Publications by authors named "Norberto Perico"

168 Publications

COVID-19 and the Kidney: Should Nephrologists Care about COVID-19 rather than Maintaining Their Focus on Renal Patients?

Contrib Nephrol 2021 Aug 3;199:1-15. Epub 2021 Aug 3.

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

Clinical Background: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly spread globally from late 2019, reaching pandemic proportions. Epidemiology: The related disease, COVID-19, exacerbates and progresses due to patients' abnormal inflammatory/immune responses, widespread endothelial damage, and complement-induced blood clotting with microangiopathy. COVID-19 manifests mainly as a respiratory illness. In cases of severe viral pneumonia, it may lead to acute respiratory distress syndrome, respiratory failure, and death. Challenges: Many extrapulmonary manifestations commonly occur, and a substantial proportion of patients with severe COVID-19 exhibit signs of kidney damage. Clinically, kidney involvement ranges from mild/moderate proteinuria and hematuria to acute kidney injury (AKI) requiring renal replacement therapy (RRT). The pathophysiologic mechanisms of kidney damage and AKI in patients with COVID-19 remain unclear but are known to be multifactorial. Current knowledge implies direct SARS-CoV-2-dependent effects on kidney cells (tubular epithelial cells and podocytes) and indirect mechanisms through the systemic effect of viral infection secondary to the critical pulmonary illness and its management. Prevention and Treatment: Standard-of-care strategies apply, as there is no specific evidence to suggest that COVID-19 AKI should be managed differently from other types in severely ill patients. If conservative management fails, RRT should be considered. The choice of RRT approaches and sequential extracorporeal therapies depends on local availability, resources, and expertise. The focus should now be on the long-term follow-up of COVID-19 patients, especially those who developed kidney injury and dysfunction. This represents an opportunity for integrated multidisciplinary research to clarify the natural history of COVID-19 renal sequelae and the best therapeutic interventions to mitigate them.
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http://dx.doi.org/10.1159/000517752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450831PMC
August 2021

Long-Term Outcomes of Kidney Transplants from Older/Marginal Donors: A Cohort Study.

Nephron 2021 Jun 15:1-11. Epub 2021 Jun 15.

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

Introduction: To safely expand the donor pool, we introduced a strategy of biopsy-guided selection and allocation to single or dual transplantation of kidneys from donors >60 years old or with hypertension, diabetes, and/or proteinuria (older/marginal donors). Here, we evaluated the long-term performance of this approach in everyday clinical practice.

Methods: In this single-center cohort study, we compared outcomes of 98 patients who received one or two biopsy-evaluated grafts from older/marginal donors ("recipients") and 198 patients who received nonhistologically assessed single graft from ideal donors ("reference-recipients") from October 2004 to December 2015 at the Bergamo Transplant Center (Italy).

Results: Older/marginal donors and their recipients were 27.9 and 19.3 years older than ideal donors and their reference-recipients, respectively. KDPI/KDRI and donor serum creatinine were higher and cold ischemia time longer in the recipient group. During a median follow-up of 51.9 (interquartile range 23.1-88.6) months, 11.2% of recipients died, 7.1% lost their graft, and 16.3% had biopsy-proven acute rejection (BPAR) versus 3.5, 7.6, and 17.7%, respectively, of reference-recipients. Overall death-censored graft failure (rate ratio 0.78 [95% CI 0.33-2.08]), 5-year death-censored graft survival (94.3% [87.8-100.0] vs. 94.2% [90.5-98.0]), BPAR incidence (rate ratio 0.87 [0.49-1.62]), and yearly measured glomerular filtration rate decline (1.18 ± 3.27 vs. 0.68 ± 2.42 mL/min/1.73 m2, p = 0.37) were similar between recipients and reference-recipients, respectively.

