Persistent proteinuria and dyslipidemia increase the risk of progressive chronic kidney disease in lupus erythematosus

Advances in immunotherapy have improved survival of patients with systemic lupus erythematosus who now face an increasing burden of chronic diseases including that of the kidney. As systemic inflammation is also thought to contribute directly to the progression of chronic kidney disease (CKD), we assessed this risk in patients with lupus, with and without a diagnosis of nephritis, and also identified modifiable risk factors. Accordingly, we enrolled 631 patients (predominantly Caucasian), of whom 504 were diagnosed with lupus within the first year and followed them an average of 11 years. Despite the presence of a chronic inflammatory disease, the rate of decline in renal function of 238 patients without nephritis was similar to that described for non-lupus patient cohorts. Progressive loss of kidney function developed exclusively in patients with lupus nephritis who had persistent proteinuria and dyslipidemia, although only six required dialysis or transplantation. The mortality rate was 16% with half of the deaths attributable to sepsis or cancer. Thus, despite the presence of a systemic inflammatory disease, the risk of progressive CKD in this lupus cohort was relatively low in the absence of nephritis. Hence, as in idiopathic glomerular disease, persistent proteinuria and dyslipidemia (modifiable risks) are the major factors for CKD progression in lupus patients with renal involvement. Advances in immunotherapy have improved survival of patients with systemic lupus erythematosus who now face an increasing burden of chronic diseases including that of the kidney. As systemic inflammation is also thought to contribute directly to the progression of chronic kidney disease (CKD), we assessed this risk in patients with lupus, with and without a diagnosis of nephritis, and also identified modifiable risk factors. Accordingly, we enrolled 631 patients (predominantly Caucasian), of whom 504 were diagnosed with lupus within the first year and followed them an average of 11 years. Despite the presence of a chronic inflammatory disease, the rate of decline in renal function of 238 patients without nephritis was similar to that described for non-lupus patient cohorts. Progressive loss of kidney function developed exclusively in patients with lupus nephritis who had persistent proteinuria and dyslipidemia, although only six required dialysis or transplantation. The mortality rate was 16% with half of the deaths attributable to sepsis or cancer. Thus, despite the presence of a systemic inflammatory disease, the risk of progressive CKD in this lupus cohort was relatively low in the absence of nephritis. Hence, as in idiopathic glomerular disease, persistent proteinuria and dyslipidemia (modifiable risks) are the major factors for CKD progression in lupus patients with renal involvement. The focus of care of patients with systemic lupus erythematosus (SLE) has traditionally emphasized control of life-threatening disease flares, and less attention has been paid to the potential burden of chronic kidney disease (CKD). Recognized as a global public health problem, CKD is associated with a high risk of mortality, end-stage renal disease, and cardiovascular disease; prevention of progressive CKD is therefore a priority.1.National Kidney Foundation K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification.Am J Kidney Dis. 2002; 39: S1-S266PubMed Google Scholar Emerging research suggests that systemic inflammation contributes directly and indirectly to progressive CKD.2.Fried L. Solomon C. Shlipak M. et al.Inflammatory and prothrombotic markers and the progression of renal disease in elderly individuals.J Am Soc Nephrol. 2004; 15: 3184-3191Crossref PubMed Scopus (189) Google Scholar, 3.Tonelli M. Sacks F. Pfeffer M. et al.Biomarkers of inflammation and progression of chronic kidney disease.Kidney Int. 2005; 68: 237-245Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar, 4.Cirillo P. Sautin Y.Y. Kanellis J. et al.Systemic inflammation, metabolic syndrome and progressive renal disease.Nephrol Dial Transplant. 