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Resistant hypertension is defined as blood pressure above goal despite adherence to a combination of at least three optimally dosed antihypertensive medications, one of which is a diuretic. Chronic kidney disease is the most frequent of several patient factors or comorbidities associated with resistant hypertension. The prevalence of resistant hypertension is increased in patients with chronic kidney disease, while chronic kidney disease is associated with an impaired prognosis in patients with resistant hypertension. Recommended low-salt diet and triple antihypertensive drug regimens that include a diuretic, should be complemented by the sequential addition of other antihypertensive drugs. New therapeutic innovations for resistant hypertension, such as renal denervation and carotid barostimulation, are under investigation especially in patients with advanced chronic kidney disease. We discuss resistant hypertension in chronic kidney disease stages 3-5 (ie, patients with an estimated glomerular filtration rate below 60 mL/min per 1·73 m(2) and not on dialysis), in terms of worldwide epidemiology, outcomes, causes and pathophysiology, evidence-based treatment, and a call for action., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: The cardiotonic steroid marinobufagenin (MBG) is increasingly suggested to be responsible for some of the cardiovascular injury that has been previously attributed to aldosterone. We examined the clinical correlates of circulating MBG concentrations in hypertensive patients and tested the hypothesis that MBG serves as a reliable diagnostic tool for detecting primary aldosteronism (PA)., Methods: Plasma MBG concentrations (mean: 0.51±0.25 nmol/l) were measured in the morning fasting samples in 20 patients with PA and 20 essential hypertensive (EH) controls matched for age, sex, body mass index, renal function, urinary sodium and intake of antihypertensive medication (mean age: 51.6 years; 52.2% women)., Results: Overall, plasma MBG was directly correlated with plasma aldosterone, aldosterone to active renin ratio (AARR), diastolic blood pressure, mean carotid intima-media thickness, serum sodium, urinary protein to creatinine ratio and inversely with serum potassium levels. Plasma MBG levels were significantly higher in patients with PA compared to EH (mean: 0.68±0.12 versus 0.35±0.24 nmol/l; p<0.001). ROC analysis yielded a greater AUC for plasma MBG compared to the AARR, PAC and serum potassium levels for detecting PA. Youden's Index analyses yielded the optimal plasma MBG cut-off score for diagnosing PA at >0.49 nmol/l with specificity and sensitivity values of 0.85 and 0.95, respectively, which were higher than those at the optimum AARR cut-off at >3.32 ng/dl/µU/ml., Conclusions: In a well-characterized cohort, values of plasma MBG were significantly related to clinical correlates of cardiovascular and renal disease. Plasma MBG emerged as a valuable alternative to the AARR for screening of PA.

Objective: Accumulating evidence supports a potential role for dopamine in the regulation of insulin secretion. We examined the association between circulating dopamine and C-peptide concentrations using data from the Graz Endocrine Causes of Hypertension (GECOH) study., Research Design and Methods: After 12 h of fasting, we measured plasma dopamine and serum C-peptide levels and established determining factors of insulin secretion in 201 nondiabetic hypertensive patients (mean age 48.1 ± 16.0 years; 61.7% women)., Results: Mean dopamine and C-peptide concentration were 33.4 ± 38.6 pg/mL and 3.1 ± 2.7 ng/mL, respectively. A strong and inverse correlation was observed between dopamine and C-peptide levels (r = -0.423, P < 0.001). There was no significant relationship between C-peptide, plasma epinephrine, and norepinephrine. C-peptide levels decreased steadily and significantly from tertile 1 of dopamine (3.6 ng/mL [95% CI 2.9-4.1]) to tertile 3 (1.6 ng/mL [1.5-2.7], P < 0.001) after multivariate adjustment., Conclusions: The inverse association between dopamine and C-peptide highlights the need to evaluate whether dopamine could be effective for modulating endocrine pancreatic function.

