Occupational

Lead Nephropathy

RICHARD P. WEDEEN. M.D. JOHN K. MAESAKA.

M.D.

BARRY WEINER, M.D. GREGORIO A. LIPAT, M.D.’ Jersey City, New Jersey MICHAEL M. LYONS, M.D. LEONARD F. VITALE, M.D. MORRIS M. JOSELOW,

Ph.D.

Newark, New Jersey

From the Department of Medicine, Jersey City Medical Center, Jersey City, New Jersey, and the Departments of Pathology, Pediatrics and Preventive Medicine, New Jersey Medical School, Newark, New Jersey. This paper was presented in part at the Seventh Annual Meeting of the American Society of Nephrology, Washington, D.C., November 25, 1974. This work was supported by USPHS National Institutes of Health Research Project Grant AM16266. Requests for reprints should be addressed to Dr. Richard P. Wedeen, Renal Section, Jersey City Medical Center, Jersey City, New Jersey 07304. Manuscript accepted April 9, 1975. Research Fellow of the American Heart Association, New Jersey Affiliate, during performance of these studies. l

630

November 1975

Among eight subjects suspected of excessive occupational exposure to lead, detailed examination of renal function identtfied abnormalities in four. Gtomerular filtration rate was less than 87 mi/min/1.73 m* in one subject with asymptomatic renal failure, and in three sdjects with preclinical renal dysfunction. In the subject with asymptomatic renal failure, chelation therapy increased the glomerular filtration rate, p-aminohippurate (PAH) extraction, the maximal PAH secretion rate (TmpAH) and improved proximal tubule ultrastructure, despite decreased renal plasma flow. This improvement in PAH transport was associated with correction of a proximal tubule defect in tritiated PAH uptake detected by section freeze-dry autoradiography of renal biopsy specimens. In three subjects, the etiologic diagnosis of lead-induced nephropathy was established by exclusion, but tubular dysfunction did not obviously exceed the reduction in giomerular filtration. Proximal tubule abnormalities were seen in each of the three patients who underwent blopsy. These studies suggest that lead nephropathy may be an important occupational hazard in the United States lead industry. Occupational lead nephropathy has been described in a number of European and Asian countries [ 1,2], but it has rarely been recognized in the United States [3]. In contrast to the childhood form of this disease, adult lead nephropathy remains poorly characterized, and its very existence is a subject of controversy [4,5]. Renal disease in adults resulting from occupational exposure to lead appears to differ from the lead nephropathy associated with childhood pica. In children and experimental animals, lead intoxication has been associated with a rapidly reversible Fanconi syndrome [ 6,7]. In adults, lead nephropathy presents as slowly progressive chronic renal failure which is only partly reversible [ 1,2,8- 131. The relationship between lead-induced chronic renal disease in adults and the transient proximal tubular disease of children remains obscure. Since it is difficult to identify etiologic factors in end-stage renal disease, we have attempted to characterize lead-induced nephropathy by examining renal function and histology in detail in lead workers before the appearance of symptomatic renal failure.

MATERIALS AND METHODS Renal function was studied in eight lead workers after screening gested excessive been hospitalized

tests sug-

body burdens of lead (Table I) [ 141. Two subjects had because of lead colic. The six additional subjects were

volunteers from a group of 22 asymptomatic lead workers examined for excessive lead exposure. On determination of the blood levels of copper, zinc and cadmium in 12 of this group, they were within normal limits. Re-

The American Journal of Medicine

Volume 59

OCCUPATIONAL

LEAD NEPHROPATHY -WEDEEN

ET AL.

sults of initial lead screening and clinical laboratory tests in the eight patients are presented in Table I. The EDTA mobilization test was performed by intramuscular administration of 1 g of calcium disodium adetate (Versenate”, Riker Laboratories, Inc., Northridge, Calif.) on two occasions 8 to 12 hours apart, during collection of a 24hour urine specimen. Ten hypertensive patients without known excessive exposure to lead (Pb) excreted C650 pg Pb/day by this method. In agreement with others [ I!%181, we consider excretion of over 650 Mg Pblday during the EDTA mobilization test to be abnormal. In two of our patients, 2 g of EDTA given intramuscularly for five days resulted in greater than 1,000 pg Pb excretion daily, further indicating that this route of administration results in lead excretion comparable to that seen with intravenous EDTA

[81. Red cell

&aminolevulinic

aciddehydratase

(ALA-D)

[ 181, free erythrocyte protoporphyrin (FEP) [ 191, blood lead (BPb)and urine lead (Upb) [20,21] were all determined by standard methods. Urine b-aminolevulinic acid concentration (U,& was determined in freshly voided specimens by the method of Osuma [22]. Normal values in this laboratory are ALA-D, > 120 U/100 ml red blood cells; FEP, 1.025 after overnight fasting in all subjects. The eight subjects were divided into three categories on tTtOSt

632

November 1975

The American Journal of Medicine

the basis of their glomerular filtration rates (Table I). Normal values for these healthy men would be expected to be 130 f

15 ml/min/l.73

m* body surface

area [24]

CASE REPORTS Renal failure was detected in one patient because of minimally elevated blood urea nitrogen and serum creatinine values found during routine laboratory testing.

Asymptomatic Renal Failure.

Case 1. This 28 year old man was employed mixing solder cream and preparing lead powder from lead ingots for five years with heavy exposure to lead vapor and dust in an unventilated room. Anemia was first noted four years before admission during a hospitalization for acute infectious hepatitis. He was hospitalized repeatedly for epigastric pain persisting for approximately five consecutive days each month associated with frequent vomiting. In January 1973, screening tests for excessive lead exposure revealed a Bpbof 48 wg/ 100 ml. Upr,of 81 pg/liter, ALA-D of 42 U/100 ml, FEP of 20 /*g/100 ml, UALn of 70 mg/liter and 24-hour urine coproporphyrin excretion of 757 hglday. Twenty-four hour urinary excretion of 21 amino acids was less than 52 per cent of the normal maximum (measured by Bio-Science Laboratories, North Hollywood, Calif.); only ornithine excretion was increased at 36 ymollday (normal maximum, 27 Fmol/day). At this time, clinical laboratory studies revealed a hemoglobin level of 9.6 g/100 ml, a hematocrit value of 28 per cent, red blood cell count of 3.81 X 106/mm3 and a white blood cell count of 3,900 cells/mm3. Basophilic stippling was seen in less than 0.5 per cent of the red cells. The urine specific gravity was 1.026. The blood urea nitrogen was 45 mg/lOO ml, serum creatinine 2.3 mg/lOO ml and serum uric acid 13.2 mg/lOO ml. Urinary protein excretion was 26 mg/day, and the uric acid excretion was 930 mg/day. Uroporphyrin and porphobilinogen were absent from the urine. The patient became asymptomatic during hospitalization. The initial EDTA mobilization test resulted in excretion of 5,200 pg Pb/24 hours. In an attempt to reduce the excessive body lead burden in this patient, oral penicillamine, 2 g daily, was administered (Table II). and he was returned to full-time employment under conditions in which there was no lead exposure. After six months of oral penicillamine therapy, a repeat EDTA mobilization test revealed lead excretion of 3,540 pglday. Chelation therapy was then continued with intramuscular administration of EDTA (1 g three times per week). After six additional months of EDTA therapy, chelation therapy was discontinued and all studies repeated. The effect of chelation therapy on laboratory tests in this patient is presented in Table II.

Renal Dysfunction. Three of the lead workers were found to have definite reductions in glomerular filtration rate without abnormal blood urea nitrogen or serum creatinine. Two were welders whose work required use of acetylene torches and lead solder in the repair of copper-plating tanks, i.e., “lead burning.” All the lead burners were asymptom-

Preclinical

atic. The third subject with preclinical lead nephropathy Volume 59

OCCUPATIONAL LEAD NEPHROPATHY - WEDEEN ET AL.

