Renal Filtration Research Articles

FEATURES OF KIDNEY DAMAGE IN HIV-INFECTED

Relevance. In HIV-infected patients, renal disease, which is characterized by severe clinical manifestations, can significantly affect the prognosis of life. Given the growing number of HIV-infected people in the world and the increase in the life expectancy of such patients, an increase in the number of HIV-infected people in need of expensive renal replacement therapy, as well as kidney transplantation, should be expected. But the question of the nature of kidney damage in HIV infection in Ukraine is still insufficiently covered.
 The objective of the work is to establish the clinical and laboratory features of kidney damage in HIV infection.
 Materials and methods. 292 patients with HIV were examined. Screening for markers of kidney damage (albuminuria/proteinuria) was performed by test systems (using urine strips). The results obtained with the help of test strips were considered as indicative. In the presence of ≥1+ proteinuria in the screening test, which corresponded to a gradation of 30 mg/l, repeated urine analyzes were performed with quantitative determination of protein on a spectrophotometer, separated in time from 3 days to one week. The functional state of the kidneys was assessed by an integrated indicator that characterizes the degree of preservation/loss of mass of active nephrons. The criterion for renal impairment was a decrease in glomerular filtration rate (GFR) <60 ml/min by 1.73 m2. Chronic kidney disease was diagnosed when proteinuria or proteinuria was detected in combination with a decrease in GFR for 3 months or more.
 Results. Based on the main markers of renal damage (persistent proteinuria (PU) and glomerular filtration rate <60 ml/min/1.73m2), 48 people were diagnosed with chronic kidney disease, which was often accompanied by dysfunction of these organs. Based on the analysis of complaints, anamnestic data, and clinical symptoms of kidney damage, patients were divided into 2 groups. The first group (n = 31, or 64.6%) - patients with tubulointerstitial, the second group (n = 17, or 35.4%) - patients with glomerular diseases. Increased PU levels are accompanied by significantly significant renal impairment and a more frequent combination with hypertension and hematuria in the absence of significant differences in the frequency of opportunistic diseases.
 Conclusions. In HIV-infected kidney damage is most often characterized by their tubulointerstitial lesions. At the same time, glomerular kidney damage, which is much less common, is accompanied by significantly higher levels of HIV RNA.

Biomimetic Nanomedicine Coupled with Neoadjuvant Chemotherapy to Suppress Breast Cancer Metastasis via Tumor Microenvironment Remodeling

AbstractThe biomimetic enzyme activity of cerium oxide nanoparticles (CeNPs) prefers ultrasmall particle size and bare surface. Unfortunately, those two features are not favorable for its in vivo application due to easy aggregation and fast renal filtration. To take advantage of the activity of CeNP for cancer therapy, a homologous targeted cerium oxide nanoparticle system, targeted CeNP (T‐CeNP), with the integration of a biodegradable dendritic mesoporous silica nanoparticle, superoxide dismutase and catalase mimicking CeNPs, and the camouflage coating of cancer cell membrane has been developed. Attributed to the homologous targeting effect of cancer cell membrane, nanoparticles with camouflage coating are retained in the tumor in an orthotopic breast cancer metastatic model. Subsequently, T‐CeNP effectively hinders cancer‐associated fibroblast transdifferentiation and reprograms it back to a normal fibroblast. Consequently, T‐CeNP coupled with doxorubicin reduces the size of primary tumors and prevents the post‐surgery lung metastasis and liver metastasis of breast cancer.

Cerebral hemispheres – cerebellum – kidney interaction in patients with acute cerebral ischemia

The nervous system, in particular the autonomic one, is well known to constantly regulate the internal functioning of the body, adapting it to changeable external and internal environmental parameters. In particular, there is a close multiple-vector correlation between the nervous system and the kidneys. The aim of this study was to specify the mechanisms, clinical and paraclinical characteristics of the concomitant lesions of the nervous system and the kidneys in patients with acute stroke. This paper presents the case report of 215 patients, aged 70 ± 8.44, who suffered from ischemic stroke. Among them, we examined 144 women and 71 men. The patients underwent a comprehensive examination, including a detailed clinical and neurological check-up (evaluating the patients’ condition severity with the National Institutes of Health Stroke Scale (NIHSS) and the Barthel index on admission and on the 21st day of the disease), laboratory analysis (electrolyte balance, nitrogen metabolism (on admission and on the 21st day of the disease) and instrumental examination (CT scan of the brain, the follow-up brain magnetic resonance imaging). The statistical methods were used to analyze the data. In the 1st day of the disease, all the surveyed patients with right hemispheric carotid stroke and the overwhelming majority of the patients with left hemispheric carotid stroke and ischemic stroke in the vertebrobasilar system had cerebral renal syndrome, represented by renal concentration-filtration dysfunction, accompanied by the reduced glomerular filtration rate. A reliable relationship was found between the renal concentration and filtration function and the right hemispheric ischemic focus in patients with ischemic stroke, the characteristics are to be specified.

