Dissertations / Theses on the topic 'End stage kidney disease'

Thesis (Ph. D.)--University of Sydney, 2006.
Title from title screen (viewed 21 May 2007). Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the School of Public Health, Faculty of Medicine. Includes bibliographical references. Also available in print form.

Introduction Kidney transplantation confers both survival and quality of life advantages over dialysis for most people with end-stage kidney disease (ESKD). The mortality rate on dialysis is 10-15% per year, compared with 2-4% per year post-transplantation. Short-term graft survival is related to control of the acute rejection process, requiring on-going immunosuppression. Most current immunosuppressive algorithms include one of the calcineurin inhibitors (CNI: cyclosporin or tacrolimus), an anti-metabolite (azathioprine or mycophenolate) and corticosteroids, with or without antibody induction agents (Ab) given briefly peri-transplantation. Despite this approach, between 15-35% of recipients undergo treatment for an episode of acute rejection (AR) within one year of transplantation. Transplantation is not without risk, and relative mortality rates for kidney recipients after the first post-transplant year remain 4-6 times that of the general population. Longer-term transplant and recipient survival are related to control of chronic allograft nephropathy (rooted in the interplay of AR, non-immunological factors, and the chronic nephrotoxicity of CNI) and limitation of the complications of chronic ESKD and long-term immunosuppression: cardiovascular disease, cancer and infection, which are responsible for 22%, 39% and 21% of deaths respectively. This thesis is presented as published works on the theme of immunosuppression and cancer after kidney transplantation. The work presented in the first chapters of this thesis has striven to identify, evaluate, synthesise and distil the entirety of evidence available of new and established immunosuppressive drug agents through systematic review of randomised trial data, with particular emphasis on quantifying harms of treatment. The final chapters use inception cohort data from the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA), which is first validated then used to explore the risk of cancer in more detail than was possible from trial data alone. Interleukin 2 receptor antagonists Interleukin-2 receptor antagonists (IL2Ra, commercially available as basiliximab and daclizumab) are humanised or chimeric IgG monoclonal antibodies to the alpha subunit of the IL2 receptor present only on activated T lymphocytes, and the rationale for their use has been as induction agents peri-transplantation. Introduced in the mid-1990s, IL2Ra use has increased globally, and by 2003 38% of new kidney transplant recipients in the United States and 25% in Australasia received an IL2Ra. This study aimed to systematically identify and synthesise the evidence of effects of IL2Ra as an addition to standard therapy, or as an alternative to other induction agents. We identified 117 reports from 38 randomised trials involving 4893 participants. Where IL2Ra were compared with placebo (17 trials; 2786 patients), graft loss was not different at one (Relative Risk -RR 0.84; 0.64 to 1.10) or 3 years (RR 1.08; 0.71 to1.64). AR was reduced at 6 months (RR 0.66; 0.59 to 0.74) and at 1 year (RR 0.66; 0.59 to 0.74) but cytomegalovirus (CMV) disease (RR 0.82; CI 0.65 to 1.03) and malignancy (RR 0.67; 0.33 to1.36) were not different. Where IL2Ra were compared with other antibody therapy no significant differences in treatment effects were demonstrated, but IL2Ra had significantly fewer side effects. Given a 40% risk of rejection, 7 patients would need treatment with IL2Ra in addition to standard therapy, to prevent 1 patient having rejection, with no definite improvement in graft or patient survival. There was no apparent difference between basiliximab and daclizumab. Tacrolimus versus cyclosporin for primary immunosuppression There are pronounced global differences in CNI use; 63% of new kidney transplant recipients in the USA but only 22% in Australia receive tacrolimus as part of the initial immunosuppressive regimen. The side effects of CNI differ: tacrolimus is associated more with diabetes and neurotoxicity, but less with hypertension and dyslipidaemia than cyclosporin, with uncertainty about equivalence of nephrotoxicity or how these relate to patient and graft survival, or impact on patient compliance and quality of life. This study aimed to systematically review and synthesise the positive and negative effects of tacrolimus and cyclosporin as initial therapy for renal transplant recipients. We identified 123 reports from 30 randomised trials involving 4102 participants. At 6 months graft loss was reduced in tacrolimus-treated recipients (RR 0•56; 0•36 to 0•86), and this effect persisted for 3 years. The relative reduction in graft loss with tacrolimus diminished with higher levels of tacrolimus (P=0.04), but did not vary with cyclosporin formulation (P=0.97) or cyclosporin level (P=0.38). At 1 year, tacrolimus patients suffered less AR (RR 0•69; 0•60 to 0•79), and less steroid-resistant AR (RR 0•49; 0•37 to 0•64), but more insulin-requiring diabetes (RR 1•86; 1•11 to 3•09), tremor, headache, diarrhoea, dyspepsia and vomiting. The relative excess in diabetes increased with higher levels of tacrolimus (P=0.003). Cyclosporin-treated recipients experienced significantly more constipation and cosmetic side-effects. We demonstrated no differences in infection or malignancy. Treating 100 recipients with tacrolimus instead of cyclosporin for the 1st year post-transplantation avoids 12 suffering acute rejection and 2 losing their graft but causes an extra 5 to become insulin dependent diabetics, thus optimal drug choice may vary among patients. Target of rapamycin inhibitors for primary immunosuppression Target of rapamycin inhibitors (TOR-I) are among the newest immunosuppressive agents and have a novel mode of action but uncertain clinical role. Sirolimus is a macrocyclic lactone antibiotic and everolimus is a derivative of sirolimus. Both prevent DNA synthesis resulting in arrest of the cell cycle. Animal models suggested TOR-I would provide synergistic immunosuppression when combined with CNI, but early clinical studies demonstrated synergistic nephrotoxicity. Since then diverse trials have explored strategies that avoid this interaction and investigated other potential benefits. The aim of this study was to systematically identify and synthesise available evidence of sirolimus and everolimus when used in initial immunosuppressive regimens for kidney recipients. We identified 142 reports from 33 randomised trials involving 7114 participants, with TOR-I evaluated in four different primary immunosuppressive algorithms: as replacement for CNI, as replacement for antimetabolites, in combination with CNI at low and high dose, and with variable dose of CNI. When TOR-I replaced CNI (8 trials, 750 participants), there was no difference in AR (RR 1.03; 0.74 to 1.44), but creatinine was lower (WMD -18.31 umol/l; -30.96 to -5.67), and bone marrow more suppressed (leucopoenia RR 2.02; 1.12 to 3.66, thrombocytopenia RR 6.97; 2.97 to 16.36, anaemia RR 1.67; 1.27 to 2.20). When TOR-I replaced antimetabolites (11 trials, 3966 participants), AR and CMV were reduced (RR 0.84; 0.71 to 0.99 and RR 0.49; 0.37 to 0.65) but hypercholesterolaemia was increased (RR 1.65; 1.32 to 2.06). When low was compared to high-dose TOR-I, with equal CNI dose (10 trials, 3175 participants), AR was increased (RR 1.23; 1.06 to 1.43) but GFR higher (WMD 4.27 ml/min; 1.12 to 7.41). When low-dose TOR-I and standard-dose CNI were compared to higher-dose TOR-I and reduced CNI AR was reduced (RR 0.67; 0.52 to 0.88), but GFR also reduced (WMD -9.46 ml/min; -12.16 to -6.76). There was no significant difference in mortality, graft loss or malignancy risk demonstrated for TOR-I in any comparison. Generally surrogate endpoints for graft survival favoured TOR-I (lower risk of acute rejection and higher GFR) and surrogate endpoints for patient outcomes were worsened by TOR-I (bone marrow suppression, lipid disturbance). Long-term hard-endpoint data from methodologically robust randomised trials are still needed. Monoclonal and polyclonal antibody therapy for treating acute rejection Strategies for treating AR include pulsed steroids, an antibody (Ab) preparation, the alteration of background immunosuppression, or combinations of these options. In 2002, in the USA 61.4% of patients with AR received steroids, 20.4% received Ab and 18.2% received both. The Ab available for AR are not new: horse and rabbit derived polyclonal antibodies (ATG and ALG) have been used for 35 years, and a mouse monoclonal antibody (muromonab-CD3) became available in the late 1980s. These preparations remove the functional T-cell population from circulation, producing powerful saturation immunosuppression which is useful for AR but which may be complicated by immediate toxicity and higher rates of infection and malignancy. The aim of this study was to systematically evaluate and synthesise all evidence available to clinicians for treating AR in kidney recipients. We identified 49 reports from 21 randomised trials involving 1394 participants. Outcome measures were inconsistent and incompletely defined across trials. Fourteen trials (965 patients) compared therapies for 1st AR episodes (8 Ab versus steroid, 2 Ab versus another Ab, 4 other comparisons). In treating first rejection, Ab was better than steroid in reversing AR (RR 0.57; CI 0.38 to 0.87) and preventing graft loss (RR 0.74; CI 0.58 to 0.95) but there was no difference in preventing subsequent rejection (RR 0.67; CI 0.43 to 1.04) or death (RR 1.16; CI 0.57 to 2.33) at 1 year. Seven trials (422 patients) investigated Ab treatment of steroid-resistant rejection (4 Ab vs another Ab, 1 different doses Ab, 1 different formulation Ab, 2 other comparisons). There was no benefit of muromonab-CD3 over ATG or ALG in reversing rejection (RR 1.32; CI 0.33 to 5.28), preventing subsequent rejection (RR 0.99; CI 0.61 to 1.59), graft loss (RR 1.80; CI 0.29 to 11.23) or death (RR 0.39; CI 0.09 to 1.65). Given the clinical problem caused by AR, comparable data are sparse, and clinically important differences in outcomes between widely used interventions have not been excluded. Standardised reproducible outcome criteria are needed. Validity of cancer data in an end stage kidney disease registry Registries vary in whether the data they collect are given voluntarily or as a requirement of law, the completeness of population coverage, the breadth of data collected and whether data are assembled directly or indirectly through linkage to other databases. Data quality is crucial but difficult to measure objectively. Formal audit of ANZDATA cancer records has not previously taken place. The aim of this study was to assess agreement of records of incident cancer diagnoses held in ANZDATA (voluntary reporting system) with those reported under statute to the New South Wales (NSW) state Central Cancer Registry (CCR), to explore the strengths and weaknesses of both reporting systems, and to measure the impact of any disagreement on results of cancer analyses. From 1980-2001, 9453 residents received dialysis or transplantation in NSW. Records from ANZDATA registrants were linked to CCR using probabilistic matching and agreement between registries for patients with 1 or more cancers, all cancers and site-specific cancer was estimated using the kappa-statistic (κ). ANZDATA recorded 867 cancers in 779 (8.2%) registrants; CCR 867 cancers in 788 (8.3%), with κ =0.76. ANZDATA had sensitivity 77.3% (CI 74.2 to 80.2), specificity 98.1% (CI 97.7 to 98.3) if CCR records were regarded as the reference standard. Agreement was similar for diagnoses whilst receiving dialysis (κ =0.78) or after transplantation (κ =0.79), but varied by cancer type. Melanoma (κ =0.61) and myeloma (κ =0.47) were less good; lymphoma (κ =0.80), leukaemia (κ =0.86) and breast cancer (κ =0.85) were very good. Artefact accounted for 20.8% non-concordance but error and misclassification did occur in both registries. Cancer risk did not differ in any important way whether estimated using ANZDATA or CCR records. Quality of cancer records in ANZDATA are high, differences largely explicable, and seem unlikely to alter results of analyses. Risk of cancer after kidney transplantation Existing data on the magnitude of excess risk of cancer across different kidney recipient groups are sparse. Quantifying an individual transplant candidate’s cancer risk informs both pre-transplant counselling, treatment decisions and has implications for monitoring, screening and follow-up after transplantation. The aims of this study were firstly to establish the risk of cancer in the post-transplant population compared to that experienced by the general population, and secondly to quantify how excess risk varied within the transplanted population, seeking to establish meaningful absolute risk estimates for post-transplant cancer based on unalterable recipient characteristics known a priori at the time of transplantation. 15,183 residents of Australia and New Zealand had a transplant between 1963 and 2004, and were followed for a median of 7.2 years (130,186 person-years), with 1642 (10.8%) developing cancer. Overall, kidney recipients had 3 times the cancer risk, with risk inversely related to age (Standardised Incidence Ratio of 15 to 30 in children reducing to 2 in people > 65 years). Female recipients aged 25 -29 had rates of cancer (779.2/100,000) equivalent to women aged 55 - 59 from the general population. The risk pattern of lymphoma, colorectal and breast cancer was similar to the overall age trend, melanoma showed less variability across ages and prostate cancer showed no risk increase. Within the transplanted population cancer risk was affected by age differently for each sex (P=0.007), and was elevated for recipients with prior non-skin malignancy (Hazard Ratio: HR 1.40; 1.03 to 1.89), of white race (HR 1.36; 1.12 to 1.89), but reduced for those with diabetic ESKD (HR 0.67; 0.50 to 0.89) Rates of cancer in kidney recipients were similar to non-transplanted people 20 -30 years older, but risk differed across patient groups. Men aged 45 - 54 at transplantation with graft function at 10 years had a risk of cancer that varied from 1 in 13 (non-white, diabetic ESKD, no prior cancer) to 1 in 5 (white, prior cancer, ESKD from other causes).

