Renal and Cardiovascular Morbidities Associated with APOL1 Status among African-American and Non-African-American Children with Focal Segmental Glomerulosclerosis

Woroniecki, Robert P.; Ng, Derek K.; Limou, Sophie; Winkler, Cheryl A.; Reidy, Kimberly; Mitsnefes, Mark; Sampson, Matthew G.; Wong, Craig S.; Warady, Bradley A.; Furth, Susan L.; Kopp, Jeffrey B.; Kaskel, Frederick J.

doi:10.3389/fped.2016.00122

Cited by 31 publications

(18 citation statements)

References 29 publications

(44 reference statements)

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“…The total DUETstudy population included only 15 (14%) black patients, thus offering limited opportunity for interpretation of results in this patient subgroup with increased genetic risk for, incidence of, and comorbidities associated with FSGS. 12,30,31 Additionally, no effect on eGFR could be detected over the 8-week, double-blind treatment period but is being studied in the ongoing open-label treatment period. Finally, additional factors could have contributed to the greater antiproteinuric effect of sparsentan.…”

Section: Discussionmentioning

confidence: 99%

DUET: A Phase 2 Study Evaluating the Efficacy and Safety of Sparsentan in Patients with FSGS

Trachtman

Nelson

Adler

et al. 2018

JASN

137

108

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Background We evaluated and compared the effects of sparsentan, a dual endothelin type A (ET A) and angiotensin II type 1 receptor antagonist, with those of the angiotensin II type 1 receptor antagonist irbesartan in patients with primary FSGS. Methods In this phase 2, randomized, double-blind, active-control Efficacy and Safety of Sparsentan (RE-021), a Dual Endothelin Receptor and Angiotensin Receptor Blocker, in Patients with Focal Segmental Glomerulosclerosis (FSGS): A Randomized, Double-blind, Active-Control, Dose-Escalation Study (DUET), patients aged 8-75 years with biopsy-proven FSGS, eGFR.30 ml/min per 1.73 m 2 , and urinary protein-to-creatinine ratio (UP/C) $1.0 g/g received sparsentan (200, 400, or 800 mg/d) or irbesartan (300 mg/d) for 8 weeks, followed by open-label sparsentan only. End points at week 8 were reduction from baseline in UP/C (primary) and proportion of patients achieving FSGS partial remission end point (FPRE) (UP/C: #1.5 g/g and .40% reduction [secondary]). Results Of 109 patients randomized, 96 received study drugs and had baseline and week 8 UP/C measurements. Sparsentan-treated patients had greater reductions in UP/C than irbesartan-treated patients did when all doses (45% versus 19%; P=0.006) or the 400 and 800 mg doses (47% versus 19%; P=0.01) were pooled for analysis. The FSGS partial remission end point was achieved in 28% of sparsentan-treated and 9% of irbesartan-treated patients (P=0.04). After 8 weeks of treatment, BP was reduced with sparsentan but not irbesartan, and eGFR was stable with both treatments. Overall, the incidence of adverse events was similar between groups. Hypotension and edema were more common among sparsentan-treated patients but did not result in study withdrawals. Conclusions Patients with FSGS achieved significantly greater reductions in proteinuria after 8 weeks of sparsentan versus irbesartan. Sparsentan was safe and well tolerated.

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Section: Discussionmentioning

confidence: 99%

DUET: A Phase 2 Study Evaluating the Efficacy and Safety of Sparsentan in Patients with FSGS

Trachtman

Nelson

Adler

et al. 2018

JASN

137

108

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“… 21 We did, however, have 96% power to detect significant associations for odds ratio > 4.5 for the recessive model, suggesting that if APOL1 HR status is associated with pediatric FSGS in this population, its penetrance is much less than we see in children or adult African Americans with FSGS. 18 , 19 , 23 …”

Section: Discussionmentioning

confidence: 99%

“… 21 Among African American children with CKD, APOL1 high-risk status was associated with glomerular disease and with more rapid decline in estimated glomerular filtration rate, 22 and among African American children with FSGS, 78% carried high-risk APOL1 genotypes. 23 The association of APOL1 with NS in children in sub-Saharan Africa has not been investigated.…”

mentioning

confidence: 99%

NPHS2 V260E Is a Frequent Cause of Steroid-Resistant Nephrotic Syndrome in Black South African Children

