6-ketoprostaglandin-f1-alpha and Acute-Kidney-Injury

Acute kidney injury (AKI) is frequently observed in critically ill patients in the intensive care unit (ICU) and is associated with increased mortality. Prostanoids regulate numerous biological functions, including hemodynamics and renal tubular transport. We herein investigated the ability of urinary prostanoid metabolites to predict the onset of AKI in critically ill adult patients.. The current study was conducted as a prospective observational study. Urine of patients admitted to the ICU at Okayama University Hospital was collected and the urinary levels of prostaglandin E2 (PGE2), PGI2 metabolite (2,3-dinor-6-OXO-PGF1α), thromboxane A2 (TXA2) metabolite (11-dehydro-TXB2) were determined.. Of the 93 patients, 24 developed AKI (AKIN criteria). Surgical intervention (93, 75 %) was the leading cause of ICU admission. Overall, the ratio of the level of serum Cr on Day 1 after ICU admission to that observed at baseline positively correlated with the urinary 2,3-dinor-6-OXO-PGF1α/Cr (r = 0.57, p < 0.0001) and 11-dehydro-TXB2/Cr (r = 0.47, p < 0.0001) ratios. In 16 cases of de novo AKI, the urinary 2,3-dinor-6-OXO-PGF1α/Cr and 11-dehydro-TXB2/Cr values were significantly elevated compared with that observed in the non-AKI group, whereas the urinary PGE2/Cr values were not. The urinary 2,3-dinor-6-OXO-PGF1α/Cr ratio exhibited the best diagnostic and predictive performance among the prostanoid metabolites according to the receiver operating characteristic (ROC) analysis [ROC-area under the curve (AUC): 0.75].. Taken together, these results demonstrate that the urinary 2,3-dinor-6-OXO-PGF1α/Cr and 11-dehydro-TXB2/Cr ratios are associated with the subsequent onset of AKI and poor outcomes in adult heterogeneous ICU patients.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Adult; Biomarkers; Creatinine; Critical Care; Critical Illness; Female; Humans; Japan; Male; Postoperative Complications; Predictive Value of Tests; Prospective Studies; Prostaglandins; Thromboxane B2; Treatment Outcome

We examined the value of inflammatory and oxidative biomarkers in predicting acute kidney injury (AKI) following orthotopic liver transplantation (OLT).. Urinary excretion of tumour necrosis factor-α (TNF-α), interleukin-8 (IL-8), interleukin-10 (IL-10), superoxide dismutase (SOD), malondialdehyde (MDA), 6-keto prostaglandin F1α (6-keto-PGF1α), hydrogen peroxide (H2O2), and 8-keto prostaglandin F2α (8-iso-PGF2α), serum creatinine (SCr), blood urea nitrogen (BUN), urinary N-acetyl-beta-D-glucosaminidase (NAG), β2-microglobulin (β2-MG) and γ-glutamyl-transferase (γ-GT), were measured before surgery (baseline), at 2 h after graft reperfusion and 24 h after OLT in 28 liver transplantation patients.. The levels of TNF-α, IL-8, IL-10, SOD, MDA, 6-keto-PGF1α, H2O2 and 8-iso-PGF2α in urine were all significantly higher in patients who had AKI than in those who did not at 2 h after graft reperfusion and 24 h after OLT (p < 0.01).

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Adult; Biomarkers; Dinoprost; Female; Humans; Hydrogen Peroxide; Interleukin-10; Interleukin-8; Liver Transplantation; Male; Malondialdehyde; Middle Aged; Postoperative Period; Preoperative Period; Prognosis; ROC Curve; Superoxide Dismutase; Time Factors; Tumor Necrosis Factor-alpha

