GFR Estimation: From Physiology to Public Health Levey, Andrew S., MD; Inker, Lesley A., MD, MS; Coresh, Josef, MD, MS, PhD
American journal of kidney diseases,
05/2014, Letnik:
63, Številka:
5
Journal Article
Recenzirano
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Estimating glomerular filtration rate (GFR) is essential for clinical practice, research, and public health. Appropriate interpretation of estimated GFR (eGFR) requires understanding the principles ...of physiology, laboratory medicine, epidemiology, and biostatistics used in the development and validation of GFR estimating equations. Equations developed in diverse populations are less biased at higher GFRs than equations developed in chronic kidney disease (CKD) populations and are more appropriate for general use. Equations that include multiple endogenous filtration markers are more precise than equations including a single filtration marker. The CKD-EPI (CKD Epidemiology Collaboration) equations are the most accurate GFR estimating equations that have been evaluated in large diverse populations and are applicable for general clinical use. The 2009 CKD-EPI creatinine equation is more accurate in estimating GFR and prognosis than the 2006 MDRD (Modification of Diet in Renal Disease) Study equation and provides lower estimates of prevalence of decreased eGFR. It is useful as a “first test” for decreased eGFR and should replace the MDRD Study equation for routine reporting of serum creatinine–based eGFR by clinical laboratories. The 2012 CKD-EPI cystatin C equation is as accurate as the 2009 CKD-EPI creatinine equation in estimating GFR, does not require specification of race, and may be more accurate in patients with decreased muscle mass. The 2012 CKD-EPI creatinine–cystatin C equation is more accurate than the 2009 CKD-EPI creatinine and 2012 CKD-EPI cystatin C equations and is useful as a confirmatory test for decreased eGFR as determined by serum creatinine-based eGFR. Further improvement in GFR estimating equations will require development in more broadly representative populations, including diverse racial and ethnic groups, use of multiple filtration markers, and evaluation using statistical techniques to compare eGFR to “true GFR.”
The US Food and Drug Administration currently accepts halving of glomerular filtration rate (GFR), assessed as doubling of serum creatinine level, as a surrogate end point for the development of ...kidney failure in clinical trials of kidney disease progression. A doubling of serum creatinine level generally is a late event in chronic kidney disease (CKD); thus, there is great interest in considering alternative end points for clinical trials to shorten their duration, reduce sample size, and extend their conduct to patients with earlier stages of CKD. However, the relationship between lesser declines in GFR and the subsequent development of kidney failure has not been well characterized. The National Kidney Foundation and Food and Drug Administration sponsored a scientific workshop to critically examine available data to determine whether alternative GFR-based end points have sufficiently strong relationships with important clinical outcomes of CKD to be used in clinical trials. Based on a series of meta-analyses of cohorts and clinical trials and simulations of trial designs and analytic methods, the workshop concluded that a confirmed decline in estimated GFR of 30% over 2 to 3 years may be an acceptable surrogate end point in some circumstances, but the pattern of treatment effects on GFR must be examined, specifically acute effects on estimated GFR. An estimated GFR decline of 40% may be more broadly acceptable than a 30% decline across a wider range of baseline GFRs and patterns of treatment effects on GFR. However, there are other circumstances in which these end points could lead to a reduction in statistical power or erroneous conclusions regarding benefits or harms of interventions. We encourage careful consideration of these alternative end points in the design of future clinical trials.
Clinical assessment of kidney function is central to the practice of medicine. GFR is widely accepted as the best index of kidney function in health and disease, and accurate values are required for ...optimal decision making. Estimated GFR based on serum creatinine is now widely reported by clinical laboratories, and in most circumstances, estimated GFR is sufficient for clinical decision making. GFR estimates may be inaccurate in the non-steady state and in people in whom non-GFR determinants differ greatly from those in whom the estimating equation was developed. If GFR estimates are likely inaccurate or if decisions based on inaccurate estimates may have adverse consequences, a measured GFR is an important confirmatory test. Endogenous creatinine clearance is the most common method used to measure GFR in clinical practice but may be difficult to obtain or fraught with error. We review methods for GFR measurement using urinary and plasma clearance of exogenous filtration markers and focus on urinary clearance of iothalamate and plasma clearance of iohexol compared with inulin clearance. We suggest plasma clearance of nonradioactive markers be more widely implemented in clinical settings. Further research is necessary on the impact of the use of measured GFR as a confirmatory test.
