Renal Failure Research Articles

Endogenous Candida albicans endophthalmitis in a patient with chronic renal failure on hemodialysis

Endogenous Candida albicans endophthalmitis in a patient with chronic renal failure on hemodialysis

Effect of Hepatic and Renal Impairment on the Pharmacokinetics of Dersimelagon (MT-7117), an Oral Melanocortin-1 Receptor Agonist.

Dersimelagon is an orally administered selective melanocortin-1 receptor agonist being investigated for treatment of erythropoietic protoporphyria, X-linked protoporphyria, and diffuse cutaneous systemic sclerosis. Dersimelagon is extensively metabolized in the liver, and potential recipients may have liver dysfunction. Further, effects of renal impairment on pharmacokinetic properties should be established in drugs intended for chronic use. Two separate studies (ClinicalTrials.gov: NCT04116476; NCT04656795) evaluated the effects of hepatic and renal impairment on dersimelagon pharmacokinetics, safety, and tolerability. Participants with mild (n=7) or moderate (n=8) hepatic impairment or normal hepatic function (n=8) received a single oral 100-mg dersimelagon dose. Participants with mild (n=8), moderate (n=8), or severe (n=8) renal impairment or normal renal function (n=8) received a single 300-mg dose. Systemic exposure to dersimelagon was comparable with mild hepatic impairment but higher with moderate hepatic impairment (maximum observed plasma concentration, 1.56-fold higher; area under the plasma concentration-time curve from time 0 extrapolated to infinity, 1.70-fold higher) compared with normal hepatic function. Maximum observed plasma concentration and area under the plasma concentration-time curve from time 0 extrapolated to infinity were similar with moderate renal impairment but higher with mild (1.86- and 1.87-fold higher, respectively) and severe (1.17- and 1.45-fold higher, respectively) renal impairment versus normal renal function. Dersimelagon was generally well tolerated.

Retrieval of Embolized WATCHMAN® Flex Atrial Appendage Occlusion Device.

This case report documents the management of a 66-year old man with atrial fibrillation with recent placement of a WATCHMAN® Flex atrial appendage occlusion device. The patient presented with renal failure, abdominal pain, and difficulty walking 2months after placement. The WATCHMAN® Flex device was found to have embolized to his abdominal aorta at the level of the renal arteries with associated thrombus. Extensive workup revealed reduced left ventricular cardiac function and decreased renal function, both of which were felt to be potentially reversible with device removal. The patient then underwent retrieval of the device and all associated thrombus via an open retroperitoneal approach. This case demonstrates a potential consequence of implanting devices such as an atrial appendage occlusion device and describes a technique for removal.

Estimating the volume of penumbra in rodents using DTI and stack-based ensemble machine learning framework

BackgroundThis study investigates the potential of diffusion tensor imaging (DTI) in identifying penumbral volume (PV) compared to the standard gadolinium-required perfusion–diffusion mismatch (PDM), utilizing a stack-based ensemble machine learning (ML) approach with enhanced explainability.MethodsSixteen male rats were subjected to middle cerebral artery occlusion. The penumbra was identified using PDM at 30 and 90 min after occlusion. We used 11 DTI-derived metrics and 14 distance-based features to train five voxel-wise ML models. The model predictions were integrated using stack-based ensemble techniques. ML-estimated and PDM-defined PVs were compared to evaluate model performance through volume similarity assessment, the Pearson correlation analysis, and Bland–Altman analysis. Feature importance was determined for explainability.ResultsIn the test rats, the ML-estimated median PV was 106.4 mL (interquartile range 44.6–157.3 mL), whereas the PDM-defined median PV was 102.0 mL (52.1–144.9 mL). These PVs had a volume similarity of 0.88 (0.79–0.96), a Pearson correlation coefficient of 0.93 (p < 0.001), and a Bland–Altman bias of 2.5 mL (2.4% of the mean PDM-defined PV), with 95% limits of agreement ranging from -44.9 to 49.9 mL. Among the features used for PV prediction, the mean diffusivity was the most important feature.ConclusionsOur study confirmed that PV can be estimated using DTI metrics with a stack-based ensemble ML approach, yielding results comparable to the volume defined by the standard PDM. The model explainability enhanced its clinical relevance. Human studies are warranted to validate our findings.Relevance statementThe proposed DTI-based ML model can estimate PV without the need for contrast agent administration, offering a valuable option for patients with kidney dysfunction. It also can serve as an alternative if perfusion map interpretation fails in the clinical setting.Key points• Penumbral volume can be estimated by DTI combined with stack-based ensemble ML.• Mean diffusivity was the most important feature used for predicting penumbral volume.• The proposed approach can be beneficial for patients with kidney dysfunction.Graphical

