Skip Navigation


NDT Advance Access originally published online on March 7, 2006
Nephrology Dialysis Transplantation 2006 21(7):1961-1965; doi:10.1093/ndt/gfl082
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
21/7/1961    most recent
gfl082v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (2)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by McLaughlin, G. E.
Right arrow Articles by Egea, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by McLaughlin, G. E.
Right arrow Articles by Egea, M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Original Articles: Dialysis and Transplantation

Adenosine receptor antagonism in acute tacrolimus toxicity

Gwenn E. McLaughlin, Maria D. Alva and Marcelo Egea

Department of Pediatrics, Divisions of Critical Care Medicine University of Miami, Miami, FL, USA

Correspondence and offprint requests to: Gwenn McLaughlin, MD, PO Box 016960 (R-131), University of Miami Miller School of Medicine, Miami, FL 33130, USA. Email: gmclaugh{at}med.miami.edu



   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
Background. Calcineurin inhibitors induce renal vasoconstriction and oliguria during acute toxicity. We previously demonstrated that the non-specific adenosine receptor antagonist theophylline improved glomerular filtration rate (GFR) and renal blood flow in the setting of acute tacrolimus (TAC) toxicity. This study was undertaken to determine which of the known adenosine receptor subtypes is responsible for the observed effect of theophylline.

Methods. The GFR was measured by clearance of 51Cr-EDTA in anaesthetized, instrumented Sprague–Dawley rats at three time points: at baseline, 60 min after intravenous administration of TAC (0.05 mg/kg) or vehicle (V) and at 100 min after TAC or V. Either DMSO (n = 5) or one of the three available specific adenosine receptor subtype antagonists 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 2 mg/kg, n = 5), a selective A1 receptor antagonist, 8-(3-chlorostyryl) caffeine (CSC, 2 mg/kg, n = 4), a selective A2a receptor antagonist and 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-dihydropyridine-3,5 dicarboxylate (MRS1191, 1 mg/kg, n = 5), a selective A3 receptor antagonist, was administered intra-peritoneally prior to the final GFR measurement. Repeated measures analysis of variance was used to detect differences between groups (P<0.05).

Results. Measured GFR declined by 30% from baseline 60 min after TAC. In DMSO treated animals, GFR decreased 51% from baseline at 100 min after TAC, but increased 45% from baseline at 100 min after TAC + MRS1191.

Conclusions. Only administration of the A3 adenosine antagonist increased GFR following TAC, suggesting that this receptor mediates the effect of theophylline on GFR.

Keywords: glomerular filtration rate; adenosine antagonist; tacrolimus; prograf; calcineurin inhibitor; adenosine; receptors; purinergic

Tacrolimus (TAC) is a potent immunosuppressant which has significantly advanced the success of transplantation through control of rejection episodes; however, both the calcineurin inhibitor and its predecessor cyclosporine A induce renal vasoconstriction [1]. Adenosine is one reputed mediator of this effect of calcineurin inhibition as it is elevated in the blood of patients receiving cyclosporine A [2]. In several types of cultured cells, incubation with calcineurin inhibitors blocks the uptake of adenosine through inhibition of adenylyl cyclase activity [3,4]. Increased adenosine has been implicated in various nephropathies associated with vasoconstriction including those induced by contrast media, amphotericin and cisplatin [2,5]. Adenosine receptors are found throughout the body and play important regulatory roles in the control of vasomotor tone and inflammatory processes [6]. In the kidney, adenosine acutely constricts pre-glomerular vessels via A1 receptor activation while dilating the efferent vessels by A2a receptor activation [6,7]. Both A1 and A2a receptors are G-coupled proteins that regulate adenylyl cyclase activity albeit in opposite directions [6]. Activation of A3 receptors, like the activation of A1 receptors increases cyclic AMP, but unlike A1 receptors increases intracellular calcium promoting vasoconstriction [8].

