Antibiotics and chronic kidney disease: Dose adjustment update for infectious disease clinical practice.

Antibiotic prescription in chronic kidney disease patients poses a twofold problem. The appropriate use of antibacterial agents is essential to ensure efficacy and to prevent the emergence of resistance, and dosages should be adapted to the renal function to prevent adverse effects. SiteGPR is a French website for health professionals to help with prescriptions to chronic kidney disease patients. A working group of infectious disease specialists and nephrology pharmacists reviewed the indications, dosing regimens, administration modalities, and dose adjustments of antibiotics marketed in France for patients with renal failure. Data available on the SiteGPR website and detailed in the present article aims to provide an evidence-based update of infectious disease recommendations to health professionals managing patients with chronic kidney disease.

Anticoagulants in frail patients. Seven situations at risk.

In the case of venous thromboembolic disease (VTE), physicians are facing more and more difficulties in managing VTE and their treatment in frail patients. These patients could present several risk situations such as: chronic kidney disease (CKD), underweight or malnourished, falls, cognitive impairment, multi-medicated patients, cancer and pregnancy. Guidelines typically recommend anticoagulation. There are multiple challenges in the safe use of anticoagulation in frail patients, including bleeding risk, monitoring and adherence, and polypharmacy. The objective of this review is to explore these at-risk situations and to suggest adequate anticoagulation therapy, when possible, in each of these complex situations.

Renal function and venous thromboembolic diseases.

Anticoagulant agents have been approved by international regulatory agencies to prevent and treat venous thromboembolism (VTE). However, chronic kidney disease (CKD) is: (1) highly frequent in VTE patients; (2) strongly linked to VTE; and (3) a risk factor for cardiovascular morbidity/mortality and fatal pulmonary embolism. Therefore, an increasing number of patients are presented with CKD and VTE and more and more physicians must face the questions of the management of these patients and that of the handling of anticoagulant agents in CKD patients because of the pharmacokinetic modifications of these drugs in this population. These modifications may lead to overdosage and dose-related side effects, such as bleeding. It is therefore necessary to screen VTE patients for CKD and to modify the doses of anticoagulants, if necessary.

Renal effects of molecular targeted therapies in oncology: a review by the Cancer and the Kidney International Network (C-KIN).

A number of cancer therapy agents are cleared by the kidney and may affect renal function, including cytotoxic chemotherapy agents, molecular targeted therapies, analgesics, antibiotics, radiopharmaceuticals and radiation therapy, and bone-targeted therapies. Many of these agents can be nephrotoxic, including targeted cancer therapies. The incidence, severity, and pattern of renal toxicities may vary according to the respective target of the drug. Here, we review the renal effects associated with a selection of currenty approved targeted cancer therapies, directed to vascular endothelial growth factor or VEGF receptor(s) (VEGF/VEGFR), epidermal growth factor receptor (EGFR), human epidermal growth factor receptor2 (HER2), BRAF, anaplastic lymphoma kinase (ALK), programmed cell death protein-1 or its ligand (PD-1/PDL-1), receptor activator of nuclear factor kappa-B ligand (RANKL), and mammalian target of rapamycin (mTOR). The early diagnosis and prompt treatment of these renal alterations are essential in the daily practice where molecular targeted therapies have a definitive role in the armamentarium used in many cancers.

Intermittent dosing of aromatase inhibitors (AI) to improve tolerance in postmenopausal women: a rationale for future clinical studies.

A significant proportion of post-menopausal, patients treated with AI reports side-effects, especially bone pain. In such patients, the difficulties to treat pain and to clearly identify its causes may lead to treatment discontinuation. Ageing is associated with physiological modifications that may impair drug pharmacokinetics (PKs). The elimination can be altered, with decreased drug clearance (CL), resulting in an increased exposure to the drug, reflected by increased AUCs. The reported increases in AI exposure being around 50 %, an intermittent dosing schedule of 1 administration every other day could result in a similar drug exposure as compared to the usual daily schedule.