Background: We have previously demonstrated in the Randomized Olmesartan and Diabetes Microalbuminuria Prevention study that the angiotensin receptor blocker (ARB) olmesartan delays the onset of microalbuminuria in patients with type 2 diabetes. Now, we investigated the effect in the subpopulation with hypertension., Methods: Overall, 4020 patients with type 2 diabetes and hypertension at baseline (defined by a SBP/DBP ≥130/80 mmHg or use of antihypertensive medication) received either 40 mg olmesartan once daily or placebo for a median of 3.2 years in a randomized, double-blind, multicenter, controlled trial. Additional antihypertensive drugs (except angiotensin-converting enzyme inhibitors or ARBs) were used as needed to lower blood pressure (BP) to less than 130/80 mmHg., Results: The average BP was 126.3/74.7 and 129.5/76.6 mmHg, respectively (P < 0.001). Olmesartan delayed the time to onset of microalbuminuria by 25% (hazard ratio = 0.75; 95% confidence interval = 0.61-0.92, P = 0.007). Patients with a baseline SBP above the median of 136.7 mmHg and a SBP reduction above the median of 17.45 mmHg had a lower incidence of microalbuminuria than patients with a SBP reduction of less than 17.45 (8.1 vs. 11.2%, P < 0.0001). Independent from the baseline BP and the degree of BP reduction a 15-39% increase in the time to onset of microalbuminuria was detectable by olmesartan treatment. Cardiovascular events were comparable and occurred in 93 (4.6%) patients taking olmesartan and 86 (4.4%) taking placebo., Conclusion: Patients with a better BP reduction are less likely to develop microalbuminuria. Treatment with olmesartan delayed the onset of microalbuminuria independent of the baseline BP and the degree of BP reduction.

Hypertension is common in patients with diabetes mellitus and is a main cause of renal and cardiovascular complications. There has been recent controversy on what should be considered the optimal blood pressure goal and the optimal antihypertensive agent. It has become apparent that one blood pressure does not fit all in diabetic patients. Major confounders are preexisting cardiovascular disease and presence or absence of proteinuric kidney disease. In proteinuric diabetic nephropathy, renin-angiotensin system blockade is clearly indicated, but monotherapy is practically always insufficient to achieve target blood pressure values., (© 2011 Wiley Periodicals, Inc.)

Objectives: With the present analysis we intended to investigate the magnitude of the effect of relative aldosterone excess in predicting peripheral as well as aortic blood pressure levels in a well-characterized cohort of patients undergoing coronary angiography., Background: The discussion on the relationship between aldosterone concentration and blood pressure has recently gone beyond the role of primary aldosteronism in the genesis of arterial hypertension., Methods: Plasma aldosterone (pg/ml) and plasma renin concentration (pg/ml) were determined in 3,056 Caucasian patients (age 62.5 +/- 11 years; 31.9% women) scheduled for coronary angiography in a single tertiary care center. We formed sex-specific deciles (D) according to plasma aldosterone/renin concentration ratio (ARR) (pg/ml/pg/ml)., Results: Mean peripheral systolic blood pressure (SBP) and diastolic blood pressure (DBP) of the entire cohort were 141 +/- 24 mm Hg and 81 +/- 11 mm Hg, respectively. Mean ARR was 10.2 +/- 15.7 in men and 14.4 +/- 19.9 in women (p < 0.0001). Median SBP and aortic SBP increased steadily and significantly from ARR D1 (126.8 mm Hg and 130.0 mm Hg, respectively) to D10 (151.0 mm Hg and 149.6 mm Hg, respectively; p < 0.0001 for both) after multivariate adjustment for age, sex, body mass index, renal function, antihypertensive medications, and various parameters potentially influencing BP. Adjusted median DBP and aortic DBP also increased significantly from 74.3 mm Hg and 66.5 mm Hg (D1) to 86.9 mm Hg and 76.7 mm Hg, respectively (D10) (p < 0.001 for both). In a multivariate stepwise regression model, ARR emerged as the second most significant independent predictor (after age) of mean SBP and as the most important predictor of mean DBP in this patient cohort., Conclusions: Our results: 1) underline that the ARR affects BP well below a cutoff used for screening for primary aldosteronism; and 2) illustrate the importance of the ARR in modulating BP over a much wider range than is currently appreciated., (Copyright 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

In the setting of primary aldosteronism, elevated aldosterone levels are associated with increased blood pressure. Aldosterone concentrations within the normal range, however, can also alter blood pressure. Furthermore, the aldosterone-to-renin ratio, an indicator of aldosterone excess, is associated with hypertension, even in patients without excessive absolute aldosterone levels. In this Review we assess the data on the role of aldosterone in the development and maintenance of hypertension. We provide an overview of the complex crosstalk between genetic and environmental factors, and about aldosterone-mediated arterial hypertension and target organ damage. The discussion is organized according to major targets of aldosterone action: the collecting duct in the kidney, the vasculature and the central nervous system. The antihypertensive efficacy of mineralocorticoid-receptor blockers, even in patients with aldosterone values in the normal range, supports the evidence that aldosterone plays a part in blood pressure elevation in the absence of primary aldosteronism.

