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Introduction: Cell-based therapies potentially delay the trajectory toward end-stage kidney disease (ESKD) in late stage 4 diabetic chronic kidney disease (DKD). We describe the trial design, baseline patient characteristics, and early results of an IRB-approved phase II multicenter clinical trial, utilizing Renal Autologous Cell Therapy (REACT) in adults with pre-ESKD due to type 2 DKD. The trial objectives were safety and tolerability of REACT by assessment of the procedure, product administration, and renal-specific adverse events in addition to evaluate the impact on renal function following injection. Methods: Ten adults with an eGFR of 14–20 mL/min/1.73 m2 were enrolled in a single-arm open-label trial. Following a percutaneous kidney biopsy, an ex vivo expansion of selected renal cells that form the REACT was injected into the cortex of the biopsied kidney with CT image guidance. Each participant received two doses of the REACT product at 6-month intervals. A 6-month observation pre-trial was required to establish patients’ “own” baseline and rate of DKD progression. Results: Five men and 5 women underwent 19 REACT injections (1 participant received only one injection). Their baseline characteristics were as follows: 3 Hispanic/Latino, 7 non-Hispanic, 7 white; mean (SD) age: 58.9 years (5.22), BMI 35.8 (8.2), eGFR (sCR) 15.5 (2.72), eGFR (sCR + Cys-C) 17.7 (3.67) mL/min/1.73 m2, sCr 3.6 mg/mL (0.73), Cys-C 2.6 mg/mL (0.52), and log random UACR 7.9 mg/g (1.01). The pre- and post-injection eGFR slope was −6.5 mL/min/1.73 m2 and −3.9 mL/min/1.73 m2. No cell-related adverse events occurred, and two procedure-related hematomas required observation without transfusion or angiographic interventions. Dialysis was delayed a mean of 16 months (range 6–28 months). At 15 months, 2 patients (20%) have eGFR slope stability and have not commenced renal replacement therapy. Conclusion: Trials that include patients with an eGFR of 2 are uncommon, and none to date involve autologous homologous cell-based treatments. REACT has the potential to stabilize or delay dialysis in high-risk late stage 4 DKD.

Patients on intermittent hemodialysis (HD) have a high symptom burden. Though studies report higher hospitalizations and mortality after the long interdialytic interval, whether symptoms vary based on the interdialytic interval is unclear.This is a prospective observational study of patients over the age of 18 who received in-center HD. Patients were surveyed on the presence and severity of 20 different symptoms at the end of 12 HD sessions. Wilcoxon signed-rank test was used for comparison of severity for each symptom by the interval. Multivariable generalized estimating equation with Poisson regression by repeated measure method was used to determine the association of interdialytic interval and symptom frequency while adjusting for potential confounders.From the 97 patients enrolled, the most common symptoms were fatigue (60.8%), cramping (58.8%), and dry skin (52.6%). There was large variability in the frequency of symptoms, ranging 0% to 8% of treatments. The most severe symptoms were bone pain (mean severity score 2.2±0.9) and diarrhea (mean severity score 2.2±0.7). Eight of the 20 symptoms were significantly more common after the long interdialytic interval including fatigue (22% vs. 15%,Symptoms are more common after the long interdialytic interval. Clinical assessment and research evaluating patient symptoms need to be cognizant of when patients are surveyed or include the length of interdialytic interval as a confounding variable.