Proteins linked to atherosclerosis and cell proliferation are associated with the shrunken pore syndrome in heart failure patients

The "Shrunken pore syndrome" (SPS) is characterized by a difference in renal filtration between cystatin C and creatinine, resulting in a low eGFRcystatinC /eGFRcreatinine -ratio. Studies have demonstrated a high risk for cardiovascular morbidity and mortality for patients with SPS. In this discovery study, we explored associations between SPS and proteins implicated in cardiovascular disease and inflammation in patients with heart failure. Plasma samples from 300 individuals in HARVEST-Malmö trial hospitalized for the diagnosis of heart failure (mean age 74.9 ± 11.5 years; 30.0% female), were analyzed with a proximity extension assay consisting of 92 proteins. A Bonferroni-corrected p-value of 0.05/92=5.4×10-4 was considered significant in the initial age and sex-adjusted analyses. Presence of SPS was defined as eGFRcystatinC ≤ 60% of eGFRcreatinine . SPS presented with significant associations (p<5.4×10-4 ) in age and sex-adjusted logistic regressions with elevated levels of six proteins; scavenger receptor cysteine rich type 1 protein M130, tumor necrosis factor receptor 1, tumor necrosis factor receptor 2, osteoprotegerin, interleukin-2 receptor subunit alpha, and tyrosine-protein kinase receptor UFO. All proteins remained associated (p<0.05) with SPS after multivariate adjustments. In heart failure patients, SPS was associated with proteins linked to atherosclerosis and cell proliferation.

Atrial Natriuretic Peptide in the Prevention of Postoperative Acute Renal Dysfunction in Patients Undergoing Heart Transplantation - An Investigator-Driven, Single-Center, Blinded, Randomized and Placebo-Controlled Trial

Purpose The development of acute kidney injury (AKI) and renal dysfunction is a common complication after heart transplantation (HTx) that is associated with increased morbidity and mortality. When used for treatment of AKI, infusion of atrial natriuretic peptide (ANP) has been shown to increase renal blood flow and glomerular filtration rate (GFR) after complicated cardiac surgery and in cyclosporine-induced AKI after HTx. Furthermore, it was shown that ANP reduced the probability of dialysis in cardiac surgery-associated AKI. The aim of this investigation was to evaluate whether ANP infusion could prevent or mitigate acute renal dysfunction after HTx. Methods After approval of Ethical Review Board and the Swedish Medical Products Agency, 72 adult patients undergoing HTx were included after informed consent. The patients were randomized to receive either ANP or placebo (saline) by a web-based computerized random-number generator. The anesthesia/intensive staff and physicians were blinded to the allocated treatment throughout the entire study. After induction of anesthesia, a continuous intravenous infusion of either ANP (HANP1000®, Daichii Sankyo Propharma, Japan) at a dose of 50 ng/kg/min or the equivalent volume of placebo (saline) was started. The administration of the study drugs continued for five postop days, or until the patient died or treatment with dialysis was started. Inclusion has been completed. Endpoints The primary end-point was measured mGFR at day five. mGFR was assessed by the infusion clearance of 52Cr-EDTA. The difference in mGFR between groups was estimated using intention-to-treat and per-protocol analyses. To detect a 30% higher mGFR in the ANP group, 31 patients per group would be required, assuming a 80% power and a two-sided error of 0.05. To compensate for drop-outs and for the use of nonparametric tests, we included 35 randomised patients per group. Secondary end-points were: the incidence of postoperative AKI (KDIGO criteria), daily postoperative serum creatinine, need for dialysis, intra- and postoperative diuresis, the use of diuretics, length of ICU and hospital stay, ICU mortality and 30-days mortality, length of mechanical ventilation, incidence of hypotension and arrhythmias and inotropic score.

CALINCA-A Novel Pipeline for the Identification of lncRNAs in Podocyte Disease.

