Blood biomarkers for the differentiation between central and peripheral vertigo in the emergency department: a systematic review and meta-analysis.

BACKGROUND/INTRODUCTION: In patients with acute vestibular syndrome (AVS), differentiating between stroke and nonstroke causes is challenging in the emergency department (ED). Correct diagnosis of vertigo etiology is essential for early optimum treatment and disposition. OBJECTIVES: The aim of this systematic review and meta-analysis was to summarize the published evidence on the potential of blood biomarkers in the diagnosis and differentiation of peripheral from central causes of AVS. METHODS: A literature search was conducted for studies published until January 1, 2023, in PubMed, Ovid Medline, and EMBASE databases analyzing biomarkers for the differentiation between central and peripheral AVS. The Quality Assessment of Diagnostic Accuracy Studies questionnaire 2 was used for quality assessment. Pooled standardized mean difference and 95% confidence intervals were calculated if a biomarker was reported in two or more studies. Heterogeneity among included studies was investigated using the I2 metric. RESULTS: A total of 17 studies with 859 central and 4844 peripheral causes of acute dizziness or vertigo, and analysis of 61 biomarkers were included. The general laboratory markers creatinine, blood urea nitrogen, albumin, C-reactive protein, glucose, HbA1c, leukocyte counts, and neutrophil counts and the brain-derived biomarkers copeptin, S100 calcium-binding protein ß (S100ß), and neuron-specific enolase (NSE) significantly differentiated central from peripheral causes of AVS. CONCLUSIONS: This systematic review and meta-analysis highlights the potential of generalized inflammatory markers and brain-specific blood protein markers of NSE and S100ß as diagnostic biomarkers for central from peripheral differentiation in AVS. These results, as a complement to clinical characteristics, provide guidance for future large-scale diagnostic research, in this challenging ED patient population.

Update of the CHIP (CT in Head Injury Patients) decision rule for patients with minor head injury based on a multicenter consecutive case series.

OBJECTIVE: To update the existing CHIP (CT in Head Injury Patients) decision rule for detection of (intra)cranial findings in adult patients following minor head injury (MHI). METHODS: The study is a prospective multicenter cohort study in the Netherlands. Consecutive MHI patients of 16 years and older were included. Primary outcome was any (intra)cranial traumatic finding on computed tomography (CT). Secondary outcomes were any potential neurosurgical lesion and neurosurgical intervention. The CHIP model was validated and subsequently updated and revised. Diagnostic performance was assessed by calculating the c-statistic. RESULTS: Among 4557 included patients 3742 received a CT (82%). In 383 patients (8.4%) a traumatic finding was present on CT. A potential neurosurgical lesion was found in 73 patients (1.6%) with 26 (0.6%) patients that actually had neurosurgery or died as a result of traumatic brain injury. The original CHIP underestimated the risk of traumatic (intra)cranial findings in low-predicted-risk groups, while in high-predicted-risk groups the risk was overestimated. The c-statistic of the original CHIP model was 0.72 (95% CI 0.69-0.74) and it would have missed two potential neurosurgical lesions and one patient that underwent neurosurgery. The updated model performed similar to the original model regarding traumatic (intra)cranial findings (c-statistic 0.77 95% CI 0.74-0.79, after crossvalidation c-statistic 0.73). The updated CHIP had the same CT rate as the original CHIP (75%) and a similar sensitivity (92 versus 93%) and specificity (both 27%) for any traumatic (intra)cranial finding. However, the updated CHIP would not have missed any (potential) neurosurgical lesions and had a higher sensitivity for (potential) neurosurgical lesions or death as a result of traumatic brain injury (100% versus 96%). CONCLUSIONS: Use of the updated CHIP decision rule is a good alternative to current decision rules for patients with MHI. In contrast to the original CHIP the update identified all patients with (potential) neurosurgical lesions without increasing CT rate.

Risk of Intracranial Complications in Minor Head Injury: The Role of Loss of Consciousness and Post-Traumatic Amnesia in a Multi-Center Observational Study.

