Download Hyperpnoea and ketonuria in an HIV-infected

Nephrol Dial Transplant (2007) 22: 649–651
doi:10.1093/ndt/gfl671
Advance Access publication 22 November 2006
Nephroquiz
(Section Editor: M. G. Zeier)
Hyperpnoea and ketonuria in an HIV-infected patient
Quiz
A 32-year-old HIV-infected man of African origin
presented to our emergency department with a 3-day
history of nausea, vomiting, abdominal pain and
muscular pain. The patient was alert and oriented.
He denied alcohol, tobacco and illicit drug use. His
current medications were lopinavir, Epivir, stavudine
and trimethoprim-sulfamethoxazole.
In the emergency room, he was afebrile; blood
pressure 110/70 mmHg and pulse rate was at 110/min.
Kussmaul breathing at a frequency of 32 breaths/min
was noted. The patient’s pulse oximetry revealed a
saturation of 99% on room air, and capillary blood
sugar was 150 mg/dl. Electrocardiogram showed normal
sinus rhythm. The patient had lost 5 kg in weight
during the previous 3 months. The abdominal, lung,
cardiovascular, neurological examinations were all
unremarkable. Laboratory investigations on admission
revealed the following abnormalities: pH: 7.49; PaCO2:
18 mmHg; PaO2: 123 mmHg; bicarbonates: 10 mmol/l;
potassium: 3.7 mmol/l; calcium: 2.1 mmol/l; sodium:
125 mmol/l; lactates: 8 mmol/l (normal value
<2.0 mmol/l); glucose: 2.4 mmol/l; CK: 3195 UI/ml
(controls <220 UI/l); ASAT: 59 UI/l (normal
range 5–35 UI/l) and ALAT: 35 UI/l (normal range
5–40 UI/l). Other pertinent labs were blood urea of
33 mg/dl and creatinine of 1.3 mg/dl. HbA1c was
normal. Urinary dipstick analysis was unremarkable,
except for an important ketonuria (4þ) without
glycosuria.
The patient received intravenous glucose and
L-Carnitine. Highly active anti-retroviral therapy
(HAART) was discontinued. The metabolic abnormalities gradually normalized over the following 2 days.
However, the patient’s lactate level remained elevated
at 2–3 mmol/l.
Questions
What is your diagnosis?
Correspondence and offprint requests to: Dr Hassane Izzedine,
Department of Nephrology, La Pitié-Salpêtrière Hospital, 47-80
Bonlevard de I’Hôpital, Assistance Publique-Hopitaux de Paris,
Pierre et Marie Curie University, 75013 Paris, France.
Email: [email protected]
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650
Answer to the quiz on the preceding page
In this case, arterial blood gases showed severe alkalosis
with decreased serum bicarbonate level and elevated
lactic acid level. This data suggested three possibilities:
primary respiratory alkalosis with compensatory
decrease of bicarbonate and elevated lactates, primary
lactic acidosis with compensatory decrease in respiratory CO2 tension, and mixed disorder involving
respiratory alkalosis and metabolic acidosis.
First hypothesis: primary respiratory alkalosis
with compensatory decrease of bicarbonate and
elevated lactates
At any given moment, the extracellular pH may be
predicted on the basis of the Henderson–Hasselbach
formula: pH ¼ pKa þ log (bicarbonate/CO2). The buffering response to acute hypocapnia is biphasic. First,
hypocapnia in the extracellular fluid results in an
immediate decrease in the intracellular fluid CO2
concentration, resulting in the transfer of chloride
ions from the intracellular fluid to the extracellular
fluid compartment. This chloride ion efflux, accompanied by a decrease in the concentrations of
bicarbonate ions in extracellular fluid, is called tissue
buffering [1]. Secondly, the renal response (inhibition
of renal tubular reabsorption of bicarbonate) can begin
within minutes and takes effect over a period of hours
to days [1]. With long-term exposure, in the presence of
normal renal function, the bicarbonate-ion level begins
to fall, and the pH decreases but does not reach the
normal value of 7.40 with an increase in arterial blood
pH of 0.1–0.3 units.
