Renal Dose Research Articles

Evaluation of the Chronic Kidney Disease Epidemiology Collaboration Equation for Dosing Antimicrobials

Since the derivation of the Modification of Diet in Renal Disease (MDRD) equation for estimating glomerular filtration rate (GFR), investigators determined that it cannot be used for drug dosing. In 2009, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) derived an equation that was more accurate than the MDRD estimation of GFR. Therefore, questions exist about which method should be preferred in making dosage adjustments for renally eliminated antimicrobials. To determine whether a difference exists when making antimicrobial dosage adjustments in patients with CKD based on estimation of GFR using the CKD-EPI and Cockcroft-Gault equations. A database of 409 patients with CKD admitted to a tertiary care facility was used. GFR was calculated using both the CKD-EPI equation(s) and the Cockcroft-Gault equation and compared using correlation and Bland-Altman methodology. Dosage discordance rates of antimicrobials were determined. Average GFRs for all patients using the Cockcroft-Gault and CKD-EPI equations were 34.8 +/- 12 mL/min and 39.9 +/- 13 mL/min, respectively (5.09 [95% CI 4.60 to 5.59]; p < 0.001). The correlation coefficient between the 2 estimations was high (r = 0.91). The Bland-Altman plot yielded limits of agreement of 15.3 and -5.1; thus, the CKD-EPI estimation may range from 5.1 mL/min below to 15.3 mL/min above the Cockcroft-Gault estimation for 95% of the cases. A discordance rate of 15-25% existed among the recommended dosing adjustments of the selected antimicrobials when comparing the Cockcroft-Gault and CKD-EPI estimations. Though this study did not determine which equation should be selected to dose adjust antimicrobials, it demonstrated statistically significant differences between the Cockcroft-Gault and CKD-EPI equations. The clinical significance of these differences is uncertain in the absence of data assessing clinical outcomes that result from the use of the discordant doses. Clinical judgment should be employed when making renal dosage adjustments of antimicrobials.

Hemofiltración de alto volumen en shock séptico

Severe sepsis and septic shock are conditions associated with high morbidity and mortality. The disproportionate release of pro-inflammatory and anti-inflammatory mediators caused by the septic insult is the promoter of multiple organ dysfunction. Conventional hemodialysis, hemofiltration or a combination of both can be a good option to replace the deteriorating renal function in critically ill patients by the removal of nitrogen compounds (small molecules). However, this “renal dose” is insufficient for the removal of inflammatory mediators (medium molecules), and therefore contributes little to the cardiovascular stabilization of patients with septic shock. In this setting, a higher dose of ultrafiltration (> 50 ml/kg/h) or “septic dose” may be needed. In this review article, we have analyzed the clinical and pathophysiological rationale for the use of high volume hemofiltration in patients with septic shock.

Eslicarbazepine acetate: A novel agent for the adjunctive treatment of epilepsy

Eslicarbazepine acetate, a novel antiepileptic agent, has recently been marketed as an adjunctive therapy in adults with partial onset seizures with or without secondary generalization. Its mode of action is not fully elucidated but it is believed that it and its metabolites stabilize the inactivated state of voltage-gated sodium channels, preventing their return to the inactivated state. Eslicarbazepine acetate is extensively converted to eslicarbazepine, its major active metabolite. Its pharmacokinetic profile is unaffected by food, gender, age or moderate hepatic impairment; clearance is dependent on renal function and dose reduction is recommended in patients with a creatinine clearance < 60 ml/min. Eslicarbazepine acetate does not induce its own metabolism or clearance. Clinical trials have demonstrated efficacy in short and long term studies (up to 1 year) together with improvements in quality of life outcomes and depressive symptoms where these existed at baseline. Most adverse events were mild to moderate in intensity and occurred early in treatment; the most frequently reported events were dizziness, somnolence and headache. Trials using eslicarbazepine acetate as monotherapy are ongoing.

