Comparative effects of calcitriol and calcimimetic on bone health in renal insufficiency.

Calcitriol and calcimimetics are used to treat hyperparathyroidism secondary to chronic kidney disease (CKD). Calcitriol administration and the subsequent increase in serum calcium concentration decrease parathyroid hormone (PTH) levels, which should reduce bone remodeling. We have previously reported that, when maintaining a given concentration of PTH, the addition of calcimimetics is associated with an increased bone cell activity. Whether calcitriol administration affects bone cell activity while PTH is maintained constant should be evaluated in an animal model of renal osteodystrophy. The aim of the present study was to compare in CKD PTH-clamped rats the bone effects of calcitriol and calcimimetic administration. The results show that the administration of calcitriol and calcimimetic at doses that induced a similar reduction in PTH secretion produced dissimilar effects on osteoblast activity in 5/6 nephrectomized (Nx) rats with secondary hyperparathyroidism and in Nx rats with clamped PTH. Remarkably, in both rat models, the administration of calcitriol decreased osteoblastic activity, whereas calcimimetic increased bone cell activity. In vitro, calcitriol supplementation inhibited nuclear translocation of ß-catenin and reduced proliferation, osteogenesis, and mineralization in mesenchymal stem cells differentiated into osteoblasts. In conclusion, besides the action of calcitriol and calcimimetics at parathyroid level, these treatments have specific effects on bone cells that are independent of the PTH level.

Poor performance of ChatGPT in clinical rule-guided dose interventions in hospitalized patients with renal dysfunction.

PURPOSE: Clinical decision support systems (CDSS) are used to identify drugs with potential need for dose modification in patients with renal impairment. ChatGPT holds the potential to be integrated in the electronic health record (EHR) system to give such dosing advices. In this study, we aim to evaluate the performance of ChatGPT in clinical rule-guided dose interventions in hospitalized patients with renal impairment. METHODS: This cross-sectional study was performed at Tergooi Medical Center, the Netherlands. CDSS alerts regarding renal dysfunction were collected from the electronic health record (EHR) during a 2-week period and were presented to ChatGPT and an expert panel. Alerts were presented with and without patient variables. To evaluate the performance, suggested medication interventions were compared. RESULTS: In total, 172 CDDS alerts were generated for 80 patients. Indecisive responses by ChatGPT to alerts were excluded. For alerts presented without patient variables, ChatGPT provided "correct and identical" responses to 19.9%, "correct and different" responses to 26.7%, and "incorrect responses to 53.4% of the alerts. For alerts including patient variables, ChatGPT provided "correct and identical" responses to 16.7%, "correct and different" responses to 16.0%, and "incorrect responses to 67.3% of the alerts. Accuracy was better for newer drugs such as direct oral anticoagulants. CONCLUSION: The performance of ChatGPT in clinical rule-guided dose interventions in hospitalized patients with renal dysfunction was poor. Based on these results, we conclude that ChatGPT, in its current state, is not appropriate for automatic integration into our EHR to handle CDSS alerts related to renal dysfunction.

Long-term cisplatin nephrotoxicity after childhood cancer: a systematic review and meta-analysis.

BACKGROUND: Cisplatin is a chemotherapeutic drug commonly used in the treatment of many childhood solid malignancies. It is known to cause long-term nephrotoxicity, most commonly manifesting as reduced glomerular filtration rate and hypomagnesaemia. Existing literature regarding the epidemiology of long-term nephrotoxicity in childhood cancer describes large variation in prevalence and risk factors. OBJECTIVES: This study is to evaluate the prevalence of, and risk factors for, long-term cisplatin nephrotoxicity after treatment for childhood cancer. STUDY ELIGIBILITY CRITERIA: Studies were eligible for inclusion if they: (i) evaluated participants treated with cisplatin who were diagnosed with cancer < 18 years of age; (ii) investigated any author-defined measure of nephrotoxicity; and (iii) performed this evaluation 3 or more months after cisplatin cessation. Studies whose scope was broader than this were included if appropriate subgroup analysis was performed. RESULTS: Prevalence of reduced glomerular filtration rate (GFR) ranged between 5.9 and 48.1%. Pooled prevalence of reduced GFR using studies with a modern consensus threshold of 90 ml/min/1.73 m2 was 29% (95% CI 0.0-58%). Prevalence of hypomagnesaemia ranged between 8.0 and 71.4%. Pooled prevalence of hypomagnesaemia was 37% (95% CI 22-51%). Substantial heterogeneity was present, with I2 statistics of 94% and 73% for reduced GFR and hypomagnesaemia respectively. All large, long-term follow-up studies described increased risk of reduced GFR with increasing cumulative cisplatin dose. Included studies varied as to whether cisplatin was a risk factor for proteinuria, and whether age was a risk factor for cisplatin nephrotoxicity. LIMITATIONS: A wide range of study methodologies were noted which impeded analysis. No studies yielded data from developing health-care settings. No non-English studies were included, further limiting generalisability. CONCLUSIONS: Both of the most common manifestations of long-term cisplatin nephrotoxicity have a prevalence of approximately a third, with increasing cumulative dose conferring increased risk of nephrotoxicity. Further work is needed to characterise the relationship between reduced GFR and hypomagnesaemia, investigate other risk factors and understand the interindividual variation in susceptibility to nephrotoxicity.

