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Biomedical subjects

A H Balk

Publications and source records attributed to A H Balk.

At least 91 records · Page 5Linked to original sources
PubMed1995

[Consensus heart failure. Centraal Begeleidingsorgaan voor de Intercollegiale Toetsing].

Consensus heart failure--On June 17th, 1994, a consensus meeting was organised to establish guidelines for the diagnosis and treatment of heart failure. Reason to do this were controversies, especially among general practitioners, cardiologists, internists and gerontologists, which arise as a consequence of new diagnostic modalities (such as echocardiography) and altered aims of the treatment (besides relief of symptoms reduction of morbidity and mortality). A number of starting points were formulated by a preparatory committee: Heart failure constitutes a major health problem. It is defined by cardiac dysfunction with accompanying symptoms. Diagnosis and treatment should focus first on causes or contributing factors. The extent of diagnostic procedures depends on possible doubts with regard to diagnosis and aetiology and therapeutic consequences. Treatment should include non-medical measures. Apart from relief of symptoms, the choice of drugs is also determined by their potential to reduce morbidity and mortality. The pharmacotherapeutic approach has to be tailored to the needs of the patient with a central role for the ACE inhibitors. Patients with concomitant arrhythmias and (very) old patients form separate risk groups. Further attention should be paid to the prevention of heart failure.

Combined Modality Therapy↗
PubMed1995

Pharmacodynamics of prophylactic antirejection therapy with an anti interleukin-2 receptor monoclonal antibody (BT563) after heart and kidney transplantation.

A mouse monoclonal antibody (BT563) directed to the alpha-chain of the IL-2 receptor was administrated immediately after transplantation in a dose of 10 mg/day prophylactically to 30 heart transplant recipients (HTx) and 40 renal transplant recipients (RTx) to induce immunosuppression. Plasma levels increased to a plateau level of 5300 ng/ml in HTx and 5900 ng/ml in RTx. BT563 plasma disappearance curves gives a mean T1/2 of respectively 39 h (range 14-112 h) and 42 h (range 8-122 h) for HTx and RTx respectively. The CD25 marker (IL-2R) on the peripheral blood lymphocytes disappeared within hours after the first gift and returned to normal within 0-20 days after the last gift. In HTx more often CD25+ cells were found in the presence of BT563 and more rejections occurred shortly after discontinuation of BT563 compared to the RTx group. Rejectors and non-rejectors within the HTX group did not differ with respect to the period of depletion of CD25 positive cells in the peripheral blood. In 56% of the patients a substantial IgM antibody response was detected. This response was similar for HTx and RTx and not related to rejection. The frequency of IgG responses was low in both HTx (13%) and RTx (21%) patients and the IgG response was not related with graft rejection or with antirejection treatment. Peripheral monitoring showed that mAb plasma levels, antimurine antibody responses and number of CD25 positive cells were not related with the clinical results. The mAb BT563 proved to be safe with respect to the generation of antimurine antibodies and, when given in combination with CsA, is a therapy with a potential for high efficacy.

Animals↗
PubMed1995

Optimising glomerular filtration rate and effective renal plasma flow measurements using a simple pharmacokinetic model.

We applied an open one compartment pharmacokinetic model for the determination of glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) based on a rapid intravenous loading dose followed by a constant infusion of 125I-iothalamate and 131I-orthoiodohippurate in order to ensure constant plasma levels of the two clearance markers. The loading dose was based on the assumption that the volume of distribution of the two markers equals the extracellular volume (25% of the body weight). The infusion rate as calculated after the clearance of thalamate was estimated from body weight, age, sex and serum creatinine using Cockcrofts formula. The clearance of hippurate was assumed to be four times that of thalamate. We studied the reliability of this model in 212 patients with insulin dependent diabetes mellitus (IDDM; n = 74), nephrotic syndrome (NS; n = 18) and heart (HTX; n = 69) or kidney (KTX; n = 51) transplants. A steady state concentration was obtained in all patient groups, even when GFR was markedly depressed. In patients with diabetes, we observed more variance between plasma and urinary clearances of thalamate, which could be due to inaccuracies in urine sampling. In these patients, GFR should be measured using a method that is not dependent on urine collection. Also, the estimation of GFR by means of Cockcrofts equation seems to underestimate GFR in diabetic subjects.

Glomerular Filtration Rate↗
PubMed1994

Differential avidity and cyclosporine sensitivity of committed donor-specific graft-infiltrating cytotoxic T cells and their precursors. Relevance for clinical cardiac graft rejection.

