Acute Failure Research Articles

Does serum neutrophil gelatinase–associated lipocalin level predict acute kidney injury in patients with acute rhabdomyolysis in the emergency department? A multicentre prospective study

ObjectivesThe major complication of rhabdomyolysis is acute kidney injury (AKI), which requires prompt treatment. Currently, few biomarkers are available for the early detection of AKI. Serum neutrophil gelatinase–associated lipocalin (NGAL) has been suggested as an early biomarker for renal ischemia. However, its capacity to predict AKI in patients presenting with rhabdomyolysis in the emergency department (ED) remains unclear. The aim of this study was to evaluate the ability of NGAL to predict 48-hour AKI.DesignProspective, multicentre study.SettingFive adult EDs in France from August 2013 to December 2015.ParticipantsNGAL levels were measured on ED admission in patients with rhabdomyolysis. A total of 197 patients were enrolled, and 189 (96%) were analysed, of whom 89 (47%) were women. Patients were included if they presented to the ED with rhabdomyolysis and a creatine phosphokinase (CPK) level above 1000 IU/L. Exclusion criteria were pregnancy, presentation with acute coronary syndrome, the need for iodinated contrast, chronic dialysis or recent use of nephrotoxic drugs (within 72 hours prior to the ED visit). Patients who withdrew consent or had AKI due to other causes were also excluded.Primary and secondary outcome measuresThe primary outcome was AKI at 48 hours, defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Secondary outcomes included in-hospital mortality, length of hospital stay, admission to intensive care and the need for renal replacement therapy.ResultsOverall, 54 (29%) patients developed AKI by day 2. The area under the ROC curve (AUC-ROC) for NGAL in predicting AKI on day 2 was 0.60 (95% CI 0.51 to 0.70), with an optimal cut-off of 129 ng/mL. The sensitivity was 0.65, and specificity was 0.50. After adjustment for CPK levels, age, sex and oxygen saturation, the AUC-ROC for predicting AKI on day 2 increased slightly to 0.64 (95% CI 0.54 to 0.74).ConclusionNGAL has limited ability to predict day 2 AKI in patients presenting with acute rhabdomyolysis in the ED.Trail registration numberNCT01544231.Comité de Protection des Personnes Sud Méditerranée III n°2011-A01059-32.

Protective effect and mechanism of CoQ10 in mitochondrial dysfunction in diquat-induced renal proximal tubular injury.

Coenzyme Q10 (CoQ10) plays an important role in improving mitochondrial function and has many beneficial effects on the kidney. However, whether CoQ10 protects against diquat (DQ)-induced acute kidney injury (AKI) remains unclear. In this study, we investigated the protective effects and mechanism of action of CoQ10 against DQ-induced AKI. Institute of Cancer Research (ICR) mice were intraperitoneally injected with DQ to induce AKI. The expression levels of serum creatinine (Cr), urea, and kidney injury molecule-1 (KIM-1) increased, those of aquaporin 1 (AQP-1) decreased, and those of mitochondrial reactive oxygen species (ROS) increased with increased depolarization of mitochondrial membranes and mitochondrial rupture. In contrast, treatment with CoQ10 significantly improved DQ-induced AKI. CoQ10 treatment reduced serum Cr, urea, and KIM-1 contents, increased the AQP-1 expression, and reduced ROS contents in mice with DQ poisoning. Our results suggest that AKI caused by DQ poisoning may be related to the disruption of mitochondrial homeostasis and that CoQ10 treatment protects against AKI caused by DQ poisoning by improving mitochondrial kinetic homeostasis. Thus, CoQ10 represents a new therapeutic option for the prevention and treatment of AKI caused by DQ poisoning.

Pre-bypass critical closing pressure predicts acute kidney injury after cardiopulmonary bypass

ObjectivesOptimal blood pressure goals during cardiopulmonary bypass (CPB) remain uncertain and new metrics to individualize perfusion targets are needed. Critical closing pressure (Pcrit) is a fundamental property of the arterial circulation related to vascular tone and represents the outflow pressure impacting flow across the systemic circulation. We examined Pcrit as a prognostic marker of acute kidney injury (AKI). DesignRetrospective cohort study. SettingSingle tertiary care hospital Participants1038 adult cardiac surgery patients that underwent CPB. InterventionsPcrit was calculated using arterial waveform data before initiation of CPB. Pcrit was examined in relation to incidence of stage 2 or higher postoperative AKI according to standard KDIGO definitions. Measurements and Main ResultsOf the 1038 patients included in the study, 50 (5%) experienced AKI. Patients that suffered AKI had significantly higher preoperative risk factors, including higher incidence of severe chronic kidney disease and higher STS risk score (p<0.01). They also had longer operative times and longer cross clamp times (p<0.01). All patients were maintained at similar mean MAP while on CPB. Patients that suffered AKI had a significantly higher pre-bypass Pcrit than those who did not (49.0 vs 44.1 mmHg, p=0.018). In a multivariate regression, Pcrit remained a significant predictor, representing a 16% increased risk of AKI for each 5 mmHg increase in pre-bypass Pcrit (p=0.011). ConclusionsA higher pre-bypass Pcrit is associated with a significantly higher incidence of postoperative AKI. Future study is warranted to investigate using intra-operative Pcrit to determine a personalized blood pressure goal during CPB.

Early acute kidney injury after tacrolimus administration in heart transplant recipients receiving basiliximab induction therapy.

In this study, we aimed to analyze the association among the timing of tacrolimus initiation, time required to reach the target blood concentration, and early acute kidney injury (AKI) after tacrolimus administration in heart transplant recipients who received basiliximab induction therapy. 88 patients treated with tacrolimus-based immunosuppressive therapy were retrospectively reviewed. Induction therapy was administered to 52 patients. AKI was evaluated within 7 days of tacrolimus administration. The rate of increase in tacrolimus trough concentration to the target trough concentration of 10 µg/mL early after its administration was set to be similar in the basiliximab induction and non-induction group; 8 and 2 patients developed AKI in the induction and non-induction group, respectively. In the induction group, there was no significant difference in the timing of tacrolimus initiation and the time required to reach the target concentration between patients who developed and did not develop AKI. In contrast, the cumulative incidence of AKI was significantly different between patients with an estimated glomerular filtration rate below and those with an estimated glomerular filtration rate above 43 mL/min/1.73m2 at the start of tacrolimus administration (37.5% and 11.4%, respectively; p=0.045). In patients receiving basiliximab induction therapy, the timing of tacrolimus initiation and the time to reach the target concentration are unlikely to be associated with early AKI after tacrolimus administration. However, the recovery of sufficient renal function after heart transplantation is important for determining the start time of tacrolimus.

Protective effect of Huashi Baidu formula against AKI and active ingredients that target SphK1 and PAI-1

BackgroundHuashi Baidu Formula (HBF) is a clinical formula known for its efficacy against coronavirus disease 2019 (COVID-19). HBF may reduce the number of patients with abnormal serum creatinine while improving respiratory symptoms, suggesting that this formula may have potential for treating acute kidney injury (AKI). However, the protective effect of HBF on AKI has not been definitively confirmed, and the mechanism remains unclear. Therefore, the present study explored the renoprotective effects and molecular mechanisms of HBF and screened for its active ingredients to identify new potential applications of renoprotection by HBF.MethodsThe present study first assessed the protective effects of HBF on AKI in a DOX-induced mouse model. Then, RNA-seq and bioinformatics analyses were used to explore the related pathological processes and potential molecular mechanisms, which were subsequently validated using qRT-PCR and Western blotting. Furthermore, candidate compounds with potential binding affinity to two pivotal targets, sphingosine kinase 1 (SphK1) and plasminogen activator inhibitor-1 (PAI-1), were screened from the 29 constituents present in the blood using Microscale Thermophoresis (MST). Finally, to identify the active ingredients, the candidate components were re-screened using the SphK1 kinase activity detection system or the uPA/PAI-1 substrate colorimetric assay system.ResultsIn the DOX-induced AKI mouse model, therapeutic administration of HBF significantly reduced the levels of CRE, BUN, TNF-α, IL-1β, IL-6, and UA in plasma and the levels of MDA, T-CHO, and TG in kidney tissue. Additionally, the levels of TP and Alb in plasma and SOD and CAT in the kidney tissue were significantly increased. Histopathological assessment revealed that HBF reduced tubular vacuolation, renal interstitial inflammatory cell infiltration, tubular atrophy, and positive staining of renal interstitial collagen. RNA-seq and bioinformatics analyses showed that oxidative stress, the immune-inflammatory response, and extracellular matrix (ECM) formation could be the pathological processes that HBF targets to exerts its renoprotective effects. Furthermore, HBF regulated the APJ/SPHK1/NF-κB and APJ/PAI-1/TGFβ signaling axes and reduced the phosphorylation levels of NF-κB p65 and SMAD2 and the expression of cytokines and the ECM downstream of the axis. Finally, six SphK1 inhibitors (paeoniflorin, astragalin, emodin, glycyrrhisoflavone, quercetin, and liquiritigenin) and three PAI-1 inhibitors (glycyrrhisoflavone, licochalcone B, and isoliquiritigenin) were identified as potentially active ingredients in HBF.ConclusionIn brief, our investigation underscores the renoprotective effect of HBF in a DOX-induced AKI model mice, elucidating its mechanisms through distinct pathological processes and identifying key bioactive compounds. These findings offer new insights for broadening the clinical applications of HBF and unravelling its molecular mode of action.

