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Tumors can induce systemic disturbances in distant organs, leading to physiological changes that enhance host morbidity. In Drosophila cancer models, tumors have been known for decades to cause hypervolemic "bloating" of the abdominal cavity. Here we use allograft and transgenic tumors to show that hosts display fluid retention associated with autonomously defective secretory capacity of fly renal tubules, which function analogous to those of the human kidney. Excretion from these organs is blocked by abnormal cells that originate from inappropriate activation of normally quiescent renal stem cells (RSCs). Blockage is initiated by IL-6-like oncokines that perturb renal water-transporting cells and trigger a damage response in RSCs that proceeds pathologically. Thus, a chronic inflammatory state produced by the tumor causes paraneoplastic fluid dysregulation by altering cellular homeostasis of host renal units.

BACKGROUND: Standard-of-care biomarkers for renal allograft rejection are lagging indicators, signaling existing organ injury. This precludes early intervention, when immunological cascades leading to rejection are most susceptible. Donor-derived cell-free DNA (dd-cfDNA) shows promise as an early indicator of rejection, allowing earlier and possibly more effective treatment. This analysis was designed to assess this promise using real-world dd-cfDNA testing evidence. METHODS: This retrospective analysis of the prospective, observational ProActive registry study (NCT04091984) assessed dd-cfDNA and serum creatinine levels before biopsy in 424 patients with ≥1 dd-cfDNA test (n = 1013) in the 6 mo before biopsy. RESULTS: Of 4667 enrolled patients, 1631 patients had ≥18 mo of follow-up data, of which 424 had a biopsy and were included in this analysis. Twenty-six biopsies showed antibody-mediated rejection (ABMR), 62 showed T cell-mediated rejection, and 336 showed nonrejection; each from a unique patient. dd-cfDNA fractions were significantly elevated 5 mo before ABMR biopsies, and 2 mo before T cell-mediated rejection biopsies, compared with nonrejection biopsies. In contrast, serum creatinine did not discriminate between rejection and nonrejection in advance, or concurrent with biopsy. Among patients with nonrejection biopsies, estimated glomerular filtration rate was significantly lower in cases with ≥2 increased dd-cfDNA results (≥1%), compared with those with 0 or 1 increased dd-cfDNA result. CONCLUSIONS: These data indicate that dd-cfDNA is an early indicator of biopsy-proven rejection, especially ABMR, suggesting a greater role for dd-cfDNA in surveillance to identify patients at high risk of ongoing or future rejection, thus requiring closer monitoring, biopsy, or other management changes.

Taurine is a conditionally essential micronutrient and one of the most abundant amino acids in humans1-3. In endogenous taurine metabolism, dedicated enzymes are involved in the biosynthesis of taurine from cysteine and in the downstream metabolism of secondary taurine metabolites4,5. One taurine metabolite is N-acetyltaurine6. Levels of N-acetyltaurine are dynamically regulated by stimuli that alter taurine or acetate flux, including endurance exercise7, dietary taurine supplementation8 and alcohol consumption6,9. So far, the identities of the enzymes involved in N-acetyltaurine metabolism, and the potential functions of N-acetyltaurine itself, have remained unknown. Here we show that the body mass index associated orphan enzyme phosphotriesterase-related (PTER)10 is a physiological N-acetyltaurine hydrolase. In vitro, PTER catalyses the hydrolysis of N-acetyltaurine to taurine and acetate. In mice, PTER is expressed in the kidney, liver and brainstem. Genetic ablation of Pter in mice results in complete loss of tissue N-acetyltaurine hydrolysis activity and a systemic increase in N-acetyltaurine levels. After stimuli that increase taurine levels, Pter knockout mice exhibit reduced food intake, resistance to diet-induced obesity and improved glucose homeostasis. Administration of N-acetyltaurine to obese wild-type mice also reduces food intake and body weight in a GFRAL-dependent manner. These data place PTER into a central enzymatic node of secondary taurine metabolism and uncover a role for PTER and N-acetyltaurine in body weight control and energy balance.

BACKGROUND: Low protein intake (LPI) has been suggested as a treatment for chronic kidney disease (CKD). However, protein intake is essential for bone health. METHODS: We studied the database of the National Health and Nutrition Examination Survey, 2005-2010. Basic variables, metabolic diseases, and bone density of different femoral areas were stratified into four subgroups according to different protein intake (DPI) (that is, 1.2 g/kg/day). RESULTS: Significant differences were found among all lumbar area bone mineral density (BMD) and T-scores (p 1.2 g/day/kg over L2 (relative risk (RR)=1.326, 95% confidence interval (CI)=1.062-1.656), subgroup >1.2 g/day/kg over L3 (RR = 1.31, 95%CI = 1.057-1.622), subgroup 1.2 g/day/kg over all L spines (RR = 0.333, 95%CI = 1.098-1.618). However, a higher risk of osteoporosis was observed only in the non-CKD group. There was an apparent trend of higher DPI coexisting with lower BMD and T scores in patients with CKD. For osteoporosis (reference:0.8-1.0 g/day/kg), lower (1.2 g/day/kg) was associated with higher risks in the non-CKD group, but not in the CKD group. CONCLUSIONS: In the CKD group, LPI for renal protection was safe without threatening L spine bone density and without causing a higher risk of osteoporosis.

BACKGROUND: Early initiation of venous thromboembolism (VTE) chemoprophylaxis in adults with blunt solid organ injury (BSOI) has been demonstrated to be safe but this is controversial in adolescents. We hypothesized that adolescent patients with BSOI undergoing non-operative management (NOM) and receiving early VTE chemoprophylaxis (eVTEP) (≤ 48 h) have a decreased rate of VTE and similar rate of failure of NOM, compared to similarly matched adolescents receiving delayed VTE chemoprophylaxis (dVTEP) (> 48 h). METHODS: The 2017-2019 Trauma Quality Improvement Program database was queried for adolescents (12-17 years of age) with BSOI (liver, kidney, and/or spleen) undergoing NOM. We compared eVTEP versus dVTEP using a 1:1 propensity score model, matching for age, comorbidities, BSOI grade, injury severity score, hypotension on arrival, and need for transfusions. We performed subset analyses in patients with isolated spleen, kidney, and liver injury. RESULTS: From 1022 cases, 417 (40.8%) adolescents received eVTEP. After matching, there was no difference in matched variables (all p > 0.05). Both groups had a similar rate of VTE (dVTEP 0.6% vs. eVTEP 1.7%, p = 0.16), mortality (dVTEP 0.3% vs. eVTEP 0%, p = 0.32), and failure of NOM (eVTEP 6.7% vs. dVTEP 7.3%, p = 0.77). These findings remained true in all subset analyses of isolated solid organ injury (all p > 0.05). CONCLUSIONS: The rate of VTE with adolescent BSOI is exceedingly rare. Early VTE chemoprophylaxis in adolescent BSOI does not increase the rate of failing NOM. However, unlike adult trauma patients, adolescent patients with BSOI receiving eVTEP had a similar rate of VTE and death, compared to adolescents receiving dVTEP.

With the increasing incidence of kidney diseases, there is an urgent need to develop therapeutic strategies to combat post-injury fibrosis. Immune cells, including platelets, play a pivotal role in this repair process, primarily through their released cytokines. However, the specific role of platelets in kidney injury and subsequent repair remains underexplored. Here, the detrimental role of platelets in renal recovery following ischemia/reperfusion injury and its contribution to acute kidney injury  to chronic kidney disease transition is aimed to investigated. In this study, it is shown that depleting platelets accelerates injury resolution and significantly reduces fibrosis. Employing advanced single-cell and spatial transcriptomic techniques, macrophages as the primary mediators modulated by platelet signals is identified. A novel subset of macrophages, termed cycling M2, which exhibit an M2 phenotype combined with enhanced proliferative activity is uncovered. This subset emerges in the injured kidney during the resolution phase and is modulated by platelet-derived thrombospondin 1 (THBS1) signaling, acquiring profibrotic characteristics. Conversely, targeted inhibition of THBS1 markedly downregulates the cycling M2 macrophage, thereby mitigating fibrotic progression. Overall, this findings highlight the adverse role of platelet THBS1-boosted cycling M2 macrophages in renal injury repair and suggest platelet THBS1 as a promising therapeutic target for alleviating inflammation and kidney fibrosis.

