Focal segmental glomerulosclerosis associated with long-term treatment with zoledronate in a myeloma patient

Bisphosphonates were designed as synthetic analogues of endogenous pyrophosphate, which act as a regulator of bone metabolism and is found abundantly in bone matrix [1,2]. Non-nitrogen containing first-generation bisphosphonates, such as clodronate or etidronate, which closely resemble pyrophosphate, primarily induce osteoclast apoptosis by intracellular accumulation of non-hydrolyzable ATP analogues [3]. Nitrogencontaining bisphosphonates, such as zoledronate, pamidronate, ibandronate and alendronate, have been found to act on bone-resorbing osteoclasts by inhibiting farnesyldiphosphate (FPP) synthase, a key regulatory enzyme in the mevalonate pathway. Inhibition of FPP synthase prevents post-translational prenylation of small GTPases, causing impaired osteoclast function and sensitizing cells for apoptosis [4–6]. To date, zoledronate is one of the most potent bisphosphonates with very high affinity to bone [7]. It is in widespread use for the treatment of patients with multiple myeloma or bone metastasis due to solid tumours as well as hypercalcaemia of malignancy [8]. Zoledronate has been associated both with dosedependent and infusion time-dependent acute and chronic renal failure [2,9–15]. Markowitz et al. [9] described six patients suffering from underlying multiple myeloma or Paget’s disease, who developed zoledronate-associated toxic acute tubular necrosis (ATN). The predominant renal biopsy findings in these patients were marked tubular degenerative changes. While all biopsies displayed some degree of global glomerular sclerosis, no one exhibited lesions of focal segmental glomerulosclerosis (FSGS) or its morphological variant collapsing glomerulopathy. Both FSGS and its variant collapsing glomerulopathy have been described following treatment with pamidronate [2,16–19] and other drugs, e.g. lithium, interferon-a or heroin [20]. FSGS has also been reported to be associated with viral infections [21], most importantly with HIV [21,22], hepatitis C and parvovirus B19 [23]. Malignant arterial hypertension and hereditary conditions [20] have also been reported to be associated with FSGS. To our knowledge, no patients with collapsing FSGS and nephrotic syndrome associated with zoledronate have so far been described in the literature.