Publications by authors named "Monica Cortinovis"

40 Publications

Preventing microalbuminuria with benazepril, valsartan, and benazepril-valsartan combination therapy in diabetic patients with high-normal albuminuria: A prospective, randomized, open-label, blinded endpoint (PROBE) study.

PLoS Med 2021 07 14;18(7):e1003691. Epub 2021 Jul 14.

Department of Renal Medicine, Clinical Research Center for Rare Diseases, "Aldo e Cele Daccò": Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Ranica, Bergamo, Italy.

Background: Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) prevent microalbuminuria in normoalbuminuric type 2 diabetic patients. We assessed whether combined therapy with the 2 medications may prevent microalbuminuria better than ACE inhibitor or ARB monotherapy.

Methods And Findings: VARIETY was a prospective, randomized, open-label, blinded endpoint (PROBE) trial evaluating whether, at similar blood pressure (BP) control, combined therapy with benazepril (10 mg/day) and valsartan (160 mg/day) would prevent microalbuminuria more effectively than benazepril (20 mg/day) or valsartan (320 mg/day) monotherapy in 612 type 2 diabetic patients with high-normal albuminuria included between July 2007 and April 2013 by the Istituto di Ricerche Farmacologiche Mario Negri IRCCS and 8 diabetology or nephrology units in Italy. Time to progression to microalbuminuria was the primary outcome. Analyses were intention to treat. Baseline characteristics were similar among groups. During a median [interquartile range, IQR] follow-up of 66 [42 to 83] months, 53 patients (27.0%) on combination therapy, 57 (28.1%) on benazepril, and 64 (31.8%) on valsartan reached microalbuminuria. Using an accelerated failure time model, the estimated acceleration factors were 1.410 (95% CI: 0.806 to 2.467, P = 0.229) for benazepril compared to combination therapy, 0.799 (95% CI: 0.422 to 1.514, P = 0.492) for benazepril compared to valsartan, and 1.665 (95% CI: 1.007 to 2.746, P = 0.047) for valsartan compared to combination therapy. Between-group differences in estimated acceleration factors were nonsignificant after adjustment for predefined confounders. BP control was similar across groups. All treatments were safe and tolerated well, with a slight excess of hyperkalemia and hypotension in the combination therapy group. The main study limitation was the lower than expected albuminuria at inclusion.

Conclusions: Risk/benefit profile of study treatments was similar. Dual renin-angiotensin system (RAS) blockade is not recommended as compared to benazepril or valsartan monotherapy for prevention of microalbuminuria in normoalbuminuric type 2 diabetic patients.

Trial Registration: EudraCT 2006-005954-62; ClinicalTrials.gov NCT00503152.
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http://dx.doi.org/10.1371/journal.pmed.1003691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279302PMC
July 2021

In search of an ideal drug for safer treatment of obesity: The false promise of pseudoephedrine.

Rev Endocr Metab Disord 2021 May 4. Epub 2021 May 4.

Department of Biomedical and Biotechnological Sciences, University of Catania School of Medicine, Catania, Italy.

Obesity is a major public health problem worldwide. Only relatively few treatment options are, at present, available for the management of obese patients. Furthermore, treatment of obesity is affected by the widespread misuse of drugs and food supplements. Ephedra sinica is an old medicinal herb, commonly used in the treatment of respiratory tract diseases. Ephedra species contain several alkaloids, including pseudoephedrine, notably endowed with indirect sympathomimetic pharmacodynamic properties. The anorexigenic effect of pseudoephedrine is attributable primarily to the inhibition of neurons located in the hypothalamic paraventricular nucleus (PVN), mediating satiety stimuli. Pseudoephedrine influences lipolysis and thermogenesis through interaction with β3 adrenergic receptors and reduces fat accumulation through down-regulation of transcription factors related to lipogenesis. However, its use is associated with adverse events that involve to a large extent the cardiovascular and the central nervous system. Adverse events of pseudoephedrine also affect the eye, the intestine, and the skin, and, of relevance, sudden cardiovascular death related to dietary supplements containing Ephedra alkaloids has also been reported. In light of the limited availability of clinical data on pseudoephedrine in obesity, along with its significantly unbalanced risk/benefit profile, as well as of the psychophysical susceptibility of obese patients, it appears reasonable to preclude the prescription of pseudoephedrine in obese patients of any order and degree.
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http://dx.doi.org/10.1007/s11154-021-09658-wDOI Listing
May 2021

Ramipril and Cardiovascular Outcomes in Patients on Maintenance Hemodialysis: The ARCADIA Multicenter Randomized Controlled Trial.

Clin J Am Soc Nephrol 2021 04 29;16(4):575-587. Epub 2021 Mar 29.

Unit of Nephrology and Dialysis, Azienda Ospedaliera Santa Croce e Carle, Cuneo, Italy.

Background And Objectives: Renin-angiotensin system (RAS) inhibitors reduce cardiovascular morbidity and mortality in patients with CKD. We evaluated the cardioprotective effects of the angiotensin-converting enzyme inhibitor ramipril in patients on maintenance hemodialysis.

Design, Setting, Participants, & Measurements: In this phase 3, prospective, randomized, open-label, blinded end point, parallel, multicenter trial, we recruited patients on maintenance hemodialysis with hypertension and/or left ventricular hypertrophy from 28 Italian centers. Between July 2009 and February 2014, 140 participants were randomized to ramipril (1.25-10 mg/d) and 129 participants were allocated to non-RAS inhibition therapy, both titrated up to the maximally tolerated dose to achieve predefined target BP values. The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included the single components of the primary end point, new-onset or recurrence of atrial fibrillation, hospitalizations for symptomatic fluid overload, thrombosis or stenosis of the arteriovenous fistula, and changes in cardiac mass index. All outcomes were evaluated up to 42 months after randomization.

Results: At comparable BP control, 23 participants on ramipril (16%) and 24 on non-RAS inhibitor therapy (19%) reached the primary composite end point (hazard ratio, 0.93; 95% confidence interval, 0.52 to 1.64; =0.80). Ramipril reduced cardiac mass index at 1 year of follow-up (between-group difference in change from baseline: -16.3 g/m; 95% confidence interval, -29.4 to -3.1), but did not significantly affect the other secondary outcomes. Hypotensive episodes were more frequent in participants allocated to ramipril than controls (41% versus 12%). Twenty participants on ramipril and nine controls developed cancer, including six gastrointestinal malignancies on ramipril (four were fatal), compared with none in controls.

Conclusions: Ramipril did not reduce the risk of major cardiovascular events in patients on maintenance hemodialysis.

Clinical Trial Registry Name And Registration Number: ARCADIA, NCT00985322 and European Union Drug Regulating Authorities Clinical Trials Database number 2008-003529-17.
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http://dx.doi.org/10.2215/CJN.12940820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092055PMC
April 2021

Preimplantation Histological Score Associates with 6-Month GFR in Recipients of Perfused, Older Kidney Grafts: Results from a Pilot Study.

Nephron 2021 22;145(2):137-149. Epub 2021 Jan 22.

Department of Renal Medicine, Clinical Research Centre for Rare Diseases "Aldo e Cele Daccò": Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy.

Background: Biopsy-guided selection of older kidneys safely expands the organ pool, and pretransplant perfusion improves the preservation of these fragile organs. Herein, we studied morphofunctional variables associated with graft outcomes in perfused, histologically evaluated older kidneys.

Methods: This single-center prospective cohort pilot study evaluated the relationships between preimplantation histologic scores and renal perfusion parameters during hypothermic, pulsatile, machine perfusion (MP) and assessed whether these morphofunctional parameters associated with GFR (iohexol plasma clearance) at 6 months after transplantation in 20 consecutive consenting recipients of a biopsy-guided single or dual kidney transplant from >60-year-old deceased donors.

