A maior parte dos casos de doença renal policística autossômica dominante (DRPAD) é causada por mutações no gene PKD1 (Polycystic Kidney Disease 1). O insulto por isquemia/reperfusão (IR) constitui-se em uma causa freqüente de lesão renal aguda, incluindo a população de pacientes com DRPAD, mas a relação entre policistina-1 e IR é essencialmente desconhecida. Uma vez que a policistina-1 modula proliferação, diferenciação celular e apoptose em sistemas de cultura de células, sua menor atividade biológica na DRPAD poderia favorecer um maior grau de lesão renal. Utilizamos uma linhagem endogâmica de camundongos 129Sv com uma mutação nula em Pkd1 para testar esta hipótese. Camundongos Pkd1+/- não apresentam cistos renais até 12 semanas de vida, constituindo-se em um modelo puro de haploinsuficiência para este gene. Um insulto IR bilateral de 32 min foi induzido em camundongos machos de 10-12 semanas de idade, heterozigotos e selvagens, por meio do clampeamento reversível de ambos os pedículos renais. Os animais foram analisados 48 h, 7 dias (d) e 14 d após o insulto. Camundongos Pkd1+/- apresentaram FENa, FEK e SCr mais elevadas que animais Pkd1+/+ 48 h após IR. O dano cortical residual foi mais severo em heterozigotos que em selvagens em todos os tempos avaliados. A marcação para PCNA também foi mais alta em camundongos Pkd1+/- que Pkd1+/+ 48 h e 7 d pós-IR, enquanto a taxa de apoptose e a infiltração inflamatória intersticial foram maiores em heterozigotos que em selvagens nos seguimentos de 48 h, 7 d e 14 d pós-IR. A expressão renal de p21 foi menor nos camundongos Pkd1+/- que Pkd1+/+ no tempo de 48 h pós-insulto, tanto no nível transcricional como traducional. Análises adicionais realizadas 6 semanas após o insulto IR revelaram dilatação tubular e formação de microcistos nos camundongos haploinsuficientes para Pkd1, assim como fibrose renal aumentada nesses animais, comparados aos camundongos selvagens. Por fim, um insulto de 35 min de isquemia/reperfusão acompanhou-se de uma mortalidade precoce substancialmente maior nos animais Pkd1+/-. Esses achados sugerem que isquemia/reperfusão induza uma lesão mais severa em rins de camundongos haploinsuficientes para Pkd1, um processo aparentemente dependente de uma deficiência relativa da atividade de p21, assim como dilatação tubular e formação de microcistos. Em conjunto, nossos resultados sugerem que a heterozigose para mutação nula em Pkd1 em camundongo (e talvez em humanos) esteja associada a um risco aumentado para lesão renal por isquemia/reperfusão e a um pior impacto desse insulto sobre a progressão da doença renal. / The majority of autosomal dominant polycystic kidney disease (ADPKD) cases are caused by mutations in the PKD1 gene. Ischemia/reperfusion is a frequent cause of acute kidney injury, including the ADPKD patient population, but the relationship between polycystin-1 and ischemia/reperfusion is essentially unknown. Since polycystin-1 modulates cell proliferation, cell differentiation and apoptosis in cell culture systems, its lower biological activity in ADPKD might amplify the degree of renal injury. Using an inbred 129Sv mouse line with a Pkd1-null mutation, 32-min renal ischemia/reperfusion was induced in 10-12 week-old male non-cystic mice, heterozygotes and wild types. The animals were analyzed at 48h, 7 days (d) and 14d after the insult. Pkd1+/- mice showed higher FENa, FEK and SCr than Pkd1+/+ animals at 48h of follow-up. The residual cortical damage was more severe in heterozygotes than wild types at all evaluated time points. The PCNA staining was also higher in Pkd1+/- than Pkd1+/+ mice at 48h and 7d, while cell apoptotic rates and the interstitial inflammatory infiltration were higher in heterozygotes than wild types at 48h, 7d and 14d postischemia/ reperfusion. The expression of p21 was lower in Pkd1+/- than Pkd1+/+ kidneys at 48h, both at the transcriptional and translational levels. Additional analyses performed 6 weeks after the insult showed tubular dilatation and microcyst formation in the haploinsufficient mice, and increased renal fibrosis in these animals compared to wild types. Thirty-fivemin ischemia/reperfusion, at last, was accompanied by a substantially higher early mortality of Pkd1+/- animals. These findings suggest that ischemia/reperfusion induces a more severe injury in kidneys of Pkd1- haploinsufficient mice, a process that is apparently dependent on a relative deficiency of p21 activity, as well as tubular dilatation and microcyst formation. Altogether, our results suggest that mouse Pkd1-null heterozygosity (and maybe human) is associated with a higher risk for renal ischemia/reperfusion injury and with a worse impact of this insult upon renal disease progression.

