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Mayo Clin Proc. 2009 November; 84(11): e5–e8.
PMCID: PMC2770914

71-Year-Old Man With Chronic Kidney Failure and Sudden Change of Mental Status

Aaron S. Mansfield, MD* and Qi Qian, MD

A 71-year-old man was admitted to the hospital for altered mental status. His wife reported that the patient had become progressively confused and had been having visual hallucinations, seeing people and animals that were not really there. These symptoms started about 2 weeks before admission as intermittent episodes. She could not identify any triggering events or temporal pattern for these episodes. In the past 2 days, the patient's symptoms had become more persistent. She added that he had become increasingly forgetful in the past year but had had no problem performing simple tasks or taking care of himself. This type of confusion had never occurred previously.

The patient had a 12-year history of type 2 diabetes, had undergone coronary artery bypass 3 years previously, had symptomatic peripheral vascular insufficiency, and had stage V chronic kidney disease primarily due to diabetic nephropathy. For the past 10 months, he had been undergoing hemodialysis 3 times weekly for 3.5 hours each time via a left arm arteriovenous fistula. He had last undergone dialysis 3 days previously and was due for his scheduled dialysis on the day of admission.

Two months before admission, the patient developed critical lower limb ischemia and a nonhealing left foot ulcer. Multiple vascular interventions failed to restore sufficient limb blood flow; a month later, the patient underwent a transmetatarsal amputation. Postoperatively, he developed surgical wound infection, necessitating repeated debridement and intravenous vancomycin administration.

The patient's medications included stable doses of aspirin, atenolol, atorvastatin, calcium acetate, insulin, gabapentin, and more recently vancomycin. He had been taking 300 mg of gabapentin 4 times daily for several years, which effectively controlled his diabetic neuropathic pain. Vancomycin was administered during hemodialysis according to blood levels. He had been adherent to his medication and dialysis regimen.

On physical examination, the patient was afebrile and somnolent but arousable. His vital signs were as follows: blood pressure, 138/88 mm Hg; pulse, 60 beats/min (regular); respiratory rate, 14 breaths/min; and oxygen saturation while breathing room air, 98%. He was euvolemic without pericardial rubs. His left metatarsal stump wound was healing. Waking up periodically, he claimed that he had missed an important appointment in court and indicated the presence of a cowboy and a bird in the room.

