Gene/Protein Disease Symptom Drug Enzyme Compound
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Rates of end-stage renal disease among Australian Aboriginal people have been increasing over the past 2 decades, particularly in the northern and more remote areas of Australia, and especially in disadvantaged communities. Proteinuria predicts the rate of loss of kidney function; it is common in young adults and virtually universal in those over 50 years of age. Cumulative independent risk factors include low birth weight, recurrent skin infections, adult obesity, diabetes or its precursors, smoking, excessive alcohol intake, and a family history of renal disease. A plausible theory is that intrauterine malnutrition permanently reduces total nephron numbers, which are then overworked in adulthood by the metabolic stresses of obesity (from excess alcohol and poor diet), by higher blood pressures, and by infections, while starved of blood supply because of smoking. Although kidney disease is often only detected when already well established, active medical intervention offers great rewards. Control of blood pressure (preferentially using angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II receptor blockers (AIIRBs) in combination) can often stop or even reverse kidney damage, even if ongoing diabetes control is poor. Adequately funded kidney health programs with active Aboriginal health worker involvement are enormously cost-effective: tight blood pressure control at least halves the rate of disease progression, and every year of dialysis deferred for 1 patient could fund the appointment of 2 health workers. Addressing the underlying social causes for this epidemic is critical.
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PMID:Deprivation and dialysis: pathways to kidney failure in Australian Aborigines. 1571 38

Proteinuria in children is a marker of kidney disease and atherosclerosis, both which are known predictors of cardiovascular mortality. Recent evidence suggests that migrant South Asian populations living in the West may be at higher risk of kidney disease than native Caucasians. However, the determinants of proteinuria in South Asian children have not been explored. Previously, we reported ethnic variation in the prevalence of proteinuria in the adult population of Pakistan. However, it is not known whether ethnic predisposition to proteinuria appears during childhood or whether it is acquired later in life as a result of prolonged exposure to undiagnosed diabetes and hypertension. Analyses were based on a subset of data for 4977 children aged 5 to less than 15 years collected as part of the broad National Health Survey of Pakistan, conducted between 1990 and 1994. Proteinuria was defined as a dipstick positive for protein on a random urine sample. Ethnicity was reported as "mother-tongue", which is specific for each of the five major ethnic subgroups of Pakistan: Muhajir, Punjabi, Sindhi, Pashtun, and Baluchi. The overall prevalence (95% CI) of proteinuria in the children was 3.3% (2.7-3.9%). It was 6.2% in Sindhis, 3.6% in Muhajirs, 2.8% in Punjabis, 2.8% in Baluchis, and 1.0% in Pashtuns (p<0.001). In multivariable analyses, proteinuria was associated with greater height (p=0.007), urban dwelling (p=0.03), lower socioeconomic status (p=0.02), and certain ethnicities (p=0.005). The ethnic variation in proteinuria in South Asian children mirrors variation among ethnic groups in adults. This suggests variations in susceptibility or early exposure to causes of chronic kidney disease, rather than long-term exposure to undiagnosed diabetes or hypertension. Further studies are needed to determine factors in early life that may differentially predispose certain ethnic groups to proteinuria.
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PMID:Proteinuria in South Asian children: prevalence and determinants. 1594 88

Hypertension in patients with chronic kidney disease (CKD) is predominantly systolic. The contribution of risk factors for hypertension to the overall systolic blood pressure (BP) is unknown. To study the relationship between risk factors for hypertension and systolic BP in patients with CKD, 232 veterans (mean age 67 years; 96% men; 20% black; 39% with diabetes mellitus; estimated glomerular filtration rate [GFR] 48 mL/min per 1.73 m2) had clinic (routine and standardized measurements) and out-of-clinic (home and 24-hour ambulatory) BPs recorded. In multivariate analysis, using 17 risk factors, the log of the urine protein/creatinine ratio was the strongest predictor of systolic BP regardless of the BP measurement technique. The strength of the relationship between proteinuria and systolic BP was in the order ambulatory > home > standardized clinic > routine clinic BP measurement. Other independent predictors were age, race, and number of antihypertensive drugs used, and the model fit was better for out-of-clinic than clinic BP recordings. Estimated GFR was not an independent predictor of systolic BP by any technique. Nocturnal dipping was associated with higher estimated GFR, higher serum albumin, younger age, and less proteinuria. Proteinuria is the most important correlate of systolic BP in older men, the strongest relationship of which was with ambulatory and home systolic BP. Out-of-clinic BP recordings correlate better with target organ damage, as measured by proteinuria, and may be of greater clinical value than clinic BP recordings in predicting hypertension-related outcomes such as end-stage renal disease and death.
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PMID:Correlates of systolic hypertension in patients with chronic kidney disease. 1611 45

