Original Article

Bone Marrow Transplantation (2007) 40, 567–572; doi:10.1038/sj.bmt.1705767; published online 16 July 2007

Post-Transplant Events

Biochemical indices for the assessment of nutritional status during hematopoietic stem cell transplantation: are they worth using? A single center experience

P Rzepecki1, J Barzal1, T Sarosiek1 and C Szczylik1

1Military Institute of Health Services, Warsaw, Poland

Correspondence: Dr P Rzepecki, BMT Unit, Military Institute of Health Services, 128 Szaserow Street, 00-909 Warsaw, Poland. E-mail: piotr_rzepecki@poczta.onet.pl

Received 4 December 2006; Revised 14 May 2007; Accepted 4 June 2007; Published online 16 July 2007.

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Abstract

Hematopoietic stem cell transplantation (HSCT) is being used increasingly in an attempt to cure many hematological disorders, solid tumors and autoimmune diseases. One of the major challenges in the post-transplant period is nutrition. The purpose of this investigation was to assess changes in the biochemical indices of nutritional status during HSCT and compare them with acute-phase protein levels to find the best parameters for nutritional support qualification. Nutritional status was assessed in 54 patients during autologous (30 cases) and allogeneic (24 cases) transplantation. Fifteen patients had to be treated with total parenteral nutrition (TPN), eight of them needing prolonged hospitalization. All nutritional indices and acute-phase protein levels were evaluated during the day before the beginning of conditioning regimen, after chemotherapy completion and every 7 days until engraftment, at least three times after stem cells infusion. Wilcoxon test and canonical analysis were used for statistical analyses. The measurement of retinol-binding protein and transferrin can be useful for nutritional assessment during autologous and allogeneic HSCT, respectively. Prealbumin level, measured 8 days after the end of conditioning regimen, is helpful in making a decision about starting TPN.

Keywords:

acute-phase proteins, biochemical indices, hematopoietic stem cell transplantation, nutritional assessment

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Introduction

One of the major adverse effects during hematopoietic stem cell transplantation (HSCT) is malnutrition. The toxicity of conditioning regimens is very debilitating to the rapidly dividing cells. It manifests as severe mucositis and enteritis that can cause painful oral ulcerations, decreased oral intake, nausea, vomiting and diarrhea. These symptoms can be exacerbated by development of graft versus host disease, and liver or renal insufficiency and it can lead to malnutrition. Increased risk of death in the early post-HSCT period as well as greater nonrelapse mortality can be observed within the underweight patient group.1, 2, 3 Better-nourished patients have a shorter time to engraftment and less probability of developing infections.1, 2, 3, 4, 5, 6 Serum albumin (ALB) level is the next prognostic factor, which is needed for evaluation before and during transplantation. The value of this parameter is as a predictor of in-patient death, nosocomial infections and length of hospitalization.7, 8 Thus, nutritional assessment in patients undergoing HSCT is very important and can rationalize nutritional support.9, 10, 11 ALB has a half-life of 20 days, so a decrease in its concentration is related to long periods of nutritional deficit, assuming that hydratation is stable.12 Plasma concentrations of so-called anabolic proteins such as ALB, transferrin (TRF), retinol-binding protein (RBP) and prealbumin (transthyretin, PAB) are frequently used to estimate nutritional status and to monitor the efficacy of nutritional support.11, 13 However, they may be affected by nonnutritional variables, such as infections, hyperhydratation or liver and renal insufficiency. They have short half-lives, merely reflecting recent nutritional changes.13, 14, 15, 16, 17, 18

The same indices are used for nutritional assessment and for monitoring total parenteral nutrition (TPN) during HSCT as well as other clinical situations. Immunological parameters of malnutrition are the sole exception. They cannot be used for evaluation of nutritional status because of the type of disease in which bone marrow transplantation is needed and the type of treatment with the use of immunosuppressive drugs.19, 20, 21, 22

Acute-phase proteins are not indices of nutritional status. Measurements of C-reactive protein (CRP), alpha1-antitrypsin (AAT), alpha2-macroglobulin (AAG) and serum precursor of amyloid A (SAA) are useful for the detection and evaluation of infection, tissue injury and inflammatory disorders. They signal increased demand for proteins, energy and probability of the appearance of malnutrition. Inflammatory response leads to depression of all protein synthesis. These proteins are indices of nutritional status, regardless of covering the human body's energy and protein requirement. Thus, when acute-phase protein levels are high, ALB, PAB, TRF and RBP can lose their function as parameters detecting malnutrition.23, 24, 25, 26, 27, 28

