Readmission and Mortality After Hospitalization With Acute Kidney Injury.

RATIONALE & OBJECTIVE: Acute kidney injury (AKI) carries high rates of morbidity and mortality. This study quantified various short- and long-term outcomes after hospitalization with AKI. STUDY DESIGN: Retrospective propensity score (PS)-matched cohort study. SETTING & PARTICIPANTS: Optum Clinformatics, a national claims database, was used to identify patients hospitalized with and without an AKI discharge diagnosis between January 2007 and September 2020. EXPOSURE: Among patients with prior continuous enrollment for at least 2years without AKI hospitalization, 471,176 patients hospitalized with AKI were identified and PS-matched to 471,176 patients hospitalized without AKI. OUTCOME(S): All-cause and selected-cause rehospitalizations and mortality 90 and 365 days after index hospitalization. ANALYTICAL APPROACH: After PS matching, rehospitalization and death incidences were estimated using the cumulative incidence function method and compared using Gray's test. The association of AKI hospitalization with each outcome was tested using Cox models for all-cause mortality and, with mortality as competing risk, cause-specific hazard modeling for all-cause and selected-cause rehospitalization. Overall and stratified analyses were performed to evaluate for interaction between an AKI hospitalization and preexisting chronic kidney disease (CKD). RESULTS: After PS matching, AKI was associated with higher rates of rehospitalization for any cause (hazard ratio [HR], 1.62; 95% CI, 1.60-1.65), end-stage renal disease (HR, 6.21; 95% CI, 1.04-36.92), heart failure (HR, 2.81; 95% CI, 2.66, 2.97), sepsis (HR, 2.62; 95% CI, 2.49-2.75), pneumonia (HR, 1.47; 95% CI, 1.37-1.57), myocardial infarction (HR, 1.48; 95% CI, 1.33-1.65), and volume depletion (HR, 1.64; 95% CI, 1.37-1.96) at 90 days after discharge compared with the group without AKI, with similar findings at 365 days. Mortality rate was higher in the group with AKI than in the group without AKI at 90 (HR, 2.66; 95% CI, 2.61-2.72) and 365 days (HR, 2.11; 95% CI, 2.08-2.14). The higher risk of outcomes persisted when participants were stratified by CKD status (P<0.01). LIMITATIONS: Causal associations between AKI and the reported outcomes cannot be inferred. CONCLUSIONS: AKI during hospitalization in patients with and without CKD is associated with increased risk of 90- and 365-day all-cause/selected-cause rehospitalization and death.

Class B Scavenger Receptors BI and BII Protect against LPS-Induced Acute Lung Injury in Mice by Mediating LPS.

Recent studies suggest an anti-inflammatory protective role for class B scavenger receptor BI (SR-BI) in endotoxin-induced inflammation and sepsis. Other data, including ours, provide evidence for an alternative role of SR-BI, facilitating bacterial and endotoxin uptake and contributing to inflammation and bacterial infection. Enhanced endotoxin susceptibility of SR-BI-deficient mice due to their anti-inflammatory glucocorticoid deficiency complicates the understanding of SR-BI's role in endotoxemia/sepsis, calling for the use of alternative models. In this study, using human SR-BI (hSR-BI) and hSR-BII transgenic mice, we found that SR-BI and, to a lesser extent, its splicing variant SR-BII protect against LPS-induced lung damage. At 20 h after intratracheal LPS instillation, the extent of pulmonary inflammation and vascular leakage was significantly lower in hSR-BI and hSR-BII transgenic mice than in wild-type mice. Higher bronchoalveolar lavage fluid (BALF) inflammatory cell count and protein content and lung tissue neutrophil infiltration found in wild-type mice were associated with markedly (2 to 3 times) increased proinflammatory cytokine production compared to these parameters in transgenic mice following LPS administration. The markedly lower endotoxin levels detected in BALF of transgenic versus wild-type mice and the significantly increased BODIPY-LPS uptake observed in lungs of hSR-BI and hSR-BII mice 20 h after the i.t. LPS injection suggest that hSR-BI- and hSR-BII-mediated enhanced LPS clearance in the airways could represent the mechanism of their protective role against LPS-induced acute lung injury.

