Interleukin 1, interleukin 6, interleukin 10, and tumor necrosis factor α in active and quiescent systemic lupus erythematosus.

OBJECTIVES: Several studies have investigated the cytokine profile of patients with systemic lupus erythematosus (SLE); however, their role is still controversial, mostly because SLE has a heterogeneous disease manifestation. We measured 4 of the most important cytokines in patients with SLE after dividing them in uniform groups according to disease activity and organ involvement. MATERIALS AND METHODS: Eighty-two adult female patients with SLE were divided into 3 groups according to disease activity and organ involvement: Group A (SLE activity index [SLEDAI] score, 7 ± 0.4) included subjects with newly diagnosed, active SLE, investigated before starting therapy. Group B (SLEDAI score, < 6) included patients without renal involvement, treated with prednisone and azathioprine or hydroxychloroquine. Group C (SLEDAI score, < 6) included patients with lupus nephritis, treated with methylprednisolone and cyclophosphamide, reaching complete remission. Fourteen healthy females served as controls. RESULTS: Interleukin-1 levels were 1.0, 0.8, 0.7, and 0.25 pg/mL in groups A, B, C, and D, respectively. Interleukin-6 levels were 3.2, 3.6, 4.0, and 1.4 pg/mL in groups A, B, C, and D, respectively; Il-10 levels, 3.05, 1.1, 1.5, and 1.65; tumor necrosis factor-α levels, 8.75, 5.8, 5.4, and 3.6. Interleukin 1, IL-6, and tumor necrosis factor-α were significantly higher in the patients with SLE than in the healthy controls; IL-1 was significantly higher in group A than in group C. Interleukin 10 showed positive correlation with C-reactive protein, whereas it showed negative correlation with C3. CONCLUSIONS: Data from our cohort, one of the largest so far reported, add to the evidence that proinflammatory cytokines such as Interleukin-1, Interleukin-6, Interleukin-10 and tumor necrosis factor-α are important in SLE pathogenesis.

Antiphospholipid syndrome nephropathy (APSN) in patients with lupus nephritis: a retrospective clinical and renal pathology study.

Data about clinical-laboratory features and outcome of antiphospholipid syndrome nephropathy (APSN) in the course of lupus nephritis (LN) are scarce. To determine prevalence, clinical correlations and outcome of APSN in patients with LN, retrospective analysis of renal specimens and review of medical records from 48 LN patients were performed. APSN was found in 12/48 (25 %) of LN. Positivity for lupus anticoagulant (LAC) and double antiphospholipids positivity [LAC plus anticardiolipin (aCL)] were significantly more frequent in APSN-LN (p = 0.02 and p = 0.01, respectively) than in LN, while single aCL positivity was not. Overt antiphospholipid syndrome appeared more frequent in patients with APSN-LN (p = 0.05). There were no statistically significant differences between APSN-LN and LN in the proportion of each World Health Organization class of LN (with the exception of a trend toward fewer Class III LN in APS-LN) and in the systemic lupus erythematosus (SLE) disease duration and severity. At the time of renal biopsy, patients with APSN-LN had median serum creatinine levels significantly higher than patients with LN [1.45 (0.6-6.6) vs. 1.00 (0.7-3.0), p = 0.02]. Double antiphospholipid positivity was the only variable significantly associated with APSN-LN at multivariate regression analysis (OR 8, 95 % CI 1.7-37, p = 0,008). APSN-LN and LN did not differ significantly as regards the rate of complete (25 vs. 19.4 %, p = 0.72) and partial treatment response (25 vs. 29 %, p = 0.82) at 6 months and the progression to end-stage renal disease after a median follow-up of 8.1 ± 3.6 years (16.6 vs. 13.8 %, p = 0.82). APSN was demonstrated in a quart of LN, appeared to be independent from underlying LN class and SLE severity, and did not seem to confer a worse prognosis to LN. The findings of higher creatinine and more interstitial fibrosis in APSN should be confirmed in future prospective larger studies.

LDL S-homocysteinylation decrease in chronic kidney disease patients undergone lipid lowering therapy.

The dyslipidemia control through lipid lowering therapy is one of the targets for the treatment of CKD. By this pilot study we aimed to evaluate the effect of hypolipidemic drugs on the levels of low molecular weight (LMW) thiols bound to LDL in nephropatic patients. We enrolled thirty CKD randomized to receive three different hypolipidemic regimens: simvastatin alone (40 mg/day) or ezetimibe/simvastatin combined therapy (10/20 or 10/40 mg/day). LMW thiols in their reduced and total form, oxidative stress indices as malondialdehyde and allantoin/uric acid ratio were evaluated. LDL thiolation decreased in all treated patients, but a greater efficacy was attained from a combined therapy with a higher simvastatin dose, by which a 31% decrease of all S-bound thiols was reached after 1 year of therapy. In particular, in this patients group the reduction of apoB-Hcy was greater than 40%. The concomitant decrease of the oxidative stress indices during the therapy brings to the hypothesis that decreased levels of protein bound thiols may be a consequence of oxidative stress improvement. Therefore lipid lowering therapy may have beneficial effects also through the reduction of LDL-S-homocysteinylation that has been reported to have antiangiogenic and proatherogenic effect on endothelial vascular cells.

