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During the academic year 1960-1961, the Department of Experimental Surgery, of the University of Cape Town, engaged in a series of experiments concerning the production of profound hypothermia in dogs. Hypothermia was induced by blood-stream cooling, via a heat exchanger incorporated in an extra-corporeal pump-oxygenator system (ef Appendix A). Progress was such that by midyear postoperative survival of experimental animals was assured. At this juncture, it was suggested that, as a member of the Renal-Metabolic Group of the Department of Medicine, I co-operate wit the surgeons, in a study of renal function during profound hypothermia in the dog. This thesis details our progress and results.

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Le rein est particulièrement exposé à de nombreux composés chimiques dont des médicaments, potentiellement néphrotoxiques. Parmi-eux, le Tacrolimus, un anti-calcineurine largement utilisé en transplantation rénale, est associé à l’apparition plus ou moins rapide de lésions histologique de toxicité conduisant à la fibrose rénale et, à terme, à la perte de fonction du greffon. Des systèmes enzymatiques et protéiques impliqués dans la prise en charge cellulaire des xénobiotiques, ainsi que des protéines aux propriétés anti-fibrosantes, telles que la cavéoline-1, lui permettent de se défendre contre ce type d’agression locale prolongée. La mesure de l’expression de 380 gènes impliqués dans la prise en charge des xénobiotiques dans des échantillons de tissu rénal humain sain nous a permis de confirmer que le rein possède un arsenal de défense important et complet. Ces différents systèmes de défense étant hautement polymorphes, le principal objectif de notre travail était de déterminer l’impact de certains polymorphismes génétiques sur la susceptibilité individuelle à la néphrotoxicité du Tacrolimus.Dans un premier temps, l’impact sur les paramètres pharmacocinétiques du Tacrolimus et le devenir du greffon de deux polymorphismes génétiques affectant les CYP3A5 et ABCB1, deux protéines participant au transport et au métabolisme du Tacrolimus, a été évalué dans une cohorte de 209 patients transplantés rénaux. Le génotypage a été réalisé à la fois sur l’ADN des receveurs et des donneurs. Les patients ont été suivis jusqu'à 2 ans après transplantation rénale. Cette étude a confirmé que les receveurs sous Tacrolimus (Prograf) porteurs d’au moins un allèle CYP3A5*1 fonctionnel nécessitent, quelque soit le moment de la greffe, des posologies de Tacrolimus plus élevées. Malgré ces doses, leur taux résiduel de Tacrolimus (C0) reste plus faible. Cependant, l’analyse de la distribution des rapports résiduelles/posologies de Tacrolimus montre qu’il existe une forte zone de chevauchement entre les deux populations *1/- vs *3/*3. Ainsi, certains patients ayant un CYP3A5 génétiquement déficitaire se comportent phénotypiquement comme des patients fonctionnels. D’autres polymorphismes génétiques sont probablement à l’origine de ce phénomène. En ce qui concerne le devenir du greffon, malgré son impact sur la pharmacocinétique du Tacrolimus, le polymorphisme génétique du CYP3A5 du donneur ou du receveur n’est statistiquement pas associé à la survenue de rejet, de retard de fonctionnement de greffon, ou n’a d’impact direct sur la fonction rénale (MDRD) et la survie du greffon. La mutation 3435C>T affectant le gène ABCB1 du donneur ou du receveur n’influence ni les paramètres pharmacocinétiques, ni le devenir clinique du greffon. Par ailleurs, le Tacrolimus est désormais disponible sous une forme à libération prolongée (Advagraf), permettant une prise unique journalière. Des pharmacocinétiques sur 24h ont été réalisées chez 32 patients (17 fonctionnels et 15 non fonctionnels pour le CYP3A5) avant conversion et quinze jours après conversion Prograf-Advagraf. Les résultats ont montré que, après conversion, l’exposition au Tacrolimus diminue de manière significative pour les patients CYP3A5 fonctionnelsEnfin, l’influence d’un polymorphisme génétique, rs4730751, affectant le gène CAV1 (codant la cavéoline-1, une protéine inhibitrice de la fibrose tissulaire) sur la survie du greffon rénal a récemment été rapporté. Nous avons confirmé dans une cohorte de 475 transplantés rénaux que les patients porteurs de ce polymorphisme génétique à l’état homozygote (ADN du greffon rénale) ont une altération de la fonction rénale significativement plus rapide. / Tacrolimus is highly effective in preventing acute rejection after renal transplantation, but displays a narrow therapeutic index and high inter-individual pharmacokinetic variations. As Tacrolimus is a substrate of CYP3A and ABCB1, the effect of potentially relevant genetic polymorphisms, CYP3A5 6986A>G and ABCB1 3435C>T, in both donors and recipients on Tacrolimus pharmacokinetics and clinical outcome was investigated in 209 kidney transplant patients. Methodology/Principal Findings:The mean duration follow-up was 21.8±9 months. Tacrolimus dose, trough blood levels (C0) and C0/dose ratio were statistically correlated with only the recipient CYP3A5 genotype. Concerning the allograft clinical outcome, CYP3A5 and ABCB1 genotypes exhibit no influence on the incidence of Biopsy Proven Acute Rejection and Delayed Graft Function. Renal function was not affected by CYP3A5 and ABCB1 genotypes. Histological evaluation of biopsies revealed also no significant association between Tacrolimus toxicity features and donor or recipient CYP3A5 and ABCB1 polymorphisms. Tacrolimus and steroids sparing was similar in groups of patients according to their genotypes. Conclusions/Significance: Recipient CYP3A5 6986A>G polymorphism explains part of the inter-individual variability in the pharmacokinetics of Tacrolimus. At two years, clinical outcome does not appear to be related to either donor’s or recipient’s CYP3A5 6986A>G and ABCB1 3435C>T polymorphisms. Interestingly, tapering of immunosuppressive therapy may be achieved even for patients experiencing extensive Tacrolimus metabolism, independently of CYP3A5 genotype.

