Kidney Failure Risk Equation Thresholds for Multidisciplinary Kidney Care Referrals: A Validation Study

Chronic kidney disease (CKD) is a highly prevalent and morbid condition. Disease progression is variable and predicting the risk of requiring kidney replacement therapy (KRT) becomes increasingly important in advanced CKD (eGFR10% as a criterion for referral of patients followed by general nephrologists to multidisciplinary CKD clinic. These clinics consist of nephrologists, nurses, dieticians, pharmacists, and social workers, who collaborate to delay and manage CKD progression, and provide education around transitioning to end-stage kidney disease. Patients and providers have reported KFRE-guided multidisciplinary CKD clinic referral improved care delivery (6Smekal M.D. Tam-Tham H. Finlay J. Donald M. Thomas C. Weaver R.G. et al.Patient and provider experience and perspectives of a risk-based approach to multidisciplinary chronic kidney disease care: A mixed methods study.BMC Nephrol. 2019; 20: 1-12Crossref Scopus (19) Google Scholar). Although the KFRE has been extensively externally validated, a recent systematic review identified that its clinical applications and impact on care have been understudied (7Bhachu H.K. Fenton A. Cockwell P. Aiyegbusi O. Kyte D. Calvert M. Use of the kidney failure risk equation to inform clinical care of patients with chronic kidney disease: A mixed-methods systematic review.BMJ Open. 2022; 12Crossref PubMed Scopus (5) Google Scholar). We explored using KFRE risk thresholds to guide clinical decision-making in advanced CKD. We conducted a retrospective cohort study using two independent multidisciplinary CKD clinic cohorts in Kingston, Ontario. The derivation cohort included prevalent patients followed in multidisciplinary clinic in 2013. The validation cohort included incident patients between 2018-2020, and all prevalent patients seen at least once in the clinic in 2018, excluding those from derivation cohort. Patients with prior kidney transplantation were excluded. Baseline KFRE-2 scores were calculated using the uACR and eGFR associated with the index clinic visit. The primary outcome was KRT initiation, defined as pre-emptive transplant or starting dialysis within 2-years of the index visit. Sensitivity, specificity, positive (PPV) and negative predictive values (NPV) were reported across the range of predicted risk probabilities to determine clinically useful thresholds. Item S1 and Table S1 include further details about methodology. There were 442 and 590 patients in the derivation and validation cohorts, respectively. The cohorts had similar baseline demographics (Table 1). Median KFRE-2 scores and uACRs were higher in the validation cohort, likely reflecting changes in provincial criteria for multidisciplinary CKD clinic eligibility (KFRE-2 >10%) implemented in 2018, resulting in fewer low-risk patients in the later validation cohort. At 2-years there were 90 (20%) KRT initiation events in the development cohort and 179 (30%) events in the validation cohort.Table 1Baseline Patient CharacteristicsDerivation n = 442ValidationN = 590Mean age (SD), years73 (12)69 (13)Female, N (%)196 (44)220 (37)Race, N (%) White427 (97)517 (88) Black2 (0.45)2 (0.34) Indigenous6 (1.4)38 (6.4) Asian4 (0.90)17 (2.9) Other3 (0.68)5 (0.85) Unknown0 (0)11 (1.9)Median urine albumin: creatinine (Q1, Q3), mg/mmol30 (5, 120)94 (19, 232) 30, N (%)220 (50)460 (78)Median eGFR CKD-EPI∗2009 CKD-EPI eGFR equation (Q1, Q3), ml/min/1.73 m220 (15, 25)19 (12, 24)CKD etiology Diabetic nephropathy, N (%)204 (46)274 (46) Hypertensive nephrosclerosis, N (%)120 (27)90 (15) Glomerulonephritis, N (%)18 (4)43 (7) Polycystic kidney disease, N (%)12 (3)16 (3) Other, N (%)88 (20)167 (28)Comorbidities Diabetes Mellitus N (%)248 (56)373 (63) Hypertension, N (%)N/A405 (69)Median KFRE-2 score (Q1, Q3)15 (5, 35)29 (19, 59)∗ 2009 CKD-EPI eGFR equation Open table in a new tab Although the 10% risk threshold (current eligibility standard) displays excellent sensitivity in the derivation cohort, with few patients who had predicted risk 10% (Table 2). The 30% threshold, however, remains