O desenvolvimento de hipertensão arterial (HAS) ocorre dez anos mais cedo em pacientes com doença renal policística autossômica dominante (DRPAD) comparados à população geral, estando presente em ~60% dos indivíduos afetados antes da perda de função renal. Déficit de concentração renal também se constitui em um achado precoce nesses pacientes. Atualmente se propõe que o sistema renina angiotensina desempenhe um papel central na HAS relacionada à DRPAD, enquanto diferentes explicações têm sido levantadas para justificar o defeito de concentração. Realizamos um cruzamento envolvendo um alelo floxed de Pkd1 com uma linhagem com expressão de nestina-Cre, de modo a gerar camundongos machos císticos viáveis (Pkd1cond/cond:Balcre, CI) com TFG preservada. Estes animais foram avaliados sistematicamente para uma série de parâmetros renais funcionais, morfológicos, celulares e moleculares. Análises paralelas foram conduzidas em camundongos haploinsuficientes para Pkd1 (Pkd1+/-, HT), os quais não desenvolvem cistos renais visíveis. Camundongos CI mostraram-se significantemente hipertensos na idade de 10-13 semanas, um fenótipo não observado em controles não císticos (Pkd1cond/cond, NC) e em animais haploinsuficientes para Pkd1. As frações de excreção de Na+ e K+ mostraram-se reduzidas e a concentração sérica de uréia discretamente elevada em camundongos CI, sugerindo reabsorção tubular de solutos aumentada. A expressão gênica de angiotensinogênio foi significantemente maior em rins CI que NC, enquanto análises imunoistoquímicas revelaram expressão da enzima conversora de angiotensina e do receptor AT1 em epitélio cístico renal. A excreção urinária de NO2 também se mostrou diminuída em camundongos CI, acompanhando-se de taxas aumentadas de proliferação celular e apoptose renais. A osmolalidade urinária máxima foi mais baixa em animais CI, um déficit não encontrado nos controles HT e NC. Interessantemente, uma tendência de níveis plasmáticos mais elevados de vasopressina foi observada em camundongos CI. Tomados em conjunto, esses resultados apoiam a hipótese de que a formação e o crescimento de cistos desempenham um papel importante no desenvolvimento de HAS na DRPAD e de que a ativação do sistema renina-angiotensina intrarrenal constitui-se em um mecanismo fundamental nesse processo. Nossos achados também sugerem fortemente que a expansão cística seja essencial para o desenvolvimento do déficit de concentração renal nessa doença, e são consistentes com a existência de áreas focais de compressão vascular e perfusão diminuída em rins com DRPAD. / Hypertension (SAH) develops ten years earlier in autosomal dominant polycystic kidney disease (ADPKD) patients compared with the general population, being present in ~60% of affected individuals before the loss of renal function. Renal concentrating deficit is also an early finding in these patients. It has been proposed that the renin-angiotensin system plays a central role in ADPKD-related SAH, while different explanations have been raised to justify the concentrating impairment. We bred a floxed allele of Pkd1 with a nestin Cre expressing line to generate viable, adult male cystic mice (Pkd1cond/cond:Balcre, CY) with preserved GFR. These animals were systematically evaluated for a series of renal functional, morphological, cellular and molecular parameters. Parallel analyses were carried out in Pkd1-haploinsuficient mice (Pkd1+/-, HT), which do not develop visible renal cysts. CY mice were significantly hypertensive by 10-13 weeks of age, a phenotype not seen in non-cystic controls (Pkd1cond/cond, NC) and Pkd1-haploinsufficient animals. The fractional excretion of Na+ and K+ were reduced and SUN slightly elevated in the CY mice, suggesting increased tubular solute reabsorption. Angiotensinogen gene expression was significantly higher in CY than NC kidneys, whereas immunohistochemical analyses revealed angiotensin-converting enzyme and AT1 receptor expression in renal cyst epithelia. Urine excretion of NO2 was also diminished in CY mice, along with increased rates of renal cell proliferation and apoptosis. Maximum urine osmolality was decreased in CY animals, a deficit not found in HT and NC controls. Interestingly, a trend toward increased serum vasopressin levels was observed in the CY mice. Taken together these results support the hypothesis that cyst formation and growth play an important role in the development of SAH in ADPKD and that activation of the intrarenal reninangiotensin system is a fundamental mechanism in this process. Our findings also strongly suggest that renal cyst expansion is essential for the development of renal concentrating deficit in this disease, and are consistent with the existence of focal areas of vascular compression and reduced perfusion in ADPKD kidneys.

