Metabolic Acidosis in AIDS Patients
Elizabeth F. Dahera, 
, 
, Lia C. Cezara, Geraldo B. Silva Juniora, , Rafael S. Limaa, Lisandra S. Damascenob, Ericka B. Lopesa, Fernanda R. Nunesa, Rosa S. Motac and Alexandre B. Libórioa
aDepartment of Internal Medicine, Division of Nephrology, Faculdade de Medicina, Hospital Universitário Walter Cantídio, Universidade Federal do Ceará, Fortaleza, Ceará, Brazil
bHospital Sáo José de Doenças Infecciosas, Fortaleza, Ceará, Brazil
cDepartment of Statistics, Universidade Federal do Ceará, Fortaleza, Ceará, Brazil
Received 3 August 2008;
Background and Aims
Metabolic acidosis (MA) is a frequent and serious complication in HIV-infected patients. The aim of the study is to compare patients with and without MA associated with HIV.
Methods
Patients were retrospectively studied involving all HIV-infected patients with blood gas analysis performed during hospital stay admitted to a single hospital between April 2004 and July 2006. Statistical analysis was performed using SPSS 10.0 for Windows.
Results
Included in the study were 159 HIV patients, 72 cases (45.3%) with MA and 87 cases (54.7%) without. The comparison of both groups showed a mean arterial pH of 7.24 ± 0.08 vs. 7.44 ± 0.05, HCO3 12 ± 5.7 vs. 21 ± 5.1 mEq/L, serum urea 81 ± 68 mg/dL vs. 39 ± 46 mg/dL and serum creatinine 2.7 ± 2.6 mg/dL vs. 1.2 ± 1.9 mg/dL in MA-HIV and non-MA-HIV, respectively (p <0.05).>p = 0.57). There was no association between the use of ART and MA. Mortality was higher in patients with acidosis (52.7 vs. 17.2%, p <0.0001).
Conclusions
In the present study, MA was associated with acute kidney injury and increased mortality. There was no association between the use of ART and MA.
Key Words: Metabolic acidosis; HIV; AIDS; Renal dysfunction; Antiretroviral therapy
Article Outline
Introduction
Metabolic acidosis (MA) has been described in human immunodeficiency virus (HIV) patients and is associated with antiretroviral therapy (ART). The majority of cases reported in the medical literature are due to lactic acidosis (LA) secondary to ART. There are several studies to investigate which factors are associated with LA in HIV-infected patients (1) and (2), but few studies investigated the factors associated with MA in general and its prognostic implication.In the last few years, ART has shown a dramatic improvement in the prognosis of HIV disease. As a result, other medical problems are assuming increasing relevance in the follow-up of HIV-infected patients (3). Among these medical problems are metabolic disturbances such as dyslipidemias, lipodystrophy, glucose intolerance and increased lactic acid, generally caused by ART drugs (3) and (4). Nucleoside reverse transcriptase inhibitors (NRTIs) induce mitochondrial toxicity by inhibiting polymerase, which lead to mitochondrial DNA depletion and respiratory chain dysfunction. Accumulation of lactate in the cytoplasm results in severe MA (5), (6), (7), (8), (9) and (10). The prevalence of hyperlactatemia in outpatients on ART is 
9–16% (11) and (12). Among untreated patients, prevalence is 2% (13). It is important to consider mitochondrial abnormalities due to ART in the differential diagnosis of MA in HIV-infected patients (14). However, other causes of MA must be considered in this population, especially in hospitalized patients.
Some studies show a prevalence of MA at 20% in HIV (2). There are multiple factors that could lead to MA in HIV including opportunistic infections, comorbidities such as diabetes, hepatitis, renal diseases, alcoholism and ART.
The aim of this study is to describe the clinical and laboratory features of HIV-associated MA, identifying its risk factors and prognostic implications.
Materials and Methods
The study was conducted at the Hospital São José de Doenças Infecciosas in Fortaleza in the northeastern region of Brazil. Clinical files of all HIV patients admitted from April 2004 to July 2006 were reviewed, and patients with blood gas analyses performed during their hospital stay were included.