Acute kidney injury (AKI) may result from perioperative renal medullary hypoxia. Despite high oxygen delivery to the kidney, the medullary thick ascending limb (mTAL) in the outer renal medulla is susceptible to hypoxia because of its high oxygen consumption and relatively low rate of blood flow. The objective of this study was to evaluate the effect of a low pO2 (8% FiO2 for 5 h) on the major function of the mTAL and to develop a strategy to protect the mTAL in this setting. Evidence of hypoxia-induced reduction in mTAL function included low interstitial and urine osmolality but only a minimal rise in Na+ excretion; this was prevented by pre-treatment with desmopressin acetate (dDAVP), a vasopressin analogue which may increase tissue pO2. A decrease in urine osmolality may be of diagnostic value for hypoxic renal damage and dDAVP may prevent acute kidney injury in the perioperative setting.

Acute kidney injury (AKI) may result from perioperative renal medullary hypoxia. Despite high oxygen delivery to the kidney, the medullary thick ascending limb (mTAL) in the outer renal medulla is susceptible to hypoxia because of its high oxygen consumption and relatively low rate of blood flow. The objective of this study was to evaluate the effect of a low pO2 (8% FiO2 for 5 h) on the major function of the mTAL and to develop a strategy to protect the mTAL in this setting. Evidence of hypoxia-induced reduction in mTAL function included low interstitial and urine osmolality but only a minimal rise in Na+ excretion; this was prevented by pre-treatment with desmopressin acetate (dDAVP), a vasopressin analogue which may increase tissue pO2. A decrease in urine osmolality may be of diagnostic value for hypoxic renal damage and dDAVP may prevent acute kidney injury in the perioperative setting.

Halogenated alkenes are a group of commercially important chemicals. For example tetrafluoroethylene is the monomer used for the production of poly- tetrafluoroethylene, hexachloro-1:3-butadiene is a by-product from the manufacture of chlorinated solvents and perchloroethylene is widely used as a dry cleaning agent. Due to possible exposure to haloalkenes and the nephrotoxicity observed in animal studies, concern has been expressed for the potential of these compounds to cause toxicity to man. Animal studies have shown that these compounds undergo inter-organ metabolism and are bioactivated by enzymes of glutathione processing. The metabolites are delivered to the kidney where they cause proximal tubular cell necrosis. This site-specific toxicity is due to accumulation of the metabolites via specific transport mechanisms and bioactivation via the enzyme C-S lyase present in high amounts in the proximal tubules. The aim of this research was to investigate the mechanisms of toxicity of haloalkene S'-conjugates in vitro using cultures of rat and human proximal tubular cells. This study demonstrates that human proximal tubular cells are sensitive to haloalkene. -conjugate toxicity, particularly DC VC. Human exposuredata has shown that workers exposed to trichloroethylene (Bimer et al, 1993) and perchloroethylene (Mutti et al, 1992) excrete nephrotoxic metabolites and markers of renal damage respectively. In the light of these findings and the toxicity of DCVC in HPT cells, exposure to halogenated alkenes should be controlled and those exposed monitored.

