Chapter 4: AKI, Apheresis, and Cross-Sections

Nakamoto H, et al. (eds): Recent Advances in Dialysis Therapy in Japan.

Contrib Nephrol. Basel, Karger, 2018, vol 196, pp 229–236 (DOI: 10.1159/000485727)

Dysnatremia in Renal Failure

Taisuke Shimizu · Masaaki Terao · Hiroaki Hara · Takatsugu Iwashita ·
Tomonari Ogawa · Koichi Kanozawa · Hajime Hasegawa
Department of Nephrology, Hypertension, and Blood Purification, Saitama Medical Center, Saitama Medical University
School of Medicine, Kawagoe, Japan

Abstract mia in particular frequently develops in patients

Proximal salt reabsorption in the hypertrophied tubules in
the early phase of chronic renal failure (CRF) would be di-
minished according to the inhibited expression of proxi-
mal salt-transporting molecules, which may be facilitated
by the inhibition of Na-K-ATPase expression. Results from
animal models suggest that patients with early-phase CRF
would easily develop hyponatremia and, in contrast, pa-
tients showing developed CRF would be more likely to
show dehydration or hypernatremia. Several large-scale
studies of individuals with chronic kidney disease (CKD)
revealed that hyponatremia is much more common than
hypernatremia in patients with earlier stages of CKD. How-
ever, patients with end-stage renal disease (ESRD) more
frequently show hypernatremia than hyponatremia.
These clinical trends in CKD and CRF patients are in agree-
ment with the results of animal experiments, suggesting
that salt loss might be a principal pathological setting in
the early stages of CKD and that water loss could over-
come the salt loss in ESRD.
© 2018 S. Karger AG, Basel
Patients with renal failure defined as a reduced
number of functional nephrons often show a va-
riety of water and electrolyte disorders. Dysnatre-
with renal failure, because the remaining func-
tional nephrons demonstrate not only the reduc-
tion of the number of nephrons but also func-
tional alterations in accord with their hypertro-
phy as a result of hyperfiltration. Here, we review
a series of experimental studies of the changes in
salt reabsorption and urine concentration in ex-
perimental chronic renal failure (CRF) models.
Morphological Changes in Nephron Segment
Associated with CRF
The severity of the renal function (as reflected by
a patient’s glomerular filtration rate) is also indi-
cated by the percentage of remaining functional
nephrons. Accordingly, the altered salt and water
balance in CRF is the result of changes in the tu-
bular reabsorption of salt and water. When the
number of functional nephrons is reduced, the
remaining tubules can show compensatory hy-
pertrophy; however, the morphological condi-
128.32.10.230 - 7/25/2018 8:57:18 PM
Univ.of California Berkeley
Downloaded by:
tion is not homogeneous, and tubules showing a
different appearance coexist with those showing
hypertrophy. It is known that the proximal side
of nephrons generally shows significant hyper-
trophy, whereas the hypertrophy of the distal side
of nephrons is limited [1]. In fact, the tubules in
a kidney with CRF can show both hypertrophy
and atrophy in a single nephron or even within
each nephron segment.
Function of Salt and Water Reabsorption in
Hypertrophied Nephron
When the number of functional nephrons is re-
duced, the remaining nephrons inhibit the kid-
ney’s salt and water reabsorption and cause an
increase in the excretion of both salt and water.
This response or adaptation is known as the
“magnification phenomenon,” which is recog-
nized as the body’s purposive response to avoid
salt and water retention [2]. Indeed, multiple an-
imal experiments have shown increased renal salt
excretion from animals with a reduced number of
nephrons because of the reduced salt reabsorp-
tion in the remaining nephrons [3, 4]. It has been
speculated that the changes in the expression of
salt-transporting molecules is highly involved in
this magnification phenomenon response, based
on studies of animals with unilateral nephrecto-
my or 5/6 nephrectomy; these studies revealed
that the hypertrophic nephrons demonstrate the
changes in the expression of salt-transporting
molecules [5, 6]. Notably, Kwon et al. [7] studied
5/6 nephrectomized rats and reported the de-
tailed expression profile of the salt-transporting
molecules.
Proximal convoluted tubules are responsible
for the reabsorption of approximately two-thirds
of filtered salt, and Na-H exchanger-3 (NHE3)
accounts for one half of the salt-transporting
molecules in this part. Kwon et al. [7] demon-
strated that the NHE3 expressions of both mRNA
and protein were reduced to approximately 50%
(Fig. 1). In that study, the mean value of creati-
nine clearance of the 5/6 nephrectomized rats
was approximately 25% of that of the control an-
230
Contrib Nephrol. Basel, Karger, 2018, vol 196, pp 229–236 (DOI: 10.1159/000485727)
imals, indicating that this rat model is very simi-
lar to the early phase of CRF. The 5/6 nephrecto-
mized rats showed a decrease in free water clear-
ance and an increase in urine volume, which
mimic the early phase of CRF. In addition, a re-
duced expression of Na-K-ATPase in the proxi-
mal convoluted tubule portion was apparent by
both immunoblotting and immunohistochemis-
try (Fig. 1), and this reduced expression might be
involved in the inhibition of salt reabsorption in
this part. However, the underlying mechanism is
unclear.
It is generally considered that an impaired
urine concentration is caused at least in part by
the degeneration of the medullary osmotic gradi-
ent, increased intraluminal osmolality in the dis-
tal nephron as a result of the inhibition of salt
reabsorption in the proximal nephron, and de-
sensitization of the distal nephron to antidiuretic
hormone (ADH) [8]. The thick ascending limb of
Henle (TAL) and distal convoluted tubules
(DCTs) also have major roles in salt reabsorp-
tion, and furosemide-sensitive Na-K-2Cl co-
transporter (NKCC2) and thiazide-sensitive Na-
Cl cotransporter (NCC) work as principle salt-
transporting molecules in the TAL and DCTs,
indicating that these segments play a critical role
in water reabsorption in the connecting distal
nephron. Kwon et al. [7] suggested that the in-
volvement of TAL and DCTs in the diminished
urine concentration ability of 5/6 nephrecto-
mized rats may be limited because the changes in
the expressions of NKCC2 and DCT were rela-
tively small. However, they studied the rats 2
weeks after the 5/6 nephrectomy was performed,
and the animals showed no apparent interstitial
fibrosis. These results suggest that this rat model
might not develop sufficient renal organic dam-
age.
In this regard, Michimata et al. [9] reported
differing results concerning NKCC and NCC ex-
pression in 5/6 nephrectomized rats studied at 8
weeks after the nephrectomy; the rats demon-
strated apparent interstitial fibrosis. The urine of
the rats indicated hypo-osmolality under the
condition of elevated plasma ADH concentra-
tion, suggesting reduced sensitivity to ADH. The
128.32.10.230 - 7/25/2018 8:57:18 PM
Univ.of California Berkeley
Shimizu · Terao · Hara · Iwashita · Ogawa · Kanozawa · Hasegawa
Downloaded by:
Nakamoto H, et al. (eds): Recent Advances in Dialysis Therapy in Japan.
 87 kDa 96 kDa

