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Lupus nephritis (LN) is a serious complication of systemic lupus erythematosus (SLE) that occurs in about half of patients. LN is characterized by glomerular deposition of immune complexes, leading to subendothelial, mesangial and subepithelial electron dense deposits, triggering immune cell infiltration and glomerular as well as tubulointerstitial injury. Monocytes and macrophages are abundantly present in inflammatory lesions, both in glomeruli and the tubulointerstitium. Here we discuss how monocytes and macrophages are involved in this process and how monocytes and macrophages may represent specific therapeutic targets to control LN., Competing Interests: Declaration of Competing Interest LV received institutional grants from Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Ionis Pharmaceuticals, NovoNordisk, Sanofi Genzyme and Vifor Pharma Group and is co-chair of European Society of Hypertension’s working group hypertension and the kidney. MTAT received grants from Astrazeneca and GlaxoSmithKline. RvV received grants from BMS, GSK, UCB, MSD, Pfizer, Roche, consulting fees from AbbVie, AstraZeneca, Biogen, BMS, Galapagos, Janssen, Miltenyi, Pfizer, UCB, and honoraria for presentations from AbbVie, Galapagos, GSK, Janssen, Pfizer, R-Pharma, UCB. HJA received an institutional grant from Deutsche Forschungsgemeinschaft (AN372/30-1) and participates in the Lupus Nephritis Trials Network and ERA Immunonephrology Working Group. All other authors declare no conflicts of interest. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: M.L. Hilhorst reports financial support was provided by Dutch Kidney Foundation. L.E. Kwant reports financial support was provided by Dutch Kidney foundation. L. Vogt reports a relationship with Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Ionis Pharmaceuticals, NovoNordisk, Sanofi Genzyme and Vifor Pharma Group that includes: speaking and lecture fees. L. Vogt reports a relationship with European society of Hypertension that includes: board membership. M.W.P. Tsang-a-Sjoe reports a relationship with AstraZeneca, GlaxoSmithKline that includes: speaking and lecture fees. R.F. van Vollenhoven reports a relationship with BMS, GSK, UCB, MSD, Pfizer, Roche that includes: funding grants. R.F. van Vollenhoven reports a relationship with AbbVie, AstraZeneca, Biogen, BMS, Galapagos, Janssen, Miltenyi, Pfizer, UCB that includes: consulting or advisory. R.F. van Vollenhoven reports a relationship with AbbVie, Galapagos, GSK, Janssen, Pfizer, R-Pharma, UCB that includes: speaking and lecture fees. H.J. Anders reports a relationship with Deutsche Forschungsgemeinschaft that includes: funding grants. H.J. Anders reports a relationship with Lupus Nephritis Trials Network and ERA Immunonephrology Working Group that includes: board membership., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Hypertension and proteinuria are important mediators of renal damage. Despite therapeutic interventions, the number of patients with end stage renal disease steadily increases. Hydrogen sulfide (H(2)S) is an endogenously produced gasotransmitter with vasodilatory, anti-inflammatory and antioxidant properties. These beneficial characteristics make H(2)S an attractive candidate for pharmacological use in hypertensive renal disease. We investigated the protective properties of H(2)S in angiotensin II (Ang II)-induced hypertensive renal disease in rats. Treatment with the H(2)S donor NaHS and major H(2)S metabolite sodium thiosulfate (STS) during three weeks of Ang II infusion reduced hypertension, proteinuria, oxidative stress and renal functional and structural deterioration. In an ex vivo isolated perfused kidney setup, NaHS, but not STS, reduced intrarenal pressure. The effect of NaHS could partially be explained by its activation of the ATP-sensitive potassium channels. In conclusion, treatment with H(2)S attenuates Ang II-associated functional and structural renal deterioration, suggesting that intervention in H(2)S production pathways has potential therapeutic benefit and might be a valuable addition to the already existing antihypertensive and renoprotective therapies., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: The cholesterol esterifying enzyme, lecithin:cholesterol acyltransferase (LCAT), plays a key