Effects of celecoxib and naproxen on renal function in the elderly

OBJECTIVE: To compare the effects of celecoxib, a cyclooxygenase 2-specific inhibitor, with the nonspecific cyclooxygenase 1 and 2 inhibitor naproxen on renal function in 29 healthy elderly subjects in a single-blind, randomized, crossover study. METHODS: Subjects received either celecoxib, 200 mg twice daily, for 5 days followed by celecoxib, 400 mg twice daily, for the next 5 days, or they received naproxen, 500 mg twice daily, for 10 days. After a 7-day washout, subjects were crossed over to receive the other regimen. RESULTS: After the first dose, the trend was for a greater decrease in glomerular filtration rate with naproxen (-5.31 mL/min per 1.73 m2) compared with celecoxib (-0.86 mL/min per 1.73 m2). The treatment difference became statistically significant on day 6 (-7.53 vs -1.11 mL/min per 1.73 m2 for naproxen and celecoxib, respectively; P=.004). Urinary prostaglandin E2 and 6-keto-prostaglandin F1alpha excretion was significantly reduced from baseline across the treatment interval with both celecoxib and naproxen (P< or =.04). There were no significant differences in prostaglandin excretion between these 2 agents (P> or =.07). Small, transient decreases (P<.05) in urinary sodium excretion were observed after the initiation of both celecoxib and naproxen treatment. Sodium excretion values returned to baseline by the end of the study. CONCLUSIONS: The results indicate that cyclooxygenase 2-specific inhibition in healthy elderly subjects may spare renal hemodynamic function, although the effects on sodium excretion, as well as urinary prostaglandin E2 and 6-keto-prostaglandin F1alpha excretion, appear to be similar to those of nonspecific cyclooxygenase inhibitors such as naproxen.     

Effects of single dose of 50mg captopril in patients with liver cirrhosis and ascites

BACKGROUND/AIMS: In patients with liver cirrhosis and ascites, the renin angiotensin system is usually activated. Such a correlation supports the hypothesis that activation of the renin-angiotensin system plays an influential role in the pathogenesis of ascites in liver cirrhosis. METHODOLOGY: In this study, 25 patients with liver cirrhosis and ascites (10 females, 15 males; age: 45-67 years) were enrolled. We evaluated the acute effects of converting enzyme inhibitor (a single dose of 50 mg captopril taken orally) on glomerular filtration rate, effective renal plasma flow, filtration fraction, plasma renin activity, and plasma aldosterone. RESULTS: Oral intake of a single 50 mg dose of captopril significantly decreased glomerular filtration rate (65 +/- 6 mL/min/1.73 m2 vs. 53 +/- 9 mL/min/1.73 m2), filtration fraction (21.2 +/- 2.7% vs. 15.5 +/- 4.1%), and plasma aldosterone (340 +/- 80 pg/mL vs. 247 +/- 42 pg/mL), but increased plasma renin activity (2.65 +/- 2.19 ng/mL/hr vs. 11.58 +/- 2.70 ng/mL/hr) and effective renal plasma flow (312 +/- 41 mL/min/1.73 vs. 356 +/- 60 mL/min/1.73 m2). CONCLUSIONS: We suggest that oral intake of a single dose of 50 mg captopril can block the renin-angiotension system, and result in changes in renal hemodynamics and function in cirrhotic patients with ascites.     

Endothelin-1 and -3 plasma concentrations in patients with cirrhosis: Role of splanchnic and renal passage and liver function

Increased as well as decreased plasma concentrations of the endothelins, endogenous vasoactive peptides, have been reported in cirrhosis. This might be caused by alterations of hepatic or renal clearance or release. Therefore, the aim of the current study was to investigate the influence of splanchnic and renal passage and of liver function on plasma concentrations of endothelin-1 (ET-1) and endothelin-3 (ET-3) in patients with cirrhosis compared with controls. Eighteen patients with cirrhosis and 8 normotensive controls of similar age were investigated. Arterial and venous plasma samples were obtained simultaneously, and ET-1 and ET-3 concentrations were determined in extracted plasma by two separate radioimmunoassays. Arterial as well as hepatic and renal venous concentrations of ET-1 in cirrhosis (17.8 ± 0.8 pg/mL, 19.1 ± 0.9 pg/mL, and 16.8 ± 0.8 pg/mL) were significantly (P < .001) higher than in controls (9.2 ± 1.7 pg/mL, 9.0 ± 2.0 pg/mL, and 8.4 ± 1.9 pg/mL, respectively). The same held true for the corresponding ET-3 plasma concentrations in cirrhosis (19.3 ± 1.6 pg/mL, 20.5 ± 1.5 pg/mL, and 18.4 ± 1.5 pg/mL, respectively) compared with controls (11.1 ± 1.8 pg/mL, 11.3 ± 1.5 pg/mL, and 10.1 ± 1.7 pg/mL, respectively; P < .01). There was a significant (P < .05) renal net extraction of ET-1 and ET-3 in cirrhosis. In contrast, a significant (P < .05) net release of ET-1 and ET-3 (2.40 ± 0.80 ng/min and 1.75 ± 1.16 ng/ min) during splanchnic passage was observed in cirrhosis, but not in controls (−0.24 ± 0.51 ng/min, and −0.46 ± 0.64 ng/min). Plasma concentrations of ET-3 in cirrhosis were correlated to the Child-Turcotte score (r = .66, P < .01) and inversely to the functional liver cell mass, determined by the galactose elimination capacity (r = −.72, P < .01). Hepatic venous ET-1 concentrations correlated to the hepatic blood flow assessed by the indocyanine green clearance (r = .48; P < .05). Net splanchnic release may contribute to elevated ET-1 and ET-3 plasma concentrations in patients with cirrhosis. Splanchnic ET-1 and ET-3 handling in cirrhosis may be influenced by different mechanisms.     

