Dialysis care, cardiovascular disease, and costs in end-stage renal disease in Brazil

OBJECTIVES: This study evaluates the cost of dialysis care in Brazil, including costs of ambulatory care and hospital admissions due to all causes and cardiovascular events. METHODS: Data were analyzed for 200 patients with end-stage renal disease (ESRD) on chronic hemodialysis in Brazil between 2001 and 2004. Main end points were all-cause mortality, all-cause hospital admissions, and cardiovascular events. Direct costs of dialysis treatment and complications were computed from the perspective of two payers, the Ministry of Health (MoH) and private health insurance (PHI). RESULTS: Mean number of days of hospitalization was 12 per patient-year. There were 105 cardiovascular events; the most frequent events were coronary disease (n = 59, 56 percent) and congestive heart failure (n = 26, 25 percent). The rate of cardiovascular events was 193 per 1,000 patient-years. There were 43 deaths, and the death rate was 79 per 1,000 patient-years. Median cost per hospital admission was US$ 675 and US$ 932 from the perspective of the MoH and PHI. For admissions due to cardiovascular causes, the corresponding costs were US$ 1,639 and US$ 4,499, respectively. Mean global cost per patient-year for chronic hemodialysis therapy was US$ 7,980 and US$ 13,428 from the perspective of the MoH and PHI, respectively. CONCLUSIONS: Patients on chronic hemodialysis care incur significant healthcare resources due to the costs of dialysis and complications, notably cardiovascular disease. New disease management programs aimed at reducing cardiovascular morbidity and efficient use of resources are critical to ensuring the sustainability of treatments for ESRD in Brazil.     

Cytotoxic T lymphocytes specific for I region determinants do not require interactions with H-2K or D gene products

Gene products coded for by the major hisocompatibility complex (MHC) can serve as target antigens for cytotoxic T lymphocytes (CTL) (1). A variety of test systems are available which have yielded information consistently reinforcing the importance of this complex of genes in the generation and effector phases of the cytotoxic immune response. Originally, it was shown that allogeneically-induced CTL had specificity primarily for the products of the K and D loci of the mouse H-2 complex (2). More recently this has also been found to be the case for xenogeneic immunizations (3,4). Additional examples of T cell-mediated lysis have been reported involving viral-infected or chemically- modified syngeneic stimulating and target cells in which homology at H-2K or H-2D was required between the responding and target cells for appreciable lysis to occur (5-7). Moreover, CTL specific for minor histocompatability antigens are able to lyse only target cells bearing these membrane antigens and sharing a common H-2K or H2-D gene product with the effector (8,9). Two hypotheses have been proposed to explain the requirement for H-2 identity between effector and targets in these systems. CTL may recognize new antigenic determinants created by the interaction of the modifier with syngeneic K and D gene products. Alternately, a dual recognition system my exist, requiring an antigen-specific receptor as well as a second receptor with specificity for homologous H-2K or H-2D determinants (5). Neither model can be excluded at this time. The I region also contains genes coding for histocompatibility loci since animals differing at the I-A or I-C regions of the H-2 complex reject skin grafts (10-12), though less rapidly than mice differing at the H-2K or H-2D regions, Also CTL can be generated to I region determinants but less efficiently than CTL specific for H-2K or H-2D gene products (12-14). The question can therefore be raised, whether the I region minor histocompatibility loci function independently from the H-2K or H-2D loci or whether I region-specific cytolysis requires the participation of H-2K or H-2D gene products of the target cell. This communication illustrates the generation of CTL showing specificity for I region determinants in primary mixed lymphocyte cultures. Further, we demonstrate by genetic analysis and byt eh use of speficit alloantisera that CTL directed to Ia determinants (a) do not see these antigens as modifications of H-2K or H-2D gene products but as independent gene products coded for by the I region, and (b) they do not require interaction with target cells bearing the same H-2K or H-2D gene product as the effect CTL.     

The I-J subregion codes for determinants on suppressor factor(s) which limit the contact sensitivity response to picryl chloride

The cell-mediated immune reactivity (CMI) of mice to contact chemicals such as picryl chloride (PCI) is influenced by thymus-derived suppressor T lymphocytes (1,2). The development of these suppressor T lymphocytes is stimulated by the intravenous administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS). Zembala and Asherson have further demonstrated that a specific suppressor factor(s) can be detected in the supernates of cultured suppressor T cells. This factor suppresses the transfer of contact sensitivity (CS) to PCl (1,2). In experiments reported elsewhere (3), we have shown that the PCl suppressor supernates of Zembala and Asherson can also suppress the development of contact sensitivity to PCl. The immunochemical analysis of suppressor factor (SF) operative in the CS response to PCl has revealed many similar properties (3) to other suppressive moieties functioning to limit the plaque-forming cell (PFC) response to dinitrophenylated-keyhole limpet hemocyanin (DNP-KLH) as well as the strict antigen specificity of each respective suppressive factor, suggested that there might be a common origin of these substances. Indeed, in each case these respective factors were found to bear determinants controlled by the H-2 gene complex (4,5). Recently, in selected systems, the I-J subregion has been found to code for the Ia determinants present on suppressor cells (6) and suppressor factors (4,5). In accord with these findings, we report that antigen-specific SF which limit the CS response to PCl bear I-J determinants, implying that analogous suppressive regulatory mechanisms in CMI as well as antibody responses may be determined by genes of one subregion of the H-2 complex.     