Aldosterone was in the past considered only as a prohypertensinogenic agent. It has recently become clear that apart from the classical endocrine action, i.e. causing blood pressure elevation as a result of salt retention, aldosterone has numerous blood-pressure-independent actions on nonepithelial tissue. Under conditions of high salt concentration, aldosterone is injurious to the kidney, heart and vasculature. Of particular interest are recent observations that aldosterone is a permissive factor for the effect of minor increases in plasma sodium concentration on endothelial cell dysfunction. Despite surprising effects of aldosterone blockade on blood pressure of anuric dialysis patients, the potential role of mineralocorticoid receptor blockade in dialysis patients is currently unclear and requires controlled investigation to define the risk of potential hazards, specifically hyperkalemia., (Copyright (c) 2010 S. Karger AG, Basel.)

Vitamin D deficiency is common and is primarily caused by a lack of ultraviolet-B (UVB) radiation from reduced sun exposure, and the consequent limiting of vitamin D production in the skin. The vitamin D endocrine system regulates about 3% of the human genome. Observational data support the concept that vitamin D is involved in the pathogenesis of cardiovascular diseases and arterial hypertension. The antihypertensive properties of vitamin D include renoprotective effects, suppression of the renin-angiotensin-aldosterone system, direct effects on vascular cells, and effects on calcium metabolism, including prevention of secondary hyperparathyroidism. The results of clinical studies largely, but not consistently, favor the hypothesis that vitamin D sufficiency promotes lowering of arterial blood pressure. Randomized, placebo-controlled trials are greatly needed to clarify and definitively prove the effect of vitamin D on blood pressure. In general, the antihypertensive effects of vitamin D seem to be particularly prominent in vitamin-D-deficient patients with elevated blood pressure. Thus, in view of the relatively safe and inexpensive way in which vitamin D can be supplemented, we believe that vitamin D supplementation should be prescribed to patients with hypertension and 25-hydroxyvitamin D levels below target values.

For centuries, salt has been regarded as essential to human health. Recent work, however, has provided further evidence that the current dietary intake of salt in Western societies is an important factor in the genesis of essential hypertension and may even partly cause blood pressure-independent target organ damage including renal damage. Accordingly, recent guidelines recommend reduction of daily consumption of salt to 6 g/day. Individuals vary with respect to the increase of blood pressure with increasing salt intake (salt sensitivity); individuals with renal disease are particularly salt sensitive. Salt causes major alterations of renal hemodynamics and accelerates progression. Despite some opinions to the contrary, salt restriction and volume control is particularly important in dialyzed patients. Understanding of how salt affects blood pressure and renal function has recently been advanced in 2 respects. The past concept that salt acts by expanding the extracellular fluid space has been challenged by the demonstration of water-free sodium storage of salt in tissues. Furthermore, salt promotes the secretion of cardiotonic steroids, i.e., mammalian "digitalis." Initial observations suggest a causal role for cardiotonic steroids in the genesis of cardiac abnormalities in advanced renal disease.

The relation of salt to hypertension and kidney disease had been well known at the turn of the last century, but the importance of salt has been grossly neglected more recently. There is a close link between salt intake and hypertension, as well as partially blood pressure-independent target organ damage including renal disease. In the general population, high salt intake is associated with hypertension and cardiovascular events. Salt loading also increases albuminuria in individuals without primary renal disease and raises excretion of albumin and protein in patients with renal disease. It aggravates proteinuria and glomerulosclerosis and accelerates progression in most animal models of renal damage. The effect of salt restriction cannot be reproduced by treatment with diuretics. Inappropriate increase of intrarenal angiotensin II and increased reactive oxygen species are the major culprits responsible for salt-related renal damage.

Essential hypertension can be defined as a rise in blood pressure of unknown cause that increases risk for cerebral, cardiac, and renal events. In industrialised countries, the risk of becoming hypertensive (blood pressure >140/90 mm Hg) during a lifetime exceeds 90%. Essential hypertension usually clusters with other cardiovascular risk factors such as ageing, being overweight, insulin resistance, diabetes, and hyperlipidaemia. Subtle target-organ damage such as left-ventricular hypertrophy, microalbuminuria, and cognitive dysfunction takes place early in the course of hypertensive cardiovascular disease, although catastrophic events such as stroke, heart attack, renal failure, and dementia usually happen after long periods of uncontrolled hypertension only. All antihypertensive drugs lower blood pressure (by definition) and this decline is the best determinant of cardiovascular risk reduction. However, differences between drugs exist with respect to reduction of target-organ disease and prevention of major cardiovascular events. Most hypertensive patients need two or more drugs for blood-pressure control and concomitant statin treatment for risk factor reduction. Despite the availability of effective and safe antihypertensive drugs, hypertension and its concomitant risk factors remain uncontrolled in most patients.

