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PubMed2002

Renal failure in the ICU: comparison of the impact of acute renal failure and end-stage renal disease on ICU outcomes.

BACKGROUND: Acute renal failure (ARF) is associated with a persistent high mortality in critically ill patients in intensive care units (ICUs). Most studies to date have focused on patients with established, intrinsic ARF or relatively severe ARF due to multiple factors. None have examined outcomes of dialysis-dependent chronic renal failure [end-stage renal disease (ESRD)] patients in the ICU. We examined the incidence and outcomes of ARF in the ICU using a standard definition and compared these to outcomes of ICU patients with either ESRD or no renal failure. We sought to determine the impact of renal dysfunction and/or loss of organ function on outcome. METHODS: We prospectively scored 1530 admissions to eight ICUs over a 10-month period for illness severity at ICU admission using the Acute Physiological and Chronic Health Evaluation (APACHE III) evaluation tool. Patients were defined as having ARF based on the definition of Hou et al (Am J Med 74:243-248,1983) designed to detect significant measurable declines in renal function based on serum creatinine. ESRD patients were identified as being chronically dialysis-dependent prior to ICU admission and the remainder had no renal failure. Clinical characteristics at ICU admission and ICU and hospital outcomes were compared between the three groups. RESULTS: We identified 254 cases of ARF, 57 cases of ESRD and 1219 cases of no renal failure for an incidence of ARF of 17%. Roughly half the ARF patients had ARF at ICU admission and the remainder developed ARF during their ICU stay. Only 11% of ARF patients required dialysis support. ARF patients had significantly higher acute illness severity scores than those with no renal failure, whereas patients with ESRD had intermediate severity scores. ICU mortality was 23% for patients with ARF, 11% for those with ESRD, and 5% for those with no renal failure. There was no difference in outcome between patients who had ARF at ICU admission and those who developed ARF in the ICU. Patients with ARF severe enough to require dialysis had a mortality of 57%. APACHE III predicted outcome very well in patients with no renal failure and patients with ARF at the time of scoring but underpredicted mortality in those who developed ARF after ICU admission and overestimated mortality in patients with ESRD. CONCLUSIONS: ARF is common in ICU patients and has a persistent negative impact on outcomes, although the majority of ARF is not severe enough to require dialysis support. The mortality of patients with ARF from all causes is almost exactly similar to that noted using the same criteria two decades ago. More profound ARF requiring dialysis continues to have an even greater mortality. Nevertheless, acute declines in renal function are associated with a mortality that is not well explained simply by loss of organ function. The majority of ARF patients who did not require dialysis still had a considerably higher mortality than the ESRD patients, all of whom required dialysis; while ARF patients who did require dialysis had a much higher morality than ESRD patients. APACHE III performs well and captures the mortality of patients with ARF at the time of scoring. Development of ARF after scoring has a profound effect on standardized mortality. We were unable to identify a unique mortality associated with ARF, but the presence of measurable renal insufficiency continues to be a sensitive marker for poor outcome.

APACHE↗
PubMed2002

p16(Ink4a) in melanocyte senescence and differentiation.

BACKGROUND: The Ink4a-Arf tumor suppressor locus encodes two growth inhibitors, p16 and Arf, both of which are also implicated as effectors in cellular senescence. Because human germline defects in the INK4A-ARF locus are associated with familial melanoma, melanocytes may have unusual INK4A-ARF functions or controls of cell senescence. Because senescence is believed to be an anticancer mechanism, we investigated the role of Ink4a-Arf and its individual components in melanocyte senescence. METHODS: Melanocytes were cultured from littermate mice with zero, one, or two functional copies of the Ink4a-Arf locus. Senescence was evaluated by cumulative population doubling curves and by the assessment of acidic beta-galactosidase (an indicator of senescence) expression. Pigmentation and cell size were evaluated by spectrophotometry and microscopy. p16 and Arf expression in primary and spontaneously immortalized melanocyte or melanocyte precursor cell lines were evaluated by immunoblotting. Retroviral vectors containing normal p16 and Arf complementary DNAs were used to restore expression of these genes in Ink4a-Arf(-/-) melanocytes. RESULTS: Wild-type melanocytes (i.e., Ink4a-Arf(+/+)) senesced within 4-5 weeks of culture. Ink4a-Arf(-/-) melanocytes did not senesce and readily became immortal. Ink4a-Arf(+/-) melanocytes showed defective senescence. Senescent Ink4a-Arf(+/+) melanocytes were heavily pigmented, but Ink4a-Arf(+/-) and Ink4a-Arf(-/-) melanocytes were less pigmented. All of six spontaneously immortalized melanocyte or melanocyte precursor lines from Ink4a-Arf(+/+) mice lacked p16 protein expression, although most retained Arf protein expression. After restoration of p16 but not Arf expression, Ink4a-Arf(-/-) melanocytes stopped growing, became highly melanized, and expressed acidic beta-galactosidase. By contrast, restoration of Arf but not p16 expression led to cell death without evidence of senescence. CONCLUSION: Normal mouse melanocyte senescence and associated pigmentation require both copies of Ink4a-Arf and appear to depend more on p16 than on Arf function. Mutations of the INK4A-ARF locus may favor tumorigenesis from melanocytes by impairing senescence, cell differentiation, and (where ARF is disrupted) cell death.

