Reversal of oliguric tacrolimus nephrotoxicity in children

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Background. Acute tacrolimus toxicity is manifest by oliguria and elevated serum creatinine. Various vasoregulatory molecules have been implicated in calcineurin inhibitor-mediated nephrotoxicity, including calcium, adenosine and endothelin. Theophylline (THEO), a non-specific adenosine-receptor antagonist prevents renal dysfunction from various nephrotoxins which mediate vasoconstriction. In the setting of acute tacrolimus toxicity, we demonstrated that administration of THEO along with a loop diuretic (LD) enhanced diuresis. This randomized, controlled trial was undertaken to confirm these earlier findings under more rigorous conditions. Methods. Children with non-renal visceral transplant(s) and evidence of tacrolimus nephrotoxicity oliguria with a 25% increase in serum creatinine concentration from baseline, a whole blood tacrolimus concentration >20 ng/dl and oliguria resistant to therapy with a LD were randomized to receive either THEO (n = 10) or normal saline placebo (n = 8). Using pre and post (6 h) timed urine collections and coincident plasma concentrations the following were measured or calculated: urine flow rate, net fluid balance, creatinine clearance, fractional excretion of chloride, free water clearance and distal delivery of chloride. Results. These patients had markedly impaired creatinine clearance at the onset of tacrolimus toxicity. Urine flow increased in the LD + THEO group by 110% over baseline, but was unchanged in the LD + NS group. An increase in creatinine clearance did not reach statistical significance (P = 0.09). Fractional excretion of chloride and distal solute delivery increased after THEO treatment. Conclusions. THEO induced a solute diuresis during furosemide-resistant oliguric tacrolimus toxicity in paediatric patients with a trend towards improved renal function.

Original languageEnglish
Pages (from-to)1471-1475
Number of pages5
JournalNephrology Dialysis Transplantation
Volume20
Issue number7
DOIs
StatePublished - Jul 1 2005

Fingerprint

Tacrolimus
Theophylline
Sodium Potassium Chloride Symporter Inhibitors
Creatinine
Oliguria
Chlorides
Diuresis
Urine
Purinergic P1 Receptor Antagonists
Kidney
Urine Specimen Collection
Water-Electrolyte Balance
Endothelins
Furosemide
Vasoconstriction
Serum
Adenosine
Randomized Controlled Trials
Placebos
Pediatrics

Keywords

  • Adenosine
  • Nephrotoxicity
  • Paediatric
  • Tacrolimus
  • Theophylline

ASJC Scopus subject areas

  • Nephrology
  • Transplantation

Cite this

Reversal of oliguric tacrolimus nephrotoxicity in children. / McLaughlin, Gwenn E; Abitbol, Carolyn.

In: Nephrology Dialysis Transplantation, Vol. 20, No. 7, 01.07.2005, p. 1471-1475.

Research output: Contribution to journalArticle

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abstract = "Background. Acute tacrolimus toxicity is manifest by oliguria and elevated serum creatinine. Various vasoregulatory molecules have been implicated in calcineurin inhibitor-mediated nephrotoxicity, including calcium, adenosine and endothelin. Theophylline (THEO), a non-specific adenosine-receptor antagonist prevents renal dysfunction from various nephrotoxins which mediate vasoconstriction. In the setting of acute tacrolimus toxicity, we demonstrated that administration of THEO along with a loop diuretic (LD) enhanced diuresis. This randomized, controlled trial was undertaken to confirm these earlier findings under more rigorous conditions. Methods. Children with non-renal visceral transplant(s) and evidence of tacrolimus nephrotoxicity oliguria with a 25{\%} increase in serum creatinine concentration from baseline, a whole blood tacrolimus concentration >20 ng/dl and oliguria resistant to therapy with a LD were randomized to receive either THEO (n = 10) or normal saline placebo (n = 8). Using pre and post (6 h) timed urine collections and coincident plasma concentrations the following were measured or calculated: urine flow rate, net fluid balance, creatinine clearance, fractional excretion of chloride, free water clearance and distal delivery of chloride. Results. These patients had markedly impaired creatinine clearance at the onset of tacrolimus toxicity. Urine flow increased in the LD + THEO group by 110{\%} over baseline, but was unchanged in the LD + NS group. An increase in creatinine clearance did not reach statistical significance (P = 0.09). Fractional excretion of chloride and distal solute delivery increased after THEO treatment. Conclusions. THEO induced a solute diuresis during furosemide-resistant oliguric tacrolimus toxicity in paediatric patients with a trend towards improved renal function.",
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AB - Background. Acute tacrolimus toxicity is manifest by oliguria and elevated serum creatinine. Various vasoregulatory molecules have been implicated in calcineurin inhibitor-mediated nephrotoxicity, including calcium, adenosine and endothelin. Theophylline (THEO), a non-specific adenosine-receptor antagonist prevents renal dysfunction from various nephrotoxins which mediate vasoconstriction. In the setting of acute tacrolimus toxicity, we demonstrated that administration of THEO along with a loop diuretic (LD) enhanced diuresis. This randomized, controlled trial was undertaken to confirm these earlier findings under more rigorous conditions. Methods. Children with non-renal visceral transplant(s) and evidence of tacrolimus nephrotoxicity oliguria with a 25% increase in serum creatinine concentration from baseline, a whole blood tacrolimus concentration >20 ng/dl and oliguria resistant to therapy with a LD were randomized to receive either THEO (n = 10) or normal saline placebo (n = 8). Using pre and post (6 h) timed urine collections and coincident plasma concentrations the following were measured or calculated: urine flow rate, net fluid balance, creatinine clearance, fractional excretion of chloride, free water clearance and distal delivery of chloride. Results. These patients had markedly impaired creatinine clearance at the onset of tacrolimus toxicity. Urine flow increased in the LD + THEO group by 110% over baseline, but was unchanged in the LD + NS group. An increase in creatinine clearance did not reach statistical significance (P = 0.09). Fractional excretion of chloride and distal solute delivery increased after THEO treatment. Conclusions. THEO induced a solute diuresis during furosemide-resistant oliguric tacrolimus toxicity in paediatric patients with a trend towards improved renal function.

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