Diss. (sammanfattning) Uppsala : Univ., 2003. / Härtill 5 uppsatser.

Background: We evaluated the concept of whether liver failure patients with a superimposed kidney injury receiving a simultaneous liver and kidney transplant (SLKT) have similar outcomes compared to patients with liver failure without a kidney injury receiving a liver transplantation (LT) alone. Methods: Using data from the United Network of Organ Sharing (UNOS) database, patients were divided into five groups based on pre-transplant model for end-stage liver disease (MELD) scores and categorized as not having (serum creatinine (sCr) <= 1.5 mg/dL) or having (sCr > 1.5 mg/dL) renal dysfunction. Of 30,958 patients undergoing LT, 14,679 (47.5%) had renal dysfunction, and of those, 5,084 (16.4%) had dialysis. Results: Survival in those (liver failure with renal dysfunction) receiving SLKT was significantly worse (P < 0.001) as compared to those with sCr < 1.5 mg/dL (liver failure only). The highest mortality rate observed was 21% in the 36+ MELD group with renal dysfunction with or without SLKT. In high MELD recipients (MELD > 30) with renal dysfunction, presence of renal dysfunction affects the outcome and SLKT does not improve survival. In low MELD recipients (16 - 20), presence of renal dysfunction at the time of transplantation does affect post-transplant survival, but survival is improved with SLKT. Conclusions: SLKT improved 1-year survival only in low MELD (16 - 20) recipients but not in other groups. Performance of SLKT should be limited to patients where a benefit in survival and post-transplant outcomes can be demonstrated.

Gadolinium (Gd) is commonly used in contrast agents (GBCAs) to improve magnetic resonance imaging. GBCAs improve tumor imaging and were thought to be stable and clear from the body through excretion after administration. However, they have been found to dissociate and remain in organs such as the liver and kidneys. In these studies, a non-invasive Cd-109 based K x-ray fluorescence (K-XRF) “Clover-Leaf” detection system to study liver and kidney Gd levels was investigated to improve the minimum detection limit (MDL). Two Cd-109 sources, one with a relatively low activity of 0.78 GBq and a second high activity source of 5 GBq irradiated a human torso water phantom containing liver and kidney phantoms with Gd concentrations ranging from 0-100 ppm. The MDL was calculated from two different time measurements 5 hours (weak source) and 30 minutes (strong source). In addition, liver and kidney phantom measurements with overlaying tissue thicknesses from 6-26 mm were investigated. At present, the K-XRF detection system is able to detect the Gd in each phantom with both sources. The MDL for the liver and kidney with the weaker source is 2.95 ppm and 3.60 ppm, respectively. The MDL for the stronger source is 3.61 ppm and 3.87 ppm, respectively. The overlaying tissue thickness MDLs decreased exponentially since the thickness increased which increases the scattering and attenuation. Simulations with MCNP successfully modelled the experiments. MCNP simulations of the kidney with varying Gd concentrations in the cortex and medulla suggest that the XRF measurement is not sensitive to the Gd distribution in the phantom. To conclude, this detection system can measure Gd in liver and kidney phantoms and has low MDLs. Future work should focus on varying the detection capabilities, measuring the effects to the organs at risk, possible clinical trials, and improving the MCNP model and peak extraction. / Thesis / Master of Science (MSc)

