Kidney International, Vol. ... sis will be placed on the role of the kidney in the defense of acid- ...... sion the kidneys of patients with DKA having a typical AG.
Kidney International, Vol. 25 (1984), pp. 591—5 98
EDITORIAL REVIEW
Diabetic ketoacidosis: Role of the kidney in the acid-base homeostasis re-evaluated The development of diabetic ketoacidosis (DKA) involves a
Alteration in volume and composition of body fluids The increase in effective osmotic pressure of the ECF consequent to the elevated glucose level effects a shift of water out of some cells, most prominently from skeletal muscle. The resulting expansion of the ECF compartment is brief due to simultaneous renal and extrarenal loss of fluids. The increased filtered
series of closely interrelated derangements of intermediary metabolism and of body fluid volume and composition whose fundamental nature has not been completely unraveled [1—81. The composite clinical picture in full-blown DKA on admission includes hyperglycemia with hyperosmolality, metabolic acido-
sis due to the accumulation of ketoacids, extracellular and
load of glucose, due to hyperglycemia, exceeds the renal
intracellular fluid (ECF and ICF, respectively) volume depletion, and varying degrees of electrolyte deficiency, particularly of potassium and phosphate [9—il]. Since proper correction of
tubular reabsorptive capacity resulting in massive glycosuria which is a hallmark of DKA [171. During this osmotic diuresis urinary water losses are disproportionately greater than the accompanying electrolyte losses, an event which further aggravates the progressive rise in serum osmolality. A special feature
the alterations in volume status, acid-base, and electrolyte composition is critical for survival, a clear understanding of the
pathogenesis of these derangements is essential for the adequate management of DKA. The present review will focus on the role of the kidney in the pathogenesis of the different patterns of electrolyte and acid-base composition observed on admission for and during recovery from DKA. Special empha-
of the osmotic diuresis during DKA is that, in contrast to mannitol diuresis, the urinary loss of sodium is significantly
greater than that of chloride because most of the urinary anions are ketones rather than chloride [17, 181. Thus, osmotic diuresis increases serum sodium and chloride, thereby counterbalancing sis will be placed on the role of the kidney in the defense of acid- the dilution of these electrolytes caused by hyperglycemia. The base homeostasis during the recovery phase. Other aspects of migration of sodium to the ICF compartment in replacement of the alterations that develop in DKA have been reviewed in potassium losses decreases the serum sodium and vomiting may detail elsewhere [12—14]. further magnify chloride losses. The difference in the magnitude
Insulin deficiency, either absolute or relative, results in
of these losses from one patient to another accounts for the differences in plasma composition observed on presentation. The clinical disorder in body fluids composition, however, results from osmotic diuresis and the urinary loss of ketone
hyperglycemia because of an impairment in glucose oxidation in most tissues and the excessive hepatic production of glucose. A
derangement in both production and utilization of ketones represents an additional hallmark in the altered metabolism of DKA. The major substrates for the production of ketones are long-chain free fatty acids which are stored in adipose tissue as triglycerides. Once released from adipocytes, free fatty acids
salts of sodium and potassium. Prerenal azotemia due to volume depletion is a classic finding in DKA and usually reversible, but occasionally it may progress to acute tubular necrosis [19—22]. Figure 1 depicts the blood composition on admission for and after recovery from DKA in a group of patients we recently evaluated [23]. The levels of urea nitrogen, creatinine, total proteins, uric acid, hematocrit, and hemoglobin were all elevated on admission, a reflection of ECF
are transported to the liver, where synthesis of a variety of lipids occurs. Fatty acids may also be used for the production of ketones, and since the liver lacks the enzymatic machinery to
further oxidize ketones, these substrates must be exported to peripheral tissues, such as muscle, brain, and kidney for their ultimate utilization. Insulin is currently considered the major regulator of both production and utilization of ketones by its triple action on adipose, hepatic, and peripheral tissues [15, 161. In the adipocyte it inhibits lipolysis thus decreasing the release of the substrate; in the hepatocyte it enhances esterification rather than oxidation of free fatty acids; and in peripheral tissues it stimulates the oxidation of ketones. Thus, insulin deficiency initiates a sequence of metabolic events that results in hyperketonemia due to both overproduction and decreased utilization
Acid-base changes During the development of DKA, ketoacids released into the ECF are titrated by bicarbonate and other body buffers. This buffering process results in an increase of plasma unmeasured anions and accounts for the classic pattern of acid-base composition, namely metabolic acidosis associated with an increased anion gap (AG) [3, 12, 24—28]. This latter term refers to those
of ketones. Ketogenesis is further stimulated by glucagon which
plasma anions, other than chloride and bicarbonate, that bal-
volume contraction, but they decreased significantly when water and electrolytes deficit were corrected.