PhD
Introduction Kidney transplantation confers both survival and quality of life advantages over dialysis for most people with end-stage kidney disease (ESKD). The mortality rate on dialysis is 10-15% per year, compared with 2-4% per year post-transplantation. Short-term graft survival is related to control of the acute rejection process, requiring on-going immunosuppression. Most current immunosuppressive algorithms include one of the calcineurin inhibitors (CNI: cyclosporin or tacrolimus), an anti-metabolite (azathioprine or mycophenolate) and corticosteroids, with or without antibody induction agents (Ab) given briefly peri-transplantation. Despite this approach, between 15-35% of recipients undergo treatment for an episode of acute rejection (AR) within one year of transplantation. Transplantation is not without risk, and relative mortality rates for kidney recipients after the first post-transplant year remain 4-6 times that of the general population. Longer-term transplant and recipient survival are related to control of chronic allograft nephropathy (rooted in the interplay of AR, non-immunological factors, and the chronic nephrotoxicity of CNI) and limitation of the complications of chronic ESKD and long-term immunosuppression: cardiovascular disease, cancer and infection, which are responsible for 22%, 39% and 21% of deaths respectively. This thesis is presented as published works on the theme of immunosuppression and cancer after kidney transplantation. The work presented in the first chapters of this thesis has striven to identify, evaluate, synthesise and distil the entirety of evidence available of new and established immunosuppressive drug agents through systematic review of randomised trial data, with particular emphasis on quantifying harms of treatment. The final chapters use inception cohort data from the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA), which is first validated then used to explore the risk of cancer in more detail than was possible from trial data alone. Interleukin 2 receptor antagonists Interleukin-2 receptor antagonists (IL2Ra, commercially available as basiliximab and daclizumab) are humanised or chimeric IgG monoclonal antibodies to the alpha subunit of the IL2 receptor present only on activated T lymphocytes, and the rationale for their use has been as induction agents peri-transplantation. Introduced in the mid-1990s, IL2Ra use has increased globally, and by 2003 38% of new kidney transplant recipients in the United States and 25% in Australasia received an IL2Ra. This study aimed to systematically identify and synthesise the evidence of effects of IL2Ra as an addition to standard therapy, or as an alternative to other induction agents. We identified 117 reports from 38 randomised trials involving 4893 participants. Where IL2Ra were compared with placebo (17 trials; 2786 patients), graft loss was not different at one (Relative Risk -RR 0.84; 0.64 to 1.10) or 3 years (RR 1.08; 0.71 to1.64). AR was reduced at 6 months (RR 0.66; 0.59 to 0.74) and at 1 year (RR 0.66; 0.59 to 0.74) but cytomegalovirus (CMV) disease (RR 0.82; CI 0.65 to 1.03) and malignancy (RR 0.67; 0.33 to1.36) were not different. Where IL2Ra were compared with other antibody therapy no significant differences in treatment effects were demonstrated, but IL2Ra had significantly fewer side effects. Given a 40% risk of rejection, 7 patients would need treatment with IL2Ra in addition to standard therapy, to prevent 1 patient having rejection, with no definite improvement in graft or patient survival. There was no apparent difference between basiliximab and daclizumab. Tacrolimus versus cyclosporin for primary immunosuppression There are pronounced global differences in CNI use; 63% of new kidney transplant recipients in the USA but only 22% in Australia receive tacrolimus as part of the initial immunosuppressive regimen. The side effects of CNI differ: tacrolimus is associated more with diabetes and neurotoxicity, but less with hypertension and dyslipidaemia than cyclosporin, with uncertainty about equivalence of nephrotoxicity or how these relate to patient and graft survival, or impact on patient compliance and quality of life. This study aimed to systematically review and synthesise the positive and negative effects of tacrolimus and cyclosporin as initial therapy for renal transplant recipients. We identified 123 reports from 30 randomised trials involving 4102 participants. At 6 months graft loss was reduced in tacrolimus-treated recipients (RR 0•56; 0•36 to 0•86), and this effect persisted for 3 years. The relative reduction in graft loss with tacrolimus diminished with higher levels of tacrolimus (P=0.04), but did not vary with cyclosporin formulation (P=0.97) or cyclosporin level (P=0.38). At 1 year, tacrolimus patients suffered less AR (RR 0•69; 0•60 to 0•79), and less steroid-resistant AR (RR 0•49; 0•37 to 0•64), but more insulin-requiring diabetes (RR 1•86; 1•11 to 3•09), tremor, headache, diarrhoea, dyspepsia and vomiting. The relative excess in diabetes increased with higher levels of tacrolimus (P=0.003). Cyclosporin-treated recipients experienced significantly more constipation and cosmetic side-effects. We demonstrated no differences in infection or malignancy. Treating 100 recipients with tacrolimus instead of cyclosporin for the 1st year post-transplantation avoids 12 suffering acute rejection and 2 losing their graft but causes an extra 5 to become insulin dependent diabetics, thus optimal drug choice may vary among patients. Target of rapamycin inhibitors for primary immunosuppression Target of rapamycin inhibitors (TOR-I) are among the newest immunosuppressive agents and have a novel mode of action but uncertain clinical role. Sirolimus is a macrocyclic lactone antibiotic and everolimus is a derivative of sirolimus. Both prevent DNA synthesis resulting in arrest of the cell cycle. Animal models suggested TOR-I would provide synergistic immunosuppression when combined with CNI, but early clinical studies demonstrated synergistic nephrotoxicity. Since then diverse trials have explored strategies that avoid this interaction and investigated other potential benefits. The aim of this study was to systematically identify and synthesise available evidence of sirolimus and everolimus when used in initial immunosuppressive regimens for kidney recipients. We identified 142 reports from 33 randomised trials involving 7114 participants, with TOR-I evaluated in four different primary immunosuppressive algorithms: as replacement for CNI, as replacement for antimetabolites, in combination with CNI at low and high dose, and with variable dose of CNI. When TOR-I replaced CNI (8 trials, 750 participants), there was no difference in AR (RR 1.03; 0.74 to 1.44), but creatinine was lower (WMD -18.31 umol/l; -30.96 to -5.67), and bone marrow more suppressed (leucopoenia RR 2.02; 1.12 to 3.66, thrombocytopenia RR 6.97; 2.97 to 16.36, anaemia RR 1.67; 1.27 to 2.20). When TOR-I replaced antimetabolites (11 trials, 3966 participants), AR and CMV were reduced (RR 0.84; 0.71 to 0.99 and RR 0.49; 0.37 to 0.65) but hypercholesterolaemia was increased (RR 1.65; 1.32 to 2.06). When low was compared to high-dose TOR-I, with equal CNI dose (10 trials, 3175 participants), AR was increased (RR 1.23; 1.06 to 1.43) but GFR higher (WMD 4.27 ml/min; 1.12 to 7.41). When low-dose TOR-I and standard-dose CNI were compared to higher-dose TOR-I and reduced CNI AR was reduced (RR 0.67; 0.52 to 0.88), but GFR also reduced (WMD -9.46 ml/min; -12.16 to -6.76). There was no significant difference in mortality, graft loss or malignancy risk demonstrated for TOR-I in any comparison. Generally surrogate endpoints for graft survival favoured TOR-I (lower risk of acute rejection and higher GFR) and surrogate endpoints for patient outcomes were worsened by TOR-I (bone marrow suppression, lipid disturbance). Long-term hard-endpoint data from methodologically robust randomised trials are still needed. Monoclonal and polyclonal antibody therapy for treating acute rejection Strategies for treating AR include pulsed steroids, an antibody (Ab) preparation, the alteration of background immunosuppression, or combinations of these options. In 2002, in the USA 61.4% of patients with AR received steroids, 20.4% received Ab and 18.2% received both. The Ab available for AR are not new: horse and rabbit derived polyclonal antibodies (ATG and ALG) have been used for 35 years, and a mouse monoclonal antibody (muromonab-CD3) became available in the late 1980s. These preparations remove the functional T-cell population from circulation, producing powerful saturation immunosuppression which is useful for AR but which may be complicated by immediate toxicity and higher rates of infection and malignancy. The aim of this study was to systematically evaluate and synthesise all evidence available to clinicians for treating AR in kidney recipients. We identified 49 reports from 21 randomised trials involving 1394 participants. Outcome measures were inconsistent and incompletely defined across trials. Fourteen trials (965 patients) compared therapies for 1st AR episodes (8 Ab versus steroid, 2 Ab versus another Ab, 4 other comparisons). In treating first rejection, Ab was better than steroid in reversing AR (RR 0.57; CI 0.38 to 0.87) and preventing graft loss (RR 0.74; CI 0.58 to 0.95) but there was no difference in preventing subsequent rejection (RR 0.67; CI 0.43 to 1.04) or death (RR 1.16; CI 0.57 to 2.33) at 1 year. Seven trials (422 patients) investigated Ab treatment of steroid-resistant rejection (4 Ab vs another Ab, 1 different doses Ab, 1 different formulation Ab, 2 other comparisons). There was no benefit of muromonab-CD3 over ATG or ALG in reversing rejection (RR 1.32; CI 0.33 to 5.28), preventing subsequent rejection (RR 0.99; CI 0.61 to 1.59), graft loss (RR 1.80; CI 0.29 to 11.23) or death (RR 0.39; CI 0.09 to 1.65). Given the clinical problem caused by AR, comparable data are sparse, and clinically important differences in outcomes between widely used interventions have not been excluded. Standardised reproducible outcome criteria are needed. Validity of cancer data in an end stage kidney disease registry Registries vary in whether the data they collect are given voluntarily or as a requirement of law, the completeness of population coverage, the breadth of data collected and whether data are assembled directly or indirectly through linkage to other databases. Data quality is crucial but difficult to measure objectively. Formal audit of ANZDATA cancer records has not previously taken place. The aim of this study was to assess agreement of records of incident cancer diagnoses held in ANZDATA (voluntary reporting system) with those reported under statute to the New South Wales (NSW) state Central Cancer Registry (CCR), to explore the strengths and weaknesses of both reporting systems, and to measure the impact of any disagreement on results of cancer analyses. From 1980-2001, 9453 residents received dialysis or transplantation in NSW. Records from ANZDATA registrants were linked to CCR using probabilistic matching and agreement between registries for patients with 1 or more cancers, all cancers and site-specific cancer was estimated using the kappa-statistic (κ). ANZDATA recorded 867 cancers in 779 (8.2%) registrants; CCR 867 cancers in 788 (8.3%), with κ =0.76. ANZDATA had sensitivity 77.3% (CI 74.2 to 80.2), specificity 98.1% (CI 97.7 to 98.3) if CCR records were regarded as the reference standard. Agreement was similar for diagnoses whilst receiving dialysis (κ =0.78) or after transplantation (κ =0.79), but varied by cancer type. Melanoma (κ =0.61) and myeloma (κ =0.47) were less good; lymphoma (κ =0.80), leukaemia (κ =0.86) and breast cancer (κ =0.85) were very good. Artefact accounted for 20.8% non-concordance but error and misclassification did occur in both registries. Cancer risk did not differ in any important way whether estimated using ANZDATA or CCR records. Quality of cancer records in ANZDATA are high, differences largely explicable, and seem unlikely to alter results of analyses. Risk of cancer after kidney transplantation Existing data on the magnitude of excess risk of cancer across different kidney recipient groups are sparse. Quantifying an individual transplant candidate’s cancer risk informs both pre-transplant counselling, treatment decisions and has implications for monitoring, screening and follow-up after transplantation. The aims of this study were firstly to establish the risk of cancer in the post-transplant population compared to that experienced by the general population, and secondly to quantify how excess risk varied within the transplanted population, seeking to establish meaningful absolute risk estimates for post-transplant cancer based on unalterable recipient characteristics known a priori at the time of transplantation. 15,183 residents of Australia and New Zealand had a transplant between 1963 and 2004, and were followed for a median of 7.2 years (130,186 person-years), with 1642 (10.8%) developing cancer. Overall, kidney recipients had 3 times the cancer risk, with risk inversely related to age (Standardised Incidence Ratio of 15 to 30 in children reducing to 2 in people > 65 years). Female recipients aged 25 -29 had rates of cancer (779.2/100,000) equivalent to women aged 55 - 59 from the general population. The risk pattern of lymphoma, colorectal and breast cancer was similar to the overall age trend, melanoma showed less variability across ages and prostate cancer showed no risk increase. Within the transplanted population cancer risk was affected by age differently for each sex (P=0.007), and was elevated for recipients with prior non-skin malignancy (Hazard Ratio: HR 1.40; 1.03 to 1.89), of white race (HR 1.36; 1.12 to 1.89), but reduced for those with diabetic ESKD (HR 0.67; 0.50 to 0.89) Rates of cancer in kidney recipients were similar to non-transplanted people 20 -30 years older, but risk differed across patient groups. Men aged 45 - 54 at transplantation with graft function at 10 years had a risk of cancer that varied from 1 in 13 (non-white, diabetic ESKD, no prior cancer) to 1 in 5 (white, prior cancer, ESKD from other causes).

