We investigated the ability of serum uric acid (SUA) to predict laboratory tumor lysis syndrome (LTLS) and compared it to common laboratory variables, cytogenetic profiles, tumor markers and prediction models in acute myeloid leukemia patients. In this retrospective study patients were risk-stratified for LTLS based on SUA cut-off values and the discrimination ability was compared to current prediction models. The incidences of LTLS were 17.8%, 21% and 62.5% in the low, intermediate and high-risk groups, respectively. SUA was an independent predictor of LTLS (adjusted OR 1.12, CI95% 1.0–1.3, p = 0.048). The discriminatory ability of SUA, per ROC curves, to predict LTLS was superior to LDH, cytogenetic profile, tumor markers and the combined model but not to WBC (AUCWBC 0.679). However, in comparisons between high-risk SUA and high-risk WBC, SUA had superior discriminatory capability than WBC (AUCSUA 0.664 vs. AUCWBC 0.520; p <0.001). SUA also demonstrated better performance than the prediction models (high-risk SUAAUC 0.695, p<0.001). In direct comparison of high-risk groups, SUA again demonstrated superior performance than the prediction models (high-risk SUAAUC 0.668, p = 0.001) in predicting LTLS, approaching that of the combined model (AUC 0.685, p<0.001). In conclusion, SUA alone is comparable and highly predictive for LTLS than other prediction models.
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 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 for 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, TNF-alpha, MCP-1, alpha-smooth muscle actin, and collagen I and TIMP1 expression. These changes were prevented in the fructokinase knockout mice.
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 (NASH).
nonalcoholic fatty liver disease; hepatic steatosis; hepatic fibrosis; fructose and ketohexokinase
The intake of added sugars, such as from table sugar (sucrose) and high-fructose corn syrup has increased dramatically in the last hundred years and correlates closely with the rise in obesity, metabolic syndrome, and diabetes. Fructose is a major component of added sugars and is distinct from other sugars in its ability to cause intracellular ATP depletion, nucleotide turnover, and the generation of uric acid. In this article, we revisit the hypothesis that it is this unique aspect of fructose metabolism that accounts for why fructose intake increases the risk for metabolic syndrome. Recent studies show that fructose-induced uric acid generation causes mitochondrial oxidative stress that stimulates fat accumulation independent of excessive caloric intake. These studies challenge the long-standing dogma that “a calorie is just a calorie” and suggest that the metabolic effects of food may matter as much as its energy content. The discovery that fructose-mediated generation of uric acid may have a causal role in diabetes and obesity provides new insights into pathogenesis and therapies for this important disease.
Idiopathic nephrotic syndrome (INS) includes three different entities: minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and mesangial proliferative glomerulonephritis. Historically, this condition has been attributed to a T cell disorder resulting in the secretion of a circulating factor that increases glomerular permeability to plasma proteins. The therapeutic approach to control the proteinuria of INS remains the use of drugs that have been considered to suppress the production of the “circulating factor” secreted by T-cells. Recently, Rituximab (RTX), a chimeric monoclonal antibody directed against the CD20 cell surface receptor expressed on B cells, has emerged as potential therapeutic agent. The number of publications reporting the experience of RTX in nephrotic syndrome has greatly increased in the last few years. However, there is currently no good evidence from clinical or experimental studies that support a role of RTX in the treatment of MCD and FSGS proteinuria. In summary, there is the need for better understanding of the pathogenesis of the proteinuria in INS and the potential role of RTX in this condition.
Idiopathic nephrotic syndrome; focal segmental glomerulosclerosis; minimal change disease; rituximab
Minimal Change Disease (MCD) is characterized by increased urinary excretion of CD80, whereas Focal Segmental Glomerulosclerosis (FSGS) is associated with increased serum suPAR. The aim of the study was to assess whether the simultaneous measurement of urinary CD80 and serum suPAR helps differentiate MCD and FSGS.
Urine and sera were collected from patients with MCD in relapse or in remission, from FSGS patients with nephrotic syndrome, and from normal subjects. CD80 and suPAR were measured by ELISA.
