Diabetic Kidney Disease in FVB/NJ Akita Mice: Temporal Pattern of Kidney Injury and Urinary Nephrin Excretion

Akita mice are a genetic model of type 1 diabetes. In the present studies, we investigated the phenotype of Akita mice on the FVB/NJ background and examined urinary nephrin excretion as a marker of kidney injury. Male Akita mice were compared with non-diabetic controls for functional and structural characteristics of renal and cardiac disease. Podocyte number and apoptosis as well as urinary nephrin excretion were determined in both groups. Male FVB/NJ Akita mice developed sustained hyperglycemia and albuminuria by 4 and 8 weeks of age, respectively. These abnormalities were accompanied by a significant increase in systolic blood pressure in 10-week old Akita mice, which was associated with functional, structural and molecular characteristics of cardiac hypertrophy. By 20 weeks of age, Akita mice developed a 10-fold increase in albuminuria, renal and glomerular hypertrophy and a decrease in the number of podocytes. Mild-to-moderate glomerular mesangial expansion was observed in Akita mice at 30 weeks of age. In 4-week old Akita mice, the onset of hyperglycemia was accompanied by increased podocyte apoptosis and enhanced excretion of nephrin in urine before the development of albuminuria. Urinary nephrin excretion was also significantly increased in albuminuric Akita mice at 16 and 20 weeks of age and correlated with the albumin excretion rate. These data suggest that: 1. FVB/NJ Akita mice have phenotypic characteristics that may be useful for studying the mechanisms of kidney and cardiac injury in diabetes, and 2. Enhanced urinary nephrin excretion is associated with kidney injury in FVB/NJ Akita mice and is detectable early in the disease process

Age-related associations of hypertension and diabetes mellitus with chronic kidney disease

<p>Abstract</p> <p>Background</p> <p>Studies suggest end-stage renal disease incidence and all-cause mortality rates among patients with chronic kidney disease (CKD) differ by age. The association of diabetes mellitus and hypertension with CKD across the adult lifespan is not well established.</p> <p>Methods</p> <p>Data from NHANES 1999–2004 were used to determine the association of risk factors for stage 3 or 4 CKD (n = 12,518) and albuminuria (n = 12,778) by age grouping (20 to 49, 50 to 69, and ≥70 years). Stage 3 or 4 CKD was defined as an estimated glomerular filtration rate of 15 to 59 ml/min/1.73 m²and albuminuria as an albumin to creatinine ratio ≥30 mg/g.</p> <p>Results</p> <p>For adults 20 to 49, 50 to 69 and ≥70 years of age, the prevalence ratios (95% confidence interval) of stage 3 or 4 CKD associated with hypertension were 1.94 (0.86 – 4.35), 1.51 (1.09 – 2.07), 1.31 (1.15 – 1.49), respectively (p-trend = 0.038). The analogous prevalence ratios (95% confidence interval) were 3.01 (1.35 – 6.74), 1.61 (1.15 – 2.25), 1.40 (1.15 – 1.69), respectively, for diagnosed diabetes mellitus (p-trend = 0.067); and 2.67 (0.53 – 13.4), 1.35 (0.69 – 2.63), 1.08 (0.78 – 1.51), respectively, for undiagnosed diabetes mellitus (p-trend = 0.369). The prevalence ratios of albuminuria associated with hypertension and diagnosed and undiagnosed diabetes mellitus were lower at older age (each p < 0.05).</p> <p>Conclusion</p> <p>Among US adults, diabetes mellitus and hypertension are associated with CKD and albuminuria regardless of age. However, the associations were stronger at younger ages.</p

Anemia status, hemoglobin concentration and outcome after acute stroke: a cohort study

