1 Department of Endocrinology and Nutrition, 2 Department of Pathology 3 Department of Nephrology, Cliniques Universitaires St Luc, Université Catholique de Louvain, Bruxelles, Belgium
Keywords: Fanconi syndrome; hypercalcaemia; hyperparathyroidism; nephrotoxicity; pamidronate; tubulointerstitial nephritis
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Introduction |
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We describe a case of severe tubulointerstitial nephritis with Fanconi syndrome induced by intravenous pamidronate in a patient with primary hyperparathyroidism.
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Case |
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In 1990, serum urea and creatinine levels were 47 (normal 1550) and 1.3 (normal 0.61.4) mg/dl, respectively. In 1999, primary hyperparathyroidism was diagnosed on the basis of hypercalcaemia, low serum phosphate and a parathyroid hormone (PTH) level of 113 pg/ml (normal <65). Serum urea, creatinine and uric acid levels were 53, 1.6 and 8.4 (normal 2.77.7) mg/dl, respectively. The urine was positive for protein (1.96 g/l), but the sediment was normal. The mild impairment of renal function was ascribed to nephrosclerosis and/or diabetic nephropathy. Other biochemical tests and lipid profile were within normal ranges apart from an alkaline phosphatase level of 255 IU/l (normal <170). HbA1c was 7% (normal 6%).
Considering the rather poor general condition of the patient, hypercalcaemia was treated with both subcutaneous calcitonin (Miacalcic®; 100 U/day) and intravenous pamidronate (Aredia, 60 mg/3 weeks). However, due to persistent hypercalcaemia (Table 1), the dosage of Aredia was progressively increased; from October 2000 to February 2001, it amounted to 90 mg/week.
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Relevant plasma measurements included: proteins 5.5 (normal 6.17.9) g/dl, urea 98 mg/dl, creatinine 4.8 mg/dl, uric acid 2.8 mg/dl, fasting glucose 124 (normal 70110) mg/dl, HbA1c 5.9%, C-reactive protein 0.3 (normal <0.5) mg/dl, fibrinogen 493 (normal 150400) mg/dl, total calcium 2.1 (normal 2.152.55) mmol/l, phosphate 1 (normal 0.771.52) mmol/l, PTH level 447 pg/ml, 25-OH vitamin D 8.9 (normal 1040) ng/ml, 1,25 (OH)2 vitamin D 16.1 (normal 1845) pg/ml. Haemoglobin was 11.0 (normal 1217) g/dl, mean corpuscular volume: 89 (normal 8595) µm3; white blood-cells 5.830 (normal 400010 000)/mm3 (neutrophils 68%) and platelets 253 000 (normal 150 000350 000)/mm3. Antinuclear factor as well as antineutrophilic cytoplasmic antibodies were negative. The sediment contained 1020 (normal 5) red and white cells per high-power field. The urine was sterile but positive for glucose (13 g/l) and protein (1.7 g/24 h; normal <0.15). Creatinine clearance was 14 ml/min. A generalized aminoaciduria was found (Table 2
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A renal biopsy was performed. Glomeruli showed no significant changes by light microscopy except that one-third of them were obsolescent. There was extensive proximal tubular epithelial cell flattening (Figure 1). Only a few lymphocytes infiltrated the interstitial tissue focally. The majority of the interstitium showed diffuse hypocellular fibrosis associated with scanty tubular atrophy. Focal segmental, moderate intimal thickening of interlobular arteries was present. No immune deposits were seen by immunofluorescent microscopy.
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As multiple lines of evidence pointed to pamidronate as the aetiological agent of tubulointerstitial damage, its administration was discontinued, while the administration of other drugs was continued. Serum creatinine subsequently stabilized. Cervical ultrasonography and parathyroid scintigraphy (123I-MIBI) were inconclusive but a right superior parathyroid adenoma was found at surgery in April 2001. The patient was discharged shortly thereafter.
Six months later, serum calcium was 2.45 mmol/l. PTH level was now 55 pg/ml. Creatinine and uric acid levels were 3.7 and 6.5 mg/dl, respectively. Aminoaciduria was no longer present (Table 2). After a further 18 months, creatinine level was 3.5 mg/dl. The overall clinical picture had improved relatively little despite treatment for hyperparathyroidism and healing of Fanconi syndrome.
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Discussion |
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In humans, pamidronate-induced nephrotoxicity has been infrequently reported hitherto. Markowitz et al. [6] recently reported the development of the nephrotic syndrome due to collapsing focal segmental glomerulosclerosis under high dose pamidronate (180360 mg/month) in seven patients with multiple myeloma (n=6) or metastatic breast carcinoma (n=1). Interestingly, in the patients of Markowitz et al. and in the similar one of Lockridge et al. [7], the nephrotic syndrome, absent in our patient, was accompanied by severe lesions of the proximal tubules. Whether signs of proximal tubular dysfunction were absent or actually present but overlooked in these patients is unclear [6,7]. On the other hand, renal failure with interstitial nephritis lesions was observed in one patient receiving small doses (6090 mg/month) of pamidronate for osteolytic bone metastases [8]. Renal biopsy showed tubular necrosis, but, unlike in our case, with a dense mixed inflammatory infiltration.
A causal relationship between pamidronate and the renal damage in our patient is very likely. The histological picture is suggestive of toxic interstitial nephritis. Moreover, temporally, the worsening of renal failure as well as the development of signs of proximal tubular dysfunction closely paralleled the administration of pamidronate in escalating doses (up to 90 mg/week over a period of 4 months) that clearly exceeded the recommended levels. Such a dose of 360 mg/month was also administered in three patients described by Markowitz et al. [6]. Finally, other causes of interstitial nephritis were excluded and, as others, we observed a decrease in serum creatinine [6] as well as normalization of aminoaciduria, a decrease of glycosuria and an increase of uric acid level a few months after discontinuation of pamidronate.
The mechanism of pamidronate nephrotoxicity remains unclear. Pamidronate, administered as a single-dose monthly therapy in bone metastases, was well tolerated by patients with renal impairment [2]. On the other hand, it is possible that the elevated serum levels resulting from weekly high-dose administration results in a toxic concentration in renal tubules, since the drug is mainly secreted by tubules. Slightly impaired renal function before initiation of pamidronate therapy, as in our patient, could then be a predisposing condition. In the study of Markowitz et al. [6], however, no subject had a serum creatinine higher than 1.2 mg/dl before starting treatment. Finally, small, elderly subjects could also be at higher risk, as suggested previously [8].
In conclusion, high-dose pamidronate administration can induce not only the nephrotic syndrome due to focal collapsing glomerulosclerosis but also severe tubulo-interstitial nephritis heralded by the development of a typical Fanconi syndrome. Therefore, caution is recommended in the use of the drug and close monitoring of renal function, in particular proximal tubular function, during chronic therapy is clearly needed.
Conflict of interest statement. None declared.
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Notes |
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References |
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