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5. Grimm PR, Coleman R, Delpire E, Welling PA: Constitutively active Cachexia with muscle wasting is prevalent and closely associated SPAK causes hyperkalemia by activating NCC and remodeling distal with mortality and morbidity in patients with CKD.1 The patho- – tubules. JAmSocNephrol28: 2597 2606, 2017 physiology of muscle wasting in CKD is complex. Inadequate 6. Moriguchi T, Urushiyama S, Hisamoto N, Iemura S, Uchida S, Natsume T, Matsumoto K, Shibuya H: WNK1 regulates phosphorylation of cation- nutritional intake, physical inactivity from muscle weakness, sys- chloride-coupled cotransporters via the STE20-related kinases, SPAK temic inflammation and aberrant signaling of neuropeptides have and OSR1. J Biol Chem 280: 42685–42693, 2005 been implicated.2 To date, there is no effective therapy. Exercise 7. YangSS,MorimotoT,RaiT,ChigaM,SoharaE,OhnoM,UchidaK,LinSH, training has well documented health benefits, including mainte- Moriguchi T, Shibuya H, Kondo Y, SasakiS,UchidaS:Molecularpatho- nance of muscle mass as well as increased physical performance genesis of pseudohypoaldosteronism type II: Generation and analysis of a fi Wnk4(D561A/1) knockin mouse model. Cell Metab 5: 331–344, 2007 resulting from changes in muscle ber phenotype leading to in- 8. Lalioti MD, Zhang J, Volkman HM, Kahle KT, Hoffmann KE, Toka HR, Nelson- creased mitochondrial biogenesis. The molecular signaling mech- Williams C, Ellison DH, Flavell R, Booth CJ, Lu Y, Geller DS, Lifton RP: Wnk4 anism underlying adaptations to increased physical activity in controls blood pressure and potassium homeostasis via regulation of mass CKD-associated muscle wasting is not well understood. – and activity of the distal convoluted tubule. Nat Genet 38: 1124 1132, 2006 Wang et al.3 investigated microRNA-23a (miR-23a) and miR- 9. Healy JK: Pseudohypoaldosteronism type II: History, arguments, an- swers, and still some questions. Hypertension 63: 648–654, 2014 27a, located in an NFAT-regulated gene cluster, as potential can- 10. Good DW, Wright FS: Luminal influences on potassium secretion: Sodium didates for exercise mimetics in mice with CKD cachexia. miR-23a concentration and fluid flow rate. Am J Physiol 236: F192–F205, 1979 expression is decreased in mice with CKD. Resistance overload 11. Hunter RW, Craigie E, Homer NZ, Mullins JJ, Bailey MA: Acute in- exercise increased muscle miR-23a and miR-27a expression in 1 hibition of NCC does not activate distal electrogenic Na reabsorption CKD. In vivo transfection of miR-23a/miR-27a cluster precursor or kaliuresis. Am J Physiol Renal Physiol 306: F457–F467, 2014 12. Loffing J, Vallon V, Loffing-Cueni D, Aregger F, Richter K, Pietri L, Bloch- in CKD mice attenuated muscle wasting, improved grip Faure M, Hoenderop JG, Shull GE, Meneton P, Kaissling B: Altered renal strength, and corrected the aberrant signaling of ubiquitin li- distal tubule structure and renal Na(1)andCa(21)handlinginamouse gases, muscle ring finger 1, and atrogin 1, which are the signa- model for Gitelman’ssyndrome.J Am Soc Nephrol 15: 2276–2288, 2004 ture of muscle wasting in CKD. In silico analysis identified 13. Reilly RF, Ellison DH: Mammalian distal tubule: Physiology, patho- PTEN and caspase-7 as targets for miR-23a and Fox-O1 as target physiology, and molecular anatomy. Physiol Rev 80: 277–313, 2000 14. Kaiser T, Ting JT, Monteiro P, Feng G: Transgenic labeling of parvalbumin- of miR-27a in muscle. The authors concluded that the miR-23a/ expressing neurons with tdTomato. Neuroscience 321: 236–245, 2016 miR-27a cluster might play an important role in the molecular 15. Gracia T, Wang X, Su Y, Norgett EE, Williams TL, Moreno P, Micklem G, signaling of exercise-induced adaptations in CKD muscle and Karet Frankl FE: Urinary exosomes contain MicroRNAs capable of para- suggested that this pathway may provide the basis of pharma- crine modulation of tubular transporters in kidney. Sci Rep 7: 40601, 2017 ceutical exercise mimetics for CKD cachexia and wasting. 