The management of lupus nephritis (LN) and concomitant thrombotic microangiopathy (TMA), with or without antiphospholipid antibodies (aPL), remains controversial and few studies are available to inform clinical management [1–4]
The purpose of this multicenter retrospective study was to analyze the impact of anticoagulation [vitamin-K-antagonists (VKA) and/or heparins] in addition to conventional immunosuppression on kidney outcomes (assessed at 12 months, according to KDIGO guidelines[5]) in patients with biopsy-proven LN and concomitant TMA.
Data source, population, and statistical analysis are detailed in the supplementary material. Anticoagulation was considered if given for at least 3 consecutive months after TMA diagnosis.
We retrospectively identified 97 patients with biopsy-proven LN and TMA (2007–2017). See online supplementary Table S1 for clinical and demographic characteristics. Laboratory parameters were collected at the time of the biopsy. The mean age of patients was 38.9 ±15.2 years (13–69) and 85 female (87.6%). Most had proliferative LN (Class IV in 84.5%). Forty-two(43%) patients presented with acute and 55 (57%) with features of chronic TMA. All patients had received treatment with standard immunosuppressants (55% mycophenolate, 39% cyclophosphamide, 6% other regimen) and steroids. At 12 months, complete response (CR) was observed in 37 patients (38.1%), partial response (PR) in 22 (22.6%) and no response in 38 (39.1%). Sixty-one patients (62.9%) were aPL positive and 37 (38.1%) of these patients received anticoagulation with a VKA and/or heparins. Mean duration of anticoagulation therapy after TMA and LN diagnosis was 7.7 months (3–12).
We observed a higher rate of clinical response (CR/PR, together or computed separately) in patients who received anticoagulation [CR in 22 (59.46%), PR in 7 (18.91%); NR in 8 (21.62%)] when compared to those without [CR in 15 (25.0%), PR in 15 (25.0%); NR in 30( 50%)], p<0.01) (Table1).
Table 1.
Univariate analysis of patient characteristicsby kidney outcome
| Characteristics | Total | % | Any response | % | CR | % | %CR | PR | % | %PR | NR | % | %NR | p | p* |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Female | 85 | 87,6 | 52 | 53,6 | 30 | 30,9 | 81,1 | 22 | 22,68 | 100 | 33 | 34,02 | 86,84 | 0,2924 | 0,85 |
| Clinical features | |||||||||||||||
| APS* | 13 | 13,4 | 10 | 10,3 | 5 | 5,2 | 13,5 | 5 | 5,2 | 22,7 | 3 | 3,1 | 7,9 | 0,2629 | 0,22 |
| aPL antibody positivity | 61 | 62,9 | 26 | 26,8 | 15 | 15,5 | 40,5 | 11 | 11,3 | 50,0 | 35 | 36,1 | 92,1 | <0.001 | <0.001 |
| LAC | 37 | 38,1 | 17 | 17,5 | 7 | 7,2 | 18,9 | 10 | 10,3 | 45,5 | 20 | 20,6 | 52,6 | 0,0079 | 0,018 |
| aCL | 35 | 36,1 | 20 | 20,6 | 8 | 8,2 | 21,6 | 12 | 12,4 | 54,5 | 15 | 15,5 | 39,5 | 0,0334 | 0,57 |
| anti-Beta2GPI | 22 | 22,7 | 12 | 12,4 | 7 | 7,2 | 18,9 | 5 | 5,2 | 22,7 | 10 | 10,3 | 26,3 | 0,7464 | 0,49 |
| Triple Positivity | 15 | 15,5 | 8 | 8,2 | 5 | 5,2 | 13,5 | 3 | 3,1 | 13,6 | 7 | 7,2 | 18,4 | 0,811 | 0,51 |
| Anti-dsDNA | 43 | 44,3 | 22 | 22,7 | 13 | 13,4 | 35,1 | 9 | 9,3 | 40,9 | 24 | 24,7 | 63,2 | 0,041 | 0,0214 |
| Low C3 levels | 77 | 79,3 | 36 | 37,1 | 25 | 25,8 | 67,6 | 11 | 11,3 | 50,0 | 38 | 39,2 | 100,0 | 0,001 | <0.001 |
| Low C4 levels | 27 | 27,8 | 15 | 15,5 | 8 | 8,2 | 21,6 | 7 | 7,2 | 31,8 | 12 | 12,4 | 31,6 | 0,5627 | 0,64 |
| Arterial hypertension | 63 | 64,9 | 36 | 37,1 | 23 | 23,7 | 62,2 | 13 | 13,4 | 59,1 | 28 | 28,9 | 73,7 | 0,4252 | 0,27 |