Animals↗
PubMed2001

Candidaemia in patients with dialysis-dependent acute renal failure: aetiology, predisposing and prognostic factors.

BACKGROUND: Infections remain the major cause of death among patients with acute renal failure (ARF), especially in severe ARF necessitating dialysis therapy (ARF(d)). Although the clinical features and outcomes of candidaemia in various patient populations have been described, data concerning candidaemic episodes among patients with ARF(d) are scarce. This study investigated the aetiology, predisposing, and prognostic factors for candidaemia in the ARF(d) patient population. Three patient groups were investigated in this study. METHODS: During an 8-year study period from January 1992 to December 1999, 37 candidaemic episodes that developed among 653 ARF(d) patients were assigned to ARF(d) candidaemic group, and 170 candidaemic episodes developing in patients without ARF(d) or chronic uraemia as the non-ARF(d) candidaemic group, and 28 matched ARF(d) patients without candidaemia were assigned to the ARF(d) control group. Among these groups, clinical characteristics in ARF(d) candidaemia patients, predisposing factors, and outcomes were compared. Four management strategies including central catheter removal, anti-fungal therapy, both, or neither were applied. The prognostic factors for attributable death were evaluated by univariate analysis followed by the multivariate logistic regression analysis. RESULTS: The proportion of ARF(d) patients with candidaemia was significantly higher than in patients who had no ARF(d) or chronic uraemia (5.7% vs 0.15%, P<0.001). Compared with the non-ARF(d) candidaemic group, systemic lupus erythematosus (SLE), administration of corticosteroid, and central venous catheter-associated candidaemia were more common in the ARF(d) candidaemic group (P<0.05). In matched case-control study, multiple antibiotic usage was shown to be a predisposing factor for developing candidaemia in patients with ARF(d), and corticosteroid therapy has a marginal significance (P=0.059). The occurrence of candidaemia increased the mortality rate of ARF(d) (71% vs 39.2% in ARF(d) control group, P<0.05). By multivariate logistic analysis, the variables associated with attributable death in ARF(d) candidaemic group were identified to be an APACHE II score of >or=18, and anti-fungal therapy for >48 h. Central venous catheters were removed in 32 (86.5%) of the 37 ARF(d) candidaemic patients, among whom the 18 patients who had received anti-fungal therapy for >48 h had a lower attributable death rate than those patients who had not (27.8% vs 64.3%, P<0.05). Of the remaining five patients who did not have their catheter removed, three patients subsequently died and two patients improved only after catheter removal. CONCLUSIONS: The higher prevalence of candidaemia in ARF(d) patients is due to their underlying illnesses and multiplicity of predisposing factors, rather than ARF and dialysis therapy per se. Predisposing factors include SLE, indwelling central venous catheter, multiple antibiotic usage, and corticosteroid therapy. Prompt anti-fungal therapy and catheter removal should be mandatory for ARF(d) patients with candidaemia.

Acute Kidney Injury↗
PubMed1997

Activation of toxin ADP-ribosyltransferases by the family of ADP-ribosylation factors.

ADP-ribosylation factors or ARFs are 20-kDa guanine nucleotide-binding proteins, initially identified as stimulators of cholera toxin-catalyzed ADP-ribosylation of Gs alpha. We now know that ARFs play a critical role in many vesicular trafficking events and ARF activation of a membrane-associated phospholipase D (PLD) has been recognized. ARF is active and associates with membranes when GTP is bound. The active state is terminated by hydrolysis of bound GTP, producing inactive ARF-GDP. The nucleotide effect on ARF association with membranes is related to alteration in orientation of the N-terminal myristoyl moiety that is important for ARF function. Cycling of ARF between active and inactive states involves guanine nucleotide-exchange proteins (GEPs) that accelerate replacement of bound GDP with GTP and GTPase-activating proteins (GAPS) that are responsible for ARF inactivation. Six mammalian ARFs have been identified by cDNA cloning. Class I ARFs 1 and 3 have been studied most extensively. Their activation (GTP binding) is catalyzed by a GEP now purified from spleen cytosol. In crude preparations, GEP was inhibited by brefeldin A (BFA), which in cells causes apparent disintegration of Golgi. Demonstration that the approximately 60 kDa purified GEP was not inhibited by BFA means that contrary to earlier belief, there must be another protein to mediate BFA inhibition. GEP activity was greatly enhanced by phosphatidyl serine. The purified GEP, equally active with ARFs 1 and 3, was inactive with ARFs 5 and 6 (Classes II and III); myristoylated ARFs were better substrates than were their non-myristoylated counterparts. ARF GAP purified from bovine spleen cytosol in our laboratory had much broader substrate specificity than the GEP. It used both ARFs 5 and 6 at least as well as ARFs 1 and 3; myristoylation was without effect. It also accelerated GTP hydrolysis by certain ARF mutants and an ARF-like protein (ARL1) that does not have ARF activity. The purified GAP also differed from the GEP in its rather specific requirement for phosphatidylinositol bisphosphate. This was also observed with a seemingly different ARF GAP that was purified and subsequently cloned in Cassel's laboratory. Activation and inactivation of ARFs present many potential sites for physiological regulation and, therefore, for pathological disruption of ARF function.

ADP-Ribosylation Factors↗
PubMed1998

Electrocardiographic alterations in chronically Trypanosoma cruzi-infected persons exposed to cardiovascular factors.