2009; 24: 1384-1387Crossref PubMed Scopus (44) Google Scholar This paradigm would suggest that patients with a systemic inflammatory disease such as SLE face a risk of progressive CKD, even in the absence of specific autoimmune kidney involvement (that is, nephritis). Impaired renal function is not only a risk factor for end-stage renal disease but CKD may also contribute to the high cardiovascular risk observed in patients with SLE.5.Urowitz M.B. Bookman A.A. Koehler B.E. et al.The bimodal mortality pattern of systemic lupus erythematosus.Am J Med. 1976; 60: 221-225Abstract Full Text PDF PubMed Scopus (847) Google Scholar, 6.Ginzler E.M. Diamond H.S. Weiner M. et al.A multicenter study of outcome in systemic lupus erythematosus. I. Entry variables as predictors of prognosis.Arthritis Rheum. 1982; 25: 601-611Crossref PubMed Scopus (300) Google Scholar, 7.Ward M.M. Premature morbidity from cardiovascular and cerebrovascular diseases in women with systemic lupus erythematosus.Arthritis Rheum. 1999; 42: 338-346Crossref PubMed Scopus (468) Google Scholar, 8.Esdaile J.M. Abrahamowicz M. Grodzicky T. et al.Traditional Framingham risk factors fail to fully account for accelerated atherosclerosis in systemic lupus erythematosus.Arthritis Rheum. 2001; 44: 2331-2337Crossref PubMed Scopus (966) Google Scholar, 9.Westerweel P.E. Luyten R.K. Koomans H.A. et al.Premature atherosclerotic cardiovascular disease in systemic lupus erythematosus.Arthritis Rheum. 2007; 56: 1384-1396Crossref PubMed Scopus (99) Google Scholar, 10.Cervera R. Khamashta M.A. Font J. et al.Morbidity and mortality in systemic lupus erythematosus during a 5-year period. A multicenter prospective study of 1,000 patients. European Working Party on Systemic Lupus Erythematosus.Medicine (Baltimore). 1999; 78: 167-175Crossref PubMed Scopus (382) Google Scholar, 11.Contreras G. Pardo V. Cely C. et al.Factors associated with poor outcomes in patients with lupus nephritis.Lupus. 2005; 14: 890-895Crossref PubMed Scopus (149) Google Scholar The long-term course of renal function in patients with SLE without autoimmune kidney involvement (according to the American College of Rheumatology (ACR) criteria12.Tan E.M. Cohen A.S. Fries J.F. et al.The 1982 revised criteria for the classification of systemic lupus erythematosus.Arthritis Rheum. 1982; 25: 1271-1277Crossref PubMed Scopus (12517) Google Scholar) is not well described; however, given the prevailing hypothesis linking inflammation and CKD, it is plausible that this is a vulnerable population. In addition to the presence of systemic inflammation, medication toxicity (drug-related hypertension and metabolic abnormalities, use of nephrotoxic non-steroidal anti-inflammatories) may also contribute to CKD in this population. With respect to patients with known lupus nephritis, available data suggest wide variation in long-term clinical outcome of patients who have SLE nephritis.13.Schwartz M.M. Korbet S.M. Lewis E.J. The prognosis and pathogenesis of severe lupus glomerulonephritis.Nephrol Dial Transplant. 2008; 23: 1298-1306Crossref PubMed Scopus (72) Google Scholar, 14.Hiramatsu N. Kuroiwa T. Ikeuchi H. et al.Revised classification of lupus nephritis is valuable in predicting renal outcome with an indication of the proportion of glomeruli affected by chronic lesions.Rheumatology (Oxford). 2008; 47: 702-707Crossref PubMed Scopus (98) , 15.Korbet S.M. Schwartz M.M. Evans J. et al.Severe lupus nephritis: racial differences in presentation and outcome.J Am Soc Nephrol. 2007; 18: 244-254Crossref PubMed Scopus (223) Google Scholar, 16.Mok C.C. Ying K.Y. Tang S. et al.Predictors and outcome of renal flares after successful cyclophosphamide treatment for diffuse proliferative lupus glomerulonephritis.Arthritis Rheum. 2004; 50: 2559-2568Crossref PubMed Scopus (152) Google Scholar, 17.Houssiau F.A. Vasconcelos C. D’Cruz D. et al.The 10-year follow-up data of the Euro-Lupus Nephritis Trial comparing low-dose and high-dose intravenous cyclophosphamide.Ann Rheum Dis. 2010; 69: 61-64Crossref PubMed Scopus (371) Google Scholar, 18.Donadio Jr, J.V. Hart G.M. Bergstralh E.J. et al.Prognostic determinants in lupus nephritis: a long-term clinicopathologic study.Lupus. 