High-risk adverse drug reactions: consideration of limited dialysis therapy for toxic epidermal necrolysis (TEN).

Toxic epidermal necrolysis (TEN) is a rare but often lethal drug reaction involving the skin. Treatment is often centered around suppurative care, and the mortality rate remains unacceptably high, although the clinical and epidemiological features of TEN have been well documented for decades. Recent studies have placed an emphasis on certain medications in the pathophysiology of severe TEN, and our colleagues previously reported several cases of clinical improvement in TEN patients following hemodialysis. Here, we discuss the major considerations for initiating dialysis in TEN patients. By doing so, we hope to encourage others to explore this potential avenue for treating TEN, one of the most serious medical emergencies in the field of dermatology.

Examining the safety and effectiveness of a 4-week supervised exercise intervention in the treatment of frailty in patients with chronic kidney disease.

Background: The optimal duration of antifrailty interventions and how best to deliver them to patients with chronic kidney disease (CKD) is unknown. The aim of this study was to examine the safety, feasibility and preliminary efficacy of a 4-week supervised exercise intervention on frailty in patients with CKD. Methods: We conducted a prospective feasibility study involving patients with ≥stage 3 CKD (1 patient with stage 3 CKD, 7 patients with stage 4 CKD and 17 patients with stage 5 CKD) who were either frail or prefrail according to the physical frailty phenotype and/or had a Short Physical Performance Battery (SPPB) score ≤10. The exercise intervention consisted of two supervised outpatient sessions per week for 4 weeks (eight total sessions). Frailty and other study measures were assessed at baseline and after 4 weeks of exercise. Results: Of the 34 participants who completed the baseline assessment and were included in the analyses, 25 (73.5%) completed the 4-week assessment. Overall, 64.0% of patients were on dialysis and 64.0% had diabetes mellitus. After 4 weeks of exercise, frailty prevalence, total SPPB scores and energy/fatigue scores improved. No adverse study-related outcomes were reported. Conclusions: The 4 weeks of supervised exercise was safe, was associated with an excellent completion rate and improved frailty parameters in CKD patients with CKD. This study provides important preliminary data for a future larger prospective randomized study. Clinical Trialgov: registration: NCT03535584.

Kidney Outcomes Following Utilization of Molecular Adsorbent Recirculating System.

Introduction: Molecular adsorbent recirculating system (MARS) is an extracorporeal system combining conventional veno-venous hemodiafiltration and adsorption to provide rescue support in fulminant hepatic failure. Acute kidney injury (AKI) is common in patients with hepatic failure warranting continuous kidney replacement therapy (CKRT). Our primary aim was to characterize a cohort of patients who received MARS therapy and examine kidney events given the current paucity of available data. Methods: Patients initiating MARS in a tertiary care setting from January 2014 through December 2020 were assessed for treatment indications, transplantation, CKRT, kidney recovery, and death. Data was collected using the REDCAP software. Results: A total of 49 patients (67% female; 75% White) received MARS therapy with 29 patients (59%) requiring concomitant CKRT. Hepatic encephalopathy (HE) was the most common indication for MARS initiation (55%). In-hospital mortality was 41% (12/29) among patients who received CKRT versus 10% (2/20) among those not requiring CKRT (relative risk [RR] 4.15, 95% confidence interval [CI] 1.04 to 16.52, P = 0.044); this persisted following adjustment for prespecified patient characteristics (all RR ≥ 3.76, all P ≤ 0.060). One-year mortality post-MARS initiation was high overall but highest among the CKRT group (59% [17/29] vs. 25% [5/20] unadjusted RR 2.92, 95% CI 1.08 to 7.94, P = 0.035). Liver transplant after MARS occurred in 41% of patients (20/49). After CKRT, 39% of patients (9/29) recovered kidney function prior to hospital discharge. Conclusions: Patients requiring MARS frequently have AKI warranting the use of concomitant CKRT, which is associated with a high rate of in-hospital and 1-year mortality.

Cellular Senescence and Frailty in Transplantation.

