Peer Reviewed
Metformin-Associated Lactic Acidosis Precipitated by Zoledronic Acid–Induced Acute Kidney Injury: A Case of Polypharmacy in an Elderly Patient
Zoledronic acid, a third-generation aminobisphosphonate, was approved by the U.S. Food and Drug Administration (FDA) in August 2007 for the treatment of osteoporosis in postmenopausal women. Although it is generally safe, careful postmarketing surveillance of patients who are prescribed zoledronic acid and are taking other nephrotoxic medications, or medications that can result in kidney failure, appears to be warranted. It may be prudent to temporarily withhold metformin therapy in patients who are to undergo zoledronic acid infusion therapy. We report a case of metformin-associated lactic acidosis precipitated by zoledronic acid–induced acute kidney injury in a 78-year-old woman with several chronic medical conditions who presented with profound hemodynamic instability, lactic acidosis with a low pH level, and a low core body temperature 3 weeks after receiving a single intravenous dose of zoledronic acid for osteoporosis treatment. The patient was in oliguric renal failure, and her serum metformin levels were approximately tenfold higher than the therapeutic reference range.
Case Presentation
A 78-year-old woman with a history of hypertension, type 2 diabetes mellitus, hyperlipidemia, and osteoporosis was found lying on the floor in her home, not alert, and unresponsive to vocal stimuli. Initial assessment by an emergency medical technician showed that the patient responded to painful stimuli by making incomprehensible sounds. There was no sign of injury. The physical examination was significant for cold and dry skin, and her pupils were unreactive to light. Her blood pressure was 40/20 mm Hg, pulse was 26 beats per minute, and respiration rate was 10 breaths per minute. Atropine was administered and transcutaneous pacing was performed. The patient was taken to the emergency department, where her blood pressure was measured at 57/43 mm Hg with a paced heart rhythm of 80 beats per minute. The patient had agonal breathing, her axillary and rectal temperatures were unmeasurable (ie, < 84oF [28.9oC]), her eyes were open, and she moved all extremities in response to painful stimuli. The abdominal examination revealed no distention or tenderness. The patient was endotracheally intubated. Because of her profound hypothermia, bilateral chest tubes, a peritoneal catheter, and a bladder catheter were placed for warm saline lavage. She was found to be anuric.
The patient’s current medication regimen, which she had followed until the day before her presentation in the emergency department, included amlodipine 10 mg daily, glimepiride 1 mg daily, rosuvastatin 5 mg daily, nateglinide 60 mg daily before breakfast, and ergocalciferol 1.25 mg daily. In addition, metoprolol 100 mg and metformin 850 mg were taken twice a day, indapamide 2.5 mg was taken 3 times a week, and furosemide 20 mg was taken once a week. She did not take nonsteroidal anti-inflammatory drugs (NSAIDs) or any other over-the-counter medications. She did not drink alcohol or use recreational drugs. The patient’s osteoporosis had been treated with risedronate for 2 years until 3 weeks prior to her presentation, when her primary care physician administered a first dose of zoledronic acid 5 mg/100 mL for infusion. (The primary care physician changed the medication regimen to zoledronic acid because it was easier to administer than risedronate.) Two weeks later (1 week prior to her hospital admission), the patient had presented to her primary care physician with new-onset bilateral leg edema. Blood work obtained at that visit showed a blood urea nitrogen (BUN) of 51 mg/dL, creatinine of 3.6 mg/dL, and an anion gap of 21 mEq/L. These laboratory results were not available when she first presented to the emergency department. Of note, laboratory data obtained 3 days before the zoledronic acid infusion revealed that the patient’s BUN and creatinine levels had remained stable at 12 mg/dL and 1.0 mg/dL, respectively, over the preceding 2 years.
Laboratory tests obtained in the emergency department revealed a serum sodium of 139 mEq/L, potassium of 6.5 mEq/L, chloride of 97 mEq/L, bicarbonate of less than 6 mEq/L, BUN of 104 mg/dL, creatinine of 5.7 mg/dL, calcium of 8.5 mg/dL, phosphorus of 13.1 mg/dL, albumin of 3.6 g/dL, white blood cell count of 23,300/µL, platelet count of 341x103/µL, and creatine phosphokinase of 170 U/L. A warmed arterial blood gas sample showed a pH of 6.68, partial pressure of carbon dioxide of 36.9 mm Hg, partial pressure of oxygen of 52 mm Hg, and lactate of 99.9 mg/dL. Other values included a thyroid-stimulating hormone level of 1.37 mIU/L, free thyroxine of 1.35 ng/dL, cortisol of 35.4 µg/dL, blood alcohol level of less than 10 mg/dL, and a negative urine drug screen. A chest radiograph showed no abnormality. Renal ultrasonography revealed hyperechoic normal-sized kidneys, which were consistent with renal parenchymal disease. The patient was transferred to the medical intensive care unit (ICU) 5 hours after presenting to the emergency department.