Polycystin-1 (PC-1) and PC-2 form a heteromeric ion channel complex that is abundantly expressed in primary cilia of renal epithelial cells. This complex functions as a non-selective cation channel, and mutations within the polycystin complex cause autosomal dominant polycystic kidney disease (ADPKD). The spatial and temporal regulation of the polycystin complex within the ciliary membrane remains poorly understood. Using both whole-cell and ciliary patch-clamp recordings, we identify a cilia-enriched oxysterol, 7β,27-dihydroxycholesterol (DHC), that serves as a necessary activator of the polycystin complex. We further identify an oxysterol-binding pocket within PC-2 and showed that mutations within this binding pocket disrupt 7β,27-DHC-dependent polycystin activation. Pharmacologic and genetic inhibition of oxysterol synthesis reduces channel activity in primary cilia. In summary, our findings reveal a regulator of the polycystin complex. This oxysterol-binding pocket in PC-2 may provide a specific target for potential ADPKD therapeutics.

BACKGROUND: An accurate, rapid estimate of glomerular filtration rate (GFR) in kidney transplant patients affords early detection of transplant deterioration and timely intervention. This study compared the performance of serum creatinine (Cr) and cystatin C (CysC)-based GFR equations to measured GFR (mGFR) using iohexol among pediatric kidney transplant recipients. METHODS: CysC, Cr, and mGFR were obtained from 45 kidney transplant patients, 1-18 years old. Cr- and CysC-estimated GFR (eGFR) was compared against mGFR using the Cr-based (Bedside Schwartz, U25-Cr), CysC-based (Gentian CysC, CAPA, U25-CysC), and Cr-CysC combination (CKiD Cr-CysC, U25 Cr-CysC) equations in terms of bias, precision, and accuracy. Bland-Altman plots assessed the agreement between eGFR and mGFR. Secondary analyses evaluated the formulas in patients with biopsy-proven histological changes, and K/DOQI CKD staging. RESULTS: Bias was small with Gentian CysC (0.1 ml/min/1.73 m2); 88.9% and 37.8% of U25-CysC estimations were within 30% and 10% of mGFR, respectively. In subjects with histological changes on biopsy, Gentian CysC had a small bias and U25-CysC were more accurate-both with 83.3% of and 41.7% of estimates within 30% and 10% mGFR, respectively. Precision was better with U25-CysC, CKiD Cr-CysC, and U25 Cr-CysC. Bland-Altman plots showed the Bedside Schwartz, Gentian CysC, CAPA, and U25-CysC tend to overestimate GFR when > 100 ml/min/1.72 m2. CAPA misclassified CKD stage the least (whole cohort 24.4%, histological changes on biopsy 33.3%). CONCLUSIONS: In this small cohort, CysC-based equations with or without Cr may have better bias, precision, and accuracy in predicting GFR.

Individuals afflicted with advanced kidney dysfunction who require dialysis for medical management exhibit different degrees of native kidney function, called residual kidney function (RKF), ranging from nil to appreciable levels. The primary focus of this manuscript is to delve into the concept of RKF, a pivotal yet under-represented topic in nephrology. To begin, we unpack the definition and intrinsic nature of RKF. We then juxtapose the efficiency of RKF against that of hemodialysis in preserving homeostatic equilibrium and facilitating physiological functions. Given the complex interplay of RKF and overall patient health, we shed light on the extent of its influence on patient outcomes, particularly in those living with advanced kidney dysfunction and on dialysis. This manuscript subsequently presents methodologies and measures to assess RKF, concluding with the potential benefits of targeted interventions aimed at preserving RKF.

Monofluoroacetate is a highly lethal toxin that causes death by inhibiting cellular adenosine triphosphate (ATP) production. The heart and brain are the primary target organs. Acute death is attributed to cardiac fibrillation and/or convulsions. Although it occurs naturally in some plants, a major source of animal intoxication is access to sodium monofluoroacetate (NaMFA) pesticide, which continues to be a concern in the USA and around the world despite restricted use in some countries including the USA. There are also concerns about misuse of this pesticide for malicious poisoning. Currently, a tissue-based diagnostic method for NaMFA intoxication in animals is lacking. There is a critical need by the veterinary diagnostic community for a simple, sensitive and reliable tissue-based diagnostic test to confirm NaMFA poisoning in animals. We have developed and extensively evaluated a sensitive novel liquid chromatography combined with tandem mass spectrometry method suitable for this purpose. The limits of detection and limits of quantitation are 1.7 and 5.0 ng/g, respectively. The accuracy and precision met or exceeded expectations. The method performance was verified using the incurred kidney obtained from animal diagnostic cases. This novel kidney-based method is now available for clinical use and can help with diagnostic purposes, including detecting potential issues related to animal foods.

BackgroundPediatric renal trauma is rare and lacks sufficient population-specific data to generate evidence-based management guidelines. A nonoperative approach is preferred and has been shown to be safe. However, bleeding risk assessment and management of collecting system injury are not well understood. We introduce the Multi-institutional Pediatric Acute Renal Trauma Study (Mi-PARTS), a retrospective cohort study designed to address these questions. This article describes the demographics and contemporary management of pediatric renal trauma at Level I trauma centers in the United States.MethodsRetrospective data were collected at 13 participating Level I trauma centers on pediatric patients presenting with renal trauma between 2010 and 2019. Data were gathered on demographics, injury characteristics, management, and short-term outcomes. Descriptive statistics were used to report on demographics, acute management, and outcomes.ResultsIn total, 1,216 cases were included in this study. Of all patients, 67.2% were male, and 93.8% had a blunt injury mechanism. In addition, 29.3% had isolated renal injuries, and 65.6% were high-grade (American Association for the Surgery of Trauma Grades III-V) injuries. The mean Injury Severity Score was 20.5. Most patients were managed nonoperatively (86.4%), and 3.9% had an open surgical intervention, including 2.7% having nephrectomy. Angioembolization was performed in 0.9%. Collecting system intervention was performed in 7.9%. Overall mortality was 3.3% and was only observed in patients with multiple injuries. The rate of avoidable transfer was 28.2%.ConclusionThe management and outcomes of pediatric renal trauma lack data to inform evidence-based guidelines. Nonoperative management of bleeding following renal injury is a well-established practice. Intervention for renal trauma is rare. Our findings reinforce differences from the adult population and highlights opportunities for further investigation. With data made available through Mi-PARTS, we aimed to answer pediatric specific questions, including a pediatric-specific bleeding risk nomogram, and better understanding indications for interventions for collecting system injuries.Level of evidencePrognostic and Epidemiological; Level IV.

PURPOSE OF REVIEW: Kidney dysfunction is challenging in liver transplant candidates to determine whether it is reversible or not. This review focuses on the pertinent data on how to best approach liver transplant candidates with kidney dysfunction in the current era after implementing the simultaneous liver kidney (SLK) allocation policy and safety net. RECENT FINDINGS: The implementation of the SLK policy inverted the steady rise in SLK transplants and improved the utilization of high-quality kidneys. Access to kidney transplantation following liver transplant alone (LTA) increased with favorable outcomes. Estimating GFR in liver transplant candidates remains challenging, and innovative methods are needed. SLK provided superior patient and graft survival compared to LTA only for patients with advanced CKD and dialysis at least 3 months. SLK can provide immunological protection against kidney rejection in highly sensitized candidates. Post-SLK transplant care is complex, with an increased risk of complications and hospitalization. SUMMARY: The SLK policy improved kidney access and utilization. Transplant centers are encouraged, under the safety net, to reserve SLK for liver transplant candidates with advanced CKD or dialysis at least 3 months while allowing lower thresholds for highly sensitized patients. Herein, we propose a practical approach to liver transplant candidates with kidney dysfunction.

