This systematic review aims to examine the relationship between the social determinants of health that significantly impact the prevalence and progression of chronic kidney disease (CKD) amongst Black Americans. The Black American population has the highest prevalence of CKD in the United States, while concurrently possessing prominent genetic risk factors for this chronic disease. The social determinants: healthcare quality and access (extended to account for health behaviors), social and community context, and economic stability were specifically assessed in this review. Key terms were utilized to search electronic databases PubMed and Web of Science, which yielded 470 unduplicated articles. Twenty-nine articles met the inclusion criteria for this systematic review, with three articles being applicable to the three selected social determinants, six being applicable to social and community context, six being applicable to economic stability, and fourteen being applicable to healthcare quality and access. Major contributors towards CKD incidence and progression amongst Black Americans were identified to be: exposure to discrimination, expectations of discrimination and prejudice, low routine medical care, limited health literacy, distrust of health providers, being of low socioeconomic status, and a lack of engagement in functional health behaviors (fruit/vegetable consumption and CKD screening). Each social determinant was seldom observed to be operating exclusively as a contributing factor towards CKD, exemplifying how the intersectionality of these factors contributes to increased CKD risk and progression. Findings from this systematic review highlight the need for targeted healthcare initiatives for Black Americans to remedy the CKD endemic.

Chronic kidney disease (CKD) is growing global public health problem affecting 1 in 10 adults in developed countries and recognised as an important risk factor for cardiovascular disease (CVD) development. CVD is the main cause of death among CKD patients. Endothelial injury and dysfunction are critical steps in atherosclerosis, a major CVD. Oxidative stress (increased level of reactive oxygen species, ROS) has been associated with CVD development. Intravenous (IV) iron preparations are widely used in the management of CKD mediated anaemia, and have been associated with increased oxidative stress and cellular dysfunction. This study examined the effect of pharmacologically-relevant concentrations of IV Venofer (iron sucrose) or IV Ferinject (Ferric carboxymaltose, FCM) on primary human umbilical vein endothelial cell (HUVEC) activation/damage and on intracellular ROS generation as well as studying the potential mechanisms responsible. Data from TUNEL assay and Annexin V-FITC/PI staining showed that, IV FCM had no effect, but IV iron sucrose increased HUVEC apoptosis at 24hr. IV iron sucrose inhibited cell proliferation and reduced cell viability. Both compounds induced EC activation through sustained activation of p38 MAPK and up-regulation of ICAM-1 and VCAM-1. Additionally, the compounds induced significant increase in total ROS and superoxide anion production, which was attenuated by the anti-oxidant N-acetylcysteine (NAC). P38 MAPK showed up-regulation of pro-apoptotic protein Bax and down-regulation of antiapoptotic Bcl-2 protein in HUVEC treated with IV iron sucrose and p38 inhibition reversed these effects. In summary, these results suggest that IV iron sucrose causes more severe EC injury than IV FCM. However, both IV iron preparations induced intracellular ROS and superoxide anion generation in HUVEC leading to EC activation/dysfunction, providing a potential explanation for vascular damage in CKD patients.

Chronic kidney disease (CKD) is a common disease that affects millions across the US and the globe. Patients with CKD experience an increased risk of venous thrombosis. Here we use two longstanding robust murine models of nephropathies in conjunction with a reliable murine model of venous thrombosis to model venous thrombosis risk in CKD. We show that in the adenine diet-induced CKD, increased concentrations of adenine in the diet result in increased histological evidence of nephropathy and increased venous thrombosis risk assessed by Inferior Vena Cava ligation. Next, we demonstrate that in unilateral ureteric obstruction models, the duration of obstruction is proportional to the nephropathies developed by histological assessment. In both models, we relate nephropathy to venous thrombosis risk. When probed for aryl hydrocarbon receptor (AHR) activation, adenine diet-induced CKD mice show increased activation assessed by nuclear translocation of the receptor. This phenotype was confirmed in vitro when treating human telomerase immortalized human umbilical endothelial cells with uremic serum. Nuclear AHR was not observed in control conditions in vivo or in vitro. Pharmacologic AHR inhibition using a novel drug, BAY Compound, and a well-known AHR inhibitor were both able to abrogate uremic activation of AHR in vitro, which was then corroborated with in vivo studies. Tissue factor (TF) and plasminogen activator inhibitor 1 (PAI-1) are prothrombogenic proteins linked to AHR activation. TF and PAI-1 showed upregulation in CKD mice which were blocked when CKD mice were given AHR inhibitor BAY Compound. This work demonstrates a unique model of venous thrombosis in CKD and suggests that AHR inhibition may be able to limit the elevated risk of venous thrombosis associated with uremia. / 2026-03-08T00:00:00Z