Lactococcus cremoris D2022 alleviates hyperuricemia and suppresses renal inflammation via potential gut-kidney axis.

Hyperuricemia (HUA) is a widespread metabolic disorder. Probiotics have drawn increasing attention as an adjunctive treatment with fewer side effects. However, thus far the effective strains are limited and the mechanisms for their serum uric acid (SUA)-lowering effect are not well understood. Along this line, we conducted the current study using a hyperuricemia mouse model induced by potassium oxonate and adenine. A novel strain of Lactococcus cremoris named D2022 was identified to have significant SUA-lowering capability. Lactococcus cremoris D2022 significantly reduced SUA levels by inhibiting uric acid synthesis and regulating uric acid transportation. It was also found that Lactococcus cremoris D2022 alleviated HUA-induced renal inflammatory injury involving multiple signaling pathways. By focusing on the expression of NLRP3-related inflammatory genes, we found correlations between the expression levels of these genes and free fatty acid receptors (FFARs). In addition, oral administration of Lactococcus cremoris D2022 increased short-chain fatty acids (SCFAs) in cecal samples, which may be one of the mechanisms by which oral probiotics alleviate renal inflammation. Serum untargeted metabolomics showed changes in a variety of serum metabolites associated with purine metabolism and inflammation after oral administration of Lactococcus cremoris D2022, further confirming its systemic bioactivity. Finally, it was proved that Lactococcus cremoris D2022 improved intestinal barrier function. In conclusion, Lactococcus cremoris D2022 can alleviate HUA and HUA-induced nephropathy by increasing the production of SCFAs in the gut and systemic metabolism.

Blood purification therapy in chronic renal failure and its impact on renal index, serological index, and inflammatory factors

Blood purification therapy in chronic renal failure and its impact on renal index, serological index, and inflammatory factors

Sildenafil and furosemide nanoparticles as a novel pharmacological treatment for acute renal failure in rats.

Hospitalized patients often develop acute renal failure (ARF), which causes severe morbidity and death. This research investigates the potential renoprotective benefits of sildenafil and furosemide in glycerol-induced ARF, and measures kidney function metrics in response to nanoparticle versions of these medications. Inducing ARF is commonly done by injecting 50% glycerol intramuscularly. Rats underwent a 24-h period of dehydration and starvation before slaughter for renal function testing. We investigated urine analysis, markers of oxidative stress, histology of kidney tissue, immunohistochemistry analysis of caspase-3 and interleukin-1 beta (IL-1 β), kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL), which are specific indicators of kidney tissue damage. The results of our study showed that the combination of sildenafil and furosemide, using both traditional and nanoparticle formulations, had a greater protective effect on the kidneys compared to using either drug alone. The recovery of renal tissue indicators, serum markers, and urine markers, which are indicative of organ damage, provides evidence of improvement. This was also indicated by the reduction in KIM-1 and NGAL tubular expression. The immunohistochemistry tests showed that the combination therapy, especially with the nanoforms, greatly improved the damaged cellular changes in the kidneys, as shown by higher levels of caspase-3 and IL-1β. According to the findings, a glycerol-induced rat model demonstrates that sildenafil and furosemide, either alone or in combination, in conventional or nanoparticulate forms, improve ARF dysfunction. The synergistic nanoparticulate compositions show remarkable effectiveness. This observation highlights the possible therapeutic implications for ARF treatment.

