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Diabetic nephropathy is a disease entity that is becoming more prevalent in the developed world. Its effect on individuals and society is profound, both in terms of cost and on patient health, especially in relation to associated cardiovascular disease. This review is an analysis of the most recent data available on diabetic nephropathy and its clinical applications to patient care. Using Medline search for relevant data from 1983 to the present, it focuses on clinical strategies that are employed to help curtail the progressive nature of this disease. Current strategies, including glycemic control, blood pressure treatment, inhibition of the renin/angiotensin system, nutrition, and hyperlipidemia, are discussed in relation to the relevant clinical data. Current clinical markers and possible future treatments are also discussed in the context of aiming to improve clinical outcomes in patients who are affected.
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PMID:Diabetic nephropathy: implications for renal and cardiovascular outcomes. 1546 14

The earliest clinical evidence of diabetic nephropathy is microalbuminuria. Progression from microalbuminuria to overt nephropathy occurs in 20-40% within a 10-year period with approximately 20% of these patients progressing to end-stage renal disease. End-stage renal disease develops in 50% of type-1 diabetes patients with overt nephropathy within 10 years and in more than 75% by 20 years in the absence of treatment. In type-2 diabetes, a greater proportion of patients have microalbuminuria and overt nephropathy at or shortly after diagnosis of diabetes. The incidence of diabetes is increasing worldwide, with subsequent increase in the incidence of diabetic nephropathy. The risk factors identified in the development of DN from longitudinal and cross-sectional studies include race, genetic susceptibility, hypertension, hyperglycemia, hyperfiltration, smoking, advanced age, male sex, and high-protein diet. Treatment interventions in diabetic nephropathy include glycemic control, treatment of hypertension, hyperlipidemia, cessation of smoking, protein restriction, and renal replacement therapy. Multifactorial approach includes combined therapy targeting hyperglycemia, hypertension, microalbuminuria, and dyslipidemia.
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PMID:Diabetic nephropathy--a review of the natural history, burden, risk factors and treatment. 1558 48

Despite more aggressive treatment of diabetes, hypertension, and hyperlipidemia, the incidence and prevalence rates of end-stage renal disease (ESRD) continue to increase worldwide. The likelihood of developing chronic kidney disease in an individual is determined by interactions between genes and the environment. Familial clustering of nephropathy has repeatedly been observed in all population groups studied and for multiple etiologies of kidney disease. A three- to nine-fold greater risk of ESRD is observed in individuals with a family history of ESRD. Marked racial variation in the familial aggregation of kidney disease exists, with high rates in African American, Native American, and Hispanic American families. Disparate etiologies of nephropathy aggregate within African American families, as well. These data have led several investigators to search for genes linked to diabetic and other forms of nephropathy. Evidence for linkage to kidney disease has been detected and replicated at several loci on chromosomes 3q (types 1 and 2 diabetic nephropathy), 10q (diabetic and nondiabetic kidney disease), and 18q (type 2 diabetic nephropathy). Multicenter consortia are currently recruiting large numbers of multiplex diabetic families with index cases having nephropathy for linkage and association analyses. In addition, large-scale screening studies are underway, with the goals of better defining the overall prevalence of chronic kidney disease, as well as educating the population about risk factors for nephropathy, including family history. Given the overwhelming burden of kidney disease worldwide, it is imperative that we develop a clearer understanding of the pathogenesis of nephropathy so that individuals at risk can be identified and treated at earlier, potentially reversible, stages of their illness.
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PMID:Genetic factors in end-stage renal disease. 1575 39

Glomerular visceral epithelial cells (GEC) or podocytes are highly differentiated, specialized cells that play a key role in the maintenance of glomerular permselectivity. Injury of GEC, leading to proteinuria, contributes to the pathogenesis of human and experimental glomerulopathies. Recent studies have demonstrated that stress proteins may be induced and may be involved in the modulation of GEC injury. The C5b-9 membrane attack complex of complement induces GEC injury and proteinuria in the passive Heymann nephritis (PHN) model of membranous nephropathy. C5b-9 induces upregulation of the endoplasmic reticulum (ER) stress proteins, bip and grp94, in part, via activation of cytosolic phospholipase A2. These ER stress proteins limit complement-mediated GEC injury. In experimental nephropathy associated with hyperlipidemia, and in experimental diabetic nephropathy, there is an upregulation of the ER heat shock protein (Hsp) 47, a chaperone protein involved in the synthesis or assembly of collagens. Hsp47 expression in GEC is associated with increased deposition of collagen, and glomerulosclerosis. Hsp27, a stress protein involved in actin polymerization, is localized in GEC, and its expression and activation are increased in the rat puromycin aminonucleoside model of focal segmental glomerulosclerosis, and in PHN. Hsp27 may preserve actin structure, and facilitates survival in the context of injury. Development of methods to induce expression/activation of stress proteins may eventually lead to novel approaches to the therapy of GEC injury and proteinuria.
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PMID:Stress proteins in glomerular epithelial cell injury. 1591 24

Proteins are particularly attractive targets for product analysis, which is used to understand pathology. Protein modifications, such as advanced glycation end products (AGEs), serve as footprints of biochemical processes and also help in the search for novel agents that efficiently inhibit protein damage. Interestingly, several medical agents that are used clinically interfere with oxidative protein damage through different mechanisms characteristic of their chemical structures. We recently found that angiotensin II receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEIs) lower the in vitro formation of the AGEs pentosidine and carboxymethyllysine. Their inhibition for AGE formation is more striking than aminoguanidine. Unlike aminoguanidine, ARBs and ACEIs do not trap reactive carbonyl precursors of AGEs. Rather, they inhibit AGE formation, possibly as a result of their potent ability to scavenge hydroxyl radicals and to chelate the transition metals necessary for the Fenton reaction. We tested their AGE-lowering ability in vivo in a unique type-2 diabetic model with nephropathic SHR/NDmcr-cp rats, which exhibits the metabolic syndrome (obesity, hyperglycemia, hyperlipidemia, hyperinsulinemia) in addition to hypertension. Obesity and associated metabolic derangements, in addition to hypertension, markedly accelerate renal injury. Expectedly, correction of hyperglycemia and hyperinsulinemia partially but significantly improves renal injury. A low-calorie diet greatly improves renal injury despite persistent hypertension. Among antihypertensive agents, ARBs, unlike nifedipine and atenolol, are renoprotective despite persistent metabolic syndrome, but their action is independent of blood pressure lowering and is observed in a dose-dependent manner despite the complete blockade of angiotensin II receptor. Interestingly, the improvement of renal injury by ARBs as well as a low-calorie diet is associated with a significant reduction in local oxidative stress and AGE formation in the kidney. During the characterization of the AGE-lowering profile of our chemical compound libraries ( approximately 2000), we identified several inhibitors of oxidative stress and advanced glycation. They are indeed renoprotective, independently of correction of hypertension and metabolic syndrome, in experimental diabetic nephropathy and other nephritis models. Altogether, our data are in good agreement with the recent therapeutic concept for diabetic nephropathy that multiple risk factor interventions are critical in the treatment of diabetic renal injury, and further implicate a therapeutic potential of inhibition of oxidative stress and advanced glycation.
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PMID:From molecular footprints of disease to new therapeutic interventions in diabetic nephropathy. 1603 1