Dotinurad restores exacerbated kidney dysfunction in hyperuricemic patients with chronic kidney disease.

BACKGROUND: In this study, we aimed to clarify the beneficial effects of urate-lowering treatment with the novel agent dotinurad on renal function in patients with chronic kidney disease (CKD) and hyperuricemia (HUA). METHODS: Thirty-five patients with CKD (mean age 65.4 ± 14.8 years, 23 men) diagnosed with HUA were recruited. Changes in eGFR before and after dotinurad administration were assessed. Patients first underwent a 3-month observation period and then 3 months treatment with dotinurad. RESULTS: During the observation period, mean eGFR (mL/min/1.73 m2) declined significantly. The baseline eGFR was 31.8 ± 16.4 and the serum urate level (sUA, mg/dL) was 8.1 ± 1.7. During the treatment period, eGFR recovered to 36.5 ± 17.5 and sUA decreased to 6.7 ± 1.0. The increase in eGFR after dotinurad administration was correlated with a decrease in sUA (R = 0.375, p = 0.0263). CONCLUSION: Dotinurad administration to patients with CKD and HUA appears to be beneficial in restoring kidney function. Dotinurad may represent a potential medication for the prevention of kidney function decline caused by HUA.

[Mechanism of Notoginseng Radix et Rhizoma in regulating PI3K/Akt/mTORC1-mitochondrial energy metabolism to treat chronic renal failure in rats with blood stasis syndrome].

This study observed the effects of Notoginseng Radix et Rhizoma on the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt)/mammalian target of rapamycin complex 1(mTORC1) signaling pathway and mitochondrial energy metabolism in the rat model of adriamycin-induced renal fibrosis with blood stasis syndrome to explore the mechanism of Notoginseng Radix et Rhizoma in protecting the kidney. Thirty male rats with adriamycin-induced renal fibrosis were randomized into model, low-, medium-, and high-dose Notoginseng Radix et Rhizoma, and positive control groups(n=6). Six clean SD male rats were selected into the normal group. The normal group and model group were administrated with normal saline, and other groups with corresponding drugs. After 8 weeks of treatment, the renal function, renal pathology, adenosine triphosphate(ATP) levels, Na~+-K~+-ATPase and Ca~(2+)-Mg~(2+)-ATPase activities, and the protein levels of ATP5B, mTORC1, 70 kDa ribosomal protein S6 kinase(P70S6K), P85, Akt, p-Akt, and SH2-containing inositol phosphatase(SHIP2) in the renal tissue were determined. Compared with the normal group, the model group showed elevated levels of blood urea nitrogen(BUN) and serum creatinine(SCr)(P<0.01). Compared with the model group, Notoginseng Radix et Rhizoma and the positive control lowered the levels of BUN and SCr, which were significant in the medium-and high-dose Noto-ginseng Radix et Rhizoma groups and the positive control group(P<0.05). Compared with the model group, Notoginseng Radix et Rhizoma and the positive control alleviated the pathological changes in the renal tissue, such as vacuolar and fibroid changes, glomerulus atrophy, cystic expansion of renal tubules, and massive infiltration of inflammatory cells. Compared with the normal group, the model group showed decreased mitochondrial ATP content and Na~+-K~+-ATPase and Ca~(2+)-Mg~(2+)-ATPase activities in the renal tissue(P<0.05), and medium-and high-dose Notoginseng Radix et Rhizoma and positive control mitigated such decreases(P<0.05). Compared with the model group, medium-and high-dose Notoginseng Radix et Rhizoma and the positive control up-regulated the protein levels of ATP5B and SHIP2 and down-regulated the protein levels of mTORC1, P70S6K, P85, Akt, and p-Akt(P<0.05 or P<0.01 or P<0.001). Notoginseng Radix et Rhizoma may exert an anti-fibrosis effect by inhibiting the activation of the PI3K/Akt/mTORC1 pathway to restore mitochondrial energy metabolism, thus protecting the kidney.