While TPN is often given to patients to maintain their nutritional status during the peritransplant period, there is conflicting evidence to support its routine use. TPN is a treatment potentially associated with significant limitations including a fluid overload state and hepatic dysfunction. It can increase the number of subclavian vein thromboses,9, 11 delay platelet engraftment,29 increase catheter-related/associated infections9, 11, 30 and suppress normal appetite.9 The current practice for the timing of TPN depends on the transplant center. Most use TPN only when severe mucositis develops.9, 11, 31, 32, 33, 34, 35, 36, 37

Because nutritional changes after HSCT have not been well studied yet, there is no common knowledge whether changes in levels of biochemical indices can be useful. We can probably use them to judge the risk of developing malnutrition, for establishing optimal candidates and also for determining the most appropriate time to start TPN.11, 30, 38, 39, 40 The best indices have to be inexpensive to carry out, easy to evaluate and should be independent of parameters of inflammation like increased levels of acute-phase proteins.

This provided us with the following aims for our study:

  1. Analysis of changes in biochemical parameters of nutritional status in patients treated with HSCT.
  2. Analysis of changes in acute-phase proteins in patients treated with HSCT.
  3. Analysis of the usefulness of the investigated parameters for making decisions about TPN.

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Materials and methods

The Hospital Ethics Committee approved the study (no 54/WIM/2006) and patients gave informed consent to participate. This was a prospective study. Nutritional status was assessed in 54 patients (33 men, 21 women) during HSCT. Autologous transplantation was performed in 30 (19 men, 11 women); allogeneic hematopoietic stem cells were infused in 24 patients (14 men, 10 women). The median age was 36 years (range: 20–65 years), the median time of hospitalization was 27 days (range: 17–58 days) in this investigated group. The source of hematopoietic stem cells was bone marrow in 26 (7 allogeneic, 19 autologous) and peripheral blood in 28 patients (17 allogeneic, 11 autologous), respectively.

Patients treated with allogeneic HSCT received hematopoietic stem cells from their matched sibling donors. No graft manipulations were performed. Patients suffered from myelodysplastic syndrome (four), acute myeloid leukemia (nine), chronic myeloid leukemia (six), acute lymphoblastic leukemia (two), sarcoma granulocyticum (one), Hodgkin's disease (one) and aplastic anemia (one). Patients with acute and chronic myeloid leukemia, sarcoma granulocyticum and myelodysplastic syndromes received busulfan and cyclophosphamide as a conditioning regimen before transplantation. Total body irradiation with etoposide and cyclophosphamide was used in patients with acute lymphoblastic leukemia. Conditioning regimen for Hodgkin's lymphoma (HD) was composed of fludarabine, melphalan and alemtuzumab; for severe aplastic anemia ATG with cyclophosphamide was administered. No T-cell depletion, apart from as a component of conditioning regimens in two patients (alemtuzumab-HD, ATG) for aplastic anemia was performed.

The patients treated with autologous transplantation suffered from HD (12) (conditioning regimen: BEAM); germ cell tumors (6) (CARBOPEC: carboplatin, etoposide, cyclophosphamide); non-Hodgkin's lymphomas (6) (BEAM); myeloma multiplex (2) (melphalan); desmoplastic small round cell tumor (2) (busulfan+melphalan) and systemic lupus erythematosus (2) (cyclophosphamide+ATG+methylprednisolone).

Fifteen patients (eight allogeneic, seven autologous) had to be treated with TPN because of severe mucositis, which made it impossible to eat and drink. In eight of them (two allogeneic, six autologous) this complication was associated with the need for prolonged hospitalization.

The following subgroups of patients were estimated:

1A
patients treated with autologous transplantation
1B
patients treated with allogeneic transplantation
2A
patients who required more than 5 weeks of hospitalization (due to severe mucositis and/or infections)
2B
patients who did not require time of hospitalization as above
3A
patients treated with TPN after receiving their graft
3B
patients who did not need TPN

The following biochemical indices of nutritional status were assessed: PAB, TRF, RBP and ALB.

The levels of acute-phase proteins listed below were estimated at the same time: CRP, AAT, AAG and SAA. All above-mentioned nutritional indices and acute-phase protein levels were evaluated during the day before the beginning of conditioning regimen (day x), after chemotherapy completion (before graft was given, day y) and every 7 days until engraftment at least three times after stem cell infusion (days y+7, y+14, y+21). The last measurement was always performed after engraftment. The levels of biochemical indices of nutritional status and acute-phase proteins were determined by an automated immunonephelometer (IMMAGE 800 Immunochemistry System, Beckman Coulter, Galway, Ireland), which uses the application of nephelometry to the quantification of antigen or antibody.

