https://orcid.org/0000-0003-4062-9412
Abstract
To characterize the clinical presentation and outcomes of LN in a Hispanic cohort from Mexico.
We studied 440 subjects with systemic lupus erythematosus and biopsy-proven LN followed for >36 months. We obtained demographic, clinical, laboratory, histopathological and treatment variables. All outcomes were analysed by survival analysis and included response to therapy, renal relapses, progression of kidney disease (decline in eGFR ≥ 30%, doubling of serum creatinine, end-stage kidney disease) and patient survival.
The median age of the study cohort was 29 years (IQR 23–37) and 96% were female. The median eGFR at inclusion was 81 mL/min/1.73m2 (IQR 48–118) and 24 h-uPCR was 3.4 g/g (IQR 1.9–5.6). Mixed class LN (III/IV+V) was the most frequently observed (69%). Over a median follow-up of 79 months, complete response rates were 22.3%, 40.5% and 51.6%, at 6, 12 and 24 months, respectively. Renal relapse rates were 32.3% and 50.6% at 3 and 5 years. By 3 and 5 years, 20.7% and 31.4% had decline in eGFR ≥30%, 14.4% and 22.5% doubled their serum creatinine, and 9.1% and 17.7% progressed to ESKD. The factors associated with loss of kidney function were age, eGFR at presentation, the histologic chronicity index in the kidney biopsy, and the type of response to therapy. Patient survival was 98.2% and 97.1% at 3 and 5 years.
Although the response to treatment and patient survival in this Latin American cohort is comparable to that observed in other regions, there is still a high rate of renal relapses and progression to decline in kidney function.
Lupus nephritis has a severe presentation in Hispanics from Mexico with a high incidence of mixed histological classes.
The rate of renal relapses and progression to adverse kidney outcomes remain too high in Hispanic populations.
Age, eGFR at presentation, the chronicity index in the kidney biopsy, and the type of response to therapy are associated with adverse kidney outcomes.
Introduction
SLE is an autoimmune disease that affects the kidneys in 30% to 60% of cases [1]. LN is associated with an increase in the standardized mortality ratio of up to 5.9 times once the patient is diagnosed with LN, and up to 26 times for patients progressing to end-stage kidney disease (ESKD) [2]. While patient survival has improved in the last few decades [3], the rates of progression to ESKD have stagnated, and 10% to 20% of patients progress to ESKD by 10 years of LN diagnosis, with higher rates in patients from less developed countries [4].
Several studies have shown differences in disease presentation and prognosis among patients from different genetic backgrounds, ethnicities and geographic regions. A higher risk for developing LN has been described in African-American and Hispanic populations from the United States, with also higher rates of progression to ESKD in these groups [5].
The present study assessed the outcomes of a well-characterized biopsy-proven LN cohort from Mexico between 2008 and 2018. Our objective was to characterize the clinical presentation and outcomes of a Hispanic population from Mexico. The outcomes evaluated included the response to treatment, renal relapses, progression to ESKD, and mortality.
Methods
In 2014, we established a local biopsy-proven LN cohort at the National Institute of Medical Sciences and Nutrition Salvador Zubiran in Mexico City. This is a national reference centre for rheumatic and glomerular diseases. This cohort retrospectively included the information from all biopsy-proven LN subjects diagnosed between 2008 and 2014, and prospectively from all patients diagnosed from 2015 to the present date. The project is approved by the National Institute of Medical Sciences and Nutrition Salvador Zubiran Ethics and Research Boards. Written informed consent was obtained from all subjects included prospectively and waived for subjects included retrospectively between 2008 and 2014. All the subjects in our cohort meet the American College of Rheumatology’s revised criteria for SLE diagnosis [6]. The full cohort comprises 570 patients; however, for this report we selected subjects with histologically active LN (ISN-RPS classes III/IV-A or III/IV-A/C or V) [7] and a minimum 3-year follow-up incorporated into the cohort between 2008 and 2018 (n = 440).
Our database included the date of the start of LN symptoms, and demographic, clinical and laboratory variables at LN flare. Histological data from the kidney biopsy included all activity and chronicity items that comprise the modified NIH activity and chronicity indices [8, 9], the ISN/RPS classification [7] and the vascular findings [10]. As the NIH activity index exclusively applies to proliferative LN (class III/IV or III/IV+V), it was registered as ‘not applicable’ for all class V LN subjects. The initial immunosuppressive therapy and use of antimalarial therapy were registered, and laboratory variables were recorded every third month for the first year.
The following outcomes were evaluated by survival analysis (time to event): partial response to therapy (PR), complete response to therapy (CR), time to renal relapse, a decline of eGFR ≥30%, doubling of serum creatinine, ESKD and patient survival. The response was defined according to the KDIGO guidelines [11]. Complete response was defined as stable kidney function [estimated glomerular filtration rate (eGFR) within 20% of baseline] plus 24 h urine protein to creatinine ratio (24 h uPCR) below 0.5 g/g. Partial response was defined as a 50% reduction of the 24 h uPCR to a value below 3.0 g/g plus stable kidney function. Non-response was defined as neither partial nor complete response. Renal relapse was defined as a persistent increase of 24 h uPCR to ≥1.0 g/g in patients with previous CR or persistent doubling of the previous 24 h uPCR in patients with a previous PR, with or without a decline in eGFR that required intensification of the immunosuppressive treatment. The time at risk of a renal flare was estimated from the date of partial response attainment; therefore, this outcome was exclusively evaluated in subjects with partial or complete response to therapy.
To assess the kidney survival outcomes, we used for reference the best estimated glomerular filtration rate (eGFR) attained within the first year of the initial treatment. Then, the time to decline in eGFR of ≥30% and the time to doubling of serum creatinine were estimated. End-stage kidney disease was defined as a persistent requirement for renal replacement therapy.
Statistical analysis
For quantitative variables, variable distribution was assessed by the Kolmogorov–Smirnov test and is presented as median (interquartile range). Categorical variables are presented as frequencies and percentages.