Sepsis-related acute kidney injury (AKI) is the leading cause of AKI in intensive care units. Endotoxin is a primary initiator of inflammatory and hemodynamic consequences of sepsis and is associated with experimental AKI. The present study was undertaken to further examine the role of the endothelium, specifically prostacyclin (PGI(2)), in the pathogenesis of endotoxemia-related AKI. A low dose of endotoxin (LPS, 1 mg/kg) in wild-type (WT) mice was associated with stable glomerular filtration rate (GFR) (164.0 +/- 16.7 vs. 173.3 +/- 6.7 microl/min, P = not significant) as urinary excretion of 6-keto-PGF(1alpha), the major metabolite of PGI(2), increased. When cyclooxygenase inhibition with indomethacin abolished this rise in 6-keto-PGF(1alpha), the same low dose of LPS significantly decreased GFR (110.7 +/- 12.1 vs. 173.3 +/- 6.7 microl/min, P < 0.05). The same dose of indomethacin did not alter GFR in WT mice. To further study the role of PGI(2) in endotoxemia, renal-specific PGI synthase (PGIs) transgenic (Tg) mice were developed that had increased PGIs expression only in the kidney and increased urinary 6-keto-PGF(1alpha). These Tg mice, however, demonstrated endotoxemia-related AKI with low-dose LPS (1 mg/kg) (GFR: 12.6 +/- 3.9 vs. 196.5 +/- 21.0 microl/min P < 0.01), which did not alter GFR in WT mice (164.0 +/- 16.7 vs. 173.3 +/- 6.7 microl/min, P = not significant). An elevation in renal cAMP, however, suggested an activation of the PGI(2)-cAMP-renin system in these Tg mice. Moreover, angiotensin-converting enzyme inhibition afforded protection against endotoxin-related AKI in these Tg mice. Thus endothelial PGIs-mediated PGI(2), as previously shown with endothelial nitric oxide synthase-mediated nitric oxide, contributes to renal protection against endotoxemia-related AKI. This effect may be overridden by excessive activation of the renin-angiotensin system in renal-specific PGIs Tg mice.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cyclooxygenase Inhibitors; Cytochrome P-450 Enzyme System; Enalapril; Endothelium; Endotoxemia; Endotoxins; Epoprostenol; Escherichia coli Infections; Glomerular Filtration Rate; Indomethacin; Intramolecular Oxidoreductases; Kidney; Lipopolysaccharides; Male; Mice; Mice, Transgenic; Prostaglandin-Endoperoxide Synthases; Regional Blood Flow

The effect in preventing and treating glycerol-induced acute renal failure (ARF) in rabbit with Ligusticum wallichii (LW) has been studied. 33 male and female rabbits weighing 2.0-3.0 Kg were divided into three groups randomly: (1) LW treated group. (2) pathological control group and (3) normal control group. The measurement of plasma 6-keto-PGF1 alpha, TXB2 concentration and 6-keto-PGF1 alpha/TXB2 ratio were carried out with radioimmunoassay after 24 hr, 48 hr and 72 hr of ARF. The results showed that plasma TXB2 concentration obviously increased (P < 0.01), 6-keto-PGF1 alpha concentration had no obvious changes (P > 0.05), 6-keto-PGF1 alpha/TXB2 ratio markedly decreased and LW could reduce plasma TXB2 concentration, slightly increase the plasma 6-keto-PGF1 alpha concentration, keep 6-keto-PGF1 alpha/TXB2 ratio in normal level after ARF. It showed that LW could inhibit effectively platelet activation, correct 6-keto-PGF1 alpha/TXB2 imbalance and have a preventing and treating effect for ARF.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Animals; Drugs, Chinese Herbal; Female; Glycerol; Male; Rabbits; Thromboxane B2

The effects of DP-1904, a thromboxane (TX) A2 synthase inhibitor, on renal function were investigated by analysis of prostanoid metabolism in hydronephrotic and ischemic rat kidney models, and in isolated perfused normal and hydronephrotic rat kidneys. The increase in production of TXB2 in hydronephrotic or ischemic kidneys was significantly suppressed by intraperitoneal DP-1904 (10 mg/kg), with the 6-keto-prostaglandin F1 alpha to TXB2 ratio being significant increased. Urine volume, glomerular filtration rate and renal plasma flow were all improved. DP-1904 (0.3 micrograms/min) blocked the effects of infused arachidonic acid on isolated perfused normal rat kidneys thus reducing TXB2 levels and perfusion pressure but the pressor response to norepinephrine or angiotensin II remained unchanged. In isolated perfused hydronephrotic rat kidneys, DP-1904 suppressed the increase in perfusion pressure and TXB2 production caused by platelet-activating factor. These findings suggested that DP-1904 improved renal failure by specifically inhibiting TXA2 production.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Animals; Hydronephrosis; Imidazoles; Ischemia; Kidney; Male; Perfusion; Rats; Rats, Inbred Strains; Tetrahydronaphthalenes; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