1 2 3 4 5 6 1 2 3 4 5 6 1 2 3 4 5 6 1 2 3 4 5 6
a CRF Sham c CRF Sham

1.4 1.2
1.2

Na-K-ATPase expression
1.0
(fraction of sham)

(fraction of sham)
NHE3 expression
1.0
0.8
0.8
* 0.6
0.6
0.4 0.4 *
0.2 0.2

0 0
CRF Sham CRF Sham
b (n = 13) (n = 11) d (n = 13) (n = 11)

e f

g h

Fig. 1. Immunoblotting (a) and densitometric analysis (b) of all samples from CRF rats and sham-oper-
ated rats revealed a marked decrease in the total kidney NHE-3 level. Immunoblotting (c) and densito-
metric analysis (d) of all samples from CRF and sham-operated rats revealed a marked decrease in total
kidney Na-K-ATPase levels in the CRF rats. Immunocytochemical analyses of NHE-3 and Na-K-ATPase
in the proximal tubules of sham-operated rats (e, g) and CRF rats (f, h). In the CRF rats, the labeling of
the proximal tubules was much weaker, consistent with the significant decrease in total kidney levels
determined by immunoblotting. Original figure is from Kwon et al. [7], by permission of the author.
128.32.10.230 - 7/25/2018 8:57:18 PM
Univ.of California Berkeley

Dysnatremia in Renal Failure 231

Downloaded by:

Nakamoto H, et al. (eds): Recent Advances in Dialysis Therapy in Japan.

