24. Bolton WK. Goodpasture’s syndrome. Kidney Int 1996; 50: 1753–1766 25. Lionaki S, Jennette JC, Falk RJ. Anti-neutrophil cytoplasmic (ANCA) and anti-glomerular basement membrane (GBM) autoantibodies in necrotizing and crescentic glomerulonephritis. Semin Immunopathol 2007; 29: 459–474 26. Lindic J, Vizjak A, Ferluga D et al. Clinical outcome of patients with coexistent antineutrophil cytoplasmic antibodies and antibodies against glomerular basement membrane. Ther Apher Dial 2009; 13: 278–281 27. De Zoysa J, Taylor D, Thein H et al. Incidence and features of dual antiGBM-positive and ANCA-positive patients. Nephrology (Carlton) 2011; 16: 725–729
28. Sinico RA, Radice A, Corace C et al. Anti-glomerular basement membrane antibodies in the diagnosis of Goodpasture syndrome: a comparison of different assays. Nephrol Dial Transplant 2006; 21: 397–401 29. Salama AD, Dougan T, Levy JB et al. Goodpasture’s disease in the absence of circulating anti-glomerular basement membrane antibodies as detected by standard techniques. Am J Kidney Dis 2002; 39: 1162–1167 30. Bomback AS. Anti-glomerular basement membrane nephritis: why we still ‘need’ the kidney biopsy. Clin Kidney J 2012; 5: 496–497 Received for publication: 26.3.2014; Accepted in revised form: 2.12.2014
Nephrol Dial Transplant (2015) 30: 821–828 doi: 10.1093/ndt/gfu380 Advance Access publication 18 December 2014
Celso Amodeo6, Juan J. Carrero4,5,† and Antonio C. Cordeiro6,† 1
Department of Nutrition, Dante Pazzanese Institute of Cardiology, São Paulo, Brazil, 2Nutrition Program, Division of Nephrology, Federal
University of São Paulo, São Paulo, Brazil, 3Department of Medicine, Division of Nephrology, University of Tennessee Health Science Center, Memphis, TN, USA, 4Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden, 5Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden and 6Department of Hypertension and Nephrology, Dante Pazzanese Institute of Cardiology, São Paulo, Brazil
Correspondence and offprint requests to: Antonio C. Cordeiro; E-mail: [email protected] † These authors share senior authorship.
A B S T R AC T Background. Malnutrition and inflammation are highly prevalent and intimately linked conditions in chronic kidney disease (CKD) patients that lead to a state of protein-energy wasting (PEW), the severity of which can be assessed by the Malnutrition-Inflammation Score (MIS). Here, we applied MIS and validated, for the first time, its ability to grade PEW and predict mortality in nondialyzed CKD patients. Methods. We cross-sectionally evaluated 300 CKD stages 3–5 patients [median age 61 (53–68) years; estimated glomerular filtration rate 18 (12–27) mL/min/1.73 m2; 63% men] referred for the first time to our center. Patients were followed during a median 30 (18–37) months for all-cause mortality. Results. A worsening in MIS scale was associated with inflammatory biomarkers increase (i.e. alpha-1 acid © The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
glycoprotein, fibrinogen, ferritin and C-reactive protein) as well as a progressive deterioration in various MIS-independent indicators of nutritional status based on anthropometrics, dynamometry, urea kinetics and bioelectric impedance analysis. A structural equation model with two latent variables (assessing simultaneously malnutrition and inflammation factors) demonstrated good fit to the observed data. During a followup, 71 deaths were recorded; patients with higher MIS were at increased mortality risk in both crude and adjusted Cox models. Conclusions. MIS appears to be a useful tool to assess PEW in nondialyzed CKD patients. In addition, MIS identified patients at increased mortality risk. Keywords: acute phase response, outcomes, renal disease, undernutrition, uremia
821
ORIGINAL ARTICLE
Fernanda C. Amparo1,2, Maria A. Kamimura2, Miklos Z. Molnar3, Lilian Cuppari2, Bengt Lindholm4,
Downloaded from http://ndt.oxfordjournals.org/ at North Dakota State University on June 25, 2015
Diagnostic validation and prognostic significance of the Malnutrition-Inflammation Score in nondialyzed chronic kidney disease patients
Malnutrition and inflammation are highly prevalent and intimately linked conditions in chronic kidney disease (CKD) patients [1–3]. While malnutrition may predispose to inflammatory states [4], inflammation may induce abnormalities in nutritional status also in patients with adequate nourishment [1]. The state of decreased body stores of protein and energy that follows as a result of these two conditions has been termed protein-energy wasting (PEW) [1]. Various clinical, nutritional and biochemical parameters are being used to diagnose and grade PEW in individuals with kidney disease. Among nutritional scoring systems, the Subjective Global Assessment (SGA) and the Malnutrition-Inflammation Score (MIS) are often employed [1]. MIS is a specific adaptation of the SGA questionnaire for hemodialysis (HD) patients proposed by Kalantar-Zadeh et al. [5]. MIS converts SGA into a semiquantitative scoring system by adding some objective clinical and laboratorial markers of relevance in CKD. MIS has been validated against other nutritional/inflammatory biomarkers and has been found to be associated with poor outcomes in patients receiving HD [5, 6], peritoneal dialysis [7, 8] and kidney transplantation [9]. MIS could be a valid nutritional assessment tool in nondialyzed CKD patients; however, to the best of our knowledge, no study has to date analyzed the diagnostic and prognostic validity of MIS in this patient population. Here, we sought to validate MIS as a surrogate marker of PEW by testing its association with markers of inflammation and nutritional status, as well as to evaluate its mortality predictive capacity in a relatively large well-characterized cohort of nondialyzed CKD patients.
