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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
ORIGINAL ARTICLE  
Year : 2022  |  Volume : 33  |  Issue : 1  |  Page : 90-105
Assessment of Lupus Nephritis in a Multicenter Retrospective Egyptian Cohort: Initial Characteristics, Influence of Age and Gender, Outcome, and Potential Association with Disease Damage


1 Rheumatology and Rehabilitation Department, Kasr Alainy Faculty of Medicine, Cairo University, Cairo, Egypt
2 Pediatric Rheumatology Department, Kasr Alainy Faculty of Medicine, Cairo University, Cairo, Egypt
3 Pediatric Department, Faculty of Medicine, Helwan University, Helwan, Egypt
4 Internal Medicine Department, Kasr Alainy Faculty of Medicine, Cairo University, Cairo, Egypt
5 Internal Medicine Department, Rheumatology Unit, Faculty of Medicine, Alexandria University, Alexandria, Egypt
6 Rheumatology, Rehabilitation, and Physical Medicine Department, Faculty of Medicine, Benha University, Benha, Egypt

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Date of Web Publication16-Jan-2023
 

   Abstract 


The study aimed to evaluate the association of demographic, clinical, and histopathologic characteristics with renal and disease outcomes. Persistent lack of partial or complete remission despite sequential induction therapy, chronic kidney disease (CKD) or endstage renal disease (ESRD), and/or mortality were determined as poor renal outcomes. Disease damage was investigated through the Systemic Lupus International Collaborating Clinics/ American College of Rheumatology Damage Index (SDI). Of 201 biopsy-proven lupus nephritis patients, a poor outcome was present in 56 (27.9%) patients, with nine (4.5%), 22 (10.9%), and 29 (14.4%) patients demonstrating lack of response, CKD, and ESRD, respectively, and the prevalence of mortality was 5.5% (11/201). The outcome was poor among males [29/201 (14.4%)] [P = 0.008; odds ratio (OR): 2.8; 95% confidence interval (CI): 1.2–6.4], yet comparable between adult- and juvenile-onset patients [80/201 (39.8%) (≤16 years)] (P = 0.6; OR: 0.8; 95% CI: 0.4–1.6). Hypertension (P <0.001; OR: 6.3; 95% CI: 2.6–14.9), elevated creatinine (P <0.001; OR: 5.2; 95% CI: 2.6–10.3), and hematuria (P <0.001; OR: 3.7; 95% CI: 1.9–7.5) at presentation, and fibrinoid necrosis [P <0.001; odds ratio (OR): 4.1; 95% confidence interval (CI): 2.1–8.1], wire loops (P = 0.006; OR: 2.4; 95% CI: 1.2–4.6), crescents (P <0.001; OR: 5.4 95% CI: 2.8–10.5), interstitial fibrosis (P = 0.001; OR: 2.7; 95% CI: 1.4–5.1), and acute vascular lesions (P = 0.004; OR: 3.6; 95% CI: 1.4–9.4) on biopsy were associated with a poor outcome. Chronic glomerular (P = 0.003) and acute vascular lesions (P <0.001), and a higher chronicity index (r = 0.1; P = 0.006) on biopsy, and frequent renal (r = 0.3; P <0.001) and extra-renal flares (r = 0.2; P <0.001) were associated with higher SDI scores. Among the studied renal and extra-renal parameters, independent predictors of higher disease damage solely included frequent renal flares (ᵝ= 1; P <0.001). To conclude, a poor renal outcome (27.9%) was associated with distinct features. Disease damage was associated with frequent renal flares.

How to cite this article:
Medhat BM, Elmaghraby A, Farag Y, Marzouk H, Mostafa N, Khalifa I, Mohammed A, Elkhalifa M, ElSayed Hassan EH, Hassan WA. Assessment of Lupus Nephritis in a Multicenter Retrospective Egyptian Cohort: Initial Characteristics, Influence of Age and Gender, Outcome, and Potential Association with Disease Damage. Saudi J Kidney Dis Transpl 2022;33:90-105

