Renal Death Research Articles

Terlipressin in combination with albumin as a therapy for hepatorenal syndrome in patients aged 65 years or older

Introduction and ObjectivesClinical data for older patients with advanced liver disease are limited. This post hoc analysis evaluated the efficacy and safety of terlipressin in patients aged ≥65 years with hepatorenal syndrome using data from 3 Phase III, randomized, placebo-controlled studies (OT-0401, REVERSE, CONFIRM). Patients and MethodsThe pooled population of patients aged ≥65 years (terlipressin, n = 54; placebo, n = 36) was evaluated for hepatorenal syndrome reversal—defined as a serum creatinine level ≤1.5 mg/dL (≤132.6 μmol/L) while receiving terlipressin or placebo, without renal replacement therapy, liver transplantation, or death—and the incidence of renal replacement therapy (RRT). Safety analyses included an assessment of adverse events. ResultsHepatorenal syndrome reversal was almost 2-times higher in terlipressin-treated patients compared with patients who received placebo (31.5% vs 16.7%; P = 0.143). Among surviving patients, the need for RRT was significantly reduced in the terlipressin group, with an almost 3-times lower incidence of RRT versus the placebo group (Day 90: 25.0% vs 70.6%; P = 0.005). Among 23 liver-transplant-listed patients, significantly fewer patients in the terlipressin versus placebo group needed RRT by Days 30 and 60 (P = 0.027 each). Fewer patients in the terlipressin group needed RRT post-transplant (P = 0.011). More terlipressin-treated patients who were listed for and received a liver transplant were alive and RRT-free by Day 90. No new safety signals were revealed in the older subpopulation compared with previously published data. ConclusionsTerlipressin therapy may lead to clinical improvements in highly vulnerable patients aged ≥65 years with hepatorenal syndrome. Clinical trial numbersOT-0401, NCT00089570; REVERSE, NCT01143246; CONFIRM, NCT02770716

RENAL12: Can Renal Autologous Cell Therapy (REACT) Delay Dialysis and Renal Transplantation in Chronic Kidney Disease with Type 2 Diabetes? The proact 1 and 2 Phase 3 Trial Design

Introduction: REACT is being developed to preserve renal function and delay or prevent ESRD. REACT is composed of bioactive selected renal cells (SRCs), isolated from a participant’s kidney, which participate in kidney repair and regeneration. Preclinical studies have demonstrated that SRCs injected directly into the kidney cortex produced a regenerative response improving kidney function and structure. Description of therapy REACT is derived from a standard kidney biopsy in an outpatient setting. SRCs are expanded ex vivo, cryopreserved, and shipped to the clinical site approximately 12 weeks later. REACT is percutaneously injected into the kidney cortex utilizing CT guidance in each kidney, 3 months apart. Participants proact 1 and proact will enroll 1200 pts from ~150 sites in the US and ~25 other countries with up to 60 months of follow-up, aged 30-80 years with type 2 diabetes who have an eGFR of 20-50 mL/min/1.73 m2, and UACR 300-5000 mg/g. Eligible participants will be randomized 1:1 to REACT or sham biopsy/injection in a single blind manner. Standard-of-care therapies including RAASi, SGLT2i, and MRAs are given per local guidance. Study Endpoints Time-to-event primary composite endpoint from first injection to the earliest of >≥40% eGFR decline, eGFR < 15 mL/min/1.73m2 sustained for 30 days, initiation of chronic dialysis, kidney transplantation, cardiovascular or renal death. Conclusion:proact 1 and 2 are global phase 3 randomized controlled trials evaluating the safety and efficacy of REACT on major kidney disease endpoints, among participants with type 2 diabetes and Stage 3a/4 CKD. REACT, a novel cell therapy comprised of SRCs, has the potential to directly preserve kidney function with a goal to prevent kidney failure.

