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PubMed2006

Acute renal failure requiring renal replacement therapy after orthotopic liver transplantation.

OBJECTIVES: Acute renal failure (ARF) is a severe complication in patients undergoing orthotopic liver transplantation (OLT), which predicts a poor outcome. The aim of this study was to analyze risk factors for the development of ARF, including severity of illness, onset time of ARF prognostic factors of outcome, and mortality in a group of critically patients requiring renal replacement therapy (RRT). METHODS: Retrospective analysis of 240 consecutive liver transplant cases from 1999 to 2001 admitted to the intensive care unit (ICU) was performed to identify risk factors for ARF development after OLT. The analyzed factors were: age, sex, CrS, BUN, diuresis, sepsis, hypovolemia, cardiac failure, nephrotoxic drugs (cyclosporine or FK506, antibiotics), hyperbilirubinemia, associated diseases (DM, CRF), onset time of renal failure and progressiveness, timing of RRT, number of days of RRT, and mortality. We examined variables upon admission to the ICU, before the first RRT, and on the last ICU day before resignation or death. We used Students' t test. Quantitative parameters were expressed as mean values +/- SD. RESULTS: Of the 240 patients, 20 (8.3%) experienced ARF needing renal replacement therapy during the postoperative period. The results of our study suggested that ARF among patients undergoing RRT conferred an excessive risk of in-hospital death: eight patients died (40%). This increased risk cannot be explained solely by a more pronounced severity of illness. CONCLUSION: Our results provide strong evidence that ARF presents a specific, independent risk factor for a poor prognosis.

Acute Disease↗
PubMed2002

p53-independent apoptosis is induced by the p19ARF tumor suppressor.

p19(ARF) is a potent tumor suppressor. By inactivating Mdm2, p19(ARF) upregulates p53 activities to induce cell cycle arrest and sensitize cells to apoptosis in the presence of collateral signals. It has also been demonstrated that cell cycle arrest is induced by overexpressed p19(ARF) in p53-deficient mouse embryonic fibroblasts, only in the absence of the Mdm2 gene. Here, we show that apoptosis can be induced without additional apoptosis signals by expression of p19(ARF) using an adenovirus-mediated expression system in p53-intact cell lines as well as p53-deficient cell lines. Also, in primary mouse embryonic fibroblasts (MEFs) lacking p53/ARF, p53-independent apoptosis is induced irrespective of Mdm2 status by expression of p19(ARF). In agreement, p19(ARF)-mediated apoptosis in U2OS cells, but not in Saos2 cells, was attenuated by coexpression of Mdm2. We thus conclude that there is a p53-independent pathway for p19(ARF)-induced apoptosis that is insensitive to inhibition by Mdm2.

Adenoviridae↗
PubMed2002

Potential role of platelet FcgammaRIIA in collagen-mediated platelet activation associated with atherothrombosis.

Collagen-mediated platelet activation contributes significantly to coronary and cerebrovascular thrombus formation associated with atherosclerotic plaque destabilization. Recent clinical and laboratory observations support a potential role for the platelet Fc receptor (FcgammaRIIA) in this process. The purpose of this study was to elucidate any association between platelet Fc receptor (FcR) expression levels and both atherosclerosis risk factors (ARFs) along with collagen-dependent platelet activation. Age and gender-independent variation has been described in the expression of this receptor that is stable over time. Platelet Fc surface expression was compared between patients experiencing an acute coronary or cerebrovascular event, healthy patients with two or more ARFs, and healthy patients with fewer than two ARFs. Platelet FcR expression was significantly and stably (6-52 weeks, mean 20 weeks) increased in 101 patients with acute myocardial infarction, unstable angina, or ischemic stroke syndrome (P<0.001) and 38 healthy patients with two or more ARFs (P=0.027) compared with 109 healthy patients with fewer than two ARFs. Patients with diabetes mellitus from all groups had significantly increased platelet FcR expression over those without diabetes (P<0.0001). Platelet aggregation studies suggested a correlation between number of ARFs per patient, platelet Fc expression levels, and relative sensitivity to collagen stimulation. Platelet FcR surface expression is increased in patients with an acute coronary or cerebrovascular event, non-acutely ill patients with two or more ARFs, and in patients with diabetes mellitus. Increased platelet FcR expression may therefore contribute towards risk for atherothrombotic events.