role in HDL maturation and remodeling. Myeloperoxidase (MPO) may compromise LCAT enzymatic activity. We tested the extent to which plasma LCAT activity is altered in acute myocardial infarction (MI) in conjunction with abnormal MPO levels. We also assessed the impact of LCAT and MPO on newly developed major adverse cardiovascular events (MACE)., Methods: Two-hundred one consecutive patients referred for acute chest pain of whom 134 had MI (95 with ST-elevation) participated. Forty-five new MACE were ascertained during 1203 (range 13-1745) days of follow-up among 185 patients. Plasma LCAT activity was measured using an exogenous substrate assay. MPO mass was assayed by chemiluminescent microparticle immunoassay., Results: Plasma LCAT activity was decreased by 15%, coinciding with 7-fold increased MPO levels in acute MI patients vs. patients with non-cardiac chest pain (p < 0.001 for both; correlation: r = -0.343, p < 0.001). MI at admission was associated independently with both lower plasma LCAT activity and higher MPO (age- and sex-adjusted odds ratio per 1 SD increment: 0.46 (95% CI, 0.31-0.68), p < 0.001 and 7.58 (95% CI, 3.34-17.11), p < 0.001, respectively). In an analysis with LCAT and MPO together these associations were modestly attenuated. MPO mass (hazard ratio: 1.59 (95% CI, 1.15-2.19), p = 0.004), but not LCAT activity (hazard ratio: 0.87 (95% CI, 0.65-1.19), p = 0.39), predicted newly manifest MACE., Conclusion: In acute MI patients, plasma LCAT activity is decreased coinciding with increased MPO levels. Higher MPO but not lower LCAT activity prospectively predicts adverse cardiac outcome., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) mass predicts future cardiovascular events in the non-acute setting. We tested the extent to which Lp-PLA2 is elevated in patients with acute coronary syndrome., Methods: A total of 231 consecutive patients referred for acute chest pain participated. Of this number, 144 were diagnosed with myocardial infarction (MI; 100 were classified as MI with ST-elevation (STEMI) and 44 as MI without ST-elevation (non-STEMI)). Eighty-seven patients had non-cardiac chest pain. Plasma Lp-PLA2 mass was measured using turbidimetric immunoassay., Results: Lp-PLA2 mass was not different between MI patients and patients with non-cardiac chest pain (231±72 μg/l vs.243±88 μg/l, p=0.29), and did not relate to MI in age- and sex-adjusted logistic regression analysis (odds ratio per SD increment, 0.92 (95% CI, 0.69-1.23), p=0.58). However, Lp-PLA2 mass was elevated in STEMI compared to non-STEMI patients (246±73 vs. 198±58 ng/ml, p<0.001), and independently predicted STEMI (odds ratio, 2.35 (95% CI, 1.46-3.79), p<0.001). Among MI patients maximal creatine kinase was correlated positively with Lp-PLA2 (r=0.183, p=0.034)., Conclusions: In the acute setting, plasma Lp-PLA2 mass is not elevated in MI patients, although Lp-PLA2 mass appears to relate to the severity of myocardial damage., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: High density lipoproteins (HDL) contain paraoxonase-1 (PON-1), which has strong anti-oxidative properties. Apolipoprotein E (apoE) may enhance PON-1 activity in vitro, but the extent to which PON-1 activity is determined by circulating apoE levels is unknown. Here we determined relationships of serum PON-1 activity with apoE in subjects without and with metabolic syndrome (MetS)., Methods: We measured PON-1 activity (arylesterase activity), plasma apoE and serum amyloid A (SAA) in 93 subjects without and in 75 subjects with MetS (25 and 54 subjects with Type 2 diabetes mellitus (T2DM), respectively; p < 0.001)., Results: PON-1 activity was lower in MetS (p < 0.005) coinciding lower HDL cholesterol, apoA-I (p < 0.001)) and SAA levels (p < 0.01), whereas apoE was increased in relation to higher triglycerides (p < 0.01). In subjects without MetS, PON-1 activity was correlated positively with apoE (r = 0.376, p < 0.001), but this relationship was absent in MetS subjects (r = 0.085, p = 0.47). Multiple linear regression analysis showed that the relationship of PON-1 activity with apoE was different in subjects with MetS compared to subjects without MetS (β = -0.270, p = 0.014 for the interaction between apoE and MetS), independently from age, sex, T2DM, use of glucose lowering drugs, anti-hypertensives and the inverse relation