Review Article

Indian J Med Res 128, October 2008, pp 335-352

Nephrotoxicity of cadmium & lead

H.C. Gonick

Division of Nephrology, West Los Angeles Healthcare Center, Los Angeles, California, USA

Received February 6, 2008

Cadmium and lead are divalent cations with a propensity to settle in the proximal tubule of the
nephron, leading to nephrotoxicity. The pathophysiological results, however, tend to diverge.
Cadmium in sufficient cumulative dosage leads to the production of the Fanconi syndrome, a
generalized proximal tubular reabsorptive defect thought to be related to inhibition of both ATP
production and Na-K-ATPase activity. On the other hand, lead accumulation in the proximal tubule
leads to hyperuricaemia and gout, presumably by inhibiting uric acid secretion, and diminished
glomerular filteration rate (GFR). Fanconi syndrome is seen unusually only in children and
experimental animals. Cadmium nephrotoxicity is heralded by increased excretion of 2microglobulin, retinol binding protein and 1-microglobulin, indicative of decreased proximal tubule
function. Beta2-microglobulinuria is not found in lead nephropathy. In lead nephropathy albuminuria
is absent or minimal whereas in cadmium nephropathy albuminuria is variable. From the standpoint
of pathology, both entities are characterized by tubulointerstitial disease and fibrosis, but only early
lead nephropathy is characterized by the presence of proximal tubule nuclear inclusion bodies, due
to the combination of lead with a lead binding-protein.

Key words Cadmium - Fanconi syndrome - glomerular filtration rate - gout - kidney - lead - nephrotoxicity - proteinuria

Introduction

obtained as a by-product of zinc refining, is used

industrially in plating of steel, pigments, plastics, alloys,
and nickel-cadmium batteries, and in nuclear and
electronic engineering1-3. Because the biologic half-life
of cadmium is long (more than 30 yr), prolonged lowlevel exposure leads to excessive accumulation in
certain tissues, especially the kidney 4. Studies of
cadmium toxicity have been performed in the
accumulator battery industry, the copper-cadmium alloy
industry, and cadmium pigment factories1-3. Chronic
poisoning typically was found to have occurred after
several years of exposure and was characterized
clinically by variable features of nasorespiratory
involvement, such as emphysema, rhinitis, alteration

Cadmium and lead are two of the most prevalent as

well as two of the most nephrotoxic metals known to
man. The focus of this review is to compare and contrast
the clinico-pathological presentations and the
pathogenesis of the nephrotoxicity of each of these
metals.
CADMIUM
Cadmium exposure sources
Nephrotoxicity caused by cadmium has been
described in settings of industrial exposure and
environmental pollution. Cadmium, a metal ordinarily
335

336

INDIAN J MED RES, OCTOBER 2008

of nasal mucosa, and anosmia, and by renal tubular

dysfunction. Yellow tooth discolouration, mild anaemia,
and disturbances in calcium metabolism, osteomalacia,
and renal toxicity also were observed occasionally.
Environmental cadmium exposure occurs in residents
living in proximity to industrial pollution5 and also in
heavy smokers6, as tobacco smoke yields high cadmium
concentrations7.
Clinically detectable proteinuria (i.e., by the
sulphosalicylic or heat and acetic acid tests) is not seen
until at least nine and more commonly 25 years of
exposure1. Initially, the proteinuria was thought to be
exclusively of tubular origin (i.e., low molecular
weight). Indeed, when sensitive tests for low molecular
weight proteinuria were used (electrophoresis,
immunoassays for 2- microglobulin, 1-microglobulin,
and retinol binding protein, or enzymatic tests for
lysozyme and ribonuclease) these tests were positive
in workers with lesser degrees of exposure and in whom
clinical proteinuria was absent8, 9. Later it was found in
both workers and experimental animals exposed to
cadmium that the proteinuria is a mixed type, with
increased excretion of both high - and low - molecular
weight proteins, indicative of both glomerular protein
loss and decreased tubular reabsorption10.
Thresholds
The threshold at which tubular proteinuria appears
has been defined in various ways. Initially the threshold
was set at a urinary cadmium value of 10 g/g creatinine,
reflecting increased kidney levels of cadmium. The
threshold for kidney cortex cadmium was similarly set
at 200 g/g wet weight3. Over the subsequent years,
the threshold for urinary cadmium has been gradually
reduced as more sensitive tests have been developed.
Alpha 1-microglobulin has commonly been substituted
for 2-microglobulin as a marker for tubular proteinuria
as the latter is sensitive to pH changes whereas the
former is not11. Another low molecular weight protein,
metallothionein, which is produced in response to
cadmium exposure, is also excreted in increased
quantities when the body burden of cadmium exceeds
a threshold limit. The latter is defined as a urinary
cadmium level greater than 3.1 g/g creatinine 12 .
Although urinary cadmium has been employed most
frequently as a measure of exposure, both blood
cadmium 13 and plasma cadmium-metallothionein14,
determined by HPLC separation of plasma and reference
to cadmium-metallothionein standards, have been used
as well. Cadmium in whole blood has a biological half-

life of 75-128 days for the fast component and 7.4 to

16.0 yr for the slow component15. Thus blood cadmium
can be used to monitor both recent and remote exposure.
In current and previous occupationally- and
environmentally-exposed individuals, a threshold blood
cadmium level of 0.78 g/l was determined13. This
stands in contrast to non-exposed individuals in whom
the mean blood cadmium concentration was 0.36 g/
l16.
Urinary excretion of N-acetyl--D-glucosaminidase
(NAG), with a molecular weight of 120 kD, also has
been reported to increase in humans exposed to
cadmium17. This is a lysosomal enzyme present in high
concentrations in the proximal tubule. Because of its
high molecular weight, its urinary origin is unlikely to
occur via glomerular sieving but rather directly from
damaged kidney tissue. Urinary NAG has been found
to be elevated when urinary cadmium is below a
threshold of 10 g/g creatinine. Three thresholds have
been noted: the first around 2 g/g creatinine (associated
with biochemical alterations), the second around 4 g/
g creatinine for high molecular weight proteins and
some tubular antigens, and the third at 10 g/g creatinine
for low molecular weight proteins18. Other indices of
cadmium-induced renal dysfunction include increased
excretion of tubular brush border antigens (BBA),
thromboxane B, intestinal alkaline phosphatase,
prostanoids, and glycosaminoglycans19. Also found in
the urine of both humans and animals intoxicated by
cadmium is glutathione S-transferase (GST), a marker
of tubular injury 20,21 . The proteinuria induced by
cadmium has been found to be irreversible, in general,
even several years after cadmium exposure. However,
microproteinuria may be reversible in some workers
whose urinary cadmium exceeds a threshold of 10 g/
g creatinine but whose initial microproteinuria is mild
(between 300 and 1,500 g/g creatinine). The findings
of generalized proximal tubular dysfunction are limited
to workers with either clinically overt or subclinical
tubular proteinuria.
Liver and kidney cadmium have been measured
both at autopsy and in vivo, using neutron activation
analysis. Roels et al22 examined workers in Belgian
cadmium-producing plants and found a good correlation
between liver cadmium and renal cortical cadmium, and
between the log of urinary cadmium and renal cortical
cadmium. The threshold level of renal cortical cadmium
was between 200 and 250 ppm, in agreement with
earlier estimates. In those workers with renal
dysfunction there was a significantly higher liver

GONICK: Cd & Pb NEPHROTOXICITY

cadmium than in those with normal renal function,

whose kidney cadmium concentrations were unchanged.
This finding led the authors to speculate that renal
cortical cadmium decreases progressively after the onset
of kidney damage. The assumption was confirmed in
another study 23 when it was found in industriallyexposed workers that liver and kidney cadmium levels
showed an increase until a concentration of 40 ppm was
reached in the liver; thereafter, kidney levels decreased
while liver levels increased.
Clinical manifestations
Glomerular filtration rate (GFR) impairment was
not reported in early studies of cadmium workers.
However, studies from Belgium found that workers with
prolonged exposure (mean 25 yr) show a significant
increase in serum creatinine and 2-microglobulin with
time, even when the effect of ageing is factored in24.
The authors suggest that prolonged cadmium exposure
exacerbates the age-related decline in GFR. When these
investigators assessed the filtration reserve capacity of
the kidney (defined as the difference between baseline
creatinine clearance and creatinine clearance after an
acute load of protein), they found that cadmium workers
with low molecular weight proteinuria had both
diminished GFR and diminished filtration reserve
capacity, whereas workers below age 50 without low
molecular weight proteinuria showed neither
abnormality. Although experimental evidence in rats has
linked cadmium to hypertension25, there is no conclusive
evidence of such an association in humans26. Mortality
studies from cadmium-polluted areas in Europe and
Japan have demonstrated that mortality rates for
nephritis and nephrosis are higher than in control areas,
although no increase in the incidence of cardiovascular
deaths has been reported27.
Itai-itai disease
The best characterized example of intoxication of
a large population by environmental exposure to
cadmium is itai-itai-byo or ouch-ouch disease, so
named because of the crippling and painful osteomalacic
component. The disease was endemic to the the Jinzu
River basin of the Toyama Prefecture in Japan, with
peak incidence shortly after World War II, and was
attributed to cadmium overload from a zinc mine
upriver. The soil and the rice fields contained large
amounts of cadmium brought with the irrigation water
from the polluted river. Autopsies of five patients with
itai-itai-byo revealed that the cadmium content of liver
was 5 to 10 times higher than in age-matched controls,

337

but the levels in kidney were lower than in the controls

because kidney damage was present28. A decrease in
kidney cortex cadmium levels occurs with advancing
age and with kidney disease of varying causes29; this is
consistent with decreased metallothionein content of
the kidney cortex under these conditions.
The typical patient with itai-itai disease was
reported to be a middle aged postmenopausal
multiparous woman who had lumbar pains, leg myalgia,
and ducklike gait. Pressure on bones, especially the
femurs, spine, and ribs, aggravated the pain.
Pseudofractures were seen on radiographic examination,
and typical findings of osteomalacia were found on bone
examination. Serum 1, 25-dihydroxy vitamin D (1,
25 (OH)2D) levels were decreased and were closely
related to serum concentrations of parathyroid hormone
(PTH), 2-microglobulin, and renal tubular phosphate
reabsorption 30 . Quantitative histomorphometric
measurements have been consistent with the clinical
impression of osteomalacia31. An interesting finding was
the presence of iron at mineralization fronts, detected
by radiographic microanalysis, suggesting a possible
synergistic adverse effect between iron and cadmium
on bone mineralization. Renal findings in these patients
were typical of the Fanconi syndrome and included low
molecular weight proteinuria, glucosuria,
aminoaciduria, decreased tubular phosphorus
reabsorption, low phenolsulphothalein excretion, and
diminished concentrating ability; renal failure occurred
in a few. In advanced cases, the kidneys were found to
be contracted. Histologically, the kidney showed tubular
atrophy and dilatation, eosinophilic casts, and interstitial
fibrosis; glomeruli were normal28.
Although the numbers of reported patients with fullblown itai-itai disease have been small and limited
primarily to women, an epidemiological survey
conducted in Japan revealed that about 45 per cent of
women and 40 per cent of men older than 70 in the
endemic area had concomitant proteinuria and
glucosuria 28 . Because the incidence of such
abnormalities in younger subjects was not different from
that seen in people living in a non endemic control area,
it appears that tubular dysfunctions resulted either from
the protracted exposure to cadmium from an early age
or from some feature of ageing.
Other environmental exposure
Environmental exposure to lower limits of cadmium
also can expose a health risk. An epidemiological survey
of 2,327 subjects in two urban and two rural areas in

