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Background In hemodialysis patients, post-dialysis treatment with intravenous antibiotics permits even severe infections to be managed on an outpatient basis. Cefepime is a fourth-generation cephalosporin with a broad spectrum of action in monotherapy. We report on the pharmacokinetics of cefepime in post-dialysis therapy. Methods Since June 2012, twelve infections were treated with post-dialysis cefepime in 9 patients on high-flux hemodialysis. The initial post-dialysis dose of cefepime was approximately 15 mg/kg. The following doses were adapted according to the trough serum levels obtained before the subsequent dialysis in order to be above the EUCAST breakpoints for susceptible organisms and above the MIC90. Residual plasma concentrations were determined before (n = 30) and after (n = 17) dialysis by liquid chromatography–mass spectrometry. Results Overall, the mean ± SD dose of cefepime was 920 ± 270 mg (14.5 ± 5.1 mg/kg), but it was significantly lower before the 48 h interval (775 ± 210 mg or 12.7 ± 4.5 mg/kg) compared to the 72 h interval (1125 ± 225 mg or 17.2 ± 4.9 mg/kg) (p 1 mg/l) with the exception of Pseudomonas aeruginosa (>8 mg/l). Cefepime concentrations were higher in anuric patients compared to those with preserved diuresis (15.6 ± 3.5 vs 9.25 ± 3.6 mg/l; p

BACKGROUND: Hyperhomocysteinaemia has been identified as an independent cardiovascular risk factor and is found in more than 85% of patients on maintenance haemodialysis. Previous studies have shown that folic acid can lower circulating homocysteine in dialysis patients. We evaluated prospectively the effect of increasing the folic acid dosage from 1 to 6 mg per dialysis on plasma total homocysteine levels of haemodialysis patients with and without a history of occlusive vascular artery disease (OVD). METHODS: Thirty-nine stable patients on high-flux dialysis were studied. Their mean age was 63 +/-11 years and 17 (43%) had a history of OVD, either coronary and/or cerebral and/or peripheral occlusive disease. For several years prior to the study, the patients had received an oral post-dialysis multivitamin supplement including 1 mg of folic acid per dialysis. After baseline determinations, the folic acid dose was increased from 1 to 6 mg/dialysis for 3 months. RESULTS: After 3 months, plasma homocysteine had decreased significantly by approximately 23% from 31.1 +/- 12.7 to 24.5 +/- 9 micromol/l (P = 0.0005), while folic acid concentrations had increased from 6.5 +/- 2.5 to 14.4+/-2.5 microg/l (P < 0.0001). However, the decrease of homocysteine was quite different in patients with and in those without OVD. In patients with OVD, homocysteine decreased only marginally by approximately 2.5% (from 29.0 +/- 10.3 to 28.3 +/- 8.4 micromol/l, P = 0.74), whereas in patients without OVD there was a significant reduction of approximately 34% (from 32.7+/-14.4 to 21.6+/-8.6 micromol/l, P = 0.0008). Plasma homocysteine levels were reduced by > 15% in three patients (18%) in the group with OVD compared with 19 (86%) in the group without OVD (P = 0.001), and by > 30% in none of the patients (0%) in the former group compared with 13 (59%) in the latter (P = 0.001). CONCLUSIONS: These results indicate that the homocysteine-lowering effect of folic acid administration appears to be less effective in haemodialysis patients having occlusive vascular disease than in those without evidence of such disease.

