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Diabetes and arterial hypertension continue to be the main causes of chronic renal failure in 2010, with a rising prevalence in part due to the worldwide obesity epidemic. Proteinuria is a main feature of chronic renal disease and mediated by defects in the glomerular filtration barrier and is as a good predictor of cardiovascular events. Indeed, chronic renal disease due to glomerulosclerosis is one of the important risk factors for the development of coronary artery disease and stroke. Glomerulosclerosis develops in response to inflammatory activation and increased growth factor production. Preclinical and first preliminary clinical studies provide strong evidence that endogenous endothelin-1 (ET-1), a 21-amino-acid peptide with strong growth-promoting and vasoconstricting properties, plays a central role in the pathogenesis of proteinuria and glomerulosclerosis via activation of its ET(A) subtype receptor involving podocyte injury. These studies have not only shown that endothelin participates in the disease processes of hypertension and glomerulosclerosis but also that features of chronic renal disease such as proteinuria and glomerulosclerosis are reversible processes. Remarkably, the protective effects of endothelin receptors antagonists (ERAs) are present even on top of concomitant treatments with inhibitors of the renin-angiotensin system. This review discusses current evidence for a role of endothelin for proteinuric renal disease and podocyte injury in diabetes and arterial hypertension and reviews the current status of endothelin receptor antagonists as a potential new treatment option in renal medicine.
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PMID:Therapeutic potential of endothelin receptor antagonists for chronic proteinuric renal disease in humans. 2035 30

Obesity is fast becoming a bane for the present civilization, as a result of sedentary lifestyle, atherogenic diet, and a susceptible thrifty genotype. The concept of metabolic syndrome, which is a constellation of metabolic disturbances, has crystallized over the last 80 years with the aim of identifying those at greater risk of developing type 2 diabetes and cardiovascular disease. These patients have visceral obesity and insulin resistance characterized by hypertyriglyceridemia. Recently, it has been realized that they are also at an increased risk of chronic renal disease. Release of adipocytokines leads to endothelial dysfunction. There is also activation of systemic and local renin-angiotensin-aldosterone system, oxidative stress, and impaired fibrinolysis. This leads to glomerular hyperfiltration, proteinuria, focal segmental glomerulosclerosis (FSGS), and ultimately end-stage renal disease (ESRD). Treatment consists of lifestyle modifications along with optimal control of blood pressure, blood sugar and lipids. Metformin and thiazolidenidiones reduce insulin resistance; while angiotensin converting enzyme inhibitors and angiotensin receptor blockers reduce proteinuria and have a renoprotective effect. Exciting new medical therapies on the horizon include rimonabant a cannabinoid receptor type 1 antagonist, soy proteins, and peroxisome proliferator-activated receptor (PPAR) agonist. Bariatric surgery for morbid obesity has also been shown to be effective in treating metabolic syndrome.
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PMID:Metabolic syndrome and chronic kidney disease. 2036 11

We present here the anatomy and histopathology of kidneys from 11 patients with renal stones following small bowel resection, including 10 with Crohn's disease and 1 resection in infancy for unknown cause. They presented predominantly with calcium oxalate stones. Risks of formation included hyperoxaluria (urine oxalate excretion greater than 45 mg per day) in half of the cases, and acidic urine of reduced volume. As was found with ileostomy and obesity bypass, inner medullary collecting ducts (IMCDs) contained crystal deposits associated with cell injury, interstitial inflammation, and papillary deformity. Cortical changes included modest glomerular sclerosis, tubular atrophy, and interstitial fibrosis. Randall's plaque (interstitial papillary apatite) was abundant, with calcium oxalate stone overgrowth similar to that seen in ileostomy, idiopathic calcium oxalate stone formers, and primary hyperparathyroidism. Abundant plaque was compatible with the low urine volume and pH. The IMCD deposits all contained apatite, with calcium oxalate present in three cases, similar to findings in patients with obesity bypass but not an ileostomy. The mechanisms for calcium oxalate stone formation in IMCDs include elevated urine and presumably tubule fluid calcium oxalate supersaturation, but a low calcium to oxalate ratio. However, the mechanisms for the presence of IMCD apatite remain unknown.
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PMID:Renal histopathology and crystal deposits in patients with small bowel resection and calcium oxalate stone disease. 2042 98

A 31-yr-old Japanese man with end-stage kidney disease caused by primary focal segmental glomerulosclerosis (FSGS) underwent living related kidney transplantation at the age of 26 yr. The allograft functioned well immediately after surgery, and we did not observe histological findings of rejection and recurrent FSGS in protocol biopsies at two months and one yr after transplantation. Four years after transplantation, the urine protein excretion reached 11 g/d, and the serum creatinine increased over 2.5 mg/dL. We diagnosed nephrotic syndrome due to recurrent FSGS with graft dysfunction and confirmed FSGS lesions with severe endothelial injury with an allograft biopsy, associated with calcineurin inhibitor (CNI) nephrotoxicity. Thereafter, we performed plasmapheresis and steroid therapy with subsequent low-density lipoprotein adsorption, combined with the reduction of tacrolimus. The nephrotic syndrome improved dramatically with the multiple therapeutic approaches. Primary FSGS recurs frequently in patients immediately after kidney transplantation. Post-transplant FSGS has various causes, such as recurrent primary disease, obesity, hyperfiltration, donor-related nephrosclerosis, and CNI-induced arteriolopathy. In the case of nephrotic syndrome after kidney transplantation, we should consider not only recurrent FSGS, but also CNI-induced nephrotoxicity to determine the optimal treatment.
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PMID:Successful treatment of recurrent focal segmental glomerulosclerosis combined with calcineurin inhibitor nephrotoxicity four yr after kidney transplantation. 2059 Jun 95

The worldwide prevalence of obesity and its associated metabolic and cardiovascular disorders has risen dramatically within the past 2 decades. Our objective is to review the mechanisms that link obesity with altered kidney function. Current evidence suggests that excess weight gain may be responsible for 65-75% of the risk for arterial hypertension. Impaired renal pressure natriuresis, initially due to increased renal tubular sodium reabsorption, is a key factor linking obesity with hypertension. Obesity increases renal sodium reabsorption by activating the renin-angiotensin and sympathetic nervous systems, and by altering intrarenal physical forces. Adipose tissue functions as an endocrine organ, secreting hormones/cytokines (e.g., leptin) which may trigger sodium retention and hypertension. Additionally, excess visceral adipose tissue may physically compress the kidneys, increasing intrarenal pressures and tubular reabsorption. Eventually, sustained obesity via hyperinsulinemia, due to resistance to insulin, causes hyperfiltration, resulting in structural changes in the kidneys--glomerular hyperthrophy and occasionally focal segmental glomerulosclerosis. The consequences of kidney injury are continuous loss of glomerular filtration rate, further increase of arterial pressure and escalation of cardiovascular morbidity and mortality. There is a growing awareness of the renal consequences of obesity, and considerable progress is being made in understanding its pathophysiology. Weight reduction results in lowered proteinuria. Aside from low sodium diet and exercises, more widespread use of renoprotective therapy (e.g., ACE inhibitors and statins) in treatment of hypertension in obese subjects should be advocated. Renal protection should result in reducing the cardiovascular complications of obesity.
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PMID:Renal consequences of obesity. 2088 59

Obesity is a common contributing factor to the development of chronic kidney disease (CKD). Obesity participates in the genesis of CKD by predisposing to diabetic nephropathy, hypertensive nephrosclerosis, and focal and segmental glomerular sclerosis. It also predisposes to calcium oxalate and urate stones. Additionally, obesity is associated with an increased prevalence and magnitude of proteinuria and a more rapid progression to CKD. There are many mechanisms by which obesity alters renal physiology and metabolism. More effective methods for treating obesity and preventing the development and progression of obesity-associated CKD are clearly needed. Therefore, there is a greater need for a better understanding of the causes of the excessive energy intake that leads to obesity and the mechanisms responsible for the refractoriness of obese individuals to treatment.
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PMID:Obesity and chronic kidney disease. 2079 67