Fundamentos: Hiperparatiroidismo secundário (HPT2), hiperfosfatemia e produto cálcio x fósforo elevado são associados com doença cardiovascular (DCV) em pacientes com doença renal crônica (DRC). Um papel mais direto exercido pelo PTH neste contexto é controvertido. O objetivo deste estudo foi avaliar como o PTH, cálcio, fósforo e produto cálcio x fósforo interagem para influenciar a função e estrutura vascular de pacientes com DRC com níveis diferentes de PTH e graus diversos de HPT2. Mais especificamente, nós procuramos verificar se o efeito do PTH sobre o sistema vascular ocorre via alterações nos níveis de cálcio e fósforo ou do estresse oxidativo. Métodos: A reatividade vascular das artérias musculares e as características morfofuncionais das artérias de condução foram determinadas em 31 pacientes com DRC tratados por hemodiálise (46 ± 13 anos de idade, 65% do sexo masculino, 48% caucasóides, 52% afro-brasileiros, em tratamento por hemodiálise por 67 meses, PTH 541 ± 389 [mediana 472, intervalo 81 1437], Ca 10,3 ± 1,0, P 6,0 ± 1,5, Ca x P 62 ± 15) e em 22 controles normais. O diâmetro da artéria braquial foi determinado por ultra-sonografia vascular de alta resolução em condições basais, depois de hiperemia reativa (vasodilatação mediada por fluxo, VMF, dependente do endotélio) e após administração de nitrato, um dilatador de ação direta sobre o músculo liso arterial (vasodilatação independente do endotélio, VIE). A rigidez e as características anatômicas das artérias elásticas foram determinadas na carótida e na aorta. Estresse oxidativo, um fator associado à disfunção endotelial, foi avaliado pela dosagem plasmática das espécies reativas ao ácido tiobarbitúrico (TBARS). Resultados: Comparados aos controles tanto a VMF (6,0 ± 4,3% versus 11,3 ± 4,5%) como a vasodilatação independente do endotélio (11,9 ± 7,7% versus 19,1 ± 6,4%) estavam significativamente reduzidas nos pacientes com DRC (p < 0,01). A VMF correlacionou-se negativamente com o PTH (r = - 0,429, p < 0.05) e com a idade (r = -0,365, p = 0,04) e positivamente com a vasodilatação independente do endotélio (r = 0,483, p < 0,01). Na análise multivariada, apenas PTH (p = 0,009) foi o preditor independente de disfunção endotelial. Cálcio, fósforo, produto cálcio x fósforo, albumina, pressão arterial, duração da diálise, hematócrito e lípides não influenciaram a VMF nos pacientes. A distensão da carótida correlacionou-se negativamente e independentemente de outros fatores com o produto cálcio x fósforo (r = - 0,565, p = 0,003) e com a idade (r = - 0,627, p = 0,003), mas não foi influenciada pelo PTH. A velocidade de onda de pulso correlacionou-se apenas com a idade (r = 0,544, p = 0,003). O estresse oxidativo foi mais elevado nos pacientes que nos controles (2,63 ± 0,51 nmoles/mL versus 1,49 ± 0,43 nmoles/mL, p < 0,001). Entre os pacientes o estresse oxidativo não se correlacionou com a reatividade vascular ou com as variáveis das artérias de condução. No entanto, no conjunto formado por pacientes e controles observamos uma correlação negativa do TBARS com a VMF (r = -0,56, p < 0,001) e positiva com a pressão arterial sistólica (r = 0,48, p < 0,001). Conclusão: Na DRC, o PTH tem efeito adverso sobre a reatividade vascular, possivelmente interferindo com a função endotelial, enquanto que a distensão das grandes artérias elásticas é influenciada negativamente pelo produto cálcio x fósforo e idade, porém não pelo PTH. Os resultados sugerem a existência de um mecanismo duplo de agressão vascular no HPT2: um efeito endotelial mediado pelo PTH e um efeito média/adventicial ligado a alterações do metabolismo mineral / Background: Secondary hyperparathyroidism (2HPT), hyperphosphataemia and a high calcium x phosphorus product are associated with cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). A more direct role played by parathormone (PTH) in this context is controversial. The purpose of this study was to evaluate how PTH, calcium, phosphorus and calcium x phosphorus product interact to influence vascular structure and function of patients with different levels of PTH and varying degrees of 2HPT. Specifically, our purpose was verify whether calcium, phosphorus and oxidative stress are involved on the effects of PTH on the vascular system. Methods: Vascular reactivity of the muscular arteries and the morpho-functional characteristics of condutance vessels were determined in 31 patients with CKD treated by hemodialysis (46 ± 13 years of age, 65% males, 48% Caucasians, 52% African- Brazilians, in haemodialysis treatment for 67 months, PTH 541 ± 389 [median 472, range 81 - 1437], Ca 10.3 ± 1.0, P 6.0 ± 1.5, Ca x P 62 ± 15) and in 22 normal controls. The diameter of the brachial artery was determined by vascular high-resolution ultrasound on baseline, after reactive hyperemia (flow-mediated vasodilation, FMD, dependent of the endothelium) and after administration of nitrate, a dilator of direct action on the smooth muscle blood (vasodilation independent of the endothelium, VIE). The stiffness and the anatomical features of elastic arteries were determined in the carotid artery and aorta. Oxidative stress, a factor associated with endothelial dysfunction, was evaluated by the level of plasma