2023 catastrophic Turkey earthquake: clinical outcomes of pediatric patients rescued under the rubble

ABSTRACT Objectives Children are the most vulnerable population affected by the earthquake. We aimed to examine the characteristics, morbidity, mortality, and the factors affecting these pediatric earthquake victims to guide the follow-up of pediatric patients who were rescued under the rubble in possible future disasters. Methods This is a retrospective observational study. The files of pediatric earthquake victims aged 0-18 years who were admitted to Adana City Training and Research Hospital between 6 February-30 April 2023 were analyzed. 318 patients were included in the study. Results Of all patients 48.7% (n = 155) were female and 51.3% (n = 163) were male. The mean age of the patients was 114.8 months. 65.4% (n = 208) of the patients were discharged from our hospital, eighteen patients (5.7%) died. Information on the hour when the patients were rescued under the rubble could be reached in 117 (36.8%) patients. The mean rescue time of these patients was 50.5 hours. 62 (53%) victims were rescued in the first 24 hours after the earthquake. There were 111 patients (34.9%) with fractures. There were 118 patients (37.1%) who underwent fasciotomy surgery. The total number of patients with amputation was 48 (15.1%). There were 36 patients (11.3%) with one limb amputated, 12 patients (%3.7) with more than one limb amputation. Internal organ injury was present in 30.5% (n = 97) of the patients. Of these patients, 85.6% (n = 83) had single organ trauma and 14.4% (n = 14) had multiple organ trauma. There were 58 patients (18.2%) with acute renal failure in follow-up. The mean rescue time for patients with amputation was 83.65 ± 62.9 hours, and for patients without amputation was 36.44 ± 50.6 hours. This difference was statistically significant (p = 0.001). No statistically significant difference was found when the ages of the patients were compared to fasciotomy, amputation, and fracture status. Conclusion While evaluating earthquake-induced trauma, pediatric patients should be approached carefully.

End-stage renal disease after renal cancer surgery: risk factors and overall survival.

Several risk factors for end-stage renal disease (ESRD), in patients undergoing surgical treatment for renal cell carcinoma (RCC), have been suggested by others. This study aimed to investigate such risk factors and disclose the effect of developing ESRD, postoperatively, on overall survival. The risk of developing ESRD after RCC diagnosis was also evaluated. The data of 16,220 patients with RCC and 162,199 controls were extracted from the Renal Cell Cancer Database Sweden, with linkages across multiple national registers between 2005 and 2020. Cox proportional hazards regression, Kaplan-Meier curves and cumulative incidence were used for statistical analysis. The 5-year cumulative incidence of ESRD following RCC diagnosis was 2.4% (95% confidence interval [CI] 2.1-2.6) and 0.4% (95% CI 0.3-0.4) for the patients with RCC and controls, respectively. Age, chronic kidney disease, higher T-stage and radical nephrectomy (RN) were significant risk factors for ESRD within 1-year of surgery. A total of 104 and 12,152 patients with and without ESRD, respectively, survived 1-year postoperatively. The 5-year overall survival rates of patients with ESRD and those with RCC only were 50% (95% CI 0.40-0.60) and 80% (95% CI 0.80-0.81), respectively. Patients who developed ESRD following renal cancer surgery had significantly poorer survival outcomes. Advanced age, comorbidities, higher-stage tumours and RN were identified as risk factors for developing ESRD. Surgical decisions are crucial. Efforts to spare renal function, including nephron-sparing surgery and active surveillance in appropriate cases, are highly relevant to reduce the development of severe kidney dysfunction.

Successful pregnancy after 10 consecutive failures in a liver transplant patient with advanced kidney failure.

