Publications by authors named "Laura Massella"

36 Publications

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

Clin J Am Soc Nephrol 2020 Dec 14. 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
December 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

The carboxy-terminus of the human ARPKD protein fibrocystin can control STAT3 signalling by regulating SRC-activation.

J Cell Mol Med 2020 Dec 28;24(24):14633-14638. Epub 2020 Oct 28.

Department of Pediatrics, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.

Autosomal recessive polycystic kidney disease (ARPKD) is mainly caused by variants in the PKHD1 gene, encoding fibrocystin (FC), a large transmembrane protein of incompletely understood cellular function. Here, we show that a C-terminal fragment of human FC can suppress a signalling module of the kinase SRC and signal transducer and activator of transcription 3 (STAT3). Consistently, we identified truncating genetic variants specifically affecting the cytoplasmic tail in ARPKD patients, found SRC and the cytoplasmic tail of fibrocystin in a joint dynamic protein complex and observed increased activation of both SRC and STAT3 in cyst-lining renal epithelial cells of ARPKD patients.
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http://dx.doi.org/10.1111/jcmm.16014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754027PMC
December 2020

Severe neurological outcomes after very early bilateral nephrectomies in patients with autosomal recessive polycystic kidney disease (ARPKD).

Sci Rep 2020 09 29;10(1):16025. Epub 2020 Sep 29.

Department of Pediatrics, Faculty of Medicine, University Hospital Cologne and University of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.

To test the association between bilateral nephrectomies in patients with autosomal recessive polycystic kidney disease (ARPKD) and long-term clinical outcome and to identify risk factors for severe outcomes, a dataset comprising 504 patients from the international registry study ARegPKD was analyzed for characteristics and complications of patients with very early (≤ 3 months; VEBNE) and early (4-15 months; EBNE) bilateral nephrectomies. Patients with very early dialysis (VED, onset ≤ 3 months) without bilateral nephrectomies and patients with total kidney volumes (TKV) comparable to VEBNE infants served as additional control groups. We identified 19 children with VEBNE, 9 with EBNE, 12 with VED and 11 in the TKV control group. VEBNE patients suffered more frequently from severe neurological complications in comparison to all control patients. Very early bilateral nephrectomies and documentation of severe hypotensive episodes were independent risk factors for severe neurological complications. Bilateral nephrectomies within the first 3 months of life are associated with a risk of severe neurological complications later in life. Our data support a very cautious indication of very early bilateral nephrectomies in ARPKD, especially in patients with residual kidney function, and emphasize the importance of avoiding severe hypotensive episodes in this at-risk cohort.
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http://dx.doi.org/10.1038/s41598-020-71956-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525474PMC
September 2020

Prolonged Impairment of Immunological Memory After Anti-CD20 Treatment in Pediatric Idiopathic Nephrotic Syndrome.

Front Immunol 2019 16;10:1653. Epub 2019 Jul 16.

Renal Diseases Research Unit, Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.

Anti-CD20 therapy is effective in idiopathic nephrotic syndrome (INS). However, transient or sustained hypogammaglobulinemia predisposing to an increased risk of infectious diseases can follow treatment in some patients. We analyzed the long-term effects of anti-CD20 therapy on immunological memory in 27 frequently-relapsing/steroid-dependent INS pediatric patients after more than 4 years from the first and at least 2 years from the last anti-CD20 infusion. Twenty-one INS children, never treated with anti-CD20 and under an intense oral immunosuppression with prednisone, mycophenolate mofetil, and calcineurin inhibitors were also included as control group. Levels of circulating B-cell subpopulations, total serum immunoglobulins and IgG and memory B cells directed against hepatitis B virus (HBV) and tetanus were determined and correlated with clinical characteristics. Nine patients never relapsed after more than 2 years from the last anti-CD20 administration (5 after the first, 3 after the second, and 1 after the fifth infusion). At last follow-up, most patients showed a complete recovery and normalization of total (27/27), transitional (27/27), and mature-naïve B cells (25/27). However, a sustained and significant reduction of total memory (20/27) and switched memory (21/27) B cells was found in most patients. 11/27 patients showed hypogammaglobulinemia at last follow-up and, among these, four presented with a severe hypogammaglobulinemia (IgG < 160 mg/dl). In contrast, no patient in the control group developed a severe hypogammaglobulinemia. Age at the time of first anti-CD20 administration was positively associated with IgG levels at last follow-up ( = 0.008); accordingly, younger patients had an increased risk of hypogammaglobulinemia ( = 0.006). Furthermore, severe hypogammaglobulinemia and delayed switched memory B-cell reconstitution were more frequent in non-relapsing patients. Reduced IgG levels against HBV and tetanus were observed at baseline and further declined at last follow-up. Antigen-specific memory B-cells were induced by re-immunization, but specific IgG titers remained low. In conclusion, anti-CD20 therapy can be disease-modifying in some INS patients. However, a prolonged impairment of immunological memory occurs frequently, independently from the number of anti-CD20 infusions, particularly in younger patients. Re-immunization may be necessary in these patients.
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http://dx.doi.org/10.3389/fimmu.2019.01653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6646679PMC
October 2020

Cardiac Abnormalities in Children with Autosomal Recessive Polycystic Kidney Disease.

Cardiorenal Med 2019 7;9(3):180-189. Epub 2019 Mar 7.