Clinical and laboratory data at admission and during the hospital stay were analyzed. Clinical data evaluated were gender, age, signs and symptoms presented at admission, comorbidities, drugs and duration of ART and length of hospital stay. Laboratory data evaluated were hemoglobin, hematocrit, white blood count, lymphocytes, platelets, serum sodium, potassium, lactate dehydrogenase levels (LDH), alkaline phosphatase, aspartate amino transaminase, alanine amino transaminase, CD4 and viral loading and blood gas analysis. Renal function was analyzed by serum urea and creatinine and acute kidney injury (AKI) was classified according to RIFLE (risk, injury, failure, loss, and end stage renal disease) criteria (15).
MA was defined as arterial pH <7.35>
The study was approved by the Ethical Committee of the Institution.
Statistical Analysis
Statistical analysis of clinical and laboratory data was performed using SPSS v. 10.0 (SPSS Inc., Chicago, IL) and Epi Info, 6.04b, 2001 (Centers for Disease Control and Prevention, Atlanta, GA). Between-group comparison were done using Student's t-test, Mann-Whitney test and Fisher's exact test. Results were expressed using tables and summary measures (mean ± SD) in the cases of quantitative variables. A logistic regression model was used for quantitative variables. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. The factors included in the multivariate model were those that showed a significance level <20%>2 test); values of p <0.05>
Results
Included in the study were 159 HIV patients with a mean age of 36 ± 10 years. There were 110 (69.1%) male patients. MA was found in 72 cases (45.2%). No difference in age or gender was observed between MA and non-MA groups. Hospital stay was longer among patients without MA (p <0.0001).>Pneumocystis jiroveci pneumonia (6.9%), neurotoxoplasmosis (6.9%), bacterial pneumonia (5.0%), and others (gastrointestinal infections, visceral leishmaniasis, herpes zoster, varicella, candidiasis). There was no association of any particular disease with mortality. Clinical characteristics of patients with and without MA are summarized in Table 1.
Clinical characteristics of HIV patients with and without MA
| MA-HIV (n = 72) | Non-MA-HIV (n = 87) | p | |
|---|---|---|---|
| Age (years) | 37 ± 8.4 | 36 ± 12 | 0.21 |
| Gender | |||
| Male, n (%) | 49 (68.1%) | 61 (70.1%) | |
| Female, n (%) | 23 (31.9%) | 26 (29.9%) | 0.86 |
| Length of hospital stay (days) | 18 ± 16 | 24 ± 22 | <0.0001 |
| Signs/symptoms | |||
| Fever | 49 (68.1%) | 55 (63.2%) | 0.61 |
| Chills | 9 (12.5%) | 16 (18.4%) | 0.38 |
| Cough | 35 (48.6%) | 53 (60.9%) | 0.14 |
| Dyspnea | 27(37.5%) | 27 (31%) | 0.40 |
| Diarrhea | 47 (65.3%) | 44 (50.6%) | 0.07 |
| Vomiting | 38 (52.8%) | 29 (33.3%) | 0.01 |
| Weight loss | 25 (34.7%) | 40 (46%) | 0.19 |
| Oliguria | 2 (2.8%) | 3 (3.4%) | 1.0 |
| Convulsions | 3 (4.2%) | 3 (3.4%) | 1.0 |
| Headache | 13 (18.1%) | 13 (14.9%) | 0.66 |
| Thoracic pain | 3 (4.2%) | 10 (11.5%) | 0.14 |
| Abdominal pain | 20 (27.8%) | 14 (16.3%) | 0.08 |
| ART use | 38 (52.8%) | 45 (51.7%) | 1.0 |
| ART administration | |||
| <1> | 12 (30.8%) | 6 (40%) | |
| 1–5 years | 20 (51.3%) | 8 (53.3%) | |
| >5 years | 7 (17.9%) | 1 (6.7%) | 0.52 |
| ART use (years) | 2.6 ± 1.1 | 2.7 ± 1.2 | 0.25 |
| Death | 38 (52.7%) | 15 (17.2%) | <0.0001 |
MA, metabolic acidosis; MA-HIV, HIV patients with MA; non-MA-HIV, HIV patients without MA; ART, antiretroviral therapy.
Fisher's exact test and Student's t-test. Values expressed as mean ± SD and %.
p <0.05>
Serum urea and creatinine were significantly higher in MA-HIV than in non-MA-HIV groups (p <0.05).>p = 0.09). Viral load was significantly higher in MA-HIV than non-MA-HIV group (p = 0.02). A comparison of laboratory data is shown in Table 2.
