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Lead exposure and renal failure: Does renal insufficiency influence lead kinetics?
Toxicology
Letters,
121
9 (1981) 121-124
0 Elsevier/North-Holland
Biomedical
Press
LEAD EXPOSURE AND RENAL FAILURE: DOES RENAL INSUFFICIENCY INFLUENCE LEAD KINETICS? B.C. CAMPBELL,
H.L.
ELLIOTT
and P.A.
MEREDITH
University Department of Materia Medica, Stobhill General Hospital, Glasgow, G2I 3UW (U.K.) (Received
February
(Accepted
March
14th, 1981) 24th,
1981)
SUMMARY Blood and urine lead concentrations function.
Derived
impairment. evidence
Lead,
renal
lead clearance
however,
of nephrotoxicity
appeared
have been measured varied
widely,
to reduce
from sub-clinical
in 40 subjects
with normal
but was not influenced
its own clearance.
and impaired
by the degree
These findings
provide
renal
of renal additional
lead exposure.
INTRODUCTION
Lead exposure which is sufficiently severe to produce symptomatic lead poisoning causes renal damage. In a recent study of lead poisoning from an industrial source, 50% of patients had elevated serum urea and 30% had hyperuricaemia [l]. Acute poisoning produces a characteristic tubular defect [2], but chronic exposure results in a nephrosclerotic pattern with cortical atrophy [3]. Recently, chronic lead exposure has been suspected of causing renal damage even in the absence of overt symptoms of lead poisoning. Lilis et al. [4] in a study of secondary lead smelter workers, few of whom had a history of lead poisoning, established a correlation between impairment of renal function and blood lead and zinc protoporphyrin levels. This was dependent on duration of lead exposure. Campbell et al. [5], investigating potential health hazard from environmental lead contamination, found an association between raised blood lead and renal insufficiency in subjects who had never had symptoms of lead poisoning but who had been exposed to lead in drinking water for an average of over 20 years. Evidence of excessive lead exposure has also been found in association with hypertension and gout [6, 71, and it seems possible that it has a role in the etiology of these conditions through an effect on renal function. Renal impairment of any etiology might depress lead excretion, thus raising blood lead concentration and giving a spurious impression of excessive lead 0378.4274/81/0000-0000/$02.50
0 Elsevier/North-Holland
Biomedical
Press
122
exposure.
The present
renal function SUBJECTS
study was undertaken
on the kinetics
to investigate
the effects,
if any,
of
of lead.
AND METHODS
40 patients, 18 males, 22 females, aged 18-72 years were studied. 13 had normal renal function, with creatinine clearance > 100 ml/min and no history of renal disease. The remainder had established renal insufficiency; they were arbitrarily divided into the categories of mild, moderate and severe renal insufficiency on the basis of creatinine clearance (Table I). None of the patients was receiving regular dialysis at that time, but several of those with severe dysfunction have since been placed on a dialysis programme. Any form of renal disease was accepted but a history of lead exposure was an exclusion criterion. Blood lead concentration and 24-h unstimulated urinary lead output were measured by flameless atomic absorption spectophotometry using a Perkin Elmer HGA 72, with graphite cell power source [6]. Concentrations of lead in plasma are too small to permit direct measurement with any degree of accuracy on a small blood sample. It is accepted, however, that about 5% of total blood lead is in the plasma compartment [7]. This figure was used to determine renal lead clearance, by the conventional equation
where U = urinary lead concentration, I/ = urine volume, and P = plasma concentration. Analysis of the results was by analysis of variance.
lead
RESULTS
There was no significant difference in blood lead concentration among the 4 groups (Table I), However, 2 subjects with blood lead concentration above the accepted maximum normal (2 pmol/l) had marked renal impairment with creatinine clearance of 12 ml/min and 16 ml/min.
