Clinical and Genetic Characteristics of CKD Patients with High-Risk APOL1 Genotypes.

SIGNIFICANCE STATEMENT: APOL1 high-risk genotypes confer a significant risk of kidney disease, but variability in patient outcomes suggests the presence of modifiers of the APOL1 effect. We show that a diverse population of CKD patients with high-risk APOL1 genotypes have an increased lifetime risk of kidney failure and higher eGFR decline rates, with a graded risk among specific high-risk genotypes. CKD patients with high-risk APOL1 genotypes have a lower diagnostic yield for monogenic kidney disease. Exome sequencing revealed enrichment of rare missense variants within the inflammasome pathway modifying the effect of APOL1 risk genotypes, which may explain some clinical heterogeneity. BACKGROUND: APOL1 genotype has significant effects on kidney disease development and progression that vary among specific causes of kidney disease, suggesting the presence of effect modifiers. METHODS: We assessed the risk of kidney failure and the eGFR decline rate in patients with CKD carrying high-risk ( N =239) and genetically matched low-risk ( N =1187) APOL1 genotypes. Exome sequencing revealed monogenic kidney diseases. Exome-wide association studies and gene-based and gene set-based collapsing analyses evaluated genetic modifiers of the effect of APOL1 genotype on CKD. RESULTS: Compared with genetic ancestry-matched patients with CKD with low-risk APOL1 genotypes, those with high-risk APOL1 genotypes had a higher risk of kidney failure (Hazard Ratio [HR]=1.58), a higher decline in eGFR (6.55 versus 3.63 ml/min/1.73 m 2 /yr), and were younger at time of kidney failure (45.1 versus 53.6 years), with the G1/G1 genotype demonstrating the highest risk. The rate for monogenic kidney disorders was lower among patients with CKD with high-risk APOL1 genotypes (2.5%) compared with those with low-risk genotypes (6.7%). Gene set analysis identified an enrichment of rare missense variants in the inflammasome pathway in individuals with high-risk APOL1 genotypes and CKD (odds ratio=1.90). CONCLUSIONS: In this genetically matched cohort, high-risk APOL1 genotypes were associated with an increased risk of kidney failure and eGFR decline rate, with a graded risk between specific high-risk genotypes and a lower rate of monogenic kidney disease. Rare missense variants in the inflammasome pathway may act as genetic modifiers of APOL1 effect on kidney disease.

Genetics of Kidney Disease: The Unexpected Role of Rare Disorders.

Hundreds of different genetic causes of chronic kidney disease are now recognized, and while individually rare, taken together they are significant contributors to both adult and pediatric diseases. Traditional genetics approaches relied heavily on the identification of large families with multiple affected members and have been fundamental to the identification of genetic kidney diseases. With the increased utilization of massively parallel sequencing and improvements to genotype imputation, we can analyze rare variants in large cohorts of unrelated individuals, leading to personalized care for patients and significant research advancements. This review evaluates the contribution of rare disorders to patient care and the study of genetic kidney diseases and highlights key advancements that utilize new techniques to improve our ability to identify new gene-disease associations.

Mainstreaming Genetic Testing for Adult Patients With Autosomal Dominant Polycystic Kidney Disease.

PURPOSE: Genetic testing results are currently obtained approximately 1 year after referral to a medical genetics team for autosomal dominant polycystic kidney disease (ADPKD). We evaluated a mainstream genetic testing (MGT) pathway whereby the nephrology team provided pre-test counseling and selection of patients with suspected ADPKD for genetic testing prior to direct patient interaction by a medical geneticist. SOURCES OF INFORMATION: A multidisciplinary team of nephrologists, genetic counselors, and medical geneticists developed an MGT pathway for ADPKD using current testing criteria for adult patient with suspected ADPKD and literature from MGT in oncology. METHODS: An MGT pathway was assessed using a prospective cohort and compared to a retrospective cohort of 56 patients with ADPKD who received genetic testing using the standard, traditional pathway prior to implementing the MGT for ADPKD. The mainstream pathway was evaluated using time to diagnosis, diagnostic yield, and a patient survey to assess patient perceptions of the MGT pathway. KEY FINDINGS: We assessed 26 patients with ADPKD using the MGT and 18 underwent genetic testing with return of results. Of them, 52 patients had data available for analysis in the traditional control cohort. The time for return of results using our MGT pathway was significantly shorter with a median time to results of 6 months compared to 12 months for the traditional pathway. We identified causative variants in 61% of patients, variants of uncertain significance in 28%, and 10% had negative testing which is in line with expectations from the literature. The patient surveys showed high satisfaction rates with the MGT pathway. LIMITATIONS: This report is an evaluation of a new genetic testing pathway restricted to a single, publicly funded health care center. The MGT pathway involved a prospective collection of a limited number of patients with ADPKD with comparison to a retrospective cohort of patients with ADPKD evaluated by standard testing. IMPLICATIONS: A MGT pathway using clearly defined criteria and commercially available gene panels for ADPKD can be successfully implemented in a publicly funded health care system to reduce the time required to obtain genetic results.

