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Objectives Following intravascular hemolysis, free hemoglobin A is bound to haptoglobin (Hp), internalized by monocytes bearing the hemoglobin scavenger receptor, CD163, and broken down via the heme-oxygenase (HO)-1 enzyme into the cytoprotective metabolites biliverdin and carbon monoxide. This triggers an IL10 positive feedback loop which augments CD163 expression; thereby increasing hemoglobin scavenging capacity and limiting the vascular insult caused by oxidative free heme. During iatrogenic hemolysis caused by cardiopulmonary bypass, we have demonstrated that serum Hp is temporarily consumed while the surface CD163 and HO-1 expression is up-regulated. In homozygous sickle cell disease (HbSS), chronic hemolysis is linked with exhaustion of serum Hp and suppression of CD163 compared to HbAA controls. Our objective was to determine if the extent of Hp depletion correlates with the CD163 suppression and with select clinical features within the Barbadian HbSS population. Design & Methods Persons with HbSS were referred from private and public hematology clinics and support groups. Exclusion criteria were blood transfusion in the last three months, a sickle crisis in the last month and the use of oral corticosteroids, since these may affect CD163 expression. A history of painful crises, leg ulcers, renal compromise and pulmonary hypertension was ascertained. Urine samples were analyzed for albumin:creatinine ratio and echocardiograms were analyzed for the tricuspid regurgitant jet velocity (TRJV). Whole blood was collected in EDTA and analyzed by two color flow cytometry for the mean fluorescent intensity (MFI) of CD163 expression on gated CD14+ monocytes. Plasma Hp was analyzed by ELISA. The association between Hp concentration and CD163 was analyzed using median regression. The effect of Hp concentration on clinical outcome was explored using logistic regression, adjusting for the effects of age, sex, and total hemoglobin. Results Forty-eight persons with HbSS participated. Forty-seven percent of participants had at least one painful crisis in the past year and 28% of participants had a history of chronic leg ulceration. Forty-one persons had urinalysis, of these 44% of persons were diagnosed with renal compromise as defined by a urinary protein/creatinine ratio of >30mg/g; at least 15% had macro-albuminuria (urinary protein/creatinine ratio of >300mg/g). Thirty-two participants had echocardiograms, 19% indicated pulmonary hypertension (pHTN) as defined by a TRJV ≥ 2.5m/s. The mean (95% CI) Hp concentration was 4 (3.2 to 4.8) [reference range in HbAA 41-165mg/dl]. Linear regression showed that for every 1mg/dl increase in Hp concentration, CD163 MFI increased by 0.17 (95% CI 0.05 – 0.3) p=0.01 (Figure 1). For every 1mg/dl decrease in Hp levels; the odds of reporting a pain crisis in the last year increase by 1.38 (95%CI 0.84 to 2.27) p=0.2; the odds of having renal compromise increase by 3.56 (1.19 to 10.7) p=0.02 and the odds of reporting a history of leg ulcer increase by 1.33 (0.71 to 2.49) p=0.37 (Figure 2). For every 1mg/dl decrease in Hp, the TRJV increases by 0.10 (-0.15 to 0.34) p=0.36. Conclusion Depletion of serum Hp correlates with diminished CD163 expression and with increasing severity of clinical features in HbSS. This suggests that the fault in the hemoglobin scavenging apparatus is probably due to chronic depletion of Hp. Replacement of Hp may therefore be a viable therapeutic prospect aimed at restoring the positive feedback loop and conferring vascular protection. Disclosures: No relevant conflicts of interest to declare.

