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Perit Dial Int 29(1): 108-111
2009
© 2009 International Society for Peritoneal Dialysis
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SHORT REPORTS

Effect of Short-Term Rosiglitazone Therapy in Peritoneal Dialysis Patients

Simon van Hooland1,*, Olivier Boey1, Patricia Van der Niepen1, Christiane Van den Branden2 and Dierik Verbeelen1

Department of Nephrology1 Universitair Ziekenhuis Brussel Department of Anatomy2 Vrije Universiteit Brussel Brussels, Belgium

* e-mail: simon00028{at}hotmail.com

Rosiglitazone, a thiazolidinedione (TZD), is a selective peroxisome proliferator-activated receptor-gamma (PPAR-{gamma}) agonist widely used in the treatment of type 2 diabetes mellitus (1). In addition to effectively controlling glycemia by improving insulin sensitivity, TZDs have pleiotropic effects on endothelial function, lipids, blood pressure, and inflammation (2). Whether the improvements in various risk factors reduce cardiovascular morbidity and mortality is a matter of debate (3,4). Data on the effect of rosiglitazone on blood pressure, peripheral edema, blood lipids, peritoneal membrane characteristics, and oxidative stress on the peritoneal dialysis (PD) population are scarce or lacking in the current literature (5,6).


   PATIENTS AND METHODS
TOP
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Patients: Twelve stable PD patients were enrolled in a prospective pilot study. Characteristics of the study population are described in Table 1. Time from start of PD to inclusion ranged from 9 to 211 weeks. Patients were advised to follow a weight-maintaining diet. No treatment changes were allowed during the study. The protocol was approved by the local ethics committee and all patients signed an informed consent.


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  		TABLE 1 Baseline Characteristics of Study Population

 

Procedures: Rosiglitazone was administered for 4 weeks, starting at 2 mg twice daily and increasing to 4 mg twice daily after 2 weeks (after a clinical visit). At baseline (T0), after completion of drug administration at week 4, and after a washout period of another 4 weeks, the study protocol was repeated. Patients arrived at 0800 hours, following an overnight fast of at least 8 hours and withdrawal of coffee at least 10 hours before any medication was taken. The patients entered a quiet temperature-controlled room (23°C – 24°C). Weight was measured after the peritoneal cavity was emptied. Height was measured at study entry. Edema was assessed by measuring foot volume based on a water-displacement method. A blood sample was taken for a full blood cell count, fibrinogen, C-reactive protein (CRP), urea, creatinine, electrolytes, albumin, glucose, liver tests, and lipid profile (standard clinical laboratory methods). Oxidized low-density lipoprotein (LDL) was determined using an ELISA assay (Mercodia AB, Uppsala, Sweden).

A beat-to-beat blood pressure measurement was performed during 15 minutes using a Portapres device (TNO Biomedical Instrumentation, Amsterdam, The Netherlands) to record beat-to-beat values for cardiac output, stroke volume, total peripheral resistance, and arterial compliance. Assessment of peritoneal transport kinetics was done using the personal dialysis capacity (PDC) test, as described by Haraldsson (7), using PDC software (Gambro Lundia AB, Lund, Sweden). On completion of the PDC test, a short 3.86% peritoneal equilibration test was performed to estimate aquaporin-1-mediated water transport (8).

Statistical Analysis: Differences between groups (treated vs non-treated) were calculated using the nonparametric Wilcoxon signed-rank test and Spearman rank correlation and processed by StatView, version 5.0 (SAS Institute, Cary, NC, USA). The results are presented as mean values with their standard deviations. A p value < 0.05 was considered statistically significant.


   RESULTS
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 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
(TABLES 2, 3, AND 4)


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  		TABLE 2 Hemodynamics (Mean±SD) at Baseline (T0; Before the Intake of Rosiglitazone), at Week 4 (at the End of Rosiglitazone Intake), and at Week 8 (After a Washout of 4 Weeks)

 

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  		TABLE 3 Peritoneal Dialysis (PD) Kinetics (Mean±SD) at Baseline (T0; Before the Intake of Rosiglitazone), at Week 4 (at the End of Rosiglitazone Intake), and at Week 8 (After a Washout of 4 Weeks)

 

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  		TABLE 4 Lipids, Inflammation, and Hemoglobin (Mean±SD) at Baseline (T0; Before the Intake of Rosiglitazone), at Week 4 (at the End of Rosiglitazone Intake), and at Week 8 (After a Washout of 4 Weeks)

 

   DISCUSSION
TOP
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Our data show that 4 weeks' treatment with rosiglitazone in PD patients resulted in a 1.8-kg increase in mean body weight. Evidence of fluid retention was provided by increased foot volume, higher body weight, and lower hemoglobin. Fluid retention was observed in all our patients irrespective of diabetes condition and in the presence of severe kidney failure.

The same gain in body weight was reported by Karaliedde et al. (9) after 12 weeks of rosiglitazone treatment in type 2 diabetic patients on oral antidiabetic medication. In PD patients, Wong et al. (6) found a 2% weight gain after 6 months of rosiglitazone, whereas others (5) reported no change after 12 weeks.

We showed a profound effect of rosiglitazone on both systolic and diastolic blood pressure. Our noninvasive beat-to-beat blood pressure measurements showed increased arterial compliance, suggesting an improvement in the elasticity of the blood vessels.

Meta-analysis of 37 clinical studies confirmed the lowering of both systolic and diastolic blood pressure. Compared with baseline, TZDs lowered systolic blood pressure by 4.7 mmHg and diastolic blood pressure by 3.79 mmHg. (10). Buchanan et al. (11) demonstrated in vitro that pioglitazone has a direct vascular effect by blockading calcium uptake by vascular smooth muscle cells, thus blunting the contractile response. The dramatic lowering of blood pressure in the present study could be explained by potentiation of antihypertensive medication.

