Looking for Sarcopenia Biomarkers

SEE RELATED ARTICLE, p. 545. SEE RELATED ARTICLE, p. 545. Sarcopenia, defined as age-associated loss of skeletal muscle mass and function, has emerged as an important public health issue. It is associated with higher mortality, morbidity, physical disability, and health care cost.1Murphy R.A. Ip E.H. Zhang Q. et al.Transition to sarcopenia and determinants of transitions in older adults: a population-based study.J Gerontol Ser A Biol Sci Med Sci. 2014; 69: 751-758Crossref PubMed Scopus (62) Google Scholar, 2Filippin L.I. Teixeira V.N. da Silva M.P. Miraglia F. da Silva F.S. Sarcopenia: a predictor of mortality and the need for early diagnosis and intervention.Aging Clin Exp Res. 2015; 27: 249-254Crossref PubMed Scopus (52) Google Scholar While sarcopenia should be diagnosed with measurements of muscle mass and function, serum biomarkers are needed for screening of sarcopenia in a large population. Serum creatinine is a known biomarker for muscle mass and kidney function because 90% of its precursor, creatine phosphate, is stored in the muscle, its production is mostly constant, and its excretion is completely via the kidney.3Stevens L.A. Coresh J. Greene T. Levey A.S. Assessing kidney function—measured and estimated glomerular filtration rate.N Engl J Med. 2006; 23: 2473-2483Crossref Scopus (2300) Google Scholar For patients with normal renal function, serum creatinine is a reasonable biomarker for sarcopenia. In this issue, Thongprayoon et al4Thongprayoon C. Cheungpasitporn W. Kittanamongkolchai W. Harrison A. Kashani K. Prognostic importance of low admission serum creatinine concentration for mortality in hospitalized patients.Am J Med. 2017; 130: 545-554Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar reported that a low serum creatinine level, most likely due to sarcopenia, is associated with a higher mortality rate. They found that the association between admission creatinine values and in-hospital and 1-year mortalities is a U-shaped distribution, suggesting that low muscle mass and poor kidney function account for the higher mortality for each end, respectively. Importantly, because males usually have larger muscle mass, the cut-off for low serum creatinine level is sex dependent. From the U curves, the nadir serum creatinine level for males is 0.9-1.0 mg/dL, and for females is 0.7-0.8 mg/dL. Male patients with serum creatinine level <0.6 mg/dL, and females <0.4 mg/dL, had increased in-hospital and 1-year mortality by about two- to threefold. For patients with a low serum creatinine level, the chance to die during the admission is about 1 in 50, and to die within 1 year after discharge would be 1 in 5.4Thongprayoon C. Cheungpasitporn W. Kittanamongkolchai W. Harrison A. Kashani K. Prognostic importance of low admission serum creatinine concentration for mortality in hospitalized patients.Am J Med. 2017; 130: 545-554Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar These results suggest that we should pay more attention to patients with low serum creatinine levels and follow them more closely after discharge. In this study, sarcopenia is probably the main cause of low admission serum creatinine levels.4Thongprayoon C. Cheungpasitporn W. Kittanamongkolchai W. Harrison A. Kashani K. Prognostic importance of low admission serum creatinine concentration for mortality in hospitalized patients.Am J Med. 2017; 130: 545-554Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar However, there are many conditions that may lower serum creatinine level and result in a misdiagnosis of sarcopenia (False positive, Table).3Stevens L.A. Coresh J. Greene T. Levey A.S. Assessing kidney function—measured and estimated glomerular filtration rate.N Engl J Med. 2006; 23: 2473-2483Crossref Scopus (2300) Google Scholar, 5Francoz C. Prié D. Abdelrazek W. et al.Inaccuracies of creatinine and creatinine-based equations in candidates for liver transplantation with low creatinine: Impact on the model for end-stage liver disease score.Liver Transpl. 