METHODS: We analyzed the potential influence that associated risk factors (ARF), such as smoking, alcoholism, overweight, and hypertension, could have on the establishment of chronic chagasic cardiomyopathy (CC). The sample was comprised of 124 individuals, 69 males and 55 females (mean age +/- SD, 41 +/- 9.5 years), who were born in en demic areas of Northern Argentina and migrated further to Rosario City, an area where autochthonous cases of Chagas' disease have never been registered. Assessments included the following: clinical examination to discard previous cardiomyopathies; search for the presence of ARF according to standard criteria; specific serology; frontal chest X-ray, and 12-lead resting electrocardiogram (ECG). Subjects were classified on the basis of their serological status and presence of ARF into four groups: Tc+ARF+ T. cruzi-infected persons with ARF (n = 41); Tc-ARF+ seronegativity in presence of ARF (n = 27); Tc+ARF- individuals showing positive serology that lacked ARF (n = 27), and Tc-ARF- seronegative individuals having no ARF (n = 29). RESULTS: Except for a higher female/male ratio in groups presenting no ARF (p < 0.02), no statistical differences as to age, length of residence in endemicity areas (LR), and ARF distribution were recorded among groups. Forty-one persons presented abnormal ECG tracings, distributed thus: Tc+ARF+, 18/41; Tc-ARF+, 14/27, Tc+ARF-, 14/27, and Tc-ARF, 4/29 (p < 0.01, in relation to the latter group). Subjects from the Tc+ARF+, Tc-ARF+, and Tc+ARF- groups had 4.89-, 6.7-, and 6.7-fold increases, respectively, if having an abnormal ECG when compared with Tc-ARF- individuals. Comparisons on the frequency of abnormal ECG between seropositives carrying ARF or not yielded a non-significant odds ratio, be it estimated as crude, or after adjusting for sex, age, and LR in multivariate analysis. CONCLUSIONS: Presence of ARF was not associated with an increasing risk of cardiac affectation in chronically T. cruzi-infected persons, but resulted in chagasic-compatible ECG abnormalities in those seronegative individuals.

Adult↗
PubMed1999

Acute renal failure following cardiac surgery.

BACKGROUND: Acute renal failure requiring dialysis (ARF-D) occurs in 1.5% of patients following cardiac surgery, and remains a cause of major morbidity and mortality. While some preoperative risk factors have been characterized, the influence of preoperative and intraoperative factors on the occurrence of ARF following cardiac surgery is less well understood. METHODS: Preoperative and intraoperative data on 2843 consecutive adult patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) from February 1, 1995 to February 1, 1997 were recorded and entered into a computerized database. Two definitions of renal failure were employed: (i) ARF defined as a rise in serum creatinine (Cr) of 1 mg/dl above baseline; and (ii) ARF-D defined as the development of ARF for which some form of dialytic therapy was required. The association between preoperative and intraoperative variables and the development of ARF was assessed by multivariate logistic regression. RESULTS: A total of 2672 of the 2844 patients underwent isolated coronary artery bypass grafting (CABG) surgery, the remaining 172 underwent valve surgery with or without bypass grafting. Of the CABG patients 7.9% developed ARF and 0.7% developed ARF-D. The mortality for patients who developed ARF was 14% (OR 15, P = 0.0001) compared with 1% among those who did not develop ARF. The mortality for CABG patients who developed ARF-D was 28% (OR 20, P = 0.0001) compared with 1.8% among those who did not require dialysis. Variables that were significantly associated with the development of ARF by multivariate analysis included: increased age, elevated preoperative serum Cr, duration of CPB, presence of a carotid artery bruit, presence of diabetes, reduced cardiac ejection fraction and increased body weight. Variables independently associated with ARF-D included serum Cr, duration of CPB, carotid artery bruit and presence of diabetes. The utility of these models for predicting the development of ARF and ARF-D was confirmed by bootstrapping techniques. Because of the small number of patients who underwent valve surgery, none of these variables were significantly associated with the development of ARF or ARF-D in this group of patients. CONCLUSION: The development of ARF or ARF-D is associated with a high mortality following CABG surgery. We have identified perioperative variables, which may be useful in stratifying risk for the development of ARF.

Acute Kidney Injury↗
PubMed1992

Differential interaction of ADP-ribosylation factors 1, 3, and 5 with rat brain Golgi membranes.

Six mammalian ADP-ribosylation factors (ARFs) identified by cDNA cloning were expressed as recombinant proteins (rARFs) that stimulated cholera toxin ADP-ribosyltransferase activity. Microsequencing of soluble ARFs I and II (sARFs I and II), purified from bovine brain, established that they are ARFs 1 and 3, respectively. Rabbit antibodies (IgG) against sARF II reacted similarly with ARFs 1, 2, and 3 (class I) on Western blots. ARFs 1 and 3 were distinguished by their electrophoretic mobilities. Antiserum against rARF 5 cross-reacted partially with rARF 4 but not detectably with rARF 6 and minimally with class I ARFs. Guanosine 5'-O-(3-thiotriphosphate) (GTP[gamma S]) increased recovery of ARF activity and immunoreactivity in organelle fractions separated by density gradient centrifugation, after incubation of rat brain homogenate with ATP and a regenerating system. ARF 1 accumulated in microsomes plus Golgi and Golgi fractions, whereas ARF 5 seemed to localize more specifically in Golgi; the smaller increment in ARF 3 was distributed more evenly among fractions. On incubation of Golgi with a crude ARF fraction, GTP[gamma S], and an ATP-regenerating system, association of ARF activity with Golgi increased with increasing ATP concentration paralleled by increases in immunoreactive ARFs 1 and 5 and, to a lesser degree, ARF 3. Golgi incubated with GTP[gamma S] and purified ARF 1 or 3 bound more ARF 1 than ARF 3. Based on immunoreactivity and assay of ARF activity, individual ARFs 1, 3, and 5 appeared to behave independently and selectively in their GTP-dependent association with Golgi in vitro.

ADP-Ribosylation Factors↗
PubMed2006

Epidemiologic trend changes in acute renal failure--a tertiary center experience from South India.

BACKGROUND: There are little data on the incidence of acute renal failure (ARF) from India due to the absence of central registry. The etiology, course, and outcome of ARF differ in various parts of India. Significant trend changes were reported even within a same center over a period of time. AIM: To find out the epidemiologic trend changes in ARF patients, the authors compared the profile of patients admitted by the Department of Nephrology from 1995-2004 with previously published data from 1987-1991. METHODS: Data collected from case records of patients admitted with ARF were systemically analyzed for age, gender, etiology, course, and outcome. A total of 32 variables were collected per person retrospectively. The chi-square test, Fisher's exact test, and student t-test were used as tests of significance (p<0.05 was taken as statistically significant). RESULTS: A total of 1112 patients were diagnosed to have ARF from 1995-2004. The mean age was 37.08 +/- 3.4 yrs. There were 669 (60.1%) males. Medical, obstetric, and surgical causes accounted for 87.6, 8.9, and 3.4 percent of ARF, respectively. Among the medical causes of ARF, acute diarrheal disease was the most common. Other causes of medical ARF included drugs, glomerulonephritis, sepsis, snake bite, leptospirosis, malaria, and copper sulphate, which accounted for 13.4, 9.3, 8.8, 7.8, 7.5, 4.4, and 4.3 percent, respectively. In comparison with the data from 1987-1991, medical ARF remained the most common cause of ARF, though without any statistical significance (87.6 percent vs 89.5 percent, p>0.32). Though surgical ARF had more than doubled from 1.5 percent from 1987-1991 to 3.4 percent (p<0.01) during the present study, it is much less when compared to similar studies in the literature. Obstetric renal failure more or less remained the same (8.9 percent vs 9 percent, p>0.4). A statistically significant decline was noted in overall as well as individual group mortality. The overall mortality declined from 26.4 percent to 19.6 percent (p<0.02). Regarding the outcome of ARF, 611 patients (54.94 percent) showed a total recovery, a partial recovery was noted in 192 patients (17.26 percent), and 91 patients (8.18 percent) had persistent dialysis-dependent renal failure. The factors noted to occur more frequently in the deceased were high entry serum creatinine (>440 micromol), jaundice, sepsis, oliguria, anemia, hypoalbuminemia, and hospital-acquired ARF. The overall requirement of dialysis was 69.0 percent. Hemodialysis was the most common modality of renal replacement therapy. CONCLUSIONS: ARF in South India differs in some important aspects when compared with data from other parts of the country. Significant trend changes were noted with time even within our center. Acute diarrheal disease was the most common cause of ARF. Leptospiral ARF was on the decline, and drugs, sepsis, and malaria were the emerging ARF causes. The incidence of surgical ARF was on the rise. Despite improvements in antenatal care, obstetric renal failure remained a significant cause of ARF. Hemodialysis became the preferred mode of renal replacement therapy.

Acute Kidney Injury↗
PubMed1983

Muscle protein turnover and glucose uptake in acutely uremic rats. Effects of insulin and the duration of renal insufficiency.

Acute renal failure (ARF) in rats is associated with increased amino acid release from peripheral tissues and insulin resistance. To study whether abnormal protein and carbohydrate metabolism are linked in ARF, the effects of insulin on net muscle protein degradation (T) and on glucose uptake were measured in the perfused hindquarters of paired ARF and sham-operated (SO) rats. The basal rate of T increased 40% after 24 and 98% after 48 h of ARF. Insulin was less effective in decreasing T in ARF (-79% SO vs. -22% ARF 24 h and -64% SO vs. -23% ARF 48 h; P less than 0.01). Protein synthesis (PS) and protein degradation (PD) were measured independently in incubated epitrochlearis muscles; the increase in T after 24 h of ARF was due specifically to increased PD, while PS was unchanged. At this stage, insulin was less effective in decreasing PD in ARF (-10% ARF vs. -23% SO; P less than 0.02), although PS responded normally. After 48 h of ARF, the further increment in T was caused by the additional appearance of depressed basal and insulin-stimulated PS. This was confirmed in the perfused hindquarter (26 +/- 3 ARF vs. 38 +/- 3 SO, basal; 54 +/- 5 ARF vs 73 +/- 7 SO, insulin-stimulated, nmol phenylalanine/g per h; P less than 0.05). Although basal glucose uptake by hindquarters of ARF and SO rats was comparable, insulin-stimulated glucose uptake was 33% less at 24 and 44% less after 48 h of ARF. After 48 h of ARF, lactate and alanine release were increased and net glycogen synthesis in muscle was depressed. These abnormalities were even more apparent in the presence of insulin. Inefficient glucose utilization, estimated as the ratio of lactate release to glucose uptake, was correlated with T (r = +0.78; P less than 0.001). In conclusion, after 24 h of ARF, both increased PD and altered glucose utilization could be detected. After 48 h of ARF, T increased further because PS was depressed. At this time, glucose utilization was clearly abnormal and the results suggest that abnormal net protein degradation in ARF may be a consequence of defective glucose utilization.