Clinical Risk Factors for High-Dose Methotrexate-Induced Oral Mucositis Following Individualized Dosing.

Oral mucositis affects about 20% of children undergoing high-dose methotrexate (HDMTX) for acute lymphoblastic leukemia (ALL), despite existing management strategies. Personalized HDMTX dosing, adjusted by pharmacokinetics and leukemia risk, has reduced mucositis incidence, but variations still occur with similar 24-h methotrexate levels. This retrospective study investigated risk factors for oral mucositis under individualized methotrexate protocols. Data from patients with ≥ Grade 2 oral mucositis (CTCAE v4.0) were analyzed from the St. Jude Children's Research Hospital total 16 trial. A 1:1 case-control matching method considered age, sex, risk classification, immunophenotype, and methotrexate course. McNemar's, Bowker's symmetry, and Wilcoxon signed-rank tests were used for statistical analyses. Risk factors for recurrent mucositis were identified in a case-only analysis. The study found significant associations between methotrexate-induced mucositis and new-onset skin rashes (p = 0.0027), fever (p = 0.0016), neutropenic fever (p = 0.0008), lower absolute neutrophil count (p < 0.0001), acute kidney injury (AKI) (p = 0.0164), delayed methotrexate clearance (p = 0.0133), and higher 42-h methotrexate levels (p = 0.0179). In the standard/high-risk group, mercaptopurine dose was also linked to mucositis (p = 0.0495). Multivariable analysis showed that skin rashes (OR 6.5, p = 0.0016), fever (OR 2.8, p = 0.009), and neutropenia (OR 2.3, p = 0.0106) were independent risk factors for mucositis. Female sex (OR 7.12, p = 0.015) and AKI (OR 3.819, p = 0.037) were associated with recurrent mucositis. Fever, skin rashes, AKI, delayed methotrexate clearance, and higher 42-h methotrexate levels were key risk factors for HDMTX-induced oral mucositis. Skin rashes, fever, and neutropenia were independent predictors, while female sex and AKI were linked to recurrent mucositis.

Cefadroxil targeting of SLC15A2/PEPT2 protects from colistin nephrotoxicity

Acute kidney injury (AKI) and chronic kidney disease (CKD) are considered interconnected syndromes, as AKI episodes may accelerate CKD progression and CKD increases the risk of AKI. Genome-wide association studies (GWAS) may identify novel actionable therapeutic targets. Human genome-wide association studies (GWAS) for AKI or CKD were combined with murine AKI transcriptomics datasets to identify 13 (ACACB, ACSM5, CNDP1, DPEP1, GATM, SLC6A12, AGXT2L1, SLC15A2, CTSS, ICAM1, ITGAX, ITGAM, PPM1J) potentially actionable therapeutic targets to modulate kidney disease severity across species and across the AKI-CKD spectrum. Among them, SLC15A2, encoding the cell membrane proton-coupled peptide transporter 2 (PEPT2), was prioritized for data mining and functional intervention studies in vitro and in vivo because of its known function to transport nephrotoxic drugs such as colistin and the possibility for targeting with small molecules already in clinical use, such as cefadroxil. Data mining disclosed that SLC15A2 was upregulated in the tubulointerstitium of human CKD, including diabetic nephropathy, and the upregulation was localized to proximal tubular cells. Colistin elicited cytotoxicity and a proinflammatory response in cultured human and murine proximal tubular cells that was decreased by concomitant exposure to cefadroxil. In proof-of-concept in vivo studies, cefadroxil protected from colistin nephrotoxicity in mice. The GWAS association of SLC15A2 with human kidney disease may be actionable and related to the modifiable transport of nephrotoxins causing repeated subclinical episodes of AKI and/or chronic nephrotoxicity.

