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.

Anaemia in chronic kidney disease (CKD) mostly results from a decrease in the production of erythropoietin (EPO) by the failing kidney. CKD progression requires treatment with erythropoiesis-stimulating agents and iron supplementation to ensure sufficient erythrocyte production. Best clinical practice guidelines should be adhered to in managing CKD to reduce morbidity and mortality related to anaemia associated cardiovascular disease. Likewise, guideline deviations create an increased strain on the resources of the treatment facility. It is uncertain to which extent these guidelines are followed by Nephrology Units in the public healthcare sector, or whether the documented international trends are prevalent locally due to the paucity of local data, and therefore further investigation is warranted. This study aimed to assess treatment trends in managing anaemia in CKD patients at the Steve Biko Academic Hospital (SBAH). Files of patients receiving treatment at the SBAH Nephrology Unit between 2 January 2018 - 31 August 2018 were reviewed. Only individuals with stage 5 CKD receiving either haemodialysis, or peritoneal dialysis were included, while those with less than three months’ treatment were excluded. Measured variables included demographical information, current EPO treatment and/or iron supplementation regimens versus serum haemoglobin/iron levels and quantity of administered blood products. Ninety-seven patients met the inclusion criteria. Haemodialysis accounted for 43% (n = 42), and peritoneal dialysis 57% (n = 55). Intergroup comparison between the number of results where both haemoglobin and iron were within the target range versus the number of results where both parameters fell outside the target range yielded a significant difference (p = 0.0031). Patients receiving peritoneal dialysis reached serum haemoglobin and iron levels closer to normal target values compared to those receiving haemodialysis. Managing anaemia in CKD is a complex process. More stringent iron control, especially for patients receiving haemodialysis, including the administration of long-acting EPO preparations once a month, is proposed. The latter will contribute to the improvement of clinical outcomes of patients with CKD. Keywords: Chronic kidney disease, anaemia, erythropoiesis stimulating agent, haemoglobin, iron / Dissertation (MSc (Pharmacology))--University of Pretoria, 2020. / Pharmacology / MSc (Pharmacology) / Unrestricted

Indiana University-Purdue University Indianapolis (IUPUI) / FGF23 is an osteocyte produced hormone necessary for maintaining systemic phosphate handling, and thus bone structure and function in both rare and common disorders such as chronic kidney disease (CKD). FGF23 is a critical factor in CKD, with elevated levels causing alterations in mineral metabolism and increased odds for mortality. However, the mechanisms directing the production of key modulators of skeletal homeostasis and biomineralization within osteocytes, and how this is altered in chronic kidney disease, remain unclear. The experimental focus of this dissertation was to dissect the molecular systems and role of oxygen sensing in the regulated production of FGF23. In CKD, up to 75% of patients have anemia and concomitant marked elevations in FGF23, increasing mortality odds. Anemia is a potent driver of FGF23 secretion, therefore, current and emerging therapies, including recombinant EPO and the hypoxia inducible factorprolyl hydroxylase inhibitors (HIF-PHI) FG-4592 and BAY 85-3934, were used to improve anemia in the adenine diet-induced mouse model of CKD. In the mice with CKD, iFGF23 was markedly elevated in control mice but was attenuated by 65-85% after delivery of EPO or HIF-PHI, with no changes in serum phosphate. This was associated with improved systemic iron utilization and reductions in mRNA markers of renal fibrosis. In osteocyte-like cell cultures treated with HIF-PHI, integrative RNAseq and ATACseq analysis identified candidate genes upregulated in response to mimicked hypoxia, concomitant with elevated Fgf23 expression. These genes were found to be downregulated in CKD bone, therefore, knock-out cells were generated using CRISPR/Cas9 technology. These cells were found to be functionally similar to in vivo conditional knockout models that have enhanced bone mass and elevated FGF23. Taken together, these results further define novel factors involved in the regulation of FGF23 and identify new therapeutic targets. / 2023-05-26