16. Terker AS, Zhang C, McCormick JA, Lazelle RA, Zhang C, Meermeier NP, Siler DA, Park HJ, Fu Y, Cohen DM, Weinstein AM, Wang WH, Yang CL, Ellison DH: miRs have long been associated with myogenesis. miR-1 Potassium modulates electrolyte balance and blood pressure through effects knockout flies show premature death from failure of skeletal on distal cell voltage and chloride. Cell Metab 21: 39–50, 2015 muscle development.4 Knockout of miRs in mice, however, produces little in terms of pathologic phenotype, such as would be predicted from in vitro studies.5 Overlap and redun- See related article, “Constitutively Active SPAK Causes Hyperkalemia by dancy of various miR members could be the reason. Double ” – Activating NCC and Remodeling Distal Tubules, on pages 2597 2606. knockout of miR-133a-1 and miR-133a-2 resulted in skeletal muscle myopathy, which was not shown in the single knockouts.6 miRs regulate satellite cell proliferation. In vitro miR-27a is known MicroRNA as Novel Exercise to promote myoblast proliferation by inhibiting myostatin.7 How- ever, miR-23a affects myoblast differentiation via regulation of Mimetic for Muscle Wasting in myosin heavy-chain gene transcription.8 Exercise has known CKD effects on miR expression. Endurance exercise increases miR-1 and miR-133 in the short term9 but decreases the resting levels 10 Robert H. Mak and Wai W. Cheung of miR-1 and miR-133 in the long term. 3 fi Division of Pediatric Nephrology, Rady Children’s Hospital, University In this study, Wang et al. rst determined the effect of re- of California, San Diego, La Jolla, California sistance exercise–prevented muscle wasting in both transverse abdominal (TA) and soleus muscles. Muscle overloading specif- J Am Soc Nephrol 28: 2557–2559, 2017. doi: https://doi.org/10.1681/ASN.2017060631 ically improved miR-23a/miR-27a expression, whereas miR-24 and miR-29a expressions did not change in CKD mice. Then, they showed that overexpression of miR-23a/27a/24–2bytrans- fection of vectors into the TA muscle improved TA muscle mass Published online ahead of print. Publication date available at www.jasn.org. as well as grip strength in CKD mice. The TA muscle provides fi Correspondence: Prof. Robert H. Mak, Division of Pediatric Nephrology, thoracic and pelvic stability, which may improve ef ciency of University of California, San Diego, 9500 Gilman Drive, MC 0630, La Jolla, CA muscle recruitment in the extremities. In this study, only grip 92093-0831. Email: [email protected] strength, which is mostly a test of upper limb muscle function, Copyright © 2017 by the American Society of Nephrology was tested. Rotarod activity and treadmill running tests, which

J Am Soc Nephrol 28: 2555–2563, 2017 Editorials 2557 EDITORIALS www.jasn.org include and are more reflective of lower limb function, were not studied. The demonstra- tion of improved grip strength is important, because the quantitation of lean body mass/ muscle mass is fraught with methodologic confounders, such as hydration and quality of muscle tissue with respect to the amount of fibrosis and fat, in CKD. Indeed, the dem- onstration of simultaneous improvements in muscle mass and muscle function is signifi- cant, because the direct correlation of the quantity and function of muscles in chronic diseases presenting with cachexia, such as CKD, cannot be assumed. This is clearly shown in a recent phase 3 trial of anamorelin in patients with cachexia from nonsmall cell lung cancer, which showed that increase in Figure 