We report a successful, albeit complicated pregnancywith a live-born healthy baby at 28 weeks' gestation, after 10pregnancy failures, in a 39-year-old patient with a history of liver transplantation and chronic kidney disease with hypertension and proteinuria. Multidisciplinary management (obstetrician, nephrologist and hepatology transplant specialist) allowed close monitoring, adaptation of immunosuppressive treatments andstrict control of fetal growth. The onset of preeclampsia at 28 weeks' gestation led to a cesarean section, resulting in the birth of a healthy 830 g boy, with subsequent normal development. Following pregnancy, the patient experienced liver transplant rejection, which resolved after adapting immunosuppressive drugs. No deterioration in kidney function was observed in the year following delivery.

Finerenone in patients with heart failure with mildly reduced or preserved ejection fraction: Rationale and design of the FINEARTS-HF trial.

Steroidal mineralocorticoid receptor antagonists (MRAs), spironolactone and eplerenone, are strongly recommended in the treatment of patients with chronic heart failure (HF) with reduced left ventricular ejection fraction (LVEF), but the balance of efficacy and safety in those with higher LVEF has not been well established. Broad use of steroidal MRAs has further been limited in part due to safety concerns around risks of hyperkalaemia, gynecomastia, and kidney dysfunction. These risks may be mitigated by the unique pharmacological properties of the non-steroidal MRA finerenone. The FINEARTS-HF trial is designed to evaluate the long-term efficacy and safety of the selective non-steroidal MRA finerenone among patients with HF with mildly reduced or preserved ejection fraction. FINEARTS-HF is a global, multicentre, event-driven randomized trial evaluating oral finerenone versus matching placebo in symptomatic patients with HF with LVEF ≥40%. Adults (≥40 years) with HF with New York Heart Association class II-IV symptoms, LVEF ≥40%, evidence of structural heart disease, and diuretic use for at least the previous 30 days were eligible. All patients required elevated natriuretic peptide levels: for patients in sinus rhythm, N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥300 pg/ml (or B-type natriuretic peptide [BNP] ≥100 pg/ml) were required, measured within 30 days (in those without a recent worsening HF event) or within 90 days (in those with a recent worsening HF event). Qualifying levels of NT-proBNP or BNP were tripled if a patient was in atrial fibrillation at screening. Estimated glomerular filtration rate <25 ml/min/1.73 m2 or serum potassium >5.0 mmol/L were key exclusion criteria. Patients were enrolled irrespective of clinical care setting (whether hospitalized, recently hospitalized, or ambulatory). The primary endpoint is the composite of cardiovascular death and total (first and recurrent) HF events. The trial started on 14 September 2020 and has validly randomized 6001 participants across 37 countries. Approximately 2375 total primary composite events are targeted. The FINEARTS-HF trial will determine the efficacy and safety of the non-steroidal MRA finerenone in a broad population of hospitalized and ambulatory patients with HF with mildly reduced or preserved ejection fraction. ClinicalTrials.gov NCT04435626 and EudraCT 2020-000306-29.

The STING inhibitor (ISD-017) reduces glomerulonephritis in 129.B6.Fcgr2b-deficient mice

The absence of stimulator of interferon genes (STING) in 129.B6.Fcgr2b-deficient mice rescue lupus phenotypes. The administration of a STING inhibitor (ISD017) into the young 129.B6.Fcgr2b-deficient mice prevents lupus nephritis development. This study mainly aimed to evaluate the effects of STING inhibition (ISD107) on established SLE in mice to prove that ISD017 could be a good therapeutic drug to reverse the already set-up autoimmunity and kidney impairment. Twenty-four-week-old Fcgr2b-deficient mice were treated with cyclophosphamide (25 mg/kg, intraperitoneal, once per week), ISD017 (10 mg/kg, intraperitoneal, three times per week), or control vehicle for 8 weeks, and were analyzed for phenotypes. Both ISD017 and cyclophosphamide treatment increased long-term survival and reduced the severity of glomerulonephritis in Fcgr2b-deficient mice. While cyclophosphamide reduced activated B cells (B220+GL-7+), ISD017 decreased activated T cells (CD4+CD69+) and neutrophils (Ly6c+Ly6g+) in Fcgr2b-deficient mice. In addition, ISD017 reduced IL-1β and interferon-inducible genes. In summary, ISD017 treatment in symptomatic 129.B6.Fcgr2b-deficient mice reduced the severity of glomerulonephritis and increased long-term survival. ISD017 worked comparably to cyclophosphamide for treating lupus nephritis in 129.B6.Fcgr2b-deficient mice. ISD017 reduced activated T cells and neutrophils, while cyclophosphamide targeted activated B cells. These results suggested that STING inhibitors can potentially be a new therapeutic drug for treating lupus.

