Nephrotoxicity of beta-lactam antibiotics: mechanisms and strategies for prevention

The nephrotoxic beta-lactam antibiotics cause acute proximal tubular necrosis. Significant renal toxicity, which has been rare with the penicillins and uncommon with the cephalosporins, is a greater risk with the penems. Mechanisms of injury include: (1) transport into the tubular cell, mainly through the antiluminal organic anion secretory carrier; (2) acylation of target proteins, causing respiratory toxicity by inactivation of mitochondrial anionic substrate carriers; and (3) lipid peroxidation. The most nephrotoxic beta-lactams available for study are cephaloridine, cephaloglycin, and imipenem; panipenem, which is comparably nephrotoxic, is currently available only in Japan. Cephaloridine has several unique properties, probably all caused by its pyridinium side-group: (1) its secretory transport into the tubular cell is followed by minimal cell to luminal fluid movement, resulting in extreme intracellular sequestration; (2) it is the only beta-lactam shown to cause significant oxidative injury; (3) it has a limited ability to attack the mitochondrial carriers for pyruvate and the short-chain fatty anions. Cephaloglycin and imipenem undergo less intracellular trapping than cephaloridine, but have sufficient tubular cell uptake, reactivity, and generalized toxicity to mitochondrial substrate carriers to be severely nephrotoxic. Cephaloridine and cephaloglycin are no longer used clinically. Imipenem and panipenem are marketed in combination with nephroprotective renal transport inhibitors. Strategies for avoiding renal toxicity with new cephalosporins and penems are discussed. Received July 12, 1996; received in revised form and accepted September 9, 1996     

Beta-lactam allergy in adults with cystic fibrosis.

BACKGROUND: Allergic reactions to one or more beta-lactam antibiotic can pose a management problem in patients with cystic fibrosis (CF), and may limit antibiotic choice. METHOD: The aim of this study was to assess the prevalence of allergy to anti-pseudomonal beta-lactam antibiotics in an adult CF centre and to assess variables, which may contribute to the development of allergic reactions. A questionnaire-based interview and a review of medical records were performed. RESULTS: Of the 150 patients, 54 (36%) had allergic reactions to one or more beta-lactam antibiotics and 20 (19%) had allergic reactions to multiple beta-lactam antibiotics. The proportion of patients allergic to specific beta-lactam antibiotics varied from 10% to 26%. Rates of reactions were highest for penicillins and cephalosporins, intermediate for carbepenems and lowest for aztreonam. Of all reactions, 40% occurred within 24 h of the commencement of an individual antibiotic course. Patients with one or more beta-lactam allergic reactions had received greater cumulative exposure (p<0.0001), were older (p=0.016) and had lower lung function (p=0.037) than patients without a history of beta-lactam allergy. Cystic Fibrosis transmembrane regulator (CFTR) status, gender, peripheral blood eosinophil count and total IgE concentrations were not different in patients with allergic reactions. CONCLUSIONS: This study demonstrates that the prevalence of allergic reactions to beta-lactam antibiotics is high in adults with CF. Increasing age; cumulative exposure and decreasing FEV(1) were associated with the development of allergy.     

Clostridium difficile infection--a poor prognostic sign in uremic patients?

Uremia has been reported as a risk factor for the occurrence of infection with Clostridium difficile. During the two-year period 1984-86, 110 episodes of Clostridium difficile infection were encountered in 70 patients on a nephrology ward. Sixty-two patients had chronic renal failure and eight had acute renal failure. Sixty-seven of the patients were uremic and were treated with hemodialysis (n = 35), CAPD (n = 21), intermittent peritoneal dialysis (n = 6) or conservatively with a low protein diet (n = 5). Most of the patients were female (n = 41) and elderly (64 +/- 2 years). Malnutrition was common as indicated by low serum albumin concentrations (26 +/- 1 g/l) prior to the Clostridium difficile infection. Clostridium difficile infection was confirmed by stool culture and/or cytotoxin assay. Asymptomatic infections were found in eight patients. The highest relative risks of subsequent Clostridium difficile infection were calculated for patients treated with cephalosporins and isoxazolyl penicillins. All patients were treated with vancomycin, which often resulted in a dramatic improvement. One to six relapses of Clostridium difficile infection were observed in 22 of the patients. Sixty of the original 70 patients died during the five-year follow-up period. Thirty-four patients died during the first year of follow-up. Seven patients were transplanted, two are still on CAPD treatment and one has only moderate chronic renal failure (serum creatinine 200 mumol/l). Elderly debilitated uremic patients are especially susceptible to infection with Clostridium difficile which may be a poor prognostic sign in chronic renal failure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Oxalic Acid as a uremic toxin.