Acute Disease↗
PubMed1996

Expression in human endothelial cells of ADP-ribosylation factors, 20-kDa guanine nucleotide-binding proteins involved in the initiation of vesicular transport.

ADP-ribosylation factors (ARFs) are approximately 20-kDa, guanine nucleotide-binding proteins, initially discovered as stimulators of cholera toxin ADP-ribosyltransferase activity and subsequently shown to participate in vesicular trafficking. Five of the six mammalian ARFs have been identified in human tissues by molecular cloning. They fall into three classes (class I: ARFs 1-3; class II: ARFs 4, 5; class III: ARF 6) based on deduced amino acid sequence, size, phylogenetic analysis, and gene structure. Similar to the rab family of approximately 20 kDa guanine nucleotide-binding proteins, the ARFs appear to function in specific trafficking pathways. The presence of a specific ARF might serve as a marker for that pathway. To verify expression of ARF mRNA and protein in human umbilical vein endothelial cells, immunoreactivity using antibodies specific for each ARF class, quantitative polymerase chain reaction (PCR) using ARF-specific, internal cRNA standards containing unique restriction enzyme cleavage sites introduced by point mutations, and Northern analysis with probes specific for ARFs 1, and 3-6, were utilized. PCR and Northern analysis were in agreement in showing that amounts of mRNA for ARF 1 and ARF 4 were similar and higher than those of ARF 3 and ARF 5 which were greater than ARF 6. Primarily, Class 1 ARF proteins were detected by immunoreactivity, with the majority in the supernatant fraction. The relative expression of ARFs in endothelial cells thus differs from that in neuronal tissues where it had been found that ARF3 is the predominant species.

ADP-Ribosylation Factor 6↗
PubMed2006

Acute renal failure in neonatal sepsis.

OBJECTIVE: To evaluate the occurrence of acute renal failure (ARF) and the factors associated with it in cases of neonatal sepsis. METHODS: The case control study was conducted in the referral neonatal intensive care unit of a tertiary teaching hospital. 200 out born neonates with sepsis admitted to the nursery from January to July 2003 were evaluated for presence of ARF (cases) or not (controls). Sepsis was diagnosed on the basis of either a positive sepsis screen (immature: total (I:T) neutrophil ratio > 0.2, micro-ESR > age in days + 2 mm or> 15 mm, CRP> 6 mg/dl, TLC< 5000 cells/mm3; 2 or more positive) or a positive blood culture in symptomatic neonates. ARF was defined as blood urea nitrogen (BUN)> 20mg/dl on two separate occasions at least 24 hours apart. Oliguria was defined as urine output < 1 ml/Kg/hr. RESULTS: 52 out of 200 (26%) neonates with sepsis had ARF; only 15% of ARF was oliguric. The mean gestation of neonates with ARF was similar to those without ARF (36.1+/-4.1 wks vs. 36.6+/-3.5 wk; p = 0.41). A significantly higher number of babies with ARF weighed less than 2500 gm as compared to those without ARF (86.5% vs 67.6%; p = 0.008). The association of meningitis, disseminated intravascular coagulation (DIC) and shock was also significantly higher in neonates with ARF (46.8% vs 26.2%, p = 0.01; 65.4% vs 20.3%, p < 0.001; 71.2% vs 27.0%, p < 0.001 respectively). Mortality in neonates who developed ARF was significantly higher (70.2% vs 25%, p < 0.001). Factors including gestational age, weight, onset of sepsis, culture positivity, associated meningitis, asphyxia, shock, prior administration of nephrotoxic drugs were subjected to univariate analysis for prediction of fatality in neonates with sepsis and ARF; only shock was found to be a significant predictor of fatality (p< 0.001). ARF had recovered in 22 out of 49 neonates in whom data was available; three patients had left against medical advice. The mean duration of recovery in these 22 neonates was 5.5 days (range 1-14 days). Presence of co-existing morbidities (perinatal asphyxia/congestive heart failure (CHF)/ necrotising enterocolitis (NEC)) or nephrotoxic drugs did not alter the frequency of recovery of ARF in septic neonates (45.5% vs 44.4%,p = 0.944; 41% vs 52%, p = 0.308 respectively). CONCLUSION: Renal failure occurred in 26% neonates with sepsis. Although ARF in neonates has been reported to be predominantly oliguric, it was observed that ARF secondary to neonatal sepsis was predominantly non oliguric. Low birth weight was an important risk factor for the development of ARF. The mortality being three times higher in neonates with ARF demands a greater awareness of this entity among practitioners and better management of this condition.

Acute Kidney Injury↗
PubMed2003

Role of thyroid hormones on the synthesis and release of atrial natriuretic peptide in rats with acute renal failure.

