Metformin-induced lactic acidosis and acute pancreatitis precipitated by diuretic, celecoxib, and candesartan-associated acute kidney dysfunction

Abstract

Polypharmacy may lead to synergistic complications from the different medications. We report the case of a 50-year-old woman who was prescribed 11 drugs, including a diuretic, celecoxib, metformin, and candesartan, and who developed acute kidney dysfunction while on these drugs, manifesting as severe proteinuria, acute azotemia, hyperkalemia. The kidney injury caused the accumulation of metformin, leading to lactic acidosis and acute pancreatitis. Sodium bicarbonate hemodialysis not only improved the metabolic abnormalities but also hastened the removal of metformin.

Keywords: :

• Metformin
• Celecoxib
• Candesartan
• Lactic acidosis
• Acute kidney injury
• Pancreatitis

Introduction

Polypharmacy is not uncommon in patients with multiple chronic medical diseases. Interactions among drugs, which increase in frequency with the number of prescribed medications, may lead to harmful side effects in patients with multiple comorbidities and where a complication from one drug may lead to toxicity of another (1). We describe a patient who developed acute renal failure while taking celecoxib and metformin concomitantly with a thiazide diuretic and an angiotensin II receptor antagonist, which then led to metformin-induced lactic acidosis and acute pancreatitis.

Case report

A 50-year-old white woman presented to Beth Israel Medical Center with nausea, vomiting, epigastric pain, and generalized weakness. The patient had been deaf-mute since birth, and for more than 10 years she had severe obesity and non-insulin-dependent diabetes mellitus complicated by peripheral neuropathy, as well as hypertension, hypercholesterolemia, hypothyroidism, osteoarthritis of her knees, and schizoaffective disorder. Six months prior to admission her urine was negative for proteinuria and microalbuminuria. Two months before admission, at which time her serum creatinine was 1.2 mg/dL, she was begun on celecoxib for knee pain. According to her caretaker, she had felt well until three days prior to admission, when she began to feel progressively weaker. She then developed mid-epigastric abdominal pain radiating to her back, accompanied by nausea and three episodes of vomiting. Coffee-ground emesis was witnessed in the Emergency Department. She denied fever, chills, sore throat, cough, shortness of breath, chest pain, flank pain, dysuria, and diarrhea. She also denied any suicidal ideation or attempt. There was no history of tobacco, alcohol, or illicit drug use. She had no known drug allergies. Her out-patient medications in addition to celecoxib were L-thyroxine, acetaminophen/codeine, aspirin (81 mg/day), metformin, simvastatin, omeprazole, pregabalin, tizanidine, candesartan, hydrochlorothiazide, and aripiprazole.

The patient's vital signs were: blood pressure 97/46 mm Hg, pulse 93/min, respirations 18/min, temperature 98.9°F rectally, and pulse oximetry 100% on room air. Finger-stick glucose level was 42 mg/dL. She was severely obese and mildly drowsy but responsive after stimulation. Lungs had decreased basal breath sounds, otherwise clear. Heart sounds were distant with no murmur, rub, or gallop. Abdomen was soft and obese with mild mid-epigastric tenderness but no guarding or rebound. No hepatosplenomegaly was noted. Extremities had no edema, clubbing, or cyanosis. Stool for occult blood was positive. Bladder catheterization yielded only 20 ml of urine. Laboratory values on arrival: arterial blood gas–pH 7.27, PaCO₂ 37 mm Hg, PO₂ 77 mm Hg on room air. Plasma bicarbonate was 9 mmol/L, sodium 144 mmol/L, potassium 8.3 mmol/L, chloride 109 mmol/L, BUN 126 mg/dL, creatinine 6.8 mg/dL, glucose less than 40 mg/dL, calcium 9.2 mg/dL, hemoglobin 11.8 g/dL, WBC 17,800 /μL, platelets 205,000 /μL, PTT 28.9 sec, INR1.2, PT 15.3 sec, albumin 3.5 g/dL, alkaline phosphatase 58 U/L, AST 25 U/L, ALT 34 U/L, lactic acid 6.3 mmol/L, serum acetone negative, serum osmolality 366 mOsm/Kg, anion gap 29, amylase 403 U/L, lipase 275 U/L. Blood cultures on admission were negative. Urinalysis: yellow, cloudy, pH 5.0, specific gravity 1.019, protein greater than 300 mg/dL (4+), glucose negative, ketone negative, bilirubin negative, blood small, nitrites negative, urobilinogen normal, leukocyte esterase negative, WBC 0–5/HPF, RBC 0–3/HPF, hyaline casts 0–5/LPF. No urinary eosinophils were seen. Urine culture had no growth. Electrocardiogram showed sinus tachycardia at a heart rate 100 bpm, peaked T waves, widened QRS, and frequent premature ventricular complexes. Urine toxicology was negative for amphetamines, barbiturates, benzodiazepines, cocaine, methadone, PCP, alcohol, and salicylates, but positive for opioids, most likely reflecting her use of acetaminophen/codeine. Chest X-ray was unremarkable. Abdominal CT scan without contrast was unremarkable except for mild bilateral perinephric stranding.