[Drug dosage adjustment in patients with renal impairment and evaluation of renal function: focus on the cardiologic patients]. / Adaptation posologique chez les patients insuffisants rénaux chroniques et évaluation de la fonction rénale : focus sur les patients de cardiologie.

Chronic kidney disease is a progressive disease which has become a real public health issue. In patients with renal disease, drugs pharmacokinetics may be altered. The handling of drugs requires a special attention in these patients. Indeed, there is a risk of accumulation and drug overdose if dosage is not adjusted to the stage of renal insufficiency. Thus, to achieve a dosage adjustment knowing how to evaluate renal function is absolutely necessary. Different formulae are available including the Cockcroft and Gault formula aMDRD and CKD-EPI. In patients with cardiac issues, it appears that the CKD-EPI formula is that of choice in terms of clinical risk stratification. However, some summaries of product characteristics (SmPC) of drugs used in cardiology, such as Dabigatran(®), mention the need to use the Cockcroft-Gault, less accurate than aMDRD and CKD-EPI, in order to adjust the dose in patients with impaired renal function. Standardization of recommendations is necessary to limit disparities in dosage and drug exposure according to the formula. SmPCs however, are not the only source of information to obtain data on the use of drugs in the renal insufficient population. Some other information sources exist, reliable, updated and easily accessible.

Management of anticancer treatment in patients under chronic dialysis: results of the multicentric CANDY (CANcer and DialYsis) study.

BACKGROUND: One million people worldwide benefit from chronic dialysis, with an increased rate in Western countries of 5% yearly. Owing to increased incidence of cancer in dialyzed patients, the management of these patients is challenging for oncologists/nephrologists. PATIENTS AND METHODS: The CANcer and DialYsis (CANDY) retrospective multicenter study included patients under chronic dialysis who subsequently had a cancer (T0). Patients were followed up for 2 years after T0. Prescriptions of anticancer drugs were studied with regard to their renal dosage adjustment/dialysability. RESULTS: A total of 178 patients from 12 institutions were included. The mean time between initiation of dialysis and T0 was 30.8 months. Fifty patients had received anticancer drug treatment. Among them, 72% and 82% received at least one drug needing dosage and one drug to be administered after dialysis sessions, respectively. Chemotherapy was omitted or prematurely stopped in many cases where systemic treatment was indicated or was often not adequately prescribed. CONCLUSIONS: Survival in dialysis patients with incident cancer was poor. It is crucial to consider anticancer drug treatment in these patients as for non-dialysis patients and to use current available specific drug management recommendations in order to (i) adjust the dose and (ii) avoid premature elimination of the drug during dialysis sessions.

Thrombosis, cancer and renal insufficiency: low molecular weight heparin at the crossroads.

BACKGROUND: Venous thromboembolism (VTE) and renal insufficiency are common in cancer patients. Prompt treatment is necessary to reduce the high rates of VTE-related mortality and morbidity. VTE prophylaxis is underused in cancer patients. We review current recommendations for the treatment and prevention of VTE in cancer patients and discuss low molecular weight heparin (LMWH) use in cases of renal failure. DESIGN: This study is a retrospective literature review. RESULTS: There are few published recommendations for LMWH use in cancer patients with renal insufficiency. Treatment guidelines largely follow recommendations for other patients with renal failure. Enoxaparin therapy is complicated by the need for regular monitoring of renal function and anti-Xa levels and for dosage adjustment to prevent bleeding. Few data are available to support the systematic use of dalteparin. Tinzaparin is least likely to bioaccumulate in patients with renal failure. CONCLUSION: VTE is the second most common cause of death in cancer patients. Renal insufficiency is present in 50-60 % of cancer patients. Data from renal patients suggest that tinzaparin may be safe and effective for VTE treatment and prevention in cancer patients with renal failure.

Cancer and renal insufficiency results of the BIRMA study.

