Urinary Macrophage Migration Inhibitory Factor Research Articles

Urinary exosomal miRNA-451a can be used as a potential noninvasive biomarker for diagnosis, reflecting tubulointerstitial damage and therapeutic response in IgA nephropathy

To investigate the potential clinical value of urinary exosomal (uE) miR-451a as a biomarker for IgAN, urinary exosomes were isolated from 40 patients with IgAN, 30 patients with primary renal diseases without IgA as disease controls (non-IgAN group) and 21 healthy controls (HCs). The expression of miR-451a within exosomes was examined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). uE miR-451a was significantly upregulated in patients with IgAN compared to non-IgAN and HCs. The uE miR-451a level was positively correlated with the change in eGFR and negatively correlated with serum creatinine, urinary macrophage migration inhibitory factor (MIF), interleukin-6 (IL-6) and tumor necrosis factor (TNF-α). A dual-luciferase reporter assay confirmed that MIF was a direct target of miR-451a. Receiver operating characteristic (ROC) curve analysis revealed that the expression of uE miR-451a showed potential diagnostic value for IgAN. Additionally, the uE miR-451a level could distinguish patients with IgAN with mild tubular atrophy/interstitial fibrosis from those with severe tubular atrophy/interstitial fibrosis. After a mean follow-up of 14.2 months, the levels of eGFR loss (ml/min/1.73 m2/year) were negatively correlated with baseline miR-451a. The levels of baseline miR-451a in the complete remission group were significantly higher than those in the non-complete remission group. uE miR-451a expression was significantly elevated in patients with IgA nephropathy and may serve as a potential biomarker for the diagnosis of IgAN and evaluation of tubulointerstitial damage, while the baseline levels of uE miR-451a may be predictors of therapeutic efficacy and disease progression.

Macrophage migration inhibitory factor promotes renal injury induced by ischemic reperfusion.

Macrophage migration inhibitory factor (MIF) is pleiotropic cytokine that has multiple effects in many inflammatory and immune diseases. This study reveals a potential role of MIF in acute kidney injury (AKI) in patients and in kidney ischemic reperfusion injury (IRI) mouse model in MIF wild‐type (WT) and MIF knockout (KO) mice. Clinically, plasma and urinary MIF levels were largely elevated at the onset of AKI, declined to normal levels when AKI was resolved and correlated tightly with serum creatinine independent of disease causes. Experimentally, MIF levels in plasma and urine were rapidly elevated after IRI‐AKI and associated with the elevation of serum creatinine and the severity of tubular necrosis, which were suppressed in MIF KO mice. It was possible that MIF may mediate AKI via CD74/TLR4‐NF‐κB signalling as mice lacking MIF were protected from AKI by largely suppressing CD74/TLR‐4‐NF‐κB associated renal inflammation, including the expression of MCP‐1, TNF‐α, IL‐1β, IL‐6, iNOS, CXCL15(IL‐8 in human) and infiltration of macrophages, neutrophil, and T cells. In conclusion, our study suggests that MIF may be pathogenic in AKI and levels of plasma and urinary MIF may correlate with the progression and regression of AKI.

Analysis of urinary macrophage migration inhibitory factor in systemic lupus erythematosus

ObjectiveTo characterise the clinical relevance of urinary macrophage migration inhibitory factor (uMIF) concentrations in patients with systemic lupus erythematosus (SLE).MethodsMIF, adjusted for urine creatinine, was quantified by ELISA in urine...

MIF/CD74 axis is a target for metformin therapy in diabetic podocytopathy - real world evidence.

