M.A. (Clinical Psychology) / This study concerns itself with relaxation training and social support as alternative forms of treatment for hypertension in renal patients. following the success of these in the treatment of essential hypertension (Lagrone et al 1986). Three groups of renal dialysis patients were chased for the study. The first group underwent relaxation training, the second group participated in group therapy sessions whieh emphasized social support. and the last group acted as a control group. The following hypotheses were made: I. Renal dialysis patients that receive progressive muscle relaxation training will show a significantly lower systolic and diastolic blood pressure rate. 2. Renal dialysis patients that participated in a number of group therapy sessions will show significant decreases in both systolic and diastolic blood pressure.

Understanding how a therapy will impact the injured kidney before being administered would be an asset to the clinical world. The work in this thesis advances the field of mathematical modeling of the kidneys to aid in this cause. The objectives of this work are threefold: 1) to develop and personalize a model to specific patients in different diseased states, via parameter estimation, in order to test therapeutic trajectories, 2) to use parameter estimation to understand the cause of different kidney diseases, differentiate between potential kidney diseases, and facilitate targeted therapies, and 3) to push forward the understanding of kidney physiology via physiology-based mathematical modeling techniques. To accomplish these objectives, we have developed two models of the kidneys: 1) a broad, steady-state, closed-loop model of the entire kidney with human physiologic parameters, and 2) a detailed, dynamic model of the proximal tubule, an important part of kidney, with rat physiologic parameters. To readily aid physicians, a human model would easily fit into the clinical workflow. Since there is a lack of invasive human renal data for validation and parameter estimation, we employ a minimal modeling approach. However, to aid in deeper understanding of renal function for future applications, targeted therapy testing, and potentially replace invasive measures, we develop a more detailed model. The development of such a model requires invasive data for validation and parameter estimation, and hence we model for rodents, where such invasive data are more readily available. The kidneys are composed of approximately one million functional units known as nephrons. The glomerular filtration rate (GFR) is the rate at which the kidney filters blood at the start of the nephron. This filtration rate is highly regulated via several control mechanisms and needs to be maintained within a small range in order to maintain a proper water and electrolyte balance. Hence, fluctuations of GFR are indicative of overall kidney health. In developing the human kidney model, we also sought to understand the relationship between blood pressure and GFR since many therapies affect blood pressure and subsequently GFR. This model describes steady-state conditions of the entire kidney, including renal autoregulation. Model validation is performed with experimental data from healthy subjects and severely hypertensive patients. The baseline model’s GFR simulation for normotensive and the manually tuned model’s GFR simulation for hypertensive intensive care unit patients had low root mean squared errors (RMSE) of 13.5 mL/min and 5 mL/min, respectively. These values are both lower than the error of 18 mL/min in GFR estimates, reported in previous studies. It has been shown that vascular resistance and renal autoregulation parameters are altered in severely hypertensive stages, and hence, a sensitivity analysis is conducted to investigate how changes in these parameters affect GFR. The results of the sensitivity analysis reinforce the fact that vascular resistance is inversely related to GFR and show that changes to either vascular resistance or renal autoregulation cause a significant change in sodium concentration in the descending limb of Henle. This is an important conclusion as it quantifies the mapping between hypertension parameters and two important kidney states, GFR and sodium urine levels. Glomerulonephritis is one of the two major intra-renal kidney diseases, characterized as a breakdown at the site of the glomerulus that affects GFR and subsequently other portions of the nephron. This disease accounts for 15% of all kidney injuries and one-fourth of end-stage renal disease patients. The human kidney model is used to estimate renal parameters of patients with glomerulonephritis. The model is an implicit system and in developing an optimization algorithm to use for parameter estimation, we modify in a novel way, the Levenberg-Marquardt optimization using the implicit function theorem in order to calculate the Jacobian and Hessian matrices needed. We further adapt the optimization algorithm to work for constrained optimization since our parameter values must be physiologically feasible within a certain range. The parameter estimation method we use is a three-step process: 1) manually adjusting parameters for the hypertension comorbidity, 2) iteratively estimating parameters that vary from person to person using no-kidney- injury (NKI) data, and 3) iteratively estimating parameters that are affected by glomerulonephritis using labeled diseased data. Such a process generates a model that is personalized to each given patient. This patient-specific model can then be used to simulate and evaluate outcomes of potential therapies (e.g., vasodilators) on the model in lieu of the patient, and observe how alterations in blood pressure or sodium level affect renal function. Parameter estimation in the presence of glomerulonephritis is a challenging task due to the complexity of the kidney physiology and the number of parameters to estimate. This is further complicated by comorbidities such as hypertension, cardiac arrythmia, and valvular disease, because they alter kidney physiology and hence, increase the number of parameters to estimate. We chose to focus on hypertension since it is very prevalent in hospitals and intensive care units. It was found that over all patients, average model estimates of GFR and urine output rate (UO) were within 9.2 mL/min and 0.71 mL/min for NKI data. These results are expectedly better than those achieved from the non-personalized model since the parameters are now specific to each patient. The results also demonstrate our ability to non-invasively estimate GFR with less error than the 18 mL/min currently possible. The estimations were validated by ensuring that the estimated parameter values were physiologically sound and matched the literature in terms of expected values for different demographic groups. It is vital for a properly functioning kidney to maintain solute transport throughout the nephron. Kidney diseases in the nephron can manifest themselves via the solute transport mechanisms. To understand how these diseases affect the kidney and to simulate transporter- targeting therapies, we have developed a detailed model, starting from the human model previously developed, of one portion of the kidneys, the proximal tubule. The proximal tubule is the site of the most active transport within the nephron and the target for several therapies. Our goal is to study and understand the dynamic behavior of the proximal tubule when solute transporters breakdown and to investigate treatment therapies targeting certain solute transporters. The proposed model is dynamic and includes several solutes’ transport mechanisms, with parameters for rats. We chose to investigate diabetic nephropathy and the associated sodium-transporter alteration (knockout) therapy. Diabetic nephropathy is characterized as kidney damage due to diabetes and affects 30% of diabetics. In terms of reducing hyperfiltration, a potential cause of diabetic nephropathy where an overabundance of solutes and fluid are filtered at the glomerulus, the model demonstrates that knockout of this transporter results in a reduction in sodium and chloride reabsorptions in the proximal tubule, thereby preventing hyperfiltration. Further, we conclude that vital flows for maintaining kidney homeostasis, fluid and ammonium reabsorptions, are corrected to healthy values by a 50% knockout (impairment) of the sodium-hydrogen transporter. Next, we use the dynamic model to detect different diseased states of the proximal tubule transporters. We have accomplished this task by using Bayesian estimation to estimate transporter density parameters (a metric for kidney health) using measured signals from the proximal tubule. This approach is validated with experimental rat data, while further investigations are conducted into the performance of the estimation in the presence of varied input signals, signal resolutions, and noise levels. Estimation accuracy within 20% of true transporter density and within 4% of true fluid and solute reabsorption was achieved for all combinations of diseased transporters. We concluded that including chloride and bicarbonate concentrations improved estimation accuracy, whereas including formic acid did not. This is an important conclusion as it can help physicians determine which blood tests to order for diagnosing kidney disease; to our knowledge, this is a first. It was also found that sodium and glucose proximal tubule concentrations are most affected by changes in the sodium-hydrogen and sodium-bicarbonate transporters. This conclusion provides insight into the interplay between solute transporter density and sodium and glucose concentrations in the proximal tubule. Such knowledge paves the way for new transporter targeted therapies.

