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In the past two decades, nephropathy in type 2 diabetes has emerged as a major public health issue. The purpose of this presentation is to review the epidemiology of diabetic [...]

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 [...]

Introduction The kidney is both a cause and victim of hypertension. High blood pressure is a key pathogenetic factor that contributes to deterioration of kidney function. Presence of kidney disease [...]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.amjmed.2006.01.012 Byline: Eberhard Ritz Keywords: Angiotensin; Angiotensin-converting enzyme inhibitor; Angiotensin II receptor blocker; Antihypertension; Kidney; Type 2 diabetes mellitus Abstract: The importance of renal function as both a marker of and risk factor for cardiovascular disease is increasingly recognized. This link is apparent even in the earliest stages of renal dysfunction, at levels that are conventionally considered 'normal.' These findings are of considerable importance, given the prevalence of high-normal levels of albuminuria (i.e., 10 to 20 mg/L) in the general population. There is also a close link between the progression of albuminuria and the development of insulin resistance and type 2 diabetes mellitus, such that kidney disease -- far from being simply a consequence of the metabolic syndrome -- may be considered a component of it. It may be hypothesized that minor derangements of renal function, such as microalbuminuria or reduced glomerular filtration rate, can lead to dysfunction of the endothelium, with the consequence of sensitizing the vasculature to the injurious effects of hypertension, dyslipidemia, and other risk factors. The renin-angiotensin system (RAS) is highly activated in patients with the metabolic syndrome, and this presumably is also true for the intrarenal RAS systems. Both angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are known to reduce the progression of renal damage. Still to be resolved, however, is the optimal dosage; several recent studies indicate that the dosage required for maximal blood pressure reduction is insufficient to provide maximal renoprotection. Author Affiliation: Department of Nephrology, Ruprecht-Karl University, Heidelberg, Germany

Chronic kidney disease (CKD) is complicated by abnormalities that reflect disruption in filtration, tubular, and endocrine functions of the kidney. Our aim was to explore the relationship of specific laboratory result abnormalities and hypertension with the estimated glomerular filtration rate (eGFR) and albuminuria CKD staging framework.

There is convincing evidence for a specific blood pressure-independent effect of ACE inhibitors and angiotensin II receptor blockers on albuminuria in glomerular diseases. Because progression of glomerular diseases is not [...]

Family studies point to important genetic determinants of diabetic nephropathy (DN). Blood pressure is higher in offspring of parents with type 2 diabetes and DN, but the patomechanisms involved have [...]

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 m2and not on dialysis), in terms of worldwide epidemiology, outcomes, causes and pathophysiology, evidence-based treatment, and a call for action.

AbstractBackground:Dose requirements of erythropoietin-stimulating agents (ESAs) can vary considerably over time and may be associated with cardiovascular outcomes. We aimed to longitudinally assess ESA responsiveness over time and to investigate its association with specific clinical end points in a time-dependent approach. Methods:The German Diabetes and Dialysis study (4D study) included 1,255 diabetic dialysis patients, of whom 1,161 were receiving ESA treatment. In those patients, the erythropoietin resistance index (ERI) was assessed every 6 months during a median follow-up of 4 years. The association between the ERI and cardiovascular end points was analyzed by time-dependent Cox regression analyses with repeated ERI measures. Results:Patients had a mean age of 66 ± 8.2 years; 53 were male. During follow-up, a total of 495 patients died, of whom 136 died of sudden death and 102 of infectious death. The adjusted and time-dependent risk for sudden death was increased by 19 per 5-unit increase in the ERI (hazard ratio, HR = 1.19, 95 confidence interval, CI = 1.07-1.33). Similarly, mortality increased by 25 (HR = 1.25, 95 CI = 1.18-1.32) and infectious death increased by 27 (HR = 1.27, 95 CI = 1.13-1.42). Further analysis revealed that lower 25-hydroxyvitamin D levels were associated with lower ESA responsiveness (p = 0.046). Conclusions:In diabetic dialysis patients, we observed that time-varying erythropoietin resistance is associated with sudden death, infectious complications and all-cause mortality. Low 25-hydroxyvitamin D levels may contribute to a lower ESA responsiveness.© 2014 S. Karger AG, Basel