Hypertension usually clusters with other cardiovascular risk factors, such as insulin resistance, visceral obesity, and dyslipidemia, greatly increasing an individual's risk for cardiovascular morbidity and death. Despite universal recognition that reduction in blood pressure and other cardiovascular risk factors is essential to improving long-term cardiovascular health, <25% of patients diagnosed with hypertension have adequate blood pressure control. Total cardiovascular risk is increased in the presence of risk factors, target organ damage, comorbid conditions, and the metabolic syndrome and may, to some extent, be prenatally determined. Individuals with "borderline" normal blood pressure and blood glucose are also at increased risk for cardiovascular disease, giving rise to the concept of individuals with "prehypertension" and "prediabetes." International treatment guidelines are now incorporating the concept of global cardiovascular risk assessment and management to improve long-term outcomes. Multifactorial intervention has proved to be highly effective at reducing cardiovascular risk and events in patients with type 2 diabetes mellitus, and studies suggest that reducing an array of risk factors by relatively small amounts can be more beneficial than achieving large reductions in a single risk factor. Clearly, isolated treatment of hypertension is no longer sufficient; risk factors and target organ damage need to be actively searched for and treated if long-term cardiovascular health is to be improved.

We are currently confronted with an epidemic of renal failure caused by diabetic nephropathy. It has become apparent that blood pressure is a major determinant of the risk of developing diabetic nephropathy; individuals with a genetic predisposition to hypertension are at increased risk of developing diabetes and diabetic nephropathy. Antihypertensive medication has an impact on development of diabetes; beyond blood-pressure lowering, the risk of diabetes is further reduced by blockade of the renin-angiotensin system (RAS). In experimental studies, blockade of the RAS in the pre-diabetic stage ameliorates the severity of subsequent diabetic nephropathy. Guidelines recommend a target blood pressure of 130/80 mmHg for diabetic patients without proteinuria and some guidelines recommend a target of less than 125/175 mmHg for diabetic patients with proteinuria. Above a systolic blood pressure of approximately 110 mmHg, the risk of progression of diabetic nephropathy increases progressively with increasing blood pressure. Blood-pressure lowering and blockade of the RAS delays or prevents onset of microalbuminuria, slows worsening of microalbuminuria and attenuates progression of diabetic nephropathy, even in advanced stages. In addition to blood pressure, proteinuria is a treatment target and should be reduced to below 1 g/24 h.

It has been known for decades that salt (NaCl) determines extracellular volume as well as blood pressure and is one cause of hypertension. The difficulty to control the NaCl balance and thus treat sodium overload and hypertension in patients on dialysis has been recognized by Scribner in the early days of dialysis. In recent years, an impressive body of evidence has accumulated indicating that in essential hypertension, NaCl--blood pressure independently--causes target organ damage such as left ventricular hypertrophy, microalbuminuria, and increased aortic stiffness. It has further been recognized that NaCl increases oxidative stress and, again blood pressure independently, amplifies tissue injury induced by aldosterone. In renal damage models, progression is dramatically accelerated by high NaCl intake. Sodium as a potential culprit in progression to target organ damage in terminal renal failure has not been well investigated so far. However, it is possible, and indeed likely, that sodium plays an adverse role in the genesis of target organ damage in terminal renal failure., (Copyright 2006 S. Karger AG, Basel.)

Elevated arterial pressure is a major risk factor for progression to ESRD in diabetic nephropathy. However, the component of arterial pressure and level of BP control for optimal renal outcomes are disputed. Data from 1590 hypertensive patients with type 2 diabetes in the Irbesartan Diabetic Nephropathy Trial (IDNT), a randomized, double-blind, placebo-controlled trial performed in 209 clinics worldwide, were examined, and the effects of baseline and mean follow-up systolic BP (SBP) and diastolic BP and the interaction of assigned study medications (irbesartan, amlodipine, and placebo) on progressive renal failure and all-cause mortality were assessed. Other antihypertensive agents were added to achieve predetermined BP goals. Entry criteria included elevated baseline serum creatinine concentration up to 266 micromol/L (3.0 mg/dl) and urine protein excretion >900 mg/d. Baseline BP averaged 159/87 +/- 20/11 mmHg. Median patient follow-up was 2.6 yr. Follow-up achieved SBP most strongly predicted renal outcomes. SBP >149 mmHg was associated with a 2.2-fold increase in the risk for doubling serum creatinine or ESRD compared with SBP <134 mmHg. Progressive lowering of SBP to 120 mmHg was associated with improved renal and patient survival, an effect independent of baseline renal function. Below this threshold, all-cause mortality increased. An additional renoprotective effect of irbesartan, independent of achieved SBP, was observed down to 120 mmHg. There was no correlation between diastolic BP and renal outcomes. We recommend a SBP target between 120 and 130 mmHg, in conjunction with blockade of the renin-angiotensin system, in patients with type 2 diabetic nephropathy.

