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T h e n e w e ngl a nd j o u r na l o f m e dic i n e
n engl j med 373;6 nejm.org August 6, 2015548
Review Article
The prevalence of diabetes is increasing rapidly, and type 2 dia-betes now accounts for 20 to 50% of cases of new-onset diabetes in young people.1 Electrolyte disturbances are common in patients with diabetes and may be the result of an altered distribution of electrolytes related to hyperglycemia-induced osmotic fluid shifts or of total-body deficits brought about by osmotic diuresis. Complications from end-organ injury and the therapies used in the man-agement of diabetes may also contribute to electrolyte disturbances. In this review, we highlight the ways in which specific electrolytes may be influenced by dys-regulation in glucose homeostasis.
Sodium
Increases in plasma glucose concentration can lead to changes in plasma sodium concentration through several mechanisms. Elevations in glucose concentration increase plasma tonicity, creating an osmotic driving force that favors the move-ment of water from the intracellular space to the extracellular space, thereby dilut-ing the extracellular concentration of sodium. The plasma sodium concentration is usually low as a result of this osmotic flux of water. Increased or normal plasma sodium concentrations in the presence of hyperglycemia indicate a clinically sig-nificant deficit in total body water. A consensus statement and clinical practice guidelines on the management of hyperglycemic crises in adults recommend the addition of a correction factor of 1.6 mg per deciliter to the measured plasma sodium concentration for each 100 mg per deciliter (5.6 mmol per liter) of glucose above 100 mg per deciliter to account for the dilutional effect of glucose.2,3 Correct-ing the plasma sodium concentration in patients with glycemia helps to assess the magnitude of the deficit of sodium and water and provides a reasonable initial estimate of the required tonicity of replacement fluids during the course of therapy. Correction factors predicting plasma sodium concentration after the normalization of hyperglycemia vary from a low of 1.35 mmol per liter to as high as 4.0 mmol per liter 4,5 (for additional discussion, see the Supplementary Appendix, available with the full text of this article at NEJM.org). Such variability in the range of cor-rection factors appears to be due to the fact that patients with preserved renal function represent an open hyperglycemic system that introduces a number of variables, all difficult to quantify, and renders the use of a standardized correction factor imprecise. It should be emphasized that the corrected sodium concentration at the time of sampling does not account for the effects of osmotic diuresis and fluid intake during treatment, both of which are highly variable and unpredict-able. Frequent calculations of the corrected sodium concentration, along with
From the Department of Internal Medi-cine, University of Texas Southwestern Medical Center, Dallas (B.F.P.); and the Biomedical Research Department, Diabe-tes and Obesity Research Division, CedarsSinai Medical Center, Beverly Hills, CA (D.J.C.). Address reprint requests to Dr. Palmer at the Department of Internal Medicine, University of Texas Southwest-ern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, or at biff . palmer@ utsouthwestern . edu.
N Engl J Med 2015;373:548-59.DOI: 10.1056/NEJMra1503102Copyright 2015 Massachusetts Medical Society.
Disorders of Fluids and ElectrolytesJulie R. Ingelfinger, M.D., Editor
Electrolyte and AcidBase Disturbances in Patients with Diabetes Mellitus
Biff F. Palmer, M.D., and Deborah J. Clegg, Ph.D.
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n engl j med 373;6 nejm.org August 6, 2015 549
Electrolyte and Acid Base Disturbances in Diabetes
close monitoring of urinary losses, are required during the management of all hyperglycemic crises.
The stabilization of hemodynamics with nor-mal saline is the initial goal of fluid therapy in patients with a hyperglycemic crisis. During the course of care, a switch to more hypotonic fluids may be required for patients in whom a deficit in total body water has been determined. Iso-tonic saline infusion should be continued when the corrected plasma sodium concentration is re-duced.2,3,6 As Kamel and Halperin recently stated, the fluids selected for administration should minimize the drop in effective osmolality, par-ticularly during the first 15 hours of therapy, in order to reduce the risk of cerebral edema.7 Be-cause children with diabetic ketoacidosis are at particular risk for cerebral edema, some degree of hypernatremia is acceptable during the course of treatment to minimize this complication. Use of the correction factor in patient care can be demonstrated in the case of a 29-year-old man with diabetic ketoacidosis who presents with a plasma glucose concentration of 1040 mg per deciliter (57.7 mmol per liter) and the following concentrations of electrolytes: sodium 135 mmol per liter, potassium 5.4 mmol per liter, chloride 97 mmol per liter, and bicarbonate 10 mmol per liter. When a correction factor of 1.6 is used, the corrected plasma sodium concentration is estimated to be approximately 150 mmol per liter (for a further discussion of the use of f luid therapy when treating a patient with dia-betic ketoacidosis, see the Supplementary Ap-pendix).