Results: The donor and recipient age was 70.4 ± 6.5 and 63.6 ± 7.9 years (p = 0.005), respectively. The kidney donor profile index (KDPI) was 93.3 ± 8.4% (>80% in 19 cases), histologic score 4.4 ± 1.4, and median (IQR) cold ischemia time 19.8 (17.8-22.8 h; >24 h in 5 cases). The 6-month GFR was 41.2 (34.9-55.7) mL/min. Vascular resistances positively correlated with global histologic score (p = 0.018) at MP start and then decreased from 0.88 ± 0.43 to 0.36 ± 0.13 mm Hg/mL/min (p < 0.001) in parallel with a three-fold renal flow increase from 24.0 ± 14.7 to 74.7 ± 31.8 mL/min (p < 0.001). Consistently, vascular resistance reductions positively correlated with global histologic score (p = 0.009, r = -0.429). Unlike KDPI or vascular resistances, histologic score was independently associated with 6-month GFR (beta standardized coefficient: -0.894, p = 0.005).

Conclusions: MP safely improves graft perfusion, particularly in kidneys with severe histologic changes that would not be considered for transplantation because of high KDPI. The preimplantation histologic score associates with the functional recovery of older kidneys even in the context of a standardized program of pulsatile perfusion.
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http://dx.doi.org/10.1159/000512341DOI Listing
November 2021

Long-term follow-up of recovered patients with COVID-19.

Lancet 2021 01 8;397(10270):173-175. Epub 2021 Jan 8.

Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 24126 Bergamo, Italy. Electronic address:

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http://dx.doi.org/10.1016/S0140-6736(21)00039-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833833PMC
January 2021

Kidney transplant tolerance associated with remote autologous mesenchymal stromal cell administration.

Stem Cells Transl Med 2020 04 24;9(4):427-432. Epub 2019 Dec 24.

Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy.

Here we report the case of successful immune tolerance induction in a living-donor kidney transplant recipient remotely treated with autologous bone marrow-derived mesenchymal stromal cells (MSC). This case report, which to the best of our knowledge is the first in the world in this setting, provides evidence that the modulation of the host immune system with MSC can enable the safe withdrawal of maintenance immunosuppressive drugs while preserving optimal long-term kidney allograft function.
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http://dx.doi.org/10.1002/sctm.19-0185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103624PMC
April 2020

Autotaxin Inhibitor Protects from Chronic Allograft Injury in Rat Kidney Allotransplantation.

Nephron 2020 24;144(1):38-48. Epub 2019 Sep 24.

Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy.

Background: Tissue fibrosis is the final common phase of chronic allograft injury, the leading cause of late graft loss in kidney transplantation. Preclinical evidence points to the involvement of lysophosphatidic acid (LPA), a bioactive phospholipid, in the development of renal fibrosis.

Objectives: We assessed whether treatment with an orally available inhibitor of autotaxin (ATXi), the main LPA-producing enzyme, could slow the progression of chronic allograft injury in a fully major histocompatibility complex-mismatched rat kidney transplant model and compared its effects with those of the angiotensin-converting enzyme inhibitor lisinopril.

Methods: Kidney allograft recipients were given ciclosporin for the first 15 postoperative days to prevent early acute rejection. Thereafter, they received either no treatment or ATXi or lisinopril and were followed for 180 days after transplantation.

Results: Renal LPA levels were increased in allograft rats, providing the rationale for using ATXi in this model. Chronic treatment with ATXi or lisinopril limited progressive proteinuria and ameliorated tubulointerstitial fibrosis compared with allograft rats, although the effects were more robust under ATX inhibition. The administration of ATXi, but not lisinopril, attenuated systemic hypertension, reduced intragraft T cell infiltration, and eventually improved renal graft survival.

Conclusions: In summary, ATXi had protective effects on indices of chronic allograft injury and could be of therapeutic add-on value in the kidney transplant setting. Notably, an ATX inhibitor is currently being investigated in 2 large phase 3 studies in idiopathic pulmonary fibrosis, underscoring the clinical relevance of our findings.
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http://dx.doi.org/10.1159/000502908DOI Listing
March 2021

Octreotide-LAR in later-stage autosomal dominant polycystic kidney disease (ALADIN 2): A randomized, double-blind, placebo-controlled, multicenter trial.

PLoS Med 2019 04 5;16(4):e1002777. Epub 2019 Apr 5.

Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent genetically determined renal disease. In affected patients, renal function may progressively decline up to end-stage renal disease (ESRD), and approximately 10% of those with ESRD are affected by ADPKD. The somatostatin analog octreotide long-acting release (octreotide-LAR) slows renal function deterioration in patients in early stages of the disease. We evaluated the renoprotective effect of octreotide-LAR in ADPKD patients at high risk of ESRD because of later-stage ADPKD.

Methods And Findings: We did an internally funded, parallel-group, double-blind, placebo-controlled phase III trial to assess octreotide-LAR in adults with ADPKD with glomerular filtration rate (GFR) 15-40 ml/min/1.73 m2. Participants were randomized to receive 2 intramuscular injections of 20 mg octreotide-LAR (n = 51) or 0.9% sodium chloride solution (placebo; n = 49) every 28 days for 3 years. Central randomization was 1:1 using a computerized list stratified by center and presence or absence of diabetes or proteinuria. Co-primary short- and long-term outcomes were 1-year total kidney volume (TKV) (computed tomography scan) growth and 3-year GFR (iohexol plasma clearance) decline. Analyses were by modified intention-to-treat. Patients were recruited from 4 Italian nephrology units between October 11, 2011, and March 20, 2014, and followed up to April 14, 2017. Baseline characteristics were similar between groups. Compared to placebo, octreotide-LAR reduced median (95% CI) TKV growth from baseline by 96.8 (10.8 to 182.7) ml at 1 year (p = 0.027) and 422.6 (150.3 to 695.0) ml at 3 years (p = 0.002). Reduction in the median (95% CI) rate of GFR decline (0.56 [-0.63 to 1.75] ml/min/1.73 m2 per year) was not significant (p = 0.295). TKV analyses were adjusted for age, sex, and baseline TKV. Over a median (IQR) 36 (24 to 37) months of follow-up, 9 patients on octreotide-LAR and 21 patients on placebo progressed to a doubling of serum creatinine or ESRD (composite endpoint) (hazard ratio [HR] [95% CI] adjusted for age, sex, baseline serum creatinine, and baseline TKV: 0.307 [0.127 to 0.742], p = 0.009). One composite endpoint was prevented for every 4 treated patients. Among 63 patients with chronic kidney disease (CKD) stage 4, 3 on octreotide-LAR and 8 on placebo progressed to ESRD (adjusted HR [95% CI]: 0.121 [0.017 to 0.866], p = 0.036). Three patients on placebo had a serious renal cyst rupture/infection and 1 patient had a serious urinary tract infection/obstruction, versus 1 patient on octreotide-LAR with a serious renal cyst infection. The main study limitation was the small sample size.

Conclusions: In this study we observed that in later-stage ADPKD, octreotide-LAR slowed kidney growth and delayed progression to ESRD, in particular in CKD stage 4.

Trial Registration: ClinicalTrials.gov NCT01377246; EudraCT: 2011-000138-12.
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http://dx.doi.org/10.1371/journal.pmed.1002777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450618PMC
April 2019

Effects of valsartan, benazepril and their combination in overt nephropathy of type 2 diabetes: A prospective, randomized, controlled trial.

Diabetes Obes Metab 2019 05 22;21(5):1177-1190. Epub 2019 Feb 22.

Department of Renal Medicine, Clinical Research Centre for Rare Diseases "Aldo e Cele Daccò": Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Ranica (Bergamo), Italy.

