Cadmium - Toxicology of Metals - page 452

is found. In reports subsequent to that of Friberg
(1950), impaired pulmonary function was also noted
in Cd workers (Lauwerys et al ., 1974; Sakurai et al .,
1982; Smith et al ., 1976). In a survey of 16,024 sub-
jects selected from the general American popula-
tion, a negative correlation was identifi ed between
pulmonary function and urinary Cd levels, and Cd
exposure was implicated in the exacerbation of pul-
monary disorders associated with cigarette smoking
(Mannino et al ., 2004).

the level of Cd not bound to MT increases in the renal
cells and injures the renal tubules because of its marked
toxicity (Figure 2; Nordberg, 1984). Accordingly, the
equilibrium between MT-bound and MT-unbound Cd
in the kidney is believed to be a determinant of the
development of renal damage. When renal damage is
manifest, MT excretion in the urine is increased (Nord-
berg M., 1998, Nordberg and Nordberg, 2000). Approx-
imately 30-40% of the total Cd, as well as total Cu, was
found to be bound to MT in the urine of Itai-Itai disease
patients. It is very common that the levels of urinary
MT and Cu (as well as Cd, but not Zn) exhibit a sig-
nifi cantly statistical relationship; the same is true for
B2-MG (Mitane et al ., 1986).
That renal injury induced by Cd exposure is an
extremely distinctive disorder was proven from a sur-
vey of 12,559 inhabitants of a Cd-polluted region and
6435 inhabitants of a non-Cd-polluted region in Japan.
In that investigation, suspected proximal tubular dys-
function (based on the fi nding of one or more of the fol-
lowing items—urinary

7.2.3 Kidney Damage

The critical organ in Cd poisoning is the kidney. After
Friberg's report (1950) describing how the proteinuria
was found in Cd workers comprised mainly of low-
molecular-weight proteins, numerous studies have
demonstrated that Cd-induced renal damage is charac-
terized by proximal tubular reabsorptive dysfunction.
The earliest manifestations of Cd-induced renal dam-
age are increased urinary excretion of low-molecular-
weight proteins, in particular β 2 -microglobulin ( β 2 -mg) β 2 -mg ≥ 10 mg/L; RBP ≥ 4 mg/L;

and α 1 -microglobulin (a 1 -mg), also called protein HC.

The amount of

lysozyme ≥ 2 mg/L—as well as glucose ≥ 100 mg/L and

β 2 -mg excreted into the urine in subjects
with Cd-induced renal damage is proportional to the
severity of damage. In severe tubular damage occur-
ring, for example, in cases of Itai-Itai disease levels of
100,000

generalized aminoaciduria 20 mmol/L) was detec-

ted in 333 of the inhabitants of the Cd-polluted region,
in contrast to only a single inhabitant of the Cd-unpol-
luted region; in addition, defi nite proximal tubular
dysfunction (%TRP < 80% and arterial blood bicarbo-
nate < 23 mEq/L in the subjects with suspected proxi-
mal tubular dysfunction) was detected in 202 of the
inhabitants of the Cd-polluted region and in none of
the inhabitants of the non-Cd-polluted region (Shige-
matsu, 1989). The appearance of kidney stones occurs
more frequently in Cd workers; this situation has been
attributed to the increased urinary calcium excretion
associated with tubular dysfunction (Elinder et al .,
1985b). It has also been suggested that exposure to
occupational and relatively low environmental levels
of Cd is a determinant for the development of end-
stage renal disease (Hellstrom et al ., 2001).
Epidemiological evidence is available on an increased
susceptibility of diabetics to the development of Cd-
induced renal dysfunction on Cd exposure (Akesson
et al ., 2005; Buchet et al ., 1990). Recent epidemiological
studies have demonstrated an increased prevalence of
tubular dysfunction related to Cd levels in the urine
of type II diabetics. Persons exhibiting increased lev-
els of serum antibodies against MT had increased risks
of tubular proteinuria at similar levels of Cd in their
urine (Chen et al ., 2006c). Data from animal experi-
ments support the possibility of an increased suscepti-
bility for Cd nephropathy in diabetics. Streptozotocin
(STZ)-induced diabetes in animals is similar to insu-
lin-dependent diabetes or type I diabetes in humans.
An increased resistance to CdMT nephrotoxicity was

≥

g/g creatinine may be found. The urinary
excretion of the enzymes N -acetyl-

µ

-D-glucosamidase
(NAG) and lysozyme also increases. Severe Cd-induced
renal damage results also in depressed glomerular
function, with rises in the levels of serum creatinine
and serum

β

β 2 -mg, and culminates in uremia in some
cases. The amount of

β 2 -mg excreted into the urine has
been found to correlate closely to the creatinine clear-
ance, percent TRP, and the arterial blood bicarbonate;
it is recognized as an excellent marker of Cd-induced
renal damage (Aoshima et al ., 1988a). Glomerular dys-
function has also been described as an early infl uence
because of the fi nding of increased albuminuria after
mild Cd exposure (Bernard et al ., 1976; 1979; Lauwerys
et al ., 1974). In Cd workers, Cd-induced renal injury
is irreversible, with progressive deterioration occur-
ring even after cessation of Cd exposure (Elinder et al .,
1985a; Roels at al ., 1982; 1989; 1997). In investigations of
inhabitants of Cd-polluted areas in Japan, irreversible
injury was noted to occur when β 2 -mg urinary excre-

tion exceeded 1000 g/g CR (Cai et al ., 2001; Iwata

et al ., 1993; Kido et al ., 1988). Decreased arterial blood
pH and elevated serum creatinine have been reported
to persist even after cessation of Cd exposure (Kido
et al ., 1990a). Metallothionein, which transports Cd in
the blood, has been implicated in the mechanism by
which Cd induces tubular damage. When Cd accumu-
lation in the kidney is excessive (Nordberg et al ., 1975),

µ