Laurie A. Tomlinson

Aortic Stiffness Is Independently Associated With Rate of Renal Function Decline in Chronic Kidney Disease Stages 3 and 4

Aortic stiffness and chronic kidney disease are closely linked by shared risk factors and associated increased cardiovascular mortality. At lower levels of renal function, aortic stiffness is independently associated with glomerular filtration rate. However, the longitudinal impact of aortic stiffness on renal function has not been reported previously. A cohort of 133 patients with chronic kidney disease stages 3 and 4 (estimated glomerular filtration rate: 15 to 59 mL/min per 1.73 m2) underwent prospective measurement of arterial stiffness parameters and monitoring of renal function. Aortic pulse wave velocity measurement was performed in 120 patients. The mean age was 69±12 years (mean±SD; 103 men, 30 women, and 23.3% diabetic). Mean systolic blood pressure was 155±21 mm Hg, and mean diastolic blood pressure was 83±11 mm Hg. The mean Modification of Diet in Renal Disease estimated glomerular filtration rate was 32±11 mL/min per 1.73 m2. Change in renal function was measured using reciprocal creatinine plots and the dichotomous combined end point of ≥25% decline in renal function or start of renal replacement therapy. After stepwise multivariate analysis, aortic pulse wave velocity was independently associated with gradient of reciprocal creatinine plot (r=0.46; P=0.014). In multivariate analysis of the end point of ≥25% decline in renal function or start of renal replacement therapy, independent predictors were aortic pulse wave velocity (r=0.48; P=0.002), systolic blood pressure (r=0.17; P=0.039), and urine protein:creatinine ratio (r=0.20; P=0.021). We, therefore, conclude that aortic stiffening is independently associated with rate of change in renal function in patients with chronic kidney disease stages 3 and 4.

Serum Calcification Propensity Predicts All-Cause Mortality in Predialysis CKD

Medial arterial calcification is accelerated in patients with CKD and strongly associated with increased arterial rigidity and cardiovascular mortality. Recently, a novel in vitro blood test that provides an overall measure of calcification propensity by monitoring the maturation time (T50) of calciprotein particles in serum was described. We used this test to measure serum T50 in a prospective cohort of 184 patients with stages 3 and 4 CKD, with a median of 5.3 years of follow-up. At baseline, the major determinants of serum calcification propensity included higher serum phosphate, ionized calcium, increased bone osteoclastic activity, and lower free fetuin-A, plasma pyrophosphate, and albumin concentrations, which accounted for 49% of the variation in this parameter. Increased serum calcification propensity at baseline independently associated with aortic pulse wave velocity in the complete cohort and progressive aortic stiffening over 30 months in a subgroup of 93 patients. After adjustment for demographic, renal, cardiovascular, and biochemical covariates, including serum phosphate, risk of death among patients in the lowest T50 tertile was more than two times the risk among patients in the highest T50 tertile (adjusted hazard ratio, 2.2; 95% confidence interval, 1.1 to 5.4; P=0.04). This effect was lost, however, after additional adjustment for aortic stiffness, suggesting a shared causal pathway. Longitudinally, serum calcification propensity measurements remained temporally stable (intraclass correlation=0.81). These results suggest that serum T50 may be helpful as a biomarker in designing methods to improve defenses against vascular calcification.

Methods for assessing arterial stiffness: technical considerations

Purpose of reviewThe metabolic and haemodynamic changes associated with chronic kidney disease result in accelerated arterial stiffening which in part explains the high cardiovascular risk associated with this condition. Measurement of arterial stiffness is a useful tool for studying cardiovascular pathophysiology and effects of therapies. Performed well, these techniques are an accurate and efficient way of collecting clinical data, requiring little training and with high repeatability. However, generation of high-quality evidence in this field has been hampered by the use of different techniques, methodological differences, limited comparability between devices and small sample sizes. This review aims to summarize the recent recommendations regarding the best techniques and technicalities of measurement. Recent findingsAortic pulse wave velocity (PWV) has been recommended as the gold-standard measure of arterial stiffness and new commercially available devices make its measurement more straightforward. To minimize the effect of confounding factors, particularly blood pressure, aortic PWV needs to be measured carefully according to the current recommendations which are outlined in this review. SummaryThese recent recommendations about the measurement of arterial stiffness and ways of comparing values from different devices should lead to rapid growth of epidemiological data and facilitate its use as a clinical tool.

