Michiko Shimada

Hypothesis: could excessive fructose intake and uric acid cause type 2 diabetes?

We propose that excessive fructose intake (>50 g/d) may be one of the underlying etiologies of metabolic syndrome and type 2 diabetes. The primary sources of fructose are sugar (sucrose) and high fructose corn syrup. First, fructose intake correlates closely with the rate of diabetes worldwide. Second, unlike other sugars, the ingestion of excessive fructose induces features of metabolic syndrome in both laboratory animals and humans. Third, fructose appears to mediate the metabolic syndrome in part by raising uric acid, and there are now extensive experimental and clinical data supporting uric acid in the pathogenesis of metabolic syndrome. Fourth, environmental and genetic considerations provide a potential explanation of why certain groups might be more susceptible to developing diabetes. Finally, we discuss the counterarguments associated with the hypothesis and a potential explanation for these findings. If diabetes might result from excessive intake of fructose, then simple public health measures could have a major impact on improving the overall health of our populace.

Urinary CD80 is elevated in minimal change disease but not in focal segmental glomerulosclerosis.

Controversy exists as to whether minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) represent different diseases or are manifestations within the same disease spectrum. Urinary excretion of CD80 (also known as B7.1) is elevated in patients with MCD and hence we tested whether urinary CD80 excretion might distinguish between patients with MCD from those with FSGS. Urinary CD80 was measured in 17 patients with biopsy-proven MCD and 22 with proven FSGS using a commercially available enzyme-linked immunosorbent assay and its molecular size determined by western blot analysis. A significant increase in urinary CD80, normalized to urinary creatinine, was found in patients with MCD in relapse compared to those in remission or those with FSGS. No significant differences were seen when CD80 urinary excretion from MCD patients in remission were compared to those with FSGS. In seven of eight MCD patients in relapse, CD80 was found in glomeruli by immunohistochemical analysis of their biopsy specimen. No CD80 was found in glomeruli of two patients with FSGS and another MCD patient in remission. Thus, our study supports the hypothesis that MCD and FSGS represent two different diseases rather than a continuum of one disease. Urinary CD80 excretion may be a useful marker to differentiate between MCD and FSGS.

Elevated Uric Acid Increases the Risk for Acute Kidney Injury

BACKGROUND Uric acid has been proposed to play a role in acute kidney injury. We therefore investigated the potential influence of preoperative serum uric acid (SUA) on acute kidney injury in patients undergoing cardiovascular (CV) surgery. The primary aims were to investigate the incidence of acute kidney injury, peak serum creatinine (SCr) concentrations, hospital length of stay, and days on mechanical ventilation. METHODS Retrospective study included patients who underwent CV surgery and had preoperative SUA available. Acute kidney injury was defined as an absolute increase in SCr ≥0.3 mg/dL from baseline within 48 hours after surgery. Univariate and multivariate logistic regression analysis was performed to determine the odds ratio for acute kidney injury. RESULTS There were 190 patients included for analysis. SUA were divided into deciles. The incidences of acute kidney injury were higher with higher deciles of SUA. When the incidences of acute kidney injury were plotted against all available values of SUA at increments of 0.5 mg/dL, a J-shaped curve emerged demonstrating higher incidences of acute kidney injury associated with both hypo- and hyperuricemia. In the univariate analysis, SUA ≥5.5 mg/dL was associated with a 4-fold (odds ratio [OR] 4.4; 95% confidence interval [CI], 2.4-8.2), SUA ≥6 mg/dL with a 6-fold (OR 5.9; 95% CI, 3.2-11.3), SUA ≥6.5 mg/dL with an 8-fold (OR 7.9; 95% CI, 3.9-15.8), and SUA ≥7 mg/dL with a 40-fold (OR 39.1; 95% CI, 11.6-131.8) increased risk for acute kidney injury. In the multivariate analysis, SUA ≥7 mg/dL also was associated with a 35-fold (OR 35.4; 95% CI, 9.7-128.7) increased risk for acute kidney injury. The 48-hour postoperative and hospital-stay mean peak SCr levels also were higher in the SUA ≥5.5 mg/dL group compared with the SUA <5 mg/dL group. SUA ≥7 mg/dL was associated with increased length of hospital stay (SUA <7 mg/dL, 18.5 ± 1.8 days vs SUA ≥7 mg/dL, 32.0 ± 6.8 days, P = 0.058) and a longer duration of mechanical ventilation support (SUA <7 mg/dL, 2.4 ± 0.4 days vs SUA ≥7 mg/dL, 20.4 ± 4.5 days, P = 0.001). CONCLUSION Preoperative SUA was associated with increased incidence and risk for acute kidney injury, higher postoperative SCr values, and longer hospital length of stay and duration of mechanical ventilation support in patients undergoing cardiac surgery. A J-shaped relationship appears to exist between SUA and acute kidney injury.

A novel role for uric acid in acute kidney injury associated with tumour lysis syndrome

Tumour lysis syndrome (TLS) is a complication associated with the treatment of tumour types with high proliferative rate, large tumour burden or high sensitivity to cytotoxic therapy. The implementation of risk stratification strategies [1], appropriate prophylactic measures, vigilant monitoring of laboratory parameters and active interventions to reduce risk factors has dramatically decreased the incidence of clinically significant morbidity that results in end organ damage and mortality. Despite these advances, 5–6% of atrisk paediatric and adult patients undergoing chemotherapy develop acute kidney injury (AKI), and 40–50% of these patients will require dialysis therapies with associated allcause mortality in excess of 50% [2–4]. Similar outcomes are reported with spontaneous TLS [5]. The lack of standardized definitions and outcome measures has hampered appreciation of the extent of adverse renal outcomes in TLS. Recent adoption of a uniform definition of AKI (increase in serum creatinine of 0.3 mg/dL from baseline or a 50% increase in serum creatinine from baseline values within 48 h) [6] and the recognition that the development of in-hospital AKI have significant implications for long-term mortality [7] underscores the need to understand the mechanisms involved in AKI associated with TLS. Furthermore, the effect of chronic kidney disease (CKD) on renal outcomes in TLS requires a study, as clinical tumour lysis occurs more frequently in patients with pretreatment renal impairment [8]. One study examining risk factors for in-hospital AKI of diverse aetiologies reported that CKD increases the risk of AKI 40-fold with a 20-fold increased risk for dialysis [9]. Here, we will briefly review the current understanding of the pathogenesis of TLS-induced AKI. In particular, a recent literature suggests that AKI and nephropathy are not simply due to intrarenal crystal deposition of urate and phosphate. Mechanism of AKI associated with intrarenal deposition of uric acid crystals TLS is a group of metabolic complications that occur after the treatment of large volume, rapidly proliferating haematological cancers including not only acute leukaemia and aggressive lymphomas but also some solid tumours. Metabolic alterations that result include hyperkalaemia, hyperphosphataemia, hyperuricaemia and hyperuricosuria, hypocalcaemia and consequent AKI. Specifically, AKI associated with TLS has been considered to be exclusively a crystal-dependent process caused by the massive and abrupt release of intracellular metabolites from chemosensitive, rapidly proliferating tumour cells that undergo rapid lysis and release nucleic acid breakdown products, phosphorus and potassium. Both urate and calcium phosphate crystals may cause crystal-dependent injury of the kidney which overwhelms the normal homeostatic mechanism(s) autoregulating normal renal physiology [10]. One of the most important mediators of AKI resulting from TLS is uric acid. When dying cells release DNA and RNA, they are degraded in the liver and other sites with the rapid production of uric acid. Serum uric acid rises acutely, resulting in marked uricosuria. Such cell death and degradation also results in acid generation, often with volume depletion, resulting in acidic urine that decreases the solubility of uric acid. When levels of urinary uric acid exceed its solubility, both micro- and macrocrystal formations occur in the distal tubules and collecting ducts with obstruction of the tubular lumen. The prevention of AKI resulting from TLS includes initiating prophylactic measures prior to and during chemotherapy, including hydration, alkalinization of the urine, use of the xanthine oxidase inhibitor allopurinol, as well as the urate oxidase inhibitor, rasburicase or its derivatives.

