Pyroglutamic acidosis in a renal transplant patient

Carole L. Foot, John F. Fraser and Daniel V. Mullany

Critical Care Research Group, The Prince Charles Hospital, Brisbane, Australia

Correspondence and offprint requests to: Dr John F. Fraser, Critical Care Research Group, The Prince Charles Hospital, Rode Road, Chermside 4032, Brisbane, Australia. Email: j.fraser{at}uq.edu.au

Keywords: Acid-base disorders; acidosis; glutathione; renal transplant



   Introduction
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Metabolic acidosis is a common acid–base disorder in critically ill patients. Elucidation of the cause usually commences with the calculation of the anion gap. Increased anion gap metabolic acidosis is commonly due to lactic acidosis, renal failure, ketoacidosis as well as a multitude of drugs including toxic alcohols. Pyroglutamic acidosis (5-oxoprolinuria) is a rare cause of increased anion gap acidosis and has not previously been reported in a renal transplant patient.



   Narrative
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A 57-year-old married female presented to the hospital with a two day history of lethargy, anorexia and increasing dyspnoea. Her past medical history was extensive. Four years ago she had a renal transplant for medullary sponge kidneys which was failing despite ongoing immunosuppression. Her baseline creatinine was 0.22 mmol/l [reference range (RR) 0.05–0.1]. She had experienced recurrent urinary tract infections, the most recent episodes due to Klebsiella and Enterococcus species, respectively. A ureteric re-anastomosis procedure had been required two years previously for stenosis, which subsequently required insertion of a stent for management of renal calculi in the collecting system the following year. She had moderately severe mitral valve regurgitation associated with mitral valve prolapse, preserved left ventricular function and mild left atrial dilatation. An adhesion-related small bowel obstruction required an ileostomy eight months before presentation, which was reversed six months after this. This was complicated by wound breakdown and sinus formation. She was colonized with methicillin-resistant Staphylococcus aureus (MRSA). Her regular medications were tacrolimus, mycophenolate, prednisolone, amlodipine, sodium bicarbonate, calcitriol, caltrate and multivitamins. Her husband admitted that she also regularly self-administered unknown quantities of analgesics for chronic abdominal pain including preparations containing aspirin, codeine and paracetamol (acetaminophen).

Clinical examination revealed a confused drowsy patient with a GCS of 13 (E3, M6, V4). She was tachycardiac (HR120 beats per minute and regular) and hypotensive (blood pressure 80/40). She was hypothermic (axillary temperature 34°C) with warm vasodilated peripheries. She had Kussmaul breathing with a respiratory rate of 32 breaths per minute. She had dry mucous membranes and ecchymoses scattered over her limbs and trunk. Her chest was clear to auscultation. Her abdomen was soft and diffusely tender without rebound or guarding. There were no signs of meningism or localizing neurological signs. Her right knee was grossly swollen and appeared painful with any movement.

The chest X-ray was unremarkable with a normal heart size and clear lung fields. A 12 lead ECG was normal except for a sinus tachycardia of 120 beats per minute. An arterial blood gas on room air revealed a pH of 6.99 (RR 7.35–7.45), paCO2 7 (RR 35–45), paO2 92 (RR75–100) and HCO3 2 (RR22–33), which was consistent with a severe metabolic acidosis with respiratory compensation. The results of initial haematological and biochemical investigations are provided in Table 1.


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Table 1. Haematological and biochemical investigations

 
The presumptive diagnosis was bacterial sepsis with severe metabolic acidosis, and liver and renal dysfunction. The most likely sources of infection included the urinary tract, abdomen and septic arthritis. In order to clarify the cause of the severe acidosis, further investigations were performed. The anion gap was 31 (RR 4–13 mmol/l) and osmolar gap was minimally elevated at 23 (RR <15 mmol/kg), with a measured osmolarity of 335 and calculated osmolarity of 312 (RR 275–295 mmol/kg). The lactate was 1.6 (RR 0.7–2.5 mmol/l). Ethanol was not detected. Paracetamol was in the therapeutic range at 20 (RR 10–25 mg/l). Similarly, the salicylate level was in the non-toxic range at 85 (RR <100 mg/l). Ketones were identified on a dip stick test of urine. Urine was sent for an organic acid screen, as pyroglutamic acidosis was suspected given the patients risk factors for this condition.

The severe metabolic acidosis was initially attributed to a combination of acute on chronic renal failure, starvation ketosis and sepsis; however, unexplained anions were thought to be present. The urine organic acid screen later confirmed a large elevation of pyroglutamate at 3700 (RR <100 mmol/l).

She was managed in an intensive care unit with fluid resuscitation, inotrope and vasopressor infusions, ventilation, haemodiafiltration, corticosteroid replacement and broad spectrum antibiotics. The cause of septic shock was septic arthritis with MRSA grown in the right knee aspirate and blood cultures. Despite washouts of the knee joint and a month of maximal supportive and specific therapies, she died in the intensive care unit from multiple organ failure.



   Discussion
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Pyroglutamic acidosis has been well described in both paediatric and adult patients. Pyroglutamic acid is an intermediate in the gamma-glutamyl cycle which is involved in the uptake of amino acids into cells. This cycle, which is regulated by five specific enzymes, is shown in Figure 1.



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Fig. 1. Outline of the pyroglutamic acid cycle.

