Prevalence and factors associated with Lupus Nephritis in Venezuelan patients.
https://doi.org/10.46856/grp.10.et098
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Aponte IF, García-Francis MV, García-Becerra JA, Fuentes-Silva YJ, Tovar-Bastidas DB, Nieto - Barrios JC, et al.. Prevalence and factors associated with lupus nephritis in Venezuelan patients [Internet]. Global Rheumatology. Vol 2 / Jul - Dic [2021]. Available from: https://doi.org/10.46856/grp.10.et098
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Prevalence and factors associated with Lupus Nephritis in Venezuelan patients.
Introduction / Objective. There are scarce data on lupus nephritis from single Latin American countries. We have assessed the prevalence and factors associated with lupus nephritis in a sample of Venezuelan patients with systemic lupus erythematosus (SLE).
Methods. A cross-sectional study of 406 SLE patients from a tertiary center in Caracas classified using the 1982 American College of Rheumatology criteria. Measures included sociodemographics, smoking, alcohol consumption, clinical features, treatment, and immunologic tests. Lupus nephritis was defined as persistent proteinuria (≥ 0.5 g per day), an active urinary sediment plus an immunological feature, either hypocomplementemia or anti-dsDNA antibodies. Logistic regression analysis was used to estimate the odds ratio (OR) of the factors associated with lupus nephritis.
Results. Thirty-three percent of patients were classified as having lupus nephritis. Logistic regression analysis showed that, for each one-year increase in age, the OR of having lupus nephritis was 0.97 (95% Confidence Interval [CI], 0.95-0.98) and, for each one-year increase in disease duration, the OR of having lupus nephritis was 0.96 (95% CI, 0.94-0.99). Current alcohol drinking, ever presence of anti-dsDNA antibodies, concurrent lupus disease activity, and accrued organ damage were significantly associated with lupus nephritis.
Conclusion. Lupus nephritis was associated with lower age and shorter disease duration. Despite being a high-risk race/ethnic population and in a geographical region of high prevalence, Venezuelan patients showed a lower proportion of lupus nephritis closer to that of patients of European descent, suggesting that renal disease expression may not be uniform and may vary even within individual Latin American countries which share a common race/ethnicity and geography.
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that predominantly affects young women worldwide (1). It is characterized by a loss of tolerance to autoantigens, leading to a chronic inflammatory response driven by the intertwined involvement of both the innate and adaptive branches of the immune system, with the potential to affect multiple organs and systems (2). The prevalence and severity of the disease vary according to race, ethnicity, socioeconomic status (SES), and geographic region (1). Individuals of African descent have the highest incidence and prevalence (1, 3, 4). The mestizo population of Latin America is a mixture of European, African American, and Native American genetic and cultural components, with proportions that vary between regions and even within specific countries (5). Patients from Latin America exhibit a prevalence of lupus nephritis that is intermediate between that observed in African American and Caucasian populations (1). In Venezuela, the prevalence of SLE has been estimated at 70 per 100,000 inhabitants (1,6). It is known that patients of African American and Hispanic origin tend to have more severe forms of the disease, due to factors related to, although not exclusively determined by, SES (7,8). The Latin American Group for the Study of Lupus (GLADEL), a multinational cohort of 1,214 patients with SLE from 9 Latin American countries (9), found that mestizo and African American patients had more severe disease, including a higher frequency of lupus nephritis, compared to white Latin American patients (10). Similar findings were previously reported in the LUpus in MInorities: NAture versus nurture (LUMINA) study, a multiethnic study that included Hispanic patients residing in the United States (11).
Lupus nephritis (LN) is one of the most common and severe manifestations in patients with SLE. The prevalence of nephritis in SLE varies significantly according to race and ethnicity (12). Latin America is a vast geographic region with a population that shares various phenotypic, ethnic, and cultural characteristics. However, ethnic/racial admixture has not occurred to the same extent across the region, resulting in variable genetic substructures that may influence the clinical expression of the disease in different Latin American countries (13). For example, the genetic ancestry of Argentinians is composed of approximately 80% European, 18% Amerindian, and 2% African origin (14). The mestizo populations of Peru show a distinctive Native American ancestral signature (15); Puerto Rico and Colombia have higher levels of European ancestral genes compared to Native American ancestry than do the mestizo populations of Mexico and Peru (16). The majority of the Venezuelan mestizo population currently lives in urban areas and, according to analyses using autosomal, Y chromosome, and mitochondrial DNA markers, shows a predominance of European genetic components (40–65%), followed by Amerindian (20–35%) and African (10–20%) components (17). This heterogeneous genetic substructure, as well as the influence of local environmental factors related to sociocultural differences across the vast Latin American region, may affect the risk and clinical expression of the disease among different countries. For example, Native American ancestry has been shown to influence the prevalence of respiratory variables in mestizo Mexican individuals (16). The aim of this study was to determine the prevalence and identify the factors associated with LN in a sample of Venezuelan patients with SLE. It was hypothesized that, given their genetic substructure and environmental context, Venezuelan patients with lupus may present distinctive clinical features, including target organ involvement, compared to what has been reported in other Latin American patient populations.