Hypocapnia may increase the metabolic demand
of tissue through cellular excitation or contraction.
Finally, alkalosis—especially respiratory alkalosis—
inhibits the usual negative feedback by which a low pH
limits the production of endogenous organic acids such
as lactate [2,3]. Alkalosis raises blood lactate concentration by a pH-mediated effect on the enzyme phosfructokinase, which converts fructose-6-phosphate
to fructose-1,6-bisphophate, an intermediary in the
glycolytic pathway [4]. In vivo, this rise is usually mild,
with lactate levels usually around 1.5 to 3 mEq/l [5,6].
Therefore, alkalaemia explains only partially the
significant serum lactate elevation in our patient.
Furthermore, elevated lactate level persisted, despite
arterial blood gases normalization. Hyperventilation
results from increased afferent drives from the chemical receptors in the lung or arterial walls. In our case,
however, evidence of pneumonia, pulmonary oedema
or heart chamber enlargement was not seen on chest
X-ray nor electrocardiogram. Furthermore, there was
no apparent dyspnoea and the arterial oxygen tension
was normal. Cerebral MRI was also normal. The
patient had not received any respiratory-stimulating
drugs, and the abnormal respiration rate persisted
during sleep. On the other hand, the hypothalamus is
considered a metabolic centre, and it controls ketone
metabolism [7]. This may explain high ketonuria in our
C. Baudron-Roubaud et al.
patient. However, there was no hypothalamus lesion
on CT scan in our patient.
In conclusion: primary respiratory alkalosis per se
does not explain all abnormalities.
Second hypothesis: primary lactic acid acidosis
(complicating NRTIs therapy) with compensatory
decrease in respiratory CO2 tension
Nucleoside reverse transcriptase inhibitors (NRTIs) in
use some months earlier and persistently elevated lactate
levels despite correction of acid–base abnormalities,
were arguments in favour of this hypothesis. Indeed,
this was confirmed by the improvement of clinical
condition following withdrawal of anti-retroviral drugs
and administration of L-Carnitine [8]. The reported
incidence rate of lactic acidosis, an uncommon
but serious complication of anti-retroviral therapy,
vary from 1.3 to 10/1000 person-years on HAART
[9,10]. Carnitine is derived from g-hydroxy-b-butyric
acid. Although a regular diet is the primary supply
of carnitine, endogenous synthesis is possible
from sulphated amino acids [11]. Carnitine levels are
decreased in HIV-infected patients through several
mechanisms, including malabsorption, increased
excretion, over-consumption of energy in fatty acids
metabolism and the use of drugs, including NRTIs
[11,12]. Carnitine is an important compound for the
mitochondria bio-energetic system that may modulate
apoptosis. It has also been observed that carnitine
could reverse the mitochondrial toxicity of NRTIs
in vitro and in vivo [11–14]. Finally, a nomograph of
acid–base equilibrium showed that the actual PaCO2
level was extremely low, below the standard deviation
of the estimate of PaCO2 at the given bicarbonate level
(18 instead to 23 mmHg) [15]. This means that the
decrease in PaCO2 was not due only to respiratory
compensation for metabolic acidosis.
In conclusion: lactic acidosis can explain most of the
presenting features. However, the blood alkalosis with
the associated important decrease in CO2 remains
unexplained.
Third hypothesis: the acid–base disturbances in
this case represent a mixed disorder of metabolic
acidosis and respiratory alkalosis
Krendel et al. [16] suggested that local cerebrospinal
fluid (CSF) acidification resulted in an increase in
hydrogen ions and stimulated chemosensitive respiratory neurons inducing respiratory alkalosis. Although
we did not measure the CSF lactate level, we supported
the CSF lactic acidosis theory, as there were no classic
causes for respiratory alkalosis found in our patient
(see subsequently). CSF lactic acidosis may explain
medullary chemoreceptor stimulation and cause the
associated hyperventilation and CO2 wash.