Prevalence and associated factors of acute kidney injury in Ethiopia, systematic review and meta-analysis.

Acute kidney injury, characterized by a sudden decline in glomerular filtration rate, presents a significant global health challenge, with its high prevalence exacerbated by hypertension and limited healthcare access. This systematic review and meta-analysis examined 19 studies encompassing 11,955 participants to assess acute kidney injury prevalence and associated factors in hospitalized patients inEthiopia. The overall pooled prevalence of acute kidney injury was found to be 3.20% (95% CI 2.91-3.48), with considerable heterogeneity (I2 = 99.3%; p < 0.001). Subgroup analyses identified elevated rates ofacute kidney injury in studies conducted post-2020 (31.656%, 95% CI 24.465-38.848), particularly in the Oromia region (41.622%, 95% CI 11.873-71.372), and smaller study sample (< 400) (44.524%, 95% CI 30.117-58.932). Hypertension, congestive heart failure, sepsis, chronic kidney diseases, and nephrotoxicity emerged as significant risk factors. Regular monitoring of renal function through blood and urine analyses is crucial for early detection and management of acute kidney injury, particularly in high-risk groups. Addressing healthcare disparities and reducing nephrotoxic medication use are essential strategies to mitigate acute kidney injury incidence and improve kidney health outcomes worldwide.

Association of testosterone replacement therapy with atrial fibrillation and acute kidney injury.

Secondary analyses of the Testosterone Replacement Therapy for Assessment of Long-Term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) trial revealed significantly higher rates of new-onset atrial fibrillation (AF) and acute kidney injury (AKI) in the testosterone replacement therapy (TRT) cohort. To validate the secondary findings of the TRAVERSE trial. We utilized the TriNetX Research Network to identify a cohort of men ages 45-80years old who met similar inclusion criteria to the TRAVERSE trial. We compared hypogonadal men (testosterone 100-300ng/dL) who had a prescription for topical testosterone therapy and men who did not. Propensity score matching was used to match patient populations. Kaplan Meier survival analysis was used to determine the relative risk of new-onset AF and AKI within 3years. New-onset AF and AKI within 3years. There were 2134 men included in each cohort after propensity score matching. Men on TRT had significantly lower testosterone (T) at the time of diagnosis compared to men not prescribed TRT (207 ± 66ng/dL vs 246 ± 140ng/dL, P< 0.001). Kaplan-Meier survival analysis showed a significantly increased risk of AKI among men on TRT (RR 1.53, 95% CI 1.07-2.18). However, TRT was not associated with a significantly increased risk of new-onset AF (RR 1.48, 95% CI 0.93-2.37). Hypogonadal men with underlying cardiovascular risk factors or pre-existing cardiovascular disease who receive TRT may be at increased risk of AKI after starting therapy. We evaluated a large global research database and utilized similar inclusion and exclusion to the TRAVERSE trial. However, our results are limited by the retrospective study design and reliance on documented claims data. Similar to the TRAVERSE trial, our study demonstrated an increased risk of AKI among men on TRT, but did not find increased risk of AF. However, further studies are required to validate these results.

Exploring the pharmacological mechanism of fermented Eucommia ulmoides leaf extract in the treatment of cisplatin-induced kidney injury in mice: Integrated traditional pharmacology, metabolomics and network pharmacology

