Is mild dehydration a risk for progression of childhood chronic kidney disease?

Abstract

Children with chronic kidney disease (CKD) can have an inherent vulnerability to dehydration. Younger children are unable to freely access water, and CKD aetiology and stage can associate with reduced kidney concentrating capacity, which can also impact risk. This article aims to review the risk factors and consequences of mild dehydration and underhydration in CKD, with a particular focus on evidence for risk of CKD progression. We discuss that assessment of dehydration in the CKD population is more challenging than in the healthy population, thus complicating the definition of adequate hydration and clinical research in this field. We review pathophysiologic studies that suggest mild dehydration and underhydration may cause hyperfiltration injury and impact renal function, with arginine vasopressin as a key mediator. Randomised controlled trials in adults have not shown an impact of improved hydration in CKD outcomes, but more vulnerable populations with baseline low fluid intake or poor kidney concentrating capacity need to be studied. There is little published data on the frequency of dehydration, and risk of complications, acute or chronic, in children with CKD. Despite conflicting evidence and the need for more research, we propose that paediatric CKD management should routinely include an assessment of individual dehydration risk along with a treatment plan, and we provide a framework that could be used in outpatient settings.

Keywords: Children; Chronic kidney disease (CKD); Dehydration; Hypohydration; Underhydration.

A higher resolution version of the Graphical abstract is available as Supplementary information

Fig. 1

A Juxtamedullary nephron — key sites of V2R-mediated regulation urine concentration. B Schematic of tubular cell osmolyte effects relevant to urine concentration and CKD. C Schematic of collecting duct tubular cell - effects relevant to urine concentration. 1A. AVP activation of V2 receptors leads to channel activity that contributes to medullary hypertonicity and water reabsorption [–6]. The receptors indicated here all give rise to substantial urinary water loss and dehydration in rodent knock-out. Green circles represent a channel with movement of water or electrolytes from the tubule lumen into the interstitium via the cell. 1B. Tubular cell osmolyte regulation. Synthesis and reabsorption of osmolytes is altered in response to changes in osmolality [7]. Increased intracellular osmolality increases activity of the nuclear factor TonEBP [8]. TonEBP increases transcription of osmolyte transporters leading to reabsorption of these compounds from the tubular lumen. TonEBP also increases transcription of aldose reductase that converts intracellular glucose to sorbitol which also acts as an osmolyte [9]. In the proximal tubule the enzyme fructokinase acting on sorbitol may contribute to damaging intracellular changes [10]. 1C. Processes contributing to water reabsorption within tubular cells of the inner medullary collecting duct. As reviewed in [1], AVP binds to the V2R receptor and stimulates adenylate cyclase with production of cAMP. Downstream effects include stimulation of aquaporin 2 transcription, and AQP2 phosphorylation. Aquaporin 2 vesicles are steered to the luminal membrane by changes to the actin cytoskeleton, with channels endocytosed into the membrane, allowing water transport. Water traverses the cell and exits the basal membrane into the intersitium via constitutively expressed AQP3 and AQP4 channels. AVP via protein kinase A phosphorylates and activates the Urea channels UTA1 and UTA3 that also allow urea transport through the cell and into the interstitium, to set up the medullary concentrating gradient that promotes water reabsorption [4]. Epac is a protein kinase A-independent promotor of urea channel ac va on [11]. AVP also promotes EnaC activation and sodium reabsorption [6]. TonEBP is a non-AVP dependent stimulator of urine concentration via AQP2 and UTA1 channel transcription [8, 12]. Created with BioRender.com. Na, sodium; Cl, chloride; K, potassium; H2O, water; mOsm/L, milliosmoles per litre; NKCC2, sodium potassium chloride cotransporter; NCC, sodium chloride symporter or thiazide sensitive NaCl cotransporter; ENaC, epithelial sodium channel; AQP2,3,4, aquaporin channels; UTA1, UTA3, urea transporters; ATP, adenosine triphosphate; Epac, exchange proteins directly ac vated by cAMP; cAMP, cyclic adenosine 3,5 monophosphate; AC, adenylate cyclase; P, phosphate; AVP, arginine vasopressin; V2R, vasopressin type 2 receptor; CREB, cAMP-response element binding protein; TonEBP, tonicity-responsive enhancer binding protein; TauT, taurine transporter; Smit, sodium myo-inositol transporter; Bgt-1, betaine GABA transporter