Change In CrCl Research Articles

Safety and efficacy of daratumumab use in patients with renal impairment and hemodialysis.

8026 Background: Targeting CD38 in multiple myeloma (MM) using daratumumab-based regimens can prolong remission in both the newly diagnosed and relapsed settings. However clinical trials have excluded patients with creatinine clearances (CrCl) <30 mL/min, warranting real-world analysis of daratumumab use in MM patients with renal insufficiency. Methods: Following IRB approval, we performed a retrospective chart review of relapsed MM patients at our institution who had reduced CrCl and received at least one dose of either daratumumab between October 2018 and January 2022. All subjects received IV daratumumab, 52% went on to receive SQ. Outcomes included change in CrCl during treatment, adverse events, and survival. Survival was estimated using product-limit estimates. CrCl groups at daratumumab initiation of more or less than 30 were compared using the chi-square test or Fisher’s exact test, as deemed appropriate, for categorical variables and the two-sample t-test or Mann-Whitney test for continuous data (SAS Institute Inc., Cary, NC). Results: 101 MM patients were included, with median age of 74 (54-92); 46 (45.5%) were female. 14% were on hemodialysis. Patients had a median of 2 prior lines of therapy. Distribution of R-ISS stages were I (20%), II (35%), and III (45%). High-risk cytogenetics were present in 20%. A median of 23 daratumumab infusions (1-60) were delivered over a median of 18 months (median IV=16, SQ=10). Daratumumab regimens included DRD (32%), DPD (35%), DKD (13%), and DVD (35%). Median CrCl at MM diagnosis and at daratumumab initiation was 45 (7.3-101) and 40 (5.3-107), respectively, with 33% having CrCl <30. Following 3, 6, and 12 months (n = 95, 89, 69) on daratumumab-based regimens, median CrCl were 45, 43, and 41, respectively. There were no differences in renal function in patients who went on to receive SQ daratumumab. 16 patients had died at the time of data collection, and the median survival was 63 months. Of the 101 patients, 16 subjects were deceased at the time of data collection, and 23% of subjects had gone on to subsequent treatments. Analysis showed that there was a progression-free survival of 54% at 5 years. The most common adverse events reported were anemia (37%) and neutropenia (15%). Infusion-related reactions were reported in 19% of patients. Conclusions: This is the largest real-world assessment of outcome for MM patients treated with daratumumab-containing regimens in the setting of renal insufficiency. There was no significant impact of the treatment on renal function at 12 months. Compared to published data on patients treated with CrCl>30, there does not appear to be a detriment to survival or an increase in adverse events when using daratumumab regimens in patients with more advanced renal insufficiency.

Scoping review of augmented renal clearance in critically ill pediatric patients.

Augmented renal clearance (ARC), a phenomenon of enhanced elimination of renal solutes, has been described in adult critically ill patients, but little is known about the phenomenon in children. The aim of this scoping review was to gather and summarize all evidence on ARC in pediatric patients to examine its breadth and depth including prevalence, risk factors, and pharmacokinetic alterations and identify any gaps for further areas of inquiry. PubMed, Embase, and Web of Science were searched for titles, abstracts, or keywords that focused on ARC. Non-English studies, reviews, and nonhuman studies were excluded. Reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews (PRISMA-ScR) guidelines. Data were extracted on article type, study details, patient population, ARC definition and prevalence, methods of renal function assessment, and study results. A total of 215 citations were found with 25 citations meeting the criteria for inclusion in pediatrics (2102 total patients); the majority of studies (84%) focused on pharmacokinetics (PK) of antimicrobial agents. The median/mean age range was 1.25-12years. There were a total of 10 different definitions of ARC. The prevalence of ARC ranged from 7.8% to 78%. The most common method for documenting creatinine clearance (CrCl) was the modified Schwartz equation (64%). Only 20% of studies reported risk factors for ARC including low serum creatinine, increasing age, febrile neutropenia, male, septic shock, and treatment with antibiotics. Glycopeptide antimicrobials were the most evaluated class (42.9%) among the 21 antimicrobial drug studies. All studies reported increased drug clearance and/or poor probability of achieving target concentrations of the agents studied. ARC showed variable prevalence in pediatric patients likely due to the lack of a standard definition and many studies not considering age-related changes in CrCl with pediatric intensive care unit (PICU) patients. ARC was shown to impact PK of antibiotics commonly administered to pediatric patients, which may necessitate changes in standard dosing regimens.