The epithelial cell of the kidney proximal convoluted tubule, like that of the small intestine, consists of two distinct plasma membrane surfaces referred to as the brush border, or luminal surface, and the basal-lateral, or contraluminal surface. Once isolated, membrane vesicles formed from the kidney cell can serve as models for the study of heavy metal mephrotoxin interaction with the two different plasma membrane surfaces. For ideal comparison between the two membranes, the isolation procedure should be identical for both. This has been accomplished by other investigators using differential centrifugation followed by free-flow electrophoresis or sucrose density centrifugation. Utilizing the self-forming gradient capabilities of Percoll, we have developed a less cumbersome procedure to effect simultaneous isolation of brush border and basal-lateral membrane vesicles. Brush border membrane vesicles isolated by this procedure exhibited 8 to 13-fold enrichment in marker enzyme activity but appeared to have impaired glucose uptake activity. Since the Percoll-prepared vesicles seemed unsuitable for uptake studies, brush border membrane vesicles isolated by a differential precipitation method were used to investigate the effect of cadmium on glucose uptake. Of the concentrations of cadmium tested, 0.1 mM CdCl slightly inhibited glucose uptake whereas 1 mM CdCl greatly reduced glucose uptake in these vesicles. / Master of Science

Much of the prior research on the psychosocial aspects of end stage renal disease (ESRD) has focused solely on the individual, without considering the family's role in patient adjustment. Little research has been conducted on the contextual elements of the patient's adjustment to renal failure and dialysis. It was the purpose of this study to assess the effect of family relationships on a patient's health locus of control as a measure of adjustment to ESRD. Health locus of control was hypothesized to be dependent on the family relationship variables of cohesiveness, adaptability and independence; as well as a communications variable measuring incongruent communications. From the general context of the double bind a path model was constructed to estimate the associations among the variables. Data was collected and analyzed on 91 ESRD patients from four dialysis treatment centers and a sample of Continuous Ambulatory Perotineal Dialysis patients. The results of this research suggest that the double bind theory may be an excellent explanatory paradigm for patient adjustment to chronic illness. It was found that the greater the perceived paradox in family communications the more likely the patient was to subscribe to an externally oriented health locus of control. The family relationship variables were found to be indirect predictors of health locus of control, acting through the family communications process. / Ph. D.

published_or_final_version / Public Administration / Master / Master of Social Sciences

published_or_final_version / abstract / Physiology / Doctoral / Doctor of Philosophy

published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

published_or_final_version / Mental Health / Master / Master of Social Sciences

No description available.

