Incorporating genetic testing into a routine kidney clinic.

Incorporating genetic testing in routine outpatient nephrology clinic can improve on chronic kidney disease (CKD) diagnosis and utilization of precision medicine. We sent a genetic test on patients with atypical presentation of common kidney diseases, electrolytes derangements, and cystic kidney diseases. We were able to identify a gene variant contributing to patients' kidney disease in more than half of our cohort. We then showed that patients with ApoL1 risk allele have likely worse kidney disease, and we were able to confirm genetic focal segmental glomerulosclerosis (FSGS) in 2 patients and avoid unnecessary immunosuppression. Genetic testing has also improved our operation to establish a polycystic kidney disease excellence center by confirming our diagnosis, especially in patients without a well-defined family history. In conclusion, utilizing genetic testing in a routine outpatient renal clinic did not cause any burden to either patients or nephrologists, with minimal administrative effort and no financial cost to our patients. We expect that genetic testing in the right setting should become routine in nephrology to achieve a patient-centered precision medicine with less invasive means of kidney disease diagnosis.

A Critical Review of Medication Adherence in Hypertension: Barriers and Facilitators Clinicians Should Consider.

Hypertension is a global public health problem, and its prevalence is increasing worldwide. Impacting all human societies and socioeconomic strata, it remains the major modifiable risk factor for global burden of cardiovascular disease all-cause mortality and the leading cause of loss of disability-adjusted life years. Despite increased awareness, the rate of blood pressure control remains unsatisfactory, particularly in low- to middle-income countries. Apparent treatment-resistant hypertension is associated with worse adverse health outcomes. It includes both true resistant and pseudo-resistant hypertension, which requires out-of-office blood pressure monitoring to exclude white-coat effect and confirmation of adherence to the agreed recommended antihypertensive therapy. The depth of medication non-adherence remains poorly recognized among medical practitioners, thus presenting an underestimated modifiable risk factor. Medication non-adherence is a complex and multidimensional variable with three quantifiable phases: initiation, implementation, and discontinuation, collectively called persistence. Non-adherence can be both intentional and non-intentional and usually involves several interconnected factors. Persistence declines over time in the treatment of chronic diseases like hypertension. The risk is higher in patients with new diagnosis, poor insurance status, polypharmacy, and multiple comorbidities, particularly psychiatric disorders. The World Health Organization divides the contributing factors impacting adherence into five categories. Screening and detection for medication non-adherence are challenging due to its dynamic nature and potential white-coat effect. Easy-to-conduct screening methods have low reliability and validity, whereas more reliable and valid methods are costly and difficult to perform. Medication non-adherence is associated with poor clinical outcome and potential negative impact on health-care costs. Evaluation of adherence should become an integral part of assessment of patients treated for hypertension. Medication adherence can significantly improve with a patient-centered approach, non-judgmental communication skills, and collaborative multidisciplinary management, including engagement of the patients in their care by self-blood pressure monitoring.

Urinary Neutrophil Gelatinase-Associated Lipocalin Predicts Intensive Care Unit Admission Diagnosis: A Prospective Cohort Study.

Background: Acute kidney injury (AKI) is most commonly caused by tubular injury and is associated with a wide variety of critical illnesses. It is well known that urinary biomarkers can lead to the early identification of AKI. However, the ability of urinary biomarkers to distinguish between different types of critical illness has been less studied. Methods: In this prospective cohort study, urinary neutrophil gelatinase-associated lipocalin (uNGAL) was measured in 107 patients consecutively admitted to the ICUs in our tertiary medical center. uNGAL samples were collected within 3-6 hours of admission to an ICU and measured by ELISA. All data were analyzed using R statistical software, and univariate analysis was used to determine the correlations of uNGAL levels with AKI stage, admission diagnoses, and ICU course. Results: uNGAL level increased by a mean of 24-fold (SD 10-59) in ICU patients with AKI and demonstrated a significant correlation with the different AKI stages. uNGAL predicted the need for RRT, with values increased by more than 15-fold (P<0.05) in patients needing RRT, and remained a useful tool to predict AKI in ICU patients with a urinary tract infection. uNGAL level was correlated with certain ICU admitting diagnoses whereby uNGAL levels were lower in ICU patients with cardiogenic shock compared with other admission diagnoses (ß=-1.92, P<0.05). Conclusions: uNGAL can be used as an early predictor of AKI and its severity in patients admitted to the ICU, including the need for RRT. uNGAL may also help in distinguishing patients with cardiogenic shock from those with other critical illnesses and identifying those at risk for poor outcomes irrespective of the presence of AKI.