Contrib Nephrol. Basel, Karger, 2018, vol 196, pp 229–236 (DOI: 10.1159/000485727)
animals in a subgroup with dehydration did not
show the elevation of NKCC expression as a nor-
mal response to the increased salt delivery by the
inhibition of proximal salt reabsorption, which
might be involved in the urine concentration im-
pairment in CRF. This result suggests that rem-
nant tubular function may depend on the time
course after the construction of a 5/6 nephrecto-
my or the progression of CRF.
Kim et al. [10] reported an interesting finding
regarding the differential expression of NKCC2
in a 5/6 nephrectomy model examined at 4, 8,
and 12 weeks after nephrectomy. In their study,
the elevation and decline of both Cr and the glo-
merular filtration rate in the nephrectomized
rats were approximately 50%, respectively, and
the fractional excretion of Na increased 2- to
3-fold, suggesting a compensatory inhibition of
remnant hypertrophied tubules. The urine vol-
ume, on the other hand, increased by 3-fold and
the urine osmolality decreased to 1/3 of that of
the control animals, which indicated a urine
concentration impairment equivalent to the in-
hibition of salt reabsorption. Interestingly, the
increased expressions of NKCC and NCC ob-
served at 4 weeks were decreased at 12 weeks
(Fig. 2). It may be possible that the early-phase
increase in NKCC2/NCC expression is a physi-
ological response to the increased salt delivery,
and those expressions are decreased in associa-
tion with the development of interstitial organic
damage or fibrosis. These decreases in the ex-
pression may result in the further impairment of
the urine concentration ability. Indeed, the study
by Kim et al. [10] showed an increase in the
urine volume with time.
In summary, proximal salt reabsorption in the
hypertrophied tubules in the early phase of CRF
would be diminished according to the inhibited
expression of proximal salt-transporting mole-
cules, which may be facilitated by the inhibition
of Na-K-ATPase expression. However, the di-
minished salt reabsorption would be compensat-
ed for by TAL and DCT to some extent, and the
impairment of urine concentration ability would
be limited. In the late phase of CRF, the compen-
sation by TAL and DCT would be weakened,
232
Contrib Nephrol. Basel, Karger, 2018, vol 196, pp 229–236 (DOI: 10.1159/000485727)
leading to a more significant impairment of the
urine concentration ability. The above-described
basic studies suggest that patients with early-
phase CRF would easily develop hyponatremia
and, in contrast, patients showing developed CRF
would be more likely to show dehydration or hy-
pernatremia.
Dysnatremia in Patients with Renal Failure
Hyponatremia is the most frequently experi-
enced electrolyte disorder, and it is observed in
4–8% of outpatients and 20–35% of hospitalized
patients in mid-size and larger hospitals [11–14].
The reported incidence of hyponatremia in criti-
cal care units is 24.1% [15], and the survival ratio
of the hyponatremic patients is significantly low
[16]. The incidence of hypernatremia is generally
lower than that of hyponatremia; approximately
9% of patients in critical care units demonstrate
hypernatremia [17]. The total mortality rate of
hypernatremic patients is approximately 20%,
but the mortality rate of patients who show hy-
pernatremia at the time of admission is >30%
[18].
Hypo- and hypernatremia were observed in
13.5 and 2.0%, respectively, of over 655,000 re-
tired US military men and women who were non-
dialysis chronic kidney disease (CKD) patients
[19]. In that study’s analysis stratified by CKD
stage, hyponatremia was more frequently ob-
served in the patients with early-stage CKD,
whereas hypernatremia was more common in the
severe stage of CKD (Fig. 3) [19, 20]. Moreover,
26 and 7.0% of the subjects developed hypo- and
hypernatremia during the 5.5-year follow-up pe-
riod, respectively [19, 20]. These clinical values
seem to be consistent with the prediction sug-
gested by the animal model studies described
above. Namely, salt loss is more obvious than wa-
ter loss in the earlier stage of CKD, and in the late
stage of CKD water loss occurs more easily than
salt loss.
In analyses of the correlation between the
existence of dysnatremia and mortality, hypo-
and hypernatremia similarly showed a signifi-
128.32.10.230 - 7/25/2018 8:57:18 PM
Univ.of California Berkeley
Shimizu · Terao · Hara · Iwashita · Ogawa · Kanozawa · Hasegawa
Downloaded by:
Nakamoto H, et al. (eds): Recent Advances in Dialysis Therapy in Japan.
 NHE3 ENaC-į
Control CRF Control CRF
105
4 wk 75 4 wk 75
105
12 wk 75 12 wk 75