Various guidelines for minor head injury focus on patients with a Glasgow Coma Scale (GCS) score of 13-15 and loss of consciousness (LOC) or post-traumatic amnesia (PTA), while clinical management for patients without LOC or PTA is often unclear. We aimed to investigate the effect of presence and absence of LOC or PTA on intracranial complications in minor head injury. A prospective multi-center cohort study of all patients with blunt head injury and GCS score of 15 was conducted at six Dutch centers between 2015 and 2017. Five centers used the national guideline and one center used a local guideline-both based on the CT in Head Injury Patients (CHIP) prediction model-to identify patients in need of a computed tomography (CT) scan. We studied the presence of traumatic findings and neurosurgical interventions in patients with and without LOC or PTA. In addition, we assessed the association of LOC and PTA with traumatic findings with logistic regression analysis and the additional predictive value of LOC and PTA compared with other risk factors in the CHIP model. Of 3914 patients, 2249 (58%) experienced neither LOC nor PTA and in 305 (8%) LOC and PTA was unknown. Traumatic findings were present in 153 of 1360 patients (11%) with LOC or PTA and in 67 of 2249 patients (3%) without LOC and PTA. Five patients without LOC and PTA had potential neurosurgical lesions and one patient underwent a neurosurgical intervention. LOC and PTA were strongly associated with traumatic findings on CT, with adjusted odds ratios of 2.9 (95% confidence interval [CI] 2.2-3.8) and 3.5 (95% CI 2.7-4.6), respectively. To conclude, patients who had minor head injury with neither LOC nor PTA are at risk of intracranial complications. Clinical guidelines should include clinical management for patients without LOC and PTA, and they should include LOC and PTA as separate risk factors rather than as diagnostic selection criteria.

External validation of computed tomography decision rules for minor head injury: prospective, multicentre cohort study in the Netherlands.

OBJECTIVE: To externally validate four commonly used rules in computed tomography (CT) for minor head injury. DESIGN: Prospective, multicentre cohort study. SETTING: Three university and six non-university hospitals in the Netherlands. PARTICIPANTS: Consecutive adult patients aged 16 years and over who presented with minor head injury at the emergency department with a Glasgow coma scale score of 13-15 between March 2015 and December 2016. MAIN OUTCOME MEASURES: The primary outcome was any intracranial traumatic finding on CT; the secondary outcome was a potential neurosurgical lesion on CT, which was defined as an intracranial traumatic finding on CT that could lead to a neurosurgical intervention or death. The sensitivity, specificity, and clinical usefulness (defined as net proportional benefit, a weighted sum of true positive classifications) of the four CT decision rules. The rules included the CT in head injury patients (CHIP) rule, New Orleans criteria (NOC), Canadian CT head rule (CCHR), and National Institute for Health and Care Excellence (NICE) guideline for head injury. RESULTS: For the primary analysis, only six centres that included patients with and without CT were selected. Of 4557 eligible patients who presented with minor head injury, 3742 (82%) received a CT scan; 384 (8%) had a intracranial traumatic finding on CT, and 74 (2%) had a potential neurosurgical lesion. The sensitivity for any intracranial traumatic finding on CT ranged from 73% (NICE) to 99% (NOC); specificity ranged from 4% (NOC) to 61% (NICE). Sensitivity for a potential neurosurgical lesion ranged between 85% (NICE) and 100% (NOC); specificity from 4% (NOC) to 59% (NICE). Clinical usefulness depended on thresholds for performing CT scanning: the NOC rule was preferable at a low threshold, the NICE rule was preferable at a higher threshold, whereas the CHIP rule was preferable for an intermediate threshold. CONCLUSIONS: Application of the CHIP, NOC, CCHR, or NICE decision rules can lead to a wide variation in CT scanning among patients with minor head injury, resulting in many unnecessary CT scans and some missed intracranial traumatic findings. Until an existing decision rule has been updated, any of the four rules can be used for patients presenting minor head injuries at the emergency department. Use of the CHIP rule is recommended because it leads to a substantial reduction in CT scans while missing few potential neurosurgical lesions.

Isolated fat pad sign in acute elbow injury: is it clinically relevant?

An isolated fat pad sign (i.e. joint effusion without a visible fracture), commonly seen in acute elbow injury, is associated with occult fracture and treated as such. However, the clinical relevance of an isolated fat pad is unclear, thereby questioning the need for specialized follow-up. In this study, 111 patients (median age 15 years, interquartile range 9-27 years) with an isolated fat pad sign after acute elbow injury were included. The clinical relevance of an isolated fat pad sign was derived from descriptives on pain, elbow function, treatment change, number of revisits and recovery time after 1 week follow-up and long-term follow-up. Treatment alterations were rarely made and none of the patients needed an operative intervention; also, none of the patients had persistent symptoms. The median recovery time was 3 weeks (interquartile range 2-12 weeks). This study shows that, unless symptoms persist or worsen, regular follow-up at a specialized outpatient clinic is not needed.

