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The precise pathogenesis of human diabetic kidney disease and the factors responsible for the susceptibility to it remain to be established. However, there is now evidence that renal disease clusters in families and that genetic factors are of central importance in determining liability. A predisposition to arterial hypertension has been suggested as playing a contributory role in the development of kidney disease. Genetically controlled hypertrophic processes may be implicated in the susceptibility to arterial wall damage and glomerular injury in diabetes. This suggestion derives from the observation that the fibroblasts of patients with diabetic nephropathy show a higher Na+/H+ antiport activity and a greater 3H-thymidine incorporation into DNA than fibroblasts of diabetic patients without nephropathy. The first sign of renal damage is the appearance of microalbuminuria and of a small elevation in arterial pressure, changes associated with significant mesangial expansion. Microalbuminuria is associated with abnormalities of lipoprotein profiles possibly as a consequence of insulin-resistance-induced hyperinsulinemia. It could be postulated that the environmental changes brought about by diabetes lead in susceptible individuals to increased systemic and intraglomerular pressure on the one hand and mesangial expansion on the other. These two processes would cause proteinuria and glomerulosclerosis. Lipid abnormalities would further aggravate the renal histological damage and, in combination with hypertension, contribute to the accelerated atherosclerosis typical of patients with diabetic kidney disease. A vicious circle would thus be triggered of reduction in renal function, more hypertension, more proteinuria, more glomerular obsolence, more hyperlipidemia and eventually end-stage renal failure or premature cardiovascular death.
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PMID:Mechanisms of diabetic renal and cardiovascular disease. 207 90

The initial treatment in the past of diabetes was one "of trial and error" as easily understandable. Carbohydrate restriction and their replacement by fats was followed, happily, last century already, by global caloric restriction. Around the fourties, after the introduction of insulin in 1922, the principle of the carbohydrate tolerance was introduced as an objective+ measure, followed by the proposal of "bread equivalencies" in the dietetic practice, assuring in this manner a figured evaluation. Around the seventies years the diet fiber came into its own and seemed very important for the evolution of the postprandial glycemia and insulinemia. Next to this, complex polysaccharides looked also of prime impact on this two biochemical parameters. The nature of this complex character is due to their liaison with other diet components (lectins, phytins, tannins etc.). So the concept of the glycemic index was born which explains why next to the presence of a given carbohydrate quantity the evolution of the glycemia is different from what is expected, just because the absorption is accelerated or retarded by the structure or the manipulation of these polysaccharides. This novel data are so much the more important because actually the hyperglycemia on the long run seems so important for the development of micro-angiopathy, at the base of the famous diabetic triad (nephropathy, retinopathy, neuropathy). The hyperlipemia is also beneficially influenced by the diet fiber and at the same level by the complex polysaccharides. All this statements are at the base of novel ways for the dietetic treatment of diabetes, as well on the quantitative as on the qualitative level and equally so for the diabetes of type I as of type II.
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PMID:[Diet treatment of the diabetic patient: yesterday and today. What has changed? What can be learned from it?]. 208 51

Chronic diseases of the kidney are characterized by progression once a certain portion of renal function is lost. End-stage kidneys, the result of progressive chronic renal disease, are characterized by sclerosis, tubulointerstitial scarring, and collapse of glomerular capillary tufts. The mechanisms and risk factors responsible for the progression of renal disease have been studied intensively in the past decade, and it now appears that multiple nonimmunologic factors are responsible. These factors include systemic hypertension, hyperlipidemia, proteinuria, excessive intake of protein, and adaptive changes in nephron function as a consequence of nephron loss. The latter adaptations, increased intraglomerular pressure, increased excretion of ammonia, "hypermetabolism," decreased afferent arteriolar tone, and renal hypertrophy, may also be responsible for the progression of renal disease. A complete understanding of the factors responsible for the progression of renal disease should permit rational development of appropriate therapeutic interventions.
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PMID:Progression of chronic renal disease. 213 99

