Publications by authors named "Andrea Pasini"

59 Publications

[Management of Primary Hyperoxaluria Type 1 in Italy].

G Ital Nefrol 2021 Apr 14;38(2). Epub 2021 Apr 14.

Ospedale Infantile Regina Margherita, Torino, Italia.

Primary hyperoxaluria type 1 is a rare genetic disease; the onset of symptoms ranges from childhood to the sixth decade of life and the disease may go unrecognized for several years. There is an urgent need for drugs able to inhibit the liver production of oxalate and to prevent the disease progression; lumasiran, an innovative molecule based on RNAi interference, is one of the most promising drugs. A group of leading Italian experts on this disease met to respond to some unmet medical needs (early diagnosis, availability of genetic tests and dosage of plasma oxalate, timing of liver transplantation, need for etiologic treatment), based on the analysis of the main scientific evidence and their personal experience. Children showing the characteristic symptoms of the disease usually undergo a metabolic screening and obtain an early diagnosis, while the experience is very limited in adults and the diagnosis difficult. It is therefore essential to increase the knowledge around this disease and the importance of metabolic and genetic screening to define a checklist of shared clinical and laboratory criteria and to establish a multidisciplinary management of potential patients. Oxalate is the cause of the disease: it is crucial to reduce both oxaluria and oxalemia through appropriate therapeutic strategies, able to prevent and/or reduce renal and systemic complications of primary type 1 hyperoxaluria. Lumasiran allows to significantly reduce the levels of oxalate both in blood and in urine, halting the course of the disease and preventing serious renal and systemic complications, if the therapy is started at an early stage of the disease.
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April 2021

The Scf/Kit pathway implements self-organized epithelial patterning.

Dev Cell 2021 Mar;56(6):795-810.e7

Aix-Marseille Univ, CNRS, IBDM, Marseille, France. Electronic address:

How global patterns emerge from individual cell behaviors is poorly understood. In the Xenopus embryonic epidermis, multiciliated cells (MCCs) are born in a random pattern within an inner mesenchymal layer and subsequently intercalate at regular intervals into an outer epithelial layer. Using video microscopy and mathematical modeling, we found that regular pattern emergence involves mutual repulsion among motile immature MCCs and affinity toward outer-layer intercellular junctions. Consistently, Arp2/3-mediated actin remodeling is required for MCC patterning. Mechanistically, we show that the Kit tyrosine kinase receptor, expressed in MCCs, and its ligand Scf, expressed in outer-layer cells, are both required for regular MCC distribution. Membrane-associated Scf behaves as a potent adhesive cue for MCCs, while its soluble form promotes their mutual repulsion. Finally, Kit expression is sufficient to confer order to a disordered heterologous cell population. This work reveals how a single signaling system can implement self-organized large-scale patterning.
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http://dx.doi.org/10.1016/j.devcel.2021.02.026DOI Listing
March 2021

Hypomethylation of NLRP3 gene promoter discriminates glucocorticoid-resistant from glucocorticoid-sensitive idiopathic nephrotic syndrome patients.

Clin Transl Sci 2020 Dec 31. Epub 2020 Dec 31.

Renal Unit, Department of Medicine, University Hospital of Verona, Verona, Italy.

To assess whether NLRP3 gene promoter methylation was able to discriminate glucocorticoid (GC)-resistant from GC-sensitive idiopathic nephrotic syndrome (INS), patients with minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS), we measured the methylation level of NLRP3 promoter in DNA from peripheral blood cells of 10 adult patients with GC-resistant FSGS already in hemodialysis and 18 patients with GC-sensitive INS (13 MCD/5 FSGS) and in 21 pediatric patients with INS with MCD/FSGS before starting any treatment. Association of NLRP3 inflammasome with GC resistance was recapitulated in vitro in monocytic cell lines (THP-1 and U937). In both adults and pediatric patients, NLRP3 promoter methylation was significantly reduced in GC-resistant compared with GC-sensitive patients. Indeed, NLRP3 methylation distinguished GC-resistant and GC-sensitive patients (area under the receiver operating characteristic curve [AUROC] 86.7% in adults, p = 0.00019, and 73.5% in children, p = 0.00097). NLRP3 knock-down augmented sensitivity to GCs in THP-1 cells, whereas NLRP3 inflammasome activation lowered GC receptor concentration, increasing GC resistance in U937 cells. Our results uncovered a new biological mechanism by which patients with INS may acquire GC resistance, that could be used in future as a novel noninvasive diagnostic tool.
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http://dx.doi.org/10.1111/cts.12961DOI Listing
December 2020

Impact of COVID-19 Pandemic in Children with CKD or Immunosuppression.

Clin J Am Soc Nephrol 2021 03 14;16(3):449-451. Epub 2020 Dec 14.

Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione Istituto di Ricerca e Cura a Carattere Scientifico Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy

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http://dx.doi.org/10.2215/CJN.13120820DOI Listing
March 2021

Expanding Phenotype of Schimke Immuno-Osseous Dysplasia: Congenital Anomalies of the Kidneys and of the Urinary Tract and Alteration of NK Cells.

Int J Mol Sci 2020 Nov 15;21(22). Epub 2020 Nov 15.

"Lalla Seràgnoli", Hematology-Oncology Unit, Department of Pediatrics, University of Bologna, 40138 Bologna, Italy.

Schimke immuno-osseous dysplasia (SIOD) is a rare multisystemic disorder with a variable clinical expressivity caused by biallelic variants in . A phenotype-genotype correlation has been attempted and variable expressivity of biallelic variants may be associated with environmental and genetic disturbances of gene expression. We describe two siblings born from consanguineous parents with a diagnosis of SIOD revealed by whole exome sequencing (WES). Results: A homozygous missense variant in the gene (c.1682G>A; p.Arg561His) was identified in both patients. Despite carrying the same variant, the two patients showed substantial renal and immunological phenotypic differences. We describe features not previously associated with SIOD-both patients had congenital anomalies of the kidneys and of the urinary tract and one of them succumbed to a classical type congenital mesoblastic nephroma. We performed an extensive characterization of the immunophenotype showing combined immunodeficiency characterized by a profound lymphopenia, lack of thymic output, defective IL-7Rα expression, and disturbed B plasma cells differentiation and immunoglobulin production in addition to an altered NK-cell phenotype and function. Conclusions: Overall, our results contribute to extending the phenotypic spectrum of features associated with mutations and to better characterizing the underlying immunologic disorder with critical implications for therapeutic and management strategies.
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http://dx.doi.org/10.3390/ijms21228604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696905PMC
November 2020

A Rare Cause of Chronic Hypokalemia with Metabolic Alkalosis: Case Report and Differential Diagnosis.

