Serum Albumin and Mortality After Renal Transplantation Carlos Guijarro, MD, Ziad A. Massy, MD, Michael R. Wiederkehr, and Bertram L. Kasiske, MD
MD, Jennie Z. Ma, MS,
0 The incidence, causes, and consequences of hypoalbuminemia after renal transplantation are not well defined. We examined clinicel correlates of serum albumin measured at 3 months, 6 months, 1 year, and annually thereafter in 706 renal transplant recipients who survived at least 6 months with a functioning allograft. Follow-up was 7.0 ? 4.2 years. Hypoalbuminemia (53.5 g/dL) was most common at 3 months (31?& n = gg2), least common at 1 year (12%, n = 666), and then became increasingly common among survivors, for example, 14% (n = [email protected]
) at 4 years, 20% (n = 204) at 8 years, and #)% (n = 77) at 12 years after transplantation. Dy multiple linear regression, variables that correlated (P <: 0.03) with lower serum albumin at 3,6,12, and 24 months included age, diabetes, proteinuria, and cytomegalovirus infection. other independent correlates on at least one of these occasions included renal function and chronic d&ease (malignancy, liver disease, and cardiovascular disease). %rum albumin, as a time-averaged and time-dependent covariate, was a strong i ndepembt risk factor for death using Cox proportional hazards analysis (relative risk for each g/dL increment, 0.2& 95% confidence interval, 0.16 to 0.44 [l.Olt = no risk)). The effects of albumin on mortalii were independent of age, diabetes, serum lipids, renal function, chronic liver dii, malignancies, and cardiovascular dii. The effects of albumin on mortality were evident even when the analysis was restricted to patients dying several years after albumin was measured. Thus, hypoalbuminemia is common and serum albumin is a strong independent risk factor for all-cause mortality after renal transplantation. 0 19M by the National Kidney Foundation, Inc. INDEX WORDS: Hypoalbuminemia;
T RECENTLY has been shown that hypoalbuminemia predicts mortality in end-stage renal disease patients treated with chronic maintenance hemodialysis.‘-’ The relationship between serum albumin levels and mortality in this population is independent of other known risk factors. Whether there is a similar relationship between serum albumin and mortality among renal transplant recipients has not been examined. In the present investigation, we examined possible causes and long-term consequences of hypoalbuminemia in a large population of renal transplant recipients from a single center. MATERIALS
Patients Records from all patients who underwent renal transplantation between January 1, 1976, and June 1, 1991, at Hennepin County Medical Center were reviewed. Since we were interested in examining the relationship between albumin and mortality in the late posttransplant period, only patients who survived at least 6 months with a functioning allograft were included. Only mortality with a functioning graft, and not deaths that occurred after patients returned to dialysis, were analyzed. Data were recorded through January 1, 1995.
