Urine Chemokines as Biomarkers of Human Systemic Lupus Erythematosus Activity
Brad H. Rovin*,
Huijuan Song*,
Dan J. Birmingham*,
Lee A. Hebert*,
Chack Yung Yu and
Haikady N. Nagaraja
* Department of Medicine and the Dorothy M. Davis Heart and Lung Research Institute, Ohio State University College of Medicine and Public Health; Columbus Children’s Hospital and Research Institute; and Department of Statistics, Ohio State University, Columbus, Ohio
Address correspondence to: Dr. Brad H. Rovin, Ohio State University, Nephrology Division, N210 Means Hall, 1654 Upham Drive, Columbus, Ohio 43210. Phone: 614-293-4997; Fax: 614-293-3073; E-mail: rovin-1{at}medctr.osu.edu
The purpose of this study was to evaluate urine monocyte chemoattractantprotein-1 (MCP-1) and IL-8 as biomarkers of SLE flare. Urinewas collected every 2 mo from patients who were followed prospectivelyin the Ohio SLE Study. Renal and nonrenal flares were identifiedand MCP-1 and IL-8 were measured by specific ELISA in samplesthat were collected at flare. When available, MCP-1 and IL-8were also measured in urine samples before and after flare.For comparison, MCP-1 and IL-8 were measured in the urine ofhealthy individuals and in renal and nonrenal SLE patients withstable disease activity (disease controls). Most patients werereceiving maintenance immunosuppressive therapy before flare.At renal flare, mean urine MCP-1 (uMCP-1) was significantlygreater than uMCP-1 at nonrenal flare and from healthy volunteersand renal disease controls. The level of uMCP-1 correlated withthe increase in proteinuria at flare and was higher in patientswith proliferative glomerulonephritis and in patients with impairedrenal function. Urine MCP-1 was increased beginning 2 to 4 mobefore flare. Patients who responded to therapy showed a slowdecline in uMCP-1 over several months, whereas nonrespondershad persistently high uMCP-1. In contrast, uIL-8 did not changewith disease activity and was not elevated at renal or nonrenalflare compared with disease controls. In conclusion, uMCP-1but not uIL-8 is a sensitive and specific biomarker of renalSLE flare and its severity, even in patients who receive significantimmunosuppressive therapy. Persistently elevated uMCP-1 aftertreatment may indicate ongoing kidney injury that may adverselyaffect renal prognosis.
Substantial animal and human evidence suggests that chemokines,in particular monocyte chemoattractant protein-1 (MCP-1) andIL-8, contribute to kidney injury in the glomerulonephritis(GN) of SLE (reviewed in 1,2). In murine models of SLE GN, geneticdeletion or pharmacologic blockade of MCP-1 attenuates glomerularand interstitial inflammation and reduces kidney damage (3–5).In humans with SLE GN, MCP-1 and IL-8 are expressed in the kidneys,and their transcripts can be detected by in situ hybridization,confirming intrarenal chemokine production (6–8). Furthermore,urine MCP-1 and IL-8 (uMCP-1, uIL-8) levels are increased inSLE patients during active renal disease and in some reportsdecrease with treatment-induced disease remission (6,7,9–11).Thus, uMCP-1, uIL-8, or both may be clinically relevant biomarkersof SLE GN. To date, however, the association of urine chemokineswith renal and nonrenal SLE activity has not been examined rigorouslythrough serial measurement of chemokine levels before, during,and after disease flares. This study was undertaken to investigatethe relationship of uMCP-1 and uIL-8 to the onset, severity,and resolution of SLE flare in a cohort of well-characterizedpatients who were followed in the Ohio SLE Study (OSS), a prospectivelongitudinal investigation of risk factors for SLE flare inpatients with renal or nonrenal SLE.