All the outcomes were assessed by survival analysis (time-to-event). A univariate Cox regression analysis was performed to identify all the factors associated with each outcome. Then, an adjusted Cox regression analysis including all variables with a P-value <0.05 in the univariate analysis was performed for each outcome. All reported P-values are two-tailed, with a probability level <0.05 indicating statistical significance. The data were analysed using SPSS 24.0 (IBM Corp., Armonk, NY, USA).
Results
Demographics and characteristics at the time of lupus nephritis flare
From 2008 to 2018, 570 subjects with biopsy-proven LN were included in our cohort. A total of 440 subjects had histologically active disease with follow-up for a minimum of 36 months. Demographics and characteristics at the time of the LN flare of the study cohort are presented in Table 1.
Characteristics of the lupus nephritis cohort at the time of diagnosis
| Parameter | n = 440 |
|---|---|
| Age, years | 29 (23–37) |
| Female, n (%) | 422 (96) |
| Race, n (%) | |
| Mexican-mestizo | 436 (99) |
| Caucasian | 4 (1) |
| Ethnicity, n (%) | |
| Hispanic | 440 (100) |
| Socioeconomic status,an (%) | |
| Low | 400 (91) |
| Medium | 28 (6) |
| Social insurance | 12 (3) |
| Antiphospholipid syndrome, n (%) | 49 (11) |
| Time from SLE diagnosis, months | 4 (0–56) |
| Time from the 1st LN symptom, months | 3 (0–46) |
| Mean arterial pressure, mmHg | 95 (87–103) |
| Haemoglobin, g/dL | 11.9 (10.5–13.3) |
| Platelets, mm3 | 242 (180–305) |
| Serum creatinine, mg/dL | 1.0 (0.7–1.4) |
| Serum creatinine, μmol/L | 88 (62–124) |
| eGFR, ml/min/1.73m2 | 81 (48–118) |
| eGFR 31–60 ml/min/1.73m2, n (%) | 85 (19) |
| eGFR ≤30 ml/min/1.73m2, n (%) | 61 (14) |
| Proteinuria (24 h-uPCR), g/g | 3.4 (1.9–5.6) |
| Proteinuria (24 h-uPCR), mg/mmol | 303 (170–496) |
| Pyuria, n (%) | 344 (78) |
| Hematuria, n (%) | 320 (73) |
| Serum albumin, g/L | 2.8 (2.3–3.4) |
| Cholesterol, mg/dL | 227 (284–287) |
| Triglycerides, mg/dL | 208 (148–280) |
| Anti-dsDNA antibodies, UI/mL | 101 (24–417) |
| Positive anti-dsDNA antibodies, n (%) | 386 (88) |
| Complement C3, mg/dL | 65 (47–84) |
| Low C3, n (%) | 342 (78) |
| Complement C4, mg/dL | 10 (8–17) |
| Low C4, n (%) | 350 (79) |
| Parameter | n = 440 |
|---|---|
| Age, years | 29 (23–37) |
| Female, n (%) | 422 (96) |
| Race, n (%) | |
| Mexican-mestizo | 436 (99) |
| Caucasian | 4 (1) |
| Ethnicity, n (%) | |
| Hispanic | 440 (100) |
| Socioeconomic status,an (%) | |
| Low | 400 (91) |
| Medium | 28 (6) |
| Social insurance | 12 (3) |
| Antiphospholipid syndrome, n (%) | 49 (11) |
| Time from SLE diagnosis, months | 4 (0–56) |
| Time from the 1st LN symptom, months | 3 (0–46) |
| Mean arterial pressure, mmHg | 95 (87–103) |
| Haemoglobin, g/dL | 11.9 (10.5–13.3) |
| Platelets, mm3 | 242 (180–305) |
| Serum creatinine, mg/dL | 1.0 (0.7–1.4) |
| Serum creatinine, μmol/L | 88 (62–124) |
| eGFR, ml/min/1.73m2 | 81 (48–118) |
| eGFR 31–60 ml/min/1.73m2, n (%) | 85 (19) |
| eGFR ≤30 ml/min/1.73m2, n (%) | 61 (14) |
| Proteinuria (24 h-uPCR), g/g | 3.4 (1.9–5.6) |
| Proteinuria (24 h-uPCR), mg/mmol | 303 (170–496) |
| Pyuria, n (%) | 344 (78) |
| Hematuria, n (%) | 320 (73) |
| Serum albumin, g/L | 2.8 (2.3–3.4) |
| Cholesterol, mg/dL | 227 (284–287) |
| Triglycerides, mg/dL | 208 (148–280) |
| Anti-dsDNA antibodies, UI/mL | 101 (24–417) |
| Positive anti-dsDNA antibodies, n (%) | 386 (88) |
| Complement C3, mg/dL | 65 (47–84) |
| Low C3, n (%) | 342 (78) |
| Complement C4, mg/dL | 10 (8–17) |
| Low C4, n (%) | 350 (79) |
The socioeconomic status variable was created by evaluating family income, household characteristics and family assets.
24 h-uPCR, urine protein to creatinine ratio estimated from a 24-h urine collection; anti-dsDNA: antibodies against double-strand DNA; eGFR: estimated glomerular filtration rate.
