Interferons, properties and applications

The main theme of this thesis is the clinical evaluation of interferon. From the biology of the interferon system and animal experiments it can be expected that exogenous interferon will exert its optimum effect when used to prevent acute infections or to modulate chronic infections. Therefore, we administered interferon to patients with chronic hepatitis B virus infection (chapter 5) and to renal transplant recipients, in whom viral infections occur frequently in the first months after transplantation (chapter 6). The other studies in this thesis are directly related to the problems we met in the clinical studies. We wanted to study interferon in an animal renal transplantation model. For us the most obvious choice was the rat. However, little was known about the production and characterization of rat interferon. Chapter 2 describes our experiences with rat interferon. While we were well underway with the study in renal transplant recipients, we were contacted by Martin Hirsch, who was conducting a similar trial in Boston. Some of his patients receiving 3 x 106 U HLI every other day showed severe bone marrow depression. We had no such problem in our trial, but we used another type of interferon: HFI. For this reason we started a study on the t'oxicity of interferons for bone marrow in vitro

Culture of graft-infiltrating cells from cryopreserved endomyocardial biopsies

Graft-infiltrating cells can be cultured from fresh endomyocardial biopsies (EMB) taken after heart transplantation to determine their growth patterns, phenotypic composition, and functional characteristics for clinical or scientific purposes. In this study we investigated whether graft-infiltrating cells can also be cultured successfully after cryopreservation of these EMB. Three different cryopreservation methods were used. One method gave successful growth in 100% of the cases (n = 6): The biopsy fragments were preincubated in 10% vol/vol dimethyl sulfoxide during 5 min at O°C, frozen to -70°C at approximately 1°C per minute, and subsequently immersed and stored in liquid nitrogen. Thawing was performed rapidly in water at 37°C. In addition, the effect of cryopreservation on cell surface phenotype and donor-specific cytotoxicity of these graft-infiltrating cells was analyzed. When compared to cultures of nonfrozen control biopsies, both qualities remained constant in most cases, although a variation in CD4+/CD8+ cell ratio was observed in 33% of these cultures. However, when nonfrozen fragments of size-matched biopsies were cultured separately, a similar variation in phenotype was noted, indicating that this phenomenon can be attributed to sampling variation and not to the cryopreservation procedure. The present findings suggest that it is no longer required to culture fresh (nonfrozen) post-transplant EMB to propagate graft-infiltrating cells: Culturing can be limited to cryopreserved EMB that are selected retrospectively, depending on actual clinical or scientific interests. Besides greatly facilitating the long-term monitoring of heart transplant recipients, this also means a substantial decrease in cost and work load for laboratories involved in heart transplantation

Living Donor Kidney Transplantation Should Be Promoted among "elderly" Patients

Background. Age criteria for kidney transplantation have been liberalized over the years resulting in more waitlisted elderly patients. What are the prospects of elderly patients on the waiting list? Methods. Between 2000 and 2013, 2622 patients had been waitlisted. Waiting time was defined as the period between dialysis onset and being delisted. Patients were categorized according to age upon listing: 64 years. Furthermore, the influence of ABO blood type and panel reactive antibodies on outflow patterns was studied. Results. At the end of observation (November 2017), 1957 (75%) patients had been transplanted, 333 (13%) had been delisted without a transplantation, 271 (10%) had died, and 61 (2%) were still waiting. When comparing the age categories, outflow patterns were completely different. The percentage of patients transplanted decreased with increasing age, while the percentage of patients that had been delisted or had died increased with increasing age, especially in the population without living donor. Within 6 years, 93% of the population 55 years, 39% received a living donor kidney, while >50% of patients without a living donor had been delisted/died. Multivariable analysis showed that the influence of age, ABO blood type, and panel reactive antibodies on outflow patterns was significant, but the magnitude of the influence of the latter 2 was only modest compared with that of age. Conclusions. "Elderly" (not only >64 y but even 55-64 y) received a living donor kidney transplantation less often. Moreover, they cannot bear the waiting time for a deceased donor kidney, resulting in delisting without a transplant in more than half the population of patients without a living donor. Promoting living donor kidney transplantation is the only modification that improves transplantation and decreases delisting/death on the waiting list in this population

Trivalent influenza vaccine in patients on haemodialysis: impaired seroresponse with differences for A-H3N2 and A-H1N1 vaccine components

One hundred and one patients on haemodialysis, 21 patients on peritoneal dialysis and 30 healthy controls received a trivalent split vaccine containing 15 micrograms haemagglutinin of a recent influenza A-H3N2, influenza A-H1N1 and influenza B strain, respectively. Antibody production after four weeks was determined by the haemagglutination-inhibition test and expressed as response rate, protection rate and overall mean fold increase. The patients on haemodialysis revealed a diminished seroresponse, as compared to patients on peritoneal dialysis and controls. For influenza A-H3N2, this was less distinct than for the other two antigens. In patients on haemodialysis the protection rate was 66% against the A-H3N2 vaccine component (versus 85% in controls, not significant), but only 25% against A-H1N1 and 27% against B (versus 84 and 77% in controls, p less than 0.001). Duration of haemodialysis up to eight years did not affect seroresponse. Patients on haemodialysis who were primed for influenza A-H1N1 in the period 1947-1957, reacted markedly better to the A-H1N1 vaccine component than subjects of other priming periods. A booster injection of the same vaccine dosage four weeks after the first immunization, performed in 98 patients on haemodialysis, was of little value: it had virtually no effect with regard to influenza A-H1N1 and influenza B, and showed, though significantly better, still poor results for A-H3N2. The differences in seroresponse between the A-H3N2 and A-H1N1 vaccine component suggest a major defect of primary, and a minor defect of secondary humoral response in patients on haemodialysis. The consequences for vaccine policy in these patients are discussed