Urinary CD80 was significantly increased in MCD patients in relapse compared with those in remission, as well as with FSGS patients and control subjects. Serum suPAR levels were significantly higher in patients with FSGS when compared to MCD patients in relapse. Urinary suPAR showed a positive correlation with proteinuria in MCD in relapse and FSGS patients, whereas urinary CD80 correlated with proteinuria only in MCD patients in relapse.
Urinary CD80 is elevated in MCD patients in relapse compared to FSGS patients. In contrast, serum suPAR is significantly elevated in FSGS patients. The consistent pattern of these two biomarkers in MCD and FSGS suggests that these two conditions represent different entities rather than a continuum spectrum of one disease.
CD80; minimal change disease; focal segmental glomerulosclerosis; suPAR; nephrotic syndrome
Uric acid affects endothelial and adipose cell function and has been linked to diseases such as hypertension, metabolic syndrome, and cardiovascular disease. Interestingly uric acid has been shown to increase endothelial progenitor cell (EPC) mobilization, a potential mechanism to repair endothelial injury. Since EPC mobilization is dependent on activity of the enzyme CD26/dipeptidyl peptidase (DPP)IV, we examined the effect uric acid has on CD26/DPPIV activity. Uric acid inhibited the CD26/DPPIV associated with human umbilical vein endothelial cells but not human recombinant (hr)CD26/DPPIV. However, triuret, a product of uric acid and peroxynitrite, could inhibit cell associated and hrCD26/DPPIV. Increasing or decreasing intracellular peroxynitrite levels enhanced or decreased the ability of uric acid to inhibit cell associated CD26/DPPIV respectively. Last, protein modeling demonstrates how triuret can act as a small molecule inhibitor of CD26/DPPIV activity. This is the first time that uric acid or a uric acid reaction product has been shown to affect enzymatic activity and suggests a novel avenue of research in the role of uric acid in the development of clinically important diseases.
uric acid; triuret; CD26/DPPIV
Serum uric acid is commonly elevated in subjects with chronic kidney disease (CKD), but was historically viewed as an issue of limited interest. Recently, uric acid has been resurrected as a potential contributory risk factor in the development and progression of CKD. Most studies documented that an elevated serum uric acid level independently predicts the development of CKD. Raising the uric acid level in rats can induce glomerular hypertension and renal disease as noted by the development of arteriolosclerosis, glomerular injury and tubulointerstitial fibrosis. Pilot studies suggest that lowering plasma uric acid concentrations may slow the progression of renal disease in subjects with CKD. While further clinical trials are necessary, uric acid is emerging as a potentially modifiable risk factor for CKD.
Gout was considered a cause of CKD in the mid-nineteenth century , and, prior to the availability of therapies to lower the uric acid level, the development of end-stage renal disease was common in gouty patients. In their large series of gouty subjects Talbott and Terplan found that nearly 100% had variable degrees of CKD at autopsy (arteriolosclerosis, glomerulosclerosis and interstitial fibrosis) . Additional studies showed that during life impaired renal function occurred in half of these subjects . As many of these subjects had urate crystals in their tubules and interstitium, especially in the outer renal medulla, the disease became known as gouty nephropathy. The identity of this condition fell in question as the presence of these crystals may occur in subjects without renal disease; furthermore, the focal location of the crystals could not explain the diffuse renal scarring present. In addition, many subjects with gout also had coexistent conditions such as hypertension and vascular disease, leading some experts to suggest that the renal injury in gout was secondary to these latter conditions rather than to uric acid per se . Indeed, gout was removed from the textbooks as a cause of CKD, and the common association of hyperuricemia with CKD was solely attributed to the retention of serum uric acid that is known to occur as the glomerular filtration rate falls.
Renewed interest in uric acid as a cause of CKD occurred when it was realized that invalid assumptions had been made in the arguments to dismiss uric acid as a risk factor for CKD . The greatest assumption was that the mechanism by which uric acid would cause kidney disease would be via the precipitation as crystals in the kidney, similar to the way it causes gout. However, when laboratory animals with CKD were made hyperuricemic, the renal disease progressed rapidly despite an absence of crystals in the kidney . Since this seminal study, there has been a renewed interest in the potential role uric acid may have in both acute and CKD. We briefly review some of the major advances that have occurred in this field in the last 15 years.
uric acid; gout; allopurinol; hyperuricemia; chronic kidney disease
Fructose acutely raises serum uric acid in normal subjects, but the effect in subjects with metabolic syndrome or subjects with chronic kidney disease is unknown. The aim of the study was to evaluate changes in serum uric acid during the fructose tolerance test in patients with chronic kidney disease, metabolic syndrome with comparison to healthy controls.