Extension test and ossal point tenderness cannot accurately exclude significant injury in acute elbow trauma.

STUDY OBJECTIVE: Elbow injury is a common presentation at the emergency department (ED). There are no guidelines indicating which of these patients require radiography, whereas clinical decision rules for other limb injuries are widely accepted and resulted in less radiography and reduced waiting times. We aim to identify clinical signs that can be used to predict the need for radiography in elbow injury. METHODS: A prospective observational study at 2 ED locations in the Netherlands was performed. For every eligible patient with acute elbow injury, elbow extension and addition of point tenderness at the olecranon, epicondyles, and radial head were evaluated for predicting the need for radiography (primary endpoint). A subgroup of patients was assessed by a blinded second investigator to analyze interobserver variability (secondary endpoint). All patients received anterior-posterior and lateral elbow radiographs. Fractures were treated according to current guidelines and patients were followed at outpatient clinics. RESULTS: In total, 587 patients were included. Normal extension was observed in 174 patients (30%). Normal extension predicted absence of a fracture or isolated fat pad with 88% sensitivity and 55% specificity. Five patients with normal extension had a fracture that required surgery. Absence of point tenderness in patients with normal extension was observed in only 24 patients, of whom 3 showed a fracture and 1 required surgery. Addition of point tenderness to the extension test to predict absence of a fracture or isolated fat pad resulted in 98% sensitivity and 11% specificity. Interobserver analysis for extension and palpation of olecranon, epicondyles, and radial head resulted in κ values between 0.6 and 0.7. CONCLUSION: In contrast with previous studies, ours shows that in acute elbow injury, the extension test alone or in combination with point tenderness assessment does not safely rule out clinically significant injury. Interobserver variability was substantial. We would not recommend the use of the extension test (+/- point tenderness assessment) as a clinical decision rule to guide radiologic diagnostics in acute elbow trauma.

Short-term erythropoietin treatment does not substantially modulate monocyte transcriptomes of patients with combined heart and renal failure.

BACKGROUND: Combined heart and renal failure is associated with high cardiovascular morbidity and mortality. Anti-oxidant and anti-inflammatory, non-hematopoietic effects of erythropoietin (EPO) treatment have been proposed. Monocytes may act as biosensors of the systemic environment. We hypothesized that monocyte transcriptomes of patients with cardiorenal syndrome (CRS) reflect the pathophysiology of the CRS and respond to short-term EPO treatment at a recommended dose for treatment of renal anemia. METHODS: Patients with CRS and anemia (n = 18) included in the EPOCARES trial were matched to healthy controls (n = 12). Patients were randomized to receive 50 IU/kg/week EPO or not. RNA from CD14(+)-monocytes was subjected to genome wide expression analysis (Illumina) at baseline and 18 days (3 EPO injections) after enrolment. Transcriptomes from patients were compared to healthy controls and effect of EPO treatment was evaluated within patients. RESULTS: In CRS patients, expression of 471 genes, including inflammation and oxidative stress related genes was different from healthy controls. Cluster analysis did not separate patients from healthy controls. The 6 patients with the highest hsCRP levels had more differentially expressed genes than the 6 patients with the lowest hsCRP levels. Analysis of the variation in log(2) ratios of all individual 18 patients indicated that 4 of the 18 patients were different from the controls, whereas the other 14 were quite similar. After short-term EPO treatment, every patient clustered to his or her own baseline transcriptome. Two week EPO administration only marginally affected expression profiles on average, however, individual gene responses were variable. CONCLUSIONS: In stable, treated CRS patients with mild anemia, monocyte transcriptomes were modestly altered, and indicated imprints of inflammation and oxidative stress. EPO treatment with a fixed dose has hematopoietic effects, had no appreciable beneficial actions on monocyte transcription profiles, however, could also not be associated with undesirable transcriptional responses.

Short- and long-term effects of erythropoietin treatment on endothelial progenitor cell levels in patients with cardiorenal syndrome.

