Summary of Lowest Lead Levels
for Lead-induced Side Effects
ATSDR, US Department of Health and Human Services. Toxicological Profile for Lead, 1990
Chronic Lead Exposure Can
Produce Chronic Interstitial
Nephritis
•
•
•
•
Progressive tubular atrophy
Interstitial fibrosis
Renal insufficiency
Gout related to hyperuricemia
Pathogenesis & Pathology
• Proximal tubule reabsorption of
filtered lead, with accumulation
in the proximal tubule cells
• Proximal tubular injury with
intranuclear inclusion bodies
composed of a lead-protein
complex
Proximal tubule of lead-exposed rat:
Intranuclear inclusion bodies in the proximal
tubule cell and loss of brush border and cells
Sanchez-Fructuoso AI, Am J Kidney Dis, 2002
Medium-sized artery in the kidneys of lead-exposed (A)
and control rats (B): Hypertrophy and vacuolization
affecting the artery of the lead-exposed rat
Sanchez-Fructuoso AI, Am J Kidney Dis, 2002
Arteriole in lead-exposed (A) and control (B)
rat kidneys: Muscular hypertrophy in the
arteriole of the lead-exposed rat
Sanchez-Fructuoso AI, Am J Kidney Dis, 2002
Putative mechanisms involved in the
luminal uptake of heavy metals along
the nephron
Barbier O, Nephron Physiol, 2006
Common Mechanisms in Metal
Induced Nephrotoxicity
Sabolic I, Nephron Physiol, 2006
Clinical Manifestations
• Early manifestations reflect
impaired proximal tubular
function
Hyperuricemia, aminoaciduria,
glucosuria
• Late stages
Chronic renal insufficiency,
hypertension, gout
Common Sources of Lead
Exposure
• Occupational involvement in the
manufacture or destruction of leadcontaining batteries or leadcontaining aerosols in the workplace
• Ingestion of moonshine whiskey
• In Children: ingestion of paint or
residence near a major highway
(leaded gasoline)
Diagnosis
• Blood lead level: recent (2-3 weeks)
ingestion
• Rise in urinary lead excretion after EDTA
infusion: excess lead burden in tissues
• X-ray fluorescence: increased bone lead
levels
• Low gamma-aminolevulinic acid
dehydratase (ALAD)-restored to ALDA
ratio: correlated well with urine lead
excretion
Blood Lead Levels Considered
Toxic
•
•
•
•
•
Prior to 1971: 60 µg/dL
1972-1975: 40 µg/dL
1975-1985: 30 µg/dL
1985-1991: 25 µg/dL
1991-present: 10 µg/dL
Impairment of renal function
with increasing BLL in general
population
• A random sample of 965 men and 1016
women [age: 20-88 years, blood lead
level (BLL):7.5 & 11.4 µg/dl. Ccr: 99 & 80
ml/min]
• The Ccr was inversely correlated with
blood lead both before and after
adjustments for age, BMI, and diuretic
treatment
• A 10-fold increase in blood lead level
was associated with a reduction of 10 to
13 ml/min in Ccr
Staessen JA, New Engl J Med, 1992
A longitudinal study of low-level lead
exposure and impairment of renal
function: The Normative Aging Study
• 459 men randomly selected between 1979
and 1994
• After adjustment for age, BMI, smoking,
alcohol, education, and hypertension, BLL
was positively associated with concurrent
serum Cr (P=.005)
• A 10-fold increase in BLL predicted an
increase of 0.08 mg/dL in serum Cr, which is
roughly equivalent to the increase predicted
by 20 years of aging
Kim R, JAMA, 1996
The Normative Aging Study
• The age-related
increase in
serum Cr was
earlier and faster
in the group with
the highestquartile BLL
Kim R, JAMA, 1996
Occult lead intoxication as a
cause of hypertension and renal
failure
By an EDTA test, 296 patients:
1. Normal (30 patients)
2. Chronic renal failure of known
etiology (30 patients)
3. Essential hypertension and normal
renal function (104 patients)
4. Renal failure of unknown etiology
with hypertension and/or gout (132
patients)
Sanchez-Fructuoso AI, Nephrol Dial Transplant, 1996
Occult lead intoxication as a
cause of hypertension and renal
failure
• No patient had a history of overt
lead toxicity
• Elevated lead levels were found
in 16 patients (15 %) with
essential hypertension, and 74
patients (56%) in the last group
Sanchez-Fructuoso AI, Nephrol Dial Transplant, 1996
Blood lead and CKD in the
general US population:
NHANES III
• N = 15211
• Among persons with and without
hypertension, mean blood lead
was 4.21 and 3.30 µg/dL,
respectively, the prevalence of
elevated serum Cr was 11.5%
and 1.8%, respectively, and CKD
was 10.0% and 1.1%, respectively
Muntner P, Kidney Int, 2003
Blood lead and CKD in the
general US population:
NHANES III
• Among persons with hypertension, a
graded association was present between
higher quartile of blood lead and a
higher odds ratio of both an elevated
serum Cr and CKD.
• Comparing the highest to lowest quartile
of blood lead, the multivariate adjusted
odds ratio (95% CI) of an elevated serum
Cr and CKD were 2.41 (1.46, 3.97) and
2.60 (1.52, 4.45), respectively.
Muntner P, Kidney Int, 2003
Blood lead and CKD in the
general US population:
NHANES III
• Among the population without
hypertension, elevated serum Cr and
CKD were not associated with blood lead
for any subgroups except for persons
with diabetes where higher blood lead
was associated with a higher prevalence
of CKD.
• In the United States population with
hypertension, exposure to lead, even at
low levels, is associated with CKD.