Introduction End stage kidney disease (ESKD) accounts for 5-10 million deaths annually worldwide. The current treatment modalities for ESKD include dialysis, transplant and supportive care. The leading cause of death for people with ESKD is cardiovascular disease (CVD). CVD is a collective term for disease affecting the heart and blood vessels including coronary, cerebral and peripheral blood vessels. CVD causes significant morbidity and has a substantial impact on quality of life for people with ESKD. Improving cardiovascular outcomes for people living with ESKD is a priority. The escalating incidence of chronic kidney disease, its progression to ESKD and the high burden of cardiovascular disease has generated an increasing amount of research in the ESKD population. The ESKD population have previously been under-represented in clinical trials and current trials in ESKD have infrequently and inconsistently reported CVD outcomes. It is important to standardise outcomes used in research. When outcome reporting is standardised it enables comparisons of findings across trials, populations and eras. It is important that the outcomes reflect patient priorities and are relevant to patients and clinicians for use in shared decision making. The Standardised Outcomes in Nephrology Group (SONG) is an international initiative to establish a set of core outcomes and outcome measures across the spectrum of kidney disease for trials and other forms of research. The SONG-Haemodialysis (SONG - HD) initiative is developing a core outcome set for use in haemodialysis. As part of SONG-HD, CVD (as well as fatigue, vascular access and mortality) has been identified as important to all stakeholders and included in the core outcome set for haemodialysis. This requires appropriate measures of CVD to be identified and used. The first aim of this thesis was to achieve consensus on a CVD outcome measure for use in haemodialysis trials. In approaching this goal I first needed to ascertain the current use of cardiovascular outcomes (Chapter 2) and then determine which ones were important to all stakeholders (Chapter 3). Consensus over which is the most appropriate measure of CVD for use in trials in people on haemodialysis (Chapter 4) will allow improved standardisation of cardiovascular outcome reporting, reducing research wastage and will propel forward cardiovascular research to improve morbidity and mortality in this high risk population. The second aim of this thesis was to further examine some of the prioritised outcomes and to review the patterns and risks of CVD in the ESKD population. The magnitude of risk for cardiac events and cardiac deaths in people with ESKD relative to the general population and the changes over time are not well described. I hypothesised that the magnitude of risk remained high in the ESKD population and that epidemiological improvements seen in CVD outcomes in the general population have not been mirrored in the ESKD population (Chapters 5 and 6). CVD and more specifically cerebrovascular disease can lead to significant cognitive impairment which has a substantial impact on the ability of ESKD patients to understand their disease, interpret education and be involved in shared decision making. The patterns of cognitive deficit in the ESKD population are not well understood and I hypothesised that cognitive deficits in the ESKD population may be different to those found in the general population and may differ by modality of renal replacement therapy. Standardising CVD outcomes, examining the epidemiology of CVD in ESKD and comparing the trends and patterns to the general population can drive hypotheses into potential causative mechanisms and new treatments. I present this thesis as a hybrid of published work, work currently under peer review for publication and work submitted for publication on the theme of priorities and outcomes in ESKD.

A national study was devised to define, using prospective methods, the Scottish renal replacement therapy (RRT) population in terms of numbers, social circumstances, age, mode of presentation for RRT, aetiology of renal failure, comorbid illness, mode of RRT, hospitalisation, mortality and quality of life. The attainment of the recommended treatment standards (UK Renal Association) and their impact along with the factors listed above, upon patient outcomes was assessed. Care by a nephrologist prior to RRT increased the likelihood of a patient having definitive vascular access and attaining the haemoglobin standard, and decreased the time spent in hospital in the first year of RRT. The recommended percentage of patients did not attain haemoglobin, adequacy, albumin or other serum biochemistry standards throughout the first 18 months of RRT. The use of erythropoietin was fundamental to attaining recommended haemoglobin levels. Attaining the haemoglobin standard reduced the risk of death over two years and had beneficial influence upon the number of days spent in hospital. The presence of a fistula (or graft) was the most important factor positively influencing urea reduction ratio (URR). Increasing URR was shown to confer a survival benefit over 2 years in the group treated purely by haemodialysis and reduced time spent in hospital during the first year of treatment. A large demand upon in-patient services was demonstrated. Increased patient cormorbidity and age adversely affected frequency of hospitalisation and total time in hospital in the first year of treatment. Mortality is high amongst patients starting RRT. One year survival was 72.5% (84.2% excluding deaths in the first 90 days), two year survival was 58.5% (68% excluding 90 day deaths). 14% of the cohort died within the first 90 days of RRT. Comorbidity, age, serum albumin and attained haemoglobin significantly affected survival. This study expands the available evidence upon which to base future refinements to clinical practice and recommended standards of care. It provides vital data upon which to base future RRT service planning and research.

Chronic kidney disease (CKD) is common, with prevalence estimates of 10-16% globally. CKD is divided into five discreet stages, with Stage 1 the earliest stage and Stage 5 the most advanced. Research efforts have primarily focused on Stage 5 patients with end stage kidney disease (ESKD) treated with dialysis or transplantation. As a result, many important questions about the experience of those with early to moderate CKD remain incompletely understood. Understanding disease progression, quality-of-life and costs of early to moderate CKD are important to inform clinical treatment decisions as well as economic evaluations of prevention strategies and treatment options. Similarly, important questions remain in specific ESKD populations including what is the optimal treatment of atrial fibrillation in the haemodialysis population, and what are the pregnancy outcomes female transplant recipients of child bearing age. This thesis seeks to address these questions. This is a thesis by publication which contains six published, and one submitted, work. Chapter one is a general introduction. Chapter two used data from AusDiab, a national longitudinal cohort study of Australian adults, to investigate factors associated with disease progression and/or death in CKD. Chapter three used data from AusDiab to estimate the costs of early-to-moderate CKD in Australia. Chapter four explored longitudinal changes in quality-of-life in a community-based CKD cohort and assessed associations between baseline quality-of-life and CKD outcomes using AusDiab data. Chapter five used published literature to develop a Markov model decision analysis for the use of anti-coagulation (or not) in haemodialysis patients with non-valvular AF. Chapters 6 and 7 examined pregnancy outcomes for women with kidney transplants and compared these to the Australian general population. Chapter 8 reviewed the diagnosis and management of recurrent IgA nephropathy following kidney transplant. The final chapter is a discussion of the work.

This thesis assessed cognitive impairment in people with end stage kidney disease. It found that over a third were cognitively impaired. More than half of those who had not yet started kidney replacement treatment and those already receiving haemodialysis were more likely than other groups to be cognitively impaired. The implications from these findings will influence people being able to make informed decisions about their healthcare, and that changes for patient education ought to occur due to altered levels of understanding.

Background: The extent and the distribution of end stage kidney disease (ESKD) in Libya have not been reported despite provision of dialysis over 4 decades. The aim of this thesis is to develop the first comprehensive description of the epidemiology of dialysis-treated ESKD in adults in Libya as well as to assess the outcomes of this treatment. Methods: A structured interview regarding dialysis provision and infection control measures was conducted with the medical directors of all 40 dialysis centres and 28 centres were visited. In the same time demographic and clinical data were obtained regarding all adult patients treated at all maintenance dialysis facilities in Libya from May to August 2009. Additional information about the patterns of vascular access used for haemodialysis (HD) as well as prevalence and incidence of hepatitis Band/or C infection was collected and analysed. Subsequently data were collected prospectively from September 2009 to August 2010. Results: There were 40 functioning maintenance dialysis centres in Libya (one of them was serving children only). The total number of adult patients was 2417. The prevalence rate of ESKD treated by dialysis was 624 per million population. Most dialysis units were located in the northern part of the country and only 12.5% were free standing units. Only three centres offered peritoneal dialysis. There were 192 HD rooms. They hosted 713 functioning HD stations, giving a ratio of one machine to 3.4 patients. Nephrologist/internist to patient ratio was 1:40 and nurse to patient ratio was 1:3.7. There was wide variation in monitoring of dialysis patients with dialysis adequacy assessed only in a minority. 85% of prevalent patients were aged <65 years and 58% were male. The prevalence of ESKD varied considerably with age with a peak at 55-64 years (2475 pmp for males; 2197 pmp for females). The annual incidence rate was 282 pmp with some regional variation and a substantially higher rate in the South (617 pmp). The most common cause of ESKD among prevalent and incident patients was diabetes. Other important causes were glomerulonephritis, hypertensive nephropathy and congenital or hereditary diseases. During one year follow- up, 458 deaths occurred, (crude annual mortality rate of 21.2%). Of these, 3 1 % were due to ischaemic heart disease, 16% cerebrovascular accidents and 16% due to infection. Annual mortality rate was 0-70% in different dialysis centres. Best survival was in age group 25-34 years. Binary logistic regression analysis identified age at onset of dialysis, physical dependency, diabetes and predialysis urea as independent determinants of increased mortality. Of all dialysis- treated patients, 34.9% were sero-positive for HBV and/or HCV (anti-HCV positive 31.1%; HBsAg positive 2.6%; both positive \.2%). The prevalence of HBV±HCV infection varied widely between HD centres from 0% to 75.9%. Sero-positive patients were younger, had longer time on dialysis and more previous blood transfusions. Prospective follow-up revealed an incidence ofsero-conversion of7.7% during 1 year (7.1% HCV; 0.6% HBV). Wide variation in rates of newly acquired infections was observed between dialysis centres. Duration of dialysis, history of previous renal transplant and history of receiving HD in another centre in Libya were significantly associated with sero-conversion. The majority of HD- treated patients (91.9%; n=1573) were using permanent vascular access in the form of arteriovenous fistula or arteriovenous graft. Patients with permanent vascular access were more likely to be male and less likely to be diabetic. Most patients had commenced HD using a temporary central venous catheter (91.8%). Vascular access- related complications were: thrombosis (46.7%), aneurysm (22.6%), infection (11.5%) and haemorrhage (10.2%). Hospitalisation for VA related complications was reported by 31.4%. Conclusion: ESKD in Libya is a major health problem where the incidence rate is among the highest in the world. Despite rapid expansion of dialysis services throughout the country, this thesis has identified that many aspects of dialysis provision are suboptimal and that outcomes are relatively poor. We have identified several major challenges to improving the quality of dialysis provision including lack of dialysis practice guidelines, absence of auditing and quality control and limited access to kidney transplantation. As Libya reorganises its health services in the post-conflict period it is hoped that this study will be the first step in establishing a renal registry and that the areas of concern highlighted will prompt the implementation of national clinical practice guidelines for dialysis.

