Publications by authors named "Jochen Reiser"

177 Publications

Biomarkers of Immune Activation and Incident Kidney Failure With Replacement Therapy: Findings From the African American Study of Kidney Disease and Hypertension.

Am J Kidney Dis 2020 Dec 31. Epub 2020 Dec 31.

Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA;; Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA;; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

Rationale & Objective: Immune activation is fundamental to the pathogenesis of many kidney diseases. Innate immune molecules such as soluble urokinase-type plasminogen activator receptor (suPAR) have been linked to incidence and progression of chronic kidney disease (CKD). Whether other biomarkers of immune activation are associated with incident kidney failure with replacement therapy (KFRT) in African Americans with non-diabetic kidney disease is unclear.

Study Design: Prospective cohort SETTING: & Participants: African American Study of Kidney Disease and Hypertension participants with available baseline serum samples for biomarker measurement.

Predictors: Baseline serum soluble tumor necrosis factor receptor 1 and 2 (sTNFR1; sTNFR2), tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ) levels.

Outcomes: Incident KFRT, all-cause mortality.

Analytic Approach: Cox proportional hazards models.

Results: Among 500 participants with available samples, mean glomerular filtration rate was 44.7 ml/min/1.73 m and median urine protein-to-creatinine ratio was 0.09 g/g at baseline. Over a median follow-up 9.6 years, there were 161 (32%) KFRT and 113 (23%) death events. In models adjusted for demographic and clinical factors and baseline kidney function, each two-fold higher baseline level of sTNFR1, sTNFR2, and TNF-α was associated with 3.66 (95% CI: 2.31,5.80), 2.29 (95% CI: 1.60,3.29), and 1.35-fold (95% CI: 1.07,1.71) greater risks of KFRT, respectively; in comparison, the association between suPAR and KFRT was 1.39 (95% CI: 1.04,1.86). These three biomarkers were also significantly associated with death (up to 2.2-fold higher risks per 2-fold higher baseline level; p≤0.01). IFN-γ was not associated with either outcome. None of the biomarkers modified the association of APOL1 high-risk status (genetic risk factors for kidney disease among individuals of African ancestry) with KFRT (p-interaction>0.05).

Limitations: Limited generalizability to other ethnic groups or CKD etiologies.

Conclusions: Among African Americans with CKD attributed to hypertension, baseline levels of sTNFR1, sTNFR2, and TNF-α but not IFN-γ were associated with KFRT and mortality.
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http://dx.doi.org/10.1053/j.ajkd.2020.11.014DOI Listing
December 2020

Glomerular filtration barrier dysfunction in a self-limiting, RNA virus-induced glomerulopathy resembles findings in idiopathic nephrotic syndromes.

Sci Rep 2020 11 5;10(1):19117. Epub 2020 Nov 5.

Department of Nephrology, Heidelberg University Hospital, Im Neuenheimer Feld 162, 69120, Heidelberg, Germany.

Podocyte injury has recently been described as unifying feature in idiopathic nephrotic syndromes (INS). Puumala hantavirus (PUUV) infection represents a unique RNA virus-induced renal disease with significant proteinuria. The underlying pathomechanism is unclear. We hypothesized that PUUV infection results in podocyte injury, similar to findings in INS. We therefore analyzed standard markers of glomerular proteinuria (e.g. immunoglobulin G [IgG]), urinary nephrin excretion (podocyte injury) and serum levels of the soluble urokinase plasminogen activator receptor (suPAR), a proposed pathomechanically involved molecule in INS, in PUUV-infected patients. Hantavirus patients showed significantly increased urinary nephrin, IgG and serum suPAR concentrations compared to healthy controls. Nephrin and IgG levels were significantly higher in patients with severe proteinuria than with mild proteinuria, and nephrin correlated strongly with biomarkers of glomerular proteinuria over time. Congruently, electron microcopy analyses showed a focal podocyte foot process effacement. suPAR correlated significantly with urinary nephrin, IgG and albumin levels, suggesting suPAR as a pathophysiological mediator in podocyte dysfunction. In contrast to INS, proteinuria recovered autonomously in hantavirus patients. This study reveals podocyte injury as main cause of proteinuria in hantavirus patients. A better understanding of the regenerative nature of hantavirus-induced glomerulopathy may generate new therapeutic approaches for INS.
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http://dx.doi.org/10.1038/s41598-020-76050-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644703PMC
November 2020

Association Between Early Treatment With Tocilizumab and Mortality Among Critically Ill Patients With COVID-19.

JAMA Intern Med 2021 01;181(1):41-51

Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts.

Importance: Therapies that improve survival in critically ill patients with coronavirus disease 2019 (COVID-19) are needed. Tocilizumab, a monoclonal antibody against the interleukin 6 receptor, may counteract the inflammatory cytokine release syndrome in patients with severe COVID-19 illness.

Objective: To test whether tocilizumab decreases mortality in this population.

Design, Setting, And Participants: The data for this study were derived from a multicenter cohort study of 4485 adults with COVID-19 admitted to participating intensive care units (ICUs) at 68 hospitals across the US from March 4 to May 10, 2020. Critically ill adults with COVID-19 were categorized according to whether they received or did not receive tocilizumab in the first 2 days of admission to the ICU. Data were collected retrospectively until June 12, 2020. A Cox regression model with inverse probability weighting was used to adjust for confounding.

Exposures: Treatment with tocilizumab in the first 2 days of ICU admission.

Main Outcomes And Measures: Time to death, compared via hazard ratios (HRs), and 30-day mortality, compared via risk differences.

Results: Among the 3924 patients included in the analysis (2464 male [62.8%]; median age, 62 [interquartile range {IQR}, 52-71] years), 433 (11.0%) received tocilizumab in the first 2 days of ICU admission. Patients treated with tocilizumab were younger (median age, 58 [IQR, 48-65] vs 63 [IQR, 52-72] years) and had a higher prevalence of hypoxemia on ICU admission (205 of 433 [47.3%] vs 1322 of 3491 [37.9%] with mechanical ventilation and a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen of <200 mm Hg) than patients not treated with tocilizumab. After applying inverse probability weighting, baseline and severity-of-illness characteristics were well balanced between groups. A total of 1544 patients (39.3%) died, including 125 (28.9%) treated with tocilizumab and 1419 (40.6%) not treated with tocilizumab. In the primary analysis, during a median follow-up of 27 (IQR, 14-37) days, patients treated with tocilizumab had a lower risk of death compared with those not treated with tocilizumab (HR, 0.71; 95% CI, 0.56-0.92). The estimated 30-day mortality was 27.5% (95% CI, 21.2%-33.8%) in the tocilizumab-treated patients and 37.1% (95% CI, 35.5%-38.7%) in the non-tocilizumab-treated patients (risk difference, 9.6%; 95% CI, 3.1%-16.0%).