It has been proposed that "nephron underdosing," i.e., a low number of nephrons at the time of birth, is linked to essential hypertension and a greater propensity to develop progressive loss of renal function after renal injury. This hypothesis was confirmed recently by examining the number of glomeruli in patients with essential hypertension. The mechanisms through which a low number of nephrons causes hypertension have not been clarified, but it is likely that functional changes in postglomerular segments of the nephron, e.g., handling of sodium, play an important role. Neonatal uninephrectomy increases BP, renders BP salt sensitive, and renders the kidney more susceptible to damage. Apart from genetic factors, fetal/maternal malnutrition during pregnancy seems to play an important role in the pathogenesis of nephron underdosing. Furthermore, intrauterine programming during organogenesis, e.g., by hyperglycemia, seems to be important: In animal experiments, offspring of either hyperglycemic or diabetic mothers have fewer nephrons.

Objective: To report: (1) on the background, design and methods of the Hypertension and Diabetes Risk Screening and Awareness (HYDRA) study, (2) on the point prevalence of hypertension in primary care and (3) on the proportion of treated, controlled, and uncontrolled hypertension., Design: Cross-sectional point prevalence study., Setting: Representative nationwide sample of 1912 primary care practices in Germany., Participants: A total of 45,125 unselected primary care attendees., Main Outcome Measures: Prevalence of hypertension based on doctor's diagnosis, self-reported diagnosis, and blood pressure (BP) measurements., Results: A total of 39% of all patients and 67% of patients aged 60 years or older, respectively, were diagnosed by their doctors as having hypertension. Eighty-four percent of diagnosed patients were on antihypertensive medication, 57% of which were rated by the physician as well controlled. When hypertension was defined as either current BP levels > or = 140/90 mmHg and/or current antihypertensive medication, the total point prevalence increased to 50%, while treatment and control rates (BP < 140/90 mmHg) dropped to 64 and 19%, respectively., Conclusions: Extrapolation of these findings to the entire primary care patient population seen in the over 20 000 primary care practices in Germany suggests that on an average day, over 700,000 patients with elevated BP are seen by primary care physicians, but that only around 132,000 of these patients are well controlled. Thus, this study not only documents the enormous burden of hypertensive patients in the primary health system, but also highlights the alarming lack of BP control in the vast majority of hypertensive patients.

The Hypertension and Diabetes Screening and Awareness (HYDRA) study is a cross-sectional point-prevalence study performed in September 2001; 45,125 primary care attendees were recruited from a representative nationwide sample of 1912 primary care practices in Germany. Around 42% of all patients presenting in these practices had hypertension (WHO definition). In approximately 70% of these patients, hypertension was diagnosed by doctors and 84% of diagnosed patients were on antihypertensive medication, but in less than 30% of treated patients was blood pressure controlled (< 140/90 mmHg). The control rate in all patients presenting with hypertension (including those patients unrecognized) was as low as 19%. The present analysis aimed to find explanations for this unsatisfactory outcome of hypertension control. The main finding was that the rate of diagnosis of hypertension is alarmingly low in young people, probably due to insufficient blood pressure screenings. The data further indicated that doctors still set their target of treatment according to outdated guidelines and that doctors still orientate their treatment primarily with regard to the diastolic pressure. These insights into the causes of unsatisfactory hypertension control may help to direct future educational programmes designed to improve hypertension management specifically to these deficits and thereby to improve control rates.

Background: A diminished number of nephrons has been proposed as one of the factors contributing to the development of primary hypertension., Methods: To test this hypothesis, we used a three-dimensional stereologic method to compare the number and volume of glomeruli in 10 middle-aged white patients (age range, 35 to 59 years) with a history of primary hypertension or left ventricular hypertrophy (or both) and renal arteriolar lesions with the number and volume in 10 normotensive subjects matched for sex, age, height, and weight. All 20 subjects had died in accidents., Results: Patients with hypertension had significantly fewer glomeruli per kidney than matched normotensive controls (median, 702,379 vs. 1,429,200). Patients with hypertension also had a significantly greater glomerular volume than did the controls (median, 6.50x10(-3) mm3 vs. 2.79x10(-3) mm3; P<0.001) but very few obsolescent glomeruli., Conclusions: The data support the hypothesis that the number of nephrons is reduced in white patients with primary hypertension., (Copyright 2003 Massachusetts Medical Society)

Indices of altered renal function (eg, microalbuminuria, increased serum creatinine concentration, or decrease in estimated creatinine clearance, particularly overt proteinuria) are independent predictors of cardiovascular morbidity and mortality. These parameters should be routinely evaluated in the elderly and in high cardiovascular risk populations, particularly when hypertension is present. Hypertensive kidney damage should be prevented by early aggressive treatment of hypertensive patients with microalbuminuria. To avoid further aggravation of high cardiovascular risk, antihypertensive agents devoid of unwanted metabolic side effects should be used. Epidemiologic information suggests that renal and cardiovascular outcome run parallel in this segment of the population.