Clinical Variables Variables recorded at the time of transplantation included age, gender, race, major causes of end-stage renal disease (diabetes, autosomal dominant polycystic kidney disease, and chronic glomerulonephritis). weight, height, body mass index (kg/m’), donor age, donor gender, pretransplant splenectomy, American
No 1 (January),
disease; cancer; liver disease; allograft. pretransplant bilateral nephrectomy, prior transplant, pretransplant blood transfusions, percent panel reactive antibodies at peak and at transplant, number of AB and DR mismatches, evidence of pretransplant ischemic heart disease (angina pectoris, myocardial infarction, or coronary artery revascularization), pretransplant cerebral vascular disease, pretransplant peripheral vascular disease, and cigarette smoking history. Variables recorded within the first 6 months after transplantation, but prior to any deaths or graft losses, included immunosuppressive agents used during the period of induction, ie, cyclosporine and Minnesota antilymphocyte globulin, delayed graft function (defined as the needed for posttransplant dialysis), and cytomegalovirus infections (characteristic clinical findings with serologic or culture confirmation). The effects of major events occurring any time after transplantation were also analyzed: acute rejection episodes, the development of posttransplant diabetes (requiring treatment with insulin or an oral hypoglycemic agent), withdrawal of cyclosporine, and the reduction of prednisone from 15 mg/d to 15 mg every other day. Similarly, the effects of major chronic diseases that developed in the posttransplant period were examined. Chronic diseases included liver disease, nonFrom the Division of Nephrology, Department of Medicine, University of Minnesota College of Medicine, Hennepin County Medical Center, Minneapolis, MN. Received May 10, 1995; accepted in revised form September 13, 1995. Supported in part by Fondo de Investigacidn Sanitaria (FIS 93/5439), Spanish Ministry of Health. Address reprint requests to Bertram L.. Kasiske, MD, Department of Medicine, Hennepin County Medical Center, 701 Park Ave. Minneapolis, MN 55415. 0 I996 by the National Kidney Foundation, Inc. 0272~6386/96/2701-0013$3.00/O 1996:
skin malignancies, and cardiovascular disease (strokes, transient ischemic attacks, myocardial infarction, or coronary revascularization). We also examined the possible effects of changes in patients or their management over time by including transplant eras as independent variables in the analysis. Eras were arbitrarily defined as early (1976 to 1982, n = 239), middle (1983 to 1986, n = 209), and late (1987 to 1991, n = 258). Serum albumin was measured at 3, 6, and 12 months, and annually thereafter with a Synchron CX7 autoanalyzer (Beckman, Brea, CA) using a calorimetric assay. Other clinical variables measured simultaneously with serum albumin included serum creatinine, 24-hour creatinine clearance, total cholesterol, fasting triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and 24-hour urine protein excretion. Hypertension was graded 0 for blood pressure less than 130/90 mm Hg while receiving no antihypertensive medications, 1 for increased blood pressure treated with at most one medication, and 2 for increased blood pressure treated with more than one medication. Also recorded was whether patients were being treated with an angiotensinconverting enzyme inhibitor, beta-blocker, calcium antagonist, diuretic, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, or another antilipemic agent.
Analysis To examine possible clinical factors that could influence serum albumin levels, we carried out stepwise, multiple linear regression analysis. Separate models were examined for semm albumin measured at 3, 6, 12, and 24 months. Only actual measured values were included in this analysis. To examine the relationship between serum albumin and mortality, univariate survival analysis was carried out using standard Kaplan-Meier lifetables and univariate Cox proportional hazards analysis. Covariates that tended to correlate with endpoints on univariate analysis (P < 0.15) were examined using multivariate analysis with Cox proportional hazards models with both fixed and time-dependent covariates. In the survival analysis, patients who returned to dialysis or were lost to follow-up were censored at that time. In the Cox analysis, posttransplant variables that could assume different values at different times (eg, albumin and cholesterol) were treated as time-averaged, time-dependent covariates, whereby the value at any time was the average of all values that occurred before that time. Discrete posttransplant events (eg, acute rejection) were handled as timedependent covariates in the Cox analysis and were treated as being absent until the time of occurrence and then present thereafter. Pretransplant variables were used as fixed (discrete or parametric) covariates in the univariam and multivariate Cox analysis. Since most cytomegalovirus infections occurred within the first 6 months posttransplant when no endpoints occurred, this was also treated as a fixed covariate. For the multivariate survival analysis, we imputed missing laboratory values so as not to exclude each case with any missing value and thereby potentially bias the results. Missing values were imputed as the average of values occurring immediately before and after the missing value when these values were. known. Others were randomly imputed assuming a normal distribution of missing values with the same mean and standard deviation as the known values at the same time