Conclusions And Relevance: Among critically ill patients with COVID-19 in this cohort study, the risk of in-hospital mortality in this study was lower in patients treated with tocilizumab in the first 2 days of ICU admission compared with patients whose treatment did not include early use of tocilizumab. However, the findings may be susceptible to unmeasured confounding, and further research from randomized clinical trials is needed.
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http://dx.doi.org/10.1001/jamainternmed.2020.6252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577201PMC
January 2021

Soluble Urokinase Receptor (SuPAR) in COVID-19-Related AKI.

J Am Soc Nephrol 2020 11 22;31(11):2725-2735. Epub 2020 Sep 22.

Division of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan

Background: AKI commonly occurs in patients with coronavirus disease 2019 (COVID-19). Its pathogenesis is poorly understood. The urokinase receptor system is a key regulator of the intersection between inflammation, immunity, and coagulation, and soluble urokinase plasminogen activator receptor (suPAR) has been identified as an immunologic risk factor for AKI. Whether suPAR is associated with COVID-19-related AKI is unknown.

Methods: In a multinational observational study of adult patients hospitalized for COVID-19, we measured suPAR levels in plasma samples from 352 adult patients that had been collected within 48 hours of admission. We examined the association between suPAR levels and incident in-hospital AKI.

Results: Of the 352 patients (57.4% were male, 13.9% were black, and mean age was 61 years), 91 (25.9%) developed AKI during their hospitalization, of whom 25 (27.4%) required dialysis. The median suPAR level was 5.61 ng/ml. AKI incidence rose with increasing suPAR tertiles, from a 6.0% incidence in patients with suPAR <4.60 ng/ml (first tertile) to a 45.8% incidence of AKI in patients with suPAR levels >6.86 ng/ml (third tertile). None of the patients with suPAR <4.60 ng/ml required dialysis during their hospitalization. In multivariable analysis, the highest suPAR tertile was associated with a 9.15-fold increase in the odds of AKI (95% confidence interval [95% CI], 3.64 to 22.93) and a 22.86-fold increase in the odds of requiring dialysis (95% CI, 2.77 to 188.75). The association was independent of inflammatory markers and persisted across subgroups.

Conclusions: Admission suPAR levels in patients hospitalized for COVID-19 are predictive of in-hospital AKI and the need for dialysis. SuPAR may be a key component of the pathophysiology of AKI in COVID-19.
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http://dx.doi.org/10.1681/ASN.2020060829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608953PMC
November 2020

Podocyte Integrin- and Activated Protein C Coordinately Restrict RhoA Signaling and Ameliorate Diabetic Nephropathy.

J Am Soc Nephrol 2020 08 24;31(8):1762-1780. Epub 2020 Jul 24.

Institute of Clinical Chemistry and Pathobiochemistry, Otto von Guericke University Magdeburg, Magdeburg, Germany

Background: Diabetic nephropathy (dNP), now the leading cause of ESKD, lacks efficient therapies. Coagulation protease-dependent signaling modulates dNP, in part the G protein-coupled, protease-activated receptors (PARs). Specifically, the cytoprotective protease-activated protein C (aPC) protects from dNP, but the mechanisms are not clear.

Methods: A combination of approaches and mouse models evaluated the role of aPC-integrin interaction and related signaling in dNP.

Results: The zymogen protein C and aPC bind to podocyte integrin-, a subunit of integrin-. Deficiency of this integrin impairs thrombin-mediated generation of aPC on podocytes. The interaction of aPC with integrin- induces transient binding of integrin- with G and controls PAR-dependent RhoA signaling in podocytes. Binding of aPC to integrin- its RGD sequence is required for the temporal restriction of RhoA signaling in podocytes. In podocytes lacking integrin-, aPC induces sustained RhoA activation, mimicking the effect of thrombin. , overexpression of wild-type aPC suppresses pathologic renal RhoA activation and protects against dNP. Disrupting the aPC-integrin- interaction by specifically deleting podocyte integrin- or by abolishing aPC's integrin-binding RGD sequence enhances RhoA signaling in mice with high aPC levels and abolishes aPC's nephroprotective effect. Pharmacologic inhibition of PAR1, the pivotal thrombin receptor, restricts RhoA activation and nephroprotects RGE-aPC and wild-type mice. aPC-integrin- acts as a rheostat, controlling PAR1-dependent RhoA activation in podocytes in diabetic nephropathy. These results identify integrin- as an essential coreceptor for aPC that is required for nephroprotective aPC-PAR signaling in dNP.
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http://dx.doi.org/10.1681/ASN.2019111163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460917PMC
August 2020

Factors Associated With Death in Critically Ill Patients With Coronavirus Disease 2019 in the US.

JAMA Intern Med 2020 07 15. Epub 2020 Jul 15.

Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts.

Importance: The US is currently an epicenter of the coronavirus disease 2019 (COVID-19) pandemic, yet few national data are available on patient characteristics, treatment, and outcomes of critical illness from COVID-19.

Objectives: To assess factors associated with death and to examine interhospital variation in treatment and outcomes for patients with COVID-19.

Design, Setting, And Participants: This multicenter cohort study assessed 2215 adults with laboratory-confirmed COVID-19 who were admitted to intensive care units (ICUs) at 65 hospitals across the US from March 4 to April 4, 2020.

Exposures: Patient-level data, including demographics, comorbidities, and organ dysfunction, and hospital characteristics, including number of ICU beds.

Main Outcomes And Measures: The primary outcome was 28-day in-hospital mortality. Multilevel logistic regression was used to evaluate factors associated with death and to examine interhospital variation in treatment and outcomes.

Results: A total of 2215 patients (mean [SD] age, 60.5 [14.5] years; 1436 [64.8%] male; 1738 [78.5%] with at least 1 chronic comorbidity) were included in the study. At 28 days after ICU admission, 784 patients (35.4%) had died, 824 (37.2%) were discharged, and 607 (27.4%) remained hospitalized. At the end of study follow-up (median, 16 days; interquartile range, 8-28 days), 875 patients (39.5%) had died, 1203 (54.3%) were discharged, and 137 (6.2%) remained hospitalized. Factors independently associated with death included older age (≥80 vs <40 years of age: odds ratio [OR], 11.15; 95% CI, 6.19-20.06), male sex (OR, 1.50; 95% CI, 1.19-1.90), higher body mass index (≥40 vs <25: OR, 1.51; 95% CI, 1.01-2.25), coronary artery disease (OR, 1.47; 95% CI, 1.07-2.02), active cancer (OR, 2.15; 95% CI, 1.35-3.43), and the presence of hypoxemia (Pao2:Fio2<100 vs ≥300 mm Hg: OR, 2.94; 95% CI, 2.11-4.08), liver dysfunction (liver Sequential Organ Failure Assessment score of 2 vs 0: OR, 2.61; 95% CI, 1.30-5.25), and kidney dysfunction (renal Sequential Organ Failure Assessment score of 4 vs 0: OR, 2.43; 95% CI, 1.46-4.05) at ICU admission. Patients admitted to hospitals with fewer ICU beds had a higher risk of death (<50 vs ≥100 ICU beds: OR, 3.28; 95% CI, 2.16-4.99). Hospitals varied considerably in the risk-adjusted proportion of patients who died (range, 6.6%-80.8%) and in the percentage of patients who received hydroxychloroquine, tocilizumab, and other treatments and supportive therapies.