Asharam

Bhimma

David

et al. 2018

Kidney International Reports

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IntroductionIn South Africa (SA), steroid-resistant nephrotic syndrome (SRNS) is more frequent in black than in Indian children.MethodsSeeking a genetic basis for this disparity, we enrolled 33 Indian and 31 black children with steroid-sensitive nephrotic syndrome (SSNS) and SRNS from KwaZulu-Natal, SA; SRNS children underwent kidney biopsy. We sequenced NPHS2 and genotyped APOL1 in 15 SSNS and 64 SRNS unrelated patients and 104 controls and replicated results in 18 black patients with steroid-resistant focal segmental glomerulosclerosis (SR-FSGS). Known FSGS genes (n = 21) were sequenced in a subset of patients.ResultsHomozygosity for NPHS2 V260E was found in 8 of 30 black children with SRNS (27%); all 260E/E carriers had SR-FSGS. Combining SR-FSGS patients from the 2 groups, 14 of 42 (33%) were homozygous for V260E. One black control was heterozygous for V260E; no Indian patients or controls were carriers. Haplotype analysis indicated that homozygosity for V260E was not explained by cryptic consanguinity. Children with NPHS2 260E/E developed SRNS at earlier age than noncarriers (34 vs. 78 months, P = 0.01), and none achieved partial or complete remission (0% vs. 47%, P = 0.002). APOL1 variants did not associate with NS. Sequencing FSGS genes identified a CD2AP predicted pathogenic variant in the heterozygous state in 1 Indian case with SR-FSGS.ConclusionNPHS2 260E/E was present in one-third of black FSGS patients, was absent in black controls and Indian patients, and affected patients were unresponsive to therapy. Genotyping V260E in black children from South Africa with NS will identify a substantial group with SR-FSGS, potentially sparing these children biopsy and ineffective steroid treatment.

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“…This limitation could be overcome by generating dual transgenic HIV-Tg 26 / APOL1 mice [48], and infecting newborn mice with rAd-Tat vectors. In addition, a significant number of Black children living with HIV develop HIVAN independently of the APOL1 risk variants [49,50], and previous studies suggest that the APOL1 risk variants may play more relevant role in adults, when compared to young children [50,51]. Thus, young kidneys might be more sensitive to the cytotoxic effects of HIV-1 genes, TNF-α, and heparin binding growth factors, and less dependent on the APOL1 risk variants to develop HIVAN.…”

Section: Discussionmentioning

confidence: 99%

An HIV-Tat inducible mouse model system of childhood HIV-associated nephropathy

Ray

Tang

Das

et al. 2020

Preprint

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statement. We developed a new inducible mouse model system of childhood HIV-associated nephropathy, and demonstrated that HIV-Tat plays a critical role in this renal disease acting in synergy with other HIV-1 genes and heparin binding cytokines. AbstractBackground: Modern antiretroviral therapies (ART) have decreased the prevalence of HIVassociated nephropathy (HIVAN). Nonetheless, we continue to see children and adolescents with HIVAN all over the world. Furthermore, once HIVAN is established in children, it is difficult to revert its long-term progression, and we need better animal models of childhood HIVAN to test new treatments. Objectives. To define whether the HIV-1 trans-activator (Tat) gene precipitates HIVAN in young mice, and to develop an inducible mouse model of childhood HIVAN. Design/Methods: An HIV-Tat gene cloned from a child with HIVAN was used to generate recombinant adenoviral vectors (rAd-Tat). rAd-Tat and LacZ control vectors (2 x 10 9 ) were expressed in the kidney of newborn wild type and HIV-transgenic (Tg 26 ) FVB/N mice without significant proteinuria (n = 5 -8 per group). Mice were sacrificed 7 and 35 days later to assess their renal outcome, the expression of HIV-genes and growth factors, and markers of cell growth and differentiation by RT-qPCR, immunohistochemistry, and/or Western blots. Results: HIV-Tat induced the expression of HIV-1 genes (env) and heparin binding growth factors in the kidney of HIV-Tg 26 mice, and precipitated HIVAN in the first month of life. No significant renal changes were detected in wild type mice infected with rAd-Tat vectors, suggesting that HIV-Tat alone does not induce renal disease. Conclusion. This new mouse model of childhood HIVAN highlights the critical role that HIV-Tat plays in the pathogenesis of HIVAN, and could be used to study the pathogenesis and treatment of HIVAN in children and adolescents.

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Renal and Cardiovascular Morbidities Associated with APOL1 Status among African-American and Non-African-American Children with Focal Segmental Glomerulosclerosis

Cited by 31 publications

References 29 publications

DUET: A Phase 2 Study Evaluating the Efficacy and Safety of Sparsentan in Patients with FSGS

DUET: A Phase 2 Study Evaluating the Efficacy and Safety of Sparsentan in Patients with FSGS

NPHS2 V260E Is a Frequent Cause of Steroid-Resistant Nephrotic Syndrome in Black South African Children

An HIV-Tat inducible mouse model system of childhood HIV-associated nephropathy

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