of follow-up.4 The percentages of values that were estimated as the means of values before and after the missing value were 5.7% for cholesterol, 6.4% for triglycerides, 16.8% for high-density lipoprotein, 6.0% for serum albumin, 5.3% for urine protein, 1.3% for creatinine, and 7.2% for creatinine clearance. The percentages of values that were randomly imputed were 4.8% for cholesterol, 5.1% for triglycerides, 24.3% for high-density lipoprotein, 5.2% for serum albumin, 8.5% for urine protein, 2.6% for serum creatinine, and 9.4% for cmatinine clearance. There were 6,029 actual and imputed values for each posttransplant variable, ie, the sum of each number of values at each time posttransplant was 6,029. The effects of the randomly imputed missing values were examined by comparing the results derived from five separate data sets, each with different randomly imputed missing values. In every case, the final Cox proportional hazards models derived from the different randomly imputed data sets were almost identical, indicating that the random imputation had little impact on the final results. Data were analyzed using the statistical software packages SPSS and BMDP.5,6 Final results were considered significant for P < 0.05. Values are reported as mean -t SD unless otherwise indicated. RESULTS
Patient Characteristics There were 706 transplants performed in 675 patients. The age of the recipients was 40.6 + 13.2 years, 56.4% were men, 4.1% were black, and 3.1% were American Indian. The cause of end-stage renal disease was diabetes in 28.2%, chronic glomerulonephritis in 33.9%, and polycystic kidney disease in 9.6%. There were 11.6% who had received a previous transplant and 11.2% who had live donors. Pretransplant splenectomy had been carried out in 68.1%, a practice largely abandoned more recently. Bilateral nephrectomy was performed prior to transplantation in 30.9%. All patients received azathioprine and corticosteroid-based immunosuppression. Minnesota antilymphocyte globulin was used for induction therapy in 88.7%. In 35.4% cyclosporine was used as prophylactic immunosuppression once renal function was established. The cyclosporine was electively withdrawn in 80% of these patients 1.2 ? 0.4 years after transplantation. An attempt was made to covert 63.8% of patients to alternate-day prednisone 1.9 + 1.2 years after transplantation. However, 36.1% of these patients returned to daily prednisone some time later. Chronic liver disease was diagnosed in 89 (12.6%) of patients 1.9 f 2.2 years (range, 0.1
Fig 1. Serum albumin levels after renal transolantation MD) and the oerAntageof‘pGiantswitkalbumin levels ~3.5 g/dL (bottom). The number of patients in whom albumin was measured each time after transplantation is shown above the abscissa in the bottom panel.
Low 3o Serum nn Albumin ” (“w
10 n=692 0
to 9.1 years) after transplantation. Malignancies were diagnosed in 45 (6.3%) patients 5.8 + 4.4 years (range, 0.2 to 16.2 years) after transplantation. A major (nonfatal) cardiovascular disease event occurred 4.1 ? 3.1 years (range, 0.1 to 11.3 years) in 97 (13.7%) patients. The time to death, return to dialysis, or last follow-up was 7.0 + 4.2 years (range, 0.5 to 18.8 years). At the time of last follow-up, 171 (24.2%) patients had died and 146 (20.1%) patients had returned to dialysis. There were 22 (3.1%) patients who transferred to another center or were lost to follow-up 4.6 & 2.8 years (range, 1.0 to 11.7 years) after transplantation. Serum Albumin Levels Serum albumin was lowest and hypoalbuminemia (53.5 g/dL) was most common at 3 months after transplantation (Fig 1). Albumin levels were highest 1 year posttransplant. Thereafter, albumin levels progressively declined in patients who survived with functioning allografts (Fig 1). Clinical Correlates to Serum Albumin A number of clinical characteristics were independently associated with serum albumin after transplantation (Table 1). Age, diabetes, cytomegalovirus infection, proteinuria, and reduced renal function were each associated with lower
591 I 2
204 I 6
122 I 10
77 I 12
Years After Transplantation
albumin after transplantation. Serum albumin was higher in patients transplanted in the earliest, pre-cyclosporine era. Glomerulonephritis as a cause of renal disease and delayed graft function were associated with lower albumin only at 3 months. Relationship Between Serum Albumin and Mortality Serum albumin levels, even when in a range considered to be normal, correlated with mortality on unadjusted, univariate analysis (Fig 2). In multivariate Cox proportional hazards analysis, the ability of albumin to predict mortality was independent of age, diabetes, serum lipids, renal function, and other variables (Table 2). In particular, the effects of albumin were independent of the development of potentially fatal chronic diseases. Analyzed separately, the relative risks and 95% confidence intervals were 2.41 (1.66, 3.50) for chronic liver disease, 8.42 (5.54, 12.82) for non-skin malignancy, and 3.19 (2.24, 4.54) for cardiovascular disease. The association between albumin and mortality was evident for albumin values measured at different times after transplantation (Table 3). Importantly, the effect of albumin on mortality was evident even when deaths occurring within several years after albumin was measured were excluded from the analysis (Table 4).