How to cite this URL:
Medhat BM, Elmaghraby A, Farag Y, Marzouk H, Mostafa N, Khalifa I, Mohammed A, Elkhalifa M, ElSayed Hassan EH, Hassan WA. Assessment of Lupus Nephritis in a Multicenter Retrospective Egyptian Cohort: Initial Characteristics, Influence of Age and Gender, Outcome, and Potential Association with Disease Damage. Saudi J Kidney Dis Transpl [serial online] 2022 [cited 2023 Jan 29];33:90-105. Available from: https://www.sjkdt.org/text.asp?2022/33/1/90/367830



   Introduction Top


Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by its multisystem affection, with renal involvement being considered one of the most important manifestations influencing morbidity and mortality.[1] The presentation of lupus nephritis (LN) could vary from asymptomatic urinary sediments to rapidly progressive renal failure.[2] This wide variation could be attributed to several intermingling factors, including renal and extra-renal factors, with coupling of clinical and laboratory characteristics with the histopathologic features of renal involvement being of crucial diagnostic and prognostic value.[2],[3],[4],[5] Moreover, several demographic factors,[3],[6],[7],[8],[9] such as race and ethnicity,[7],[10] could be considered key factors influencing the presentation, course, and outcome of LN, and hence disease damage, our ultimate outcome.

The aim of this study was to retrospectively evaluate various features of renal involvement in a cohort of biopsy-proven LN patients managed at four tertiary centers in Egypt, and their potential association with disease damage.


   Patients and Methods Top


Study design and data collection

Three hundred and seventy consecutive medical records of patients with biopsy-proven LN managed at the rheumatology and rehabilitation, internal medicine, and pediatric rheumatology departments of Cairo, Benha, Alexandria, and Helwan University hospitals were retrospectively reviewed, with duration of data collection being from December 2018 to December 2019. One hundred and sixty-nine out of 370 patients were excluded due to the absence of more than 50% of the data and/or having duration of nephritis of <6 months, with this duration being determined to assess response to treatment and disease damage. The study was approved by the local Ethics Committee, according to the provisions of the World Medical Association Declaration of Helsinki.

The following data were collected from the patients’ medical records:



  1. Demographic data:




    1. Age at the last recorded visit or mortality.


    2. Age at onset which was defines as the onset of initial manifestation(s), with a juvenile-onset being determined at ≤16 years in concordance with several Egyptian studies.[12],[13],[14] Adult patients at the time of data collection with a juvenile onset were not included in the study due to a potentially extended disease duration and higher damage.


    3. Disease duration was calculated from the onset of symptom(s) till the last recorded visit or mortality.




  2. Cumulative clinical characteristics were recorded including comorbidities, with hypertension, chronic kidney disease (CKD), and end-stage renal disease (ESRD) being excluded as comorbidities because they were considered among the characteristics of renal involvement.


  3. Patients were diagnosed with secondary antiphospholipid syndrome (APS) according to the modified Sapporo criteria.[15]


  4. Serologic markers done throughout the course of the disease were recorded.


  5. Disease activity at the last visit was assessed through the Systemic Lupus Erythematosus Disease Activity Index-2K (SLEDAI-2K).[16]


  6. Damage at the last visit was investigated utilizing the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI).[17]




Assessment of characteristics of nephritis

The first recorded renal biopsies of all patients were classified according to the World Health Organization classification.[18] Baseline laboratory renal activity was evaluated through the renal SLEDAI (rSLEDAI) which is scored based on four components detected in the urine analysis, being proteinuria, urinary casts, hematuria, and leukocyturia, with each component scoring 4.[19]

Renal outcome

The primary end point of the study was the development of a poor renal outcome, which was defined as the presence of any of the following: persistent lack of complete or partial response despite sequential induction therapy, development of CKD or ESRD, and/or mortality; hence, a favorable outcome was defined in the absence of all these end points.