Calcimimetics are indicated for secondary hyperparathyroidism in chronic kidney disease, and some data have suggested their protective role for progression of renal damage. We aimed to evaluate whether a calcimimetic can slow the progression of kidney damage in uninephrectomized apolipoprotein E (ApoE)-deficient (ApoE−/−) mice. To this end, we compared its effect with that of calcitriol. Male ApoE−/−mice (12 wk old) were randomized to undergo sham operation (sham) or unilateral nephrectomy (UNX) and subsequently received the calcimimetic R-568 (4 μg·kg−1·day−1), calcitriol (0.03 μg·kg−1·day−1), or vehicle intraperitoneally. Glomerular number and volume, damage indexes (glomerular, vascular, and interstitial), and glomerular (podocytes, mesangial, and endothelial) cell number and volume were assessed in perfused kidneys after a 12-wk treatment period. Lower numbers of podocytes per glomerulus were observed in the UNX + vehicle group compared with the sham group, and this was prevented in the UNX + R-568 group but not in the UNX + calcitriol group. In parallel, albuminuria was higher in the untreated UNX group compared with the sham group, and the increase was prevented in the UNX + R-568 group. Interstitial fibrosis was more prevalent in the vehicle-treated UNX group compared with the sham group, and this was prevented in the UNX group treated with R-568 and less effectively with calcitriol treatment. In all UNX groups, the weight of the residual kidney was significantly higher compared with all sham groups. No differences were observed in serum ionized calcium and systolic blood pressure between the groups. The calcimimetic R-568 prevented interstial fibrosis and podocyte loss after uninephrectomy in ApoE−/−mice. Minor renal dysfunction, lack of secondary hyperparathyroidism, and hypertension in this model support the hypothesis of direct effects of this compound on glomerular cells.

After several decades during which little attention was paid to vasopressin and/or urine concentration in clinical practice, interest in vasopressin has renewed with the availability of new, potent, orally active vasopressin-receptor antagonists—the vaptans—and with the results of epidemiological studies evaluating copeptin (a surrogate marker of vasopressin) in large population-based cohorts. Several experimental studies in rats and mice had previously shown that vasopressin, acting via vasopressin V2 antidiuretic receptors, contributes to the progression of chronic kidney disease; in particular, to autosomal dominant polycystic kidney disease. New epidemiological studies now suggest a role for vasopressin in the pathogenesis of diabetes mellitus and metabolic disorders via activation of hepatic V1a and/or pancreatic islet V1b receptors. The first part of this Review describes the adverse effects of vasopressin, as revealed by clinical and experimental studies in kidney diseases, hypertension, diabetes and the metabolic syndrome. The second part provides insights into vasopressin physiology and pathophysiology that may be relevant to the understanding of these adverse effects and that are linked to the excretion of concentrated nitrogen wastes and associated hyperfiltration. Collectively, the studies reviewed here suggest that more attention should be given to the vasopressin–thirst–urine concentration axis in clinical investigations and in patient care. Whether selective blockade of the different vasopressin receptors may provide therapeutic benefits beyond their present indication in hyponatraemia requires new clinical trials.

Introduction:Effective therapeutic strategies are warranted to reduce the burden of parathyroid hormone excess related morbidity and mortality. The calcimimetic agent cinacalcet hydrochlorideis a promising treatment strategy in hyperparathyroidism.Areas covered:This review provides an overview of the pharmacokinetics, clinical efficacy, cost-effectiveness, safety and the efficacy profile of cinacalcet in the setting of primary and secondary hyperparathyroidism (p/sHPT). The authors searched PubMed database for English language articles related to cinacalcet in human subjects, published till Dec 2012 – focusing on the period between 2008 and 2012.Expert opinion:The use of cinacalcet in pHPT can be considered on those hypercalcemic patients in whom parathyroidectomy is not performed. However, data on the impact of cinacalcet on hard clinical outcomes in pHPT are missing. Despite effective improvements of biochemical parameters of sHPT, the intention-to-treat-based analysis of the EVOLVE trial did not support the notion that cinacalcet significantly reduces the risk of death or major cardiovascular events in dialysis patients with moderate-to-severe sHPT. Considering the strong evidence indicating beneficial effects of cinacalcet in the setting of HPT, further randomized controlled trials are definitely warranted to evaluate whether calcimimetic treatment might improve mortality and cardiovascular risk in patients with parathyroid hormone excess over a broad spectrum of kidney function.

