Podocytopathies related to either COVID-19 infection or its vaccination, our experience and literature review.

Coronavirus disease 2019 (COVID-19) affects several organs including the kidney resulting in acute kidney injury (AKI) and variants of podocytopathies. From the beginning to the middle period of the COVID-19 pandemic, we have collected eight renal biopsies with various renal diseases including 4 podocytopathies. In addition, from the middle period to the near end of the COVID-19 pandemic, we have seen two of the patients who developed nephrotic syndrome following COVID-19 vaccination. Three of 4 podocytopathies were collapsing glomerulopathy (also called collapsing focal segmental glomerulosclerosis) and the fourth was a minimal change disease (MCD). Two of three collapsing glomerulopathy were found in African American patients, one of who was tested positive for having the high-risk allele APOL-1 G1. In addition, the two renal biopsies showed either MCD or replaced MCD following COVID-19 vaccination. MCD can be a rare complication following COVID-19 infection and COVID-19 vaccination, raising the question if there are similar antigens induced by the infection or by the vaccination that trigger the MCD. This article reports our experience of diagnosing podocytopathies related to either COVID-19 infection or its vaccination and provides a literature review regarding the incidence and potential pathophysiology in the field.

Myeloperoxidase immunohistochemical staining can identify glomerular endothelial cell injury in dense deposit disease.

BACKGROUND: Previous studies have demonstrated residual complement-mediated deposits in repeat kidney biopsies of C3 glomerulopathies (C3G) (dense deposit disease (DDD) and C3 glomerulonephritis) following eculizumab treatment, despite some clinical improvement. With residual complement deposition, it is difficult to determine whether there is a reduced complement-mediated endothelial cell injury. We validated that myeloperoxidase (MPO) immunohistochemical staining identified glomerular endothelial cell injury in crescentic glomerulonephritis and C3G. CASE (DIAGNOSIS/TREATMENT): We report that MPO staining in the glomerular endothelium of the post-treatment kidney biopsy was significantly reduced after 3 years of eculizumab treatment and clinical improvement in a 5-year-old boy with initial DDD and secondary crescent formation. CONCLUSION: We find that immunostaining for MPO is a useful method to compare glomerular endothelial injury in C3G following eculizumab treatment. This finding also supports the notion that eculizumab, a C5 blocker, may not mainly block C3 deposits in the glomeruli but significantly blocks final activation of the complement cascade, thus reducing glomerular endothelial cell injury.

Myeloid-Specific Gene Deletion of Protein Phosphatase 2A Magnifies MyD88- and TRIF-Dependent Inflammation following Endotoxin Challenge.

Protein phosphatase 2A (PP2A) is a member of the intracellular serine/threonine phosphatases. Innate immune cell activation triggered by pathogen-associated molecular patterns is mediated by various protein kinases, and PP2A plays a counter-regulatory role by deactivating these kinases. In this study, we generated a conditional knockout of the α isoform of the catalytic subunit of PP2A (PP2ACα). After crossing with myeloid-specific cre-expressing mice, effective gene knockout was achieved in various myeloid cells. The myeloid-specific knockout mice (lyM-PP2Afl/fl) showed higher mortality in response to endotoxin challenge and bacterial infection. Upon LPS challenge, serum levels of TNF-α, KC, IL-6, and IL-10 were significantly increased in lyM-PP2Afl/fl mice, and increased phosphorylation was observed in MAPK pathways (p38, ERK, JNK) and the NF-κB pathway (IKKα/ß, NF-κB p65) in bone marrow-derived macrophages (BMDMs) from knockout mice. Heightened NF-κB activation was not associated with degradation of IκBα; instead, enhanced phosphorylation of the NF-κB p65 subunit and p38 phosphorylation-mediated TNF-α mRNA stabilization appear to contribute to the increased TNF-α expression. In addition, increased IL-10 expression appears to be due to PP2ACα-knockout-induced IKKα/ß hyperactivation. Microarray experiments indicated that the Toll/IL-1R domain-containing adaptor inducing IFN-ß/ TNFR-associated factor 3 pathway was highly upregulated in LPS-treated PP2ACα-knockout BMDMs, and knockout BMDMs had elevated IFN-α/ß production compared with control BMDMs. Serum IFN-ß levels from PP2ACα-knockout mice treated with LPS were also greater than those in controls. Thus, we demonstrate that PP2A plays an important role in regulating inflammation and survival in the setting of septic insult by targeting MyD88- and Toll/IL-1R domain-containing adaptor inducing IFN-ß-dependent pathways.

