Costs and length of stay associated with antimicrobial resistance in acute kidney injury patients with bloodstream infection.

INTRODUCTION: Antimicrobial resistance negatively impacts on prognosis. Intensive care unit (ICU) patients, and particularly those with acute kidney injury (AKI), are at high risk for developing nosocomial bloodstream infections (BSI) due to multi-drug-resistant strains. Economic implications in terms of costs and length of stay (LOS) attributable to antimicrobial resistance are underevaluated. This study aimed to assess whether microbial susceptibility patterns affect costs and LOS in a well-defined cohort of ICU patients with AKI undergoing renal replacement therapy (RRT) who developed nosocomial BSI. METHODS: Historical study (1995-2004) enrolling all adult RRT-dependent ICU patients with AKI and nosocomial BSI. Costs were considered as invoiced in the Belgian reimbursement system, and LOS was used as a surrogate marker for hospital resource allocation. RESULTS: Of the 1330 patients with AKI undergoing RRT, 92 had microbiologic evidence of nosocomial BSI (57/92, 62% due to a multi-drug-resistant microorganism). Main patient characteristics were equal in both groups. As compared to patients with antimicro-4 bial-susceptible BSI, patients with antimicrobial-resistant BSI were more likely to acquire Gram-positive infection (72.6% vs 25.5%, P<0.001). No differences were found neither in LOS (ICU before BSI, ICU, hospital before BSI, hospital, hospital after BSI, and time on RRT; all P>0.05) or hospital costs (all P>0.05) when comparing patients with antimicrobial-resistant vs antimicrobial-susceptible BSI. However, although not statistically significant, patients with BSI caused by resistant Gram-negative-, Candida-, or anaerobic bacteria incurred substantial higher costs than those without. CONCLUSION: In a cohort of ICU patients with AKI and nosocomial BSI undergoing RRT, patients with antimicrobial-resistant vs antimicrobial-susceptible Gram-positive BSI did not have longer hospital stays, or higher hospital costs. Patients with resistant "other" (i.e. Gram-negative, Candida, or anaerobic) BSI were found to have a distinct trend towards increased resources use as compared to patients with susceptible "other" BSI, respectively.

Inhibition of vascular endothelial growth factor (VEGF) does not affect early renal changes in a rat model of lean type 2 diabetes.

Type 2 diabetes is the most frequent cause of end-stage renal failure in many Western countries. Approximately 10-15 % of all type 2 diabetics are lean. Various growth factors and cytokines have been implicated in the pathophysiology of diabetic kidney disease, including vascular endothelial growth factor (VEGF). To elucidate a role for VEGF in the renal changes associated with type 2 diabetes, we examined the effect of a VEGF-antibody (ab) on early renal changes in the Goto-Kakizaki (GK) rat, a lean type 2 diabetes model. GK-rats were treated for 6 weeks with the VEGF-ab or with an isotype-matched irrelevant IgG. Wistar rats were used as non-diabetic controls. Placebo-treated GK-rats showed a pronounced increase in glomerular volume and urinary albumin excretion (UAE) and no change in the renal expression of endothelial nitric oxide synthase (eNOS) compared to placebo-treated non-diabetic controls. Kidney weight and creatinine clearance were no different between the groups. VEGF-ab treatment had no effect on glomerular volume, UAE, eNOS expression, body weight, blood glucose levels or food intake, but lowered serum insulin levels in non-diabetic and diabetic animals. We conclude that VEGF inhibition has minimal effects on early renal changes in GK-rats.

Lipid and apoprotein changes during atorvastatin up-titration in hemodialysis patients with hypercholesterolemia: a placebo-controlled study.

BACKGROUND: Patients with end-stage renal disease commonly present with an atherogenic lipid profile characterized by the accumulation of triglyceride-rich, apoprotein B-containing "remnant" lipoproteins, small dense low-density lipoprotein, and low levels of high-density lipoprotein. They are at increased cardiovascular risk and may benefit from drastic lipid-lowering treatment with atorvastatin, a potent, broadacting lipid regulator. This study aims to assess the effects of atorvastatin on the lipid profile in hemodialysis patients, to determine wether atorvastatin is also effective at lowering lipid levels in this particular high-risk subgroup. METHODS: In this randomized, placebo-controlled, double-blind study in hemodialysis patients with hypercholesterolemia (n = 42, mean total cholesterol 243 +/- 33 mg/dl (6.3 +/- 0.8 mmol/l)), the efficacy of 4-weekly increasing doses of atorvastatin (10 - 40 mg daily) was investigated. Lipids and apoproteins were measured in plasma and isolated lipoprotein fractions. RESULTS: Mean total cholesterol and low-density lipoprotein cholesterol progressively decreased with increasing doses of atorvastatin (total cholesterol -33%, low-density lipoprotein cholesterol -43% after 12 weeks), while high-density lipoprotein cholesterol remained unchanged. Plasma levels of apoprotein B and apoprotein E were also significantly reduced by atorvastatin 10 mg, while up-titration to 20 and 40 mg daily provided additional benefits by lowering triglycerides and apoprotein C-III. At week 12, the fraction of small dense low-density lipoprotein was significantly reduced from 23% - 18%, and apoprotein B-containing intermediate-density lipoproteins were no longer detectable. CONCLUSION: In conclusion, atorvastatin not only treated hypercholesterolemia but also favorably affected the uremic lipid profile in patients on hemodialysis. Atorvastatin 4-weekly dose escalation up to 40 mg daily was well-tolerated. Further prospective studies are needed to evaluate the impact of this improved lipid profile on morbidity and mortality.