1. Molecular targets of miR-23a and miR-27a as exercise mimetic in CKD wasting. MuRF1, muscle ring finger 1. lean body mass was not accompanied by im- provements in handgrip strength.11 Demonstration of improved obesity and insulin resistance in rodents fed a high-fat diet. PPARb/ muscle function has obvious translational implication in the d agonist treatment did not increase endurance in sedentary mice, therapeutic approach for muscle wasting in CKD. Significantly, despite its molecular effects. However, PPARb/d agonist treatment there is recent evidence of the prognostic value of grip strength in and exercise training did synergistically improve physical endurance predicting all-cause and cardiovascular mortality in a large lon- as well as oxidative muscle phenotype. Impressively, the pharma- gitudinal population study of .140,000 healthy participants in cologic AMPK activation by AICAR increases running endurance 17 countries of varying incomes and sociocultural settings.12 by as much as 44% in untrained mice.14 Wang et al.3 explored the molecular mechanism of the effect Furthermore, exercise training leads to multiorgan adaptations of the miR-23a/miR-27a cluster on CKD-associated muscle wast- in addition to those shown in skeletal muscle. Thus, it would be ing by focusing on the atrophy-related signaling. They showed simplistic to attribute the multiple health benefits of increased improvements in Akt/FoxO signaling, caspase-3–mediated pro- physical performance from exercise training to merely adaptations teolysis, muscle regeneration pathway, and myostatin signaling as in skeletal muscle phenotype and genotype. Physical inactivity has well as inflammatory cytokines. Furthermore, they performed in been recognized as a major health hazard responsible for modern silico exploration and identified PTEN and caspase-7 as potential epidemics of lifestyle disorders, such as cardiovascular disease, molecular targets for miR-23a as well as FoxO and myostatin for obesity, and type 2 diabetes.15 Although not established as yet in miR-27a. In addition to maintaining muscle mass or preventing CKD, the same pathophysiology may be similar. Thus, exercise muscle wasting, exercise training is known to trigger in skeletal mimetic for treating muscle wasting is an interesting and novel muscle remodeling that progressively enhances substrate utiliza- approach, but its validity in improving cachexia and its associated tion; this acts to reduce muscle fatigue, leading to improved mus- mortality and morbidity effects needs to be established in more cle strength and performance. Furthermore, exercise training can robust rodent and human studies before it can be established. cause muscle fiber type remodeling from less to more oxidative fibers, leading to high maximal oxidative capacity and improve- DISCLOSURES ment in exercise endurance. Wang et al.3 did not investigate None. whether miR-23a/miR-27a has an effect on substrate utilization or muscle fiber–type remodeling. A summary of miR effects on REFERENCES skeletal muscle biology in CKD with respect to pathways related 1. Mak RH, Ikizler AT, Kovesdy CP, Raj DS, Stenvinkel P, Kalantar-Zadeh K: to exercise mimetics is summarized in Figure 1. Wasting in chronic kidney disease. J Cachexia Sarcopenia Muscle 2: 9–25, 2011 Theconceptofexercisemimetics(thatgeneticmanipulationand 2. Cheung W, Yu PX, Little BM, Cone RD, Marks DL, Mak RH: Role of leptin drug treatment may result in similar molecular adaptations elicited and melanocortin signaling in uremia-associated cachexia. J Clin Invest 115: 1659–1665, 2005 by exercise) has stimulated intense investigations. This approach fi 3. Wang B, Zhang C, Zhang A, Cai H, Price SR, Wang XH: MicroRNA-23a makes the assumption that arti cial reproduction of