Hyperlipidemia and its treatment are currently recognized as important modulators of cardio-vascular mortality in the presence of disordered glucose control. On the other hand, the effects of hyperglycemia and its treatment on hyperlipidemia are not widely appreciated. Hyperglycemia is commonly associated with an increase in intestinal lipoproteins and a reduction in high-density lipoprotein (HDL). This could be a consequence of hyperglycemia-induced glycation of lipoproteins, which reduces the uptake and catabolism of the lipoproteins via the classical low-density lipoprotein (LDL) receptor. A high dietary carbohydrate load increases the glycation of intestinal lipoproteins, prolongs their circulation, and increases their plasma concentration. Hyperglycemia also leads to inhibition of lipoprotein lipase, further aggravating hyperlipidemia. Circulating advanced glycation end-products (AGEs) also bind lipoproteins and delay their clearance, a mechanism that has particularly been implicated in the dyslipidemia of diabetic nephropathy. As uptake via scavenger receptors is not inhibited, glycation increases the proportion of lipoproteins that are taken up via inflammatory cells and decreases the proportion taken up by hepatocytes via classical LDL receptors. This promotes the formation of atheromatous plaques and stimulates inflammation. Hyperglycemia increases the formation of oxidized LDL and glycated LDL, which are important modulators of atherosclerosis and cardiovascular death. The risk of cardiovascular death is increased by even short-term derangement of blood sugar control, owing perhaps to the glycation of lipoproteins and other critical proteins. Glycated LDL could prove very useful in measuring the effect of hyperglycemia on cardiovascular disease, its risk factors, and its complications. Comparing different glucose-lowering and lipid-lowering drugs in respect to their influence on glycated LDL could increase knowledge of the mechanism by which they alter cardiovascular risk.
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PMID:Hyperglycemia, lipoprotein glycation, and vascular disease. 1607 28

We aimed to investigate prognostic factors for a composite end-point of end-stage renal disease (ESRD) and the progression of renal disease in Japanese patients with chronic renal disease. Using a composite end-point comprising a doubling of serum creatinine (sCr), an increase in sCr level to 6.0 mg/dL, or initiation of dialysis and renal transplantation caused by ESRD, we examined data obtained in a prospective cohort study. The present study consisted of 641 patients who were 20 years of age or older with chronic renal disease caused by diabetic nephropathy, glomerulonephritis, or nephrosclerosis, and who had baseline sCr levels of 5.0 mg/dL or less. The following criteria were examined as prognostic factors: sex; age; elapsed time from initial diagnosis; disease underlying the nephropathy (diabetic or non-diabetic); complications with hypertension, hyperlipidemia, or anemia; baseline sCr level; therapeutic regimen, including use of ACE inhibitors or Ca2+ -channel blockers; and diet. A log-rank test was used for univariate analysis, and Cox regression analysis was used for multivariate analysis. Underlying disease (diabetic or non-diabetic), baseline sCr level, and Ca2+ -channel blocker therapy were significantly related to event incidence. In the present study, we identified underlying disease and baseline sCr level as important prognostic factors for a composite end-point in a predialysis patient population in both the early and middle stages of renal disease. These factors should be considered as balancing variables for randomization in future clinical studies.
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PMID:Prognostic factors for a composite end-point of renal outcomes in patients with chronic kidney disease. 1655 40

Genetic mouse models provide a unique opportunity to investigate gene function in the natural course of the disease. Although diabetic nephropathy (DN) in models of type II diabetes has been well characterized, diabetic renal disease in hypoinsulinemic diabetic mice is still incompletely understood. Here, we characterized renal changes in the pdx1(PB)-HNF6 transgenic mouse that exhibits beta-cell dysfunction and nonobese hypoinsulinemic diabetes. Male transgenic mice developed hyperglycemia by the age of 7 wk and survived for over 1 yr without insulin treatment. Diabetes ensued earlier and progressed more severely in the HNF6 males than the females. The HNF6 males exhibited albuminuria as early as 10 wk of age, and the urinary albumin excretion increased with age, exceeding 150 microg/24 h at 11 mo of age. Diabetic males developed renal hypertrophy after 7 wk of age, whereas glomerular hyperfiltration was not observed in the mice. Hypertension and hyperlipidemia were not observed in the diabetic mice. Histological analysis of the HNF6 kidneys displayed diabetic glomerular changes, including glomerular enlargement, diffuse mesangial proliferation and matrix expansion, thickened glomerular basement membrane, and arteriolar hyalinosis. Mesangial matrix accumulation increased with age, resulting in nodular lesions by 44 wk of age. Immunohistochemistry showed accumulation of type IV collagen and TGF-beta1 in the mesangial area. No significant immune complex deposition was observed in the HNF6 glomeruli. Thus the HNF6 mouse exhibits diabetic renal changes that parallel the early phase of human DN. The model should facilitate studies of genetic and environmental factors that may affect DN in hypoinsulinemic diabetes.
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PMID:Characterization of diabetic nephropathy in a transgenic model of hypoinsulinemic diabetes. 1670 46