Diseases of the renal filtration unit—the glomerulus—are the most common cause of chronic kidney disease. Podocytes are the pivotal cell type for the function of this filter and focal-segmental glomerulosclerosis (FSGS) is a classic example of a podocytopathy leading to proteinuria and glomerular scarring. Currently, no targeted treatment of FSGS is available. This lack of therapeutic strategies is explained by a limited understanding of the defects in podocyte cell biology leading to FSGS. To date, most studies in the field have focused on protein-coding genes and their gene products. However, more than 80% of all transcripts produced by mammalian cells are actually non-coding. Here, long non-coding RNAs (lncRNAs) are a relatively novel class of transcripts and have not been systematically studied in FSGS to date. The appropriate tools to facilitate lncRNA research for the renal scientific community are urgently required due to a row of challenges compared to classical analysis pipelines optimized for coding RNA expression analysis. Here, we present the bioinformatic pipeline CALINCA as a solution for this problem. CALINCA automatically analyzes datasets from murine FSGS models and quantifies both annotated and de novo assembled lncRNAs. In addition, the tool provides in-depth information on podocyte specificity of these lncRNAs, as well as evolutionary conservation and expression in human datasets making this pipeline a crucial basis to lncRNA studies in FSGS.

The impact of type III sodium-dependent phosphate transporters (Pit 1 and Pit 2) on podocyte and kidney function.

The sodium-dependent phosphate transporters Pit 1 and Pit 2 belong to the solute carrier 20 (SLC20) family of membrane proteins. They are ubiquitously distributed in the human body. Their crucial function is the intracellular transport of inorganic phosphate (Pi) in the form of H2 PO4- . They are one of the main elements in maintaining physiological phosphate homeostasis. Recent data have emerged that indicate novel roles of Pit 1 and Pit 2 proteins besides the well-known function of Pi transporters. These membrane proteins are believed to be precise phosphate sensors that mediate Pi-dependent intracellular signaling. They are also involved in insulin signaling and influence cellular insulin sensitivity. In diseases that are associated with hyperphosphatemia, such as diabetes and chronic kidney disease (CKD), disturbances in the function of Pit 1 and Pit 2 are observed. Phosphate transporters from the SLC20 family participate in the calcification of soft tissues, mainly blood vessels, during the course of CKD. The glomerulus and podocytes therein can also be a target of pathological calcification that damages these structures. A few studies have demonstrated the development of Pi-dependent podocyte injury that is mediated by Pit 1 and Pit 2. This paper discusses the role of Pit 1 and Pit 2 proteins in podocyte function, mainly in the context of the development of pathological calcification that disrupts permeability of the renal filtration barrier. We also describe the mechanisms that may contribute to podocyte damage by Pit 1 and Pit 2.

The unique molecular mechanism of diabetic nephropathy: a bioinformatics analysis of over 250microarray datasets.

Background/AimsDiabetic nephropathy (DN) is one of the main causes of end-stage kidney disease worldwide. Emerging studies have suggested that its pathogenesis is distinct from nondiabetic renal diseases in many aspects. However, it still lacks a comprehensive understanding of the unique molecular mechanism of DN.MethodsA total of 255 Affymetrix U133 microarray datasets (Affymetrix, Santa Calra, CA, USA) of human glomerular and tubulointerstitial tissues were collected. The 22 215 Affymetrix identifiers shared by the Human Genome U133 Plus 2.0 and U133A Array were extracted to facilitate dataset pooling. Next, a linear model was constructed and the empirical Bayes method was used to select the differentially expressed genes (DEGs) of each kidney disease. Based on these DEG sets, the unique DEGs of DN were identified and further analyzed using gene ontology and pathway enrichment analysis. Finally, the protein–protein interaction networks (PINs) were constructed and hub genes were selected to further refine the results.ResultsA total of 129 and 1251 unique DEGs were identified in the diabetic glomerulus (upregulated n = 83 and downregulated n = 203) and the diabetic tubulointerstitium (upregulated n = 399 and downregulated n = 874), respectively. Enrichment analysis revealed that the DEGs in the diabetic glomerulus were significantly associated with the extracellular matrix, cell growth, regulation of blood coagulation, cholesterol homeostasis, intrinsic apoptotic signaling pathway and renal filtration cell differentiation. In the diabetic tubulointerstitium, the significantly enriched biological processes and pathways included metabolism, the advanced glycation end products–receptor for advanced glycation end products signaling pathway in diabetic complications, the epidermal growth factor receptor (EGFR) signaling pathway, the FoxO signaling pathway, autophagy and ferroptosis. By constructing PINs, several nodes, such as AGR2, CSNK2A1, EGFR and HSPD1, were identified as hub genes, which might play key roles in regulating the development of DN.ConclusionsOur study not only reveals the unique molecular mechanism of DN but also provides a valuable resource for biomarker and therapeutic target discovery. Some of our findings are promising and should be explored in future work.

