Download Effects of glucosamine, chondroitin, or placebo in patients with

Chronic renal failure from lead:
myth or evidence-based fact?
Kidney International (2011) 79, 272–279
F1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 daminolevulinic 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 AND
INDICATORS 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 59year-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 endstage 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 SCr; 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 pcreatinine
Thanks for your listening