The American College of Rheumatology (ACR) 2006 response criteria were utilized to define baseline characteristics and response to treatment:[20]



  1. Renal insufficiency at presentation: serum creatinine (SCr) ≥1.2 mg/dL and Cr clearance (CrCl) lower than 75 mL/min


  2. Non-nephrotic proteinuria: proteinuria ranging from 0.21 to 3.5 g/24 h


  3. Nephrotic syndrome: proteinuria >3.5 g/24 h with plasma albumin <3 g/dL


  4. Chronic renal insufficiency (CKD): doubling of plasma Cr lasting for at least six months with a value of plasma Cr of at least 2 mg/dL and CrCl ≤40 mL/min without any improvement over time


  5. ESRD: the need of dialysis therapy


  6. Complete renal remission: SCr ≤1.2 mg/dL, and 25% increase of baseline CrCl if abnormal, or stable value if normal at baseline, proteinuria <0.2 g/24 h, and inactive sediment defined as ≤5 red blood cells/high-power field (hpf), ≤5 white blood cells/hpf, and no cellular casts


  7. Partial renal remission: proteinuria from 0. 21 to 2 g/day and SCr ≤1.2 mg/dL, and 25% increase of baseline CrCl if abnormal, or stable value if normal at baseline


  8. Lack of remission was defined as persistent proteinuria of >3 g/day or more or progressive or worsening renal impairment.




Definition of flares

An extra-renal flare was defined as an increase in disease activity necessitating an adjustment or increase of therapy,[21] whereas a renal flare was defined according to the ACR response criteria:[20] (a) nephritic flare: sudden increase in plasma Cr of at least 30% over the last value associated with nephritic urinary sediment and increased proteinuria. (b) proteinuric flare: an increase in proteinuria without modification of plasma Cr. Proteinuria had to increase by at least 2 g/day if the basal proteinuria was <3.5 g/day, or doubled, if the patient already had nephrotic proteinuria.

Treatment

LN was managed in our centers according to the ACR guidelines of 2012.[22] Sequential induction was defined as the change of the treatment plan due to a lack of response at six months or evidence of worsening at three months of initiation of therapy (50% or more worsening of proteinuria or SCr).


   Statistical Analysis Top


Data were coded and entered using the IBM SPSS Statistics software version 25 (IBM Corp., Armonk, NY, USA). Data were summarized using mean, standard deviation, median, minimum, and maximum for quantitative variables and frequencies (number of cases) and relative frequencies (percentages) for categorical variables. Comparisons between quantitative variables were done using the nonparametric Mann–Whitney test. For comparing categorical data, Chi-square test was performed. Exact test was used instead when the expected frequency is <5. Correlations between quantitative variables were done using Spearman correlation coefficient. Linear regression analysis was done to predict SDI. Logistic regression was done to detect the independent predictors of poor outcome. P <0.05 was considered statistically significant.


   Results Top


Baseline characteristics

This retrospective cohort included 201 SLE patients with biopsy-proven nephritis, including 29 (14.4%) males and 80 (39.8%) juvenile-onset patients. The mean age at onset was 20.3 ± 9.1 years, whereas the mean age at the last visit or mortality was 24.1 ± 10.1 years. The mean disease duration of the cohort was 3.8 ± 3 years. Among the cumulative clinical features recorded, constitutional, mucocutaneous, hematologic, and neurologic manifestations were present in 91 (45.3%), 105 (52.2%), 135 (67.2%), 31 (15.4%) patients, respectively, while arthritis, serositis, APS, and comorbidities were present in 122 (60.7%), 95 (47.3%), 27 (13.4%), and 46 (22.9%) patients, respectively. Of the serological investigations documented, antinuclear antibodies, anti-double-stranded deoxyribonucleic acid, hypocomplementemia, and antiphospholipid antibodies were present in 196 (97.5%), 178 (88.6%), 154 (76.6%), and 69 (34.3%) patients, respectively. The mean SLEDAI-2K score at the last visit was 13.2 ± 8.9, whereas the mean SDI score was 1.6 ± 1.9.

Characteristics of renal involvement

In our study, delineating the onset of nephritis in correlation with extra-renal manifestation(s) was feasible in 191 patients, of whom 96 patients (50.3%) developed nephritis at disease onset, with the mean time to nephritis being 10.5 ± 16.8 months. The features of renal involvement are shown in [Table 1].
Table 1: Clinical, laboratory, and histopathologic characteristics of renal involvement in our cohort (201 patients).

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Characteristics of nephritis across different age groups

The study included 80 (39.8%) and 121 (60.2%) juvenile-and adult-onset patients, respectively
Table 2: Demographic, clinical, and histopathologic characteristics of nephritis in juvenile-and adultonset systemic lupus erythematosus patients.