BACKGROUND/AIMS: High atrial natriuretic peptide (ANP) serum levels are seen in acute renal failure (ARF) due to impaired ANP clearance, but the response of ANP to blood volume expansion is blunted. ARF-associated hypothyroidism influences ANP clearance but it may also play a role in the synthesis and release of ANP because in primary hypothyroidism both mechanisms are disturbed. The aim of this study is to analyze whether thyroxin (T4) supplementation improves the synthesis and release of ANP in ARF. METHODS: Four groups of rats were studied: group C (control); group ARF; Group ARF-T4 (ARF supplemented with T4), and group Tx (thyroidectomized). Serum creatinine (SCr), creatinine clearance (CrCl), total T4, total triiodothyronin (T3), plasma ANP, ANP response to acute saline load and atrial content of mRNA-ANP were measured 5 days after ARF induction with potassium dichromate. RESULTS: CrCl was 1.8 +/- 0.4 ml/min in group C, and it significantly dropped to 0.6 +/- 0.5 in ARF (p < 0.01), T4 improved it (1.7 +/- 0.7 in ARF-T4, p < 0.01) and Tx did not change it. Plasma ANP was higher in ARF as compared with C (152 +/- 23 vs. 52 +/- 21 fmol/l, p < 0.01). In ARF-T4, ANP was higher than in C but lower than in ARF (85 +/- 28 fmol/l, p < 0.01). No changes were observed in Tx rats (48 +/- 17 fmol/l). The atrial content of mRNA-ANP was 0.06 +/- 0.025 mRNA-ANP/mRNA-beta-actin ratio units in group C, it was higher in ARF (0.13 +/- 0.025, p < 0.01) and lower in Tx (0.04 +/- 0.01, p < 0.05) as compared to C. Supplementation with T4 increased the mRNA-ANF content (0.18 +/- 0.2 mRNA-ANP/mRNA-beta-actin ratio units, p < 0.05) over ARF. Plasma ANP response to saline load was 45 +/- 7% in C, but it was reduced in ARF and Tx (20 +/- 10 and 26 +/- 10%, p < 0.01). In ARF-T4 the response was restored (36 +/- 9%, p < 0.01 vs. ARF). CONCLUSION: Thyroid hormones modulate the synthesis and release of ANP in ARF. Although the effect is probably direct, T4-induced amelioration of renal damage may also play a significant role by improving the uremic milieu.

Acute Kidney Injury↗
PubMed1996

Management of acute renal failure in the elderly. Treatment options.

Renal changes that occur with aging mainly consist of impairment in the ability to concentrate urine and to conserve sodium and water. These physiological changes increase the risk of volume depletion and the prerenal type of acute renal failure (ARF) in elderly people. Bladder outlet obstruction caused by benign prostatic hypertrophy is a common cause of ARF in elderly men. Another frequent cause of ARF in the elderly is drug-induced nephropathy. Nonsteroidal anti-inflammatory drugs (NSAIDs) and antibiotics are most often implicated in the development of ARF in the elderly. However, considering the high usage of these drugs, the incidence of drug-induced nephropathy is relatively small. NSAIDs are more likely to cause ARF in patients with congestive heart failure, chronic renal disease (including diabetic nephropathy) or chronic liver disease than in otherwise healthy individuals. NSAID-induced ARF is often of the prerenal type, but may be caused by acute interstitial nephritis (AIN). The presence of heavy proteinuria or nephrotic syndrome differentiates NSAID-induced AIN from AIN caused by other drugs. Antibiotics, especially semisynthetic penicillins, more commonly give rise to AIN associated with peripheral blood eosinophilia and eosinophiluria than NSAIDs. Ciprofloxacin is increasingly reported to cause AIN. Fever commonly accompanies AIN, especially when induced by antibiotics. Aminoglycosides produce ARF by inducing acute tubular necrosis (ATN), which results from the excessive accumulation of myeloid bodies in the tubules. In all cases of ARF it is essential to obtain a good history, to perform a through physical examination, with particular attention to skin turgor, and to measure blood pressure, pulse rate (supine and upright), urinary electrolyte and creatinine levels. Fractional excretion of sodium and the urine:plasma creatinine ratio are reliable indices that distinguish prerenal ARF from ATN. A prompt response to fluid challenge, with an increase in urine output and urinary sodium excretion, and a rapid decrease in blood urea nitrogen, constitutes strong evidence for prerenal ARF. However, these indices are unreliable when prerenal ARF has progressed to ATN or when ARF has an obstructive pattern to begin with. In all cases of ARF, especially in elderly men, urinary tract obstruction should be suspected unless the history is otherwise clear cut. Ultrasound of the kidneys and bladder is a simple, non-invasive and meaningful test that can be used to rule out obstructive causes of ARF. If obstruction is the cause of ARF, ultrasound will be positive; in contrast, urinary obstruction is very unlikely if ultrasound findings are normal in a patient who has been oliguric or anuric for 48 hours or more. Similarly, acute glomerulonephritis, including rapidly progressive glomerulonephritis, should be suspected when ARF is associated with heavy proteinuria. In such instances, percutaneous renal biopsy is essential to document the diagnosis. It is of utmost importance to establish whether ARF is of prerenal or postrenal type, both of which are potentially fully reversible. In contrast, patients with ATN or rapidly progressive glomerulonephritis may not recover, or may only partially recover, their renal function. Haemodialysis and nutritional support are common measures for patients with severe ATN and a highly catabolic state. Corticosteroids and immunosuppressive therapy should be instituted for rapidly progressive glomerulonephritis, in addition to haemodialysis. haemodiafiltration instead of haemodialysis is recommended for patients who are haemodynamically unstable [i.e., with a persistently low blood pressure (systolic < or = 100 mm Hg)]. Haemodiafiltration has been shown to improve acid-base balance and uraemia better than standard haemodialysis. However, despite dialysis, mortality in patients with ARF associated with ischaemic ATN remains high.

