Association of adiponectin and leptin with serum lipids and erythrocyte omega-3 and omega-6 fatty acids in dialysis patients.

AIMS: Besides regulating energy metabolism, leptin promotes and adiponectin suppresses inflammation which is a common feature of end-stage renal disease (ESRD). Omega-3 fatty acids (n-3FA) exert anti-inflammatory actions by inhibiting pro-inflammatory signal transduction pathways whereas arachidonic acid (an n-6FA) facilitates inflammation by mediating inflammatory signals and serving as precursor of pro-inflammatory eicosanoids. Given the functional overlap between adipokines and n-3FA and n-6FA, we sought to explore their interrelationship in patients with ESRD. METHODS: 44 ESRD patients maintained on hemodialysis (HD), 29 patients receiving peritoneal dialysis (PD), and 10 healthy subjects were enrolled. Body mass index (BMI), plasma leptin, adiponectin, lipids and CRP and erythrocyte fatty acids were measured. RESULTS: Compared to controls adiponectin was elevated and leptin level was reduced in the ESRD group. Adiponectin levels were comparable among PD and HD patients, but leptin and BMI were higher in PD than in HD patients. Despite comparable BMIs, female patients had higher leptin than male patients. Leptin levels were positively associations with BMI, total and LDL cholesterol whereas adiponectin was inversely related with BMI, triglycerides and CRP and directly associated with HDL cholesterol in ESRD patients. Plasma adiponectin was directly associated with erythrocyte n-3 FA (r = 0.581, p = 0.023) and inversely associated with n-6FA (r = -0.640, p = 0.010) in the HD patients. CONCLUSION: A direct association was found between plasma levels of adiponectin and HDL and erythrocyte n-3FA in ESRD patients. Prospective trials are needed to explore the effect of n-3FA supplementation on plasma adipokines and markers of oxidative stress and inflammation in this population.

Increased monocyte adhesion-promoting capacity of plasma in end-stage renal disease - response to antioxidant therapy.

UNLABELLED: End-stage renal disease (ESRD) causes accelerated atherosclerosis which is mediated by oxidative stress and inflammation. Activation and infiltration of monocytes represent the critical steps in atherogenesis which is advanced by oxidized LDL and inhibited by HDL. Via its main apolipoprotein (apoA-I) and constituent enzymes (paraoxonase; glutathione peroxidase (GPX), LCAT) HDL exerts potent antioxidant/anti-inflammatory functions. We have found marked reduction of HDL antioxidant/anti-inflammatory and heightened LDL pro-oxidant/pro-inflammatory activities in ESRD patients. Given the inseparable link between oxidative stress and inflammation, we tested the hypothesis that antioxidant therapy may improve anti-inflammatory (monocyte adhesion-promoting capacity) properties of plasma in ESRD patients. METHODS: We studied 20 hemodialysis patients who after a 4-week wash-out period were treated with a potent antioxidant cocktail (vitamin (v) E, 800 IU; vC, 250 mg; vB6, 100 mg; vB12, 250 µg and folic acid 10 mg daily) for 8 weeks. Twelve healthy volunteers served as control. Pre-dialysis plasma samples were obtained at the onset and conclusion of the study. Markers of oxidative stress and inflammation, apoA-I, HDL-associated enzymes and monocyte adhesion assay were measured using cultured aortic endothelial cells. RESULTS: ESRD patients exhibited reduced plasma level of apoA-1 and antioxidant enzymes, elevated markers of oxidative stress and inflammation and heightened monocyte adhesion-promoting capacity. Antioxidant therapy failed to improve these abnormalities. CONCLUSIONS: High doses of antioxidant vitamins fail to improve oxidative stress, inflammation or plasma monocyte adhesion-promoting capacity in ESRD patients. Thus, high doses of vitamins beyond the routinely-prescribed supplements do not appear to be beneficial in this patient population.

Comparison of fatty acid contents of erythrocyte membrane in hemodialysis and peritoneal dialysis patients.

