Educating the Next-Generation Expert in Nephrology Genetics.

The importance of genetics and genomics in general nephrology has rapidly ascended within the last decade. While the genetic literacy of all nephrologists must improve, there is a particular need to develop the next generation of leaders and educators in nephrology genetics. In this review, we summarize how nephrology genetics could fit into the nephrology landscape and discuss components of a nephrology genetics training program.

Association of Clonal Hematopoiesis of Indeterminate Potential with Cardiovascular Events in Patients with CKD.

Key Points: In patients with CKD, non- clonal hematopoiesis of indeterminate potential (CHIP) was associated with higher risk of cardiovascular events. There was no significant difference in the CHIP–cardiovascular disease association based on baseline eGFR, diabetes status, or race. The protective effect of p.

Clonal Hematopoiesis of Indeterminate Potential and Progression of CKD.

Key Points: Non- clonal hematopoiesis of indeterminate potential was associated with CKD progression in a meta-analysis of 5654 individuals with CKD. In an adenine-induced CKD mouse model, -clonal hematopoiesis of indeterminate potential was linked to lower GFR, increased kidney inflammation, tubular injury, and fibrosis.

Background: Clonal hematopoiesis of indeterminate potential (CHIP) is a common inflammatory condition of aging that causes myriad end-organ damage.

Donor and Recipient Polygenic Risk Scores Influence Kidney Transplant Function.

Kidney transplant outcomes are influenced by donor and recipient age, sex, HLA mismatch, donor type, anti-rejection medication adherence and disease recurrence, but variability in transplant outcomes remains unexplained. We hypothesise that donor and recipient polygenic burden for traits related to kidney function may also influence graft function. We assembled a cohort of 6,060 living and deceased kidney donor-recipient pairs.

Polygenic risk scores for eGFR are associated with age at kidney failure.

Background: The genetic architecture of chronic kidney disease (CKD) is complex, including monogenic and polygenic contributions. CKD progression to kidney failure is influenced by factors including male sex, baseline estimated glomerular filtration rate (eGFR), hypertension, diabetes, proteinuria, and the underlying kidney disease. These traits all have strong genetic components, which can be partially quantified using polygenic risk scores.

Endoplasmic reticulum stress as a driver and therapeutic target for kidney disease.

The endoplasmic reticulum (ER) has crucial roles in metabolically active cells, including protein translation, protein folding and quality control, lipid biosynthesis, and calcium homeostasis. Adverse metabolic conditions or pathogenic genetic variants that cause misfolding and accumulation of proteins within the ER of kidney cells initiate an injurious process known as ER stress that contributes to kidney disease and its cardiovascular complications. Initiation of ER stress activates the unfolded protein response (UPR), a cellular defence mechanism that functions to restore ER homeostasis.

Whole body resistance training on functional outcomes of patients with Stage 4 or 5 chronic kidney disease: A systematic review.

Chronic kidney disease (CKD) causes skeletal muscle wasting, resulting in reduced function and inability to live independently. This systematic review critically appraised the scientific literature regarding the effects of full-body resistance training on clinically-relevant functional capacity measures in CKD. The study population included studies of people with Stage 4 or 5 CKD and a mean age of 40+ years old.

Clonal hematopoiesis of indeterminate potential contributes to accelerated chronic kidney disease progression.

Background: Clonal hematopoiesis of indeterminate potential (CHIP) is a common inflammatory condition of aging that causes myriad end-organ damage. We have recently shown associations for CHIP with acute kidney injury and with kidney function decline in the general population, with stronger associations for CHIP driven by mutations in genes other than (non- CHIP). Longitudinal kidney function endpoints in individuals with pre-existing chronic kidney disease (CKD) and CHIP have been examined in two previous studies, which reported conflicting findings and were limited by small sample sizes.

Kidney Volume and Risk of Incident Kidney Outcomes.

Key Points: Low kidney volume was a risk factor of incident CKD. A nonlinear relationship existed whereby individuals in the bottom tenth percentile of kidney volume exhibited exaggerated risk of CKD and albuminuria. Kidney volume could improve the classification of kidney disease risk.

How Does ADPKD Severity Differ Between Family Members?

Thousands of pathogenic variants in more than 100 genes can cause kidney cysts with substantial variability in phenotype and risk of subsequent kidney failure. Despite an established genotype-phenotype correlation in cystic kidney diseases, incomplete penetrance and variable disease expressivity are present as is the case in all monogenic diseases. In family members with autosomal dominant polycystic kidney disease (ADPKD), the same causal variant is responsible in all affected family members; however, there can still be striking discordance in phenotype severity.

Clonal hematopoiesis of indeterminate potential is associated with acute kidney injury.

Age is a predominant risk factor for acute kidney injury (AKI), yet the biological mechanisms underlying this risk are largely unknown. Clonal hematopoiesis of indeterminate potential (CHIP) confers increased risk for several chronic diseases associated with aging. Here we sought to test whether CHIP increases the risk of AKI.

The Good and the Bad of SHROOM3 in Kidney Development and Disease: A Narrative Review.

Purpose Of Review: Multiple large-scale genome-wide association meta-analyses studies have reliably identified an association between genetic variants within the gene and chronic kidney disease. This association extends to alterations in known markers of kidney disease including baseline estimated glomerular filtration rate, urinary albumin-to-creatinine ratio, and blood urea nitrogen. Yet, an understanding of the molecular mechanisms behind the association of SHROOM3 and kidney disease remains poorly communicated.

Assessing the Risk of Progression to Kidney Failure in Patients With Autosomal Dominant Polycystic Kidney Disease.

While autosomal dominant polycystic kidney disease (ADPKD) is a dichotomous diagnosis, substantial variability in disease severity exists. Identification of inherited risk through family history, genetic testing, and environmental risk factors through clinical assessment are important components of risk assessment for optimal management of patients with ADPKD. Genetic testing is especially helpful in cases with diagnostic uncertainty, particularly in cases with no apparent family history, in young cases (age less than 25 years) where a definitive diagnosis is sought, or in atypical presentations with early, severe, or discordant findings.

Clonal haematopoiesis, ageing and kidney disease.

Clonal haematopoiesis of indeterminate potential (CHIP) is a preclinical condition wherein a sizeable proportion of an individual's circulating blood cells are derived from a single mutated haematopoietic stem cell. CHIP occurs frequently with ageing - more than 10% of individuals over 65 years of age are affected - and is associated with an increased risk of disease across several organ systems and premature death. Emerging evidence suggests that CHIP has a role in kidney health, including associations with predisposition to acute kidney injury, impaired recovery from acute kidney injury and kidney function decline, both in the general population and among those with chronic kidney disease.

A novel multi-ancestry proteome-wide Mendelian randomization study implicates extracellular proteins, tubular cells, and fibroblasts in estimated glomerular filtration rate regulation.

Estimated glomerular filtration rate (eGFR) impacts the concentration of plasma biomarkers confounding biomarker association studies of eGFR with reverse causation. To identify biomarkers causally associated with eGFR, we performed a proteome-wide Mendelian randomization study. Genetic variants nearby biomarker coding genes were tested for association with plasma concentration of 1,161 biomarkers in a multi-ancestry sample of 12,066 participants from the Prospective Urban and Rural Epidemiological (PURE) study.