Vancomycin-induced Acute Kidney Injury Research Articles

The preventive effect of Gastrodia elata Blume extract on vancomycin-induced acute kidney injury in rats.

Gastrodia elata Blume (GEB), a traditional medicinal herb, has been reported to have pharmacological effect including protection against liver, neuron and kidney toxicity. However, explanation of its underlying mechanisms remains a great challenge. This study investigated the protective effects of GEB extract on vancomycin (VAN)-induced nephrotoxicity in rats and underlying mechanisms with emphasis on the anti-oxidative stress, anti-inflammation and anti-apoptosis. The male Sprague-Dawley rats were randomly divided three groups: control (CON) group, VAN group and GEB group with duration of 14 days. The kidney weight and the serum levels of blood urea nitrogen and creatinine in the GEB group were lower than the VAN group. Histological analysis using hematoxylin & eosin and periodic acid Schiff staining revealed pathological changes of the VAN group. Immunohistochemical analysis revealed that the expression levels of N-acetyl-D-glucosaminidase, myeloperoxidase and tumor necrosis factor-alpha in the GEB group were decreased when compared with the VAN group. The number of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells, phosphohistone and malondialdehyde levels were lower in the GEB group than VAN group. The levels of total glutathione in the GEB group were higher than the VAN group. The findings of this study suggested that GEB extract prevents VAN-induced renal tissue damage through anti-oxidation, anti-inflammation and anti-apoptosis.

Time-Dependent Differences in Vancomycin Sensitivity of Macrophages Underlie Vancomycin-Induced Acute Kidney Injury.

Although vancomycin (VCM)-frequently used to treat drug-resistant bacterial infections-often induces acute kidney injury (AKI), discontinuation of the drug is the only effective treatment; therefore, analysis of effective avoidance methods is urgently needed. Here, we report the differences in the induction of AKI by VCM in 1/2-nephrectomized mice depending on the time of administration. Despite the lack of difference in the accumulation of VCM in the kidney between the light (ZT2) and dark (ZT14) phases, the expression of AKI markers due to VCM was observed only in the ZT2 treatment. Genomic analysis of the kidney suggested that the time of administration was involved in VCM-induced changes in monocyte and macrophage activity, and VCM had time-dependent effects on renal macrophage abundance, ATP activity, and interleukin (IL)-1β expression. Furthermore, the depletion of macrophages with clodronate abolished the induction of IL-1β and AKI marker expression by VCM administration at ZT2. This study provides evidence of the need for time-dependent pharmacodynamic considerations in the prevention of VCM-induced AKI as well as the potential for macrophage-targeted AKI therapy. SIGNIFICANCE STATEMENT: There is a time of administration at which vancomycin (VCM)-induced renal injury is more and less likely to occur, and macrophages are involved in this difference. Therefore, there is a need for time-dependent pharmacodynamic considerations in the prevention of VCM-induced acute kidney injury as well as the potential for macrophage-targeted acute kidney injury therapy.

2558. Association of Vancomycin-Induced Acute Kidney Injury with Trough Versus AUC Monitoring in Patients Receiving Extended Durations of Therapy