Laboratory data in HIV patients with and without MA
| MA-HIV (n = 72) | Non-MA-HIV (n = 87) | p | |
|---|---|---|---|
| Arterial pH | 7.24 ± 0.08 | 7.44 ± 0.05 | <0.001 |
| pCO2 (mm Hg) | 28 ± 15 | 31 ± 7.8 | 0.007 |
| HCO3 (mEq/L) | 12 ± 5.7 | 21 ± 5.1 | <0.001 |
| pO2 (mm Hg) | 111 ± 51 | 93 ± 42 | 0.02 |
| O2 saturation (%) | 93 ± 7.2 | 95 ± 6.8 | 0.16 |
| Base excess (mEq/L) | −13 ± 5.4 | −1.5 ± 4.7 | <0.001 |
| Serum sodium (mEq/L) | 133 ± 8.9 | 130 ± 6.1 | 0.03 |
| Serum potassium (mEq/L) | 3.8 ± 1.1 | 3.7 ± 0.7 | 0.67 |
| Hemoglobin (g/dL) | 10 ± 2.5 | 9.9 ± 2.7 | 0.35 |
| Hematocrit (%) | 30 ± 7.3 | 28 ± 8.7 | 0.16 |
| White blood count (mm3) | 7140 ± 5407 | 5478 ± 3279 | 0.15 |
| Lymphocytes (mm3) | 1165 ± 140 | 566 ± 132 | <0.0001 |
| Platelets (×103/mm3) | 172 ± 129 | 204 ± 128 | 0.10 |
| LDH (U/L) | 614 ± 709 | 881 ± 1381 | 0.45 |
| Urea (mg/dL) | 81 ± 68 | 38 ± 45 | <0.0001 |
| Creatinine (mg/dL) | 2.7 ± 2.6 | 1.2 ± 1.9 | <0.0001 |
| AP (U/L) | 281 ± 354 | 377 ± 292 | 0.40 |
| AST (IU/L) | 162 ± 171 | 132 ± 263 | 0.16 |
| ALT (IU/L) | 106 ± 165 | 107 ± 318 | 0.21 |
| CD4 (cells/mm3) | 228 ± 239 | 185 ± 283 | 0.09 |
| Viral loading (copies/mm3) | 147,313 ± 32,106 | 60,651 ± 39,107 | 0.02 |
MA-HIV, HIV patients with MA; non-MA-HIV, HIV patients without MA; AP, alkaline phosphatase; AST, aspartate amino transaminase; ALT, alanine amino transaminase; LDH, lactate dehydrogenase.
Fisher exact test, Student t-test and Mann-Whitney test. Values expressed as mean ± SD. Significant at p <0.05.
ART was administered in 83 patients (52.2%), 38 in MA-HIV and 45 in non-MA-HIV (p = 0.57). The mean time of ART use was 2.7 ± 1.2 years. There was no difference in the mean time of ART between MA-HIV and non-MA-HIV groups (p = 0.25; Table 1). There was no association between the use of ART and MA.
AKI was found in 53 patients (33.3%). The majority of patients with AKI had MA (66%). Patients were classified according to Risk (26.5%), Injury (24.5%) and Failure (49%) according to RIFLE classification. Failure was significantly high in MA-HIV group (p <0.0001) name="btbl3">Table 3). Death occurred in 53 cases (33.3%). Mortality was higher in patients with MA (52.7% vs. 17.2%, p <0.0001).
Classification of HIV patients with and without MA-associated AKI according to RIFLE
| MA-HIV (n = 35) | Non-MA-HIV (n = 18) | p | |
|---|---|---|---|
| “Risk”, n = 14 (26.5%) | 8 (57.1%) | 6 (42.9%) | 0.44 |
| “Injury”, n = 13 (24.5%) | 7 (53.8%) | 6 (46.2%) | 0.69 |
| “Failure”, n = 26 (49%) | 20 (76.9%) | 6 (23.1%) | 0.0001 |
AKI, acute kidney injury.
MA-HIV, HIV patients with MA; non-MA-HIV, HIV patients without MA;
Fischer exact test. Significant at p <0.05.
