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PubMed1990

Selective amplification of an mRNA and related pseudogene for a human ADP-ribosylation factor, a guanine nucleotide-dependent protein activator of cholera toxin.

ADP-ribosylation factors (ARFs) are approximately 20-kDa proteins that act as GTP-dependent allosteric activators of cholera toxin. With deoxyinosine-containing degenerate oligonucleotide primers corresponding to conserved GTP-binding domains in ARFs, the polymerase chain reaction (PCR) was used to amplify simultaneously from human DNA portions of three ARF genes that include codons for 102 amino acids, with intervening sequences. Amplification products that differed in size because of differences in intron sizes were separated by agarose gel electrophoresis. One amplified DNA contained no introns and had a sequence different from those of known ARFs. Based on this sequence, selective oligonucleotide probes were prepared and used to isolate clone psi ARF 4, a putative ARF pseudogene, from a human genomic library in lambda phage EMBL3. Reverse transcription-PCR was then used to clone from human poly(A)+ RNA the cDNA corresponding to the expressed homolog of psi ARF 4, referred to as human ARF 4. It appears that psi ARF 4 arose during human evolution by integration of processed ARF 4 mRNA into the genome. Human ARF 4 differs from previously identified mammalian ARFs 1, 2, and 3. Hybridization of ARF 4-specific oligonucleotide probes with human, bovine, and rat RNA revealed a single 1.8-kilobase mRNA, which was clearly distinguished from the 1.9-kilobase mRNA for ARF 1 in these tissues. The PCR provides a powerful tool for investigating diversity in this and other multigene families, especially with primers targeted at domains believed to have functional significance.

ADP-Ribosylation Factors↗
PubMed2004

Acute renal failure in the neonatal period.

Acute renal failure (ARF) is a common problem in the neonatal intensive care unit (NICU). In most cases, ARF is associated with a primary condition such as sepsis, metabolic diseases, perinatal asphyxia and/or prematurity. This retrospective study investigated the course of illness, therapeutic interventions, early prognosis and risk factors associated with development of ARF in the neonatal period. A total of 1311 neonates were treated in our NICU during the 42-month study period, and 45 of these babies had ARF. This condition was defined as serum creatinine level above 1.5 mg/dL despite normal maternal renal function. The data collected for each ARF case were contributing condition, cause and clinical course of ARF, gestational age and birth weight, age at the time of diagnosis, treatment, presence of perinatal risk factors and need for mechanical ventilation. The frequency of ARF in the NICU during the study period was 3.4%. Premature newborns constituted 31.1% of the cases. The mean birth weight in the group was 2863 +/- 1082 g, and the mean age at diagnosis was 6.2 +/- 7.4 days. The causes of ARF were categorized as prerenal in 29 patients (64.4%), renal in 14 patients (31.1%) and postrenal in 2 patients (4.4%). Forty-seven percent of the cases were nonoliguric ARF. Asphyxia was the most common condition that contributed to ARF (40.0%), followed by sepsis/metabolic disease (22.2%) and feeding problems (17.8%). Therapeutic interventions were supportive in 77.8% of the cases, and dialysis was required in the other 22.2%. The mortality rate in the 45 ARF cases was 24.4%. Acute renal failure of renal origin, need for dialysis, and need for mechanical ventilation were associated with significantly increased mortality (p<0.05). There were no statistical correlations between mortality rate and perinatal risk factors, oliguria, prematurity or blood urea nitrogen and creatinine levels. The study showed that, at our institution, ARF in the neonatal period is frequently associated with preventable conditions, specifically asphyxia, sepsis and feeding problems. Supportive therapy is effective in most cases of neonatal ARF. Acute renal failure of renal origin, need for dialysis, and need for mechanical ventilation were identified as indicators of poor prognosis in these infants. Early recognition of risk factors and rapid effective treatment of contributing conditions will reduce mortality in neonatal ARF.

Acute Kidney Injury↗
PubMed2003

Measurement of tubular enzymuria facilitates early detection of acute renal impairment in the intensive care unit.