Indiana University-Purdue University Indianapolis (IUPUI) / Chronic kidney disease (CKD) currently affects ~37 million Americans and causes substantially increased risk of skeletal fracture and fracture-related mortality. Current methods to treat CKD-related bone loss remain alarmingly ineffective. Skeletal fragility in CKD is predominately driven by deteriorations in cortical bone, highlighted by significant cortical porosity development. It is hypothesized that cortical porosity is largely driven by chronically high levels of parathyroid hormone (PTH), which alters the balance of bone remodeling in favor of rampant osteoclast activity and bone resorption. Restricting cortical bone deterioration and the development of cortical pores is likely essential to improve CKD patients’ bone health and reduce their fracture risk. The goal of this series of studies was to answer the following key questions: (1) to what degree do bisphosphonates, an approved pharmacological agent used in metabolic bone disease, accumulate in the skeleton of animals with CKD; (2) can smaller and more frequent doses of bisphosphonates alter skeletal accumulation and improve cortical architecture and the mechanical integrity of bone; (3) can non-bisphosphonate pharmacological interventions more specifically affect cortical bone deterioration. Utilizing epi-fluorescence and two-photon microscopy, our results show that bisphosphonates accumulate more in rats with renal impairment and fractionating bisphosphonates lowered skeletal accumulation irrespective of disease state. Further, studies in both rat and mouse models of CKD demonstrated different bisphosphonate treatments alone do not recover declines in cortical microarchitecture or mechanical properties in CKD. These findings demonstrate that a single intervention is not sufficient in managing CKD-induced bone alterations. Utilizing individual pore tracking analysis, we demonstrated cortical pores can be modulated with therapeutic interventions and can infill, despite the presence of CKD. Potent suppression of PTH led to significant pore infilling while more subtle reductions in PTH, via a calcimimetic, had less striking effects on bone. Calcimimetics mitigated cortical microarchitecture deterioration and reduced the rate of cortical pore expansion. Overall, these findings highlight the importance of PTH management for treating cortical deterioration in CKD. Although bisphosphonates can be utilized in ways that reduce skeletal accumulation, they appear to need co-therapies to reduce skeletal fragility associated with CKD.

INTRODUCTION Apixaban has revolutionized anticoagulation in patients with atrial fibrillation in preventing strokes. Anticoagulant-induced nephropathy with warfarin is well known, but nephropathy with apixaban is a rare entity, and here we present a case of Apixaban-induced nephropathy. Case Description A 71-year-old patient with a medical history of persistent atrial fibrillation on apixaban, Ischemic cardiomyopathy, and chronic kidney disease stage (CKD) IIIa presented to the hospital with complaints of dyspnea and hemoptysis and tea-colored urine of three-day duration. On admission, the patient had acute kidney injury (AKI) on CKD, Methicillin sensitive Staphylococcus aureus (MSSA) bacteremia, and elevated international normalized ratio (INR) and apixaban were held. The hemoptysis worsened and prompted bronchoscopy revealing diffuse alveolar hemorrhage. The urinalysis showed gross hematuria with high red blood cell (RBC) count and 1+ proteinuria presumed secondary to MSSA associated glomerulonephritis. Evaluation for coagulopathy with serum mixing studies and autoimmune workup has been unremarkable. The patient's coagulopathy was considered secondary to decreased clearance of apixaban with AKI on CKD. However, the patient's kidney function continued to worsen, needing continuous renal replacement therapy and a kidney biopsy for a definitive diagnosis for his decline in kidney function. Kidney biopsy revealed IgA dominant infection associated glomerulitis with one out of hundred glomeruli with the crescent formation and signs of anticoagulant induced nephropathy with several intratubular RBC casts out of proportion to the degree of glomerular injury causing acute tubular damage. The patient's INR improved on dialysis. However, he continued to be oliguric before being terminally extubated. DISCUSSION With the increasing incidence of atrial fibrillation and the use of oral anticoagulants, it is vital to have anticoagulant induced as a differential in patients presenting with supra therapeutic INR and AKI. Apixaban-induced nephropathy is a subset of anticoagulant-induced nephropathy and an uncommon cause of the acute decline in kidney function needing dialysis. Prompt recognition and treatment will prevent further deterioration in kidney function and possible improvement.

Indiana University-Purdue University Indianapolis (IUPUI) / Chronic kidney disease (CKD) results in an increased fracture risk, partially due to elevations in parathyroid hormone (PTH) that lead to substantial bone loss. On its own, bone loss does not explain bone fragility in CKD, suggesting that changes in skeletal tissue (bone quality) may also be present. Understanding the factors that lead to fracture in these patients will have a substantial impact on patient care and could lead to a better understanding of how to reduce their fracture risk. Due to their suppression of PTH, calcitriol and its analogues are the current standard of care for bone disease in CKD. Yet, surprisingly little is known of their effects on bone. Agents effective in treating osteoporosis are not recommended in advanced CKD due to the lack of data regarding their efficacy and safety in these patients. The goals of the current study were to determine (1) the impact of CKD on bone quality, (2) the ability of calcitriol to improve skeletal parameters, and (3) the efficacy of various pharmacological interventions (calcium, bisphosphonates, anti-sclerostin antibody, and raloxifene) on bone mass, quality, and mechanical properties in CKD bone disease. Using a slowly progressive rat model of CKD, renal and mineral metabolism, bone morphology, bone quality, and bone mechanics (at several length scales) were assessed. Primarily due to elevated PTH, mechanical testing and tissue-level assessments revealed compromised bone quantity (high cortical porosity and low trabecular volume) and quality (high collagen cross-linking and low matrix bound water). Despite clinically relevant reductions in PTH, calcitriol treatment had no positive impact on skeletal properties. Most agents were only effective when PTH levels were normal. Raloxifene, however, led to greater whole bone and material toughness (the ability of bone to tolerate existing damage) despite modest PTH suppression. While the examination of bone quality in CKD is still in its infancy, these results indicate that enhancing bone quality with raloxifene may be an effective means to compensate for bone loss in CKD.