202 uncontrolled type 2 diabetics, who were previously prescribed sulfonylurea monotherapy(n=100) or sulfonylurea in combination with metformin (n=102) were enrolled in the study. The amount of macrophage migration inhibitory factor(MIF) and CD74 in serum, urinary MIF to creatine ratio(UMCR), urinary CD74 to creatine ratio(UCCR), urinary albumin to creatine ratio(UACR) and urinary podocalyxin to creatine ratio (UPCR) were determined. Metabolic parameters including fasting blood glucose, postprandial 2 hours blood glucose, hemoglobin A1c, MIF and CD74 in serum were comparable between the two groups. Moreover, metformin add-on therapy showed significantly better efficacy in reducing UMCR, UCCR, UPCR and UACR in comparison with those in sulfonylurea monotherapy group, respectively. UPCR had positive correlation with UACR, UMCR and UCCR (r＝0.73, r=0.69, r=0.62, P < 0.01), respectively. Metformin could present its podocyte-protective capacity in type 2 diabetics and the underlying mechanisms may be partly attributed to its effects in suppressing MIF-CD74 axis mediated inflammatory cascade response. < p > < /p >.

The protective role of macrophage migration inhibitory factor in acute kidney injury after cardiac surgery.

Acute kidney injury (AKI) represents the most frequent complication after cardiac surgery. Macrophage migration inhibitory factor (MIF) is a stress-regulating cytokine that was shown to protect the heart from myocardial ischemia-reperfusion injury, but its role in the pathogenesis of AKI remains unknown. In an observational study, serum and urinary MIF was quantified in 60 patients scheduled for elective conventional cardiac surgery with the use of cardiopulmonary bypass. Cardiac surgery triggered an increase in MIF serum concentrations, and patients with high circulating MIF (>median) 12 hours after surgery had a significantly reduced risk of developing AKI (relative risk reduction, 72.7%; 95% confidence interval, 12 to 91.5%; P = 0.03). Experimental AKI was induced in wild-type and Mif-/- mice by 30 min of ischemia followed by 6 or 24 hours of reperfusion, or by rhabdomyolysis. Mif-deficient mice exhibited increased tubular cell injury, increased regulated cell death (necroptosis and ferroptosis), and enhanced oxidative stress. Therapeutic administration of recombinant MIF after ischemia-reperfusion in mice ameliorated AKI. In vitro treatment of tubular epithelial cells with recombinant MIF reduced cell death and oxidative stress as measured by glutathione and thiobarbituric acid reactive substances in the setting of hypoxia. Our data provide evidence of a renoprotective role of MIF in experimental ischemia-reperfusion injury by protecting renal tubular epithelial cells, consistent with our observation that high MIF in cardiac surgery patients is associated with a reduced incidence of AKI.

Comparison of macrophage migration inhibitory factor and neutrophil gelatinase-associated lipocalin-2 to predict acute kidney injury after liver transplantation: An observational pilot study.

IntroductionSeveral biomarkers have been suggested as early predictors of acute kidney injury (AKI) after orthotopic liver transplantation (OLT). Neutrophil gelatinase-associated lipocalin-2 (NGAL) appears to be a promising predictor of AKI after OLT, but the clinical benefit remains to be proven. Recently, systemic macrophage migration inhibitory factor (MIF) has been proposed as early indicator for requirement of renal replacement therapy after OLT. The aim of this prospective, observational pilot study was to compare the predictive values of serum and urinary MIF for severe AKI after OLT to those of serum and urinary NGAL.MethodsConcentrations of MIF and NGAL were measured in serum and urine samples collected from patients undergoing OLT. Acute kidney injury was classified according to the KDIGO criteria, with stages 2 and 3 summarized as severe AKI. Areas under the receiver operating curves (AUC) were calculated to assess predictive values of MIF and NGAL for the development of severe AKI.ResultsForty-five patients (mean age 55±8 years) were included. Nineteen patients (38%) developed severe AKI within 48 hours after reperfusion. At the end of OLT, serum MIF was predictive of severe AKI (AUC 0.73; 95% confidence intervals, CI 0.55–0.90; P = 0.03), whereas urinary MIF, serum NGAL, and urinary NGAL were not. On the first postoperative day, serum MIF (AUC 0.78; CI 0.62–0.93; P = 0.006), urinary MIF (AUC 0.71; CI 0.53–0.88; P = 0.03), and urinary NGAL (AUC 0.79; CI 0.64–0.93; P = 0.02) were predictive for severe AKI, while serum NGAL was not.ConclusionIn the setting of OLT, MIF and NGAL had similar predictive values for the development of severe AKI.

Urinary Macrophage Migration Inhibitory Factor as a Noninvasive Biomarker in Pediatric Henoch-Schönlein Purpura Nephritis.

The aims of this study were to investigate urinary macrophage migration inhibitory factor (MIF) levels and their clinical significance in Henoch-Schönlein purpura (HSP) children with or without nephritis (N) and to assess the influence of steroid treatment on the urine MIF levels of HSPN patients. Group I comprised 35 children with HSPN who were examined twice (A before treatment and B after steroid treatment). Group II comprised 41 children with HSP. The control group included 32 healthy children. Urinary MIF levels were measured via enzyme linked immunosorbent assay. The levels of serum creatinine, blood urea nitrogen, urinary microalbumin (mAlb), and 24-hour proteinuria were performed to determine their associations with MIF levels. Urinary MIF levels were significantly higher in group I compared with group II and the control group (P < 0.01); however, no significant difference was found between group II and the control group (P > 0.05). Upon examination, albeit urinary MIF concentration was significantly lower in group IB compared with group IA (P < 0.05), these concentrations were statistically higher than that of group II (P < 0.05). In addition, in the HSPN patients, the urinary MIF was positively associated with urinary microalbumin and 24-hour proteinuria but no association with serum creatinine and blood urea nitrogen. Elevated urinary MIF levels were found to be correlated with proteinuria in pediatric HSPN. An obvious decrease in urinary MIF concentrations among the children with HSPN was associated with steroid treatment. Urinary MIF can be used as a noninvasive biomarker in pediatric HSPN.

MP72-01 URINE LEVELS OF MACROPHAGE MIGRATION INHIBITORY FACTOR ARE INCREASED IN PATIENTS WITH BLADDER INFLAMMATION

You have accessJournal of UrologyInfections/Inflammation/Cystic Disease of the Genitourinary Tract: Interstitial Cystitis1 Apr 2016MP72-01 URINE LEVELS OF MACROPHAGE MIGRATION INHIBITORY FACTOR ARE INCREASED IN PATIENTS WITH BLADDER INFLAMMATION Fei Ma, Dimotrios E. Kouzoukas, Magnus M. Fall, Robert Moldwin, David M. Preston, Deborah R. Erickson, Barbara Kahn, Katherine Meyer-Siegler, and Pedro L. Vera Fei MaFei Ma More articles by this author , Dimotrios E. KouzoukasDimotrios E. Kouzoukas More articles by this author , Magnus M. FallMagnus M. Fall More articles by this author , Robert MoldwinRobert Moldwin More articles by this author , David M. PrestonDavid M. Preston More articles by this author , Deborah R. EricksonDeborah R. Erickson More articles by this author , Barbara KahnBarbara Kahn More articles by this author , Katherine Meyer-SieglerKatherine Meyer-Siegler More articles by this author , and Pedro L. VeraPedro L. Vera More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.1614AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine, which appears to mediate bladder inflammation and pain in rodents (Vera et al, 2010; Kouzoukas et al, 2014). We hypothesized that urinary MIF levels would increase in patients with inflammatory diseases of the bladder, and therefore examined urine from patients with conditions including: interstitial cystitis (IC) with and without Hunner lesions, urinary tract infection (UTI), and radiation cystitis. We compared these samples to those of a control population. METHODS Urine samples were collected and studied in 3 male and 3 female groups: Specimens from males included those from patients with culture confirmed UTI, those with radiation cystitis (after undergoing radiation therapy) and a control population. Specimens from females include those from IC patients with and without Hunner lesions, and those from control subjects. Urine samples from patients with Interstitial Cystitis met NIDDK diagnostic criteria. All IC patients were symptomatic at the time of urine collection. Urinary MIF and Creatinine levels were assayed using commercially available kits (R&D; Enzo). RESULTS MIF levels were significantly increased in the urine of UTI patients (>4-fold; N=51) or radiation cystitis patients (10-fold; N=18) when compared to controls (N=117), either as total concentration or normalized to creatinine levels (Table 1). Similarly, MIF levels were significantly increased (5-fold; Table 2) in the urine of IC patients with Hunner lesions (N=47) when compared to female controls (N=102). Urine MIF levels in IC patients without Hunner lesions (N=63) were not different from controls. CONCLUSIONS Urinary MIF is increased in a variety of bladder inflammatory conditions including interstitial cystitis with Hunner lesions, UTI and radiation cystitis. Conversely, urine MIF levels from IC patients without Hunner lesions are similar to controls. These findings may represent differences in pathogenesis between these conditions and may serve as a marker to distinguish them from each other. MIF may be useful for diagnosis or prognosis of IC patients with Hunner lesions and may represent a novel therapeutic target for reducing bladder pain in IC and other bladder inflammatory disorders. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e952 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Fei Ma More articles by this author Dimotrios E. Kouzoukas More articles by this author Magnus M. Fall More articles by this author Robert Moldwin More articles by this author David M. Preston More articles by this author Deborah R. Erickson More articles by this author Barbara Kahn More articles by this author Katherine Meyer-Siegler More articles by this author Pedro L. Vera More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Uropathogenic Escherichia coli causes cortical tubular necrotic cell death and the release of macrophage migration inhibitory factor

The macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine, is deregulated in acute kidney injury (AKI) through an unknown mechanism. In the present study, we used a previously described mouse model of ascending urinary tract infection in which uropathogenic Escherichia coli (UPEC) were transurethrally inoculated to induce kidney infections. Here, we show that urinary MIF was upregulated during AKI while MIF was abundantly expressed in the renal cortical tubules and that UPEC infection caused a decrease in tubular MIF. Infections with UPEC in vitro caused MIF release in a cell type-dependent manner, which was independent of receptor-mediated internalization, signal transduction, and transcription. Indeed, UPEC infection-induced necrotic cell death in vitro and in vivo correlated with extracellular acidification and processed MIF secretion. These data suggest that MIF is released by necrotic renal cortical tubular cells during UPEC infection.

Macrophage Migration Inhibitory Factor Is a Possible Candidate for the Induction of Microalbuminuria in Diabetic &lt;i&gt;db&lt;/i&gt;/&lt;i&gt;db&lt;/i&gt; Mice

Preventing the onset of microalbuminuria in diabetic nephropathy is a problem that needs urgent rectification. The use of a mouse model for diabetes is vital in this regard. For example, db/db mice exhibit defects in the leptin receptor Ob-Rb sub-type, while the ob/ob strain exhibits defects in the leptin ligand. These mouse strains demonstrate type 2 diabetes, either with or without microalbuminuria, respectively. The purpose of the present study was to use DNA microarray technology to screen for the gene responsible for the onset of diabetic microalbuminuria. Using Affymetrix Mouse Gene ST 1.0 arrays, microarray analysis was performed using total RNA from the kidneys of ob control, ob/ob, db/m, and db/db mice. Microarray and quantitative reverse transcription-polymerase chain reaction (RT-PCR) indicated that transcription of the macrophage migration inhibitory factor (MIF) gene was significantly enhanced in the kidneys of db/db mice. Western blotting showed that levels of MIF protein was enhanced in the kidneys of both diabetic db/db and ob/ob mice. On the other hand, elevation of urinary MIF excretion detected by enzyme-linked immunosorbent assay (ELISA) was only in db/db mice and preceded the onset of microalbuminuria. Immunofluorescence studies revealed that MIF was expressed in mouse kidney glomeruli. While MIF expression was enhanced in the diabetic kidneys of both mouse strains, the elevated secretion from db/db mouse kidneys may be responsible for initiating the onset of microalbuminuria in diabetic nephropathy.

Urinary Macrophage Migration Inhibitory Factor Serves as a Potential Biomarker for Acute Kidney Injury in Patients with Acute Pyelonephritis

Conventional markers of kidney function that are familiar to clinicians, including the serum creatinine and blood urea nitrogen levels, are unable to reveal genuine injury to the kidney, and their use may delay treatment. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine, and the predictive role and pathogenic mechanism of MIF deregulation during kidney infections involving acute kidney injury (AKI) are not currently known. In this study, we showed that elevated urinary MIF levels accompanied the development of AKI during kidney infection in patients with acute pyelonephritis (APN). In addition to the MIF level, the urinary levels of interleukin (IL)-1β and kidney injury molecule (KIM)-1 were also upregulated and were positively correlated with the levels of urinary MIF. An elevated urinary MIF level, along with elevated IL-1β and KIM-1 levels, is speculated to be a potential biomarker for the presence of AKI in APN patients.