BACKGROUND: Early detection of acute tubular necrosis (ATN) could permit implementation of salvage therapies and improve patient outcomes in acute renal failure (ARF). The utility of single and combined measurements of urinary tubular enzymes in predicting ARF in critically ill patients has not been evaluated using the receiver-operating characteristic (ROC) plot method. METHODS: In this prospective pilot study, 26 consecutive critically ill adult patients admitted to the intensive-care unit were studied. Urine samples were collected twice daily for up to 7 days. ARF was defined as an increase in plasma creatinine of > or = 50% and > or = 0.15 mmol/l. ROC plot analysis was applied to the tubular marker data to derive optimum cut-offs for ARF. RESULTS: Four of the 26 study subjects (15.4%) developed ARF. Indexed to urinary creatinine concentration, gamma glutamyl transpeptidase (gamma GT), alkaline phosphatase (AP), N-acetyl-glucosaminidase (NAG), and alpha- and pi-glutathione S-transferase (alpha- and pi-GST) but not lactate dehydrogenase (LDH) were higher in the ARF group on admission (P<0.05). gamma GT, and alpha- and pi-GST remained elevated at 24 h. The onset of ARF based on changes in plasma creatinine varied from 12 h to 4 days (median 36 h). ROC plot analysis showed that gamma GT, pi-GST, alpha-GST, AP and NAG had excellent discriminating power for ARF (AUC 0.950, 0.929, 0.893, 0.863 and 0.845, respectively). The discriminating strength of creatinine clearance, while lower, was still significant (AUC 0.796). Positive and negative predictive values for ARF on admission were 67/100% for gamma GT, 67/90% for AP, 60/95% for alpha-GST, and 67/100% for pi-GST indices. Positive and negative predictive values for ARF for creatinine clearance < or = 23 ml/min were 50 and 91%, respectively. Creatinine clearances tended to be lower in ARF than in non-ARF patients on admission (P=0.06) and were significantly lower (P=0.008) after 12 h. Plasma urea and fractional sodium excretion were unhelpful. CONCLUSIONS: Tubular enzymuria on admission to the ICU is useful in predicting ARF. The cheapness and wide availability of automated assays for gamma GT and AP suggests that estimation of these enzymes in random urine samples may be particularly useful for identifying patients at high risk of ARF.

Acetylglucosaminidase↗
PubMed2002

Ratio of expression of p16INK4a to p14ARF correlates with the progression of non-small cell lung cancer.

The CDKN2 gene is located on the short arm of chromosome 9p and encodes two unrelated proteins, p16(INK4a) and p14(ARF), through the use of independent first exons and shared exons 2 and 3. p16(INK4a) is a cyclin-dependent kinase inhibitor, whereas p14(ARF) regulates the cell cycle through a p53 and MDM2-dependent pathway. We have examined the expression of p16(INK4a) and p14(ARF) using competitive RT-PCR in 60 non-small cell lung cancers (NSCLCs) and matching normal lung tissues. The intensities of bands for p16(INK4a) and p14(ARF) were nearly equal or the intensity of the p16(INK4a) band slightly exceeded that of p14(ARF) in the normal lung tissues (n = 60). In 38 tumors the intensity of the p16(INK4a) band was similar to or slightly weaker than that of p14(ARF). In 6 tumors the intensity of the p16(INK4a) band was weaker than that of p14(ARF). In 15 tumors the intensity of the p14(ARF) band was very strong and the p16(INK4a) band was barely visible. In only one tumor was the intensity of the p16(INK4a) band very strong, while the band of p14(ARF) was barely visible. The ratio of the intensity of p16(INK4a) to p14(ARF) had an interesting correlation with the tumor's clinicopathological characteristics. The p stage II - IV tumors had significantly lower p16(INK4a) to p14(ARF) ratios than the p stage I tumors (P = 0.036). The T2 - 4 tumors had significantly lower p16(INK4a) to p14(ARF) ratios than the T1 tumors (P = 0.005). The N1 - 3 tumors had significantly lower p16(INK4a) to p14(ARF) ratios than the N0 tumors (P = 0.014). Our results suggest that the ratio of expression of p16(INK4a) to p14(ARF) tends to decrease during the progression of NSCLC.

Adult↗
PubMed2005

Acute renal failure after myeloablative hematopoietic cell transplant: incidence and risk factors.