Nephrotic syndrome (NS) is associated with a complex acquired hypercoagulopathy and a strong predilection for venous thromboembolic (VTE) complications. Thromboembolic disease complicates an estimated 27% of adult and 3% of pediatric NS cases. Nonetheless, routine prophylactic anticoagulation for NS remains controversial due to a lack of randomized trials demonstrating safety (bleeding) and efficacy as well as a lack to validated VTE-risk markers. We and others have previously shown that NS disease severity, as determined by proteinuria and serum albumin, is correlated with VTE-risk and may thus be a useful guide to thromboprophylaxis in the future. In animal models we have shown that hypercoagulopathy, as determined by thrombin generation assay (TGA), is proportional to NS severity and others have shown that TGA has predictive value for both incident and recurrent VTE in non-NS patients. We thus sought to determine the relationship between TGA and NS severity in human disease. Standard sodium citrate plasma aliquots (N=150) were obtained from the Nephrotic Syndrome Study Network (NEPTUNE) biorepository. Patients taking anticoagulants or antiplatelet agents were excluded. Correlated phenotypic data for each sample was collected from the NEPTUNE database. The NEPTUNE protocol defined complete NS remission a priori as UP:C TGA was undetectable in 3 (2%) of the NEPTUNE samples and those samples were excluded from further analysis. Univariate linear regression of ETP on the remaining 147 samples revealed significant relationships with age (B -16), proteinuria (log-urinary protein:creatinine ratio (UP:C); B 490), plasma albumin (B -657), and lipid profile components (e.g. total cholesterol B 2,129). Histologic classification of NS was not associated with ETP. ETP was significantly higher during active disease (no remission) than during complete or partial remission (Figure A). Non-linear regression modeling revealed a polynomial relationship between UP:C and ETP (Figure B) with a nadir ETP at UP:C 0.28. Multivariable modeling revealed that log-Total Cholesterol, log-UP:C (polynomial), Plasma Albumin, and Age were independently predictive of ETP (P values Proteinuria, plasma albumin, and hyperlipidemia are strongly associated with hypercoagulopathy as assessed by ETP during active NS. Analyzing these NS severity markers and ETP in relation to thrombotic events in future studies may inform their utility to guide the clinical application of thromboprophylaxis for NS patients. Disclosures Kerlin: Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Research Funding.

Background: Patients (pts) with transfusion-dependent anemias now have longer life expectancy due to improved quality of care, in particular iron chelation therapy (ICT). Longer life and drug exposure increase the chance of complications, such as changes in renal function, which may be age-, disease- or drug-related. In light of lifelong transfusions and dependence on ICT, it is relevant to understand the long-term ICT safety profile. Published data show some pts receiving ICT experience changes in markers of renal function, mostly within normal limits, non-progressive and reversible with dose reduction and/or interruption, although follow-up was limited to ≤5 years. This retrospective study assessed long-term renal safety of deferasirox in Italian pts with transfusional hemosiderosis who participated in the deferasirox registration studies and continued treatment for up to 10 or more yrs. Methods: Italian pts with β thalassemia, sickle cell disease, MDS or other anemias who participated in deferasirox registration studies and extensions (studies 105, 106, 107, 108 or 109), received ≥1 dose of deferasirox, had ≥1 post-baseline (BL) serum creatinine (SCr) measurement, and had medical records available could be included. BL and worst values were recorded during the prospective studies; values were collected retrospectively in 3-month periods from registration trial end until the latest pt assessment for SCr, urinary protein/creatinine ratio (UPCR) and creatinine clearance (CrCl, if available). Primary endpoint was SCr trend over time. Secondary endpoints included notable renal function values (SCr >33% increase from BL and >ULN at two consecutive measurements ≥7 days apart; CrCl Results: Of the 366 Italian pts in the registration studies, 282 pts received ≥1 dose of deferasirox in registration studies and were included (Table). In the registration studies (n=282), mean (SD) duration of deferasirox exposure was 3.5 (1.6) yrs and mean daily deferasirox dose was 1032.2 (438.8) mg. In the retrospective period (n=215), mean (SD) duration of deferasirox exposure was 6.1 (2.8) yrs and mean daily deferasirox dose was 1385.6 (500.0) mg. 63.5% of pts received other ICT during the retrospective period either as combination therapy or alone (Table). In the overall population, mean SCr and UPCR values were within normal limits and stable over time during the retrospective period (Figure). In the registration studies, notable SCr values were observed in 12 (4.3%) pts, notable UPCR values in 16 (5.7%) pts and notable CrCl values in 17 (6.0%) pts (CrCl values missing n=91). In the retrospective period, notable SCr values were observed in 15 (5.3%) pts, notable UPCR values in 17 (6.0%) pts (UPCR values missing n=99) and notable CrCl values in 14 (5.0%) pts (missing n=207). In the retrospective period, regardless of ICT received, renal AEs were reported in 86 (30.5%) pts, severe renal AEs in 7 (2.5%) pts. 54% of pts with a renal AE took one concomitant medication associated with potential nephrotoxicity. The most common renal AEs were nephrolithiasis (n=31, 11.0%), renal colic (n=28, 9.9%), increased/abnormal UPCR (n=16, 5.7%), increased blood creatinine (n=12, 4.3%) and proteinuria (n=13, 4.6%). 8 pts (2.8%) had 10 serious renal AEs: nephrolithiasis, renal colic (n=2 each), increased blood creatinine, acute kidney injury, hematuria, hydronephrosis, renal failure, urethral stenosis (n=1 each); at the time of serious AE pts were receiving deferasirox (n=4), deferoxamine or deferiprone (n=3) or no ICT (n=1). Of 86 pts who had renal AEs, 33 (11.7%) were suspected to be deferasirox-related, most commonly increased UPCR (n=14, 5.0%), proteinuria (n=11, 3.9%) and increased blood creatinine (n=8, 2.8%). 5 (1.8%) pts discontinued because of renal AEs: increased blood creatinine, glycosuria (n=2 each), proteinuria (n=1). Conclusions: This is the longest follow-up analysis in pts with transfusion-dependent anemias available today and indicates stable renal function and a lack of any progressive worsening of renal function during long-term deferasirox treatment (3.5 yrs registration studies; 6.1 yrs retrospective period). Results support a favorable long-term risk:benefit renal safety profile for deferasirox in the treatment of transfusional iron overload. Disclosures Origa: Novartis: Honoraria; Apopharma: Honoraria. Piga:Apopharma: Honoraria; Novartis: Research Funding. El-Ali:Novartis: Employment. Han:Novartis: Employment. Castiglioni:Novartis: Employment. Forni:Novartis, Celgene: Research Funding.

Introduction AL amyloidosis is a systemic disease where the immunoglobin light chains produced by clonal plasma cells accumulate as insoluble fibrils causing end organ damage. In patients with AL amyloidosis, renal involvement is common, and proteinuria is frequently detected. Current treatment for AL amyloidosis aims at reducing production of these pathological immunoglobulin light chains by eliminating the clonal plasma cell population. Following treatment and normalisation of serum free light chains (SFLCs), improvement in end organ function, as demonstrated by reduction of proteinuria in patients with renal AL amyloidosis, occurs at a much slower rate. Although reduction in proteinuria has been linked to improved outcomes, the rate of this reduction has not been documented in detail in the literature. The purpose of this study is to analyse the tempo of proteinuria resolution in patients with renal AL amyloidosis following bortezomib based chemotherapy. Methods Cases were selected by retrospectively reviewing the hospital electronic database. All patients with biopsy confirmed renal AL amyloidosis were included. Induction chemotherapy was a combination of weekly bortezomib (1.6mg/m2), cyclophosphamide (300mg/m2) and dexamethasone (40mg) given in 4-weekly cycles. During the follow-up period, proteinuria was measured by urinary protein / creatinine ratio (PCR) from random urine samples. The results of the PCR over time were plotted on a scatter plot, and a best fit curve was fitted using IBM SPSS Statistics 20 software to determine the trend of PCR over time. Patients who did not complete bortezomib chemotherapy, or did not have follow-up urinary PCR were excluded. Results After applying the exclusion criteria, seven patients were analysed, and the baseline characteristics are listed in table 1. The median follow-up was 30.9 months (range: 13.2 – 44.1 months). The median age was 68.8 years (range: 52.5 – 80.5 years). Patients received a median of 6 cycles of chemotherapy (range: 2 – 9 cycles), and all patients received full doses of bortezomib based on their body surface area (average dose of 1.6mg/m2, range: 1.53 – 1.64mg/m2). Five of the 7 patients normalised their SFLCs after one cycle of chemotherapy, and the median time to normalisation was 26 days (range: 13 – 185 days). PCR was used to monitor the level of proteinuria following chemotherapy. One patient was excluded in this part of the analysis due to progressive diabetic and hypertensive nephropathy following an initial improvement in PCR after normalisation of SFLCs. Although there was marked fluctuation of PCR (figure 1), the PCRs followed an exponential decay pattern over time (R2 between 0.223 – 0.976). The median half-life of reduction was 6.2 months (range: 3.4 – 18.2 months). Conclusions PCR from random urine samples is a useful and convenient way of assessing proteinuria in everyday outpatient setting. Although PCR fluctuates over time in patients with renal AL amyloidosis, there is a general downward trend following bortezomib based chemotherapy and normalisation of SFLCs. This downward trend appears to follow an exponential decay pattern, and most patients have a protracted delay between normalisation of SFLCs and improvement in proteinuria. In view of such delay, normalisation of SFLCs should be the goal of initial therapy, rather than reduction in proteinuria when treating patients with renal AL amyloidosis. Table 1. Baseline patient characteristics Value (range) Age (median) 68.8 years (52.5 – 80.5 years) Male (%) 55.6% Plasma cell burden (median) 12.5% (6 – 25%) Kappa/Lambda light chain ratio (median) 0.164 (0.011 – 37.333) eGFR > 30ml/min (%) 88.9% Protein / creatinine ratio at diagnosis (mean) 698mg/L (243 – 1636mg/L) Figure 1 Figure 1. Disclosures Simpson: Onyx: Honoraria, Research Funding; Celgene: Honoraria; Janssen Cilag: Honoraria.