  1. Which one of the following is the most likely cause of this patient's altered mental status?
    1. Infection
    2. Stroke
    3. Lewy body dementia
    4. Uremia
    5. Medication toxicity
    Altered mental status is common in patients with multiple comorbid conditions and can be triggered by a variety of acute illnesses. On occasion, it may be the sole symptom of systemic infection. Therefore, infections such as pneumonia and urinary tract infections should be included in the differential diagnosis and be ruled out. However, our patient was afebrile, had no other respiratory or urinary symptoms, and had recently been treated with antibiotics. Therefore, infection would not be the most likely cause of his presentation.
    The vivid hallucinations and intermittent symptoms of altered mental status are atypical for stroke, especially without any focal neurologic deficits. Therefore, stroke would not be a likely cause of this presentation.
    Lewy body dementia (LBD) is associated with Parkinson disease or Parkinson-like motor disorder. Patients with LBD exhibit fluctuations in alertness and complex hallucinations that often involve people or animals. The hallucinations may precede overt dementia and movement disorder. Although LBD could be consistent with this patient's presentation, the abrupt onset and rapid progression would be very atypical in LBD, making this diagnosis unlikely.
    The patient's history of adherence to regular dialysis and the absence of the physical signs of uremia suggest that the decreased alertness and hallucinations are not a result of uremia. Moreover, at the time dialysis was initiated he was truly uremic and failed to demonstrate similar symptoms.
    Multiple agents (contrast agents for computed tomography and magnetic resonance imaging as well as perioperative and postoperative antibiotics) had been given to the patient recently. Medication toxicity, especially in the setting of renal failure, should be considered as a potential and likely cause of his presentation.
    This patient underwent dialysis on the day of admission. Immediately after dialysis, his hallucinations improved transiently but recurred between dialysis sessions.
  2. Which one of the following laboratory and/or imaging studies is least likely to yield useful information at this point in the evaluation?
    1. Complete blood cell count (CBC) and serum electrolyte panel including measurement of glucose levels
    2. Electroencephalography
    3. Magnetic resonance imaging (MRI) of the head
    4. Serum gabapentin level
    5. Arterial blood gas
    Our patient was known to have diabetes, to be undergoing dialysis, and to have had recent surgery and wound infection. An electrolyte panel with measurement of glucose concentration and a CBC were indicated to provide clues for active infection and to rule out substantial electrolyte abnormalities and hypoglycemia. Although seizure was unlikely given the patient's history, electroencephalography could provide useful corroborative information. Structural abnormalities, such as brain atrophy and mass lesion, can be evaluated using MRI of the head. Gabapentin is eliminated exclusively in urine; it accumulates in blood in patients with renal failure. Excessive accumulation can cause varying neurologic toxicities, including hallucinations and coma. Thus, gabapentin level should be obtained.
    Arterial blood gas would be least helpful at this point because the patient had no respiratory symptoms or signs of labored breathing and his oxygen saturation while breathing room air was 98%.
    In our patient, a CBC revealed the following: hemoglobin, 11.3 g/dL (reference ranges provided parenthetically) (13.5-17.5 g/dL); white blood cells, 5.7 × 109/L (3.5-10.5 × 109/L); and platelets, 228 × 109/L (150-450 × 109/L). The results of the electrolyte panel were as follows: sodium, 130 mEq/L (135-145 mEq/L); potassium, 5.4 mEq/L (3.6-4.8 mEq/L); bicarbonate, 21 mEq/L (22-29 mEq/L); chloride, 102 mEq/L (100-108 mEq/L); blood urea nitrogen, 48 mg/dL (8-24 mg/dL); creatinine, 5.2 mg/dL (0.8-1.3 mg/dL); and glucose, 128 mg/dL (70-100 mg/dL). An MRI of the head revealed mild brain atrophy without mass lesion, acute ischemia, or hemorrhage. Electroencephalography showed nonepileptogenic, mild bitemporal slowing.
    The patient underwent a full dialysis session; about 2 hours after dialysis (and before the next dosing), gabapentin levels were 26.8 μg/mL. Because circulating gabapentin is eliminated efficiently during dialysis, this level reflects the tissue rebound and indicates that the patient's predialysis level was markedly elevated.
  3. Which one of the following is most likely responsible for the elevated serum gabapentin level?
    1. Batch-to-batch variations of gabapentin administered to the patient
    2. Drug-drug interaction
    3. Acute overdosing
    4. Loss of residual kidney function
    5. Inadequate hemodialysis
    Gabapentin is well absorbed and is not known to have batch-to-batch variations in its bioavailability. In the blood-stream, gabapentin is not bound by protein. Thus, coadministered medications that bind serum protein do not affect the circulating level of gabapentin. Gabapentin is not metabolized hepatically and thus is not affected by the variations in the activities of the hepatic cytochrome system, and its effect is not induced or inhibited by coadministered medications. Therefore, molecular or pharmacokinetic drug-drug interactions are unlikely to account for the gabapentin accumulation. This patient had been taking his medications as prescribed, and no history of acute overdosing either by himself or family members was elicited.