Modulation by Antenatal Therapies of Cardiovascular and Renal Programming in Male and Female Offspring of Preeclamptic Rats

Morbidity and mortality risks are enhanced in preeclamptic (PE) mothers and their offspring. Here we asked if sexual dimorphism exists in (i) cardiovascular and renal damage evolved in offspring of PE mothers, and (ii) offspring responsiveness to antenatal therapies. PE was induced by administering NAME (50 mg/kg/day, oral gavage) to pregnant rats for 7 days starting from gestational day 14. Three therapies were co-administered with L-NAME, atrasentan (ETA receptor blocker), terutroban (TXA2 receptor blocker), or α-methyldopa (central sympatholytic drug). Cardiovascular and renal profiles were assessed in 3-month-old offspring. Compared with offspring of non-PE rats, PE offspring exhibited elevated systolic blood pressure and proteinuria and reduced heart rate and creatinine clearance (CrCl). Apart from a greater bradycardia in male offspring, similar PE effects were noted in male and female offspring. While terutroban, atrasentan, or α-methyldopa partially and similarly blunted the PE-evoked changes in CrCl and proteinuria, terutroban was the only drug that virtually abolished PE hypertension. Rises in inflammatory (TNFα) and oxidative (isoprostane) markers in cardiac and renal tissues of PE offspring were mostly and equally eliminated by all therapies in the two sexes, except for a greater dampening action of atrasentan, compared with α-methyldopa, on tissue TNFα in female offspring only. Histopathologically, antenatal terutroban or atrasentan was more effective than α-methyldopa in rectifying cardiac structural damage, myofiber separation and cytoplasmic alterations, in PE offspring. Overall, the repair by antenatal terutroban or atrasentan of cardiovascular and renal anomalies in PE offspring is mostly sex-independent and surpasses the protection offered by α-methyldopa, the conventional PE therapy.

Alendronate use in older patients with reduced renal function: challenges and opportunities in clinical practice.

Oral bisphosphonates are not recommended in patients with creatinine clearance (CrCl) <35ml/min, although this is not supported by post hoc analyses of pivotal oral bisphosphonate studies. As both osteoporosis and renal insufficiency are more prevalent with advancing age, it is important to determine the safety and efficacy of oral bisphosphonates among these patients. Patients with CrCl <35ml/min on alendronate (group A, n=98), with CrCl <35ml/min conservatively managed (group B, n=96), and with CrCl ≥35ml/min on alendronate (group C, n=96) were followed up to 22 months. Primary outcomes were mean change in CrCl from baseline in group A compared with groups B and C, respectively. Secondary outcomes were the incidence of osteoporotic fractures and adverse events between groups. There was no significant change in CrCl from baseline when comparing group A (-1.53±6.83ml/min) with group B (0.59±5.17ml/min) (p=0.075), and group A with group C (-3.71±7.54ml/min) (p=0.163). There was no significant increase in incidences of osteoporotic fractures in group A compared with group B (adjusted relative risk (aRR) 2.02, 95% confidence interval (CI) 0.64-6.37) and group A compared with group C (aRR 1.15, 95% CI 0.46-2.89). There was no significant difference in incidences of acute kidney injury (AKI) in group A compared with group B (aRR 0.48, 95% CI 0.20-1.12). Although statistically non-significant, there was an increase in AKI incidence in group A compared with group C (RR 7.84, 95% CI 0.98-62.66). Among patients with CrCl <35ml/min, alendronate therapy was not associated with significant deterioration in renal function from baseline. Although not powered for secondary outcomes, there were no statistically significant differences in osteoporotic fracture or AKI incidence between the groups.

Comparison of Combined/Carvedilol Moderate Dose Atorvastatin to Single High Dose Atorvastatin for the Prevention of Contrast-Induced Nephropathy after Cardiac Catheterization

Background: Contrast-induced nephropathy (CIN) is associated with increased morbidity, and the need for short-term hemodialysis. Although several preventive measures have been used, the best approach to prevent CIN is still controversial. Objectives: This study is intended to evaluate the protective effect of carvedilol/ medium dose statin compared to the recommended high dose atorvastatin on the development CIN in patients undergoing elective cardiac catheterization (CC). Methods: A total of 144 patients planned for CC were randomly assigned to: • Group (A): 49 patients received atorvastatin as single high dose 80 mg 12 hours before CC and another 40 mg of atorvastatin 2 hours before PCI. • Group (B): 48 patients were prescribed carvedilol 12.5 mg twice daily for seven days before CC and continued for 24 hours post CC, plus 40 mg atorvastatin 12 hours before CC. • Group (C): 47 patients received 40 mg atorvastatin 12 hours before CC. Results: The baseline characteristics of the 3 groups were comparable. CIN incidence was the lowest in group A, but was not significantly different (p=0.420). CIN developed in 4 (8.2%), 6(12.2%), and 8(17%) patients in groups A, B, and C respectively. Median change in CrCl 48 hours, and serum NGAL 4 hours post CC was significantly lower in group A compared to group C (p=0.0330, p=0.0348 respectively). Conclusions: The present study revealed that, combined carvedilol/statin regimen was comparable to single high dose atorvastatin in CIN prevention. However, short high dose of atorvastatin might be preferable in terms of kidney function preservation.

Amlodipine and calcineurin inhibitor-induced nephrotoxicity following allogeneic hematopoietic stem cell transplant.