Characteristics of the lupus nephritis cohort at the time of diagnosis
| Parameter | n = 440 |
|---|---|
| Age, years | 29 (23–37) |
| Female, n (%) | 422 (96) |
| Race, n (%) | |
| Mexican-mestizo | 436 (99) |
| Caucasian | 4 (1) |
| Ethnicity, n (%) | |
| Hispanic | 440 (100) |
| Socioeconomic status,an (%) | |
| Low | 400 (91) |
| Medium | 28 (6) |
| Social insurance | 12 (3) |
| Antiphospholipid syndrome, n (%) | 49 (11) |
| Time from SLE diagnosis, months | 4 (0–56) |
| Time from the 1st LN symptom, months | 3 (0–46) |
| Mean arterial pressure, mmHg | 95 (87–103) |
| Haemoglobin, g/dL | 11.9 (10.5–13.3) |
| Platelets, mm3 | 242 (180–305) |
| Serum creatinine, mg/dL | 1.0 (0.7–1.4) |
| Serum creatinine, μmol/L | 88 (62–124) |
| eGFR, ml/min/1.73m2 | 81 (48–118) |
| eGFR 31–60 ml/min/1.73m2, n (%) | 85 (19) |
| eGFR ≤30 ml/min/1.73m2, n (%) | 61 (14) |
| Proteinuria (24 h-uPCR), g/g | 3.4 (1.9–5.6) |
| Proteinuria (24 h-uPCR), mg/mmol | 303 (170–496) |
| Pyuria, n (%) | 344 (78) |
| Hematuria, n (%) | 320 (73) |
| Serum albumin, g/L | 2.8 (2.3–3.4) |
| Cholesterol, mg/dL | 227 (284–287) |
| Triglycerides, mg/dL | 208 (148–280) |
| Anti-dsDNA antibodies, UI/mL | 101 (24–417) |
| Positive anti-dsDNA antibodies, n (%) | 386 (88) |
| Complement C3, mg/dL | 65 (47–84) |
| Low C3, n (%) | 342 (78) |
| Complement C4, mg/dL | 10 (8–17) |
| Low C4, n (%) | 350 (79) |
| Parameter | n = 440 |
|---|---|
| Age, years | 29 (23–37) |
| Female, n (%) | 422 (96) |
| Race, n (%) | |
| Mexican-mestizo | 436 (99) |
| Caucasian | 4 (1) |
| Ethnicity, n (%) | |
| Hispanic | 440 (100) |
| Socioeconomic status,an (%) | |
| Low | 400 (91) |
| Medium | 28 (6) |
| Social insurance | 12 (3) |
| Antiphospholipid syndrome, n (%) | 49 (11) |
| Time from SLE diagnosis, months | 4 (0–56) |
| Time from the 1st LN symptom, months | 3 (0–46) |
| Mean arterial pressure, mmHg | 95 (87–103) |
| Haemoglobin, g/dL | 11.9 (10.5–13.3) |
| Platelets, mm3 | 242 (180–305) |
| Serum creatinine, mg/dL | 1.0 (0.7–1.4) |
| Serum creatinine, μmol/L | 88 (62–124) |
| eGFR, ml/min/1.73m2 | 81 (48–118) |
| eGFR 31–60 ml/min/1.73m2, n (%) | 85 (19) |
| eGFR ≤30 ml/min/1.73m2, n (%) | 61 (14) |
| Proteinuria (24 h-uPCR), g/g | 3.4 (1.9–5.6) |
| Proteinuria (24 h-uPCR), mg/mmol | 303 (170–496) |
| Pyuria, n (%) | 344 (78) |
| Hematuria, n (%) | 320 (73) |
| Serum albumin, g/L | 2.8 (2.3–3.4) |
| Cholesterol, mg/dL | 227 (284–287) |
| Triglycerides, mg/dL | 208 (148–280) |
| Anti-dsDNA antibodies, UI/mL | 101 (24–417) |
| Positive anti-dsDNA antibodies, n (%) | 386 (88) |
| Complement C3, mg/dL | 65 (47–84) |
| Low C3, n (%) | 342 (78) |
| Complement C4, mg/dL | 10 (8–17) |
| Low C4, n (%) | 350 (79) |
The socioeconomic status variable was created by evaluating family income, household characteristics and family assets.
24 h-uPCR, urine protein to creatinine ratio estimated from a 24-h urine collection; anti-dsDNA: antibodies against double-strand DNA; eGFR: estimated glomerular filtration rate.
The median age was 29 years (IQR 23–37), 422 (96%) were female, and all had Hispanic ethnicity. A total of 257 (58%) subjects were included at their first LN flare, 101 (23%) at their second LN flare and 82 (19%) at their third or higher LN flare. The median eGFR at presentation was 81 mL/min/1.73m2 (IQR 48–118) with a median 24 h uPCR of 3.4 g/g (IQR 1.9–5.6). A total of 385 (88%) subjects had positive anti-double-stranded DNA (anti-dsDNA) antibodies, 341 (78%) had low serum complement C3 and 349 (79%) had low serum complement C4 levels. Forty-nine (11%) had a concurrent diagnosis of APS.
Histology
The histological findings in the kidney biopsy at LN flare are shown in Supplementary Table S1, available at Rheumatology online. A total of 79 (18%) patients were diagnosed as class III or IV LN, 58 (13%) as class V, and 303 (69%) as a mixed class (III/IV+V). Among those with ‘proliferative’ LN (class III/IV±V), 277 (73%) were classified as histologically active (A), and 105 (27%) as both active and chronic (A/C). The median NIH activity score was 5 points (IQR 2–9), and the median NIH chronicity score was 3 points (IQR 2–5). At least one vascular lesion was observed in 230 (52%) subjects, being arteriosclerosis the most common (46%), followed by thrombotic microangiopathy (TMA, 4%), lupus vasculopathy (2%) and necrotizing vasculitis (1%). Among the 17 patients with TMA, five (29%) corresponded to antiphospholipid syndrome nephropathy, one (6%) to thrombotic thrombocytopenic purpura, and 11 (65%) had negative antiphospholipid antibodies and normal ADAMTS13 activity.
Treatment and follow-up
The most frequent initial immunosuppressive treatment was the combination of MMF and glucocorticoids (GCs) in 206 (47%) patients, followed by i.v. cyclophosphamide (modified NIH protocol) in 156 (35%). A total of 44 (10%) patients received azathioprine plus GCs, 26 (6%) participated in a research protocol with background MMF as the standard of care therapy and eight (2%) were treated with a combination of calcineurin inhibitor, MMF and GCs. The median cumulative cyclophosphamide dose was 6.0 g (IQR 4.8–6.6) equivalent to 3.7 g/m2 per body surface area (IQR 2.9–4.2). The median MMF dose was 2.0 g (IQR 2.0–3.0), and the median azathioprine dose was 1.9 mg/kg (IQR 1.7–2.0). Two hundred and ninety-six (67%) patients received concomitant antimalarial (hydroxychloroquine or chloroquine) therapy. As for maintenance therapy, 133 (30%) received azathioprine, 284 (65%) MMF and 23 (5%) a combination of a calcineurin inhibitor and MMF.