338

INDIAN J MED RES, OCTOBER 2008

Belgium with different environmental pollution by

cadmium revealed a probability of tubular dysfunction
of 10 per cent when urinary cadmium levels reached
2 g/day32. There was a statistically significant doseresponse relationship between the urinary cadmium
excretion and five affected parameters: urinary
excretion of retinol-binding protein, 2-microglobulin,
NAG, amino acids, and calcium. No statistical
association was found between environmental exposure
to cadmium and blood pressure elevation.
Animal experiments
Experimental work in rabbits, rats, and mice
indicates that renal functional or morphological changes
appear only after the cadmium concentration in renal
cortex reaches saturation levels of about 150 to 200
ppm wet weight (approximately 100 times normal)33.
Repeated intraperitoneal cadmium administration in
small dosages to rats produces renal tubular atrophy
and interstitial fibrosis, and the first pathological
alterations in cadmium-treated rabbits were seen in the
proximal tubular epithelial cells 34 . Cadmium is
deposited chiefly in the renal cortex and is localized
mainly in the proximal segment of the tubules. The metal
deposits and renal tubular changes persist for several
weeks after cessation of cadmium injections. Of
particular interest is the observation that there is a long
delay between initiation of cadmium injections in
experimental animals and the first appearance of tubular
dysfunction and increased urinary cadmium excretion.
Anaemia in rats appears to be related to messenger
ribonucleic acid (mRNA) hypoinduction for
erythropoietin in the kidneys35.
Role of metallothionein
The role of metallothionein, the low molecular
weight cadmium-binding protein, is central to an
understanding of cadmium nephrotoxicity. The purified
protein was named metallothionein because of its high
content of sulphur and metals, chiefly cadmium and
zinc. Metallothionein synthesis probably occurs through
formation of a specific mRNA because both
cycloheximide and actinomycin D, administered
concomitantly with cadmium, block the incorporation
of [ 35 S] cystine into cadmium-binding protein 36 .
Metallothionein can act as a transport protein, as well
as a storage protein, for cadmium. When cadmium is
injected together with metallothionein, there is a
selective deposition of cadmium in the kidney, and the
renal tubular damage produced is greater than that seen
when cadmium is given alone37. The increased renal

damage can be attributed to the much more profound

uptake of cadmium by the kidney when cadmium is
given as metallothionein rather than free cadmium. The
critical concentration of cadmium-metallothionein in
kidney is 10 g/g, in contrast to that of inorganic
cadmium (130-200 g/g). These observations are in
accord with suggestions that cadmium bound to
metallothionein is preferentially filtered through the
glomeruli and subsequently reabsorbed and stored in
tubules or enters the renal tubules directly from the
peritubular capillaries. Zinc-metallothionein, in contrast
to cadmium-metallothionein, is nontoxic when given
in comparable dosage and appears to insert a protective
effect against cadmium-metallothionein-induced
nephrotoxicity38.
Sato and Kondoh39 have published a review on the
role of metallothionein in cadmium toxicity.
Metallothionein synthesis is induced by various stimuli
such as cadmium, mercury, zinc, oxidative stress,
glucocorticoid, and anticancer agents. In recent studies
using metallothionein-null mice, the ability of
metallothionein to protect against cadmium-induced
renal, liver and bone injuries has been confirmed40,41.
Metallothionein is also capable of scavenging oxygen
free radicals. Unexpectedly, metallothionein-null mice
were apparently in good health, raising a question as to
the critical biological role of metallothionein.
Experiments were performed in control and
metallothionein-null mice, injected subcutaneously with
a wide range of cadmium chloride doses, six times per
week for up to 10 wk. In control mice, renal cadmium
burden increased in a dose and time-dependent manner,
reaching as high as 140 g of cadmium per gram kidney,
along with 150-fold increases in renal metallothionein
concentrations, reaching 800 g metallothionein per
gram kidney. In metallothionein-null mice, renal
cadmium concentration was much lower and renal
metallothionein was nonexistent. Metallothionein-null
mice were more susceptible than controls to cadmiuminduced renal injury, as evidenced by increased urinary
excretion of protein, glucose, gammaglutamyltransferase, and NAG as well as by increased
blood urea nitrogen levels. Kidneys of cadmium treated
mice were enlarged and histopathology showed various
types of lesions including proximal tubular
degeneration, apotosis, atrophy, interstitial
inflammation, and glomerular swelling. These lesions
were more severe in metallothionein-null than in control
mice40,41. Thus cadmium-induced renal injury was not
necessarily mediated through the cadmium-

GONICK: Cd & Pb NEPHROTOXICITY

metallothionein complex, although metallothionein

appears to be an important intracellular protein in
protecting against chronic cadmium nephrotoxicity.
Pathogenesis
In our laboratory, an experimental model of
cadmium-induced Fanconi syndrome was achieved by
repetitive intraperitoneal administration of cadmium
chloride in adult rats42-44. Glucosuria and aminoaciduria
were noted to appear abruptly after three weeks of
injections, and the complete expression of the Fanconi
syndrome (i.e., diuresis, glucosuria, and aminoaciduria,
proteinuria, and increased sodium, potassium, calcium,
magnesium, phosphate and urate clearance) was then
elicited. At the peak of Fanconi syndrome, renal cortical
adenosine 5-triphosphate (ATP) levels were decreased
by 38 per cent and cortex homogenate sodiumpotassium-adenosine triphosphatase (Na-K-ATPase)
activity was decreased by 60 per cent. Ultrastructural
changes at this stage paralleled the biochemical findings
in that the mitochondria were dramatically altered in
size and shape and there was extensive loss of the basal
plasma membrane infoldings together with complex
cisternal proliferation in proximal tubular cells. The
structural and biochemical findings were reversed
within one week after cessation of cadmium injections
despite persistence of total renal cortical cadmium
concentration at levels close to 200 ppm wet weight.
Analysis of subcellular fractions of the renal cortex
revealed cadmium migration from the soluble
cytoplasmic fraction (where metallothionein is located)
to the mitochondrial fraction (where ATP is maximal)
and to the microsomal fraction (where Na-K-ATPase
activity is maximal) at the time of appearance of Fanconi
syndrome, with reversal after cadmium injection
discontinuation. Microsomal Na-K-ATPase activity
decreased in tandem with the increase in microsomal
cadmium concentration, and in vivo microsomal NaK-ATPase inhibition was found to be precisely that
predicted by in vitro titration of renal microsomal NaK-ATPase with cadmium. When experimental animals
were injected with [109Cd] 24 h before death and kidney
cortex soluble cytoplasm was fractionated on Sephadex
G-75, the radiolabeled cadmium was found to be
associated principally with high molecular weight
proteins in control animals but with the metallothionein
fraction after cadmium injections were given. At the
time of Fanconi syndrome development, the
radiolabeled cadmium was again found mainly in
association with high molecular weight proteins. These
findings suggested that injected cadmium initially is

339

segregated in a nontoxic complexed form as

metallothionein in the cytoplasm of the proximal tubule,
but when the organisms capacity to synthesize new
metallothionein is exhausted, the cadmium, now less
firmly bound to high molecular weight proteins, moves
to other cell organelles, where the ATP-Na-K-ATPase
transport system is affected42-44.
To further explore this possibility, animals were
studied after 3,6,9,14 (pre-Fanconi), and 15 (Fanconi)
injections of cadmium. In addition, a post-Fanconi group
was sacrificed 7 days after resolution of tubular
dysfunction. Metallothionein was measured in liver and
kidney cortex homogenates in each group of animals
by tracing metallothionein with radioactive mercury as
described by Zelazowski et al 45 . Metallothionein
concentration increased gradually from control values
of 0.02 mg/g wet weight to a maximum of 2.90 mg/g
wet weight in Fanconi animals, with relatively little
further change in post-Fanconi animals. The binding
capacity for [109Cd] of purified metallothionein from
kidney cortex in each group of animals was assessed
by Scatchard plot analysis. The number of binding sites
were determined for both metallothionein and metal free
thionein. These measurements were essentially
unchanged in animals sacrificed at 3, 6, 9, and 14 days
or in Fanconi animals. The number of binding sites in
thionein was approximately 7 g atoms/mol and in
metallothionein was about 0.6 g atoms/mol. The
dissociation constant for thionein was 9 x 10-3 mol/liter
and for metallothionein was 4 x 10-4 mol/liter. The
cadmium and zinc content and the cadmium /zinc ratio
were also determined in purified metallothionein from
liver and kidney homogenates of pre-Fanconi and
Fanconi animals. The most striking finding was a
marked increase in the cadmium/zinc ratio in kidney
metallothionein from Fanconi animals (50 in Fanconi
animals versus 3 in pre-Fanconi)44. Thus, the previously
observed saturation level of cadmium in kidney cortex
and the long delay after exposure before development
of Fanconi syndrome may be ascribed both to a limit in
the kidneys capability of synthesizing metallothionein
and the displacement by cadmium of zinc from common
binding sites on the protein. The excess cadmium
presented to the kidney spills over from the saturated
protein-binding sites in the soluble cytoplasm to
microsomal and mitochondrial fractions, where
cadmium-sensitive enzyme systems are located. Thus,
there is strong evidence that the ATP-Na-K-ATPase
transport system is profoundly affected and appears to
be the metabolic basis for altered transport in the
proximal tubule44.