Purpose of review: To summarizes the literature on cellular senescence and frailty in solid-organ transplantation and highlight the emerging role of senotherapeutics as a treatment for cellular senescence. Recent findings: Solid-organ transplant patients are aging. Many factors contribute to aging acceleration in this population, including cellular senescence. Senescent cells accumulate in tissues and secrete proinflammatory and profibrotic proteins which result in tissue damage. Cellular senescence contributes to age-related diseases and frailty. Our understanding of the role cellular senescence plays in transplant-specific complications such as allograft immunogenicity and infections is expanding. Promising treatments, including senolytics, senomorphics, cell-based regenerative therapies, and behavioral interventions, may reduce cellular senescence abundance and frailty in patients with solid-organ transplants. Summary: Cellular senescence and frailty contribute to adverse outcomes in solid-organ transplantation. Continued pursuit of understanding the role cellular senescence plays in transplantation may lead to improved senotherapeutic approaches and better graft and patient outcomes.

Changes in Kidney Function After Diagnosis of Advanced Heart Failure.

BACKGROUND: Kidney function and its association with outcomes in patients with advanced heart failure (HF) has not been well-defined. METHODS AND RESULTS: We conducted a retrospective cohort study comprising all adult residents of Olmsted County, Minnesota, with HF who developed advanced HF from 2007 to 2017. Patients were grouped by estimated glomerular filtration rate (eGFR) at advanced HF diagnosis using the 2021 Chronic Kidney Disease Epidemiology Collaboration equation. A linear mixed effects model was fitted to assess the relationship between development of advanced HF and longitudinal eGFR trajectory. A total of 936 patients with advanced HF (mean age 77 years, 55% male, 93.7% White) were included. Twenty-two percent of these patients had an eGFR of <30 at advanced HF diagnosis, 22% had an eGFR of 30-44, 23% had an eGFR of 45-59, and 32% had an eGFR of ≥60 mL/min/1.73 m2. The eGFR decreased faster after advanced HF (7.6% vs 10.9% annual decline before vs after advanced HF), with greater decreases after advanced HF in those with diabetes and preserved ejection fraction. An eGFR of <30 mL/min/1.73 m2 was associated with worse survival after advanced HF compared with an eGFR of ≥60 mL/min/1.73 m2 (adjusted hazard ratio 1.30, 95% confidence interval 1.07-1.57). CONCLUSIONS: eGFR deteriorated faster after patients developed advanced HF. An eGFR of <30 mL/min/1.73 m2 at advanced HF diagnosis was associated with higher mortality.

Renal MRI: From Nephron to NMR Signal.

Renal diseases pose a significant socio-economic burden on healthcare systems. The development of better diagnostics and prognostics is well-recognized as a key strategy to resolve these challenges. Central to these developments are MRI biomarkers, due to their potential for monitoring of early pathophysiological changes, renal disease progression or treatment effects. The surge in renal MRI involves major cross-domain initiatives, large clinical studies, and educational programs. In parallel with these translational efforts, the need for greater (patho)physiological specificity remains, to enable engagement with clinical nephrologists and increase the associated health impact. The ISMRM 2022 Member Initiated Symposium (MIS) on renal MRI spotlighted this issue with the goal of inspiring more solutions from the ISMRM community. This work is a summary of the MIS presentations devoted to: 1) educating imaging scientists and clinicians on renal (patho)physiology and demands from clinical nephrologists, 2) elucidating the connection of MRI parameters with renal physiology, 3) presenting the current state of leading MR surrogates in assessing renal structure and functions as well as their next generation of innovation, and 4) describing the potential of these imaging markers for providing clinically meaningful renal characterization to guide or supplement clinical decision making. We hope to continue momentum of recent years and introduce new entrants to the development process, connecting (patho)physiology with (bio)physics, and conceiving new clinical applications. We envision this process to benefit from cross-disciplinary collaboration and analogous efforts in other body organs, but also to maximally leverage the unique opportunities of renal physiology. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 2.