Study design
This was an observational and cross-sectional study that included 406 consecutive patients seen at the Division of Rheumatology of the University Hospital of Caracas, Venezuela, during the period from 2013 to 2017.
Patient population and clinical evaluation
Patients aged over 18 years were classified as having SLE if they met 4 or more of the 1982 American College of Rheumatology (ACR) criteria. All patients were interviewed and examined at the time of enrollment, following a detailed protocol to collect sociodemographic, clinical, and laboratory data at baseline. The study was approved by the Bioethics Committee of the University Hospital of Caracas (protocol #24/2013), and all participants signed a written informed consent.
Sociodemographics
Data were collected on age, sex, years of formal education, and marital status. Socioeconomic status (SES) was determined using the modified Graffar scale, which includes five categories from 1 to 5 in descending order of SES. These were grouped into three variables, resulting in a Graffar SES scale from 1 to 3, with level 3 corresponding to poverty.
Clinical characteristics
Data were collected on disease duration, age at onset, clinical and laboratory findings, family history of lupus, comorbidities (hypertension, dyslipidemia, and diabetes mellitus), body mass index (BMI: weight in kilograms divided by height in meters squared), and treatment modality. Disease activity at the time of the interview was assessed using the SLEDAI (Systemic Lupus Erythematosus Disease Activity Index); a cut-off value of ≥6 was used to define active disease. Damage accumulation was assessed using the SLICC/ACR Damage Index (Systemic Lupus International Collaborating Clinics / American College of Rheumatology) as a binary variable (No = 0, Yes = >0) or as a continuous variable.
Patients were classified in the neuropsychiatric lupus subgroup if they presented at least one of the components defined in the ACR criteria for neuropsychiatric manifestations, divided into central and peripheral components. Classification into the mucocutaneous (cutaneous manifestations and oral ulcers) and hematologic subgroups was made if patients met at least one of the corresponding 1982 ACR criteria for SLE at the time of enrollment.
Laboratory tests were obtained within three months prior to study enrollment. Estimated glomerular filtration rate (eGFR) was calculated in mL per minute per 1.73 m². Antinuclear antibodies (ANA) were assessed by indirect immunofluorescence on Hep-2 cells; anti-dsDNA antibodies were analyzed using the Crithidia luciliae immunofluorescence test (CLIFT); lupus anticoagulant was measured using dilute Russell's viper venom time and activated partial thromboplastin time (APTT); all other autoantibodies were detected using commercially available enzyme-linked immunosorbent assays (ELISA). Immunological positivity was defined as having at least two positive results separated by a minimum of six months during the course of the disease. Low levels of C3 and C4 were defined as <60 mg/dL and <15 mg/dL, respectively.
The diagnosis of lupus nephritis (LN) was established if the patient met the revised ACR criteria for LN, consisting of persistent proteinuria ≥0.5 g per day plus active urinary sediment, along with an additional immunologic feature: hypocomplementemia or presence of anti-dsDNA antibodies. Exclusion criteria for classification in the renal subgroup included renal lithiasis (N = 25), hydronephrosis (N = 2), polycystic kidney disease (N = 2), and a history of renal cancer (N = 1), leaving a total of 376 patients. An additional 23 patients lacked sufficient urinary data for classification, resulting in a final total of 353 patients analyzed in the renal lupus subgroup.
Statistical analysis
Descriptive statistics included means or medians with corresponding standard deviations and interquartile ranges. T-tests and chi-square tests were used to assess differences in sociodemographic and clinical characteristics according to the presence of renal disease. Logistic regression analysis was performed to evaluate the association of LN with sociodemographic characteristics, current tobacco and alcohol use, comorbidities, laboratory data, and clinical features. A p-value < 0.05 was considered statistically significant. Analyses were performed using the statistical package Stata15 (StataCorp. LLC, Stata Statistical Software: Release 15. College Station, TX).