Living kidney donation among ethnic minorities: A Dutch qualitative study on attitudes, communication, knowledge and needs of kidney patients

Background: Terminal kidney patients are faced with lower quality of life during dialysis treatment, restricted diets and high morbidity and mortality rates while waiting for a deceased donor kidney transplantation. Fortunately, living donor kidney transplantation offers an alternative with considerable advantages in terms of waiting time and graft survival rates. Nevertheless, we observed an inequality in the proportion of living kidney transplantations performed between the non-European patients and the European patients in our centre. To date little is known about the factors contributing towards this racial disparity. Previous research from our centre did not find any medical reasons to explain this racial disparity. We believe that non-medical psychosocial and cultural factors predominantly account for this discrepancy. Purpose Focus group discussions and in-depth interviews were conducted in order to gain insight in the attitudes, (non-)communication and knowledge of our non-European patients (compared to European patients) regarding living donor kidney transplantation (LDKT). Additionally, we investigated their attitudes towards professional support in finding an eligible living donor. Methods: The interviews were held in line with the focus group method and analyzed according to the grounded theory. The interviews were focused on six main topics (kidney transplantation, living kidney donation, communication, information, knowledge and intervention needs). European patients were included as a comparison group. The qualitative data analyses were performed in Atlas.ti. Results:We found nearly all our patient to be in favour of a living kidney transplantation (96%). However multiple prohibiting intertwined factors play a role when actually considering a living donor. We found four major barriers to the living donor transplantation process in our non-European patients: 1) not (so easily) comprehensible non-patient-centered information 2) cognitions and emotions (based on fears, concerns and misconceptions) 3) a state of basically non-communication with the potential donor(s) on this issue (as a consequence of personal and cultural beliefs) 4) and social influences. We also found some similar factors playing a role in the donation course of our European patients without a living donor. Finally, our patients held a welcoming attitude towards an intervention aimed at assisting them getting though the living donation program. Discussion: This study has identified several modifiable determinants underlying racial disparity in our living donor kidney transplantation program and investigated patients’ attitude towards two interventions aimed at alleviating this inequality. We realize that our list of barriers may not be thorough enough and surely more is to be said on this topic, the findings offer possible targets for intervention. In accordance with our patients’ preference, we argue that a home-based educatio

Independent risk factors for urological complications after deceased donor kidney transplantation

Urological complications after kidney transplantation are mostly related to the ureteroneocystostomy, often requiring interventions with additional costs, morbidity and mortality. Our aim was to assess risk factors for urological complications in deceased donor kidney transplantation. Between January 2000 and December 2011, 566 kidney transplantations were performed with deceased donor kidneys. Recipients were divided in a group with, and a group without urological complications, defined as the need for a percutaneous nephrostomy catheter or surgical revision of the ureteroneocystostomy. Univariate and multivariate analyses were performed. Univariate analysis showed increased number of male donors (p = 0.041), male recipients (p = 0.002), pre-emptively transplanted recipients (p = 0.007), and arterial reconstructions (p = 0.004) in the group with urological complications. Less urological complications occurred in recipients on hemodialysis (p = 0.005). More overall surgical interventions (p<0.001), surgical site infections (p = 0.042), urinary tract infections (p<0.001) and lymphoceles (p<0.001) occurred in the group with urological complications. Multivariate analysis showed that male recipients (p = 0.010) and arterial reconstructions (p = 0.019) were independent risk factors. No difference was found between both groups in patient or graft survival. In conclusion, recipient male gender and arterial reconstruction are independent risk factors for urological complications after deceased donor kidney transplantation. Nevertheless, graft and recipient survival is not different between both groups

Living renal donors: optimizing the imaging strategy--decision- and cost-effectiveness analysis

PURPOSE: To determine the most cost-effective strategy for preoperative imaging performed in potential living renal donors. MATERIALS AND METHODS: In a decision-analytic model, the societal cost-effectiveness of digital subtraction angiography (DSA), gadolinium-enhanced magnetic resonance (MR) angiography, contrast material-enhanced spiral computed tomographic (CT) angiography, and combinations of these imaging techniques was evaluated. Outcome measures included lifetime cost, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. A base-case analysis was performed with a 40-year-old female donor and a 40-year-old female recipient. RESULTS: For the donor, MR angiography (24.05 QALYs and 9,000 dollars) dominated all strategies except for MR angiography with CT angiography, which had an incremental ratio of 245,000 dollars per QALY. For the recipient, DSA and DSA with MR angiography yielded similar results (10.46 QALYs and 179,000 dollars) and dominated all other strategies. When results for donor and recipient were combined, DSA dominated all other strategies (34.51 QALYs and 188,000 dollars). If DSA was associated with a 99% specificity or less for detection of renal disease, MR angiography with CT angiography was superior (34.47 QALYs and 190,000 dollars). CONCLUSION: For preoperative imaging in a potential renal donor, DSA is the most cost-effective strategy if it has a specificity greater than 99% for detection of renal disease; otherwise, MR angiography with CT angiography is the most cost-effective strategy