Abstract Background Vancomycin (VAN) therapy is associated with an increased risk of AKI. Previous studies suggest that AUC monitoring reduces the risk of AKI, but literature is lacking in patients receiving longer durations of VAN therapy. This study assessed the clinical impact of AUC monitoring on patients receiving at least 14 days of VAN. Methods Adult inpatients at our academic medical center that received ≥ 14 days of VAN with levels obtained during a 4-year period were included in this analysis. Our primary outcome was the incidence of AKI between trough monitoring and AUC monitoring groups using the KDIGO change in serum creatinine from baseline criteria. Secondary outcomes included inpatient mortality, inpatient LOS, and ICU LOS. Multivariable logistic regression models were performed for AKI incidence and inpatient mortality. Results A total of 582 patients were included. The majority of patients were male (58.2%) and Caucasian (94.3%). The median duration of VAN therapy was 23 days (IQR, 16-39). Patients within the trough monitoring group had a higher incidence of AKI compared to the AUC monitoring group (45.6% vs. 28.4%, p< 0.001). In each KDIGO stage, there was a higher incidence of AKI in the trough monitoring group compared to the AUC monitoring group (Stage 1: 22.0% vs. 15.9%, Stage 2: 10.7% vs. 7.6%, and Stage 3: 12.9% vs. 4.9%, p< 0.001). Logistic regression analysis showed AUC monitoring was associated with a 54% lower incidence of AKI (OR 0.46, 95% CI [0.31-0.69]). ICU LOS within the trough monitoring group was longer compared to the AUC monitoring group (13 days [6-24] vs. 10 days [3-19], p=0.008). All-cause inpatient mortality was numerically higher in the trough monitoring group (12.9% vs. 8.3%, p=0.078). In the second multivariable regression analysis, AUC monitoring was not a significant predictor of mortality, but patients with AKI were five times more likely to die (OR 5.00, 95% CI [2.40-10.46], p< 0.001). Conclusion AUC monitoring can reduce the risk of AKI in patients receiving ≥ 14 days of VAN and indirectly reduce the risk of inpatient mortality. Consideration should be given to implementing AUC monitoring as a standard of practice. Disclosures All Authors: No reported disclosures

Recombinant Klotho alleviates vancomycin-induced acute kidney injury by upregulating anti-oxidative capacity via JAK2/STAT3/GPx3 axis

Emerging studies support that Klotho protects against different kidney diseases. However, the role of Klotho in vancomycin induced acute kidney injury (Van-AKI) is largely unclear. Hence this study aimed to explore the regulatory mechanism of Klotho in Van-AKI. The mRNA expression of Klotho and the JAK2/STAT3/GPx3 in renal tissue were assessed by RNA sequence analysis after 600 mg/kg Van daily for seven days; Small interfering RNA and recombinant protein are applied to examine the mechanism action of Klotho in vitro and in vivo respectively. Flow cytometry and spectrophotometry detected the expression of reactive oxygen species and antioxidant enzymes. Transmission electron microscopy scanned the structural damage of mitochondria. Western blotting, qPCR, and immunofluorescence were employed to explore the JAK2/STAT3/GPx3 expression. RNA sequence analysis found that Van challenging reduced Klotho and GPx3 expression but increased JAK2/STAT3 in renal tissue. In HK-2 cells, Klotho were decreased by Van in a dose-dependent manner. Klotho siRNA enhanced the production of reactive oxygen species and the cell apoptosis ratio by regulating the JAK2/STAT3, and JAK2/STAT3 inhibitors prevented the decrease of GPx3. Meanwhile, 1 μg/ml recombinant human Klotho showed the opposite function to 120 pmol Klotho siRNA. In Van-AKI BALB/c mice, 20 μg/kg recombinant mouse Klotho once every two days improved the anti-oxidative enzyme expression, mitochondria structure, renal dysfunction, and histological damage. In conclusion, Klotho enhances antioxidant capacity through the JAK2/STAT3/GPx3 axis, which in turn improves Van-AKI.

Association of vancomycin-induced acute kidney injury with trough versus AUC monitoring in patients receiving extended durations of therapy.