Conclusions: Biopsy-guided selection and allocation of kidneys from older/marginal donors can safely increase transplant activity in clinical practice without affecting long-term outcomes. This may help manage the growing gap between organ demand and supply without affecting long-term recipient and graft outcomes.
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http://dx.doi.org/10.1159/000516534DOI Listing
June 2021

A simple, home-therapy algorithm to prevent hospitalisation for COVID-19 patients: A retrospective observational matched-cohort study.

EClinicalMedicine 2021 Jul 9;37:100941. Epub 2021 Jun 9.

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

Background: Effective home treatment algorithms implemented based on a pathophysiologic and pharmacologic rationale to accelerate recovery and prevent hospitalisation of patients with early coronavirus disease 2019 (COVID-19) would have major implications for patients and health system.

Methods: This academic, matched-cohort study compared outcomes of 90 consecutive consenting patients with mild COVID-19 treated at home by their family physicians between October 2020 and January 2021 in Northern and Central Italy, according to the proposed recommendation algorithm, with outcomes for 90 age-, sex-, and comorbidities-matched patients who received other therapeutic regimens. Primary outcome was time to resolution of major symptoms. Secondary outcomes included prevention of hospitalisation. Analyses were by intention-to-treat.

Findings: All patients achieved complete remission. The median [IQR] time to resolution of major symptoms was 18 [14-23] days in the 'recommended schedule' cohort and 14 [7-30] days in the matched 'control' cohort ( = 0·033). Other symptoms persisted in a lower percentage of patients in the 'recommended' than in the 'control' cohort (23·3% versus 73·3%, respectively, <0·0001) and for a shorter period ( = 0·0107). Two patients in the 'recommended' cohort were hospitalised compared to 13 (14·4%) controls ( = 0·0103). The prevention algorithm reduced the days and cumulative costs of hospitalisation by >90%.

Interpretation: Implementation of an early home treatment algorithm failed to accelerate recovery from major symptoms of COVID-19, but reduced the risk of hospitalisation and related treatment costs. Given the study design, additional research would be required to consolidate the proposed treatment recommendations.

Funding: Fondazione Cav.Lav. Carlo Pesenti.
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http://dx.doi.org/10.1016/j.eclinm.2021.100941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189543PMC
July 2021

Trends in cardiovascular diseases burden and vascular risk factors in Italy: The Global Burden of Disease study 1990-2017.

Eur J Prev Cardiol 2021 05;28(4):385-396

School of Medicine and Surgery, Research Centre on Public Health (CESP), University of Milano-Bicocca, Italy.

Aims: An exhaustive and updated estimation of cardiovascular disease burden and vascular risk factors is still lacking in European countries. This study aims to fill this gap assessing the global Italian cardiovascular disease burden and its changes from 1990 to 2017 and comparing the Italian situation with European countries.

Methods: All accessible data sources from the 2017 Global Burden of Disease study were used to estimate the cardiovascular disease prevalence, mortality and disability-adjusted life years and cardiovascular disease attributable risk factors burden in Italy from 1990 to 2017. Furthermore, we compared the cardiovascular disease burden within the 28 European Union countries.

Results: Since 1990, we observed a significant decrease of cardiovascular disease burden, particularly in the age-standardised prevalence (-12.7%), mortality rate (-53.8%), and disability-adjusted life years rate (-55.5%). Similar improvements were observed in the majority of European countries. However, we found an increase in all-ages prevalence of cardiovascular diseases from 5.75 m to 7.49 m Italian residents. Cardiovascular diseases still remain the first cause of death (34.8% of total mortality). More than 80% of the cardiovascular disease burden could be attributed to known modifiable risk factors such as high systolic blood pressure, dietary risks, high low density lipoprotein cholesterol, and impaired kidney function.

Conclusions: Our study shows a decline in cardiovascular mortality and disability-adjusted life years, which reflects the success in reducing disability, premature death and early incidence of cardiovascular diseases. However, the burden of cardiovascular diseases is still high. An approach that includes the cooperation and coordination of all stakeholders of the Italian National Health System is required to further reduce this burden.
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http://dx.doi.org/10.1177/2047487320949414DOI Listing
May 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

Bergamo and Covid-19: How the Dark Can Turn to Light.