Certain medications that are prescribed for the management of diabetes mellitus are also associ-ated with hyponatremia.8 Tricyclic antidepres-sants, which are used to treat diabetic neuropa-thy, are known to stimulate the release of vasopressin. Oral hypoglycemic agents, such as chlorpropamide and tolbutamide, can cause hypo-natremia, possibly by augmenting the effect of endogenous vasopressin at the level of the renal collecting duct. Insulin stimulates the argininevasopressindependent expression of aquaporin-2 in the renal collecting duct, possibly augmenting the hydro-osmotic effect of vasopressin when circulating levels are increased in response to other influences.9 The latter effect may explain the reported association between insulin use and
hospital-acquired hyponatremia in patients with diabetes.10 Hyponatremia can also develop if a patient with uncontrolled diabetes has marked hypertriglyceridemia, even when the sodium concentration in plasma water is normal a phenomenon called pseudohyponatremia11 (see the Supplementary Appendix for additional dis-cussion).
Po ta ssium
Insulin deficiency, which is more common in type 1 diabetes than in type 2 diabetes, is an important factor in the net efflux of potassium from the cell. In patients with type 2 diabetes, the insulin-mediated uptake of glucose is im-paired, but the cellular uptake of potassium re-mains normal, a situation that is consistent with the divergence of intracellular pathways that follows activation of the insulin receptor.12 Hy-perkalemia can be caused by an increase in plasma tonicity that results from the redistribu-tion of potassium from the intracellular space to the extracellular space.13 The efflux of potassium from the cell is due to intracellular dehydration, which results from the osmotically induced, transcellular movement of water. This movement creates a favorable gradient for the efflux of potassium.14 The administration of dextrose in water as a short-term therapy for hyperkalemia without the concomitant administration of insu-lin may worsen hyperkalemia in patients with diabetes, since the endogenous secretion of in-sulin in these patients may be insufficient or unpredictable and may thereby result in increas-es in plasma tonicity. Consider a 35-year-old woman with diabetic ketoacidosis whose labora-tory values are as follows: sodium 143 mmol per liter, potassium 5.8 mmol per liter, chloride 97 mmol per liter, bicarbonate 12 mmol per liter, creatinine 1.4 mg per deciliter (123.8 mol per liter), blood urea nitrogen 28 mg per deciliter (10 mmol per liter), and glucose 680 mg per deciliter (37.8 mmol per liter). On examination, ortho-static hypotension is noted. Initial treatment should consist of 0.9% normal saline to stabilize hemodynamic status but with no added potas-sium chloride, since the plasma potassium con-centration is elevated (see the Supplementary Appendix for a discussion of potassium manage-ment in this patient).
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T h e n e w e ngl a nd j o u r na l o f m e dic i n e
Hyperkalemia is frequently present on admis-sion in patients with diabetic ketoacidosis, even though total-body potassium is reduced. This condition is caused by potassium wasting, which results from the increased delivery of sodium to the distal nephron coupled with increased min-eralocorticoid activity15,16 (Fig. 1). In these cir-cumstances, the hyperkalemia is caused by a redistribution of potassium that results from hypertonicity and insulin deficiency not by
metabolic acidosis. Potassium shifts caused by metabolic acidosis are more pronounced in hy-perchloremic, nonanion-gap acidosis (also called mineral acidosis) than in organic acidosis (in-creased anion-gap acidosis), which is present in diabetic ketoacidosis (Fig. S1 in the Supplemen-tary Appendix).17 In addition, potassium shifts that are the result of hypertonicity and insulin deficiency are counterbalanced by marked in-creases in sympathetic-nerve activity; this in-creased activity moves potassium into cells by stimulating 2-adrenergic receptors.
18 In pa-tients receiving nonselective beta-blockers, in-creased adrenergic activity may worsen hyper-kalemia because unopposed stimulation of -adrenergic receptors favors the cellular eff lux of potassium.19
Acid B a se Dis t ur b a nces
Diabetic ketoacidosis is characterized by the ac-cumulation of acetoacetic acid and -hydroxy-butyric acid.20 Ketoacidosis results when the rate at which hepatic ketoacid is generated exceeds peripheral utilization and the concentration of ketoacid in the blood increases. The accumula-tion of protons in extracellular fluid causes the decomposition of bicarbonate to carbon dioxide and water, whereas the concentration of keto-acid anions increases. Reductions in plasma concentrations of bicarbonate initially approxi-mate increases in the anion gap (an important relationship discussed more fully by Kamel and Halperin).7 Although anion-gap acidosis is the dominant disturbance in diabetic ketoacidosis, hyperchloremic normal-gap acidosis can also be present, depending on the stage of the disease process21-23 (Fig. 2). Resuscitation with balanced electrolyte solutions can mitigate the severity of normal-gap acidosis during the recovery phase.24
The kidneys are not a site of primary involve-ment in diabetic ketoacidosis; in patients with normal renal function, the kidney compensates with an increase in the net excretion of acid, which is reflected primarily in high levels of urinary ammonium. When there is a loss of organic acid anions, the amount of ammonium in the urine can be estimated by measurement of the urinary osmolal gap, which is defined as the difference between measured urinary osmo-
Figure 1. Volume Regulation in Persons with and without Diabetes.
In the regulation of effective arterial blood volume (Panel A), there is a balanced, reciprocal relationship between the delivery of sodium to the distal nephron and the circulating level of aldosterone that serves to main-tain potassium balance. In patients with uncontrolled diabetes (Panel B), the osmotic diuretic effect of glucose (glucose Tmax denotes the maximum rate of the reabsorption of glucose in the proximal tubule) and the excre-tion of sodium ketoacid salts cause an increase in the delivery of sodium to the distal nephron. At the same time, mineralocorticoid activity is in-creased in response to volume depletion. The coupling of the increased delivery of sodium with the increased mineralocorticoid activity results in renal potassium wasting and total-body depletion. The use of loop or thia-zide diuretics also contributes to renal potassium wasting by means of this coupling effect. In addition, high flow rates in the distal nephron lower the luminal potassium concentration, providing a more favorable gradient for the diffusion of potassium into the luminal fluid. High flow in the distal nephron also activates potassium secretion by means of the calcium- activated potassium channel (or the maxi-K+channel).
Decreased effectivearterial blood volume
Increased proximalNa+ reabsorption
Decreased proximalNa+ reabsorption
Decreased distalNa+ delivery
Increased renin Decreased renin
Increased effectivearterial blood volume
Increased aldosterone andincreased distal Na+ delivery
Increasedaldosterone
Increased distalNa+ delivery
Increased renalK+ excretion
Osmotic diuresis(above glucose Tmax)
Decreasedaldosterone
Loop andthiazide diuretics
Increased urinaryexcretion of sodium
ketoacid salts
Coupling effect of Na+ and aldosterone in uncontrolled diabetesB
Normal reciprocal relationship between Na+ and aldosteroneA
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n engl j med 373;6 nejm.org August 6, 2015 551
Electrolyte and Acid Base Disturbances in Diabetes
lality and estimated urinary osmolality, which is derived from the following equation25,26:
Urinary osmolality = ([2 urinary Na+] + [2 urinary K+]) + (urinary urea
nitrogen in milligrams per deciliter 2.8) + (urinary glucose in milligrams per deciliter 18).
In the absence of glycosuria, the glucose por-tion of the equation can be deleted. A large increase in the urinary osmolal gap suggests increased excretion of ammonium coupled with
either chloride or ketoanions, a process that is consistent with the extrarenal nature of the aci-dosis and intact renal function. However, in some patients with diabetic acidosis, the gap may be lower in the absence of a defect in the renal response to the acid load. Such a response would occur in patients with a low glomerular filtration rate (GFR) when the filtered load of sodium is reduced. The resultant decrease in the rate of ATP expenditure required for sodium
Figure 2. Phases of Metabolic Acidosis in Patients with Diabetes.
