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Rheumatology Advance Access originally published online on November 28, 2006
Rheumatology 2007 46(4):683-689; doi:10.1093/rheumatology/kel347
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Systemic lupus erythematosus in a multiethnic US cohort (LUMINA) XL II: factors predictive of new or worsening proteinuria

H. M. Bastian1, G. S. Alarcón1, J. M. Roseman2, G. McGwin, Jr2,3, L. M. Vilá4, B. J. Fessler1, J. D. Reveille5 and for the LUMINA study group*

1Department of Medicine, Division of Clinical Immunology and Rheumatology, 2Department of Epidemiology, 3School of Medicine and Public Health, Surgery (Section of Trauma and Burns and Critical Care) and The University of Alabama, Birmingham, 4Department of Internal Medicine, Division of Rhematology, University of Puerto Rico, San Juan, Puerto Rico and 5Department of Medicine, Division of Rheumatology, University of Texas Health Science Center, Houston, Texas.

Correspondence to: Graciela S. Alarcón, MD, MPH, 830 Faculty Office Tower, 1530 3rd Ave S, Birmingham, AL, 35294-3408, USA. E-mail: graciela.alarcon{at}ccc.uab.edu


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Outcome variables
 Results
 Univariable analyses
 Multivariable analyses
 Discussion
 References
 
Objectives. To determine the factors predictive of new or worsening proteinuria in a large multiethnic cohort of patients with systemic lupus erythematosus (SLE).

Methods. Five hundred and twenty-nine SLE patients from a multiethnic US cohort [LUpus in MInorities: NAture versus Nurture (LUMINA)] were evaluated for new or worsening proteinuria using the categories of the Systemic Lupus Activity Measure-Revised: (1), normal; (2), trace or 1+ proteinuria on the dipstick; (3), 2–3+ proteinuria and (4), ≥4+ proteinuria. A rise in urinary protein was considered a positive event visit. Basic demographic and socioeconomic variables were assessed at baseline (T0). Clinical and immunological variables including disease features, activity, duration, comorbidities (such as hypertension and diabetes), medications and autoantibodies were assessed at the visit preceding a positive event visit. Selected HLA-DR and HLA-DQ alleles, and FCGR receptor polymorphisms were assessed. Data were analysed using logistic regression analyses and generalized estimating equations.

Results. There were 243 patients (59.1% of 93 Texan Hispanics, 37.0% of 100 Puerto Rican Hispanics, 58.0% of 181 African Americans and 29.7% of 155 Caucasians) with new or worsening proteinuria, and 364 positive events in 2801 visits. Younger age [Odds ratio (OR) = 1.013, 95% confidence limits (CL) = 1.001–1.024, P < 0.0334], anti-dsDNA (OR = 1.554, CL = 1.149–2.100, P < 0.0042), and HLA-DRB1*1503 (OR = 1.746, 95% CL = 1.573–2.2673, P < 0.0103) were found to independently predict the occurrence of new or worsening proteinuria.

Conclusion. The factors predictive of new or worsening proteinuria include traditional factors associated with lupus nephritis, such as age and anti-dsDNA, as well as HLA-DRB1*1503, which has not been previously described in association with lupus nephritis, new or worsening proteinuria.

KEY WORDS: SLE, New or worsening proteinuria, Predictors


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Outcome variables
 Results
 Univariable analyses
 Multivariable analyses
 Discussion
 References
 
Lupus nephritis remains a major cause of morbidity among patients with systemic lupus erythematosus (SLE) [1–3]. Sociodemographic, clinical, immunological and genetic features have been associated with the occurrence of lupus nephritis [4–7]. We have previously reported that patients of African American or Hispanic ethnicity (predominantly of Mexican ancestry), those who are not married/living together, with greater disease activity (excluding the renal items) and those who exhibit anti-dsDNA or anti-RNP antibodies are more likely to develop lupus nephritis after being diagnosed with SLE [8]. Several investigators have examined the factors associated with declining renal function in lupus nephritis, defined as a rise in proteinuria and/or serum creatinine levels. These studies focused primarily on the factors associated with the occurrence of end-stage renal disease (ESRD) [9–14], the response, safety and efficacy of different therapies, as well as the potential for a drug-induced remission [15–19]. Not surprisingly, early and aggressive treatment of lupus nephritis can lead to improved outcomes [20, 21]. Thus, identification of the factors associated with the occurrence of new or worsening proteinuria, an event which usually precedes a rise in serum creatinine levels, seems to be inherently advantageous.