Six hours after glycerol (G) injection in normal rats (NR), creatinine clearance (Ccr) decreased while urinary TXB2 (TXA2), 6-keto-PGF1 alpha (PGI2) and PGE2 significantly increased. The administration of OKY-046, a selective TXA-synthase inhibitor in glycerol-treated rats (GTR), significantly prevented the decrease in Ccr (indicating a partial protection against the development of acute renal failure) (ARF) and the increase in urinary TXA2 excretion, while it did not significantly alter urinary prostaglandin (PG) excretion. However, although TXB2 synthesis by the isolated glomeruli (IG) obtained from rats sacrificed 2 and 6 h after G injection was significantly enhanced, PGE2 and 6-keto-PGF1 alpha (6kPGF1 alpha) synthesis was augmented only by the IG obtained from rats killed 6 h after G administration. TXB2 and 6kPGF1 alpha synthesis by the IG obtained from rats killed 24 h after G injection returned to normal levels, while PGE2 synthesis continued to be elevated. Thus the enhanced release of PGE2 and 6kPGF1 alpha observed in intact animals in the early phase of ARF must be of medullary origin, while the augmented release of TXB2 (TXA2) by the IG must be responsible for the afferent arteriolar contraction during the early phase of this syndrome.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Animals; Creatinine; Dinoprostone; Female; Glycerol; In Vitro Techniques; Kidney Glomerulus; Prostaglandins; Rats; Rats, Inbred Strains; Thromboxane A2

Ischemia-induced renal injury is prevented by inhibition of thromboxane (Tx) synthesis. This protection was believed to be secondary to a high prostaglandin (PG)/TxA2 ratio. This study tests whether increasing the PG/Tx ratio by administration of vasodilating PGs protects the reperfused ischemic kidney. Anesthetized rats underwent right nephrectomy and 45 minutes of left renal pedicle clamping. Beginning 10 minutes before clamp release, animals were treated intravenously with the following: saline placebo (n = 10); the cyclooxygenase inhibitor ibuprofen (Ibu), 12.5 mg/Kg in a bolus (n = 8); a stable analogue of prostacyclin (PGI2), 500 ng/kg/minute for 2 hours (n = 9); PGE1, 400 ng/kg/minute for 2 hours (n = 8); the combination Ibu and PGI2 (n = 8) or PGE1 (n = 8). In saline treated ischemic controls, 5 minutes after reperfusion plasma, thromboxane (TxB2) and 6-keto-PGF1 levels were 2537 and 317 pg/ml, respectively--higher than the TxB2 and 6-keto-PGF1 levels of 750 and 80 pg/ml, respectively, in nephrectomized but nonischemic sham controls (n = 7) (p less than 0.05). In ischemic control animals at 24 hours, creatinine levels were 4.6 mg/dl, relative to 0.9 ml/dl in sham animals (p less than 0.05); the weight of the left (L) ischemic kidney relative to the right (R) normal kidney was 118%, compared with 99% in sham animals (p less than 0.05); and renal histology of ischemic control animals at 24 hours showed acute tubular necrosis (ATN) relative to normal findings in sham animals. Pretreatment with Ibu led to: TxB2 and 6-keto-PGF1 levels of 116 and 40 pg/ml, lower than those of sham animals (p less than 0.05); creatinine levels of 4.6 mg/dl, L/R renal weight of 119%; and ATN similar to that of ischemic controls. Treatment with a PGI2 analogue or PGE1 was not protective and led to increases in TxB2, 6-keto-PGF1, creatinine, L/R renal weight, and ATN similar to that of ischemic controls. The combination of Ibu and either PGI2 or PGE1 led to: reduced levels of TxB2 and 6-keto-PGF1 (p less than 0.05); attenuated increases in creatinine to 2.2 and 2.3 mg/dl, respectively (p less than 0.05); and limited ATN (p less than 0.05). These data indicate that the vasodilating PG protect the ischemic reperfused kidney only when Tx is inhibited.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Animals; Creatinine; Disease Models, Animal; Drug Combinations; Drug Evaluation, Preclinical; Epoprostenol; Ibuprofen; Ischemia; Kidney; Male; Organ Size; Prostaglandins E; Rats; Rats, Inbred Strains; Thromboxane B2; Vasodilator Agents