Faible masse musculaire a été peu étudiée chez les patients avant le stade terminal de la maladie rénale chronique (MRC). Nous avons évalué la masse musculaire à partir de la créatininurie des 24h pour étudier ses déterminants, son évolution avec le déclin de la fonction rénale ainsi que ses liens avec les risques de progression vers l’insuffisance rénale terminale traitée (IRTT) et de décès avant IRTT. Dans la cohorte NephroTest incluant 1429 patients avec une MRC stades 1 à 4, le débit de filtration glomérulaire a été mesuré par la clairance du 51Cr-EDTA (DFGm) et estimé par l’équation CKD EPI (DFGe). La créatininurie moyenne à l’inclusion diminuait de 15.3±3.1 à 12.1±3.3 mmol/24 chez les hommes et de 9.6±1.9 à 7.6±2.5 chez les femmes, pour une baisse du DFGm de ≥ 60 à < 15 mL/min/1.73 m2. Être plus âgé, avoir un diabète, un faible IMC ou un niveau faible de protéinurie et d’apports protidiques était associé à un niveau faible de créatininurie. Un déclin annuel du DFGm de 5 mL/min/1.73 m2 était lié à une baisse de créatininurie, indépendamment de ces déterminants. Au cours d’un suivi médian de 3.6 ans, 229 patients ont développé une IRTT, et 113 sont décédés avant IRTT. Après ajustement sur les facteurs de confusion, le hasard ratio (HR) était de 1.6 (0.88-2.9) pour le risque de décès et de 0.60 (0.39-0.91) pour le risque d’IRTT, dans le 1er vs 4ème quartile de créatininurie. La baisse de la créatininurie apparait précocement dans la MRC et est liée au décès avant dialyse. La diminution du risque d’IRTT pourrait s’expliquer par un démarrage plus tardif de la dialyse en raison d’une surestimation du DFGm par le DFGe chez les patients avec une faible créatininurie
Mainly described in patients on dialysis, muscle wasting has received little attention in early stage chronic kidney disease (CKD). We used 24-hour creatininuria to assess determinants of low muscle mass and its putative associations with CKD outcomes, using data from the NephroTest cohort, including 1429 non-dialysis patients with CKD stages 1 to 5. Kidney function was assessed with both measured (mGFR, by 51Cr-EDTA renal clearance) and estimated glomerular filtration rate (eGFR, by CKD-EPI equation). End-stage renal disease (ESRD) and pre-ESRD death were the main studied outcomes. The mean baseline creatininuria decreased from 15.3±3.1 to 12.1±3.3 mmol/24 h in men and from 9.6±1.9 to 7.6±2.5 in women, when mGFR fell from ≥ 60 to < 15 mL/min/1.73 m2. Other determinants of low creatininuria were an older age, diabetes, a lower body mass index, a lower level of proteinuria or protein intake. A fast annual decline in mGFR of 5 mL/min/1.73 m2 was linked with a 2-fold decrease in creatininuria, independent of changes in protein intake and other determinants of muscle mass. Over a median follow-up of 3.6 years, 229 patients developed ESRD and 113 patients died before ESRD. After adjustment for confounders, patients with low muscle mass showed a significantly higher risk for pre-ESRD death (HR 1.6, 95% CI 0.88-2.9), but a lower risk for ESRD (HR 0.60, 95% CI 0.39-0.91). The latter was reversed (HR 1.5, 95% CI 1.01-2.4) when mGFR was replaced by eGFR. Decrease in 24-hour creatininuria may appear early in CKD patients, is related to pre-ESRD death. The lower risk for ESRD may reflect later dialysis start due to overestimation of true GFR by eGFR in patients with low muscle mass

The escalating burden of end-stage kidney disease has spurred an increase in randomised trials in this population, yet health outcomes and quality of life remain poor. The causes of this may in part be attributable to fundamental flaws in the design and reporting of these studies, particularly outcome selection. Problems include using outcomes of little patient relevance, under-use of outcomes of high patient relevance, highly variable outcomes selection and outcomes reporting bias. Core outcome sets have been developed to ensure consistent reporting of outcomes in a specified area of health or condition. Through the Standardised Outcomes in Nephrology (SONG) Initiative, core outcomes have been established for trials in haemodialysis (fatigue, cardiovascular disease, mortality, vascular access) and kidney transplantation (graft loss, life participation, cardiovascular disease, cancer, infection). This thesis provides novel and comprehensive evidence on priorities and preferences of patients with end-stage kidney disease regarding the PROMs that should be used in trials to assess outcomes that are important to them – specifically fatigue in haemodialysis, and life participation in kidney transplantation. This directly informs the identification and validation of core patient-reported outcome measures for fatigue and life participation. This thesis aims to develop and establish core patient-reported outcome measures (PROMs) for fatigue and life participation. Implementing core outcome measures that are psychometrically robust can ultimately improve the value of trial-based evidence to support decision based on outcomes that are meaningful and important to patients with end-stage kidney disease.

Depression is common in haemodialysis (HD) patients and is often unrecognised and undertreated, though associated with excess morbidity and mortality. Diagnosis is challenging due to symptom overlap with kidney failure, with fatigue being the most common overlapping symptom. Research on the effectiveness of antidepressant medication in this setting is sparse. A recent systematic review advocated well-designed Randomised Controlled Trials (RCTs) in this setting. The studies reported in this thesis had a number of aims. The main aim was to undertake a multicentre feasibility randomised, double blind, placebo-controlled trial of sertraline in patients on HD with Major Depressive Disorder (MDD). To identify suitable patients for this, a screening phase was required, which also allowed determination of the prevalence of depression in this setting and of the relative effectiveness of screening tools Patient Health Questionnaire-2 (PHQ-2), Patient Health Questionnaire-9 (PHQ-9), and Beck Depression Inventory-II (BDI-II). It also allowed examination of the relationships of fatigue in this setting (assessed mainly by the Multidimensional Fatigue Inventory (MFI), including those with a diagnosis, and management of depression. The finding, during screening, that a large proportion of the HD cohort was already on antidepressant treatment, presented the opportunity to study 'real-life' practice patterns in the management of antidepressant treatment in this setting. Recruitment into the RCT was difficult. 1,355 patients in five HD centres were considered for screening, but 243 of these were excluded, mainly because of their inability to read and understand English. Of the remaining 1,110 patients, 709 consented to screening. 231 of these screened positive for high depression symptoms but 130 were not considered for the trial phase, mainly because of concurrent treatment for depression (68 patients), and other contraindicated conditions and medication. In addition, 38 patients declined to take part in the psychiatric interview necessary for diagnosis of MDD. Of the 63 who underwent the diagnostic interview, 37 (58.7%) were diagnosed with MDD and 30 consented to enter the RCT and were randomised into sertraline or placebo groups. This was half of the anticipated recruitment into the RCT. Twenty-one patients (70%) completed the six-month study, eight of 15 in the sertraline group and 13 of 15 in the placebo group (p < 0.05). Drop out was mainly due to adverse or serious adverse events. Depression scores (BDI-II and Montgomery-Åsberg Depression Rating Scale (MADRS)) improved significantly in both the sertraline and placebo groups over six months but there were no significant differences between the treatment groups. There was a slight suggestion of more rapid improvement over the first two months on sertraline, but this was not significant. Fatigue scores were high in all sub-domains - with only a weak relationship with age and comorbidity. Mental fatigue was the strongest independent predictor of high depressive symptoms (BDI-II ≥16, PHQ-9 ≥8), while physical fatigue had the strongest relationship with dialysis recovery time, and survival. Distinguishing between these components of fatigue may have a role in refining the diagnosis and management of MDD. Forty-one of the 76 patients on antidepressant medication at screening were followed up for a mean of 14±5 months. Ten different antidepressant agents were being taken - the most common being Citalopram (39%). Most had been prescribed by GPs. Two-thirds of patients either deteriorated or failed to improve in terms of BDI-II scores during follow-up, many of whom had had no adjustment of medication during this time. Diagnostic evaluation at follow-up showed 37% to be suffering from current or recurrent major depressive episodes (MDE), 48% to have evidence of past MDE, and 15% to have no evidence of ever having been depressed. These empirical studies confirm that depression is very common in HD patients. Its diagnosis is complicated due to symptom overlap with the uraemic syndrome. Fatigue seems to be a key area of overlap with symptoms of depression with a complex relationship. There was no obvious benefit from antidepressants in this feasibility RCT and there was a high drop-out rate due to adverse events, particularly in the sertraline group. These findings raise concerns about the benefits and risks of antidepressants in patients on HD. Current practice patterns may be subjecting patients to substantial risk for little or no benefit. Identifying whether antidepressant medication is effective in this context is a major clinical need, hence the requirement for a definitive study. There is no doubt that to undertake a definitive study would pose considerable recruitment challenges. The findings presented here emphasise the importance of finding ways to overcome these challenges that might include efforts to incorporate patients already taking antidepressants.

Background: End-stage kidney disease (ESKD) burden is increasing particularly amongst the elderly. For older patients, ESKD treatment decisions involve choosing between dialysis versus supportive (non-dialysis) therapies. Registry data provides information on dialysis survival however no systematic data collection exists for supportive care. Methods: This thesis systematically evaluates treatment decision-making from the perspectives of nephrologists and elderly patients/carers using a discrete choice experiment (DCE) and an in-depth interview study respectively. It then scrutinises one of the important factors, survival through a systematic review and meta-analysis and registry cohort studies. Results: The DCE and interview study demonstrate that quality-of-life is critical in decisions. The interview study reveals that patients/carers consider choices in the context of their sense-of-self. The meta-analysis shows that the survival benefit between therapies cannot be confidently estimated due to data limitations. The cohort studies indicate that patient and practice variables predict elderly dialysis patient survival and that automatic estimated glomerular filtration rate reporting led to positive impacts on elderly late referral rates. Conclusion: This thesis emphasises the need for patient-centred treatment discussions which highlight the impact of therapies on dignity, quality-of-life, relationships and life purpose. Survival with both pathways has also been outlined improving prognostication which further enhances decision-making.

Adults with end-stage kidney disease (ESKD) treated with haemodialysis (HD) experience 15-20% mortality each year, mostly due to excess cardiovascular causes. Despite decades of research, the high rates of premature death remain largely unchanged. There is an unmet need for strategies to reduce this risk. Dietary modifications are important potential lifestyle intervention to improve health outcomes in HD and have been prioritized as an important area of research uncertainty by patients and healthcare professionals. The aim of this thesis is to investigate the association between diet at different levels (nutrients, food groups and dietary patterns) and survival in adults receiving HD. The “DIETary intake, death and hospitalization in adult with end-stage kidney disease treated with Haemodialysis (DIET-HD) study”, an international prospective cohort study of around 10000 patients treated with HD in Europe and South America, is the core of this work. The primary exposure of the study was informed by a systematic review of randomized controlled trials evaluating the benefits and harms of omega-3 fatty acids (n-3 PUFA) supplementation in chronic kidney disease. Low quality evidence suggested some cardiovascular benefit of omega-3 supplements in HD patients. However, this survival benefit was not seen in patients with higher consumption of dietary n-3 PUFA within the DIET-HD study. Overall, while the DIET-HD study found no association between n-3 PUFA dietary intake, existing dietary patterns considered healthy in the general population (such as Mediterranean and Dietary Approaches to Stop Hypertension diets) or data driven dietary patterns specific to the HD population and mortality, there was some evidence that higher fruit and vegetable intake may be associated with reduced all-cause death through non-cardiovascular pathways. Definitive answers on the role of diet on the health of HD patients will be provided only by large-scale, pragmatic interventions studies.

