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Introduction: The French National Authority for health recommends that the adjustment of the dosage of drugs in patients with renal insufficiency be carried out on the basis of an estimate of renal function using the Cockcroft-Gault formula, while the estimation of the glomerular filtration rate using the Modification of Diet in Renal Disease or CKD-EPI formula is recommended for the diagnosis and monitoring of renal insufficiency. The argument put forward is that the recommendations for dosage adjustment of the summaries of product characteristics would have been established on the basis of the use of this formula. Service ICAR aimed at verifying the evidence supporting this argument., Methods: In all, 2447 summaries of product characteristics were analyzed to identify the renal function criterion specified for dose adjustment recommendations. When no formulas were found in the summary of product characteristics, the firms were contacted to obtain information on renal function estimation methods used in developmental studies. Their responses were analyzed., Results: Of the 2447 summaries of product characteristics studied, 438 (17.9%) propose a dosage adjustment in case of renal insufficiency. No formula is mentioned in the summarie of product characteristics for 90.0% of them. The Cockcroft-Gault and Modification of Diet in Renal Disease/CKD-EPI formulas are found in 8.7% and 0.7% respectively of these 438 summaries of product characteristics. After contacting pharmaceutical companies and analysis of the data available in the studies on which the summaries of product characteristics were based, the information cannot be found for 63.0% of the summaries of product characteristics, in spite they mention the need to adjust the dosage in case of renal insufficiency., Conclusion: The majority of summaries of product characteristics do not mention the Cockcroft-Gault formula and in the majority of cases it is not possible to identify the formula or technique used in the studies on which is based the reference to dosage adjustment in the summarie of product characteristics. In addition, there are discrepancies between the wording of the summaries of product characteristics and the data from development studies. The use of Cockcroft-Gault for dosage adjustment is to be questioned, especially since the Isotope-dilution mass spectrometry, or IDMS, standardization of creatinine dosage makes obsolete studies based on Cockcroft-Gault formula and a non-standardized dosage, and thus the use of Cockcroft-Gault not transposable to current clinical practice., (Copyright © 2019 Société francophone de néphrologie, dialyse et transplantation. Published by Elsevier Masson SAS. All rights reserved.)

The development of interventional radiology techniques regularly exposes patients to the potential renal toxocity of iodinated contrast media. Faced with this risk of nephrotoxicity, gadolinium-based contrast agents have long been considered as a safe alternative to iodinated contrast media, especially in sensitive or at risk patients. However, these gadolinium-based contrast agents are not devoid of nephrotoxicity and present another risk, a complication related to renal failure, the nephrogenic systemic fibrosis. European and US recommendations from health agencies have recently come closer, defining groups of patients at risk of nephrogenic systemic fibrosis according to their level of renal function and the type of gadolinium-based contrast agent used. What are the real renal risks for these products? How to evaluate the benefit-risk balance of the patient to choose a radiological examination in an informative, effective and safe way? This article focuses on the description of the risks of gadolinium-based contrast agents, reviews existing recommendations and best practices to guide the choice of clinicians., (Copyright © 2018. Published by Elsevier Masson SAS.)

Background: Pemetrexed, a multitargeted antifolate cytotoxic agent, is currently used primarily in combination with cisplatin for metastatic non-small cell lung cancer and for malignant mesothelioma. Acute renal toxicity of pemetrexed has been recently described with polychemotherapy, in which the individual responsibility of each drug is difficult to establish. Only one recent report documents renal involvement in long-term exposed patients., Case Presentation: We report on a case of rapidly progressive nephropathy leading to the cessation of platinum salts and the secondary interruption of pemetrexed and bevacizumab. Acute tubular necrosis shown on the renal biopsy could potentially be due to pemetrexed. Persistent severe renal failure after the resumption of all drugs led to new treatment lines with gemcitabine (while the glomerular filtration rate was below 30 ml/min/1.73m 2 ), then followed by Taxol., Conclusions: The optimal strategy with regard to renal complications in cancer patients is not clear. Acute or chronic loss in renal function generally leads to a new treatment line, possibly impairing the overall success of the treatment. The use of chemotherapy in patients with a glomerular filtration rate below 30 ml/min/1.73m 2 is usually associated with an increased risk of side effects when not contraindicated by renal elimination of the drug.

