Chronic kidney disease is a substantial health problem effecting a large portion of the US population. Presence of excess protein, particularly albumin, in the urine of patients with chronic kidney disease is an independent risk factor for cardiovascular disease and progression to end stage renal disease. In addition, excess protein reabsorption in the proximal tubule is sufficient to cause damage to the proximal tubule independent of the initial condition that lead to chronic disease. In the last decade, excess protein reabsorption by the proximal tubule as a result of chronic kidney damage has been shown to cause oxidative and ER stress, cell death, as well as tubule inflammation and fibrosis in the proximal tubule cell. Only recently have two studies investigated the role of autophagy in protein-induced tubule damage. Autophagy is a dynamic catabolic mechanism used to degrade cytosolic elements in times of cell starvation and is an important process in the cell's response to stress. The results of the studies by Wei Jin Liu et al. and Yamahara et. al. provide important first steps to determine whether autophagy of excess protein in proteinuric states prevents proximal tubule cell toxicity and potentially slow the progression of chronic kidney disease (CKD). This thesis will explore the results of these two studies in the context of proximal tubule damage in chronic kidney disease, and discuss the potential for protein autophagy to improve our understanding and treatment of chronic kidney disease.

Type II diabetes mellitus is currently on the rise and reaching epidemic proportions in the United States. In addition to this increase, the number of cases of diabetic complication such as kidney disease has increased. Currently diabetic kidney disease is the leading cause for end stage renal disease in the United States accounting for nearly half of all cases. Type II diabetes is the result of metabolic, hemodynamic and inflammatory alterations within the body. Currently there is a standard of care to treat both metabolic and hemodynamic perturbations by enforcing tight glycemic control and utilizing anti-hypertensive drugs, most notably RAS inhibitors. These therapeutic interventions however, are not sufficient as many patients with type II diabetes will still develop diabetic kidney disease therefore another treatment option is imperative. Currently there are no treatments available to counteract the adverse inflammatory responses associated with type II diabetes which are strong contributors to the progression of the diabetic kidney disease. Among the inflammatory parameters studied as potential targets for therapeutic intervention the inflammatory cytokine tumor necrosis factor-α (TNF-α) stands out among the rest for its multifaceted role in disease progression. TNF-α has been shown to both directly and indirectly involved in development and progression of diabetic kidney disease. The inflammatory cytokine itself is toxic to renal cells initially increasing the permeability of the glomerular filtration barrier and contributing to proteinuria which eventually causes cellular apoptosis. TNF-α also activates second messengers and up-regulates transcription factors that further contribute to the progression of diabetic kidney disease. Two TNF-α inhibitors, pentoxifylline and chrysin have stood out among the other investigational drugs which have been studied as potential therapeutic options to delay the progression of diabetic kidney disease. Pentoxifylline is a methyl-xanthine derivative that is currently used to treat peripheral vascular disease. It has shown good effect in clinical trials decreasing both urinary TNF-α concentrations as well as urinary protein excretion. Chrysin is a natural plant derivative belonging to the flavonoid family and is known for its anti-inflammatory and anti-oxidant properties. Currently chrysin has only been studied in animal models of diabetic kidney disease but has shown to not only decrease concentrations of inflammatory cytokines to control levels and improve renal functions but also prevented the histopathological changes associated with diabetic kidney disease suggesting that chrysin has the ability to not only slow the progression of disease and preserve renal function, it has the ability to prevent the disease from ever taking root. Diabetic kidney disease is a devastating disease affecting millions of people worldwide. It is important for further investigation with these investigational drugs to be performed in large scale clinical trials to produce safety and efficacy data with the end goal of becoming approved as new treatments for diabetic kidney disease.