 
Congenital pyroglutamic acidosis arises from specific enzyme defects (e.g. glutathione synthetase or 5-oxoprolinase deficiency), which cause a disease marked by neonatal metabolic acidosis, haemolytic anaemia and progressive encephalopathy [2]. There is some evidence that children with malnutrition have a relative glycine deficiency contributing to their impaired growth, that may be detected by screening for urinary pyroglutamic acid [3]. This is because glycine combines with gamma-glutamyl cysteine to form glutathione in a reaction catalyzed by the enzyme glutathione synthetase. If glycine is deficient, precursors in the cycle, including gamma-glutamyl cysteine, glutamate and pyroglutamic acid, accumulate. A similar phenomenon has been described during normal pregnancy [4] and severe burns with relative glycine deficiency [5].

In adults, transient pyroglutamic acidosis is distinguished by an acute onset, without chronic symptoms or a family history, and has been well described [6–9]. A major risk factor for this condition is paracetamol (acetaminophen) ingestion. The acetaminophen metabolite N-acetylbenzoquinonimine reacts irreversibly with glutathione and it is hypothesized that precursors accumulate as they are unable to be converted to glutathione because of a relative depletion or inhibition of the rate limiting enzyme glutathione synthetase. In the absence of glutathione, N-acetylbenzoquinonimine forms compounds that are hepatotoxic. This sequence of events explains both the mechanism of pyroglutamic acid accumulation as well as acetaminophen associated toxicity [1]. Other identified risk factors for pyroglutamic acidosis are flucloxacillin ingestion (which may inhibit the enzyme 5-oxoprolinase that converts pyroglutamic acid to glutamate), vigabatrin, sepsis, hepatic and/or renal dysfunction [8] and female sex [1].

N-acetylcysteine is the well known antidote for acetaminophen toxicity by virtue of its ability to regenerate liver glutathione stores. Theoretically, it may help limit pyroglutamic acid synthesis by restoring intermediates in the gamma-glutamyl cycle; however, its efficacy in this scenario has been largely unexplored [8]. There is no data concerning the use of N-acetylcysteine in patients with pyroglutamate acidosis in renal transplant patients.

This case report serves as a succinct review of an uncommon disorder, and is the first report of this condition in patients who have had a renal transplant. The patient presented demonstrated most of the risk factors for transient pyroglutamic acidosis. In patients with inexplicable raised anion gap acidosis and risk factors, the diagnosis of pyroglutamic acidosis should be considered. A relatively simple urinary organic acid screen will confirm the diagnosis. Finally, the presence of unmeasured anions is also a marker of illness severity, superior to blood lactate anion gap or base excess in predicting mortality [10].

Conflict of interest statement. None declared.



   References
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 Introduction
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 Discussion
 References
 

  1. Pitt J, Hauser S. Transient 5-oxoprolinuria and high anion gap metabolic acidosis: clinical and biochemical findings in eleven subjects. Clin Chem 1998; 44: 336–340[Abstract/Free Full Text]
  2. Al-Jishi E, Meyer B, Rashed M et al. Clinical, biochemical, and molecular characterization of patients with glutathione synthetase deficiency. Clin Genet 1999; 55: 444–449[CrossRef][ISI][Medline]
  3. Persaud C, Forrester T, Jackson A. Urinary excretion of 5-L-oxoproline (pyroglutamic acid) is increased during recovery from severe childhood malnutrition and responds to supplemental glycine. J Nutr 1996; 126: 2823–2830[ISI][Medline]
  4. Persaud C, McDermott J, De Benoist B et al. The excretion of 5-oxoproline (pyroglutamic acid) as on index of glycine status during normal pregnancy. Br J Obstet Gynaecol 1989; 96: 440–444[ISI][Medline]
  5. Yong-Ming Y, Ryan C, Zhe-Wei F et al. Plasma L-5-oxoproline kinetics and whole blood glutathione synthesis rates in severely burned adult humans. Am J Physiol Endocrinol Metab 2002; 282: 247–258
  6. Creer H, Lau B, Jones J, Chan K. Pyroglutamic acidemia in an adult patient. Clin Chem 1989; 35: 684–686[Abstract/Free Full Text]
  7. Croal B, Glen A, Kelly C, Logan R. Transient 5-oxoprolinuria (pyroglutamic aciduria) with systemic acidosis in an adult receiving antibiotic therapy. Clin Chem 1998; 44: 336–340[Abstract/Free Full Text]
  8. Dempsey G, Lyall H, Corke C, Scheinkestel C. Pyroglutamic acidemia: a cause of high anion gap metabolic acidosis. Crit Care Med 2000; 28: 1803–1807[CrossRef][ISI][Medline]
  9. Mizock B, Belyaev S, Mecher C. Unexplained metabolic acidosis in critically ill patients: the role of pyroglutamic acid. Intensive Care Med 2004; 30: 502–505[CrossRef][ISI][Medline]
  10. Balasubramanyan N, Havens P, Hoffman G. Unmeasured anions identified by the fencl-Stewart method predict mortality better than base excess, anion gap, and lactate in patients in the pediatric intensive care unit. Crit Care Med 1999; 27: 1577–1581[CrossRef][ISI][Medline]
Received for publication: 20. 7.05
Accepted in revised form: 6. 9.05





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