Chronic renal failure from lead: myth or evidence-based fact?

Kidney International (2011) 79, 272–279F1陳筱惠

指導醫師：尤俊成醫師

Lead poisoning: Blood lead levels (PbB) > 80 ug/dl Anemia, colic pain, peripheral neuropathy,

encephalopathy, nephropathy and chronic renal failure (CRF)

Cardiovascular mortality and high blood pressure

The epidemiological and pathophysiological evidence of lead exposure as a risk factor for the development of CRF?

Searched database: PubMed Keywords: ‘lead’, ‘nephrotoxicity’,

‘epidemiologic’, ‘experimental’, ‘kidney disease, chronic’, and ‘renal’

HUMAN EXPOSURE AND ACCUMULATION OF LEAD Lead enters the human body by ingestion

or inhalation. Data from the National Health and Nutrition

Examination Survey study in the United States: a decline in the geometric mean PbB level in the general population from 13.1 ug/dl in 1976–1988 to 1.6 ug/dl in 1999–2002

Factors that have been linked to higher PbB: older age, male sex, lead in old paint and water pipes, smoking, moonshine drinking, lower socioeconomic status, urban residence, and housing in older buildings

95% of the absorbed lead is stored in the bones of adults Half life: 4–20 years Cortical bone > trabecular bone The clinical importance of the stored lead is not

clear an endogenous source of lead in plasma

PbB : <5% free in the plasma, and the rest bound to the erythrocytes (the enzyme d-aminolevulinic acid, ALAD) Half life: 30 days

The exchange of lead is greater during increased bone turnover such as pregnancy, immobilization, or hyperparathyroidism.

BIOMARKERS OF LEAD EXPOSURE PbB: on-going exposure

Affected by higher bone turnover, acidosis, and inflammation

Lead burden: mobilization test using a chelating agent Intramuscular or intravenous administration of

CaNa2 EDTA Lead–EDTA complex in the urine during the

following 24h, >600 ug excreted lead/24h)

In patients with CRF, the urinary elimination of the lead–EDTA complex is delayed 72h

The sensitivity and specificity of the EDTA diagnostic test in the levels of patients below the toxic limit (<600 ug/72 h), especially in patients with different glomerular filtration rates (GFRs) are uncertain.

In vivo X-ray fluorescence: Poor sensitivity and specificity compared with the

EDTA diagnostic test among CRF patients

GENERAL TOXICITY OF LEAD Inactivation of ALAD enzyme systems by

binding to sulfhydryl groups Accumulation of aminolevulinic acid and zinc

protoporphyrin in blood, plasma, and urine Interference with heme biosynthesis

COMMONLY DESCRIBED RENAL EFFECTS FROM LEAD The classical lead nephropathy exhibited at

toxic levels: Minimal proteinuria, a benign urinary sediment,

hyperuricemia, and often hypertension

Glomerular hyperfiltration: Rats fed with lead increased their GFR at 3

months compared with control rats, but had lower GFR at 6 and 12 months.

Chelate treatment improved GFR both among lead-fed rats and among control rats and reduced the morphological changes seen after lead exposure was discontinued.

The kidneys are granular and contracted. Renal biopsies:

The glomeruli are sclerotic. The arterioles often show intima proliferation and

hyaline degeneration of the media. Tubular atrophy and interstitial fibrosis without

cellular infiltration

Proximal tubules: acid-fast nuclear inclusion bodies, consisting of a lead–protein-binding complex, observed during the initial phases of acute lead exposure, and rarely at later stages

ENVIRONMENTALLY EXPOSED POPULATIONS ANDINDICATORS OF RENAL EFFECTS

Most of the general population studies are also cross-sectional.

The majority of the studies with renal function outcomes use S-Cr or creatinine clearance, whereas some studies used cystatin C.

The mean PbB levels ranged between 2.2 and 43.5 ug/dl.

Most of these studies showed an association between higher PbB and lower creatinine clearance or estimated GFR.

Continued decline in blood lead levels among adults in the United States. Arch Intern Med 2005; 165: 2155–2161 People in the highest quartile of PbB (>=2.47 ug/dl) were

2.72 times more likely to have chronic kidney disease stage 3 or less based on estimated GFR compared with the lowest quartile (<1.06 ug/dl).

Hypothesis causative association??

RENAL EFFECTS IN ENVIRONMENTALLY EXPOSED CHILDREN An investigation of the extraordinary

incidence of chronic nephritis in young people in Queensland. Med J Aust 1929; 2: 145–159 High frequency of childhood plumbism high

incidence of young people with chronic nephritis However, the relationship between childhood

lead intoxication and chronic nephritis has been difficult to confirm.