MOTIF: Actuellement, les résultats du dépistage génétique pour la maladie polykystique rénale autosomique dominante (ADPKD) sont obtenus environ un an après l'aiguillage en médecine génique. Nous avons évalué un parcours de dépistage génétique intégré (DGI) où l'équipe de néphrologie fournit des conseils pré-dépistage et sélectionne les patients soupçonnés d'ADPKD pour un test génétique avant l'interaction directe du patient avec un généticien médical. SOURCES: Une équipe multidisciplinaire constituée de néphrologues, de conseillers en génétique et de généticiens médicaux a développé un parcours de DGI à partir des critères existants pour les patients adultes soupçonnés d'ADPKD et de la littérature portant sur le DGI en oncologie. MÉTHODOLOGIE: Le parcours de DGI a été évalué dans une cohorte prospective puis comparé à une cohorte rétrospective de 56 patients atteints d'ADPKD ayant subi un dépistage génétique selon le parcours traditionnel, avant la mise en œuvre d'un parcours de DGI pour l'ADPKD. Le parcours intégré a été évalué en tenant compte du temps requis pour poser le diagnostic, du rendement diagnostique et d'un sondage auprès des patients évaluant leurs perceptions à l'égard du parcours lui-même. PRINCIPAUX RÉSULTATS: Le parcours de DGI a permis d'évaluer 26 patients atteints d'ADPKD, dont 18 ont subi des tests génétiques avec retour des résultats. Dans la cohorte témoin (dépistage traditionnel), 52 patients disposaient de données disponibles pour l'analyse. Le délai médian pour l'obtention des résultats était significativement plus court avec le parcours de DGI qu'avec le parcours traditionnel (6 mois c. 12 mois). Des variantes causales ont été relevées chez 61 % des patients, 28 % des patients présentaient des variantes de signification incertaine et 10 % ont obtenu des résultats négatifs, ce qui est conforme aux attentes posées par les résultats rapportés dans la littérature. Les sondages menés auprès des patients ont montré des taux de satisfaction élevés à l'égard du parcours de DGI. LIMITES: Ce rapport constitue l'évaluation d'un nouveau parcours de dépistage génétique limitée à un seul centre de soins de santé public. Ce parcours de DGI a été évalué dans une cohorte prospective formée d'un nombre limité de patients atteints d'ADPKD par rapport à une cohorte rétrospective de patients atteints d'ADPKD évalués par la méthode traditionnelle. IMPLICATIONS: Un parcours de DGI utilisant des critères clairement définis et des panels génétiques pour l'ADPKD disponible commercialement peut être mis en œuvre avec succès dans un système de santé public et accélérer l'obtention des résultats génétiques.

Altered fear learning across development in both mouse and human.

The only evidence-based behavioral treatment for anxiety and stress-related disorders involves desensitization techniques that rely on principles of extinction learning. However, 40% of patients do not respond to this treatment. Efforts have focused on individual differences in treatment response, but have not examined when, during development, such treatments may be most effective. We examined fear-extinction learning across development in mice and humans. Parallel behavioral studies revealed attenuated extinction learning during adolescence. Probing neural circuitry in mice revealed altered synaptic plasticity of prefrontal cortical regions implicated in suppression of fear responses across development. The results suggest a lack of synaptic plasticity in the prefrontal regions, during adolescence, is associated with blunted regulation of fear extinction. These findings provide insight into optimizing treatment outcomes for when, during development, exposure therapies may be most effective.

Pharmacological cognitive enhancers: comment on Smith and Farah (2011).

Smith and Farah (2011) provided a thought-provoking and perhaps deliberately provocative literature review of the use of stimulants to improve cognitive functioning in humans. They addressed the apparently increasing willingness of individuals mostly in the United States to use stimulants for this purpose and then summarized published literature that explores whether stimulants actually improve specific aspects of neurocognitive function. Although calling for more research, they tentatively concluded that stimulants indeed may be "smart pills" for some people under certain circumstances. This comment emphasizes that they never actually defined the desired qualities of a smart pill, seemed to accept the unproven axiom that slight improvements in specific tests constitute meaningful enhancement of intelligence, and failed to consider the possible costs to individuals and to society of promoting the use of this class of medications for such a purpose.