We have used limiting dilution analysis to study the qualitative and quantitative differences between graft-infiltrating cytotoxic T cell populations propagated from endomyocardial biopsies of heart transplant patients who experienced one or more acute rejection episodes and patients who never showed signs of rejection. Limiting dilution cultures were stimulated with autologous or donor cells both in the absence or in presence of cyclosporine and of CD8 in the cytotoxic phase. Almost all antigen-primed, committed cytotoxic T cells (cCTL) present in the graft of patients with rejections were CsA resistant. In contrast, in most patients of the nonrejector group, a substantial part of the cCTL could be inhibited by CsA. The CTL precursors (pCTL) in both groups were predominantly CsA sensitive. Addition of CD8 mAb during the cytotoxicity phase of the limiting dilution analysis was used to differentiate between CTL populations with high avidity for donor antigens and populations with low avidity. The predominant subpopulation in the graft of rejectors was a CsA-resistant cCTL with high avidity, while in the graft of most nonrejectors, cCTL with low avidity dominated. In most rejectors, CD8 mAb had only a minor influence on the pCTL frequency estimates, and thus on T cells with high avidity. CsA-sensitive pCTL with high avidity might represent an intermediate stage between the naive pCTL and mature, functional, CsA-insensitive cCTL with high avidity for donor antigens.

Antibodies, Monoclonal↗
PubMed1994

Cytomegalovirus infection and allospecific cytotoxic activity of graft-infiltrating cells after heart transplantation.

We have investigated whether cytomegalovirus (CMV) infection has an effect on donor directed cytotoxicity of graft-infiltrating cells in human heart transplants. Our study group consisted of 89 heart transplant recipients. Thirty-eight (43%) showed signs of CMV infection; in 28 of them, cytolytic activity of biopsy derived cultures could be tested during the infection. Eight patients had a primary and 20 a secondary infection. We found that during CMV infection, both primary and secondary, a significantly higher proportion of the biopsy-derived cultures showed cytotoxicity against donor HLA antigens (chi 2 test; P < 0.01 in comparison with 51 patients without infection). This was most evident in patients with both infection and acute rejection episodes when compared to patients with only one of these complications. This suggests that one process amplifies the other with regard to the up-regulation of alloreactivity within the transplanted heart. In secondary infections, only an increase of donor class I-directed cytotoxicity was found, while in primary infections cytotoxicity against donor class I and II antigens was increased (P < 0.005 vs. secondary infection).

Adolescent↗
PubMed1994

Characteristics of graft-infiltrating lymphocytes after human heart transplantation. HLA mismatches and the cellular immune response within the transplanted heart.

The influence of HLA mismatches between donor and recipient on the phenotypes, function, and specificity of T-lymphocyte cultures derived from endomyocardial biopsies was studied in 118 heart transplant recipients. In case of HLA-DR mismatches, the majority of the EMB-derived cultures were dominated by CD4+ T cells while, in patients with HLA-A and -B mismatches but without DR mismatches, CD8+ T cells comprised the predominant T-cell subset. Cytotoxicity against donor antigens was observed in 75% of the cultures. A significantly (p < 0.005) lower proportion of the cultures showed cytotoxicity against HLA-A antigens (36%) when compared with HLA-B (53%) or HLA-DR (49%). An HLA-A2 mismatch elicited a cytotoxic response that was comparable to that found against HLA-B and -DR antigens: 62% of the cultures from HLA-A2 mismatched donor-recipient combinations was reactive against A2. A higher number of A, B, or DR mismatches resulted in a higher number of cytotoxic cultures directed against these antigens. A higher number of HLA-B and -DR mismatches was associated with a lower freedom from rejection. Our data indicate that, despite the use of adequate immunosuppressive therapy, the degree of HLA matching plays a crucial role in the immune response against a transplanted heart, resulting in a significant effect on freedom from rejection.

Acute Disease↗
PubMed1994

Prophylactic therapy with OKT3 does not affect donor specific reactivity of peripheral blood lymphocytes from heart transplant recipients.

To avoid the nephrotoxic effect of high-dose cyclosporin A (CsA) immediately posttransplant, heart transplant recipients received as prophylactic therapy intravenous OKT3 for seven days instead of intravenous CsA. Patients receiving OKT3 were compared with patients receiving CsA with respect to specific proliferation and cytotoxicity of their peripheral blood mononuclear cells (PMNC) against donor antigens, at different times within three months post-transplant. No effect of the initial immunosuppressive therapy was observed on these parameters. Acute rejection did not induce a consistent effect on the relative proliferation. PMNC from patients who experienced one or more rejection episodes showed a decrease in donor specific relative proliferative response in time after transplantation, while nonrejectors did not or only slightly, independent of the initial immunosuppressive protocol. Within the group of patients not receiving OKT3, this effect of rejection reached significance. In conclusion, no effect of prophylactic OKT3 therapy compared with prophylactic CsA therapy was observed on donor reactivity of PMNC in vitro during the subsequent three to four months post-transplant.