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. Although the determined renal outcome was comparable between juvenile-onset LN (JLN) and adult-onset LN (ALN) patients in our cohort (P = 0.6; OR: 0.8; 95% CI: 0.4–1.6), there were several differences between both age groups, with JLN patients showing several clinical, laboratory, and histopathologic factors indicative of activity, as opposed to ALN patients who showed several biopsy findings evident of chronicity [Table 2].{Table 2}

Gender differences

Male patients constituted about 15% of our cohort and showed several parameters suggestive of a more severe disease compared to the female group [Table 3] and required successive implementation of induction therapies more frequently (P = 0.008), which was further followed by lower renal remission rates (P = 0. 009) and more subsequent renal flares (P = 0. 03), and an unfavorable outcome (P = 0.008; OR: 2.8; 95% CI: 1.2–6.4).
Table 3: Demographic, clinical, and histopathologic characteristics of nephritis in male and female SLE patients.

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Renal outcome

Complete and partial remission was achieved in 111 (55.2%) and 81 (40.3%) patients, respectively. On the other hand, a poor renal outcome, the primary end point of the study was present in 56 (27.9%) patients, of whom nine (4.5%) patients showed a persistent lack of response despite sequential induction therapy, 22 (10.9%) and 29 (14.4%) patients developed CKD and ESRD, respectively, and 11 (5.5%) patients died during their recorded follow-up period or by the end of data collection Apart from a lower female predominance among those with an unfavorable outcome (P = 0.008; OR: 2.8; 95% CI: 1.2–6.4), the outcome of the nephritis showed no association with any of the other investigated demographic characteristics. Patients developing a poor renal outcome showed a higher prevalence of constitutional (P = 0.007; OR: 2.3; 95% CI: 1.2–4.4), hematologic (P = 0.01; OR: 2.5; 95% CI: 1.1–5.2), and neurologic (P = 0.02; OR: 2.5; 95% CI: 1.1–5.5) involvement, serositis (P = 0.01; OR: 2.1; 95% CI: 1.1–3.9), and hypocomplementemia (P = 0.02; OR: 2.6; 95% CI: 1.1–6.3). Moreover, there were several clinical and laboratory differences between those with and without an unfavorable renal outcome [Table 4], and they demonstrated distinct histopathologic features [Table 5].
Table 4: Demographic, clinical, and serologic differences between patients with poor and favorable renal outcomes.

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Table 5: Differences in biopsy findings between patients with poor and favorable outcomes.

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Renal and extra-renal features associated with disease damage

The SDI score at the last visit was 1.6 ± 1.9, with 132 (65.7%) and 42 (20.9%) patients developing any (SDI ≥1) and severe (SDI ≥3) damage, respectively. Among the demographic features studied, male (P = 0.001) and juvenile (P = 0.001) patients showed higher SDI scores; moreover, the disease duration was associated with a higher SDI score (r = 0.1; (P = 0.02). Of the renal characteristics reviewed, patients presenting with nephrotic proteinuria (P = 0.03) showed higher SDI scores, with no association with any of the other baseline clinical or laboratory characteristics (data not shown), or the rSLEDAI (r = 0.1; P = 0.07). Among the biopsy findings investigated, chronic glomerular lesions (P = 0.003) including interstitial fibrosis (P = 0.003), glomerular sclerosis (P = 0.001), and tubular atrophy (P = 0.001) were associated with higher SDI scores; moreover, patients with acute vascular lesions (P <0.001) demonstrated a higher median SDI score. Although the activity index showed no association with the SDI score (r = 0.07; P = 0.2), the chronicity index demonstrated a positive correlation with the SDI score (r = 0.1; P = 0.006). The number of renal (r = 0.3; P <0.001) and extra-renal (r = 0.2; P <0.001) flares showed a positive correlation with the SDI. Interestingly, upon assessing the investigated parameters through linear regression analysis, predictors solely included frequent renal flares (ᵦ = 1; P <0.001).