causes an increase in substrate supply and stimulates the oxidation of fatty acids in the liver. Other counterregulatory hormones involved in the metabolic derangements of DKA are
catecholamines and cortisol. The net effect of the complex hormonal imbalance that results is stimulation of gluconeogenesis, ketogenesis, and lipolysis, and depression of glycolysis and glycogenesis.
591
Received for publication March 8, 1983 and in revised form June 21, 1983
© 1984 by the International Society of Nephrology
592
Adrogué et a! BUN
Creatinine
50
5.0 S
40
4.0
I.
30
3.0 0)
0)
E 20
E 2.0
10
1.0
initial 30 to 36 hr, and were associated with a reciprocal
0
8
Protein
Uric acid
10
20
•%•.
0)
..
C)
4%.
10
E
expected in typical AG acidosis. In addition there was a
5
4
S.
o'
0
Hct
60
Fib
20
50..
-,-*.
40 30
significant impairment of renal function, as indicated by the increased BUN level on admission. In contrast to the previous case, recovery from metabolic acidosis was considerably faster.
By hour 16 after admission, total carbon dioxide was 16 mmoles/liter; blood pH was almost normal. Thus, a striking characteristic of patients presenting with hyperchloremic acido-
15
0
0)
10
20 5
O
0
Admission Recovery
Admission Recovery
Fig. 1. Laboratory data on admission (left side of each panel) and after
recovery (right side of each panel) from diabetic ketoacidosis. Each symbol represents an admission. A significant decrease in all parameters from the admission values was observed in the recovery period.
ance the positive charges of sodium and potassium:
AG = (Nat + K) —
decrement in the plasma AG. The AG, although not elevated on admission, progressively fell with treatment due at least in part
to a major reduction in the concentration of plasma proteins [23]. In this patient the findings and the course of illness are in contrast to those of patients presenting with pure AG acidosis illustrated in Figure 3. The plasma bicarbonate deficit on admission was fully accounted for by the excess AG, as is
15
•••
6
respiratory response, was present on admission, but the decrement in plasma bicarbonate was associated with an AG within 4 mEq/liter). A notable additional the normal range (16 feature was that on admission BUN level was within normal limits, Despite treatment, 60 hr elapsed before the serum total carbon dioxide rose to 17 mmoles/liter. Serum chloride levels, although elevated on admission, increased further during the
(C1
+ HC03)
In uncomplicated DKA the increment in AG above its normal
sis is a slower recovery from metabolic acidosis when compared to patients presenting with the AG variety. It should be evident from the foregoing that, for the mean excess of AG to equal the mean deficit in plasma bicarbonate (Table 1), there must be patients in whom the excess AG exceeds the decrement in plasma bicarbonate to average the patients with hyperchloremic acidosis. To understand these different acid-base and electrolyte patterns in DKA, the factors known to alter the stoichiometric relationship between the increment in AG and the decrement in serum bicarbonate will be outlined first [23, 27, 321. The ratio of excess AG/bicarbonate deficit describes this relationship and represents the fraction of
the bicarbonate deficit per liter of plasma that is accounted for by an increment in the unmeasured plasma anions. A decrement
of the numerator or an increment of the denominator will decrease the magnitude of the ratio whereas changes in the
value should be approximately equal to the decrement in opposite direction will increase the value. The mechanisms that plasma bicarbonate. Thus, the ratio of excess AG to that of can alter this ratio will be reviewed briefly. bicarbonate deficit should be about one: Excess AG — Bicarbonate deficit — where
1
0
excess AG (mEq/liter) equals measured AG minus
normal AG, and bicarbonate deficit (mEq/liter) equals normal plasma bicarbonate minus measured plasma bicarbonate. Table 1 presents admission data obtained andlor calculated from several published reports of patients presenting with DKA [6—8, 23, 29—31]. In every study the mean plasma bicarbonate
Increase above unity of the ratio of excess AG/bicarbonate deficit Any condition that increases plasma bicarbonate, AG, or
both will result in a ratio of excess AG/bicarbonate deficit greater than one. The most common conditions in which this
disclose any specific abnormality in the regulation of acid-base homeostasis that could lead to hyperchloremic acidosis; complete recovery from metabolic acidosis is observed within a few days. Values from one such patient are depicted in Figure 2.