Incidence and risk factors of postoperative delirium following hepatic resection: a retrospective national inpatient sample database study

BackgroundPostoperative delirium (POD) is a common complication after major surgery and can cause a variety of adverse effects. However, no large-scale national database was used to assess the occurrence and factors associated with postoperative delirium (POD) following hepatic resection.MethodsPatients who underwent hepatic resection from 2015 to 2019 were screened using the International Classification of Diseases (ICD) 10th edition clinical modification code from the National Inpatient Sample (NIS) Database. Peri-operative factors associated with delirium were screened and underwent statistical analysis to identify independent predictors for delirium following hepatic resection.ResultsA total of 80,070 patients underwent hepatic resection over a five-year period from 2015 to 2019. The overall occurrence of POD after hepatic resection was 1.46% (1039 cases), with a slight upward trend every year. The incidence of elective admission was 6.66% lower (88.60% vs. 81.94%) than that of patients without POD after hepatic resection and 2.34% (45.53% vs. 43.19%) higher than that of patients without POD in teaching hospitals (P < 0.001). In addition, POD patients were 6 years older (67 vs. 61 years) and comprised 9.27% (56.69% vs. 47.42%) more male patients (P < 0.001) compared to the unaffected population. In addition, the occurrence of POD was associated with longer hospitalization duration (13 vs. 5 days; P < 0.001), higher total cost ($1,481,89 vs. $683,90; P < 0.001), and higher in-hospital mortality (12.61% vs. 4.11%; P < 0.001). Multivariate logistic regression identified hepatic resection-independent risk factors for POD, including non-elective hospital admission, teaching hospital, older age, male sex, depression, fluid and electrolyte disorders, coagulopathy, other neurological disorders, psychoses, and weight loss. In addition, the POD after hepatic resection has been associated with sepsis, dementia, urinary retention, gastrointestinal complications, acute renal failure, pneumonia, continuous invasive mechanical ventilation, blood transfusion, respiratory failure, and wound dehiscence / non-healing.ConclusionAlthough the occurrence of POD after hepatic resection is relatively low, it is beneficial to investigate factors predisposing to POD to allow optimal care management and improve the outcomes of this patient population.

The entactogen 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) as a treatment aid in psychotherapy and its safety concerns.

