Shinichiro Inaba

High‐fat and high‐sucrose (western) diet induces steatohepatitis that is dependent on fructokinase

Fructose intake from added sugars has been implicated as a cause of nonalcoholic fatty liver disease. Here we tested the hypothesis that fructose may interact with a high‐fat diet to induce fatty liver, and to determine if this was dependent on a key enzyme in fructose metabolism, fructokinase. Wild‐type or fructokinase knockout mice were fed a low‐fat (11%), high‐fat (36%), or high‐fat (36%) and high‐sucrose (30%) diet for 15 weeks. Both wild‐type and fructokinase knockout mice developed obesity with mild hepatic steatosis and no evidence of hepatic inflammation on a high‐fat diet compared to a low‐fat diet. In contrast, wild‐type mice fed a high‐fat and high‐sucrose diet developed more severe hepatic steatosis with low‐grade inflammation and fibrosis, as noted by increased CD68, tumor necrosis factor alpha, monocyte chemoattractant protein‐1, alpha‐smooth muscle actin, and collagen I and TIMP1 expression. These changes were prevented in the fructokinase knockout mice. Conclusion: An additive effect of high‐fat and high‐sucrose diet on the development of hepatic steatosis exists. Further, the combination of sucrose with high‐fat diet may induce steatohepatitis. The protection in fructokinase knockout mice suggests a key role for fructose (from sucrose) in this development of steatohepatitis. These studies emphasize the important role of fructose in the development of fatty liver and nonalcoholic steatohepatitis. (Hepatology 2013;58:1632–1643)

Fructokinase activity mediates dehydration-induced renal injury

The epidemic of chronic kidney disease in Nicaragua (Mesoamerican nephropathy) has been linked with recurrent dehydration. Here we tested whether recurrent dehydration may cause renal injury by activation of the polyol pathway, resulting in the generation of endogenous fructose in the kidney that might subsequently induce renal injury via metabolism by fructokinase. Wild-type and fructokinase-deficient mice were subjected to recurrent heat-induced dehydration. One group of each genotype was provided water throughout the day and the other group was hydrated at night, after the dehydration. Both groups received the same total hydration in 24 h. Wild-type mice that received delayed hydration developed renal injury, with elevated serum creatinine, increased urinary NGAL, proximal tubular injury, and renal inflammation and fibrosis. This was associated with activation of the polyol pathway, with increased renal cortical sorbitol and fructose levels. Fructokinase-knockout mice with delayed hydration were protected from renal injury. Thus, recurrent dehydration can induce renal injury via a fructokinase-dependent mechanism, likely from the generation of endogenous fructose via the polyol pathway. Access to sufficient water during the dehydration period can protect mice from developing renal injury. These studies provide a potential mechanism for Mesoamerican nephropathy.

Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome

Carbohydrates with high glycemic index are proposed to promote the development of obesity, insulin resistance and fatty liver, but the mechanism by which this occurs remains unknown. High serum glucose concentrations glucose are known to induce the polyol pathway and increase fructose generation in the liver. Here we show that this hepatic, endogenously-produced fructose causes systemic metabolic changes. We demonstrate that mice unable to metabolize fructose are protected from an increase in energy intake and body weight, visceral obesity, fatty liver, elevated insulin levels and hyperleptinemia after exposure to 10% glucose for 14 weeks. In normal mice, glucose consumption is accompanied by aldose reductase and polyol pathway activation in steatotic areas. In this regard, we show that aldose reductase deficient mice were protected against glucose-induced fatty liver. We conclude that endogenous fructose generation and metabolism in the liver represents an important mechanism whereby glucose promotes the development of metabolic syndrome.

Endogenous Fructose Production and Fructokinase Activation Mediate Renal Injury in Diabetic Nephropathy

Diabetes is associated with activation of the polyol pathway, in which glucose is converted to sorbitol by aldose reductase. Previous studies focused on the role of sorbitol in mediating diabetic complications. However, in the proximal tubule, sorbitol can be converted to fructose, which is then metabolized largely by fructokinase, also known as ketohexokinase, leading to ATP depletion, proinflammatory cytokine expression, and oxidative stress. We and others recently identified a potential deleterious role of dietary fructose in the generation of tubulointerstitial injury and the acceleration of CKD. In this study, we investigated the potential role of endogenous fructose production, as opposed to dietary fructose, and its metabolism through fructokinase in the development of diabetic nephropathy. Wild-type mice with streptozotocin-induced diabetes developed proteinuria, reduced GFR, and renal glomerular and proximal tubular injury. Increased renal expression of aldose reductase; elevated levels of renal sorbitol, fructose, and uric acid; and low levels of ATP confirmed activation of the fructokinase pathway. Furthermore, renal expression of inflammatory cytokines with macrophage infiltration was prominent. In contrast, diabetic fructokinase-deficient mice demonstrated significantly less proteinuria, renal dysfunction, renal injury, and inflammation. These studies identify fructokinase as a novel mediator of diabetic nephropathy and document a novel role for endogenous fructose production, or fructoneogenesis, in driving renal disease.