Acute Kidney Injury↗
PubMed1993

Activation of ADP-ribosylation factor by Golgi membranes. Evidence for a brefeldin A- and protease-sensitive activating factor on Golgi membranes.

Recent evidence has implicated ADP-ribosylation factor (ARF) proteins as critical regulators of the protein secretory pathway, particularly in the endoplasmic reticulum-Golgi pathway. We have examined whether Golgi membranes contain activators of ARF and the consequences of ARF activation and acylation on its membrane association. Two means were used to assess ARF activation. First, guanosine 5'-3-O-(thio)triphosphate (GTP gamma S) binding to protein was found to be greater when ARF and Golgi were incubated together than when either was incubated alone. These data suggested that ARF GTP gamma S was formed. This was confirmed by showing that the GTP gamma S-bound protein functioned as a cofactor for cholera toxin-stimulated ADP-ribosylation of Gs alpha, a reaction for which activated ARF is a necessary cofactor. Trypsin treatment of Golgi, an inhibitory ARF peptide, and brefeldin A each inhibited Golgi-mediated activation by approximately 70%, demonstrating that a specific protein interaction is required for the majority of the ARF activation. This ARF-activating protein is a strong candidate for the molecular target for brefeldin A. The ubiquitous nature of ARF proteins and their importance in both the exocytic and endocytic pathways may explain the effects of brefeldin A on both exocytic and endocytic membrane traffic in animal cells. A protease-insensitive activation of ARF by Golgi could also be demonstrated and was the dominant activity observed in submicromolar concentrations of magnesium. We believe this to be the lipid-mediated process described previously for purified ARF proteins. ARF activation resulted in tight association of ARF with phospholipid vesicles. Vesicle association required amino-terminal myristoylation of ARF whereas activation did not. These studies indicate that the brefeldin A-sensitive ARF-activating protein and other factors that determine the level of activation of ARF in animal cells are fundamental regulators of membrane traffic in animal cells.

ADP-Ribosylation Factors↗
PubMed1989

Tissue and species distribution of mRNA encoding two ADP-ribosylation factors, 20-kDa guanine nucleotide binding proteins.

Cholera toxin catalyzed ADP-ribosylation of Gs alpha, the stimulatory guanine nucleotide binding protein of the adenylyl cyclase system, is enhanced by approximately 20-kDa guanine nucleotide binding proteins, termed ADP-ribosylation factors or ARFs. ARF is an allosteric activator of the A1 catalytic protein of the toxin. Bovine ARF cDNA clones, ARF-1 isolated from adrenal (Sewell & Kahn, 1988) and ARF-2B from retina (Price et al., 1988), exhibit nucleotide and deduced amino acid sequences that are 80% and 96% identical, respectively, in the coding region. To determine tissue and species distribution of ARF-like mRNAs, bovine ARF-2B and human ARF-1 cDNAs and 30- or 48-base oligonucleotide probes that distinguish between ARF-1 and ARF-2B cDNAs in coding and 3'-untranslated regions were used for Northern analysis of poly(A+) RNA from different tissues and species. On the basis of hybridization with specific oligonucleotide probes, all bovine tissues contained mRNAs of 1.7 and 2.1 kb that were related to ARF-1 and ARF-2B, respectively. Northern analysis of brain poly(A+) RNA from different species with ARF-2B and ARF-1 cDNAs at low stringency demonstrated several bands varying in size from 0.9 to 3.7 kb. A 1.7-kb band consistently hybridized with an ARF-1 30-base coding-region probe but not with a probe for the 3'-untranslated region. Similar ARF-2B oligonucleotide probes did not hybridize with rat, mouse, rabbit, or human brain mRNA. Cleavage of ARF-2B cDNA with PvuII generated two fragments, one containing coding and the other 3'-noncoding region.(ABSTRACT TRUNCATED AT 250 WORDS)

ADP-Ribosylation Factors↗
PubMed1996

Epidemiology of acute renal failure: a prospective, multicenter, community-based study. Madrid Acute Renal Failure Study Group.