OBJECTIVE: Oxalic acid (OA) is thought to be a uremic toxin that participates in the pathogenesis of uremic syndrome. The objectives of this study were to: (1) evaluate the plasma levels of OA in patients with chronic renal disease with various levels of glomerular filtration rate and after renal transplantation; (2) investigate the salivary secretion of OA and ascorbic acid in healthy subjects and in patients with chronic renal failure (CRF); (3) examine the influence of water and sodium diuresis and furosemide administration on the urinary excretion of OA and ascorbic acid in healthy subjects and in CRF patients without dialysis treatment; and (4) evaluate the influence of renal replacement therapy (RRT) on secondary hyperoxalemia in hemodialysis patients. DESIGN AND SETTING: This study was conducted at the Nephrological Department of P.J. Safárik University. Sixty-one patients with chronic renal disease, 64 CRF patients, 32 continuous ambulatory peritoneal dialysis (CAPD) patients, 15 hemodialysis patients, 21 patients after renal transplantation, and 15 healthy subjects were examined. Maximal water diuresis, diets with low (2 g/day) and high (15 g/day) sodium intake, administration of intravenous furosemide (20 mg), and renal replacement therapy (CAPD, hemodialysis, hemofiltration, and postdilution hemodiafiltration) were utilized in the study. RESULTS: In patients with chronic renal disease and those after renal transplantation, direct relationships between plasma OA and serum creatinine were found (r = 0.904 and 0.9431, respectively, P < .01). Despite a high level of plasma OA in uremic patients (23.1 +/- 10 micromol/L), there was no significant difference in salivary OA between control subjects (128 +/- 19 micromol/L) and CRF patients (135 +/- 24 micromol/L). The urinary excretion of OA during maximal water diuresis (from 37.5 to 110.3 micromol/4 hours) and after intravenous furosemide (from 34.5 to 66.7 micromol/3 hours) increased significantly, but was not affected by high intake of NaCl. The most significant decrease of plasma OA was observed during postdilution hemodiafiltration (63.3%). CONCLUSION: Our study indicates that renal replacement therapy is not effective for a permanent reduction of elevated plasma levels of OA.     

Hypertension is associated with hyperlipidemia, coronary heart disease and chronic graft failure in kidney transplant recipients.

BACKGROUND: Hypertension is a common concomitant condition in renal transplant recipients. There is accumulating evidence that this disorder is an important risk factor for chronic renal graft failure and other cardiovascular complications in these patients. SUBJECTS AND METHODS: The current retrospective study in 330 patients treated with cyclosporin or azathioprin covered 5 years and aimed to further characterize the interrelation between hypertension and renal graft failure. Furthermore, the association of hypertension with hyperlipidemia and the prevalence of coronary heart disease was evaluated. RESULTS: Altogether, before transplantation 182 patients were normotensive (no antihypertensive medication except diuretics) and 105 were hypertensive (blood pressure > 160/95 mmHg or patients requiring antihypertensive medication); for the remaining 43 patients no data were available. After transplantation the prevalence of hypertension in the cyclosporin group was 71, 76 and 70% after 1, 3 and 5 years, respectively. The respective numbers for the azathioprin group were 60, 59 and 58%. Hypertension was associated with graft dysfunction both in cyclosporin- and azathioprin-treated patients. Hyperlipidemia (cholesterol, triglycerides) was more severe in hypertensive than in normotensive patients. The prevalence for hypertension was higher in patients with coronary artery disease than in patients without the disease. CONCLUSION: The results further support the view that hypertension may be a risk factor for the development of chronic renal graft failure and coronary artery disease in this population. Furthermore, the association of hypertension with hyperlipidemia hints to an unfavorable accumulation of renal and cardiovascular risk factors in a large number of renal allograft recipients.     