Renal prostacyclin influences renal function in non-azotemic cirrhotic patients treated with furosemide

The influence of prostaglandins on renal function changes induced by furosemide was analyzed in 21 non-azotemic cirrhotic patients with ascites. Patients were studied in two periods of 120 min immediately before and after furosemide infusion (20 mg, ev). Furosemide caused an increase in creatinine clearance in 15 patients (group A: 99 +/- 7 vs. 129 +/- 5 ml/min; mean +/- S.E.) and a reduction in the remaining six (group B: 102 +/- 13 vs. 71 +/- 9 ml/min). Parallel changes were observed in the urinary excretion of 6-Keto-prostaglandin-F1 alpha (metabolite of renal prostacyclin) which augmented after furosemide in 14 of the 15 patients from group A (478 +/- 107 vs. 1034 +/- 159 pg/min, p less than 0.001) and decreased in all patients from group B (1032 +/- 240 vs. 548 +/- 136 pg/min, p less than 0.05). In contrast, the urinary excretion of prostaglandin E2 was stimulated by furosemide in all patients (group A, 92 +/- 19 vs. 448 +/- 60 pg/min, p less than 0.001; and group B, 209 +/- 63 vs. 361 +/- 25 pg/min, p less than 0.05). In all of the patients furosemide-induced changes (post- minus pre-furosemide values) in creatinine clearance were closely correlated in a direct and linear fashion with those in 6-Keto-prostaglandin-F1 alpha (r = 0.74; p less than 0.001). These changes were associated with a higher furosemide-induced natriuresis in group A than in group B (641 +/- 68 vs. 302 +/- 46 mumol/min, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Serum thrombopoietin levels in patients with chronic hepatitis and liver cirrhosis,and its relationship with circulating thrombocyte counts

BACKGROUND/AIMS: Thrombocytopenia in chronic liver diseases may be related to deficient production of thrombopoietin. The aim of this study was to measure serum thrombopoietin levels and to examine the relationship between serum thrombopoietin concentration, circulating platelet counts and clinical stage of the disease in patients with chronic hepatitis and liver cirrhosis. METHODOLOGY: The study included 18 patients with chronic hepatitis, 48 with liver cirrhosis and 27 healthy volunteers. Serum thrombopoietin levels were measured by enzyme-linked immunosorbent assay. Additionally, serum albumin levels, prothrombin time, circulating platelet counts and spleen volume index were determined. RESULTS: Mean serum thrombopoietin level (100.96 +/- 41.67 pg/mL) in the chronic hepatitis group was similar to that of the healthy group (97.60 +/- 43.99 pg/mL), however serum thrombopoietin levels in patients with liver cirrhosis (69.60 +/- 30.23 pg/mL) were lower than patients with chronic hepatitis and controls (p < 0.05 for both). In patients with liver cirrhosis, serum thrombopoietin levels were found to be decreased as the disease progressed (80.99 +/- 24.85 pg/mL in patients at Child-Pugh stage A, 67.92 +/- 39.37 in patients at stage B and 57.62 +/- 21.09 pg/mL in patients at stage C). Cirrhotic patients had increased prothrombin time (17.12 +/- 3.52 sec) and spleen volume index (94.38 +/- 26.48 cm2), and decreased serum albumin level (3.11 +/- 0.56 g/dL) and platelet counts (102,368 +/- 30,653/mm3) when compared to both chronic hepatitis and control groups. Thrombocytopenia was found in 31 (65%) of the patients with liver cirrhosis. In patients with liver cirrhosis, while there was a positive correlation between serum thrombopoietin and albumin levels (r = 0.36, p = 0.004), no correlation was found between platelet counts and serum thrombopoietin level, and spleen volume index. CONCLUSIONS: The findings reveal that serum thrombopoietin levels are normal in patients with chronic hepatitis, but in patients with liver cirrhosis, serum thrombopoietin levels decrease, as degree of cirrhosis progresses. The impaired production of thrombopoietin may contribute to the development of thrombocytopenia in advanced stage of liver disease.     

