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Geriatric Nephrology
The Urine-concentrating Mechanism in the Aging Kidney
a report by
Jeff M Sands, MD
Juha P Kokko Professor of Medicine and Physiology, Director, Renal Division, and
Associate Dean, Clinical and Translational Research, Emory University School of Medicine
A decrease in maximal urine-concentrating ability is one of the physiological The mechanism for urine concentration in the inner medulla is less
changes that occurs during normal aging.
1–3
The Baltimore Longitudinal established. The best accepted hypothesis is the passive mechanism
Study of Aging showed that individuals who were 60–79 years of age had hypothesis, which proposes that NaCl is passively reabsorbed across the thin
approximately a 100% increase in minimal urine flow rate, a 50% decrease ascending limb of the loop of Henle. The thin ascending limb luminal fluid
in the ability to conserve solute, and a 20% reduction in maximum urine has a higher concentration of NaCl and a lower concentration of urea than
osmolality compared with individuals 20–59 years of age.
1
These individuals the inner medullary interstitial fluid, thereby establishing chemical gradients
did not have changes in glomerular filtration rate that could account for the favoring passive NaCl reabsorption and urea secretion. Since the thin
reduction in urine-concentrating ability.
1
In addition, the relationship ascending limb has a higher permeability to NaCl than urea, NaCl
between plasma osmolality and vasopressin is preserved, or perhaps even reabsorption exceeds urea secretion and results in the dilution of the luminal
enhanced, in aged individuals, despite a reduction in thirst.
3
Thus, neither fluid as it ascends towards the outer medulla. Since the ascending limb
an abnormality in vasopressin secretion nor a reduction in renal function segments are water-impermeable, NaCl reabsorption results in both
seems to be the mechanism responsible for the decrease in urine- the hypertonic medullary interstitium needed to concentrate urine and the
concentrating ability in normal aging.
1,3,4
During the past decade, animal delivering of fluid that is dilute relative to plasma to the distal nephron.
studies into the molecular mechanisms underlying the reduction in urine- The collecting duct is impermeable to water in the absence of vasopressin
concentrating ability that occur during aging have been possible thanks to (also called antidiuretic hormone), so the dilute fluid is excreted as dilute
the cloning of the vasopressin receptor and key water and solute transport urine. In contrast, the collecting duct becomes highly permeable to water in
proteins involved in the urine-concentrating mechanism.
5–7
the presence of vasopressin, and if the medulla is hypertonic, water is
reabsorbed and concentrated urine is excreted.
Urine-concentrating Mechanism
The generation of concentrated or dilute urine occurs in the kidney medulla Aquaporins
(see Figure 1). The nephron segments located in the loops of Henle must Vasopressin regulates water reabsorption across the entire collecting
generate a hypertonic medullary interstitium, and the collecting duct must be duct.
5,8
Vasopressin binds to the V
2
-receptor, stimulates cyclic adenosine
permeable to water in order to generate a concentrated urine. A hypertonic monophosphate (cAMP) production, stimulates protein kinase A, and
medullary interstitium is generated by countercurrent multiplication, a ultimately results in the insertion of aquaporin-2 (AQP2) water channels into
process by which a small osmotic gradient generated at any level of the the apical plasma membrane of collecting duct principal cells
5,8
medulla (by active sodium chloride [NaCl] reabsorption) is magnified down (see Figure 2). Vasopressin-mediated accumulation of AQP2 in the apical
toward the papillary tip. NaCl is actively reabsorbed in the outer medulla by plasma membrane involves the phosphorylation AQP2 at serines 256, 261,
the thick ascending limb of the loop of Henle, which has the NKCC2/BSC1 and 264.
8–10
The reabsorbed water exits the cell through AQP3 and AQP4
Na-K-2Cl co-transporter in its apical membrane; the reabsorbed potassium is water channels in the basolateral plasma membrane. Water reabsorption
secreted back into the lumen via the potassium secretory channel ROMK. ceases when the stimulation by vasopressin ends; AQP2 is endocytosed
back into the cell, where it is recycled until the next vasopressin stimulus. A
reduction in V
2
-receptors in the aged kidney could be a potential
Jeff M Sands, MD, is the Juha P Kokko Professor of Medicine
mechanism for the aging-related reduction in urine-concentrating ability. A
and Physiology, Director of the Renal Division, and Associate
Dean for Clinical and Translational Research at Emory University
decrease in V2-receptors and messenger RNA (mRNA) abundance has been
School of Medicine. He served as Editor in Chief of the American
detected in some rat studies,
11
but not in others.
12–14
Journal of Physiology—Renal between 2001 and 2007, and as a
Councilor of the American Physiological Society (APS) between
2003 and 2006. Dr Sands is a member of the American
In contrast, the abundance of some AQPs are reduced in the aged rat
Association of Physicians (AAP) and the American Society for
kidney,
12,15
which would reduce urine-concentrating ability. In both the outer
Clinical Investigation (ASCI). He has served on study sections for
and inner medulla, AQP2 protein abundance is reduced in aged rats
the National Insitutes of Health (NIH), the American Heart Association (AH), and the National
Kidney Foundatoin (NKF). He served as Chair of the 2004 American Society of Nephrology (ASN)
compared with those who are 10 months of age.
11,12,15
Older rats also have
Program Committee. His research focuses on urea transport and the urine-concentrating
a reduced abundance of AQP2 that is phosphorylated at serine 256 (serines
mechanism. Dr Sands is a graduate of Harvard College and Boston University School of Medicine.
261 and 264 have not been studied to date).
15
AQP3 protein abundance is
E: jeff.sands@emory.edu
reduced in the inner medulla of rats at 30 months of age (compared with
10-month-old rats), but not in outer medulla.
12,15
The reduction in AQP2 and
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