SGLT-1 ENaC-DŽ
Control CRF Control CRF

4 wk 75 4 wk 75

12 wk 75 12 wk 75

NKCC2 ENaC-Dž
Control CRF Control CRF
250 105
4 wk 160 4 wk 75
250 12 wk 105
12 wk 160 75

NCC
Control CRF

4 wk 250
160
250
12 wk
160
a

600 * * * NHE3
SGLT1
500 NKCC2
NCC
400 ENaC-į
ENaC-DŽ
Expression (fraction of sham), %

300 ENaC-Dž

200

*
100
* *
* *
0
b CRF at 4 weeks CRF at 12 weeks

Fig. 2. Immunoblot (a) and densitometric analysis (b) of major renal Na transporters from chronic renal failure (CRF) and
sham-operated (control) rats. In the CRF group, the expressions of NHE3 and SGLT1 did not change, and the densities
of NKCC2, NCC, ENaC-α, and ENaC-γ were significantly increased at 4 weeks. In contrast, the expressions of NKCC2 and
NCC were markedly decreased in the CRF rats at 12 weeks. Original figure is from Kim et al. [10], by permission of the
author.
128.32.10.230 - 7/25/2018 8:57:18 PM
Univ.of California Berkeley

Dysnatremia in Renal Failure 233

Downloaded by:

Nakamoto H, et al. (eds): Recent Advances in Dialysis Therapy in Japan.

Contrib Nephrol. Basel, Karger, 2018, vol 196, pp 229–236 (DOI: 10.1159/000485727)
 35

Prevalence of hyponatremia, % 30

25

20

15

10

0
1 2 3A 3B 4 5
(n = 17,081) (n = 31,756) (n = 407,865) (n = 158,853) (n = 36,386) (n = 4,383)
a CKD stage

3.5
Prevalence of hypernatremia, %

3.0

2.5

2.0

1.5

1.0

0.5

0
1 2 3A 3B 4 5
(n = 17,081) (n = 31,756) (n = 407,865) (n = 158,853) (n = 36,386) (n = 4,383)
b CKD stage

Fig. 3. Prevalence of hyponatremia (a) and hypernatremia (b) in patients with different stages of CKD among >655,000
US veterans with non-dialysis-dependent CKD. a The prevalence of hyponatremia did not correlate with the stage of
CKD, as it was essentially identical in the patients with CKD stages 3A and above. b The prevalence of hypernatremia
was approximately one magnitude lower overall compared to that of hyponatremia, but it showed a significant increase
with advancing stages of CKD. Original figure is from Kovesdy [20], by permission of the author.

cant correlation with mortality (Fig. 4) [19, 20]. dences of new-onset hypo- and hypernatremia
In that research, both types of dysnatremia in their study during the 3.6-year follow-up
showed significant correlations with the occur- were 27.0 and 6.0%, respectively [21]. Huang et
rence of congestive heart failure, liver diseases, al. [21] reported that hyponatremia was more
and various cancers [19, 20]. The clinical profile common in CKD patients, but a clear correla-
of dysnatremia in CKD patients is in agreement tion between CKD severity and dysnatremia
with another large-scale study by Huang et al. was not observed. In contrast, Wallia et al. [22]
[21]. They studied 45,333 patients with stage 3 reported that 70 patients with end-stage renal
or 4 CKD, and the incidences of hypo- and hy- failure showed no apparent dysnatremia. These
pernatremia in these patients were 8.0 and differing findings may be due to differences in
1.2%, respectively [21]. In addition, the inci- the study populations’ medication usage and
128.32.10.230 - 7/25/2018 8:57:18 PM
Univ.of California Berkeley

234 Shimizu · Terao · Hara · Iwashita · Ogawa · Kanozawa · Hasegawa

Downloaded by:

Nakamoto H, et al. (eds): Recent Advances in Dialysis Therapy in Japan.

