Increase In Urinary Albumin Excretion Research Articles

Impact of glucose load in an oral glucose tolerance test on urinary albumin excretion varies with 2-h glucose levels.

The aim of the present study was to investigate whether an oral glucose load can induce an increase in urinary albumin excretion (UAE). One hundred and thirty subjects without macroalbuminuria or increased fasting serum glucose (≥7.0 mmol/L) were included in the study. At 0600 hours, subjects were asked to empty their bladder and drink 300 mL water. At 0800 hours, venous blood and 2-h urine were collected for fasting examination. Subjects were then asked to drink 300 mL solution containing 75 g glucose and, at 1000 hours, samples were collected again for post-challenge examination. Concentrations of serum glucose, urinary glucose, albumin, N-acetyl-β-D-glucosaminidase and retinol-binding protein were measured. Based on the results of the oral glucose tolerance test, subjects were divided into three groups: (i) normal glucose tolerance (NGT; n = 55); (ii) impaired glucose tolerance (IGT; n = 39); and (iii) newly diagnosed diabetes mellitus (NDM; n = 36). In the NDM group, post-challenge urinary excretion of glucose and albumin was 14- and 1.6-fold greater than fasting values, respectively. In the IGT and NGT groups, although post-challenge urinary glucose excretion was 2.6- and 1.6-fold greater than fasting values, UAE did not increase. There was a positive correlation between post-challenge serum glucose and the UAE rate (UAER; r = 0.24, P < 0.01) and the UAER increment (ΔUAER; r = 0.19, P < 0.05), as well as between the serum glucose increment and post-challenge UAER (r = 0.23, P < 0.01) and ΔUAER (r = 0.18, P < 0.05). Post-challenge serum glucose levels were independently correlated with logarithmically converted post-challenge UAER (β = 0.322, P = 0.008). Oral glucose load can induce a significant increase in UAE in NDM subjects. The main mechanism may be glomerular hyperfiltration.

Critical role of renal dipeptidyl peptidase-4 in ameliorating kidney injury induced by saxagliptin in Dahl salt-sensitive hypertensive rats

Saxagliptin, a potent dipeptidyl peptidase-4 (DPP-4) inhibitor, is currently used to treat type 2 diabetes mellitus, and it has been reported to exhibit a slower rate of dissociation from DPP-4 compared with another DPP-4 inhibitor, sitagliptin. In this study, we compared the effects of saxagliptin and sitagliptin on hypertension-related renal injury and the plasma and renal DPP-4 activity levels in Dahl salt-sensitive hypertensive (Dahl-S) rats. The high-salt diet (8% NaCl) significantly increased the blood pressure and quantity of urinary albumin excretion and induced renal glomerular injury in the Dahl-S rats. Treatment with saxagliptin (14mg/kg/day via drinking water) for 4 weeks significantly suppressed the increase in urinary albumin excretion and tended to ameliorate glomerular injury without altering the blood glucose levels and systolic blood pressure. On the other hand, the administration of sitagliptin (140mg/kg/day via drinking water) did not affect urinary albumin excretion and glomerular injury in the Dahl-S rats. Meanwhile, the high-salt diet increased the renal DPP-4 activity but did not affect the plasma DPP-4 activity in the Dahl-S rats. Both saxagliptin and sitagliptin suppressed the plasma DPP-4 activity by 95% or more. Although the renal DPP-4 activity was also inhibited by both drugs, the inhibitory effect of saxagliptin was more potent than that of sitagliptin. These results indicate that saxagliptin has a potent renoprotective effect in the Dahl-S rats, independent of its glucose-lowering actions. The inhibition of the renal DPP-4 activity induced by saxagliptin may contribute to ameliorating renal injury in hypertension-related renal injury.