Diabetes has become the most common single cause of end-stage renal disease in many countries. The coexistence of diabetes mellitus and hypertension dramatically increases the risk of developing target organ complications including renal disease. There are good arguments that ESRD in the patient with diabetes is largely preventable with the interventions currently available. For type 2 diabetes the UK Prospective Diabetes Study Group Trial clearly documented that the frequency of microangiopathic sequelae can be diminished by glycaemic control and even more impressively by intensified antihypertensive treatment. An analysis of recent randomized long-term clinical trials that evaluated the rate of decline in renal function demonstrated that the lower the blood pressure within the range of normotensive values, the greater the preservation of renal function. Since the 1994 Working Group Report on Hypertension and Diabetes suggested a goal blood pressure of 130/80 mmHg should be achieved in patients with diabetes and/or renal insufficiency; lower blood pressure levels, i.e. less than 125/75 mmHg are recommended for patients with proteinuria > 1 g/d and renal insufficiency regardless of etiology. Antihypertensive regimens should include an ACE inhibitor or an AT1-receptor blocker in order to provide maximum renal benefits in diabetic and non-diabetic renal diseases. Such low blood pressure are virtually impossible to achieve with monotherapy. In most cases the combination of two and more antihypertensive drugs is necessary. The purpose of this report is to update the previous recommendations with a focus on level of blood pressure control, proteinuria reduction and retarding the progression of renal disease.

Cardiovascular disease (CVD) is the most common cause of death in industrialized nations. Type 2 diabetes is a CVD risk factor that confers risk similar to a previous myocardial infarction in an individual who does not have diabetes. In addition, the most common cause of chronic kidney disease (CKD) is diabetes. Together, diabetes and hypertension account for more than two-thirds of CVD risk, and other risk factors such as dyslipidemia contribute to the remainder of CVD risk. CKD, particularly with presence of significant albuminuria, should be considered an additional cardiovascular risk factor. There is no consensus on how to assess and stratify risk for patients with kidney disease across subspecialties that commonly treat such patients. This paper summarizes the results of a consensus conference utilizing a patient case to discuss the integrated management of hypertension, kidney disease, dyslipidemia, diabetes, and heart failure across disciplines.

Although not all renal disease that diabetic patients develop is due to diabetic glomerulosclerosis, the great majority of patients progressing to advanced renal failure suffer from diffuse or nodular (Kimmelstiel Wilson′s) diabetic glomerulosclerosis. This condition has become the single most frequent cause of end-stage renal failure in the Western world. Recent studies indicate that an interplay between genetic predisposition and other factors such as hyperglycemia, blood pressure, age, gender, smoking and ethnicity, predispose to nephropathy both in type 1 and type 2 diabetes mellitus. It has also become clear that trace albuminuria ("microalbuminuria") provides a unique opportunity to recognize incipient renal involvement early on, particularly in type 1 and less specifically in type 2 diabetes. Increasing evidence indicates that early intervention delays progression of nephropathy. Factors which promote progression of nephropathy include hypertension, proteinuria, smoking, poor glycemic control and, less certainly, high dietary protein intake and hyperlipidemia. The most important strategies to combat the medical catastrophe of increasing numbers of diabetic patients with end-stage renal failure include (i) prevention of diabetes (mainly type 2), (ii) glycemic control to prevent onset of renal involvement and (iii) meticulous antihypertensive treatment to avoid progression of nephropathy. Survival of diabetic patients on dialysis and after transplantation is inferior to that of non-diabetic patients, mainly because of high rate of cardiovascular death. There is consensus that in the absence of major vascular disease the best treatment is renal transplantation in the type 2 diabetic patient and combined kidney and pancreas transplantation in the type 1 diabetic patient.

