Serum albumin: a late-reacting negative acute-phase protein in clinically evident inflammation in dialysis patients
1 Department of Nephrology General Hospital of Athens2 Department of Cell Biology and Biophysics University of Athens3 Renal Unit Dragini Clinic4 Department of Medical Biopathology Eginition Hospital University of Athens5 Renal Unit Alexandra General Hospital Athens Greece Email: tsipg{at}hellasnet.gr
Sir,
In their interesting study, Nascimento et al. [1] found that baseline C-reactive (CRP) was not correlated with serum albumin (S-albumin) level in the group of haemodialysis (HD) patients that they examined. We had a similar finding in a longitudinal study conducted in a similar patient population [2]. Measuring CRP, serum amyloid A (SAA), interleukin-6 (IL-6) and S-albumin for 16 consecutive weeks in 37 HD patients and recording every inflammatory clinical event during this time period [2], we found that CRP and SAA were negatively but insignificantly correlated with S-albumin (r = –0.1384, P = 0.33 and r = 0.0024, P = 0.98, respectively) measured immediately (1–7 days) after a clinical event. However, when we examined the same correlation with S-albumin measured in the following week (7–14 days from a clinical event), this became highly significant for CRP and SAA (r = –0.1899, P<0.0001 and r = –0.2323, P<0.0001, respectively) and changed for IL-6 (r = –0.0810, P = 0.079). Furthermore, in the repeated measurements ANOVA that we conducted, while the effect of the independent variable ‘clinical events’ on S-albumin levels measured in the same week (1–7 days) of a clinical event was found insignificant (F = 2.05, P = 0.081), when we used the S-albumin levels of the week following (7–14 days) a clinical event it became highly significant (F = 54.51, P<0.0001). Also, in weeks with clinical events, CRP in the group of HD patients included in the study was indicative of a ‘real inflammation’ while in weeks free of clinical events this positive acute-phase protein was significantly lower, indicating a microinflammatory process [2].
Our findings may explain the unexpected result in the study of Nascimento et al. [1] showing that S-albumin in HD patients behaves as a negative acute-phase protein but with a delay of 1–2 weeks after a clinically significant inflammation. Our data are also in accordance with the findings in the studies of Kaysen et al. [3,4], who have shown that ceruloplasmin and 
1 acid glycoprotein (two more long-lived acute-phase proteins) predict future albumin concentration [3] and correlate with albumin fractional catabolic rate, but that CRP does not [4,3]. They have also shown that S-albumin correlates inversely with CRP level for a CRP level >13 mg/l in HD patients [5].
Pending confirmation of these findings by future similar studies, we consider that two points of interest are worth highlighting. The first one is related to everyday clinical practice in HD patients. Low S-albumin can be attributed to inflammation when a clinically significant inflammatory event has occurred to these patients 1–2 weeks before (and preferably when a high CRP was measured during this event); otherwise, other causes of its decline have to be investigated. The second point is related to the exploration of S-albumin as a nutritional or inflammatory index, in cross-sectional studies in the same population. The simultaneous measurement of S-albumin with the relatively short-lived acute-phase proteins, such as CRP and SAA, may be not appropriate when S-albumin is investigated as a negative acute-phase protein and used for diverse clinical outcomes prediction.
Conflict of interest statement. None declared.
References
- Nascimento MM, Pecoits-Filho R, Qureshi AR et al. The prognostic impact of fluctuating levels of C-reactive protein in Brazilian haemodialysis patients: a prospective study. Nephrol Dial Transplant 2004; 19: 2803–2809
[Abstract/Free Full Text] - Tsirpanlis G, Bagos P, Ioannou D et al. Exploring inflammation in hemodialysis patients: persistent and superimposed inflammation. Kidney Blood Press Res 2004; 27: 63–70[Medline]
- Kaysen GA, Dubin JA, Muller HG et al. Levels of alpha acid glycation, and ceruloplasmin predict future albumin levels in hemodialysis patients. Kidney Int 2001; 60: 2360–2366[CrossRef][Medline]
- Kaysen GA, Dubin JA, Muller HG et al. Relationships among inflammation nutrition and physiologic mechanisms establishing albumin levels in hemodialysis patients. Kidney Int 2002; 61: 2240–2249[CrossRef][Medline]
- Kaysen GA, Greene T, Daugirdas JT et al. Longitudinal and cross-sectional effects of C-reactive protein, equilibrated normalized protein catabolic rate, and serum bicarbonate on creatinine and albumin levels in dialysis patients. Am J Kidney Dis 2003; 42: 1200–1211[Medline]
Reply
Sir,We are grateful to Tsirpanlis and colleagues for their letter and comments with reference to our recent study [1]. Tsirpanlis et al. [2] previously reported on the predictive value of serum albumin (S-albumin), simultaneously measured with relatively short-lived acute-phase proteins, such as C-reactive protein (CRP). Moreover, they pointed out that low values of S-albumin could be attributed to inflammation, especially when a clinically significant inflammatory event has taken place 1–2 weeks before the serum analysis of S-albumin and this is usually reflected in elevated levels of CRP. S-albumin concentration may be decreased by the presence of malnutrition, inflammation and urinary losses, although this effect is considered to be more prominent in inflammation [3]. Kaysen et al. [4] demonstrated that in well-dialysed patients, inflammation is the principal cause of a decrease in S-albumin while a low protein intake plays a less significant role. In their study, a decrease in S-albumin by 0.3 g/dl, persisting for a period of 6 weeks, was, in general, associated with activation of the acute-phase response. On the other hand, nutritional support can improve nutritional markers and survival in haemodialysis (HD) patients with low levels of S-albumin, which attenuates the effect of inflammation [5]. The capability of S-albumin, when not adjusted by the influence of inflammation, to predict mortality in HD patients has been questioned. Stenvinkel et al. [5] showed a strong association between malnutrition, inflammation and atherosclerosis in pre-dialysis patients. In addition, Zimmermann et al. [6] and Qureshi et al. [8] reported that inflammation is associated with hypoalbuminaemia and increased mortality in HD patients.
