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Background: Estimation of glomerular filtration rate using equations based on creatinine is widely used to manage chronic kidney disease. In the UK, the Chronic Kidney Disease Epidemiology Collaboration creatinine equation is recommended. Other published equations using cystatin C, an alternative marker of kidney function, have not gained widespread clinical acceptance. Given higher cost of cystatin C, its clinical utility should be validated before widespread introduction into the NHS., Objectives: Primary objectives were to: (1) compare accuracy of glomerular filtration rate equations at baseline and longitudinally in people with stage 3 chronic kidney disease, and test whether accuracy is affected by ethnicity, diabetes, albuminuria and other characteristics; (2) establish the reference change value for significant glomerular filtration rate changes; (3) model disease progression; and (4) explore comparative cost-effectiveness of kidney disease monitoring strategies., Design: A longitudinal, prospective study was designed to: (1) assess accuracy of glomerular filtration rate equations at baseline ( n  = 1167) and their ability to detect change over 3 years ( n  = 875); (2) model disease progression predictors in 278 individuals who received additional measurements; (3) quantify glomerular filtration rate variability components ( n  = 20); and (4) develop a measurement model analysis to compare different monitoring strategy costs ( n  = 875)., Setting: Primary, secondary and tertiary care., Participants: Adults (≥ 18 years) with stage 3 chronic kidney disease., Interventions: Estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration and Modification of Diet in Renal Disease equations., Main Outcome Measures: Measured glomerular filtration rate was the reference against which estimating equations were compared with accuracy being expressed as P30 (percentage of values within 30% of reference) and progression (variously defined) studied as sensitivity/specificity. A regression model of disease progression was developed and differences for risk factors estimated. Biological variation components were measured and the reference change value calculated. Comparative costs of monitoring with different estimating equations modelled over 10 years were calculated., Results: Accuracy (P30) of all equations was ≥ 89.5%: the combined creatinine-cystatin equation (94.9%) was superior ( p  < 0.001) to other equations. Within each equation, no differences in P30 were seen across categories of age, gender, diabetes, albuminuria, body mass index, kidney function level and ethnicity. All equations showed poor (< 63%) sensitivity for detecting patients showing kidney function decline crossing clinically significant thresholds (e.g. a 25% decline in function). Consequently, the additional cost of monitoring kidney function annually using a cystatin C-based equation could not be justified (incremental cost per patient over 10 years = £43.32). Modelling data showed association between higher albuminuria and faster decline in measured and creatinine-estimated glomerular filtration rate. Reference change values for measured glomerular filtration rate (%, positive/negative) were 21.5/-17.7, with lower reference change values for estimated glomerular filtration rate., Limitations: Recruitment of people from South Asian and African-Caribbean backgrounds was below the study target., Future Work: Prospective studies of the value of cystatin C as a risk marker in chronic kidney disease should be undertaken., Conclusions: Inclusion of cystatin C in glomerular filtration rate-estimating equations marginally improved accuracy but not detection of disease progression. Our data do not support cystatin C use for monitoring of glomerular filtration rate in stage 3 chronic kidney disease., Trial Registration: This trial is registered as ISRCTN42955626., Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 11/103/01) and is published in full in Health Technology Assessment ; Vol. 28, No. 35. See the NIHR Funding and Awards website for further award information.