Sulforaphane attenuation of experimental diabetic nephropathy involves GSK-3 beta/Fyn/Nrf2 signaling pathway

Sulforaphane (SFN), the bioactive component of cruciferous vegetables, is a potent indirect antioxidant. Oxidative stress and activation of glycogen synthase kinase 3beta (GSK3β) are two major contributors to the pathogenesis of diabetic nephropathy (DN). Here, we investigated whether and how SFN affected GSK3β in experimental models of DN in vivo and in vitro. SFN treatment obviously prevented the increase in urine albumin excretion, matrix expansion, transforming growth factor-β1 expression, fibronectin and type IV collagen deposition in the diabetic kidney. Simultaneously, the level of 8-oxo-deoxyguanosine, an indicator of oxidative damage, was markedly lowered in SFN-treated diabetic rats, together with a significant reduction in activity of the GSK-3β/Fyn axis and an evident activation of Nrf2 signaling. Similarly, antifibrotic effects of SFN, parallel to enhanced inhibitory Ser9-phosphorylation of GSK3β and Fyn/Nrf2 nuclear export/import, were observed in the cultured rat mesangial cells (RMC) exposed to high glucose. The salutary effects of SFN on high-glucose-stimulated RMC were abolished by overexpression of GSK3β while being rescued by lithium chloride, a well-known GSK3β inhibitor. Taken together, our findings suggested that SFN ameliorated experimental diabetic nephropathy, at least in part, via GSK3β/Fyn/Nrf2 signaling pathway.

Sirtuin1 Maintains Actin Cytoskeleton by Deacetylation of Cortactin in Injured Podocytes.

Recent studies have highlighted the renoprotective effect of sirtuin1 (SIRT1), a deacetylase that contributes to cellular regulation. However, the pathophysiologic role of SIRT1 in podocytes remains unclear. Here, we investigated the function of SIRT1 in podocytes. We first established podocyte-specific Sirt1 knockout (SIRT1(pod-/-)) mice. We then induced glomerular disease by nephrotoxic serum injection. The increase in urinary albumin excretion and BUN and the severity of glomerular injury were all significantly greater in SIRT1(pod-/-) mice than in wild-type mice. Western blot analysis and immunofluorescence showed a significant decrease in podocyte-specific proteins in SIRT1(pod-/-) mice, and electron microscopy showed marked exacerbation of podocyte injury, including actin cytoskeleton derangement in SIRT1(pod-/-) mice compared with wild-type mice. Protamine sulfate-induced podocyte injury was also exacerbated by podocyte-specific SIRT1 deficiency. In vitro, actin cytoskeleton derangement in H2O2-treated podocytes became prominent when the cells were pretreated with SIRT1 inhibitors. Conversely, this H2O2-induced derangement was ameliorated by SIRT1 activation. Furthermore, SIRT1 activation deacetylated the actin-binding and -polymerizing protein cortactin in the nucleus and facilitated deacetylated cortactin localization in the cytoplasm. Cortactin knockdown or inhibition of the nuclear export of cortactin induced actin cytoskeleton derangement and dissociation of cortactin from F-actin, suggesting the necessity of cytoplasmic cortactin for maintenance of the actin cytoskeleton. Taken together, these findings indicate that SIRT1 protects podocytes and prevents glomerular injury by deacetylating cortactin and thereby, maintaining actin cytoskeleton integrity.

Cumulative systolic BP and changes in urine albumin-to-creatinine ratios in nondiabetic participants of the multi-ethnic study of atherosclerosis.

Cumulative exposure to elevated systolic BP (cumSBP) may affect progression of urine albumin excretion in the absence of diabetes. The objective of this study was to examine the association between cumSBP exposure and progression of spot urine albumin-to-creatinine ratio (UACR) in a multi-ethnic cohort of adults without diabetes. The analysis included 3789 participants without severely increased urine albumin excretion or diabetes in the Multi-Ethnic Study of Atherosclerosis, a cohort of 6814 adults aged 45-84 years. UACR was measured at baseline and approximately 1.6, 3.1, and 9.4 years after the baseline examination. cumSBP was calculated as the summed average systolic BP (SBP; mmHg) between two consecutive examinations multiplied by the time between the two examinations (mmHg × year) and categorized as ≤ 1128 (SBP<120 mmHg), 1129-1222 (SBP ≥ 120-129 mmHg), 1223-1316 (SBP ≥ 130-130 mmHg), and > 1316 (SBP ≥ 140 mmHg). Baseline UACR was categori zed as normal, mildly increased, or moderately increased, and definite progression of UACR was defined as a persistently higher UACR category at subsequent examinations. No UACR progression was defined as remaining in the same UACR category across all examinations or regressing. In fully adjusted models, compared with cumSBP ≤ 1128 mmHg, cumSBP 1223-1316 and >1316 mmHg was associated with a 85% and 130% significantly higher odds of definite UACR progression (95% confidence interval, 24% to 178% and 56% to 243%, respectively) versus no UACR progression. Every 100-mmHg higher level of cumSBP was associated with a 1.23-fold higher odds of definite UACR progression (95% confidence interval, 1.13 to 1.34) versus no UACR progression. Exposure to higher cumSBP was associated with increased UACR progression among adults without diabetes.