Studies were performed in 36 subjects with obesity (body mass index >30) and metabolic syndrome, 14 patients with stage 3 chronic kidney disease, and 25 healthy volunteers. The fructose tolerance test was performed in each patient. The change in serum uric acid during the fructose challenge was correlated with baseline ambulatory blood pressure, serum uric acid, metabolic, and inflammatory markers, and target organ injury including carotid intima media thickness and renal resistive index (determined by Doppler).
Absolute serum uric acid values were highest in the chronic kidney disease group, followed by the metabolic syndrome and then healthy controls. Similar increases in serum uric acid in response to the fructose tolerance test was observed in all three groups, but the greatest percent rise was observed in healthy controls compared to the other two groups. No significant association was shown between the relative rise in uric acid and clinical or inflammatory parameters associated with kidney disease (albuminuria, eGFR) or metabolic syndrome.
Subjects with chronic kidney disease and metabolic syndrome have higher absolute uric acid values following a fructose tolerance test, but show a relatively smaller percent increase in serum uric acid. Changes in serum uric acid during the fructose tolerance test did not correlate with changes in metabolic parameters, inflammatory mediators or with target organ injury. These studies suggest that acute changes in serum uric acid in response to fructose do not predict the metabolic phenotype or presence of inflammatory mediators in subjects with obesity, metabolic syndrome or chronic kidney disease.
The study was registered in ClinicalTrials.gov. Identifier : NCT01332526. www.register.clinicaltrials.gov/01332526
Electronic supplementary material
The online version of this article (doi:10.1186/s12882-015-0048-y) contains supplementary material, which is available to authorized users.
Chronic kidney disease; Obesity and metabolic syndrome; Fructose tolerance test; Uric acid; Organ damage
Decreased insulin sensitivity (IS) exists in type 1 diabetes. Serum uric acid (SUA), whose concentration is related to renal clearance, predicts vascular complications in type 1 diabetes. SUA is also inversely associated with IS in non-diabetics, but has not been examined in type 1 diabetes. We hypothesized SUA would be associated with reduced IS in adolescents and adults with type 1 diabetes.
The cross-sectional and longitudinal associations of SUA with IS was investigated in 254 adolescents with type 1 diabetes and 70 without in the Determinants of Macrovascular Disease in Adolescents with Type 1 Diabetes Study, and in 471 adults with type 1 diabetes and 571 without in the Coronary Artery Calcification in Type 1 diabetes (CACTI) study.
SUA was lower in subjects with type 1 diabetes (p<0.0001), but still remained inversely associated with IS after multivariable adjustments- in adolescents (β±SE: −1.99±0.62, p=0.001, R2=2%) and adults (β±SE:−0.91±0.33, p=0.006, R2=6%) with type 1 diabetes, though less strongly than in non-diabetic controls (adolescents: β±SE: −2.70±1.19, p=0.03, R2=15%, adults: β±SE:−5.99±0.75, p<0.0001, R2=39%).
We demonstrated a significantly weaker relationship between SUA and reduced IS in subjects with type 1 diabetes than non-diabetic controls.
insulin sensitivity; type 1 diabetes; serum uric acid; adolescents and adults
Fructose is a simple sugar present in honey and fruit, but can also exist as a polymer (fructans) in pasture grasses. Mammals are unable to metabolize fructans, but certain gram positive bacteria contain fructanases and can convert fructans to fructose in the gut. Recent studies suggest that fructose generated from bacteria, or directly obtained from the diet, can induce both increased intestinal permeability and features of metabolic syndrome, especially the development of insulin resistance. The development of insulin resistance is driven in part by the metabolism of fructose by fructokinase C in the liver, which results in oxidative stress in the hepatocyte. Similarly, the metabolism of fructose in the small bowel by intestinal fructokinase may lead to increased intestinal permeability and endotoxemia. While speculative, these observations raise the possibility that the mechanism by which fructans induce laminitis could involve intestinal and hepatic fructokinase. Further studies are indicated to determine the role of fructanases, fructose and fructokinase in equine metabolic syndrome and laminitis.
