No description available.

It has been reported that the presence of Fc receptor blocking antibodies is associated with normal pregnancy and improved cadaver donor renal transplant survival. The demonstration of the development of such antibody activity in the animal model during one or more pregnancies and the effect of these pregnancies on the survival of a subsequent renal allograft form the major aims of the studies presented in this thesis.A microsurgical laboratory was therefore established at Aberdeen University and the rat renal transplant model developed. Fc receptor blocking activity was assessed using the EA inhibition assay.The results indicate that:I Fc receptor blocking activity was not found in the sera of virgin rats.2 Significant levels of these antibodies were only found after two pregnancies and they occurred in 50% of such cases3 Primiparous animals and those multiparous animals which did not develop EA inhibiting activity rejected renal allografts from the paternal strain in the same time as virgin animals.4 Only multiparous rats sharing over 30% EA inhibition failed to reject transplants carrying paternal specificities. Those animals were capable of rejecting grafts from third party donors suggesting that the Fc receptor blocking antibodies were directed towards paternal antigens.It is therefore suggested that Fc receptor blocking activity occurring as a result of pregnancy in the rat renal transplant model may enhance a renal allograft from the paternal strain. These antibodies may therefore represent a form of donor specific immunosuppression.

ABSTRACT Diabetes mellitus is a major cause of morbidity and mortality and is the leading cause of end-stage renal disease worldwide. New onset diabetes post renal transplantation is associated with reduced graft function, decreased patient survival and increased risk of graft loss. The immunosuppressive regimes used and dosage of corticosteroid therapy appear to impact on the incidence of new onset diabetes post renal transplantation. The objectives of this study were: to ascertain the prevalence of new onset diabetes post transplantation; to determine the association between new onset diabetes with immunosuppressive regimens and ethnicity; and to assess outcomes in terms of morbidity and mortality. The study design consisted of a retrospective analysis of 398 patient files transplanted between 01/07/1994 and 30/06/2004. Information retrieved from the files consisted of patient demographics ( age, race, gender ), weight, date of onset of diabetes, immunosuppressive regimens used, infections, cardiovascular and overall morbidity and mortality. The diagnosis of diabetes was based on the American Diabetes Association (ADA) criteria or the requirement for anti-diabetic agents. Results obtained showed that 15.58% (62/398) of patients became diabetic. The mean time to onset of diabetes was 22.9 months ( range 1 week to 100 months ). 20.21% Black patients (p=0.100), 9.42% White, 12.5% Coloured and 12% Indian patients became diabetic. Treatment with Cyclosporine( CyA) had an incidence of diabetes of 14.44%, Tacrolimus 20.25% p = 0.228, Rapamune 11.36% and Mycophenolate Mofetil 11.97%. Infections occurred in 96.77% of diabetic patients, p = <0.0001. Cardiovascular morbidity and mortality was 11.29%, p = 0.82. Overall mortality was 79.3% in the diabetic group p = 0.237, HR 1.45. In conclusion, the incidence of new onset diabetes is significant as it confers a higher risk of infections and overall mortality. Black patients are more affected, with an increased risk for those treated with Tacrolimus.

Renal transplantation is the optimum treatment for end-stage renal failure. B cells have been identified in chronic allograft damage (CAD) and are associated with the development of tertiary lymphoid tissue within the human renal allograft. To investigate this pathology we utilized a mouse model of renal transplantation. A mouse model of kidney transplantation was first described in 1973. Although the mouse model is technically difficult it is attractive for several reasons: the mouse genome has been characterized and in many aspects is similar to man and there is a greater diversity of experimental reagents and techniques available for mouse studies than other experimental models. We reviewed the literature on all studies of mouse kidney transplantation to report the donor and recipient strain combinations that have been investigated and the resultant survival and histological outcomes. Some models of kidney transplantation have used the transplanted kidney as a life-supporting organ, however in many studies the recipient mouse’s native kidney has been left in situ. Several different combinations of inbred mouse strains have been reported, with varying degrees of injury, survival, or tolerance due to haplotype differences. Both cellular and humoral rejection processes have been observed. This model has been exceptionally useful as an investigational tool to understand multiple aspects of transplantation including acute rejection, cellular and humoral rejection mechanisms and their treatment. Furthermore this model has been used to investigate disease mechanisms beyond transplant rejection including intrinsic renal disease and infection-associated pathology. We performed renal transplantation in mice to model CAD and identified B cells forming tertiary lymphoid tissue with germinal centres. Intra-allograft B220+ B cells comprised of IgMhigh CD23- marginal zone, IgMlo CD23+ follicular zone and IgMlo CD23- transitional-type B cells similar to spleen, and these compartments had elevated expression of CD86. Depletion of B cells with anti-CD20 was associated with an improvement in CAD but only when administered after transplantation and not before. Isolated intra-allograft B cells were cultured and shown to synthesise multiple cytokines, the most abundant of these being GRO-α (CXCL1), RANTES (CCL5), IL-6 and MCP-1 (CCL2). Tubular loss was associated with T cell mediated injury and interstitial fibrosis, whilst type III collagen deposition driven by F4/80+ macrophages and PDGFR-β+ and transgelin+ fibroblasts, all of which were reduced by B cell depletion. In this report we show that intra-allograft B cells are key mediators of chronic damage to the transplant allograft kidney by cytokine orchestration of T cell, macrophage infiltration and fibroblast activation.