2010; 16: 1169-1177Crossref PubMed Scopus (135) Google Scholar, 6Udy A.A. Baptista J.P. Lim N.L. et al.Augmented renal clearance in the ICU.Crit Care Med. 2014; 42: 520-527Crossref PubMed Scopus (199) Google Scholar Among them, the augmented renal clearance is still not fully understood. It is seen in young intensive care unit patients, probably due to fluid overload, systemic inflammation, and other unknown causes.6Udy A.A. Baptista J.P. Lim N.L. et al.Augmented renal clearance in the ICU.Crit Care Med. 2014; 42: 520-527Crossref PubMed Scopus (199) Google Scholar On the other hand, many sarcopenic patients may not have low serum creatinine levels due to the conditions that raise serum creatinine levels (False negative, Table).3Stevens L.A. Coresh J. Greene T. Levey A.S. Assessing kidney function—measured and estimated glomerular filtration rate.N Engl J Med. 2006; 23: 2473-2483Crossref Scopus (2300) Google Scholar In this study, 4.6% of male and 2.0% of female hospital patients may have sarcopenia based on low serum creatinine levels.4Thongprayoon C. Cheungpasitporn W. Kittanamongkolchai W. Harrison A. Kashani K. Prognostic importance of low admission serum creatinine concentration for mortality in hospitalized patients.Am J Med. 2017; 130: 545-554Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar These numbers could be significantly underestimated, most likely due to chronic kidney disease.TableFalse Positive and Negative Conditions for Diagnosing Sarcopenia Based on Low Serum Creatinine LevelsFalse positive (low serum creatinine level without sarcopenia) Volume expansion: SIADH, nephrotic syndrome, pregnancy, fluid overload Advanced liver disease Augmented renal clearance Vegetarian diet Limb amputation Paraplegia, hemiplegia, and other neuromuscular disordersFalse negative (high serum creatinine level with sarcopenia) Chronic kidney disease Volume depletion Inhibitors of creatinine secretion: cimetidine, trimethoprim Ingestion of cooked meat Ingestion of creatine supplementSIADH = syndrome of inappropriate antidiuretic hormone secretion. Open table in a new tab SIADH = syndrome of inappropriate antidiuretic hormone secretion. To overcome the problems related to chronic kidney disease, Kashani et al7Kashani K.B. Frazee E.N. Kukrálová L. et al.Evaluating muscle mass by using markers of kidney function: development of the sarcopenia index.Crit Care Med. 2017; 45: e23-e29Crossref PubMed Scopus (108) Google Scholar proposed using another renal function marker, cystatin,3Stevens L.A. Coresh J. Greene T. Levey A.S. Assessing kidney function—measured and estimated glomerular filtration rate.N Engl J Med. 2006; 23: 2473-2483Crossref Scopus (2300) Google Scholar for correction. They found that a sarcopenia index, calculated as (serum creatinine/serum cystatin C) × 100, correlates with the paraspinal muscle surface area at the L4 vertebrae obtained from an abdominal computed tomography scan (r2 = 0.27). This sarcopenia index is an independent predictor of the hospital and 90-day mortality, but not for intensive care unit mortality or long-term physical and mental performance.7Kashani K.B. Frazee E.N. Kukrálová L. et al.Evaluating muscle mass by using markers of kidney function: development of the sarcopenia index.Crit Care Med. 2017; 45: e23-e29Crossref PubMed Scopus (108) Google Scholar This relatively low coefficient between the sarcopenia index and muscle surface area suggests that there is room for improvement. As we know that, except in some rare conditions (Table), timed urine creatinine value is dependent solely on muscle mass, providing the renal function is in a steady state, estimated glomerular filtration rate (eGFR) based on serum cystatin level (eGFRcystatin) is a better way to estimate renal function than creatinine in patients with low muscle mass.8Tetsuka S. Morita M. Ikeguchi K. Nakano I. Utility of cystatin C for renal function in amyotrophic lateral sclerosis.Acta Neurol Scand. 2013; 128: 386-390Crossref PubMed Scopus (16) Google Scholar Because timed urine creatinine = serum creatinine × creatinine clearance × time, if we replace creatinine clearance with eGFRcystatin, then timed urine creatinine = serum creatinine × eGFRcystatin × time. Therefore, from the physiological point of view, a better sarcopenia index would be calculated as serum creatinine × eGFRcystatin. (Time is a constant and can be removed). This sarcopenia index is expected to be sex dependent; thus, separate normal ranges should be developed for each sex. In addition, this index should not be applied to those who had a loss of muscle mass due to other causes such as limb amputation and hemi- or paraplegia. It would be interesting to see whether future studies based on this proposed sarcopenia index would show a better correlation with sarcopenia, and a stronger predictive power for mortality and morbidity. Prognostic Importance of Low Admission Serum Creatinine Concentration for Mortality in Hospitalized PatientsThe American Journal of MedicineVol. 130Issue 5PreviewThe study objective was to assess the association between low serum creatinine value at admission and in-hospital mortality in hospitalized patients. Full-Text PDF