with SAA levels (p = 0.008). Of the individual MetS components, apoE only interacted with low HDL-C on PON-1 activity (β = -0.175, p = 0.074). The relationship of apoE with PON-1 activity was neither modified by T2DM (p = 0.49), nor by SAA (p = 0.79)., Conclusion: Higher apoE levels may confer higher PON-1 activity. The relationship of PON-I activity with total plasma apoE is apparently abrogated in MetS., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Plasma cholesteryl ester transfer (CET), reflecting endogenous transfer of cholesteryl esters from HDL to very low and low density lipoproteins, is elevated in Type 2 diabetes mellitus (T2DM), and may predict (subclinical) cardiovascular disease. Low normal thyroid function may adversely affect lipoprotein metabolism and atherosclerosis development. We tested whether plasma CET is related to thyroid function in euthyroid T2DM and non-diabetic subjects., Subjects and Methods: Plasma CET was measured in 74 T2DM and 82 non-diabetic subjects with thyroid-stimulating hormone (TSH) and free thyroxine levels within the reference range., Results: Plasma CET was 20% higher in T2DM (P = 0.003) coinciding higher cholesteryl ester transfer protein (CETP) mass (P = 0.009) and triglycerides (P = 0.02). In univariate analysis, plasma CET was correlated positively with TSH in T2DM only (r = 0.330, P = 0.004). Multiple linear regression analysis revealed a positive interaction between the presence of T2DM and TSH on plasma CET after controlling for age, sex, body mass index, non-HDL cholesterol, triglycerides and CETP mass (β = 0.167, P = 0.030). The relationship of plasma CET with TSH was also positively modified by plasma glucose and HbA1c (interaction terms: β = 0.119, P = 0.036, β = 0.170, P = 0.001, respectively). Additionally, plasma triglycerides interacted positively with TSH on plasma CET in T2DM (β = 0.198, P = 0.011)., Conclusions: Low normal thyroid function, as inferred from higher TSH, confers increased plasma CET in the context of chronic hyperglycemia. Effects of thyroid function on plasma CET may be particularly relevant in hypertriglyceridemic T2DM. Low normal thyroid function could influence atherosclerosis susceptibility in T2DM by affecting the plasma cholesteryl ester transfer process., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Objective: LDL-receptor deficiency may provide a mechanism which contributes to atherogenic lipoprotein abnormalities in experimental nephrosis and in humans with glomerular proteinuria. The proprotein convertase subtilisin-kexin type 9 (PCSK9) pathway plays a key role in lipoprotein metabolism by promoting LDL-receptor degradation. We tested whether plasma PCSK9 is elevated in proteinuric states, and determined relationships of PCSK9 with lipoprotein responses to proteinuria reduction., Methods: Thirty-nine kidney patients (e-GFR 61 ± 29 mL/min/1.73 m(2), proteinuria 1.9 [0.9-3.3] g/day; 19 on statin treatment) were studied during 2 randomized double-blind 6-week periods on either lisinopril (40 mg/day) and a regular sodium diet (194 ± 49 mmol Na+/day; baseline treatment) or lisinopril plus valsartan (320 mg/day) and a low sodium diet (102 ± 52 mmol Na(+)/day; maximal treatment), and compared to age- and sex-matched controls. Maximal treatment decreased proteinuria to 0.5 [0.3-1.1] g/day (P < 0.001)., Results: Plasma PCSK9 was increased at baseline in proteinuric subjects (213 [161-314] vs. 143 [113-190] ug/L in controls, P ≤ 0.001), irrespective of statin use, e-GFR and BMI. PCSK9 correlated with proteinuria at baseline (R = 0.399, P = 0.018) and at maximal antiproteinuric treatment (R = 0.525, P = 0.001), but did not decrease during proteinuria reduction (P = 0.84). Individual changes in total cholesterol (R = 0.365, P = 0.024), non-HDL cholesterol (R = 0.333, P = 0.041), and LDL cholesterol (R = 0.346, P = 0.033) were correlated positively with individual PCSK9 responses. PCSK9 at baseline independently predicted the total/HDL cholesterol ratio response to treatment (P = 0.04)., Conclusion: Plasma PCSK9 was elevated in proteinuria, predicted lipoprotein responses to proteinuria reduction but remained unchanged after proteinuria reduction. Inhibition of the PCSK9 pathway may provide a novel treatment strategy in proteinuric subjects., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)