FGF-23 and osteoprotegerin are independently associated with myocardial damage in chronic kidney disease stages 3 and 4. Another link between chronic kidney disease–mineral bone disorder and the heart

BACKGROUND Extra-skeletal calcification and disordered phosphate metabolism are hallmarks of chronic kidney disease-mineral bone disorder (CKD-MBD). Osteoprotegerin (OPG) and fibroblast growth factor 23 (FGF-23) are increased in chronic kidney disease (CKD) and have been associated with arterial and cardiac dysfunction and reduced survival. Troponin T (cTnT) is released from cardiac myocytes under conditions of stress and is predictive of mortality across a range of renal functions. However, the utility of this biomarker was formerly limited by the lower limit of assay detection. The introduction of a high-sensitivity assay has enabled more detailed study of myocyte stress below the previous limit of detection. We studied the association of mediators of CKD-MBD with arterial stiffness and also of these mediators and arterial stiffness with myocardial damage in patients with CKD stages 3-4. METHODS OPG and FGF-23 were measured in 200 CKD stages 3-4 patients. cTnT was measured using a high-sensitivity assay. Aortic stiffness was assessed using aortic pulse wave velocity (APWV). RESULTS Mean age was 69 ± 11 years, mean systolic and diastolic blood pressure was 151 ± 22/81 ± 11 mmHg and renal function was 33 ± 11 mL/min/1.73 m(2). OPG, FGF-23, high-sensitivity troponin T (hs-cTnT) and APWV all correlated with renal function. After multivariate analysis, OPG and age remained independently associated with aortic stiffness. OPG and FGF-23 were independently associated with hs-cTnT in addition to other non-traditional risk factors (Model R(2) = 0.596). CONCLUSION We have shown that changes in bone mediators and phosphate metabolism induced by CKD are independently associated with vascular and cardiomyocyte dysfunction. Our findings suggest that cardiac dysfunction may be specifically associated with such abnormalities in addition to recognized increases in vascular stiffness.

Elastin Degradation Is Associated With Progressive Aortic Stiffening and All-Cause Mortality in Predialysis Chronic Kidney Disease

In the large conduit arteries, elastin is important in maintaining vascular compliance. Studies in animal models suggest that elastin degradation may promote arteriosclerotic vascular changes. There is already a well-established link between aortic stiffening and mortality in the general population and in patients undergoing dialysis. Elastin degradation is mediated by several proteases, including matrix metalloproteinase 2 and cathepsin S. Elastin turnover may be inferred by measuring serum levels of elastin-derived peptides. We analyzed the serum concentration of these biomarkers, their endogenous inhibitors, and aortic pulse wave velocity in 200 patients with stages 3 and 4 chronic kidney disease and then serially in a subgroup of 65 patients over 36 months. Serum matrix metalloproteinase 2, cathepsin S, and elastin-derived peptide levels were independently associated with baseline aortic pulse wave velocity and changes in stiffness over the follow-up period. Higher matrix metalloproteinase 2 and elastin-derived peptide levels were also independently associated with preexisting cardiovascular disease. In multivariable Cox regression, higher serum elastin-derived peptide levels were independently associated with increased all-cause mortality (hazard ratio per SD increase=1.78; P=0.021). In predialysis chronic kidney disease, elastin degradation is an important determinant of arterial stiffness and is associated with all-cause mortality.

Urinary neutrophil gelatinase-associated lipocalin may aid prediction of renal decline in patients with non-proteinuric Stages 3 and 4 chronic kidney disease (CKD)