BACKGROUND: Survival after myeloablative therapy followed by hematopoietic cell transplant (HCT) is limited by substantial treatment-related toxicities. Acute renal failure (ARF) develops in 25% to 50% of patients after HCT. METHODS: One hundred forty-seven patients were followed prospectively from time of transplant. ARF was defined as a doubling of baseline serum creatinine at any time during the first 100 days post-transplant. We conducted a nested case-control study to identify precipitants of ARF. For each person who developed ARF, 2 controls were selected at random from patients who had not developed ARF as of that time. An exposure period was defined for each case as the 2 weeks prior to the day on which the matched case met the criteria for ARF. The risk of ARF in relation to demographic and anthropometric characteristics, and to types of treatment and comorbidity, was examined using univariable and multivariable conditional logistic regression models. Odds ratios for the associations with ARF were estimated, taking into account the matching. RESULTS: Fifty-three patients (36%) developed ARF at a median of 33 days after transplant (range 1 to 97). Elevated risks were observed in patients who received liposomal amphotericin (OR 6.58; 95%CI 1.45-29.95) and conventional (OR 3.60; 95%CI 0.79-16.55), and in those patients with sinusoidal obstruction syndrome (SOS) (previously termed veno-occlusive disease) (OR 9.37; 95%CI 2.29-38.38). For every 0.1 mg/dL increase in baseline serum Cr, the risk of ARF decreased by 30%. Neither total body irradiation (TBI) dose, levels of metabolites of cyclophosphamide, sepsis, acute graft versus host disease (GVHD), nor cyclosporine (CSA) levels was associated with an increased risk of ARF. CONCLUSION: The cumulative incidence of ARF after HCT remains high. Amphotericin use during the 2-week exposure period and presence of hepatic sinuosoidal injury increased the risk of ARF within the first 100 days after HCT. Higher levels of serum creatinine at baseline were associated with a lower risk of ARF.

Acute Kidney Injury↗
PubMed2005

DNA damage disrupts the p14ARF-B23(nucleophosmin) interaction and triggers a transient subnuclear redistribution of p14ARF.

The p14 alternate reading frame (ARF) tumor suppressor plays a central role in cancer by binding to mdm2 (Hdm2 in humans) and enhancing p53-mediated apoptosis following DNA damage and oncogene activation. It is unclear, however, how ARF initiates its involvement in the p53/mdm2 pathway, as p53 and mdm2 are located in the nucleoplasm, whereas ARF is largely nucleolar in tumor cells. We have used immunofluorescence and coimmunoprecipitation to examine how the subnuclear distribution and protein-protein interactions of ARF change immediately after DNA damage and over the time course of the DNA damage response in human tumor cells. We find that DNA damage disrupts the interaction of ARF with the nucleolar protein B23(nucleophosmin) and promotes a transient p53-independent translocation of ARF to the nucleoplasm, resulting in a masking of the ARF NH2 terminus that correlates with the appearance of ARF-Hdm2 complexes. The translocation also results in an unmasking of the ARF COOH terminus, suggesting that redistribution disrupts a nucleolar interaction of ARF involving this region. By 24 hours after irradiation, DNA repair has ceased and the pretreatment immunofluorescence patterns and complexes of ARF have been restored. Although the redistribution of ARF is independent of p53 and likely to be regulated by interactions other than Hdm2, ARF does not promote UV sensitization unless p53 is expressed. The results implicate the nucleolus and nucleolar interactions of the ARF, including potentially novel interactions involving its COOH terminus as sites for early DNA damage and stress-mediated cellular events.

Amino Acid Sequence↗
PubMed2002

Incidence and prognostic importance of acute renal failure after percutaneous coronary intervention.

BACKGROUND: In patients undergoing percutaneous coronary intervention (PCI) in the modern era, the incidence and prognostic implications of acute renal failure (ARF) are unknown. METHODS AND RESULTS: With a retrospective analysis of the Mayo Clinic PCI registry, we determined the incidence of, risk factors for, and prognostic implications of ARF (defined as an increase in serum creatinine [Cr] >0.5 mg/dL from baseline) after PCI. Of 7586 patients, 254 (3.3%) experienced ARF. Among patients with baseline Cr <2.0, the risk of ARF was higher among diabetic than nondiabetic patients, whereas among those with a baseline Cr >2.0, all had a significant risk of ARF. In multivariate analysis, ARF was associated with baseline serum Cr, acute myocardial infarction, shock, and volume of contrast medium administered. Twenty-two percent of patients with ARF died during the index hospitalization compared with only 1.4% of patients without ARF (P<0.0001). After adjustment, ARF remained strongly associated with death. Among hospital survivors with ARF, 1- and 5-year estimated mortality rates were 12.1% and 44.6%, respectively, much greater than the 3.7% and 14.5% mortality rates in patients without ARF (P<0.0001). CONCLUSIONS: The overall incidence of ARF after PCI is low. Diabetic patients with baseline Cr values <2.0 mg/dL are at higher risk than nondiabetic patients, whereas all patients with a serum Cr >2.0 are at high risk for ARF. ARF was highly correlated with death during the index hospitalization and after dismissal.