Diabetic kidney disease induces transcriptome alterations associated with angiogenesis activity in human mesenchymal stromal cells.

BACKGROUND: Therapeutic interventions that optimize angiogenic activities may reduce rates of end-stage kidney disease, critical limb ischemia, and lower extremity amputations in individuals with diabetic kidney disease (DKD). Infusion of autologous mesenchymal stromal cells (MSC) is a promising novel therapy to rejuvenate vascular integrity. However, DKD-related factors, including hyperglycemia and uremia, might alter MSC angiogenic repair capacity in an autologous treatment approach. METHODS: To explore the angiogenic activity of MSC in DKD, the transcriptome of adipose tissue-derived MSC obtained from DKD subjects was compared to age-matched controls without diabetes or kidney impairment. Next-generation RNA sequencing (RNA-seq) was performed on MSC (DKD n = 29; Controls n = 9) to identify differentially expressed (DE; adjusted p < 0.05, |log2fold change|> 1) messenger RNA (mRNA) and microRNA (miRNA) involved in angiogenesis (GeneCards). Paracrine-mediated angiogenic repair capacity of MSC conditioned medium (MSCcm) was assessed in vitro using human umbilical vein endothelial cells incubated in high glucose and indoxyl sulfate for a hyperglycemic, uremic state. RESULTS: RNA-seq analyses revealed 133 DE mRNAs (77 upregulated and 56 down-regulated) and 208 DE miRNAs (119 up- and 89 down-regulated) in DKD-MSC versus Control-MSC. Interestingly, miRNA let-7a-5p, which regulates angiogenesis and participates in DKD pathogenesis, interacted with 5 angiogenesis-associated mRNAs (transgelin/TAGLN, thrombospondin 1/THBS1, lysyl oxidase-like 4/LOXL4, collagen 4A1/COL4A1 and collagen 8A1/COL8A1). DKD-MSCcm incubation with injured endothelial cells improved tube formation capacity, enhanced migration, reduced adhesion molecules E-selectin, vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 mRNA expression in endothelial cells. Moreover, angiogenic repair effects did not differ between treatment groups (DKD-MSCcm vs. Control-MSCcm). CONCLUSIONS: MSC from individuals with DKD show angiogenic transcriptome alterations compared to age-matched controls. However, angiogenic repair potential may be preserved, supporting autologous MSC interventions to treat conditions requiring enhanced angiogenic activities such as DKD, diabetic foot ulcers, and critical limb ischemia.

Measuring copeptin, a surrogate for vasopressin in patients with hypertension - Can it identify those who are volume Responsive?

BACKGROUND: Among hypertensive patients, plasma renin activity is lower and the response to diuretic monotherapy greater in volume responsive hypertensive patients. We hypothesized that hormones influencing extracellular volume such as vasopressin / antidiuretic hormone (ADH) might permit the development of a simple test to identify those with volume-related hypertension. Such a test might be of particular benefit to the Black population which is purported to have a higher incidence of volume-related and responsive hypertension. Thus, using copeptin, a surrogate marker for ADH, we studied if there were differences in this hormone between those with and without volume responsive hypertension. METHODS: Serum copeptin was measured in biobanked blood samples from the Genetic Epidemiology of Responses to Antihypertensives (GERA) I study and analyzed with other variables from the study dataset. RESULTS: There was no relationship between PRA and copeptin values nor could the response in blood pressure be predicted by the copeptin values. However, baseline copeptin levels were higher in Black than in White subjects (7.5 pmol/L vs 5.4 pmol/L, P < 0.001) while plasma sodium and calculated plasma osmolality were slightly lower in keeping with the concept that Black subjects have more volume-related hypertension. In addition, after hydrochlorothiazide (HCTZ), copeptin was significantly lower in Black (6.2 pmol/L, P = 0.004) but unchanged in White subjects (5.2 pmol/L, P = 0.901) and there were also changes in sodium. CONCLUSION: The current study suggests differences in ADH physiology between hypertensive Black and White patients. However, the use of copeptin to identify volume responsive patients could not be confirmed.