Effect of an educational program on the predialysis period for patients with chronic renal failure

BackgroundThe purpose of the treatment and management of chronic renal failure during the predialysis period is mainly to retard the progression of the deterioration of renal function. Optimal dialysis initiation is important to improve the patients outcome after therapy. We investigated whether providing information through an original educational program could facilitate dialysis initiation, with the patient in a better condition, and therefore greater cost-effectiveness.MethodsOne hundred and seventy-six patients who underwent dialysis initiation for chronic renal failure in our hospital between April 2002 and March 2005 were divided into two groups according to their participation or nonparticipation in an educational program. Participation in the education program was of their own free will. The instructors consisted of nephrologists, nursing staff, clinical engineering technologists, national registered dietitians, and medical social workers. We investigated whether the education program facilitated trouble-free dialysis initiation by comparing findings of blood tests at the start, the existence of heart-failure symptoms, type of blood access, percentage of scheduled initiation, and the number of days and cost of hospitalization as indices between participating and nonparticipating groups.ResultsThe number of patients using a double-lumen dialysis catheter, and the duration and cost of hospitalization in training the participating group, were significantly less than those in the nonparticipating group. Although there was no significant difference in renal function at the initiation of renal replacement therapy (RRT) between the two groups, serum albumin, hemoglobin, and hematocrit in the participating group were significantly higher than those of the nonparticipating group.ConclusionsThis study suggests that providing sufficient information before dialysis initiation may be effective in both physical condition at dialysis initiation, and medical economic benefits through the understanding of the dialysis.

Plasma CD147 reflects histological features in patients with lupus nephritis

Objective A glycosylated transmembrane protein, CD147, has been implicated in regulating lymphocyte responsiveness and leukocyte recruitment. As lupus nephritis (LN) often follows a relapsing-remitting disease course, accurate understanding of the disease activity would be extremely helpful in improving prognosis. Unfortunately, neither clinical nor serological data can accurately reflect the histological features of LN. The present study investigated whether CD147 can accurately predict pathological features of LN. Methods Plasma and spot urine samples were collected from 64 patients who underwent renal biopsy between 2008 and 2011. Disease activity for LN tissues was evaluated using the biopsy activity index, and compared to levels of biomarkers including CD147. Results In LN tissues, CD147 induction was striking in injured glomeruli and infiltrating inflammatory cells, but not in damaged tubules representing atrophy. Plasma CD147 levels accurately reflected the histological disease activity. However, prediction using a single molecule would be quite difficult because of the complex pathogenesis of LN. The diagnostic accuracy of multiplex parameters indicated that the combination including plasma CD147 might yield excellent diagnostic abilities for guiding ideal LN therapy. Conclusion Plasma CD147 levels might offer useful insights into disease activity as a crucial biomarker in patients with LN.

Relationship between renal function at the time of percutaneous coronary intervention and prognosis in ischemic heart disease patients

BackgroundAs hypertension and diabetes mellitus increase, the number of patients developing complications of cardiovascular disease (CVD) associated with conventional risk factors is increasing. In addition to these risk factors for CVD, chronic kidney disease (CKD) has also been reported to play an important role. We investigated the association of representative ischemic heart disease and CKD.MethodsBetween July 1, 2000, and June 30, 2005, a total of 790 patients who underwent percutaneous coronary intervention (PCI) for angina pectoris or myocardial infarction in our division of cardiovascular disease were reviewed. Serum markers at the implementation of PCI were compared in patients classified according to renal function. For prognosis, in-hospital mortality, 1-year survival rate, overall mortality, and CVD death were investigated. Changes in renal function were also monitored during the follow-up period. The glomerular filtration rate (GFR) was calculated by the Modification of Diet in Renal Disease Study Group (MDRD) formula.ResultsThe mean estimated GFR (eGFR) at PCI implementation was 66.2 ± 21.0 ml/min/1.73 m2. Stage 2 CKD was shown in 51.5% of all the patients. During the overall follow-up period, 126 patients died. With the progression of CKD stage, all-cause, CVD, and in-hospital mortality increased, and the 1-year survival rate decreased. It was proved that a medical history of hypertension, hyperlipidemia, and diabetes, multiple vessel lesions, hypoalbuminemia, C-reactive protein (CRP), and estimated GFR were independent risk factors for all-cause death. In CVD death, in addition to the above risk factors, anemia and total cholesterol were also an independent risk factor. Renal function deteriorated significantly during the follow-up period.ConclusionsPatients with ischemic heart disease requiring PCI often develop renal dysfunction, which may considerably affect prognosis.

