Pamidronate-induced tubulointerstitial nephritis with Fanconi syndrome in a patient with primary hyperparathyroidism

Martin Buysschaert1, Jean-Pierre Cosyns2, Leonel Barreto1 and Michel Jadoul3,

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



   Introduction
 Top
 Introduction
 Case
 Discussion
 References
 
Pamidronate disodium (Aredia®) is a member of the class of biphosphonates, widely used in the treatment of malignancy-associated osteolytic lesions and osteoporosis. At the recommended doses, renal toxicity of biphosphonates is very infrequent [13]. However, higher doses have produced nephrotoxicity in animal models [4,5]. More recently, the nephrotic syndrome with renal failure has also been reported in a few patients treated with pamidronate [6,7].

We describe a case of severe tubulointerstitial nephritis with Fanconi syndrome induced by intravenous pamidronate in a patient with primary hyperparathyroidism.



   Case
 Top
 Introduction
 Case
 Discussion
 References
 
A 75-year-old male was transferred to our hospital in February 2001 for surgical treatment of primary hyperparathyroidism and investigation of progressive renal failure. He had a history of obesity, type 2 diabetes, dyslipidaemia, myocardial infarction, hypertension and, recently, recurrent stroke.

In 1990, serum urea and creatinine levels were 47 (normal 15–50) and 1.3 (normal 0.6–1.4) 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 2.7–7.7) 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 1Go), the dosage of Aredia was progressively increased; from October 2000 to February 2001, it amounted to 90 mg/week.


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Table 1.  Evolution of biochemical parameters

 
At this stage, the patient, a workman, was transferred to our hospital. His medications included, besides calcitonin and pamidronate, gliquidone, molsidomine, diltiazem, simvastatin, aspirin, folic acid, acenocoumarol and furosemide. He complained of tiredness. Body mass index was now 24 kg/m2. Blood pressure was 130/80 mmHg and heart rate 76/min. Physical examination showed a grade 3 systolic murmur at the left femoral level, an absence of deep-tendon reflexes, a slight peripheral oedema and weakness in both legs.

Relevant plasma measurements included: proteins 5.5 (normal 6.1–7.9) g/dl, urea 98 mg/dl, creatinine 4.8 mg/dl, uric acid 2.8 mg/dl, fasting glucose 124 (normal 70–110) mg/dl, HbA1c 5.9%, C-reactive protein 0.3 (normal <0.5) mg/dl, fibrinogen 493 (normal 150–400) mg/dl, total calcium 2.1 (normal 2.15–2.55) mmol/l, phosphate 1 (normal 0.77–1.52) mmol/l, PTH level 447 pg/ml, 25-OH vitamin D 8.9 (normal 10–40) ng/ml, 1,25 (OH)2 vitamin D 16.1 (normal 18–45) pg/ml. Haemoglobin was 11.0 (normal 12–17) g/dl, mean corpuscular volume: 89 (normal 85–95) µm3; white blood-cells 5.830 (normal 4000–10 000)/mm3 (neutrophils 68%) and platelets 253 000 (normal 150 000–350 000)/mm3. Antinuclear factor as well as antineutrophilic cytoplasmic antibodies were negative. The sediment contained 10–20 (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 2Go).


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Table 2.  Aminoaciduria

 
Renal ultrasound showed hyper-reflective, normal-sized kidneys. Colour Doppler investigation of renal arteries showed a right-sided 50% ostial stenosis but no significant haemodynamic alteration on the left artery. A CT scan of the abdomen and pelvis (without administration of contrast material) excluded nephrocalcinosis. Ocular fundus showed no signs of diabetic retinopathy but did show stage II hypertensive retinopathy. Skeletal X-rays showed neither Loosers' zones nor osteolytic lesions suggestive of myeloma.

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 1Go). 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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Fig. 1.  Extensive hypocellular interstitial fibrosis with flattened proximal tubular epithelial cells. Masson's trichrome, x250.

 
Thus, the main causes of interstitial nephritis with signs of proximal tubular dysfunction (Fanconi syndrome) were excluded, in particular light-chain deposition disease. Heavy metal intoxication was also ruled out: blood levels of cadmium, lead and mercury were 0.1 µg/100 ml (normal <0.5), 3.8 µg/100 ml (normal <15.0) and 0.5 µg/100 ml (normal <1.0), respectively. Urine measurements of cadmium and mercury were also normal (1.3 and 5.7 µg/g creatinine, respectively).

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 2Go). 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.



   Discussion
 Top
 Introduction
 Case
 Discussion
 References
 
We report the development of renal failure under high-dose intravenous pamidronate in a patient with primary hyperparathyroidism. Our case was remarkable for the simultaneous development of the Fanconi syndrome (low serum uric acid, generalized aminoaciduria and marked glycosuria in the face of mild hyperglycaemia). Histologically, we observed lesions of acute tubular damage reminiscent of those observed in experimental animals [3,4]. Indeed, high-dose pamidronate administration was followed, both in rats and in mice by focal, sometimes extensive, tubular necrosis with brush-border loss. These lesions were heralded by an early (24–48 h) dose-dependent reduction of creatinine clearance and a marked increase in urinary {gamma}-glutamyltranspeptidase, a marker of renal brush-border lesion [4].

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 (180–360 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 (60–90 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.



   Notes
 
Correspondence and offprint requests to: Professor M. Jadoul, Service de Néphrologie, Cliniques Universitaires St Luc, Avenue Hippocrate 10, B-1200 Bruxelles, Belgium. Email: jadoul{at}nefr.ucl.ac.be Back



   References
 Top
 Introduction
 Case
 Discussion
 References
 

  1. Fitton A, McTavish D. Pamidronate: a review of its pharmacological properties and therapeutic efficacy in resorptive bone disease. Drugs 1991; 41:289–318[ISI][Medline]
  2. Berenson J, Rosen L, Vescio R et al. Pharmacokinetics of pamidronate disodium in patients with cancer with normal or impaired renal function. J Clin Pharmacol 1997; 37:285–290[Abstract/Free Full Text]
  3. Bounameaux H, Schifferli J, Montani JP, Jung A, Chatelanat F. Renal failure associated with intravenous diphosphonates. Lancet 1983; 1:471
  4. Hoggarth C, Bennett R, Daley-Yates PT. The pharmacokinetics and distribution of pamidronate for a range of doses in the mouse. Calcif Tissue Int 1991; 49:416–420[ISI][Medline]
  5. Cal JC, Daley-Yates PT. Disposition and nephrotoxicity of 3-amino-1-hydroxypropylidene-1, 1-biphosphonate (APD), in rats and mice. Toxicology 1990; 65:179–197[CrossRef][ISI][Medline]
  6. Markowitz GS, Appel G, Fine P et al. Collapsing focal segmental glomerulosclerosis following treatment with high-dose pamidronate. J Am Soc Nephrol 2001; 12:1164–1172[Abstract/Free Full Text]
  7. Lockridge L, Papac RJ, Perazella MA. Pamidronate-associated nephrotoxicity in a patient with Langerhans' histiocytosis. Am J Kidney Dis 2002; 40:E2.[CrossRef][Medline]
  8. Janssen van Doorn K, Neyns B, Van der Niepen P, Verbeelen D. Pamidronate-related nephrotoxicity (tubulointerstitial nephritis) in a patient with osteolytic bone metastases. Nephron 2001; 89:467–468[CrossRef][ISI][Medline]
Received for publication: 25. 7.02
Accepted in revised form: 5.12.02





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