thiobarbituric acid-reactive species (TBARS). Results: Compared to the controls, both the FMD (6.0 ± 4.3% versus 11.3 ± 4.5%) as well as VIE (11.9 ± 7.7% versus 19.1 ± 6.4 %) were significantly reduced in patients with CKD (p <0.01). The FMD was negatively correlated with PTH (r = - 0429, p <0.05) and with age (r = -0365, p = 0.04) and positively with the endothelium-independent vasodilation (r = 0483, p < 0.01). In the multivariate analysis, only PTH (p = 0009) was an independent predictor of endothelial dysfunction. Calcium, phosphorus, calcium x phosphorus product, alkaline phosphatase, albumin, blood pressure, duration of dialysis, hematocrit and lipids did not influence the FMD. The distension of the carotid artery was negatively correlated the calcium x phosphorus product (r = - 0565, p = 0003) and with age (r = - 0627, p = 0003), but was not influenced by PTH . Pulse wave velocity correlated only with age (r = 0544, p = 0003). Oxidative stress was higher in patients than in controls (2.63 ± 0.51, nmoles/ml versus 1.49 ± 0.43 nmoles/ml, p <0001) and correlated with FMD (r = - 0,56, p< 0,001) and systolic blood pressure (r = 0,48, p < 0,001) in the totality of individuals (patients and controls). Conclusion: In CKD, PTH adversely affects vascular reactivity, possibly by interfering with endothelial function, while large vessel distension is influenced by the calcium x phosphorus product and age, but not by PTH. This result suggests a dual mechanism of vascular aggression in vascular 2HPT: an endothelial effect mediated by PTH and a media/adventitial effect linked to alterations of mineral metabolism

INTRODUÇÃO: Poucas são as estratégias testadas para reduzir o volume de contraste durante angioplastia coronária. Levantamos a hipótese de que o ultrassom intravascular teria o potencial de substituir muitas informações fornecidas pela angiografia, reduzindo, dessa forma, o volume total de contraste utilizado durante a angioplastia coronária. MÉTODOS: No total, 83 pacientes foram randomizados para realização de angioplastia guiada pela angiografia isolada ou angioplastia guiada pelo ultrassom intravascular. Ambos os grupos foram tratados com estratégias rigorosas para redução de contraste, tendo como objetivo primário o volume final de contraste utilizado na angioplastia coronária. Os pacientes foram acompanhados por um período médio de 4 meses. RESULTADOS: A mediana do volume total de contraste foi de 64,5 ml (intervalo interquartil [ITQ], 42,8-97 ml; mínimo de 19 ml e máximo de 170 ml) no grupo angioplastia guiada pela angiografia isolada vs. 20 ml (ITQ, 12,5-30 ml; mínimo de 3 ml e máximo de 54 ml) no grupo angioplastia guiada pelo ultrassom intravascular (P < 0,001). De forma semelhante, a mediana da razão entre o volume de contraste e o clearance de creatinina foi significantemente menor entre os pacientes submetidos a angioplastia guiada pelo ultrassom intravascular, quando comparados aos pacientes do grupo angioplastia guiada pela angiografia isolada (1 [ITQ, 0,6-1,9] vs. 0,4 [ITQ, 0,2- 0,5], respectivamente; P < 0,001). Os desfechos intra-hospitalares e aos 4 meses de acompanhamento não foram diferentes entre os pacientes randomizados para o grupo angioplastia guiada pela angiografia isolada e aqueles do grupo angioplastia guiada pelo ultrassom intravascular. CONCLUSÕES: A utilização racional do ultrassom intravascular como método de imagem para guiar a angioplastia foi segura e reduziu de forma significativa o volume de contraste, comparativamente à angioplastia guiada pela angiografia isolada. O uso do ultrassom intravascular para esse propósito deve ser considerado para pacientes de elevado risco para o desenvolvimento de nefropatia induzida pelo contraste ou sobrecarga de volume e que serão submetidos a angioplastia coronária / BACKGROUND: To date, few approaches have been described to reduce the final dose of contrast agent in percutaneous coronary intervention. We hypothesized that intravascular ultrasound might serve as an alternative imaging tool to angiography in many steps during percutaneous coronary intervention, thereby reducing the use of iodine contrast. METHODS: A total of 83 patients were randomized to angiography alone-guided percutaneous coronary intervention or intravascular ultrasound-guided percutaneous coronary intervention. Both groups were treated according to a pre-defined meticulous procedural strategy, and the primary endpoint was the total volume contrast agent used during percutaneous coronary intervention. Patients were followed clinically for an average of 4 months. RESULTS: The median total volume of contrast was 64.5 mL (interquartile range [IQR], 42.8 to 97 mL; minimum, 19 mL; maximum, 170 mL) in the angiography alone-guided group vs. 20 mL (IQR, 12.5 to 30 mL; minimum, 3 mL; maximum, 54 mL) in the intravascular ultrasound-guided group (P < 0.001). Similarly, the median volume of contrast/creatinine clearance ratio was significantly lower among patients treated with intravascular ultrasound-guided percutaneous coronary intervention when compared with patients treated with angiography alone-guided percutaneous coronary intervention (1 [IQR, 0.6 to 1.9] vs. 0.4 [IQR, 0.2 to 0.6], respectively; P < 0.001). In-hospital and 4-month outcomes were not different between patients randomized to angiography alone-guided and intravascular ultrasound-guided percutaneous coronary intervention. CONCLUSIONS: Thoughtful and extensive use of intravascular ultrasound as the primary imaging tool to guide percutaneous coronary intervention was safe and markedly reduced the volume of iodine contrast compared with angiographyalone guidance. The use of intravascular ultrasound should be considered for patients at high risk of contrast-induced acute kidney injury or volume overload undergoing coronary angioplasty