Background
Chronic pain is defined as pain lasting beyond normal tissue healing time, generally taken to be 12 weeks. It contributes to disability, anxiety, depression, sleep disturbances, poor ...quality of life, and healthcare costs. Chronic pain has a weighted mean prevalence in adults of 20%.
For many years, the treatment choice for chronic pain included recommendations for rest and inactivity. However, exercise may have specific benefits in reducing the severity of chronic pain, as well as more general benefits associated with improved overall physical and mental health, and physical functioning.
Physical activity and exercise programmes are increasingly being promoted and offered in various healthcare systems, and for a variety of chronic pain conditions. It is therefore important at this stage to establish the efficacy and safety of these programmes, and furthermore to address the critical factors that determine their success or failure.
Objectives
To provide an overview of Cochrane Reviews of adults with chronic pain to determine (1) the effectiveness of different physical activity and exercise interventions in reducing pain severity and its impact on function, quality of life, and healthcare use; and (2) the evidence for any adverse effects or harm associated with physical activity and exercise interventions.
Methods
We searched theCochrane Database of Systematic Reviews (CDSR) on the Cochrane Library (CDSR 2016, Issue 1) for systematic reviews of randomised controlled trials (RCTs), after which we tracked any included reviews for updates, and tracked protocols in case of full review publication until an arbitrary cut‐off date of 21 March 2016 (CDSR 2016, Issue 3). We assessed the methodological quality of the reviews using the AMSTAR tool, and also planned to analyse data for each painful condition based on quality of the evidence.
We extracted data for (1) self‐reported pain severity, (2) physical function (objectively or subjectively measured), (3) psychological function, (4) quality of life, (5) adherence to the prescribed intervention, (6) healthcare use/attendance, (7) adverse events, and (8) death.
Due to the limited data available, we were unable to directly compare and analyse interventions, and have instead reported the evidence qualitatively.
Main results
We included 21 reviews with 381 included studies and 37,143 participants. Of these, 264 studies (19,642 participants) examined exercise versus no exercise/minimal intervention in adults with chronic pain and were used in the qualitative analysis.
Pain conditions included rheumatoid arthritis, osteoarthritis, fibromyalgia, low back pain, intermittent claudication, dysmenorrhoea, mechanical neck disorder, spinal cord injury, postpolio syndrome, and patellofemoral pain. None of the reviews assessed 'chronic pain' or 'chronic widespread pain' as a general term or specific condition. Interventions included aerobic, strength, flexibility, range of motion, and core or balance training programmes, as well as yoga, Pilates, and tai chi.
Reviews were well performed and reported (based on AMSTAR), and included studies had acceptable risk of bias (with inadequate reporting of attrition and reporting biases). However the quality of evidence was low due to participant numbers (most included studies had fewer than 50 participants in total), length of intervention and follow‐up (rarely assessed beyond three to six months). We pooled the results from relevant reviews where appropriate, though results should be interpreted with caution due to the low quality evidence.
Pain severity: several reviews noted favourable results from exercise: only three reviews that reported pain severity found no statistically significant changes in usual or mean pain from any intervention. However, results were inconsistent across interventions and follow‐up, as exercise did not consistently bring about a change (positive or negative) in self‐reported pain scores at any single point.
Physical function: was the most commonly reported outcome measure. Physical function was significantly improved as a result of the intervention in 14 reviews, though even these statistically significant results had only small‐to‐moderate effect sizes (only one review reported large effect sizes).
Psychological function and quality of life: had variable results: results were either favourable to exercise (generally small and moderate effect size, with two reviews reporting significant, large effect sizes for quality of life), or showed no difference between groups. There were no negative effects.
Adherence to the prescribed intervention: could not be assessed in any review. However, risk of withdrawal/dropout was slightly higher in the exercising group (82.8/1000 participants versus 81/1000 participants), though the group difference was non‐significant.
Healthcare use/attendance: was not reported in any review.
Adverse events, potential harm, and death: only 25% of included studies (across 18 reviews) actively reported adverse events. Based on the available evidence, most adverse events were increased soreness or muscle pain, which reportedly subsided after a few weeks of the intervention. Only one review reported death separately to other adverse events: the intervention was protective against death (based on the available evidence), though did not reach statistical significance.
