Hydration and endocrine responses to intravenous fluid and oral glycerol.

Athletes use intravenous (IV) saline in an attempt to maximize rehydration. The diuresis from IV rehydration may be circumvented through the concomitant use of oral glycerol. We examined the effects of rehydrating with differing regimes of oral and IV fluid, with or without oral glycerol, on hydration, urine, and endocrine indices. Nine endurance-trained men were dehydrated by 4% bodyweight, then rehydrated with 150% of the fluid lost via four protocols: (a) oral = oral fluid only; (b) oral glycerol = oral fluid with added glycerol (1.5 g/kg); (c) IV = 50% IV fluid, 50% oral fluid; and (d) IV with oral glycerol = 50% IV fluid, 50% oral fluid with added glycerol (1.5 g/kg), using a randomized, crossover design. They then completed a cycling performance test. Plasma volume restoration was highest in IV with oral glycerol > IV > oral glycerol > oral. Urine volume was reduced in both IV trials compared with oral. IV and IV with oral glycerol resulted in lower aldosterone levels during rehydration and performance, and lower cortisol levels during rehydration. IV with oral glycerol resulted in the greatest fluid retention. In summary, the IV conditions resulted in greater fluid retention compared with oral and lower levels of fluid regulatory and stress hormones compared with both oral conditions.

Serum 25-hydroxy vitamin D concentrations are more deficient/insufficient in peritoneal dialysis than haemodialysis patients in a sunny climate.

BACKGROUND: Research has identified associations between serum 25(OH)D and a range of clinical outcomes in chronic kidney disease and wider populations. The present study aimed to investigate vitamin D deficiency/insufficiency in dialysis patients and the relationship with vitamin D intake and sun exposure. METHODS: A cross-sectional study was used. Participants included 30 peritoneal dialysis (PD) (43.3% male; 56.87 ± 16.16 years) and 26 haemodialysis (HD) (80.8% male; 63.58 ± 15.09 years) patients attending a department of renal medicine. Explanatory variables were usual vitamin D intake from diet/supplements (IU day(-1) ) and sun exposure (min day(-1) ). Vitamin D intake, sun exposure and ethnic background were assessed by questionnaire. Weight, malnutrition status and routine biochemistry were also assessed. Data were collected during usual department visits. The main outcome measure was serum 25(OH)D (nm). RESULTS: Prevalence of inadequate/insufficient vitamin D intake differed between dialysis modality, with 31% and 43% found to be insufficient (<50 nm) and 4% and 33% found to be deficient (<25 nm) in HD and PD patients, respectively (P < 0.001). In HD patients, there was a correlation between diet and supplemental vitamin D intake and 25(OH)D (ρ = 0.84, P < 0.001) and average sun exposure and 25(OH)D (ρ = 0.50, P < 0.02). There were no associations in PD patients. The results remained significant for vitamin D intake after multiple regression, adjusting for age, gender and sun exposure. CONCLUSIONS: The results highlight a strong association between vitamin D intake and 25(OH)D in HD but not PD patients, with implications for replacement recommendations. The findings indicate that, even in a sunny climate, many dialysis patients are vitamin D deficient, highlighting the need for exploration of determinants and consequences.

Arterial stiffness, central blood pressure and body size in health and disease.

