Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
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Traditionally, microvascular disease resulting in a glomerulopathy and an increase in albumin excretion rate (AER) is believed to be the only significant mechanism by which diabetic renal disease develops. However, recent results have challenged the concept that a decline in renal function in patients with diabetes is always accompanied by an increased AER. This has led to the concept that subjects with diabetes, especially those with type 2 diabetes, can progress to renal impairment via either an albuminuric or non-albuminuric pathway. The natural history, renal morphological changes and exaggerated cardiovascular risk associated with the albuminuric-pathway to renal impairment have been well documented. Interventions to attenuate the progression of this pathway, especially inhibition of the renin-angiotensin system (RAS), are also a routine part of clinical practice. Subjects who follow the albuminuric pathway are detected by screening for the presence of microalbuminuria. The finding of microalbuminuria in this setting should provoke an intensified modification of the common risk factors for renal and cardiovascular disease, i.e. hyperglycemia, hypertension, dyslipidemia and smoking. In contrast, little is known about the natural history and structural basis of the non-albuminuric pathway to renal impairment and the best way to retard its progression is also not known. The prevalence of impaired renal function and normoalbuminuria is relatively common and in subjects with type 2 diabetes is at least 20% after accounting for the use of RAS inhibitors. It is therefore recommended that screening for diabetic renal disease should include an estimation of glomerular filtration rate (GFR) in addition to measuring AER. This will allow the detection of subjects following either an albuminuric or non-albuminuric pathway to renal impairment.
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PMID:Albuminuric and non-albuminuric pathways to renal impairment in diabetes. 1620 6

Diabetes mellitus and arterial hypertension are the leading causes of end-stage renal disease in industrialized countries. Although attention has focused on renal disease and insulin-dependent diabetes mellitus (type 1 diabetes), a silent epidemic of renal disease caused by type 2, noninsulin-dependent diabetes mellitus is rapidly developing. The course of renal function is heterogeneous in type 2 diabetic patients and reflects heterogeneous patterns of renal lesions. A subset of patients with microalbuminuria and proteinuria is characterized by the typical diabetic glomerulopathy usually observed in type 1 diabetic patients, with altered albumin excretion rate (AER), for example, glomerular basement membrane thickening and mesangial fractional volume expansion. These patients also have diabetic retinopathy and rapidly lose renal function despite tight blood pressure control. In contrast, a second subset of type 2 diabetic patients has normal or near-normal patterns of glomerular structure, despite abnormalities of AER comparable to those of the patients with diabetic glomerulopathy. Thus abnormalities of AER have a different renal prognostic value depending on the underlying renal structure. The patients with worse clinical prognosis and typical diabetic glomerulopathy also have diabetic retinopathy, whereas those with a better course of renal function quite often have no diabetic retinopathy. Several findings, albeit not unanimous, suggest that HbA1c levels above 7.5 to 8.0 % are closely associated with a rapid decay of renal function in type 2 diabetes. Tight blood pressure control plays a further important role in determining the progression of renal a damage in type 2 diabetes mellitus. Convincing evidence has been provided that drugs capable of inhibiting the renin-angiotensin hormonal system are quite effective in preventing and delaying the evolution of renal damage in both type 1 and 2 diabetes. Equally strong data support the view that other antihypertensive compounds such as beta-blockers and calcium antagonists also delay the progression of renal damage in diabetes mellitus. Whatever the drug used to treat hypertension, the majority of the authors conclude that blood pressure levels should be maintained below 130/85 mmHg in diabetic patients. While it is well established that uncontrolled diabetes underlies the development of diabetic nephropathy, newer evidence suggests that genetically determined susceptibility to hyperglycemia-caused glomerular injury is also necessary. More information on this issue will help to design new therapeutical approaches to treat hypertension and renal complications in type 2 diabetes.
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PMID:Hypertension and renal complications in type 2 diabetes. 1622 1

Excess body weight may be associated with various functional/structural lesions of the kidney. The spectrum ranges from glomerulomegaly with or without focal or segmental glomerulosclerosis, to diabetic nephropathy, to carcinoma of the kidney and nephrolithiasis. The first sign of renal injury is microalbuminuria or frank proteinuria, in particular in the presence of hypertension. The occurrence of microalbuminuria and/or chronic kidney insufficiency (glomerular filtration rate < 60 mL/min/1.73 m2) is related to the increasing number of components of the metabolic syndrome, ie, central obesity, elevated fasting blood glucose level, hypertriglycerides, low high-density lipoprotein cholesterol, and hypertension. In the long run, end-stage renal failure may develop. An increased body mass index is particularly harmful in patients with reduced renal functional mass (unilateral renal agenesis or nephrectomy) and other renal diseases (immunoglobulin A nephritis and chronic graft dysfunction after kidney transplantation). In the pathogenesis of obesity-associated glomerulopathy, hyperfiltration is of fundamental importance. The factors involved are energy intake (high protein and salt), hyperinsulinemia, and enhanced tubuloglomerular feedback because of increased sodium reabsorption. The adrenergic and renin-angiotensin-aldosterone systems as well as glucocorticoids are stimulated. In addition, several active proteins generated in the central adipose tissue, such as leptin, proinflammatory cytokines, plasminogen activator inhibitor-1, angiotensinogen, and growth factors (transforming growth factor-beta1), as well as low levels of the protective adiponectin, may contribute to renal injury. Of greatest importance is the development of hypertension and of diabetes, which are directly related to the severity of central obesity. Obesity-associated renal disease should be prevented or retarded by weight reduction following lifestyle modification (salt restriction, hypocaloric diet, aerobic exercise), or eventually by antiobesity medication or bariatric surgery. In the presence of glomerulopathy and/or hypertension, angiotensin converting enzyme inhibitors or angiotensin II type I receptor blockers are the drugs of choice to improve glomerular hyperfiltration.
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PMID:Renal disease in obesity: the need for greater attention. 1682 23