The prescription of multivitamin supplements for dialysis patients is routine practice, but the doses prescribed differ greatly from one dialysis center to another. Few data are available concerning long-term vitamin supplementation and its effects on patients either on high-flux hemodialysis or receiving postdialysis supplementation. For several years, we have systematically prescribed to our patients an oral postdialysis multivitamin supplement containing thiamine hydrochloride 100 mg, riboflavin 20 mg, pyridoxine hydrochloride 50 mg, folic acid 6 mg, and ascorbic acid 500 mg. The aim of this study was to perform a cross-sectional long-term evaluation of the vitamin levels in patients who received this vitamin supplement for at least 12 months. We also were interested in investigating the plasma oxalic acid and total homocysteine levels associated with the long-term prescription of these vitamin supplements. Thirty-three patients on high-flux dialysis were studied. Vitamin levels and/or vitamin-dependent enzymatic activities were within the normal range (N) in all patients. The mean results (+/-SD) were plasma ascorbic acid 13.6 +/- 6.4 mg/L (N4), plasma folate 14.1 +/- 1.1 microg/L (N3), for vitamin B1, alpha-ETK 1.02 +/- 0.02 (N1.18) and ETKo 100 +/- 13 U/L (N70), for vitamin B2, alpha-EGR 1.00 +/- 0.07 (N1.52) and EGRo 1282 +/- 213 U/L (N672), and for vitamin B6, alpha-EGOT 1.34 +/- 0.10 (N1.8) and EGOTo 380 +/- 84 U/L (N228). Plasma oxalic acid was higher than normal in all patients (mean = 61 +/- 15 micromol/L, N33). However, all patients had oxalic acid levels within the range reported in the literature for patients not taking extra ascorbic acid. Mean total homocysteine was 24 +/- 8 micromol/L with only 4 patients (12%) having normal levels (N15). In conclusion, the postdialysis supplement given provides adequate vitamin levels in almost all patients in the long term. Postdialysis prescription allows an optimal compliance with the treatment, is well accepted by the patients, and is cost-effective.

QUESTIONS UNDER STUDY Diagnosis of acute kidney injury (AKI) relies on measurement of serum creatinine (SCr). SCr is a late marker of impaired renal function. Urinary Neutrophil Gelatinase-Associated Lipocalin (uNGAL) has given encouraging results for an early and sensitive detection of AKI. This cohort study was conducted (1) to assess the value of uNGAL as early marker of contrast-induced AKI (CI-AKI) in unselected patients undergoing percutaneous coronary procedure (PCP) and (2) to investigate whether uNGAL levels correlate with the volume of contrast medium (CM) used during the procedure. METHODS We enrolled 244 consecutive adult patients undergoing PCP done with the low-osmolar CM Iomeprolum (median volume of CM 122 [88-168] ml per procedure). uNGAL was measured at its peak with a standardised clinical laboratory platform (ARCHITECT uNGAL assay, Abbott). RESULTS Overall, the post-PCP uNGAL levels were extremely low in our cohort with a median value of 7.7 [4.0-14.5] ng/ml (N ≤132 ng/ml). Twenty-five (10%) patients developed CI-AKI according to the classical diagnostic criteria (≥25% or ≥44.2 µmol/l increase in SCr) and 8 (3.3%) patients according to the AKIN criteria. Regardless of the definition considered, uNGAL levels did not significantly differ in patients with or without CI-AKI. Similarly, we found no significant correlation between the volume of CM used and the post-PCP uNGAL levels (r = -0.11). CONCLUSIONS In a large cohort of unselected adult patients, uNGAL measured four to six hours after PCP was ineffective to predict the risk of CI-AKI and did not correlate with the volume of CM used during the procedure.

Urea kinetic modeling: An in vitro and in vivo comparative study. The urea kinetic model (UK) and the direct dialysis quantification method based on dialysate collection (DDQ) were used to determine the urea distribution volume (V) identified with the total body water and the urea generation rate (G) for different dialysis times, both in vivo during short hemodialysis (N = 20) and in vitro using an experimental single-pool urea system (N = 10). Both UK and DDQ allowed a satisfactory in vitro estimation of V and G for all dialysis times. On the other hand in vivo V and G estimations by both methods showed an increase of more than 50% between the determinations performed after 30 minutes of dialysis and at the end of dialysis. Our theoretical analysis shows that the in vivo changes of V are compatible with those expected for a two-compartment system in which one compartment is cleared faster than the other. Furthermore, given that urea is allowed to equilibrate in the body at the end of dialysis, DDQ permits an accurate estimate of V, G and PCR even for short hemodialysis, which UK does not.

