Peripheral Resistance to Arginine Vasopressin and Its Relationship with Plasmaosmolarityinaged Population

  

    
 
    
All
    
Women
    
Men
    
p
    
70-79 y
    
=80 y
    
p
  
  

    
Copeptin, mean (SD)pmol/L 
    
10.0

      (7.3)
    
8.4

      (6.5)
    
12.2

      (7.7)
    
<0.001
    
9.8

      (7.3)
    
10.7

      (7.5)
    
0.528
  
  

    
u-Osm/C ratio, mean (SD)
    
80.4 (46.2)
    
87.2 (50.3)
    
71.1 (38.4)
    
0.045
    
84.2 (47.8)
    
63.0 (33.4)
    
0.020
  
  

    
R-AVP prevalence (95% CI)
    
14.1% (8.8-19.4)
    
12.8% (6.0-19.6)
    
15.9% (7.3-24.5)
    
0.565
    
12.7% (7.1-18.3)
    
20.7% (6.0-35.4)
    
0.252
  

Table 2: Copeptin levels and R-AVP in a community-dwelling population aged 70 years and older by sex and age.

R-AVP Association with Plasma Osmolarity

Plasmaosmolarity was greater in subjects with vs without R-AVP (287.6 mOsm/L vs 285.4 mOsm/L; p=0.023), while prevalence of plasma hyperosmolarity (>295 mOsm/L) for those same groups was 8.7% and 0.7% (p=0.053), respectively. Linear regression analysis showed an R-AVP effect on plasma osmolarity, reflected in a beta of 2.13(p=0.069); however, this effect was neither significant after adjusting for creatinine levels and loop diuretic use. In men, plasma hyperosmolarity was associated with R-AVP with accrued OR of 12.4 (p=0.048). Plasma osmolarity also showed a negative correlation with the u-Osm/C ratio (r_s=-0.257; p<0.001).

U-Osm/C Ratio and R-AVP Associations with Clinical Factors and Drugs

A part from age and sex groups, the capacity to concentrate urine measured as u-Osm/C ratio was associated with gastric ulcer (82.7 vs 51.8 if not present vs present; p=0.031), chronic renal failure (83.1 vs 55.9 if not present vs present; p=0.042),and loop diuretic use (82.9 vs 36.4 in non-users and users; p=0.005). U-Osm/C ratio was also correlated with insulin resistance measured by HOMA index (rs=- 0.174; p=0.027), IL-6 (r_s=-0.173; p=0.027), urea (r_s=-0.164; p=0.036), creatinine (r_s=-0.215; p=0.006), and Na (r_s=-0.158; p=0.044).

R-AVP was related with loop diuretic use (11.9% vs 66.7% in non-users vs users; p<0.001), IL-6 (4.4 vs 7.1 pg/mL in non R-AVP vs R-AVP; p=0.030), and creatinine (0.8 vs 0.9 mg/dLin non R-AVP vs R-AVP; p=0.048). Differences in R-AVP prevalence approached, but did not reach, statistical significance for patients with vs without diabetes (24.1% vs 11.7%; p=0.133), with vs without chronic renal failure (25.0% vs 13.4%; p=0.311), or with vs without a previous stroke (30.8% vs 12.5%; p=0.088), or for users vs non-users of oral hypoglycaemic agents (24.1% vs 11.7%; p=0.133).

Discussion

Ourmain findings regarding plasma and urine osmolarity levels and R-AVP in a community-dwelling population aged 70 years and older indicate that: (a) plasma hyperosmolarity (>295 mOsm/L) is present in 4.5% of men and 0% of women, and increases to 20% in men in the ≥80 year old group; (b) the ability to concentrate urine decreases with age and is lower in men; (c) R-AVP prevalence of 12% in the 70-79 year old group increases to 20% in the ≥80 year old group; (d) R-AVP greatly increases the risk of plasma hyperosmolarity; and (e) ability to concentrate urine is associated with insulin resistance, renal failure and inflammation, while R-AVP is also associated with loop diuretic use.

The fact that men showed slightly higher levels of plasma and urineosmolarity than women, that plasma osmolarity in men, but not in women, increased with age (from 80 years), that men presented poorer capacity to concentrate urine, and that hyperosmotic stress (>295 mOsm/L) was only observed in men, raise the question of whether those differences are intrinsically due to sex, or conversely, to other sex-related clinical conditions acting as possible confounders. The fact that sex differences in plasma osmolarity disappeared after adjusting for creatinine levels suggests not an effect of sex but of renal function. However, sex differences have been reported for baseline plasma osmolality and for the plasma osmolarity threshold for AVP release during hyperosmotic saline infusion [20]. The fact that oestrogens, progesterone, and testosterone modulate the osmotic regulation of AVP release, as reported in other studies [21,22], may explain plasma osmolarity differences between men and women. It has also been reported that the increasing sensitivity of collecting ducts to AVP is greater in women than in men after a period of water deprivation [23]. That result agrees with our study suggesting lower R-AVP in women, and may explain the lower plasma osmolarity levels and the lack of hyperosmotic stress observed in women. Nonetheless, there is a need for further studies to determine issues such as whether the detrimental health effects of altered plasma osmolarity levels are the same for men and women, which comorbidities or drugs may act as confounders, and what mechanisms may account for sex differences in body fluid regulation.

