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Nephrol Dial Transplant (2006) 21: 3606 gene develop extensive calcifications of the vascular system Advance Access publication 26 September 2006 and other soft tissues [2]. However, several clinical observa-tions revealed a positive association between OPG and vascular calcification, the advancement of coronary arterydisease expressed semi-quantitatively and even mortality[3–6]. Some authors suggested that serum OPG may be We thank Stompor et al. for sharing their valuable the marker of low-turnover bone disease, which in turn observations. Indeed, the presence of relations between is a well-recognized risk factor for developing vascular vascular wall properties and markers of bone turnover, and calcification [7–8]. Further studies are needed to clarify the disappearance of these relations in multivariate analysis role of OPG in vascular calcification and atherosclerosis, but are in agreement with our observations. However, it should in our opinion this factor may link these processes with be mentioned that, although vascular stiffness is related bone metabolism. In summary, our study confirms the lack to vascular calcification, it is not synonymous. Neither of an association between aortic stiffness and fetuin-A in Dr Stompor nor we assessed vascular calcifications directly.
end-stage renal disease patients, found previously by Several other factors beyond calcification also influenceaortic stiffness, such as blood pressure, age, etc. In ESRD Hermans et al. [1]. The correlations between PWV and patients, a negative association between serum fetuin-A serum OC and OPG identified in univariate analysis levels and coronary artery calcification (CAC) [1] and heart may indicate the relationship between aortic stiffness and valve calcification [2] was recently observed. Interestingly, in bone turnover. This observation appears to be the first diabetic patients with chronic kidney disease (CKD), the ever in this issue performed exclusively in patients treated association between between fetuin-A and CAC was positive [3].
Thus, vascular calcification in dialysis patients and patients with CKD is a complex, only partially understood This work was financially supported by scientific grant form and sometimes seemingly paradoxical phenomenon. It would the Jagiellonian University No. 501/NKL/80/L.
be of interest to assess the relation between the parametersstudied by Stompor et al. and vascular wall properties in Conflict of interest statement. None declared.
a young dialysis or CKD population. This group has farless traditional cardiovascular risk factors that potentially obscure the association between arterial stiffness and arterial Chair and Department Tomasz Stompo´r1 Marcin Krzanowski1 2Department of Clinical Beata Kus´nierz-Cabala2 Conflict of interest statement. None declared.
3Department of Internal Medicine Malgorzata Stompo´r3 Tomasz Grodzicki3 Academic Hospital Maastricht Jagiellonian University Wladyslaw Sulowicz1 calcification inhibitors in the pathogenesis of vascular calcification 1. Hermans MMH, Brandenburg V, Ketteler M et al. Study on in chronic kidney disease (CKD). Kidney Int 2005; 67: 2295–2304 the relationship of serum fetuin-A concentration with aortic 2. Wang AY, Woo J, Lam CW et al. Associations of serum fetuin- A stiffness in patients on dialysis. Nephrol Dial Transplant 2006; 21: with malnutrition, inflammation, atherosclerosis and valvular calcification syndrome and outcome in peritoneal dialysis 2. Bucay N, Sarosi I, Dunstan CR et al. Osteoprotegerin-deficient patients. Nephrol Dial Transplant 2005; 20: 1676–1685 mice develop early onset osteoporosis and arterial calcification.
3. Mehrotra R, Westenfeld R, Christenson P et al. Serum Genes Dev 1998; 12: 1260–1268 fetuin-A in nondialyzed patients with diabetic nephropathy: 3. Jono S, Ikari Y, Shioi A et al. Serum osteoprotegerin levels are relationship with coronary artery calcification. Kidney Int 2005; associated with the presence and severity of coronary artery disease. Circulation 2002; 106: 1192–1194 4. Kiechl S, Schett G, Wenning G et al. Osteoprotegerin is a risk factor for progressive atherosclerosis and cardiovascular disease.
Circulation 2004; 109: 2175–2180 5. Nitta K, Akiba T, Uchida K et al. Serum osteoprotegerin levels and the extent of vascular calcification in haemodialysis patients.