Background. The prevalence and significance of higher than normal cardiac troponin I (cTnI) levels in asymptomatic chronic hemodialysis (HD) patients remains a source of discussion. The aim of the present study was to evaluate the prevalence of higher than normal cTnI levels in asymptomatic HD patients, as determined by the last generation of immunoassay, and to perform further cardiological investigations in those patients with persistently elevated cTnI levels. Methods. All chronic HD patients in our center who had exhibited no symptoms of coronary artery disease (CAD) during the previous four weeks were screened. cTnI levels were determined before dialysis in all patients using the last generation AccuTnI™ assay (UniCel DxI 800, Beckman Coulter). The cTnI levels of those patients with elevated cTnI at the screening evaluation were then measured monthly for six months. We were thus able to identify a group of patients with persistently elevated cTnI levels (> 3 consecutive months) who subsequently underwent cardiac echography and dipyridamole-exercise (D-E) thallium testing. If stress myocardial ischemia was detected, a coronary angiography was then performed. Results. Fifty patients (32 males) were included: mean age 62.8 ± 13.6 years, 20 (40%) with a history of CAD, and 21 (42%) diabetic. At the initial screening, the mean cTnI concentration was 0.05 ± 0.06 μg/L and the cTnI levels were higher than normal (> 0.09 μg/L) in six patients (12%). In the follow-up, the cTnI normalized immediately in two patients but remained persistently elevated (range, 0.10–0.48 μg/L) in four (8%). These four patients (all males, one diabetic) had a mean age of 70.2 ± 6.6 years, and all had heart failure with a history of severe CAD with previous myocardial infarction (n = 4), coronary stenting (n = 3), and/or bypass (n = 2). D-E thallium imaging showed reversible myocardial ischemia in all. The stress ischemia involved one to four cardiac segments and was slight to moderate in three patients and severe in the diabetic patient. A coronary angiogram was performed in all patients, and showed lesions of variable severity: severe three-vessel CAD with severe systolic dysfunction in two patients (including the diabetic), and non-critical/ peripheral coronary stenosis in the other two. Conclusions. Among the asymptomatic HD patients in our center, we identified four (8%) with persistently elevated cTnI levels, as determined using the last generation AccuTnI™ assay. All of them had a history of severe CAD with heart failure and exhibited reversible myocardial ischemia upon D-E thallium imaging; coronary angiography revealed coronary lesions of variable severity. Overall, our data indicate that persistent low-grade cTnI elevation occurs in HD patients having longstanding severe cardiac disease, but, from our data, it is difficult to reach a conclusion as to the best clinical approach for this group of patients.