Children (Basel) 2020 Nov 5;7(11). Epub 2020 Nov 5.

Nephrology and Dialysis Unit, Department of Pediatrics, Azienda Ospedaliero Universitaria Sant'Orsola-Malpighi, 40138 Bologna, Italy.

Hypokalemia and metabolic alkalosis can be present in different rare diseases, and the differential diagnosis of these forms is challenging. Apparent mineralcorticoid (AME) excess syndrome is one of these conditions. Characterized by increased blood pressure due to excessive sodium retention and plasma volume, it is caused by a mutation in the gene encoding the oxydoreductase enzyme 11β-hydroxysteroide dehydrogenase type 2. We report the case of a child presenting with failure to thrive associated with early detection of hypokalemia, metabolic alkalosis, nephrocalcinosis and hypertension in which AME syndrome was detected. A novel mutation in the gene was identified in this patient. In clinical pictures characterized by metabolic alkalosis and hypokalemia, the evaluation of renin, aldosterone and blood pressure is crucial for accurate diagnosis. AME syndrome is a rare disorder that can be an insidious but lethal disease, if untreated. With clinical signs appearing during the first days of life. Early diagnosis is imperative in order to enable prompt and adequate treatment to improve the outcome of these patients.
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http://dx.doi.org/10.3390/children7110212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694404PMC
November 2020

Results of the PROPINE randomized controlled study suggest tapering of prednisone treatment for relapses of steroid sensitive nephrotic syndrome is not necessary in children.

Kidney Int 2021 02 2;99(2):475-483. Epub 2020 Nov 2.

Division of Nephrology and Dialysis, Department of Pediatric Subspecialties, Bambino Gesù Children's Hospital-IRCCS, Rome, Italy. Electronic address:

Corticosteroid-related toxicity in children with steroid-sensitive nephrotic syndrome is primarily related to the cumulative dose of prednisone. To optimize treatment of relapses, we conducted the PROPINE study, a multicentric, open-label, randomized, superiority trial. Seventy-eight relapsing children aged 3-17 years who had not received steroid-sparing medications during the previous 12 months were randomized to receive, from day five after remission, either 18 doses of 40 mg/m of prednisone on alternate days (short arm), or the same cumulative dose tapered over double the time (long arm). Patients were monitored with an ad-hoc smartphone application, allowing daily reporting. The primary outcome was the six-month relapse rate at which time, 23/40 and 16/38 patients had relapsed in the long and short arms, respectively (no significant difference). Additionally, 40/78 patients were also enrolled in a secondary crossover study and were allocated to the opposite arm. Altogether, at six months, the relapse rate was 32/40 and 28/40 in the long and short arms, respectively (no significant difference). A post-hoc analysis excluding 30 patients treated with low-dose prednisone maintenance therapy failed to show significant differences between the two arms. No differences in adverse events, blood pressure and weight gain were observed. Thus, our data do not support the prescription of prolonged tapering schedules for relapses of steroid-sensitive nephrotic syndrome in children.
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http://dx.doi.org/10.1016/j.kint.2020.09.024DOI Listing
February 2021

Gene Panel Analysis in a Large Cohort of Patients With Autosomal Dominant Polycystic Kidney Disease Allows the Identification of 80 Potentially Causative Novel Variants and the Characterization of a Complex Genetic Architecture in a Subset of Families.

Front Genet 2020 7;11:464. Epub 2020 May 7.

Nephrology, Dialysis and Transplantation Unit, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S. Orsola-Malpighi University Hospital, Bologna, Italy.

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inherited disorders in humans and the majority of patients carry a variant in either or . Genetic testing is increasingly required for diagnosis, prognosis, and treatment decision, but it is challenging due to segmental duplications of , genetic and allelic heterogeneity, and the presence of many variants hypomorphic or of uncertain significance. We propose an NGS-based testing strategy for molecular analysis of ADPKD and its phenocopies, validated in a diagnostic setting. Our protocol is based on high-throughput simultaneous sequencing of and after long range PCR of coding regions, followed by a masked reference genome alignment, and MLPA analysis. A further screening of additional 14 cystogenes was performed in negative cases. We applied this strategy to analyze 212 patients with a clinical suspicion of ADPKD. We detected causative variants (interpreted as pathogenic/likely pathogenic) in 61.3% of our index patients, and variants of uncertain clinical significance in 12.5%. The majority (88%) of genetic variants was identified in , 12% in . Among 158 distinct variants, 80 (50.6%) were previously unreported, confirming broad allelic heterogeneity. Eleven patients showed more than one variant. Segregation analysis indicated biallelic disease in five patients, digenic in one, variant with unknown phase in two. Furthermore, our NGS protocol allowed the identification of two patients with somatic mosaicism, which was undetectable with Sanger sequencing. Among patients without / variants, we identified three with possible alternative diagnosis: a patient with biallelic mutations in , confirming the overlap between recessive and dominant PKD, and two patients with variants in and , respectively. Genotype-phenotype correlations showed that patients with variants predicted to truncate (T) the protein experienced end-stage renal disease 9 years earlier than patients with non-truncating (NT) mutations and >13 years earlier than patients with mutations. ADPKD- cases showed a disease onset significantly earlier than ADPKD- and ADPK-, as well as a significant earlier diagnosis. These data emphasize the need to combine clinical information with genetic data to achieve useful prognostic predictions.
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http://dx.doi.org/10.3389/fgene.2020.00464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7224062PMC
May 2020

Born with a solitary kidney: at risk of hypertension.

Pediatr Nephrol 2020 08 24;35(8):1483-1490. Epub 2020 Mar 24.

Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico di Milano, Milan, Italy.

Background: Subjects with a congenital solitary kidney (CSK) are believed to be at risk of hypertension due to their low number of nephrons. However, as CSK is a congenital abnormality of the kidney or urinary tract (CAKUT), subtle dysplastic changes contributing to hypertension cannot be excluded.