Renal insufficiency (RI) is a frequent complication in heart transplant (HT) patients. The main objectives of the Cardiac trAnsplantation and Renal INsufficiency (CARIN) study were to follow the evolution of renal function after heart transplantation (HTx), to identify the factors associated with the decline of renal function, to describe the impact of RI on mortality during 3 years after the HT, and to observe the renal profile of the prescriptions. CARIN was a French retrospective, multicentric, study. Data were collected for patients who received a HT between 2000 and 2005. Data collection was performed at five time points: before HTx (T0), 1(T1), 6(T6), 12 (T12), and 36 (T36) months after HTx. Glomerular filtration rate (GFR) was estimated with aMDRD formula. RI was defined as GFR < 60 ml/min/1.73 m². Four hundred and forty-one patients from five HT centers were included. The prevalences of RI were 28.8% (T0), 54.0% (T1), 50.4% (T6), 51.6% (T12), and 59.6% (T36). Age and cyclosporine were independently linked to the decline of renal function. Hypertension and GFR < 60 at T0 were independent risk factors of mortality. 48.7-64.7% of the nonimmunosuppressive prescriptions were drugs that required dosage adjustment in RI patients or for which no data were available concerning administration in RI patients. RI is highly frequent after HTx. Because RI is a risk factor of mortality, any sparing renal strategies have to be undertaken., (© 2014 Steunstichting ESOT.)

Tenofovir disoproxil fumarate (TDF), the first nucleotidic inhibitor of HIV reverse transcription, became available in 2001. It has been extensively used worldwide and is now the most prescribed antiretroviral (ARV) drug. Its high antiviral activity and favorable metabolic profile are responsible for its success. Furthermore, TDF has been associated with other ARVs to form new combined antiretroviral treatments in only one tablet once-a-day, which increases treatment adherence. Fears of potential nephrotoxicity that tenofovir would have in common with two other drugs from the same family (adefovir, used to treat hepatitis B, and cidofovir, used to treat cytomegalovirus infections) were alleviated by the early clinical trials. Yet, in 2001, the first case of TDF-induced acute nephrotoxicity was published. Numerous cases have been published since then, and it is now established that TDF presents a tubular toxicity risk. Some facilitating factors have been identified, such as co-prescription of didanosine or boosted protease inhibitor, preexisting CKD, low body weight, and associated diabetes mellitus. Conversely, whether TDF is nephrotoxic in the long term is a highly debated question. Some studies suggest a decreased GFR when TDF is prescribed for a long period, while others indicate that TDF is safe for the kidneys even after many years of use. Here we review the differences in patient characteristics, study designs, and measured outcomes that can possibly explain these conflicting findings. We conclude with rational recommendation for appropriate TDF prescription.

Malaria is an endemic and potentially lethal disease transmitted by the protozoan parasite Plasmodium. It is currently endemic in more than 100 countries, which are visited by 125 million international travellers every year. For dialysis and renal insufficiency patients it becomes increasingly easier to travel to these countries thanks to the recent advances in renal replacement therapy. However, the pharmacokinetics of some prophylactic agents in malaria are altered, which may modify the effectiveness and safety of such treatments and the way they should be prescribed. Clinicians should be aware of these alterations which require subsequent dosage adjustments. This review provides recommendations on the use of antimalarial drugs, alone or in combination, in patients with renal impairment. These recommendations depend on the prevalence of Plasmodium falciparum chloroquine resistance, as defined by the WHO. Furthermore, fixed-dose combinations cannot be used in patients with creatinine clearance below 60 mL/min since the tablets available do not allow appropriate dosage adjustment for each drug. Chloroquine and proguanil require dosage adjustments, while atovaquone, doxycycline and mefloquine do not.

