Introduction Prognosis of lupus nephritis (LN) among patients of African descent living in Europe has been understudied.
Methods In a retrospective study performed in two European university hospitals, we compared the prognosis of LN in patients of African descent or Caucasians. Remission was defined as a urine protein to creatinine (uP/C) ratio<0.5 g/g and a serum creatinine value<120% of baseline. Renal relapse was defined as the reappearance of a uP/C>1 g/g, leading to a repeat kidney biopsy and/or immunosuppressive treatment change. Chronic kidney disease (CKD) was defined as estimated glomerular filtration rate≤60 mL/min/1.73 m2. Adherence was retrospectively assessed through medical files and/or hydroxychloroquine level measurements.
Results 52 patients of African descent and 85 Caucasian patients were included in this analysis. Class III and isolated class V LN were more common among patients of African descent. Time to first renal remission did not differ between ethnic subgroups. By contrast, patients of African descent suffered from earlier renal flares, CKD was more common and time to CKD was shorter after a flare. In a multivariate analysis, African ancestry was an independent risk factor for progression to CKD. We observed no significant difference in non-adherence to treatment between the two groups.
Conclusion LN patients of African descent have worse renal outcomes, mainly explained by a higher rate of renal flare.
- Lupus Nephritis
- Lupus Erythematosus, Systemic
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WHAT IS ALREADY KNOWN ON THIS TOPIC
In the USA, lupus nephritis (LN) is more severe among patients of African descent, but whether this is true for patients living in Europe, where access to care is easier, is poorly studied.
WHAT THIS STUDY ADDS
We demonstrate that LN patients of African descent living in Europe exhibit worse renal outcomes, mainly due to higher risk of flares.
Despite similar remission rates after initial treatment, subsequent renal flares are more frequent and lead more often to chronic kidney disease in patients of African descent.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
European patients of African descent should be closely followed up after an episode of LN as they have a higher risk of flares and progression to chronic kidney disease.
Renal involvement remains a major disease burden in systemic lupus erythematosus (SLE) leading to chronic kidney disease (CKD) in 30% of patients at 5 years with 10% of end-stage kidney disease (ESKD) at 10 years.1
In SLE patients of African descent, lupus nephritis (LN) is considered to be more common and more severe, leading more frequently to ESKD or death.2–6 Of note, these conclusions mostly rely on American cohorts, where restricted access to the healthcare system might be an important confounding factor. In a recent study on LN long-term outcome by Petri et al, poor outcome of patients of African descent remained statistically significant after adjustment for education level, but this might not properly reflect inequities in access to care.3
In Europe, only one cohort study originating from the Netherlands confirmed that non-white SLE patients had a poorer renal outcome, with more frequent flares and evolution to ESKD, but no specific data were available on patients of African descent.7
In France and Belgium, as in many other European countries, a nationwide social insurance system allows general access to healthcare, thereby minimising the impact of socioeconomic factors on disease prognosis. Therefore, we sought to investigate long-term outcomes in LN patients of African descent living in Europe.
We screened files of SLE patients of African descent followed at the UCLouvain academic hospital in Belgium. As we did in a previous work 8, we selected patients who had a history of proteinuria>0.5 g/day and who underwent a kidney biopsy and selected those who had an incident LN with International Society of Nephrology/Renal Pathology Society (ISN/RPS) class III, IV and/or V histology. We excluded patients with a follow-up of <12 months, who had a previous history of LN or CKD or with insufficient data at baseline or during follow-up. As the number of patients of African descent retrieved was too small, we collaborated with Hôpital Cochin in Paris to retrieve additional patients of African descent using with the same inclusion/exclusion criteria (online supplemental figure 1).
We compared LN patients of African descent with Caucasian patients included in our previously reported long-term outcome incident cohort.8
Renal remission was defined by a urine protein to creatinine (uP/C) value<0.5 g/g (confirmed on at least two subsequent samples) combined with a serum creatinine value<120% of baseline, consistent with current KDIGO (Kidney Disease: Improving Global Outcomes) definition. 9 .