Adult↗
PubMed2002

Alterations in the INK4a/ARF locus and their effects on the growth of human osteosarcoma cell lines.

Two different proteins, p16(INK4a) and p14(ARF), encoded by the INK4a/ARF locus play important roles in the RB and p53 pathways, respectively. This study was performed to determine genetic and epigenetic alterations in the INK4a/ARF locus and their effects on the growth of osteosarcoma. Among six cell lines examined, both p16(INK4a) and p14(ARF) exons were homozygously deleted in two cell lines, MG63 and HOS, and both p16(INK4a) and p14(ARF) promoters were methylated in one cell line, U2OS. Wild-type mRNA and proteins for p16(INK4a) and p14(ARF) were expressed in three other cell lines, SaOS2, HuO9, and G292. Transfection studies were performed using two cell lines, U2OS and MG63. Both the RB and p53 genes were wild types in U2OS, whereas p53 but not RB was mutated in MG63. Both p16(INK4a) and p14(ARF) suppressed the growth of U2OS, whereas p16(INK4a) but not p14(ARF) suppressed the growth of MG63. p53 only did not suppress the growth of MG63 either; however, coexpression of p14(ARF) with p53 increased the fraction of the G0/G1 phase in MG63 cells. The data presented here demonstrate the importance of genetic and epigenetic alterations in the INK4a/ARF locus for the growth of osteosarcoma and thus will be useful to further understand the biologic behavior of osteosarcoma in association with the defects in the p53 and RB pathways.

Blotting, Western↗
PubMed1998

Potential of dopamine A-1 agonists in the management of acute renal failure.

Many therapeutic approaches have been undertaken both to prevent acute ischemic or nephrotoxic renal injury and, once acute renal failure (ARF) has developed, to improve renal function and reduce mortality. To date, most therapeutic studies have investigated the effects of diuretics (eg, mannitol, furosemide), vasoactive agents (calcium channel blockers, atrial natriuretic peptide), or dopamine (a nonselective dopaminergic agent [DAA]) in one or more phases of ARF. Unfortunately, studies of the use of DAA in ARF are complicated by the existence of at least two different DAA receptors (DA-1 and DA-2), and by the stimulation of alpha- and/or beta-adrenergic receptors by high doses of DAA. The undesirable side effects of high doses of dopamine and the inconclusive results using low doses (ie, "renal doses") of dopamine (a nonselective DAA) have prompted consideration of the use of more selective dopaminergic agonists for the prophylaxis and treatment of ARF. Selective DA-1 agonists exhibit many desirable renal effects that theoretically support their use for the prophylaxis and/or treatment of ARF, including decreases in renal vascular resistance accompanied by increases in renal blood flow and glomerular filtration rate, and increases in sodium excretion and urine volume. Even at high doses, some selective DA-1 agonists, such as fenoldopam, do not stimulate DA-2 receptors, or adrenergic alpha- or beta-receptors, and thus are free of unwanted side effects (eg, arrhythmias). Results of several studies in normal and hypertensive humans, and a few studies in animal models, are consistent with the notion that DA-1 agonists may be useful in preventing or treating ARF. Careful randomized prospective clinical trials of DA-1 agonists in human ARF are needed to test this hypothesis.

Acute Kidney Injury↗
PubMed2002

Mechanism of domain closure of Sec7 domains and role in BFA sensitivity.

Activation of small G proteins of the Arf family is initiated by guanine nucleotide exchange factors whose catalytic Sec7 domain stimulates the dissociation of the tightly bound GDP nucleotide. The exchange reaction involves distinct sequential steps that can be trapped by the noncompetitive inhibitor brefeldin A, by mutation of an invariant catalytic glutamate, or by removal of guanine nucleotides. Arf-GDP retains most characteristics of its GDP-bound form at the initial low-affinity Arf-GDP-Sec7 step. It then undergoes large conformational changes toward its GTP-bound form at the next step, and eventually dissociates GDP to form a nucleotide-free high-affinity Arf-Sec7 complex at the last step. Thus, Arf proteins evolve through different conformations that must be accommodated by Sec7 domains in the course of the reaction. Here the contribution of the flexibility of Sec7 domains to the exchange reaction was investigated with the crystal structure of the unbound Sec7 domain of yeast Gea2. Comparison with Gea2 in complex with nucleotide-free Arf1 Delta 17 [Goldberg, J. (1998) Cell 95, 237-248] reveals that Arf induces closure of the two subdomains that form the sides of its active site. Several residues that determine sensitivity to brefeldin A are involved in interdomain and local movements, pointing to the importance of the flexibility of Sec7 domains for the inhibition mechanism. Altogether, this suggests a model for the initial steps of the exchange reaction where Arf docks onto the C-terminal domain of the Sec7 domain before closure of the N-terminal domain positions the catalytic glutamate to complete the reaction.