Front Med (Lausanne) 2021 19;8:609440. Epub 2021 Feb 19.

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

The novel coronavirus, SARS-CoV-2, continues to spread rapidly. Here we discuss the dramatic situation created by COVID-19 in Italy, particularly in the province of Bergamo (the most severely affected in the first wave), as an example of how, in the face of an unprecedented tragedy, acting (albeit belatedly)-including imposing a very strict lockdown-can largely resolve the situation within approximately 2 months. The measures taken here ensured that Bergamo hospital, which was confronted with rapidly rising numbers of severely ill COVID-19 patients requiring hospitalization, was able to meet the initial challenges of the pandemic. We also report that local organization and, more important, the large natural immunity against SARS-CoV-2 of the Bergamo population developed during the first wave of the epidemic, can explain the limited number of new COVID-19 cases during the more recent second wave compared to the numbers in other areas of Lombardy. Furthermore, we highlight the importance of coordinating the easing of containment measures to avoid what is currently observed in other countries, especially in the United States, Latin American and India, where this approach has not been adopted, and a dramatic resurgence of COVID-19 cases and an increase in the number of hospitalisations and deaths have been reported.
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http://dx.doi.org/10.3389/fmed.2021.609440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933506PMC
February 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

Third-party bone marrow-derived mesenchymal stromal cell infusion before liver transplantation: A randomized controlled trial.

Am J Transplant 2021 08 22;21(8):2795-2809. Epub 2021 Feb 22.

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

Mesenchymal stromal cells (MSC) have emerged as a promising therapy to minimize the immunosuppressive regimen or induce tolerance in solid organ transplantation. In this randomized open-label phase Ib/IIa clinical trial, 20 liver transplant patients were randomly allocated (1:1) to receive a single pretransplant intravenous infusion of third-party bone marrow-derived MSC or standard of care alone. The primary endpoint was the safety profile of MSC administration during the 1-year follow-up. In all, 19 patients completed the study, and none of those who received MSC experienced infusion-related complications. The incidence of serious and non-serious adverse events was similar in the two groups. Circulating Treg/memory Treg and tolerant NK subset of CD56 NK cells increased slightly over baseline, albeit not to a statistically significant extent, in MSC-treated patients but not in the control group. Graft function and survival, as well as histologic parameters and intragraft expression of tolerance-associated transcripts in 1-year protocol biopsies were similar in the two groups. In conclusion, pretransplant MSC infusion in liver transplant recipients was safe and induced mild positive changes in immunoregulatory T and NK cells in the peripheral blood. This study opens the way for a trial on possible tolerogenic efficacy of MSC in liver transplantation. ClinicalTrials.gov identifier: NCT02260375.
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http://dx.doi.org/10.1111/ajt.16468DOI Listing
August 2021

The emergence of regenerative medicine in organ transplantation: 1st European Cell Therapy and Organ Regeneration Section meeting.

Transpl Int 2020 08 28;33(8):833-840. Epub 2020 Apr 28.

Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.

Regenerative medicine is emerging as a novel field in organ transplantation. In September 2019, the European Cell Therapy and Organ Regeneration Section (ECTORS) of the European Society for Organ Transplantation (ESOT) held its first meeting to discuss the state-of-the-art of regenerative medicine in organ transplantation. The present article highlights the key areas of interest and major advances in this multidisciplinary field in organ regeneration and discusses its implications for the future of organ transplantation.
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http://dx.doi.org/10.1111/tri.13608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497223PMC
August 2020

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

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

Effect of Timing and Complement Receptor Antagonism on Intragraft Recruitment and Protolerogenic Effects of Mesenchymal Stromal Cells in Murine Kidney Transplantation.