In the early phase of ketoacidosis, when the volume of extracellular fluid (ECF) is close to normal, the ketoacid anions produced will be rapidly excreted by the kidney as sodium and potassium salts. The urinary loss of ketone salts leads to the contraction of the volume of ECF and signals the renal retention of dietary sodium chloride. The proton of the ketoacid reacts with bicarbonate to generate water and carbon dioxide, which are expired through the lungs. The net effect is the development of a hyperchloremic normal-gap acidosis. This process has been referred to as an indirect loss of sodium bicarbonate.7 As the ketogenic process becomes more accelerated and as volume depletion becomes more severe, a larger proportion of the generated ketoacid salts are retained within the body, thus in-creasing the anion gap. At this point, glomerular filtration rate (GFR) is typically reduced and a patient requires treatment and admis-sion to a hospital. During the recovery phase, the anion-gap metabolic acidosis is transformed once again into a hyperchloremic, nor-mal anion-gap acidosis. Treatment leads to the termination of ketoacid production. As the ECF volume is restored, there is increased renal excretion of the sodium salts of the ketoacid anions. The indirect loss of bicarbonate, combined with the retention of adminis-tered sodium chloride, accounts for the redevelopment of the hyperchloremic, normal-gap acidosis. In addition, the potassium and sodium administered in solutions containing sodium chloride and potassium chloride enter into cells in exchange for hydrogen ions. The net effect is the infusion of hydrogen chloride into the extracellular fluid. The normalization of the acidbase balance is accom-plished over a period of several days as the bicarbonate deficit is corrected as bicarbonate is regenerated by the kidney.
Early Phase Treatment Phase Recovery Phase
ECF volume near normal Ketogenesis increases Ketoacid salts promptly excreted
Ketogenesis markedly increased ECF volume contracted Aldosterone level increases GFR reduced Ketoacid salts accumulate in blood
Ketogenesis ceases ECF volume restored with NaCl GFR restored Ketoacid salts excreted or metabolized
KA
Potassium ketoacid anion (KA)
NH4Cl
NaCl
Hyperchloremic, normalanion-gap metabolic acidosis
Hyperchloremic, normalanion-gap metabolic acidosisAnion-gap metabolic acidosis
NaCl NaClin fluids
AldosteroneNaCl
NaCl
NaCl
NaCl NaCl
NaCl
Ammonium ketoacid anion (NH4A)
NH4A NH4A NH4Cl
NaA
NaANaA
NaANaA
Sodium ketoacid anion (NaA)
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T h e n e w e ngl a nd j o u r na l o f m e dic i n e
transport and the oxidation of ketoacid anions in cells of the proximal tubule lower the utiliza-tion of glutamine and hence diminish the rate of ammoniagenesis.27,28 Measurement of the uri-nary osmolal gap is most useful in the evalua-tion of patients with hyperchloremic acidosis and a normal gap. (This condition typically de-velops during the recovery phase of diabetic ketoacidosis, after normalization of the anion gap.) The urinary osmolal gap is measured to determine whether there is an appropriate in-crease in the urinary excretion of ammonium, which leads to resolution of the acidbase disor-der. A low urinary osmolal gap in patients with persistent hyperchloremic normal-gap acidosis suggests tubular dysfunction.
In the past, nitroprusside tablets or reagent strips were used to detect ketoacids. Despite re-cent advances that permit direct quantification of -hydroxybutyrate levels, measured concentra-tions of ketone bodies often cannot completely account for the increased anion gap, and in many patients hyperlactatemia may be contribu-tory.29 Lactate levels may increase in response to hyperadrenergic activity, even in the absence of tissue hypoperfusion.30 Another contributor to the increased gap is the accumulation of d-lactic acid caused by the increased production of methylglyoxal through the glyoxalase path-way.31 Although factors such as acidosis, hyper-osmolality, and cerebral hypoperfusion have been implicated in the altered sensorium that is often present in patients with diabetic ketoaci-dosis, we speculate that d-lactate may also play a role.32
The treatment of diabetic ketoacidosis in-volves the administration of insulin and intrave-nous fluids to correct volume depletion. Alkali therapy is generally not required because insulin administration will slow the rate of ketoacid production, and the oxidation of ketoanions will lead to the regeneration of bicarbonate,33 but there are certain circumstances in which alkali therapy may be indicated.7 Alkali therapy has been linked to an increased risk of cerebral edema in children.7,33
Metformin, which is used in the treatment of type 2 diabetes, can in rare circumstances lead to lactic acidosis, but the risk is quite low and is
