IL-2 and IFN-gamma are associated with acute rejection (AR) and graft vascular disease (GVD) after clinical heart transplantation. Polymorphisms in the genes of IL-2 (T-330G in the promoter) and IFN-gamma (CA repeat in the first intron) influence the production levels of these cytokines. Therefore, these polymorphisms might have an effect on the outcome after transplantation. To investigate possible effects of genetic variations in IL-2 and IFN-gamma genes on AR and GVD, we analyzed the IL-2 T-330G and the IFN-gamma CA repeat polymorphism in DNA of 301 heart transplant recipients. No associations were found for allele or genotype distributions between patients with or without AR (IL-2 allele frequency: P=0.44, genotype distribution: P=0.46; IFN-gamma allele frequency P=0.10, genotype distribution 12 repeats allele: P=0.21). Also, no associations were found analyzing the number (0 vs. 1 vs. >or=1) of AR (IL-2 allele frequency: P=0.59; genotype distribution: P=0.37; IFN-gamma allele frequency: P=0.27, genotype distribution 12 repeats allele: P=0.41) or analyzing the polymorphisms in patients with AR within the first month or thereafter (IL-2 allele frequency: P=0.45, genotype distribution: P=0.38; IFN-gamma allele frequency: P=0.21, genotype distribution 12 repeats allele: P=0.41). Analyzing both polymorphisms in relation to GVD, resulted in comparable allele and genotype distributions (IL-2 allele frequency: P=0.75; genotype distribution: P=0.77; IFN-gamma allele frequency: P=0.70, genotype distribution 12 repeats allele: P=0.63). In conclusion, we did not detect an association between the IL-2 T-330G promoter polymorphism and CA repeat polymorphism in the first intron of the IFN-gamma gene and AR or GVD after heart transplantation.

Adult↗

PubMedDate not supplied

Simulation study of the intercompartmental fluid shifts during hemodialysis.

Hypotension is the most frequent complication during hemodialysis. An important cause of hypotension is a decrease in the intravascular volume. In addition, a decrease in plasma osmolality may be a contributing factor. Modeling of sodium and ultrafiltration (UF) may help in the understanding of underlying relationships. We therefore simulated, in a mathematical model, the intercompartmental fluid shifts during standard hemodialysis (SHD), diffusive hemodialysis (DHD), and isolated ultrafiltration (IU). We analyzed the relative theoretical effect of hydration status, dialysate sodium concentration, the initial plasma concentrations of sodium and urea, and tissue permeation to solutes on the magnitude and direction of intracellular and intravascular volume changes. This theoretical analysis shows that the transcellular fluid shifts taking place during hemodialysis treatment are, to a great part, due to inhomogeneous distribution of regional blood flow and tissue fluid volumes. During hemodialysis treatment, the cellular fluid shifts in tissue groups with relatively high perfusion and small volume occur from the intra- to the extracellular spaces. However, the fluid shift in tissue groups with a low perfusion and large volume takes place in the opposite direction. The UF volume and rates, and the size of the sodium (Na+) gradient between the dialysate and blood side of the dialyzer membrane are the most important factors influencing the fluid shifts. Higher UF volumes and flow rates cause an increasing decline in the plasma volume in both SHD and IU. High dialysate sodium concentration (150 mEq L(-1)) helps plasma refilling slightly when compared with a normal dialysate sodium concentration (140 mEq L(-1)). However, a high dialysate sodium concentration is associated with a high plasma sodium rebound, which in turn may lead to interdialytic water intake resulting from thirst and may cause increased weight gain and hypertension.

Body Fluids↗

PubMedDate not supplied

Continuous renal replacement therapy for critically ill patients: an update.

Despite continuous progress in intensive care during the last decades, the outcome of critically ill patients in whom acute renal failure (ARF) develops is still poor. This outcome may be explained partially by the frequent occurrence of ARF as part of multiple organ systems failure (MOSF). In this complex and unstable patient population, the provision of adequate renal support with either intermittent hemodialysis or peritoneal dialysis may pose major problems. Continuous renal replacement therapy (CRRT) is now increasingly accepted as the preferred treatment modality in the management of ARF in these patients. The technique offers adequate control of biochemistry and fluid balance in hemodynamically unstable patients, thereby enabling aggressive nutritional and inotropic support without the risk of exacerbating azotemia or fluid overload. In addition, experimental and clinical data suggest that CRRT may have a beneficial influence on hemodynamics and gas exchange in patients with septic shock and (nonrenal) MOSF, independent of an impact on fluid balance. We review both technical and clinical aspects of various continuous therapies, including their impact on serum drug levels and nutrient balance. In addition, an attempt is made to clarify the possible beneficial role of CRRT in reducing patient morbidity and mortality in the ICU.