Advanced Age as a Risk Factor of Drug-Induced Diseases

Some patients are more likely to have drug-induced diseases due to a number of risk factors, such as older age. The aim of the study was to analyse the effect of older age on pharmacokinetics and pharmacodynamics of medicines and the risk of developing drug-induced diseases. The analysis of scientific literature demonstrated that changes in the functions of body organs and systems caused by natural aging processes may potentially affect pharmacokinetics and pharmacodynamics of medicines and increase the risk of adverse drug reactions. For instance, older people have a decreased cardiac output both at rest and during exercise, weight loss, loss of elasticity of elastic vessels, a reduced number of functioning nephrons, poorer renal filtration capacity, decreased liver volume, a reduced number of functioning hepatocytes, decreased hepatic blood flow. These changes directly affect absorption, metabolism, distribution, and excretion of medicines, which in turn can affect their safety profiles. Consideration of age-related changes in the functions of body organs and systems, regular monitoring of the efficacy and safety of the prescribed medicine, changing the dosage regimen, and revision of the treatment sheet by healthcare professionals will help optimize pharmacotherapy and reduce the risk of adverse reactions and drug-induced diseases in older patients.

Restoration of afferent arteriolar autoregulatory behavior in ischemia-reperfusion injury in rat kidneys.

Renal autoregulation is critical in maintaining stable renal blood flow (RBF) and glomerular filtration rate (GFR). Renal ischemia-reperfusion (IR)-induced kidney injury is characterized by reduced RBF and GFR. The mechanisms contributing to renal microvascular dysfunction in IR have not been fully determined. We hypothesized that increased reactive oxygen species (ROS) contributed to impaired renal autoregulatory capability in IR rats. Afferent arteriolar autoregulatory behavior was assessed using the blood-perfused juxtamedullary nephron preparation. IR was induced by 60 min of bilateral renal artery occlusion followed by 24 h of reperfusion. Afferent arterioles from sham rats exhibited normal autoregulatory behavior. Stepwise increases in perfusion pressure caused pressure-dependent vasoconstriction to 65 ± 3% of baseline diameter (13.2 ± 0.4 μm) at 170 mmHg. In contrast, pressure-mediated vasoconstriction was markedly attenuated in IR rats. Baseline diameter averaged 11.7 ± 0.5 µm and remained between 90% and 101% of baseline over 65-170 mmHg, indicating impaired autoregulatory function. Acute antioxidant administration (tempol or apocynin) to IR kidneys for 20 min increased baseline diameter and improved autoregulatory capability, such that the pressure-diameter profiles were indistinguishable from those of sham kidneys. Furthermore, the addition of polyethylene glycol superoxide dismutase or polyethylene glycol-catalase to the perfusate blood also restored afferent arteriolar autoregulatory responsiveness in IR rats, indicating the involvement of superoxide and/or hydrogen peroxide. IR elevated mRNA expression of NADPH oxidase subunits and monocyte chemoattractant protein-1 in renal tissue homogenates, and this was prevented by tempol pretreatment. These results suggest that ROS accumulation, likely involving superoxide and/or hydrogen peroxide, impairs renal autoregulation in IR rats in a reversible fashion.NEW & NOTEWORTHY Renal ischemia-reperfusion (IR) leads to renal microvascular dysfunction manifested by impaired afferent arteriolar autoregulatory efficiency. Acute administration of scavengers of reactive oxygen species, polyethylene glycol-superoxide dismutase, or polyethylene glycol-catalase following renal IR restored afferent arteriolar autoregulatory capability in IR rats, indicating that renal IR led to reversible impairment of afferent arteriolar autoregulatory capability. Intervention with antioxidant treatment following IR may improve outcomes in patients by preserving renovascular autoregulatory function and potentially preventing the progression to chronic kidney disease after acute kidney injury.

