Determinants of change in arterial stiffness over 5 years in early chronic kidney disease.

BACKGROUND: Arterial stiffness (AS) is an established and potentially modifiable risk factor for cardiovascular disease associated with chronic kidney disease (CKD). There have been few studies to evaluate the progression of AS over time or factors that contribute to this, particularly in early CKD. We therefore investigated AS over 5 years in an elderly population with CKD Stage 3 cared for in primary care. METHODS: A total of 1741 persons with an estimated glomerular filtration rate of 30-59 mL/min/1.73 m2 underwent detailed clinical and biochemical assessment at baseline and Years 1 and 5. Carotid to femoral pulse wave velocity (PWV) was measured to assess AS using a Vicorder device. RESULTS: 970 participants had PWV assessments at baseline and 5 years. PWV increased significantly by a mean of 1.1 m/s (from 9.7 ± 1.9 to 10.8 ± 2.1 m/s). Multivariable linear regression analysis identified the following independent determinants of ΔPWV at Year 5: baseline age, diabetes status, baseline systolic blood pressure (SBP) and diastolic blood pressure, baseline PWV, ΔPWV at 1 year, ΔSBP over 5 years and Δserum bicarbonate over 5 years (R2 = 0.38 for the equation). CONCLUSIONS: We observed a clinically significant increase in PWV over 5 years in a cohort with early CKD despite reasonably well-controlled hypertension. Measures of BP were identified as the most important modifiable determinant of ΔPWV, suggesting that interventions to prevent arterial disease should focus on improved control of BP, particularly in those who evidence an early increase in PWV. These hypotheses should now be tested in prospective trials.

The association of skin autofluorescence with cardiovascular events and all-cause mortality in persons with chronic kidney disease stage 3: A prospective cohort study.

BACKGROUND: Tissue advanced glycation end product (AGE) accumulation has been proposed as a marker of cumulative metabolic stress that can be assessed noninvasively by measurement of skin autofluorescence (SAF). In persons on haemodialysis, SAF is an independent risk factor for cardiovascular events (CVEs) and all-cause mortality (ACM), but data at earlier stages of chronic kidney disease (CKD) are inconclusive. We investigated SAF as a risk factor for CVEs and ACM in a prospective study of persons with CKD stage 3. METHODS AND FINDINGS: Participants with estimated glomerular filtration rate (eGFR) 59 to 30 mL/min/1.73 m2 on two consecutive previous blood tests were recruited from 32 primary care practices across Derbyshire, United Kingdom between 2008 and 2010. SAF was measured in participants with CKD stage 3 at baseline, 1, and 5 years using an AGE reader (DiagnOptics). Data on hospital admissions with CVEs (based on international classification of diseases [ICD]-10 coding) and deaths were obtained from NHS Digital. Cox proportional hazards models were used to investigate baseline variables associated with CVEs and ACM. A total of 1,707 of 1,741 participants with SAF readings at baseline were included in this analysis: The mean (± SD) age was 72.9 ± 9.0 years; 1,036 (60.7%) were female, 1,681 (98.5%) were of white ethnicity, and mean (±SD) eGFR was 53.5 ± 11.9 mL/min/1.73 m2. We observed 319 deaths and 590 CVEs during a mean of 6.0 ± 1.5 and 5.1 ± 2.2 years of observation, respectively. Higher baseline SAF was an independent risk factor for CVEs (hazard ratio [HR] 1.12 per SD, 95% CI 1.03-1.22, p = 0.01) and ACM (HR 1.16, 95% CI 1.03-1.30, p = 0.01). Additionally, increase in SAF over 1 year was independently associated with subsequent CVEs (HR 1.11 per SD, 95% CI 1.00-1.22; p = 0.04) and ACM (HR 1.24, 95% CI 1.09-1.41, p = 0.001). We relied on ICD-10 codes to identify hospital admissions with CVEs, and there may therefore have been some misclassification. CONCLUSIONS: We have identified SAF as an independent risk factor for CVE and ACM in persons with early CKD. These findings suggest that interventions to reduce AGE accumulation, such as dietary AGE restriction, may reduce cardiovascular risk in CKD, but this requires testing in prospective randomised trials. Our findings may not be applicable to more ethnically diverse or younger populations.

The clinical utility and cost impact of cystatin C measurement in the diagnosis and management of chronic kidney disease: A primary care cohort study.