Circadian variation in the release of small extracellular vesicles can be normalized by vesicle number or TSG101.

Numerous candidate biomarkers in urine extracellular vesicles (EVs) have been described for kidney diseases, but none are yet in clinical use, possibly due to a lack of proper normalization. Proper normalization corrects for normal biological variation in urine flow rate or concentration, which can vary by over one order of magnitude. Here, we observed inter- and intra-animal variation in urine excretion rates of small EVs (<200 nm in diameter) in healthy rats as a series of six 4-h fractions. To visualize intra-animal variation, we normalized a small EV excretion rate to a peak excretion rate, revealing a circadian pattern for each rat. This circadian pattern was distinct from urine volume, urine albumin, urine creatinine, and urine albumin-to-creatinine ratio. Furthermore, urine small EV excretion was not significantly altered by sex, food/water deprivation, or ischemic acute kidney injury. Urine excretion of the exosomal/small EV marker protein tumor susceptibility gene 101 (TSG101) displayed a similar circadian pattern to urine small EV excretion; both measurements were highly correlated (R2 = 0.85), with an average stoichiometry of 10.0 molecules of TSG101/vesicle in healthy rats. The observed stoichiometry of TSG101/vesicle in rat urine translated to human spot urine samples (10.2 molecules/vesicle) and cultured kidney-derived cell lines (human embryonic kidney-293 and normal rat kidney 52E cells). Small EV number and its surrogate, TSG101 protein, can normalize for circadian variation when testing candidate biomarkers in small EVs. Just as creatinine has emerged as the customary normalization factor for liquid-phase urine biomarkers, vesicle number and its surrogate, molecules of exosome/small EV-associated TSG101, should be considered as viable, normalizing factors for small EV biomarkers.

Chronic kidney diseases in agricultural communities: report from a workshop.

In June 2018, the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of Environmental Health Sciences sponsored a workshop to identify research gaps in an increasingly common form of chronic kidney disease in agricultural communities, often termed "CKDu." The organizers invited a broad range of experts who provided diverse expertise and perspectives, many of whom had never addressed this particular epidemic. Discussion was focused around selected topics, including identifying and mitigating barriers to research in CKDu, creating a case definition, and defining common data elements. All hypotheses regarding etiology were entertained, and meeting participants discussed potential research strategies, choices in study design, and novel tools that may prove useful in this disease. Achievements of the workshop included robust cross-disciplinary discussion and preliminary planning of research goals and design. Specific challenges in implementing basic and clinical research and interventions in low- and middle-income countries were recognized. A balanced approach to leveraging local resources and capacity building without overreaching was emphasized.

Statistical methods for building better biomarkers of chronic kidney disease.

The last two decades have witnessed an explosion in research focused on the development and assessment of novel biomarkers for improved prognosis of diseases. As a result, best practice standards guiding biomarker research have undergone extensive development. Currently, there is great interest in the promise of biomarkers to enhance research efforts and clinical practice in the setting of chronic kidney disease, acute kidney injury, and glomerular disease. However, some have questioned whether biomarkers currently add value to the clinical practice of nephrology. The current state of the art pertaining to statistical analyses regarding the use of such measures is critical. In December 2014, the National Institute of Diabetes and Digestive and Kidney Diseases convened a meeting, "Toward Building Better Biomarker Statistical Methodology," with the goals of summarizing the current best practice recommendations and articulating new directions for methodological research. This report summarizes its conclusions and describes areas that need attention. Suggestions are made regarding metrics that should be commonly reported. We outline the methodological issues related to traditional metrics and considerations in prognostic modeling, including discrimination and case mix, calibration, validation, and cost-benefit analysis. We highlight the approach to improved risk communication and the value of graphical displays. Finally, we address some "new frontiers" in prognostic biomarker research, including the competing risk framework, the use of longitudinal biomarkers, and analyses in distributed research networks.

Gut Leakage of Fungal-Derived Inflammatory Mediators: Part of a Gut-Liver-Kidney Axis in Bacterial Sepsis.

