Nephrol Dial Transplant (1996) 11: 1653-1655
Continuing Nephrological Education (CNE)
Nephrology
Dialysis
Transplantation
An acid-base conundrum for a rainy afternoon
F. C. Luft
Franz Volhard Clinic at the Max Delbruck Center for Molecular Medicine, Virchow Klinikum, Humboldt University of
Berlin
Introduction
Acid-base and fluid and electrolyte disturbances are
the particular purview of nephrologists, since these
derangements intimately involve the kidney. Moreover,
it is the nephrologist's obligation to teach this area of
clinical medicine to students and physicians entering
other fields of medicine. Although the body is resilient
and the philosophy of 'letting the kidneys figure it out
for themselves' is frequently successful, fatal outcomes
regularly occur. This fact should weigh heavily on our
consciences. The acid truth and basic facts with a sweet
touch of enlightenment are best learned by students
and teachers alike from the booklet with the same
name by Halperin [1].
The macroscopicfindingsat autopsy did not disclose
the cause of death. The microscopic findings on the
other hand solved the puzzle. The renal tubules were
filled with crystalline structures that were strongly
birefringent. The leptomininges showed diffuse
inflammatory infiltration. The blood vessel walls in
this area were filled with the same crystals as were
present in the kidneys. A sample of urine was then
analysed by means of gas chromatography and
revealed an ethylene glycol concentration of 1740 mg/1.
A search of the patient's home after his death revealed
several containers of antifreeze.
Comment
The high H + , (low pH) and low HCO3 in plasma
established the presence of metabolic acidosis in this
patient. The expected physiological response would
Case report
be a lowered pCO2 to minimize the fall in pH.
A 63-year-old man with a history of suicidal depression Quantitatively, the fall
in pCO from 40 mmHg should
was found stuporous on the floor of his garage. The equal the fall in plasma HCO23 from 25 mmol/1. The
patient failed to respond to verbal commands, could respiratory compensation exhibited by this patient
not speak coherently, but reacted defensively to painful resulted in a decrease of the pCO2 to 19 mmHg, about
stimuli. The blood pressure was 205/100 mmHg, the as well as a man of 63 years can accomplish, and
heart rate was 120 beats per minute, and no abnormal represents a doubling of the alveolar ventilation
findings were elicited on physical examination. An (Kussmaul's respiration). The kidneys in metabolic
arterial blood sample revealed the pH to be 6.83, the acidosis would be expected to excrete NH 4 to make
PO2 was 120 mmHg, and the PCO2 was 19 mmHg. new HCO3. Normally the NH4 excretion is about
The standard HCO3 was 3 mmol/1. The plasma lactate 40 mmol/day,
which can be increased to 300 mmol/day.
level was 4 mmol/1, while the negative base excess (base
There are two major categories of metabolic acidosis,
deficit) was 31 mmol/1. The serum creatinine concen- gain of acid and loss or failure to generate HCO3.
tration was 3.1 mg/dl. The urinalysis showed trace These two categories represent three mechanisms:
protein and numerous red cells. Blood and urine were (1) net acid gain (endogenous overproduction or exoscreened for various toxins; however, the results were genous administration of acids); (2) net alkali loss
negative. Despite 200 mmol HCO3 as 50 mmol intra- (gastrointestinal or renal loss); (3) failure of the kidney
venous bolus injections followed by a HCO3 infusion, to excrete acids normally produced and to thereby
the acidosis did not improve and the reasons for the generate HCO3 (renal insufficiency and distal forms of
condition remained unclear. After 24 h, the serum renal tubular acidosis). Acid gain is recognized by
creatinine concentration increased to 5.5 mg/dl and finding a wide plasma anion gap (AG). A masterful
nephrological consultation was obtained. As prepara- and scholarly paper on the subject was published by
tions were being made for acute haemodialysis, the Oh and Carrol [2]. The AG ([Na]-[C1]-[HCO 3 ] =
patient suffered cardiac arrest and could not be 12 + 2 mmol/1) establishes the presence of acid gain.
resuscitated.
There are very few clinically relevant exceptions.
Admittedly, administration of NH4C1, HC1, or
Cl-containing amino acids such as arginine in hyperaliCorrespondence and offprint requests to: Friedrich C. Luft MD, Franzmentation fluids could represent acid gain with Cl
Volhard Clinic, Wiltberg Strasse 50, 13122 Berlin, Germany.