Contrib Nephrol. Basel, Karger, 2018, vol 196, pp 229–236 (DOI: 10.1159/000485727)
 2.5 100,000

2.0 10,000

log hazard mortality

Number of defaults
1.5 1,000

1.0 100

0.5
10

0
1
115 120 125 130 135 140 145 150 155 160
Serum sodium, mEq/L

Fig. 4. Multivariable adjusted hazard ratios (95% confidence intervals) of all-cause mortality associ-
ated with various categories of serum sodium level in >655,000 men and women with non-dialysis-
dependent CKD. The association of serum sodium with mortality was U-shaped, with both lower
and higher serum sodium levels showing a significant association with higher mortality. Original
figure is from Kovesdy et al. [19], by permission of the author.

patient education regarding salt and water
intake.
There are few reports about dysnatremia in
patients with dialysis therapy. In dialysis pa-
tients, if the ideal body weight is achieved, the
incidence of water depletion resulting in hyper-
natremia is likely to be rare. Indeed, among pa-
tients on maintenance hemodialysis [21] and
peritoneal dialysis [22] who showed dysnatre-
mia, hyponatremia was common. Those studies
reported incidences of hyponatremia in 29.3%
of the patients on hemodialysis [23] and 14.5%
of those on peritoneal dialysis [24]. However,
these data must be assessed based on the rem-
nant kidney function, remaining urine volume
and underlying disease in each patient, and
it  is  difficult to make a definite and general
conclusion.
In conclusion, as expected from the results of
experiments using animal models, we should pay
much more attention to hyponatremia in pa-
tients with early-phase CRF, and we should be
more careful to prevent the onset of hypernatre-
mia in patients with late-phase CRF.

References

1 Hayslett JP, Kashgarian M, Epstein
FH: Functional correlates of compen-
satory renal hypertrophy. J Clin Invest
1968;47:774–799.
2 Bricker NS, Fine LG, Kaplan M, Ep-
stein M, Bourgoignie JJ, Light A:
“Magnification phenomenon” in
chronic renal disease. N Engl J Med
1978;299:1287–1293.
3 Lubowitz H, Purkerson ML, Rolf DB,
Weisser F, Bricker NS: Effect of neph-
ron loss on proximal tubular bicar-
bonate reabsorption in the rat. Am J
Physiol 1971;220:457–461.
4 Schultze RG, Weisser F, Bricker NS:
The influence of uremia on fractional
sodium reabsorption by the proximal
tubule of rats. Kidney Int 1972;2:59–
5 Fine LG, Trizna W, Bourgoignie JJ,
Bricker NS: Functional profile of the
isolated uremic nephron. Role of com-
pensatory hypertrophy in the control
of fluid reabsorption by the proximal
straight tubule. J Clin Invest 1978;61:
1508–1518.
128.32.10.230 - 7/25/2018 8:57:18 PM

65.
Univ.of California Berkeley

Dysnatremia in Renal Failure 235

Downloaded by:

Nakamoto H, et al. (eds): Recent Advances in Dialysis Therapy in Japan.