Methods: We retrospectively compared office blood pressure (OBP) and ambulatory blood pressure monitoring (ABPM) between two groups of children with CAKUT, aged 6-18 years: Group A with a CSK and Group B with two kidneys. All had normal renal parenchyma on scintigraphy and normal renal function. OBP and mean systolic and diastolic 24-h, daytime and nighttime ambulatory BP records were analyzed. The distribution of OBP and APBM as continuous values and the prevalence of hypertension (ambulatory/severe ambulatory or masked hypertension) in the two groups were compared.

Results: There were 81 patients in Group A and 45 in Group B. Median OBP standard deviation scores were normal in both groups, without significant differences. Median ABPM standard deviation scores, although normal, were significantly higher in Group A and the prevalence of hypertension was higher (ambulatory/severe ambulatory or masked) (33.3 vs. 13.3%, p = 0.019), mainly because of the greater occurrence of masked hypertension.

Conclusions: Our data show that a CSK per se can be associated with an increased risk of hypertension from the pediatric age. Therefore, ABPM, which has proved valuable in the screening of hypertension, is warranted in children with a CSK, even if laboratory and imaging assessment is otherwise normal.
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http://dx.doi.org/10.1007/s00467-020-04535-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316689PMC
August 2020

Reverse Phenotyping after Whole-Exome Sequencing in Steroid-Resistant Nephrotic Syndrome.

Clin J Am Soc Nephrol 2020 01 12;15(1):89-100. Epub 2019 Dec 12.

Department of Clinical and Experimental Biomedical Sciences "Mario Serio,"

Background And Objectives: Nephrotic syndrome is a typical presentation of genetic podocytopathies but occasionally other genetic nephropathies can present as clinically indistinguishable phenocopies. We hypothesized that extended genetic testing followed by reverse phenotyping would increase the diagnostic rate for these patients.

Design, Setting, Participants, & Measurements: All patients diagnosed with nephrotic syndrome and referred to our center between 2000 and 2018 were assessed in this retrospective study. When indicated, whole-exome sequencing and filtering of 298 genes related to CKD were combined with subsequent reverse phenotyping in patients and families. Pathogenic variants were defined according to current guidelines of the American College of Medical Genetics.

Results: A total of 111 patients (64 steroid-resistant and 47 steroid-sensitive) were included in the study. Not a single pathogenic variant was detected in the steroid-sensitive group. Overall, 30% (19 out of 64) of steroid-resistant patients had pathogenic variants in podocytopathy genes, whereas a substantial number of variants were identified in other genes, not commonly associated with isolated nephrotic syndrome. Reverse phenotyping, on the basis of a personalized diagnostic workflow, permitted to identify previously unrecognized clinical signs of an unexpected underlying genetic nephropathy in a further 28% (18 out of 64) of patients. These patients showed similar multidrug resistance, but different long-term outcome, when compared with genetic podocytopathies.

Conclusions: Reverse phenotyping increased the diagnostic accuracy in patients referred with the diagnosis of steroid-resistant nephrotic syndrome.
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http://dx.doi.org/10.2215/CJN.06060519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946071PMC
January 2020

Effect of Body Mass Index on Estimated Glomerular Filtration Rate Levels in Children With Congenital Solitary Kidney: A Cross-Sectional Multicenter Study.

J Ren Nutr 2020 May 6;30(3):261-267. Epub 2019 Sep 6.

Department of Woman, Child and of General and Specialized Surgery, Università degli Studi della Campania "Luigi Vanvitelli", Napoli, Italy. Electronic address:

Rationale & Objective: The objective of this study is to evaluate the effect of body mass index (BMI) on estimated glomerular filtration rate (eGFR) levels in children with congenital solitary kidney (CSK). Moreover, we evaluated if other factors could influence this relationship.

Study Design: Multicenter cross-sectional study.

Setting & Participants: University hospital pediatrics departments.

Subjects: Two hundred eighty-one patients with CSK.

Predictors: Weight, height, BMI-SDS (standard deviation score), duration of overweight/obesity, pubertal stage, systolic (SBP) and diastolic (DBP) blood pressure, eGFR, and renal ultrasound were obtained at the last follow-up visit. The population was classified on the basis of nutritional status and divided in tertiles for duration of overweight/obesity. We compared eGFR levels among these categories. A simple regression was used to correlate eGFR with BMI-SDS. To evaluate if other factors could influence the relationship between eGFR and BMI-SDS, a general linear model was performed, including gender, birth weight<2.5 kg, age, BMI-SDS, SBP-SDS, DBP-SDS, RL-SDS (renal length), and presence of kidney injury at last follow-up as covariates.

Results: The eGFR levels reduced gradually from underweight to obese patients (P = .047). The eGFR levels significantly increased across first and second tertiles of duration of overweight/obesity while they decreased across second and third tertiles of duration of overweight/obesity (P = .005). The eGFR and BMI-SDS at last follow-up were indirectly correlated (coefficient = -0.30, r = 9.2%, P = .0004). A general linear model for eGFR variance (model R = 26.37%; P = .02) confirmed an indirect and significant association of eGFR values with BMI-SDS as the only significant finding.

Conclusions: In patients with CSK, the higher the BMI-SDS and the duration of overweight/obesity, the lower the eGFR levels. Primary prevention strategies to counteract overweight/obesity are mandatory in CSK patients.
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http://dx.doi.org/10.1053/j.jrn.2019.07.003DOI Listing
May 2020

MIF plasma level as a possible tool to predict steroid responsiveness in children with idiopathic nephrotic syndrome.

Eur J Clin Pharmacol 2019 Dec 28;75(12):1675-1683. Epub 2019 Aug 28.

Department of Life Sciences, University of Trieste, Trieste, Italy.

Purpose: Idiopathic nephrotic syndrome (INS) is the most frequent form of childhood nephrotic syndrome. Steroids represent the best therapeutic option; however, inter-individual differences in their efficacy and side effects have been reported. To date, there is no way to predict patients' resistance and/or dependence. Alterations in the cytokine profile of INS patients might contribute to proteinuria and glomerular damage and affect drug sensitivity.

Methods: The cytokine plasma levels were measured in 21 INS children at diagnosis to investigate the association among cytokines pattern and clinical response. Patients were selected on the basis of their clinical response: 7 steroid sensitive (SS), 7 dependent (SD), and 7 resistant (SR). Significant results were then analyzed in 41 additional pediatric INS patients.

