Heterogeneous Genetic Alterations in Sporadic Nephrotic Syndrome Associate with Resistance to Immunosuppression

Giglio, Sabrina; Provenzano, Aldesia; Mazzinghi, Benedetta; Becherucci, Francesca; Giunti, Laura; Sansavini, Giulia; Ravaglia, Fiammetta; Roperto, Rosa Maria; Farsetti, Silvia; Benetti, Elisa; Rotondi, Mario; Murer, Luisa; Lazzeri, Elena; Lasagni, Laura; Materassi, Marco; Romagnani, Paola

doi:10.1681/asn.2013111155

Cited by 90 publications

(87 citation statements)

References 37 publications

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“…Indeed, patient-specific cells were obtained from children with genetic forms of steroid-resistant nephrotic syndrome (SRNS), differentiated into podocytes after exposure to specific medium and then used to functionally evaluate the role of known pathogenic mutations in two patients carrying homozygous or compound heterozygous mutations of the NPHS2 gene, that were indeed characterized by a reduced or absent synthesis of podocin. 34 In addition, this method allowed establishment of the role of a variant of unknown clinical significance in the LMX1B gene, [24][25][26] a crucial controller of podocyte cytoskeleton integrity, in inducing functional alterations of the podocyte cytoskeleton in a child with SRNS. 34 This method may similarly apply to other inherited disorders of the kidney, such as tubulopathies, and used for functional studies of potentially pathogenic mutations of unknown significance to complement diagnosis of genetic kidney disorders.…”

Section: Discussionmentioning

confidence: 99%

Human Urine-Derived Renal Progenitors for Personalized Modeling of Genetic Kidney Disorders

Lazzeri¹,

Ronconi

Angelotti³

et al. 2015

Journal of the American Society of Nephrology

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The critical role of genetic and epigenetic factors in the pathogenesis of kidney disorders is gradually becoming clear, and the need for disease models that recapitulate human kidney disorders in a personalized manner is paramount. In this study, we describe a method to select and amplify renal progenitor cultures from the urine of patients with kidney disorders. Urine-derived human renal progenitors exhibited phenotype and functional properties identical to those purified from kidney tissue, including the capacity to differentiate into tubular cells and podocytes, as demonstrated by confocal microscopy, Western blot analysis of podocyte-specific proteins, and scanning electron microscopy. Lineage tracing studies performed with conditional transgenic mice, in which podocytes are irreversibly tagged upon tamoxifen treatment (NPHS2.iCreER;mT/mG), that were subjected to doxorubicin nephropathy demonstrated that renal progenitors are the only urinary cell population that can be amplified in longterm culture. To validate the use of these cells for personalized modeling of kidney disorders, renal progenitors were obtained from (1) the urine of children with nephrotic syndrome and carrying potentially pathogenic mutations in genes encoding for podocyte proteins and (2) the urine of children without genetic alterations, as validated by next-generation sequencing. Renal progenitors obtained from patients carrying pathogenic mutations generated podocytes that exhibited an abnormal cytoskeleton structure and functional abnormalities compared with those obtained from patients with proteinuria but without genetic mutations. The results of this study demonstrate that urine-derived patient-specific renal progenitor cultures may be an innovative research tool for modeling of genetic kidney disorders. 26: 196126: -197426: , 201526: . doi: 10.1681 The incidence of AKI and CKD is rising and reaching epidemic proportions. 1 In patients with CKD, the progressive decline in renal function is multifactorial and attributable to a variety of mechanisms. 2 In particular, the critical role of genetic factors in the etiology, pathogenesis, and progression of many renal disorders is gradually becoming clear, especially in children. 3 Indeed, the advent of high-throughput sequencing techniques has fostered the identification of novel causative genes and allows the continuous discovery of genetic variants of unknown clinical significance, often raising the problem of the functional testing of their pathogenic role. 4 However, emerging evidence suggests that influence of the J Am Soc Nephrol

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Section: Discussionmentioning

confidence: 99%

Human Urine-Derived Renal Progenitors for Personalized Modeling of Genetic Kidney Disorders