Case series: coronavirus disease 2019 infection as a precipitant of atypical hemolytic uremic syndrome: two case reports.

BACKGROUND: Atypical hemolytic uremic syndrome is an exceedingly rare thrombotic microangiopathy caused by accelerated activation of the alternative complement pathway. CASE PRESENTATION: Here, we report two cases of patients presenting with suspected atypical hemolytic uremic syndrome precipitated by coronavirus disease 2019 infection. The first patient, a 25-year-old Hispanic male, had one prior episode of thrombotic microangiopathy presumed to be atypical hemolytic uremic syndrome precipitated by influenza A, and re-presented with thrombocytopenia, microangiopathic hemolytic anemia, nonoliguric renal failure, and normal ADAMTS13 activity, with confirmed coronavirus disease 2019 positivity. The second patient, a 31-year-old Caucasian female, had no personal history of thrombotic microangiopathy, though reported a family history of suspected atypical hemolytic uremic syndrome. She presented with similar laboratory derangements, oliguric renal failure requiring hemodialysis, and confirmed coronavirus disease 2019 positivity. Both patients were treated with eculizumab with complete resolution of their hematologic and renal complications. CONCLUSION: To our knowledge, this represents the largest case series of atypical hemolytic uremic syndrome precipitated by coronavirus disease 2019 in adults.

Development and Validation of a Web-Based Prediction Model for AKI after Surgery.

Background: AKI after surgery is associated with high mortality and morbidity. The purpose of this study is to develop and validate a risk prediction tool for the occurrence of postoperative AKI requiring RRT (AKI-dialysis). Methods: This retrospective cohort study had 2,299,502 surgical patients over 2015-2017 from the American College of Surgeons National Surgical Quality Improvement Program Database (ACS NSQIP). Eleven predictors were selected for the predictive model: age, history of congestive heart failure, diabetes, ascites, emergency surgery, hypertension requiring medication, preoperative serum creatinine, hematocrit, sodium, preoperative sepsis, and surgery type. The predictive model was trained using 2015-2016 data (n=1,487,724) and further tested using 2017 data (n=811,778). A risk model was developed using multivariable logistic regression. Results: AKI-dialysis occurred in 0.3% (n=6853) of patients. The unadjusted 30-day postoperative mortality rate associated with AKI-dialysis was 37.5%. The AKI risk prediction model had high area under the receiver operating characteristic curve (AUC; training cohort: 0.89, test cohort: 0.90) for postoperative AKI-dialysis. Conclusions: This model provides a clinically useful bedside predictive tool for postoperative AKI requiring dialysis.

Repetitive ischemic injuries to the kidneys result in lymph node fibrosis and impaired healing.

The contribution of the kidney-draining lymph node (KLN) to the pathogenesis of ischemia-reperfusion injury (IRI) of the kidney and its subsequent recovery has not been explored in depth. In addition, the mechanism by which repetitive IRI contributes to renal fibrosis remains poorly understood. Herein, we have found that IRI of the kidney is associated with expansion of high endothelial venules (HEVs) and activation of fibroblastic reticular cells (FRCs) in the KLN, as demonstrated by significant expansion in the extracellular matrix. The lymphotoxin α signaling pathway mediates activation of FRCs, and chronic treatment with lymphotoxin ß receptor-immunoglobulin fusion protein (LTßr-Ig) resulted in marked alteration of the KLN as well as augmentation of renal fibrosis. Depletion of FRCs reduced T cell activation in the KLN and ameliorated renal injury in acute IRI. Repetitive renal IRI was associated with senescence of FRCs, fibrosis of the KLN, and renal scarring, which were ameliorated by FRC administration. Therefore, our study emphasizes the critical role of FRCs in both the initiation and repair phases of injury following IRI of the kidney.