Fructose; Fructans; Fructokinase; Laminitis; Equine Metabolic Syndrome
Hibernating animals develop fatty liver when active in summertime and undergo a switch to a fat oxidation state in the winter. We hypothesized that this switch might be determined by AMP and the dominance of opposing effects: metabolism through AMP deaminase (AMPD2) (summer) and activation of AMP-activated protein kinase (AMPK) (winter). Liver samples were obtained from 13-lined ground squirrels at different times during the year, including summer and multiples stages of winter hibernation, and fat synthesis and β-fatty acid oxidation were evaluated. Changes in fat metabolism were correlated with changes in AMPD2 activity and intrahepatic uric acid (downstream product of AMPD2), as well as changes in AMPK and intrahepatic β-hydroxybutyrate (a marker of fat oxidation). Hepatic fat accumulation occurred during the summer with relatively increased enzymes associated with fat synthesis (FAS, ACL and ACC) and decreased enoyl CoA hydratase (ECH1) and carnitine palmitoyltransferase 1A (CPT1A), rate limiting enzymes of fat oxidation. In summer, AMPD2 activity and intrahepatic uric acid levels were high and hepatic AMPK activity was low. In contrast, the active phosphorylated form of AMPK and β-hydroxybutyrate both increased during winter hibernation. Therefore, changes in AMPD2 and AMPK activity were paralleled with changes in fat synthesis and fat oxidation rates during the summer-winter cycle. These data illuminate the opposing forces of metabolism of AMP by AMPD2 and its availability to activate AMPK as a switch that governs fat metabolism in the liver of hibernating ground squirrel.
Adults with type 1 diabetes have lower serum uric acid levels compared to non-diabetic adults. Little is known about the relationship between serum uric acid and blood pressure in type 1 diabetes and whether it differs from the positive relationship found in non-diabetic adults.
We assessed the cross-sectional and longitudinal relationships over 6-years between serum uric acid and blood pressure in adults with (35±9 years, n=393) and without (38±9 years n=685) T1D in the Coronary Artery Calcification in Type 1 Diabetes study.
In non-diabetic adults, serum uric acid was associated with systolic blood pressure in multivariable-models adjusted for cardiovascular risk-factors. In adults with type 1 diabetes, a negative association was observed between serum uric acid and systolic blood pressure after multivariable-adjustments.
A positive association was observed between serum uric acid and systolic blood pressure in non-diabetic adults. In contrast, an inverse relationship was demonstrated after multivariable-adjustments in type 1 diabetes.
Uric acid; hypertension; type 1 diabetes
We addressed if oxidative stress in the renal cortex plays a role in the induction of hypertension and mitochondrial alterations in hyperuricemia. A second objective was to evaluate whether the long-term treatment with the antioxidant Tempol prevents renal oxidative stress, mitochondrial alterations, and systemic hypertension in this model. Long-term (11-12 weeks) and short-term (3 weeks) effects of oxonic acid induced hyperuricemia were studied in rats (OA, 750 mg/kg BW), OA+Allopurinol (AP, 150 mg/L drinking water), OA+Tempol (T, 15 mg/kg BW), or vehicle. Systolic blood pressure, renal blood flow, and vascular resistance were measured. Tubular damage (urine N-acetyl-β-D-glucosaminidase) and oxidative stress markers (lipid and protein oxidation) along with ATP levels were determined in kidney tissue. Oxygen consumption, aconitase activity, and uric acid were evaluated in isolated mitochondria from renal cortex. Short-term hyperuricemia resulted in hypertension without demonstrable renal oxidative stress or mitochondrial dysfunction. Long-term hyperuricemia induced hypertension, renal vasoconstriction, tubular damage, renal cortex oxidative stress, and mitochondrial dysfunction and decreased ATP levels. Treatments with Tempol and allopurinol prevented these alterations. Renal oxidative stress induced by hyperuricemia promoted mitochondrial functional disturbances and decreased ATP content, which represent an additional pathogenic mechanism induced by chronic hyperuricemia. Hyperuricemia-related hypertension occurs before these changes are evident.