Blood Transfusion↗
PubMed1994

Fatal hepatitis C virus infection in a heart transplant recipient detectable by polymerase chain reaction only.

Rapidly progressive and ultimately fatal liver failure with evolution to cirrhosis developed in a heart transplant recipient following infection by hepatitis C virus. Antiviral antibodies and the presence of viral RNA were analyzed throughout the course of the disease. After a weak initial response to a single viral epitope (c22-3), serology became negative, the infection remaining detectable by polymerase chain reaction only. This case demonstrates the potentially severe consequences of hepatitis C virus infection under immunosuppression. The incidence of this infection may be underestimated, as the presented case apparently would not have been detected if serology had been used for diagnosis.

Base Sequence↗
PubMed1994

Cytokine mRNA expression in endomyocardial biopsies during acute rejection from human heart transplants.

The immune response to an allograft is regulated by cytokines produced by cells infiltrating the allograft. However, the immunopathogenesis of allograft rejection is not completely understood. To investigate the role of cytokines after clinical heart transplantation, we analysed the expression of cytokine genes in sequentially taken endomyocardial biopsies (EMB) by using the reverse transcriptase-polymerase chain reaction (RT-PCR). We analysed 44 EMB from 11 recipients: 21 EMB before or during rejection, and 23 EMB without histological evidence of acute rejection. A strong correlation was found between IL-2 gene expression and histologically proved rejection (16/21 versus 1/23 without rejection, P < 0.001; chi 2 test). Also, expression of IL-4 and IL-6 genes was more often found in EMB during rejection than in EMB without signs of rejection (IL-4, 62% versus 35%; and IL-6, 81% versus 39%, respectively). No relation with rejection or with immunological quiescence was observed for the presence of IL-10 gene transcripts. IL-10, but also IL-6 mRNA were detectable in donor heart tissue before transplantation (9/10). In contrast, IL-2 and IL-4 gene transcripts were absent in these samples. These differences could not be explained by the presence or absence of T cells, since the gene for the constant region of the beta-chain (C beta) of the T cell receptor (TCR) not only was expressed in post-transplant EMB but also in pre-transplant donor heart tissue. Our results provide strong evidence that the immunoregulatory cytokines IL-2, IL-4 and IL-6 are important local regulators in the graft during acute rejection. The role of IL-10 in the immunologic response to the transplanted organ needs further investigation.

Base Sequence↗
PubMed1994

The development of transplant coronary artery disease after cardiac transplantation is correlated with a predominance of CD8+ T lymphocytes in endomyocardial biopsy derived T cell cultures.

Long-term survival of heart transplant recipients is limited by the development of transplant coronary artery disease (TCAD). We analysed whether the development of TCAD is correlated with the incidence of acute rejection episodes, with the formation of anti-HLA antibodies or with the composition and function of T lymphocyte cultures derived from endomyocardial biopsies. TCAD was assessed by visual analysis of annually performed coronary angiograms and defined as the presence of all vascular changes, including minor wall irregularities. One year after transplantation, 31 of the 77 patients studied had TCAD (40%). The median age and mean number of HLA mismatches in patients with or without TCAD were highly comparable. The patient groups did not differ in incidence of acute rejection episodes, nor in percentage of endomyocardial biopsies yielding T cell cultures. At 1 year after transplantation, lymphocyte cultures from 18/31 TCAD+ patients (58%) and 27/46 TCAD- patients (57%) were analysed. The TCAD+ patients had, compared with the TCAD- patients, a higher median percentage of CD8+ T cells (71% versus 25%, P = 0.06) and a lower median percentage of CD4+ T cells (4% versus 40%, P = 0.04). Similar differences were found in a longitudinal analysis of the culture results of endomyocardial biopsies (EMBs) obtained during the first year. The cytotoxic reactivity of the cultures against donor HLA class I or class II antigens was comparable in the two groups, although a difference in recognition of heart specific antigens remains possible. The fact that EMB-derived cultures from TCAD+ and TCAD- patients differed in T cell phenotype populations gives some support to the hypothesis that cellular immunological processes are involved in the development of TCAD. However, while the median values differed, the overlap of the percentages of CD8+ cells in cultures from TCAD- and TCAD+ patients shows that other factors besides CD8+ T cells also play a role.

Adolescent↗
PubMed1994

In vitro and in vivo effects of BT 563, an anti-interleukin-2 receptor monoclonal antibody.