Toll-like receptor 3 ligands induce CD80 expression in human podocytes via an NF-κB-dependent pathway

BACKGROUND Recent studies suggest that CD80 (also known as B7.1) is expressed on podocytes in minimal-change disease (MCD) and may have a role in mediating proteinuria. CD80 expression is known to be induced by Toll-like receptor (TLR) ligands in dendritic cells. We therefore evaluated the ability of TLR to induce CD80 in human cultured podocytes. METHODS Conditionally immortalized human podocytes were evaluated for TLR expression. Based on high expression of TLR3, we evaluated the effect of polyinosinic-polycytidylic acid (polyIC), a TLR3 ligand, to induce CD80 expression in vitro. RESULTS TLR1-6 and 9 messenger RNA (mRNA) were expressed in podocytes. Among TLR ligands 1-9, CD80 mRNA expression was significantly induced by polyIC and lipopolysaccharide (TLR4 ligand) with the greatest stimulation by polyIC (6.8 ± 0.7 times at 6 h, P < 0.001 versus control). PolyIC induced increased expression of Cathepsin L, decreased synaptopodin expression and resulted in actin reorganization which suggested a similar injury pattern as observed with lipopolyssaccharide. PolyIC induced type I and type II interferon signaling, nuclear factor kappa B (NF-κB) activation and the induction of CD80 expression. Knockdown of CD80 protected against actin reorganization and reduced synaptopodin expression in response to polyIC. Dexamethasone, a corticosteroid commonly used to treat MCD, also blocked both basal and polyIC-stimulated CD80 expression, as did inhibition of NF-κB. CONCLUSIONS Activation of TLR3 on cultured human podocytes induces CD80 expression and phenotypic change via an NF-κB-dependent mechanism and is partially blocked by dexamethasone. These studies provide a mechanism by which viral infections may cause proteinuria.

Idiopathic Nephrotic Syndrome and Atopy: Is There a Common Link?

Numerous reports during the last 60 years have reported a strong association between idiopathic nephrotic syndrome and atopic disorders. Idiopathic nephrotic syndrome can be precipitated by allergic reactions and has been associated with both aeroallergens (pollens, mold, and dust) and food allergies. Patients with idiopathic nephrotic syndrome also may show increased serum immunoglobulin E (IgE) levels. A review of the literature suggests that although some idiopathic nephrotic syndrome cases may be associated with allergies, evidence that it is a type of allergic disorder or can be induced by a specific allergen is weak. Rather, it is likely that the proteinuria and increased IgE levels in patients with idiopathic nephrotic syndrome are caused by increased levels of interleukin 13 observed in these patients. Recent studies suggest that interleukin 13, a known stimulator of IgE response, may mediate proteinuria in patients with minimal change disease because of its ability to directly induce CD80 expression on the podocyte.

Intracellular Signaling for Vasoconstrictor Coupling Factor 6. Novel Function of β-Subunit of ATP Synthase as Receptor

Coupling factor 6 (CF6), a component of adenosine triphosphate (ATP) synthase, is circulating and functions as an endogenous vasoconstrictor by inhibiting cytosolic phospholipase A2. We showed a high plasma level of CF6 in human hypertension. The present study focused on the identification and characterization of a receptor for CF6 and its post-receptor signaling pathway. Incubation of human umbilical vein endothelial cells (HUVECs) with an excess of free CF6 reduced by 50% the immunoreactivity for the antibody to &bgr;-subunit of ATP synthase at the cell surface, but unaffected that for the &agr;-subunit antibody. A significant displacement of radioligand was observed at 3×10−9 through 10−7 M unlabeled CF6, and the Kd was 7.6 nM. Adenosine diphosphate (ADP) at 10−7 M and &bgr;-subunit antibody suppressed the binding of 125I-CF6 by 81.3±9.7% and 32.0±2.0%, respectively, whereas the &agr;-subunit antibody unaffected it. The hydrolysis activity of ATP to ADP was increased by 1.6-fold by CF6 at 10−7 M, and efrapeptin at 10−5 M, an inhibitor of ATP synthase, blocked it. CF6 at 10−7 M decreased intracellular pH in 2′,7′-bis(carboxyethyl-5 (6))-carboxyfluorescein-loaded HUVEC. Amyloride at 10−4 M augmented the pH decrease in response to CF6, whereas efrapeptin at 10−5 M blocked it. Arachidonic acid release was suppressed by CF6, and it was reversed by efrapeptin at 10−5 M or &bgr;-subunit antibody or ADP at 10−7 M. The &bgr;-subunit antibody suppressed coupling factor 6–induced increase in blood pressure. These indicate that membrane-bound ATP synthase functions as a receptor for CF6 and may have a previously unsuspected role in the genesis of hypertension by modulating the concentration of intracellular hydrogen.