O complexo esclerose tuberosa (CET) e as doenças renais policísticas autossômica dominante (DRPAD) e autossômica recessiva (DRPAR) são doenças monogênicas associadas a cistogênese renal. Os produtos dos genes mutados nessas enfermidades, respectivamente tuberina e hamartina para CET, policistina-1 (PC1) e policistina-2 para DRPAD, e poliductina/fibrocistina para DRPAR, modulam proliferação, diferenciação, apoptose, crescimento e/ou migração celular. Neste estudo empregamos um sistema tridimensional de cultura de células IMCD para caracterizar os perfis de expressão dessas proteínas durante a tubulogênese. Usando uma matriz de colágeno tipo I/Matrigel e fator de crescimento de hepatócito (HGF), a formação de estruturas alongadas se iniciou dois dias após o plaqueamento in vitro (2 DIV), ao passo que o desenvolvimento de lúmen ocorreu entre 10-14 DIV. A marcação para caspase-3 ativa foi mais intensa nas fases iniciais da tubulogênese, enquanto a marcação para Ki-67 foi uniformemente pronunciada em estágios mais tardios. A tuberina e a hamartina apresentaram expressão citoplasmática e co-localização acentuada em 6 e 12 DIV. A PC1 apresentou maior expressão nas porções ramificadas dos túbulos que nas não ramificadas no 12 DIV, um padrão não verificado para a PC2. Estas proteínas exibiram expressão citoplasmática, assim como expressão ocasional e pontual na membrana plasmática. PD1 também apresentou expressão citoplasmática. Nossos dados sugerem que a apoptose e a ciclagem celular sincrônica durante a tubulogênese in vitro são mais acentuadas, respectivamente, em fases mais precoces e mais tardias da formação tubular. Nossos achados demonstram, além disso, que as proteínas relacionadas ao CET e às DRPs são expressas in vitro durante a tubulogênese, apoiando um papel importante para a interação tuberina-hamartina na formação tubular, e são consistentes com o padrão de expressão diferencial da PC1 observado durante a nefrogênese / Tuberous sclerosis complex (TSC) and autosomal dominant and recessive polycystic kidney diseases (ADPKD and ARPKD) are monogenic diseases associated with renal cystogenesis. The products of the genes mutated in these disorders, respectively tuberin and hamartin for TSC, and polycystin-1 (PC1), polycystin-2 (PC2) and polyductin/fibrocystin (PD1) for PKD, modulate cell proliferation, differentiation, apoptosis, growth and/or migration. We have employed an IMCD tridimensional cell culture system to characterize their expression profiles along tubulogenesis. Using a type I collagen/Matrigel matrix and hepatocyte growth factor (HGF), the formation of elongated structures initiated 2 days after in vitro plating (2 DIV) while lumen developed between 10-14 DIV. Active caspase-3 labeling was more intense in initial phases of tubulogenesis while Ki-67 staining was uniformly pronounced in later stages. Tuberin and hamartin showed cytoplasmic expression and marked co- localization at 6 and 12 DIV. PC1 displayed higher expression in branching than non- branching portions of the tubules at 12 DIV, a pattern not verified for PC2. These proteins presented cytoplasmic and occasional, punctate membrane expression. PD1 also showed cytoplasmic expression. Our data suggest that apoptosis and synchronous cell cycling during in vitro tubulogenesis are more remarkable, respectively, in early and later steps of tubule formation. In addition, our findings demonstrate that the TSC and PKD proteins are expressed in vitro during tubulogenesis, supporting an important role for tuberin-hamartin interaction in tubular formation, and are consistent with the differential PC1 expression pattern observed during nephrogenesis

Background. The kidney is one of the major organs involved in whole-body homeostasis and it is well understood that chronic renal impairment is further complicated with deranged carbohydrate metabolism, dyslipidemia, altered abdominal fat distribution and the activation of renin-angiotensin system (RAS). Recently, RAS blockades of angiotensinconverting enzyme inhibitor (ACEI) and angiotensin II receptor blocker (ARB) have been noticed for their potential effects on improve glucose and lipid metabolisms and lowering the risk of new-onset diabetes. However, underlying cellular and molecular mechanisms are not fully established. / Conclusions. (1) UNX induces progressive renal impairment and dysregulation of pancreatic and renal RAS in rats. (2) Pancreatic RAS activation leads to intra-islet fibrosis, insulin-secreting beta-cell deficit and insulin secretory deficiency. (3) Renal cortex RAS dysregulation induces ectopic adipocyte differentiation and