BACKGROUND:Nephropathic cystinosis is an autosomal recessive disease resulting from intracellular accumulation of cystine leading to multiple organ failure.CASE REPORT:We describe the clinical course of a patient managed from the age of six until his death at the age of 33 years. He underwent multiple surgery, including two renal transplants, developed transplant renal artery stenosis that was managed medically, and progressive heart failure at the age of 33 years. His death from a ruptured pseudoaneurysm associated with a restrictive cardiomyopathy is noteworthy. A limited cardiac autopsy revealed the presence of cystine crystals in interstitial cardiac histiocytes and one myocardial cell, along with 1000-fold higher tissue cystine content of the left ventricular myocardium compared to patients without cystinosis, suggesting the possibility of direct cystine mediated metabolic injury.

No description available.

ABSTRACT Introduction: Renal transplant recipients (RTR) with abnormal glucose tolerance (AGT) are at an increased risk of graft failure and cardiovascular disease (CVD). CVD is the major cause of death in RTR. Whilst there are numerous known risk factors for AGT in RTR, it is unknown whether lifestyle factors are found in the presence or play a role in the development of AGT in RTR. The nutritional status of RTR in an Australian population has also not been extensively investigated. Investigation into these areas could help identify modifiable areas for change in the RTR population. Multidisciplinary lifestyle modification, including diet and physical activity (PA) advice from a dietitian, may help reduce modifiable risk factors for CVD in RTR with AGT. Aims: The principle aims of this thesis are to; 1) assess the incidence of obesity and central obesity in RTR and compare to rates in the general Australian population, 2) investigate and compare modifiable lifestyle factors and adipokine levels in RTR with AGT and normal glucose tolerance (NGT) and 3) investigate the effect of a multidisciplinary lifestyle intervention (including dietetic advice) on modifiable CVD risk factors in RTR with AGT. Methods: Chapter 1 presents a review of the literature describing the main nutritional challenges in RTR, cardiovascular risk factors in RTR including adipokine profiles and the role of body composition, diet and PA in RTR. Chapter 2 details the clinical, biochemical, nutritional, body composition, PA and statistical methodologies used in this thesis. In Chapter 3 a descriptive analysis of the anthropometry and cardiovascular risk profile of RTR in an Australian setting is investigated. Chapter 4 investigates the nutritional status of RTR with NGT and AGT in more detail, assessing diet, PA, adipokines and body composition. In Chapter 5, the current literature on lifestyle intervention management (including nutritional management) for obesity and type 2 diabetes mellitus in the general population is discussed. Building on previous chapters, Chapter 6 investigates the effect of a multi-disciplinary lifestyle intervention (with dietetic input) on modifiable cardiovascular risk factors in RTR with AGT. Results: In Chapter 3 it was found that RTR are significantly more centrally obese than those in the general population, and this was particularly the case in younger RTR. Central obesity was associated with CVD risk factors in RTR. Chapter 4 found that a lower level of PA, obesity and central obesity are associated with AGT in RTR, whereas no difference in adipokines or dietary intake was found. In Chapter 6, multidisciplinary lifestyle intervention with dietetic input was found to improve certain risk factors for CVD in RTR with AGT, such as dietary factors (total fat and saturated fat intake) and lipid levels. Conclusions: Central obesity is a common problem in RTR, particularly in those with AGT. Higher levels of PA are associated with lower risk of AGT in RTR, and may help reduce the incidence of central obesity in RTR. Multidisciplinary lifestyle intervention, with dietetic input, can improve some modifiable CVD risk factors in RTR with AGT, however more intensive intervention is required to significantly reduce the incidence of obesity. Key Words: Renal Transplant; Abnormal Glucose Tolerance, Obesity; Cardiovascular Disease; Physical Activity Australian and New Zealand Standard Research Classifications (ANZSRC) 1111 Nutrition and Dietetics, 1102 Cardiovascular medicine and Haematology, 1199 Other Medicine and Health Sciences

No description available.