TABLE
I Creatinine
Group Normal Mild failure Moderate Severe
Number
13 9 8 10
clearance
24-h
(ml/min)
Age (years)
> 100
32.6~
31-80 16-30 < 16
Blood lead
urine lead
&mol/l)
bmol/24
Pb clearance h)
(ml/min)
9.1
0.95 + 0.49
0.11 kO.08
1.68 * 1.12
33.2 k 9.8 36.4 + 15.0
1.17kO.38 0.77 zk 0.29
0.15 + 0.08 0.14 rt 0.05
1.94 k 1.28 3.14 + 2.18
39.2 f 14.7
1.15 + 0.73
0.13 * 0.10
1.88 k 1.30
123
Similarly, unstimulated 24-h urinary output did not vary significantly among the groups. In view of the severe degrees of renal insufficiency included, this was perhaps surprising. It is worth noting, however, that none of the subjects was oliguric. There was a wide inter-individual variation in derived renal lead clearance, 0.44-7.92 ml/min. But, again, there was no significant difference among the groups. Notwithstanding these similarities among the groups, there was a highly significant inverse correlation between blood lead concentration and renal lead clearance
(r = 0.49
P < 0.005).
DISCUSSION
It appears from these results that severe renal insufficiency in the absence of oliguria does not impair urinary lead output. Urinary lead output cannot be considered in isolation from blood lead concentration and we attempted to derive a value for renal lead clearance. Pinto et al. [8] made an estimate based on whole blood lead concentration, of 0.284 ml/min (mean). It has been accepted, however, that only about 5% of blood lead is in the plasma compartment and this has been supported by a study of lead kinetics using zo3Pb chloride [9]. A clearance figure based on whole blood concentration will be inaccurate and will probably be an appreciable underestimate. Our derived figure of 2.08 ml/min (mean) may be regarded as more accurate in the subjects studied, since it is only at much higher lead concentration, when red cell saturation is approached, that proportionally higher plasma concentrations are found [lo]. It is possible that the proportion of free lead in the plasma may increase in uraemia due to accompanying anaemia. Even severe renal failure did not alter lead clearance by the kidney. This may be because the normal kidney has a large reserve for clearing lead. Perhaps the various groups would have responded differently to acute lead poisoning. This does not alter the conclusion that blood lead concentration as an index of chronic lead exposure is uninfluenced by renal function. On the other hand, there was an inverse correlation between blood lead concentration and renal lead clearance. It would appear that even at these quite low concentrations lead has a detrimental effect on its own clearance. It may be that lead is more tightly bound to red cells as its concentration increases. A low molecular weight lead-binding protein has been isolated from reticulocytes in industrially exposed lead workers [ 111. An alternative, and possibly more likely, explanation is low-grade nephrotoxicity. The principal mechanism by which the kidney excretes lead has not yet been clearly established, but it is thought to be mainly by glomerular filtration [12]. At higher blood lead concentrations, diminished tubular reabsorption, or active tubular secretion, may contribute to lead clearance [ 131. The proximal convoluted tubule is susceptible to damage by lead, intra-nuclear inclusion
124
bodies being a characteristic finding in lead posoining. In addition many enzymes are poisoned by quite low amounts of lead such as may be encountered in normal urban conditions [14]. It is possible, therefore, that lead may interfere with enzymedependent active tubular transport mechanisms. ~yperuricaemia has been shown to occur more frequently with blood lead concentrations in the upper normal range, reflecting, perhaps, subtle changes in real tubular function [7]. In conclusion, we have shown that even severe renal failure does not affect lead clearance. Blood lead concentration, therefore, remains a valid index of lead exposure even in such circumstances. This lends weight to the evidence from population studies that excessive environmental lead exposure is a factor in the aetiology of some cases of hypertension and renal diseases [8]. At the same time the finding of an inverse correlation between blood lead concentration and renal lead clearance provides further direct evidence of sub-clinical lead-induced nephrotoxicity. REFERENCES 1 B.C. Campbell and A.W. Baird, Lead poisoning in a group of demolition workers, Br. .I. Ind. Med., 34 (1977) 298-304. 