Francesco L Ierino

University of Melbourne, Melbourne, Victoria, Australia

Are you Francesco L Ierino?

Claim your profile

Publications (65)200.95 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: B-type natriuretic peptide (BNP) concentration predicts outcome in patients undergoing dialysis. Because survival and cardiovascular risk change across the CKD continuum, serial changes in BNP were compared in patients at different CKD stages and after kidney transplantation. Patients with CKD stages 3 and 4 (CKD 3-4), dialysis patients, and kidney transplant recipients (KTRs) from one center had two measurements of BNP taken a median of 161 days apart in 2003-2004 and were followed until July 2012. Both BNP-32 (Triage BNP; Biosite Diagnostics) and NT-BNP-76 (proBNP; Roche Diagnostics) were assayed. The interaction between change in log-transformed BNP concentration over time and patient group was tested by fitting regression models on panel data with random effects. Survival after the second measurement was compared by tertile of change in BNP. Patients with CKD 3-4 (n=48), dialysis patients (n=102), and KTRs (n=73) were followed for a median of 5.7, 4.8, and 5.9 years, respectively. The interaction between patient group and BNP measurements over time was significant for NT-BNP-76 (P<0.001) and BNP-32 (P<0.01). Median NT-BNP-76 increased in dialysis patients and those with CKD 3-4 from 3850 pg/ml (interquartile range [IQR], 1776-12,323 pg/ml) to 18,830 pg/ml (IQR, 6114-61,009 pg/ml; P<0.001) and from 698 pg/ml (IQR, 283-2922 pg/ml) to 2529 pg/ml (IQR, 347-9277 pg/ml; P=0.002), respectively. Change was not significant for KTRs or comparisons made with BNP-32. Survival rate was significantly lower for patients with the highest tertile of change in NT-BNP-76 among patients with CKD 3-4 (P=0.02), but not in the dialysis or KTR groups. In 11 patients who received a kidney transplant during the study, median NT-BNP-76 decreased from 9607 pg/ml (IQR, 2292-31,282 pg/ml) to 457 pg/ml (IQR, 203-863 pg/ml) after transplant (P<0.01). The temporal trajectory of BNP differs between dialysis patients and those with CKD 3-4 and KTRs. This has important implications for the development of BNP-guided management strategies in CKD.
    Clinical Journal of the American Society of Nephrology 04/2014; · 5.07 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Angiotensin-converting enzyme 2 (ACE2) is a novel regulator of the renin-angiotensin system that counteracts the adverse effects of angiotensin II. In heart failure patients, elevated plasma ACE2 activity predicted adverse events and greater myocardial dysfunction. We aimed to describe plasma ACE2 activity and its clinical associations in patients with kidney disease.Methods Patients recruited from a single centre comprised of chronic kidney disease Stage III/IV (CKD), haemodialysis patients and kidney transplant recipients (KTRs). Plasma ACE2 enzyme activity was measured using a fluorescent substrate assay in plasma, collected at baseline and stored at -80°C. Linear regression was performed in both males and females separately to determine the covariates associated with log-transformed ACE2.ResultsThe median (interquartile range) plasma ACE2 activity in pmol/mL/min was 15.9 (8.4-26.1) in CKD (n = 59), 9.2 (3.9-18.2) in haemodialysis (n = 100) and 13.1 (5.7-21.9) in KTR (n = 80; P < 0.01). In male haemodialysis patients, ACE2 activity was 12.1 (6.8-19.6) compared with 4.4 (2.5-10.3) in females (P < 0.01). Log-transformed ACE2 plasma activity was associated with post-haemodialysis systolic blood pressure in females [β-coefficient 0.04, 95% confidence interval (95% CI) 0.01-0.06, P = 0.006]. In males, log-transformed ACE2 plasma activity was associated with B-type natriuretic peptide (β-coefficient 0.39, 95% CI 0.19-0.60, P < 0.001). Plasma ACE2 activity was not associated with mortality.Conclusions Plasma ACE2 activity is reduced in haemodialysis patients compared with CKD patients, and in female haemodialysis patients compared with male. The different associations of plasma ACE2 activity between male and female haemodialysis patients indicate that the role of ACE2 in cardiovascular disease may differ by gender.