Minimal change disease: a "two-hit" podocyte immune disorder?

Minimal change disease (MCD) is the most common nephrotic syndrome in children and is commonly thought to be a T-cell disorder mediated by a circulating factor that alters podocyte function resulting in massive proteinuria. We suggest that MCD is a “two-hit” disorder. As originally hypothesized by Reiser et al. in 2004, we propose that the initial hit is the induction of CD80 (also known as B7.1) on the podocyte, and that this results in an alteration in shape with actin rearrangement that alters glomerular permeability and causes proteinuria. We propose that CD80 expression may result from either direct binding of the podocyte by cytokines from activated T cells or by activation of podocyte toll-like receptors (TLR) by viral products or allergens. We further hypothesize that under normal circumstances, CD80 expression is only transiently expressed and proteinuria is minimal due to rapid autoregulatory response by circulating T regulatory cells or by the podocyte itself, probably due to the expression of factors [cytotoxic T-lymphocyte-associated (CTLA)-4, interleukin (IL)-10, and possibly transforming growth factor (TGF)-β] that downregulate the podocyte CD80 response. In MCD, however, there is a defect in CD80 podocyte autoregulation. This results in persistent CD80 expression and persistent proteinuria. If correct, this hypothesis may lead to both new diagnostic tests and potential therapeutics for this important renal disease.

Uric acid: a novel risk factor for acute kidney injury in high-risk cardiac surgery patients?

Background: Uric acid has been reported to be a risk factor for the development of chronic kidney disease; however, no study has examined whether uric acid may confer a risk for acute kidney injury. Methods: We investigated the relation between serum uric acid and the incidence of postoperative acute kidney injury in patients undergoing high-risk cardiovascular surgery (cardiac valve and aneurysm surgery). Results: Following cardiovascular surgery, 18 of 58 patients (31%) developed acute kidney injury, with 11 of 24 (45.8%) in the elevated uric acid group (defined as >6 mg/dl) and 7 of 34 (20.5%) in the normal uric acid group (p = 0.05). After controlling for baseline renal function, left ventricular ejection fraction, use of nesiritide, type of surgery, and history of previous surgery, an elevated preoperative uric acid conferred a 4-fold risk for acute kidney injury (OR: 3.98, CI: 1.10–14.33, p = 0.035) and longer hospital stay (36.35 vs. 24.66 days, p = 0.009). Conclusion: This preliminary study suggests that uric acid may be a novel risk factor for acute kidney injury in patients undergoing high-risk cardiovascular surgery.

Toll-like receptor 3 ligand, polyIC, induces proteinuria and glomerular CD80, and increases urinary CD80 in mice

BACKGROUND We have reported that children with biopsy-proven minimal change disease (MCD) express CD80 (also known as B7.1) in their podocytes and excrete high levels of CD80 in their urine during active nephrotic syndrome. We also reported that polyIC, a Toll-like receptor 3 ligand, increases CD80 mRNA and protein expression in cultured human podocytes dose-dependently, with actin re-organization and a reduction in synaptopodin expression. METHODS To determine the effect of polyIC in the kidney, we subjected mice to systemic injection of polyIC or phosphate buffered saline. RESULTS Mice injected with polyIC developed significant proteinuria with increased urinary CD80 excretion. Glomeruli from mice injected with polyIC were normal by light microscopic examination, but showed increased CD80 production in podocytes by immunofluorescence staining. In isolated glomeruli from mice injected with polyIC, expressions of CD80 and interleukin 10 significantly increased with a mild non-significant increase in CTLA-4, and synaptopodin expression decreased significantly. CONCLUSIONS Our study demonstrates that systemically administered polyIC can induce transient proteinuria and urinary CD80 excretion with an increase in CD80 production in podocytes, increased glomerular CD80 and reduced synaptopodin expression. These findings may be relevant to the pathogenesis of proteinuria in MCD.