In conclusion: metabolic lactic acidosis is induced by
NRTIs and a mixed respiratory alkalosis is related to
compensatory decrease in respiratory CO2 tension and
CSF lactic acidosis in our patient.
Hyperpnoea and ketonuria in HIV patient
651
Conflict of interest statement. None declared.
References
1. Adrogue HJ, Madias NE. Management of life-threatening acid–
base disorders. N Engl J Med 1998; 338: 107–111
2. Hood VL, Tannen RL. Protection of acid–base balance by pH
regulation of acid production. N Engl J Med 1998; 339: 819–826
3. Madias NE, Cohen JJ, Adrogue HJ. Influence of acute and
chronic respiratory alkalosis on preexisting chronic metabolic
alkalosis. Am J Physiol 1990; 258: F479–F485
4. Ui M. A role of phosfructokinase in pH-dependent regulation of
glycolysis. Biochim Biophys Acta 1966; 124: 310–322
5. Madias NE, Ayus JC, Adrogue HJ. Increased anion gap in
metabolic alkalosis: the role of plasma-protein equivalency.
N Engl J Med 1979; 300: 1421–1423
6. Arbus GS, Hebert LA, Levesque PR, Etsten BE, Schwartz WB.
Characterization and clinical application of the ‘significance band’
for acute respiratory alkalosis. N Engl J Med 1969; 280: 117–123
7. Suzuki M, Kawakatsu T, Kamoshita S, Kawaguchi H,
Suzuki Y. A case of pontine tumor associated with repeated
episodes of hyperventilation and ketosis. Clin Neurol 1964; 4:
54–59
8. Ilias I, Manoli I, Blackman MR, Gold PW, Alesci S. L-Carnitine
and acetyl-L-carnitine in the treatment of complications
associated with HIV infection and antiretroviral therapy.
Mitochondrion 2004; 4: 163–168
9. Fortgang IS, Belitsos PC, Chaisson RE et al. Hepatomegaly and
steatosis in HIV-infected patients receiving nucleoside analog
antiretroviral therapy. Am J Gastroent 1995; 90: 1433–1436
10. John M, Moore CB, James IR et al. Chronic hyperlactatemia in
HIV-infected patients taking antiretroviral therapy. AIDS 2001;
15: 717–723
11. Famularo G, Matricardi F, Nucera E, Santini G, De Simone C.
Carnitine deficiency: primary and secondary syndromes.
12.
13.
14.
15.
16.
In: De Simone C, Famularo G, eds. Carnitine Today. Landes
Bioscience, Heidelberg: 1997; 119–161
De Simone C, Tzantzoglou S, Jirillo E, Marzo A, Vullo V,
Arrigoni Martelli E. L-carnitine deficiency in AIDS patients.
AIDS 1992; 6: 203–205
Loignon M, Toma E. L-carnitine for the treatment of highly
active antiretroviral therapy-related hypertriglyceridemia in
HIV-infected adults. AIDS 2001; 15: 1194–1195
Brinkman K, Vrouenraets S, Kauffmann R, Weigel H, Frissen J.
Treatment of nucleoside reverse transcriptase inhibitor induced
lactic acidosis. AIDS 2000; 14: 2801–2802
Albert MS, Dell RB, Winters RW. Quantitative displacement of
acid-base equilibrium in metabolic acidosis. Ann Int Med 1966;
66: 312–322
Krendel DA, Pilch JF, Stahl RL. Central hyperventilation in
primary CNS lymphoma: evidence implicating CSF lactic acid.
Neurology 1991; 41: 1156–1157
C. Roubaud-Baudron1
Edward Bourry1
Valerie Martinez2
Ana Canestri2
Gilbert Deray1
Hassane Izzedine1
1
Department of Nephrology
2
Department of Infectious Diseases
Pitie-Salpetriere Hospital
Paris
France
Received for publication: 9.10.06
Accepted in revised form: 17.10.06