Pediatric nonaortic arterial aneurysms.

OBJECTIVE: Pediatric arterial aneurysms are extremely uncommon. Indications for intervention remain poorly defined and treatments vary. The impetus for this study was to better define the contemporary surgical management of pediatric nonaortic arterial aneurysms. METHODS: A retrospective analysis was conducted of 41 children with 61 aneurysms who underwent surgical treatment from 1983 to 2015 at the University of Michigan. Arteries affected included: renal (n = 26), femoral (n = 7), iliac (n = 7), superior mesenteric (n = 4), brachial (n = 3), carotid (n = 3), popliteal (n = 3), axillary (n = 2), celiac (n = 2), ulnar (n = 2), common hepatic (n = 1), and temporal (n = 1). Intracranial aneurysms and aortic aneurysms treated during the same time period were not included in this study. Primary outcomes analyzed were postoperative complications, mortality, and freedom from reintervention. RESULTS: The study included 27 boys and 14 girls, with a median age of 9.8 years (range, 2 months-18 years) and a weight of 31.0 kg (range, 3.8-71 kg). Multiple aneurysms existed in 14 children. Obvious factors that contributed to aneurysmal formation included: proximal juxta-aneurysmal stenoses (n = 14), trauma (n = 12), Kawasaki disease (n = 4), Ehlers-Danlos type IV syndrome (n = 1), and infection (n = 1). Preoperative diagnoses were established using arteriography (n = 23), magnetic resonance angiography (n = 6), computed tomographic arteriography (n = 5), or ultrasonography (n = 7), and confirmed during surgery. Indications for surgery included risk of expansion and rupture, potential thrombosis or embolization of aneurysmal thrombus, local soft tissue and nerve compression, and secondary hypertension in the case of renal artery aneurysms. Primary surgical techniques included: aneurysm resection with reanastomsis, reimplantation, or angioplastic closure (n = 16), interposition (n = 10) or bypass grafts (n = 2), ligation (n = 9), plication (n = 8), endovascular occlusion (n = 3), and nephrectomy (n = 4) in cases of unreconstructable renal aneurysmal disease. Later secondary operations were required to treat stenoses at the site of the original aneurysm repairs (n = 2) and new aneurysmal development (n = 1). Postoperative follow-up averaged 47 months (range, 1-349 months). No major perioperative morbidity and no mortality was encountered in this experience. CONCLUSIONS: Pediatric arterial aneurysms represent a complex disease that affects multiple vascular territories. Results of the current series suggest that individualized surgical treatment, ranging from simple ligations to major arterial reconstructions, was durable and can be undertaken with minimal risk.

Remedial operations for failed endovascular therapy of 32 renal artery stenoses in 24 children.

BACKGROUND: Percutaneous transluminal angioplasty (PTA) for the treatment of pediatric renovascular hypertension (RVH) in contemporary practice is accompanied with ill-defined complications. This study examines the mode of pediatric renal PTA failures and the results of their surgical management. METHODS: Twenty-four children underwent remedial operations at the University of Michigan from 1996 to 2014 for failures of renal PTA. Their clinical courses were retrospectively reviewed and results analyzed. RESULTS: Renal PTA of 32 arteries, including 13 with stenting, was performed for severe RVH in 12 boys and 12 girls, having a mean age of 9.3 years. Developmental ostial stenoses affected 22 children. PTA failures included: 27 restenoses and five thromboses. Remedial operations included: 13 renal artery-aortic reimplantations, one segmental renal artery-main renal artery reimplantation, ten aortorenal bypasses, one arterioplasty, one iliorenal bypass, and six nephrectomies for unreconstructable arteries; the latter all in children younger than 10 years. Follow-up averaged 2.1 years. Postoperatively, hypertension was cured, improved, or unchanged in 25, 54, and 21 %, respectively. There was no perioperative renal failure or mortality. CONCLUSIONS: Renal PTA for the treatment of pediatric RVH due to ostial disease may be complicated by failures requiring complex remedial operations or nephrectomy, the latter usually affecting younger children.

