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.

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.

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.

HIV and the body: a review of multidisciplinary management.

The increase in the life expectancy achieved following the introduction of more effective antiretroviral therapy (ART) in recent years now means that the HIV-infected population are for the first time being exposed to the age-related diseases that affect the general population. Nevertheless, the prevalence of these diseases (which include cardiovascular disease, dyslipidaemia, glucose intolerance and diabetes) is higher, and their onset earlier in the HIV population, probably due to the complex interplay between HIV infection, coinfection with hepatitis B and C, and ART. As a result, HIV physicians are now required to adopt a new approach to the management of HIV, which involves screening and regular monitoring of all HIV-infected individuals for the presence of comorbidities and prompt referral to other clinical specialties when required. If this challenge to patient management is to be overcome, it is clear that educating physicians in the diagnosis and treatment of age-associated comorbidities is essential, either through ongoing programmes such as the HIV and the Body initiative, an overarching independent medical education programme established in 2007 and overseen by an independent Steering Committee, organized and funded by Gilead, and/or through internal training. To assist in this process, this article provides an overview of common comorbidities affecting HIV-infected persons and provides practical guidance on their management.

Antimyeloperoxidase antibodies are a useful marker of disease activity in antineutrophil cytoplasmic antibody-associated vasculitides.

OBJECTIVE: To evaluate the relevance of monitoring antimyeloperoxidase antibody levels in the management of antimyeloperoxidase-associated vasculitides. METHODS: Thirty-eight patients with antimyeloperoxidase-associated vasculitides were included: microscopic polyangiitis (n = 18), Wegener's granulomatosis (n = 15) and Churg-Strauss syndrome (n = 5). Baseline characteristics and outcomes were recorded. Serial measurements of antimyeloperoxidase antibody levels were performed (ELISA, positive > or = 20 IU/ml). RESULTS: All patients achieved vasculitis remission after a mean time of 2.0 months (SD 0.9), with a significant decrease in the mean antimyeloperoxidase antibody level at remission (478 vs 41 IU/ml (SD 598 vs 100); p<0.001). Twenty-eight (74%) patients became antimyeloperoxidase antibody negative. After a mean follow-up of 54 months (SD 38), 12 cases of clinical relapse occurred in 11/38 (29%) patients. Relapses were associated with an increase in antimyeloperoxidase antibody levels in 10/11 (91%) patients (34 vs 199 IU/ml (88 vs 314); p = 0.002). The reappearance of antimyeloperoxidase antibodies after achieving negative levels was significantly associated with relapse (odds ratio 117; 95% CI 9.4 to 1450; p<0.001). Antimyeloperoxidase antibodies showed a positive predictive value of 90% and a negative predictive value of 94% for relapse of vasculitis. Up to 60% of cases of relapse occurred less than 12 months after the reappearance of antimyeloperoxidase antibodies. Relapse-free survival was significantly worse for patients who exhibited a reappearance of antimyeloperoxidase antibodies than in those with persistent negative antimyeloperoxidase antibodies (p<0.001). The antimyeloperoxidase antibodies serum level was strongly correlated with the Birmingham vasculitis activity score and the disease extent index (r = +0.49; p = 0.002). CONCLUSION: Through monitoring, antimyeloperoxidase antibodies are a useful marker of disease activity and a good predictor of relapse in antimyeloperoxidase-associated vasculitides.

[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.

[Impact on renal function of an early switch from conventional to liposomal amphotericin B formulation in the empirical treatment of fungal infections]. / Impact sur la fonction rénale d'un relais précoce de la formulation conventionnelle de l'amphotéricine B par sa formulation liposomale dans le cadre d'un traitement empirique antifongique (Etude Nephemat).