Conclusions And Relevance: This study identified demographic, clinical, and hospital-level risk factors that may be associated with death in critically ill patients with COVID-19 and can facilitate the identification of medications and supportive therapies to improve outcomes.
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http://dx.doi.org/10.1001/jamainternmed.2020.3596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364338PMC
July 2020

Soluble Urokinase Receptor and Acute Kidney Injury. Reply.

N Engl J Med 2020 05;382(22):2167-2168

Rush University Medical Center, Chicago, IL.

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http://dx.doi.org/10.1056/NEJMc2003613DOI Listing
May 2020

Sex Differences in Circulating Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR) Levels and Adverse Outcomes in Coronary Artery Disease.

J Am Heart Assoc 2020 03 22;9(5):e015457. Epub 2020 Feb 22.

Division of Cardiology Department of Medicine Emory Clinical Cardiovascular Research Institute Emory University School of Medicine Atlanta GA.

Background Women have higher circulating levels of soluble urokinase-type plasminogen activator receptor (suPAR), and elevated suPAR is associated with cardiovascular risk. The independent association of sex with suPAR and the impact of sex on its association with cardiovascular risk are unknown. Methods and Results Plasma suPAR was measured using ELISA in 2 cohorts of 666 asymptomatic individuals (49 years, 65% women) and 4184 patients with coronary artery disease (63 years, 37% women). Independent association of sex with suPAR was studied using linear regression models adjusted for demographics, risk factors, and visceral adiposity in asymptomatic participants. Impact of sex on association of suPAR with all-cause mortality was studied in patients with coronary artery disease using multivariable-adjusted Cox models. Sex-specific suPAR cutoffs for predicting all-cause mortality were calculated. Asymptomatic women had 10% higher suPAR compared with men after adjusting for confounders, and visceral adiposity partly accounted for this association. Over a median follow-up of 5.2 years, 795 deaths were recorded in patients with coronary artery disease. Log-transformed suPAR was independently associated with mortality (hazard ratio per 1-SD 1.72, 95% CI 1.60-1.85) and an interaction with sex was noted (=0.005). Association of suPAR with mortality was slightly weaker in women (hazard ratio 1.61, 95% CI 1.41-1.83) compared with men (hazard ratio 1.83, 95% CI 1.67-2.00). However, using sex-specific suPAR cut-offs (4392 pg/mL for women and 3187 pg/mL for men), a similar mortality incidence was observed for both sexes (38.5% and 35.5%, respectively, =0.3). Conclusions Women have 10% higher plasma suPAR levels compared with men. Elevated sex-specific plasma suPAR levels are equally predictive of risk of adverse events in both sexes.
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http://dx.doi.org/10.1161/JAHA.119.015457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335555PMC
March 2020

Soluble Urokinase Receptor and Acute Kidney Injury.

N Engl J Med 2020 01;382(5):416-426

From the Division of Cardiology, Department of Medicine, University of Michigan, Ann Arbor (S.S.H.); the Divisions of Renal Medicine (D.E.L., S. Sharma, S.S.W.) and Pulmonary and Critical Care Medicine (R.M.B.), Brigham and Women's Hospital, the Section of Nephrology, Department of Medicine, Boston University School of Medicine (S.S.W.), and the Divisions of Nephrology (S. Sever) and Cardiology (A.C., N.E.I., J.L.J.), Massachusetts General Hospital - all in Boston; Emory Clinical Cardiovascular Research Institute, Emory University School of Medicine, Atlanta (A.S.T., M.R., A.A.Q.); the Department of Medicine, Rush University Medical Center, Chicago (X.W., R.R.D., M.M.A., C.W., J.R.); the Section of Nephrology, Department of Medicine, Baylor College of Medicine, Houston (D.S.-H., J.S.-C.P., M.W.H.); and the Veterans Affairs Pittsburgh Healthcare System and the University of Pittsburgh School of Medicine, Pittsburgh (S.D.W.).

Background: Acute kidney injury is common, with a major effect on morbidity and health care utilization. Soluble urokinase plasminogen activator receptor (suPAR) is a signaling glycoprotein thought to be involved in the pathogenesis of kidney disease. We investigated whether a high level of suPAR predisposed patients to acute kidney injury in multiple clinical contexts, and we used experimental models to identify mechanisms by which suPAR acts and to assess it as a therapeutic target.

Methods: We measured plasma levels of suPAR preprocedurally in patients who underwent coronary angiography and patients who underwent cardiac surgery and at the time of admission to the intensive care unit in critically ill patients. We assessed the risk of acute kidney injury at 7 days as the primary outcome and acute kidney injury or death at 90 days as a secondary outcome, according to quartile of suPAR level. In experimental studies, we used a monoclonal antibody to urokinase plasminogen activator receptor (uPAR) as a therapeutic strategy to attenuate acute kidney injury in transgenic mice receiving contrast material. We also assessed cellular bioenergetics and generation of reactive oxygen species in human kidney proximal tubular (HK-2) cells that were exposed to recombinant suPAR.

Results: The suPAR level was assessed in 3827 patients who were undergoing coronary angiography, 250 who were undergoing cardiac surgery, and 692 who were critically ill. Acute kidney injury developed in 318 patients (8%) who had undergone coronary angiography. The highest suPAR quartile (vs. the lowest) had an adjusted odds ratio of 2.66 (95% confidence interval [CI], 1.77 to 3.99) for acute kidney injury and 2.29 (95% CI, 1.71 to 3.06) for acute kidney injury or death at 90 days. Findings were similar in the surgical and critically ill cohorts. The suPAR-overexpressing mice that were given contrast material had greater functional and histologic evidence of acute kidney injury than wild-type mice. The suPAR-treated HK-2 cells showed heightened energetic demand and mitochondrial superoxide generation. Pretreatment with a uPAR monoclonal antibody attenuated kidney injury in suPAR-overexpressing mice and normalized bioenergetic changes in HK-2 cells.

