Toxicology Letters, 6 1 (1992) 205-2 12 0 1992 Elsevier Science Publishers B.V. All rights reserved
TOXLET
205 0378-42741921s
5.00
02733
The renal handling of sodium and potassium in environmental cadmium-exposed subjects with renal dysfunction
Teruhiko Kido”, Koji Nogawa”, Masayoshi Ohmichi”, Ryumon Hondab, Ikiko Tsuritanib, Masao Ishizakib and Yuichi Yamadab “Department of Hygiene, Chiba University School of Medicine, Cllibu und hDepurtment of Hygiene, KanrrruwuMedical Universit~~.Ishikuwu I Jupan) (Received
19 December
(Accepted
19 February
Key ww&; Sodium;
1991) 1992)
Potassium:
Renal handling:
Cadmium:
Renal dysfunction
SUMMARY To clarify
using clearance
environmental
cadmium
methods
(Cd)-induced
the renal handling
of sodium
renal dysfunction,
76 Cd-exposed
and potassium subjects
in a population
with
(32 men and 44 women)
and 36 non-exposed subjects (18 men and 18 women) were selected. Fractional excretions of potassium and µglobulin were higher in the Cd-exposed subjects than in the non-exposed subjects. while the fractional excretion urinary
excretion
exposed
subjects,
of sodium
in the Cd-exposed
rate of sodium
subjects
was significantly
while no significant
difference
was equal to that of the non-exposed lower
was found
in the Cd-exposed in the urinary
tional excretion of sodium showed a significant correlation potassium significantly correlated with serum /I?-microglobulin. fractional
excretion
of sodium
or potassium
or potassium in Cd-induced renal tubular affected by Cd-induced renal dysfunction,
do not directly
subjects
potassium
subjects.
than
The
in the non-
excretion
rate. Frac-
with age in all the subjects, while that of These results indicate that increases in the signify increased
urinary
excretion
of sodium
dysfunction. The fractional excretion of potassium may be more while that of sodium appears to be more related to age.
INTRODUCTION
Exposure to environmental cadmium (Cd) initially causes renal tubular dysfunction [1,2]. Low-molecular-weight proteins in the urine, e.g., µglobulin (j??-
Correspondence to: T. Kido, Department
of Hygiene,
Chiba
University
School of Medicine,
Chiba,
Japan
206
MG), a,-microglobulin, and metallothionein are useful markers of this renal dysfunction [224]. Exposure to Cd also causes decreased renal glomerular filtration [2,5], and Cd-induced renal dysfunction is aggravated even after cessation of Cd exposure [6,7], progressing in some cases to renal failure or uremia [7,8]. Itai-itai disease is the most severe stage of environmental exposure to Cd and it is accompanied by renal and bone damage [9]. In itai-itai disease patients and inhabitants in the Cd-polluted area in which this disease is endemic, it is reported that the fractional excretions of sodium and potassium increase in proportion to the degree of renal dysfunction [lo. 1 11. It is also reported that mortality rates due to all causes, specifically cerebrovascular disease, of the inhabitants in the Cd-polluted area are lower than those of a non-exposed area [12]. This is thought to be attributable to an increase in urinary sodium excretion because renal tubular dysfunction may cause decreased reabsorption of sodium in the renal tubuli. However, little information is available on the relationship between electrolytes such as sodium and potassium and Cd-induced renal disorder. In the present study, the renal handling of sodium and potassium in inhabitants with renal dysfunction in a Cd-polluted area other than the area in which itai-itai disease is endemic is assessed using clearance methods. MATERIALS
AND
METHODS
Target population The subjects in this study consisted of 32 men and 44 women, all of whom were over 50 years of age and lived in the Cd-polluted Kakehashi River basin in Ishikawa Prefecture. They all showed Cd-induced renal tubular dysfunction and were officially recognized as ‘subjects requiring observation’ by the Research Committee organized by the Prefectural Health Authority [13]. Cd compounds were transported by the Kakehashi River from a mine upstream to rice fields where river water was used for irrigation. As non-Cd-exposed subjects, 18 men and 18 women over 50 years of age living in a non-Cd-polluted area were selected. They presented for an annual routine health checkup.
