Kidney Burden Research Articles

Vancomycin-arginine (STM-001) abrogates ESBL carrier and carbapenem-resistant Escherichia coli burden in a murine complicated urinary tract infection model.

ObjectivesSTM-001, a retargeted glycopeptide, is active against MDR E. coli expressing ESBLs including carbapenemases. Herein, we assessed its capability to combat E. coli complicated urinary tract infections (cUTI) in mice driven by clinically important serine (CTX-M-15) and metallo-β-lactamases (NDM-1).MethodsPlasma and urine pharmacokinetics following IV administration of STM-001 (1–50 mg/kg) were determined in mice via LC-MS/MS. The effects on bacterial burden (kidney, bladder and urine) were determined in a 7 day mouse cUTI model whereby STM-001 was administered q12h or q24h at 2–100 mg/kg/day from Day 4. Efficacy was assessed by the change in log10 cfu/g or log10 cfu/mL from vehicle-treated infected mice.ResultsMICs of STM-001 for CTX-M-15 and NDM-1 E. coli were 8 and 16 mg/L, respectively. Blood pharmacokinetic profile was linear and dose-dependent with low clearance of 9.49 ± 0.31 mL/min/kg, V = 0.63 ± 0.02 L/kg and t½ = 1.16 ± 0.03 h. High STM-001 concentrations were recovered in urine 0–8 h post-administration, reaching up to 120-fold above its MIC. In cUTI efficacy studies, STM-001 (1–50 mg/kg, q12h) reduced CTX-M-15 burden by log10 4.31 (kidney), 3.95 (bladder) and 4.82 (urine) compared with vehicle-treated animals (P < 0.0001). STM-001 also reduced NDM-1 burden by log10 3.89 (kidney), 3.76 (bladder) and 3.08 (urine) (P < 0.0001), with similar inhibitory effects following q24h dosing.ConclusionsSTM-001 was highly effective in reducing E. coli burden in kidney, bladder and urine in mouse cUTI models. The observed efficacy with either dosing regimen indicates potential low humanized doses of 1–5 mg/kg. These data support further development of STM-001 as an innovative, carbapenem-sparing antibiotic to combat human cUTIs.

Function of the phosphatidylinositol synthase Pis1 in maintenance of endoplasmic reticulum function and pathogenicity in Candida albicans

Candida albicans is a common conditional pathogenic fungus in the human body, and its infections have received widespread attention in recent years. Phosphatidylinositol and its derivatives have significant regulatory effects on many physiological processes, such as cell metabolism and growth. In this study, we identified and studied the function of the phosphatidylinositol synthase Pis1 in Candida albicans. The protein has a conserved CAPT motif and multiple transmembrane domains. GFP tagging revealed that Pis1 was located at the endoplasmic reticulum (ER). The PIS1 knockout mutant was constructed using an induction system regulated by the MET3 promoter. Growth assays showed that PIS1 is an essential gene for normal growth of Candida albicans. Overexpression of PIS1 led to high sensitivity to both ER stress and cell wall stress, and down-regulated expression of the genes involved in ER stress response and maintenance of cell wall integrity. Interestingly, PIS1 overexpression enhanced secretion of the extracellular hydrolases. Virulence assays further revealed that PIS1 overexpression increased the fungal virulence, leading to quicker death of the fungus-infected mice and more severe fungal burden in the mouse kidneys. In summary, Pis1 is involved in ER stress response, maintenance of cell wall integrity, and pathogenicity of Candida albicans.

Impact of dialysis modality conversion on the health-related quality of life of peritoneal dialysis patients: a retrospective cohort study in China.