Accumulating evidence from experimental and epidemiological studies suggests that vitamin D deficiency might be a causal risk factor for cancer and therewith associated mortality. We performed a systematic review in Medline up to February 2012 to identify prospective studies on 25-hydroxyvitamin D (25[OH]D) and cancer mortality as well as on 25(OH)D and survival in cancer patients. Our search retrieved 13 studies on cancer-specific mortality and 20 studies on overall mortality in cancer patients. Data on 25(OH)D and cancer mortality were mainly derived from general populations. The results were inconsistent and yielded either no, inverse or positive associations. By contrast, the majority of studies in cancer patients showed that patients with higher 25(OH)D levels had a decreased risk of mortality. This relationship was particularly evident in cohorts of colorectal cancer patients. In contrast, there was no indication for increased mortality risk with higher vitamin D levels in any cancer cohort. In conclusion, the relationship of vitamin D status and cancerspecific mortality is still unclear and warrants further studies. Our results provide a strong rationale to perform prospective randomized controlled studies to document a potential effect of vitamin D supplementation on survival in cancer patients.

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.

Wasting is common in hemodialysis patients and often is accompanied by cardiovascular disease and inflammation. The cardiovascular risk profile meaningfully changes with the progression of kidney disease, and little is known about the impact of wasting on specific clinical outcomes. This study examined the effects of wasting on the various components of cardiovascular outcome and deaths caused by infection in hemodialysis patients.

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 1and 12and the expression of proteins of interest at term and at week 1. Blood pressure was measured in male offspring by telemetry from postnatal month 2to postnatal month 9. The numbers of glomeruli at weeks 1and 12were significantly lower and, in males, telemetrically measured mean arterial blood pressure after month 5was 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.

We have previously shown that plasma aldosterone levels within the physiologic reference range predicted increased all-cause and cardiovascular disease (CVD) mortality in patients referred for coronary angiography. Decreased kidney function is associated with a marked increase in CVD mortality that is not explained fully by known cardiovascular risk factors. We hypothesized that level of kidney function might modify the association between plasma aldosterone level and CVD mortality.

Despite an only minor reduction in the glomerular filtration rate, uninephrectomy (UNX) markedly accelerates the rate of growth of atherosclerotic plaques in ApoE−/− mice. It has been suggested that vitamin D receptor (VDR) activation exerts an antiproliferative effect on vascular smooth muscle cells, but the side effects may limit its use. To assess a potentially different spectrum of actions, we compared the effects of paricalcitol and calcitriol on remodeling and calcification of the aortic wall in sham-operated and UNX ApoE−/− mice on a diet with normal cholesterol content. Sham-operated and UNX mice were randomly allotted to treatment with solvent, calcitriol (0.03 μg/kg) or paricalcitol (0.1 μg/kg) 5 times/wk intraperitoneally for 10 wk. Semithin (0.6 μm) sections of the aorta were analyzed by 1) morphometry, 2) immunohistochemistry, and 3) Western blotting of key proteins involved in vascular calcification and growth. Compared with sham-operated animals (5.6 ± 0.24), the wall-to-lumen ratio (x100) of the aorta was significantly higher in solvent- and calcitriol-treated UNX animals (6.64 ± 0.27 and 7.17 ± 0.81, respectively, P< 0.05), but not in paricalcitol-treated UNX (6.1 5 ± 0.32). Similar differences were seen with respect to maximal plaque height. Expression of transforming growth factor (TGF)-β1 in aortic intima/plaque was also significantly higher in UNX solvent and UNX calcitriol compared with sham-operated and UNX paricalcitol animals. Treatment with both paricalcitol and calcitriol caused significant elevation of VDR expression in the aorta. While at the dose employed paricalcitol significantly reduced TGF-β expression in plaques, calcitriol in contrast caused significant vascular calcification and elevated expression of related proteins (BMP2, RANKL, and Runx2).