Cardiovascular Outcomes in Kidney Transplant Recipients With ADPKD.

Introduction: Cardiovascular disease leads to high morbidity and mortality in patients with kidney failure. Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a systemic disease with various cardiac abnormalities. Details on the cardiovascular profile of patients with ADPKD who are undergoing kidney transplantation (KT) and its progression are limited. Methods: Echocardiographic data within 2 years before KT (1993-2020), and major adverse cardiovascular events (MACEs) after transplantation were retrieved. The primary outcome is to assess cardiovascular abnormalities on echocardiography at the time of transplantation in ADPKD as compared with patients without ADPKD matched by sex (male, 59.4%) and age at transplantation (57.2 ± 8.8 years). Results: Compared with diabetic nephropathy (DN, n = 271) and nondiabetic, patients without ADPKD (NDNA) (n = 271) at the time of KT, patients with ADPKD (n = 271) had lower rates of left ventricular hypertrophy (LVH) (39.4% vs. 66.4% vs. 48.6%), mitral (2.7% vs. 6.3% vs. 7.45) and tricuspid regurgitations (1.8% vs. 6.6% vs. 7.2%). Patients with ADPKD had less diastolic (25.3%) and systolic (5.6%) dysfunction at time of transplantation. Patients with ADPKD had the most favorable post-transplantation survival (median 18.7 years vs. 12.0 for diabetic nephropathy [DN] and 13.8 years for nondiabetic non-ADPKD [NDNA]; P < 0.01) and the most favorable MACE-free survival rate (hazard ratio = 0.51, P < 0.001). Patients with ADPKD had worsening of their valvular function and an increase in the sinus of Valsalva diameter post-transplantation (38.2 vs. 39.9 mm, P < 0.01). Conclusion: ADPKD transplant recipients have the most favorable cardiac profile pretransplantation with better patient survival and MACE-free survival rates but worsening valvular function and increasing sinus of Valsalva diameter, as compared with patients with other kidney diseases.

A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues.

Although cellular senescence drives multiple age-related co-morbidities through the senescence-associated secretory phenotype, in vivo senescent cell identification remains challenging. Here, we generate a gene set (SenMayo) and validate its enrichment in bone biopsies from two aged human cohorts. We further demonstrate reductions in SenMayo in bone following genetic clearance of senescent cells in mice and in adipose tissue from humans following pharmacological senescent cell clearance. We next use SenMayo to identify senescent hematopoietic or mesenchymal cells at the single cell level from human and murine bone marrow/bone scRNA-seq data. Thus, SenMayo identifies senescent cells across tissues and species with high fidelity. Using this senescence panel, we are able to characterize senescent cells at the single cell level and identify key intercellular signaling pathways. SenMayo also represents a potentially clinically applicable panel for monitoring senescent cell burden with aging and other conditions as well as in studies of senolytic drugs.

Cellular senescence: the good, the bad and the unknown.

Cellular senescence is a ubiquitous process with roles in tissue remodelling, including wound repair and embryogenesis. However, prolonged senescence can be maladaptive, leading to cancer development and age-related diseases. Cellular senescence involves cell-cycle arrest and the release of inflammatory cytokines with autocrine, paracrine and endocrine activities. Senescent cells also exhibit morphological alterations, including flattened cell bodies, vacuolization and granularity in the cytoplasm and abnormal organelles. Several biomarkers of cellular senescence have been identified, including SA-ßgal, p16 and p21; however, few markers have high sensitivity and specificity. In addition to driving ageing, senescence of immune and parenchymal cells contributes to the development of a variety of diseases and metabolic disorders. In the kidney, senescence might have beneficial roles during development and recovery from injury, but can also contribute to the progression of acute kidney injury and chronic kidney disease. Therapies that target senescence, including senolytic and senomorphic drugs, stem cell therapies and other interventions, have been shown to extend lifespan and reduce tissue injury in various animal models. Early clinical trials confirm that senotherapeutic approaches could be beneficial in human disease. However, larger clinical trials are needed to translate these approaches to patient care.