We have sought to identify the sociodemographic, clinical, immunological and genetic factors associated with new or worsening proteinuria utilizing the longitudinal data from LUMINA (LUpus in MInorities: NAture versus Nurture), a multiethnic cohort of SLE patients.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Outcome variables
 Results
 Univariable analyses
 Multivariable analyses
 Discussion
 References
 
Study population
LUMINA is a longitudinal study of outcome in patients with SLE. Details about the constitution of the LUMINA cohort have been published previously [5]. In short, patients with SLE as per the American College of Rheumatology (ACR) criteria [22], with disease of 5 yrs or less at enrolment, living within the catchment areas of the participating institutions (The University of Alabama at Birmingham, The University of Texas Health Science Center at Houston and The University of Puerto Rico Medical Science Campus), of defined Hispanic (Mexican/Central American or Puerto Rican), African American or Caucasian ethnicity, were eligible for enrolment (T0) into the study. The time of diagnosis of SLE (herein TD) was defined as the time at which a patient met ACR criteria. TL was defined as the time of the last study visit. Disease duration at T0 was defined as the time elapsing between TD and T0. Total disease duration was defined as the time between TD and TL. Patients were evaluated at 6 month intervals for the first year and then yearly. The Institutional Review Boards of the participating institutions approved the study in accordance with the Declaration of Helsinki's guidelines for the involvement of humans in research; all patients signed an informed consent.

Variables
Our comprehensive database, which includes variables from the socioeconomic–demographic, clinical, immunological and genetic domains, has been described in detail elsewhere [5].

We will now describe in some detail the variables included in the analyses to be presented. From the socioeconomic–demographic domain, the age, gender, ethnicity, education, housing, marital status and poverty (as defined by the US federal government and adjusted for the number of members in the household) [23] were assessed at T0, and if absent, at a subsequent visit since they have been shown to be stable [24].

From the clinical domains, body mass index (BMI, kg/m2 body surface area), disease activity [ascertained with the Systemic Lupus Activity Measure-Revised (SLAM-R) [25], excluding the renal items], comorbidities (hypertension and diabetes), medications [including the use of glucocorticoids, hydroxychloroquine, cyclophosphamide, mycophenolate mofetil, azathioprine, methotrexate, statins, angiotensin converting enzyme (ACE) inhibitors, traditional non-steroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase-2 (COX-2) inhibitors] and unhealthy behaviors [including smoking, drinking, not exercising, and using recreational drugs (marijuana, cocaine, crack, heroin, methamphetamines, etc.)] were assessed at the visit preceding the occurrence of new or worsening proteinuria. Family history of renal disease, and/or cardiovascular disease (CVD) and/or hypertension was assessed cumulatively up to the time of the visit being analysed. Total cholesterol, low-density lipoprotein (LDL) cholesterol (using the Friedewald formula), and high-sensitivity C-reactive protein (hsCRP) [by immunometric assay (Immulite 2000; Diagnostic Products; Los Angeles, CA)] were also assessed at T0.

From the immunological and genetic domains: anti-dsDNA titres [obtained by indirect immunofluorescence (IIF) against Crithidia luciliae as substrate] were assessed at the visit preceding the occurrence of new or worsening proteinuria; anti-RNP titres (by immunofluorescence), IgG and IgM anti-phospholipid antibodies (by ELISA) and the lupus anti-coagulant (by staclot test) were assessed at T0. HLA-DRB1, HLA-DQB1, FCGR2A, FCGR3A and FCGR3B genotyping was carried out in previously extracted genomic DNA (following standard laboratory techniques) [26, 27].