Bisphenol-A induces podocytopathy with proteinuria in mice.

Bisphenol-A, a chemical used in the production of the plastic lining of food and beverage containers, can be found in significant levels in human fluids. Recently, bisphenol-A has been associated with low-grade albuminuria in adults as well as in children. Since glomerular epithelial cells (podocytes) are commonly affected in proteinuric conditions, herein we explored the effects of bisphenol-A on podocytes in vitro and in vivo. On cultured podocytes we first observed that bisphenol-A-at low or high concentrations-(10 nM and 100 nM, respectively) was able to induce hypertrophy, diminish viability, and promote apoptosis. We also found an increase in the protein expression of TGF-β1 and its receptor, the cyclin-dependent kinase inhibitor p27Kip1, as well as collagen-IV, while observing a diminished expression of the slit diaphragm proteins nephrin and podocin. Furthermore, mice intraperitoneally injected with bisphenol-A (50 mg/Kg for 5 weeks) displayed an increase in urinary albumin excretion and endogenous creatinine clearance. Renal histology showed mesangial expansion. At ultrastructural level, podocytes displayed an enlargement of both cytoplasm and foot processes as well as the presence of condensed chromatin, suggesting apoptosis. Furthermore, immunohistochemistry for WT-1 (specific podocyte marker) and the TUNEL technique showed podocytopenia as well as the presence of apoptosis, respectively. In conclusion, our data demonstrate that Bisphenol-A exposure promotes a podocytopathy with proteinuria, glomerular hyperfiltration and podocytopenia. Further studies are needed to clarify the potential role of bisphenol-A in the pathogenesis as well as in the progression of renal diseases.

Slight increase in urinary albumin excretion within the normal range predicts incident hypertension in a community-based Japanese population: the Takahata study.

Recent studies have suggested that urine albumin excretion in the high normal range predicts hypertension. However, the relationship between urinary albumin excretion in spot urine and incident hypertension remains unclear in the general Japanese population. To clarify this relationship, we conducted a cohort study in a community-based population of 412 normotensive individuals without diabetes and renal insufficiency and examined the incidence of hypertension using the urinary albumin-to-creatinine ratio (UACR) at baseline. Incident hypertension was defined as new-onset systolic blood pressure ⩾ 140 mm Hg and/or diastolic blood pressure ⩾ 90 mm Hg and/or the use of anti-hypertensive drugs. During the follow-up period (median, 6.7 years), 133 subjects (32.3%) newly developed hypertension. The incidence of hypertension increased with an increase in baseline UACR (20.4% for UACR <5 mg g(-1), 34.0% for 5-9.9 mg g(-1) UACR and 40.4% for 10-29.9 mg g(-1), P=0.002). Multivariate logistic regression analysis, after adjustment for possible confounders, showed that UACR 5-9.9 mg g(-1) and 10-29.9 mg g(-1) were independent risks for incident hypertension compared with UACR <5 mg g(-1) (odds ratio (OR) 2.15, 95% confidence interval (CI) 1.16-4.10 and OR 2.67, 95% CI 1.36-5.38, respectively). Subgroup analysis revealed that subjects with increased UACR (⩾ 5 mg g(-1)) had a higher risk of incident hypertension than did those with low UACR (<5 mg g(-1)), irrespective of their backgrounds (age, sex, smoking, alcohol consumption, obesity and urinary sodium excretion). In conclusion, this study showed that a slight increase in urinary albumin excretion might predict incident hypertension in a community-based Japanese population.