BURDEN OF CARDIOVASCULAR DISEASES, KIDNEY DISEASES AND DEMENTIA ATTRIBUTABLE TO HYPERTENSION IN FRANCE

Objective: Cardiovascular and renal diseases and dementia constitute major hypertension-related conditions and have a high burden for public health. The aim of our study was to estimate the burden of these diseases attributable to hypertension in France by providing the number of hospital stays and deaths attributable to hypertension in 2017. Design and method: Age- and sex-specific attributable fractions were calculated by combining relative risks extracted from the literature with the prevalence of hypertension (defined as a systolic blood pressure higher than 140mmHg) estimated in the Esteban Study, a national representative survey. These fractions were applied to the nationwide statistics of death and hospitalization stays with a primary diagnosis for cardiovascular or renal diseases, or dementia whose risk is known to increase with hypertension. Data were extracted from the French National Health Insurance Information System (SNDS) which contains nationwide and exhaustive hospital stays and deaths occurring in France. Results: In France in 2017, 1 043 207 hospital stays and 185 459 deaths related to cardiovascular, renal or dementia condition occurred. Of these, 164 093 hospital stays (119 640 in men and 44 453 in women) and 35 017 deaths (17 436 in men and 16 142 in women) were estimated to be attributable to hypertension, representing 16% of all cardiovascular, renal and dementia-related hospital stays and 19% of all cardiovascular renal and dementia deaths. Regarding the attributable fraction, the largest impact was observed on hemorrhagic stroke (26.8% of cases attributable to hypertension in men and 15.8% in women) and on ischemic heart disease (25.0% in men and 15.4% in women). For all cardiovascular diseases the highest attributable fraction were reach in adults aged 55-74 years old. Conclusions: In France, the burden attributable to hypertension is high and is expected to increase in the coming years given the aging of the population. The reduction of the burden attributable to hypertension requires ambitious public health policies aimed at promoting healthy lifestyles but also an improvement in the awareness and management of hypertension, which has not improved over the last 20 years, unlike in several other European countries.

MiR-147 Represses NDUFA4, Inducing Mitochondrial Dysfunction and Tubular Damage in Cold Storage Kidney Transplantation.

Cold storage-associated transplantation (CST) injury occurs in renal transplant from deceased donors, the main organ source. The pathogenesis of CST injury remains poorly understood, and effective therapies are not available. This study has demonstrated an important role of microRNAs in CST injury and revealed the changes in microRNA expression profiles. Specifically, microRNA-147 (miR-147) is consistently elevated during CST injury in mice and in dysfunctional renal grafts in humans. Mechanistically, NDUFA4 (a key component of mitochondrial respiration complex) is identified as a direct target of miR-147. By repressing NDUFA4, miR-147 induces mitochondrial damage and renal tubular cell death. Blockade of miR-147 and overexpression of NDUFA4 reduce CST injury and improve graft function, unveiling miR-147 and NDUFA4 as new therapeutic targets in kidney transplantation. Kidney injury due to cold storage-associated transplantation (CST) is a major factor determining the outcome of renal transplant, for which the role and regulation of microRNAs remain largely unclear. The kidneys of proximal tubule Dicer (an enzyme for microRNA biogenesis) knockout mice and their wild-type littermates were subjected to CST to determine the function of microRNAs. Small RNA sequencing then profiled microRNA expression in mouse kidneys after CST. Anti-microRNA-147 (miR-147) and miR-147 mimic were used to examine the role of miR-147 in CST injury in mouse and renal tubular cell models. Knockout of Dicer from proximal tubules attenuated CST kidney injury in mice. RNA sequencing identified multiple microRNAs with differential expression in CST kidneys, among which miR-147 was induced consistently in mouse kidney transplants and in dysfunctional human kidney grafts. Anti-miR-147 protected against CST injury in mice and ameliorated mitochondrial dysfunction after ATP depletion injury in renal tubular cells in intro . Mechanistically, miR-147 was shown to target NDUFA4, a key component of the mitochondrial respiration complex. Silencing NDUFA4 aggravated renal tubular cell death, whereas overexpression of NDUFA4 prevented miR-147-induced cell death and mitochondrial dysfunction. Moreover, overexpression of NDUFA4 alleviated CST injury in mice. microRNAs, as a class of molecules, are pathogenic in CST injury and graft dysfunction. Specifically, miR-147 induced during CST represses NDUFA4, leading to mitochondrial damage and renal tubular cell death. These results unveil miR-147 and NDUFA4 as new therapeutic targets in kidney transplantation.

Single-Cell RNA-Seq Analysis Reveals Ferroptosis in the Tumor Microenvironment of Clear Cell Renal Cell Carcinoma.

In this study, we investigated the role of ferroptosis in the tumor microenvironment (TME) of clear cell renal cell carcinoma (ccRCC), the leading cause of renal cancer-related death. We analyzed single-cell data from seven ccRCC cases to determine cell types most correlated with ferroptosis and performed pseudotime analysis on three myeloid subtypes. We identified 16 immune-related ferroptosis genes (IRFGs) by analyzing differentially expressed genes between cell subgroups and between high and low immune infiltration groups in the TCGA-KIRC dataset and the FerrDb V2 database. Using univariate and multivariate Cox regression, we identified two independent prognostic genes, AMN and PDK4, and constructed an IRFG score model immune-related ferroptosis genes risk score (IRFGRs) to evaluate its prognostic value in ccRCC. The IRFGRs demonstrated excellent and stable performance for predicting ccRCC patient survival in both the TCGA training set and the ArrayExpress validation set, with an AUC range of 0.690-0.754, outperforming other commonly used clinicopathological indicators. Our findings enhance the understanding of TME infiltration with ferroptosis and identify immune-mediated ferroptosis genes associated with prognosis in ccRCC.

Kidney protection with canagliflozin: A combined analysis of the randomized CANVAS program and CREDENCE trials.