Pharmacodynamic interaction of naproxen with low-dose aspirin in healthy subjects

OBJECTIVES: We investigated the occurrence of pharmacodynamic interaction between low-dose aspirin and naproxen. BACKGROUND: The uncertainty of cardioprotection by naproxen has encouraged its combination with aspirin in patients with arthritis and cardiovascular disease. METHODS: The incubation of washed platelets with naproxen for 5 min before the addition of aspirin reduced the irreversible inhibition of thromboxane (TX)B(2) production by aspirin. The pharmacodynamic interaction between the two drugs was then investigated in four healthy volunteers who received aspirin (100 mg daily) for 6 days and then the combination of aspirin and naproxen for further 6 days: aspirin 2 h before naproxen (500 mg, twice-daily dosing). After 14 days of washout, naproxen was given 2 h before aspirin for further 6 days. RESULTS: The inhibition of serum TXB(2) production (index of platelet cyclooxygenase [COX]-1 activity) and platelet aggregation ex vivo and urinary 11-dehydro-TXB(2) levels (index of TXB(2) biosynthesis in vivo) by aspirin alone (99 +/- 0.2%, 95 +/- 0.6%, and 81 +/- 4%, respectively) was not significantly altered by the co-administration of naproxen, given either 2 h after aspirin or in reverse order. In a second study, the concurrent administration of a single dose of aspirin and naproxen did not affect platelet TXB(2) production and aggregation at 1 h after dosing, when aspirin alone causes maximal inhibitory effect. Moreover, the rapid recovery of platelet COX-1 activity and function supports the occurrence of a pharmacodynamic interaction between naproxen and aspirin. CONCLUSIONS: Naproxen interfered with the inhibitory effect of aspirin on platelet COX-1 activity and function. This pharmacodynamic interaction might undermine the sustained inhibition of platelet COX-1 that is necessary for aspirin's cardioprotective effects.     

Platelet function is inhibited by non-selective non-steroidal anti-inflammatory drugs but not by cyclo-oxygenase-2-selective inhibitors in patients with rheumatoid arthritis

BACKGROUND: Interaction with platelet function by non-steroidal anti-inflammatory drugs (NSAIDs) is related to the inhibition of cyclo-oxygenase-1 (COX-1). In patients with rheumatoid arthritis (RA), only one of the COX-2-selective NSAIDs (nabumetone) has been demonstrated to spare platelet function partially. OBJECTIVE: To compare the effects of the COX-2-selective inhibitor, meloxicam, with those of the non-selective NSAID, naproxen, on platelet function and thromboxane levels in RA patients. METHODS: In this randomized, controlled, cross-over trial, 10 RA patients used meloxicam 7.5 mg bid and naproxen 500 mg bid, each during a 2-week period. Washout periods were applied. Before and after each 2-week period of NSAID intake, laboratory studies were performed. RESULTS: Platelet aggregation was significantly less influenced, thromboxane levels were less inhibited (246 vs 117 pg/ml) and bleeding times were less prolonged with meloxicam than with naproxen (3.2 vs 2.3 min). Moreover, the results of all tests during meloxicam exposure were comparable with baseline values. CONCLUSION: In RA patients, meloxicam, a representative of the selective COX-2 inhibitors, does not interfere with platelet function and thromboxane levels, in contrast with naproxen (a non-selective COX inhibitor).     

Serum levels of soluble Fas, nitric oxide and cytokines in acute decompensated cirrhotic patients

AIM： To evaluate plasma levels of nitrite/nitrate （NOx）, soluble Pas （spas） antigen, tumor necrosis factor alpha （TNF-α） and interleukin-6 （IL-6） in patients with compensated and acute decompensated cirrhosis and to evaluate mediators causing acute decompensation in liver cirrhosis,
METHODS： This prospective study was conducted in the medical intensive care unit of an academic tertiary center, Fifty-five patients with acute decompensation （gastrointestinal hemorrhage, encephalopathy, hydropic decompensation） and twenty-five patients with compensated liver drrhosis were included, Blood samples were taken for analyses of spas, Nox, IL-6, TNF-α, Liver enzymes and kidney functions were also tested,
RESULTS： In patients with acute decompensation, plasma spas levels were higher than in non-decompensated patients （15305 ± 4646 vs 12458± 4322 pg/mL, P 〈 0.05）. This was also true for the subgroup of patients with alcoholic liver cirrhosis （P 〈 0.05）. The other mediators were not different and none of the parameters predicted survival, except for ALT （alanine-aminotransferase）. In patients with portal-hypertension-induced acute hemorrhage, NOx levels were significantly lower than in patients with other forms of decompensation （70.8 ± 48.3 vs 112.9 ± 74.9 pg/mL, P 〈 0.05）. When NOx levels were normalized to creatinine levels, the difference disappeared. IL-6, TNF-α and spas were not different between bleeders and non-bleeders. In decompensated patients spas, IL-6 and NOx levels correlated positively with creatinine levels, while IL-6 levels were dependent on Child class.
CONCLUSION： In acute decompensated cirrhotic patients sPas is increased, suggesting a role of apoptosis in this process and patients with acute bleeding have lower NOx levels, However, in this acute complex clinical situation, kidney function seems to have a predominant influence on mediator levels,     