M AT E R I A L S A N D M E T H O D S Patients and study design This study is an ancillary analysis of the Malnutrition, Inflammation and Vascular Calcification (MIVC) cohort which was established to evaluate associations between traditional, novel and uremic risk factors with cardiovascular and general morbimortality in CKD patients [10, 11]. MIVC comprises 300 consecutive nondialyzed CKD stages 3–5 patients {median age of 61 [interquartile range (IQR) 53–68] years; 63% men; 57% current or former smokers} recruited at the outpatient clinic of the Hypertension and Nephrology Division at Dante Pazzanese Institute of Cardiology in Sao Paulo, Brazil. Recruitment took place between March 2010 and March 2013 and included patients referred to begin nephrologic assessment. Thus, the majority of them had not yet received pharmacological treatment or dietary therapy at the time of evaluation. Exclusion criteria were age below 18 and above 80 years, clinical signs of acute infection during the month preceding the inclusion, active cancer or liver disease at the time of evaluation, previous diagnosis of immunological diseases and unwillingness to participate in the study. CKD was defined as a glomerular filtration rate (GFR) 8. Patient characteristics according to tertiles of the Malnutrition-Inflammation Score Table 1 describes general patient characteristics according to the tertiles of MIS. Across increasing tertiles, patients were more often women, and also had a lower GFR. Whereas albuminuria, phosphorus and PTH were increased, the levels
823
ORIGINAL ARTICLE
Laboratory parameters Morning blood samples were taken after an overnight fast for generation of plasma and serum which were stored at −70°C, if not analyzed immediately. Parathyroid hormone (PTH) and ferritin were measured by chemiluminescence, plasma ‘25hydroxy-vitamin D’ by high-performance liquid chromatography [16] and serum leptin by a commercial ELISA kit (LDN, Nordhorn, Germany). Transferrin, alpha-1 acid glycoprotein (a1-AGP) and high-sensitivity C-reactive protein (CRP) were measured by immuno-turbidimetry, albumin was measured by colorimetry and fibrinogen by a modified Clauss assay [17]. 24-h urinary albumin excretion was analyzed by turbidimetry. Normalized protein nitrogen appearance (nPNA) was calculated according to the equation proposed by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative clinical practice guideline [18]. Circulating levels of hemoglobin, total cholesterol, high-density lipoprotein cholesterol, triglycerides and creatinine were analyzed using certified methods at the Department of Laboratory Medicine at Dante Pazzanese Institute of Cardiology.