Pharmacokinetics of oral valganciclovir solution and intravenous ganciclovir in pediatric renal and liver transplant recipients

In an open-label, prospective, pharmacokinetic assessment, we evaluated total drug exposure (area under the curve [AUC]) of intravenous (IV) ganciclovir (GCV) and oral (p.o.) valganciclovir when normalized for body surface area (BSA) in pediatric liver (n=20) and renal (n=26) transplant patients Reference doses for IV GCV (200 mg/m(2)) and p.o. valganciclovir (520 mg/m(2)) were based on adult doses, and adjusted for BSA initially, and BSA and renal function (estimated via creatinine clearance [CrCL]) thereafter. Renal transplant patients received GCV on days 1-2, valganciclovir 260 mg/m(2) on day 3, and valganciclovir 520 mg/m(2) on day 4. Liver transplant patients received twice daily GCV from enrollment to day 12, and then valganciclovir twice daily on days 13-14. GCV pharmacokinetics were described using a population pharmacokinetic approach. Type of solid organ transplant (kidney or liver) had no effect on GCV pharmacokinetics. Median GCV exposure following valganciclovir 520 mg/m(2) was similar to that with IV GCV, and to that reported in adults. Patients <5 years of age had AUC values approximately 50% of those compared with older age ranges; dosing based on both BSA and CrCL increased drug exposure in younger patients. A dosing algorithm based on BSA and CrCL should be tested in future studies.

Targeted Radiopharmaceutical Therapy for Advanced Lung Cancer: Phase I Trial of Rhenium Re188 P2045, a Somatostatin Analog

Both small cell and non-small cell lung cancer overexpress somatostatin receptors (SSTR). P2045 peptide is an 11-amino acid somatostatin analog that binds with high affinity to SSTR and can be labeled with Tc-99m to gauge receptor prevalence or with Re-188 for 2.1 MeV beta radiotherapy. To evaluate the safety of this approach, a phase I dose-escalation study of Re-188 P2045 in SSTR-positive lung cancer was performed. Patients were required to have stage IIIb or IV or recurrent non-small cell lung cancer or extensive stage or recurrent small cell lung cancer, performance status 0 to 1, and normal organ function. There were no limitations on the number of prior therapies. Tumor SSTR was detected with Tc-99m P2045. If positive and projected renal dose of radiation from Re-188 P2045 was less than 20 Gy, treatment with escalating doses of Re-188 P2045 was instituted. Three doses were evaluated 30 mCi/m2, 60 mCi/m2, and 90 mCi/m2. A single dose of Re-188 P2045 was allowed. Dose-limiting toxicity was defined as > or = grade 3 nonhematologic toxicity or grade 4 hematologic toxicity. Fifteen patients were enrolled. The median age was 61 years. Fourteen patients had > or = 2 prior chemotherapy regimens. All were imaged with Tc-99m P2045, eight patients received Re-188 P2045. The most common toxicity was mild lymphopenia. The trial was halted at the 90 mCi/m2 level when three patients were projected to have renal radiation doses above 20 Gy. The monoclonal antibody was not determined, and no responses were seen. Five of the eight patients (62.5%, 95% CI: 24-91%) had stable disease for at least 8 weeks, all of whom entered the study with progressive disease. Median overall survival was 11.5 months. This trial demonstrated that Re-188 P2045 was well tolerated. Tc-99m P2045 imaging allows identification of patients who may benefit from this treatment. Although responses were not seen, survival for these heavily pretreated patients is interesting and merits further research.

Occurrence of adverse, often preventable, events in community hospitals involving nephrotoxic drugs or those excreted by the kidney

Medication errors in patients with reduced creatinine clearance are harmful and costly; however, most studies have been conducted in large academic hospitals. As there are few studies regarding this issue in smaller community hospitals, we conducted a multicenter, retrospective cohort study in six community hospitals (100 to 300 beds) to assess the incidence and severity of adverse drug events (ADEs) in patients with reduced creatinine clearance. A chart review was performed on adult patients hospitalized during a 20-month study period with serum creatinine over 1.5 mg/dl who were exposed to drugs that are nephrotoxic or cleared by the kidney. Among 109,641 patients, 17,614 had reduced creatinine clearance, and in a random sample of 900 of these patients, there were 498 potential ADEs and 90 ADEs. Among these ADEs, 91% were preventable, 51% were serious, 44% were significant, and 4.5% were life threatening. Of the potential ADEs, 54% were serious, 44% were significant, 1.6% were life threatening, and 96.6% were not intercepted. All 82 preventable events could have been intercepted by renal dose checking. Our study shows that ADEs were common in patients with impaired kidney function in community hospitals, and many appear potentially preventable with renal dose checking.