No description available.

First year death rates remain unacceptable high for the end-stage renal disease (ESRD) population. New effective methods are vital to improve first year morbidity and mortality outcomes for the population transitioning from Stage 4 chronic kidney disease (CKD) to ESRD)/Stage 5 CKD. Based on current methods, evidence-based recommendations made by nephrology providers are frequently not heeded by patients in Stage 4 CKD. Low levels of patient knowledge, self-efficacy, and a poor ability to self-manage CKD negatively influence a patient’s ability to follow provider recommendations. The group visit (GV) intervention has demonstrated improvements in disease-related outcomes through increased levels of patient knowledge, self-efficacy, and disease self-management for other chronic diseasses such as diabetes and congestive heart failure (CHF). No data are available for the use of GVs in CKD The purpose of the study was to develop and test a nurse practitioner-facilitated chronic CKD GV model versus usual nephrology care for Stage 4 CKD patients (knowledge, selfefficacy/self-management, physiological data, and satisfaction). As classified by the National Kidney Foundation’s (NKF) staging system, Stage 4 CKD is considered severe kidney disease, with a decrease in the functional capacity of the kidney as determined by a glomerular filtration rate (GFR) of 15-30 ml/min. It is common for patients with Stage 4 CKD to progress to Stage 5 CKD/end-stage renal disease (ESRD), requiring dialysis or transplantation to survive. Preliminary instrumentation and feasibility studies were conducted prior to a pilot study of a CKD GV model. The development and validation of the Stage 4 CKD Knowledge Instrument was completed with 59 Stage 4 patients. Findings supported reliability (KuderRichardson-20 [KR] = .89) and content validity (I-CVI = .97, S-CVI= 1.0) Feasibility of the CKD GV model was assessed with a single group, pretest-posttest design using a convenience iv sample of eight Stage 4 patients. Results demonstrated an improvement in knowledge of CKD from a median of 69% to 86% (p =.012). No improvements were noted in self-efficacy scores (p = .230). GV satisfaction ranged from very good to excellent. Feasibility was supported by a high retention rate (100%). No barriers to participant recruitment or GV implementation were encountered. The pilot study used a two-group, repeated measures experimental design, with a sample of 30 Stage 4 CKD patients from two office locations of an outpatient nephrology practice. Patients were randomized to the GV intervention or to usual nephrology care. CKD-knowledge, self-efficacy, and self-management scores were collected at baseline, six months, and nine months. Physiological data were measured at baseline, six months, and nine months. GV satisfaction was obtained after the completion of GVs (six months). Nephrology practice satisfaction was obtained from by both groups at nine months. MANOVA for repeated measures was calculated for data collected at the three time points. Twenty-six of 30 patients completed the study, with four patients ineligible to complete the study due to progression to ESRD and dialysis initiation. GV attendance was 92%. CKD knowledge was statistically improved for both groups (F(1.498, 34.446) = 6.363, P = .008). While not statistically significant, a favorable upward trend in the mean scores for the subscales of self-management (communication, partnership in care, and self-care) was demonstrated in the GV patients, with a lack of improvement found in the usual care group for these subscales. Selfefficacy scores revealed a non-significant improvement in mean scores for the GV patients during the GVs, not seen with usual care patients. GV satisfaction was again high with the vast majority of patients requesting use of GVs in their future nephrology care. v Current methods of intervention in the Stage 4 CKD population have made little impact on reducing first-year ESRD mortality and morbidity rates. Opportunities to intervene in the poor outcomes begin in the predialysis care of Stage 4 patients. Based on the documented success of multidisciplinary approaches in predialysis care, of GVs in other chronic diseases, and of chronic illness care based on the CCM, a high probability for success exists with the application of GVs in CKD. Although limited by a small sample size, promising improvements in the subscales of disease self-management, self-efficacy, CKD knowledge, and high satisfaction with the GV model for GV participants were revealed in this study. Further research is warranted for the CKD GV model on a larger randomized sample in other locations. Much needed data would be provided on which to base decisions for use of the CKD GV intervention in the predialysis care of Stage 4 patients.