340

INDIAN J MED RES, OCTOBER 2008

An alternative, or perhaps complementary,

explanation has been provided by Thevenod 46,47. Recent
research had indicated that cadmium, as well as other
heavy metals, induce oxidative damage in cells.
Thevenod and Friedmann 47 showed that cadmium
chloride increased the production of reactive oxygen
species in a rat proximal tubule cell line, as determined
by oxidation of dihydrorhodamine 123 to fluorescent
rhodamine 123. This was prevented by co-incubation
with the thiol antioxidant N-acetylcysteine (NAC).
Cadmium also increased apoptosis but not necrosis.
Exposure of proximal tubular cells to cadmium
decreased protein levels of the catalytic subunit of NaK-ATPase, as determined by immunoblotting, by
approximately 50 per cent, and NAC largely prevented
this effect. In addition, the effect of quercetin, a potent
reactive oxygen species scavenger, on metallothionein,
nitric oxide synthases (NOS), and cyclooxygenase-2
(COX-2) renal expression following chronic cadmium
administration to rats was studied by Morales et al48,49.
These studies indicated that renal eNOS expression was
significantly higher in rats receiving cadmium and
quercetin than in animals receiving cadmium alone or
in control rats. In the rats that received cadmium, COX2 and iNOS expression was markedly higher than in
control rats. In the group given cadmium plus quercetin,
no changes in COX-2 and iNOS expression were
observed compared with the control group. In addition,
animals receiving both cadmium and quercetin showed
better renal function than those receiving cadmium
alone. Total plasma antioxidants and renal SOD and
glutathione-reductase activities were higher in the group
that received cadmium and quercetin than in rats that
received cadmium alone. Thus, in addition to direct
inhibition of the ATP-Na-K-ATPase transport
mechanism by cadmium, a second mechanism, namely
stimulation of reactive oxygen species, may be operative
in decreasing renal Na-K-ATPase activity, thereby
reducing proximal tubular transport.
Immunologic renal disease
Because of the demonstrated ability of certain heavy
metals, such as gold and mercury, to produce an immune
complex nephritis, and because there is some evidence
that cadmium-exposed workers developed glomerular
lesions, studies have been conducted in experimental
animals to determine whether cadmium can also induced
immune complex nephritis. In one study, oral exposure
of rats to either 100 or 200 ppm cadmium chloride in
drinking water for 30 wk resulted in a diffuse
membranous glomerulopathy with electron-dense

deposits within mesangial cells on electron microscopy

and granular dense deposits of immunoglobulin G (IgG)
in most glomeruli by immunofluorescence50. In another
study of rats given 100 ppm cadmium chloride for up
to 13 months, about 25 per cent of the rats had IgG
glomerular deposits in the mesangial area. At 8 months,
the rats had demonstrable circulating anti-laminin
antibodies, suggesting that cadmium can induce
autoantibody formation51.
Treatment
Treatment for chronic or acute cadmium
nephrotoxicity should be preventive. Once there is
demonstrable renal disease, the person should be
removed from all further exposure to cadmium. British
anti-lewisite (BAL) should not be administered because
there is evidence that the cadmium-BAL complex is
more toxic to the kidney than cadmium alone. Of the
chelating agents tested in experimental animals after
acute oral cadmium intoxication, the most effective in
both enhancing survival and leaving minimal residual
levels of cadmium in liver and kidney was meso-2, 3dimercaptosuccinic acid (DMSA, Succimer)52 and its
esters. Carbodithioates have also proved to be effective
in removing cadmium from rats53. At present there is
limited experience with the use of chelating agents, such
as calcium disodium ethylenediaminetetraacetic acid
(calcium EDTA), in treating acute or chronic cadmium
poisoning in humans54.
LEAD
Lead exposure sources
Lead is found in several industrial sources (Table
I). Chief among these are the accumulator battery
industry, lead smelters, lead or silver ore mining and
lead refining. Non-industrial sources are air-borne lead
from leaded gasoline fumes and lead-based paints. In
the US lead was gradually removed from gasoline
beginning in 1973, and was eliminated from gasoline
in 199655. Lead in lead-based house paint was likewise
eliminated in 197855. Because of these measures there
was a gradual fall in mean blood lead values in the US
population aged 1-74 from 12.8 g/dl in the National
Health and Nutrition Examination Survey (NHANES)
II (conducted from 1976-1980) to 2.8 g/dl in Phase 1
of NHANES III (conducted from 1988-1991) 56 . A
further drop in mean blood lead occurred in the third
phase of NHANES III (conducted from 1999-2002) to
1.64 g/dl57. Other countries, where lead controls on
gasoline and paint have been less stringent, continue to

GONICK: Cd & Pb NEPHROTOXICITY

Table I. Major occupations associated with risk of lead poisoning
Battery makers
Bronzers
Brass workers
Lead burners/smelters
Cable makers/splicers
Stained glass makers
Gun shot makers
Jewelers

Metal grinders
Painters
Pigment makers
Pipe cutters
Pottery workers
Printers (lino/electrotype)
Solderers
Welders

have evidence of low level lead intoxication. In Dhaka,

Bangladesh, where one of the highest air lead levels in
the world are found, the mean blood lead level in 779
school children studied in 2000 was 15.0 g/dl58. Even
in Bombay (now Mumbai), India, where lead was
removed from gasoline in 1997, blood lead levels in
754 children studied in 2002 yielded a mean values of
9.1 g/dl59. The lead content of paint samples from
China, India, and Malaysia were found to contain 5000
ppm or more lead60. This may account for the current
scare in the US of painted toys imported from China.
Other sources of lead include some Chinese and Indian
herbal remedies 61 and even candy 62. Ingestion of
moonshine whiskey (distilled in car radiators) yields a
distinctive form of lead nephropathy, described mainly
from the southern US63. Returning servicemen with
retained bullets or shrapnel and employees or
participants in indoor firing ranges are also exposed to
lead64. Finally users of skin products containing lead,
such as litharge deodorant65 or kohl eye shadow66, may
absorb sufficient lead through the skin to become lead
intoxicated.
Lead dose measures
Lead in whole blood has a short half-life (35 days)67.
Thus the use of blood lead measurements are restricted
to monitoring concurrent lead exposure. For assessment
of more remote lead exposure, other methods must be
employed. Lead eventually settles in bone, where it
comprises over 90 per cent of the total body lead burden
in adults68. Lead has a half-life in cancellous bone of
16 yr and in cortical bone of 27 yr69. For this reason,
measurements of the body burden of lead have been
made by use of bone biopsy70, non-invasive X-ray
fluorescence of bone lead69, or the chelation of lead by
means of either calcium EDTA infusions 71 or oral
DMSA72. The original studies of the calcium EDTA test
in adults with childhood lead poisoning in Queensland,
Australia73 defined an abnormal test as >600 g lead
excreted in the urine 24 h after infusion of 1.0 g of
calcium EDTA. Subsequently, the test collection was

341

expanded to 72 h in patients with renal impairment74.

Batuman et al75 utilized this test to demonstrate that
hypertensive patients with modest azotemia (serum
creatinine > 1.5 mg/dl) had abnormal tests in contrast
to hypertensive patients with normal renal function. The
implication was that such patients had been intoxicated
by lead at a remote time, with or without their
knowledge. The oral DMSA chelation test has been used
successfully in Korean lead workers72 to define the
chelatable portion of the lead body burden. This test
consists of administering DMSA in a dose of 10 mg/kg
body weight and collecting the next 4 h urine.
The definition of an abnormal calcium EDTA test
has gradually shifted. Lin et al76-78 from Taiwan have
utilized repetitive calcium EDTA infusions in patients
with predialysis chronic renal disease due both to
diabetes and non-diabetes and have concluded that lead
contributes to the progression of kidney diseases, and
that chelation with calcium EDTA may slow or improve
the deterioration of GFR. These authors initially defined
an abnormal body lead burden as consisting of 80 to
600 g lead following calcium EDTA; later, the
definition was reduced to greater than 20 g/ 72 h79.
(Blood lead levels in Taiwan have been similar to those
in the US, allowing for extrapolation of these
conclusions). In a well-publicized study, Lin et al77
presented the results on 202 patients with chronic renal
insufficiency (serum creatinine levels between 1.5 and
3.9 mg/dl). These patients were observed for 24 months
and then they were randomly assigned to a control group
and a group which received lead chelation therapy with
calcium EDTA. For a three-month period the 32 patients
in the chelation group received intensive lead chelation
therapy, followed by repeated chelation therapy weekly
for an ensuing 24 months, until the body lead burden
fell below 60 g. GFR improved significantly by the
end of the 27 month intervention in patients receiving
chelation therapy. The mean change in GFR in this
group was 2.1 ml/min per 1.73 m2 body surface area as
compared with -6 ml/min per 1.73 m 2 in the 32
controls77.
Radiographic fluorescence techniques provide a
noninvasive method of measuring lead at various bone
sites. Both L-line radiographic fluorescence (L-XRF)
and K-line radiographic fluorescence (K-XRF) have
been used to measure lead at tibial and forefinger sites,
representative of cortical bone, and patellar and
calcaneus sites, representative of trabecular bone; most
experience to date is with measurements at the midshaft
of the tibia. The L-XRF technique uses energy of low

342

INDIAN J MED RES, OCTOBER 2008

penetrating power and measures lead primarily in the

outer 0.5 mm of bone. This measurement correlates well
with the results of the calcium EDTA mobilization test.
On the other hand, K-XRF, which uses higher intensity
energy (derived from radioisotopes such as57cobalt or
109
cadmium), measures the concentration of lead
throughout the bone thickness 69. The radiographic
fluorescence techniques have been used successfully
for epidemiological studies of lead exposure, as an index
of cumulative exposure in occupationally exposed
patients, as a measure of success of lead removal by
chelation in lead-intoxicated children, and as a way to
verify remote lead exposure in patients with suspected
chronic lead nephropathy. By means of the K-XRF test,
it was established that the mean tibia lead was 20.8 g/g
bone mineral in 719 participants in the Boston, MA
Normative Aging Study80. These men had environmental
but not occupational exposure to lead. Mean tibia bone
lead in Korean lead workers was 37.2 g/g81.

is the inducible 10 kD erythrocyte lead-binding protein

found in lead workers, which appears once blood lead
exceeds 39 g/dl83 and seems to bind lead in a non toxic
form. A subset of workers who are incapable of
responding to lead exposure by mounting a response in
the 10 kD lead-binding protein demonstrated evidence
of toxicity at low blood lead levels 84 . A similar
phenomenon has been described in the genotypic
polymorphism of ALAD. The ALAD gene contains two
codominant alleles: ALAD-1 and ALAD-2. ALAD-1 is
the predominant allele. Workers who are heterozygous
or homozygous for ALAD-2 have blood lead values
higher than those of similarly exposed workers who are
homozygous for ALAD-185. The difference apparently
results from the greater propensity for ALAD-2 to bind
lead in a non toxic form. Less bone lead, urinary deltaaminolevulinic acid, zinc protoporphyrin, and DMSAchelatable lead (all markers of lead accumulation or
toxicity) are found in ALAD-2 patients85.

Measurement of enzymes in the blood that are

sensitive to lead, have also been used to follow both acute
and remote lead intoxication. Fontanellas et al from
Spain 82 explored the use of the ratio of deltaaminolevulinic acid dehydratase (ALAD) to restored
ALAD (restored by adding zinc and dithiothreitol to
blood) in a number of patients with chronic renal failure
at a pre-dialysis stage, dividing them into two groups
after the EDTA mobilization test had determined whether
lead pools were expanded. The study included 24 healthy
controls, 12 patients with clinical plumbism and
biochemical demonstration of lead poisoning, 18 patients
with chronic renal failure with no evidence of high lead
storage, and 8 patients with chronic renal failure with
high urinary excretion of lead (greater than 600 g/ 72 h
after calcium EDTA). The ALAD/restored ALAD ratio
correlated closely with urinary lead excretion. It was
normal in healthy controls, and in the chronic renal failure
patients without excessive urinary lead but was
significantly reduced in the patients with clinical
plumbism and in the chronic renal failure patients with
increased excretion of lead in their urine. It should be
noted, however, that this study was carried out in Spain
at a time when the mean blood lead value was 18 g/dl.

