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"Atkins, Robert C"
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Nonalbuminuric Renal Impairment in Type 2 Diabetic Patients and in the General Population (National Evaluation of the Frequency of Renal Impairment cO-existing with NIDDM NEFRON 11)
OBJECTIVE: Most diabetic patients with impaired renal function have a urinary albumin excretion rate in the normal range. In these patients, the etiology of renal impairment is unclear, and it is also unclear whether this nonalbumunuric renal impairment is unique to diabetes. RESEARCH DESIGN AND METHODS: In this study, we examined the frequency and predictors of nonalbumunuric renal impairment (estimated glomerular filtration rate [eGFR] <60 ml/min per 1.73 m²) in a nationally representative cohort of 3,893 patients with type 2 diabetes and compared our findings with rates observed in the general population from the Australian Diabetes, Obesity and Lifestyle Study (AusDiab) survey (n = 11,247). RESULTS: Of the 23.1% of individuals with type 2 diabetes who had eGFR <60 ml/min per 1.73 m² (95% CI 21.8-24.5%), more than half (55%) had a urinary albumin excretion rate that was persistently in the normal range. This rate of renal impairment was predictably higher than that observed in the general population (adjusted odds ratio 1.3, 95% CI 1.1-1.5, P < 0.01) but was solely due to chronic kidney disease associated with albuminuria. In contrast, renal impairment in the absence of albuminuria was less common in those with diabetes than in the general population, independent of sex, ethnicity, and duration of diabetes (0.6, 0.5-0.7, P < 0.001). CONCLUSIONS: Nonalbuminuric renal impairment is not more common in those with diabetes. However, its impact may be more significant. New studies are required to address the pathogenesis, prevention, and treatment of nonalbuminuric renal disease.
Journal Article
The epidemiology of chronic kidney disease
The epidemiology of chronic kidney disease. The world's disease profile is changing, and chronic diseases now account for the majority of global morbidity and mortality, rather than infectious diseases. The causes of chronic kidney diseases reflect this change and diabetes, together with hypertension, is now the major cause of end-stage renal failure worldwide, not only within the developed world, but also increasingly within the emerging world.
Diabetes is of epidemic proportions, and its prevalence will double in the next 25 years, particularly in the developing countries. This will place an enormous financial burden on countries, including the cost of the management of end-stage renal failure. Thus, it is medically and economically imperative for awareness, detection, and prevention programs to be introduced across the world, particularly in the developing countries. This will require concerted action from global institutions, governments, health service providers, and medical practitioners.
Journal Article
Television Viewing Time and Risk of Chronic Kidney Disease in Adults: The AusDiab Study
Background
Television viewing time independent of physical activity is associated with a number of chronic diseases and related risk factors; however, its relationship with chronic kidney disease is unknown.
Purpose
The purpose of this study is to examine the cross-sectional and prospective relationships of television viewing time with biomarkers of chronic kidney disease.
Methods
Participants of the Australian Diabetes, Obesity and Lifestyle Study attended the baseline (
n
= 10,847) and 5-year follow-up (
n
= 6,293) examination.
Results
Television viewing was significantly associated with increased odds of prevalent albuminuria and low estimated glomerular filtration rate. In the gender-stratified analyses this pattern was seen for men, but not for women. In the longitudinal analyses, odds of de novo albuminuria and low estimated glomerular filtration rate were increased only in unadjusted models.
Conclusions
Television viewing time may be directly related to markers of chronic kidney disease and through intertwined associated risk factors such as diabetes, hypertension, and obesity.
Journal Article
Expression of macrophage migration inhibitory factor in human glomerulonephritis
Expression of macrophage migration inhibitory factor in human glomerulonephritis.
We have recently demonstrated that macrophage migration inhibitory factor (MIF) plays a pathogenic role in experimental glomerulonephritis (GN). The aim of the current study was to investigate MIF expression in human GN.
MIF expression was examined by in situ hybridization and immunohistochemistry staining in 65 biopsies from a variety of glomerulonephridities.
There is constitutive expression of MIF mRNA and protein in normal human kidney that is largely restricted to tubular epithelial cells and to some glomerular epithelial cells. There was little change in the pattern of MIF expression in nonproliferative forms of GN such as minimal change disease and membranous GN. However, there was a marked increase in both glomerular and tubular MIF expression in proliferative forms of GN, including focal segmental glomerulosclerosis (FGS), lupus nephritis, crescentic GN, and mesangiocapillary proliferative GN. The prominent macrophage and T-cell infiltrate in these diseases were largely restricted to areas with marked up-regulation of MIF expression, contributing to glomerular hypercellularity, glomerular focal segmental lesions, crescent formation, tubulitis, and granulomatous lesions. De novo MIF expression was evident in glomerular endothelial cells and mesangial cells in proliferative forms of GN. In addition, many infiltrating macrophages and T cells showed MIF mRNA and protein expression. Quantitative analysis found that increased glomerular and tubular MIF expression gave a highly significant correlation with macrophage and T-cell accumulation, the severity of histologic lesions, and the loss of creatinine clearance.
Renal MIF expression is markedly up-regulated in proliferative forms of human GN, and this correlates with leukocyte infiltration, histologic damage, and renal function impairment. These results suggest that MIF may be an important mediator of renal injury in progressive forms of human GN. Based on these findings, together with the known pathogenic role of MIF in experimental GN, we propose that MIF is an attractive therapeutic target in the treatment of progressive forms of GN.
Journal Article
Macrophages in mouse type 2 diabetic nephropathy: Correlation with diabetic state and progressive renal injury
Macrophages in mouse type 2 diabetic nephropathy: Correlation with diabetic state and progressive renal injury.
Macrophage-mediated renal injury has been implicated in progressive forms of glomerulonephritis; however, a role for macrophages in type 2 diabetic nephropathy, the major cause of end-stage renal failure, has not been established. Therefore, we examined whether macrophages may promote the progression of type 2 diabetic nephropathy in db/db mice.
The incidence of renal injury was examined in db/db mice with varying blood sugar and lipid levels at 8months of age. The association of renal injury with the accumulation of kidney macrophages was analyzed in normal db/+ and diabetic db/db mice at 2, 4, 6, and 8months of age.
In db/db mice, albuminuria and increased plasma creatinine correlated with elevated blood glucose and hemoglobin A1c (HbA1c) levels but not with obesity or hyperlipidemia. Progressive diabetic nephropathy in db/db mice was associated with increased kidney macrophages. Macrophage accumulation and macrophage activation in db/db mice correlated with hyperglycemia, HbA1c levels, albuminuria, elevated plasma creatinine, glomerular and tubular damage, renal fibrosis, and kidney expression of macrophage chemokines [monocyte chemoattractant protein-1 (MCP-1), osteopontin, migration inhibitory factor (MIF), monocyte-colony-stimulating factor (M-CSF)]. The accrual and activation of glomerular macrophages also correlated with increased glomerular IgG and C3 deposition, which was itself dependent on hyperglycemia.
Kidney macrophage accumulation is associated with the progression of type 2 diabetic nephropathy in db/db mice. Macrophage accumulation and activation in diabetic db/db kidneys is associated with prolonged hyperglycemia, glomerular immune complex deposition, and increased kidney chemokine production, and raises the possibility of specific therapies for targeting macrophage-mediated injury in diabetic nephropathy.
Journal Article
Activation of the ERK pathway precedes tubular proliferation in the obstructed rat kidney
Activation of the ERK pathway precedes tubular proliferation in the obstructed rat kidney.
In vitro studies suggest that activation of the extracellular signal-regulated kinase (ERK) pathway plays a critical role in the proliferation of tubular epithelial and myofibroblast-like cells. However, little is known of ERK activation in individual cell types in normal or diseased kidney. The aims of this study were to (1) localize ERK activation within the kidney, and (2) examine the relationship between ERK activation and cell proliferation in the injured kidney.