Ischemia augments alloimmune injury through IL-6-driven CD4+ alloreactivity.

Ischemia reperfusion injuries (IRI) are unavoidable in solid organ transplantation. IRI augments alloimmunity but the mechanisms involved are poorly understood. Herein, we examined the effect of IRI on antigen specific alloimmunity. We demonstrate that ischemia promotes alloimmune activation, leading to more severe histological features of rejection, and increased CD4+ and CD8+ T cell graft infiltration, with a predominantly CD8+ IFNγ+ infiltrate. This process is dependent on the presence of alloreactive CD4+ T cells, where depletion prevented infiltration of ischemic grafts by CD8+ IFNγ+ T cells. IL-6 is a known driver of ischemia-induced rejection. Herein, depletion of donor antigen-presenting cells reduced ischemia-induced CD8+ IFNγ+ allograft infiltration, and improved allograft outcomes. Following prolonged ischemia, accelerated rejection was observed despite treatment with CTLA4Ig, indicating that T cell costimulatory blockade failed to overcome the immune activating effect of IRI. However, despite severe ischemic injury, treatment with anti-IL-6 and CTLA4Ig blocked IRI-induced alloimmune injury and markedly improved allograft survival. We describe a novel pathway where IRI activates innate immunity, leading to upregulation of antigen specific alloimmunity, resulting in chronic allograft injury. Based on these findings, we describe a clinically relevant treatment strategy to overcome the deleterious effect of IRI, and provide superior long-term allograft outcomes.

Human regulatory T cells undergo self-inflicted damage via granzyme pathways upon activation.

Tregs hold great promise as a cellular therapy for multiple immunologically mediated diseases, given their ability to control immune responses. The success of such strategies depends on the expansion of healthy, suppressive Tregs ex vivo and in vivo following the transfer. In clinical studies, levels of transferred Tregs decline sharply in the blood within a few days of the transfer. Tregs have a high rate of apoptosis. Here, we describe a new mechanism of Treg self-inflicted damage. We show that granzymes A and -B (GrA and GrB), which are highly upregulated in human Tregs upon stimulation, leak out of cytotoxic granules to induce cleavage of cytoplasmic and nuclear substrates, precipitating apoptosis in target cells. GrA and GrB substrates were protected from cleavage by inhibiting granzyme activity in vitro. Additionally, we show - by using cytometry by time of flight (CYTOF) - an increase in GrB-expressing Tregs in the peripheral blood and renal allografts of transplant recipients undergoing rejection. These GrB-expressing Tregs showed an activated phenotype but were significantly more apoptotic than non-GrB expressing Tregs. This potentially novel finding improves our understanding of Treg survival and suggests that manipulating Gr expression or activity might be useful for designing more effective Treg therapies.

Correction: Does NGAL reduce costs? A cost analysis of urine NGAL (uNGAL) & serum creatinine (sCr) for acute kidney injury (AKI) diagnosis.

[This corrects the article DOI: 10.1371/journal.pone.0178091.].

Does NGAL reduce costs? A cost analysis of urine NGAL (uNGAL) & serum creatinine (sCr) for acute kidney injury (AKI) diagnosis.