Patients
The patients in this investigation were enrolled in the OSS,a prospective, longitudinal study of patients with four or moreAmerican College of Rheumatology criteria for SLE. Patientswere recruited for this study when they had currently activeSLE, two or more SLE flares that required an increase in therapyin the previous 3 yr, or persistently active SLE defined as>4 mo of activity despite therapy. Patients with renal SLEwere required to have kidney biopsy evidence of immune complex-mediatedGN, plus evidence of major renal manifestations past or presenttaken as 24-h urine protein/creatinine (Pr/Cr) ratio >1,serum creatinine >1.1 mg/dl (women) or 1.3 mg/dl (men) attributableto SLE, or both. Biopsies were not done for purposes of entryinto the study but for the standard clinical indications of24-h proteinuria exceeding 1 g, impaired kidney function, ordecline in kidney function despite appropriate therapy for SLEnephritis. Patients with nonrenal SLE were defined as neverhaving shown major renal manifestations attributable to SLEGN. These patients had a normal serum creatinine (1.1 mg/dlfor women; 1.3 for men), a Pr/Cr <0.3, and urine sedimentwith <5 red blood cells per high-power field and no casts.Each patient was evaluated clinically and with laboratory testsevery 2 mo and provided a freshly voided urine specimen at thevisit. These urine samples were placed at 4°C and transporteddirectly to the laboratory, where they were centrifuged to removesediment and frozen in aliquots at –80°C for laterchemokine analysis. No other manipulations were done. Urinechemokines are stable in long-term frozen storage (9). Sampleswere thawed up to two times during analysis. We have previouslyshown that as many as four freeze-thaw cycles do not affectuMCP-1 (12).
MCP-1 and IL-8 were measured in the freshly voided urine samplesfrom patients at renal flare. When available, additional urinespecimens collected 4 and 2 mo before the renal flare and 2and 4 mo after the renal flare were analyzed from the same patients.For comparison, chemokines were also measured in the urine ofhealthy volunteers, patients with nonrenal flare, and SLE patientswith physician-defined stable renal and nonrenal disease activity.
Adjudication and Classification of SLE Activity Status
After all clinical results were compiled from each 2-mo studyvisit, the patient’s study physician determined whetheran SLE flare had occurred; whether it was renal, nonrenal, orboth; and whether the flare was mild, moderate, or severe. Confirmationof the flare was required by independent review of the databy another study physician. Identification of renal flares wasbased on prespecified, previously reported criteria (13,14)that are summarized in Table 1. In using these criteria, itis implied that changes in serum creatinine and proteinuriaare attributable to SLE. Daily urine protein excretion ratewas estimated by measuring the Pr/Cr ratio in a 24-h urine collection(15). A nonrenal flare was declared when the patient developedone or more symptoms or signs of nonrenal SLE (Table 1) thatwere attributable to SLE and were of sufficient severity thatthe managing study physician increased therapy. The severityof nonrenal relapse was based on the British Isle Lupus AssessmentGroup severity categories (16).
Urine Chemokine Measurement
The levels of uMCP-1 and uIL-8 were measured by specific ELISA,according to manufacturer’s directions (BioSource International,Camarillo, CA; and Pierce Endogen, Rockford, IL, respectively).For uMCP-1 measurement, we determined the ELISA intra- and interassaycoefficients of variation to be 8.5 and 11.2%, respectively.The recovery of MCP-1 in urine was 88%, based on adding a knownamount of human recombinant MCP-1 to urine samples from differentindividuals. The lower range of the MCP-1 assay is 31.2 pg/ml.Urine values below this were considered undetectable and assigneda value of zero. The IL-8 ELISA was validated for urine measurementby the manufacturer and had intra- and interassay coefficientsof variation of <10% and an average urine recovery of 120%.The lower range of the IL-8 ELISA is 25 pg/ml. Urine valuesbelow this were considered undetectable and assigned a valueof zero. Urine chemokine levels were standardized to urine creatininemeasured in the same spot urine and expressed as pg/mg Cr.
