Chronic kidney disease (CKD) affects more than 30 million adults in the U.S. and is strongly associated with cardiovascular events and mortality. Venous thromboembolism (VTE) is the third leading vascular disease, affects up to 900,000 Americans each year and contributes to as many as 100,000 deaths annually. The relationship of CKD and VTE has been described in patients receiving dialysis, kidney transplants recipients and in nephrotic syndrome, however, data supporting the association of VTE in mild to moderate CKD is conflicted. The overall goal of this research was to study the association of CKD and VTE and to understand the mechanisms of this association. To accomplish this goal we studied participants of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study, a nationally representative cohort of 30,239 blacks and whites in the U.S.. The first chapter provides a review of the state-of-the science on CKD and VTE and potential mechanisms for this association. We focus on factor VIII as a potential mediator of VTE risk in CKD by reviewing the biochemistry and epidemiology linking factor VIII and CKD. In Chapter 2, we use a cohort study design and a competing risk analysis to determine the risk of VTE with albuminuria (ACR) and with various equations for estimated glomerular filtration rate (eGFR). There was no association of ACR and VTE and the risk of VTE was similar among eGFR equations. Compared to a normal eGFR (>90 ml/min/1.73m2), eGFR < 45 ml/min/1.73m2 was associated with a two-fold risk of VTE. The association of eGFR and unprovoked VTE was similar to the association with provoked VTE. The population attributable fraction of CKD (eGFR<60 ml/min/1.73m2) was modest at 5%. In Chapter 3, we utilize a case-cohort study to determine if biomarkers of inflammation (C-reactive protein) and procoagulation (Factor VIII and D-dimer) attenuate the risk of VTE in CKD. These biomarkers were higher in lower kidney function and were also strongly associated with VTE. Adjustment for factor VIII fully attenuated the risk of VTE in CKD, thus factor VIII is a potential mediator of the association of CKD and VTE. We assessed whether lifestyle factors and medications mitigate the risk of VTE in those with and without CKD. Exercise frequency and use of statins were associated with reduced risk of VTE in the presence and absence of CKD, but normal BMI was associated with reduced VTE risk only in those without CKD. We conclude that CKD is a risk factor for VTE, and findings shed light on the mechanisms of this association. Interventions that might lower VTE risk in CKD patients include exercise and statin therapy, but not weight loss. Factor VIII is a potential mediator of VTE in CKD and deserves further study. We suggest several avenues for future research to explore the relationship of Factor VIII and CKD.

Chronic kidney disease (CKD) is a global health problem and efforts are needed to improve the care of individuals affected by the disease. A recent strategy for improving care within the healthcare system is patient engagement. Nurses and other health care clinicians can apply patient engagement into their clinical practice to improve the care they provide to their patients. Therefore, the purpose of this project was to increase the knowledge and awareness of patient engagement among clinicians who work with CKD patients. This quality improvement project used Lewin's force field analysis to analyze driving and restraining forces to help develop and implement strategies to develop an e-learning module. The project used practice-focused questions to determine if knowledge about patient engagement and the Shared End-Stage Renal Patients - Decision Making Tool could improve staff knowledge and awareness about patient engagement. A quantitative pretest, posttest approach was used to compare pretest scores to posttest scores after the e-learning module was viewed. Nine clinicians participated in the project study. Results showed that clinicians' knowledge and awareness about patient engagement increased from a mean pretest score of 5.22 to a mean posttest score of 6.22, (p = 0.08617). The sample of only 9 participants may have contributed to the lack of statistical significance after viewing the educational presentation. The e-learning module will provide positive social change as staff and students of renal programs learn about and apply the principles of patient engagement to their clinical practice.