    Nephrology Dialysis Transplantation 03/2013; · 3.37 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: AIM: Cyclosporine (CsA), dosed to achieve C2 targets, has been shown to provide safe and efficacious immunosuppression when used with a mycophenolate and steroids for de novo kidney transplant recipients. This study examined whether use of enteric-coated mycophenolate sodium (EC-MPS) together with basiliximab and steroids would enable use of CsA dosed to reduced C2 targets in order to achieve improved graft function. METHODS: 12-month, prospective, randomized, open label trial in de novo kidney transplant recipients in Australia. Seventy-five patients were randomized to receive either usual exposure (n= 33) or reduced exposure (n= 42) CsA, EC-MPS 720mg twice daily, basiliximab and corticosteroids. RESULTS: There was no significant difference in mean Cockcroft Gault CrCl (60.2±17.6ml/min/1.72m2 versus 63.2±24.3, p=0.64 for usual versus reduced exposure respectively) at 6 months. There was no significant difference between treatment groups in the incidence of treatment failure defined as biopsy proven acute rejection, graft loss or death (secondary endpoint: 30.3% full exposure vs 35.7% reduced exposure). At 12 months the incidence of overall AEs was the same in both groups. CONCLUSION: This exploratory study suggests de novo renal transplant patients can safely receive a treatment regimen of either full or reduced exposure CsA in combination with EC-MPS, corticosteroids and basiliximab, with no apparent difference in efficacy or graft function during the first year after transplant.
    Nephrology 10/2012; · 1.69 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The association between blood pressure and cardiovascular outcomes in patients undergoing hemodialysis remains controversial. This may relate in part to the technique and device used and the timing of the blood pressure measurement in relation to the hemodialysis procedure. Emerging evidence indicates that standardized hemodialysis unit blood pressure measurements or measurements obtained at home, either by the patient or using an ambulatory blood pressure monitor, may offer advantages over routine hemodialysis unit blood pressure measurements for determining cardiovascular risk and treatment. This review discusses the available evidence and implications for clinicians and clinical trials.
    American Journal of Kidney Diseases 06/2012; 60(3):463-72. · 5.29 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Immunophenotype peripheral blood T cells from renal transplant recipients (RTR) using cellular markers of regulatory T cells (Tregs) and flow cytometry, including Foxp3, and correlate these findings with clinical parameters. Expression of phenotypic markers of Tregs was assessed by flow cytometric analysis of peripheral blood lymphocytes (PBL) from (i) RTR (n = 95); (ii) patients with end-stage renal failure (ESRF) awaiting transplantation (n = 17); and (iii) normal healthy controls (n = 18). The percentage of CD4(+) CD25(+) Foxp3(+) cells within the CD4(+) cell population did not significantly alter at different time points post-transplant. However, the percentage of CD4(+) CD25(+) Foxp3(+) cells within the CD4(+) population was significantly lower in RTR compared with patients with ESRF. In contrast, RTR and ESRF had a similar percentage of CD4(+) CD25(+) cells expressing Foxp3. Multivariate analysis of PBL and clinical parameters demonstrated (i) a positive linear relationship between the percentage CD4(+) CD25(+) cells expressing Foxp3 and estimated glomerular filtration rate and (ii) a higher percentage of CD4(+) CD25(+) cells in the CD4(+) cell population in patients with malignancy (the majority were skin cancers). Malignancy also correlated strongly with time post-transplant and age of the RTR. Immune monitoring of the PBL phenotype in RTR using CD4, CD25 and Foxp3 may stratify RTR and predict graft outcome and function, and risk of complications from immunosuppression. Longitudinal and functional studies of Tregs are essential to extend the findings of the present study.