Results are expressed as median levels from the particular days of measurements. The Wilcoxon test was used for the statistical evaluation of the data obtained (to compare results received before chemotherapy with those obtained after the end of conditioning regimens, that is levels of investigated parameters on day x versus day y, y+7, y+14, y+21, respectively). The correlation between parameters of nutritional status and acute-phase proteins was checked to assess whether these indices are reliable indicators of nutritional status in patients treated with HSCT. To check the correlation, canonical analysis was used for statistical analyses.

There were no life-threatening complications, and acute graft versus host disease was not observed during the study period. None of the patients were administered ALB supplement or enteral nutrition. TPN (if necessary) started between the second and the third measurement after graft transfusion (8–15 days after chemotherapy). The reason for starting this therapy was severe mucositis with a prolonged period (at least 5 days) of minimal oral intake or weight loss of more than 10% during treatment. The TPN was discontinued when patients were able to consume orally at least 50% of their daily requirements for 3 consecutive days.

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Results

Initially all patients had normal values for nutritional status parameters and acute-phase protein levels, except for SAA (maybe because of presence of central venous catheter). The starting value of SAA exceeded the normal range of this parameter by only a little. None of the patients had symptoms or signs of infection (before the start of the conditioning regimen).

Biochemical indices of nutritional status and acute-phase protein levels in patients who were treated with autologous HSCT (Table 1) started to change in the 8 days after the end of the conditioning regimen. A decrease of ALB, RBP, PAB, TRF and the increased levels of AAT, AAG and CRP could be observed. Statistically significant changes in investigated parameters before and after chemotherapy were noticed in all biochemical indices and acute-phase proteins (Wilcoxon test) (Table 2). When canonical analysis was used, changes in acute-phase protein levels were significantly correlated with changes of levels in biochemical indices of nutritional status (high negative correlation (r<-0.5 and P<0.05). There was one exception: changes in RBP levels were not influenced by the acute-phase response and high negative correlation was not observed.



Indices of nutritional status and acute-phase proteins for patients who have been treated with allogeneic transplantation from sibling donors (Table 3) started to change in the 8 days after the end of conditioning regimen. We observed a decrease in ALB, RBP, PAB and TRF on days y+14 and y+21. TRF was also below normal range on day y+7. Minimum level of TRF and RBP was observed at the time of the third and ALB and PAB at the time of the fourth measurement, respectively. All parameters became normal 1 month after graft injection. All values of CRP, AAG and AAT increased from the day after the end of conditioning regimen, days y+7 and y+14, respectively, and became regular on the day of the last measurement. The highest values of CRP and SAA were seen on the day y+7, ATG on the day y+14 and AAT on the day y+21. Statistically significant changes in investigated parameters before and after chemotherapy were noticed in all biochemical indices and acute-phase proteins, based on the Wilcoxon test (Table 4). In canonical analysis only changes of TRF levels were independent of those of acute-phase proteins (lack of high negative correlation, r>-0.5, P<0.05).



Indices of nutritional status for patients who required hospitalization beyond 5 weeks (due to severe mucositis and/or infections) started to change in the 8 days after the end of the conditioning regimen. Minimum level of ALB and TRF was observed at the time of the fourth measurement, and of RBP and PAB at the time of the third measurement, respectively. Acute-phase protein levels for the patients started to increase from the time of the third measurement for CRP and SAA, and from the time of the fourth measurement for AAT and AAG. Maximum levels were reached for CRP and SAA on day y+7, for AAG on day y+14 and for AAT on day y+21.

Indices of nutritional status for patients who did not require hospitalization beyond 5 weeks started to change in the period of 8 days (RBP) or 15 days (ALB, PAB and TRF) after the end of the conditioning regimen. The minimum level of ALB, RBP and PAB was observed at the time of the fifth measurement, and TRF at the time of the third measurement, respectively. Acute-phase protein levels for these patients started to increase from the time of the third measurement for AAT, CRP and SAA, and from the time of the fourth measurement for AAG. Maximum levels were reached for CRP and SAA on day y+7, and for AAG and AAT on day y+21.

Statistically significant differences (Wilcoxon test) in investigated parameters were found in the following cases: RBP and PAB at day y+7, CRP at day y+14 and SAA at days x, y+7 and y+14. Values of acute-phase proteins were higher and levels of RBP and PAB were lower in patients who required hospitalization beyond 5 weeks.

Prealbumin level, measured 8 days after conditioning regimen (day y+7), was normal in the group with 'short' hospitalization and decreased below normal in terms of another group. In this measurement the high negative correlation between PAB and acute-phase proteins was observed in neither patient group (canonical analysis, r>-0.5, P<0.05).