   Outcome variables
Top
 Abstract
 Introduction
 Patients and Methods
 Outcome variables
Results
 Univariable analyses
 Multivariable analyses
 Discussion
 References
 
Proteinuria was defined as per the categories of the SLAM-R: category (0), normal or absent proteinuria; category (1), trace or 1+ proteinuria on the dipstick; category (2), 2–3+ proteinuria; and category (3), ≥4+ proteinuria. For study purposes, the dependent variable new or worsening proteinuria was defined as an increase in urinary protein from absent to 1+ or greater, or a rise in proteinuria from one SLAM-R category to a higher one in a subsequent visit.

The occurrence of new or worsening proteinuria was considered a positive observation. All other occurrences (persistently absent, consistently present or improved) were considered negative observations. Changes in proteinuria could be of one (from 0 to 1, 1 to 2 or 2 to 3), two (from 0 to 2 or 1 to 3) or three (0 to 3) categories of the SLAM-R. Ceiling effect was controlled to a certain extent by allowing patients with 4+ proteinuria to contribute another positive observation subsequent to reaching a lower level of proteinuria.

Statistical analyses
Univariable and multivariable analyses were performed using logistic regression analyses to estimate the association between new or worsening proteinuria and variables from the different domains occurring at the visit preceding new or worsening proteinuria or at T0. Odds ratios (OR) and 95% confidence limits (CL) were used as the primary measures of association and calculated using generalized estimating equations (GEE) to account for the possible multiple observations within a given subject. A P ≤ 0.10 was chosen as the level of significance for the inclusion of the variables into the Basic Model of multivariable regression analyses, as shown in Fig. 1; variables with a high proportion of missing data were not included. Gender and ethnicity were entered into this Basic Model regardless of their level of significance in the univariable analyses.


Figure 1
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  		FIG. 1. Basic and alternative models of the factors predictive of new or worsening proteinuria. {dagger}Systemic Lupus Activity Measure-Revised (renal items excluded). Items included in the Basic Model are shaded. The alternative models include the items that are linked (shaded and not). A second set of models were run that included the change-in-SLAM-R score instead of SLAM-R score for a total of 16 models. Additional alternative models are described in the text.

 
Variables retained in the Basic Model constituted the platform in which alternative models were built by adding some variables as shown in Fig. 1. The Basic Model, as well as all alternative models, was examined twice; first, including the SLAM-R score at the preceding visit and second, including instead, the change in the SLAM-R score between visits. Alternative multiple regression models, not depicted in Fig. 1, were also examined to account for variables felt to be clinically relevant that had not achieved a P < 0.10 (e.g. hypertension and diabetes), and variables for which there were missing data. For the multivariable analyses, variables with CL not overlapping one were considered to be significantly associated with new or worsening proteinuria. All analyses were performed using SAS, version 8.1 (SAS Institute, Cary, NC).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Outcome variables
 Results
Univariable analyses
 Multivariable analyses
 Discussion
 References
 
There were 529 patients in the LUMINA cohort at the time these analyses were performed (93 Texan Hispanics, 100 Puerto Rican Hispanics, 181 African Americans and 155 Caucasians). The mean age (S.D.) of patients in the cohort was 37.1 (12.4) yrs. Ninety-one percent were women; 52.7% were married/living together, 31.5% were living in poverty, but 80.2% were insured; the mean number of years of education was 13.2 (3.2). The mean (S.D.) disease duration at T0 for the entire group was 1.5 (1.4) yrs. The mean (S.D.) total disease duration at the time of these analyses (TL–TD) for all patients was 5.1 (3.3) yrs; it was 6.1 (3.5) yrs for the Hispanics from Texas, 3.4 (1.8) for the Puerto Ricans, 5.2 (3.4) for the African Americans and 5.3 (3.5) for the Caucasians, P < 0.0001.