Assessment in African populations suggest adjustment for ethnicity in estimated glomerular filtration rate (eGFR) equations derived from African Americans lead to overestimation of GFR and failure to determine severity in chronic kidney disease (CKD). However, studies in African Europeans are limited. We aimed to assess accuracy of eGFR equations, with and without ethnicity adjustment compared with measured GFR in people of Black ethnicity in the United Kingdom. Performance of MDRD, CKD-EPI (with and without ethnicity adjustment), Full Age Spectrum (FAS), revised Lund Malmö (LM Revised), and European Kidney Function Consortium (EKFC) eGFR equations were assessed compared to 51Cr-EDTA GFR studies extracted from hospital databases. Participants with albumin <30g/l, liver disease, <18 years, of non-Black or non-White self-reported ethnicity were excluded. Agreement was assessed by bias, precision and 30%-accuracy and was stratified for ethnicity and GFR. 1888 51Cr-EDTA studies were included (Mean age-53.7yrs; 43.6% female; 14.1% Black ethnicity). Compared to White participants, eGFR-MDRD and eGFR-CKD-EPI equations in Black participants significantly overestimated GFR (bias 20.3 and 19.7 ml/min/1.73m2 respectively, p<0.001). Disregarding the ethnicity adjustment significantly improved GFR estimates for Black participants (bias 6.7 and 2.4ml/min/1.73m2 for eGFR-MDRD and eGFR-CKD-EPI respectively, p<0.001). The LM Revised equation had the smallest bias for both White and Black participants (5.8ml and -1.1ml/min/1.73m2 respectively). 30%-accuracy was superior for GFR≥60ml/min/1.73m2 compared to <60ml/min/1.73m2 using eGFR-CKD-EPI equation for both White and Black participants (p<0.001). Multivariate regression methodology with adjustment for age, sex and log(serum creatinine) in the cohort yielded an ethnicity coefficient of 1.018 (95% CI: 1.009-1.027). Overestimation of measured GFR with eGFR equations using ethnicity adjustment factors may lead to reduced CKD diagnosis and under-recognition of severity in people of Black ethnicity. Our findings suggest that ethnicity adjustment for GFR estimation in non-African Americans may not be appropriate for use in people of Black ethnicity in the UK., Competing Interests: The authors have declared that no competing interests exist.

Chronic Kidney Disease is a growing problem across the world and can lead to end-stage kidney disease and cardiovascular disease. Fibrosis is the underlying mechanism that leads to organ dysfunction, but as yet we have no therapeutics that can influence this process. Ras monomeric GTPases are master regulators that direct many of the cytokines known to drive fibrosis to downstream effector cascades. We have previously shown that K-Ras is a key isoform that drives fibrosis in the kidney. Here we demonstrate that K-Ras expression and activation are increased in rodent models of CKD. By knocking down expression of K-Ras using antisense oligonucleotides in a mouse model of chronic folic acid nephropathy we can reduce fibrosis by 50% and prevent the loss of renal function over 3 months. In addition, we have demonstrated in vitro and in vivo that reduction of K-Ras expression is associated with a reduction in Jag1 expression; we hypothesise this is the mechanism by which targeting K-Ras has therapeutic benefit. In conclusion, targeting K-Ras expression with antisense oligonucleotides in a mouse model of CKD prevents fibrosis and protects against renal dysfunction.

When assessing changes in glomerular filtration rate (GFR) it is important to differentiate pathological change from intrinsic biological and analytical variation. GFR is measured using complex reference methods (e.g., iohexol clearance). In clinical practice measurement of creatinine and cystatin C are used in the Modification of Diet in Renal Disease [MDRD] or Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equations to provide estimated GFR. Here we studied the biological variability of measured and estimated GFR in twenty nephrology outpatients (10 male, 10 female; median age 71, range 50-80 years) with moderate CKD (GFR 30-59 ml/min per 1.73 m 2 ). Patients underwent weekly GFR measurement by iohexol clearance over four consecutive weeks. Simultaneously, GFR was estimated using the MDRD, CKD-EPI creatinine , CKD-EPI cystatinC and CKD-EPI creatinine+cystatinC equations. Within-subject biological variation expressed as a percentage [95% confidence interval] for the MDRD (5.0% [4.3-6.1]), CKD-EPI creatinine (5.3% [4.5-6.4]), CKD-EPI cystatinC (5.3% [4.5-6.5]), and CKD-EPI creatinine+cystatinC (5.0% [4.3-6.2]) equations were broadly equivalent. The within-subject biological variation for MDRD and CKD- EPI creatinine+cystatinC estimated GFR were each significantly lower than that of the measured GFR (6.7% [5.6-8.2]). Reference change values, the point at which a true change in a biomarker in an individual can be inferred to have occurred with 95% probability were calculated. By the MDRD equation, positive and negative reference change values were 15.1% and 13.1% respectively. If an individual's baseline MDRD estimated GFR (ml/min per 1.73 m 2 ) was 59, significant increases or decreases would be to values over 68 or under 51 respectively. Within-subject variability of estimated GFR was lower than measured GFR. Reference change values can be used to understand GFR changes in clinical practice. Thus, estimates of GFR are at least as reliable as measured GFR for monitoring patients over time., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)

