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PubMed1999

Influence of glycerol-induced acute renal failure on the pharmacokinetics of cyclosporin in rats.

Although it is widely believed that renal dysfunction has no effect on the pharmacokinetics of cyclosporin, many clinical reports suggest that renal dysfunction after renal transplantation is closely related to the pharmacokinetics of cyclosporin. To clarify the relationship between renal dysfunction and the pharmacokinetics of cyclosporin, we examined the influence of acute renal failure (ARF) on its pharmacokinetics in glycerol-induced ARF rats. The values of indicators of renal function (serum creatinine, blood urea nitrogen), but not those of indicators of hepatic function, were significantly increased in ARF rats that received glycerol compared with values for control rats. The area under the blood cyclosporin concentration-time curve after oral administration (AUCpo) were 4.976+/-0.847 mghL(-1) for ARF rats and 9.684+/-1.100 mghL(-1) for control rats; AUCpo in ARF was significantly reduced in a manner dependent on renal function. The oral clearance of cyclosporin in ARF and control rats was 1.172+/-0.207 and 0.544+/-0.062Lh(-1) kg(-1), respectively, whereas total body clearance in ARF and control rats was 0.151+/-0.008 and 0.183+/-0.010Lh(-1)kg(-1), respectively. The relative bioavailability of cyclosporin in ARF and control rats was 0.118 and 0.336, respectively. In an in-vitro study using everted sac and liver-slice methods, the apparent first-order rate constants for cyclosporin uptake (k(uptake)) and metabolism (k(metab)) in gut tissues were reduced, whereas k(uptake) and k(metab) in liver were increased. Gastric emptying, measured by use of paracetamol, was significantly reduced in ARF rats. These results suggest that glycerol-induced ARF results in several changes in the pharmacokinetics of cyclosporin in rats. From these results, we conclude that reduction of the absorbed fraction of cyclosporin strongly contributes to the decrease in AUCpo in the presence of ARF.

Acetaminophen↗
PubMed2002

The epidemiology of acute respiratory failure in critically ill patients(*).

STUDY OBJECTIVES: To describe the risk factors for the development of and mortality resulting from acute respiratory failure (ARF) in a large patient population. DESIGN: A substudy of a prospective, multicenter, observational cohort study, which was designed to validate the sequential organ failure assessment score. SETTING: Forty ICUs in 16 countries. PATIENTS: All critically ill patients who were admitted to one of the participating ICUs during a 1-month period were observed until the end of their hospital course. MEASUREMENTS AND RESULTS: Of the 1,449 patients who were enrolled into the study, 458 (32%) were admitted to an ICU with ARF, as defined by a PaO(2)/fraction of inspired oxygen ratio of < 200 mm Hg and the need for respiratory support. Patients who presented with ARF were older than the other patients (63 vs 57 years, respectively; p < 0.001) and more commonly had an infection (47% vs 20%, respectively; p < 0.001). The length of ICU stay was longer (6 vs 4 days, respectively; p < 0.001) and the ICU mortality rate was more than double (34% vs 16%, respectively; p < 0.001) in ARF patients compared to non-ARF patients. Of the 991 patients who were admitted to an ICU without ARF, 352 (35%) developed ARF later during the ICU stay. The independent risk factors for the development of ARF were infection developing in the ICU (odds ratio [OR], 7.59; 95% confidence interval [CI], 5.08 to 11.33) or present on ICU admission (OR, 2.3; 95% CI, 1.68 to 3.16), the presence of neurologic failure on ICU admission (OR, 2.73; 95% CI, 1.90 to 3.91), and older age (OR, 1.70; 95% CI, 1.30 to 2.22). Of all 810 patients with ARF, 253 (31%) died. The independent risk factors for death were multiple organ failure following ICU admission, history of hematologic malignancy, chronic renal failure or liver cirrhosis, the presence of circulatory shock on ICU admission, the presence of infection, and older age. CONCLUSIONS: The present study stresses that ARF is common in the ICU (56% of all patients) and that a number of extrapulmonary factors are related to the risk of development of ARF and to mortality rate in these patients.