Of the 529 patients, 243 (45.9%) experienced 364 positive observations in 2801 visits; 151 patients had one episode, 69 had two, 17 had three and 6 had four episodes of new or worsening proteinuria. In general, the frequency of new or worsening proteinuria was evenly distributed with the exception of visit 8 where this seemed to occur at a slightly higher frequency (range 12.9–18.5 at other visits vs 23.6 at visit 8). New or worsening proteinuria, as expected, occurred more frequently in the Hispanics from Texas (59.1%) and in the African Americans (58.0%), followed by the Hispanics from Puerto Rico (37.0%), while the lowest frequency occurred in the Caucasians (29.7%), P < 0.001. Furthermore, when the frequency of new or worsening proteinuria per categories of the SLAM-R were examined (Table 1), there was a trend towards a higher frequency of change of one category in the Hispanics from Puerto Rico and the Caucasians (86.0 and 88.6%, respectively) than in the Hispanics from Texas and the African Americans (73.6 and 72.0%, respectively); the opposite is true for changes of two and three categories.


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  		TABLE 1. Frequency of new or worsening proteinuria per categories of the SLAM-R by ethnic group and in all LUMINA patients

 

   Univariable analyses
Top
 Abstract
 Introduction
 Patients and Methods
 Outcome variables
 Results
 Univariable analyses
Multivariable analyses
 Discussion
 References
 
Socioeconomic–demographic and health behaviors
The relationship between new or worsening proteinuria and variables from this domain are shown in Table 2. Variables positively associated (or marginally associated and therefore included in the multivariate analysis) with the outcome of interest were African American ethnicity (OR = 1.677, 95% CL = 1.167–2.408, P = 0.0052), Texan-Hispanic ethnicity (OR = 1.456, 95% CL = 0.982–2.160, P = 0.0613), younger age (OR = 1.031, 95% CL = 1.019–1.042, P < 0.0001), poverty (OR = 1.465, 95% CL = 1.114–1.883, P = 0.0029), not exercising (OR = 1.356, 95% CL = 1.049–1.752, P = 0.0201) and using recreational drugs (OR = 1.560, 95% CL = 0.936–2.600, P = 0.088). In contrast, being insured (OR = 0.725, 95% CL = 0.553–0.950, P = 0.0199) or married/living together (OR = 0.538, 95% CL = 0.420–0.690, P < 0.0001) were associated with a decreased risk of developing new or worsening proteinuria. Education, smoking or drinking was not found to be associated with the outcome of interest.


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  		TABLE 2. Selected baselinea sociodemographic and health behaviour variables associated with worsening proteinuria by univariable generalized estimating equation analysesb

 
Clinical
Table 3 lists the clinical variables associated (or marginally associated) with the occurrence of new or worsening proteinuria. Disease duration (OR = 1.109, 95% CL = 1.020–1.206, P = 0.0152), disease activity (OR = 1.056, 95% CL = 1.030–1.083, P < 0.0001), the presence of anti-dsDNA (OR = 1.974, 95% CL = 1.513–2.578, P < 0.0001) or anti-RNP (OR = 1.592, 95% CL = 1.239–2.045, P = 0.0003) antibodies and glucocorticoid use (OR = 2.051, 95% CL = 1.551–2.711, P < 0.0001) were positively associated with the occurrence of new or worsening proteinuria, while the use of NSAIDs/COX-2 inhibitors (OR = 0.788, 95% CL = 0.598–1.037, P = 0.0886) was negatively (and marginally) associated. Acute disease onset, BMI, hsCRP, total cholesterol, LDL, anti-Sm antibodies, use of medications (ACE inhibitors, mycophenolate mofetil, azathioprine, methotrexate or statins), family history of renal disease and family history of CVD and/or of hypertension were not associated with new or worsening proteinuria.


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  		TABLE 3. Selected baselinea clinical variables associated with new or worsening proteinuria by univariable generalized estimating equation analysesb

 
Genetic
HLA-DRB1*1503 (OR = 1.942, 95% CL = 1.469–2.567, P < 0.0001) was strongly associated with worsening proteinuria whereas HLA-DRB1*0301 and HLA-DQB1*0201, which are in linkage disequilibrium, were found to be negatively associated with the outcome of interest (OR = 0.699, 95% CL = 0.510–0.958, P = 0.0261 and OR = 0.684, 95% CL = 0.980–0.494, P = 0.0193, respectively). HLA-DQA1*0102 (OR = 0.780, 95% CL = 0.611–0.996, P = 0.0461) was also found to have a marginally negative association with worsening proteinuria. This is especially noteworthy because nearly all HLA-DRB1*1503 positive individuals also have DQA1*0102. However, the HLA-DQA1*0102 allele is also associated with other DRB1 alleles, including DRB1*1302, *1601, *1602 (in African Americans) and occasionally with DRB1*11 alleles (especially in African Americans). When the data for the FCGR polymorphisms were examined for all patients taken together, no association with worsening proteinuria was found. When examined by ethnic group, only FCGR2A*RR was found to be negatively associated with worsening proteinuria in the Texan-Hispanic patients (reference category FCGR2A*RH/HH), but not in the other ethnic groups. These data are shown in Table 4.


