Search

Background: Most patients starting chronic in-center hemodialysis (HD) receive conventional hemodialysis (CHD) with three sessions per week targeting specific biochemical clearance. Observational studies suggest that patients with residual kidney function can safely be treated with incremental prescriptions of HD, starting with less frequent sessions and later adjusting to thrice-weekly HD. This trial aims to show objectively that clinically matched incremental HD (CMIHD) is non-inferior to CHD in eligible patients., Methods: An unblinded, parallel-group, randomized controlled trial will be conducted across diverse healthcare systems and dialysis organizations in the USA. Adult patients initiating chronic hemodialysis (HD) at participating centers will be screened. Eligibility criteria include receipt of fewer than 18 treatments of HD and residual kidney function defined as kidney urea clearance ≥3.5 mL/min/1.73 m 2 and urine output ≥500 mL/24 h. The 1:1 randomization, stratified by site and dialysis vascular access type, assigns patients to either CMIHD (intervention group) or CHD (control group). The CMIHD group will be treated with twice-weekly HD and adjuvant pharmacologic therapy (i.e., oral loop diuretics, sodium bicarbonate, and potassium binders). The CHD group will receive thrice-weekly HD according to usual care. Throughout the study, patients undergo timed urine collection and fill out questionnaires. CMIHD will progress to thrice-weekly HD based on clinical manifestations or changes in residual kidney function. Caregivers of enrolled patients are invited to complete semi-annual questionnaires. The primary outcome is a composite of patients' all-cause death, hospitalizations, or emergency department visits at 2 years. Secondary outcomes include patient- and caregiver-reported outcomes. We aim to enroll 350 patients, which provides ≥85% power to detect an incidence rate ratio (IRR) of 0.9 between CMIHD and CHD with an IRR non-inferiority of 1.20 (α = 0.025, one-tailed test, 20% dropout rate, average of 2.06 years of HD per patient participant), and 150 caregiver participants (of enrolled patients)., Discussion: Our proposal challenges the status quo of HD care delivery. Our overarching hypothesis posits that CMIHD is non-inferior to CHD. If successful, the results will positively impact one of the highest-burdened patient populations and their caregivers., Trial Registration: Clinicaltrials.gov NCT05828823. Registered on 25 April 2023., (© 2024. The Author(s).)

The global burden of kidney disease is increasing, paralleled by a rising number of natural and man-made crises. During these tumultuous times, accessing vital health care resources becomes challenging, posing significant risks to individuals, particularly those with kidney disease. This review delves into the impact of crises on kidney disease, with a particular focus on acute kidney injury (AKI), kidney failure, and kidney transplant. Patients experiencing crush injuries leading to AKI may encounter delayed diagnosis due to the chaotic nature of disasters and limited availability of resources. In chronic crises such as conflicts, patients with kidney failure are particularly affected, and deviations from dialysis standards are unfortunately common, impacting morbidity and mortality rates. Additionally, crises also disrupt access to kidney transplants, potentially compromising transplant outcomes. This review underscores the critical importance of preparedness measures and proactive management for kidney disease in crisis settings. Collaborative efforts among government bodies, rescue teams, health care providers, humanitarian agencies, and nongovernmental organizations are imperative to ensure equitable and reasonable care for kidney disease patients during times of crises, with the aim of saving lives and improving outcomes., (Copyright © 2024 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Continuous renal replacement therapy (CRRT) is a form of renal replacement therapy that is used in modern intensive care units (ICUs) to help manage acute kidney injury (AKI), end stage kidney disease (ESKD), poisonings, and some electrolyte disorders. CRRT has transformed the care of patients in the ICU over the past several decades. In this setting, it is important to recognize CRRT-associated complications but also up-to-date management of these complications. Some of these complications are minor, but others may be more significant and even life-threatening. Some CRRT complications may be related to dialysis factors and others to specific patient factors. Our overarching goal in this article is to review and discuss the most significant CRRT-related complications at the different stage of management of CRRT. With the advent of newer solutions, there have been newer complications as well., Competing Interests: S.C. Gautam reports ownership interest in BNGO, Criper, Invitae (stockholder), Sensonics, and Pacific Biosciences. B.G. Jaar reports honoraria from the American Board of Internal Medicine—Nephrology; patents or royalties from UpToDate; and an advisory or leadership role for the American Board of Internal Medicine, BMC Medicine, BMC Nephrology, the Clinical Journal of the American Society of Nephrology, and the National Kidney Foundation. The remaining author has nothing to disclose., (Copyright © 2022 by the American Society of Nephrology.)