situation will be encountered are: Vomiting or exogenous bicarbonate therapy. Failure of the measured serum bicarbonate to fall by the amount predicted from the calculated excess AG has been classically regarded as the result of a coexisting metabolic alkalosis. Vomiting, which frequently accompanies the development of DKA, is the most prominent potential source of a "hidden" metabolic alkalosis. However, analysis of the electrolyte composition of specimens of vomitus from patients with DKA revealed that the sodium concentration actually equalled or exceeded that of the chloride concentration [3]. Bicarbonate therapy also increases plasma bicarbonate without altering the AG. Hyperproteinemia. Alterations in the concentration of pro-
Severe metabolic acidosis, accompanied by the appropriate
teins may lead to changes in the AG independent of any
deficit was approximately equal to the mean excess AG. However, in apparent contradiction with these results, one often encounters patients admitted with DKA having severe metabolic acidosis of the hyperchloremic variety, instead of the
expected AG variety. Evaluation of these patients does not
593
Diabetic ketoacidosis Table 1. Comparison of admission data in diabetic ketoacidosis
Danowski et a!
(N = 8, [6])
Seldin et al (N = 10, [7])
Nabarro et al (N = 7, [8])
Shaw et al (N = 30, [29])
Assal et al (N = 9, [30]) 7.06
Blood pH [Naip, mEq/liter [K]p, mEqiliter [Clip, mEqiliter [HCO3]p, mEqiliter Anion gap, mEqiliter [HCO3]p, mEq/literc
130
4.9
Anion gap, mEqiliter"
3.2
3.7 0.2 3.5
129 4.7
94 7.0
0.5 2.8 0.8
34.3
1.3
32.1
17.0
0.8
16.6
1.5 1.0
18.3
1.3
16.1
1.5
94 7.4
1.0
136
5.7 93 7.5
40.8 16.5 24.8
0.5 0.2 1.0
131
5.8 96 5.0
1.1 2.1 1.1 2.1
36.7 22.0 20.7
1.4 0.3 1.3 0.6a 1.7 0.6a 1.7
146 5.6 106 5.6
0.03 3.0 0.3 3.0 1.0
Oh et al (N = 35, [31]) 7.07 136 101
9.6
40.0
25.0
18.4 24.0
14.4 13.0
Adrogue et al
(N = 150, [231)
0 1.6 1.4
0.3 l.2b 0.3 0.9
7.06 132
0.01
0.6
5.7 98
0.1
6.2
0.2a
33.5
0.6
20.8
0.2 0.6
17.5
0.6
TCO2 was measured. The value was calculated without [K]p. The values were derived from either 24 mEqlliter or 27 mM/liter depending if [HCO3]p or TCO2 were measured, respectively. d The values were derived from 16 mEq/liter. b
-
Admission
00 o—.o
7.6
30
an exogenous acid load in nephrectomized animals; therefore,
Hours postadmission
48
16
24 30 36
the applicability of these observations to DKA in humans, having an endogenous ketoacidemia and a variable level of renal function, remains to be determined.