Contrib Nephrol. Basel, Karger, 2018, vol 196, pp 229–236 (DOI: 10.1159/000485727)
 6 Buerkert J, Martin D, Prasad J,
Chambless S, Klahr S: Response of
deep nephrons and the terminal col-
lecting duct to a reduction in renal
mass. Am J Physiol 1979;236:F454–
F464.
7 Kwon TH, Frokiaer J, Fernandez-Lla-
ma P, Maunsbach AB, Knepper MA,
Nielsen S: Altered expression of Na
transporters NHE-3, NaPi-II, Na-K-
ATPase, BSC-1, and TSC in CRF rat
kidneys. Am J Physiol 1999;277:F257–
F270.
8 Klahr S, Schwab SJ, Stokes TJ: Meta-
bolic adaptations of the nephron in
renal disease. Kidney Int 1986;29:
80–89.
9 Michimata M, Kazama I, Mizukami K,
Araki T, Nakamura Y, Suzuki M,
Wang W, Fujimori K, Satomi S, Ito S,
Imai Y, Matsubara M: Urinary con-
centration defect and limited expres-
sion of sodium cotransporter, rbsc1,
in a rat model of chronic renal failure.
Nephron Physiol 2003;93:p34–p41.
10 Kim S, Heo NJ, Jung JY, Son MJ, Jang
HR, Lee JW, Oh YK, Na KY, Joo KW,
Han JS: Changes in the sodium and
potassium transporters in the course
of chronic renal failure. Nephron
Physiol 2010;115:p31–p41.
Prof. Hajime Hasegawa
Department of Nephrology and Hypertension, Center of Blood Purification
Saitama Medical Center, Saitama Medical University
1981 Kamoda, Kawagoe, Saitama 350-8550 (Japan)
E-Mail hase2126@saitama-med.ac.jp
236
11 Stelfox HT, Ahmed SB, Khandwala F,
Zygun D, Shahpori R, Laupland K:
The epidemiology of intensive care
unit-acquired hyponatraemia and
hypernatraemia in medical-surgical
intensive care units. Crit Care 2008;
12:R162.
12 Funk GC, Lindner G, Druml W, Met-
nitz B, Schwarz C, Bauer P, Metnitz
PG: Incidence and prognosis of dys-
natremias present on ICU admission.
Intensive Care Med 2010;36:304–311.
13 Liamis G, Rodenburg EM, Hofman A,
Zietse R, Stricker BH, Hoorn EJ: Elec-
trolyte disorders in community sub-
jects: prevalence and risk factors. Am
J Med 2013;126:256–263.
14 Schrier RW, Sharma S, Shchekochikh-
in D: Hyponatraemia: more than just
a marker of disease severity? Nat Rev
Nephrol 2013;9:37–50.
15 DeVita MV, Gardenswartz MH, Ko-
necky A, Zabetakis PM: Incidence and
etiology of hyponatremia in an inten-
sive care unit. Clin Nephrol 1990;34:
163–166.
16 Gankam-Kengne F, Ayers C, Khera A,
de Lemos J, Maalouf NM: Mild hypo-
natremia is associated with an in-
creased risk of death in an ambulatory
setting. Kidney Int 2013;83:700–706.
17 Lindner G, Funk GC, Schwarz C,
Kneidinger N, Kaider A, Schneeweiss
B, Kramer L, Druml W: Hypernatre-
mia in the critically ill is an indepen-
dent risk factor for mortality. Am J
Kidney Dis 2007;50:952–957.
Shimizu · Terao · Hara · Iwashita · Ogawa · Kanozawa · Hasegawa
Nakamoto H, et al. (eds): Recent Advances in Dialysis Therapy in Japan.
Contrib Nephrol. Basel, Karger, 2018, vol 196, pp 229–236 (DOI: 10.1159/000485727)
18 Polderman KH, Schreuder WO, Strack
van Schijndel RJ, Thijs LG: Hyperna-
tremia in the intensive care unit: an
indicator of quality of care? Crit Care
Med 1999;27:1105–1108.
19 Kovesdy CP, Lott EH, Lu JL, Mal-
akauskas SM, Ma JZ, Molnar MZ,
Kalantar-Zadeh K: Hyponatremia,
hypernatremia, and mortality in pa-
tients with chronic kidney disease
with and without congestive heart
failure. Circulation 2012;125:677–684.
20 Kovesdy CP: Significance of hypo-
and hypernatremia in chronic kidney
disease. Nephrol Dial Transplant
2012;27:891–898.
21 Huang H, Jolly SE, Airy M, Arrigain S,
Schold JD, Nally JV, Navaneethan SD:
Associations of dysnatremias with
mortality in chronic kidney disease.
Nephrol Dial Transplant 2017;32:
1204–1210.
22 Wallia R, Greenberg A, Piraino B,
Mitro R, Puschett JB: Serum electro-
lyte patterns in end-stage renal dis-
ease. Am J Kidney Dis 1986;8:98–104.
23 Lee CT, Guo HR, Chen JB: Hyponatre-
mia in the emergency department.
Am J Emerg Med 2000;18:264–268.
24 Waikar SS, Curhan GC, Brunelli SM:
Mortality associated with low serum
sodium concentration in maintenance
hemodialysis. Am J Med 2011;124:
77–84.
128.32.10.230 - 7/25/2018 8:57:18 PM
Univ.of California Berkeley
Downloaded by: