Abstract
Objective Chronic kidney disease (CKD) has significant clinical and therapeutic implications. This study assessed CKD prevalence, risk factors, and long-term outcomes in patients with systemic lupus erythematosus (SLE), both with and without lupus nephritis (LN).
Methods This single-center, retrospective, medical records review study, conducted between 2014 and 2023, included adult patients with SLE. CKD was defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 or albuminuria ≥ 30 mg/24 h in ≥ 2 consecutive tests, spaced ≥ 3 months apart. Statistical analyses included chi-square tests, t tests, multivariable regression, and Cox proportional hazards models.
Results A total of 175 patients with SLE were included, with a mean follow-up of 18.3 (SD 14.7) years. Of these patients, 12 required kidney replacement therapy. CKD was diagnosed in 54.6% (89/163) of patients, including 15.7% with reduced eGFR only, 52.8% with albuminuria only, and 31.5% with both. LN was associated with a higher hazard ratio (HR) of 5.4 for CKD, and 46.1% of patients with CKD had no history of LN. CKD was associated with increased cardiovascular morbidity and hospitalization rates for SLE exacerbations and infections. Cox analyses identified LN as the strongest predictor of CKD, with age and lower eGFR at diagnosis identified as other predictors. CKD was an important predictor of mortality among patients with SLE, in both univariate and multivariable analyses (19.1% vs 1.4%, P < 0.001).
Conclusion CKD is highly prevalent in SLE, including in patients without prior LN. CKD is associated with increased morbidity and mortality. This study emphasizes the clinical relevance of CKD diagnosis and management in patients with SLE.
- albuminuria
- antiphospholipid antibody syndrome
- chronic kidney disease
- kidney function
- lupus nephritis
- systemic lupus erythematosus
Systemic lupus erythematosus (SLE) frequently involves the kidneys (30-60% of cases) and its prevalence and outcomes vary between different studies, including with regard to ethnicity.1-4 Sex differences have been reported; although SLE is rare among male individuals, their renal and cardiovascular (CV) outcomes are 2- to 5-fold worse compared with female individuals.4 Sociodemographic variations in SLE emphasize the heterogeneity of this unique population, and therefore the need for further investigation and long-term follow-up.
Kidney involvement in SLE significantly contributes to morbidity and mortality. Mortality rates are notably higher in patients with lupus nephritis (LN) compared to those without it. Specifically, death directly attributable to kidney disease occurs in approximately 5% to 25% of patients with proliferative LN within 5 years of onset.5 Despite available treatments, end-stage kidney disease (ESKD) remains prevalent among patients with SLE, estimated at approximately 10%, varying with population characteristics. The critical predictors for progression to ESKD included elevated serum creatinine, class III/IV LN, male sex, non-White ethnicity (ie, mainly Black or Asian populations), and hypertension (HTN).6 This condition significantly contributes to both morbidity and mortality in affected individuals.5,7
LN is the most common and extensively investigated type of kidney involvement in patients with SLE. Most studies aiming to improve prognosis focus on the immunosuppressive treatment of LN.5-7
Patients with LN are often regarded as having chronic kidney disease (CKD), since kidney damage and nephron loss occur very early during the course of LN.8 Untreated or poorly responsive proliferative LN may progress to more advanced stages of CKD and ESKD.6,7 Moreover, patients with SLE without LN are also at increased risk for CKD owing to the inherent risk factors and outcomes of SLE, such as inflammatory state, accelerated atherosclerosis, endothelial dysfunction, and HTN.9-12 The conventional definition of CKD is kidney function impairment lasting ≥ 3 months and, according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, it includes persistent albuminuria > 30 mg/g creatinine in 2 consecutive tests or an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 in 2 consecutive tests.13 Although a CKD diagnosis has significant clinical and therapeutic implications, it is still underdiagnosed, even in high-risk populations for CKD such as patients with SLE, and its actual prevalence in the era of advanced treatment options should be assessed.
We aimed to assess CKD prevalence and risk factors among patients with SLE, with and without a history of LN, and to evaluate CKD progression and the long-term clinical outcomes of patients with both SLE and CKD.
METHODS
Study design and population. This single-center, retrospective, observational, medical records review study was conducted at Meir Medical Center (MMC). MMC is a 795-bed academic hospital in the Sharon district in central Israel with inpatient and outpatient services. MMC is the largest hospital in the district, comprising a primarily urban population of Jewish and Arab peoples. The current study was based on MMC’s electronic medical record (EMR). All medical information obtained from the ambulatory clinics, emergency room, and departments is recorded in the EMR and can be accessed at the individual patient level. The EMR database includes all diagnoses, demographics, clinical data, and laboratory values.