OBJECTIVE: Patients with cardiorenal syndrome (CRS) have high cardiovascular morbidity. Endothelial progenitor cells (EPC) constitute an endogenous vascular repairsystem, protecting against atherosclerosis development. Erythropoietin (EPO) treatment may have beneficial effects by mobilizing EPC from the bonemarrow. Our objective is to determine EPC levels and effects of EPO therapy on EPC levels in CRS patients. DESIGN: Open-label randomized trial. SETTING: Part of the EPOCARES-trial, conducted in Utrecht (Netherlands). PATIENTS: Patients with CRS and anaemia and healthy controls were included. Interventions Patients were randomized to receive EPO therapy (50 IU/kg/wk) for 52 weeks or no EPO therapy. MAIN OUTCOME MEASURES: CD34(+)KDR(+)-EPC, cultured EPC outgrowth and function at baseline, after 18 days and after 52 weeks. RESULTS: Patients showed lower CD34(+)KDR(+)-cell numbers compared to controls (6(12) vs. 19(19) cells/10(5) granulocytes; p = 0.010), despite increased levels of stromal cell-derived factor-1α; (3.1(0.8) vs 2.6(0.3) ng/ml; p = 0.001). EPC outgrowth and function were not different between patients and controls. EPC levels did not change after 18 days with or without EPO treatment. CD34(+)KDR(+)-cells significantly declined after 52 weeks in the non-treated group (p = 0.028). Long-term EPO therapy did not significantly affect this reduction in CD34(+)KDR(+)-EPC levels. CONCLUSIONS: CRS patients showed reduced CD34(+)KDR(+)-EPC levels compared to controls, consistent with a reduced vascular regenerative potential and despite upregulated SDF-1α levels. Over a one-year follow-up period a marked 68% further reduction in EPC levels was observed in the patient group without EPO treatment. In spite of promising experimental studies, our longitudinal, randomized study did not show significant influence of either short- or long-term EPO therapy on reduced EPC levels in CRS patients.

Reduced endothelial progenitor cells in children with hemodialysis but not predialysis chronic kidney disease.

In adults with chronic kidney disease (CKD), reduced levels of vasculoprotective endothelial progenitor cells (EPCs) may contribute to their increased risk of cardiovascular disease. Children with CKD also show signs of cardiovascular disease. However, to our knowledge, there have been no studies on circulating EPC levels in pediatric patients with CKD. We investigated CD34+KDR+ EPC numbers by using flow cytometry in 15 children with predialysis CKD, 13 children on hemodialysis, and 18 age-matched healthy controls. Children on hemodialysis showed 47% reduced EPC levels compared with controls, whereas no significant difference was found for patients with predialysis CKD. Lower EPC levels were found in patients with higher levels of inflammatory marker high-sensitivity C-reactive protein. Our data show, for the first time, that children on hemodialysis have reduced CD34+KDR+ EPC levels, which potentially contributes to their increased cardiovascular risk. In children with predialysis CKD, a decline in renal function was not associated with reduced EPC levels, which may reflect a capacity for preservation of the endogenous repair system during relatively moderate disturbances of the systemic environment.

Hepcidin-25 is a marker of the response rather than resistance to exogenous erythropoietin in chronic kidney disease/chronic heart failure patients.

AIMS: Erythropoietin (EPO) resistance, an important cause of anaemia in patients with heart and renal failure, is associated with increased mortality. The hypothesis of the present study was that exogenous EPO decreases hepcidin levels and that the decrease in hepcidin levels upon EPO treatment is related to the bone marrow response. METHODS AND RESULTS: In the EPOCARES trial, patients with renal failure (glomerular filtration rate 20-70 mL/min), heart failure, and anaemia were randomized to receive 50 IU/kg/week EPO (n = 20) or not (n = 13). Haemoglobin (Hb), hepcidin-25, ferritin, reticulocytes, serum transferrin receptor (sTfR), IL-6, and high-sensitivity C-reactive protein were measured at baseline and during treatment. Hepcidin-25 was measured by weak cation exchange chromatography/matrix assisted laser desorption ionization time-of-flight mass spectrometry. Baseline hepcidin levels were increased compared with a healthy reference population and were inversely correlated with Hb (r(2) = 0.18, P = 0.02), and positively with ferritin (r(2) = 0.51, P < 0.001), but not with renal function, high-sensitivity C-reactive protein or IL-6. Erythropoietin treatment increased reticulocytes (P < 0.001) and sTfR (P < 0.001), and decreased hepcidin (P < 0.001). Baseline hepcidin levels and the magnitude of the decrease in hepcidin correlated with the increase in reticulocytes (r(2) = 0.23, P = 0.03) and sTfR (r(2) = 0.23, P = 0.03) and also with the Hb response after 6 months (r(2) = 0.49, P = 0.001). CONCLUSION: In this group of patients with combined heart and renal failure and anaemia, increased hepcidin levels were associated with markers of iron load and not with markers of inflammation. The (change in) hepcidin levels predicted early and long-term bone marrow response to exogenous EPO. In our group hepcidin seems to reflect iron load and response to EPO rather than inflammation and EPO resistance.