Fluid Overload Is Associated With Late Poor Outcomes in Neonates Following Cardiac Surgery.

OBJECTIVES: Acute kidney injury is a severe complication of cardiac surgery associated with increased morbidity and mortality; yet, acute kidney injury classification for neonates remains challenging. We characterized patterns of postoperative fluid overload as a surrogate marker for acute kidney injury and as a risk factor of poor postoperative outcomes in neonates undergoing cardiac surgery. DESIGN: Retrospective cohort study. SETTING: Single, congenital heart center destination program. PATIENTS: Four hundred thirty-five neonates undergoing cardiac surgery with cardiopulmonary bypass from January 2006 through December 2010. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Demographics, diagnosis, and perioperative clinical variables were collected, including daily weights and serum creatinine levels. A composite poor clinical outcome (death, need for renal replacement therapy or extracorporeal life support within 30 postoperative days) was considered the primary outcome measure. Twenty-one neonates (5%) had a composite poor outcome with 7 (2%) requiring renal replacement therapy, 8 (2%) requiring extracorporeal life support, and 14 (3%) dying between 3 and 30 days post surgery. Neonates with a composite poor outcome had significantly higher maximum fluid overload (> 20%) and were slower to diurese. A receiver-operating characteristic curve determined that fluid overload greater than or equal to 16% and serum creatinine greater than or equal to 0.9 on postoperative day 3 were the optimal cutoffs for significant discrimination on the primary outcome (area under the curve = 0.71 and 0.76, respectively). In multivariable analysis, fluid overload greater than or equal to 16% (adjusted odds ratio = 3.7) and serum creatinine adjusted odds ratio 0.9 (adjusted odds ratio = 6.6) on postoperative day 3 remained an independent risk factor for poor outcome. Fluid overload greater than or equal 16% was also significantly associated with cardiac arrest requiring cardiopulmonary resuscitation, prolonged ICU stay, and chest reexploration. CONCLUSIONS: This study highlights the importance of monitoring fluid balance in the neonatal cardiac surgical population and suggests that daily fluid overload, a readily available, noninvasive marker of renal function, may be a sensitive and specific predictor of adverse outcomes.

Therapeutic plasma exchange may improve hemodynamics and organ failure among children with sepsis-induced multiple organ dysfunction syndrome receiving extracorporeal life support.

OBJECTIVE: To determine the effect of therapeutic plasma exchange on hemodynamics, organ failure, and survival in children with multiple organ dysfunction syndrome due to sepsis requiring extracorporeal life support. DESIGN: A retrospective analysis. SETTING: A PICU in an academic children's hospital. PATIENTS: Fourteen consecutive children with sepsis and multiple organ dysfunction syndrome who received therapeutic plasma exchange while on extracorporeal life support from 2005 to 2013. INTERVENTIONS: Median of three cycles of therapeutic plasma exchange with median of 1.0 times the estimated plasma volume per exchange. MEASUREMENTS AND MAIN RESULTS: Organ Failure Index and Vasoactive-Inotropic Score were measured before and after therapeutic plasma exchange use. PICU survival in our cohort was 71.4%. Organ Failure Index decreased in patients following therapeutic plasma exchange (mean ± SD: pre, 4.1 ± 0.7 vs post, 2.9 ± 0.9; p = 0.0004). Patients showed improved Vasoactive-Inotropic Score following therapeutic plasma exchange (median [25th-75th]: pre, 24.5 [13.0-69.8] vs post, 5.0 [1.5-7.0]; p = 0.0002). Among all patients, the change in Organ Failure Index was greater for early therapeutic plasma exchange use than late use (early, -1.7 ± 1.2 vs late, -0.9 ± 0.6; p = 0.14), similar to the change in Vasoactive-Inotropic Score (early, -67.5 [28.0-171.2] vs late, -12.0 [7.2-18.5]; p = 0.02). Among survivors, the change in Organ Failure Index was greater among early therapeutic plasma exchange use than late use (early, -2.3 ± 1.0 vs late, -0.8 ± 0.8; p = 0.03), as was the change in Vasoactive-Inotropic Score (early, -42.0 [16.0-76.3] vs late, -12.0 [5.3-29.0]; p = 0.17). The mean duration of extracorporeal life support after therapeutic plasma exchange according to timing of therapeutic plasma exchange was not statistically different among all patients or among survivors. CONCLUSIONS: The use of therapeutic plasma exchange in children on extracorporeal life support with sepsis-induced multiple organ dysfunction syndrome is associated with organ failure recovery and improved hemodynamic status. Initiating therapeutic plasma exchange early in the hospital course was associated with greater improvement in organ dysfunction and decreased requirement for vasoactive and/or inotropic agents.

