Long-term outcomes of CMV disease treatment with valganciclovir versus IV ganciclovir in solid organ transplant recipients.

Though an important cause of morbidity and mortality in solid organ transplantation (SOT), the long-term outcomes of cytomegalovirus (CMV) disease treatment have not been well studied. In a randomized trial, 321 SOT recipients with CMV disease were followed 1 year after treatment with either twice daily intravenous ganciclovir or oral valganciclovir (for 21 days) followed by once daily valganciclovir until day 49 in all patients. Clinical and viral eradication of CMV disease was similar between groups. Clinical recurrence beyond day 49 was found in 15.1% and virological recurrence in 30.0%, no difference between groups (p > 0.77). In a multivariable logistic regression analysis, the only independent predictor for recurrence was failure to eradicate DNAemia by day 21 (clinical: OR 3.9 [1.3-11.3], p = 0.012; virological: OR 5.6 [2.5-12.6], p < 0.0001). Eight patients developed ganciclovir resistance, with no difference between groups (p = 0.62). Twenty patients (valganciclovir: 11, ganciclovir: 9, p = 0.82) died, 12 due to infections, two involving CMV disease. There were no differences in long-term outcomes between treatment arms, further supporting the use of oral valganciclovir for treatment of CMV disease. Persistent DNAemia at day 21, CMV IgG serostatus and development of resistance may be relevant factors for further individualization of treatment.

Should Children Be Given Priority in Kidney Allocation?

Kidneys for transplantation are scarce, and many countries give priority to children in allocating them. This paper explains and criticizes the paediatric priority. We set out the relevant ethical principles of allocation, such as utility and severity, and the relevant facts to do with such matters as sensitization and child development. We argue that the facts and principles do not support and sometimes conflict with the priority given to children. We next consider various views on how age or the status of children should affect allocation. Again, these views do not support priority to children in its current form. Since distinctions based on age ought to be positively justified, the failure of all these attempts at justification implies that the priority to children is ethically mistaken. Finally, the paper points to evidence that the paediatric priority reduces the overall supply of kidneys, at least in the United States. Paediatric priority is a real-world policy that seems discriminatory, in some places probably reduces the supply of organs, has no robust official defence, and is unsupported by mainstream ethical principles. Consequently, it should be ended.

Tacrolimus for the treatment of gout in renal transplantation: two case reports and review of the literature.

Episodes of gout are common in the setting of renal transplantation. Hyperuricemia and gout have been associated with the use of the calcineurin inhibitor, cyclosporine. We report two cases of severe polyarticular gout resistant to conventional therapy in renal transplant recipients that resolved after switching from cyclosporine to tacrolimus-based immunosuppression. There was no alteration in renal function, and trough concentrations of both cyclosporine and tacrolimus were within the recommended range. Resolution of gout occurred within a month of discontinuation of cyclosporine and commencement of tacrolimus. Use of tacrolimus may be beneficial in the renal transplant recipient with refractory gout.

Modified cytotoxic T lymphocyte precursor frequency assay by measuring released europium in a time resolved fluorometer.

The frequency of cytotoxic T lymphocyte precursors (CTLpf) can be quantified by using the principle of limiting dilution analysis (LDA). Chromium 51 (51Cr) and europium (Eu) release assays are based on the measurement of marker release after lysis of targets by the effector cells. Although, 51Cr release has been widely used to quantify cell lysis since its introduction, it has several disadvantages such as handling and disposal of radioisotopes as well as health risk to personnel involved performing the assay. This situation has led us to adopt a non-radioactive cytotoxicity assay. After 7 days culture the PHA-stimulated targets are labeled with europium DTPA chelate. Lysis of labeled targets by effectors releases the Eu-DTPA complex in culture medium--a highly fluorescent substance. The amount of fluorescence can be measured in a time resolved fluorometer. We describe here some modifications of the original protocol which include optimising IL-2 requirements, reduction of incubation times, addition of an extra spin before 37 degrees C incubation, readjustment of target cells per volume of labeling buffer and other crucial parameters increasing the specificity and sensitivity of CTLpf assay. We are in agreement with others that the Eu-release assay is specific and reproducible. It can be used for the CTLpf estimation as well as other T cell and non-T cell cytotoxicity assays.

