Myoclonic jerks in a post-transplant patient: is tacrolimus the sole culprit?

Ze'ev Korzets1, Suzy Kovatz2, Jacques Bernheim1, Ahmed Iraqi2 and Louis Shenkman2

1 Department of Nephrology 2 Department of Internal MedicineMeir Hospital Sapir Medical Center Kfar-Saba Israel Email: zeevko{at}clalit.org.il

Case

A 35-year-old female, 2 months post-transplant, was admitted because of a transient loss of consciousness. She had developed end-stage renal disease due to lupus nephritis and after 3 months of peritoneal dialysis received a living donor transplant from her mother. The graft functioned immediately post-operation, with serum creatinine stable at 0.8 mg/dl. Maintenance immunosuppressive regimen consisted of prednisone 15 mg o.d., mycophenolate mofetil (MMF) 500 mg b.i.d. and tacrolimus 4 mg b.i.d. Adjunctive prophylactic therapy included co-trimoxazole 500 o.d. and ganciclovir 1 g b.i.d. On admission, she was extremely agitated and disoriented with a marked coarse tremor and multiple myoclonic jerks involving all four limbs. Her body temperature was 37.5°C and supine blood pressure 110/70 mmHg. Generalized hyperreflexia was elicited. There was a haematoma on her chin but no signs of tongue bites or nuchal rigidity.

Relevant history obtained from the parents disclosed that the patient had chronic diarrhoea (up to three loose stools per day) with an exacerbation of bowel motions possibly due to food poisoning over the preceding 12 h.

Laboratory data showed: haemoglobin 13.8 g/dl, WBC 4900/µl, platelets 200 000/µl, urea 57 mg/dl, creatinine 1.4 mg/dl, sodium 140 mEq/l, potassium 3.7 mEq/land calcium 9.5 mg/dl. Blood gases analysis yielded a pH of 7.43, pCO2 31 mmHg and HCO3 21 mEq/l.

Computed tomography of the brain demonstrated no signs of a subdural or intracerebral bleed. Lumbar puncture showed normal cerebrospinal fluid findings. An ultrasound examination of the grafted kidney showed it to be of normal structure and perfusion. A chest X-ray was without pathology.

The patient was administered intravenous ceftriaxone and 2.5 l isotonic saline. On the following day she was much improved, being completely oriented but complaining of generalized paraesthesia and muscle cramps. Her tremor had diminished in intensity but she was still hyperreflexic. Chvostek's and Trousseau's signs were negative. Her laboratory results were: haemoglobin 11.7 g/dl, WBC 3500/µl, sodium 140 mEq/l, potassium 3.1 mEq/l, urea 20 mg/dl, creatinine 1.0 mg/dl, calcium 6.6 mg/dl, albumin 3.1 g/dl and phosphorus 0.7 mg/dl.

Questions

Which is the missing electrolyte?

What factors contributed to this electrolyte's deficiency?

What is the explanation for this patient's profound hypophosphataemia?

Answers to the quiz on the previous page

The appearance of neurological manifestations and/or toxicity in a post-transplant patient implicates a wide differential diagnosis. It includes acute rejection, hypertensive encephalopathy, cytomegalovirus encephalitis, CNS fungal infections, calcineurin inhibitor neurotoxicity and electrolyte disorders. Our patient presented with a temporary loss of consciousness due, in all probability, to vasovagal syncope as a result of volume depletion. Her main neurological picture consisted of a very marked coarse tremor, generalized hyperreflexia and diffuse myoclonal jerks. Diagnostic work-up ruled out a CNS lesion, bleed, infection and encephalitis. In view of her basic underlying disease, lupus cerebritis was considered but eliminated in the presence of a negative anti-DNA and normal complement levels. We are then left with the possibility of either calcineurin inhibitor (tacrolimus)-induced neurotoxicity or an electrolyte disorder. The patient's serum tacrolimus level was 17.7 ng/ml which, at 2 months post-transplant, is within, although towards, the upper acceptable limit [1]. Consequently, the tacrolimus dose was reduced by 50%. Her electrolyte profile was initially masked by her volume-depleted state. Only after volume repletion did her true electrolyte status emerge. It revealed hypokalaemia, hypocalcaemia and hypophosphataemia. This constellation of electrolyte perturbations should always evoke the consideration of hypomagnesaemia. Such, indeed, was the case in our patient in whom the serum magnesium, determined upon finding the above electrolytes, was 0.9 mg/dl. She, therefore, exhibited acute neurotoxicity due to magnesium deficiency possibly aggravated by tacrolimus. Hypomagnesaemia has, in fact, been shown to predispose to calcineurin inhibitor neurotoxicity [2].

The magnesium deficiency in our patient resulted from both gastrointestinal and renal loss. She was known to be suffering from chronic diarrhoea probably induced by MMF. Serum magnesium, 2 weeks previous, was 1.6 mg/dl. Gastrointestinal loss was undoubtedly exacerbated by her bout of food poisoning immediately prior to admission. Renal loss, that is hypermagnesuria (urinary excretion of 110 mg/day with a fractional magnesium excretion of 27%), was due to tacrolimus. Drugs associated with renal magnesium wasting include diuretics (most common), aminoglycosides, cisplatin, amphotericin B, pentamidine and the calcineurin inhibitors.

The patient's profound hypophosphataemia is more of an enigma. With this degree of hypomagnesaemia, parathyroid hormone (PTH) secretion is essentially abolished and is coupled with bone resistance to PTH action [3]. Parenteral magnesium administration leads to an almost immediate rise in plasma PTH levels. However, restoration of PTH responsiveness occurs significantly later. This hypoparathyroid state is one of the major factors responsible for the hypocalcaemia seen concomitantly with hypomagnesaemia. In alcoholic patients, hypophosphataemia is a frequent accompaniment probably due to these patients' low baseline phosphorus levels as a result of malnutrition. This, however, was not applicable in our patient who was in a good nutritional state and in whom pre-admission serum phosphorus was within the normal range. Her extreme hypophosphataemia is attributable to gastrointestinal loss and phosphaturia as judged by a tubular reabsorption of phosphate of 75%. Post-transplant hypophosphataemia has been associated with, among other factors, impaired expression of the proximal tubule brush border membrane type IIa Na/Pi cotransporter [4]. It is tempting to speculate that magnesium may modulate the activity of this cotransporter.

Our patient was administered intravenous magnesium, calcium and phosphorus. She developed polyuria due both to increased free water excretion and a solute diuresis. Hypomagnesaemia proved to be somewhat refractory due to the known inhibitory action of a raised magnesium level on renal magnesium reabsorption. Eventually, correction of the hypomagnesaemia resulted in a return to normal values of all her electrolytes. She was discharged on an immunosuppressive regimen as outlined above with a reduction of tacrolimus dose to 2 mg b.i.d. and oral magnesium supplementation of 24 mmol/day. Her latest serum magnesium is 1.7 mg/dl. Obviously, future management entails close monitoring of serum magnesium and, accordingly, possible withdrawal of tacrolimus.

References

  1. Shapiro R. Tacrolimus in renal transplantation—A review. Graft 2000; 3:64–80
  2. Bechstein WO. Neurotoxicity of calcineurin inhibitors: impact and clinical management. Transplant Int 2000; 13:313–326[CrossRef][ISI][Medline]
  3. Agus ZA. Hypomagnesemia. J Am Soc Nephrol 1999; 10:1616–1622[Free Full Text]
  4. Levi M. Nephrology Forum. Post-transplant hypophosphatemia. Kidney Int 2001; 59:2377–2387[CrossRef][ISI][Medline]




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