Renal flare was pragmatically defined by an increase in proteinuria (uP/C>1 g/g) leading to a kidney biopsy showing a class III/IV or V with signs of activity and/or intensification of the immunosuppressive treatment. CKD was defined as an estimated glomerular filtration rate (eGFR)<60 mL/min/1.73 m² according to CKD–EPI (Chronic Kidney Disease Epidemiology Collaboration) formula. ESKD was defined as eGFR<15 mL/min/1.73 m², requiring dialysis or renal transplantation.
We considered patients to be severely non-adherent when they completely discontinued medical follow-up for a significant period of time (at least 1 year), admitted that they were not taking their medications for several weeks or months, or when whole blood hydroxychloroquine (HCQ) level was<200 µg/L in at least one sample.10–12 We considered them partially adherent when they admitted frequent omissions of their treatment (ie, at least 2–3/week) or when we found at least two whole blood HCQ levels<500 µg/L.
Chi-square tests, Fischer’s exact tests, unpaired t-tests and Mann-Whitney tests were performed as appropriate with GraphPad Prism V.5.0. Survival curves, drawn according to Kaplan-Meier method, were statistically tested by the log-rank test. Multivariate analysis was performed using a time-adjusted Cox regression proportional hazards model, performed with Jamovi V.2.0 software with ClinicoPath package. For this purpose, we included in the model factors already well known as risk factors for progression to CKD (ever or never achievement of renal remission, ever or never renal flare) and those that differed between two populations at baseline (ie, decade of diagnosis, histologic class at diagnosis, initial treatment by cyclophosphamide or mycophenolate mofetil, prescription of intravenous methylprednisolone (MP), positivity of anti-DNA antibodies), which could be potential confounding factors.
Overall, 52 patients of African descent and 85 Caucasians patients were included and their baseline characteristics are shown in table 1. Initial disease severity based on standard renal parameters did not differ between the two groups. Isolated class V LN was significantly over-represented among patients of African descent (25% vs 7%, p=0.003), and mycophenolate mofetil was more frequently prescribed as initial immunosuppressant in this group (48% vs 17%, p<0.001). Median follow-up was significantly longer in Caucasians (148 vs 81 months, p<0.001), and patients treated before 2000’s were also over-represented in the Caucasian cohort (22% vs 2%, p<0.001).
Renal outcome across ethnic groups
By Kaplan-Meir analyses, time to first renal remission did not differ between ethnic subgroups (figure 1A). By contrast, time to renal flare (figure 1B), to CKD (figure 1C) and to ESKD (figure 1D) was significantly shorter in patients of African descent compared with Caucasians.
Progression to CKD did not significantly differ between patients of African descent treated either with cyclophosphamide-based regimens or mycophenolate mofetil (HR1.6; 95 CI (0.38 to 6.9); p=0.52). There was also no difference for time to renal flare (p=0.158).
In a multivariate analysis, we included variables known as prognostic factors for CKD (ever or never achievement of renal remission, ever or never renal flare) and baseline characteristics that differed between the two groups (decade of diagnosis, histologic class at diagnosis, initial treatment by cyclophosphamide or mycophenolate mofetil, prescription of intravenous MP, positivity of anti-DNA antibodies). Ethnicity and absence of remission were the two independent risk factors for progression to CKD (HR 2.63, 95 CI (1.01 to 6.89), p=0.048 and HR 70.60, 95 CI (14.18 to 351.45), p<0 .001, respectively; see online supplemental table).
Impact of absence of renal remission and of renal flares across ethnic groups
As depicted in figure 2A, time to CKD was shorter in patients who never achieved renal remission, irrespectively of their ethnic background. In the subgroup of patients achieving renal remission but further experiencing a flare, time to CKD was significantly shorter for patients of African descent (figure 2B). By contrast, time to CKD did not differ between patients from the two ethnic groups who never suffered from a renal relapse (figure 2C).