GUIJARRO ET AL
120 Table 1. Independent
to Serum Albumin Posttransplant
Pretransplant renal disease Diabetes Glomerulonephritis Early transplant era Age (each decade) Proteinuria (each g/24 hr) Estimated GFR (each 10 mUmin) Cytomegalovirus infection Delayed graft function Chronic disease Living donor Constant
-0.13 -0.09 0.16 -0.10 -0.11 0.03 -0.25 -0.07
(-0.21, -0.05) (-0.16, -0.02) (0.09, 0.22) (-0.13. -0.08) (-0.15, -0.06) (0.02, 0.04) (-0.32, -0.19) (-0.13, -0.00)
0.18 -0.07 -0.06 0.03 -0.08
(0.12, 0.25) (-0.10, -0.05) (-0.09, -0.03) (0.02, 0.04) (-0.14, -0.01)
0.13 (0.07, 0.19) -0.07 (-0.09, -0.05) -0.10 (-0.14, -0.06) -0.08
4.11 (3.94, 4.28)
The relationship between albumin and mortality was independent of cause of death. For example, 32 of the 171 deaths were due to cardiovascular disease. In multivariate Cox proportional hazards analyses, serum albumin was an independent risk factor for both cardiovascular deaths (relative risk = 0.28; 95% confidence interval = 0.09, 0.94) and noncardiovascular deaths (relative risk = 0.19; 95% confidence interval = 0.11, 0.33).
The present results demonstrate that hypoalbuminemia is common in the late posttransplant period and serum albumin is a strong predictor of mortality in this population. Although the causes of hypoalbuminemia in this setting are unclear, a number of clinical findings correlate
4.29 (4.19, 4.40)
0.15 -0.06 -0.07 0.01
(0.09. 0.21) (-0.08, -0.04) (-0.09, -0.05) (0.00, 0.02)
-0.15 (-0.24, -0.07) 0.16 (0.08, 0.25) 4.12 (3.98, 4.25)
each P < 0.05, for serum
24 ma (n = 524)
with low serum albumin. However, none of these clinical correlates could entirely explain the relationship between albumin and mortality. Few studies have systematically examined serum albumin after renal transplantation.7W’0 Albumin levels have been reported to decline in the very early posttransplant ~eriod,~ and low albumin has been attributed to the effects of surgery and corticosteroids.’ Although serum albumin measured late after renal transplantation generally has been reported to be normal, the numbers of patients were relatively small in these investigations.“” In the present study, hypoalbuminemia became increasingly common with longer duration of follow-up in the late posttransplant period (Fig 1). There are a number of potential causes of hypoalbuminemia after renal transplantation. In
207 L -----*-----c----,
3.99 (3.84, 4.14)
NOTE. Values are multiple linear regression coefficients and (in parentheses) (g/dL) measured at 3,6,12. and 24 months posttransplant. Abbreviation: GFR, glomerular filtration rate.
12 mo (II = 610)
Serum Abumin 18.104.22.168 gdL (n=407)
Serum Abumin S3.5 g&l (n=BO)
Fig 2. Actuarial survival (Kaplan-M&r) for three lew els of mean postbamplant 55wm albumin. Th5 numkr5indiith5numb5fof patied analyzed at 5aoh
ences were signlfkant Mantel-cox (P < O.am).