Can increased albumin excretion provide evidence of early renal and cardiovascular disease in adolescents with Type 1 diabetes?

an age-adjusted incidence risk rate for a first CVD event of 3.0 (95% CI: 2.4–3.8) in females and 2.3 (95% CI: 2.0–2.7) in males when compared to the non-diabetic population, and highlighted a higher rate of CVD events in subjects younger than 40 years [4]. Risk for CVD in patients with T1D seems to be strongly associated with the presence of DN, being tenfold greater for patients with DN compared with those without this complication [5]. This is also highlighted by recent studies reporting that, in the absence of renal complications, mortality in patients with T1D is similar to that in the general population, whereas it significantly increases in the presence of microalbuminuria or more advanced stages of DN [6,7]. DN is a common microvascular complication in patients with T1D, which manifests with progressive increases in urinary albumin excretion, along with changes in glomerular filtration rate, ultimately

Bile acid sequestrants activate novel signaling pathways in the kidney and prevent obesity‐induced renal disease (767.10)

Bile acid sequestrants (BAS) are orally administered nonabsorbable polymers that decrease serum cholesterol and serum glucose in patients and animal models with type 2 diabetes mellitus. The effects of BAS on renal dysfunction in obesity and insulin resistance or type 2 diabetes mellitus have not been studied. Our goal was to evaluate the effect of BAS on metabolic and renal parameters in diet induced obesity. Our studies were performed in C57BL/6J male mice fed a control low fat (LF) diet (10 kcal% fat) or high fat (HF) diet (60 kcal% fat). The diets were supplemented with a) no addition or b) 2% sevelamer a BAS. Treatment with BAS prevented HF diet induced body weight gain, improved fasting blood glucose and glucose tolerance, and prevented the increases in serum cholesterol as well as insulin and leptin levels in HF mice. BAS prevented the increase in urine albumin excretion and decreased the PAS staining in the kidney of HF mice. Treatment with BAS decreased the renal lipid accumulation as shown by oil red O staining. HF diet induced upregulation of profibrotic genes (TGF‐β, CTGF, and PAI‐1) and proinflammatory genes (MCP‐1, TLR2, and TLR4) in the kidney which were decreased by treatment with BAS. In addition BAS induced downregulation of extracellular matrix protein fibronectin and macrophage marker CD68 expression in the kidney. The beneficial effects of BAS were also associated with decreases in renal gluconeogenic gene expression (PEPCK and G6Pase) and renal glucose transporter (SGLT2). Treatment with BAS also and most notably increased renal expression of Nrf1, SIRT1, PGC‐1a,SIRT3, ERRa, that mediate mitochondrial biogenesis, MCAD and LCAD, that mediate fatty acid oxidation, and Nrf2, HO‐1, and SOD, that mediate anti‐oxidative stress. In summary, our study showed a novel renoprotective role for bile acid sequestrant treatment in mice with diet induced obesity, insulin and leptin resistance.Grant Funding Source: NIH, VA, Genzyme, Daiichi Sankyo

Reactive oxygen species and acute kidney injury after trauma in obese rats (859.2)

Acute kidney injury (AKI) occurs more often in obese than in lean patients after blunt trauma, with similar results observed in obese rats. While studies have suggested that reactive oxygen species (ROS) are involved in the pathogenesis of organ failure after trauma, their role in the context of obesity is not known. We hypothesized that antioxidant treatment would prevent the development of AKI in obese rats. Trauma was induced in obese (OZ) and lean (LZ) Zucker rats (12‐13 wks old) by soft tissue injury, fibula fracture, and bone component injection in both hindlimbs. In OZ and LZ without trauma, glomerular filtration rate (GFR)(1.7±0.1 vs 1.5±0.1 mL/min/g), renal plasma flow (RPF)(5.8±0.1 vs 5.5±0.2 mL/min/g), and urine albumin excretion (0.63±0.3 vs 0.27±0.1 mg/24hrs) were not different (p=ns; n=6). One day after trauma, OZ had increased urine albumin excretion as compared to LZ (6.6±1.2 vs .22±0.1 mg/24hrs; p&lt;.05; n=6), and decreased GFR (0.9±0.1 vs 1.4±0.2 mL/min/g; p&lt;.05; n=6) and RPF (2.5±0.2 vs 5.2±0.3 mL/min/g; p&lt;.05; n=6). Treatment directly after trauma with a NADPH oxidase inhibitor, Apocynin (50mg/kg i.p.), led to an average GFR of 1.6±0.3 mL/min/g, RPF of 5.1±1.1 mL/min/g, and urine albumin excretion of 2.5±1.0 mg/24hrs in OZ (n=3). These data suggest that ROS may be responsible for the increased incidence of AKI after trauma in obesity, and thus may be a potential therapeutic target in this demographic.Grant Funding Source: Supported by NIH HL‐51971, HL‐89581, AHA‐12SDG12050525

Diabetic kidney disease in children and adolescents

Diabetes, more frequently type 1, but increasingly also type 2, commonly occurs in childhood. While more advanced diabetic kidney disease (DKD), e.g., loss of glomerular filtration rate (GFR), does not occur until adulthood, kidney biopsies show DKD structural changes as early as 1.5-5 years after the onset of type 1 diabetes. Earliest clinical sign of DKD, increased urine albumin excretion, commonly appears during childhood and adolescence and presents an important opportunity to detect and intervene in early DKD, perhaps more successfully than later in the disease course. Longitudinal studies of type 1 diabetes have enriched our understanding of the DKD natural history and modifiable risk factors for DKD progression. These studies have also shown that the presence of DKD marks a subset of people with diabetes who are at the highest risk of early mortality, supporting an enhanced focus on DKD detection, prevention, and treatment. Early studies suggest that youth-onset type 2 diabetes is associated with a higher prevalence of comorbidities and risk factors and follows a more aggressive natural history. A deeper understanding of the natural history, risk factors, underlying mechanisms and therapeutic options for DKD in young-onset type 2 diabetes awaits further studies.

Markers of and Risk Factors for the Development and Progression of Diabetic Kidney Disease

Diabetic kidney disease (DKD) occurs in 25%-40% of patients with diabetes. Given the dual problems of a significant risk of progression from DKD to end-stage renal disease (ESRD) and increased cardiovascular morbidity and mortality, it is important to identify patients at risk of DKD and ESRD and initiate protective renal and cardiovascular therapies. The importance of preventive therapy is emphasized further by worldwide increases in the incidence of diabetes. This review summarizes the evidence regarding the prognostic value and benefits of targeting established and novel risk markers for DKD development and progression. Family history of DKD, smoking history, and glycemic, blood pressure, and plasma lipid level control are established factors for identifying people at greatest risk of DKD development and progression. Absolute albumin excretion rate (AER) and glomerular filtration rate (GFR) measurements also are important, although AER categorization generally lacks the necessary specificity and sensitivity, and estimates of declining GFR are compromised by methodological limitations for GFRs in the normal-to-high range. Emerging risk markers for progressive loss of kidney function include markers of oxidation and inflammation, profibrotic cytokines, uric acid, advanced glycation end products, functional and structural markers of vascular dysfunction, kidney structural changes, and tubular biomarkers. Among these, the most promising are serum uric acid and soluble tumor necrosis factor receptor (type 1 and type 2) levels, especially in relation to GFR changes. At present, these can only be considered as risk markers because they only identify an individual at increased risk of progressive DKD and not necessarily related to the causal pathway promoting kidney damage. Further work is needed to establish whether modulating these factors improves the prognosis in DKD. Although change in urinary peptidome levels also is a promising marker, there currently is neither a clinical assay nor adequate studies defining its prognostic value. Until these or other novel markers become available for clinical use, predictive accuracy often may be increased with greater attention to established markers.