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  		TABLE 4. Selected genetic features associated with new or worsening proteinuria in LUMINA patients by univariable generalized estimating equation analyses

 

   Multivariable analyses
Top
 Abstract
 Introduction
 Patients and Methods
 Outcome variables
 Results
 Univariable analyses
 Multivariable analyses
Discussion
 References
 
Basic model
Two hundred and ninety-seven positive observations and 2095 visits were included in this model. The results of this model are shown in Table 5. Younger age (OR = 1.013, 95% CL = 1.001–1.024, P = 0.0334), anti-dsDNA antibodies (OR = 1.554, 95% CL = 1.149–2.100, P = 0.0042) and HLA-DRB1*1503 (OR = 1.746, 95% CL = 1.573–2.673, P = 0.0103) were shown to be predictive of new or worsening proteinuria. The results were comparable whether the preceding SLAM-R score or the change-in-SLAM-R scores were entered into the Basic Model (data not shown).


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  		TABLE 5. Features predictive of new or worsening proteinuria by multivariable generalized estimating equation analysesa

 
Alternative models
When age was omitted from the Basic Model, the results were unchanged. The inclusion of poverty or of the FCG receptor polymorphism (FCGR2A*RR FCGR2A* HR/HH) did not significantly alter the findings from the Basic Model. When change-in-SLAM-R score was used instead of SLAM-R score, and anti-dsDNA excluded, the absence of HLA-DRB1*0301 was also shown to be predictive of new or worsening proteinuria (OR = 1.4050, 95% CL = 1.001–1.972, P = 0.0492). The addition of the variables with relatively larger proportions of missing data (anti-RNP antibodies, NSAID/COX-2 inhibitors, family history of hypertension, diabetes mellitus, hypertension, not exercising and using recreational drugs) to the Basic Model did not change substantially the results.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Outcome variables
 Results
 Univariable analyses
 Multivariable analyses
 Discussion
References
 
Because early diagnosis and treatment may lead to improved outcomes in lupus nephritis, we chose to examine the factors which predict new or worsening proteinuria as an earlier indication of a less favourable outcome in LUMINA, a multiethnic cohort of lupus patients. To maximize the utilization of the available data and to account for the longitudinal nature of the database, GEE was chosen for the analyses presented. Regardless of the model examined, the results were consistent. Younger age and HLA-DRB1*1503 were associated with new or worsening proteinuria. The presence of anti-dsDNA antibodies was strongly associated with the outcome of interest, when included in the models. No other variable (genetic or otherwise) was consistently associated with new or worsening proteinuria with the exception of HLA-DRB1*0301 which was found to be protective in some models. It should be noted that because of the relatively limited number of observations, ethnic-specific regressions for the FCGR alleles, particularly for FCGR2A, could not be performed.

Younger age has been shown to be associated with increased disease activity [24, 28] and with the occurrence of renal involvement [29]. In addition, Hispanic and African American patients diagnosed with SLE and lupus nephritis tend to be younger than Caucasians patients with SLE in general, as well as Caucasians with lupus nephritis [8, 30, 31]. Our data are in agreement with these findings reinforcing the notion that young patients are at greater risk of developing new or worsening proteinuria, when all other factors are considered.

With reference to anti-dsDNA antibodies, data from both animal models and humans have shown that these antibodies are pathogenic [32]. Furthermore, anti-dsDNA antibody levels have been shown to rise prior to a major lupus exacerbation and to decrease subsequent to it [16, 33–36]. In addition, the association between anti-dsDNA antibodies and the occurrence of lupus nephritis has been clearly shown [37–39]. Our data further emphasize that these antibodies also predispose to the subsequent occurrence of new or worsening proteinuria and indirectly they may contribute to disease progression; these observations have direct clinical applicability.