Lazzeri¹,

Ronconi

Angelotti³

et al. 2015

Journal of the American Society of Nephrology

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“…Several studies highlight that monogenic SRNS is largely steroid resistant, irrespective of the causative mutation [6,69,91]. Subsequent management of such patients often includes various immunosuppressive agents, all with associated adverse side effects and often limited clinical benefit [6,91].…”

Section: Immunosuppressionmentioning

confidence: 99%

“…Subsequent management of such patients often includes various immunosuppressive agents, all with associated adverse side effects and often limited clinical benefit [6,91].…”

Section: Immunosuppressionmentioning

confidence: 99%

“…Furthermore, there does not appear to be a notable difference in the frequency of histological lesions found in patients with or without a recognised genetic cause [6]. For these reasons, in cases of primary SRNS, rapid genetic testing has the potential to obviate the need for renal biopsy for diagnostic purposes and serves as a less invasive diagnostic method; this is of particular significance in the younger SRNS cohort, for whom a genetic aetiology is more likely.…”

Section: Renal Biopsymentioning

confidence: 99%

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Genetic testing in steroid-resistant nephrotic syndrome: why, who, when and how?

2017

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Steroid-resistant nephrotic syndrome (SRNS) is a common cause of chronic kidney disease in childhood and has a significant risk of rapid progression to end-stage renal disease. The identification of over 50 monogenic causes of SRNS has revealed dysfunction in podocyte-associated proteins in the pathogenesis of proteinuria, highlighting their essential role in glomerular function. Recent technological advances in high-throughput sequencing have enabled indication-driven genetic panel testing for patients with SRNS. The availability of genetic testing, combined with the significant phenotypic variability of monogenic SRNS, poses unique challenges for clinicians when directing genetic testing. This highlights the need for clear clinical guidelines that provide a systematic approach for mutational screening in SRNS. The likelihood of identifying a causative mutation is inversely related to age at disease onset and is increased with a positive family history or the presence of extra-renal manifestations. An unequivocal molecular diagnosis could allow for a personalised treatment approach with weaning of immunosuppressive therapy, avoidance of renal biopsy and provision of accurate, well-informed genetic counselling. Identification of novel causative mutations will continue to unravel the pathogenic mechanisms of glomerular disease and provide new insights into podocyte biology and glomerular function.

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“…Typically, patients with hereditary forms of disease exhibit significantly lower rates of recurrence compared to those with non-genetic primary disease. In fact, in some series, none of the patients with FSGS who had a causative genetic mutation responded to immunosuppressive treatment for disease in their native kidney but had minimal likelihood of recurrence in the allograft [18]. The gene coding for podocin, NPHS2, located on chromosome 1q25-31, has been the focus of many studies of recurrent FSGS because it is one of the most common genetic causes of primary disease [16,17].…”

Section: Pathogenesismentioning

confidence: 99%

Recurrent focal segmental glomerulosclerosis after kidney transplantation

2015

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Focal segmental glomerulosclerosis (FSGS) is an important cause of glomerular disease in children and adolescents and nearly 50 % of affected patients will progress to endstage kidney disease over a 5 to 10-year period. Unfortunately, there is no established treatment for disease in the native kidney. Moreover, up to 55 % of patients develop recurrent disease after receiving a kidney transplant, with a substantially higher risk in patients who have already experienced recurrent disease in a prior transplant. A number of clinical and laboratory factors have been identified as risk factors for this complication. In addition, new investigations into podocyte biology and circulating permeability factors have shed light on the cause of recurrent the disease. While a number of novel therapeutic agents have been applied in the management of this problem, there still is no proven treatment. In this review, we summarize recent advances in the epidemiology, pathophysiology, and treatment of recurrent FSGS in pediatric patients who have received a kidney transplant.

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Heterogeneous Genetic Alterations in Sporadic Nephrotic Syndrome Associate with Resistance to Immunosuppression

Cited by 90 publications

References 37 publications

Human Urine-Derived Renal Progenitors for Personalized Modeling of Genetic Kidney Disorders

Human Urine-Derived Renal Progenitors for Personalized Modeling of Genetic Kidney Disorders

Genetic testing in steroid-resistant nephrotic syndrome: why, who, when and how?

Recurrent focal segmental glomerulosclerosis after kidney transplantation

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