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NDT Advance Access originally published online on April 16, 2007
Nephrology Dialysis Transplantation 2007 22(7):2095-2096; doi:10.1093/ndt/gfm218
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Reply—PPAR agonists in diabetic nephropathy

Email: h.boulanger{at}clinique-estree.fr

Sir,

Pistrosch et al. [1] have reported that intrarenal haemodynamic changes and corrections of endothelial dysfunction by peroxisome proliferators-activated receptors (PPAR){gamma} agonists are two possible mechanisms to explain the decrease of microalbumunuria in diabetic nephropathy. In our editorial comment, addressed to clinicians, the main purpose of the chapter related to human PPAR{gamma} agonist effects on the human kidney was above all to provide clear evidence for a renal protection of these drugs [2]. In this way and aiming to be concise, we focused primarily on the final impact of PPAR{gamma} agonists on renal alteration surrogate markers such as microalbuminuria, rather than on the putative mechanisms by which these drugs can reduce microalbuminuria. Furthermore, in an attempt to avoid the risk of a catalogue chapter, we tried to retain only the first published and the most statistically powerful studies that demonstrate a reduction of microalbuminuria. Thus, we do not think we significantly altered the principal message for the clinician, which is the following: a reduction of micro albuminuria, a surrogate marker of renal alteration. However, it is effectively very interesting to go thoroughly into the mechanism by which the PPAR{gamma} agonists could exert their renal protection. Pistrosch et al. emphasize more specifically the intrarenal haemodynamic effect (reduction of glomerular hyperfiltration rate and filtration fraction) and the reverse of endothelial dysfunction, but it is important to note that the renal protection could also be attributed to other numerous haemodynamic (blood pressure lowering, decrease in endothelin-1 levels) and non-haemodynamic effects (anti-proliferative and anti-inflammatory actions, attenuation of intracellular lipid accumulation, interference with renin-angiotensin system, increase in tubular cell albumin intake, etc) of these drugs [3]. To some extent, there are some similarities with angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARB) that exert both haemodynamic and non-haemodynamic renal effects [4]. Indeed, several observations support the direct blockage of the angiotensin II type-1 receptors by PPAR{gamma} agonists [5]. Unfortunately and unlike to ACE inhibitors and ARB, there are currently no trials to demonstrate renoprotective effects on diabetic kidney progression, such as doubling of serum creatinine or time to onset of end-stage renal disease with PPAR{gamma} agonists [6–10]. It would be best to clearly and definitively demonstrate evidence for renal protection of PPAR{gamma} agonists in diabetic nephropathy progression and to consider PPAR receptors {gamma} as real new therapeutic targets in diabetic nephropathy.

Conflict of interest statement. None declared.

Henri Boulanger1, Rafik Mansouri2, Jean Francois Gautier3 and Denis Glotz2

1Service of Nephrology and Dialysis
Clinique de l’Estrée, 35 rue
d’Amiens 93240 Stains, France
2Department of Nephrology
and Transplantation
3Department of Diabetes and
Endocrinology, Saint-Louis Hospital
Paris, France

References

  1. Pistrosch F, Herbrig K, Kindel B, Passauer J, Fischer S, Gross P. Rosiglitazone improves glomerular hyperfiltration renal endothelial dysfunction, and microalbuminuria of incipient diabetic nephropathy in patients. Diabetes (2005) 54:2206–2211.[Abstract/Free Full Text]
  2. Boulanger H, Mansouri R, Gautier JF, Glotz D. Are peroxisome proliferator-activated receptors new therapeutic targets in diabetic and non diabetic nephropathies? Nephrol Dial Transplant (2006) 21:2696–2702.[Free Full Text]
  3. Sarafidis PA, Bakris GL. Protection of the kidney by thiazolidinediones: an assessment from bench to bedside. Kidney Int (2006) 70:1223–1233.[CrossRef][Web of Science][Medline]
  4. Ruiz-Ortega M, Lorenzo O, Ruperz M, Edigo J. ACE inhibitors and AT1 receptor antagtonists–beyond the haemodynamic effect. Neprol Dial Transplant (2000) 15:561–565.[CrossRef]
  5. Schupp M, Janke J, Clasen R, Unger T, Kintscher U. Angiotensin type I receptor blockers induce peroxisome proliferator-activated receptor gamma activity. Circulation (2004) 109:2054–2057.[Abstract/Free Full Text]
  6. Lewis EJ, Huniscker LG, Bain RP, Rohde RD. The effect of angiotensin-converting enzyme inhibition on diabetic nephropathy. N Engl J Med (1993) 329:1456–1462.[Abstract/Free Full Text]
  7. Yokoyama H, Tomonaga O, Hirayama M, et al. Predictors of the progression of diabetic nephropathy and the beneficial effect of angiotensin-converting enzyme inhibitors in NIDDM patients. Diabetologia (1997) 40:405–411.[CrossRef][Web of Science][Medline]
  8. 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]
  9. Lewis E, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med (2001) 345:851–860.[Abstract/Free Full Text]
  10. Parving HH, Lehnert H, Brochner-mortensen J, et al. The effect of ibesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med (2001) 345:870–878.[Abstract/Free Full Text]

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This Article
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