Background: The global burden of kidney disease continues to rise but important gaps exist in our understanding of the prevalence of CKD and its complications globally and by region. Scarcity of evidence to guide public health decisions about CKD presents a serious challenge. There is a critical need to identify patterns of disease prevalence, risk factors and potential treatments. Methods: This thesis, based on contemporary evidence, has reported various epidemiological indices in kidney disease at a global and regional level, and explored whether regional dietary patterns might be associated with improved clinical outcomes. This research programme has utilised a series of quantitative methodologies, including meta-analysis of published randomised control trials (RCTs) and observational studies. Results: This research programme included a pooled analysis of disparate data sources to estimate the global burden of ESKD, the development of a novel collaboration among leading researchers in the field of nephrology in Asia: the Asian Renal Collaboration (ARC). Through a series of meta-analyses and pooled data analyses, the main findings of this thesis are that 1) 2.62 million people received RRT in 2010, but at least that many more did not have access to it and died prematurely due to ESKD, 2) 370 million adults have earlier stage CKD in Asia, 3) renal anaemia prevalence increased with progressively worsening CKD and treatment patterns varied dramatically, 4) a major shortage of evidence in exploring the Mediterranean diet as a potential therapeutic intervention for CKD, 5) potential beneficial effects of the Mediterranean diet on cardiovascular outcomes, 6) a lack of systematic data recording system in most countries in Asia. Conclusion: This thesis highlights the importance of kidney disease as a global and regional problem, and the urgent need for a standardised data collection system for kidney disease to inform public health and clinical strategies. It also highlights the need for improved access to treatment for ESKD, and for methods to standardise evidence based care for the complications of kidney disease. Future research and resources to develop methods for prevention, early detection, and delay progression of CKD will also be key. The Mediterranean diet has shown moderate beneficial effects for multiple determinants of vascular risk, exploring the role of the Mediterranean diet in the onset and progression of CKD may be an important area of future research.

There is clear evidence in the literature that the global burden of chronic kidney disease (CKD) is increasing. CKD patients are at high risk of cardiovascular morbidity and mortality which appeared to proportionally increase as kidney function deteriorates toward end-stage kidney disease (ESKD) requiring dialysis. Given the increasing prevalence, worsened outcomes associated with CKD as well as the financial cost associated with its management, there is a clear need for evidence-based interventions to lower the risk and improve outcomes in this high-risk population. This thesis aimed at improving outcomes in CKD patients. We have shown that glucagon-like peptide-1 receptor agonists (GLP-1 RA) have renoprotective effects in type 2 diabetic patients and these effects appear more pronounced in patients with CKD. These results suggested GLP-1 RA may be attractive treatment options in patients with type 2 diabetes to slow CKD progression. In addition, our work provided important evidence demonstrating the important benefits of blood pressure lowering drugs in ESKD patients, as well as the comparative efficacy of different classes of blood pressure lowering agents in lowering cardiovascular events and mortality with clearer support for the use of aldosterone antagonists, β blockers and angiotensin receptor blockers to other classes in this patient population. This thesis also provided important insight regarding the safety of extended hours dialysis. Extended hours dialysis increased the risk of hypokalaemia and hypophosphatemia compared with standard dialysis. Awareness of such risk by patients and clinicians as well as close monitoring of potassium and phosphate may help lower this risk. The work presented in this thesis provided important evidence that may guide the management of patients with CKD, inform clinical practice guidelines globally and may potentially improve outcomes for this high-risk population.

The worldwide population of patients with chronic kidney disease (CKD) is growing, with estimated prevalence at 12-15% of adults. Of particular concern are those with late stage CKD, defined as an estimated glomerular filtration rate (eGFR)of less than 30 ml/min/1.73m2, as they are susceptible to the highest risk of adverse outcomes such as progression to end stage kidney disease (ESKD), cardiovascular disease and all-cause mortality (1, 2). As such, late stage CKD patients are often managed in specialized clinics with set clinical targets, standardized education and multi-disciplinary care(3). A key clinical target for therapeutic intervention and prevention of the progression of CKD is blood pressure (BP) reduction(4). Yet, multiple relevant questions remain regarding the strength and nature of association of BP with clinical outcomes in late stage CKD. As the risks of hypotension-related complications are high in late stage CKD, it remains unclear whether strict BP control delays CKD progression in a real world clinic population(5). Furthermore, it is unclear how to appropriately specify the nature of the longitudinal association between BP and clinical outcomes of ESKD and mortality. The overall objective of this thesis is to examine the longitudinal association of BP and adverse clinical outcomes in a cohort of 1203 patients (mean eGFR 17.8 ml/min/1.73m2; mean of 6.7 BP measures per patient) with late stage CKD. In our first paper we examined the association of repeat measures of BP with CKD progression, defined as a decline in eGFR. When modeling eGFR using longitudinal linear regression, we found that its over-time trajectory was non-linear and that this trajectory was modified by BP; thus, we found a significant time-dependant association between BP and eGFR. When modeling time to eGFR decline ≥ 30% using Cox proportional hazards regression with categorized BP specified as a time-dependent exposure, BP was significantly associated with risk of eGFR decline; in particular, extremes of low and high systolic blood pressure (SBP) and high diastolic blood pressure (DBP) significantly increased the risk of eGFR decline. In our second paper, we examined different methods of modelling longitudinal BP and its association with time to mortality and ESKD. We found that elevations in SBP and DBP, in particular, when expressed as current (most recent visit), lag (previous visit), and cumulative exposure were significantly associated with increased risk of ESKD while low SBP (current, lag and cumulative exposure) was significantly associated with increased risk of mortality. Baseline BP measures were not statistically significantly associated with any outcomes. In patients with more moderate ranges of SBP (121-140) or DBP (60-85) at baseline, a subsequent rise to >160 or > 85 respectively, was associated with an increased risk of ESKD. Thus, longitudinal BP measures in late-stage CKD are significantly associated with adverse outcomes and convey important information beyond baseline BP measures.

Introduction This study was carried out in Ghana, where the incidence of end stage kidney disease (ESKD) is increasing in a context of limited treatment options. Understanding the issues patients with ESKD grapple with when diagnosed with this life-threatening condition is essential to improve healthcare policy and practice in such low- and middle-income settings. In the absence of evidence related to the African ESKD patient journey, this study aimed at exploring how decisions about ESKD management are being made, especially in under-resourced settings where specific treatment modalities are not always available. The study addresses an important gap in the literature concerning choice and decision making in an international context. The key research question for this study is, in terms of the context, does the problem of limited resources in low- and middle-income countries present different choices to the patient with ESKD facing decisions about their treatment? Methodology and Methods The study employed a qualitative research design, using grounded theory methodology. Twenty-seven participants in three renal centres, comprising twenty-two patients with ESKD and five clinicians, were selected using the theoretical sampling approach and interviewed for this study. Constant comparative analysis was employed in data analysis. Results A conceptual map depicting the ESKD patient journey and key phases of decision making was developed from this study. Ghanaian patients with ESKD are mostly unaware of the implications of their initial symptoms, and end up delaying seeking healthcare from a hospital. Some of those who seek care from hospitals are initially diagnosed with and treated for other conditions other than ESKD. Thus, many patients with ESKD in Ghana present late to a renal centre. Treatment for ESKD is initiated for various reasons, including, initially, the urgent need to avoid premature death. Many approach their condition in terms of hoping for a cure and do not always understand the chronic nature of their condition. Decisions on initiating haemodialysis (HD) are mostly shared between clinicians and patients and/or their families but the process is mainly driven by the need to ascertain patient and family’s ability to finance HD, rather than considering other aspects of treatment burden. The subject of death or conservative management is not openly discussed and, once this is brought up, patients usually do everything possible to opt for another form of treatment, including the simultaneous use of other non-RRT and traditional or faith-based healing approaches. Clinicians play vital roles in the decision making of patients with ESKD although they have general feelings of helplessness while supporting these patients. Convergence between individuals’ experiences of realities of living with and managing ESKD, and support from clinicians in the renal setting ultimately leads to a reconstruction of health expectations that commensurate management goals of ESKD. This sums up the substantive theory of ‘reconstructing health expectations’ that was generated from this study. Conclusions Financial and geographical inaccessibility of renal replacement therapy (RRT) as well as the relative lack of biomedical treatment choices make decision making daunting for the individual with ESKD in Ghana. Reluctance to discuss death as a potential outcome is a hindrance to the consideration of conservative management as a treatment option. Effective realignment of healthcare policies to address changing patterns of diseases is necessary to contribute to prevention, early detection and effective management of ESKD in the country. An improved approach to conservative management is urgently required, including training support for clinicians on shared decision making as well as sensitisation of patients on this modality.

The aim of the study was to evaluate the effects of patient education on measures of compliance amongst patients with End Stage Renal Disease (ESRD) on haemodialysis. The patients included in the study were receiving haemodialysis at the time of recruitment. The primary measure of compliance was interdialytic fluid gain; the data was collected from the patients‟ dialysis records on a monthly basis. Prior to the education program a Kidney Disease Questionnaire (KDQ) was administered to assess baseline knowledge. The percentage change in knowledge score after the education program was also recorded, with any change in knowledge score correlated to any change in compliance behaviours. After providing written consent, study participants (n=51) were randomised to either the intervention (education) group n=26 or control group n=25. The intervention group were participants in a newly developed structured education program conducted over a four - week period. The control group received their normal standard therapy, which included ad hoc education from the nurses in their haemodialysis unit. Compliance in the study group appeared to be affected by gender, and Aboriginality appeared to have a direct influence on compliance. Using the measures of compliance, fluid gains improved by 42% with a 75% improvement in knowledge in the intervention group compared to a 19% improvement in fluid gains in the control group with a 52% improvement in knowledge. Whilst there was some improvement in attendance (missed dialysis) following the education program, a noted trend was all the patients who were non-compliant with attendance were Aboriginal. Whilst the sample was small the results were encouraging; the effect of education on compliance in the ESRD patient was shown in the clinical outcomes as being associated with an improvement in the principal outcome measure of interdialytic session fluid gain. However, the findings also suggest a structured program design may not meet the needs of many of the patients who receive dialysis. Treatment programs need to be designed to encompass the needs of all patient groups with an emphasis on self management, in order to provide adequate health care and maximise clinical outcomes. Recommendations have been made with regard to a more structured, directed approach to patient education programs. Aboriginal patients clearly had the greatest problem with compliance, as did the younger age groups and males. Any future educational program should address social, financial and physical benefit to patients and their care givers which in the longer term will provide cost savings and ultimately improved patient well being. This project demonstrated the usefulness of a formal education program in assisting the majority of participants to improve their knowledge and in some improve their compliance with fluid management and other aspects of ESRD management.

Thesis (M.S.)--University of Toledo, 2006.
"In partial fulfillment of the requirements for the degree of Master of Science in Nursing." Major advisor: Jane C. Evans. Includes abstract. Document formatted into pages: v, 53 p. Title from title page of PDF document. Bibliography: pages 42-43.