京都大学 / 新制・課程博士 / 博士(医学) / 甲第25004号 / 医博第5038号 / 新制||医||1070(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 長船 健二, 教授 生田 宏一, 教授 上野 英樹 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Background: Autosomal polycystic kidney disease is distinguished into dominant (ADPKD) and recessive (ARPKD) inheritance usually caused by either monoallelic (PKD1/PKD2) or biallelic (PKHD1) germline variation. Clinical presentations are genotype-dependent ranging from fetal demise to mild chronic kidney disease (CKD) in adults. Additionally, exemptions from dominant and recessive inheritance have been reported in both disorders resulting in respective phenocopies. Here, we comparatively report three young adults with microcystic-hyperechogenic kidney morphology based on unexpected genetic alterations beyond typical inheritance. Methods: Next-generation sequencing (NGS)-based gene panel analysis and multiplex ligation-dependent probe amplification (MLPA) of PKD-associated genes, familial segregation analysis, and reverse phenotyping. Results: Three unrelated individuals presented in late adolescence for differential diagnosis of incidental microcystic-hyperechogenic kidneys with preserved kidney and liver function. Upon genetic analysis, we identified a homozygous hypomorphic PKHD1 missense variant causing pseudodominant inheritance in a family, a large monoallelic PKDH1-deletion with atypical transmission, and biallelic PKD1 missense hypomorphs with recessive inheritance. Conclusion: By this report, we illustrate clinical presentations associated with atypical PKD-gene alterations beyond traditional modes of inheritance. Large monoallelic PKHD1-alterations as well as biallelic hypomorphs of both PKD1 and PKHD1 may lead to mild CKD in the absence of prominent macrocyst formation and functional liver impairment. The long-term renal prognosis throughout life, however, remains undetermined. Increased detection of atypical inheritance challenges our current thinking of disease ontology not only in PKD but also in Mendelian disorders in general.

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Chronic kidney disease is an urgent public health problem in the U.S., affecting 15% of all adults, and more than 740,000 have progressed to end-stage renal disease (ESRD), requiring life-sustaining renal replacement therapy (RRT). ESRD has devastating health, quality-of-life, and economic consequences, rendering most patients unable to maintain employment and costing Medicare $36 billion in 2017. Arguably, the most disadvantaged subgroup is the subset of patients that received no or minimal pre-ESRD nephrology care, which currently accounts for one third of the total ESRD population. This subgroup suffers increased morbidity and mortality, and has limited access to kidney transplantation, the optimal RRT. Despite this subgroup representing a large minority of the ESRD patient population, there has been no U.S.-based examination of their ESRD diagnosis experiences, coping styles and strategies, and RRT decision-making preferences. Therefore, we conducted a study that compared the ESRD diagnosis experiences, coping styles and strategies, and RRT decision-making preferences among patients with varying amounts of pre-ESRD nephrology care. We also assessed nephrologists’ current practices and perspectives on the manner and timing of RRT education for patients with varying amounts of pre-ESRD care. This mixed methods study provides a comprehensive understanding of the diagnosis experiences, coping styles and strategies, and RRT decision-making preferences of patients facing sudden and unexpected ESRD diagnosis. The study contributes important knowledge about this subgroup of patients that can influence and improve health care delivery. The results of this research will inform future intervention-based investigations to improve care for patients with minimal or no pre-ESRD nephrology care. / Public Health

<p> Physical activity improves physical and psychological functioning in patients with chronic kidney disease (CKD). However, no studies have investigated the determinants of physical activity in the CKD population. The purpose of the study was to evaluate the utility of the Theory of Planned Behaviour (TPB) for understanding physical activity in the CKD population. A secondary purpose of this study was to examine alternate conceptualizations of the subjective norm construct within the TPB framework. We hypothesized that attitude, subjective norm (injunctive and descriptive norms), perceived behavioural control (PBC), and social support would predict intention to engage in physical activity and that both intention and PBC would predict physical activity behaviour.</p> <p> Participants (52 male, 28 female, mean age = 68.43 (13.21)) were recruited from nephrologists' clinics and were all predialysis (mean serum creatinine = 310.55 (148.75) μmol/L). Participants completed a questionnaire assessing attitude, subjective norm, PBC, and social support. One week later, participants were phoned for a follow-up interview to assess their physical activity during the preceding week.</p> <p> In a regression model, 61% of the variance in intention to perform physical activity was explained, with PBC (β=.69,p<.001) emerging as the sole significant predictor, while attitude (β=.17, p=.10), subjective norm (β=.02, p=.89), informational support from family (β=-.10,p=.33), and informational support from doctors (β=-.05, p=.54) were non-significant predictors. In a regression model to explain physical activity, 28% of the variance in physical activity was explained, with intention emerging as a significant predictor (β=.53, p=.02), but not PBC (β=.18, p=.29).</p> <p> The hypotheses were only partially supported, as PBC emerged as a significant predictor of physical activity intention, while attitude, subjective norm, and social support did not. Furthermore, intention, but not PBC, predicted physical activity behaviour. These results demonstrate the utility of the TPB for explaining physical activity in the CKD population. Additional research is required to clarify if targeting PBC may be an effective means for intervention to increase physical activity in the CKD population.</p> / Thesis / Master of Science (MSc)