Background/Aims: Cyclosporine A (CsA) is a commonly used immunosuppressive agent. In some patients treatment with CsA has to be continued during pregnancy. The aim of the study was to assess in an experimental model whether the exposure to CsA during fetal life influences the number and volume of glomeruli, kidney function and blood pressure in the offspring. Methods: Eight pregnant female Sprague-Dawley rats were allocated to 2 treatment regimens: with CsA or solvent. Blood pressure was measured in the offspring at 7 and 11 weeks of age and albuminuria was determined at 11 weeks of age. In the kidney the number and mean volume of glomeruli was assessed using stereological methods. Results: In the offspring of pregnant rats treated with CsA the number of glomeruli was significantly lower and the mean volume of glomeruli was higher when compared to the offspring of pregnant rats receiving solvent. Systolic and diastolic blood pressures as well as albuminuria were significantly higher in the offspring of mothers treated with CsA during gestation compared to the offspring from the control group. Conclusions: Exposure of rats to CsA during fetal life impairs kidney development, thus potentially predisposing to chronic kidney disease and hypertension in the adult life. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular disease is the primary cause of mortality in patients with chronic kidney disease (CKD). Heart remodeling in CKD comprises mainly interstitial fibrosis and capillary loss. Beyond correcting renal anemia, erythropoietin (Epo) has potentially beneficial pleiotropic effects on heart remodeling. Methods: 12-week-old male Sprague-Dawley rats were randomized to 5/6 nephrectomy (NX) or sham operation (sham-op); subsequently, they received murine Epo (2.5 μg/kg/week), enalapril (12 mg/kg/day), Epo + enalapril, Epo + dihydralazine (25 mg/kg/day), or vehicle. Heart function and morphology was assessed after 16 weeks of treatment. Results: Compared with sham-op (81.2%), left ventricle fractional shortening was reduced in vehicle-treated NX (66.3%) and this was ameliorated by Epo (72.6%) and even prevented by enalapril (80.6%). Capillary length density was lower and the area of fibrosis more marked in vehicle-treated NX compared to sham-op. Capillary rarefaction and heart fibrosis were prevented in NX treated with Epo + enalapril and reduced in NX treated with enalapril and Epo + dihydralazine. Despite higher blood pressure, treatment with Epo reduced heart fibrosis but failed to prevent capillary loss. In parallel, expression of the p47phox NADPH oxidase was higher in untreated NX and was effectively reduced in NX treated with Epo + enalapril. Under basal conditions there was no difference between the groups regarding myocardial hypoxia as reflected by pimonidazole staining. Conclusion: Epo in combination with enalapril caused additive reduction of cardiac fibrosis and microvessel disease in 5/6 nephrectomized rats presumably by decreasing myocardial oxidative stress. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Do detrimental effects on the vasculature of a high dietary sodium intake precede the development of hypertension?Background High salt intake causes hypertension, adverse cardiovascular outcomes and potentially also blood pressure (BP)-independent target organ damage. Excess salt intake in pregnancy is known to affect BP in the offspring. The present study was designed to assess whether high salt intake in pregnancy affects BP and vascular morphology in the offspring. Methods Sprague–Dawley rats were fed a standard rodent diet with low–normal (0.15%) or high (8.0%) salt content during pregnancy and lactation. After weaning at 4 weeks of age, offspring were maintained on the same diet or switched to a high- or low-salt diet, respectively. Vascular geometry was assessed in male offspring at 7 and 12 weeks postnatally. Results Up to 12 weeks of age, there was no significant difference in telemetrically measured BP between the groups of offspring. At 12 weeks of age, wall thickness of central (aorta, carotid), muscular (mesenteric) and intrapulmonary arteries was significantly higher in offspring of mothers on a high-salt diet irrespective of the post-weaning diet. This correlated with increased fibrosis of the aortic wall, more intense nitrotyrosine staining as well as elevated levels of marinobufagenin (MBG) and asymmetric dimethyl arginine (ADMA). Conclusions High salt intake in pregnant rats has long-lasting effects on the modeling of central and muscular arteries in the offspring independent of postnatal salt intake and BP. Circulating MBG and ADMA and local oxidative stress correlate with the adverse vascular modeling. [ABSTRACT FROM PUBLISHER]

Although significant progress has been made in the treatment of chronic kidney disease (CKD), treatment is not yet satisfactory, particularly when it is started in the late stages of the disease. Novel modes of intervention to mitigate the burden of disease are required. The reduction of dietary salt intake (which is high in the industrialized world) is one such option. Better understanding of the deleterious effects of salt on renal and cardiovascular health is necessary to raise awareness of the importance of reduction of the salt content in food products. Therefore, we (i) review pathways through which high salt intake exerts damaging effects, (ii) provide an assessment of recent observational studies linking dietary salt intake to the progression of renal and cardiovascular disease and (iii) discuss the interaction between salt intake and rennin–angiotensin–aldosterone-system inhibitors, i.e. the first choice antihypertensive agents for the treatment of CKD. [ABSTRACT FROM PUBLISHER]