Acute Disease↗
PubMed2005

Slightly elevated serum creatinine predicts renal failure requiring hemofiltration after cardiac surgery.

BACKGROUND: Acute renal failure (ARF) after cardiac surgery is a serious adverse event that is associated with high perioperative mortality and prolonged hospitalization. The aim of our study was to evaluate pre- and intraoperative risk factors for the development of ARF requiring hemofiltration after cardiac surgery. METHODS: From February 2002 through February 2003, 913 patients underwent cardiac surgery at our institution. Seventy-three patients developed ARF (8.1%), 16 patients were excluded from the study because of chronic end-stage renal insufficiency. Patient characteristics and operative variables were analyzed. A multivariate logistic regression analysis was performed to determine risk factors for ARF. RESULTS: Patients who developed ARF were older (P < .001; odds ratio [OR], 1.084; 95% confidence interval [CI], 1.0371.133) than patients who did not develop ARF. Furthermore, cardiopulmonary bypass duration (P = .007; OR, 1.013; 95% CI, 1.004-1.032) and emergent surgery (P = .011; OR, 6.667; CI, 1.538-28.571) were predictive for development of ARF. The strongest predictor for ARF was a preoperative creatinine level >or=2 mg/dL (P < .001; OR, 97.519; 95% CI, 22.363425.252). Most interestingly, even moderately elevated preoperative creatinine levels (1.3-1.99 mg/dL) independently predict ARF after cardiac surgery (P = .001; OR, 3.838; 95% CI, 1.793-8.217). CONCLUSION: Our data indicate that emergent surgery as well as advanced age and long duration of cardiopulmonary bypass independently predict ARF after cardiac surgery. Most importantly, even slightly impaired preoperative creatinine levels predict the development of ARF requiring hemofiltration after cardiac surgery.

Age Factors↗
PubMed2001

Exacerbated inflammatory response induced by insulin-like growth factor I treatment in rats with ischemic acute renal failure.

In agreement with recent studies showing a deleterious effect of growth hormone treatment in critically ill patients, preliminary data showed that insulin-like growth factor I (IGF-I) administration increased the mortality rate of rats with ischemic acute renal failure (ARF). The present study was designed to investigate the mechanism responsible for this unexpected effect. Male rats with ischemic ARF were given subcutaneous IGF-I, 50 microg/100 g at 0, 8, and 16 h after reperfusion (ARF+IGF-I, n = 5) or were untreated (ARF, n = 5). A group of 5 sham-operated rats were used as controls. Rats were killed 48 h after declamping, and the following studies were performed: in serum, creatinine and urea nitrogen; and in kidneys, histologic damage score, cellular proliferation by bromodeoxyuridine labeling, apoptosis by morphologic criteria, macrophage infiltration by immunohistochemistry using a specific antibody against ED-1, neutrophil infiltration by naphthol AS-D chloroacetate esterase staining, and levels of IGF-I and IGF-I receptor mRNA by RNase protection assay. ARF and ARF+IGF-I groups had a severe and similar degree of renal failure. Kidney damage was histologically more evident in ARF+IGF-I (1.9 +/- 0.1) than in ARF (1.3 +/- 0.2) rats, and the number of neutrophils/mm(2) of tissue was significantly greater in ARF+IGF-I than in ARF rats at the corticomedullary junction (52.3 +/- 5.2 versus 37.2 +/- 4.1) as well as at the renal medulla (172.5 +/- 30.0 versus 42.1 +/- 9.6). No other differences between the groups were found. It is concluded that IGF-I treatment enhanced the inflammatory response in rats with ischemic ARF. Cell toxicity derived from increased neutrophil accumulation might play a key role in the greater mortality risk of critically ill patients that are treated with growth hormone.

Acute Kidney Injury↗
PubMed1995

Insulin-like growth factor-1 (IGF-1) enhances recovery from HgCl2-induced acute renal failure: the effects on renal IGF-1, IGF-1 receptor, and IGF-binding protein-1 mRNA.