Genetic control of specific immune suppression. IV. Responsiveness to the random copolymer L-glutamic acid(50)-L-tyrosine(50) induced in BALB/c mice by cyclophosphamide

Previous reports from our laboratory have demonstrated the stimulation of specific suppressor T cells in genetic nonresponder mice after immunization with the terpolymer of L- glutamic acid, L-alanine, and L-tyrosine (GAT) (1,2) and with the copolymer of L-glutamic acid and L-tyrosine (GT) (3-5). These findings raise two important questions: (a) do the specific suppressor T cells inhibit an antibody response which would otherwise develop in nonresponder mice; and, (b) can specific helper T cells inhibit an antibody response which would otherwise develop in nonresponder mice; and, (b) can specific helper T-cell activity be detected in these animals. Responsiveness appears to be completely dominant over suppression in (responder x suppressor)F(1) hybrids, therefore, we have been unable to detect suppressor cells in these hybrids after conventional immunization with GAT (2). However , using special conditions of antigen administration, GAT helper activity could be demonstrated in nonresponder DBA/1 (“suppressor”) mice. Thus, GAT-specific helper activity was not detected in these nonresponder animals after immunization with GAT irrespective of the adjuvant used, but could be stimulated by macrophage-bound GAT or by GAT complexed with methylated bovine serum albumin GAT-MBSA (6). In the current report we have taken advantage of the fact that suppressor T-cell activity is more sensitive to cyclophosphamide treatment than T-cell helper activity (7) to demonstrate the presence of GT-specific helper activity in “nonresponder” BALB/c mice. We describe: (a) the dose of cyclophosphamide and conditions of treatment which inhibits the well-documented stimulation of specific suppressor T cells in BALB/c mice injected with GT previous to immunization with GT-MBSA, and (b) the ability of cyclophosphamide to permit the development of primary PFC responses to GT in these “nonresponder” mice. These cyclophosphamide-induced responses are not characterized by the high levels of antibody detected in genetic responder animals.     

Richter's syndrome with different immunoglobulin light chains and different heavy chain gene rearrangements

In a patient with Richter's syndrome, the chronic lymphocytic leukemia (CLL) expressed lambda, mu, and delta immunoglobulin (lg) chains and the non-Hodgkin lymphoma (NHL) kappa, mu, and delta lg chains. The difference in lg light chain expression suggests that the CLL and NHL are independent malignancies, or that the oncogenic event occurred in a B cell differentiation stage after the heavy chain gene rearrangements but before the selection of the light chain. Analysis of DNA by Southern blotting revealed that the lg heavy chain genes of the two malignancies were rearranged in a different way. We therefore conclude that in this patient the NHL cannot be regarded as a progression of the CLL but should most likely be considered as an independent B cell malignancy, which arose in a susceptible host.     

The presence of clonogenic cells in high-grade malignant lymphoma: a prognostic factor

A culture system has been developed that promotes growth of clonogenic lymphoma cells of some patients with intermediate and high-grade malignant lymphoma. The formation of colonies in bone marrow, lymph nodes, and peripheral blood samples is best supported by human plasma. Colony formation of some patients was dependent upon growth factors, which in this study were added in the form of medium conditioned by phytohemagglutinin (PHA)-stimulated leukocytes (PHA-LCM). Some gave rise to lymphoma colonies without PHA-LCM but improved their frequency with PHA-LCM; others were completely independent of PHA-LCM. Colonies grown in primary cultures were routinely recloned and propagated as Epstein-Barr virus (EBV)-negative cell lines with stable B cell phenotype. The cell lines showed the same immunoglobulin rearrangement pattern as that observed in the primary lymphoma sample. In addition, a significant clinical correlation was observed between culture data and clinical outcome. Survival of patients who formed lymphoma colonies at any time during their clinical course was significantly shorter than survival of patients who did not give rise to colonies (P = 0.0009). The same observation was made when the survival assessment was performed for the subset of patients studied at diagnosis (P = 0.0014).     

The coagulant-active phospholipid content is a major determinant of in vivo thrombogenicity of prothrombin complex (Factor IX) concentrates in rabbits

In vitro evaluation of prothrombin complex concentrates in a thrombin generation assay, using DAPA and purified components of the prothrombinase complex, demonstrated significant levels of coagulant- active "phospholipid replacing" activity. Quantification of this activity showed a significant correlation (r = 0.8747, p less than 0.01) with thrombogenicity measured in vivo in a stasis model in rabbits. Extracted lipid material retained full phospholipid replacing activity in the vitro assay. Thin-layer chromatographic characterization confirmed the presence of phospholipids with known coagulant activity in vitro. In vivo, the extracted material was nonthrombogenic but augmented the thrombogenicity of purified factor Xa. Substitution of a synthetic coagulant-active phospholipid (phosphatidylcholine-phosphatidylserine lipid vesicles) for the extracted phospholipid produced a similar augmentation of a factor-Xa- induced thrombogenicity in vivo. It is concluded that the coagulant- active phospholipid content of prothrombin complex concentrates is a major determinant of thrombogenicity but requires the presence of activated clotting factors for its expression in vivo.     

A technique for the flow cytometric analysis of lymphocytes bearing histamine receptors

Histamine receptors have been demonstrated on lymphocyte membranes by a variety of techniques. We now report a method that allows for the flow cytometric analysis of histamine receptors on human peripheral T cells. Histamine is conjugated to fluoresceinated human albumin by the coupling agent ECDI. This conjugated histamine compound (FHA-his) binds to approximately 45% of T cells. Fluoresceinated human albumin alone (FHA), not conjugated to histamine, does not bind to T cells. In addition, unconjugated histamine can inhibit completely the binding seen with FHA-his. We conclude that this technique demonstrates specific FHA-his binding to histamine receptors on T cells and can be used to determine the number of cells bearing such receptors. In addition, the reagent could be used with a cell sorter to isolate distinct histamine-receptor-bearing (HR+) cells for further immunologic study.