Aims: To evaluate whether angiotensin-converting enzyme (ACE) inhibitor and angiotensin II receptor blocker (ARB) combination therapy is more nephroprotective than ACE inhibitor or ARB monotherapy in people with type 2 diabetes and overt nephropathy.

Materials And Methods: In this prospective, randomized, open, blind-endpoint phase III trial sponsored by the Italian Drug Agency, 103 consenting patients with type 2 diabetes, aged >40 years, with serum creatinine levels 159 to 309 μmol/L, spot morning urinary albumin-creatinine ratio > 1000 mg/g (or > 500 mg/g in those on ACE inhibitor or ARB therapy at inclusion) were stratified by centre and randomized to 4.5-year treatment with valsartan 320 mg/d (n = 36), benazepril 20 mg/d (n = 34) or halved doses of both medications (n = 33). The primary endpoint was end-stage renal disease (ESRD). Modified intention-to-treat analyses were performed.

Results: Recruitment took place between June 2007 and February 2013 at 10 centres in Italy and one in Slovenia. A total of 77 participants completed the study and 26 were prematurely withdrawn. During a median (interquartile range) of 41 (18-54) months, 12 participants on benazepril (35.3%) and nine on combination therapy (27.3%) progressed to ESRD, versus five on valsartan (13.9%). Differences between benazepril (hazard ratio [HR] 3.59, 95% confidence interval [CI] 1.25-10.30; P = 0.018) or combination therapy (HR 3.28, 95% CI 1.07-10.0; P = 0.038) and valsartan were significant, even after adjustment for age, gender and baseline serum creatinine, systolic blood pressure and 24-hour proteinuria (HR 5.16, 95% CI 1.50-17.75, P = 0.009 and HR 4.75, 95% CI 1.01-22.39, P = 0.049, respectively). Adverse events were distributed similarly among the groups.

Conclusions: In people with type 2 diabetes with nephropathy, valsartan (320 mg/d) safely postponed ESRD more effectively than benazepril (20 mg/d) or than halved doses of both medications.
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http://dx.doi.org/10.1111/dom.13639DOI Listing
May 2019

Maternal and environmental risk factors for neonatal AKI and its long-term consequences.

Nat Rev Nephrol 2018 11;14(11):688-703

Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy.

Acute kidney injury (AKI) is a common and life-threatening complication in critically ill neonates. Gestational risk factors for AKI include premature birth, intrauterine growth restriction and low birthweight, which are associated with poor nephron development and are often the consequence of pre-gestational and gestational factors, such as poor nutritional status. Our understanding of how to best optimize renal development and prevent AKI is in its infancy; however, the identification of pre-gestational and gestational factors that increase the risk of adverse neonatal outcomes and the implementation of interventions, such as improving nutritional status early in pregnancy, have the potential to optimize fetal growth and reduce the risk of preterm birth, thereby improving kidney health. The overall risk of AKI among critically ill and premature neonates is exacerbated postnatally as these infants are often exposed to dehydration, septic shock and potentially nephrotoxic medications. Strategies to improve outcomes - for example, through careful evaluation of nephrotoxic drugs - may reduce the incidence of AKI and its consequences among this population. Management strategies and updated technology that will support neonates with AKI are greatly needed. Extremely premature infants and those who survive an episode of AKI should be screened for chronic kidney disease until early adulthood. Here, we provide an overview of our current understanding of neonatal AKI, focusing on its relationship to preterm birth and growth restriction. We describe factors that prevent optimal nephrogenesis during pregnancy and provide a framework for future explorations designed to maximize outcomes in this vulnerable population.
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http://dx.doi.org/10.1038/s41581-018-0054-yDOI Listing
November 2018

Long-Term Clinical and Immunological Profile of Kidney Transplant Patients Given Mesenchymal Stromal Cell Immunotherapy.

Front Immunol 2018 14;9:1359. Epub 2018 Jun 14.

IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy.

We report here the long-term clinical and immunological results of four living-donor kidney transplant patients given autologous bone marrow-derived mesenchymal stromal cells (MSCs) as part of a phase 1 study focused on the safety and feasibility of this cell therapy. According to study protocols implemented over time, based on initial early safety findings, the patients were given MSC at day 7 posttransplant ( = 2) or at day -1 pretransplant ( = 2) and received induction therapy with basiliximab and low-dose rabbit anti-thymocyte globulin (RATG) or RATG alone, and were maintained on low-dose ciclosporin (CsA)/mycophenolate mofetil (MMF). All MSC-treated patients had stable graft function during the 5- to 7-year follow-up, without increased susceptibility to infections or neoplasm. In three MSC recipients, but not historical control patients, circulating memory CD8 T cell percentages remained lower than basal, coupled with persistent reduction of donor-specific cytotoxicity. Two patients showed a long-lasting increase in the regulatory T cell/memory CD8 T cell ratio, paralleled by high circulating levels of naïve and transitional B cells. In one of these two patients, CsA was successfully discontinued, and currently the low-dose MMF monotherapy is on the tapering phase. The study shows that MSC therapy is safe in the long term and could promote a pro-tolerogenic environment in selected patients. Extensive immunomonitoring of MSC-treated kidney transplant recipients could help selection of patients for safe withdrawal of maintenance immunosuppressive drugs (NCT00752479 and NCT02012153).
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http://dx.doi.org/10.3389/fimmu.2018.01359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6014158PMC
June 2018

Blood Pressure and Metabolic Effects of Acetyl-l-Carnitine in Type 2 Diabetes: DIABASI Randomized Controlled Trial.

J Endocr Soc 2018 May 22;2(5):420-436. Epub 2018 Mar 22.

Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.

Context: Acetyl-l-carnitine (ALC), a mitochondrial carrier involved in lipid oxidation and glucose metabolism, decreased systolic blood pressure (SBP), and ameliorated insulin sensitivity in hypertensive nondiabetic subjects at high cardiovascular risk.

Objective: To assess the effects of ALC on SBP and glycemic and lipid control in patients with hypertension, type 2 diabetes mellitus (T2D), and dyslipidemia on background statin therapy.

Design: After 4-week run-in period and stratification according to previous statin therapy, patients were randomized to 6-month, double-blind treatment with ALC or placebo added-on simvastatin.

Setting: Five diabetology units and one clinical research center in Italy.

Patients: Two hundred twenty-nine patients with hypertension and dyslipidemic T2D >40 years with stable background antihypertensive, hypoglycemic, and statin therapy and serum creatinine <1.5 mg/dL.

Interventions: Oral ALC 1000 mg or placebo twice daily on top of stable simvastatin therapy.

Outcome And Measures: Primary outcome was SBP. Secondary outcomes included lipid and glycemic profiles. Total-body glucose disposal rate and glomerular filtration rate were measured in subgroups by hyperinsulinemic-euglycemic clamp and iohexol plasma clearance, respectively.

Results: SBP did not significantly change after 6-month treatment with ALC compared with placebo (-2.09 mm Hg -3.57 mm Hg, = 0.9539). Serum cholesterol, triglycerides, and lipoprotein(a), as well as blood glucose, glycated hemoglobin, fasting insulin levels, homeostatic model assessment of insulin resistance index, glucose disposal rate, and glomerular filtration rate did not significantly differ between treatments. Adverse events were comparable between groups.

Conclusions: Six-month oral ALC supplementation did not affect blood pressure, lipid and glycemic control, insulin sensitivity and kidney function in hypertensive normoalbuminuric and microalbuminuric T2D patients on background statin therapy.
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http://dx.doi.org/10.1210/js.2017-00426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5912091PMC
May 2018

Global Cardiovascular and Renal Outcomes of Reduced GFR.