OBJECTIVE: Membrane fatty acid composition plays an important role in the cellular function. Erythrocyte fatty acid composition mirrors that of myocardium and is influenced by diet. Earlier studies have shown significant alterations of membrane fatty acid composition in ethnically mixed patients with end-stage renal disease. Given the impact of ethnic and dietary factors, we sought to examine membrane fatty acid composition in an ethnically homogeneous end-stage renal disease population residing in a coastal region of Korea with high fish consumption. DESIGN: Cross-sectional study. SETTING: Outpatient facility at Dong-A University Hospital, Busan, Republic of Korea. PATIENTS: We recruited 15 stable hemodialysis patients, 14 peritoneal dialysis patients, and 10 age- and gender-matched normal controls. Patients with significant malnutrition, short duration of dialysis, recent infection, malignancy, or liver disease were excluded. Dietary intake and use of omega-3 fatty acid supplements were determined. MAIN OUTCOME MEASURE: Erythrocyte membrane fatty acid contents measured by gas chromatography. RESULTS: Palmitoleic acid and alpha-linolenic acid levels were lower, whereas oleic acid, linoleic acid, and arachidonic acid levels were higher in patients with end-stage renal disease compared with the control group. Total monounsaturated fatty acids (palmitoleic acid and oleic acid) were significantly higher in peritoneal dialysis than in hemodialysis patients. Eicosapentaenoic acid and omega-3 docosapentaenoic acid were significantly higher, but total omega-6 fatty acids, omega-6/omega-3, and arachidonic acid/eicosapentaenoic acid ratios were significantly lower in hemodialysis patients consuming omega-3 supplements compared with those who did not. CONCLUSION: Patients with end-stage renal disease exhibited significant alterations in erythrocyte membrane fatty acids, which were partially modified by the dialysis modality and omega-3 fatty acid supplementation.

Erythropoietin and transferrin metabolism in nephrotic syndrome.

Nephrotic syndrome is characterized by marked urinary excretion of albumin and other intermediate-size plasma proteins. This results in a profound alteration of the metabolism of many plasma proteins and protein-bound substances, as well as certain cellular and tissue proteins. This review summarizes available data on the effect of nephrotic syndrome on the metabolism and regulation of erythropoietin (EPO) and transferrin, which are essential for erythropoiesis. Studies of humans and animals have documented significant urinary losses of both EPO and transferrin in nephrotic syndrome. Urinary losses of EPO have been shown to cause EPO-deficiency anemia and prevent the normal increase in plasma EPO level in response to anemia and hypoxia in nephrotic syndrome. Similarly, transferrinuria and increased transferrin catabolism have been shown to cause hypotransferrinemia and, in some cases, iron-deficiency anemia. In addition, dissociation of iron from filtered transferrin, occasioned by a reduction in tubular fluid pH, can promote tubulointerstitial injury through the iron-catalyzed generation of oxygen free radicals. This can account in part for the role of proteinuria as a risk factor for the progression of renal disease. Subcutaneous administration of recombinant EPO has been successfully used in the management of EPO-deficiency anemia in nephrotic syndrome. Similarly, iron supplementation and nutritional support are indicated in nephrotic patients with severe transferrinuria and iron-deficiency anemia. However, correction or amelioration of the underlying proteinuria, when possible, is the ideal approach to reversal of these complications.

Enhanced NO inactivation and hypertension induced by a high-fat, refined-carbohydrate diet.

We have recently demonstrated that long-term consumption of a high-fat, refined-carbohydrate (HFS) diet induces hypertension (HTN) in normal rats compared with a low-fat, complex-carbohydrate (LFCC) diet. Limited evidence suggests that high-fat or high-sugar diets cause enhanced generation of reactive oxygen species (ROS). We therefore hypothesized that by inducing oxidative stress, the HFS diet may promote nitric oxide (NO) inactivation and HTN. To test this hypothesis, female Fischer rats were placed on either the HFS or the LFCC diet starting at 2 months of age. Blood pressure, urinary NO metabolites (NO(x)), and total renal NO synthase activity were monitored, and the tissue abundance of nitrotyrosine (NT), which is the stable "footprint" of NO oxidation by ROS, was determined. The HFS diet group exhibited a gradual rise in arterial blood pressure and were hypertensive by 18 months. This trend was accompanied by a marked accumulation of NT in all tested tissues, an initial rise and a subsequent fall in NO synthase activity, and a fall in urinary NO(x) excretion. The HFS diet-fed animals had a blunted blood pressure response to the NO synthase inhibitor N:(omega)-nitro-L-arginine methyl ester (L-NAME) compared with the LFCC diet group, which showed a marked hypertensive response to L-NAME. L-NAME-induced HTN was reversible with L-arginine in the LFCC diet group; however, HTN was not corrected by L-arginine supplementation in the HFS diet group. These findings point to enhanced ROS-mediated inactivation and sequestration of NO, which may contribute to the reduction of bioactive NO and HTN in the HFS diet-fed animals.