TAFRO syndrome: A disease that known is half cured.

Thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly (TAFRO) syndrome is rare in clinical practice. It is a systemic inflammatory disease caused by a cytokine storm. Its clinical manifestations include thrombocytopenia, systemic edema, fever, bone marrow fibrosis, renal insufficiency, and organ enlargement. The high mortality rate of TAFRO syndrome is due to the difficulty of acquiring biopsy samples for diagnosis and the rapid disease progression. This disease is poorly understood by clinicians. Early detection, accurate diagnosis, and timely treatment play key roles in prolonging the survival of the patients. This review summarizes the latest progress in the pathogenesis, diagnostic criteria, and treatment regimens of TAFRO syndrome, aiming to help clinicians better understand TAFRO syndrome and improve its diagnosis and treatment.

Sotagliflozin, a dual sodium-glucose co-transporter-1 and sodium-glucose co-transporter-2 inhibitor, reduces the risk of cardiovascular and kidney disease, as assessed by the Steno T1 Risk Engine in adults with type 1 diabetes.

AIMS: Sotagliflozin (SOTA) as adjunct to insulin therapy improves glycemic control, reduces body weight and blood pressure, and increases time in range in adults with type 1 diabetes (T1D). SOTA demonstrated CV and kidney benefits in high-risk adults with type 2 diabetes. These potential benefits using SOTA for T1D may collectively outweigh the risk of diabetic ketoacidosis. The present analysis estimated the risk of CVD and kidney failure in adults with T1D treated with SOTA. MATERIALS AND METHODS: Participant-level data were used from the inTandem trials evaluating 2980 adults with T1D randomized to once-daily placebo, SOTA 200 mg, or SOTA 400 mg for 24 weeks. For each participant, the cumulative risks of developing CVD and kidney failure were estimated using the Steno T1 Risk Engine. A subgroup analysis was performed in participants with BMI ≥ 27 kg/m2 . RESULTS: SOTA significantly reduced the predicted 5- and 10-year CVD risk in the SOTA 200 and 400 mg pooled group with a relative change in the SOTA group compared to the relative change in the placebo group of (mean [95%-confidence interval (CI)]) -6.6 (-7.9, -5.3) % and -6.4 (-7.6, -5.1) % (p < 0.0001 for both) respectively. For the 5-year ESKD risk there was a significant reduction with a relative change of -5.0 (-7.6, -2.3) % (p = 0.0003). Similar results were observed with the individual doses and in participants with BMI ≥ 27 kg/m2 . CONCLUSION: This analysis provides additional clinical results that may positively balance the benefit/risk assessment of SGLT inhibition use in T1D.

The effect of renal impairment and obesity on anti-Xa peak and trough levels in patients receiving therapeutic doses of nadroparin: a comparison with control patients.

PURPOSE: Anti-Xa peak level monitoring is recommended during LMWH treatment in renal impairment or obesity. The trough level has been proposed as marker for bleeding. We studied the influence of renal impairment and obesity on anti-Xa levels. METHODS: Peak and trough levels were collected during therapeutic nadroparin treatment in patients with renal impairment, obese patients, and controls. 27 patients (n = 68 samples) were evaluated and combined with published data (n = 319 samples from 35 patients) using population pharmacokinetic (popPK) modelling. RESULTS: Median peak level was 0.44 and 0.95 IU/mL in renal impairment with and without dose reduction and 0.60 and 0.43 IU/mL in obesity and controls, respectively. Trough levels were < 0.5 IU/mL in all patients with renal impairment with dose reduction and in 5/6 control patients. In the popPK model, total body weight and eGFR were covariates for clearance and lean body weight for distribution volume. Model-based evaluations demonstrated peak levels below the therapeutic window in controls and increased levels in renal impairment. Dose reductions resulted in a different effect on peak and trough levels. Obese patients (BMI up to 32 kg/m2) had similar levels upon weight-based dosing. CONCLUSION: In renal impairment, anti-Xa peak levels after dose reduction are comparable to those in controls. Weight-based dosing is suitable for obese patients. Aiming for peak levels between 0.6 and 1.0 IU/mL in these patients would result in overexposure compared to controls. Considering the association of trough levels and bleeding risk and our findings, trough monitoring seems to be a suitable parameter to identify nadroparin accumulation.