BACKGROUND: Body size is associated with increased brachial systolic blood pressure (SBP) and aortic stiffness. The aims of this study were to determine the relationships between central SBP and body size (determined by body mass index (BMI), waist circumference and waist/hip ratio) in health and disease. We also sought to determine if aortic stiffness was correlated with body size, independent of BP. METHODS: BMI, brachial BP and estimated central SBP (by SphygmoCor and radial P2) were recorded in controls (n=228), patients with diabetes (n=211), coronary artery disease (n=184) and end-stage kidney disease (n=68). Additional measures of waist circumference and arterial stiffness (aortic and brachial pulse wave velocity (PWV)) were recorded in a subgroup of 75 controls (aged 51 ± 12 years) who were carefully screened for factors affecting vascular function. RESULTS: BMI was associated with brachial (r=0.30; P<0.001) and central SBP (r=0.29; P<0.001) in the 228 controls, but not the patient populations (r<0.13; P>0.15 for all comparisons). In the control subgroup, waist circumference was also significantly correlated with brachial SBP (r=0.29; P=0.01), but not central SBP (r=0.22; P=0.07). Independent predictors of aortic PWV in the control subgroup were brachial SBP (ß=0.43; P<0.001), age (ß=0.37; P<0.001), waist circumference (ß=0.39; P=0.02) and female sex (ß=-0.24; P=0.03), but not BMI. CONCLUSION: In health, there are parallel increases in central and brachial SBP as BMI increases, but these relationships are not observed in the presence of chronic disease. Moreover, BP is a stronger correlate of arterial stiffness than body size.

Cardiovascular disease in peritoneal dialysis patients.

Patients on peritoneal dialysis have a high level of morbidity and mortality associated with atherosclerotic cardiovascular disease and they also have an increased risk of sudden death. The atherosclerosis seen in peritoneal dialysis patients is associated with both traditional cardiovascular risk factors such as low levels of physical activity, hyperlipidemia, hypertension, diabetes and smoking as well as non-traditional risk factors such as elevated oxidative stress and inflammation. The atherosclerosis may be preceded by endothelial dysfunction and increased arterial stiffness. Measures of arterial stiffness such as aortic pulse wave velocity predict morbidity and mortality. Numerous studies have reported that the elevated levels of oxidative stress and inflammation in this population are associated with arterial stiffness and in turn with the development of cardiovascular disease. A number of studies have reported that peritoneal dialysis is associated with lower levels of oxidative stress and inflammation compared to haemodialysis. A small number of trials have extended this work to determine associations between oxidative stress and inflammation with vascular or myocardial structure and function with equivocal results. The decision to undergo either peritoneal or haemodialysis is based on many factors which include the differential damage the renal replacement therapy may have on the cardiovascular system. Current evidence suggests this may vary over time. Previous randomised controlled trials and many other observational studies have produced conflicting results as to which therapy may have a cardiovascular advantage. Some registry data suggests peritoneal dialysis is associated with a lower mortality than haemodialysis in the first one-two years but thereafter may be higher on peritoneal dialysis than haemodialysis. Other registry data do not support this. Further long-term studies assessing surrogate and hard endpoint cardiovascular outcomes in peritoneal dialysis are required.

Folate supplementation fails to affect vascular function and carotid artery intima media thickness in cyclosporin A-treated renal transplant recipients.

BACKGROUND: Cyclosporin A (CsA)-treated renal transplant recipients (RTR) exhibit relative hyperhomocystinemia and vascular dysfunction. Folate supplementation lowers homocysteine and has been shown to improve vascular function in healthy subjects and patients with coronary artery disease. The aim of this study was to assess the effects of 3 months of folate supplementation (5 mg/day) on vascular function and structure in RTR. METHODS: A double-blind, placebo-controlled crossover study was conducted in 10 CsA-treated RTR. Vascular structure was measured as carotid artery intima media thickness (IMT) and function was assessed as changes in brachial artery diameter during reactive hyperemia (RH) and in response to glyceryl trinitrate (GTN). Function data were analyzed as absolute and percent change from baseline and area under the diameter/time curve. Blood samples were collected before and after supplementation and analyzed for total plasma homocysteine, folate, vitamin B12 and asymmetric dimethyl arginine (ADMA) in addition to regular measures of hemoglobin, hematocrit, mean corpuscular volume (MCV) and serum creatinine. RESULTS: Folate supplementation significantly increased plasma folate by 687% (p < 0.005) and decreased homocysteine by 37% (p < 0.05) with no changes (p > 0.05) in vitamin B12 or ADMA. There were no significant (p > 0.05) changes in vascular structure or function during the placebo or the folate supplementation phases; IMT; placebo pre mean +/- SD, 0.52 +/- 0.12, post 0.50 +/- 0.11; folate pre 0.55 +/- 0.17, post 0.49 +/- 0.20 mm, 5% change in brachial artery diameter (RH, placebo pre 10 +/- 8, post 6 +/- 5; folate pre 9 +/- 7, post 7 +/- 5; GTN, placebo pre 18 +/- 10, post 17 +/- 9, folate pre 16 +/- 9, post-supplementation 18 +/- 8). CONCLUSION: Three months of folate supplementation decreases plasma homocysteine but has no effect on endothelial function or carotid artery IMT in RTR.