Biology of sepsis: its relevance to pediatric nephrology.

Because of its multi-organ involvement, the syndrome of sepsis provides clinical challenges to a wide variety of health care providers. While multi-organ dysfunction triggered by sepsis requires general supportive critical care provided by intensivists, the impact of sepsis on renal function and the ability of renal replacement therapies to modulate its biologic consequences provide a significant opportunity for pediatric nephrologists and related care providers to impact outcomes. In this review, we aim to highlight newer areas of understanding of the pathobiology of sepsis with special emphasis on those aspects of particular interest to pediatric nephrology. As such, we aim to: (1) review the definition of sepsis and discuss advances in our mechanistic understanding of sepsis; (2) review current hypotheses regarding sepsis-induced acute kidney injury (AKI) and describe its epidemiology based on evolving definitions of AKI; (3) review the impact of renal failure on the immune system, highlighting the sepsis risk in this cohort and strategies that might minimize this risk; (4) review how renal replacement therapeutic strategies may impact sepsis-induced AKI outcomes. By focusing the review on these specific areas, we have omitted other important areas of the biology of sepsis and additional interactions with renal function from this discussion; however, we have aimed to provide a comprehensive list of references that provide contemporary reviews of these additional areas.

Fluid overload in infants following congenital heart surgery.

OBJECTIVE: To describe postoperative fluid overload patterns and correlate degree of fluid overload with intensive care morbidity and mortality in infants undergoing congenital heart surgery. DESIGN: Prospective, observational study. Fluid overload (%) was calculated by two methods: 1) (Total fluid in - Total fluid out)/(Preoperative weight) × 100; and 2) (Current weight - Preoperative weight)/(Preoperative weight) × 100. Composite poor outcome included: need for renal replacement therapy, upper quartile time to extubation or intensive care length of stay (> 6.5 and 9.9 days, respectively), or death ≤ 30 days after surgery. SETTING: University hospital pediatric cardiac ICU. PATIENTS: Forty-nine infants < 6 months of age undergoing congenital heart surgery with cardiopulmonary bypass during the period of July 2009 to July 2010. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients had a median age of 53 days (21 neonates) and mean weight of 4.5 ± 1.3 kg. Forty-two patients (86%) developed acute kidney injury by meeting at least Acute Kidney Injury Network and Kidney Disease Improving Global Outcomes stage 1 criteria (serum creatinine rise of 50% or ≥ 0.3mg/dL). The patients with adverse outcomes (n = 17, 35%) were younger (7 [5 - 10] vs. 98 [33 - 150] days, p = 0.001), had lower preoperative weight (3.7 ± 0.7 vs. 4.9 ± 1.4 kg, p = 0.0002), higher postoperative mean peak serum creatinine (SCr) (0.9 ± 0.3 vs. 0.6 ± 0.3mg/dL, p = 0.005), and higher mean maximum fluid overload by both method 1 (12% ± 10% vs. 6% ± 4%, p = 0.03) and method 2 (24% ± 15% vs. 14% ± 8%, p = 0.02). Predictors of a poor outcome from multivariate analyses were cardiopulmonary bypass time, use of circulatory arrest, and increased vasoactive medication requirements postoperatively. CONCLUSIONS: Early postoperative fluid overload is associated with suboptimal outcomes in infants following cardiac surgery. Because the majority of patients developed kidney injury without needing renal replacement therapy, fluid overload may be an important risk factor for adverse outcomes with all degrees of acute kidney injury.