Managing patients with kidney allografts largely depends on biopsy diagnosis which is based on semiquantitative assessments of rejection features and extent of acute and chronic changes within the renal parenchyma. Current methods lack reproducibility while digital image data-driven computational models enable comprehensive and quantitative assays. In this study we aimed to develop a computational method for automated assessment of histopathology transformations within the tubulointerstitial compartment of the renal cortex. Whole slide images of modified Picrosirius red-stained biopsy slides were used for the training (n = 852) and both internal (n = 172) and external (n = 94) tests datasets. The pipeline utilizes deep learning segmentations of renal tubules, interstitium, and peritubular capillaries from which morphometry features were extracted. Seven indicators were selected for exploring the intrinsic spatial interactions within the tubulointerstitial compartment. A principal component analysis revealed two independent factors which can be interpreted as representing chronic and acute tubulointerstitial injury. A K-means clustering classified biopsies according to potential phenotypes of combined acute and chronic transformations of various degrees. We conclude that multivariate analyses of tubulointerstitial morphometry transformations enable extraction of and quantification of acute and chronic components of injury. The method is developed for renal allograft biopsies; however, the principle can be applied more broadly for kidney pathology assessment.

In autosomal dominant polycystic kidney disease (ADPKD) with germline mutations in a PKD1 or PKD2 gene, innumerable cysts develop from tubules, and renal function deteriorates. Second-hit somatic mutations and renal tubular epithelial (RTE) cell death are crucial features of cyst initiation and disease progression. Here, we use established RTE lines and primary ADPKD cells with disease-associated PKD1 mutations to investigate genomic instability and DNA damage responses. We found that ADPKD cells suffer severe chromosome breakage, aneuploidy, heightened susceptibility to DNA damage, and delayed checkpoint activation. Immunohistochemical analyses of human kidneys corroborated observations in cultured cells. DNA damage sensors (ATM/ATR) were activated but did not localize at nuclear sites of damaged DNA and did not properly activate downstream transducers (CHK1/CHK2). ADPKD cells also had the ability to transform, as they achieved high saturation density and formed colonies in soft agar. Our studies indicate that defective DNA damage repair pathways and the somatic mutagenesis they cause contribute fundamentally to the pathogenesis of ADPKD. Acquired mutations may alternatively confer proliferative advantages to the clonally expanded cell populations or lead to apoptosis. Further understanding of the molecular details of aberrant DNA damage responses in ADPKD is ongoing and holds promise for targeted therapies.

MRI plays an important role in the evaluation of kidney allografts for vascular complications as well as parenchymal insults. Transplant renal artery stenosis, the most common vascular complication of kidney transplant, can be evaluated by MRA using gadolinium and nongadolinium contrast agents as well as by unenhanced MRA techniques. Parenchymal injury occurs through a variety of pathways, including graft rejection, acute tubular injury, BK polyomavirus infection, drug-induced interstitial nephritis, and pyelonephritis. Investigational MRI techniques have sought to differentiate among these causes of dysfunction as well as to assess the degree of interstitial fibrosis or tubular atrophy (IFTA)-the common end pathway for all of these processes-which is currently evaluated by invasively obtained core biopsies. Some of these MRI sequences have shown promise in not only assessing the cause of parenchymal injury but also assessing IFTA noninvasively. This review describes current clinically used MRI techniques and previews promising investigational MRI techniques for assessing complications of kidney grafts.

BACKGROUND: Kidney transplant (KT) candidates with HIV face higher mortality on the waitlist compared with candidates without HIV. Because the HIV Organ Policy Equity (HOPE) Act has expanded the donor pool to allow donors with HIV (D + ), it is crucial to understand whether this has impacted transplant rates for this population. METHODS: Using a linkage between the HOPE in Action trial (NCT03500315) and Scientific Registry of Transplant Recipients, we identified 324 candidates listed for D + kidneys (HOPE) compared with 46 025 candidates not listed for D + kidneys (non-HOPE) at the same centers between April 26, 2018, and May 24, 2022. We characterized KT rate, KT type (D + , false-positive [FP; donor with false-positive HIV testing], D - [donor without HIV], living donor [LD]) and quantified the association between HOPE enrollment and KT rate using multivariable Cox regression with center-level clustering; HOPE was a time-varying exposure. RESULTS: HOPE candidates were more likely male individuals (79% versus 62%), Black (73% versus 35%), and publicly insured (71% versus 52%; P

BACKGROUND: Leveraging the Accelerating Medicines Partnership (AMP) Lupus Nephritis (LN) dataset, we evaluated longitudinal patterns, rates, and predictors of response to standard-of-care therapy in patients with lupus nephritis. METHODS: Patients from US academic medical centers with class III, IV, and/or V LN and a baseline urine protein/creatinine (UPCR) ratio ≥ 1.0 (n = 180) were eligible for this analysis. Complete response (CR) required the following: (1) UPCR  50% reduction in UPCR; (2) normal serum creatinine or, if abnormal, ≤ 125% of baseline; and (3) prednisone dose ≤ 15 mg/day. RESULTS: Response rates to the standard of care at week 52 were CR = 22.2%; PR = 21.7%; non-responder (NR) = 41.7%, and not determined (ND) = 14.4%. Only 8/180 (4.4%) patients had a week 12 CR sustained through week 52. Eighteen (10%) patients attained a week 12 PR or CR and sustained their responses through week 52 and 47 (26.1%) patients achieved sustained PR or CR at weeks 26 and 52. Week 52 CR or PR attainment was associated with baseline UPCR > 3 (ORadj = 3.71 [95%CI = 1.34-10.24]; p = 0.012), > 25% decrease in UPCR from baseline to week 12 (ORadj = 2.61 [95%CI = 1.07-6.41]; p = 0.036), lower chronicity index (ORadj = 1.33 per unit decrease [95%CI = 1.10-1.62]; p = 0.003), and positive anti-dsDNA antibody (ORadj = 2.61 [95%CI = 0.93-7.33]; p = 0.069). CONCLUSIONS: CR and PR rates at week 52 were consistent with the standard-of-care response rates observed in prospective registrational LN trials. Low sustained response rates underscore the need for more efficacious therapies and highlight how critically important it is to understand the molecular pathways associated with response and non-response.

Systemic acid-base status is primarily determined by the interplay of net acid production (NEAP) arising from metabolism of ingested food stuffs, buffering of NEAP in tissues, generation of bicarbonate by the kidney, and capture of any bicarbonate filtered by the kidney. In chronic kidney disease (CKD), acid retention may occur when dietary acid production is not balanced by bicarbonate generation by the diseased kidney. Hormones including aldosterone, angiotensin II, endothelin, PTH, glucocorticoids, insulin, thyroid hormone, and growth hormone can affect acid-base balance in different ways. The levels of some hormones such as aldosterone, angiotensin II and endothelin are increased with acid accumulation and contribute to an adaptive increase in renal acid excretion and bicarbonate generation. However, the persistent elevated levels of these hormones can damage the kidney and accelerate progression of CKD. Measures to slow the progression of CKD have included administration of medications which inhibit the production or action of deleterious hormones. However, since metabolic acidosis accompanying CKD stimulates the secretion of several of these hormones, treatment of CKD should also include administration of base to correct the metabolic acidosis.

BACKGROUND: Up to one third of survivors of AKI that required dialysis (AKI-D) during hospitalization remain dialysis dependent at hospital discharge. Of these, 20%-60%, depending on the clinical setting, eventually recover enough kidney function to stop dialysis, and the remainder progress to ESKD. METHODS: To describe the challenges facing those still receiving dialysis on discharge, the AKINow Committee conducted a group discussion comprising 59 participants, including physicians, advanced practitioners, nurses, pharmacists, and patients. The discussion was framed by a patient who described gaps in care delivery at different transition points and miscommunication between care team members and the patient. RESULTS: Group discussions collected patient perspectives of ( 1 ) being often scared and uncertain about what is happening to and around them and ( 2 ) the importance of effective and timely communication, a comfortable physical setting, and attentive and caring health care providers for a quality health care experience. Provider perspectives included ( 1 ) the recognition of the lack of evidence-based practices and quality indicators, the significant variability in current care models, and the uncertain reimbursement incentives focused on kidney recovery and ( 2 ) the urgency to address communication barriers among hospital providers and outpatient facilities. CONCLUSIONS: The workgroup identified key areas for future research and policy change to ( 1 ) improve communication among hospital providers, dialysis units, and patients/care partners; ( 2 ) develop tools for risk classification, subphenotyping, and augmented clinical decision support; ( 3 ) improve education to providers, staff, and patients/care partners; ( 4 ) identify best practices to improve relevant outcomes; ( 5 ) validate quality indicators; and ( 6 ) assess the effect of social determinants of health on outcomes. We urge all stakeholders involved in the process of AKI-D care to align goals and work together to fill knowledge gaps and optimize the care to this highly vulnerable patient population.