Acute Kidney Injury↗

PubMedDate not supplied

Intragraft monitoring of rejection after prophylactic treatment with monoclonal anti-interleukin-2 receptor antibody (BT563) in heart transplant recipients.

BACKGROUND: Anti-interleukin-2 receptor monoclonal antibodies have been used successfully in the prevention of rejection in cardiac allografts in several animal models. METHODS: In an open randomized study murine monoclonal CD3 antibody and BT563, a murine anti-interleukin-2 receptor monoclonal antibody, were given as rejection prophylaxis during the first week after heart transplantation. Cyclosporine therapy was initiated at the third postoperative day. RESULTS: In half the BT563-treated patients an early rejection was histologically shown at week 1, whereas heart transplant recipients treated with murine monoclonal CD3 antibody had a rejection incidence at week 1 of only 9%. During BT563 treatment CD25-positive cells (i.e., cells bearing the interleukin-2 receptor) were not detectable in peripheral blood. However, immunohistologic studies of endomyocardial biopsy specimens taken 1 week after transplantation showed the presence of CD25-positive cells within these specimens in 8 of 10 (80%) of patients with rejection. In patients without rejection CD25-positive cells were present in the biopsy specimens of only two of nine patients (22%). Reverse-transcriptase polymerase chain reaction studies on biopsy material showed the presence of messenger RNA for the interleukin-2 receptor in all and for interleukin-2 in three of five (60%) of biopsy specimens of rejecting grafts. CONCLUSIONS: Although CD25-positive cells were not detectable in peripheral blood during BT563 treatment, these cells were at the same time found to be present within 80% of the endomyocardial biopsy specimens from the rejecting grafts. By initiating cyclosporine treatment at day 0, the synergistic effect of combining cyclosporine and anti-interleukin-2 receptor monoclonal antibodies may result in a lower rejection incidence.

Animals↗

PubMedDate not supplied

Effect of cryopreservation and HLA-DR matching on the cellular immunogenicity of human cardiac valve allografts.

The cellular immunogenicity of fresh and cryopreserved human cardiac valve leaflets was measured in a lymphocyte proliferation assay. One fresh leaflet and a cryopreserved leaflet derived from the same valve were cut into 2 mm diameter pieces and incubated with responder peripheral blood mononuclear cells, matched or mismatched for HLA-DR. The tritiated thymidine incorporation into the lymphocytes measured after 7 days, was expressed as stimulation index. Fresh, HLA-mismatched valve pieces induced high stimulation index in all cases (median 9, range 4 to 117). The cryopreservation procedure resulted in a significantly lower stimulation index (p = 0.002, Wilcoxon), with a median stimulation index of 2 (range 0 to 9). In the instances where HLA-DR matched combinations were studied, cryopreservation was also associated with lower stimulation index. HLA matching itself was able to reduce the stimulation index both with cryopreserved and fresh valve pieces as stimulator, resulting in a median stimulation index of 4 (range 2 to 117) for the HLA-DR-mismatched and 1 (range 0 to 5) for the matched lymphocytes (p = 0.006, Wilcoxon). In conclusion, human cardiac valves are able to stimulate immune competent cells in vitro, even after cryopreservation. The cellular allogeneic response in vitro could be an explanation for valve allograft degeneration observed in the clinic. Matching for HLA-DR may reduce these effects.

Cryopreservation↗

PubMedDate not supplied

Pulsed-wave transmitral Doppler do not diagnose moderate acute rejection after heart transplantation.