The thesis that this dissertation aims to defend is: Certain self-management behaviours in End Stage Renal Disease are predicted by self-efficacy, patient activation, and psychological distress, and in turn predict clinical status. However, self-management is often oversimplified and poorly operationalised, in both the literature and in clinical practice, to adherence and 'good/bad' distinctions that may impede future investigations and interventions. End Stage Renal Disease (ESRD) is a chronic condition associated with significant morbidity and increased risk of death. It is commonly treated with haemodialysis, a life sustaining treatment that last approximately four hours, repeated in a healthcare centre or at home, at least three times a week. ESRD also necessitates adherence to a complex set of dietary and fluid intake guidelines, in addition to a complex medication regimen, if the person is to avoid a further increase in the risk of severe symptoms and death. Chronic illness self-management is more than just adherence to prescribed medical treatments however, and requires an individual to preserve their emotional wellbeing, maintain social support networks, and continue to function in a variety of social roles and situations. While this has long been recognised in the theoretical literature about self-management, these concepts are often not well translated into clinical practice or empirical investigations of self-management behaviour in ESRD. When operationalising self-management, some investigations treat the 'behaviour' element of self-management as being limited to dialysis, medication, and fluid adherence, or are ignored in favour of psychological correlates such as self-efficacy. A frequent criticism of the self-management literature is that self-efficacy is often treated as an outcome, rather than a psychological component of changes in behaviour, wellbeing, or clinical outcomes. The investigations presented in this dissertation seek to investigate self-management in terms of specific behaviours that go beyond adherence. In doing so, they explore two different types of self-management behaviour, here termed 'cooperative' and 'defensive' self-management. These behaviours can then be examined in relation to adherence and self-efficacy, as well as other theoretically related factors including patient activation, psychological distress, and illness perceptions. The first three chapters set out the background to the empirical investigations reported in this dissertation. Chapter one covers the background on ESRD and its treatment. Chapter two describes the current state of the conceptual and empirical literature concerning self-management. Chapter three combines a narrative review of empirical investigations into self-management in ESRD, and a review of publically available resources concerning self-management in ESRD. Chapter four describes the methods used in the following empirical chapters. Chapters five, six, seven and eight report original empirical investigations on self-management in ESRD. Chapter nine is a discussion of the combined findings, and their implications in the wider clinical and academic context. Chapter 5 presents the results of a series of focus groups conducted with people on in-centre haemodialysis for ESRD, and the healthcare professionals involved in their care. These explored what each group understood by 'self-management', the behaviours and tasks that were important, and the practical, social, and emotional facilitators and barriers. A series of interviews conducted with patients eighteen months later revisited these concepts, focusing on motivations for engaging in self-management behaviours. The combined findings revealed that patient and HCP concepts around self-management overlap, but have a different focus, with HCPs seeing self-management as being about adherence, and patients seeing it as a complex balancing act to maintain their health, emotional wellbeing, and social roles. HCPs identified some patients as 'good' and others as 'bad'. Chapter 6 presents the results of a cross-sectional investigation of self-management behaviour and theoretically related psychological factors, including self-efficacy and psychological distress. Self-management was operationalised using an available scale that covered a variety of the behaviours patients and HCPs identified as important in chapter 5, which included both 'cooperative' and 'defensive' subscales. Self-efficacy, patient activation, and psychological distress were related to 'defensive' behaviours, with higher levels of psychological distress being related to the performance of more defensive behaviours. Higher self-efficacy was related to less frequent performance of defensive behaviours. A novel finding was that psychological distress mediated the relationship between self-efficacy and self-management behaviours. The implication that some proactive self-management behaviours may be associated with poorer emotional wellbeing is discussed. Chapter 7 presents the results of an 18 month longitudinal study of self-management behaviour and clinical markers of adherence. It also reports a survival analysis in the same cohort followed up to 30 months. Higher frequency of cooperative self-management behaviours were associated with lower levels of adherence as indicated by clinical markers. This may be due to the dialysis units in which the study took place, and may in fact reflect how self-management support was conducted in the units at the time of the study. Higher self-efficacy was found to be associated with lower mortality over 30 months after controlling for factors such as age and residual kidney function, an original and potentially important finding. The findings in chapters 6 and 7 raised additional questions about how self-management behaviours are measured and what those measurements indicate. To further investigate, and lay the groundwork for a new scale and general guidelines on the operationalisation of self-management in ESRD, a series of cognitive interviews were conducted. These are reported in chapter 8. They were conducted with people on home haemodialysis, a population whose engagement in a whole range of self-management behaviours is likely to be high. The role of social and emotional factors in the scale and behaviours discussed was also explored. The chapter concludes with a series of suggestions for measuring self-management behaviour in ESRD. This dissertation will explore the concept of self-management for people on haemodialysis, the behaviours involved, and their relationship with psychosocial and clinical status.

Background: Chronic kidney disease (CKD) affects approximately 26 million individuals in the United States and is a top priority in the objectives for Healthy People 2020. Despite efforts to improve awareness, discussion of CKD is often minimal or ineffective in the primary care setting. This leads to a lack of patient awareness and knowledge of self-care skills to prevent or slow progression of the disease. A lack of communication of has been attributed to the provider's lack of confidence and knowledge to discuss CKD and to avoid unnecessary stress. Purpose: The purpose of the DNP project is to provide a systematic review of patient-provider communication processes used to influence self-management or behavioral change in primary care and propose a tool to enhance communication and slow progression of CKD. Methods: A systematic review was conducted following the method guidelines of the Cochrane Collaboration. Six electronic databases were searched. Inclusion criteria were adult humans, primary research studies, systematic and literature reviews, focus on communication of self-management or behavioral change strategies, primary outcomes of improving self-management and/or patient outcomes and availability of full-text online or by request. Outcomes: Of the 5765 articles initially identified, 28 studies met inclusion criteria. The studies revealed a lack of evidence directed towards CKD and communication was not directly addressed in a majority of the studies. Interventions most successful in improving patient outcomes were individualized, elicited collaboration or interaction with the patient and provider, were motivational or encouraging and aided in barrier identification and problem solving. A communication tool was developed from the evidence in order to stimulate more meaningful conversation between the patient and provider.

Hyperphosphataemia occurs in end-stage kidney disease and is managed by diet, drinks, drugs, and dialysis. Adherence to the 4Ds is challenging for patients. This thesis reports a pragmatic randomised controlled trial that evaluated the effectiveness of an innovative educational intervention "Taking control of your phosphate with the 4Ds" to improve adherence to phosphate control in adults receiving haemodialysis. The 4Ds, a bundled self-management intervention, was effective in improving patient's confidence about phosphate control methods. Importantly, the intervention was brief and feasible for nurses to deliver during haemodialysis treatment.

Purpose: To evaluate the diagnostic performance of Coronary Computed Tomography Angiography (CCTA) in predicting Myocardial Perfusion Scintigraphy (MPS) perfusion defects in low likelihood patients with End Stage Renal Disease (ESRD) awaiting transplant. Materials and Methods: In total, 131 consecutive patients with ESRD awaiting transplant were prospectively enrolled in this study (86 men; 54±9years). All patients underwent MPS as per standard of care and in addition non-enhanced CT for calcium scoring (CAC score) and Coronary Computed Tomography Angiography (CCTA). Results: The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of CAC score in predicting MPS perfusion defects were 88%, 35%, 28% and 92%, respectively. The sensitivity, specificity, PPV and NPV of CCTA in predicting MPS perfusion defects at the patient level were 55%, 87%, 57% and 87%, respectively, and 48%, 92%, 41% and 94% at the vessel level. The diagnostic performance of CCTA in predicting MPS perfusion defects improved when patients with CAC score higher than 1000 (15/70, 21%) were excluded from the analysis. In patients with positive CAC score up to 1000 sensitivity, specificity, PPV and NPV at the patient level were 60%, 93%, 75% and 86% respectively. These were 53%, 91%, 36% and 95%, respectively, at the vessel level. Conclusion: Non-enhanced CT for CAC score and CCTA can be considered useful diagnostic tools in the ESRD population, particularly in identifying patients without coronary artery disease. This approach however had limitations in the presence of high CAC score.

The aim of this study sets out to better understand nephrology nurses’ lived experiences of dying and deaths of patients with ESKD following withdrawal of dialysis. A qualitative research design using an interpretative phenomenological approach was used to explore the experiences of a purposive heterogeneous sample of eight nephrology nurses who were working in private dialysis units. Information was gathered by phenomenological conversations and feed-back sessions. Colaizzi’s phenomenological method was employed to formulate four main themes: 1. Emotional trauma 2. Detachment 3. Loss of altruistic values in nursing 4. being-with-death For the participants in this study, emotional trauma was the most significant. The participants experienced a sense of powerlessness which caused emotions of hopelessness and anger and subsequently a sense of premature mourning and detachment. This state of hopelessness proved to be an obstacle in patient care, resulting in the altruistic values of nursing to be no longer applied. The participants’ ontological confrontation of being-with-death was evident, as they came to terms with the reality of their own death. Recommendations are offered to address the educational aspects of death and dying for nephrology nurses. This study endorses the need for further research into patients with ESKD ‘end-of-life’ which can influence how healthcare professionals should treat these patients during this phase.

Cadmium and lead accumulate in humans and can have toxic effects. Exposure to cadmium is well known to cause kidney damage. Cadmium binds to metallothioneins, proteins that play a role in cadmium transport. Lead exposure’s main effect is on the central nervous system, but associations with kidney disease have also been found, although it is unknown if the latter is a causal association. The main source of both metals within the non-smoking population is from the diet. This thesis aims to 1) compare the biomarkers lead and cadmium concentration in whole-blood, plasma and urine with regard to their ability to discriminate between individuals with different mean concentrations, and to describe the effect of urinary dilution, 2) estimate the association between end-stage renal disease and blood concentrations of cadmium, lead and mercury, using prospectively collected samples for exposure evaluation, 3) use longitudinal data on kidney function makers to evaluate kidney recovery after a substantial decrease in cadmium exposure, and 4) assess the influence of metallothionein polymorphisms (MT1A rs11076161, MT2A rs10636 and MT2A rs28366003) on cadmium-associated kidney toxicity and recovery due to a reduction in Cd exposure. Repeated sampling of whole-blood, plasma and urine was conducted on 48 occupationally lead-exposed men and 20 individuals under normal environmental lead exposure, for estimation of the day-to-day and between individual-variation. Prospective samples were obtained for 118 cases that later in life developed end-stage renal disease, and 378 matched controls. Erythrocyte cadmium, lead, and mercury concentrations were determined and the risk of developing end-stage renal disease associated with metal concentrations was estimated. For evaluation of kidney recovery after a reduction in cadmium exposure and to test for gene-environment interactions, follow-up data on N-acetyl-β‑d-glucosaminidase, β2‑microglobulin, albumin, and gene polymorphisms were obtained for 412 individuals within the Chinese population and the relation to blood and urinary cadmium was assessed. The concentration of lead in blood was found to be the biomarker with the largest fraction of the total variance attributable to between-individual variation, and was therefore the biomarker with the best ability to discriminate between individuals with different mean concentrations, both for individuals under occupational and normal environmental exposure (91 and 95%, respectively). Adjusting for urinary dilution had a great effect on the fraction of the total variance attributable to between-individual variation among individuals with normal lead exposure but only a minor effect among those who were occupationally exposed. Variance analysis showed that blood concentrations were also the best discriminating biomarker for cadmium. Erythrocyte lead was, in a univariate model, associated with an increased risk of developing end-stage renal disease [odds ratio (OR) = 1.54 for an interquartile range increase, with a 95% confidence interval (CI) = 1.18-2.00], while erythrocyte mercury was negatively associated (OR = 0.75 for an interquartile range increase, with a 95% CI = 0.56-0.99). For erythrocyte cadmium, the OR was 1.15 with a 95% CI of 0.99-1.34. Associations with lead and cadmium were only seen among men. In the study on kidney recovery, the proportion of individuals with albumin level above the 95th percentile decreased between baseline and follow up, but no decrease was found for the tubular markers N-acetyl-β‑d-glucosaminidase and β2-microglobulin. Metallothionein polymorphisms modified cadmium-associated effects on N-acetyl-β‑d-glucosaminidase and β2-microglobulin levels but did not modify cadmium-associated change in any of the kidney function markers between baseline and follow up after a substantial decrease in exposure. Blood concentrations of lead and cadmium are the biomarkers with the best ability to discriminate between individuals with different mean concentrations. Adjustment for urinary dilution has great influence on the fraction of the total variance attributed to between individual variation among urine samples with low lead concentrations, but only a small influence on samples with high lead concentrations. This suggests a difference in excretion. The association between end-stage renal disease and low-level lead exposure, as assessed through prospective erythrocyte samples, gives reason for concern, although further studies are needed to determine causality. A cadmium-associated increase in albumin is reversible after a substantial reduction in exposure, but this is not the case for the observed tubular effects. The tubular kidney effects of cadmium might be modified by the MT1A rs11076161 polymorphism.
För att bedöma exponering för kadmium och bly mäts ofta deras koncentrationer i blod eller urin. Dessa studerades i longitudinella data för 48 blyarbetare och 20 individer med normal miljömässig exponering. Blod- och urinprover togs var annan till var tredje månad. Kadmium- och blykoncentrationer mättes sedan i helblod, plasma och urin. Koncentrationer av bly i blod var den biomarkör som hade den största andelen av den totala variationen som kunde förklaras av skillnader mellan individer, och var därför den biomarkör med den bästa förmågan att särskilja på individer med olika medelkoncentration, både för individer med yrkesexponering och normal miljömässig exponering (91 respektive 95% av variansen berodde på vilken individ blodprovet kom ifrån). Justering för urinens utspädning av bly i urin förbättrar oftast urins användbarhet som biomarkör. För bly stämde detta bara hos dem som inte var blyarbetare. Blodkoncentrationer var också den biomarkör med störst andel av den totala variation som kunde förklaras med skillnader mellan individer för kadmium. Kadmium och bly ackumuleras i njure respektive ben och kan ha toxikologiska effekter. Det är välkänt att höga exponeringsnivåer av kadmium orsakar njurskada och även vid lägre exponeringsnivåer har studier funnit samband med markörer för njurfunktion. Exponering för bly påverkar i första hand det centrala nervsystemet. Studier har dock funnit samband mellan koncentrationer av bly i blod och njurens glomerulära filtrationshastighet. Det är oklart både om dessa associationer, vid låga exponeringsnivåer, är viktiga för hälsan och om de verkligen beror på att kadmium och bly orsakar njurskada. För att studera end-stage renal disease användes prospektiva kohorter där personer lämnat blodprov för forskning: Västerbottens interventionsprogram med prover som tagits vid Västerbottens hälsoundersökningar, MONICA-undersökningar i Norr- och Västerbotten, mammografiundersökningarna i Västerbotten och Malmö kost cancer. Sammanlagt ingick över ett hundra tusen individer i dessa kohorter. Med hjälp av det Svenska njurregistret identifierades sedan 118 personer som senare i livet fått end-stage renal disease. Dessa jämfördes med 378 kontroller. För dessa 496 personer tinades blodprovet (närmare bestämt röda blodkroppar) upp och analyserades för kadmium och bly. För att undersöka njurens förmåga till återhämtning studerades tre områden i Kina varav ett tidigare varit kraftigt kadmiumexponerat. Erytrocytkoncentrationer av bly var, utan att ta hänsyn till några andra variabler, associerat med en ökad risk för att utveckla end-stage renal disease (med oddskvoten 1.54 för en interquartile range ökning av erytrocytbly, med ett 95% konfidensintervall 1.18-2.00). Sambanden kvarstod också efter att ha tagit hänsyn till övriga variabler. För erytrocytkadmium var oddskvoten 1.15 med 95% konfidensintervall 0.99-1.34, och sambandet försvagades när hänsyn togs till andra variabler. Associationerna sågs bland män men inte bland kvinnor. Eftersom kadmium vid höga nivåer orsakar njurskada är det också av intresse att studera om påverkan på njuren går över om exponeringen minskas. Totalt följdes 412 individer upp med mätningar av markörer för njurfunktion och kadmiumkoncentrationer i blod och urin. Första undersökningen gjordes 1998, då man just hade slutat äta kadmiumförorenat ris. En andra undersökning gjordes 2006. Andelen individer med avvikande albuminvärde i urin var lägre vid uppföljningen jämfört med vid baslinjen, men ingen minskning sågs för markörer för tubulär förmåga att återta proteiner. Åttioprocent av kadmium i celler är bundet till proteinet metallotheonin, vilket skyddar mot cellskada, men har också en roll i transporten av kadmium från levern till njurarna. En tidigare studie har visat att njurens känslighet för kadmiumexponering var associerad med genetiska skillnader i detta protein. För att studera genetiska associationer studerades de 412 personerna i den kinesiska studien [då också individernas genotyper av metallotheonin-polymorfierna MT1A rs11076161 (G/A), MT2A rs10636 (G/C) och MT2A rs28366003 (A/G) bestämdes]. Genetiken spelade roll för sambandet mellan förmåga att återta proteiner och kadmium men påverkade inte förändring av njurfunktion efter att man slutat äta kadmiumförorenat ris. Kadmium- och blykoncentrationer i blod är de biomarkörer, av koncentrationer i blod, plasma och urin, med den bästa förmågan att skilja på individer med olika medelkoncentrationer. Justering för urinutspädning påverkade andelen av den totala variationen som kunde förklaras av skillnader mellan individer i stor utsträckning för individer med normal miljömässig exponering men inte bland yrkesexponerade, vilket tyder på en skillnad i hur utsöndringen går till. Associationen mellan end-stage renal disease och låg exponering för bly, uppmätta i prospektiva erytrocytprover, ger orsak till oro, men ytterligare studier behövs för att kunna utvärdera om detta är ett kausalt samband. En kadmiumrelaterad skada av den glomerulära filtrationen är reversibel efter en kraftig reducering i exponering, men detta är inte fallet för tubulär skada. De tubulära njureffekterna av kadmiumexponering kan påverkas av metallotheonin-polymorfier.