Results: Within the 48 cytokines analyzed, macrophage migration inhibitory factor (MIF) was a good predictor of steroid response. Indeed, SR patients showed significantly higher MIF plasma levels compared with all others (p = 0.022; OR = 4.3, 95%CI = 1.2-25.4): a cutoff concentration of MIF > 501 pg/ml significantly discriminated SR patients (sensitivity = 85.7%, specificity = 71.4%). On the contrary, SD patients showed lower MIF plasma levels compared with others (p = 0.010; OR = 0.12, 95%CI = 9.2 × 10-6.7 × 10). Significant results were confirmed in the entire cohort.

Conclusions: Our comprehensive cytokine analysis indicates that assessing MIF plasma levels at diagnosis could predict response to glucocorticoids in children with INS.
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http://dx.doi.org/10.1007/s00228-019-02749-3DOI Listing
December 2019

Acute dialysis in children: results of a European survey.

J Nephrol 2019 Jun 4;32(3):445-451. Epub 2019 Apr 4.

Nephrology and Dialysis Unit, Pediatric Subspecialties Department, Institute for Scientific Research, Bambino Gesù Children's Hospital, Piazza S. Onofrio 4, 00165, Rome, Italy.

The number of children with acute kidney injury (AKI) requiring dialysis is increasing. To date, systematic analysis has been largely limited to critically ill children treated with continuous renal replacement therapy (CRRT). We conducted a survey among 35 European Pediatric Nephrology Centers to investigate dialysis practices in European children with AKI. Altogether, the centers perform dialysis in more than 900 pediatric patients with AKI per year. PD and CRRT are the most frequently used dialysis modalities, accounting for 39.4% and 38.2% of treatments, followed by intermittent HD (22.4%). In units treating more than 25 cases per year and in those with cardiothoracic surgery programs, PD is the most commonly chosen dialysis modality. Also, nearly one quarter of centers, in countries with a gross domestic product below $35,000/year, do not utilize CRRT at all. Dialysis nurses are exclusively in charge of CRRT management in 45% of the cases and pediatric intensive care nurses in 25%, while shared management is practiced in 30%. In conclusion, this survey indicates that the choice of treatment modalities for dialysis in children with AKI in Europe is affected by the underlying ethiology of the disease, organization/set-up of centers and socioeconomic conditions. PD is utilized as often as CRRT, and also intermittent HD is a commonly applied treatment option. A prospective European AKI registry is planned to provide further insights on the epidemiology, management and outcomes of dialysis in pediatric AKI.
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http://dx.doi.org/10.1007/s40620-019-00606-1DOI Listing
June 2019

C5 Convertase Blockade in Membranoproliferative Glomerulonephritis: A Single-Arm Clinical Trial.

Am J Kidney Dis 2019 08 28;74(2):224-238. Epub 2019 Mar 28.

Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy; L. Sacco Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy. Electronic address:

Rationale & Objective: Primary membranoproliferative glomerulonephritis (MPGN) is a rare glomerulopathy characterized by complement dysregulation. MPGN progresses rapidly to kidney failure when it is associated with nephrotic syndrome. We assessed the effects of C5 convertase blockade in patients with MPGN and terminal complement activation.

Study Design: Prospective off-on-off-on open-label clinical trial.

Setting & Participants: Consenting patients with immune complex-mediated MPGN (n=6) or C3 glomerulonephritis (n=4) with sC5b-9 (serum complement membrane attack complex) plasma levels>1,000ng/mL and 24-hour proteinuria with protein excretion>3.5g identified from the Italian Registry of MPGN and followed up at the Istituto di Ricerche Farmacologiche Mario Negri IRCCS (Bergamo, Italy) between March 4, 2014, and January 7, 2015.

Intervention: Anti-C5 monoclonal antibody eculizumab administered during 2 sequential 48-week treatment periods separated by one 12-week washout period.

Outcomes: Primary outcome was change in 24-hour proteinuria (median of 3 consecutive measurements) at 24 and 48 weeks.

Results: Median proteinuria decreased from protein excretion of 6.03 (interquartile range [IQR], 4.8-12.4) g/d at baseline to 3.74 (IQR, 3.2-4.4) g/d at 24 weeks (P=0.01) and to 5.06 (IQR, 3.1-5.8) g/d (P=0.006) at 48 weeks of treatment, recovered toward baseline during the washout period, and did not significantly decrease thereafter. Hypoalbuminemia, dyslipidemia, and glomerular sieving function improved during the first treatment period. 3 patients achieved partial remission of nephrotic syndrome and all had undetectable C3 nephritic factors before treatment. Mean measured glomerular filtration rate was 69.7±35.2 versus 87.4±55.1 and 75.8±42.7 versus 76.6±44.1mL/min/1.73m at the start versus the end of the first and second treatment periods, respectively, among all 10 study participants. Unlike C3, sC5b-9 plasma levels normalized during both treatment periods and recovered toward baseline during the washout in all patients.

Limitations: Single-arm design, small sample size.

Conclusions: Eculizumab blunted terminal complement activation in all patients with immune complex-mediated MPGN or C3 glomerulonephritis and nephrotic syndrome, but persistently reduced proteinuria in just a subgroup.

Trial Registration: Registered in the EU Clinical Trials Register with study no. 2013-003826-10.
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http://dx.doi.org/10.1053/j.ajkd.2018.12.046DOI Listing
August 2019

Infants with congenital nephrotic syndrome have comparable outcomes to infants with other renal diseases.

Pediatr Nephrol 2019 04 29;34(4):649-655. Epub 2018 Oct 29.

Great Ormond Street Hospital for Children NHS Foundation Trust, London, WC1N 3JH, UK.

Background: Children with congenital nephrotic syndrome (CNS) commonly develop end stage renal failure in infancy and require dialysis, but little is known about the complications and outcomes of dialysis in these children.

Methods: We conducted a retrospective case note review across members of the European Society for Pediatric Nephrology Dialysis Working Group to evaluate dialysis management, complications of dialysis, and outcomes in children with CNS.