2 R.A. Goyer, D.L. Leonard, J.F. Moore, B. Rhyne and M.R. Krigman, Lead dosage and the role of the intranuclear inclusion body, Arch. Environ. Health, 20 (1970) 705-711. 3 B.T. Emmerson, in D.A.K. Black (Ed.) Renal Disease, 2nd ed., Blackwell, Oxford, 1967 p. 561. 4 R. Lilis, J. Valciukas, A. Fischbein, C. Andrews, I.J. Selikoff and W. Bfumberg, Renal function impairment in secondary lead smelter workers: Correlations with zinc protoporphyrin and blood lead levels, J. Environ. Pathol. Toxicol., 2 (1979) 1447-1474. 5 B.C. Campbell, A.D. Beattie, M.R. Moore, A. Goldberg and A.G. Reid, Renal insufficiency associated with excessive lead exposure, Br. Med. J., 1 (1977) 482-485. 6 D.G. Beevers, E. Erskine, M. Robertson, A.D. Beattie, B.C. Campbell, A. Goldberg, M.R. Moore and V.M. Hawthorne, Blood-lead and hypertension, Lancet, 2 (1976) l-3. 7 B.C. Campbell, M.R. Moore, A. Goldberg, L.A. Hernandez and W.C. Dick, W.C. Subclinical lead exposure: a possible cause of gout, Br. Med. J. 2 (1978) 1403-1404. 8 P.A. Meredith, M.R. Moore and A. Goldberg, Effects of aluminium, lead and zinc on A-ALAD, Enzyme, 22 (1977) 22-27. 9 R.A. Kehoe, J. Cholak, R.V. Story, A sp~tr~hem~ca1 study of the normal ranges of concentration of certain trace metals in biological material, J. Nutr., 19 (1940) 579-592. 10 S.S. Pinto, H.B. Elkins and J.F. Ege, J. Ind. Hyg. Toxicol., 23 (1941) 313. 11 B.C. Campbell, Lead poisoning, clinical, subclinical and metabolic, M.D. Thesis, University of Glasgow, 1977 86-89. I2 H.A. Waldron and D. Stofen, in Subclinical Lead Poisoning, Academic Press, London, 1974, p. 47. 13 S.R.V. Raghavan and H.C. Gonick, Isolation of low-molecular weight lead binding protein from human erythrocytes, Proc. Sot. Exp. Biol. Med., 155 (1977) 164167. 14 J. Vostal, Mechanism of renal lead excretion, Biochem. Pharmacol., 12 (1963) Suppl. 207. 15 J. Vostal and J. Heller, Renal excretory mechanisms of heavy metals, I. Transtubular transport of heavy metal ions in avian kidney, Environ. Res., 2 (1968) l-10. 16 S. Hernberg and J. Nikkanen, Enzyme inhibition by lead under normal urban conditions, Lancet, 1 (1970) 63-66.
Letters,
121
9 (1981) 121-124
0 Elsevier/North-Holland
Biomedical
Press
LEAD EXPOSURE AND RENAL FAILURE: DOES RENAL INSUFFICIENCY INFLUENCE LEAD KINETICS? B.C. CAMPBELL,
H.L.
ELLIOTT
and P.A.
MEREDITH
University Department of Materia Medica, Stobhill General Hospital, Glasgow, G2I 3UW (U.K.) (Received
February
(Accepted
March
14th, 1981) 24th,
1981)
SUMMARY Blood and urine lead concentrations function.
Derived
impairment. evidence
Lead,
renal
lead clearance
however,
of nephrotoxicity
appeared
have been measured varied
widely,
to reduce
from sub-clinical
in 40 subjects
with normal
but was not influenced
its own clearance.
and impaired
by the degree
These findings
provide
renal
of renal additional
lead exposure.
INTRODUCTION
Lead exposure which is sufficiently severe to produce symptomatic lead poisoning causes renal damage. In a recent study of lead poisoning from an industrial source, 50% of patients had elevated serum urea and 30% had hyperuricaemia [l]. Acute poisoning produces a characteristic tubular defect [2], but chronic exposure results in a nephrosclerotic pattern with cortical atrophy [3]. Recently, chronic lead exposure has been suspected of causing renal damage even in the absence of overt symptoms of lead poisoning. Lilis et al. [4] in a study of secondary lead smelter workers, few of whom had a history of lead poisoning, established a correlation between impairment of renal function and blood lead and zinc protoporphyrin levels. This was dependent on duration of lead exposure. Campbell et al. [5], investigating potential health hazard from environmental lead contamination, found an association between raised blood lead and renal insufficiency in subjects who had never had symptoms of lead poisoning but who had been exposed to lead in drinking water for an average of over 20 years. Evidence of excessive lead exposure has also been found in association with hypertension and gout [6, 71, and it seems possible that it has a role in the etiology of these conditions through an effect on renal function. Renal impairment of any etiology might depress lead excretion, thus raising blood lead concentration and giving a spurious impression of excessive lead 0378.4274/81/0000-0000/$02.50
0 Elsevier/North-Holland
Biomedical
Press
122
exposure.
