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

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

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

BackgroundTissue 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 findingsParticipants 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.ConclusionsWe 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

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

Risk prediction and outcomes in chronic kidney disease stage 3: a prospective cohort study in primary care

Introduction Chronic Kidney Disease (CKD) is common, and affects many people who are predominantly managed in primary care. Guidelines for management of CKD are often based around evidence from referred secondary care populations. Many risk factors for progressive CKD have been described, but not examined in a primary care population. Outcomes in CKD are variable, and concern long-term changes. Therefore, risk stratification is key to guide clinical management. This thesis will examine outcomes over 5 years in a cohort of people with CKD stage 3 recruited from primary care. It will evaluate cystatin C, Fibroblast Growth Hormone (FGF23), vitamin D and parathyroid hormone (PTH) as biochemical markers of risk in this population, and additionally will assess Skin autofluorescence (SAF) as a non-invasive measure of tissue advanced glycation endproducts (AGEs) and another potential strategy for risk stratification. Methods The Renal Risk in Derby (RRID) study is a prospective cohort of 1,741 people with CKD stage 3, defined by two GFR measurements more than 90 days apart, prior to study entry. Participants were individually assessed at baseline, 1 year, and 5 year follow-up visits. Blood and urine were sampled for biochemistry, and anthropometric data were additionally collected. SAF was measured at each study visit using an AGE reader (Diagnoptics). Results Five-year follow-up demonstrated low rates of CKD progression. The largest group of participants (593 of 1,741, 34.1%) evidenced stable CKD over the 5 year study period. End Stage Kidney Disease (ESKD) was rare, and was seen in 0.2% (4 of 1,741) of participants. Additionally, a significant minority of participants (19.3%, 336 of 1,741) demonstrated no evidence of CKD at their year 5 visit. The risk of CKD progression can be predicted with moderate accuracy using common clinical variables including age, gender, baseline eGFR, urine albumin to creatinine ratio (uACR), haemoglobin, bicarbonate, and diabetes. Cystatin C was evaluated in the context of national and international guidance suggesting it be used to confirm diagnosis of CKD in those with CKD 3a A1 on creatinine based estimates of GFR. In this cohort, mean cystatin C based eGFR values were significantly lower than those derived from creatinine (45.1 ml/min/1.73m2, 95% Confidence Interval (CI) 44.4 to 45.9 versus 53.6 ml/min/1.73m2, 95% CI 53.0 to 54.1). Use of cystatin C based eGFR in this population would therefore reclassify many participants as having more severe disease. Markers of mineral bone disease, including FGF23, vitamin D, and parathyroid hormone (PTH) have been of interest in CKD risk prediction. In the RRID study, vitamin D deficiency (Hazard Ratio 1.62, 95% CI 1.01 to 2.58) and raised PTH (HR 1.42, 95% CI 1.09 to 1.84) were independently associated with increased risk of all-cause mortality, but FGF23 was not. Skin Autofluorescence (SAF) was examined as a risk marker of all-cause mortality and CKD progression. In fully adjusted multivariable analysis, both baseline SAF (HR 1.16, 95% CI 1.02 to 1.32), and the change in SAF over the first year of the study (HR 1.16, 95% CI 1.00 to 1.34) were associated with all-cause mortality but not CKD progression. Conclusions The results presented in this thesis show that, in a primary care cohort of predominantly older adults, CKD progression is uncommon and can be predicted using common clinical variables. Cystatin C did not improve diagnosis or risk prediction in CKD in the way that it was intended in recent national and international guidance. Some novel risk markers evaluated in this study did predict risk in this population, including SAF, vitamin D, and PTH; however, these do not necessarily contribute additionally to common clinical variables. Risk prediction models in primary care should therefore focus on these. Thus, these results suggest that people with CKD stage 3 can be adequately managed and risk stratified in primary care without the need for additional, potentially expensive, investigations

The burden of comorbidity in people with chronic kidney disease stage 3: a cohort study

BACKGROUND: Multimorbidity is a growing concern for healthcare systems, with many countries experiencing demographic transition to older population profiles. Chronic kidney disease (CKD) is common but often considered in isolation. The extent and prognostic significance of its comorbidities is not well understood. This study aimed to assess the extent and prognostic significance of 11 comorbidities in people with CKD stage 3.METHODS: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. Comorbidity was defined by self-reported doctor-diagnosed condition, disease-specific medication or blood results (hemoglobin), and treatment burden as number of ongoing medications. Logistic regression was used to identify associations with greater treatment burden (taking &gt;5 medications) and greater multimorbidity (3 or more comorbidities). Kaplan Meier plots and multivariate Cox proportional hazards models were used to investigate associations between multimorbidity and all-cause mortality.RESULTS:One thousand seven hundred forty-one people were recruited, mean age 72.9 +/-9 years. Mean baseline eGFR was 52 ml/min/1.73 m(2). Only 78/1741 (4 %) had no comorbidities, 453/1741 (26 %) had one, 508/1741 (29 %) had two and 702/1741 (40 %) had &gt;2. Hypertension was common (88 %), 30 % had 'painful condition', 24 % anemia, 23 %, ischaemic heart disease, 17 % diabetes and 12 % thyroid disorders. Median medication use was 5 medications (interquartile range 3-8) and increased with degree of comorbidity. Greater treatment burden and multimorbidity were independently associated with age, smoking, increasing body mass index and decreasing eGFR. Treatment burden was also independently associated with lower education status. After median 3.6 years follow-up, 175/1741 (10 %) died. Greater multimorbidity was independently associated with mortality (hazard ratio 2.81 (95 % confidence intervals 1.72-4.58), p &lt; 0.001) for 3 or more comorbidities vs 0 or 1).CONCLUSIONS: Isolated CKD was rare and multimorbidity the norm in this cohort of people with moderate CKD. Increasing multimorbidity was associated with greater medication burden and poorer survival. CKD management should include consideration of comorbidities

Basic cohort descriptive statistics and breakdown by year 5 outcome.

<p>Basic cohort descriptive statistics and breakdown by year 5 outcome.</p