Several growth factors have been found to play an important role in the recovery from acute renal failure (ARF). The effect of the continuous subcutaneous infusion of human recombinant insulin-like growth factor (IGF)-1 (125 micrograms daily by osmotic minipumps) in a rat model of mercuric chloride (HgCl2)-induced ARF was examined. HgCl2 (4 mg/kg) induced ARF with a mortality that was unaffected by IGF-1. However, IGF-1 significantly enhanced functional and histologic recovery in the survivors, as measured by serum creatinine and creatinine clearance and by histologic scoring. Solution hybridization RNAase protection assays showed that renal IGF-1 mRNA, IGF-1 receptor (IGF-1R) mRNA, and IGF-binding protein-1 (IGFBP-1) mRNA were unaffected by exogenous IGF-1, but this treatment significantly increased renal IGF-1 in ARF rats compared with normal rats and ARF rats not receiving IGF-1. After ARF renal mRNA for IGF-1 was decreased, IGF-1R was unchanged and IGFBP-1 was increased. Similar changes occurred in IGF-1-infused ARF rats. Thus, (1) IGF-1 enhances recovery from nephrotoxic ARF both functionally and histologically; (2) in nephrotoxic ARF, there is (a) a reduction in IGF-1 mRNA expression that is not prevented by IGF-1 infusion, and (b) an increase in renal IGFBP-1 mRNA. This may allow a significant increase in renal IGF-1 levels in IGF-1-infused ARF rats, despite the decrease in renal IGF-1 mRNA. A local increase in renal IGFBP-1 and IGF-1 may explain the accelerated recovery from ATN in this model. It was concluded that HgCl2-induced ARF is amenable to improvement by IGF-1 infusion and that the increase in renal IGFBP-1 mRNA may be an important modulator in the recovery of the kidney.

Acute Kidney Injury↗
PubMed1992

Renal vasculature and ischemic injury.

Functionally similar ischemic acute renal failure (ARF), as estimated by glomerular filtration rates (GFR), was induced by renal artery clamping (RAC) or intrarenal norepinephrine (NE) in rats and renovascular reactivity was examined at 1 week. With RAC-ARF induction there was total renal ischemia followed by abrupt return of renal blood flow (RBF). With NE-ARF induction there was subtotal ischemia (10-15% of basal RBF) with RBF recovery over several hours. Renovascular resistance (RVR) did not change to renal perfusion pressure (RPP) reduction in the autoregulatory range in RAC-ARF but paradoxically increased in NE-ARF. There was an exaggerated response to renal nerve stimulation in NE-ARF but no response in RAC-ARF. There was a vasoconstrictor response to intrarenal norepinephrine in the former but a negligible response in the latter. There was no vasodilation to acetylcholine in either group, but there was a normal response to prostacyclin in NE-ARF. Smooth muscle necrosis was found in 46% of resistance arterial vessels in RAC- but in only 8% of NE-ARF (p less than .001). When mean arterial pressure was reduced to 90 mm Hg for 4 h at 1 week, recurrent azotemia and fresh ischemic injury were noted in NE- but not RAC-ARF. It is concluded that different models of ischemic ARF induction result in different patterns of abnormal postischemic vascular reactivity. Differences in vascular smooth muscle and endothelial injury are due to differences in initial ischemia or rates of postischemic reperfusion.

Acute Kidney Injury↗
PubMed1999

Activation of toxin ADP-ribosyltransferases by eukaryotic ADP-ribosylation factors.