    Gabapentin is renally excreted. A reduction in the capacity of renal excretion could elevate the blood level of gabapentin, triggering neurologic symptoms, as reported previously.1,2 Our patient had only recently begun undergoing dialysis and was expected to have substantial residual renal clearance. However, the repeated exposure to intravenous contrast agent for the evaluation of limb ischemia could have eradicated his residual renal clearance, leading to gabapentin accumulation.
    The patient had been adherent to the dialysis regimen, and the delivered dialysis (determined by Kt/V) had been adequate in the past several months. Thus, insufficient dialysis is unlikely to be the major inciting factor.
    On further questioning, our patient acknowledged a progressive decline in urine output; he was almost anuric on admission. The loss of residual kidney function likely resulted in the escalating accumulation of gabapentin.
  4. Which one of the following is the most likely risk factor for hallucinations as a manifestation of gabapentin toxicity in our patient?
    1. Concomitant β-blocker intake
    2. Diffuse atherosclerotic vascular disease
    3. Diabetic nephropathy
    4. Excessive inhibition of presynaptic Ca2+ influx
    5. Mild degree of dementia
    β-Blockers are known to inhibit the release of certain adrenergic neurotransmitters. Although the analgesic effect of gabapentin is generally thought to lie in the blockade of presynaptic release of neurotransmitters, including acetylcholine, norepinephrine, and serontonin,3,4 β-blockers are not known to alter the effects of gabapentin. Our patient had been taking atenolol and gabapentin concurrently for years without any apparent toxicity.
    Gabapentin is actively transported to brain tissue. Atherosclerotic vascular changes have not been shown to diminish its entry to brain tissue or alter the pattern of its delivery or distribution. It remains efficacious in pain control for patients with severe atherosclerotic vascular disease, as in our patient.
    Diabetic nephropathy was the major cause of kidney failure in our patient. However, diabetic nephropathy per se is not known to elicit a predilection for gabapentin-induced neurotoxicity, including hallucinations, over other causes of kidney failure.
    Inhibition of presynaptic Ca2+ influx by gabapentin is the major putative mechanism that leads to the desired analgesic effect. Such a mechanism does not necessarily account for the underlying cause of neurotoxicity.
    Dementia, mild or severe, is associated with an increased occurrence of gabapentin-induced changes in mental status.5,6 In patients with mild dementia, gabapentin has been shown to dramatically worsen the neuropsychiatric disturbances, leading to a psychoagitation complex dominated by ideas of reference and persistent hallucinations.5
    Our patient had notable memory loss, suggesting a possible incipient dementia, a condition that could have predisposed him to neuropsychiatric symptoms triggered by gabapentin toxicity.
  5. Which one of the following interventions would be most appropriate for this patient?
    1. Reduce gabapentin to 100 mg 3 times daily
    2. Reduce gabapentin to 300 mg after each dialysis
    3. Discontinue gabapentin
    4. Add flumazenil to the patient's regimen
    5. Increase the duration of each hemodialysis session
    Gabapentin is excreted through the kidneys with a half-life of 5 to 7 hours in individuals with normal kidney clearance. In patients with reduced kidney function, its half-life increases up to 132 hours (without dialysis).7
    The reference dosing range for gabapentin in patients with chronic kidney dysfunction (stage III to V) is 100 to 1400 mg/d. However, for individual patients, gabapentin dosing should be further adjusted on the basis of the degree of kidney dysfunction and the estimated drug half-life.
    The tissue content of gabapentin is linearly proportional to the blood level, and hemodialysis efficiently removes circulating gabapentin. A reduction in dosage but not in dosage frequency could result in an initial subtherapeutic drug level after dialysis and a supratherapeutic level before the next dialysis. Therefore, reducing only the dosage, eg, 100 mg 3 times daily, is not appropriate. Reducing the dosing frequency to 300 mg after each dialysis will maintain an adequate blood level8 and is most appropriate for our patient.
    Gabapentin is efficacious for controlling neuropathic pain, such as that experienced by our patient. Discontinuation would not be appropriate. Flumazenil is used for reversal of central nervous system depression secondary to benzodiazepines. It has not been established for the treatment of gabapentin toxicity.
    Increasing the duration of each hemodialysis session without changing dosing frequency will not prevent gabapentin toxicity because repeated doses between dialysis sessions will result in excessive gabapentin accumulation.
    In our patient, gabapentin was withheld for 1 day and reinitiated at 300 mg after dialysis 3 times weekly. His predialysis gabapentin level decreased to 16.6 μg/mL, and his mental status was restored to baseline.