Thesis (M.S.M.) PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / BACKGROUND: Although novel anticoagulant drugs have proven safety and efficacy profiles from Phase III clinical trials, those patients with significant kidney disease were excluded. The lack of knowledge about incidence, severity and risk factors for severe renal dysfunction in patients requiring oral anticoagulation impedes development of strategies to mitigate risks of hemorrhage associated with renally-eliminated novel oral anticoagulants. METHODS: Patients taking warfarin for atrial fibrillation (AF) or venous thromboembolism (VTE) were consecutively enrolled from January 2007 to December 2010. Baseline kidney function was assessed and patients were followed to their first decline in Glomerular Filtration Rate (GFR) to < 30 ml/min estimated by the Cockcroft-Gault calculation. Independent risk factors for development of severe kidney dysfunction were assessed by multivariate analysis. RESULTS: Of 787 patients identified, 34 were excluded for baseline eGFR < 30 ml/min. The mean age of the cohort was 71 years. At baseline, 23% (n=174) had moderate renal impairment, or Stage 3 CKD (eGFR 30-59 ml/min), while 31% had mild disease. Overall, those with hypertension, congestive heart failure (CHF), diabetes mellitus (DM), and coronary artery disease (CAD) were 74%, 33%, 31%, 24%, and 9% of the cohort, respectively. A decline in eGFR to < 30 ml/min (the primary outcome) occurred in 91 patients, 25% of which happened within 5.3 months. Of those with baseline Stage 3 CKD, 37% experienced the primary outcome. In multiple logistic regression analysis, a baseline eGFR 30–59 ml/min conferred a greater than 14-fold increased risk in the development of eGFR < 30 ml/min (OR 14.5, 99% CI: 5.3 to 39.8, P<0.001) during the warfarin exposure period. CAD was associated with a greater than two-fold increased risk (OR 2.2, 95% CI 1.1 to 4.4, P=0.004). After adjusting for baseline kidney function, age was not an independent risk factor for a decline in eGFR to < 30 ml/min. CONCLUSIONS: Acute and chronic renal dysfunction is common among individuals on chronic warfarin therapy. Better understanding of the fluctuations in renal function would inform patient selection and monitoring strategies for optimal use of novel anticoagulants. / 2031-01-01

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / A doenÃa renal crÃnica (DRC) à caracterizada pela perda normalmente lenta, progressiva e irreversÃvel da funÃÃo renal. Sugere-se que, nesta patologia, a resposta natriurÃtica do organismo à ingestÃo de sal e a expansÃo de volume encontra-se reduzida em consequÃncia da lesÃo dos nÃfrons. Nesse contexto, mostram-se necessÃrios estudos que estabeleÃam uma relaÃÃo entre a DRC e a regulaÃÃo de peptÃdeos natriurÃticos, como guanilina (Gn), uroguanilina (UGn) e peptÃdeo natriurÃtico atrial (PNA), e o efeito da angiotensina II (AngII) sobre a regulaÃÃo destes peptÃdeos. Assim, buscou-se avaliar uma possÃvel modulaÃÃo da via das guanilinas pelo enalapril no modelo de nefrectomia 5/6 (nx5/6). Utilizou-se ratos Wistar, machos, com peso entre 250-300g. Os animais foram divididos em 4 grupos (n=8): grupos controle sem tratamento ou tratado com enalapril (10mg/kg v.o.) (SHAM e SHAM+E) e grupos submetidos à nx 5/6 sem tratamento ou tratado com enalapril (10 mg/kg v.o.) (Nx e Nx+E). Ao final da 10 semana apÃs a cirurgia, foram determinados alguns marcadores de funÃÃo renal. As amostras de rim foram encaminhadas para anÃlise histolÃgica e avaliaÃÃo expressÃo de RNAm para Gn, UGn, PNA e dos receptores da guanilato ciclase de membrana, GC-A e GC-C e do receptor de clearence (NPR-C). No intestino, determinou-se a expressÃo de RNAm para Gn, UGn e G-C. Nx apresentou os nÃveis sÃricos de creatinina (Nx= 1.28  0.07; SHAM= 0.67  0.02 mg/dL), urÃia (Nx=108.0  5.57; SHAM=96.83  4.08 mg/dL), proteinÃria (Nx=129.10  13.87 SHAM=96.83  4.07; mg/24hrs) e FENa+ (Nx=3.552  0.56; SHAM=1.43  0.16) aumentados, e a TFG (Nx=0.44  0.10  0.04; SHAM=0.97  0.07 mL/min) diminuÃda. Nx+E, quando comparado a Nx, apresentou nÃveis reduzidos de creatinina (Nx+E= 0.97  0.08; Nx=1.28  0.07 mg/dL), de proteinÃria (Nx+E=31.94  6.46 Nx= 129.10  13.87 mg/24hrs) e da FENa+ (Nx+E= 2.02  0.28; Nx=3.55  0.56), alÃm elevar a TFG (Nx+E=0.70  0.08; Nx=0.44  0.10 mL/min). Nx apresentou aumento da expressÃo gÃnica intra-renal de Gn (Nx=13.92  5.13; SHAM=1.08  0.20), UGn (Nx=12.77  7.00; SHAM=1.04  0.13), GC-A (Nx=5.91  1.36; SHAM=1.06  0.17) e NPR-C (Nx=7.835  1.72; SHAM=1.15  0.27), e Nx+E teve genes reduzidos para UGn (Nx+E=0.10  0.03; Nx=1.75  0.96), GC-A (Nx+E=0.031  0.01; Nx=1.18  0.27) e NPR-C (Nx+E=0.03  0.01; Nx=1.08  0.24) quando comparados a Nx. No intestino, houve uma reduÃÃo da transcriÃÃo de GC-C (Nx=0,22Â0,04; SHAM=1.12  0.22) em Nx, e o enalapril aumentou os nÃveis de expressÃo deste gene (Nx+E=3.94  0.57; Nx=1.15  0.22). Em conjunto, estes dados sugerem uma hiperativaÃÃo na via das guanilinas na DRC, alÃm de modulaÃÃo dessa classe de peptÃdeos por parte da AngII.