Albumin excretion in adolescents with diabetes

If you would like to express interest in reviewing or writing papers for the Journal of Renal Nursing, please contact the journal’s editor via email (natasha.devan@markallengroup.com) Albumin excretion in adolescents with diabetes O ver the last 20 years, two longitudinal studies—the Oxford Regional Prospective Study (ORPS) and Nephropathy Family Study (NFS), facilitated by UK research nurses—have improved our understanding of the natural history of microalbuminuria in young people with type 1 diabetes. Microalbuminuria, a marker of early-stage renal damage and an independent risk factor for nephropathy and cardiovascular disease, has been found in around 26% of adolescents with type 1 diabetes 10–20 years after diagnosis. Early increases in urinary albumin excretion predict progression to microalbuminuria and more severe renal disease. In adults with type 1 diabetes, such early increases in albumin excretion have also been associated with risk for cardiovascular disease, but data from adolescents with type 1 diabetes has been lacking. The Adolescent Type 1 Diabetes cardio-renal Intervention Trial (AdDIT), designed to explore the effects of lipid-lowering drugs (statins) and blood pressure lowering drugs (angiotensin-converting-enzyme (ACE) inhibitors) on risk for diabetic nephropathy and cardiovascular disease, has allowed exploration of the relationship between cardiovascular risk and urinary albumin excretion in adolescents with type 1 diabetes. Research nurses in the UK, Australia and Canada screened over 3000 people aged 10–16 years with type 1 diabetes to identify those with higher than average albumin excretion. Participants were found to have renal hyperfiltration and an increase in both risk markers and direct measures of cardiovascular disease. Around 850 participants have now been recruited to a clinical trial of ACE inhibitors and/or statins, which has the potential to change diabetes management during adolescence and improve the long-term prognosis of young patients with type 1 diabetes.

Association of renin-angiotensin system genes polymorphism with progression of diabetic nephropathy in patients with type 1 diabetes mellitus.

Diabetic nephropathy (DN) as a major microvascular complication of diabetes mellitus (DM) include a progressive increase in urinary albumin excretion in association with an increase in blood pressure and to end stage renal failure. Hypertension connected with renin-angiotensin system (RAS) hyperactivity and corresponding genotypes, angiotensinogen (AGT), angiotensine-converting enzyme (ACE) and angiotensin II type 1 receptor (AT1R), predispose the increasing risk of DN. The aim of this study was to assess the distribution of AGT, ACE and AT1R gene polymorphisms in patients with type 1 DM according to the level of DN and patients clinical characteristics. The study included 79 type 1 diabetic patients. Inclusion criteria were: age between 20-40, duration of diabetes > 5 years, and no other severe diseases. Clinical characteristics were gained from interviewing the patients. Polymorphism was detected by polymerase chain reaction (PCR) and restriction fragment length polymorphism using restriction enzymes Psy I (Tth 111 I) and Hae III. The patients with proteinuria compared with normo- and microalbuminuric patients, highly differed in age, diabetes duration, blood pressure level, hypertension, rethynopathy and urinary albumin excretion values (p < 0.001). No statistically significant difference between the groups was found for the ACE and AT1R gene polymorphisms distribution. The presence of TT genotype of the M235T polymorphism was significantly higher in the group with proteinuria (p < 0.05). The patients with hypertension raised nephropathy 5.2 times higher (OR = 5.20, p < 0.05) while carriers of TT allel developed nephropathy 28.38 times higher (OR = 28.389, p < 0.01) than those with MM genotype. Increased association of hypertension and TT angiotensinogen gene polymorphism in patients with diabetes mellitus with proteinuria could be a significant marker of diabetic nephropathy.

Slight increase of urinary albumin excretion predicts incident hypertension in the Japanese general population