Clinical manifestations of lead intoxication

Susceptibility to lead intoxication

There has been considerable interest in determining
the factors that dictate individual susceptibility to lead.
Lead in whole blood resides primarily in the erythrocyte
(99%), wherein it is bound primarily to a 240 kD protein,
identified as the enzyme, ALAD. An additional factor

In the early 20th century, there were several reports

of industrially related progressive renal failure from lead
poisoning. Initial reports were scanty, suggesting the
possibility that improved working conditions and
medical surveillance might have aborted the
development of significant renal disease. However, a
1968 study of 102 industrially exposed workers in
Romania demonstrated that 17 had evidence of renal
impairment when tested by discrete renal function tests
such as creatinine clearance or urea clearance86. A
subsequent epidemiological survey of American lead
workers revealed that after adjustment for the effect of
age, there was a direct correlation of both serum
creatinine and blood urea nitrogen (BUN) with the
length of lead exposure 87. Another survey of American
lead workers in 1979 found that GFR, as measured by
iothalamate-125 clearances, was reduced in 21 of 57
lead workers in whom excessive body lead burdens had
been shown by the urinary excretion of more than 1,000
g lead per day during a calcium EDTA lead
mobilization test71. A Swedish study of five lead workers
with different periods of lead exposure revealed that
despite an abnormal GFR in only one of five, all had
abnormal renal biopsies. Proximal tubule nuclear lead
inclusion bodies were found in the biopsies of two
workers who had less than one years exposure to lead,
whereas the biopsies of the three subjects with
exposures of four to more than 12 years did not contain
these inclusions, but showed varying degrees of diffuse
interstitial or peritubular fibrosis88.

GONICK: Cd & Pb NEPHROTOXICITY

The presence of lead-induced renal disease may

relate to the severity of the body burden of lead. A 1992
survey of 70 active and 30 retired Swedish lead smelter
workers found no evidence of renal abnormalities, as
measured by plasma creatinine, creatinine clearance,
2-microglobulin clearance, urinary albumin, or urinary
excretion of the enzyme NAG, compared with a control
cohort. The mean blood lead values in these workers
had gradually diminished from 63 to 34 g/dl from 1950
to 1987 as controls over lead exposure improved89.
Although the relationship between body burden of lead
and development of chronic lead nephropathy has not
been defined strictly, a World Health Organization Task
Group concluded that prolonged lead exposure with
blood lead levels greater than 70 g/dl can result in
chronic irreversible nephropathy90. Studies of low lead
exposure in industry (blood lead consistently below
60g/dl) have failed to show convincing evidence of
nephropathy91. However, an epidemiologic survey of a
Belgian population with known environmental exposure
to both lead and cadmium (blood lead range 1.7 to 72.5
g/dl, geometric mean 11.4 g/dl) revealed an inverse
correlation between blood lead and creatinine clearance
after adjustment for age and body mass index. A tenfold increase in blood lead was associated with a
creatinine clearance reduction of 10 to 13 ml/min92.
Similar findings were reported by Payton et al in the
Normative Aging study of Boston veterans93, where the
mean blood lead level was 8.1 g/dl. In children, the
generally accepted blood lead value which signifies a
potential hazard is 10 g/dl. Values above this level are
reportable94. The lower limit of blood lead, below which
no toxicity is observed, has not been established.
In addition to occupation-related disease, two
unusual forms of lead nephropathy have been described
in adults, one related to remote childhood lead exposure
and the other to illicit moonshine whiskey ingestion. In
both situations, there has been a high incidence of
saturnine gout. Evidence indicates that a large
proportion of the cases of chronic renal failure in adults
in Queensland, Australia, was attributable to childhood
lead poisoning95. There was an unusually high incidence
of acute lead poisoning in children around the beginning
of the 20th century related to ingestion of large quantities
of lead-based paint, deposited as flakes in the dirt
surrounding the verandas of their homes. Twenty or
more years later, many of these children developed
chronic renal failure, with granular contracted kidneys.
Lead was confirmed as the cause when the bone lead
content of these patients with cryptogenic kidney

343

disease was found to be significantly greater than in

other patients with chronic nephropathy of recognized
cause. Subsequent studies used calcium EDTA to
mobilize lead from bone96. Urinary lead excretion after
1 g calcium EDTA invariably exceeded 600 g/day in
patients with renal insufficiency attributable to
childhood lead poisoning, whereas lead excretion was
below this figure in normal controls and in the majority
of patients with renal insufficiency resulting from causes
other than lead.
Although the Queensland experience seems
incontrovertible, attempts to confirm that childhood
plumbism leads to adult renal insufficiency in other parts
of the world have been unsuccessful; the difference may
lie in the degree of childhood lead exposure or factors
influencing the subsequent mobilization of lead from
bone. Indeed, in a 50-year follow up of childhood
plumbism in the United States, studies comparing 21
lead-exposed subjects with age-, sex-, race-, and
neighbourhood-matched controls revealed supernormal
creatinine clearance in the lead exposed subjects, who
also had a higher risk of hypertension97. On the other
hand, a longitudinal study of low level lead exposure,
determined by repetitive blood lead measurements in
459 men during the Normative Aging Study, found that
blood lead concentration was significantly and
positively associated with serum creatinine
concentration; a ten-fold increase in blood lead
predicted an increase of 0.08 mg/dl in serum creatinine.
Furthermore, there was an acceleration of age-related
changes in renal function in association with long-term
low lead exposure98.
A chronic lead nephropathy remarkably similar to
the Queensland variety has been described in moonshine
whiskey drinkers in the southern United States99. The
renal pathological findings were similar to those seen
in the Queensland cases, and intranuclear inclusion
bodies were found commonly. A diagnostic infusion of
calcium EDTA provided confirmatory evidence of
excessive lead storage in these subjects. In addition to
the high incidence of hyperuricaemia and gout
mentioned earlier, these patients also have unusually
high rates of salt wasting, acidosis and hyperkalaemia.
These findings may be attributable to hyporeninemic
hypoaldosteronism, subsequent to lead intoxication, as
well as to inhibition of distal tubular Na-K-ATPase100.
The incidence of lead related end-stage renal failure
in the general adult population is unknown, although
attempts to estimate the incidence have been made

344

INDIAN J MED RES, OCTOBER 2008

through measurements of bone lead in patients on

dialysis. In one study, lead and lead: calcium ratios were
measured in trans- iliac bone biopsies obtained from
153 patients on dialysis from units in several European
countries70. Elevated bone lead was found in 5 per cent
of the patients on haemodialysis, approximating levels
found in active workers (20 g/g in the patients on
dialysis, 30 g/g in Belgian lead workers, and 6 g/g in
normal subjects). Bone lead concentrations in patients
with analgesic nephropathy receiving dialysis were
comparable to control measurements in deceased
subjects who had normal renal function, indicating that
neither end-stage renal failure nor dialysis treatment
contributes to the total body burden of lead. What
remains unclear is whether the 5 per cent incidence of
elevated bone lead in the patients on dialysis represents
a 5 per cent incidence of lead-induced chronic renal
failure or whether 5 per cent of patients on dialysis had
increased exposure to and thus retention of lead, with
the lead either playing no role or contributing to
progressive renal failure initiated by other causes.
Relationship to gout
Covert lead poisoning may be responsible for
sporadic cases of pre-end-stage renal failure gouty or
hypertensive nephrosclerosis. In separate studies
conducted in the United States 101 , Germany and
Australia102, and Italy103, higher urinary lead excretion
after calcium EDTA mobilization was seen in patients
with gout and moderate degrees of renal failure than in
patients with no gout but comparable degrees of renal
impairment. Elevated urinary lead was less common in
patients who had gout before renal failure than in those
who presented with renal failure before gout. Another
study from Spain of 297 subjects (30 normal controls,
105 patients with essential hypertension, 132 patients
with chronic renal failure and hypertension or gout, and
30 patients with chronic renal failure of known cause)
revealed that groups II and III had abnormal calcium
EDTA tests (15.4% in group II and 56.1% in group
III)104.
From a functional standpoint, lead nephropathy
often is accompanied by hyperuricaemia and reduced
renal excretion of urate, sometimes in association with
overt gouty arthritis. The pyrazinamide suppression test
initially demonstrated that this constellation of findings
is caused by an enhanced tubular reabsorption of urate
rather than by reduced secretion 105 . However,
subsequent studies revealed that urate handling by the
kidney was a four-component system, namely filtration,

pre-secretory reabsorption, secretion, and post-secretory

reabsorption106. In clinical gout there is diminished
secretion of uric acid107; most likely this occurs in lead
nephropathy accompanied by hyperuricaemia as well.
Lin et al108 have demonstrated that gouty patients are
more likely to have high normal lead excretion after
calcium EDTA infusions compared to normals without
gout and that such infusions in patients with gout
increase urate excretion and lower serum uric acid,
further confirming the relationship between gout and
lead intoxication.
Diagnosis of lead nephropathy
The clinical characteristics of lead nephropathy are
listed in Table II. Unlike in most other renal diseases,
proteinuria is absent or minimal and the urinary
sediment is benign. The presence of renal disease is
recognized primarily by abnormalities in overall renal
function (i.e., elevated BUN or serum creatinine
concentration and decreased urea or creatinine
clearances). Detection improves when discrete renal
function tests are used, such as inulin (or iodothalamate125 or chromium-51 EDTA) clearance measurements
of GFR or p-aminohippurate (PAH) clearance
measurements of renal blood flow. As indicated earlier99,
lead nephropathy resulting from ingestion of moonshine
whiskey also can show a greater propensity toward salt
wasting, acidosis, and hyperkalaemia than other renal
diseases with a comparable degree of renal failure.
Expression of elements of proximal tubule dysfunction
is seen primarily in children who have had acute highlevel lead poisoning 109 . Overt manifestations of
proximal tubular dysfunction are rare in adults with lead
nephropathy, although one study demonstrated a
Table II. Clinical and pathologic abnormalities of lead nephropathy
Reduced glomerular filtration rate
Reduced renal blood flow
Absent or minimal proteinuria
Normal urine sediment
Variable hypertension
Hyperuricaemia, low urate clearance, and gout common
Acidosis and hyperkalaemia sometimes seen
Increased urinary excretion of the enzymes NAG, GST and 1microglobulin
Proximal tubular dysfunction seen only in acutely intoxicated
children
Interstitial nephritis and proximal tubular nuclear inclusion bodies
on renal biopsy

