Skip Navigation



NDT Advance Access published online on January 30, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfm864
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
23/5/1742    most recent
gfm864v1
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 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 arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Mitterbauer, C.
Right arrow Articles by Oberbauer, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Mitterbauer, C.
Right arrow Articles by Oberbauer, R.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


ACE-inhibitor or AT2-antagonist therapy of renal transplant recipients is associated with an increase in serum potassium concentrations

Christa Mitterbauer1,*, Georg Heinze2,*, Alexander Kainz1,3, Reinhard Kramar4, Walter H. Hörl1 and Rainer Oberbauer1,3,4,

1 Department of Nephrology, Medical University of Vienna, Vienna 2 Core Unit of Medical Statistics and Informatics, Medical University of Vienna, Vienna 3 Department of Nephrology, KH Elisabethinen, Linz, Austria 4 Austrian Dialysis and Transplant Registry, Wels, Austria

Correspondence and offprint requests to: Rainer Oberbauer, Department of Nephrology, KH Elisabethinen, Fadingerstrasse 1, 4010 Linz, Austria. Tel: +43-732-7676-4005; Fax: +43-732-7676-4706; E-mail: rainer.oberbauer{at}elisabethinen.or.at



   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Supplementary material
 References
 
Background. Angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II type 1 receptor blockers (ARB) are frequently prescribed to renal transplant recipients with a reduced glomerular filtration rate (GFR). The aim of this study was to investigate the association of ACEI/ARB use and serum potassium levels in renal graft recipients.

Methods. We conducted an open cohort study of 2041 first renal allograft recipients, transplanted at the Medical University of Vienna between 1990 and 2003. Serum potassium levels were compared over an up to 10 years of observation period between subjects with versus without ACEI/ARB therapy using a mixed effects general linear model. The analysis was adjusted for several covariables known to influence serum potassium such as the use of diuretics, beta blockers, calcineurin inhibitor (CNI) based immunosuppression, estimated GFR, time since renal transplantation, diabetes, years on dialysis and recipient age.

Results. The overall adjusted estimated serum potassium difference between recipients with versus without ACEI/ARB therapy was 0.08 mmol/l (P < 0.001). The use of diuretics was associated with a 0.11 mmol/l (P < 0.001) lower potassium concentration whereas each GFR decrease by 10 ml/min led to an increase of 0.04 mmol/l (P < 0.001). CNI intake increased serum potassium by 0.06 mmol/l (P = 0.002). Furthermore, serum potassium increased by 0.17 mmol/l within the first decade after transplantation (P < 0.001) while holding the other covariables constant. No effect modification between ACEI/ARB and time since transplantation was observed. Nineteen subjects (2.4%) discontinued the ACEI/ARB therapy due to hyperkalaemia.

Conclusions. In summary, relevant hyperkalaemia associated with ACEI/ARB therapy is negligible in renal transplant recipients during long-term follow-up. The hyperkalaemic effect of ACEI/ARB is balanced by the use of diuretics.

Keywords: angiotensin-converting enzyme inhibitors; angiotensin receptor blocker; hyperkalaemia; renal transplantation; serum potassium



   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Supplementary material
 References
 
The use of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II type 1 receptor blockers (ARB) increased over the last decade in renal transplant recipients despite the fact that no adequately controlled studies exist [1]. The effectiveness of these classes of medication in preventing cardiovascular events has been shown in the general population and in subgroups with certain comorbidities such as diabetes mellitus [2–4]. In these randomized controlled trials, patients with advanced renal failure were excluded and the incidence of subjects discontinuing the medication due to hyperkalaemia was not provided.

The majority of patients after renal transplantation however exhibit a moderate, some even a more severe impaired glomerular filtration rate (GFR), which is among the strongest predictors of hyperkalaemia [5]. Furthermore, almost all transplant recipients are hypertensive and take a median of more than two different blood pressure medications of which beta blockers are frequent [1]. Additionally, some of the patients with heart failure are treated by aldosterone antagonists, which inhibit the last chance of the organism to counterbalance hyperkalaemia by urinary potassium excretion.

In a recently published small randomized trial comparing the efficacy and safety of amlodipine versus losartan within the first year after transplantation, Formica and co-workers found no differences in graft function and rate of anaemia but reported a higher incidence of hyperkalaemia in subjects with ARB therapy [6]. The authors reported that in roughly one-fifth of the subjects the ARB had to be withdrawn due to severe hyperkalaemia defined as serum potassium levels above 6 mmol/l. Beyond this small study focusing on the early post-transplant months, no long-term follow-up trial exists that evaluated the incidence of relevant hyperkalaemia in patients treated with ACEI or ARB.