Antibiotic-induced neurotoxicity in dialysis patients: a retrospective study

Abstract

Objective: The study was to evaluate neurotoxicity caused by antibiotics in dialysis patients, including incidence, clinical features, treatments and prognosis. Methods: In this retrospective study, we reviewed the medical records of 1066 dialysis patients (254 peritoneal dialysis [PD] cases and 812 hemodialysis [HD] cases) who also received intravenous antibiotics in our hospital during July 2006 – April 2012. Naranjo scale was used for estimating the probability of an adverse drug reaction. Results: The incidence of antibiotic-induced neurotoxicity was 5.66% in patients receiving HD, and 7.87% in patients receiving PD. There was no significant difference between the two dialysis modalities about the incidence of antibiotic-induced neurotoxicity (p?>?0.05). The risk factors included extremely old age, history of central nervous system disorder, low residual renal function, hypoalbuminemia, and the use of multiple antibiotics that share one mechanism. The neurotoxic antibiotics included cephalosporins, penicillins, carbapenems and quinolones in our study. Most patients could be properly diagnosed early according to their medical history, symptoms, signs, electroencephalography (EEG), other related auxiliary examination, and with the help of experienced neurologists. Most neurotoxic patients showed clinical improvement after the discontinuation of antibiotics and active treatment. Conclusions: The adverse neurotoxic effects of antibiotics were common in dialysis patients due to wide and incorrect usage. Neurotoxicity could be prevented in high-risk cases with dosage adjustments. Better prognosis can be achieved with early and proper diagnosis, decisive withdrawal, and aggressive treatment including enhanced HD.     

Continuous beta-lactam antibiotic therapy in a double-lung transplanted patient with a multidrug-resistant Pseudomonas aeruginosa infection

BACKGROUND: It is well known that the bactericidal effect of beta-lactam antibiotics is closely related to the time which the serum concentration of the antibiotic remains above the minimal inhibitory concentration of the target pathogen. Thus, the optimal administration of beta-lactam antibiotics would be the continuous infusion of the drug. METHODS: We present a case report with a critically ill double-lung transplanted patient with pneumonia due to a multidrug-resistant Pseudomonas aeruginosa who received continuously 8 g meropenem/24 hr. Based on a previous pharmacokinetic study showing that continuous infusion of meropenem is at least equivalent to intermittent administration this case report is reported to demonstrate the clinical efficacy of continuous infusion. RESULTS: C-reactive protein and pneumonia decreased rapidly when clinical conditions were improved significantly. Continuous administration of meropenem did not interfere with cyclosporine, no side effects were seen, and the patient's renal function was not impaired during the whole period of treatment. CONCLUSION: The continuous administration of beta-lactam antibiotics is a powerful application in critically ill patients to intensify antimicrobial therapy.     

Antibiotic concentration in human wound fluid after intravenous administration.

Since the wound is the most common focus of infection in the surgical patient, adequate levels of antibiotic within the wound ar essential. This study examines the concentrations of antibiotic achieved in human wounds. Fluid was collected at timed intervals on the first postoperative day from the wounds of 56 patients receiving antibiotics after regional lymph node dissection. Antibiotic concentration was determined by bioassay. Six antibiotics were studied: cephalothin, cefazolin, cephapirin, oxacillin, ampicillin and clindamycin. The cephalosporins and penicillins showed similar patterns of appearance in the wound fluid. The peak level occurred early (1--1 1/2 hours) with subsequent slow decrease. Clindamycin produced nearly constant levels in wound fluid. The concentration of each antibiotic in wound fluid surpassed the serum levels after 2.5 hours. At the dosages studied each antibiotic produced wound fluid concentrations greater than the MIC for most susceptible organisms. Higher doses provided higher wound fluid levels. The rate of appearance and the levels achieved should be considered in the choice of antibiotics in the surgical subject.     