Cisplatin (CP) is a widely utilized anticancer drug, which also produces significant side effects, notably acute kidney injury (AKI). Fermented Eucommia ulmoides leaf (FEUL), a medicinal and edible Chinese herbal remedy, is known for its renoprotective properties. However, the effect and underlying mechanism of FEUL in AKI therapy have remained largely unexplored. This research aimed to elucidate the protective roles of FEUL in an AKI mouse model through biochemical assays, histopathological examinations, and investigating the underlying mechanisms based on metabolomics and network pharmacology. The findings demonstrated that pretreatment with orally administered FEUL significantly reduced blood urea nitrogen (BUN), and serum creatinine (SCr) levels, and ameliorated CP-induced kidney histopathological injuries. Moreover, FEUL attenuated CP-induced endoplasmic reticulum (ER) stress by reducing the protein expressions of PERK, IRE 1α, GRP78, ATF6, ATF4, and CHOP. The metabolomics results indicated that a total of 31 metabolites, involved in taurine and hypotaurine metabolism, lysine degradation, and steroid hormone biosynthesis, were altered after FEUL administration. Furthermore, metabolomics integrated with network pharmacology revealed that 8 targets, 4 metabolites, and 3 key pathways including steroid hormone biosynthesis, purine metabolism, and tryptophan metabolism were the main mechanisms of FEUL in treating CP-induced AKI. These findings suggested that FEUL could offer valuable insights for potential CP-induced AKI treatment strategies.

P44 An acutely unwell and rare presentation of systemic lupus erythematosus; a case report

Abstract Introduction Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with multisystem involvement. The condition has varying clinical presentations from mild mucocutaneous manifestations to severe multiorgan and central nervous system involvement. It is challenging to diagnose someone with SLE during acute admission. Apart from infection and malignancies, autoimmune and connective tissue diseases should always be one of our differentials in an acutely unwell patient with multisystem involvement. This case demonstrates how unwell and rare a patient with SLE can present. We also acknowledge the need to further understand and raise awareness of this uncommon condition. Case description A 48 year old Thai lady with no known medical illness presented with 2-3 weeks history of viral like illness. On admission, she was tachycardic, hypotensive and hypoxic. Clinical examination revealed bi-basal crepitations and elevated JVP. Her ECG showed sinus tachycardia. Admission bloods showed anemia, raised white cell count, lymphopenia, thrombocytopenia, raised inflammatory markers and acute kidney injury (AKI). CT scan revealed evidence of pericardial effusion with small free fluid in abdomen and pelvis. ECHO showed large pericardial effusion and pericardiocentesis was performed which drained purulent fluid. Blood culture was positive for E. Coli. 3rd Day blood tests were strongly positive for CTD screening. She was reviewed by the rheumatology team and was diagnosed as acute presentation of SLE causing serositis having fulfilled the SLICC criteria with E. Coli bacteremia. SLE DAI – 2K score was 11. She reported history of Raynaud’s since moving to UK, hair loss and two miscarriages in the past. She denied history of oral ulcers, facial rash or significant joint involvement. Renal team advised that AKI was due to infection rather than lupus. She was commenced on high dose oral prednisolone (40 mg/day) and antibiotics. Her condition responded to steroids and subsequently was commenced on mycophenolate as outpatient. Discussion SLE is an autoimmune disease that affects multiple organ systems. Symptoms and signs can vary although majority of patients present with cutaneous manifestation. Most of the clinical manifestations of the disease are due to abnormal inflammatory response. Patients with SLE are usually diagnosed at outpatient settings although they can present acutely unwell as seen in this patient. Serositis refers to inflammation of serous tissue which includes pleura, pericardium and peritoneum. It is considerably a rare condition which is only seen in only around 10% of patients with SLE. Patients can present with shortness of breath, abdominal pain, diarrhoea, fatigue chest pain and even cardiac tamponade. Due to the heterogeneity of SLE presentations, it is challenging for clinicians to diagnose and manage the symptoms. Besides infection and malignancies, it is always important to consider connective tissue disease as one of the differentials in an acutely unwell patient presenting with multisystem involvement. SLICC criteria can be used as a diagnosing tool for SLE which includes clinical and immunological criteria. SLEDAI-2K score can be used to assess disease activity. Her biochemical parameters as well as clinical symptoms drastically improved following steroid initiation. Early recognition and treatment initiation can improve mortality and morbidity significantly. Despite how unwell she was during admission; she improved quickly and was discharged relatively early. Her condition continues to improve on DMARDs, and she is on regular clinic follow up. Key learning points • A good clinical history and examination is essential and aids reaching a diagnosis. As reflected in this case, our patient was a female at childbearing age, south Asian (non-Caucasian ethnicity) who presented with multisystem involvement. Her initial finding of serositis, acute kidney injury, anemia, raised ESR and E. coli bacteremia were not fitting with a typical sepsis picture. There should be strong grounds for considering SLE during such clinical presentations. Suspecting SLE in an acute setting is really challenging due to various reasons, like wide symptomology of SLE, minimal exposure of SLE to physicians and their tendency of leaning towards other common conditions, like sepsis. As SLE is mostly diagnosed as outpatient, inpatient presentations are rare. Furthermore, blood results for connective tissue disease which is a major criteria for diagnosis, can take between 3 to 5 working days to be reported. However, early and appropriate consideration of autoimmune conditions as differentials of an acutely ill patient with multisystem involvement can expedite the process of diagnosis, involvement of related specialty and commencement of appropriate treatment. This approach will benefit patients producing favourable outcomes and minimal hospital stay.