Introduction: Psychoactive substance use among medical students is common. This may not only pose a threat to their health and academic performance but may have medico-legal and ethical ramifications. The aim of this study was to find out the prevalence of six psychoactive substances (alcohol, tobacco, cannabis, cocaine, benzodiazepines, opioids) among second year and third year medical students., Methods: A descriptive cross-sectional study was done in a medical college. Whole sampling was done and ethical approval was taken from the Institutional Review Committee (Reference Number: 54-074/075). The study was conducted from May 2018 to June 2018. A semi-structured self-administered questionnaire modified and adapted from World Health Organization's guidelines for student substance use survey was used to collect data from second year and third year medical students. Statistical Package for Social Sciences version 16.0 was used for analysis. Point estimate at 95% Confidence Interval was calculated along with frequency and proportion for binary data., Results: Out of 226 total respondents, 95 (42.0%) (35.55- 48.45 at 95% Confidence Interval) reported current use of one or more psychoactive substances. Most frequently used substance was alcohol with current use prevalence of 87 (38.5%), followed by smoking 39 (17.3%) and cannabis 27 (11.9%). Cocaine, benzodiazepines and opioids were the least consumed substances with current use prevalence of 2 (0.9%) each., Conclusions: Almost half of the students were currently using one or more psychoactive substances which is concerning, and therefore strategies must be adopted to alleviate such use.

Competing Interests: All authors have nothing to disclose.

Acute kidney injury (AKI) is a common clinical syndrome characterized by rapid impairment of kidney function. The incidence of AKI and its severe form AKI requiring dialysis (AKI-D) has been increasing over the years. AKI etiology may be multifactorial and is substantially associated with increased morbidity and mortality. The outcome of AKI-D can vary from partial or complete recovery to transitioning to chronic kidney disease, end stage kidney disease, or even death. Predicting outcomes of patients with AKI is crucial as it may allow clinicians to guide policy regarding adequate management of this problem and offer the best long-term options to their patients in advance. In this manuscript, we will review the current evidence regarding the determinants of AKI outcomes, focusing on AKI-D.

Background: Owing to its impact on weight loss, remission of diabetes mellitus and metabolic syndrome, bariatric surgery has offered hope for grossly obese individuals. In recent years, obesity has increased in the UAE and the use of bariatric surgery has increased in-line with this trend. However, data regarding bariatric surgery outcomes in diabetic Emirati people is scarce., Objective: To evaluate the effect of bariatric surgery in patients with diabetes mellitus., Methods: This is a retrospective analysis of diabetic patients treated with bariatric surgery with a minimal follow-up of 1 year and extended for some patients (21) to 2 years follow up. A total of 80 patients underwent bariatric surgery. Two surgical procedures were used; laparoscopic sleeve gastrectomy (n=53) or mini-gastric bypass between January 1, 2015, and July 20, 2017., Results: Mean baseline weight was 119.2±31.2 kg, this has significantly dropped to 100.1±23.1, 91.2±22.3, 82.3±17.5, and 81.3±15.3 kg at 3, 6, 12, and 24 months respectively, and this change was statistically significant P <0.001 at each time point. Mean baseline HbA1c was 8.6% ± 2.3% and this dropped significantly to 6.5±1.7, 5.9±1.2, 5.6±0.8, and 5.4±0.7 at 3, 6, 12, and 24 months respectively ( P <0.000). In 49 (61.3%) we considered fatty liver based on ultrasound features either with or without elevation in alanine aminotransferase (ALT). We noticed a significant decrease in ALT at 3, 6, and 12 months after surgery. Furthermore, 11 patients (22.4%) showed sonographic features of improvement in fatty liver in addition to normalization of ALT., Conclusions: Bariatric surgery was effective over a follow-up period of 2 years in achieving significant weight loss as well as resulting in improvements in glycemic control, blood pressure, and fatty liver., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Trichothecenes are powerful mycotoxins that inhibit protein synthesis and induce ribotoxic stress response in mammalian cells. Verrucarin A (VC-A) is a Type D macrocyclic mycotoxin which inhibits cell proliferation and induces apoptosis in cancer cells. However, the antitumor activity of VC-A for prostate cancer cells has not been investigated. The objective of the present study was to determine the anticancer activity and its mechanism of action in hormone-responsive (LNCaP) and hormone-refractory (PC-3) carcinoma of the prostate (CaP) cell lines. VC-A strongly inhibited the proliferation and induced cell cycle arrest in G2/M phase associated with the inhibition of cell cycle regulatory proteins cyclin D, cyclin E, cyclin-dependent kinases (cdks) cdk2, cdk4, cdk6 and cdk inhibitors WAF1/21 and KIP1/27. VC-A also induced apoptosis in CaP cells as characterized by the cleavage of poly (ADP-ribose) polymerase (PARP-1), procaspases-3, -8 and -9 and the inhibition of Bcl-2 family proteins that regulate apoptosis (Bcl-2, Bcl-xL, Bax, Bak and Bad). In addition, VC-A also down-regulated the expression of prosurvival phospho-AKT (p-AKT), nuclear factor kappa B (NF-kB) (p65) and phospho-mammalian target of rapamycin (p-mTOR) signaling proteins. Taken together, these results demonstrated strong antiproliferative and apoptosis-inducing activity of verrucarin A against CaP cells through cell cycle arrest and inhibition of the prosurvival (antiapoptotic) AKT/NF-kB/mTOR signaling pathway., (© 2016 Old City Publishing, Inc.)

Pancreatic ductal adenocarcinoma (PDA) remains one of the most difficult to treat of all malignancies. Multimodality regimens provide only short-term symptomatic improvement with minor impact on survival, underscoring the urgent need for novel therapeutics and treatment strategies for PDA. Trichothecenes are powerful mycotoxins that inhibit protein synthesis and induce ribotoxic stress response in mammalian cells. Verrucarin A (VC-A) is a Type D macrocyclic mycotoxin which inhibited cell proliferation and induced apoptosis in breast cancer cells. However, the antitumor activity of VC-A for PDA cells has not been investigated. Here we show potent antitumor activity and the mechanism of action of VC-A in PDA cell lines. VC-A strongly inhibited the proliferation and arrested cells in the S phase of the cell cycle. The blocking of cell cycle progression by VC-A was associated with the inhibition of cell cycle regulatory proteins cyclin D1, cyclin E, cyclin-dependent kinases (cdks) cdk2, cdk4 and cdk inhibitor WAF1/21. VC-A induced apoptosis in PDA cells as indicated by the increased Annexin V FITC-binding, cleavage of poly(ADP-ribose) polymerase‑1 (PARP-1) and procaspases-3, -8 and -9. VC-A also induced mitochondrial depolarization and release of cytochrome c and it inhibited Bcl-2 family proteins that regulate apoptosis (Bcl-2, Bcl-xL, Bax and Bad). In addition, VC-A reduced the levels of inhibitors of apoptosis survivin and c-IAP-2. Finally, VC-A downregulated the expression of prosurvival phospho-Akt (p-Akt), nuclear factor κB (NF-κB) (p65) and mammalian target of rapamycin (p-mTOR) signaling proteins and their downstream mediators. Together, these results demonstrated strong antiproliferative and apoptosis-inducing activity of verrucarin A for PDA cells through cell cycle arrest and inhibition of the prosurvival (antiapoptotic) AKT/NF-κB/mTOR signaling.