The metabolic syndrome refers to a constellation of signs including abdominal obesity, elevated serum triglycerides, low HDL-cholesterol, elevated blood pressure and insulin resistance. Today approximately one third of the adult population has the metabolic syndrome. While there is little doubt that the signs constituting the metabolic syndrome frequently cluster, much controversy exists over the definition, pathogenesis, or clinical utility. Here we present evidence from the field of comparative physiology that the metabolic syndrome is similar to the biological process that animals engage to store fat in preparation for periods of food shortage. We propose that the metabolic syndrome be changed to fat storage condition to more clearly align with its etiology. Obesity in humans is likely the consequences of both genetic predisposition (driven in part by thrifty genes) and environment. Recent studies suggest that the loss of the uricase gene may be one factor that predisposes humans to obesity today. Understanding the process animals engage to switch from a lean insulin-sensitive to an obese insulin-resistant state may provide novel insights into the cause of obesity and diabetes in humans, and unique opportunities for reversing their pathology.
hibernation; insulin resistance; metabolic syndrome; obesity
Patients with gout have lower calcitriol levels that improve when uric acid is lowered. The mechanism of these observations is unknown. We hypothesized that uric acid inhibits 1- αhydroxylase.
Materials and methods
In vivo, Sprague Dawley rats were randomized to control (n=5), allantoxanamide (n=8), febuxostat (n=5), or allantoxanamide+febuxostat (n=7). Vitamin D, PTH, and 1-αhydroxylase protein were evaluated. In order to directly evaluate the effect of uric acid on 1-αhydroxylase, we conducted a series of dose response and time course experiments in vitro. Nuclear factor κ-B (NFκB) was inhibited pharmacologically. Finally, to evaluate the potential implications of these findings in humans, the association between uric acid and PTH in humans was evaluated in a cross-sectional analysis of data from the NHANES (2003-2006); n= 9773.
1,25(OH)2D and 1-αhydroxylase protein were reduced in hyperuricemic rats and improved with febuxostat treatment. Uric acid suppressed 1-αhydroxylase protein and mRNA expression in proximal tubular cells. This was prevented by NFκB inhibition. In humans, for every 1 mg/dL increase in uric acid, the adjusted odds ratio for an elevated PTH (>65 pg/mL) was 1.21 (95% C.I. 1.14, 1.28; P< 0.0001), 1.15 (95% C.I. 1.08, 1.22; P<0.0001), and 1.16 (95% C.I. 1.03, 1.31; P=0.02) for all subjects, subjects with estimated GFR ≥60, and subjects with estimated GFR <60 mL/min/1.73 m2 respectively.
Hyperuricemia suppresses 1-αhydroxylase leading to lower 1,25(OH)2D and higher PTH in rats. Our results suggest this is mediated by NFκB. The association between uric acid and PTH in NHANES suggests potential implications for human disease.
uric acid; parathyroid hormone; mineral and bone disorders
Erectile dysfunction (ED) is a frequent complaint of elderly subjects, and is closely associated with endothelial dysfunction and cardiovascular disease. Uric acid is also associated with endothelial dysfunction, oxidative stress and cardiovascular disease, raising the hypothesis that an increased serum uric acid might predict erectile dysfunction in patients who are at risk for coronary artery disease.
To evaluate the association of serum uric acid levels with presence and severity of ED in patients presenting with chest pain of presumed cardiac origin.
This is a cross-sectional study of 312 adult male patients with suspected coronary artery disease who underwent exercise stress test (EST) for workup of chest pain and completed a sexual health inventory for men (SHIM) survey form to determine the presence and severity of ED. Routine serum biochemistry (and uric acid levels) were measured. Logistic regression analysis was used to assess risk factors for ED.
Main Outcome Measures
The short version of the international index of erectile function (IIEF-5) questionnaire diagnosed ED (cutoff score ≤21). Serum Uric acid levels were determined. Patients with chest pain of suspected cardiac origin underwent an exercise stress test.