Urinary macrophage migration inhibitory factor in children with urinary tract infection

Macrophage migration inhibitory factor (MIF) plays an essential pathophysiological role in inflammatory reactions. The aim of this study was to investigate the clinical utility of urine MIF (uMIF) level in predicting urinary tract infections (UTI). This multicenter, prospective study was conducted over a 1-year period between March 2008 and March 2009. Sixty patients with symptomatic culture-proven UTI and 29 healthy children were recruited. Urine MIF was measured by enzyme-linked immunosorbent assay. The mean MIF level was found to be significantly higher in the UTI group than in the control group (1082.82 vs. 211.45 pg/ml, p = 0.0001). Receiver operating characteristic (ROC) analysis revealed that the optimal cut-off uMIF level was 295 pg/ml for uMIF to predict UTI. The sensitivity and specificity of this cut-off level were 91.7% and 69%, respectively. Mean uMIF/creatinine (Cr) was also significantly higher in the UTI group than in the control group (2400.69 vs. 267.56 pg/mgCr, p = 0.0001). At a cut-off of 815 pg/mgCr for uMIF/Cr, the sensitivity and specificity were 95 and 79%, respectively. The area under curve (AUC) was 0.848 (standard error 0.040, 95% confidence interval 0.756-0.915) for uMIF and 0.889 (0.034, 0.805-0.946) for uMIF/Cr. Urine MIF/Cr was significantly higher in the patients with a positive leukocyte esterase reaction in the urine (p = 0.047), leukocytosis (p = 0.0001) and positive C-reactive protein level in serum (p = 0.003). The uMIF level was not related to leukocytosis, positive CRP level in serum and leukocyte esterase reaction in the urine. Neither uMIF nor uMIF/Cr were correlated to the positive urine nitrite test, pyuria, urine pH and specific gravity (p > 0.05). These results suggest that urine MIF and uMIF/Cr can be used for the early prediction of UTI in children.

Urine macrophage migration inhibitory factor (MIF) in children with urinary tract infection: a possible predictor of acute pyelonephritis

Macrophage migration inhibitory factor (MIF) is an important pro-inflammatory cytokine expressed at sites of inflammation. We have assessed this factor (MIF) in urinary tract infections with the aim of determining a non-invasive and sensitive method to differentiate upper and lower renal involvement. Thirty-three pediatric patients with urinary track infection (25 with acute pyelonephritis, eight with acute cystitis) and 40 healthy subjects were recruited for this prospective case-control study. Pyelonephritis was differentiated from cystitis by dimercaptosuccinic acid (DMSA) scan. Urinary MIF concentration was determined using an enzyme-linked immunosorbent assay method. The urine MIF/creatinine (Cr) ratio was significantly higher in pyelonephritis patients than in those with acute cystitis and the control group (P < 0.001). The optimal cut-point of 4.90 pg/micromol Cr for the urine MIF/Cr ratio has the potential to be a biomarker for distinguishing patients with acute pyelonephritis from those with acute cystitis. Determination of the urinary MIF was also useful in selecting the patients at risk of permanent renal damage. Of those patients with pyelonephritis, based on the DMSA scan at the time of infection, scarring on follow-up DMSA scan 9-12 months later occurred in patients with the highest urinary MIF/Cr ratios. We conclude that the urine MIF/Cr ratio is a sensitive test for differentiating acute pyelonephritis from acute cystitis and also for detecting children with acute pyelonephritis who are at a higher risk for permanent renal scars in the future.