BACKGROUND: To reduce over-diagnosis of chronic kidney disease (CKD) resulting from the inaccuracy of creatinine-based estimates of glomerular filtration rate (GFR), UK and international guidelines recommend that cystatin-C-based estimates of GFR be used to confirm or exclude the diagnosis in people with GFR 45-59 ml/min/1.73 m2 and no albuminuria (CKD G3aA1). Whilst there is good evidence for cystatin C being a marker of GFR and risk in people with CKD, its use to define CKD in this manner has not been evaluated in primary care, the setting in which most people with GFR in this range are managed. METHODS AND FINDINGS: A total of 1,741 people with CKD G3a or G3b defined by 2 estimated GFR (eGFR) values more than 90 days apart were recruited to the Renal Risk in Derby study between June 2008 and March 2010. Using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations, we compared GFR estimated from creatinine (eGFRcreat), cystatin C (eGFRcys), and both (eGFRcreat-cys) at baseline and over 5 years of follow-up. We analysed the proportion of participants with CKD G3aA1 reclassified to 'no CKD' or more advanced CKD with the latter two equations. We further assessed the impact of using cystatin-C-based eGFR in risk prediction equations for CKD progression and all-cause mortality and investigated non-GFR determinants of eGFRcys. Finally, we estimated the cost implications of implementing National Institute for Health and Care Excellence (NICE) guidance to use eGFRcys to confirm the diagnosis in people classified as CKD G3aA1 by eGFRcreat. Mean eGFRcys was significantly lower than mean eGFRcreat (45.1 ml/min/1.73 m2, 95% CI 44.4 to 45.9, versus 53.6 ml/min/1.73 m2, 95% CI 53.0 to 54.1, P < 0.001). eGFRcys reclassified 7.7% (50 of 653) of those with CKD G3aA1 by eGFRcreat to eGFR ≥ 60 ml/min/1.73 m2. However, a much greater proportion (59.0%, 385 of 653) were classified to an eGFR category indicating more severe CKD. A similar pattern was seen using eGFRcreat-cys, but lower proportions were reclassified. Change in eGFRcreat and eGFRcys over 5 years were weakly correlated (r = 0.33, P < 0.001), but eGFRcys identified more people as having CKD progression (18.2% versus 10.5%). Multivariable analysis using eGFRcreat as an independent variable identified age, smoking status, body mass index, haemoglobin, serum uric acid, serum albumin, albuminuria, and C reactive protein as non-GFR determinants of eGFRcys. Use of eGFRcys or eGFRcreat-cys did not improve discrimination in risk prediction models for CKD progression and all-cause mortality compared to similar models with eGFRcreat. Application of the NICE guidance, which assumed cost savings, to participants with CKD G3aA1 increased the cost of monitoring by £23 per patient, which if extrapolated to be applied throughout England would increase the cost of testing and monitoring CKD by approximately £31 million per year. Limitations of this study include the lack of a measured GFR and the potential lack of ethnic diversity in the study cohort. CONCLUSIONS: Implementation of current guidelines on eGFRcys testing in our study population of older people in primary care resulted in only a small reduction in diagnosed CKD but classified a greater proportion as having more advanced CKD than eGFRcreat. Use of eGFRcys did not improve risk prediction in this population and was associated with increased cost. Our data therefore do not support implementation of these recommendations in primary care. Further studies are warranted to define the most appropriate clinical application of eGFRcys and eGFRcreat-cys.

Chronic Kidney Disease in Primary Care: Outcomes after Five Years in a Prospective Cohort Study.

BACKGROUND: Chronic kidney disease (CKD) is commonly managed in primary care, but most guidelines have a secondary care perspective emphasizing the risk of end-stage kidney disease (ESKD) and need for renal replacement therapy. In this prospective cohort study, we sought to study in detail the natural history of CKD in primary care to better inform the appropriate emphasis for future guidance. METHODS AND FINDINGS: In this study, 1,741 people with CKD stage 3 were individually recruited from 32 primary care practices in Derbyshire, United Kingdom. Study visits were undertaken at baseline, year 1, and year 5. Binomial logistic regression and Cox proportional hazards models were used to model progression, CKD remission, and all-cause mortality. We used Kidney Disease: Improving Global Outcomes (KDIGO) criteria to define CKD progression and defined CKD remission as the absence of diagnostic criteria (estimated glomerular filtration rate [eGFR] >60 ml/min/1.73 m2 and urine albumin-to-creatinine ratio [uACR] <3 mg/mmol) at any study visit. Participants were predominantly elderly (mean ± standard deviation (SD) age 72.9 ± 9.0 y), with relatively mild reduction in GFR (mean ± SD eGFR 53.5 ± 11.8 mL/min/1,73 m2) and a low prevalence of albuminuria (16.9%). After 5 y, 247 participants (14.2%) had died, most of cardiovascular causes. Only 4 (0.2%) developed ESKD, but 308 (17.7%) evidenced CKD progression by KDIGO criteria. Stable CKD was observed in 593 participants (34.1%), and 336 (19.3%) met the criteria for remission. Remission at baseline and year 1 was associated with a high likelihood of remission at year 5 (odds ratio [OR] = 23.6, 95% CI 16.5-33.9 relative to participants with no remission at baseline and year 1 study visits). Multivariable analyses confirmed eGFR and albuminuria as key risk factors for predicting adverse as well as positive outcomes. Limitations of this study include reliance on GFR estimated using the Modification of Diet in Renal Disease study (MDRD) equation for recruitment (but not subsequent analysis) and a study population that was predominantly elderly and white, implying that the results may not be directly applicable to younger populations of more diverse ethnicity. CONCLUSIONS: Management of CKD in primary care should focus principally on identifying the minority of people at high risk of adverse outcomes, to allow intervention to slow CKD progression and reduce cardiovascular events. Efforts should also be made to identify and reassure the majority who are at low risk of progression to ESKD. Consideration should be given to adopting an age-calibrated definition of CKD to avoid labelling a large group of people with age-related decline in GFR and low associated risk as having CKD.

Reduction in sodium intake is independently associated with improved blood pressure control in people with chronic kidney disease in primary care.