Statistical Analyses
Data are shown as mean ± SEM. Comparison between twogroups was done with t test. Multiple groups were compared usingone-way ANOVA or repeated-measures ANOVA as appropriate. Datathat were nonnormal were either log-transformed before analysisor analyzed by a Kruskal-Wallis ANOVA. Specific groups thenwere compared with Bonferroni or Student-Newman-Keuls post hoctests or Dunn’s multiple comparisons test for nonnormaldata. Associations were tested by linear regression. P <0.05 was considered significant.
Table 2 shows the demographics and number and severity of SLEflares of the patients described in this report. In additionto healthy volunteers, control subjects for this study included15 patients who had a history of SLE nephritis and 18 patientswho had a history of nonrenal SLE and did not have an SLE flareduring the observation period. These patients served as diseasecontrol subjects for renal and nonrenal SLE, respectively. Thedisease control subjects were taking similar maintenance immunosuppressivemedications as the patients who had flares.
Figure 1 shows uMCP-1 and uIL-8 values at renal and nonrenalflare. The mean uMCP-1 of patients at renal flare was significantlyhigher than that of healthy control subjects, renal diseasecontrol subjects, and SLE patients with nonrenal flare. Despitesome overlap between control and patient levels, uMCP-1 seemsto be a sensitive indicator of renal flare. Seventy-three percentof flare values were above the 95th percentile of those of diseasecontrol subjects. In contrast to renal flare, uMCP-1 did notincrease during nonrenal flare. The absolute levels of uMCP-1were much higher than uIL-8 levels, and there was no correlationbetween uMCP-1 and uIL-8 at renal flare. Furthermore, therewas no difference between uIL-8 at renal flare and uIL-8 fromrenal disease control subjects and, although statistically significant,only a modest increase compared with healthy control subjects.
Figure 1. Urine chemokines at renal and nonrenal SLE flare. Each symbol represents an individual flare. The bars indicate mean chemokine values. (A) The mean urine monocyte chemoattractant protein-1 (uMCP-1) level at renal flare (Flare-R) was significantly higher than the mean value at nonrenal flare (Flare-NR; *P < 0.001) and from healthy individuals (control; *P < 0.001) and SLE renal disease control subjects (SLE Cont-R; *P < 0.001). (B) IL-8 levels at flare were significantly increased only in comparison with healthy control subjects (*P < 0.01).
The influence of immunosuppressive and renoprotective therapybefore renal flare on uMCP-1 was examined. At the time of eachflare, most patients had been receiving therapy with steroids(n = 27), immunosuppressive agents (mycophenolate mofetil, n= 20; azathioprine, n = 3; or cyclophosphamide, n = 2), or both.There was no relationship between urinary chemokine levels atflare and the cumulative amount of prednisone or immunosuppressivesreceived during the preceding 30 d (data not shown). During11 renal flares, patients were taking an angiotensin-convertingenzyme inhibitor or angiotensin receptor blocker. This grouphad a similar level of uMCP-1 as that of patients who were nottaking these medications (data not shown).
Analysis of uMCP-1 and indices of renal injury showed a positivecorrelation between uMCP-1 at renal flare and the increase inproteinuria from 2 mo before flare to flare (P = 0.01; r = 0.68).There was no correlation with the absolute magnitude of proteinuriaat flare. The mean level of uMCP-1 during renal flares withimpaired renal function, identified by elevated serum creatinine(range, 1.2 to 5.5 mg/dl; n = 14), was significantly higherthan uMCP-1 during renal flares with normal renal function (2719± 846 versus 805 ± 230 pg/mg Cr; P < 0.05).In addition, uMCP-1 after renal flare was positively associatedwith serum creatinine 2 mo after flare (Figure 2) and 4 mo afterflare (P < 0.002, r = 0.62).
Figure 2. Association between uMCP-1 and serum creatinine. Serum creatinine level 2 mo after renal flare was plotted against uMCP-1 level 2 mo after renal flare. As indicated, there was a significant correlation between creatinine and uMCP-1.
