Karen Laliberte

Fibroblast Growth Factor 23 and Left Ventricular Hypertrophy in Chronic Kidney Disease

Background— Fibroblast growth factor 23 (FGF-23) is a phosphorus-regulating hormone. In chronic kidney disease (CKD), circulating FGF-23 levels are markedly elevated and independently associated with mortality. Left ventricular hypertrophy and coronary artery calcification are potent risk factors for mortality in CKD, and FGFs have been implicated in the pathogenesis of both myocardial hypertrophy and atherosclerosis. We conducted a cross-sectional study to test the hypothesis that elevated FGF-23 concentrations are associated with left ventricular hypertrophy and coronary artery calcification in patients with CKD. Methods and Results— In this study, 162 subjects with CKD underwent echocardiograms and computed tomography scans to assess left ventricular mass index and coronary artery calcification; echocardiograms also were obtained in 58 subjects without CKD. In multivariable-adjusted regression analyses in the overall sample, increased log FGF-23 concentrations were independently associated with increased left ventricular mass index (5% increase per 1-SD increase in log FGF-23; P=0.01) and risk of left ventricular hypertrophy (odds ratio per 1-SD increase in log FGF-23, 2.1; 95% confidence interval, 1.03 to 4.2). These associations strengthened in analyses restricted to the CKD subjects (11% increase in left ventricular mass index per 1-SD increase in log FGF-23; P=0.01; odds ratio of left ventricular hypertrophy per 1-SD increase in log FGF-23, 2.3; 95% confidence interval, 1.2 to 4.2). Although the highest tertile of FGF-23 was associated with a 2.4-fold increased risk of coronary artery calcification ≥100 versus <100 U compared with the lowest tertile (95% confidence interval, 1.1 to 5.5), the association was no longer significant after multivariable adjustment. Conclusions— FGF-23 is independently associated with left ventricular mass index and left ventricular hypertrophy in patients with CKD. Whether increased FGF-23 is a marker or a potential mechanism of myocardial hypertrophy in CKD requires further study.

Contaminated Cocaine and Antineutrophil Cytoplasmic Antibody-Associated Disease

BACKGROUND AND OBJECTIVES Approximately 70% of illicit cocaine consumed in the United States is contaminated with levamisole. Most commonly used as a veterinary antihelminthic agent, levamisole is a known immunomodulating agent. Prolonged use in humans has been associated with cutaneous vasculitis and agranulocytosis. We describe the development of a systemic autoimmune disease associated with antineutrophil cytoplasmic antibodies (ANCA) in cocaine users. This complication appears to be linked to combined cocaine and levamisole exposure. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Cases were identified between March 2009 and November 2010 at Massachusetts General Hospitals ANCA laboratory. Cocaine exposure was identified from patient history in all cases. Medical records were reviewed for clinical presentation and for laboratory and diagnostic evaluation. RESULTS Thirty cases of ANCA positivity associated with cocaine ingestion were identified. All had antimyeloperoxidase antibodies and 50% also had antiproteinase 3 antibodies. Complete clinical and laboratory data were available for 18 patients. Arthralgia (83%) and skin lesions (61%) were the most frequent complaints at presentation. Seventy-two percent of patients reported constitutional symptoms, including fever, night sweats, weight loss, or malaise. Four patients had biopsy-proven vasculitis. Two cases of acute kidney injury and three cases of pulmonary hemorrhage occurred. From the entire cohort of 30, two cases were identified during the first 3 months of our study period and nine cases presented during the last 3 months. CONCLUSIONS We describe an association between the ingestion of levamisole-contaminated cocaine and ANCA-associated systemic autoimmune disease. Our data suggest that this is a potentially life-threatening complication of cocaine use.

Long-Term Maintenance Therapy Using Rituximab-Induced Continuous B-Cell Depletion in Patients with ANCA Vasculitis

BACKGROUND AND OBJECTIVES Remission in the majority of ANCA vasculitis patients is not sustained after a single course of rituximab, and risk of relapse warrants development of a successful strategy to ensure durable remission. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A retrospective analysis of ANCA vasculitis patients who underwent maintenance therapy using rituximab-induced continuous B-cell depletion for up to 7 years was performed. Maintenance therapy with rituximab was initiated after achieving remission or converting from other prior maintenance therapy. Continuous B-cell depletion was achieved in all patients by scheduled rituximab administration every 4 months. Disease activity, serologic parameters, adverse events, and survival were examined. RESULTS In the study, 172 patients (mean age=60 years, 55% women, 57% myeloperoxidase-ANCA) treated from April of 2006 to March of 2013 underwent continuous B-cell depletion with rituximab. Median remission maintenance follow-up time was 2.1 years. Complete remission (Birmingham Vasculitis Activity Score [BVAS] = 0) was achieved in all patients. Major relapse (BVAS ≥ 3) occurred in 5% of patients and was associated with weaning of other immunosuppression drugs. Remission was reinduced in all patients. Survival mirrored survival of a general age-, sex-, and ethnicity-matched United States population. CONCLUSION This analysis provides evidence for long-term disease control using continuous B-cell depletion. This treatment strategy in ANCA vasculitis patients also seems to result in survival rates comparable with rates in a matched reference population. These findings suggest that prospective remission maintenance treatment trials using continuous B-cell depletion are warranted.