Linezolid pharmacokinetics: a systematic review for the best clinical practice.

OBJECTIVES: To summarize the pharmacokinetics of linezolid to optimize the dosing regimen in special populations. METHODS: A literature search was performed in three largest medical databases, including Embase, Scopus, and PubMed. The main applied keywords were linezolid and pharmacokinetics. Of 3663 retrieved publications in the English language, 35 original research articles, clinical studies, and case reports about linezolid pharmacokinetics in different populations such as pregnant women, pediatrics, elderly subjects, obese people, individuals with organ dysfunction, and critically ill patients were included. RESULTS AND CONCLUSION: Dose adjustment is not currently recommended for linezolid in patients with mild to moderate renal or hepatic impairment, older adults, and pregnant women. Although dose adjustment is not recommended in patients with severe renal or hepatic impairment, it should be considered that these patients are more vulnerable to linezolid adverse effects and drug interactions. In pediatrics, reducing the linezolid dosing interval to 8 h is suggested. Despite the lack of sufficient information in obese individuals, dosing based on body weight or use of higher dose seems to be justifiable to prevent sub-therapeutic concentrations. Although dose adjustment of linezolid is not recommended in critically ill patients, administration of linezolid as continuous intravenous infusion is suggested in this population. Blood level monitoring should be considered in populations that are vulnerable to linezolid underexposure (such as critically ill patients with augmented renal clearance, pediatrics, overweight, and obese patients) or overexposure (such as elderly, patients with hepatic and renal impairment). To assess the efficacy and safety of linezolid, the area under the concentration-time curve over 24 h to minimum inhibitory concentration (AUC0-24 h/MIC) equal to 80-120, percentage of time above the MIC ≥ 85%, and serum trough concentration between 2 and 7 mg/L are suggested.

Nitrofurantoin for the treatment of uncomplicated urinary tract infection in female patients: the impact of dosing regimen, age, and renal function on drug exposure.

PURPOSE: The aim of this study is to determine nitrofurantoin exposure in female patients with different age and renal function with complaints of an uncomplicated UTI. Also the nitrofurantoin exposure in relation to the dosage regimen will be studied. METHODS: Eight general practitioners (GP) participated in the study and included 38 patients with symptoms of an uncomplicated UTI, treated either with a dose of 50 mg q6h or 100 mg q12h, upon the discretion of the GP. Nitrofurantoin exposure was quantified in the patient's 24-h urine samples by UHPLC-UV and the area under the curve was calculated. RESULTS: The 38 patients provided a range of 2-17 urine samples. The urine nitrofurantoin exposure was 1028 mg h/L for the patients receiving 50 mg q6h and 1036 mg h/L for those treated with 100 mg q12h (p = 0.97) and was not affected by age and eGFR (p = 0.64 and p = 0.34, respectively). CONCLUSION: The data obtained do not support the discouragement of nitrofurantoin use in the elderly and in patients with impaired renal function. Since only a small number of patients were included, a larger study with more patients is warranted to evaluate nitrofurantoin exposure and adverse effects.

Comparative polymyxin B pharmacokinetics in critically ill patients with renal insufficiency and in continuous veno-venous hemodialysis.

PURPOSE: The aim of this study was to assess polymyxin B pharmacokinetics (PK) in patients with varying degrees of renal dysfunction and in patients who require continuous veno-venous hemodialysis (CVVHD). METHODS: The study enrolled 37 patients with sepsis, including 13 patients with glomerular filtration rate (GFR) below 80 mL/min and 11 patients on CVVHD. Each patient received a loading dose of polymyxin B (200-300 mg) and at least 3 subsequent doses of 100-150 mg every 12 h. For every patient, 6-8 blood samples were collected between doses. Polymyxin B (PMB) serum concentration was determined using enzyme-linked immunosorbent assay. RESULTS: In sepsis, patients with preserved renal function mean area under the curve over 24 h (AUC0-24 h) value reached 67.8 ± 9.8 mg*h/L, while in patients with GFR below 80 mL/min, mean AUC0-24 h was 87 ± 5.8 mg*h/L. PMB PK in patients with renal insufficiency was characterized by significantly lower clearance (CL) compared to the normal renal function group (2.1 ± 0.1 L/h vs 3.9 ± 0.4 L/h respectively). In patients on CVVHD, mean AUC0-24 h was 110.4 ± 10.3 mg*h/L, while CL reached 2 ± 0.23 L/h. The median recovery rate from dialysate constituted 22%. Simulation of different dosage regimens that indicate a fixed maintenance dose of 100 mg q12h with a loading dose of 200 mg is optimal for patients on CVVHD, and no dosage increase is required. CONCLUSION: This study demonstrates decreased clearance of PMB in patients with renal insufficiency, which puts them at risk of toxicity. Therefore, patients with extremes of renal function might benefit from therapeutic drug monitoring. For patients with anuria, who require CVVHD, we suggest a fixed dose of 100 mg q12h.