Pulmonary hypertension (PH) is a progressive, fatal pulmonary circulatory disease that is characterized by elevated pulmonary arterial pressure and secondary right ventricular failure. PH has been reported to be highly prevalent in patients with chronic kidney disease, and especially among end-stage renal disease patients undergoing haemodialysis. However, only few data are available on drug dosage adjustment to renal function for those drugs that are commonly used in the treatment of PH. We reviewed the literature and gathered information, although sparse, to propose guidelines for using these drugs in renal insufficiency patients.

The Renal Insufficiency and Anticancer Medications (IRMA) study is a French national, observational study, which demonstrated the high prevalence of abnormal renal function in a population of 4,684 solid tumour patients, treated in 15 cancer centers. Among them, 7.2% had a SCR level ≥ 110 mmol/L. In the 1,898 patients with breast cancer, only 31 patients (1.63%) had a SCR level ≥ 110 mmol/L. Nevertheless, respectively 51.8 and 50.8% had a creatinine clearance estimated with the Cockcroft-Gault and aMDRD formulae, below 90 mL/min. Even if the most used medications (anthracyclins, taxanes, trastuzumab, hormone therapies) are not nephrotoxic, these results are important because bevacizumab modifies the need for renal management. In case of renal insufficiency, some other treatments such biphosphonates IV, capecitabin and platin salts need drug dosage adjustment or interruption.

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., (2010 Cancer Resaerch UK.)

The Renal Insufficiency and Anticancer Medications (IRMA) study is a French national, observational study which demonstrated the high prevalence of abnormal renal function in a population of 4,684 solid tumour patients. Among them, 50-60% had decreased renal function defined as CrCl below 90 and 80% were treated with anticancer drugs that either necessitated dosage adjustment in case of RI or were potentially nephrotoxic drugs. Since patients and drugs used differ depending on the type of tumour, the IRMA Study Group started analyses in different subgroups of patients. In the 1898 IRMA patients with breast cancer, the prevalence of RI was still very high in spite of a normal serum creatinine in almost all cases. Some anticancer drugs, as in particular some bisphosphonates, capecitabine and platinum salts, may be nephrotoxic and/or need dosage adjustment. However other important drugs in breast cancer do not require dose reduction, and do not present with potential nephrotoxicity (anthracyclines, taxanes, trastuzumab). Both issues seem to be slightly but significantly more important in patients with bone metastases as compared to patients with a non-metastatic disease.

Purpose: Nephrogenic systemic fibrosis (NSF) is characterized by widespread tissue fibrosis, mainly affecting the skin. Gadolinium chelates have been implicated in the onset of NSF in patients with renal impairment (RI). The FINEST study (FIbrose Néphrogénique SysTémique) was designed to determine the prevalence of NSF after magnetic resonance imaging (MRI) in French RI patients., Materials and Methods: We studied all patients with RI who had at least one MRI examination during a one-year period, with or without gadolinium chelate administration. Data were collected retrospectively from 9 Nephrology Departments in France, and included sex, age, renal function, type of gadolinium administered, and subsequent cutaneous disorders. If a patient presented a cutaneous disorder, a skin biopsy was performed to confirm the diagnostic., Results: The 308 eligible patients had a mean age of 59.9 years, 59% were men, and 54% had stage 5 RI. 75% of those 308 patients received a Gadolinium chelate. Among those patients who received a gadolinium chelate, 76% received gadoterate, 20% gadopentetate, 3% gadodiamide and 1% gadobenate. No cutaneous disorders were recorded after MRI., Conclusion: These results confirm that NSF is a rare disease. Based on a reported frequency, approximately 3.5% in patients with glomerular filtration rate <30ml/min/1.73m(2)), some cases should have been observed in our study which included 308 patients. Most patients received gadoterate, a macrocyclic gadolinium chelate for which no case of NSF has been observed worldwide. This suggests that more stable macrocyclic agents may be less likely to induce NSF., (Copyright (c) 2008 Elsevier Ireland Ltd. All rights reserved.)