Telehealth versus face-to-face visits: A comprehensive outpatient perspective-based cohort study of patients with kidney disease.

BACKGROUND: Telenephrology has become an important health care delivery modality during the COVID-19 pandemic. However, little is known about patient perspectives on the quality of care provided via telenephrology compared to face-to-face visits. We aimed to use objective data to study patients' perspectives on outpatient nephrology care received via telenephrology (phone and video) versus face-to-face visits. METHODS: We retrospectively studied adults who received care in the outpatient Nephrology & Hypertension division at Mayo Clinic, Rochester, from March to July 2020. We used a standardized survey methodology to evaluate patient satisfaction. The primary outcome was the percent of patients who responded with a score of good (4) or very good (5) on a 5-point Likert scale on survey questions that asked their perspectives on access to their nephrologist, relationship with care provider, their opinions on the telenephrology technology, and their overall assessment of the care received. Wilcoxon rank sum tests and chi-square tests were used as appropriate to compare telenephrology versus face-to-face visits. RESULTS: 3,486 of the patient encounters were face-to-face, 808 phone and 317 video visits. 443 patients responded to satisfaction surveys, and 21% of these had telenephrology encounters. Established patients made up 79.6% of telenephrology visits and 60.9% of face-to-face visits. There was no significant difference in patient perceived access to health care, satisfaction with their care provider, or overall quality of care between patients cared for via telenephrology versus face-to-face. Patient satisfaction was also equally high. CONCLUSIONS: Patient satisfaction was equally high amongst those patients seen face-to-face or via telenephrology.

Dialysis Initiation in Patients With Chronic Coronary Disease and Advanced Chronic Kidney Disease in ISCHEMIA-CKD.

Background In participants with concomitant chronic coronary disease and advanced chronic kidney disease (CKD), the effect of treatment strategies on the timing of dialysis initiation is not well characterized. Methods and Results In ISCHEMIA-CKD (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches-Chronic Kidney Disease), 777 participants with advanced CKD and moderate or severe ischemia were randomized to either an initial invasive or conservative management strategy. Herein, we compare the proportion of randomized participants with non-dialysis-requiring CKD at baseline (n=362) who initiated dialysis and compare the time to dialysis initiation between invasive versus conservative management arms. Using multivariable Cox regression analysis, we also sought to identify the effect of invasive versus conservative chronic coronary disease management strategies on dialysis initiation. At a median follow-up of 23 months (25th-75th interquartile range, 14-32 months), dialysis was initiated in 18.9% of participants (36/190) in the invasive strategy and 16.9% of participants (29/172) in the conservative strategy (P=0.22). The median time to dialysis initiation was 6.0 months (interquartile range, 3.0-16.0 months) in the invasive group and 18.2 months (interquartile range, 12.2-25.0 months) in the conservative group (P=0.004), with no difference in procedural acute kidney injury rates between the groups (7.8% versus 5.4%; P=0.26). Baseline clinical factors associated with earlier dialysis initiation were lower baseline estimated glomerular filtration rate (hazard ratio [HR] associated with 5-unit decrease, 2.08 [95% CI, 1.72-2.56]; P<0.001), diabetes (HR, 2.30 [95% CI, 1.28-4.13]; P=0.005), hypertension (HR, 7.97 [95% CI, 1.09-58.21]; P=0.041), and Hispanic ethnicity (HR, 2.34 [95% CI, 1.22-4.47]; P=0.010). Conclusions In participants with non-dialysis-requiring CKD in ISCHEMIA-CKD, randomization to an invasive chronic coronary disease management strategy (relative to a conservative chronic coronary disease management strategy) is associated with an accelerated time to initiation of maintenance dialysis for kidney failure. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01985360.

Older Patients with Advanced Chronic Kidney Disease and Their Perspectives on Prognostic Information: a Qualitative Study.