Brefeldin A↗
PubMed2004

[Evaluation of parameters for the differentiation of acute from chronic renal failure in the dog].

The differentiation of acute (ARF) from chronic (CRF) renal failure is important for therapeutic and prognostic reasons and should be established as soon as possible. In practice this differentiation is often based on history, physical examination and laboratory results. In this retrospective study the diagnostic accuracy of parameters to differentiate ARF from CRF was tested in 19 dogs with ARF and 49 dogs with CRF. The diagnostic accuracy of body condition was 65%, of the hematocrit 78%, of serum potassium levels 28%, of total CO2 48%, of urinary casts 77%, of glucosuria 90% and of the urine protein-to-urine creatinine ratio 43%. Of all the parameters evaluated only glucosuria revealed an acceptable discriminating quality with a sensitivity of 92% and a specificity of 89%. A limitation of this factor is, that glucosuria depends on the cause of ARF. The single parameters tested are not very useful and the diagnosis of ARF or CRF is based on a combination of parameters from history, physical examination, laboratory results and diagnostic imaging. If a diagnosis can't be established immediately, treatment for ARF is recommended. With an immediate, aggressive treatment the possibility of total recovery from ARF is increased.

Acute Kidney Injury↗
PubMed2000

Impact of acute renal failure on antioxidant status in multiple organ failure.

BACKGROUND: Acute renal failure (ARF) can be triggered or aggravated by reactive oxygen species (ROS) but established ARF per se might also affect the antioxidant defence mechanisms of the organism. We evaluated a broad pattern of antioxidants in critically ill patients with multiple organ failure with (MOF-ARF) and without acute renal failure (MOF) to identify any potential involvement of renal dysfunction in the depletion of the antioxidant system. METHODS: Observational study; 13 patients with MOF were investigated (9 with and 4 without ARF), and 17 healthy subjects served as controls. Blood samples were drawn after establishment of MOF. Plasma levels of ascorbate, alpha-tocopherol, retinol, beta-carotene, selenium and lipid peroxidation products (MDA) were determined and the activities of the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD) and glutathione-peroxidase (GSH-PX) in erythrocytes were measured. In addition, ROS production (superoxide anion and hydrogen peroxide) in activated neutrophils was assessed. RESULTS: Plasma levels of ascorbate, beta-carotene and selenium were reduced in both patient groups, when compared to controls. Decrease in selenium was more pronounced in the MOF-ARF group. MDA levels were increased in both groups, again being more pronounced in MOF-ARF patients compared to MOF patients. Hydrogen peroxide production by neutrophils from both patient groups was lower than from controls. CONCLUSION: A depression of the antioxidative system is present in critically ill patients with MOF. In patients with associated ARF this was even more pronounced and plasma MDA levels were higher, suggesting an additional effect on the antioxidative potential in the presence of renal dysfunction and/or renal replacement therapy.

Acute Kidney Injury↗
PubMed1980

Renal tubular function in glycerol-induced acute renal failure.

The purpose of this study was to examine proximal and distal tubular function in rats with nonoliguric, myohemoglobinuric acute renal failure (ARF). ARF was induced with glycerol (50%, 10 ml/kg of body wt, i.m.), and renal function was studied 24 hours after glycerol or saline (controls) injection. Glycerol injection caused a 50 to 90% depression in GFR and a significant rise in blood urea nitrogen concentration. Animals with ARF exhibited glycosuria with normal blood sugar levels and a striking depression in tubular glucose reabsorption per milliliter of GFR. The capacity to reabsorb (mEq/liter GFR) was intact at normal blood bicarbonate levels, but was markedly depressed when blood bicarbonate was raised. The tubular maximum for para-aminohippurate (PAH) secretion and the renal extraction fraction of PAH were strikingly depressed in rats with ARF. Distal acidification as assessed by the urine-to-blood gradient of PCO2 (UB PCO2) was normal both during maximal alkalinization of the urine with bicarbonate (urine pH, approximately 7.8) or during neural phosphate infusion (urine pH, approximately 7.0). Net acid excretion per milliliter GFR and minimal urine pH (less than 5.5) following 3 days of ammonium chloride ingestion was similar in control and ARF animals. Potassium excretion was intact in maximal urinary osmolality were significantly altered in animals with ARF. Cortical and outer medullary Na-K-ATPase specific activities were significantly depressed in ARF rats. This occurred as a consequence of enzyme loss and not secondary to alterations in enzyme kinetics of absolute tubular sodium reabsorption. Light and electron microscopy showed diffuse proximal tubular damage, whereas glomeruli and distal tubules were intact. These data demonstrate that glycerol injection produces a diffuse proximal tubular transport defect associated with histologic and enzymatic alterations.