Proteinuria is a known risk factor for both cardiovascular disease and progression of established kidney disease. Observational studies and intervention trials have established that even low levels of albuminuria (microalbuminuria) are associated with increased risk for cardiovascular morbidity and mortality in general, and especially in high-risk populations such as those with diabetes mellitus. People with hypertension are at increased risk for proteinuria and arguably should be treated with regimens that not only lower blood pressure but also reduce proteinuria. Clinical trials indicate that lowering proteinuria in those with chronic kidney disease is associated with reduced risk for progression to end-stage kidney disease and cardiovascular outcomes. Many of these trials employ antihypertensive agents that block the renin-angiotensin-aldosterone system (RAAS), and indicate that these drugs are, in general, more effective than other antihypertensive regimens for reducing proteinuria. In addition, several small studies suggest that nondihydropyridine calcium channel blockers are comparable with angiotensin-converting enzyme inhibitors and more effective than dihydropyridine calcium channel blockers for reducing proteinuria in type 2 diabetics with advanced kidney disease. Based on the combined evidence from epidemiologic and intervention studies, it seems prudent to make proteinuria reduction a mandatory consideration in the selection of antihypertensive regimens.
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PMID:Proteinuria reduction: mandatory consideration or option when selecting an antihypertensive agent? 1615 82

Diabetes mellitus (DM) has been the leading cause of incident dialysis in Japan since 1998, according to the Japanese Society for Dialysis Therapy (JSDT). In particular, the number of male DM dialysis patients is increasing. DM is becoming a worldwide epidemic in both developed and developing countries. Strategies to detect individuals at high-risk of developing CKD and end-stage renal disease (ESRD) are needed that can be implemented on a population-basis. Among the commonly measured variables, dipstick urinalysis (proteinuria, haematuria), blood pressure, serum creatinine, body mass index (BMI), and serum uric acid are significant predictors of ESRD. Recently, we evaluated the effect of DM as a risk factor of developing ESRD. DM was diagnosed when the fasting plasma glucose (FPG) was 126 mg/dL or more in participants (n = 78529) of the 1993 screening program in Okinawa. The prevalence of DM was 5.2%. The odds ratio (95% CI) of DM for developing ESRD was 3.098 (1.738-5.525, P = 0.0001) after adjusting for possible confounding variables. Early detection and treatment of DM might prevent DM-related ESRD. We examined 7125 non-DM screenees who underwent a 1-day health check between April 1997 and March 1998. They were followed-up until March 2000 to determine whether they developed DM. Over the 2 years, the cumulative incidence of DM was 2.3%, 2.9% in men and 1.3% in women. Proteinuria was the most robust predictor of the development of DM; the adjusted relative risk (95% CI) was 1.90 (1.14-3.17). Obesity, per se, is also recognized as a risk factor for developing proteinuria. The higher the BMI, the higher the risk of developing ESRD; the adjusted odds ratio (95% CI) was 1.273 (1.121-1.446, P = 0.0002) for men. Other than being overweight (BMI = 25.0 kg/m2), a smoking habit was a significant predictor of developing proteinuria. The prevalence of obesity and DM is increasing in Japan. It is possible that the impact of obesity and complications of DM are different among races and ethnicities. Public relations regarding the risk of DM and its complications are especially important in Asian countries. Asians have more fat than non-Asians, even at the same BMI levels. Knowledge of the predictors of DM-ESRD is crucial as a first step toward prevention. Consistent with this notion, initiatives on the management of CKD and ESRD were recently organized in Japan and internationally.
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PMID:Predictors of diabetic end-stage renal disease in Japan. 1617 82