Down-regulation of renal endothelial nitric oxide synthase expression in experimental glomerular thrombotic microangiopathy.

Infection with certain strains of Escherichia coli and endotoxemia results in renal glomerular thrombotic microangiopathy (TMA) characterized by endothelial swelling and prominent glomerular microthrombus formation. Nitric oxide (NO) is an endogenous biologic modulator with diverse physiologic functions including vasodilation and inhibition of platelet adhesion and aggregation. NO is synthesized from conversion of L-arginine to L-citrulline by a family of NO synthases (NOS), which include constitutive and inducible isoforms. Indirect evidence supports the hypothesis that TMA is associated with depressed intrarenal NO production. However, the effect of TMA on renal tissue NOS expression has not been fully elucidated. We studied rats with TMA induced by iv bolus injection of high dose (20 mg/kg) E. coli endotoxin. Subgroups of six animals each were sacrificed before or at 30, 90, 180, 360, and 720 minutes after the administration of endotoxin. Renal histology and tissue expression of endothelial and inducible nitric oxide synthases (eNOS and iNOS) were examined. Additionally, we examined the effect of endotoxin on glomerular NO production, and eNOS and iNOS protein expression in vitro. Glomerular capillary thrombosis developed by 180 minutes after endotoxin administration in approximately half of the animals. The glomeruli without thrombotic lesions apparent by light microscopy disclosed early signs of TMA characterized by endothelial swelling, platelet accumulation/adhesion, and patchy fibrinogen deposition. These morphologic changes were associated with a marked reduction of renal tissue eNOS expression beyond 180 minutes after the endotoxin administration. The fall in eNOS expression was coupled with a significant rise in iNOS protein abundance, which was expressed largely by glomerular circulating neutrophils and endothelial cells, peritubular vascular endothelium, and collecting ducts of cortex and medulla. In vitro incubation of isolated glomeruli with endotoxin also resulted in a marked reduction in eNOS expression and a significant rise in iNOS content. Administration of E. coli endotoxin leads to a sustained fall in renal eNOS expression both in vivo and in vitro. The associated decline in intrarenal endothelial NO production/availability may result in renal vasoconstriction and a hypercoagulative state, which may contribute to the pathogenesis of endotoxin-induced TMA.

Induction of oxidative stress by glutathione depletion causes severe hypertension in normal rats.

Several recent studies have shown that certain forms of genetic or acquired hypertension are associated with oxidative stress and that animals with those types of hypertension respond favorably to antioxidant therapy. We hypothesize that oxidative stress may cause hypertension via (among other mechanisms) enhanced oxidation and inactivation of nitric oxide (NO). To test this hypothesis, Sprague-Dawley rats were subjected to oxidative stress by glutathione (GSH) depletion by means of the GSH synthase inhibitor buthionine sulfoximine (BSO, 30 mmol/L in drinking water) for 2 weeks. The control group was given drug-free drinking water. In parallel experiments, subgroups of animals were provided vitamin E-fortified chow and vitamin C-supplemented drinking water. The BSO-treated group showed a 3-fold decrease in tissue GSH content, a marked elevation in blood pressure, and a significant reduction in the urinary excretion of the NO metabolite nitrate plus nitrite, which suggests depressed NO availability. These characteristics were associated with a significant accumulation in various tissues of nitrotyrosine, which is the footprint of NO inactivation by reactive oxygen species. Administration of vitamin E plus vitamin C ameliorated hypertension, improved urinary nitrate-plus-nitrite excretion, and mitigated nitrotyrosine accumulation (despite GSH depletion) in the BSO-treated animals but had no effect in the control group. In conclusion, GSH depletion resulted in perturbation of the NO system and severe hypertension in normal animals. The effects of BSO were mitigated by concomitant antioxidant therapy despite GSH depletion, which supports the notion that oxidative stress was involved in the pathogenesis of hypertension in this model.

Increased nitric oxide inactivation by reactive oxygen species in lead-induced hypertension.

BACKGROUND: We have recently found evidence for increased reactive oxygen species (ROS) in rats with lead-induced hypertension. We hypothesized that increased ROS activity may contribute to hypertension by enhancing inactivation of nitric oxide (NO) in this model. METHODS: Rats were treated for 12 weeks with either lead acetate (100 p.p.m.) alone (Pb group) or lead acetate plus vitamin E-fortified food (5000 U/kg rat chow, Pb + E group). The control animals were fed either regular rat chow or a vitamin E-fortified diet. Blood pressure, creatinine clearance, and urinary excretion of stable NO metabolites (NOx) were monitored, and plasma and tissue abundance of nitrotyrosine, which is the footprint of NO oxidation by ROS, were determined. RESULTS: The Pb group showed a marked rise in blood pressure, a significant increase in plasma and kidney, heart, liver, and brain nitrotyrosine abundance, and a substantial fall in urinary NOx excretion. Concomitant administration of high-dose vitamin E in the Pb + E group ameliorated hypertension and normalized both urinary NOx excretion and tissue nitrotyrosine without altering tissue lead content. However, vitamin E supplementation had no discernible effect on either blood pressure or nitrotyrosine abundance in the normal controls. CONCLUSIONS: These findings point to enhanced ROS-mediated inactivation and sequestration of NO, which can potentially contribute to hypertension, tissue damage, and reduced urinary NOx excretion in rats with lead-induced hypertension. The beneficial effects of high-dose vitamin E on blood pressure, tissue nitrotyrosine burden, and urinary NOx excretion support the role of increased ROS activity in the pathogenesis of these abnormalities in this model.

Nitric oxide synthase expression in the course of lead-induced hypertension.

We recently showed elevated reactive oxygen species (ROS), reduced urinary excretion of NO metabolites (NOx), and increased NO sequestration as nitrotyrosine in various tissues in rats with lead-induced hypertension. This study was designed to discern whether the reduction in urinary NOx in lead-induced hypertension is, in part, due to depressed NO synthase (NOS) expression. Male Sprague-Dawley rats were randomly assigned to a lead-treated group (given lead acetate, 100 ppm, in drinking water and regular rat chow), a group given lead and vitamin E-fortified chow, or a normal control group given either regular food and water or vitamin E-fortified food for 12 weeks. Tail blood pressure, urinary NOx excretion, plasma malondialdehyde (MDA), and endothelial and inducible NOS (eNOS and iNOS) isotypes in the aorta and kidney were measured. The lead-treated group exhibited a rise in blood pressure and plasma MDA concentration, a fall in urinary NOx excretion, and a paradoxical rise in vascular and renal tissue eNOS and iNOS expression. Vitamin E supplementation ameliorated hypertension, lowered plasma MDA concentration, and raised urinary NOx excretion while significantly lowering vascular, but not renal, tissue eNOS and iNOS expression. Vitamin E supplementation had no effect on either blood pressure, plasma MDA, or NOS expression in the control group. The study also revealed significant inhibition of NOS enzymatic activity by lead in cell-free preparations. In conclusion, lead-induced hypertension in this model was associated with a compensatory upregulation of renal and vascular eNOS and iNOS expression. This is, in part, due to ROS-mediated NO inactivation, lead-associated inhibition of NOS activity, and perhaps stimulatory actions of increased shear stress associated with hypertension.

Role of endothelin and nitric oxide imbalance in the pathogenesis of hypoxia-induced arterial hypertension.