The number of people with end-stage kidney disease (ESKD) requiring dialysis is rising around the world. Dialysis sustains life at enormous cost, both in terms of health care spending and, more importantly, in terms of poor quality of life, short life expectancy and high rates of cardiovascular disease. Despite this, the evidence base available to guide treatment decisions is small compared to other internal medicine specialties. This means that key aspects of treatment, such as the optimal amount of dialysis therapy, remain based on evidence that is at significant risk of bias. Even where randomised controlled trials (RCTs) do exist, it is unclear how representative the trial population is compared to the increasingly elderly and co-morbid general dialysis population. This thesis aimed to contribute to the development of a better RCT evidence base in dialysis. This was achieved, firstly, by analysis of the landscape of large RCTs enrolling dialysis patients from the point of view of generalisability and with reference to the global distribution of dialysis recipients. Secondly, current evidence concerning the dose of haemodialysis was reviewed and added to by a series of analyses of the A Clinical Trial of IntensiVE (ACTIVE) Dialysis trial of extended hours, compared to standard hours, haemodialysis. Thirdly, contributions were made to three new RCTs, employing different designs, including cluster randomisation and simplified consent models – which may increase the generalisability of the enrolled study cohort. Finally, two projects were established aiming to foster RCTs in nephrology, particularly in areas underserved by research infrastructure. Collectively, this thesis provides novel evidence for the benefits and limitations of extended hours haemodialysis, and advances our understanding of the state of RCTs in nephrology and of novel RCT designs. It also leaves a legacy of ongoing trials and useful resources for clinical researchers.

Thesis (Ph.D. )--University of Tennessee Health Science Center, 2008.
Title from title page screen (viewed on May 16, 2008 ). Research advisor: Mona N. Wicks, PhD. Document formatted into pages (vii, 87 p. : ill.). Vita. Abstract. Includes bibliographical references (p. 63-73).

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

There has been an increasing recognition over the last ten years of the importance of integrating palliative care alongside other aspects of care for people with life-limiting illness including kidney disease. Over the same time period, policy initiatives have aimed to address and improve the end of life care for all adults with kidney disease. However, little is known about the transitions experienced by people with end-stage kidney disease (ESKD) as they approach the end of life. This qualitative study explored the transitions experienced by people with ESKD as they approached the end of their lives. A constructivist grounded theory methodology was used, and unstructured interviews were conducted with twelve people living with ESKD who were deemed to be approaching the end of their lives. The interview data were analysed and interpreted using the constant comparative method. The core category of ‘restructuring reality’ emerged from the data analysis alongside three dynamic, interrelated conceptual categories and the subcategories within these. These conceptual categories were: ‘striving to maintain autonomy and control in decision making’, ‘managing uncertainty: knowing without clarity or confirmation’, and ‘the importance of personal virtues in transitioning through the illness’. The substantive theory which emerged from the data analysis and which conceptualised the process and experience of transition for people with ESKD in this study was defined as 'the restructuring of reality during transition for people with ESKD approaching the end of life’. The study findings provided valuable insight into the experience of people with ESKD as they approach the end of their lives. The tentative theory presented in this study added to the knowledge of the transitions experienced by people with ESKD as they approached the end of their life. The theory captured how participants made sense of and adjusted to the changes they experienced as their health deteriorated; it emphasised that being able to continue to contribute and be involved in decision-making about care was an important aspect of the transition process as people approached the end of their lives. The study findings also highlighted the importance of healthcare professionals undertaking end of life discussions with patients throughout their illness trajectory to ensure people with ESKD are afforded the opportunity to be involved in timely decision making and provided with good quality end of life care.

The objective of the study is to analyze the factors associated with the severity of pruritus in patients with terminal chronic kidney disease undergoing hemodialysis. The methodology used is based on a cross-sectional study in patients receiving hemodialysis at the Centro Nacional de Salud Renal. Severe pruritus was defined as a score on the visual analogue scale greater than or equal to 7, and the strength of association with the possible risk factors was assessed by calculating prevalence ratios. Regarding the results, 264 patients were included, 59.9% were male, with a mean time on hemodialysis of 10.26 ± 7.14 years. 75% experienced pruritus, of this group, 1 in 3 presented severe pruritus. Hyperphosphatemia and the use of antihistamines were associated with a higher prevalence of severe pruritus (RP 1.71, 95% CI 1.09-267 and RP 2.39, 95% CI 1.51-3.75, respectively). The positive serology for Hepatitis C Virus was described as a protective factor for presenting severe pruritus (RP 0.55, 95% CI 0.33 - 0.89). In conclusion, severe uremic pruritus is a frequent problem in patients with chronic terminal kidney disease who have hyperphosphatemia and treatment with antihistamines independently of the time they have been on hemodialysis.
Revisión por pares

The high levels of end-stage renal disease among Indigenous Australians, particularly in remote areas of the country, are a serious public health concern. The magnitude of the problem is reflected in figures from the Australian and New Zealand Transplant and Dialysis Registry that show that Indigenous Australians experience end-stage renal disease at a rate almost 9–10 times higher than other non-Indigenous Australians. A majority of Indigenous Australians have to relocate to receive appropriate renal dialysis treatment. In some Australian states, renal treatment is based on self-care dialysis which allows those Indigenous Australians to be treated back in their community. Evidence clearly shows that reuniting renal patients with community and family improves overall health and well-being for those Indigenous Australians. With the appropriate resources, training, and support, self-care management of renal dialysis treatment is an effective way for Indigenous people with end-stage renal failure to be treated at home. In this context, the study was used to gain insight and further understanding of the impact that end-stage renal disease and renal dialysis treatment has had on the lives of Indigenous community members. The study findings are from 14 individually interviewed people from South East Queensland. Data from the interviews were analysed using a combination of thematic and content analysis. The study methodology was based on qualitative data principles where the Indigenous community members were able to share their experiences and journeys living with end-stage renal disease. Many of the experiences and understanding closely relate to the renal disease pattern and the treatment with other outside influences, such as social, cultural, and environmental influences, all having an equal impact. Each community member’s experience with end-stage renal disease is unique; some manage with family and medical support, while others try to manage independently. From the study, community members who managed their renal dialysis treatment independently were much more aware of their renal health status. The study provides recommendations towards a model of care to improve the health and well-being is based on self-care and self-determination principles.

Objective: The objective of this integrative review was to synthesise evidence on perceived self-efficacy among patients receiving home dialysis. The review also aimed to identify measures utilised and interventions employed to assess and improve self-efficacy. Research problem: Home dialysis requires a multidimensional approach that is associated with adherence to dialysis regimes, fluid management, dietary restrictions and medications. Effective self-care strategies involve lifelong behavioural changes and adherence with treatment regimens that can create challenges and a sense of burden among patients, their families or caregivers. With a growing body of evidence linking improved health outcomes to high self-efficacy, it is imperative to understand self-reported levels of self-efficacy, the measurements used to assess self-efficacy and the effectiveness of interventions to enhance self-efficacy in this population. Inclusion criteria: This review considered research studies reporting on perceived self-efficacy, measures of self-efficacy, and interventions to enhance self-efficacy in patients on home dialysis. Studies that focused on self-efficacy of patients undergoing in-centre dialysis and pre-dialysis were excluded. Methods: An integrative review was employed using Whittemore and Knafl’s (2005) methodology. CINAHL, MEDLINE, Embase and Scopus databases were searched without a date limit for studies published in English. Fifteen studies met the inclusion criteria and were critically appraised by two independent reviewers using Joanna Briggs Institute critical appraisal tools. Narrative synthesis of the findings was conducted because meta-analysis was not possible owing to the heterogeneity of the findings. Results: The included studies were predominantly quantitative studies (n = 10) examining training programs to promote self-efficacy and the report of levels of self-efficacy in patients on home dialysis. The majority of studies reported on peritoneal dialysis in the home setting (n = 649, 91.5%). Narrative synthesis led to the generation of two themes; gaining skills to develop self-efficacy; and building and maintaining knowledge. The findings highlight the importance of health professionals, families and peer support in developing self-efficacy. To advance research and Self-efficacy in patients undergoing home dialysis: An integrative review practice in this area, it is recommended to address the sociodemographic factors that influence self-efficacy and evaluate the long-term impact of interventions on self-efficacy.

