Lead Exposure Associated with Decreased Kidney Function

It has long been recognized that lead is nephrotoxic at high levels of occupational exposure; however, there are few data available from studies examining low levels of lead exposure. Florenica Harari, MD, PhD, and colleagues recently conducted a large, prospective, population-based cohort study to determine whether there is an association between environmental low-level lead exposure and kidney function, assessed using estimated glomerular filtration rate (eGFR) based on serum creatinine  and the combination of serum, creatinine and cystatin-C levels. The study also examined the association between low-level lead exposure and incident chronic kidney disease (CKD). Results were reported in the American Journal of Kidney Diseases [2018;72(3):381-389].

The outcomes of interest were change in eGFR between baseline and the follow-up visit based on serum creatinine level alone or in combination with cystatin C level, and the incidence of CKD through 2013 detected using a national registry.

The cohort was drawn from the cardiovascular cohort of the MDCS-C (Malmö Diet and Cancer Study), a random sample of the larger prospective MDCS study. The MDCS-C cohort included 6103 individuals living in Malmö, Sweden, between 1991 and 2004 (baseline). The current study invited those still living and still residing in Malmö (n=4924) to a follow-up examination in 2007 to 2012; of those, 3734 attended the follow-up visit (mean follow-up, 16 years).

Of participants with available data for smoking habits and lead levels at baseline (n=4341), 361 were excluded due to missing data for serum creatinine and cystatin C levels; of the remaining 3980 individuals, 65% (n=2567) had complete data at follow-up and were included in the analyses of change in eGFR from baseline to follow-up.

The median blood lead level was 25 mg/L (range, 1.5-258 mg/L). Participants were stratified into quartiles based on lead levels: (1) 1.5 to <18.5 mg/L (n=1086); (2) 18.5 to <24.7 mg/L (n=1085); (3) 24.7 to <33.0 mg/L (n=1085); and (4) 33.0 to 258.0 mg/L (n=1085).

At baseline, alcohol intake, proportion of men, and proportion of current smokers were higher in Q4 of lead levels compared with the three lower quartiles. Blood pressure and waist circumference increased with blood lead levels. Overall, mean age was 57 years at baseline and 73 years at follow-up.

Mean changes in eGFR from baseline to follow-up were –6 mL/min/1.73 m² for the CKD Epidemiology Collaboration serum creatine equation and –24 mL/min/1.73 m² for the combined serum creatinine and cystatin-C equations.

Following adjustment for age, sex, smoking status, alcohol intake, hypertension, diabetes mellitus, waist circumference, eGFR at baseline, and education level, there was an association between higher blood lead levels and a greater decrease in eGFR over time. The change in eGFR was higher in Q3 and Q4 compared with Q1 (P for trend=.001). The associations were similar for both the serum creatine-based and the combined eGFR equations.

From baseline until the end of follow-up, there were 185 incident cases of CKD, 61% of which occurred in men. Mean time to diagnosis was 19 years. Following adjustment, the hazard ratio (HR) for those in Q4 was 1.49 compared with those in Q1 to Q3 (95% confidence interval [CI], 1.07-2.08; P=.01). In the adjusted model, statistically significant predictors of CKD were sex, age, diabetes mellitus, hypertension, alcohol intake, eGFR at baseline, and waist circumference; smoking status was not an independent predictor.

Following stratification, in comparisons of Q3 with Q4, HRs for incident CKD were higher and statistically significant in individuals with hypertension (HR, 1.57; 95% CI, 1.1-2.2), those older than the median of 58 years (HR, 1.61; 95% CI, 1.1-2.4), and in those without diabetes (HR, 1.62; 95% CI, 1.1-2.4).

Study limitations cited by the authors included using a single lead level at baseline as the measure of lead exposure, the moderate number of cases of incident CKD, and the potential for residual confounding.

“in conclusion, this study found consistent inverse associations between blood levels and kidney function and positive associations with incidence of CKD, adding evidence of lead nephrotoxicity at low levels of exposure. The findings strengthen the need to reduce lead exposure in the general population,” the researchers said.

Takeaway Points

1. Researchers in Sweden conducted a prospective population-based cohort study to examine the association between low levels of lead exposure and kidney function and incident chronic kidney disease (CKD).
2. Participants were stratified into quartiles based on blood lead levels. After a mean follow-up of 16 years, change in estimated glomerular filtration rate was higher in individuals with higher blood lead levels compared with those with lower blood levels.
3. The hazard ratio for incident CKD in the quartile with the higher blood lead levels was 1.49 (95% confidence interval, 1.07-2.08) compared with the first three quartiles combined.