Mitogen-activated protein kinase phosphatase 2, MKP-2, regulates early inflammation in acute lung injury.

Acute lung injury (ALI) is mediated by an early proinflammatory response resulting from either a direct or indirect insult to the lung mediating neutrophil infiltration and consequent disruption of the alveolar capillary membrane ultimately leading to refractory hypoxemia. The mitogen-activated protein kinase (MAPK) pathways are a key component of the molecular response activated by those insults triggering the proinflammatory response in ALI. The MAPK pathways are counterbalanced by a set of dual-specific phosphatases (DUSP) that deactivate the kinases by removing phosphate groups from tyrosine or threonine residues. We have previously shown that one DUSP, MKP-2, regulates the MAPK pathway in a model of sepsis-induced inflammation; however, the role of MKP-2 in modulating the inflammatory response in ALI has not been previously investigated. We utilized both MKP-2-null (MKP-2(-/-)) mice and MKP-2 knockdown in a murine macrophage cell line to elucidate the role of MKP-2 in regulating inflammation during ALI. Our data demonstrated attenuated proinflammatory cytokine production as well as decreased neutrophil infiltration in the lungs of MKP-2(-/-) mice following direct, intratracheal LPS. Importantly, when challenged with a viable pathogen, this decrease in neutrophil infiltration did not impact the ability of MKP-2(-/-) mice to clear either gram-positive or gram-negative bacteria. Furthermore, MKP-2 knockdown led to an attenuated proinflammatory response and was associated with an increase in phosphorylation of ERK and induction of a related DUSP, MKP-1. These data suggest that altering MKP-2 activity may have therapeutic potential to reduce lung inflammation in ALI without impacting pathogen clearance.

Fluid overload and fluid removal in pediatric patients on extracorporeal membrane oxygenation requiring continuous renal replacement therapy.

OBJECTIVE: In pediatric patients, fluid overload at continuous renal replacement therapy initiation is associated with increased mortality. The aim of this study was to characterize the association between fluid overload at continuous renal replacement therapy initiation, fluid removal during continuous renal replacement therapy, the kinetics of fluid removal and mortality in a large pediatric population receiving continuous renal replacement therapy while on extracorporeal membrane oxygenation. DESIGN: Retrospective chart review. SETTING: Tertiary children's hospital. PATIENTS: Extracorporeal membrane oxygenation patients requiring continuous renal replacement therapy from July 2006 to September 2010. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Overall intensive care unit survival was 34% for 53 patients that were initiated on continuous renal replacement therapy while on extracorporeal membrane oxygenation during the study period. Median fluid overload at continuous renal replacement therapy initiation was significantly lower in survivors compared to nonsurvivors (24.5% vs. 38%, p = .006). Median fluid overload at continuous renal replacement therapy discontinuation was significantly lower in survivors compared to nonsurvivors (7.1% vs. 17.5%, p = .035). After adjusting for percent fluid overload at continuous renal replacement therapy initiation, age, and severity of illness, the change in fluid overload at continuous renal replacement therapy discontinuation was not significantly associated with mortality (p = .212). Models investigating the rates of fluid removal in different periods, age, severity of illness, and fluid overload at continuous renal replacement therapy initiation found that fluid overload at continuous renal replacement therapy initiation was the most consistent predictor of survival. CONCLUSIONS: Our data demonstrate an association between fluid overload at continuous renal replacement therapy initiation and mortality in pediatric patients receiving extracorporeal membrane oxygenation. The degree of fluid overload at continuous renal replacement therapy discontinuation is also associated with mortality, but appears to reflect the effect of fluid overload at initiation. Furthermore, correction of fluid overload to ≤ 10% was not associated with improved survival. These results suggest that intervening prior to the development of significant fluid overload may be more clinically effective than attempting fluid removal after significant fluid overload has developed. Our findings suggest a role for earlier initiation of continuous renal replacement therapy in this population, and warrant further clinical studies.