Case Report and Supporting Documentation: Acute Kidney Injury Manifested as Oliguria Is Reduced by Intravenous Magnesium Before Cisplatin

After more than four decades of post-approval, cisplatin is still an important treatment for numerous cancers. However, acute kidney injury (AKI), defined as significant impairment of renal filtration as discussed below, is the major limiting side effect of cisplatin, occurring in approximately 30% of patients (25–33% after the first course). Cisplatin also damages the kidneys’ ability to reabsorb magnesium in 40–100% of patients, with collateral health risks due to subsequent hypomagnesemia. Multiple methods and drugs have been proposed for preventing cisplatin-induced AKI, including saline infusion with or without mannitol, which has not always prevented AKI and has been found to activate a cellular stress response in renal tubular cells. While numerous reports and trials, as well as the National Comprehensive Cancer Network (NCCN), support premedication with magnesium and hydration, this practice has not been universally accepted. Many clinics administer intravenous magnesium (IV) only after identification of hypomagnesemia post-cisplatin treatment, thus placing patients at risk for AKI and chronic renal loss of magnesium. We present the following case report and additional supporting evidence identifying the immediate effect of IV magnesium prior to intraperitoneal cisplatin for cycle 4 because of documented hypomagnesemia resulting in normalization of oliguria, which had been experienced for the first three cycles. The patient subsequently requested and received IV magnesium before cisplatin for the next two cycles with continuation of normal urinary output. The effect of pretreatment with IV magnesium on urine output following cisplatin has not been previously reported and further supports pre-cisplatin administration. In addition, two recent meta-analyses of clinical trials and pre-clinical research are reviewed that demonstrate effectiveness of magnesium pretreatment to preventing AKI without reducing its chemotherapeutic efficacy. This case report with additional evidence supports the adoption of administration of 1–3 g IV magnesium before cisplatin as best practice to prevent cisplatin induced AKI and hypomagnesemia regardless of patient baseline serum magnesium levels.

Enhanced photoluminescence of boron nitride quantum dots by encapsulation within polymeric nanoparticles

Boron nitride quantum dots (BNQDs) have been proposed as probes for bioimaging owing their to outstanding photoluminescent properties, although their hydrophobic nature and strong aggregation tendency in aqueous media limit their application in the biomedical field. In this work, we synthesize BNQDs by a liquid exfoliation–solvothermal process under pressure from boron nitride nanoparticles in N,N-dimethylformamide. The BNQDs display an average size of 3.3 ± 0.6 nm, as measured by transmission electron microscopy, and a (100) crystalline structure. In addition, a quantum yield of 21.75 ± 0.20% was achieved. To ensure complete dispersibility in water and prevent possible elimination by renal filtration upon injection, the BNQDs (20% w/w) are encapsulated within poly(ethylene glycol)-b-poly(epsilon-caprolactone) nanoparticles by a simple and scalable nanoprecipitation method, and hybrid nanocomposite particles with significantly stronger photoluminescence than their free counterparts are produced. Finally, their optimal cell compatibility and bioimaging features are demonstrated in vitro in murine macrophage and human rhabdomyosarcoma cell lines.

Renal excretion function in primary hyperparathyroidism: cardio-renal syndrome

Background. Primary hyperparathyroidism (PHPT) is an endocrine disease, due to the formation of excess parathyroid hormone secretion and a disturbance of phosphorus-calcium metabolism. PHPT is associated with reduced renal function and related increased mortality, therefore renal function impairment defined as a glomerular filtration rate (GFR) less than 60 mL/ min/1.73 m 2 is considered as an indication for surgical treatment. Some patients with PHPT have secondary cardio-renal syndrome (type 5), which is characterized by the presence of combined renal and cardiac pathology. THE AIM: Evaluate the GFR in patients with mild and symptomatic PHPT and its changes after parathyroidectomy and on medical treatment. Patients and methods : A cross-sectional comparative and prospective study was conducted on 100 patients with confirmed PHPT. A clinical and laboratory examination was performed at 6, 12, and/or 24 months and included an assessment of the PHPT complications as well as expression of cardio-renal syndrome according to the selected management tactics. Changes in GFR were evaluated in 29 patients after surgical treatment and in 27 patients on conservative management. Glomerular filtration rate was calculated by the Modification of Diet in Renal Disease Study (MDRD) formula. The chronic kidney disease (CKD) stage was estimated accordingly to current recommendations. Results: We included 100 patients (10 men and 90 women) with PHPT: 33 with mild and 67 with symptomatic PHPT. The median age was 57 years [51;61]. Mean GFR was 84,1 [73,3; 97,9] ml/ min/1,73 m 2 . Prevalence of CKD 3-4 in patients with PHPT was recorded at 11 %. Patient management tactics were determined in accordance with international recommendations. In the long-term period after surgery, we observed the decrease of GFR in patients with mild form within the limits of CKD 1-2 (p=0,013, W-test). No significant changes in GFR were noted during medical management and monitoring. Summary, the cardio-renal syndrome (CKD of any stage and cardiovascular pathology) was revealed in 26 % of patients. Arterial hypertension was registered in 40 %. Conclusions : We found a high frequency of renal function impairment in patients with PHPT, including patients with a mild form of the disease. We did not observe any significant improvement in renal filtration function, after surgical treatment and remission of PHPT. The safety of conservative tactics has been confirmed. The high frequency of cardiovascular pathology in patients with PHPT is beyond doubt and requires prospective studies in the larger cohorts of patients.