Allograft biopsies with lesions of Antibody-Mediated Rejection (ABMR) with Microvascular Inflammation (MVI) have shown heterogeneous etiologies and outcomes.To examine factors associated with outcomes in biopsies that meet histologic ABMR criteria, we retrospectively evaluated for-cause biopsies at our center between 2011 and 2017. We included biopsies that met the diagnosis of ABMR by histology, along with simultaneous evaluation for anti-Human Leukocyte Antigen (HLA) donor-specific antibodies (DSA). We evaluated death-censored graft loss (DCGL) and used a principal component analysis (PCA) approach to identify key predictors of outcomes.Out of the histologic ABMR cohort (n = 118), 70 were DSA-positive ABMR, while 48 had no DSA. DSA(+)ABMR were younger and more often female recipients. DSA(+)ABMR occurred significantly later post-transplant than DSA(-)ABMR suggesting time-dependence. DSA(+)ABMR had higher inflammatory scores (i,t), chronicity scores (ci, ct) and tended to have higher MVI scores. Immunodominance of DQ-DSA in DSA(+)ABMR was associated with higher i+t scores. Clinical/histologic factors significantly associated with DCGL after biopsy were inputted into the PCA. Principal component-1 (PC-1), which contributed 34.8% of the variance, significantly correlated with time from transplantation to biopsy, ci/ct scores and DCGL. In the PCA analyses, i, t scores, DQ-DSA, and creatinine at biopsy retained significant correlations with GL-associated PCs.Time from transplantation to biopsy plays a major role in the prognosis of biopsies with histologic ABMR and MVI, likely due to ongoing chronic allograft injury over time.

Individuals with diabetic kidney disease (DKD) are at risk for progression, heart failure, and death. We assessed the association of KidneyIntelX, a bioprognostictest validated for DKD progression, with a composite time-to-event endpoint of 57% eGFR decline, kidney failure, heart failure hospitalization (HFH) , or death in a posthoc analysis of a subgroup of CANVAS participants with DKD. sTNFR-1, sTNFR-2, and KIM-1 were measured via proprietary assays, and KidneyIntelX scores were calculated using the existing algorithm. Hazard ratios for high vs. low-risk strata for the composite outcome were adjusted for age, sex, race, treatment arm, baseline CVD, HbA1c, SBP, DBP, LDL, BMI) . During 5.6 years follow-up, 282 (22%) of the 1278 CANVAS participants with DKD experienced the outcome (57% decline in eGFR/ESKD 3%, HFH 6%, death 16%) . The adjusted HR for the composite outcome in KidneyIntelX high-risk group was 2.7 (95% CI 1.9 to 3.8) vs. the low-risk group. Canagliflozin reduced the risk for the composite event vs. placebo, with larger absolute risk reductions for the high-risk stratum (11%) , compared to intermediate (6%) or low-risk strata (4%) (p In conclusion, KidneyIntelX successfully risk-stratified adults with DKD for clinical outcomes. Absolute risk reductions with canagliflozin were greatest in the high-risk stratum, thereby potentially allowing its use to identify patients most likely to benefit from treatment. Disclosure G.N.Nadkarni: Advisory Panel; Renalytix, Consultant; AstraZeneca, Reata Pharmaceuticals, Inc., Renalytix, Siemens, Other Relationship; Renalytix, Stock/Shareholder; Renalytix. D.Takale: None. B.Neal: Other Relationship; Janssen Research & Development, LLC. K.W.Mahaffey: Consultant; Novo Nordisk. Y.Yavin: Employee; Janssen Research & Development, LLC. M.K.Hansen: Employee; Janssen Research & Development, LLC. F.Fleming: Employee; Renalytix. H.L.Heerspink: Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Chinook Therapeutics Inc., CSL Behring, Gilead Sciences, Inc., Goldfinch Bio, Inc., Janssen Research & Development, LLC, Mitsubishi Tanabe Pharma Corporation, Mundipharma, Traveere Pharmaceuticals, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. S.Coca: Advisory Panel; 3ive Labs, Nuwellis, Reprieve Cardiovascular, Consultant; Axon Therapies, Bayer AG, Boehringer Ingelheim International GmbH, Vifor Pharma Management Ltd., Stock/Shareholder; pulseData, Renalytix. Funding Renalytix