Nephrol Dial Transplant 2004; 19: 1886–1889 6. Schoppet M, Sattler AM, Schaefer JR, Herzum M, Maisch B, Advance Access publication 24 June 2006 Hofbauer LC. Increased osteoprotegerin serum levels in menwith coronary artery disease. J Clin Endocrinol Metab 2003; 88: Pharmacokinetics and dosage adjustment of oseltamivir and zanamivir in patients with renal failure 7. Coen G, Ballanti P, Balducci A et al. Serum osteoprotegerin and renal osteodystrophy. Nephrol Dial Transplant 2002; 17:233–238 8. Haas M, Leko-Mohr Z, Roschger P et al. Osteoprotegerin and In the last few months, more and more countries in Asia, parathyroid hormone as markers of high-turnover osteodystro- Europe and Africa have reported cases of avian influenza phy and decreased bone mineralization in hemodialysis patients.
in migrating birds as well as in cats and humans. The virus Am J Kidney Dis 2002; 39: 580–586 has expanded its geographical area, being propagated tonew countries, and increasing, as a result, the size of the population at risk. As of 21 April 2006, the World Health Nephrol Dial Transplant (2006) 21:3607 Organization (WHO) has reported 204 confirmed human Although increased drug exposure is not associated with cases of influenza A (H5N1) across nine countries, with 113 poor tolerance, dosage adjustment is recommended for deaths (a 55% mortality rate for identified cases) [1].
patients with CrCl <30 ml/min. For patients with CrCl Chronic renal insufficiency is frequently encountered in between 15 and 30 ml/min (stage 4), a dosage reduction of the general population. In the US adult population, the 50% (75 mg once daily in curative treatment and 75 mg every prevalence of chronic kidney disease is 11%. In this study, other day in prophylactic treatment) is recommended [5].
3.0% had a glomerular filtration rate [estimated with There are no data on the pharmacokinetics and/or the Modification of Diet in Renal Disease (MDRD) prediction tolerance of oseltamivir in patients with CrCl <15 ml/min <80 ml/min/1.73 m2, and in patients on dialysis. It is therefore impossible to 1.73 m2, 0.2% had <30 ml/min/1.73 m2 and 0.2% had provide recommendations for dosage adjustment in those <15 ml/min/1.73 m2 [2].
patients (Table 1). In severe infection, higher doses (150 mg The neuraminidase inhibitors oseltamivir and zanamivir twice a day for adults) and treatment for 7–10 days are are active against H5N1. In the context of epidemia or recommended [3]. If the administration of such doses is pandemia of avian influenza, these two drugs will be necessary, it is recommended to apply the same dosage prescribed to patients presenting a reduction in renal reductions (Table 1). Oseltamivir is generally well-tolerated, function. Clinicians should thus be aware of the pharmaco- but gastrointestinal side effects and dizziness may appear with kinetics and potential dosage adjustments of those drugs in increasing doses, particularly in patients with renal failure.
such patients. According to available data in the literature,we provide guidelines for dosage adjustment of oseltamivirand zanamivir in patients with altered renal function.
Zanamivir is another neuraminidase inhibitor which maybe recommended for the treatment of H5N1 influenza.
H5N1 virus is susceptible to oseltamivir in vitro. Moreover, Topical zanamivir is active in animal models of influenza A oral oseltamivir is active in animal models of influenza A (H5N1) but has not been studied in humans with (H5N1) [3]. However, there is no clear evidence showing that influenza A (H5N1) [3]. Nevertheless, treatment with oseltamivir may be effective in human H5N1 disease. Despite nebulized zanamivir has been recommended in patients the absence of clinical trial, oseltamivir is recommended by with H5N1 infection and with resistance to oseltamivir [6].
the WHO for use in both treatment and prophylaxis of H5N1 The recommended dosage of zanamivir by oral inhalation is infection [3]. The evidence of the effectiveness of oseltamivir 10 mg twice a day for 5 days.
