Identification of genetic causes for sporadic steroid-resistant nephrotic syndrome in adults

Gribouval, Olivier; Boyer, Olivia; Hummel, Aurélie; Dantal, Jacques; Martinez, Frank; Sberro-Soussan, Rébecca; Étienne, Isabelle; Chauveau, Dominique; Delahousse, Michel; Lionet, Arnaud; Allard, Julien; Noble, Claire Pouteil; Tête, Marie-Josèphe; Heidet, Laurence; Antignac, Corinne; Servais, Aude

doi:10.1016/j.kint.2018.07.024

Cited by 62 publications

(46 citation statements)

References 52 publications

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“…As expected (Eddy & Symons, 2003), the children with SRNS were significantly older at presentation, otherwise the groups were demographically similar. Genetics are known to play a role in steroid-responsiveness (Adeyemo et al, 2018;Asharam et al, 2018;Govender et al, 2019;Gribouval et al, 2018Gribouval et al, , 2019. However, while genetic and other mechanisms underlying steroid-responsiveness in this small cohort were not evaluated in the present study, they have been the subject of previously reported biomarker studies (Agrawal et al, 2020;Gooding et al, 2020).…”

Section: Hypercoagulopathy Improves In Children With Steroid-sensitmentioning

confidence: 83%

Nephrotic syndrome‐associated hypercoagulopathy is alleviated by both pioglitazone and glucocorticoid which target two different nuclear receptors

et al. 2020

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Background: Thrombosis is a potentially life-threatening nephrotic syndrome (NS) complication. We have previously demonstrated that hypercoagulopathy is proportional to NS severity in rat models and that pioglitazone (Pio) reduces proteinuria both independently and in combination with methylprednisolone (MP), a glucocorticoid (GC). However, the effect of these treatments on NS-associated hypercoagulopathy remains unknown. We thus sought to determine the ability of Pio and GC to alleviate NS-associated hypercoagulopathy. Methods: Puromycin aminonucleoside-induced rat NS was treated with sham, Lowor High-dose MP, Pio, or combination (Pio + Low-MP) and plasma was collected at day 11. Plasma samples were collected from children with steroid-sensitive NS (SSNS) and steroid-resistant NS (SRNS) upon presentation and after 7 weeks of GC therapy. Plasma endogenous thrombin potential (ETP), antithrombin (AT) activity, and albumin (Alb) were measured using thrombin generation, amidolytic, and colorimetric assays, respectively. Results: In a rat model of NS, both High-MP and Pio improved proteinuria and corrected hypoalbuminemia, ETP and AT activity (p < .05). Proteinuria (p = .005) and hypoalbuminemia (p < .001) were correlated with ETP. In childhood NS, while ETP was not different at presentation, GC therapy improved proteinuria, hypoalbuminemia, and ETP in children with SSNS (p < .001) but not SRNS (p = .330). Conclusions: Both Pio and GC diminish proteinuria and significantly alleviate hypercoagulopathy. Both Pio and MP improved hypercoagulopathy in rats, and successful GC therapy (SSNS) also improved hypercoagulopathy in childhood NS. These data suggest that even a partial reduction in proteinuria may reduce NS-associated thrombotic risk. How to cite this article: Waller AP, Agrawal S, Wolfgang KJ, et al. Nephrotic syndrome-associated hypercoagulopathy is alleviated by both pioglitazone and glucocorticoid which target two different nuclear receptors.

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Section: Hypercoagulopathy Improves In Children With Steroid-sensitmentioning

confidence: 83%

Nephrotic syndrome‐associated hypercoagulopathy is alleviated by both pioglitazone and glucocorticoid which target two different nuclear receptors

et al. 2020

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“…The proportion of patients newly diagnosed with genetic podocytopathies declines with age at onset. Nevertheless, pathogenetic mutations occur in 14-21% of adults with steroid-resistant glomerular disorders and, therefore, genetic testing is warranted in adults with treatment-resistant proteinuria 68,153,154 (FiG. 9).…”

Section: Kidney Biopsymentioning

confidence: 99%

“…For example, patients with pathogenetic mutations in coenzyme Q 10 biosynthesis (COQ2, COQ6 and ADCK4) may respond to oral coenzyme Q 10 supplementation 72,73,166 . Patients with pathogenetic mutations in collagen genes benefit from early diagnosis and administration of a RASi, while avoiding calcineurin inhibitors to prevent CKD progression 154,205 . Patients with Dent disease should be treated to avoid failure to thrive and kidney stones 64,65,206 .…”