Fibroblast Growth Factor 23, High-Sensitivity Cardiac Troponin, and Left Ventricular Hypertrophy in CKD

BACKGROUND Detectable levels of cardiac troponins are common in individuals with chronic kidney disease (CKD), even in the absence of symptomatic cardiovascular disease. Abnormal cardiac troponin values are associated with coronary artery disease and left ventricular hypertrophy (LVH) and predict poor clinical outcomes. Elevated levels of fibroblast growth factor 23 (FGF-23) contribute to LVH in CKD. We investigated the association of FGF-23 and hs-cTnI (high-sensitivity cardiac troponin I) and hs-cTnT (high-sensitivity cardiac troponin T) levels in CKD and examined the role of LVH in this association. STUDY DESIGN Cross-sectional observational study. SETTING & PARTICIPANTS 153 stable outpatients with non-dialysis-dependent CKD. PREDICTOR The primary predictor was FGF-23 level. OUTCOMES hs-cTnI, hs-cTnT. MEASUREMENTS FGF-23, hs-cTnI, hs-cTnT; left ventricular mass index (LVMI) assessed by echocardiography; coronary artery calcification (CAC) measured by computed tomography. LVMI and CAC were evaluated as potential mediators of the effect of FGF-23 on hs-cTnI/T. RESULTS Mean age was 64 ± 12 (SD) years, mean estimated glomerular filtration rate was 34 ± 11 mL/min/1.73 m(2), median FGF-23 level was 120 (25th-75th percentile, 79-223) reference unit (RU)/mL, median hs-cTnI level was 6.5 (25th-75th percentile, 3.5-14.5) pg/mL, and median hs-cTnT level was 16.8 (25th-75th percentile, 11.1-33.9) pg/mL. cTnI and cTnT concentrations were higher than the 99th percentile of a healthy population in 42% and 61% of patients, respectively. In unadjusted and multivariable-adjusted analyses, hs-cTnI/T levels were associated significantly with FGF-23 levels. Adjusting for LVMI, but not CAC, weakened the association of FGF-23 and hs-cTnI/T levels. LIMITATIONS Vitamin D levels were not measured. The prevalence of coronary artery disease may have been underestimated because it was ascertained by self-report. CONCLUSIONS Minimally elevated cTnI and cTnT levels, detectable by high-sensitivity assays, are associated with elevated FGF-23 levels in stable outpatients with CKD. FGF-23-associated LVH may contribute to detectable hs-cTnI/T levels observed in non-dialysis-dependent patients with CKD.

Fetal outcomes after rituximab exposure in women with autoimmune vasculitis

Rituximab is an approved B-lymphocyte depleting agent for induction of remission in patients with granulomatosis with polyangiitis and microscopic polyangiitis.1 ,2 Unlike cyclophosphamide, rituximab is not known to interfere with fertility and appears to be a safe and effective alternative. Pregnancy outcomes after maternal exposure to rituximab have been described,3 primarily in women with lymphoma, rheumatoid arthritis and lupus, but little is known about the impact of rituximab exposure on fetal outcomes, and more specifically, fetal B-lymphocyte populations among women with vasculitis. We performed a retrospective analysis of women with vasculitis who received rituximab in our centre and who achieved pregnancy, and their resultant offspring. While receiving rituximab, women were counselled extensively to avoid pregnancy. Urine levels of human chorionic gonadotropin were measured and negative before each dose. …

Choice of replacement solution and anticoagulant in continuous venovenous hemofiltration

BACKGROUND Several types of replacement fluid and methods of anticoagulation have been employed for continuous renal replacement therapy, but there is no consensus on a preferred approach. We evaluated the indications for the selection of replacement fluid and anticoagulant among critically ill patients receiving continuous venovenous hemofiltration (CVVH) and assessed the effect of the selection on the efficacy of anticoagulation and complications. METHODS We retrospectively studied 29 consecutive patients who received CVVH in the Medical Intensive Care Unit at Massachusetts General Hospital. There were 3 types of replacement solution available, an isotonic citrate solution which was also used for regional anticoagulation of the extracorporeal circuit, and bicarbonate and lactate solutions which were used with low-dose heparin or no anticoagulant. Blood flow rate was set at 120 ml/min when citrate replacement fluid was used and at 200 ml/min with bicarbonate or lactate. The replacement fluid was administered proximal to the hemofilter at a constant rate of 1,600 ml/h. RESULTS There were 22 patients who received citrate replacement fluid which was mainly chosen for the purpose of anticoagulation in the setting of contraindications to heparin. 12 patients received bicarbonate, predominantly when citrate was considered contraindicated due to liver failure or high-anion gap metabolic acidosis, and 2 received lactate; 8 of these 14 patients were anticoagulated with heparin and 6 were managed without anticoagulation. There were 44 filters used in the patients receiving citrate with a median filter life of 42.0 (interquartile range 22.2 - 70.7) hours. Only 8 of the 44 filters were lost due to clotting. Heparin was used for anticoagulation of 17 filters and no anticoagulation was used in the case of 15 filters, resulting in a median filter life of 43.0 (13.5 - 75.0) and 12.0 (4.0 - 33.0) hours, respectively. Clinically significant bleeding occurred in 2 patients, 1 receiving citrate and another receiving heparin. No patient had evidence for citrate toxicity, metabolic alkalosis or hypernatremia. 14 (48.3%) patients survived. CONCLUSIONS The use of regional citrate anticoagulation of the CVVH circuit appears advantageous in patients with increased risk of bleeding and bicarbonate-based replacement fluid seems desirable in patients with lactic acidosis due to shock and/or severe liver failure. Tailoring the type of replacement fluid and method of anticoagulation to the individual patient leads to long filter lives, excellent metabolic control and minimal complications.

