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Back in the early 2000’s we had a regional collaborative on CKD (chronic kidney disease) in Western New York that involved all the hospitals, payers, nephrologists and primary care physicians. Our goal was to increase the early referral of patients with advanced CKD to nephrologists. That goal was based on data that showed those patients referred to nephrologists more than a year prior to dialysis had reduced mortality in the first year of dialysis. Patients referred late often had their first dialysis done under emergent conditions and tended not to fare as well as those who had plans for dialysis in advance of the actual need for dialysis. Potential benefits of earlier referral would include not only reduced mortality but also reduced hospital stays, fewer catheter-related complications, and lower costs.
We were very pleased that a major offshoot of our collaborative was adoption of reporting the eGFR by the major national commercial labs in addition to our local hospital labs.
At the time, we recognized that there were far too few nephrologists both locally and nationally to handle all the potential patients that would be identified as having late stage CKD. So, a big part of our collaborative was to provide primary care physicians with the tools to manage early CKD better. In addition to early referral of those patients with later stage CKD, a major focus was on factors that could reduce progression of early CKD to later stages.
But doing the logical thing does not always result in the desired outcome and it can sometimes have unintended consequences. In our February 2009 What's New in the Patient Safety World column “Unintended Consequences of eGFR Reporting” we discussed a study (den Hartog 2009) raising concerns about automatic eGFR reporting. That study confirmed the positive outcomes of using eGFR (identifying CKD earlier, preventing some deaths and progression to ESRD. However, it also notes the potential impact of false negative test results (identifying some incorrectly as having CKD). Those patients often undergo further testing that may not have been necessary.
A couple recent studies have also suggested we are probably overdiagnosing CKD. Duggal et al. (Duggal 2021) did a retrospective analysis of almost 400,000 veterans with CKD and looked at laboratory referral criteria based on VA/Department of Defense guidelines, predicted risk for kidney failure using the Kidney Failure Risk Equation (which incorporates age, eGFR, gender, and urine albumin-to-creatinine ratio), and the combination of laboratory referral criteria and predicted risk.
Slightly more than 66,000 patients met laboratory indications for referral and 17.7% of these were referred to nephrology in the following year. But the median two-year predicted risk of kidney failure was 1.5% among all patients meeting laboratory referral criteria. If referral were restricted to patients with predicted risk ≥1% in addition to laboratory indications, the potential referral volume would be reduced from 66,276 to 38,229 patients. If referrals were based on predicted risk alone, a two-year risk threshold of 1% or higher would identify a similar number of patients (N=72,948) as laboratory-based criteria with median predicted risk of 2.3%.
Note that NICE (National Institute for Health and Care Excellence) recently updated its guideline for chronic kidney disease assessment and management (NICE 2021) and recommends referral of adults with CKD for specialist assessment if they have a five year risk of needing renal replacement therapy of >5% (measured with the Kidney Failure Risk Equation).
Liu et al. (Liu 2021) noted that using the same level of estimated glomerular filtration rate (eGFR) to define chronic kidney disease (CKD) regardless of patient age may classify many elderly people with a normal physiological age-related eGFR decline as having a disease. So, they constructed an age-adapted model, comparing a fixed eGFR threshold of 60 vs thresholds of 75, 60, and 45 mL/min/1.73 m2 for age younger than 40, 40 to 64, and 65 years or older, respectively.
With this age-adapted approach, the size of the affected population shrank by more than one-third (from127,132 to 81,209 cohort members) compared with the standard approach based on a fixed eGFR cut point of 60 mL/min/1.73m2. That reduction was largely driven by a reclassification of older adults with isolated mild to moderate reductions in eGFR. Of those individuals 65 years or older in the fixed-threshold cohort who had baseline eGFR of 45 to 59 mL/min/1.73 m2 with normal/mild albuminuria, the 5-year risks of kidney failure and death were similar to those of non-CKD controls. The authors conclude that the current criteria for CKD that use the same eGFR threshold for all ages may result in overestimation of the CKD burden in an aging population, overdiagnosis, and unnecessary interventions in many elderly people who have age-related loss of eGFR.
In an editorial accompanying the Liu study, O’Hare et al. (O'Hare 2021) note that guidelines for the management of CKD developed in 2002 and updated in 2012 did not differentiate risk based on patient age. They also noted that, though the entities producing those guidelines were not-for-profits, they did have significant sponsorship by industry. They note that the Liu article highlights an important truth: how diseases are defined can have major implications for who meets the case definition, what treatments are and are not recommended, and the size and characteristics of the population affected. They note that “labeling many adults with isolated mild to moderate reductions in eGFR with a diagnosis of CKD exposes them to the potential harms of unnecessary medical tests, procedures, and treatments and possible psychological distress while offering little or nothing in return.”