Outcomes of steroid-resistant nephrotic syndrome in children not treated with intensified immunosuppression.

BACKGROUND: The aim of the current PodoNet registry analysis was to evaluate the outcome of steroid-resistant nephrotic syndrome (SRNS) in children who were not treated with intensified immunosuppression (IIS), focusing on the potential for spontaneous remission and the role of angiotensin blockade on proteinuria reduction. METHODS: Ninety-five pediatric patients who did not receive any IIS were identified in the PodoNet Registry. Competing risk analyses were performed on 67 patients with nephrotic-range proteinuria at disease onset to explore the cumulative rates of complete or partial remission or progression to kidney failure, stratified by underlying etiology (genetic vs. non-genetic SRNS). In addition, Cox proportional hazard analysis was performed to identify factors predicting proteinuria remission. RESULTS: Eighteen of 31 (58.1%) patients with non-genetic SRNS achieved complete remission without IIS, with a cumulative likelihood of 46.2% at 1 year and 57.7% at 2 years. Remission was sustained in 11 children, and only two progressed to kidney failure. In the genetic subgroup (n = 27), complete resolution of proteinuria occurred very rarely and was never sustained; 6 (21.7%) children progressed to kidney failure at 3 years. Almost all children (96.8%) received proteinuria-lowering renin-angiotensin-aldosterone system (RAAS) antagonist treatment. On antiproteinuric treatment, partial remission was achieved in 7 of 31 (22.6%) children with non-genetic SRNS and 9 of 27 children (33.3%) with genetic SRNS. CONCLUSION: Our results demonstrate that spontaneous complete remission can occur in a substantial fraction of children with non-genetic SRNS and milder clinical phenotype. RAAS blockade increases the likelihood of partial remission of proteinuria in all forms of SRNS. A higher resolution version of the Graphical abstract is available as Supplementary information.

Association of Metformin, Dipeptidyl Dipeptidase-4 Inhibitors, and Insulin with Coronavirus Disease 2019-Related Hospital Outcomes in Patients with Type 2 Diabetes.

OBJECTIVE: The effects of diabetes medications on COVID-19 hospitalization outcomes have not been consistent. We sought to determine the effect of metformin, dipeptidyl peptidase-4 inhibitors (DPP-4i), and insulin on admission to the intensive care unit (ICU), need for assisted ventilation, development of renal insufficiency, and mortality in patients admitted with COVID-19 infection after controlling for clinical variables and other relevant diabetes-related medications in patients with type 2 diabetes mellitus (DM). METHODS: This was a retrospective study of patients hospitalized with COVID-19 from a single hospital system. Univariate and multivariate analyses were performed that included demographic data, glycated hemoglobin, kidney function, smoking status, insurance, Charlson comorbidity index, number of diabetes medications, and use of angiotensin-converting enzyme inhibitors and statin prior to admission and glucocorticoids during admission. RESULTS: A total of 529 patients with type 2 DM were included in our final analysis. Neither metformin nor DPP4i prescription was associated with ICU admission, need for assisted ventilation, or mortality. Insulin prescription was associated with increased ICU admission but not with need for assisted ventilation or mortality. There was no association of any of these medications with development of renal insufficiency. CONCLUSIONS: In this population, limited to type 2 DM and controlled for multiple variables that have not been consistently studied (such as a measure of general health, glycated hemoglobin, and insurance status), insulin prescription was associated with increased ICU admission. Metformin and DPP4i prescriptions did not have an association with the outcomes.

Prevalence and predictors of inappropriate dosing of direct oral anticoagulants.