Made available in DSpace on 2014-06-11T19:35:12Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-01-28Bitstream added on 2014-06-13T20:06:47Z : No. of bitstreams: 1 lima_lc_dr_botfm.pdf: 1702555 bytes, checksum: 4476cc5a576c0c45223065d48539806c (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Efeito das catecolaminas sobre a expansão volêmica sustentada e função renal em coelhos. Os autores estudaram os efeitos das catecolaminas α, β e dopa sobre a expansão volêmica e a função renal de coelhos anestesiados antes, durante e após infusão em bolus de solução fisiológica a 0,9%.foram estudados 24 coelhos, distribuídos aleatoriamente em quatro grupos experimentais de estudo. Respostas à infusão de um bolus de 24 mL.kg-1 de SF 0,9% em 20 minutos foram avaliadas durante a infusão da catecolamina. Os quatro grupos experimentais eram o controle, SF 0,9% 6 mL.kg-1.h-1, fenilefrina 3,0 ug.kg-1.min-1 (6 mL.kg-1.h-1), isoprenalina 0,1 ug.kg-1.min-1 (6 mL.kg-1.h-1) e dopamina 20 ug.kg-1.min-1 (6 mL.kg-1.h-1). A expansão do volume plasmático foi calculada a partir da variação do hematócrito. Medidas de depuração urinária também foram avaliadas.ao término da expansão volêmica com 24 mL.kg-1 de SF 0,9%, a expansão do volume plasmático foi maior no grupo isoprenalina, seguida dos grupos fenilefrina e controle. O grupo da dopamina mostrou a menor expansão. Terminado o experimento, o grupo isoprenalina mantinha a maior expansão volêmica e o grupo dopamina, uma expansão maior que a do grupo controle. Porém, o grupo da fenilefrina apresentou uma diminuição sustentada da expansão do volume plasmático, atingindo valores próximos aos basais (antes da expansão). Após a expansão com SF 0,9%, o maior aumento no débito urinário ocorreu no grupo fenilefrina comparado com os outros grupos, que não diferiram entre si. Finalizado o procedimento, o grupo submetido a infusão de fenilefrina, mantinha o maior débito urinário, mantendo-se até o término da infusão da catecolamina, seguido do grupo isoprenalina. Com relação à função renal, o clearance de creatinina, 30 minutos após a expansão com solução fisiológica, estava aumentado no grupo da dopamina... / Effects of catecholamines on sustained volume expansion and renal function in rabbits.The authors studied the effects of cathecholamines (alpha, beta and dopamine agonists) on volume expansion and renal function in anesthetized rabbits, before, during, and after a bolus infusion of 0.9% saline.after Institutional Ethics Committee approval, 24 rabbits were randomly distributed in four experimental groups: Control (CRL) - NaCl 0.9% 6 ml.Kg-1.h-1 + 1 ml.Kg-1 of creatinine (Cr), no catecholamines infusion; Phenylephrine (PHE) - 3 ug/kg/min (NaCl 0.9% 6 ml.Kg-1.h-1 + 1 ml.Kg-1 of Cr); isoproterenol (ISU) - 0,1 μg.kg-1.min-1 (NaCl 0.9% 6 ml.Kg-1.h-1 + 1 ml.Kg-1 of Cr); and Dopamine DOP) - 20 μg.kg-1.min-1 (NaCl 0.9% 6 ml.Kg-1.h-1 + 1 ml.Kg-1 of Cr). All groups received a 0.9% NaCl 24 ml.Kg-1 over 20 minutes for volume expansion, starting 30 minutes after the initiation of catecholamine and creatinine infusion. The catecholamine infusion was sustained for 120 minutes after the end of the saline bolus. The plasma volume expansion was calculated based on estimated plasma volume and change in hematocrit. Renal function was also evaluated using Cr infusion since the beginning of the experiment. catecholamines infusion without saline did not change the plasma volume. The plasma volume expansion, after the 24 ml.Kg-1 of NaCl 0.9%, was most sustained in the ISU group, followed by DOP and CRL. The PHE group showed the lowest plasma expansion (least retention of vascular fluid). PHE was associated with the greatest dieresis compared to the other test groups, which did not differ significantly from one another. Regarding the renal function, the Cr clearance 30 minutes after plasma expansion with saline was increased in the DOP group compared to the other groups.The Na+ excretion and clearance 30 minutes after the ending of volume expansion with saline were significantly higher in the PHE group when... (Complete abstract click electronic access below)