The present
renal function SUBJECTS
study was undertaken
on the kinetics
to investigate
the effects,
if any,
of
of lead.
AND METHODS
40 patients, 18 males, 22 females, aged 18-72 years were studied. 13 had normal renal function, with creatinine clearance > 100 ml/min and no history of renal disease. The remainder had established renal insufficiency; they were arbitrarily divided into the categories of mild, moderate and severe renal insufficiency on the basis of creatinine clearance (Table I). None of the patients was receiving regular dialysis at that time, but several of those with severe dysfunction have since been placed on a dialysis programme. Any form of renal disease was accepted but a history of lead exposure was an exclusion criterion. Blood lead concentration and 24-h unstimulated urinary lead output were measured by flameless atomic absorption spectophotometry using a Perkin Elmer HGA 72, with graphite cell power source [6]. Concentrations of lead in plasma are too small to permit direct measurement with any degree of accuracy on a small blood sample. It is accepted, however, that about 5% of total blood lead is in the plasma compartment [7]. This figure was used to determine renal lead clearance, by the conventional equation
where U = urinary lead concentration, I/ = urine volume, and P = plasma concentration. Analysis of the results was by analysis of variance.
lead
RESULTS
There was no significant difference in blood lead concentration among the 4 groups (Table I), However, 2 subjects with blood lead concentration above the accepted maximum normal (2 pmol/l) had marked renal impairment with creatinine clearance of 12 ml/min and 16 ml/min.
TABLE
I Creatinine
Group Normal Mild failure Moderate Severe
Number
13 9 8 10
clearance
24-h
(ml/min)
Age (years)
> 100
32.6~
31-80 16-30 < 16
Blood lead
urine lead
&mol/l)
bmol/24
Pb clearance h)
(ml/min)
9.1
0.95 + 0.49
0.11 kO.08
1.68 * 1.12
33.2 k 9.8 36.4 + 15.0
1.17kO.38 0.77 zk 0.29
0.15 + 0.08 0.14 rt 0.05
1.94 k 1.28 3.14 + 2.18
39.2 f 14.7
1.15 + 0.73
0.13 * 0.10
1.88 k 1.30
123
Similarly, unstimulated 24-h urinary output did not vary significantly among the groups. In view of the severe degrees of renal insufficiency included, this was perhaps surprising. It is worth noting, however, that none of the subjects was oliguric. There was a wide inter-individual variation in derived renal lead clearance, 0.44-7.92 ml/min. But, again, there was no significant difference among the groups. Notwithstanding these similarities among the groups, there was a highly significant inverse correlation between blood lead concentration and renal lead clearance
(r = 0.49
P < 0.005).
DISCUSSION
It appears from these results that severe renal insufficiency in the absence of oliguria does not impair urinary lead output. Urinary lead output cannot be considered in isolation from blood lead concentration and we attempted to derive a value for renal lead clearance. Pinto et al. [8] made an estimate based on whole blood lead concentration, of 0.284 ml/min (mean). It has been accepted, however, that only about 5% of blood lead is in the plasma compartment and this has been supported by a study of lead kinetics using zo3Pb chloride [9]. A clearance figure based on whole blood concentration will be inaccurate and will probably be an appreciable underestimate. Our derived figure of 2.08 ml/min (mean) may be regarded as more accurate in the subjects studied, since it is only at much higher lead concentration, when red cell saturation is approached, that proportionally higher plasma concentrations are found [lo]. It is possible that the proportion of free lead in the plasma may increase in uraemia due to accompanying anaemia. Even severe renal failure did not alter lead clearance by the kidney. This may be because the normal kidney has a large reserve for clearing lead. Perhaps the various groups would have responded differently to acute lead poisoning. This does not alter the conclusion that blood lead concentration as an index of chronic lead exposure is uninfluenced by renal function. On the other hand, there was an inverse correlation between