lipid infiltration, in combination with lipodystrophy and lipid peroxidation, results to insulin resistance. (4) Pancreatic insulin-secretion deficit and insulin resistance contribute to the development of glucose intolerance and hyperglycemia. (5) Kidney impacting on glucose and lipid metabolism by affecting pancreatic islet and adipocyte, suggesting an essential role of the kidney in maintaining the whole-body homeostasis. (6) RAS blockade with ACEI or ARB may prevent the development of chronic renal impairment and glucose and lipid dysmetabolisms in UNX rats. (7) Common pathways modulating blood pressure, glucose and lipid metabolism warrant future studies for the better management of the global epidemic of metabolic syndrome. / Materials and methods. Chronic renal impairment and RAS disturbance were induced by unilateral nephrectomy (UNX) in adult Sprague-Dawley rats undergoing as long as 10 months of observation. Three-month old male rats were randomized into 4 groups: (1) sham operated control rats (n=10), (2) untreated UNX model rats (n=10), (3) ACEI---lisinopril treated UNX rats (n=10), and (4) ARB-olmesartan treated UNX rats (n=10). Blood glucose levels during fasting and oral glucose tolerance test (OGTT) conditions, lipids, insulin and renal function were measured at 3, 6, 8 and 10 months after operation. Histological changes of kidney, pancreas, liver, and adipose tissue were examined at 10 months post-operation. / Objectives. (1) To set up a rat model with persistent chronic renal impairment and RAS activation. (2) To examine changes of fasting blood glucose, glucose tolerance, blood lipids and insulin sensitivity. (3) To examine changes of pancreatic islets and the factors contributing to pancreatic islet damage such as RAS, transforming growth factor (TGF)-beta and alpha-smooth muscle actin (SMA). (4) To examine changes of systemic and renal adipose tissue and the factors contributing to adipopathy such as RAS, peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and hydroxy-3-methylglutary coenzyme A reductase (HMGCR). (5) To investigate preventive effect of RAS blockades by the ACEI-lisinopril (4 mg/kg body weight) and ARB-olmesartan (4 mg/kg body weight) on the rat model of progressive renal deficiency. / Results. (1) UNX rats developed time-dependent progressive renal functional impairment and marked glomerulosclerosis and tubulointerstitial lesions. (2) UNX rats showed fasting hyperglycemia, progressive glucose intolerance, hyperlipidemia and insulin resistance. (3) UNX rats demonstrated insulin secretory deficiency in parallel to pancreatic islet fibrosis, beta-cell deficit, and overexpression of RAS components, TGF-beta, and alpha-SMA. (4) UNX rats displayed adipopathy evidenced by shifts the subcutaneous and visceral fats to the ectopic fat with lipid accumulation, lipofuscin pigmentation and adipocytes transformation. The adipopathy associated with down-regulation of AT1R and over-expression of angiotensin, AT2R, PPAR-gamma and HMGCR in the remnant kidney. (5) Treatment with lisinopril and olmesartan significantly attenuated the development of chronic renal impairment, RAS dysregulation and aberrant proteins expression, islet damage, adipose redistribution, and glucose and lipid dysmetabolism. / Sui, Yi. / Source: Dissertation Abstracts International, Volume: 70-06, Section: B, page: 3422. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2008. / Includes bibliographical references (leaves 195-220). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

This thesis is comprised of four studies and concerns haemodialysis patients’ confidence in being able to manage fluid intake between treatment sessions, and whether the fluid intake is influenced by certain modifiable characteristics of the persons in question. The overall aim was to study aspects of excessive fluid overload and haemodialysis patients’ self-regulation of fluid allotment from a bio-psychosocial and behavioural medicine perspective. The extent of non-adherence to fluid allotment was described in Study I. National registry data were used. Three out of ten Swedish haemodialysis patients had excessive fluid overload and one out of five was at risk for treatment related complications due to too rapid ultrafiltration rate. The objective in Study II was to develop and psychometrically evaluate a self-administered scale to measure situation-specific self-efficacy to low fluid intake. The measure (the Fluid Intake Appraisal Inventory) was found to be reliable and valid in haemodialysis settings. Subgroups based on individual profiles of self-efficacy, attentional style and depressive symptoms were explored in Study III using a cluster analytic approach. Three distinct subgroups were found and the subgroup structure was validated for clinical relevance. The individuals’ profile concerning self-efficacy, attentional style and depressive symptoms has to be taken into account in nursing interventions designed to reduce haemodialysis patients’ fluid intake. In Study IV, an intervention designed to reduce haemodialysis patients’ fluid intake was introduced and its acceptability, feasibility and efficacy were evaluated and discussed. Acceptability of such an intervention was confirmed. Addressing beliefs, behaviours, emotions and physical feelings is clinically feasible and may reduce haemodialysis patient’s excessive fluid overload. This thesis indicates that there is a potential for improvement in the fluid management care of haemodialysis patients. Behavioural nursing strategies that aim to assist patients to achieve fluid control should be applied more extensively. Cognitive profiles of the patients should be taken into account when targeted nursing intervention aiming to encourage and maintain the patient’s fluid control is introduced.