C3 glomerulopathy (C3G) encompasses a group of severe renal diseases characterized by “dominant C3” deposition in the renal glomerulus. Patients typically present as nephritic nephrotics, with hematuria, hypertension, heavy proteinuria and edema. Within ten years of diagnosis, 50% of affected patients progress to end-stage renal disease and require dialysis or renal transplantation. No treatment is available to halt disease progression and thus both disease recurrence and allograft loss are common after transplantation. Genetic studies of C3G have firmly implicated dysregulation of the alternative pathway (AP) of complement in disease pathogenesis. In addition to genetic factors, acquired factors like autoantibodies can also exaggerate AP activity in the circulation to cause C3G. Although AP dysregulation in the circulation (i.e. fluid-phase dysregulation) has been well studied in these patients, AP activity in the glomerular microenvironment is not well understood. In this body of work, we used MaxGel, an ex-vivo surrogate for the glomerular extracellular matrix, to study AP activity and regulation. We showed that C3 convertase can be assembled on MaxGel and elucidated the dynamics of its formation and decay in the presence of complement regulators. We confirm that on MaxGel factor H (fH) inhibits C3 convertase formation and accelerates its decay, while properdin has a stabilizing effect. We also show that the complement factor H-related proteins (FHRs) are vital to the regulation of AP activity. Consistent with our MaxGel data, CFHR gene-fusion events have been reported as genetic drivers of disease in a few familial cases of C3G. One such familial case in which we identified and characterized the rearrangement event results from a novel CFHR5-CFHR2 fusion gene. The fusion gene is translated into a circulating FHR-5/-2 protein that consists of the first two SCRs of FHR-5 followed by all four SCRs of FHR-2. The structural repetition of SCR1-2 followed by another SCR1-2 motif facilitates the formation of complex FHR-1, FHR-2 and FHR-5 multimers, which have enhanced affinity for C3b and by out-competing fH, lead to impaired C3 convertase regulation in the glomerular microenvironment. Finally, we tested gene therapy as a tool to rescue the disease phenotype and restore fluid-phase AP complement control in a mouse model of C3G (Cfh-/-/huCR1-Tg mice). Using the piggyBac transposon system, we introduced a construct derived from complement regulator 1 (CR1) into Cfh-/-/huCR1-Tg mice. Delivery of sCR1-AC via hydrodynamic tail vein injection provided constitutive circulatory expression of sCR1-AC, and in animals followed for 6 months, we found that long-term expression of this complement regulator rescued the renal phenotype. These results suggest that sCR1 may be a potential therapy for patients with this disease.

<p>Det finns lite forskning om livskvalitet hos patienter med kronisk njursvikt som ännu inte startat i dialysbehandling och det är viktigt att ha kunskap om hur livskvaliteten påverkas hos dessa patienter. Syftet med litteraturstudien var att belysa olika faktorers påverkan på livskvaliteten hos patienter med kronisk njursvikt som inte startat i dialys. I studien har 16 vetenskapliga artiklar granskats och analyserats. I resultatet framkom att Hb-nivå, nutrition, sjukdomens svårighetsgrad och komorbiditet var faktorer som kunde påverka livskvaliteten. Även patienters upplevelser av antal och svårighetsgrad av symtom var påverkande faktorer. Ålder, kön, civilstånd, utbildning och arbetsstatus visade sig också kunna påverka livskvaliteten. I faktorer som patienterna kunde påverka, framkom copingstrategier och egenvård. I livskvalitet relaterat till planerad vård och omvårdnad framkom vårdplanering och specialistsjuksköterske-mottagning som faktorer som kunde påverka livskvaliteten. Genom kunskap inom detta område kan sjuksköterskan ge information och stöd till patienter och närstående och via omvårdnadsåtgärder förebygga och lindra symtom för att förbättra patienternas livskvalitet. Undersökningar av livskvalitet hos patienter med njursvikt som inte startat i dialys kan vara av värde vid utvärdering av vård och omvårdnad. Mer kvalitativ forskning om livskvalitet, coping och egenvård inom detta område behövs och sjuksköterskor behöver mer utbildning inom dessa områden för att kunna förbättra omvårdnaden.</p> / <p>There is little research on quality of life in patients with chronic renal failure not undergoing dialysis and it is important to know how the quality of life is affected in these patients. The aim of this literature review was to illustrate the impact of different factors on the quality of life in patients with chronic renal failure not undergoing dialysis. This study has been reviewed 16 scientific articles and analyzed. The result showed that the Hb-level, nutrition, the severity of the disease and co-morbidity were factors that could affect the quality of life. Also patients' perceptions of the number and severity of symptoms were influencing factors. Age, sex, marital status, education and work status also appeared to affect the quality of life. Among factors that patients themselves could affect were coping strategies and self-care. Well planned care and care delivered by specialist nurses did also affect the quality of life. The patients‟ quality of life may improve by the acts of the nurse, for example by providing information and support to patients and relatives, and by different nursing interventions directed towards prevention or relief of symptoms. Studies of quality of life in patients with renal failure not started in dialysis may be useful in the evaluation of health care and nursing. There is a need for more qualitative research on quality of life, coping and self-care in this field and nurses need more training in these areas in order to improve the nursing care.</p>