Upregulation of Macrophage Migration Inhibitory Factor (MIF) and CD74, Receptor for MIF, in Rat Bladder During Persistent Cyclophosphamide-Induced Inflammation

The objective of this study was to determine if macrophage migration inhibitory factor (MIF) is upregulated in the bladder during persistent cystitis. MIF is a pro-inflammatory cytokine found pre-formed in the urothelium. Previous findings showed that acute bladder inflammation increased MIF release into the bladder lumen while upregulating MIF and CD74 (MIF receptor) in the bladder. Because the effects of persistent cystitis on MIF and CD74 are not known, MIF and CD74 changes in the bladder were examined after short-term (1-day) or persistent (8-day) cyclophosphamide (CYP)-induced bladder inflammation. Anesthetized male Sprague-Dawley rats received either a single CYP treatment (150 mg/kg, ip; saline, control) and examined 1 day after treatment (short-term), or repeated CYP doses (20-75 mg/ kg, ip; saline, control; every third day for 8 days) and examined after 8 days of treatment (persistent). MIF protein levels in urine and bladder were determined. In addition, Mif, CD74, and cox-2 expression in the bladder was determined. Histology verified cystitis and MIF and CD74 immunoreactivity in the bladder. Repeated CYP doses were decreased to avoid toxicity. Short-term or repeated low CYP doses (40 mg/kg; 8 days) increased urinary MIF and decreased bladder MIF amounts while upregulating bladder Mif and CD74 mRNA expression. Persistent CYP-induced bladder inflammation (even at 40 mg/kg; 8-day treatment) also upregulated other inflammatory cytokines (CCL5, IL-11, iNOS) in the bladder. Short-term and persistent (low dose) CYP cystitis are associated with markedly increased MIF release into the urine and upregulation of Mif and CD74 in bladder. This supports the hypothesis that MIF and CD74 play a significant role in both acute and persistent stages of bladder inflammation.

Elevated macrophage migration inhibitory factor (MIF) levels in the urine of patients with focal glomerular sclerosis

The pathogenesis of focal glomerular sclerosis (FGS) is poorly understood. Macrophage migration inhibitory factor (MIF) is a potent pro-inflammatory cytokine released from T cells and macrophages, and is a key molecule in inflammation. To examine further the possible role of MIF in FGS, we measured MIF levels in the urine. The purpose of the present study was to evaluate the involvement of MIF in FGS. Urine samples were obtained from 20 FGS patients. The disease controls included 40 patients with minimal-change nephrotic syndrome (MCNS) and membranous nephropathy (MN). A group of healthy subjects also served as controls. Biopsies were performed in all patients prior to entry to the study. The samples were assayed for MIF protein by a sandwich enzyme-linked immunosorbent assay (ELISA). The levels of MIF in the urine of FGS patients were significantly higher than those of the normal controls and patients with MCNS and MN. In contrast, the levels of urinary MIF (uMIF) in patients with MCNS and MN did not differ significantly from normal values. In the present study, attention also focused on the relationship between uMIF levels and pathological features. Among the patients with FGS, uMIF levels were significantly correlated with the grade of mesangial matrix increase and that of interstitial fibrosis. There was also a significant correlation between uMIF levels and the number of both intraglomerular and interstitial macrophages. Although the underlying mechanisms remain to be determined, our study presents evidence that urinary excretion of MIF is increased in FGS patients with active renal lesions.

Urinary Levels of Macrophage Migration Inhibitory Factor in Patients with IgA Nephropathy

Background/Aim: The processes involved in development of IgA nephropathy (IgAN) are not yet well understood. Macrophage migration inhibitory factor (MIF) is a potent pro-inflammatory cytokine and is an essential component of immune and inflammatory responses. To examine further the possible role of MIF in IgAN, we measured MIF levels in the urine. The purpose of the present study was to evaluate the involvement of MIF in IgAN. Methods: Urine samples were obtained from 20 IgAN patients. The disease controls included 20 patients with minimal-change nephrotic syndrome (MCNS). A group of healthy subjects served as control. The samples were assayed for MIF protein by a sandwich enzyme-linked immunosorbent assay (ELISA). Results: The MIF levels in the urine of patients with IgAN examined were significantly higher than those of the healthy control subjects. In contrast, the levels of urinary MIF (uMIF) in patients with MCNS did not differ significantly from normal values. In IgAN patients, uMIF significantly correlated with the magnitude of proteinuria, but not with the grade of hematuria. We also investigated the relationship between uMIF levels and pathological features. Among patients with IgAN, uMIF levels were significantly correlated with the grade of glomerular crescent formation and that of mesangial cell proliferation. There was also a significant correlation between uMIF levels and the number of both intraglomerular and interstitial macrophages. Conclusion: Although the underlying mechanisms remain to be determined, these data provide evidence that urinary excretion of MIF is increased in IgAN patients with active renal lesions.