TABLE

II

Lead Screening

and Clinical

Laboratory

Blood Urine Nitrogen

Serum Creatinine

Data-Case

1 During

Control

Hematocrit

Date _________

(g/100 ml)

(%I

(mgl 100 ml)

(mgl lOOmI)

Mar 1973

9.3

30

43

1.8

Apr-Sept Jul 1973

12.1

33

42

Penicillamine, 1.5 35

Sept-Feb Nov 1973 ___

12.3 ___-

34

45

1.5

22

53

Feb 1974

12.7

36

47

1.6

-

26

*Abbreviations as in Table t January 1973.

TABLE ____--

III

Clearance

Time (min)

Bph kg/ 100 ml)

No chelation 27

Data-Case

40-60 60-70 70-102-Reposition

43 55

1 Following

1,500

CPAH (ml/min)

prime,

-3O-0-lnulin

3.75%

305

5,200

2 g/day orally 30 71

8

23

206

3.540

82

2,220

135

1,535

three times a week 84 5 27

-

4

26

ml Oral Water

Load

RPF (ml/min)

RBF (ml/min)

prime for TmpAH,

prime,

77 70

35-56 56-87 87-111 Ill-135-Reposition

57

Tmr’AH (mg/min)

3.75%

3.75%

(R) (R) mannitol

Chelation

mannitol

370 320 300 renal vein catheter

60 60 prime for TmpAH 45 49 47 41

309 300

PPAH (mg/lOO ml) -.___

443 480

515 679

1.3 1.3

615 667

1.3 1.2

in water at 20 ml/min

intravenously 41 42 36

and PAH

Pb (pg/dav)

757t

0.71 (L) 371 0.71 (L) 389 from left to right renal vein 0.74 0.73

After -30-O-lnulin

Pb (ug/dav)

6

54 54 46

30-45 45-57 57-69

135-159 159-184 197-PAH 233-258 258-282 ‘282-302 302-328

Copro (pg/dav)

hg/ liter)

Before Treatment-March 1973 mannitol in water at 20 ml/min intravenously

330 356

and PAH

therapy 41

EPAH

262 345 renal vein catheter

60 55

102-l 12 112-122

(l-lgl 100 ml)

EDT-A

UALA

30

1 g/intramuscularly,

-~ and PAH

FEP

ALA-D (U/100 ml)

I.

GFR (ml/min)

-30-O-lnulin

Therapy* 24.Hour Urine

Hemoglobin

Edetate,

Chelation

Therapy-February

in water at 20 ml/min

1974 intravenously

440 -

687

0.80 (L) 375 left to right renal vein

586

2.4 2.4 2.5

0.84 0.84

575 562

2.5 2.5

0.84 (L) from

30.0 26.3 29.5

(R) (R)

368 360

75 64 66 59

36.5 53.5 51.0 49.0

NOTE: GFR = glomerular filtration rate, CPAH = p-aminohippurate clearance, EPAH = arteriovenous extraction ratio for PAH, RPF = renal plasma flow, RBF = renal blood flow, TmpAH = maximal secretion rate of PAH, Pra~rr = plasma concentration of PAH. L = left, R = right.

November 1975

The American Journal of Medicine

Volume 59

633

OCCUPATIONAL LEAD NEPHROPATHY-WEDEEN

TABLE IV

ET AL

Summary of Clearance Data* Case No.

Category

Date

RPF

GFRt

CPAH

(ml/min)

(ml/min)

(%I

(ml/min)

____

EPAH

RBF (ml/min)

T”‘I~At~ (mg/min)

Asymptomatic renal failure

1 1

Mar 1973 Mar 1974

52 65

323 319

72 82

452 390

627 610

40 64

Preclinical renal

2 3

Apr 1974 Jul 1973

87 75

568 477

93 87

954 845 790

93 62 69

1,308 1,133 986 1,202

8Y 85 78 72

dysfunction Normal kidney function

*Clearance

Nov 1973

72

410

90

5

Nov

1973

125

677

6 7 8

Dee 1973 Feb 1974 Aug 1974

122 99 105

565 466 637

93 90 88 100

726 622 573 637

data corrected

presented in detail.

Case 2.

