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Chronic kidney disease (CKD), cardiovascular disease, and diabetes are major health challenges in Canada. In the last 5 years, a series of large randomized controlled trials (RCTs) have demonstrated that sodium-glucose cotransporter-2 inhibitors (SGLT2is) reduce the risk of kidney failure, cardiovascular mortality, and hospitalization for heart failure in people with albuminuric CKD irrespective of diabetes status. Ensuring SGLT2is are optimally used provides a key means for Canada to respond to these looming population health challenges. Exploring the generalizability of these landmark clinical trials to understand the potential impact of SGLT2i use in a Canadian population helps establish the support for their widespread use. A cohort of patients under the care of nephrologists in the province of British Columbia was compared with the participants in two landmark SGLT2i RCTs in order to characterize the burden of disease and explore the generalizability of the findings to the people in British Columbia with CKD. The study indicated that the British Columbia CKD population was older, with a greater proportion of females, and a higher risk group with worse outcomes than the cohorts in the clinical trials. Given the discrepancies in age and sex between the British Columbia CKD population and the trial cohorts, a literature review was firstly conducted to better understand the interaction between sex and the burden and progression of cardiovascular disease in those with CKD. The narrative review highlighted that the prevalence and incidence of cardiovascular disease in patients with CKD by sex is not well described. It also illustrated that all patients with CKD, regardless of sex, are at an elevated risk for cardiovascular disease thus creating a compelling case for the use of effective treatments to reduce this risk. A secondary analysis of a landmark SGLT2i trial was conducted according to age categories and sex to explore whether age or sex led to differences in treatment effect or adverse events. This analysis supports the safety and efficacy of canagliflozin, an SGLT2i, with consistent benefits in kidney and cardiovascular outcomes with minimal differences in the risk of adverse events in patients with CKD across a wide age span and in both males and females. This newly established evidence supports the efforts to increase SGLT2i use across the spectrum of age and both sexes in the British Columbia CKD population. Poor medication adherence is a frequently neglected challenge in healthcare that prevents full realization of the benefits of evidence-based therapies. Forgetting to take medication was identified as one of the most significant patient-reported reason for suboptimal medication adherence in the general CKD literature, with evidence of decline in adherence to SGLT2is to 50-70% within the first year. To better understand additional factors that affect the loss of medication adherence and the challenges in management of SGLT2is, a study was conducted to interview clinicians in British Columbia to determine the barriers and facilitators to utilizing SGLT2is in the local context. The major findings from the clinicians were that some patients do not tolerate adverse effects such as mycotic genital infections and have difficulty remembering information regarding SGLT2is, but many were enthusiastic about the potential benefits. This generated the hypothesis that medication taking reminders and repeated education may be a strategy to improve medication adherence. Given the large geographic area and varying available resources in British Columbia, accessibility and scalability are key practical considerations for an adherence intervention targeting this population. A review of digital and mobile health (mHealth) interventions was conducted in search of a potential intervention that could accommodate these design requirements. The review highlighted examples of effective integration of mHealth into clinical medicine, such as mobile alert detecting acute kidney injury in hospitalized patients resulting in substantial cost savings per patient. Leveraging the ubiquity and low cost of mobile phone communication, a text messaging intervention study was developed with the goal of improving medication adherence to SGLT2is in British Columbia. This hybrid effectiveness-implementation study will determine the effectiveness of a 12-month text message-based intervention covering content regarding the benefits of SGLT2is, adverse reactions, and general health advice and medication reminders. The trial will recruit patients with CKD, cardiovascular disease and/or diabetes, starting a new SGLT2i prescription, and with access to a smart phone. The primary endpoint is medication adherence to SGLT2is at 12 months with secondary assessments at 24 months to assess persistence of any effect after cessation of the intervention. The primary outcome will be measured by mean proportion of days covered (PDC) with an active prescription at 12 months, and implementation outcomes will assess any barriers and facilitators to the incorporation of the text messaging intervention in the local setting. Overall, this thesis describes in detail the potential for SGLT2is to reduce the burden of kidney and cardiovascular disease in the context of a Canadian provincial population. A means of maximizing the benefit of these medications via improved adherence is described and serves as the groundwork for a practical and fundable clinical trial.