for prophylaxis of H5N1 infection is based on the results of Zanamivir is formulated as a dry powder for oral trials on the prevention of ordinary influenza. The recom- inhalation. Less than 20% of the dose is absorbed mended dose in adults with normal renal function is 75 mg systemically, and 90% of the absorbed drug is excreted twice a day for 5 days for curative treatment and 75 mg once unchanged in urine [7]. In a pharmacokinetic study, the AUC a day for preventive treatment.
was on average increased 2-fold in patients with CrCl Oseltamivir is extensively converted by hepatic esterases to between 25 and 70 ml/min and 3.5-fold in those with CrCl its active metabolite, oseltamivir carboxylate. Neither oselta- <25 ml/min as compared with healthy individuals after single mivir nor oseltamivir carboxylate are substrates for, or doses administered intravenously: 4 mg for patients with inhibitors of, cytochrome P450 isoforms. Renal elimination CrCl between 25 and 70 ml/min and healthy participants, of oseltamivir carboxylate accounts for more than 99% of 2 mg for patients with CrCl< 25 ml/min [8]. There are no the administered dose. Renal clearance (313.3 ml/min) occurs data on the pharmacokinetics of zanamivir after oral through both glomerular filtration and tubular secretion [4].
inhalation in patients with renal failure. However, given the It is therefore suggested that it is necessary to adjust good tolerance after daily intravenous dosages as high as oseltamivir dosage in patients with renal impairment.
1200 mg [8], and the limited systemic absorption after oral Indeed, the pharmacokinetics of oseltamivir are modified in inhalation, the increased drug exposure for patients with patients with renal failure. The clearance of the parent compound and its metabolite decrease proportionally with Therefore, for orally inhaled zanamivir, no dosage adjust- the reduction of creatinine clearance (CrCl). The area under ment is required in patients with renal impairment [5,8] the serum concentration–time curve (AUC) of the active (Table 1). Because the drug is almost not absorbed, it is metabolite was on average increased 10-fold in patients with unlikely to be removed by haemodialysis to a significant severe renal impairment (CrCl <30 ml/min) as compared extent. It may thus be administered before or after the session with individuals without renal impairment [4].
on haemodialysis days without significant influence on its Table 1. Dosing schedule of neuraminidase inhibitors for the treatment and prevention of influenza, in patients with renal insufficiency Creatinine clearance (ml/mn) 75 mg twice daily 10 mg twice daily 75 mg twice daily 10 mg twice daily 75 mg every other day 10 mg twice daily <15 and dialysis 10 mg twice daily NA, not available.
Nephrol Dial Transplant (2006) 21: 3608 pharmacokinetics. Adverse effects with zanamivir comprise creatinine (SCr), monitoring of VCM–serum concentrations nasal and throat discomfort, headache and cough.
is disputable [2]. We retrospectively studied 19 patients(age 51  19 years, 12 women) who had a 50% increase oftheir normal baseline SCr (ARF) during VCM therapy.
Trough serum concentration of VCM was monitored oncethe ARF diagnosis was made and it was >40 mg/ml in allpatients (VCMmax). Initial VCM dosing regime was Chronic renal disease is frequent in the general population.
unchanged up to ARF, when VCM administration was In the case of epidemia or pandemia of avian influenza A stopped. Spearman's correlations between VCMmax and (H5N1), the two neuraminidase inhibitors, oseltamivir and age, duration of therapy (iT), peak SCr, albumin and zanamivir will therefore be used in patients with renal bilirubin were calculated. Results (mean  SD): VCMmax, impairment. Although zanamivir does not necessitate any 83  12 mg/ml (range 50–289); iT, 12  9 days; baseline SCr, adjustment of its dosage in patients with renal failure, because it is not absorbed after oral inhalation, oseltamivir 3.8  7.2 mg/dl.
dosage must be reduced by half in patients with CrCl present in nine patients (47%) and seven (37%) needed between 15 and 30 ml/min and may be used at the usual dose dialysis. Twelve patients worsened and were admitted when CrCl is higher.
to ICU. Concurrent with VCM, eight patients (42%)received another nephrotoxic drug (amphotericin in five).
Conflict of interest statement. None declared.
All the patients had other cause for ARF besides VCM[severe sepsis in 16 (84%)]. Survivors were six (47%), ICAR, Department of Nephrology and in two of them SCr did not return to baseline. There Pitie´-Salpeˆtrie re Hospital Vincent Launay-Vacher was no correlation between VCMmax and any of the evaluated parameters. In conclusion, in order to avoid nephrotoxic levels, even in patients with normal SCr, VCM–serum concentration monitoring should be startedand its dose appropriately adjusted as soon as any potentialfactor for ARF superimposes.
Conflict of interest statement. None declared.
21 April 2006.
2. Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS.
Prevalence of chronic kidney disease and decreased kidneyfunction in the adult US population: Third National Health and Hospital das Clı´nicas Vinı´cius S. Colares Nutrition Examination Survey. Am J Kidney Dis 2003; 41: 1–12 Nephrology Division Rodrigo B. Oliveira 3. The Writing Committee of the World Health Organization (WHO) University of Sa˜o Regina C. R. M. Abdulkader Consultation on Human Influenza A/H5. Avian influenza A Paulo Medical School (H5N1) infection in humans. N Engl J Med 2005; 353: 1374–1385 4. He G, Massarella J, Ward P. Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite Ro 64-0802. Clin Email: [email protected] Pharmacokinet 1999; 37: 47–84 5. Izzedine H, Launay-Vacher V, Deray G. GPR Antiviraux.
Guide de prescription des medicaments chez le patient insuffi- 1. Farber BF, Moellering RC,Jr. Retrospective study of the sant renal. Me´ditions International, Paris: 2003.
toxicity of preparations of vancomycin from 1974 to 1981.
6. de Jong MD, Thanh TT, Khanh TH et al. Oseltamivir resistance Antimicrob Agents Chemother 1983; 23: 138–141 during treatment of influenza A (H5N1) infection. N Engl J Med 2. Iwamoto T, Kagawa Y, Kojima M. Clinical efficacy of 2005; 353: 2667–2672 therapeutic drug monitoring in patients receiving vancomycin.
7. Cass LM, Efthymiopoulos C, Bye A. Pharmacokinetics of zanamivir Biol Pharm Bull 2003; 26: 876–879 after intravenous, oral, inhaled or intranasal administration tohealthy volunteers. Clin Pharmacokinet 1999; 36 [Suppl 1]: 1–11 8. Cass LM, Efthymiopoulos C, Marsh J, Bye A. Effect of renal impairment on the pharmacokinetics of intravenous zanamivir.
Clin Pharmacokinet 1999; 36 [Suppl 1]: 13–9 Advance Access publication 24 July 2006 Associations of chronic kidney disease with themetabolic syndrome in non-diabetic elderly Advance Access publication 21 July 2006 Sir,Chronic kidney disease (CKD) and the metabolic syndrome Nephrotoxicity of vancomycin in patients are worldwide public health problems. Few studies have with normal serum creatinine reported that persons with mildly reduced kidney functionare at greater risk for cardiovascular disease [1], but it remains unclear whether CKD contributes to prevalent The reported rate of nephrotoxicity of vancomycin (VCM) metabolic syndrome in non-diabetic population. In addition, has been 7–16%. It can reach 35% with concurrent there are no studies that have focused on the elderly to aminoglycosides and is associated with serum concentration evaluate the relationship between level of kidney function >40 mg/ml [1]. However, in patients with normal serum and prevalent metabolic syndrome.


Guida alla Terapia Anticoagulante Orale di Medicina Generale componenti della task-force Alessandro Filippi Responsabile del Centro Emostasi e Trombosi Medico di Medicina Generale Divisione di Ematologia SIMG,Società Italiana di Medicina Generale Ospedali Riuniti di Bergamo Area Cardiovascolare Gualtiero Palareti Augusto Zaninelli Presidente della Federazione dei Centri

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