Included in our study were patients with SLE, ≥ 18 years of age, who had been diagnosed for ≥ 12 months and treated at the MMC between January 1, 2014, and December 31, 2023. Patients were required to fulfill the European Alliance of Associations for Rheumatology (EULAR)/American College of Rheumatology (ACR) 2019 classification criteria for SLE to be included. All medical records were reviewed by a rheumatologist with expertise in SLE (OETS) to ascertain the diagnosis of SLE. Due to their unique characteristics, patients receiving kidney replacement therapy (KRT) were excluded from most of the analysis.
CKD definition. CKD was defined as either decreased eGFR (< 60 mL/min/1.73 m2) or albuminuria ≥ 30 mg/24 h persisting in ≥ 2 consecutive urine tests spaced ≥ 3 months apart, as defined in the CKD KDIGO 2024 guidelines.13
Measured outcomes. Albuminuria was assessed using urine albumin-to-creatinine ratio. In the absence of sufficient data for urine albumin, we used measurements of urinary protein as a proxy (considering proteinuria levels ≥ 300 mg/dL equal to albuminuria levels ≥ 30 mg/dL). Using the Modification of Diet in Renal Disease (MDRD) formula, eGFR was calculated individually for each patient at 5 different time points: (1) at baseline, ≥ 1 year before SLE diagnosis; (2) at SLE diagnosis; (3) 2 years following SLE diagnosis; (4) 5 years following SLE diagnosis; and (5) at the last follow-up. LN was defined on a kidney biopsy. Damage was measured at the last follow-up by the Systemic Lupus International Collaborating Clinics/ACR Damage Index (SDI), excluding the 3 renal items. Comorbidities were assessed at the end of the follow-up period. The number of patients with emergent hospitalizations (ie, all hospitalizations that were not elective) was recorded and categorized according to hospitalization cause, SLE exacerbation, infection, or CV event. KRT was defined as either chronic dialysis of > 3 months or kidney transplantation. All-cause mortality data were collected using the national data center, including in-hospital and home deaths. Additional demographic, clinical, and laboratory data, including SLE treatments, were recorded and analyzed.
Statistical analysis. Descriptive data are presented as mean (SD) for continuous variables and as numbers and percentages for nonmetric variables. Chi-square test was used to compare categorical variables and t test was applied for continuous variables comparison. A P value < 0.05 was considered statistically significant.
To identify predictors of CKD, we performed a multivariable Cox proportional hazards analysis. Variables were selected based on statistical significance in univariable analysis or clinical relevance to CKD risk. A receiver-operating characteristic curve (ROC) was conducted to assess the discriminative ability of the model.
A multivariable Cox proportional hazards analysis was used to identify predictors of mortality. Variables were selected based on their clinical relevance to mortality risk. In addition, a Cox proportional hazards model was performed to assess survival in relation to CKD status, adjusted for the clinically relevant variables.
To analyze the trajectory of eGFR over time, we applied a linear mixed model (LMM) with eGFR as the longitudinal outcome and time (in years) as a continuous predictor. The model included both random intercepts and random slopes for each patient, allowing for individual variability in baseline kidney function and rate of change. To examine whether clinical variables influenced the rate of eGFR decline, we included interaction terms between time and the key predictors LN, albuminuria, and diabetes mellitus (DM). This modeling strategy enabled us to formally test whether these covariates modified the slope of eGFR over time. A general linear model (repeated measures ANOVA) was used solely for visual representation of estimated marginal means and complements the inferential analysis provided by the LMM. All statistical analyses were performed using SPSS version 29 (IBM).
RESULTS
A total of 175 patients with SLE were included, with a mean follow-up of 18.3 (SD 14.7) years from SLE diagnosis. Twelve patients required KRT and were removed from the rest of the analysis. Out of the 163 remaining patients, CKD was defined in 89 patients (54.6%). Among them, 41 patients (46.1%) had no history of LN (Figure 1). Forty-seven of the patients with CKD (27.4%) had albuminuria only, 14 (8.6%) had decreased eGFR only, and 28 (21.7%) patients had both albuminuria and reduced eGFR.
Study flowchart. CKD: chronic kidney disease; KRT: kidney replacement therapy; LN: lupus nephritis; SLE: systemic lupus erythematosus.