Background: The Renal Insufficiency and Anticancer Medications (IRMA) study reported a renal insufficiency (RI) prevalence of 50%-60% in a population of almost 5000 patients with solid tumors, 80% of whom were being treated with anticancer drugs that either necessitated dosage adjustment or were potentially nephrotoxic drugs. A national multicenter study from 15 cancer centers in France analyzed IRMA data on patients with prostate cancer., Patients and Methods: Data on patients with prostate cancer from the IRMA study were analyzed. Renal function was calculated using Cockcroft-Gault and abbreviated Modification of Diet in Renal Disease (aMDRD) formulas to estimate the prevalence of RI. Anticancer drugs' potential renal toxicity and need for dosage adjustment were detailed., Results: Of the 222 IRMA patients with prostate cancer, 14.9% had a serum creatinine (SCr) level of > 110 micromol/L. When using Cockcroft-Gault and aMDRD formulas, 62.6% and 55.9%, respectively, of the patients had RI. Of the 228 anticancer drug prescriptions, 82.9% required dose adjustments for RI or were drugs with no available data on their administration in patients with RI. Of the patients treated, 86.9% received >or= 1 such drug, but only 29.1% received nephrotoxic drugs., Conclusion: The prevalence of RI in patients with prostate cancer was very high in spite of a normal SCr level in most cases. Some anticancer drugs, particularly some bisphosphonates and platinum salts, might be nephrotoxic and/or need dosage adjustment. However, other important drugs in prostate cancer, such as docetaxel, neither require dose reduction nor present with potential nephrotoxicity. Both issues were significantly more important in the patients with bone metastases compared with those with nonmetastatic disease.

The prevalence of renal insufficiency before and at 1, 12, and 60 months after liver transplantation (LTx; primary endpoint) and the changes in the glomerular filtration rate (GFR) at same time points according to the immunosuppressive regimen (coprimary endpoint) were investigated. The primary outcome was determined for the entire cohort, whereas the coprimary endpoint was determined only for 2 groups of patients: those who started and remained on a calcineurin inhibitor (CNI) alone, that is, the CNI-alone group (n = 624), and those who started and remained on a CNI in combination with mycophenolate mofetil (MMF), that is, the MMF group (n = 117). GFR was <60 mL/minute/1.73 kg/m(2) in 11%, 48%, 51% and 58% of the patients at baseline and at 1, 12, and 60 months, respectively. The decrease in GFR was significantly lower in the MMF group compared to the CNI-alone group at 12 and 60 months (-16% versus -30% and -15% versus -33%, respectively), whereas the GFR decrease at 1 month was not different between the 2 groups. There were no significant differences between the 2 groups in CNI doses or blood levels at 12 and 60 months. In conclusion, there was a worsening of renal failure in 83% of patients post-LTx; 58% and 5% had GFRs of <60 and <30 mL/minute/1.73 kg/m(2), respectively, at 5 years after LTx. The reduction of the GFR was significantly less marked in the MMF group compared to the CNI-alone group, and this could be related to less important CNI exposure early after LTx. It seems likely that early intervention for CNI reduction is best for reducing the use of CNIs in the long term., ((c) 2009 AASLD.)

The Renal Insufficiency and Anticancer Medications (IRMA) study is a French national, observational study which demonstrated the high prevalence of abnormal renal function in a population of 4684 solid tumor patients. Among them, 50-60% had decreased renal function, and 80% were treated with anticancer drugs that either necessitated dosage adjustment in case of renal insufficiency (RI) or were potentially nephrotoxic drugs. Since elderly patients are well-known to have reduced renal function, either due to physiological aging or their disease/medication history, a subgroup analysis of this particular population of patients was performed. In 1553 IRMA patients whose age was > or =65 years, the prevalence of RI was very high in spite of normal serum creatinine values in most cases. Anticancer drugs used may be nephrotoxic or need dosage adjustment in a high number of cases.