Baseline serum lipids and renal function in chronic kidney disease patients entering the LORD trial.

OBJECTIVE: Previous studies investigating associations between serum lipids and renal disease have generally not taken into account dietary intake or physical activity both known to influence circulating lipids. Furthermore, inclusion of patients on HMG-CoA reductase inhibitors may also have influenced findings due to the pleiotropic effect of this medication. Therefore, the aim of this study is to determine the relationships between serum lipids and renal function in a group of patients not taking lipid-lowering medication and taking into account dietary intake and physical activity. METHODS: Data from 100 patients enrolled in the Lipid Lowering and Onset of Renal Disease (LORD) trial were used in this study. Patients were included with serum creatinine > 120 micromol/l, and excluded if they were taking lipid-lowering medication. Unadjusted and adjusted relationships were determined between fasting serum lipid concentrations (total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol/HDL ratio) and measures of renal function (estimated glomerular filtration rate (eGFR), creatinine clearance and serum creatinine) and urinary protein excretion. RESULTS: Significant (p < 0.05) negative unadjusted relationships were found between lipids (total cholesterol, LDL and HDL cholesterol) and serum creatinine. In support of these findings, logarithmically-transformed lipids (total cholesterol, LDL and HDL cholesterol) were significantly associated with eGFR and creatinine clearance although the effects were of a smaller magnitude. Adjustment for dietary saturated fat intake and physical activity did not substantially change these effects. CONCLUSION: These data do not support the premise that lipids are associated with renal dysfunction in patients with normocholesterolemia.

Acute exposure to cyclosporine does not increase plasma homocysteine in rats.

There is interest in the postulate that cyclosporine a (CsA) contributes to the elevated homocysteine levels seen in organ transplant recipients, as hyperhomocysteinemia is now considered an independent risk factor for cardiovascular disease (CVD) and may partially explain the increased prevalence of CVD in this population. The main purpose of this investigation was to determine the effect of CsA administration on plasma homocysteine. Eighteen female Sprague Dawley rats (4 months old) were randomly assigned to either a treatment or a control group. For 18 days the treatment group received of CsA (25 mg/kg/d) while the control group received the same volume of the vehicle. Blood samples obtained following sacrifice to measure CsA, total homocysteine, and plasma creatinine. There were no significant differences in plasma homocysteine (mean values +/- SD: treatment = 4.79 +/- 0.63 micromol/L, control = 4.46 +/- 0.75 micromol/L; P = .37). Homocysteine was not significantly correlated with final CsA concentrations (r = .17; P = .69). There was a significant difference in plasma creatinine values between the two groups (treatment = 60.44 +/- 7.68 micromol/L, control = 46.33 +/- 1.66 micromol/L; P < .001). Furthermore, plasma homocysteine and creatinine were positively correlated with the treatment group (r = .73; P < .05) but not the controls (r = -.10; P = .81). In conclusion, CsA does not influence plasma homocysteine concentrations in rats.

Changes in bone histoquantitative parameters and histochemical staining reactions for aluminium in a group of patients with chronic renal failure following a reduction in the aluminium concentration of the haemodialysis fluid.