Oxidative stress improvement is associated with increased levels of taurine in CKD patients undergoing lipid-lowering therapy.

Lipid-lowering therapy has been reported to reduce several oxidative stress (OS) markers in hypercholesterolemia. Since OS is frequently associated with renal dysfunction, we aimed to investigate the effect of hypolipidemic drugs on oxidative stress and plasma taurine (Tau), a sulfur amino acid with a marked antioxidant effect, in chronic kidney disease (CKD). We enrolled 30 CKD randomized to receive three different hypolipidemic regimens for 12 months: simvastatin alone (40 mg/day) or ezetimibe/simvastatin combined therapy (10/20 or 10/40 mg/day). Low molecular weight (LMW) thiols including homocysteine, cysteine, cysteinylglycine, glutathione, and glutamylcysteine in their reduced and total form and oxidative stress indices as malondialdehyde (MDA) and allantoin/uric acid (All/UA) ratio were also evaluated. Tau concentration significantly increased throughout the therapy. The rise of taurine was more striking for the group with the concomitant administration of ezetimibe/simvastatin 10/40 mg/day (+31.6% after 1 year of therapy). A significant decrease of both MDA and All/UA ratio was observed during therapy for all patients (-19% for both MDA and All/UA ratio) with a more pronounced effect in patients treated with ezetimibe/simvastatin 10/40 mg/day (-26% for MDA and -28% for All/UA ratio). Besides, an increase of thiols reduced forms was found (+20.7% of LMW thiols redox status) with a greater effect in subjects treated with ezetimibe/simvastatin 10/40 mg/day (+24.7%). Moreover, we demonstrated that oxidative stress improvement during therapy was correlated with increased taurine levels. We hypothesize that taurine may be responsible for the oxidative stress improvement observed during lipid-lowering treatment through the reduction of superoxide anion production at the respiratory chain activity level.

Increased low-density lipoprotein S-homocysteinylation in chronic kidney disease.

BACKGROUND: Since low-density lipoprotein (LDL) S-homocysteinylation has been recently reported to enhance atherogenicity of lipoprotein, we have investigated the levels of homocysteine (Hcy) linked to LDL in chronic proteinuric patients in which lipid abnormalities highly contribute to the excess of morbidity and mortality. METHODS: We used capillary electrophoresis to measure LDL-bound thiol Hcy, cysteine (Cys), cysteinylglycine (Cys-Gly), glutathione (GSH), and glutamylcysteine (Glu-Cys) in 30 chronic kidney disease (CKD) individuals and 60 healthy volunteers. RESULTS: We found more elevated levels of total plasma Hcy, Cys, GSH and Glu-Cys in patients than in controls and also found that Hcy and Cys bound to LDL were significantly increased in nephropathic subjects. By multiple linear regression, we found that in healthy people, total Hcy was the most important determinant of LDL-bound Hcy and Cys-Gly was negatively associated with apoB-Hcy concentrations. In CKD the most important determinant of homocysteinylation was creatinine while total plasma Hcy is weakly associated with apoB-Hcy. CONCLUSIONS: The increased levels in Hcy-LDL observed in CKD patients might account, at least in part, for the excess of cardiovascular risk; thus LDL S-homocysteinylation can be considered a key marker of risk for cardiovascular disease in these individuals.

Hormonal strategies for fertility preservation in patients receiving cyclophosphamide to treat glomerulonephritis: a nonrandomized trial and review of the literature.

BACKGROUND: Prepubertal patients receiving chemotherapy are relatively resistant to cyclophosphamide-induced germinal cell alterations. We studied the possible protective effect of testosterone and triptorelin to inhibit gonadal activity in men and women receiving cyclophosphamide, respectively. STUDY DESIGN: Nonrandomized trial. SETTING & PARTICIPANTS: 28 consecutive patients, 11 men and 17 women, from a university medical center with various forms of glomerulonephritis, treated with cyclophosphamide. INTERVENTION: Men received cyclophosphamide plus testosterone; women were divided into 2 groups: 13 patients (group A) received cyclophosphamide plus triptorelin; 4 (group B) received only cyclophosphamide. OUTCOMES & MEASUREMENTS: Serum follicle-stimulating hormone (FSH) and serum luteinizing hormone levels and, in addition, sperm counts and testosterone levels in men and estradiol levels in women were measured before and after treatment with cyclophosphamide. RESULTS: All 10 men became azoospermic or severely oligospermic during treatment; after 12 months, all except 1 had a normal sperm count and FSH levels were normal. In women during cyclophosphamide therapy, amenorrhea occurred in all patients. After cessation of therapy, all women in group A started to menstruate regularly, and at the end of follow-up, ovulatory cycles were demonstrated in all women. Hormone levels showed no significant changes throughout the observation period. Six women conceived, and the pregnancies were brought to term successfully without complications. In group B, all 4 women developed sustained amenorrhea; serum FSH and luteinizing hormone levels at the end of therapy and follow-up were significantly higher with respect to baseline; estradiol levels at the end of follow-up were significantly lower compared with baseline and corresponding values in group A. LIMITATIONS: The substudy in men is uncontrolled, the substudy in women is nonrandomized. CONCLUSIONS: The study suggests a protective effect of testosterone and triptorelin against cyclophosphamide-induced gonadal damage in men and women with various forms of kidney disease, respectively.