Sensitive Detection of Renal Function in Multiple Myeloma (MM) Patients (pts) Via Estimated Glomerular Filtration Rate (eGFR) Unmasks Manifest Renal Function in Pts Receiving Lenalidomide and Suggests to Serve as An Additional Predictive Tool of Treatment Response.

Abstract 4945 IntroductionCurrent goals in MM-treatment are to achieve prolonged remission- and treatment-free-intervals and to transform the disease into an indolent course. Effective anti-MM-substances are IMIDs, such as thalidomide and lenalidomide, the latter showing a different mode of action and favorable side-effect profile. Lenalidomide-induced side effects may, however, increase with renal impairment (RI) and dose adjustments are recommended, thus sensitive RI-monitoring is desirable. We assessed renal function (RF) via estimated glomerular filtration rate (eGFR by MDRD) and correlated this with lenalidomide-response, since we have shown that eGFR-monitoring is a sensitive method to detect RI in various hematological and solid tumor- (Kleber M. et al., Ann Oncol 2007) and explicitly valuable in MM-pts (Kleber M. et al., EJH 2009). MethodsThirty-two consecutive MM pts received lenalidomide in G1-4 treatment groups at our center between 6/2006-7/2009 (G1=lenalidomide 25mg/dex 40mg [n=12]; G2: lenalidomide 25mg/low-dose-dex-[n=10]; G3: lenalidomide 10mg [n=7]; G4: lenalidomide plus chemotherapy [n=3]). Serum creatinine and eGFR were determined before lenalidomide and after 1, 3 and 6 months. RI was assessed by NKDOQI- and MM-response according to EBMT-criteria. ResultsThe median pt age was 67 years (range; 44-78), with most having stage II/III disease by Durie&Salmon (97%; ISS II/III: 75%). IgG-myeloma and normal cytogenetics were present in 84% and 56%, respectively. Pretreatment was considerable with ≥2 previous therapy lines in 71% and autologous or allogeneic stem cell transplantations performed in 62% and 12%, respectively. Median β2-MG- and hemoglobin-levels were 3.4mg/dl and 11.3mg/dl, respectively. Before lenalidomide-initiation, RF appeared normal with median creatinine levels of 1.0mg/dl (range; 0.6-2.7), nevertheless, mild RI was readily detectable via eGFR (81ml/min/1.73m2, range; 27-119). Of note, mild (eGFR<90) and moderate RI (eGFR<60) before lenalidomide-initiation was prominent in 65% and 31% of pts, respectively. In pts achieving a PR due to lenalidomide treatment, median creatinine-values before and during treatment (1, 3 and 6 months) decreased from 1.0mg/dl to 0.9, 0.9 and 0.8mg/dl, which was even more prominently detectable via eGFR with 71 at baseline, increasing to 86, 85 and 97ml/min/1.73m2, respectively. Pts with SD showed creatinine-values before and during treatment (1, 3 and 6 months) of 0.9 at baseline, increasing to 1.1, 1.0 and 1.1mg/dl, whereas eGFR changed from 86 to 69, 77 and 70ml/min/1.73m2, respectively (Fig. 1). With PD, the creatinine increased from 0.9 to 1.3mg/dl, and eGFR values substantially deteriorated from 87 to 61ml/min/1.73m2; this demonstrating that with lenalidomide response, RI recovered and response was readily detected via eGFR-assessment. The median lenalidomide treatment duration lasted 36 weeks (range; 4-96), inducing an ORR (CR/PR) in 31% (n=10), clinical benefit rate (CBR=CR+PR+MR) in 37% (n=12) and stunning disease stabilisation rate (CBR+SD) in 97% (n=31 pts), this comparing favorably with previous reports, albeit our pt cohort was older, more pretreated and bearing substantial comorbidities than in both trials leading to lenalidomide/dex-FDA-approval. Lenalidomide was well tolerated with WHO-CTC-grade (G) ≥2 side effects in 8 pts (25%): 3 showed neutropenia (G2+3), 2 pts skin rash/exanthema (G2), and disorientation (G2), GvHD-exacerbation (G3) and atrial fibrilation (G3) in each one pt. ConclusionsWe highlight the importance to detect RI by means of eGFR-assessment, which allows to identify mild and moderate RI more prominently and reliably than via creatinine determination. Our results underline that lenalidomide in elderly MM pts is feasible and well tolerated. Renal improvement by eGFR analysis was associated with lenalidomide-response which is currently being assessed in even more detail. [Display omitted] DisclosuresKleber:Celgene: Research Funding. Haas:Celgene: Research Funding. Engelhardt:Celgene: Research Funding.