OBJECTIVE: The authors had for aim to define the threshold of nephrotoxicity before switching to other antifungal treatment in hematological patients treated by conventional amphotericin B (AmB) as an empiric antifungal treatment. DESIGN: A prospective randomised multicenter study was made on 32 neutropenic hematological patients receiving conventional AmB for empirical antifungal treatment. The patients were randomised after a greater than or equal to 30% increase of serum creatinine (sCr). Patients in the early-switch group received liposomal AmB just after randomisation and patients in the late-switch group received liposomal AmB only when serum creatinine increase was greater or equal to 100% or sCr reached 170mumol/L. RESULTS: Thirty-one patients were analysed: 16 patients in the early-switch group and 15 patients in the late-switch group (seven switched to liposomal AmB and eight continued conventional AmB treatment). The mean age of patients was 48 years and 68% were men. The most frequent underlying haematological malignancy was acute leukemia (94%). In the late-switch group, the degradation of renal function continued after randomisation contrary to the early-switch group: median variations of calculated sCr clearance in early- and late-switch groups were -16.8 and -1.5%, respectively (P=0.03). Moreover, an early switch was cost-effective with a sCr lower duration of hospitalisation in comparison with a late switch. CONCLUSIONS: This randomised trial suggests that an early switch to Liposomal AmB improves and preserves renal function in comparison with a late switch.

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.

Chronic caffeine administration exacerbates renovascular, but not genetic, hypertension in rats.

The purpose of this study was to determine whether or not caffeine would exacerbate renovascular hypertension. Therefore, we examined the effects of chronic caffeine administration on arterial blood pressure in rats subjected to either unilateral renal artery clipping (2K-1C rats) or sham-operation. Animals in each group were randomly assigned to receive either 0.1% caffeine in their drinking water or normal drinking water, and systolic blood pressure was monitored for 6 wk. Caffeine markedly exacerbated the severity of hypertension in 2K-1C rats and caused histological changes consistent with malignant hypertension. 6 wk after surgery, systolic blood pressure, plasma renin activity, and creatinine clearance in control 2K-1C rats were 169 +/- 5 mmHg (mean +/- SEM), 4.4 +/- 0.5 ng AI X ml-1 X h-1, and 2.9 +/- 0.2 ml/min, respectively; as compared with 219 +/- 4 mmHg, 31.8 +/- 7.8 ng AI X ml-1 X h-1, and 1.4 +/- 0.3 ml/min, respectively, in 2K-1C rats receiving caffeine (all values were significantly different compared with control 2K-1C). Chronic caffeine administration did not alter systolic blood pressure, plasma renin activity, or creatinine clearance in sham-operated rats or spontaneously hypertensive rats. Chronic treatment with enalapril (a converting enzyme inhibitor) prevented the development of hypertension in control 2K-1C rats and caffeine-treated 2K-1C rats; however, withdrawal of enalapril precipitated a rapid rise in systolic blood pressure in caffeine-treated 2K-1C rats, but not in control 2K-1C rats. These experiments indicate that caffeine specifically exacerbates experimental renovascular hypertension and might worsen the hypertensive process in patients with renovascular hypertension.

[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.

Dialysis and iodinated contrast media.

Contrast media are excreted mainly by glomerular filtration. There is thus, a significant correlation between both body and renal clearances of contrast media and glomerular filtration rate, and their renal excretion will be delayed in patients with renal insufficiency. Contrast media can be efficiently removed from blood by hemodialysis (HD). Since most contrast media are middle-sized molecules, the main factors potentially influencing their removal by HD are blood flow, membrane surface area, molecular size, transmembrane pressure, and dialysis time. Peritoneal dialysis is also effective in removing contrast agents from the body but takes longer than HD. Dialysis immediately after radiographic contrast studies has been suggested for two groups of patients. Those on chronic HD and those at very high risk for contrast nephropathy. Three studies have examined the necessity of immediate dialysis after intravascular injection of contrast media in chronic HD patients; the authors found no evidence that it is effective at preventing contrast nephropathy. The reasons why HD treatment was not beneficial in those three studies are not known. Perhaps, the rapid onset of renal injury after administration of contrast media is one answer. It is also possible that HD per se was nephrotoxic and might have offset the beneficial effect of the removal of contrast media. Marenzi et al. randomized 114 consecutive patients with chronic renal failure undergoing coronary interventions to either hemofiltration in an intensive care unit or isotonic saline hydration. The authors concluded that periprocedural hemofiltration given in an intensive care unit setting appears to be effective in preventing the deterioration of renal function due to contrast agent induced nephropathy and is associated with improved in-hospital and long term outcomes. The concentration of contrast media can effectively be reduced by HD and peritoneal dialysis. HD does not offer any protection against contrast media induced nephrotoxicity. Hemofiltration may decrease the risk of contrast induced nephropathy and have some long-term benefits, but additional studies are needed to better define the appropriate population for this treatment.