Table 2. Independent Risk Factors for Death After Renal Transplantation Relative Risk (95% Confidence Interval) Independent
Serum albumin (each g/dL) Age (each decade) ESRD from diabetes HDL cholesterol (each 10 mg/dL) Creatinine clearance (each 10 mUmin) Alternate-day prednisone Chronic disease
0.26 1.53 1.71 0.83
(0.16, (1.34, (1.22, (0.74,
0.44) 1.75) 2.40) 0.93)
0.85 0.44 4.26
(0.79, (0.23, (3.11,
0.92) 0.87) 5.85)
NOTE. Results of multivariate Cox proportional hazards analysis. Failure of a confidence interval to include 1 .OO (no risk) indicates P < 0.05. Abbreviations: ESRD, end-stage renal disease; HDL, high-density lipoprotein.
general, hypoalbuminemia can result from decreased hepatic synthesis, increased catabolism, protein loss from the intravascular space, or plasma dilution. Decreased synthesis and increased catabolism of albumin secondary to corticosteroids could play a role in transplant recipients.‘* However, serum albumin was not different whether patients were treated with daily or alternate day prednisone (15 mg every other day) in the late posttransplant period. Not surprisingly, conditions known to be associated with low serum albumin (eg, chronic diseases and proteinuria) were associated with low serum albumin after transplantation (Table 1). Table 3. Relative Risk Associated With Serum Albumin Levels at Different Times After Transplantation Time After Transplantation’
3 6 12 24-60 ~60
mo mo mo mo mo
Relative Risk Confidence Interval)
0.43 0.28 0.27 0.28 0.25
(0.31, (0.19, (0.18, (0.19, (0.16,
0.58) 0.42) 0.41) 0.42) 0.39)
NOTE. Results of univariate Cox proportional hazards analysis. Failure of a confidence interval to include 1 .OO (no risk) indicates P < 0.05. Relative risk is for each g/dL increment in serum albumin. * Cases were excluded from analysis if survival or follow-up time did not exceed this interval.
Table 4. Relationship Between Time of Albumin Determination and its Association Wti Death Interval Years Between Albumin Determination and Death (yr)
0 >2 >4 >6 >8 >lO
706 625 525 374 255 161
Relative Risk Confidence Interval)
0.09 0.15 0.29 0.23 0.21 0.30
(0.06, (0.09, (0.15, (0.15, (0.07, (0.08,
0.15) 0.28) 0.58) 0.54) 0.59) 1.07)
NOTE. Results of univariate Cox proportional hazards analysis. Failure of a confidence interval to include 1.00 (no risk) indicates P < 0.05. Relative risk is for each g/dL increment in serum albumin. * Cases were excluded from analysis if survival or follow-up time did not exceed this interval.