4

617 492 473

for

1.73 m2 body

surface

area.

with lead colic, and his history is presented

A 38 year old man had recurrent

abdominal

pain

for one and a half years. His blood lead level was reported

as 182 fig/100 ml. He had worked at a rifle firing range sweeping up spent bullets for three years prior to the time of hospitalization. Periumbilical and epigastric pain had recurred for two or three days each week for the preceding three months. During this period, he lost 25 pounds. Initial laboratory data are presented in Table I. In addition, 24-hour urinary protein excretion was 14 mg, and uric acid excretion was 844 mg. Fractional uric acid excretion (C “rate/GFR) equalled 8 per cent. Following overnight fasting, the urine osmolality was 814 mOsm/liter. After three days of hospitalization, lead colic subsided spontaneously.

Normal Kidney Function. Four subjects, including three lead burners (Cases 5, 6 and 7, Table I) and one in charge of quality control in the manufacture of lead-tin solder, were

found to have entirely normal

Figure I. Case 7. Section freeze-dry autoradiograph from renal biopsy specimen obtained before chelation therapy. A proximal tubule with periodic acid-Schiff-positive brush border shows no tritium accumulation after incubation in Cross and Taggarf medium containing 6 mg/lOO ml PAH-3H for 1 hour at 25%. Periodic acid-Schiff and hematoxylin stain; original magnificatrbn X 790, reduced by 30 per cent. 634

November 1975

The American Journalof Medkine

f CIOT or Ci, and Crol

results by routine clinical and laboratory examination, except for lead screening tests (Table I). Each of these subjects had abnormal reductions in ALA-D, and two had definite increases in FEP. In three, the EDTA mobilization test was abnormal; in one, this test was within normal limits.

RESULTS Asymptomatic

Detailed clearance Renal Failure. data are presented for Case 1 (Table Ill) before and after one year of chelation therapy. These data are summarized in Table IV. Since the glomerular filtration rate tended to decrease during measurement of TmpAH, Only CkarSnCeS obtained before the administration of the TmpAu prime were used for summary purposes. At the time of the initial study, March 1973, GFR, RPF, EpAu and TWIpAH were reduced. After one year of chelation therapy the glomerular filtration rate increased from 62 to 65 ml/min, TmpAH. increased from 40 to 64 mg/min, reaching the lower

Figure 2. Case 1. Biopsy specimen obtained after one year of chelation therapy. Proximal tubules show cellular accumulation and luminal secretion of PAH-3H. Same incubation conditions as in Figure 1. Chelation therapy apparently reversed tubular transport defect for PAH-3 H. Periodic acti-Schiff and hematoxyln stain; original magnification X 500, reduced by 30 per cent.

Volume 59

OCCUPATIONAL

limit of the normal range, and EnAH rose from 0.72 to 0.82, although the RPF fell from 452 to 390 ml/min. The fall in RPF was in part counterbalanced by an increase in hematocrit so that RBF actually showed only a trivial reduction. The apparent improvement in PAH transport noted in the physiologic measurements following chelation therapy corresponded to improvements in morphology and PAH uptake in the renal biopsy specimen. Section freeze-dry autoradiography of the initial renal specimen did not demonstrate concentrative uptake of PAH-3H in proximal tubules (Figure 1). In contrast,

LEAD NEPHROPATHY-WEDEEN

ET AL.

the second specimen obtained after chelation therapy demonstrated concentrative uptake of PAH-3H by proximal tubules (Figure 2). The initial biopsy specimen demonstrated glomerular obsolescence, periglomerular fibrosis and diffuse damage to proximal tubules (Figure 3). In the initial biopsy specimen, proximal tubules showed destruction of brush borders and subapical swelling of the cytoplasm (Figure 4). Mitochondria were scarce. When present, mitochondria were distorted: they appeared rounded, cristae were broken and distributed peripherally (Figures 4 and 5). The tubular basement mem-

Figure 3. Case 1. Biopsy specimen obtained before chekstion therapy shows one severely damaged glomerulus and one glomerulus with periglomerular fibrosis. Diffuse swelling and vacuolizatlon are present in proximal tubular cells. This is from the outer portion of the same biopsy specimen used for autoradiographs before therapy (Figure 1). Original magnification X 304, reduced by 34 per cent.

