Mobilization of lead from bone in end-stage renal failure patients with secondary hyperparathyroidism

Michèle Kessler, Pierre Y. Durand, Than Cao Huu, M. José Royer-Morot2, Jacques Chanliau, Patrick Netter2 and Michel Duc1

Departments of Nephrology and 1 Internal Medicine and 2 Laboratory of Pharmacology and Toxicology, University Hospital of Nancy, France

Correspondence and offprint requests to: Professor Michèle Kessler, Service de Néphrologie, Hôpitaux de Nancy, 54500 Vandoeuvre les Nancy, France.

Abstract

Background. It is now recognized that long-term exposure to even low levels of lead may increase bone lead content. Lead can then be released in toxicologically significant amounts during critical states of increased bone turnover.

Methods. Two patients with end-stage renal failure, one on haemodialysis and the other on continuous ambulatory peritoneal dialysis (CAPD), had been exposed to lead and developed secondary hyperparathyroidism. An edetate calcium disodium (EDTA) test was performed in combination with haemofiltration or CAPD before and after parathyroidectomy.

Results. Before parathyroidectomy, both patients had low delta aminolaevulinic acid dehydrase (ALA-D) and high concentrations of chelated lead. After parathyroidectomy, there was a dramatic decrease in chelated lead and the ALA-D returned to normal.

Conclusion. Secondary hyperparathyroidism increases mobilization of bone lead in dialysis patients with an elevated lead burden. This may cause toxic effects.

Keywords: end-stage renal failure; haemodialysis; lead poisoning; peritoneal dialysis; secondary hyperparathyroidism

Introduction

Most of the lead accumulated by humans over time is deposited in bone [1] with a half-life of ~20 years [2]. Such deposition has generally been considered a process of detoxification which removes lead from the circulation and from contact with lead-sensitive target cells. Marked changes in blood lead have been reported [36] under conditions of bone demineralization. As a result, long-term exposure to even low levels of lead may result in an elevated body burden of lead, so that toxicologically significant amounts could be released from bone when bone turnover increases.

We observed two patients who had been exposed to lead in the past and developed end-stage renal failure (ESRF). Increased mobilization of lead from bone was documented when the patients developed advanced secondary hyperparathyroidism.

Subjects and methods

In the first case, a 65-year-old hypertensive woman, chronic renal failure was discovered fortuitously in 1983. Both kidneys were contracted and she progressed to ESRF in February 1987 when chronic haemodialysis was started. She lived in an area of the Vosges mountains, with a notoriously high prevalence of lead poisoning from drinking water. The patient lived in an old house with lead pipes. In September 1987, the first stream of tap water taken in the morning contained a very high concentration (4500 µg/l) of lead and the concentration was still 1300 µg/l after running the water for 20 min.

Her blood lead measured by atomic spectrometry was 28 µg/dl (moderately elevated) and her plasma delta aminolaevulinic dehydratase (ALA-D) activity, assayed using Bourdon's colorimetric method, was very low: 0.01 µmol of porphobilinogen/ml of red blood cells/h (N>=0.40). As described previously [7], an edetate calcium disodium (EDTA) test was performed together with haemofiltration. EDTA (1 g in 250 ml of normal saline) was perfused over 1 h immediately prior to the haemofiltration using a polyamide filter and 20 l of re-injection solution. The lead in the ultrafiltrate and in the urine excreted during the 24 h period following the infusion was assayed. The total amount of lead mobilized was 3307 µg/24 h. Her husband also had an elevated lead body burden with urinary lead excretion of 2160 µg/24 h after EDTA challenge. He subsequently was treated with four consecutive courses of five EDTA infusions over a period of 6 months.

Although the woman had no obvious symptom of lead poisoning, she was given seven courses of five infusions of EDTA combined with five consecutive sessions of haemofiltration between March 1988 and September 1989 (Figure 1Go). Lead exposure was interrupted by substituting PVC tubes for the lead pipes. The lead concentration in the initial morning tap water was then 52 µg/l and it was 19 µg/l after leaving the tap running for 20 min.



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Fig. 1. Amounts of lead chelated after infusion of 1 g of EDTA, in the urine and ultrafiltrate of patient 1 (top), and in the urine and in the CAPD bags for patient 2 (bottom) before and after parathyroidectomy. Results are expressed as the average amount of lead extracted per 24 h after the five EDTA infusions of each course of treatment.