48 60
":
50
A major decrement in systemic pH, due to severe DKA, may also result in the progressive recruitment of tissue nonbicarbon-
ate buffers, such as some tissue proteins, having a lower pK
145 ..
-
rnEq/iitr 1: E 5.0
130mEq/Iiter 100L
mEq/Iiter
I
[37]. The contribution of these additional buffer systems in the defense of the acid-base status will lead to a smaller decrement in plasma bicarbonate for a given increment in plasma unmeasured anions. Renal acid excretion. Prerenal azotemia, that frequently accompanies DKA, results in an increased AG due to retention
of acids other than ketoacids. In this condition, the plasma bicarbonate deficit exceeds the level of ketones, but the decrement in bicarbonate remains approximately equal to the incre-
ment in AG, since the retained acids, independent of their
2iter
1?:
Gce 1oH4: t SOOr
55
Fig. 2. Laboratory data on admission and follow-up values during the
hospital course in a patient admitted for diabetic ketoacidosis but presenting with pure hyperchloremic acidosis. Each symbol represents
a single measurement.
deviation in the plasma bicarbonate [25, 33—35]. Thus, the ECF volume deficit frequently present in DKA results in hyperpro-
teinemia (Fig. 1), which will be reflected in an increase of plasma undetermined anions. Also, since a variable degree of acidemia is present in DKA, the pH-related decrement in the net negative charge of plasma proteins should be considered. The net effect of a change in concentration of proteins and the acidemia-induced decrease in their negative charge will influence the ratio of excess AG to bicarbonate deficit. Tissue titration. Titration of intracellular buffers by the retained ketoacids results in an exchange of cellular sodium and potassium for extracellular hydrogen ions. The displacement of sodium to the ECF should result in transfer of water leading to dilution of all serum electrolytes other than sodium. Madias Ct
nature, titrate plasma bicarbonate. By contrast, urinary excretion of hydrogen ions with anions other than ketones, promote the correction of the bicarbonate deficit without altering the
excess anion gap. Since a several-fold increase in net acid excretion occurs in DKA, this mechanism has the potential for substantially altering the relationship between AG and bicarbonate concentration. The daily renal excretion of hydrogen
ion, as titratable acidity and ammonium, in DKA, has been shown to attain levels as high as 250 and 500 mEq, respectively [38].
Selective cellular uptake of hydrogen ions. If the distribution space of protons includes the ICF compartment, whereas the distribution space of the anions is limited to the ECF volume, the decrement in serum bicarbonate would be smaller than the actual increment in AG. One implication of this assumption is that, in the recovery phase from DKA, a larger number of protons than of ketone anions would return to the ECF resulting in a smaller rise in plasma bicarbonate than the actual decrease in AG achieved. Oh et al [31] and Oh, Banerji, and Carroll [391
have observed a disparity between the fall in AG and the increment in serum bicarbonate during the recovery phase of
DKA, which resulted in a hyperchloremic acidosis. They
al have shown this phenomenon in different types of AG
suggested that a difference in the distribution volume of bicarbonate and ketone anions was the most probable explanation for the observed electrolyte disturbance. This hypothesis, however, has not been experimentally verified. Moreover, experi-
acidosis [36]. However, their experiments were performed with
mental data we have presented strongly suggest a different
594
Adrogué et al
sion I
00 o—o
8
16
24
50 ••
7.5
- ir 143 ss
30
ft1O
E
0-0 110 r [ci 1,
exchange for ICF hydrogen ions, while most of the chloride will
I I
Hours postadmission
I
i 8.0 4 I
I..
14.0
AG
45r
—i45
30F
H30 BUN
I
mEq/Iiter 15[ 1000.p-
__]15 55
mg/dI
S.
remain in the ECF. Since the hydrogen ions extruded will be titrated by extracellular bicarbonate, the net effect will be the development of hyperchloremic acidosis. Hypocapnia. Hyperventilation, a classic accompaniment of DKA, is an adaptive response secondary to metabolic acidosis.