Conclusions: High suPAR levels were associated with acute kidney injury in various clinical and experimental contexts. (Funded by the National Institutes of Health and others.).
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http://dx.doi.org/10.1056/NEJMoa1911481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065830PMC
January 2020

Phase I trial of donor-derived modified immune cell infusion in kidney transplantation.

J Clin Invest 2020 05;130(5):2364-2376

Transplantation Immunology, Institute of Immunology.

BACKGROUNDPreclinical experiments have shown that donor blood cells, modified in vitro by an alkylating agent (modified immune cells [MICs]), induced long-term specific immunosuppression against the allogeneic donor.METHODSIn this phase I trial, patients received either 1.5 × 106 MICs per kg BW on day -2 (n = 3, group A), or 1.5 × 108 MICs per kg BW on day -2 (n = 3, group B) or day -7 (n = 4, group C) before living donor kidney transplantation in addition to post-transplantation immunosuppression. The primary outcome measure was the frequency of adverse events (AEs) until day 30 (study phase) with follow-up out to day 360.RESULTSMIC infusions were extremely well tolerated. During the study phase, 10 treated patients experienced a total of 69 AEs that were unlikely to be related or not related to MIC infusion. No donor-specific human leukocyte antigen Abs or rejection episodes were noted, even though the patients received up to 1.3 × 1010 donor mononuclear cells before transplantation. Group C patients with low immunosuppression during follow-up showed no in vitro reactivity against stimulatory donor blood cells on day 360, whereas reactivity against third-party cells was still preserved. Frequencies of CD19+CD24hiCD38hi transitional B lymphocytes (Bregs) increased from a median of 6% before MIC infusion to 20% on day 180, which was 19- and 68-fold higher, respectively, than in 2 independent cohorts of transplanted controls. The majority of Bregs produced the immunosuppressive cytokine IL-10. MIC-treated patients showed the Immune Tolerance Network operational tolerance signature.CONCLUSIONMIC administration was safe and could be a future tool for the targeted induction of tolerogenic Bregs.TRIAL REGISTRATIONEudraCT number: 2014-002086-30; ClinicalTrials.gov identifier: NCT02560220.FUNDINGFederal Ministry for Economic Affairs and Technology, Berlin, Germany, and TolerogenixX GmbH, Heidelberg, Germany.
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http://dx.doi.org/10.1172/JCI133595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190926PMC
May 2020

Intratumoral injection of the seasonal flu shot converts immunologically cold tumors to hot and serves as an immunotherapy for cancer.

Proc Natl Acad Sci U S A 2020 01 30;117(2):1119-1128. Epub 2019 Dec 30.

Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901;

Reprogramming the tumor microenvironment to increase immune-mediated responses is currently of intense interest. Patients with immune-infiltrated "hot" tumors demonstrate higher treatment response rates and improved survival. However, only the minority of tumors are hot, and a limited proportion of patients benefit from immunotherapies. Innovative approaches that make tumors hot can have immediate impact particularly if they repurpose drugs with additional cancer-unrelated benefits. The seasonal influenza vaccine is recommended for all persons over 6 mo without prohibitive contraindications, including most cancer patients. Here, we report that unadjuvanted seasonal influenza vaccination via intratumoral, but not intramuscular, injection converts "cold" tumors to hot, generates systemic CD8 T cell-mediated antitumor immunity, and sensitizes resistant tumors to checkpoint blockade. Importantly, intratumoral vaccination also provides protection against subsequent active influenza virus lung infection. Surprisingly, a squalene-based adjuvanted vaccine maintains intratumoral regulatory B cells and fails to improve antitumor responses, even while protecting against active influenza virus lung infection. Adjuvant removal, B cell depletion, or IL-10 blockade recovers its antitumor effectiveness. Our findings propose that antipathogen vaccines may be utilized for both infection prevention and repurposing as a cancer immunotherapy.
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http://dx.doi.org/10.1073/pnas.1904022116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6969546PMC
January 2020

Soluble Urokinase Receptor and Liver Disease.

Clin Liver Dis (Hoboken) 2019 Nov 20;14(5):163-166. Epub 2019 Dec 20.

Department of Internal Medicine Rush University Medical Center Chicago IL.

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http://dx.doi.org/10.1002/cld.850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924968PMC
November 2019

Apolipoprotein C3 induces inflammation and organ damage by alternative inflammasome activation.

Nat Immunol 2020 01 9;21(1):30-41. Epub 2019 Dec 9.

Department of Internal Medicine IV (Nephrology and Hypertension), Saarland University, Homburg, Germany.

NLRP3-inflammasome-driven inflammation is involved in the pathogenesis of a variety of diseases. Identification of endogenous inflammasome activators is essential for the development of new anti-inflammatory treatment strategies. Here, we identified that apolipoprotein C3 (ApoC3) activates the NLRP3 inflammasome in human monocytes by inducing an alternative NLRP3 inflammasome via caspase-8 and dimerization of Toll-like receptors 2 and 4. Alternative inflammasome activation in human monocytes is mediated by the Toll-like receptor adapter protein SCIMP. This triggers Lyn/Syk-dependent calcium entry and the production of reactive oxygen species, leading to activation of caspase-8. In humanized mouse models, ApoC3 activated human monocytes in vivo to impede endothelial regeneration and promote kidney injury in an NLRP3- and caspase-8-dependent manner. These data provide new insights into the regulation of the NLRP3 inflammasome and the pathophysiological role of triglyceride-rich lipoproteins containing ApoC3. Targeting ApoC3 might prevent organ damage and provide an anti-inflammatory treatment for vascular and kidney diseases.
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http://dx.doi.org/10.1038/s41590-019-0548-1DOI Listing
January 2020

Cell Cycle Biomarkers and Soluble Urokinase-Type Plasminogen Activator Receptor for the Prediction of Sepsis-Induced Acute Kidney Injury Requiring Renal Replacement Therapy: A Prospective, Exploratory Study.

Crit Care Med 2019 12;47(12):e999-e1007

Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany.

Objectives: Sepsis-induced acute kidney injury is the dominant acute kidney injury etiology in critically ill patients and is often associated with a need for renal replacement therapy. The indication and timing of renal replacement therapy are controversially discussed. We hypothesized that the product of the G1-cell cycle arrest biomarkers tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 ([TIMP-2] × [IGFBP7]), and the soluble urokinase-type plasminogen activator receptor are of diagnostic value for the prediction of septic acute kidney injury courses requiring renal replacement therapy.