Sepsis is a life-threatening response to systemic infection. In addition to frank gastrointestinal (GI) rupture/puncture, sepsis can also be exacerbated by translocation of pathogen-associated molecular patterns (PAMPs) from the GI tract to the systemic circulation (gut origin of sepsis). In the human gut, Gram-negative bacteria and Candida albicans are abundant, along with their major PAMP components, endotoxin (LPS) and (1 → 3)-ß-D-glucan (BG). Whereas the influence of LPS in bacterial sepsis has been studied extensively, exploration of the role of BG in bacterial sepsis is limited. Post-translocation, PAMPs enter the circulation through lymphatics and the portal vein, and are detoxified and then excreted via the liver and the kidney. Sepsis-induced liver and kidney injury might therefore affect the kinetics and increase circulating PAMPs. In this article, we discuss the current knowledge of the impact of PAMPs from both gut mycobiota and microbiota, including epithelial barrier function and the "gut-liver-kidney axis," on bacterial sepsis severity.

Mesenchymal stromal cell potency to treat acute kidney injury increased by ultrasound-activated interferon-γ/interleukin-10 axis.

Mesenchymal stromal cell (MSC) therapies combined with renal pulsed focused ultrasound (pFUS) pretreatment increase MSC homing and improve cisplatin-induced acute kidney injury (AKI) better than MSC alone. However, mechanisms underlying improved outcomes remain unknown. We hypothesize pFUS up-regulates renal interferon-γ (IFNγ) and stimulates MSC to produce interleukin-10 (IL-10) after migrating to kidneys. To demonstrate initially, MSC cultured with IFNγ up-regulated IL-10. More MSC-derived IL-10 was detected in kidneys when IFNγ-stimulated MSC were infused and they improved AKI better than unstimulated MSC. Next, IFNγ-knockout mice with AKI received pFUS+MSC, but MSC-derived IL-10 expression and AKI were similar to using MSC alone. AKI in wild-type mice receiving pFUS and IL-10-deficient MSC was also unimproved compared to administering IL-10-deficient MSC alone. Indoleamine 2,3-dioxygenase (IDO), an anti-inflammatory enzyme up-regulated in MSC by IFNγ, was up-regulated during AKI, but was not further elevated in MSC from pFUS-treated kidneys, suggesting that IDO is not involved in improved AKI healing by pFUS+MSC. These data suggest IFNγ is up-regulated by pFUS and after i.v.-infused MSC home to pFUS-treated kidneys, IFNγ stimulates additional IL-10 production by MSC to improve AKI. Analogous mechanisms of ultrasound-treated tissue microenvironments stimulating therapeutic MSC may exist in other pathologies where adjuvant ultrasound techniques are successful.

The role of adenosine 1a receptor signaling on GFR early after the induction of sepsis.

Sepsis and acute kidney injury (AKI) synergistically increase morbidity and mortality in the ICU. How sepsis reduces glomerular filtration rate (GFR) and causes AKI is poorly understood; one proposed mechanism includes tubuloglomerular feedback (TGF). When sodium reabsorption by the proximal tubules is reduced in normal animals, the macula densa senses increased luminal sodium chloride, and then adenosine-1a receptor (A1aR) signaling triggers tubuloglomerular feedback, reducing GFR through afferent arteriole vasoconstriction. We measured GFR and systemic hemodynamics early during cecal ligation and puncture-induced sepsis in wild-type and A1aR-knockout mice. A miniaturized fluorometer was attached to the back of each mouse and recorded the clearance of FITC-sinistrin via transcutaneous fluorescence to monitor GFR. Clinical organ injury markers and cytokines were measured and hemodynamics monitored using implantable transducer telemetry devices. In wild-type mice, GFR was stable within 1 h after surgery, declined by 43% in the next hour, and then fell to less than 10% of baseline after 2 h and 45 min. In contrast, in A1aR-knockout mice GFR was 37% below baseline immediately after surgery and then gradually declined over 4 h. A1aR-knockout mice had similar organ injury and inflammatory responses, albeit with lower heart rate. We conclude that transcutaneous fluorescence can accurately monitor GFR and detect changes rapidly during sepsis. Tubuloglomerular feedback plays a complex role in sepsis; initially, TGF helps maintain GFR in the 1st hour, and over the subsequent 3 h, TGF causes GFR to plummet. By 18 h, TGF has no cumulative effect on renal or extrarenal organ damage.