    Nephrology 02/2012; 17(4):415-22. · 1.69 Impact Factor
  • Source
    Transplantation 10/2011; 92(8):e39. · 3.78 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Long-term acceptance of transplanted organs without requirement for indefinite immunosuppression remains the ultimate goal of transplant clinicians and scientists. This clinical state of allograft acceptance termed "operational tolerance" has been elusive in routine practice. However, there are published reports of recipients where immunosuppression has been discontinued, by intention or patient noncompliance, in which the outcome is a nondestructive immune response and normal function. The question now arises how clinical operational tolerance might be achieved in the majority of recipients. This review provides an overview of current approaches to achieve operational tolerance, including the use of donor bone marrow and depletion of recipient T cells and the resistance of liver transplants to rejection. It also describes the key role of clinical immune monitoring and future approaches to tolerance induction including inhibition of T-cell signaling, manipulation of costimulatory pathways, and expansion of regulatory T cells. The principles of these experimental approaches may ultimately be extended to provide safe and effective control of transplant rejection and induction of clinical operational tolerance.
    Transplantation 05/2011; 91(10):1065-74. · 3.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Blockade of the inducible costimulator (ICOS) pathway has been shown to prolong allograft survival; however, its utility in xenotransplantation is unknown. We hypothesize that local expression of ICOS-Ig by the xenograft will suppress the T-cell response resulting in significant prolonged graft survival. Pig iliac artery endothelial cells (PIEC) secreting ICOS-Ig were generated and examined for the following: (1) inhibition of allogeneic and xenogeneic proliferation of primed T cells in vitro and (2) prolongation of xenograft survival in vivo. Grafts were examined for Tregs by flow cytometry and cytokine levels determined by quantitative reverse-transcriptase polymerase chain reaction. Soluble ICOS-Ig markedly decreased allogeneic and xenogeneic primed T-cell proliferation in a dose-dependent manner. PIEC-ICOS-Ig grafts were significantly prolonged compared with wild-type grafts (median survival, 34 and 12 days, respectively) with 20% of PIEC-ICOS-Ig grafts surviving more than 170 days. Histological examination showed a perigraft cellular accumulation of Forkhead box P3 (Foxp3(+)) cells in the PIEC-ICOS-Ig grafts, these were also shown to be CD3(+)CD4(+)CD25(+). Survival of wild-type PIEC grafts in a recipient simultaneously transplanted with PIEC-ICOS-Ig were also prolonged, with a similar accumulation of Foxp3(+) cells at the periphery of the graft demonstrating ICOS-Ig induces systemic graft prolongation. However, this prolongation was specific for the priming xenograft. Intragraft cytokine analysis showed an increase in interleukin-10 levels, suggesting a potential role in induction/function of CD4(+)CD25(+)Foxp3(+) cells. This study demonstrates prolonged xenograft survival by local expression of ICOS-Ig, we propose that the accumulation of CD4(+)CD25(+)Foxp3(+) cells at the periphery of the graft and secretion of interleukin-10 is responsible for this novel observation.
    Transplantation 05/2011; 91(10):1090-7. · 3.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cardiovascular mortality rates in the general population have decreased over time. We hypothesized that cardiovascular mortality rates in dialysis patients, which are higher than in the general population, have not decreased as much as those in the general population. Comparison of registry data with population data. Data for prevalent Australian patients for whom dialysis was the first renal replacement therapy were obtained from the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry for 1992-2005. Data for a comparable Australian general population were obtained from the Australian Bureau of Statistics. Cardiovascular mortality rates per 100 person-years were calculated from ANZDATA Registry data, and age-specific relative risks were calculated relative to cardiovascular mortality rates in the general population. Included in this cohort were 34,741 dialysis patients with 93,112 person-years of follow-up and 7,267 cardiovascular deaths. Cardiovascular mortality rates decreased over time in the general population and in dialysis patients older than 55 years. In patients aged 55-64 years, cardiovascular mortality rates were 9.0 (95% CI, 7.8-10.3) per 100 person-years in 1992-1994 and 6.4 (95% CI, 5.5-7.3) in 2004-2005; corresponding relative risks were 32.4 (95% CI, 28.2-37.2) and 52.0 (95% CI, 45.2-59.9), respectively. The corresponding cardiovascular mortality rates for dialysis patients aged 65-74 years were 11.6 (95% CI, 10.4-13.0) and 8.3 (95% CI, 7.4-9.3); relative risks were 12.9 (95% CI, 11.6-14.5) and 20.8 (95% CI, 18.7-23.2). Using negative binomial regression, the relative risk associated with dialysis compared with the general population increased over time (P for interaction = 0.001). Causes of death used to define cardiovascular mortality were not coded using identical systems in the ANZDATA Registry and the Australian population. Despite decreasing cardiovascular mortality rates in some dialysis patients, the excess cardiovascular risk compared with the general population is increasing.
    American Journal of Kidney Diseases 04/2011; 58(1):64-72. · 5.29 Impact Factor
  • Matthew A Roberts, Adam J Hedley, Francesco L Ierino
    [Show abstract] [Hide abstract]
    ABSTRACT: A novel strategy in the management of cardiovascular disease in patients with end-stage kidney disease is the use of biochemical markers to facilitate the detection of cardiovascular abnormalities in the hope that this will allow effective therapy to be instituted earlier. The cardiac troponins and B-type natriuretic peptide are among the best studied of these biochemical markers of cardiovascular disease. However, controversy remains regarding the interpretation of such results and the subsequent clinical application of these biomarkers, particularly when abnormal in patients with end-stage kidney disease. This review addresses some of the important issues to consider with the interpretation of abnormal cardiac troponin and B-type natriuretic peptide results in patients undergoing dialysis.
    Nephrology 03/2011; 16(3):251-60. · 1.69 Impact Factor
  • Matthew J Damasiewicz, Francesco L Ierino
    Nephrology 12/2010; 15(8):779-80. · 1.69 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Renal impairment is a major risk factor for cardiovascular disease. This study addressed clinical predictors of outcome following cardiac surgery, focusing on pre-operative renal dysfunction. All patients undergoing cardiac surgery at Austin Health from June 1, 2001 to June 30, 2006, were included in the analysis. Logistic regression models were used to evaluate clinical factors predicting "operative mortality" and common post-operative complications. The operative mortality was 1.36% for coronary artery bypass grafting (CABG) alone (n=1027), 5.07% for valve surgery alone (n=217), 4.43% for combined CABG and valve surgery (n=158) and 11.11% for other cardiac surgical procedures (n=270). Amongst CABG alone patients, pre-operative renal impairment was a strong predictor of operative mortality, with a 35-43% increased risk of death (p=0.005) for every 10 ml/min/1.73 m(2) that the glomerular filtration rate was lower. Peripheral vascular disease, recent myocardial infarction and congestive cardiac failure also predicted operative mortality. Pre-operative renal impairment also increased the rate of various post-operative complications, as well as duration of admission. Renal dysfunction is significantly associated with increased mortality and morbidity following cardiac surgery and necessitates careful consideration in risk benefit analysis when considering cardiac surgery.
    Heart Lung &amp Circulation 04/2010; 19(8):453-9. · 1.25 Impact Factor
  • Transplantation 01/2010; 90. · 3.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Dendritic cells (DCs) and CTLA4Ig are important in regulating T-cell responses and therefore represent potential therapeutic tools in transplantation. In this study, CTLA4Ig was expressed in a C57BL/6 murine DC line (JAWS II) by lentiviral transduction and these cells were used to examine T-cell immunomodulatory effects in vitro and in vivo. A lower stimulation index to C57BL/6 was observed with splenocytes from BALB/c mice primed with JAWS II-CTLA4Ig compared with control JAWS II-green fluorescent protein (JAWS II-GFP). Mice primed with JAWS II-CTLA4Ig cells had significantly prolonged antigen-specific C57BL/6 skin graft survival compared with either JAWS II-GFP-primed or naïve mice (median 13, 11 and 11 days, respectively, P=0.0001). Furthermore, JAWS II-CTLA4Ig-primed mice that had been previously transplanted with skin grafts were re-transplanted with skin grafts 6 months later without immune manipulation. These mice demonstrated specific prolongation of second-set rejection responses, indicating systemic immune modulation induced by genetically modified DC. The mechanism was not due to expression of indoleamine 2,3-dioxygenase or induction of circulating regulatory T cells as assessed by flow cytometry of the peripheral blood lymphocytes. This potent effect demonstrated with skin grafts and second-set responses highlights the potential use of this strategy for transplantation more generally.
    Immunology and Cell Biology 01/2010; 88(8):846-50. · 3.93 Impact Factor
  • Transplantation 01/2010; 90. · 3.78 Impact Factor
  • Transplantation 01/2010; 90. · 3.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A single detectable cardiac troponin predicts mortality in patients treated with dialysis. There are limited data on changes in troponin concentration over time and the clinical implications of serial troponin measurement. Serial cardiac troponin T (cTnT) was assayed five times over 12 months in a prospective cohort study of patients with end-stage kidney disease treated with haemodialysis. A concentration of cTnT > or = 0.04 microg/L was considered increased. Mortality and cardiovascular events were analysed by survival analysis, according to the serial troponin results. From 100 patients who provided a baseline sample for cTnT, 81 completed five serial measurements. The analysis of patients who completed serial cTnT measurements demonstrated that 28 patients (35%) had normal cTnT concentrations in all five samples, 20 patients (24%) had between one and four increased cTnT measurements and 33 patients (41%) had increased concentrations of cTnT in all five samples. The 1.7-y patient survival was 100%, 90% and 78% for patients with zero, one to four, or five out of five concentrations of cTnT increased, respectively (P = 0.037), and the corresponding cardiovascular event-free survival was 100%, 91% and 78%, respectively (P = 0.027). Serial measurements of cTnT concentration were frequently increased in patients receiving haemodialysis. The number of abnormal measurements over time predicted mortality and cardiovascular adverse events.
    Annals of Clinical Biochemistry 06/2009; 46(Pt 4):291-5. · 1.92 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Immune reactivity against products of the major histocompatibility complex (MHC) is the major barrier to allotransplantation. Conversely, sharing of MHC class II antigens I appears to be of overwhelming importance in permitting the induction of immune tolerance to vascularized organ allografts, as demonstrated previously in miniature swine. Class II antigen has also been shown to be recognized predominantly in human anti-pig xenoreactions in vitro. To achieve tolerance in the xenogeneic pig-to-primate model, we are therefore investigating an approach involving retrovirus-mediated gene therapy to transfer swine MHC (SLA) class II genes into primate primitive hematopoietic stem cells, so that swine MHC class II antigens may participate in the education of the recipient's newly developing T cell repertoire. We report here the in vitro and in vivo use of a recombinant retrovirus containing a polycistronic retroviral vector which carries swine MHC class II DRA and DRB cDNA sequences to transduce CD34+ bone marrow cells (BMC) from a cynomolgus monkey. Transduction efficiency was assessed by reverse transcriptase-polymerase chain reaction analysis of the colony-forming unit progenitor colonies grown in the absence of gentamycin; 55% and 24% of the progenitor colonies were determined to express the retroviral transcript at 1 week and 3 weeks post-transduction, respectively. These in vitro studies have been extended to the transplantation of retrovirally transduced autologous stem cells into a cynomolgus monkey prepared with a non-myeloablative conditioning regimen. Prolonged expression of SLA-DR transcripts in monkey peripheral blood mononuclear cells (PBMC) has been documented over a 56-week period after transplantation of retrovirus-transduced bone marrow cells. However, we could not detect any protein expression by FACS analysis on the surface of primate PBMC or bone marrow, using a porcine SLA-DR-specific antibody. Engraftment of hematopoietic cells with the transduced genes was further detected in the progenitor colonies grown from the bone marrow cells harvested at 4 weeks and 25 weeks after bone marrow transplantation. Our results thus document that long-term engraftment of retrovirally transduced hematopoietic cells can be achieved in a primate model using a non-myeloablative preparative I regimen.
    Xenotransplantation 11/2008; 4(3):174 - 185. · 2.57 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Porcine dendritic cells (DC) are likely to be pivotal cells in the initiation of stimulatory and potential tolerogenic responses to xenoantigens, however, there are limited studies characterizing these antigen presenting cells. Porcine PBMC (CD172a(+)) were cultured with GM-CSF and IL-4 and phenotype and functional capabilities assessed. Lipopolysaccharide (LPS), IL-10, and IL-3 were added to the GM-CSF/IL-4 DC cultures to determine phenotypic and functional changes. Quantitative real-time polymerase chain reaction (PCR) for key cytokines was performed and the modified porcine DC were further assessed by primary mixed lymphocyte reaction to determine the effect of LPS, IL-10, and IL-3 on stimulatory capability. Porcine PBMC (CD172(+)) cultured with GM-CSF and IL-4 produced cells with DC morphology, which were major histocompatability complex (MHC) class II(+), CD14(-/lo), and CD1a(lo). Addition of IL-10 or IL-3 to GM-CSF/IL-4 DC cultures produced cells with lower levels of MHC class II and higher levels of antigen uptake consistent with less mature DC. Quantitative real-time PCR of DC showed the addition of IL-10 induced an increase in IL-10 mRNA, no detectable IL-12, and reduced IL-6 mRNA. The addition of IL-3 to DC cultures decreased IL-12, IL-6 and tumor necrosis factor (TNF), with no change in IL-10 mRNA. GM-CSF/IL-4 DC induced strong human lymphocyte proliferation, compared with significantly reduced stimulatory capacity induced by IL-10 and IL-3 treated DC cultures. The profound effect on differential DC cytokine profile and reduced human anti-pig responses has important therapeutic implications in xenotransplantation. The mechanism of altered regulation warrants further investigation.
    Xenotransplantation 08/2008; 15(4):257-67. · 2.57 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Left ventricular abnormalities contribute to cardiovascular disease in patients with chronic kidney disease and may be detected by measurement of B-type natriuretic peptide in serum. In a prospective cohort study of predialysis patients, patients who were on dialysis, and kidney transplant recipients, serum was collected and assayed for both B-type natriuretic peptide and its N-terminal fragment. Median levels were compared using nonparametric tests, and predictors of B-type natriuretic peptide were determined by linear regression. Survival analysis and Cox regression were performed to examine the association of levels of B-type natriuretic peptide with cardiovascular events and death. Levels of B-type natriuretic peptide were highest in patients who were on dialysis. Patients who were receiving dialysis and had known cardiovascular disease, were not on the waiting list for kidney transplantation, or had left ventricular systolic dysfunction on echocardiography had significantly higher levels of B-type natriuretic peptide than patients without these characteristics. Glomerular filtration rate was an important predictor of B-type natriuretic peptide levels for patients who were not on dialysis (predialysis and renal transplant recipients). Left ventricular systolic dysfunction predicted B-type natriuretic peptide levels in patients who were on dialysis. Both forms of B-type natriuretic peptide were associated with a two- to three-fold increased risk for death in patients who were on dialysis. Levels of B-type natriuretic peptide are greatest in patients who are on dialysis and have cardiovascular comorbidities and are strong predictors of death.
    Clinical Journal of the American Society of Nephrology 07/2008; 3(4):1057-65. · 5.07 Impact Factor

Publication Stats

965 Citations
200.95 Total Impact Points

Institutions

  • 2006–2012
    • University of Melbourne
      • • Department of Surgery
      • • Department of Medicine (Austin)
      Melbourne, Victoria, Australia
  • 2005–2011
    • Austin Health
      Melbourne, Victoria, Australia
  • 2008
    • National and Kapodistrian University of Athens
      • Department of Surgery
      Athens, Attiki, Greece
    • Australian Animal Health Laboratory
      Geelong, Victoria, Australia
  • 1997–2008
    • Massachusetts General Hospital
      • Transplantation Biology Research Center
      Boston, MA, United States
  • 1998–2001
    • Harvard Medical School
      Boston, Massachusetts, United States