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Allowable levels of lead in U.S. drinking water may still put Americans with kidney failure at risk for hematologic toxicity and lead poisoning, a cross-sectional analysis suggested.

In a nationwide sample of patients starting on dialysis, each increase in household drinking water lead contamination category was associated with a 15% higher odds of being on the maximum monthly erythropoiesis-stimulating agent (ESA) dose for anemia (OR 1.15, 95% CI 1.04-1.27), along with a 4.5 μg higher monthly ESA dose (95% CI 0.8-8.2, P=0.02), and a 0.48% higher monthly ESA resistance index (95% CI 0.002-0.960, P=0.05).

In fact, even levels of lead below the maximal allowable threshold of 15 μg/L set by the Environmental Protection Agency were tied to a higher odds of patients needing a maximum recommended ESA dose, reported John Danziger, MD, MPhil, of Beth Israel Deaconess Medical Center in Boston, and colleagues in .

Compared with the patients whose household water lead levels were under 2 μg/L, those with levels of 7.5-15 μg/L had a 73% higher odds of being on the maximum ESA dose while those above that 15 μg/L threshold had more than twice the odds:

• 7.5-15 μg/L: OR 1.73 (95% CI 1.09-2.75)
• >15 μg/L: OR 2.08 (95% CI 1.18-3.65)

"Our findings suggest that lead contamination has detectable, clinically relevant adverse effects in at-risk individuals, even at levels below the current Environmental Protection Agency actionable threshold for U.S. households," Danziger's group pointed out.

"In addition to the direct hematologic effects of lead poisoning, including the financial burden of higher ESA dosing and morbidity of lower hemoglobin levels, further consequences are possible," they noted. "ESA therapy carries dose-dependent clinical risk, including thromboembolism and cardiovascular disease."

No level of lead in drinking water is considered safe, but measurable concentrations were common in the study population, with 12% having household levels of 2 μg/L or above.

Chronic kidney disease (CKD) patients are disproportionately susceptible to accumulation of heavy metals, and "given the prolonged biologic half-life of ingested lead, which deposits widely in soft tissues and bone throughout the body, repeated low levels of lead exposure may result in progressive accumulation and toxicity in CKD," the researchers explained.

Prior work has also shown environmental lead levels to be associated with clinically meaningful toxicity in . "In this respect, patients with CKD may serve as bellwethers for even larger scale toxicity across the U.S. population, including among children," wrote Danziger and co-authors.

In a subset of patients in the study with pre-kidney failure hemoglobin measures, a higher household lead categorization was tied with a 0.12 g/dL lower hemoglobin concentration. This was even more pronounced for patients with concurrent iron deficiency -- which is thought to increase absorption of ingested lead -- who had 0.25 g/dL lower hemoglobin concentrations.

Finding that the hematologic toxic effects were magnified in those with iron deficiency has "biological credibility," said Chi-yuan Hsu, MD, MSc, of the University of California San Francisco, and co-authors, writing in . They explained that the mechanism by which lead causes anemia is through the inhibition of ferrochelatase, which is a crucial enzyme in heme synthesis, thus preventing the insertion of iron into the porphyrin ring.

"Patients with chronic kidney disease often exhibit both true iron deficiency and functional iron deficiency; the latter is characterized by inadequate iron availability despite sufficient iron stores," they wrote. "Lead competes with iron for the divalent metal transporter 1, located at the brush border of intestinal enterocytes, which is responsible for absorbing elemental iron. In iron-deficient states, this transporter is upregulated, contributing to the increased absorption of lead."

Patients in the analysis began dialysis at a Fresenius Medical Care outpatient facility between January 2017 and December 2021. This included 6,404 patients with incident kidney failure who at some point had water sampling taken to assess the suitability for home hemodialysis. Lead levels were categorized as follows: <2 μg/L, 2 to <5 μg/L, 5 to <7.5 μg/L, 7.5 to ≤15 μg/L, and >15 μg/L. The most common modality was hemodialysis at an outpatient dialysis center (70%), followed by home hemodialysis (21%) and peritoneal dialysis (9%).

The average patient age was 57 and 65% were men. Most lived in homes with water lead concentrations under 2 μg/L, with 1.6% in households with concentrations of 7.5 to 15 μg/L and 1.1% with concentrations of 15 μg/L or higher. Higher lead exposure categories tended to include fewer women and racial and ethnic minority groups, and those with an earlier calendar year of kidney failure onset.

Within the first 90 days of kidney failure care, the average monthly ESA dose was 112 μg, ESA resistance index was 13%, and maximum monthly ESA dose (360 μg or higher) was administered in 7% of the months.

Limitations included that exposure quantification was potentially affected by a lag between kidney failure initiation and water sampling, that an individual's water consumption was not known, and that lead assessment used running water rather than stagnant water sampling, potentially introducing non-differential misclassification that may have led to underestimation of lead in this population.

The editorialists also suggested future research directly measure blood lead levels and zinc protoporphyrin levels -- a biomarker for lead poisoning -- which wasn't done in this study.

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