As for urine osmolarity, the observation of lower levels in both men and women in the older age group agrees with previous scientific literature reporting a diminished capacity to concentrate urine with age [16]. This fact inspired our hypothesis that a low capacity to concentrate urine is due to peripheral (renal) R-AVP. While the men in our study had higher copeptin levels, coherent with their higher plasma osmolarity, we observed no significant age group differences in copeptin levels. Those results suggest preserved AVP release with advanced age, reinforcing the idea that peripheral R-AVP is responsible for poor urine concentration – an idea supported by the higher AVP levels reported for elderly compared to younger adults by Johnson et al. [24]. We have proposed, as an indicator of renal capacity to concentrate urine, the u-Osm/C ratio after 10 hours of absolute fasting, and have proposed a ratio cut-off consistent with reference values for healthy adults that also maximize the correlation between urinary osmolarity and copeptin. This indicator is acceptable to patients and professionals, as it does not cause significant patient discomfort, is easily and quickly calculated, is a relatively inexpensive measure, and behaves consistently in increasing as plasma osmolarity increases. We suggest that it could be useful in identifying the onset of age-related water dysregulation, most especially after the age of 80.

Our results show that hyperosmotic stress prevalence in aged subjects with R-AVP is a statistically significant 12 times greater than in aged subjects without R-AVP, suggesting a major peripheral R-AVP role in water dysregulation. AVP acts, at the renal level, primarily through expression of aquaporin 2 (AQP-2), which promotes water reabsorption, and whose levels may be altered in the elderly, especially from the age of 80 years. A study with rats showed that aquaporin2 expression was down regulated by 80% and markedly redistributed into the intracellular compartment in inner medulla of senescent rats, but not in renal cortex, and suggested that age-related polyuria was associated with a down regulation of AQP2 expression [24]. We have observed that plasma osmolarity is associated with diabetes and impaired renal function, and that the effect of R-AVP disappears after adjusting for urea or creatinine levels. The relationship between impaired renal function and R-AVP in humans needs to be studied in more detail, and more research is also needed on AQP-2 expression in aged populations and on its association with copeptin, plasma and urine osmolarities, and R-AVP.

On the other hand, hydration status is known to be altered by the chronic consumption of certain drugs [26]. Aged adults are more exposed to pharmacological side effects due to physiological changes, comorbidities, and polypharmacy [27]. In this population, already at increased risk of dehydration, the consumption of certain drugs may aggravate dehydration status [28]. Drugs can alter hydration status through several mechanisms, including increased elimination of water through diarrhoea, urine, and sweat, reduced thirst, decreased appetite, and alterations to central thermoregulation [29]. Our study points to a relationship between plasma hyperosmolarity and treatments with loop diuretics, ARBs, and PPIs. Diuretics can cause dehydration due to excess urine production [30], with the increased volume contributing to volume depletion occurring in conjunction with electrolyte and acid-base disturbances [31]. The fact that diuretics are frequently used in elderly patients with cardiovascular disease places these at greater risk of dehydration [32]. As for ARBs, the inhibition of angiotensin II reduces the thirst sensation and, consequently, fluid intake [30], both related with the fundamental role played by the renin-angiotensin system in blood pressure and fluid homeostasis. Finally, regarding PPIs, diarrhoea has been described as a mechanism that alters hydration status [29]. More specifically, PPIs have been associated with the presence of microscopic colitis in several studies, especially in prolonged treatment and in combination with anti-inflammatory drugs [33]. The link between antidiabetic drugs and plasma osmolarity may be due to the underlying hyperglycaemia or to other related factors. Metformin, for instance, can cause both gastrointestinal disorders (nausea and diarrhoea), decreased appetite, and taste alterations that may contribute to alterations in hydration status [29,34]. In summary, since certain medications affect hydration status, there is a need to monitor their use by elderly subjects. Further studies are undoubtedly needed to determine the independent effect of the afore-mentioned drugs on hydration status and their impact on the health of aged adults in usual clinical practice [35].

The main limitations of this study include its cross-sectional design, which does not allow any causal relationship to be established between R-AVP and plasma osmolarity, and the relatively small sample size, which reflects poor statistical power regarding the detection of weak associations, risk factors with low prevalence, and possible multivariate analyses. Regarding the use of the u-Osm/C ratio as an indicator of renal capacity to concentrate urine and also as an indicator of R-AVP, although this parameter has not been previously or formally validated, it would seem to be a reasonable (and useful) indicator of R-AVP, given that R-AVP develops when urine osmolarity levels are relatively low for a given level of AVP, and given that it behaves consistently and as expected in relation to plasma osmolarity levels.The selection of the cut-off point at 35 can be considered a bit conservative since a copeptin level of 12 pmol/ L(considered as high) corresponds to a urinary osmolarity of 450 mOsm/L (very low for such copeptin levels). A cut-off point at 50 would also have been reasonable (it would correspond to a urinary osmolarity of 600 mOsm/L for the same mentioned copeptin level), so a u-Osm/C ratio between 35 and 50 could be considered as at risk of R-AVP. Further studies are required to assess clinical relevance of such cut-offs.

In summary, the results of our study show that, in a sample of community-dwelling aged population, urine concentration capacity decreases and plasma hyperosmolarity increases with age, most especially after the age of 80. Our findings also point to R-AVP as a clinical condition, affecting12% of 70-79-year-olds and rising to 20% of =80-year-olds, that is related to plasma osmolality and that increases hyperosmotic stress risk. Moreover, ability to concentrate urine and R-AVP are related with inflammation, impaired renal function, insulin resistance and loop diuretic use. More studies are required to assess reasons for low grade chronic dehydration or water imbalance in aged populations, as well as its potential impact on cell functioning and health.

Statements and Declarations

• The project was carried out according to ethical standards and current legislation.The local ethics committee approved the study protocol (code CEIm CSdM 65/19).

• All participants gave their informed consent by writing before inclusion.

• All authors declare that they have no conflict of interest in relation to this study.

• This study was funded by a grant from the Spanish Ministry of Health-Instituto de Salud Carlos III (ISCIII), reference code PI19/00500.

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