Fibroblast growth factor-23 (FGF23) was initially identified as the causative factor of autosomal dominant hypophosphatemic rickets. Further studies confirmed that FGF23 is predominantly expressed in the osteocytes and osteoblasts of bone and that circulating FGF23 acts on the kidney to inhibit renal phosphate reabsorption and 1,25(OH)2D3 hydroxylation. With the progression of chronic kidney disease (CKD), the kidneys become insufficient to maintain a normal systemic mineral homeostasis, resulting in various abnormalities of bone and mineral metabolism, generally referred to as Chronic Kidney Disease – Mineral and Bone Disorders (CKD-MBD). FGF23 increases early in the course of CKD in order to maintain normal serum phosphate levels; long before a significant increase in serum phosphate can be detected. Recent studies suggest that increased FGF23 levels are associated with progression of CKD, mortality, and the development of refractory secondary hyperparathyroidism. Because FGF23 is the very earliest marker of CKD-MBD, it is of particular interest to evaluate the relation between FGF23 and CKD-MBD abnormalities, in the setting of early CKD and also in individuals with normal renal function. In the present work, we show that FGF23 is linked to several dynamic measurements of vascular function, including endothelial dysfunction, arterial stiffness, and atherosclerosis. FGF23 is also positively associated with left ventricular mass index and an increased risk of having left ventricular hypertrophy. All associations were independent of serum phosphate and were strengthened in subjects with diminished renal function. Furthermore, we found significant evidence for an association between higher FGF23 and increased fat mass and dyslipidemia, which could represent a novel pathway linking FGF23 to cardiovascular disease. Finally, we show that FGF23 is a significant predictor of future fracture risk. Although these associations could be reflecting the increased risk associated with hyperphosphatemia and calcitriol deficiency, current evidence points towards FGF23 being more than an innocent bystander. At the very least, FGF23 holds promise of being a bio-marker of cardiovascular status and phosphate-related toxicity both in CKD and in the general population, and might be a therapeutic target that could improve the fatal prognosis in CKD patients.

This thesis is comprised of four studies and concerns haemodialysis patients’ confidence in being able to manage fluid intake between treatment sessions, and whether the fluid intake is influenced by certain modifiable characteristics of the persons in question. The overall aim was to study aspects of excessive fluid overload and haemodialysis patients’ self-regulation of fluid allotment from a bio-psychosocial and behavioural medicine perspective. The extent of non-adherence to fluid allotment was described in Study I. National registry data were used. Three out of ten Swedish haemodialysis patients had excessive fluid overload and one out of five was at risk for treatment related complications due to too rapid ultrafiltration rate. The objective in Study II was to develop and psychometrically evaluate a self-administered scale to measure situation-specific self-efficacy to low fluid intake. The measure (the Fluid Intake Appraisal Inventory) was found to be reliable and valid in haemodialysis settings. Subgroups based on individual profiles of self-efficacy, attentional style and depressive symptoms were explored in Study III using a cluster analytic approach. Three distinct subgroups were found and the subgroup structure was validated for clinical relevance. The individuals’ profile concerning self-efficacy, attentional style and depressive symptoms has to be taken into account in nursing interventions designed to reduce haemodialysis patients’ fluid intake. In Study IV, an intervention designed to reduce haemodialysis patients’ fluid intake was introduced and its acceptability, feasibility and efficacy were evaluated and discussed. Acceptability of such an intervention was confirmed. Addressing beliefs, behaviours, emotions and physical feelings is clinically feasible and may reduce haemodialysis patient’s excessive fluid overload. This thesis indicates that there is a potential for improvement in the fluid management care of haemodialysis patients. Behavioural nursing strategies that aim to assist patients to achieve fluid control should be applied more extensively. Cognitive profiles of the patients should be taken into account when targeted nursing intervention aiming to encourage and maintain the patient’s fluid control is introduced.