Background: Clinical practice guidelines support an early invasive approach after NSTE-ACS in patients with chronic kidney disease (CKD). There is no direct randomised controlled trial evidence in the CKD population, and whether the benefit of an early invasive approach is maintained across the spectrum of severity of CKD remains controversial., Methods: We conducted a systematic review to evaluate the association between an early invasive approach and all-cause mortality in patients with CKD. We searched MEDLINE and EMBASE (1990-May 2015) and article reference lists. Data describing study design, participants, invasive management strategies, renal function, all-cause mortality and risk of bias were extracted., Results: 3,861 potentially relevant studies were identified. Ten studies, representing data on 147,908 individuals with NSTE-ACS met the inclusion criteria. Qualitative heterogeneity in the definitions of early invasive approach, comparison groups and renal dysfunction existed. Meta-analysis of the RCT derived and observational data were generally supportive of an early invasive approach in CKD (RR0.76 (95% CI 0.49-1.17) and RR0.50 (95%CI 0.42-0.59) respectively). Meta-analysis of the observational studies demonstrated a large degree of heterogeneity (I2 79%) driven in part by study size and heterogeneity across various kidney function levels., Conclusions: The observational data support that an early invasive approach after NSTE-ACS confers a survival benefit in those with early-moderate CKD. Local opportunities for quality improvement should be sought. Those with severe CKD and the dialysis population are high risk and under-studied. Novel and inclusive approaches for CKD and dialysis patients in cardiovascular clinical trials are needed.

Background: The prevalence of chronic kidney disease (CKD) is high in general populations around the world. Targeted testing and screening for CKD are often conducted to help identify individuals that may benefit from treatment to ameliorate or prevent their disease progression., Aims: This systematic review examines the methods used in economic evaluations of testing and screening in CKD, with a particular focus on whether test accuracy has been considered, and how analysis has incorporated issues that may be important to the patient, such as the impact of testing on quality of life and the costs they incur., Methods: Articles that described model-based economic evaluations of patient testing interventions focused on CKD were identified through the searching of electronic databases and the hand searching of the bibliographies of the included studies., Results: The initial electronic searches identified 2,671 papers of which 21 were included in the final review. Eighteen studies focused on proteinuria, three evaluated glomerular filtration rate testing and one included both tests. The full impact of inaccurate test results was frequently not considered in economic evaluations in this setting as a societal perspective was rarely adopted. The impact of false positive tests on patients in terms of the costs incurred in re-attending for repeat testing, and the anxiety associated with a positive test was almost always overlooked. In one study where the impact of a false positive test on patient quality of life was examined in sensitivity analysis, it had a significant impact on the conclusions drawn from the model., Conclusion: Future economic evaluations of kidney function testing should examine testing and monitoring pathways from the perspective of patients, to ensure that issues that are important to patients, such as the possibility of inaccurate test results, are properly considered in the analysis.

Background: Uncertainty exists regarding the optimal method to estimate glomerular filtration rate (GFR) for disease detection and monitoring. Widely used GFR estimates have not been validated in British ethnic minority populations., Methods/design: Iohexol measured GFR will be the reference against which each estimating equation will be compared. The estimating equations will be based upon serum creatinine and/or cystatin C. The eGFR-C study has 5 components: 1) A prospective longitudinal cohort study of 1300 adults with stage 3 chronic kidney disease followed for 3 years with reference (measured) GFR and test (estimated GFR [eGFR] and urinary albumin-to-creatinine ratio) measurements at baseline and 3 years. Test measurements will also be undertaken every 6 months. The study population will include a representative sample of South-Asians and African-Caribbeans. People with diabetes and proteinuria (ACR ≥30 mg/mmol) will comprise 20-30% of the study cohort.2) A sub-study of patterns of disease progression of 375 people (125 each of Caucasian, Asian and African-Caribbean origin; in each case containing subjects at high and low risk of renal progression). Additional reference GFR measurements will be undertaken after 1 and 2 years to enable a model of disease progression and error to be built.3) A biological variability study to establish reference change values for reference and test measures.4) A modelling study of the performance of monitoring strategies on detecting progression, utilising estimates of accuracy, patterns of disease progression and estimates of measurement error from studies 1), 2) and 3).5) A comprehensive cost database for each diagnostic approach will be developed to enable cost-effectiveness modelling of the optimal strategy.The performance of the estimating equations will be evaluated by assessing bias, precision and accuracy. Data will be modelled as a linear function of time utilising all available (maximum 7) time points compared with the difference between baseline and final reference values. The percentage of participants demonstrating large error with the respective estimating equations will be compared. Predictive value of GFR estimates and albumin-to-creatinine ratio will be compared amongst subjects that do or do not show progressive kidney function decline., Discussion: The eGFR-C study will provide evidence to inform the optimal GFR estimate to be used in clinical practice., Trial Registration: ISRCTN42955626.