Studies in the renal transplant population have suggested calcium-channel blockers (CCBs) may protect against calcineurin inhibitor (CNI)-induced nephrotoxicity. However, this has not been evaluated in the hematopoietic stem cell transplant (HSCT) population. This retrospective study reviews data from 350 consecutive patients who underwent allogeneic HSCT to determine whether amlodipine improved renal outcomes. Subject data included up to one year from CNI initiation. Patients in the amlodipine group (n=130) received an average of 143days treatment with amlodipine and experienced a smaller decrease in creatinine clearance (CrCl) through day 180. At day 30, change in CrCl was -17.4mL/min in the amlodipine cohort and -33.8mL/min in the control (P<0.001). At day 180, change in CrCl was -40.9 and -50.6mL/min, respectively (P=0.005). Incidence of hospitalization with acute kidney injury (AKI) was significantly lower in patients receiving amlodipine, 7.7% (10/132) vs 16.4% (36/220) (hazard ratio [HR] 0.44; 95% confidence interval [CI] 0.22-0.89). Median blood pressure in the amlodipine group remained <132/78 through day 360. Our data support the use of amlodipine for hypertension in the allogeneic HSCT population and provide evidence suggesting that CCBs protect against CNI-induced nephrotoxicity.

Ruxolitinib Therapy Improves Renal Function in Patients with Primary Myelofibrosis

Introduction. Renal dysfunction is commonly observed in patients with primary myelofibrosis (PMF), but its etiology remains largely unknown. Recent evidence suggests that in many cases it may be a direct consequence of PMF, rather than simply reflecting individual aging. Glomerulopathy, in fact, can be observed in PMF, presenting with mesangial proliferation and hypercellularity, likely as a consequence of abnormal cytokine expression, and case reports show that the use of ruxolitinib may improve its outcome.Methods. We performed a retrospective analysis of 100 patients with previously untreated PMF, receiving frontline treatment with single agent ruxolitinib at our institution between 07/2004 and 11/2013. Creatinine clearance (CrCl) values were calculated by Cockcroft-Gault equation at baseline and serially during treatment. Renal improvement was defined as best percentage change in CrCl during treatment as compared to baseline value. A group of 105 patients with PMF, receiving frontline treatment with a non-ruxolitinib-based therapy on protocol during the same time range, and matched by age, sex and CrCl, was used as control.Results. Baseline characteristics of 100 patients with previously untreated PMF receiving frontline ruxolitinib are shown in the Table. Eighty-one (81%) patients in the ruxolitinib group had an increase in CrCl while on treatment (as compared to baseline) vs 61 (58%) in the control group (p<0.001). A renal improvement (RI) ≥ 10% was achieved in 73 (73%) patients in the ruxolitinib group and 52 (50%) patients in the control group (p=0.01), after a median time of 11 and 7 months, respectively (p=0.32)(Figure). A RI ≥ 25% was achieved in a small population sample (33% and 23%, respectively).The association between baseline patient characteristics and achievement of a RI ≥ 10% was evaluated among all patients. On univariate analysis (UVA), factors associated with a RI ≥ 10% were non-Caucasian race (99% vs 88%, p=0.006), elevated baseline serum creatinine (1 mg/dL vs 0.9 mg/dL, p=0.05), low baseline CrCl (66 ml/min vs 78 mL/min, p<0.001) and use of a JAKi (58% vs 34%, p=0.001). On multivariate analysis (MVA), use of a JAKi maintained its independent association with a RI ≥ 10% (odd ratio 3, 95% confidence interval [CI] 1.6-5.5, p <0.001).After a median follow-up of 41 months (range, 1-159 months), all patients failed frontline treatment, and median failure-free survival (FFS) was 14 months (range, 1-117 months). Factors associated with prolonged FFS on UVA were intermediate-1 DIPSS plus score as compared to intermediate-2 and high score (53 months vs 24 months and 6 months, p<0.001), use of ruxolitinib (39 months vs 6 months, p<0.001) and achievement of a RI ≥ 10% (24 months vs 8 months, p=0.01). Achievement of a RI ≥ 10% maintained its independent association with prolonged FFS on MVA (hazard ratio 1.4, 95% CI 1.1-2, p=0.02).DiscussionThis is the first study showing that the use of ruxolitinib is associated with improved renal function in patients with PMF. Similarly to what is done in other hematological malignancies, routine kidney biopsies in patients with PMF and unexplained renal dysfunction may shed light on its etiology and help assess the efficacy on ruxolitinib for the treatment of PMF-related glomerulopathy. [Display omitted] DisclosuresVerstovsek:Incyte: Consultancy; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Circulating leptin levels predict the decline in renal function with age in a sample of adult men (The Olivetti Heart Study).

Leptin (LPT) is associated with a number of cardiovascular risk factors, such as high blood pressure (BP), insulin resistance and excess in body weight. Some studies find an unfavorable cross-sectional association between LPT and renal disease, in particular in patients with already known kidney dysfunction. There are few data on the relationship between LPT and changes in renal function over time in subjects without evidence of kidney dysfunction. Hence, the aim of this study is to estimate the predictive role of LPT on the decline in renal function occurring in an 8-year follow-up observation of a sample of adult apparently healthy men (The Olivetti Heart Study). The study includes 319 untreated normotensive and nondiabetic men without clinical evidence of renal dysfunction (creatinine clearance-CrCl > 60mL/min/1.73m2) at baseline. At baseline, LPT is significantly and positively associated with BMI, abdominal circumference, BP and Homa index, no relationship is found with CrCl. At the end of the 8-year follow-up, a significant association is detected between baseline LPT and changes occurring in BP. Moreover, an inverse correlation with changes in CrCl is found (r=- 0.12). This unfavorable relationship between baseline LPT and decline in renal function is also confirmed in the multivariate analyses, after adjustment for all potential confounders (R2 = 0.42, p < 0.01). The results of this prospective investigation suggest a predictive role of circulating LPT levels on decline in renal function over time, independently of main potential confounders, in normotensive and nondiabetic men with normal renal function at baseline.