| Hyperlipemia | 45 | 46,3 | 27 | 27,8 | 17 | 17,5 | 45,9 | 10 | 10,3 | 45,5 | 18 | 18,6 | 47,4 | 0,98 | 1 |
| aGAPSS ≥ 12 | 24 | 24,7 | 10 | 10,3 | 6 | 6,2 | 16,2 | 4 | 4,1 | 18,2 | 14 | 14,4 | 36,8 | 0,0846 | 0,0267 |
| LN class IV | 82 | 84,5 | 50 | 51,5 | 32 | 33,0 | 86,5 | 18 | 18,6 | 81,8 | 32 | 33,0 | 84,2 | 0,8891 | 1 |
| Therapy | |||||||||||||||
| Mycophenolate mofetil | 53 | 54,6 | 32 | 33,0 | 21 | 21,6 | 56,8 | 11 | 11,3 | 50,0 | 21 | 21,6 | 55,3 | 0,8764 | 1 |
| Cyclophosphamide | 38 | 39,2 | 22 | 22,7 | 14 | 14,4 | 37,8 | 8 | 8,2 | 36,4 | 16 | 16,5 | 42,1 | 0,888 | 0,67 |
| EUROLUPUS regimen | 28 | 28,9 | 16 | 16,5 | 11 | 11,3 | 29,7 | 5 | 5,2 | 22,7 | 12 | 12,4 | 31,6 | 0,7583 | 0,65 |
| Other immunosuppresants | 6 | 6,2 | 4 | 4,1 | 2 | 2,1 | 5,4 | 2 | 2,1 | 9,1 | 2 | 2,1 | 5,3 | 0,8128 | 1 |
| Anticoagulation | 37 | 38,1 | 29 | 29,9 | 22 | 22,7 | 59,5 | 7 | 7,2 | 31,8 | 8 | 8,2 | 21,1 | 0,0022 | 0,0059 |
computing together any response, CR+PR. CR, complete response; PR, partial response; NR, no response; aGAPPS, adjusted global antiphospholipid score.
When limiting the analysis on the 61 patients with aPL, we observed a higher rate of complete response in those receiving anticoagulation [patients receiving anticoagulant therapy: CR in 22 (59.46%), PR in 7 (18.91%); NR in 8 (21.62%) Vs. patients non receiving VKA/heparins: CR in 8 (30.77%), PR in 7 (26.92%); NR in 8 (34.62%),p=0.046](Figure 1).
Figure 1.
Comparison of kidney outcomes between patients receiving anticoagulation and those without (Panel A, all 97 patients; Panel B, limiting to patients positive for antiphospholipid antibodies)
After multivariate analysis, aPL positivity (any) (β=1.23,OR, 2.4;95% confidence interval-CI-, 1.2–7.3;p=0.03), anti-dsDNA positivity (β=1.98,OR,12.8; 95% CI 3.0–71.3; p=0.002), and chronic features of TMA (β=1.31,OR 3.0; 95%CI 1.2–17.5; p =0.04) were all associated with no kidney response.
When limiting the analysis to aPL positive patients, after adjusting for type of immunosuppressant therapy and LN class, variables that were significantly associated with CR+PR were features of acute TMA rather than chronic (β=1.95, OR, 8.62; 95% CI 1.4–97.1; p = 0.03) and the use of VKA/heparins (β=1.21OR, 2.1; 95% CI, 1.02–16.2; P = 0.046).
In summary, in our study the use of anticoagulation was associated with any response to treatment at 1 year, in line with the fact that about 60% of the patients with CR received VKA or heparins. Similarly, when limiting the analysis to patients with aPL, we observed a rate of any response (either CR+PR) as high as 66% in patients receiving anti-coagulant treatment when compared to those receiving immunosuppression alone (34%).
Despite its limitations (the relatively short duration of follow-up to gauge the relapse rate; lack of standardized protocol for LN treatment; the use of anticoagulation agents was not randomized but based on the treating physicians’ judgment), this study represents the largest available multicentre cohort of real-life SLE patients with biopsy proven LN and concomitant TMA.
To conclude, in patients with concomitant LN and TMA, the use of anticoagulation appeared protective and warrants further investigation as a therapeutic tool; the presence of aPL, anti-dsDNA antibodies and chronic features of TMA were associated with poorer kidney outcomes.
Supplementary Material
Footnotes
The authors declare no conflict of interest and declare: no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work.
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