Since the kidney responds in an identical fashion to both primary and secondary hypocapnia, there should be a suppres-
sion of renal bicarbonate reabsorption [42]. However, the simultaneous stimulation of renal acidification, as a result of the
coexistent metabolic acidosis, may offest any depression of bicarbonate reabsorption that might be due to hypocapnia. Renal tubular acidosis. Two isolated case reports have suggested the existence of a transient impairment of renal acidification in the recovery phase of DKA [43, 44]. The described defect, which seems to involve the distal nephron, however, appears to be very unusual. On the other hand, the biochemical derangements that occur in DKA and the renal disease commonly present in diabetic patients might potentially
alter the renal mechanisms of acidification. Thus, a defect in proximal acidification may result from severe hypophosphate-
ing with pure anion gap acidosis. Each symbol represents a single
mia commonly encountered in DKA [45]. Other causes of distal renal tubular acidosis in DKA include interstitial renal disease, hypoaldosteronism, and hyperkalemia with or without reduced mineralocorticoid levels. Differences in the distribution space of hydrogen ions and its
measurement.
accompanying anions. If the distribution space of the anions exceeds the ECF volume while that of the protons is restricted to this compartment, there will be a displacement of chloride
mechanism as the major determinant of the hyperchioremic
from cells by the entering organic anions, resulting in a decrease
Glucose mg/dI
Hct
Fig. 3. Laboratory data on admission and follow-up values during the hospital course in a patient admitted for diabetic ketoacidosis present-
in the ratio of excess AG/bicarbonate deficit. It must be considered subsequently in the section on the Role of the emphasized however, that any differences in the space of acidosis observed in the recovery phase from DKA [231. This is kidney.
Decrease below unity of the ratio of excess AG/bicarbonate deficit Events which cause a decrement in AG, plasma bicarbonate,
or both will result in a decrease below unity of the ratio of excess AG/bicarbonate deficit. The major causes responsible
distribution between the hydrogen ions and its accompanying ketone anions remains as of yet, purely speculative and based on unproven assumptions [23]. Since the kidney participates in multiple ways in modulating the acid-base pattern in DKA, a more detailed evaluation of the renal function in this condition is in order.
for such a decrease are: Renal excretion of sodium salts of ketones. Since the renal
Role of the kidney
effect will be the development of a hyperchloremic acidosis due
episode [19, 20]. Azotemia, usually considered prerenal, results
to replacement of the excreted or metabolized ketones with chloride in the ECF.
from reduced clearance of urea as evidenced by its prompt
Chloride containing infusions. Fifty years ago it was suggested that saline infusions in the treatment of DKA may result in
diuresis is established. Increased urea production from the
The alterations in water and electrolyte composition that threshold for plasma ketones is low and the production of accompany the development of DKA, particularly the ECF ketoacids can reach levels as high as 1,000 to 2,000 mEq/day, volume deficit, often result in impaired renal function. A the urinary excretion of the sodium salts of the ketoacids may decrease in the renal concentrating ability, as a result of be enormous [40]. This renal "wasting" of ketone salts will osmotic diuresis and potassium depletion, will further aggravate result in a contraction of the ECF volume which will signal the the water depletion [18, 22]. Both GFR and RBF have been kidney to retain dietary or infused sodium chloride. As the documented to decrease in patients with DKA, with recovery to urinary losses of ketones are replaced with chloride, the net normal values in most patients within a few weeks from the
the development of hyperchloremic metabolic acidosis [41]. Volume replacement with large quantities of saline infusions is
known to result in dilution of both ketones and bicarbonate; thus, the AG will decrease due to replacement of an unmeasured anion (plasma ketones) with a measured anion (chloride). Additionally, correction of potassium depletion with the chlo-
ride salt will result in the cellular uptake of potassium in
correction after repletion of the volume deficit is initiated and a enhanced catabolism of amino acids resulting from DKA or due to any coexistent infectious process might also play some role in the elevation of BUN levels.