Vancomycin therapy is associated with an increased risk of acute kidney injury (AKI). Previous studies suggest that area under the curve (AUC) monitoring reduces the risk of AKI, but literature is lacking to support this in patients receiving longer durations of vancomycin therapy. Retrospective cohort study. Patients ≥18 years old, admitted between August 2015 and July 2017 or October 2017 and September 2019, and received at least 14 days of intravenous (IV) vancomycin therapy were included in the study. Our primary outcome was the incidence of AKI between trough monitoring and AUC monitoring groups using Kidney Disease Improving Global Outcomes criteria. Secondary outcomes included inpatient mortality, median inpatient length of stay, and median intensive care unit length of stay. Overall, 582 patients were included in the study, with 318 patients included in the trough monitoring group and 264 included in the AUC monitoring group. The median duration of vancomycin therapy was 23 days (interquartile range, 16-39). Patients within the trough monitoring group had a higher incidence of AKI compared to the AUC monitoring group (45.6% vs 28.4%, p < 0.001). Furthermore, logistic regression analysis showed that AUC monitoring was associated with a 54% lower incidence of AKI (OR 0.46, 95% CI [0.31-0.69]). All-cause inpatient mortality was numerically higher in the trough monitoring group (12.9% vs 8.3%, p = 0.078). In patients who received at least 14 days of IV vancomycin therapy, AUC monitoring was associated with a lower incidence of AKI.

Vancomycin area under the curve versus trough only guided dosing and the risk of acute kidney injury: Systematic review and meta-analysis.

Vancomycin is commonly used to treat methicillin‐resistant Staphylococcus aureus infections and is known to cause nephrotoxicity. Previous Vancomycin Consensus Guidelines recommended targeting trough concentrations but the 2020 Guidelines suggest monitoring vancomycin area under the curve (AUC) given the reduced risk of acute kidney injury (AKI) at similar levels of efficacy. This meta‐analysis compares vancomycin‐induced AKI incidence using AUC‐guided dosing strategies versus trough‐based monitoring. Literature was queried from Medline (Ovid), Web of Science, and Google Scholar from database inception through November 5, 2021. Interventional or observational studies reporting the incidence of vancomycin‐induced AKI between AUC‐ and trough‐guided dosing strategies were included. In the primary analysis, the Vancomycin Consensus Guidelines definition for AKI was used if reported; otherwise, the Risk, Injury, and Failure; and Loss, and End‐stage kidney disease (RIFLE) or Kidney Disease Improving Global Outcomes (KDIGO) definitions were used. The incidence of nephrotoxicity was evaluated between the two strategies using a Mantel–Haenszel random‐effects model, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Subgroup analyses for adjusted ORs and AKI definitions were performed. Heterogeneity was identified using Cochrane's Q test and I 2 statistics. A total of 10 studies with 4231 patients were included. AUC‐guided dosing strategies were associated with significantly less vancomycin‐induced AKI than trough‐guided strategies [OR 0.625, 95% CI (0.469–0.834), p = 0.001; I 2 = 25.476]. A subgroup analysis of three studies reporting adjusted ORs yielded similar results [OR 0.475, 95% CI (0.261–0.863), p = 0.015]. Stratification by AKI definition showed a significant reduction in AKI with the Vancomycin Consensus Guidelines definition [OR 0.552, 95% CI (0.341–0.894), p = 0.016] but failed to find significance in the alternative definitions. Area under the curve‐guided dosing strategies are associated with a lower incidence of vancomycin‐induced AKI versus trough‐guided dosing strategies (GRADE, low). Limitations included the variety of AKI definitions and the potential for confounding bias.

Mmu-lncRNA 121686/hsa-lncRNA 520657 induced by METTL3 drive the progression of AKI by targeting miR-328-5p/HtrA3 signaling axis

