Rapid Response to Cyclosporin A and Favorable Renal Outcome in Nongenetic Versus Genetic Steroid–Resistant Nephrotic Syndrome

Büscher, Anja; Beck, Bodo B.; Melk, Anette; Hoefele, Julia; Kranz, Birgitta; Bamborschke, Daniel; Baig, Sabrina; Lange-Sperandio, Bärbel; Jungraithmayr, Theresa; Weber, Lutz T.; Kemper, Markus J.; Tönshoff, Burkhard; Hoyer, Peter F.; Konrad, Martin; Weber, Stefanie

doi:10.2215/cjn.07370715

Cited by 122 publications

(94 citation statements)

References 38 publications

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“…Therapy for genetic FSGS is generally conservative and on the basis of RAAS antagonism. Calcineurin inhibitors may have an effect in a minority of patients (78). As noted above, coenzyme Q10 may benefit individuals with mutations in certain mitochondrial defects.…”

Section: Genetic Fsgsmentioning

confidence: 99%

Focal Segmental Glomerulosclerosis

Rosenberg

Kopp

2017

CJASN

434

366

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Focal segmental glomerulosclerosis (FSGS) is a leading cause of kidney disease worldwide. The presumed etiology of primary FSGS is a plasma factor with responsiveness to immunosuppressive therapy and a risk of recurrence after kidney transplant-important disease characteristics. In contrast, adaptive FSGS is associated with excessive nephron workload due to increased body size, reduced nephron capacity, or single glomerular hyperfiltration associated with certain diseases. Additional etiologies arenow recognized asdrivers of FSGS: high-penetrance geneticFSGSdue to mutations in one of nearly 40 genes, virus-associated FSGS, and medication-associated FSGS. Emerging data support the identification of a sixth category: APOL1 risk allele-associated FSGS in individuals with sub-Saharan ancestry. The classification of a particular patient with FSGS relies on integration of findings from clinical history, laboratory testing, kidney biopsy, and in some patients, genetic testing. The kidney biopsy can be helpful, with clues provided by features on light microscopy (e.g., glomerular size, histologic variant of FSGS, microcystic tubular changes, and tubular hypertrophy), immunofluorescence (e.g., to rule out other primary glomerulopathies), and electron microscopy (e.g., extent of podocyte foot process effacement, podocyte microvillous transformation, and tubuloreticular inclusions). A complete assessment of renal histology is important for establishing the parenchymal setting of segmental glomerulosclerosis, distinguishing FSGS associated with one of many other glomerular diseases from the clinical-pathologic syndrome of FSGS. Genetic testing is beneficial in particular clinical settings. Identifying the etiology of FSGS guides selection of therapy and provides prognostic insight. Much progress has been made in our understanding of FSGS, but important outstanding issues remain, including the identity of the plasma factor believed to be responsible for primary FSGS, the value of routine implementation of genetic testing, and the identification of more effective and less toxic therapeutic interventions for FSGS.

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Section: Genetic Fsgsmentioning

confidence: 99%

Focal Segmental Glomerulosclerosis

Rosenberg

Kopp

2017

CJASN

434

366

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“…Oral prednisone is usually reduced to alternate days and gradually tapered until discontinuation within 6 months (10). Response to CsA, when present, is gradual, and has been observed even many months after the introduction of CsA in about 80% of patients (58). In about 30% of children, the presence of a genetic mutation determines the course of the disease (59), and in this case the chances of response to treatment are extremely low.…”

Section: Steroid-resistant Formsmentioning

confidence: 99%

Minimal Change Disease

Vivarelli

Massella

Ruggiero

et al. 2016

CJASN

417

383

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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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“…The discovery of these genes has shed insight into the molecular mechanisms underlying NS (in particular implicating the podocyte as the major cell affected by NS). From a clinical perspective, genotype-phenotype studies suggest patients classified with monogenic NS are resistant to immunosuppressive therapy and have faster renal functional decline, but do not develop disease recurrence following transplant [5–9]. …”

Section: Introductionmentioning

confidence: 99%

Evaluating Mendelian nephrotic syndrome genes for evidence for risk alleles or oligogenicity that explain heritability

et al. 2016

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Background More than 30 genes can harbor rare exonic variants sufficient to cause nephrotic syndrome (NS), and the number of genes implicated in monogenic NS continues to grow. However, outside the first year of life, the majority of affected patients, particularly in ancestrally mixed populations, do not have a known monogenic form of NS. Even in those children classified with a monogenic form of NS, there is phenotypic heterogeneity. Thus, we have only discovered a fraction of the heritability of NS – the underlying genetic factors contributing to phenotypic variation. Part of the “missing heritability” for NS has been posited to be explained by patients harboring coding variants across one or more previously implicated NS genes, insufficient to cause NS in a classical Mendelian manner, but that nonetheless impact protein function enough to cause disease. However, systematic evaluation in patients with NS for rare or low-frequency risk alleles within single genes, or in combination across genes (“oligogenicity”), has not been reported. Objective To determine whether, as compared to a reference population, patients with NS have either a significantly increased burden of protein-altering variants (“risk-alleles”), or unique combination of them (“oligogenicity”), in a set of 21 genes implicated in Mendelian forms of NS. Methods In 303 patients with NS enrolled in the Nephrotic Syndrome Study Network (NEPTUNE), we performed targeted amplification paired with next-generation sequencing of 21 genes implicated in monogenic NS. We created a high-quality variant call set and compared it to a variant call set of the same genes in a reference population composed of 2535 individuals from Phase 3 of 1000 Genomes Project. We created both a “stringent” and “relaxed” pathogenicity filtering pipeline, applied them to both cohorts, and computed the (1) burden of variants in the entire gene set per cohort, (2) burden of variants in the entire gene set per individual, (3) burden of variants within a single gene per cohort, and (4) unique combinations of variants across two or more genes per cohort. Results With few exceptions when using the relaxed filter, and which are likely the result of confounding by population stratification, NS patients did not have significantly increased burden of variants in Mendelian NS genes in comparison to a reference cohort, nor was there any evidence of oligogenicity. This was true when using both the relaxed and stringent variant pathogenicity filter. Conclusion In our study, the burden or particular combinations of low-frequency or rare protein altering variants in previously implicated Mendelian NS genes cohort does not significantly differ between North American patients with NS and a reference population. Studies in larger independent cohorts or meta-analyses are needed to assess generalizability of our discoveries and also address whether there is in fact small but significant enrichment of risk alleles or oligogenicity in NS cases undetectable with this current sample size. It is s...

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Rapid Response to Cyclosporin A and Favorable Renal Outcome in Nongenetic Versus Genetic Steroid–Resistant Nephrotic Syndrome

Cited by 122 publications

References 38 publications

Focal Segmental Glomerulosclerosis

Focal Segmental Glomerulosclerosis

Minimal Change Disease

Evaluating Mendelian nephrotic syndrome genes for evidence for risk alleles or oligogenicity that explain heritability

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