ADP-ribosylation factors (ARFs) are members of a multigene family of 20-kDa guanine nucleotide-binding proteins that are regulatory components in several pathways of intracellular vesicular trafficking. The relatively small (approximately 180-amino acids) ARF proteins interact with a variety of molecules (in addition to GTP/GDP, of course). Cholera toxin was the first to be recognized, hence the name. Later it was shown that ARF also activates phospholipase D. Different parts of the molecule are responsible for activation of the two enzymes. In vesicular trafficking, ARF must interact with coatomer to recruit it to a membrane and thereby initiate vesicle budding. ARF function requires that it alternate between GTP- and GDP-bound forms, which involves interaction with regulatory proteins. Inactivation of ARF-GTP depends on a GTPase-activating protein or GAP. A guanine nucleotide-exchange protein or GEP accelerates release of bound GDP from inactive ARF-GDP to permit GTP binding. Inhibition of GEP by brefeldin A (BFA) blocks ARF activation and thereby vesicular transport. In cells, it causes apparent disintegration of Golgi structure. Both BFA-sensitive and insensitive GEPs are known. Sequences of peptides from a BFA-sensitive GEP purified in our laboratory revealed the presence of a Sec7 domain, a sequence of approximately 200 amino acids that resembles a region in the yeast Sec7 gene product, which is involved in Golgi vesicular transport. Other proteins of unknown function also contain Sec7 domains, among them a lymphocyte protein called cytohesin-1. To determine whether it had GEP activity, recombinant cytohesin-1 was synthesized in E. coli. It preferentially activated class I ARFs 1 and 3 and was not inhibited by BFA but failed to activate ARF5 (class II). There are now five Sec7 domain proteins known to have GEP activity toward class I ARFs. It remains to be determined whether there are other Sec7 domain proteins that are GEPs for ARFs 4, 5, or 6.

ADP-Ribosylation Factors↗
PubMedDate not supplied

Severe acute renal failure in malaria.

BACKGROUND: We have noticed a recent rise in the incidence and severity of acute renal failure (ARF) in malaria. AIM: To study the incidence, severity and outcome of ARF in malaria. SETTING AND DESIGN: It is a retrospective analysis of data of one year from a tertiary medical centre in a metropolitan city. MATERIALS AND METHODS: Patients with ARF and smear positive malaria were evaluated. STATISTICAL ANALYSIS: Results were expressed as mean, range and standard deviation. RESULTS: Out of 402 detected smear positive malaria, 24 had ARF. Eighteen were of the age group 21-40 years. Plasmodium falciparum (PF) was detected in 16, Plasmodium vivax in three, and mixed infection in five. Non-oliguric ARF was seen in 14. Eighteen showed severe ARF (Serum creatinine >5 mg%). Twenty-two patients needed dialysis. Prolonged ARF lasting for 2-6 weeks was seen in eight. Seventeen patients recovered completely, while seven showed fatal combination of disseminated intravascular coagulation (DIC), acute respiratory distress syndrome (ARDS), severe ARF and PF malaria. No response was seen to chloroquine and artesunate given alone and twenty patients required quinine. CONCLUSION: ARF necessitating dialysis was seen in 92% of patients with ARF in malaria. PF infection, severe ARF, DIC and ARDS were poor prognostic factors. Resistance was noted to both chloroquine and artesunate.

Acute Kidney Injury↗
PubMed1991

Isolation and characterization of the human gene for ADP-ribosylation factor 3, a 20-kDa guanine nucleotide-binding protein activator of cholera toxin.

ADP-ribosylation factors (ARFs) are approximately 20-kDa guanine nucleotide-binding proteins that stimulate the ADP-ribosyltransferase activity of cholera toxin in vitro. Five different human ARFs have been identified by cDNA cloning. Northern analysis using ARF 3-specific oligonucleotides identified two mRNAs of 3.7 and 1.2 kilobases (kb). We report here the complete nucleotide sequence of the 3.7-kb ARF 3 mRNA derived from three overlapping cDNAs isolated from human hippocampus and fetal brain cDNA libraries, as well as the structure of human ARF 3 gene. Sequences of two overlapping genomic clones indicated that the ARF 3 gene spans approximately 18.3 kb and contains five exons and four introns. The conserved amino acid sequences involved in guanine nucleotide binding by ARF 3 are distributed among separate exons, as found in other GTP-binding protein genes. Translation initiates in exon 2 which includes the sequence GXXXXGK that probably participates in phosphate binding and GTP hydrolysis. The sequence DVGG in exon 3 coordinates binding of Mg2+ and the beta-phosphate of GDP. In the ARF 3 gene in contrast to those of other GTP-binding proteins, the sequence NKXD (which is thought to contribute to the specificity of interaction with the guanine ring) is divided between exons 4 and 5. The latter encodes the COOH-terminal 53 amino acids of ARF 3 and contains greater than 2500 base pairs of untranslated DNA. The sequence AATTAA is 19 bases 5' to the polyadenylation addition site of the 3.7-kb mRNA. Multiple transcription start sites were identified by primer extension and S1 and mung bean nuclease analyses. The 5'-flanking region of exon 1 contains neither a TATA nor a CAAT box, but is high in GC content (greater than 70%) and includes three potential Sp1-binding sites (GC box), consistent with the promoters described for several housekeeping genes. The 1.2-kb ARF 3 mRNA is shown to arise by use of an alternative polyadenylation signal (AACAAA) at nucleotide 1091 within the ARF 3 cDNA.