Nephrology and Dialysis Unit, Department of Pediatric Subspecialties, Bambino Gesù Children's Hospital - IRCSS, Rome, Italy.

Background: No previous study has defined the prevalence of cardiac geometric and mechanical function abnormalities through the analysis of advanced echocardiographic parameters in children with autosomal recessive polycystic kidney disease (ARPKD).

Aim: The purpose of this study was to evaluate cardiac geometry and function through advanced echocardiography in a well-characterized sample of pediatric patients with ARPKD.

Methods: Standard echocardiograms were obtained in 27 children with ARPKD (0-18 years) and in 88 healthy children of similar age, gender distribution, and body build. Left ventricular (LV) hypertrophy was defined as LV mass > 45g/(m2.16 + 0.09) and cardiac remodeling was defined by age-adjusted relative wall thickness (RWT). Systolic function was assessed by ejection fraction, midwall fractional shortening (mFS), and global longitudinal (GLS) and circumferential strain (GCS).

Results: Patients with ARPKD exhibited a higher LV mass index as compared to controls, and a more concentric LV geometry (both p < 0.001). Accordingly, the prevalence of abnormal LV geometry was significantly higher in ARPKD (33 vs. 0%; p < 0.005). No differences could be observed in the two groups for ejection fraction or GLS (both p = n.s.), while a significantly lower mFS (p < 0.05) as well as GCS (p < 0.001) could be observed. In the analysis of covariance, both LV mass index and RWT remained significantly higher in the ARPKD group, while mFS and GCS remained significantly lower (all p < 0.05). The prevalence of subclinical systolic dysfunction was significantly higher in patients with ARPKD as compared with control subjects (33 vs. 0%; p < 0.001).

Conclusions: Children with ARPKD show significantly impaired cardiac phenotype, characterized by high rates of LV abnormal geometry paired with systolic mechanical dysfunction.
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http://dx.doi.org/10.1159/000496473DOI Listing
August 2019

Risk Factors for Early Dialysis Dependency in Autosomal Recessive Polycystic Kidney Disease.

J Pediatr 2018 08 9;199:22-28.e6. Epub 2018 May 9.

Department of Pediatrics, University Hospital of Cologne, Cologne, Germany; Center for Molecular Medicine, University Hospital of Cologne, Cologne, Germany.

Objective: To identify prenatal, perinatal, and postnatal risk factors for dialysis within the first year of life in children with autosomal recessive polycystic kidney disease (ARPKD) as a basis for parental counseling after prenatal and perinatal diagnosis.

Study Design: A dataset comprising 385 patients from the ARegPKD international registry study was analyzed for potential risk markers for dialysis during the first year of life.

Results: Thirty-six out of 385 children (9.4%) commenced dialysis in the first year of life. According to multivariable Cox regression analysis, the presence of oligohydramnios or anhydramnios, prenatal kidney enlargement, a low Apgar score, and the need for postnatal breathing support were independently associated with an increased hazard ratio for requiring dialysis within the first year of life. The increased risk associated with Apgar score and perinatal assisted breathing was time-dependent and vanished after 5 and 8 months of life, respectively. The predicted probabilities for early dialysis varied from 1.5% (95% CI, 0.5%-4.1%) for patients with ARPKD with no prenatal sonographic abnormalities to 32.3% (95% CI, 22.2%-44.5%) in cases of documented oligohydramnios or anhydramnios, renal cysts, and enlarged kidneys.

Conclusions: This study, which identified risk factors associated with onset of dialysis in ARPKD in the first year of life, may be helpful in prenatal parental counseling in cases of suspected ARPKD.
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http://dx.doi.org/10.1016/j.jpeds.2018.03.052DOI Listing
August 2018

Prevalence of Hypertension in Children with Early-Stage ADPKD.

Clin J Am Soc Nephrol 2018 06 19;13(6):874-883. Epub 2018 Apr 19.

Division of Nephrology, Department of Pediatric Subspecialties, and

Background And Objectives: Autosomal dominant polycystic kidney disease is the most common inheritable kidney disease, frequently thought to become symptomatic in adulthood. However, patients with autosomal dominant polycystic kidney disease may develop signs or symptoms during childhood, in particular hypertension. Although ambulatory BP monitoring is the preferred method to diagnose hypertension in pediatrics, data in children with autosomal dominant polycystic kidney disease are limited.

Design, Setting, Participants, & Measurements: Our retrospective multicenter study was conducted to collect ambulatory BP monitoring recordings from patients with autosomal dominant polycystic kidney disease age <18 years old. Basic anthropometric parameters as well as data on kidney function, BP treatment, and kidney ultrasound were also collected.

Results: Data from 310 children with autosomal dominant polycystic kidney disease with a mean age of 11.5±4.1 years old were collected at 22 European centers. At the time when ambulatory BP monitoring was performed, 95% of children had normal kidney function. Reference data for ambulatory BP monitoring were available for 292 patients. The prevalence rates of children with hypertension and/or those who were treated with antihypertensive drugs were 31%, 42%, and 35% during daytime, nighttime, or the entire 24-hour cycle, respectively. In addition, 52% of participants lacked a physiologic nocturnal BP dipping, and 18% had isolated nocturnal hypertension. Logistic regression analysis showed a significant association between a categorical cyst score that was calculated on the basis of the number of cysts >1 cm per kidney and daytime hypertension (odds ratio, 1.70; 95% confidence interval, 1.21 to 2.4; =0.002), nighttime hypertension (odds ratio, 1.31; 95% confidence interval, 1.05 to 1.63; =0.02), or 24-hour hypertension (odds ratio, 1.39; 95% confidence interval, 1.08 to 1.81; =0.01). Kidney length, expressed as SD score, was also significantly associated with nighttime hypertension (odds ratio, 1.23; 95% confidence interval, 1.06 to 1.42; =0.10).