BT 563, a murine anti-IL-2R MoAb, was found to be more potent than anti-Tac in inhibiting proliferation in the mixed lymphocyte reaction. Results obtained with 33B3.1 in these experiments were similar to those with BT 563. The anti-IL-2R MoAb 2A3 was shown to be a suitable agent for monitoring the effect of BT 563 on peripheral blood. IL-2R-positive cells were not detected in peripheral blood samples from 1 h after the first dose until 8 days after the last dose. Plasma trough levels were measured in patients receiving 5 or 10 mg daily. The administration of BT 563 to allograft recipients did not lead to clinically significant side effects.

Antibodies, Monoclonal↗
PubMed1994

Discrepancy between mRNA expression and production of IL-2 and IL-4 by cultured graft infiltrating cells propagated from endomyocardial biopsies.

We studied whether acute rejection correlated with the cytokine production pattern and mRNA expression of interleukin-2 (IL-2) and interleukin-4 (IL-4) in lymphocyte cultures derived from endomyocardial biopsies (EMB) that were stimulated with B cell lines of donor origin. Unstimulated biopsy cultures neither expressed mRNA nor produced IL-2 or IL-4. All stimulated biopsy cultures contained mRNA transcripts for IL-2 and IL-4. In contrast, we found different IL-2 and IL-4 production patterns. Within the first 90 days after heart transplantation (HTx), higher levels of IL-4 were measured in cultures derived from EMB with myocytolysis than in cultures from EMB without signs of myocytolysis. More than 90 days after HTx, this phenomenon was reversed and more IL-4 was produced in cultures derived from EMB without myocytolysis. These differences were not detected for IL-2 production.

Biopsy↗
PubMed1994

Time course of the decline in renal function in cyclosporine-treated heart transplant recipients.

The renal side-effects are a major limitation of the use of cyclosporine A (CsA) following heart transplantation. In an effort to define the time course of the decline in renal function and to identify a group of patients especially prone to the nephrotoxic effects of CsA, we studied 187 orthotopic heart transplant recipients who had a follow-up of at least 1 month. All patients received oral CsA in a starting dose of 8 mg/kg and low-dose steroids. Renal function decreased steadily after transplantation. Serum creatinine was > 150 mumol/l in 52% of the patients after 2 years. After 4 years serum creatinine was > 250 mumol/l in 13% of the patients. No relation could be found between the decline in renal function (as defined by the slope of serum creatinine-1 versus time) and age, sex, creatinine levels before transplantation, blood pressure, CsA blood levels, the number of rejections or the use of calcium channel blocking drugs. We conclude that, despite reduction of CsA dosage, progressive renal insufficiency can be observed in an increasing percentage of heart transplant recipients. We were not able to identify patients with a poor renal prognosis in an early phase after transplantation.

Adult↗
PubMed1994

Abnormal diurnal variation of blood pressure, cardiac output, and vascular resistance in cardiac transplant recipients.

BACKGROUND: An attenuated or absent nocturnal decline in blood pressure has repeatedly been documented in cardiac transplant recipients. The present study was aimed at investigating the hemodynamic mechanism underlying this abnormality. METHODS AND RESULTS: In 23 cardiac transplant recipients (11 to 36 months after transplantation) and in 23 control subjects matched for age and 24-hour mean arterial pressure, invasive 24-hour ambulatory blood pressure was measured by means of the Oxford technique. Beat-to-beat relative values of stroke volume were determined by means of a pulse-contour method, and relative changes of cardiac output (stroke volume x heart rate) and total peripheral vascular resistance (blood pressure/cardiac output) over the 24-hour period were calculated. The nocturnal decline in blood pressure was 20 +/- 8% (mean +/- SD) in control subjects but only 5 +/- 9% (P < .001) in cardiac transplant recipients. In control subjects, the nocturnal decline in blood pressure was associated with a nocturnal fall in cardiac output of 24 +/- 13%, whereas vascular resistance compared with daytime value did not change. The small nocturnal decline in blood pressure in cardiac transplant recipients was associated with an attenuated nocturnal fall in cardiac output of 14 +/- 12% (P < .05 versus control subjects). In addition, vascular resistance compared with daytime value was increased by 9 +/- 9% (P < .05) during the night. Both in cardiac transplant recipients and in control subjects, the nocturnal changes in blood pressure were correlated with the nocturnal changes in cardiac output but not with the nocturnal changes in total peripheral vascular resistance. CONCLUSIONS: This study confirms the attenuated nocturnal fall in blood pressure in cardiac transplant recipients. Hemodynamically, this attenuated blood pressure decline is characterized by a reduced nocturnal fall in cardiac output, and it is associated with a nocturnal increase in vascular resistance.

Adolescent↗