Section: Personalized Treatmentmentioning

confidence: 99%

Podocytopathies

Kopp

Anders

Suszták

et al. 2020

Nat Rev Dis Primers

334

270

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Podocytopathies are kidney diseases in which direct or indirect podocyte injury drives proteinuria or nephrotic syndrome. In children and young adults, genetic variants in >50 podocyte-expressed genes, syndromal non-podocyte-specific genes and phenocopies with other underlying genetic abnormalities cause podocytopathies associated with steroid-resistant nephrotic syndrome or severe proteinuria. A variety of genetic variants likely contribute to disease development. Among genes with non-Mendelian inheritance, variants in APOL1 have the largest effect size. In addition to genetic variants, environmental triggers such as immune-related, infection-related, toxic and haemodynamic factors and obesity are also important causes of podocyte injury and frequently combine to cause various degrees of proteinuria in children and adults. Typical manifestations on kidney biopsy are minimal change lesions and focal segmental glomerulosclerosis lesions. Standard treatment for primary podocytopathies manifesting with focal segmental glomerulosclerosis lesions includes glucocorticoids and other immunosuppressive drugs; individuals not responding with a resolution of proteinuria have a poor renal prognosis. Renin-angiotensin system antagonists help to control proteinuria and slow the progression of fibrosis. Symptomatic management may include the use of diuretics, statins, infection prophylaxis and anticoagulation. This Primer discusses a shift in paradigm from patient stratification based on kidney biopsy findings towards personalized management based on clinical, morphological and genetic data as well as pathophysiological understanding.

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“…The likelihood for identifying a disease-causing variant resulting in FSGS/SRNS is inversely related to age of onset due to usually early manifestation in monogenic cases [1,5,11,12]. The diagnostic yield in patients above 21 years at study entry with glomerulopathies ranges from 7% in unselected cohorts [13] to 12-14% in selected cohorts [14,15]. Overall, genetic and phenotypic data on patients with FSGS or SRNS disease onset above 18 years are scarce.…”

Section: Introductionmentioning

confidence: 99%

Identification of disease-causing variants by comprehensive genetic testing with exome sequencing in adults with suspicion of hereditary FSGS

et al. 2020

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In about 30% of infantile, juvenile, or adolescent patients with steroid-resistant nephrotic syndrome (SRNS), a monogenic cause can be identified. The histological finding in SRNS is often focal segmental glomerulosclerosis (FSGS). Genetic data on adult patients are scarce with low diagnostic yields. Exome sequencing (ES) was performed in patients with adult disease onset and a high likelihood for hereditary FSGS. A high likelihood was defined if at least one of the following criteria was present: absence of a secondary cause, ≤25 years of age at initial manifestation, kidney biopsy with suspicion of a hereditary cause, extrarenal manifestations, and/or positive familial history/reported consanguinity. Patients were excluded if age at disease onset was <18 years. In 7/24 index patients with adult disease onset, a disease-causing variant could be identified by ES leading to a diagnostic yield of 29%. Eight different variants were identified in six known genes associated with monogenic kidney diseases. Six of these variants had been described before as disease-causing. In patients with a diseasecausing variant, the median age at disease onset and end-stage renal disease was 26 and 38 years, respectively. The overall median time to a definite genetic diagnosis was 9 years. In 29% of patients with adult disease onset and suspected hereditary FSGS, a monogenic cause could be identified. The long delay up to the definite genetic diagnosis highlights the importance of obtaining an early genetic diagnosis to allow for personalized treatment options including weaning of immunosuppressive treatment, avoidance of repeated renal biopsy, and provision of accurate genetic counseling.

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Identification of genetic causes for sporadic steroid-resistant nephrotic syndrome in adults

Cited by 62 publications

References 52 publications

Nephrotic syndrome‐associated hypercoagulopathy is alleviated by both pioglitazone and glucocorticoid which target two different nuclear receptors

Nephrotic syndrome‐associated hypercoagulopathy is alleviated by both pioglitazone and glucocorticoid which target two different nuclear receptors

Podocytopathies

Identification of disease-causing variants by comprehensive genetic testing with exome sequencing in adults with suspicion of hereditary FSGS

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