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Animals; Fatty Acids, Essential; Female; gamma-Linolenic Acid; Glomerular Filtration Rate; Hypolipidemic Agents; Linoleic Acids; Mercuric Chloride; Oenothera biennis; Plant Oils; Prostaglandins E; Rats; Rats, Inbred BN; Thromboxane B2

Treatment with thromboxane (Tx) synthase inhibitors or free radical scavengers has been shown to afford protection from renal ischemia. Since free radicals are closely associated with thromboxane (Tx) synthesis, this study examines the thesis that free radical scavengers inhibit formation of Tx. Anesthetized rats (n = 42) underwent right nephrectomy. By random choice, before 45 min of left renal pedicle clamping, rats received: 0.5 ml dextrose placebo IV (n = 6); the hydroxyl radical scavenger dimethyl-thiourea (DMTU), 500 mg/kg IV (n = 10); or the superoxide scavenger superoxide dismutase (SOD), 24,000 Sigma Units (SU)/kg IV (n = 12). This dose of SOD was repeated before release of the clamp. Treatment with DMTU and SOD decreased plasma TxB2 levels following 5 min of reperfusion from 2,480 pg/ml in dextrose treated controls to 1,155 pg/ml (p less than 0.01) and 1,419 pg/ml (p less than 0.03), respectively. At 24 hr, DMTU and SOD therapy decreased creatinine from 3.0 mg/dl in controls to 1.6 mg/dl (p less than 0.01) and 2.1 mg/dl (p less than 0.05), respectively. At 24 hr, DMTU but not SOD decreased left renal weight from 113 to 94% (p less than 0.0003) of the weight of the previously removed right kidney, and histologically prevented acute tubular necrosis (p less than 0.05). In nephrectomized but nonischemic sham control rats (n = 7) plasma TxB2 and 6-keto-PGF1 alpha concentrations were 757 pg/ml and 82 pg/ml, creatinine level 0.9 mg/dl and kidney weight 94% of the previously removed right kidney.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Animals; Epoprostenol; Humans; Kidney; Kidney Tubular Necrosis, Acute; Male; Rats; Renal Artery Obstruction; Superoxide Dismutase; Thiourea; Thromboxane B2; Thromboxane-A Synthase