Diabetes-induced microvascular dysfunction in the hydronephrotic kidney: role of nitric oxide.

BACKGROUND: Renal hemodynamics in early diabetes are characterized by preglomerular and postglomerular vasodilation and increased glomerular capillary pressure, leading to hyperfiltration. Despite intensive research, the etiology of the renal vasodilation in diabetes remains a matter of debate. The present study investigated the controversial role of nitric oxide (NO) in the renal vasodilation in streptozotocin-induced diabetic rats. METHODS: In the renal microcirculation, basal tone and response to NO synthase blockade were studied using the in vivo hydronephrotic kidney technique. L-arginine analog N-nitro-L-arginine methyl ester (L-NAME) was administered locally to avoid confounding by systemic blood pressure effects. The expression of endothelial NO synthase (eNOS) was investigated in total kidney by immunocytochemistry and in isolated renal vascular trees by Western blotting. Urinary excretion of nitrites/nitrates was measured. RESULTS: Diabetic rats demonstrated a significant basal vasodilation of all preglomerular and postglomerular vessels versus control rats. Vasoconstriction to L-NAME was significantly increased in diabetic vessels. After high-dose L-NAME, there was no difference in diameter between diabetic and control vessels, suggesting that the basal vasodilation is mediated by NO. Immunocytochemically, the expression of eNOS was mainly localized in the endothelium of preglomerular and postglomerular vessels and glomerular capillaries, and was increased in the diabetic kidneys. Immunoblots on isolated renal vascular trees revealed an up-regulation of eNOS protein expression in diabetic animals. The urinary excretion of nitrites/nitrates was elevated in diabetic rats. CONCLUSION: The present study suggests that an up-regulation of eNOS in the renal microvasculature, resulting in an increased basal generation of NO, is responsible for the intrarenal vasodilation characteristic of early diabetes.

Intravital microscopy: an integrated evaluation of peritoneal function and structure.

Peritoneal dialysis (PD) solutions may affect various aspects of peritoneal function and structure. The present communication describes the application of an intravital microscopy technique for the study of peritoneal pathophysiology. The technique allows the in vivo measurement of peritoneal blood flow rate, microvascular permeability to macromolecules, leukocyte-endothelial interactions, microvascular density and lymph vessel kinetics. The off-line coupling to a computer-assisted image analysis system permits the rapid quantitation and integrated evaluation of these different parameters. The model may be an attractive tool for the study of the pathophysiological consequences of acute or long-term dialysate exposure, as well as for the development and evaluation of novel PD solutions.

Renal function in the oldest-old on an acute geriatric ward.

AIM: Evaluation of renal function and relation to risk factors for renal failure in very old patients admitted to an acute geriatric ward. METHODS: Retrospective chart review of patients aged 80 years and over, admitted to the acute geriatric ward from August 1998 till August 1999. Recorded data were: age, gender, previous medical history, primary diagnosis, medication use, weight, serum creatinine, BUN, sodium, potassium, cholesterol, urine and ultrasound of the kidney. The creatinine clearance was estimated by the Cockcroft-Gault formula, the glomerular filtration rate by the MDRD equation. RESULTS: 220 (60 males/160 females) patients were included. The mean serum creatinine on admisssion and discharge was 1.17 +/- 0.45 mg/dL and 1.11 +/- 0.48 mg/dL respectively. The mean estimated creatinine clearance in the very old was 38.11 +/- 12.04 mL/min on admission and 39.00 +/- 11.01 mL/min on discharge. Renal failure arbitrarily defined as an estimated creatinine clearance on admission of less than 30 mL/min was found in 26.4% of the patients. Only a significant correlation between failure to thrive and renal failure was found (p < 0.0001). The correlation coefficient between the Cockcroft-Gault and the MDRD formula was r = 0.66 (p < 0.0001); between the Cockcroft-Gault and the reciprocal serum creatinine was r = 0.60 (p < 0.0001) and between the MDRD and the reciprocal serum creatinine was r = 0.87 (p < 0.0001). CONCLUSION: The weak correlation between the Cockcroft-Gault and other estimations of GFR in the acutely ill elderly, confirms the need to have a reliable estimation of glomerular filtration rate in the elderly. Renal failure defined as a Cockgroft-Gault <30 mL/min is found in 26.4% of the oldest-old admitted to an acute geriatric department. The elderly with renal failure is more often admitted for failure to thrive. No great differences were observed between renal function on admission and discharge.