Background: Previous studies suggested that urine albumin excretion in the high normal range predicts hypertension. However, this still remains unclear in the Japanese general population. Aim: To clarify the relationship between the levels of urinary albumin-creatinine ratio (UACR) and incident hypertension among subjects without diabetes and renal insufficiency. Methods: We conducted a cohort study of 459 normotensives without diabetes and renal insufficiency (eGFR ≤60 ml/min/1.73m2) in a community-based study in Japan and followed for 7 years (median 6.7 years). We examined the incidence of hypertension depending on the UACR levels at baseline. The incident hypertension was defined as new onset of systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg or taking any anti-hypertensive drugs. Results: During follow-up period, 256 subjects (55.8%) developed hypertension. The incidence of hypertension was increased along with the increase in UACR at baseline (41.5% in UACR <5mg/g, 59.1% in 5-14 mg/g and 66.0% in 15-29 mg/g, P<0.05). Multivariate logistic regression analysis after adjustment with age, sex, obesity, smoking status, alcohol consumption, and estimated 24-hour urinary excretion of sodium showed that UACR 5-14 mg/g and 15-29 mg/g were independent risk for incident hypertension, compared with UACR <5 mg/g (odds ratio [OR] 1.99, 95% confidence interval [CI] 1.20-3.30 and OR 2.12, 95% CI 1.01-4.54, respectively). Subgroup analysis showed that UACR 5-29 mg/g was a significant risk for incident hypertension compared with UACR <5 mg/g, especially in the subjects conventionally regarded as low risk, such as women, young (<60 years), non-obese, non-smoker, no habitual drinker, and subjects on low sodium diet (NaCl <10 g/day). Conclusions: This study showed that a slight increase of urinary albumin excretion might predict incident hypertension in the Japanese general population, especially in the subjects conventionally regarded as low risk group.

Microalbuminuria: A Neglected Cardiovascular Risk Factor in Non-diabetic Individuals?

Microalbuminuria (MA), excessive albumin excretion in the urine, is defined in different ways. MA is more prevalent among patients with diabetes mellitus (DM) and/or hypertension and correlates with adverse renal and cardiovascular (CV) outcomes. Several cross-sectional and prospective studies have demonstrated a positive association between MA and CV outcomes in the general population but also specific populations such as patients with previous MI and hypertensives. The relationship between MA and hypertension is of particular importance. Increased urine albumin excretion (UAE) has been associated with left ventricular hypertrophy (LVH), subclinical markers of atherosclerosis and vascular dysfunction. Metabolic syndrome (MetS), insulin resistance (IR), inflammatory markers, lipid parameters and measures of obesity also correlate with increased UAE. Accumulating evidence suggests that a UAE value lower than the "traditionally" considered microalbuminuric threshold is associated with increased CV risk. The revision of MA definition according to the levels which confer increased CV risk in the general population should probably be considered. Further prospective studies with uniform methods of urine collection and UAE measurement as well as consistent threshold values and units may provide additional information regarding MA (or low-grade albuminuria) as a predictor of CV outcomes.

Predictors of Progression in Albuminuria in the General Population: Results from the PREVEND Cohort

BackgroundUrinary albumin excretion is known to be independently associated with progression of renal and cardiovascular disease. The aim of this study was to identify predictors for progression in albuminuria in the general population.MethodsData were used of the first 4 screening rounds of a community-based prospective cohort study (PREVEND). Included were 5,825 subjects that at baseline had no known renal disease or macroalbuminuria. Subjects were defined as having progressive albuminuria when they belonged to the quintile of subjects with highest absolute increase in urinary albumin excretion per year and a urinary albumin excretion during the last screening in which they participated of ≥150 mg/24 h. Change in urinary albumin excretion per year was calculated as last available urinary albumin excretion minus baseline UAE divided by follow-up time.ResultsDuring 9.3 years follow-up 132 subjects had progressive albuminuria. These subjects were significantly older, more often of male gender and had a worse cardiovascular risk profile. In a multivariable model, testing baseline values, significant predictors of progressive albuminuria were male gender (OR 2.23; p<0.001), age (OR 1.03; p<0.001), BMI (OR 1.06; p = 0.02) and baseline albuminuria (OR 5.71; p<0.001). Based on these findings a risk score was made to estimate a subject's risk for progressive albuminuria.ConclusionA high baseline albuminuria is by far the most important predictor of progressive albuminuria. Thus, screening for baseline albuminuria will be more important than screening for cardiovascular risk factors in order to identify subjects at risk for progressive albuminuria.

Albuminuria is an independent predictor of all-cause and cardiovascular mortality in the Japanese population: the Takahata study

Albuminuria is a known risk factor for cardiovascular events and premature deaths. However, the association between urinary albumin excretion and mortality is unknown in the Japanese population. To clarify this, we conducted a community-based longitudinal study. This study included 3,445 registered Japanese subjects (mean age 62.6years), with a 7-year follow-up. Albuminuria was defined as a urine albumin-creatinine ratio (ACR)≥30mg/g in the morning spot urine. Subjects with albuminuria (n=514, 14.9%) were older and showed a higher prevalence of hypertension, obesity, and diabetes and lower values of estimated glomerular filtration rate (eGFR) than those without albuminuria (n=2931, 85.1%). During the follow-up, 138 subjects died. A Kaplan-Meier analysis showed that all-cause mortality significantly increased along with the increase in urine albumin excretion (log-rank test, P<0.001). The subjects with albuminuria showed a significantly higher mortality rate than those without albuminuria (7.4 vs. 3.4%; log-rank test, P<0.001). A Cox proportional hazard model analysis after adjusting for possible confounders showed that albuminuria was an independent risk factor for all-cause and cardiovascular mortality (hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.12-2.56 and HR 2.27, 95% CI 1.10-4.70, respectively) but not for noncardiovascular mortality. These associations were preserved after excluding subjects with high ACR (≥300mg/g). Albuminuria was a risk factor for all-cause and cardiovascular mortality in the Japanese population. To detect subjects with a high risk for premature death, measuring urinary albumin excretion might be useful.

Serum Fetuin-A Levels Related with Microalbuminuria in Diet-Induced Obese Rats

The aim of the study was to investigate the association between elevated serum fetuin-A and increased urine albumin excretion in obese rats, and whether increased urine albumin excretion was modified by improving hepatic steatosis and lipid metabolism disorder. Male Wistar rats 4 weeks in age were randomly divided into three groups and fed with normal chow (control group), high-fat chow (obesity group), or high-fat chow plus fenofibrate (fenofibrate group). After 24 weeks, both body weight and visceral fat/body weight ratio in obese rats were higher than in controls. A difference in serology markers and pathology associated with hepatic steatosis was also found among the three groups. Serum fetuin-A and the expression of NF-κB in the liver were increased, while serum adiponectin was decreased in obese rats in comparison to controls (P < 0.01). Urinary albumin/creatinine ratio (ACR) was increased in the obesity group compared to controls (P < 0.01). The fenofibrate intervention reduced serum fetuin-A and NF-κB expression in the liver and increased serum adiponectin compared to obese rats and was accompanied by decrease in ACR. A positive correlation was found between ACR and fetuin-A (r = 0.602, P < 0.01), and a negative correlation was found between ACR and adiponectin (r = −0.635, P < 0.01). We conclude that elevated fetuin-A levels are associated with microalbuminuria in obese rats, and abnormal albuminuria is reversible by improving hepatic steatosis.

High-fat/fructose feeding during prenatal and postnatal development in female rats increases susceptibility to renal and metabolic injury later in life

Accumulating evidence suggests that both an adverse prenatal and early postnatal environment increase susceptibility to renal and metabolic dysfunction later in life; however, whether exposure to adverse conditions during both prenatal and postnatal development act synergistically to potentiate the severity of renal and metabolic injury remains unknown. Sprague-Dawley rats were fed either a standard diet or a diet high in fat/fructose throughout pregnancy and lactation. After being weaned, female offspring were randomized to either standard diet or the high-fat/high-fructose diet, resulting in the following treatment groups: NF-NF, offspring of mothers fed a standard diet and fed a standard diet postnatally; NF-HF, offspring of mothers fed a standard diet and fed a high-fat/fructose diet postnatally; HF-NF, offspring of mothers fed a high-fat/fructose diet and fed a standard diet postnatally; HF-HF, offspring of mothers fed a high-fat/fructose diet and fed a high-fat/fructose diet postnatally. At the time of euthanasia (17 wk of age), HF-HF offspring weighed 30% more and had 110% more visceral fat than NF-NF offspring. The HF-HF offspring also had elevated blood glucose levels, glucose intolerance, 286% increase in urine albumin excretion, and 60% increase in glomerulosclerosis compared with NF-NF. In addition, HF-HF offspring exhibited a 100% increase in transforming growth factor-β protein expression and 116% increase in the abundance of infiltrated macrophages compared with the NF-NF offspring. These observations suggest that high-fat/fructose feeding during prenatal and throughout postnatal life increases the susceptibility to renal and metabolic injury later in life.