Acute Kidney Injury↗
PubMed1989

Atrial natriuretic peptide and dopamine in a rat model of ischemic acute renal failure.

Atrial natriuretic peptide (ANP) has been shown to reverse experimental models of ischemic acute renal failure (ARF). However, infusion of ANP has been associated with systemic hypotension making its use in clinical ARF impractical. Therefore, in this investigation, dopamine (D) was combined with intravenous (i.v.) atriopeptin III (AP III) to determine if this regimen was effective in reversing ARF while preventing systemic hypotension and maintaining renal blood flow (RBF). Four groups of Munich-Wistar rats were studied. Group 1, sham-ARF; Group 2, renal artery (RA) clamp (55 min) followed by i.v. saline; Group 3, RA clamp followed by i.v. AP III-D; and Group 4, RA clamp followed by i.v. D only. All infusions were begun after RA clamp release and continued for four hour. Mean arterial pressure in Group 3 rats given AP III-D were similar to that in Group 2, slightly less than that in Groups 1 and 4 (P less than 0.05), but consistently greater than 100 mm Hg during the four hour infusion. RBF in Group 3 was elevated above the level in Group 1 at P less than 0.05. Glomerular filtration rate (GFR), depressed by 52% in Group 2, was corrected to control (sham-ARF) levels in Group 3. In Group 4 there was a small but significant increase in GFR compared to Group 2 (P less than 0.05), but it remained less than that in sham-ARF or AP III-D treated ARF rats (P less than 0.01). Urine flow rate and urine sodium excretion rate were more than sixfold higher in Group 3 than any other group.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗
PubMed1997

Renal adenosine A1 receptor binding characteristics and mRNA levels during the development of acute renal failure in the rat.

1. The binding characteristics and mRNA levels for renal adenosine A1 receptors were investigated in normal rats and rats with acute renal failure (ARF) induced by either glycerol or HgCl2. 2. Saturation isotherms determined from the binding of [3H]-1,3-dipropyl-8-cyclopentylxanthine ([3H]-DPCPX), a selective adenosine A1 antagonist, to renal membranes of untreated rats gave values of 0.62 nM for the equilibrium dissociation constant (Kd) and 19.9 fmol mg-1 protein for the density of binding sites (Bmax). No saturable binding was observed with [3H]-2-(p-(carboxylethyl)-phenylethylamino)-5'-N-ethylcar box amido adenosine ([3H]-CGS 21680), a selective adenosine A2a agonist. 3. By contrast to time-matched controls, renal membranes obtained from rats 16 and 48 h following the induction of ARF with glycerol, showed statistically significant increases (2-4 fold) in both Bmax and Kd for the binding of [3H]-DPCPX. No significant changes in the binding characteristics of [3H]-DPCPX were noted with membranes from rats 48 h following the production of ARF with HgCl2. 4. Adenosine A1 receptor mRNA levels were significantly elevated 0.5, 16 and 48 h following induction of ARF with glycerol, whilst no change was noted in mRNA levels for beta-actin at the same time points. No statistically significant changes in adenosine A1 receptor or beta-actin mRNA levels were noted 48 h after the induction of ARF with HgCl2. 5. This study indicates that glycerol-induced ARF in the rat is associated with an increase in renal adenosine A1 receptor density which appears to result from increased transcription of the gene for this receptor. An increase in adenosine A1 receptor density in renal resistance vessels may explain, at least in part, the enhanced renal vasoconstrictor response to adenosine in glycerol-induced ARF that was noted in a previous study.