The role of specific risk factors in the development of diabetic nephropathy was examined among noninsulin-dependent diabetic subjects attending the Diabetes Clinic of Christian Medical College Hospital, Vellore during 1986-87. Seventy-three subjects with normal protein excretion (less than 150 mg/24 hr) were compared with 66 microproteinuric (150-500 mg/24 hr) and 61 macroproteinuric subjects (greater than 500 mg/24 hr). The risk factors included family history of diabetes, tobacco use, dietary habits and metabolic control; the latter was assessed from an average of 5 clinic blood sugar determinations done annually per patient. Patients who had developed proteinuria were characterized as mostly men, with increased tobacco consumption and early onset of proteinuria in relation to duration of diabetes. The mean blood sugar value was significantly high in both the proteinuric groups compared to the group with no proteinuria (p less than 0.01). There was a striking increase in the prevalence of ischemic heart disease, hypertension and retinopathy in the macroproteinuric group compared to the other two groups (p less than 0.01). It is concluded that the risk of developing nephropathy was significantly higher in men, in smokers and in those with poor metabolic control (mean postprandial blood sugar more than 200 mg/dL). Furthermore, it was clearly evident from our study that the diabetic subjects with nephropathy had a higher incidence of hypertension, retinopathy, hyperlipidemia and ischemic heart diseases.
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PMID:Nephropathy in noninsulin-dependent diabetes mellitus: comparative study with normoproteinuric and microproteinuric subjects. 214 34

Nephron loss is a common progression of a diverse range of kidney diseases. Recent experimental models of chronic renal disease have suggested that hemodynamic and nonhemodynamic mechanisms play key roles in progressive renal injury. Extensive renal ablation in the rat was followed by development of altered glomerular hemodynamics. Albuminuria and histologic damage leading to focal glomerulosclerosis were preceded by the development of increased glomerular pressures and were prevented by interventions such as severe dietary protein restriction and angiotensin-converting enzyme (ACE) inhibitor therapy. Both experimental interventions ameliorated glomerular hypertension. It was therefore concluded that these interventions ameliorated injury by glomerular hemodynamic effect. Similar findings were obtained in a rat model of type I diabetes mellitus induced by streptozotocin in which glomerular hemodynamic factors appeared important to the development of progressive renal disease. Recent studies have suggested that nonhemodynamic factors have important roles in the progression of glomerular injury. For example, although the predominant effects of ACE inhibitor therapy appear to be hemodynamically mediated, data are emerging which suggest that these agents may also influence growth/proliferation of glomerular cells. Because hyperplasia/hypertrophy may influence glomerular susceptibility to injury, this may also be a potential mechanism whereby ACE inhibitor therapy influences glomerular damage. In addition, a variety of studies have suggested that hyperlipidemia, which is frequent accompaniment of glomerular disease, is an important modulator of glomerular injury independent of glomerular hemodynamic effects. Coagulation factors, calcium phosphorus balance, as well as the genetic susceptibility of the glomerulus to injury, all appear to contribute to progressive nephron destruction.
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PMID:Renal protective effects of angiotensin-converting enzyme inhibition. 218 11

Part I of this article, which appeared in the previous issue of the Journal, discussed the implications of variations in plasma protein levels in a number of diseases: hepatic and renal disease, acute myocardial infarction, burns, cancer, diabetes mellitus, hyperlipidaemia and inflammatory diseases. In Part II the authors continue their review with a further range of disease states, and consider their import for drug dosages.
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PMID:Disease-induced variations in plasma protein levels. Implications for drug dosage regimens (Part II). 220 81

Hypertension and diabetes mellitus are chronic medical conditions that frequently coexist. In the United States, it is estimated that 10 million persons suffer from diabetes mellitus, 60 million from hypertension, and 3 million from the combination of the two. There may be a causal relationship between hypertension and diabetes. Obesity may be a precipitating factor for both hypertension and non-insulin-dependent diabetes mellitus. Those with insulin-dependent diabetes mellitus generally become hypertensive only with the onset of nephropathy. Glucose tolerance, insulin resistance, and hyperinsulinemia frequently occur with essential hypertension and may be aggravated by hypertension therapy, especially with diuretics and beta-blockers. Hyperinsulinemia may be an important common factor promoting sodium retention, sympathetic nervous system stimulation, and inhibition of the sodium pump. The Working Group on Hypertension in Diabetes has outlined a flexible modified version of the stepped-care approach to the treatment of hypertension in diabetes. Management is complex because diabetes is associated with autonomic neuropathy, sexual dysfunction, hyperlipidemia, and fluid and electrolyte disorders. All these problems can be exacerbated by antihypertensive treatment. Nonpharmacologic measures, which address weight reduction and sodium restriction, are logical, but aggressive antihypertensive medication is invariably necessary. Diuretics and/or beta-blockers were the mainstay of treatment until the introduction of angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers. These newer agents have no deleterious effects on carbohydrate metabolism and are generally better tolerated. Antihypertensive therapy may slow the rate of deterioration in diabetic nephropathy. This was first shown with diuretics, beta-blockers, and hydralazine and more recently with ACE inhibitors, which provide effective blood pressure control and a significant drop in albuminuria without affecting the glomerular filtration rate adversely. ACE inhibition may also lead to increased insulin sensitivity and glucose disposal rate. Long-term trials are needed to assess the effects of these new agents on the treatment of hypertension in the diabetic population.
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PMID:Diabetes mellitus and hypertension. 222 Jul 97