1995; 4: 109-115Crossref PubMed Scopus (197) Google Scholar, 19.Bono L. Cameron J.S. Hicks J.A. The very long-term prognosis and complications of lupus nephritis and its treatment.QJM. 1999; 92: 211-218Crossref PubMed Scopus (149) Google Scholar, 20.Illei G.G. Takada K. Parkin D. et al.Renal flares are common in patients with severe proliferative lupus nephritis treated with pulse immunosuppressive therapy: long-term followup of a cohort of 145 patients participating in randomized controlled studies.Arthritis Rheum. 2002; 46: 995-1002Crossref PubMed Scopus (264) Google Scholar It is also important to define the rate of kidney function decline in patients with renal autoimmune involvement to help clinicians balance the risks of immunosuppressive drugs with the risk of progressive CKD. Accordingly, we have studied the course of long-term kidney function in a large predominantly Caucasian inception cohort of prospectively followed up subjects with SLE (with and without known renal involvement), in an effort to better understand the long-term course of kidney function in these individuals. We determined the proportion of patients who develop CKD according to the KDIGO (Kidney Disease: Improving Global Outcomes) 21.Levey A.S. Eckardt K.U. Tsukamoto Y. et al.Definition and classification of chronic kidney disease: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO).Kidney Int. 2005; 67: 2089-2100Abstract Full Text Full Text PDF PubMed Scopus (2510) Google Scholar definitions to contextualize their loss of kidney function and characterize the risk of CKD according to internationally accepted guidelines. Recognizing that this definition may not reflect CKD that is likely to evolve into advanced renal insufficiency, we also identified whether the CKD was progressive in nature by studying the rate of renal function decline over time. Finally, we related clinical parameters to the rate of renal function decline to maximize our ability to refine therapeutic goals to prevent loss of kidney function. This was a predominantly female (87%) Caucasian (77%) cohort; the balance was African Caribbean (9.4%) or Chinese (7%). The mean body mass index at the time of enrollment was 27.4±8.1 kg/m2. Only 9 subjects (1.8%) were diabetic, and 109 subjects (22%) smoked at baseline. During 11 years of follow-up, half of the subjects (53%) developed evidence of renal involvement of SLE according to the ACR criteria.12.Tan E.M. Cohen A.S. Fries J.F. et al.The 1982 revised criteria for the classification of systemic lupus erythematosus.Arthritis Rheum. 1982; 25: 1271-1277Crossref PubMed Scopus (12517) Google Scholar An additional 35 subjects developed diabetes during the course of follow-up; a total of 8.7% ever had diabetes. In total, 18% of the population had CKD at the time of last follow-up (Table 1). Of patients who never had ACR-defined renal lupus, only a small group had evidence of CKD (n=28) according to the KDIGO criteria at the time of last follow-up. These patients were older (54 years) and had renal insufficiency at the time of enrollment, but had a low rate of renal function decline over time (-0.662 ml/min per 1.73 m2 per year), suggesting that these patients have non-progressive CKD. Of patients who did have ACR-defined renal lupus, 63/266 (24%) had CKD at last follow-up. Although these subjects also had impaired renal function at the time of enrollment, they were younger (39 years) and their rate of renal function decline was -4.35 ml/min per 1.73 m2 per year, suggesting a progressive course. Only six patients developed end-stage renal disease requiring long-term dialysis or transplantation; all had renal lupus nephritis.Table 1Characteristics of patients according to whether they ever had lupus renal involvement (by the ACR criteria) and development of CKDFull cohort (N=504)Never renal involvement, no CKD (N=210)Never renal involvement, CKD at last follow-up (N=28)Renal involvement, no CKD (N=203)Renal involvement, CKD at last follow-up (N=63)Age at enrollment (years)35±1435±1254±1433±1239±17Duration of follow-up (years)11.3±8.39.6±7.411.6±8.312.6±8.812.7±8.5eGFR at enrollment (ml/min per 1.73 m2)*(*P<0.05 for ANOVA).89±2995±2263±2094±2964±34Rate of renal function decline* (ml/min per 1.73 m2 per year)-1.513±7.1-1.255±6.0-0.662±3.1-1.018±6.3-4.35±11.9Adjusted mean