Severe Vitamin D Deficiency is Associated with Mortality Risk in Critically Ill Patients with Acute Kidney Injury.

Deficiency in vitamin D is associated with adverse outcomes in several health conditions. However, the specific impact of vitamin D levels on mortality in acute kidney injury (AKI) patients remains inadequately explored. This study aims to investigate the association between serum vitamin D concentrations and mortality risk in critically ill patients diagnosed with AKI. We hypothesize that severe vitamin D deficiency is associated with an increased risk of 90-day all-cause mortality in these patients. This study retrospectively enrolled 259 adult AKI patients admitted to the intensive care unit (ICU) at The Fifth Clinical Medical College of Henan University of Chinese Medicine (Zhengzhou People's Hospital) between July 2021 and June 2023. Based on 25-hydroxyvitamin D (25-OHD) levels, they were categorized into 4 groups: severe deficiency (<10 ng/mL), deficiency (10-20 ng/mL), insufficiency (20-30 ng/mL), and sufficiency (>30 ng/mL). Multivariate survival analysis using Cox's regression model was used to analyze the impact of vitamin D concentrations on the 90-day all-cause mortality risk after controlling for potential confounders. The 90-day all-cause mortality rate was the highest in patients with severe deficiency (50.8%), followed by those with deficiency (35.0%), insufficiency (23.9%), and sufficiency (12.2%). Multivariate Cox regression showed that compared with sufficiency, severe deficiency (HR=3.34, 95% CI: 1.14-9.77; P=0.03) was independently associated with a higher risk of 90-day all-cause mortality, but deficiency and insufficiency were not significantly associated with 90-day all-cause mortality risk. Severe vitamin D deficiency (<10 ng/mL) significantly increases the risk of mortality in AKI patients, underlining the need for monitoring and potentially supplementing vitamin D in this population.

Intramuscular injection of Bothrops jararaca venom provoked acute kidney injury (AKI): Underpinned by impaired renal filtration, Na+ handling, and tissue damage

Globally, about 2.5 million people are victims of snakebites annually. In Brazil, the most clinically relevant snake is the Bothrops jararaca. The symptoms of envenomation are acute inflammation at the bite site and bleeding disorders. Despite kidney failure being the main cause of death after envenomation, kidney damage is not completely understood, and there are no clinically representative in vivo models. This work aimed to characterize the acute kidney injury (AKI) induced by intramuscular injection (IM) of Bothrops jararaca (Bjc) venom in male Wistar rats. The control group received 0.9% saline solution. Three doses of venom (3.5, 6.0, and 8.0 mg/kg) were administered IM into the posterior region of the right knee. After the injection, the rats were kept in metabolic cages. The following parameters were analyzed after 24 h: the extent of muscle damage and kidney damage (urinary creatinine, proteinuria, plasma creatinine, and renal tissue histology). All rats presented a hemorrhagic lesion at the injection site in a dose-dependent manner. Biochemical parameters indicated kidney damage: plasma creatinine accumulation, decreased glomerular filtration rate, albuminuria and proteinuria, and disturbance in Na+ homeostasis. Histological analyses showed glomerular injury, tissue discontinuity more evident in the cortex and tubular dilatation, and collagen deposition. The decline in renal function and tissue damage indicated the occurrence of AKI. Therefore, a Bjc venom-induced in vivo model of renal injury has been established for future studies.