The updated NICE guideline also recommended discontinuing adjustment for ethnicity when calculating estimated glomerular filtration rate (eGFR) in people from black ethnic groups. The UK Kidney Association and partner organizations have supported that change on the grounds that it further exacerbates health inequalities by overestimating kidney function in these groups.
A joint task force of the National Kidney Foundation and American Society of Nephrology has also just recommended a new Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation, which excludes the race variable (Delgado 2021).
Two studies published in the New England Journal of Medicine in September analyzed multiple eGFR equations and concluded that the race variable should be excluded from equations estimating GFR. Inker et al. (Inker 2021) found that new eGFR equations that incorporate creatinine and cystatin C but omit race are more accurate and led to smaller differences between Black participants and non-Black participants than new equations without race with either creatinine or cystatin C alone. Hsu et al. (Hsu 2021) also analyzed various methods of estimating renal function using equations. They found that using serum cystatin C instead of serum creatinine would yield equivalent GFR estimation without the need to consider race or ancestry. They do note that challenges regarding the cost, calibration, and standardization of cystatin C measurements would have to be addressed, but they anticipate that cost reduction could occur with broad adoption over time.
The editorial accompanying those 2 studies (Williams 2021) points out that all equations that estimate GFR are imperfect but that meaningful ways to alleviate health care inequities are overdue and the new recommendations do so without compromising the utility of these estimates. Williams et al. noted that these promising options will take time to implement, since measurement of cystatin C is currently neither routine nor uniform.
The Duggal and Liu studies provide a stark reminder that our best intentions often result in actions that have unintended consequences. We are in much better position today to tailor the guidelines to focus on those individuals who are most likely to have progression of decline in renal function that is likely to become significant in their lifetime. Focusing on those patients should lead to more rational use of resources and avoid unnecessary testing and interventions in those not likely to have progression.
Some of our prior columns on dialysis, CKD, and ESRD:
March 26, 2007 “Alarms Should Point to the Problem”
February 2009 “Unintended Consequences of eGFR Reporting”
September 20, 2011 “When Practice Changes the Evidence: The CKD Story”
September 2013 “Is Nephrologist Caseload Related to Dialysis Mortality?”
September 2014 “New Tubing Connections”
June 23, 2015 “Again! Mistaking Antiseptic Solution for Radiographic Contrast”
November 1, 2016 “CMS Emergency Preparedness Rule”
April 25, 2017 “Dialysis and Alarm Fatigue”
July 16, 2019 “Avoiding PICC’s in CKD”
December 10, 2019 “Dialysis Line Dislodgements”
February 4, 2020 “Drugs and Chronic Kidney Disease”
den Hartog JR, Reese PP, Cizman B, Feldman HI. The costs and benefits of automatic estimated glomerular filtration rate reporting. Clinical Journal of the American Society of Nephrology (CJASN) 2009 4(2): 419-427 February 1, 2009
Duggal V, Montez-Rath ME, Thomas I-C, et al. Nephrology Referral Based on Laboratory Values, Kidney Failure Risk, or Both: A Study Using Veterans Affairs Health System Data. Am J Kidney Diseases 2021; Published online: August 24, 2021
The Kidney Failure Risk Equation (KFRE)
NICE (National Institute for Health and Care Excellence). Chronic kidney disease: assessment and management. NICE guideline [NG203] Published: 25 August 2021
Liu P, Quinn RR, Lam NN, et al. Accounting for Age in the Definition of Chronic Kidney Disease. JAMA Intern Med 2021; Published online August 30, 2021
O’Hare AM, Rodriguez RA, Rule AD. Overdiagnosis of Chronic Kidney Disease in Older Adults—An Inconvenient Truth. JAMA Intern Med 2021; Published online August 30, 2021
Delgado C, Baweja M, Crews DC, et al. A Unifying Approach for GFR Estimation: Recommendations of the NKF-ASN Task Force on Reassessing the Inclusion of Race in Diagnosing Kidney Disease. American Journal of Kidney Diseases 2021; Published online September 23, 2021
Inker LA, Eneanya ND, Coresh J, et al. New Creatinine- and Cystatin C–Based Equations to Estimate GFR without Race. NEJM 2021; September 23, 2021
Hsu C, Yang W, Parikh RV, at al. Race, Genetic Ancestry, and Estimating Kidney Function in CKD. NEJM 2021; September 23, 2021
Williams WW, Hogan JW, Ingelfinger JR. Time to Eliminate Health Care Disparities in the Estimation of Kidney Function. NEJM 2021; September 23, 2021
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