Umami: the taste that drives purine intake.

Rheumatologists commonly recommend low purine diets to gouty subjects based on studies linking the purine contents of food to increased risk for gout1. However, most rheumatologists, as well as physicians in general, do not know that one of the basic 5 human tastes is for purine-rich foods, a taste known as umami (oo-mah-mee). We present evidence of this revelation and why this may have occurred. Historically, an elevation in serum urate was considered benign except for carrying an increased risk for gout. Recently, soluble urate has been found to have myriad biologic effects, including raising blood pressure, increasing hepatic fat stores, and inducing insulin resistance2,3. Indeed, the uricase mutation that occurred in the mid-Miocene likely provided a survival advantage to our ancestors during a period of famine that occurred during that time in Europe4. If uric acid has an important role in human survival, then it is logical that there should be a taste receptor that would encourage the ingestion of foods that raise serum urate. In addition to the classic tastes of sour, bitter, sweet, and salt, there is a fifth basic taste, umami. Umami is the “savory” flavor and was first identified in traditional Japanese foods such as kombu (sea kelp), where it was found to result from the presence of free glutamate. The umami receptor in the taste buds is complex, and consists of the metabotropic glutamate receptor-4, the G-protein-coupled heterodimer of taste receptor type 1 member 1 (TAS1R1), and taste receptor type 1 receptor3 … Address correspondence to Dr. R.J. Johnson, Division of Kidney Diseases and Hypertension, University of Colorado Denver, Aurora, Colorado 80045, USA. E-mail: richard.johnson{at}ucdenver.edu

Protective role of fructokinase blockade in the pathogenesis of acute kidney injury in mice

Acute kidney injury is associated with high mortality, especially in intensive care unit patients. The polyol pathway is a metabolic route able to convert glucose into fructose. Here we show the detrimental role of endogenous fructose production by the polyol pathway and its metabolism through fructokinase in the pathogenesis of ischaemic acute kidney injury (iAKI). Consistent with elevated urinary fructose in AKI patients, mice undergoing iAKI show significant polyol pathway activation in the kidney cortex characterized by high levels of aldose reductase, sorbitol and endogenous fructose. Wild type but not fructokinase knockout animals demonstrate severe kidney injury associated with ATP depletion, elevated uric acid, oxidative stress and inflammation. Interestingly, both the renal injury and dysfunction in wild-type mice undergoing iAKI is significantly ameliorated when exposed to luteolin, a recently discovered fructokinase inhibitor. This study demonstrates a role for fructokinase and endogenous fructose as mediators of acute renal disease.

Evaluation of the Relationship between the Serum Alkaline Phosphatase Level at Dialysis Initiation and All-Cause Mortality: A Multicenter, Prospective Study

Background/Aim: High serum alkaline phosphatase (ALP) levels predict mortality independent of bone metabolism parameters and liver function test results in patients on hemodialysis. The relationship between serum ALP at dialysis initiation and mortality during maintenance dialysis is unknown; therefore, we aimed to identify an association. Methods: This multicenter, prospective cohort study analyzed 1,213 patients registered in the Aichi Cohort Study of Prognosis in Patients Newly Initiated into Dialysis from October 2011 to September 2013. Patients were divided into 2 groups based on serum ALP levels. All-cause mortality and incidences of cardiovascular events after dialysis initiation were compared using the log-rank test and multivariate Cox proportional hazard regression analysis. We performed stratified analysis based on parathyroid hormone (PTH) levels. Results: During the follow-up, 109 (18.0%) and 86 (14.1%) patients died in the high ALP group (232 ≥IU/L; High ALP group) and low ALP group (232 <IU/L; Low ALP group), respectively. All-cause mortality was significantly higher in the High ALP group than in the Low ALP group (p = 0.014). The serum ALP level was significantly correlated with the all-cause mortality rate (hazard ratio = 1.17 per 100 IU/L increase of ALP, 95% confidence interval: 1.11–1.24, p < 0.001). The all-cause mortality rate was significantly higher in the High ALP group among patients with low (<150 pg/mL) or normal (150–300 pg/mL) PTH levels (p = 0.012 and p = 0.005, respectively) than in the Low ALP group; there was no significant difference among patients with a high (≥300 pg/mL) PTH level (p = 1.000). Conclusion: The serum ALP level at dialysis initiation is associated with all-cause mortality during maintenance dialysis.