The phenylethylamine, 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy'), is the prototypical example of an entactogen. Its original placement in highly restrictive drug usage categories in the US and UK, led to an inevitable restriction on MDMA neuroscience research and treatment. The dominant pharmacological effects of MDMA are its properties of release and inhibition of reuptake of amine neurotransmitter transporters for dopamine, norepinephrine, and serotonin. MDMA is an agonist of a wide range of receptors; its mood-altering effects are mediated via 5-HT2A receptors; this receptor may also mediate its effects on body temperature, analgesia, and anxiolytic properties. The mechanisms underlying MDMA's entactogenic properties of sociability and interpersonal closeness are not known but release and involvement of oxytocin, a peptide thought by some to be involved in social bonding, has been suggested. Adverse effects of MDMA are mostly transient; acute multiorgan adverse effects occurring during raves or crowded dance gatherings include dehydration, hyperthermia, seizures, rhabdomyolysis, disseminated intravascular coagulation, and acute renal failure. Deaths following MDMA taken by itself are rare compared to fatalities following coadministration with other drugs. A recent FDA-approved phase 3 clinical trial of MDMA for post-traumatic stress disorder (PTSD) led to the conclusion that MDMA-assisted therapy represents a potential breakthrough treatment meriting expedited clinical evaluation. Despite the ongoing deliberations by the FDA and EMA for approval of MDMA treatment of PTSD, the Australian Therapeutic Goods Administration (TGA) recently announced that after an evaluation of the therapeutic value, benefits, and risks of MDMA, it will permit its prescribing for the treatment of PTSD. Further examples of regulatory relaxation toward MDMA-assisted psychotherapy are underway. These include the FDA's recently approved clinical trial to assess MDMA's efficacy in the treatment of "asociality" in patients with schizophrenia and an open trial of MDMA treatment for alcohol-use disorder which showed decreased alcohol consumption. There are also ongoing studies on the little understood startle response, anxiety associated with life-threatening illness, and social anxiety in autistic adults.

Unraveling TAFRO Syndrome: An In-Depth Look at the Pathophysiology, Management, and Future Perspectives

TAFRO syndrome is a rare and aggressive inflammatory entity characterized by thrombocytopenia, anasarca, fever, renal failure, reticulin fibrosis, and organomegaly. This entity supposes a diagnostic and therapeutic challenge due to its significant overlap with Castleman’s disease. However, distinct clinical and histological features warrant its classification as a separate subtype of idiopathic multicentric Castleman’s disease (iMCD). While recent modifications have been made to the diagnostic criteria for iMCD, these criteria lack specificity for this particular condition, further complicating diagnosis. Due to its inflammatory nature, several complex molecular signaling pathways are involved, including the JAK-STAT pathway, NF-kB, and signal amplifiers such as IL-6 and VEGF. Understanding the involvement of immune dysfunction, some infectious agents, genetic mutations, and specific molecular and signaling pathways could improve the knowledge and management of the condition, leading to effective treatment strategies. The current therapeutic approaches include corticosteroids, anti-IL6 drugs, rituximab, and chemotherapy, among others, but response rates vary, highlighting the need for personalized strategies. The prognosis is uncertain due to diagnostic difficulties, emphasizing the importance of early intervention and appropriate targeted treatment. This comprehensive review examines the evolving landscape of TAFRO syndrome, including the pathophysiology, diagnostic criteria, treatment strategies, prognosis, and future perspectives.

Against all odds: successful pregnancy in an adult patient with unrepaired coarctation of the aorta.

According to the modified World Health Organization classification, pregnant women with unrepaired aortic coarctation are at very high risk for both maternal and fetal complications and should, therefore, be counselled against pregnancy. The most frequent maternal complications include systemic hypertension, renal failure, preeclampsia, and aortic dissection. Herein, we describe a successful pregnancy in an adult patient with unrepaired aortic coarctation.

Unraveling Phenotypic Variability in Action Myoclonus with Renal Failure with SCARB2 Mutation in Siblings.

Unraveling Phenotypic Variability in Action Myoclonus with Renal Failure with SCARB2 Mutation in Siblings.

A chronic intermittent haemodialysis pig model for functional evaluation of dialysis membranes.

Performance evaluation of new dialysis membranes is primarily performed in vitro, which can lead to differences in clinical results. Currently, data on dialysis membrane performance and safety are available only for haemodialysis patients. Herein, we aimed to establish an in vivo animal model of dialysis that could be extrapolated to humans. We created a bilateral nephrectomy pig model of renal failure, which placed a double-lumen catheter with the hub exposed dorsally. Haemodialysis was performed in the same manner as in humans, during which clinically relevant physiologic data were evaluated. Next, to evaluate the utility of this model, the biocompatibility of two kinds of membranes coated with or without vitamin E used in haemodiafiltration therapy were compared. Haemodialysis treatment was successfully performed in nephrectomized pigs under the same dialysis conditions (4 h per session, every other day, for 2 weeks). In accordance with human clinical data, regular dialysis alleviated renal failure in pigs. The vitamin E-coated membrane showed a significant reduction rate of advanced oxidation protein products during dialysis than non-coated membrane. In conclusion, this model mimics the pathophysiology and dialysis condition of patients undergoing haemodialysis. This dialysis treatment model of renal failure will be useful for evaluating the performance and safety of dialysis membranes.