Results: Eighty children (50% male) with CNS were identified form 17 centers over a 6-year period. Chronic dialysis was started in 44 (55%) children at a median age of 8 (interquartile range 4-14) months. Of these, 17 (39%) were on dialysis by the age of 6 months, 30 (68%) by 1 year, and 40 (91%) by 2 years. Peritoneal dialysis (PD) was the modality of choice in 93%, but 34% switched to hemodialysis (HD), largely due to catheter malfunction (n = 5) or peritonitis (n = 4). The peritonitis rate was 0.77 per patient-year. Weight and height SDS remained static after 6 months on dialysis. In the overall cohort, at final follow-up, 29 children were transplanted, 18 were still on dialysis (15 PD, 3 HD), 19 were in pre-dialysis chronic kidney disease (CKD), and there were 14 deaths (8 on dialysis). Median time on chronic dialysis until transplantation was 9 (6-18) months, and the median age at transplantation was 22 (14-28) months.

Conclusions: Infants with CNS on dialysis have a comparable mortality, peritonitis rate, growth, and time to transplantation as infants with other primary renal diseases reported in international registry data.
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http://dx.doi.org/10.1007/s00467-018-4122-0DOI Listing
April 2019

Determination of adjusted reference intervals of urinary biomarkers of oxidative stress in healthy adults using GAMLSS models.

PLoS One 2018 23;13(10):e0206176. Epub 2018 Oct 23.

Unit of Epidemiology and Medical Statistics (SESM), Department of Diagnostics and Public Health, University of Verona, Verona, Italy.

In this study we aimed at identifying main demographic, laboratory and environmental factors influencing the level of urinary biomarkers (DNA-derived 8-oxodG and lipid membrane-derived 8-isoprostane), and deriving their adjusted 95% reference intervals (RI) in a sample of healthy people from the general population. Data from 281 healthy subjects from the Gene Environment Interactions in Respiratory Diseases survey were used in this study. Generalized additive models for location, scale and shape (GAMLSS) were used to find determinants of the biomarkers among gender, age, season and distance from collection (DFC), and to predict their RI. The RI of the biomarkers stratified by season and adjusted for DFC showed a slight statistically significant decrease in the biomarkers at the increasing DFC in two seasons, except the 8-oxodG during the warm season: median levels at the min and max values of DFC were (ng/mgcreat) 7.0-1.1 in the cold and 3.9-3.9 in the warm seasons for 8-oxodG, 0.7-0.2 in the cold and 1.3-0.6 in the warm seasons for 8-isoprostane. Both the biomarkers should be evaluated in association with the DFC and season in large epidemiological studies. The (semi)parametric GAMLSS method is a useful and flexible technique, which makes it possible to estimate adjusted RI.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0206176PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198964PMC
April 2019

Management of children with congenital nephrotic syndrome: challenging treatment paradigms.

Nephrol Dial Transplant 2019 08;34(8):1369-1377

Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

Background: Management of children with congenital nephrotic syndrome (CNS) is challenging. Bilateral nephrectomies followed by dialysis and transplantation are practiced in most centres, but conservative treatment may also be effective.

Methods: We conducted a 6-year review across members of the European Society for Paediatric Nephrology Dialysis Working Group to compare management strategies and their outcomes in children with CNS.

Results: Eighty children (50% male) across 17 tertiary nephrology units in Europe were included (mutations in NPHS1, n = 55; NPHS2, n = 1; WT1, n = 9; others, n = 15). Excluding patients with mutations in WT1, antiproteinuric treatment was given in 42 (59%) with an increase in S-albumin in 70% by median 6 (interquartile range: 3-8) g/L (P < 0.001). Following unilateral nephrectomy, S-albumin increased by 4 (1-8) g/L (P = 0.03) with a reduction in albumin infusion dose by 5 (2-9) g/kg/week (P = 0.02). Median age at bilateral nephrectomies (n = 29) was 9 (7-16) months. Outcomes were compared between two groups of NPHS1 patients: those who underwent bilateral nephrectomies (n = 25) versus those on conservative management (n = 17). The number of septic or thrombotic episodes and growth were comparable between the groups. The response to antiproteinuric treatment, as well as renal and patient survival, was independent of NPHS1 mutation type. At final follow-up (median age 34 months) 20 (80%) children in the nephrectomy group were transplanted and 1 died. In the conservative group, 9 (53%) remained without dialysis, 4 (24%; P < 0.001) were transplanted and 2 died.

Conclusion: An individualized, stepwise approach with prolonged conservative management may be a reasonable alternative to early bilateral nephrectomies and dialysis in children with CNS and NPHS1 mutations. Further prospective studies are needed to define indications for unilateral nephrectomy.
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http://dx.doi.org/10.1093/ndt/gfy165DOI Listing
August 2019

Biomarkers related to respiratory symptoms and lung function in adults with asthma.

J Breath Res 2018 02 20;12(2):026012. Epub 2018 Feb 20.

Unit of Epidemiology and Medical Statistics, Department of Diagnostics and Public Health, University of Verona, Verona, Italy.

Background: There is a need for easily measurable biomarkers that are able to identify different levels of asthma severity.

Aim: To assess the association between peripheral blood cell counts, fractional nitric oxide in exhaled air (FeNO), urinary biomarkers of oxidative stress (8-hydroxy-2'-deoxyguanosine and 8-isoprostane), and asthma severity in adult patients from the general population.

Methods: In the Gene Environment Interactions in Respiratory Diseases study, 287 subjects with asthma (aged 20-64) were identified from the general population in Verona (Italy) (2008-2010). Self-reported asthma attacks, asthma-like symptoms and the use of hospital services in the past year were synthesized in a score of respiratory symptoms (SRS). The association of biomarkers with SRS and lung function measures (pre-bronchodilator FEV% predicted and FEV/FVC) was assessed using quasi-Poisson and Gaussian regression models, respectively.

Results: Eosinophils (ratio of expected scores: RES[95%CI] = 1.19[1.09,1.30]), basophils (RES[95%CI] = 1.24[1.10,1.40]), lymphocytes (RES[95%CI] = 1.27[1.12,1.45]) and FeNO (RES[95%CI] = 1.18[1.02,1.37]) were positively associated with SRS. However, only eosinophils (RES[95%CI] = 1.15[1.02,1.30]) and lymphocytes (RES[95%CI] = 1.25[1.06,1.47]) showed an independent association. Furthermore, eosinophils (change in the expected outcome for 1-SD increase: CEO[95%CI] = -1.18[-2.09, -0.27]%), basophils (CEO[95%CI] = -1.24[-2.16, -0.33]%) and lymphocytes (CEO[95%CI] = -1.07[-1.99, -0.14]%) were individually, but not independently, associated with FEV/FVC. Finally, neutrophils were negatively associated with FEV% predicted (CEO[95%CI] = -2.22[-4.00, -0.44]%).