Erythropoietin treatment in patients with combined heart and renal failure: objectives and design of the EPOCARES study.

BACKGROUND: Anemia is common in patients with the combination of chronic heart failure and chronic kidney disease and is associated with increased mortality. Recent clinical studies suggest that recombinant human erythropoietin (EPO) treatment has desirable as well as undesirable effects, related to its hematopoietic or nonhematopoietic effects. Therefore a translational study is needed to elucidate mechanistic aspects of EPO treatment. METHODS: In this open-label randomized 12-month trial (the Mechanisms of Erythropoietin Action in the Cardiorenal Syndrome [EPOCARES]), patients with the combination of chronic heart failure and chronic kidney disease (glomerular filtration rate 20-70 ml/min) and mild anemia (hemoglobin 10.3-12.6 g/dL in men, and 10.3-11.9 g/dL in women) are being randomized into 3 groups: 1 group (n=25) receives a fixed dose of 50 IU/kg per week EPO to increase hemoglobin level to a maximum of 13.7 g/dL for men and 13.4 g/dL for women; another group (n=25) is treated with 50 IU/kg per week EPO maintaining baseline hemoglobin levels for the first 6 months by phlebotomy. The control group (n=25) receives standard care without EPO. RESULTS: Cardiac and renal function as well as a panel of biomarkers and iron parameters are being assessed. Furthermore, the effects of EPO on monocyte gene expression profiles and on endothelial progenitor cells are being evaluated. CONCLUSION: This translational study is designed primarily to discern hematopoietic from nonhematopoietic effects of EPO in cardiorenal patients. The study will add insights into the mechanisms that could explain the fragile balance between desirable and undesirable effects of EPO (Trial registration: ClinicalTrials.gov identifier NCT00356733).

Progenitor cells and vascular function are impaired in patients with chronic kidney disease.

BACKGROUND: Endothelial dysfunction contributes to accelerated atherosclerosis in chronic kidney disease (CKD). Bone marrow-derived endothelial progenitor cells (EPC) constitute an endogenous vascular repair system protecting against atherosclerosis. Smooth muscle progenitor cells (SPC) may stimulate atherosclerosis development. We hypothesized that an imbalance in EPC and SPC occurs in CKD, which may contribute to the increased cardiovascular disease (CVD) risk. METHODS: EPC and SPC outgrowth from mononuclear cells (MNC), EPC migratory function and circulating CD34(+)KDR(+)-EPC were measured in 49 patients with varying degrees of CKD on regular therapy and 33 healthy volunteers. Renal function, CKD cause, CVD history and endothelial dysfunction parameters were determined as factors of influence on progenitor cells. RESULTS: Patients had reduced EPC outgrowth compared to controls [9 (2-22) vs 12 (1-38) cells/10(3) MNC, P = 0.026], independent of CKD cause and degree, whereas SPC outgrowth levels were higher in patients with more impaired kidney function (r = -0.397, P = 0.008). Patients had lower CD34(+)KDR(+)-EPC compared to controls [9 (0-52) vs 19 (4-110) cells/10(5) granulocytes, P = 0.004]. CVD history and increased endothelial dysfunction markers were related to lower EPC levels. Progenitor cell outgrowth was shifted towards SPC with progression of endothelial damage. Reduction in EPC could not be attributed to decreases in progenitor cell-mobilizing factors SDF-1 alpha and VEGF as levels increased with progressive kidney and endothelial dysfunction, while EPC remained low. CONCLUSIONS: Our data suggest that, already in mild CKD, EPC-mediated endogenous vascular regeneration is impaired, while SPC levels increase with declining kidney function.

Circulating endothelial progenitor cell levels are higher during childhood than in adult life.

