Acquired 5-oxoproline acidemia successfully treated with N-acetylcysteine

Abstract

Acquired 5-oxoprolinemia is increasingly recognized as a cause of anion gap metabolic acidosis. It predominantly occurs in chronically ill, malnourished women with impaired renal function and chronic acetaminophen ingestion. Depletion of glutathione and cysteine stores leads to elevated 5-oxoproline levels. N-acetylcysteine, given its effect in repleting glutathione and cysteine stores, has been proposed as a potential treatment for 5-oxoprolinemia, though reports of its successful use are lacking. We present a case of 5-oxoproline metabolic acidosis that persisted despite discontinuation of acetaminophen. However, the acidosis rapidly resolved with N-acetylcysteine administration.

We report a case of an anion gap metabolic acidosis due to 5-oxoprolinemia that rapidly resolved with administration of N-acetylcysteine (NAC).

CASE REPORT

A 38-year-old woman who had bilateral lung transplantation 4 months earlier for restrictive lung disease was transferred from a rehabilitation facility to the hospital because of acidemia. Her posttransplant course was complicated by an episode of acute rejection, several episodes of pneumonia, malnutrition requiring gastric feeding tube placement with nutrition primarily through tube feedings, and several episodes of acute kidney injury (AKI) requiring renal replacement therapy (RRT). Her immunosuppression regimen included tacrolimus, mycophenolate mofetil, and prednisone. She had been discharged from this same hospital 2 weeks prior when she was admitted for pneumonia with oliguric AKI in the setting of sepsis that required a prolonged course of RRT. During the final 2 weeks of this prior hospitalization, she had renal recovery with adequate urine output and a serum creatinine of 0.91 mg/dL at the time of discharge. Over this same time period, she experienced abdominal pain around the site of her feeding tube that was treated with 650 mg to 1300 mg of acetaminophen daily. On the day of discharge, her anion gap had risen to 29 mEq/L.

After 2 weeks in a rehabilitation facility, she was transferred back to the hospital for persistent acidemia. A blood gas on admission revealed a pH of 7.29 with serum bicarbonate of 12 mg/dL, partial pressure of carbon dioxide of 27 mm Hg, anion gap of 28 mEq/L, and albumin of 1.8 g/dL. These results suggested an anion gap metabolic acidosis with appropriate respiratory compensation. Based on the delta-delta calculation, she had a simultaneous metabolic alkalosis likely related to oral bicarbonate administered at the rehabilitation facility. Evaluation into the etiology of her anion gap metabolic acidosis included serum creatinine 0.91 mg/dL, L-lactate 0.8 mmol/L, undetectable D-lactate, undetectable urine ketones and serum salicylates, calculated serum osmolality of 295 mosm/kg, and a measured serum osmolality of 304 mosm/kg. Urine pH was 5.0 with a calculated urine anion gap of +23. A serum acetaminophen level was <2.0 μg/mL. Ultimately, a urine organic acid screen was performed and revealed a markedly elevated 5-oxoproline level of 17,455 mmol/mol creatinine (reference range <62) with no other unusual organic acids detected.

Given a high degree of suspicion for 5-oxoprolinemia, acetaminophen was discontinued at the time of readmission. However, the anion gap remained elevated in the 25 to 31 mEq/L range for the next 7 days while the urine organic acid screen was pending. Once the results of the urine organic acid screen returned, NAC was administered intravenously at a dose of 150 mg/kg over 60 minutes followed by 50 mg/kg over 4 hours followed by 100 mg/kg over 16 hours. Subsequently, the anion gap declined rapidly and her acidemia resolved (Figure 1).

Figure 1.

Anion gap trend over the patient's hospital courses. Anion gap (mEq/L) is represented on the y axis, and the timing of acetaminophen and N-acetylcysteine (NAC) is marked on the plot.

DISCUSSION

5-oxoprolinemia is increasingly recognized as a cause of anion gap metabolic acidosis. Many cases likely go undiagnosed due to lack of a universally available assay for 5-oxoproline. The patient described above fits the classic profile for a patient with 5-oxoproline metabolic acidosis: a chronically ill, malnourished woman with chronic kidney disease (1–4). She had multiple serious complications after lung transplantation. She suffered from malnutrition due to recurrent infections and deconditioning, which left her reliant on tube feedings. Though her serum creatinine was in the “normal” range, that value was likely deceptive due to her low muscle mass and her recurrent episodes of AKI requiring RRT suggestive of chronic kidney disease.

5-oxoproline is an organic acid intermediate of the γ-glutamyl cycle (Figure 2), which produces the antioxidant glutathione. 5-oxoprolinemia and its resultant anion gap metabolic acidosis can occur from both hereditary and acquired mechanisms. Hereditary causes include rare deficiencies in two essential enzymes in the γ-glutamyl cycle: glutathione synthetase and 5-oxoprolinase (5). Acquired 5-oxoprolinemia results from longstanding depletion of glutathione and cysteine stores that occurs due to malnutrition, sepsis, and chronic acetaminophen use (6). The acetaminophen is typically not in the toxic range and is more often due to chronic use within the accepted therapeutic range. Reduced glutathione levels eliminate the feedback inhibition of γ-glutamyl cysteine synthetase (Figure 2), causing accumulation of γ-glutamyl cysteine that is subsequently metabolized to 5-oxoproline. Reduced cysteine levels prevent conversion of γ-glutamyl phosphate to γ-glutamyl cysteine despite the increased activity of γ-glutamyl cysteine synthetase, as cysteine is required for this reaction. Instead, γ-glutamyl phosphate is converted to 5-oxoproline as part of a futile ATP-depleting cycle (4).

Figure 2.

The γ-glutamyl cycle. Reprinted from Fenves et al, 2006 (2) with permission from the American Society of Nephrology.

The utility of NAC for acute acetaminophen toxicity is well known (7). It has also been postulated that NAC may be of benefit in cases of acquired 5-oxoprolinemia, as it has been shown to increase glutathione and cysteine levels in patients with hereditary glutathione synthetase deficiency (8). Theoretically, repletion of glutathione stores should reestablish the feedback inhibition of γ-glutamyl cysteine synthetase, thereby reducing the conversion of γ-glutamyl cysteine to 5-oxoproline. Repletion of cysteine stores should reestablish conversion of γ-glutamyl phosphate to γ-glutamyl cysteine, thereby preventing conversion of γ-glutamyl phosphate to 5-oxoproline and breaking the futile ATP-depleting cycle. Reported evidence in the literature supporting NAC administration for 5-oxoprolinemia is limited (9, 10). Although the profound anion gap metabolic acidosis persisted for a week in our patient despite discontinuation of acetaminophen, the anion gap metabolic acidosis rapidly resolved after NAC administration. We suggest that NAC, along with discontinuation of acetaminophen, is the preferred treatment for 5-oxoproline metabolic acidosis.