Background: In the country of Bangladesh, arsenic (As) exposure and high plasma homocysteine (hyperhomocysteinemia; HHcys) are widely prevalent. An estimated 35-77 million people in Bangladesh are exposed to As above the World Health Organization standard of 10 μg/L, while a cross-sectional study by our group estimated that 63% of men and 26% of women had HHcys. Both As exposure and HHcys are associated with adverse health outcomes. Arsenic exposure is an established cause of skin, lung, and bladder cancer, and cardiovascular disease, while HHcys is a strongly associated with increased risk for cardiovascular disease. Chronic kidney disease is emerging as an As-linked disease outcome. Potential mechanisms for adverse health effects induced by As (e.g. nephrotoxicity) include oxidative stress and inflammation. Inorganic As is metabolized through a series of methylation and reduction reactions which facilitate As excretion in urine; arsenite (AsIII), the primary form of As in Bangladesh drinking water, is converted to monomethylarsonic acid (MMAV), monomethylarsonous acid (MMAIII), and dimethylarsinic acid (DMAV). The methyl donor for these methylation reactions is S-adenosylmethionine (SAM). Because the availability of SAM is modulated by various nutritional parameters, nutritional interventions have the potential to enhance As methylation. Supplementation with folic acid (FA), which increases liver SAM, has been shown by our group to enhance As methylation and lower blood As in folate-deficient Bangladeshi adults. The endogenous synthesis of creatine from guanidinoacetate (GAA) consumes a large proportion of SAM, and creatine supplementation in the diet can downregulate endogenous creatine synthesis by inhibiting GAA production. In this way, creatine supplementation has the potential to spare SAM, enhance As methylation, and also lower homocysteine (Hcys), a by-product of SAM-dependent methylation. The potential for dietary creatine to enhance As methylation may explain the frequently observed associations of urinary creatinine with a decreased proportion of inorganic As in urine out of total urinary As (u%InAs), and an increased proportion of DMA in urine out of total urinary As (u%DMA) in epidemiological studies. Alternatively, it is possible that these associations are due to confounding by renal function, which could influence both As and creatinine excretion. Objectives: Our objectives were to determine (1) whether folic acid and creatine lower blood As in a mixed folate-deficient and replete population, (2) whether creatine lowers plasma total homocysteine (tHcys), (3) whether As exposure is associated with increased inflammation and decreased estimated glomerular filtration rate (eGFR), and whether these effects are greater in those with a more oxidized plasma glutathione redox potential (EhGSH), and (4) whether As metabolite proportions in urine and blood are associated with eGFR, and whether these associations may explain the relationship between As metabolite proportions and urinary creatinine. Methods: We addressed these objectives in five epidemiologic investigations of As-exposed Bangladeshi adults, employing data from a randomized placebo-controlled trial (the Folic Acid and Creatine Trial (FACT)) and two cross-sectional studies (the Nutritional Influences on Arsenic Toxicity (NIAT) study, and the Folate and Oxidative Stress (FOX) study). In the 24-week FACT study, participants were randomized to receive either placebo, 400 μg/day FA (FA400), 800 μg/day FA (FA800), 3 g/day creatine (Cr), or 3 g/day creatine + 400 μg/day FA (Cr+FA400). At week 12, half of the participants in the FA400 and FA800 groups were switched to placebo, while the other half continued their assigned supplements. Additionally, at week 12 participants in the Cr and Cr+FA400 groups were switched to placebo. In Chapter 4 (FACT), we examined whether FA400, FA800, Cr, or Cr+FA00 lowered blood As to a greater extent than placebo over the first 12 weeks of the trial, and whether a rebound in blood As occurred from week 12 to 24 related to cessation of FA supplementation. In Chapter 5 (FACT), we examined whether Cr or Cr+FA400 lowered plasma tHcys to a greater extent than placebo or FA400 alone, respectively, over the first 12 weeks of the trial. In Chapter 6 (NIAT), we examined the associations of water and urinary As with eGFR, and whether eGFR confounded the associations between urinary creatinine and the urinary %As metabolites; we