Supplementary Material for: Plasma and Urinary KIM-1 in Chronic Kidney Disease: Prognostic Value, Associations with Albuminuria, and Implications for Kidney Failure and Mortality

Introduction
Kidney injury molecule-1 (KIM-1) expression reflects proximal renal tubular damage, but plasma and urine KIM-1 have not been jointly studied in a CKD cohort.

Methods
Plasma and urine KIM-1 were measured in 2581 adults from the NURTuRE-CKD cohort, a multicentre, non-dialysis-dependent CKD cohort. Survival analyses, C-statistics, and net reclassification improvement were used to assess associations and predictive performance of plasma and urine KIM-1 for kidney failure (KF), all-cause mortality and a secondary endpoint of combined CKD progression end-point (CKE) (KF or >40% decline in eGFR) in the total cohort, and in KDIGO albuminuria categories, early CKD (eGFR >45ml/min/1.73m2) and four plasma/urine KIM-1 groups, dichotomised above and below the median value.

Results
Median age was 65 years, baseline eGFR 34.8 ml/min/1.73m², and urine albumin-to-creatinine ratio (uACR) 22.3 mg/mmol. During median follow-up of 48.8 months, 616 (23.9%) participants developed KF, 817 (32%) experienced CKE and 344 (13.3%) died. Plasma and urine KIM-1 levels increased with lower eGFR, higher uACR, and diabetes. Plasma KIM-1 was independently associated with kidney failure, while urine KIM-1 was associated with pre-kidney failure death. The combination of high plasma and high urine KIM-1 conferred the greatest hazards of kidney failure and all-cause mortality. Combining plasma and urine KIM-1 led to a 24.1% improvement in net reclassification index for kidney failure. In earlier stages of CKD, both biomarkers were associated with CKD progression and there were large improvements in risk prediction for plasma KIM-1 alone. Increased albuminuria amplified the relationship between plasma and urine KIM-1 and kidney failure risk.

Conclusions
This study highlights distinct prognostic associations of plasma and urine KIM-1 in CKD. Measuring both may be useful in improving risk stratification in people with CKD. For early stage CKD the need to use a combined CKD progression end-point, including decline in eGFR, is emphasised as few of these people developed KF.