the exercise- and microRNA-27a mimic exercise by ameliorating CKD-induced induced molecular adaptations in disease conditions leading to muscle atrophy. J Am Soc Nephrol 28: 2631–2640, 2017 physical inactivity may have the same salutary benefits of exercise 4. Sokol NS, Ambros V: Mesodermally expressed Drosophila microRNA-1 is training. The results of this line of investigation are, however, mixed. regulated by Twist and is required in muscles during larval growth. Genes Dev 19: 2343–2354, 2005 Wang et al.13 showed that reproducing molecular signatures of an d 5. Chen JF, Mandel EM, Thomson JM, Wu Q, Callis TE, Hammond SM, Conlon oxidative phenotype of skeletal muscle by overexpressing PPAR or FL, Wang DZ: The role of microRNA-1 and microRNA-133 in skeletal muscle treatment of PPARd agonist may protect against development of proliferation and differentiation. Nat Genet 38: 228–233, 2006

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6. Liu N, Bezprozvannaya S, Shelton JM, Frisard MI, Hulver MW, McMillan RP, Living kidney donation has been performed for more than six Wu Y, Voeklder KA, Grange RW, Richardson JA, Bassel-Duby R, Olson EN: decades and contributed tremendously to the treatment of ESRD – Mice lacking microRNA 133a develop dynamin 2 dependent centronuclear in the United States and around the world. The benefits of living myopathy. J Clin Invest 121: 3258–3268, 2011 7. Huang Z, Chen X, Yu B, He J, Chen D: MicroRNA-27a promotes myo- kidney donation to transplant recipients and importantly, the blast proliferation by targeting myostatin. Biochem Biophys Res donors themselves are of no question, making this modality Commun 423: 265–269, 2012 the treatment of choice for many patients with ESRD. However, 8. Wang L, Chen X, Zheng Y, Li F, Lu Z, Chen C, Liu J, Wang Y, Peng Y, the continued success of living kidney donation depends on Shen Z, Gao J, Zhu M, Chen H: MiR-23a inhibits myogenic differenti- securing a favorable postdonation outcome, especially by mini- ation through down regulation of fast myosin heavy chain isoforms. Exp Cell Res 318: 2324–2334, 2012 mizing the risk of developing kidney disease that progresses to 9. Nielsen S, Scheele C, Yfanti C, Akerström T, Nielsen AR, Pedersen BK, dialysis or kidney transplantation. Initial studies on long-term Laye MJ: Muscle specific microRNAs are regulated by endurance ex- outcomes of living kidney donors suggested that there was no or ercise in human skeletal muscle. JPhysiol588: 4029–4037, 2010 minimal risk for developing ESRD after kidney donation when 10. McCarthy JJ, Esser KA: MicroRNA-1 and microRNA-133a expression compared with the general population primarily on the basis of are decreased during skeletal muscle hypertrophy. J Appl Physiol 1,2 (1985) 102: 306–313, 2007 studies that were mostly limited to white donors. However, 11. Temel JS, Abernethy AP, Currow DC, Friend J, Duus EM, Yan Y, Fearon more recent publications suggested a relative increased ESRD KC: Anamorelin in patients with non-small-cell lung cancer and ca- risk among certain groups, particularly blacks and those with a chexia (ROMANA 1 and ROMANA 2): Results from two randomised, family history of kidney disease.3,4 This increased relative risk – double-blind, phase 3 trials. Lancet Oncol 17: 519 531, 2016 remains small in absolute numbers. Nonetheless, considering 12. Leong DP, Teo KK, Rangarajan S, Lopez-Jaramillo P, Avezum Jr. A, Orlandini A, Seron P, Ahmed SH, Rosengren A, Kelishadi R, Rahman O, Swaminathan S, that the long-term health of each donor is paramount to the IqbalR,GuptaR,LearSA,OguzA,YusoffK,ZatonskaK,ChifambaJ,Igumbor success of living kidney donation, we, as the health care com- E, Mohan V, Anjana RM, Gu H, Li W, Yusuf S; Prospective Urban Rural Epi- munity caring for