BACKGROUND Chronic kidney disease (CKD) is an increasing public health issue. It is therefore potentially highly advantageous to identify patients at risk of accelerated renal progression and death. Neutrophil gelatinase-associated lipocalin (NGAL) is an established urinary biomarker for acute kidney injury, but it is not known whether adding urinary NGAL (uNGAL) measurements to conventional risk factors will improve risk assessment in the setting of chronic disease. METHODS This is a prospective observational cohort study of 158 patients with Stage 3 or 4 CKD. The ability of baseline uNGAL to improve prediction of outcome was assessed by multivariate modelling and a number of metrics including net reclassification analysis. A primary composite endpoint of all-cause mortality or progression to end-stage renal disease (ESRD) requiring renal replacement therapy (RRT) at 2 years and a secondary endpoint of ≥5 mL/min/1.73 m(2) decline in the estimated glomerular filtration rate (eGFR) after 1 year were considered. RESULTS Forty patients (25%) reached the primary composite endpoint, 20 of whom died. Twenty-seven patients (19%) reached the secondary endpoint of a ≥5 mL/min/1.73 m(2) decline in the eGFR. The baseline uNGAL-to-creatinine ratio (uNCR) was associated with the combined endpoint of death or initiation of RRT (HR per 5 µg/mmol increase 1.27, 95% CI: 1.01-1.60, P = 0.036) independent of conventional cardiovascular and renal risk factors, including proteinuria. In separate analysis of these two competing endpoints, however, uNCR only remained associated with increased risk of progression to ESRD requiring RRT. Higher baseline uNCR was also independently predictive of rapid renal decline over 1 year (HR per 5 µg/mmol increase 1.47, 95% CI: 1.06-2.06, P = 0.022). Addition of uNCR to the base model resulted in a significant increase in discrimination for the secondary (C-statistic 0.76-0.85, P = 0.001) but not the primary endpoint (P = 0.276). Reclassification analysis on the other hand, demonstrated an improvement in risk predication of both primary and secondary endpoints by incorporating uNCR into the base model, but only in those with low-level urine protein excretion (<28 mg/mmol), with category-free net reclassification improvement (NRI) scores of 64% (95% CI: 8-70; P = 0.019) and 79% (95% CI: 12-83; P = 0.009), respectively. CONCLUSION The utilization of uNCR in addition to conventional established cardiovascular and renal risk factors may improve the prediction of disease progression in elderly Caucasian pre-dialysis CKD patients with low-grade proteinuria.

ACE inhibitor and angiotensin receptor-II antagonist prescribing and hospital admissions with acute kidney injury: a longitudinal ecological study.

Background ACE Inhibitors (ACE-I) and Angiotensin-Receptor Antagonists (ARAs) are commonly prescribed but can cause acute kidney injury (AKI) during intercurrent illness. Rates of hospitalization with AKI are increasing. We aimed to determine whether hospital AKI admission rates are associated with increased ACE-I/ARA prescribing. Methods and Findings English NHS prescribing data for ACE-I/ARA prescriptions were matched at the level of the general practice to numbers of hospital admissions with a primary diagnosis of AKI. Numbers of prescriptions were weighted for the demographic characteristics of general practices by expressing prescribing as rates where the denominator is Age, Sex, and Temporary Resident Originated Prescribing Units (ASTRO-PUs). We performed a mixed-effect Poisson regression to model the number of admissions for AKI occurring in each practice for each of 4 years from 1/4/2007. From 2007/8-2010/11, crude AKI admission rates increased from 0.38 to 0.57 per 1000 patients (51.6% increase), and national annual ACE-I/ARA prescribing rates increased by 0.032 from 0.202 to 0.234 (15.8% increase). There was strong evidence (p<0.001) that increases in practice-level prescribing of ACE-I/ARA over the study period were associated with an increase in AKI admission rates. The increase in prescribing seen in a typical practice corresponded to an increase in admissions of approximately 5.1% (rate ratio = 1.051 for a 0.03 per ASTRO-PU increase in annual prescribing rate, 95%CI 1.047-1.055). Using the regression model we predict that 1,636 (95%CI 1,540-1,780) AKI admissions would have been avoided if prescribing rates were at the 2007/8 level, equivalent to 14.8% of the total increase in AKI admissions. Conclusion In this ecological analysis, up to 15% of the increase in AKI admissions in England over a 4-year time period is potentially attributable to increased prescribing of ACE-I and ARAs. However, these findings are limited by the lack of patient level data such as indication for prescribing and patient characteristics.

Instability of fibroblast growth factor-23 (FGF-23): implications for clinical studies.

