Lister Renal Unit, Renal Medicine Stevenage, Hertforshire, UK Email: jon.stratton{at}lister.org.uk
Sir,
We report on two patients with steroid-sensitive relapsing nephrotic syndrome, who experienced relapse of their nephrotic syndrome following initiation of an oral biphosphonate preparation.
Case 1
A 42-year-old man had had steroid-dependent nephrotic syndrome from the age of 2 years. Renal biopsies had revealed minimal-change disease at ages 3 and 19 years. After the second biopsy, oral cyclophosphamide was introduced, but later withdrawn because of myelosuppression. Relapses commonly occurred in the early summer and were associated with seasonal rhinitis. The patient was maintained on 7.5 mg of oral prednisolone. A bone densitometry scan indicated hip osteopenia, and an oral biphosphonate preparation (Didronel PMO, Procter and Gamble Pharm) was started (in late summer). He relapsed after 3 weeks with proteinuria increasing from negative dip-stick to 2+. He self treated, stopping the biphosphonates and increasing prednisolone to 30 mg for a week. No 24-h urine collections were performed. With resolution of dip-stick proteinuria, he reduced his prednisolone to 10 mg.
With doubts regarding the cause of the relapse, the patient was re-challenged with the same biphosphonate, but after 3 weeks his proteinuria increased from negative dip-stick to 9 g protein/24 h. After withdrawal of the drug and an increase in steroid dosage he quickly settled. Between relapses he excretes minimal proteinuria (<0.5 g/24 h) and has normal renal function.
Case 2
A 23-year-old man had had steroid-dependent nephrotic syndrome from 18 months of age. A renal biopsy had demonstrated minimal-change glomerulonephritis when he was 10 years of age. He had been treated with cyclophosphamide, cyclosporin A and levamisole at various times as a child, but remained dependent on prednisolone. He was transferred to our unit at the age of 17 years, having remained in remission for the previous 2 years. A steroid-responsive relapse occurred shortly after cessation of levamisole (to allow alcohol consumption at university), but otherwise he remained in remission on minimal steroid replacement. There had been no relapse for 5 years when a bone densitometry scan indicated hip and lumbar spine osteoporosis. A biphosphonate (Didronel PMO, Procter and Gamble Pharm) was prescribed. Within 1 week the patient relapsed, with proteinuria increasing from 0.1 to 3.8 g/24 h. The Didronel was stopped and prednisolone started at 40 mg/day. He responded within a week with resolution of the proteinuria.
Biphosphonates are widely used for prophylaxis and treatment of steroid-induced osteopenia. Recognized renal side-effects include acute renal failure, worsening of renal impairment, and oedema. Proteinuria has been reported in association with biphosphonate-induced nephrotoxicity [1,2], transient proteinuria after treatment for metastatic breast cancer [3], and development of collapsing focal segmental glomerulosclerosis with nephrotic syndrome in seven patients with malignant disease (six with multiple myeloma and one with breast cancer) prescribed intravenous biphosphonates (pamidronate) [4].
We report relapses of nephrotic syndrome temporally related to the initiation of an oral biphosphonate. The relapse responded in each case to withdrawal of the drug and an increase in prednisolone therapy. The efficacy of oral prednisolone may have been reduced by either decreased absorption or increased metabolism (such as with rifamycin antibiotics, anti-epileptics, mifepristone). To date, Didronel has not been found to alter prednisolone pharmacokinetics. Whilst the relationship may be coincidental, clinicians should be aware of a potential for biphosphonate to induce nephrotic syndrome relapse.
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