in fact indistinguishable from the background rate of lactic acidosis among patients with type 2 diabetes.34 The risk increases when renal func-tion declines abruptly; because metformin is cleared by the kidneys, metformin levels become elevated when renal function is impaired. For instance, a patient with clinically stable type 2 diabetes who is being treated with metformin and in whom gastroenteritis then develops will be subject to volume depletion. The resulting increase in efferent arteriolar tone mediated by angiotensin II will raise the intraglomerular pressure to counterbalance the decrease in renal perfusion, thereby stabilizing the GFR and pre-venting the accumulation of metformin. If such a patient is receiving an angiotensin-convertingenzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB), this counterbalancing effect will be lost because of the decrease in efferent arte-riolar tone that results from treatment with in-hibitors of the reninangiotensin system.35 Met-formin accumulates if there is a severe reduction in the GFR, which may lead to lactic acidosis. Nonsteroidal antiinflammatory drugs can in-crease the risk of metformin accumulation be-cause they increase afferent arteriolar tone, especially in patients with decreased renal perfusion, thereby causing an abrupt and sig-nificant reduction in the GFR. Metformin is readily removed with dialysis therapy since it has a low molecular weight and does not bind proteins; however, prolonged extracorporeal therapy is generally required to lower the level of metformin, since it has a high volume of distribution and two-compartment elimination kinetics.36,37
H y per k a lemic R ena l T ubul a r Acid osis
Hyperkalemic renal tubular acidosis (type 4 re-nal tubular acidosis) is a common condition among patients with diabetes and overt ne-phropathy. The disease is characterized by dis-turbances in nephron function, which lead to impaired renal excretion of hydrogen and potas-sium and result in hyperkalemia and a hyper-chloremic normal-gap acidosis (Fig. 3). Type 4 renal tubular acidosis may be present even in
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n engl j med 373;6 nejm.org August 6, 2015 553
Electrolyte and Acid Base Disturbances in Diabetes
Figure 3. Pathogenesis of the Electrolyte Pattern in Type 4 Renal Tubular Acidosis.
In normal circumstances, the reabsorption of sodium in the collecting duct, driven by aldosterone, generates negative potential in the lumen, which serves as a driving force for the secretion of potassium by the principal cell and of hydrogen ions by the -intercalated cell. Impaired sodium reabsorption in the principal cell caused by either hyporeninemic hypoaldosteronism or impairment in the function of the collecting duct leads to a decrease in luminal electronegativity. This decrease impairs secretion of potassium and of hydrogen ions, contributing to hy-perkalemia and metabolic acidosis. The hyperkalemia further impairs acidification by decreasing the amount of ammonium available to act as a urinary buffer. First, hyperkalemia decreases the production of ammonium in the proximal tubule. The precise mechanism by which this occurs is not currently known, but it may involve the entry of potassium into cells in exchange for protons, which would raise the intracellular pH. Second, the transport of ammonium in the thick ascending limb is inhibited by the large increase in the concentration of potassium in the lumen, which effectively competes with ammonium for transport on the sodiumpotassiumchloride cotransporter. Ammonium normally exits the basolateral surface of the cell through sodiumproton exchanger 4 (NHE4). The net excretion of acid decreases as a result of the limited availability of a buffer combined with a decreased capacity for the secretion of hydrogen ions. The urinary osmolal gap is not increased, which indicates that there is little or no excretion of ammonium in the urine. Patients in whom type 4 renal tubular acidosis is caused by a defect in mineralo-corticoid activity typically have a urinary pH of less than 5.5, reflecting a more severe defect in the availability of ammonium than in the secretion of hydrogen ions. In patients with structural damage, the secretion of hydrogen ions is impaired throughout the collecting duct (both cortical and medullary segments) such that the urinary pH may be more alkaline than it is in patients who have impaired mineralocorticoid activity alone.
Thick ascending limb
Hyperkalemia develops owing todecrease in luminal electronegativityin lumen of collecting duct
Renin Aldosterone
Decreased buffering capacityand decreased H+ secretion
Hyperkalemic normal-gap metabolicacidosis (type 4 renal tubular acidosis)Decreased medullary ammonium transfer
Glutamine NH4+
NHE4
K+ K+
H+
NH4+ or K+
Na+
Na+
Na+
Mitochondrion
NH4+ Na+
Cl
2 Cl
HCO3
Proximal tubule
Collecting duct
K+
Na+
Decreased ammoniagenesis
NH4+
Na+
-INTERCALATED CELL
PRINCIPAL CELL
DUCTLUMEN
DUCTLUMEN
DUCTLUMEN
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n engl j med 373;6 nejm.org August 6, 2015554
T h e n e w e ngl a nd j o u r na l o f m e dic i n eTa
ble
1. E
lect
roly
te D
istu
rban
ces
in D
iabe
tes
Mel
litus
.