Factors associated with CKD. Table 1 provides the sociodemographic and clinical characteristics of patients with CKD compared to patients without CKD. Mean age at diagnosis was comparable between CKD and non-CKD groups; however, eGFR at SLE diagnosis was lower among patients with CKD and their follow-up period was longer compared with patients in the non-CKD group (81.2 [SD 34.6] vs 95.9 [SD 30.3], P < 0.001, and 20.1 [SD 16.3] vs 15.6 [SD 11.6], P = 0.049, respectively). CKD diagnosis was associated with higher rates of LN and CV disease.
Demographic and clinical characteristics of patients with CKD compared to patients without CKD (n = 163).
Among patients with CKD, eGFR at SLE diagnosis was lower, and their mean 2019 ACR/EULAR classification criteria total cumulative score was higher than in controls (P < 0.001) but comparable when excluding the renal domain. Damage, measured by SDI, was higher in the patients with CKD compared to controls, even after excluding the renal items (2.9 [SD 2.6] vs 1.6 [SD 1.7], P < 0.001). Patients with CKD were treated more often with corticosteroids and immunosuppressants.
As for outcomes, CKD was significantly associated with emergent hospitalizations (70.8% vs 49.3%, P = 0.005). Specifically, patients with CKD had higher hospitalization rates for SLE exacerbations and infections than those without CKD (42.7% vs 23.9%, P = 0.01, and 44.9% vs 26.8%, P = 0.02, respectively). Rates of hospitalization for nonfatal CV events were comparable (21.3% vs 12.7%, P = 0.15). Patients with CKD had significantly higher mortality rates compared with those in the non-CKD group (19.1% vs 1.4%, P < 0.001) on univariate analysis (Table 1).
LN class and CKD. Kidney biopsy results were available for 46 patients in the cohort. Among them, 1 (2.2%) had lupus podocytopathy, 1 (2.2%) had class II LN, 9 (19.6%) had pure class V, 12 (26.1%) had class III ± V, and 23 (50%) patients had class IV ± V. All patients with class III or class IV LN eventually developed CKD by definition, with the majority manifesting albuminuria alone. Among those with pure class III and class IV LN, 42.8% and 26.3%, respectively, exhibited both albuminuria and a decline in eGFR. Of the 9 patients with class V LN, 7 remained with albuminuria, thus meeting the definition of CKD, whereas 2 also experienced a decline in eGFR during the follow-up period. Overall, in the group with pure class V LN, the eGFR decreased from 127.7 (SD 46.3) to 103.2 (SD 76.2) mL/min/1.73 m2 (P < 0.01), whereas in the group with a proliferative component in the kidney biopsy, the eGFR declined from 92.1 (SD 37.6) to 86.2 (SD 51.4) mL/min/1.73 m2 (P < 0.001).
Predictors of CKD development. Lower eGFR at SLE diagnosis and history of LN were both associated with CKD in univariate analysis and remained significant predictors in the multivariable Cox proportional hazards analysis (Table 2). The presence of LN was the strongest predictor of CKD (hazard ratio [HR] 7.25, 95% CI 3.28-16.04, P < 0.001), and patients with LN developed CKD earlier than the non-LN group, with a significantly higher HR over time (Supplementary Figure S1, available with the online version of this article). The ROC curve analysis (Supplementary Figure S2) demonstrated excellent discriminative ability of the model, with an area under the curve of 0.93.
Multivariable Cox proportional hazards analysis identifying predictors of CKD development.
CKD and mortality. A Cox model was constructed to identify predictors of mortality. In this analysis (Table 3), CKD showed a trend toward increased mortality (HR 6.33, 95% CI 0.77-52.19, P = 0.08). Ischemic heart disease (IHD), hypertension (HTN), and sex were not significantly associated with mortality. Figure 2 provides a Cox proportional hazards model, adjusted for age at last follow-up, sex, CHF, IHD, HTN, DM, and antiphospholipid syndrome (APS), which demonstrated a trend toward increased mortality in patients with CKD (HR 6.84, 95% CI 0.82-57.41, P = 0.07).
Cox model for predictors of mortality in patients with SLE with CKD.
Cox survival plot for patients with CKD compared to those without CKD, adjusted for age at last follow-up, sex, congestive heart failure, ischemic heart disease, hypertension, diabetes mellitus, and antiphospholipid syndrome. CKD: chronic kidney disease.
Progression of CKD. Among patients with CKD, eGFR decreased from a mean of 92.9 mL/min/1.73 m2 before SLE diagnosis to 69.2 mL/min/1.73 m2 at the last follow-up after 20.3 years (P < 0.01). This represents an average rate of decrease of 1.2 mL/min/1.73 m2/year.