BACKGROUND: We have recently demonstrated that prolonged hypobaric hypoxia can lead to a hematocrit-independent sustained arterial hypertension (HTN) in genetically normotensive Sprague-Dawley rats. The rise in blood pressure in the hypoxic animals was accompanied by a marked but transient increase in plasma endothelin level. In addition, hypoxia has been shown to decrease nitric oxide (NO) production by cultured endothelial cells. This study was designed to test the hypothesis that hypoxia-induced HTN may be mediated by increased endothelin and/or decreased NO production. METHODS: Blood pressure, plasma endothelin and urinary NO metabolites (NOx)were monitored in rats during a 24-hour exposure to hypobaric hypoxia (air pressure = 390 mm Hg). The results were compared with hypoxia (air pressure = 390 mm Hg). The results were compared with those obtained in animals maintained under normoxic condition (control group). To test the possible role of excess endothelin and depressed NO production, the studies were repeated using subgroups of animals treated with either an endothelin receptor ET-A/B blocker (L-754,142) or L-arginine. RESULTS: The untreated hypoxic group exhibited a threefold rise in plasma endothelin and a threefold fall in urinary NOx, prior to the onset of HTN. Endothelin receptor blockade led to a further fall in urinary NOx excretion and failed to mitigate HTN. In contrast, L-arginine supplementation improved the urinary NOx excretion and prevented HTN. Neither therapy affected the hypoxia-induced erythrocytosis. CONCLUSIONS: We conclude that hypoxia-induced HTN is associated with depressed NO production and can be mitigated by L-arginine supplementation.

Dysregulation of melatonin metabolism in chronic renal insufficiency: role of erythropoietin-deficiency anemia.

Chronic renal failure (CRF) is associated with a variety of neurological and endocrine disorders. In this study, we examined the effect of CRF and the associated anemia on circadian variation of pineal hormone, melatonin. Animals were studied six weeks after 5/6 nephrectomy (CRF group, N = 26) or sham operation (control group, N = 28). A group of erythropoietin-treated CRF animals (CRF/EPO, N = 6) was included to discern the possible role of EPO-deficiency anemia. Compared with the normal control group, the CRF group showed a marked attenuation of the nocturnal surge in serum melatonin concentration. In addition, pineal gland melatonin content measured after a 12-hour dark cycle (< or = 2 lux) was significantly depressed in the CRF group when compared to that obtained in the control group. However, the CRF animals exhibited appropriate suppression of serum concentration and pineal tissue melatonin content in response to bright light (> or = 2500 lux). Administration of EPO led to correction of the CRF anemia and a marked improvement of the defective nocturnal rhythm of serum melatonin. Based on our results, experimental CRF is associated with a marked attenuation of the normal nocturnal surge of serum melatonin concentration. Regular EPO administration results in the correction of anemia and substantial reversal of this abnormality suggesting the partial role of EPO deficiency. The possible role of melatonin dysregulation in the pathophysiology of CRF and the potential value of melatonin supplementation in this condition is uncertain and awaits future investigations.

In vivo and in vitro pressor effects of erythropoietin in rats.

Hypertension (HTN) is a common complication of recombinant erythropoietin (EPO) therapy, but the mechanism of the EPO-associated HTN is uncertain. In the present study we examined the effects of EPO and the vehicle alone on rat caudal artery contractile response and basal and thrombin-stimulated platelet cytosolic Ca2+ concentration ([Ca2+]i) in vitro and on blood pressure (BP) and heart rate in vivo. At high concentrations (200 U/ml) EPO caused a small but consistent contraction in the caudal artery rings (P < 0.01) without affecting the response to either angiotensin II (ANG II) or the alpha 1-agonist methoxamine. Incubation with EPO significantly increased basal platelet [Ca2+]i (P < 0.01) and augmented the thrombin-induced rise of [Ca2+]i in Ca(2+)-free medium (P < 0.05). Long-term EPO administration led to a significant elevation of BP within 2 wk regardless of whether the hematocrit was allowed to rise or was kept constant by dietary iron deficiency. In contrast, single intravenous administration of high-dose EPO (400 and 5,000 U/kg), estimated to yield plasma concentrations comparable with those employed in vitro, failed to either alter BP or modify the BP response to ANG II during a 60-min observation period. This was associated with a significant rise in plasma guanosine 3',5'-cyclic monophosphate but no discernible change in plasma atrial natriuretic peptide, suggesting enhanced nitric oxide (NO) release. Thus, at high concentrations, EPO appears to possess a fast-acting pressor effect in vitro but not in vivo. The observed discrepancy may be due to enhanced NO release with EPO administration in vivo. However, HTN does occur with repeated EPO administration in a time-dependent and hematocrit-independent manner. This suggest that expression of the hypertensive effect of EPO in vivo involves a gradual conditioning process.