Acute Kidney Injury↗
PubMed2006

Sepsis-induced organ failure is mediated by different pathways in the kidney and liver: acute renal failure is dependent on MyD88 but not renal cell apoptosis.

Toll-like receptors (TLRs) are important in sepsis. Myeloid differentiation factor 88 (MyD88) is a key molecule involved in signal transduction by multiple TLRs. The objective of this study was to investigate the contribution of TLR4 and MyD88 to acute renal failure (ARF) induced by polymicrobial sepsis. Liver dysfunction and apoptosis in the spleen contribute to sepsis severity after cecal ligation and puncture (CLP). Therefore, we also investigated liver injury and splenic apoptosis. We used a mouse model of sepsis-induced ARF using CLP to generate polymicrobial sepsis. Despite fluid and antibiotic resuscitation the mice developed multi-organ failure, including ARF, which resembles human sepsis. We investigated the role of the TLR4 receptor by comparing C3H/HeJ mice (which lack TLR4) with C3H/He0UJ normal controls. The role of MyD88 was investigated by comparing MyD88 knockout mice (MyD88(-/-)) with wild-type controls. Following CLP, mice lacking TLR4 and wild-type mice both developed comparable ARF. However, MyD88(-/-) mice did not develop ARF compared to wild-type controls. In contrast, MyD88(-/-) mice developed liver injury comparable to wild type. After CLP, MyD88(-/-) mice had significantly reduced apoptosis in the spleen compared with wild type. Apoptosis was not detected in the kidney of wild-type or MyD88(-/-) mice after CLP. In summary, ARF induced by polymicrobial sepsis is dependent on MyD88, but not TLR4. The absence of MyD88 dissociates ARF from liver injury; liver injury is MyD88-independent. There was MyD88-dependent apoptosis in the spleen, but no apoptosis in the kidney. MyD88 may be a good drug target for some, but not all, organ dysfunctions following sepsis.

Acute Kidney Injury↗
PubMed2006

Role of caspases on cell death, inflammation, and cell cycle in glycerol-induced acute renal failure.

Caspases are the main executioners of apoptosis as well as interleukin (IL)-1beta and IL-18 conversion to active forms. They are activated after acute kidney injuries. In this study, we evaluated the importance of the caspase family in the pathogenesis and recovery of glycerol-induced acute renal failure in rats (Gly-ARF). Rats were treated with pan-caspase or selective caspase 1 and 3 inhibitors at the moment we injected glycerol. Renal function, renal histology (HE), transferase-mediated deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling staining for apoptosis, leukocytes infiltration (immunohistochemistry), renal expression of IL-1beta and IL-18 (immunohistochemistry and Western blot), tubular regeneration (5-bromo-2'-deoxyuridine (BrdU) incorporation), and P27(Kip) expression (Western blot) were evaluated at appropriate times. All inhibitors reduced the renal function impairment. Pan-caspase and caspase-3 inhibitors reduced cellular death (necrosis and apoptosis) 24 h after Gly-ARF. All caspases inhibitors reduced macrophages infiltration. The expression of total IL-1beta was enhanced in Gly-ARF, but the active IL-1beta and IL-18 forms were abolished in pan-caspase treated rats. Caspase-1 inhibitor attenuated Gly-ARF but not tubular injury suggesting glomerular hemodynamic improvement. There was striking regenerative response 48 h after Gly-ARF characterized by enhanced BrdU incorporation and reduced expression of p27(Kip). This response was not blunted by caspases inhibition. Our findings demonstrate that caspases participate in important pathogenic mechanisms in Gly-ARF such as inflammation, apoptosis, vasoconstriction, and tubular necrosis. The early inhibition of caspases attenuates these mechanisms and reduces the renal function impairment in Gly-ARF.

Acute Kidney Injury↗
PubMed2003

p14ARF induces G2 arrest and apoptosis independently of p53 leading to regression of tumours established in nude mice.

Until recently, the ability of ARF (human p14(ARF), murine p19(ARF)) tumour-suppressor protein, encoded by the INK4A/ARF locus, to inhibit cell growth in response to various stimuli was related to its ability to stabilize p53 through the so-called ARF/MDM2/p53 pathway. However, recent data have demonstrated that ARF is not implicated in this unique p53-dependent pathway. By use of transient and stable expression, we show here that human p14(ARF) inhibits the growth of human tumoral cells lacking functional p53 by inducing a transient G(2) arrest and subsequently apoptosis. This p14(ARF)-induced G(2) arrest was correlated with inhibition of CDC2 activity, inactivation of CDC25C phosphatase and induction of the CDK inhibitor p21(WAFI). Apoptosis was demonstrated using Hoechst 33352 staining, proteolytic activation of caspase-3 and PARP cleavage. Similar results were obtained in experiments with cells synchronized by hydroxyurea block. Importantly, we were able to reproduce these effects 'in vivo' by showing that p14(ARF) inhibits the growth of p53 nullizygous human tumours in nude mice and induces the regression of p53 -/- established tumours. In these experiments, tumoral regression was associated with inhibition of cell proliferation as well as induction of apoptosis confirming the data obtained in cell lines.

Animals↗
PubMed2001

Regulation of mammalian phospholipase D2: interaction with and stimulation by G(M2) activator.

We have previously reported that a heat-stable activator for ganglioside metabolism, G(M2) activator, potently stimulates ADP-ribosylation factor (ARF)-dependent phospholipase D (PLD) activity (presumably PLD1) in an in vitro system [Nakamura, Akisue, Jinnai, Hitomi, Sarkar, Miwa, Okada, Yoshida, Kuroda, Kikkawa and Nishizuka (1998) Proc. Natl. Acad. Sci. U.S.A. 95, 12249-12253]. However, little is known about the regulation of PLD2. In the present studies we have investigated the regulation of PLD2 by G(M2) activator and various other regulators including ARF. PLD2 was potently stimulated in vitro by G(M2) activator in a time- and dose-dependent manner. Neither ARF nor protein kinase C caused any significant changes in PLD2 activity. Importantly, PLD2 responsiveness to ARF was greatly enhanced by G(M2) activator, suggesting a possible role for G(M2) activator as a coupling factor. G(M2) activator was also demonstrated to physically associate with PLD2 in a stoichiometric manner. Further, PMA stimulation of COS-7 cells overexpressing both G(M2) activator and PLD2 resulted in a marked increase in the association of the two molecules. Interestingly, ARF association with PLD2 was greatly increased by G(M2) activator. Moreover, G(M2) activator enhanced PMA-induced PLD activity in a synergistic manner with ARF in streptolysin-O-permeabilized, cytosol-depleted HL-60 cells, suggesting that G(M2) activator may regulate PLD in a concerted manner with other factors, including ARF, inside the cells.

Amino Acid Sequence↗
PubMed1991

Redistribution of ADP-ribosylation factor during stimulation of permeabilized cells with GTP analogues.

Low-molecular-mass GTP-binding proteins of the ras family were analysed by [32P]GTP binding after PAGE and transfer to nitrocellulose membranes. By this technique, several GTP-binding proteins in the 20-30 kDa range were detected in both cytosolic and microsomal fractions of RINm5F cells. One of these, displaying an apparent molecular mass of about 20 kDa and a pI of 6.7, was mainly cytosolic and was shown to be the ADP-ribosylation factor (ARF) by using specific antibodies. When permeabilized RINm5F cells were incubated with the stable GTP analogues guanosine 5'-[gamma-thio]triphosphate (GTP[S]) and guanosine 5'-[beta gamma-imido]triphosphate (p[NH]ppG) the amount of ARF increased in a fraction containing both Golgi and plasma-membrane markers, but not in the fraction containing secretory granules, mitochondria and lysosomes. GTP, GDP and its beta-thio analogue did not enhance ARF binding to membranes, smg25/rab3 and rho, as well as all the other small GTP-binding proteins detected by the [32P]GTP binding, did not redistribute under these conditions. As GTP[S] stimulates insulin secretion in these cells, we also examined the relationship between ARF translocation and insulin secretion. Both phenomena were elicited by GTP[S] with an EC50 (median effective concentration) of about 10 microM. p[NH]ppG was equipotent with GTP[S] in inducing insulin secretion (EC50 about 10 microM), but higher concentrations (about 500 microns) were required to achieve the same maximal ARF redistribution. These results suggest that: (1) ARF is subject to cycling between a membrane-associated and a free/loosely attached form, determined by the species of bound guanine nucleotide; (2) ARF alone does not seem to regulate exocytosis in insulin-secreting cells.

ADP-Ribosylation Factors↗
PubMed1998

Pharmacokinetics of intramuscular artemether in patients with severe falciparum malaria with or without acute renal failure.