Secondary hyperparathyroidism in patients with untreated and treated congestive heart failure

BACKGROUND: The congestive heart failure syndrome includes a systemic illness with wasting of soft tissues and bone. We hypothesized secondary hyperparathyroidism (HPT) would be found in hospitalized patients with decompensated congestive heart failure (CHF), where secondary aldosteronism is expected, and who were either untreated or treated medically. METHODS: In 9 consecutive patients (7 males, 2 females; 8 African-American, 1 Caucasian; 33-60 yrs) admitted to the Regional Medical Center during a 28-day period with chronic left ventricular systolic dysfunction (EF<35%) and decompensated CHF (5 untreated; 4 treated with an angiotensin converting enzyme inhibitor, furosemide, and small-dose spironolactone), we measured: plasma parathyroid hormone (PTH); serum calcium corrected for albumin, magnesium, and phosphorus; serum creatinine and calculated creatinine clearance. RESULTS: Plasma PTH was elevated above the normal range (6-65 pg/mL) in both untreated and treated patients with CHF (204+/-60 and 134+/-14 pg/mL, respectively). Serum corrected calcium was normal (8.4-10.2 mg/dL) in both untreated and treated CHF (9.7+/-0.l and 9.1+/-0.2 mg/dL, respectively) as were serum magnesium and phosphorus. Calculated creatinine clearance did not differ between untreated and treated patients (74+/-15 and 83+/-21 mL/min, respectively). CONCLUSIONS: Secondary HPT was found in 5 untreated and 4 treated patients consecutively hospitalized over a 28-day period with decompensated CHF. Corrected serum calcium was normal. Plasmaionized calcium, a determinant of PTH secretion, was not measured. Although vitamin D levels were not assessed, the presence of hypovitaminosis D in these housebound patients with symptomatic CHF cannot be discounted. HPT may contribute to the systemic illness that accompanies CHF, including bone wasting.     

Adrenomedullin in cirrhotic and non-cirrhotic portal hypertension

AIM:Adrenomedullin (ADM) is a potent vasodilator peptide.ADM and nitric oxide (NO) are produced in vascular endothelial cells. Increased ADM level has been linked to hyperdynamic circulation and arterial vasodilatation in cirrhotic portal hypertension (CPH). The role of ADM in non-cirrhotic portal hypertension (NCPH) is unknown, plasma ADM levels were studied in patients with NCPH, compensated and decompensated cirrhosis in order to determine its contribution to portal hypertension (PH) in these groups.METHODS: There were 4 groups of subjects. Group 1consisted of 27 patients (F/M: 12/15) with NCPH due to portal and/or splenic vein thrombosis (mean age: 41±12years), group 2 consisted of 14 patients (F/M: 6/8) with compensated (Child-Pugh A) cirrhosis (mean age: 46±4),group 3 consisted of 16 patients (F/M: 6/10) with decompensated (Child-Pugh C) cirrhosis (mean age: 47±12).Fourteen healthy subjects (F/M: 6/8) (mean age: 44±8) were used as controls in Group 4. ADM level was measured by ELISA. NO was determined as nitrite/nitrate level by chemoluminescence.RESULTS: Adl level in Group 11 (236±61.4 pg/mL) was significantly higher than that in group 2 (108.4±28.3 pg/mL)and group 4 (84.1±31.5 pg/mL) (both P＜0.0001) but was lower than that in Group3 (324±93.7 pg/mL) (P=0.002). NO level in group 1 (27±1.4 μmol/L) was significantly higher than that in group 2 (19.8±2.8 μmol/L) and group 4 (16.9±1.6μmol/L) but was lower than that in Group 3 (39±3.6 μmol/L)(for all three P＜0.0001). A strong correlation was observed between ADM and NO levels (r=0.827, P＜0.0001).CONCLUSION: Adrenomedullin and NO levels were high in both non-cirrhotic and cirrhotic portal hypertension and were closely correlated, Adrenomedullin and NO levels increased proportionally with the severity of cirrhosis, and were significantly higher than those in patients with NCPH.Portal hypertension plays an important role in the increase of ADM and NO. Parenchymal damage in cirrhosis may contribute to the increase in these parameters.     

