Kidney disease in the setting of HIV infection: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference

Kidney International, Journal Year: 2018, Volume and Issue: 93(3), P. 545 - 559

Published: Feb. 3, 2018

HIV-positive individuals are at increased risk for kidney disease, including HIV-associated nephropathy, noncollapsing focal segmental glomerulosclerosis, immune-complex and comorbid as well injury resulting from prolonged exposure to antiretroviral therapy or opportunistic infections. Clinical guidelines disease prevention treatment in largely extrapolated studies the general population, do not fully incorporate existing knowledge of unique HIV-related pathways genetic factors that contribute this population. We convened an international panel experts nephrology, renal pathology, infectious diseases define pathology setting HIV infection; describe role genetics natural history, diagnosis, individuals; characterize risk-benefit prevention; best practices management individuals.

Language: Английский

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APOL1 Nephropathy: From Genetics to Clinical Applications

Clinical Journal of the American Society of Nephrology, Journal Year: 2020, Volume and Issue: 16(2), P. 294 - 303

Published: July 2, 2020

Rates of many types severe kidney disease are much higher in Black individuals than most other ethnic groups. Much this disparity can now be attributed to genetic variants the apoL1 (APOL1) gene found only with recent African ancestry. These greatly increase rates hypertension-associated ESKD, FSGS, HIV-associated nephropathy, and forms nondiabetic disease. We discuss population genetics APOL1 risk clinical spectrum nephropathy. then consider issues that arise for practicing nephrologist caring patient who may have

Language: Английский

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The glomerular filtration barrier: a structural target for novel kidney therapies

Nature Reviews Drug Discovery, Journal Year: 2021, Volume and Issue: 20(10), P. 770 - 788

Published: July 14, 2021

Language: Английский

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Inaxaplin for Proteinuric Kidney Disease in Persons with Two APOL1 Variants

New England Journal of Medicine, Journal Year: 2023, Volume and Issue: 388(11), P. 969 - 979

Published: March 15, 2023

Persons with toxic gain-of-function variants in the gene encoding apolipoprotein L1 (APOL1) are at greater risk for development of rapidly progressive, proteinuric nephropathy. Despite known genetic cause, therapies targeting kidney disease persons two APOL1 (G1 or G2) lacking. Download a PDF Research Summary. We used tetracycline-inducible human embryonic (HEK293) cells to assess ability small-molecule compound, inaxaplin, inhibit channel function. An G2–homologous transgenic mouse model was inaxaplin treatment proteinuria. then conducted single-group, open-label, phase 2a clinical study which administered participants who had variants, biopsy-proven focal segmental glomerulosclerosis, and proteinuria (urinary protein-to-creatinine ratio ≥0.7 <10 [with protein creatinine both measured grams] an estimated glomerular filtration rate ≥27 ml per minute 1.73 m2 body-surface area). Participants received daily 13 weeks (15 mg 2 45 11 weeks) along standard care. The primary outcome percent change from baseline urinary week least 80% adherence therapy. Safety also assessed. In preclinical studies, selectively inhibited function vitro reduced model. Sixteen were enrolled study. Among treated met threshold, mean −47.6% (95% confidence interval, −60.0 −31.3). analysis that included all regardless therapy, reductions similar those observed but 1 participant. Adverse events mild moderate severity; none led discontinuation. Targeted inhibition glomerulosclerosis. (Funded by Vertex Pharmaceuticals; VX19-147-101 ClinicalTrials.gov number, NCT04340362.) QUICK TAKE VIDEO SUMMARYInaxaplin Proteinuric Kidney Disease High-Risk Variants 02:06

Language: Английский

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The evolving story of apolipoprotein L1 nephropathy: the end of the beginning

Nature Reviews Nephrology, Journal Year: 2022, Volume and Issue: 18(5), P. 307 - 320

Published: Feb. 25, 2022

Language: Английский

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APOL1-mediated monovalent cation transport contributes to APOL1-mediated podocytopathy in kidney disease

Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 134(5)

Published: Jan. 16, 2024

Two coding variants of apolipoprotein L1 (APOL1) called G1 and G2 explain much the excess risk kidney disease in African Americans. While various cytotoxic phenotypes have been reported experimental models, proximal mechanism by which cause is poorly understood. Here, we leveraged three models a recently small molecule blocker APOL1 protein, VX-147, to identify upstream G1-induced cytotoxicity. In HEK293 cells, demonstrated that G1-mediated Na+ import/K+ efflux triggered activation G protein-coupled receptor (GPCR)-IP3-mediated calcium release from endoplasmic reticulum (ER), impaired mitochondrial ATP production, translation, were all reversed VX-147. human podocyte-like epithelial cells (HUPEC), caused cytotoxicity was again reversible Finally, podocytes isolated transgenic mice, showed Interferon gamma (IFNγ)-mediated induction K+ efflux, GPCR-IP3 signaling, inhibition podocyte injury, proteinuria, Together, these results establish APOL1-mediated Na+/K+ transport as driver disease.

Language: Английский

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APOL1 Bi- and Monoallelic Variants and Chronic Kidney Disease in West Africans

New England Journal of Medicine, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 26, 2024

Apolipoprotein L1 gene (

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Small molecule APOL1 inhibitors as a precision medicine approach for APOL1-mediated kidney disease

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 2, 2025

Chronic kidney disease affects ~10% of people worldwide and there are no modifying therapeutics that address the underlying cause any form disease. Genome wide association studies have identified G1 G2 variants in apolipoprotein L1 (APOL1) gene as major contributors to a subtype proteinuric now referred APOL1-mediated (AMKD). We hypothesized inhibition APOL1 could therapeutic potential for this genetically-defined Here we describe development preclinical assays discovery potent specific inhibitors with drug-like properties. provide evidence channel activity drives podocyte injury stops cell death damage transgenic mouse model. These data, combined clinical data from our previously published phase 2 proof-of-concept study, support treatment AMKD. Apolipoprotein genetic contribute authors report characterization selective ion

Language: Английский

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Advances in kidney disease: pathogenesis and therapeutic targets

Frontiers in Medicine, Journal Year: 2025, Volume and Issue: 12

Published: Feb. 14, 2025

Chronic kidney disease (CKD) is a global public health issue characterized by progressive loss of function, which end-stage (ESKD) the last stage. The increase in prevalence CKD linked to increasing traditional risk factors, including obesity, hypertension, and diabetes mellitus, as well metabolic particularly insulin resistance, dyslipidemia, hyperuricemia. Mortality comorbidities, such cardiovascular complications, rise steadily function deteriorates. Patients who progress ESKD require long-term replacement therapy, transplantation or hemodialysis/peritoneal dialysis. It currently understood that crucial aspect involves persistent, low-grade inflammation. In addition, increased oxidative stress, endothelial dysfunction, vascular calcification from poor calcium phosphate metabolism, difficulties with coagulation are some complex molecular pathways underlying CKD-related ESKD-related issues. Novel mechanisms, microbiome dysbiosis apolipoprotein L1 gene mutation, have improved our understanding mechanisms. High Africa has been APOL1 high-risk alleles. 3-fold African Americans compared European mainly attributed variants chromosome 22q12 locus. Additionally, role new therapies SGLT2 inhibitors, mineralocorticoid receptor antagonists, channel inhibitors offers therapeutic targets slowing down progression chronic disease. This review describes recent mechanisms emerging targets.

Language: Английский

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APOL1-Associated Nephropathy: A Key Contributor to Racial Disparities in CKD

American Journal of Kidney Diseases, Journal Year: 2018, Volume and Issue: 72(5), P. S8 - S16

Published: Oct. 18, 2018

Language: Английский

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