Transplantation 2019 06;103(6):1121-1130

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

Background: Mesenchymal stromal cells (MSCs) have protolerogenic effects in renal transplantation, but they induce long-term regulatory T cells (Treg)-dependent graft acceptance only when infused before transplantation. When given posttransplant, MSCs home to the graft where they promote engraftment syndrome and do not induce Treg. Unfortunately, pretransplant MSC administration is unfeasible in deceased-donor kidney transplantation.

Methods: To make MSCs a therapeutic option also for deceased organ recipients, we tested whether MSC infusion at the time of transplant (day 0) or posttransplant (day 2) together with inhibition of complement receptors prevents engraftment syndrome and allows their homing to secondary lymphoid organs for promoting tolerance. We analyzed intragraft and splenic MSC localization, graft survival, and alloimmune response in mice recipients of kidney allografts and syngeneic MSCs given on day 0 or on posttransplant day 2. C3a receptor (C3aR) or C5a receptor (C5aR) antagonists were administered to mice in combination with the cells or were used together to treat MSCs before infusion.

Results: Syngeneic MSCs given at day 0 homed to the spleen increased Treg numbers and induced long-term graft acceptance. Posttransplant MSC infusion, combined with a short course of C3aR or C5aR antagonist or administration of MSCs pretreated with C3aR and C5aR antagonists, prevented intragraft recruitment of MSCs and graft inflammation, inhibited antidonor T-cell reactivity, but failed to induce Treg, resulting in mild prolongation of graft survival.

Conclusions: These data support testing the safety/efficacy profile of administering MSCs on the day of transplant in deceased-donor transplant recipients and indicate that complement is crucial for MSC recruitment into the kidney allograft.
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http://dx.doi.org/10.1097/TP.0000000000002611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934941PMC
June 2019

The incessant search for renal biomarkers: is it really justified?

Curr Opin Nephrol Hypertens 2019 03;28(2):195-202

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

Purpose Of Review: This review summarizes the most recent and relevant findings in the search for novel biomarkers for the most common renal diseases.

Recent Findings: Unprecedented, fast-paced technical advances in biomedical research have offered an opportunity to identify novel and more specific renal biomarkers in several clinical settings. However, despite the huge efforts made, the molecules identified so far have generally failed to provide relevant information beyond what has already been generated by established biomarkers, such as serum creatinine and proteinuria, whereas the complexity and costs of these technology platforms hamper their widespread implementation.

Summary: No novel renal biomarkers have added clear-cut additional value in clinical decision-making. The only exception is anti-phospholipase A2 receptor antibodies, which have been implemented successfully as a diagnostic and prognostic biomarker of membranous nephropathy. This achievement, along with the large number of ongoing collaborative projects worldwide, should lead the renal community to be quite confident regarding the successful qualification of novel and effective diagnostic, prognostic and therapeutic response biomarkers for kidney diseases, hopefully in the next few years.
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http://dx.doi.org/10.1097/MNH.0000000000000481DOI Listing
March 2019

A comparison of metrics and performance characteristics of different search strategies for article retrieval for a systematic review of the global epidemiology of kidney and urinary diseases.

BMC Med Res Methodol 2018 10 19;18(1):110. Epub 2018 Oct 19.

Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via G.-B. Camozzi 3 -, 24020, Bergamo, Ranica, Italy.

Background: Conducting a systematic review requires a comprehensive bibliographic search. Comparing different search strategies is essential for choosing those that cover all useful data sources. Our aim was to develop search strategies for article retrieval for a systematic review of the global epidemiology of kidney and urinary diseases, and evaluate their metrics and performance characteristics that could be useful for other systematic epidemiologic reviews.

Methods: We described the methodological framework and analysed approaches applied in the previously conducted systematic review intended to obtain published data for global estimates of the kidney and urinary disease burden. We used several search strategies in PubMed and EMBASE, and compared several metrics: number needed to retrieve (NNR), number of extracted data rows, number of covered countries, and when appropriate, sensitivity, specificity, precision, and accuracy.