Bone biopsies from a group of 16 patients in chronic renal failure treated by intermittent haemodialysis were available for histoquantitative and histochemical assessment before and after the introduction of reverse osmosis treatment of the dialysis fluid. This treatment reduced the aluminium concentration of the fluid from 1.15 mg/l to less than 0.06 mg/l. After the changeover there was an increase in the extent of calcification fronts. Overall, there was a decrease in the histochemical staining reactions for aluminium, although a few cases showed increased reactions. A large percentage of cases showing decreased reactions also had decreased osteoid volumes. It is concluded that reduction of the concentration of aluminium in the dialysis fluid is associated with an improvement in mineralisation state, and this is further evidence of the importance of minimising the aluminium burden of patients with chronic renal failure.

Bone histoquantitative findings and histochemical staining reactions for aluminium in chronic renal failure patients treated with haemodialysis fluids containing high and low concentrations of aluminium.

A total of 112 undecalcified bone biopsies from 67 patients under treatment for chronic renal failure by maintenance haemodialysis was available for retrospective study. The patients were divided into three groups. Group I (15 cases) had been dialysed for the majority of the time in their own homes with a fluid containing a low concentration of aluminium. Group II (28 cases) had been dialysed exclusively in hospital (prior to 1978) with a fluid containing a high concentration of aluminium and group III (24 cases) had been treated exclusively in hospital (from 1978 onwards) with a fluid of low aluminium concentration. The tissues from these groups were subjected to histoquantitative assessment and stained by a histochemical technique to demonstrate aluminium salt. In group II, 71.4% of cases showed positive aluminium staining reactions (at the osteoid/mineralised tissue interface) compared to 26.6% in group I and 37.5% in group III. Staining reactions were also more extensive in group II cases. The osteoid volume was significantly increased and the calcification front extents significantly decreased in group II compared to both groups I and III. A comparison of histochemically positive with negative cases in each group showed a significantly increased osteoid volume and significantly decreased calcification fronts in the positive cases. It was, therefore, concluded that haemodialysis against a fluid containing a high concentration of aluminium leads to intraosseous aluminium accumulation of greater degree in a larger number of patients than a fluid with low aluminium content and that there is an accompanying osteomalacia manifest by an increase in osteoid volume together with diminution in the extent of the calcification fronts.

Pathophysiology of renal fluid retention.

Central to a unifying hypothesis of body fluid regulation is maintenance of arterial circulatory integrity. This may be disturbed by arterial underfilling, either from reduction in cardiac output or by peripheral arterial vasodilation. In cardiac failure (CF), cardiac output falls and the nonosmotic release of arginine vasopressin (AVP) and expression of AVP mRNA in the hypothalamus are stimulated. V2 AVP receptor antagonists correct the impaired water excretion in rats with low-output CF, increase solute free water clearance, correct the hyponatremia in congestive CF patients, and normalize urinary concentrations of the aquaporin-2 (AQP-2) water channels. In conditions associated with peripheral vasodilation, such as cirrhosis, nonosmotic release of AVP also occurs, and AQP-2 gene expression in the rat kidney is up-regulated. In cirrhosis, nitric oxide-mediated vasodilation occurs early prior to water retention. V2 antagonists reverse the latter. In normal pregnancy, plasma AVP is relatively high for the degree of hypoosmolality. Pregnant rats up-regulate AQP-2 in the renal papilla, an effect reversed by V2 receptor antagonists. This supports the hypothesis that AVP is an important mediator of renal water retention in pregnancy. In summary, AVP-mediated water retention through collecting duct AQP-2 water channels is important in both low-output CF and high-output states such as cirrhosis and pregnancy. V2 receptor antagonists reverse the water retention and down-regulate AQP-2 water channels.

Bone disease in analgesic nephropathy.