Background: Chronic Kidney Disease (CKD) is a worldwide public health problem. There are few studies in Latin America, especially in primary care settings. Our objective was to determine the prevalence, stages, and associated factors of CKD in primary care setting. Methods: We did a retrospective secondary analysis of a database from the Diabetes and Hypertension Primary Care Center of the Peruvian Social Security System (EsSalud) in Lima, Peru. We defined CKD as the presence of eGFR <60 mL/min and/or albuminuria >30 mg/day in 24 h, according to Kidney Disease: Improving Global Outcomes (KDIGO). Factors associated with CKD were evaluated with Poisson Regression models; these factors included age, gender, type 2 diabetes mellitus (DM2), hypertension (HTN), body mass index (BMI), and uric acid. Associations were described as crude and adjusted prevalence ratios (PR) and their 95% confidence intervals (95% CI). Results: We evaluated 1211 patients (women [59%], mean age 65.8 years [SD: 12.7]). Prevalence of CKD was 18%. Using the estimated glomerular filtration rate (eGFR), the prevalence was 9.3% (95% CI 5.3 – 13.3) in patients without HTN or DM2; 20.2% (95% CI 17.6 – 22.8) in patients with HTN, and 23.9% (95% CI 19.4 – 28.4) in patients with DM2. The most common stages were 1 and 2 with 41.5% and 48%, respectively. Factors associated with CKD in the adjusted analysis were: age in years (PR = 1.03, 95% CI 1.01 – 1.04), DM2 (PR = 3.37, 95% CI 1.09 – 10.39), HTN plus DM2 (PR = 3.90, 95% CI 1.54 – 9.88), and uric acid from 5 to <7 mg/dL (PR = 2.04, 95% CI 1.31 – 3.19) and ≥7 mg/dL (PR = 5.19, 95% CI 3.32 – 8.11). Conclusions: Prevalence of CKD in the primary care setting population was high. CKD is more frequent in the early stages of the disease, and individuals with hypertension, DM2, older age and hyperuricemia have higher prevalence of CKD.

INTRODUCTION Chronic kidney disease (CKD) affects 50 million people globally. Several studies show the importance of implementing interventions that enhance patients’ knowledge about their disease. In 2011 the Kidney Disease Knowledge Survey (KiKS) was developed: a questionnaire that assesses the specific knowledge about chronic kidney disease in pre-dialysis patients. OBJECTIVE To translate to Spanish, culturally adapt and validate the Kidney Disease Knowledge Survey questionnaire in a population of patients with pre-dialysis chronic kidney disease. METHODS We carried out a Spanish translation and cross-cultural adaptation of the Kidney Disease Knowledge Survey questionnaire. Subsequently, we determined its validity and reliability. We determined the validity through construct validity; and reliability by evaluating its internal consistency and its intra- observer reliability (test-retest). RESULTS We found a good internal consistency (Kuder-Richardson = 0.85). The intra-observer reliability was measured by the intra-class correlation coefficient that yielded a value of 0.78 (95% CI: 0.5-1.0). This value indicated a good reproducibility; also, the mean difference of -1.1 test-retest SD 6.0 (p = 0.369) confirms this finding. CONCLUSION The translated Spanish version of the Kidney Disease Knowledge Survey is acceptable and equivalent to the original version; it also has a good reliability, validity and reproducibility. Therefore, it can be used in a population of patients with pre-dialysis chronic kidney disease.