Decreasing sodium intake has been associated with improvements in blood pressure (BP) and proteinuria, two important risk factors for CVD and chronic kidney disease (CKD) progression. We aimed to investigate the role of sodium intake by examining the effect of changes in sodium intake over 1 year on BP and proteinuria in people with early stage CKD. From thirty-two general practices, 1607 patients with previous estimated glomerular filtration rate of 59-30 ml/min per 1.73 m² and mean age of 72.9 (sd 9.0) years were recruited. Clinical assessment, urine and serum biochemistry testing were performed at baseline and after 1 year. Sodium intake was estimated from early morning urine specimens using an equation validated for this study population. We found that compared with people who increased their sodium intake from ≤ 100 to >100 mmol/d over 1 year, people who decreased their intake from >100 to ≤ 100 mmol/d evidenced a greater decrease in all BP variables (Δmean arterial pressure (ΔMAP) = -7.44 (SD 10.1) v. -0.23 (SD 10.4) mmHg; P<0.001) as well as in pulse wave velocity (ΔPWV = -0.47 (SD 1.3) v. 0.08 (SD 1.88) m/s; P<0.05). Albuminuria improved only in albuminuric patients who decreased their sodium intake. BP improved in people who maintained low sodium intake at both times and in those with persistent high intake, but the number of anti-hypertensive increased only in the higher sodium intake group, and PWV improved only in participants with lower sodium intake. Decreasing sodium intake was an independent determinant of ΔMAP. Although more evidence is needed, our results support the benefits of reducing and maintaining sodium intake below 100 mmol/d (2.3-2.4 g/d) in people with early stages of CKD.

The impact of vitamin D status on the relative increase in fibroblast growth factor 23 and parathyroid hormone in chronic kidney disease.

Fibroblast growth factor (FGF) 23 is an important regulator of phosphaturia. Its serum level was found to increase before that of parathyroid hormone (PTH) in early chronic kidney disease (CKD) in some but not all previous studies. As vitamin D insufficiency is associated with elevated PTH, we determined the effect of vitamin D status on FGF23 and PTH levels in relation to glomerular filtration rate (GFR) in people with CKD stage 3. Serum intact FGF23, PTH, and 25(OH)vitamin D3 were measured in 1664 patients who were prospectively recruited from primary care. Mean or median values for key variables were an age of 73 years, estimated GFR (eGFR) of 53 ml/min per 1.73 m(2), PTH 46 pg/ml, FGF23 42 pg/ml, and 25(OH)vitamin D3 53 nmol/l. FGF23 and PTH concentrations were elevated in similar proportions of people with lower eGFR in the whole cohort. However, when 752 people with vitamin D insufficiency or deficiency were excluded, FGF23 was elevated in a greater proportion than PTH at all levels of eGFR. Conversely, among people with vitamin D insufficiency, PTH was elevated in a greater proportion than FGF23 at all GFR levels of ⩾40 ml/min per 1.73 m(2). In this cohort, we were able to triangulate the relationship between 25(OH)vitamin D3, PTH, and FGF23, showing that vitamin D status critically determines whether FGF23 or PTH becomes elevated first in the context of lower GFR. Future studies of FGF23 in people with CKD should routinely determine their vitamin D status.

Development of a formula for estimation of sodium intake from spot urine in people with chronic kidney disease.

BACKGROUND/AIMS: High sodium intake is associated with adverse cardiovascular and renal outcomes in people with chronic kidney disease (CKD), and simple methods to facilitate assessment of sodium intake are required. The objective of this study was to develop a new formula to estimate 24-hour urinary sodium (24hUNa) excretion from urinary Na concentration measured on an early morning urine specimen (EM UNa). METHODS: Seventy participants from a prospective cohort of patients with CKD stage 3 in primary care, the Renal Risk in Derby (RRID) study, agreed to collect an additional EM UNa on the day after completing a 24-hour urine collection. A formula to estimate 24hUNa from EM UNa and body weight was developed using the coefficients from a multivariable linear regression equation. The accuracy of the formula was tested by calculating the P30 (proportion of estimates within 30% of measured sodium exection), and the ability of the estimated 24hUNa to discriminate between measured sodium intake above or below 100 mmol/day was assessed by receiver operating characteristic (ROC) curve. A Bland-Altman plot was used to estimate the bias and limits of agreement between estimated and measured 24hUNa. Seventy-four additional paired 24hUNa and EM UNa from 50 CKD stage 3 patients in the RRID study were used to validate the formula. RESULTS: The mean difference between measured and estimated 24hUNa was 2.08 mmol/day. Measured and estimated 24hUNa were significantly correlated (r = 0.55; p < 0.001) but accuracy of estimated 24hUNa was low (P30 = 60%). Analysis of the ROC curve with a cut-off point >100 mmol/day yielded an area under the curve of 0.668, sensitivity of 0.85 and specificity of 0.52. CONCLUSIONS: We have developed a simple formula to identify people with a high sodium intake from EM UNa, suitable for use in large-cohort or population studies.

Demographic associations of high estimated sodium intake and frequency of consumption of high-sodium foods in people with chronic kidney disease stage 3 in England.