The effects of diabetes on cytochrome P450 dependent drug metabolizing enzymes have not to be clarified yet. The most widely used animals in these studies have been rats, and information regarding the effects of diabetes on cytochrome P450 dependent procarcinogen/carcinogen metabolism in rabbits is limited. In the present study, we investigated, for the first time, the influence of benzene on liver, kidney and lung microsomal cytochrome P450 dependent drug metabolizing enzyme activities, protein and mRNA levels in diabetic and non-diabetic rabbits. Male New Zealand rabbits were made diabetic by a single dose of alloxan treatment in this study. AST, ALT and LDH enzyme activities in the blood serum and lipid peroxidation in liver microsomes were found to increase in diabetic, benzene treated and benzene treated diabetic rabbits. Besides these, CYP2E1 dependent NDMA N-demethylase and p-nitrophenol hydroxylase activities and CYP2E1 protein level were found to increase in liver and kidney of diabetic and benzene-treated rabbits. The combined effects of benzene and diabetes on these activities and protein level were found to be additive. Although diabetes caused induction of pulmonary CYP2E1 protein level and associated enzyme activities, benzene treatment of rabbits resulted in no change in enzyme activities and protein level in lung. The level of mRNA was investigated by Real-Time PCR. Accordingly, hepatic CYP2E1 mRNA level was increased 6.71-, 10.53- and 12.93-fold in diabetic, benzene treated and benzene treated diabetic rabbits with respect to the control animals. Similarly, renal CYP2E1 mRNA level was found in increase in these rabbits. In addition to CYP2E1, CYP3A6 associated enzyme activity, erythromycin N-demethylase, CYP3A6 protein and mRNA level were found to increase in diabetic rabbit liver and lung. Unlike diabetes, benzene treatment caused suppression of CYP3A6 protein and inhibition of associated enzyme activity in liver. There was no significant change in the erythromycin N-demethylase activity and CYP3A6 level of liver and lung as a result of benzene treatment of diabetic rabbits. Moreover, diabetes induced CYP1A2 protein and mRNA level and CYP1A associated enzyme activities in the rabbit liver. On the other hand, benzene caused statistically insignificant decreases in CYP1A dependent enzyme activities and CYP1A2 protein level in liver. CYP1A associated enzyme activities, CYP1A2 protein and mRNA levels were not changed in the liver of benzene treated diabetics. The results of the present work indicate that both diabetes and benzene stimulate metabolic activation toxic chemicals metabolized by CYP2E1 such as NDMA and benzene by inducing CYP2E1 which results in the formation of increased amounts of reactive metabolites. Application of benzene to diabetic rabbits further elevates expression and activities of the CYP2E1. As a result of additive induction of the CYP2E1 in benzene treated diabetics, further increase the risk of hepatotoxicity produced by toxins may be observed when compared to the separate treatments. This may in turn further potentiate the risk of organ toxicity and mutagenesis in liver and kidney of these subjects. As in the case of CYP2E1, the risk of carcinogenesis due to induction of CYP1A may be increased in diabetic subjects. Moreover, in diabetic and benzene exposed subjects, alteration of drug clearance and clinical drug toxicity may be observed due to induction or suppression of CYP3A.

The use of quality-of-life as an outcome measure provides detailed information about the effectiveness of medical treatments than morbidity or mortality rates alone. The use of quality-of-life data in the clinical setting can inform patients regarding treatment options, treatment benefits and costs. In competing health care markets, outcome measurement is regarded as important as it is concerned with the impact of health care practice and affects health policy decisions. Doessel (1978) conducted the first Australian study on the cost-effectiveness analysis of renal replacement therapies. The study was based on Klarman, Francis & Rosenthal's (1968) the study, where the output was measured in terms of the number of life years gained from kidney transplantation, and a twenty-five percent weight was allocated in an attempt to capture quality-of-life from kidney transplantation. Doessel (1978) used two sources of data: Australian data (Disney 1974) and European data (Gurland et al. 1973; Shiel et al. 1974). The study measured life years gained, and agreed with the Klarman et al. (1974) findings that transplantation is the most effective way to increase life expectancy of persons with chronic renal disease (Butler & Doessel 1989). The outputs of the alternative treatments were not reported in monetary terms; the study focused on life years gained as the output measure. Hence the importance of this current study, which includes a cost-effectiveness analysis for cadaver liver, and living kidney transplantation for end-stage liver and kidney disease patients. Calls to respect patient autonomy and to produce patient-centered outcomes have recently brought the patient’s point of view back into the center of clinical medicine (Sullivan 2003). Survival rates indicate one measure of outcome however they do not reflect patients’ perceptions of health benefit or experiences. Noting that patients’ psychosocial effect on functioning is of more concern to them than their physical Thesis Preamble iii ability, that more accurate knowledge of patients’ conditions be measured prior to transplantation (Tarter et al. 1991). Recently researchers advocated investigating transplant patients' states of health to assess the social benefit of these expensive health care services from their perspective (Joralemon & Fujinaga 1997). The current study's mixed method, bridges the gaps in treatment outcome measurements, as the mixed method applied (Creswell 1994; Sim & Sharp 1998) prospectively measured quality-oflife, determined health utility, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs). The study reported the living donors experience of the donation process, described their needs; expressed using a new psychosocial model supporting future living kidney donor's during the donation process.