139 - Amlodipine and Calcineurin Inhibitor Induced Nephrotoxicity Following Allogeneic Hematopoietic Stem Cell Transplant

Background: Previous studies, primarily in the renal transplant population, have suggested that calcium channel blockers (CCBs) may protect against calcineurin inhibitor (CNI)-induced nephrotoxicity. However, this has not been evaluated in the hematopoietic stem cell transplant population. Methods: We reviewed data from 350 consecutive patients who underwent allogeneic hematopoietic stem cell transplant (allo-HSCT) between 2006 and 2016 at a single institution to determine whether patients receiving amlodipine for hypertension had improved renal outcomes compared to patients who did not receive amlodipine. Subject data included up to one year from the initiation of a CNI. Results: Patients in the amlodipine group (n = 130) received 76 median days treatment with amlodipine and experienced a lesser median decline in creatinine clearance (CrCl) at predefined time points through day 180, as determined by a 2-tailed Mann-Whitney U-test. This trend remained through day 360 but did not reach statistical significance. At day 30, change in CrCl was -17.4 mL/min in the amlodipine cohort and -33.8 mL/min in the control group (P < .001). At day 180, median change in CrCl was -40.9 and -50.6 mL/min respectively (P = .005). A mixed-effects logistic regression model was used for multivariate analysis and found supra-therapeutic CNI levels (P < .0001), older age (P = .0006), past medical history of hypertension (P = .0171), and the use of antihypertensive medications other than amlodipine (P < .0001) correlated to a greater CrCl decline. For our secondary endpoint, we found that patients receiving amlodipine had a significantly lower risk of being hospitalized with acute kidney injury (AKI) (Figure 1). Probabilities of hospitalization were estimated utilizing the Kaplan-Meier method. Curves were compared and hazard-ratios calculated using log-rank tests. Hospitalization with AKI kidney injury occurred in 7.7% (10/130) of patients in the amlodipine cohort and 16.4% (36/220) of patients in the control group (P = .0218). Multivariate analysis found supratherapeutic CNI levels to also be an independent risk factor for hospitalization with AKI (P = .004). Patients receiving amlodipine were older (P = .005) and more likely to have a greater BMI (P = .0021), a greater baseline systolic and diastolic blood pressure (P < .0001), a lower baseline creatinine clearance (P = .016), and a past history of diabetes mellitus (P = .013) and hypertension (P < .0001) . Also, a higher rate of supratherapeutic CNI levels was found in the amlodipine cohort. Conclusion: Overall, we found more favorable renal outcomes in the amlodipine group despite holding greater baseline risks for renal decline compared to the control group. Our data support the use of amlodipine for hypertension in the allo-HSCT population and provide evidence suggesting that CCBs protect against CNI-induced nephrotoxicity.

Everolimus as a Calcineurin Inhibitor-Sparing Immunosuppressive Agent in Lung Transplant Recipients With Renal Impairment

SESSION TITLE: Transplant SESSION TYPE: Original Investigation Poster PRESENTED ON: Wednesday, November 1, 2017 at 01:30 PM - 02:30 PM PURPOSE: Calcineurin inhibitors (CNI) are considered a key component of maintenance immunosuppression following lung transplantation. However, CNI nephrotoxicity is a common and serious problem amongst lung transplant recipients. Everolimus (ERL), an inhibitor of the mechanistic target of rapamycin (mTOR), has been used as a CNI sparing immunosuppressive agent to allow renal recovery in patients with progressive renal impairment. Nevertheless, there is limited evidence to support the efficacy of this strategy to prevent rejection. This study aimed to evaluate the effect of ERL on renal and lung function in lung transplant recipients. METHODS: We conducted a retrospective analysis within a state-wide lung transplant service in Australia. Medical and pharmacy records were used to identify lung transplant recipients who were commenced on ERL from 2004 to 2015. Patients who received at least 6 consecutive months of ERL therapy during this period were included in the analysis. We recorded renal function and lung function 6 months before and 6 months after the initiation of ERL. Creatinine clearance (CrCl), derived from the Cockroft-Gault equation, was used as a measure of renal function. Lung function was reported as the percent predicted FEV1 and FVC. RESULTS: 44 patients were included in the analysis. The mean age was 49 ± 15 years. ERL was initiated at a median of 476 days (interquartile range 219-1247) post-transplant. The indication for ERL was renal impairment in 94%, malignancy in 4% and CNI related neurotoxicity in 2% of patients. After initiating ERL, 46% of patients had CNI ceased and the rest had a substantial dose reduction. At ERL initiation, mean CrCl was 52.6 ± 3.3 ml/min, mean percent predicted FEV1 70 ± 3% and FVC 77 ± 3%. In the 6 months prior to commencing ERL, there was a mean change in CrCl of -8.9 ± 2.4 ml/min (P=0.003), FEV1 -3.4 ± 1.9% (p=0.696), and FVC -1.2 ± 1.5% (p=1.000). 6 months after initiating ERL, the mean change in CrCl was +11.2 ± 2.4 ml/min (p<0.0001), FEV1 -5.3 ± 1.7% (p=0.024), and FVC -3.9 ± 1.4% (p=0.049). Excluded from the analysis were 8 patients who were on ERL for less than 6 months. 6 patients had ERL ceased; 2 for rejection, 2 for suspected pneumonitis, 1 for drug intolerance and 1 to aid wound healing after a motor vehicle accident. There were 2 deaths during this period; one due to chest sepsis and the other from liver failure, neither of which could be directly related to toxicity from ERL. These 8 patients received ERL for at least 3 months and were included in a 3-months analysis. At 3 months, there was a similar increase in CrCl of +11.6 ± 2.3 ml/min (p<0.0001) and no significant change in FEV1 and FVC. CONCLUSIONS: In lung transplant recipients with renal impairment, the use of ERL as a CNI sparing agent is associated with improvement in renal function. However, the efficacy of this maintenance immunosuppression strategy in preventing rejection requires elucidation with further studies. CLINICAL IMPLICATIONS: The use of ERL allows CNI withdrawal and renal recovery in lung transplant recipients with renal impairment. These patients should be closely followed up with frequent monitoring of lung function. DISCLOSURE: The following authors have nothing to disclose: Shaun Yo, Tim Coughlan, Steve Ivulich, Eldho Paul, Gregory Snell, Solomon Menahem No Product/Research Disclosure Information