GONICK: Cd & Pb NEPHROTOXICITY

reduced glucose reabsorption capacity, but normal

bicarbonate reabsorption capacity and normal PAH
reabsorption capacity in four occupationally exposed
workers with minimally reduced GFR110.
Attempts to develop markers of renal dysfunction
in patients with early lead nephropathy (e.g., in the
industrial setting) have met with variable success. Not
only is albuminuria absent in early stages of renal
disease, but 2-microglobulinuria, which has proved to
be a very useful marker of cadmium nephrotoxicity, also
is absent in lead-induced renal disease. The urinary
excretion of certain renal tubular lysosomal enzymes,
such as NAG and lysozyme, has been found to be
elevated in some lead workers 111. A collaborative
European study examined more than 20 potential
indicators of renal changes in 50 workers exposed to
lead (with average blood lead 48 g/dl) and found that
the most outstanding effect was a lowered urinary
excretion of the eicosanoid 6-keto-PGF1, and enhanced
excretion of thromboxane (TXB2)112. In another study
of 81 exposed workers with a mean blood lead of 42
g/dl, enhanced 6-keto-PGF1, and TXB2 excretion was
found, together with enhanced intestinal alkaline
phosphatase, brush border antigen (BBA) and
prostaglandin PGF2 and PGE2 excretion, together with
decreased fibronectin excretion113. The authors claim
that glomerular injury is heralded by the alterations in
6-keto-PGF1, TX B2, and fibronectin, proximal tubular
injury by intestinal alkaline phosphatase and BBA, and
collecting tubule or medullary interstitial cell injury by
PGF2 and PGE2.
In animal studies only glutathione-S-transferase
(GST) and 1-microglobulin seemed to be appropriate
urinary markers. NAG, which has been most extensively
investigated in humans, appears to be upregulated early
rather than a response to tubular injury, increasing in
low lead treated animals despite an absence of
pathological changes on ultrastructural study (vide
infra). Beta2-microglobulin, and possibly retinol binding
protein, which are low molecular weight proteins
reabsorbed by the proximal tubule, appeared to be
elevated only with high levels of blood lead (> 80 g/
dl)114. None of these markers are specific for lead.
Pathology of lead nephropathy
The gross pathologic finding of chronic lead
nephropathy is that of a granular contracted kidney.
Tubular atrophy and dilatation with interstitial fibrosis,
but minimal cellular infiltration, typically are seen.
Glomeruli become sclerotic secondary to blood flow

345

impairment, but there is no evidence of a primary

glomerulonephritis of immune pathogenesis. Vascular
lesions, with intimal proliferation and hyaline
degeneration of the media, may be prominent95,115. The
eosinophilic proximal tubular nuclear inclusion body,
once thought to be pathognomonic of lead nephropathy,
is present only during the early years of lead exposure.
Thus, the diagnosis of lead nephropathy usually is
inferential, based primarily on a history of lead
exposure, evidence of renal impairment by functional
testing, and renal biopsy disclosure of a non
immunologically mediated interstitial nephritis.
Sanchez-Fructuoso et al116 evaluated pathological
changes as well as the response of ALAD activity before
and after calcium EDTA treatment in rats fed 500 ppm
lead acetate for 90 days. In the lead-treated animals the
main findings were hypertrophy and vacuolization of
medium and small arteries, mucoid oedema and muscular
hypertrophy in arterioles, loss of cell brush borders, cell
loss, and intranuclear inclusion bodies in the proximal
tubule, and fibrosis and the presence of infiltrates in the
interstitial component. Treatment with calcium EDTA
slowed the progression of most alterations and resulted
in a diminution in nuclear inclusion bodies. ALAD
activity was reduced in the lead exposed rats but was
restored in the rats treated with calcium EDTA.
Animal studies
An experimental model of lead nephropathy has
helped to elucidate the effects of lead on the function
and ultrastructure of renal proximal tubule lining cells.
Moore and colleagues117,118 were principally responsible
for defining the role of renal proximal tubular nuclear
inclusion bodies (a lead-protein complex) in the
response to lead intoxication. The main component of
the protein in the inclusion body has an approximate
molecular weight of 27 kD118 or 32 kD119, that is rich in
glutamate and aspartate and contained about 40 to 50
g lead per milligram of protein. Isolated mitochondrial
preparations from these animals have been
demonstrated to have impaired oxidative and
phosphorylative abilities compared with mitochondria
from control rats. When lead-poisoned rats were treated
with EDTA, the nuclear inclusion bodies were disrupted
and removed from the nuclei concomitant with an
increased urinary lead excretion 120. Kidney cytosol has
been shown to contain 3 lead-binding protein fractions11.5, 63, and >200 kD121. Only the 11.5 kD fraction
was capable of reversing lead-induced ALAD inhibition
in liver homogenates122.

346

INDIAN J MED RES, OCTOBER 2008

Our laboratory has developed long-term models of

both low and high lead nephropathy in male SpragueDawley rats fed a low calcium diet123- 125. Lead acetate
was used in concentrations of 0.5 per cent (high dose)
and 0.01 per cent (low dose) in drinking water for
periods from 1 to 12 months and lead-exposed animals
were compared to pair-fed control rats. In all studies
GFR was measured as125I-iothalamate clearance by a
single injection technique. Urinary markers included
NAG, GST, and brush border antigens (BB50,HF5, and
CG9) and were expressed as units/ g creatinine. Blood
and urine lead were measured prior to sacrifice in each
group of animals. Kidneys were processed for light,
electron and immunofluorescent microscopy. Animals
treated with continuous high dose lead for 12 months
reached a maximum blood lead of 125.4 10.1 g/dl
after 6 months, at which time the dose of lead was
reduced from 0.5 to 0.1 per cent123. Blood lead at the
end of 12 months averaged 55 g/dl. Urine lead
remained above 100 g/ g creatinine at all times but
was highest at 3 months, averaging 340 g/ g creatinine.
In the lead-treated animals, GFR was increased above
controls at 3 months (1.00 0.14 vs 0.83 0.26 ml/
min/ 100 g body wt, P=0.05), then declined after 6
months to 0.78 0.16 vs 0.96 0.08 ml/min/100 g body
wt in controls. With regard to urinary markers, both
NAG and GST were elevated above control values after
3 months of lead exposure. No significant differences
were observed in brush border antigens. Pathology
examination revealed that proximal tubular nuclear
inclusion bodies were present at all time periods in leadtreated animals. Enlargement of proximal tubular cells
and nuclei were seen beginning at 3 months. At
6 months, focal tubular atrophy and interstitial fibrosis
appeared, increasing in extent up to 12 months.
Mitochondrial alterations, consisting of rounding and
elongation, appeared by 1 month and were persistent.
Glomeruli were normal through 9 months, but at
12 months showed focal and segmental sclerosis. There
were no electron dense deposits and immunofluorescent
studies were negative. Renal arteries and arterioles were
normal at all times.
In the second study124 the course of events was
examined over 12 months in continuous low level leadexposed animals. Maximum blood lead levels in
experimental animals were reached at three months,
averaging 29.4 4.1 g/dl. GFR was found to be
significantly increased above pair-fed controls at 1 and
3 months, but was normal at other time periods (1 month
experimental, 1.18 0.12 vs control, 0.76 0.15 ml/

min/100 g; P<0.001; 3 month experimental, 1.12 0.16

, vs control, 0.86 0.10 ml/min/100 g.; P<0.001). Levels
of urinary NAG exceeded levels found in controls at
essentially all time periods, whereas urinary GST, a
more specific marker of metal-associated proximal
tubular injury, was normal. Proximal tubular nuclear
inclusion bodies were sparse and were observed only
at 1 and 3 months. There were no other pathological
alterations in the kidneys up to 12 months, when mild
tubular atrophy and interstitial fibrosis were seen. The
absence of changes in urinary GST accorded with the
relative absence of morphological changes, whereas the
observed increase in urinary NAG suggests that this
enzyme may be an overly sensitive indicator of tubular
injury, more probably reflecting upregulation of the
enzyme in the absence of tubular injury. It should be
noted that both low dose lead-treated and high dose leadtreated animals showed a hyperfiltration phenomenon
during the first 3 months of lead exposure. Thus these
studies join those in humans81,97,126 which indicate that
lead nephropathy should be added to diabetic
nephropathy as diseases which may lead to
hyperfiltration early in the course.
A third study125 consisted of discontinuation of both
high and low dose lead after 6 months, then treatment
with 3 courses of DMSA or discontinuation of high dose
lead alone after 1, 6 and 9 months of lead feeding in
rats. Controls were pair-fed, exposed to lead for six
months, then removed from exposure for six months
without receiving the DMSA. Low dose lead-treated
rats showed no significant pathological changes with
or without DMSA treatment but exhibited a significant
increase in GFR after DMSA (1.09 0.19 vs 0.88
0.22 ml/min/100 g body weight; P<0.03). Urinary
markers remained unchanged, and there were no
structural alterations by light or electron microscopy.
High dose lead-treated animals showed no functional
or pathological changes when lead exposure was
discontinued after one month. However, when duration
of exposure was six or nine months, GFR was decreased
and serum creatinine and urea nitrogen were increased
as compared to controls. Tubulointerstitial disease was
severe. Administration of DMSA resulted in an
improvement in GFR and a decrease in albuminuria,
together with a reduction in size and number of nuclear
inclusion bodies in proximal tubules. However,
tubulointerstitial scarring was only minimally reduced.
Treatment with the chelator, DMSA, improved renal
function, but had less effect on pathological alterations.
As GFR improved after DMSA treatment in both low

GONICK: Cd & Pb NEPHROTOXICITY

dose and high dose lead-treated animals, irrespective

of the degree of pathological alterations, it may be
concluded that the DMSA effect is most likely mediated
by haemodynamic changes.
Pathogenesis
As with other heavy metals, lead administration
leads to accumulation of reactive oxygen species, and
treatment with scavengers results in lowering of blood
pressure and improvement in GFR. A sequence of
reactive oxygen species can be demonstrated in leadinduced disease, i.e., an increase in superoxide radical,
hydroxyl radical, hydrogen peroxide, and peroxynitrite,
together with a diminution in GSH in liver, brain, and
aorta. Nitric oxide is most commonly decreased (by
reactive oxygen species) as is urinary cyclic GMP.
Aortic guanylate cyclase is decreased. The enzyme
responsible for an increase in the production of free
radicals, NAD(P)H oxidase, is increased by lead,
whereas eNOS and iNOS, the enzymes involved in
production of nitric oxide, are also increased, attesting
to the importance of free radical destruction of nitric
oxide rather than decreased formation. Antioxidants
reverse these changes and diminish blood pressure.
Various antioxidants have been used in conjunction with
chelators, to both remove lead from tissue and to
diminish free radicals127. N-acetyl cysteine, taurine,
lipoic acid, arginine, vitamin C, vitamin E, thiamine,
tempol, and lazaroids all improve free radical
diminution128.
Captopril, an angiotensin-converting enzyme
inhibitor, acts as an antioxidant in lead-exposed rats129.
In one study lead acetate was given in water for six
weeks; captopril-administered animals received
captopril (10 mg/day) during the sixth week. Blood lead
in the control group measured 0.8 g/dl, in the lead
treated group 24.6 20 g/dl, in the lead plus captopril
group 23.8 1.6 g/dl. MDA concentrations (a measure
of reactive oxygen species) in liver, brain and kidney
were increased by lead administration and reduced to
or towards normal by lead plus captopril treatment.
Fox et al130 explored the effect of lead exposure in
vivo on adult rat retinal and kidney Na-K-ATPase. Pups,
exposed to lead through the milk of dams consuming
zero, 0.02 or 0.2 per cent lead solutions, had mean blood
lead concentrations of 1.2, 18.8, and 59.4 g/dl at
weaning, respectively, and 5-7 g/dl as 90-100 day old
adults. Prior lead exposure produced significant dose
dependent decreases in isolated retinal Na-K-ATPase
activity whereas activity in the kidney was unchanged