Introduction—Chronic kidney disease (CKD) affects 50 million people globally. Several studies show the importance of implementing interventions that enhance patients' knowledge about their disease. In 2011, the Kidney Disease Knowledge Survey (KiKS) was developed, a questionnaire that assesses the specific knowledge about CKD in pre-dialysis patients. Objective—To translate to Spanish, culturally adapt and validate the questionnaire KiKS in a population of patients with pre-dialysis CKD. Methods—The translation and cultural adaptation of KiKS was performed. Subsequently, its validity and reliability were determined. The validity was evaluated by construct validity; and the reliability by its internal consistency and its intra-observer reliability (test-retest). Results—A good internal consistency was found (Kuder-Richardson = 0.85). Regarding intraobserver reliability, the intraclass correlation coefficient with a value of 0.78 (95% CI: 0.5–1.0) indicated a good reproducibility; the mean difference of −1.1 test-retest S.D. 6.0 (p = 0.369) confirm this.

Meeting the health care needs of people with chronic conditions presents one of the greatest challenges for 21st century health care system renewal. Appropriate redesign of health care delivery with this complex patient population in mind requires information from many sources. Although much is known about the patient experience of chronic illness much less is understood about how patients navigate their health care delivery context. The purpose of this qualitative study was to examine the point of view of patients dealing with multi-morbidity. These people have a unique understanding of how health care delivery links across time, place, and settings because of the care they require for their multiple chronic conditions. An interpretive descriptive design was used to examine patient navigation from the perspective of 20 adult patients with chronic kidney disease, and co-existing diagnoses of diabetes mellitus and/or cardiovascular disease. The findings generated from iterative, constant comparative analysis add important patient perspectives about health care system navigation. From the consumer perspective health care navigation is challenging, requiring (a) ongoing discovery about the complex social structures that make up the health care system, and (b) learning how to strategically use this knowledge to manage the health care system. The findings highlight the disjunctures and misalignments in the health care delivery system, the cumulative health care-related burden of multiple chronic conditions for consumers, and consumer concerns about subtle inequities in the health care system. As health care renewal efforts gain momentum new knowledge from the perspective of consumers, such as that captured in this research, is important. The consumer perspective provides a valuable opportunity for stakeholders in health care policy- and decision-making to contextualize and make greater sense of the information used in making decisions about health care service delivery for vulnerable populations, like patients with multiple chronic conditions. / Applied Science, Faculty of / Nursing, School of / Graduate

Cardiovascular complications represent the leading cause of death in chronic kidney disease (CKD) patients. Significant renal mass reduction induced by 5/6 subtotal nephrectomy (Nx) animal model leads to a chain of events that culminates in hypertension and CKD. The renin angiotensin (Ang) system (RAS) is known to be dysregulated, specifically Ang type 1 receptor (AT1R) plays a major role in development and progression of the disease. However, conflicting results have been reported on intrarenal AT1R levels, and the impact of antihypertensive drugs on RAS signaling is divergent. We hypothesize that PET imaging will be able to quantify kidney AT1R expression reliably in healthy and disease states. The broad objectives of this research project were: (i) to develop a positron emission tomography (PET) probe capable of detecting changes in the AT1R binding in the kidney; (ii) to elucidate the nature/temporal role of renal AT1R in Nx rat model of CKD; and (iii) to explore the predictive value of non-invasive PET imaging of AT1R to guide the use of antihypertensive therapy in preventing the progression of the disease. The novel selective AT1R PET radioligand [18F]FPyKYNE-losartan was successfully used with PET in detecting renal AT1Rs at early and late stages of the CKD. The PET results correlated well with in vitro [125I]-[Sar1, Ile8]Ang II autoradiography. Over the time-course of the study (10-20 weeks), the Nx rats exhibited renal impairment, proteinuria and sustained hypertension. Echocardiography indicated the development of cardiac hypertrophy most likely secondary to the hyperdynamic circulation. These abnormalities were associated with increasing plasma and kidney levels of Ang II, and compensatory downregulation of renal AT1Rs. ACEI enalapril attenuated renal impairment, hypertension and prevented progression of cardiac hypertrophy in Nx rats. This was successfully accomplished through reduction of systemic and kidney Ang II, and consequent normalization of renal AT1R as measured by PET (and autoradiography). The non-dihydropyridine CCB diltiazem also reduced blood pressure but did not normalize renal AT1R expression. Diltiazem induced elevation in Ang II levels in plasma, kidney and heart, associated with exacerbation of renal and cardiac dysfunction, and no change in AT1R renal expression. This outcome adds value to the use of [18F]FPyKYNE-losartan PET for determination of receptor abnormalities with progression of the disease and monitoring of therapy.