SLEDAI5.1±3.44.4±2.93.6±2.25.4±3.4 (non-renal 3.7±2.8)7.2±4.2 (non-renal 4.2±2.2)Average CRP/hsCRP6.03/4.25.0/3.412.3/9.56.3/4.46.5/5.0TA cholesterol*(*P<0.05 for ANOVA).5.1±1.114.8±0.85.3±1.05.1±1.16.1±1.5TA MAP*(*P<0.05 for ANOVA). (mm Hg)93.0±9.489.9±8.399.7±7.592.5±8.4102.1±8.4TA proteinuria*(*P<0.05 for ANOVA). (g/day) med (min, max)0.71 (0, 10)0.09 (0, 0.45)0.11 (0.05, 0.45)0.35 (0, 6.2)1.1 (0.06, 10)Diabetes, N (%)*(*P<0.05 for ANOVA).44 (8.7)10 (4.8)024 (11.8)10 (15.9)Deceased at last follow-up*(*P<0.05 for ANOVA). (%)73 (14.5)14 (6.7)6 (21)29 (14)24 (38)Abbreviations: ACR, American College of Rheumatology; ANOVA, analysis of variance; CKD, chronic kidney disease; CRP, c-reactive protein; eGFR, estimated glomerular filtration rate; hsCRP, high-sensitivity CRP; MAP, mean arterial pressure; SLEDAI, systemic lupus erythematosus disease activity index; TA, time-averaged.Values are mean±s.d., unless otherwise indicated. Variables with statistically significant differences across groups are indicated by* (*P<0.05 for ANOVA). Open table in a new tab Abbreviations: ACR, American College of Rheumatology; ANOVA, analysis of variance; CKD, chronic kidney disease; CRP, c-reactive protein; eGFR, estimated glomerular filtration rate; hsCRP, high-sensitivity CRP; MAP, mean arterial pressure; SLEDAI, systemic lupus erythematosus disease activity index; TA, time-averaged. Values are mean±s.d., unless otherwise indicated. Variables with statistically significant differences across groups are indicated by Although the adjusted mean SLE disease activity index (SLEDAI) (AMS) score across the four groups differed, the non-renal-adjusted mean SLEDAI did not and the difference in AMS was mostly related to the presence of renal disease activity parameters. In addition, measures of c-reactive protein (CRP) did not differ across groups, although there was a trend toward a higher level in the group of older individuals with non-progressive CKD without nephritis (P>0.05). Patients with CKD, according to the KDIGO definition, had higher cholesterol, sustained time-averaged (TA) mean arterial pressure (MAP), and sustained TA proteinuria. During the course of their follow-up, 35 patients developed diabetes (9 patients had diabetes at the time of enrollment). The proportion of patients with diabetes diagnosed either at inception or during follow-up did differ across groups (Table 1), and the impact of this on kidney function decline is described below. There was no difference in the proportion of patients who smoked (33%) at the time of enrollment or during the course of follow-up across groups. To better understand predictors of the rate of kidney function loss, clinical variables were related to the rate of renal function decline as previously described.22.Bartosik L.P. Lajoie G. Sugar L. et al.Predicting progression in IgA nephropathy.Am J Kidney Dis. 2001; 38: 728-735Abstract Full Text Full Text PDF PubMed Scopus (308) Google Scholar, 23.Geddes C.C. Rauta V. Gronhagen-Riska C. et al.A tricontinental view of IgA nephropathy.Nephrol Dial Transplant. 2003; 18: 1541-1548Crossref PubMed Scopus (156) Google Scholar, 24.Troyanov S. Wall C.A. Miller J.A. et al.Idiopathic membranous nephropathy: definition and relevance of a partial remission.Kidney Int. 2004; 66: 1199-1205Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar, 25.Troyanov S. Wall C.A. Miller J.A. et al.Focal and segmental glomerulosclerosis: definition and relevance of a partial remission.J Am Soc Nephrol. 2005; 16: 1061-1068Crossref PubMed Scopus (218) Google Scholar, 26.Reich H.N. Troyanov S. Scholey J.W. et al.Remission of proteinuria improves prognosis in IgA nephropathy.J Am Soc Nephrol. 2007; 18: 3177-3183Crossref PubMed Scopus (410) Google Scholar, 27.Cattran D.C. Reich H.N. Beanlands H.J. et al.The impact of sex in primary glomerulonephritis.Nephrol Dial Transplant. 