BACKGROUND: Information on inappropriate dosing of direct oral anticoagulants (DOACs) is scarce in the Australian context. AIM: To describe the prevalence and potential predictors of inappropriate dosing of DOACs. METHODS: Patients who received DOACs during admission under a general medical unit over a 2-year period (from January 2017 to December 2018) were retrospectively studied. Appropriateness of the dosing regimen was verified against the recommendations of the Therapeutic Goods Administration of Australia. Data were obtained from medical records and analysed in univariate and multivariate logistic regression models. The variables associated with under- and overdosing were also determined. RESULTS: A total of 203 (mean age 71.6 ± 14.5 years, females 52%) patients were studied. Inappropriate dosing occurred in 44 (22%) patients: underdosing 27 (13%) and overdosing 17 (8%). Age ≥75 years (P < 0.01), lower estimated creatinine clearance (CrCl) (P < 0.01), prescription of DOAC prior to index admission (P < 0.01) and higher Charlson Comorbidity Index (P < 0.01), HAS-BLED (P < 0.01) and CHA2 DS2 -VASc (P < 0.01) scores had a significant univariate association with inappropriate dosing. However, in the multivariate logistic regression only lower CrCl (odds ratio (OR) 1.04, 95% confidence interval (CI): 1.01-1.07, P < 0.01) and prescription of DOAC prior to index admission (OR 2.62, 95% CI: 1.01-6.75, P = 0.047) remained significantly associated with inappropriate dosing. Impaired renal function also had a significant association with underdosing (OR 1.04, 95% CI: 1.01-1.07, P = 0.01) and borderline significance with overdosing (OR 1.03, 95% CI: 1.00-1.07, P = 0.06). CONCLUSION: Inappropriate dosing of DOACs, especially underdosing, is common in clinical practice. Clinicians should exercise due diligence when prescribing DOACs to patients with renal impairment and in outpatient settings.

Optimizing the dosing of vancomycin in patients receiving intermittent haemodialysis with low-flux filters, and the potential impact of dosing software.

AIM: Iterative approaches to vancomycin dosing (e.g., dosing when trough concentrations <15-20 mg/L) can be inadequate. Computer-guided dosing may be superior but has not been evaluated in patients with kidney failure receiving replacement therapy. We evaluated vancomycin concentrations using a hospital protocol and a pharmacokinetic software. We measured vancomycin clearance by the FX8 low-flux filter because data are absent. METHODS: We retrospectively reviewed records of adults with kidney failure requiring replacement therapy receiving vancomycin and dialysed with the FX8 low-flux filter, and calculated the proportion of pre-dialysis concentrations that were within, above or below a specified range. One and two-compartment models in the pharmacokinetic software were assessed by computing mean prediction error (MPE) and root mean square error (RMSE) of observed versus predicted concentrations. Vancomycin extracorporeal clearance was prospectively determined using the extraction method. RESULTS: In 24 patients (34 courses; 139 paired observed and predicted concentrations), 62/139 (45%) pre-dialysis concentrations were 15-25 mg/L, 29/139 (21%) were above, and 48/139 (35%) were below. MPE for the one-compartment model was -0.2 mg/L, RMSE 5.3 mg/L. MPE for the two-compartment model was 2.0 mg/L, RMSE 5.6 mg/L. Excluding the first paired concentrations, the subsequent MPE (n = 105) using one-compartment model was -0.5 mg/L, RMSE 5.6 mg/L. The MPE for the two-compartment model was 2.1 mg/L, RMSE 5.8 mg/L. The median extracorporeal clearance was 70.7 mL/min (range: 10.3-130.3; n = 22). CONCLUSIONS: Vancomycin dosing was suboptimal and the pharmacokinetic software was not sufficiently predictive. These may improve with a loading dose. The substantial removal of vancomycin by low-flux filters is not accounted for by the models tested.

Comparison of the effect of vitamin C and selenium nanoparticles on gentamicin-induced renal impairment in male rats: a biochemical, molecular and histological study.