The sample included a total of 406 patients. The mean age was 41.0 ± 12.2 years; 95% were women and 98% were of Hispanic ethnicity. The average number of years of formal education was 11.9 ± 4.0. Most patients were single (48%), and 29% were classified as level 3 (poverty level) according to the Graffar socioeconomic scale (Table 1).
Clinical Characteristics
The mean disease duration was 10.0 ± 8.2 years, and the mean age at disease onset was 30.9 ± 11.3 years. The most commonly accumulated 1982 ACR criteria at the time of enrollment were: arthritis (89%), malar rash (60%), photosensitivity (57%), renal involvement (43%), oral ulcers (42%), and hematologic disorders (40%). Mucocutaneous, hematologic, and neurologic manifestations of lupus were observed in 87%, 40%, and 14% of patients, respectively. The mean SLEDAI score was 5.2 ± 5.6, and the proportion of clinically active patients at study entry (SLEDAI ≥ 6) was 41%. The mean SLICC-DI score was 0.8 ± 1.4, with 43% of patients showing a SLICC-DI > 0. At the time of the study, 94% of patients were taking oral prednisone, 77% were taking antimalarials, 23% mycophenolate mofetil, and 21% azathioprine (Table 1).
ANA were positive in 97% of cases, followed by anti-DNA (51%), anti-Sm (35%), anti-Ro (35%), anti-RNP (23%), and anti-La (17%) antibodies. Antiphospholipid antibodies were observed in 23% of cases. The mean serum levels of C3 and C4 were 75.8 ± 42.7 mg/dL and 20.6 ± 12.1 mg/dL, respectively.
Lupus Nephritis
Among the 353 patients with complete data for renal disease analysis, 117 (33%) were classified as having lupus nephritis at the time of study entry. The mean creatinine clearance was 106.1 ± 51.8 ml/min, the mean estimated glomerular filtration rate (eGFR) was 101.6 ± 38.4 ml/min/1.73 m² of body surface area, and the median 24-hour urinary protein excretion was 0.18 g (interquartile range 75–25: 0.08–0.42). Renal biopsy was performed in 65 patients, with the highest frequency observed in class II (27.6%), followed by class IV (21.5%), class I (20.0%), class V (16.9%), and class III (13.85%). In the total study population, 24 patients (5.9%) had persistent proteinuria > 3.5 g in 24 hours, and 8 patients (1.9%) had end-stage renal disease.
Compared to patients without renal involvement, those with lupus nephritis were significantly younger [38.4 vs. 42.6 years (mean ± standard deviation, p-value = 0.001)], had a higher frequency of current alcohol consumption (33%), shorter disease duration, a higher frequency of previous anti-DNA antibody positivity, greater concurrent disease activity, more accumulated organ damage, and were more likely to have received intravenous pulses of cyclophosphamide or methylprednisolone (Table 2).
Logistic regression analysis showed a 2.8% and 3.0% decrease in the likelihood of having lupus nephritis for each additional year of age and disease duration, respectively (Table 3). Current alcohol consumption (OR = 1.64; 95% CI = 1.00–2.68), ever-positivity for anti-dsDNA antibodies (OR = 30; 95% CI = 14.7–61.3), SLEDAI ≥ 6 (OR = 4.95; 95% CI = 3.06–8.03), and SLICC-DI > 0 (OR = 2.32; 95% CI = 1.46–3.69) were independently associated factors with renal lupus.
We examined the prevalence of lupus nephritis (LN) and associated factors in Venezuelan patients with systemic lupus erythematosus (SLE) treated at a tertiary center in Caracas. We found that LN prevalence was lower than expected and higher among younger patients and those with a shorter disease duration. Alcohol consumption, prior anti-dsDNA positivity, disease activity, and cumulative organ damage were also associated with LN.
Female sex predominated in a 9:1 ratio, consistent with global patterns (1, 24), and similarly to what has been previously reported in Hispanic patients (25). The average age at disease onset in our patients ranged between 15 and 45 years, which is typical in SLE populations worldwide (1) and among Hispanic patients (8, 9). The average years of schooling were comparable to findings from the GLADEL studies in Latin America and the mestizo subgroup of the LUMINA study. A lower proportion of our patients, 29%, were classified in the poverty level of SES, compared to 63% in the mestizo GLADEL subgroup (9) and 39% in the mestizo LUMINA subgroup (11). The frequency of current smokers, diabetes as a comorbidity, and average BMI were similar to those in the multinational and multiracial SLICC study (26).
The distribution of clinical manifestations in our series was comparable to that of a large national registry of Spanish lupus patients (27) and the GLADEL and PROFILE cohorts (9, 28), except for a higher frequency of hematological and renal manifestations in the latter two. Musculoskeletal symptoms are the most prevalent manifestations of SLE, affecting up to 95% of patients, followed by mucocutaneous manifestations (9, 27–31). Serositis, as well as renal and neurological manifestations, are more common in African American patients (1). Progression to end-stage renal disease occurs more frequently among African American (1, 32) and Hispanic (33) patients. Interestingly, LN was observed in a lower proportion of our patients (33%) compared to the Hispanic subgroup in the PROFILE study (59%) (28) and the GLADEL cohort (52%) (9), and closer to the 34% seen in white patients in the Spanish national lupus registry (27), 31.9% in the Michigan Lupus Registry (29), and 39.5% in the California Lupus Surveillance Project (30). It is possible that the stricter criteria used in our study to define renal disease — including the requirement of an immunologic criterion for disease activity (presence of anti-DNA or low complement levels) (23) — may explain these differences. However, even using the original, less strict 1982 ACR criteria for renal disease, the proportion of our patients with LN was 43%, still lower than that described in other Hispanic cohorts.
It is known that European ancestry genes protect against renal disease in patients with lupus (1, 9, 28, 34–36). Therefore, it is possible that the genetic substructure of our patient population, with a relatively high European component (17), may partly explain these findings. The more recent post-World War II migration wave from Europe to Venezuela added to prior waves from Spain, Germany, and Corsica during the colonial and postcolonial periods (17).
It is worth noting that in the limited subsample of our patients with a renal biopsy (N = 65), only 21% had type IV glomerulonephritis, the most aggressive form of LN; additionally, only 6% of the total study population had persistent nephrotic-range proteinuria, and only 2% had progressed to end-stage renal disease at the time of enrollment. A possible selection bias for renal biopsy, prioritizing patients with less overt clinical evidence of LN over those with overt renal disease, cannot be ruled out as an explanation for the low proportion of severe LN forms. Compared with the mestizo subgroup of the LUMINA study and the GLADEL cohort, a relatively smaller proportion of our patients (29%) were classified as poor in SES, another variable associated with increased risk of renal disease (37–39). However, as in a multiethnic lupus study (36), we found no effect of SES on LN predisposition, possibly due to the cross-sectional nature of our study. Additionally, data from the LUMINA study support the notion that genetic factors prevail over socioeconomic status in renal disease susceptibility (11).
A younger average age and shorter disease duration were associated with a higher frequency of LN, as previously reported in Hispanic patients (1, 10, 39). The relationship between alcohol and lupus risk has been a controversial topic, with one study showing a moderate protective effect (40) and another showing no effect (41).
Clinical disease activity and cumulative organ damage correlated with the presence of LN in our study, in line with previous reports (8, 20, 42, 43). However, a lower proportion of our patients (43%) had cumulative tissue damage compared to Hispanic and African American patients in the LUMINA cohort (61% and 51%, respectively).
Limitations of our study include its cross-sectional design, which may obscure the role of sociodemographic and clinical factors in conferring LN risk over time; being conducted at a tertiary referral hospital, which limits generalizability; and the low proportion of patients with histological confirmation of LN. Strengths include the racial/ethnic homogeneity of the study population; the single-country design, allowing for the assessment of interactions between genetic and cultural factors within one population; and the geographic location of Venezuela in the Caribbean, a region known for high LN risk, which serves as a test of environmental influence.
In summary, the prevalence of lupus nephritis was lower than expected for a Hispanic population with SLE. Independent factors associated with LN included age, disease duration, current alcohol use, prior anti-DNA positivity, lupus activity, and cumulative tissue damage. The lower frequency of renal disease observed in Venezuelan patients compared to other Hispanic lupus populations underscores the need to examine differences in the clinical expression of SLE across individual Latin American countries.
In summary, the prevalence of lupus nephritis was lower than expected for a Hispanic population with systemic lupus erythematosus (SLE). Independent factors associated with lupus nephritis included age, disease duration, current alcohol consumption, prior presence of anti-DNA antibodies, lupus disease activity, and cumulative tissue damage. The lower frequency of renal involvement observed in Venezuelan patients, compared to other Hispanic populations with SLE, highlights the need to examine differences in the clinical expression of SLE across individual Latin American countries.
The authors declare no conflicts of interest.
No specific funding was received from public, commercial, or not-for-profit sectors for the work described in this article.
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