BACKGROUND: half of anticancer drugs are predominantly excreted in urine. Dosage adjustment in renal insufficiency (RI) is, therefore, a crucial issue. Moreover, patients with abnormal renal function are at high risk for drug-induced nephrotoxicity. The Belgian Renal Insufficiency and Anticancer Medications (BIRMA) study investigated the prevalence of RI in cancer patients, and the profile/dosing of anticancer drugs prescribed. METHODS: primary end point: to estimate the prevalence of abnormal glomerular filtration rate (GFR; estimated with the abbreviated Modification of Diet in Renal Disease formula) and RI in cancer patient. Secondary end point: to describe the profile of anticancer drugs prescribed (dose reduction/nephrotoxicity). Data were collected for patients presenting at one of the seven Belgian BIRMA centres in March 2006. RESULTS: a total of 1218 patients were included. The prevalence of elevated SCR (> or =1.2 mg per 100 ml) was 14.9%, but 64.0% had a GFR<90 ml min(-1) per 1.73 m(2). In all, 78.6% of treated patients (n=1087) were receiving at least one drug needing dosage adjustment and 78.1% received at least one nephrotoxic drug. In all, 56.5% of RI patients receiving chemotherapy requiring dose reduction in case of RI did not receive dose adjustment. CONCLUSIONS: the RI is highly frequent in cancer patients. In all, 80% of the patients receive potentially nephrotoxic drugs and/or for which dosage must be adjusted in RI. Oncologists should check the appropriate dose of chemotherapeutic drugs in relation to renal function before prescribing.

Proposal for dosage adjustment and timing of chemotherapy in hemodialyzed patients.

BACKGROUND: The increased incidence of malignancies in patients with chronic renal failure has been discussed since the mid-70s. On the other hand, the high frequency of chronic renal insufficiency among cancer patients has been recently assessed in the Insuffisance Rénale et Médicaments Anticancéreux Study which demonstrated a prevalence as high as 50%-60% of the patients for all stages of kidney disease. Furthermore, the incidence of end-stage renal disease is growing worldwide and so is the number of patients on chronic dialysis, hemodialysis (HD) for the large majority of them. As a result, the question of cytotoxic drug handling in those patients in terms of dosage adjustment and time of administration regarding the dialysis sessions needs to be addressed to optimize cytotoxic drug therapy in those patients. METHODS: We reviewed the international literature on the pharmacokinetics, efficacy, tolerance and dosage adjustment of cytotoxic drugs used to treat solid tumor patients and when available, specific literature on HD cancer patients. RESULTS: From these data, dosing recommendations are given for the most prescribed cytotoxic drugs in clinical practice. CONCLUSIONS: Dosage adjustments are often necessary in HD cancer patients. These adaptations have to be carefully carried out to optimize drug exposure, ensure efficacy and reduce the risk of side-effects.

[Description of erlotinib-related skin effects management in France. Results of the PRECEDE study]. / Prise en charge des effets dermatologiques sous erlotinib. Résultats de l'étude PRECEDE.

INTRODUCTION: Dermatological effects are among the most frequent side-effects in patients receiving erlotinib (Tarceva). However, there no official recommendations on the preventive or curative management of those erlotinib-related skin effects (ERSE). The "Prise En Charge des Effets Dermatologiques sous Erlotinib" (PRECEDE) study was designed to study how ERSE are being managed in France. MATERIAL AND METHODS: The PRECEDE study is an observational retrospective study which included every nonsmall cell lung cancer patients treated with erlotinib in seven cancer centers in France from January 2005 to December 2007. Data related to preventive or curative treatment of ERSE were collected from the medical files of the patients. RESULTS: Two hundred and thirty-four patients were included; 48.7% of them had been delivered information on the potential occurrence of ERSE and 15.8% of those 234 patients had had prescription of drugs to be taken in case of ERSE, while 65.0% presented with ERSE which resolved in the majority of cases (86.2% of the patients), either spontaneously or under treatment. In the 85 patients in whom treatment was successful, 178 drug prescriptions comprising 35 different drugs were recorded. CONCLUSION: ERSE are frequent but regress in most cases, spontaneously or under treatment. However, there is still a wide variety of drugs used. This demonstrates that there is a need for recommendations on the management of ERSE in order to prevent and treat this erlotinib-related effect.

