REVIEW www.jasn.org Fructose Production and Metabolism in the Kidney Takahiko Nakagawa,1,2 Richard J. Johnson,3 Ana Andres-Hernando,3 Carlos Roncal-Jimenez,3 Laura G. Sanchez-Lozada ,4 Dean R. Tolan,5 and Miguel A. Lanaspa 3 1Department of Nephrology, Rakuwakai Otowa Hospital, Kyoto, Japan; 2Department of Biochemistry, Shiga University of Medical Science, Shiga, Japan; 3Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, Colorado; 4Department of Cardio-Renal Physiopathology, National Institute of Cardiology Ignacio Chavez, Mexico City, Mexico; and 5Department of Biology, Boston University, Boston, Massachusetts ABSTRACT Understanding fructose metabolism might provide insights to renal pathophysiol- the metabolism of endogenous fructose ogy. To support systemic glucose concentration, the proximal tubular cells reabsorb can slow the development and progres- fructose as a substrate for gluconeogenesis. However, in instances when fructose sion of kidney injury. intake is excessive, fructose metabolism is costly, resulting in energy depletion, uric Fructose biology is complex because acid generation, inflammation, and fibrosis in the kidney. A recent scientificadvance fructose metabolism may be associated is the discovery that fructose can be endogenously produced from glucose under with beneficial physiologic responses pathologic conditions, not only in kidney diseases, but also in diabetes, in cardiac and pathologic responses. Here, we dis- hypertrophy, and with dehydration. Why humans have such a deleterious mecha- cuss the various roles of fructose in the nism to produce fructose is unknown, but it may relate to an evolutionary benefitin kidney. the past. In this article, we aim to illuminate the roles of fructose as it relates to gluconeogenesis and fructoneogenesis in the kidney. JASN 31: ccc–ccc, 2020. doi: https://doi.org/10.1681/ASN.2019101015 CLINICAL ASSOCIATIONS OF FRUCTOSE WITH KIDNEY DISEASES Fructose is a simple sugar in fruits that of serum glucose,8 to support fetal organ Fructose, as a component of high- has a role in storage of fat and glycogen, development,9 and to offer protection fructose corn syrup or table sugar, is a development of insulin resistance, and from hypoxic insults.10 major component in most sugar-sweetened an increase in sodium reabsorption, all In modern society, dietary sugars, soft drinks. The dramatic increase in of which are likely survival processes for particularly fructose, have emerged as fructose consumption has stimulated animals during time of food shortage.1 culprits for the current epidemic of obe- a heated debate over the potential danger The freshwater pacu fish actively feasts sity, diabetes, and metabolic syndrome.11 of sugar-sweetened beverages.22,23 on ripe fruits that have fallen into the The rise in fructose consumption over In 2009, Bomback et al.24 combined river and becomes fat in the rainy sea- the last century has paralleled the rising cross-sectional and longitudinal analy- son.2 To increase their fat stores before prevalence of obesity, diabetes, and kid- ses to evaluate the association between beginning their migration, birds that mi- ney diseases, leading to the hypothesis CKD and sugar-sweetened beverages, grate long distances develop a seasonal that excessive fructose might be a causal but found no association between sugar- dietary preference for fruits.3 Hibernat- factor for the development of kidney dis- sweetened soda and incidence or preva- ing mammals, such as bears and ground ease. One proposed mechanism is via the lence of CKD. Although the outcomes of squirrels, use their accumulated fat as an metabolism of fructose (fructolysis) be- energy supply during winter.4,5 Likewise, cause it can result in intracellular energy Published online ahead of print. Publication date for early primates, fresh fruits were the depletion, mitochondrial oxidative available at www.jasn.org. main dietary staple.6,7 Fructose remains stress, and the production of inflamma- an important nutrient for humans and tory mediators such as uric acid.12 Re- Correspondence: Dr. Takahiko Nakagawa, Depart- ment of Nephrology, Rakuwakai Otowa Hospital, 2 wild animals because the kidney, the cently, it has emerged that fructose can Otowa-Chinji-cho, Yamashina-ku, Kyoto, Japan. Email: placenta, and hypoxic tissues use it as be endogenously produced in humans13,14 [email protected] 15–21 a substrate for gluconeogenesis to and nonhuman animals, particularly Copyright © 2020 by the American Society of maintain physiologic concentrations in diseased kidneys, and that blocking Nephrology JASN 31: ccc–ccc,2020 ISSN : 1046-6673/3105-ccc 1 REVIEW www.jasn.org this study should be noted, renal effects by Benoy and Elliott32 showing that rat depends on the oxygen level, because