Unilateral ureteric obstruction (UUO) was induced in groups of six Wistar rats, which were killed at 30 minutes, 6 hours, and 1, 4, or 7 days after obstruction. Activation of ERK was identified using antibodies specific for the phosphorylated form of ERK (pERK) in Western blots and immunostaining. Proliferating cells were detected using bromodeoxyuridine (BrdU).
Western blotting showed abundant expression of the two ERK isoforms, ERK-1 and ERK-2, in normal rat kidney. Low levels of activated ERK (pERK-2> pERK-1) were detected in normal rat kidney by Western blotting. Immunostaining showed that ERK activation in normal kidney was largely restricted to collecting ducts in the outer medulla. Within 30 minutes of ureter obstruction, Western blotting showed a sixfold increase in ERK activation followed by a second peak (14-fold increase) on days 4 and 7. The initial peak of ERK activation was localized to medullary collecting ducts and the thick ascending limb of Henle (TALH), whereas the second peak corresponded to a progressive increase in ERK activation in dilated collecting ducts and in interstitial cells in the cortex. Proliferation of tubular epithelial cells closely followed the pattern of ERK activation, being evident first in medullary collecting ducts and TALH on day 1, and then in cortical collecting ducts from day 4.
This study has identified a discrete pattern of ERK activation in normal rat kidney and an increase in ERK activation following obstruction. The temporal and spatial relationship in which ERK activation preceded tubular cell proliferation suggest that ERK signaling plays a key role in tubular epithelial cell proliferation in the injured kidney.
Journal Article
Renoprotective Effect of the Angiotensin-Receptor Antagonist Irbesartan in Patients with Nephropathy Due to Type 2 Diabetes
Blockade of angiotensin type 1 receptors slows the progression of nephropathy. This effect is independent of the reduction in blood pressure.
Diabetes mellitus is increasing in prevalence worldwide and is currently estimated to affect more than 6.5 percent of the population of the United States.
1
Diabetes is the most common cause of end-stage renal disease in this country, accounting for 40 percent of cases.
2
Although the inhibition of the effects of angiotensin II has a beneficial effect in patients with nephropathy caused by type 1 diabetes,
3
no published study with definitive renal outcomes has addressed the issue of renoprotection in patients with type 2 diabetes — a population that differs substantially from patients with type 1 diabetes in terms of demographic . . .
Journal Article
25-hydroxyvitamin D Levels and chronic kidney disease in the AusDiab (Australian Diabetes, Obesity and Lifestyle) study
Background
Low 25-hydroxy vitamin D (25(OH)D) levels have been associated with an increased risk of albuminuria, however an association with glomerular filtration rate (GFR) is not clear. We explored the relationship between 25(OH)D levels and prevalent chronic kidney disease (CKD), albuminuria and impaired GFR, in a national, population-based cohort of Australian adults (AusDiab Study).
Methods
10,732 adults ≥25 years of age participating in the baseline survey of the AusDiab study (1999–2000) were included. The GFR was estimated using an enzymatic creatinine assay and the CKD-EPI equation, with CKD defined as eGFR <60 ml/min/1.73 m
2
. Albuminuria was defined as a spot urine albumin to creatinine ratio (ACR) of ≥2.5 mg/mmol for men and ≥3.5 for women. Serum 25(OH)D levels of <50 nmol/L were considered vitamin D deficient. The associations between 25(OH)D level, albuminuria and impaired eGFR were estimated using multivariate regression models.
Results
30.7% of the study population had a 25(OH)D level <50 nmol/L (95% CI 25.6-35.8). 25(OH)D deficiency was significantly associated with an impaired eGFR in the univariate model (OR 1.52, 95% CI 1.07-2.17), but not in the multivariate model (OR 0.95, 95% CI 0.67-1.35). 25(OH)D deficiency was significantly associated with albuminuria in the univariate (OR 2.05, 95% CI 1.58-2.67) and multivariate models (OR 1.54, 95% CI 1.14-2.07).
Conclusions
Vitamin D deficiency is common in this population, and 25(OH)D levels of <50 nmol/L were independently associated with albuminuria, but not with impaired eGFR. These associations warrant further exploration in prospective and interventional studies.
Journal Article