Conclusions: These data indicate high prevalence of hypertension in children with autosomal dominant polycystic kidney disease starting at young ages.
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http://dx.doi.org/10.2215/CJN.11401017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989684PMC
June 2018

Alport syndrome: a unified classification of genetic disorders of collagen IV α345: a position paper of the Alport Syndrome Classification Working Group.

Kidney Int 2018 05 16;93(5):1045-1051. Epub 2018 Mar 16.

Clinic of Nephrology and Rheumatology, University Medical Center Goettingen, University of Goettingen, Goettingen, Germany.

Mutations in the genes COL4A3, COL4A4, and COL4A5 affect the synthesis, assembly, deposition, or function of the collagen IV α345 molecule, the major collagenous constituent of the mature mammalian glomerular basement membrane. These mutations are associated with a spectrum of nephropathy, from microscopic hematuria to progressive renal disease leading to ESRD, and with extrarenal manifestations such as sensorineural deafness and ocular anomalies. The existing nomenclature for these conditions is confusing and can delay institution of appropriate nephroprotective therapy. Herein we propose a new classification of genetic disorders of the collagen IV α345 molecule with the goal of improving renal outcomes through regular monitoring and early treatment.
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http://dx.doi.org/10.1016/j.kint.2017.12.018DOI Listing
May 2018

Urine-derived podocytes-lineage cells: A promising tool for precision medicine in Alport Syndrome.

Hum Mutat 2018 02 22;39(2):302-314. Epub 2017 Nov 22.

Medical Genetics, University of Siena, Siena, Italy.

Alport Syndrome (ATS) is a rare genetic disorder caused by collagen IV genes mutations, leading to glomerular basement membrane damage up to end-stage renal disease. Podocytes, the main component of the glomerular structure, are the only cells able to produce all the three collagens IV alpha chains associated with ATS and thus, they are key players in ATS pathogenesis. However, podocytes-targeted therapeutic strategies have been hampered by the difficulty of non-invasively isolating them and transcripts-based diagnostic approaches are complicated by the inaccessibility of other COL4 chains-expressing cells. We firstly isolated podocyte-lineage cells from ATS patients' urine samples, in a non-invasive way. RT-PCR analysis revealed COL4A3, COL4A4, and COL4A5 expression. Transcripts analysis on RNA extracted from patient's urine derived podocyte-lineage cells allowed defining the pathogenic role of intronic variants, namely one mutation in COL4A3 (c.3882+5G>A), three mutations in COL4A4 (c.1623+2T>A, c.3699_3706+1del, c.2545+143T>A), and one mutation in COL4A5 (c.3454+2T>C). Therefore, our cellular model represents a novel tool, essential to unequivocally prove the effect of spliceogenic intronic variants on transcripts expressed exclusively at a glomerular level. This process is a key step for providing the patient with a definite molecular diagnosis and with a proper recurrence risk. The established system also opens up the possibility of testing personalized therapeutic approaches on disease-relevant cells.
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http://dx.doi.org/10.1002/humu.23364DOI Listing
February 2018

A randomized clinical trial indicates that levamisole increases the time to relapse in children with steroid-sensitive idiopathic nephrotic syndrome.

Kidney Int 2018 02 18;93(2):510-518. Epub 2017 Oct 18.

Department of Pediatric Nephrology, Emma Children's Hospital/Academic Medical Center, Amsterdam, The Netherlands; Department of Pediatric Nephrology, Hôpital Universitaire des Enfants Reine Fabiola, Brussels, Belgium.

Levamisole has been considered the least toxic and least expensive steroid-sparing drug for preventing relapses of steroid-sensitive idiopathic nephrotic syndrome (SSINS). However, evidence for this is limited as previous randomized clinical trials were found to have methodological limitations. Therefore, we conducted an international multicenter, placebo-controlled, double-blind, randomized clinical trial to reassess its usefulness in prevention of relapses in children with SSINS. The efficacy and safety of one year of levamisole treatment in children with SSINS and frequent relapses were evaluated. The primary analysis cohort consisted of 99 patients from 6 countries. Between 100 days and 12 months after the start of study medication, the time to relapse (primary endpoint) was significantly increased in the levamisole compared to the placebo group (hazard ratio 0.22 [95% confidence interval 0.11-0.43]). Significantly, after 12 months of treatment, six percent of placebo patients versus 26 percent of levamisole patients were still in remission. During this period, the most frequent serious adverse event (four of 50 patients) possibly related to levamisole was asymptomatic moderate neutropenia, which was reversible spontaneously or after treatment discontinuation. Thus, in children with SSINS and frequent relapses, levamisole prolonged the time to relapse and also prevented recurrence during one year of treatment compared to prednisone alone. However, regular blood controls are necessary for safety issues.
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http://dx.doi.org/10.1016/j.kint.2017.08.011DOI Listing
February 2018

Low renal but high extrarenal phenotype variability in Schimke immuno-osseous dysplasia.