Figure 4. Case 1. Electron micrograph of proximal convoluted tubule demonstrating partial loss of brush border and disruption of luminal aspect of tubule lining cell. There is a marked diminution of basal infoktings of cell. Lysosomal-like structures containing electron dense bodies are present. Mitochondrra are sparse and show loss of crlstae. This electron micrograph demonstrates nonspecific cellular damage from same biopsy specimen which showed failure of PAH-=H uptake (Figure 1) before chelation therapy. Original magnification X 7,000, reduced by 42 per cent. November

1975

The American

Journal

of Medlclne

Volume 59

635

OCCUPATIONAL LEAD NEPHROPATHY-WEDEEN

ET AL.

branes were focally thickened (Figure 5), and basilar infoldings were virtually absent (Figures 4 and 5). Fibroblasts and collagen deposits were increased in the interstitial region of the cortex (Figure 5). The biopsy specimen obtained after chelation therapy showed definite improvement in proximal tubule morphology (Figure 6). Brush borders were usually normal, and mitochondria more frequent and less distorted. There were, however, no changes in the interstitial or tubular basement membrane abnormalities. A few lysosomal structures containing electron dense bodies were present within the cytoplasm of proximal tubules (Figure 6). Although this patient never had sustained hypertension, the second renal biopsy specimen showed an arteriole with apparent endothelial proliferation obliterating the lumen associated with reduction in number and distortion of endothelial mitochondria. In both specimens, glomerular sclerosis was evident along with mesangial cell hyperplasia and accumulation of mesangial matrix. Clearance determinations designed to evaluate tubular reabsorption of salt, water, phosphate and urate failed to demonstrate any unique abnormalities (Table V). (r&o + C&/GFR was 18 per cent before

and 10 per cent after chelation therapy: proximal tubular reabsorption of sodium remained within the range reported during comparable nonelectrolyte solute excretion in patients with moderately reduced glomerular filtration rate due to a variety of renal diseases [25]. After chelation therapy, the serum uric acid level fell to 10.1 mg/lOO ml, and the fractional urate excretion was 4 per cent. Similarly, fractional phosphate excretion was comparable to that reported in other renal diseases with comparable glomerular filtration rates [26-281. The clearance data thus did not demonstrate any unusual tubular reabsorptive defect for sodium, water, phosphate or urate which would assist in differentiating occupational lead nephropathy from other causes of renal dysfunction. Preclinlcal Renal Dysfunction. Three workers with excessive body lead burdens without evidence of renal dysfunction on routine laboratory examination were found to have reduced glomerular filtration rates (Table IV) and are designated “preclinical renal dysfunction.” None of these had remarkable reductions in Ep~u or TmpAH, and their solute and phosphate clearance values were within or close to the normal range [24-291. Although one (Case 2) had experienced lead colic

Figure 5. Case 1. Electron micrograph of proximal convoluted tubules showing virtual absence of basilar infokflngs of tubular lining cell and marked diminution of cell&r organelles. There is a moderate increase in collagen in interstitial space (small arrow) and focal thickening of tub&r basement membrane. Note nonspecific intranuclear chromatb condensation (large arrow). From same biopsv tissue that showed failure of PAH-3H uptake p&r to chelat&n therapy (Flgure 1). Original magnlfL cation X 3,500, reduced by 42 per cent. 636

November 1975

The American Journal ol Medklne

Volume 59

OCCUPATIONAL

TABLE V

was obtained on this subject. The biopsy specimen in Case 3 showed reduced and abnormal mitochondria, a few lysosomal dense bodies, thickening of tubular basement membranes and loss of basilar infoldings. Proximal tubule brush borders were intact, and no interstitial infiltrate was present in the cortex (Figure 8). No definite glomerular abnormalities were observed. lmmunofluorescent microscopy (performed by Dr. Norman Ende) revealed no evidence of glomerular or tubular deposi-

* Data obtained

UNI

Occupational lead nephropathy.

Among eight subjects suspected of excessive occupational exposure to lead, detailed examination of renal function identified abnormalities in four. Gl...
7MB Sizes 0 Downloads 0 Views