Acute Kidney Injury↗
PubMed1998

Mechanisms contributing to muscle-wasting in acute uremia: activation of amino acid catabolism.

Acute uremia (ARF) causes metabolic defects in glucose and protein metabolism that contribute to muscle wasting. To examine whether there are also defects in the metabolism of essential amino acids in ARF, we measured the activity of the rate-limiting enzyme for branched-chain amino acid catabolism, branched-chain ketoacid dehydrogenase (BCKAD), in rat muscles. Because chronic acidosis activates muscle BCKAD, we also evaluated the influence of acidosis by studying ARF rats given either NaCl (ARF-NaCl) or NaHCO3 (ARF-HCO3) to prevent acidosis, and sham-operated, control rats given NaHCO3. ARF-NaCl rats became progressively acidemic (serum [HCO3] = 21.3 +/- 0.7 mM within 18 h and 14.7 +/- 0.8 mM after 44 h; mean +/- SEM), but this was corrected with NaHCO3. Plasma valine was low in ARF-NaCl and ARF-HCO3 rats. Plasma isoleucine, but not leucine, was low in ARF-NaCl rats, and isoleucine tended to be lower in ARF-HCO3 rats. Basal BCKAD activity (a measure of active BCKAD in muscle) was increased more than 17-fold (P < 0.01) in ARF-NaCl rat muscles, and this response was partially suppressed by NaHCO3. Maximal BCKAD activity (an estimate of BCKAD content), subunit mRNA levels, and BCKAD protein content were not different in ARF and control rat muscles. Thus, ARF increases branched-chain amino acid catabolism by activating BCKAD by a mechanism that includes acidosis. Moreover, in a muscle-wasting condition such as ARF, there is a coordinated increase in protein and essential amino acid catabolism.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMedDate not supplied

[Acute renal insufficiency caused by burn injury].

Acute renal failure (ARF) in burn disease results in a range of phenomena important not only from theoretical, but also from practical point of views, whose causes are manifold. ARF is generally defined as a rapid renal failure resulting in accumulation of protein metabolism degradation products (catabolism). It has been known, for some time, that thermal agents do not produce only local skin damages, but also disturb the integrity of the whole organism producing major functional damages of all organs and systems. Most frequently organs affected by burn disease are the following: the lungs, the heart, the kidney, the liver and blood coagulation systems. There are many factors influencing the renal function during the burns. The most important are: decreased cardiac output, respiratory failure with hypoxia and acidosis, toxaemia and sepsis [1, 4, 6 7, 8-10, 12, 19]. ARF in burn disease may be early due to hypovolaemia and hypoperfusion of the kidneys or late, occurring after a week as a consequence of infection and endotoxaemia. Development of ARF in burn disease is a very unfavorable prognostic sign necessitating a complex evaluation. Anuria in an early phase of burn disease may indicate the development of ARF, particularly if urine findings are positive to haemoglobin, proteins, myoglobin, which is of the utmost importance in deep burns inflicted by high voltage current. The immediate cause of anuria in burn disease may be a reflex transfer and penetration of the large quantities of toxic materials into the circulation form the region affected by burns leading to the spasm of afferent glomerular arteriolae producing sudden discontinuation of glomerular filtration. After burns, sudden increase in the osmotic activity ensues in the affected tissue. Some low molecular links may result, and such particles tend to change the osmotic balance and stimulate the development of oedema, and if not excreted, they increase osmolarity. In 20-30% of the patients with burn disease anuria is absent [2, 5, 11, 14, 18, 20]. The genesis of burn disease-associated anaemias is therefore multifactorial. These factors are the following: haemorrhage, haemolysis and etrythropoiesis level decrease. In massive burns, large amounts of non-specific inflammatory components are produced as well: prostaglandins, histamine, quinines leukocyte phenomena, bacterial toxins, etc. [1, 6, 13-16]. The study based on a years-long treatment of our patients with burn disease included on 100 patients. The youngest of the patients was 14 years old, and the oldest 65 years. The percent of burns-affected body surface ranged from 25% to 75%. In 3/4 of the patients the picture of an early renal failure developed, with oliguria immediately after infliction of the burns with rapid increase of serum urea and creatinine levels, while in 1/4 of the patients ARF occurred on the eighth day following the infliction of the burns. "late form of acute renal failure". Among our series with burn disease, anuria was present in 34.0% of patients and oliguria in 25.0%. ARF (early phase) occurred in 59 patients, 38 patients had no sing of ARF, while late ARF developed only in 3 patients. ARF-associated mortality rate was high among these patients (23%), being 6% among anuric patients with ARF and 17% in patients with ARF with anuria. Seventy-seven percent of the patients survived, and their serum and urine analyses performed upon subsequent out-patient follow-up examinations ranged within normal values. Such high percentage of survival among our patients included in the study is based on an early diagnosis of ARF, understanding of pathophysiology of shock associated with burn disease, adequate therapeutic approaches, including both medicamentous treatment and extracorporeal haemodialysis along with early surgical management (Shema 1, 2). For the time being, haemodialysis is the most effective therapeutical procedure in the treatment of ARF, although the mortality rate of dialyzable patients