Background After accounting for known risk factors for CKD progression in children, clinical outcomes among children with CKD still vary substantially. Biomarkers of tubular injury (such as KIM-1), repair (such as YKL-40), or inflammation (such as MCP-1, suPAR, TNF receptor-1 [TNFR-1], and TNFR-2) may identify children with CKD at risk for GFR decline. Methods We investigated whether plasma KIM-1, YKL-40, MCP-1, suPAR, TNFR-1, and TNFR-2 are associated with GFR decline in children with CKD and in subgroups defined by glomerular versus nonglomerular cause of CKD. We studied participants of the prospective CKiD Cohort Study which enrolled children with an eGFR of 30-90 ml/min per 1.73 m2 and then assessed eGFR annually. Biomarkers were measured in plasma collected 5 months after study enrollment. The primary endpoint was CKD progression, defined as a composite of a 50% decline in eGFR or incident ESKD. Results Of the 651 children evaluated (median age 11 years; median baseline eGFR of 53 ml/min per 1.73 m2), 195 (30%) had a glomerular cause of CKD. Over a median follow-up of 5.7 years, 223 children (34%) experienced CKD progression to the composite endpoint. After multivariable adjustment, children with a plasma KIM-1, TNFR-1, or TNFR-2 concentration in the highest quartile were at significantly higher risk of CKD progression compared with children with a concentration for the respective biomarker in the lowest quartile (a 4-fold higher risk for KIM-1 and TNFR-1 and a 2-fold higher risk for TNFR-2). Plasma MCP-1, suPAR, and YKL-40 were not independently associated with progression. When stratified by glomerular versus nonglomerular etiology of CKD, effect estimates did not differ significantly. Conclusions Higher plasma KIM-1, TNFR-1, and TNFR-2 are independently associated with CKD progression in children.

Background Acute kidney injury (AKI) is a known complication of COVID-19 and is associated with an increased risk of in-hospital mortality. Unbiased proteomics using biological specimens can lead to improved risk stratification and discover pathophysiological mechanisms. Methods Using measurements of ~4000 plasma proteins in two cohorts of patients hospitalized with COVID-19, we discovered and validated markers of COVID-associated AKI (stage 2 or 3) and long-term kidney dysfunction. In the discovery cohort (N= 437), we identified 413 higher plasma abundances of protein targets and 40 lower plasma abundances of protein targets associated with COVID-AKI (adjusted p Results We demonstrate that COVID-AKI is associated with increased markers of tubular injury (NGAL) and myocardial injury. Using estimated glomerular filtration (eGFR) measurements taken after discharge, we also find that 25 of the 62 AKI-associated proteins are significantly associated with decreased post-discharge eGFR (adjusted p desmocollin-2, trefoil factor 3, transmembrane emp24 domain-containing protein 10, and cystatin-Cindicating tubular dysfunction and injury. Conclusions Using clinical and proteomic data, our results suggest that while both acute and long-term COVID-associated kidney dysfunction are associated with markers of tubular dysfunction, AKI is driven by a largely multifactorial process involving hemodynamic instability and myocardial damage.

Introduction: The critical path for novel treatment and prevention strategies, both pharmacological and non-pharmacological, requires clinical outcomes trials, which are slow, expensive and retard patient access to successful therapies. For marketed drugs, unreliable residual risk stratification hinders precision-directed therapy and facilitates payor reticence. Hypothesis: Large-scale proteomics and machine learning can identify a reliable, individualized, and dynamic surrogate of cardiovascular risk, synoptic for multiple biologic mechanisms, with a resulting multimarker model that is more robust than individual biomarkers. Avoidance of immutable prognostic factors (e.g. age, sex, medical diagnoses) will enhance sensitivity to change in risk. Methods: We quantified ~5000 proteins in >31,000 archived samples from >21,000 higher risk individuals in nine clinical datasets, generating ~150M plasma protein measurements. We derived and validated a 27-protein model encompassing 10 biologic processes to predict the four-year likelihood of myocardial infarction, stroke, hospitalization for heart failure or death. We assessed the association of model-predicted change with observed outcomes in a variety of conditions in four clinical intervention trials. Results: See table for details. In validation, observed event rates were 7.8 fold higher in quintile 5 than quintile 1 for proteins vs. 2.9 for an optimized clinical factor model; the Net Reclassification Index was +0.43. AUCs were 0.73 for proteins vs. 0.63 for clinical, and c-statistics 0.71 vs. 0.62. The protein model also responded concordantly with outcomes in four intervention studies. Conclusions: A 27-protein model is more prognostic than clinical factors in higher risk populations and has directionally concordant responsiveness to all mechanistic challenges to date. These features are consistent with surrogacy, and may prove useful in clinical trials and precision medicine.