The median follow-up of the cohort was 79 months (IQR 55–108). At last follow-up, 21 subjects died (5%), 100 (23%) subjects lost follow-up [35 (8%) referred to other institutions for renal replacement therapy] and 320 (73%) subjects continue follow-up at our institution.
Response to therapy
Complete remission rates at 6, 12 and 24 months were 22.3%, 40.5% and 51.6%, respectively. Partial remission rates were 58.2%, 73.0% and 78.8% at 6, 12, and 24 months from LN flare. The rates of complete remission increased over time and plateaued by 18–24 months of follow-up. Conversely, the rates of no response to therapy decreased from the 6th to the 12th month and then plateaued (Fig. 1).
Kaplan–Meier curves for time to complete and partial response to therapy
The factors associated with the time to complete response in the multivariate analysis were age (HR 1.15, 95% CI 1.02, 1.30), proteinuria at the flare (HR 0.94, 95% CI 0.90, 0.99), the use of antimalarial therapy (HR 1.42, 95% CI 1.07, 1.87), and the histological chronicity score in the diagnostic kidney biopsy (HR 0.87, 95% CI 0.82, 0.93) (Table 2, Supplementary Tables S2 and S3, available at Rheumatology online).
Multivariate Cox regression analyses for factors associated with outcomes
| Univariate | Multivariate | ||||||
|---|---|---|---|---|---|---|---|
| HR | 95% CI | P-value | HR | 95% CI | P-value | ||
| Complete responsea | |||||||
| Age, per 10 years | 1.11 | 0.99–1.25 | 0.081 | 1.15 | 1.02–1.30 | 0.020 | |
| Proteinuria, per g/g | 0.92 | 0.88–0.96 | <0.001 | 0.94 | 0.90–0.99 | 0.023 | |
| Pyuria, vs not | 1.38 | 1.02–1.88 | 0.037 | 1.54 | 1.12–2.13 | 0.008 | |
| Chronicity index, per point | 0.87 | 0.83–0.91 | <0.001 | 0.87 | 0.82–0.92 | <0.001 | |
| Antimalarial therapy, vs not | 1.47 | 1.12–1.93 | 0.006 | 1.42 | 1.07–1.87 | 0.015 | |
| Response to therapyb | |||||||
| Age, per 10 years | 1.13 | 1.03–1.25 | 0.014 | 1.16 | 1.04–1.28 | 0.007 | |
| Proteinuria, per g/g | 0.94 | 0.91–0.97 | 0.001 | 0.97 | 0.93–1.01 | 0.141 | |
| Complement C3, per 10 mg/dL | 0.96 | 0.93–0.99 | 0.015 | 0.94 | 0.91–0.98 | 0.001 | |
| Chronicity index, per point | 0.92 | 0.89–0.96 | <0.001 | 0.93 | 0.88–0.98 | 0.003 | |
| Antimalarial therapy, vs not | 1.27 | 1.01–1.59 | 0.039 | 1.20 | 0.95–1.51 | 0.136 | |
| Renal relapsec | |||||||
| PR by 6 months, vs CR | 1.55 | 1.10–2.20 | 0.013 | 1.55 | 1.09–2.19 | 0.014 | |
| Loss of 30% of eGFRd | |||||||
| Age, per 10 years | 0.85 | 0.73–0.99 | 0.049 | 0.80 | 0.67–0.96 | 0.016 | |
| eGFR at flare, per 10 ml/min/1.73 | 0.89 | 0.85–0.92 | <0.001 | 0.90 | 0.85–0.94 | <0.001 | |
| Chronicity index, per point | 1.21 | 1.15–1.28 | <0.001 | 1.08 | 1.01–1.16 | 0.030 | |
| PR by 12 months, vs CR | 2.15 | 1.41–3.28 | <0.001 | 2.21 | 1.43–3.39 | 0.001 | |
| NR by 12 months, vs CR | 7.61 | 5.09–13.7 | <0.001 | 7.64 | 4.90–11.9 | <0.001 | |
| Antimalarial therapy, vs not | 0.65 | 0.48–0.88 | 0.005 | 0.67 | 0.49–0.93 | 0.016 | |
| Doubling of serum creatinined | |||||||
| Age, per 10 years | 0.70 | 0.57–0.86 | 0.001 | 0.65 | 0.51–0.82 | <0.001 | |
| eGFR at flare, per 10 ml/min/1.73 | 0.85 | 0.81–0.90 | <0.001 | 0.88 | 0.83–0.93 | <0.001 | |
| Chronicity index, per point | 1.26 | 1.18–1.34 | <0.001 | 1.09 | 1.01–1.18 | 0.031 | |
| PR by 12 months, vs CR | 2.90 | 1.66–5.06 | <0.001 | 2.59 | 1.47–4.57 | 0.001 | |
| NR by 12 months, vs CR | 10.5 | 6.19–17.6 | <0.001 | 8.80 | 4.94–15.7 | <0.001 | |
| Antimalarial therapy, vs not | 0.55 | 0.39–0.78 | 0.001 | 0.55 | 0.37–0.80 | 0.002 | |
| End-stage kidney diseased | |||||||
| Age, per 10 years | 0.66 | 0.52–0.84 | 0.001 | 0.62 | 0.47–0.82 | 0.001 | |
| eGFR at flare, per 10 ml/min/1.73 | 0.82 | 0.77–0.87 | <0.001 | 0.86 | 0.80–0.92 | <0.001 | |