Human SR-BI and SR-BII Potentiate Lipopolysaccharide-Induced Inflammation and Acute Liver and Kidney Injury in Mice.

The class B scavenger receptors BI (SR-BI) and BII (SR-BII) are high-density lipoprotein receptors that recognize various pathogens, including bacteria and their products. It has been reported that SR-BI/II null mice are more sensitive than normal mice to endotoxin-induced inflammation and sepsis. Because the SR-BI/II knockout model demonstrates multiple immune and metabolic disorders, we investigated the role of each receptor in the LPS-induced inflammatory response and tissue damage using transgenic mice with pLiv-11-directed expression of human SR-BI (hSR-BI) or human SR-BII (hSR-BII). At 6 h after i.p. LPS injection, transgenic hSR-BI and hSR-BII mice demonstrated markedly higher serum levels of proinflammatory cytokines and 2- to 3-fold increased expression levels of inflammatory mediators in the liver and kidney, compared with wild-type (WT) mice. LPS-stimulated inducible NO synthase expression was 3- to 6-fold higher in the liver and kidney of both transgenic strains, although serum NO levels were similar in all mice. Despite the lower high-density lipoprotein plasma levels, both transgenic strains responded to LPS by a 5-fold increase of plasma corticosterone levels, which were only moderately lower than in WT animals. LPS treatment resulted in MAPK activation in tissues of all mice; however, the strongest response was detected for hepatic extracellular signal-regulated protein kinase 1 and 2 and kidney JNK of both transgenic mice. Histological examination of hepatic and renal tissue from LPS-challenged mice revealed more injury in hSR-BII, but not hSR-BI, transgenic mice versus WT controls. Our findings demonstrate that hSR-BII, and to a lesser extent hSR-BI, significantly increase LPS-induced inflammation and contribute to LPS-induced tissue injury in the liver and kidney, two major organs susceptible to LPS toxicity.

Quantification of Exosomes.

Exosomes are released by cells as self-contained vesicles with an intact lipid bilayer that encapsulates a small portion of the parent cell. Exosomes have been studied widely as information-rich sources of potential biomarkers that can reveal cellular physiology. We suggest that quantification is essential to understand basic biological relationships between exosomes and their parent cells and hence the underlying interpretation of exosome signals. The number of methods for quantifying exosomes has expanded as interest in exosomes has increased. However, a consensus on proper quantification has not developed, making each study difficult to compare to another. Overcoming this ad hoc approach will require widely available standards that have been adequately characterized, and multiple comparative studies across platforms. We outline the current status of these technical approaches and our view of how they can become more coherent. J. Cell. Physiol. 232: 1587-1590, 2017. © 2016 Wiley Periodicals, Inc.

Future Directions of Research and Care for Urinary Incontinence: Findings from the National Institute of Diabetes and Digestive and Kidney Diseases Summit on Urinary Incontinence Clinical Research in Women.

PURPOSE: Female urinary incontinence is prevalent, costly and morbid. Participants in a NIDDK (National Institute of Diabetes and Digestive and Kidney Diseases) sponsored summit reviewed findings from NIH (National Institutes of Health) funded clinical research on urinary incontinence in women and discussed the future of urinary incontinence research. MATERIALS AND METHODS: The NIDDK convened the Summit on Urinary Incontinence Clinical Research in Women on March 14, 2014. Participants representing a broad range of clinical expertise reviewed completed NIH sponsored urinary incontinence related studies, including results from community based epidemiological studies such as the BACH (Boston Area Community Health) Survey and from randomized clinical trials such as PRIDE (Program to Reduce Incontinence by Diet and Exercise), and studies conducted by the Pelvic Floor Disorders Network and the Urinary Incontinence Treatment Network. RESULTS: BACH Survey results improved our understanding of precursors, incidence, prevalence and natural history of urinary incontinence in a diverse group of women. The Pelvic Floor Disorders Network study found that anticholinergic medications and onabotulinumtoxinA are efficacious for treating urge urinary incontinence, and Burch colposuspension and retropubic mid urethral polypropylene slings are efficacious for decreasing stress urinary incontinence following pelvic organ prolapse surgery in women with potential stress urinary incontinence. The Urinary Incontinence Treatment Network study found that fascial slings were better than colposuspension, and that retropubic and transobturator mid urethral polypropylene slings were equivalent for stress urinary incontinence. In patients with stress urinary incontinence a preoperative urodynamic study was noninferior to basic office examinations for surgical outcome. The addition of behavioral intervention did not allow female patients to discontinue antimuscarinics for urge urinary incontinence. PRIDE showed that modest weight reductions significantly decreased urinary incontinence. CONCLUSIONS: Strategies for future research on urinary incontinence should include a focus on early disease, risk factor identification, better phenotyping, incorporation of new technologies, patient centered research and prevention.