The Renal Insufficiency and Anticancer Medications (IRMA) study reported the high prevalence of renal insufficiency in cancer patients. In this special report, we focused on patients with lung cancer, emphasizing some specific findings in this population of patients. Data on patients with lung cancer who were in the IRMA study were analyzed. Renal function was calculated using Cockcroft-Gault and abbreviated Modification of Diet in Renal Disease (aMDRD) formulas to estimate the prevalence of renal insufficiency (RI) according to the KDOQI-KDIGO definition. Anticancer drugs were studied with regard to their potential renal toxicity and need for dosage adjustment. Of the 445 IRMA lung cancer patients, 14.4% had a serum creatinine (SCR) level > or =110 micromol/L. However, when they were assessed using the formulas, 62.1 and 55.9% had abnormal renal function. Of the 644 anticancer drug prescriptions, 67.5% required dose adjustments for RI or were drugs with no available data, and 78.3% of the patients received at least one such drug. Furthermore, 71.6% received potentially nephrotoxic drugs. Seventy percent of the patients had anemia but prevalence was not significantly associated with the existence of associated renal insufficiency. In the 445 IRMA patients with lung cancer, the prevalence of RI was high in spite of a normal SCR in most cases. Some anticancer drugs such as platinum salts may be nephrotoxic and need dosage adjustment. However, other important drugs such as gemcitabine do not require dose reduction and do not present with a high potential for nephrotoxicity. Lung cancer patients often present with anemia, which was not associated with the presence of RI.

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.

Background: The Renal Insufficiency and Cancer Medications (IRMA) study is a French national observational study. The results from this study of nearly 5,000 patients demonstrated the high prevalence of renal impairment in a population of patients with solid tumors., Methods: Every cancer patient who presented at oncology departments that participated in the study over at least 1 of 2 predefined periods during 2004 were included. Renal function was calculated using Cockcroft-Gault and abbreviated Modification of Diet in Renal Disease (aMDRD) formulae to estimate the prevalence of renal insufficiency (RI) according to the Kidney Disease Outcomes Quality Initiative-Kidney Disease Improving Global Outcomes definition and stratification. Anticancer drugs were studied with regard to their potential renal toxicity and dosage adjustment., Results: Of the 4,684 patients from the 15 centers, 7.2% had serum creatinine levels >110 micromol/L. However, when they were assessed using Cockcroft-Gault and aMDRD formulae, 57.4% and 52.9% of patients had abnormal renal function or RI, respectively. Of the 7,181 anticancer drug prescriptions, 53.4% required dose adjustments for RI. Of the patients treated, 79.9% received at least 1 such drug. And 80.1% received potentially nephrotoxic drugs., Conclusions: RI was common in patients with cancer, and drug dosage adjustments often were necessary. Renal function should be evaluated in all cancer patients using either the Cockcroft-Gault formula or the aMDRD formula, including patients with normal serum creatinine levels. In patients who are at high risk for drug toxicity, the dosage should be adapted to renal function, and the use of nephrotoxic therapies should be avoided whenever possible., ((c) 2007 American Cancer Society.)

Methotrexate (MTX) has become the most commonly prescribed disease-modifying anti-rheumatic drug. However, toxicity is an important drawback of MTX therapy and permanent discontinuation of MTX for adverse effects occurs in 1 patient out of 10. Although high-dose MTX is known to be nephrotoxic, data on low-dose MTX renal effects are scanty. We report an insidious and progressive deterioration of renal function during long-term low-dose MTX in a 59-year-old woman. Kidney biopsy revealed advanced kidney fibrosis with extensive interstitial and glomerular fibrosis, and vascular sclerosis. We suggest that patients on low-dose MTX therapy even alone, should be periodically monitored for creatinine levels.

Dyslipidemia is frequent in patients with renal failure and in transplant recipient patients. This lead to a wide use of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) in patients with impaired renal function or in patients treated with cyclosporine as post-transplantation immunosuppressive therapy. As a result, it is crucial for those patients' physicians to be aware of how to handle these drugs when renal function is impaired and/or when cyclosporine is co-administered. Most statins have an extensive hepatic elimination and the renal route is usually a minor elimination pathway. However, pharmacokinetic alterations have been described for some of these drugs in patients with renal insufficiency. Cyclosporine is a widely used immunosuppresive therapy in solid organ transplant patients and drug-drug interactions are likely to occur when statins and cyclosporine are administered together. Those interactions may theoretically result in increased statins and/or cyclosporine serum levels with potential muscle and/or renal toxicity. As a result, caution is warranted if concurrent administration is performed. In this review, we synthesized the data from the literature on (1) the pharmacokinetics and dosage adjustment of atorvastatin, fluvastatin, pravastatin, rosuvastatin, and simvastatin in patients with renal failure and (2) the potential drug-drug interactions between these drugs and cyclosporine in transplant recipient patients.

