LCD L39726: KidneyIntelX and KidneyIntelX.dkd Testing

Indications of Coverage

Once in a lifetime KidneylntelX or KidneyIntelX.dkd test is considered reasonable and necessary when all the following criteria are met:

• The results are used to facilitate therapeutic prognostic decision-making in the medical management of a selected patient population, and

• The results are used to assess the risk of progressive decline in kidney function in patients over the age of 21 years of age with:

• Type 2 diabetes (T2D) and existing early-stage chronic kidney disease (CKD) (stages 1-3b), and

• The test is ordered by the treating physician or qualified non-physician practitioner, and

• The test is performed in a CLIA certified laboratory qualified to perform high complexity testing, and

• The specific reason for the test must be documented by the treating practitioner in the medical documentation and demonstrate that the test is medically reasonable and necessary.

Note: Kidney function decline is defined as:

• a decline in eGFR slope of ≥: 5 ml/min/l.73m 2 /year; or

• a sustained decrease in eGFR ≥40% confirmed at least 3 months apart; or

• kidney failure, defined by sustained eGFR

Limitations of Coverage

• KidneylntelX or KidneyIntelX.dkd test is not medically reasonable and necessary for:

• Patients with eGFR

• KidneylntelX or KidneyIntelX.dkd is not covered as a screening or standalone diagnostic.

Tokita et al- conducted a prospective data collection study which enrolled 1686 patients in a large metro health system over 16 months to assess the impact of the KidneyIntelX test result on clinical decision-making and outcomes. The median age was 68 years, 52% were female, 26% self-identified as Black, and 94% had hypertension. Determination of a new referral to a specialty consult service (i.e., nephrology, endocrinology, nutrition), any new prescriptions, or modification to any existing prescription medication for ACEi/ARB, SLGT2i, or GLP-1 agonists was based on a 6-month pre-baseline to 6-month post-test assessment. Limitations included patient compliance with filling prescriptions were not available. 53% of all KidneyIntelX high risk patients had a follow-up within a month while standard of care for follow-up is every 12 months. 1 The authors found that 53% of all KidneyIntelX high-risk patients had a follow-up visit within 1 month and 57% had action taken (medication change or referral) within 3 months compared to 13% and 35%, respectively, for low-risk individuals. Traditionally, the standard-of-care for follow-up visit frequency is every 12 months. Thus, these results reflect a needed change in management for high-risk patients regarding visit frequency and any action taken. When evaluating new or modified prescriptions for antihypertensive at 6-months, both ACEi and ARBs achieved a greater than 20% change in the high-risk group (ACEi, OR = 1.36; 95% CI: 0.77-2.30; ARBs, OR = 1.65; 95% CI: 1.01-2.63). Early evidence suggests that the introduction of the SGLT2i lowered HbA1c levels most notably in the high-risk category (median 8.2% HbA1c at 6 months pre KidneyIntelX vs 7.45% post-test. In conclusion, the authors found that patients with early-stage DKD who were identified as high-risk via the KidneyIntelX score received earlier follow-up visits, necessary change in medications or specialist referral compared to those who were identified as low- or intermediate-risk patients. Specifically, high-risk patients were more likely to be referred to a nephrologist and by 6 months, these patients had a significant increase in anti-hypertension medications compared to those of intermediate- and low-risk who were more likely to receive standard of care.

Nadkarni et al- The authors conducted a post hoc analysis, assessing the association of KidneyIntelX at baseline with the time-to-event composite end point of 57% decline in eGFR or adjudicated ESKD, HHF, or death. The authors studied 1278 participants in the CANagliflozin Cardiovascular Assessment Study (CANVAS) trial as they hypothesized that KidneyIntelX would also risk stratify patients with prevalent DKD for a clinically relevant kidney outcome, HHF, and all-cause mortality. KidneyIntelX was evaluated in the subgroup of the CANVAS population that met the criteria for prevalent DKD (eGFR ≥30–59.9 ml/min per 1.73 m2 [G3a and G3b] or those with an eGFR ≥60 ml/min per 1.73 m2 with a urine albumin-creatinine ratio [uACR] ≥30 mg/g) at the time of enrollment with existing bio banked blood samples. Measurements were obtained of soluble TNF receptors (sTNFR) 1 and 2, and kidney injury molecule-1 (KIM-1) via proprietary assays, and calculated KidneyIntelX scores using the existing validated algorithm. Among the 1278 CANVAS participants in this post hoc analysis, the mean age was 64 years, 32% were women, the mean baseline eGFR was 65 ml/min per 1.73 m2, the median uACR was 56 mg/g, 498 (40%) had an eGFR 2

Lam et al- The authors measured soluble tumor necrosis factor receptor (TNFR)-1, soluble TNFR-2, and kidney injury molecule 1 on banked samples from 1325 CANagliflozin cardioVascular Assessment Study (CANVAS) trial participants with baseline DKD (estimated glomerular filtration rate [eGFR] 30–59 mL/min/1.73 m2 or urine albumin-to-creatinine ratio [UACR] ≥30 mg/g) and generated KidneyIntelX risk scores at baseline and years 1, 3, and 6. The mean age of the full study population was 64 years, where 32% were female, the mean eGFR was 65 mL/min/1.73 m2, and the median UACR was 56 mg/g. Overall, stratified by the baseline KidneyIntelX score and adjusted for the treatment arm, each 10% reduction in KidneyIntelX risk was associated with a 20% lower risk of experiencing the composite kidney outcome (adjusted odds ratio per 10% reduction of 0.80 [95% CI: 0.77, 0.83]; p 3 The authors found the effects of the SGLT2i canagliflozin on the chronic eGFR slope were numerically greater in magnitude in participants who scored as high risk by KidneyIntelX at enrollment. Second, canagliflozin decreased KidneyIntelX risk scores over time compared to an increase in the placebo, and this improvement in prognosis was maintained over the follow-up period.

Chauhan et al- studied 1369 patients that were selected from a biobank at an institutional review board–approved biorepository that includes consented access to the patients’ EHR from NYC. The authors selected two cohorts from the biobank: (1) T2D, enrollment eGFR 45–90 ml/min, and ≥3 years of follow-up data (n=871); and (2) APOL1-HR with African ancestry, enrollment eGFR >30 ml/min and ≥3 years of follow-up data (n=498). The authors measured plasma tumor necrosis factor receptors (TNFR) 1 and 2 and kidney injury molecule-1 (KIM-1) and used random forest algorithms to integrate biomarker and EHR data to generate a risk score for a composite outcome: RKFD (eGFR decline of ≥5 ml/min per year), or 40% sustained eGFR decline, or kidney failure. Performance was compared to a validated clinical model and thresholds applied to assess the utility of the prognostic test (KidneyIntelX) to accurately stratify patients into risk categories. The positive predictive values for KidneyIntelX were 62% and 62% versus 46% and 39% for the clinical models (P 4