Ailing bones and failing kidneys: a case of chronic cadmium toxicity

Abstract

Heavy metal toxicity is often caused by occupational exposure. Chronic cadmium toxicity is a significant health concern among workers engaged in zinc smelting, battery production and silver jewellery industries, particularly in developing countries. We report the case of a 48-year-old man who presented with severe osteoporosis, impaired renal function and acquired Fanconi syndrome. He was finally diagnosed with chronic cadmium toxicity resulting from long-term occupational exposure. Cadmium has a long biological half-life and there is no effective treatment for people who are exposed to it. Therefore, an early diagnosis and prevention of further exposure are important.

Case report

A 48-year-old Indian non-smoker male patient presented with progressively worsening skeletal pain for the previous five years. X-rays of the lumbosacral spine and hip showed markedly reduced bone density with prominent trabecular markings. Dual-energy X-ray absorptiometry (DEXA) confirmed the presence of severe osteoporosis (T score <−2.5 in the lumbar vertebrae and left femoral neck). He also had impaired renal function, with serum creatinine concentration of 250 µmol/L (reference interval 53–106 µmol/L) and serum urea concentration of 10 mmol/L (reference interval 2.5–7.5 mmol/L). He was referred to our hospital for further evaluation of his impaired renal function. The patient was not diabetic or hypertensive nor did he have any history of corticosteroid therapy. Full blood count showed mild normochromic normocytic anaemia: haemoglobin 10.9 g/dL (reference interval 12.0–15.0 g/dL). Total and differential white blood cell counts were within reference limits. Biochemical investigations showed hypophosphataemia (0.6 mmol/L, reference interval 0.8–1.5 mmol/L), hypouricaemia (100 µmol/L, reference interval 208–416 µmol/L) and increased alkaline phosphatase (412 U/L, reference interval 108–306 U/L). Other liver function tests were within the reference limits, as were the serum concentrations of sodium, potassium, calcium and magnesium. Serum vitamin D was within the reference interval but parathyroid hormone concentration was increased (93 ng/L, reference interval 15–65 ng/L).

Routine urinalysis showed trace albumin and 2+ glucose on urine dipstick but plasma glucose was normal. Fractional excretion of uric acid (18%, reference interval 5–11%) and phosphate (31%, reference interval 5–20%) were elevated. Urine protein:creatinine ratio was 310 mg/mmol (reference interval <22 mg/mmol), and urine albumin:creatinine ratio was 5.3 mg/mmol (reference interval <2.5 mg/mmol of creatinine). Urine and serum protein electrophoreses were unremarkable. Subsequently, the patient was re-evaluated. On further questioning, the patient gave an occupational history of working in a silver jewellery industry for the past 15 years.

Discussion

Our patient had extensive bone mineral loss along with impaired renal function. The presence of hyperuricosuria, phosphaturia and renal glycosuria is suggestive of a Fanconi syndrome. This was first described by the Swiss paediatrician Guido Fanconi and classically presents in infants and children. Acquired Fanconi syndrome is also recognized. ¹

Urine chemistry showed marked proteinuria and comparatively mild albuminuria. This discordance led to the suspicion of tubular proteinuria. This was confirmed with a grossly elevated urinary β-2 microglobulin (>40,000 µg/L, reference interval 5–150 µg/L). Impaired renal function along with severe osteoporosis in this male patient prompted the suspicion of heavy metal toxicity. The characteristic occupational history of cadmium exposure in the silver jewellery industry and grossly elevated blood cadmium concentrations (3736 nmol/L, reference interval: non-smokers 27–106 nmol/L, smokers 54–424 nmol/L) confirmed the diagnosis of cadmium toxicity. Urine cadmium was 75 µg/g of urinary creatinine (reference interval 0.5–3.0 µg/g), suggesting chronic exposure. Both blood and urine cadmium were measured using atomic absorption spectroscopy. Cadmium is widely used in silver jewellery industries: silver is mixed with cadmium and the alloy is used to make silver jewellery. In the process, cadmium fumes are released that contribute to toxicity.