It is known that rosiglitazone treatment in diabetics is associated with congestive heart failure (4). This is probably the result of TZD-related fluid retention and diastolic dysfunction in susceptible patients. None of our patients experienced an episode of pulmonary edema during the study period. Our study population is too small and the duration of study drug administration too short to draw any conclusions on this matter. This was also not the intention of our study.

Human peritoneal membrane expresses PPAR-{gamma} and rosiglitazone can increase the expression of receptors. We found an increase in the area parameter (A0/{Delta}x) of the PDC test, reflecting an increase in small solute transport. This may be explained by calcium influx inhibition, as described earlier. Although TZDs have been shown to have a potent antioxidant effect and to increase the release of nitric oxide from endothelial cells (12), this could not be confirmed in our study as oxidized LDL, a well-established measure of oxidative stress (13), increased significantly due to the increased total LDL after 4 weeks of rosiglitazone administration. We observed a significant increase in serum triglycerides after 4 weeks of treatment. One month after stopping rosiglitazone, serum triglycerides remained elevated. A possible explanation could be enhanced glucose absorption from the peritoneal cavity but we cannot prove this hypothesis.

We did not observe an effect of rosiglitazone treatment on sodium sieving, suggesting that PPAR-{gamma} agonists do not influence aquaporin-1-related free water transport.

In PD patients, Wong et al. (6) showed a reduction in CRP levels in type 2 diabetic patients treated with rosiglitazone, whereas Lin et al. (5) did not see a significant decrease in CRP after 12 weeks of rosiglitazone treatment.

We observed decreases in serum CRP and fibrinogen that reached borderline statistical significance (p = 0.059 for both). No effect on white cell counts was seen.


   CONCLUSIONS
TOP
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Rosiglitazone has a profound blood pressure-lowering effect without affecting diuresis or ultrafiltration. The vasodilatory effect responsible for blood pressure lowering is also effective in the peritoneal membrane, causing increased perfusion area. The favorable effects on blood pressure and inflammation are accompanied by negative effects on body weight (fluid retention), serum lipids, and oxidative stress.

Based on our results and in addition to the recent concerns of the increased cardiovascular morbidity and mortality associated with rosiglitazone (3), we do not recommend its use in PD patients until large studies in PD patients show conclusive results.


   REFERENCES
TOP
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

  1. Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006;355 : 2427-43.[Abstract/Free Full Text]
  2. Vasudevan A, Balasubramanyam A. Thiazolidinediones: a review of their mechanisms of insulin sensitisation, therapeutic potential, clinical efficacy, and tolerability. Diabetes Technol Ther2004; 6:850 -63.[Medline]
  3. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356:2457 -71.[Abstract/Free Full Text]
  4. Lago RM, Singh PP, Nesto RW. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials. Lancet 2007;370 (9593):1129 -36.[Medline]
  5. Lin SH, Kin YF, Kuo SW, Hsu YJ, Hung YJ. Rosiglitazone improves glucose metabolism in non diabetic uremic patients on CAPD. Am J Kidney Dis 2003; 42:774 -80.[Medline]
  6. Wong TY, Szeto CC, Chow KM, Leung CB, Lam CW, Li PK. Rosiglitazone reduces insulin requirement and C-reactive protein levels in type 2 diabetic patients receiving peritoneal dialysis. Am J Kidney Dis 2005; 46:713 -18.[Medline]
  7. Haraldsson B. Assessing the individual peritoneal dialysis capacities of individual patients. A clinical tool based on the three pore model. Kidney Int 1995;47 : 1187-98.[Medline]
  8. La Milia V, Pozzoni P, Virga G, Crepaldi M, Del Vecchio L, Andrulli S, et al. Peritoneal transport assessment by PET with 3.86% glucose: a long-term prospective evaluation. Kidney Int2006; 69:927 -33.[Medline]
  9. Karalliedde J, Buckingham R, Starkie M, Lorand D, Stewart M, Viberti G. Effect of various diuretic treatments on rosiglitazone-induced fluid retention. J Am Soc Nephrol 2006;17 : 3482-90.[Abstract/Free Full Text]
  10. Qayyum R, Adomaityte J. A meta-analysis of the effect of thiazolidinediones on blood pressure. J Clin Hypertens (Greenwich) 2006; 8:19 -28.[Medline]
  11. Buchanan TA, Meehan WP, Jeng YY, Yang D, Chan TM, Nadler JL, et al. Blood pressure lowering by pioglitazone, evidence for a direct vascular effect. J Clin Invest 1995,96 : 354-60.[Medline]
  12. Calnek DS, Mazzella L, Roser S, Roman J, Hart CM. Peroxisome proliferator-activated receptor gamma ligands increase the release of nitric oxide from endothelial cells. Arterioscler Thromb Vasc Biol 2003; 23:52 -7.[Abstract/Free Full Text]
  13. Mazière C, Meignotte A, Dantin F, Conte MA, Mazière JC. Oxidized LDL induces an oxidative stress and activates the tumor suppressor P53 in MRC5 human fibroblasts. Biochem Biophys Res Commun 2000; 276:718 -23.[Medline]



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C.-C. Szeto and K.-M. Chow
THIAZOLIDINEDIONES IN PERITONEAL DIALYSIS PATIENTS
Perit. Dial. Int., May 1, 2009; 29(3): 248 - 251.
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