Nicole Barthe

Distribution of [14C]-trans-resveratrol, a cancer chemopreventive polyphenol, in mouse tissues after oral administration

Trans-resveratrol, a phenolic compound present in wine, has been reported to be a potential cancer chemopreventive agent. However, although it has numerous biological activities in vitro, there are few data about its bioavailability and tissue distribution in vivo. The objectives of this study were to investigate the absorption and tissue distribution of 14C-trans-resveratrol following oral administration to mice. Male Balb/c mice were given a single oral dose of 14C-trans-resveratrol and were sacrificed at 1.5, 3 or 6 h postdose. The distribution of radioactivity in tissues was evaluated using whole-body autoradiography, quantitative organ-level determination and microautoradiography. In addition, identification of radioactive compounds in kidney and liver was done with high-performance liquid chromatography. Autoradiographic survey of mice sections as well as radioactivity quantification in various organs revealed a preferential fixation of 14C-trans-resveratrol in the organs and biological liquids of absorption and elimination (stomach, liver, kidney, intestine, bile, urine). Moreover, we show that 14C-trans-resveratrol derived radioactivity is able to penetrate the tissues of liver and kidney, a finding supported by microautoradiography. The presence of intact 14C-trans-resveratrol together with glucurono- and/or sulfoconjugates in these tissues was also shown. This study demonstrates that trans-resveratrol is bioavailable following oral administration and remains mostly in intact form. The results also suggest a wide range of target organs for cancer chemoprevention by wine polyphenols in humans.

Outcome of nutritional status and body composition of uremic patients on a very low protein diet

Concern has been raised about the nutritional adequacy of a very low protein diet (VLPD). Monthly clinical evaluation by a physician and dietitian and quarterly dietary records, anthropometric measurements, blood testing, and dual energy X-ray absorptiometry (DEXA) were used to assess the course of nutritional status for 1 year in 10 clinically stable patients (six men, four women; age, 57.1 +/- 9.3 years) with advanced chronic renal failure (mean glomerular filtration rate, 13.2 +/- 4.8 mL/min/1.73 m(2)). These patients received a VLPD providing 0.3 g/kg/d of protein and were supplemented with amino acids and ketoanalogues. Conventional nutritional markers remained unchanged after 1 year of the VLPD. However, during the same period, whole-body DEXA showed a significant decrease in lean tissue from 46.2 +/- 10.2 to 45.0 +/- 9. 8 kg (P < 0.02); limb-trunk lean tissue ratio was reduced from 0.86 +/- 0.12 to 0.82 +/- 0.12 (P < 0.02), total-body fat increased from 20.0 +/- 6.9 to 21.4 +/- 7.0 kg (P < 0.05), and the percentage of total-body fat increased from 29.2% +/- 8.7% to 31.7% +/- 8.8% (P < 0.03). These different modifications occurred abruptly during the first 3 months, then stabilized or slightly improved thereafter. These mild changes do not appear to be deleterious given the favorable long-term outcome of these patients, even after they began treatment by dialysis or after renal transplantation.

Body composition of patients on a very low-protein diet: a two-year survey with DEXA.

BACKGROUNDnIt has been reported that patients on a very-low-protein diet (VLPD) maintain a satisfactory nutritional status because of a conserved adaptive metabolic response. However, only few studies have examined the course of nutritional status and body composition in the long term (2 years).nnnMETHODSnThirteen stable patients (8 men; age, 55 +/- 12 years; glomerular filtration rate (GFR), 15 +/- 5 mL/min) receiving a VLPD (0.3 g/kg/day protein) supplemented with amino acids and ketoanalogues (SVLPD) were studied for 2 years. A joint visit with a physician and a dietitian and routine blood and urine analyses were performed every month. Dual-energy x-ray absorptiometry (DEXA), which was used to assess modification of body composition, and GFR (urinary 51Cr-EDTA) and urinary urea and creatinine excretion, which were used to assess nutritional status and compliance to the diet, were assessed every 3 months.nnnRESULTSnGFR, albumin, and prealbumin levels remained stable. Urea urinary excretion decreased at 3 months and then slightly increased at 2 years, but the calculated protein intake remained low at 0.38 +/- 0.1 g/kg/day. Energy intake remained close to 30 kcal/kg/day. No significant change was observed for total fat mass or percent fat mass. After an initial decrease, lean body mass stabilized at 6 months and then increased significantly from 6 to 24 months (P =.02, paired t-test); the mean increase during this period was of 2 kg, that is, 4.6%. Urinary creatinine excretion showed the same profile. Total bone mass, lumbar or hip site bone mass, and Z-score significantly decreased from T0 to 1 and 2 years (P <.05).nnnCONCLUSIONnThis study confirms that a supplemented VLPD is nutritionally safe for a long period, but attention must be paid to bone mass.