2 recent studies on adolescents show the same positive cross-sectional relationship between PbB and cystatin C or S-Cr observed among adults. Blood lead level and kidney function in US

adolescents. Arch Intern Med 2010; 170: 75–82. A longitudinal study of the effects of long-term

exposure to lead among lead battery factory workers in Taiwan (1989–1999). Sci Total Environ 2001; 279: 151–158.

Renal function 17 to 23 years after chelation therapy for childhood plumbism. Kidney Int 1992; 42: 1226–1231 No significant difference in elevation of serum

creatinine (S-Cr), proteinuria, or blood pressure after 17–23 years compared with sibling controls

A 50-year follow-up of childhood plumbism: hypertension, renal function, and hemoglobin levels among survivors. AJDC 1991; 145: 681–687 No significant difference in S-Cr compared with

controls, but the exposed subjects had higher creatinine clearance and higher blood pressure

OCCUPATIONAL LEAD EXPOSURE AND CRF Since 1985, 19 reports, all cross-sectional

studies

In spite of all that has been reported on the effects from acute or ongoing excessive exposure, there are only a few of the studies presented in Table in which the GFR is significantly reduced.

The approximate frequency of CRF (GFR < 60 ml/min) from these observations is 1.5% almost identical to the population prevalence of stage 3 chronic kidney disease (1.4%) among 40- to 59-year-old subjects

Longitudinal associations between lead dose and renal function in lead workers. Environ Res 2009;109: 101–107. 537 lead workers followed for 42.1 years showed no general

effect of PbB (mean baseline 31.3 mg/dl) on creatinine clearance.

Occupational lead exposure and severe CKD: a population-based case-control and prospective observational cohort study in Sweden. Am J Kidney Dis 2010; 55: 497–506. Not find a more rapid decline in the estimated GFR during

5–7 years among patients occupationally exposed to lead compared with those non-exposed.

Neither was renal survival significantly decreased (hazard ratio 0.92 (95% confidence interval 0.7–1.2) for ever exposed participants compared with never-exposed)

LEAD EXPOSURE AND CRF OUTCOMES Only 4 case–control studies: no association

New occupational risk factors for chronic renal failure. Lancet 1995; 346: 7–11

Odds ratio (OR) for CRF associated with lead exposure was 2.1 (95% confidence interval 1.2–4.4)

Association of tibia lead and blood lead with end-stage renal disease: a pilot study of African Americans. Environ Res 2007; 104: 396–401

The OR for end-stage renal disease associated with tibia lead > 20 ug/g was 1.6 (95% confidence interval 0.6–4.4)

A higher lead burden measured by the EDTA diagnostic test is associated with a more rapid deterioration rate in CRF patients of different etiologies

The patients treated with repeated chelate therapy progressed slower than those who did not receive any treatment. Confounding factors, such as acidosis, inflammation, and

hyperparathyroidism, were not measured Patients were followed only through S-Cr.

DISCUSSION In the occupational studies, in which individuals

had been exposed to lead at high levels for many years giving rise to PbB >60 ug/dl or an EDTA test diagnostic test >600 ug/24h, there is possibly a risk of developing acute lead nephropathy

CRF or end-stage renal disease?? In Europe, the number of individuals with lead

nephropathy as a reported causes of ESRD 7/143,733

The possible effect from lead exposure on the progression of kidney disease?? The very few longitudinal studies on exposed workers

have not supported a deteriorating renal function except in some risk populations of patients with diabetes or hypertension.

Animal studies have also failed to demonstrate reliable evidence for a long-term effect on the glomerular function when lead levels are below toxic.

Hyperfiltration kidney damage

Selection bias in occupational studies ?? Healthy worker effect: workers are generally

healthier compared with the general population If workers with early signs of renal function loss were removed from the work force

Screen for kidney failure on a regular basis

Positive associations between PbB and S-Cr; Whether there is causality??

PbB is elevated CRF patients. Altered bioavailability, acidosis, malnutrition,

inflammation, disturbed bone and mineral metabolism, and hyperparathyroidism increase the decline in GFR

The old ‘fact’ ?? Well-controlled longitudinal studies with

adequate exposure and effect variables; experimental evidence

Biomarkers of lead exposure among patients with renal failure

More precise measurements of the GFR than p-creatinine

Thanks for your listening