Analysis of blood and urine In the morning, urine specimens were obtained for clearance methods 2 h after the subjects drank approximately 300 ml of water. Blood specimens were drawn at the midpoint of the collection period. Serum sodium (S-Na) and potassium (S-K) were determined by electrode methods. Urinary sodium (U-Na) and potassium (U-K) were measured by flame atomic absorption spectrometry. The &MG levels in serum and urine were analyzed by the Phadebas B2-microtest (Pharmacia, Sweden). Creatinine concentrations in serum and urine were determined by Jaffe’s method [14]. Phosphorus levels in serum and urine were analyzed by Taussky’s method using a kit (P-Test Wako, Wako Inc., Japan) and Allen’s method [ 151, respectively. Fractional excretion of sodium (FENa), filtered load of sodium (F-Na), urinary excretion rate of sodium
207
(E-Na), and tubular reabsorption the formula [16]:
rate of sodium (R-Na) were estimated according to
FENa (%) = C* CCr x 100 (%) = SUZ,x x”;C; x 100 where UV = urinary volume (ml/min); F-Na (mEq/min) = S-Na x CCr; E-Na (mEq/ min) = UV x U-Na; R-Na (mEq/min) = F-Na - E-Na. Both poassium and P,-MG were also estimated according to the same method used for sodium. It should be noted that the tubular reabsorption rate of potassium is less than the real reabsorption rate since potassium is secreted at the distal tubule, and this secretion value is included in the urinary excretion rate in this calculation.
I
TABLE RESULTS
OF SERUM
AND URINARY
ANALYSIS
IN Cd-EXPOSED
AND NON-EXPOSED
SUB-
JECTS Cd-exposed
subjects
Men
Women
Men 4
11
40
7
59.0 k 2.8
58.8 k 1.5
56.4 f 5.5
75.9 k 5.4
14.1 +_ 5.8
73.1 f 5.0
139.6
I .o**
140.6
1.0
1.0**
141.6
l.O**
K (mEq/l)
140.3 4.25
Creatinine
(mgi100 ml)
136.1 135.8
9 9 56.0 f 4.7 71.8 k 3.3
1.0
136.5
1.0
1.0
138.0
1.19
4.16
I .08
3.94
1.0 1.11
1.09’
3.90
1.08
3.91 1510
1.06 1.2
1950
1.2
1.13
4.18
2065
1.10 1.2’
4.13 2371
2.1
1618
3006
1.3**
2710
1.5**
1919
4.15 @s/l)
Women
4
Serum Na (mEq/l)
B,-MG
subjects
28
Number Age”
Non-exposed
1.3 1.4
1.25
1.12+
1.14
1.72
I .03
1.22
0.72
1.09
1.45
1.24**
1.19
1.38**
1.03
1.16
0.80
1.13
6
5.0
Urine
t%-MG Olgiw.)
1472
Cd @gig.cr.)
6918 10.16 8.87
Upper
values: subjects
14.0** 5.9** 2.05** 1.60**
4295
11.4**
10914 10.30 11.69
5.5** 2.05** 1.68**
aged under 65 years; lower values: subjects
60 1.60 2.38
30 306
3.7 1.58 1.72
aged 65 years or over.
a Arithmetic ‘Difference
mean and SD. Others are expressed as geometric mean and geometric (PcO.1) between Cd-exposed and non-exposed subjwts,
*Significant *%ignificant
difference (P c 0.05) between Cd-exposed difference (P < 0.01) between Cd-exposed
and non-exposed and non-exposed
subjects. subjects.
SD.