Cardiovascular disease (CVD) is a major cause of mortality among people with diabetic kidney disease (DKD). The pathophysiology is inadequately explained by traditional CVD risk factors. The uremic solutes trimethylamine-N-oxide (TMAO) and asymmetric and symmetric dimethylarginine (ADMA, SDMA) have been linked to CVD in kidney failure with replacement therapy (KFRT), but data are limited in populations with diabetes and less severe kidney disease.Observational cohort.Random subcohort of 555 REGARDS (Reasons for Geographic and Racial Differences in Stroke) study participants with diabetes and estimated glomerular filtration rate (eGFR) 60 mL/min/1.73 mADMA, SDMA, and TMAO assayed by liquid chromatography-mass spectrometry in plasma and urine.Cardiovascular mortality (primary outcome); all-cause mortality and incident KFRT (secondary outcomes).Plasma concentrations and ratios of urine to plasma concentrations of ADMA, SDMA, and TMAO were tested for association with outcomes. Adjusted Cox regression models were fitted and hazard ratios of outcomes calculated per standard deviation and per doubling, and as interquartile comparisons.The mean baseline eGFR was 44 mL/min/1.73 mSingle cohort, restricted to patients with diabetes and eGFR 60 mL/min/1.73 mHigher plasma concentrations and lower ratios of urine to plasma concentrations of uremic solutes were independently associated with cardiovascular and all-cause mortality in DKD. Associations of ratios of urine to plasma concentrations with mortality suggest a connection between renal uremic solute clearance and CVD pathogenesis.

Objectives Therapies for patients with respiratory failure from coronavirus disease 2019 are urgently needed. Early implementation of prone positioning ventilation improves survival in patients with acute respiratory distress syndrome, but studies examining the effect of proning on survival in patients with coronavirus disease 2019 are lacking. Our objective was to estimate the effect of early proning initiation on survival in patients with coronavirus disease 2019-associated respiratory failure. Design Data were derived from the Study of the Treatment and Outcomes in Critically Ill Patients with coronavirus disease 2019, a multicenter cohort study of critically ill adults with coronavirus disease 2019 admitted to 68 U.S. hospitals. Using these data, we emulated a target trial of prone positioning ventilation by categorizing mechanically ventilated hypoxemic (ratio of PaO2 over the corresponding FIO2 ≤ 200 mm Hg) patients as having been initiated on proning or not within 2 days of ICU admission. We fit an inverse probability-weighted Cox model to estimate the mortality hazard ratio for early proning versus no early proning. Patients were followed until death, hospital discharge, or end of follow-up. Setting ICUs at 68 U.S. sites. Patients Critically ill adults with laboratory-confirmed coronavirus disease 2019 receiving invasive mechanical ventilation with ratio of PaO2 over the corresponding FIO2 less than or equal to 200 mm Hg. Interventions None. Measurements and main results Among 2,338 eligible patients, 702 (30.0%) were proned within the first 2 days of ICU admission. After inverse probability weighting, baseline and severity of illness characteristics were well-balanced between groups. A total of 1,017 (43.5%) of the 2,338 patients were discharged alive, 1,101 (47.1%) died, and 220 (9.4%) were still hospitalized at last follow-up. Patients proned within the first 2 days of ICU admission had a lower adjusted risk of death compared with nonproned patients (hazard ratio, 0.84; 95% CI, 0.73-0.97). Conclusions In-hospital mortality was lower in mechanically ventilated hypoxemic patients with coronavirus disease 2019 treated with early proning compared with patients whose treatment did not include early proning.

