KFRE sharply predicts kidney failure risk with greater clinical nuance than eGFR, potentially triggering a paradigm shift in practice

Ibrahim Ali
Ibrahim Ali

With national guideline writers in the UK and other countries weighing up the role of the Kidney Failure Risk Equation (KFRE) from a renal referrer’s perspective, including in primary care, new research finds that both the four- and eight-variable KFRE prediction models demonstrate “adequate discrimination and calibration” in predicting end-stage renal disease (ESRD) in an advanced chronic kidney disease (CKD) population. Vitally, KFRE is more clinically useful than an estimated glomerular filtration rate- (eGFR-)based strategy, they write.

Ibrahim Ali (Salford Royal NHS Foundation Trust, Salford, UK ), first author of the paper, published in BMC Nephrology, tells Renal Interventions: “The KFRE is designed to predict the risk of ESRD in patients with CKD stages three to five at two and five years. We recognised that the KFRE is a well-validated tool and wanted to translate it into routine clinical practice but were also keen to address a gap in the literature by looking at the clinical utility of the KFRE, specifically against eGFR-based thresholds. Our research presents novel insight by showing the KFRE is better at risk prediction than our current standard practice of using eGFR thresholds to guide further management for patients. Certainly, eGFR cut-offs, such as referral to a predialysis clinic when a patient’s eGFR is less than 20ml/min/1.73m2, represent inflexible, non-personalised management strategies to patient care whereas the KFRE is an objective, accurate tool that can help deliver personalised care. Our work is significant and paves the way for a paradigm shift towards using the KFRE to prioritise resource allocation to target high-risk individuals who are likely to progress to ESRD.”

Four-variable works sufficiently well as the eight-variable equation

The KFRE, first published in 2011, remains the most validated risk prediction tool in nephrology. In 2016, it underwent multinational external validation in over 30 countries and in over 700,000 patients. The study by Ali et al set out to validate the four- and eight-variable KFREs in an advanced CKD population in the UK by evaluating discrimination, calibration and clinical utility. The researchers found that the four-variable KFRE was sufficiently good at risk prediction, in comparison to the eight-variable equation. “The four-variable equation relies on age, sex, eGFR and urine albumin to creatinine ratio. These are routine measures, making this a very accessible prediction tool, and reliance on the extra variables of the eight-variable equation, including calcium, phosphate, bicarbonate and albumin is not necessary,” contends Ali. An important consideration, he says, is that KFRE can be integrated into electronic patient records “so you have an up-to-date, automated risk tool immediately at hand using accessible measures, which removes the barrier of manually inputting data into an online calculator.”

KFRE offers a better strategy to guide patient care than eGFR thresholds

The study included patients enrolled in the Salford Kidney Study who were referred to the Advanced Kidney Care Service (AKCS) clinic at Salford Royal NHS Foundation Trust between 2011 and 2018. The four- and eight-variable KFREs were calculated on the first AKCS visit and the primary outcome was based on the observed events of ESRD (dialysis or pre-emptive transplantation) at two and five years.

The researchers evaluated the discrimination and calibration of the equation in the whole group of patients as well as in specific disease subgroups: diabetic nephropathy, hypertensive nephropathy, glomerulonephritis, autosomal dominant polycystic kidney disease (ADPKD) and other diseases. They further assessed the clinical utility of the equation by comparing the benefit of using the KFREs against eGFR cut-offs of <20ml/min/1.73m2 and <15ml/min/1.73m2 to guide further treatment.

The Salford research involved 743 patients in the two-year analysis and 613 patients in the five-year analysis. The researchers showed that discrimination was good in the whole cohort both for predicting ESRD at two- and five-years, and there was good-to-excellent discrimination across disease aetiologies.

Calibration plots also revealed underestimation of risk at two-years and overestimation of risk at five-years, especially in high-risk patients. There was, however, underestimation of risk in patients with ADPKD for all KFRE calculations.