Leukocyte CD11b and CD18 expression are increased in blood salvaged for autotransfusion.

To investigate whether activated leukocytes are present in salvaged blood, we measured complete blood counts and quantified the surface expression of the leukocyte adhesion receptors CD11b and CD18 in salvaged blood and arterial blood from six male patients undergoing elective abdominal aortic aneurysm repair. Salvaged blood contained 5,450 +/- 1010 leukocytes/microL and 7600 +/- 6200 platelets/microL and had a hematocrit of 50.6 +/- 3.7%. CD 11b expression was 3.3 +/- 0.5 fold higher on neutrophils and 3.8 +/- 1.0 fold higher on monocytes from salvaged blood compared with arterial blood (P < 0.05 for both). CD18 expression was increased 3.2 +/- 0.2 fold on neutrophils and 2.5 +/- 0.4 fold on lymphocytes (P < 0.05) in salvaged compared to arterial blood (P < .05). Monocyte expression of CD18 was increased 4.50 +/- 1.1 fold in salvaged blood, but this difference was not statistically significant. We conclude that a substantial number of activated leukocytes are present in salvaged blood. Because activated leukocytes could potentially be detrimental to the recipient, our findings raise theoretical concerns about the use of salvaged blood and emphasize the need for further refinement of the procedure.

Vitamin D absorption, plasma concentration and urinary excretion of 25-hydroxyvitamin D in nephrotic syndrome.

Nephrotic syndrome (NS) is commonly associated with vitamin D deficiency. Urinary losses of the protein-bound intermediary metabolite of this vitamin is thought to contribute to the deficiency state. The role of possible changes, if any, of vitamin D absorption has not been investigated previously in NS. We determined intestinal absorption of vitamin D3 as well as plasma concentration and urinary excretion of 25-hydroxyvitamin D3 in rats with puromycin aminonucleoside-induced NS. In vivo recirculating perfusion technique was employed at 100 and 600 nM perfusate concentrations. The results were compared with those obtained in animals receiving placebo injections provided with either free access to food (normal controls) or those pair-fed with their NS counterparts (pair-fed group). The NS group showed heavy proteinuria and hypoalbuminemia. In addition, the NS group exhibited marked urinary losses and significantly reduced plasma concentration of 25-hydroxyvitamin D. The rate of vitamin D3 absorption (given as nmol/100 cm/min) at 100 nM perfusate concentration in the NS group (0.161 +/- 0.029) was not significantly different from those obtained in the pair-fed group (0.202 +/- 0.058) and the normal control group (0.143 +/- 0.053). Likewise, no significant difference was found in the rats of vitamin D absorption at 600 nM concentration among the NS (1.073 +/- 0.383), pair-fed (0.955 +/- 0.229), and normal control (0.756 +/- 0.314) groups. Accordingly, intestinal absorption of vitamin D appears to be unaffected by the presence of experimental NS and as such the associated vitamin D deficiency can be managed by enteral supplementation.

Effects of dietary fatty acid saturation on serum and tissue cholesterol concentrations and fecal sterol excretion: a chronic metabolic study in the rat.

We studied the effect of the degree of fatty acid saturation on cholesterol metabolism in rats fed either a low cholesterol-low fat diet (control group), high cholesterol-low fat diet (Chol group), high cholesterol-high saturated fat diet (Chol-SF) or high cholesterol-high PUF diet (Chol-PUF). The highest serum cholesterol levels were found in the Chol-SF group. No significant difference in serum cholesterol was found between the Chol and Chol-PUF groups. The Chol-PUF group showed the greatest accumulation of cholesterol in the liver. There was no significant difference in fecal excretion of acidic sterols, cholesterol and coprostanol between the Chol-PUF and Chol-SF groups. We conclude that in chronic feeding experiments in rats: a) high dietary cholesterol intake results in hypercholesterolemia; b) the hypercholesterolemia is accentuated by high dietary SF but is unaffected by PUF; c) addition of PUF to high cholesterol diet leads to massive cholesterol accumulation in the liver which can partly account for the apparent hypocholesterolemic effect of PUF relative to SF; and d) differences in serum and tissue cholesterol levels between SF and PUF supplemented groups are unlikely to be due to their effects on fecal sterol excretion.