The relationship between uMCP-1 and the clinical and pathologicseverity of renal flare is shown in Figure 3. As expected, MCP-1levels increased with flare severity (Figure 3A). Furthermore,patients with proliferative forms of SLE GN (World Health Organizationclasses III and IV) had higher uMCP-1 at renal flare than patientswho had nonproliferative GN (World Health Organization classV; Figure 3B). The kidney biopsies of 14 of the 25 patientswith renal flare were obtained well before OSS enrollment, sothe histology may have changed over time, possibly accountingfor some of the variability in uMCP-1 seen in Figure 3B. However,biopsies of 11 patients with renal flare were done around thetime urine was obtained for chemokine measurement and couldbe used to examine patterns of kidney injury associated withhigh uMCP-1. Patients with class IV GN and prominent glomerularcrescents and/or necrosis had the highest levels of uMCP-1 (1000to 12,000 pg/mg Cr; n = 5). Patients with class III and IV GNand occasional glomerular crescents and/or necrosis (n = 3)had more modest uMCP-1 levels (400 to 900 pg/mg Cr). It is interestingthat high uMCP-1 (1000 to 2000 pg/mg Cr) was also observed intwo patients (class IV and class V) whose biopsies demonstratedglomerulosclerosis, interstitial fibrosis, and interstitialinflammation, in the absence of active necrotizing, crescenticglomerular lesions.
Figure 3. Relationship between clinical and pathologic severity of renal SLE and uMCP-1 level. (A) The severity of renal flare was determined by the prespecified criteria outlined in Table 1. The central tendency of uMCP-1 showed an increase from mild to more severe renal flares. The level of uMCP-1 was significantly higher for patients who experienced a severe flare than for those who had mild or moderate flares (*P < 0.05). (B) Patients were divided into proliferative (World Health Organization classes III and IV) and nonproliferative (membranous; World Health Organization class V) groups on the basis of renal biopsy reports done when SLE glomerulonephritis (GN) was documented. Patients with classes III and IV nephritis had a higher uMCP-1 at renal flare than patients with class V nephritis (P < 0.04).
Urine chemokine expression before, during, and after renal flareis illustrated in Figure 4A. Mean uIL-8 showed no relationshipto flare status. At 4 and 2 mo preceding renal flare, the meanuMCP-1 levels were numerically higher than those of renal diseasecontrol subjects (compare with Figure 1) and renal flare patientswho were sampled during stable renal disease activity (209 ±28.6 pg/mg Cr; n = 7). There was a significant increase in uMCP-1at flare, and uMCP-1 levels declined only gradually in the 4mo after flare, despite increased therapy (Table 3). The postflarerelationship of uMCP-1 to serum creatinine and proteinuria wasexamined in more detail in 12 flares, and three general patternsemerged (Figure 4B). uMCP-1 decreased, and proteinuria, creatinine,or both improved after treatment of six flares. In a secondgroup of three flares, uMCP-1 remained high for several monthsin association with elevated creatinine, nephrotic-range proteinuria,or both. Finally, uMCP-1 was persistently high after three flaresdespite a marked improvement in proteinuria. Two of these lastpatients also had a persistently abnormal creatinine after flare.
Figure 4. Time course of urine chemokine levels in relation to SLE renal flare. (A) uMCP-1 and uIL-8 were measured in samples from the same patients obtained 4 and 2 mo before renal flare, at renal flare, and 2 and 4 mo after renal flare. Mean uIL-8 did not change over the course of an SLE flare cycle. Mean uMCP-1 increased significantly at flare (*P < 0.002 versus preflare time period), and levels remained elevated for at least 4 mo after flare. (B) The pattern of recovery of uMCP-1 after treatment for renal flare was examined. Serial measurements of serum creatinine, urine Pr/Cr, and uMCP-1 were made before (-2), during (F), and after treatment of renal flare. Three patterns of uMCP-1 expression after flare emerged. In six of 12 flares, uMCP-1 levels declined and patients improved (B-1, representative time course). A second group (three patients) did not improve, and uMCP-1 levels remained high for months (B-2, representative time course). Finally, three patients showed persistently high uMCP-1 after flare despite marked improvement in proteinuria (B-3, representative time course).