| Chronicity index, per point | 1.32 | 1.23–1.42 | <0.001 | 1.13 | 1.03–1.25 | 0.009 | |
| PR by 12 months, vs CR | 3.01 | 1.49–6.09 | 0.002 | 2.56 | 1.25–5.25 | 0.010 | |
| NR by 12 months, vs CR | 12.1 | 6.36–23.2 | <0.001 | 9.96 | 4.97–19.9 | <0.001 | |
| Antimalarial therapy, vs not | 0.54 | 0.36–0.81 | 0.003 | 0.56 | 0.36–0.87 | 0.010 | |
| Univariate | Multivariate | ||||||
|---|---|---|---|---|---|---|---|
| HR | 95% CI | P-value | HR | 95% CI | P-value | ||
| Complete responsea | |||||||
| Age, per 10 years | 1.11 | 0.99–1.25 | 0.081 | 1.15 | 1.02–1.30 | 0.020 | |
| Proteinuria, per g/g | 0.92 | 0.88–0.96 | <0.001 | 0.94 | 0.90–0.99 | 0.023 | |
| Pyuria, vs not | 1.38 | 1.02–1.88 | 0.037 | 1.54 | 1.12–2.13 | 0.008 | |
| Chronicity index, per point | 0.87 | 0.83–0.91 | <0.001 | 0.87 | 0.82–0.92 | <0.001 | |
| Antimalarial therapy, vs not | 1.47 | 1.12–1.93 | 0.006 | 1.42 | 1.07–1.87 | 0.015 | |
| Response to therapyb | |||||||
| Age, per 10 years | 1.13 | 1.03–1.25 | 0.014 | 1.16 | 1.04–1.28 | 0.007 | |
| Proteinuria, per g/g | 0.94 | 0.91–0.97 | 0.001 | 0.97 | 0.93–1.01 | 0.141 | |
| Complement C3, per 10 mg/dL | 0.96 | 0.93–0.99 | 0.015 | 0.94 | 0.91–0.98 | 0.001 | |
| Chronicity index, per point | 0.92 | 0.89–0.96 | <0.001 | 0.93 | 0.88–0.98 | 0.003 | |
| Antimalarial therapy, vs not | 1.27 | 1.01–1.59 | 0.039 | 1.20 | 0.95–1.51 | 0.136 | |
| Renal relapsec | |||||||
| PR by 6 months, vs CR | 1.55 | 1.10–2.20 | 0.013 | 1.55 | 1.09–2.19 | 0.014 | |
| Loss of 30% of eGFRd | |||||||
| Age, per 10 years | 0.85 | 0.73–0.99 | 0.049 | 0.80 | 0.67–0.96 | 0.016 | |
| eGFR at flare, per 10 ml/min/1.73 | 0.89 | 0.85–0.92 | <0.001 | 0.90 | 0.85–0.94 | <0.001 | |
| Chronicity index, per point | 1.21 | 1.15–1.28 | <0.001 | 1.08 | 1.01–1.16 | 0.030 | |
| PR by 12 months, vs CR | 2.15 | 1.41–3.28 | <0.001 | 2.21 | 1.43–3.39 | 0.001 | |
| NR by 12 months, vs CR | 7.61 | 5.09–13.7 | <0.001 | 7.64 | 4.90–11.9 | <0.001 | |
| Antimalarial therapy, vs not | 0.65 | 0.48–0.88 | 0.005 | 0.67 | 0.49–0.93 | 0.016 | |
| Doubling of serum creatinined | |||||||
| Age, per 10 years | 0.70 | 0.57–0.86 | 0.001 | 0.65 | 0.51–0.82 | <0.001 | |
| eGFR at flare, per 10 ml/min/1.73 | 0.85 | 0.81–0.90 | <0.001 | 0.88 | 0.83–0.93 | <0.001 | |
| Chronicity index, per point | 1.26 | 1.18–1.34 | <0.001 | 1.09 | 1.01–1.18 | 0.031 | |
| PR by 12 months, vs CR | 2.90 | 1.66–5.06 | <0.001 | 2.59 | 1.47–4.57 | 0.001 | |
| NR by 12 months, vs CR | 10.5 | 6.19–17.6 | <0.001 | 8.80 | 4.94–15.7 | <0.001 | |
| Antimalarial therapy, vs not | 0.55 | 0.39–0.78 | 0.001 | 0.55 | 0.37–0.80 | 0.002 | |
| End-stage kidney diseased | |||||||
| Age, per 10 years | 0.66 | 0.52–0.84 | 0.001 | 0.62 | 0.47–0.82 | 0.001 | |
| eGFR at flare, per 10 ml/min/1.73 | 0.82 | 0.77–0.87 | <0.001 | 0.86 | 0.80–0.92 | <0.001 | |
| Chronicity index, per point | 1.32 | 1.23–1.42 | <0.001 | 1.13 | 1.03–1.25 | 0.009 | |
| PR by 12 months, vs CR | 3.01 | 1.49–6.09 | 0.002 | 2.56 | 1.25–5.25 | 0.010 | |
| NR by 12 months, vs CR | 12.1 | 6.36–23.2 | <0.001 | 9.96 | 4.97–19.9 | <0.001 | |
| Antimalarial therapy, vs not | 0.54 | 0.36–0.81 | 0.003 | 0.56 | 0.36–0.87 | 0.010 | |
Adjusted for gender, eGFR and anti-dsDNA antibodies at flare, ISN/RPS class and initial immunosuppressive therapy.
Adjusted for gender, mean arterial pressure, proteinuria, haemoglobin, albumin, histological activity index, ISN/RPS class and initial immunosuppressive therapy.
Adjusted for age and gender.
Adjusted for gender, mean arterial pressure, proteinuria, haemoglobin, albumin, histological activity index, ISN/RPS class and initial immunosuppressive therapy.
GFR: estimated glomerular filtration rate; NR: no response; PR: partial response.