This study explored multiple aspects of social support from patients, caregivers and healthcare staff’s perspectives in the Vietnamese haemodialysis context. The study identified the interconnection of roles of patients, caregivers and healthcare staff as members of caregiving triad or support network in providing support in haemodialysis. Contextual factors including financial burden and family culture were found to be important factors affecting the provision of social support. This study’s novel contribution could lead to improving the provision of social support for people on haemodialysis which is crucial due to the growing global burden of end stage kidney disease.

A inicios del año 2020, se registraron 4,300 asegurados a EsSalud diagnosticados con Enfermedad Renal Crónica Terminal (ERCT) en el departamento de Lima, quienes han venido recibiendo sesiones de hemodiálisis en el Centro Nacional de Salud Renal (CNSR) y clínicas contratadas para este servicio, según lo reportado por la IAFAS antes mencionada. Por parte de los asegurados al SIS, el Fondo Intangible Solidario en Salud (FISSAL) informó que a inicios del 2020 que 6 mil 268 asegurados vienen recibiendo hemodiálisis en centros particulares de salud de Lima Metropolitana y las diferentes regiones del país. El presente proyecto plantea brindar el servicio ambulatorio de hemodiálisis a pacientes con Enfermedad Renal Crónica Terminal afiliados a la IAFAS EsSalud, puesto que tiene una sobredemanda que requieren del servicio de Hemodiálisis, y que actualmente no se encuentra cubierta ni por la oferta propia ni por la subcontratada con otros centros de hemodiálisis.  Nuestra estrategia es de “Liderazgo en costos”, con una propuesta de valor basada en atención personalizada con un equipo multidisciplinario, altos estándares de calidad y un modelo de gestión centrado en el paciente, según los Términos de Referencia (TDR) requeridos por EsSalud. Desde el punto de vista financiero, la inversión total del proyecto es de S/. 447,110.00 presentando un VAN de S/. 2,676,707.15 y un TIR es 86.1%. Los principales riesgos del proyecto son los financieros y económicos, como la falta de liquidez y lograr la contratación por la IAFAS EsSalud.
At the beginning of 2020, 4,300 insured persons were registered with EsSalud diagnosed with Terminal Chronic Kidney Disease (ESRD) in the department of Lima, who have been receiving hemodialysis sessions at the National Renal Health Center (CNSR) and clinics hired for this service, as reported by the aforementioned IAFAS. On the part of those insured to the SIS, the Intangible Solidarity in Health Fund (FISSAL) reported that at the beginning of 2020, 6,268 insured have been receiving hemodialysis in private health centers in Metropolitan Lima and the different regions of the country. This project proposes to provide the outpatient hemodialysis service to patients with Terminal Chronic Kidney Disease affiliated to IAFAS EsSalud, since it has an over-demand for them that require the Hemodialysis service, and which is currently not covered even by its own offer nor by the one subcontracted to other hemodialysis centers. Our strategy is “Cost Leadership”, with a value proposition based on personalized attention with a multidisciplinary team, high quality standards and a patient-centered management model, according to the Terms of Reference (TOR) required by EsSalud. From a financial point of view, the total investment of the project is S /. 447,110.00 presenting a NPV of S /. 2,676,707.15 and an IRR is 86.1%. The main risks of the project are financial and economic, such as lack of liquidity and being hired by IAFAS EsSalud
Trabajo de investigación

La Polykystose Rénale Autosomique Dominante (PKRAD) est une des pathologies héréditaires les plus fréquentes et affecte environ un individu sur 1000. Elle se caractérise par une importante variabilité clinique, notamment dans l’âge de survenue de l’insuffisance rénale terminale. Deux gènes sont en cause : le gène PKD1 situé sur le chromosome 16 (85% des cas) et le gène PKD2 situé sur le chromosome 4 (15% des cas). Les progrès majeurs dans la compréhension des mécanismes moléculaires impliqués ont permis le développement de stratégies thérapeutiques spécifiques, et de nouvelles questions surgissent : quels patients traiter ? Quand débuter les traitements ? La cohorte Genkyst, qui vise à inclure tous les patients suivis pour PKRAD dans la région Grand Ouest, nous a d’abord permis de décrire la variabilité génétique rencontrée dans la PKRAD. Nous avons ensuite démontré l’existence de fortes corrélations génotype-phénotype, en rapportant l’influence sur l’âge de survenue de l’insuffisance rénale terminale non seulement du gène en cause, mais aussi du type de mutation pour le gène PKD1. Enfin, l’analyse des données cliniques et génétiques de 1341 patients nous a permis de développer un algorithme pronostique, baptisé le PROPKD score, permettant de stratifier le risque de progression vers l’insuffisance rénale terminale. Nous espérons que ces travaux participeront à l’individualisation de la prise en charge des patients atteints de PKRAD, ce qui est un enjeu crucial à l’arrivée des nouveaux traitements
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is one of the most frequent Mendelian inherited disorders, and affects approximately one individual out of 1000. ADPKD is marked by a high clinical variability, especially regarding age at end-stage renal disease (ESRD). Two genes are identified: PKD1 located on the chromosome 16 (85% of the pedigrees) and PKD2 located on the chromosome 4 (15% of the pedigrees). Substantial progress in understanding the cellular mechanisms underlying ADPKD has triggered the development of targeted therapies, and new questions are arising: which patients should be treated? When should we begin these treatments? Thanks to Genkyst cohort, which aims to include all consenting ADPKD patients from the western part of France, we first described the important allelic variability encountered in ADPKD. Secondly, we demonstrated the important influence of not only the gene involved, but also of PKD1 mutation type. Last, the analysis of clinical and genetic characteristics of 1341 patients from the Genkyst cohort allowed us to develop a prognostic algorithm, named the PROPKD score for predicting renal outcome in ADPKD. Our hope is that these works will participate in the development of individualized medicine in ADPKD, which is crucial in the context of the emerging targeted therapies

La maladie rénale chronique (MRC) affecte environ 10% de la population adulte et est associée à un risque élevé de progression vers l’insuffisance rénale terminale (IRT), d’événements cardiovasculaires et de décès précoce. Des mesures sont recommandées pour prévenir la progression et les complications de la MRC, mais elles sont souvent basées sur un niveau de preuve faible ou sur la seule opinion d’experts. Dans cette thèse, nous avons utilisé des données observationnelles pour évaluer les pratiques cliniques dans deux domaines clés de la MRC : les abords artérioveineux (AV) en hémodialyse et le contrôle de l’hypertension artérielle (HTA) dans la MRC non terminale. Avec le registre national REIN des traitements de suppléance de l'IRT, nous avons montré que seuls 56% des 53 092 patients adultes incidents en hémodialyse de 2005 à 2013 avaient une voie d’abord AV (fistule ou pontage) créée, telle que recommandée, avant le démarrage de la dialyse, dont 16% étaient non fonctionnelles, nécessitant l'utilisation d'un cathéter associé à une sur-mortalité. La conversion en abord AV fonctionnel était associée à un meilleur pronostic, mais concernait dans les trois premières années de dialyse moins de deux patients sur trois ayant démarré sur cathéter. Dans l’étude de cohorte CKD-REIN, chez 1658 patients avec une MRC modérée à sévère, nous avons mis en évidence un moins bon contrôle de l'HTA et des niveaux de pression artérielle systolique plus élevés en lien avec des apports élevés en sodium, mais pas avec des apports faibles en potassium, évalués sur échantillon urinaire ponctuel. Le ratio sodium/potassium urinaire n'était pas plus discriminant que le sodium seul. Enfin, grâce au réseau International Network of Chronic Kidney Disease cohorts (iNET-CKD), qui inclut 17 cohortes sur 4 continents (N=34 602 patients avec un débit de filtration glomérulaire estimé < 60 mL/min/1,73 m2) nous avons mis en lumière le contrôle médiocre de l’HTA en général dans la MRC au regard des recommandations, avec d'importantes variations entre pays (27 à 61% de pression artérielle ≥140/90 mm Hg) expliquées en partie par les caractéristiques des patients et associées à des profils de traitements antihypertenseurs très différents. En conclusion, cette thèse pointe des écarts importants aux recommandations dans la prise en charge de la MRC en vie réelle et des pistes de prévention des complications liées aux abords AV et un meilleur contrôle de l'HTA
Chronic kidney disease (CKD) affects about 10% of the adult population and is associated with high risk of end-stage kidney disease (ESKD), cardiovascular complications, and premature death. Guidelines recommend a number of measures for the prevention of CKD progression and complications, but these recommendations are often based on low evidence or expert opinion. In this thesis, we used observational data to assess clinical practices in two key areas of CKD: arteriovenous (AV) access for hemodialysis, and hypertension control in moderate to severe CKD. Using data from the French REIN registry of renal replacement therapy for ESKD, we showed that only 56% of the 53,092 adult incident patients on hemodialysis from 2005 through 2013 had an AV access (either fistulae or grafts) created at hemodialysis initiation as recommended, of which 16% were nonfunctional, requiring catheter use associated with high mortality risk. Conversion into functional AV access was associated with better outcome, but less than two out of three patients starting hemodialysis with a catheter experienced this conversion within 3 years after dialysis start. In the CKD-REIN cohort study, among 1658 patients with moderate to severe CKD, we found less hypertension control and higher systolic blood pressure to be associated with higher sodium intake assessed from spot urine, but not with lower potassium intake. Spot urinary sodium/potassium ratio did not appear to add value than sodium alone for patient monitoring. Finally, using data from the International Network of Chronic Kidney Disease cohorts (iNET-CKD), including 17 cohort studies over 4 continents (N=34,602 patients with an estimated glomerular filtration rate < 60 mL/min/1.73 m2), we highlighted a global poor hypertension control in CKD with regards to recommendations, with large variations across countries (from 27 to 61% blood pressure ≥140/90 mm Hg). These variations are partly explained by patients’ characteristics, and associated with very different antihypertensive treatment profiles. In conclusion, this thesis points out major gaps between guideline recommendations and CKD management in real life, and provide clues for the prevention of AV access-related complications and better hypertension control

Thesis (Sc.D.)--Boston University PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.
Chronic Kidney Disease (CKD) and End-Stage Renal Disease (ESRD) are serious threats to the public health in the United States. Medicare costs related to the treatment of these conditions are projected to reach $54 billion by 2020. Using data from the US Department of Veterans Affairs we conducted three retrospective cohort studies that examined impacts of different exposures on the incidence of CKD and ESRD. In study one, we estimated the effect of race on the rate of ESRD in a population with CKD after accounting for the competing risk of death. After accounting for the competing risks and after controlling for age, diabetes status, and the presence of hypertension, black veterans have a significantly higher rate of ESRD than do white veterans (HR: 2.32; 95% CI: 2.26, 2.39). In study two, we estimated the association between acute kidney injury (AKI) and CKD among patients with normal kidney function that were admitted to the hospital. Patients that experience AKI while hospitalized have 3.23 (95% CI: 1.46, 7.11) times the hazard of CKD than do patients that do not experience an event, after adjusting for age, CHF, diabetes, hypertension, baseline eGFR, and CAD. In study three, we compared the rate of CKD and ESRD in veterans taking an angiotensin receptor blocker (ARB) to the rate in veterans taking an angiotensin converting enzyme inhibitor. After adjusting for baseline glomerular filtration rates (eGFR), age, sex, race, hypertension and diabetes status, those veterans taking an ARB had 0.55 (95% CI: 0.53, 0.57) times the rate of kidney disease than did veterans taking an ACE. Decreased rates were seen in all dose groups and persisted in the high risk subgroups of the population. The results of the current studies highlight segments of the population that may benefit from prevention and intervention efforts and describe the comparative effectiveness of two potential pharmacologic interventions.