fairly sensitive (76%), and is more specific (80%), with few false positives exceeding this threshold. NPV is also high, with 93% of patients who had lower predicted risk not initiating KRT within 2 years, and PPV is modest (48%), indicating that only approximately half of patients with risk above this threshold initiated KRT. Thus, a 30% KFRE-2 threshold may be more reasonable to guide multidisciplinary clinic referral. Patients below this threshold would still need careful management under general nephrology care to slow CKD progression, while those who progress could then be transferred to multidisciplinary clinic. This could enable more appropriate allocation of costly, finite resources required for multidisciplinary care to those with the greatest need, and spare low-risk patients undue anxiety.Table 2Performance characteristics of KFRE-2 ThresholdsDerivation Cohort10%20%30%40%50%60%70%80%90%Sensitivity90%78%76%62%52%39%26%16%5%Specificity48%66%80%88%92%95%97%99%100%PPV30%36%48%56%63%68%72%74%80%NPV95%93%93%90%89%86%84%83%81%AUC (95% CI)0.83 (0.78-0.88)Validation Cohort10%20%30%40%50%60%70%80%90%Sensitivity97%83%74%64%55%47%37%26%12%Specificity10%48%67%81%89%93%97%98%100%PPV32%41%49%59%68%75%83%87%91%NPV87%86%85%84%82%80%78%75%72%AUC (95% CI)0.78 (0.73-0.82) Open table in a new tab The 40-50% thresholds in the derivation cohort are highly specific (88-92%), indicating most patients who do not initiate KRT have predicted risk below these thresholds, but sensitivities are modest (52-62%), indicating many patients who initiate KRT have lower KFRE scores. NPVs are high, with most patients below these thresholds not initiating KRT (89%-90%), and the PPVs (56-63%) indicate more than half the patients with higher predicted risk initiate KRT. Thus, using KFRE-2 ≥40-50% to guide KRT education and planning could prevent unnecessary, expensive, and potentially invasive interventions. This is in keeping with the 2012 KDIGO recommendation of 10-20% 1-year predicted risk for KRT planning, the KDOQI recommendation of ≥50% 2-year risk for vascular access referrals, and the draft 2023 KDIGO CKD recommendation of >40% 2-year risk for education and KRT preparation (8Eknoyan G. Lameire N. Eckardt K.-U. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease.Kidney Int. 2013; 3Google Scholar, 9Lok C.E. Huber T.S. Lee T. Shenoy S. Yevzlin A.S. Abreo K. et al.KDOQI Clinical Practice Guideline for Vascular Access: 2019 Update.Am J Kidney Dis. 2020; 75 (Available from:): S1-164https://doi.org/10.1053/j.ajkd.2019.12.001Abstract Full Text Full Text PDF PubMed Scopus (959) Google Scholar, 10Eknoyan G, Lameire N, Winkelmayer WC, Jadoul M, Grams ME. Kdigo 2023 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease Public Review Draft. 2023;(July).Google Scholar). The 30% threshold in the validation cohort is similarly sensitive to the derivation cohort (74% vs. 76%) albeit somewhat less specific (67% vs. 80%). Likewise, characteristics are comparable at the 50% threshold with high specificities (89% vs. 92%). Based on the KFRE-2 performance characteristics in two independent advanced CKD cohorts, we propose using KFRE-2 ≥30% to guide referral to multidisciplinary clinic programs and KFRE-2 ≥50% to guide referrals for modality education, transplant, and access planning. These thresholds require further validation in diverse settings, including cohorts with less advanced CKD managed by general nephrology, as well as impact studies on patient outcomes and resource utilization. Research idea and study design: CAW, SJT; data acquisition: SJT, EAI; data analysis/ interpretation: PAN, AGD, CAW, SJT, AA, GLH; statistical analysis: PAN, AGD; supervision or mentorship: CAW, EAI. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. None. The authors declare that they have no relevant financial interests. Received September 1, 2023. Evaluated by 2 external peer reviewers, with direct editorial input from the Statistical Editor and the Editor-in-Chief. Accepted in revised form December 3, 2023. The authors acknowledge Andrew Goss and Frances MacLeod. Download .pdf (.05 MB) Help with pdf files