Adipose-derived mesenchymal stem cells from patients with atherosclerotic renovascular disease have increased DNA damage and reduced angiogenesis that can be modified by hypoxia

Representative flow cytometric plots (FACS) showing that AMSCs expressed HLA-ABC, CD44, CD90, CD29, CD73, and CD105 markers, and did not express HLA-DR, CD45, CD14 or CD34 markers. (JPG 233 kb

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

Severe Hyponatremia as the Initial Sign Preceding Guillain-Barré Syndrome, an Acute Inflammatory Demyelinating Polyneuropathy: A Case Report

Guillain-Barré syndrome is an immune-mediated polyneuropathy that frequently presents with progressive muscle weakness. Hyponatremia has recently been described as a feature of this condition, generally appearing over the course of the illness and following the diagnosis of this demyelinating process. We report a case of Guillain-Barré syndrome presenting with severe hyponatremia that is further exacerbated by intravenous immune globulin therapy. Awareness should be raised for consideration of both Guillain-Barré syndrome and its treatment with intravenous immune globulin therapy as the cause of hyponatremia

Progress toward the clinical application of mesenchymal stromal cells and other disease-modulating regenerative therapies

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-associate acute kidney injury (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, pro-fibrotic 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 pre-clinical 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 pathophysiological basis for renal tissue injury and the experience gained from pioneering early-phase clinical trials provide optimism that impactful, regenerative treatments for diverse kidney diseases will emerge in the years ahead.LJH is supported by grants from Regenerative Medicine Minnesota (grant number RMM 091718), the National Institute of Health (NIH) (grant numbers DK109134 and DK123492), and NIDDK Diabetic Complications Consortium (RRID:SCR_001415, www.diacomp.org; grant numbers DK076169 and DK115255). SMH is supported by the NIH (grant number DK118120) and by a Mary Kathryn and Michael B. Panitch Career Development Award. MDG is supported by grants from the European Commission [Horizon 2020 Collaborative Health Project NEPHSTROM (grant number 634086) and FP7 Collaborative Health Project VISICORT (grant number 602470)], from Science Foundation Ireland [REMEDI Strategic Research Cluster (grant number 09/SRC-B1794; MDG) and CÚRAM Research Centre (grant number 13/RC/2073; MDG)] and the European Regional Development Fund

Validation of prognostic indices for short term mortality in an incident dialysis population of older adults >75.

Rational and objectivePrognosis provides critical knowledge for shared decision making between patients and clinicians. While several prognostic indices for mortality in dialysis patients have been developed, their performance among elderly patients initiating dialysis is unknown, despite great need for reliable prognostication in that context. To assess the performance of 6 previously validated prognostic indices to predict 3 and/or 6 months mortality in a cohort of elderly incident dialysis patients.Study designValidation study of prognostic indices using retrospective cohort data. Indices were compared using the concordance ("c")-statistic, i.e. area under the receiver operating characteristic curve (ROC). Calibration, sensitivity, specificity, positive and negative predictive values were also calculated.Setting & participantsIncident elderly (age ≥75 years; n = 349) dialysis patients at a tertiary referral center.Established predictorsVariables for six validated prognostic indices for short term (3 and 6 month) mortality prediction (Foley, NCI, REIN, updated REIN, Thamer, and Wick) were extracted from the electronic medical record. The indices were individually applied as per each index specifications to predict 3- and/or 6-month mortality.ResultsIn our cohort of 349 patients, mean age was 81.5±4.4 years, 66% were male, and median survival was 351 days. The c-statistic for the risk prediction indices ranged from 0.57 to 0.73. Wick ROC 0.73 (0.68, 0.78) and Foley 0.67 (0.61, 0.73) indices performed best. The Foley index was weakly calibrated with poor overall model fit (p LimitationsSmall sample size, use of secondary data, need for imputation, homogeneous population.ConclusionMost predictive indices for mortality performed moderately in our incident dialysis population. The Wick and Foley indices were the best performing, but had issues with under and over calibration. More accurate indices for predicting survival in older patients with kidney failure are needed

Metabolic Syndrome Induces Release of Smaller Extracellular Vesicles from Porcine Mesenchymal Stem Cells

Mesenchymal stromal/stem cells (MSCs) belong to the endogenous cellular reparative system, and can be used exogenously in cell-based therapy. MSCs release extracellular vesicles (EVs), including exosomes and microvesicles, which mediate some of their therapeutic activity through intercellular communication. We have previously demonstrated that metabolic syndrome (MetS) modifies the cargo packed within swine EV, but whether it influences their phenotypical characteristics remains unclear. This study tested the hypothesis that MetS shifts the size distribution of MSC-derived EVs. Adipose tissue-derived MSC-EV subpopulations from Lean ( n = 6) and MetS ( n = 6) pigs were characterized for number and size using nanoparticle-tracking analysis, flow cytometry, and transmission electron microscopy. Expression of exosomal genes was determined using next-generation RNA-sequencing (RNA-seq). The number of EV released from Lean and MetS pig MSCs was similar, yet MetS-MSCs yielded a higher proportion of small-size EVs (202.4 ± 17.7 nm vs. 280.3 ± 15.1 nm), consistent with exosomes. RNA-seq showed that their EVs were enriched with exosomal markers. Lysosomal activity remained unaltered in MetS-MSCs. Therefore, MetS alters the size distribution of MSC-derived EVs in favor of exosome release. These observations may reflect MSC injury and membrane recycling in MetS or increased expulsion of waste products, and may have important implications for development of adequate cell-based treatments

Care of the dialysis patient: Primary provider involvement and resource utilization patterns - a cohort study

Abstract Background Efficient and safe delivery of care to dialysis patients is essential. Concerns have been raised regarding the ability of accountable care organizations to adequately serve this high-risk population. Little is known about primary care involvement in the care of dialysis patients. This study sought to describe the extent of primary care provider (PCP) involvement in the care of hemodialysis patients and the outcomes associated with that involvement. Methods In a retrospective cohort study, patients accessing a Midwestern dialysis network from 2001 to 2010 linked to United States Renal Database System and with >90 days follow up were identified (n = 2985). Outpatient visits were identified using Current Procedural Terminology (CPT)-4 codes, provider specialty, and grouped into quartiles-based on proportion of PCP visits per person-year (ppy). Top and bottom quartiles represented patients with high primary care (HPC) or low primary care (LPC), respectively. Patient characteristics and health care utilization were measured and compared across patient groups. Results Dialysis patients had an overall average of 4.5 PCP visits ppy, ranging from 0.6 in the LPC group to 6.9 in the HPC group. HPC patients were more likely female (43.4% vs. 35.3%), older (64.0 yrs. vs. 60.0 yrs), and with more comorbidities (Charlson 7.0 vs 6.0). HPC patients had higher utilization (hospitalizations 2.2 vs. 1.8 ppy; emergency department visits 1.6 vs 1.2 ppy) and worse survival (3.9 vs 4.3 yrs) and transplant rates (16.3 vs. 31.5). Conclusions PCPs are significantly involved in the care of hemodialysis patients. Patients with HPC are older, sicker, and utilize more resources than those managed primarily by nephrologists. After adjusting for confounders, there is no difference in outcomes between the groups. Further studies are needed to better understand whether there is causal impact of primary care involvement on patient survival