Metabolic Acidosis in AIDS Patients

Archives of Medical Research 40 (2009) 109e113

ORIGINAL ARTICLE

Metabolic Acidosis in AIDS Patients Elizabeth F. Daher,a Lia C. Cezar,a Geraldo B. Silva Junior,a Rafael S. Lima,a Lisandra S. Damasceno,b Ericka B. Lopes,a Fernanda R. Nunes,a Rosa S. Mota,c and Alexandre B. Libo´rioa a

Department of Internal Medicine, Division of Nephrology, Faculdade de Medicina, Hospital Universita´rio Walter Cantı´dio, Universidade Federal do Ceara´, Fortaleza, Ceara´, Brazil b Hospital Sa´o Jose´ de Doenc¸as Infecciosas, Fortaleza, Ceara´, Brazil c Department of Statistics, Universidade Federal do Ceara´, Fortaleza, Ceara´, Brazil Received for publication August 3, 2008; accepted November 14, 2008 (ARCMED-D-08-00347).

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). Antiretroviral therapy (ART) was being administered to 38 subjects (52.8%) in MA-HIV group and 45 (51.7%) in non-MA-HIV group ( p 5 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. Ó 2009 IMSS. Published by Elsevier Inc. Key Words: Metabolic acidosis, HIV, AIDS, Renal dysfunction, Antiretroviral therapy.

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 (1,2), 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

Address reprint requests to: Elizabeth de Francesco Daher, Rua Vicente Linhares, 1198, Fortaleza, CE, Brasil-CEP: 60135-270; E-mail addresses: [email protected] or [email protected]

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 (3,4). 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 (5e10). The prevalence of hyperlactatemia in outpatients on ART is |9e16% (11,12). 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

0188-4409/09 $esee front matter. Copyright Ó 2009 IMSS. Published by Elsevier Inc. doi: 10.1016/j.arcmed.2008.12.004

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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 S~ao Jose´ de Doenc¸as 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 and arterial bicarbonate !22 mEq/L. Patients with HIV MA (MA-HIV) and non-MA (non-MA-HIV) were analyzed. We compared these two groups in order to investigate the clinical manifestations, laboratory features and outcome. 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% in the univariate analysis (Mann-Whitney test and c2 test); values of p !0.05 were considered statistically significant. 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). The main cause of hospital admission was opportunistic infections including pulmonary tuberculosis (17.6%), disseminated histoplasmosis (10.0%), 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. Serum urea and creatinine were significantly higher in MA-HIV than in non-MA-HIV groups ( p !0.05). CD4 cell count was not significantly different between MAHIV and non-MA-HIV groups ( p 5 0.09). Viral load was significantly higher in MA-HIV than non-MA-HIV group ( p 5 0.02). A comparison of laboratory data is shown in Table 2. ART was administered in 83 patients (52.2%), 38 in MA-HIV and 45 in non-MA-HIV ( p 5 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 5 0.25; Table 1). There was no association between the use of ART and MA. Table 1. Clinical characteristics of HIV patients with and without MA MA-HIV (n 5 72) Non-MA-HIV (n 5 87) Age (years) Gender Male, n (%) Female, n (%) Length of hospital stay (days) Signs/symptoms Fever Chills Cough Dyspnea Diarrhea Vomiting Weight loss Oliguria Convulsions Headache Thoracic pain Abdominal pain ART use ART administration !1 year 1e5 years O5 years ART use (years) Death

37  8.4

36  12

49 (68.1%) 23 (31.9%) 18  16

61 (70.1%) 26 (29.9%) 24  22

49 (68.1%) 9 (12.5%) 35 (48.6%) 27(37.5%) 47 (65.3%) 38 (52.8%) 25 (34.7%) 2 (2.8%) 3 (4.2%) 13 (18.1%) 3 (4.2%) 20 (27.8%) 38 (52.8%)

55 16 53 27 44 29 40 3 3 13 10 14 45

12 (30.8%) 20 (51.3%) 7 (17.9%) 2.6  1.1 38 (52.7%)

6 (40%) 8 (53.3%) 1 (6.7%) 2.7  1.2 15 (17.2%)

(63.2%) (18.4%) (60.9%) (31%) (50.6%) (33.3%) (46%) (3.4%) (3.4%) (14.9%) (11.5%) (16.3%) (51.7%)

p 0.21

0.86 !0.0001

0.61 0.38 0.14 0.40 0.07 0.01 0.19 1.0 1.0 0.66 0.14 0.08 1.0

0.52 0.25 !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 was considered significant.