Cobicistat-Boosted Protease Inhibitors in HIV-Infected Patients with Mild to Moderate Renal Impairment

Background: Cobicistat (COBI) is a pharmacoenhancer that optimizes systemic exposures of protease inhibitors (PIs) such as atazanavir (ATV) and darunavir (DRV). Objective: To evaluate the efficacy and safety of switching ritonavir (RTV) to COBI in patients with creatinine clearance (CrCl) 50 to 89 mL/min who are virologically suppressed on a stable regimen containing ritonavir (RTV)-boosted ATV or DRV. Other components of the regimen remained unchanged. Methods: A phase 3, non-comparative, open-label clinical trial. Results: Seventy-three patients were enrolled. At week 48, 82% maintained virologic suppression. No emergent resistance developed. Serious adverse events (AEs) occurred in 7%, and study drug discontinuation due to AEs occurred in 10% (7 patients). There were 2 renal discontinuations and no cases of proximal renal tubulopathy. Small reductions in CrCl (median [IQR]) were observed as early as week 2, after which they were nonprogressive through week 48 (-3.8 [-9 to 0.8]). Changes in CrCl by baseline CrCl (< 70 vs ≥ 70) were -1.1 [-6.5 to 6.3] versus -6.6 [-12.4 to -0.7], respectively. Conclusions: In HIV–1–infected patients with CrCl 50 to 89 mL/min switching from RTV to COBI, COBI-boosted PIs in combination with 2 nucleos(t)ide reverse transcriptase inhibitors were well-tolerated and effective in maintaining virologic suppression. The renal safety profile of COBI in this study was consistent with the long-term data in patients without renal impairment from the phase 3 studies of COBI-containing regimens.

Switching from ritonavir to cobicistat in HIV patients with renal impairment who are virologically suppressed on a protease inhibitor.

IntroductionCobicistat (COBI) is a pharmacoenhancer and one of the components of ECF/TDF (elvitegravir/cobicistat/emtricitabine/tenofovir DF), which is approved in treatment-naïve HIV patients with creatinine clearance (CrCl) ≥70 mL/min. Study 118 assessed the renal safety of COBI-containing regimens in HIV patients with mild to moderate renal impairment.Material and MethodsPhase 3, open label study in HIV-1-infected patients with CrCl 50–89 mL/min who are virologically suppressed on a stable regimen containing ritonavir (RTV)-boosted atazanavir (ATV) or darunavir (DRV). Patients switched RTV to COBI, while keeping the rest of their regimen unchanged. We present the 96-week (Wk) data.ResultsSeventy-three patients were enrolled. Mean age was 54 years; male 82%; white 77%; hypertension 38%; diabetes 18%; baseline proteinuria (≥trace) 51%; median CrCl 71 mL/min (range: 42–98). At Wk 96, 89% maintained virologic suppression (95% CI 77.4–95.8%). No emergent resistance developed. Reductions in CrCl (median [IQR]) were observed as early as Wk 2, after which they were nonprogressive through Wk 96 (Wk 48: −3.8 [−9–0.8]; Wk 96: −5.0 [−13.0–0.1]). Changes in CrCl by baseline CrCl (<70 vs ≥70) at Wk 96 were: −3.1 [−5.1–0.5] vs −7.6 [−15.2 to −3.6], respectively. Cystatin C-based eGFR remained stable through Wk 96 (median [IQR]: −2.8 [−7.4–8.9 mL/min/1.73 m2). Actual GFR assessment using CLiohexol (n=14) was unaffected over 24 Wks (median at baseline: 82.5, median changes from baseline at Wks 2, 4, and 24: 1.6, 7.0, −4.1 mL/min, respectively). Three renal discontinuations occurred (two worsening CrCl and one proteinuria/hematuria); none had proximal renal tubulopathy [PRT]. No patient had laboratory evidence of PRT (>1 confirmed renal laboratory abnormalities [increase in serum Cr≥0.4 mg/dL, ≥2-grade increase in proteinuria,≥1-grade increase in normoglycemic glycosuria or hypophosphatemia]).ConclusionsIn HIV-infected patients with CrCl 50–89 mL/min, on ATV- or DRV-based regimen switching to COBI from RTV, demonstrated that COBI was well tolerated with no cases of PRT through 96 Wks. The renal safety profile of COBI in patients with mild to moderate renal impairment was consistent with the long-term data in patients without renal impairment (CrCl≥70 mL/min) from the phase 3 studies of COBI-containing regimens.