In the CANVAS Program and CREDENCE trials, the sodium glucose co-transporter 2 inhibitor canagliflozin reduced the risk of cardiovascular and kidney events in patients with type 2 diabetes. The current study analysed a pooled population to ascertain the kidney protection provided by canagliflozin across the full spectrum of kidney parameters. This post-hoc pooled analysis of the CANVAS Program (N = 10 142) and CREDENCE trial (N = 4401), assessed the risk of the primary kidney composite (doubling of serum creatinine, end-stage kidney disease, renal death), in all patients and subgroups defined by baseline estimated glomerular filtration rate (<30, 30 to <45, 45 to <60 and ≥60 ml/min/1.73 m2 ), albuminuria [<30, 30-300, >300 mg/g (<3.39, 3.39-33.9, >33.9 mg/mmol)] and 2012 Kidney Disease: Improving Global Outcomes (KDIGO) classification of chronic kidney disease (low/moderate, high and very high risk). In the overall population, the risk for the primary kidney composite outcome was 37% lower in the canagliflozin group versus placebo (HR: 0.63; 95% CI: 0.53, 0.77; p < .001). There was no evidence of heterogeneity in the kidney protective effects of canagliflozin across a range of kidney risks when stratified by baseline estimated glomerular filtration rate, albuminuria or KDIGO risk category (all pinteraction > .05). A statistically significant risk reduction of the primary kidney composite outcome was sustained by approximately 18 months after randomization. These results emphasize a critical role of canagliflozin in kidney protection across a broad spectrum of participants with type 2 diabetes with varying levels of kidney function.

Urinary neutrophil gelatinase-associated lipocalin and plasma IL-6 in discontinuation of continuous venovenous hemodiafiltration for severe acute kidney injury: a multicenter prospective observational study

BackgroundPatients with severe acute kidney injury (AKI) who require continuous venovenous hemodiafiltration (CVVHDF) in intensive care unit (ICU) are at high mortality risk. Little is known about clinical biomarkers for risk prediction, optimal initiation, and optimal discontinuation of CVVHDF.MethodsThis prospective observational study was conducted in seven university-affiliated ICUs. For urinary neutrophil gelatinase-associated lipocalin (NGAL) and plasma IL-6 measurements, samples were collected at initiation, 24 h, 48 h after, and CVVHDF discontinuation in adult patients with severe AKI. The outcomes were deaths during CVVHDF and CVVHDF dependence.ResultsA total number of 133 patients were included. Twenty-eight patients died without CVVHDF discontinuation (CVVHDF nonsurvivors). Urinary NGAL and plasma IL-6 at the CVVHDF initiation were significantly higher in CVVHDF nonsurvivors than in survivors. Among 105 CVVHDF survivors, 70 patients were free from renal replacement therapy (RRT) or death in the next 7 days after discontinuation (success group), whereas 35 patients died or needed RRT again (failure group). Urinary NGAL at CVVHDF discontinuation was significantly lower in the success group (93.8 ng/ml vs. 999 ng/ml, p < 0.01), whereas no significant difference was observed in plasma IL-6 between the groups. Temporal elevations of urinary NGAL levels during the first 48 h since CVVHDF initiation were observed in CVVHDF nonsurvivors and those who failed in CVVHDF discontinuation.ConclusionsUrinary NGAL at CVVHDF initiation and discontinuation was associated with mortality and RRT dependence, respectively. The serial changes of urinary NGAL might also help predict the prognosis of patients with AKI on CVVHDF.Graphical

A Rare Case of Fatal Penile Strangulation in a Transgender Woman.

Penile strangulation is a surgical emergency with significant morbidity and potential mortality. It is often associated with psychiatric disorders; objects such as metal rings, plastic bottles, and rubber bands are commonly used. The San Francisco Office of the Chief Medical Examiner was presented with a 50-year-old transgender female decedent with a medical history of psychiatric and substance use disorders. Autopsy revealed external genitalia entrapped by a plastic bottle encircling the penile shaft at the base, causing severe edema and skin blebs of the penile shaft and glans, and evidence of urinary obstruction. We describe the accidental death of an adult transgender female decedent due to penile strangulation, which ultimately led to acute renal failure and death.

Acrolein produced during acute kidney injury promotes tubular cell death

Acute kidney injury is an important global health concern as it is associated with high morbidity and mortality. Polyamines, essential for cell growth and proliferation, are known to inhibit cardiovascular disease. However, under conditions of cellular damage, toxic acrolein is produced from polyamines by the enzyme spermine oxidase (SMOX). We used a mouse renal ischemia-reperfusion model and human proximal tubule cells (HK-2) to investigate whether acrolein exacerbates acute kidney injury by renal tubular cell death. Acrolein visualized by acroleinRED was increased in ischemia-reperfusion kidneys, particularly in tubular cells. When HK-2 cells were cultured under 1% oxygen for 24 h, then switched to 21% oxygen for 24 h (hypoxia-reoxygenation), acrolein accumulated and SMOX mRNA and protein levels were increased. Acrolein induced cell death and fibrosis-related TGFB1 mRNA in HK-2 cells. Administration of the acrolein scavenger cysteamine suppressed the acrolein-induced upregulation of TGFB1 mRNA. Cysteamine also inhibited a decrease in the mitochondrial membrane potential observed by MitoTrackerCMXRos, and cell death induced by hypoxia-reoxygenation. The siRNA-mediated knockdown of SMOX also suppressed hypoxia-reoxygenation-induced acrolein accumulation and cell death. Our study suggests that acrolein exacerbates acute kidney injury by promoting tubular cell death during ischemia-reperfusion injury. Treatment to control the accumulation of acrolein might be an effective therapeutic option for renal ischemia-reperfusion injury.

Predictors of long-term outcomes in pediatric focal segmental glomerulosclerosis.

Available data on primary focal segmental glomerulosclerosis (FSGS) in children usually report on short follow-up and small samples. Furthermore, the application of the Columbia classification for FSGS in children has not yet been fully agreed. We aimed to confirm the prognosis and risk factors of FSGS in a large cohort of Chinese children. Two hundred seventy-four children with primary FSGS from a single center were enrolled from 2003 to 2018. Long-term renal survival and related risk factors were evaluated by the Kaplan-Meier method and Cox multivariate regression analysis. Receiver operating characteristic (ROC) curve analysis further tested the effect of various risk factors in predicting renal outcomes. The composite end-point included ≥ 50% reduction in estimated glomerular filtration rate and/or end-stage renal disease or death. One hundred twenty-five children were diagnosed with not otherwise specified (NOS) (45.6%) variant; 79 with tip lesions (28.8%), 32 with collapsing (11.7%), 31 with cellular (11.3%), and 7 with perihilar lesions (2.6%). The renal survival rate was 80.73% at 5years, 62.58% at 10years and 34.66% at 15years. Multivariate analysis showed that chronic tubulointerstitial damage ≥ 25% (HR 4.14, 95% CI 1.49-11.50, P < 0.01), collapsing variant [(reference: NOS) HR 2.16, 95% CI 1.10-4.27, P = 0.03], segmental sclerosis (HR 1.03, 95% CI 1.01-1.04, P < 0.01) and age at biopsy (HR 0.91, 95% CI 0.85-0.98, P = 0.01) were significantly associated with renal outcomes. ROC curve analysis showed an excellent diagnostic yield of the Columbia classification. The combination of Columbia classification, CTI ≥ 25% and segmental sclerosis had the best predictive value for renal outcomes (AUC = 0.867, sensitivity = 77.78%, specificity = 82.27%, P < 0.01). This study reports a renal survival rate of Chinese children with FSGS of 62.58% at 10years and 34.66% at 15years. Prognosis is poorer in patients with collapsing variant or CTI ≥ 25% and good in patients with tip variant. The Columbia classification is confirmed as a valuable tool for predicting prognosis of Chinese children with FSGS.

The association of oral health with length of stay and mortality in the intensive care unit.

To analyze the relationship between the oral and systemic health status of adult patients admitted to the intensive care unit (ICU) with the length of stay and mortality. A daily oral examination and oral hygiene were performed in patients admitted to an adult ICU. Dental and oral lesions, systemic health status, the need for mechanical ventilation, length of stay, and mortality were registered. Multivariate linear and logistic regression analyses were performed to identify associations between length of stay and death of patients, respectively, with oral and systemic health status. In total, 207 patients were included, 107 (51.7%) male. Ventilated patients presented an increased length of stay (p < 0.001), mortality (p < 0.0001), number of medications (p < 0.0001), edentulism (p = 0.001), mucous lesions and bleeding (p < 0.0001), oropharyngitis (p = 0.03), and drooling (p < 0.001) compared to non-ventilated patients. The number of days in the ICU was associated with mechanical ventilation (p = 0.04), nosocomial pneumonia (p = 0001), end-stage renal disease (p < 0.0007), death (p < 0.0001), mucous bleeding (p = 0.01), tongue coating (p = 0.001), and cheilitis (p = 0.01). Mortality was associated with length of stay in the ICU (p < 0.0001), number of medications (p < 0.0001), and the need for mechanical ventilation (p = 0.006). ICU patients present poor oral health. Soft tissue biofilm and mucous ulcerations were associated with the length of stay in the ICU, but not with the mortality rate. Mucous lesions are associated with an increased length of stay in the ICU, and critically ill patients should receive oral care to control oral foci of infection and mucous lesions.