Clinical, biochemical, radiological and bone biopsy findings were studied in 15 patients with end stage renal disease due to analgesic nephropathy and compared with data from age and sex matched controls who had end stage renal disease from other causes. Patients with analgesic nephropathy had significantly higher osteoid volume (P less than 0.04), reduced calcification fronts (P less than 0.001) and lower percentage mineralization (P less than 0.04). Serum alkaline phosphatase was significantly higher in the analgesic group (P less than 0.005). It is concluded that osteomalacia is more common and severe in the group of patients with end stage renal disease due to analgesic nephropathy. There was no relationship between osteomalacia and the duration of renal failure, acidosis, aluminium deposition or other serum biochemical abnormalities.

Scanning electron microscopy of glomerular and non glomerular red blood cells.

Phase contrast microscopic examination of the urine has been recently shown to be of value in predicting whether hematuria is due to glomerulonephritis or lesions of the lower urinary tract. Glomerular red cells show variations in size and shape and have distorted surfaces. Non glomerular red cells are uniform in size and shape and have smooth surfaces. Scanning electron microscopy was performed on urine sediment containing either glomerular or non glomerular red cells to better define their surface characteristics. Glomerular red cells exhibited a variety of forms, most cells having lumpy projections from the surface, some showing fragmentation of the membrane and others showing gross distortion. In contrast non glomerular red cells show smooth surfaces and usually maintain the normal biconcave disc shape of peripheral red blood cells. Scanning electron microscopy can better define surface structural abnormalities of urinary glomerular and non glomerular red blood cells.

Homocysteine-lowering therapy in renal disease.

Hyperhomocysteinemia is a potential risk factor for vascular disease and is associated with endothelial dysfunction, a predictor of adverse cardiovascular events. Renal patients (end-stage renal failure (ESRF) and transplant recipients (RTR)) exhibit both hyperhomocysteinemia and endothelial dysfunction with increasing evidence of a causative link between the 2 conditions. The elevated homocysteine appears to be due to altered metabolism in the kidney (intra-renal) and in the uremic circulation (extra-renal). This review will discuss 18 supplementation studies conducted in ESRF and 6 in RTR investigating the effects of nutritional therapy to lower homocysteine. The clinical significance of lowering homocysteine in renal patients will be discussed with data on the effects of B vitamin supplementation on cardiovascular outcomes such as endothelial function presented. Folic acid is the most effective nutritional therapy to lower homocysteine. In ESRF patients, supplementation with folic acid over a wide dose range (2 - 20 mg/day) either individually or in combination with other B vitamins will decrease but not normalize homocysteine. In contrast, in RTR similar doses of folic acid normalizes homocysteine. Folic acid improves endothelial function in ESRF patients, however this has yet to be investigated in RTR. Homocysteine-lowering therapy is more effective in ESRF patients than RTR.

Left ventricular function in uremia: echocardiographic and radionuclide assessment in patients on maintenance hemodialysis.

Echocardiography and radionuclide ventriculography were performed in 37 uremic patients on maintenance hemodialysis with no apparent coronary artery disease, pericardial effusion, valvular heart disease or heart failure. These non-invasive studies were performed during the interdialytic period (about 18 hours after a dialysis). Sixty-two percent of our patients had abnormal left ventricular function with one or more abnormal echocardiographic parameters. The significant abnormalities were enlargement of the left ventricular cavity, a reduction of myocardial contractility, and thickening of the left ventricular posterior wall. Similar findings were found in 10 undialyzed uremic patients. Measurement of cardiac index and ejection fraction were found to be inadequate for a full assessment of left ventricular function and other parameters such as the mean velocity of circumferential fiber shortening and mean normalized posterior wall velocity should be included. There is a significant number of hemodialysis patients (7/37) with congestive cardiomyopathic features on the echocardiogram. Their clinical features are no different from the other patients in this study, except they have a significantly higher prevalence of uremic hyperparathyroidism. Our findings support that the existence of a specific uremic cardiomyopathy and uremic hyperparathyroidism may play an important role in the pathogenesis.