Glomerulopathy, associated with initial glomerular hyperfiltration followed by the development of microalbuminuria/proteinuria, is a well recognised complication of Sickle Cell Disease. There is evidence for the efficacy of Angiotensin-Converting Enzyme Inhibitors (ACE-I) or Angiotensin II Receptor Blockers (ARB) in reducing microalbuminuria in this population, and in common with other proteinuric kidney diseases the use of these agents is increasingly commonplace. In children the additional benefit of Hydroxyurea (HU) with microalbuminuria/proteinuria has previously been shown. The effect of HU on kidney function and proteinuria in adult Sickle Cell patients, alone or in combination with ACE-I/ARB, has not been fully explored. The aim of this study was to review the impact in real clinical practice of HU alone or in concurrent use with ACE-I/ARB on estimated Glomerular Filtration Rate (eGFR) and Urinary Protein-Creatinine Ratio (uPCR). A retrospective analysis of data from 59 adult Sickle Cell Disease patients taking HU was undertaken and patients were classified as haematological responders to HU if HbF > 8%. Patients with no haematological response were excluded from further analysis as the majority of them had intermittent adherence to HU therapy. Creatinine (Cr), uPCR, Haemoglobin (Hb), Haemoglobin F (HbF) and Lactate Dehydrogenase (LDH) data were extracted on a monthly basis over the preceding 11 years. eGFR was calculated using the MDRD formulation. Commencement dates of HU / ACE-I/ARB were confirmed by note review. Patients were not further divided according to sex, age or other co-morbidities. 44/59 were deemed haematological responders to HU and of these 17 (39%) were also taking an ACE-I/ARB. 42/44 had HbSS, 1 patient HbSC and 1 HbSBoThal. Mean age was 36.7 years (range 18-76). The sample population was divided into three groups. Group A (27 patients) were taking HU alone, Group B (9 patients) were initially treated with HU and subsequently commenced ACE-I/ARB treatment, and Group C (7 patients) were initially treated with ACE-I/ARB and subsequently HU was added. 1 patient initiated the two therapies simultaneously. Group A (mean age 33 years, range 19 – 53), had been on HU for a mean of 7 years. 22 patients had been treated for >10 years or had moved from another hospital already on HU. None of these patients showed any progression of proteinuria or eGFR during the time studied. In 5/27 patients uPCR results before and 1 year after commencing HU were analysed and there was no difference in uPCR or eGFR results. Group B, (mean age 46 years, range 26-76), showed no response or worsening of uPCR on HU alone and were commenced on ACE-I/ARB. They had been taking HU for a mean of 10 years and ACE-I or ARB for a mean of 5 years. Following the addition of ACE-I/ARB 7/9 patients showed a reduction in proteinuria. All patients had stable eGFR. Group C (mean age 41 years, range 23-59), were commenced on HU for non-renal factors. They had been taking HU for a mean of 3 years and ACE-I/ARB for a mean of 7 years. Addition of HU to ACE-I/ARB showed no consistent effect; in 2 patients uPCR was increasing prior to addition of HU; it subsequently stabilised in 1 patient and reduced in the other. The remaining patient's uPCR were stable (3/7 patients) or increased (2/7). eGFR was stable in all patients. The patient commenced on HU and ACE-I concurrently was aged 59 years and had been on both therapies for 12 years. Both her uPCR and eGFR were stable. HU and ACE-I/ARBs are often used together in adult patients with SCD. From our retrospectve data it seems possible that the combination of HU with ACE-I/ARB may offer benefit in adult patients with SCD who have persistent proteinuria. HU could be considered as part of the treatment options in this group of patients. The potential use of this combination treatment needs further study, ideally in a controlled trial. Disclosures: Breen: Baxter: Membership on an entity’s Board of Directors or advisory committees. Howard:Sangart: Membership on an entity’s Board of Directors or advisory committees.