Dis
turb
ance
Mec
hani
sm o
r C
ause
Com
men
tTr
eatm
ent
Hyp
onat
rem
iaO
smot
ical
ly in
duce
d m
ovem
ent o
f wat
er fr
om
intr
acel
lula
r to
ext
race
llula
r sp
ace;
in-
crea
sed
thir
st a
nd w
ater
inta
ke; i
ncre
ased
se
cret
ion
of v
asop
ress
in, w
hich
lim
its re
nal
excr
etio
n of
wat
er
Net
effe
ct o
f inc
reas
ed g
luco
se le
vels
in b
lood
is
mov
emen
t of w
ater
from
intr
acel
lula
r to
ex
trac
ellu
lar
com
part
men
ts; r
enal
loss
of
wat
er c
ause
d by
gly
cosu
ria
dete
rmin
es s
o-di
um c
once
ntra
tion
In h
yper
glyc
emic
cris
is, a
fter
flui
d re
susc
itatio
n, c
ontin
ue
adm
inis
trat
ion
of 0
.9%
nor
mal
sal
ine
for
corr
ecte
d
sodi
um c
once
ntra
tion
of 145
mm
ol/l
iter
Hyp
okal
emia
Cel
l shi
ft in
whi
ch p
otas
sium
mov
es fr
om e
x-tr
acel
lula
r to
intr
acel
luar
spa
ce; m
ay o
ccur
af
ter
adm
inis
trat
ion
of in
sulin
, cor
rect
ion
of h
yper
toni
city
, or
2-
adre
nerg
ic s
timul
a-tio
n*
Incr
ease
d re
nal e
xcre
tion
resu
lts fr
om in
-cr
ease
d de
liver
y of
sod
ium
to c
olle
ctin
g du
ct in
pre
senc
e of
incr
ease
d m
iner
alo-
cort
icoi
d ac
tivity
Dur
ing
trea
tmen
t of h
yper
glyc
emic
cri
sis
with
3.5
5.2
m
mol
pot
assi
um/l
iter,
add
20
40 m
mol
pot
assi
um to
ea
ch li
ter
of fl
uid
Hyp
erka
lem
iaC
ell s
hift
intr
acel
luar
to e
xtra
cellu
lar
spac
e-ca
used
by
insu
lin d
efic
ienc
y or
hyp
erto
nici
-ty
(no
t met
abol
ic a
cido
sis)
*
Cel
l shi
ft c
ause
s tr
ansi
ent h
yper
kale
mia
In h
yper
glyc
emic
cris
is in
whi
ch p
otas
sium
con
cent
ratio
n is
>5.
2 m
mol
/lite
r, d
o no
t add
pot
assi
um to
rep
lace
-m
ent f
luid
s (r
eche
ck p
otas
sium
con
cent
ratio
n ev
ery
2 hr
)
Impa
ired
ren
al e
xcre
tion
Impa
ired
ren
al e
xcre
tion
caus
es c
hron
ic h
y-pe
rkal
emia
In ty
pe 4
ren
al tu
bula
r ac
idos
is, s
tart
low
-pot
assi
um d
iet,
disc
ontin
ue o
ffend
ing
med
icat
ions
if p
ossi
ble,
max
i-m
ize
use
of d
iure
tics,
cor
rect
aci
dosi
s if
pres
ent,
con-
side
r flu
droc
ortis
one
in a
bsen
ce o
f flu
id o
verl
oad
or
hype
rten
sion
Ani
on-g
ap m
etab
olic
aci
dosi
sFu
lly e
stab
lishe
d ke
toac
idos
is (
volu
me
depl
e-tio
n, o
ften
with
red
uced
glo
mer
ular
filtr
a-tio
n ra
te)
Leve
ls o
f l-la
ctat
e an
d d-la
ctat
e ar
e in
crea
sed
in d
iabe
tic k
etoa
cido
sis
Initi
ate
fluid
res
usci
tatio
n an
d in
sulin
; bic
arbo
nate
ther
a-py
not
rou
tinel
y in
dica
ted,
but
if p
H
6.9,
infu
se 1
00
mm
ol b
icar
bona
te in
400
ml s
teri
le w
ater
plu
s 20
m
mol
pot
assi
um c
hlor
ide
at r
ate
of 2
00 m
l/hr
ove
r 2
hr a
nd r
epea
t unt
il pH
7.
