Uric acid lowering to prevent kidney function loss in diabetes: The preventing early renal function loss (PERL) allopurinol study

David M. Maahs, Luiza Caramori, David Z.I. Cherney, Andrzej T. Galecki, Chuanyun Gao, Diana Jalal, Bruce A. Perkins, Rodica Pop-Busui, Peter Rossing, Michael Mauer, Alessandro Doria

Research output: Contribution to journalArticlepeer-review

108 Scopus citations

Abstract

Diabetic kidney disease causes significant morbidity and mortality among people with type 1 diabetes (T1D). Intensive glucose and blood pressure control have thus far failed to adequately curb this problem and therefore a major need for novel treatment approaches exists. Multiple observations link serum uric acid levels to kidney disease development and progression in diabetes and strongly argue that uric acid lowering should be tested as one such novel intervention. A pilot of such a trial, using allopurinol, is currently being conducted by the Preventing Early Renal Function Loss (PERL) Consortium. Although the PERL trial targets T1D individuals at highest risk of kidney function decline, the use of allopurinol as a renoprotective agent may also be relevant to a larger segment of the population with diabetes. As allopurinol is inexpensive and safe, it could be cost-effective even for relatively low-risk patients, pending the completion of appropriate trials at earlier stages.

Original languageEnglish (US)
Pages (from-to)550-559
Number of pages10
JournalCurrent diabetes reports
Volume13
Issue number4
DOIs
StatePublished - Aug 2013

Bibliographical note

Funding Information:
The consistency and strength of these prospective data and their independence from other DN risk factors and potential confounders strongly suggests that moderately elevated serum uric acid may have a role in the pathogenesis of DN and the deterioration of kidney function observed in T1D. This hypothesis is supported by population-based studies [42–45] in which hyperuricemia predicted chronic renal failure. In animal models mild uric acid elevation has also been shown to cause renal disease [10, 11]. Hypothesized pathogenic mechanisms of elevated uric acid in kidney disease include alterations of nitric oxide (NO) pathways, activation of the RAAS [46], induction of pro-inflammatory cytokines [12, 13], and increased oxidative stress resulting from the generation of uric acid by xanthine oxidase [14, 15]. In vitro, uric acid leads to decreased NO production [47], increased CRP [48], and induction of cyclooxygenase-2 [10]. In addition to suppressing NO production, uric acid may directly deplete NO [49]. Consistent with the in vitro data, experimental hyperuricemia induced in the rat by a uricase inhibitor has led to endothelial dysfunction and similar associations have been made in humans [50, 51]. Increased uric acid has also been shown to activate the intrarenal RAAS, leading to tubulointerstitial disease in animals and humans [13, 37, 52, 53]. Other mechanisms by which uric acid may contribute to DN include stimulation of cytokines such as TNF-α, TGFβ-1 [54, 55] and chemokines such as monocyte chemoattractant protein-1[10, 56] (Fig. 1). While the extent of the pathogenic role of uric acid in endothelial dysfunction, inflammation, and kidney disease in humans is still debated, such studies lend plausibility to a contribution of hyperuricemia to the development and progression of diabetic kidney disease.

Funding Information:
Acknowledgments Dr. Maahs was supported by a grant from NIDDK (DK075360). Dr. Caramori is supported by a Career Development Award from the Juvenile Diabetes Research Foundation. This project was supported by NIH grants R03 DK094484 and R34 DK097808, and by grant 17-2012-377 from the Juvenile Diabetes Research Foundation (JDRF). Its contents are the authors’ sole responsibility and do not necessarily represent official NIH or JDRF views.

Keywords

  • Allopurinol
  • Diabetes
  • Diabetic kidney disease
  • Diabetic nephropathy
  • Glomerular filtration rate
  • Kidney disease
  • PERL trial
  • Randomized clinical trial
  • Type 1 diabetes
  • Uric acid

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