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.

There is an increasing evidence for a specific form of focal segmental glomerulosclerosis (FSGS) related to obesity. Its prevalence has progressively increased in past decades. This form of FSGS represents the tip of an iceberg a much broader spectrum of renal malfunction is linked to visceral obesity, which is closely connected to, but not completely identical with, the concept of ‘metabolic syndrome’.

Despite treatment with renin–angiotensin–aldosterone system (RAAS) inhibitors, patients with diabetes have increased risk of progressive renal failure that correlates with albuminuria. We aimed to assess whether paricalcitol could be used to reduce albuminuria in patients with diabetic nephropathy.

Raised levels of aldosterone, but also concentrations within the normal range are associated with elevated blood pressure. The authors of this Review assess evidence for the role of aldosterone in the development and maintenance of hypertension, including experimental and clinical studies, and discuss the genetic and environmental mechanisms that underlie its effects.

At all stages of chronic kidney disease (CKD) cardiovascular death is the most prominent cause of mortality. Current treatment options are still not completely satisfactory in this group of high cardiovascular risk patients. Experimental data and clinical observations suggest a role of secondary hyperparathyroidism, hyperphosphatemia, and hypercalcemia in the genesis of cardiovascular complications of CKD. The ubiquitous expression of the calcium-sensing receptor, which is targeted by calcimimetics and the pleiotropic effects of calcimimetics, make this class of drugs potential candidates for cardiovascular intervention.

In this extensive Review, Stefan Pilz and colleagues discuss the potential mechanisms by which vitamin D might affect blood pressure and explore the clinical evidence for an association between vitamin D and arterial hypertension. The authors also make recommendations for vitamin D supplementation in patients with hypertension and 25-hydroxyvitamin D levels below target values.

This article summarizes the current hypotheses that link visceral obesity and kidney malfunction and provides information on the epidemiology and renal pathology resulting from visceral obesity.

The prevalence of chronic kidney disease (CKD) continues to increase worldwide as does end-stage renal disease. The most common, but not the only, causes of CKD are hypertension and diabetes. CKD is associated with a significant increase in cardiovascular risk as most patients with CKD die of a cardiovascular cause. Moreover, cardiovascular risk increases proportionally as estimated glomerular filtration rate falls below 60 ml/min. Cardiovascular causes of death in CKD are more prevalent than those from cancer; as a result, the identification and reduction of CKD is a public health priority. High blood pressure is a key pathogenic factor that contributes to the deterioration of kidney function. The presence of kidney disease is a common and underappreciated preexisting medical cause of resistant hypertension. Therefore, treatment of hypertension has become the most important intervention in the management of all forms of CKD. For this reason, the forthcoming World Kidney Day on 12 March 2009 will emphasize the role of hypertension.

AbstractSorry, there is no abstract. Copyright © 2008 S. Karger AG, Basel

Even minor reduction in glomerular filtration rate accelerates atherogenesis and increases cardiovascular risk. The current study on the apolipoprotein E −/− mouse was designed to investigate whether nephron reduction by uninephrectomy causes cardiac remodeling and whether this is prevented by antioxidative treatment.

Angiotensin II accelerates and renin-angiotensin system blockade halts progression; blockade with high doses even reverses established glomerulosclerosis. Aldosterone also accelerates progression of glomerulosclerosis, partially independently of angiotensin II. The purpose of this study was to assess the relative ability of an angiotensin receptor type 1 (AT1) blocker, a mineralocorticoid receptor blocker, and their combination to reverse glomerulosclerosis. Sprague-Dawley rats were subjected to subtotal renal ablation (SNX) or sham operation. Eight weeks after surgery, they were either euthanized or allocated to treatment with vehicle, losartan, spironolactone, their combination, or unspecific antihypertensive treatment (dihydralazine) for 4 wk. Renal morphology was evaluated by stereology in tissues obtained using pressure-controlled perfusion fixation. Systolic blood pressure was significantly higher in SNX compared with sham-operated animals and decreased in all treatment groups. Compared with wk 8after SNX, the glomerulosclerosis index (GSI) had increased further by week 12in the vehicle- and dihydralazine-treated groups but was significantly lowered in the SNX+losartan as well as in the SNX+losartan+spironolactone groups and had not progressed further in the SNX+spironolactone group. The study confirms the partial regression of established glomerulosclerosis in subtotally nephrectomized rats after high-dose AT1receptor blockade. Nonhyperkalemic doses of spironolactone prevented the increase but failed to decrease the GSI below the 8-wk level and preserved podocyte numbers. Combining the AT1blocker with mineralocorticoid receptor blockade failed to further increase the regression of glomerulosclerosis.