The Effects of cyclooxygenase-2 inhibitors and nonsteroidal anti-inflammatory therapy on 24-hour blood pressure in patients with hypertension, osteoarthritis, and type 2 diabetes mellitus

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) inhibitors may attenuate the efficacy of antihypertensive agents in high-risk patients. Therefore, we conducted a double-blind, randomized trial to evaluate the effects of celecoxib, rofecoxib, and naproxen on 24-hour blood pressure (BP) in patients with type 2 diabetes, hypertension, and osteoarthritis. METHODS: Patients were randomly assigned to treatment with 200 mg of celecoxib once daily (n = 136), 25 mg of rofecoxib once daily (n = 138), or 500 mg of naproxen twice daily (n = 130) for 12 weeks. Twenty-four-hour ambulatory BP monitoring and validated arthritis efficacy assessments were conducted at randomization and at weeks 6 and 12 of treatment. The primary end point was the mean change from baseline in average 24-hour systolic BP at week 6. RESULTS: Reductions in osteoarthritis symptoms, including pain, mobility, and stiffness, were similar in all treatment groups. The mean +/- SE 24-hour systolic BP following 6 weeks of therapy was increased significantly by rofecoxib (from 130.3 +/- 1.2 to 134.5 +/- 1.4 mm Hg; P < .001) but not by celecoxib (132.0 +/- 1.3 to 131.9 +/- 1.3 mm Hg; P = .54) or naproxen (133.7 +/- 1.5 to 133.0 +/- 1.4 mm Hg; P = .74). The BP difference between rofecoxib and celecoxib was 3.78 mm Hg (95% confidence interval, 1.18-6.38; P = .005); between rofecoxib and naproxen, 3.85 mm Hg (95% confidence interval, 1.15-6.55; P = .005). The proportion of patients with controlled hypertension at baseline who developed ambulatory hypertension by week 6 (24-hour systolic BP>135 mm Hg) was significantly greater with rofecoxib (30%) than with celecoxib (16%) (P = .05) but not significantly greater than with naproxen (19%). CONCLUSIONS: At equally effective doses for osteoarthritis management, treatment with rofecoxib but not celecoxib or naproxen induced a significant increase in 24-hour systolic BP. However, destabilization of hypertension control occurred to some extent in all 3 treatment groups; this phenomenon was seen more often in patients treated with rofecoxib than with the other therapies.     

Treatment of hepatorenal syndrome as defined by the international ascites club by albumin and furosemide infusion according to the central venous pressure: a prospective pilot study

OBJECTIVE: Hepatorenal syndrome (HRS) is a functional renal failure that occurs late during cirrhosis. The prognosis is extremely poor with a mean survival of 1.7 wks from the time of diagnosis. The aim of the present study was to examine the effects of albumin and furosemide administration tailored to central venous pressure (CVP) on renal function and clinical outcome. METHODS: We treated 20 consecutive patients with HRS. Albumin was given to increase and/or maintain CVP above 3 cm H(2)O. If diuresis remained below 50 mL/h despite effective volume expansion, furosemide was administrated. Patients were considered responders and treatment was discontinued when creatinine clearance rose above 40 mL/min or serum creatinine fell under 132 mumol/L. RESULTS: The need for albumin varied from patient to patient (extremes 40-600 g) and in the same patient from day to day. All but one needed furosemide. Eleven patients (55%) responded to treatment. In this population, diuresis, serum creatinine, and creatinine clearance were all significantly improved. Creatinine clearance at baseline was predictive of treatment efficacy. Survival increased in these patients compared to nonresponders defined as patients with no improvement in renal function (259 days +/- 113 compared to 14 days +/- 3, p < 0.0005). Response to treatment and the type of HRS were the only variables with an independent prognostic value. CONCLUSION: This study shows that HRS as defined by the International Ascites Club can be treated by albumin administration alone or with furosemide given according to the patient's specific need using CVP.     

Effect of compensated renal dysfunction on approved heart failure markers: direct comparison of brain natriuretic peptide (BNP) and N-terminal pro-BNP

Brain natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) are markers of heart failure. Although renal dysfunction may increase plasma concentrations, the magnitude of this effect has not been assessed in a head-to-head comparison between the clinically approved tests. We assessed the effect of compensated renal dysfunction on BNP (Triage BNP; Biosite) and NT-proBNP (elecsys proBNP; Roche) in 469 randomly selected stable outpatients after myocardial infarction (MI; Monitoring Trends and Determinants in Cardiovascular Diseases [MONICA] register Augsburg) who were characterized with respect to renal function (glomerular filtration rate [GFR]; Cockroft method) and left ventricular (LV) ejection fraction (EF) and mass (2D echocardiography). BNP and NT-proBNP were elevated in MI patients with LV dysfunction (LVD; EF <35%) compared with MI patients with preserved EF ( >45%; BNP 139+/-27 pg/mL versus 75+/-6; NT-proBNP 816+/-237 pg/mL versus 243+/-20; both P <0.03). Among all MI patients, the prevalence of renal dysfunction (GFR <85 mL/min) was 24%. BNP and NT-proBNP were significantly elevated in MI patients with renal dysfunction (BNP 132+/-17 pg/mL versus 68+/-4 without renal dysfunction; NT-proBNP 535+/-80 pg/mL versus 232+/-19; both P <0.05), and both markers were correlated with GFR in univariate and multivariate analyses (all P <0.01). When binary cut-off values were stratified according to the absence or presence of renal dysfunction (BNP 75 pg/mL and 125 pg/mL, respectively; NT-proBNP 100 pg/mL and 350 pg/mL, respectively), the predictive power of both markers for the detection of LVD increased substantially. BNP and NT-proBNP are almost similarly influenced by mild-to-moderate renal dysfunction. Renal dysfunction is a potential cause of elevated marker concentrations in the absence of LVD, and cut-off concentrations should be stratified according to renal function.     