Previous studies reported cardiac troponin I (cTnI) and T (cTnT) levels to be higher than normal in a significant proportion of asymptomatic chronic hemodialysis (HD) patients without evidence of acute myocardial injury. We have therefore evaluated in such patients the accuracy of cTnI and cTnT determinations measured with last generation assays. Fifty chronic HD patients (34 males) without symptoms of acute myocardial ischemia were studied. Their mean age (+/-SD) was 64.4+/-12.7 years, 22 patients (44%) had an history of cardiac ischemic disease and 19 (38%) were diabetics. Serum cardiac markers were measured with last generation assays before and after a single HD session and in a control group including 30 hospitalized patients without renal failure. The cTnI were determined with Dimension RxL "Improved method" assay (Dade Behring), the cTnT with Elecys "Third generation" assay (Roche Diagnostics) and the creatine kinase (CK) with Integra (Roche Diagnostics). The cTnI were also simultaneously determined with the assay previously used at our institution (Dimension RxL, Dade Behring), indicated as old-method-cTnI. With the last generation assay only 1 patient (2%) had elevated cTnI (0.1 microg/l) in the study group compared to none in the control group (P=NS). Instead, with the old-method-cTnI assay 11 patients (22%) had elevated (0.3 microg/l) predialysis cTnI levels (P0.01 compared to the "Improved method" assay). The predialysis cTnT levels were higher than normal (0.1 microg/l) in 23 patients (46%), compared to none in the control group (P0.01). The CK levels were elevated (170 IU/L) in 4 dialysis patients (8%) compared to one (3,3%) in the control group (P=NS). The cTnT levels slightly but non-significantly diminished during dialysis (from 0.102+/-0.070 to 0.085+/-0.067 mug/l, P=NS), while in the same time no changes were observed for cTnI and CK levels. In conclusion, the specificity of cTnI determinations in HD patients is greatly improved by the last generation assay (from 78 to 98%), and is actually similar to that observed in a population with normal renal function. Therefore cTnI, determined with the last generation assay used in the present study, can be reliably used for the diagnosis of acute coronary syndromes in HD patients. Instead, cTnT levels remain higher than normal in a significant proportion of asymptomatic HD patients (46%) and the reasons for this fact need further investigations.

Calciphylaxis, also called calcific uraemic arteriolopathy, is a rare disease characterized by medial calcification of the small arteries and ischaemia of the subcutaneous tissue, often leading to necrosis of subcutaneous fat and skin. It affects mainly women with chronic renal insufficiency and/or obesity. According to recent studies, calciphylaxis seems to occur more frequently than previously believed, with an incidence of 1% per year [1] and a prevalence of 4% in dialysis patients [2]. The pathogenesis of calciphylaxis is poorly understood and its treatment is largely empirical and somewhat controversial. Recent studies have emphasized the crucial role of a multidisciplinary therapeutic approach focusing on the correction of the underlying abnormalities of the calcium and phosphorus plasma concentrations (using non-calcium-containing phosphate binders), local wound care with debridement of necrotic tissues and aggressive treatment of infectious complications [3]. The utility of parathyroidectomy, corticoid therapy and hyperbaric oxygen therapy remains controversial. However, despite intensive combined treatments, the prognosis of calciphylaxis remains poor: the overall 1 year survival is 45% and the 5 year survival is 35%, with a relative risk of death of 8.5 compared with other dialysis patients [4]. Bisphosphonates have a powerful inhibitory effect on osteoclast activity and bone resorption and are largely used in the treatment of osteoporosis, tumoral hypercalcaemia and Paget’s disease. Some previous studies have shown that bisphosphonates also have beneficial effects on the evolution of experimental calciphylaxis [5,6] and tumoral calcinosis with systemic inflammatory response [7]. According to these latter observations, we decided to treat a woman with chronic renal failure and rapidly worsening calciphylaxis with pamidronate. This treatment brought a spectacular and rapid improvement of the patient’s clinical condition and a rapid decrease of the inflammatory syndrome. We report this case, which is, to our knowledge, the first one in which a bisphosphonate has been used to treat a patient with calciphylaxis.