A phase 1 study of interleukin-15 in combination with mogamulizumab in relapsed and refractory T-cell malignancies

IntroductionRecombinant human interleukin-15 (rhIL-15) is an immunotherapeutic which enhances NK-cells to augment the antibody directed cellular cytotoxicity (ADCC) of monoclonal antibodies. Mogamulizumab is a CCR4 directed monoclonal antibodies that exerts cytotoxicity through ADCC and depletes regulatory T-cells within the tumor microenvironment. MethodsWe conducted a phase 1 clinical trial of rhIL-15 combined with mogamulizumab. Patients with relapsed or refractory adult T-cell leukemia/lymphoma (ATLL), mycosis fungoides (MF) and Sezary syndrome (SS) received fixed dose mogamulizumab combined with escalating doses of rhIL-15 to identify the maximum tolerated dose (MTD). ResultsSix patients were enrolled, 4 with ATLL and 2 with MF/SS. The most common adverse events were rash, infection and fever (67%, in all). Two patients (33%) had grade 4 acute kidney injury and 25% of cycles had grade ≥3 anemia. The MTD was dose level 1. One patient with ATLL had a partial response despite receiving only 4 cycles due to grade 4 myositis. Circulating NK cells were increased in all patients during the first cycle and a rapid reduction in tumor cells within the peripheral circulation was noted. Ex vivo assessment demonstrated increased NK cell activation and increased cell lysis in the presence of monoclonal antibodies after only 5 days. DiscussionOur small study suggests that rhIL-15 combined with mogamulizumab leads to effector NK cell activation and regulatory T-cell depletion but has an unfavorable safety profile. Future development of combinations of immunotherapy that target the microenvironment in relapsed or refractory T-cell lymphomas remain rational. NCT04185220

Stroke-Induced Renal Dysfunction: Underlying Mechanisms and Challenges of the Brain-Kidney Axis.

Stroke, a major neurological disorder and a leading cause of disability and death, often inflicts damage upon other organs, particularly the kidneys. While chronic kidney disease (CKD) has long been established as a significant risk factor for cerebrovascular disease, stroke can induce renal dysfunction, manifesting as acute kidney injury (AKI) or CKD. Mounting clinical and basic research evidence supports the existence of a bidirectional brain-kidney crosstalk following stroke, implicating specific mechanisms and pathways in stroke-related renal dysfunction. This review analyzes pertinent experimental studies, elucidating the underlying mechanisms of this cerebro-renal interaction following stroke. Additionally, we summarize the current landscape of clinical research investigating brain-kidney interplay and discuss potential challenges in the future. By enhancing our understanding of the scientific underpinnings of brain-kidney crosstalk, this review paves the way for improved treatment strategies and outcomes for stroke patients. Recognizing the intricate interplay between the brain and kidneys after stroke holds profound clinical implications.

What is the spectrum of kidney pathology associated with COVID-19?

Kidney involvement occurs in almost one third of patients hospitalised with coronavirus disease 2019 (COVID-19) and is associated with increased disease severity. This review aims to outline the spectrum of kidney pathology involved in COVID-19. Literature was reviewed systematically on the databases Medline OVID and Scopus in search of case reports, case series, cohort studies and autopsy studies of patients with COVID-19 who underwent kidney biopsies. Studies were published between August 2020 and November 2021. Fourteen studies consisting of 159 patients were included in this review. Acute tubular necrosis is the most common pathology followed by collapsing glomerulopathy, occurring in 40.1% and 28.9% of patients respectively. Of the 46 patients with collapsing glomerulopathy, 44 were of African descent with high-risk apolipoprotein L1 genotypes. Less common glomerular diseases include membranous nephropathy, secondary focal segmental glomerulosclerosis, minimal change disease and primary focal segmental glomerulosclerosis occurring in 5%, 4.4%, 3.1% and 2.5% of patients respectively. Glomerulonephritis occurred in a minority of patients. Direct viral infection has not been found as a definitive aetiology. Acute kidney injury occurs frequently in hospitalised COVID-19 patients and is associated with increased morbidity and mortality. The mechanisms underpinning acute kidney injury are multifactorial. Acute tubular necrosis is the most common. Collapsing glomerulopathy is the most common glomerular injury and is strongly linked to apolipoprotein L1 genotypes. Improved understanding of COVID-19-related kidney pathologies can guide treatment to improve patient outcomes and reduce progression of chronic kidney disease. The longitudinal impact of COVID-19-related kidney disease requires further research.