In utero and in vitro exposure to beta-lactams impair kidney development in the rat

beta-Lactam antibiotics are widely used because of their lack of toxicity in humans. However, during pregnancy, exposure of the fetus is likely to occur because beta-lactam antibiotics cross the placenta. The potential adverse effects of two penicillins (ampicillin, amoxicillin) and of one cephalosporin (ceftriaxone) were examined in rat kidney development. Two experimental approaches were used: metanephros organ cultures to analyze the direct effect of the drug and maternal treatment to assess the consequences of in utero exposure. For in vitro experiments, metanephroi were removed from 14-d-old fetuses and grown with or without the antibiotic at a concentration ranging from 10 to 1000 microg/ml for 6 d. For in vivo experiments, pregnant rats were treated with penicillin at 100 mg/kg per d for 5 d, a period overlapping early renal organogenesis. Both penicillins alter renal development in vitro in a dose-dependent manner, from a dose of 10 microg/ml for ampicillin and 100 microg/ml for amoxicillin. In young animals exposed to penicillins in utero, a mild oligonephronia was present and cystic tubule dilation was observed in newborn and in young animals as well. Ceftriaxone weakly impairs in vitro nephrogenesis except at the dose of 1000 microg/ml that blocks kidney development completely. No effect on nephron ontogeny was observed following in utero exposure, but an interstitial inflammation was present in the medulla of 2-wk-old rats. In conclusion, these data show that beta-lactams, at therapeutic doses, are harmful to fetal rat kidneys.     

Ethyl pyruvate decreases sepsis-induced acute renal failure and multiple organ damage in aged mice

BACKGROUND: Sepsis is a common cause of acute renal failure (ARF). The incidence of sepsis increases dramatically after 50 years of age; however, most ARF studies are performed in young mice. METHODS: We performed two common sepsis models, lipopolysaccharide (LPS) administration and cecal ligation puncture (CLP) in aged mice. We developed a fully treated CLP model in aged mice by treating mice with fluid resuscitation and antibiotics. RESULTS: LPS induced renal injury in aged but not young mice. However, volume resuscitation starting within 6 hours decreased renal injury. We then used this fluid resuscitation scheme, along with antibiotics, to develop a fully treated CLP model in aged mice. Mice subjected to CLP developed functional and histologic ARF and multiple organ damage. Treatment with ethyl pyruvate, even when started 12 hours after surgery, decreased serum creatinine, tubular damage, and multiple organ injury at 24 hours. Ethyl pyruvate decreased plasma tumor necrosis factor-alpha (TNF-alpha), and kidney mRNA for TNF alpha, tissue factor, and plasminogen activator inhibitor-1 (PAI-1), and increased mRNA for urokinase-like plasminogen activator. CONCLUSION: CLP in aged mice causes functional and histologic changes consistent with human ARF. A single dose of ethyl pyruvate inhibits renal and multiple organ damage, and is still effective when given 12 hours after surgery.     

Multicenter prospective study of nonruptured abdominal aortic aneurysm. Part II. Variables predicting morbidity and mortality