Indices of nutritional status for patients who required TPN started to change at the time of the second measurement for TRF and in the 8 days after the end of conditioning regimen for ALB, PAB and RBP. The minimum level of ALB, PAB and TRF was observed at the time of the fourth measurement, but of RBP at the time of the third measurement (day y+7). Acute-phase protein levels for these patients started to increase from the time of the second measurement. Maximum levels were reached for CRP and SAA on the day y+7, and for AAG and AAT on the day y+14.

Indices of nutritional status for patients who did not require TPN were still within normal ranges. Acute-phase protein levels for these patients started to increase from the third measurement. Maximum levels were reached as follows: for CRP and SAA on the day y+7, for AAG and AAT on the day y+21.

Statistically significant differences (Wilcoxon test) in investigated parameters were found in the following cases: RBP on days x and y, PAB on day y, TRF on day y+14, AAT on day y+14 and CRP on day y+14.

Comparison of patients requiring TPN with those who did not require this kind of nutritional support indicates a statistically significant difference in TRF value. PAB value being measured 8 days after conditioning regimen was below the lower limit in patients who required TPN later on, and was normal for patients with no need of this kind of nutritional support.

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Discussion

In spite of normal nutritional status on hospital admission many patients need nutritional support during transplantation. This is caused by the conditioning regimens, composed of high doses of chemo- or radiochemotherapy, and leads to the development of nausea, vomiting, diarrhea and severe mucositis. These complications deny patients the ability to eat and drink and together with the development of systemic inflammatory response syndrome can lead to anorexia and cachexia. Thus, nutritional assessment in patients undergoing hematopoietic stem cells transplantation is very important and can rationalize nutritional support.10, 11

We investigated changes in biochemical indices of nutritional status and acute-phase protein levels during HSCT. Then the correlation between parameters of nutritional status and acute-phase proteins was obtained, to assess whether these indices are reliable indicators of nutritional status in HSCT patients (canonical analysis).

We found that in patients treated with autologous HSCT, the estimation of RBP levels can be useful for nutritional assessment. During this kind of HSCT, changes in the acute-phase proteins observed in our study were not significantly correlated with changes of RBP levels (canonical analysis, r>-0.5, P<0.05).

Similar observation was made during allogeneic HSCTs from sibling donors, applied to TRF. We found that the estimation of TRF levels can be useful for nutritional assessment during this kind of treatment.

Prealbumin level, measured 8 days after conditioning regimen, provided the best illustration of the difference between patients who required hospitalization for less than 5 weeks and those who did not require it. It was also a good indicator for showing who needed TPN. On that day (day y+7) the level was normal in the group with 'short' hospitalization and decreased below normal in terms of another group. A similar phenomenon was observed when comparison was made between patients who required and those who did not require TPN. PAB level was below the lower limit in patients who needed TPN later on and was normal for patients with no need of this kind of nutritional support. In this measurement the high negative correlation between levels of PAB and CRP was not observed in either group of patients (canonical analysis). TPN was started between the second and the third measurement after graft transfusion (8–15 days after chemotherapy). Therefore the PAB value that was checked 8 days after conditioning regimen can be used as an index for predicting the development of malnutrition after transplantation.

In summary, our study did not confirm results from other studies performed earlier. These pointed out that biochemical indices are not sufficiently reliable in the nutritional assessment of hematopoietic stem cells transplantation in patients because the levels of these substances are markedly affected by the acute-phase response (measured with acute-phase protein levels) secondary to infections, which frequently complicate transplantation.11, 13, 37 We found that changes in the levels of PAB, RBP and TRF can be helpful for nutritional assessment in specific patients and at the right moment during HSCT. We concluded that a PAB level below the normal range (<17 mg%), measured 8 days after the end of conditioning regimen, is helpful in making a decision about starting TPN. Then, estimating RBP level at the same time in patients treated with autologous HSCT can provide additional information about their nutritional status. Levels reduced over 50% below the lower limit of standard (that is, 3 mg%) indicate development of malnutrition in this group of patients. During allogeneic HSCTs from sibling donors we found that estimating TRF is of great importance. The level, measured 8 days after the end of conditioning regimen and reduced above 30% under lower limit of norm (that is, 168 mg%), can play the same role as an indicator of the development of malnutrition. RBP plays a similar role in autologous HSCT.

Thus, nutritional assessment of HSCT patients using selected biochemical parameters is possible and provides very important information, which can rationalize nutritional support during HSCT.

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