Acute Kidney Injury↗
PubMedDate not supplied

Identification of ADP-ribosylation factor-6 in brush-border membrane and early endosomes of human kidney proximal tubules.

The expression and distribution of ADP-ribosylation factor (ARF) small GTP-binding proteins in kidney tissue was examined. Various anti-ARF antibodies were raised against purified rec-ARF 1 and rec-ARF 6 and their specificity was determined. Using indirect immunofluorescence analysis of intact kidney, ARF proteins were found to be predominantly expressed in kidney tubules as compared to glomeruli. This result was further supported by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot analysis of purified human kidney glomeruli and proximal tubules. Both ARF 1 and ARF 6 were detected in purified human glomeruli and proximal tubules; however, ARF 1 was more abundant than ARF 6 in these kidney structures. Brush-border membrane vesicles (BBMV) and early endosomes (EE) derived from the receptor-mediated endocytosis pathway were isolated from purified proximal tubules of rat, dog and human kidney using a combination of magnesium precipitation and wheat-germ agglutinin negative selection techniques. We demonstrated that ARF 6 is associated with BBMV and with EE derived from receptor-mediated endocytosis pathway of human kidney proximal tubules. Using a combination of SDS-PAGE and quantitative enhanced chemiluminescence Western blot analysis, the quantification of the ARF 6 distribution in membrane and cytoplasmic fractions of proximal tubules was made and its predominance in membrane fractions was demonstrated. By analogy with the functional role of ARF 1 in Golgi protein transport, we suggest that ARF 6 may play an important role in the regulation of receptor-mediated endocytosis and protein reabsorption by kidney proximal tubules.

ADP-Ribosylation Factor 6↗
PubMed2006

Risk factors of acute renal failure after liver transplantation.

The objective of this study was to determine the risk factors of postoperative acute renal failure (ARF) in orthotopic liver transplantation (OLT). We reviewed 184 consecutive OLT. Postoperative ARF was defined as a persistent rise of 50% increase or more of the S-creatinine (S-Cr). The patients were classified as early postoperative ARF (E-ARF) (first week) and late postoperative ARF (L-ARF) (second to fourth week). Preoperative variables were age, sex, comorbidity, indication for OLT, Child-Pugh stage, united network for organ sharing status, analysis of the blood and urine, and donor's data. Intraoperative variables were systolic arterial pressure, mean arterial pressure, pulmonary capillary wedge pressure, cardiac index, and systemic vascular resistance index. Surgical technique, number of blood products transfused, need for adrenergic agonist drugs, and intraoperative complications were also important. Postoperative variables were duration of stay in the intensive care unit, time on mechanic ventilation, liver graft dysfunction, need for adrenergic agonist drugs, units of blood products infused, episodes of acute rejection, re-operations, and bacterial infections. Firstly we carried out a univariate statistical analysis, and secondly a logistic regression analysis. The risk factors for E-ARF were: pretransplant ARF (odds ratio (OR)=10.2, P=0.025), S-albumin (OR=0.3, P=0.001), duration of treatment with dopamine (OR=1.6, P=0.001), and grade II-IV dysfunction of the liver graft (OR=5.6, P=0.002). The risk factors for L-ARF were: re-operation (OR=3.1, P=0.013) and bacterial infection (OR=2.9, P=0.017). The development of E-ARF is influenced by preoperative factors such as ARF and hypoalbuminemia, as well as postoperative factors such as liver dysfunction and prolonged treatment with dopamine. The predicting factors of L-ARF differ from E-ARF and correspond to postoperative causes such as bacterial infection and surgical re-operation.