BackgroundTo analyze the health-related quality of life associated with the conversion of dialysis modality among end-stage renal disease patients in China.MethodsPatients were recruited from hospitals and a dialysis center in Kunshan, China. Patients converting from continuous ambulatory peritoneal dialysis to automated peritoneal dialysis were recruited as the observation group (n = 64), and patients continuing with continuous ambulatory peritoneal dialysis treatment were included in the control group (n = 64) after matching in this retrospective cohort study. Their health-related quality of life was measured using the kidney disease quality of life instrument in 2019 and 2020, respectively. Baseline socio-demographic characteristics and clinical data were collected in 2019. The before-and-after cross-group comparisons of subscale scores of two groups were conducted using a Student‘s t-test. Multiple linear regression models were fitted to identify the factors associated with the change of each scale.ResultsThe health-related quality of life scores of the two groups was comparable in baseline, while the observation group had higher scores in Physical Component Summary (51.92 ± 7.50), Kidney Disease Component Summary (81.21 ± 8.41), Symptoms (90.76 ± 6.30), Effects (82.86 ± 11.42), and Burden (69.04 ± 15.69) subscales after one year. In multivariate regression analysis, the change of Physical Component Summary was significantly associated with conversion to APD (β = 11.54, 95% CI [7.26–15.82]); the change of Mental Component Summary with higher education (β = − 5.96, 95% CI [−10.18–−1.74]) and CCI (>2) (β = 5.39, 95% CI [1.05–9.73]); the change of Kidney Disease Component Summary with conversion to APD (β = 15.95, 95% CI [10.19–21.7]) and age (>60 years) (β = − 7.36, 95% CI [−14.11–−0.61]); the change of Symptoms with CCI (>2) (β = 7.96, 95% CI [1.49–14.44]); the change of Effects with conversion to APD (β = 19.23, 95% CI [11.57–26.88]); and the change of Burden with conversion to APD (β = 22.40, 95% CI [13.46–31.34]), age (>60 years) (β = − 12.12, 95% CI [−22.59–−1.65]), and higher education (β = − 10.38, 95% CI [−19.79–−0.98]).ConclusionsThe conversion of dialysis modality had a significant impact on the scores of most subscales. Patients converting from continuous ambulatory peritoneal dialysis to automated peritoneal dialysis generally had improved health-related quality of life scores.

KIdney aNd blooD prESsure ouTcomes in Childhood Cancer Survivors: Description of Clinical Research Protocol of the KINDEST-CCS Study.

Approximately 30% of childhood cancer survivors (CCSs) will develop chronic kidney disease (CKD) or hypertension 15 to 20 years after treatment ends. The incidence of CKD and hypertension in the 5-year window after cancer therapy is unknown. Moreover, extent of monitoring of CCS with CKD and associated complications in current practice is underexplored. To inform the development of new and existing care guidelines for CCS, the epidemiology and monitoring of CKD and hypertension in the early period following cancer therapy warrants further investigation. To describe the design and methods of the KIdney aNd blooD prESsure ouTcomes in Childhood Cancer Survivors study, which aims to evaluate the burden of late kidney and blood pressure outcomes in the first ~10 years after cancer therapy, the extent of appropriate screening and complications monitoring for CKD and hypertension, and whether patient, disease/treatment, or system factors are associated with these outcomes. Two distinct, but related studies; a prospective cohort study and a retrospective cohort study. Five Ontario pediatric oncology centers. The prospective study will involve 500 CCS at high risk for these late effects due to cancer therapy, and the retrospective study involves 5,000 CCS ≤ 18 years old treated for cancer between January 2008 and December 2020. Chronic kidney disease is defined as Estimated glomerular filtration rate <90 mL/min/1.73 m2 or albumin-to-creatinine ratio ≥ 3mg/mmol. Hypertension is defined by 2017 American Academy of Pediatrics guidelines. Prospective study: we aim to investigate CKD and hypertension prevalence and the extent to which they persist at 3- and 5-year follow-up in CCS after cancer therapy. We will collect detailed biologic and clinical data, calculate CKD and hypertension prevalence, and progression at 3- and 5-years post-therapy. Retrospective study: we aim to investigate CKD and hypertension monitoring using administrative and health record data. We will also investigate the validity of CKD and hypertension administrative definitions in this population and the incidence of CKD and hypertension in the first ~10 years post-cancer therapy. We will investigate whether patient-, disease/treatment-, or system-specific factors modify these associations in both studies. Results from the prospective study may not be generalizable to non-high-risk CCS. The retrospective study is susceptible to surveillance bias. Our team and knowledge translation plan is engaging patient partners, researchers, knowledge users, and policy group representatives. Our work will address international priorities to improve CCS health, provide the evidence of new disease burden and practice gaps to improve CCS guidelines, implement and test revised guidelines, plan trials to reduce CKD and hypertension, and improve long-term CCS health.

Evaluation of the in vitro Activity and in vivo Efficacy of Anidulafungin-Loaded Human Serum Albumin Nanoparticles Against Candida albicans.

