Low-fructose Diet Lowers Blood Pressure and Inflammation in Patients With Chronic Kidney Disease

Low-fructose Diet Lowers Blood Pressure and Inflammation in Patients With Chronic Kidney Disease

Andrzej Brymora; Mariusz Flisiński; Richard J. Johnson; Grażzyna Goszka; Anna Stefańska; Jacek Manitius

Posted: 03/14/2012; Nephrol Dial Transplant. 2012;27(2):608-612. © 2012 Oxford University Press

 
 
 
 
 

Abstract and Introduction

Abstract

Background. Fructose has been strongly linked with hypertension, hyperuricemia and inflammation in experimental models and humans. However, the effect of low-fructose diet on inflammation, hyperuricemia and the progression of renal disease has not yet been evaluated in patients with chronic kidney disease (CKD).
Methods. Twenty-eight patients (age 59 ± 15 years, 17 males/11 females) with Stages 2 and 3 CKD were switched from a regular (basal) (60.0 g/24 h) to a low (12.0 g/24 h) fructose diet for 6 weeks, followed by a resumption of their regular diet for another 6 weeks. Diet was monitored by a dietician. At the baseline, low- and regular-fructose diet ambulatory blood pressure (BP) was measured and blood sampled for renal function (creatinine), inflammatory markers, fasting glucose and insulin and serum uric acid. Twenty-four-hour urine collections were also obtained for creatinine, uric acid, monocyte chemotatic protein-1, transforming growth factor-beta and N-acetyl-beta-D-glucosaminidase.
Results. The low-fructose diet tended to improve BP for the whole group (n = 28), while significant reduction of BP was only seen in dippers (n = 20) but not in non-dippers (n = 8). No effects on estimated glomerular filtration rate (eGFR) or proteinuria were observed. Serum uric acid was lowered non-significantly with low-fructose diet (7.1 ± 1.3 versus 6.6 ± 1.0 mg/dL, P < 0.1), whereas a significant decrease in fasting serum insulin was observed (11.2 ± 6.1 versus 8.2 ± 2.9 mIU/mL, P < 0.05) and the reduction persisted after return to the regular diet. A slight but not significant reduction in urinary uric acid and fractional uric acid excretion was observed while the patients were on the low fructose diet. The low-fructose diet also decreased high sensitivity C-reactive protein (hsCRP) (4.3 ± 4.9 versus 3.3 ± 4.5 mg/L; P < 0.01) and soluble intercellular adhesion molecule (sICAM) (250.9 ± 59.4 versus 227 ± 50.5 ng/mL; P < 0.05). The hsCRP returned to baseline with resumption of the regular diet, whereas the reduction in sICAM persisted.
Conclusion. Low-fructose diet in subjects with CKD can reduce inflammation with some potential benefits on BP. This pilot study needs to be confirmed by a larger clinical trial to determine the long-term benefit of a low-fructose diet compared to other diets in subjects with CKD.

Introduction

Fructose intake from added sugars has increased dramatically over the last century and has recently been implicated as a potential contributor to hypertension, inflammation and kidney disease.[1] Fructose is distinct from other sugars as uric acid is generated during its metabolism.[2] Serum uric acid levels have been found to correlate with the intake of fructose and added sugars.[3] In turn, an elevated serum uric acid has also been shown to be associated with hypertension, inflammation and chronic kidney disease (CKD),[4] and early intervention trials with xanthine oxidase inhibitors such as allopurinol have been found to have benefits on these parameters in both subjects with normal and decreased renal function.[5–8]

To date, there have been no published studies to examine the effect of a low-fructose diet in subjects with or without CKD. In particular, the usefulness of a low-fructose diet in subjects with CKD could theoretically be unhelpful given the fact that decreased glomerular filtration rate (GFR) itself may lead to the retention of uric acid and sodium which can cause hyperuricemia and hypertension, respectively.[9] Furthermore, both inflammation and oxidative stress characterize subjects with reduced renal function and is likely to have multiple causes.[10]

Given how little is known in this area, we performed an open pilot study to determine the effect of a low-fructose diet on serum uric acid, blood pressure (BP) and markers of inflammation [especially high-sensitivity C-reactive protein (hsCRP) and soluble intercellular adhesion molecule (sICAM) 1] in subjects with stable CKD (Stages 2 and 3). For this pilot study, we estimated fructose intake while patients were on their regular diet along with baseline parameters, followed by a 6-week trial of a low-fructose diet. Subjects then resumed to their regular diet for an additional 6 weeks to determine if the effects of the low-fructose diet were persistent.

Excessive intake of fructose, primarily from added sugars, has emerged as a risk factor for hyperuricemia,[3] hypertension,[11–13]metabolic syndrome[14] and kidney disease.[15] Furthermore, the administration of fructose to animals can experimentally induce hypertension[16,17] renal injury,[17–19] inflammation[20] and metabolic syndrome.[21] Nevertheless, to date, the use of a low-fructose diet has not been tested for its protective effects in either patients with metabolic syndrome or patients with CKD. As such, we decided to perform an exploratory pilot study to determine if a low-fructose diet can reduce serum uric acid or improve BP, renal function or markers of inflammation in a stable population with Stage 2 and 3 CKD. For this purpose, we identified 28 subjects with non-diabetic stable CKD as noted by minimal change in eGFR during the prior 6 months. A dietician met with each subject and reviewed their intake of fructose from natural sources (primarily fruit) and added sugars. Subjects were then placed on a low-fructose diet for 6 weeks. In order to determine if the benefits of the low-fructose diet would persist, we continued to follow subjects after they had resumed their regular diet for an additional 6 weeks.