Background and Objectives: Recent studies evaluated the prevalence of hyperkalemia and related risk factors in patients with CKD of various stages, but there is limited relevant information in predialysis patients. This study aimed to examine the prevalence and factors associated with hyperkalemia in the structured environment of a low-clearance clinic., Design, Setting, Participants, & Measurements: In a cross-sectional fashion over a prespecified period of 4 months, information on serum potassium and relevant laboratory variables, comorbidities, medications, and dietician input in patients with advanced CKD under follow-up in the low-clearance clinic of our department was recorded. Univariate and multiple logistic regression analyses were used to identify factors associated with serum potassium ≥ 5.5 meq/L., Results: The study population consisted of 238 patients aged 66.2 ± 4.2 years with estimated GFR of 14.5 ± 4.8 ml/min per 1.73 m(2). The prevalence of hyperkalemia. defined as potassium > 5.0, ≥ 5.5, and ≥ 6.0 meq/L., was at 54.2%, 31.5%, and 8.4%, respectively. In univariate comparisons, patients with potassium ≥ 5.5 meq/L had significantly higher urea and lower estimated GFR and serum bicarbonate; also, they were more often using sodium bicarbonate and had received potassium education and attempts for dietary potassium lowering. Use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was not associated with hyperkalemia. In multivariate analyses, estimated GFR<15 ml/min per 1.73 m(2) and sodium bicarbonate use were independently associated with hyperkalemia., Conclusions: The prevalence of hyperkalemia in predialysis patients with CKD is high. Even at this range of renal function, low estimated GFR seems to be the most important factor associated with hyperkalemia among the wide range of demographic, clinical, and laboratory characteristics studied.

Background/aims: Data on the prevalence, treatment and control of hypertension in patients with advanced chronic kidney disease (CKD) are limited. This study aimed to examine the above factors in a cohort of predialysis patients., Methods: During a period of 4 months, we recorded information on blood pressure (BP), comorbidities, medications and related parameters of patients followed up in the Low-Clearance Clinic of our Department. Control rates of hypertension were calculated at two thresholds: <130/80 and <140/90 mm Hg. Univariate and multiple linear regression analyses were employed to assess factors associated with BP control., Results: In the population studied [n = 238, males 58.4%, age 66.21 ± 4.2 years (mean ± SD), estimated glomerular filtration rate 14.5 ± 4.8 ml/min/1.73 m(2)], the prevalence of hypertension was 95.0%. Treatment rate among hypertensives was at 99.1%. On average, 3.04 ± 1.32 antihypertensive drugs were used, ranging from 1 to 7 agents. BP control rates at the <130/80 and <140/90 mm Hg thresholds were 26.5% and 48.2%, respectively. The systolic goal was achieved in 31.0% and 50.4%, whereas the diastolic goal was achieved in 67.7% and 91.2% of patients, respectively. In multivariate analysis, only black race was independently and inversely related with hypertension control (β = -0.187, p = 0.030). No specific antihypertensive class showed independent associations with control., Conclusions: Hypertension is highly prevalent in predialysis CKD patients. An almost universal treatment, employing a multi-agent regime, can help towards improved rates of control. Systolic BP is the main barrier to successful control and black race is associated with poorer control rates., (Copyright © 2012 S. Karger AG, Basel.)