Contrasting approaches to end of life and palliative care in end stage kidney disease.

With increased numbers of the elderly, including nursing home patients, being accepted for end-stage kidney disease (ESKD) management, there is heightened interest and focus on end of life decisions, advanced care planning and directives, withdrawal from dialysis and palliative care in this setting. Despite this, care at the individual patient level can vary greatly. Here, we present two contrasting cases to highlight the importance of early and ongoing involvement of palliative care in patients with ESKD. In the first case, a high quality of life was preserved before the patient died with dignity, with early interdisciplinary palliative care involvement. In the second case there was a long protracted period of poor quality of life prior to death. This was associated with resistance to the involvement of palliative care, mainly from the family. Addressing end of life care issues early in the chronic kidney disease (CKD) trajectory and ensuring patients, their families and health care providers are well informed, may contribute to a better outcome for the patient and their family.

Effects of a gliadin-combined plant superoxide dismutase extract on self-perceived fatigue in women aged 50-65 years.

Fatigue syndromes exist on a continuum of severity from mild and transient to the disabling chronic fatigue syndrome, with oxidative stress linked to its pathogenesis. A thermolabile gliadin-combined plant superoxide dismutase (SOD) extract has shown potential in clinical trials as a therapeutic antioxidant. This study investigated the effects of 12 weeks of 500 mg/day of a SOD/gliadin supplement on fatigue. Thirty-eight women aged 50-65 years with self-perceived fatigue entered this randomized, double-blind, placebo-controlled trial. The primary outcome measure was general fatigue determined by the Multidimensional Fatigue Inventory (MFI). Secondary outcome measures included other measures of fatigue from the MFI and blood measures of oxidative stress, antioxidant status and hormones. There were no significant (P>0.05) differences between, or within groups, for decreases in general fatigue (active=1.6%, placebo=4.1%). There were no within or between group differences (P>0.05) in other measures of fatigue (physical fatigue, reduced activity, reduced motivation, mental fatigue and total fatigue score). In regard to the biochemical measures, there were non-significant (P>0.05) differences in increases in plasma SOD activity (active=7.1%, placebo=12.2%), plasma GPx activity (active=2.4%, placebo=0.7%), red blood cell GPx activity (active=9.8%, placebo=4.4%). Markers of oxidative stress were decreased but there were no differences (P>0.05) within or between groups; malondialdehyde (active=4.1%, placebo=1.6%), F-2 isoprostanes (active=14.7%, placebo=22.4%). There was a trend (P=0.08) for a decrease in cortisol in the active group (24.6%), however this was not significantly different from the decrease in the placebo participants (4.1%). DHEA differences were not significant (P<0.05) and declined 1.3% in the active group and 14.4% in the placebo group. In summary, the thermolabile SOD/gliadin supplement had no significant effect on self-perceived fatigue, antioxidants, oxidative stress or hormones in women aged 50-65 years.

Bile pigment pharmacokinetics and absorption in the rat: therapeutic potential for enteral administration.