Recent decades have seen a significant increase in invasive fungal infections, resulting in unacceptably high mortality rates. Anidulafungin (AN) is the newest echinocandin and appears to have several advantages over existing antifungals. However, its poor water solubility and burdensome route of administration (i.e., repeated, long-term intravenous infusions) have limited its practical use. The objective of this study was to develop anidulafungin-loaded Human Serum Albumin (HSA) nanoparticles (NP) so as to increase both its solubility and antifungal efficacy. HSA was reduced using SDS and DTT, allowing liberation of free thiols to form the intermolecular disulfide network and nanoassembly. Reduced HSA was then added to MES buffer (0.1 M, pH 4.8) and magnetically stirred at 350 rpm and 25°C with AN (m/m 50:1) for 2 h to form nanoparticles (AN NP). We next performed routine antifungal susceptibility testing of Candida strains (n = 31) using Clinical and Laboratory Standards Institute (CLSI) methodologies. Finally, the in vivo efficacy of both AN and AN NP was investigated in a murine model of invasive infection by one of the most common fungal species—C. albicans. The results indicated that our carrier formulations successfully improved the water solubility of AN and encapsulated AN, with the latter having a particle size of 29 ± 1.5 nm with Polymer dispersity index (PDI) equaling 0.173 ± 0.039. In vitro AN NP testing revealed a stronger effect against Candida species (n = 31), with Minimum Inhibitory Concentration (MIC) values 4- to 32-fold lower than AN alone. In mice infected with Candida and having invasive candidiasis, we found that AN NP prolonged survival time (P < 0.005) and reduced fungal burden in kidneys compared to equivalent concentrations of free drug (P < 0.0001). In conclusion, the anidulafungin nanoparticles developed here have the potential to improve drug administration and therapeutic outcomes for individuals suffering from fungal diseases.

Global, regional, and national burden of kidney, bladder, and prostate cancers and their attributable risk factors, 1990\u20132019

BackgroundThe burden of kidney, bladder, and prostate cancers has changed in recent decades. This study aims to investigate the global and regional burden of, and attributable risk factors for genitourinary cancers during the past 30 years.MethodsWe extracted data of kidney, bladder, and prostate cancers from the Global Burden of Disease 2019 database, including incidence, mortality, disability-adjusted life-years (DALYs), and attributable risk factors from 1990 to 2019. Estimated annual percentage changes (EAPC) were calculated to assess the changes in age-standardized incidence rate, age-standardized mortality rate (ASMR), and age-standardized DALYs rate (ASDR). The associations between cancers burden and socio-demographic index (SDI) were also analyzed.ResultsCompared with 1990, the global incident cases in 2019 were higher by 154.78%, 123.34%, and 169.11% for kidney, bladder, and prostate cancers, respectively. During the 30-year study period, there was a downward trend in ASMR and ASDR for bladder cancer (EAPC = − 0.68 and − 0.83, respectively) and prostate cancer (EAPC = − 0.75 and − 0.71, respectively), but an upward trend for kidney cancer (EAPC = 0.35 and 0.12, respectively). Regions and countries with higher SDI had higher incidence, mortality, and DALYs for all three types of cancers. The burden of bladder and prostate cancers was mainly distributed among older men, whereas the burden of kidney cancer increased among middle-aged men. Smoking related mortality and DALYs decreased, but high body mass index (BMI) and high fasting plasma glucose (FPG) related mortality and DALYs increased among kidney, bladder, and prostate cancers during the study period.ConclusionsKidney, bladder, and prostate cancers remain major global public health challenges, but with distinct trend for different disease entity across different regions and socioeconomic status. More proactive intervention strategies, at both the administrative and academic levels, based on the dynamic changes, are needed.

Dissemination of Candida auris to deep organs in neonatal murine invasive candidiasis

Candida auris is an emerging multidrug resistant fungal pathogen, which represents a major challenge for newborns systemic infections worldwide. Management of C. auris infections is complicated due to its intrinsic antifungal resistance and the limited information available on its pathogenesis, particularly during neonatal period. In this study, we developed a murine model of C. auris neonatal invasive infection. C. auris dissemination was evaluated by fungal burden and histopathological analysis of lung, brain, liver, kidney, and spleen at different time intervals. We found fungal cells in all the analyzed tissues, neonatal liver and brain were the most susceptible tissues to fungal invasion. This model will help to better understand pathogenesis mechanisms and facilitate strategies for control and prevention of C. auris infections in newborns.

Female participation in U.S. oncology clinical trials registered on ClinicalTrials.gov from 2008 to 2020.