An unusual case of membranous nephropathy associated with an ovarian tumor.

Secondary membranous nephropathy (MN) associated with malignancy is not uncommon in adults, but it is rare in children. We report a 6-year-old girl who developed nephrotic-range proteinuria following diagnosis of a Sertoli-Leydig ovarian tumor. A renal biopsy was performed, which led to the diagnosis of MN. The patient maintained normal renal function and gradually showed improvement in proteinuria over several months without the use of corticosteroids or angiotensin-converting enzyme inhibitors. Our case highlights the importance of performing screening urinalyses in children with tumors to recognize the presence of clinically significant, but potentially asymptomatic kidney disease.

Eculizumab-Associated Moraxella lacunata Bacteremia and Systemic Inflammatory Response Syndrome in a Toddler with Atypical Hemolytic Uremic Syndrome.

Moraxella lacunata, a low-virulence Gram-negative coccobacillus, is classically associated with conjunctivitis and upper respiratory tract infections; systemic infections such as sepsis have rarely been reported, especially in children. We describe a 28-month-old girl with atypical hemolytic uremic syndrome and stage II chronic kidney disease on long-term eculizumab therapy who presented with systemic inflammatory response syndrome and was found to have Moraxella lacunata bloodstream infection. Eculizumab, a humanized monoclonal anti-C5 antibody, has been associated with susceptibility to infections with encapsulated bacteria, especially Neisseria meningitidis. This is the first report of an invasive bacterial infection with Moraxella lacunata in a pediatric eculizumab recipient.

Epidemiology and risk factors for thromboembolic complications of childhood nephrotic syndrome: a Midwest Pediatric Nephrology Consortium (MWPNC) study.

OBJECTIVES: To identify clinical variables predictive of the risk of thromboembolism (TE), and to confirm the incidence of TE in primary and secondary childhood nephrotic syndrome (NS). STUDY DESIGN: A comprehensive chart review identified 326 children with NS from any cause evaluated between 1999 and 2006. These patients had a total of 1472.8 patient-years of follow-up. Comparison statistics, survival analysis, and logistic regression were used to define TE epidemiology and clinical risk factors. RESULTS: We found that 9.2% of our cohort had experienced at least 1 TE. The overall incidence was 20.4 patients with TEs/1000 patient-years. The median time to the first TE was 70.5 days after diagnosis of NS. Deep venous thrombosis was the most common TE (76%) and was frequently associated with the use of a central venous catheter (45%). Significant independent predictors of TE included age > or = 12 years at onset of NS (P < .0001), severity of proteinuria (P < .0001), and history of TE preceding diagnosis of NS (P < .0001). Life- or limb-threatening TEs represented 23.7% of the events. CONCLUSIONS: Children with NS should be carefully followed for TE, particularly those who are age 12 years or older, have severe proteinuria, or have a previous history of TE.

Bz-423 superoxide signals apoptosis via selective activation of JNK, Bak, and Bax.

Bz-423 is a proapoptotic 1,4-benzodiazepine with potent therapeutic properties in murine models of lupus and psoriasis. Bz-423 modulates the F(1)F(0)-ATPase, inducing the formation of superoxide within the mitochondrial respiratory chain, which then functions as a second messenger initiating apoptosis. Herein, we report the signaling pathway activated by Bz-423 in mouse embryonic fibroblasts containing knockouts of key apoptotic proteins. Bz-423-induced superoxide activates cytosolic ASK1 and its release from thioredoxin. A mitogen-activated protein kinase cascade follows, leading to the specific phosphorylation of JNK. JNK signals activation of Bax and Bak which then induces mitochondrial outer membrane permeabilization to cause the release of cytochrome c and a commitment to apoptosis. The response of these cells to Bz-423 is critically dependent on both superoxide and JNK activation as antioxidants and the JNK inhibitor SP600125 prevents Bax translocation, cytochrome c release, and cell death. These results demonstrate that superoxide generated from the mitochondrial respiratory chain as a consequence of a respiratory transition can signal a sequential and specific apoptotic response. Collectively, these data suggest that the selectivity of Bz-423 observed in vivo results from cell-type specific differences in redox balance and signaling by ASK1 and Bcl-2 proteins.