Effect of Continuous B Cell Depletion With Rituximab on Pathogenic Autoantibodies and Total IgG Levels in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

To evaluate the effect of rituximab on pathogenic autoantibodies and total Ig levels, and to identify serious adverse events in patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) treated with continuous B cell depletion.

The effect of continuous B cell depletion with rituximab on pathogenic autoantibodies and total IgG levels in ANCA vasculitis

To evaluate the effect of rituximab on pathogenic autoantibodies and total Ig levels, and to identify serious adverse events in patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) treated with continuous B cell depletion.

Reducing glucocorticoid duration in ANCA-associated vasculitis: A pilot trial

OBJECTIVE Therapeutic advances in ANCA-associated vasculitis (AAV) have improved patient survival, but mortality rates remain higher than the general population. Glucocorticoids contribute to AAV morbidity and mortality. We examined whether an 8-week glucocorticoid course in combination with rituximab (RTX) would induce disease remission in patients with AAV. METHODS Patients with active AAV received an 8-week prednisone taper and RTX 375mg/m2 weekly for 4 weeks. Patients with severe glomerulonephritis or diffuse alveolar hemorrhage requiring mechanical ventilation were excluded. In-person and telephone visits were scheduled for disease activity assessment. The primary endpoint was complete remission at 24 weeks (no disease activity while being off prednisone with no intercedent relapses). Secondary analysis included comparing study outcomes to historical controls from the Rituximab in AAV (RAVE) trial. RESULTS Fourteen of 20 patients (70%) achieved the primary outcome. The patients in our trial achieved the primary outcome at a rate similar to that of controls from the RAVE trial (adjusted OR 1.31 [0.26-6.56]), had fewer median adverse events per patient (2 versus 8, p < 0.001) but were more likely to relapse (30% versus 7%, p = 0.03). Most relapses occurred in patients who had severe vasculitic manifestations at trial entry. Disease damage did not differ between the two trial populations. CONCLUSION An 8-week course of prednisone with RTX resulted in a similar rate of complete remission at 6 months as in the RAVE trial, with fewer adverse events but more frequent relapses. Further study of this protocol is warranted in selected patient populations.

Continuous B-cell depletion in frequently relapsing, steroid-dependent and steroid-resistant nephrotic syndrome

Abstract Background Patients with frequently relapsing (FR), steroid-dependent (SD) and steroid-resistant (SR) nephrotic syndrome are a therapeutic challenge with limited treatment options. Here, we retrospectively analyze the efficacy and safety of rituximab-induced continuous B-cell depletion in these populations. Methods Patients were included if they were at least 18 years of age and had FR, SD or SR minimal change disease (MCD) or primary focal segmental glomerulosclerosis (FSGS) and were treated with a strategy of continuous B-cell depletion. Partial remission (PR) was defined as a urinary protein:creatinine ratio (UPCR) of ≤3.5 g/g and a 50% reduction in the UPCR from baseline. Complete remission (CR) was defined as a UPCR ≤0.3 g/g. Results We identified 20 patients with MCD (n = 13) or FSGS (n = 7) who fulfilled the inclusion criteria. All patients had either SD (n = 12), SR (n = 7) or FR (n = 1) disease. Patients received a median of nine rituximab doses [interquartile range (IQR) 7.5, 11] and were treated for a median time of 28 months (IQR 23, 41). Prednisone was weaned from a median of 60 mg daily (IQR 40, 60) at rituximab initiation to 4.5 mg daily (IQR 0, 5.5) by 12 months. All patients achieved PR. CR occurred in 11 of 13 patients with FR or SD disease, but only 1 of 7 patients with SR disease (logrank P = 0.01). Four relapses occurred, all in patients with SR disease. Three serious infections occurred over 70.3 patient-years. Conclusion Continuous B-cell depletion is a therapeutic option in the management of complicated nephrotic syndrome. Additional studies are needed to clarify the utility of this strategy.