Heavy metal toxicity is mainly caused as a result of occupational exposure. Lead, mercury and cadmium are all examples of ‘heavy toxic metals’. Exposure to cadmium is a serious health concern for industrial workers associated with zinc smelting, battery production and silver jewellery industries, and also for populations living in polluted areas, especially in the developing and under-developed countries. ² Industrial exposure occurs by inhalation as well as ingestion. Apart from industrial exposure, chronic cadmium toxicity can occur from foods as a result of plant uptake of cadmium from soil. Cadmium is also present in tobacco smoke and contributes to cadmium toxicity by inhalation. The human lungs reabsorb 40–60% of the cadmium in tobacco smoke and thus smokers have four to five times higher blood cadmium concentrations than those of non-smokers. ³

Chronic cadmium toxicity has a major toxic effect on the kidneys. Because of the extremely long biological half-life of cadmium (>30 years), prolonged low-concentration exposure leads to excessive accumulation in tissues, especially the renal cortex. ⁴ A progressive decline in glomerular filtration rate and tubular proteinuria are hallmarks of cadmium nephrotoxicity. A classical example of cadmium toxicity by environmental exposure is itai-itai disease. The disease was endemic to the Jinzu river basin of the Toyama region in Japan, as a result of environmental pollution of cadmium, a by-product of zinc mining in that region. ‘Itai-itai’ in Japanese means ‘ouch-ouch’, indicating painful osteoporosis resulting from chronic cadmium toxicity. ⁵ Even a minimal environmental exposure to cadmium may cause skeletal demineralization. ⁶ Bone demineralization in cadmium toxicity may be due to the impairment of osteoblast and osteoclast function as a result of renal dysfunction. Cadmium also interacts with renal mitochondrial hydroxylases of the vitamin D₃ endocrine complex, thereby contributing to skeletal injury.^5,6 Coonse et al. ⁷ reported that cadmium induces apoptosis in the cultured osteoblast-like cell line Saos-2. Thus, there is a possibility of a direct effect of cadmium on bone health.

After absorption into the bloodstream, cadmium is initially transported to the liver where it is taken up by hepatocytes and this induces the synthesis of metallothionein, which binds to cadmium. Cadmium reaches the kidneys in the form of cadmium-metallothionein (Cd-MT). Cd-MT is filtered at the glomerulus and then reabsorbed in the proximal tubules. It remains in the tubular cells contributing substantially to the body cadmium load. Previous studies suggested that Cd-MT causes tubular injury but recent evidence shows that ionic cadmium (Cd⁺⁺) is possibly the most important contributor to tubular injury. ⁸ A significant renal deposition of cadmium leads to acquired Fanconi syndrome, a generalized proximal tubular reabsorptive defect due to cadmium-induced inhibition of both ATP production and Na–K-ATPase activity. Cadmium also disrupts cadherin-mediated cell-to-cell adhesion thus contributing to nephrotoxicity. This proximal tubular dysfunction leads to increased urinary loss of calcium and phosphate, which contributes to the development of osteoporosis.^9,10

The diagnosis of chronic cadmium toxicity requires strong clinical suspicion and an occupational history of exposure. Estimation of urinary low-molecular weight proteins such as β2-microglobulin, α1-microglobulin and retinol-binding protein can be helpful in the evaluation of tubular proteinuria. These proteins are elevated in cadmium-exposed workers even with lesser degrees of exposure and in whom clinical proteinuria is absent. ¹¹ Metallothionein, a low-molecular weight protein which is produced by hepatocytes in response to cadmium exposure, is also excreted in increased quantity when the body load of cadmium exceeds a threshold limit. Elevated urine and blood cadmium concentrations are diagnostic of cadmium toxicity. Urinary cadmium excretion has been shown to correlate well with the degree of cadmium nephrotoxicity. ³ Chronic lead poisoning also leads to nephrotoxicity, but there are significant differences from the nephrotoxicity of cadmium: β-2 microglobulinuria is absent in lead nephrotoxicity when compared with cadmium toxicity; also, in lead nephropathy albuminuria is absent or minimal, whereas in cadmium nephropathy it is variable. ⁴

Treatment

There is no specific, safe and effective treatment for chronic cadmium toxicity. British anti-Lewisite (BAL) chelates cadmium but the BAL–cadmium complex is much more nephrotoxic than cadmium alone. ¹² Thus, the focus here was the prevention of further cadmium exposure and maintenance of adequate hydration in order to prevent further renal injury. The patient was advised to refrain from non-steroidal anti-inflammatory drugs and was prescribed bisphosphonate therapy for osteoporosis. Garlic consumption has been claimed to be protective in cadmium toxicity ¹³ and our patient was encouraged to eat garlic – a common ingredient in traditional Indian diets.