Authors' conclusions
The quality of the evidence examining physical activity and exercise for chronic pain is low. This is largely due to small sample sizes and potentially underpowered studies. A number of studies had adequately long interventions, but planned follow‐up was limited to less than one year in all but six reviews.
There were some favourable effects in reduction in pain severity and improved physical function, though these were mostly of small‐to‐moderate effect, and were not consistent across the reviews. There were variable effects for psychological function and quality of life.
The available evidence suggests physical activity and exercise is an intervention with few adverse events that may improve pain severity and physical function, and consequent quality of life. However, further research is required and should focus on increasing participant numbers, including participants with a broader spectrum of pain severity, and lengthening both the intervention itself, and the follow‐up period.
Surrogate end points are needed to assess whether treatments are effective in the early stages of CKD. GFR decline leads to kidney failure, but regulators have not approved using differences in the ...change in GFR from the beginning to the end of a randomized, controlled trial as an end point in CKD because it is not clear whether small changes in the GFR slope will translate to clinical benefits.
To assess the use of GFR slope as a surrogate end point for CKD progression, we performed a meta-analysis of 47 RCTs that tested 12 interventions in 60,620 subjects. We estimated treatment effects on GFR slope (mean difference in GFR slope between the randomized groups), for the total slope starting at baseline, chronic slope starting at 3 months after randomization, and on the clinical end point (doubling of serum creatinine, GFR<15 ml/min per 1.73 m
, or ESKD) for each study. We used Bayesian mixed-effects analyses to describe the association of treatment effects on GFR slope with the clinical end point and to test how well the GFR slope predicts a treatment's effect on the clinical end point.
Across all studies, the treatment effect on 3-year total GFR slope (median
=0.97; 95% Bayesian credible interval BCI, 0.78 to 1.00) and on the chronic slope (
0.96; 95% BCI, 0.63 to 1.00) accurately predicted treatment effects on the clinical end point. With a sufficient sample size, a treatment effect of 0.75 ml/min per 1.73 m
/yr or greater on total slope over 3 years or chronic slope predicts a clinical benefit on CKD progress with at least 96% probability.
With large enough sample sizes, GFR slope may be a viable surrogate for clinical end points in CKD RCTs.
GFR as the “Gold Standard”: Estimated, Measured, and True Levey, Andrew S., MD; Inker, Lesley A., MD, MS
American journal of kidney diseases,
2016, January 2016, 2016-Jan, 2016-01-00, 20160101, Letnik:
67, Številka:
1
Journal Article
Kidney Disease, Race, and GFR Estimation Levey, Andrew S; Titan, Silvia M; Powe, Neil R ...
Clinical journal of the American Society of Nephrology,
08/2020, Letnik:
15, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Assessment of GFR is central to clinical practice, research, and public health. Current Kidney Disease Improving Global Outcomes guidelines recommend measurement of serum creatinine to estimate GFR ...as the initial step in GFR evaluation. Serum creatinine is influenced by creatinine metabolism as well as GFR; hence, all equations to estimate GFR from serum creatinine include surrogates for muscle mass, such as age, sex, race, height, or weight. The guideline-recommended equation in adults (the 2009 Chronic Kidney Disease Epidemiology Collaboration creatinine equation) includes a term for race (specified as black versus nonblack), which improves the accuracy of GFR estimation by accounting for differences in non-GFR determinants of serum creatinine by race in the study populations used to develop the equation. In that study, blacks had a 16% higher average measured GFR compared with nonblacks with the same age, sex, and serum creatinine. The reasons for this difference are only partly understood, and the use of race in GFR estimation has limitations. Some have proposed eliminating the race coefficient, but this would induce a systematic underestimation of measured GFR in blacks, with potential unintended consequences at the individual and population levels. We propose a more cautious approach that maintains and improves accuracy of GFR estimates and avoids disadvantaging any racial group. We suggest full disclosure of use of race in GFR estimation, accommodation of those who decline to identify their race, and shared decision making between health care providers and patients. We also suggest mindful use of cystatin C as a confirmatory test as well as clearance measurements. It would be preferable to avoid specification of race in GFR estimation if there was a superior, evidence-based substitute. The goal of future research should be to develop more accurate methods for GFR estimation that do not require use of race or other demographic characteristics.
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