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Introduction: β-lactams are widely used as first-line treatment in critically ill patients. It has been shown that creatinine clearance (CrCl) influences the pharmacodynamics of these drugs. Hypothesis: Variations in CrCl are correlated with changes in β-lactams concentrations. Methods: We reviewed the data of all adult patients admitted to our Dept of Intensive Care (ICU) from January 2010 to June 2012, in whom routine therapeutic drug monitoring (TDM) of broad-spectrum β-lactams (ceftazidime, cefepime, piperacillin and meropenem) was performed. Patients were included if they had at least two TDMs during their ICU stay for the same antibiotic and if they were not concomitantly treated by any extracorporeal replacement therapy. Serum drug concentrations were measured by high-performance liquid chromatography (HPLC-UV). Blood samples were taken twice during the elimination phase after a 30-min intravenous drug administration. Antibiotic PKs were calculated using a one-compartment model and the percentage of time spent above four times the MIC (%T>4xMIC) for Pseudomonas aeruginosa as well as antibiotic clearance (ATB-CL) were obtained. CrCl was measured using 24-hours urine collection on the same period than TDM. Results: We included 56 patients (median age 59 years; 40/56 male gender, median APACHE II score on admission 19; 73% treated by mechanical ventilation, ICU mortality 20%). Median time from the start of antibiotic therapy to the first and second TDM was 2 and 5 days, respectively. We found that %T>4xMIC and ATB-CL were significantly correlated with CrCl on the first TDM (Spearman r = -0.41, p=0.002; r = 0.56, p<0.001, respectively) and the second TDM (Spearman r = -0.61, p<0.001; r = 0.62, p<0.001, respectively). Nevertheless, the changes in the %T>4xMIC and ATB-CL were not correlated to the changes in CrCl (Spearman r =0.22, p=0.09 and Spearman r = -0.17, p=0.2). Conclusions: Although CrCl was significantly correlated with the concentrations of broad-spectrum β-lactams, changes in CrCl do not reliably predict variations in drug clearance and pharmacodynamics.

How Long Should Initiation of Calcineurin Inhibitors Be Delayed to Protect Renal Function in Liver Transplantation?

Background and aim Delayed introduction of calcineurin inhibitors (CNI) in liver transplantation (OLT) seeks to protect renal function, although the optimal length of the delay is not well established. The aim of this study was to analyze the effects on renal function of CNI initiation on different days after OLT. Methods We reviewed the charts of 260 OLT recipients. Group D1-a ( n = 36) underwent the standard initial immunosuppression at our center: namely, CNI introduction on day 1 with further daily administration to achieve target levels of 8 to 15 ng/mL for tacrolimus or 150 to 300 ng/mL for cyclosporine. Due to renal concerns, 126 patients (group D1-b) had CNI introduced on day 1 either not daily or at doses to achieve less than the target on at least two occasions. In 43 patients (group D2), CNI were introduced on day 2 in 23 on day 3 (group D3), in 12 on day 4 (group D4), and at least at day 5 in 20 others (group D5). In periods without CNI treatment, patients received mycophenolate mofetil. Steroids were administered to all patients. The study period included the first 3 months post-OLT. Renal function was estimated as creatinine clearance (CrCl) using the Cockcroft-Gault equation. Results Changes in CrCl from pre-OLT to month 3 were −19% ± 28% in group D1-a; −27% ± 19% in group D1-b; −29% ± 19% in group D2; −23% ± 26% in group D3; −4% ± 38% in group D4, and +4% ± 33% in group D5 ( P < .05 vs groups D1-a, D1-b, D2, and D3). On multivariate analysis, CNI introduction at day ≥5 was protective for kidneys when adjusted for other variables that potentially influence renal function. Conclusion CNI should be introduced at day 5 after OLT to protect renal function.