ADP-Ribosylation Factors↗
PubMed1993

Acute renal failure in patients with acute pancreatitis: prevalence, risk factors, and outcome.

A total of 267 consecutive patients presenting with acute pancreatitis were studied retrospectively. We analysed the collected data to determine the prevalence of acute renal failure (ARF), and factors significantly predisposing to its occurrence and outcome. The prevalence of ARF in our patients was 16%. Only 2% had isolated ARF. Seventy-three percent of patients with additional organ system failure suffered ARF after the onset of other organ failure. The number of organ system failure was significantly greater before, compared to after, the development of ARF. Using multiple logistic regression we found that pre-existing chronic disease and cardiovascular and haematological failure were independent risk factors positively related to the development of ARF, whereas systemic infection was not. Overall mortality from ARF was 81%. Chronic disease, local complications and the presence of additional organ system failure and their number significantly increased mortality in ARF patients. No patients requiring renal replacement therapy survived. ARF is a common complication of severe acute pancreatitis, but occurs late in the disease course, and mostly preceded by other organ system failure. The prognosis of patients with ARF is extremely poor, indicating that more emphasis should be placed on prevention of ARF.

Acute Disease↗
PubMed1998

[Acute renal failure in the allogeneic transplantation of hemopoietic progenitors. The clinical characteristics in a series of 92 patients].

BACKGROUND: Analysis of clinical characteristics of acute renal failure (ARF) after allogeneic bone marrow transplantation (BMT). PATIENTS AND METHODS: Analysis of 92 patients who developed ARF of 260 patients following BMT. RESULTS: ARF incidence was 35.4%. Sixty three percent of ARF occurred before day 20 after BMT. Duration of ARF was less of 10 days in 72.8%. ARF was non oliguric in the 80.4% of cases. Most common ARF etiologies were: multifactorial (37%), nephrotoxicity (NPH) (33.7%) and veno-occlusive disease of the liver (VOD) (14.1%). ARF secondary to VOD was the most severe: and the longest, where the secondary to NPH was less lever and shorter. Hemodialysis (HD) was necessary in 22.8% of ARF. Mortality in ARF group was 45.6%, higher in HD group (80.9%) than in non-HD group (35.2%) (p < 0.0002). CONCLUSIONS: ARF is a frequent complication following BMT. It occurs early, has short duration, is non oliguric, mainly hemodynamic and carries a whose prognosis.

Acute Kidney Injury↗
PubMed1999

Determinants of short- and long-term outcome in patients with respiratory failure caused by AIDS-related Pneumocystis carinii pneumonia.

