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Original Investigation |

Amyotrophic Lateral Sclerosis Outcome Measures and the Role of Albumin and Creatinine:  A Population-Based Study

Adriano Chiò, MD1,2,3; Andrea Calvo, MD, PhD1,2; Giacomo Bovio, MD4; Antonio Canosa, MD1; Davide Bertuzzo, MD1; Francesco Galmozzi1; Paolo Cugnasco1; Marinella Clerico, MD, PhD5; Stefania De Mercanti, MD5; Enrica Bersano, MD6; Stefania Cammarosano, MD1; Antonio Ilardi, MD1; Umberto Manera, MD1; Cristina Moglia, MD1; Riccardo Sideri, PharmD7; Kalliopi Marinou, MD7; Edo Bottacchi, MD8; Fabrizio Pisano, MD9; Roberto Cantello, MD10; Letizia Mazzini, MD6; Gabriele Mora, MD7 ; for the Piemonte and Valle d’Aosta Register for Amyotrophic Lateral Sclerosis (PARALS)
[+] Author Affiliations
1Amyotrophic Lateral Sclerosis Center, Rita Levi Montalcini Department of Neuroscience, University of Turin, Turin, Italy
2Città della Salute e della Scienza, Azienda Ospedaliero Universitaria, Turin, Italy
3Neuroscience Institute of Torino, Turin, Italy
4Salvatore Maugeri Foundation, Istituto Di Ricovero e Cura a Carattere Scientifico, Scientific Institute of Pavia, Pavia, Italy
5Department of Biological and Clinical Science, Azienda Ospedaliero Universitaria San Luigi Gonzaga, University of Turin, Orbassano, Italy
6Amyotrophic Lateral Sclerosis Center, Department of Neurology, Azienda Ospedaliero Universitaria Maggiore di Novara, Novara, Italy
7Salvatore Maugeri Foundation, Istituto Di Ricovero e Cura a Carattere Scientifico, Scientific Institute of Milano, Milano, Italy
8Department of Neurology, Azienda Ospedaliera Regionale di Aosta, Azienda Unità Sanitaria Locale Valle d’Aosta, Aosta, Italy
9Salvatore Maugeri Foundation, Istituto Di Ricovero e Cura a Carattere Scientifico, Scientific Institute of Veruno, Pavia, Italy
10Eastern Piedmont University, Department of Neurology, Novara, Italy
JAMA Neurol. 2014;71(9):1134-1142. doi:10.1001/jamaneurol.2014.1129.
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Importance  There is an urgent need to identify reliable biomarkers of amyotrophic lateral sclerosis (ALS) progression for clinical practice and pharmacological trials.

Objectives  To correlate several hematological markers evaluated at diagnosis with ALS outcome in a population-based series of patients (discovery cohort) and replicate the findings in an independent validation cohort from an ALS tertiary center.

Design, Setting, and Participants  The discovery cohort included 712 patients with ALS from the Piemonte and Valle d’Aosta Register for Amyotrophic Lateral Sclerosis from January 1, 2007, to December 31, 2011. The validation cohort comprised 122 patients with ALS at different stages of disease consecutively seen at an ALS tertiary center between January 1, 2007, and January 1, 2009.

Main Outcomes and Measures  The following hematological factors were investigated and correlated with survival: total leukocytes, neutrophils, lymphocytes, monocytes, glucose, creatinine, uric acid, albumin, bilirubin, total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, creatine kinase, thyroid-stimulating hormones, and erythrocyte sedimentation rate; all analyses were performed separately by sex. The patient of the validation cohort also underwent bioelectrical impedance analysis for the calculation of fat-free mass.

Result  Of the 712 patients in the examined period in Piemonte and Valle d’Aosta, 638 (89.6%) were included in the study. Only serum albumin (men: ≤4.3 vs >4.3 mg/dL, P < .001; women: ≤4.3 vs >4.3 mg/dL, P < .001) and creatinine levels (men: ≤0.82 vs >0.82 mg/dL, P = .004; women: ≤0.65 vs >0.05 mg/dL, P = .004) and lymphocyte count (men: ≤1700 vs >1700/μL, P = .04; women: ≤1700 vs >1700/μL, P = .02) were significantly associated with ALS outcome in both sexes with a dose-response effect (better survival with increasing levels). These findings were confirmed in the validation cohort. Multivariable analysis showed that serum albumin (men: hazard ratio [HR], 1.39; 95% CI, 1.05-1.90; P = .02; women: HR, 1.73; 95 % CI, 1.35-2.39; P = .001) and creatinine (men: HR, 1.47; 95% CI, 1.11-1.95; P = .007; women: HR, 1.49; 95% CI, 1.07-2.05; P = .02) were independent predictors of survival in both sexes; no other hematological factor was retained in the model. In patients with ALS, serum albumin was correlated with markers of inflammatory state while serum creatinine was correlated with fat-free mass, which is a marker of muscle mass.

Conclusions and Relevance  In ALS, serum albumin and creatinine are independent markers of outcome in both sexes. Creatinine reflects the muscle waste whereas albumin is connected with inflammatory state. Both creatinine and albumin are reliable markers of the severity of clinical status in patients with ALS and can be used in defining prognosis at the time of diagnosis.

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Figure 1.
Discovery Cohort Kaplan-Meier Curves

Survival was stratified by serum creatinine levels at diagnosis. A, Men: ≤0.82 vs >0.82 mg/dL (P = .004). B, Women: ≤0.65 vs >0.65 mg/dL (P = .004). Survival was stratified by serum albumin levels at diagnosis. C, Men: ≤4.3 vs >4.3 g/dL (P < .001). D, Women: ≤4.3 vs >4.3 g/dL (P < .001). Survival was stratified by serum lymphocytes count at diagnosis. E, Men: ≤1700 vs >1700 /μL (P = .04). F, Women: ≤1700 vs >1700 /μL (P = .02). To convert lympohcytes to ×109/L, multiply by 0.001; albumin to grams per liter, multiply by 10; and creatinine to micromoles per liter, multiply by 76.25.

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Figure 2.
Discovery Cohort Associations

A, Correlation between Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) score and serum creatinine levels (men: r = 0.165, y = 0.006x + 0.591, P = .003; women: r = 0.256, y = 0.005x + 0.416, P < .001). B, Correlation between forced vital capacity (FVC) and serum creatine levels (men: r = 0.24, y = 0.002x + 0.622, P = .003; women: r = 0.151, y = 0.001x + 0.544, P < .001). C, Correlation between ALSFRS-R score and serum albumin levels (men: r = 0.465, y = 0.033x + 2.961, P < .001; women: r = 0.324, y = 0.019x + 3.505, P < .001). D, Correlation between FVC of predicted percentage and serum albumin levels (men: r = 0.379, y = 0.007x + 3,633, P < .001; women: r = 0.268, y = 0.004x + 0.3.902, P < .001). To convert albumin to grams per liter, multiply by 10 and creatinine to micromoles per liter, multiply by 76.25.

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