149 of 312 (47.7%) male subjects had ED by survey criteria. Patients with ED were older and had more frequent CAD, hypertension, diabetes, and impaired renal function, and also had significantly higher levels of uric acid, fibrinogen, glucose, CRP, triglycerides compared with patients without ED. Uric acid levels were associated with ED by univariate analysis (OR = 1.36, p = 0.002); however, this association was not observed in multivariate analysis adjusted for eGFR.
Subjects presenting with chest pain of presumed cardiac origin are more likely to have ED if they have elevated uric acid levels.
Uric Acid; Erectile Dysfunction; Coronary Artery Disease; Endothelial Dysfunction
Attention-deficit/hyperactivity disorder (ADHD) affects nearly 10% of children in the United States, and the prevalence of this disorder has increased steadily over the past decades. The cause of ADHD is unknown, although recent studies suggest that it may be associated with a disruption in dopamine signaling whereby dopamine D2 receptors are reduced in reward-related brain regions. This same pattern of reduced dopamine-mediated signaling is observed in various reward-deficiency syndromes associated with food or drug addiction, as well as in obesity. While genetic mechanisms are likely contributory to cases of ADHD, the marked frequency of the disorder suggests that other factors are involved in the etiology. In this article, we revisit the hypothesis that excessive sugar intake may have an underlying role in ADHD. We review preclinical and clinical data suggesting overlaps among ADHD, sugar and drug addiction, and obesity. Further, we present the hypothesis that the chronic effects of excessive sugar intake may lead to alterations in mesolimbic dopamine signaling, which could contribute to the symptoms associated with ADHD. We recommend further studies to investigate the possible relationship between chronic sugar intake and ADHD.
ADHD; sucrose; fructose; high-fructose corn syrup; reward-deficiency syndrome; dopamine; D2 receptor; obesity
Diabetic nephropathy (DN) is a major cause of mortality in type 1 diabetes. Reduced insulin sensitivity is a well-documented component of type 1 diabetes. We hypothesized that baseline insulin sensitivity would predict development of DN over 6 years.
RESEARCH DESIGN AND METHODS
We assessed the relationship between insulin sensitivity at baseline and development of early phenotypes of DN—microalbuminuria (albumin-creatinine ratio [ACR] ≥30 mg/g) and rapid renal function decline (glomerular filtration rate [GFR] loss >3 mL/min/1.73 m2 per year)—with three Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations over 6 years. Subjects with diabetes (n = 449) and without diabetes (n = 565) in the Coronary Artery Calcification in Type 1 Diabetes study had an estimated insulin sensitivity index (ISI) at baseline and 6-year follow-up.
The ISI was lower in subjects with diabetes than in those without diabetes (P < 0.0001). A higher ISI at baseline predicted a lower odds of developing an ACR ≥30 mg/g (odds ratio 0.65 [95% CI 0.49–0.85], P = 0.003) univariately and after adjusting for HbA1c (0.69 [0.51–0.93], P = 0.01). A higher ISI at baseline conferred protection from a rapid decline of GFR as assessed by CKD-EPI cystatin C (0.77 [0.64–0.92], P = 0.004) and remained significant after adjusting for HbA1c and age (0.80 [0.67–0.97], P = 0.02). We found no relation between ISI and rapid GFR decline estimated by CKD-EPI creatinine (P = 0.38) or CKD-EPI combined cystatin C and creatinine (P = 0.50).
Over 6 years, a higher ISI independently predicts a lower odds of developing microalbuminuria and rapid GFR decline as estimated with cystatin C, suggesting a relationship between insulin sensitivity and early phenotypes of DN.
Minimal Change Disease (MCD) is the most common cause of nephrotic syndrome in children and is associated with the expression of CD80 in podocytes with increased excretion of CD80 in urine. We hypothesized that serum from patients with MCD might stimulate CD80 expression in cultured podocytes.
Sera and peripheral blood mononuclear cells were collected from subjects with MCD in relapse and remission, and normal controls. Immortalized human podocytes were incubated with culture media containing patient sera or supernatants from patient and control peripheral blood mononuclear cell (PBMC) cultures. CD80 expression was measured by quantitative PCR and western blot analysis.
