The presence of lupus nephritis additionally increases the risk of preeclampsia among pregnant women with systemic lupus erythematosus

Introduction Pregnant women with systematic lupus erythematosus (SLE) have an increased risk of obstetric complications, such as preeclampsia and premature births. Previous studies have suggested that renal involvement could further increase the risk for adverse obstetric outcomes. Aims: The aim of this study was to compare the obstetric outcomes in a Swedish cohort of patients with SLE with and without lupus nephritis (LN). Patients and methods The study was conducted as a retrospective observational study on 103 women with SLE, who gave birth at the Karolinska University Hospital between the years 2000-2017. Thirty-five women had previous or active LN and 68 women had non-renal lupus. Data was collected from digital medical records. The outcomes that were analysed included infants born small for gestational age (SGA), premature birth, preeclampsia, SLE- or nephritis flare and caesarean section. Results Women with LN, both with previous and with renal flare during pregnancy suffered from pre-eclampsia more often compared to women with non-renal lupus (25.7% vs 2.9%, p = 0.001) and this complication was associated with premature birth (p = 0.021) and caesarean section (p = 0.035). Conclusions Lupus nephritis is a significant risk factor for adverse obstetric outcomes in women with SLE, including preeclampsia. Those patients could benefit from more frequent antenatal controls and more vigorous follow-up.

Clinico-pathological associations of serum VCAM-1 and ICAM-1 levels in patients with lupus nephritis

Objective We investigated the clinico-pathological associations of serum VCAM-1 and ICAM-1 levels in patients with biopsy-proven Class III/IV±V lupus nephritis (LN). Methods Serum VCAM-1 and ICAM-1 levels were determined by ELISAs. Sera from patients with non-renal SLE or non-lupus chronic kidney disease (CKD), and healthy subjects served as controls. Results Seropositivity rate for VCAM-1 and ICAM-1 was 93.10% and 37.93% respectively at the time of nephritic flare, and 44.83% and 13.79% respectively at remission, with both showing higher levels during flare ( P < 0.05, for both). VCAM-1 level correlated with proteinuria, serum creatinine, and anti-dsDNA antibodies, and inversely correlated with C3. VCAM-1 level also correlated with leukocyte infiltration and fibrinoid necrosis/karyorrhexis scores in active LN kidney biopsies. ICAM-1 level correlated with proteinuria, but not anti-dsDNA or C3, nor histopathological features. VCAM-1 level increased 4.5 months before renal flare, while ICAM-1 increase coincided with flare, and both decreased after treatment. ROC analysis showed that VCAM-1 distinguished active LN from healthy subjects, LN in remission, active non-renal lupus, and CKD (ROC AUC of 0.98, 0.86, 0.93 and 0.90 respectively). VCAM-1 level in combination with either proteinuria or C3 was superior in distinguishing active LN from remission compared to the measurement of individual markers. Serum ICAM-1 level distinguished active LN from healthy subjects and LN patients in remission (ROC AUC of 0.75 and 0.66 respectively), but did not distinguish between renal versus non-renal lupus. ICAM-1 level in combination with markers of endothelial cell activation (syndecan-1, hyaluronan and thrombomodulin) was superior to proteinuria, anti-dsDNA, or C3 in distinguishing active LN from quiescent disease. Conclusion Our findings suggest potential utility of serum VCAM-1 and ICAM-1 in clinical management. Monitoring VCAM-1 may facilitate early diagnosis of flare. Combining selected biomarkers may be advantageous in diagnosing active LN. VCAM-1 may have a pathogenic role in renal parenchymal inflammation in active LN.