blood lead concentration and renal lead clearance. It would appear that even at these quite low concentrations lead has a detrimental effect on its own clearance. It may be that lead is more tightly bound to red cells as its concentration increases. A low molecular weight lead-binding protein has been isolated from reticulocytes in industrially exposed lead workers [ 111. An alternative, and possibly more likely, explanation is low-grade nephrotoxicity. The principal mechanism by which the kidney excretes lead has not yet been clearly established, but it is thought to be mainly by glomerular filtration [12]. At higher blood lead concentrations, diminished tubular reabsorption, or active tubular secretion, may contribute to lead clearance [ 131. The proximal convoluted tubule is susceptible to damage by lead, intra-nuclear inclusion
124
bodies being a characteristic finding in lead posoining. In addition many enzymes are poisoned by quite low amounts of lead such as may be encountered in normal urban conditions [14]. It is possible, therefore, that lead may interfere with enzymedependent active tubular transport mechanisms. ~yperuricaemia has been shown to occur more frequently with blood lead concentrations in the upper normal range, reflecting, perhaps, subtle changes in real tubular function [7]. In conclusion, we have shown that even severe renal failure does not affect lead clearance. Blood lead concentration, therefore, remains a valid index of lead exposure even in such circumstances. This lends weight to the evidence from population studies that excessive environmental lead exposure is a factor in the aetiology of some cases of hypertension and renal diseases [8]. At the same time the finding of an inverse correlation between blood lead concentration and renal lead clearance provides further direct evidence of sub-clinical lead-induced nephrotoxicity. REFERENCES 1 B.C. Campbell and A.W. Baird, Lead poisoning in a group of demolition workers, Br. .I. Ind. Med., 34 (1977) 298-304. 2 R.A. Goyer, D.L. Leonard, J.F. Moore, B. Rhyne and M.R. Krigman, Lead dosage and the role of the intranuclear inclusion body, Arch. Environ. Health, 20 (1970) 705-711. 3 B.T. Emmerson, in D.A.K. Black (Ed.) Renal Disease, 2nd ed., Blackwell, Oxford, 1967 p. 561. 4 R. Lilis, J. Valciukas, A. Fischbein, C. Andrews, I.J. Selikoff and W. Bfumberg, Renal function impairment in secondary lead smelter workers: Correlations with zinc protoporphyrin and blood lead levels, J. Environ. Pathol. Toxicol., 2 (1979) 1447-1474. 5 B.C. Campbell, A.D. Beattie, M.R. Moore, A. Goldberg and A.G. Reid, Renal insufficiency associated with excessive lead exposure, Br. Med. J., 1 (1977) 482-485. 6 D.G. Beevers, E. Erskine, M. Robertson, A.D. Beattie, B.C. Campbell, A. Goldberg, M.R. Moore and V.M. Hawthorne, Blood-lead and hypertension, Lancet, 2 (1976) l-3. 7 B.C. Campbell, M.R. Moore, A. Goldberg, L.A. Hernandez and W.C. Dick, W.C. Subclinical lead exposure: a possible cause of gout, Br. Med. J. 2 (1978) 1403-1404. 8 P.A. Meredith, M.R. Moore and A. Goldberg, Effects of aluminium, lead and zinc on A-ALAD, Enzyme, 22 (1977) 22-27. 9 R.A. Kehoe, J. Cholak, R.V. Story, A sp~tr~hem~ca1 study of the normal ranges of concentration of certain trace metals in biological material, J. Nutr., 19 (1940) 579-592. 10 S.S. Pinto, H.B. Elkins and J.F. Ege, J. Ind. Hyg. Toxicol., 23 (1941) 313. 11 B.C. Campbell, Lead poisoning, clinical, subclinical and metabolic, M.D. Thesis, University of Glasgow, 1977 86-89. I2 H.A. Waldron and D. Stofen, in Subclinical Lead Poisoning, Academic Press, London, 1974, p. 47. 13 S.R.V. Raghavan and H.C. Gonick, Isolation of low-molecular weight lead binding protein from human erythrocytes, Proc. Sot. Exp. Biol. Med., 155 (1977) 164167. 14 J. Vostal, Mechanism of renal lead excretion, Biochem. Pharmacol., 12 (1963) Suppl. 207. 15 J. Vostal and J. Heller, Renal excretory mechanisms of heavy metals, I. Transtubular transport of heavy metal ions in avian kidney, Environ. Res., 2 (1968) l-10. 16 S. Hernberg and J. Nikkanen, Enzyme inhibition by lead under normal urban conditions, Lancet, 1 (1970) 63-66.