6.3
4.08
3.7 1.44
5.70
1.39
208
TABLE
II
RESULTS
OF PARAMETERS
OF RENAL
CLEARANCE
IN Cd-EXPOSED
AND NON-EXPOSED
SUBJECTS Cd-exposed
subjects Women
Men Number
4 28
Cc,(ml/min) % TRP” Frcrctionul
cscwtion
subjects Women
Men 4 40
II 7
53.6 2 17.5’
47.9 I23.6’
87.1 -t 30.5
43.5 k 19.3**
40.9 + 14.5**
76.0 k 16.4
75.9 + 76.6 -t
79.9 k 8.9’ 76.8 -t 10.3**
85.6 k 80.8 i
0.8** 5.9
9 9 86.2 i
8.8 69.3 -t 16.9 86.9 i 5.1 X6.X I 4.2
5.1 6.2
(%)
FENa FEK
2.13
I .32**
1.89
1.35
0.91
1.5x
1.40
1.38
1.67
1.97
1.80
1.89
1.40
2.07
1.33
I .48**
9.16
I.41
II.56
1.19
I .49**
18.41 16.33
FEB,-MC Filterd
Non-exposed
I .32**
20.46
1.50
20.84
1.55
12.65
1.32
13.96
I.33
0.89
0.13**
2.05
0.1 I’
0.03
0.04
0.06
0.02
3.35
0.06**
4.81
0.05**
0.05
0.07
0.13
0.03
loud
F-Na (x10-’ mEq/min)
7129 5521
1.5I .6**
6053 5370
1.7 I .5**
11143 10093
1.5 1.3
11722 9290
I.1 I.3
F-K (x10-’ mEq/min)
217
1.5-
180
1.6-
340
I.5
338
I.’
F-/&-MC
163 IO’
I .6’* 0.00 I
157 102
1.5** 0.00 I
290 I32
I.3 0.001
263 I30
1.3 0.001
II8
0.002’
103
0.001*
143
tl.001
131
0.001
1.5
119.9
@g/mitt)
(irinuql~ cscretion
rcrtr
E-Na (x10-’ mEq/min) E-K (x10
’ mEq/min)
E-/&-MC ug/min)
155.2
1.3
113.0
I.4
157.0
1.6
76.0
2.1**
YO.8
1.7**
202.8
1.5
179.9
1.5
40.7
2.2
38.5
I .2
34.6
1.5
37.6
1.3
26.1 0.96
2.0 0.01 I **
‘8.1 2.21
1.5 0.010~
39.1 0.04
I.5 0.004
34.5 0.07
1.5 0.002
0.007**
4.27
0.005**
0.08
0.006
0.16
0.003
3.96 Tuhulur
rrtrhsorption
rut
TOXLET
205 0378-42741921s
5.00
02733
The renal handling of sodium and potassium in environmental cadmium-exposed subjects with renal dysfunction
Teruhiko Kido”, Koji Nogawa”, Masayoshi Ohmichi”, Ryumon Hondab, Ikiko Tsuritanib, Masao Ishizakib and Yuichi Yamadab “Department of Hygiene, Chiba University School of Medicine, Cllibu und hDepurtment of Hygiene, KanrrruwuMedical Universit~~.Ishikuwu I Jupan) (Received
19 December
(Accepted
19 February
Key ww&; Sodium;
1991) 1992)
Potassium:
Renal handling:
Cadmium:
Renal dysfunction
SUMMARY To clarify
using clearance
environmental
cadmium
methods
(Cd)-induced
the renal handling
of sodium
renal dysfunction,
76 Cd-exposed
and potassium subjects
in a population
with
(32 men and 44 women)
and 36 non-exposed subjects (18 men and 18 women) were selected. Fractional excretions of potassium and µglobulin were higher in the Cd-exposed subjects than in the non-exposed subjects. while the fractional excretion urinary
excretion
exposed
subjects,
of sodium
in the Cd-exposed
rate of sodium
subjects
was significantly
while no significant
difference
was equal to that of the non-exposed lower
was found
in the Cd-exposed in the urinary
tional excretion of sodium showed a significant correlation potassium significantly correlated with serum /I?-microglobulin. fractional
excretion
of sodium
or potassium
or potassium in Cd-induced renal tubular affected by Cd-induced renal dysfunction,
do not directly
subjects
potassium
subjects.
than
The
in the non-
excretion
rate. Frac-
with age in all the subjects, while that of These results indicate that increases in the signify increased
urinary
excretion
of sodium
dysfunction. The fractional excretion of potassium may be more while that of sodium appears to be more related to age.