Non anticoagulant effects of heparin: implications for animal models of peritoneal dialysis.

Heparin is a glycosaminoglycan with well-known anticoagulant activity. That property is used in animal models of peritoneal dialysis to maintain catheter patency and to prevent the development of peritoneal adhesions. However, heparin has a host of biologic actions beyond its role as an anticoagulant. Heparin modulates the activity of various inflammatory cells, affects the synthesis of extracellular matrix, has antiproliferative effects on several cell types, and influences neoangiogenesis. By virtue of those actions, intraperitoneally administered heparin may interfere with peritoneal membrane homeostasis. The potential side effects of heparin use in animal models of peritoneal dialysis should be recognized to permit correct interpretation of experimental studies conducted in those models.

The impaired renal vasodilator response attributed to endothelium-derived hyperpolarizing factor in streptozotocin--induced diabetic rats is restored by 5-methyltetrahydrofolate.

AIMS/HYPOTHESIS: Endothelial dysfunction contributes to the development of diabetic vascular complications. A better understanding of the pathophysiology of endothelial dysfunction in diabetes could lead to new approaches to prevent microvascular disease. METHODS: Endothelium-dependent and endothelium-independent vasodilator responses were investigated in the renal microcirculation of streptozotocin-induced diabetic rats. We measured renal blood flow changes with an electromagnetic flow probe. In addition, the responses of the different segments of the renal microcirculation were evaluated with videomicroscopy using the hydronephrotic kidney technique. Because endothelial cells release different relaxing factors (nitric oxide, prostacyclin and an unidentified endothelium-derived hyperpolarizing factor), responses to acetylcholine were measured before and after treatment with the nitric oxide synthase inhibitor L-NG-nitroarginine methylester HCI (L-NAME) and the cyclooxygenase inhibitor indomethacin. We evaluated with the effect of 5-methyltetrahydrofolate, the active form of folate, on the responses. RESULTS: The L-NAME- and indomethacin-resistant vasodilation to intra-renal acetylcholine was significantly reduced in the diabetic compared with control rats, suggesting impaired endothelium-derived hyperpolarizing factor-mediated vasodilation. The responses to the nitric oxide donor (Z)-1-[-2-(aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-i um-1,2-diolate (DETA-NONOate) and to the K+-channel opener pinacidil were similar in diabetics and controls, indicating intact endothelium-independent vasodilator mechanisms. The contribution of endothelium-derived hyperpolarizing factor to vasodilation induced by acetylcholine was greatest in the smallest arterioles. In diabetic rats, the response to acetylcholine was increasingly impared as vessel size decreased. Defective vasodilation in diabetic kidneys was rapidly normalized by 5-methyltetrahydrofolate. CONCLUSION-INTERPRETATION: Endothelium-derived hyperpolarizing factor-mediated vasodilation is impaired in the renal microcirculation of diabetic rats, in particular in the smallest arteries. Treatment with folate restores the impaired endothelial function in diabetes.

Endothelial dysfunction in diabetes.

Endothelial dysfunction plays a key role in the pathogenesis of diabetic vascular disease. The endothelium controls the tone of the underlying vascular smooth muscle through the production of vasodilator mediators. The endothelium-derived relaxing factors (EDRF) comprise nitric oxide (NO), prostacyclin, and a still elusive endothelium-derived hyperpolarizing factor (EDHF). Impaired endothelium-dependent vasodilation has been demonstrated in various vascular beds of different animal models of diabetes and in humans with type 1 and 2 diabetes. Several mechanisms of endothelial dysfunction have been reported, including impaired signal transduction or substrate availibility, impaired release of EDRF, increased destruction of EDRF, enhanced release of endothelium-derived constricting factors and decreased sensitivity of the vascular smooth muscle to EDRF. The principal mediators of hyperglycaemia-induced endothelial dysfunction may be activation of protein kinase C, increased activity of the polyol pathway, non-enzymatic glycation and oxidative stress. Correction of these pathways, as well as administration of ACE inhibitors and folate, has been shown to improve endothelium-dependent vasodilation in diabetes. Since the mechanisms of endothelial dysfunction appear to differ according to the diabetic model and the vascular bed under study, it is important to select clinically relevant models for future research of endothelial dysfunction.