In humans, low glomerular numbers are related to hypertension, cardiovascular, and renal disease in adult life. The present study was designed 1) to explore whether above- or below-normal dietary salt intake during pregnancy influences nephron number and blood pressure in the offspring and 2) to identify potential mechanisms in kidney development modified by maternal sodium intake. Sprague-Dawley rats were fed low (0.07%)-, intermediate (0.51%)-, or high (3.0%)-sodium diets during pregnancy and lactation. The offspring were weaned at 4 wk and subsequently kept on a 0.51% sodium diet. The kidney structure was assessed at postnatal weeks 1 and 12 and the expression of proteins of interest at term and at week 1. Blood pressure was measured in male offspring by telemetry from postnatal month 2 to postnatal month 9. The numbers of glomeruli at weeks 1 and 12 were significantly lower and, in males, telemetrically measured mean arterial blood pressure after month 5 was higher in offspring of dams on a high- or low- compared with intermediate-sodium diet. A high-salt diet was paralleled by higher concentrations of marinobufagenin in the amniotic fluid and an increase in the expression of both sprouty-1 and glial cell-derived neutrophic factor in the offspring's kidney. The expression of FGF-10 was lower in offspring of dams on a low-sodium diet, and the expression of Pax-2 and FGF-2 was lower in offspring of dams on a high-sodium diet. Both excessively high and excessively low sodium intakes during pregnancy modify protein expression in offspring kidneys and reduce the final number of glomeruli, predisposing the risk of hypertension later in life. [ABSTRACT FROM AUTHOR]

Impaired intrauterine nephrogenesis-most clearly illustrated by low nephron number-is frequently associated with low birthweight and has been recognized as a powerful risk factor for renal disease; it increases the risks of low glomerular filtration rate, of more rapid progression of primary kidney disease, and of increased incidence of chronic kidney disease or end-stage renal disease. Another important consequence of impaired nephrogenesis is hypertension, which further amplifies the risk of onset and progression of kidney disease. Hypertension is associated with low nephron numbers in white individuals, but the association is not universal and is not seen in individuals of African origin. The derangement of intrauterine kidney development is an example of a more general principle that illustrates the paradigm of plasticity during development-that is, that transcription of the genetic code is modified by epigenetic factors (as has increasingly been documented). This Review outlines the concept of prenatal programming and, in particular, describes its role in kidney disease and hypertension. [ABSTRACT FROM AUTHOR]

Current salt intake is too high. Current evidence documents that salt is crucial to the genesis of hypertension. [ABSTRACT FROM AUTHOR]

Hypertension is an important independent risk factor for renal disease. If hypertension and chronic renal disease co-exist, as is common in patients with diabetes mellitus, the risk of cardiovascular disease is heightened. The importance of rigorous blood pressure control is recognized in current guidelines, with a recommended target of office blood pressure of < 130/80 mmHg; although ambulatory blood pressure may be more appropriate in order to identify the 24-hour hypertensive burden. Even lower blood pressure may further reduce the progression of chronic kidney disease, but the incidence of cardiovascular events may increase. Albuminuria not only indicates renal damage, but is also a powerful predictor of cardiovascular morbidity and mortality at least in patients with high cardiovascular risk and potentially pre-existing vascular damage. Management of the multiple factors for renal and cardiovascular disease is mandatory in the diabetic patient. The renin-angiotensin system (RAS) plays a pivotal role in the progression of renal disease, as well as in hypertension and target-organ damage. The use of agents that target the RAS confer renoprotection in addition to antihypertensive activity. There is extensive evidence of the renoprotective effect of angiotensin II receptor blockers (ARBs), and specifically telmisartan. In addition to providing 24-hour blood pressure control, clinical studies in patients with diabetes show that telmisartan improves renal endothelial function, prevents progression from microalbuminuria to macroalbuminuria, slows the decline in glomerular filtration rate and reduces proteinuria in overt nephropathy. These effects cannot be solely attributed to blood pressure control. In contrast to other members of the ARB class, the renoprotective effect of telmisartan is not confined to the management of diabetic nephropathy; slowing the progression of albuminuria has been demonstrated in the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET ®), which included diabetic and non-diabetic patients at high risk of cardiovascular events. [ABSTRACT FROM AUTHOR]

The article offers information about the forthcoming World Kidney Day slated on March 12, 2009 which will emphasize the role of hypertension in renal disease.