Streptococcal Toxic Shock Syndrome: A Case Series Emphasizing the Urgency of Recognition and Tailored Treatment

BackgroundStreptococcal toxic shock syndrome (TSS) is a rare but lethal condition associated with Streptococcus Pyogenes Group A (GAS). With rising incidence and high mortality, timely recognition and management are crucial. This case series presents two adult TSS cases caused by invasive GAS, highlighting the importance of early identification and multidisciplinary management. Case PresentationsThe first case involves a 42-year-old male who presented with fever, dizziness, and a tender, erythematous olecranon following an elbow laceration. Despite negative imaging for necrotizing fasciitis, a positive throat swab for GAS prompted immediate broad-spectrum antibiotics and aggressive resuscitation. Clindamycin and intravenous immunoglobulin (IVIG) were administered. The patient developed TSS and acute kidney injury, requiring intensive care and hemodialysis.The second case features a previously healthy 43-year-old female presenting with systemic symptoms and a rash, without trauma history. Positive GAS blood cultures confirmed TSS, leading to similar management and subsequent renal complications requiring hemodialysis. Why should an Emergency Physician be aware of this?These cases highlight the evolving epidemiology of invasive GAS infections and the associated risk of TSS. Early identification and appropriate tailored treatment are essential to reduce morbidity and mortality, especially given the recent surge in invasive GAS. Clinical vigilance for skin changes and thorough laboratory investigations, including non-sterile site cultures, are critical. Early identification enables the use of adjunctive treatments like clindamycin and IVIG, and facilitates appropriate de-escalation of antibiotics. Prompt consultation with infectious disease, intensive care, and surgical teams is necessary to ensure optimal treatment.

Acute Kidney Injury in Cirrhosis Revisited- Implications in Clinical Practice

Acute Kidney Injury in Cirrhosis Revisited- Implications in Clinical Practice

Impact of Baseline Left Ventricular Ejection Fraction on Mid-term Outcomes in Women Undergoing Transcatheter Aortic Valve Implantation: Insight from the WIN TAVI Registry

Limited evidence exists concerning the prognostic impact of baseline left ventricular ejection fraction (LVEF) on outcomes among women undergoing transcatheter aortic valve implantation (TAVI), which we aimed to investigate in the current analysis. Patients from the WIN-TAVI registry were categorized according to baseline LVEF into three groups: reduced (LVEF≤40%), mildly reduced (40%< LVEF<50%), and preserved (LVEF≥50%) LVEF. The primary Valve Academic Research Consortium 2 (VARC-2) efficacy endpoint was as a composite of mortality, stroke, myocardial infarction (MI), hospitalization for valve-related symptoms or heart failure, or valve-related dysfunction at 1-year. The primary (VARC-2) safety endpoint included all-cause mortality, stroke, major vascular complication, life-threatening bleeding, stage 2-3 acute kidney injury, coronary artery obstruction requiring intervention, or valve-related dysfunction requiring repeated procedures. A Cox regression model was performed using the preserved LVEF group as reference. Among the 944 patients included, 764 (80.9%) exhibited preserved, 80 (8.5%) had mildly reduced, and 100 (10.6%) had reduced LVEF. The 1-year incidence of VARC-2 efficacy endpoint was numerically higher in patients with reduced LVEF, albeit not resulting in a significant risk difference. Notably, reduced LVEF was associated with a higher risk of the 1-year VARC-2 safety endpoint, still significant after adjustment (28.0% vs 19.6%, HR: 1.78; 95% CI 1.12 – 2.82, p=0.014). These differences were primarily driven by trends toward increased rates of all-cause mortality, cardiovascular mortality, and major vascular complications. Clinical outcomes were similar between patients with mildly reduced and preserved LVEF. In conclusion, when performed in women with reduced LVEF, TAVI was associated with a worse (VARC-2) safety profile at 1-year follow-up. In contrast, patients with mildly reduced LVEF appeared to align more closely with outcomes observed in the preserved LVEF group than with the reduced LVEF group.

Acute kidney injury with Fanconi syndrome following intake of a Red Yeast Rice Supplement

Acute kidney injury with Fanconi syndrome following intake of a Red Yeast Rice Supplement