2008; 23: 2247-2253Crossref PubMed Scopus (91) Google Scholar The mean rate of renal function decline or slope of estimated glomerular filtration rate (eGFR) of all subjects was -1.5 ml±7.1 ml/min per 1.73 m2 per year. The age at first presentation, eGFR at presentation, TA sustained proteinuria, TA cholesterol, adjusted mean SLEDAI score (including renal components), number of renal flares, and MAP at inception were predictive of the rate of progression of renal function decline by univariate linear regression analysis (Table 2). There was a statistically important interaction between cholesterol and proteinuria.Table 2Factors predictive of the rate of renal function declineUnivariate regressionMultivariate regressionVariableUnadjusted β-coefficient±s.e.P-valueβ-Coefficient±s.e.P-valueAge at inception0.059±0.0220.01-0.03±0.030.46eGFR at inception-0.077±0.010<0.001-0.094±0.013<0.0001MAP at inception0.05±0.020.10.04±0.030.2TA proteinuria-0.965±0.292<0.0013.5±1.40.02Mean average cholesterol-1.320±0.276<0.001-1.25±0.4<0.0001Interaction term (proteinuria × cholesterol)See text-0.55±0.200.009Adjusted mean SLEDAI with renal components-0.314±0.092<0.001-0.28±0.110.03Number of Renal SLE flare-0.561±0.1890.003-0.5±0.230.25Abbreviations: eGFR, estimated glomerular filtration rate; MAP, mean arterial pressure; SLE, systemic lupus erythematosus; SLEDAI, SLE disease activity index; TA, time-averaged.Results of univariate and multivariate linear regression analyses. The β-coefficients provided are derived from the full multivariate model. Open table in a new tab Abbreviations: eGFR, estimated glomerular filtration rate; MAP, mean arterial pressure; SLE, systemic lupus erythematosus; SLEDAI, SLE disease activity index; TA, time-averaged. Results of univariate and multivariate linear regression analyses. The β-coefficients provided are derived from the full multivariate model. By univariate analysis, it was determined that several variables were not related to the rate of renal function decline. Slope did not differ according to smoking status or race. Although more patients with lupus nephritis and CKD developed diabetes during the course of follow-up, diabetes was not associated with a more rapid rate of renal function decline. The adjusted mean non-renal SLEDAI was not predictive of slope, nor were the average CRP or high-sensitivity CRP values. The body mass index, 24-h urine protein, anti-ds-DNA, and C3 titers at the time of first presentation were not predictive of the slope, nor was the TA MAP; these variables were therefore not considered in the multivariate model. There were too few male subjects to detect effects of gender on the rate of renal function decline. The rate of renal function decline did not differ between subjects whether they did or did not receive ACE inhibitors or angiotensin receptor blockers. When the multivariate model was analyzed, age and baseline MAP no longer remained a significant predictor of slope. However, the baseline renal function at the time of presentation, TA proteinuria, TA cholesterol, and adjusted mean SLEDAI score (with renal components) remained significant independent predictors of the rate of renal function decline (adjusted R2 for the multivariate model is 0.245, P<0.0001). The rate of renal function decline differed significantly according to the level of TA proteinuria (Table 3, P<0.05 adjusted for unequal variance). The slope was 6–7 times greater in subjects with over 2 g/day of TA proteinuria compared with subjects with under 2 g/day of proteinuria (adjusted P-values <0.05).Table 3Rate of renal function decline according to category of TA proteinuriaTA urine protein excretion (g/day)*P<0.05 comparing slope across categories of TA proteinuria.Number of subjectsSlope of eGFR (ml/min per 1.73 m2 per year)0–1275-1.15±5.371–2320.32±8.98>236-6.68±14.6Abbreviations: eGFR, estimated glomerular filtration rate; TA, time-averaged.* P<0.05 comparing slope across categories of TA proteinuria. Open table in a new tab Abbreviations: eGFR, estimated glomerular filtration rate; TA, time-averaged. Although many patients had renal SLE involvement according to the ACR criteria, 98 subjects had biopsy-proven, WHO or ISN-RPS class III, IV, or V lupus nephritis (Table 4). Subjects who did not reach a complete or partial remission of their nephritis flare had a rate of renal function decline that was 30 times faster than that of subjects who did (P<0.05).Table 4Clinical characteristics of subjects with biopsy-proven WHO class III, IV, or V SLE nephritis, and the rate of renal function decline according to remission