Abstract 631: Single-cell analysis of immune and stroma cell remodeling in renal cell carcinoma primary tumors and bone metastatic lesions

Abstract Background: Renal cell carcinoma (RCC) is the most common renal tumor in adults, and among these clear cell RCC (ccRCC) is most common subtype and accounts for most renal cancer-related deaths. One-third of patients with advanced ccRCC present with bone metastases at the time of diagnosis. Despite therapeutic advances, once cancer has metastasized to the bone, it represents a highly morbid and ultimately lethal disease. Comprehensive genomic studies in ccRCC have provided important insights into the somatic alterations and intra-tumor heterogeneity. However, the bone metastatic niche in humans, including the immune and stromal microenvironments, has not been well-defined. Methods: We collected fresh patient samples directly from the operating room and performed single-cell transcriptomic profiling of human ccRCC tumors (ccRCC primary), solid metastatic tissue (Bone Met), liquid bone marrow at the vertebral level of spinal cord compression (Involved), liquid bone marrow from a different vertebral body distant from the tumor site but within the surgical field (Distal), as well as bone marrow stroma cells from patients undergoing hip replacement surgery (Benign) as control. We provide a comparative single cell transcriptomic analysis between ccRCC primary tumors and bone metastatic lesions. Results: Comparison of malignant cells from primary and metastatic sites reveal a distinct transcriptional signature that is predictive of metastatic potential and patient survival. The bone marrow in metastatic patients has sustained immune-suppressive microenvironment, featuring increased, exhausted CD8+ cytotoxic T-cells, T-regulatory cells and tumor-associated macrophages (TAM) with distinct transcriptional states in metastatic lesions. Bone marrow stroma from tumor samples demonstrated a tumor-associated mesenchymal stromal cell population (TA-MSC) that appears to be supportive of epithelial-to mesenchymal transition (EMT), bone remodeling, and a cancer-associated fibroblast (CAFs) phenotype. This stromal subset is associated with poor progression-free and overall survival, markedly upregulates bone remodeling through the dysregulation of RANK/RANKL/OPG signaling activity in bone cells, ultimately leading to bone resorption. Conclusions: These results provide insights into mechanisms underlying of ccRCC tumors progression leading bone metastasis. We also highlight potential communication channels and therefore therapeutic targets within both the immune and the tumor cell populations. Citation Format: Shenglin Mei, Adele M. Alchahin, Ioanna Tsea, Youmna Kfoury, Taghreed Taghreed, Hirak Sarkar, Shulin Wu, Alexander O. Subtelny, Yida Zhang, Keyan Salari, Chin-Lee Wu, Mark A. Randolph, David T. Scadden, Douglas Dahl, John Shin, Peter Kharchenko, Philip Saylor, David Sykes, Ninib Baryawno. Single-cell analysis of immune and stroma cell remodeling in renal cell carcinoma primary tumors and bone metastatic lesions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 631.

Severity of kidney involvement as predictor of death, severe heart failure and renal events in patients with type 2 diabetes: Data from a prospective cohort

Type 2 diabetes is associated with an increased risk for end-stage renal disease and heart failure, contributing to premature death. All these 3 events are inter-related, suggesting common risk factors and/or pathophysiological pathways. The SURDIAGENE (SUrvie Rénale DIAbète et GENEtique) cohort is a single center hospital-based cohort of persons living with type 2 diabetes, recruiting participants at Poitiers university hospital, France, from 2002 to 2011 with further follow-up till 2015. Here, we describe the cumulative prevalence of hard renal events (sustained doubling of serum creatinine and/or renal replacement therapy), heart failure leading to hospitalization (HFH) and all-cause death, according to the KDIGO classification, which considers CKD stages according to CKD EPI equation [1–5] and albuminuria (A1, A2, A3) according to albumin/creatinine ratio with thresholds at 30 and 300 mg/g. We considered 1450 participants with KDIGO stage available at baseline. Considering a cumulated follow-up duration of 10,667 patient.years with 100 renal events, 247 HFH and 527 deaths, our study showed that the more severe the KDIGO stage, the higher the incidence rate not only for renal event, but also for HFH and for all-cause death. For instance, in CKD1A1 and CKD4A3 the incidence rates for hard renal events, HFH and death were 0.98 and 140.70, 4.46 and 107.09, 13.64 and 156.56 per 1000 patient.years, respectively. Interestingly, the incidence of renal event was lower than the incidence of all-cause death in all KDIGO stages, at variance with the data from recent renal outcome trials on SGLT2 inhibitors and finerenone. We conclude that KDIGO stages should be considered for renal but also for HFH risk classification. The analysis of the respective incidence of renal events and deaths in observational studies and RCTs deserves further evaluation in type 2 diabetes.

