A Low-Iron-Available, Polyphenol-Enriched, Carbohydrate-Restricted Diet to Slow Progression of Diabetic Nephropathy

Abstract

Diabetic nephropathy has become the leading cause of uremia. Several lines of evidence suggest dietary factors other than protein intake have a substantial role in the progression of diabetic nephropathy to end-stage renal disease. The present investigation was initiated to evaluate whether a carbohydrate-restricted, low-ironavailable, polyphenol-enriched (CR-LIPE) diet may delay and improve the outcome of diabetic nephropathy to a greater extent than standard protein restriction. To this aim, 191 diabetic patients, all with type 2 diabetes, were randomized to either CR-LIPE or standard protein restriction and the following outcomes monitored: doubling of serum creatinine, cumulative incidence of endstage renal disease, and all cause mortality. Over a mean follow-up interval of 3.9 ؎ 1.8 years, serum creatinine concentration doubled in 19 patients on CR-LIPE (21%) and in 31 control subjects (39%) (P < 0.01). Renal replacement therapy or death occurred in 18 patients on CR-LIPE (20%) and in 31 control subjects (39%) (P < 0.01). These differences were independent from followup interval, sex, mean arterial blood pressure, HbA 1c , initial renal dysfunction, and angiotensin system inhibitor use. In conclusion, CR-LIPE was 40 -50% more effective than standard protein restriction in improving renal and overall survival rates.

Assessing the Validity of Surrogate Outcomes for ESRD

“…Studies were conducted in some or all of the United States, Canada, Europe, Asia, and Oceania, with trial results published between 1992 and 2013. A variety of interventions were assessed, including BP lowering (16 trials 12,13,17,19,[21][22][23][24][25][26]28,29,[31][32][33][34] ), lipid-lowering therapy (3 trials 9,11,15 ), intensive glucose-lowering therapy (4 trials 16,20,27,30 ), anemia therapy (2 trials 14,18 ), dietary intervention (1 trial 10 ), and chelation therapy (1 trial 8 ).…”

“…The trials had a sample size that ranged from 50 to 17,118 participants with follow-up periods from 1.6 to 10.0 years. Of the 27 trials identified, 3 were single-center studies [8][9][10] and 24 were multicenter studies. Studies were conducted in some or all of the United States, Canada, Europe, Asia, and Oceania, with trial results published between 1992 and 2013.…”

“…Eighteen trials specified the presence of diabetes as part of their inclusion criteria. [8][9][10]12,13,[15][16][17][19][20][21][22][23][24][25][26][27]30 The mean GFR of the study participants ranged from 17.3 to 90.0 ml/min per 1.73 m 2 . Quality assessment of included trials based on key indicators of trial quality showed that earlier, smaller studies provided few details about the process of randomization, allocation concealment, and the use of intention-to-treat analysis techniques (Supplemental Material 1).…”

The Role of Iron in Diabetes and Its Complications

“…Most importantly, the pathogenic role of iron in progression is indicated by the observation that progression can be prevented either by an iron-deficient diet or chelators (76 -78). More specifically, in diabetes, a recent randomized trial involving 191 patients with diabetes, proteinuria, and a decreased glomerular filtration rate showed that a low-iron-available, carbohydraterestricted, polyphenol-enriched diet compared with a standard proteinrestricted diet had a renoprotective effect (67).…”

Stored Iron and Vascular Reactivity

“…21 The small but growing literature on the effects of induced iron depletion/deficiency in various experimental models of oxidative or inflammatory injury strongly supports beneficial effects of eliminating storage iron. [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] Correlation of in vitro with in vivo endothelial iron status will be assisted by future studies into the basis for an interesting phenomenon seen in human umbilical vein endothelial cells (HUVEC). Sensitivity of HUVEC to oxidative injury or high glucose levels decreases sharply with subculture in vitro after a few passages.…”