Muntner P, Kidney Int, 2003
Blood lead and CKD in the
general US population:
NHANES III
With hypertension
Without hypertension
Muntner P, Kidney Int, 2003
Environmental Exposure to
Lead and Progression of CKD
• A 4-year prospective longitudinal
study
• To elucidate the long-term
relationship between low-level
environmental lead exposure and
progression of CKD in patients
without diabetes
• N = 121
YU CC, J Am Soc Nephrol, 2004
Environmental Exposure to
Lead and Progression of CKD
• 63 patients had body lead burden
(BLB) ≧80 µg and < 600 µg (highnormal group): BLL 3.4 ±1.3 µg/dl
• 58 patients had BLB < 80 µg (lownormal group): BLL 4.9 ±2.6 µg/dl
• The primary end point was an
increase in the serum Cr level to
double the baseline value
YU CC, J Am Soc Nephrol, 2004
Significantly more patients with highnormal body lead burden reached the
primary end point
YU CC, J Am Soc Nephrol, 2004
Environmental Exposure to
Lead and Progression of CKD
• The BLB and BLL at baseline were the
most important risk factors to predict
progression of renal insufficiency.
• Each increase of 10 µg in the BLB or 1
µg/dl in the BLL reduced the GFR by
1.3 (P = 0.002) or 4.0 ml/min (P = 0.01)
during the study period.
YU CC, J Am Soc Nephrol, 2004
Environmental Exposure to
Lead and Progression of CKD
• Low-level environmental lead
exposure is associated with
accelerated deterioration of renal
insufficiency. Even at levels far
below the normal ranges, both
increased BLL and BLB predict
accelerated progression of
chronic renal diseases.
YU CC, J Am Soc Nephrol, 2004
Marsden PA, New Engl J Med, 2003
Blood lead and CKD in the
general US population:
NHANES III
• The less steep
decrease in GFR
associated with
higher blood lead in
persons without
hypertension
suggests that renal
function per se
dose not cause
increased BLL.
Muntner P, Kidney Int, 2003
Lead concentration and lead/calcium ratio
in bone of dialysis patients vs. subjects
with normal renal function
• Chronic renal
failure or
dialysis
treatment per se
does not lead to
bone lead
accumulation
D’Haese PC, Clinical Chemistry, 1999
Lin JL, New Engl J Med, 2001
Lin JL, New Engl J Med, 2001
• Low-level
environmental lead
exposure may
accelerate
progressive renal
insufficiency in
patients without
diabetes who have
chronic renal disease.
• Repeated chelation
therapy may improve
renal function and
slow the progression
of renal insufficiency.
Lin JL, New Engl J Med, 2001
Lead, Diabetes, Hypertension, and
Renal Function: the Normative
Aging Study
• A prospective study, examining changes in
renal function during 6 years in relation to
baseline lead levels, diabetes, and
hypertension among 448 middle-age and
elderly men, a subsample of the Normative
Aging Study.
• Lead levels were generally low at baseline,
with mean blood lead, patella lead, and tibia
lead values of 6.5 µg/dL, 32.4 µg/g, and 21.5
µg/g, respectively.
Tsaih SW, Environ Health Perspect, 2004
Lead, Diabetes, Hypertension, and
Renal Function: the Normative
Aging Study
• longitudinal decline of
renal function among
middle-age and elderly
individuals appears to
depend on both longterm lead stores and
circulating lead, with an
effect that is most
pronounced among
diabetics and
hypertensives, subjects
who likely represent
particularly susceptible
groups.
Tsaih SW, Environ Health Perspect, 2004
Lin JL, Kidney Int, 2006
Lin JL, Kidney Int, 2006
Lin JL, Kidney Int, 2006
Environmental exposure to lead and
progressivediabetic nephropathy in
patients with type II diabetes
• Low-level environmental lead
exposure accelerates
progressive diabetic
nephropathy and lead-chelation
therapy can decrease its rate of
progression.
Lin JL, Kidney Int, 2006
Low-level Environmental Exposure
to Lead and Progressive Chronic
Kidney Diseases
• 108 CKD patients (serum Cr: 1.5-2.9
mg/dL, BLL 2.9 ±1.4 µg/dl, BLB 40.2
±21.2 µg) with low-normal BLB (<80
µg) and no lead exposure history
were observed for 24 months.
• Following the observation, 32 patients
with low-normal BLB (≧20 µg and <80
µg) were randomly assigned to
chelation and control groups.
Lin JL, Am J Med, 2006
Low-level Environmental Exposure
to Lead and Progressive Chronic
Kidney Diseases
Lin JL, Am J Med, 2006
Low-level Environmental Exposure
to Lead and Progressive Chronic
Kidney Diseases
Lin JL, Am J Med, 2006
Low-level Environmental Exposure
to Lead and Progressive Chronic
Kidney Diseases
Lin JL, Am J Med, 2006
Low-level Environmental Exposure
to Lead and Progressive Chronic
Kidney Diseases
• Environmental exposure to lead,
even at low levels, may
accelerate progressive renal
insufficiency of nondiabetic
patients with CKD.
Lin JL, Am J Med, 2006
Additional Factors in Accessing
Lead Induced Nephrotoxicity
• Coexposure of other toxic metals,
such as cadmium
• Aminolevulinic acid dehydratase
(ALAD) polymorphism ( Wu MT, environ
Health Perspect 2003)
• Lead-related hyperfiltration in the
early stages ( Khalil-Manesh F, Arch Environ Health 1993;
Weaver VM, Occup Environ Med 2003)
Conclusions
• Chronic lead exposure can produce a
chronic interstitial nephritis.
• Populations with diabetes,
hypertension and/or CKD appear to
be at great risk for adverse renal
effects from lead.
• Environmental exposure to lead, even
at low levels, may accelerate
progressive renal insufficiency.