Browsing by Subject "Chronic kidney disease"

Chronic kidney disease (CKD) is a degenerative disorder that affects millions of people worldwide and there are no targeted therapeutics. Given the global burden and increasing prevalence of CKD, the kidneys represent an attractive target for regenerative medicine. The most severe forms of CKD involve irreversible damage to kidney glomerular podocytes - the specialized epithelial cells that encase glomerular capillaries and regulate the removal of toxins and waste from blood. Therefore, the goal of this research proposal was to develop a novel strategy to protect or promote repair of injured human kidney tissues with an initial focus on glomerular podocytes. To achieve this goal, we leveraged advances in the directed differentiation of stem cells and in vitro disease modeling techniques to develop translationally relevant human models of podocyte injury. We used these models to identify potential biomarkers of early onset podocyte dysfunction, endogenous therapeutic targets, and reno-protective drug candidates, with a particular emphasis on studying pathways implicated in biomechanical signaling. Our studies revealed that the mechanosensitive proteins YAP, CTGF, and Cyr61 may be viable endogenous therapeutic targets, while CTGF and Cyr61 expression could serve as biomarkers of podocyte mechanical integrity and cell health. Additionally, our preliminary high-throughput drug screens have identified promising podocyte-protective drug candidates, which will be the subject of future studies.

Background: Chronic kidney disease (CKD) is increasingly prevalent worldwide. Several low and middle income countries, including Nicaragua, are particularly affected by CKD of unknown etiology (CKDu). CKDu disproportionately affects young people who lack traditional risk factors for CKD, and it may be due to heat stress, environmental exposures, nephrotoxic medications, or genetic conditions. The purpose of this study is to define the prevalence of CKD, CKD diagnosis awareness in those affected, and determine risk factors for CKD from traditional risk factors and CKDu in Nicaragua. Methods: Surveys and testing of urine and serum for CKD markers were performed in participants 15-59 years old in households of the León municipality in northwest Nicaragua. Surveys included data on demographics, health behaviors, occupation, and medical history. Those with CKD were subdivided into CKD with traditional risk factors and suspected CKDu. Statistical analysis includes proportions, non-parametric comparison tests, and multinomial logistic regression models. Results: CKD prevalence in 1795 study participants is 8.6%, and awareness of CKD among those affected was low (22%). Of those with CKD, 30% were suspected to have CKDu, which was associated with male sex, decreased socioeconomic status, water source of river or well, agricultural occupation, lower BMI, and smoking. Use of nephrotoxic medications and family history of CKD were associated with CKD from traditional risk factors. Conclusions: CKD from both traditional risk factors and CKDu is a significant burden in this region. Our study supports some previous hypotheses of CKDu etiology and emphasizes the importance of CKD screening.

Background: Chronic kidney disease (CKD) is a progressive, irreversible condition that affects 15% of the US population, causing poor health outcomes and enormous social and economic burden. Rural and minority populations bear significant disparity in CKD outcome. Self-management of CKD and comorbid conditions is important in slowing the progression of CKD and preventing end stage renal disease.

Methods: This study uses a mixed-methods study design to investigate the association between positive mental health and self-efficacy and to qualitatively explore the dimensions of positive mental health that influence self-efficacy. A cross-sectional study involving 257 individuals was conducted from May to July 2016. Quantitative data collection involved administration of a questionnaire and clinical assessment of kidney function. Participants were asked about their medical history and attitudes on the chronic disease management (self-efficacy for chronic disease management, coping, social support, and perceived stress), and mental health and illness (positive mental health, depression, anxiety, and PTSD). Ordered logistic regression was used to assess the relationship between positive mental health and self-efficacy, controlling for depression, the interaction between positive mental health and depression, and other covariates. Qualitative data collection involved conducting six focus group discussions involving 35 individuals who experience significant life impact due to kidney disease to explore facilitators and barriers of CKD self-management.