The pathogenesis of acute kidney injury (AKI) is still not fullyunderstood, and effective interventions are lacking. Here, we explored whether methyltransferase 3 (METTL3) was involved in the progression of AKI via regulation of cell death. We reported that PT（proximal tubule）-METTL3-knockout (KO) noticeably suppressed ischemic-induced AKI via inhibition of renal cell apoptosis. Furthermore, we also found that the expression of mmu-long non-coding RNA (lncRNA) 121686 was upregulated in antimycin-treated Boston University mouse proximal tubule (BUMPT) cells and a mouse ischemia-reperfusion (I/R)-induced AKI model. Functionally, mmu-lncRNA 121686 could promote I/R-induced mouse renal cell apoptosis. Mechanistically, mmu-lncRNA 121686 acted as a competing endogenous RNA (ceRNA) to prevent microRNA miR-328-5p-mediated downregulation of high-temperature requirement factor A 3 (Htra3). PT-mmu-lncRNA 121686-KO mice significantly ameliorated the ischemic-induced AKI via the miR-328-5p/HtrA3 axis. In addition, hsa-lncRNA 520657, homologous with lncRNA 121686, sponged miR-328-5p andupregulated Htra3 to promote I/R-induced human renal cell apoptosis. Interestingly, we found that mmu-lncRNA 121686/hsa-lncRNA 520657 upregulation were dependent onMETTL3 via N6-methyladenosine (m6A) modification. The mmu-lncRNA 121686/miR-328-5p or hsa-lncRNA 520657/miR-328-5p /HtrA3 axis was induced invitro by METTL3 overexpression; in contrast, this effect was attenuated by METTL3 small interfering RNA (siRNA). Furthermore, we found that PT-METTL3-KO or METTL3 siRNA significantly suppressed ischemic, septic, and vancomycin-induced AKI via downregulation of the mmu-lncRNA 121686/miR-328-5p/HtrA3 axis. Taken together, our data indicate that the METTL3/mmu-lncRNA 121686/hsa-lncRNA 520657/miR-328-5p/HtrA3 axis potentially acts as a therapeutic target for AKI.

MO367: Non-Invasive Diagnosis of Vancomycin-Induced Acute Kidney Injury Using Urine Microscopy

Abstract BACKGROUND AND AIMS Vancomycin stands out both as being a potent cause of AKI (V-AKI) and as one of the most universally prescribed antimicrobial drugs. From a pathophysiological standpoint, it was hitherto believed that V-AKI stemmed from the intracellular accumulation of vancomycin in the proximal tubule, which elicits oxidative stress and ultimately translates in cell apoptosis. Recently, a study has shown that vancomycin in the setting of overt drug overdose, can co-precipitate with uromodulin causing microspheric obstructive aggregates in the tubular lumen both in experimental models and in patients [1]. Further documentation of this novel mechanism has been hindered by the need to procure kidney tissue so as to perform ad hoc immunostaining. Furthermore, it remains to be proven that the presence of vancomycin microspheres represents a reliable marker for V-AKI. Urine based vancomycin-immunostaining may represent a valuable non-invasive approach. METHOD The urine of patients presenting with vancomycin overdose determined by plasma trough levels &amp;gt;15 mg/L along with acute kidney injury (according to KDIGO guidelines) were subjected to light microscopic urinalysis. Whenever microscopic urinalysis yielded the presence of casts, immunostaining was performed. Briefly, a pellet of urine was spread on a slide and immunostaining performed with a specific anti-vancomycin antibody (Abbot 6E-4421, 1/1000) prior to repeat microscopic examination. Infrared spectrophotometry was performed to ascertain the nature of the casts by comparing the spectrum to a reference vancomycin spectrum. Patients were deemed to have V-AKI whenever at least one vancomycin positive cast was observed following immunostaining. The urine of control patients was subjected to the same procedure: they were defined as patients exposed to vancomycin with or without vancomycin overdose but with no AKI. RESULTS A total of 5 patients with vancomycin overdose KDIGO stage 3 AKI were found to exhibit casts with positive vancomycin immunostaining (Fig. 1). On light microscopic urinalysis, vitreous casts devoid of refringence after polarization could be observed in each case. Upon infrared spectrophotometry, the casts displayed a Fourier transform spectrum consistent with vancomycin. In three of the cases, V-AKI was considered the sole or primary cause of AKI. The patient displayed abundant and markedly stained casts upon anti-vancomycin immunostaining (Fig. 1A). Overt and massive vancomycin overdosing was evidenced in all cases. In one case, the patient concurrently received piperacillin-tazobactam and in another case the patient was exposed to iodinated contrast media. The renal function course was favourable with full recovery in all three instances. In two cases, competing causes of AKI were either evidenced or not. In one case, the patient displayed septic shock which indicated vancomycin therapy. In another case, the patient was suspected to have immunoallergic intersititial nephritis. The patients exhibited rare casts with only faint staining (Fig. 1B). In both cases, vancomycin overdose could not be documented. V-AKI was deemed a possible concurrent cause of AKI. None of the 5 control patients yielded casts after light microscopic urinalysis. CONCLUSION Vancomycin cast detection on urine microscopy is feasible and can be enhanced by a straightforward immunostaining technique and represents a unique opportunity for a non-invasive diagnosis of V-AKI. Further studies are required to refine diagnostic criteria-based urine immunostaining detection. They also needed to determine whether detection of V-AKI merely reflects impaired vancomycin urinary excretion in the setting of AKI or can be regarded as a sensitive and specific marker of vancomycin-induced tubular obstruction and injury.