Benzodiazepine-induced superoxide signals B cell apoptosis: mechanistic insight and potential therapeutic utility.

The properties of a proapoptotic 1,4-benzodiazepine, Bz-423, identified through combinatorial chemistry and phenotype screening are described. Bz-423 rapidly generated superoxide (O(2)(-)) in transformed Ramos B cells. This O(2)(-) response originated from mitochondria prior to mitochondrial transmembrane gradient collapse and opening of the permeability transition pore. Bz-423-induced O(2)(-) functioned as an upstream signal that initiated an apoptotic program characterized by cytochrome c release, mitochondrial depolarization, and caspase activation. Pretreatment of cells with agents that either block the formation of Bz-423-induced O(2)(-) or scavenge free radicals attenuated the death cascade, which demonstrated that cell killing by Bz-423 depends on O(2)(-). Parallels between Ramos cells and germinal center B cells prompted experiments to determine whether Bz-423 had therapeutic activity in vivo. This possibility was tested using the (NZB x NZW)F(1) murine model of lupus, in which the pathologically enhanced survival and expansion of germinal center B cells mediate disease. Administration of Bz-423 for 12 weeks specifically controlled germinal center hyperplasia and reduced the histological evidence of glomerulonephritis. Collectively, these studies define a new structure-function relationship for benzodiazepines and point to a new target and mechanism that could be of value for developing improved drugs to manage systemic lupus erythematosus and related disorders.

Validation of the KDIGO acute kidney injury criteria in a pediatric critical care population.

PURPOSE: Acute kidney injury (AKI) occurs commonly in critically ill children and has been associated with increased mortality of up to 50 %. The Kidney Disease: Improving Global Outcomes (KDIGO) AKI working group has proposed a standardized definition of AKI. Utilizing routinely available clinical data, we evaluated the KDIGO AKI criteria and the relationship of AKI with relevant outcomes in a single center tertiary pediatric intensive care (PICU) and cardiac intensive care unit (CICU) population. METHODS: The University of Michigan Pediatric Critical Care Database was probed for all discharges from the pediatric intensive care and cardiac intensive care units between July 2011 and October 2013 (N = 4,645). The KDIGO serum creatinine (SCr)-based criteria staged AKI with the modification that a minimum SCr of greater than 0.5 mg/dL was required to be classified as AKI. Exclusion: end-stage renal disease, new renal transplant, missing PRISM III data, or no measured Cr during intensive care unit (ICU) admission (N = 1,636). RESULTS: AKI occurred in 737 (24.5 %, stage 1 = 193, stage 2 = 189, and stage 3 = 355) of 3,009 discharges (PICU N = 1,870, CICU N = 1,139) that included 2,415 patients. In multivariate analysis AKI was associated with increased ICU length of stay (LOS) in hours (stage I ß = 42.2, p = 0.024, II ß = 74.1, p = 0.003, III ß = 215.8, p < 0.001). Multivariate analysis showed that AKI was associated with increased odds of ICU mortality (OR 3.4, 95 % CI 2.0-6.0) and increased length of mechanical ventilation among those requiring mechanical ventilation (ß = 2.3 days, p < 0.001). CONCLUSIONS: Using the KDIGO criteria to define AKI, we observed a high prevalence of AKI among critically ill children. Worsening stages of AKI were associated with increased ICU LOS, and AKI was independently associated with prolonged mechanical ventilation and increased mortality. The KDIGO criteria describe clinically relevant AKI in a broad pediatric critical care population.