Terlipressin improves renal function in patients with cirrhosis and ascites without hepatorenal syndrome

Patients with advanced cirrhosis and ascites are characterized by circulatory dysfunction with splanchnic vasodilatation and renal vasoconstriction, which often lead to ascites. The vasoconstrictor terlipressin improves renal function in hepatorenal syndrome (HRS). The aim of this study was to evaluate if terlipressin also improves renal function in patients with ascites without HRS. Twenty-three patients with cirrhosis participated; 15 with nonrefractory ascites were randomized to either terlipressin (N group, n = 11) or a placebo (P group, n = 4), and 8 had refractory ascites and received terlipressin (R group). The glomerular filtration rate (GFR), sodium clearance (C(Na)), lithium clearance (C(Li)), osmolal clearance (C(Osm)), and urine sodium concentration (U(Na)) were assessed before and after the injection of 2 mg of terlipressin or the placebo. GFR increased in the N group (69 +/- 19 versus 92 +/- 25 mL/min, P < 0.005) and in the R group (31 +/- 19 versus 41 +/- 31 mL/min, P < 0.05) after terlipressin. In the N group, terlipressin induced an increase in C(Na) (0.89 +/- 0.21 versus 1.52 +/- 1.45 mL/min, P < 0.05), C(Li) (17.3 +/- 8.9 versus 21.5 +/- 11.6 mL/min, P < 0.05), and C(Osm) (2.10 +/- 0.81 versus 3.06 +/- 2.0 mL/min, P < 0.05). In the R group, terlipressin induced an increase in C(Na) (0.11 +/- 0.18 versus 0.35 +/- 0.40 mL/min, P < 0.05) and C(Li) (5.5 +/- 4.2 versus 9.5 +/- 8.55 mL/min, P < 0.05). U(Na) increased in both groups after terlipressin (P < 0.005). Plasma norepinephrine (P < 0.05) and renin (P < 0.05) decreased after terlipressin. All parameters remained unchanged after the placebo. Conclusion: The vasopressin 1 receptor agonist terlipressin improves renal function and induces natriuresis in patients with cirrhosis and ascites without HRS. Vasoconstrictors may represent a novel future treatment modality for these patients.     

Selective inhibition of cyclooxygenase-2 (COX-2) reduces prostaglandin E2 production and attenuates systemic disease sequelae in experimental pancreatitis

BACKGROUND/AIMS: Prostaglandins and prostaglandin-derived mediators play an important role in mediating the systemic inflammatory response in acute pancreatitis. COX (cyclooxygenase) is the key enzyme of prostaglandin synthesis. Whereas COX-1 produces prostaglandin mediators for physiological reactions, COX-2 is overexpressed in acute pancreatitis. The aim of this study was to investigate whether a selective COX-2 inhibitor alters prostaglandin production and attenuates systemic disease sequelae in severe acute pancreatitis in rats. METHODOLOGY: Severe acute pancreatitis was induced in 36 rats by standardized intraductal infusion of bile salt and intravenous cerulein infusion. Six hours after acute pancreatitis induction, rats were randomized to receive either no COX inhibition (saline), nonselective COX inhibition by indomethacin (3 mg/kg, i.v.) or selective COX-2 inhibition by NS-398 (10 mg/kg, i.v.). Serum concentrations of prostaglandin E2 were measured before and after acute pancreatitis induction and 24 hrs after starting therapy. Routine cardiorespiratory and renal parameters were monitored to assess organ function. RESULTS: Animals treated with the selective COX-2 inhibitor had significantly lower prostaglandin E2 values (211 +/- 17 vs. 366 +/- 37 and 435 +/- 13 pg/mL), produced more urine (18 +/- 4 vs. 13 +/- 3 and 12 +/- 3 mL/6-24 h) and had significantly fewer episodes of respiratory distress (defined as a pO2 < 80 mmHg or pCO2 > 50 mmHg for > 15 min; 12 vs. 57 and 71%) during the observation period than animals without or with nonselective COX inhibition. CONCLUSIONS: Selective inhibition of COX-2 reduces prostaglandin E2 serum levels in this model of acute pancreatitis. This together with improved renal and respiratory function suggests an attenuation of the systemic response to pancreatic injury. COX-2 inhibition may be another step toward optimizing therapy in severe acute pancreatitis.     