Urine macrophage migration inhibitory factor concentrations as a diagnostic tool in human renal allograft rejection.

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that is a potent activator of macrophages and T cells. Previous studies have shown that local MIF production is increased in acute renal allograft rejection, suggesting that it may play an important role in the rejection process. To determine if urine and serum MIF concentrations: (1) are increased in acute rejection, and (2) can be used as noninvasive tools to discriminate between acute rejection (AR) and cyclosporine nephrotoxicity (CyA toxicity). In a prospective study of nine renal allograft patients (five acute rejection and four stable), serial urine MIF concentrations were measured by ELISA in the first 14 days after transplantation. In a retrospective study, MIF concentrations in urine and serum were measured in 24 patients who were biopsied for acute renal transplant dysfunction (11 AR, 13 CyA toxicity). Urine and serum MIF were also measured in 23 stable renal transplant patients and 10 normals. MIF was readily detected in the urine of normal healthy controls (106+/-61 pg/micromol creatinine). In the prospective study, the urinary MIF concentration was increased substantially on day 1 posttransplantation and subsequently fell in parallel with the serum creatinine. However, urine MIF increased before episodes of biopsy proven acute rejection. The retrospective study showed that urine MIF concentrations in patients with AR were increased 5-fold compared to normal controls (439+/-313 pg/micromol Cr; P<0.01). In contrast, urine MIF concentrations in CyA toxicity were not significantly different to normal controls (145+/-119 pg/micromol Cr; P=NS). A marked increase in MIF immunostaining was seen in biopsies of AR, but not in CyA toxicity. No significant differences were evident in serum MIF levels between normals and any transplant patient group. These results suggest that measurement of urine MIF concentration may be useful in monitoring renal transplant patients for acute rejection and as a discriminator from cyclosporine nephrotoxicity.

Involvement of Macrophage Migration Inhibitory Factor (MIF) in Experimental Uric Acid Nephropathy

Deposition of uric acid in the kidney can lead to progressive tubulointerstitial injury with granuloma formation. We hypothesized that uric acid crystal deposition may induce granuloma formation by stimulating local expression of macrophage migration inhibitory factor (MIF), which is a known mediator of delayed type hypersensitivity (DTH). A model of acute uric acid nephropathy was induced in rats by the administration of oxonic acid (an inhibitor of uricase), together with uric acid supplements. MIF expression and local cellular response were examined by in situ hybridization and immunohistochemistry. Kidney tissue examined at 35 days posttreatment showed widespread tubulointerstitial damage with intratubular uric acid crystal deposition and granuloma formation. Tubules within the areas of granuloma showed a six-fold increase in MIF mRNA, compared with uninvolved areas by in situ hybridization. Moreover, the areas of increased MIF mRNA expression correlated with sites of dense accumulation of macrophages and T cells, and these cells were activated when assessed by the expression of interleukin-2R (IL-2R) and (MHC) class II. Interestingly, cytoplasmic staining for MIF protein in the uric acid (UA) crystal-associated granulomatous lesions was reduced, indicating a rapid MIF secretion by damaged tubules and macrophages secondary to uric acid crystal stimulation. This was confirmed by the demonstration of a marked increase in urinary MIF protein by Western blot analysis. Control rats fed either a normal diet or only oxonic acid had no discernible evidence of renal disease by routine light microscopy and minimal tubular expression of MIF mRNA and protein. These data suggest that intrarenal granulomas in urate nephropathy may be the consequence of a crystal induced DTH reaction mediated by MIF.