Altered Mental Status from Acyclovir

Acyclovir is widely used in the treatment of herpes virus infections, particularly herpes simplex virus and varicella-zoster virus. Acyclovir, when given promptly upon the start of a herpes zoster eruption, speeds healing and diminishes acute pain. Because acyclovir is a commonly used medication, it is crucial for health providers to be aware of appropriate dosing as well as possible side effects. We present this case to increase awareness of the potential for inappropriate dosing of acyclovir and the presentations of patients with toxic effects. We report the case of a 65-year-old man with a past medical history significant for chronic kidney disease who presented to the Emergency Department with progressive confusion and ataxia over 2 days. Thorough questioning in the patient's native language revealed that he had recently started a medication for a "rash." Neither he nor his family knew the name of the new medication; further investigation revealed it to be acyclovir. Although other diagnoses were considered in the differential diagnosis for this patient with altered mental status, he was treated for presumed acyclovir toxicity and given prompt dialysis, upon which his symptoms resolved. It is important for physicians to remember that even common medications such as acyclovir can have serious side effects and complications. In this case, renal dosing was not used in a patient on hemodialysis. Acyclovir must be renally dosed and carefully monitored through drug level measurement in patients with limited kidney function to prevent serious side effects, such as the neurological sequelae demonstrated in this case report. Emergency physicians should be aware of the potential for inappropriate dosing of this medication and the presentations of patients with toxic effects.

Kidney protection during peptide receptor radionuclide therapy with somatostatin analogues

This review focuses on the present status of kidney protection during peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues. This treatment modality for somatostatin receptor-positive tumours is limited by renal reabsorption and retention of radiolabelled peptides resulting in dose-limiting high kidney radiation doses. Radiation nephropathy has been described in several patients. Studies on the mechanism and localization demonstrate that renal uptake of radiolabelled somatostatin analogues largely depends on the megalin/cubulin system in the proximal tubule cells. Thus methods are needed that interfere with this reabsorption pathway to achieve kidney protection. Such methods include coadministration of basic amino acids, the bovine gelatin-containing solution Gelofusine or albumin fragments. Amino acids are already commonly used in the clinical setting during PRRT. Other compounds that interfere with renal reabsorption capacity (maleic acid and colchicine) are not suitable for clinical use because of potential toxicity. The safe limit for the renal radiation dose during PRRT is not exactly known. Dosimetry studies applying the principle of the biological equivalent dose (correcting for the effect of dose fractionation) suggest that a dose of about 37 Gy is the threshold for development of kidney toxicity. This threshold is lower when risk factors for development of renal damage exist: age over 60 years, hypertension, diabetes mellitus and previous chemotherapy. A still experimental pathway for kidney protection is mitigation of radiation effects, possibly achievable by cotreatment with amifostine (Ethylol), a radiation protector, or with blockers of the renin-angiotensin-aldosterone system. Future perspectives on improving kidney protection during PRRT include combinations of agents to reduce renal retention of radiolabelled peptides, eventually together with mitigating medicines. Moreover, new somatostatin analogues with lower renal retention may be developed. Furthermore, knowledge on kidney protection from radiolabelled somatostatin analogues may be expanded to other peptides.