Abstract 4062 Poster Board III-997 Background Over 70% of deaths in regularly transfused patients with β-thalassemia major (TM) are related to iron-induced cardiomyopathy. Deferasirox (Exjade®), in a sub-study of the 1-year multicenter prospective EPIC trial, demonstrated efficacy in reducing myocardial iron in TM patients with mild, moderate and severe cardiac siderosis, as evidenced by a statistically significant improvement in myocardial T2*. We herein report the extension phase results from the same study in patients who have received up to 2 years of deferasirox therapy. Methods Patients aged ≥10 years with myocardial T2* >5–2500 ng/mL, MR (R2) LIC >10 mg Fe/g dry weight (dw), and a lifetime minimum of 50 transfused blood units were included in the cardiac sub-study. Deferasirox was initiated at 30 mg/kg/day and increased to 40 mg/kg/day by the time patients had entered the 1-year extension. Dose decreases were allowed for safety reasons. The primary endpoint was change in myocardial T2* from baseline to 2 years. Results Out of 100 patients who entered the 1-year extension phase, 85 completed (85%); 24-month CMR data are available for 81 patients. Mean age was 20.6 ±7.3 years. Baseline cardiac T2* was Reasons for discontinuation were: unsatisfactory therapeutic effect (n=8), consent withdrawal (n=3), protocol violation (n=2), lost to follow up (n=1) and abnormal laboratory value (increased urinary protein/creatinine ratio) leading to consent withdrawal (n=1); no deaths were reported. Incidence of investigator-assessed drug-related AEs (≥5%) decreased overall from the core phase to the extension: increased blood creatinine (n=21 [21.0%] vs n=18 [18.0%]), rash (n=15 [15.0%] vs n=0), increased alanine aminotransferase (ALT) (n=6 [6.0%] vs n=4 [4.0%]) and increased aspartate aminotransferase (n=4 [4.0%] vs n=3 [3.0%]). There were no drug-related serious AEs over 2 years. In total, 4 patients (4.0%) had increased serum creatinine >33% above baseline and the upper limit of normal (ULN) on two consecutive visits; 3 patients (3.0%) during the core and 1 (1.0%) during the extension. 4 (4.0%) patients had increased ALT >10xULN on two consecutive visits; 2 patients (2.0%) during the core and 2 (2.0%) during the extension; levels were already >ULN at baseline in these patients. Conclusions This is the first large prospective study to report 2-year data on cardiac iron removal for any iron chelator. Results show that continued therapy with deferasirox for up to 2 years at doses 30–40 mg/kg/day was effective in removing iron from the heart in TM patients with mild, moderate and severe cardiac siderosis. Myocardial T2* continued to improve in year 2 and the statistically significant improvement from baseline was associated with maintenance of normal cardiac function and a concomitant decrease in hepatic and total body iron burden. Overall, deferasirox was well tolerated. Disclosures: Pennell: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Apopharma: Consultancy, Honoraria; Cardiovascular Imaging Solutions: Equity Ownership; Siemens: Research Funding. Off Label Use: THE SPECIFIC USE OF CHELATION FOR CARDIAC SIDEROSIS IS OFF-LABEL. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Vifor International: Membership on an entity's Board of Directors or advisory committees. Cappellini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genzyme: Membership on an entity's Board of Directors or advisory committees. Chan:Novartis: Honoraria, Research Funding. Aydinok:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ibrahim:Novartis: Research Funding. Li:Novartis: Consultancy, Speakers Bureau. Viprakasit:Thai Government : Employment; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Government Pharmaceutical Organization of Thailand: Honoraria, Research Funding. Kattamis:Novartis: Consultancy, Honoraria, Speakers Bureau. Smith:Novartis Pharma AG: Consultancy, Employment at Royal Brompton Hospital funded by Novartis Pharma AG. Habr:Novartis Pharmaceuticals: Employment. Domokos:Novartis Pharma AG: Employment. Roubert:Novartis Pharma AG: Employment. Taher:Novartis: Honoraria, Research Funding.