Abstract Number ‐ 254: Yield of CTA in Patients over 50 with Brain Hemorrhages at Sites Typical for Hypertension

Introduction Approximately 10%–15% of acute strokes are spontaneous, nontraumatic intraparenchymal cerebral hemorrhage (IPH). Hypertension (HTN), amyloid angiopathy, or impaired coagulation cause most spontaneous IPHs, in which case the CTA is unlikely to identify an underlying vascular lesion. Prior investigators have identified clinical and non‐contrast CT (NCCT) features that increase the likelihood of identifying a vascular etiology for an IPH, including younger age (&lt; 40–50), absence of hypertension, and presence of subarachnoid (SAH) or intraventricular hemorrhage (IVH). Findings from earlier studies of patients with IPH suggested that older age, HTN, together with certain locations (basal ganglia, thalamus, cerebellum, and pons) could reliably exclude IPH patients with underlying lesions. We aimed to assess the yield of CTA, a costly study with risks of radiation, contrast induced renal injury and death, in identifying vascular lesions in this group. Methods This retrospective study involved reviewing medical records of all patients admitted to Carilion RMH hospital for brain hemorrhage during the period 2008–2020, inclusive. Patients were considered if they were over 50 year of age, had HTN (and/or left ventricular hypertrophy on electrocardiograms or echocardiograpy) and IPH in the thalamus, basal ganglia, cerebellum or pons. Patients with SAH, lobar IPH, traumatic IPH, pure IVH, and patients with known vascular lesions were excluded. Imaging of all patients was reviewed with attention to finding CTAs showing vascular lesions that might have caused of the recent symptomatic IPH (arteriovenous malformations, aneurysms, venous anomalies and dural venous sinus thrombosis). Small saccular aneurysms at remote sites were not considered relevant, nor were intra‐ or extracranial stenoses. Results A total of (446) charts were reviewed, of which 143 met the inclusion criteria (94 males and 49 females). Family history was positive for cerebral aneurysm in one patient and Alzheimer’s with brain hemorrhage in another. Twenty‐six patients were on anticoagulation: 10 on NOAC, 14 on Warfarin (INR was &lt; 2 in 8, 2–3 in 5, and &gt;3 in only one patient). One was on subcutaneous heparin (PTT was 53). No other patient had major coagulation abnormalities; only 5 patients had platelets count &lt; 100K, the lowest was 62K. CTA was negative for underlying vascular lesion at the site of bleeding in all 143 patients, confidence interval 2.6% using Confidence intervals for proportions, using Wilson’s method for proportions. Conclusions In patients over 50 year of age with evidence of hypertension, and ICH in the basal ganglia, thalamus, brain stem and cerebellum; the diagnostic yield of CTA is negligible. Performing this study routinely in the evaluation of these patient increases health care costs, and exposes patients to the risks of unnecessary radiation, contrast induced kidney injury and death. We recommend against the routine use of CTA in patients meeting the above criteria.

Effects of finerenone in people with chronic kidney disease and type 2 diabetes are independent of HbA1c at baseline, HbA1c variability, diabetes duration and insulin use at baseline.

To evaluate the effect of finerenone by baseline HbA1c, HbA1c variability, diabetes duration and baseline insulin use on cardiorenal outcomes and diabetes progression. Composite efficacy outcomes included cardiovascular (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for heart failure), kidney (kidney failure, sustained ≥ 57% estimated glomerular filtration rate decline or renal death) and diabetes progression (new insulin initiation, increase in antidiabetic medication, 1.0% increase in HbA1c from baseline, new diabetic ketoacidosis diagnosis or uncontrolled diabetes). In 13 026 participants, risk reductions in the cardiovascular and kidney composite outcomes with finerenone versus placebo were consistent across HbA1c quartiles (P interaction .52 and .09, respectively), HbA1c variability (P interaction .48 and .10), diabetes duration (P interaction .12 and .75) and insulin use (P interaction .16 and .52). HbA1c variability in the first year of treatment was associated with a higher risk of cardiovascular and kidney events (hazard ratio [HR] 1.20; 95% confidence interval [CI] 1.07-1.35; P= .0016 and HR 1.36; 95% CI 1.21-1.52; P< .0001, respectively). There was no effect on diabetes progression with finerenone or placebo (HR 1.00; 95% CI 0.95-1.04). Finerenone was well-tolerated across subgroups; discontinuation and hospitalization because of hyperkalaemia were low. Finerenone efficacy was not modified by baseline HbA1c, HbA1c variability, diabetes duration or baseline insulin use. Greater HbA1c variability appeared to be associated with an increased risk of cardiorenal outcomes.

Divergent manifestations and outcomes of diffuse crescentic immunoglobulin A nephropathy and pauci-immune crescentic glomerulonephritis on long-term.