The World Health Organization established official recommendations for managing pain in cancer patients. Since then, this stepladder approach has been widely adopted as a conceptual framework to treat all types of pain. However, those guidelines have not been critically evaluated for use in patients with renal insufficiency. In these patients, the questions of drug dosage adjustment and renal toxicity must be considered. This article reviews the pharmacokinetics of major analgesic drugs and data on their use and/or behavior in renal failure and considers their potential nephrotoxicity. Finally, according to available data in the international literature on pharmacokinetics, recommendations for dosage adjustment in patients with renal failure, and their potential nephrotoxicity, the World Health Organization three-step ladder for the treatment of pain was modified and adapted for patients with impaired renal function. Perspective This well-known treatment strategy now adapted for use in patients with renal insufficiency should secure and rationalize pain treatment in those patients.

Tuberculosis is re-emerging in patients with altered immune status, such as those with chronic renal failure. Clinicians should thus be aware of the pharmacokinetics and dosage adjustment of antitubercular drugs in patients with renal insufficiency. Among patients with renal insufficiency, those who are dialysed should be treated with special care. Indeed, dosage should always be closely adjusted in these patients and potential removal by dialysis must be taken into account. However reliable the dosage adjustment recommendations are for these drugs in patients with renal failure, further pharmacokinetic investigations need to be performed, especially in dialysis patients in whom the influence of haemodialysis and continuous ambulatory peritoneal dialysis on drug pharmacokinetics needs to be detailed. In the meantime, it could be generally advised to administer all antitubercular drugs after the haemodialysis session, even though some drugs are known to be non-dialysable.

HYPERKALIEMIA AND RENAL FAILURE: Nonsteroidal anti-inflammatory drugs (NSAIs) may induce hyperkaliemia and renal failure. With regard to these complications, the notion of a risk factor is fundamental. Selective cyclooxygenase-2 inhibitors (Cox-2) do not provide any notable advantages with regard to the incidence of hyperkaliemia and renal failure. OEDEMA AND BLOOD PRESSURE: The NSAIs provoke salt-water retention which is responsible for oedema in 2 to 5% of patients (here again the notion of a risk factor is important). The salt-water retention is implied in the increase in blood pressure and the decompensation of heart failure. It has been shown that the incidence of oedema and the increase in blood pressure was significantly reduced with celecoxib compared with rofecoxib. This might have a crucial impact on the mean and long term follow-up of cardiovascular risk in these patients., Cardiovascular Risk: The results of the VIGOR study that demonstrated an increase in risk of myocardial infarction with rofecoxib, can probably be explained by an anti-thrombotic effect of naproxene, the high dose of rofecoxib used, the type of patients included or the fact that aspirin had been contraindicated. A recent study suggested that the cardiovascular risk was greater with rofecoxib than with celecoxib and with NSAIs when the dose of rofecoxib used was greater than 25mg/day. In this case control study, the cardiovascular risk was identical with celecoxib and NSAIs, whatever the dose used, but increased with a relative risk rate of 1.7 with the doses of rofecoxib greater than 50mg/day. In cases treated with aspirin Some NSAIs can reduce the anti-aggregant effects of aspirin whereas this effect is not observed with Cox-2 selective inhibitors. Hence, the latter should be the pharmacological agents of choice in patients treated with aspirin.