INTRODUCTION
Exposure to environmental cadmium (Cd) initially causes renal tubular dysfunction [1,2]. Low-molecular-weight proteins in the urine, e.g., µglobulin (j??-
Correspondence to: T. Kido, Department
of Hygiene,
Chiba
University
School of Medicine,
Chiba,
Japan
206
MG), a,-microglobulin, and metallothionein are useful markers of this renal dysfunction [224]. Exposure to Cd also causes decreased renal glomerular filtration [2,5], and Cd-induced renal dysfunction is aggravated even after cessation of Cd exposure [6,7], progressing in some cases to renal failure or uremia [7,8]. Itai-itai disease is the most severe stage of environmental exposure to Cd and it is accompanied by renal and bone damage [9]. In itai-itai disease patients and inhabitants in the Cd-polluted area in which this disease is endemic, it is reported that the fractional excretions of sodium and potassium increase in proportion to the degree of renal dysfunction [lo. 1 11. It is also reported that mortality rates due to all causes, specifically cerebrovascular disease, of the inhabitants in the Cd-polluted area are lower than those of a non-exposed area [12]. This is thought to be attributable to an increase in urinary sodium excretion because renal tubular dysfunction may cause decreased reabsorption of sodium in the renal tubuli. However, little information is available on the relationship between electrolytes such as sodium and potassium and Cd-induced renal disorder. In the present study, the renal handling of sodium and potassium in inhabitants with renal dysfunction in a Cd-polluted area other than the area in which itai-itai disease is endemic is assessed using clearance methods. MATERIALS
AND
METHODS
Target population The subjects in this study consisted of 32 men and 44 women, all of whom were over 50 years of age and lived in the Cd-polluted Kakehashi River basin in Ishikawa Prefecture. They all showed Cd-induced renal tubular dysfunction and were officially recognized as ‘subjects requiring observation’ by the Research Committee organized by the Prefectural Health Authority [13]. Cd compounds were transported by the Kakehashi River from a mine upstream to rice fields where river water was used for irrigation. As non-Cd-exposed subjects, 18 men and 18 women over 50 years of age living in a non-Cd-polluted area were selected. They presented for an annual routine health checkup.
Analysis of blood and urine In the morning, urine specimens were obtained for clearance methods 2 h after the subjects drank approximately 300 ml of water. Blood specimens were drawn at the midpoint of the collection period. Serum sodium (S-Na) and potassium (S-K) were determined by electrode methods. Urinary sodium (U-Na) and potassium (U-K) were measured by flame atomic absorption spectrometry. The &MG levels in serum and urine were analyzed by the Phadebas B2-microtest (Pharmacia, Sweden). Creatinine concentrations in serum and urine were determined by Jaffe’s method [14]. Phosphorus levels in serum and urine were analyzed by Taussky’s method using a kit (P-Test Wako, Wako Inc., Japan) and Allen’s method [ 151, respectively. Fractional excretion of sodium (FENa), filtered load of sodium (F-Na), urinary excretion rate of sodium
207
(E-Na), and tubular reabsorption the formula [16]:
rate of sodium (R-Na) were estimated according to
FENa (%) = C* CCr x 100 (%) = SUZ,x x”;C; x 100 where UV = urinary volume (ml/min); F-Na (mEq/min) = S-Na x CCr; E-Na (mEq/ min) = UV x U-Na; R-Na (mEq/min) = F-Na - E-Na. Both poassium and P,-MG were also estimated according to the same method used for sodium. It should be noted that the tubular reabsorption rate of potassium is less than the real reabsorption rate since potassium is secreted at the distal tubule, and this secretion value is included in the urinary excretion rate in this calculation.
