Cadmium Nephropathy

Cadmium nephropathy is chronic tubulointerstitial kidney disease caused by long term exposure to cadmium. It is characterised by proximal tubular dysfunction with low molecular weight proteinuria, followed by a fall in glomerular filtration. Cadmium has a biological half life of 10 to 30 years in the kidney, which accumulates it, and early tubular injury is irreversible.

The main sources are:

• Tobacco smoking, the largest non-occupational source. Smokers have about twice the blood cadmium of non-smokers.
• Occupational exposure: nickel cadmium battery manufacture, smelting, welding, pigment and plastic production, electroplating, e-waste recycling.
• Diet: rice, leafy vegetables, shellfish, offal, and crops grown on contaminated soil or irrigated with polluted water, fertilisers.

Severe environmental poisoning in Japan (itai itai disease) caused osteomalacia and kidney failure in post-menopausal women. Exposure is associated with higher rates of kidney stones, osteoporosis, hypertension, and lung and prostate cancer.

Pathophysiology. Cadmium bound to metallothionein is filtered and reabsorbed in the proximal tubule. Released cadmium damages tubular cells, causing loss of reabsorption (low molecular weight proteinuria, glycosuria, phosphaturia, hypercalciuria), and later glomerular sclerosis. Calcium and phosphate loss produce osteomalacia and bone loss.

• Often silent in early disease; low molecular weight proteinuria (beta-2 microglobulin, retinol binding protein) found on screening.
• Proximal tubulopathy: glycosuria with normal blood glucose, phosphaturia with hypophosphataemia, aminoaciduria, hypercalciuria, kidney stones, tubular acidosis.
• Progressive loss of eGFR, usually slowly, with little albuminuria (under 500 mg daily) until late.
• Bone pain, fractures and pseudofractures (osteomalacia), kyphosis and loss of height.
• Anosmia, yellow dental rings in long term occupational exposure; emphysema and hypertension.

Red flags

• Bone pain or fractures with hypophosphataemia and a high alkaline phosphatase.
• Renal stones with tubular dysfunction in an exposed worker or heavy smoker.
• Urinary cadmium above 10 microg/g creatinine or blood cadmium above 10 microg/L.
• Rapid loss of kidney function or progressive proteinuria.
• Pregnancy in a smoker with high cadmium.

• Blood cadmium reflects recent exposure. It is normal under 1 microg/L in non-smokers and 1 to 2 microg/L in smokers; above 5 microg/L indicates excess exposure.
• Urinary cadmium adjusted for creatinine reflects chronic body burden. Above 2 microg/g creatinine is raised; above 5 microg/g creatinine is associated with tubular damage.
• Urinary tubular markers: beta-2 microglobulin (above 300 microg/g creatinine), retinol binding protein, alpha-1 microglobulin, N-acetyl-beta-D-glucosaminidase; albumin:creatinine ratio, urine protein:creatinine ratio.
• Creatinine, cystatin C-based eGFR, phosphate, calcium, magnesium, bicarbonate, uric acid, alkaline phosphatase, 25-hydroxyvitamin D, parathyroid hormone, glucose.
• Bone: radiographs, bone density scan.
• Exposure history including smoking, occupation, diet, and residence near mines or smelters.
• Kidney biopsy rarely, showing tubular atrophy and interstitial fibrosis.

Differential diagnosis

• Other tubulointerstitial diseases (lead, aristolochic acid, analgesic nephropathy), Fanconi syndromes (genetic, drug induced, light chain), Dent disease, diabetic kidney disease, osteomalacia from vitamin D deficiency, hyperparathyroidism, chronic kidney disease of uncertain cause.

First line: end the exposure

• Stop smoking with nicotine replacement: patch 21 mg daily for 6 weeks, then 14 mg for 2 weeks, then 7 mg for 2 weeks, with lozenges as needed.
• Alternatively use varenicline 0.5 mg daily for 3 days, then 0.5 mg twice daily for 4 days, then 1 mg twice daily for 12 weeks (maximum 0.5 mg twice daily when eGFR is under 30).
• Occupational controls (ventilation, respirators, hygiene, change of clothes, removal from exposure), reduced intake of contaminated foods (rice, shellfish, offal from polluted areas), and public health notification.
• Dietary iron, zinc and calcium adequacy reduce absorption.

Chelation. Not advised: edetate and dimercaprol can worsen kidney injury because they mobilise cadmium into the kidney. Succimer has limited evidence. No treatment reverses established tubular injury.

Kidney protection and complications

• Blood pressure below 130/80 mmHg: ramipril 2.5 mg daily increased to 10 mg daily. Check creatinine and potassium at 1 to 2 weeks, accept a rise up to 30%, and stop if potassium exceeds 6.0 mmol/L.
• Dapagliflozin 10 mg daily (eGFR at least 25) or empagliflozin 10 mg daily (eGFR at least 20) when albuminuria is present.
• Hypophosphataemia: neutral phosphate 500 to 1000 mg elemental phosphate daily in 3 to 4 divided doses, with alfacalcidol 0.25 to 0.5 microg daily. Adjust to serum phosphate 0.8 to 1.2 mmol/L; diarrhoea limits dose; maximum 3 g elemental phosphate daily.
• Osteomalacia: cholecalciferol 50 000 units weekly for 6 to 8 weeks, then 800 to 2000 units daily. Calcium 500 mg elemental calcium daily with meals (up to 1.5 g elemental calcium daily). Target 25-hydroxyvitamin D at least 50 nmol/L.
• Treat pain and fractures conventionally. Avoid bisphosphonates with osteomalacia until vitamin D and phosphate are corrected.
• Metabolic acidosis: sodium bicarbonate 500 mg to 1 g two to three times daily to bicarbonate at least 22 mmol/L.
• Stones: fluid intake above 2.5 litres daily, and urological care. Potassium citrate 30 to 60 mEq (3 to 6 g) daily in divided doses where acidosis or hypocitraturia is present (monitor potassium when eGFR is under 45).
• Anaemia: iron and epoetin alfa 50 to 100 units/kg three times weekly when haemoglobin is under 100 g/L.
• Kidney failure: dialysis at eGFR 5 to 10 with symptoms; transplantation after exposure ends.

Cancer screening. Lung and prostate cancer risk in exposed workers; smoking cessation and age appropriate screening.

Monitoring. Urinary cadmium and beta-2 microglobulin every 6 to 12 months in exposed workers; eGFR, phosphate, calcium and bicarbonate every 3 to 6 months; bone density every 1 to 2 years; blood pressure at each visit.

Referral and escalation. Nephrology for eGFR under 60, progressive loss of function, or proteinuria; occupational health; metabolic bone specialist for fractures.

Special groups

• Women after menopause and pregnant or breastfeeding women with low iron stores absorb more cadmium; counsel on diet.
• Children: environmental exposure through contaminated soil and rice; paediatric nephrology and public health.
• Smokers: the principal modifiable group; support cessation.
• Low resource and mining regions: screen communities near smelters and agricultural land irrigated with polluted water.