Multivariate Cox regression analyses for factors associated with outcomes
| Univariate | Multivariate | ||||||
|---|---|---|---|---|---|---|---|
| HR | 95% CI | P-value | HR | 95% CI | P-value | ||
| Complete responsea | |||||||
| Age, per 10 years | 1.11 | 0.99–1.25 | 0.081 | 1.15 | 1.02–1.30 | 0.020 | |
| Proteinuria, per g/g | 0.92 | 0.88–0.96 | <0.001 | 0.94 | 0.90–0.99 | 0.023 | |
| Pyuria, vs not | 1.38 | 1.02–1.88 | 0.037 | 1.54 | 1.12–2.13 | 0.008 | |
| Chronicity index, per point | 0.87 | 0.83–0.91 | <0.001 | 0.87 | 0.82–0.92 | <0.001 | |
| Antimalarial therapy, vs not | 1.47 | 1.12–1.93 | 0.006 | 1.42 | 1.07–1.87 | 0.015 | |
| Response to therapyb | |||||||
| Age, per 10 years | 1.13 | 1.03–1.25 | 0.014 | 1.16 | 1.04–1.28 | 0.007 | |
| Proteinuria, per g/g | 0.94 | 0.91–0.97 | 0.001 | 0.97 | 0.93–1.01 | 0.141 | |
| Complement C3, per 10 mg/dL | 0.96 | 0.93–0.99 | 0.015 | 0.94 | 0.91–0.98 | 0.001 | |
| Chronicity index, per point | 0.92 | 0.89–0.96 | <0.001 | 0.93 | 0.88–0.98 | 0.003 | |
| Antimalarial therapy, vs not | 1.27 | 1.01–1.59 | 0.039 | 1.20 | 0.95–1.51 | 0.136 | |
| Renal relapsec | |||||||
| PR by 6 months, vs CR | 1.55 | 1.10–2.20 | 0.013 | 1.55 | 1.09–2.19 | 0.014 | |
| Loss of 30% of eGFRd | |||||||
| Age, per 10 years | 0.85 | 0.73–0.99 | 0.049 | 0.80 | 0.67–0.96 | 0.016 | |
| eGFR at flare, per 10 ml/min/1.73 | 0.89 | 0.85–0.92 | <0.001 | 0.90 | 0.85–0.94 | <0.001 | |
| Chronicity index, per point | 1.21 | 1.15–1.28 | <0.001 | 1.08 | 1.01–1.16 | 0.030 | |
| PR by 12 months, vs CR | 2.15 | 1.41–3.28 | <0.001 | 2.21 | 1.43–3.39 | 0.001 | |
| NR by 12 months, vs CR | 7.61 | 5.09–13.7 | <0.001 | 7.64 | 4.90–11.9 | <0.001 | |
| Antimalarial therapy, vs not | 0.65 | 0.48–0.88 | 0.005 | 0.67 | 0.49–0.93 | 0.016 | |
| Doubling of serum creatinined | |||||||
| Age, per 10 years | 0.70 | 0.57–0.86 | 0.001 | 0.65 | 0.51–0.82 | <0.001 | |
| eGFR at flare, per 10 ml/min/1.73 | 0.85 | 0.81–0.90 | <0.001 | 0.88 | 0.83–0.93 | <0.001 | |
| Chronicity index, per point | 1.26 | 1.18–1.34 | <0.001 | 1.09 | 1.01–1.18 | 0.031 | |
| PR by 12 months, vs CR | 2.90 | 1.66–5.06 | <0.001 | 2.59 | 1.47–4.57 | 0.001 | |
| NR by 12 months, vs CR | 10.5 | 6.19–17.6 | <0.001 | 8.80 | 4.94–15.7 | <0.001 | |
| Antimalarial therapy, vs not | 0.55 | 0.39–0.78 | 0.001 | 0.55 | 0.37–0.80 | 0.002 | |
| End-stage kidney diseased | |||||||
| Age, per 10 years | 0.66 | 0.52–0.84 | 0.001 | 0.62 | 0.47–0.82 | 0.001 | |
| eGFR at flare, per 10 ml/min/1.73 | 0.82 | 0.77–0.87 | <0.001 | 0.86 | 0.80–0.92 | <0.001 | |
| Chronicity index, per point | 1.32 | 1.23–1.42 | <0.001 | 1.13 | 1.03–1.25 | 0.009 | |
| PR by 12 months, vs CR | 3.01 | 1.49–6.09 | 0.002 | 2.56 | 1.25–5.25 | 0.010 | |
| NR by 12 months, vs CR | 12.1 | 6.36–23.2 | <0.001 | 9.96 | 4.97–19.9 | <0.001 | |
| Antimalarial therapy, vs not | 0.54 | 0.36–0.81 | 0.003 | 0.56 | 0.36–0.87 | 0.010 | |
| Univariate | Multivariate | ||||||
|---|---|---|---|---|---|---|---|
| HR | 95% CI | P-value | HR | 95% CI | P-value | ||
| Complete responsea | |||||||
| Age, per 10 years | 1.11 | 0.99–1.25 | 0.081 | 1.15 | 1.02–1.30 | 0.020 | |
| Proteinuria, per g/g | 0.92 | 0.88–0.96 | <0.001 | 0.94 | 0.90–0.99 | 0.023 | |
| Pyuria, vs not | 1.38 | 1.02–1.88 | 0.037 | 1.54 | 1.12–2.13 | 0.008 | |
| Chronicity index, per point | 0.87 | 0.83–0.91 | <0.001 | 0.87 | 0.82–0.92 | <0.001 | |
| Antimalarial therapy, vs not | 1.47 | 1.12–1.93 | 0.006 | 1.42 | 1.07–1.87 | 0.015 | |
| Response to therapyb | |||||||
| Age, per 10 years | 1.13 | 1.03–1.25 | 0.014 | 1.16 | 1.04–1.28 | 0.007 | |
| Proteinuria, per g/g | 0.94 | 0.91–0.97 | 0.001 | 0.97 | 0.93–1.01 | 0.141 | |
| Complement C3, per 10 mg/dL | 0.96 | 0.93–0.99 | 0.015 | 0.94 | 0.91–0.98 | 0.001 | |
| Chronicity index, per point | 0.92 | 0.89–0.96 | <0.001 | 0.93 | 0.88–0.98 | 0.003 | |
| Antimalarial therapy, vs not | 1.27 | 1.01–1.59 | 0.039 | 1.20 | 0.95–1.51 | 0.136 | |
| Renal relapsec | |||||||
| PR by 6 months, vs CR | 1.55 | 1.10–2.20 | 0.013 | 1.55 | 1.09–2.19 | 0.014 | |
| Loss of 30% of eGFRd | |||||||
| Age, per 10 years | 0.85 | 0.73–0.99 | 0.049 | 0.80 | 0.67–0.96 | 0.016 | |
| eGFR at flare, per 10 ml/min/1.73 | 0.89 | 0.85–0.92 | <0.001 | 0.90 | 0.85–0.94 | <0.001 | |