INTRODUCTION: Urine neutrophil gelatinase-associated lipocalin (uNGAL) is a sensitive and specific diagnostic test for acute kidney injury (AKI) in the Emergency Department (ED), but its economic impact has not been investigated. We hypothesized that uNGAL used in combination with serum creatinine (sCr) would reduce costs in the management of AKI in patients presenting to the ED in comparison to using sCr alone. MATERIALS AND METHODS: A cost simulation model was developed for clinical algorithms to diagnose AKI based on sCr alone vs. uNGAL plus sCr (uNGAL+sCr). A cost minimization analysis was performed to determine total expected costs for patients with AKI. uNGAL test characteristics were validated with eight-hundred forty-nine patients with sCr ≥1.5 from a completed study of 1635 patients recruited from EDs at two U.S. hospitals from 2007-8. Biomarker test, AKI work-up, and diagnostic imaging costs were incorporated. RESULTS: For a hypothetical cohort of 10,000 patients, the model predicted that the expected costs were $900 per patient (pp) in the sCr arm and $950 in the uNGAL+sCr arm. uNGAL+sCr resulted in 1,578 fewer patients with delayed diagnosis and treatment than sCr alone (2,013 vs. 436 pts) at center 1 and 1,973 fewer patients with delayed diagnosis and treatment than sCr alone at center 2 (2,227 vs. 254 patients). Although initial evaluation costs at each center were $50 pp higher in with uNGAL+sCr, total costs declined by $408 pp at Center 1 and by $522 pp at Center 2 due to expected reduced delays in diagnosis and treatment. Sensitivity analyses confirmed savings with uNGAL + sCr for a range of cost inputs. DISCUSSION: Using uNGAL with sCr as a clinical diagnostic test for AKI may improve patient management and reduce expected costs. Any cost savings would likely result from avoiding delays in diagnosis and treatment and from avoidance of unnecessary testing in patients given a false positive AKI diagnosis by use of sCr alone.

Acellular Hypothermic Extracorporeal Perfusion Extends Allowable Ischemia Time in a Porcine Whole Limb Replantation Model.

BACKGROUND: One of the major challenges in traumatic amputation is the need to keep ischemia time brief (4 to 6 hours) to avoid ischemic damage and enable successful replantation. The current inability to meet this challenge often leads to traumatic limb loss, which has a considerable detrimental impact on the quality of life of patients. METHODS: The authors' team built a portable extracorporeal membrane oxygenator device for the perfusion of amputated extremities with oxygenated acellular solution under controlled parameters. The authors amputated forelimbs of Yorkshire pigs, perfused them ex vivo with acellular Perfadex solution for 12 hours at 10°C in their device, and subsequently replanted them into the host animal. The authors used limbs stored on ice slurry for 4 hours before replantation as their control group. RESULTS: Clinical observation and histopathologic evaluation both demonstrated that there was less morbidity and less tissue damage to the cells during preservation and after replantation in the perfusion group compared with the standard of care. Significant differences in blood markers of muscle damage and tissue cytokine levels underscored these findings. CONCLUSIONS: The authors demonstrated the feasibility and superiority of ex vivo hypothermic oxygenated machine perfusion for preservation of amputated limbs over conventional static cold storage and herewith a substantial extension of the allowable ischemia time for replantation after traumatic amputation. This approach could also be applied to the field of transplantation, expanding the potential pool of viable donor vascularized composite allografts.

Targeted Delivery of Immunomodulators to Lymph Nodes.

Active-targeted delivery to lymph nodes represents a major advance toward more effective treatment of immune-mediated disease. The MECA79 antibody recognizes peripheral node addressin molecules expressed by high endothelial venules of lymph nodes. By mimicking lymphocyte trafficking to the lymph nodes, we have engineered MECA79-coated microparticles containing an immunosuppressive medication, tacrolimus. Following intravenous administration, MECA79-bearing particles showed marked accumulation in the draining lymph nodes of transplanted animals. Using an allograft heart transplant model, we show that targeted lymph node delivery of microparticles containing tacrolimus can prolong heart allograft survival with negligible changes in tacrolimus serum level. Using MECA79 conjugation, we have demonstrated targeted delivery of tacrolimus to the lymph nodes following systemic administration, with the capacity for immune modulation in vivo.

Paracrine Wnt1 Drives Interstitial Fibrosis without Inflammation by Tubulointerstitial Cross-Talk.

AKI with incomplete epithelial repair is a major contributor to CKD characterized by tubulointerstitial fibrosis. Injury-induced epithelial secretion of profibrotic factors is hypothesized to underlie this link, but the identity of these factors and whether epithelial injury is required remain undefined. We previously showed that activation of the canonical Wnt signaling pathway in interstitial pericytes cell autonomously drives myofibroblast activation in vivo. Here, we show that inhibition of canonical Wnt signaling also substantially prevented TGFß-dependent myofibroblast activation in vitro. To investigate whether Wnt ligand derived from proximal tubule is sufficient for renal fibrogenesis, we generated a novel mouse strain with inducible proximal tubule Wnt1 secretion. Adult mice were treated with vehicle or tamoxifen and euthanized at 12 or 24 weeks postinjection. Compared with vehicle-treated controls, kidneys with tamoxifen-induced Wnt1 expression from proximal tubules displayed interstitial myofibroblast activation and proliferation and increased matrix protein production. PDGF receptor ß-positive myofibroblasts isolated from these kidneys exhibited increased canonical Wnt target gene expression compared with controls. Notably, fibrotic kidneys had no evidence of inflammatory cytokine expression, leukocyte infiltration, or epithelial injury, despite the close histologic correlation of each with CKD. These results provide the first example of noninflammatory renal fibrosis. The fact that epithelial-derived Wnt ligand is sufficient to drive interstitial fibrosis provides strong support for the maladaptive repair hypothesis in the AKI to CKD transition.

Pharmacological GLI2 inhibition prevents myofibroblast cell-cycle progression and reduces kidney fibrosis.

Chronic kidney disease is characterized by interstitial fibrosis and proliferation of scar-secreting myofibroblasts, ultimately leading to end-stage renal disease. The hedgehog (Hh) pathway transcriptional effectors GLI1 and GLI2 are expressed in myofibroblast progenitors; however, the role of these effectors during fibrogenesis is poorly understood. Here, we demonstrated that GLI2, but not GLI1, drives myofibroblast cell-cycle progression in cultured mesenchymal stem cell-like progenitors. In animals exposed to unilateral ureteral obstruction, Hh pathway suppression by expression of the GLI3 repressor in GLI1+ myofibroblast progenitors limited kidney fibrosis. Myofibroblast-specific deletion of Gli2, but not Gli1, also limited kidney fibrosis, and induction of myofibroblast-specific cell-cycle arrest mediated this inhibition. Pharmacologic targeting of this pathway with darinaparsin, an arsenical in clinical trials, reduced fibrosis through reduction of GLI2 protein levels and subsequent cell-cycle arrest in myofibroblasts. GLI2 overexpression rescued the cell-cycle effect of darinaparsin in vitro. While darinaparsin ameliorated fibrosis in WT and Gli1-KO mice, it was not effective in conditional Gli2-KO mice, supporting GLI2 as a direct darinaparsin target. The GLI inhibitor GANT61 also reduced fibrosis in mice. Finally, GLI1 and GLI2 were upregulated in the kidneys of patients with high-grade fibrosis. Together, these data indicate that GLI inhibition has potential as a therapeutic strategy to limit myofibroblast proliferation in kidney fibrosis.

PI3kα and STAT1 Interplay Regulates Human Mesenchymal Stem Cell Immune Polarization.