Candidates for area under the concentration–time curve (AUC)-guided dosing and risk reduction based on analyses of risk factors associated with nephrotoxicity in vancomycin-treated patients

Compared with vancomycin trough concentration (Cmin)-guided dosing, area under the concentration-time curve (AUC)-guided dosing is associated with decreased acute kidney injury (AKI). However, whether Cmin-guided or AUC-guided dosing should be used in patients other than those with serious MRSA infections remains uncertain. The purposes of this multicentre study were to identify risk factors for early- and late-phase vancomycin-induced AKI and to identify candidates for AUC-guided dosing, rather than Cmin-guided dosing, who require a more accurate dose titration to reduce the AKI risk. A multivariate logistic regression analysis was applied to identify risk factors for AKI. Additionally, the cut‑off day for AKI onset, cut-off Cmin for AKI, safe Cmin for reduced AKI risk and probability of AKI were calculated. In total, 8.4% (159/1882) of patients developed AKI. AKI occurred within the first 7 days of therapy (early phase) in the vast majority of patients. Significant risk factors for AKI during the early phase were identified as Cmin > 20 mg/L, ICU stay, concurrent diuretic or piperacillin/tazobactam use, and pre-existing renal dysfunction. A temporarily elevated Cmin (>15-20 mg/L) was not associated with a greater risk of AKI. In patients with risk factors, the cut-off Cmin for AKI and the estimated safe Cmin for reduced AKI risk were 18.8-21.0 mg/L and <11.7-13.5 mg/L, respectively. Patients with known AKI risk factors require a low target Cmin. The presence of several risk factors for AKI may indicate a need for more accurate dose titration using AUC-guided dosing.

Of Rats and Men: a Translational Model To Understand Vancomycin Pharmacokinetic/Toxicodynamic Relationships.

Vancomycin area under the concentration curve (AUC) is known to predict vancomycin-induced acute kidney injury (AKI). Data were analyzed from a rat model (n = 48) and two prospective clinical studies (PROVIDE [n = 263] and CAMERA2 [n = 291]). A logit-link model was used to calculate the multiplicative factors between the probability of AKI from clinical studies and in the rat. The rat was 2.7 to 4.2 times more sensitive to AKI between AUCs of 199.5 and 794.3 mg·h/liter, respectively.

Kidney biopsy findings in vancomycin-induced acute kidney injury: a pooled analysis