It has been suggested that the development of renal disease results in an improvement in the course of diabetes mellitus; for decades clinicians have been aware that glycosuria in diabetic
patients frequently disappears once kidney disease is established [46]. About 30 years ago, Zubrod, Eversole, and Dana
Diabetic ketoacidosis
30
BUN
Creatinine
20
595
analyzed as a group, the results obtained were consistent with the classic pattern of AG acidosis in all the patients (Table 1). The overall level of renal function on admission was found to be the major determinant of the type of metabolic acidosis. Laboratory data indicative of the status of the ECF volume were
compared in patients who on admission had mainly "AG acidosis" to those of patients who had mainly "hyperchloremic acidosis." As depicted in Figure 4, the mean values of BUN, serum creatinine, plasma proteins, uric acid, and hematocrit
kI Protein
Uric acid
and hemoglobin values were all lower in patients with "hyperchloremic acidosis" than in those with "AG acidosis." These results indicate that the severity of ECF volume deficit is greater in patients presenting with AG acidosis as compared to those with hyperchloremic acidosis. These findings were taken
C)
to mean that patients with DKA who develop significant
E
volume depletion, as a result of osmotic diuresis and vomiting,
will present with the classic AG type of metabolic acidosis because of a reduced excretion of ketone salts consequent to Hct
Hb
volume depletion. Conversely, patients with DKA who are able to maintain salt and water intake, thus preventing the development of volume depletion, will present with variable degrees of hyperchloremic acidosis, due to the urinary excretion of ketone
salts and a concomitant retention of chloride. Strong support
for this hypothesis was obtained from a group of balance studies, which demonstrated that the retention of chloride in excess of sodium, associated with urinary excretion of ketones of a magnitude comparable to that of retained chloride, fully Hyperchloremic Anion gap Hyperchioremic Anion gap explained the development of hyperchloremic acidosis in the acidosis acidosis acidosis acidosis early period after admission [23]. A similar mechanism could Fig. 4. Comparison of laboratory data on admission for diabetic account for the development of hyperchloremic acidosis prior ketoacidosis in patients presenting with hyperchioremic acidosis (left to admission. side of each panel) and those presenting with anion gap acidosis (right Considering that in DKA the patient is unable to properly side of each panel). Patients were classified by their type of acidosishyperchloremic or anion gap, according to the excess anion gap/bicar- metabolize ketoacids, whether their salts are retained in the bonate deficit ratio values. Hyperchioremic acidosis was arbitrarily ECF or are lost in the urine as sodium and/or potassium salts, defined to exist when the excess anion gap/bicarbonate deficit ratio was theoretically should not have any major effect on the severity of below 80%. Each bar depicts mean values 1 SE. the acid-base disorder. The data gathered confirmed this prediction because no difference in the severity of the hypobicarbona[461 described an amelioration of diabetes, as manifested by a temia was found between the two forms of metabolic acidosis at lesser insulin requirement, and the rarity of metabolic acidosis the time of admission [23]. One may wonder why hyperchlore-
in patients having developed the renal lesion of KimmelstielWilson. The observation that DKA was uncommon in patients with the clinical syndrome of Kimmeistiel-Wilson was subsequently confirmed by other investigators [47, 48]. It is currently well established that insulin requirements commonly decrease with the progression of renal failure in patients with diabetic glomerulosclerosis. Diminished carbohydrate intake due to
mic acidosis is repeatedly recognized only in the recovery phase of DKA but not at the time of admission. Since the accepted treatment of DKA involves the administration of rather large amounts of saline infusions, most patients develop obvious hyperchloremic acidosis in the early period after ad-