We therefore evaluated the association between ACEI/ARB treatment and serum potassium concentrations in renal graft recipients adjusted for several covariables known to influence serum potassium levels.



   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Supplementary material
 References
 
Study population
A detailed description of the OEsterreichisches Dialysis and Transplant Registry (OEDTR) can be found elsewhere [1]. In brief, the OEDTR and part of the EUROTRANSPLANT database were merged to define the population of this retrospective analysis. We analysed patients who received their first renal allograft at the Medical University of Vienna between 1 January 1990 and 31 December 2003 and survived at least 3 months. This selection led to a sample of 2041 study patients, which were followed up until 31 December 2005. The majority of transplant recipients received organs from deceased donors (90.7%). We restricted the analysis to subjects that were engrafted after December 1989 because the use of ACEI/ARB was negligible before this time.

Database variables
All variables and their definitions used for analysis are depicted in Appendix 1 of a previous publication [1]. In summary, the database holds entries about donor and transplant characteristics, kidney biopsy readings, recipient demographics, medications and comorbidities as well as laboratory values. These parameters as well as the status of patient and graft survival were updated annually. The modification of diet in renal disease (MDRD) method was used to estimate GFR [7].

Statistical analysis
Patient characteristics listed in Table 1 were compared between the two groups defined by ACEI/ARB therapy at the time of transplantation. Continuous variables are presented as mean and standard deviation or, for variables exhibiting a skew distribution, as median and quartiles. Categorical variables are displayed as proportions. Continuous variables were compared using the two-sample t-test; skewed variables were analysed by the Mann–Whitney U-test. Categorical variables were compared by utilizing the chi-square test.


View this table:
[in this window]
[in a new window]

  		Table 1 Patient characteristics of overall study cohort and stratified by ACEI/ARB use at transplantation

 
For the current analysis, we selected all baseline information that has been shown to potentially influence serum potassium values such as recipient age, years on dialysis and diabetes status, as well as annually collected data starting with first kidney transplantation until graft failure or death. The longitudinal data included serum potassium levels, the intake of ACEI/ARB, beta blockers, CNI immunosuppression and diuretics, as well as the GFR. The use of prostaglandin inhibitors and aldosterone antagonists was negligible and thus not included into the model.

We implemented a multivariable mixed effects general linear model to assess the association of ACEI/ARB therapy with serum potassium levels over time. This approach accounts for the correlation among repeated measurements of serum potassium from the same transplant recipients by assuming an autoregressive variance structure of the first order.

Independent variables of this general linear model included the intake of ACEI/ARB, but also the use of diuretics, beta blockers, CNIs, the estimated GFR, the number of years on dialysis before transplantation, diabetes status as well as the recipient age. The inclusion of serum bicarbonate levels led to collinearity with GFR and was thus avoided. A potential interaction of ACEI/ARB use and years since renal transplantation was investigated by including an interaction term in the model.

A two-sided P-value <0.05 was considered as indicating statistical significance. Statistical analysis was conducted using the SAS for Windows software, version 9.1.3 (The SAS Institute, Inc., Cary, NC, USA).



   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Supplementary material
 References
 
Patient characteristics
The characteristics of all study patients as well as those grouped by the use of ACEI/ARB at the time of transplantation are listed in Table 1. A total of 2041 patients received their first kidney allograft during the entire study period of 14 years; 780 of them used ACEI/ARB treatment at the time of engraftment, whereas 1261 subjects did not. Out of the 2041 first transplant recipients, 884 (43.3% of total) never received ACEI/ARB therapy, 484 (23.7%) used ACEI/ARB during the entire follow-up and 673 (33%) received this treatment during various times of observation. At the beginning of the study in 1990, the prevalence of ACEI treatment was 9% and increased to 47% in 2003. Substantial ARB use started in 1997 and reached roughly 18% of all allograft recipients in late 2003.

As depicted in Table 1, the ACEI/ARB group consisted of significantly older recipients of older donor organs than the no ACEI/ARB group. Graft recipients with diabetes type 2 or cardiovascular disease at the time of transplantation were more likely to be treated with an ACEI/ARB. The incidence of arterial hypertension and the number of antihypertensive drugs used were higher in the ACEI/ARB subjects compared to the no ACEI/ARB patients. Whereas systolic blood pressure was equally controlled and not different in both groups, the diastolic blood pressure was slightly higher in the ACEI/ARB arm at the time of transplantation.