Patients with renal insufficiency develop secondary hyperparathyroidism. Monotherapy with active vitamin D or calcimimetics ameliorates secondary hyperparathyroidism. We compared kidney damage in subtotally nephrectomized (SNX) rats treated with active vitamin D (calcitriol) or the calcimimetic R-568. Male Sprague-Dawley SNX and sham-operated (sham-op) rats were randomized into the following treatment groups: SNX + R-568, SNX + calcitriol, SNX + vehicle, sham-op + R-568, sham-op + calcitriol, and sham-op + vehicle. Albuminuria and blood pressure were monitored and kidneys were examined using morphometry, immunohistochemistry, quantitative RT-PCR, and in situ hybridization. Parathyroid hormone concentrations were lowered to the same extent by the two interventions, although phosphorus and the calcium-phosphorus product were reduced only by R-568 treatment. SNX rats developed marked albuminuria, which was significantly reduced in ad libitum- and pair-fed animals treated with R-568 and animals treated with calcitriol. Mean glomerular volume (6.05 ± 1.46 vs. 2.70 ± 0.91 mm3), podocyte volume (831 ± 127 vs. 397 ± 67 μm3), the degree of foot process fusion (mean width of foot processes = 958 ± 364 vs. 272 ± 35 nm), and glomerular basement membrane thickness (244 ± 6 vs. 267 ± 23 nm), as well as desmin staining, were significantly higher in vehicle-treated SNX than sham-operated animals. These changes were ameliorated with R-568 and calcitriol. In SNX, as well as sham-operated, animals, expression of the calcium-sensing receptor (protein and mRNA) was upregulated by treatment with the calcimimetic, but not calcitriol. Calcitriol and R-568 were similarly effective in ameliorating kidney damage.

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.

Renal failure causes sympathetic overactivity and inadequate capillary growth in response to cardiomyocyte hypertrophy in experimental renal failure, as well as in uremic patients. In nonuremic animals, sympathetic overactivity was shown to suppress capillary growth. The purpose of this study was to examine whether blockade with α- and β-adrenoblockers ameliorates the capillary deficit that was documented in the hearts of rats with moderate renal failure. Male Sprague–Dawley rats, 3 days after surgical ablation [subtotal nephrectomy (SNX)] or sham operation (sham), were treated with phenoxybenzamine, metoprolol, or a combination of both: After 12 weeks, the hearts were investigated using morphometric and stereologic techniques. The length density of myocardial capillaries was lower (p<0.05) in untreated SNX than in sham (2,786±372 vs 3,397±602 mm/mm3); the decrease was abrogated by metoprolol (3,305±624 mm/mm3), but not by phenoxybenzamin (2,628±480 mm/mm3). The intercapillary distance increased (p<0.05) in SNX (20.5±1.5 μm) and tended to be lower after metoprolol treatment (19.0±1.9 μm). The media area of intramyocardial arterioles was significantly higher in untreated SNX (1,158±1,343 vs 686±771 μm2in sham). Metoprolol in nonhypotensive doses prevents the capillary deficit in the hearts of rats with moderate renal failure and presents an argument for an important role of sympathetic overactivity in the genesis of the capillary deficit in moderate chronic renal insufficiency.Renal failure causes sympathetic overactivity and inadequate capillary growth in response to cardiomyocyte hypertrophy in experimental renal failure, as well as in uremic patients. In nonuremic animals, sympathetic overactivity was shown to suppress capillary growth. The purpose of this study was to examine whether blockade with α- and β-adrenoblockers ameliorates the capillary deficit that was documented in the hearts of rats with moderate renal failure. Male Sprague–Dawley rats, 3 days after surgical ablation [subtotal nephrectomy (SNX)] or sham operation (sham), were treated with phenoxybenzamine, metoprolol, or a combination of both: After 12 weeks, the hearts were investigated using morphometric and stereologic techniques. The length density of myocardial capillaries was lower (p<0.05) in untreated SNX than in sham (2,786±372 vs 3,397±602 mm/mm3); the decrease was abrogated by metoprolol (3,305±624 mm/mm3), but not by phenoxybenzamin (2,628±480 mm/mm3). The intercapillary distance increased (p<0.05) in SNX (20.5±1.5 μm) and tended to be lower after metoprolol treatment (19.0±1.9 μm). The media area of intramyocardial arterioles was significantly higher in untreated SNX (1,158±1,343 vs 686±771 μm2in sham). Metoprolol in nonhypotensive doses prevents the capillary deficit in the hearts of rats with moderate renal failure and presents an argument for an important role of sympathetic overactivity in the genesis of the capillary deficit in moderate chronic renal insufficiency.