Renal Safety of a Tenofovir-Containing First Line Regimen: Experience from an Antiretroviral Cohort in Rural Lesotho

IntroductionCurrent guidelines contraindicate TDF use when creatinine clearance (CrCl) falls below 50 ml/min. We report prevalence of abnormal renal function at baseline and factors associated with abnormal renal function from a community cohort in Lesotho.MethodsWe calculated changes in CrCl from baseline for patients initiated on TDF at 6 and 12 months and the proportion of patients initiated on TDF who developed renal impairment. Screening algorithms were developed using risk factors determined by multivariate analysis.ResultsAmong 933 adults for whom baseline creatinine was available, 176 (18.9%) presented with a baseline CrCl <50 ml/min. Renal function improved during follow-up. 19 patients who developed renal toxicity during follow up remained on TDF; renal function improved (CrCl≥50 ml/min) in all but 3 of these patients. Among 15 patients with a baseline CrCl <50 ml/min were started in error, none developed severe renal impairment.ConclusionIn this setting TDF-associated renal toxicity is rare and mainly transient. Further studies to assess TDF safety at lower CrCl thresholds are warranted.

Conversion from a calcineurin inhibitor to everolimus therapy in maintenance liver transplant recipients: A prospective, randomized, multicenter trial

Calcineurin inhibitors (CNIs) contribute to renal dysfunction following liver transplantation. This prospective, randomized, multicenter, 6-month study (with an additional 6 months of follow-up) evaluated whether everolimus with CNI reduction or discontinuation would improve renal function in maintenance liver transplant recipients experiencing CNI-related renal impairment. Patients started everolimus therapy with CNI reduction or discontinuation (n = 72) or continued receiving standard-exposure CNI (n = 73). At month 6, 80% of the patients who had converted to everolimus had discontinued the CNI. The mean change in creatinine clearance (CrCl) from baseline to month 6 was similar between groups (everolimus, 1.0 +/- 10.2 mL/minute; controls, 2.3 +/- 7.8 mL/minute; P = 0.46), so the primary study endpoint (8 mL/minute difference in the change in CrCl) was not achieved. Among patients who continued everolimus according to the protocol, the mean increase in CrCl was 2.1 (n = 53) and 3.8 mL/minute (n = 38) at months 6 and 12, respectively, versus 2.4 (n = 68) and 3.5 mL/minute in controls (n = 51). The high frequency of CNI dose reductions in controls (77% of the patients) and the relatively long mean time post-transplant (>3 years) likely contributed to the small difference in CrCl. Biopsy-proven acute rejection occurred in 1.4% of the patients in each group, with no graft losses. Study drug discontinuation was higher in everolimus-treated patients, and adverse events were more frequent. These data demonstrate that everolimus allows for discontinuation or a major reduction of CNI exposure in liver allograft recipients suffering CNI-related renal dysfunction without a loss of efficacy. Trials targeting earlier conversion post-transplantation are required to confirm the efficacy and safety of everolimus for improving renal function after liver transplantation.

Major issues in the treatment of metastatic bone disease: renal safety and maintained bone pain effectiveness of ibandronate in breast cancer patients in clinical practice; interim results of a non interventional study in Germany.

Abstract Abstract #1159 Background: Bone pain is one of the most debilitating manifestations of metastatic bone disease (MBD) due to breast cancer (BC). Bisphosphonates (BP) effectively prevent skeletal related events (SRE) in MBD and independently reduce bone pain. As kidney is a main target organ of BP related toxicity, renal safety is of major importance for risk/benefit assessment of BPs. Ibandronate (IBA), a third generation amino-BP has shown its clinical efficacy and safety in randomized clinical trials (RCT). The present non interventional study (NIS) was initiated to verify those results under real life conditions.&amp;#x2028; Patients and methods: This interim analysis is based on 1897 clinically evaluable BC patients with MBD, mean age 63.3 +11.9 years. 1219 (64 %) were BP-naive, 213 (11.2 %) had been pretreated with (IBA), 465 (24.5 %) with other BPs, mainly zoledronic acid (ZOL) (294; 15.5 %) and pamidronate (PAM) (157; 8.3 %). Mean duration [months + SD] of BP pretreatment was considerably longer for PAM (22.7 + 22.7) and ZOL (20 + 17.9) than for IBA (12.8 +11.9). After inclusion patients received 6 mg IBA i. v. every 4 weeks or 50 mg p. o. daily at the physician's discretion over 24 weeks, additionally to their individual cancer treatment. Pain status (10 point VAS), analgesic use (WHO escalation stages), renal function (serum creatinine; Creatinine clearance (CrCl) calc.), standard lab-data and SRE incidence were recorded at regular 4 weeks intervals.&amp;#x2028; Results: Baseline pain score differed by BP pretreatment and was highest in BP-naive patients (3.5 + 2.4), compared to pretreated with other BPs (3.2 + 2.5) or IBA (2.8 + 2.2), being the lowest. Mean pain score gradually decreased by every visit, reaching its min. value at study end. This represented a pain reduction of 10 – 40 %, depending of BP pretreatment status, and was achieved in 66 % of total study population. In parallel, there was an overall reduction in analgesic use of 9.2 % (WHO staging), with an increase of 5 % in patients with no need for analgesics. Changes in renal function during the observation period were balanced across all subgroups, with 8 – 15 ml/min maximum change in CrCl and no severe renal adverse events had been reported; significantly more patients pretreated with ZOL (26 %) showed signs of decreased renal function at baseline (S-Crea &amp;lt; 1.2 mg/dl), compared to IBA- (11 %), PAM- (16 %) or without BP-pretreatment (8 %). There was no significant correlation between decreased renal function at baseline and BP-pretreatment duration. 6 cases of osteonecrosis of the jaw had been reported, in two of which IBA was the only BP involved. There were 11 % premature study terminations. In 99 % of the remaining patients IBA treatment was intended to be continued.&amp;#x2028; Conclusion: In this interim analysis of a large scale NIS, IBA showed marked and sustained pain relief in BC patients with MBD without escalation of analgesic use and a renal safety profile comparable to results of RCTs. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1159.