statusBaseline (n=98) Number with only class V lesion16 Baseline eGFR (ml/min per 1.73 m2)81.08±30.6 Median baseline proteinuria (range) (g/24 h)1.00 (0.2–36) Duration of follow-up (years)12.36±8.4Follow-upSlope (ml/min per 1.73 m2 per year)±s.d. All subjects-1.38±6.8 Complete remission, n=73-0.429±6.34 Partial remission, n=9-0.058±5.87 No remission, n=16-6.49±7.33Abbreviations: eGFR, estimated glomerular filtration rate; SLE, systemic lupus erythematosus. Open table in a new tab Abbreviations: eGFR, estimated glomerular filtration rate; SLE, systemic lupus erythematosus. At the time of last follow-up, 15% of subjects had died (Table 1). The rate of renal function decline was significantly related to the risk of death; when accounting for renal function at the time of inception, for every 1 ml/min per 1.73 m2 faster rate of GFR loss per year, there was a 1.15-fold increased risk of death (95% confidence interval for hazard ratio 1.11–1.19, P<0.0001). The primary cause of death (ICD-9 code) was available for 84% of the deceased; half of the coded deaths were attributable to cancer or sepsis, and the remainder was mostly due to cardiovascular disease. The patient mortality during follow-up is illustrated in Figure 1. This figure is provided for descriptive purposes, as the survival time would be highly correlated with the time to development of CKD. In the 98 patients with biopsy-proven lupus nephritis, mortality risk was evaluated using survival analysis; survival was calculated from the time of first biopsy evidence of class III, IV, or V nephritis. The risk of mortality in this subgroup was not related to renal function at the time of biopsy, but was independently related to sustained proteinuria and MAP during the 2 years of follow-up following biopsy. We studied a large, primarily Caucasian inception cohort of subjects with and without renal SLE involvement to describe the burden of CKD in this population and identify risk factors associated with progressive renal function decline. Our first finding was that two distinct groups of patients with SLE develop CKD during long-term follow-up. The first group includes individuals diagnosed with SLE at an older age who do not have documented ACR-defined autoimmune renal involvement. The second group comprises individuals with renal lupus who have sustained proteinuria and dyslipidemia. Given the important contribution of age and baseline renal function to the KDIGO definition of CKD used in this study, the rate of renal function decline in these patients is an important indicator as to whether this represents stable or progressive CKD. The subgroup of patients with ‘CKD’ who were older at the time of diagnosis (n=28) had minimal renal function decline during the period of follow-up (−0.662±3.1 ml/min per 1.73 m2 per year), which is comparable to that observed in healthy populations.28.Lindeman R.D. Tobin J.D. Shock N.W. Association between blood pressure and the rate of decline in renal function with age.Kidney Int. 1984; 26: 861-868Abstract Full Text PDF PubMed Scopus (311) Google Scholar, 29.Lindeman R.D. Tobin J. Shock N.W. Longitudinal studies on the rate of decline in renal function with age.J Am Geriatr Soc. 1985; 33: 278-285Crossref PubMed Scopus (1239) Google Scholar, 30.Eriksen B.O. Ingebretsen O.C. The progression of chronic kidney disease: a 10-year population-based study of the effects of gender and age.Kidney Int. 2006; 69: 375-382Abstract Full Text Full Text PDF PubMed Scopus (398) Google Scholar The relatively low rate of renal function decline observed in our cohort as a whole is surprising,11.Contreras G. Pardo V. Cely C. et al.Factors associated with poor outcomes in patients with lupus nephritis.Lupus. 2005; 14: 890-895Crossref PubMed Scopus (149) Google Scholar, 15.Korbet S.M. Schwartz M.M. Evans J. et al.Severe lupus nephritis: racial differences in presentation and outcome.J Am Soc Nephrol. 2007; 18: 244-254Crossref PubMed Scopus (223) Google Scholar, 31.Faurschou M. Dreyer L. Kamper A.L. et al.Long-term mortality and renal outcome in a cohort of 100 patients with lupus nephritis.Arthritis Care Res (Hoboken). 