The immunomodulatory capacity of mesenchymal stem cells (MSCs) is critical for their use in therapeutic applications. MSC response to specific inflammatory cues allows them to switch between a proinflammatory (MSC1) or anti-inflammatory (MSC2) phenotype. Regulatory mechanisms controlling this switch remain to be defined. One characteristic feature of MSC2 is their ability to respond to IFNγ with induction of indoleamine 2,3-dioxygenase (IDO), representing the key immunoregulatory molecule released by human MSC. Here, we show that STAT1 and PI3Kα pathways interplay regulates IFNγ-induced IDO production in MSC. Chemical phosphoinositide 3-kinase (PI3K) pan-inhibition, PI3Kα-specific inhibition or shRNA knockdown diminished IFNγ-induced IDO production. This effect involved PI3Kα-mediated upregulation of STAT1 protein levels and phosphorylation at Ser727. Overexpression of STAT1 or of a constitutively active PI3Kα mutant failed to induce basal IDO production, but shifted MSC into an MSC2-like phenotype by strongly enhancing IDO production in response to IFNγ as compared to controls. STAT1 overexpression strongly enhanced MSC-mediated T-cell suppression. The same effect could be induced using short-term pretreatment of MSC with a chemical inhibitor of the counter player of PI3K, phosphatase and tensin homolog. Finally, downregulation of STAT1 abrogated the immunosuppressive capacity of MSC. Our results for the first time identify critical upstream signals for the induced production of IDO in MSCs that could be manipulated therapeutically to enhance their immunosuppressive phenotype.

Wnt signaling in kidney tubulointerstitium during disease.

The evolutionary conserved Wnt signaling transduction pathway plays essential roles in a wide array of biologic processes including embryonic development, branching morphogenesis, proliferation and carcinogenesis. Over the past ten years it has become increasingly clear that Wnt signaling also regulates the response of adult organs to disease processes, including kidney disease. This review will focus on the growing literature implicating important roles for Wnt signaling during disease in two separate kidney compartments: the tubular epithelium and the interstitium.

Discovery of new glomerular disease-relevant genes by translational profiling of podocytes in vivo.

Identifying new biomarkers and therapeutic targets for podocytopathies such as focal segmental glomerulosclerosis (FSGS) requires a detailed analysis of transcriptional changes in podocytes over the course of disease. Here we used translating ribosome affinity purification (TRAP) to isolate and profile podocyte-specific mRNA in two different models of FSGS. We expressed enhanced green fluorescent protein-tagged to ribosomal protein L10a in podocytes under the control of the collagen-1α1 promoter, enabling one-step podocyte-specific mRNA isolation over the course of disease. This TRAP protocol robustly enriched known podocyte-specific mRNAs. We crossed Col1α1-eGFP-L10a mice with the Actn4(-/-) and Actn4(+/K256E) models of FSGS and analyzed podocyte transcriptional profiles at 2, 6, and 44 weeks of age. Two upregulated podocyte genes in murine FSGS (CXCL1 and DMPK) were found to be upregulated at the protein level in biopsies from patients with FSGS, validating this approach. There was no dilution of podocyte-specific transcripts during disease. These are the first podocyte-specific RNA expression data sets during aging and in two models of FSGS. This approach identified new podocyte proteins that are upregulated in FSGS and defines novel biomarkers and therapeutic targets for human glomerular disease.

Matrix Producing Cells in Chronic Kidney Disease: Origin, Regulation, and Activation.

Chronic injury to the kidney causes kidney fibrosis with irreversible loss of functional renal parenchyma and leads to the clinical syndromes of chronic kidney disease (CKD) and end-stage renal disease (ESRD). Regardless of the type of initial injury, kidney disease progression follows the same pathophysiologic processes characterized by interstitial fibrosis, capillary rarefaction and tubular atrophy. Myofibroblasts play a pivotal role in fibrosis by driving excessive extracellular matrix (ECM) deposition. Targeting these cells in order to prevent the progression of CKD is a promising therapeutic strategy, however, the cellular source of these cells is still controversial. In recent years, a growing amount of evidence points to resident mesenchymal cells such as pericytes and perivascular fibroblasts, which form extensive networks around the renal vasculature, as major contributors to the pool of myofibroblasts in renal fibrogenesis. Identifying the cellular origin of myofibroblasts and the key regulatory pathways that drive myofibroblast proliferation and transdifferentiation as well as capillary rarefaction is the first step to developing novel anti-fibrotic therapeutics to slow or even reverse CKD progression and ultimately reduce the prevalence of ESRD. This review will summarize recent findings concerning the cellular source of myofibroblasts and highlight recent discoveries concerning the key regulatory signaling pathways that drive their expansion and progression in CKD.