Age-related vascular dysfunction contributes to the increased cardiovascular risk in elderly. Endothelial progenitor cells (EPC), a hematopoietic stem cell (HSC) subtype, can improve vascular repair. Therefore, it is hypothesized that a decrease in these circulating progenitor cells during aging plays a role in the enhanced cardiovascular risk. Until now, research has focused on EPC and HSC in the aging adult, but no studies have been conducted in children whereas animal studies specifically suggest a benefit of juvenile bone marrow. We investigated CD34(+)/KDR(+) EPC and CD34(+) HSC numbers by flow cytometry in healthy humans aged 1- to 81-years old. An inverse relation with age was observed for EPC counts [r=-0.37, p=0.007] as well as for HSC counts [r=-0.37, p=0.008]. During childhood significantly higher levels of EPC [p<0.0001] and HSC [p=0.001] were found compared to adults. These findings may have great clinical relevance since increasing circulating EPC levels is a promising therapeutic target to enhance the endogenous regenerative capacity. Better insight in the mechanisms underlying the higher EPC levels in children may provide options to increase EPC counts in adults, thereby potentiating endothelial repair mechanisms.

Mechanisms of Disease: erythropoietin resistance in patients with both heart and kidney failure.

Anemia is common in patients who have both heart failure and chronic kidney disease, and there is an association between anemia and progression of both diseases. The main causes of anemia are deficient production of erythropoietin (EPO), iron deficiency, and chronic disease with endogenous EPO resistance. EPO has been successfully used for over a decade to treat anemia in patients with chronic kidney disease. Less obvious are the safety and efficacy of EPO treatment in patients with both heart failure and renal disease. Up to 10% of patients receiving EPO are hyporesponsive to therapy and require large doses of the agent. Several mechanisms could explain resistance to endogenous and exogenous EPO. Proinflammatory cytokines antagonize the action of EPO by exerting an inhibitory effect on erythroid progenitor cells and by disrupting iron metabolism (a process in which hepcidin has a central role). EPO resistance might also be caused by inflammation, which has a negative effect on EPO receptors. Furthermore, neocytolysis could have a role. As resistance to exogenous EPO is associated with an increased risk of death, it is important to understand how cardiorenal failure affects EPO production and function.

Erythropoietin and the cardiorenal syndrome: cellular mechanisms on the cardiorenal connectors.

We have recently proposed severe cardiorenal syndrome (SCRS), in which cardiac and renal failure mutually amplify progressive failure of both organs. This frequent pathophysiological condition has an extremely poor prognosis. Interactions between inflammation, the renin-angiotensin system, the balance between the nitric oxide and reactive oxygen species and the sympathetic nervous system form the cardiorenal connectors and are cornerstones in the pathophysiology of SCRS. An absolute deficit of erythropoietin (Epo) and decreased sensitivity to Epo in this syndrome both contribute to the development of anemia, which is more pronounced than renal anemia in the absence of heart failure. Besides expression on erythroid progenitor cells, Epo receptors are present in the heart, kidney, and vascular system, in which activation results in antiapoptosis, proliferation, and possibly antioxidation and anti-inflammation. Interestingly, Epo can improve cardiac and renal function. We have therefore reviewed the literature with respect to Epo and the cardiorenal connectors. Indeed, there are indications that Epo can diminish inflammation, reduce renin-angiotensin system activity, and shift the nitric oxide and reactive oxygen species balance toward nitric oxide. Information about Epo and the sympathetic nervous system is scarce. This analysis underscores the relevance of a further understanding of clinical and cellular mechanisms underlying protective effects of Epo, because this will support better treatment of SCRS.

MIP-3alpha/CCL20 in renal transplantation and its possible involvement as dendritic cell chemoattractant in allograft rejection.

Graft-infiltrating dendritic cells (DC) and alloreactive T lymphocytes play a critical role in renal allograft rejection. Renal proximal tubular epithelial cells (TEC) are considered as active players in the attraction of leukocytes during renal inflammatory responses. Macrophage inflammatory protein (MIP)-3alpha/CCL20 is a major chemokine expressed by epithelial cells that attracts immature DC. In the present study, we present evidence that also the transplanted kidney can be a major source of MIP-3alpha/CCL20. Renal transplant recipients with rejection showed significantly increased excretion of urinary MIP-3alpha/CCL20 that correlated with transplant function. The tubular staining for MIP-3alpha/CCL20 in renal biopsies of patients with rejection as well as in vitro studies with primary human TEC indicated that TEC might be responsible for the increased urinary MIP-3alpha/CCL20. Furthermore, MIP-3alpha/CCL20 produced by activated TEC was highly potent in the attraction of CD1a+CD34+-derived DC precursors. These data suggest a role for MIP-3alpha/CCL20 in amplification of the immune response during renal allograft rejection by attraction of CCR6+ inflammatory cells, which may include DC, to the site of inflammation.