Acute kidney injury represents a major adverse effect of vancomycin administration. The aim of the present study is to accumulate all biopsy-proven cases of vancomycin nephrotoxicity and assess the association of histopathological features with renal prognosis. Medline, Scopus, CENTRAL, Web of Science, and Clinicaltrials.gov were systematically searched from inception to 29 September 2020. All case reports/series providing individual data of patients with biopsy-proven vancomycin nephrotoxicity were held eligible. A time-to-event analysis was performed evaluating the effects of histological diagnosis on renal recovery. Overall, 18 studies were included, comprising 21 patients. Acute tubulointerstitial nephritis was the predominant pattern in 9 patients and was associated with a significantly higher risk of permanent renal dysfunction (HR: 5.08, 95% CI: [1.05-24.50)] compared to acute tubular necrosis. Tubulitis and eosinophilic infiltration were the most common histopathological findings, while interstitial fibrosis was linked to significantly worse renal prognosis (HR: 5.55, 95% CI: 1.13-27.27). Immunofluorescence and electron microscopy features were non-specific. Obstruction by tubular casts composed of vancomycin aggregates and uromodulin has been identified as a new mechanism of nephrotoxicity. Acute tubular necrosis and tubulointerstitial nephritis represent the main histological patterns of vancomycin-induced acute kidney injury. The presence of fibrosis in the context of interstitial inflammation may be linked to lower recovery rates and worse long-term renal outcomes. A novel cast nephropathy obstructive mechanism has been suggested, necessitating further confirmation. Large-scale studies should define the exact indications of kidney biopsy in cases with suspected vancomycin nephrotoxicity.

Urinary Exosomes Identify Inflammatory Pathways in Vancomycin Associated Acute Kidney Injury.

Background: Vancomycin is commonly used as a first line therapy for gram positive organisms such as methicillin resistant Staphylococcus aureus. Vancomycin-induced acute kidney injury (V-AKI) has been reported in up to 43% of patients, especially in those with higher targeted trough concentrations. The precise mechanism of injury in humans remains elusive, with recent evidence directed towards proximal tubule cell apoptosis. In this study, we investigated the protein contents of urinary exosomes in patients with V-AKI to further elucidate biomarkers of mechanisms of injury and potential responses. Methods: Urine samples from patients with V-AKI who were enrolled in the DIRECT study and matched healthy controls from the UAB-UCSD O’Brien Center Biorepository were included in the analysis. Exosomes were extracted using solvent exclusion principle and polyethylene glycol induced precipitation. Protein identity and quantification was determined by label-free liquid chromatography mass spectrometry (LC/MS). The mean peak serum creatinine was 3.7 ± 1.4 mg/dL and time to kidney injury was 4.0 ± 3.0 days. At discharge, 90% of patients demonstrated partial recovery; 33% experienced full recovery by day 28. Proteomic analyses on five V-AKI and 7 control samples revealed 2009 proteins in all samples and 251 proteins significantly associated with V-AKI (Pi-score > 1). The top discriminatory proteins were complement C3, complement C4, galectin-3-binding protein, fibrinogen, alpha-2 macroglobulin, immunoglobulin heavy constant mu and serotransferrin. Conclusion: Urinary exosomes reveal up-regulation of inflammatory proteins after nephrotoxic injury in V-AKI. Further studies are necessary in a large patient sample to confirm these findings for elucidation of pathophysiologic mechanisms and validation of potential injury biomarkers.

Determination of vancomycin exposure target and individualised dosing recommendations for neonates: model-informed precision dosing