Potential influence of tacrolimus and steroid avoidance on early graft function in pediatric renal transplantation

With the increasing adoption of steroid-sparing immunosuppression protocols in renal transplantation, it is important to evaluate any adverse effects of steroid avoidance on graft function. Early graft function, measured by CrCl was retrospectively studied in 158 consecutive pediatric renal transplant recipients from 1996 to 2005, receiving either steroid-free or steroid-based immunosuppression. Patients receiving steroid-free immunosuppression vs. steroid-based immunosuppression had no difference change in CrCl (DeltaCrCl) in the first week post-transplantation (p = 0.12). When stratified by corticosteroid usage, patients with higher tacrolimus trough levels (> or =14 ng/mL) had slower graft function recovery in the first week post-transplantation than those with lower tacrolimus trough levels (p = 0.008) in the steroid-free group only. Despite initial slower graft function recovery in this subgroup, there was no negative impact on graft function in the steroid-free group; in fact steroid-free patients trended towards better CrCl at six months (p = 0.047) and 12 months (p < 0.001) post-transplant than the steroid-based group. With the improved immunological outcomes with steroid avoidance, close surveillance should be performed of tacrolimus levels to avoid levels >14 ng/mL. In patients with slow recovery of early graft function, short-term perioperative steroids may be considered.

Prospective study of progression of kidney dysfunction in community‐dwelling older adults

Few prospective studies have assessed renal dysfunction in older persons. We sought to define kidney dysfunction among a community-based cohort of elderly subjects and to determine the factors for its progression. The Epidemiologia do Idoso (EPIDOSO) Study is a prospective study of individuals > or =65 years old (mean 72.6 +/- 0.3), living in the community in the city of São Paulo. The creatinine clearance (CrCl) of 269 individuals of this cohort was estimated during 8 years of follow-up. The rate of decline in CrCl was calculated using linear regression analysis and dividing the group into tertiles of CrCl change. Overall mean change in CrCl was -2.37 +/- 0.23 mL/min per year. Mean age increased with the greatest degree of decline in renal function (71.1 +/- 0.59, 72.5 +/- 0.54 and 74.3 +/- 0.58, for the first, second and third CrCl change tertiles, respectively, P < 0.01). A higher value of baseline CrCl was associated with progressive decline in CrCl (P < 0.01). Diastolic BP was greater in the second versus the first estimated glomerular filtration rate tertile (83 +/- 1 vs 80 +/- 1 mmHg, P < 0.05). High-density lipoprotein (HDL) cholesterol was inversely associated with CrCl decline (P < 0.05). Progression of kidney dysfunction occurs in most community-dwelling elderly. Strategies aimed at slowing the progression should be considered for possible risk factors of older age, baseline CrCl, BP and HDL.

Greater Tenofovir‐Associated Renal Function Decline with Protease Inhibitor–Based versus Nonnucleoside Reverse‐Transcriptase Inhibitor–Based Therapy

Plasma concentrations of tenofovir increase when the drug is coadministered with some ritonavir-boosted protease inhibitors (PI/r). We hypothesized that tenofovir disoproxil fumarate (TDF)-treated patients taking PI/r-based regimens would have a greater decline in renal function than patients receiving nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based therapy. We compared the estimated decline in renal function among 146 human immunodeficiency virus type 1 (HIV-1)-infected patients receiving a TDF+PI/r- (n = 51), TDF+NNRTI- (n = 29), or non-TDF-containing (n = 66) regimen. Plasma tenofovir concentrations were measured at study week 2, and rates of creatinine clearance (CrCl) were estimated using the Cockcroft-Gault (C-G) and Modification of Diet in Renal Disease (MDRD) equations. Mixed-effects models were used to analyze regimen type and tenofovir concentration as predictors of change in CrCl from baseline to weeks 24 and 48. Decreases in C-G estimates of CrCl were not significantly different among the 3 groups during the first 24 weeks of therapy. However, in adjusted analyses, patients receiving TDF+PI/r had a greater rate of decline in CrCl than did the TDF+NNRTI group (for C-G, -13.9 vs. -6.2 mL/min/year [P = .03]; for MDRD, -14.7 vs. -4.5 mL/min/1.73 m(2)/year [P = .02]). Among TDF-treated patients, tenofovir plasma concentration was not associated with CrCl over time. Treatment with TDF and PI/r was associated with greater declines in renal function over 48 weeks compared with TDF+NNRTI-based regimens.