In the ICU, the patient was given norepinephrine 40 mcg/kg/minute as well as vancomycin 1 gram dosed by renal function and piperacillin/tazobactam 4.5 grams every 12 hours as empirical antibiotic therapy. Because of the patient’s severe metabolic acidosis, continuous venovenous hemofiltration (CVVH) was initiated 2.5 hours after her admission to the ICU. Two serum metformin levels measured prior to the start of CVVH were 19 µg/mL and 17.5 µg/mL (therapeutic range, 1-2 µg/mL). On days 1 and 2 after the initiation of CVVH, these levels dropped to 3 µg/mL and 1.6 µg/mL, respectively. No organism was identified from four sets of blood, urine, and respiratory cultures. Complement component 3 (C3) and 4 (C4) were within normal range. Hepatitis B, hepatitis C, antiglomerular basement membrane antibody, and antinuclear antibody screens were negative. The patient’s core body temperature returned to 98.4oF (36.9oC) 16 hours after admission. Her hemodynamic status dramatically improved within the first 24 hours after receiving CVVH, and the norepinephrine was stopped after 35 hours. On hospital day 4, a random spot urine protein to creatinine ratio indicated proteinuria of 5.5 g/day. A review of laboratory findings from 6 months prior to the patient’s hospitalization revealed a random spot urine protein to creatinine ratio of 0.325 g/day. The patient was extubated on hospital day 5 and was transferred to a general medical floor on day 6. She was still oliguric and required hemodialysis at the time of the transfer. The patient’s family decided to withdraw medical care, and she died on hospital day 73.
Discussion
The case patient developed acute kidney injury with nephrotic range proteinuria after receiving a zoledronic acid infusion. Although she appeared to have had normal kidney function at baseline (prior to the use of zoledronic acid), as her serum creatinine measurement was 1.0 mg/dL at that time, the Cockcroft-Gault equation revealed that her glomerular filtration rate (GFR) was 40 mL/min/1.73 m2 at baseline, which is indicative of stage 3 chronic kidney disease. On admission to the emergency department, her GFR was calculated at 11.1 mL/min/1.73 m2. Could zoledronic acid have been the cause of the patient’s acute kidney injury?
For the treatment of osteoporosis, zoledronic acid is administered as a once-a-year infusion of 5 mg in 100 mL administered over at least 15 minutes to minimize the risk of renal toxicity. Zoledronic acid has other indications, including for the treatment of metastatic bone disease and Paget’s disease. Acute renal failure, although rare, is one of the side effects of zoledronic acid, and there are multiple mechanisms by which this drug can cause acute renal failure. Zoledronic acid–induced renal toxicity is dose- and infusion time–dependent.1, Zoledronic acid acts as an epithelial toxin that targets proximal tubules in the absence of glomerular abnormalities or interstitial inflammation and can cause tubulitis, acute tubular necrosis, and focal segmental glomerulosclerosis.3 Renal failure has also been reported with other bisphosphonates, including etidronate, clodronate (not FDA-approved for use in the United States), and tiludronate. Zoledronic acid is predominantly excreted unchanged via the kidneys, and the time from drug initiation to the diagnosis of renal failure varies from days to months.4 While recommendations are to check serum calcium levels and renal function before each administration, there are no current guidelines that suggest the monitoring of renal function after an infusion of zoledronic acid.