A previous article (Part I) described the patient population and operative management of 666 patients who had surgery for nonruptured abdominal aortic aneurysms. This article details the perioperative complications and, by chi-square and logistic regression analysis, identifies the variables that are associated with each complication. In summarizing the results (below) the incidence of each complication is listed, along with the predictive risk factors in parentheses that have significance levels less than 0.05. Vascular morbidity data are as follows: intraoperative bleeding, 4.8%; postoperative bleeding requiring transfusion, 2.3% or repeat operation, 1.4% (large volume of blood transfusion and/or use of an autotransfusion device); intraoperative limb ischemia, 3.5%; graft thrombosis, 0.9% (femoropopliteal disease and/or distal anastomosis at the femoral level); distal thromboembolism, 3.3% (male sex, femoral popliteal disease, and/or intraoperative graft thrombosis); amputation, 1.2%; graft infection, 1 case. General morbidity data are as follows: cerebrovascular event, 0.6%; paraplegia, 1 case; cardiac event, 15.1% (age, previous episode of congestive heart failure, and/or electrocardiogram [ECG] evidence of a previous myocardial infarction); myocardial infarction, 5.2% (advancing age, angina, and/or prolonged aortic cross-clamp time); congestive heart failure, 8.9% (previous history of congestive heart failure, ECG evidence of ischemia, and/or chronic obstructive lung disease); arrhythmia requiring treatment, 10.5% (preoperative ventricular premature beats and/or respiratory failure requiring ventilation for more than 48 hours); new arrhythmia, 8.4% (angina and/or chronic obstructive lung disease); respiratory failure, 8.4% (chronic obstructive lung disease, large volume of blood transfused, and/or occurrence of postoperative bleeding, cerebrovascular accident, congestive heart failure, or myocardial infarction); renal damage with rise in creatinine or blood urea nitrogen, 5.4% and/or renal failure requiring dialysis, 0.6% (elevated preoperative creatinine, suprarenal aortic cross-clamping, and/or renal vein ligation); diarrhea without evidence of ischemia colitis, 7.1% and ischemic colitis, 0.6% (pelvic flow interrupted); prolonged ileus, 11.0% (aortoiliac occlusive disease, deterioration of renal function, prolonged ventilation, and/or preoperative history of angina); superficial wound infection, 1.5% and deep infection, 0.5% (femoral anastomosis and/or female sex); coagulopathy, 1.1% (large volume of blood transfused).(ABSTRACT TRUNCATED AT 400 WORDS)     

IBUPROFEN COMBINED WITH ANTIBIOTICS SUPPRESSES RENAL SCARRING DUE TO ASCENDING PYELONEPHRITIS IN RATS

PURPOSE: In acute pyelonephritis renal scarring may be decreased by immediate antibiotic therapy. Unfortunately in children there is often a delay in starting treatment, which increases the likelihood of renal scarring. In rodents immediate antibiotic therapy is effective for preventing renal scar formation resulting from experimentally induced pyelonephritis. However, the same treatment beginning 72 hours after infection does not prevent renal scarring in this paradigm. We examined whether delayed administration of the nonsteroidal anti-inflammatory agent ibuprofen only or combined with antibiotics suppresses renal scarring in a model of ascending pyelonephritis in rats. MATERIALS AND METHODS: An inoculum of 5x10(9) organisms per ml. of Escherichia coli strain BH-5 was instilled into the bladder of rats and the urethra was occluded for 4 hours. Groups of animals were and were not treated with 15 mg./kg. cefadroxil or 10 mg./kg. ibuprofen given twice daily for 5 days, or the 2 drugs combined. Treatment began 72 hours after inoculation. In an additional group of rats sterile phosphate buffered saline was instilled into the bladder. In each rat the kidneys were examined grossly and microscopically 6 weeks later. RESULTS: Combined antibiotics and ibuprofen significantly inhibited gross renal scarring compared with no treatment or antibiotics only (p<0.05). No difference in renal scarring was detected in animals that received no treatment versus those that received antibiotics or ibuprofen only (p>0.05). CONCLUSIONS: Renal scarring resulting from acute pyelonephritis in this rat model is not decreased by delayed treatment with antibiotics only. The addition of ibuprofen to antibiotic therapy is effective for decreasing renal scarring due to acute pyelonephritis even when treatment is delayed for 72 hours.     

Mannitol, furosemide, and dopamine infusion in postoperative renal failure complicating cardiac surgery