Acute Kidney Injury↗
PubMed1998

IGF-I binding proteins, IGF-I binding protein mRNA and IGF-I receptor mRNA in rats with acute renal failure given IGF-I.

BACKGROUND: Recombinant human insulin-like growth factor-I (rhIGF-I) accelerates recovery from acute renal failure (ARF) in rats. IGF-I acts through the IGF-I receptor (IGF-IR) and its actions may be modified by IGF-I binding proteins (IGFBPs). It therefore would be of value to determine the effects of both ARF and rhIGF-I treatment on serum IGFBPs and mRNA for IGFBPs and IGF-IR. METHODS: Rats with ARF and sham-operated control rats were randomized to receive rhIGF-I or vehicle injections thrice daily for 72 to 74 hours starting five hours after surgery. Serum IGFPBs 1 to 6 were measured serially, and mRNA for IGFBPs 1 to 6 and for IGF-IR were measured in several tissues obtained 72 to 74 hours after surgery. RESULTS: At 72 to 74 hours, serum IGFBP-1 and IGFBP-2 levels were higher in rhIGF-I treated rats. Serum IGFBP-3 was affected by both ARF and rhIGF-I. IGFBP-4 rose transiently only in ARF groups. At 72 to 74 hours, mRNA for several IGFBPs was reduced in renal cortex of ARF rats. Low mRNA for IGFBP-4 and -6 was observed in renal medulla of the ARF rats, particularly in comparison to the sham-operated rats receiving vehicle. Renal medullary IGFBP-2 mRNA was decreased in ARF and sham rats given rhIGF-I as compared to sham animals given vehicle. Hepatic IGFBP-2 mRNA was higher in both rhIGF-I treated groups versus those given vehicle. Otherwise, there were no differences in IGFBP mRNAs among the four groups in lung, heart, and skeletal muscle. IGF-IR mRNA was decreased in renal cortex and medulla of both ARF groups and was not detected in liver in any group. CONCLUSIONS: Thus, ARF and rhIGF-I treatment each affected certain serum IGFBPs and jointly affected some IGFBPs. ARF suppressed gene transcription for renal cortical and medullary IGF-IR and some IGFBPs. rhIGF-I independently affected some renal cortical or medullary IGFBP mRNAs. rhIGF-I increased hepatic IGFBP-2 mRNA and serum IGFBP-2. These effects of ARF or rhIGF-I may influence rhIGF-I actions in rats with ischemic ARF.

Acute Kidney Injury↗
PubMed2005

Isoform-selective effects of the depletion of ADP-ribosylation factors 1-5 on membrane traffic.

The ADP-ribosylation factors (Arfs) are six proteins within the larger Arf family and Ras superfamily that regulate membrane traffic. Arfs all share numerous biochemical activities and have very similar specific activities. The use of dominant mutants and brefeldin A has been important to the discovery of the cellular functions of Arfs but lack specificity between Arf isoforms. We developed small interference RNA constructs capable of specific depletion of each of the cytoplasmic human Arfs to examine the specificity of Arfs in live cells. No single Arf was required for any step of membrane traffic examined in HeLa cells. However, every combination of the double knockdowns of Arf1, Arf3, Arf4, and Arf5 yielded a distinct pattern of defects in secretory and endocytic traffic, demonstrating clear specificity for Arfs at multiple steps. These results suggest that the cooperation of two Arfs at the same site may be a general feature of Arf signaling and provide candidates at several cellular locations that when paired with data on the localization of the many different Arf guanine nucleotide exchange factors, Arf GTPase activating proteins, and effectors will aid in the description of the mechanisms of specificity in this highly conserved and primordial family of regulatory GTPases.

ADP-Ribosylation Factors↗
PubMed2004

Relative roles of endothelin-1 and angiotensin II in experimental post-ischaemic acute renal failure.