This review of 2,586 renal biopsies over the past 3 decades in Singapore documents the changing pattern of glomerulonephritis (GN) from that of a third world country to that of a developed nation. In the 1st decade, mesangial proliferative glomerulonephritis was the most common form of primary GN, just as it was in the surrounding Asian countries. In the 2nd decade, the prevalence of mesangial proliferative GN decreased with a rise in membranous, GN which is also seen in China and Thailand. In the 3rd decade, there was a dramatic increase in focal sclerosing glomerulosclerosis. This increase reflects aging and obesity in keeping with more developed countries like Australia, India, Thailand and the United States of America. IgA nephritis remains the most common GN. Apart from the geographical influence, other socioeconomic factors play a significant role in the evolution of the renal biopsy pattern. Mesangial proliferative GN remains prevalent in many Asian countries, but in Singapore the prevalence is decreasing just as it is in Japan, Korea and Malaysia. Worldwide, the prevalence of focal sclerosing glomerulosclerosis continues to increase in many countries.
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PMID:The changing pattern of primary glomerulonephritis in Singapore and other countries over the past 3 decades. 2097 46

Obesity is a risk factor for both de novo disease and as a complication of existing chronic kidney disease. Obesity related disease is characterized by albuminuria, glomerulomegaly and secondary focal glomerulosclerosis. Traditionally altered renal hemodynamics causing hyperfiltration and upregulated renin angiotensin system have been associated with these changes. Recently identified circulating factors produced by fat stores such as adiponectin, leptin and inflammatory markers have shown to directly affect the cells in the renal glomeruli and cause pathological changes. Weight loss, blockade of the renin angiotensin system and restoration of adipokine levels may be beneficial to ameliorate the progression of obesity related disease.
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PMID:Obesity related kidney disease. 2106 8

Overweightness and obesity are associated with many hemodynamic, structural, and histopathologic alterations in the kidney and with metabolic and biochemical changes that predispose to these abnormalities. Consequent to these disorders, these individuals are more likely to develop chronic kidney disease and end-stage renal failure. Overweight and obese people are more prone to develop albuminuria and, for at least some types of kidney disease, a greater amount of albuminuria and more rapid progression of renal failure. These individuals are more likely to develop diabetes mellitus and hypertension. Diabetic nephropathy, hypertensive nephrosclerosis, focal and segmental glomerulosclerosis, renal cell carcinoma, and urate and calcium oxalate urolithiasis are the more common kidney and urological diseases reported in obese people. Preliminary data indicate that many of the clinical and nephropathologic manifestations associated with obesity can be reversed or ameliorated with reductions in body fat induced by dietary energy restriction or surgical procedures that reduce intake and gastrointestinal absorption of calories.
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PMID:The effect of obesity on chronic kidney disease. 2119 23

The steady increase in the prevalence of obesity contributes to the increase in the prevalence of chronic kidney disease, through renal damages associated with type-2 diabetes and hypertension. Obesity is also an independent risk factor for the kidney, since it is associated with an increased risk of albuminuria and glomerulosclerosis, and worsens the course of chronic kidney disease regardless of the primary renal disease. The existence of a metabolic syndrome, constant in type-2 diabetes, and associated with abdominal obesity, is not the only requirement for renal anomalies of which the translation is a functional hyperfiltration, a clinical microalbuminuria and histologically a glomerulomegaly and glomerulosclerosis. The estimated glomerular filtration rate (GFR) in obese patients is strongly influenced by the weight or indexation to body surface area, and it is logical to take into account the value of non-indexed GFR to assess renal risk and treatment effects, especially if they lead to weight loss. Hypertension is promoted by salt sensitivity, potentially reversible, and overactivity of the renin-angiotensin system (RAS) in part due to adipose tissue. The cytokines secreted by adipose tissue (adipokines), induce sympathetic hyperactivity through leptin, and low-grade inflammatory state that contributes to the development of glomerular sclerosis lesions, especially because a resistance to adiponectin. The treatment relies on weight loss, possibly through bariatric surgery, and antagonists of the RAS.
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PMID:[Renal consequences of obesity]. 2120 37


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