OBJECTIVE: The objective of this study was to investigate sodium intake in a cohort of people with chronic kidney disease (CKD) Stage 3 in England to identify demographic characteristics of subgroups with high sodium intake and specific foods that contribute to excessive sodium intake. DESIGN AND METHODS: Study subjects (N = 1,729) included CKD patients from 32 general practices in the Renal Risk in Derby study. Patients had a glomerular filtration rate between 30 and 59 mL/min per 1.73 m(2) on 2 or more occasions at least 3 months apart before recruitment. Sodium excretion (assumed to be equal to intake) was estimated from early morning urine specimens using an equation validated for this study population. The frequency of intake of 12 salty foods was assessed by a food frequency questionnaire. RESULTS: The mean estimated urinary sodium excretion was 110.5 ± 33.8 mmol/day; 60.1% had values above the National Kidney Foundation recommendation (<100 mmol/day). Subgroups with a greater percentage of participants having sodium excretion above the recommendation were as follows: men, those younger than 75 years of age, those with central obesity or diabetes, those with formal educational qualifications, and those who were previous or current smokers. In multivariable analysis, gender, younger age, waist-to-hip ratio, and diabetes mellitus status were the main independent determinants of excessive sodium excretion. Specific food items that contributed to excessive intake were table and cooking salt, salted snacks, hard cheeses, processed meat, and tinned fish. The most important source of sodium varied by subgroup. CONCLUSION: A high prevalence of sodium excretion above the recommended value was detected, and independent determinants were gender, age, waist-to-hip ratio, and diabetes mellitus. Specific food items that contributed to excessive intake were also identified and varied in different subgroups. These data will be helpful in informing strategies to target dietetic advice to those most likely to have high sodium intake and will allow dietitians to focus on the most likely sources of sodium in different subgroups.

Applying the lessons of design thinking: a unique programme of care for acutely unwell, community-dwelling COVID-19 patients.

BACKGROUND: The COVID-19 pandemic limited access to primary care and in-person assessments requiring healthcare providers to re-envision care delivery for acutely unwell outpatients. Design thinking methodology has the potential to support the robust evolution of a new clinical model. AIM: To demonstrate how design thinking methodology can rapidly and rigorously create and evolve a safe, timely, equitable and patient-centred programme of care, and to share valuable lessons for effective implementation of design thinking solutions to address complex problems. METHOD: We describe how design thinking methodology was employed to create a new clinical model of care. Using the example of a novel telemedicine programme to support acutely unwell, community-dwelling COVID-19-positive patients called the London Urgent COVID-19 Care Clinic (LUC3), we show how continuous quality outcomes (safety, timeliness, equity and patient-centredness), as well as patient experience survey responses, can drive iterative changes in programme delivery. RESULTS: The inspiration phase identified four key needs for this patient population: monitoring COVID-19 signs and symptoms; self-managing COVID-19 symptoms; managing other comorbidities in the setting of COVID-19; and escalating care as needed. Guided by these needs, a cross-disciplinary stakeholder group was engaged in the ideation and implementation phases to create a unique and comprehensive telemedicine programme (LUC3). During the implementation phase, LUC3 assessed 2202 community-based patients diagnosed with acute COVID-19; the collected quality outcomes and end-user feedback led to evolution of programme delivery. CONCLUSION: Design thinking methodology provided an essential framework and valuable lessons for the development of a safe, equitable, timely and patient-centred telemedicine care programme. The lessons learnt here-the importance of inclusive collaboration, using empathy to guide equity-focused interventions, leveraging continuous metrics to drive iteration and aiming for good-if-not-perfect plans-can serve as a road map for using design thinking for targeted healthcare problems.

Suboptimal blood pressure control in chronic kidney disease stage 3: baseline data from a cohort study in primary care.

BACKGROUND: Poorly controlled hypertension is independently associated with mortality, cardiovascular risk and disease progression in chronic kidney disease (CKD). In the UK, CKD stage 3 is principally managed in primary care, including blood pressure (BP) management. Controlling BP is key to improving outcomes in CKD. This study aimed to investigate associations of BP control in people with CKD stage 3. METHODS: 1,741 patients with CKD 3 recruited from 32 general practices for the Renal Risk in Derby Study underwent medical history, clinical assessment and biochemistry testing. BP control was assessed by three standards: National Institute for Health and Clinical Excellence (NICE), National Kidney Foundation Kidney Disease Outcome Quality Initiative (KDOQI) and Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. Descriptive statistics were used to compare characteristics of people achieving and not achieving BP control. Univariate and multivariate logistic regression was used to identify factors associated with BP control. RESULTS: The prevalence of hypertension was 88%. Among people with hypertension, 829/1426 (58.1%) achieved NICE BP targets, 512/1426 (35.9%) KDOQI targets and 859/1426 (60.2%) KDIGO targets. Smaller proportions of people with diabetes and/or albuminuria achieved hypertension targets. 615/1426 (43.1%) were only taking one antihypertensive agent. On multivariable analysis, BP control (NICE and KDIGO) was negatively associated with age (NICE odds ratio (OR) 0.27; 95% confidence interval (95% CI) 0.17-0.43) 70-79 compared to <60), diabetes (OR 0.32; 95% CI 0.25-0.43)), and albuminuria (OR 0.56; 95% CI 0.42-0.74)). For the KDOQI target, there was also association with males (OR 0.76; 95% CI 0.60-0.96)) but not diabetes (target not diabetes specific). Older people were less likely to achieve systolic targets (NICE target OR 0.17 (95% CI 0.09,0.32) p < 0.001) and more likely to achieve diastolic targets (OR 2.35 (95% CI 1.11,4.96) p < 0.001) for people >80 compared to < 60). CONCLUSIONS: Suboptimal BP control was common in CKD patients with hypertension in this study, particularly those at highest risk of adverse outcomes due to diabetes and or albuminuria. This study suggests there is scope for improving BP control in people with CKD by using more antihypertensive agents in combination while considering issues of adherence and potential side effects.

Socio-economic disparities in the distribution of cardiovascular risk in chronic kidney disease stage 3.