0
Hyp
erch
lore
mic
nor
mal
-gap
m
etab
olic
aci
dosi
sIn
the
earl
y ph
ase
or in
the
reco
very
pha
se o
f di
abet
ic k
etoa
cido
sis
Hyp
oald
oste
roni
sm o
r di
stur
banc
es in
func
-tio
n of
col
lect
ing
duct
acc
ount
for
im-
pair
ed e
xcre
tions
of p
otas
sium
and
hyd
ro-
gen
in ty
pe 4
ren
al tu
bula
r ac
idos
is
Mon
itor
patie
nt; r
esol
utio
n w
ill o
ccur
dur
ing
reco
very
ph
ase
of d
iabe
tic k
etoa
cido
sis
unle
ss r
enal
func
tion
is im
pair
ed
Ren
al tu
bula
r ac
idos
is o
f ren
al in
suffi
cien
cy,
type
4 r
enal
tubu
lar
acid
osis
In ty
pe 4
ren
al tu
bula
r ac
idos
is, t
reat
hyp
erka
lem
ia a
s in
-di
cate
d ab
ove
Met
abol
ic a
lkal
osis
Vom
iting
, whi
ch o
ften
occ
urs
in p
atie
nts
with
di
abet
ic k
etoa
cido
sis
and
diab
etic
gas
tro-
pare
sis
Plas
ma
bica
rbon
ate
conc
entr
atio
n hi
gher
th
an e
xpec
ted
give
n ex
tent
of i
ncre
ase
in
anio
n ga
p in
ket
oaci
dosi
s
Res
tore
vol
ume
of e
xtra
cellu
lar
fluid
with
0.9
% n
orm
al
salin
e, c
orre
ct p
otas
sium
def
icit
if pr
esen
t
Adm
inis
trat
ion
of lo
op o
r th
iazi
de d
iure
tics
Dis
cont
inue
dru
g, if
feas
ible
, adm
inis
ter c
hlor
ide-
cont
ain-
ing
solu
tions
intr
aven
ousl
y if
indi
cate
d
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n engl j med 373;6 nejm.org August 6, 2015 555
Electrolyte and Acid Base Disturbances in Diabetes
Dis
turb
ance
Mec
hani
sm o
r C
ause
Com
men
tTr
eatm
ent
Hyp
omag
nese
mia
Ren
al m
agne
sium
was
ting
caus
ed b
y os
mot
ic
diur
etic
effe
ct o
f gly
cosu
ria
and
met
abol
ic
acid
osis
, im
pair
ed g
astr
oint
estin
al a
bsor
p-tio
n, a
dmin
istr
atio
n of
pro
ton-
pum
p in
hib-
itors
or
thia
zide
diu
retic
s
Effe
cts
of h
ypoa
lbum
inem
ia c
an b
e co
rrec
ted
by a
djus
tmen
t of s
erum
mag
nesi
um c
on-
cent
ratio
n to
0.0
1
(40
m
easu
red
albu
-m
in le
vel [
in g
/lite
r]);
hyp
omag
nese
mia
ca
n ca
use
hypo
kale
mia
as
resu
lt of
ren
al
pota
ssiu
m w
astin
g an
d hy
poca
lcem
ia
Prov
ide
mag
nesi
um s
uppl
emen
t; or
al s
uppl
emen
ts p
re-
ferr
ed, w
ith in
trav
enou
s m
agne
sium
indi
cate
d in
sy
mpt
omat
ic p
atie
nts
(e.g
., th
ose
with
arr
hyth
mia
s or
ne
urom
uscu
lar i
rrita
bilit
y); m
agne
sium
sup
plem
enta
-tio
n m
ay r
educ
e ri
sk o
f dia
bete
s
Met
abol
ic a
cido
sis,
whi
ch in
crea
ses
conc
en-
trat
ion
of u
ltraf
ilter
able
mag
nesi
um
Gas
troi
ntes
tinal
loss
of m
agne
sium
as
a re
sult
of d
iarr
hea,
whi
ch m
ay o
ccur
in a
uton
omic
ne
urop
athy
Hyp
erm
agne
sem
iaIn
sulin
def
icie
ncy
and
met
abol
ic a
cido
sis,
le
adin
g to
cel
l shi
ft in
whi
ch m
agne
sium
flo
ws
out o
f cel
l
Deg
ree
of e
leva
tion
is m
ild; c
orre
ctio
n of
aci
-do
sis,
adm
inis
trat
ion
of in
sulin
, and
2
adre
nerg
ic s
timul
atio
n ca
n un
mas
k to
tal-
body
def
icit
if pr
esen
t
No
spec
ific
ther
apy
indi
cate
d
Hyp
ocal
cem
iaU
rina
ry lo
ss o
f vita
min
Dc
arry
ing
prot
ein
in
the
neph
rotic
syn
drom
e, a
ltere
d se
t poi
nt
for
rele
ase
of p
arat
hyro
id h
orm
one
To c
orre
ct fo
r effe
ct o
f hyp
oalb
umin
emia
, add
0.