Univariate logistic regression showed that the predictors for death were high serum level of potassium and urea and low level of bicarbonate and platelets. These data are shown in Table 4. Multivariate regression model was built with the variables that showed a significance level <20%>3, hyperkalemia, hemoglobin level, platelet count and urea at admission). The independent risk factors for death were MA, hyperkalemia and low CD4 count (Table 5).
Risk factors for death in patients in HIV with and without MA by univariate logistic regression
| OR | 95% CI | p | |
|---|---|---|---|
| HCO3− | 0.95 | 0.903–0.999 | 0.046 |
| High urea | 1.008 | 1.002–1.015 | 0.013 |
| Platelets | 0.999 | 0.998–0.999 | <0.001 |
| Hyperkalemia | 1.54 | 1.025–2.321 | 0.038 |
| CD4 level | 0.998 | 0.996–1.001 | 0.208 |
OR, odds ratio; CI, confidence interval.
Discussion
In our data we identified that MA in HIV-infected patients is prevalent in patients with AKI, especially in those with its severe form (failure in RIFLE classification). Moreover, it was independently associated with a higher mortality in HIV hospitalized patients.
Clinical manifestations related to MA are nonspecific, such as gastrointestinal symptoms present in >50% of cases (16). Dyspnea and tachypnea classically associated with MA are seen in 41% of cases in the same review (16). In the present study, the most frequent clinical manifestations found in patients with MA were diarrhea, vomiting, weight loss and dyspnea. The only manifestation that was statistically different between the two groups was vomiting, although it was classically associated with metabolic alkalosis. This symptom can be more a consequence of acidosis than its etiology.
Several studies showed an association between MA and the use of ART, mainly the NRTIs (3), (17), (18), (19), (20), (21), (22), (23), (24), (25) and (26). In the present study we were unable to determine any relationship between any ART drug and MA. In a population study, this suggests LA is not as frequent as other causes of MA. Otherwise, renal dysfunction was more frequent in patients with acidosis, especially in its severe form, suggesting this is greatly responsible for MA in this population causing MA directly due non-measurable anion accumulation or through higher serum levels of ART drugs. Lactate levels were unavailable because lactase measurement was not performed by the hospital where the study was performed. In the absence of lactate monitoring, periodic aminotransferase measurements are recommended (27) and (28).
RIFLE classification is an improvement in predicting outcome of patients with AKI (29) and (30). AKI classified as “failure” was significantly high in MA-HIV group. This finding strongly supports the hypothesis that MA is mainly due to renal dysfunction. Because the number of patients in each group according to RIFLE criteria is small, association with mortality may be significant if the sample was larger.
In our study, average hospital stay was higher among patients without MA. These data corroborate with severe clinical conditions of those patients with MA-HIV. Therefore, mortality was higher in patients with MA (52%). Our study is similar to previous reviews that have reported fatality ratio associated with LA in 33–60% (16), (26) and (31).
Independent risk factors for death were MA, hyperkalemia and low CD4. There are few studies to investigate the factors associated with mortality in HIV patients. Peak venous lactate level was the best predictor of mortality in HIV patients. Zidovudine is associated with higher lactate levels and higher mortality than stavudine and lamivudine (32). The presence of hypokalemia, MA, and renal failure are significantly associated with mortality in AIDS (2).
This study has some limitations: 1) it is a retrospective study, being difficult to define a cause-effect relationship; 2) we do not have chloride values to perform anion gap analyses; 3) lactate levels were not measured, making it impossible to evaluate the exact importance of its accumulation in MA.
In summary, MA is an important complication observed in HIV patients, which per se increases mortality. It was not directly associated with ART in the present study, although the lack of association is possible due to its low incidence compared with other causes of MA. There was a significant association between MA and AKI. It is possible that renal dysfunction plays an important role in the pathogenesis of HIV-associated MA. It is important to search for the occurrence of MA in all hospitalized HIV patients, investigate its causes and promptly correct it. Further studies, including a randomized controlled trial, are required to better establish the etiology of MA in HIV.
Acknowledgments
We are very grateful to the team of physicians, residents, medical students and nurses of the Hospital São José de Doenças Infecciosas for the assistance provided to the patients. This research was financially supported by the Brazilian Research Council (Conselho Nacional de Desenvolvimento Científico e Tecnológico-CNPq, Brazil).
References
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