There are very limited data on overall epidemiology of ARF. It is crucial to know the incidence, etiology and clinical feature of ARF to promote prevention strategies and to implement adequate resources for the management of this entity. During a nine month period, a collaborative prospective protocol with 98 variables was developed to assess all ARF episodes encountered in the 13 tertiary-care hospitals in Madrid, Spain (covering 4.2 million people of over 14 years of age). ARF was considered when a sudden rise in serum creatinine concentration (SCr) to more than 177 mumol/liter was found in patients with normal renal function, or when the sudden rise (50% or more) was observed in patients with previous mild-to-moderate chronic renal failure (SCr < 264 mumol/liter). Of the 748 cases of ARF studied, 665 episodes presented in inhabitants from the Madrid area. This gives an overall incidence of ARF of 209 cases per million population (p.m.p.; 95% CJ 195 to 223). The incidence of acute tubular necrosis (ATN) was 88 cases p.m.p. (95% CI 79 to 97), prerenal ARF 46 p.m.p (95% CI 40 to 52), acute-onset chronic ARF 29 p.m.p. (95% CI 24 to 34), and obstructive ARF 23 p.m.p. (95% CI 19 to 27). The mean age was 63 +/- 17 years. The most frequent causes of ARF were ATN (45%), prerenal (21%), acute-onset chronic renal failure (12.7%) and obstructive ARF (10%). Renal function was normal at admission in 48% of patients who later developed ARF. Mortality (45%) was much higher than that of the other patients admitted (5.4%, P < 0.001). This real outcome correlated extremely well with the expected outcome calculated through out the severity index of ARF (SI) 0.433 +/- 0.246 (mean +/- SD). In 187 cases, mortality was attributed to underlying disease, thus corrected mortality due to ARF was 26.7%. Dialysis was required in 36% of patients, and was associated with a significantly higher SI of ARF (0.57 +/- 0.23 vs. 0.35 +/- 0.19, P < 0.001) and mortality (65.9 vs. 33.2%, P < 0.001). Mortality in patients hemodialyzed with biocompatible synthetic membranes (N = 50) was similar to that observed with cellulosic ones (N = 84; 66% vs. 59.5%, NS). Mortality was higher in patients with coma, assisted respiration, hypotension, jaundice (all P < 0.001) and oliguria (P < 0.02). This study gives, for the first time, the incidence of all forms of ARF in a developed country. ARF is iatrogenically induced at a high rate by modern medicine. Prevention strategies, particularly in the perioperative period, are needed to decrease its impact.

Acute Kidney Injury↗
PubMed2004

Early detection of acute renal failure by serum cystatin C.

BACKGROUND: Acute renal failure (ARF) is associated with high mortality. Presently, no specific therapy for ARF exists. Therefore, early detection of ARF is critical to prevent its progression. However, serum creatinine, the standard marker to detect ARF, demonstrates major limitations. We prospectively evaluated whether serum cystatin C detected ARF earlier than serum creatinine. METHODS: In 85 patients at high risk to develop ARF, serum creatinine and cystatin C were determined daily. ARF was defined according to the Risk of renal dysfunction, Injury to the kidney, Failure of kidney function, Loss of kidney function, and ESRD (RIFLE) classification when creatinine increased by >/=50% (R-criteria), by >/=100% (I-criteria), or by >/=200% (F-criteria). In analogy, ARF was detected when cystatin C increased by >/=50%, by >/=100%, or by >/=200%. RESULTS: Forty-four patients developed ARF and 41 served as controls. In ARF by R-, I-, and F-criteria, the increase of cystatin C significantly preceded that of creatinine. Specifically, serum cystatin C increased already by >/=50% 1.5 +/- 0.6 days earlier compared to creatinine. Serum cystatin C demonstrated a high diagnostic value to detect ARF as indicated by area under the curve of the ROC analysis of 0.82 and 0.97 on the two days before the R-criteria was fulfilled by creatinine. Cystatin C detected ARF according to the R-criteria with a sensitivity of 55% and 82% on these days, respectively. Cystatin C also performed excellently, detecting ARF defined by the I- and F-criteria two days prior to creatinine, and moderately well predicting renal replacement therapy in the further course of ARF. Additionally, low T(3)- or T(3)/T(4) syndrome, glucocorticoid deficiency and excess did not affect cystatin C levels, adding to its usefulness in critically ill patients with ARF. CONCLUSION: Serum cystatin C is a useful detection marker of ARF, and may detect ARF one to two days earlier than creatinine.

Acute Kidney Injury↗
PubMed2006

Incidence and mortality of acute renal failure in Medicare beneficiaries, 1992 to 2001.

This study's objective was to determine the incidence and mortality of acute renal failure (ARF) in Medicare beneficiaries. Data were from hospitalized Medicare beneficiaries (5,403,015 discharges) between 1992 and 2001 from the 5% sample of Medicare claims. For 1992 to 2001, the overall incidence rate of ARF was 23.8 cases per 1000 discharges, with rates increasing by approximately 11% per year. Older age, male gender, and black race were strongly associated (P < 0.0001) with ARF. The overall in-hospital death rate was 4.6% in discharges without ARF, 15.2% in discharges with ARF coded as the principal diagnosis, and 32.6% in discharges with ARF as a secondary diagnosis. In-hospital death rates were 32.9% in discharges with ARF that required renal dialysis and 27.5% in those with ARF that did not require dialysis. Death within 90 d after hospital admission was 13.1% in discharges without ARF, 34.5% in discharges with ARF coded as the principal diagnosis, and 48.6% in discharges with ARF as a secondary diagnosis. Discharges with ARF were more (P < 0.0001) likely to have intensive care and other acute organ dysfunction than those without ARF. For discharges both with and without ARF, rates for death within 90 d after hospital admission showed a declining trend. In conclusion, the incidence rate of ARF in Medicare beneficiaries has been increasing. Those of older age, male gender, and black race are more likely to have ARF. These data show ARF to be a major contributor to morbidity and mortality in hospitalized patients.

Acute Kidney Injury↗