<p>Abstract</p> <p>Background</p> <p>In the setting of an acute stroke, anemia has the potential to worsen brain ischemia, however, the relationship between the entire range of hemoglobin to long-term outcome is not well understood.</p> <p>Methods</p> <p>We examined the association between World Health Organization-defined admission anemia status (hemoglobin<13 in males, <12 g/dl in women) and hemoglobin concentration and 1-year outcome among 859 consecutive patients with acute stroke (ischemic or intracerebral hemorrhage).</p> <p>Results</p> <p>The mean baseline hemoglobin concentration was 13.8 ± 1.7 g/dl (range 8.1 - 18.7). WHO-defined anemia was present in 19% of patients among both women and men. After adjustment for differences in baseline characteristics, patients with admission anemia had an adjusted OR for all-cause death at 1-month of 1.90 (95% CI, 1.05 to 3.43) and at 1-year of 1.72 (95% CI, 1.00 to 2.93) and for the combined end-point of disability, nursing facility care or death of 2.09 (95% CI, 1.13 to 3.84) and 1.83 (95% CI, 1.02 to 3.27) respectively. The relationship between hemoglobin quartiles and all-cause death revealed a non-linear association with increased risk at extremes of both low and high concentrations. In logistic regression models developed to estimate the linear and quadratic relation between hemoglobin and outcomes of interest, each unit increment in hemoglobin squared was associated with increased adjusted odds of all-cause death [at 1-month 1.06 (1.01 to 1.12; p = 0.03); at 1-year 1.09 (1.04 to 1.15; p < 0.01)], confirming that extremes of both low and high levels of hemoglobin were associated with increased mortality.</p> <p>Conclusions</p> <p>WHO-defined anemia was common in both men and women among patients with acute stroke and predicted poor outcome. Moreover, the association between admission hemoglobin and mortality was not linear; risk for death increased at both extremes of hemoglobin.</p

Chronic kidney disease increases cardiovascular unfavourable outcomes in outpatients with heart failure

<p>Abstract</p> <p>Background</p> <p>Chronic heart failure (CHF) has a high morbidity and mortality. Chronic kidney disease (CKD) has consistently been found to be an independent risk factor for unfavorable cardiovascular (CV) outcomes. Early intervention on CKD reduces the progression of CHF, hospitalizations and mortality, yet there are very few studies about CKD as a risk factor in the early stages of CHF. The aims of our study were to assess the prevalence and the prognostic importance of CKD in patients with systolic CHF stages B and C.</p> <p>Methods</p> <p>This is a prospective cohort study, dealing with prognostic markers for CV endpoints in patients with systolic CHF (ejection fraction ≤ 45%).</p> <p>Results</p> <p>CKD was defined as estimated glomerular filtration rate <60 mL/min/1.73 m²and CV endpoints as death or hospitalization due to CHF, in 12 months follow-up. Eighty three patients were studied, the mean age was 62.7 ± 12 years, and 56.6% were female. CKD was diagnosed in 49.4% of the patients, 33% of patients with CHF stage B and 67% in the stage C. Cardiovascular endpoints were observed in 26.5% of the patients. When the sample was stratified into stages B and C of CHF, the occurrence of CKD was associated with 100% and 64.7%, respectively, of unfavorable CV outcomes. After adjustments for all other prognostic factors at baseline, it was observed that the diagnosis of CKD increased in 3.6 times the possibility of CV outcomes (CI 95% 1.04-12.67, p = 0.04), whereas higher ejection fraction (R = 0.925, IC 95% 0.862-0.942, p = 0.03) and serum sodium (R = 0.807, IC 95% 0.862-0.992, p = 0.03) were protective.</p> <p>Conclusion</p> <p>In this cohort of patients with CHF stages B and C, CKD was prevalent and independently associated with increased risk of hospitalization and death secondary to cardiac decompensation, especially in asymptomatic patients.</p

Hyperhomocysteinemia is independently associated with albuminuria in the population-based CoLaus study