Non-Caucasian ethnicity has been associated with proteinuria, worsening renal function and ESRD [31, 40–43]. Our univariable analyses support the association between African American and Hispanic ethnicity and the occurrence of new or worsening proteinuria (African American more strongly than Hispanic). However, neither ethnic group was retained in the different models examined. HLA-DRB1*1503 is a uniquely African HLA-DR2 subtype and may here be a proxy for African ancestry [6]. Given the tight association between non-Caucasian ethnicity, younger age and the presence of HLA-DRB1*1503 (particularly for the African Americans) and of anti-dsDNA antibodies (for both), it is possible that the effect of ethnicity is present through those other variables. However, we were unable to verify this assertion in our alternative models. It is also conceivable that ethnicity per se may be associated with the onset of lupus nephritis or its late progression to ESRD, as we and others have shown [8, 31, 42, 44], rather than with intermediate events; alternatively, the effect may be there, and we just have not been able to uncover it. As to the Hispanics from Puerto Rico, we observed a higher frequency of proteinuria over the duration of follow-up than we had expected based on our previous observation that these patients may have milder disease. It must be noted, however, that this figure represents any magnitude of proteinuria as per the categories of the SLAM and not necessarily nephrotic-range proteinuria; in fact, this ethnic group appears to be less likely to experience the highest category of proteinuria as per the SLAM-R.

HLA DRB1*15 has been shown to be associated with the occurrence of SLE in several different ethnic groups but particularly in African Americans [5, 45, 46]; it has also been variably associated with the occurrence of lupus nephritis [4–6, 39, 47]. We have now been able to demonstrate that it also associates with new or worsening proteinuria. To our knowledge, this is the first documentation of such association; we believe this association is primarily driven by the African Americans, although ethnic-specific regressions were not examined. As noted above, the fact that HLA-DQA1*0102, which was found in all DRB1*1503 positive individuals in this study, was marginally negatively associated with proteinuria is noteworthy, but this HLA-DQA1 allele is also found on numerous other common HLA-DRB1 haplotypes, especially in African Americans, which explains this apparent contradiction. In contrast, HLA-DRB1*08, which has been shown to be associated with SLE in the Hispanics of Mexican ancestry (Texas) [5, 21], was not found to be associated with new or worsening proteinuria.

Our study is not without some limitations. First, the intervals between study visits were, by design, somewhat long, which may have decreased the strength of some of the associations or may have masqueraded others. Second, as per the LUMINA protocol, we only routinely obtained urine analyses as part of the SLAM-R using the dipstick method, which in itself has several limitations, rather than a more accurate measurement of protein excretion such as spot protein to creatinine ratios. Of course, the accuracy of our determination would have improved if we had considered the specific gravity of the urine samples. Although these data are, in theory, available, they are not part of the LUMINA database and thus were not available. Dipsticks are now read using automation, and samples with a specific gravity >1.045 are repeated and are diluted. This, plus the fact that in the out-patient setting, where most of the LUMINA visits take place, patients are unlikely to be volume-depleted, allays our concerns in terms of over diagnosing a higher degree of proteinuria. Finally, although we did not examine the same urine samples at the three sites to be sure the results obtained were the same, all laboratories at the three participating institutions have basic certification by the Clinical Laboratory Improvements Amendments (CLIA), and they use approved kits for analysing urine specimens. In addition to this basic certification, all universities involved in research are accredited by the American College of Pathologists (ACP) and the Joint Council on Accreditation of Healthcare Organizations (JCAHO), which have more stringent requirements. Thus, samples examined at these different laboratories are expected to produce comparable results. Third, proteinuria was entered as categories rather than as a continuous variable. This reduced our ability to differentiate between 2+ and 3+ proteinuria. Fourth, the categories of the SLAM also include haematuria, pyuria, granular or red blood cell casts; it is therefore possible that we could be measuring variables other than proteinuria. However, it would be unlikely for these findings to be related to SLE in the absence of proteinuria. In general, urinary findings are only recorded in the SLAM-R if they are related to SLE. Fifth, there were ceiling effects which we attempted to control for by allowing patients with 4+ proteinuria to contribute to the analyses again once their proteinuria decreased below that level; however, if a decrement never occurred, worsening could not have been detected. Sixth, our sample size, even though large, did not allow us to examine ethnic-specific models; this might have been particularly useful for the analysis of the influence of FCGR alleles. Seventh, even though it would have been nice to have complement data in our patients, they were not available as they were not part of the original protocol and it is costly to do them. Furthermore, samples need to be kept on ice, given that complement CH50, and C4 and C3 to a lesser degree, is heat-labile; thus, even if resources were available, we would have had difficulty obtaining reliable data at a central laboratory because of the time constraints between sample procurement and processing. Finally, although NSAIDs/selective COX-2 inhibitors were not retained in the final model (or alternative ones), we were puzzled by the direction of the association in the univariable analyses. This, however, may indicate that NSAIDs/selective COX-2 inhibitors were used sparingly and/or discontinued as soon as renal abnormalities were detected. This, in combination with the long interval between visits, may have contributed to the negative association observed.