Metabolic Acidosis in AIDS Patients Table 2. Laboratory data in HIV patients with and without MA MA-HIV (n 5 72) Arterial pH 7.24 28 pCO2 (mm Hg) 12 HCO3 (mEq/L) 111 pO2 (mm Hg) 93 O2 saturation (%) Base excess (mEq/L) 13 Serum sodium (mEq/L) 133 Serum potassium 3.8 (mEq/L) Hemoglobin (g/dL) 10 Hematocrit (%) 30 7140 White blood count (mm3) 1165 Lymphocytes (mm3) 172 Platelets (103/mm3) LDH (U/L) 614 Urea (mg/dL) 81 Creatinine (mg/dL) 2.7 AP (U/L) 281 AST (IU/L) 162 ALT (IU/L) 106 228 CD4 (cells/mm3) 147,313 Viral loading (copies/mm3)

       

0.08 15 5.7 51 7.2 5.4 8.9 1.1

 2.5  7.3  5407          

Table 4. Risk factors for death in patients in HIV with and without MA by univariate logistic regression

Non-MA-HIV (n 5 87)

p

       

!0.001 0.007 !0.001 0.02 0.16 !0.001 0.03 0.67

7.44 31 21 93 95 1.5 130 3.7

0.05 7.8 5.1 42 6.8 4.7 6.1 0.7

9.9  2.7 28  8.7 5478  3279

140 566 129 204 709 881 68 38 2.6 1.2 354 377 171 132 165 107 239 185 32,106 60,651

         

0.35 0.16 0.15

132 !0.0001 128 0.10 1381 0.45 45 !0.0001 1.9 !0.0001 292 0.40 263 0.16 318 0.21 283 0.09 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.

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) (Table 3). Death occurred in 53 cases (33.3%). Mortality was higher in patients with MA (52.7% vs. 17.2%, p !0.0001). 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% in the univariate analysis (ART use, CD4 count, pH, HCO3, hyperkalemia, hemoglobin level, platelet count and urea Table 3. Classification of HIV patients with and without MAassociated AKI according to RIFLE

‘‘Risk’’, n 5 14 (26.5%) ‘‘Injury’’, n 5 13 (24.5%) ‘‘Failure’’, n 5 26 (49%)

111

MA-HIV (n 5 35)

Non-MA-HIV (n 5 18)

p

8 (57.1%) 7 (53.8%) 20 (76.9%)

6 (42.9%) 6 (46.2%) 6 (23.1%)

0.44 0.69 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.

HCO3 High urea Platelets Hyperkalemia CD4 level

OR

95% CI

p

0.95 1.008 0.999 1.54 0.998

0.903e0.999 1.002e1.015 0.998e0.999 1.025e2.321 0.996e1.001

0.046 0.013 !0.001 0.038 0.208

OR, odds ratio; CI, confidence interval.

at admission). The independent risk factors for death were MA, hyperkalemia and low CD4 count (Table 5).

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 O50% 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 (3,17e26). 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 (27,28). Table 5. Independent risk factors for death in HIV patients with and without MA by multivariate logistic regression

MA Hyperkalemia CD4 level

OR

95% CI

p

10.32 5.4268 0.9916

2.09e50.92 1.63e18.00 0.9850e0.9983

0.0042 0.0057 0.0136

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RIFLE classification is an improvement in predicting outcome of patients with AKI (29,30). 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 33e60% (16,26,31). 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 S~ao Jose´ de Doenc¸as Infecciosas for the assistance provided to the patients. This research was financially supported by the Brazilian Research Council (Conselho Nacional de Desenvolvimento Cientı´fico e Tecnolo´gico-CNPq, Brazil).

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