PLoS One 2017 10;12(8):e0180926. Epub 2017 Aug 10.

Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany.

Schimke immuno-osseous dysplasia (SIOD) is a rare multisystem disorder with early mortality and steroid-resistant nephrotic syndrome (SRNS) progressing to end-stage kidney disease. We hypothesized that next-generation gene panel sequencing may unsurface oligosymptomatic cases of SIOD with potentially milder disease courses. We analyzed the renal and extrarenal phenotypic spectrum and genotype-phenotype associations in 34 patients from 28 families, the largest SMARCAL1-associated nephropathy cohort to date. In 11 patients the diagnosis was made unsuspectedly through SRNS gene panel testing. Renal disease first manifested at median age 4.5 yrs, with focal segmental glmerulosclerosis or minimal change nephropathy on biopsy and rapid progression to end-stage kidney disease (ESKD) at median age 8.7 yrs. Whereas patients diagnosed by phenotype more frequently developed severe extrarenal complications (cerebral ischemic events, septicemia) and were more likely to die before age 10 years than patients identified by SRNS-gene panel screening (88 vs. 40%), the subgroups did not differ with respect to age at proteinuria onset and progression to ESKD. Also, 10 of 11 children diagnosed unsuspectedly by Next Generation Sequencing were small at diagnosis and all showed progressive growth failure. Severe phenotypes were usually associated with biallelic truncating mutations and milder phenotypes with biallelic missense mutations. However, no genotype-phenotype correlation was observed for the renal disease course. In conclusion, while short stature is a reliable clue to SIOD in children with SRNS, other systemic features are highly variable. Our findings support routine SMARCAL1 testing also in non-syndromic SRNS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0180926PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5552097PMC
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

Minimal Change Disease.

Clin J Am Soc Nephrol 2017 02 9;12(2):332-345. Epub 2016 Dec 9.

Division of Nephrology and Dialysis, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy; and.

Minimal change disease (MCD) is a major cause of idiopathic nephrotic syndrome (NS), characterized by intense proteinuria leading to edema and intravascular volume depletion. In adults, it accounts for approximately 15% of patients with idiopathic NS, reaching a much higher percentage at younger ages, up to 70%-90% in children >1 year of age. In the pediatric setting, a renal biopsy is usually not performed if presentation is typical and the patient responds to therapy with oral prednisone at conventional doses. Therefore, in this setting steroid-sensitive NS can be considered synonymous with MCD. The pathologic hallmark of disease is absence of visible alterations by light microscopy and effacement of foot processes by electron microscopy. Although the cause is unknown and it is likely that different subgroups of disease recognize a different pathogenesis, immunologic dysregulation and modifications of the podocyte are thought to synergize in altering the integrity of the glomerular basement membrane and therefore determining proteinuria. The mainstay of therapy is prednisone, but steroid-sensitive forms frequently relapse and this leads to a percentage of patients requiring second-line steroid-sparing immunosuppression. The outcome is variable, but forms of MCD that respond to steroids usually do not lead to chronic renal damage, whereas forms that are unresponsive to steroids may subsequently reveal themselves as FSGS. However, in a substantial number of patients the disease is recurrent and requires long-term immunosuppression, with significant morbidity because of side effects. Recent therapeutic advances, such as the use of anti-CD20 antibodies, have provided long-term remission off-therapy and suggest new hypotheses for disease pathogenesis.
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http://dx.doi.org/10.2215/CJN.05000516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5293332PMC
February 2017

Increased Wnt and Notch signaling: a clue to the renal disease in Schimke immuno-osseous dysplasia?

Orphanet J Rare Dis 2016 11 5;11(1):149. Epub 2016 Nov 5.

Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.

Background: Schimke immuno-osseous dysplasia (SIOD) is a multisystemic disorder caused by biallelic mutations in the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily A-like 1 (SMARCAL1) gene. Changes in gene expression underlie the arteriosclerosis and T-cell immunodeficiency of SIOD; therefore, we hypothesized that SMARCAL1 deficiency causes the focal segmental glomerulosclerosis (FSGS) of SIOD by altering renal gene expression. We tested this hypothesis by gene expression analysis of an SIOD patient kidney and verified these findings through immunofluorescent analysis in additional SIOD patients and a genetic interaction analysis in Drosophila.

Results: We found increased expression of components and targets of the Wnt and Notch signaling pathways in the SIOD patient kidney, increased levels of unphosphorylated β-catenin and Notch1 intracellular domain in the glomeruli of most SIOD patient kidneys, and genetic interaction between the Drosophila SMARCAL1 homologue Marcal1 and genes of the Wnt and Notch signaling pathways.

Conclusions: We conclude that increased Wnt and Notch activity result from SMARCAL1 deficiency and, as established causes of FSGS, contribute to the renal disease of most SIOD patients. This further clarifies the pathogenesis of SIOD and will hopefully direct potential therapeutic approaches for SIOD patients.
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http://dx.doi.org/10.1186/s13023-016-0519-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5097426PMC
November 2016

Rituximab in steroid-dependent or frequently relapsing idiopathic nephrotic syndrome.

J Am Soc Nephrol 2014 Apr 30;25(4):850-63. Epub 2014 Jan 30.