The pathophysiology of renal dysfunction in generalized sepsis remains unknown. In this study, 24 hours after surgical induction of peritonitis in 20 volume-loaded sheep, three patterns of renal function were seen. In group 1 (n = 8), glomerular filtration rate (GFR) decreased by 70%, urine volume by 85%, absolute sodium excretion by 95%, and fractional sodium excretion by 83%. Group 2 (n = 4) exhibited similar sodium retention but GFR did not fall. Group 3 (n = 8) showed no change in GFR or urine volume and only minimally reduced sodium excretion. Mean arterial pressure fell 17% in group 1 only; central venous pressure, pulmonary capillary wedge pressure, and plasma volume were maintained at or above presepsis values in all groups. Cardiac index was either increased or unchanged, and renal plasma flow was maintained in all groups; there was thus no hemodynamic evidence to suggest volume contraction. Histologic examination showed only minor changes with no consistent pattern. Renal functional changes correlated with other manifestations of severe sepsis--GFR and sodium retention correlated significantly with increased cardiac index, decreased systemic vascular resistance, pulmonary arterial hypertension, leukopenia, hypoproteinemia, and hypoglycemia. All of these changes were most marked in group 1. In groups 1 and 2, plasma renin activity (PRA) increased and urinary kallikrein excretion decreased. PRA correlated inversely with GFR, urine volume, and sodium excretion; urinary kallikrein excretion correlated positively with urine volume and sodium excretion. Urinary excretion of 6-keto-PGF1 alpha was increased in groups 1 and 2 and correlated inversely with mean arterial pressure in group 1 animals. During sepsis, urinary thromboxane B2 excretion continued at presepsis values in all groups. The results suggest that unusual reciprocal changes in activity of the renin-angiotensin and renal kallikrein-kinin systems may play a role in the renal response to sepsis. PGI2 synthesis is increased and may affect systemic hemodynamics and renal function; the role of thromboxane A2 in this context is unknown.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Animals; Glomerular Filtration Rate; Hemodynamics; Kallikreins; Kidney; Kinins; Natriuresis; Peritonitis; Prostaglandins; Renin; Renin-Angiotensin System; Sheep; Thromboxane B2

Vasodepressor prostanoids have been suggested to regulate renal hemodynamics after nephrotoxic injury and thus protect the kidney against the effects of prolonged ischemia. This study assessed whether changes in two microvascular vasodilator prostanoids would correlate with changes seen in renal hemodynamics in rabbits with nephrotoxic renal injury produced by either uranyl nitrate or mercuric chloride. Rabbits were killed at 3, 24, and 72 h after the nephrotoxin injections and 6-ketoprostaglandin (PG) F1 alpha and PGE2 synthesis was measured in vitro in isolated renal microvessels. At the end of 24 h, synthesis of both prostanoids was significantly increased in all nephrotoxin-treated animals, an observation not noted at the end of 3 h. At 72 h, 6-keto-PGF1 alpha production remained elevated. Pretreatment with mepacrine blocked the increased prostanoid production seen in uranyl nitrate-treated animals. Thus, renal microvascular vasodilator prostanoid biosynthesis is increased 24-72 h after nephrotoxin administration. These data suggest that the biosynthesis of prostacyclin and PGE2 may contribute to the maintenance of renal blood flow in the first few days after acute renal injury and further suggest that a mechanism for this increase may be stimulation of phospholipase A2.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Animals; Arteries; Arterioles; Fatty Acids; Kidney; Male; Mercuric Chloride; Microcirculation; Prostanoic Acids; Rabbits; Uranyl Nitrate

Eighteen patients with fulminant liver failure were studied, 10 with normal renal function (group A) and eight with renal failure (group B, plasma creatinine greater than 200 mumol/l). Renal function was assessed by standard clearance techniques and patients in group B had a marked reduction compared with group A in both renal plasma flow and glomerular filtration rate. Raised plasma renin activity was observed in both groups, but levels in group B were significantly higher than in group A. Renal prostacyclin production was estimated by radioimmunoassay (RIA) of 6-keto-prostaglandin F1 alpha in urine, and the excretion rate was markedly increased in group A as compared with nine healthy controls, but was low in group B. The plasma concentrations of 6-keto-prostaglandin F1 alpha and thromboxane B2 were similar in groups A and B and were both significantly higher than in controls. Haemodynamic measurements showed a high cardiac output with low vascular resistance and mean arterial pressure within normal limits in both groups. The pulse pressure, however, was significantly higher in group B than in group A. In conclusion, patients in FHF with renal failure have marked renal vasoconstriction with increased plasma renin activity and reduced renal prostaglandin excretion indicative of an imbalance between vasoactive forces.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Adolescent; Adult; Female; Hemodynamics; Humans; Kidney Function Tests; Liver Diseases; Male; Middle Aged; Renin; Thromboxane B2