A prospective study of central venous hemodialysis catheter colonization and peripheral bacteremia.

BACKGROUND: Sepsis as a consequence of central venous hemodialysis catheter colonization is a major cause of morbidity in the hemodialysis population. We have previously shown that the majority of catheters become colonized and that this is associated with peripheral bacteremia. The time period over which this colonization occurs is unknown. METHOD: A prospective study of 31 central venous hemodialysis catheters was performed. Central venous blood cultures were taken from the catheter weekly after insertion. When the central cultures became positive, indicating catheter colonization, peripheral venous blood cultures were taken during dialysis to detect peripheral bacteremia. RESULTS: Twenty-one catheters (68%) became colonized before their removal for reasons other than infection (mean time to colonization 27 days, range 5-115 days). Eleven patients (35%) developed peripheral bacteremia with the same organisms (mean time from colonization to bacteremia 32 days, range 5-26 days). Bacteremia only occurred when blood drawn from the catheter cultured more than 3000 colony forming units per ml. CONCLUSIONS: Bacterial colonization of central venous catheters often leads to bacteremia. The time between insertion and colonization is very variable, but is universally present after 16 weeks. The risk of subsequent bacteremia is related not only to time left in situ, but also the degree of colonization. Surveillance cultures would allow clinicians to detect colonization before bacteremia occurs and take preventative measures.

Non-insulin-dependent diabetes mellitus in New Zealand Maori: a relationship with Class I but not Class II histocompatibility locus antigens.

AIMS: To investigate the possibility of a relationship between the major histocompatibility complex (MHC) and non-insulin-dependent diabetes mellitus (NIDDM) in Maori. Such relationships have previously been shown in non-European races with a high incidence of NIDDM. METHODS: We performed serological Class I and PCR-SSP Class II HLA typing on 44 Maori with NIDDM and renal failure and compared the results with normal Maori. RESULTS: A strong relationship with the HLA-B40 groups of antigens (relative risk 5.1 chi 2 = 16.8, p < 0.001) was found; this was mainly attributable to HLA-B48 and HLA-B60. There was no HLA Class II relationship. CONCLUSION: The relationship with HLA-B40 antigens suggests that the MHC or other genes on chromosome 6 play a role in NIDDM in Maori.

A critique of a New Zealand health care service by parents of handicapped preschool children.

Parents of intellectually and physically handicapped preschool children were asked to nominate helpful and unhelpful elements in the care of their child. Their subjective responses are described. A large proportion were critical of medical services. Doctors seen as helpful recognised and verbally acknowledged the parental contribution to the child's welfare.

Frequencies of cytotoxic T lymphocyte precursor estimate in three different populations.

There is speculation that high cytotoxic T lymphocyte precursor frequencies (CTLpf) correlate with poor clinical outcome of bone marrow/organ transplantation. It is also believed that human umbilical cord blood is immunologically naive, and, therefore cord blood T cells may be less able to mediate graft versus host disease than marrow-derived T cells. CTLpf were determined in peripheral blood mononuclear cells collected from healthy adults, human umbilical cord blood and renal dialysis patients who were randomly selected and entered into this study. A highly sensitive non-radioactive Europium release cytotoxicity assay was optimized and modified to carry out the CTLpf estimation by using the principle of limiting dilution analysis. The results of CTLpf in healthy adults ranged from 1/694 to 1/66,666, median 1/7,339 (n=10); cord blood ranged from 1/1,562 to 1/35,714, median 1/10,162 (n=6) and dialysis patients ranged from 1/1,054 to 1/17,857 median 1/5,208 (n=9). The results demonstrated that there is little difference of CTLpf median values between the groups, but there is a wide variation of CTLpf between individuals within a population. It suggests that this variation should be taken into account when considering CTLpf assay as pre-transplantation cross-match procedure.

Validation of the Banff criteria for acute rejection in renal transplant biopsies.