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

The outcome of steroid-dependent or frequently relapsing nephrotic syndrome of minimal change disease (MCD), mesangial proliferative GN (MesGN), or FSGS may be poor and with major treatment toxicity. This academic, multicenter, off-on trial (ClinicalTrials.gov #NCT00981838) primarily evaluated the effects of rituximab therapy followed by immunosuppression withdrawal on disease recurrence in 10 children and 20 adults with MCD/MesGN (n=22) or FSGS who had suffered ≥2 recurrences over the previous year and were in steroid-induced remission for ≥1 month. Participants received one dose (n=28) or two doses of rituximab (375 mg/m(2) intravenously). At 1 year, all patients were in remission: 18 were treatment-free and 15 never relapsed. Compared with the year before rituximab treatment, total relapses decreased from 88 to 22 and the per-patient median number of relapses decreased from 2.5 (interquartile range [IQR], 2-4) to 0.5 (IQR, 0-1; P<0.001) during 1 year of follow-up. Reduction was significant across subgroups (children, adults, MCD/MesGN, and FSGS; P<0.01). After rituximab, the per-patient steroid maintenance median dose decreased from 0.27 mg/kg (IQR, 0.19-0.60) to 0 mg/kg (IQR, 0-0.23) (P<0.001), and the median cumulative dose to achieve relapse remission decreased from 19.5 mg/kg (IQR, 13.0-29.2) to 0.5 mg/kg (IQR, 0-9.4) (P<0.001). Furthermore, the mean estimated GFR increased from 111.3±25.7 to 121.8±29.2 ml/min per 1.73 m(2) (P=0.01), with the largest increases in children and in FSGS subgroups. The mean height z score slope stabilized in children (P<0.01). Treatment was well tolerated. Rituximab effectively and safely prevented recurrences and reduced the need for immunosuppression in steroid-dependent or frequently relapsing nephrotic syndrome, and halted disease-associated growth deficit in children.
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http://dx.doi.org/10.1681/ASN.2013030251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3968490PMC
April 2014

Bone marrow transplantation in Schimke immuno-osseous dysplasia.

Am J Med Genet A 2013 Oct 15;161A(10):2609-13. Epub 2013 Aug 15.

Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.

Schimke immuno-osseous dysplasia (SIOD, OMIM 242900) is a rare autosomal recessive multisystem childhood disorder characterized by short stature, renal failure, T-cell immunodeficiency, and hypersensitivity to genotoxic agents. SIOD is associated with biallelic mutations in SMARCAL1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily a-like 1), which encodes a DNA stress response enzyme with annealing helicase activity. Two features of SIOD causing much morbidity and mortality are bone marrow failure and T-cell deficiency with the consequent opportunistic infections. To address the safety and efficacy of bone marrow transplantation (BMT) in SIOD, we reviewed the outcomes of the only five SIOD patients known to us in whom bone marrow or hematopoietic stem cell transplantation has been attempted. We find that only one patient survived the transplantation procedure and that the existing indicators of a good prognosis for bone marrow transplantation were not predictive in this small cohort. Given these observations, we also discuss some considerations for the poor outcomes.
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http://dx.doi.org/10.1002/ajmg.a.36111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3788057PMC
October 2013

Prognostic value of glomerular collagen IV immunofluorescence studies in male patients with X-linked Alport syndrome.

Clin J Am Soc Nephrol 2013 May 31;8(5):749-55. Epub 2013 Jan 31.

Nephrology and Dialysis Unit, Department of Nephrology and Urology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Background And Objectives: X-linked Alport syndrome (X-AS) is caused by mutations of the COL4A5 gene, which encodes for the collagen IV α5 chain (α5[COLIV]), resulting in structural and functional abnormalities of the glomerular basement membrane (GBM) and leading to CKD. The aim of the present study was to evaluate the prognostic value of residual collagen IV chain expression in the GBM of patients with X-AS.

Design, Setting, Participants, & Measurements: The medical records of 22 patients with X-AS from 21 unrelated families collected between 1987 and 2009 were reviewed (median age at last follow-up, 19.9 years; range, 5.4-35.1 years); GBM expression of α1, α3, and α5(COLIV) chains was assessed by immunofluorescence microscopy.

Results: GBM distribution of the α5(COLIV) chain was diffuse in 1 and segmental or absent in 21 of the 22 patients; the expression of the α3(COLIV) chain was diffuse in 5 of 22 patients and segmental or absent in 17 of 22 patients. Patients with diffuse staining for the α3(COLIV) chain presented with proteinuria significantly later (median age, 16.9 versus 6.1 years; P=0.02) and reached an estimated GFR < 90 ml/min per 1.73 m(2) at an older age (median age, 27.0 versus 14.9 years; P=0.01) compared with patients with segmental or absent staining. Two thirds of patients with abnormal α3(COLIV) expression by immunofluorescence studies had null or truncating COL4A5 mutations, as opposed to none of the 4 tested patients with diffuse α3(COLIV) chain glomerular distribution.

Conclusions: These results indicate that maintained expression of the α3(COLIV) chain is an early positive prognostic marker in patients with X-linked Alport symdrome.
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http://dx.doi.org/10.2215/CJN.07510712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3641614PMC
May 2013

Reduced elastogenesis: a clue to the arteriosclerosis and emphysematous changes in Schimke immuno-osseous dysplasia?