Results: Individuals with flourishing positive mental health were significantly more likely to have high self-efficacy compared to individuals with languishing positive mental health (p < 0.001, Figure 10). Overall, in the fully adjusted model, the proportional odds ratio of improved self-efficacy was 2.89 (95% CI 1.29-6.47), all else held constant. For individuals with CKD, the proportional odds ratio of improved self-efficacy was 7.67 (95% CI 2.42-24.29), all else held constant. For individuals without CKD, positive mental health was not a significant predictor of self-efficacy (p-value > 0.05). Qualitative data showed support for the broaden and build theory as a possible mechanism linking positive mental health and CKD self-management. Positive emotions derived from positive mental health allowed individuals to acquire personal and social resources such as resilience, optimism, and social support that encourage self-management of CKD.

Conclusion: These findings suggest that positive mental health should be incorporated into existing CKD self-management programs to fully address the psychosocial needs of patients and effectively encourage sustainable behavioral changes for CKD self-management. Future efforts should focus on identifying positive mental health interventions that builds on the strong familial relationships, and spiritual and religious organizations in the community to improve positive mental health in this population.

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Background: Traditional medicine use is increasingly recognized as a common and important component of healthcare globally. Our study aim was therefore to identify the commonly used traditional medicines in Moshi, Tanzania, the factors influencing their use and associations between traditional medicine use & prevalence of chronic diseases. Methods: We performed a secondary data analysis of a mixed methods study in Moshi, comprising 42 extended interviews and 5 focus group discussions with key informants, and cross-sectional household survey using interviewer-administered questionnaires and field-based diagnostic tests for CKD, diabetes, hypertension and HIV. Results: We identified 168 traditional medicines, of which 15 (8.9%) and 5 (3%) were used to treat chronic diseases and CKD, respectively. Participants reported seeking healthcare advice from medical doctors (97%), family members (52%), pharmacists (24%) and friends or neighbors (14%). In a fully adjusted model, CKD patients were more likely than the non-CKD population to report a history of traditional medicine use (AOR=1.99; p=0.04), and family tradition (OR=1.97), difficulty finding a medical doctor (OR=2.07) and fewer side effects with traditional medicines (OR=2.07) as their reasons for preferring traditional medicines to hospital medicines. Conclusions: Traditional medicine use is high in Moshi, and more so among the CKD population. A history of traditional medicine use is associated with the prevalence of CKD in Moshi. Most of these traditional medicines have biologically active substances that could potentially be developed into therapeutic and prophylactic therapies for CKD, and CKD-associated co-morbidities.