Effect of rapid weight loss with supplemented fasting on serum electrolytes, lipids, and blood pressure.

The effect of rapid weight reduction with supplemented fasting was studied in a group of 46 individuals with moderate to severe obesity. The preparation used contained a mixture of protein, carbohydrate, and essential fatty acids providing 420 kcal daily. It was supplemented with a complement of electrolytes, minerals, and vitamins.Serum concentrations of electrolytes, urea nitrogen, creatinine, uric acid, glucose, cholesterol, and triglycerides were measured prior to the onset of the study and at two-week intervals for a six-week study period. In addition, blood pressure, heart rate, and body weight were recorded regularly. A mild and transient fall in serum bicarbonate concentration and a rise in uric acid level was observed.In contrast to other regimens, hypokalemia was not observed in the present study. In fact, serum K+ concentration rose slightly while serum Na+ concentration remained virtually unchanged. There was a transient rise in serum creatinine concentration followed by a fall to values below the baseline. Serum glucose, cholesterol and triglyceride levels, blood pressure, and heart rate decreased significantly. Body weight fell from 232.7 ± 58 lb at the onset of the study to 176.4 ± 47.9 lb at the conclusion of the study.The protocol was well tolerated and the side effects were mild and infrequent. In conclusion, the present protocol provides a safe and effective means for rapid weight reduction in individuals with moderate to marked obesity without producing severe electrolyte disturbances seen with other modalities.

Hypomagnesemia and renal magnesium wasting in renal transplant recipients receiving cyclosporine.

Following the adoption and use of cyclosporine as the drug of choice in the management of renal allograft recipients, several cases of symptomatic hypomagnesemia were noted. These observations prompted the current prospective study of serum concentration and urinary excretion of magnesium in 27 renal transplant recipients treated with cyclosporine and prednisone. Relevant laboratory measurements were obtained shortly before and regularly after transplantation. The results were compared with those obtained in a group of 17 allograft recipients treated with azathioprine and prednisone. The cyclosporine-treated patients showed a significant reduction in the serum magnesium concentration and an inappropriately increased urinary excretion and fractional excretion of magnesium, suggesting renal magnesium wasting. The observed hypomagnesemia required magnesium supplementation in nearly all cyclosporine-treated patients. In contrast, azathioprine-treated patients showed normal serum magnesium concentrations and required no magnesium supplementation. In conclusion, administration of cyclosporine in renal allograft recipients appears to be commonly associated with renal magnesium wasting and hypomagnesemia. Therefore, it is recommended that serum levels of magnesium be monitored regularly in renal allograft recipients receiving cyclosporine and that magnesium supplementation be employed as needed to avoid magnesium depletion.

Effect of rapid weight loss with supplemented fasting on liver tests.

We monitored serum liver tests in 46 obese persons undergoing rapid weight reduction with a supplemented fasting diet containing a mixture of protein, glucose, essential fatty acids, vitamins, and minerals. Levels of SGOT, SGPT, alkaline phosphatase, lactic dehydrogenase (LDH) and serum concentrations of bilirubin, total protein, and albumin were within normal limits at the onset of the study. SGOT, SGPT, LDH, alkaline phosphatase, and serum total bilirubin rose mildly but significantly 2 weeks after the institution of the supplemented fasting program. Thereafter, the values began to decline, approaching baseline levels within 4-6 weeks despite the continued dietary restrictions. We conclude that rapid weight reduction using a supplemented fasting regimen can lead to a mild hepatic test abnormality. The resultant liver test abnormalities are transient and reversible and may not require extensive diagnostic investigations.

Severe hyperkalemia caused by indomethacin and potassium supplementation.

Treatment with a combination of indomethacin and potassium chloride supplementation resulted in severe hyperkalemia in a patient with Bartter's syndrome. The clinical and electrocardiographic findings and hyperkalemia improved promptly with intravenous administration of sodium bicarbonate, glucose, and insulin, discontinuation of the potassium supplement, and reduction of the indomethacin dose. This case suggests that life-threatening hyperkalemia can occur when indomethacin and potassium supplementation are prescribed simultaneously in Bartter's syndrome.