Chronic kidney disease (CKD) is a major public health problem in the United States. It is estimated that nearly 20 million Americans have some degree of chronic kidney disease defined as an estimated glomerular filtration rate of less than sixty milliliters per minute or evidence of kidney damage by imaging study, biopsy, biochemical testing or urine tests with an estimated glomerular filtration rate more than sixty milliliters per minute. Hypertension is present in more than 80% of patients with CKD and contributes to progression of kidney disease toward end stage (ESRD) as well as to cardiovascular events such as heart attack and stroke. In fact the risk for cardiovascular death in this patient population is greater than the risk for progression to ESRD. Proteinuria is an important co-morbidity in hypertensives with CKD and increase risk of disease progression and cardiovascular events. Treatment of hypertension is therefore imperative. The National Kidney Foundation clinical practice guidelines recommend a blood pressure goal of <130 mmHg systolic and <80 mmHg diastolic for all CKD patients. Recent post-hoc analyses of the Modification of Diet in Renal Disease study indicate that lower blood pressure may provide long-term kidney protection in patients with nondiabetic kidney disease. Specifically a mean arterial pressure <92 mmHg (e.g. 120/80 mmHg) as compared to 102-107 mmHg (e.g. 140/90 mmHg) is associated with reduced risk for ESRD. In most cases achieving this goal requires both non-pharmacologic and pharmacologic intervention. Dietary sodium restriction to no more than 2 grams daily is important. In addition, moderate alcohol intake, regular exercise, weight loss in those with a body mass index greater than 25 kg/M(2) and reduced amount of saturated fat help to reduce blood pressure. The first line pharmacologic intervention should be an angiotensin converting enzyme inhibitor or angiotensin II type 1 receptor blocker in those with diabetes or non-diabetics with more than 200 mg protein/gram creatinine on a random urine sample. For non-diabetics with less than 200 mg protein/gram creatinine on a random urine sample, no specific first-line drug class is recommended. After initial dosing with an ACEi, ARB or other drug, a diuretic should be added to the regimen. Thereafter, beta-blockers, calcium channel blockers, apha blockers and alpha 2 agonists (e.g. clonidine) and finally vasodilators (e.g. minoxidil) should be added to achieve blood pressure goal. Combinations of ACEi and ARB are helpful in reducing proteinuria and may also lower blood pressure further in some some cases. Blood pressure should be monitored closely in hypertensive patients with CKD and both clinic and home blood pressure measurements may help the clinician adjust treatment.
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PMID:Treatment of hypertension in chronic kidney disease. 1629 69

Hypertension is common in chronic renal disease and is a risk factor for the faster progression of renal damage, and reduction of blood pressure (BP) is an efficient way of preventing or slowing the progression of this damage. International guidelines recommend lowering BP to 140/90 mm Hg or less in patients with uncomplicated hypertension, and to 130/80 mm Hg or less for patients with diabetic or chronic renal disease. The attainment of these goals needs to be aggressively pursued with multidrug antihypertensive regimens, if needed. The pathogenesis of hypertensive renal damage involves mediators from various extracellular systems, including the renin-angiotensin system (RAS). Proteinuria, which occurs as a consequence of elevated intraglomerular pressure, is also directly nephrotoxic. As well as protecting the kidneys by reducing BP, antihypertensive drugs can also have direct effects on intrarenal mechanisms of damage, such as increased glomerular pressure and proteinuria. Antihypertensive drugs that have direct effects on intrarenal mechanisms may, therefore, have nephroprotective effects additional to those resulting from reductions in arterial BP. Whereas BP-lowering effects are common to all antihypertensive drugs, intrarenal effects differ between classes and between individual drugs within certain classes. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) have beneficial effects on proteinuria and declining renal function that appear to be mediated by factors additional to their effects on BP. These RAS inhibitors are recommended as a first-line antihypertensive approach in patients with chronic kidney disease. The addition of diuretics and calcium channel antagonists to RAS inhibitor therapy is also considered to be a rational strategy to reduce BP and preserve renal function. Calcium channel antagonists are a highly heterogeneous class of compounds, and it appears that some agents are more suitable for use in patients with chronic renal disease than others. Manidipine is a third-generation dihydropyridine (DHP) calcium channel antagonist that blocks both L and T-type calcium channels. Unlike older-generation DHPs, which preferentially act on L-type channels, manidipine has been shown to have beneficial effects on intrarenal haemodynamics, proteinuria and other measures of renal functional decline in the first clinical trials involving hypertensive patients with chronic renal failure. Preliminary results from a trial in diabetic patients who had uncontrolled hypertension and microalbuminuria despite optimal therapy with an ACE inhibitor or an ARB suggest that manidipine may be an excellent antihypertensive drug in combination with RAS inhibitor treatment in order to normalise BP and albumin excretion in patients with diabetes.
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PMID:Renal protection in hypertensive patients: selection of antihypertensive therapy. 1639 60