An evaluation was made of 106 surgical patients with Gram-negative septic shock, both for clinical criteria as well as the biochemical mediators endotoxin, prostaglandin F2 alpha, prostaglandin I2 (prostacyclin), and thromboxane. These data were correlated to various defined shock phases, functional data of vital organs, and clinical outcome. Patients underwent invasive organ function monitoring and the usual laboratory tests of intensive care. Prostaglandins and thromboxane were measured radioimmunologically, endotoxin by the limulus amebocyte lysate test. Endotoxin proved to be a more accurate predictor of severe sepsis than did positive blood cultures. Endotoxin as well as prostaglandins and thromboxane are predominantly released in early shock phases, appearing in plasma concentrations, which correlate with the severity of organ failure. Sepsis-induced respiratory failure coincides with a deterioration of pulmonary prostaglandin inactivation, which contributes to the release mechanism. High systemic prostacyclin activity benefits the patients' organ functions and clinical outcomes, while a predominance of thromboxane seems to effect the opposite. Transpulmonary-thromboxane gradients correlate significantly with pulmonary hypertension in the early phases of septic shock.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Adolescent; Adult; Aged; Dinoprost; Endotoxins; Epoprostenol; Humans; Middle Aged; Peritonitis; Prostaglandins; Prostaglandins F; Respiratory Insufficiency; Shock, Septic; Surgical Wound Infection; Thromboxanes

Urinary excretion rates of prostaglandin (PG) E2, PGF2 alpha, 6-keto-PGF1 alpha, and thromboxane (TX) B2 were evaluated in three groups of cirrhotic patients [without ascites (group 1, 13 cases), with ascites and normal renal function (group 2, 15 cases), and with ascites and renal failure (group 3, 5 cases)] and in 14 healthy controls. All urinary arachidonate metabolites were significantly increased in group 2 patients. Patients with renal failure showed lower PGE2, PGF2 alpha, and TXB2 values than those from group 2; PGF2 alpha values were also lower than controls. Platelet TXA2 production during whole blood clotting was significantly reduced in all groups of patients. Administration of low-dose aspirin and sulindac, two cyclooxygenase inhibitors selectively sparing renal cyclooxygenase activity, effectively inhibited platelet TXA2 production without affecting urinary TXB2 excretion, thus ruling out platelets as a possible source of urinary TXB2. We conclude that patients with ascites and normal renal function show an overall activation of the renal PG system. Renal production of vasodilating PGE2 and PGI2 may be involved in supporting renal function in these patients. A reduced platelet synthesis of proaggregatory TXA2 also occurs in cirrhotic patients. This may play a role in the bleeding tendency of cirrhosis.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Adult; Aged; Arachidonic Acid; Arachidonic Acids; Aspirin; Blood Platelets; Creatinine; Cyclooxygenase Inhibitors; Dinoprost; Dinoprostone; Epoprostenol; Female; Humans; Kidney; Liver Cirrhosis; Male; Middle Aged; Natriuresis; Prostaglandins E; Prostaglandins F; Renin-Angiotensin System; Sulindac; Thromboxane A2; Thromboxane B2

The aim of the study was to investigate the urinary excretion of 6-keto-PGF1 alpha (a stable metabolite of PGI2), thromboxane B2 (TxB2; a stable metabolite of TxA2), and PGE2 in 18 normal subjects, 49 cirrhotics with ascites without renal failure (GFR = 90 +/- 4 ml/min, means +/- S.E.M.) and 20 cirrhotics with functional renal failure (FRF) (GFR = 36 +/- 3). The study was made after 5 days on a 50 mEq sodium diet and without diuretics. Plasma renin activity (PRA), plasma norepinephrine concentration (NE) and plasma antidiuretic hormone concentration (ADH) were also measured. Cirrhotics without FRF showed a significantly higher urinary excretion of 6-keto-PGF1 alpha, TxB2 and PGE, (15.9 +/- 1.7 ng/h, 3.0 +/- 0.3 ng/h, and 6.2 +/- 1.0 ng/h) than did normal subjects (9.2 +/- 0.9, 1.3 +/- 0.1 and 2.3 +/- 0.4). On the contrary, the urinary excretion of these prostaglandins was normal or reduced in patients with FRF (5.3 +/- 0.8, 1.3 +/- 0.2 and 1.9 +/- 0.4). PRA, NE and ADH were significantly increased in cirrhotics with FRF (15.2 +/- 3.9 ng/ml/h, 1026 +/- 149 pg/ml and 4.1 +/- 0.3 pg/ml) and in patients without FRF (8.0 +/- 1.4, 667 +/- 67 and 3.9 +/- 0.3) as compared to normal controls (1.3 +/- 0.2, 275 +/- 46 and 2.4 +/- 0.2). These results suggest that renal hemodynamics in cirrhosis depends upon a critical equilibrium between the activity of endogenous vasoconstrictor systems and the renal production of the vasodilator prostaglandins PGI2 and PGE2. In addition, they do not support FRF in cirrhosis being related to an increased renal production of the vasoconstrictor prostaglandin TxA2.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Dinoprostone; Female; Glomerular Filtration Rate; Humans; Kidney; Liver Cirrhosis; Male; Prostaglandins E; Renal Circulation; Syndrome; Thromboxane B2