Synaptic plasticity is obstructed by pathogenic tau in the brain, representing a key mechanism that underlies memory loss in Alzheimer's disease (AD) and related tauopathies. Here, we found that reduced levels of the memory-associated protein KIdney/BRAin (KIBRA) in the brain and increased KIBRA protein levels in cerebrospinal fluid are associated with cognitive impairment and pathological tau levels in disease. We next defined a mechanism for plasticity repair in vulnerable neurons using the C-terminus of the KIBRA protein (CT-KIBRA). We showed that CT-KIBRA restored plasticity and memory in transgenic mice expressing pathogenic human tau; however, CT-KIBRA did not alter tau levels or prevent tau-induced synapse loss. Instead, we found that CT-KIBRA stabilized the protein kinase Mζ (PKMζ) to maintain synaptic plasticity and memory despite tau-mediated pathogenesis. Thus, our results distinguished KIBRA both as a biomarker of synapse dysfunction and as the foundation for a synapse repair mechanism to reverse cognitive impairment in tauopathy.

Renal epithelioid angiomyolipoma (EAML) (epithelioid PEComa of the kidney), is a rare subtype of renal angiomyolipoma with the potential for aggressive behavior and a known diagnostically challenging entity. We present a renal EAML with unusual papillary architecture and tumor cells with abundant eosinophilic cytoplasm and cherry-red nucleoli with perinucleolar halos, strongly mimicking a fumarate hydratase (FH) deficient renal cell carcinoma (RCC). We herein report our findings and discuss the morphologic, immunohistochemical, and molecular pitfalls to consider in the differential of EAML, including with FH-deficient RCC and more recently described entities: TFEB-amplified RCC and other renal tumors with alterations in TSC1/2. Novel findings in this tumor include papillary morphology and a novel telomerase reverse transcriptase promoter rearrangement, which has not been previously reported in EAML.

BACKGROUND: After approval for clinical use in 2017 early investigations of ultra-high-field abdominal magnetic resonance imaging (MRI) have demonstrated the feasibility as well as diagnostic capabilities of liver, kidney, and prostate MRI at 7-Tesla. However, the elevation of the field strength to 7-Tesla not only brought advantages to abdominal MRI but also presented considerable challenges and drawbacks, primarily stemming from heightened artifacts and limitations in Specific Absorption Rate, etc. Furthermore, evidence in the literature is relatively scarce concerning human studies in comparison to phantom/animal studies which necessitates an investigation into the evidence so far in humans and summarizing all relevant evidence. AIM: To offer a comprehensive overview of current literature on clinical abdominal 7T MRI that emphasizes current trends, details relevant challenges, and provides a concise set of potential solutions. METHODS: This systematic review adheres to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A PubMed search, utilizing Medical Subject Headings terms such as 7-Tesla and organ-specific terms, was conducted for articles published between January 1, 1985, and July 25, 2023. Eligibility criteria included studies exploring 7T MRI for imaging human abdominal organs, encompassing various study types (in-vivo/ex-vivo, method development, reviews/meta-analyses). Exclusion criteria involved animal studies and those lacking extractable data. Study selection involved initial identification via title/abstract, followed by a full-text review by two researchers, with discrepancies resolved through discussion. Data extraction covered publication details, study design, population, sample size, 7T MRI protocol, image characteristics, endpoints, and conclusions. RESULTS: The systematic review included a total of 21 studies. The distribution of clinical 7T abdominal imaging studies revealed a predominant focus on the prostate (n = 8), followed by the kidney (n = 6) and the hepatobiliary system (n = 5). Studies on these organs, and in the pancreas, demonstrated clear advantages at 7T. However, small bowel studies showed no significant improvements compared to traditional MRI at 1.5T. The majority of studies evaluated originated from Germany (n = 10), followed by the Netherlands (n = 5), the United States (n = 5), Austria (n = 2), the United Kingdom (n = 1), and Italy (n = 1). CONCLUSION: Further increase of abdominal clinical MRI field strength to 7T demonstrated high imaging potential, yet also limitations mainly due to the inhomogeneous radiofrequency (RF) excitation field relative to lower field strengths. Hence, further optimization of dedicated RF coil elements and pulse sequences are expected to better optimize clinical imaging at high magnetic field strength.

Acute kidney injury (AKI) is increasing in prevalence and causes a global health burden. AKI is associated with significant mortality and can subsequently develop into chronic kidney disease (CKD). The kidney is one of the most energy-demanding organs in the human body and has a role in active solute transport, maintenance of electrochemical gradients, and regulation of fluid balance. Renal proximal tubular cells (PTCs) are the primary segment to reabsorb and secrete various solutes and take part in AKI initiation. Mitochondria, which are enriched in PTCs, are the main source of adenosine triphosphate (ATP) in cells as generated through oxidative phosphorylation. Mitochondrial dysfunction may result in reactive oxygen species (ROS) production, impaired biogenesis, oxidative stress multiplication, and ultimately leading to cell death. Even though mitochondrial damage and malfunction have been observed in both human kidney disease and animal models of AKI and CKD, the mechanism of mitochondrial signaling in PTC for AKI-to-CKD transition remains unknown. We review the recent findings of the development of AKI-to-CKD transition with a focus on mitochondrial disorders in PTCs. We propose that mitochondrial signaling is a key mechanism of the progression of AKI to CKD and potential targeting for treatment.

High dietary phosphorus intake (P-In) and high acid loads may adversely affect kidney function. In animal models, excessive phosphorus intake causes renal injury, which, in humans, is also inducible by chronic metabolic acidosis. We thus examined whether habitually high P-In and endogenous acid production during childhood and adolescence may be early indicators of incipient renal inflammatory processes later in adulthood. P-In and acid-base status were longitudinally and exclusively determined by biomarker-based assessment in 277 healthy children, utilizing phosphate and net acid excretion (NAE) measurements in 24 h urine samples repeatedly collected between the ages of 3 and 17 years. Standard deviation scores (by sex and age) were calculated for anthropometric data and for the urinary biomarkers available within age range 3-17 years. Multivariable linear regression was used to analyze the relations of phosphate excretion and NAE with the adulthood outcome circulating interleukin-18 (IL-18), a marker of inflammation and kidney dysfunction. After adjusting for growth- and adulthood-related covariates and pro-inflammatory biomarkers to rule out confounding by non-renal inflammatory processes, regression models revealed a significant positive relationship of long-term NAE (p = 0.01), but not of long-term phosphate excretion with adult serum IL-18. Similar significant positive regression results were obtained after replacing NAE with 24 h urinary ammonium excretion as the exposition variable. Our results suggest that even moderate elevations in renal ammonia production, as caused by habitually higher acid loading during growth, may affect the intrarenal pro-inflammatory system in the long-term, known to be boosted by acidosis-induced raised ammoniagenesis.

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.

There is a need to define regions of gene activation or repression that control human kidney cells in states of health, injury, and repair to understand the molecular pathogenesis of kidney disease and design therapeutic strategies. Comprehensive integration of gene expression with epigenetic features that define regulatory elements remains a significant challenge. We measure dual single nucleus RNA expression and chromatin accessibility, DNA methylation, and H3K27ac, H3K4me1, H3K4me3, and H3K27me3 histone modifications to decipher the chromatin landscape and gene regulation of the kidney in reference and adaptive injury states. We establish a spatially-anchored epigenomic atlas to define the kidneys active, silent, and regulatory accessible chromatin regions across the genome. Using this atlas, we note distinct control of adaptive injury in different epithelial cell types. A proximal tubule cell transcription factor network of ELF3, KLF6, and KLF10 regulates the transition between health and injury, while in thick ascending limb cells this transition is regulated by NR2F1. Further, combined perturbation of ELF3, KLF6, and KLF10 distinguishes two adaptive proximal tubular cell subtypes, one of which manifested a repair trajectory after knockout. This atlas will serve as a foundation to facilitate targeted cell-specific therapeutics by reprogramming gene regulatory networks.