BACKGROUND: The relative roles of endothelin (ET)-1 and angiotensin (ANG) II in post-ischaemic acute renal failure (ARF) have not been fully established so far. With the aim of contributing to this goal, we assessed in this study the effect of ANG II and ET-1 blockade on the course of post-ischaemic-ARF. METHODS: Anaesthetized Wistar rats received i.v. either bosentan (a dual ET receptor antagonist; 10 mg/kg body weight) or losartan [ANG II type 1 (AT(1)) receptor antagonist; 5 or 10 mg/kg body weight] or both, 20 min before, during and 20 min after ischaemia. Rats in the control group received the vehicle via the same route. Survival and renal function were monitored up to 8 days after the ischaemic challenge, while haemodynamic parameters were measured 24 h after ARF. RESULTS: Our results demonstrate that bosentan treatment has a more beneficial effect on experimental ARF than losartan. The survival rate was remarkably higher in bosentan-treated rats than in both rat groups treated with losartan. In the ARF group treated with bosentan, renal blood flow (RBF) was increased by 129% in comparison with the untreated ARF group, whereas in the losartan-treated ARF groups, RBF was only approximately 35 or 38% higher than in control ARF rats. The glomerular filtration rate was markedly higher in bosentan-treated rats than in all other ARF groups on the first and second day after ischaemia. Tubular cell injury was less severe in bosentan-treated rats than in the control ARF rats, but in losartan-treated groups it was similar to that in the ARF group. Concurrent blockade of both ET and AT(1) receptors did not improve ARF because this treatment induced a marked decrease in blood pressure. CONCLUSIONS: These results suggest that ET-1 blockade is more efficient in improving the early course of post-ischaemic renal injury than ANG II inhibition, and that blockade of ET-1 might be effective in prophylaxis of ischaemic ARF.

Acute Kidney Injury↗
PubMed2003

Acute renal failure in patients with sepsis in a surgical ICU: predictive factors, incidence, comorbidity, and outcome.

Acute renal failure (ARF) is a common complication in intensive care unit (ICU) patients. Although there are several reports on outcome of septic patients with ARF, there are no data regarding predisposing factors for ARF. Therefore, the incidence of ARF was investigated in 185 sepsis patients admitted in a surgical ICU during a 16-mo period. Variables predisposing to ARF on day 1 of sepsis were evaluated with univariate and multivariable analyses. APACHE II and SOFA scores were compared during a 14-d period. Additionally, the impact of organ failure on mortality was evaluated. ARF developed in 16.2% of the patients, and 70.0% of these needed renal replacement therapy (RRT). Patients with ARF were more severely ill and had a higher mortality. Remarkably, serum creatinine was already increased on day 1. Creatinine > 1 mg/dl and pH < 7.30, both on day 1 of sepsis, were independently associated with ARF. Age, need for vasoactive therapy, mechanical ventilation, and RRT, but not ARF itself, were associated with mortality. In conclusion, ARF was a frequent complication in sepsis. Sepsis patients with ARF were more severely ill and had a higher mortality. Need for RRT was independently associated with mortality. A simple risk model for ARF, on basis of two readily available parameters on day 1 of sepsis, was developed. This model allows initiating specific therapeutic measures earlier in the course of sepsis, hopefully resulting in a lower incidence of ARF and needi for RRT, thereby lowering mortality.

Acute Kidney Injury↗
PubMed1995

Acute renal failure following cardiac surgery: incidence, outcomes and risk factors.

BACKGROUND: Acute renal failure (ARF) is a recognised complication following cardiac surgery, but the incidence varies widely in the published literature and there are no Australian data available to help predict the risks of ARF in patients with pre-existing renal disease. AIM: To determine the incidence, outcome and risk factors for ARF following cardiac surgery. METHODS: A retrospective case control analysis of 903 consecutive patients who had cardiac surgery (795 CABG, 68 valve/septal surgery, 40 combined valve/CABG) in 1992-93. ARF was defined as doubling of serum creatinine concentration (Cr) to > 0.13 mmol/L if serum Cr was < or = 0.13 mmol/L pre-operatively, or else a rise in serum Cr of > or = 0.10 mmol/L after cardiac surgery. For each subject with ARF, two case control subjects were matched for date of surgery, surgeon, age, sex, type of surgery and pre-operative serum Cr to permit analysis of the influence of pre-operative factors (hypertension, diabetes mellitus, left ventricular systolic dysfunction) and for the comparison of cardiopulmonary bypass time upon the development of ARF. Subsidiary endpoints were mortality, need for dialysis and length of hospital stay. RESULTS: ARF developed in only 1.1% of patients with 'normal' pre-operative renal function (creatinine < or = 0.13 mmol/L) and none required dialysis. ARF developed in 16% of those with impaired pre-operative renal function, 20% of whom required dialysis. Mortality from ARF was 13%. The risk of ARF rose from 10.4% in those with pre-operative serum Cr 0.14-0.20 mmol/L to 36.8% if the serum Cr was > 0.20 mmol/L (p < 0.01). Mortality was higher (4.2% vs 0.7%, p < 0.01) and length of hospital stay longer (14.5 vs nine days [median], p < 0.001) in those with impaired pre-operative renal function. ARF was more likely in those over 65 years, if valve surgery was included and where there was prolonged cardiopulmonary bypass time. CONCLUSIONS: These data confirm that ARF following cardiac surgery is uncommon without pre-operative impairment of renal function but currently carries a mortality rate of 13%. Impaired renal function alone is associated with higher mortality and prolonged hospital stay. Studies to prevent ARF in this setting should focus on the high risk subsets described in this study.