347

(? effect of lead-binding proteins). In contrast, Na-KATPase from both isolated control tissues was inhibited
by lead in vitro. The half-maximal inhibitory dose of
lead for retinal and renal Na-K-ATPase was 5.21 x 10-7
and 1.25 x 10-5 M, respectively. Kramer et al131 had also
explored the half-maximal inhibitory dose for lead
chloride on renal cortical homogenate Na-K-ATPase.
This was found to be 7 x 10-5 M. There was a competitive
inhibition by lead with regard to the substrate, ATP.
Treatment
Acute lead intoxication without renal involvement
or lead nephropathy ordinarily is treated with EDTA
chelation. Although sodium EDTA has been shown to
have toxic propensities because of its calcium chelation
properties, calcium EDTA in appropriate dosages is
useful and relatively harmless. The usual
recommendation is for a course of 5 to 7 consecutive
days in a dosage of 50 mg/kg/day or less, and an
administration rate of 20 mg/min or less. A common
practice is to use 1.0 g calcium EDTA in 250 ml normal
saline, delivered intravenously over 2 h. No adverse
side effects have been reported with this technique. A
small number of cases of acute tubular necrosis have
been described with sodium or calcium EDTA therapy,
related mainly to very large dosages, rapid
administration, or severe pre-existing renal or metabolic
disease (e.g., hypercalcaemia and multiple myeloma).
Trace metal depletion, although of theoretical concern,
has not yet been shown to be clinically important,
although zinc excretion is known to be markedly
elevated by calcium EDTA. Advanced renal disease
related to lead intoxication (GFR less than 50% of
normal) must be treated cautiously, because EDTA is
filtered by the glomerulus, much as inulin is. In such
instances, the dosage and infusion rate of EDTA should
be reduced in proportion to the serum creatinine
elevation. Lead nephropathy should be treated
energetically, however, because treatment may stabilize
or improve renal function.
Penicillamine can be used as an oral chelating agent,
but only when the worker has been totally removed from
a lead environment, because this agent can enhance
gastrointestinal absorption of ingested lead132. It is less
effective as a chelator than calcium EDTA, and, with
prolonged administration, can produce renal toxicity
(nephrotic syndrome), leukopoenia, and anaemia. Two
new oral chelating agents, dimercaptopropane
sulphonate (DMPS) and DMSA, water-soluble
derivatives of BAL, have been shown to be effective

348

INDIAN J MED RES, OCTOBER 2008

lead chelators in experimental animals133. DMSA has

been approved for treating children with lead
intoxication134 and is effective in lead workers135.
Conclusions
Both cadmium and lead are nephrotoxic and can
lead to progressive renal failure. While cadmium
toxicity presents as a generalized disorder of proximal
tubular function, including increased uric acid clearance
and hypouricaemia, lead toxicity (except in children)
is commonly accompanied by hyperuricaemia and/or
gout. Markers for early renal disease reflect these
differences. Cadmium nephrotoxicity is heralded by
increased excretion of 2-microglobulin, retinol binding
protein and 1-microglobulin, indicative of decreased
proximal tubule function. Beta2-microglobulinuria is
not found in lead nephropathy, while NAG and GST,
indicative of tubular injury, are seen in both cadmium
nephropathy and lead nephropathy. In lead nephropathy
there is minimal albuminuria, whereas albuminuria in
cadmium nephropathy is variable. From the standpoint
of pathology, both entities are characterized by
tubulointerstitial disease and fibrosis, but only lead
nephropathy is associated with proximal tubular nuclear
inclusion bodies. In humans, these disappear early in
the course, thereby removing this characteristic feature.
References
1.

Adams RG, Harrison JF, Scott P. The development of cadmiuminduced proteinuria, impaired renal function, and osteomalacia
in alkaline battery workers. Q J Med 1969; 38 : 425-43.

9.

Bernard A, Buchet JP, Roels H, Masson P, Lauwerys R. Renal

excretion of proteins and enzymes in workers exposed to
cadmium. Eur J Clin Invest 1979; 9 : 11-22.

10. Bernard A, Goret A, Roels H, Buchet JP, Lauwerys R.

Experimental confirmation in rats of the mixed type proteinuria
observed in workers exposed to cadmium. Toxicology 1978;
10 : 369-75.
11. Kido T, Honda R, Yamada Y, Tsuritani I, Ishizaki M, Nogawa
K. Alpha 1 microglobulin determination in urine for the early
detection of renal tubular dysfunctions caused by exposure to
cadmium. Toxicol Lett 1985; 24 :195-201.
12. Chen L, Jin T, Huang B, Nordberg G, Nordberg M. Critical
exposure level of cadmium for elevated urinary
metallothionein-An occupational population study in China.
Toxicol Appl Pharmacol 2006; 215 : 93-9.
13. Alfven A, Jarup L, Elinder C-G. Cadmium and lead in blood
in relation to low bone mineral density and tubular proteinuria.
Environ Health Perspect 2002; 110 : 699-702.
14. Nomiyama K, Nomiyama H, Kameda N. Plasma cadmiummetallothionein, a biological exposure index for cadmiuminduced renal dysfunction, based on the mechanism of its
action. Toxicology 1998; 129 : 157-68.
15. Jarup L, Rogenfelt A, Elinder CG, Nogawa K, Kjellstrom T.
Biological half-time of cadmium in the blood of workers after
cessation of exposure. Scand J Work Environ Health 1983; 9
: 327-31.
16. Baecklund M, Pedersom NL, Bjorkman L, Vahter M.
Variations in blood concentrations of cadmium and lead in
the elderly. Environ Res 1999; 80 : 222-30.
17. Bernard A, Thielemans N, Roels H, Lauwerys R. Association
between NAG-B and cadmium in urine with no evidence of a
threshold. Occup Environ Med 1995; 52 : 177-80.
18. Roels H, Bernard AM, Cardenas A, Buchet JP, Lauwerys RR,
Hotter G, et al. Markers of early renal changes induced by
industrial pollutants. III. Application to workers exposed to
cadmium. Br J Ind Med 1993; 50 : 37-48.

2.

Kazantzis G, Flynn FV, Spowage JS, Trott DG. Renal tubular

malfunction and pulmonary emphysema in cadmium pigment
workers. Q J Med 1963; 32 : 165-92.

3.

Friberg L. Cadmium and the kidney. Environ Health Perspect

1984; 54 : 1-11.

4.

Gonick HC. Trace metals and the kidney. Miner Electrolyte

Metab 1978; 1 : 107-20.

5.

Nikic D, Stojanovic D, Stankovic A. Cadmium in urine of

children and adults from industrial area. Cent Eur J Public
Health 2005; 13 : 149-52.

20. Sundberg A, Appelkvist E-L, Dallner G, Nilsson R. Glutathione

transferases in the urine: sensitive methods for detection of
kidney damage induced by nephrotoxic agents in humans.
Environ Health Perspect 1994; 102 (Suppl 3) : 293-6.

6.

Bachelet M, Pinot F, Polla RI, Francois D, Richard MJ,

Vayssier-Taussat M, et al. Toxicity of cadmium in tobacco
smoke: protection by antioxidants and chelating resins. Free
Radic Res 2002; 36 : 99-106.

21. Stajn A, Zikic RV, Ognjavonic B, Saicic ZS, Pavlovic SZ, Kostic
MM, et al. Effect of cadmium and selenium on the antioxidant
defense system in rat kidneys. Comp Biochem Physiol C
Pharmacol Toxicol Endocrinol 1997; 117 : 167-72.

7.

Landsberger S, Larson S, Wu D. Determination of airborne

cadmium in environmental tobacco smoke by industrial
neutron activation analysis with a Compton suppression
system. Anal Chem 1993; 65 : 1506-9.

22. Roels H, Bernard A, Buchet JP, Goret A, Lauwerys R, Chettle

DR, et al. Critical concentration of cadmium in renal cortex
and urine. Lancet 1979; 1 : 221.

8.

Bernard AM, Lauwerys RR. Dose-reponse relations between

urinary cadmium and tubular proteinuria in adult workers. Am
J Ind Med 1997; 31 : 116-8.

19. Taylot SA, Chivers ID, Price RG, Arce-Thomas M, Milligan

P, Francini I, et al. The assessment of biomarkers to detect
nephrotoxicity using an integrated database. Environ Res 1997;
75 : 23-33.

23. Ellis KJ, Morgan WD, Zanzi I, Yasumura S,Vartsky D, Cohn

SH. In vivo measurement of critical level of kidney cadmium:
dose effect studies in cadmium smelter workers. Am J Ind
Med 1980; 1 : 339-48.

GONICK: Cd & Pb NEPHROTOXICITY

24. Lauwerys R, Bernard A, Cardenas A. Monitoring of early
nephrotoxic effects of industrial chemicals. Toxicol Lett 1992;
64-65 Spec No: 33-42.
25. Balaraman R, Gulati OD, Bhatt JD, Rathod SP, Hemavathi
KG. Cadmium-induced hypertension in rats. Pharmacology
1989; 38 : 226-34.
26. Whittemore AS,Diciccio Y, Provenzano G. Urinary cadmium
and blood pressure: results from the NHANES II survey.
Environ Health Perspect 1991; 91 : 133-40.
27. Nakagawa H, Nishijo M, Morikawa Y, Miura K, Tawara K,
Kuriwaki J, et al. Urinary cadmium and mortality among
inhabitants of a cadmium-polluted area in Japan. Environ Res
2006; 100 : 323-9.
28. Effects of cadmium on human health. A review of studies
mainly performed in Japan. Japan Public Health Association.
1976. p. 1-23.
29. Indraprasit S, Alexander GV, Gonick HC. Tissue composition
of major and trace elements in uremia and hypertension.
Autopsy studies in man. J Chron Dis 1974; 27 : 135-61.
30. Nogawa K, Tsuritani I, Kido T, Honda R, Yamada Y, Ishizaki
M. Mechanism for bone disease found in inhabitants
environmentally exposed to cadmium: decreased serum 1
alpha, 25-hydroxyvitamin D level. Int Arch Occup Environ
Health 1987; 59 : 21-30.
31. Noda M, Kitagawa M. A quantitative study of iliac bone
histopathology on 62 cases with itai-itai disease. Calcif Tissue
Int 1990; 47 : 66-74.
32. Staessen J, Lauwerys R. Health effects of environmental
exposure to cadmium in a population study. J Hum Hypertens
1993; 7 : 195-9.
33. Aoyagi T, Hayakawa K, Miyaji K, Ishikawa H, Hata M.
Cadmium nephrotoxicity and evacuation from the body in a
rat modeled subchronic intoxication. Int J Urol 2003; 10 :
332-8.
34. Stowe H, Wilson M, Goyer RA. Clinical and morphological
effects of of oral cadmium toxicity in rabbits. Arch Pathol
1972; 94 : 389-405.
35. Horiguchi H, Sato M, Konno N, Fukushima M. Long-term
cadmium exposure induces anemia in rats through
hypoinduction of erythropoietin in the kidneys. Arch Toxicol
1996; 71 : 11-9.
36. Shaikh ZA, Smith JC. The mechanisms of hepatic and renal
metallothionein biosynthesis in cadmium-exposed rats. Chem
Biol Interact 1977; 19 : 161-71.
37. Maitani T, Cuppage FE, Klaassen CD. Nephrotoxicity of
intravenously injected cadmium-metallothionein: critical
concentration and tolerance. Fundam Appl Toxicol 1988; 10 :
98-108.
38. Dorian C, Klaassen CD. Protection by zinc-metallothionein
(ZnMT) against cadmium-metallothionein-induced
nephropathy. Fundam Appl Toxicol 1995; 26 : 99-106.
39. Sato M, Kondoh M. Recent studies on metallothionein:
protection against toxicity of heavy metals and oxygen free
radicals. Tohoku J Exp Med 2002; 196 : 9-22.