Results: The initial search obtained 29,460 records from PubMed, and 4247 from EMBASE. After the revision, the full text of 381 and 14 articles respectively was obtained for data extraction (the percentage of useful records is 1.3% for PubMed, 0.3% for EMBASE). For PubMed we developed two search strategies and compared them with a 'gold standard' formed by merging their results: free word search strategy (FreeWoSS) was based on the search for keywords in all fields, and subject headings based search strategy (SuHeSS) used only MeSH-mapped conditions and countries names. SuHeSS excluded almost 15% of useful articles and data rows extracted from them, but had a lower NNR of 40 and higher specificity. FreeWoSS had better sensitivity and was able to cover the vast majority of articles and extracted data rows, but had a higher NNR of 65.

Conclusions: The sensitive FreeWoSS strategy provides more data for modelling, while the more specific SuHeSS strategy could be used when resources are limited. EMBASE has limited value for our systematic review.
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http://dx.doi.org/10.1186/s12874-018-0569-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6194627PMC
October 2018

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

Addressing acute kidney injury in critically ill newborn babies.

Lancet Child Adolesc Health 2017 Nov 8;1(3):161-163. Epub 2017 Sep 8.

IRCCS Istituto di Ricerche Farmacologiche Mario Negri, 24126 Bergamo, Italy; Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy; L Sacco Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy. Electronic address:

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http://dx.doi.org/10.1016/S2352-4642(17)30071-8DOI Listing
November 2017

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

Disparities in Chronic Kidney Disease Prevalence among Males and Females in 195 Countries: Analysis of the Global Burden of Disease 2016 Study.

Nephron 2018 23;139(4):313-318. Epub 2018 May 23.

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

Background: Chronic kidney disease (CKD) imposes a substantial burden on health care systems. There are some especially vulnerable groups with a high CKD burden, one of which is women. We performed an analysis of gender disparities in the prevalence of all CKD stages and renal replacement therapy (defined as impaired kidney function [IKF]) in 195 countries.

Methods: We used estimates produced by the Global Burden of Disease (GBD) Study 2016 revision using a Bayesian-regression analytic tool, DisMoD-MR 2.1. Data on gross domestic product based on purchasing power parity per capita (GDP PPP) was obtained via the World Bank International Comparison Program database. To estimate gender disparities, we calculated the male:female all-age prevalence rate ratio for each IKF condition.

Results: In 2016, the global number of individuals with IKF reached 752.7 million, including 417.0 million females and 335.7 million males. The most prevalent form of IKF in both groups was albuminuria with preserved glomerular filtration rate. Geospatial analysis shows a very heterogeneous distribution of the male:female ratio for all IKF conditions, with the most prominent contrast found in kidney transplant patients. The median male:female ratio varies substantially according to GDP PPP quintiles; however, countries with different economic states could have similar male:female ratios. A strong correlation of GDP PPP with dialysis-to-transplant ratio was found.

Conclusions: The GBD study highlights the prominent gender disparities in CKD prevalence among 195 countries. The nature of these disparities, however, is complex and must be interpreted cautiously taking into account all possible circumstances.
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http://dx.doi.org/10.1159/000489897DOI Listing
September 2019

Safety of Iohexol Administration to Measure Glomerular Filtration Rate in Different Patient Populations: A 25-Year Experience.

Nephron 2018 17;140(1):1-8. Epub 2018 May 17.

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

Background/aim: In clinical research setting, accurate and precise measurement of glomerular filtration rate (GFR) is essential to overcome the limitations of GFR estimation with equations, which are often unreliable. In recent decades, a method for measuring GFR by plasma clearance of iohexol, a non-ionic radiocontrast agent, was developed. To evaluate the safety of the procedure, we aimed to review all immediate adverse reactions that could be related to iohexol administration in our group's 25 years worth of experience.

Methods: We retrospectively reviewed all GFR investigations in 2,891 patients, between 1992 and 2016, as part of 37 clinical trials coordinated by our group. Subjects with disparate renal diseases, kidney transplant recipients, and living donors - all with different renal function categories - were included in the surveyed clinical trials.

Results: During 15,147 GFR measurements, only one treatment-related event of moderate intensity was identified. Flushing, urticaria, and itching were observed in a diabetic patient a few minutes after iohexol administration during the first GFR measurement. The event recovered without sequelae after intravenous injection of methylprednisolone sodium succinate. The patient was not hospitalized and the event was categorized as non-serious. Eight additional non-serious events observed closely following iohexol injection were considered as not related to treatment. Thus, independent of disease conditions and GFR categories, the overall rate of treatment-related events was 0.0066%.

Conclusion: Iohexol administration for GFR measurement is a safe procedure, even in repeated investigations in the same subject, that should be adopted in clinical research and, when needed, also in clinical practice.
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http://dx.doi.org/10.1159/000489898DOI Listing
September 2019

A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes.

Diabetes 2018 07 27;67(7):1414-1427. Epub 2018 Apr 27.

Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.

Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near (rs9942471, = 4.5 × 10) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at and , both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.
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http://dx.doi.org/10.2337/db17-0914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6014557PMC
July 2018

Early and late scanning electron microscopy findings in diabetic kidney disease.

Sci Rep 2018 03 20;8(1):4909. Epub 2018 Mar 20.

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

Diabetic nephropathy (DN), the single strongest predictor of mortality in patients with type 2 diabetes, is characterized by initial glomerular hyperfiltration with subsequent progressive renal function loss with or without albuminuria, greatly accelerated with the onset of overt proteinuria. Experimental and clinical studies have convincingly shown that early interventions retard disease progression, while treatment if started late in the disease course seldom modifies the slope of GFR decline. Here we assessed whether the negligible renoprotection afforded by drugs in patients with proteinuric DN could be due to loss of glomerular structural integrity, explored by scanning electron microscopy (SEM). In diabetic patients with early renal disease, glomerular structural integrity was largely preserved. At variance SEM documented that in the late stage of proteinuric DN, glomerular structure was subverted with nearly complete loss of podocytes and lobular transformation of the glomerular basement membrane. In these circumstances one can reasonably imply that any form of treatment, albeit personalized, is unlikely to reach a given cellular or molecular target. These findings should persuade physicians to start the putative renoprotective therapy soon after the diagnosis of diabetes or in an early phase of the disease before structural integrity of the glomerular filter is irreversibly compromised.
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http://dx.doi.org/10.1038/s41598-018-23244-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5861033PMC
March 2018

Mesenchymal stromal cells for tolerance induction in organ transplantation.

Hum Immunol 2018 May 27;79(5):304-313. Epub 2017 Dec 27.

IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy; Unit of Nephrology and Dialysis, Azienda Socio Sanitaria Territoriale (ASST), Papa Giovanni XXIII, Bergamo, Italy; L. Sacco Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy. Electronic address:

The primary challenge in organ transplantation continues to be the need to suppress the host immune system long-term to ensure prolonged allograft survival. Long-term non-specific immunosuppression can, however, result in life-threatening complications. Thus, efforts have been pursued to explore novel strategies that would allow minimization of maintenance immunosuppression, eventually leading to transplant tolerance. In this scenario, bone marrow-derived mesenchymal stromal cells (MSC), given their unique immunomodulatory properties to skew the balance between regulatory and memory T cells, have emerged as potential candidates for cell-based therapy to promote immune tolerance. Here, we review our initial clinical experience with bone marrow-derived MSC in living-donor kidney transplant recipients and provide an overview of the available results of other clinical programs with MSC in kidney and liver transplantation, highlighting hurdles and success of this innovative cell-based therapy.
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http://dx.doi.org/10.1016/j.humimm.2017.12.008DOI Listing
May 2018

Mesenchymal Stromal Cells for AKI after Cardiac Surgery.