85 Background: Females are thought to be underrepresented in clinical trials, which may lead to care disparities. We characterized female enrollment trends in U.S. oncology trials registered on ClinicalTrials.gov and identified features associated with accurate representation. Methods: We employed a cross-sectional study design with descriptive, logistic regression, and cox regression analyses. We downloaded 270,172 studies registered on the Aggregate Analysis of the ClinicalTrials.gov database from October 1, 2008 to March 9, 2020, excluding non-interventional and reproductive organ specific trials. We then applied cancer/oncology specific Medical Subject Heading terms and manually reviewed the remaining 27,521 trials for true oncology content. Prevalence-corrected estimates for female participation were calculated as the percentage of females among trial participants divided by the percentage of females in the disease population per U.S. Surveillance, Epidemiology, and End Results Program (SEER) data (participation to prevalence ratio [PPR]), with a range between 0.8 and 1.2 reflecting accurate female representation in the trial. Results: Of 26,894 trials meeting eligibility criteria, 9,059 trials were completed in the U.S., 2,499 trials reported completed study status, and only 1,256 trials reported sex. Among 1,256 oncology trials and 229,056 participants, overall female representation was 46.9% (95% CI, 45.4-48.4%). 43% of trials were industry funded, 29% academic, and 28% U.S. government. Females were underrepresented compared to their disease burden in anal canal (PPR 0.21), thyroid (PPR 0.57), stomach (PPR 0.68), kidney (PPR 0.77), and bone (PPR 0.79) cancer trials. They were accurately represented in head and neck (PPR 0.80), lung (PPR 0.84), bladder (PPR 0.85), skin (PPR 0.88), pancreas (PPR 0.88), colon (PPR 0.90), hematologic (PPR 0.91), liver (PPR 1.01), CNS (PPR 1.03), soft tissue (PPR 1.05), and esophagus (PPR 1.05) cancer trials. Accurate representation was significantly associated with industry funding and pancreas cancer trial focus, but not associated with trial type (medical, surgical, radiation, other invasive, other) (Table). Conclusions: Females are underrepresented compared to their disease burden in many solid tumor clinical trials. Stakeholders can look to industry funded and pancreas cancer trials as models of improvement, but must increase female representation in clinical trials to improve cancer care. [Table: see text]

In vitro and in vivo interaction of caspofungin with isavuconazole against Candida auris planktonic cells and biofilms.

The in vitro and in vivo efficacy of caspofungin was determined in combination with isavuconazole against Candida auris. Drug-drug interactions were assessed utilizing the fractional inhibitory concentration indices (FICIs), the Bliss independence model and an immunocompromised mouse model. Median planktonic minimum inhibitory concentrations (pMICs) of 23 C. auris isolates were between 0.5 and 2mg/l and between 0.015 and 4mg/l for caspofungin and isavuconazole, respectively. Median pMICs for caspofungin and isavuconazole in combination showed 2-128-fold and 2-256-fold decreases, respectively. Caspofungin and isavuconazole showed synergism in 14 out of 23 planktonic isolates (FICI range 0.03-0.5; Bliss cumulative synergy volume range 0-4.83). Median sessile MICs (sMIC) of 14 biofilm-forming isolates were between 32 and >32mg/l and between 0.5 and >2mg/l for caspofungin and isavuconazole, respectively. Median sMICs for caspofungin and isavuconazole in combination showed 0-128-fold and 0-512-fold decreases, respectively. Caspofungin and isavuconazole showed synergistic interaction in 12 out of 14 sessile isolates (FICI range 0.023-0.5; Bliss cumulative synergy volume range 0.13-234.32). In line with the in vitro findings, synergistic interactions were confirmed by in vivo experiments. The fungal kidney burden decreases were more than three log volumes in mice treated with combination of 1mg/kg caspofungin and 20mg/kg isavuconazole daily; this difference was statistically significant compared with control mice (P<0.001). Despite the favorable effect of isavuconazole in combination with caspofungin, further studies are needed to confirm the therapeutic advantage of this combination when treating an infection caused by C. auris.

Piscirickettsia salmonis shedding and tissue burden, and hematological responses during cohabitation infections in chum Oncorhynchus keta, pink O. gorbuscha and Atlantic salmon Salmo salar.