Long-Term Renal Toxicity in Children Following Fractionated Total-Body Irradiation (TBI) Before Allogeneic Stem Cell Transplantation (SCT)

To retrospectively assess the incidence and time course of renal dysfunction in children (< or = 16 years) following total- body irradiation (TBI) before allogeneic stem cell transplantation (SCT). Between 1986 and 2003, 92 children (median age, 11 years; range, 3-16 years) underwent TBI before allogeneic SCT. 43 of them had a minimum follow-up of 12 months (median, 51 months; range, 12-186 months) and were included into this analysis. Conditioning regimen included chemotherapy and fractionated TBI with 12 Gy (n = 26) or 11.1 Gy (n = 17). In one patient, renal dose was limited to 10 Gy by customized renal shielding due to known nephropathy prior to SCT. Renal dysfunction was defined as an increase of serum creatinine > 1.25 times the upper limit of age-dependent normal. Twelve children (28%) experienced an episode of renal dysfunction after a median of 2 months (range, 1-10 months) following SCT. In all but one patient renal dysfunction was transient and resolved after a median of 8 months (range, 3-16 months). One single patient developed persistent renal dysfunction with onset at 10 months after SCT. None of these patients required dialysis. The actuarial 3-year freedom from persistent renal toxicity for children surviving > 12 months after SCT was 97.3%. The incidence of persistent renal dysfunction after fractionated TBI with total doses < or = 12 Gy was very low in this analysis.

Identification of optimal renal dosage adjustments for traditional and extended-infusion piperacillin-tazobactam dosing regimens in hospitalized patients.

This study examined the effect of various levels of renal impairment on the probability of achieving free drug concentrations that exceed the MIC for 50% of the dosing interval (50% fT > MIC) for traditional and extended-infusion piperacillin-tazobactam (TZP) dosing strategies. It also identified optimal renal dosage adjustments for traditional and extended-infusion dosing schemes that yielded probability of target attainment (PTA) and exposure profiles that were isometric to those of the parent regimens. Data from 105 patients were analyzed using the population pharmacokinetic modeling program BigNPAG. To assess the effect of creatinine clearance (CL(CR)) on overall clearance, TZP clearance was made proportional to the estimated CL(CR). A Monte Carlo simulation (9,999 subjects) was performed for the traditional dosing scheme (4.5 g infused during 30 min every 6 h) and the extended-infusion TZP dosing scheme (3.375 g infused during 4 h every 8 h). The fraction of simulated subjects who achieved 50% fT > MIC was calculated for the range of piperacillin MICs from 0.25 to 32 mg/liter and stratified by CL(CR). The traditional TZP regimen displayed the greatest variability in PTA across MIC values, especially for MIC values exceeding 4 mg/liter, when stratified by CL(CR). In contrast, the PTA for the extended-infusion TZP regimen exceeded >or=80% for MIC values of <or=8 mg/liter across all CL(CR) strata. All regimens were associated with suboptimal PTA for MIC values of >or=32 mg/liter irrespective of the CL(CR). The CL(CR) adjustments for traditional and extended-infusion TZP dosing regimens should be considered at a CL(CR) of <or=20 ml/min.

Impact of a Renal Drug Dosing Service on Dose Adjustment in Hospitalized Patients with Chronic Kidney Disease

Appropriate drug selection and dosing for patients with chronic kidney disease (CKD) is important to avoid unwanted drug effects and ensure optimal patient outcomes. To assess the rate of inappropriate dosing in patients with CKD in a nephrology unit and to evaluate the impact on dose adjustment, adverse drug events (ADEs), and drug cost of having a pharmacist accompany a team of physicians on their rounds. This was a comparative study with a preintervention and postintervention design. The preintervention phase served as the control; it was prospective and observational only and was conducted from the beginning of February to the end of May 2007. The second phase (intervention phase) was conducted from the beginning of March to the end of June 2008. Two random samples of 300 patients with an estimated creatinine clearance less than or equal to 50 mL/min were included. During the intervention phase, a clinical pharmacist made rounds with the nephrology unit team and gave dosing adjustment recommendations when needed. A collection of reliable and up-to-date drug information references that are commonly used globally were used during the intervention. In the preintervention group, drug dosage adjustment or avoidance, based on renal function, was necessary in 607 of 2814 (21.6%) prescriptions. Of these, 322 (53.0%) did not comply with guidelines. In the intervention group, adjustment was necessary for 640 of 2981 (21.5%) prescriptions. The pharmacist made 388 recommendations related to dosing adjustment, 212 (54.6%) of which were accepted by physicians. Clinicians' noncompliance with dosing guidelines decreased to 176 (27.5%) (p < 0.001). In the preintervention group, 64 (21.3%) patients had a suspected ADE, with a total of 73 events. In the intervention group, this number was significantly lower with 49 events in 48 (16.0%) patients (p < 0.05). The intervention resulted in drug cost savings of $2250 US. A renal drug dosing service for patients hospitalized with CKD can increase the proportion of drug dosing that is adjusted to take into account renal function. This can save drug costs and may prevent ADEs.

