Fructose increases the activity of sodium hydrogen exchanger in renal proximal tubules that is dependent on ketohexokinase.

High fructose intake has been known to induce metabolic syndrome in laboratory animals and humans. Although fructose intake enhances sodium reabsorption and elevates blood pressure, role of fructose metabolism in this process has not been studied. Here we show that by ketohexokinase - the primary enzyme of fructose - is involved in regulation of renal sodium reabsorption and blood pressure via activation of the sodium hydrogen exchanger in renal proximal tubular cells. First, wild-type and ketohexokinase knockout mice (Male, C57BL/6) were fed fructose water or tap water with or without a high salt diet. Only wild type mice fed the combination of fructose water and high salt diet displayed increased systolic blood pressure and decreased urinary sodium excretion. In contrast, ketohexokinase knockout mice were protected. Second, urinary sodium excretion after intraperitoneal saline administration was reduced with the decreased phosphorylation of sodium hydrogen exchanger 3 in fructose-fed WT; these changes were not observed in the ketohexokinase knockout mice, however. Third, knockdown of ketohexokinase attenuated fructose-mediated increases of NHE activity with decreased cAMP levels in porcine renal proximal tubular cells (LLC-PK1). In conclusion, fructose metabolism by ketohexokinase increases sodium hydrogen exchanger activity in renal proximal tubular cells via decreased intracellular cAMP level, resulting in increased renal sodium reabsorption and blood pressure in mice.

Lacking ketohexokinase-A exacerbates renal injury in streptozotocin-induced diabetic mice.

OBJECTIVE: Ketohexokinase (KHK), a primary enzyme in fructose metabolism, has two isoforms, namely, KHK-A and KHK-C. Previously, we reported that renal injury was reduced in streptozotocin-induced diabetic mice which lacked both isoforms. Although both isoforms express in kidney, it has not been elucidated whether each isoform plays distinct roles in the development of diabetic kidney disease (DKD). The aim of the study is to elucidate the role of KHK-A for DKD progression. MATERIALS AND METHODS: Diabetes was induced by five consecutive daily intraperitoneal injections of streptozotocin (50 mg/kg) in C57BL/6J wild-type mice, mice lacking KHK-A alone (KHK-A KO), and mice lacking both KHK-A and KHK-C (KHK-A/C KO). At 35 weeks, renal injury, inflammation, hypoxia, and oxidative stress were examined. Metabolomic analysis including polyol pathway, fructose metabolism, glycolysis, TCA (tricarboxylic acid) cycle, and NAD (nicotinamide adenine dinucleotide) metabolism in kidney and urine was done. RESULTS: Diabetic KHK-A KO mice developed severe renal injury compared to diabetic wild-type mice, and this was associated with further increases of intrarenal fructose, dihydroxyacetone phosphate (DHAP), TCA cycle intermediate levels, and severe inflammation. In contrast, renal injury was prevented in diabetic KHK-A/C KO mice compared to both wild-type and KHK-A KO diabetic mice. Further, diabetic KHK-A KO mice contained decreased renal NAD+ level with the increase of renal hypoxia-inducible factor 1-alpha expression despite having increased renal nicotinamide (NAM) level. CONCLUSION: These results suggest that KHK-C might play a deleterious role in DKD progression through endogenous fructose metabolism, and that KHK-A plays a unique protective role against the development of DKD.

Aging-associated renal disease in mice is fructokinase dependent.

Aging-associated kidney disease is usually considered a degenerative process associated with aging. Recently, it has been shown that animals can produce fructose endogenously, and that this can be a mechanism for causing kidney damage in diabetic nephropathy and in association with recurrent dehydration. We therefore hypothesized that low-level metabolism of endogenous fructose might play a role in aging-associated kidney disease. Wild-type and fructokinase knockout mice were fed a normal diet for 2 yr that had minimal (<5%) fructose content. At the end of 2 yr, wild-type mice showed elevations in systolic blood pressure, mild albuminuria, and glomerular changes with mesangial matrix expansion, variable mesangiolysis, and segmental thrombi. The renal injury was amplified by provision of high-salt diet for 3 wk, as noted by the presence of glomerular hypertrophy, mesangial matrix expansion, and alpha smooth muscle actin expression, and with segmental thrombi. Fructokinase knockout mice were protected from renal injury both at baseline and after high salt intake (3 wk) compared with wild-type mice. This was associated with higher levels of active (phosphorylated serine 1177) endothelial nitric oxide synthase in their kidneys. These studies suggest that aging-associated renal disease might be due to activation of specific metabolic pathways that could theoretically be targeted therapeutically, and raise the hypothesis that aging-associated renal injury may represent a disease process as opposed to normal age-related degeneration.