Emerging roles for lymphatics in acute kidney injury: Beneficial or maleficent?

Acute kidney injury, a sudden decline in renal filtration, is a surprisingly common pathology resulting from ischemic events, local or systemic infection, or drug-induced toxicity in the kidney. Unchecked, acute kidney injury can progress to renal failure and even recovered acute kidney injury patients are at an increased risk for developing future chronic kidney disease. The initial extent of inflammation, the specific immune response, and how well inflammation resolves are likely determinants in acute kidney injury-to-chronic kidney disease progression. Lymphatic vessels and their roles in fluid, solute, antigen, and immune cell transport make them likely to have a role in the acute kidney injury response. Lymphatics have proven to be an attractive target in regulating inflammation and immunomodulation in other pathologies: might these strategies be employed in acute kidney injury? Acute kidney injury studies have identified elevated levels of lymphangiogenic ligands following acute kidney injury, with an expansion of the lymphatics in several models post-injury. Manipulating the lymphatics in acute kidney injury, by augmenting or inhibiting their growth or through targeting lymphatic-immune interactions, has met with a range of positive, negative, and sometimes inconclusive results. This minireview briefly summarizes the findings of lymphatic changes and lymphatic roles in the inflammatory response in the kidney following acute kidney injury to discuss whether renal lymphatics are a beneficial, maleficent, or a passive contributor to acute kidney injury recovery.

A Self-Assembling and Disassembling (SADA) Bispecific Antibody (BsAb) Platform for Curative Two-step Pretargeted Radioimmunotherapy.

Many cancer treatments suffer from dose-limiting toxicities to vital organs due to poor therapeutic indices. To overcome these challenges we developed a novel multimerization platform that rapidly removes tumor-targeting proteins from the blood to substantially improve therapeutic index. The platform was designed as a fusion of a self-assembling and disassembling (SADA) domain to a tandem single-chain bispecific antibody (BsAb, anti-ganglioside GD2 × anti-DOTA). SADA-BsAbs were assessed with multiple in vivo tumor models using two-step pretargeted radioimmunotherapy (PRIT) to evaluate tumor uptake, dosimetry, and antitumor responses. SADA-BsAbs self-assembled into stable tetramers (220 kDa), but could also disassemble into dimers or monomers (55 kDa) that rapidly cleared via renal filtration and substantially reduced immunogenicity in mice. When used with rapidly clearing DOTA-caged PET isotopes, SADA-BsAbs demonstrated accurate tumor localization, dosimetry, and improved imaging contrast by PET/CT. When combined with therapeutic isotopes, two-step SADA-PRIT safely delivered massive doses of alpha-emitting (225Ac, 1.48 MBq/kg) or beta-emitting (177Lu, 6,660 MBq/kg) S-2-(4-aminobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (DOTA) payloads to tumors, ablating them without any short-term or long-term toxicities to the bone marrow, kidneys, or liver. The SADA-BsAb platform safely delivered large doses of radioisotopes to tumors and demonstrated no toxicities to the bone marrow, kidneys, or liver. Because of its modularity, SADA-BsAbs can be easily adapted to most tumor antigens, tumor types, or drug delivery approaches to improve therapeutic index and maximize the delivered dose.See related commentary by Capala and Kunos, p. 377.

Acute aortic dissection type A: Impact of aortic specialists on short and long term outcomes.