“Prediction statistics such as discrimination and calibration are important measures that can assess a model’s performance but clinical utility, assessed with decision curve analyses, helps provide a meaningful message for clinicians, as it provides a graphical output that shows which tool or management strategy offers the best net benefit for patients,” Ali notes.

“Despite the degree of miscalibration at higher risk scores, when you look at the decision curve analyses with the threshold probability that we used, which was 40% risk of ESRD at two years, the KFRE still outperformed eGFR-based thresholds of less than 20ml/min/1.73m2 and less than 15ml/min/1.73m2. Importantly, we showed that this benefit was maintained across the risk probabilities of 20–40%, which is the range the literature suggests should be used to prioritise patients for dialysis planning and transplantation,” he adds.

KFRE predicts ESRD, not death

“This tool is very specific to one outcome: ESRD. This can have a slight disadvantage when managing  patients in an advanced predialysis clinic, who often face the dual threat of both ESRD and mortality. Clinicians therefore need to weigh up the competing risk of mortality because, in some patients, the risk of mortality supersedes the risk of ESRD. In these situations, the KFRE should not replace the clinician’s ability to use their judgement in making key decisions about patient care,” Ali warns.

He also counsels against its use in patients with ADPKD in whom the KFRE was found to significantly underestimate ESRD across all risk scores. “These patients typically show a rapid linear form of progression that is genetically determined and is not well captured by the parameters of the KFRE,” he explains.

Translating the KFRE into secondary care

According to Ali, the KFRE “as a simple basic tool” is fantastic. “Our primary aim is to improve pre-emptive transplantation rates for our patients who are advancing towards ESRD, as this offers the best long-term outcomes. For this, we need to have patients with the highest risk of progression to be identified earlier, counselled earlier and given preparation and education about the prospects of renal replacement therapy. The KFRE, I believe, will undoubtedly have a major impact by providing a personalised, quantifiable measure of an individual’s future risk. Secondly, what we also want to do is improve the rates of patients who initiate haemodialysis with definitive access via a fistula as opposed to a tunnelled dialysis line, which is associated with an increased risk of infection. What we found was that if patients have a 40% or more risk of ESRD at two years, the median time to reach ESRD was 11 months. Hopefully, that timeframe could provide us a better degree of certainty as to when these patients should be referred for fistula formation.”

Ali notes that transplant surgeons are going to be very important stakeholders once the KFRE becomes routinely implemented because it will impact access planning. “We have had discussions with the transplant surgeons at our centre about referring them the right patients at the right time. Referral for access planning has relied on eGFR thresholds, but for a long while the surgeons have raised concerns about patients coming to them either too late or too early. Sometimes a fistula is created but fails to function or has not matured in time, and patients continue to progress at a rate that results in them having to start dialysis with a tunnelled line. In contrast, some patients have a fistula created but do not progress and continue to have stable kidney function for many months thereafter. This is a perfect example of how non-personalised eGFR cut-offs fail to identify high-risk patients likely to progress and therefore fail to adequately prioritise resources in an effective way.” Thirdly, an important element to using the KFRE is education and engagement with patients, Ali explains. “I am not sure how well we routinely talk about risk stratification in an outpatient setting but having a validated, accessible risk score to hand could be used as a jumping point to engage, counsel, educate, and potentially modify behaviour for patients who are deemed to be high risk for ESRD.”

Quality improvement project

Ali says: “In nephrology, there are very few risk prediction tools, so when you have something that has shown to be well validated, it is exciting to see its implementation in clinical practice.”

The team at Salford has now set up a quality improvement project to use the KFRE in clinical practice, specifically in the advanced predialysis clinic. They are assessing the feasibility of using the tool in the AKCS clinic and how it can help inform decision-making. “If we collect some positive data, we will look to extend our net to using the KFRE in other renal clinics  in order to establish a cohort of ‘high-risk progressors’ who would then be fast-tracked into the AKCS clinic, with a view to then preparing and optimising their care towards renal replacement therapy in a timely manner.”




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