BACKGROUND: The histological criteria for the diagnosis of mild acute rejection in renal transplant biopsies have not been well defined. AIM: To ascertain the value of the Banff criteria for transplant biopsy reporting, particularly for the diagnosis of acute rejection, and the 'borderline' category. METHODS: We compared two systems of histological assessment in 23 transplant biopsy specimens and compared histological diagnoses to separately defined clinical diagnoses. The histological criteria applied were those of the recently described Banff criteria which were compared with our traditional diagnostic method for each specimen. RESULTS: We found the Banff diagnoses more closely related to the clinical outcome than the system of histological diagnosis that we had previously been using. CONCLUSIONS: We conclude that the Banff criteria more accurately reflect the clinical situation.

High bicarbonate dialysate in haemodialysis patients: effects on acidosis and nutritional status.

BACKGROUND: Metabolic acidosis adversely affects both protein and bone metabolism in patients with chronic renal failure, and could also affect morbidity and mortality. This trial aimed to investigate the effects of different dialysate bicarbonate concentrations on control of acid base balance, and nutritional status. METHODS: Forty-six stable haemodialysis patients were dialysed using LowBic. (30 mmol/l) or HighBic. (40 mmol/l) bicarbonate dialysate in a single blind double crossover trial, of two consecutive six-month periods. Blood gas analysis, anthropometric indices and dialysis dose were measured, in addition to biochemical indices. RESULTS: Predialysis 'arterial' plasma pH values were significantly higher when using the HighBic. dialysate (LowBic. 7.38 +/- 0.05, HighBic. 7.43 +/- 0.04, P < 0.001), as was predialysis serum total CO2 at all times during the study (P < 0.01). Kt/V, (LowBic. 1.27 +/- 0.19, HighBic. 1.27 +/- 0.25), urea generation rates (UGR) (LowBic. 1.99 +/- 0.77, HighBic. 1.92 +/- 0.77 mmol/min), and normalized protein catabolic rate (NPCR) (LowBic. 1.04 +/- 0.26, HighBic. 0.99 +/- 0.28 g/kg/day) did not differ, and values of parathroid hormone (PTH) were comparable. Triceps skinfold thickness (TSF) showed a significant change (LowBic. 14.8 +/- 6.9-11.8 +/- 5.5, HighBic. 14.9 +/- 6.3-15.8 +/- 6.4 mm, P < 0.05) which was reversed following dialysate change (HighBic. 11.8 +/- 5.5-13.3 +/- 7.2, LowBic. 15.8 +/- 6.4-13.8 +/- 6.7 mm, P < 0.05). No differences in mid upper arm circumference were found. CONCLUSIONS: Bicarbonate dialysate concentrations of 40 mmol/l were safe, well tolerated, and produced better control of acidosis, with an increase in TSF, compared to a bicarbonate concentration of 30 mmol/l.

Quantitation of cyclosporine-sensitive and -resistant allospecific cytotoxic cells at birth.

In the absence of clinically relevant models of acute rejection we have attempted to develop an assay to measure cyclosporine-resistant allospecific cytotoxic cells in vitro, beginning at birth. The principle of limiting dilution analysis was applied to investigate umbilical cord bloods as responders. Responders were incubated for 1 h in different concentrations of cyclosporine and irradiated HLA mismatched stimulator cells from healthy adults added, followed by recombinant IL-2. After 7 days, responders were tested against three europium-labelled PHA blasts: stimulator, responder and third party. A significant number of cyclosporine-resistant allospecific cytotoxic cell precursors were found in cord blood indicating prior activation. They may have been primed in utero against non-inherited maternal HLA antigens. Cyclosporine-resistant allospecific cytotoxic cell precursors were demonstrated in human umbilical cord blood using a quantitative assay. These cells may influence the reaction to subsequent transplants.

Impact of a handicapped child on mental health of parents.

In a cross sectional study the mental health of parents of physically and mentally handicapped preschool children was compared with that of parents of healthy preschool children. The social networks of the parents with handicapped children were also studied to determine factors that might influence psychiatric morbidity. The mothers of the handicapped children showed significantly more psychiatric morbidity than the control mothers, but the fathers did not show the same deleterious effect on mental health.