8 m
g ca
lciu
m/d
l for
eve
ry d
ecre
ase
of
1 g/
dl in
pla
sma
albu
min
con
cent
ratio
n
Cor
rect
def
icie
ncy
in v
itam
in D
, if
pres
ent
Cor
rect
mag
nesi
um d
efic
it, if
pre
sent
Hyp
erca
lcem
iaV
olum
e de
plet
ion,
thia
zide
diu
retic
sSe
veri
ty u
sual
ly m
ild w
hen
asso
ciat
ed w
ith
thia
zide
diu
retic
s or
vol
ume
depl
etio
nR
esto
re e
xtra
cellu
lar
volu
me,
dis
cont
inue
or
min
imiz
e do
se o
f diu
retic
Hyp
opho
spha
tem
iaTo
tal-b
ody
depl
etio
n re
sulti
ng fr
om o
smot
ic
diur
esis
In d
iabe
tic k
etoa
cido
sis,
trea
tmen
t with
insu
-lin
and
cor
rect
ion
of a
cido
sis
unm
asks
ph
osph
ate
defic
it
Con
side
r ph
osph
ate
supp
lem
enta
tion
n
ot r
outin
ely
indi
cate
d in
dia
betic
ket
oaci
dosi
s bu
t is
indi
cate
d fo
r sk
elet
al-m
uscl
e w
eakn
ess,
res
pira
tory
sup
pres
sion
, or
rha
bdom
yoly
sis,
with
20
30 m
mol
pot
assi
um
phos
phat
e/lit
er a
dded
to r
epla
cem
ent f
luid
; max
imal
ra
te o
f inf
usio
n sh
ould
be
no g
reat
er th
an 4
.5 m
mol
/hr
to a
void
hyp
ocal
cem
ia a
nd h
ypom
agne
sem
ia
Hyp
erph
osph
atem
iaPr
esen
t in
diab
etic
ket
oaci
dosi
s, a
s a
resu
lt of
in
sulin
def
icie
ncy
and
met
abol
ic a
cido
sis
Elev
ated
ser
um c
once
ntra
tions
of p
hosp
hate
ca
n be
pre
sent
des
pite
tota
l-bod
y de
ple-
tion
in d
iabe
tic k
etoa
cido
sis
In d
iabe
tic k
etoa
cido
sis,
pro
vide
insu
lin th
erap
y an
d co
r-re
ct a
cido
sis,
bot
h of
whi
ch w
ill c
orre
ct h
yper
phos
-ph
atem
ia
Adv
ance
d ch
roni
c ki
dney
dis
ease
In d
iabe
tic n
ephr
opat
hy, m
anag
e hy
perp
hosp
hate
mia
as
sugg
este
d fo
r ot
her
caus
es o
f chr
onic
kid
ney
dise
ase
(e.g
., lo
w-p
hosp
hate
die
t, ph
osph
ate
bind
ers)
* A
cel
l shi
ft r
efer
s to
the
flow
of e
lect
roly
tes
into
or
out
of a
cel
l.
Bic
arbo
nate
the
rapy
may
be
cons
ider
ed w
hen
a m
ajor
frac
tion
of a
cide
mia
is c
ause
d by
nor
mal
ani
on-g
ap a
cido
sis,
sin
ce t
he a
mou
nt o
f cir
cula
ting
keto
acid
ani
ons
avai
labl
e fo
r m
etab
o-lis
m t
o bi
carb
onat
e, c
ombi
ned
with
rap
id in
fusi
on o
f sal
ine,
can
wor
sen
acid
emia
.7 Pa
tient
s w
ith d
iabe
tic n
ephr
opat
hy a
nd a
n es
timat
ed g
lom
erul
ar fi
ltrat
ion
rate
of