Natasha J. McIntyre

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.

Tissue-Advanced Glycation End Product Concentration in Dialysis Patients

BACKGROUND AND OBJECTIVES Tissue-advanced glycation end products (AGE) are a measure of cumulative metabolic stress. Assessment of tissue AGE by skin autofluoresence (AF) correlates well with cardiovascular outcomes in hemodialysis (HD) patients. This study aimed to measure and compare tissue AGE levels in HD and peritoneal dialysis (PD) patients and to evaluate the impact of systemic PD glucose exposure. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Tissue AGE were measured in 115 established dialysis patients (62 HD and 53 PD) using a cutaneous AF device (AGE Reader; DiagnOptics). Values were compared with an age-matched non-chronic kidney disease database. Review of all previous PD solution delivery/prescription data determined PD glucose exposure. RESULTS PD patients were similar in age to HD patients but had a shorter dialysis vintage. There were no differences in ischemic heart disease or smoking history, statin or angiotensin-converting enzyme inhibitor (ACEi) use, lipids, biochemistry, or prevalence of diabetes. More than 90% of both groups had met current dialysis adequacy targets. Skin AF values in PD and HD patients were similar and strongly correlated with historical PD glucose exposure. Skin AF correlated with age in both groups but with dialysis vintage only in PD patients CONCLUSIONS Cumulative metabolic stress and transient hyperglycemia results in grossly elevated levels of tissue AGE in dialysis patients. In PD patients, this high level of AGE deposition is associated with historical glucose exposure. This observation provides a previously unappreciated potential link between PD exposure to glucose and systemic cardiovascular disease.

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 m2 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.

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.

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

BackgroundPoorly 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.Methods1,741 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.ResultsThe 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).ConclusionsSuboptimal 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.

How to measure proteinuria

Purpose of reviewTo examine the use of urine total protein compared with albumin measurements to assess and monitor patients with chronic kidney disease. Recent findingsUrine albumin or total protein-to-creatinine ratio measurements on a single-voided specimen provide a convenient and reliable alternative to 24-h urine measurements. The majority of studies that inform current renoprotective strategies have relied upon urine total protein measurements. Urine albumin measurements are required to detect microalbuminuria. The proportion of urinary protein composed of albumin is variable and may depend on the underlying renal disease. SummaryUrine protein-to-creatinine measurements should continue to be used for the assessment and monitoring of patients with nondiabetic chronic kidney disease. Urine albumin-to-creatinine measurements should be reserved for detecting microalbuminuria and monitoring patients with diabetic nephropathy. Further research is required to investigate the relationship between urine total protein and albumin in different renal diseases and to compare the prognostic significance of urine total protein with that of albumin.

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 m2; 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 R2 = 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.

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 m2 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 m2 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.

Tissue Advanced Glycation End Product Deposition after Kidney Transplantation

Background: Tissue advanced glycation end products (AGEs) accumulate in chronic kidney disease (CKD) and are a measure of cumulative metabolic stress. Measurement of tissue AGEs by skin autofluorescence (SAF) correlates well with cardiovascular outcomes in dialysis patients. SAF levels in transplant recipients relative to CKD and dialysis patients have not been previously studied, and the impact of transplantation on SAF levels in dialysis patients is unknown. Methods: SAF was measured using an AGE reader in 66 patients who had received a kidney transplant. Values were compared to those obtained in 1,707 patients with CKD stage 3 and in 115 patients on dialysis. Results: Mean SAF in transplant recipients [2.81 ± 0.64 arbitrary units (AU)] was significantly lower than in patients on haemodialysis (3.73 ± 0.88 AU) and peritoneal dialysis (3.57 ± 0.75 AU; p < 0.001), but was no different from CKD stage 3 (2.79 ± 0.66 AU; p = 0.42). In the transplant group, SAF correlated most strongly with age (r = 0.316). There was no correlation between SAF and estimated glomerular filtration rate or renal replacement therapy vintage. A small cohort of patients with SAF recorded on dialysis and following transplantation showed a drop in SAF over a mean time of 16 months after transplantation. Discussion: Tissue AGE values in kidney transplant recipients are significantly lower than in patients receiving dialysis and similar to those in patients with CKD stage 3. Our data suggest that transplantation may be associated with a reduction in tissue AGEs, and this might be an important component of the observed reduction in cardiovascular risk in transplant recipients compared to patients on dialysis.

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.