THESIS SUBMITED IN FULFILMENT OF THE REQUIREMENT FOR THE AWARD OF THE DEGREE OF DOCTOR OF TECHNOLOGY OF BIOMEDICAL TECHNOLOGTY IN THE FACULTY OF HEALTH AND WELLNESS SCIENCES AT THE CAPE PENINSULA UNIVERSITY OF TECHNOLOGY SUPERVISORS: PROF T.E. MATSHA PROF R.T. ERASMUS DR A. ZEMLIN SUBMITED DECEMBER 2013 / Introduction: Cardiovascular diseases (CVD) have become the leading cause of morbidity and mortality amongst the global population. Originally thought to be a health burden of high income countries, the prevalence is rapidly increasing in developing countries. For example, in 2008, an estimated 17.3 million died from CVD, and 80% of these (13.8 mil) were from low to middle income countries. Epidemiological data on CVD in Africa is scanty and of poor quality and national vital registration is available in only 5% of Africa’s 53 countries. Furthermore, data on CVD risk amongst the South African population and specifically the mixed ancestry community is poorly described. The increasing global population of people with CVD has been largely attributed to increasing rates of determinants and risk factors which include obesity, metabolic syndrome (MetS), type 2 diabetes mellitus (DM) and chronic kidney diseases (CKD). The prevalence of DM in South Africa is known to be on the rise with more affected communities being South African Asians followed by coloureds. Aims and objectives: The aim of this study was to determine the CVD risk profile of the Bellville South community during a baseline and three year follow-up study, by assessment of known risk factors, MetS, type 2 DM, obesity and CKD. Methods: Participants for this study were drawn from an urban community of the Bellville South suburb of Cape Town. At baseline (January 2008 and March 2009) 946 individuals aged 16 to 95 participated. All participants received a standardized interview and physical examination during which anthropometric measurements were performed three times and their average used for analysis: weight (kg), height (cm), waist (cm) and hip (cm) circumferences. Body Mass Index (BMI) was calculated as weight per square metre (kg/m2). A blood sample was obtained from all participants after an overnight fast for the determination of biochemical profiles: glucose, glycated haemoglobin, creatinine, total cholesterol, high density lipoprotein cholesterol (HDL-C), triglycerides and low density lipoprotein cholesterol (LDL-C) which was calculated using Friedewald’s formula. Kidney function test was assessed through estimated glomerular filtration rate (eGFR) using the cockcroft-Gault and MDRD equations. Blood pressure was measured according to the World Health Organisation (WHO) guidelines. Participants with no history of doctor diagnosed DM underwent a 75 g oral glucose tolerance test as recommended by the WHO. Metabolic syndrome was determined using JIS, NCEP ATPIII and IDF criteria. The follow-up examination was conducted in 2011 (3 years from vii baseline) using similar procedures. A total of 198 participants formed the follow-up cohort whose measurements were compared to those of the baseline. Finally, the prediction and processes/progression of the risk factors were determined. Results: At both baseline and follow-up studies, females had a higher BMI compared to their male counterparts. The crude prevalence of type 2 DM, including the previously diagnosed type 2 DM was 28.59% (age-adjusted = 33.5%, 95%CI: 30.01 – 36.92), and that of undiagnosed type 2 DM was 17.8% (age-adjusted = 12.4%, 95%CI: 9.8 – 14.8). The overall prevalence of CKD was 28.7% (269) and was higher in females (31.4%) compared to 20.2% in males. MetS was present in 46.5% of the participants. Gender-specific prediction for CVD risk calculated using the 30-year CVD interactive risk calculator showed that high CVD risk was present in normoglycaemic and younger subjects (under 35 years). At follow-up, the cumulative incidence of progression in glucose tolerance status was: 16.2% (32 participants including 11 with new-onset diabetes), and increased in a stepwise fashion with the number of components of MetS. Between baseline and 3-year evaluation glomerular filtration rate (eGFR) increased by 8.7 ml/min (95% confidence interval: 6.9-10.7), reflecting variables trajectories across baseline strata of kidney functions. Conclusion: Given the findings of this study and the estimated increases in the determinants and risk factors of CVD in the mixed ancestry population of South Africa this trend may continue to worsen if current trajectories do not change.