Klotho and Mesenchymal Stem Cells: A Review on Cell and Gene Therapy for Chronic Kidney Disease and Acute Kidney Disease

Chronic kidney disease (CKD) and acute kidney injury (AKI) are public health problems, and their prevalence rates have increased with the aging of the population. They are associated with the presence of comorbidities, in particular diabetes mellitus and hypertension, resulting in a high financial burden for the health system. Studies have indicated Klotho as a promising therapeutic approach for these conditions. Klotho reduces inflammation, oxidative stress and fibrosis and counter-regulates the renin-angiotensin-aldosterone system. In CKD and AKI, Klotho expression is downregulated from early stages and correlates with disease progression. Therefore, the restoration of its levels, through exogenous or endogenous pathways, has renoprotective effects. An important strategy for administering Klotho is through mesenchymal stem cells (MSCs). In summary, this review comprises in vitro and in vivo studies on the therapeutic potential of Klotho for the treatment of CKD and AKI through the administration of MSCs.

Application of Machine Learning to Predict Acute Kidney Disease in Patients With Sepsis Associated Acute Kidney Injury

Background: Sepsis-associated acute kidney injury (AKI) is frequent in patients admitted to intensive care units (ICU) and may contribute to adverse short-term and long-term outcomes. Acute kidney disease (AKD) reflects the adverse events developing after AKI. We aimed to develop and validate machine learning models to predict the occurrence of AKD in patients with sepsis-associated AKI.Methods: Using clinical data from patients with sepsis in the ICU at Beijing Friendship Hospital (BFH), we studied whether the following three machine learning models could predict the occurrence of AKD using demographic, laboratory, and other related variables: Recurrent Neural Network-Long Short-Term Memory (RNN-LSTM), decision trees, and logistic regression. In addition, we externally validated the results in the Medical Information Mart for Intensive Care III (MIMIC III) database. The outcome was the diagnosis of AKD when defined as AKI prolonged for 7–90 days according to Acute Disease Quality Initiative-16.Results: In this study, 209 patients from BFH were included, with 55.5% of them diagnosed as having AKD. Furthermore, 509 patients were included from the MIMIC III database, of which 46.4% were diagnosed as having AKD. Applying machine learning could successfully achieve very high accuracy (RNN-LSTM AUROC = 1; decision trees AUROC = 0.954; logistic regression AUROC = 0.728), with RNN-LSTM showing the best results. Further analyses revealed that the change of non-renal Sequential Organ Failure Assessment (SOFA) score between the 1st day and 3rd day (Δnon-renal SOFA) is instrumental in predicting the occurrence of AKD.Conclusion: Our results showed that machine learning, particularly RNN-LSTM, can accurately predict AKD occurrence. In addition, Δ SOFAnon−renal plays an important role in predicting the occurrence of AKD.

Recent Advances in Therapeutic Drug Monitoring of Voriconazole, Mycophenolic Acid, and Vancomycin: A Literature Review of Pediatric Studies

The review includes studies dated 2011–2021 presenting the newest information on voriconazole (VCZ), mycophenolic acid (MPA), and vancomycin (VAN) therapeutic drug monitoring (TDM) in children. The need of TDM in pediatric patients has been emphasized by providing the information on the differences in the drugs pharmacokinetics. TDM of VCZ should be mandatory for all pediatric patients with invasive fungal infections (IFIs). Wide inter- and intrapatient variability in VCZ pharmacokinetics cause achieving and maintaining therapeutic concentration during therapy challenging in this population. Demonstrated studies showed, in most cases, VCZ plasma concentrations to be subtherapeutic, despite the updated dosages recommendations. Only repeated TDM can predict drug exposure and individualizing dosing in antifungal therapy in children. In children treated with mycophenolate mofetil (MMF), similarly as in adult patients, the role of TDM for MMF active form, MPA, has not been well established and is undergoing continued debate. Studies on the MPA TDM have been carried out in children after renal transplantation, other organ transplantation such as heart, liver, or intestine, in children after hematopoietic stem cell transplantation or cord blood transplantation, and in children with lupus, nephrotic syndrome, Henoch-Schönlein purpura, and other autoimmune diseases. MPA TDM is based on the area under the concentration–time curve; however, the proposed values differ according to the treatment indication, and other approaches such as pharmacodynamic and pharmacogenetic biomarkers have been proposed. VAN is a bactericidal agent that requires TDM to prevent an acute kidney disease. The particular group of patients is the pediatric one. For this group, the general recommendations of the dosing may not be valid due to the change of the elimination rate and volume of distribution between the subjects. The other factor is the variability among patients that concerns the free fraction of the drug. It may be caused by both the patients’ population and sample preconditioning. Although VCZ, MMF, and VAN have been applied in pediatric patients for many years, there are still few issues to be solve regarding TDM of these drugs to ensure safe and effective treatment. Except for pharmacokinetic approach, pharmacodynamics and pharmacogenetics have been more often proposed for TDM.