Pristimerin (PM) is a quinonemethide triterpenoid with cytotoxic activity against a wide range of cancer cell lines. However, the effect of PM on IL-2 induced activation of T lymphocytes, which play a major role in antitumor immunity has not been studied. The objective of the present study was to evaluate the effect of PM on IL-2 induced proliferation of T cells, generation of lymphokine activated killer cells (LAK cells) and the signaling pathways involved in activation of T cells by IL-2. PM inhibited the IL-2 induced proliferation of mouse splenic T cells and the generation LAK cells at very low concentrations. The suppression of T cell proliferation by PM was associated with the inhibition of IL-2 induced Janus kinase/signal transducers and activators of transcription (Jak/STAT) and extracellular signal-regulated kinase 1 and 2 (Erk1/2) signaling pathways. PM also inhibited the proliferation and differentiation-related immediate early gene products such as p-c-fos, p-c-jun, c-myc and cyclin D1. In addition, antiapoptotic (prosurvival) NF-кB, p-Akt and p-mTOR were also inhibited by PM. These data demonstrated that PM inhibits IL-2 induced T cell activation and generation of LAK cells by disrupting multiple cell signaling pathways induced by IL-2., (© 2016 Old City Publishing, Inc.)

Methyl-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate (CDDO-Me) has shown potent antitumorigenic activity against a wide range of cancer cell lines in vitro and inhibited the growth of liver, lung and prostate cancer in vivo. In the present study, we examined the antitumor activity of CDDO-Me for pancreatic ductal adenocarcinoma (PDAC) cells with and without activating K-ras mutations. Treatment of K-ras mutant MiaPaCa-2 and K-ras normal BxPC-3 cells with CDDO-Me elicited strong antiproliferative and proapoptopic responses in both cell lines in culture. The inhibition of cell proliferation and induction of apoptosis was accompanied by the inhibition of antiapoptotic/prosurvival p-Akt, NF-кB and p-mTOR signaling proteins. For testing efficacy of CDDO-Me in vivo heterotopic and orthotopic xenografts were generated by implanting BxPC-3 and MiaPaCa-2 cells subcutaneously and in the pancreatic tail, respectively. Treatment with CDDO-Me significantly inhibited the growth of BxPC-3 xenografts and reduced the levels of p-Akt and p-mTOR in tumor tissue. In mice with orthotopic MiaPaCa-2 xenografts, treatment with CDDO-Me prolonged the survival of mice when administered following the surgical resection of tumors. The latter was attributed to the eradication of residual PDAC remaining after resection of tumors. These preclinical data demonstrate the potential of CDDO-Me for treating primary PDAC tumors and for preventing relapse/recurrence through the destruction of residual disease.

Pristimerin (PM) is a promising anticancer agent that has exhibited strong antiproliferative and apoptosis-inducing activity in various types of cancer cells. In the present study, we investigated the role of telomerase in mediating the antitumor activity of PM in pancreatic ductal adenocarcinoma (PDA) cells. PM inhibited cell proliferation, arrested cells in the G1 cell cycle phase and induced apoptosis in MiaPaCa-2 and Panc-1 PDA cells. These antitumor activities of PM correlated well with the inhibition of human telomerase reverse transcriptase (hTERT), the gene that codes for the catalytic subunit of telomerase complex. Gene knockin and knockdown approaches demonstrated that hTERT regulates the response of PDA cells to PM. PM inhibited hTERT expression by suppressing the transcription factors Sp1, c-Myc and NF-κB which control hTERT gene expression. PM also inhibited protein kinase Akt, which phosphorylates and facilitates hTERT nuclear importation and its telomerase activity. These findings identified hTERT (telomerase) as a potential therapeutic target of PM for the treatment of PDA.