Nonbiologic factors that impact management in women with urinary incontinence: review of the literature and findings from a National Institute of Diabetes and Digestive and Kidney Diseases workshop.

INTRODUCTION AND HYPOTHESIS: Urinary incontinence (UI)-defined as a complaint of involuntary loss of urine-is common in women, with major public health, financial, and quality of life (QoL) implications. Despite the high toll of UI and the availability of effective conservative treatments, many women with UI do not seek care. Those who do often continue to experience symptoms. Improving UI treatment may require a comprehensive approach to urology research, including a broad set of potentially influential factors beyond biologic. METHODS: To explore the effects of nonbiologic factors (NBF) on UI management and treatment response, the National Institute of Diabetes and Digestive and Kidney Diseases convened a workshop for clinical and psychosocial researchers. Participants proposed a UI treatment pathway: recognizing the problem, willingness to seek treatment, access to care, receiving quality treatment, engaging in self-management, and adhering to chosen treatments; discussed potential NBFs that may affect the pathway; and identified areas for future research. After the meeting, a rapid literature review was conducted to assess the current state of research on NBFs in women with UI. RESULTS: Participants identified several patient-level NBFs that may influence the UI management pathway, including QoL and perceived bother; stigma, shame, and embarrassment; knowledge and perceptions; social determinants of health; cultural and language characteristics; personal characteristics and skills; and physical abilities. Additionally, participants acknowledged that provider- and system-level factors also play a role and likely interact with patient-level factors. CONCLUSIONS: NBFs that potentially affect the UI management pathway are not well understood, and a comprehensive, interdisciplinary approach to research is needed to understand and appropriately support effective UI treatment.

Social Determinants of Racial Disparities in CKD.

Significant disparities in CKD rates and outcomes exist between black and white Americans. Health disparities are defined as health differences that adversely affect disadvantaged populations, on the basis of one or more health outcomes. CKD is the complex result of genetic and environmental factors, reflecting the balance of nature and nurture. Social determinants of health have an important role as environmental components, especially for black populations, who are disproportionately disadvantaged. Understanding the social determinants of health and appreciating the underlying differences associated with meaningful clinical outcomes may help nephrologists treat all their patients with CKD in an optimal manner. Altering the social determinants of health, although difficult, may embody important policy and research efforts, with the ultimate goal of improving outcomes for patients with kidney diseases, and minimizing the disparities between groups.

Antagonism of scavenger receptor CD36 by 5A peptide prevents chronic kidney disease progression in mice independent of blood pressure regulation.

Scavenger receptor CD36 participates in lipid metabolism and inflammatory pathways important for cardiovascular disease and chronic kidney disease (CKD). Few pharmacological agents are available to slow the progression of CKD. However, apolipoprotein A-I-mimetic peptide 5A antagonizes CD36 in vitro. To test the efficacy of 5A, and to test the role of CD36 during CKD, we compared wild-type to CD36 knockout mice and wild-type mice treated with 5A, in a progressive CKD model that resembles human disease. Knockout and 5A-treated wild-type mice were protected from CKD progression without changes in blood pressure and had reductions in cardiovascular risk surrogate markers that are associated with CKD. Treatment with 5A did not further protect CD36 knockout mice from CKD progression, implicating CD36 as its main site of action. In a separate model of kidney fibrosis, 5A-treated wild-type mice had less macrophage infiltration and interstitial fibrosis. Peptide 5A exerted anti-inflammatory effects in the kidney and decreased renal expression of inflammasome genes. Thus, CD36 is a new therapeutic target for CKD and its associated cardiovascular risk factors. Peptide 5A may be a promising new agent to slow CKD progression.