The patient was immediately treated with IV calcium chloride, insulin/glucose, inhaled albuterol, sodium polystyrene sulfonate, and volume resuscitation. She was transferred to the medical intensive care unit where she underwent emergent hemodialysis and had a second hemodialysis the following day. No further dialysis was required. The patient's urine output started to improve by the third hospital day and normalized by the fourth hospital day. Abdominal ultrasound performed on the third hospital day did not reveal gallstones. She was discharged home after one week with a BUN of 19 mg/dL and a creatinine of 1.2 mg/dL. Within one month the serum amylase and lipase had normalized, and the patient tested negative for protein on urinalysis. The patient's hemoglobin remained stable throughout the admission. She was scheduled for outpatient gastrointestinal evaluation of her incidental guaiac-positive stool.

Discussion

Celecoxib, like the nonspecific cyclo-oxygenase inhibitors, can cause acute kidney dysfunction by several mechanisms, as well as nephrotic syndrome (2,3).This patient had severe acute azotemia, hyperkalemia, and new-onset proteinuria, consistent with this complication. Her acute azotemia was likely secondary to both glomerular hemodynamic factors and glomerular injury. The patient had intravascular volume depletion, much of it likely due to the thiazide diuretic. In this settting, the glomerular filtration pressure is maintained by afferent arteriolar dilatation and efferent arteriolar constriction. However, celecoxib inhibits afferent vasodilatation by inhibiting vascular prostaglandin production. The patient was also on candesartan, an angiotensin II receptor antagonist, which further reduced glomerular filtration pressure by blocking angiotensin-mediated efferent arteriolar constriction. The glomerular filtration may have been further compromised by direct glomerular injury caused by celecoxib, since the 4+ proteinuria was not present before she started taking this drug and subsequently remitted after the drug was discontinued. The cyclo-oxygenase 2 inhibitors, like the non steroidal anti-inflammatory drugs (4) may cause nephrotic syndrome resembling minimal change disease on renal biopsy (3). While drugs in this class may cause interstitial nephritis as well as proteinuria, the bland urine sediment and rapid recovery make this entity less likely.

The acute renal dysfunction led to accumulation of metformin, which precipitated two of the known side effects of this drug: lactic acidosis and acute pancreatitis. There is one previous report of metformin-induced lactic acidosis precipitated by renal failure caused by a cyclo-oxygenase-2 inhibitor (5). Acetaminophen can cause an anion gap metabolic acidosis by depleting reduced glutathione, leading to increased formation of glutamyl cysteine, which is then metabolized to pyroglutamic acid (5-oxoproline) (6). However, our patient clearly had lactic acidosis not induced by acetaminophen, since the lactate level paralleled the rise in anion gap, and the acidosis resolved while the patient continued to receive acetaminophen. Although acetaminophen has been associated with acute renal dysfunction (7), this invariably occurs in patients taking a large overdose of the drug, unlike our patient who took only therapeutic doses.

Despite the initial negative abdominal CT scan, we feel that this patient did have pancreatitis. The amylase and lipase levels did not peak until two days after the scan, suggesting that the scan may have been done too early in the course, and the peak levels of the two enzymes were more than five times the upper limit of normal. Metformin-induced pancreatitis is uncommon (8,9). Our case is similar to that of Mallick (8) in that this complication occurred in the setting of acute renal failure caused by simultaneous inhibition of cyclo-oxygenase and angiotensin II. In our case, the diuretic was probably also a factor, as decreased extracellular fluid volume makes glomerular filtration more angiotensin II-dependent. Hence, the synergistic adverse renal effects of several drugs brought on the untoward effects of another.

In our case, the diagnosis of metformin-associated acute pancreatitis is supported by the lack of other well known causes. The patient did not consume ethanol, had no gallstones, and did not have hypertriglyceridemia, hypercalcemia, or any evidence of trauma. She was on a thiazide diuretic, which has been implicated as a cause of drug-induced acute pancreatitis (10); however, she had been on this drug for many years without this complication. Celecoxib has also been reported to cause acute pancreatitis (11–14). However, our patient had been on celecoxib without acquiring this problem for two months, and the cyclo-oxygenase 2 inhibitors are felt to pose a low risk for pancreatitis (12). Simvastatin, like other drugs in its class, has been associated with acute pancreatitis, particularly in combination with lisinopril and salicylates (15–17). Our patient had been taking simvastatin for several years with no complications and has had no abdominal symptoms for several months after discharge from this hospitalization while continuing to take the drug. Similarly, there is a report of an angiotensin II receptor antagonist causing pancreatitis (18). Our patient was taking candesartan prior to the episode but was restarted on it after discharge without any further abdominal complaints and resolution of her elevated amylase and lipase levels.

Hemodialysis is often required to treat patients with severe metabolic acidosis secondary to the type B lactic acidosis induced by metformin, especially in the setting of impaired renal lactate clearance. The use of sodium bicarbonate hemodialysis is reported not only to help correct the acid-base abnormality, but also to hasten the removal of metformin (19).

Conclusion

In summary, our case illustrates the complications that can arise from multiple drug interactions as the result of polypharmacy in a patient with multiple comorbidities. Particularly noteworthy is the fact that this patient began with apparently normal renal function and developed acute renal failure while on a therapeutic dose of metformin. The combined effect on glomerular hemodynamics of her diuretic, cyclo-oxygenase 2 inhibitor, and angiotensin II receptor antagonist, probably exacerbated by a cyclo-oxygenase 2 inhibitor-induced glomerular injury, led to acute renal failure with accumulation of metformin in the body and subsequently, to two toxic effects of this biguanide (lactic acidosis and pancreatitis). This raises the concern that patients should be counseled to stop taking metformin during periods of acute illness that predispose to volume depletion, especially while concurrently taking drugs that might further compromise kidney function, such as diuretics and cyclo-oxygenase or angiotensin-inhibiting agents (20).