Renal failure caused by gentamicin is mainly mediated through oxidative damage, inflammation, and apoptosis. Hence, vitamin C and selenium, which have antioxidant, anti-inflammatory, and anti-apoptotic properties, and their nanoparticle forms, which have recently received attention, may reduce gentamicin-induced side effects. Therefore, the aim of this study was to investigate the therapeutic effects of vitamin C and selenium, and their nanoparticles on gentamicin-induced renal damage in male rats. 128 adult male Wistar rats were randomly divided into equal sixteen controlled and treated groups. Serum levels of uric acid, blood urea nitrogen, urea, and creatinine were measured. Renal levels of oxidative parameters such as MDA, SOD, and CAT and inflammatory parameters including IL-1ß, and TNF-α were measured. Renal expression of Nrf2, NF-κB, Bcl-2, caspase-3, BAX and mTORc1 was also evaluated. The results showed that gentamicin causes oxidative damage, inflammation, apoptosis and disruption of autophagy in kidney tissue in a dose-dependent manner. However, treatment with vitamin C, selenium and their nanoparticles could significantly improve these effects. Also, the results showed that the inflammatory and oxidative parameters and the expression of genes involved in them and apoptosis in the gentamicin groups treated with vitamin C nanoparticles and selenium nanoparticles reduced significantly compared to those treated with vitamin C and selenium. It can be concluded that vitamin C, selenium and their nanoparticles can improve gentamicin-induced kidney damage by inhibiting oxidative damage, inflammation and apoptosis-induced by autophagy, and can be a good option for kidney damage caused by gentamicin or as an adjunctive treatment to reduce its side effects.

Relationship between Vancomycin Trough Serum Concentrations and Clinical Outcomes in Children: a Systematic Review and Meta-Analysis.

To systematically evaluate the relationships between vancomycin trough serum concentrations and clinical outcomes in children using meta-analysis. Several databases, including PubMed, Elsevier, Web of Science, EMBASE, Medline, clinicaltrials.gov, the Cochrane Library, and three Chinese databases (Wanfang Data, China National Knowledge Infrastructure, and SINOMED), were comprehensively searched to obtain research articles on vancomycin use in children from inception through December 2021. All studies were screened and evaluated using the Cochrane systematic review method. Then, the feature information was extracted for meta-analysis. The evaluated results included clinical efficacy, vancomycin-associated nephrotoxicity, hepatotoxicity, ototoxicity, mortality, and microbial clearance. A total of 35 studies involving 4820 children were included in the analysis. The meta-analysis showed that compared with children with vancomycin trough concentrations <10 µg/mL, those with vancomycin trough concentrations ≥10 µg/mL had a higher clinical efficacy rate [OR: 2.23, 95% CI: 1.29 to 3.84, P = 0.004] and higher incidences of nephrotoxicity [OR: 2.76, 95% CI: 1.51 to 5.07, P = 0.001], ototoxicity [OR: 1.87, 95% CI: 1.08 to 3.23, P = 0.02] and microbial clearance [OR: 2.36, 95% CI: 1.53 to 3.64, P = 0.0001]. All-cause mortality [OR: 1.07, 95% CI: 0.45 to 2.53, P = 0.88] and hepatotoxicity [OR: 0.84, 95% CI: 0.46 to 1.53, P = 0.57] were similar between the two groups. Subgroup analysis showed that compared with children with vancomycin trough concentrations of 10 to 15 µg/mL, those with vancomycin trough concentrations >15 µg/mL had a higher incidence of nephrotoxicity [OR: 2.64, 95% CI: 1.28 to 5.43, P = 0.008], but there was no significant difference in clinical efficacy [OR: 0.85, 95% CI: 0.30 to 2.44, P = 0.76]. A vancomycin trough concentration of 10 to 15 µg/mL can improve clinical efficacy in children. Additionally, avoidance of trough concentrations >15 µg/mL can reduce the incidence of adverse reactions.

Safety and Pharmacokinetics of Taniborbactam (VNRX-5133) with Cefepime in Subjects with Various Degrees of Renal Impairment.

Taniborbactam, an investigational ß-lactamase inhibitor that is active against both serine- and metallo-ß-lactamases, is being developed in combination with cefepime to treat serious infections caused by multidrug-resistant Gram-negative bacteria. Anticipating the use of cefepime-taniborbactam in patients with impaired renal function, an open-label, single-dose clinical study was performed to examine the pharmacokinetics of both drugs in subjects with various degrees of renal function. Hemodialysis-dependent subjects were also studied to examine the amounts of cefepime and taniborbactam dialyzed. Single intravenous infusions of 2 g cefepime and 0.5 g taniborbactam coadministered over 2 h were examined, with hemodialysis-dependent subjects receiving doses both on- and off-dialysis. No subjects experienced serious adverse events or discontinued treatment due to adverse events. The majority of adverse events observed were mild in severity, and there were no trends in the safety of cefepime-taniborbactam related to declining renal function or the timing of hemodialysis. Clinically significant and similar decreases in drug clearance with declining renal function were observed for both cefepime and taniborbactam. The respective decreases in geometric mean clearance for subjects with mild, moderate, and severe renal impairment compared to subjects with normal renal function were 18%, 63%, and 78% for cefepime and 15%, 63%, and 81% for taniborbactam, respectively. Decreases in clearance were similar for both drugs and were shown to be proportional to decreases in renal function. Both cefepime and taniborbactam were dialyzable, with similar amounts removed during 4 h of hemodialysis. This study is registered at ClinicalTrials.gov as NCT03690362.