Treatment of lupus nephritis Induction of nephritis was implemented through intravenous cyclophosphamide (CYC) in 126 (62.7%) patients, whereas 61 (30.3%) and 14 (7%) patients received mycophenolate mofetil (MMF) and azathioprine (AZA) as initial induction regimens, respectively, with 74 (36.8%) patients requiring sequential induction therapy. Interestingly, the necessity of shifting to the opposing drug after induction with either MMF or CYC was comparable (P = 0.4), so was the rate of remission achieved with both drugs (P = 0.3). Although the number of renal flares throughout the course of the disease was similar between patients receiving MMF and CYC (P = 0.5), patients receiving developed subsequent extra-renal flares more frequently (P = 0.02) [Table 4].

By the end of the included follow-up period, 198 (98.5%) patients were receiving maintenance therapy in addition to adjunctive therapy, with AZA and MMF being received by 121 (60.2%) and 77 (38.3%) patients, respectively. There was a difference in the number of subsequent renal (P = 0.4) or extra-renal flares (P = 0.7) between both groups; however, the time to renal flare was shorter among patients receiving MMF maintenance therapy (P = 0.01) [Table 6]. Nevertheless, there was no difference in the renal outcome between those receiving AZA and MMF (P = 1).
Table 6: Evaluation of the induction and maintenance treatment regimens.

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   Discussion Top


Determinants of the course, presentation, and outcome of LN are multifarious and rather controversial. The prevalence of a poor renal outcome widely varied across previous studies, ranging from 19% to 41%.[3],[4],[23],[24] This disparity could be attributed to the differences in the defined end points and patients’ inclusion criteria. In our study, a poor renal outcome was present in 56 (27.9%) patients and was determined as the persistent failure to achieve partial or complete remission despite sequential induction therapy, progression to CKD or ESRD, and/or mortality.

Among the demographic features investigated, the age at onset was not associated with a poor renal outcome (P = 0.6; OR: 0.8; 95% CI: 0.4–1.6). Although these findings are contradictory to several reports that showed worse renal outcomes among JLN patients,[2],[25],[26],[27],[28],[29],[30] they are similar to those detected in previous studies from Egypt,[3] Saudi Arabia,[23] and worldwide.[4],[9] Nevertheless, JLN patients showed several clinical, laboratory, and histopathologic indicators of disease activity; thus, resembling their peers from a previous study;[26] moreover, JLN patients showed higher SLEDAI-2K (P <0.001) and SDI (P = 0.001) scores at the last visit, hence suggesting a more severe disease.

Contrary to the age of onset, gender differences showed an association with an unfavorable renal outcome among male patients (P = 0.008; OR: 2.8; 95%: 1.2–6.4), which is similar to a previous study from Egypt,[3] yet contradictory to previous studies from Saudi Arabia.[23],[31] Other potential indicators of severity among our male LN patients included a higher prevalence of overall crescents on biopsy (P = 0.03). The presence of cellular crescents has been reported to be more prevalent among male LN patients.[9]

Of the clinical and laboratory parameters studied, patients with an unfavorable outcome presented with hypertension (P <0.001; OR: 6.3; 2.6–14.9), elevated SCr levels (P <0.001; OR: 5.2; 95% CI: 2.6–10.3), hematuria (P <0.001; OR: 3.7; 95% CI: 1.9–7.5), and a higher mean rSLEDAI (P = 0.001) score more commonly. Moreover, they developed renal flares (P <0.001) more frequently. In agreement with our findings, hypertension,[2],[3],[4],[23],[30],[31] urinary casts,[3] hematuria[23], a Cr of ≥1.2 mg/dL,[3],[4],[23],[31] and renal flares[2],[3],[4],[32],[33] have been associated with unfavorable renal outcomes in previous reports.

Several distinct renal biopsy features could influence the management, course, and outcome of LN. In our study, patients with an unfavorable renal outcome showed higher activity (P = 0.004) and chronicity (P = 0.006) indices; moreover, acute glomerular lesions including fibrinoid necrosis (P <0.001; OR; 4.1; 95% CI: 2.1–8.1), wire loops (P = 0.006; OR: 2.4; 95% CI: 1.2–4.6), and fibrocellular (P = 0.001; OR: 11.9; 95% CI: 2.4–58) and cellular (P <0.001; OR: 4.9; 95% CI: 2.5–9.6) crescents were detected more frequently, whereas of the chronic glomerular lesions recorded, interstitial fibrosis (P = 0.001; OR: 2.7; 95% CI: 1.4–5.1) was detected more commonly among this group. Biopsy findings including higher activity[23],[30] and chronicity indices,[2],[3],[5],[30],[31] and prevalent crescents and interstitial fibrosis[3],[4],[23] have been associated with poor renal outcomes across several previous studies, hence resembling our results. Other biopsy findings that have been associated with worse renal outcomes were hyaline thrombi[7] and glomerular sclerosis,[3],[5] which were more prevalent among patients with an unfavorable renal outcome in our study, yet the difference did not reach statistical significance.