The novel hypoglycemic agent, YM440 ((Z)-1,4-bis{4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl) methyl] phenoxy}but-2-ene) is a ligand of the peroxisome proliferator-activated receptor, (PPAR) gamma. YM440 has been shown to counteract insulin resistance in diabetic rodent models. However, it is not clear whether this compound has a significant effect on hyperlipidemia in vivo. Hyperlipidemia has been reported to be a risk factor for the early development of renal disease. The aim of this study is to examine the effects of chronic treatment with YM440 on hyperlipidemia and renal injury in obese Zucker fatty (ZF) rats. Treatment of 8-week-old ZF rats with YM440 (100 mg/kg/day) for 16 weeks decreased plasma triglyceride and cholesterol concentrations. YM440 markedly reduced the rate of progression of both albuminuria and proteinuria. YM440 normalized urinary N-acetyl-beta-D-glucosaminidase (NAG) activity, which is a marker for renal proximal tubular damage, and ameliorated the rise in systolic blood pressure compared to the vehicle control. YM440 also blocked the development of nephromegaly. Histological analyses revealed that both glomerular area expansion and tubular cast accumulation gradually lessened in YM440-treated ZF rats. Regression analyses between the plasma triglyceride levels and the renal parameters (urinary protein excretion and albumin excretion) indicated that the renal parameters correlated positively with the plasma triglyceride levels. In conclusion, the hypolipidemic effects of YM440 prevent renal injury in ZF rats. YM440 might be useful for preventing the early development of diabetic nephropathy in subjects with type 2 diabetes by ameliorating metabolic control problems.
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PMID:YM440, a novel hypoglycemic agent, protects against nephropathy in Zucker fatty rats via plasma triglyceride reduction. 1698 6

People with diabetes have an increased risk of developing microvascular complications, diabetic retinopathy, diabetic nephropathy and diabetic neuropathy, which, if undetected or left untreated, can have a devastating impact on quality of life and place a significant burden on health care costs. In addition, diabetic microvascular complications can reduce life expectancy. The strongest risk factors are glycaemic control and diabetes duration; however, other modifiable risk factors such as hypertension, hyperlipidaemia and smoking, and unmodifiable risk factors including age at onset of diabetes and genetic factors may all play a part. Along with the presence of external risk factors, some associations have also been noted between diabetic microvascular complications themselves. There is evidence that diabetic retinopathy in association with increased blood pressure is an important risk factor for diabetic nephropathy progression. Significant correlations have also been shown between the presence of diabetic peripheral neuropathy and the presence of background or proliferative diabetic retinopathy. Clinical trials are currently in progress looking at a number of approaches to designing treatments to prevent the adverse effects of hyperglycaemia. It is essential however, that risk factors associated with the progression and development of diabetic microvascular complications are detected and treated at an early stage in order to further reduce morbidity and mortality. Considering all three complications as interrelated may well facilitate early detection of microvascular disease. Despite good long-term glycaemic and blood pressure control, diabetes remains a major cause of blindness, renal failure and amputations. As the incidence of diabetes continues to rise, the burden of diabetic microvascular complications will increase in future, hence the need for early detection. Considering the microvascular complications of diabetes as related, and enquiring proactively about complications, may well facilitate early detection of microvascular disease.
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PMID:Diabetic microvascular complications: can patients at risk be identified? A review. 1707 42


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