Adherence to treatment
Using definitions detailed supra, no significant difference in adherence to treatment could be unmasked between the two ethnic groups, with 15% and 48% of patients of African descent considered as partially adherent or non-adherent, respectively, versus 7% and 46% of Caucasians patients.
Several US series have demonstrated that LN patients of African descent experience poorer outcomes than Caucasian patients (ref). Since access to the healthcare system in the US is not uniform and depends on wealthiness, socioeconomic factors introduce a bias in studies aimed at identifying long-term prognostic factors in LN across ethnic groups.
Here, we confirm a worse prognosis of LN in patients of African descent followed in two European university expert centres located in countries with generalised access to healthcare. Several hypotheses can be made to explain this difference.
First, early remission is known to be a key prognostic factor for CKD, but we did not observe a delayed kinetics to achieve remission among patients of African descent. This said, patients of African descent who did not achieve remission seem to have a catastrophic outcome, although the limited number of patients does not allow to draw robust conclusions and this should be confirmed in larger cohorts.
Second, this difference in outcome could be attributed to discrepancies observed between populations’ characteristics at baseline. Thus, class V LN was over-represented among patients of African descent, as already described,13 ,14 which is considered to expose patients to a lower risk of progression to CKD. Mycophenolate treatment as more commonly prescribed among LN patients of African descent. However, these two variables did not influence prognosis in a multivariate analysis. To strengthen our results, we also included in this multivariate analysis confounding factors inherent to methodological biases due to the retrospective nature of our study. Thus, neither diagnosis decade (patients treated before the 2000s were over-represented among Caucasians) nor intravenous MP treatment (over-represented among patients of African descent given intravenous PM as standard of care in the UCLouvain centre) nor immunosuppressive induction treatment predicted CKD in a multivariate analysis.
Third, we tested the hypothesis that the poor outcome among patients of African descent stemmed from the frequency and severity of flares. We show that flares are not only more common in patients of African descent (figure 1), as already reported for Maghrebian patients living in Belgium and France,15 but also that progression to CKD was more frequent after a flare (figure 2).
Our study has some limitations. First, we acknowledge that we might have introduced a bias by comparing Caucasian patients followed in one centre (Louvain) with patients of African descent followed in two departments (Louvain and Cochin), in order to increase the numbers of the second group. This said, analyses performed on patients followed only at Louvain revealed the same trend, with time to ESKD being shorter in patients of African descent (p=0.056). Second, we were not able to investigate APOL1 distribution, a gene that encodes the trypanolytic L1 apolipoprotein and confers an increased risk of developing renal impairment in African-Americans with various kidney diseases,16 including LN.17 APOL1 genotyping was obviously beyond the scope of this retrospective analysis while its allele distribution is a likely contributor to the disease severity in European LN patients of African descent. Nonetheless, while such a mechanism might explain a higher rate of CKD, it does not support a higher risk of disease flare. Third, assessment of non-adherence in this retrospective series was limited to data available in the files and therefore likely inaccurate. HCQ measurements became routinely performed only over the last decade while many of our patients have a much longer follow-up. Using a very approximate estimate, we could not identify differences between the two ethnic subgroups. We suggest that this issue should be further investigated with an appropriate prospective methodology including iterative HCQ measurements, as non-adherence to therapy could explain a higher rate of flares among LN patients of African descent.
In conclusion, we confirm that patients of African descent leaving in Europe have a worse renal outcome compared with Caucasians. Renal flares seem a key explanation for more frequent progression to CK. Taken together, these observations are especially relevant given the shorter overall survival of patients of African descent once they have reached ESKD stage.6
Patient consent for publication
This study involves human participants but was not approved by According to French and Belgian laws, consent is not mandatory for retrospective observationnal studies.
Contributors AE and VP collected the data. AE did the statistical analyses. AE, FT, NC-C and FH contributed to the writing of the manuscript. All authors contributed to the follow-up of the patients.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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