Sera from MCD in relapse, but not in remission, significantly increased CD80 expression (1.8±0.7 vs 0.8±0.2) (mean±SD) (p<0.004) and CD80 protein secretion by podocytes (p<0.05 between relapse and normal controls). No such CD80 increase was observed when podocytes were incubated with supernatants of PBMC cultures from patients in relapse.
MCD sera from patients in relapse, but not in remission, stimulates CD80 expression in cultured podocytes. Identifying this factor in sera could provide insights into the pathogenesis of this disorder. No role in CD80 expression by podocytes was found for cytokines released by PBMCs.
CD80; Minimal change disease; nephrotic syndrome
To determine whether baseline estimated glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR) independently predict coronary artery calcification (CAC) progression, and to determine how eGFR changes over 6 years in adults with type 1 diabetes compared with nondiabetic adults.
RESEARCH DESIGN AND METHODS
The Coronary Artery Calcification in Type 1 Diabetes study participants (n = 1,066) with complete data for eGFR assessment at baseline and 6 years were included. Three Chronic Kidney Disease Epidemiology Collaboration equations (serum creatinine, cystatin C, and both) were used to estimate eGFR. The association of baseline ACR and eGFR with CAC progression was analyzed using multiple logistic regression.
Increasing categorical baseline ACR (<10, 10–30, and >30 µg/mg) predicted CAC progression in participants with type 1 diabetes (odds ratio [OR], 2.15; 95% CI, 1.50–3.09; 7.19 [3.90–13.26]; and 18.09 [8.48–38.62]), respectively, compared with nondiabetic subjects. Baseline eGFR <60 mL/min/1.73 m2 also predicted CAC progression (OR, 5–7, compared with nondiabetic participants). ORs for CAC progression were higher in women than in men when using the cystatin C–based Chronic Kidney Disease Epidemiology Collaboration equations. Participants with type 1 diabetes had greater eGFR decreases over 6 years than nondiabetic participants using cystatin C–based equations.
Although increasing ACR or decreasing eGFR predicts CAC progression, coronary atherosclerosis progresses faster in people with type 1 diabetes even in the absence of diabetic kidney disease. These findings emphasize the interaction between kidney disease and cardiovascular disease in type 1 diabetes and highlight the public health importance of lowering cardiorenal risk in people with type 1 diabetes.
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.
To determine the effect of polyIC in the kidney, we subjected mice to systemic injection of polyIC or phosphate buffered saline.
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.
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.
animal models; CD80; minimal change disease; nephrotic syndrome; proteinuria
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.
Experimental and observational studies suggest a role for uric acid in non-alcoholic fatty liver disease (NAFLD). We examined the association between serum uric acid levels and NAFLD in a large population-based study from the United States.
A cross-sectional analysis of 10,732 nondiabetic adults who participated in the National Health and Nutrition Examination Survey 1988–1994. Sex specific uric acid quartiles were defined: ≤5.2, 5.3–6.0, 6.1–6.9, and >6.9 mg/dL for men and ≤3.7, 3.8–4.5, 4.6–5.3, and >5.3 mg/dL for women. NAFLD presence and severity were defined by ultrasonographic detection of steatosis in the absence of other liver diseases. We modeled the probability that more severe NAFLD would be associated with the highest quartiles of uric acid.
Compared to the 1st quartile, the odds ratio for NAFLD was 1.79 (95% C.I. 1.49–2.15, p < 0.001) and 3.14 (95% C.I. 2.63–3.75, p < 0.001) for the 3rd and 4th quartiles, respectively. After adjusting for demographics, hypertension, waist circumference, triglycerides, high-density lipoprotein-cholesterol, homeostasis model assessment-estimated insulin resistance, estimated glomerular filtration rate, and aspartate aminotransferase, uric acid (4th quartile) was significantly associated with NAFLD (odds ratio 1.43; 95% C.I. 1.16–1.76, p < 0.001). Positive parameter estimates suggest increasing uric acid is associated with greater severity of NAFLD.
Elevated uric acid level is independently associated with ultrasound-diagnosed NAFLD in a nationally representative sample of United States nondiabetic adults. Increasing uric acid is associated with increasing severity of NAFLD on ultrasonography. These findings warrant further studies on the role of uric acid in NAFLD.
hyperuricemia; NHANES; metabolic syndrome