OBJECTIVES: To determine (1) predictors of in-hospital mortality and long-term survival in patients with acute respiratory failure (ARF) caused by acquired immunodeficiency syndrome-related Pneumocystis carinii pneumonia (PCP) and (2) long-term survival for patients with ARF relative to those without ARF. METHODS: A retrospective medical chart review was conducted of all cases of PCP-related ARF for which the patient was admitted to the intensive care unit of a single tertiary care institution between 1991 and 1996. Data were extracted regarding physiologic scores, relevant laboratory values, and duration of previous maximal therapy with combined anti-PCP agents and corticosteroids at entry to the intensive care unit. Duration of survival was determined by Kaplan-Meier methods from date of first hospital admission and compared for patients with and without ARF. RESULTS: There were 41 admissions to the intensive care unit among 39 patients, with 56.4% in-hospital mortality. Higher physiologic scores (Acute Physiology and Chronic Health Evaluation II [APACHE II], Acute Lung Injury, and modified Multisystem Organ Failure scores) were predictive of in-hospital mortality. Duration of previous maximal therapy also predicted in-hospital mortality (45% for patients with <5 days of previous maximal therapy vs 88% for those with > or =5 days of previous maximal therapy; P = .03). Combining physiologic scores and duration of previous maximal therapy enhanced prediction of in-hospital mortality. There was no difference in long-term survival between patients with PCP with ARF and those without ARF (P = .80), and baseline characteristics did not predict long-term survival. CONCLUSIONS: In-hospital mortality of patients with acquired immunodeficiency syndrome-related PCP and ARF is predicted by duration of previous maximal therapy and physiologic scores, and their combination enhances predictive accuracy. Long-term survival of patients with ARF caused by PCP is comparable to that of patients with PCP who do not develop ARF, and determinants of in-hospital mortality do not predict long-term survival.

AIDS-Related Opportunistic Infections↗
PubMed2007

Predictors of mortality in elderly patients with acute renal failure in a developing country.

This prospective study was undertaken to systematically analyze the predictors of mortality in the elderly in a developing country. All elderly patients with ARF hospitalized at this tertiary care centre over 1 year were studied. Various predictors analyzed were hospital-acquired ARF, causative factors of ARF, preexisting hypertension and diabetes mellitus, severity of renal failure (initial and peak serum creatinine, need for dialysis), and complications of ARF: infection during the course of illness; serum albumin levels and critical illness defined as presence of two or more organ system failures excluding renal failure. Of 33,301 patients admitted, 4,255 (12.7%) were elderly. Of these 69 (1.6%) had ARF. On analysis of the whole group, both young and elderly, age >60 years had an independent predictor of mortality (odds ratio 5.6, P = 0.001). Forty-two of the 69 (60.9%) elderly ARF patients died. The mortality was significantly increased in those elderly with hospital-acquired ARF (79.2%, P = 0.027), those with sepsis as a cause of ARF (71.2%, P = 0.004), those who required dialysis (72.5%, P = 0.022), those developing an infection during the course of ARF (87.9%, P = 0.000) and in those with a critical illness (90.0%, P = 0.00). On logistic regression analysis of those variables that were significant on univariate analysis, only critical illness (odds ratio 9.97) and infection during course (odds ratio 9.72) were the independent predictors of mortality. To conclude, ARF complicates only 1.6% of hospitalized elderly patients but is associated with a high mortality rate of 61%. Infection during the course of illness and critical illness were the independent predictors of mortality.

Acute Kidney Injury↗
PubMed1996

Hemostasis, platelet function and serotonin in acute and chronic renal failure.

A pathogenetic role for fibrin deposition and platelet activation in the kidney is thought to play a role in the pathogenesis of acute renal failure (ARF). Thus, some fibrinolytic parameters and platelet function have been studied in 17 patients with ARF and compared to healthy volunteers and subjects with chronic renal failure (CRF). Since serotonin may participate in pathological processes resulting from platelet/vessel wall interactions, its level in the whole blood and plasma was also assayed. In ARF and CRF platelet aggregatory responses in both whole blood and in platelet rich plasma upon stimulation with various agonists (collagen, arachidonic acid, ADP, ristocetin) were lower than those obtained in healthy volunteers. Increased levels of lipoprotein (a), von Willebrand factor (vWF) and fibronectin were found in ARF relative to controls. Protein C activity was significantly lower in patients with ARF. Euglobulin clot lysis time was prolonged in ARF and CRF, reflecting a decreased overall fibrinolytic activity. Activity of tissue plasminogen activator (tPA) inhibitor (PAI) and PAI:Ag were higher in ARF, whereas tPA:Ag, urokinase, tPA/PAI complexes, thrombin-antithrombin complexes (TAT), plasmin-antiplasmin (PAP) complexes, fibrinogen, and F1+2 did not differ between ARF and controls. In CRF elevated levels of TAT, PAP, fibrinogen and prothrombin fragments F1+2 were found, whereas concentration of fibronectin was lowered when compared to controls. In both groups of renal failure patients increased levels of fibrin monomers and d-dimer were found relative to healthy volunteers. Whole blood serotonin was significantly lower, whereas plasma serotonin was significantly higher in patients with ARF and CRF relative to controls. Serotonin uptake and its release from platelets were markedly diminished in patients with ARF and CRF. Chronic renal failure exhibit a slightly different pattern of coagulopathies that acute renal failure.