Serum syndecan-1, hyaluronan and thrombomodulin levels in patients with lupus nephritis

Objectives We investigated circulating syndecan-1, HA and thrombomodulin levels in patients with biopsy-proven Class III/IV ± V LN and their clinico-pathological associations. Patients with non-renal SLE or non-lupus chronic kidney disease, and healthy subjects served as controls. Methods Serum syndecan-1, HA and thrombomodulin levels were determined by ELISAs. Results Syndecan-1, HA and thrombomodulin levels were significantly higher during active LN compared with remission (P &lt; 0.01, for all), and correlated with the level of proteinuria, estimated glomerular filtration rate, anti-dsDNA antibodies, complement 3 and serum creatinine. Longitudinal studies showed that syndecan-1 and thrombomodulin levels increased prior to clinical renal flare by 3.6 months, while HA level increased at the time of nephritic flare, and the levels decreased in parallel with treatment response. Receiver operating characteristic curve analysis showed that syndecan-1 and thrombomodulin levels distinguished patients with active LN from healthy subjects, LN patients in remission, patients with active non-renal lupus and patients with non-lupus chronic kidney disease (receiver operating characteristic area under curve of 0.98, 0.91, 0.82 and 0.95, respectively, for syndecan-1; and area under curve of 1.00, 0.84, 0.97 and 0.79, respectively, for thrombomodulin). HA level distinguished active LN from healthy subjects, LN patients in remission and non-lupus chronic kidney disease (receiver operating characteristic area under curve of 0.82, 0.71 and 0.90, respectively) but did not distinguish between renal vs non-renal lupus. Syndecan-1 and thrombomodulin levels correlated with the severity of interstitial inflammation, while HA level correlated with chronicity grading in kidney biopsies of active LN. Conclusion Our findings suggest potential utility of serum syndecan-1, thrombomodulin and HA levels in clinical management, and their potential contribution to LN pathogenesis.

The patient with systemic lupus erythematosus

Major progress has been achieved in the field of lupus nephritis (LN) treatment over the last decade. Glucocorticoids and other immunosuppressants (including cyclophosphamide) are now used in a more patient-friendly way, minimizing their untoward effects. Mycophenolate mofetil is now an option, both for induction and maintenance immunosuppression. Ever increased standards for optimal global care have further contributed to lower end-stage renal disease rates.Better understanding of the mechanisms underlying lupus raises hopes for more targeted therapies with biologics. Thus, the anti-B-lymphocyte stimulator belimumab has been officially labelled for non-renal lupus by the medical agencies, which has not happened for more than 50 years, when cortisone and hydroxychloroquine were approved.These exciting developments should, however, not disguise the fact that LN still impacts survival of lupus patients and that no cure can be offered so far.

Anti-heparan sulfate antibody and functional loss of glomerular heparan sulfate proteoglycans in lupus nephritis

Background The purpose of this study was to evaluate the features of heparan sulfate proteoglycans (HSPGs) as agrins of the glomerular basement membrane (GBM) and circulating anti–heparan sulfate (HS) antibodies in lupus nephritis, comparing titers among the following groups: lupus nephritis (LN), non-renal lupus, non-lupus nephritis, and healthy controls. Methods The stage of nephritis was determined based on the kidney biopsy. Alcian blue staining and immunohistochemical (IHC) staining for agrin were performed for histological evaluation of GBM HSPGs in normal glomeruli, non-lupus membranous glomerulonephritis (MGN), and lupus MGN. The results were used for measurement of the serum anti-HS antibody titers using an enzyme-linked immunosorbent assay (ELISA) in the following groups: 38 healthy controls, 38 non-lupus nephritis, 37 non-renal lupus, and 38 LN. Results Glomerulus HSPGs were stained bluish-green along the GBM with Alcian blue. However, IHC staining against agrin was almost completely negative in the lupus MGN group compared with the normal and non-lupus MGN groups, which showed brown staining of GBM. A higher level of anti-HS IgG was detected in LN compared with other groups, respectively. Higher titers were associated with the presence of SLE and nephritis. A higher degree of proteinuria normalized to glomerular filtration rate (eGFR) was observed in association with higher anti-HS antibody titers in LN. Conclusion This study demonstrated a functional loss of GBM HSPGs and higher levels of circulating anti-HS antibodies as a characteristic feature of lupus nephritis, suggesting their involvement in the pathogenesis of lupus nephritis and proteinuria.