Pharmacokinetics of Oral Tebipenem Pivoxil Hydrobromide in Subjects with Various Degrees of Renal Impairment.

Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral carbapenem prodrug antimicrobial agent with broad-spectrum activity that includes multidrug-resistant (MDR) Enterobacterales. This study evaluated the safety, tolerability, and pharmacokinetics of TBP-PI-HBr in healthy subjects with normal renal function (cohort 1) and subjects with various degrees of renal impairment (RI [cohorts 2 to 4]) or end-stage renal disease (ESRD) receiving hemodialysis (HD) (cohort 5). Subjects in cohorts 1 to 4 received a single oral dose of TBP-PI-HBr (600 mg). Subjects in cohort 5 received single-dose administration (600 mg) in 2 separate periods: pre-HD (period 2) and post-HD (period 1). Pharmacokinetic (PK) parameters for TBP, the active moiety, were determined using noncompartmental analysis. Compared with cohort 1, the TBP plasma area under the curve (AUC) increased 1.4- to 4.5-fold among cohorts 2 to 4, the maximum concentration of drug in plasma (Cmax) increased up to 1.3-fold and renal clearance (CLR) decreased from 13.4 L/h to 2.4 L/h as the severity of RI increased. Plasma TBP concentrations decreased over 8 to 12 h in cohorts 1 to 4, and apparent total body clearance (CL/F) correlated (R2 = 0.585) with creatinine clearance (CLCR). TBP urinary excretion ranged from 38% to 64% of the administered dose for cohorts 1 to 4. Subjects in cohort 5 had an approximately 7-fold increase in TBP AUC and elimination half-life (t1/2) versus cohort 1. After 4 h of HD, mean TBP plasma exposure decreased by approximately 40%. Overall, TBP plasma exposure increased with increasing RI, highlighting the renal route importance in TBP elimination. A dose reduction of TBP-PI-HBr may be needed in patients with RI (CLCR of ≤50 mL/min) and those with ESRD on HD. TBP-PI-HBr was well tolerated across all cohorts. (This study has been registered at ClinicalTrials.gov under registration no. NCT04178577.).

Application of Population Pharmacokinetic Modeling, Exposure-Response Analysis, and Classification and Regression Tree Analysis to Support Dosage Regimen and Therapeutic Drug Monitoring of Plazomicin in Complicated Urinary Tract Infection Patients with Renal Impairment.

In 2018, the FDA approved plazomicin for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis in adult patients with limited or no alternative treatment options. The objective of this article is to provide the scientific rationales behind the recommended dosage regimen and therapeutic drug monitoring (TDM) of plazomicin in cUTI patients with renal impairment. A previous population pharmacokinetic (PK) model was used to evaluate the dosage regimen in cUTI patients with different degrees of renal impairment. The exposure-response analysis was conducted to identify the relationship between plazomicin exposure and nephrotoxicity incidence in cUTI patients with renal impairment. Classification and regression tree (CART) analysis was utilized to assess the TDM strategy. The receiver operating characteristics curve was plotted to compare two TDM thresholds in cUTI patients with renal impairment. The analyses suggested that dose reduction is necessary for cUTI patients with moderate or severe renal impairment. TDM should be implemented for cUTI patients with mild, moderate, or severe renal impairment to reduce the risk of nephrotoxicity. The trough concentration of 3 µg/mL is a reasonable TDM threshold to reduce the nephrotoxicity incidence while maintaining efficacy in cUTI patients with renal impairment. The application of population PK modeling, exposure-response analysis, and CART analysis allowed for the evaluation of a dosage regimen and TDM strategy for plazomicin in cUTI patients with renal impairment. Our study demonstrates the utility of pharmacometrics and statistical approaches to inform a dosage regimen and TDM strategy for drugs with narrow therapeutic windows.