A Pilot Study Examining the Effects of Tolvaptan on Residual Renal Function in Peritoneal Dialysis for Diabetics.

BACKGROUND: For patients with end-stage renal disease (ESRD), peritoneal dialysis (PD) serves as a possible renal replacement therapy. However, most PD patients, particularly those with ESRD and diabetes mellitus, reportedly discontinue PD early, resulting in shorter survival periods and poorer prognosis because of overhydration. Recently, the vasopressin-2 receptor antagonist tolvaptan was approved for volume control in patients with heart failure. The present study aimed to identify the effects of tolvaptan in diabetic PD patients. METHODS: In this pilot study, the tolvaptan group (n = 12) were treated with 15 mg/day of tolvaptan 2 weeks after PD initiation and were prospectively analyzed for 1 year, and patients in the control group (n = 12) did not receive tolvaptan and were retrospectively analyzed for 1 year. In addition to the biochemical tests, echocardiograms, serum atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) levels, peritoneal Kt/V, and creatinine clearance (CCr) were examined at baseline and at 6 and 12 months after PD initiation. RESULTS: In the control group, the urine volume, renal Kt/V, and renal CCr levels consistently decreased; however, these parameters were stably maintained during the study period in the tolvaptan group. Atrial natriuretic peptide, CRP levels and the left ventricular mass index of the tolvaptan-treated group were significantly lower than those in the control group, whereas total protein and albumin levels were significantly higher at 6 and 12 months in the tolvaptan group. There were no obvious adverse effects. CONCLUSIONS: These data suggest that tolvaptan may preserve residual renal function and improve volume control in PD patients with diabetes mellitus.

When should icodextrin be started to improve atherosclerosis in peritoneal dialysis patients?

Icodextrin-based peritoneal dialysis (PD) has many advantages over glucose-based PD. The present study aimed to investigate when icodextrin should be started for better management of cardiovascular status (as defined by echocardiography findings) and residual renal function (RRF). We retrospectively analyzed 40 patients treated with continuous ambulatory PD or automated PD. The patients were divided into these groups: Group A: started icodextrin within 2 weeks after PD onset. Group B: started icodextrin 1 year after PD onset. Group C: started icodextrin 2 years after PD onset. Group D: never used icodextrin during the study period. At the start of PD, we observed no significant difference in left ventricular mass index (LVMI) or urine volume (UV) between the groups. At 4 years, LVMI and UV were both significantly improved in group A compared with group D. The amelioration in LVMI was negatively associated with phosphate elimination. Our study showed that icodextrin preserved RRF and ameliorated left ventricular hypertrophy. Moreover, the timing of icodextrin introduction in PD patients influenced the clinical effects, including progression of cardiac hypertrophy and RRF.

Icodextrin eliminates phosphate and ameliorates cardiac hypertrophy and valvular calcification in patients with end-stage renal disease and diabetes mellitus undergoing peritoneal dialysis.

Among end-stage renal disease (ESRD) patients, cardiovascular disease is a common comorbidity and one of most important factors affecting clinical prognosis. Calcium deposition has been reported to correlate with plasma phosphate. Icodextrin (Ico)-based peritoneal dialysis (PD) has many advantages over glucose (Glu)-based PD. We aimed to identify factors that suppress arteriosclerosis and valvular disease in patients with ESRD and diabetes mellitus (DM) undergoing Ico-based PD. In this retrospective study, we evaluated the effects of Ico-based PD (n = 20) on phosphate elimination and cardiovascular disease progression in patients with ESRD andDM, and we compared the results with those for Glu-based PD (n = 20). Left ventricular mass index (LVMI) and aortic valve calcification (AVC) score were significantly decreased and daily phosphate elimination was significantly increased in the Ico group compared with the Glu group. Furthermore, mean daily phosphate elimination was significantly and negatively correlated with the amelioration in LVMI and AVC score. Our study suggests that, compared with glucose, icodextrin has the ability to eliminate more phosphate from the body, indicating that phosphate elimination might potentially be a means of controlling cardiovascular disease in PD patients with DM.

A case of acute renal failure caused by cholesterol embolization after carotid artery stenting that was improved by peritoneal dialysis.

A 68-year-old man was admitted with acute renal failure caused by cholesterol embolization after undergoing carotid artery stenting. Hemodialysis therapy (HD) was immediately required because of uremia, using nafamostat mesilate as an anticoagulant for HD. However, blue toes and gangrene of the feet worsened. To prevent use of anticoagulants and stabilize BP, HD was changed to peritoneal dialysis (PD). After starting PD, blue toes and gangrene improved markedly. Residual renal function also partially recovered. Although BP was unstable during HD, stability of BP and avoidance of anticoagulants during PD therapy might have contributed to the good results.