Diabetes is a chronic disease that induces many comorbidities, including cardiovascular disease, nephropathy, and liver damage. Many mechanisms have been suggested as to how diabetes leads to these comorbidities, of which increased oxidative stress in diabetic patients has been strongly implicated. Limited knowledge of antioxidative antidiabetic drugs and substances that can address diabetic comorbidities through the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway calls for detailed investigation. This review will describe how diabetes increases oxidative stress, the general impact of that oxidative stress, and how oxidative stress primarily contributes to diabetic comorbidities. It will also address how treatments for diabetes, especially focusing on their effects on the Nrf2 antioxidative pathway, have been shown to similarly affect the Nrf2 pathway of the heart, kidney, and liver systems. This review demonstrates that the Nrf2 pathway is a common pathogenic component of diabetes and its associated comorbidities, potentially identifying this pathway as a target to guide future treatments.

MOTIVATION: Pediatric kidney disease is a widespread, progressive condition that severely impacts growth and development of children. Chronic kidney disease is often more insidious in children than in adults, usually requiring a renal biopsy for diagnosis. Biopsy evaluation requires copious examination by trained pathologists, which can be tedious and prone to human error. In this study, we propose an artificial intelligence (AI) method to assist pathologists in accurate segmentation and classification of pediatric kidney structures, named as AI-based Pediatric Kidney Diagnosis (APKD). RESULTS: We collected 2935 pediatric patients diagnosed with kidney disease for the development of APKD. The dataset comprised 93 932 histological structures annotated manually by three skilled nephropathologists. APKD scored an average accuracy of 94% for each kidney structure category, including 99% in the glomerulus. We found strong correlation between the model and manual detection in detected glomeruli (Spearman correlation coefficient r = 0.98, P

There is a need to reconsider the acceptance of organs from donors considered suboptimal, in the absence of data. Toxoplasma antibody-positive donors (TPD) constitute one such group. The objective of our study was to compare graft survival in deceased donor renal transplant (Tx) recipients, stratified by Toxoplasma IgG status, using the Organ Procurement and Transplantation Network (OPTN) database. A log-linear event history regression model for graft failure categorized by Toxoplasma IgG status, adjusting for confounders was applied to first kidney-only Tx recipients from 2018 to 2022. Of the 51,422 Tx, 4,317 (8.4%) were from TPD. Acute rejection and graft failure (5% each) were similar between groups. Crude graft failure was 7.3 failures per 100 person-years for TPD recipients compared to 6.5 failures per 100 person-years for the Toxoplasma-negative group (p 0.008). The crude failure rate ratio was 1.14 with an adjusted hazard rate ratio of 1.04 (95% CI: 0.94, 1.15, p 0.39). In renal Tx recipients, TPD graft recipients have comparable survival to Tx from Toxoplasma-negative recipients. While caution and close monitoring of recipients post-Tx for surveillance of disseminated toxoplasmosis are still warranted, our study suggests that patients can be successfully managed using TPD organs.

BACKGROUND: Pathology reports contain key information about the patients diagnosis as well as important gross and microscopic findings. These information-rich clinical reports offer an invaluable resource for clinical studies, but data extraction and analysis from such unstructured texts is often manual and tedious. While neural information retrieval systems (typically implemented as deep learning methods for natural language processing) are automatic and flexible, they typically require a large domain-specific text corpus for training, making them infeasible for many medical subdomains. Thus, an automated data extraction method for pathology reports that does not require a large training corpus would be of significant value and utility. OBJECTIVE: To develop a language model-based neural information retrieval system that can be trained on small datasets and validate it by training it on renal transplant-pathology reports to extract relevant information for two predefined questions: (1) What kind of rejection does the patient show?; (2) What is the grade of interstitial fibrosis and tubular atrophy (IFTA)? METHODS: Kidney BERT was developed by pre-training Clinical BERT on 3.4K renal transplant pathology reports and 1.5M words. Then, exKidneyBERT was developed by extending Clinical BERTs tokenizer with six technical keywords and repeating the pre-training procedure. This extended the models vocabulary. All three models were fine-tuned with information retrieval heads. RESULTS: The model with extended vocabulary, exKidneyBERT, outperformed Clinical BERT and Kidney BERT in both questions. For rejection, exKidneyBERT achieved an 83.3% overlap ratio for antibody-mediated rejection (ABMR) and 79.2% for T-cell mediated rejection (TCMR). For IFTA, exKidneyBERT had a 95.8% exact match rate. CONCLUSION: ExKidneyBERT is a high-performing model for extracting information from renal pathology reports. Additional pre-training of BERT language models on specialized small domains does not necessarily improve performance. Extending the BERT tokenizers vocabulary library is essential for specialized domains to improve performance, especially when pre-training on small corpora.

BK virus (BKV) is a small DNA virus, a member of the polyomavirus family, that causes an opportunistic infection in immunocompromised patients, especially kidney transplant patients. This virus establishes a lifelong infection in most of the population, and once it reactivates in an immunocompromised state, leads to BKV nephropathy. This review seeks to assess the correlation between severe immunosuppression, evident by low CD4 cell counts in HIV-positive patients, and the reactivation of BKV, causing nephropathy. A literature review was conducted, extracting, and analyzing case reports of HIV-positive patients showing correlations between their degree of immunosuppression, as evidenced by their CD4 counts, and the degree of BKV infectivity, confirmed by kidney biopsy. A total of 12 cases of BKV nephropathy in HIV-infected patients were reviewed. A common finding was the presence of profound immunosuppression, with most patients having CD4 counts ≤50 cells/ mm3. A substantial number also had comorbid malignancies, with some undergoing chemotherapy, potentially increasing the risk of BKV reactivation. In addition to the HIV status and malignancies, other risk factors for BKV reactivation included older age, male gender, diabetes mellitus, Caucasian race, and ureteral stent placement. BKV nephropathy in HIV patients with native kidneys is closely correlated with severe immunosuppression. Although therapeutic strategies exist for post-transplant patients, aside from the treatment of HIV with highly active anti-retroviral therapy (HAART), which potentially helps with clearing BKV by increasing CD4 count, there is no definitive treatment for a native kidney BKV nephropathy in patients with AIDS. The complexity of the cases and severity of comorbidities indicate the need for further research to develop therapeutic strategies tailored to this population.

OBJECTIVE: For the majority of patients with lupus nephritis-related end-stage kidney disease (LN-ESKD), kidney transplant is associated with better outcomes than dialysis. Access to kidney transplant requires an initial referral to a transplant center and medical evaluation prior to waitlisting. The studys objective was to examine access to these early steps in the kidney transplant process among patients with LN-ESKD. METHODS: Adults who began treatment for ESKD in the Southeast, Northeast, New York, or Ohio River Valley U.S. regions from 1/1/2012 to 12/31/2019, followed through 6/30/2021, were identified from the United States Renal Data System. Referral and evaluation start data were collected from 28 of 48 transplant centers across these regions. The exposure was primary cause of ESKD (LN-ESKD vs other-ESKD). The outcomes were referral and evaluation start at a transplant center. Cox models quantified the association between LN-ESKD (vs other-ESKD) and referral and evaluation start. RESULTS: Among 192,318 patients initiating treatment for ESKD, 0.4% had LN-ESKD. Over half (58%) of LN-ESKD patients were referred before study end, and among those referred, 66% started the evaluation. In adjusted analyses, patients with LN-ESKD were referred (HR: 1.09, 95% CI: 0.99, 1.19) and started the transplant evaluation (HR: 1.13, 95% CI: 1.00, 1.28) at a higher rate than patients with other-ESKD. Among referred patients with LN-ESKD, the median time from ESKD start to referral was 2.9 months (IQR:

OBJECTIVE: To examine the relationship between thyroid status and incident kidney dysfunction/chronic kidney disease (CKD) progression. PATIENTS AND METHODS: We examined incident thyroid status, ascertained by serum thyrotropin (TSH) levels measured from January 1, 2007, through December 31, 2018, among 4,152,830 patients from the Optum Labs Data Warehouse, containing deidentified retrospective administrative claims data from a large national health insurance plan and electronic health record data from a nationwide network of provider groups. Associations of thyroid status, categorized as hypothyroidism, euthyroidism, or hyperthyroidism (TSH levels >5.0, 0.5-5.0, and 5.0-10.0, >10.0-20.0, and >20.0 mIU/L, respectively) were associated with increasingly higher risk of the composite end point (reference: TSH level, 0.5 to

Frugivory evolved multiple times in mammals, including bats. However, the cellular and molecular components driving it remain largely unknown. Here, we use integrative single-cell sequencing (scRNA-seq and scATAC-seq) on insectivorous (Eptesicus fuscus; big brown bat) and frugivorous (Artibeus jamaicensis; Jamaican fruit bat) bat kidneys and pancreases and identify key cell population, gene expression and regulatory differences associated with the Jamaican fruit bat that also relate to human disease, particularly diabetes. We find a decrease in loop of Henle and an increase in collecting duct cells, and differentially active genes and regulatory elements involved in fluid and electrolyte balance in the Jamaican fruit bat kidney. The Jamaican fruit bat pancreas shows an increase in endocrine and a decrease in exocrine cells, and differences in genes and regulatory elements involved in insulin regulation. We also find that these frugivorous bats share several molecular characteristics with human diabetes. Combined, our work provides insights from a frugivorous mammal that could be leveraged for therapeutic purposes.

Chronic kidney disease is a leading cause of death and disability globally and impacts individuals of African ancestry (AFR) or with ancestry in the Americas (AMS) who are under-represented in genome-wide association studies (GWASs) of kidney function. To address this bias, we conducted a large meta-analysis of GWASs of estimated glomerular filtration rate (eGFR) in 145,732 AFR and AMS individuals. We identified 41 loci at genome-wide significance (p

CoVID-19 has been linked to long-term consequences on several human body organs, including lung ailments, kidney malfunctions, heart dysrhythmia, alterations in brain nutrient levels, psychological difficulties, abrupt changes in blood pressure, and more. Because of the considerable variety in the impacts on different body parts, researchers find it challenging to create models that can incorporate these effects for treatment recommendations and future disease prevention scenarios. Thus, this article examines some of the most recently proposed models for identifying the impacts of CoVID19 on various human organs. This review examines the underlying theories in terms of clinical nuances, functional advantages, contextual limits, and potential empirical applications. Based on this discussion, researchers will be able to find the best models for detecting particular diseases on specific body parts. It was discovered that hybrid bioinspired models, when paired with deep learning-based classification algorithms, can effectively detect these impacts. This text also parametrically analyses these models in terms of accuracy, precision, and recall, allowing readers to select the best models for their performance-specific use cases. To expand on this discussion, this book evaluates a unique CoVID19 Classification Rank Metric (CCRM) that integrates these factors for thorough model identification. Based on this criteria, researchers will be able to develop appropriate models for clinical scenarios that have high accuracy, low delay, and scalability while costing less. [ABSTRACT FROM AUTHOR]

The protective effect of Fe against Cd‐induced toxicity in the liver and kidney of rats during concurrent administration of both metals was investigated in this study. Fifty female rats (130–150 g) were distributed into five groups of 10 rats each (n = 10): Group I (control), received normal saline solution; Group II (1.2 mg CdCl2/kg b.w.); Group III (1.2 mg CdCl2 + 0.25 mg FeCl2/kg b.w.); Group IV (1.2 mg CdCl2 + 0.75 mg FeCl2/kg b.w.); and Group V (1.2 mg CdCl2 + 1.5 mg FeCl2/kg b.w.). Administration of both tested substances lasted for 47 days. Cd was injected intraperitoneally once a week, while Fe was administered to the Cd‐exposed animals by oral gavage thrice weekly. The animals were killed at the end of the study, their blood was collected, and their liver and kidneys were harvested for biochemical and histological analysis. Following Cd administration, the kidney and liver showed a significant increase in Cd concentration, while Fe concentration in the kidney decreased. However, cotreatment with Fe decreased Cd concentration in the kidney and liver and increased Fe concentration in the kidney but not the liver, and the effect was more pronounced in the higher than lower doses. In the kidney, cotreatment with Fe especially at higher doses inhibited Cd‐induced lipid peroxidation and plasma uric acid concentration. In the liver, lipid peroxidation which Cd did not alter was found to be elevated after cotreatment with the highest dose Fe. Inflammatory cell infiltrations of the central vein and renal tubular and glomeruli injury induced by Cd were not obviated by Fe cotreatment. It seems that both tissues respond differently to the concurrent administration of these metals and that Fe protected the kidney against oxidative injury‐induced by Cd but not histopathological changes in both tissues. [ABSTRACT FROM AUTHOR]

Background: During diabetes, prorenin is highly produced by the renal collecting ducts. The binding of prorenin to (pro)renin receptor (PRR) on the apical plasma membrane triggers intracellular profibrotic genes, including TGF-β and CTGF. However, the underlying mechanisms contributing to the stimulation of these pathways remain unclear. Hence, we hypothesize that the glucose transporter-1 (GLUT1) favors the PRR-dependent stimulation of TGF-β and CTGF in the distal nephron segments during high glucose (HG) conditions. Methods: To test this hypothesis, primary cultured renal inner medullary collecting duct (IMCD) cells were treated with normal glucose (NG, 5 mM) or high glucose (HG, 25 mM) for 48 h in the presence or absence of the GLUT1-specific inhibitor BAY 876 (2 nM). Additionally, IMCD cells were treated with the PRR antagonist PRO20. The expression of TGF-β and CTGF was quantified by immunoblot and qRT-PCR. Results: HG increased GLUT1 mRNA and protein abundance, while BAY 876 inhibited these responses. HG treatment upregulated PRR, but the concomitant treatment with BAY 876 partially prevented this effect. TGF-β and CTGF expressions were augmented in IMCD cells treated with HG. However, PRO20 prevented the increases in TGF-β but not those of CTGF. GLUT1 inhibition partially prevented the increases in reactive oxygen species (ROS) during HG while PRO20 did not. ROS scavenging impaired CTGF upregulation during HG conditions. Additionally, long-term exposure to HG increases lipid peroxidation and reduced cell viability. Conclusions: The data indicate that glucose transportation via GLUT1 is implicated in the PRR-dependent upregulation of TGF-β while CTGF is mediated mainly via a mechanism depending on ROS formation in renal medullary collecting duct cells. [ABSTRACT FROM AUTHOR]

At the onset of egg production, physiological changes governing calcium and phosphorus utilization must occur to meet demands for medullary bone formation and eggshell mineralization. The objective of this study was to identify these changes and determine if they are influenced by dietary supplementation with 1α-hydroxycholecalciferol (AlphaD3™, Iluma Alliance). Commercial laying hens fed either a control or AlphaD3-supplemented diet beginning at 18 weeks of age were sampled at 18 (n = 8) and 31 weeks (n = 8/diet) to evaluate mRNA expression associated with calcium and phosphorus utilization in kidney, shell gland, ileum, and liver, circulating vitamin D3 metabolites, and bone quality parameters in humerus, tibia, and keel bone. Though diet did not heavily influence gene expression at 31 weeks, several significant differences were observed between 18- and 31-week-old hens. Heightened sensitivity to hormones regulating calcium and phosphorus homeostasis was observed at 31 weeks, indicated by increased parathyroid hormone receptor 1, calcium-sensing receptor, calcitonin receptor, and fibroblast growth factor 23 receptors in several tissues. Increased renal expression of 25-hydroxylase and vitamin D binding protein ( DBP ) at 31 weeks suggests kidney participates in local vitamin D3 25-hydroxylation and DBP synthesis after egg production begins. Biologically active 1,25(OH)2D3 was higher at 31 weeks, with correspondingly lower inactive 24,25(OH)2D3. Increased expression of plasma membrane calcium ATPase 1 and calbindin in kidney, shell gland, and ileum suggests these are key facilitators of calcium uptake. Elevated renal inorganic phosphorus transporter 1 and 2 and sodium-dependent phosphate transporter IIa at 31 weeks suggests increased phosphorus excretion following hyperphosphatemia due to bone breakdown for eggshell formation. Diet did influence bone quality parameters. Bone mineral density in both humerus and tibia was higher in AlphaD3-supplemented hens at 31 weeks. Tibial bone mineral content increased between 18 and 31 weeks, with AlphaD3-supplemented hens increasing more than control hens. Moreover, control hens exhibited diminished tibial breaking strength at 31 weeks compared to hens at 18 weeks, while AlphaD3-supplemented hens did not. Together, these results indicate supplementation with AlphaD3 enhanced bone mineralization during the medullary bone formation period and elucidate the adaptive pathways regulating calcium and phosphorus utilization after the onset of lay. [ABSTRACT FROM AUTHOR]