BACKGROUND: Acute renal failure occurring in the postoperative period, requiring dialysis after cardiac surgery is an important risk factor for an early mortality, and the overall mortality of this complication is as high as 40% to 60%. Dialysis in the early postoperative period is often complicated by acute hemodynamic, metabolic, and hematologic effects that adversely affect cardiopulmonary function in patients stabilizing from recent surgery. The purpose of this study was to avoid the need for dialysis by infusion of the solution of mannitol, furosemide, and dopamine in the early postoperative period in oliguric renal failure. METHODS: One hundred patients with postoperative oliguric or anuric renal failure despite adequate postoperative cardiac output and hemodynamic function were randomized. Forty patients (group A) were given intermittent doses of diuretics (furosemide, bumetadine, and ethracrynic acid) and fluids. Sixty patients (group B) were given continuous infusion of the solution of mannitol, furosemide, and dopamine; the infusion was started within 6 hours (mean 3.5 hours) in subgroup B1 (n = 30), and later than 6 hours (mean 7.5 hours) in subgroup B2 (n = 30) after the onset of renal failure. RESULTS: Diuresis occurred in 93.3% of group B (n = 56) versus 10% in group A (n = 4; patients with preop normal renal function). Ninety percent of group A (n = 36) required dialysis versus only 6.7% of group B (n = 4; patients with preexisting renal disease of subgroup B2). Renal function returned to preoperative normal (serum creatinine 0.9 +/- 0.05, p < 0.0001) or baseline value (serum creatinine 2.5 +/- 0.01, p < 0.0001) after first postoperative week in subgroup B1 and third postoperative week in subgroup B2. CONCLUSIONS: Infusion of solution of mannitol, furosemide, and dopamine promoted diuresis in patients with acute postoperative renal failure with adequate postoperative cardiac output and had decreased the need for dialysis in the majority of patients. Early administration of this solution in acute renal failure caused early restoration of renal function to normal or baseline status. It remains to be determined whether routine administration of this solution in the early postoperative period for oliguric renal failure influences the long-term mortality and morbidity in those patients who do require dialysis.     

Low risk of contrast nephropathy in high-risk patients undergoing spiral computed tomography angiography with the contrast medium iopromide and prophylactic oral hydratation

BACKGROUND: Spiral computed tomography angiography (CTA) is a sensitive and specific technique for visualizing renal arteries and diagnosing renal artery stenosis (RAS). Whether spiral CTA is associated with increased risk of contrast nephropathy (CN) in patients with impaired renal function is unknown. METHODS: We prospectively studied 50 patients with chronic renal insufficiency (serum creatinine concentration greater than 1.58 mg/dl) who underwent spiral CTA with iopromide, a nonionic, low-osmolar contrast agent. Fourteen patients had diabetes mellitus. Patients were encouraged to drink 1 l of water 12 hours before and 2 l over 24 hours after the procedure. The presence of CN was defined by an increase of 20% or more in the baseline serum creatinine level within or 72 hours after administration of the radio-contrast agent. RESULTS: In the entire group, mean serum creatinine levels increased significantly from 2.92 +/- 1.39 to 3.06 +/- 1.55 mg/dl (p = 0.02) and mean creatinine clearance decreased from 29.8 +/- 12.9 to 28.9 +/- 12.8 ml/min (p = 0.009) 72 h after administration of the contrast medium. Two patients experienced an increase in serum creatinine level of 20%. Renal function returned to baseline within seven days in the 2 patients. Absolute changes in creatinine clearance after the administration of radiocontrast medium were similar in nondiabetic and diabetic patients and in the subgroup of patients, with a baseline serum creatinine of < 3 mg/dl and > or = 3 mg/dl. CONCLUSIONS: In patients with chronic renal insufficiency, spiral CTA performed with iopromide, a nonionic, low-osmolar contrast medium and a prophylactic oral hydratation, is a minimally invasive technique with low risk of contrast nephropathy.     

Rate of and risk factors for acute inpatient mortality after orthopaedic surgery

BACKGROUND: Orthopaedic surgeons operate on a diverse group of patients, and many of these patients have concomitant medical problems. The purpose of this study was to identify the rate of mortality and to evaluate the risk factors associated with mortality after orthopaedic surgery. METHODS: Data from the National Hospital Discharge Survey, a nationwide sample of hospital admissions, were obtained for the years 1995 through 1997. The study was limited to hospital admissions. Univariate and multivariate analyses were performed. RESULTS: The 43,215 inpatient orthopaedic operations that we evaluated were associated with a mortality rate of 0.92%. Seventy-seven percent of all deaths occurred after procedures performed for patients who were more than seventy years old, and 50% of all deaths occurred after operations performed for the treatment of hip fractures. The independent preoperative medical risk factors for death included chronic renal failure, congestive heart failure, metastasis to bone, atrial fibrillation, chronic obstructive pulmonary disease, and osteomyelitis. The risk factors of diabetes, coronary artery disease, peripheral vascular disease, septic arthritis, and rheumatoid arthritis did not achieve significance. Among orthopaedic subspecialty categories, operations for tumors, trauma, and infection were associated with elevated mortality rates. In a predictive model, five critical risk factors were identified as most helpful in identifying patients at risk for death: chronic renal failure, congestive heart failure, chronic obstructive pulmonary disease, hip fracture, and an age of greater than seventy years. The mortality rate was 0.25% for patients with no critical risk factors. A linear increase in mortality was seen with increasing numbers of critical risk factors (p < 0.005). CONCLUSION: Death is rare after orthopaedic operations. In the United States, the rate of acute mortality after inpatient orthopaedic surgical procedures is approximately 1% for all patients, 3.1% for patients with a hip fracture, and 0.5% for patients without a hip fracture. These data will aid orthopaedic surgeons in predicting operative mortality for their patients.     