Acute renal failure (ARF) was induced in 35 week-old conscious female Wistar rats, by intramuscular (IM) injection of glycerol. Intraperitoneal (IP) injection of imidazole, an inhibitor of thromboxane (TXA2) synthesis, partially protected the animals against ARF. This protection was accompanied by a significant decrease in renal TXB2 (the stable chemical metabolite of TXA2) and a significant increase in renal 6-keto-PGF1 alpha (the stable chemical metabolite of PGI2) synthesis. Intraperitoneal injection of captopril (SQ 14225) an angiotensin-converting-enzyme inhibitor, did not protect the animals against ARF. This lack of protection was accompanied by a significant increase in renal TXB2 and a significant decrease in renal 6-keto-PGF1 alpha synthesis. The results suggest that: (a) the renin-angiotensin (R-A) system does not play a role, or has only a secondary one in the development of ARF; (b) thromboxane A2 (the most potent vasoconstrictor and platelet aggregator agent known) is the preponderant agent responsible for the development of this pathological syndrome.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Angiotensin II; Animals; Captopril; Dinoprostone; Female; Glycerol; Imidazoles; Prostaglandins; Prostaglandins E; Rats; Thromboxane A2; Thromboxane B2; Thromboxanes

Urinary prostaglandin excretion was studied in 42 patients with liver cirrhosis and in nine control subjects on restricted sodium intake and on bed rest. Creatinine clearance (CCr), sodium excretion (UNaV), plasma renin activity (PRA) and plasma aldosterone were also evaluated. Patients without ascites and ascitic patients without renal failure showed increased urinary excretion of immunoreactive 6-ketoprostaglandin F1 alpha (i6-keto-PGF1 alpha), prostaglandin E2 (iPGE2) and thromboxane B2 (iTXB2) when compared with controls, while immunoreactive PGF2a (iPGF2 alpha) levels did not differ from those in the control group. Patients with functional renal failure (FRF) presented a significant reduction of vasodilator prostaglandins but urinary excretion of iTXB2 was higher than in controls. On the whole, cirrhotic patients with higher urinary excretion of prostaglandins had normal or nearly normal PRA and aldosterone levels. i6-keto-PGF1 alpha and iPGE2 inversely correlated with PRA and aldosterone. The relationship between i6-ketoPGF alpha alpha and CCr was found to be highly significant in cirrhotic patients but not in the control group. On the other hand, iPGE2 significantly correlated with UNaV and with the fractional excretion of sodium (FENa). We concluded that: (a) enhanced renal prostaglandin synthesis in cirrhosis, inversely related to PRA and aldosterone, may be dependent on volume status; and (b) preserved renal function in these patients is associated with the ability to synthesize prostacyclin and PGE2.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Adult; Aged; Aldosterone; Creatinine; Dinoprost; Dinoprostone; Female; Humans; Liver Cirrhosis; Male; Middle Aged; Prostaglandins; Prostaglandins E; Prostaglandins F; Renin; Sodium; Thromboxane B2

