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Role of mTORC2 in Rapid Renal Responses improve prediction of treatment effects on the clinical end to Dietary Potassium point for Phase 2 trials with study sample sizes of 100–200 patients and duration of follow-up ranging from 1 to 2 years. Rapid renal responses to ingested potassium are essential to In smaller Phase 2 trials, prediction of clinical benefitis prevent hyperkalemia and also play a central role in regulating almost exclusively due to treatment effects on albuminuria. 1 1 blood pressure. Although extracellular K concentration [K ] These findings may help inform design of clinical trials in kidney tissue is recognized as an important regulator of K for interventions aimed at slowing CKD progression. See secretion, the underlying mechanisms that are relevant in vivo Heerspink et al., pages 955–968. remain controversial. Growing evidence implicates the signal- ing kinase mTOR complex-2 (mTORC2) in rapid renal re- sponses to changes in plasma [K ]. To explore this, Saha et al. compared the effects of K given via gavage in wild-type mice and in knockout mice with kidney tubule–specific inactivation of mTORC2. They found that mTORC2 was rapidly activated to trigger K secretion and maintain electrolyte homeostasis and that downstream targets of mTORC2 implicated in ep- ithelial sodium channel regulation were concomitantly phos- phorylated in wild-type mice but not knockout mice. A related editorial says that the work clearly shows that mTORC2 plays an important role in signaling to the epithelium sodium Kidney Failure in Childhood and Life Years Lost channel in the distal tubule, noting that these results contrib- ute to solving the mysteries of aldosterone action on the kidney Survival and long-term health are the outcomes most im- distal tubule. See Saha et al., pages 1019–1038. Also see editorial portant to children with CKD and their caretakers. However, by Ellison and McCormick, pages 936–938. rigorous data have not been available to predict treatment trajectories or the effects of kidney failure on lifetime sur- vival and years of life lost. A population-based cohort study of children who developed kidney failure in Australia and New Zealand during 1980–2019, with a median follow-up of 13.1 years, found that of the 2013 children, most received a transplant after initiating dialysis (74%) or had a preemptive kidney transplant (14%). Mortality rates were highest in the first 3–6 months after kidney failure. Life expectancy in- creased with older age at kidney failure, but more life years were spent on dialysis than with a functioning transplant. Combining Kidney Failure Surrogate End Points to The expected years of life lost ranged from 16 to 32 years, Help Predict Drug Effects on Clinical End Points with women and those who developed kidney failure at a younger age experiencing the greatest loss. Although the Change in albuminuria and GFR slope are individually used as excess mortality rate in children with kidney failure has surrogate end points in clinical trials of CKD progression, and improved over the years, it has remained high. These data studies have demonstrated that each is associated with treat- should be valuable in counseling families. See Wyld et al., ment effects on clinical end points. The contrasting strengths pages 1057–1068. and limitations of surrogate end points on the basis of change in urinary albumin-to-creatinine ratio (UACR) and GFR slope led the authors of this study to explore strategies that incorporate both of these surrogate end points to strengthen inferences about clinical benefit. In this meta-analysis, Heerspink et al. developed a multivariate meta-regression model that relates treatment effects on early change in UACR, GFR slope, and the clinical end point to each other. They then applied this model to the design and analysis of Phase 2 clinical trials. The results show that information from the combined treatment effects on albuminuria and GFR slope
Journal of the American Society of Nephrology – Wolters Kluwer Health
Published: Jun 1, 2023
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