BackgroundSalmonid rickettsial septicemia is an emergent and geographically widespread disease of marine-farmed salmonids caused by infection with the water-borne bacterium Piscirickettsia salmonis. Very little is known about the route, timing, or magnitude of bacterial shedding from infected fish.Methodology/principal findingsA cohabitation challenge model was used to assess shedding from chum Oncorhynchus keta, pink O. gorbuscha and Atlantic salmon Salmo salar. Infections in donor fish were established by intraperitoneal injection of P. salmonis. Naïve recipients were cohabitated with donor fish after which cumulative percent morbidity and mortality (CMM) was monitored, and bacterial burdens in kidney and in tank water were measured by qPCR. All donor fish died with mean days-to-death (MDD) among species ranging from 17.5 to 23.9. Among recipients, CMM ranged from 42.7% to 77.8% and MDD ranged from 49.7 to 56.4. In each trial, two peaks of bacterial DNA concentrations in tank water closely aligned with the MDD values of donor and recipient fish. Bacterial tissue burden and shedding rate, and plasma physiological parameters were obtained from individual donors and recipients. Statistically significant positive correlations between the shedding rate and P. salmonis kidney burden were measured in donor pink and in donor and recipient chum salmon, but not in donor or recipient Atlantic salmon. In Atlantic salmon, there was a negative correlation between kidney bacterial burden and hematocrit, plasma Ca++ and Mg++ values, whereas in infected chum salmon the correlation was positive for Na+ and Cl- and negative for glucose.ConclusionsA dependency of bacterial shedding on species-specific patterns of pathogenesis was suggested. The coincidence of bacterial shedding with mortality will inform pathogen transmission models.

1272. Efficacy of a Non-Peptide, Small Molecule Mimic of Host Defense Proteins in Mouse Models of Disseminated Candidiasis and Aspergillosis

BackgroundWe are developing a series of small nonpeptide mimics of host defense proteins (smHDPs) for antifungal applications. MICs < 0.1 µg/ ml have been demonstrated against multiple yeast and mold species. Their potential therapeutic utility has been evaluated in animal models of disseminated fungal infections.MethodsSusceptibility testing against clinical isolates of Candida albicans (CA) and Aspergillus fumigatus (AF) was done according to CLSI guidelines. Cytotoxicity (CC50) in mouse 3T3 and human HepG2 cells was determined in an MTS assay (Promega Cell Titer 96). For candidiasis, neutropenic CD-1 mice were infected IV with 3.5 x 104 CFU CA and test agents were administered subcutaneously (SC) once (QD) or twice (BID) daily beginning 2 hrs post-infection (PI). The positive control was fluconazole (20 mg/kg PO QD). Kidney burdens were measured at 24 hrs PI (n = 5/grp) and survival was measured at 2 weeks after 5 days of treatment (n = 8/grp). For aspergillosis, neutropenic CD-1 mice were infected IV with 4.5 log10 spores AF and test agents were administered SC BID for 5 days beginning 24 hrs PI. The positive control was posaconazole (20 mg/kg PO QD). Liver and kidney fungal burdens were measured 24 hrs after the last dose (n = 10/grp).ResultsThe lead smHDP, FC-5096, has MICs of 0.08 and 0.024 ug/ml, respectively, against the CA and AF clinical isolate strains used in the mouse efficacy studies. Selectivity for antifungal vs. mammalian cell cytotoxicity (MIC/CC50) was >1,000 fold. In the disseminated candidiasis model, FC-5096 significantly reduced fungal kidney burdens relative to untreated mice to levels found at treatment onset (P < 0.0001). Full survival over 2 weeks was observed after 5 days of BID treatment with FC-5096. All untreated mice succumbed between days 3 – 6 PI. Efficacy was comparable to fluconazole. In the disseminated aspergillosis model, FC-5096 produced up to 2.5 log10 reductions in fungal liver burdens and efficacy was significantly better than posaconazole (P = 0.0251). In kidney, both FC-5096 and posaconazole caused > 1.6 log10 reductions in fungal burdens that exceeded the limit of detection.ConclusionThe high antifungal potency, low cytotoxicity and robust in vivo efficacy support further study of FC-5096 for clinical development.DisclosuresRichard W. Scott, PhD, Fox Chase Chemical Diversity Center (Employee) Simon DP Baugh, PhD, Fox Chase Chemical Diversity Center (Employee) Mark E Pulse, MS, Fox Chase Chemical Diversity Center (Independent Contractor)

PUK26 Quantitative Exploration to Characterize the Burden of END-STAGE Kidney Disease (ESKD) with Dialysis