Analysis of Clinical and Dosimetric Factors Associated With Change in Renal Function in Patients With Gastrointestinal Malignancies After Chemoradiation to the Abdomen

To analyze clinical and dosimetric factors associated with change in renal function in patients with gastrointestinal malignancies after chemoradiation to the abdomen. A retrospective review of 164 patients with gastrointestinal malignancies treated between 2002 and 2007 was conducted to evaluate change in renal function after concurrent chemotherapy and three-dimensional conformal abdominal radiotherapy (RT). Laboratory and biochemical endpoints were determined before RT and after RT at 6-month intervals. Factors assessed included smoking, diabetes, hypertension, blood urea nitrogen, creatinine, creatinine clearance (CrCl), chemotherapy, and dose-volume parameters. Renal toxicity was assessed by decrease in CrCl and scored using the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer late radiation morbidity scoring schema. Of 164 patients, 63 had clinical and dosimetric data available. Median follow-up was 17.5 months. Creatinine clearance declined from 98.46 mL/min before RT to 74.20 mL/min one year after chemoradiation (p < 0.0001). Mean decrease in CrCl was 21.37%. Pre-RT CrCl, percentage of bilateral renal volume receiving at least 10 Gy (V(10)), and mean kidney dose were significantly associated with development of Grade > or =2 renal complications at 1 year after chemoradiation (p = 0.0025, 0.0170, and 0.0095, respectively). We observed correlation between pre-RT CrCl, V(10), and mean kidney dose and decline in CrCl 1 year after chemoradiation. These observations can assist in treatment planning and renal dose constraints in patients receiving chemotherapy and abdominal RT and may help identify patients at increased risk for renal complications.

Neurotoxicity Associated with Standard Doses of Piperacillin in an Elderly Patient with Renal Failure

Piperacillin–tazobactam, a b-lactam–b-lactamase inhibitor combination, is a penicillin derivative with a broad spectrum of antibacterial activity against most Gram-positive and Gram-negative bacteria. Although tazobactam is non-toxic, piperacillin, like other b-lactam antibiotics, is neurotoxic to some extent if excessively accumulated. Neurotoxicity caused by excessive doses of b-lactam antibiotics is well-known [1], but its association with the renal failure package insert dose of piperacillin (4 g/day) has not been reported to date. Herein, we describe the development of acute unexplained encephalopathy in an 87-year-old man with advanced renal failure who had been treated for 3 days with piperacillin/tazobactam 2.25 g every 12 h. Withdrawal of piperacillin/tazobactam and initiation of high-flux hemodialysis rapidly reversed his encephalopathy. This is the first report of piperacillin-induced neurotoxicity caused by the minimum recommended dose in an elderly man with advanced renal failure.

Renal atrophy secondary to chemoradiation treatment of abdominal malignancies

e15532 Background: Information on renal atrophy following abdominal chemoradiation (CRT) is limited. Methods: Patients who received concurrent CRT to the abdomen between 2002 and 2008 were identified for this study to evaluate change in renal size (RS) and function following CRT. Imaging and biochemical data were obtained prior to radiation (RT) and after RT in 6 month intervals. RS was defined by craniocaudal measurement on CT images. Renal function was assessed by serum creatinine and creatinine clearance (CrCl) using the Cockcroft-Gault formula. The primarily irradiated kidney (PK) was defined as the kidney that received the greater mean kidney dose. Results: Median patient age was 64 years (range 31–87), 51.5% of 130 patients were male. Primary disease sites were pancreas (61.5%), periampullary (16.1%), stomach (10.8%), gastroesophageal junction (10%), and retroperitoneum (1.5%). Median follow up was 9.4 months (range 0–55.4 mos). Median radiation dose was 50.4Gy (range 12.6- 55.8Gy). Mean dose to the PK was 18.6 Gy. Compensatory hypertrophy of the non-PK was not seen. Age, gender, hypertension, diabetes, smoking, pre-RT CrCl, and pre-RT RS were not associated with renal atrophy at 12 months post RT. Percent volumes of the PK receiving ≥10Gy (V10), 15Gy (V15), and 20Gy (V20) were significantly associated with renal atrophy at 12 months post RT (p=0.0030, 0.0041, and 0.0046 respectively). Conclusions: Significant detriments in PK size and renal function were seen following abdominal CRT. V10, V15, and V20 were associated with renal atrophy at 12 months post RT. These observations can assist with renal dose constraints in CRT treatment planning for patients at increased risk for renal complications. [Table: see text] No significant financial relationships to disclose.

The influence of Bz-DOTA and CHX-A″-DTPA on the biodistribution of ABD-fused anti-HER2 Affibody molecules: implications for 114mIn-mediated targeting therapy

Affibody molecules represent a novel class of high-affinity agents for radionuclide tumour targeting. Fusion of the Affibody molecules with an albumin-binding domain (ABD) enables modification of the blood kinetics of the Affibody molecules and reduction of the renal dose. (177)Lu-CHX-A''-DTPA-ABD-(Z(HER2:342))(2), an anti-HER2 Affibody molecule-ABD fusion protein has earlier demonstrated promising results in treatment of HER2-expressing micro-xenografts in mice. The use of the in vivo generator (114m)In/(114)In as a label for ABD-fused Affibody molecules would create preconditions for efficient treatment of both micrometastases (due to conversion and Auger electrons of (114m)In) and bulky tumours (due to high-energy beta particles from the daughter nuclide (114)In). The goal of this study was to investigate if different chelators influence the biodistribution of ABD-(Z(HER2:342))(2) and to find an optimal chelator for attachment of (114m)In to the Affibody molecule-ABD fusion protein. Isothiocyanate derivatives of Bz-DOTA and CHX-A''-DTPA were coupled to ABD-(Z(HER2:342))(2). The cellular processing of both conjugates was studied in vitro. The influence of chelators on the biodistribution was investigated in mice using double isotope ((114m)In and (111)In) labelling. The apparent affinity of CHX-A''-DTPA-ABD-(Z(HER2:342))(2) and Bz-DOTA-ABD-(Z(HER2:342))(2) to the extracellular domain of HER2 was similar, 13.5 and 15.0 pM, respectively. It was found that both conjugates were internalized by SKOV-3 cells. The use of CHX-A''-DTPA provided better cellular retention of the radioactivity, better tumour accumulation of radioactivity and better tumour to organ dose ratios than Bz-DOTA-ABD-(Z(HER2:342))(2). CHX-A''-DTPA is more suitable for (114m)In labelling of Affibody molecule-ABD fusion proteins for radionuclide therapy.

Amphotericin B-induced nephrotoxicity: characterization of blood and urinary biochemistry and renal morphology in mice

This study was conducted to characterize blood and urinary biochemistry, and renal morphology, after single or 1-week repeated dosing of mice with the polyene macrolide antibiotic, amphotericin B (AMB). AMB was intravenously administered to mice at 2 or 4 mg/kg for the single-dose experiment or once daily at 1 or 2 mg/kg for 1 week for the repeated-dose experiment. The most prominent histopathological findings included necrosis of the tubular epithelial cells in the thick ascending limb of Henle's loop in the renal outer medulla at a single dose of 2 or 4 mg/kg, and the severity of the lesion was dose-dependent. Blood chemistry and urinalysis revealed several changes suggestive of renal dysfunction such as reduction of plasma filtration ability (increases in plasma creatinine and blood urea nitrogen, a decrease in creatinine clearance) and polyuria accompanied with dehydration (decrease in renal water reabsorption, increases in plasma total protein and albumin) at a dose of 4 mg/kg in the single-dose experiment. Among the parameters analyzed, urinary lactate dehydrogenase was the most sensitive and reliable parameter for the prediction of AMB-induced nephrotoxicity in mice. These data provided comprehensive information on the nephrotoxicity of AMB and indicate useful markers for the sensitive detection of AMB-induced renal injury in mice.