Kidney disease in RA patients: prevalence and implication on RA-related drugs management: the MATRIX study.

OBJECTIVES: The prevalence of kidney disease (KD) indicators together with the profile of RA drugs prescribed in RA patients was investigated in the MATRIX study (MeThotreXate And Renal Insufficiency). METHODS: Renal function (RF) was assessed using Cockcroft-Gault (CG) and abbreviated Modification of Diet in Renal Disease (aMDRD) study formulae. RESULTS: Serum creatinine (SCr) was normal in 81.4% of the 129 patients included. According to the National Kidney Foundation (NKF) classification, the distribution by stage of KD was, using the aMDRD and CG formulae, as follows: stage 1: 11.3% and 11.4%; stage 2: 20.0% and 20.3%; stage 3: 15.0% and 24.1%; stage 4: 0% and 1.3%; stage 5: 0%. Proteinuria, haematuria and leucocyturia were observed in 16%, 17% and 20% of the patients, respectively. Using the aMDRD and CG formulae, 36% and 38% of the prescriptions made in patients with glomerular filtration rate (GFR) <60 ml/min required a dosage adjustment. Among the patients with GFR <60 ml/min, 83-90% received at least one drug that required a dosage adjustment and 67-70% received at least one drug that was potentially nephrotoxic, according to aMDRD or CG formulae, respectively. Five (50%) and 8 (47%) patients did not have appropriate MTX dosage adjustment according to their stage of KD with aMDRD or CG formulae, respectively. CONCLUSION: Systematic estimation of RF with CG or aMDRD formulae and urine dipstick are necessary in RA patients. In patients with KD at high risk for drug toxicity, dosage should be adapted to RF.

[Pharmacokinetics of amprenavir in HIV-1 patients with renal insufficiency]. / Pharmacocinétique de l'amprénavir chez deux patients infectés par le VIH-1 et présentant une insuffisance rénale sévère et terminale.

Amprenavir is an HIV-1 protease inhibitor which is hepatically metabolized (>80%) with a low renal elimination. It has thus been suggested that no dosage adjustment is necessary in patients with renal dysfunction. However, no data are available on the pharmacokinetics of amprenavir in patients with renal insufficiency. We report on the pharmacokinetics of amprenavir in two HIV patients with severe and end-stage renal insufficiency. Amprenavir pharmacokinetics did not differ in our patients as compared with normal renal function subjects. Furthermore, amprenavir was not dialysable (FHD<25%). As a result, the drug may be administered at its normal dose in patients with renal failure, even when severe. In dialysis patients, amprenavir may be administered before or after the session.

Renal insufficiency in elderly cancer patients: International Society of Geriatric Oncology clinical practice recommendations.

BACKGROUND: Elderly cancer patients commonly have renal function decline. This warrants particular caution during the administration of renally excreted cancer drugs or those with established nephrotoxicity. DESIGN: An International Society for Geriatric Oncology task force was formed to discuss treatment recommendations for this group of patients. RESULTS: Before drug therapy, the assessment and optimization of hydration status and evaluation of renal function is required. Serum creatinine alone is insufficient as a means of evaluating renal function, and creatinine clearance should at least be calculated in every patient by the abbreviated modification of diet in renal disease or Cockcroft-Gault equations. In the extremes of obesity and cachexia and at very high and low creatinine values, no single tool is really accurate. In these patients, the best estimate of glomerular filtration rate is provided by direct methods such as (51)Cr-EDTA or inulin measurement. Within each drug class, preference may be given to agents less likely to be influenced by renal clearance, which are minimally nephrotoxic, or for which appropriate methods of prevention for renal toxicity exist. Coadministration of known nephrotoxic drugs should be avoided or minimized. CONCLUSIONS: Future trials should be designed to present data in a way that allows evaluation of the contribution of renal function to toxicity and efficacy.