microm pore size, a 0.65 m2 surface area, and a cellulose diacetate (CDA) membrane. It has been used in the United States and Japan for treatment of rheumatoid arthritis and cryoglobulinemia. A major disadvantage was frequent filter plugging, which was cumbersome and it is no longer used in the United States. The G3 cryofilter (Gelman Sciences, Ann Arbor, MI, U.S.A.) with a 3 microm pore size was tried in vitro but proved inadequate by design. Currently in our institution, the cryoglobulin filter (Pall Medical, Ann Arbor, MI, U.S.A.) is used with a 4.3 microm pore size, a 0.135 m2 surface area, and an acrylic co-polymer pleat membrane. We performed over 1,200 procedures in 40 patients in the last 8 years. The second type of cryofiltration removes cryogel, which is an agglutination complex of fibrinogen, fibronectin, fibrin split products, and cold insoluble proteins with a heparin core, at temperatures between 2 and 10 degrees C. The AP06M, the AC1740 (Asahi Medical) with a 0.02 microm pore size, a 1.70 m2 surface area, and a CDA membrane, and the Evaflux-4A (Kuraray Company, Osaka, Japan) with a 0.03 microm pore size, a 2 m2 surface area, and an ethylene vinyl alcohol membrane are used to remove cryogel to treat ABO-incompatible transplants as well as rheumatoid arthritis and other previously mentioned diseases. This article will discuss each cryofiltration treatment modality.

Membrane plasmapheresis in the United States: a review over the last 20 years.

Plasmapheresis is a general term involving extracorporeal plasma separation by centrifugation or primary membrane plasma separator (MPS). Further plasma processing can be accomplished by the use of secondary membrane plasma fractionation (PF), as in double filtration plasmapheresis, also called cascade filtration, low-density lipoprotein pheresis, thermofiltration, and cryofiltration apheresis. Otherwise, the separated plasma is replaced by colloid solution as in plasma exchange (PE). PE is used, unselectively, to treat patients with immunological, neurological, hematological, renal, and metabolic disorders. Secondary PF may be a more selective alternative. In general, the primary MPS and secondary PF are safe, effective, and biocompatible. The advantages of the primary MPS include its simplicity to use with blood pumps and no observed white blood cell or platelet loss, compared with centrifugation. The disadvantages are lack of versatility, the need to monitor transmembrane pressure to prevent hemolysis, and possible biocompatibility issues such as use of polyvinyl alcohol membranes. The advantages of secondary PF, compared with PE, include selective removal of macromolecules according to molecular weight and filter pore size. No deficiency syndromes or sepsis are observed, nor is replacement solution required. More than 1 plasma volume may be processed, and it is less expensive than PE. Cryofiltration apheresis, using the cryoglobulin filter, selectively removes cryoproteins and is a specific treatment for cryoprecipitate-induced diseases. The disadvantages of PF include biocompatibility, especially with concomitant ACE inhibitor use, and membrane plugging. An important disadvantage is that most PFs are investigational in the United States. This article reviews the availability, safety, efficacy, and biocompatibility of primary MPSs and secondary PF in the United States.

Plasmapheresis by using secondary membrane filters: twelve years of experience.

Over 1,600 plasmapheresis procedures have been performed by using secondary on-line membrane plasma filters in 62 patients over the past 12 years in our institution. The disease categories treated include cryoprotein induced diseases such as cryoglobulinemia, immune mediated disorders, and familial type II-A hypercholesterolemia (FHC). Depending upon the molecular size of the offending agent, we used plasma filters (PF) with different pore sizes ranging from 0.02 microm to 0.04 microm or the cryoglobulin filter (CF) with an average pore size of 4.3 microm to remove cryoprecipitable proteins. One plasma volume was processed in each treatment. The results of treating 25 patient in over 550 procedures by using PF show it is safe and effective in treating immune mediated disorders and FHC. PF selectively removes macromolecules according to pore size and are more specific for the treatment of immune mediated diseases and FHC than plasma exchange. The results of treating 37 patients in over 1,100 procedures by using CF show it is safe and effective in selectively removing cryoproteins, and it is very specific for the treatment of cryoprotein induced diseases. Both PF and CF are biocompatible, with no complement activation. Unlike plasma exchange, secondary membrane plasma filters do not cause deficiency syndromes and do not require albumin or fresh frozen plasma as replacement fluid, making them more cost effective than plasma exchange.

Intensive tandem cryofiltration apheresis and hemodialysis to treat a patient with severe calciphylaxis, cryoglobulinemia, and end-stage renal disease.