The level of proteinuria is one of the most determinant risk factors for the progression of proteinuric renal diseases. Several studies have shown that weight loss, either induced by low calorie diets, physical exercise, or bariatric surgery is accompanied by an important antiproteinuric effect. Reduction in proteinuria is already observed after a few weeks from the onset of weight loss and it is evident even in patients with modest weight losses. The magnitude of body weight loss and proteinuria decrease show a significant correlation. Reduction in proteinuria by weight loss has been described in obesity-induced glomerulopathy, obese diabetic patients and overweight or obese patients with different types of chronic proteinuric nephropathies. Attenuation of the obesity-induced glomerular hyperfiltration, decrease in the activity of renin-angiotensin-aldosterone system and modifications in the serum concentrations of adipocyte-derived cytokine are likely to be involved in the anti-proteinuric effect of weight loss, together with a better control of blood pressure, and improvement of serum lipid profile and insulin sensitivity.
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PMID:Weight loss and proteinuria. 1692 45

The hypertensive rat strain transgenic for the mouse Ren-2 renin gene (TGR) strain name TGR [mRen 2] 27 is a valuable monogenic model of renin-dependent and thus angiotensin II dependent hypertension. It carries a salt -sensitive component. Homozygous animals exhibit clinically and morphologically typical sings of fulminant hypertension. Glomerular changes in accelerated (malignant) hypertension are acute or chronic. The acute changes have focal character; the most obvious change is segmental fibrinoid necrosis. Fibrinoid necrosis may extend from a similar lesion in the afferent arteriole and may be associated with crescent. Chronic changes are of two different types. The first is similar to that seen in benign hypertension, in that there is collapse of the capillary tuft with wrinkling of the glomerular basement membrane accompanied by collagenization of Bowmann's space. In the second type, glomeruli are also collapsed but seem almost acellular. Male heterozygous TGR are more suitable for experiments because their hypertension is lower and this model is much more similar to clinical situation. Morphologically prominent hyalinosis and segmental sclerotisation of capillary tuft of some glomeruli is present. These features correspond to secondary form of focal segmental glomerulosclerosis (FSGS). High salt diet in heterozygous animals induces a transition from benign to malignant phase of hypertension. In such case ischemic changes are superimposed on the pre-existing renal parenchymal disease (secondary FSGS). Selective blockade of endothelin receptors ET(A) is superior to non-selective ET(A)/ET(B) blockade in attenuating of hypertension and also morphology. ET receptor blockade in homozygous and heterozygous TGR has similar effect on morphological structure of renal parenchyma applied in rats with established hypertension as in young animals. Podocyte injury is crucial also in experimental hypertensive glomerulopathy. Podocytes showed degenerative changes and thickening of glomerular basement membrane was also present. Degree of morphological podocyte injury rather than hypertension correlated with mortality in homozygous TGR.
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PMID:[Morphological characteristic of renal injury in hypertensive rat strain transgenic for the mouse Ren-2 renin gene (TGR [mRen2] 27]. 1769 84

Fibrillary glomerulonephritis belongs to a group of disorders characterized by pathogenic deposition of fibrils in glomeruli. This glomerulopathy tends to progress to end-stage kidney disease, and there currently are no treatments of proven benefit, including corticosteroids and cytotoxic agents. Because the glomerular deposits contain an immunoglobulin component, it was postulated that anti-B-cell therapy with rituximab, an anti-CD20 monoclonal antibody, may be effective in the treatment of patients with fibrillary glomerulonephritis. We describe 3 patients with fibrillary glomerulonephritis who were treated with rituximab for nephrotic-range proteinuria. Each patient also received standard antiproteinuria therapy, including blockade of the renin-angiotensin system and strict blood pressure control. All patients showed a decrease in proteinuria to less than 1.5 g/d of protein by 27 months, and kidney function was preserved throughout the duration of therapy and follow-up. No adverse effects were seen with rituximab. These outcomes suggest that treatment with rituximab may be a promising approach to the management of fibrillary glomerulonephritis, an entity previously considered refractory to therapy.
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PMID:Rituximab treatment of fibrillary glomerulonephritis. 1882 85