Design: In this prospective study, critically ill patients were enrolled immediately after the fulfillment of Sepsis-3 criteria. Urinary [TIMP-2] × [IGFBP7] levels over time and serum soluble urokinase-type plasminogen activator receptor levels once at inclusion were measured. The primary endpoint was the development of septic acute kidney injury with the need for renal replacement therapy. Area under the receiver operating characteristic curves, de Long's tests, and logistic regression models were calculated.

Setting: Two ICUs at Heidelberg University Hospital between May 2017 and July 2018.

Patients: One-hundred critically ill patients with positive Sepsis-3 criteria.

Interventions: None.

Measurement And Main Results: Nineteen patients required renal replacement therapy. Diagnostic performance of urinary [TIMP-2] × [IGFBP7] improved over time with the highest area under the receiver operating characteristic curve of 0.89 (95% CI, 0.80-0.98) 24 hours after study inclusion. Soluble urokinase-type plasminogen activator receptor levels at inclusion showed an area under the receiver operating characteristic curve of 0.83 (0.75-0.92). The best discrimination ability for the primary outcome measure was achieved for [TIMP-2] × [IGFBP7] at 24 hours after inclusion by applying a cutoff value of greater than or equal to 0.6 (ng/mL)/1,000 (sensitivity 90.9, specificity 67.1). Soluble urokinase-type plasminogen activator receptor performed best by using a cutoff value of greater than or equal to 8.53 ng/mL (sensitivity 84.2, specificity 82.7). A combination of newly tested biomarkers with cystatin C resulted in a significantly improved diagnostic accuracy. Cystatin C in combination with [TIMP-2] × [IGFBP7] 24 hours outperformed all standard renal parameters (area under the receiver operating characteristic curve 0.93 [0.86-1.00]).

Conclusions: [TIMP-2] × [IGFBP7] and soluble urokinase-type plasminogen activator receptor are promising biomarker candidates for the risk stratification of septic acute kidney injury patients with the need for renal replacement therapy.
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http://dx.doi.org/10.1097/CCM.0000000000004042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6867703PMC
December 2019

Contribution of Coiled-Coil Assembly to Ca/Calmodulin-Dependent Inactivation of TRPC6 Channel and its Impacts on FSGS-Associated Phenotypes.

J Am Soc Nephrol 2019 09 2;30(9):1587-1603. Epub 2019 Jul 2.

Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering,

Background: TRPC6 is a nonselective cation channel, and mutations of this gene are associated with FSGS. These mutations are associated with TRPC6 current amplitude amplification and/or delay of the channel inactivation (gain-of-function phenotype). However, the mechanism of the gain-of-function in TRPC6 activity has not yet been clearly solved.

Methods: We performed electrophysiologic, biochemical, and biophysical experiments to elucidate the molecular mechanism underlying calmodulin (CaM)-mediated Ca-dependent inactivation (CDI) of TRPC6. To address the pathophysiologic contribution of CDI, we assessed the actin filament organization in cultured mouse podocytes.

Results: Both lobes of CaM helped induce CDI. Moreover, CaM binding to the TRPC6 CaM-binding domain (CBD) was Ca-dependent and exhibited a 1:2 (CaM/CBD) stoichiometry. The TRPC6 coiled-coil assembly, which brought two CBDs into adequate proximity, was essential for CDI. Deletion of the coiled-coil slowed CDI of TRPC6, indicating that the coiled-coil assembly configures both lobes of CaM binding on two CBDs to induce normal CDI. The FSGS-associated TRPC6 mutations within the coiled-coil severely delayed CDI and often increased TRPC6 current amplitudes. In cultured mouse podocytes, FSGS-associated channels and CaM mutations led to sustained Ca elevations and a disorganized cytoskeleton.

Conclusions: The gain-of-function mechanism found in FSGS-causing mutations in TRPC6 can be explained by impairments of the CDI, caused by disruptions of TRPC's coiled-coil assembly which is essential for CaM binding. The resulting excess Ca may contribute to structural damage in the podocytes.
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http://dx.doi.org/10.1681/ASN.2018070756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727271PMC
September 2019

Soluble Urokinase Plasminogen Activator Receptor and Decline in Kidney Function in Autosomal Dominant Polycystic Kidney Disease.

J Am Soc Nephrol 2019 07 6;30(7):1305-1313. Epub 2019 Jun 6.

Department of Medicine, Rush University Medical Center, Chicago, Illinois;

Background: Levels of soluble urokinase plasminogen activator receptor (suPAR), an inflammation marker, are strongly predictive of incident kidney disease. Patients with autosomal dominant polycystic kidney disease (ADPKD) experience progressive decline in renal function, but rates of decline and outcomes vary greatly. Whether suPAR levels are predictive of declining kidney function in patients with ADPKD is unknown.

Methods: We assessed suPAR levels in 649 patients with ADPKD who underwent scheduled follow-up for at least 3 years, with repeated measurements of height-adjusted total kidney volume and creatinine-derived eGFR. We used linear mixed models for repeated measures and Cox proportional hazards to characterize associations between baseline suPAR levels and follow-up eGFR or incident ESRD.

Results: The median suPAR level was 2.47 ng/ml and median height-adjusted total kidney volume was 778, whereas mean eGFR was 84 ml/min per 1.73 m. suPAR levels were associated with height-adjusted total kidney volume (=0.02; 95% confidence interval, 0.01 to 0.03), independent of age, sex, race, hypertension, and eGFR. Patients in the lowest suPAR tertile (<2.18 ng/ml) had a 6.8% decline in eGFR at 3 years and 22% developed CKD stage 3, whereas those in the highest tertile (suPAR>2.83 ng/ml) had a 19.4% decline in eGFR at 3 years and 68% developed CKD stage 3. suPAR levels >2.82 ng/ml had a 3.38-fold increase in the risk of incident ESRD.

Conclusions: suPAR levels were associated with progressive decline in renal function and incident ESRD in patients with ADPKD, and may aid early identification of patients at high risk of disease progression.
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http://dx.doi.org/10.1681/ASN.2018121227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6622421PMC
July 2019

Nonimmune cell-derived ICOS ligand functions as a renoprotective αvβ3 integrin-selective antagonist.

J Clin Invest 2019 04 18;129(4):1713-1726. Epub 2019 Mar 18.

Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.