<p>Abstract</p> <p>Background</p> <p>Increased serum levels of homocysteine and uric acid have each been associated with cardiovascular risk. We analyzed whether homocysteine and uric acid were associated with glomerular filtration rate (GFR) and albuminuria independently of each other. We also investigated the association of <it>MTHFR </it>polymorphisms related to homocysteine with albuminuria to get further insight into causality.</p> <p>Methods</p> <p>This was a cross-sectional population-based study in Caucasians (<it>n </it>= 5913). Hyperhomocysteinemia was defined as total serum homocysteine ≥ 15 μmol/L. Albuminuria was defined as urinary albumin-to-creatinine ratio > 30 mg/g.</p> <p>Results</p> <p>Uric acid was associated positively with homocysteine (r = 0.246 in men and r = 0.287 in women, <it>P </it>< 0.001). The prevalence of albuminuria increased across increasing homocysteine categories (from 6.4% to 17.3% in subjects with normal GFR and from 3.5% to 14.5% in those with reduced GFR, <it>P </it>for trend < 0.005). Hyperhomocysteinemia (OR = 2.22, 95% confidence interval: 1.60-3.08, <it>P </it>< 0.001) and elevated serum uric acid (OR = 1.27, 1.08-1.50, per 100 μmol/L, <it>P </it>= 0.004) were significantly associated with albuminuria, independently of hypertension and type 2 diabetes. The 2-fold higher risk of albuminuria associated with hyperhomocysteinemia was similar to the risk associated with hypertension or diabetes. <it>MTHFR </it>alleles related to higher homocysteine were associated with increased risk of albuminuria.</p> <p>Conclusions</p> <p>In the general adult population, elevated serum homocysteine and uric acid were associated with albuminuria independently of each other and of renal function.</p

Renoprotective effects of atorvastatin in diabetic mice: downregulation of RhoA and upregulation of Akt/GSK3

Potential benefits of statins in the treatment of chronic kidney disease beyond lipid-lowering effects have been described. However, molecular mechanisms involved in renoprotective actions of statins have not been fully elucidated. We questioned whether statins influence development of diabetic nephropathy through reactive oxygen species, RhoA and Akt/GSK3 pathway, known to be important in renal pathology. Diabetic mice (db/db) and their control counterparts (db/+) were treated with atorvastatin (10 mg/Kg/day, p.o., for 2 weeks). Diabetes-associated renal injury was characterized by albuminuria (albumin:creatinine ratio, db/+: 3.2 ± 0.6 vs. db/db: 12.5 ± 3.1*; *P&lt;0.05), increased glomerular/mesangial surface area, and kidney hypertrophy. Renal injury was attenuated in atorvastatin-treated db/db mice. Increased ROS generation in the renal cortex of db/db mice was also inhibited by atorvastatin. ERK1/2 phosphorylation was increased in the renal cortex of db/db mice. Increased renal expression of Nox4 and proliferating cell nuclear antigen, observed in db/db mice, were abrogated by statin treatment. Atorvastatin also upregulated Akt/GSK3β phosphorylation in the renal cortex of db/db mice. Our findings suggest that atorvastatin attenuates diabetes-associated renal injury by reducing ROS generation, RhoA activity and normalizing Akt/GSK3β signaling pathways. The present study provides some new insights into molecular mechanisms whereby statins may protect against renal injury in diabetes

Tangential beam IMRT versus tangential beam 3D-CRT of the chest wall in postmastectomy breast cancer patients: A dosimetric comparison

<p>Abstract</p> <p>Background</p> <p>This study evaluates the dose distribution of reversed planned tangential beam intensity modulated radiotherapy (IMRT) compared to standard wedged tangential beam three-dimensionally planned conformal radiotherapy (3D-CRT) of the chest wall in unselected postmastectomy breast cancer patients</p> <p>Methods</p> <p>For 20 unselected subsequent postmastectomy breast cancer patients tangential beam IMRT and tangential beam 3D-CRT plans were generated for the radiotherapy of the chest wall. The prescribed dose was 50 Gy in 25 fractions. Dose-volume histograms were evaluated for the PTV and organs at risk. Parameters of the dose distribution were compared using the Wilcoxon matched pairs test.</p> <p>Results</p> <p>Tangential beam IMRT statistically significantly reduced the ipsilateral mean lung dose by an average of 21% (1129 cGy versus 1437 cGy). In all patients treated on the left side, the heart volume encompassed by the 70% isodose line (V70%; 35 Gy) was reduced by an average of 43% (5.7% versus 10.6%), and the mean heart dose by an average of 20% (704 cGy versus 877 cGy). The PTV showed a significantly better conformity index with IMRT; the homogeneity index was not significantly different.</p> <p>Conclusions</p> <p>Tangential beam IMRT significantly reduced the dose-volume of the ipsilateral lung and heart in unselected postmastectomy breast cancer patients.</p

An update on the use of animal models in diabetic nephropathy research

In the current review, we discuss limitations and recent advances in animal models of diabetic nephropathy (DN). As in human disease, genetic factors may determine disease severity with the murine FVB and DBA/2J strains being more susceptible to DN than C57BL/6J mice. On the black and tan, brachyuric (BTBR) background, leptin deficient (ob/ob) mice develop many of the pathological features of human DN. Hypertension synergises with hyperglycemia to promote nephropathy in rodents. Moderately hypertensive endothelial nitric oxide synthase (eNOS(−/−)) deficient diabetic mice develop hyaline arteriosclerosis and nodular glomerulosclerosis and induction of renin-dependent hypertension in diabetic Cyp1a1mRen2 rats mimics moderately severe human DN. In addition, diabetic eNOS(−/−) mice and Cyp1a1mRen2 rats recapitulate many of the molecular pathways activated in the human diabetic kidney. However, no model exhibits all the features of human DN; therefore, researchers should consider biochemical, pathological, and transcriptomic data in selecting the most appropriate model to study their molecules and pathways of interest

A Coarse-Grained Biophysical Model of E. coli and Its Application to Perturbation of the rRNA Operon Copy Number

We propose a biophysical model of Escherichia coli that predicts growth rate and an effective cellular composition from an effective, coarse-grained representation of its genome. We assume that E. coli is in a state of balanced exponential steadystate growth, growing in a temporally and spatially constant environment, rich in resources. We apply this model to a series of past measurements, where the growth rate and rRNA-to-protein ratio have been measured for seven E. coli strains with an rRNA operon copy number ranging from one to seven (the wild-type copy number). These experiments show that growth rate markedly decreases for strains with fewer than six copies. Using the model, we were able to reproduce these measurements. We show that the model that best fits these data suggests that the volume fraction of macromolecules inside E. coli is not fixed when the rRNA operon copy number is varied. Moreover, the model predicts that increasing the copy number beyond seven results in a cytoplasm densely packed with ribosomes and proteins. Assuming that under such overcrowded conditions prolonged diffusion times tend to weaken binding affinities, the model predicts that growth rate will not increase substantially beyond the wild-type growth rate, as indicated by other experiments. Our model therefore suggests that changing the rRNA operon copy number of wild-type E. coli cells growing in a constant rich environment does not substantially increase their growth rate. Other observations regarding strains with an altered rRNA operon copy number, such as nucleoid compaction and the rRNA operon feedback response, appear to be qualitatively consistent with this model. In addition, we discuss possible design principles suggested by the model and propose further experiments to test its validity

Cardiac disease in patients with mucopolysaccharidosis: presentation, diagnosis and management

The mucopolysaccharidoses (MPSs) are inherited lysosomal storage disorders caused by the absence of functional enzymes that contribute to the degradation of glycosaminoglycans (GAGs). The progressive systemic deposition of GAGs results in multi-organ system dysfunction that varies with the particular GAG deposited and the specific enzyme mutation(s) present. Cardiac involvement has been reported in all MPS syndromes and is a common and early feature, particularly for those with MPS I, II, and VI. Cardiac valve thickening, dysfunction (more severe for left-sided than for right-sided valves), and hypertrophy are commonly present; conduction abnormalities, coronary artery and other vascular involvement may also occur. Cardiac disease emerges silently and contributes significantly to early mortality