Renal function and structure in subacute hepatic failure

BACKGROUND AND AIMS: Subacute hepatic failure (SHF) is a fatal complicaton of acute viral hepatitis. Renal failure has been implicated as the main cause of death in this disease. However, renal functional and structural evaluation in such patients have not been performed. The present prospective study evaluated the renal functional and structural abnormalities in patients with subacute hepatic failure. METHODS: Fourteen consecutive patients with SHF, 11 with acute liver failure (ALF) and 15 with cirrhosis of the liver (Child's B or C) were included in the present study. All 40 patients had liver disease caused by hepatitis viruses. The glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) estimations were measured in all patients by the use of technetium-99m diethylenetriaminepentaacetic acid and [131I]-labeled ortho-iodohippuric acid, respectively. Ante-mortem or post-mortem liver biopsies were performed in all patients. In three patients with SHF, post-mortem kidney biopsies were also performed. RESULTS: Thirty six percent (5/14) of patients with SHF, 18% (2/11) of patients with ALF and 20% (3/15) of patients with cirrhosis had renal failure. Seven patients with SHF, seven with ALF and nine with cirrhosis died. All the patients with renal failure in each of the three groups were among the deceased patients. Glomerular function was markedly affected among patients with SHF, which was shown by significantly higher (P < 0.05) proteinuria levels (0.367 +/- 0.38 g/24 h) compared to levels in patients with ALF (0.178 +/- 0.11 g/24 h) and cirrhosis (0.212 +/- 0.133 g/24 h). The GFR in SHF (56 +/- 27 mL/min per 1.73 m2) and cirrhotic patients (58 +/- 36 mL/min per 1.73 m2) was significantly lower compared to those in ALF patients (102 +/- 51 mL/min per 1.73 m2; P < 0.05). A significantly higher proportion (P < 0.05) of patients with SHF and cirrhosis (64 and 73%, respectively) had a GFR below 80 mL/min per 1.73 m2 compared to patients with ALF (18%). The GFR value among the deceased SHF patients (46 +/- 26 mL/min per 1.73 m2) was significantly lower (P < 0.05) than those SHF patients who survived (65 +/- 25 mL/min per 1.73 m2). However, similar features could not be documented among patients with ALF or cirrhosis. Subtle structural changes in the glomerulus were also noted in patients with SHF. These included mesangial proliferation and thickening, basal membrane thickening and increased cellularity with interstitial edema. The ERPF was markedly reduced (P = 0.058) among patients with SHF (347 +/- 131 mL/min per 1.73 m2) and cirrhosis (395 +/- 137 mL/min per 1.73 m2) in comparison to ERPF documented among patients with ALF (436 +/- 217 mL/min per 1.73 m2). Such a reduction in renal tubular blood flow, along with histologic documentation of hyaline presence, bile and grannular cast in the tubule, indicated a possible tubular dysfunction in patients with SHF. CONCLUSION: It is concluded that glomerular and tubular dysfunction with subtle structural abnormalities does occur in patients with SHF. These are similar to renal changes in cirrhosis and may have similar pathogenetic mechanisms that require further evaluation.     

Marked Prolongation in Disappearance Half-Time of Plasma Cholecystokinin-Octapeptide in Patients with Hepatic Cirrhosis

For exploration on the elimination of cholecystokinin from the circulation, the disappearance half-time of cholecystokinin-octapeptide was estimated with cholecystokinin specific radioimmunoassay in normal subjects and patients with chronic renal failure and with hepatic cirrhosis. With a brief infusion of 30.4 ng/kg of cholecystokinin-octapeptide for 2 min, plasma cholecystokinin level rose from 16.1 +/- 3.6 pg/ml (mean +/- SE) to 216.5 +/- 6.1 pg/ml at 3 min after starting infusion, and decreased rapidly in a single exponential fashion for 10 min in hepatic cirrhosis. The disappearance half-time of cholecystokinin-octapeptide in patients with hepatic cirrhosis was 2.45 +/- 0.07 min, and it was significantly longer than that in normal subjects (1.30 +/- 0.07) or patients with chronic renal failure (1.70 +/- 0.11). These findings suggest that the liver plays a major role in cholecystokinin-octapeptide elimination in humans.     