Acute kidney injury (AKI) has been reported to be associated with excess risks of death, kidney disease progression and cardiovascular events although previous studies have important limitations. To further examine this, we prospectively studied adults from four clinical centers surviving three months and more after hospitalization with or without AKI who were matched on center, pre-admission CKD status, and an integrated priority score based on age, prior cardiovascular disease or diabetes mellitus, preadmission estimated glomerular filtration rate (eGFR) and treatment in the intensive care unit during the index hospitalization between December 2009-February 2015, with follow-up through November 2018. All participants had assessments of kidney function before (eGFR) and at three months and annually (eGFR and proteinuria) after the index hospitalization. Associations of AKI with outcomes were examined after accounting for pre-admission and three-month post-discharge factors. Among 769 AKI (73% Stage 1, 14% Stage 2, 13% Stage 3) and 769 matched non-AKI adults, AKI was associated with higher adjusted rates of incident CKD (adjusted hazard ratio 3.98, 95% confidence interval 2.51-6.31), CKD progression (2.37,1.28-4.39), heart failure events (1.68, 1.22-2.31) and all-cause death (1.78, 1.24-2.56). AKI was not associated with major atherosclerotic cardiovascular events in multivariable analysis (0.95, 0.70-1.28). After accounting for degree of kidney function recovery and proteinuria at three months after discharge, the associations of AKI with heart failure (1.13, 0.80-1.61) and death (1.29, 0.84-1.98) were attenuated and no longer significant. Thus, assessing kidney function recovery and proteinuria status three months after AKI provides important prognostic information for long-term clinical outcomes., Graphical abstract

Introduction: The failure to recognize an ischemic stroke in the emergency department (ED) is a missed opportunity for acute interventions and for prompt treatment with secondary prevention therapy. Our study examined the characteristics of misdiagnosed strokes in the ED of an academic teaching hospital and a large community hospital. Methods: A retrospective chart review was performed from February 2013 to February 2014. A stroke was “missed” if practitioners in the ED did not initially consider stroke in the differential, or the diagnosis was delayed causing the patient to miss the therapeutic window for thrombolytic therapy. Results: A total of 465 ischemic stroke patients were included; 280 patients from the academic hospital and 185 patients from the community hospital. One hundred three strokes were initially misdiagnosed. Fifty-five of these were missed at the academic hospital (22%) and 48 were at the community hospital (26%, p=0.11). Of the missed stroke patients, 26 at the academic hospital (47%) and 10 at the community hospital (21%) presented within 3 hours of symptom onset. At the academic hospital where a neurologist is consulted on all potential acute strokes, a neurologist was called for 95% of the accurate stroke diagnoses but only 36% of the stroke misses (p Factors independently associated with greater odds of a missed stroke diagnosis were nausea/vomiting (OR=4.02, 95% CI=1.60-10.1), dizziness (OR=1.99, 95% CI=1.03-3.84), and a positive stroke history (OR=2.40, 95% CI=1.30-4.42). Thirty-seven percent of posterior strokes were initially misdiagnosed compared with 16% of anterior strokes (p Conclusion: Greater than 20 percent of stroke patients admitted through the ED at both an academic center and community hospital had a missed diagnosis. These strokes were more likely to be posterior circulation strokes and associated with nausea, vomiting and dizziness. A neurologist consultation decreased the likelihood of a missed stroke. Next steps are the development of improved identification systems and tools in the ED to improve the accuracy of stroke diagnosis.