Aim: Studies have shown that renal hypertrophy seen in experimental hyperthyroidism induced by thyroxine (T4) is due to angiotensin (Ang) II. However, other renal effects of Ang II in experimental hyperthyroidism have not been investigated. In addition, Ang 1–7 is believed to be protective against renal injury, but its possible role in thyroxine-induced renal injury is not known. The aim of this study is to elaborate the role of Ang II in thyroxine-induced renal injury and the possible protective role of Ang 1–7. We hypothesize that Ang 1–7 will be as protective against thyroxine-induced renal injury as the use of an ACE inhibitor or an Ang II receptor blocker. Methods: Adult Sprague Dawley rats were used in this study and were divided into 5 groups: (1) Control (treated with vehicle), (2) Treated with thyroxine (T4, 100 µg/kg), (3) Treated with T4 and Ang 1–7 (500 µg/kg), (4) Treated with T4 and captopril (20 mg/kg), and (5) Treated with T4 and losartan (10 mg/kg). Parameters tested after fourteen days of treatment were creatinine clearance, protein excretion rate, glomerular volume, renal ACE1 and ACE2 protein expression. Data were compared using One-way-ANOVA followed by Tukey's HSD post hoc test. Results: Thyroxine caused glomerular hypertrophy and proteinuria but had no effect on glomerular filtration rate (GFR). Glomerular hypertrophy was prevented by losartan and captopril, but not by Ang 1–7. Captopril and losartan had no effect on GFR; however, Ang 1–7 caused an increase in GFR in T4-treated rats. The increase in protein excretion rate was prevented by losartan but not by captopril or Ang 1–7. Renal expression of ACE1 protein was not altered in any of the treatment groups except in captopril treated rats were ACE1 expression was increased. Renal ACE2 protein expression was only increased in T4-losartan-treated rats and not affected by any of the other treatments. Conclusion: We conclude that losartan was more protective than captopril against thyroxine-induced renal changes while Ang 1–7 offered no protection. [ABSTRACT FROM AUTHOR]

The heart and kidney have a high energy requirement, but relatively little is known about their utilization of ketones as a potential energy source. We assessed the metabolism of the ketone tracer, carbon-11 acetoacetate (11C-AcAc), by the left and right ventricles of the heart and by the kidney using positron emission tomography (PET) in n = 10 healthy adults under four experimental conditions: a 4-h fast (fasted) ± a single 12 g oral dose of D-beta-hydroxybutyrate (D-BHB), and a single complete, liquid replacement meal (hereafter referred to as the "fed" condition) ± a single 12 g oral dose of D-BHB. Under these experimental conditions, the kinetics of 11C-AcAc metabolism fitted a two-compartment model in the heart and a three-compartment model in the kidney. Plasma ketones were about 10-fold higher with the oral dose of D-BHB. During the four conditions, tracer kinetics were broadly similar in the myocardium and kidney cortex. 11C-AcAc metabolism by the kidney pelvis was similar in three of the four study conditions but, later, peaked significantly higher than that in the cortex; the exception was that the tracer uptake was significantly lower in the fed condition without D-BHB. 11C-AcAc uptake was significantly inversely correlated with age in the kidney cortex, and its oxidative metabolism was significantly positively correlated with age in the left ventricle. D-BHB blunted the insulin, gastric inhibitory peptide, and C-peptide response to the meal. This PET methodology and these acute metabolic perturbations would be suitable for future studies assessing cardiorenal ketone metabolism in conditions in which heart and kidney functions are experimentally modified or compromised by disease. [ABSTRACT FROM AUTHOR]

Objective: The objective of this case series is to describe the indications, methodology, and short-term outcomes of three cats with severe azotemia managed with pleural dialysis. Case summary: Three cats were presented separately to the emergency room (ER) on referral for severe azotemia of varying etiologies. Despite aggressive medical and/or surgical management, none of the cats showed improvement in their blood urea nitrogen (BUN) or creatinine values. Renal replacement therapy was recommended, but for varying reasons, the patients were unable to undergo a traditional extracorporeal method, such as intermittent hemodialysis (IDH). Instead, pleural dialysis was performed, and all three cats showed improvement in their renal values during and after their treatment. No significant complications were documented as a result of pleural dialysis. Two of the three cats were discharged from the hospital and the third cat was humanely euthanized due to poor prognosis. New or unique information provided: Pleural dialysis is a novel therapeutic procedure that is not documented in veterinary or human literature. This method of renal replacement therapy was well-tolerated and had no reported complications. Careful case selection and risk-benefit analysis should be considered before attempting this procedure. Further studies are necessary to further define the utility of this therapeutic intervention, evaluate the incidence of complications, and determine long term outcomes following the procedure. [ABSTRACT FROM AUTHOR]

The populations in countries that have the highest number of individuals with chronic kidney disease (CKD) are the low and middle-income countries which are ethnically diverse. The regional and international data highlighting the need for continuous monitoring of renal function warrants that such countries use equations that give the best estimates of glomerular filtration rate for their settings. While chronic disease conditions such as diabetes and hypertension are the main conditions associated with CKD in adult populations and complicated urinary tract infections and congenital anomalies in the kidney and the urinary tract in the young, the management of patients with CKD at any age can be impacted by medical and non-biological factors. This communication seeks to posit issues that may be germane to consider when using the CKD-EPI 2021 equations in the adult and young adult populations. These equations, by excluding the race factor, have put the spotlight on the relevance of the cultural and economic context concerning the management of renal patents. The social determinants of health, how an individual defines their gender, the cultural acceptance of such or the lack thereof, factors influencing the choice of the test, communication, and technology among others may all affect renal care. These issues together may have a greater impact on renal patient care and outcome than racial disparity. While the racial divide may have been a driver for differential treatment in developed nations with different ethnic groups they may be less so when compared with more homogenous populations. [ABSTRACT FROM AUTHOR]

Background: Hypertension is a major cause of mortality worldwide. The kidneys play a crucial role in regulating blood pressure and fluid volume. The relationship between the kidneys and hypertension is complex, involving factors such as the renin–angiotensin system, oxidative stress, and inflammation. This study aims to assess the levels of inflammatory markers, oxidative stress, and metabolic factors in the kidneys, focusing on their potential role in early renal damage and their association with the development of hypertension. Methods: This study was designed to compare the levels of selected inflammatory markers, e.g., interleukins, tumor necrosis factor-α (TNF-α), transforming growth factor, and serine/threonine-protein (mTOR); oxidative stress markers such as malondialdehyde, sulfhydryl group, and glucose (GLC); and metabolic markers among other enzymes, such as alanine transaminase (ALT), aspartate transaminase (AST), hexokinase II (HK-II), and hypoxia-inducible factor-1α (HIF-1α), as well as creatinine in the kidneys of spontaneously hypertensive rats (SHR/NCrl, n = 12) and Wistar Kyoto rats (WKY/NCrl, n = 12). Both juvenile (5 weeks old) and maturing (10 weeks old) specimens were examined using spectrophotometric methods, e.g., ELISA. Results: Juvenile SHRs exhibited reduced renal levels of all studied cytokines and chemokines, with lower oxidative stress and deficits in the mTOR and HK-II levels compared to the age-matched WKYs. Maturing SHRs showed increased renal levels of interleukin-1β (IL-1β), IL-6, IL-18, and TNF-α, alongside elevated carbonyl stress and increased HIF-1α as opposed to their control peers. The levels of all other studied markers were normalized in these animals, except for ALT (increased), ALP, and GLC (both reduced). Conclusions: This study underscores the significant impact of inflammatory, oxidative stress, and metabolic marker changes on renal function. Juvenile SHRs display lower marker levels, indicating an immature immune response and potential subclinical kidney damage that may contribute to hypertension development. In contrast, mature SHRs exhibit chronic inflammation, oxidative dysregulation, and metabolic disturbances, suggesting cellular damage. These changes create a feedback loop that worsens kidney function and accelerates hypertension progression, highlighting the kidneys' crucial role in both initiating and exacerbating this condition. [ABSTRACT FROM AUTHOR]