IntroductionFew studies incorporating population pharmacokinetic/pharmacodynamic (Pop-PK/PD) modelling have been conducted to quantify the exposure target of vancomycin in neonates. A retrospective observational cohort study was undertaken in neonates to determine this target and dosing recommendations (chictr.org.cn, ChiCTR1900027919). MethodsA Pop-PK model was developed to estimate PK parameters. Causalities between acute kidney injury (AKI) occurrence and vancomycin use were verified using Naranjo criteria. Thresholds of vancomycin exposure in predicting AKI or efficacy were identified via classification and regression tree analysis. Associations between exposure thresholds and clinical outcomes, including AKI and efficacy, were analysed by logistic regression. Dosing recommendations were designed using Monte Carlo simulations based on the optimised exposure target. ResultsPop-PK modelling included 182 neonates with 411 observations. On covariate analysis, neonatal physiological maturation, renal function and concomitant use of vasoactive agents (VAS) significantly affected vancomycin PK. Seven cases of vancomycin-induced AKI were detected. Area under the concentration-time curve from 0–24 hours (AUC0–24) ≥ 485 mg•h/L was an independent risk factor for AKI after adjusting for VAS co-administration. The clinical efficacy of vancomycin was analysed in 42 patients with blood culture-proven staphylococcal sepsis. AUC0–24 to minimum inhibitory concentration (AUC0–24/MIC) ≥ 234 was the only significant predictor of clinical effectiveness. Monte Carlo simulations indicated that regimens in Neonatal Formulary 7 and Red Book (2018) were unsuitable for all neonates. ConclusionAn AUC0–24 of 240–480 (assuming MIC = 1 mg/L) is a recommended exposure target of vancomycin in neonates. Model-informed dosing regimens are valuable in clinical practice.

Posterior Reversible Encephalopathy Syndrome in a Case of Vancomycin-Induced Acute Kidney Injury.

Posterior Reversible Encephalopathy Syndrome in a Case of Vancomycin-Induced Acute Kidney Injury.

Retraction: PVT1 knockdown alleviates vancomycin-induced acute kidney injury by targeting miR-124 via inactivation of NF-κB signaling.

Retraction of ‘PVT1 knockdown alleviates vancomycin-induced acute kidney injury by targeting miR-124 via inactivation of NF-κB signaling’ by Xiaoguang Zhu et al., RSC Adv., 2018, 8, 31725–31734, DOI: 10.1039/C8RA05724A.

A Risk Prediction Flowchart of Vancomycin-Induced Acute Kidney Injury to Use When Starting Vancomycin Administration: A Multicenter Retrospective Study.

We previously constructed a risk prediction model of vancomycin (VCM)-associated nephrotoxicity for use when performing initial therapeutic drug monitoring (TDM), using decision tree analysis. However, we could not build a model to be used at the time of initial administration due to insufficient sample size. Therefore, we performed a multicenter study at four hospitals in Japan. We investigated patients who received VCM intravenously at a standard dose from the first day until the initial TDM from November 2011 to March 2019. Acute kidney injury (AKI) was defined according to the criteria established by the “Kidney disease: Improving global outcomes” group. We extracted potential risk factors that could be evaluated on the day of initial administration and constructed a flowchart using a chi-squared automatic interaction detection algorithm. Among 843 patients, 115 (13.6%) developed AKI. The flowchart comprised three splitting variables (concomitant drugs (vasopressor drugs and tazobactam/piperacillin) and body mass index ≥ 30) and four subgroups. The incidence rates of AKI ranged from 9.34 to 36.8%, and they were classified as low-, intermediate-, and high-risk groups. The accuracy of flowchart was judged appropriate (86.4%). We successfully constructed a simple flowchart predicting VCM-induced AKI to be used when starting VCM administration.

Baseline kidney function is associated with vancomycin-induced acute kidney injury in children: a prospective nested case-control study.

Children with kidney insufficiency are susceptible to vancomycin-induced acute kidney injury (VIAKI), but there is a lack of compelling clinical data. We conducted a nested case-control study to evaluate the relationship between kidney insufficiency and incidence of VIAKI in children. Patients were considered to have VIAKI if they met the criteria for eGFR change according to pRIFLE-I or p-RIFLE-F. Case group comprised patients who developed VIAKI. Case-control ratio was 1:3; patients were matched for age, severity, and nature of illness and initial vancomycin dose. Primary endpoint was incidence of VIAKI at three levels of kidney function, calculated using Kaplan-Meier curve and log-rank test. Secondary endpoint was treatment-related in-hospital mortality amongst case and control groups. Amongst 386 children who fit study criteria, 31 developed VIAKI (8.03%). Thirty-one cases and 93 controls were selected from the observed cohort. Three risk factors were identified for VIAKI: moderate kidney insufficiency (OR 8.8, 2.4-32.8), vancomycin trough concentration ≥ 15μg/mL (OR 7.7, 1.7-34.4), and furosemide use (OR 24.8, 6.4-98.2). A significant difference in time to VIAKI was noted between patients with moderate kidney insufficiency and patients with mild kidney insufficiency or normal kidney function (p < 0.001). In-hospital mortality rate in case group was 45.2%, compared to 18.3% in control group (p < 0.01). Children with moderate kidney insufficiency are more likely to develop VIAKI than those with normal and mild kidney insufficiency. Patients who develop VIAKI have higher in-hospital mortality than those who do not develop VIAKI.