Orphanet J Rare Dis 2012 Sep 22;7:70. Epub 2012 Sep 22.

Provincial Medical Genetics Program, Department of Medical Genetics, Children's and Women's Health Centre of BC, 4500 Oak Street, Room C234, Vancouver, BC, V6H 3N1, Canada.

Background: Arteriosclerosis and emphysema develop in individuals with Schimke immuno-osseous dysplasia (SIOD), a multisystem disorder caused by biallelic mutations in SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1). However, the mechanism by which the vascular and pulmonary disease arises in SIOD remains unknown.

Methods: We reviewed the records of 65 patients with SMARCAL1 mutations. Molecular and immunohistochemical analyses were conducted on autopsy tissue from 4 SIOD patients.

Results: Thirty-two of 63 patients had signs of arteriosclerosis and 3 of 51 had signs of emphysema. The arteriosclerosis was characterized by intimal and medial hyperplasia, smooth muscle cell hyperplasia and fragmented and disorganized elastin fibers, and the pulmonary disease was characterized by panlobular enlargement of air spaces. Consistent with a cell autonomous disorder, SMARCAL1 was expressed in arterial and lung tissue, and both the aorta and lung of SIOD patients had reduced expression of elastin and alterations in the expression of regulators of elastin gene expression.

Conclusions: This first comprehensive study of the vascular and pulmonary complications of SIOD shows that these commonly cause morbidity and mortality and might arise from impaired elastogenesis. Additionally, the effect of SMARCAL1 deficiency on elastin expression provides a model for understanding other features of SIOD.
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http://dx.doi.org/10.1186/1750-1172-7-70DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3568709PMC
September 2012

Rituximab in children with resistant idiopathic nephrotic syndrome.

J Am Soc Nephrol 2012 Jun 10;23(6):1117-24. Epub 2012 May 10.

Division of Nephrology, Dialysis and Transplantation and Laboratory on Pathophysiology of Uremia, Istituto G. Gaslini, Largo G. Gaslini 5, Genoa, Italy.

Idiopathic nephrotic syndrome resistant to standard treatments remains a therapeutic dilemma in pediatric nephrology. To test whether the anti-CD20 monoclonal antibody rituximab may benefit these patients, we conducted an open-label, randomized, controlled trial in 31 children with idiopathic nephrotic syndrome unresponsive to the combination of calcineurin inhibitors and prednisone. All children continued prednisone and calcineurin inhibitors at the doses prescribed before enrollment, and one treatment group received two doses of rituximab (375 mg/m(2) intravenously) as add-on therapy. The mean age was 8 years (range, 2-16 years). Rituximab did not reduce proteinuria at 3 months (change, -12% [95% confidence interval, -73% to 110%]; P=0.77 in analysis of covariance model adjusted for baseline proteinuria). Additional adjustment for previous remission and interaction terms (treatment by baseline proteinuria and treatment by previous remission) did not change the results. In conclusion, these data do not support the addition of rituximab to prednisone and calcineurin inhibitors in children with resistant idiopathic nephrotic syndrome.
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http://dx.doi.org/10.1681/ASN.2011080775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3358759PMC
June 2012

Advances in Alport syndrome diagnosis using next-generation sequencing.

Eur J Hum Genet 2012 Jan 7;20(1):50-7. Epub 2011 Sep 7.

Medical Genetics Section, Biotechnology Department, University of Siena, Siena, Italy.

Alport syndrome (ATS) is a hereditary nephropathy often associated with sensorineural hypoacusis and ocular abnormalities. Mutations in the COL4A5 gene cause X-linked ATS. Mutations in COL4A4 and COL4A3 genes have been reported in both autosomal recessive and autosomal dominant ATS. The conventional mutation screening, performed by DHPLC and/or Sanger sequencing, is time-consuming and has relatively high costs because of the absence of hot spots and to the high number of exons per gene: 51 (COL4A5), 48 (COL4A4) and 52 (COL4A3). Several months are usually necessary to complete the diagnosis, especially in cases with less informative pedigrees. To overcome these limitations, we designed a next-generation sequencing (NGS) protocol enabling simultaneous detection of all possible variants in the three genes. We used a method coupling selective amplification to the 454 Roche DNA sequencing platform (Genome Sequencer junior). The application of this technology allowed us to identify the second mutation in two ATS patients (p.Ser1147Phe in COL4A3 and p.Arg1682Trp in COL4A4) and to reconsider the diagnosis of ATS in a third patient. This study, therefore, illustrates the successful application of NGS to mutation screening of Mendelian disorders with locus heterogeneity.
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http://dx.doi.org/10.1038/ejhg.2011.164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3234521PMC
January 2012

[TRPC6 mutations in children with steroid-resistant nephrotic syndrome].

G Ital Nefrol 2011 Jul-Aug;28(4):350-2

Dipartimento di Scienze Biomediche, Universita' degli Studi di Foggia, Foggia, Italy.

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November 2011

TRPC6 mutations in children with steroid-resistant nephrotic syndrome and atypical phenotype.

Clin J Am Soc Nephrol 2011 Jul;6(7):1626-34

Department of Biomedical Sciences, University of Foggia, Viale Pinto, 1, 71100 Foggia, Italy.

Background And Objectives: Mutations in the TRPC6 gene have been recently identified as the cause of late-onset autosomal-dominant focal segmental glomerulosclerosis (FSGS). To extend the screening, we analyzed TRPC6 in 33 Italian children with sporadic early-onset SRNS and three Italian families with adult-onset FSGS.