Hyperglycemia is only one of several metabolic derangements that are prevalent in diabetes mellitus. Of these, hyperlipidemia, obesity, and co-existent hypertension may make more important contributions to complications than persistently elevated blood sugars. The role of hyperglycemia in the genesis of diabetic complications is uncertain and there is little evidence from prospective randomized controlled studies to support rigorous hypoglycemic treatment. Adverse consequences of pharmacologic therapy can be severe, including death, and are most frequent in the elderly. The group of elderly diabetic ambulatory patients is markedly heterogeneous and individualization of therapy is required. Obese persons require dietary therapy, and additional dietary manipulations are needed for patients with the complications of hyperlipidemia, hypertension, and nephropathy. Pharmacologic hypoglycemic therapy may be required to control symptoms, but its use in asymptomatic diabetic persons is for the most part unwarranted.
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PMID:Glycemic control in elderly people with diabetes. 222 56

Chronic renal disease is a progressive process. Implicated factors include abnormalities of the clotting cascade, altered prostaglandin metabolism, increased dietary protein intake, and abnormalities of lipoprotein metabolism. Several animal models have associated increased serum concentrations of cholesterol and triglycerides with progressive decline in renal function. The mechanism(s) of lipid-associated renal injury are unknown but may relate to lipid uptake by glomerular mesangial cells, hyperviscosity secondary to the hyperlipidemia, and a direct effect of the lipids on the glomerular basement membrane. Patients with chronic renal disease have well recognized increases in serum lipid concentrations. Whether lowering these concentrations will delay or prevent progressive renal failure or renal histologic abnormalities is unknown, but studies are underway to evaluate the effect of lipid-lowering agents in patients at risk for chronic progressive renal disease.
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PMID:Lipoprotein abnormalities in the progression of renal disease. 222 43

Normotensive rats of the Milan strain (MNS) spontaneously develop focal glomerulosclerosis. In order to explore the contribution of glomerular thromboxane (TX) A2 synthesis to the development of the disease, we have characterized the time course of renal functional and biochemical changes, and their modification by long-term treatment with a TX-synthase inhibitor. Oral administration (150 mg.kg-1 from 1 to 14 months of age) of FCE 22178 suppressed enhanced glomerular TXB2 production at all experimental times (mean inhibition 80%) and proteinuria (varying between 27.1 and 73.0%) while preserving renal blood flow and glomerular filtration rate. These effects of TX-synthase inhibition were seen in the absence of any statistically significant changes in systemic blood pressure. Moreover, FCE 22178 had no antihypertensive effects in hypertensive rats of the Milan strain (MHS) nor in spontaneously hypertensive rats (SHR). Treatment also prevented the age-related hypoalbuminemia and hyperlipidemia observed in control MNS and significantly (P less than 0.01) reduced glomerular histologic damage, as demonstrated by light microscopy studies and measurement of sclerotic area. We conclude that: 1) MNS rats provide an animal model of long-lasting proteinuria characterized by an age-related increase in glomerular TXB2 production paralleled by progressive loss of renal structural integrity and function and by a secondary dyslipidemia; 2) pharmacological inhibition of glomerular TX-synthase attenuates the structural as well as the functional expression of kidney disease, without a primary effect on systemic blood pressure. These data are suggestive of an important modulating role of TXA2 in the progression of MNS renal disease.
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PMID:Role of enhanced glomerular synthesis of thromboxane A2 in progressive kidney disease. 223 87


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