Dealing With Variable Drug Exposure DuetoVariable Hepatic Metabolism: A Proof-of-Concept Application of Liquid Biopsy in Renal Impairment.

Precision dosing strategies require accounting for between-patient variability in pharmacokinetics (PK), affecting drug exposure, and in pharmacodynamics (PD), affecting response achieved at the same drug concentration at the site of action. Although liquid biopsy for assessing different levels of molecular drug targets has yet to be established, individual characterization of drug elimination pathways using liquid biopsy has recently been demonstrated. The feasibility of applying this approach in conjunction with modeling tools to guide individual dosing remains unexplored. In this study, we aimed to individualize physiologically-based pharmacokinetic (PBPK) models based on liquid biopsy measurements in plasma from 25 donors with different grades of renal function who were previously administered oral midazolam as part of a microdose cocktail. Virtual twin models were constructed based on demographics, renal function, and hepatic expression of relevant pharmacokinetic pathways projected from liquid biopsy output. Simulated exposure (AUC) to midazolam was in agreement with observed data (AFE = 1.38, AAFE = 1.78). Simulated AUC variability with three dosing approaches indicated higher variability with uniform dosing (14-fold) and stratified dosing (13-fold) compared with individualized dosing informed by liquid biopsy (fivefold). Further, exosome screening revealed mRNA expression of 532 targets relevant to drug metabolism and disposition (169 enzymes and 361 transporters). Data related to these targets can be used to further individualize PBPK models for pathways relevant to PK of other drugs. This study provides additional verification of liquid biopsy-informed PBPK modeling approaches, necessary to advance strategies that seek to achieve precise dosing from the start of treatment.

Development and validation of a new drug-focused predictive risk score for postoperative delirium in orthopaedic and trauma surgery patients

BackgroundPostoperative delirium (POD) is the most common complication following surgery in elderly patients. During pharmacist-led medication reconciliation (PhMR), a predictive risk score considering delirium risk-increasing drugs and other available risk factors could help to identify risk patients.MethodsOrthopaedic and trauma surgery patients aged ≥ 18 years with PhMR were included in a retrospective observational single-centre study 03/2022-10/2022. The study cohort was randomly split into a development and a validation cohort (6:4 ratio). POD was assessed through the 4 A’s test (4AT), delirium diagnosis, and chart review. Potential risk factors available at PhMR were tested via univariable analysis. Significant variables were added to a multivariable logistic regression model. Based on the regression coefficients, a risk score for POD including delirium risk-increasing drugs (DRD score) was established.ResultsPOD occurred in 42/328 (12.8%) and 30/218 (13.8%) patients in the development and validation cohorts, respectively. Of the seven evaluated risk factors, four were ultimately tested in a multivariable logistic regression model. The final DRD score included age (66–75 years, 2 points; > 75 years, 3 points), renal impairment (eGFR < 60 ml/min/1.73m2, 1 point), anticholinergic burden (ACB-score ≥ 3, 1 point), and delirium risk-increasing drugs (n ≥ 2; 2 points). Patients with ≥ 4 points were classified as having a high risk for POD. The areas under the receiver operating characteristic curve of the risk score model were 0.89 and 0.81 for the development and the validation cohorts, respectively.ConclusionThe DRD score is a predictive risk score assessable during PhMR and can identify patients at risk for POD. Specific preventive measures concerning drug therapy safety and non-pharmacological actions should be implemented for identified risk patients.