Downloaded from http://ndt.oxfordjournals.org/ at North Dakota State University on June 25, 2015
Malnutrition-Inflammation Score MIS is a scoring system for assessment of malnutrition and inflammation [5]. MIS has 10 components derived from medical history, physical examination, BMI and laboratory parameters. Each score component is classified according to four levels of severity, from 0 (normal) to 3 (severely abnormal). The sum of all 10 MIS components ranges from 0 (normal) to 30 (severe degree of malnutrition and inflammation status). For the present analysis, and given the nature of the included patients, we excluded dialysis vintage from the score. Thus, comorbidity was scored as 0 if there were no other medical illnesses present; as Score 1 for mild comorbidity, excluding such major comorbid conditions as congestive heart failure class III or IV, severe coronary artery diseases, moderate-to-severe chronic obstructive pulmonary disease or major neurological sequels; as score of 2 for moderate comorbidity (including one of the diseases listed under major comorbid conditions) and as score of 3 for two or more major comorbid conditions. Furthermore, serum transferrin was used instead of total iron binding capacity. Thus, serum transferrin was scored as 0 ≥ 200 mg/dL; Score 1, 170–199 mg/dL; Score 2, 140–169 mg/dL and Score 3,
28. Sinico RA, Radice A, Corace C et al. Anti-glomerular basement membrane antibodies in the diagnosis of Goodpasture syndrome: a comparison of different assays. Nephrol Dial Transplant 2006; 21: 397–401 29. Salama AD, Dougan T, Levy JB et al. Goodpasture’s disease in the absence of circulating anti-glomerular basement membrane antibodies as detected by standard techniques. Am J Kidney Dis 2002; 39: 1162–1167 30. Bomback AS. Anti-glomerular basement membrane nephritis: why we still ‘need’ the kidney biopsy. Clin Kidney J 2012; 5: 496–497 Received for publication: 26.3.2014; Accepted in revised form: 2.12.2014
Nephrol Dial Transplant (2015) 30: 821–828 doi: 10.1093/ndt/gfu380 Advance Access publication 18 December 2014
Celso Amodeo6, Juan J. Carrero4,5,† and Antonio C. Cordeiro6,† 1
Department of Nutrition, Dante Pazzanese Institute of Cardiology, São Paulo, Brazil, 2Nutrition Program, Division of Nephrology, Federal
University of São Paulo, São Paulo, Brazil, 3Department of Medicine, Division of Nephrology, University of Tennessee Health Science Center, Memphis, TN, USA, 4Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden, 5Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden and 6Department of Hypertension and Nephrology, Dante Pazzanese Institute of Cardiology, São Paulo, Brazil
Correspondence and offprint requests to: Antonio C. Cordeiro; E-mail: [email protected] † These authors share senior authorship.
A B S T R AC T Background. Malnutrition and inflammation are highly prevalent and intimately linked conditions in chronic kidney disease (CKD) patients that lead to a state of protein-energy wasting (PEW), the severity of which can be assessed by the Malnutrition-Inflammation Score (MIS). Here, we applied MIS and validated, for the first time, its ability to grade PEW and predict mortality in nondialyzed CKD patients. Methods. We cross-sectionally evaluated 300 CKD stages 3–5 patients [median age 61 (53–68) years; estimated glomerular filtration rate 18 (12–27) mL/min/1.73 m2; 63% men] referred for the first time to our center. Patients were followed during a median 30 (18–37) months for all-cause mortality. Results. A worsening in MIS scale was associated with inflammatory biomarkers increase (i.e. alpha-1 acid © The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
glycoprotein, fibrinogen, ferritin and C-reactive protein) as well as a progressive deterioration in various MIS-independent indicators of nutritional status based on anthropometrics, dynamometry, urea kinetics and bioelectric impedance analysis. A structural equation model with two latent variables (assessing simultaneously malnutrition and inflammation factors) demonstrated good fit to the observed data. During a followup, 71 deaths were recorded; patients with higher MIS were at increased mortality risk in both crude and adjusted Cox models. Conclusions. MIS appears to be a useful tool to assess PEW in nondialyzed CKD patients. In addition, MIS identified patients at increased mortality risk. Keywords: acute phase response, outcomes, renal disease, undernutrition, uremia
821
ORIGINAL ARTICLE
Fernanda C. Amparo1,2, Maria A. Kamimura2, Miklos Z. Molnar3, Lilian Cuppari2, Bengt Lindholm4,
Downloaded from http://ndt.oxfordjournals.org/ at North Dakota State University on June 25, 2015
Diagnostic validation and prognostic significance of the Malnutrition-Inflammation Score in nondialyzed chronic kidney disease patients
Malnutrition and inflammation are highly prevalent and intimately linked conditions in chronic kidney disease (CKD) patients [1–3]. While malnutrition may predispose to inflammatory states [4], inflammation may induce abnormalities in nutritional status also in patients with adequate nourishment [1]. The state of decreased body stores of protein and energy that follows as a result of these two conditions has been termed protein-energy wasting (PEW) [1]. Various clinical, nutritional and biochemical parameters are being used to diagnose and grade PEW in individuals with kidney disease. Among nutritional scoring systems, the Subjective Global Assessment (SGA) and the Malnutrition-Inflammation Score (MIS) are often employed [1]. MIS is a specific adaptation of the SGA questionnaire for hemodialysis (HD) patients proposed by Kalantar-Zadeh et al. [5]. MIS converts SGA into a semiquantitative scoring system by adding some objective clinical and laboratorial markers of relevance in CKD. MIS has been validated against other nutritional/inflammatory biomarkers and has been found to be associated with poor outcomes in patients receiving HD [5, 6], peritoneal dialysis [7, 8] and kidney transplantation [9]. MIS could be a valid nutritional assessment tool in nondialyzed CKD patients; however, to the best of our knowledge, no study has to date analyzed the diagnostic and prognostic validity of MIS in this patient population. Here, we sought to validate MIS as a surrogate marker of PEW by testing its association with markers of inflammation and nutritional status, as well as to evaluate its mortality predictive capacity in a relatively large well-characterized cohort of nondialyzed CKD patients.