BACKGROUND Fibroblast growth factor-23 (FGF-23) is a bone secreted hormone that regulates phosphate homeostasis and calcitriol levels. FGF-23 concentrations are elevated in chronic kidney disease (CKD), oncogenic osteomalcia and a number of rare hereditary disorders. Studies systematically evaluating the pre-analytical stability of intact FGF-23 are lacking. METHODS The stability of FGF-23 was assessed in timed experiments using blood taken into K2-EDTA plasma specimen tubes from a group of healthy participants and from a group with mild-to-moderate CKD. We evaluated the use of aprotinin, a serine protease inhibitor, and a commercially available protease inhibitor cocktail to preserve intact FGF-23 after blood collection. FGF-23 measurements were made using both intact and C-terminal assays. RESULTS Both whole blood and separated sample studies demonstrated a rapid loss of intact FGF-23 within 2 h, while concentrations increased using the C-terminal assay. The addition of protease inhibitor cocktail stabilised FGF-23 concentrations for 4 h after blood collection. Intact and C-terminal assay FGF-23 measurements showed poor correlation in both healthy and CKD cohorts. CONCLUSION K2-EDTA plasma samples, even when promptly separated, are unsuitable for measurement of FGF-23 unless stabilised with a protease inhibitor cocktail.

Fetuin-A is an independent determinant of change of aortic stiffness over 1 year in non-diabetic patients with CKD stages 3 and 4

BACKGROUND Vascular calcification is highly prevalent in chronic kidney disease (CKD) patients. This calcification leads to arterial stiffening. Fetuin-A is an endogenous inhibitor of vascular calcification and has been associated with arterial stiffness and mortality in dialysis patients. We tested the relationship between fetuin-A and change in arterial stiffness in CKD stages 3 and 4. METHODS We measured fetuin-A concentrations in 92 patients with CKD stages 3 and 4 and studied the association with clinical, biochemical and vascular parameters including arterial stiffness measured by carotid-femoral pulse wave velocity (PWV) at 0 and 12 months. RESULTS Fetuin-A was significantly lower in the non-diabetic group (n = 73) compared to the diabetic group (n = 19, P = 0.018). There was a significant interaction between diabetic status and fetuin-A concentration. Univariate analysis of the non-diabetic group showed association between change in aortic stiffness over 1 year with fetuin-A (r = -0.481, P < 0.0001) and systolic blood pressure (r = 0.389, P = 0.001) and baseline PWV (r = 0.240, P = 0.041). In multivariate analysis, fetuin-A, systolic blood pressure and baseline PWV independently predicted change in carotid-femoral PWV at 1 year (beta = -0.355, P = or< 0.001; beta = 0.426, P < 0.001; and beta = -0.383, P < 0.001, respectively; model R(2) = 0.455). CONCLUSIONS In patients with non-diabetic CKD stages 3 and 4, fetuin-A is an independent risk factor for progressive arterial stiffness.

Acute kidney injury—how does automated detection perform?

Background Early detection of acute kidney injury (AKI) is important for safe clinical practice. NHS England is implementing a nationwide automated AKI detection system based on changes in blood creatinine. Little has been reported on the similarities and differences of AKI patients detected by this algorithm and other definitions of AKI in the literature. Methods We assessed the NHS England AKI algorithm and other definitions using routine biochemistry in our own health authority in Scotland in 2003 (adult population 438 332). Linked hospital episode codes (ICD-10) were used to identify patients where AKI was a major clinical diagnosis. We compared how well the algorithm detected this subset of AKI patients in comparison to other definitions of AKI. We also evaluated the potential ‘alert burden’ from using the NHS England algorithm in comparison to other AKI definitions. Results Of 127 851 patients with at least one blood test in 2003, the NHS England AKI algorithm identified 5565 patients. The combined NHS England algorithm criteria detected 91.2% (87.6–94.0) of patients who had an ICD-10 AKI code and this was better than any individual AKI definition. Some of those not captured could be identified by algorithm modifications to identify AKI in retrospect after recovery, but this would not be practical in real-time. Any modifications also increased the number of alerted patients (2-fold in the most sensitive model). Conclusions The NHS England AKI algorithm performs well as a diagnostic adjunct in clinical practice. In those without baseline data, AKI may only be seen in biochemistry in retrospect, therefore proactive clinical care remains essential. An alternative algorithm could increase the diagnostic sensitivity, but this would also produce a much greater burden of patient alerts.