These studies and many others suggest that inflammation plays a central role in the development of malnutrition and cardiovascular mortality in patients with chronic kidney disease. On the other hand, more recently, Pupim et al. [7] showed that surrogate markers of nutritional status (S-albumin, pre-albumin and serum creatinine) were, indeed, significantly related to all-cause mortality in HD patients, even after adjustment for serum CRP. Although in our study we could not confirm a negative correlation between S-albumin and CRP, taking into account only the baseline measurements, it should be noted that in patients who were persistently inflamed in our study, a negative correlation was, indeed, found between S-albumin and CRP in the four consecutive measurements preceding the study, demonstrating the influence of inflammation on S-albumin levels. We could speculate why this finding could not be verified in the patients who were not persistently inflamed. One reason could be the high prevalence of malnutrition, verified by SGA, in the Brazilian HD population, which differs from American and European HD populations where the majority of earlier studies on these relationships were done. Another reason is that we excluded patients with clinically significant inflammatory events, which in turn could be reflected by the absence of correlation in the whole studied HD population.
In summary, we agree with Tsirpanlis and colleagues that (i) clinically significant inflammatory events modify the levels of S-albumin, (ii) this effect is not immediate and (iii) these factors should be taken into account when analysing the relationship between S-albumin and short acute-phase reactants, such as CRP. We therefore advocate [9] sequential measurements of CRP, which may provide a better approach in the interpretation of decreasing S-albumin levels. On the other hand, it seems reasonable to assume that the S-albumin will remain as a valuable predictor of uraemic malnutrition, inflammation and increased risk for mortality.
Conflict of interest statement. None declared.
1 Renal, Diabetes and Hypertension Research Center Pró-Renal Foundation Brazil2 Karolinska University Huddinge Hospital Divisions of Renal Medicine and Baxter Novum Karolinska Institutet Sweden
References
- Nascimento MM, Pecoits-Filho R, Qureshi AR et al. The prognostic impact of fluctuating levels of C-reactive protein in Brazilian haemodialysis patients: a prospective study. Nephrol Dial Transpl 2004; 19: 2803–2809
[Abstract/Free Full Text] - Tsirpanlis G, Bagos P, Ioannou D et al. Exploring inflammation in hemodialysis patients: persistent and superimposed inflammation. Kidney Blood Press Res 2004; 27: 63–70[Medline]
- Kaysen GA, Dubin JA, Müller HG, Rosales L, Levin NW, Mitch WE and the HEMO Study Group. Inflammation and reduced albumin synthesis associated with stable decline in serum albumin in hemodialysis patients. Kidney Int 2004; 65: 1408–1415[CrossRef][Web of Science][Medline]
- Kaysen GA, Chertow GM, Adillkarla R et al. Inflammation and dietary protein intake exert competing effects on serum albumin and creatinine in haemodialysis patients. Kidney Int 2001; 60: 333–340[CrossRef][Web of Science][Medline]
- Stenvinkel P, Heimburger O, Paultre F et al. Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure. Kidney Int 1999; 55: 1899–1911[CrossRef][Web of Science][Medline]
- Zimmermann J, Herrlinger S, Pruy A, Metzger T, Wanner C. Inflammation enhances cardiovascular risk and mortality in hemodialysis patients. Kidney Int 1999; 55: 648–658[CrossRef][Web of Science][Medline]
- Pupim LCK, Hakim RM, Shiyr Y, Ikitzler TA. Uremic malnutrition is a predictor of death independent of inflammatory status. Kidney Int 2004; 66: 2054–2060[CrossRef][Medline]
- Stenvinkel P, Heimbürger O, Lindholm B, Kaysen GA, Bergström J. Are there two types of malnutrition in chronic renal failure? Evidence for relationships between malnutrition, inflammation and atherosclerosis (MIA-syndrome). Nephrol Dial Transplant 2000; 15: 953–960
[Free Full Text] - Stenvinkel P and Lindholm B. CRP in end-stage renal disease – are there reasons to measure it? Blood Purif 2005; 23: 72–78[Medline]
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