Midodrine, octreotide, albumin, and TIPS in selected patients with cirrhosis and type 1 hepatorenal syndrome

Hepatorenal syndrome (HRS) is a functional renal disorder complicating decompensated cirrhosis. Treatments to date, except liver transplantation, have been able to improve but not normalize renal function. The aim of this study was to determine the efficacy of transjugular intrahepatic portosystemic stent shunt (TIPS) as a treatment for type 1 HRS in ascitic cirrhotic patients, following improvement in systemic hemodynamics with a combination of midodrine, octreotide, and albumin (medical treatment). Fourteen ascitic cirrhotic patients with type 1 HRS received medical therapy until their serum creatinine reached below 135 micromol/L for at least 3 days, followed by a TIPS if there were no contraindications. Patients were assessed before and after medical treatment, as well as at 1 week and 1, 3, 6, and 12 months post-TIPS with measurements of renal function, sodium handling, systemic hemodynamics, central blood volume, and hormonal markers. Medical therapy for 14 +/- 3 days improved renal function (serum creatinine: 233 +/- 29 micromol/L vs. 112 +/- 8 micromol/L, P =.001) and renal sodium excretion (5 +/- 2 mmol/d vs. 9 +/- 2 mmol/d, P =.002) in 10 of the 14 patients. TIPS insertion in five of the responders further improved renal function and sodium excretion, so that by 12 months post-TIPS, glomerular filtration rate (96 +/- 20 mL/min, P <.01 vs. pre-TIPS) and urinary sodium excretion (119 +/- 15 mmol/d, P <.01 vs. pre-TIPS) were normal, associated with normalization of plasma renin and aldosterone levels and elimination of ascites. In conclusion, TIPS is an effective treatment for type 1 HRS in suitable patients with cirrhosis and ascites, following the improvement of renal function with combination therapy of midodrine, octreotide, and albumin.     

Acute vasoconstrictor response to intravenous furosemide in patients with chronic congestive heart failure. Activation of the neurohumoral axis

Hemodynamic and neurohumoral responses to acute diuretic therapy were measured in 15 patients with severe chronic heart failure given intravenous furosemide, 1.3 +/- 0.6 (SD) mg/kg body weight. Left ventricular pump function deteriorated by 20 minutes, as indicated by a fall in stroke volume index (27 +/- 8 to 24 +/- 7 mL/min X m2 body surface area, p less than 0.01) and an increase in left ventricular filling pressure (28 +/- 7 to 33 +/- 9 mm Hg, p less than 0.01). Increases occurred in heart rate (87 +/- 13 to 91 +/- 16 beats/min, p less than 0.01), mean arterial pressure (90 +/- 15 to 96 +/- 15 mm Hg, p less than 0.01), systemic vascular resistance (1454 +/- 394 to 1676 +/- 415 dynes X s X cm-5, p less than 0.01), plasma renin activity (9.9 +/- 8.5 to 17.8 +/- 16 ng/mL X h, p less than 0.05), plasma norepinephrine level (667 +/- 390 to 839 +/- 368 pg/mL, p less than 0.01), and plasma arginine vasopressin level (6.2 +/- 1.3 to 8.3 +/- 2.0 pg/mL, p less than 0.01). During the next 3.5 hours the patients had diuresis (2085 +/- 1035 mL) and the expected fall in filling pressure (28 +/- 7 to 22 +/- 10 mm Hg, p less than 0.01). Neurohumoral indicators also returned toward the control levels. Intravenous furosemide, in patients with severe chronic heart failure, is associated with acute pump dysfunction temporally related to activation of the neurohumoral axis.     

Hypovitaminosis D in African Americans residing in Memphis, Tennessee with and without heart failure

BACKGROUND: Factors contributing to heart failure (HF) in African Americans (AA) are under investigation. Reduced 25(OH)D confers increased cardiovascular risk, including HF. METHODS: We monitored serum 25(OH)D, 1,25(OH)2D3, parathyroid hormone (PTH), and creatinine clearance in 102 AA residing in Memphis: 58 hospitalized with decompensated HF of >or=4 weeks in 34 (21 men; 53.3 +/- 1.8 years) or of 1 to 2 weeks in 24 (17 men; 49.6 +/- 2.4 years) and associated with a dilated cardiomyopathy and reduced ejection fraction (<35%); 19 outpatients with compensated HF (14 men; 52.6 +/- 2.7 years) with comparable ejection fraction; 16 outpatients (9 men; 55.4 +/- 2.9 years) with heart disease, but without HF; and 9 healthy volunteers (3 men; 35.8 +/- 3.5 years). RESULTS: Serum 25(OH)D 65 pg/mL was found in all AA with decompensated HF of >or=4 weeks (132.4 +/- 12.0 pg/mL) and 67% with 1 to 2 weeks duration (82.3 +/- 7.9 pg/mL), but only 11% with compensated HF (45.8 +/- 6.1 pg/mL), 12% without HF (29.6 +/- 5.4 pg/mL), and none of the volunteers (31.1 +/- 3.9 pg/mL). Creatinine clearance did not differ between patient groups. CONCLUSIONS: Hypovitaminosis D is prevalent amongst AA residing in Memphis, with or without HF. Elevations in serum PTH in keeping with secondary hyperparathyroidism are only found in AA with decompensated HF, where hypovitaminosis D and other factors are contributory.