Safety data for zoledronic acid come largely from the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) study, the largest multicenter, randomized, double-blind, placebo-controlled study to date of women taking zoledronic acid for osteoporosis.5,6 Participants of the HORIZON study had a mean age of 73 years and experienced a significant increase in serum creatinine levels (P = 0.001; defined as a rise of > 0.5 mg/dL in serum creatinine) at 9 to 11 days after infusion of zoledronic acid. Although transient, 1.3% of patients receiving zoledronic acid developed acute renal failure within 30 days, as compared with 0.4% of persons in the placebo group. Proteinuria was considered another adverse effect in the HORIZON study, and its frequency increased in the zoledronic acid group (P = 0.06).5
The case patient’s zoledronic acid-associated acute kidney failure led to severe toxicity from metformin, one of her other prescribed medications. Metformin is a biguanide that is indicated as a first-line medication for the treatment of type 2 diabetes mellitus. In 2006, almost 35 million metformin prescriptions were filled.7 Lactic acidosis is a well-reported but rare complication of metformin therapy, with an overall incidence of 9 per 100,000 patient-years.8 While the half-life of metformin is 6.5 hours in patients with normal creatinine clearance, reductions in metformin clearance occur proportionately to the reductions in creatinine clearance. Positive correlation of excessive plasma metformin concentrations with lactic acidosis suggests a direct toxicity of the drug. Several case reports have shown that severe metformin-associated lactic acidosis is accompanied by hemodynamic instability, hypothermia, and bradycardia.9-11 In the case patient, the development of renal failure from zoledronic acid put her at risk for metformin-associated lactic acidosis. Unfortunately, the patient was unaware of her acute kidney injury and had continued her usual metformin dosage until the day prior to her hospital admission.
The issue of polypharmacy in the elderly has been a long-standing challenge for healthcare providers. Since the prevalence of osteoporosis is so high in elderly women, a once-a-year bisphosphonate infusion is an attractive regimen for many patients. In addition, many commonly used medications in the elderly are nephrotoxic (eg, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, diuretics, NSAIDs, cyclooxygenase-2 inhibitors, antibiotics), and while interactions between zoledronic acid and these medications are unknown, it is likely that the more nephrotoxic drugs one takes, the higher the risk of renal failure. This may pose a concern for the safety of this medication in elderly patients who may take multiple nephrotoxic medications, even if their GFRs are normal.
Conclusion
The case patient’s severe metformin-associated lactic acidosis was precipitated by zoledronic acid–induced acute kidney injury. This occurred despite the patient having strictly met eligibility criteria for initiating treatment with zoledronic acid. For clinicians who treat elderly patients, we recommend that close monitoring of serum creatinine during the first month after infusion be considered. Additionally, withholding other nephrotoxic medications as well as medications that can accumulate in the body and are toxic in renal failure (eg, metformin) may be warranted prior to infusion. Finally, since the renal toxicity of zoledronic acid depends on dose and infusion time, studies investigating longer infusion times or dose division should be undertaken. The incident involving the case patient was reported to MedWatch, the FDA’s safety information and adverse event reporting program (www.fda.gov/Safety/MedWatch/HowToReport/default.htm) and to the respective pharmaceutical companies. We recommend careful additional postmarketing surveillance of zoledronic acid infusion in higher-risk patients so that specific treatment guidelines geared toward patient safety may be developed.
The authors report no relevant financial relationships.
Dr. Leung and Dr. Eisen are from the Division of Critical Care Medicine, and Dr. LeFrancois is from the Division of General Internal Medicine, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, NY.
References
1. Diel IJ, Bergner R, Grötz KA. Adverse effects of bisphosphonates: Current issues. J Support Oncol 2007;5(10):475-482.
2. Perazella MA, Markowitz GS. Bisphosphonate nephrotoxicity. Kidney Int2008;74(11):1385-1393.
3. Bodmer M, Amico P, Mihatsch MJ, et al. Focal segmental glomerulosclerosis associated with long-term treatment with zoledronate in a myeloma patient. Nephrol Dial Transplant 2007;22(8):2366-2370.
4. Tanvetyanon T, Stiff PJ. Management of the adverse effects associated with intravenous bisphosphonates. Ann Oncol 2006;17(6):897-907.
5. Black DM, Delmas PD, Eastell R, et al; HORIZON Pivotal Fracture Trial. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007;356(18):1809-1822.
6. Boonen S, Sellmeyer DE, Lippuner K, et al. Renal safety of annual zoledronic acid infusions in osteoporotic postmenopausal women. Kidney Int 2008;74(5):641-648.
7. Top 200 generic drugs by units in 2006. Drug Topics. Accessed December 15, 2010.
8. Stang M, Wysowski DK, Butler-Jones D. Incidence of lactic acidosis in metformin users. Diabetes Care 1999;22(6):925-927.
9. Bruijstens LA, van Luin M, Buscher-Jungerhans PM, Bosch FH. Reality of severe metformin-induced lactic acidosis in the absence of chronic renal impairment. Neth J Med 2008;66(5):185-190.
10. Ahmad S, Beckett M. Recovery from pH 6.38: Lactic acidosis complicated by hypothermia. Emerg Med J 2002;19(2):169-171.
11. Schure PJ, de Gooijer A, van Zanten AR. Unexpected survival from severe metformin-associated lactic acidosis. Neth J Med 2003;61(10):331-333.