The importance of assessing the course and outcome of LN rises from the necessity of implementing tailored and personalized treatment which shares a bidirectional relationship with renal outcomes;[8] yet, data about the superiority of various induction and maintenance strategies are rather inconsistent. In our study, rates of remission achieved with CYC and MMF were comparable (P = 0.3), with no difference in the outcome attained by the last visit between the two drugs (P = 0.9). Our results are similar to several previous studies.[2],[8],[34],[35],[36] However, a previous Egyptian study[24] showed a higher remission rate with CYC induction therapy, whereas Ginzler et al[37] showed the superiority of MMF. Studies investigating maintenance therapy in SLE nephritis showed conflicting results, with the Aspreva Lupus Management Study[38] and a previous Egyptian study[24] showing the superiority of MMF, whereas the long-term follow-up of the MAINTAIN trial[39] showed comparable efficacy of both maintenance regimens, which is similar to our results. Although patients included in the MAINTAIN trial showed a similar time to renal flare between those receiving AZA and MMF, patients maintained on MMF in our study developed renal flares after 11.4 ± 8.6 months as opposed to 18.5 ± 19.9 months in patients receiving AZA (P = 0.01). It is of note that the higher SLEDAI-2K (P <0.001) and SDI (P <0.001) scores among patients receiving MMF maintenance therapy suggest a more severe disease among those patients, and maintenance with MMF in those patients could be considered a continuum to MMF induction therapy owing to a more severe disease.

Recurrent renal and extra-renal features could contribute to disease damage. In interest of renal characteristics per se, patients showing interstitial fibrosis (P = 0.003), glomerular sclerosis (P = 0.001), tubular atrophy (P = 0.001), and acute vascular lesions (P <0.001) on biopsy showed higher SDI scores. Moreover, a higher chronicity index was associated with disease damage (r = 0.1; P = 0.006). In agreement with our findings, glomerular sclerosis and a higher chronicity index were associated with disease damage in a previous report.[11] Furthermore, in our study, the number of renal (r = 0.3; P <0.001) and extra-renal (r = 0.2; P <0.001) flares showed a positive correlation with the SDI, which is similar to previous reports that demonstrated that the number of lupus flares is associated with higher damage.[40],[41] Interestingly, among the studied renal and extra-renal parameters assessed, frequent renal flares were the only independent predictor for a higher damage score in our study (ᵦ = 1; P <0.001). Similarly, sustained renal remission, the other end of the disease spectrum, has been associated with more favorable renal and disease outcomes.[42],[43]

The retrospective nature of the study could be considered its main limitation, which has led to the absence of some data. On the other hand, our multicenter study has many strong points as it analyzed the influence of the age at onset and gender on the outcome of LN, and investigated the potential impact of renal characteristics on disease damage.

In conclusion, complete and partial remission was achieved in 55.2% and 40.3% of patients, respectively, whereas 27.9% of our patients developed a poor renal outcome, which was associated with a male predominance, a higher prevalence of hypertension, elevated SCr, and hematuria at onset. Of the histopathologic characteristics recorded, fibrinoid necrosis, wire loops, crescents, interstitial fibrosis, and acute vascular lesions were more prevalent among patients with an unfavorable renal outcome. Among the studied renal and extrarenal characteristics investigated, frequent renal flares were the only predictor of higher disease damage.

Conflict of interest: None declared.



 
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Correspondence Address:
Basma M Medhat
Department of Rheumatology and Rehabilitation, Kasr Alainy Faculty of Medicine, Cairo University, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1319-2442.367830

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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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    Abstract
   Introduction
   Patients and Methods
   Statistical Analysis
   Results
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