The prevalence of hypertension in type 2 diabetics is high, though there is no published data for Switzerland. This prospective cohort survey determined the frequency of type 2 diabetes mellitus associated with hypertension from medical practitioners in Switzerland, and collected data on the diagnostic and therapeutic work-up for cardiovascular risk patients. The Swiss Hypertension And Risk Factor Program (SHARP) is a two-part survey: The first part, I-SHARP, was a survey among 1040 Swiss physicians to assess what are the target blood pressure (BP) values and preferred treatment for their patients. The second part, SHARP, collected data from 20,956 patients treated on any of 5 consecutive days from 188 participating physicians. In I-SHARP, target BP?135/85 mmHg, as recommended by the Swiss Society of Hypertension, was the goal for 25% of physicians for hypertensives, and for 60% for hypertensive diabetics; values >140/90 mmHg were targeted by 19% for hypertensives, respectively 9% for hypertensive diabetics. In SHARP, 30% of the 20,956 patients enrolled were hypertensive (as defined by the doctors) and 10% were diabetic (67% of whom were also hypertensive). Six per cent of known hypertensive patients and 4% of known hypertensive diabetics did not receive any antihypertensive treatment. Diabetes was not treated pharmacologically in 20% of diabetics. Proteinuria was not screened for in 45% of known hypertensives and in 29% of known hypertensive diabetics. In Switzerland, most physicians set target BP levels higher than recommended in published guidelines. In this country with easy access to medical care, high medical density and few financial constraints, appropriate detection and treatment for cardiovascular risk factors remain highly problematic.
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PMID:Swiss Hypertension and Risk Factor Program (SHARP): cardiovascular risk factors management in patients with type 2 diabetes in Switzerland. 1640 87

Proteinuria has been recognized in association with diabetes mellitus as early as the 18th century. This form of renal disease is known as diabetic nephropathy. It is now clear that diabetic nephropathy is the principal cause of end stage renal disease (ESRD) in the western world. According to reports by the United States Renal Data System (USRDS), in the past two decades there has been a continual increase in the incidence of ESRD among patients with diabetes. Many patients have diabetes that progresses to diabetic nephropathy, which is often not discovered until overt nephropathy is present. Many of the complications of diabetes could be minimized if patients received a comprehensive health maintenance program that includes vigorous cardiac risk reduction, routine eye examinations; routine foot examinations; screening and treatment for microalbuminuria, optimal hypertension management; and improved glycemic control. Hence, the key is not only prudent screening of these patients, but referral as well. Using a case study approach, this article illustrates the care of patients with diabetic nephropathy in type 1 diabetes mellitus.
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PMID:Diabetic nephropathy in patients with type 1 diabetes mellitus. 1653 25

Cardiovascular risk is generally high in patients with both hypertension and diabetes and should be specifically assessed for each individual. The blood pressure target is<130/80 mm Hg. Two or even three different drugs are often necessary to reach this rather difficult goal. Angiotensin-converting enzyme (ACE) inhibitors are preferred for patients with renal damage. Proteinuria should be reduced to less than 0.5 g/day. Associated risk factors should be treated with equal effectiveness. In particular, LDL cholesterol should be lowered to less than 1 g/L when additional risk factors are present. Aspirin (0.75 mg a day) should be given routinely as soon as blood pressure is controlled.
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PMID:[Management of hypertension in patients with diabetes]. 1678 70


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