Les phases de transitions entre les différentes stratégies de prise en charge de l'insuffisance rénale chronique terminale peuvent être associées à une augmentation de la morbidité et de la mortalité lorsqu’elles ne sont pas anticipées. Il faut donc pouvoir définir des trajectoires de patient et faire en sorte de maîtriser les changements d’état afin d’améliorer la prise en charge du patient insuffisant rénal chronique. Cela ne peut être atteint sans une phase exploratoire préalable visant à étudier les phases de transition du parcours de soins intégrés. L’objectif de ce travail était donc d’étudier trois transitions présentes dans le parcours de soins du patient atteint d’insuffisance rénale chronique.Nous avons montré que chez le patient qui débute la dialyse péritonéale, le temps passé au préalable dans un autre traitement de suppléance, que ce soit en hémodialyse ou en transplantation rénale, peut précocement impacter son devenir dans la technique. Cette importance du traitement antérieur renforce notre conviction qu’il faut avoir une vision globale et intégrée de la prise en charge du patient insuffisant rénal chronique terminal. De même, la survenue d’une péritonite dans les premiers mois en dialyse péritonéale est associée à l’arrêt précoce de la technique. Il est donc indispensable à la prise en charge initiale et au cours des premiers mois de traitement en dialyse péritonéale de s’interroger sur le risque de transfert précoce en hémodialyse du patient et sur la nécessité de lui créer une fistule artério-veineuse. Nous avons également rapporté le fait que les infections liées à la fistule en dialyse hors centre sont des événements relativement peu fréquents. Cependant, une approche différente de ces infections, en distinguant le risque de première infection et le risque de récidive infectieuse chez un patient, permettra de diminuer la fréquence de ces événements responsables de transition non programmée entre les différentes structures de dialyse. Enfin, nous avons choisi d’étudier la transition entre stade V de l’insuffisance rénale et le traitement par dialyse dans la population des patients atteints de cancer. Nous avons montré que l’incidence de la dialyse dans cette population n’est pas plus importante que dans la population générale. La survie en dialyse de ces sujets semble également comparable à celle des dialysés sans cancer diagnostiqué. Nos résultats suggèrent que seuls les patients avec un cancer en bonne condition générale ont la possibilité d’être traité par dialyse chronique. Il existe un réel rationnel scientifique à considérer le parcours de soins du patient insuffisant rénal chronique stade V comme un parcours intégré, comprenant plusieurs états et de nombreuses phases de transition, qui doivent être explorées finement tout en tenant compte de l’ensemble de la trajectoire du patient. / Transitions between treatment strategies in chronic kidney disease are often not prepared and can lead to morbidity and mortality. It is necessary to anticipate these transitions to improve patients outcomes and health care organisation. We aimed at studying three pathways observed in the career of chronic kidney disease patients.We have shown that patients treated by hemodialysis before peritoneal dialysis start and failed transplant patients had a higher risk of early peritoneal dialysis failure. Early peritonitis was also associated with a higher risk of early technical failure. It is therefore important to evaluate the necessity to create an arterio-venous fistula in peritoneal dialysis patients during the first months on dialysis, to avoid transfer in hemodialysis on a central venous catheter.We reported that the rate of arterio-venous fistula infections in satellite dialysis units was low. However, it seems necessary to distinguish the risk for having a first infection and the risk for having a relapse of infection. This consideration can help decreasing the number of fallback between stallite units and hospital dialysis centers.Finally, we studied transition between end-stage renal disease and dialysis in cancer patients. We showed that incidence of chronic dialysis initiation in that population was not higher then the one observed in the general population. Survival in dialysis was not different in cancer patients compared to matched patients without malignancy. We can hypothesise that only cancer patients in good condition are proposed for dialysis programs.It is necessary to consider the chronic kidney disease patients' care as an integrated care program, with transitions between treatment strategies that can be improved and anticipated.