Clinical trial recommendations for potential Alport syndrome therapies

Weinstock, Benjamin; Feldman, David L.; Fornoni, Alessia; Groß, Oliver; Kashtan, Clifford E.; Lagas, Sharon; Lennon, Rachel; Miner, Jeffrey H.; Rheault, Michelle N.; Simon, James F.; Bonebrake, Lisa; Dunleavy, Marty; Kumnick, Phil; Parziale, Gina; Reed, J.S.; Weinstock, André; Gear, Susie; Binaso, Kristen; Manuel, Raymond C.; Appel, Gerald B.; Blank, Melanie; Tang, Winson W.; Thompson, Aliza; Torrá, Roser; Lieberman, Kenneth V.; Licht, Christoph; Dahan, Karin; Nozu, Kandai; Kai, Hirofumi; Ricardo, Sharon D.; Pariser, Anne; Cook, H. Terence; Chin, Melanie; Goldsberry, Angela; Meyer, Colin; Melia, Lisa Anne; Komers, Radko; Markels, M.; Mercer, Alex; Prunotto, Marco; Morgenstern, Bruce Z.; Modur, Vijay; Turner, Neil; Baigent, Colin; DeSacco, Stephano; Perin, Laura; Barua, Moumita; Nakanishi, Koichi; Jarad, George

doi:10.1016/j.kint.2020.02.029

Cited by 9 publications

(5 citation statements)

References 32 publications

(26 reference statements)

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“…Whereas the phenotype of female individuals is generally mild, male XLAS patients show progressive renal failure, especially when carrying truncating mutations. Extra-renal manifestations include hearing loss and ocular lesions, uncommon findings in hemizygote female carriers [ 27 ]. Biallelic mutations in COL4A3 and COL4A4 genes cause the autosomal recessive forms of AS, accounting for 15% of all AS patients, with a phenotype resembling male XLAS patients.…”

Section: Discussionmentioning

confidence: 99%

Next-Generation Sequencing (NGS) Analysis Illustrates the Phenotypic Variability of Collagen Type IV Nephropathies

Zacchia

Capolongo

Blanco

et al. 2023

Genes

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Mutations in COL4A3-A5 cause a spectrum of glomerular disorders, including thin basement membrane nephropathy (TBMN) and Alport syndrome (AS). The wide application of next-generation sequencing (NGS) in the last few years has revealed that mutations in these genes are not limited to these clinical entities. In this study, 176 individuals with a clinical diagnosis of inherited kidney disorders underwent an NGS-based analysis to address the underlying cause; those who changed or perfected the clinical diagnosis after molecular analysis were selected. In 5 out of 83 individuals reaching a molecular diagnosis, the genetic result was unexpected: three individuals showed mutations in collagen type IV genes. These patients showed the following clinical pictures: (1) familial focal segmental glomerulosclerosis; (2) end-stage renal disease (ESRD) diagnosed incidentally in a 49-year-old man, with diffuse cortical calcifications on renal imaging; and (3) dysmorphic and asymmetric kidneys with multiple cysts and signs of tubule–interstitial defects. Genetic analysis revealed rare heterozygote/compound heterozygote COL4A4-A5 variants. Our study highlights the key role of NGS in the diagnosis of inherited renal disorders and shows the phenotype variability in patients carrying mutations in collagen type IV genes.

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Section: Discussionmentioning

confidence: 99%

Next-Generation Sequencing (NGS) Analysis Illustrates the Phenotypic Variability of Collagen Type IV Nephropathies

Zacchia

Capolongo

Blanco

et al. 2023

Genes

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“…[52][53][54] Finally, the identification of a genetic cause for a kidney disorder has implications for determining the eligibility of patients for genetically stratified clinical trials. 55,56 Whom to Test?…”

Section: Box 1 (Continued) Casementioning

confidence: 99%

The Role of Genetic Testing in Adult CKD

Knoers,

van Eerde

2024

JASN

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Mounting evidence indicates that monogenic disorders are the underlying cause in a significant proportion of chronic kidney disease patients. In recent years, the diagnostic yield of genetic testing in these patients has increased significantly as a result of revolutionary developments in genetic sequencing techniques and sequencing data analysis. Identification of disease-causing genetic variant(s) in chronic kidney disease patients may facilitate prognostication and personalized management, including nephroprotection and decisions around kidney transplantation, and is crucial for genetic counseling and reproductive family planning. A genetic diagnosis in a chronic kidney disease patient allows for screening of at-risk family members, which is also important for determining their eligibility as kidney transplant donors. Despite evidence for clinical utility, increased availability, and data supporting the cost-effectiveness of genetic testing in chronic kidney disease, especially when applied early in the diagnostic process, many nephrologists do not use genetic testing to its full potential because of multiple perceived barriers. Our aim in this paper is to empower nephrologists to (further) implement genetic testing as a diagnostic means in their clinical practice, based on the most recent insights and exemplified by patient vignettes. We stress why genetic testing is of significant clinical benefit to many chronic kidney disease patients, provide recommendations for which patients to test and which test(s) to order, give guidance about interpretation of genetic testing results, and highlight the necessity for and essential components of pre- and post-test genetic counseling.

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“…If it comes to use of ACE-inhibitor in children with chronic kidney disease, we do not want to make a profit with a drug, but use it safely and effectively with the help of a Benefit-risk assessment by the European Medicines Agency EMA and the Food and Drug Administration FDA, which is absolutely possible due to the wide range of data for ACE-inhibitors in Alport syndrome. 2,[4][5][6][7]12,13,19 Now that ACE-inhibitors are and will remain standard of care anyway, why do we need advice by regulatory authorities? An assessment by the European Medicines Agency EMA and the Food and Drug Administration FDA would be extremely helpful, because the regulatory authorities have global expertise and an overall view of the data situation that is outstanding worldwide.…”

Section: ) Legal Risk Aspects For Pediatricians Of Sglt2inhibitor Off...mentioning

confidence: 99%

SGLT2 Inhibitors are Blockbusters in Adults - But Not Studied in Children with Kidney Disease due to Industry Conflicts of Commercial Interest: A Call for Help To Regulators

Gross

2023

MRAJ

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This article reviews the circumstances why and how the pharmaceutical industry is avoiding the pediatric investigation plans for their block-buster drugs in chronic kidney diseases. The "why" is easy to answer because it is just about economic reasons. This is much to the disadvantage of sick children, who are thus deprived of the opportunity for evidence-based therapy. Just as in the time prior to the pediatric trial regulation, pediatricians remain in a legal gray zone of off-label use and expose themselves to the risk of lawsuits. The article is intended to start a discussion on how regulatory authorities could support the development of better treatment recommendations for children with kidney disease for drugs that are not promoted by the industry. This could be by working more closely with patient representatives and academia, by supporting the planning phase of investigator-initiated trials, or by scientific advice on cumulative real world and randomized controlled trial data on specific medications or substance groups.

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Clinical trial recommendations for potential Alport syndrome therapies

Cited by 9 publications

References 32 publications

Next-Generation Sequencing (NGS) Analysis Illustrates the Phenotypic Variability of Collagen Type IV Nephropathies

Next-Generation Sequencing (NGS) Analysis Illustrates the Phenotypic Variability of Collagen Type IV Nephropathies

The Role of Genetic Testing in Adult CKD

SGLT2 Inhibitors are Blockbusters in Adults - But Not Studied in Children with Kidney Disease due to Industry Conflicts of Commercial Interest: A Call for Help To Regulators

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