 
Advanced secondary hyperparathyroidism was first diagnosed in September 1987. Intact parathyroid hormone (iPTH) was >1600 pg/ml (N<70). The patient refused parathyroidectomy, and her iPTH was >1700 pg/ml in September 1989, together with increased alkaline phosphatase (477 UI/l, N<260) and major signs of osteitis fibrosa. She had total parathyroidectomy and autograft in October 1989. The average amount of lead excreted during the seventh EDTA treatment given 2 weeks before surgery was 2590 µg/24 h. EDTA tests performed 2 months and 12 months after parathyroidectomy showed that the amount of extracted lead had decreased dramatically to 618 (2 months) and 284 µg/24 h (12 months). At the same time, iPTH was 15 and 27 pg/ml, and alkaline phosphatase was 115 and 73 Ul/l, respectively. There was a concomitant increase in ALA-D from 0.05 before surgery to 0.24 (2 months) and 0.33 (12 months) after surgery.

The second case, a 48-year-old man, had renal dysplasia and had been treated by continuous ambulatory peritoneal dialysis (CAPD) since 1986. He lived in a new house in a limestone region, but he had lived for 25 years in an old house with lead pipes in the Ardennes, where the soil is acidic. He had left this region 23 years previously. He complained of abdominal pain and was screened for lead poisoning in October 1987. His ALA-D activity was 0.05 and his blood lead concentration was 26.5 µg/dl. As described previously, an EDTA test was performed [8] with infusion of 1 g of EDTA in 250 ml of normal saline over 1 h just after drainage and, following infusion, the lead was assayed in the bags and in a 24-h urine sample collected. This first test extracted 714 µg/24 h. From 1988 to 1994 the patient was treated with six courses of five infusions of EDTA (Figure 1Go).

Secondary hyperparathyroidism was first diagnosed in November 1987 (iPTH:332 pg/ml). It progressed until December 1994 (alkaline phosphatase: 497 Ul/l, iPTH: 857 pg/ml), at which time subtotal parathyroidectomy was performed. The amount of chelated lead was 700 µg/24 h before surgery and decreased to 105 µg/24 h, 15 months later, with concomitant normalization of ALA-D (0.59). At this time, alkaline phosphatase activity was 212 Ul/l and iPTH 28 pg/ml.

Discussion

Long-term lead poisoning due to contaminated drinking water continues to be a major problem in the Vosges mountains and on the Ardennes plateau [9]. It may also be a problem in geologically similar areas with acid soil. Exposure to lead results from corrosion of lead water pipes. We demonstrated [7] (i) that measurement of ALA-D is an accurate screening test for lead overload in dialysis patients provided that the threshold of normal is lowered from 0.4 to 0.2 and (ii) that lead poisoning can be diagnosed and treated by administring EDTA in conjunction with haemofiltration or CAPD [7,8]. These tests were used to diagnose an elevated lead burden in the above two patients. The patients were monitored before and after parathyroidectomy. The results document a profound decrease of cheletable lead after reversal of hyperparathyroidism.

There have been few reports on the relationship between hyperparathyroidism and bone lead. Gouty patients with chronic renal failure have higher mean serum PTH concentrations than controls [9]. A significant correlation was found between PTH and EDTA-induced urinary lead excretion. The authors suggested that the high PTH was responsible for increased mobilization of lead from bone. A study of 15 subjects with primary hyperparathyroidism showed that blood lead concentrations decreased after parathyroidectomy. EDTA chelation challenges before and after parathyroidectomy gave similar results, but the very low amounts of chelated lead indicate that these patients were not previously exposed to lead [10]. The results of this study and ours suggest that a high bone turnover increases exchangeable lead in patients with past exposure to lead. In cross-sectional studies, PTH concentrations were similar in uraemic patients with or without chronic or acute lead poisoning [11]. Furthermore, no significant difference in PTH concentration was found between dialysis patients with high and low iliac bone lead [12]. Although bone lead was not measured before and after parathyroidectomy in our patients, the results obtained strongly suggest that hyperparathyroidism increased mobilization of bone lead years after cessation of lead exposure and caused toxic effects.

References

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Received for publication: 15. 2.99
Accepted in revised form: 7. 4.99





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