<p><strong>Objective</strong><em>:</em> Estimation of glomerular filtration rate (GFR) is an important tool in the diagnosis and management of chronic kidney disease. Today creatinine is the most frequently used marker for kidney function though several studies indicate that cystatin C is a superior marker. The purpose of this study was to validate Abbott Diagnostics turbidimetric cystatin C assay and enzymatic creatinine assay.</p><p><strong>Methods</strong><em>:</em> The validation was performed by studies of CV for the two methods and correlations between the two and other available methods for assessing GFR. The stability of cystatin C at room temperature was also evaluated.</p><p><strong>Results</strong><em>: </em>Both methods showed good precision. The Abbott cystatin C assay generally gave lower values and thereby higher estimated GFRs than the correlated Gentian method. The Abbott enzymatic creatinine assay gave higher values than the correlated Jaffe method. Those results are generally unexpected, but in this study the cause is an automatically applied negative intercept used together with the Jaffe method. Cystatin C showed high stability when stored at room temperature.</p><p><strong>Conclusions</strong><em>:</em> Estimated GFRs tend to differ depending on the choice of method for analyzing cystatin C or creatinine and this study gives an overview of the range of variation. The study also enlightens the need for an international calibrator for the cystatin C methods presented by different manufacturers.</p>

Det finns lite forskning om livskvalitet hos patienter med kronisk njursvikt som ännu inte startat i dialysbehandling och det är viktigt att ha kunskap om hur livskvaliteten påverkas hos dessa patienter. Syftet med litteraturstudien var att belysa olika faktorers påverkan på livskvaliteten hos patienter med kronisk njursvikt som inte startat i dialys. I studien har 16 vetenskapliga artiklar granskats och analyserats. I resultatet framkom att Hb-nivå, nutrition, sjukdomens svårighetsgrad och komorbiditet var faktorer som kunde påverka livskvaliteten. Även patienters upplevelser av antal och svårighetsgrad av symtom var påverkande faktorer. Ålder, kön, civilstånd, utbildning och arbetsstatus visade sig också kunna påverka livskvaliteten. I faktorer som patienterna kunde påverka, framkom copingstrategier och egenvård. I livskvalitet relaterat till planerad vård och omvårdnad framkom vårdplanering och specialistsjuksköterske-mottagning som faktorer som kunde påverka livskvaliteten. Genom kunskap inom detta område kan sjuksköterskan ge information och stöd till patienter och närstående och via omvårdnadsåtgärder förebygga och lindra symtom för att förbättra patienternas livskvalitet. Undersökningar av livskvalitet hos patienter med njursvikt som inte startat i dialys kan vara av värde vid utvärdering av vård och omvårdnad. Mer kvalitativ forskning om livskvalitet, coping och egenvård inom detta område behövs och sjuksköterskor behöver mer utbildning inom dessa områden för att kunna förbättra omvårdnaden. / There is little research on quality of life in patients with chronic renal failure not undergoing dialysis and it is important to know how the quality of life is affected in these patients. The aim of this literature review was to illustrate the impact of different factors on the quality of life in patients with chronic renal failure not undergoing dialysis. This study has been reviewed 16 scientific articles and analyzed. The result showed that the Hb-level, nutrition, the severity of the disease and co-morbidity were factors that could affect the quality of life. Also patients' perceptions of the number and severity of symptoms were influencing factors. Age, sex, marital status, education and work status also appeared to affect the quality of life. Among factors that patients themselves could affect were coping strategies and self-care. Well planned care and care delivered by specialist nurses did also affect the quality of life. The patients‟ quality of life may improve by the acts of the nurse, for example by providing information and support to patients and relatives, and by different nursing interventions directed towards prevention or relief of symptoms. Studies of quality of life in patients with renal failure not started in dialysis may be useful in the evaluation of health care and nursing. There is a need for more qualitative research on quality of life, coping and self-care in this field and nurses need more training in these areas in order to improve the nursing care.

Objective: Estimation of glomerular filtration rate (GFR) is an important tool in the diagnosis and management of chronic kidney disease. Today creatinine is the most frequently used marker for kidney function though several studies indicate that cystatin C is a superior marker. The purpose of this study was to validate Abbott Diagnostics turbidimetric cystatin C assay and enzymatic creatinine assay. Methods: The validation was performed by studies of CV for the two methods and correlations between the two and other available methods for assessing GFR. The stability of cystatin C at room temperature was also evaluated. Results: Both methods showed good precision. The Abbott cystatin C assay generally gave lower values and thereby higher estimated GFRs than the correlated Gentian method. The Abbott enzymatic creatinine assay gave higher values than the correlated Jaffe method. Those results are generally unexpected, but in this study the cause is an automatically applied negative intercept used together with the Jaffe method. Cystatin C showed high stability when stored at room temperature. Conclusions: Estimated GFRs tend to differ depending on the choice of method for analyzing cystatin C or creatinine and this study gives an overview of the range of variation. The study also enlightens the need for an international calibrator for the cystatin C methods presented by different manufacturers.