This study aimed to quantitatively assess the burden of end-stage kidney disease (ESKD) and time on dialysis from a patient perspective across multiple countries and ESKD stages. Fifty stage 4/5 ESKD patients on dialysis from the US (n=24), UK (n=9), Germany (n=9) and France (n=8) completed the EuroQol five-dimensional questionnaire (EQ-5D-5L) and Kidney Disease Quality of Life Short Form 1.3 (KDQoL-SF). Descriptive statistics examined EQ-5D-5L response, index, EQ-VAS scores (mean [SD]) and KDQoL domain scores (median [SD]). Due to sample size, median values are reported where appropriate. Comparisons between years on dialysis (<1, 1-5, 2-5, 5-10, >10) and ESKD stage (4/5) were made. Results were triangulated to a separate qualitative study (N=37). Across all countries, EQ-5D-5L response distributions indicate universal problems for mobility, usual activities, pain/discomfort and anxiety/depression in late stage ESKD patients on dialysis. Stage-5 ESKD patients had received dialysis for relatively longer than Stage-4 ESKD patients and response distributions were consistently worse for stage-5 patients. UK patients reported the lowest EQ-VAS score (40.4 [18.3]), while France (0.44 [0.28]) and UK (0.45 [0.25]) provided the lowest index scores. Low KDQoL-SF scores (indicating worse disease state) were observed across all patients for work status, general health, physical and burden of kidney disease/KD. US patients on dialysis >1 year had lower KDQoL scores than <1 year. Across all countries, EQ-VAS and KDQoL-SF scores were consistently worse among patients on dialysis 2-5 years than <2 years; although improved with longer-term dialysis (>5 years). The study contributes insights on the universal HRQoL burden of ESKD with dialysis. Utility values conveyed higher burden for UK and France patients. Burden of disease measured by EQ-VAS and KDQoL-SF increased with years of dialysis and greater time since last dialysis. Burden decreased with longer-term dialysis; suggesting acquiescence similar to other long-term chronic diseases.

High Burden of In-Person Kidney Cancer Surveillance in a Low Resource Population.

Postoperative kidney cancer surveillance is predominantly based on imaging and laboratory evaluation rather than physical exam. We sought to characterize the burden of kidney cancer surveillance in a low resource population with an aim to identify opportunities for telehealth implementation. We retrospectively reviewed patients who underwent partial or radical nephrectomy between November, 2016 and May, 2018 at an academic medical center. We reviewed patient demographic characteristics, travel distance to hospital, and Center for Medicare & Medicaid Services designation of home ZIP code as low income area or health professional shortage area. Followup visits were reviewed for imaging and laboratory studies as well as new physical exam findings. We identified 156 patients who attended 234 followup visits at mean 2.4 months (SD=2.9 months) postoperatively. Patient home ZIP codes were designated as low income area or health professional shortage area in 93 (59.6%) cases. One-way travel was mean 194 miles (SD=438 miles) per visit. When intended, laboratory or imaging studies were not obtained ahead of followup visits in 34 of 196 cases (17%). Based on the absence of new physical exam findings or procedures performed 201 (86%) visits could have potentially been performed remotely. Patients living in low income areas and health professional shortage areas are asked to travel long distances to perform kidney cancer surveillance often to review data that could be obtained remotely. Necessary imaging or laboratory studies are frequently not obtained ahead of appointments, further diminishing visit value. Kidney cancer surveillance may offer a promising opportunity for telehealth implementation within urology.

The in vivo roles of galectin-2 from Nile tilapia (Oreochromis niloticus) in immune response against bacterial infection

Our previous study has recorded that the recombinant protein of Nile tilapia (Oreochromis niloticus) galectin-2 (rOnGal-2) can enhance immune response against Streptococcus agalactiae (S.agalactiae) infection in vitro. In this study, we further explored the effects of OnGal-2 in immune response against bacterial infection in vivo. The administration of rOnGal-2 could improve serum antibacterial activity (ALKP, ACP, and LZM) and antioxidant capacity (CAT, POD, and SOD). After S. agalactiae infection, rOnGal-2 injection could reduce bacterial burden and decrease tissue damage in head kidney, spleen, and liver of tilapia. Also, rOnGal-2 regulated the inflammatory-related genes expression including IL-6, IL-8 and IL-10 during bacterial infection. Furthermore, rOnGal-2 administration could increase the relative percentage survival of tilapia infected with S.agalactiae. Taken together, our results indicate that OnGal-2 can protect fish from bacterial infection through reducing bacterial burden, impairing tissue damage and modulating anti-bacterial immune response, which also can be applied as a potential vaccine adjuvant in O.niloticus culture.