Acute Kidney Injury↗
PubMed2005

Role of the E2F1-p19-p53 pathway in ischemic acute renal failure.

BACKGROUND: Cell cycle progression and arrest of renal tubular cells after acute injury is a reactive process of renal regeneration. The p16(INK4a)/p19(ARF) (alternative reading frame) locus encodes two proteins involved in cell cycle regulation. We investigated the transcriptional regulation and tissue distribution of p19(ARF) in ischemic acute renal failure (ARF). METHODS: We examined the time course and immunohistochemistry of p19(ARF) in rat kidneys following the induction of ischemic ARF. We also examined the effect of p19(ARF) overexpression on p53 levels and cell cycle progression in MDCK cells. RESULTS: The protein expression of p19(ARF) strongly increased 72 h after the ischemia. Immunohistochemical studies showed that the renal tubular cells in the outer medulla expressed p19(ARF) protein 72 h after ischemic injury. The time course of E2F1 induction was observed at 6-24 h, and it was found to precede p19(ARF) expression. In MDCK cells, the overexpression of E2F1 increased promoter activity and the protein level of p19(ARF) and induced apoptosis. Transfection of the p19(ARF) expression vector caused an increase in p53 protein, cell cycle arrest and apoptosis. CONCLUSIONS: These data support the hypothesis that the E2F1-p19(ARF)-p53 pathway forms a negative feedback loop to regulate the cell cycle of renal tubular cells in the ischemic ARF.

Acute Kidney Injury↗
PubMed2006

Allopurinol and enalapril failed to conserve urinary NOx and sodium in ischemic acute renal failure in spontaneously hypertensive rats.

BACKGROUND: Ischemia-reperfusion-induced acute renal failure (ARF) is associated with a high mortality in patients with hypertension and with an unfavorable outcome of kidney transplants from marginal donors. AIM: The influence of allopurinol and enalapril on urinary nitrate/nitrite (UNOx), glomerular filtration rate, plasma and urinary sodium, and hemodynamic parameters was examined in spontaneously hypertensive rats (SHR) with ARF. METHODS: ARF was induced by right-kidney removal and clamping the left renal artery for 40 min in 50 male 26-week-old SHR weighing 300 +/- 23 g. The rats were randomly allocated to five groups: (1) sham operated; (2) ARF; (3) ARF after pretreatment with 40 mg/kg allopurinol; (4) ARF after pretreatment with 40 mg/kg enalapril, and (5) ARF after pretreatment with 40 mg/kg allopurinol and 40 mg/kg enalapril. Creatinine clearance, UNOx (Griess reaction), cardiac output (dye dilution technique), mean arterial blood pressure, and renal blood flow were measured 24 h after reperfusion. Total vascular resistance and renal vascular resistance were calculated and compared between the groups. RESULTS: A nonsignificant decrease was found in both daily UNOx excretion and creatinine clearance when pretreated ARF groups and the ARF group without pretreatment were compared (p > 0.05). Significantly lower plasma sodium values (139.5 +/- 4.86 mmol/l) in the allopurinol-pretreated ARF group were found than in the ARF group without pretreatment, in the ARF group pretreated with enalapril, and in the sham SHR group (p = 0.029). The urinary sodium loss was greater in the enalapril-pretreated than in the allopurinol-pretreated ARF group (p = 0.047). Allopurinol and/or enalapril pretreatment decreased total vascular resistance (p = 0.003) in comparison with the sham SHR group. CONCLUSION: Neither allopurinol nor enalapril nor both were protective against ischemia-reperfusion injury in SHR, nor altered glomerular filtration rate and UNOx in a favorable direction.

Acute Kidney Injury↗