Acute aortic dissection type-A (AADA) is a life threatening condition which requires emergency surgery. Surgery is usually performed by cardiac surgeons with various levels of aortic surgical experience. We compared the short-term perioperative outcome and long-term survival of patients operated by specialist aortic surgeons (SASs)and those who were operated by surgeons without specialist expertise. A single center retrospective review of 232 patients who underwent acute surgery for AADA was conducted between 2005 and 2020. The cohort was divided into those operated on by SASs (Group A, n = 186) and those operated on by nonaortic surgeons (Group B, n = 46). Statistical comparison was done using regression modelling and groups were propensity matched. Kaplan-Meier comparison was undertaken using STATA14. Of 232 patients, 186 were operated on by an aortic specialist and 46 were operated by a nonaortic specialist. Overall 30-day mortality was 10% in Group A compared to 26.0% in Group B (unadjusted: p = .01, multivariate: p = .02, and propensity matched p = .05). Long-term mortality at 14 years was 26% in Group A compared to 52.0% in Group B (unadjusted: p = .001, multivariate: p = .001, and propensity matched: p = .01). Aortic surgeons performed a significantly higher number of aortic root procedures (43.0% vs. 17.3%, p = .001). The cross-clamp time and bypass time was significantly shorter in Group A patients (89 vs. 105 min, p < .01 and 153 vs. 185, p = < .001). Postoperative requirement for renal filtration was (19% vs. 37%, unadjusted p = .01, multivariate p = .03 and propensity matched p = .04). Although postoperative bleeding was less in Group A (4.0% vs. 11.0%, unadjusted p = .05) after propensity matching it was not statistically significant. In patients with AADA, surgery performed by aortic specialist's results in improved outcomes. Aortic specialists replaced more of dissected aorta, resulting in an increased number of complex procedures, which may explain improved long-term survival after AADA in this cohort. This study adds further support in establishing a specialist aortic surgical service in cardiac centers.

Renovascular Disease Induces Senescence in Renal Scattered Tubular-Like Cells and Impairs Their Reparative Potency.

Scattered tubular-like cells (STCs), dedifferentiated renal tubular epithelial cells, contribute to renal self-healing, but severe injury might blunt their effectiveness. We hypothesized that ischemic renovascular disease (RVD) induces senescence in STC and impairs their reparative potency. CD24+/CD133+ STCs were isolated from swine kidneys after 16 weeks of RVD or healthy controls. To test their reparative capabilities in injured kidneys, control or RVD-STC (5×105) were prelabeled and injected into the aorta of 2 kidneys, 1-clip (2k,1c) mice 2 weeks after surgery. Murine renal function and oxygenation were studied in vivo 2 weeks after injection using micro-magnetic resonance imaging, and fibrosis, tubulointerstitial injury, capillary density, and expression of profibrotic and inflammatory genes ex vivo. STC isolated from swine RVD kidneys showed increased gene expression of senescence and senescence-associated secretory phenotype markers and positive SA-β-gal staining. Delivery of normal pig STCs in 2k,1c mice improved murine renal perfusion, blood flow, and glomerular filtration rate, and downregulated profibrotic and inflammatory gene expression. These renoprotective effects were blunted using STC harvested from RVD kidneys, which also failed to attenuate hypoxia, fibrosis, tubular injury, and capillary loss in injured mouse 2k,1c kidneys. Hence, RVD may induce senescence in endogenous STC and impair their reparative capacity. These observations implicate cellular senescence in the pathophysiology of ischemic kidney disease and support senolytic therapy to permit self-healing of senescent kidneys.

Renal Dysplasia in a Free-Living Giant Anteater Cub (Myrmecophaga tridactyla) - Ultrasonographic and Tomographic Aspects

Background: Renal dysplasia is a congenital disorder that occurs during differentiation of the renal parenchyma or as a consequence of a functional and/or structural obstruction of the lower urinary tract. In wild animals, this pathology has been reported in cynomolgus monkeys (Macaca fascicularis), golden hamsters (Mesocricetus auratus) and African elephants (Loxodanta africana). However, there are no reports of the disease in the giant anteater (Myrmecophaga tridactyla). Thus, this paper describes a case of renal dysplasia in a free-living giant anteater cub, which was sent to the wild animal clinic of the Federal University of Mato Grosso (UFMT) in Cuiabá, MT, Brazil. Case: The rescued animal had a good body condition score and clinical parameters within the normal range for the species. After a routine clinical evaluation, the anteater cub was subjected to radiography and ultrasound tests. Blood tests, serum tests for hepatic and renal profiles, urinalysis, urinary protein creatinine ratio, and chest X-rays did not reveal significant changes. However, the abdominal ultrasound examination revealed a volumetric loss of about 1.17 cm in length in the left kidney, and a renal length to aortic artery diameter ratio of approximately 2.8. This kidney showed irregular contours, loss of corticomedullary demarcation, with preserved echogenicity and cortical echotexture. The right kidney showed the standard size of the species, with a length of approximately 3.08 cm. In view of the suspicion of renal dysplasia, a contrast-enhanced CT scan was performed in order to assess the dynamics of uptake and excretion of the contrast medium in the affected kidney and in the ipsilateral collecting system. An examination of the tomographic images indicated that the volume of the left kidney was reduced, isodense in relation to the right kidney, with discrete and homogeneous uptake in all phases after administration of the contrast medium, no occurrence of nephrogram and pyelogram phases, or any detection of contrast in the corresponding ureter.Discussion: Giant anteaters (Myrmecophaga tridactyla) are animals classified as a species vulnerable to extinction. Today, most research involving this species focuses on its ecology, behavior, diet, morphology and parasitology, but little is known about the imaging aspects of the species or about congenital changes such as renal dysplasia. Although the definitive diagnosis of this pathology depends on a histopathological examination, the same diagnosis can be made with a wide margin of safety by assessing the epidemiological aspects and the dynamics of renal uptake of the contrast medium through computed tomography. In this analysis, both vascularization and renal filtration capacity can be assessed. Thus, based on CT imaging, it was concluded that this was a case of renal dysplasia, since the left kidney showed a discrete homogeneous uptake stable in both the arterial and venous phases, without producing any accumulation of contrast medium in the pelvic region or the collecting system, proving to be completely nonfunctional. These findings differ from cases of renal hypoplasia, which, although they reduce renal volume, do not cause structural changes in the renal parenchyma or disturbances in the filtration dynamics of contrast media. They also differ from cases of acquired chronic nephropathy, since, albeit associated with reduced renal volume and changes in renal filtration dynamics, they produce different parenchymal ultrasound changes that usually occur in elderly animals and generally produce bilateral lesions.