I
TABLE RESULTS
OF SERUM
AND URINARY
ANALYSIS
IN Cd-EXPOSED
AND NON-EXPOSED
SUB-
JECTS Cd-exposed
subjects
Men
Women
Men 4
11
40
7
59.0 k 2.8
58.8 k 1.5
56.4 f 5.5
75.9 k 5.4
14.1 +_ 5.8
73.1 f 5.0
139.6
I .o**
140.6
1.0
1.0**
141.6
l.O**
K (mEq/l)
140.3 4.25
Creatinine
(mgi100 ml)
136.1 135.8
9 9 56.0 f 4.7 71.8 k 3.3
1.0
136.5
1.0
1.0
138.0
1.19
4.16
I .08
3.94
1.0 1.11
1.09’
3.90
1.08
3.91 1510
1.06 1.2
1950
1.2
1.13
4.18
2065
1.10 1.2’
4.13 2371
2.1
1618
3006
1.3**
2710
1.5**
1919
4.15 @s/l)
Women
4
Serum Na (mEq/l)
B,-MG
subjects
28
Number Age”
Non-exposed
1.3 1.4
1.25
1.12+
1.14
1.72
I .03
1.22
0.72
1.09
1.45
1.24**
1.19
1.38**
1.03
1.16
0.80
1.13
6
5.0
Urine
t%-MG Olgiw.)
1472
Cd @gig.cr.)
6918 10.16 8.87
Upper
values: subjects
14.0** 5.9** 2.05** 1.60**
4295
11.4**
10914 10.30 11.69
5.5** 2.05** 1.68**
aged under 65 years; lower values: subjects
60 1.60 2.38
30 306
3.7 1.58 1.72
aged 65 years or over.
a Arithmetic ‘Difference
mean and SD. Others are expressed as geometric mean and geometric (PcO.1) between Cd-exposed and non-exposed subjwts,
*Significant *%ignificant
difference (P c 0.05) between Cd-exposed difference (P < 0.01) between Cd-exposed
and non-exposed and non-exposed
subjects. subjects.
SD.
6.3
4.08
3.7 1.44
5.70
1.39
208
TABLE
II
RESULTS
OF PARAMETERS
OF RENAL
CLEARANCE
IN Cd-EXPOSED
AND NON-EXPOSED
SUBJECTS Cd-exposed
subjects Women
Men Number
4 28
Cc,(ml/min) % TRP” Frcrctionul
cscwtion
subjects Women
Men 4 40
II 7
53.6 2 17.5’
47.9 I23.6’
87.1 -t 30.5
43.5 k 19.3**
40.9 + 14.5**
76.0 k 16.4
75.9 + 76.6 -t
79.9 k 8.9’ 76.8 -t 10.3**
85.6 k 80.8 i
0.8** 5.9
9 9 86.2 i
8.8 69.3 -t 16.9 86.9 i 5.1 X6.X I 4.2
5.1 6.2
(%)
FENa FEK
2.13
I .32**
1.89
1.35
0.91
1.5x
1.40
1.38
1.67
1.97
1.80
1.89
1.40
2.07
1.33
I .48**
9.16
I.41
II.56
1.19
I .49**
18.41 16.33
FEB,-MC Filterd
Non-exposed
I .32**
20.46
1.50
20.84
1.55
12.65
1.32
13.96
I.33
0.89
0.13**
2.05
0.1 I’
0.03
0.04
0.06
0.02
3.35
0.06**
4.81
0.05**
0.05
0.07
0.13
0.03
loud
F-Na (x10-’ mEq/min)
7129 5521
1.5I .6**
6053 5370
1.7 I .5**
11143 10093
1.5 1.3
11722 9290
I.1 I.3
F-K (x10-’ mEq/min)
217
1.5-
180
1.6-
340
I.5
338
I.’
F-/&-MC
163 IO’
I .6’* 0.00 I
157 102
1.5** 0.00 I
290 I32
I.3 0.001
263 I30
1.3 0.001
II8
0.002’
103
0.001*
143
tl.001
131
0.001
1.5
119.9
@g/mitt)
(irinuql~ cscretion
rcrtr
E-Na (x10-’ mEq/min) E-K (x10
’ mEq/min)
E-/&-MC ug/min)
155.2
1.3
113.0
I.4
157.0
1.6
76.0
2.1**
YO.8
1.7**
202.8
1.5
179.9
1.5
40.7
2.2
38.5
I .2
34.6
1.5
37.6
1.3
26.1 0.96
2.0 0.01 I **
‘8.1 2.21
1.5 0.010~
39.1 0.04
I.5 0.004
34.5 0.07
1.5 0.002
0.007**
4.27
0.005**
0.08
0.006
0.16
0.003
3.96 Tuhulur
rrtrhsorption
rut