BACKGROUND/AIMS: For most people with chronic kidney disease (CKD), cardiovascular disease (CVD) risk exceeds risk of progression to end-stage renal disease. This study aimed to investigate the distribution of cardiovascular risk in CKD stage 3 by socio-economic status (SES; measured by area deprivation and educational attainment) and CKD diagnosis awareness. METHODS: 1,741 patients with CKD 3 recruited from primary-care practices for the Renal Risk in Derby Study were assessed for cardiovascular risk factors. Ten-year cardiovascular risk, estimated using Framingham and QRISK2 risk prediction algorithms in eligible subgroups, was dichotomised at ≥ 20% (a threshold for clinical action in the UK), and compared by SES and awareness of CKD diagnosis using logistic regression. RESULTS: Patients with lower SES had greater adjusted odd ratios (OR) of smoking, diabetes and previous CVD, but not of central obesity, hypertension, elevated total/high-density-lipoprotein cholesterol ratio or albuminuria. Using Framingham scoring (n = 672), the adjusted OR of having ≥ 20% 10-year risk were 2.87 [95% confidence interval (CI) 1.41-5.84] in the lowest deprivation quintile compared to the highest, 2.52 (95% CI: 1.52-4.00) in those without qualifications compared to those with qualifications, and 1.54 (95% CI: 1.09-2.17) in those unaware of their CKD diagnosis compared to those aware of it. QRISK2 scoring (n = 1,071) showed a similar association with education status [OR: 2.45 (95% CI: 1.63-3.67)] and lack of CKD awareness [OR: 1.46 (95% CI: 1.05-2.03)], but not with deprivation [OR: 1.12 (95% CI: 0.55-2.27)]. CONCLUSION: An elevated CVD risk is associated with a lower education status and lack of awareness of CKD diagnosis in people with CKD 3.

Risk profile in chronic kidney disease stage 3: older versus younger patients.

BACKGROUND: The prevalence of chronic kidney disease (CKD) increases with age, but its significance in older patients is uncertain and is regarded by some as part of 'normal aging'. Moreover, subjects ≥75 years are often excluded from research studies. We therefore undertook a prospective study of patients with CKD stage 3 in primary care to compare the risk profile of older versus younger subjects. METHODS: Subjects with an estimated glomerular filtration rate (eGFR) 59-30 ml/min/1.73 m(2) on two measurements were recruited from 32 primary care practices. Medical history and demographic data were obtained and participants underwent clinical assessment as well as urine and serum biochemistry tests. RESULTS: 1,741 participants were recruited: mean age 72.9 ± 9 years; 60% female; 98% white; 17% diabetic. Mean eGFR was 52.5 ± 10 ml/min/1.73 m(2) and 16.9% had albuminuria. Subjects ≥75 years had a significantly lower eGFR than younger subjects and a higher risk profile characterised by greater albuminuria, more arterial stiffness and higher serum uric acid levels. CONCLUSION: Older subjects with CKD stage 3 evidenced a higher risk profile for CKD progression and cardiovascular events than younger patients. This implies that CKD is not a benign condition in all elderly patients, but further investigation is required to identify those at greatest risk who may benefit from intervention.

Health-related quality of life, functional impairment and comorbidity in people with mild-to-moderate chronic kidney disease: a cross-sectional study.