Background: Acquired immunodeficiency syndrome (AIDS)-related kidney disorders concern 30% of those patients and can lead to end-stage renal disease (ESRD; 0.6 to 1%). Therefore, administration of antiretroviral drugs in human immunodeficiency virus (HIV) patients with nephropathy is not uncommon., Aim of the Review: Since renal insufficiency is not uncommon among HIV-infected patients treated with antiretroviral drugs, guidelines on how to use these drugs in the pattern of an altered renal function are mandatory. This review provides such guidelines established on the basis of pharmacokinetic and clinical studies reported in the international literature. In addition, some of these drugs may be nephrotoxic. Mechanisms and clinical and/or biological manifestations are reviewed to help monitor renal tolerance in patients receiving these drugs., Conclusion: Antiretroviral drugs' dosage in HIV-infected patients with altered renal function should be cautiously determined. Drug dosage should not be systematically reduced since dosage adjustment is not mandatory for all therapies (ie. protease inhibitors). Furthermore, when dose reduction is necessary, pharmacokinetic and clinical data from the literature allows to establish practical guidelines on how to use these drugs in such patients.

Objectives: The potential consequences of medication misuse in renal impairment have not been assessed in a population of in-patients. The purpose of this study was to determine the frequency and potential consequences of a lack of dosage adjustment in hospitalized patients with renal impairment., Design: Order sheets for in-patients having a creatinine above 0.7 mg/dl were analysed. We considered the appropriateness of prescriptions for medications having potential nephrotoxicity and/or eliminated through renal excretion or metabolism (TEM medications) and having manufacturer's guidelines for dosage adjustment in renal impairment., Main Measures: On the basis of these guidelines, each line of prescription was rated as 'appropriate order', 'inappropriate dosage', or 'contra-indicated order'. Experts also rated prescriptions as potentially fatal or severe, serious, significant, or without potential for increased adverse effects., Results: Two hundred and two order sheets were completed for 164 patients. They totalled 1469 lines of prescription, 85% of which were TEM medications, with guidelines for dosage adjustment for 71% of them (n = 886). Of these 886 prescriptions, 34% were inappropriate, 14% being contra-indicated and 20% with inappropriate dosage given the patient's renal function. Among the 202 order sheets, 75% included at least one inappropriate prescription. Sixty-three per cent included at least one prescription with potentially adverse consequences, 3% of these having potentially fatal or severe consequences., Conclusion: This study confirms that physicians do not take into account sufficiently patient renal function when prescribing. In light of these results, improving the quality of drug prescription in patients with renal impairment could be of importance for improving the quality of care.

Background: Abacavir is a potent, novel 2'-deoxyguanosine analogue reverse transcriptase inhibitor (NRTI) which effectively suppresses HIV-1 replication. To date, there is no pharmacokinetic study in patients with renal impairment., Methods: Five HIV-1-infected patients with various degrees of renal dysfunction (creatinine clearance 60, 40, 25, 20 and 1 haemodialyzed patient) were evaluated after being treated for at least 2 months with multi-antiretroviral therapy including abacavir. After an overnight fast, the subjects received their abacavir dosage (600 or 300 mg). Blood samples were withdrawn and plasma concentrations determined. A nonparametric pharmacokinetic analysis was then performed. The dialysability of abacavir was also evaluated., Results: Time of maximum plasma concentration (T(max)) was constant among the subjects with a mean value of 0.7 +/- 0.27 h (range 0.33-1). Maximum plasma concentration (C(max)) ranged from 2.76 to 4.15 mg/l (mean 3.44 +/- 0.59). The elimination half-life ranged from 1.31 to 2.67 h (mean 2.08 +/- 0.51). Normalized C(max)/dose ranged from 0.007 to 0.014 mg/l and normalized AUC(0-inf)/dose ranged from 0.014 to 0.035 mg.h/l. In haemodialysis the dialysance was 60-80 ml/min with a fractional drug removal of 24% during a 4-hour haemodialysis session with a high permeability membrane., Discussion: In our patients, absorption, elimination and distribution phases were not altered by renal insufficiency. Furthermore, our pharmacokinetic data are similar to those obtained in patients with normal renal function. Therefore, dosage adjustment is not necessary in patients with renal insufficiency. In haemodialyzed patients, treatment can be administered independently to the dialysis session because of the negligible elimination of abacavir in the dialysate., (Copyright 2001 S. Karger AG, Basel)

