Plasma KIM-1 Levels and Risk of CKD Progression

Kidney injury molecule 1 (KIM-1) is virtually undetectable in healthy kidneys. KIM-1, also known as hepatitis A virus receptor (HANCR-1; also known as TIM-1) is a type 1 transmembrane glycoprotein that is strongly upregulated by ischemic and toxic kidney injuries. In acute kidney injury (AKI) and chronic kidney disease (CKD), KIM-1 expression is upregulated in proximal tubules. There are few data available on the association between KIM-1 and risks of adverse clinical outcomes across a variety of kidney diseases.

Insa M. Schmidt, MD, MPH, and colleagues conducted a prospective, observational cohort study to test the hypothesis that there is an association between higher levels of plasma KIM-1 and underlying histopathologic lesions, clinicopathologic diagnoses, and increased risks of subsequent progression to kidney failure and death in patients with CKD. Results were reported in the American Journal of Kidney Diseases [2022; 79(2):231-243].

The study cohort included 524 patients enrolled in the Boston Kidney Biopsy Cohort (BKBC) Study undergoing clinically indicated native kidney biopsy with biopsy specimens adjudicated for semiquantitative scores of histology by two kidney pathologists and 3800 individuals with common forms of CKD who were enrolled in the CRIC (Chronic Renal Insufficiency Cohort (CRIC) study.

The study exposure was histopathologic lesions and clinicopathologic diagnosis in cross-sectional analyses, and baseline plasma KIM-1 levels in prospective analyses. Outcomes of interest were baseline plasma KIM-1 levels in cross-sectional analyses, kidney failure (initiation of kidney replacement therapy [dialysis or kidney transplantation]), and death in prospective analyses.

Associations of plasma KIM-1 levels with future kidney failure were assessed using Cox proportional hazards models. Associations of plasma KIM-1 levels with histopathologic lesions and clinicopathologic diagnoses were tested using multivariable-adjusted linear regression models.

BKBC Study

At baseline, the median plasma KIM-1 concentration using the monoclonal detection antibody from Enzo Life Sciences was 210.2 pg/mL. Mean age was 53 years and mean estimated glomerular filtration rate (eGFR) was 56 mL/min/1.73 m². The most common primary clinicopathologic diagnoses were proliferative glomerulonephritis (29.1%), nonproliferative glomerulopathy (18.3%), advanced glomerulosclerosis (11.3%), and diabetic nephropathy (11.1%). There was a negative correlation of plasma KIM-1 and eGFR and a positive correlation of plasma KIM-1 and proteinuria.

Plasma KIM-1 levels were significantly higher in participants with more severe interstitial fibrosis/tubular atrophy, acute tubular injury, inflammation in the nonfibrosed and fibrosed interstitium, global glomerulosclerosis, mesangial expansion, and arterial and arteriolar sclerosis compared with those with less severe lesions. Following adjustment for age, sex, race, and eGFR, plasma KIM-1 levels were significantly higher in participants with more severe acute tubular injury, more severe mesangial expansion, and the presence of inflammation in the nonfibrosed interstitium than those with less severe lesions. Following adjustment for proteinuria, plasma KIM-1 levels remained significantly higher in those with more severe acute tubular injury and the presence of inflammation in the nonfibrosed interstitium.

During a median follow-up time of 5 years, CKD progressed in 124 participants and 85 participants died. In the fully adjusted model, there was an association between each doubling of plasma KIM-1 level and a 1.19-fold increased risk of progression to kidney failure (hazard ratio [HR], 1.19; 95% CI, 1.03-1.38). Participants in the highest tertile of plasma KIM-1 had a higher risk of kidney failure; however, the confidence interval crossed 1.0 in the fully adjusted model. There was no evidence of statistical interaction between plasma KIM-1 level and primary clinicopathologic diagnosis for progression to kidney failure (P=3 for interaction) or death (P=7 for interaction). There were associations between higher levels of plasma KIM-1 and higher risk of death; however, the associations were not statistically significant following multivariable adjustment, including eGFR.

CRIC Study

Median plasma of the 3800 CRIC Study participants using the polyclonal detection antibody from R&D Systems was 1073.0 pg/mL. Mean age was 58 years and mean eGFR was 45 mL/min/1.73 m². Participants with higher levels of plasma KIM-1 were more likely to be non-White, had greater prevalence of diabetes mellitus and cardiovascular disease, had higher systolic blood pressure, and had lower hemoglobin levels. There was a negative correlation between plasma KIM-1 and eGFR and a positive correlation between plasma KIM-1 and urine albumin-creatinine ratio.

A total of 1153 participants with CKD progressed to kidney failure during a median follow-time of 11.5 years; 1356 participants died during the follow-up period. In a fully adjusted model, each doubling of plasma KIM-1 level was associated with a 1.10-fold increased risk for progression to kidney failure (HR, 1.10; 95% CI, 1.06-1.15). Among participants in the highest quintile of plasma KIM-1 level, there was a 1.58-fold increased risk of progression to kidney failure compared with those in the lowest quintile.

There was an association between higher levels of plasma KIM-1 and higher risk of death. However, following adjustment for eGFR, the association was attenuated and no longer statistically significant.

Strengths of the study noted by the authors included the inclusion of two large cohorts of individuals with established kidney disease; both studies have long follow-up duration and low rates of missing data on outcomes. The researchers also cited limitations to the findings, including differences between the two studies in the ascertainment of variables, and the possibility of residual confounding from unmeasured confounders.

In conclusion, the researchers said, “We found that higher levels of plasma KIM-1 are associated with more severe tubulointerstitial and mesangial lesions and progression to kidney failure in two cohort studies of individuals with kidney diseases. The strong associations with histopathologic lesions and progression to kidney failure suggest that plasma KIM-1 may potentially serve as a kidney-specific marker to enhance estimation of the risk of progression to kidney failure across a broad spectrum of kidney diseases.”

Takeaway Points

1. Researchers analyzed data from the Boston Kidney Biopsy Cohort (BKBC) and the Chronic Renal Insufficiency Cohort (CRIC) studies to examine the association between level of plasma kidney injury molecule (KIM-1) and risks of adverse clinical outcomes across various kidney diseases.
2. In BKBC, there were associations between higher plasma KIM-1 levels and more severe acute tubular injury, tubulointerstitial inflammation, and more severe mesangial expansion.
3. In both cohorts, each doubling of plasma KIM-1 level was associated with an increased risk of kidney failure. There was no statistically significant association between plasma KIM-1 level and death in either cohort.