Soluble urokinase receptor (suPAR) is a circulatory molecule that activates αvβ3 integrin on podocytes, causes foot process effacement, and contributes to proteinuric kidney disease. While active integrin can be targeted by antibodies and small molecules, endogenous inhibitors haven't been discovered yet. Here we report what we believe is a novel renoprotective role for the inducible costimulator ligand (ICOSL) in early kidney disease through its selective binding to podocyte αvβ3 integrin. Contrary to ICOSL's immune-regulatory role, ICOSL in nonhematopoietic cells limited the activation of αvβ3 integrin. Specifically, ICOSL contains the arginine-glycine-aspartate (RGD) motif, which allowed for a high-affinity and selective binding to αvβ3 and modulation of podocyte adhesion. This binding was largely inhibited either by a synthetic RGD peptide or by a disrupted RGD sequence in ICOSL. ICOSL binding favored the active αvβ3 rather than the inactive form and showed little affinity for other integrins. Consistent with the rapid induction of podocyte ICOSL by inflammatory stimuli, glomerular ICOSL expression was increased in biopsies of early-stage human proteinuric kidney diseases. Icosl deficiency in mice resulted in an increased susceptibility to proteinuria that was rescued by recombinant ICOSL. Our work identified a potentially novel role for ICOSL, which serves as an endogenous αvβ3-selective antagonist to maintain glomerular filtration.
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http://dx.doi.org/10.1172/JCI123386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436851PMC
April 2019

uPAR isoform 2 forms a dimer and induces severe kidney disease in mice.

J Clin Invest 2019 04 2;129(5):1946-1959. Epub 2019 Apr 2.

Department of Medicine, Rush University Medical Center, Chicago, Illinois, USA.

Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived circulating signaling molecule that has been implicated in chronic kidney disease, such as focal segmental glomerulosclerosis (FSGS). Typically, native uPAR (isoform 1) translates to a 3-domain protein capable of binding and activating integrins, yet the function of additional isoforms generated by alternative splicing is unknown. Here, we characterized mouse uPAR isoform 2 (msuPAR2), encoding domain I and nearly one-half of domain II, as a dimer in solution, as revealed by 3D electron microscopy structural analysis. In vivo, msuPAR2 transgenic mice exhibited signs of severe renal disease characteristic of FSGS with proteinuria, loss of kidney function, and glomerulosclerosis. Sequencing of the glomerular RNAs from msuPAR2-Tg mice revealed a differentially expressed gene signature that includes upregulation of the suPAR receptor Itgb3, encoding β3 integrin. Crossing msuPAR2-transgenic mice with 3 different integrin β3 deficiency models rescued msuPAR2-mediated kidney function. Further analyses indicated a central role for β3 integrin and c-Src in msuPAR2 signaling and in human FSGS kidney biopsies. Administration of Src inhibitors reduced proteinuria in msuPAR2-transgenic mice. In conclusion, msuPAR2 may play an important role in certain forms of scarring kidney disease.
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http://dx.doi.org/10.1172/JCI124793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486353PMC
April 2019

Soluble urokinase plasminogen activation receptor and long-term outcomes in persons undergoing coronary angiography.

Sci Rep 2019 01 24;9(1):475. Epub 2019 Jan 24.

Vth Department of Medicine, Medical Faculty Mannheim of the University of Heidelberg, Mannheim, Germany.

Soluble urokinase plasminogen activation receptor (suPAR) is risk factor for kidney disease and biomarker for cardiovascular outcomes but long term longitudinal analyses in a large European cohort have not been perfomed. To hus, we studied suPAR in participants of the Ludwigshafen Risk and Cardiovascular Health study over a very long follow-up time of nearly 10 years. We estimated overall risk of all-cause and cardiovascular death by Cox proportional hazards regression according to quartiles of suPAR, including age, sex, use of lipid-lowering drugs, body mass index, diabetes mellitus, hypertension, smoking, lipids, as well as glomerular filtration rate (eGFR), NT-proBNP, interleukin-6 and high-sensitive CRP as covariates. A total of 2940 participants (age 62.7 ± 10.5years) having a median eGFR of 83.8 mL/min/1.73 m were included. The median suPAR concentration was 3010 pg/mL (interquartile range, 2250-3988 pg/mL). Using the lowest quartile of suPAR as the reference, crude hazard ratio for cardiovascular mortality were 1.58 (95% CI 1.16-2.16), 1.85 (95% CI 1.37-2.52) and 2.75 (95% CI 2.03-3.71) in the second, third and fourth quartile, respectively. Adjusting for NT-proBNPeGFR or inflammation (interleukin-6 and high-sensitive CRP) confirmed results. suPAR predicts all-cause and cardiovascular death over a period of ten years in persons undergoing coronary angiography, independent of the natriuretic peptide NT-proBNP, kidney function and of markers of systemic inflammation. Future investigation into a potential causal role of suPAR in cardiovascular disease is warranted.
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http://dx.doi.org/10.1038/s41598-018-36960-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346054PMC
January 2019

MeSsAGe risk score: tool for renal biopsy decision in steroid-dependent nephrotic syndrome.

Pediatr Res 2019 03 15;85(4):477-483. Epub 2019 Jan 15.

Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Level 12 NUHS Tower Block, 1E Kent Ridge Road, Singapore, 119228, Singapore.

Background: A lack of consensus exists as to the timing of kidney biopsy in children with steroid-dependent nephrotic syndrome (SDNS) where minimal change disease (MCD) predominates. This study aimed at examining the applicability of a biomarker-assisted risk score model to select SDNS patients at high risk of focal segmental glomerulosclerosis (FSGS) for biopsy.

Methods: Fifty-five patients with SDNS and biopsy-proven MCD (n = 40) or FSGS (n = 15) were studied. A risk score model was developed with variables consisting of age, sex, eGFR, suPAR levels and percentage of CD8 memory T cells. Following multivariate regression analysis, total risk score was calculated as sum of the products of odds ratios and corresponding variables. Predictive cut-off point was determined using receiver operator characteristics (ROC) curve analysis.

Results: Plasma suPAR levels in FSGS patients were significantly higher, while percentage of CD45ROCD8CD3 was significantly lower than in MCD patients and controls. ROC analysis suggests the risk score model with threshold score of 16.7 (AUC 0.84, 95% CI 0.72-0.96) was a good predictor of FSGS on biopsy. The 100% PPV cut-off was >24.0, while the 100% NPV was <13.3.

Conclusion: A suPAR and CD8 memory T cell percentage-based risk score model was developed to stratify SDNS patients for biopsy and for predicting FSGS.
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http://dx.doi.org/10.1038/s41390-019-0277-zDOI Listing
March 2019

Monitoring suPAR levels in post-kidney transplant focal segmental glomerulosclerosis treated with therapeutic plasma exchange and rituximab.

BMC Nephrol 2018 12 17;19(1):361. Epub 2018 Dec 17.

Department of Medicine, Rush University Medical Center, 1735 W Harrison ST, Cohn Bldg, 7th Floor, Suite 716, Chicago, IL, 60612, USA.

Background: Therapeutic plasma exchange (TPE) is an important therapy for recurrent focal segmental glomerulosclerosis (rFSGS) post kidney transplant. suPAR has been causally implicated in rFSGS, and shown to be a unique biomarker for the occurrence and progression of chronic kidney disease. This study was targeted to evaluate the application of monitoring suPAR in TPE treated rFSGS.

Methods: A retrospective (n = 19) and a prospective (n = 15) cohort of post transplant FSGS patients treated with TPE and rituximab were enrolled. We measured serum suPAR levels before and after the combined therapies, and assessed the role of suPAR changes on proteinuria reduction and podocyte β3- integrin activity.

Results: Treatment with TPE and rituximab resulted in significant decrease in proteinuria and suPAR levels. Among the variables including baseline suPAR, serum creatinine, proteinuria, eGFR, age at diagnosis, age at transplantation, transplantation numbers, time to recurrence, and TPE course numbers, only the reduction in suPAR levels and baseline proteinuria significantly correlated with the changes in proteinuria after treatment, with the former performed better in predicting proteinuria alteration. Additionally, the mean podocyte β3 integrin activity significantly decreased after TPE and rituximab treatment (1.10 ± 0.08) as compared to before treatment (1.34 ± 0.08), p < 0.05. Only the reduction in suPAR predicted the response to therapies with an odds ratio of 1.43, 95% CI (1.02, 2.00), p < 0.05.

Conclusions: Serum suPAR levels reduced significantly after TPE and rituximab treatment in post transplant FSGS patients. The reduction in suPAR levels may be utilized to assess the changes in proteinuria and monitor the response to the therapies. Larger, multi-centered prospective studies monitoring serum suPAR levels in TPE managed post transplant FSGS are warranted.
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http://dx.doi.org/10.1186/s12882-018-1177-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296111PMC
December 2018

More expression, less function: cleaved dynamin in glomerular kidney disease.

J Pathol 2019 Apr 25;247(4):413-415. Epub 2019 Jan 25.

Department of Medicine, Rush University Medical Center, Chicago, IL, USA.

The role of dynamin in regulation of kidney filtration barrier is well documented. Dynamin binds to and produces filamentous actin, which is a key component of healthy podocyte foot processes (FPs). Destruction of dynamin, for example by cathepsin L, leads to loss of a functional actin network and uncoordinated membrane signaling, a situation that allows for effacement of FPs and proteinuria. Now, Khalil et al have examined the dynamin expression in kidneys of proteinuric animal models as well as in kidney patients and produced data that further clarifies the role of dynamin in glomerular and tubular proteinuria and may aid in pinpointing patients who are affected by loss of dynamin function and may benefit from appropriate therapeutic approaches. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5217DOI Listing
April 2019

Podocytes: Way to Go.

Am J Pathol 2019 02 11;189(2):226-228. Epub 2018 Dec 11.

Department of Medicine, Rush University Medical Center, Chicago, Illinois.

This commentary highlights the article by Hara et al that discusses the clinical implications of mitotic catastrophe in podocyte health during diabetic kidney disease.
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http://dx.doi.org/10.1016/j.ajpath.2018.11.003DOI Listing
February 2019

Motility of human renal cells is disturbed by infection with pathogenic hantaviruses.

BMC Infect Dis 2018 Dec 12;18(1):645. Epub 2018 Dec 12.

Department of Nephrology, University of Heidelberg, Im Neuenheimer Feld 162, 69120, Heidelberg, Germany.

Background: Hemorrhagic fever with renal syndrome (HFRS) caused by pathogenic hantaviruses in Europe and Asia is often characterized by acute kidney injury (AKI) with massive proteinuria. Renal filtration depends on the integrity of epithelial and endothelial monolayers in the tubular and glomerular apparatus. Tubular and glomerular cells represent target cells of hantavirus infection. However, the detailed mechanisms of renal impairment induced by hantaviruses are not well understood.

Methods: We analyzed the cellular consequences of hantavirus infection by measuring adhesion and migration capacity of human renal cells infected with Puumala (PUUV) or Hantaan (HTNV) virus. The impact of hantaviral nucleocapsid proteins (N proteins) on motility was examined by transfection of podocytes.

Results: Infection of kidney cells with hantavirus species PUUV and HTNV causes a significant reduction of migration capacity. The impaired motility depends on viral replication and transfection of podocytes with N protein of PUUV or HTNV reveals that the expression of N protein alone is sufficient to deteriorate podocyte function. The cellular effects are more pronounced for the more pathogenic HTNV than for PUUV that causes a milder form of HFRS.

Conclusions: The direct impairment of migration capacity of renal cells by hantaviral N proteins may contribute substantially to proteinuria observed in the clinical picture of hantavirus infection.
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http://dx.doi.org/10.1186/s12879-018-3583-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292036PMC
December 2018

Virus- and cell type-specific effects in orthohantavirus infection.

Virus Res 2019 01 30;260:102-113. Epub 2018 Nov 30.

Department of Nephrology, University of Heidelberg, Heidelberg, Germany. Electronic address:

Orthohantaviruses Hantaan (HTNV) and Puumala (PUUV) virus cause hemorrhagic fever with renal syndrome (HFRS), that is characterized by acute renal failure with often massive proteinuria and by morphological changes of the tubular and glomerular apparatus. Orthohantaviral N protein is found in renal cells and plays a key role in replication. However, the replication in human renal cells is not well characterized. Therefore, we examined the orthohantaviral infection in different human renal cells. Differences in localization of N protein, release of particles, and modulation of the actin cytoskeleton between both virus species are observed in human renal cells. A substantial portion of HTNV N protein demonstrates a filamentous pattern in addition to the typical punctate pattern. Release of HTNV depends on an intact actin and microtubule cytoskeleton. In contrast, PUUV N protein is generally localized in a punctate pattern and release of PUUV does not require an intact actin cytoskeleton. Infection of podocytes results in cytoskeletal rearrangements that are more pronounced for HTNV. Analyzing Vero E6 cells revealed differences compared to human renal cells. The pattern of N proteins is strictly punctate, release does not depend on an intact actin cytoskeleton and cytoskeletal rearrangements are not present. No virus-specific variations between HTNV and PUUV are observed in Vero E6 cells. Using human renal cells as cell culture model for orthohantavirus infection demonstrates virus-specific differences and orthohantavirus-induced cytoskeletal rearrangements that are not observed in Vero E6 cells. Therefore, the choice of an appropriate cell culture system is a prerequisite to study orthohantavirus pathogenicity.
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http://dx.doi.org/10.1016/j.virusres.2018.11.015DOI Listing
January 2019

Soluble Urokinase Plasminogen Activator Receptor Is Predictive of Non-AIDS Events During Antiretroviral Therapy-mediated Viral Suppression.