Abstract: Kidneys stabilize renal blood flow (RBF) in response to fluctuations in blood pressure by employing two mechanisms, the myogenic response (MR) and the tubuloglomerular feedback (TGF) mechanism. The TGF mechanism stabilizes macula densa solute delivery via controlling afferent arteriolar diameter. Furthermore, TGF generates oscillations within each nephrovascular unit (NVU), each nephron and its afferent and efferent arteriole, and oscillatory systems with similar frequencies can entrain and become synchronized. SGLT2 inhibitors can improve renal function in the early and advanced diabetic nephropathy by increasing macula densa solute delivery, activating the TGF mechanism and presumably improving synchronization among NVUs. Consequently, enhancing synchronization among NVUs by activating the TGF mechanism might improve renal hemodynamics and preserve renal function in diabetic nephropathy and non-diabetic chronic kidney disease (CKD). This is prominent as more than 3 million Canadians are suffering from CKD [1], which puts a great financial burden on the health care system. We used different compounds that could change TGF activity to understand synchronization among NVUs better and to see how the synchronization among NVUs would be affected. In our first aim, we tried to inhibit the sensing step of the TGF mechanism by administering high dose furosemide to assess synchronization among nearby NVUs in male Lewis rats (n=8). We hypothesized that inhibiting the TGF mechanism by administrating high dose furosemide would weaken synchronization among nearby NVUs. In our second and third aim, we tested the effects of activating the TGF mechanism on synchronization among nearby NVUs, by administrating acetazolamide (n=6) and low dose furosemide (n=6) in male Lewis rats. We hypothesized that administrating acetazolamide and low dose furosemide enhance synchronization among nearby NVUs by activating TGF. In all the experiments, laser speckle contrast imaging (LSI), which can probe surface renal perfusion, was used to assess TGF phase coherence (PC), the number of edges with PC > 0.6, the magnitude of decay of TGFPC and the initial and secondary decay associated with TGFPC. These parameters can be used to assess strength of synchronization among NVUs. Our results illustrate that high dose furosemide did not change PC and the number of edges with PC > 0.6, indicating no changes in synchronization among nearby NVUs. Interestingly, high dose furosemide decreased the magnitude of decay of TGFPC showing stronger synchronization among NVUs. The inconsistency in these findings suggests the complexity of high dose furosemide as it causes vasodilation, increases macula densa solute delivery, changes TGF responsiveness and affects renin and ANG II levels. Moreover, technical issues could be another explanation for inconsistent findings as movements of the kidney surface due to pulse or/and respiration could be also captured by the LSI, which would affect the number of edges and PC. Additionally, acetazolamide and low dose furosemide increased mean PC, the number of edges with PC > 0.6 and decreased the magnitude of decay of TGFPC, indicating stronger synchronization among nearby NVUs. It can be concluded from these findings that synchronization among NVUs can be enhanced by activating the TGF mechanism.

Objective: To learn the rates at which patients at UT Family Medicine–St. Francis (UTFM–SF) with type II diabetes mellitus are being prescribed recommended medications—namely metformin, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and glucagon-like peptide 1 receptor agonists (GLP1RAs)—whether these rates correspond to the severity of hyperglycemia (as indicated by HbA1C level). A secondary goal of the study was to investigate if HbA1C levels are being checked at recommended intervals. Methods: A retrospective chart review was conducted using records of patients seen at the clinic in the previous four years between the ages of 18 and 65 who had visits with ICD 10 codes for type II diabetes mellitus (E11) and long term insulin use (Z79.4). Patients with an HbA1C result from January 1, 2018 or later and a chart history of an insulin prescription were selected for further analysis. Results: 234 patients met the search criteria and were divided into three groups based on an average of the three most recent HbA1C labs: Below the American Diabetes Association (ADA) recommended HbA1C of 7% (n=40), between 7% and the insurance quality metric goal of 9% (n=66), and above 9% (n=128). A chi-square test revealed there was no significant association between HbA1C group and the rate of prescription of metformin (2-sided, p=.631), SGLT2 inhibitors (P=.221), or GLP1RAs (P=.223); a chi-square test also showed there was no association between group and the number of medications prescribed (P=.236). A one-way ANOVA revealed no statistically significant differences between group with regards to frequency of HbA1C checks (P=.295). Conclusion: Patients at UTFM–SF with lower levels of glycemic control are not receiving significantly different treatment from patients who demonstrate better glycemic control—they are not being prescribed recommended medication classes at a different rate, they are not having medications combined at a different rate, and their HbA1Cs are not being monitored differently. Increased utilization of metformin, SGLT2 inhibitors, and GLP1Ras, as well as quarterly HbA1C checks, are necessary to bring diabetic care at UTFM–SF more in line with ADA recommendations.