To assess the longitudinal trajectory of kidney function, we constructed an LMM with eGFR as the outcome and time (in years) as a continuous predictor. This model included interaction of eGFR with time and different relevant clinical covariates—including history of LN, presence of albuminuria, and DM—to evaluate their effect on the rate of eGFR decline, and it incorporated random intercepts and slopes for each patient to account for individual variability. The model showed a nonsignificant trend toward eGFR decline over time (β −0.98; P = 0.07). LN was associated with a higher baseline eGFR (β 12.93; P = 0.20), but the time–LN interaction was not significant, suggesting no differential rate of eGFR decline. Similarly, albuminuria and DM were not significantly associated with either baseline eGFR or its slope over time. Full model estimates are presented in Supplementary Table S1 (available with the online version of this article). Visual representation of estimated marginal means of eGFR at different timepoints using a repeated measures ANOVA model is shown in Figure 3. These findings suggest that although eGFR declines over time, this decline is not significantly modified by LN, albuminuria, or DM in this cohort.
Estimated marginal means model of eGFR at different timepoints among patients with and without CKD, with 95% CI error bars. This figure is provided for descriptive purposes only. Formal analysis of eGFR trajectory was performed using a linear mixed model, accounting for individual variability over time. CKD: chronic kidney disease; eGFR: estimated glomerular filtration rate; SLE: systemic lupus erythematosus.
DISCUSSION
The key finding in this study is the high prevalence of CKD among patients with SLE—even higher than the prevalence of LN, the most significant and extensively studied renal manifestation of SLE. More than half of the patients in this cohort had CKD, according to the KDIGO definition (89/163 patients, with an additional 12 requiring KRT). Although LN was identified as a significant risk factor for CKD with an HR of 7.25, 41/89 patients with CKD (46.1%) had no previous diagnosis of LN.
Most studies assessing CKD in patients with SLE included only patients with LN, and a limited number of studies also evaluated CKD in non-LN populations. Those studies mostly used only eGFR and not albuminuria for the definition of CKD, and thus probably underestimated CKD prevalence. Pokroy-Shapira et al14 investigated the development of CKD (based on eGFR alone) in 256 patients with SLE followed for 8.8 (SD 6.6) years. The prevalence of CKD was 46.7% in patients with ACR-defined renal lupus disease and 16.4% in those without. Mageau et al15 explored CKD diagnosis in patients with SLE using French nationwide hospital data. In their cohort, only 6.7% of patients with SLE had CKD at baseline, and another 10.1% of the remaining patients developed CKD over the 6 years that followed. Again, they defined CKD only by eGFR and not by albuminuria. In our cohort, solely using eGFR to diagnose CKD would have resulted in a CKD prevalence of only 25.8%. The much higher prevalence of CKD in our study is probably a consequence of a significantly more extended follow-up period, as well as a broader definition of CKD depending on eGFR and albuminuria as guided by the KDIGO, which stresses the importance of measuring albuminuria.13 Albuminuria is a substantial and early indicator of CKD, reflecting kidney damage, and is associated with a significantly higher risk of all-cause and CV mortality, ESKD, acute kidney injury, CKD progression, and increased CV risk compared to individuals with lower levels of albuminuria, even with a preserved eGFR.16 Early diagnosis and treatment of CKD, before the decline in eGFR, enables the prevention of CKD progression and has been proven in several clinical studies to have significant clinical benefits.17,18
In our study, CKD diagnosis was associated with higher rates of CV disease. Previous studies showed that CKD was positively associated with LN, HTN, older age at diagnosis, and past CV history, and negatively associated with hydroxychloroquine treatment.14,15 The association between CKD and closely related comorbidities is extensively documented in the literature as a complex cause-and-effect relationship. However, causation cannot be conclusively inferred due to the study’s design. Comorbidities were assessed at the end of the follow-up period, and as such, they could have been diagnosed at any time before or after the diagnosis of CKD. DM, HTN, CKD, and kidney disease are interconnected and share common pathophysiological mechanisms, such as endothelial dysfunction and arteriosclerosis. These mechanisms may also account for the elevated prevalence of CKD among patients with SLE without previously documented LN.15-19,20
Another suggested risk factor for developing CKD is APS. Renal involvement in APS is well known and includes renal vessel thrombosis and stenosis, as well as intrarenal lesions known as antiphospholipid nephropathy. Antiphospholipid nephropathy encompasses thrombotic microangiopathy, proliferative and fibrotic lesions of the intrarenal vessels, and ischemic modifications of the renal parenchyma.21 APS nephropathy is documented in approximately two-thirds of patients with SLE who have been diagnosed with secondary APS independently of LN. It is also associated with HTN, increased serum creatinine levels, and histologic progression, all of which are linked to a poor renal outcome.22,23 Nevertheless, in the current cohort, we did not demonstrate a statistically significant association between APS and the development of CKD. These differences suggest that although APS may be associated with CKD, its long-term effect on renal outcomes may be more complex and requires further investigation.