Jeopardy of COVID-19: Rechecking the Perks of Phytotherapeutic Interventions

The novel coronavirus disease (COVID-19), the reason for worldwide pandemic, has already masked around 220 countries globally. This disease is induced by Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2). Arising environmental stress, increase in the oxidative stress level, weak immunity and lack of nutrition deteriorates the clinical status of the infected patients. Though several researches are at its peak for understanding and bringing forward effective therapeutics, yet there is no promising solution treating this disease directly. Medicinal plants and their active metabolites have always been promising in treating many clinical complications since time immemorial. Mother nature provides vivid chemical structures, which act multi-dimensionally all alone or synergistically in mitigating several diseases. Their unique antioxidant and anti-inflammatory activity with least side effects have made them more effective candidate for pharmacological studies. These medicinal plants inhibit attachment, encapsulation and replication of COVID-19 viruses by targeting various signaling molecules such as angiotensin converting enzyme-2, transmembrane serine protease 2, spike glycoprotein, main protease etc. This property is re-examined and its potency is now used to improve the existing global health crisis. This review is an attempt to focus various antiviral activities of various noteworthy medicinal plants. Moreover, its implications as prophylactic or preventive in various secondary complications including neurological, cardiovascular, acute kidney disease, liver disease are also pinpointed in the present review. This knowledge will help emphasis on the therapeutic developments for this novel coronavirus where it can be used as alone or in combination with the repositioned drugs to combat COVID-19.

8. Sepsis-Associated Acute Kidney Injury and Acute Kidney Disease: A 15-Year Cohort Study of 4,226 Adult Sepsis Inpatient Survivors at a Tertiary Medical Center in Taiwan

Background Sepsis is the most common cause of acute kidney injury (AKI) and about one-third of patients with sepsis-associated AKI (SA-AKI) develop acute kidney diseases (SA-AKD) and may progress to unfavorable outcomes. We aimed to study the characteristics and outcomes associated with SA-AKI and SA-AKD. Methods This cohort study included adult inpatients with first-time sepsis who were admitted during 2003-2017, had qualifying serum creatinine (SCr) measurements at baseline (-365 to -3 days), -2 to +7 days, and +8 to +90 days of sepsis index day, and survived the first 90 days (Figure 1). Sepsis was identified using an electronic medical records-based Sepsis-3 criteria. We classified sepsis inpatients into SA-AKI(-), SA-AKD(-), SA-relapsed-AKD, and SA-nonrecovery-AKD (Figure 2). ESRD and mortality were ascertained by linking to the Catastrophic Illness records and to National Death Registry, respectively. Multivariable Cox proportional hazard model was used to evaluate the risk of mortality and end-stage renal disease (ESRD) associated with SA-AKI/AKD subtypes. Figure 1. Flowchart of the selection process of adult sepsis survivors (N = 4226 patients). Figure 2. Definitions of sepsis associated-acute kidney injury (SA-AKI) and sepsis associated-acute kidney disease (SA-AKD). Results Of 4,226 eligible sepsis inpatient survivors, 47.1% developed SA-AKI and 10.1% progressed to SA-AKD (5.4% relapsed and 4.7% nonrecovery). Patient with AKI and non-recovered AKD had the worst baseline renal function (SCr, 1.3 mg/dL) (Table 1). The multivariable analyses revealed that SA-relapsed AKD was significantly associated with increased risk of all-cause mortality for 1-year (aHR 1.67; 95% CI 1.25, 2.24), 3-year (aHR 1.38; 95% CI 1.11, 1.71), and overall (aHR 1.35; 95% CI 1.12, 1.61), compared with SA-AKI(-). SA-relapsed AKD and SA-nonrecovery AKD were both significantly associated with 1-year, 3-year, and overall ESRD, with the risk of about 4-fold or higher than SA-AKI(-) (Table 2). Table 1. Baseline characteristics and outcomes among adult sepsis survivors, by different SA-AKI/AKD subtypes. Table 2. Risk of all-cause mortality and end stage renal disease (ESRD) among adult sepsis survivors. Conclusion Sepsis survivors who initially had AKI and developed relapsed or nonrecovery AKD tended to have worse outcomes of all-cause and ESRD, compared with those without AKI. Unexpectedly, patients with non-recovered AKD did not have a higher mortality risk, possibly because we have selected those who survived the first 90 days of sepsis. We will develop two-stage prediction models to identify sepsis patients at risk of developing AKI and SA-AKI patients at risk of developing different types of AKD. Disclosures All Authors: No reported disclosures