Off-line analysis of red blood cell velocity in renal arterioles.

Videomicroscopic methods with off-line analysis of microcirculatory parameters by multifunctional computer-assisted image analysis systems have significant advantages for in vivo microvascular research. A limitation of these methods is, however, that red blood cell velocities (V(RBC)) exceeding 2 mm/s cannot be measured using standard video framing rates. In the present study, a high-speed video camera, recording up to 600 frames per second, was incorporated in the set-up, and V(RBC) was measured off-line with the line-shift-diagram method. The aim of this study was to test the reproducibility and validity of the method using a high-speed video camera and to evaluate its applicability in vivo. V(RBC) were measured in arterioles of the split hydronephrotic kidney. The intra- and interindividual variability was small for V(RBC) below 40 mm/s. The validity of the method was tested using the mass conservation principle and found to be at least as good as that of the dual-slit photometric technique. The present approach extends the application of videomicroscopy coupled to image analysis systems to the analysis of high V(RBC).

The role of selectins in glomerular leukocyte recruitment in rat anti-glomerular basement membrane glomerulonephritis.

Leukocytes play a central role in the pathogenesis of anti-glomerular basement membrane glomerulonephritis (anti-GBM GN). Understanding the mechanisms underlying their recruitment in the glomerulus is of critical importance, because this may lead to more specific anti-inflammatory drug design. The requirement for integrins, especially from the beta2 group, and their Ig superfamily counter-receptors has been established, however, the role of selectins remains controversial. An intravital microscopy technique was developed to study concomitantly the glomerular and venular leukocyte kinetics and the hemodynamic alterations in a rat model of anti-GBM GN, induced by injection of 10 mg of nephrotoxic serum (NTS). Histologic studies of the kidney were performed in parallel and urinary protein excretion was measured. The animals received NTS alone or were pretreated with either a monoclonal antibody against the beta2 integrin CD11b (OX42, 4 mg/kg) or fucoidan F7 (FF7, 8 mg/kg), an oligosaccharide that blocks both L- and P-selectin function. Administration of NTS resulted in a time-dependent increase in the number of adherent leukocytes in the glomeruli and a parallel decrease of the perfused glomerular capillary area. Substantial proteinuria was observed. Pretreatment with OX42 significantly attenuated these changes. FF7 almost abolished the rolling of the leukocytes in the venules, thus demonstrating efficient anti-selectin activity. Nevertheless, FF7 had no influence on the glomerular events or on the development of proteinuria. These results confirm that glomerular leukocyte adhesion in anti-GBM GN is CD11b-dependent. However, selectin-mediated interaction between the leukocytes and the glomerular capillary endothelium does not appear to be a prerequisite for leukocyte adhesion in the glomerulus. These results therefore question the potential utility of anti-selectin therapy in the treatment of anti-GBM GN.

Cytokine removal during continuous hemofiltration in septic patients.

A potential application of the continuous renal replacement therapies is the extracorporeal removal of inflammatory mediators in septic patients. Cytokine elimination with continuous renal replacement therapies has been demonstrated in several clinical studies, but so far without important effects on their serum concentrations. Improved knowledge of the cytokine removal mechanisms could lead to the development of more efficient treatment strategies. In the present study, 15 patients with septic shock and acute renal failure were observed during the first 24 h of treatment with continuous venovenous hemofiltration (CVVH) with an AN69 membrane. After 12 h, the hemofilter was replaced and the blood flow rate (QB) was switched from 100 ml/min to 200 ml/min or vice versa. Pre- and postfilter plasma and ultrafiltrate concentrations of selected inflammatory and anti-inflammatory cytokines were measured at several time points allowing the calculation of a mass balance. Cytokine removal was highest 1 h after the start of CVVH and after the change of the membrane (ranging from 25 to 43% of the prefilter amount), corresponding with a significant fall in the serum concentration of all cytokines. The inhibitors of inflammation were removed to the same extent as the inflammatory cytokines. Adsorption to the AN69 membrane appeared to be the main clearance mechanism, being most pronounced immediately after installation of a new membrane and decreasing steadily thereafter, indicating rapid saturation of the membrane. A QB of 200 ml/min was associated with a 75% increase of the ultrafiltration rate and a significantly higher convective elimination and membrane adsorption than at a QB of 100 ml/min. The results indicate that optimal cytokine removal with CVVH with an AN69 membrane could be achieved with a combination of a high QB/ultrafiltration rate and frequent membrane changes.