Cyclophosphamide treatment for hypertension and renal injury in an experimental model of systemic lupus erythematosus

Abstract

Cardiovascular disease is the major cause of mortality among patients with the autoimmune disorder systemic lupus erythematosus (SLE). Our laboratory previously reported that immunosuppression with mycophenolate mofetil, a common therapy in patients with SLE, attenuates the development of hypertension in an experimental model of SLE. Cyclophosphamide (CYC) is another common therapy for patients with SLE that has contributed to improved disease management; however, its impact on the development of hypertension associated with SLE is not clear. We tested whether treatment with CYC (25 mg/kg, once/week, IP injection) for 4 weeks would attenuate hypertension in an established female mouse model of SLE with hypertension (30‐week‐old NZBWF1 females). Plasma anti‐dsDNA IgG levels, pathogenic for the disease, were lower in CYC‐treated SLE mice compared to vehicle‐treated SLE mice, suggesting efficacy of the therapy to suppress aberrant immune system function. Mean arterial pressure (MAP) was assessed by carotid artery catheters in conscious mice. Treatment did not attenuate the development of hypertension when compared to vehicle‐treated SLE mice; however, urinary albumin excretion was lower in CYC‐treated animals. Corresponding with the reduction in autoantibodies, data suggest that CYC treatment lowered circulating CD45R + B cells. Paradoxically, circulating CD11b + Ly6G + neutrophils were increased in CYC‐treated SLE mice compared to vehicle treated. Estrus cycling data also suggest that CYC treatment had an impact on ovarian function that may be consistent with reduced circulating estrogen levels. Taken together, these data suggest that CYC treatment attenuates autoantibody production and renal disease during SLE, but that the potential to affect MAP may be blunted by the increase in circulating neutrophils and CYC's impact on ovarian function.

Hypertensive Cardiotoxicity in Cancer Treatment—Systematic Analysis of Adjunct, Conventional Chemotherapy, and Novel Therapies—Epidemiology, Incidence, and Pathophysiology

“…Symptomatic LVD cardiotoxicity has been reported in up to 25% of patients treated with doses greater than 1.55 g/m 2 /day, compared to less than 3% of patients at lower doses [ 82 ]. Cyclophosphamide is not implicated in direct hypertensive cardiotoxicity [ 68 ], and in fact may have anti-hypertensive benefit in systemic lupus erthryromatosis [ 83 ]. However, as a corollary, ifosfamide nephrotoxicity may explain why adults, and in particular, 10% of children from small long term follow up studies develop hypertension with its use [ 84 ].…”

The STING inhibitor (ISD-017) reduces glomerulonephritis in 129.B6.Fcgr2b-deficient mice

“…Fcgr2b -deficient mice, both male and female mice, were followed up to the age of 6 months and screened for anti-dsDNA to confirm the development of the lupus phenotype before randomly enrolling into three groups. The three treatments were cyclophosphamide (CYC) (25 mg/kg, intraperitoneal, once per week) 36 , ISD-017 (10 mg/kg, intraperitoneal, three times per week) 34 , or control vehicle (PBS), and the treatment period lasted for 8 weeks. We assessed the anti-double-stranded DNA (anti-dsDNA) in all groups of mice before initiating treatment and after treatment for 8 weeks.…”

Low estimated glomerular filtration rate and high body mass index are risk factors for acute kidney injury in systemic lupus erythematosus patients after cardiac surgery

“…Systemic lupus erythematosus (SLE) is an autoimmune disease that has deleterious effects on multiple systems, mainly the heart, kidneys, lungs and nervous system ( 1 ). As therapeutic approaches evolve, overall mortality secondary to SLE complications has promisingly decreased, but mortality hazard from cardiovascular burden has remained steady in SLE patients ( 2 ). Patients with long-term SLE owned a three- to fourfold increased hazard of cardiovascular events and cardiovascular-related mortality in comparison with those without SLE, despite no disparity in the distribution of traditional cardiovascular risk factors ( 3 ).…”