Clin Infect Dis 2019 08;69(4):676-686

Division of Infectious Diseases, Department of Medicine, University of California San Diego, Austria.

Background: Despite effective antiretroviral therapy (ART), human immunodeficiency virus (HIV) infection remains associated with higher morbidity and mortality, driven, in part, by increased inflammation. Our objective was to identify associations between levels of plasma biomarkers of chronic inflammation, microbial translocation, and monocyte activation, with occurrence of non-AIDS events.

Methods: Participants (141 cases, 310 matched controls) were selected from a longitudinal observational trial; all were virally suppressed on ART at year 1 and thereafter. Soluble urokinase plasminogen activator receptor (suPAR), lipopolysaccharide binding protein (LBP), beta-D-glucan (BDG), intestinal fatty-acid binding protein, oxidized low-density lipoproteins, and soluble CD163 were measured pre-ART, after 1-year of ART, and pre-event. At each time point, conditional logistic regression analysis assessed associations of the biomarkers with events and adjusted for relevant covariates to calculate odds ratios (ORs) according to 1 interquartile range (IQR) difference.

Results: At all time points, higher levels of suPAR were associated with increased risk of non-AIDS events (OR per 1 IQR was 1.7 before ART-initiation, OR per 1 IQR was 2.0 after 1 year of suppressive ART, and OR 2.1 pre-event). Higher levels of BDG and LBP at year 1 and pre-event (but not at baseline) were associated with increased risk of non-AIDS events. No associations were observed for other biomarkers.

Conclusions: Elevated levels of suPAR were strongly, consistently, and independently predictive of non-AIDS events at every measured time point. Interventions that target the suPAR pathway should be investigated to explore its role in the pathogenesis of non-AIDS-related outcomes in HIV infection.
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http://dx.doi.org/10.1093/cid/ciy966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669298PMC
August 2019

Fetal Renal Echogenicity Associated with Maternal Focal Segmental Glomerulosclerosis: The Effect of Transplacental Transmission of Permeability Factor suPAR.

J Clin Med 2018 Oct 4;7(10). Epub 2018 Oct 4.

Department of Medicine, Division of Nephrology, Sunnybrook Science Health Sciences Centre, University of Toronto, Toronto, ON M4N 3M5, Canada.

We report a case of a pregnant woman with nephrotic syndrome due to biopsy-proven focal segmental glomerulosclerosis (FSGS) whose fetus developed echogenic kidneys and severe oligohydramnios by 27 weeks of gestation. Maternal treatment with prednisone resulted in normalization of the amniotic fluid indices and resolution of fetal renal echogenicity. The newborn was noted to have transient renal dysfunction and proteinuria, resolving by 6 weeks postpartum. The transplacental passage of permeability factors is postulated to have caused both the fetal and newborn renal presentation, with significantly elevated levels of soluble urokinase-type plasminogen activator receptor (suPAR) noted in the cord blood. This case documents the transplacental maternal-fetal transmission of suPAR, demonstrating the potential for maternal-fetal transmission of deleterious, disease-causing entities, and adds to the differential diagnosis of fetal echogenic kidneys. Further, this is the first documentation of a fetal response to maternal systemic therapy.
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http://dx.doi.org/10.3390/jcm7100324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209924PMC
October 2018

Kidney-derived c-kit progenitor/stem cells contribute to podocyte recovery in a model of acute proteinuria.

Sci Rep 2018 10 3;8(1):14723. Epub 2018 Oct 3.

Interdisciplinary Stem Cell Institute, Leonard M Miller School of Medicine University of Miami, Miami, 33136, Florida, USA.

Kidney-derived c-kit cells exhibit progenitor/stem cell properties and can regenerate epithelial tubular cells following ischemia-reperfusion injury in rats. We therefore investigated whether c-kit progenitor/stem cells contribute to podocyte repair in a rat model of acute proteinuria induced by puromycin aminonucleoside (PAN), the experimental prototype of human minimal change disease and early stages of focal and segmental glomerulosclerosis. We found that c-kit progenitor/stem cells accelerated kidney recovery by improving foot process effacement (foot process width was lower in c-kit group vs saline treated animals, P = 0.03). In particular, these cells engrafted in small quantity into tubules, vessels, and glomeruli, where they occasionally differentiated into podocyte-like cells. This effect was related to an up regulation of α-Actinin-4 and mTORC2-Rictor pathway. Activation of autophagy by c-kit progenitor/stem cells also contributed to kidney regeneration and intracellular homeostasis (autophagosomes and autophagolysosomes number and LC3A/B-I and LC3A/B-II expression were higher in the c-kit group vs saline treated animals, P = 0.0031 and P = 0.0009, respectively). Taken together, our findings suggest that kidney-derived c-kit progenitor/stem cells exert reparative effects on glomerular disease processes through paracrine effects, to a lesser extent differentiation into podocyte-like cells and contribution to maintenance of podocyte cytoskeleton after injury. These findings have clinical implications for cell therapy of glomerular pathobiology.
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http://dx.doi.org/10.1038/s41598-018-33082-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170432PMC
October 2018

Renal Dysfunction and Recovery following Initial Treatment of Newly Diagnosed Multiple Myeloma.

Int J Nephrol 2018 5;2018:4654717. Epub 2018 Sep 5.

Division of Hematology/Oncology, Rush University Medical Center, Chicago, IL, USA.

Introduction: Renal insufficiency (RI) in Multiple Myeloma (MM) portends a higher tumor burden and worse prognosis. Reversal of RI in newly diagnosed MM (NDMM) improves patient outcomes, but it is unknown if there is a disparity in renal recovery in NDMM between African Americans (AA) and non-African Americans.

Methods: A retrospective chart review was conducted of 690 patients with NDMM at Rush University Medical Center from 2005 to 2016. 118 patients (59 AA and 59 non-AA) with NDMM and an estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73 m at the time of diagnosis were identified and analyzed. The time to best renal response and best eGFR achieved during initial myeloma therapy were tabulated.

Results: Median eGFR at the time of diagnosis was similar between the AA and non-AA groups (47.89 versus 51.95, p=0.56). Median absolute change in eGFR after initial therapy was significantly higher in the AA (+33.64) versus the non-AA group (+21.07, p=0.00183). This difference remained whether the baseline eGFR at diagnosis was <90 or <60 mL/min/1.73 m.

Discussion: AA patients with NDMM treated in the era of novel agents have greater improvement in renal function in comparison to non-AA patients, regardless of myeloma response. The biological underpinnings for this disparity require further investigation.
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http://dx.doi.org/10.1155/2018/4654717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145056PMC
September 2018