Large kidneys predict poor renal outcome in subjects with diabetes and chronic kidney disease

BackgroundRenal hypertrophy occurs early in diabetic nephropathy, its later value is unknown. Do large kidneys still predict poor outcome in patients with diabetes and Chronic Kidney Disease (CKD)?MethodsSeventy-five patients with diabetes and CKD according to a Glomerular Filtration Rate (GFR, by 51Cr-EDTA clearance) below 60 mL/min/1.73 m2 or an Albumin Excretion Rate above 30 mg/24 H, had an ultrasound imaging of the kidneys and were cooperatively followed during five years by the Diabetology and Nephrology departments of the Centre Hospitalier Universitaire de Bordeaux.ResultsThe patients were mainly men (44/75), aged 62 ± 13 yrs, with long-standing diabetes (duration:17 ± 9 yrs, 55/75 type 2), and CKD: initial GFR: 56.5 (8.5-209) mL/min/1.73 m2, AER: 196 (20-2358) mg/24 H. Their mean kidney lenght (108 ± 13 mm, 67-147) was correlated to the GFR (r = 0.23, p < 0.05). During the follow-up, 9/11 of the patients who had to start dialysis came from the half with the largest kidneys (LogRank: p < 0.05), despite a 40% higher initial isotopic GFR. Serum creatinine were initially lower (Small kidneys: 125 (79-320) μmol/L, Large: 103 (50-371), p < 0.05), but significantly increased in the large kidneys group at the end of the follow-up (Small kidneys: 129 (69-283) μmol/L, Large: 140 (50-952), p < 0.005 vs initial). The difference persisted in the patients with severe renal failure (KDOQI stages 4,5).ConclusionsLarge kidneys still predict progression in advanced CKD complicating diabetes. In these patients, ultrasound imaging not only excludes obstructive renal disease, but also provides information on the progression of the renal disease.

Bone loss in diabetic patients with chronic kidney disease

Objectiveu2003 We investigated whether loss of bone is detectable during follow‐up of diabetic patients with chronic kidney disease (CKD).

Progression-related bias in the monitoring of kidney function in patients with diabetes and chronic kidney disease.

The Cockcroft and Gault (CG) and Modification of Diet in Renal Disease (MDRD) equations underestimate the glomerular filtration rate (GFR) decline in diabetes. Do this decline and the albumin excretion rate (AER) influence their validity? In 161 diabetic patients, isotopically determined GFR (i-GFR) (51Cr-EDTA) was compared with estimated GFR (e-GFR) by the CG, MDRD, and the new Mayo Clinic Quadratic (MCQ) equations. We searched for a relation between the error in e-GFR and the AER. An influence of the AER outcome on the e-GFR decline was evaluated in 63 subjects followed up over 3 years. The MDRD and the MCQ were more precise and accurate than the CG, but they were biased. The error increased with AER for the CG (r = 0.25, P = .001) and the MDRD (r = 0.20, P = .009), but not for the MCQ. For the 63 patients followed up, the e-GFR declines by the 3 estimations were related to the initial AER, whereas no relation with arterial blood pressure, hemoglobin A(1C), hemoglobin, and blood lipids emerged. The MCQ declines were more pronounced: -10.5% +/- 8.9% in the macroalbuminuric group (P < .05 vs both microalbuminuric [-2.6% +/- 10.1%] and normoalbuminuric [-0.1% +/- 6.6%] groups), and were related to the outcome of the AER (r = 0.33, P < .05). As chronic kidney disease progresses in diabetes, the declining GFR and rising AER influence the estimation of GFR by the CG and MDRD equations, underestimating the GFR decline and the benefit of reducing the AER. The less affected MCQ evidences a slower e-GFR decline with AER control.

Prediction of mortality rate in type 2 diabetes: estimated glomerular filtration rate underestimates the true rate

To the Editor: In their paper published in Diabetologia [1], Bruno et al. assessed whether a reduction in estimated glomerular filtration rate (eGFR), calculated using the abbreviated Modification of Diet in Renal Disease (MDRD) study equation [2], predicted mortality in type 2 diabetes. Although an eGFR of <60 ml min 1.73 m was associated with a twofold increase in the mortality rate, further analyses using smaller eGFR categories (15–29, 30–44, 45–59 ml min 1.73 m) revealed that this was due to the increased risk in patients with eGFR values between 15 and 29 ml min 1.73 m, with hazard ratios even suggesting a benefit for the non-proteinuric, moderate renal failure strata. To investigate whether this unexpected finding was due to the inaccuracy of the abbreviated MDRD equation in estimating GFR, we compared eGFR values with GFR values determined by Cr-labelled EDTA clearance (isotopic GFR [iGFR]) in a group of volunteers, stratifying the results as per Bruno et al. [1]. In total, 128 patients with type 2 diabetes (age 67±9 years, BMI 28.8±4.8, HbA1c 8.5±1.6% [data presented as means ± SD], 53 women) gave informed consent to participate in this study, which was conducted in accordance with the Declaration of Helsinki. In the group as a whole, iGFR was 54.5±32.7 ml min 1.73 m. Although the eGFR (48.2±18.8 ml min 1.73 m) showed a strong correlation with i-GFR (r=0.80, p<0.001), it underestimated it (p<0.001). The comparisons of eGFR and iGFR for each eGFR stratum as defined by Bruno et al. are shown in Table 1. In the group as a whole, most of the subjects (55.5%) were wrongly classified by the MDRD-estimated GFR in the four GFR strata. This suggests that the majority of patients followed by Bruno et al. would have been classified in other strata if measured GFR rather than eGFR values had been used. In particular, many patients in the 45–60 and 60–89 ml min 1.73 m eGFR intervals, who had hazard ratios of <1.00 for all-cause and cardiovascular mortality in the paper [1], would have been in higher GFR strata. Although it is the best predictor of GFR in diabetic patients with renal insufficiency [3], the MDRD equation is well known to underestimate GFR values at the upper end of the normal range [4]. This explains the high proportion of patients with chronic kidney disease in the population Diabetologia (2007) 50:2410–2411 DOI 10.1007/s00125-007-0796-8