AIMS: The pharmacokinetics of intramuscular artemether and its major plasma metabolite-dihydroartemisinin, were investigated in patients with severe manifestations of falciparum malaria. METHODS: Six severe falciparum malaria patients with acute renal failure (ARF) and 11 without ARF were recruited into the study. They were treated with intramuscular artemether at a loading dose of 160 mg, followed by daily doses of 80 mg for another 6 days (total dose 640 mg). RESULTS: Patients with and without ARF showed a good initial response to treatment; the parasite and fever clearance times were 66(30-164) and 76(36-140) h [median(range)], respectively. None had reappearance of parasitaemia in their peripheral blood smear within 7 days of initiation of treatment. In comatose patients, the time to recovery of consciousness was 51.6(22-144) h. Artemether was detected in plasma as early as 1 h after a 160 mg dose, and declined to undetectable levels within 24 h in most cases. Patients with ARF had significantly higher Cmax [2.38(1.89-3.95) vs 1.56(1.05-3.38) ng ml(-1) mg(-1) dose], AUC [35.4(22-52.9) vs 25.2(13.4-52.9) ng ml(-1) h mg(-1) dose], and lower Vz/F [5.45(3.2-6.9) vs 8.6(4.2-12.3) l kg(-1)] and CL/F [7.4(5.4-13.8) vs 19.1(8.5-25.1) ml min(-1) kg(-1)] when compared with those without ARF. In addition, t1/2,z was significantly longer in ARF patients [7.0(5.5-10.0) vs 5.7(4.2-6.6) h]. The pharmacokinetics of dihydroartemisinin in the two groups of patients were comparable. CONCLUSIONS: ARF significantly modified the pharmacokinetics of intramuscular artemether. The changes could be attributed to either improved absorption/bioavailability, a reduction of systemic clearance, or a change in plasma protein binding of the drug.

Acute Kidney Injury↗
PubMed2002

Protective effect of alpha-lipoic acid against ischaemic acute renal failure in rats.

1. In the present study, we investigated whether treatment with alpha-lipoic acid (LA), a powerful and universal anti-oxidant, has renal protective effects in rats with ischaemic acute renal failure (ARF). 2. Ischaemic ARF was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Blood urea nitrogen (BUN), plasma concentrations of creatinine (Pcr) and urinary osmolality (Uosm) were measured for the assessment of renal dysfunction. Creatinine clearance (Ccr) and fractional excretion of Na+ (FENa) were used as indicators of glomerular and tubular function, respectively. 3. Renal function in ARF rats decreased markedly 24 h after reperfusion. Intraperitoneal injection of LA at a dose of 10 mg/kg before the occlusion tended to attenuate the deterioration of renal function. A higher dose of LA (100 mg/kg) significantly (P < 0.01) attenuated the ischaemia/reperfusion-induced increases in BUN (19.1 +/- 0.7 vs 7.2 +/- 0.7 mmol/L before and after treatment, respectively), Pcr (290 +/- 36 vs 78.1 +/- 4.2 micromol/L before and after treatment, respectively) and FENa (1.39 +/- 0.3 vs 0.33 +/- 0.09% before and after treatment, respectively). Treatment with 100 mg/kg LA significantly (P < 0.01) increased Ccr (0.70 +/- 0.13 vs 2.98 +/- 0.27 mL/min per kg before and after treatment, respectively) and Uosm (474 +/- 39 vs 1096 +/- 80 mOsmol/kg before and after treatment, respectively). 4. Histopathological examination of the kidney of ARF rats revealed severe lesions. Tubular necrosis (P < 0.01), proteinaceous casts in tubuli (P < 0.01) and medullary congestion (P < 0.05) were significantly suppressed by the higher dose of LA. 5. A marked increase in endothelin (ET)-1 content in the kidney after ischaemia/reperfusion was evident in ARF rats (0.43 +/- 0.02 ng/g tissue) compared with findings in sham- operated rats (0.20 +/- 0.01 ng/g tissue). Significant attenuation (P < 0.01) of this increase occurred in ARF rats treated with the higher dose of LA (0.24 +/- 0.03 ng/g tissue). 6. These results suggest that administration of LA to rats prior to development of ischaemic ARF prevents renal dysfunction and tissue injury, possibly through the suppression of overproduction of ET-1 in the postischaemic kidney.

Acute Kidney Injury↗