Background: Acquired immunodeficiency syndrome (AIDS)-related kidney disorders concern 30% of those patients and can lead to end-stage renal disease (ESRD; 6 to 10%). Therefore, the administration of antiretroviral drugs in human immunodeficiency virus (HIV) patients with nephropathy is not uncommon., Methods: The influence of ESRD on the different phases of the pharmacokinetic profile of drugs in general is examined in light of bioavailability, distribution, protein binding, metabolism, and elimination. Then, the pharmacokinetics of antiretroviral drugs in hemodialysis are detailed., Results: From these data, dosing recommendations are given for nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs, and protease inhibitors (PIs)., Conclusion: Dosage adjustments are often necessary for patients with renal insufficiency. These adaptations have to be carefully performed to optimize drug exposure and reduce the risk of side effects.

DRUG PHARMACOKINETICS: One of the first steps in the clinical development of drugs consists in studies of their pharmacokinetics. Dosage and administration interval necessary to ensure secure and efficient plasma levels are derived from the values of pharmacokinetic parameters. Renal disease usually implies multiple pathophysiological modifications that generate alteration in drugs pharmacokinetic profile. Those modifications mainly occur on elimination phase but also to a significant extent on absorption and distribution. PATHOPHYSIOLOGICAL CHANGES: In this article we describe potential alteration in drugs absorption, distribution (volume of distribution, binding to plasma proteins), hepatic or renal metabolism, and parent compound and/or metabolites elimination in patients with renal insufficiency. Furthermore, in patients with end-stage renal disease treated by dialysis, drugs are likely to be removed by extracorporal epuration and dosage and/or interval modifications should thus be applied to treatments in those patients., Clinical Assessment: Pharmacokinetics of drugs should be evaluated in patients with renal failure to determine whereas dosage and/or administration interval should thus be modified to enhance tolerance and pharmacological efficacy. Such studies are obviously necessary for drugs that are mainly excreted unchanged in urine. They should also be performed for drugs that are mainly degraded in the liver with emphasis on metabolites pharmacokinetics.

Résumé La maladie rénale chronique est une maladie progressive devenue un véritable enjeu de santé publique. Chez les patients présentant une maladie rénale, la pharmacocinétique des médicaments peut être altérée. Le maniement des médicaments nécessite ainsi une attention toute particulière chez ces patients. En effet, il existe un risque d’accumulation et de surdosage médicamenteux si les posologies ne sont pas adaptées au niveau d’insuffisance rénale. Ainsi, pour réaliser une adaptation posologique, il faut savoir comment évaluer la fonction rénale. Différentes formules sont disponibles notamment celle de Cockcroft et Gault, la formule aMDRD et la CKD-EPI. Chez le patient cardiologique, il semblerait que la formule CKD-EPI soit celle de choix en termes de stratification du risque clinique à long terme. Toutefois, certaines monographies de médicaments utilisés en cardiologie, tels que le Dabigatran, mentionnent la nécessité d’utiliser la formule de Cockcroft et Gault, plus ancienne et moins précise qu’aMDRD et CKD-EPI, afin d’adapter les doses chez les patients insuffisants rénaux. Une uniformisation des recommandations est nécessaire afin de limiter les disparités de doses et d’exposition au médicament selon la formule d’estimation utilisée. Les RCP ne sont toutefois pas la seule source d’information permettant d’obtenir des données quant à l’utilisation des médicaments dans la population insuffisante rénale. En France, un service d’aide à la prescription chez le patient insuffisant rénal existe depuis 1999 au sein du service de néphrologie de la Pitié-Salpêtrière à Paris et propose des recommandations d’adaptation posologique en ligne. 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. [ABSTRACT FROM AUTHOR]

Abstract: Renal insufficiency is frequently seen in patients with cardiovascular disease. In contrast, coronary artery disease is the leading cause of death in patients with renal impairment. The recognition of renal insufficiency is essential in these patients and preventive measures must be put in place to prevent the progression or onset of cardiovascular disease. In this article, we explain the methods to assess kidney function, the epidemiology of coronary heart disease in patients with renal impairment, risk factors conventional and non-conventional found in these patients and the main recommendations for their therapeutic care. [Copyright &y& Elsevier]