Conclusions: We identified a pattern of association between a set of biomarkers and asthma endotypes in adult patients from the general population, which could improve understanding of the heterogeneity and severity of the disease and could be useful in defining targeted therapeutic approaches.
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http://dx.doi.org/10.1088/1752-7163/aa9c86DOI Listing
February 2018

High-protein goat's milk diet identified through newborn screening: clinical warning of a potentially dangerous dietetic practice.

Public Health Nutr 2017 Oct 24;20(15):2806-2809. Epub 2017 Jul 24.

1Department of Pediatrics,Regional Centre for Newborn Screening,Diagnosis and Treatment of Inherited Metabolic Diseases and Congenital Endocrine Diseases,Azienda Ospedaliera Universitaria Integrata,Piazzale L.A. Scuro 10,37134 Verona,Italy.

Objective: Breast-feeding is an unequalled way of providing optimal food for infants' healthy growth and development and the WHO recommends that infants should be exclusively breast-fed for the first 6 months of life. For mothers who are unable to breast-feed or who decide not to, infant formulas are the safest alternative. Despite recommendations, it is possible that parents make potentially harmful nutritional choices for their children because of cultural beliefs or misinformation on infant nutrition. We describe a possible health risk of not breast-feeding, highlighting a potentially dangerous dietetic practice. Design/Setting/Subjects We report the case of a newborn who was fed with undiluted goat's milk because her mother could not breast-feed and was not aware of infant formulas.

Results: The dietary mistake was detected because of a positive expanded newborn screening result, characterized by severe hypertyrosinaemia with high methionine and phenylalanine levels, a pattern suggestive of severe liver impairment. The pattern of plasma amino acids was related to a goat's milk diet, because of its very different composition compared with human milk and infant formula.

Conclusions: Our experience demonstrates that, when breast-feeding is not possible or is not exclusive, infants may be at risk of dangerous nutritional practices, including diets with very high protein content, such as a goat's milk diet. Families of not breast-fed infants may need appropriate advice on safe alternatives for infant nutrition to avoid the risks of inappropriate diets.
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http://dx.doi.org/10.1017/S1368980017001628DOI Listing
October 2017

The Italian Society for Pediatric Nephrology (SINePe) consensus document on the management of nephrotic syndrome in children: Part I - Diagnosis and treatment of the first episode and the first relapse.

Ital J Pediatr 2017 Apr 21;43(1):41. Epub 2017 Apr 21.

Institute of Maternal and Child Health IRCCS "Burlo Garofolo", Department of Pediatrics, Trieste, Italy.

This consensus document is aimed at providing an updated, multidisciplinary overview on the diagnosis and treatment of pediatric nephrotic syndrome (NS) at first presentation. It is the first consensus document of its kind to be produced by all the pediatric nephrology centres in Italy, in line with what is already present in other countries such as France, Germany and the USA. It is based on the current knowledge surrounding the symptomatic and steroid treatment of NS, with a view to providing the basis for a separate consensus document on the treatment of relapses. NS is one of the most common pediatric glomerular diseases, with an incidence of around 2-7 cases per 100000 children per year. Corticosteroids are the mainstay of treatment, but the optimal therapeutic regimen for managing childhood idiopathic NS is still under debate. In Italy, shared treatment guidelines were lacking and, consequently, the choice of steroid regimen was based on the clinical expertise of each individual unit. On the basis of the 2015 Cochrane systematic review, KDIGO Guidelines and more recent data from the literature, this working group, with the contribution of all the pediatric nephrology centres in Italy and on the behalf of the Italian Society of Pediatric Nephrology, has produced a shared steroid protocol that will be useful for National Health System hospitals and pediatricians. Investigations at initial presentation and the principal causes of NS to be screened are suggested. In the early phase of the disease, symptomatic treatment is also important as many severe complications can occur which are either directly related to the pathophysiology of the underlying NS or to the steroid treatment itself. To date, very few studies have been published on the prophylaxis and treatment of these early complications, while recommendations are either lacking or conflicting. This consensus provides indications for the prevention, early recognition and treatment of these complications (management of edema and hypovolemia, therapy and prophylaxis of infections and thromboembolic events). Finally, recommendations about the clinical definition of steroid resistance and its initial diagnostic management, as well as indications for renal biopsy are provided.
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http://dx.doi.org/10.1186/s13052-017-0356-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399429PMC
April 2017

SXR rs3842689: a prognostic factor for steroid sensitivity or resistance in pediatric idiopathic nephrotic syndrome.

Pharmacogenomics 2016 07 5;17(11):1227-1233. Epub 2016 Jul 5.

Pediatric Nephrology & Dialysis, Milano. Fondazione IRCCS Cà Grande Ospedale Maggiroe Policlinico, Italy.

Aim: of the study was to analyse the impact of SXR rs3842689 polymorphism on the response to corticosteroids in pediatric idiopathic nephrotic syndrome.

Patients & Methods: 66 children (56 steroid-sensitive, ten steroid-resistant) were studied for SXR gene polymorphism distribution.

Results: Steroid sensitive patients accounted for 96% of cases with In/In polymorphism, but only for 53% of cases with Del/Del polymorphism At odds ratio analysis, Del/Del represented a clear risk factor of steroid resistance (OR: 20.57; p = 0.009), while In/In was a favourable prognostic factor of steroid sensitivity.

Conclusion: The analysis of SXR polymorphism is a promising tool to predict both the favourable response to corticosteroids and the risk of developing steroid resistance.
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http://dx.doi.org/10.2217/pgs-2016-0029DOI Listing
July 2016

[Kidney Transplantation and inborn errors of metabolism].

