A “Set Point” for Water Homeostasis Disturbed with Altered Kidney Transplantation Outcome

Mazloum et al.1 performed a water-loading test in 1258 kidney transplant recipients 3 months after transplantation. A total of 163 healthy kidney donors served as controls. Plasma sodium slope was flatter during the waterload test in kidney transplant patients, and a steeper plasma sodium reduction, that is hyponatremia, was associated with mortality, allograft lost, and lower GFR. These interesting results need to be confirmed in other kidney transplantation centers, but they suggest water-loading could be a useful clinical surveillance tool. The waterload test done by the Necker team consists of water administered orally at 6 ml/kg of water over 30 minutes, followed by 150 ml of water every hour. It is different from the classic test, 20 ml/kg body wt of water load administered intravenously, which is used to assess, for example, hyponatremic cirrhotic patients or patients with suspected syndrome of inappropriate antidiuretic hormone secretion.2,3 This modified “Necker” waterload is likely to represent the day-to-day changes in plasma sodium observed in real life in kidney transplant recipients, many of whom are accustomed to restricting their water intake during hemodialysis prior to transplantation. Oral administration of water is better understood from a physiologic point of view since recent optogenetic experiments have demonstrated how thirst and arginine-vasopressin (AVP) producing neurons perceive an oral water intake.4 AVP or copeptin measurements were not done by Mazloum et al.,1 but it reasonable to postulate that high AVP and copeptin levels not suppressed by hyponatremia would be observed in kidney transplant recipients, especially those with poorer outcomes. This result would favor an extrarenal explanation of the osmoregulatory defect. Alternatively, normal suppression of AVP/copeptin by hyponatremia would indicate an intrarenal defect; that is, less water presented to the collecting duct, therefore a reduced possibility to excrete urine with a low osmolality. Measurements of suppressed levels of plasma AVP are not simple since there is large intra- and inter-assay variability (around 20%) for plasma vasopressin levels between 0.5 and 1.0 pg/ml.5 Copeptin is the C-terminal fragment of the AVP prohormone. It is released in equimolar amounts with AVP in response to osmotic stimulation and its measurement is likely more robust than that of AVP.6 Plasma copeptin of <25 pmol/L have been observed in normal subjects for plasma sodium <140 mEq/L.7 Measurement of copeptin is established as an important tool to differentiate polyuric disorders, but the use of copeptin in the evaluation and treatment of the hyponatremic osmoregulatory defects is not considered to have diagnostic value.6,8 What do these findings mean for clinical practice? High AVP/copeptin may be associated with hyperfiltration and has been postulated to induce a progressive deterioration of kidney function (well reviewed by Bankir et al.9). As a consequence, a modest increase in water intake could be hypothesized to be of value in transplant recipient patients demonstrating a defect in water-load excretion. Nevertheless, the CKD Water Intake Trial conducted in patients with CKD stage 3, coaching to increase water intake compared with coaching to maintain the same water intake, did not significantly slow the decline in kidney function after 1 year.10 A mean water intake from 0.43 to 1.35 L/d has been found to decrease plasma copeptin levels in normal subjects.11 In summary, at this point we do not know if AVP is elevated in those kidney transplant patients with abnormal waterload. Data from recent publications do not demonstrate an eGFR benefit of an increased water intake. We are therefore left with an abnormal set-point for water homeostasis as a clinical biomarker of a severe outcome in kidney transplantation. Clearly the interesting results of Mazloum and coauthors raise important questions that will require further study. The recent experimental optogenetic data could suggest further studies to explore a central, stress component of central, that is hypothalamic, osmoregulation4 (Figure 1). The Median Pre-Optic Nucleus (MnPO) neurons integrate information about fluid balance that arises from the oropharynx, gastrointestinal tract, and blood4 and suppress thirst and vasopressin during a waterload. Three clusters of neurons in the MnPo have been identified: cluster 1, which receives ingestion signals from the oropharynx, satiation signals from the gastrointestinal tract, and homeostatic signals from blood and relay this information to the supra-optic neurons to suppress vasopressin release. Neurons from cluster 2 showed only transient responses that could represent stress or pain, whereas neurons from cluster 3 (49%) are largely unresponsive.4 MnPO neurons project to a number of other structures, including the paraventricular hypothalamus, supra-optic nucleus, lateral hypothalamus, paraventricular thalamus, arcuate nucleus, and dorsomedial hypothalamus. As these structures have been linked to ingestive behavior and cardiovascular regulation,12 they represent candidates to explain the altered osmoregulation observed in the subset of kidney transplant patients with poorer outcomes. The MnPO is a highly heterogeneous nucleus that in addition to thirst, regulates body temperature, sleep, cardiovascular function, and sodium excretion. It is plausible that altered cardiovascular function and/or changes in sodium excretion of the transplanted kidney may contribute to changes in osmosensation perceived at the level of the median preoptic nucleus.Figure 1.: It is proposed here, in this schematic representation of central hypothalamic pathways, that glutamatergic neurons in the subfornical organ, SFONos1 neurons that promote drinking and directly monitor blood osmolarity, are suppressed in patients with a better outcome, during the waterload experiments reported by Mazloum et al. 1 Following the detection of water in the mouth and its gulping, there is a gut-to-brain signal: the osmolarity of the ingested fluid is perceived early in the digestive tract, probably in the small intestine or hepatic portal circulation, relayed by the vagus nerve, and inhibits SFONos1 neurons well before any change in blood osmolality perceived by osmoreceptor cells. MnPOGLP1R →SFOnNOS form an inhibitory circuit where MnPOGLP1R neurons are sensing volume in the oropharyngeal and osmolarity in the gastrointestinal tract (represented schematically by blue arrows).13 There is an integrated central representation of fluid balance at the level of individual MnPO neurons, which use this information to dynamically control drinking behavior and vasopressin secretion in real time. GI, gastrointestinal; GLP1R, glucagon-like peptide 1 receptor; nNOS, nitric oxide synthase; OVLT, organum vasculosum of the lamina terminalis; PP, posterior pituitary; PVN, paraventricular hypothalamic nucleus; SFO, subfornical organ; SON, supraoptic nucleus. Figure modified from extended data from figure 10 of reference 4 and figure 2 of reference 14, with permission.Disclosures None.

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