Die Hyperlipidämie wird als Risikofaktor für die Nierentransplantatfunktionsverschlechterung und den -verlust diskutiert. Wir untersuchten den Zusammenhang zwischen Lipidstoffwechsel und Nierentransplantatfunktion und ihre Beziehungen zu Immunsuppression, Rejektionen, Transplantatalter und Dialysedauer. Im 1. Quartal 1996 wurde allen nierentransplantierten Patienten der Ambulanz die Bestimmung eines umfassenden Lipidstatus (Cholesterine (HDL, LDL, VLDL), Triglyzeride, Apolipoproteine A1, A2, B, Lp(a) und Apo E-Genotyp) angeboten. Die ermittelten Laborwerte wurden zum klinischen Verlauf der Patienten in Beziehung gesetzt. Es wurden 201 Patienten in die Studie eingeschlossen, deren mittleres Alter bei 46,2 ± 11,4 Jahren lag. Die Transplantation lag bei den 146 Männer (72,6 %) und 55 Frauen (27,4 %) 7,7 ± 4,9 Jahre zurück. Eine auf Cyclosporin A basierende Immunsuppression erfolgte bei 143 Patienten (71,1 %), 87 Patienten (43,3 %) erhielten eine lipidsenkende Therapie. Kreatinin 122 ± 86,9 µmol/l; Cholesterin 253,6 ± 52,9 mg/dl; atherogene Risikoratio (Chol/HDL) 5,3 ± 2,3. Das Kreatinin korreliert signifikant mit dem Cholesterin (p < 0,001) und der atherogenen Risikoratio (p < 0,001) - auch in der Untergruppe ohne lipidsenkende Therapie (p = 0,001 bzw. p < 0,001), ebenso LDL, Triglyzeride, VLDL und Apo B. Die Rejektionshäufigkeit war bei Patienten mit und ohne Fettstoffwechselstörung nahezu gleich. Der Apo E-Genotyp scheint keinen Einfluss auf den Lipid- und Nierenstoffwechsel zu haben. Die Lipidparameter unserer Patienten korrelieren in der Querschnittsuntersuchung signifikant mit der Nierentransplantatfunktion, scheinen aber keinen Einfluss auf die Rejektionshäufigkeit zu haben / Hyperlipidemia is discussed as a risk factor for deterioration of the renal transplant function and the graft loss. We examined the relations between the lipid metabolism and renal transplant function and their connections to factors like immunsuppression, rejections, transplant age und time of dialysis. In the first months of 1996 all patients having a renal transplant were offered an extensive blood control including cholesterol, HDL, LDL, VLDL, triglycerides, apolipoproteins A1, A2, B, Lp(a) und Apo E-Genotype. Afterwards the lipid parameters were put into relation to the clinical course of each patient. We included 201 patients in our study, they were 46,2 ± 11,4 years old. The renal transplantation was in 146 men (72,6 %) und 55 women (27,4 %) 7,7 ± 4,9 years ago. 143 patients got a Cyclosporin A based immunsuppression (71,1 %), 87 patients (43,3 %) were set on lipid lowering therapie. Creatinin 122 ± 86,9 µmol/l; cholesterol 253,6 ± 52,9 mg/dl; Chol/HDL-quotient 5,3 ± 2,3. Creatinin correlates significantly with cholesterol (p < 0,001) and the Chol/HDL-quotient (p < 0,001) - even in the group of patients without lipid lowering therapie (p = 0,001 and p < 0,001) - and LDL, Triglyzeride, VLDL and Apo B. The frequency of rejections did not differ between patients with and without hyperlipidemia. The Apo E-Genotype seems to have no influence on the lipid- and renal metabolism. The lipid parameters our patients correlate in our study significantly with the renal transplant function, but seem to have no influence on the frequency of rejections.

Introdução: A isquemia e reperfusão, que ocorre durante cirurgia renal, pode desencadear lesões que são mediadas por radicais livres produzidos na fase de reperfusão. A glutamina exerce propriedades positivas no sistema antioxidante por ação da glutationa. O pré- condicionamento isquêmico aumenta a tolerância a tecidos que sofrem isquemia. Objetivo: Avaliar a ação da glutamina associada ao pré-condicionamento isquêmico na isquemia e reperfusão renal em modelo animal. Métodos: Cinquenta ratos winstar machos foram submetidos à nefrectomia a direita. No oitavo dia de pós-operatório os animais foram randomizados em cinco grupos (n=10) que foram assim divididos: grupo I - grupo Sham, grupo II - grupo isquemia e reperfusão, grupo III - grupo pré-condicionamento isquêmico, grupo IV - grupo glutamina e grupo V- pré-condicionamento isquêmico associado a glutamina. Os grupos IV e V receberam glutamina através de gavagem por sete dias. Ao final do 14º dia da nefrectomia procedeu-se a isquemia renal esquerda por 45 minutos. Após 1 e 7 dias, cinco animais de cada subgrupo foram submetidos a nova cirurgia com coleta de sangue e retirada de tecido renal. Resultados: Após um dia de reperfusão o grupo V apresentou os níveis mais elevados de glutationa reduzida (2,55±0,34mmol/g tecido) quando comparado aos outros grupos. A atividade da enzima superóxido dismutase apresentou-se elevada no grupo V quando comparado ao grupo II (p=0.018). Já no sétimo dia de reperfusão o grupo V apresentou-se com a maior atividade da enzima glutationa peroxidase dentre todos os grupos (p=0.009), bem como a atividade da enzima glutationa reduzida (p=0,001). Neste mesmo dia a superóxido dismutase mostrou-se mais elevada no grupo V quando comparado aos grupos que sofreram intervenção isquêmica (p=0.02). No sétimo dia a caspase-3 e a proteína carbonilada do grupo V se mostraram com maiores valores quando comparados aos grupos restantes. A associação da glutamina ao pré-condicionamento isquêmico elevou a glutationa reduzida e superóxido dismutase no grupo no primeiro dia após a reperfusão. No sétimo dia após a reperfusão se observa uma persistente elevação da superóxido dismutase, enzimas glutationa peroxidase e glutationa redutase bem como os níveis de caspase-3 e proteína carbonilada. Conclusão: Neste modelo de isquemia renal por clampeamento de pedículo seguido de reperfusão se conclui que há uma potencialização do efeito antioxidante da associação da glutamina e pré-condicionamento isquêmico após 24 horas de reperfusão, entretanto tal efeito não é mantido até o sétimo dia após a reperfusão. / Introduction: Ischemia and reperfusion injury that occurs during renal surgery can trigger injuries that are mediated by free radicals generated in the reperfusion phase. Glutamine exerts positive properties in the antioxidant system by the action of glutathione. Ischemic preconditioning increases tolerance to tissue suffering ischemia. Objective: To evaluate the action of glutamine associated with ischemic preconditioning in ischemia and reperfusion in animal models. Methods: Fifty rats Winstar males underwent nephrectomy right. On the eighth day after the operation the animals were randomized into five groups (n = 10) were divided as follows: Group I - sham group, II - ischemia and reperfusion group, III - ischemic preconditioning group, IV - glutamine group and group V- ischemic preconditioning group associated with glutamine. Groups IV and V received glutamine via gavage for seven days. At the end of 14 days nephrectomy proceeded to the left renal ischemia for 45 minutes. After 1 and 7 days, five animals in each subgroup underwent new surgery with blood collection and removal of kidney tissue. Results: After one day reperfusion group V showed higher levels of reduced glutathione (2.55 ± 0,34mmol / g tissue) compared to other groups. The enzyme activity superoxide dismutase showed up high in the V group compared to group II (p = 0.018). In the seventh day of reperfusion group V presented with the increased activity of glutathione peroxidase enzyme among all groups (p = 0.009) as well as the activity of reduced glutathione (p = 0.001). On the same day the superoxide dismutase was shown to be higher in the V group compared to groups who have suffered ischemic intervention (p = 0.02). On the seventh day caspase- 3 and protein carbonyl group V are shown with larger values when compared to the other groups. The association of glutamine to ischemic preconditioning increased the reduced glutathione and superoxide dismutase in the group on the first day after reperfusion. On the seventh day after reperfusion is observed a persistent elevation of superoxide dismutase, glutathione peroxidase enzymes and glutathione reductase and the levels of caspase-3 and protein carbonyl. Conclusion: In this model of renal ischemia by clamping the pedicle followed by reperfusion is concluded that there is a potentiation of the antioxidant effect of glutamine association and ischemic preconditioning after 24 hours of reperfusion, however this effect is not maintained until the seventh day after reperfusion.