Evidence-Based Practice Habits: Transforming Research Into Bedside Practice

Evidence-Based Practice Habits: Transforming Research Into Bedside Practice

Nephrotoxicity of tacrolimus and preventive effect of diltiazem: experiment with rats

To study the nephrotoxicity tacrolimus (FK506) at the therapeutic dose the preventive effect of diltiazem (Dil), a calcium antagonist against the FK506-induced pathological changes. 24 Sprague-Dawley male rats were randomly divided into 4 equal groups: cyclosporine A (CsA) group, undergoing treatment of CsA at the therapeutic dose after kidney transplantation (25 mg x kg(-1) x d(-1)) for 4 weeks, FK506 group treated with FK506 (0.8 mg x kg(-1) x d(-1)), FK506 + Dil group treated with FK506 (0.8 mg x kg(-1) x d(-1)) and Dil at the dose of 8 mg x kg(-1) x d(-1), and control group. Four weeks later body weight was measured and 24 h urine sample was collected. Then the rats were killed. Their kidneys underwent light and transmission electron microscopy. The body weight ad weight gain, and the weights of both kidney of the CsA group were all significantly lower than those of the other 3 groups (all P < 0.05), and there were not significant differences in there parameters among the other 3 groups. The serum creatinine levels of the FK506 and CsA groups were (36.0 +/- 2.6) and (34.2 +/- 4.5) micromol/L respectively, both significantly higher than those of the FK506 + Dil and control groups [(28.5 +/- 2.1) and (29.2 +/- 3.428) micromol/L respectively, all P < 0.05], however, there was no significant difference between the FK506 + Dil and control groups. The creatinine clearance rate of the FK506 and CsA groups were (0.63 +/- 0.45) and (0.58 +/- 0.39) ml x min(-1) x 100 g(-1) respectively, significantly lower than those of the FK506 + Dil and control groups [(1.55 +/- 0.91) and (1.02 +/- 0.62) mlxmin(-1) x 100 g(-1) respectively, all P < 0.05]. Pathological examination showed epithelial cell cloudy swelling and vacuolization and interstitial fibrosis in the renal tubules, mitochondria swelling and vacuolization in renal tubular epithelial cells, renal arteriole hyalinization, and foot cell conjugation glomerulus, mitochondria swelling and vacuolization in the FK506 and CsA groups, and such changes were relatively mild in the FK506 + Dil group. FK506 at renal transplantation therapeutic dose, as well as CsA, induces pathological changes in renal tissues and ultrastructural organization. Dil is able to prevent FK506-induced these pathological changes.

Population Pharmacokinetics of High-Dose, Prolonged-Infusion Cefepime in Adult Critically Ill Patients with Ventilator-Associated Pneumonia

A population pharmacokinetic model of cefepime was constructed from data from adult critical care patients with ventilator-associated pneumonia (VAP). A total of 32 patients treated with high-dose cefepime, 2 g every 8 h (3-h infusion) or a renal function-adjusted equivalent dose, were randomized into two groups--26 for the initial model and 6 for model validation. Serum samples of cefepime were collected at steady state. Nonparametric adaptive grid population modeling was employed using a two-compartment K(slope) pharmacokinetic model relating the elimination rate constant (K(10)) to renal function, as defined by creatinine clearance (CL(CR)), and central distribution volume (V(1)) to total body weight (TBW). The final model was described by the following equations: K(10) = 0.0027 x CL(CR) + 0.071 h(-1) and V(1) = TBW x 0.21 liter/kg. The median intercompartmental transfer constants K(12) and K(21) were 0.780 h(-1) and 0.472 h(-1), respectively. Using these median parameter estimates, the bias, precision, and coefficient of determination for the initial model were 11.3 microg/ml, 24.0 microg/ml, and 26%, respectively. The independent validation group displayed a bias, precision, and coefficient of determination of -1.64 microg/ml, 17.1 microg/ml, and 62%, respectively. Time-concentration profiles were assessed for various dosing regimens, using 5,000-patient Monte Carlo simulations. Among the regimens, the likelihoods of 2 g every 8 h (3-h infusion) achieving free drug concentrations above the MIC for 50% of the dosing interval were 91.8%, 78.1%, and 50.3% for MICs of 8, 16, and 32 microg/ml, respectively. This study provides a pharmacokinetic model capable of predicting cefepime concentrations in critically ill patients with VAP.