SDF-1 activates papillary label-retaining cells during kidney repair from injury.

The adult kidney contains a population of low-cycling cells that resides in the papilla. These cells retain for long periods S-phase markers given as a short pulse early in life; i.e., they are label-retaining cells (LRC). In previous studies in adult rat and mice, we found that shortly after acute kidney injury many of the quiescent papillary LRC started proliferating (Oliver JA, Klinakis A, Cheema FH, Friedlander J, Sampogna RV, Martens TP, Liu C, Efstratiadis A, Al-Awqati Q. J Am Soc Nephrol 20: 2315-2327, 2009; Oliver JA, Maarouf O, Cheema FH, Martens TP, Al-Awqati Q. J Clin Invest 114: 795-804, 2004) and, with cell-tracking experiments, we found upward migration of some papillary cells including LRC (Oliver JA, Klinakis A, Cheema FH, Friedlander J, Sampogna RV, Martens TP, Liu C, Efstratiadis A, Al-Awqati Q. J Am Soc Nephrol 20: 2315-2327, 2009). To identify molecular cues involved in the activation (i.e., proliferation and/or migration) of the papillary LRC that follows injury, we isolated these cells from the H2B-GFP mice and found that they migrated and proliferated in response to the cytokine stromal cell-derived factor-1 (SDF-1). Moreover, in a papillary organ culture assay, the cell growth out of the upper papilla was dependent on the interaction of SDF-1 with its receptor Cxcr4. Interestingly, location of these two proteins in the kidney revealed a complementary location, with SDF-1 being preferentially expressed in the medulla and Cxcr4 more abundant in the papilla. Blockade of Cxcr4 in vivo prevented mobilization of papillary LRC after transient kidney ischemic injury and worsened its functional consequences. The data indicate that the SDF-1/Cxcr4 axis is a critical regulator of papillary LRC activation following transient kidney injury and during organ repair.

Diagnostic and prognostic stratification in the emergency department using urinary biomarkers of nephron damage: a multicenter prospective cohort study.

OBJECTIVES: This study aimed to determine the diagnostic and prognostic value of urinary biomarkers of intrinsic acute kidney injury (AKI) when patients were triaged in the emergency department. BACKGROUND: Intrinsic AKI is associated with nephron injury and results in poor clinical outcomes. Several urinary biomarkers have been proposed to detect and measure intrinsic AKI. METHODS: In a multicenter prospective cohort study, 5 urinary biomarkers (urinary neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, urinary liver-type fatty acid binding protein, urinary interleukin-18, and cystatin C) were measured in 1,635 unselected emergency department patients at the time of hospital admission. We determined whether the biomarkers diagnosed intrinsic AKI and predicted adverse outcomes during hospitalization. RESULTS: All biomarkers were elevated in intrinsic AKI, but urinary neutrophil gelatinase-associated lipocalin was most useful (81% specificity, 68% sensitivity at a 104-ng/ml cutoff) and predictive of the severity and duration of AKI. Intrinsic AKI was strongly associated with adverse in-hospital outcomes. Urinary neutrophil gelatinase-associated lipocalin and urinary kidney injury molecule 1 predicted a composite outcome of dialysis initiation or death during hospitalization, and both improved the net risk classification compared with conventional assessments. These biomarkers also identified a substantial subpopulation with low serum creatinine at hospital admission, but who were at risk of adverse events. CONCLUSIONS: Urinary biomarkers of nephron damage enable prospective diagnostic and prognostic stratification in the emergency department.