Acute Kidney Injury↗
PubMed1994

Effects of efonidipine hydrochloride (NZ-105), a new calcium antagonist, against acute renal failure in rats.

1. We investigated the effect of efonidipine hydrochloride (NZ-105) against acute renal failure (ARF) in male Wistar rats. ARF was produced by ischemia or glycerol. 2. Ischemia-induced ARF was produced by right nephrectomy and clamping of the left renal artery for 60 min, followed by reperfusion. NZ-105 (20 mg/kg) was orally administered twice a day for 3 days before ARF. The plasma creatinine and urea nitrogen concentrations were markedly elevated in the ischemia ARF group on the 1st day, but the elevation was significantly suppressed by NZ-105 treatment. 3. Glycerol-induced ARF was produced by intramuscular injection of 50% (v/v) glycerol (10 ml/kg) in rats which were restricted to drinking water for 24 hr. NZ-105 (20 mg/kg) was orally administered twice a day for 3 days before ARF. NZ-105 significantly attenuated the severe impairment of creatinine and urea nitrogen clearances and the elevated fractional sodium excretion (FENa) caused by ARF. 4. In the kidney homogenate, NZ-105 (10(-6)-10(-4) M) inhibited lipid peroxidation induced by ascorbic acid and Fe or by NADPH and the inhibitory effect of NZ-105 was stronger than alpha-tocopherol, an antioxidant agent. NZ-105 (10(-5)-10(-3) M) showed radical scavenging action against diphenyl-p-picrylhydrazyl and galvinoxyl induced radicals. 5. These findings suggest that NZ-105 prevents the renal damage caused by the two kinds of ARF. Moreover, the inhibitory effects of NZ-105 against lipid peroxidation and radical formation may be one of the mechanisms involved in the prevention of ARF.

Acute Kidney Injury↗
PubMed2004

Lack of association between the HLA-DRB1 locus and post-streptococcal reactive arthritis and acute rheumatic fever in Italian children.

OBJECTIVE: Post-streptococcal reactive arthritis (PSReA) may be a variant of acute rheumatic fever (ARF), but there still is debate on the relationship between the 2 entities. Possible associations with HLA class II antigens of PSReA (DRB1*01) and ARF (DRB1*16) were described previously in white Americans. To confirm these findings, we studied DRB1 alleles in a group of Italian children with PSReA and ARF. METHODS: We performed low-resolution HLA-DRB1 typing by a sequence-specific primer polymerase chain reaction method in 33 children with PSReA and 25 children with ARF. We also compared the DRB1 genotypes of our patients with 200 normal subjects from the same geographic area and typed in the same laboratory with the same methods. RESULTS: The allele distributions at the DRB1 locus observed in PSReA patients, ARF patients, and controls were not significantly different from each other (chi-square test with small numbers, P = .65). The positivity for each of the 13 HLA-DRB1 alleles was compared in disease groups (PSReA and ARF) and controls, and failed to show any significant association. Comparisons of the frequency of the DRB1*01 allele among PSReA, ARF, and controls did not show any statistical differences. No significant difference in the frequency of DRB1*16 was present between ARF vs the control group, between ARF vs PSReA, and in PSReA patients when compared with controls. CONCLUSIONS: Our data do not confirm in Italian patients the previously reported associations of DRB1*01 and DRB1*16 with PSReA and ARF, respectively.

Acute Disease↗
PubMed1995

What dialysis dose should be provided in acute renal failure? A review.