Advancing a Comprehensive Approach to the Study of Lower Urinary Tract Symptoms.

PURPOSE: Lower urinary tract symptoms are common in the United States population, leading to significant economic, quality of life and public health issues. The burden will increase as the population ages, and risk factors for lower urinary tract symptoms, including diabetes and obesity, remain highly prevalent. Improving clinical management and establishing the knowledge base to prevent lower urinary tract symptoms will require a comprehensive research approach that examines factors beyond the lower urinary tract. While the study of extra-lower urinary tract factors has increased recently, current urological research does not systematically account for the broad set of potential contributing factors spanning biological, behavioral, psychological/executive function and sociocultural factors. A comprehensive assessment of potential contributors to risk, treatment response and progression is necessary to reduce the burden of this condition in the United States. MATERIALS AND METHODS: We considered challenges to continuing the predominantly lower urinary tract dysfunction centric approach that has dominated previous research of lower urinary tract symptoms. RESULTS: We developed a new, comprehensive framework for urology research that includes a broader set of potential factors contributing to lower urinary tract symptoms. This framework aims to broaden research to consider a comprehensive set of potential contributing factors and to engage a broad range of researchers in the investigation of as many extra-lower urinary tract factors as possible, with the goal of improving clinical care and prevention. CONCLUSIONS: We propose a new framework for future urology research, which should help to reduce the medical and economic burden of lower urinary tract symptoms in the United States population.

Pulsed focused ultrasound pretreatment improves mesenchymal stromal cell efficacy in preventing and rescuing established acute kidney injury in mice.

Animal studies have shown that mesenchymal stromal cell (MSC) infusions improve acute kidney injury (AKI) outcomes when administered early after ischemic/reperfusion injury or within 24 hours after cisplatin administration. These findings have spurred several human clinical trials to prevent AKI. However, no specific therapy effectively treats clinically obvious AKI or rescues renal function once advanced injury is established. We investigated if noninvasive image-guided pulsed focused ultrasound (pFUS) could alter the kidney microenvironment to enhance homing of subsequently infused MSC. To examine the efficacy of pFUS-enhanced cell homing in disease, we targeted pFUS to kidneys to enhance MSC homing after cisplatin-induced AKI. We found that pFUS enhanced MSC homing at 1 day post-cisplatin, prior to renal functional deficits, and that enhanced homing improved outcomes of renal function, tubular cell death, and regeneration at 5 days post-cisplatin compared to MSC alone. We then investigated whether pFUS+MSC therapy could rescue established AKI. MSC alone at 3 days post-cisplatin, after renal functional deficits were obvious, significantly improved 7-day survival of animals. Survival was further improved by pFUS and MSC. pFUS prior to MSC injections increased IL-10 production by MSC that homed to kidneys and generated an anti-inflammatory immune cell profile in treated kidneys. This study shows pFUS is a neoadjuvant approach to improve MSC homing to diseased organs. pFUS with MSC better prevents AKI than MSC alone and allows rescue therapy in established AKI, which currently has no meaningful therapeutic options.

Microparticles: markers and mediators of sepsis-induced microvascular dysfunction, immunosuppression, and AKI.

Sepsis is a severe and complex syndrome that lacks effective prevention or therapeutics. The effects of sepsis on the microvasculature have become an attractive area for possible new targets and therapeutics. Microparticles (MPs) are cell membrane-derived particles that can promote coagulation, inflammation, and angiogenesis, and they can participate in cell-to-cell communication. MPs retain cell membrane and cytoplasmic constituents of their parental cells, including two procoagulants: phosphatidylserine and tissue factor. We highlight the role of microparticles released by endothelial and circulating cells after sepsis-induced microvascular injury, and we discuss possible mechanisms by which microparticles can contribute to endothelial dysfunction, immunosuppression, and multiorgan dysfunction--including sepsis-AKI. Once viewed as cellular byproducts, microparticles are emerging as a new class of markers and mediators in the pathogenesis of sepsis.