BACKGROUND: Prognostic information is key to shared decision-making, particularly in life-limiting illness like advanced chronic kidney disease (CKD). OBJECTIVE: To understand the prognostic information preferences expressed by older patients with CKD. DESIGN AND PARTICIPANTS: Qualitative study of 28 consecutively enrolled patients over 65 years of age with non-dialysis dependent CKD stages 3b-5, receiving care in a multi-disciplinary CKD clinic. APPROACH: Semi-structured telephone or in-person interviews to explore patients' preference for and perceived value of individualized prognostic information. Interviews were analyzed using inductive content analysis. KEY RESULTS: We completed interviews with 28 patients (77.7 ± SD 6.8 years, 69% men). Patients varied in their preference for prognostic information and more were interested in their risk of progression to end-stage kidney disease (ESKD) than in life expectancy. Many conflated ESKD risk with risk of death, perceiving a binary choice between dialysis and quick decline and death. Patients expressed that prognostic information would allow them to plan, take care of important business, and think about their treatment options. Patients were accepting of prognostic uncertainty and imagined leveraging it to nurture hope or motivate them to better manage risk factors. They endorsed the desire to receive prognosis of life expectancy even though it may be hard to accept or difficult to talk about but worried it could create helplessness for other patients in their situation. CONCLUSION: Most, but not all, patients were interested in prognostic information and could see its value in motivating behavior change and allowing planning. Some patients expressed concern that information on life expectancy might cause depression and hopelessness. Therefore, prognostic information is most appropriate as part of a clinical conversation that fosters shared decision-making and helps patients consider treatment risks, benefits, and burdens in context of their lives.

Frailty in CKD and Transplantation.

The population is aging. Although older adults have higher rates of comorbidities and adverse health events, they represent a heterogeneous group with different health trajectories. Frailty, a clinical syndrome of decreased physiological reserve and increased susceptibility to illness and death, has emerged as a potential risk stratification tool in older patients with chronic kidney disease (CKD). Frailty is commonly observed in patients with CKD and associated with numerous adverse outcomes, including falls, decreased quality of life, hospitalizations, and death. Multiple pathologic factors contribute to the development of frailty in patients with CKD, including biological mechanisms of aging and physiological dysregulation. Current interventions to reduce frailty are promising, but additional investigations are needed to determine whether optimizing frailty measures improves renal and overall health outcomes. This review of frailty in CKD examines frailty definitions, the impact of frailty on health outcomes across the CKD spectrum, mechanisms of frailty, and antifrailty interventions (e.g., exercise or senescent cell clearance) tested in CKD patients. In addition, existing knowledge gaps, limitations of current frailty definitions in CKD, and challenges surrounding effective antifrailty strategies in CKD are considered.

Progress toward the Clinical Application of Mesenchymal Stromal Cells and Other Disease-Modulating Regenerative Therapies: Examples from the Field of Nephrology.

Drawing from basic knowledge of stem-cell biology, embryonic development, wound healing, and aging, regenerative medicine seeks to develop therapeutic strategies that complement or replace conventional treatments by actively repairing diseased tissue or generating new organs and tissues. Among the various clinical-translational strategies within the field of regenerative medicine, several can be broadly described as promoting disease resolution indirectly through local or systemic interactions with a patient's cells, without permanently integrating or directly forming new primary tissue. In this review, we focus on such therapies, which we term disease-modulating regenerative therapies (DMRT), and on the extent to which they have been translated into the clinical arena in four distinct areas of nephrology: renovascular disease (RVD), sepsis-associated AKI (SA-AKI), diabetic kidney disease (DKD), and kidney transplantation (KTx). As we describe, the DMRT that has most consistently progressed to human clinical trials for these indications is mesenchymal stem/stromal cells (MSCs), which potently modulate ischemic, inflammatory, profibrotic, and immune-mediated tissue injury through diverse paracrine mechanisms. In KTx, several early-phase clinical trials have also tested the potential for ex vivo-expanded regulatory immune cell therapies to promote donor-specific tolerance and prevent or resolve allograft injury. Other promising DMRT, including adult stem/progenitor cells, stem cell-derived extracellular vesicles, and implantable hydrogels/biomaterials remain at varying preclinical stages of translation for these renal conditions. To date (2021), no DMRT has gained market approval for use in patients with RVD, SA-AKI, DKD, or KTx, and clinical trials demonstrating definitive, cost-effective patient benefits are needed. Nonetheless, exciting progress in understanding the disease-specific mechanisms of action of MSCs and other DMRT, coupled with increasing knowledge of the pathophysiologic basis for renal-tissue injury and the experience gained from pioneering early-phase clinical trials provide optimism that influential, regenerative treatments for diverse kidney diseases will emerge in the years ahead.