J Am Soc Nephrol 2017 Jul 13;28(7):2167-2179. Epub 2017 Apr 13.

National Heart, Lung, and Blood Institute, Framingham, MA.

The burden of premature death and health loss from ESRD is well described. Less is known regarding the burden of cardiovascular disease attributable to reduced GFR. We estimated the prevalence of reduced GFR categories 3, 4, and 5 (not on RRT) for 188 countries at six time points from 1990 to 2013. Relative risks of cardiovascular outcomes by three categories of reduced GFR were calculated by pooled random effects meta-analysis. Results are presented as deaths for outcomes of cardiovascular disease and ESRD and as disability-adjusted life years for outcomes of cardiovascular disease, GFR categories 3, 4, and 5, and ESRD. In 2013, reduced GFR was associated with 4% of deaths worldwide, or 2.2 million deaths (95% uncertainty interval [95% UI], 2.0 to 2.4 million). More than half of these attributable deaths were cardiovascular deaths (1.2 million; 95% UI, 1.1 to 1.4 million), whereas 0.96 million (95% UI, 0.81 to 1.0 million) were ESRD-related deaths. Compared with metabolic risk factors, reduced GFR ranked below high systolic BP, high body mass index, and high fasting plasma glucose, and similarly with high total cholesterol as a risk factor for disability-adjusted life years in both developed and developing world regions. In conclusion, by 2013, cardiovascular deaths attributed to reduced GFR outnumbered ESRD deaths throughout the world. Studies are needed to evaluate the benefit of early detection of CKD and treatment to decrease these deaths.
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http://dx.doi.org/10.1681/ASN.2016050562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5491277PMC
July 2017

Conversion from Brand-Name Neoral to the Generic Ciqorin in Stable Renal Transplant Recipients.

Nephron 2017 10;135(3):173-180. Epub 2016 Dec 10.

Clinical Research Center for Rare Diseases Aldo and Cele Daccò, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy.

Background/aims: Transplant physicians and patients are often reluctant to change to generic versions of immunosuppressive drugs with a narrow therapeutic index, such as ciclosporin (CsA). Thus, in routine follow-up for kidney transplant patients receiving CsA maintenance immunosuppressive therapy in our center, we evaluated the exchangeability of the brand name, Neoral, and the recently approved CsA generic formulation, Ciqorin.

Methods: We assessed the complete 12-h CsA pharmacokinetic profile and direct measurement of glomerular filtration rate (mGFR) of 10 patients receiving stable doses of Neoral (138 ± 43 mg/day), at least 6 months after kidney transplantation (Neoral 1). The same evaluations were repeated 10 days after conversion to Ciqorin on a milligram-to-milligram basis and 10 days after reinstituting Neoral (Neoral 2).

Results: The mean CsA area under the concentration-time curve increased slightly after switching from Neoral to Ciqorin (p = 0.03), but did not change significantly after Neoral was reintroduced (Neoral 1: 2,234 ± 783, Ciqorin: 2,452 ± 767, Neoral 2: 2,472 ± 784 ng × h/mL). There were no appreciable differences between the 2 CsA formulations in trough levels, maximum concentrations, or time to reach maximum concentrations. In all patients, renal function remained stable throughout the monitoring period (mGFR, Neoral 1: 52.0 ± 16.2; Ciqorin: 55.0 ± 19.0; Neoral 2: 55.8 ± 18.9 mL/min/1.73 m2), as did urinary and hematochemical parameters.

Conclusions: In stable kidney transplant recipients, switching from Neoral to Ciqorin resulted in similar pharmacokinetic parameters and did not change renal allograft function, reassuring physicians and patients regarding the exchangeability of reference and generic CsA formulations.
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http://dx.doi.org/10.1159/000453671DOI Listing
March 2017

[Renal transplantation in Autosomal Dominant Polycystic Kidney Disease (ADPKD)].

G Ital Nefrol 2016 Sep-Oct;33(5)

Transplantation is the optimal choice for renal replacement therapy in patients with autosomal dominant polycystic kidney disease (ADPKD). However, some specific issues should be addressed before transplantation, including nephrectomy of native kidneys, cystic liver involvement, screening for intracranial aneurysms and living related-donor transplantation. After kidney transplantation, patient and graft survival rates are excellent and the size of native kidneys typically declines. Nevertheless, a number of renal and extrarenal complications have been documented in kidney transplant recipients with ADPKD. In particular, renal cyst infections may occur in patients who did not undergo pretransplant nephrectomy. Moreover, an increased risk in new-onset diabetes mellitus and non-melanoma skin cancer has been reported, even though recent studies challenged these findings. In patients with ADPKD who did not undergo preventive nephrectomy, the risk of malignancy in native kidneys after renal transplantation is comparable to that reported in patients with other nephropathies. There is no evidence supporting the preferential use of mammalian target of rapamycin inhibitors as immunosuppressive drugs in transplant recipients with ADPKD.
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November 2017

[Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD): Somatostatin analogues and mTOR inhibitors].

G Ital Nefrol 2016 Sep-Oct;33(5)

Recent advances in the understanding of the molecular mechanisms underlying autosomal dominant polycystic kidney disease (ADPKD) set the stage for the development of various treatments aimed to arrest or delay disease progression. In particular, clinical trials showed that the use of somatostatin analogues in patients with ADPKD is able to slow down the increase in total kidney volume and the progressive decline in renal function over the long-term. Treatment with these agents is generally well tolerated and it also enables to control cyst growth in the liver in patients with this extra-renal manifestation of the disease. By contrast, mammalian target of rapamycin (mTOR) inhibitors, although promising in different experimental models of kidney and liver disease, in most clinical studies they were not effective in slowing cystic kidney growth and/or improving the progressive renal function decline in patients with ADPKD. Therapy with mTOR inhibitors is also limited by the elevated incidence of adverse events, which frequently requires drug withdrawal or dose reduction, eventually nullifying the potential renoprotective effect.
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November 2017

Should We Still Believe in Randomized Controlled Trials in Nephrology?

Nephron 2017 20;136(4):281-286. Epub 2016 Sep 20.

Clinical Research Center for Rare Diseases 'Aldo and Cele Daccò', IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy.

The randomized controlled trial (RCT) is the cornerstone upon which clinical decision-making is based. Pivotal RCTs in the nephrology area efficiently demonstrated the renoprotective effects of treatment with renin-angiotensin system inhibitors in patients with diabetic and non-diabetic proteinuric nephropathies. However, there is concern about the increasing cost, complexity and duration of clinical studies. Moreover, recent large RCTs addressing key issues for patients with renal disease failed to achieve definitive conclusions mainly due to critical flaws in the investigational strategies, including the adoption of excessive/fixed doses of the study medications, inappropriate use of the placebo-controlled design, enrollment of low-risk individuals, poor reporting of adverse events or unreliable evaluation of renal function. The information now available on the biases that characterize the current RCTs should serve as a tool to rethink the design, patient selection and implementation of future RCTs in nephrology.
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http://dx.doi.org/10.1159/000450618DOI Listing
May 2018

Progression, Remission and Regression of Chronic Renal Diseases.

Nephron 2016 21;134(1):20-4. Epub 2016 Apr 21.

IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases 'Aldo and Cele Daccò', Bergamo, Italy.

Progression to end-stage renal disease is common in chronic nephropathies, independent of the initial insult. While genetic factors may contribute to susceptibility and progression of renal disease, proteinuria has been documented as an independent predictor of outcome. Reduction of urinary protein levels by restoration of glomerular sieving function with renin-angiotensin system (RAS) blockers has been shown to limit renal function decline in individuals with non-diabetic and diabetic nephropathies to the point that remission of the disease and regression of renal lesions have been observed in experimental animals and even in humans. In animal models, regression of glomerular structural changes is associated with remodeling of glomerular architecture. This review briefly describes our understanding of the mechanism of renal disease progression, the therapeutic advantages of ameliorating glomerular sieving dysfunction and proteinuria of RAS inhibitors and how remission/regression of renal injury can be achieved with multifactorial interventions.
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http://dx.doi.org/10.1159/000445844DOI Listing
March 2017

Effect of Sirolimus on Disease Progression in Patients with Autosomal Dominant Polycystic Kidney Disease and CKD Stages 3b-4.