Renal effects of N-acetylcysteine in patients at risk for contrast nephropathy: decrease in oxidant stress-mediated renal tubular injury.

BACKGROUND: N-Acetylcysteine has been shown to protect against contrast nephropathy, although the mechanisms underlying such an effect are unclear. Surprisingly, studies have shown that post-radiocontrast renal function actually improves in chronic renal failure patients receiving N-acetylcysteine. However, there have been no studies investigating the cause of this improvement. METHODS: In a double-blind, placebo-controlled study, 24 patients (aged 65+/-2 years) suffering from stable mild-to-moderate renal insufficiency and undergoing elective coronary angiography were randomized to receive either placebo or N-acetylcysteine. All received similar hydration. Renal function parameters were assessed 48 h before and 48 h after radiocontrast administration. Urinary 15-isoprostane F2(t), a specific marker of oxidative stress, was measured immediately before and after the procedure. Expression of urinary alpha-glutathione S-transferase protein, a specific proximal tubular injury marker, was assessed after the procedure. RESULTS: Comparing creatinine clearance values before and after angiography, a significant increase was seen in N-acetylcysteine patients (44.7+/-4.2 vs 57.2+/-6.3 ml/min/1.73 m(2); P = 0.02), whereas placebo patients presented no change (46.6+/-5.0 vs 46.9+/-4.3 ml/min/1.73 m(2); P = 0.90). After radiocontrast, urinary 15-isoprostane F2(t) levels in placebo patients increased significantly over baseline values (2.9+/-0.7 vs 10.3+/-2.1 ng/mg creatinine; P = 0.007), whereas urinary 15-isoprostane F2(t) levels in N-acetylcysteine patients remained basically unchanged (3.5+/-0.5 vs 4.1+/-0.9 ng/mg creatinine; P = 0.63). Furthermore, N-acetylcysteine treatment led to lower levels of alpha-glutathione S-transferase than did placebo treatment (0.8+/-0.2 vs 2.4+/-0.7 micro g/g; P = 0.046). CONCLUSIONS: In chronic renal failure patients, the improvement in renal function induced by post-radiocontrast administration of N-acetylcysteine is strongly associated with suppression of oxidant stress-mediated proximal tubular injury.     

Increased lipoprotein(a) concentrations in chronic renal failure.

Subjects with chronic renal failure have a greatly increased risk of coronary heart disease and dyslipidemia. Relatively few studies have examined the relationship of chronic renal failure to lipoprotein (Lp)(a) concentrations, an important risk factor for coronary heart disease. Diabetic subjects have been reported to have both increased Lp(a) concentrations and an increased risk of renal failure, thereby possibly confounding the Lp(a)-renal failure association. The association between Lp(a) and chronic renal failure in 359 control subjects and 111 subjects with renal failure was examined. Lp(a) (in milligrams per deciliter) was elevated in subjects with chronic renal failure, regardless of ethnicity (Mexican Americans, 19.8 +/- 2.7 versus 14.1 +/- 1.3; P = 0.03; non-Hispanic white patients, 24.9 +/- 3.0 versus 16.3 +/- 1.2; P = 0.006;). These differences persisted after adjustment for diabetes and ethnicity (P < 0.001). The type of treatment for chronic renal failure (diet, hemodialysis, or peritoneal dialysis) did not have an effect on Lp(a) concentrations. Lp(a) levels were not correlated with the level of creatinine in subjects with chronic renal failure. Thus, the elevation of Lp(a) levels in renal failure must occur early in renal failure, or alternatively, elevated Lp(a) levels may promote progression to chronic renal failure. These results indicate that Lp(a) concentrations are increased in chronic renal failure and may increase the risk for coronary heart disease in these subjects.     