Aus unterschiedlichen Gründen kann es zu massiven Flüssigkeitseinlagerungen im Subkutangewebe kommen. In extremen Fällen kann das zu Aszites oder Lungenödem führen. Nicht in allen Fällen ist eine Behandlung mit Diuretika nötig und sinnvoll.

In experimental models of renal transplantation, upregulation of the endothelin (ET) system and amelioration of renal injury by ET-receptor blockers have been documented. In contrast, little information is available on the expression of the ET system in human kidney allografts. It was the purpose of the present study to analyse by immunohistology the expression of ET-1 as well as of the two ET receptors (ET-RA and ET-RB) in the different cells and compartments of kidney grafts and control kidneys.

The population of incident dialysis patients is progressively ageing and dialysis outcome is particularly poor in the elderly. There is little documentation whether late referral is more frequent in the very elderly (> or =75 years) as compared with non-elderly patients and whether it contributes, at least in part, to their particularly poor outcome.

Diabetic nephropathy has developed into a worldwide epidemic and is responsible for the majority of end-stage renal disease in most countries. Antihypertensive treatment slows the progression of the disease. In addition, blockade of the renin–angiotensin system reduces the degree of albuminuria and angiotensin II receptor blockers (ARBs) have been shown to delay the progression from microalbuminuria to overt proteinuria in patients with diabetes. However, few studies have examined whether the initial stage of diabetic nephropathy (i.e. the development of microalbuminuria) in patients with type 2 diabetes can be slowed or prevented by ARB treatment. The Randomised Olmesartan And Diabetes MicroAlbuminuria Prevention (ROADMAP) study is a placebo-controlled, multicentre, double-blind, parallel group study investigating the effect of the ARB, olmesartan medoxomil, on the incidence of microalbuminuria. A total of 4400 type 2 diabetes patients with normoalbuminuria will be randomized to treatment with 40 mg of olmesartan medoxomil once daily or placebo. Goal blood pressure will be 130/80 mmHg. The primary endpoint of the study is the occurrence of microalbuminuria. In ROADMAP, we will also assess as secondary endpoints the effects of olmesartan on fatal and non-fatal cardiovascular events in patients with diabetes. In addition, within subgroups of the ROADMAP patients, the effects of olmesartan on retinopathy and other microvascular circulations will be analysed. The study is expected to last a median of 5 years. The ROADMAP study will answer the question whether an ARB can prevent or delay the onset of microalbuminuria and whether this translates into protection against cardiovascular events and renal disease.

It has been hypothesized that in renal failure, exogenous glycation compounds from food accumulate and play a major pathogenetic role when renal excretion is impaired.

AbstractIt 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

Smoking increases the risk of end-stage renal failure in patients with primary renal disease. Whether and to what extent smoking affects the kidneys in diabetic patients with normal renal function and variable degrees of proteinuria has not been fully studied.

Family studies point to important genetic determinants of diabetic nephropathy (DN). Blood pressure (BP) is higher in offspring of patients with type 2 diabetes and DN, but the pathomechanisms involved have not been elucidated.