Clin J Am Soc Nephrol 2016 05 22;11(5):785-94. Epub 2016 Feb 22.

Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Bergamo, Italy; Units of Nephrology and Dialysis, Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy

Background And Objectives: The effect of mammalian target of rapamycin (mTOR) inhibitors has never been tested in patients with autosomal dominant polycystic kidney disease (ADPKD) and severe renal insufficiency.

Design, Setting, Participants, & Measurements: In this academic, prospective, randomized, open label, blinded end point, parallel group trial (ClinicalTrials.gov no. NCT01223755), 41 adults with ADPKD, CKD stage 3b or 4, and proteinuria ≤0.5 g/24 h were randomized between September of 2010 and March of 2012 to sirolimus (3 mg/d; serum target levels of 5-10 ng/ml) added on to conventional therapy (n=21) or conventional treatment alone (n=20). Primary outcome was GFR (iohexol plasma clearance) change at 1 and 3 years versus baseline.

Results: At the 1-year preplanned interim analysis, GFR fell from 26.7±5.8 to 21.3±6.3 ml/min per 1.73 m(2) (P<0.001) and from 29.6±5.6 to 24.9±6.2 ml/min per 1.73 m(2) (P<0.001) in the sirolimus and conventional treatment groups, respectively. Albuminuria (73.8±81.8 versus 154.9±152.9 μg/min; P=0.02) and proteinuria (0.3±0.2 versus 06±0.4 g/24 h; P<0.01) increased with sirolimus. Seven patients on sirolimus versus one control had de novo proteinuria (P=0.04), ten versus three patients doubled proteinuria (P=0.02), 18 versus 11 patients had peripheral edema (P=0.04), and 14 versus six patients had upper respiratory tract infections (P=0.03). Three patients on sirolimus had angioedema, 14 patients had aphthous stomatitis, and seven patients had acne (P<0.01 for both versus controls). Two patients progressed to ESRD, and two patients withdrew because of worsening of proteinuria. These events were not observed in controls. Thus, the independent data and safety monitoring board recommend early trial termination for safety reasons. At 1 year, total kidney volume (assessed by contrast-enhanced computed tomography imaging) increased by 9.0% from 2857.7±1447.3 to 3094.6±1519.5 ml on sirolimus and 4.3% from 3123.4±1695.3 to 3222.6±1651.4 ml on conventional therapy (P=0.12). On follow-up, 37% and 7% of serum sirolimus levels fell below or exceeded the therapeutic range, respectively.

Conclusions: Finding that sirolimus was unsafe and ineffective in patients with ADPKD and renal insufficiency suggests that mTOR inhibitor therapy may be contraindicated in this context.
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http://dx.doi.org/10.2215/CJN.09900915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4858487PMC
May 2016

Mesenchymal stromal cells in renal transplantation: opportunities and challenges.

Nat Rev Nephrol 2016 Apr 8;12(4):241-53. Epub 2016 Feb 8.

IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases "Aldo &Cele Daccò", Via G.B. Camozzi 3, 24020 Ranica, Bergamo, Italy.

Lifelong immunosuppressive therapy is essential to prevent allograft rejection in transplant recipients. Long-term, nonspecific immunosuppression can, however, result in life-threatening complications and fail to prevent chronic graft rejection. Bone marrow (BM)-derived multipotent mesenchymal stromal cells (MSCs) have emerged as a potential candidate for cell-based therapy to modulate the immune response in organ transplantation. These cells can repair tissue after injury and downregulate many of the effector functions of immune cells that participate in the alloimmune response, converting them into regulatory cells. The findings of preclinical and initial clinical studies support the potential tolerance-inducing effects of MSCs and highlight the unanticipated complexity of MSC therapy in kidney transplantation. In animal models of transplantation MSCs promote donor-specific tolerance through the generation of regulatory T cells and antigen-presenting cells. In some settings, however, MSCs can acquire proinflammatory properties and contribute to allograft dysfunction. The available data from small clinical studies suggest that cell infusion is safe and well tolerated by kidney transplant recipients. Ongoing and future trials will provide evidence regarding the long-term safety of MSC therapy and determine the optimum cell source (either autologous or allogeneic) and infusion protocol to achieve operational tolerance in kidney transplant recipients. These studies will also provide additional evidence regarding the risks and benefits of MSC infusion and will hopefully offer definitive answers to the important questions of when, where, how many and which types of MSCs should be infused to fully exploit their immunomodulatory, pro-tolerogenic and tissue-repairing properties.
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http://dx.doi.org/10.1038/nrneph.2016.7DOI Listing
April 2016

Recent advances in immunosuppression and acquired immune tolerance in renal transplants.

Am J Physiol Renal Physiol 2016 Mar 20;310(6):F446-53. Epub 2016 Jan 20.

IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Transplant Research Center "Chiara Cucchi de Alessandri e Gilberto Crespi," Ranica, Bergamo, Italy; IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," Ranica, Bergamo, Italy; Unit of Nephrology and Dialysis, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy; and Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.

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http://dx.doi.org/10.1152/ajprenal.00312.2015DOI Listing
March 2016

Global, regional, and national disability-adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990-2013: quantifying the epidemiological transition.

Lancet 2015 Nov 28;386(10009):2145-91. Epub 2015 Aug 28.

Background: The Global Burden of Disease Study 2013 (GBD 2013) aims to bring together all available epidemiological data using a coherent measurement framework, standardised estimation methods, and transparent data sources to enable comparisons of health loss over time and across causes, age-sex groups, and countries. The GBD can be used to generate summary measures such as disability-adjusted life-years (DALYs) and healthy life expectancy (HALE) that make possible comparative assessments of broad epidemiological patterns across countries and time. These summary measures can also be used to quantify the component of variation in epidemiology that is related to sociodemographic development.

Methods: We used the published GBD 2013 data for age-specific mortality, years of life lost due to premature mortality (YLLs), and years lived with disability (YLDs) to calculate DALYs and HALE for 1990, 1995, 2000, 2005, 2010, and 2013 for 188 countries. We calculated HALE using the Sullivan method; 95% uncertainty intervals (UIs) represent uncertainty in age-specific death rates and YLDs per person for each country, age, sex, and year. We estimated DALYs for 306 causes for each country as the sum of YLLs and YLDs; 95% UIs represent uncertainty in YLL and YLD rates. We quantified patterns of the epidemiological transition with a composite indicator of sociodemographic status, which we constructed from income per person, average years of schooling after age 15 years, and the total fertility rate and mean age of the population. We applied hierarchical regression to DALY rates by cause across countries to decompose variance related to the sociodemographic status variable, country, and time.

Findings: Worldwide, from 1990 to 2013, life expectancy at birth rose by 6·2 years (95% UI 5·6-6·6), from 65·3 years (65·0-65·6) in 1990 to 71·5 years (71·0-71·9) in 2013, HALE at birth rose by 5·4 years (4·9-5·8), from 56·9 years (54·5-59·1) to 62·3 years (59·7-64·8), total DALYs fell by 3·6% (0·3-7·4), and age-standardised DALY rates per 100 000 people fell by 26·7% (24·6-29·1). For communicable, maternal, neonatal, and nutritional disorders, global DALY numbers, crude rates, and age-standardised rates have all declined between 1990 and 2013, whereas for non-communicable diseases, global DALYs have been increasing, DALY rates have remained nearly constant, and age-standardised DALY rates declined during the same period. From 2005 to 2013, the number of DALYs increased for most specific non-communicable diseases, including cardiovascular diseases and neoplasms, in addition to dengue, food-borne trematodes, and leishmaniasis; DALYs decreased for nearly all other causes. By 2013, the five leading causes of DALYs were ischaemic heart disease, lower respiratory infections, cerebrovascular disease, low back and neck pain, and road injuries. Sociodemographic status explained more than 50% of the variance between countries and over time for diarrhoea, lower respiratory infections, and other common infectious diseases; maternal disorders; neonatal disorders; nutritional deficiencies; other communicable, maternal, neonatal, and nutritional diseases; musculoskeletal disorders; and other non-communicable diseases. However, sociodemographic status explained less than 10% of the variance in DALY rates for cardiovascular diseases; chronic respiratory diseases; cirrhosis; diabetes, urogenital, blood, and endocrine diseases; unintentional injuries; and self-harm and interpersonal violence. Predictably, increased sociodemographic status was associated with a shift in burden from YLLs to YLDs, driven by declines in YLLs and increases in YLDs from musculoskeletal disorders, neurological disorders, and mental and substance use disorders. In most country-specific estimates, the increase in life expectancy was greater than that in HALE. Leading causes of DALYs are highly variable across countries.

Interpretation: Global health is improving. Population growth and ageing have driven up numbers of DALYs, but crude rates have remained relatively constant, showing that progress in health does not mean fewer demands on health systems. The notion of an epidemiological transition--in which increasing sociodemographic status brings structured change in disease burden--is useful, but there is tremendous variation in burden of disease that is not associated with sociodemographic status. This further underscores the need for country-specific assessments of DALYs and HALE to appropriately inform health policy decisions and attendant actions.

Funding: Bill & Melinda Gates Foundation.
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http://dx.doi.org/10.1016/S0140-6736(15)61340-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4673910PMC
November 2015

Maintenance Dialysis throughout the World in Years 1990 and 2010.

J Am Soc Nephrol 2015 Nov 24;26(11):2621-33. Epub 2015 Jul 24.

Institute for Health Metrics and Evaluation, University of Washington, Seattle, Washington;

Rapidly rising global rates of chronic diseases portend a consequent rise in ESRD. Despite this, kidney disease is not included in the list of noncommunicable diseases (NCDs) targeted by the United Nations for 25% reduction by year 2025. In an effort to accurately report the trajectory and pattern of global growth of maintenance dialysis, we present the change in prevalence and incidence from 1990 to 2010. Data were extracted from the Global Burden of Disease 2010 epidemiologic database. The results are on the basis of an analysis of data from worldwide national and regional renal disease registries and detailed systematic literature review for years 1980-2010. Incidence and prevalence estimates of provision of maintenance dialysis from this database were updated using a negative binomial Bayesian meta-regression tool for 187 countries. Results indicate substantial growth in utilization of maintenance dialysis in almost all world regions. Changes in population structure, changes in aging, and the worldwide increase in diabetes mellitus and hypertension explain a significant portion, but not all, of the increase because increased dialysis provision also accounts for a portion of the rise. These findings argue for the importance of inclusion of kidney disease among NCD targets for reducing premature death throughout the world.
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http://dx.doi.org/10.1681/ASN.2014101017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4625679PMC
November 2015

Mesenchymal stromal cells to control donor-specific memory T cells in solid organ transplantation.

Curr Opin Organ Transplant 2015 Feb;20(1):79-85

Clinical Research Center for Rare Diseases 'Aldo & Cele Daccò', IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Bergamo, Italy.

Purpose Of Review: Mesenchymal stromal cells (MSCs) represent a promising cell therapy to promote transplant tolerance, as they influence many cells involved in immune response. Herein, we review recent evidence on the ability of MSCs to inhibit antigen-induced memory T cell response in vitro and in preclinical studies as well as immunological studies in kidney transplant recipients highlighting the effects of MSC therapy on memory CD8 T-cell proliferation and function.

Recent Findings: MSCs are able to inhibit in-vitro proliferation and effector functions of memory T cells in response to auto-antigen and allo-antigen stimulation. MSC infusion in animal transplant models resulted in a skew of the balance between regulatory T cells and effector/memory T cells towards a pro-tolerogenic profile. MSC in clinical transplantation is in its infancy and limited numbers of clinical studies have performed immunomonitoring of MSC-treated patients. However, available data support the capability of MSCs to control effector/memory CD8 T-cell proliferation and donor-specific CD8 T-cell function long lasting in kidney transplant setting.

Summary: Recent studies of MSCs in kidney transplantation highlight the anticipated add-on value of the immunomodulatory properties of bone marrow derived MSCs in persistently inhibiting donor-specific effector/memory CD8 T cells, an effect not shared by the current immunosuppressive drugs.
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http://dx.doi.org/10.1097/MOT.0000000000000145DOI Listing
February 2015

Paricalcitol for secondary hyperparathyroidism in renal transplantation.

J Am Soc Nephrol 2015 May 5;26(5):1205-14. Epub 2014 Sep 5.

IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Clinical Research Center for Rare Diseases "Aldo & Cele Daccò," Bergamo, Italy; and.

Secondary hyperparathyroidism contributes to post-transplant CKD mineral and bone disorder. Paricalcitol, a selective vitamin D receptor activator, decreased serum parathyroid hormone levels and proteinuria in patients with secondary hyperparathyroidism. This single-center, prospective, randomized, crossover, open-label study compared the effect of 6-month treatment with paricalcitol (1 μg/d for 3 months and then uptitrated to 2 µg/d if tolerated) or nonparicalcitol therapy on serum parathyroid hormone levels (primary outcome), mineral metabolism, and proteinuria in 43 consenting recipients of renal transplants with secondary hyperparathyroidism. Participants were randomized 1:1 according to a computer-generated sequence. Compared with baseline, median (interquartile range) serum parathyroid hormone levels significantly declined on paricalcitol from 115.6 (94.8-152.0) to 63.3 (52.0-79.7) pg/ml (P<0.001) but not on nonparicalcitol therapy. At 6 months, levels significantly differed between treatments (P<0.001 by analysis of covariance). Serum bone-specific alkaline phosphatase and osteocalcin decreased on paricalcitol therapy only and significantly differed between treatments at 6 months (P<0.001 for all comparisons). At 6 months, urinary deoxypyridinoline-to-creatinine ratio and 24-hour proteinuria level decreased only on paricalcitol (P<0.05). L3 and L4 vertebral mineral bone density, assessed by dual-energy x-ray absorption, significantly improved with paricalcitol at 6 months (P<0.05 for both densities). Paricalcitol was well tolerated. Overall, 6-month paricalcitol supplementation reduced parathyroid hormone levels and proteinuria, attenuated bone remodeling and mineral loss, and reduced eGFR in renal transplant recipients with secondary hyperparathyroidism. Long-term studies are needed to monitor directly measured GFR, ensure that the bone remodeling and mineral effects are sustained, and determine if the reduction in proteinuria improves renal and cardiovascular outcomes.
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http://dx.doi.org/10.1681/ASN.2013111185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413751PMC
May 2015

In kidney transplant patients, alemtuzumab but not basiliximab/low-dose rabbit anti-thymocyte globulin induces B cell depletion and regeneration, which associates with a high incidence of de novo donor-specific anti-HLA antibody development.

J Immunol 2013 Sep 2;191(5):2818-28. Epub 2013 Aug 2.

Centro Ricerche Trapianti "Chiara Cucchi de Alessandri e Gilberto Crespi" Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto di Ricerche Farmacologiche "Mario Negri," Bergamo 24020, Italy.

In this single-center matched-cohort study, we evaluated the phenotype of repopulating B cells and its correlation with donor-specific anti-HLA Ab development and long-term graft function in 16 renal transplant recipients and 32 age- and gender-matched controls induced with alemtuzumab or basiliximab (Bas)/low-dose rabbit anti-thymocyte globulin (rATG), respectively. Alemtuzumab, but not Bas/rATG, profoundly depleted peripheral B cells in the first 2 mo posttransplantation. Early posttransplant, naive B cells were significantly depleted, whereas Ag-experienced and memory B cells were partially spared. Transitional B cells transiently increased 2 mo posttransplant. At month 6 posttransplant, pregerminal center B cells emerged, a process promoted by increased BAFF serum levels. Thereafter, B cell counts increased progressively, mainly due to expansion of naive B cells. Conversely, Bas/rATG did not modify the B cell phenotype throughout the follow-up period. Alemtuzumab was associated with a higher incidence of de novo DSA compared with Bas/rATG. DSA development was predicted by changes in the B cell compartment and correlated with worse long-term graft function. Thus, alemtuzumab-induced B cell depletion/reconstitution may promote chronic humoral responses against the graft.
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http://dx.doi.org/10.4049/jimmunol.1203261DOI Listing
September 2013

Mesenchymal stromal cells and kidney transplantation: pretransplant infusion protects from graft dysfunction while fostering immunoregulation.

Transpl Int 2013 Sep 6;26(9):867-78. Epub 2013 Jun 6.

Department of Immunology and Transplantation, Azienda Ospedaliera - IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy.

Bone marrow-derived mesenchymal stromal cells (MSC) have emerged as useful cell population for immunomodulation therapy in transplantation. Moving this concept towards clinical application, however, should be critically assessed by a tailor-made step-wise approach. Here, we report results of the second step of the multistep MSC-based clinical protocol in kidney transplantation. We examined in two living-related kidney transplant recipients whether: (i) pre-transplant (DAY-1) infusion of autologous MSC protected from the development of acute graft dysfunction previously reported in patients given MSC post-transplant, (ii) avoiding basiliximab in the induction regimen improved the MSC-induced Treg expansion previously reported with therapy including this anti-CD25-antibody. In patient 3, MSC treatment was uneventful and graft function remained normal during 1 year follow-up. In patient 4, acute cellular rejection occurred 2 weeks post-transplant. Both patients had excellent graft function at the last observation. Circulating memory CD8(+) T cells and donor-specific CD8(+) T-cell cytolytic response were reduced in MSC-treated patients, not in transplant controls not given MSC. CD4(+) FoxP3(+) Treg expansion was comparable in MSC-treated patients with or without basiliximab induction. Thus, pre-transplant MSC no longer negatively affect kidney graft at least to the point of impairing graft function, and maintained MSC-immunomodulatory properties. Induction therapy without basiliximab does not offer any advantage on CD4(+) FoxP3(+) Treg expansion (ClinicalTrials.gov number: NCT 00752479).
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http://dx.doi.org/10.1111/tri.12132DOI Listing
September 2013

Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010.

Lancet 2012 Dec;380(9859):2197-223

Institute for Health Metrics and Evaluation, Seattle 98121, WA, USA.

Background: Measuring disease and injury burden in populations requires a composite metric that captures both premature mortality and the prevalence and severity of ill-health. The 1990 Global Burden of Disease study proposed disability-adjusted life years (DALYs) to measure disease burden. No comprehensive update of disease burden worldwide incorporating a systematic reassessment of disease and injury-specific epidemiology has been done since the 1990 study. We aimed to calculate disease burden worldwide and for 21 regions for 1990, 2005, and 2010 with methods to enable meaningful comparisons over time.

Methods: We calculated DALYs as the sum of years of life lost (YLLs) and years lived with disability (YLDs). DALYs were calculated for 291 causes, 20 age groups, both sexes, and for 187 countries, and aggregated to regional and global estimates of disease burden for three points in time with strictly comparable definitions and methods. YLLs were calculated from age-sex-country-time-specific estimates of mortality by cause, with death by standardised lost life expectancy at each age. YLDs were calculated as prevalence of 1160 disabling sequelae, by age, sex, and cause, and weighted by new disability weights for each health state. Neither YLLs nor YLDs were age-weighted or discounted. Uncertainty around cause-specific DALYs was calculated incorporating uncertainty in levels of all-cause mortality, cause-specific mortality, prevalence, and disability weights.

Findings: Global DALYs remained stable from 1990 (2·503 billion) to 2010 (2·490 billion). Crude DALYs per 1000 decreased by 23% (472 per 1000 to 361 per 1000). An important shift has occurred in DALY composition with the contribution of deaths and disability among children (younger than 5 years of age) declining from 41% of global DALYs in 1990 to 25% in 2010. YLLs typically account for about half of disease burden in more developed regions (high-income Asia Pacific, western Europe, high-income North America, and Australasia), rising to over 80% of DALYs in sub-Saharan Africa. In 1990, 47% of DALYs worldwide were from communicable, maternal, neonatal, and nutritional disorders, 43% from non-communicable diseases, and 10% from injuries. By 2010, this had shifted to 35%, 54%, and 11%, respectively. Ischaemic heart disease was the leading cause of DALYs worldwide in 2010 (up from fourth rank in 1990, increasing by 29%), followed by lower respiratory infections (top rank in 1990; 44% decline in DALYs), stroke (fifth in 1990; 19% increase), diarrhoeal diseases (second in 1990; 51% decrease), and HIV/AIDS (33rd in 1990; 351% increase). Major depressive disorder increased from 15th to 11th rank (37% increase) and road injury from 12th to 10th rank (34% increase). Substantial heterogeneity exists in rankings of leading causes of disease burden among regions.

Interpretation: Global disease burden has continued to shift away from communicable to non-communicable diseases and from premature death to years lived with disability. In sub-Saharan Africa, however, many communicable, maternal, neonatal, and nutritional disorders remain the dominant causes of disease burden. The rising burden from mental and behavioural disorders, musculoskeletal disorders, and diabetes will impose new challenges on health systems. Regional heterogeneity highlights the importance of understanding local burden of disease and setting goals and targets for the post-2015 agenda taking such patterns into account. Because of improved definitions, methods, and data, these results for 1990 and 2010 supersede all previously published Global Burden of Disease results.

Funding: Bill & Melinda Gates Foundation.
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http://dx.doi.org/10.1016/S0140-6736(12)61689-4DOI Listing
December 2012

Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010.

Lancet 2012 Dec;380(9859):2163-96

School of Population Health, Brisbane, QLD, Australia.

Background: Non-fatal health outcomes from diseases and injuries are a crucial consideration in the promotion and monitoring of individual and population health. The Global Burden of Disease (GBD) studies done in 1990 and 2000 have been the only studies to quantify non-fatal health outcomes across an exhaustive set of disorders at the global and regional level. Neither effort quantified uncertainty in prevalence or years lived with disability (YLDs).

Methods: Of the 291 diseases and injuries in the GBD cause list, 289 cause disability. For 1160 sequelae of the 289 diseases and injuries, we undertook a systematic analysis of prevalence, incidence, remission, duration, and excess mortality. Sources included published studies, case notification, population-based cancer registries, other disease registries, antenatal clinic serosurveillance, hospital discharge data, ambulatory care data, household surveys, other surveys, and cohort studies. For most sequelae, we used a Bayesian meta-regression method, DisMod-MR, designed to address key limitations in descriptive epidemiological data, including missing data, inconsistency, and large methodological variation between data sources. For some disorders, we used natural history models, geospatial models, back-calculation models (models calculating incidence from population mortality rates and case fatality), or registration completeness models (models adjusting for incomplete registration with health-system access and other covariates). Disability weights for 220 unique health states were used to capture the severity of health loss. YLDs by cause at age, sex, country, and year levels were adjusted for comorbidity with simulation methods. We included uncertainty estimates at all stages of the analysis.