Is Water-Only Fasting Safe?

BackgroundWater-only fasting (WF) is a practice used to improve and maintain health.ObjectiveThe aim of the study was to show whether WF performed for 8 days may be a threat to the health and/or life of people undergoing this practice.MethodsTwelve middle-aged men participated in the study. During the 8-day WF, the subjects ate no food except for drinking mineral water. Before and after WF, all subjects had a series of tests performed, beginning with the level of perceived stress and somatic measurements. The concentrations of creatinine, sodium (Na+), potassium (K+), total calcium (Ca), magnesium (Mg++), urea (U), uric acid (UA) and total protein were determined in this urine and in the serum. For these substances, the values ​​of clearance, renal filtration and fractional excretion were calculated. The osmotic clearance and free water clearance as well as the amount of daily urinary excretion of creatinine, Na+, K+, Ca, Mg++, U and UA were also calculated. Moreover, the concentration of glucose in the serum and the concentration of β-hydroxybutyrate in the plasma were determined. In urine, specific gravity, pH and osmolality were also measured.ResultsAfter 8 days of WF, the study showed a significant reduction in the level of perceived stress, weight loss, changes in body composition, dehydration, increased ketogenesis, hyperuricemia, decreased serum glucose concentration, and hyponatremia. These changes were accompanied by Na+, K+ and protein sparing, decreased serum Ca and Mg++ concentrations, and reduced daily volume of more acidic urine with elevated specific gravity.ConclusionsAfter 8 days of WF, all subjects were found to remain safe and feel the sense of well-being. However, the appearance of the above-mentioned adverse metabolic effects, despite partially effective renal compensations, suggests that the further continuation of fasting intervention by the subjects would be detrimental to their body.

Dynamic Contrast Enhancement (DCE) MRI-Derived Renal Perfusion and Filtration: Basic Concepts.

Dynamic contrast-enhanced (DCE) MRI monitors the transit of contrast agents, typically gadolinium chelates, through the intrarenal regions, the renal cortex, the medulla, and the collecting system. In this way, DCE-MRI reveals the renal uptake and excretion of the contrast agent. An optimal DCE-MRI acquisition protocol involves finding a good compromise between whole-kidney coverage (i.e., 3D imaging), spatial and temporal resolution, and contrast resolution. By analyzing the enhancement of the renal tissues as a function of time, one can determine indirect measures of clinically important single-kidney parameters as the renal blood flow, glomerular filtration rate, and intrarenal blood volumes. Gadolinium-containing contrast agents may be nephrotoxic in patients suffering from severe renal dysfunction, but otherwise DCE-MRI is clearly useful for diagnosis of renal functions and for assessing treatment response and posttransplant rejection.Here we introduce the concept of renal DCE-MRI, describe the existing methods, and provide an overview of preclinical DCE-MRI applications to illustrate the utility of this technique to measure renal perfusion and glomerular filtration rate in animal models.This publication is based upon work from the COST Action PARENCHIMA, a community-driven network funded by the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers. This introduction is complemented by two separate publications describing the experimental procedure and data analysis.