Diffuse crescentic IgAN (CIgAN) is an uncommon phenotype of IgAN, which presents as rapidly progressive renal failure, similar to patients with pauci-immune crescentic glomerulonephritis(PCGN). There are limited data on outcomes comparisons between the two. In this single-center, retrospective cohort study, we compared the clinical features, pathological presentation, and renal outcomes of 52 patients with CIgAN and 42 patients with renal-limited PCGN from January 2007 to December 2019. The CIgAN patients were younger (30.5 ± 13.8years) than PCGN patients (46.1 ± 11.8years) (P = 0.001). The CIgAN patients had a higher prevalence of hypertension (86.5% Vs. 41.3%, P = 0.001); and degree of proteinuria (4.2 ± 2.7g/24h Vs. 2.3 ± 1.16g/24h; P = 0.001) than PCGN patients. The chronicity in terms of global glomerulosclerosis, interstitial fibrosis, and tubular atrophy was higher in the CIgAN group than in the PCGN group. The remission rate with immunosuppression was significantly higher in the PCGN group than in the CIgAN group (P = 0.016). The end-stage renal disease (ESRD) or death within 1year of diagnosis was significantly more in the CIgAN group (62.3% Vs. 39.1%) than PCGNgroup. For patients who were dialysis-dependent at presentation, the primary outcome of ESRD or death within one year was seen in 90.9% of patients of CIgAN and 44.1% in the PCGN group (P = 0.001). The long-term death non-censored renal survival is poor in the CIgAN group than in PCGN patients. However, patient survival is poor in PCGN patients. CIgAN is a different form of RPGN compared to PCGN and carries a poor prognosis despite similar immunosuppressive therapy in the long term.

Balanced Nonopioid General Anesthesia With Lidocaine Is Associated With Lower Postoperative Complications Compared With Balanced Opioid General Anesthesia With Sufentanil for Cardiac Surgery With Cardiopulmonary Bypass: A Propensity Matched Cohort Study.

There are no data on the effect of balanced nonopioid general anesthesia with lidocaine in cardiac surgery with cardiopulmonary bypass. The main study objective was to evaluate the association between nonopioid general balanced anesthesia and the postoperative complications in relation to opioid side effects. Patients undergoing cardiac surgery with cardiopulmonary bypass between 2019 and 2021 were identified. After exclusion of patients for heart transplantation, left ventricular assistance device, and off-pump surgery, we classified patients according to an opioid general balanced anesthesia or a nonopioid balanced anesthesia with lidocaine. The primary outcome was a collapsed composite of postoperative complications that comprise respiratory failure and confusion, whereas secondary outcomes were acute renal injury, pneumoniae, death, intensive care unit (ICU), and hospital length of stay. We identified 859 patients exposed to opioid-balanced general anesthesia with lidocaine and 913 patients exposed to nonopioid-balanced general anesthesia. Propensity score matching yielded 772 individuals in each group with balanced baseline covariates. Two hundred thirty-six patients (30.5%) of the nonopioid-balanced general anesthesia versus 186 patients (24.1%) presented postoperative composite complications. The balanced lidocaine nonopioid general anesthesia group was associated with a lower proportion with the postoperative complication composite outcome OR, 0.72 (95% CI, 0.58-0.92; P = .027). The number of patients with acute renal injury, death, and hospital length of stay did not differ between the 2 groups. A balanced nonopioid general anesthesia protocol with lidocaine was associated with lower odds of postoperative complication composite outcome based on respiratory failure and confusion.

The Impact of Metabolic Syndrome on the Prognosis of High-Risk Alcoholic Hepatitis Patients: Redefining Alcoholic Hepatitis.

Alcoholic hepatitis (AH) is characterized by acute symptomatic hepatitis associated with heavy alcohol use. This study was designed to assess the impact of metabolic syndrome on high-risk patients with AH with discriminant function (DF) score ≥ 32 and its effect on mortality. We searched the hospital database for ICD-9 diagnosis codes of acute AH, alcoholic liver cirrhosis, and alcoholic liver damage. The entire cohort was categorized into two groups: AH and AH with metabolic syndrome. The effect of metabolic syndrome on mortality was evaluated. Also, an exploratory analysis was used to create a novel risk measure score to assess mortality. A large proportion (75.5%) of the patients identified in the database who had been treated as AH had other etiologies and did not meet the American College of Gastroenterology (ACG)-defined diagnosis of acute AH, thus had been misdiagnosed as AH. Such patients were excluded from analysis. The mean body mass index (BMI), hemoglobin (Hb), hematocrit (HCT), and alcoholic liver disease/non-alcoholic fatty liver disease index (ANI) were significantly different between two groups (P < 0.05). The results of a univariate Cox regression model showed that age, BMI, white blood cells (WBCs), creatinine (Cr), international normalized ratio (INR), prothrombin time (PT), albumin levels, albumin < 3.5, total bilirubin, Na, Child-Turcotte-Pugh (CTP), model for end-stage liver disease (MELD), MELD ≥ 21, MELD ≥ 18, DF score, and DF ≥ 32 had a significant effect on mortality. Patients with a MELD greater than 21 had a hazard ratio (HR) (95% confidence interval (CI) of 5.81 (2.74 - 12.30) (P < 0.001). The adjusted Cox regression model results showed that age, Hb, Cr, INR, Na, MELD score, DF score, and metabolic syndrome were independently associated with high patient mortality. However, the increase in BMI and mean corpuscular volume (MCV) and sodium significantly reduced the risk of death. We found that a model including age, MELD ≥ 21, and albumin < 3.5 was the best model in identifying patient mortality. Our study showed that patients admitted with a diagnosis of alcoholic liver disease with metabolic syndrome had an increased mortality risk compared to patients without metabolic syndrome, in high-risk patients with DF ≥ 32 and MELD ≥ 21. A bivariate correlation analysis revealed that patients with AH with metabolic syndrome were more likely to have infection (43%) compared to AH (26%) with correlation coefficient of 0.176 (P = 0.03, CI: 0.018 - 1.0). In clinical practice, the diagnosis of AH is inaccurately applied. Metabolic syndrome significantly increases the mortality risk in high-risk AH. It signifies that the presence of features of metabolic syndrome modifies the behavior of AH in acute settings, warranting different therapeutic strategies. We propose that in defining AH, patients overlapping with metabolic syndrome may need to be excluded as their outcome is different with regard to risk of renal dysfunctions, infections and death.