mission. By contrast, the magnitude of the hyperchloremic acidosis before admission is smaller making its recognition less
anorexia, decreased renal gluconeogenesis as a result of a likely. Furthermore, unless the ratio of excess in AG to that of reduced functioning nephron mass, and prolonged insulin half-
bicarbonate deficit is evaluated in each patient on admission for
life due to reduced renal catabolism are some of the factors DKA, a large number of patients having only a component of responsible for the reduction in insulin requirements [49, 50]. hyperchloremic acidosis will go unrecognized. Finally, previUntil recently, the role of the kidney as a major factor in the ous studies have evaluated the relationship between the excess pathogenesis of the variable acid-base and electrolyte pattern in AG and the bicarbonate deficit on admission by comparing the DKA was unrecognized [23J. It has been long established, mean values of both parameters, so that individual variations in
however, that impairment of renal function in the course of the excess AG/bicarbonate deficit ratio were, by necessity, DKA might lead to more severe hyperglycemia and hyperosmo- hidden. lality as a result of a marked decrement in the urinary excretion The hyperchloremic acidosis observed in DKA is usually
of glucose [7, 51]. Recently, we have demonstrated that on brief, and it is considered to have no adverse clinical conseadmission for DKA, some patients had pure AG acidosis, quence [52]. Since the development of this variety of acidosis others had pure hyperchloremic acidosis, and the rest a combi- results from the renal loss of bicarbonate precursors (ketone nation of both disturbances. However, when the data was salts other than ammonium) accompanied by the retention of
596
Adrogue et al
chloride, these patients should theoretically have a slower rate of recovery from the acid-base disturbance. Indeed, prospective studies have demonstrated that patients admitted with a greater component of hyperchloremic acidosis had, at any given
Table 2. Role of the kidney in the acid-base defense in physiological conditions and during recovery from diabetic ketoacidosisa Physiological conditionsb TA + NH4 HCO
bicarbonate above their admission levels [23]. It appears that Postthe more rapid recovery from metabolic acidosis in patients admission with DKA presenting with AG acidosis is consequent to the 0 to 4 hr equimolar conversion of the retained ketone salts to bicarbon4 to 8 hr ate after insulin administration. It might then be postulated that 8 to 12 hr in patients with severe renal insufficiency who develop DKA, 12 to 16 hr
the underlying reduction in renal function will assure the retention of bicarbonate precursors, thus the acid-base disturbance will be rapidly reversed once insulin is provided. Whereas, to our knowledge, data in support of such a notion are not
currently available, in the few instances we have had the opportunity to observe severe DKA in subjects with reduced renal function, the recovery from the acid-base disturbance was notably fast. The capacity of renal acidification under normal conditions is
Diabetic ketoacidosis TA + NH4 HCO
-
-
time after admission, a smaller increment in their plasma
16 to 20 hr 20 to 24 hr
Balance Cum balance
Balance
mEq
12.7 12.7 12.7 12.7 12.7 12.7
Cum balance mEq
12.7
—45.0
8.2
25.4
—10.3
13.5
38.1
1.8
50.8 63.5 76.2
16.5 14.3 21,2
6.8 2.0 2.3 4.8
—45.0 —55.3 —53.5 —37.0 —22.7 —1.5
8.2 20.8 27.1
28.3 28.9 31.2
values presented are means s of four studies. b The values are estimated according to the mean body weight of the diabetic patients (61 kg) and considering the normal net acid excretion equal to 1.25 mEq/kg body weight/day. Actual plus potential bicarbonate is shown; ketone salts other than ammonium represent potential bicarbonate. a The
1
such that the excretion of fixed metabolic acids is accomplished without the development of sodium and/or potassium depletion.