This is the first report on tandem cryofiltration apheresis (CFA) and hemodialysis (HD). A 44 year old white man with Type II mixed cryoglobulinemia, hepatitis C virus (HCV), severe skin lesions, and end-stage renal disease (ESRD) on maintenance hemodialysis was air-transferred for CFA, which is only available at our medical center. The patient failed to respond to high dose steroids, immunosuppression, intravenous immunoglobulin (IVIG), and plasma exchange for the treatment of his cryoglobulinemia, and he failed alpha-interferon therapy for his HCV. On arrival, he was also found to have severe calciphylaxis secondary to ESRD with generalized, painful skin ulceration, necrosis, and penile gangrene. To treat both conditions, intensive, tandem CFA/HD was initiated. He received extensive wound care and surgical debridement. To prevent pressure ulcers and worsening of skin lesions, he was placed on the FluidAir (Kinetic Concepts Inc., San Antonio, TX) controlled air bed. The patient received 18 tandem CFA/HD treatments, and four extra HD treatments in one month. Sodium citrate was used as an anticoagulant for the CFA procedure. His plasma cryoglobulin (CG) level dropped from 6,157 to 420 microg/ml, and his calciphylaxis also improved. The CFA effectively removed 93% of CG, without significant removal of IgG, IgM, IgA, albumin, and fibrinogen. No albumin or fresh frozen plasma (FFP) was required as replacement fluid for CFA. No citrate toxicity or evidence of complement activation with the cryofilter was observed. The entire CFA procedure time (3(1/2) hours) was considered. Intensive, tandem CFA/HD was performed in a critically ill patient with no apparent adverse consequences.

Plasmapheresis and paraproteinemia: cryoprotein-induced diseases, monoclonal gammopathy, Waldenström's macroglobulinemia, hyperviscosity syndrome, multiple myeloma, light chain disease, and amyloidosis.

Therapeutic plasmapheresis has been in widespread use as either a primary or adjunctive therapy in the United States since the 1960s. There are several types of plasmapheresis procedures used to treat various diseases. Plasma exchange with a centrifugal plasma separator using replacement fluid such as human albumin solution is the most widely used method in the United States. Other forms of plasmapheresis include membrane plasma separation, membrane fractionation, cryofiltration apheresis, immunoadsorption, and chemical affinity column pheresis. Therapeutic plasmapheresis has been used for the treatment of paraproteinemia to remove harmful paraproteins. Paraproteinemia is a disease classification in which abnormal or large amounts of plasma proteins such as cryoproteins or immunoglobulins are produced. In most cases, plasmapheresis is used in combination with corticosteroids and immunosuppressive drugs to prevent production of abnormal proteins or to treat the underlying disease. Cryoprotein-induced diseases, which include cryoglobulinemia, cryofibrinogenemia, and cold IgM antibody agglutinin with cryoglobulin properties, are a subclass of paraproteinemia. Other categories of paraproteinemia include monoclonal gammopathy, Waldenström's macroglobulinemia, hyperviscosity syndrome, multiple myeloma, light chain disease, and amyloidosis. Some of these diseases may be interrelated, and they may be associated with one another. In this review paper, we discuss the role of plasmapheresis in the specific classes of paraproteinemia in the United States, including our own experience.

Cryofiltration apheresis in the United States.

There are approximately 2,000 cases of cryoglobulinemia reported each year in the United States. The number of cases has been and is expected to continue growing exponentially since the advent of its association with the hepatitis C virus (HCV). Cryofiltration apheresis is a specific therapy for the treatment of cryoprotein induced diseases that selectively removes cryoprecipitates. We are currently the only center in the United States performing cryofiltration apheresis. We report on 32 patients treated with over 920 cryofiltration apheresis procedures over the last 6 years under the Investigational Device Exemption of the Food and Drug Administration Office of Orphan Devices. Twenty-seven patients were treated for cryoglobulinemia. Twelve of these patients received maintenance cryofiltration apheresis at some point, and 5 patients died. Five of the 32 patients were treated for cold IgM agglutinin disease. Only 2 of these patients, having plasma positive for cryoprotein and a high titer antibody, responded to therapy. None of these patients received maintenance therapy. No complement activation was observed using the cryofilter by measuring C3a and C5a. Although cryoproteins were effectively removed from the plasma, the other vital proteins such as immunoglobulins, albumin, and fibrinogen were preserved. Therefore cryofiltration apheresis is safe and effective in treating cryoprotein induced diseases. We would like to see widespread use of this cryofilter so that all patients with cryoprotein induced diseases such as cryoglobulinemia may benefit from this procedure.

Cryofiltration apheresis in the treatment of cryoprecipitate induced diseases.