Glutathione metabolism rewiring protects renal tubule cells against cisplatin-induced apoptosis and ferroptosis

ABSTRACTRenal proximal tubular cells are highly vulnerable to different types of assaults during filtration and reabsorption, leading to acute renal dysfunction and eventual chronic kidney diseases (CKD). The chemotherapeutic drug cisplatin elicits cytotoxicity causing renal tubular cell death, but its executing mechanisms of action are versatile and elusive. Here, we show that cisplatin induces renal tubular cell apoptosis and ferroptosis by disrupting glutathione (GSH) metabolism. Upon cisplatin treatment, GSH metabolism is impaired leading to GSH depletion as well as the execution of mitochondria-mediated apoptosis and lipid oxidation-related ferroptosis through activating IL6/JAK/STAT3 signaling. Inhibition of JAK/STAT3 signaling reversed cell apoptosis and ferroptosis in response to cisplatin induction. Using a cisplatin-induced acute kidney injury (CAKI) mouse model, we found that inhibition of JAK/STAT3 significantly mitigates cisplatin nephrotoxicity with a reduced level of serum BUN and creatinine as well as proximal tubular distortion. In addition, the GSH booster baicalein also reclaims cisplatin-induced renal tubular cell apoptosis and ferroptosis as well as the in vivo nephrotoxicity. In conclusion, cisplatin disrupts glutathione metabolism, leading to renal tubular cell apoptosis and ferroptosis. Rewiring glutathione metabolism represents a promising strategy for combating cisplatin nephrotoxicity.

Shenkang recipe alleviates renal aging in diabetic kidney disease by interfering with the lysine-specific demethylase KDM6B to modulate the PPAR-γ signaling pathway

ObjectiveDiabetic kidney diseases (DKD) is one of the most common and serious microvascular complications of diabetes, and is also a major cause of end-stage renal diseases and death in diabetic patients. Shenkang Recipe (SKR) is a traditional Chinese medicine formula that has been shown to be effective against DKD in clinical practice, however, its mechanism of action remains unclear. The study is to explore the anti-aging effects and potential molecular mechanisms of SKR in the renal aging process. MethodsThe active ingredients of SKR were identified by UHPLC-MS/MS. A DKD mouse model was induced using unilateral nephrectomy combined with intraperitoneal injection of STZ (60 mg/kg), followed by gavage of SKR (14.18, 28.36, 56.72 g/kg/d, ig) for 12 weeks in DKD mice, Dagliflozin (5 mg/kg/d, ig) was used as a positive control. The renal pathological damage was observed by HE, PAS and Masson staining. The expression levels of aging-related biomarkers were measured by RT-qPCR and Western blot. In vitro experiments, D-galactose was used to induce senescence in HMC cells, and the molecular mechanisms involved in the improvement of senescence by SKR were explored through the administration of GSK-J1 and FH535. ResultsIt was found that SKR treatment significantly attenuated renal pathological damage, alleviated the renal aging process in DKD mice and inhibited the activation of histone demethylase KDM6B. Transcriptomic analysis suggested that the PPAR signaling pathway was identified to be most significantly changed in the kidneys of DKD mice, including PPAR-α, PPAR-β, and PPAR-γ. The pharmacological inhibition of KDM6B demethylase activity by GSK-J1 could alleviate D-galactose-induced senescence in HMC cells, but this effect could be reversed by FH535, an inhibitor of PPAR-γ. ConclusionThese results suggest that SKR plays a role in delaying the renal aging process in DKD mice by interfering KDM6B to promote the PPAR-γ signaling pathway.