As anticipated, eGFR among patients with SLE with CKD decreased from an average of 92.9 mL/min/1.73 m2 before SLE diagnosis to 69.2 mL/min/1.73 m2 at the last follow-up after a mean of 20.3 years. This indicates a mean decline rate in eGFR of 1.2 mL/min/1.73 m2/year in patients with CKD, which, though acceptable, underscores the gap and the necessity for intervention in the era of novel CKD treatment options.
CKD was associated with worse outcomes among patients with SLE. Increased extrarenal damage, emergent hospitalizations, severe SLE exacerbations, and severe infections were all more common among patients with SLE and CKD compared to those without CKD. Further, despite comparable follow-up times, patients with CKD had significantly higher mortality rates compared to patients without CKD (19.1% vs 1.4%, P < 0.001) on univariate analysis. This difference remained significant after adjusting for covariables and aligns with the known increased risk associated with CKD. The worse outcomes for patients with SLE and CKD emphasize the need for early diagnosis, which would facilitate the initiation of appropriate treatment. In recent years, there has been growing evidence for the role of kidney protective agents, such as sodium-glucose transport 2 inhibitors and renin-angiotensin system blockade, to improve kidney outcomes and mortality in CKD of various causes.24
Limitations of our study include the retrospective design based on medical record data. One of the consequences of this is the probable underestimation of CKD prevalence. Creatinine levels are collected from all patients; however, urine albumin is not routinely monitored in patients with SLE, with LN (where urine protein is the rule) or without LN. This study also has important strengths, as it involves real-world data from a homogeneous Middle Eastern population and uses diagnoses based on individual assessment, including evaluation of both eGFR and albuminuria at different time points over the long term, starting before the diagnosis of SLE and continuing with follow-up for approximately 20 years postdiagnosis. There was variability in the timing and type of albuminuria measurements due to the retrospective design of the study and heterogeneity in patients’ compliance with follow-up, disease activity, and physician recommendations, among other factors. The majority of included patients had both proteinuria and albuminuria measurement (170/175 patients). We used extrapolation of proteinuria measurement to assess albuminuria in order to define CKD in the remaining 5 patients.
In conclusion, CKD is prevalent among patients with SLE, including those without a diagnosis of LN. CKD in patients with SLE is associated with higher rates of comorbidities, severe disease exacerbations, infections, and markedly increased mortality. These findings highlight the importance of proactive monitoring in patients with SLE, including the measurement of albuminuria in addition to proteinuria for early diagnosis of CKD. This approach may allow tailored intervention, reducing the substantial morbidity and mortality associated with CKD in SLE.
ACKNOWLEDGMENT
The authors thank Mohamad Kabaha, Department of Emergency Medicine, Meir Medical Center, Kfar Saba, Israel.
Footnotes
CONTRIBUTIONS
OETS, KCH: conceptualization, data curation, formal analysis, methodology, supervision, writing the original draft, and writing (review and editing). DBZ, YPPB, NN: data curation. SB: conceptualization, methodology, and writing (review and editing). M. Saban: methodology and data analysis. SK, OW, M. Shashar, AG: methodology, supervision, and writing (review and editing).
FUNDING
No specific funding was received from any bodies in the public, commercial, or not-for-profit sectors to carry out the work described in this article.
COMPETING INTERESTS
KCH is an employee of Meir Medical Center; a consultant for Fresenius Medical Care; an invited speaker for AstraZeneca, CTS, and GSK; and an editorial board member of ASN and BMC Nephrology. SB is an employee of Meir Medical Center and a consultant for Fresenius Medical Care. OETS was an invited speaker for AstraZeneca, GSK, and AbbVie. SK was an invited speaker for AstraZeneca. The remaining authors declare no conflicts of interest relevant to this article.
ETHICS AND PATIENT CONSENT
The study was conducted after receiving the approval of the Institutional Human Subjects Ethics Committee (no. MMC 0041-22). All data were collected anonymously. All methods were carried out in accordance with the relevant guidelines and regulations. In accordance with the Ministry of Health regulations, the Institutional Ethics Committee did not require written informed consent since data were collected anonymously from the electronic medical record without active patient participation.
- Accepted for publication June 13, 2025.
- Copyright © 2025 by the Journal of Rheumatology
REFERENCES
SUPPLEMENTARY DATA
Supplementary material accompanies the online version of this article.