M AT E R I A L S A N D M E T H O D S Patients and study design This study is an ancillary analysis of the Malnutrition, Inflammation and Vascular Calcification (MIVC) cohort which was established to evaluate associations between traditional, novel and uremic risk factors with cardiovascular and general morbimortality in CKD patients [10, 11]. MIVC comprises 300 consecutive nondialyzed CKD stages 3–5 patients {median age of 61 [interquartile range (IQR) 53–68] years; 63% men; 57% current or former smokers} recruited at the outpatient clinic of the Hypertension and Nephrology Division at Dante Pazzanese Institute of Cardiology in Sao Paulo, Brazil. Recruitment took place between March 2010 and March 2013 and included patients referred to begin nephrologic assessment. Thus, the majority of them had not yet received pharmacological treatment or dietary therapy at the time of evaluation. Exclusion criteria were age below 18 and above 80 years, clinical signs of acute infection during the month preceding the inclusion, active cancer or liver disease at the time of evaluation, previous diagnosis of immunological diseases and unwillingness to participate in the study. CKD was defined as a glomerular filtration rate (GFR) 8. Patient characteristics according to tertiles of the Malnutrition-Inflammation Score Table 1 describes general patient characteristics according to the tertiles of MIS. Across increasing tertiles, patients were more often women, and also had a lower GFR. Whereas albuminuria, phosphorus and PTH were increased, the levels
823
ORIGINAL ARTICLE
Laboratory parameters Morning blood samples were taken after an overnight fast for generation of plasma and serum which were stored at −70°C, if not analyzed immediately. Parathyroid hormone (PTH) and ferritin were measured by chemiluminescence, plasma ‘25hydroxy-vitamin D’ by high-performance liquid chromatography [16] and serum leptin by a commercial ELISA kit (LDN, Nordhorn, Germany). Transferrin, alpha-1 acid glycoprotein (a1-AGP) and high-sensitivity C-reactive protein (CRP) were measured by immuno-turbidimetry, albumin was measured by colorimetry and fibrinogen by a modified Clauss assay [17]. 24-h urinary albumin excretion was analyzed by turbidimetry. Normalized protein nitrogen appearance (nPNA) was calculated according to the equation proposed by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative clinical practice guideline [18]. Circulating levels of hemoglobin, total cholesterol, high-density lipoprotein cholesterol, triglycerides and creatinine were analyzed using certified methods at the Department of Laboratory Medicine at Dante Pazzanese Institute of Cardiology.
Downloaded from http://ndt.oxfordjournals.org/ at North Dakota State University on June 25, 2015
Malnutrition-Inflammation Score MIS is a scoring system for assessment of malnutrition and inflammation [5]. MIS has 10 components derived from medical history, physical examination, BMI and laboratory parameters. Each score component is classified according to four levels of severity, from 0 (normal) to 3 (severely abnormal). The sum of all 10 MIS components ranges from 0 (normal) to 30 (severe degree of malnutrition and inflammation status). For the present analysis, and given the nature of the included patients, we excluded dialysis vintage from the score. Thus, comorbidity was scored as 0 if there were no other medical illnesses present; as Score 1 for mild comorbidity, excluding such major comorbid conditions as congestive heart failure class III or IV, severe coronary artery diseases, moderate-to-severe chronic obstructive pulmonary disease or major neurological sequels; as score of 2 for moderate comorbidity (including one of the diseases listed under major comorbid conditions) and as score of 3 for two or more major comorbid conditions. Furthermore, serum transferrin was used instead of total iron binding capacity. Thus, serum transferrin was scored as 0 ≥ 200 mg/dL; Score 1, 170–199 mg/dL; Score 2, 140–169 mg/dL and Score 3,