Favorable outcome of IgA nephropathy on antituberculous treatment.

We report the case of an association of IgA nephropathy and tuberculosis with superimposed vasculitis lesions on the renal biopsy. Three previous cases of the same association are discussed. The nephropathy had a favorable course in all of these cases on antituberculous treatment only. Tuberculosis is another infection related to IgA nephropathy.

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.

Is low-dose methotrexate nephrotoxic? Case report and review of the literature.

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.

Tuberculosis after conversion from azathioprine to mycophenolate mofetil in a long-term renal transplant recipient.

We report the third case in the literature of a patient with a long-lasting renal allograft who experienced tuberculosis just after the switch from azathioprine to mycophenolate mofetil. The switch was likely responsible for the reactivation of dormant tuberculosis; prophylactic antituberculous treatment should be considered in cases of such a therapeutic change.

PPAR-gamma-agonists' renal effects.

PPAR-gamma ligands, including thiazolidinediones, have recently become clinically available for treating insulin-resistant diabetes mellitus. Accumulating evidence suggests that these drugs not only significantly improve insulin sensitivity but also may have antiproteinuric effects in genetically obese diabetic rodents and patients with type II diabetes and diabetic nephropathy. Moreover, troglitazone reduced expression of ECM proteins and transforming growth factor-beta in glomeruli from streptozotocin-induced diabetic rats. Many other properties including antiproteinuric, hemodynamic, and antihypertensive effects in insulin-dependent diabetes mellitus suggest that PPAR-gamma ligands might have a direct, beneficial renal effect, independent of their capacity to improve glucose tolerance. Besides their antidiabetic effects, thiazolidinediones have been shown to lower blood pressure in diabetic patients with hypertension and patients with diabetic nephropathy through multiple mechanisms. Several studies showed the efficacy of PPAR-gamma agonists to ameliorate the progression of glomerulosclerosis. The effect is independent of insulin effects and could only be partially due to lipid effects. These renal protective effects of PPAR-gamma agonists suggest that they may provide a novel intervention strategy to prevent vascular and glomerular sclerosis.

[Kidney and glitazones]. / Rein et glitazones.

PPARgamma nuclear receptors are mainly expressed in adipose tissue. However, they are also expressed in renal glomerular tissue and in vascular walls, thus participating through various and complex mechanisms, to glomerular and vascular sclerosis and to nephropathy development and progression. Studies carried out with glitazones, pharmacological agonists of nuclear receptor PPARgamma, in experimental models, either in vitro, or in vivo in animal models, have demonstrated their favourable effects on arterial blood pressure and on prevention and/or progression of diabetic nephropathy. The few clinical studies conducted in type 2 diabetic patients to assess these effects, are also in favor of a beneficial effect of glitazones on blood pressure and nephropathy in these patients. Thus, it appears extremely important and fully justified to conduct specific studies in patients with type 2 diabetes, with the aim to establish and to better characterize these effects in various clinical conditions (antihypertensive effect in treated hypertensive patients according to the class of antihypertensive agents used, prevention of diabetic nephropathy and/or effect on its progression, renal protection, etc.). Some adverse events, although with a low incidence, may be associated with glitazone use (weight gain, peripheral oedema, fluid retention, etc.), and may limit their use in some patients. It is clearly important to better understand the pathophysiological mechanisms of these effects and their possible long term consequences. Finally, it is important to emphasize the easiness to use glitazones in patients with renal insufficiency, without the need to adjust the drug regimen.

[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.