Findings: Global prevalence for all ages combined in 2010 across the 1160 sequelae ranged from fewer than one case per 1 million people to 350,000 cases per 1 million people. Prevalence and severity of health loss were weakly correlated (correlation coefficient -0·37). In 2010, there were 777 million YLDs from all causes, up from 583 million in 1990. The main contributors to global YLDs were mental and behavioural disorders, musculoskeletal disorders, and diabetes or endocrine diseases. The leading specific causes of YLDs were much the same in 2010 as they were in 1990: low back pain, major depressive disorder, iron-deficiency anaemia, neck pain, chronic obstructive pulmonary disease, anxiety disorders, migraine, diabetes, and falls. Age-specific prevalence of YLDs increased with age in all regions and has decreased slightly from 1990 to 2010. Regional patterns of the leading causes of YLDs were more similar compared with years of life lost due to premature mortality. Neglected tropical diseases, HIV/AIDS, tuberculosis, malaria, and anaemia were important causes of YLDs in sub-Saharan Africa.

Interpretation: Rates of YLDs per 100,000 people have remained largely constant over time but rise steadily with age. Population growth and ageing have increased YLD numbers and crude rates over the past two decades. Prevalences of the most common causes of YLDs, such as mental and behavioural disorders and musculoskeletal disorders, have not decreased. Health systems will need to address the needs of the rising numbers of individuals with a range of disorders that largely cause disability but not mortality. Quantification of the burden of non-fatal health outcomes will be crucial to understand how well health systems are responding to these challenges. Effective and affordable strategies to deal with this rising burden are an urgent priority for health systems in most parts of the world.

Funding: Bill & Melinda Gates Foundation.
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http://dx.doi.org/10.1016/S0140-6736(12)61729-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350784PMC
December 2012

Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010.

Lancet 2012 Dec;380(9859):2095-128

Institute for Health Metrics and Evaluation, Seattle, WA, USA.

Background: Reliable and timely information on the leading causes of death in populations, and how these are changing, is a crucial input into health policy debates. In the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010), we aimed to estimate annual deaths for the world and 21 regions between 1980 and 2010 for 235 causes, with uncertainty intervals (UIs), separately by age and sex.

Methods: We attempted to identify all available data on causes of death for 187 countries from 1980 to 2010 from vital registration, verbal autopsy, mortality surveillance, censuses, surveys, hospitals, police records, and mortuaries. We assessed data quality for completeness, diagnostic accuracy, missing data, stochastic variations, and probable causes of death. We applied six different modelling strategies to estimate cause-specific mortality trends depending on the strength of the data. For 133 causes and three special aggregates we used the Cause of Death Ensemble model (CODEm) approach, which uses four families of statistical models testing a large set of different models using different permutations of covariates. Model ensembles were developed from these component models. We assessed model performance with rigorous out-of-sample testing of prediction error and the validity of 95% UIs. For 13 causes with low observed numbers of deaths, we developed negative binomial models with plausible covariates. For 27 causes for which death is rare, we modelled the higher level cause in the cause hierarchy of the GBD 2010 and then allocated deaths across component causes proportionately, estimated from all available data in the database. For selected causes (African trypanosomiasis, congenital syphilis, whooping cough, measles, typhoid and parathyroid, leishmaniasis, acute hepatitis E, and HIV/AIDS), we used natural history models based on information on incidence, prevalence, and case-fatality. We separately estimated cause fractions by aetiology for diarrhoea, lower respiratory infections, and meningitis, as well as disaggregations by subcause for chronic kidney disease, maternal disorders, cirrhosis, and liver cancer. For deaths due to collective violence and natural disasters, we used mortality shock regressions. For every cause, we estimated 95% UIs that captured both parameter estimation uncertainty and uncertainty due to model specification where CODEm was used. We constrained cause-specific fractions within every age-sex group to sum to total mortality based on draws from the uncertainty distributions.

Findings: In 2010, there were 52·8 million deaths globally. At the most aggregate level, communicable, maternal, neonatal, and nutritional causes were 24·9% of deaths worldwide in 2010, down from 15·9 million (34·1%) of 46·5 million in 1990. This decrease was largely due to decreases in mortality from diarrhoeal disease (from 2·5 to 1·4 million), lower respiratory infections (from 3·4 to 2·8 million), neonatal disorders (from 3·1 to 2·2 million), measles (from 0·63 to 0·13 million), and tetanus (from 0·27 to 0·06 million). Deaths from HIV/AIDS increased from 0·30 million in 1990 to 1·5 million in 2010, reaching a peak of 1·7 million in 2006. Malaria mortality also rose by an estimated 19·9% since 1990 to 1·17 million deaths in 2010. Tuberculosis killed 1·2 million people in 2010. Deaths from non-communicable diseases rose by just under 8 million between 1990 and 2010, accounting for two of every three deaths (34·5 million) worldwide by 2010. 8 million people died from cancer in 2010, 38% more than two decades ago; of these, 1·5 million (19%) were from trachea, bronchus, and lung cancer. Ischaemic heart disease and stroke collectively killed 12·9 million people in 2010, or one in four deaths worldwide, compared with one in five in 1990; 1·3 million deaths were due to diabetes, twice as many as in 1990. The fraction of global deaths due to injuries (5·1 million deaths) was marginally higher in 2010 (9·6%) compared with two decades earlier (8·8%). This was driven by a 46% rise in deaths worldwide due to road traffic accidents (1·3 million in 2010) and a rise in deaths from falls. Ischaemic heart disease, stroke, chronic obstructive pulmonary disease (COPD), lower respiratory infections, lung cancer, and HIV/AIDS were the leading causes of death in 2010. Ischaemic heart disease, lower respiratory infections, stroke, diarrhoeal disease, malaria, and HIV/AIDS were the leading causes of years of life lost due to premature mortality (YLLs) in 2010, similar to what was estimated for 1990, except for HIV/AIDS and preterm birth complications. YLLs from lower respiratory infections and diarrhoea decreased by 45-54% since 1990; ischaemic heart disease and stroke YLLs increased by 17-28%. Regional variations in leading causes of death were substantial. Communicable, maternal, neonatal, and nutritional causes still accounted for 76% of premature mortality in sub-Saharan Africa in 2010. Age standardised death rates from some key disorders rose (HIV/AIDS, Alzheimer's disease, diabetes mellitus, and chronic kidney disease in particular), but for most diseases, death rates fell in the past two decades; including major vascular diseases, COPD, most forms of cancer, liver cirrhosis, and maternal disorders. For other conditions, notably malaria, prostate cancer, and injuries, little change was noted.

Interpretation: Population growth, increased average age of the world's population, and largely decreasing age-specific, sex-specific, and cause-specific death rates combine to drive a broad shift from communicable, maternal, neonatal, and nutritional causes towards non-communicable diseases. Nevertheless, communicable, maternal, neonatal, and nutritional causes remain the dominant causes of YLLs in sub-Saharan Africa. Overlaid on this general pattern of the epidemiological transition, marked regional variation exists in many causes, such as interpersonal violence, suicide, liver cancer, diabetes, cirrhosis, Chagas disease, African trypanosomiasis, melanoma, and others. Regional heterogeneity highlights the importance of sound epidemiological assessments of the causes of death on a regular basis.

Funding: Bill & Melinda Gates Foundation.
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http://dx.doi.org/10.1016/S0140-6736(12)61728-0DOI Listing
December 2012
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