A nephrotoxicity-free, iron-based contrast agent for magnetic resonance imaging of tumors

Gadolinium-based contrast agents (GBCAs) are the most widely used T1 contrast agents for magnetic resonance imaging (MRI) and have achieved remarkable success in clinical cancer diagnosis. However, GBCAs could cause severe nephrogenic systemic fibrosis to patients with renal insufficiency. Nevertheless, GBCAs are quickly excreted from the kidneys, which shortens their imaging window and prevents long-term monitoring of the disease per injection. Herein, a nephrotoxicity-free T1 MRI contrast agent is developed by coordinating ferric iron into a telodendritic, micellar nanostructure. This new nano-enabled, iron-based contrast agent (nIBCA) not only can reduce the renal accumulation and relieve the kidney burden, but also exhibit a significantly higher tumor to noise ratio (TNR) for cancer diagnosis. In comparison with Magnevist (a clinical-used GBCA), Magnevist induces obvious nephrotoxicity while nIBCA does not, indicating that such a novel contrast agent may be applicable to renally compromised patients requiring a contrast-enhanced MRI. The nIBCA could precisely image subcutaneous brain tumors in a mouse model and the effective imaging window lasted for at least 24 h. The nIBCA also precisely highlights the intracranial brain tumor with high TNR. The nIBCA presents a potential alternative to GBCAs as it has superior biocompatibility, high TNR and effective imaging window.

Pharmacokinetics/Pharmacodynamics (PK/PD) of Ciprofloxacin in the Complicated Urinary Tract Infection (cUTI) Model in Diabetic Mice.

The translation of Pharmacokinetics (PK)/Pharmacodynamics (PD) from preclinical models to the clinic has not been studied in detail for drugs used to treat complicated urinary tract infections (cUTI). The PK/PD of Ciprofloxacin (CIP), a drug used to treat cUTI, was evaluated in a mouse model of cUTI infected with Escherichia coli, and compared with clinical PK/PD in cUTI patients. Streptozotocin induced diabetic female BALB/c mice were infected transurethrally with Escherichia coli. Four hours post infection, CIP oral doses of 3, 10, 30,100, and 300 mg/kg, were administered as single doses (for PK and dose response) and repeated doses (PD and PK/PD). Bacterial burden in kidneys, bladder, urine, body temperature, and other clinical signs were assessed twenty-four hours post-treatment. CIP displayed linear PK with dose proportional increase in Cmax and AUCinf in plasma. In PD time course studies, CIP showed rapid onset, intensity and duration of anti-bacterial effect in target tissues. In intrinsic PD studies, CIP showed a maximum effect at plasma AUC/MIC=1705 (300 mg/kg, twice daily) for bacterial load in bladder (r2=0.979), kidney (r2=0.951) and rectal temperature (r2=0.67). A plasma AUC/MIC ratio of 412 was associated with maximum PD effect of Imax=3.7 Log10CFU/bladder and Imax=1.97 Log10CFU/kidney. In dose fractionation studies, plasma AUC/MIC ratio showed highest correlation with efficacy in bladder (r2=0.77) and kidney (r2=0.80) followed by Cmax/MIC ratio in bladder (r2=0.68). Plasma AUC/MIC showed the highest correlation with the efficacy of Ciprofloxacin on E. coli in diabetic mice with cUTI.

Comparative pharmacokinetics of amphotericin B after single- and multiple-dose administration of G-ABCD and conventional amphotericin B deoxycholate to rats

ObjectiveG-ABCD is a biosimilar product of amphotericin B colloidal dispersion (ABCD). This study was designed to systematically examine the plasma pharmacokinetics (PK) and tissue distribution of G-ABCD in rats, using amphotericin B deoxycholate (DAmB) as a positive control. MethodsMale Sprague-Dawley rats received single dose or 14 doses of G-ABCD (1.0, 2.0 or 5.0 mg/kg) or the conventional micellar formulation DAmB) (1.0 mg/kg) via intravenous injection. Plasma and tissue samples were obtained for analysis of amphotericin B concentration by liquid chromatography-tandem mass spectrometry. ResultsAfter a single-dose administration of 1 mg/kg, G-ABCD resulted in a significantly lower plasma peak drug concentration (Cmax) (1536 vs. 5256 ng/mL) and area under the curve from time 0 to ∞ (AUC0–∞) (3972 vs. 7006 h ng/mL) of non-complexed amphotericin B than DAmB. G-ABCD was associated with quicker distribution but slower elimination of amphotericin B than DAmB. Amphotericin B concentration reached a steady state after seven doses of G-ABCD. After multiple doses of 1 mg/kg, G-ABCD showed a lower peak level and longer half-life of amphotericin B in plasma than DAmB. G-ABCD treatment in rats was associated with relatively higher distribution to liver and spleen, but reduced amphotericin B delivery to kidneys, the major target organ of toxicity. ConclusionThese results suggest that G-ABCD provides a flatter but more lasting plasma level of amphotericin B and lower kidney burden in rats than DAmB.

Generation and Characterization of Single Chain Variable Fragment against Alpha-Enolase of Candida albicans.