We retrospectively studied the prevalence, histologic features, clinical correlations, and long-term outcome of the intrarenal vascular lesions of lupus nephritis (LN) in a series of 169 renal biopsies performed between 1980 and 1994 in 132 patients with systemic lupus erythematosus. The most common vascular lesions were nonspecific sclerotic changes, found in 37% of the biopsies (24% if only the cases with moderate to severe changes are considered). The other common vascular lesions were "immunoglobulin microvascular casts," found in 24% of the biopsies. Vasculitis and thrombotic microangiopathy were rare lesions and were seen in only 4 (2.4%) and 1 (0.6%) cases, respectively. Isolated sclerotic vascular changes were present in biopsies from older patients with a longer duration of LN, compared with the group with no vascular lesions, and were associated with a significantly higher prevalence of hypertension. Overall, however, the long-term renal and patient survival of this group did not differ significantly from that of the patients without vascular changes. Immunoglobulin microvascular casts (IMCs) ("lupus vasculopathy") were characterized by the presence of immunoglobulin deposition within the glomerular capillaries and small arterioles. In the present study we extensively investigated the morphologic and immunologic features of this lesion. The lesions were notable for the absence of endothelial or parietal vascular lesions and of fibrin, platelets, and leukocytes, which indicates that thrombosis is not involved in the vascular obstruction. According to our data immunoglobulin precipitation in the microvasculature seems to play a central role in the pathogenesis of this lesion, which is why we propose the term "immunoglobulin microvascular casts." In general, IMCs were associated with the most severe and active forms of diffuse proliferative lupus nephritis (World Health Organization [WHO] class IV). However our data show that, in contrast to previous studies, the long-term outcome of patients with IMCs is not worse than that of other patients with class IV LN. It may even be somewhat better, suggesting that this type of lesion may reverse with immunosuppressive therapy. In addition, we did not find any association between the presence of IMCs and the lupus anticoagulant, IgG anticardiolipin antibodies, or extrarenal vascular manifestations. Concerning vasculitis and thrombotic microangiopathy, our results confirm that their occurrence is quite rare in-lupus nephritis. The outcome of our 4 patients with vasculitis was not particularly poor, which could be related to early and/or aggressive treatment. Taken as a whole, our data confirm that the presence of active and severe forms of diffuse proliferative LN (WHO class IV) carries a worse prognosis compared with the other forms of LN. In our study, and in agreement with previous reports (23), the long-term renal survival of patients with class IV LN was significantly worse than that of patients with other forms of LN, with a 10-year renal survival of 70% compared with 85%, respectively. However our data do not support the conclusions of some previous studies that the presence of intrarenal vascular lesions is a marker of poor renal prognosis in lupus nephritis. More precisely, our data show that the somewhat poorer renal outcome observed in patients with IMCs is related to the fact that in most cases these lesions are associated with class IV lupus nephritis, and not related to the presence of the vascular lesion per se.

Water soluble vitamins in chronic hemodialysis patients and need for supplementation. Forty-three patients on chronic hemodialysis who before the present study had only received a low-dose supplement of folic and ascorbic acid were studied prospectively for one year. After baseline values were obtained in month one, increasing doses of postdialysis vitamin supplements were prescribed for the vitamins which were found to be insufficient in order to determine the minimal amount of oral postdialysis supplement necessary to normalize vitamin levels. According to our results no systematic supplement was indicated for biotin, riboflavin or vitamin B12. For folic acid and vitamin C, supplementation with lower doses than those prescribed in many dialysis units allowed optimal vitamin levels in the majority of patients; 2 to 3 mg/week (300 to 400 µg/day) of folic acid and of 1000 to 1500 mg/week (150 to 200 mg/day) of vitamin C was considered sufficient. A severe pyridoxine deficiency was present in most (> 80%) unsupplemented patients, either as judged by pyridoxal-5-phosphate determinations in plasma or determination of specific enzyme activation in erythrocytes (EGOTo and α-EGOT); a postdialysis supplement of at least 100 to 150 mg/week of pyridoxine hydrochloride (> 15 to 20 mg/day) corrects this deficiency. The activity of the thiamine-dependent enzyme transketolase in erythrocytes (ETKo) was insufficient in 35% and marginal in 21% of the patients, while whole blood thiamine determined simultaneously in 10 of the ETKo-deficient patients was within the normal range. These results suggest that in uremia insufficient transketolase activity may be related to inhibition of the enzymatic system rather than to true vitamin deficiency. On a long-term basis a supplement of 200 to 300 mg/week of thiamine hydrochloride (30 to 45 mg/day) restored ETKo to satisfactory levels in most patients; whether this supplement is to be recommended warrants further studies.