J Am Soc Nephrol 2018 01 11;29(1):7-9. Epub 2017 Dec 11.

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

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http://dx.doi.org/10.1681/ASN.2017111207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748931PMC
January 2018

Clinical Translation of Mesenchymal Stromal Cell Therapies in Nephrology.

J Am Soc Nephrol 2018 02 30;29(2):362-375. Epub 2017 Nov 30.

Department of Renal Medicine and Molecular Medicine, IRCCS, Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy.

Mesenchymal stromal cells have emerged as potential candidates for cell-based therapies to modulate the immune response in organ transplantation and repair tissues after acute or chronic injury. Preclinical studies have shown convincingly in rodent models that mesenchymal stromal cells can prolong solid organ graft survival and that they can induce immune tolerance, accelerate recovery from AKI, and promote functional improvement in chronic nephropathies. Multiple complex properties of the cells, including immunomodulatory, anti-inflammatory, and proregenerative effects, seem to contribute. The promising preclinical studies have encouraged investigators to explore the safety, tolerability, and efficacy of mesenchymal stromal cell-based therapy in pilot clinical trials, including those for bone marrow and solid organ transplantation, autoimmune diseases, and tissue and organ repair. Here, we review the available data on culture-expanded mesenchymal stromal cells tested in renal transplantation, AKI, and CKD. We also briefly discuss the relevant issues that must be addressed to ensure rigorous assessment of the safety and efficacy of mesenchymal stromal cell therapies to allow the translation of this research into the practice of clinical nephrology.
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http://dx.doi.org/10.1681/ASN.2017070781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791082PMC
February 2018

Do attributes of persons with chronic kidney disease differ in low-income and middle-income countries compared with high-income countries? Evidence from population-based data in six countries.

BMJ Glob Health 2017 9;2(4):e000453. Epub 2017 Oct 9.

Division of Nephrology, Stanford University School of Medicine, Stanford, California, USA.

Kidney biopsies to elucidate the cause of chronic kidney disease (CKD) are performed in a minority of persons with CKD living in high-income countries, since associated conditions-that is, diabetes mellitus, vascular disease or obesity with pre-diabetes, prehypertension or dyslipidaemia-can inform management targeted at slowing CKD progression in a majority. However, attributes of CKD may differ substantially among persons living in low-income and middle-income countries (LMICs). We used data from population or community-based studies from five LMICs (China, urban India, Moldova, Nepal and Nigeria) to determine what proportion of persons with CKD living in diverse regions fit one of the three major clinical profiles, with data from the US National Health Nutrition and Examination Survey as reference. In the USA, urban India and Moldova, 79.0%-83.9%; in China and Nepal, 62.4%-66.7% and in Nigeria, 51.6% persons with CKD fit one of three established risk profiles. Diabetes was most common in urban India and vascular disease in Moldova (50.7% and 33.2% of persons with CKD in urban India and Moldova, respectively). In Nigeria, 17.8% of persons with CKD without established risk factors had albuminuria ≥300 mg/g, the highest proportion in any country. While the majority of persons with CKD in LMICs fit into one of three established risk profiles, the proportion of persons who have CKD without established risk factors is higher than in the USA. These findings can inform tailored CKD detection and management systems and highlight the importance of studying potential causes and outcomes of CKD without established risk factors in LMICs.
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http://dx.doi.org/10.1136/bmjgh-2017-000453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5640036PMC
October 2017

ACE and SGLT2 inhibitors: the future for non-diabetic and diabetic proteinuric renal disease.

Curr Opin Pharmacol 2017 04 5;33:34-40. Epub 2017 May 5.

IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo & Cele Daccò, Bergamo, Italy; Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy; Department of Biomedical and Clinical Sciences "L. Sacco", University of Milan, Milan, Italy. Electronic address:

Most chronic nephropathies progress relentlessly to end-stage kidney disease. Research in animals and humans has helped our understanding of the mechanisms of chronic kidney disease progression. Current therapeutic strategies to prevent or revert renal disease progression focus on reduction of urinary protein excretion and blood pressure control. Blockade of the renin-angiotensin system (RAS) with angiotensin-converting enzyme inhibitors and/or angiotensin II type 1 receptor blockers is the most effective treatment to achieve these purposes in non-diabetic and diabetic proteinuric renal diseases. For those individuals in which nephroprotection by RAS blockade is only partial, sodium-glucose linked cotransporter-2 (SGLT2) inhibitors could be a promising new class of drugs to provide further renoprotective benefit when added on to RAS blockers.
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http://dx.doi.org/10.1016/j.coph.2017.03.006DOI Listing
April 2017

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

Child and Adolescent Health From 1990 to 2015: Findings From the Global Burden of Diseases, Injuries, and Risk Factors 2015 Study.

JAMA Pediatr 2017 06;171(6):573-592

The Hospital for Sick Children, Centre for Child Health, Toronto, Ontario, Canada.

Importance: Comprehensive and timely monitoring of disease burden in all age groups, including children and adolescents, is essential for improving population health.

Objective: To quantify and describe levels and trends of mortality and nonfatal health outcomes among children and adolescents from 1990 to 2015 to provide a framework for policy discussion.

Evidence Review: Cause-specific mortality and nonfatal health outcomes were analyzed for 195 countries and territories by age group, sex, and year from 1990 to 2015 using standardized approaches for data processing and statistical modeling, with subsequent analysis of the findings to describe levels and trends across geography and time among children and adolescents 19 years or younger. A composite indicator of income, education, and fertility was developed (Socio-demographic Index [SDI]) for each geographic unit and year, which evaluates the historical association between SDI and health loss.

Findings: Global child and adolescent mortality decreased from 14.18 million (95% uncertainty interval [UI], 14.09 million to 14.28 million) deaths in 1990 to 7.26 million (95% UI, 7.14 million to 7.39 million) deaths in 2015, but progress has been unevenly distributed. Countries with a lower SDI had a larger proportion of mortality burden (75%) in 2015 than was the case in 1990 (61%). Most deaths in 2015 occurred in South Asia and sub-Saharan Africa. Global trends were driven by reductions in mortality owing to infectious, nutritional, and neonatal disorders, which in the aggregate led to a relative increase in the importance of noncommunicable diseases and injuries in explaining global disease burden. The absolute burden of disability in children and adolescents increased 4.3% (95% UI, 3.1%-5.6%) from 1990 to 2015, with much of the increase owing to population growth and improved survival for children and adolescents to older ages. Other than infectious conditions, many top causes of disability are associated with long-term sequelae of conditions present at birth (eg, neonatal disorders, congenital birth defects, and hemoglobinopathies) and complications of a variety of infections and nutritional deficiencies. Anemia, developmental intellectual disability, hearing loss, epilepsy, and vision loss are important contributors to childhood disability that can arise from multiple causes. Maternal and reproductive health remains a key cause of disease burden in adolescent females, especially in lower-SDI countries. In low-SDI countries, mortality is the primary driver of health loss for children and adolescents, whereas disability predominates in higher-SDI locations; the specific pattern of epidemiological transition varies across diseases and injuries.

Conclusions And Relevance: Consistent international attention and investment have led to sustained improvements in causes of health loss among children and adolescents in many countries, although progress has been uneven. The persistence of infectious diseases in some countries, coupled with ongoing epidemiologic transition to injuries and noncommunicable diseases, require all countries to carefully evaluate and implement appropriate strategies to maximize the health of their children and adolescents and for the international community to carefully consider which elements of child and adolescent health should be monitored.
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http://dx.doi.org/10.1001/jamapediatrics.2017.0250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540012PMC
June 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
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