Relationship of vancomycin trough levels with acute kidney injury risk: an exposure-toxicity meta-analysis.

Nephrotoxicity represents a major complication of vancomycin administration, leading to high rates of morbidity and treatment failure. The aim of this meta-analysis was to evaluate the association between trough levels and risk of renal impairment, by defining an exposure-toxicity relationship and assessing its accuracy in predicting the development of acute kidney injury (AKI). Medline, Scopus, CENTRAL, Clinicaltrials.gov and Google Scholar databases were systematically searched from inception. Studies examining the effects of trough levels on nephrotoxicity risk in adult patients were deemed eligible. The meta-analysis was based on 60 studies, including 13 304 patients. The development of AKI was significantly linked to both higher initial [standardized mean difference (SMD): 0.82; 95% CI: 0.65-0.98] and maximum (SMD: 1.06; 95% CI: 0.82-1.29) trough levels. Dose-response analysis indicated a curvilinear relationship between trough levels and nephrotoxicity risk (χ2 = 127.1; P value < 0.0001). A cut-off of 15 mg/L detected AKI with a sensitivity of 62.6% (95% CI: 55.6-69.2) and a specificity of 65.5% (95% CI: 58.9-71.6), while applying a 20 mg/L threshold resulted in a sensitivity of 42.9% (95% CI: 34-52.2) and a specificity of 82.5% (95% CI: 73.9-88.8). The present findings suggest that the development of vancomycin-induced AKI is significantly associated with higher initial and maximum trough levels. An exposure-response relationship was defined, indicating that increasing trough levels correlate with a significant rise of nephrotoxicity risk. Future studies should verify the effectiveness of individualized pharmacokinetic tools that would enable the attainment of trough level targets and minimize the risk of renal toxicity.

Low-dose Methotrexate Toxicity in the Setting of Vancomycin-induced Acute Kidney Injury

Methotrexate is a disease-modifying anti rheumatic drug (DMARD) that is often used in low dosages as the first line drug for rheumatoid arthritis patients. The chemotherapeutic agent works by inhibiting dihydrofolate reductase, and the primary route of clearance of the drug is via the kidneys. Kidney injury may delay this clearance and lead to toxic level accumulation of the drug- toxicity presenting as diarrhea, vomiting, mucositis, rash, transaminitis and myelosuppression. Antibiotics such as vancomycin may induce acute kidney injury (AKI) through various mechanisms include damage to the renal tubular epithelial cells. In this report, we describe a case in which an elderly female suffered AKI secondary to vancomycin induced nephrotoxicity. The AKI subsequently led to methotrexate accumulation and toxicity presenting as bleeding mouth ulcers, transaminitis and pancytopenia. The condition was managed with leucovorin rescue therapy and sodium bicarbonate to enhance methotrexate excretion. Renally dosing methotrexate in patients on other nephrotoxic drugs, and monitoring creatinine clearance are methods for preventing such a toxicity.

Assessment of initial vancomycin trough levels and risk factors of vancomycin-induced nephrotoxicity in neonates

ObjectivesVancomycin is a glycopeptide antibiotic commonly used in neonatal intensive care units (NICUs) to treat late onset sepsis. It is recommended that vancomycin trough levels at steady state following intermittent...