Antibiotic prophylaxis for cardiothoracic operations. Meta-analysis of thirty years of clinical trials.

Antistaphylococcal penicillins and first-generation cephalosporins have traditionally been the prophylactic antibiotics of choice for patients undergoing cardiothoracic operations. Recently published studies have claimed improved outcomes with respect to postoperative wound infection when second-generation cephalosporins were used for prophylaxis. The purpose of this study was to critically review the infectious outcomes of prospective, randomized, and controlled studies of cardiothoracic surgery prophylaxis by means of meta-analytic techniques. For each of 28 studies meeting the meta-analysis entry criteria, odds ratios with 95% confidence intervals were calculated to compare the prophylactic efficacy of the antibiotic regimens. Odds ratios were then pooled, and a summary odds ratio was calculated for each pairing of antibiotic treatments. Placebo-controlled trials of cardiothoracic prophylaxis demonstrated a consistent benefit to the administration of antibiotic prophylaxis, with an approximate fivefold reduction in wound infection rate. The second-generation cephalosporins, cefamandole and cefuroxime, performed better than cefazolin, with an approximate one and one-half-fold reduction in wound infection rate. Administration of prophylaxis beyond 48 hours was not associated with improved infectious outcomes.     

Renal injury in the elderly: diagnosis, biomarkers and prevention

Acute kidney injury (AKI) in the elderly patient is a common iatrogenic complication of major surgery that impacts morbidity, mortality and resource use. Several renal functional and structural changes have been described, including a substantially decreased nephron mass. Loss of renal function defines AKI and is classified by the RIFLE (R: renal risk, I: injury, F: failure, L: Loss and E: End-stage renal disease) criteria; however, it frequently occurs many hours to several days after the injury to the kidney. Therefore, novel biomarkers indicating tubulo-interstitial damage are needed for early AKI diagnosis. The limitations of serum creatinine are much more pronounced in the elderly, including its dependence on muscle mass and the presence of multiple drug use and co-morbidities. Although it is conceivable that earlier AKI diagnosis and application of classical preventive measurements, including postponement of surgery or preference of medical treatment, optimisation of haemodynamics, euvolaemia, aggressive avoidance of nephrotoxic antibiotics or analgesics may translate into better patient outcomes, much more data are needed in this specific cohort.     

Aluminum administration in the rat separately affects the osteoblast and bone mineralization

Aluminum administration in the experimental animal results in osteomalacia as characterized by osteoid accumulation and decreased mineralization. Previous in vivo and in vitro studies have indicated that either aluminum directly inhibits mineralization or is toxic to the osteoblast. In the present study, PTH was continuously infused in rats with aluminum-induced osteomalacia to evaluate whether aluminum administration decreased mineralization without a concomitant decrease in osteoblasts. Four groups of rats were studied: chronic renal failure (CRF); CRF + aluminum (AL); CRF + PTH; and CRF + PTH + AL. Rats were sacrificed 5 and 12 days after aluminum or diluent administration; in the PTH groups, bovine PTH (1-34) was administered at 2 units/h via a subcutaneously implanted Alzet pump. Aluminum administration decreased osteoblast surface, increased osteoid accumulation, and produced a cessation of bone formation. The infusion of PTH alone increased osteoblast surface and bone formation. The simultaneous administration of aluminum and PTH resulted in an osteoblast surface intermediate between aluminum and PTH alone; however, despite a PTH-induced restoration of osteoblast surface, bone formation did not increase. These findings indicate (1) aluminum is toxic to osteoblasts and also directly inhibits mineralization even when osteoblasts are not decreased; (2) PTH is capable of increasing osteoblasts even in the presence of aluminum; and (3) despite a PTH-induced increase in osteoblast surface, mineralization of osteoid was not improved.