Toxic acute tubular necrosis following treatment with zoledronate (Zometa).
BACKGROUND
Renal failure and toxic acute tubular necrosis (ATN) may be seen following exposure to a variety of therapeutic agents. Zoledronate (Zometa) is a new, highly potent bisphosphonate used in the treatment of hypercalcemia of malignancy. We report the first clinical-pathologic study of nephrotoxicity associated with this agent.


METHODS
A cohort of six patients (four males and two females) with a mean age of 69.2 years received bisphosphonate therapy for multiple myeloma (five patients) or Paget's disease (one patient). In all patients, zoledronate was administered at a dose of 4 mg intravenously monthly, infused over at least 15 minutes, and the duration of therapy was mean 4.7 months (range, 3 to 9 months).


RESULTS
All patients developed renal failure with a rise in serum creatinine from a mean baseline level of 1.4 mg/dL to 3.4 mg/dL. Renal biopsy revealed toxic ATN, characterized by tubular cell degeneration, loss of brush border, and apoptosis. Immunohistochemical staining revealed a marked increase in cell cycle-engaged cells (Ki-67 positive) and derangement in tubular Na+,K+-ATPase expression. Importantly, although all patients had been treated with pamidronate prior to zoledronate, no biopsy exhibited the characteristic pattern of collapsing focal segmental glomerulosclerosis observed in pamidronate nephrotoxicity. Following renal biopsy, treatment with zoledronate was discontinued and all six patients had a subsequent improvement in renal function (mean final serum creatinine, 2.3 mg/dL at 1 to 4 months of follow-up).


CONCLUSIONS
The close temporal relationship between zoledronate administration and the onset of renal failure and the partial recovery of renal function following drug withdrawal strongly implicate this important and widely used agent in the development of toxic ATN.
Markowitz
Glen S
GS
Department of Pathology, Columbia College of Physicians & Surgeons, New York, New York 10032, USA. gsm17@columbia.edu
Fine
Paul L
PL
Stack
Jay I
JI
Kunis
Cheryl L
CL
Radhakrishnan
Jai
J
Palecki
Winicjusz
W
Park
Jin
J
Nasr
Samih H
SH
Hoh
Shirley
S
Siegel
David S
DS
D'Agati
Vivette D
VD
D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D001706:Biopsy; D015331:Cohort Studies; D004164:Diphosphonates / Q000009:adverse effects*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects*; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D007683:Kidney Tubular Necrosis, Acute / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D051437:Renal Insufficiency / Q000139:chemically induced; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013997:Time Factors; D000077211:Zoledronic Acid
D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D000254:Sodium-Potassium-Exchanging ATPase