Objectives: The failure to recognize an acute stroke in the ED represents a missed opportunity for potential thrombolytic therapy and for prompt treatment for secondary prevention. The aim of this study was to examine the diagnostic accuracy of acute ischemic strokes at a large academic center and to identify common characteristics of these missed strokes. Methods: A retrospective review was performed on a random sample of patients >18 years old with a discharge diagnosis of ischemic stroke in 2013. All acute strokes were confirmed on CT or MRI. A stroke was “missed” if practitioners in the ED did not initially consider stroke in the differential, or the diagnosis was delayed causing the patient to miss the therapeutic window for thrombolytic therapy. Results: Two hundred ischemic stroke patients were included in the study. The mean patient age was 72 years, and the mean initial NIHSS was 7. There were 36 “missed” strokes (18%) in this population. Of the strokes that were initially misdiagnosed, 20 of 36 (56%) presented in the time window for thrombolytic therapy and potentially could have received intervention. Posterior circulation strokes were more likely to be missed overall (20/58 posterior, 34%, vs 16/142 anterior, 11%, p < 0.001). Seventy-six percent of patients with posterior stroke had stroke in the original differential compared with 96% in those with anterior circulation stroke (p < 0.001). Symptoms independently associated with posterior circulation strokes included nausea/vomiting (OR=6.9, 95% CI: 2.0-23), headache (OR=6.4, 95% CI: 1.5-27) and difficulty walking (OR=3.5, 95% CI: 1.3-9.5). Anterior circulation patients more commonly presented with focal weakness (OR=0.11, 95% CI: 0.05-0.25) and aphasia (OR=0.17, 95% CI: 0.06-0.45). Conclusions: Despite having a certified stroke program in a large academic medical center, 18% of acute ischemic strokes were missed in the ED. Posterior circulation strokes were 3 times more likely than anterior strokes to be missed. Posterior stroke patients were more likely to present with nausea/vomiting, headache and difficulty walking, and these symptoms should serve as triggers to consider ischemic stroke in the ED.

In this multicenter, prospective study of 288 children (half under 2 years of age) undergoing cardiac surgery, we evaluated whether the measurement of pre- and postoperative serum cystatin C (CysC) improves the prediction of acute kidney injury (AKI) over that obtained by serum creatinine (SCr). Higher preoperative SCr-based estimated glomerular filtration rates predicted higher risk of the postoperative primary outcomes of stage 1 and 2 AKI (adjusted odds ratios (ORs) 1.5 and 1.9, respectively). Preoperative CysC was not associated with AKI. The highest quintile of postoperative (within 6 h) CysC predicted stage 1 and 2 AKI (adjusted ORs of 6 and 17.2, respectively). The highest tertile of percent change in CysC independently predicted AKI, whereas the highest tertile of SCr predicted stage 1 but not stage 2 AKI. Postoperative CysC levels independently predicted longer duration of ventilation and intensive care unit length of stay, whereas the postoperative SCr change only predicted longer intensive care unit stay. Thus, postoperative serum CysC is useful to risk-stratify patients for AKI treatment trials. More research, however, is needed to understand the relation between preoperative renal function and the risk of AKI.

Purpose Myocardial necrosis and apoptosis have been observed following experimentally induced renal dysfunction (RD). Given that adverse cardiac outcomes remain strongly associated with acute kidney injury even after RD completely normalizes, many have theorized that the adverse outcomes directly result from RD-induced myocardial injury. However, it remains unclear whether this risk is the result of the RD itself, or if RD is identifying a “sicker” population. As such, we hypothesized that if the adverse cardiovascular outcomes associated with RD result primarily from irreversible RD-induced myocardial injury, transplantation of a heart from a donor with RD should lead to inferior graft survival. Methods and Materials Adult patients in the UNOS registry who underwent cardiac transplantation from 1994 through June 30, 2011 with donor creatinine and urine protein available were evaluated (n=20,438). Results Mean donor GFR was 90.5 ± 48.4 ml/min and 22.3% of donors had RD (GFR 40 (HR=1.4, p 4 hrs (HR=1.2, p Conclusions RD in cardiac allograft donors is not associated with reduced post-transplant graft survival. These data support the hypothesis that irreversible myocardial injury induced by RD is not primarily responsible for the strong epidemiologic association between RD and adverse cardiovascular outcomes.