It has been well established that proinflammatory chemokinesplay a critical role in the pathogenesis of experimental SLEnephritis (1–3,5,17) and that the presence of chemokinesin the urine of patients with SLE nephritis reflects intrarenalchemokine expression (6–9,18). To characterize betterthe relationship of chemokines to SLE flare and to investigatethe possibility that urine chemokines may be useful for noninvasivelymonitoring disease activity and response to therapy, we obtainedserial measurements of urine chemokines in a cohort of prospectivelyfollowed SLE patients. We found that uMCP-1 but not uIL-8 isa sensitive and specific biomarker of renal flare and the severityof kidney injury in SLE. The evidence for this is summarizedas follows: (1) uMCP-1 increased significantly at renal flarecompared with a control group matched for disease and medicationuse. In addition, the changes in uMCP-1 over time paralleledthe onset and resolution of flare. In contrast, uIL-8 at flaredid not increase compared with renal disease control subjectsand showed no relationship to flare status. (2) Nonrenal SLEflares were not accompanied by increases in uMCP-1 or uIL-8,indicating that urine chemokines do not reflect generalizedsystemic SLE activity. (3) High levels of uMCP-1 at flare weresignificantly associated with manifestations of severe renalinjury, including abnormal renal function, proliferative GN,and the degree of change in proteinuria.
This study verifies earlier reports of increased uMCP-1 in untreatedpatients with active SLE nephritis (6,9) but importantly extendsthis observation to patients who developed active SLE whileon maintenance immunosuppressive therapy. uMCP-1 increased significantlyat renal flare despite moderate to intense immunosuppression(prednisone, mycophenolate mofetil, azathioprine, or cyclophosphamide)before chemokine measurement, suggesting that uMCP-1 is a robustmarker of SLE activity that is valid in patients who have chronicdisease and are on long-term therapy. However, this backgroundof immunosuppression may partially account for the fact thatuIL-8 did not significantly increase at flare, in contrast toother investigations that measured uIL-8 in untreated SLE patients(7,10,11).
Another key feature that distinguishes this investigation fromprevious studies of urine chemokines and other cytokines inSLE (6,9,19,20) is the extensive serial measurements of chemokinesmade during the flare cycle. These measurements demonstratedthat mean uMCP-1 levels were greater than healthy and renaldisease control levels as early as 2 to 4 mo preceding a renalflare. This observation is consistent with a pathogenic rolefor MCP-1 in the initiation of SLE flare and suggests that earlyincreases in uMCP-1 may predict flare onset. However, becausebaseline urine specimens from 6 mo or more before flare werenot available for most of the renal patients who had a flare,we are prospectively collecting additional baseline samplesto validate uMCP-1 as a flare predictor. Although unlikely,it will also be relevant to verify that uMCP-1 does not increasein patients with acute changes in creatinine not attributableto SLE nephritis (e.g., hemodynamically or medication mediated).
The importance of serial versus isolated measurement of uMCP-1is further emphasized by examining uMCP-1 levels at flare betweensubgroups with different levels of renal flare severity. Althougha causal relationship between MCP-1 and renal injury is suggestedby the significant trend of increased uMCP-1 with increasedseverity, the overlap between groups somewhat diminishes theutility of uMCP-1 as a clinical marker of severity. By usingindividuals as their own controls, the specificity of uMCP-1for the clinical manifestations of renal flare should improve.
Examination of uMCP-1 after flare demonstrated a close relationshipbetween uMCP-1 and response to therapy. Consistent with previousinvestigations (6,9), we found that uMCP-1 decreased in patientswho responded to treatment. However, serial measurements ofuMCP-1 showed that it did not normalize rapidly after treatmentbut declined over 4 or more months, paralleling the improvementin proteinuria or creatinine. In contrast, uMCP-1 remained elevatedin patients who did not respond to therapy. These findings supportthe experimental animal data showing a causal role for MCP-1in renal injury during SLE GN and highlight the inadequacy ofconventional immune therapy in suppression of renal MCP-1 expression.This suggests that specifically targeting MCP-1 could reducetime to remission and result in a more complete resolution ofdisease flare in patients with SLE nephritis.