bances. The association of hyperchloremic metabolic acidosis,
metabolic acids overwhelms the renal mechanisms of acidification and a progressive acidosis occurs accompanied by major urinary losses of sodium and potassium. It should be recalled that a voltage-dependent stimulus for proton secretion occurs in the distal nephron when sodium is absorbed without an accompanying anion. A significant electrical gradient favoring distal hydrogen ion secretion is expected to be present in DKA as a result of the increased distal sodium delivery (ketonuria and osmotic diuresis), avid sodium absorption (ECF volume contraction), and the presence of nonabsorbable anions (ketones). However, failure of the kidney to compensate for the acid load is the result of the high rate of delivery to the distal nephron and the physicochemical properties of ketoacids [381. It has been long recognized that the larger the renal excretion of betahydroxybutyrate the greater is the deviation from the theoretical maximum rate of acid excretion, therefore increasing the fraction that is excreted in the urine as sodium or potassium salts [53, 54]. The low renal threshold of ketoacids results in significant urinary excretion of ketones at plasma concentrations only slightly above normal [55, 561. In addition, betahydroxybutyric and acetoacetic acids are relatively strong acids (PKa of 4.70 and 3.58, respectively) so that at the urine pH found in patients with DKA, they are excreted to a significant extent as sodium and potassium salts, which represents a loss of bicarbonate precursors. In fact, from studies in experimental ketoacidosis, it was concluded that despite maximal stimulation of urinary acidification, the efficiency of the kidney to restore the cation of the ketone salts to the blood is such that, for each millimole of betahydroxybutiric acid excreted, the kidney could salvage only about half a milliequivalent of potential base [5]. Although ketones have been shown to inhibit the rate of renal ammoniagenesis in the experimental animal [57, 58], this effect most probably plays only a minor role in humans, since a sizable increment in urinary ammonium excretion is present in DKA [38]. A reduction in the renal excretion of ammonia may be present as a result of functional (that is, hyperkalemia, hypoaldosteronism) or anatomical (that is, interstitial nephritis) distur-
ly known as type IV renal tubular acidosis [59—62]. Balance studies carried out in the early period after admission
hyporeninemia, hypoaldosteronism, and hyperkalemia has On the other hand, in DKA the excessive production of been repeatedly documented in diabetic patients and is currentrevealed that correction of volume depletion resulted in massive urinary loss of bicarbonate precursors that exceeded the elevated levels of urinary titratable acidity and ammonium (Table 2). The urinary loss of the sodium and potassium salts of ketone anions precludes their conversion to bicarbonate when insulin is administered. Thus, in the initial period after admission the kidneys of patients with DKA having a typical AG acidosis behave in a maladaptive fashion relevant to the systemic acid-base composition. Only, when the plasma ketones have fallen substantially, is stimulation of urinary excretion of titratable acidity and ammonia responsible for the initiation of the socalled renal compensation of DKA.
Concluding remarks The interaction of multiple factors during the development of
and recovery from DKA is responsible for the wide variation in the acid-base and electrolyte pattern encountered in this disor-
der. Most prominent among these factors are: the primary derangements in the electrolyte composition as a result of the acute acid-base stress, the regulatory defense mechanisms of renal and extra-renal origin, and the therapeutic interventions. As a consequence, although theoretically DKA is a typical AG acidosis, careful evaluation of the laboratory data in individual patients presenting with this disorder demonstrates a complete spectrum of values that ranges from pure AG acidosis to pure hyperchloremic acidosis. A number of the mechanisms that may alter the relationship between the excess plasma AG and plasma bicarbonate deficit in these patients have been outlined. However, it appears that only some of them play a major role as determinants of the serum electrolyte pattern. Differences in the supply of water and electrolytes during the development of DKA, by virtue of their effects on renal function, seem to be among the most prominent factors that modulate the ECF level of plasma ketones. The more severe the volume depletion, the greater is the degree of impairment of the renal function and
597
Diabetic ketoacidosis
retention of ketones, and the less prominent the component of hyperchloremic acidosis, The development of hyperchloremic
acidosis in the course of DKA appears to be the result of
16. FENSELAU A: Ketone body metabolism in normal and diabetic man, in Handbook of Diabetes Mellitus, edited by BROWNLEE M, New York, Garland STPM, 1981, vol 3, pp 143—208 WA, RAPOPORT 5, WEST CD: The mechanism of glycos-
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chloride retention in excess of sodium associated with significant urinary losses of ketone salts of sodium and potassium. Reevaluation of the role of the kidney in the development of and recovery from DKA indicates that maximal stimulation of renal acidification may not suffice to compensate for the massive urinary loss of bicarbonate precursors in the form of ketone salts other than ammonium. Therefore, the end result may be a nonhemostatic role for the kidney in the defense of the acidbase equilibrium in the early phase of DKA.
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