Background: Acute kidney injury (AKI) is a frequent complication of hospitalized patients and is associated with poor outcomes. Hospitalized patients with AKI may need prolonged dialysis, necessitating post-hospitalization dialysis (PHD-AKI). Scarce information is available to stratify the risks and predict outcomes. This study aims to assess outcomes and identify predictors of outcomes of PHD-AKI within 90 days., Methods: All adult AKI patients initiating hemodialysis (HD) at the University of Virginia (UVA) between June 1, 2012, and September 30, 2013 were retrospectively studied. PHD-AKI patients continued treatment at a specifically designated unit. They were followed until an outcome (end-stage renal disease [ESRD], death or dialysis-independence) was achieved., Results: During the study period, 108 patients required outpatient dialysis out of 365 AKI patients initiating in-patient HD at UVA. An additional 11 patients who developed dialysis-requiring AKI at referring hospitals but underwent HD at our unit were included for a total of 119 patients studied. ESRD was declared in 48.7%, while 9.2% expired and 42.0% achieved dialysis independence. Congestive heart failure, baseline renal function and a prior episode of AKI within the preceding 6 months were statistically significant predictors of renal outcomes., Conclusion: Dialysis independence of PHD-AKI patients is not uncommon. Certain clinical parameters may help predict renal outcome. Identifying predictors of renal recovery will guide further interventions, especially with the Centers for Medicare and Medicaid Services soon to allow AKI patients to be dialyzed at outpatient ESRD facilities. Ongoing biomarkers research may add further knowledge for optimum diagnosis and prognosis of AKI., (© 2015 S. Karger AG, Basel.)

Pristimerin (PM) is a quinonemethide triterpenoid present in various plant species with strong antiprolifertive and proapoptotic activities in cancer cells. The effect of PM on telomerase which is reactivated in most cancers including carcinoma of the prostate (CaP) has not been studied. We investigated the effect of PM on the expression of human telomerase reverse transcriptase (hTERT) gene that codes for the catalytic subunit of the telomerase holoenzyme complex in prostate cancer cell lines LNCaP and PC-3 cells. The inhibition of cell proliferation and induction of apoptosis by PM in both cell lines was associated with the inhibition of hTERT mRNA expression, suppression of native and phosphorylated hTERT protein and hTERT telomerase activity. The ablation of hTERT expression increased the sensitivity of cancer cells to PM. In addition, results also revealed that the inhibition of hTERT expression is attributed to the inhibition of transcription factors SP1, c-Myc and STAT3 and protein kinase B/Akt which regulate hTERT transcriptionally and post-translationally, respectively. These data provide evidence that telomerase is a potential target of PM in prostate cancer.

Pristimerin (PM), a quinonemethide triterpenoid, is a promising anticancer agent with potent antiproliferative and apoptosis-inducing activities against cancer cell lines. However, the anticancer activity and mechanisms of PM in prostate cancer cells have not been adequately investigated. Here we report that the degradation of survivin plays an important role in the antiproliferative and proapoptotic effects of PM in carcinoma of the prostate (CaP) cell lines. Treatment with PM inhibited proliferation and induced apoptosis in LNCaP and PC-3 cells as characterized by the loss of cell viability and an increase in Annexin V-binding and cleavage of PARP-1, respectively. The antiproliferative and apoptosis-inducing effects of PM were associated with the inhibition of cell cycle regulatory proteins, antiapoptotic survivin and members of the Bcl-2 family. Data showed that response to PM is regulated by survivin since overexpression of survivin rendered CaP cells resistant to PM. Furthermore, downregulation of survivin by PM was mediated through the ubiquitin-proteasomal degradation. Together, these data demonstrate that pristimerin inhibits proliferation and induces apoptosis in CaP cells by abolishing survivin through the ubiquitin-proteasome pathway.