| Chronicity index, per point | 1.21 | 1.15–1.28 | <0.001 | 1.08 | 1.01–1.16 | 0.030 | |
| PR by 12 months, vs CR | 2.15 | 1.41–3.28 | <0.001 | 2.21 | 1.43–3.39 | 0.001 | |
| NR by 12 months, vs CR | 7.61 | 5.09–13.7 | <0.001 | 7.64 | 4.90–11.9 | <0.001 | |
| Antimalarial therapy, vs not | 0.65 | 0.48–0.88 | 0.005 | 0.67 | 0.49–0.93 | 0.016 | |
| Doubling of serum creatinined | |||||||
| Age, per 10 years | 0.70 | 0.57–0.86 | 0.001 | 0.65 | 0.51–0.82 | <0.001 | |
| eGFR at flare, per 10 ml/min/1.73 | 0.85 | 0.81–0.90 | <0.001 | 0.88 | 0.83–0.93 | <0.001 | |
| Chronicity index, per point | 1.26 | 1.18–1.34 | <0.001 | 1.09 | 1.01–1.18 | 0.031 | |
| PR by 12 months, vs CR | 2.90 | 1.66–5.06 | <0.001 | 2.59 | 1.47–4.57 | 0.001 | |
| NR by 12 months, vs CR | 10.5 | 6.19–17.6 | <0.001 | 8.80 | 4.94–15.7 | <0.001 | |
| Antimalarial therapy, vs not | 0.55 | 0.39–0.78 | 0.001 | 0.55 | 0.37–0.80 | 0.002 | |
| End-stage kidney diseased | |||||||
| Age, per 10 years | 0.66 | 0.52–0.84 | 0.001 | 0.62 | 0.47–0.82 | 0.001 | |
| eGFR at flare, per 10 ml/min/1.73 | 0.82 | 0.77–0.87 | <0.001 | 0.86 | 0.80–0.92 | <0.001 | |
| Chronicity index, per point | 1.32 | 1.23–1.42 | <0.001 | 1.13 | 1.03–1.25 | 0.009 | |
| PR by 12 months, vs CR | 3.01 | 1.49–6.09 | 0.002 | 2.56 | 1.25–5.25 | 0.010 | |
| NR by 12 months, vs CR | 12.1 | 6.36–23.2 | <0.001 | 9.96 | 4.97–19.9 | <0.001 | |
| Antimalarial therapy, vs not | 0.54 | 0.36–0.81 | 0.003 | 0.56 | 0.36–0.87 | 0.010 | |
Adjusted for gender, eGFR and anti-dsDNA antibodies at flare, ISN/RPS class and initial immunosuppressive therapy.
Adjusted for gender, mean arterial pressure, proteinuria, haemoglobin, albumin, histological activity index, ISN/RPS class and initial immunosuppressive therapy.
Adjusted for age and gender.
Adjusted for gender, mean arterial pressure, proteinuria, haemoglobin, albumin, histological activity index, ISN/RPS class and initial immunosuppressive therapy.
GFR: estimated glomerular filtration rate; NR: no response; PR: partial response.
Renal relapses
Renal relapses were exclusively assessed in patients who achieved a partial or complete response to therapy. As shown in Fig. 2, the relapse rate increased progressively to 32.3% by 36 months, and 50.6% by 60 months. The time to renal relapse was shorter in patients with partial response compared with those with complete response (HR 1.55, 95% CI 1.09, 2.19, P =0.014) (Fig. 2, Supplementary Table S4, available at Rheumatology online).
Time to renal relapse in the full cohort (A) and by response group (B)
Kaplan–Meier plot (A) and Cox regression plot (B). CR: complete remission; NR: no response; PR: partial remission.
Kidney and patient survival
A total of 176 (40%), 128 (29%) and 81 (18%) subjects progressed to a decline of ≥30% of the eGFR, doubling of serum creatinine, or ESKD, respectively. The 3-year and 5-year progression rates to decline of ≥30% of eGFR were 20.7% and 31.4%; the 3-year and 5-year progression rates to doubling of serum creatinine were 14.4% and 22.5%; and the 3-year and 5-year progression rates to ESKD were 9.1% and 17.7% (Fig. 3).
Progression to loss of kidney function by response status
The figure represents the status of the patient at the last follow-up according to the response status (complete, partial or no response) attained at a particular month of follow-up. DSCr: doubling of serum creatinine; ESKD: end stage kidney disease; loss 30% eGFR: loss of 30% of the best eGFR attained in the first year after initial therapy; stable: stable kidney function.
As expected, the type of response to the initial therapy (CR, PR or NR) was associated with the long-term preservation of kidney function. By 36 months of follow-up, only 5% of complete responders progressed to a loss of kidney function (decline ≥30% of eGFR, doubling of serum creatinine, or ESKD), while 20% and 68% of partial responders and no responders progressed to this outcome (Fig. 4).
Time to progression to loss of kidney function and patient survival
Kaplan–Meier curves for time to decline of 30% of the estimated glomerular filtration rate (A), doubling of serum creatinine (B), end-stage kidney disease (C) and patient survival (D). eGFR: estimated glomerular filtration rate; SCr: serum creatinine.