Design, Setting, Participants, & Measurements: TRPC6 mutation analysis was performed through PCR and sequencing. The effects of the detected amino acid substitutions were analyzed by bioinformatics tools and functional in vitro studies. The expression levels of TRPC6 and nephrin proteins were evaluated by confocal microscopy.

Results: Three heterozygous missense mutations (c.374A>G_p.N125S, c.653A>T_p.H218L, c.2684G>T_p.R895L) were identified. The first new mutation, p.H218L, was found in a 18-year-old boy who presented a severe form of FSGS at the age of 8 years. The second, p.R895L, a new de novo mutation, was identified in a girl with collapsing glomerulosclerosis at the age of 2 years. The former mutation, p.N125S, was found in two siblings with early-onset steroid-resistant nephrotic syndrome (SRNS) at the ages of 4 and 14 years. Renal immunofluorescence revealed upregulated expression of TRPC6 and loss of nephrin in glomeruli. The intracellular calcium concentrations were significantly higher in the cells expressing all mutant TRPC6 channels compared with cells expressing wild-type TRPC6.

Conclusions: Our findings suggest that TRPC6 variants can also be detected in children with early-onset and sporadic SRNS (4 of 33 patients). Moreover, in one patient a new de novo TRPC6 mutation was associated with a rare severe form of childhood collapsing glomerulosclerosis with rapid progression to uremia.
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http://dx.doi.org/10.2215/CJN.07830910DOI Listing
July 2011

Cobalamin C defect presenting as severe neonatal hyperammonemia.

Eur J Pediatr 2011 Jul 10;170(7):887-90. Epub 2010 Dec 10.

Division of Metabolism, Bambino Gesù Children's Hospital, Rome, Italy.

Unlabelled: Cobalamin C (Cbl-C) defect is the most common inborn error of cobalamin metabolism which causes a block in the pathway responsible for the synthesis of its two metabolically active forms methyl- and adenosylcobalamin. Cbl-C defect causes the accumulation of methylmalonic acid and homocysteine and decreased methionine synthesis. The clinical presentation of patients with early-onset Cbl-C defect, characterized by a multisystem disease with severe neurological, ocular, hematological, renal, gastrointestinal, cardiac, and pulmonary manifestations, differs considerably from what observed in the "classical" form of methylmalonic aciduria caused by defect of methylmalonyl-CoA mutase. This last condition is in most cases dominated in the neonatal period by a metabolic encephalopathy "intoxication type" with severe hyperammonemia and ketoacidosis. We report a Cbl-C defect patient presenting a neonatal encephalopathy with severe hyperammonemia and ketoacidosis who was successfully treated with peritoneal dialysis.

Conclusion: To the best of our knowledge, there are no reported cases of Cbl-C defect showing an acute presentation resembling a classical methylmalonic aciduria. This observation enlarges the spectrum of inherited diseases to be considered in the differential diagnosis of neonatal hyperammonemia.
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http://dx.doi.org/10.1007/s00431-010-1371-8DOI Listing
July 2011

Cyclosporine A treatment in patients with Alport syndrome: a single-center experience.

Pediatr Nephrol 2010 Jul 18;25(7):1269-75. Epub 2010 Mar 18.

Department of Nephrology and Urology, Bambino Gesù Children's Hospital and Research Institute, Nephrology and Dialysis Unit, Piazza S. Onofrio 4, 00165, Rome, Italy.

Limited and discordant data are available on cyclosporine A (CsA) treatment for proteinuria in Alport syndrome (AS). To address this lack of consistent data, we have studied 15 AS patients (14 males; mean age 15.3 +/- 6.0 years) treated with CsA. Patient selection criteria included a urinary protein/creatinine ratio > or =1 mg/mg and a creatinine clearance >40 ml/min/1.73 m(2). CsA treatment was started at an initial dose of 5 mg/kg/day and subsequently adjusted to reach target C2 levels of 500 ng/ml. Renal function, proteinuria, and blood pressure were monitored. Blood pressure was treated to avoid the administration of angiotensin converting enzyme or angiotensin receptor blockers for the first 2 years of therapy. The average follow-up was 3.5 years. Five patients had chronic renal failure at the beginning of treatment, of whom three and one reached end-stage renal failure within 1 and 3 years, respectively. In the remaining 11 patients, the glomerular filtration rate declined by 11 +/- 6% within 6 months, but remained stable thereafter. Proteinuria decreased by 63 +/- 21% from baseline, but returned nearly to baseline after 2.5 years of follow-up. Based on these results, we suggest that CsA is effective in reducing proteinuria in patients with Alport syndrome but that this effect is temporary. Our data do not support the use of CsA therapy for proteinuric patients with AS, particularly if they have chronic renal failure.
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http://dx.doi.org/10.1007/s00467-010-1484-3DOI Listing
July 2010

Time for initial response to steroids is a major prognostic factor in idiopathic nephrotic syndrome.

J Pediatr 2010 Jun 10;156(6):965-971. Epub 2010 Mar 10.

Division of Nephrology and Dialysis, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy.

Objective: To identify early prognostic factors for idiopathic nephrotic syndrome (INS) in childhood.