Chronic kidney disease of unknown etiology (CKDu) has been prevalent in the North Central Province of Sri Lanka since 1994 and has steadily increased over the last 3 decades. Currently, many researchers believe that contaminated drinking water due to agrochemical pollution is driving CKDu incidence. Suspect chemicals have included organic contaminants, heavy metals, hard water, and fluoride. However, there is a lack of studies that have tried to characterize chemical pollutants in CKDu endemic wells in Sri Lanka and compare these profiles to non-endemic wells. The objective of this dissertation was to utilize various mass spectrometric techniques and water quality monitoring methods to characterize various chemical pollutants in CKDu endemic wells. Specifically, I (1) developed a novel analytical method for the detection of a prime suspect in CKDu onset; (2) measured major chemical contaminant suspects in CKDu endemic wells and statistically assessed the relevance to CKDu incidence by comparing to non-endemic wells; and (3) utilized recent developments in high – resolution mass spectrometry and non-targeted analysis to annotate novel chemical pollutants in Sri Lankan well water and determine sources of chemical pollution on drinking wells.In Chapter 2, I developed a direct injection LC-MS/MS method for the detection of glyphosate and AMPA, the main chemical suspect for CKDu incidence and its metabolite, in hard water systems, similar to those in endemic regions of Sri Lanka. Previous detection methods either required large sample volumes, time consuming derivatization techniques, or were just not sensitive enough to detect low concentrations of the pesticide. The method I developed required little sample preparation and had the lowest detection limits for the two analytes than any other previously published method. Additionally, I was able to show that the addition of a strong chelating agent, EDTA, was able to reduce the ionic interference in MS systems caused by hard water and improve the response of anionic analytes across a wide range of water hardness, demonstrating robustness of the method. This method has implications in allowing for the environmental detection and monitoring of glyphosate, which was previously challenging to accomplish. In Chapter 3, I measured various water quality parameters hypothesized to be linked to CKDu in endemic and non-endemic wells to better understand which parameters were significant for CKDu presence. The parameters measured were: glyphosate and AMPA, water hardness, fluoride, and a suite of heavy metals. My results found significantly higher levels of glyphosate, water hardness, and fluoride in CKDu endemic wells compared to non-endemic wells. I also found endemic and non-endemic wells with heavy metals exceeding drinking water quality guidelines. Through intensive statistical analysis and calculation of Odds Ratios, glyphosate and fluoride appear to be the most significant parameters for CKDu incidence in Sri Lanka. These two parameters had significantly higher odds ratios than any other parameter measured in the study. Results demonstrate that the water hardness and abundance of metal ions in endemic regions allows glyphosate to persist in the wells and potentially induce nephrotoxicity in conjunction with high concentrations of fluoride. This is the first time a study of this size was carried out in Sri Lanka and the first to statistically link specific water quality parameters to CKDu incidence. In Chapter 4, I utilized novel high-resolution mass spectrometric and non-targeted analysis techniques to characterize contaminant profiles in endemic wells in Sri Lanka. I was able to confirm the presence of multiple pharmaceuticals, agrochemicals, polymer additives, and personal care products. Additionally, I was able to annotate probable and tentative structures within the data set acquired from endemic and non-endemic wells. A majority of these compounds have never been identified are reported to be found in Sri Lankan waters. The results demonstrate, based on the use of compounds annotated, that most of the chemical pollution in these wells is due to agricultural runoff and wastewater intrusion due to the overwhelming presence of pharmaceuticals, agrochemicals, additives, and surfactants annotated. Additionally, based on differential analysis and abundance comparisons between endemic and non-endemic wells, CKDu wells have a higher contaminant load than non-endemic wells, potentially due to the lower economic status of the North Central Province having poor drinking water infrastructure. Additionally, annotated compounds were predicted for nephrotoxicity, and compounds predicted to be nephrotoxic were significantly more abundant in endemic wells compared to non-endemic wells. In this study, I was able to use mass spectrometry to postulate main sources of pollution in Sri Lankan wells and demonstrate that endemic wells have a higher abundance of chemical pollution and potentially nephrotoxic compounds that could be related to CKDu incidence. Mass spectrometry and other analytical techniques allowed me to fully investigate the chemical contamination relevant to CKDu incidence in Sri Lanka. I measured significantly higher concentrations of glyphosate and fluoride in CKDu endemic wells, which are both suspected nephrotoxins. Additionally, I was able to calculate significant Odds Ratios for glyphosate and fluoride that demonstrate that for increasing levels of these two contaminants, the potential odds for CKDu to be present at that well significantly increases by 3 to 17-fold, respectively. Lastly, I was able to use novel high-resolution mass spectrometry and non-targeted analysis to demonstrate that the major chemical pollutant pathways in Sri Lankan wells is most likely agricultural runoff and wastewater intrusion. Additionally, I demonstrated that endemic wells appear to have a significantly higher chemical pollutant burden than non-endemic wells, with some of these pollutants potentially being nephrotoxic. These studies are some of the most comprehensive in examining chemical water quality in Sri Lanka in relation to CKDu and will aide in future research in pinpointing the exact cause for this disease in this region while also helping to advocate for cleaner drinking water in these endemic regions.