OBJECTIVES: To determine the associations between comorbidities, health-related quality of life (HRQoL) and functional impairment in people with mild-to-moderate chronic kidney disease (CKD) in primary care. DESIGN: Cross-sectional analysis at 5-year follow-up in a prospective cohort study. SETTING: Thirty-two general practitioner surgeries in England. PARTICIPANTS: 1008 participants with CKD stage 3 (of 1741 people recruited at baseline in the Renal Risk in Derby study) who survived to 5 years and had complete follow-up data for HRQoL and functional status (FS). PRIMARY AND SECONDARY OUTCOME MEASURES: HRQoL assessed using the 5-level EQ-5D version (EQ-5D-5L, with domains of mobility, self-care, usual activities, pain/discomfort and anxiety/depression and index value using utility scores calculated from the English general population), and FS using the Karnofsky Performance Status scale (functional impairment defined as Karnofksy score ≤70). Comorbidity was defined by self-reported or doctor-diagnosed condition, disease-specific medication or blood result. RESULTS: Mean age was 75.8 years. The numbers reporting some problems in EQ-5D-5L domains were: 582 (57.7%) for mobility, 166 (16.5%) for self-care, 466 (46.2%) for usual activities, 712 (70.6%) for pain/discomfort and 319 (31.6%) for anxiety/depression. Only 191 (18.9%) reported no problems in any domain. HRQoL index values showed greater variation among those with lower FS (eg, for those with Karnofsky score of 60, the median (IQR) EQ-5D index value was 0.45 (0.24 to 0.68) compared with 0.94 (0.86 to 1) for those with Karnofsky score of 90). Overall, 234 (23.2%) had functional impairment.In multivariable logistic regression models, functional impairment was independently associated with experiencing problems for all EQ-5D-5L domains (mobility: OR 16.87 (95% CI 8.70 to 32.79, p<0.001, self-care: OR 13.08 (95% CI 8.46 to 20.22), p<0.001, usual activities: OR 8.27 (95% CI 5.43 to 12.58), p<0.001, pain/discomfort: OR 2.94 (95% CI 1.86 to 4.67), p<0.001, anxiety/depression: 3.08 (95% CI 2.23 to 4.27), p<0.001). Higher comorbidity count and obesity were independently associated with problems in mobility, self-care, usual activities and pain/discomfort: for three or more comorbidities versus none: (mobility: OR 2.10 (95% CI 1.08 to 4.10, p for trend 0.002), self-care: OR 2.64 (95% CI 0.72 to 9.67, p for trend 0.05), usual activities: OR 4.20 (95% CI 2.02 to 8.74, p for trend <0.001), pain/discomfort: OR 3.06 (95% CI 1.63 to 5.73, p for trend <0.001)), and for obese (body mass index (BMI) ≥30 kg/m2) versus BMI <25 kg/m2: (mobility: OR 2.44 (95% CI 1.61 to 3.69, p for trend <0.001), self-care: OR 1.98 (95% CI 1.06 to 3.71, p for trend 0.003), usual activities: OR 1.82 (95% CI 1.19 to 2.76, p for trend 0.019), pain/discomfort: OR 2.37 (95% CI 1.58 to 3.55, p for trend <0.001)). Female sex, lower FS and lower educational attainment were independently associated with anxiety/depression (ORs 1.60 (95% CI 1.18 to 2.16, p 0.002), 3.08 (95% CI 2.23 to 4.27, p<0.001) and 1.67 (95% CI 1.10 to 2.52, p 0.009), respectively). Older age, higher comorbidity count, albuminuria (≥30 mg/mmol vs <3 mg/mmol), lower educational attainment (no formal qualifications vs degree level) and obesity were independently associated with functional impairment (ORs 1.07 (95% CI 1.04 to 1.09, p<0.001), 2.18 (95% CI 0.80 to 5.96, p for trend <0.001), 1.74 (95% CI 0.82 to 3.68, p for trend 0.005), 2.08 (95% CI 1.26 to 3.41, p for trend <0.001) and 4.23 (95% CI 2.48 to 7.20), respectively). CONCLUSIONS: The majority of persons with mild-to-moderate CKD reported reductions in at least one HRQoL domain, which were independently associated with comorbidities, obesity and functional impairment. TRIAL REGISTRATION NUMBER: National Institute for Health Research Clinical Research Portfolio Study Number 6632.

Associations of fibroblast growth factor 23, vitamin D and parathyroid hormone with 5-year outcomes in a prospective primary care cohort of people with chronic kidney disease stage 3.

OBJECTIVES: Vitamin D deficiency, elevated fibroblast growth factor 23 (FGF23) and elevated parathyroid hormone (PTH) have each been associated with increased mortality in people with chronic kidney disease (CKD). Previous studies have focused on the effects of FGF23 in relatively advanced CKD. This study aims to assess whether FGF23 is similarly a risk factor in people with early CKD, and how this risk compares to that associated with vitamin D deficiency or elevated PTH. DESIGN: Prospective cohort study. SETTING: Thirty-two primary care practices. PARTICIPANTS: One thousand six hundred and sixty-four people who met Kidney Disease: Improving Global Outcomes (KDIGO) definitions for CKD stage 3 (two measurements of estimated glomerular filtration rate (eGFR) between 30 and 60 mL/min/1.73 m2 at least 90 days apart) prior to study recruitment. OUTCOME MEASURES: All-cause mortality over the period of study follow-up and progression of CKD defined as a 25% fall in eGFR and a drop in GFR category, or an increase in albuminuria category. RESULTS: Two hundred and eighty-nine participants died during the follow-up period. Vitamin D deficiency (HR 1.62, 95% CI 1.01 to 2.58) and elevated PTH (HR 1.42, 95% CI 1.09 to 1.84) were independently associated with all-cause mortality. FGF23 was associated with all-cause mortality in univariable but not multivariable analysis. Fully adjusted multivariable models of CKD progression showed no association with FGF23, vitamin D status or PTH. CONCLUSIONS: In this cohort of predominantly older people with CKD stage 3 and low risk of progression, vitamin D deficiency and elevated PTH were independent risk factors for all-cause mortality but elevated FGF23 was not. While FGF23 may have a role as a risk marker in high-risk populations managed in secondary care, our data suggest that it may not be as important in CKD stage 3, managed in primary care. TRIAL REGISTRATION NUMBER: National Institute for Health Research Clinical Research Portfolio Study Number 6632.

Skin autofluorescence and all-cause mortality in stage 3 CKD.

BACKGROUND AND OBJECTIVES: Novel markers may help to improve risk prediction in CKD. One potential candidate is tissue advanced glycation end product accumulation, a marker of cumulative metabolic stress, which can be assessed by a simple noninvasive measurement of skin autofluorescence. Skin autofluorescence correlates with higher risk of cardiovascular events and mortality in people with diabetes or people requiring RRT, but its role in earlier CKD has not been studied. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A prospective cohort of 1741 people with CKD stage 3 was recruited from primary care between August 2008 and March 2010. Participants underwent medical history, clinical assessment, blood and urine sampling for biochemistry, and measurement of skin autofluorescence. Kaplan-Meier plots and multivariate Cox proportional hazards models were used to investigate associations between skin autofluorescence (categorical in quartiles) and all-cause mortality. RESULTS: In total, 1707 participants had skin autofluorescence measured; 170 (10%) participants died after a median of 3.6 years of follow-up. The most common cause of death was cardiovascular disease (41%). Higher skin autofluorescence was associated significantly with poorer survival (all-cause mortality, P<0.001) on Kaplan-Meier analysis. Univariate and age/sex-adjusted Cox proportional hazards models showed that the highest quartile of skin autofluorescence was associated with all-cause mortality (hazard ratio, 2.64; 95% confidence interval, 1.71 to 4.08; P<0.001 and hazard ratio, 1.84; 95% confidence interval, 1.18 to 2.86; P=0.003, respectively, compared with the lowest quartile). This association was not maintained after additional adjustment to include cardiovascular disease, diabetes, smoking, body mass index, eGFR, albuminuria, and hemoglobin. CONCLUSIONS: Skin autofluorescence was not independently associated with all-cause mortality in this study. Additional research is needed to clarify whether it has a role in risk prediction in CKD.