It has recently been postulated that thromboxane A2 may participate in the pathogenesis of acute myohemoglobinuric experimental acute renal failure. To investigate this further, the effect of selective inhibition of thromboxane synthesis on the course of glycerol-induced acute renal failure was determined. Despite significant inhibition of thromboxane synthesis by 4-imidazole-yl-acetophenone, the functional and morphologic disturbance induced by glycerol was unaltered. Moreover, pretreatment with 4-imidazole-yl-acetophenone failed to prevent the fall in renal blood flow seen following glycerol administration. These results argue against a major role for thromboxane A2 in the pathogenesis of this form of experimental acute renal failure.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Animals; Glycerol; Imidazoles; Male; Rats; Rats, Inbred Strains; Renal Circulation; Thromboxanes; Vascular Resistance

Since prostacyclin (PGI2) is known to regulate renal cortical blood flow and since ischemia stimulates thromboxane (Tx) A2 synthesis, the role of these prostanoids in moderating the response to renal ischemia was studied in the rat. At baseline, plasma TxB2 concentration in untreated animals (n = 13) was 357 pg/ml. The left renal pedicle was clamped for 45 minutes after a right nephrectomy (n = 16), which led after 5 minutes of reperfusion to a rise in TxB2 to 2825 pg/ml (p less than 0.001), but there was no change in 6-keto-PGF1 alpha. After 24 hours creatinine levels rose from 0.4 to 3.0 mg/dl (p less than 0.001), and left renal weight rose from 94% to 117% (p less than 0.001) relative to the weight of the right kidney. In nephrectomized but nonischemic sham control rats (n = 7), creatinine level was 0.9 mg/dl and kidney weight 91% after 24 hours. Pretreatment with OKY 046 (n = 13) (2 mg/kg administered intravenously) blocked ischemia-induced TxB2 synthesis, while 6-keto-PGF1 alpha levels rose from 96 to 302 pg/ml (p less than 0.001). There was no increase in creatinine levels or kidney weight relative to the sham group. Pretreatment with ibuprofen (n = 10) (12 mg/kg) or OKY 046 and ibuprofen (n = 9) inhibited TxB2 and 6-keto-PGF1 alpha synthesis, but creatinine levels and renal weight rose (p less than 0.001). Renal histology in OKY 046-pretreated animals was equal to that in nephrectomized controls, while all other ischemic groups showed tubular necrosis. Results indicate that a high PGI2/TxA2 ratio protects against renal ischemia.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Animals; Epoprostenol; Ibuprofen; Ischemia; Male; Methacrylates; Premedication; Rats; Renal Circulation; Thromboxane A2; Thromboxane B2; Thromboxanes

Urinary excretion of the vasoconstrictor metabolite thromboxane B2 is increased in some patients with the hepatorenal syndrome. To define the role of thromboxanes in this syndrome and to evaluate a potential treatment for the renal impairment, we administered the thromboxane synthetase inhibitor dazoxiben to 5 patients with alcoholic hepatitis and rapidly progressive renal failure. Dazoxiben 200 mg/day followed by 400 mg/day reduced urinary thromboxane B2 by approximately 50% without altering prostaglandin E2 or 6-keto prostaglandin F1 alpha and without improving creatinine clearance (6 +/- 2 to 6 +/- 3 ml/min). In 3 additional patients, a higher dose of dazoxiben of 600 mg/day reduced thromboxane B2 by approximately 75% without consistent improvement in renal function. Thus, as judged by selective thromboxane inhibition with dazoxiben, thromboxanes are unlikely to be the key renal vasoconstrictor factor in the hepatorenal syndrome.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Adult; Creatinine; Dinoprostone; Drug Evaluation; Hepatitis, Alcoholic; Humans; Imidazoles; Middle Aged; Oxidoreductases; Prostaglandins E; Syndrome; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Animals; Glycerol; Hydronephrosis; Kidney; Prostaglandins; Prostaglandins F; Rabbits; Thromboxane A2; Thromboxane B2; Ureteral Obstruction; Vascular Resistance