Type 2 diabetes mellitus (T2D) represents a sig- nificant public health problem, with a dramat- ically increasing prevalence. T2D is considered a progressive disease that develops macro- and microvascular complications such as cardiovas- cular disease (CVD), heart failure (HF), and chronic kidney disease (CKD), which are closely interconnected and constitute the main causes of morbidity and mortality in these patients. Over time, finding new pharmacological approaches to protect against these cardiorenal events (the ‘‘cardiorenal continuum’’) has become the fundamental objective of research aimed at these patients.

Abstract: Renal autoregulation, comprised of the myogenic response (MR) and the kidney-specific tubuloglomerular feedback (TGF), maintains steady perfusion to the kidneys despite blood pressure fluctuations. The emphasis of this work is on TGF, the dynamics of which generate autonomous oscillations that synchronize extensively across the kidney. Synchronization occurs through endothelial gap junctions formed by connexin40 (Cx40) proteins which allow a nephrovascular unit (NVU), consisting of the nephron, glomerulus, afferent arteriole and efferent arteriole, to communicate electrically over long distances upstream to other NVUs via the vascular tree. Clusters of NVUs form dynamic small-world networks across the kidney, meaning that NVUs are tightly connected to each other in one cluster, but clusters are loosely interconnected to each other. Synchronization, or coupling, between NVUs spatiotemporally optimizes blood flow distribution to ensure that NVUs receive appropriate perfusion to match the energy-intensive and oxygen-dependent reabsorption of sodium. Many patients with diabetes mellitus or hypertension have chronic kidney disease (CKD) secondary to their conditions. In Canada, recent estimates suggest that 4 million people suffer from CKD; this is associated with a health burden upwards of $40 billion per year 1. Loss of synchronization impairs autoregulation and is implicated in the progression of kidney disease, but synchronization has not been studied in pathophysiological models. We hypothesized that improving synchronization may preserve renal function by improving network behavior. To advance our understanding of the nephrovascular network’s role in physiology with clinical relevance, we explored the impact of manipulating TGF signaling on synchronization in our first aim. In healthy male Lewis rats (n = 6), we inhibited the sensor component of the TGF to study synchronization and network behavior using acute administration of the loop diuretic furosemide. The sodium glucose cotransporter-2 (SGLT2) inhibitor dapagliflozin was acutely administered in healthy rats (n = 6) to enhance TGF signaling by increasing sodium chloride delivery to the macula densa cells in the distal tubule. In the second aim, we tested the impact of renal disease on TGF synchronization and network behavior using the remnant kidney model of experimental CKD to gain greater insight into the nephrovascular network’s role in pathophysiology. Male Lewis rats were subjected to 5/6th nephrectomy or sham-operations and were assessed after 1 week (n = 4) or 6 weeks (n = 6) (n = 7, 1 week shams; n = 7, 6 week shams). Our third aim was to determine whether the SGLT2 inhibitor dapagliflozin would enhance synchronization in the pathophysiological context of experimental CKD. We used male Lewis rats that were subjected to 5/6th nephrectomy to create a remnant kidney for 6 weeks (n = 6) or sham operations (n = 6). After 6 weeks had elapsed, animals were acutely administered dapagliflozin. In all three aims, laser speckle contrast imaging (LSCI) was used to assess renal cortical perfusion and determine the strength and variability in the synchronization of TGF and MR, the decay in TGF synchronization over distance, and the spatiotemporal heterogeneity of cortical perfusion. Our results demonstrate furosemide induced a rapid decay in TGF synchronization over long distances, whereas dapagliflozin improved entrainment of regions across the renal surface in intact rats. Disruption of the nephrovascular network in the remnant kidney at 1 week enhanced MR synchronization, and at 6 weeks TGF synchronization and the maximum distance over which synchronization occurs was diminished. Breaking the network impaired the communication pathway necessary for TGF signals to travel because the remnant kidney at both 1 and 6 weeks induced a rapid decay in the spread of the TGF signal, reduced synchronization amongst kidney regions and induced heterogeneity in cortical perfusion. Intervention with dapagliflozin improved the strength of TGF synchronization and reduced the magnitude of its decay with distance, suggesting these changes may underlie SGLT2 inhibition’s renoprotective effects. These findings suggest that TGF is best regarded as a distributed network process that regulates the microcirculation by synchronized adjustments in vascular resistance amongst communicating NVUs so that all elements in the network effectively respond to blood pressure perturbations. The implications of these findings includes a greater understanding of nephrovascular network regulation that can be enhanced by intervention to restore coordinated vascular responses among NVUs with better oxygenation/perfusion matching and prevention of renal injury as a consequence.