A systematic review and meta-analysis of cell-based interventions in experimental diabetic kidney disease.

Regenerative, cell-based therapy is a promising treatment option for diabetic kidney disease (DKD), which has no cure. To prepare for clinical translation, this systematic review and meta-analysis summarized the effect of cell-based interventions in DKD animal models and treatment-related factors modifying outcomes. Electronic databases were searched for original investigations applying cell-based therapy in diabetic animals with kidney endpoints (January 1998-May 2019). Weighted or standardized mean differences were estimated for kidney outcomes and pooled using random-effects models. Subgroup analyses tested treatment-related factor effects for outcomes (creatinine, urea, urine protein, fibrosis, and inflammation). In 40 studies (992 diabetic rodents), therapy included mesenchymal stem/stromal cells (MSC; 61%), umbilical cord/amniotic fluid cells (UC/AF; 15%), non-MSC (15%), and cell-derived products (13%). Tissue sources included bone marrow (BM; 65%), UC/AF (15%), adipose (9%), and others (11%). Cell-based therapy significantly improved kidney function while reducing injury markers (proteinuria, histology, fibrosis, inflammation, apoptosis, epithelial-mesenchymal-transition, oxidative stress). Preconditioning, xenotransplantation, and disease-source approaches were effective. MSC and UC/AF cells had greater effect on kidney function while cell products improved fibrosis. BM and UC/AF tissue sources more effectively improved kidney function and proteinuria vs adipose or other tissues. Cell dose, frequency, and administration route also imparted different benefits. In conclusion, cell-based interventions in diabetic animals improved kidney function and reduced injury with treatment-related factors modifying these effects. These findings may aid in development of optimal repair strategies through selective use of cells/products, tissue sources, and dose administrations to allow for successful adaptation of this novel therapeutic in human DKD.

Progressive Cellular Senescence Mediates Renal Dysfunction in Ischemic Nephropathy.

BACKGROUND: Peripheral vascular diseases may induce chronic ischemia and cellular injury distal to the arterial obstruction. Cellular senescence involves proliferation arrest in response to stress, which can damage neighboring cells. Renal artery stenosis (RAS) induces stenotic-kidney dysfunction and injury, but whether these arise from cellular senescenceand their temporal pattern remain unknown. METHODS: Chronic renal ischemia was induced in transgenic INK-ATTAC and wild type C57BL/6 mice by unilateral RAS, and kidney function (in vivo micro-MRI) and tissue damage were assessed. Mouse healthy and stenotic kidneys were analyzed using unbiased single-cell RNA-sequencing. To demonstrate translational relevance, cellular senescence was studied in human stenotic kidneys. RESULTS: Using intraperitoneal AP20187 injections starting 1, 2, or 4 weeks after RAS, selective clearance of cells highly expressing p16Ink4a attenuated cellular senescence and improved stenotic-kidney function; however, starting treatment immediately after RAS induction was unsuccessful. Broader clearance of senescent cells, using the oral senolytic combination dasatinib and quercetin, in C57BL/6 RAS mice was more effective in clearing cells positive for p21 (Cdkn1a) and alleviating renal dysfunction and damage. Unbiased, single-cell RNA sequencing in freshly dissociated cells from healthy and stenotic mouse kidneys identified stenotic-kidney epithelial cells undergoing both mesenchymal transition and senescence. As in mice, injured human stenotic kidneys exhibited cellular senescence, suggesting this process is conserved. CONCLUSIONS: Maladaptive tubular cell senescence, involving upregulated p16 (Cdkn2a), p19 (Cdkn2d), and p21 (Cdkn1a) expression, is associated with renal dysfunction and injury in chronic ischemia. These findings support development of senolytic strategies to delay chronic ischemic renal injury.