G Ital Nefrol 2015 ;32 Suppl 64

Inherited kidney diseases constitute at least 150 different disorders and they have an overall prevalence of about 6080 cases per 100,000 in Europe and in USA. At least 10% of adults and nearly all children who progress to renal-replacement therapy have an inherited kidney disease, representing the fifth most common cause of end-stage renal disease after diabetes, hypertension, glomerulonephritis, and pyelonephritis. These conditions include both structural and functional disorders, among which are counted diseases resulting from inborn errors of metabolism (IEM). Some inborn errors of metabolism primarily affect kidney and because of progress in renal replacement therapy, patients with inherited kidney disorders rarely die when their disease progresses and can live for many years. However, these patients often have compromised health with a poor quality of life. Renal transplantation offers a viable treatment option for those inborn errors of metabolism characterized by primary renal damage caused by dysfunction of a mutated protein, as in cystinuria. In this case, the indication to renal transplantation makes it possible to overcome the specific enzyme defect. However this option remains valid even when the genetic defect is expressed systemically and renal involvement is just one of the clinical manifestations of the disease, as in Anderson-Fabry disease, cystinosis, hereditary amyloidosis and primary hyperoxaluria. In these conditions, renal transplantation is combined with the liver (primary hyperoxaluria) or cardiac transplant (familial amyloidosis) improving the quality and life expectancy of patients.
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December 2016

Glucocorticoid pharmacogenetics in pediatric idiopathic nephrotic syndrome.

Pharmacogenomics 2015 30;16(14):1631-48. Epub 2015 Sep 30.

Department of Life Sciences, University of Trieste, I-34127 Trieste, Italy.

Idiopathic nephrotic syndrome represents the most common type of primary glomerular disease in children: glucocorticoids (GCs) are the first-line therapy, even if considerable interindividual differences in their efficacy and side effects have been reported. Immunosuppressive and anti-inflammatory effects of these drugs are mainly due to the GC-mediated transcription regulation of pro- and anti-inflammatory genes. This mechanism of action is the result of a complex multistep pathway that involves the glucocorticoid receptor and several other proteins, encoded by polymorphic genes. Aim of this review is to highlight the current knowledge on genetic variants that could affect GC response, particularly focusing on children with idiopathic nephrotic syndrome.
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http://dx.doi.org/10.2217/pgs.15.101DOI Listing
July 2016

miR-34/449 control apical actin network formation during multiciliogenesis through small GTPase pathways.

Nat Commun 2015 Sep 18;6:8386. Epub 2015 Sep 18.

CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), UMR-7275, 660 route des Lucioles, 06560 Sophia-Antipolis, France.

Vertebrate multiciliated cells (MCCs) contribute to fluid propulsion in several biological processes. We previously showed that microRNAs of the miR-34/449 family trigger MCC differentiation by repressing cell cycle genes and the Notch pathway. Here, using human and Xenopus MCCs, we show that beyond this initial step, miR-34/449 later promote the assembly of an apical actin network, required for proper basal bodies anchoring. Identification of miR-34/449 targets related to small GTPase pathways led us to characterize R-Ras as a key regulator of this process. Protection of RRAS messenger RNA against miR-34/449 binding impairs actin cap formation and multiciliogenesis, despite a still active RhoA. We propose that miR-34/449 also promote relocalization of the actin binding protein Filamin-A, a known RRAS interactor, near basal bodies in MCCs. Our study illustrates the intricate role played by miR-34/449 in coordinating several steps of a complex differentiation programme by regulating distinct signalling pathways.
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http://dx.doi.org/10.1038/ncomms9386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4595761PMC
September 2015

Nephrotic-range Albuminuria as the presenting symptom of Dent-2 disease.

Ital J Pediatr 2015 Jun 25;41:46. Epub 2015 Jun 25.

Nephrology and Dialysis Unit, Department of Pediatrics, Azienda Ospedaliero-Universitaria Sant'Orsola-Malpighi Bologna, Via Massarenti 11, 40138, Bologna, Italy.

Unlabelled: Dent disease is a rare X-linked tubulopathy with low molecular weight proteinuria, hypercalciuria, nephrolithiasis, nephrocalcinosis and progressive renal failure. We describe the case of a 9-year-old boy who presented with nephrotic-range albuminuria at the age of 3 years. In the absence of a clear diagnosis, a renal biopsy was performed at 4 years, which revealed minimal change disease. Due to the presence of low molecular weight proteinuria, even in the absence of hypercalciuria, a diagnosis of Dent disease was considered. While there were no mutations in the CLCN5 gene, the diagnosis was confirmed by the presence of a missense mutation (p.Arg318Cys) in the OCRL gene.

Conclusion: Given the large phenotypic variability of the disease and based on our experience, we believe that children with low molecular weight proteinuria, even without hypercalciuria, should be investigated for Dent disease.
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http://dx.doi.org/10.1186/s13052-015-0152-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4479313PMC
June 2015

BMP signalling controls the construction of vertebrate mucociliary epithelia.

Development 2015 Jul 19;142(13):2352-63. Epub 2015 Jun 19.

Aix-Marseille Université, CNRS, IBDM, Marseille 13288, France

Despite the importance of mucociliary epithelia in animal physiology, the mechanisms controlling their establishment are poorly understood. Using the developing Xenopus epidermis and regenerating human upper airways, we reveal the importance of BMP signalling for the construction of vertebrate mucociliary epithelia. In Xenopus, attenuation of BMP activity is necessary for the specification of multiciliated cells (MCCs), ionocytes and small secretory cells (SSCs). Conversely, BMP activity is required for the proper differentiation of goblet cells. Our data suggest that the BMP and Notch pathways interact to control fate choices in the developing epidermis. Unexpectedly, BMP activity is also necessary for the insertion of MCCs, ionocytes and SSCs into the surface epithelium. In human, BMP inhibition also strongly stimulates the formation of MCCs in normal and pathological (cystic fibrosis) airway samples, whereas BMP overactivation has the opposite effect. This work identifies the BMP pathway as a key regulator of vertebrate mucociliary epithelium differentiation and morphogenesis.
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http://dx.doi.org/10.1242/dev.118679DOI Listing
July 2015

Endoplasmic reticulum stress and Nrf2 signaling in cardiovascular diseases.

Free Radic Biol Med 2015 Nov 4;88(Pt B):233-242. Epub 2015 Jun 4.

Section of Internal Medicine, Department of Medicine, University of Verona, 37134 Verona, Italy.

Various cellular perturbations implicated in the pathophysiology of human diseases, including cardiovascular and neurodegenerative diseases, diabetes mellitus, obesity, and liver diseases, can alter endoplasmic reticulum (ER) function and lead to the abnormal accumulation of misfolded proteins. This situation configures the so-called ER stress, a form of intracellular stress that occurs whenever the protein-folding capacity of the ER is overwhelmed. Reduction in blood flow as a result of atherosclerotic coronary artery disease causes tissue hypoxia, a condition that induces protein misfolding and ER stress. In addition, ER stress has an important role in cardiac hypertrophy mainly in the transition to heart failure (HF). ER transmembrane sensors detect the accumulation of unfolded proteins and activate transcriptional and translational pathways that deal with unfolded and misfolded proteins, known as the unfolded protein response (UPR). Once the UPR fails to control the level of unfolded and misfolded proteins in the ER, ER-initiated apoptotic signaling is induced. Furthermore, there is considerable evidence that implicates the presence of oxidative stress and subsequent related cellular damage as an initial cause of injury to the myocardium after ischemia/reperfusion (I/R) and in cardiac hypertrophy secondary to pressure overload. Oxidative stress is counterbalanced by complex antioxidant defense systems regulated by a series of multiple pathways, including the UPR, to ensure that the response to oxidants is adequate. Nuclear factor-E2-related factor (Nrf2) is an emerging regulator of cellular resistance to oxidants; Nrf2 is strictly interrelated with the UPR sensor called pancreatic endoplasmic reticulum kinase. A series of studies has shown that interventions against ER stress and Nrf2 activation reduce myocardial infarct size and cardiac hypertrophy in the transition to HF in animals exposed to I/R injury and pressure overload, respectively. Finally, recent data showed that Nrf2/antioxidant-response element pathway activation may be of importance also in ischemic preconditioning, a phenomenon in which the heart is subjected to one or more episodes of nonlethal myocardial I/R before the sustained coronary artery occlusion.
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http://dx.doi.org/10.1016/j.freeradbiomed.2015.05.027DOI Listing
November 2015

[Kidney Transplantation and inborn errors of metabolism].

G Ital Nefrol 2015 Mar-Apr;32(2)

Inherited kidney diseases constitute at least 150 different disorders and they have an overall prevalence of about 6080 cases per 100 000 in Europe and in USA. At least 10% of adults and nearly all children who progress to renal-replacement therapy have an inherited kidney disease, representing the fifth most common cause of end-stage renal disease after diabetes, hypertension, glomerulonephritis, and pyelonephritis. These conditions include both structural and functional disorders, among which are counted diseases resulting from inborn errors of metabolism (IEM). Some inborn errors of metabolism primarily affect kidney and because of progress in renal replacement therapy, patients with inherited kidney disorders rarely die when their disease progresses and can live for many years. However, these patients often have compromised health with a poor quality of life. Renal transplantation offers a viable treatment option for those inborn errors of metabolism characterized by primary renal damage caused by dysfunction of a mutated protein, as in cystinuria. In this case, the indication to renal transplantation makes it possible to overcome the specific enzyme defect. However this option remains valid even when the genetic defect is expressed systemically and renal involvement is just one of the clinical manifestations of the disease, as in Anderson-Fabry disease, cystinosis, hereditary amyloidosis and primary hyperoxaluria. In these conditions, renal transplantation is combined with the liver (primary hyperoxaluria) or cardiac transplant (familial amyloidosis) improving the quality and life expectancy of patients.
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December 2016

Supervised exercise training reduces oxidative stress and cardiometabolic risk in adults with type 2 diabetes: a randomized controlled trial.

Sci Rep 2015 Mar 18;5:9238. Epub 2015 Mar 18.

Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.

To evaluate the effects of supervised exercise training (SET) on cardiometabolic risk, cardiorespiratory fitness and oxidative stress status in 2 diabetes mellitus (T2DM), twenty male subjects with T2DM were randomly assigned to an intervention group, which performed SET in a hospital-based setting, and to a control group. SET consisted of a 12-month supervised aerobic, resistance and flexibility training. A reference group of ten healthy male subjects was also recruited for baseline evaluation only. Participants underwent medical examination, biochemical analyses and cardiopulmonary exercise testing. Oxidative stress markers (1-palmitoyl-2-[5-oxovaleroyl]-sn-glycero-3-phosphorylcholine [POVPC]; 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphorylcholine [PGPC]) were measured in plasma and in peripheral blood mononuclear cells. All investigations were carried out at baseline and after 12 months. SET yielded a significant modification (p < 0.05) in the following parameters: V'O₂max (+14.4%), gas exchange threshold (+23.4%), waist circumference (-1.4%), total cholesterol (-14.6%), LDL cholesterol (-20.2%), fasting insulinemia (-48.5%), HOMA-IR (-52.5%), plasma POVPC (-27.9%) and PGPC (-31.6%). After 12 months, the control group presented a V'O₂max and a gas exchange threshold significantly lower than the intervention group. Plasma POVC and PGPC were significantly different from healthy subjects before the intervention, but not after. In conclusion, SET was effective in improving cardiorespiratory fitness, cardiometabolic risk and oxidative stress status in T2DM.
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http://dx.doi.org/10.1038/srep09238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4363871PMC
March 2015

The atherosclerotic plaque vulnerability: focus on the oxidative and endoplasmic reticulum stress in orchestrating the macrophage apoptosis in the formation of the necrotic core.

Curr Med Chem 2015 ;22(13):1565-72

Department of Medicine, Section of Internal Medicine, University of Verona, 10, Piazzale L.A. Scuro 37134 Verona, Italy.

Although the understanding the pathophysiology of atherogenesis and atherosclerosis progression has been one of the major goals of cardiovascular research during the last decades, the precise mechanisms underlying plaque destabilization are still unknown. The disruption of the plaque and the thrombosis in the lumen that are mostly determined by the expansion of the necrotic core (NC) are driven by various mechanisms, including accelerated macrophage apoptosis and defective phagocytic clearance (defective efferocytosis). Oxidative stress is implicated in the expansion of the NC: in fact, many oxidized compounds and processes contribute to the macrophage apoptosis; in addition, the oxidized derivatives of polyunsatured fatty acids promote defective efferocytosis, with the final result of NC expansion. In the last years the role of the endoplasmic reticulum (ER) stress is under investigation to better define its possible contribution in affecting the NC expansion. The abnormal amount of apoptotic cells in the vulnerable plaque has been demonstrated to be related both to the sustained ER stress and to the expression of survival and protective genes, such as the unfolded protein response or/and the nuclear erytroid- related factor 2. In this review the authors focus on the promising results of the oxidative and ER stress in contributing to triggering and orchestrating the atherosclerotic plaque vulnerability.
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http://dx.doi.org/10.2174/0929867322666150311150829DOI Listing
January 2016