also explored the associations of eGFR with the urinary %As metabolites. In Chapter 7 (FOX), we examined the associations of eGFR with the urinary and blood %As metabolites; we also examined whether the relationship between blood and urinary %As metabolites was decreased among those with reduced renal function. In Chapter 8 (FOX), we examined the associations of water, blood, and urinary As with markers of inflammation (C-reactive protein (CRP) and α-1 acid glycoprotein (AGP)), and eGFR, and investigated whether these associations were modified by the plasma EhGSH. Results: FA800 lowered blood As to a significantly greater extent than placebo over the 24 weeks of the FACT study, with no rebound in blood As related to cessation of FA supplementation. FA400, Cr, and Cr+FA400 did not lower blood As to a greater extent than placebo (Chapter 4). Cr and Cr+FA400 did not lower plasma tHcys to a greater extent than placebo or FA400 alone, respectively. However, in the Cr+FA400 group we observed a significant correlation between a decrease in plasma GAA over time and a decrease in plasma tHcys over time (Chapter 5). Total urinary As was marginally associated with a decrease in eGFR in the NIAT study, though water As was not. Additionally in the NIAT study, while eGFR did not confound the relationship between urinary creatinine and urinary %As metabolites, we observed a positive association between eGFR and u%InAs, and a negative association between eGFR and u%DMA (Chapter 6). Likewise in the FOX study, eGFR was positively associated with u%InAs and negatively associated with u%DMA; the associations of eGFR with the blood %As metabolites were in the same direction, although not statistically significant. We additionally observed that for a given increase in blood %InAs, the increase in urinary %InAs tended to be smaller in those with reduced renal function, compared to those with normal renal function (Chaper 7). In the FOX study we also observed the total blood As and urinary As were marginally associated with decreased eGFR, while water As was not. Water As, urinary As, and blood As were significantly positively associated with plasma CRP in those with low plasma GSH or a more oxidized plasma EhGSH (Chapter 8). Conclusions: Strategies to reduce risk for As-induced diseases are sorely needed, particularly due to barriers to As exposure removal and/or persistent elevated risk from past As exposure. Several susceptibility factors which can potentially be intervened upon have been discussed in this dissertation, namely folate nutritional status, redox status, and renal capacity to excrete As. Our finding that folic acid supplementation (800 μg/day) lowered blood As to a greater extent than placebo in a randomized trial indicates that improving the folate status of the general Bangladeshi population may reduce the body burden of As. Folate fortification of food in Bangladesh, in addition to potentially reducing risk for As-induced diseases, would have the additional benefit of substantially lowering the prevalence of HHcys. Our finding in a cross-sectional study that individuals with a more oxidized plasma glutathione redox potential were susceptible to As-induced inflammation may indicate that improving redox status can protect against As-induced inflammation. Randomized trials are needed to confirm a protective effect of antioxidants; upon confirmation, antioxidant dietary recommendations for As-exposed populations could potentially be implemented. Finally, our cross-sectional finding of a positive association between eGFR and urinary %InAs, and that eGFR modified the relationship between blood and urinary %InAs, suggests that InAs excretion may be impaired among individuals with reduced renal function. A decreased renal capacity to excrete InAs may lead to accumulation of InAs in tissues, and related health effects. Potential interventions related to renal function include treatment of risk factors for chronic kidney disease (e.g. blood pressure, blood glucose) in order to prevent onset of renal function deterioration, or to screen for chronic kidney disease in order to identify susceptible individuals and conduct directed interventions. Of these three susceptibility factors, the strongest evidence exists for the potential of folic acid to lower blood As. In Bangladesh, where As exposure and HHcys are widely prevalent, folate fortification should be considered a viable option for reducing risk for As- and Hcys-related diseases.