Serum neurofilament light protein correlates with unfavorable clinical outcomes in hospitalized patients with COVID-19.

Brain imaging studies of patients with COVID-19 show evidence of macro- and microhemorrhagic lesions, multifocal white matter hyperintensities, and lesions consistent with posterior reversible leukoencephalopathy. Imaging studies, however, are subject to selection bias, and prospective studies are challenging to scale. Here, we evaluated whether serum neurofilament light chain (NFL), a neuroaxonal injury marker, could predict the extent of neuronal damage in a cohort of 142 hospitalized patients with COVID-19. NFL was elevated in the serum of patients with COVID-19 compared to healthy controls, including those without overt neurological manifestations. Higher NFL serum concentrations were associated with worse clinical outcomes. In 100 hospitalized patients with COVID-19 treated with remdesivir, a trend toward lower NFL serum concentrations was observed. These data suggest that patients with COVID-19 may experience neuroaxonal injury and may be at risk for long-term neurological sequelae. Neuroaxonal injury should be considered as an outcome in acute pharmacotherapeutic trials for COVID-19.

Hypoxic preconditioning induces epigenetic changes and modifies swine mesenchymal stem cell angiogenesis and senescence in experimental atherosclerotic renal artery stenosis.

BACKGROUND: Atherosclerotic renal artery stenosis (ARAS) is a risk factor for ischemic and hypertensive kidney disease (HKD) for which autologous mesenchymal stem cell (MSC) appears to be a promising therapy. However, MSCs from ARAS patients exhibit impaired function, senescence, and DNA damage, possibly due to epigenetic mechanisms. Hypoxia preconditioning (HPC) exerts beneficial effects on cellular proliferation, differentiation, and gene and protein expression. We hypothesized that HPC could influence MSC function and senescence in ARAS by epigenetic mechanisms and modulating gene expression of chromatin-modifying enzymes. METHODS: Adipose-derived MSC harvested from healthy control (N = 8) and ARAS (N = 8) pigs were cultured under normoxia (20%O2) or hypoxia (1%O2) conditions. MSC function was assessed by migration, proliferation, and cytokine release in conditioned media. MSC senescence was evaluated by SA-ß-gal activity. Specific pro-angiogenic and senescence genes were assessed by reverse transcription polymerase chain reaction (RT-PCR). Dot blotting was used to measure global genome 5-hydroxymethylcytosine (5hmC) levels on DNA and Western blotting of modified histone 3 (H3) proteins to quantify tri-methylated lysine-4 (H3K4me3), lysine-9 (H3K9me3), and lysine-27 (H3K27me3) residues. RESULTS: Specific pro-angiogenic genes in ARAS assessed by RT-PCR were lower at baseline but increased under HPC, while pro-senescence genes were higher in ARAS at baseline as compared healthy MSCs. ARAS MSCs under basal conditions, displayed higher H3K4me3, H3K27me3, and 5hmC levels compared to healthy MSCs. During HPC, global 5hmC levels were decreased while no appreciable changes occurred in histone H3 tri-methylation. ARAS MSCs cultured under HPC had higher migratory and proliferative capacity as well as increased vascular endothelial growth factor and epidermal growth factor expression compared to normoxia, and SA-ß-gal activity decreased in both animal groups. CONCLUSIONS: These data demonstrate that swine ARAS MSCs have decreased angiogenesis and increased senescence compared to healthy MSCs and that HPC mitigates MSC dysfunction, senescence, and DNA hydroxymethylation in ARAS MSC. Thus, HPC for MSCs may be considered for their optimization to improve autologous cell therapy in patients with nephropathies.