The value of pulsed-wave transmitral Doppler for the diagnosis of moderate acute rejection was examined in a total of 347 Doppler recordings obtained in 32 consecutive cardiac allograft recipients. Serial Doppler examinations (median, 11 per patient; range, 1 to 23) were performed simultaneously with endomyocardial biopsies from the first week after heart transplantation to a follow-up of 186 days (median; range, 10 to 395 days after transplantation). Pulsed-wave transmitral Doppler did not allow noninvasive diagnosis of moderate acute rejection in individual patients. Peak filling rate normalized for mitral stroke volume, early diastolic velocity, and mean diastolic velocity were significantly increased, whereas diastolic filling period was decreased during moderate acute rejection compared to other biopsy classes. The wide overlap of measurements in individual recipients with or without rejection may be due, however, to a variety of hemodynamic factors after transplantation affecting diastolic function, which are superimposed on the restrictive left ventricular filling pattern caused by persistent mild acute rejection and left ventricular hypertrophy. These hemodynamic factors include pulmonary hypertension, perioperative ischemia, reperfusion injury, and changes in both blood pressure and loading conditions caused by hypertension and its treatment. Differences between studies with regard to the detection of moderate acute rejection by transmitral Doppler may be caused by chance, because most studies were relatively small. Differences in methods, patient selection, duration of follow-up, prevalence of hypertension and left ventricular hypertrophy, and differences in antihypertensive drug regimens may also play a role. Furthermore differences in the incidence of mild acute rejection, its treatment, and the type of maintenance immunosuppressive regimen used may have influenced the outcome of these studies considerably.

Acute Disease↗

PubMedDate not supplied

Coronary artery disease after heart transplantation: timing of coronary arteriography.

The increasing numbers of long-term survivors after heart transplantation make yearly coronary arteriography, used by most centers to study the development of transplant coronary artery disease, less practical. Therefore the prevalence and clinical relevance of coronary artery disease in 119 one-year survivors of heart transplantation were studied. Visual analysis revealed two main patterns of vascular changes: abnormalities of the epicardial vessels and their major branches and abnormalities of the tertiary branches. The prevalence of all abnormalities in the coronary vascular tree increased from 34% after 1 year to 79% after 5 years. The prevalence of anatomically significant lesions (more than 50% stenosis in the epicardial branches or abrupt ending/proximal occlusion of tertiary branches) was only 11% after 5 years. During follow-up of 25 to 87 (median, 43) months, no significant coronary artery disease developed in the 101 patients who showed normal epicardial vessels or abnormal tertiary branches only at their first year angiography, and none of the patients died of ischemic heart disease. Of the 18 patients with abnormal epicardial vessels, three patients died of ischemic heart disease; one of these patients was treated with atherectomy and is alive at the moment of this report, and two patients showed progression of discrete lesions without evidence of ischemia until now. Based on these findings, a schedule for timing of arteriography was developed depending on the first-year coronary findings.

Adolescent↗

PubMedDate not supplied

Different patterns in donor-specific production of T-helper 1 and 2 cytokines by cells infiltrating the rejecting cardiac allograft.

BACKGROUND: Cytokines play an important role in allograft rejection. The local production of cytokines by T-helper 2 cells within an allograft could influence the induction of graft rejection. METHODS: Therefore we studied the in vitro production of cytokines by cells infiltrating the graft. graft-infiltrating cell cultures derived from human endomyocardial biopsy specimens more often produced interleukin-2 (p < 0.001), interferon-gamma (p < 0.001), interleukin-4 (p = 0.02), and interleukin-6 (p = 0.04) after stimulation with a B-cell line obtained from the heart donor than after stimulation with a third-party B-cell line. Furthermore, the levels of these cytokines were significantly higher after donor stimulation than after third-party stimulation (p < 0.001). RESULTS: Within the first 90 days after heart transplantation, significantly higher levels of interleukin-2 (p = 0.050 and interferon-gamma (p = 0.02) were produced by donor-stimulated lymphocyte cultures derived from biopsy specimens taken during a rejection episode compared with cultures from biopsy specimens taken during a period without rejection. After 90 days, the levels of T-helper 1 cytokine (interleukin-2 and interferon-gamma) production were, irrespective of the rejection grade, comparable with those found in the cultures from rejection biopsy specimens taken early after transplantation. With regard to T-helper 2 cytokines (interleukin-4 and interleukin-6), no relation was found with the presence of rejection at any time after transplantation. CONCLUSIONS: These data suggest that in the first 3 months after heart transplantation, acute rejection is associated with the production of increased levels of T-helper 1 cytokines but not of T-helper 1 cytokines but not of T-helper 2 cytokines by donor stimulated graft-infiltrating lymphocytes. Thereafter, the T-helper 1 cytokine production of graft-infiltrating lymphocytes remained high, suggesting a continuous state of immunologic activity even in the absence of rejection.

B-Lymphocytes↗