Candida albicans (C. albicans) is an opportunistic human pathogen responsible for approximately a half of clinical candidemia. The emerging Candida spp. with resistance to azoles is a major challenge in clinic, suggesting an urgent demand for new drugs and therapeutic strategies. Alpha–enolase (Eno1) is a multifunctional protein and represents an important marker for invasive candidiasis. Thus, C. albicans Eno1 (CaEno1) is believed to be an important target for the development of therapeutic agents and antibody drugs. Recombinant CaEno1 (rCaEno1) was first used to immunize chickens. Subsequently, we used phage display technology to construct two single chain variable fragment (scFv) antibody libraries. A novel biopanning procedure was carried out to screen anti-rCaEno1 scFv antibodies, whose specificities were further characterized. The polyclonal IgY antibodies showed binding to rCaEno1 and native CaEno1. A dominant scFv (CaS1) and its properties were further characterized. CaS1 attenuated the growth of C. albicans and inhibited the binding of CaEno1 to plasminogen. Animal studies showed that CaS1 prolonged the survival rate of mice and zebrafish with candidiasis. The fungal burden in kidney and spleen, as well as level of inflammatory cytokines were significantly reduced in CaS1-treated mice. These results suggest CaS1 has potential of being immunotherapeutic drug against C. albicans infections.

Human resources for nephrology in South Africa: A mixed-methods study.

The global nephrology workforce is shrinking and, in many countries, is unable to meet healthcare needs. Accurate data pertaining to human resources in nephrology in South Africa is lacking. This data is critical for the planning and delivery of renal services and the training of nephrologists in South Africa to meet the challenge of the growing burden of chronic kidney disease. A cross-sectional study of adult and paediatric nephrologists currently delivering nephrology services in South Africa was conducted. Participants were identified using various data sources, including the register of the Health Professions Council of South Africa. This cohort of doctors was described in terms of their demographics and distribution. A survey was then conducted among these nephrologists to collect additional information on their training, scope of practice, job satisfaction, challenges and future plans. Finally, two focus group interviews were conducted to probe themes identified from the survey data. A total of 120 adult nephrologists and 22 paediatric nephrologists were identified (an overall density of 2.5 per million population). There is a male predominance (66%) and the median age is 45 years. The bulk of the workforce (128 nephrologists, 92%) is distributed in three of the nine South African provinces, and two provinces have no nephrologist at all. The survey was completed by 57% of the nephrologists. Most reported positive attitudes to their chosen profession; however, 35 nephrologists (43%) reported an excessive workload, 9 (11%) were planning emigration and 15 (19%) were planning early retirement. A higher frequency of dissatisfaction regarding remuneration (39% vs. 15%) and unsatisfactory work conditions (35% vs. 13%) was observed amongst nephrologists working in the public sector compared to the private sector. A total of 13 nephrologists participated in the focus group interviews. The themes which were identified included that of a rewarding profession, an overall shortage of nephrologists, poor career planning, a need for changes to nephrologists' training, excessive workloads with inadequate remuneration, and challenging work environments. There are insufficient numbers of nephrologists in South Africa, with a markedly uneven distribution amongst the provinces and healthcare sectors. Qualitative data indicate that South African nephrologists are faced with the challenges of a high workload, obstructive policies and unsatisfactory remuneration. In the public sector, a chronic lack of nephrologist posts and other resources are additional challenges. A substantial proportion of the workforce is contemplating emigration.

Kidney transplantation and cardiomyopathy: Concepts and controversies in clinical decision-making.

Increasing comorbidities and an aging population have led to a tremendous increase in the burden of both kidney and cardiac dysfunction. Concomitant cardiomyopathy exposes the patients with kidney disease to further physiological, hemodynamic, and pathologic alterations. Kidney transplantation imposes lesser anesthetic and surgical complexities compared to another solid organ transplant. The surgical decision-making remains an unsettled issue in these conditions. The surgical choices, techniques, and sequences in kidney transplant and cardiac surgery depend on the pathophysiological perturbations and perioperative outcomes. The absence of randomized controlled trials eludes us from suggesting definite management protocol in patients with end-stage kidney disease with cardiomyopathy. Nevertheless, in this review, we extracted data from published literature to understand the pathophysiologic interactions between end-stage renal diseases with cardiomyopathy and also proposed the management algorithm in this challenging scenario. The proposed management algorithm would ensure consensus across all stakeholders involved in decision-making. Our simplistic evidence-based approach would augur future randomized trials and would further ensure refinement in our management approach after the emergence of more definitive evidence.