Despite these limitations, our data have clearly and consistently identified predictors of new or worsening proteinuria that should be considered when treating patients with lupus. In support of our findings is the fact that when we examined the creatinine categories of the SLAM, we found that patients with new or worsening proteinuria were twice as likely to develop a change in those categories compared with those who did not develop proteinuria (data not shown). Although we failed to demonstrate the association with non-Caucasian ethnicity, data from us and from others suggest that ethnicity is an important contributor to the occurrence of lupus nephritis, the response to cytotoxic treatment and the development of ESRD [8, 16, 31, 41, 44]. In fact, in our patients, the Hispanics from Texas and the African Americans were the only ones developing ESRD at frequencies of 7.5 and 6.2, respectively (P < 0.0005), compared with all others. Taken together, our data indicate that young lupus patients with nephritis, positive anti-dsDNA antibodies and positive HLA-DRB1*1503 (if obtained) are at risk of developing new or worsening proteinuria (and potentially of evolving to ESRD). These patients should be followed closely and treated aggressively if renal survival is to occur.

Formula


   Acknowledgments
 
Thanks to our patients for participating in the LUMINA study, and to Jeffrey R. Edberg, PhD, and Robert P. Kimberly, MD, for allowing us to use the data on FCG receptor genotyping. Thanks also to Robert P. Kimberly, MD, Denise Thornley-Brown, MD, and Paul W. Sanders, MD, for their critical review of our manuscript, and to Brenda Robinson and Maria Tyson for their assistance in its preparation. Supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases #R01-AR42503, General Clinical research Centers #M01-RR02558 (UTH-HSC) and M01-RR00032 (UAB), and from the National Center for Research Resources (NCRR/NIH) RCMI Clinical Research Infrastructure Initiative (RCRII) award 1P20RR11126 (UPR-MSC).


   Notes
 
*Current LUMINA investigators and staff:

The University of Alabama at Birmingham: Graciela S. Alarcón, MD, MPH, Holly M. Bastian, MD, MSPH, Barri J. Fessler, MD, Gerald McGwin, Jr, MS, PhD, Jeffrey M. Roseman, MD, MPH, PhD, Mónica Fernández, MD, Rosa Andrade, MD, Martha L. Sanchez, MD, MPH, Ellen Sowell, AA and Bernadette Johnson, BS.

The University of Texas Health Science Center at Houston: John D. Reveille, MD and Robert Sandoval, BA.

The University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico: Luis M. Vilá, MD and Carmine Pinilla-Diaz, MT. Back


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Outcome variables
 Results
 Univariable analyses
 Multivariable analyses
 Discussion
 References
 

  1. Rosner S, Ginzler E, Diamond H, et al. (1982) A multicenter study of outcome in systemic lupus erythematosus. II. Causes of death. Arthritis Rheum 25:612–7.[Web of Science][Medline]
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Submitted 12 February 2006; revised version accepted 8 September 2006.
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