The combination of diabetes and chronic kidney disease is associated with increased mortality and reduced quality of life. Recent studies have shown that, in general, late referral of patients to the renal unit increases mortality, and that patients with diabetes who are referred late have a particularly poor prognosis. Several co-morbid conditions have been shown to contribute to poor patient outcomes, including both cardiovascular disease and anaemia. In patients with diabetic nephropathy, anaemia is more severe and is seen earlier than in patients with non-diabetic renal disease. Although the treatment of anaemia with recombinant human erythropoietin (rhEPO; epoetin) is well established, the only data currently available concerning the effects of early intervention in patients with diabetic nephropathy are from small-scale studies. Therefore, two large-scale studies have been designed to provide information on the efficacy of epoetin treatment and on how current management strategies might be improved. The Anaemia CORrection in Diabetes (ACORD) study will provide information on the potential cardiac benefits of early anaemia management in patients with early, type 2 diabetic nephropathy. The Individualised Risk-profiling In DIabEtes Mellitus (IRIDIEM) study will provide evidence-based guidance in risk factor management, by assessing the efficacy of individualized interventions.

The recent recognition that hyperphosphatemia is a strong predictor of survival on dialysis has rekindled interest in the regulation and control of serum phosphate. In incipient renal failure hyperphosphatemia is prevented by increased fractional renal phosphate excretion mediated via an increase in parathyroid hormone and the novel phosphaturic hormone FGF-23 (and possibly others). At a glomerular filtration rate of approximately 30 ml/min this compensatory mechanism fails and hyperphosphatemia ensues. Pre-dialytic serum phosphate concentrations of >6 mg/dl increase cardiac mortality presumably to a large extent, but not exclusively, via promoting vascular calcification. It has recently been recognized that vascular calcification is not only a passive precipitation process following transgression of the critical Ca-×-P product, but is an active process accompanied by expression of osteoblastic bone markers in the vessel wall. Because of the recent recognition of the relation between vascular calcification and serum phosphate as well as serum calcium, there is a need for novel calcium-free phosphate binders. Currently sevelamer and lanthanum carbonate have been introduced and trivalent iron preparations are under development.

Sympathetic overactivity is a hallmark of chronic renal failure. In a previous experimental study, the sympatholytic drug moxonidine (MOX) had beneficial effects on progression of chronic renal failure. The present study investigates whether moxonidine influences the expression of genes associated with adaptive changes in kidneys of subtotally nephrectomized rats.

Background:Interleukin-8 (IL-8) is considered a deleterious chemokine involved in renal injury in glomerulonephritis (GN). IL-8 may be released as a 77-amino acid (AA) peptide or 72-AA protein. Methods:We evaluated gene and protein expression of IL-8 in 53 renal biopsy specimens from patients with GN and 9 control kidneys. Nonradioactive in situ hybridization and reverse-transcriptase polymerase chain reaction (RT-PCR) were applied to detect IL-8 messenger RNA (mRNA). In immunohistochemistry, a double-staining technique with the use of antibodies against the 77-AA and 72-AA forms of IL-8, as well as glomerular cell antigens, was used. Results:By in situ hybridization, IL-8 mRNA was detected in normal glomerular, tubular, and some interstitial cells. The RT-PCR study showed that IL-8 mRNA expression in control kidneys significantly exceeds that in specimens with GN (0.89 ± 0.82 versus 0.21 ± 0.20; P< 0.003). In control kidneys, major sources of 77-AA IL-8 were podocytes and endothelial cells of interstitial vessels, whereas tubular epithelial cells expressed minute amounts of 72-AA IL-8. In GN specimens, podocyte expression of 72-AA IL-8 varied notably, with the greatest level found in minimal change disease and the lowest level found in acute endocapillary GN. Conversely, increased glomerular expression of the 72-AA form of IL-8 was a general feature of GN, with its level significantly exceeding that of the 77-AA form in acute endocapillary GN (P< 0.01). Conclusion:Our results suggest that intrinsic glomerular cell production of IL-8, in particular the 77-AA form, may be relevant for preservation of the glomerular architecture.