Assessment of proteinuria in patients with chronic kidney disease stage 3: albuminuria and non-albumin proteinuria.

BACKGROUND AND OBJECTIVE: Proteinuria assessment is key in investigating chronic kidney disease (CKD) but uncertainty exists regarding optimal methods. Albuminuria, reflecting glomerular damage, is usually measured, but non-albumin proteinuria (NAP), reflecting tubular damage, may be important. This study investigated the prevalence and associations of albuminuria and NAP, and the optimum number of urine specimens required. METHODS: 1,741 patients with CKD stage 3, recruited from primary care, underwent medical history, clinical assessment, blood sampling, and submitted three early morning urine samples for albumin to creatinine ratio (uACR) and protein to creatinine ratios (uPCR). Albuminuria was defined as uACR ≥ 3 mg/mmol in at least two of three samples. Isolated NAP was defined as uPCR ≥ 17 mg/mmol in two of three samples and uACR <3 mg/mmol in all three. Prevalence and associations of albuminuria and NAP, degree of agreement between single uACR and average of three uACRs, and urine albumin to protein ratio (uAPR  =  uACR/uPCR) were identified. RESULTS: Albuminuria prevalence was 16% and NAP 6%. Using a <1 mg/mmol threshold for uACR reduced NAP prevalence to 3.6%. Independent associations of albuminuria were: males (OR 3.06 (95% CI, 2.23-4.19)), diabetes (OR 2.14 (1.53-3.00)), lower estimated glomerular filtration rate ((OR 2.06 (1.48-2.85) 30-44 vs 45-59), and high sensitivity CRP ((OR 1.70 (1.25-2.32)). NAP was independently associated with females (OR 6.79 (3.48-13.26)), age (OR 1.62 (1.02-2.56) 80 s vs 70-79) and high sensitivity CRP ((OR 1.74 (1.14-2.66)). Of those with uPCR ≥ 17 mg/mmol, 62% had uAPR<0.4. Sensitivity of single uACR was 95%, specificity 98%, PPV 90%. Bland Altman plot one vs average of three uACRs showed: mean difference 0.0064 mg/mmol (SD 4.69, limits of agreement -9.19 to +9.20, absolute mean difference 0.837). CONCLUSIONS: In CKD stage 3, albuminuria has associations distinct from those of isolated NAP (except for inflammatory markers). Single uACR categorised albuminuria but average of three performed better for quantification.

Determinants of arterial stiffness in chronic kidney disease stage 3.

BACKGROUND: Early chronic kidney disease (CKD) is associated with increased cardiovascular (CV) risk but underlying mechanisms remain uncertain. Arterial stiffness (AS) is associated with increased CV risk in advanced CKD, but it is unclear whether AS is relevant to CV disease (CVD) in early CKD. STUDY DESIGN: Cross-sectional. SETTING AND PARTICIPANTS: 1717 patients with previous estimated glomerular filtration rate (eGFR) 59-30 mL/min/1.73 m(2); mean age 73±9y, were recruited from 32 general practices in primary care. OUTCOMES: Increased arterial stiffness. MEASUREMENTS: Medical history was obtained and participants underwent clinical assessment, urine and serum biochemistry testing. Carotid to femoral pulse wave velocity (PWV) was determined as a measure of AS, using a Vicorder™ device. RESULTS: Univariate analysis revealed significant correlations between PWV and risk factors for CVD including age (r = 0.456; p<0.001), mean arterial pressure (MAP) (r = 0.228; p<0.001), body mass index (r = -0.122; p<0.001), log urinary albumin to creatinine ratio (r = 0.124; p<0.001), Waist to Hip ratio (r = 0.124, p<0.001), eGFR (r = -0.074; p = 0.002), log high sensitivity c-reactive protein (r = 0.066; p = 0.006), HDL (r = -0.062; p = 0.01) and total cholesterol (r = -0.057; p = 0.02). PWV was higher in males (9.6 m/sec vs.10.3 m/sec; p<0.001), diabetics (9.8 m/sec vs. 10.3 m/sec; p<0.001), and those with previous CV events (CVE) (9.8 m/s vs. 10.3 m/sec; p<0.001). Multivariable analysis identified age, MAP and diabetes as strongest independent determinants of higher PWV (adjusted R²â€Š= 0.29). An interactive term indicated that PWV increased to a greater extent with age in males versus females. Albuminuria was a weaker determinant of PWV and eGFR did not enter the model. LIMITATIONS: Data derived from one study visit, with absence of normal controls. CONCLUSION: In this cohort, age and traditional CV risk factors were the strongest determinants of AS. Albuminuria was a relatively weak determinant of AS and eGFR was not an independent determinant. Long-term follow-up will investigate AS as an independent risk factor for CVE in this cohort.