349

40. Liu J, Liu Y, Habeebu SS, Klaassen CD. Susceptibility of MTnull mice to chronic CdCl2-induced nephrotoxicity indicates
that renal injury is not mediated by the CdMT complex. Toxicol
Sci 1998; 46 : 197-203.
41. Liu Y, Liu J, Habeebu SM, Waalkes MP, Klaassen CD.
Metallothionein-I/II null mice are sensitive to chronic oral
cadmium-induced nephrotoxicity. Toxicol Sci 2000; 57 : 167-76.
42. Gonick HC, Indraprasit S, Rosen VJ, Neustein H, Van de Velde
R, Raghavan SRV. Experimental Fanconi syndrome. III. Effect
of cadmium on renal tubular function, the ATP-Na-K-ATPase
transport system and renal tubular ultrastructure. Miner
Electrolyte Metab 1980; 3 : 21-35.
43. Raghavan SRV, Gonick HC. Experimental Fanconi syndrome.
IV. Effects of repetitive injections of cadmium on tissue
distribution and protein-binding of cadmium. Miner
Electrolyte Metab 1980; 3 : 36-43.
44. Gonick HC, Kramer HJ. Pathogenesis of the Fanconi
syndrome. In: Gonick HC, Buckalew VM, editors. Renal
tubular disorders. Pathophysiology, diagnosis, and
management. New York : Marcel Dekker, Inc.; 1985. p. 55869.
45. Zelazowski AJ, Piotrowski JK. A modified procedure for
determination of metallothionein-like proteins in animal
tissues. Acta Biochim Pol 1972; 24 : 419-25.
46. Thevenod F. Nephrotoxicity and the proximal tubule. Insights
from cadmium. Nephron Physiol 2003; 93 : 87-93.
47. Thevenod F, Friedmann JM. Cadmium-mediated oxidative
stress in kidney proximal tubule cells induces degradation of
Na+/K+-ATPase through proteasomal and endo-/lysosomal
proteolytic pathways. FASEB J 1999; 13 : 1751-61.
48. Morales AI, Vicente-Sanchez C, Jerkic M, Santiago JM,
Sanchez-Gonzales PD, Perez-Barriocanal F, et al. Effect of
quercetin on metallothionein, nitric oxide synthases and
cyclooxygenase-2 expression on experimental chronic
cadmium nephrotoxicity in rats. Toxicol Appl Pharmacol 2006;
210 : 128-35.
49. Morales AI, Vicente-Sanchez C, Sandoval JM, Egido J,
Mayoral P, Arevalo MA, et al. Protective effect of quercetin
on experimental chronic cadmium nephrotoxicity in rats is
based on its antioxidant properties. Food Chem Toxicol 2006;
44 : 2092-100.
50. Joshi BC, Dwivedi C, Powell A, Holscher M. Immune complex
nephritis in rats induced by long-term oral exposure to
cadmium. J Comp Pathol 1981; 91 : 11-5.
51. Bernard A, Lauwerys R, Gengoux P, Mahieu P, Foidart JM,
Druet P, et al. Anti-laminin antibodies in Sprague-Dawley and
brown Norway rats chronically exposed to cadmium.
Toxicology 1984; 31 : 307-13.
52. Blanusa M, Kostial K, Restek-Samarzija N, Piasek M, Jones
MM, Singh PK. Mobilization of cadmium by meso- and
racemic-2,3-dimrcaptosuccinic acid (DMSA) in rats.
Pharmacol Toxicol 2000; 87 : 179-81.
53. Blaha K, Nerudova J, Jehlicova H, Cikrt M, Jones MM, Singh
PK. In vivo and in vitro efficacy of a new carbodithioate for
the mobilization of cadmium. J Toxicol Environ Health 1995;
44 : 87-100.

350

INDIAN J MED RES, OCTOBER 2008

54. Waters RS, Bryden NA, Patterson KY, Veillon C, Anderson

RA. EDTA chelation effects on urinary losses of cadmium,
calcium, chromium, cobalt, copper, lead, magnesium, and zinc.
Biol Trace Elem Res 2001; 63 : 207-21.
55. Patrick L. Lead toxicity, a review of the literature. Part I:
Exposure, evaluation, and treatment. Altern Med Rev 2006;
11 : 2-22.
56. Pirkle JL, Brody DJ, Gunter EW, Kramer RA, Paschal DC,
Flegal KM, et al. The decline in blood lead levels in the United
States. The National Health and Nutrition Examination
Surveys (NHANES). JAMA 1994; 272 : 284-91.
57. Muntner P, Menke A, DeSalvo KB, Rabito FA, Batuman V.
Continued decline in blood lead levels among adults in the
United States: the National Health and Nutrition Examination
Surveys. Arch Intern Med 2005; 165 : 2155-61.
58. Kaiser R, Henderson AK, Daley WR, Naughton M, Khan MH,
Rahman M, et al. Blood lead levels of primary school children
in Dhaka, Bangladesh. Environ Health Perspect 2001; 109 :
563-6.
59. Nichani V, Li WI, Smith MA, Noonan G, Kulkarni M, Kodavor
M, et al. Blood lead levels in children after phase-out of leaded
gasoline in Bombay, India. Sci Total Environ 2006; 363 :
95-106.
60. Clark CS, Rampal KG, Thuppil V, Chen CK, Clark R, Roda
S. The lead content of currently available new residential paint
in several Asian countries. Environ Res 2006; 102 : 9-12.
61. Saper RB, Kales SN, Paquin J, Burns MJ, Eisenberg DM,
Davis RB, et al. Heavy metal content of ayurvedic herbal
medicine products. JAMA 2004; 292 : 2868-73.
62. Medlin J. Sweet candy, bitter poison. Environ Health Perspect
2004; 1112 : A803.
63. Silverberg M, Chu J, Nelson L. Elevated blood lead levels in
urban moonshine drinkers. Ann Emerg Med 2001; 38 : 460-1.
64. Abudhaise BA, Alzoubi MA, Rabi AZ, Alwash RM. Lead
exposure in indoor firing ranges: environmental impact and
health risk to the range users. Int J Occup Med Environ Health
1996; 9 : 323-9.
65. Centers for Disease Control and Prevention. Lead poisoning
associated with use of litargirio - Rhode Island, 2003. MMWR
Morb Mortal Wkly Rep 2005; 54 : 227-9.
66. al-Hazzaa SA, Krahn PM. Kohl: a hazardous eyeliner.
Int Ophthalmol 1995; 19 : 83-8.
67. Rabinowitz MB,Wetherill GW, Kopple JD. Kinetic analysis
of lead metabolism in healthy humans. J Clin Invest 1976;
58 : 260-70.
68. Barry PS. A comparison of concentrations of lead in human
tissues. Br J Ind Med 1975; 32 : 119-39.
69. Gerhardsson L, Attewell R, Chettle DR, Englyst V, Lundstrom
NG, Nordberg GF, et al. In vivo measurements of lead in bone
in long-term exposed lead smelter workers. Arch Environ
Health 1993; 48 : 147-56.
70. Van de Vyver FL, DHaese PC, Visser WJ, Elseviers MM,
Knippenberg LJ, Lamberts LV, et al. Bone lead in dialysis
patients. Kidney Int 1988; 33 : 601-7.

71. Wedeen RP, Malik DK, Batuman V. Detection and treatment

of occupational lead nephropathy. Arch Intern Med 1979;
139 : 53-7.
72. Schwartz BS, Lee BK, Stewart W, Sithisarankul P, Strickland
PT, Ahn KD, et al. Delta-aminolevulinic acid dehydratase
genotype modifies four hour urinary lead excretion after oral
administration of dimercaptosuccinic acid. Occup Environ
Health 1997; 54 : 241-6.
73. Emmerson BT. Chronic lead nephropathy: The diagnostic use
of calcium EDTA and the association with gout. Australas
Ann Med 1963; 12 : 310-24.
74. Lin JL, Lim PS. Elevated lead burden in Chinese patients
without occupational lead exposure. Miner Electrolyte Metab
1992; 18 : 1-5.
75. Batuman V, Landy E, Maesaka JK, Wedeen RP. Contribution
of lead to hypertension with renal impairment. N Engl J Med
1983; 309 : 17-21.
76. Lin JL, Lin-Tan DT, Yu CC, Li YJ, Huang YY, Li KL.
Environmental exposure to lead and progressive diabetic
nephropathy in patients with type II diabetes. Kidney Int 2006;
69 : 2049-56.
77. Lin JL, Lin-Tan DT, Hsu KH, Yu CC. Environmental lead
exposure and progression of chronic renal disease in patients
without diabetes. N Engl J Med 2003; 348 : 277-86.
78. Lin JL, Ho HH, Yu CC. Chelation therapy for patients with
elevated body lead burden and progressive renal insufficiency.
A randomized, controlled trial. Ann Intern Med 1999; 130 :
7-15.
79. Lin JL, Lin-Tan DT, LI, YJ, Chen KH, Huang YL. Low-level
environmental exposure to lead and progressive chronic kidney
diseases. Am J Med 2006; 119 : 707-23.
80. Hu H, Payton M, Korrick S, Aro A, Sparrow D, Weiss ST, et
al. Determinants of bone and blood lead levels among
community-exposed middle-aged to elderly men. The
Normative Aging Study. Am J Epidemiol 1996; 144 : 749-59.
81. Weaver VM, Lee BK, Ahn KD, Lee GS, Todd AC, Stewart
WF, et al. Associations of lead biomarkers with renal function
in Korean lead workers. Occup Environ Med 2003; 60 :
551-62.
82. Fontanellas A, Navarro S, Moran-Jimenez MJ, SanchezFructuoso AI, Veigh I, Barrientos A, et al. Erythrocyte
aminolevulinate dehydratase activity as a lead marker in
patients with chronic renal failure. Am J Kidney Dis 2002;
40 : 43-50.
83. Lolin Y, OGorman P. An intra-erythrocytic low molecular
weight lead-binding protein in acute and chronic lead exposure
and its possible role in lead toxicity. Ann Clin Biochem 1988;
25 : 688-97.
84. Raghavan SR, Culver BD, Gonick HC. Erythrocyte leadbinding protein after occupational exposure. I. Relationship
to lead toxicity. Environ Res 1980; 22 : 264-70.
85. Scinicariello F, Murray HE, Moffett DB, Abadin HG, Sexton
MJ, Fowler BA. Lead and delta-aminolevulinic acid
dehydratase polymorphism: where does it lead? A metaanalysis. Environ Health Perspect 2007; 115 : 35-41.