© 1996 European Dialysis and Transplant Association-European Renal Association
1654
F. C. Luft
anions. In quantitative terms, the rise in plasma AG (called a negative urine net charge). Urines containing
should equal the fall in the plasma HCO3. The major little NH4 will have more Na + K than Cl (urine net
acids are: (1) L-lactic acid (tissue hypoxia); charge is positive). Thus, Urine NH4 = Urine
(2) ketoacids (insulin deficiency); (3) D-lactic acid ( C l - N a - K ) + 80; When Cl = (Na + K), NH4 =
(blind loops); (4) intoxications which are or become 80 mmol/1. The urine osmolal gap: if NH4 is excreted
acids (methanol to formic acid, ethylene glycol to with an anion other than Cl, the concentration of
glyoxylic acid, paraldehyde to acetic acid, acetosalicylic NH4 can still be deduced as follows: Urine NH4 =
acid, toluene to hippuric acid); (5) accumulation of (measured—calculated UOsm/2, where calculated
endogenous acids due to renal failure. In severe renal U0sm=2(Na + K) + glucose + urea (all in mmol/1).
in confirming a low
failure the clinical presentation is frequently a wide The urine PCO2 can be helpful
+
AG metabolic acidosis; however, an acid load is not rate of distal nephron H secretion in patients susthe major problem. Instead, failure of the kidney to pected of having distal renal tubular acidosis. The
patients must first be alkalinized to a urine pH ^ 7. A
make new HCO3 is the cause of the acidosis.
PCO2 < 55 mmHg indicates defective H +
urine
The three endogenous causes of increased AG,
namely lactic acid, ketoacids, severely decreased renal secretion.
function, can be diagnosed in minutes with standard
laboratory tests. Salicylate intoxication rarely causes
severe metabolic acidosis except in small children. Conundrum
Tinnitus, light headedness, the presence of respiratory Clinicians usually prefer to bury their mistakes; howalkalosis complicating the metabolic acidosis, unex- ever, a pathologist eventually solved this enigma.
plained ketosis from activation of hepatic lipase, Through various coincidences, I had occasion to obtain
hypouricaemia, and an increased urine net charge from the medical record, which revealed conscientious but
salicylate excretion suggest the diagnosis, which is clueless young people concerned with 'balancing'
confirmed by detecting salicylate in the blood. The (German: ausgleicheri) the acidosis with copious infuosmolal gap in plasma is very helpful to recognize the sions of HCO3, rather than coming to the diagnosis
intoxicants methanol and ethylene glycol; it will also and proper treatment. Had the urine sediment (the
be elevated by ethanol. Plasma osmolal gap = measured urine contained 1740 mg/1 ethylene glycol) been
plasma osmolality —(2x [Na] +[glucose] + [urea]), all glanced at by a clinician, the characteristic envelopein mmol/1. Ifmg/1 are used, then [glucose/1.8] and shaped (dihydrate) or needle-like (monohydrate) crys[blood urea nitrogen/2.8]. A large discrepancy between tals would surely have been seen [3]. Had ethanol to
the measured and estimated plasma osmolality suggests block the formation of glyoxylic acid been given, and
the presence of something that should not really be had the patient been dialysed immediately, he might
there. Thus, metabolic acidosis from acid gain is easy have been saved. The method of thought failed here.
to work up. In the German language the name of The metabolic acidosis was not characterized with
Adolph Kussmaul, that notable clinician who first respect to acid gain—anion gap (AG versus non-AG)
observed respiratory compensation, makes a helpful metabolic acidosis. Thus, the clues provided by
mnemonic: Ketoazidose, Uramie, Salizylsaure, Kussmaul's name were not available. Although a
Methanol, Athylenglykol, Uramie (twice for begin- screen for toxins was ordered, there was no inference
ners), Laktat.
from the record that the clinicians had informed the
Loss of HCO3, metabolic acidosis with a normal laboratory of an AG acidosis or had discussed the
AG, can be caused by: (1) loss of NaHCO3 via the patient with a clinical pathologist or toxicologist. I
gastrointestinal tract; (2) loss of NaHCO3 in the urine; was able to find a serum Cl value in the chart indicat(3) failure of the kidney to make new HCO3; and ing that the patient's AG on admission exceeded
(4) acid production and excretion of the acid anion 30 mmol/1. I lay the fault here not on the shoulders of
without H + or NH4. The first is characterized by the managing physicians, who were neither better nor
> 80 mmol/day NH4 excretion with a net negative worse than physicians anywhere. Instead, the fault as
urine charge, the second by urine pH>6 unless the nephrologists is ours.