In the multivariate analysis, the factors associated with all the loss of kidney function outcomes (decline ≥30% of eGFR, doubling of serum creatinine, end-stage kidney disease) were age, eGFR at flare, the histological chronicity index in the diagnostic biopsy, the use of antimalarials, and the type of response to therapy, with different coefficients and 95% CIs for each outcome as shown in Table 2 and Supplementary Tables S5–S7, available at Rheumatology online.
At the last follow-up, 21 (5%) subjects died with a 3-year and 5-year patient survival rate of 98.2% and 97.1%, respectively. Eighteen deaths (86%) occurred in patients who progressed with ESKD undergoing haemodialysis or peritoneal dialysis. Progression to ESKD was associated with increased mortality (HR 6.47, 2.68–15.6, P <0.001) (Supplementary Table S8, available at Rheumatology online). Of all deaths, 11 (52%) were secondary to infections, seven (33%) to cardiovascular events, two (10%) to dialysis requirement with no acceptance of the procedure, and one (5%) to an accident unrelated to SLE.
Discussion
In this study, we showed the characteristics and outcomes of lupus nephritis in a well-characterized cohort of Hispanic patients with biopsy-proven lupus nephritis from Mexico. While the response rates are similar to those reported in other populations, there is a high incidence of renal relapses, and high rates of progression to decline of kidney function and ESKD.
The pathogenesis of SLE is influenced by genetic and environmental factors. Genetic studies have shown that a higher percentage of genes from European ancestry are protective for LN, whereas an Amerindian and African ancestry increases the risk [12]. The incidence of LN seems higher in African-Americans [13] and patients categorized as ‘Hispanics’ living in the United States [14], Spain [15] or Latin America [16]. Furthermore, lupus nephritis develops earlier in the course of the disease and has been associated with a worse prognosis in Hispanics and African-Americans [17, 18]. The genetic composition of certain populations may also explain differences in response to specific treatments [19, 20].
However, the term ‘Hispanics’, which is largely used in the medical literature, is controversial and fails to capture the genetic admixture of this population. The Latin American region has >650 million inhabitants, with a mix of different ancestries with a large genetic and ethnic variability [21]. Therefore, there is a need to better define the risk and outcomes in specific regions and populations englobed within the term ‘Hispanics’.
Our institution is referred patients from the centre and south of Mexico, with over 3000 (three thousand) SLE subjects and over 700 LN subjects currently followed in our local cohorts. The response rates to current first-line therapies (MMF and cyclophosphamide combined with glucocorticoids) were similar to those reported in previous studies and clinical trials [22–24]. As shown, the rate of partial or complete response increases with longer follow-up; however, it reaches a plateau around 12–18 months, suggesting this to be the ideal time to evaluate response in clinical trials. As previously reported by Chen et al. [25], the prognosis of kidney function is highly dependent on the type of response achieved after the initial immunosuppressive therapy. Here, we showed that <5% of patients with a complete response will progress to declines in kidney function, while 15% to 19% of patients with partial response still lose some kidney function. This observation may be explained by a higher risk for renal relapses in partial responders, as well as the potential for persistent histological inflammation in this group despite the clinical response [26, 27].
Renal relapses have been reported to occur in 27% to 66% of patients [28, 29], and have an adverse impact on long-term kidney function [30]. In our cohort, the relapse rate was high, with progressive increases to 50% by 5 years. We hypothesize this may be partly secondary to poor adherence to therapy, patient education and access to medications. Our cohort was predominantly comprised of subjects from low socioeconomic status and medication cost was not covered by the institution for most of them. Previous studies have suggested lower adherence to treatment in disadvantaged groups due to economic, social and behavioural factors [31]. Specifically, a previous study from the United States reported an increased incidence of non-adherence to azathioprine therapy in subjects of Hispanic ethnicity [32].
As mentioned above, partial responders had a higher risk for renal relapse than complete responders, reinforcing the need to aim for complete response in the management of these patients.
Although there have been reports of improved kidney survival in LN in some geographic regions [3, 33], the rates of progression to decline of kidney function remain elevated in our population, with numbers even higher than those reported in studies including subjects from developing countries [4]. In contrast to other studies, we exclusively included proliferative and membranous LN, some of them experiencing their second or third LN flare, which may partly explain these numbers. The observation of already established kidney damage in the diagnostic biopsy suggests the need for a timelier diagnosis, and the need for better treatment options to improve the initial response to prevent organ damage and prolong kidney survival.
Antimalarial therapy has been previously associated with a better response to therapy [34, 35], lower incidence of disease relapses [36], and less damage accrual in SLE, among other benefits [37, 38]. We observed a better response to therapy and better kidney outcomes in patients treated with antimalarials, although it did not affect renal relapses. This observation should be cautiously interpreted as we did not register the duration and adherence to this medication.
This study has the following limitations. Although we have a strict prospective follow-up of this cohort, there are residual confounding variables that were not recorded and may influence the outcomes (e.g. treatment adherence). The minimal follow-up time of 36 months may be considered short, still, we observed a high number of events for all our outcomes. Almost all subjects in this cohort are of Mexican origin; therefore, these numbers and observations may not apply to other ethnic groups in Latin America. Finally, this study was developed in an experienced referral centre and may not represent the practice of other Latin American centres.
In conclusion, we showed that although the response to initial treatment and patient survival for this Hispanic cohort is comparable to other parts of the globe, there is still a high rate of renal relapses and progression to adverse kidney outcomes, which warrants the need to improve care for LN in our country.
Acknowledgements
This study was performed in partial fulfilment for the Master in Medical Sciences Program of the National Autonomous University of Mexico (UNAM). M.F.Z.-M. is an MSc student from this program.
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. This work was performed with local funding from the Department of Nephrology and Mineral Metabolism of the National Medical Sciences and Nutrition Institute Salvador Zubirán. M.F.Z.-M. received a student grant from the National Council of Science and Technology (CONACYT).
Disclosure statement: The authors have declared no conflicts of interest.
Data availability statement
The data underlying this article will be shared on reasonable request to the corresponding author.
Supplementary data
Supplementary data are available at Rheumatology online.
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