BACKGROUND AND PURPOSE: Bilirubin and biliverdin possess antioxidant and anti-inflammatory properties and their exogenous administration protects against the effects of inflammation and trauma in experimental models. Despite the therapeutic potential of bile pigments, little is known about their in vivo parenteral or enteral absorption after exogenous administration. This study investigated the absorption and pharmacokinetics of bile pigments after i.v., i.p. and intraduodenal (i.d.) administration in addition to their metabolism and routes of excretion. EXPERIMENTAL APPROACH: Anaesthetized Wistar rats had their bile duct, jugular and portal veins cannulated. Bile pigments were infused and their circulating concentrations/biliary excretion were measured over 180 min. KEY RESULTS After i.v. administration of unconjugated bilirubin, biliverdin and bilirubin ditaurate, their plasma concentrations decreased exponentially over time. Subsequently, native and metabolized compounds appeared in the bile. When administered i.p., their absolute bioavailabilities equalled 14.0, 16.1 and 33.1%, respectively, and correspondingly 38, 28 and 34% of the same bile pigment doses were excreted in the bile. Administration of unconjugated bilirubin and bilirubin ditaurate i.d. increased their portal and systemic concentrations and their systemic bioavailability equalled 1.0 and 2.0%, respectively. Correspondingly, 2.7 and 4.6%, of the doses were excreted in the bile. Biliverdin was rapidly metabolized and these products were absorbed and excreted via the urine and bile. CONCLUSIONS AND IMPLICATIONS: Bile pigment absorption from the peritoneal and duodenal cavities demonstrate new routes of administration for the treatment of inflammatory and traumatic pathology. Oral biliverdin administration may lead to the production of active metabolite that protect from inflammation/complement activation.

Antioxidant supplementation enhances erythrocyte antioxidant status and attenuates cyclosporine-induced vascular dysfunction.

The aim of this study was to determine the effects of dietary antioxidant supplementation with alpha-tocopherol and alpha-lipoic acid on cyclosporine-induced alterations to erythrocyte and plasma redox balance, and cyclosporine-induced endothelial and smooth muscle dysfunction. Rats were randomly assigned to either control, antioxidant, cyclosporine or cyclosporine + antioxidant treatments. Cyclosporine A was administered for 10 days after an 8-week feeding period. Plasma was analyzed for alpha-tocopherol, total antioxidant capacity, malondialdehyde and creatinine. Erythrocytes were analyzed for glutathione, methemoglobin, superoxide dismutase, catalase, glutathione peroxidase, glucose-6-phosphate dehydrogenase, alpha-tocopherol and malondialdehye. Vascular endothelial and smooth muscle function was determined in vitro. Antioxidant supplementation resulted in significant increases in erythrocyte alpha-tocopherol concentration and glutathione peroxidase activity in both of the antioxidant-supplemented groups. Cyclosporine administration caused significant decreases in glutathione concentration, methemoglobin concentration and superoxide dismutase activity. Antioxidant supplementation attenuated the cyclosporine-induced decrease in superoxide dismutase activity. Cyclosporine therapy impaired both endothelium-independent and -dependent relaxation of the thoracic aorta, and this was attenuated by antioxidant supplementation. In summary, dietary supplementation with alpha-tocopherol and alpha-lipoic acid attenuated the cyclosporine-induced decrease in erythrocyte superoxide dismutase activity and attenuated cyclosporine-induced vascular dysfunction.

Pathogenesis of sodium and water retention in cardiac failure.

The pathophysiology of sodium and water retention in heart failure is discussed in the context of a unifying hypothesis of body fluid volume regulation. Critical to this hypothesis is the maintenance of arterial circulatory integrity, which can be disturbed by either a reduction in cardiac output or a fall in systemic vascular resistance secondary to arterial vasodilatation, as seen in high output heart failure. The filling of the arterial circulation is sensed by receptors in the left ventricle, carotid artery, aortic arch and renal afferent arteriole. Effector mechanisms involve non-osmotic vasopressin synthesis and release, the renin-angiotensin-aldosterone system and the sympathetic nervous system. In low output heart failure non-peptide selective orally active vasopressin V2-receptor antagonists correct the hyponatremia, hypoosmolality, and water retention and decrease urinary aquaporin-2 water channels, supporting the role of vasopressin in the water retention seen in heart failure. In advanced heart failure aldosterone escape does not occur because of diminished distal delivery of sodium which also contributes to the resistance to atrial natriuretic peptide seen in heart failure. In high output cardiac failure arterial underfilling associated with arterial vasodilation stimulates activation of neurohumoral systems. Tailored specific selective inhibition of these neurohumoral systems, perhaps in combination, may enable more effective treatment of cardiac failure.