it are unlikely to be observed at a dosage of kidney slices were capable of producing is slower under anaerobic conditions only one sugar-sweetened beverage per glucose in response to pyruvate and lac- compared with aerobic conditions.43 Glu- day.25 Similarly, Lin and Curhan26 identi- tate. A study using hepatectomized dogs coneogenesis is driven by the activation of fied 3318 women participating in the subsequently confirmed this phenome- phosphoenolpyruvate carboxykinase, Nurses’ Health Study with data on soda non by demonstrating that blood sugar enzymes of the glucose 6-phosphatase intake and albuminuria and found no as- declined more rapidly with removal of system, and fructose bisphosphatase ex- sociation between daily consumption of the kidneys.33 Reinecke and Hauser34 clusively in the proximal tubular cells,44,45 one or more serving and incidence of also showed in dogs that serum glucose but not in the distal nephron46,47 (Figure 2). CKD;but,giventhatonly3%ofpartici- concentrationintherenalveinwas The proximal straight tubule is a pri- pants had this level of consumption, this higher than in the renal artery. Three de- mary site for fructose metabolism. also might account for the negative results. cades later, research demonstrated that There, glucose transporter 5, expressed In contrast, Saldana et al.27 examined the rat kidney is capable of producing on the apical side of the cell membrane, the effect of higher doses in a case-control approximately 26% of serum glucose mediates absorption of urinary fructose, study, and found that an intake of two or in the normal fed state, and that renal which is then metabolized by fructoki- more sugar-sweetened beverages per glucose release increases 46% after nase in the cytosol.48 However, fructose day was associated with an increased starvation35; the human kidney similarly metabolism is not restricted to the prox- incidence of kidney disease. Likewise, provides approximately 45% of total imal straight tubule; it has also been Shoham et al.28 found that consumption blood glucose after starvation.8 Interest- documented in the proximal convoluted of two or more sugar-sweetened beverages ingly, diabetes also increases renal glucose tubule (Figure 1). In fact, the proximal per day was associated with a higher level release by 360% in rats and 300% in hu- convoluted tubule expresses fructokinase, of urinary albumin excretion compared mans compared with the nondiabetic as well as aldolase B, which is readily in- with consumption of less than two sugar- condition.35,36 In metabolic acidosis in duced.48 A lack of aldolase B in patients sweetened beverages per day. More re- the rat, gluconeogenesis has also been with hereditary fructose intolerance cau- cently, a 2019 study of a community-based found to be activated in the proximal tu- ses fructose 1-phosphate accumulation in cohort of black Americans also showed that bules, as opposed to the liver.37,38 the proximal convoluted tubule.49 a higher sugar-sweetened beverage con- Renal gluconeogenesis may result sumption was associated with signifi- from classic substrates such as lactate, Glycolysis Is Less Activated in the cantly greater odds of incident CKD.29 glutamine, alanine, and pyruvate, but Proximal Tubules Moreover, in an intervention study in fructose appears to be the preferred sub- In the late 20th century, several researchers which a low-fructose diet was administered strate, based on the speed and efficiency demonstrated that the potential for glycol- to participants with CKD, researchers ob- of the reaction.39,40 In 1961, by using in ysis is very low in the proximal tubules served a reduction in BP and systemic situ perfusion in the rat, Salomon et al.41 compared with other parts of the nephron, inflammation.30 directly measured the arteriovenous dif- including from the medullary ascend- Although the possible association of ference of fructose and glucose concen- ing limb to the medullary collecting sugar-sweetened beverages with kidney trations after bolus infusion of 25 mg of tubule. For example, key enzymes for disease may reflect the sugar (and espe- fructose into the peripheral vessels. They glycolysis—hexokinase, phosphofructo- cially fructose) content, sugar-sweetened found that decreases in fructose concen- kinase, and pyruvate kinase—are min- beverages also contain substantial tration on the passage of blood through imally expressed in proximal tubular amount of phosphorus, which could be the kidney—about 19% on average— epithelial cells.38,50 Hexokinase, the gate- an alternative risk factor for obesity, vas- were accompanied by equivalent in- way enzyme of glucose metabolism, phos- cular injury, systemic hypertension, and creases in renal venous glucose.41 In phorylates glucose to glucose