We previously demonstrated that the administration of theophylline, a non-specific adenosine receptor antagonist, ameliorated the TAC-induced decreases in renal blood flow (RBF) and glomerular filtration rate (GFR) seen in rats [9]. We also demonstrated that the addition of theophylline to standard loop diuretic therapy improves diuresis in children with acute TAC toxicity [10]. In the present study, available specific adenosine receptor antagonists were administered to rats after acute administration of TAC in order to identify which receptor(s) was (were) responsible for the vasoconstrictor effect of TAC and the vasodilator and diuretic effects of theophylline.



   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Materials and reagents
The TAC was obtained in powdered form as a gift from Fujisawa Healthcare USA (Deerfield, IL). The powder was dissolved in a 1:3 solution of ethanol and Tween 80 to a concentration of 3 mg/ml. Just before administration the TAC solution was further diluted into 0.9% saline to a final concentration of 0.3 mg/ml. A similarly diluted 3:1 Ethanol–Tween 80 solution was used as vehicle (V) for control studies. The three specific adenosine receptor subtypes were 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), a selective A1 receptor antagonist, 8-(3-chlorostyryl) caffeine (CSC), a selective A2a receptor antagonist and 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-dihydropyridine-3,5 dicarboxylate (MRS1191), a selective A3 adenosine receptor antagonist. Each was obtained from Sigma-Aldrich chemical (St Louis, MO) in the powdered form and stored as per the manufacturer's recommendation. Prior to use each was dissolved in the vehicle DMSO.

Animal preparation
All methods were described previously [9]. Briefly the rats were allowed food and water ad libitum. They were anaesthetized with isoflorane 1.5% and artificial ventilatory via tracheostomy to normal blood gases. The rectal temperature was kept at ~38°C with radiant heat. Catheters implanted in the carotid artery, internal jugular and femoral vein were used for infusions, arterial blood sampling and continuous monitoring of mean arterial pressure and heart rate. The left kidney was exposed through a midline incision extending to the flank, and the left ureter was cannulated with polyethylene 10 tubing for urine collection into pre-weighed vials. Continuous free flow of clear urine was directly visualized. Heat and fluid loss was reduced by plastic wrap covering the rats and isoflorane was decreased to 0.5%.

Experimental protocol
Animals were divided into four subgroups who received either the adenosine receptor antagonist vehicle DMSO, DPCPX (2 mg/kg), CSC (2 mg/kg) and MRS1191 (1 mg/kg). These doses were used in the previously published studies to reverse receptor subtype activity when given by the intraperitoneal route [11–17]. These adenosine receptor antagonists do not produce haemodynamic effects [11]. Due to concerns about the shelf-life of each reagent these experiments were conducted in series. After assignment to a specific adenosine receptor antagonist, animals were randomly assigned to receive either TAC or V (identical volume). Single kidney GFR was measured as described by Leyssac and Christensen [18] at baseline, for 40 min starting 1 h after TAC administration, and after administration of one of the three adenosine receptor subtype antagonists or DMSO. After completion of all surgical procedures, the animals received a loading dose of 90 µCi 51Cr EDTA in 1.5 ml of saline followed by a continuous intravenous infusion of 250 µCi mixed in 20 ml of saline infused at the rate of 6 ml/h. After an equilibration period of 60 min, 0.5 ml of blood was collected from the left femoral artery at the start and completion of a 20 min-timed urine collections into pre-weighed plastic vials. Thereafter, 0.5 mg/kg intravenous TAC was given slowly over 5 min. After 60 min, two 20 min-timed urine collections were obtained followed immediately thereafter by intraperitoneal injection of DMSO or an adenosine receptor subtype antagonist followed by two additional 20 min-timed urine collections. Again blood was collected as described above. At the end of the experiment the kidney was removed, drained and weighed. Blood samples were centrifuged at 10,000 revs/min for 10 min and 100 µl of plasma was assayed for radioactivity. Urine vials were weighed at the end of the experiment and the difference from baseline vial weights recorded as urine volume. These were also assayed for radioactivity. Renal clearance of 51Cr EDTA was calculated according to the conventional expression: Cs = (U/P)s x (Vu/KW)(ml/min/g KW) in which (U/P)s denotes the urine-to-plasma concentration ratio of the substance (s), or 51Cr-EDTA and Vu/KW denotes rate of urine flow divided by the kidney weight (KW). The average radioactivity of the plasma sampled at the start and completion of each collection period was used as Ps. The average of the two 20 min collections is reported for post-TAC and post-adenosine receptor antagonist results. Urine flow was calculated as ml/min/100 g of body weight. Blood gas determinations were performed with the pH/blood gas analyser.

All results are expressed as mean±SEM. The data were analysed using one-way analysis of variance (ANOVA) for repeated measurements. Post-hoc testing was performed using Tukey's comparisons. A P-value <0.05 was considered statistically significant.



   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
The three groups were similar for weight and all baseline data. The mean arterial pressure and blood gas data are shown in the Table 1. There were relatively minor but statistically significant differences between groups in PaO2, but no animal experienced hypoxia. The adenosine receptor antagonists did not produce haemodynamic changes. Haemoglobin did not differ between groups or over time (data not shown).


View this table:
[in this window]
[in a new window]
  		Table 1. Physiological data for TAC administered animals followed by an adenosine receptor subtype antagonist

 
The GFR data is displayed in Figure 1. In the control group (V + DMSO), GFR did not change over time. The GFR, over time, in TAC treated animals was significantly different from normal controls. The GFR declined by 30 and 51% at 60 and 100 min after TAC, respectively. TAC resulted in a significant drop in GFR from baseline at 1 h in all the TAC treated groups except in those animals subsequently treated with the A3 antagonist MRS1191 (P = 0.051). In animals treated with CSC and DPCPX, a further decline in GFR at 100 min was not observed. The GFR increased significantly following MRS1191 administration to 145% of the baseline value.


Figure 1
View larger version (20K):
[in this window]
[in a new window]
  		Fig. 1. Single kidney glomerular filtration rate (GFR) in ml/min 100 g of kidney weight (KW) measured by clearance of 51Cr EDTA in rats exposed to tacrolimus (TAC) or vehicle (V) followed by administration of one of the three adenosine receptor subtype (A1, A2a or A3) antagonists (ARA). N = 4–7 animals/group. *P<0.05 by repeated measures ANOVA.

 
The urine flow data is displayed in Figure 2. Urine flow exhibited greater variability in general, therefore no statistical differences were detected. Administration of DPCPX did produce a trend toward increased diuresis in TAC-treated animals (P = 0.09).


Figure 2
View larger version (15K):
[in this window]
[in a new window]
  		Fig. 2. Single kidney urine flow rate expressed in ml/min/kg of body weight (BW) measured gravimetrically in rats exposed to tacrolimus (TAC) or vehicle (V) followed by administration of one of three adenosine receptor subtype (A1, A2a or A3) antagonists (ARA). N = 4–7 animals/group. Due in part to the wide variability in urine volume no significant differences were detected.

 


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
In a previous study, we demonstrated that the methylxanthine theophylline, a non-specific adenosine receptor antagonist reversed parallel changes in RBF and GFR observed in response to intravenous TAC in rats. We initially hypothesized that the A1 receptor antagonist, DPCPX, would reduce vasoconstriction in response to TAC. This agent has been shown to reverse hypoxia-induced vasoconstriction in isolated perfused rabbit kidney [19]. However, DPCPX did not fully prevent the fall in GFR, whereas theophylline was fully protective. These findings are consistent with a similar study after cyclosporine A exposure demonstrating that DPCPX attenuated the fall in RBF measured by electromagnetic flow meter by 57%, but was less effective than theophylline [20]. This data suggests that A1 receptor activation alone does not explain the decrease in RBF observed after TAC administration.

In children with oliguria, due to elevated TAC concentrations, low dose aminophylline promoted a brisk diuresis [10]. Intact adenosine A1 receptors are required for the diuretic and natriuretic effects attributed to methylxanthines [21,22]. Administration of FK 838, another A1 adenosine antagonist in chronically instrumented awake rats promoted a brisk diuresis, but no significant change in GFR [23]. A trend toward an increased urine flow was observed after DPCPX in both TAC- and V-treated animals. This suggests that theophylline enhances diuresis in children with TAC toxicity through its A1 adenosine antagonist property.

Because A2a agonists reportedly increase GFR and RBF through enhanced medullary vasodilation [24,25], we anticipated that A2a receptor inhibition would potentiate the vasoconstriction observed in response to TAC. Furthermore, in an animal model of renal ischaemia-reperfusion, A2a receptor activation prevents renal impairment through modulation of inflammation [6,24,25]. However, we observed no significant response in either GFR or urine volume in response to A2a receptor blockade. This may be explained by the fact that A2a receptors are only expressed at very low levels in the pre-glomerulus where TAC-induced vasoconstriction occurs [26].

Whereas A1 and A2a receptors are probably activated under normal physiological conditions, A3 receptors require relatively higher levels of adenosine for activation and therefore may be more important in pathological conditions [8]. To date A3 receptors have not been as well-studied as the A1 and A2a subtypes. In cultured renal epithelial cells, A3 receptor blockade with MRS 1191, but not A1 or A2a receptor inhibition, prevented calcium influx [27]. Calcineurin inhibition results in intracellular calcium influx which may be further aggravated by A3 receptor activation or ameliorated by A3 receptor antagonism. Lee and colleagues [11,28] have published a body of work which suggests that A3 receptor antagonism is renal protective in rats and mice. Using both agonists and antagonists, they evaluated several adenosine subtype receptors and identified that A3 receptor activation decreased creatinine clearance, while A3 receptor inhibition improved creatinine clearance in renal ischaemia [11]. They also demonstrated that knockout mice lacking A3 receptors are protected against both ischaemia and myoglobin-induced renal failure [28]. Our finding that A3 receptor antagonism improves GFR following TAC-induced vasoconstriction is consistent with these investigations.

Chronic renal failure is a consequence of long-term exposure to calcineurin inhibition which in turn contributes to morbidity and mortality from cardiovascular disease [29]. It is plausible that prevention of renal ischaemia can delay renal failure; however, there is conflicting available data. Several authors demonstrated that while acute non-specific adenosine receptor antagonism with theophylline may prevent renal vasoconstriction, there is no significant benefit to creatinine clearance over several weeks [19,30–32]. This may be due to the diuretic effect of theophylline mediated through A1 receptor inhibition. Sodium depletion aggravates calcineurin inhibitor-induced renal insufficiency and therefore, the sodium and water loss induced by A1 receptor antagonism is undesirable [33]. In fact, Lee et al. [34] demonstrated that ischaemic reperfusion injury worsened in A1 receptor knockout mice and DPCPX-treated wild-type mice as evidenced by higher serum creatinine and worse histology. In contrast, A3 receptor antagonism which improves GFR without promoting sodium excretion may be renoprotective in TAC-induced nephropathy.

Application of the results of this study to patient care should proceed cautiously for several reasons. First, unopposed high-dose A3 receptor antagonists induce apoptosis in cultured cell lines, but low doses appear cytoprotective [8]. Second, the appropriate dose of MRS1191 in humans is unknown at the present time. Third, the ubiquitous nature of adenosine receptors in vivo raises concerns about the effects of A3 receptor inhibition on non-renal organs [8]. Nevertheless, research to address these concerns should proceed more rapidly, particularly because A3 receptor inhibition has no apparent haemodynamic effect and can therefore be tolerated in states of hypoperfusion.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Methods
 Results
 Discussion
 References
 

  1. Scott LJ, McKeage K, Keam SJ, Plosker GL. Tacrolimus: a further update of its use in the management of organ transplantation. Drugs 2003; 63: 1247–1297[CrossRef][Medline]
  2. Guieu R, Dussol B, Devaux C et al. Interactions between cyclosporine A and adenosine in kidney transplant recipients. Kidney Int 1998; 53: 200–204[CrossRef][Medline]
  3. Hwang K, Hall CS, Spielman WS, Sparks HV. FK506 promotes adenosine release from endothelial cells via inhibition of adenosine kinase. Eur J Pharmacol 2001; 425: 85–93[Medline]
  4. Spychala J, Mitchell BS. Cyclosporin and FK506 decrease adenosine kinase activity and adenosine uptake in T-lymphocytes. J Lab Clin Med 2002; 140: 84–91[Medline]
  5. Osswald H, Gleiter C, Muhlbauer BP. Therapeutic use of theophylline to antagonize renal effects of adenosine. Clin Nephrol 1995; 43: S33–S37[Medline]
  6. Yaar R, Jones MR, Chen JF, Ravid K. Animal models for the study of adenosine receptor function. J Cell Physiol 2005: 202; 9–20[CrossRef][ISI][Medline]
  7. Modlinger PS, Welch WJ. Adenosine A1 receptor antagonist in the kidney. Curr Opin Nephrol Hypertens 2003; 12: 487–502
  8. Jacobson KA. Adenosine A3 receptors: novel ligands and paradoxical effects. TiPS 1998; 19: 184–191[Medline]
  9. McLaughlin GE, Kashimawo L, Steele B, Kuluz JW. Reversal of acute tacrolimus-induced renal vasoconstriction by theophylline in rats. Pediatr Crit Care Med 2003; 4: 358–362[Medline]
  10. McLaughlin GE, Abitbol CL. Reversal of oliguric tacrolimus nephrotoxicity in children. Nephrol Dial Transplant 2005; 20: 1471–1475[Abstract/Free Full Text]
  11. Lee TH, Emala CW. Protective effects of renal ischemic preconditioning and adenosine pretreatment: role of A1 and A3 receptors. Am J Physiol Renal Physiol. 2000; 278: F380–F387[Abstract/Free Full Text]
  12. Hiraide T, Katsura K, Muramatsu H, Asano G, Katayama Y. Adenosine receptor antagonists cancelled the ischemic tolerance phenomenon in gerbil. Brain Res 2001; 910: 94–98[CrossRef][ISI][Medline]
  13. Phillis JW. The effects of selective A1 and A2a adenosine receptor antagonists on cerebral ischemic injury in the gerbil. Brain Res 1995; 705: 79–84[CrossRef][Medline]
  14. Jacobson KA, Nikodijevic O, Padgett WL, Gallo-Rodriguez C, Maillard M, Daly JW. 8-(3-chlorostyryl) caffeine is a selective A2 adenosine antagonist in vivo and in vitro. FEBS Letters 1993; 323: 141–144[CrossRef][ISI][Medline]
  15. Tomic MA, Vuckovic SM, Stepanovic-Petrovic RM, Ugresic N, Prostram MS, Boskovic B. The anti-hyperalgesic effects of carbamazepine and oxcarbazepine are attenuated by treatment with adenosine receptor antagonists. Pain 2004; 111: 253–260[Medline]
  16. Von Lubitz DKJE, Lin RCS, Jacobson KA. Cerebral ischemia in gerbils: effects of acute and chronic treatment with adenosine A2a receptor agonist and antagonist. Eur J Pharmacol 1995; 287: 295–302[CrossRef][Medline]
  17. Rivo J, Zeira E, Galun E, Matot I. Activation of A3 adenosine receptors attenuates lung injury after in vivo reperfusion. Anesthesiology 2004; 101: 1153–1159[Medline]
  18. Leyssac PP and Christensen P. [51Cr] EDTA for measuring total and single nephron glomerular filtration rate in rat. Acta Physiol Scand 1995; 153: 271–277[ISI][Medline]
  19. Prevot A, Mosig D, Rijtema M, Guignard J-P. Renal effects of adenosine A1-receptor blockade with 8-cyclopentyl-1,3-dipropylxanthine in hypoxemic newborn rabbits. Pediatr Res 2003; 54: 400–405[Medline]
  20. Heyne N, Wolf S, Petersen et al. Adenosine receptor antagonism in the prevention of acute cyclosporine A nephrotoxicity in normal, diabetic antihypertensive rats. Nephrol Dial Transplant 1999; 14 [Suppl 4]: 232–234
  21. Kost CK, Herzer WA, Rominski BR, MI Z, Jackson EK. Diuretic response to adenosine A1 receptor blockade in normal tests about spontaneously hypertensive rats: role of pertussis toxin-sensitive G-proteins. J Pharmacol Exp Ther 2002; 292: 752–760
  22. Rieg T, Steigele H, Schnermann J, Richter K, Osswald H, Vallon V. Requirement of intact adenosine A1 receptors for the diuretic and natriuretic action of the methylxanthines theophylline and caffeine. J Pharmacol Exp Ther 2005; 313: 403–409[Abstract/Free Full Text]
  23. Bak M, Thomsen K. Effects of the adenosine A1 receptor inhibitor K838 on proximal tubular fluid output in rats. Nephrol Dial Transplant 2004: 19; 1077–1082[Abstract/Free Full Text]
  24. Okusa MD. A2a adenosine receptor: a novel therapeutic target in renal disease. Am J Physiol Renal Physiol 2002: 282; F10–F18[Abstract/Free Full Text]
  25. Lee HT, Emala CW. Systemic adenosine given after ischemia protects renal function via A(2a) adenosine receptor activation. Am J Kidney Dis 2001; 38: 610–618[ISI][Medline]
  26. Jackson EK, Zhu C, Tofovic SP. Expression of adenosine receptors in the preglomerular microcirculation. Am J Physiol Renal Physiol 2002; 283: F41–F51[Abstract/Free Full Text]
  27. Reshkin SJ, Guerra L, Bagorda A et al. Activation of A3 adenosine receptor induces calcium entry and chloride secretion in A6 cells. J Membrane Biol 2000: 178; 103–113[CrossRef][ISI][Medline]
  28. Lee HT, Ota-Setlik A, Xu H, D’Agati VD, Jacobson MA, Emala CW. A3 adenosine receptor knockout mice are protected against ischemia and myoglobinuria-induced renal failure. Am J Physiol Renal Physiol 2003; 284: F267–F273[Abstract/Free Full Text]
  29. Ojo AO, Held PJ, Port FK et al. Chronic renal failure after transplantation of a nonrenal organ. New Engl J Med 2003; 349: 931–940[Abstract/Free Full Text]
  30. Prevot A, Liet JM, Semama DS, Justrabo E, Guignard JP, Gouyon JB. Disparate effects of chronic and acute theophylline on cyclosporine A nephrotoxicity. Pediatr Nephrol 2002; 17: 418–424[Medline]
  31. McLaughlin GE, Schober M, Perez M, Ruiz P, Steele BW, Abitbol C. Benefit of theophylline administration in tacrolimus-induced nephrotoxicity in rats. Pediatr Nephrol 2003; 18: 860–864[Medline]
  32. Gerkens JF, Smith AJ. Effect of captopril and theophylline treatment in cyclosproine induced nephrotoxicity in rats. Transplantation 1985; 40: 213–214[Medline]
  33. Andoh TF, Burdmann EA, Lindsley J, Houghton DC, Bennett WM. Functional and structural characteristics of experimental FK 506 nephrotoxicity. Clin Experimental Pharmacol Physiol 1995; 22: 646–654
  34. Lee HT, Xu H, Nasr SH, Schnermann J, Emala CW. A1 adenosine receptor knockout mice exhibit increased renal injury following ischemia and reperfusion. Am J Physiol Renal Physiol 2004; 286: F298–F306[Abstract/Free Full Text]
Received for publication: 4.10.05
Accepted in revised form: 7. 2.06


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Nephrol Dial TransplantHome page
S. Malacarne, S. Moll, K. Hadaya, L. Buhler, and P.-Y. Martin
Renal ischaemic injuries during the use of zolmitriptan for treatment of migraines in a transplanted patient under tacrolimus therapy
Nephrol. Dial. Transplant., November 1, 2007; 22(11): 3341 - 3343.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
21/7/1961    most recent
gfl082v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (2)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by McLaughlin, G. E.
Right arrow Articles by Egea, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by McLaughlin, G. E.
Right arrow Articles by Egea, M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?