Study Design: A retrospective analysis of 103 patients with INS at onset, all treated in a single center with the same induction protocol, was conducted. Minimum length of follow-up was 2 years; median length of follow-up was 43 months. Survival data were assessed with Cox-Mantel analysis. Predictive values were estimated with receiver operating characteristic curves.

Results: The median time of response to steroid therapy was 7 days. A significant association was found between the interval from onset of steroid therapy to remission and the risk of relapsing within 3 months after steroid therapy discontinuation (P < .0001). A similar association was found between the time to achieve remission and the risk of developing frequent relapsing or steroid-dependent nephrotic syndrome (P < .0001), the prescription of maintenance steroid therapy (P < .003), and the prescription of all other non-steroid drugs (P < .0001) during follow-up. Patients with non-relapsing and infrequent relapsing nephrotic syndrome had a median time to achieve remission <7 days; in patients with frequent relapsing and steroid-dependent nephrotic syndrome, this median was >7 days.

Conclusion: The interval from onset of steroid therapy to remission is an accurate early prognostic factor in INS.
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http://dx.doi.org/10.1016/j.jpeds.2009.12.020DOI Listing
June 2010

Idiopathic membranous nephropathy associated with polycystic kidney disease.

Pediatr Nephrol 2010 May 22;25(5):961-3. Epub 2009 Dec 22.

Division of Nephrology and Dialysis, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy.

Membranous nephropathy (MN) and polycystic kidney disease are both relatively rare diseases in children. On rare exceptions, these two conditions have been associated in adults. We report here the first case of a pediatric patient with this association. This 6-year-old child presented with gross hematuria, nephrotic syndrome, and mild renal failure. A renal ultrasound subsequently revealed that the patient also had polycystic kidney disease.
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http://dx.doi.org/10.1007/s00467-009-1398-0DOI Listing
May 2010

Risk factors for cyclosporin A nephrotoxicity in children with steroid-dependant nephrotic syndrome.

Clin J Am Soc Nephrol 2009 Sep 23;4(9):1409-16. Epub 2009 Jul 23.

Division of Nephrology, Bambino Gesù Children's Hospital and Research Institute, 00165 Rome, Italy.

Background And Objectives: Cyclosporin A (CsA) is a well-established treatment for steroid-dependent nephrotic syndrome (SDNS) that may, however, cause chronic ischemic renal lesions. The objective of the study was to assess the prevalence of CsA nephrotoxicity (CsAN) in protocol biopsies of children with SDNS.

Design, Settings, Participants, & Measurements: From 1990 through 2008, we performed 71 renal biopsies in 53 patients with SDNS. The mean CsA C2 levels were 466 +/- 134 ng/ml, and the mean duration of treatment was 4.7 +/- 2.0 yr before biopsy (range 2.9 to 12.7 yr).

Results: CsAN was observed in 22 (31%) of 71 renal biopsies. Of these, 11 corresponded to isolated vascular or tubular lesions, and 11 corresponded to combined vascular and tubular lesions. The majority of CsAN lesions were mild (17 of 22). In no cases were lesions graded as severe. By regression analysis, CsAN was positively associated with the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) and with hyperuricemia and negatively associated with minimal-change lesions. By multivariate analysis, only association with the use of ACEIs or ARBs retained significance. Stratification of the population according to CsA C2 levels showed increased risk for CsAN for C2 levels >600 ng/ml.

Conclusions: Mild to moderate CsAN occurs in approximately one third of patients who have SDNS and are treated with CsA for >3 yr. Our data suggest that patients who require high dosages of CsA or treatment for hypertension, in particular when ACEIs/ARBs are used, are at higher risk for CsAN.
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http://dx.doi.org/10.2215/CJN.01520209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2736699PMC
September 2009

Type VII collagen in Alport syndrome.

Nephrol Dial Transplant 2007 Dec 1;22(12):3501-7. Epub 2007 Aug 1.

Department of Experimental Medicine, La Sapienza University, Viale Regina Elena, 324, 00161 Rome Italy.

Background: Absence or segmental distribution of the alpha5(IV) collagen chain along the epidermal basement membrane (EBM) is diagnostic of X-linked Alport syndrome (X-AS), but the typical morphologic alterations usually observed along the glomerular basement membrane (GBM) are lacking. However, several differences in protein composition exist between GBM and EBM, and such differences could account for a different phenotype with the same genetic defect. Type VII collagen is one of the major collagenous components of the EBM; the purpose of this study was to investigate the modifications of protein synthesis and expression of type VII collagen in the skin of patients with X-AS.

Methods: The distribution of type VII collagen has been studied in 15 skin biopsies (10 from X-AS patients and 5 controls) by means of electron microscopy, immunofluorescence and confocal microscopy; type VII collagen mRNA expression was also measured by RT-PCR on the same skin fragments.

Results: Protein and mRNA amounts for type VII collagen were significantly higher in skin samples from X-AS patients than in controls (P < 0.001); highest values were in cases in which alpha5(IV) was completely absent.

Conclusions: Our results indicate that lack of alpha5(IV) molecule significantly alters the assembly of extracellular matrix molecules other than alphax(IV) chains also at the EBM level. We suggest that the increased synthesis and deposition of type VII collagen is likely to balance the absence of stabilizing activity normally exerted by alpha5(IV).
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http://dx.doi.org/10.1093/ndt/gfm481DOI Listing
December 2007