NaHCO 3 loss occurred previously (proximal renal
In the United States and in most European countries,
tubular acidosis), a net urine positive charge (distal a request for 'electrolytes' results in determination of
renal tubular acidosis), and a positive charge in the Na, K, Cl, and CO2 content. The CO2 content is
urine in the face of high urine NH 4 concentrations obtained by acidifying the serum sample, converting
(usually salicylate in the urine or the renal failure to all HCO3 present to CO2, and measuring the total.
reabsorb beta-hydroxybutyrate).
Since the relationship between HCO3/PCO2 x 0.03
To elucidate non-AG metabolic acidosis, the deter- from the Henderson-Hasselbalch equation is 20:1, the
mination of NH 4 in urine would be extremely helpful; error provided by accepting the CO2 content as the
however, this test is generally not supplied by clinical HCO3 concentration is 5% (close enough for govlaboratories. Acid-base aficionados have developed ernment work). HCO3 cannot be measured in bodily
clever ways around this problem. The urine net charge: fluids directly. An alternative, provided by modern
since NH 4 is a cation, NH 4 can be assumed to be blood gas analysers, is to calculate the HCO3 concenpresent if the sum of the major cations (Na + K) is tration with the pH and PCO2 values from the
less than the sum of the major anion (Cl) in urine Henderson-Hasselbalch equation. However, this step
An acid-base conundrum for a rainy afternoon
requires a separate blood sample. It also demands that
the acid-base disturbance is clinically obvious. Ask
your house staff about a patient's respiratory rate.
Most will stare at the floor and mumble 'unremarkable'; the rest will lie.
In Germany, 'electrolytes' are thought of as Na, K,
and Ca; the anions are generally ignored. The Cl
concentration is determined separately by autoanalysers and house staff physicians dutifully memorize the
normal range of values without having any idea that
without the HCO3 concentration, the Cl value is totally
useless. As opposed to the United States, the AG
receives short shrift in German medical education. In
German review articles, the topic is generally mentioned [4], but not emphasized [5]. However, the
problem lies more in the failure to routinely estimate
HCO3. If three simultaneously obtained blood samples
are necessary, one for 'electrolytes', one for chloride,
and still another for 'blood gases', the chances of
affecting this sorry situation positively are zero.
I once consulted a clinical pathologist (laboratory
physician) to ask where my total CO2 had gone. After
all, this method of estimating HCO3 was commonly
used in Germany back in the 1930s. He explained that
the corresponding autoanalyser channel was now used
to determine cholinesterase, apparently as requested
by some gastroenterologists who held this value to be
more important than the CO2 content. Thus, the
routine estimation of HCO3, and thereby a practical
method of estimating AG, disappeared from the
German landscape, to be substituted for by 'negative'
base excess and similar semantic non-sequiturs. In my
present hospital, I have unsuccessfully attempted to
resurrect the lowly CO2 content. Our clinical pathologist was unwilling to oust the cholinesterase and instead
offers a separate test called the AG (German: (AL
1655
or Anionenlucke) for my own personal amusement.
Unfortunately, this kindly gesture is only available
during working hours on weekdays, and I am the only
one who ever orders it.
I have broken countless lances against numerous
windmills; however, none irks me more than my failure
with the AG. If we can't manage the serum AG, then
our chances with osmolar gaps or the other numerous
helpful tips from Halperin [1] and others [2,6] have
no prospects. In my view, the nephrological community
should mount an effort to regard acid-base disturbances as being at least equal in importance to the
serum cholinesterase determination. My purpose with
these polemics is after all not to teach the nephrological
readership about acid-base disturbances. That goal
would be presumptuous and I know that many in the
readership are more knowledgeable in this area than I
am. Instead, my purpose is to plead a rethinking and
reworking of our teaching skills in this area. Let's
bring the CO2 content back and make sure the youngsters all calculate and work with the AG. Indeed,
they—and the patients—have earned no less!
References
1. Halperin ML. The Acid Truth And Basic Facts With A Sweet
Touch—An EnLYTEnment. LetroMac Design and Printing Inc.
Montreal, Canada, 1991
2. Oh, MS, Carroll HJ. The anion gap. N Engl J Med 1977;
297: 814-817
3. Jacobsen D, Hewlett TP, Webb R, Brown ST, Ordinario AT,
McMartin KE. Ethylene glycol intoxication: evaluation of kinetics
and crystalluria. Am J Med 1988; 84: 145-152
4. Heidbreder E, Heidland A. Diagnostik der Lactatacidose. Dtsch
Med Wochenschr 1987; 112: 726-728
5. Peer G, Graf H. Therapie der metabolischen Acidose. Dtsch Med
Wochenschr 1991; 116: 1116-1119
6. Narins RG. Diagnostic strategies in disorders of fluid, electrolyte,
and acid-base balance. Am J Med 1982; 72: 496-520