Serum potassium concentration
The mean serum potassium concentrations of ACEI/ARB treated and non-treated renal allograft recipients over a 10-year observation period following transplantation are listed in Table 2. At all times, the annually obtained mean potassium levels were higher in the group with current ACEI/ARB intake. However, the discrepancy between ACEI/ARB treated and non-treated patients was moderate with 0.21 mmol/l as the largest absolute difference in mean serum potassium measured at year 6 after engraftment.


View this table:
[in this window]
[in a new window]

  		Table 2 Serum potassium levels (mmol/l) of renal allograft recipients with and without current use of ACEI/ARB over a 10-year observation period following transplantation

 
The results of the performed mixed effects general linear model with serum potassium as a dependent variable are presented in Table 3. The estimated difference in serum potassium between graft recipients with versus without ACEI/ARB intake, adjusted for diuretics, beta blocker and CNI use, GFR, time since transplantation, diabetes status, number of years on dialysis and recipient age was 0.08 mmol/l (P < 0.001). The intercept of the linear model was 4.59, which is the theoretical serum potassium concentration at transplantation in mmol/l when all other covariables were set to zero/reference (i.e. no medication of ACEI/ARB, diuretics, CNI, beta blocker).


View this table:
[in this window]
[in a new window]

  		Table 3 Predictors of serum potassium concentrations over time using a multivariable mixed effects general linear model of longitudinal data

 
The use of diuretic drugs was associated with a significantly lower potassium concentration of 0.11 mmol/l (P < 0.001), again adjusted for all other parameters in the linear regression model for longitudinal data. CNI intake led to a serum potassium increase of 0.06 mmol/l (P = 0.002) when compared with non-users. Interestingly, beta-blocker therapy adjusted for the covariables was not associated with a significant change in potassium levels (P = 0.76). Each decrease in GFR by 10 ml/min however raised the serum potassium by 0.04 mmol/l (P < 0.001). Over a period of 10 years after transplantation, serum potassium increased by 0.17 mmol/l (P < 0.001) while holding all other covariables constant.

There was no effect modification between ACEI/ARB use and years since renal transplantation (P = 0.20) and thus the interaction term was dropped from the final model. Furthermore, no effect modification was observed between ACEI/ARB and CNI therapy (P = 0.204 for the interaction term).

In an additional analysis, we defined the study groups not based on the actual administration of ACEI/ARB; instead, patients remained in the ACEI/ARB arm once started, even after later ACEI/ARB withdrawal. In an alternative model, patients were removed when groups changed. The results did not change materially (data not shown in the manuscript but provided as supplementary data on the website http:// www.meduniwien.ac.at/nephrogene) with a comparable estimated serum potassium difference between ACEI/ARB treated and non-treated renal transplant recipients.

The prescription of ACEI/ARB was stopped in 19 out of 780 patients (2.4%) due to hyperkalaemia at a single measurement. The numbers of at least one median annual serum potassium level above 6, 6.5 or 7.0 mmol/l were 10, 4 and 2 respectively.



   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Supplementary material
 References
 
This analysis was designed to examine the impact of renin–angiotensin system (RAS) blockade on serum potassium concentration in renal graft recipients during long-term follow-up. The main finding of our analysis is that ACEI/ARB use in kidney graft recipients was associated with a statistically significant but clinically negligible serum potassium increase of 0.08 mmol/l compared with non-users. Furthermore, we showed that the hypokalaemic effect of diuretic therapy equalized the small increase in serum potassium caused by ACEI/ARB use.

So far, only few trials were designed to assess the safety of ACEI/ARB treatment in renal allograft recipients with regards to hyperkalaemia as potential serious adverse event. The power of these studies, however, is generally limited due to the small number of participants and the short follow-up period. In the recent paper by Formica et al., 21% of the patients (6 out of 29 subjects) had to be withdrawn from losartan therapy within the follow-up of 12 months due to severe hyperkalaemia, i.e. serum potassium levels above 6 mEq/l [6]. However, the number of subjects with moderately elevated potassium levels between 5.5 and 5.9 mEq/l was not different compared to the control group treated with amlodipine. It is noteworthy that five of these six patients developed hyperkalaemia within the first post-transplant months when their renal allograft function was still impaired. Moreover, contrary to daily medical routine, this protocol required promptly ARB discontinuation in the case of hyperkalaemia instead of first attempting dietary potassium restriction and diuretic use. Consequently, the rate of clinically relevant severe hyperkalaemia following ARB intake may have been overestimated.

Midtvedt and colleagues, who also prospectively investigated these agents in the first two post-transplant years, found no differences in terms of potassium levels [8]. The authors reported only one study withdrawal out of 76 patients caused by ACEI-induced hyperkalaemia as compared to calcium antagonists, although the mean GFR was significantly lower in the lisinopril group.

The efficacy and safety of ACEI/ARB initiation in stable long-term transplant recipients was elucidated by El-Agroudy and co-workers [9]. The investigators found no differences in serum potassium concentrations after 12 months of treatment with losartan, captopril or amlodipine.

In a recent paper, Halimi and colleagues reported a significant potassium increase of 0.2 mmol/l after 6 months of enalapril intake, whereas amlodipine use was associated with a potassium decrease when compared to baseline values [10]. Neither of both small randomized trials described withdrawals from treatment due to hyperkalaemia.

A retrospective analysis by Stigant and colleagues showed a nonsustained potassium increase from 4.4 at baseline to 4.6 mEq/l at 3 months after ACEI/ARB initiation, but no further increase beyond this time; 3% of patients (6 out of 177) discontinued because of hyperkalaemia [11]. The reported increase in serum potassium was similar to what we found. However, in contrast to our analysis, the time of study entry varied considerably among the graft recipients from immediately post-transplant to almost 20 years later when ACEI/ARB prescription started.

The effectiveness of ACEI and ARB in protecting against the progression of nephropathy has been shown in a variety of native kidney diseases. Particularly, the role of RAS blockade in patients with nephropathy due to type 2 diabetes was addressed by large randomized controlled trials of the last years [12–14]. Unfortunately, none of these studies provided information about baseline and follow-up serum potassium concentrations after ACEI/ ARB initiation. However, hyperkalaemia necessitating study discontinuation occurred only in 1.9% and 1.1%, respectively, of patients in the ARB group as compared with 0.4% and 0.5% of placebo-treated subjects [12,13]. Whether or not these data can be applied to renal transplant recipients remains unknown. In fact, many well-established medical interventions with drugs such as statins failed to work in patients with end-stage renal disease [15], or remain inconclusive after renal transplantation [16].

The present associational study cannot answer the pathophysiology behind the elevated serum potassium levels. It is commonly accepted, however, that calcineurin inhibitor (CNI)-based immunosuppression leads to hyperkalaemia due to hyporeninaemic hypoaldosteronism [17]. Furthermore, we showed recently that distal renal tubular acidosis is present in roughly 12% of subjects after renal transplantation. The development of renal tubular acidosis was significantly predicted by the use of ACEI/ARB and CNI immunosuppression as well as reduced GFR, all associated with serum potassium levels [18].

Some limitations apply to the data obtained in the current analysis. First, patients did not receive ACEI/ARB treatment randomly, and confounding by indication may exist. We addressed this issue by applying a multivariable statistical analysis and accounted for factors that potentially influence serum potassium concentrations in renal transplant recipients. An unrectifiable shortcoming of cohort studies is the unmeasured confounding, which we also cannot rule out in the present analysis. A further caveat is the missing information on dietary potassium intake and the use of dietary potassium binders. Moreover, we did not study any dose dependence of the association of interest or the existence of a class effect among ACEI and ARB. Thus, it is possible that our results underestimate the true effect of ACEI/ARB on serum potassium levels after renal transplantation.

On the other hand, the present analysis represents the first thorough attempt to address this issue in a long-term clinical practice setting. Due to the complete reporting of subjects to the registry and the negligible number of patients that had been lost to follow, we are confident that we derived a sound estimate of the association of hyperkalaemia in patients after renal transplantation.

Based on these data, we conclude that ACEI/ARB use was associated with a statistical but clinical negligible increase in serum potassium concentrations. The use of diuretics counterbalanced the increase of serum potassium by ACEI/ARB therapy.



   Supplementary material
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Supplementary material
References
 
Additional information is available through the website http://www.meduniwien.ac.at/nephrogene (see data ACEI_ARF & potassium, user: guest, pw: potassium) and as supplementary data available at NDT Journal online.



   Acknowledgments
 
The authors thank the administrators and all contributors of the Austrian Dialysis and Transplant Registry who are listed elsewhere [19]. This study was supported by the Austrian Science Fund (FWF P-18325) and the Austrian Academy of Science (OELZELT EST370/04).

Conflict of interest statement. None of the authors report any conflict of interest.



   Notes
 
* Both authors contributed equally to the paper. Back



   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Supplementary material
 References
 

  1. Heinze G, Mitterbauer C, Regele H, et al. Angiotensin-converting enzyme inhibitor or angiotensin II type 1 receptor antagonist therapy is associated with prolonged patient and graft survival after renal transplantation. J Am Soc Nephrol (2006) 17:889–899.[Abstract/Free Full Text]
  2. Yusuf S, Sleight P, Pogue J, et al. (The Heart Outcomes Prevention Evaluation Study Investigators) Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. In: N Engl J Med (2000) 342:145–153.[Abstract/Free Full Text]
  3. Fox KM. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet (2003) 362:782–788.[CrossRef][Web of Science][Medline]
  4. Lindholm LH, Ibsen H, Dahlof B, et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet (2002) 359:1004–1010.[CrossRef][Web of Science][Medline]
  5. Vereijken TL, Bellersen L, Groenewoud JM, et al. Risk calculation for hyperkalemia in heart failure patients. Br J Clin Pharmacol (2007) 63:507.[Medline]
  6. Formica RN, Friedman AL, Lorber MI, et al. A randomized trial comparing losartan with amlodipine as initial therapy for hypertension in the early post-transplant period. Nephrol Dial Transplant (2006) 21:1389–1394.[Abstract/Free Full Text]
  7. Levey AS, Bosch JP, Lewis JB, et al. (Modification of Diet in Renal Disease Study Group) A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med (1999) 130:461–470.[Abstract/Free Full Text]
  8. Midtvedt K, Hartmann A, Foss A, et al. Sustained improvement of renal graft function for two years in hypertensive renal transplant recipients treated with nifedipine as compared to lisinopril. Transplantation (2001) 72:1787–1792.[CrossRef][Web of Science][Medline]
  9. el-Agroudy AE, Hassan NA, Foda MA, et al. Effect of angiotensin II receptor blocker on plasma levels of TGF-beta 1 and interstitial fibrosis in hypertensive kidney transplant patients. Am J Nephrol (2003) 23:300–306.[CrossRef][Web of Science][Medline]
  10. Halimi JM, Giraudeau B, Buchler M, et al. Enalapril/amlodipine combination in cyclosporine-treated renal transplant recipients: a prospective randomized trial. Clin Transplant (2007) 21:277–284.[CrossRef][Web of Science][Medline]
  11. Stigant CE, Cohen J, Vivera M, et al. ACE inhibitors and angiotensin II antagonists in renal transplantation: an analysis of safety and efficacy. Am J Kidney Dis (2000) 35:58–63.[Web of Science][Medline]
  12. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med (2001) 345:861–869.[Abstract/Free Full Text]
  13. Lewis EJ. The role of angiotensin II receptor blockers in preventing the progression of renal disease in patients with type 2 diabetes. Am J Hypertens (2002) 15:123S–128S.[CrossRef][Web of Science][Medline]
  14. Parving HH, Lehnert H, Brochner-Mortensen J, et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med (2001) 345:870–878.[Abstract/Free Full Text]
  15. Wanner C, Krane V, Marz W, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med (2005) 353:238–248.[Abstract/Free Full Text]
  16. Holdaas H, Fellstrom B, Cole E, et al. Long-term cardiac outcomes in renal transplant recipients receiving fluvastatin: the ALERT extension study. Am J Transplant (2005) 5:2929–2936.[CrossRef][Web of Science][Medline]
  17. Heering P, Grabensee B. Influence of ciclosporin A on renal tubular function after kidney transplantation. Nephron (1991) 59:66–70.[Web of Science][Medline]
  18. Schwarz C, Benesch T, Kodras K, et al. Complete renal tubular acidosis late after kidney transplantation. Nephrol Dial Transplant (2006) 21:2615–2620.[Abstract/Free Full Text]
  19. Mitterbauer C, Kramar R, Oberbauer R. Age and sex are sufficient for predicting fractures occurring within 1 year of hemodialysis treatment. Bone (2007) 40:516–521.[Medline]
Received for publication: 29. 8.07
Accepted in revised form: 14.11.07


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



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
23/5/1742    most recent
gfm864v1
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 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 arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Mitterbauer, C.
Right arrow Articles by Oberbauer, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Mitterbauer, C.
Right arrow Articles by Oberbauer, R.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?