Increased dialysis dose has been shown to improve morbidity and survival in chronic hemodialysis patients. Despite improvement in care and technological aspects of renal replacement therapy, mortality rates of acute renal failure (ARF) have remained essentially unchanged for over two decades, exceeding 50% in most studies. The occurrence of ARF in older patients with more complicated medical and surgical conditions has contributed to this lack of outcome amelioration, and death of ARF patients is now more frequently caused by underlying disease than ARF itself. A recent prospective survey at this institution found a mortality rate of 79.1% among a total of 363 ARF medical and surgical intensive care unit patients, with a mean age near 60 years and a mean admission APACHE II score of over 20, who were treated by intermittent hemodialysis and continuous renal replacement therapy (CRRT). Nonsurvivors had a mean of over four failed systems, in addition to the renal failure, compared with survivors who had less than four. The standards for dialysis adequacy in ARF are not currently defined. Increased catabolism seen in ARF patients in the intensive care unit may justify large dialysis dose delivery. An apparent influence of delivered dialysis dose on the outcome of ARF intensive care unit patients has been recently observed at our institution. Compared with nonsurvivors, survivors had received significantly higher dialysis dose, as assessed by Kt/V and urea reduction ratio. In ARF patients, the discrepancy between delivered versus prescribed dialysis dose may be particularly important and contributed to by the following: reduced blood flow rate and dialysis time consequent to patient intolerance; lower dialyzer in vivo clearances, particularly in heparin-free dialysis; blood recirculation when using temporary vascular access; and postdialysis urea rebound. Prolonging the course of renal failure is one of the risks attributed to frequent dialysis; hypotension and ultrafiltration combined with a deficient renal autoregulation can result in further renal damage. The detrimental effects of bioincompatible membranes have been demonstrated with an induced-delay of renal function recovery. A recent study has reported benefits of biocompatible membranes in terms of potential for renal recovery and maintenance of urine output during dialytic support when compared with bioincompatible membranes. CRRT offers many advantages over intermittent hemodialysis for ARF intensive care unit patients: better hemodynamic tolerance, avoidance of solute rebound, and removal of serum sepsis mediators. However, CRRT have not yet been firmly shown to improve survival rates. Recently, urea kinetics have been used to estimate dialysis dose provided by CRRT.(ABSTRACT TRUNCATED AT 400 WORDS)

Acute Kidney Injury↗
PubMed2003

Mild acute renal failure potentiates metformin accumulation in the diabetic rat kidney without further impairment of renal function.

OBJECTIVES: To analyze, in acute renal failure (ARF) in diabetic rats, how moderate functional ARF would modify metformin (MET) pharmacokinetics and if plasma and renal tissue MET accumulation could aggravate renal insufficiency and/or elicit plasma lactate accumulation. METHODS: Streptozotocin-induced diabetic rats were allocated to four groups: control, MET, ARF, ARF-MET (6-7 rats per group). MET (100 mg/kg/day) was given per os for two weeks before ARF was induced by drinking restriction and enalapril treatment. The effects of MET and/or ARF were examined in vivo on renal function in conscious rats (metabolic cages) and ex vivo on renal vascular reactivity (isolated kidney). RESULTS: MET treatment (plasma level: 5.3 +/- 1.4 microg/ml, mean+/-SEM), resulted in biguanide accumulation in cortex and medulla (53 +/- 17 and 80 +/- 40 microg/g respectively). MET was devoid of any effect on creatinine clearance, mean blood pressure or renal vascular resistance, but moderately increased plasma lactate (3.8 +/- 0.5 vs 3.2 +/- 0.2 mM, P<0.05) and decreased angiotensin II-induced renal vasoconstriction. ARF, although mild, decreased renal MET clearance (0.29 +/- 0.05 vs 1.01 +/- 0.31 ml/min/100 g, P<0.05) and increased plasma and renal tissue MET levels (x 2-4). MET however did not worsen the fall in glomerular filtration rate, nor modify renal vascular reactivity. ARF did not change the MET-elicited moderate increase in plasma lactate. CONCLUSION: Despite the increase in MET plasma and renal tissue levels subsequent to moderate ARF, no harmful metabolic effect on plasma lactate and no further impairment of renal function was observed in MET-treated diabetic rats subjected to ARF.

Acute Kidney Injury↗