Obesity-related glomerulopathy (ORG) is a secondary form of focal and segmental glomerulosclerosis (FSGS) occurring in severely obese patients. A significant percentage of individuals with ORG will develop renal insufficiency or end stage renal disease. We report here a 17-year-old girl with morbid obesity (body mass index 56.8 kg/m(2)) and ORG presenting with nephrotic range proteinuria, who failed to improve following treatment with diet, exercise and angiotensin-converting enzyme inhibitor (ACEi)/angiotensin receptor blocker (ARB) therapy. Laparoscopic gastric bypass surgery was performed, and within 2 weeks following the surgery, the patient had lost 5.7 kg body weight and showed a remarkable decrease in protein excretion to one tenth of pre-surgery levels. More than 1 year after surgery, the patient's urine protein and kidney function have remained normal while off renin-angiotensin system inhibition therapy. This is the first report of successful use of gastric bypass surgery for obesity-related glomerulopathy in an adolescent. We propose that gastric bypass surgery be considered for patients with ORG.
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PMID:Obesity-related focal and segmental glomerulosclerosis: normalization of proteinuria in an adolescent after bariatric surgery. 1894 98

Immunoglobulin A (IgA) nephropathy is recognized worldwide as the most common primary glomerulopathy. Although the mechanisms underlying the development of IgA nephropathy are gradually being clarified, their details remain unclear, and a radical cure for this condition has not yet been established. It has been clinically demonstrated that the immunoreactivities of intrarenal heme oxygenase-1 (HO-1) and 4-hydroxy-2-nonenal (4-HNE) markers of reactive oxygen species (ROS) and those of intrarenal angiotensinogen (AGT) and angiotensin II (Ang II) markers of renin angiotensin system (RAS) in IgA nephropathy patients were significantly increased as compared to those of control subjects. In an animal study, high IgA of ddY (HIGA) mice were used as an IgA nephropathy model and compared with BALB/c mice, which served as the control. The levels of markers for ROS (urinary 8-isoprostane and intrarenal 4-HNE), RAS (intrarenal AGT and Ang II), and renal damage in the HIGA mice were significantly increased as compared to those in the BALB/c mice. Moreover, an interventional study using HIGA mice demonstrated that the expressions of 2 lines of intrarenal ROS markers (4-HNE and HO-1), 2 lines of intrarenal RAS markers (AGT and Ang II) and renal damage decreased significantly in HIGA mice receiving treatment with the Ang II receptor blocker olmesartan but not in HIGA mice receiving treatment with RAS-independent antihypertensive drugs (hydralazine, reserpine, and hydrochlorothiazide) when compared with HIGA mice that were not treated. These data suggest that intrarenal ROS and RAS activation plays a pivotal role in the development of IgA nephropathy.
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PMID:Activated intrarenal reactive oxygen species and renin angiotensin system in IgA nephropathy. 1941 26

1. Although IgA nephropathy is the most common form of primary glomerulopathy, the detailed mechanisms underlying its development remain uncertain. 2. In the present study, we used male high IgA strain of ddY (HIGA) mice as the IgA nephropathy model and age-matched male BALB/c mice as the control. Recent studies have demonstrated that reactive oxygen species (ROS)-dependent enhancement of the renin-angiotensin system (RAS) plays a potential role in the development and progression of renal injury. Therefore, in the present study we periodically measured the systolic blood pressure (SBP) of mice over the period 21-25 weeks of age and estimated markers for ROS, RAS and renal damage after mice had been killed at 25 weeks of age. 3. Markers for ROS (urinary 8-isoprostane excretion and renal 4-hydroxy-2-nonenal accumulation), RAS (renal angiotensinogen protein expression, urinary angiotensinogen excretion and renal angiotensin II) and renal damage (desmin-positive area and urinary protein excretion), as well as SBP, were significantly increased in HIGA mice compared with control BALB/c mice. 4. The data suggest that both ROS and the RAS are activated at an early phase in IgA nephropathy model mice.
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PMID:Activation of reactive oxygen species and the renin-angiotensin system in IgA nephropathy model mice. 1967 33

Proteinuria is highly prevalent after kidney transplant, occurring in up to 45% of patients, depending on the definition. In addition to glomerulonephritis, proteinuria in kidney transplant recipients is associated commonly with such transplant-specific diagnoses on biopsy as allograft nephropathy, transplant glomerulopathy, and acute rejection. Proteinuria is associated with decreased patient and allograft survival, as well as an increased risk of cardiovascular events. In proteinuric chronic kidney disease in the nontransplant setting, randomized trials have confirmed that blockade of the renin-angiotensin system is associated with improved clinical outcomes. In proteinuric transplant recipients, treatment with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker can decrease proteinuria, but there is no evidence from randomized trials that this strategy improves patient or graft survival. This review focuses on the measurement, prevalence, pathological findings, prognostic significance, and evidence-based management of proteinuria in kidney transplant recipients.
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PMID:Proteinuria in kidney transplant recipients: prevalence, prognosis, and evidence-based management. 1972 15


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