This case exemplifies the complexity of caring for patients with chronic kidney disease and multiple comorbid conditions; devastating toxicity can occur with a seemingly well-tolerated medication, even at the reference dosing range.

Chronic kidney failure has become a global epidemic,9,10 and one of the major causes is diabetes. Patients with diabetes and nephropathy commonly exhibit concurrent diabetic neuropathy. Gabapentin has frequently been used to palliate neuropathic pain.

Gabapentin was released in the United States in 1993 as an anticonvulsant agent. In a number of clinical and preclinical trials, gabapentin has been shown to be not only a well-tolerated and efficacious anticonvulsant agent but also an anxiolytic and analgesic agent. In recent years, it has increasingly been used off-label for expanded indications, including phantom limb pain, uremic pruritus, hot flashes, and diabetic neuropathy.

A water-soluble 1-(aminomethyl)-cyclohexaneacetic acid and an analogue of γ-aminobutyric acid, gabapentin (C9H17NO2) readily crosses the blood-brain barrier and is actively transported into the brain tissue via system L.11 The concentration of gabapentin in brain tissue is shown to be similar to or higher than that in blood.

At neuronal synapses, gabapentin binds to the presynaptic auxiliary subunit of voltage-sensitive Ca2+ channels (VSCCs) and inhibits depolarization-induced Ca2+ influx via VSCCs. Voltage-sensitive Ca2+ channels are composed of a Ca2+-channel—forming α1 subunit, a disulfide-linked auxiliary α2δ subunit, and an intracellular γ subunit.12 Four subtypes of α2δ (α2δ-1 to α2δ-4) allosterically modulate the channel-forming α1 subunit. Gabapentin binds primarily to α2δ-1. In human neocortical slices, gabapentin binds α2δ-1 and inhibits the voltage-induced presynaptic Ca2+ influx, leading to a diminution in the exocytic release of neurotransmitters, including acetylcholine, noradrenaline, and serotonin.3 Targeted deletion of the gabapentin-binding α2δ-1 in mice results in a loss of gabapentin-mediated analgesia.4

Although these experimental data indicate that gabapentin mediates analgesia by inhibiting presynaptic VSCC, investigators have also discovered the existence of less well-defined, α2δ-1—mediated regulatory pathways, independent of VSCC function.13 Thus, a complete spectrum of gabapentin-mediated pharmacological and toxicological effects has yet to be fully elucidated. Moreover, gabapentin shows minimal effects under physiologic conditions but markedly alters the profile of synaptic neurotransmitters during neuronal hyperexcitability. Thus, the final outcome in patients with underlying structural and functional alterations of the brain, as in dementia, may be dictated by the interplay of multiple variables: the density, distribution, and responsiveness of presynaptic VSCCs; the degree of Ca2+-independent regulatory effects; and the state of neuronal excitability.

Gabapentin is well absorbed from the gastrointestinal tract, has a consistent 50% to 60% bioavailability, and is unaltered in patients with kidney dysfunction.7 In circulation, it is neither bound by protein nor metabolized. Although a target blood level is not defined, 8 to 20 μg/mL has been found to correlate with clinical efficacy. Gabapentin is eliminated in urine at a rate proportional to creatinine clearance.7 Thus, with preserved gastrointestinal absorption and diminished kidney elimination, progressive kidney failure (frequently underrecognized) poses a considerable risk of gabapentin toxicity.

In our patient, the transient improvement in mental status immediately after hemodialysis provided an important clue to the diagnosis. Because gabapentin can be readily dialyzed, a postdialysis level of 26.4 μg/mL predicted a highly elevated predialysis level in at least the mid-40s.8

Another clue to possible gabapentin toxicity was the diminution in urine output that preceded the onset of neurologic symptoms. For several years, our patient had been taking the same dosage of gabapentin without neurologic manifestations. The new symptoms associated with an elevated blood gabapentin level likely resulted from further loss of kidney clearance due to repeated exposure to intravenous contrast agent. This possibility was confirmed when the patient's predialysis gabapentin level decreased to an acceptable range after the dose reduction (the only modification made in the patient's regimen). Concurrently, he regained mental alertness, and the hallucinations disappeared.

This case offers several learning points. First, patients with incipient dementia are susceptible to mental status alterations as a result of systemic disorders, including drug toxicity. Second, a seemingly well-tolerated medication with an excellent pharmacokinetic profile can cause devastating and potentially life-threatening toxicities. Third, residual kidney function is important for patients receiving long-term dialysis; loss of residual function could lead to serious clinical consequences and should be considered in formulating a diagnosis. Fourth, medication toxicity can occur in patients with kidney failure, even within the general reference dosing range. Even before the loss of residual kidney clearance, our patient was receiving an inappropriately high dosage of gabapentin. His residual kidney clearance had prevented him from developing overt toxicity. Thus, it is imperative that drug dosing be tailored to the individual patient and monitored on an ongoing basis.

As the population ages, an ever larger number of our patients will be elderly and have kidney dysfunction and multiple comorbid conditions. Medical care for these patients has become increasingly complex and challenging. Subtle changes in the baseline level of organ function can dramatically affect patients' responses to treatment. Recognizing such complexity will help avoid excessive investigative work-ups and improve quality of care.


See end of article for correct answers to questions.

Correct answers: 1. e, 2. e, 3. d, 4. e, 5. b


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