Treatment needs and diagnosis awareness in primary care patients with chronic kidney disease.

BACKGROUND: GPs in England are required to keep a register of patients with chronic kidney disease (CKD). National Institute for Health and Clinical Excellence (NICE) guidelines recommend regular follow-up, but patients are perceived to be low risk and not requiring active management. AIM: To assess treatment needs of CKD stage 3 patients in primary care, as well as their awareness of CKD. DESIGN AND SETTING: A cross-sectional analysis from a longitudinal prospective study in 32 general practices. METHOD: A total of 1741 participants underwent clinical assessment including urine and blood tests. Participants were asked about awareness of their CKD. Results were reviewed and a letter recommending treatment in line with NICE guidelines was sent to their GP. RESULTS: The mean age of participants was 73 ± 9 years; 60% (n = 1052) were female and diabetes was present in 17%; 67% of participants required further intervention. Most required improved control of hypertension (n = 1576; 33.1% of cohort). Other recommendations included advice to investigate anaemia (n = 1142; 8.2%) or stop nephrotoxic drugs (n = 1120; 7.5%). Less than 6% of participants met NICE criteria for referral to nephrology services and 41% were unaware of their CKD diagnosis. Multivariable analysis identified subjects with formal educational qualifications, age <75 years, estimated glomerular filtration rate (eGFR) 30-44 ml/min/1.73 m(2), and significant albuminuria as more likely to be aware of their diagnosis. CONCLUSION: The study data show that the majority of patients required at least one intervention to improve the management of their CKD. Most interventions could be delivered in primary care and only a minority required nephrology referral. Many patients were unaware of their CKD diagnosis, and efforts should be made to improve this to facilitate involvement in their care.

Anthropomorphic measurements that include central fat distribution are more closely related with key risk factors than BMI in CKD stage 3.

BACKGROUND: Body Mass Index (BMI) as a marker of obesity is an established risk factor for chronic kidney disease (CKD) and cardiovascular disease (CVD). However, BMI can overestimate obesity. Anthropomorphic measurements that include central fat deposition are emerging as a more important risk factor. We studied BMI, waist circumference (WC), waist-to-height ratio (WHtR), waist-to-hip ratio (WHR) and conicity index (CI) in a cohort of patients with CKD stage 3 and compared the associations with other known risk factors for CKD progression and CVD. METHODS: 1740 patients with CKD stage 3 were recruited from primary care for the Renal Risk in Derby study. Each participant underwent clinical assessment, including anthropomorphic measurements and pulse wave velocity (PWV), as well as urine and serum biochemistry tests. RESULTS: The mean age of the cohort was 72.9±9 years with 60% females. The mean eGFR was 52.5±10.4 ml/min/1.73 m(2) and 16.9% of the cohort had diabetes. With the cohort divided into normal and increased risk of morbidity and mortality using each anthropomorphic measurement, those measurements that included increased central fat distribution were significantly associated with more risk factors for CKD progression and CVD than increased BMI. Univariable analysis demonstrated central fat distribution was correlated with more risk factors than BMI. Subgroup analyses using recognised BMI cut-offs to define obesity and quartiles of WHR and CI demonstrated that increasing central fat distribution was significantly associated with more CKD and CVD risk factors than increasing BMI. CONCLUSION: Anthropomorphic measurements that include a measure of central fat deposition are related to more key risk factors in CKD stage 3 patients than BMI. Central fat deposition may be of greater importance as a risk factor in CKD than BMI and reliance on BMI alone may therefore underestimate the associated risk.

Skin autofluorescence and the association with renal and cardiovascular risk factors in chronic kidney disease stage 3.

BACKGROUND AND OBJECTIVES: Tissue advanced glycation end products (AGE) accumulation is a measure of cumulative metabolic stress. Assessment of tissue AGE by skin autofluorescence (SAF) correlates well with cardiovascular (CV) outcomes in diabetic, transplant, and dialysis patients, and may be a useful marker of CV risk in earlier stages of chronic kidney disease (CKD). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: 1707 patients with estimated GFR 59 to 30 ml/min per 1.73 m(2) were recruited from primary care practices for the Renal Risk In Derby (RRID) study. Detailed medical history was obtained, and each participant underwent clinical assessment as well as urine and serum biochemistry tests. SAF was assessed (mean of three readings) as a measure of skin AGE deposition using a cutaneous AF device (AGE Reader™, DiagnOptics, Groningen, The Netherlands). RESULTS: Univariate analysis revealed significant correlations between AF readings and several potential risk factors for cardiovascular disease (CVD) and progression of CKD. SAF readings (arbitrary units) were also significantly higher among males (2.8 ± 0.7 versus 2.7 ± 0.6), diabetics (3.0 ± 0.7 versus 2.7 ± 0.6), patients with evidence of self-reported CVD (2.9 ± 0.7 versus 2.7 ± 0.6), and those with no formal educational qualifications (2.8 ± 0.6 versus 2.6 ± 0.6; P < 0.01 for all). Multivariable linear regression analysis identified hemoglobin, diabetes, age, and eGFR as the most significant independent determinants of higher SAF (standardized coefficients -0.16, 0.13, 0.12, and -0.10, respectively; R(2) = 0.17 for equation). CONCLUSION: Increased SAF is independently associated with multiple CV and renal risk factors in CKD 3. Long-term follow-up will assess the value of SAF as a predictor of CV and renal risk in this population.