these individuals, have the obligation to pro- demiology (PURE) Study investigators: Prognostic value of grip strength: vide the donor candidate with the best available information for Findings from the Prospective Urban Rural Epidemiology (PURE) appropriate informed consent and decision making. Develop- study. Lancet 386: 266–273, 2015 13. Wang YX, Zhang CL, Yu RT, Cho HK, Nelson MC, Bayuga-Ocampo CR, ing tools that help us estimate any unacceptable increased Ham J, Kang H, Evans RM: Regulation of muscle fiber type and running ESRD risk is an important but undoubtedly, very difficult task. endurance by PPARdelta. PLoS Biol 2: e294, 2004 A recent draft of the upcoming Kidney Disease Improving 14. Narkar VA, Downes M, Yu RT, Embler E, Wang YX, Banayo E, Mihaylova Global Outcomes (KDIGO) Living Kidney Donor Work Group MM, Nelson MC, Zou Y, Juguilon H, Kang H, Shaw RJ, Evans RM: AMPK fi – ClinicalPracticeGuidelines( nalguidelinesarenot yetpublished) and PPARdelta agonists are exercise mimetics. Cell 134: 405 415, 2008 “ ” 15. Richter EA, Kiens B, Wojtaszewski JF: Can exercise mimetics substitute proposes a quantitative framework to estimate ESRD risk in for exercise? Cell Metab 8: 96–98, 2008 potential kidney donors.5 These guidelines recommend using this approach to determine donor candidacy or provide appropriate informed consent to facilitate decision making. In this quantita- See related article, “MicroRNA-23a and MicroRNA-27a Mimic Exercise by tive framework, kidney donor candidate predonation ESRD risk Ameliorating CKD-Induced Muscle Atrophy,” on pages 2631–2640. couldbeestimated,andthen,transplantcenterscoulddefine an acceptable risk permissible of donation. This estimate would be considered the baseline risk for any individual willing to become a Synthesizing Absolute and donor. If this risk is deemed unacceptably high as defined by the transplant center or transplant community, then a donor candi- Relative Risks and the Many date would not be considered. To build on this framework, Unknowns to Inform Living Grams et al.6 developed a calculator using demographic (age, sex, and race) and laboratory/history (eGFR, systolic BP, use of an- Kidney Donors tihypertensive medications, body mass index, history of smoking or diabetes mellitus, and urine albumin) data derived from non- † Emilio D. Poggio* and Jesse D. Schold donor populations that resemble potential kidney donor candidates. *Department of Nephrology and Hypertension, Glickman Urological This calculator estimates lifelong ESRD risk if a subject does not † and Kidney Institute and Department of Quantitative Health donate a kidney (that is, baseline ESRD risk). However, it may be Sciences, Cleveland Clinic, Cleveland, Ohio possible that donation per se increases the risk for developing J Am Soc Nephrol 28: 2559–2561, 2017. progressive kidney disease in a few individuals with certain predis- doi: https://doi.org/10.1681/ASN.2017040375 posing factors. Per the proposed KDIGO quantitative framework, this increased future risk is to be added to each individual base- Published online ahead of print. Publication date available at www.jasn.org. line risk to estimate the accumulated lifetime ESRD risk for a par- 7 Correspondence: Dr. Emilio D. Poggio, Department of Nephrology and Hy- ticular prospective kidney donor. In this regard, Massie et al. pertension, Glickman Urological and Kidney Institute, 9500 Euclid Avenue, published in this issue of the Journal of the American Society of Desk Q7, Cleveland, OH 44195. Email: [email protected] Nephrology a new calculator that estimates postdonation ESRD Copyright © 2017 by the American Society of Nephrology risk, complementing the predonation baseline risk proposed by

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