Cryoprecipitates include cryoglobulins, cryofibrinogen, cryoparaproteins, and some cold hemagglutinins. We used 3 different methods: plasma exchange (PE), plasma filter (PF), and cryofilter (CF) to remove cryoproteins. Twenty-four patients received more than 800 CF, PF, and PE treatments. The PF and CF methods have average pore sizes of 0.03 microm and 4.3 microm and surface areas of 2.0 m2 and 0.135 m2, respectively. The plasma was separated by centrifugation, cooled to 4 degrees C, and the cryoprecipitate was removed by CF. Albumin solution 5% was used as a replacement fluid in PE, but no albumin was required when using PF or CF. Our results show that the CF and PF methods do not cause complement activation. Although PE is effective for removal of cryoproteins, it is nonspecific, nonselective, and requires human albumin or fresh frozen plasma. If intensive PE is required, it may cause depletion of immunoglobulins and coagulation factors and other vital plasma components. The PF removes macromolecules such as IgM and IgG effectively and it is semiselective. It removes any protein with a molecular weight > or = 200,000, which makes it semispecific treatment. CF is very effective and selectively removes cryoproteins; therefore it is a specific therapy. In conclusion, cryofiltration apheresis is the best method to remove cryoproteins in the treatment of cryoprecipitate induced diseases.

Cryofiltration apheresis and plasma fractionation causing anaphylactoid reactions in patients receiving angiotensin converting enzyme inhibitors.

Severe anaphylactoid reactions and even death have been reported in hemodialysis patients using certain membrane dialyzers while receiving angiotensin converting enzyme (ACE) inhibitors. We report mild to moderate anaphylactoid reactions in 4 patients receiving plasmapheresis with on-line membrane filters after being placed on ACE inhibitors. Of 21 patients receiving 497 plasma fractionation procedures, only the 2 patients who were receiving ACE inhibitors developed anaphylactoid reactions. Of 28 patients who had 680 cryofiltration procedures, only 2 of 5 patients who were taking ACE inhibitors developed anaphylactoid reactions. All patients developed facial flushing, increased warmth, bradycardia, and hypotension after approximately 1/2 to 1 L of plasma was processed during the procedures. Only a few procedures caused severe hypotension requiring discontinuation of the procedure. We quantified vasodilatory mediators in 1 patient, who developed pronounced symptoms. Results were obtained for 6-keto PGF1alpha, PGD-M, and methyl histamine in plasma. In addition, in the same patient, 2,3 dinor 6-keto PGF1alpha and methyl histamine were quantified in urine samples. Our results showed that plasma and urinary metabolites were not grossly elevated although they did increase slightly. Mild to moderate anaphylactoid reactions were observed in some patients on ACE inhibitors receiving plasma fractionation or cryofiltration apheresis. This was resolved by discontinuing either the ACE inhibitor, plasma fractionation, or cryofiltration apheresis.

Cryofiltration apheresis for treatment of cryoglobulinemia associated with hepatitis C.

Cryofiltration apheresis (CA) is a specific therapy for treatment of patients with cryoglobulinemia. We evaluated the safety and efficacy of CA in patients with mixed cryoglobulinemia associated with hepatitis C. As reported previously, the Cryoglobulin Filter comprises a membrane module inside a refrigeration unit on-line with a Spectra Apheresis System (COBE, Denver, CO). The efficacy of cryofiltration was measured by comparing the sieving coefficient of cryoprecipitable proteins (CPP) to that of albumin and comparing the systemic CPP concentration ratio post to pre treatment. Five patients were enrolled in this study, and a minimum of 10 procedures were performed for each patient. The risk for hepatitis C was multiple blood transfusions, intravenous drug abuse, immunosuppressive therapy, or renal transplantation. Four patients had Type II mixed cryoglobulinemia, and one patient had Type III. Four patients had chronic renal failure; one with liver cirrhosis received alpha interferon along with CA. One patient had no response to conventional plasma exchange and immunosuppressive therapy secondary to repeated infections and sepsis; CA was the only viable therapy for this patient. The maximum CPP concentration before therapy ranged from 1,440 to 7,440 micrograms/ml. The plasma CPP sieving coefficient at 1 L filtrate ranged from 0.25 to 0.74 (average +/- SE, 0.51 +/- 0.19; n = 39). The sieving coefficient for albumin was 1 (n = 50). The systemic CPP ratio post to pre treatment ranged from 0.28 to 0.83 (average +/- SE, 0.59 +/- 0.20; n = 37). No adverse effects specific to CA were observed. The CA was safe and effective and possibly the only choice of therapy in patients with cryoglobulinemic hepatitis C who have no response to plasma exchange and immunosuppressive therapy.