Postflare MCP-1 measurements also identified a subset of patientswhose proteinuria significantly improved with treatment butwho continued to have persistently elevated uMCP-1 levels. Itis intriguing to speculate that the elevated uMCP-1 in thisgroup reflects ongoing subacute renal injury without activeglomerular inflammation. Although this study and others foundthe highest levels of uMCP-1 to be associated with crescenticor necrotizing class IV glomerulonephritis (6), high uMCP-1levels have been reported in class V nephritis (18) and correlatedto glomerular scarring and interstitial inflammation in SLEnephritis and IgA nephropathy (8,21). Cases of high uMCP-1 associatedwith glomerulosclerosis, interstitial inflammation, and interstitialfibrosis, in the absence of active glomerular lesions, werealso observed in our SLE cohort. These data suggest that MCP-1may initiate renal injury through multiple mechanisms. Thisis feasible because in addition to proinflammatory activity,MCP-1 is profibrotic in vitro (22) and mediates renal fibrosisin experimental kidney diseases (23–25). Therefore, persistentexpression of MCP-1 could result in chronic glomerular and tubulointerstitialinjury, which may explain the association of high uMCP-1 andelevated serum creatinine in the postflare period.
In summary, serial measurement of uMCP-1 shows that it is asensitive biomarker of renal but not nonrenal SLE, even in chronicpatients who are on maintenance immunosuppressive therapy. UrineMCP-1 levels seem to predict impending flare, flare severity,and response to treatment but may be less useful for predictingrenal histology. In addition, abnormal uMCP-1 levels may identifypatients with ongoing subclinical renal injury. Unlike mostconventional clinical biomarkers, MCP-1 is also a potentialtherapeutic target in SLE nephritis. Therefore, serial uMCP-1measurements can be used to appropriately identify and monitorrecipients of novel antichemokine therapies that become available.
Acknowledgments
This work was supported in part by P01 DK 55546, M01 RR 00034,and the Lupus Clinical Trials Consortium. Portions of this workwere presented in abstract form at the 2004 American Societyof Nephrology Meeting in St. Louis, MO, October 31, 2004.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
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Received for publication August 11, 2004.
Accepted for publication November 5, 2004.
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T. Wu, C. Xie, H. W. Wang, X. J. Zhou, N. Schwartz, S. Calixto, M. Mackay, C. Aranow, C. Putterman, and C. Mohan Elevated Urinary VCAM-1, P-Selectin, Soluble TNF Receptor-1, and CXC Chemokine Ligand 16 in Multiple Murine Lupus Strains and Human Lupus Nephritis
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[Abstract][Full Text][PDF]
S. A. Varghese, T. B. Powell, M. N. Budisavljevic, J. C. Oates, J. R. Raymond, J. S. Almeida, and J. M. Arthur Urine Biomarkers Predict the Cause of Glomerular Disease
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K. Mosley, F. W. K. Tam, R. J. Edwards, J. Crozier, C. D. Pusey, and L. Lightstone Urinary proteomic profiles distinguish between active and inactive lupus nephritis
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A. Y. Hoi, M. J. Hickey, P. Hall, J. Yamana, K. M. O'Sullivan, L. L. Santos, W. G. James, A. R. Kitching, and E. F. Morand Macrophage Migration Inhibitory Factor Deficiency Attenuates Macrophage Recruitment, Glomerulonephritis, and Lethality in MRL/lpr Mice
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L C W Lit, C K Wong, L S Tam, E K M Li, and C W K Lam Raised plasma concentration and ex vivo production of inflammatory chemokines in patients with systemic lupus erythematosus
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[Abstract][Full Text][PDF]
Top
Abstract
Introduction
1.1 mg/dl for women; 
2-microglobulin, IL-6, and IL-8 and decreased excretion of Tamm-Horsfall glycoprotein in the urine of patients with active lupus nephritis.
Nephron 85
: 207
–214, 2000[CrossRef][Medline]