GONICK: Cd & Pb NEPHROTOXICITY

86. Lilis R, Gavrilescu N, Nestorescu B, Dumitriu C, Roventa A.
Nephropathy in chronic lead poisoning. Br J Ind Med 1968;
25 : 196-202.
87. Lilis R, Valciukas J, Fischbein A, Andrews G, Selikoff IJ,
Blumberg W. Renal function impairment in secondary lead
smelter workers; correlation with zinc protoporphyrin
and blood lead levels. J Environ Pathol Toxicol 1979; 2 :
1447-74.
88. Cramer K, Goyer RA, Jagenburg R, Wilson MH. Renal
ultrastructure, renal function, and parameters of lead toxicity
in workers with different periods of lead exposure. Br J Ind
Med. 1974; 31 : 113-27.
89. Gerhardsson L, Chettle DR, Englyst V, Nordberg GF, Nyhlin
H, Scott MC, et al. Kidney effects in long term exposed lead
smelter workers. Br J Ind Med 1992; 49 : 186-92.
90.

Recommended health-based limits in occupational exposure

to heavy metals. Reports of a WHO study group. World Health
Organ Tech Rep Ser 1980; 647 : 1-116.

351

chronic renal failure-a comparative German and Australia

study. Sci Total Environ 1987; 66 : 17-28.
103. Colleoni N, DAmico G. Chronic lead accumulation as a
possible cause of renal failure in gouty patients. Nephron
1986; 44 : 32-5.
104. Sanchez-Fructuoso AI, Torralbo A, Arroyo M, Luque M,
Ruilope LM, Santos JL, et al. Occult lead intoxication as a
cause of hypertension and renal failure. Nephrol Dial
Transplant 1996; 11 : 1775-80.
105. Emmerson BT, Mirosch W, Douglas JB. The relative
contribution of tubular reabsorption and secretion to urate
excretion in lead nephropathy. Aust N Z J Med 1971; 1 : 35362.
106. Levinson DJ, Sorensen LB. Renal handling of uric acid in
normal and gouty subjects: evidence for a 4-component
system. Ann Rheum Dis 1980; 39 : 173-9.
107. Puig JG, Mateos F, Munoz F, Gaspar G, Ramos T, Gijon Banos
J. Renal handling of uric acid in gout by means of the
pyrazinamide and probenecid tests. Adv Exp Med Biol 1984;
165 : 201-3.

91.

Omae K, Sakurai H, Higashi T, Muto T, Ichikawa M, Sasaki

N. No adverse effects of lead on renal function in lead-exposed
workers. Ind Health 1990; 28 : 77-83.

92.

Staessen J. Low-level lead exposure, renal function and blood

pressure. Verh K Acad Geneeskd Belg 1995; 57 : 527-74.

108. Lin JL, Yu CC, Lin-Tan DT, Ho HH. Lead chelation therapy
and urate excretion in patients with chronic renal disease and
gout. Kidney Int 2001; 60 : 266-71.

93.

Payton M, Hu H, Sparrow D, Weiss ST. Low-level lead

exposure and renal function in the Normative Aging Study.
Am J Epidemiol 1994; 140 : 821-9.

109. Loghman-Adham M. Aminoaciduria and glycosuria following

severe childhood lead poisoning. Pediatr Nephrol 1998; 12 :
218-21.

94.

Center for Disease Control and Prevention (CDC) Advisory

Committee on Childhood Lead Poisoning Prevention,
Interpreting and managing blood lead levels < 10 microg/dL
in children and reducing childhood exposure to lead:
recommendations of CDCs Advisory Committee on
Childhood Lead Poisoning Prevention. MMWR Recomm Rep
2007; 56 : 1-16.

110. Hong CD, Hanenson IB, Lerner S, Hammond PB, Pesce AJ,
Pollak VE. Occupational exposure to lead: effects on renal
function. Kidney Int 1980; 18 : 489-94.

95.

Inglis JA, Henderson DA, Emmerson BT. The pathology and

pathogenesis of chronic lead nephropathy occurring in
Queensland. J Pathol 1978; 124 : 65-76.

96.

Emmerson BT, Thiele BR. Calcium versenate in the diagnosis

of chronic lead nephropathy. Med J Aust 1960; 47 : 243-8.

97.

Hu H. A 50-year follow-up of childhood plumbism.

Hypertension, renal function, and hemoglobin levels among
survivors. Am J Dis Child 1991; 145 : 681-7.

98.

Kim R, Rotnitsky A, Sparrow D, Weiss S, Wager C, Hu H. A

longitudinal study of low-level lead exposure and impairment
of renal function. The Normative Aging Study. JAMA 1996;
275 : 1177-81.

99.

Morgan JM, Hartley MW, Miller RE. Nephropathy in chronic

lead poisoning. Arch Int Med 1966; 118 : 17-29.

100. Morgan JM. Hyperkalemia and acidosis in lead nephropathy.

South Med J 1976; 69 : 881-3,6.
101. Batuman V, Maesaka JK, Haddad B, Tepper E, Landy E,
Wedeen RP. The role of lead in gout nephropathy. N Engl J
Med 1981; 304 : 520-3.
102. Craswell PW, Price J, Boyle PD, Behringer D, Stoeppler M,
Ritz E. Patterns of lead excretion in patients with gout and

111. Pergande M, Jung K, Precht S, Fels LM, Herbort C, Stolte

H. Changed excretion of urinary proteins and enzymes by
chronic exposure to lead. Nephrol Dial Transplant 1994; 9 :
613-8.
112. Cardenas A, Roels H, Bernard AM, Barbon R, Buchet JP,
Lauwerys RR, et al. Markers of early renal changes induced
by industrial pollutants. II. Application to workers exposed
to lead. Br J Ind Med 1993; 50 : 28-36.
113. Fels LM, Herbort C, Pergande M, Jung K, Hotter G, Rosello
J, et al. Nephron target sites in chronic exposure to lead.
Nephrol Dial Transplant 1994; 9 : 1740-6.
114. Vyskocil A, Fiala Z, Salandova J, Popler A, Ettlerova E,
Emminger S. The urinary excretion of specific proteins in
workers exposed to lead. Arch Toxicol 1991; 14 : 218-21.
115. Albaharry C, Richet G, Guillaume J, Morel-Maroger L. The
kidney in occupational lead poisoning. Arch Mal Prof 1965;
26 : 5-19.
116. Sanchez-Fructuoso AI, Blanco J, Cano M, Ortega L, Arroyo
M, Fernandez C, et al. Experimental lead nephropathy:
treatment with calcium disodium ehylenediaminetetraacetate.
Am J Kidney Dis 2002; 40 : 59-67.
117. Moore JF, Goyer RA, Wilson M. Lead-induced inclusion
bodies. Solubility, amino acid content and relationship to
residual acidic nuclear proteins. Lab Invest 1973; 29 :
488-94.

352

INDIAN J MED RES, OCTOBER 2008

118. Moore JF, Goyer RA. Lead-induced inclusion bodies:

composition and probable role in lead metabolism. Environ
Health Perspect 1974; 7 : 121-7.

127. Gurer H, Ercal N. Can antioxidants be beneficial in the

treatment of lead poisoning? Free Radic Biol Med 2000; 29 :
927-45.

119. Shelton KR, Egle PM. The proteins of lead-induced intranuclear

inclusion bodies. J Biol Chem 1982; 257 : 11802-7.

128. Tandon SK, Singh S, Prasad S, Srivastava S, Siddiqui MK.

Reversal of lead-induced oxidative stress by chelating agent,
antioxidant, or their combination. Environ Res 2002; 90 :
61-6.

120. Goyer RA, Wilson MH. Lead-induced inclusion bodies: result

of ethylenediaminetetraacetic acid treatment. Lab Invest 1975;
32 : 149-56.
121. Mistry P, Lucier GW, Fowler BA. High-affinity lead-binding
proteins in rat kidney cytosol mediate cell-free nuclear
translocation of lead. J Pharmacol Exp Ther 1985; 232 : 462-9.
122. Goering PL, Fowler BA. Regulation of lead inhibition of
delta-aminolevulinic acid dehydratase by a low molecular
weight, high affinity renal lead-binding protein. J Pharmacol
Exp Ther 1984; 231 : 66-71.
123. Khalil-Manesh F, Gonick HC, Cohen AH, Alinovi R,
Bergamaschi E, Mutti A, et al. Experimental model of lead
nephropathy. I. Continuous high-dose lead administration.
Kidney Int 1992; 41 : 1192-203.
124. Khalil-Manesh F, Gonick HC, Cohen AH. Experimental
model of lead nephropathy. III. Continuous low-level lead
administration. Arch Environ Health 1993; 48 : 271-8.

129. Gurer H, Neal R, Yang P, Oztezcan S, Ercal N, Captopril as

an antioxidant in lead-exposed Fischer 344 rats. Hum Exp
Toxicol 1999; 18 : 27-32.
130. Fox DA, Rubinstein SD, Hsu P. Developmental lead exposure
inhibits adult rat retinal, but not kidney, Na+, K(+)-ATPase.
Toxicol Appl Pharmacol 1991; 109 : 482-93.
131. Kramer HJ, Gonick HC, Lu E. In vitro inhibition of Na-KATPase by trace metals: relation to renal and cardiovascular
damage. Nephron 1986; 44 : 329-36.
132. Jugo S, Maljkovic T, Kostial K. Influence of chelating agents
on the gastrointestinal absorption of lead. Toxicol Appl
Pharmacol 1975; 34 : 259-63.
133. Aposhian HV. DMSA and DMPS-water soluble antidotes for
heavy metal poisoning. Annu Rev Pharmacol Toxicol 1983;
23 : 193-215.

125. Khalil-Manesh F, Gonick HC, Cohen A, Bergamaschi E,

Mutti A. Experimental model of lead nephropathy. II. Effect
of removal from lead exposure and chelation treatment with
dimercaptosuccinic acid (DMSA). Environ Res 1992; 58 :
35-54.

134. Chisolm JJ Jr. Safety and efficacy of meso-2,3dimercaptosuccinic acid (DMSA) in children with elevated
blood lead concentrations. J Toxicol Clin Toxicol 2000; 38 :
365-75.

126. Roels H, Lauwerys R, Konings J, Buchet JP, Bernard A, Green

S, et al. Renal function and hyperfiltration capacity in lead
smelter workers with high bone lead. Occup Environ Med
1994; 51 : 505-12.

135. Restek-Samarzija N, Blanusa M, Pizent A, Samarzija M, Turk

R, Corovic N, et al. Meso-2,3- dimercaptosuccinic acid in
the treatment of occupationally exposed lead workers. Arh
Hig Rada Toksikol 1998; 49 : 137-45.

Reprint requests: Dr Harvey C. Gonick, Research Service 151, West Los Angeles Healthcare Center, 11301 Wilshire Blvd
Los Angeles, CA, 90073, USA
e-mail: hgonick@ucla.edu