Multiciliated cells (MCCs) serve many important functions, including fluid propulsion and chemo- and mechanosensing. Diseases ranging from rare conditions to the recent COVID-19 global health pandemic have been linked to MCC defects. In recent years, the zebrafish has emerged as a model to investigate the biology of MCCs. Here, we review the major events in MCC formation including centriole biogenesis and basal body docking. Then, we discuss studies on the role of MCCs in diseases of the brain, respiratory, kidney and reproductive systems, as well as recent findings about the link between MCCs and SARS-CoV-2. Next, we explore why the zebrafish is a useful model to study MCCs and provide a comprehensive overview of previous studies of genetic components essential for MCC development and motility across three major tissues in the zebrafish: the pronephros, brain ependymal cells and nasal placode. Taken together, here we provide a cohesive summary of MCC research using the zebrafish and its future potential for expanding our understanding of MCC-related disease states. [ABSTRACT FROM AUTHOR]

• Renal proximal tubular epithelial cells (RPTECs) are the main targets of drug-induced kidney injury; however, no useful evaluation system is currently available. • We evaluated kidney injuries induced by 32 nephrotoxic drugs for up to 28 days using three-dimensional cultured RPTECs (3D-RPTECs) with enhanced expression of drug transporters. • The predictive performance of 3D-RPTECs for drug-induced kidney injury was better than conventional 2D-cultured RPTECs and HK-2 cells. • 3D-RPTECs are useful for in vitro evaluation of RPTEC injury by measuring intracellular ATP levels. Drug-induced kidney injury (DIKI) is the major cause of acute kidney injury (AKI). Renal proximal tubular epithelial cells (RPTECs) are the primary target sites of DIKI and express transporters involved in renal drug disposition. In the present study, we focused on three-dimensionally cultured human RPTECs (3D-RPTECs) with elevated expression of drug transporters to investigate their utility in DIKI evaluation. Intracellular ATP levels in 3D-RPTECs are reduced by tenofovir and cisplatin that are substrates of an organic anion transporter 1 and an organic cation transporter 2, respectively. In addition, 3D-RPTECs were exposed to 17 and 15 drugs that are positive and negative to RPTEC toxicity, respectively, for up to 28 d. The 20 % decreasing concentration of drugs for ATP amount (EC 20) was obtained, and the ratio of EC 20 values and clinical maximum concentration (C max) ≤100 were used as cut-off value to evaluate potential of DIKI. The sensitivities of 3D-RPTECs were 82.4 % and 88.2 % after 7 d and 28 d of drug exposure, respectively, and the specificities were 100 % and 93.3 %, respectively. The predictive performance of 3D-RPTECs was higher than that of two-dimensional cultured RPTECs and the kidney cell line HK-2. In conclusion, 3D-RPTECs are useful for in vitro evaluation of RPTEC injury by measuring intracellular ATP levels. [ABSTRACT FROM AUTHOR]

Nous proposons une sélection non exhaustive des principaux essais cliniques présentés courant 2023–2024 ayant retenu notre attention dans le cadre de l'oncologie-radiothérapie appliquée aux cancers urologiques et incluant la prise en charge du cancer de la prostate (radiothérapie du cancer localisé, radiothérapie après prostatectomie, réirradiation, récidive biochimique après traitement local, radiothérapie du cancer métastatique), du cancer de vessie infiltrant le muscle et du primitif rénal. Herein, we provide a non-exhaustive selection of the main clinical trials presented in 2023–2024 related to radiation-oncology used in the treatment of urological cancers including prostate cancer (radiotherapy of localized prostate cancer, post-prostatectomy irradiation, reirradiation, biochemical recurrence following local treatment, radiotherapy for metastatic cancer), muscle invasive bladder cancer and primary kidney cancer. [ABSTRACT FROM AUTHOR]

Contrast-enhanced ultrasound (CEUS) is an advanced ultrasound (US) technique utilizing ultrasound contrast agents (UCAs) to provide detailed visualization of anatomic and vascular architecture, including the depiction of microcirculation. CEUS has been well-established in echocardiography and imaging of focal hepatic lesions and recent studies have also shown the utility of CEUS in non-hepatic applications like the urinary system. The updated guidelines by the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) from 2018 describe the use of CEUS for non-hepatic applications. CEUS' excellent safety profile and spatial resolution make it a superior modality to conventional US and is often comparable and even superior to CECT in some instances. In comparison to other cross-sectional imaging modalities such as CECT or MRI, CEUS offers a safe (by virtue of non-nephrotoxic US contrast agents), accurate, cost-efficient, readily available, and a quick means of evaluation of multiple pathologies of the urinary system. CEUS also has the potential to reduce the overall economic burden on patients requiring long-term follow-up due to its low cost as compared to CT or MRI techniques. This comprehensive review focuses on the applications of CEUS in evaluating the urinary system from the kidneys to the urinary bladder. CEUS can be utilized in the kidney to evaluate complex cystic lesions, indeterminate lesions, pseudotumors (vs solid renal tumors), renal infections, and renal ischemic disorders. Additionally, CEUS has also been utilized in evaluating renal transplants. In the urinary bladder, CEUS is extremely useful in differentiating a bladder hematoma and bladder cancer when conventional US techniques show equivocal results. Quantitative parameters of time-intensity curves (TICs) of CEUS examinations have also been studied to stage and grade bladder cancers. Although promising, further research is needed to definitively stage bladder cancers and classify them as muscle-invasive or non-muscle invasive using quantitative CEUS to guide appropriate intervention. CEUS has been very effective in the classification of cystic renal lesions, however, further research is needed in differentiating benign from malignant renal masses. [ABSTRACT FROM AUTHOR]

Background: Long‐term renal function and survival after kidney transplantation rely on appropriate immunosuppressive treatment to prevent the risk of rejection. New biomarkers are needed to accurately assess the degree of immunosuppression in renal transplant recipients in order to avoid organ rejection and the development of opportunistic infections. Highly prevalent in humans, torque teno virus (TTV), which belongs to the family Anelloviridae, is a small, nonenveloped, single‐stranded DNA virus which has not been linked with any specific human illness, but which constitutes a major component of the human virome. Host antiviral responses allow TTV levels to be controlled; however, viral persistence remains, explaining the high prevalence in human populations, including healthy individuals. Important confounders of TTV load include time since transplantation, age, gender, obesity, and smoking status. Aims: TTV‐based guidance of immunosuppressive drug dosing could help with risk stratification, reducing the risk of infection, graft rejection and oncologic disease on an individual level, enabling long‐term patient and graft survival. Methods: Original studies were accessed by a systematic search from electronic databases including PubMed, ScienceDirect and Wiley Online Library. Results: The presented data mainly derive from adult transplant recipients showing an association between TTV plasma levels and the immune status of the host: High‐TTV load and high immunosuppression are associated with a risk of infection, and low‐TTV load and low immunosuppression indicate a risk of rejection. However, there is minimal information on pediatric transplant recipients with further research required in this cohort. To date, it has been demonstrated that longer posttransplant times are significantly associated with lower TTV levels in children with renal transplant. Meanwhile, an association between lower TTV loads and increased risk of graft reject during the first year of transplantation was also reported. More recently, Eibensteiner et al. revealed a robust, independent association between TTV plasma load and the onset of Cytomegalovirus and BK virus infections. Conclusion: Data from randomized controlled trials are still missing, even in adults, but a multicenter randomized controlled trial for TTV‐guided immunosuppression in adult kidney recipients (TTVguideIT) began in 2022. There is, therefore, great promise for TTV levels to be used as a biomarker that could potentially improve both graft and patient survival in transplantation. [ABSTRACT FROM AUTHOR]