A primary interest was whether this diet could reduce serum uric acid levels. Uric acid levels are modulated by numerous factors, including dietary intake of purines and fructose, endogenous generation, and renal and gastrointestinal excretion. Serum uric acid increases in patients with reduced renal function due to impaired renal excretion, and levels of 7.0 mg/dL or higher are present in ~50% of subjects on dialysis.[9] In the current study, a low-fructose diet reduced serum uric acid by ~0.5 mg/dL which did not meet statistical significance. It is possible that with a larger number of subjects, or with a longer duration of the diet, significance might have been achieved. However, it seems likely that to reduce uric acid levels in subjects with CKD to 5.0–5.5 mg/dL, which is what correlates epidemiologically with good BP or renal function[4] that additional measures besides diet are likely necessary.

We also found that the low-fructose diet tended to reduce BP, but this effect was most significant in dippers in whom BP falls at night. Fructose may increase BP via multiple mechanisms but one effect may be by stimulation of the sympathetic nervous system.[22] In addition, the effects of fructose to raise BP mostly manifests when animals are ingesting fructose.[16] Indeed, in humans, the ingestion of fructose results in increases in BP occur shortly after ingestion[23] and tend to be most elevated during the day.[24] Hence, the inability for low-fructose diet to reduce BP in non-dippers could be due to the fact that the diet is least effective during the night and that non-dippers have an elevation in nocturnal BP that is not mediated by sympathetic nervous system activation.

Of note, we did not identify any benefit of low-fructose diet on renal function, although a trend was observed for an improvement in serum creatinine and creatinine clearance. It is possible that with longer follow-up or more subjects, a change might have been observed. Our subjects were also selected to have relatively stable renal function, so very little progression was seen in either group. We did note, however, some improvement in markers of inflammation (sICAM-1 and hsCRP) and in serum insulin levels. The significance of these findings remains to be established.

One interesting observation was that the benefits on serum uric acid, BP and inflammation tended to remain even after returning to the regular diet. In this regard, the intake of fructose is known to upregulate the expression of both the transporter for fructose in the gut (Glut5) as well as its key metabolizing enzyme, fructokinase, in the liver.[25] Subjects with non-alcoholic fatty liver disease have a history of high-fructose ingestion from added sugars and show elevated levels of fructokinase messenger RNA in their liver.[26] Furthermore, a pilot study showed that subjects on a high-fructose diet show an enhanced increase in serum uric acid in response to a set dose of fructose, whereas the same subjects on a low-fructose diet show the opposite.[27] Thus, one possible explanation is that the implementation of a low-fructose diet may have led to a down-regulation of Glut5 and fructokinase, resulting in a reduction in fructose absorption and metabolism that persisted despite resuming the regular diet. Another possibility is that characteristics in the resumed regular diet was different from the basal regular diet in respect to fructose content. While total fructose intake was not different, subjects resuming their ‘regular’ diet did reduce the relative percent of added sugars with a relative increase in natural fructose sources (Table 1). Some studies suggest that it is the fructose content from added sugars that confers the risk for hypertension as opposed to fructose from fruits that also contain a host of beneficial substances such as antioxidants.[11] Therefore, it remains possible that some of the benefits in the resumed regular diet may reflect a relative shift in fructose intake from added sugars to natural fruits.

This study has several limitations. Firstly, since a low-fructose diet has never been administered to subjects with CKD, the study was of necessity exploratory and did not include a power analysis. Secondly, for this initial study, there was no placebo group, and data were compared to baseline levels. However, we did ensure these subjects had stable renal function for the prior 6 months, and no alterations in medications were provided during the course of the study. A third problem relates to the persistent effect of the low-fructose diet after reinstitution of the regular diet. Although it could be due to the downregulation of fructokinase and Glut5 as proposed, it is important to have a control group that is followed for the same duration that has not received a low-fructose diet. Finally, it is also possible that some of the benefits may have related to the 1 kg reduction in weight observed, even though this was not significant. However, meta-analyses suggest that a reduction of weight of 1 kg will only lower systolic BP by 1 mmHg, so it seems unlikely that this is a significant factor.[28] Furthermore, there were no changes in total calorie (energy intake) during all three phases of the study.

Despite the limitations, the study provides some very interesting findings. Firstly, we demonstrate the feasibility of using a low-fructose diet in subjects with CKD, and we have found that it can reduce some markers of inflammation. While there were no benefits on renal function in this pilot study, we did observe a reduction in BP in subjects with a ‘dipper’ physiology. Finally, this pilot study will also provide data required to develop a prospective study with the appropriate power calculations. We therefore hope this study will be useful for others who are interested in dietary approaches to improve metabolic and physiological outcomes in subjects with CKD.

 

 

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