2010; 62: 873-880Crossref PubMed Scopus (138) Google Scholar given the prevailing theory that systemic inflammation contributes directly to kidney injury and progressive CKD,2.Fried L. Solomon C. Shlipak M. et al.Inflammatory and prothrombotic markers and the progression of renal disease in elderly individuals.J Am Soc Nephrol. 2004; 15: 3184-3191Crossref PubMed Scopus (189) Google Scholar, 3.Tonelli M. Sacks F. Pfeffer M. et al.Biomarkers of inflammation and progression of chronic kidney disease.Kidney Int. 2005; 68: 237-245Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar, 4.Cirillo P. Sautin Y.Y. Kanellis J. et al.Systemic inflammation, metabolic syndrome and progressive renal disease.Nephrol Dial Transplant. 2009; 24: 1384-1387Crossref PubMed Scopus (44) Google Scholar potentially by precipitating microvascular injury. SLE is regarded as a prototype of systemic inflammatory conditions, and this systemic inflammation is thought to contribute to the elevated risk of cardiovascular events in this population;32.Shoenfeld Y. Gerli R. Doria A. et al.Accelerated atherosclerosis in autoimmune rheumatic diseases.Circulation. 2005; 112: 3337-3347Crossref PubMed Scopus (470) Google Scholar however, this has not previously been extended to the study of loss of kidney function in patients with SLE who do not have documented autoimmune renal involvement. The incremental risk of kidney failure is likely small if one projects this rate of renal function declines to 30 years of follow-up. One possible explanation for this observation is that the majority of the population consists of premenopausal women, and the protective effects of estrogen during the observation period may in part counterbalance the effects of systemic inflammation on the vasculature,33.Neugarten J. Gender and the progression of renal disease.J Am Soc Nephrol. 2002; 13: 2807-2809Crossref PubMed Scopus (85) Google Scholar unless patients have severe or poorly responsive autoimmune renal disease. Another possible factor affecting CKD risk in this population is the competing risk of death, which considers that premature mortality prevents the development of CKD. Finally, it may be that the inflammatory aspect of lupus was not as prominent in this cohort; patients without SLE-related nephritis had relatively low adjusted mean SLEDAI scores, reflecting low average levels of disease activity over the period of follow-up. Our second finding is that in the cohort of patients with lupus nephritis, both TA proteinuria and cholesterol are important interrelated and modifiable risk factors for progressive loss of kidney function. This approach relating TA variables to the rate of kidney function decline (eGFR slope) in patients with SLE builds upon previous work indicating that, in the shorter term, proteinuria is a predictor of doubling of serum creatinine and kidney failure in patients with SLE nephritis.11.Contreras G. Pardo V. Cely C. et al.Factors associated with poor outcomes in patients with lupus nephritis.Lupus. 2005; 14: 890-895Crossref PubMed Scopus (149) Google Scholar This approach also permits finer resolution in terms of proteinuria targets for long-term preservation of kidney function in patients with SLE. Although sustained proteinuria is recognized as the most important predictor of the rate of renal function decline in primary glomerulonephritis,24.Troyanov S. Wall C.A. Miller J.A. et al.Idiopathic membranous nephropathy: definition and relevance of a partial remission.Kidney Int. 2004; 66: 1199-1205Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar, 25.Troyanov S. Wall C.A. Miller J.A. et al.Focal and segmental glomerulosclerosis: definition and relevance of a partial remission.J Am Soc Nephrol. 2005; 16: 1061-1068Crossref PubMed Scopus (218) Google Scholar, 26.Reich H.N. Troyanov S. Scholey J.W. et al.Remission of proteinuria improves prognosis in IgA nephropathy.J Am Soc Nephrol. 2007; 18: 3177-3183Crossref PubMed Scopus (410) Google Scholar this has not been as extensively explored in patients with secondary forms of glomerular disease. Similar to subjects with immunoglobulin A nephropathy,26.Reich H.N. Troyanov S. Scholey J.W. et al.Remission of proteinuria improves prognosis in IgA nephropathy.J Am Soc Nephrol. 2007; 18: 3177-3183Crossref PubMed Scopus (410) Google Scholar incremental degrees o