The incidence of chronic kidney disease (CKD) is increasing. CKD is characterized by a gradual decrease in renal function leading to end stage renal disease (ESRD). Damage to the glomerular podocytes, is one of the first hallmarks of CKD. We hypothesized that podocyte prostaglandin E2 (PGE2) receptors contribute to the progression of glomerular injury in models of CKD. To test this hypothesis, transgenic mice were generated with either podocyte-specific overexpression or deletion of the PGE2 EP4 receptor (EP4pod+and EP4pod-/- respectively). Mice were next tested in the 5/6 nephrectomy (5/6 Nx) or angiotensin II (Ang II) models of CKD. These studies revealed increased proteinuria and decreased survival for EP4pod+ mice while EP4pod-/- mice were protected against the development of glomerular injury. Furthermore, our findings were supported by in vitro studies using cultured mouse podocytes where an adhesion defect was uncovered for cells overexpressing the EP4 receptor. Additionally, our investigations have demonstrated a novel synergy between angiotensin II AT1 receptors and prostaglandin E2 EP4 receptors. This was revealed by in vitro studies using isolated mouse glomeruli. There we were able to show that Ang II stimulation leads to increased expression of cyclooxygenase 2 (COX-2), the enzyme responsible for synthesis of PGE2, in a p38 mitogen activated protein kinase (MAPK) dependent fashion. Moreover increased PGE2 synthesis was measured in response to Ang II stimulation. We confirmed the presence of this synergy in our cultured mouse podocytes and showed an adhesion defect in response to Ang II stimulation which was COX-2 and EP4 dependent. These findings suggest that Ang II AT1 receptors and PGE2 EP4 receptors act in concert to exacerbate glomerulopathies. Studies using mice with either podocyte-specific overexpression of a dominant negative p38 MAPK or mice with global deletion of the EP1 receptor did not provide conclusive results as to their respective signaling involvement in podocyte injury. Altogether our findings provide novel insight for podocyte PGE2 EP4 and Ang II AT1 receptor signaling in models of CKD. These studies provide novel avenues for pursuing therapeutic interventions for individuals with progressive kidney disease.

Relative changes are detectable in the blood of end-stage renal disease (ESRD) patients during hemodialysis (HD) treatment using optical spectroscopy. However, the potential impacts of several confounding factors that could affect the detection of these changes have not been evaluated. The objectives of this thesis were to: 1) investigate how the variations and/or changes in acid-base and oxygen parameters during HD treatment can affect the optical signature of whole blood of ESRD patients, 2) to investigate the effect of heparin on the optical properties of whole blood and its impact on our method. Blood samples were drawn from 23 ESRD patients at 5 time points during a 4 hour HD treatment and sent for blood gas and blood spectroscopy analyses. No significant correlations were found between the changes in the blood transmittance spectra and acid-base and oxygen parameters. This indicates that the perturbations in these parameters due to HD procedures do not confound the detection of changes in the blood transmittance spectra of ESRD patients during HD treatment. Additionally, the effect of heparin in modifying the optical properties of whole blood does not confound the detection of changes in the blood of ESRD patients due to HD treatment using whole blood-based optical spectroscopy. ANOVA revealed significant (P<0.05) measurable changes in the blood transmittance spectra of ESRD patients during HD treatment. Significant spectral differences (P<0.05) were found between ESRD patients. The lack of uniform spectral characteristics across patients is

Angiotensin-(1-7) [Ang-(1-7)] is a heptapeptide component of the renin angiotensin system and the endogenous ligand for the Mas receptor. Ang-(1-7) is generated mainly via angiotensin converting enzyme 2 (ACE2)-dependent cleavage of Angiotensin (Ang) II. Studies suggest Ang-(1-7) may protect against progression of renal injury in experimental models of chronic kidney disease, although the responses may be dose dependent. The role of Ang-(1-7) in the progression of renal fibrosis in unilateral ureteral obstruction (UUO) remains unclear. We tested the hypothesis that endogenous Ang-(1-7) and low dose exogenous Ang-(1-7) would protect against renal injury in the UUO model, while high dose Ang-(1-7) would exacerbate renal injury. Male C57Bl/6 mice underwent UUO and received vehicle, the Ang-(1-7) antagonist A779, or one of three doses of Ang-(1-7) for 10 days. Treatment with A779 exacerbated renal injury as seen by increased fibronectin, transforming growth factor-β (TGF-β), and α-smooth muscle actin (α-SMA) expression, increased tubulointerstitial fibrosis scores, macrophage infiltration, apoptosis, and NADPH oxidase activity in obstructed kidneys. Paradoxically, delivery of exogenous Ang-(1-7) was associated with increased renal injury regardless of dose. Taken together, these data indicate the Mas receptor may be sensitive to concentrations of Ang-(1-7) within the obstructed kidney and that exogenous Ang-(1-7) stimulates pro-fibrotic and pro-inflammatory signalling through unclear pathways.