Older individuals had lower serum albumin, a finding also reported in the general population (Table 1).‘“-‘5 The association between diabetes and reduced albumin could be a result of poor nutrition, or, as recently suggested, could be caused by a generalized transcapillary escape phenomenon.16 The lower serum albumin in patients with cytomegalovirus is consistent with the effects of other acute infections on serum albumin.17 Also not surprising was the fact that delayed graft function was associated with lower albumin, but only at 3 months after transplantation. Interestingly, patients in whom end-stage renal disease was caused by glomerulonephritis also had lower albumin 3 months after transplantation, possibly due to proteinuria from the native kidneys. Reduced renal function was associated with lower albumin (Table 1). However, renal function was also inversely correlated with the number of acute rejection episodes at 3 months (r = -0.35, P < O.OOl), 6 months (r = -0.30, P < O.OOl), 1 year (r = -0.27, P < O.OOl), and 2 years (r = -0.36, P < 0.001). Thus, whether renal function per se caused lower albumin or whether acute rejections, their treatment, and their complications caused the lower albumin levels is unclear. It is also unclear why patients transplanted in the early, pre-cyclosporine era (1976 to 1983) had higher albumin levels (Table 1). However, several variables associated with serum albumin
on univariate analysis (eg, years of pretransplant dialysis, proportion of living-related donors, and use of cyclosporine [data not shown]) were less in the early transplant era. Thus, these and other factors could explain the association between transplant era and serum albumin. Although it is unclear why serum albumin predicted mortality after renal transplantation, our analysis suggests that this association was not entirely attributable to severe disease and preterminal conditions. In fact, serum albumin levels correlated with mortality even when the analysis was restricted to patients dying several years after albumin was measured (Table 4). Determining the maximum interval over which albumin had an effect on mortality seemed to be limited only by the number of cases with sufficiently long duration of follow-up. In addition, the relationship between serum albumin and mortality was independent of clinically apparent, chronic diseases (Table 2). It is possible, of course, that chronic disease not measured by the clinical parameters included in the present analysis influenced serum albumin levels. It is also possible that the effect of inadequate nutrition reflected in low serum albumin may have continued to influence mortality over many years. The independent association between serum albumin and mortality after renal transplantation adds to the growing list of populations in which albumin has been shown to be a strong predictor of all-cause mortality. Indeed, the association between albumin and mortality observed in the present study is similar to that reported for patients treated with hemodialysis’-’ and to that noted in the general population.“-‘5.‘8-20 A number of possible mechanisms have been suggested to explain the association between low serum albumin and mortality, including (1) immune dysfunction and a chronic inflammatory state associated with potentially deleterious increases in rytokine production,‘7,2’ (2) generalized increased vascular permeability due to underlying disease,16 (3) increased availability to cells of potentially toxic iron,18 and (4) a decrease in the antioxidant potential of plasma.22 In addition, in transplant recipients changes in serum albumin levels could have important effects on the pharmacokinetic and/or pharmacodynamic actions of immunosuppressive medications. Clearly, additional studies are needed to better define the pos-
sible mechanisms linking albumin levels to mortality. Ultimately, controlled clinical trials may be warranted to determine whether nutritional intervention can raise serum albumin levels and whether such intervention may influence mortality. ACKNOWLEDGMENT The authors thank Jan Lovick for help in preparing this manuscript. REFERENCES 1. Lowrie EG, Lew NL: Death risk in hemodialysis patients: The predictive value of commonly measured variables and an evaluation of death rate differences between facilities. Am J Kidney Dis 15458482, 1990 2. Lowrie EG, Lew NL: Commonly measured laboratory variables in hemodialysis patients: Relationships among them and to death risk. Semin Nephrol 12:276-283, 1992 3. Is&i K, Kawazoe N, Fukiyama K: Serum albumin is a strong predictor of death in chronic dialysis patients. Kidney Int 44:115-119, 1993 4. Rubin DB, Schenker N: Multiple imputation in heahhcare databases: An overview and some applications. Stat Med 10585-598, 1991 5. Norusis MJ: Statistical Package for the Social Sciences (SPSS/PC+ V2.0): Base Manual. Chicago, IL, SPSS Inc. 1988 6. Dixon WJ, Brown MB, Engelman L, Franc JW, Hill MA, Jemnich RI, Toporek JD: Statistics: BMDP Statistical Software.. Berkeley, CA, University of California Press, 1985 7. Vaziri ND, Forthal D: Hypoalbuminemia after renal transplantation. Arch Surg 115:286-289, 1980 8. Aplasca EC, Rammohan M: The effect of prednisone on the levels of serum albumin of 20 patients with renal transplants. J Am Diet Assoc 86:1404-1405, 1986 9. Miller DG, Levine SE, D’Elia JA, Bistrian BR: Nutritional status of diabetic and nondiabetic patients after renal transplantation. Am J Clin Nutr 4466-69, 1986 IO. Qureshi AR, Lindholm B, Alvestrand A, Bergstrom J, Tollemar J, Huhman E, Groth CG: Nutritional status, muscle composition and plasma and muscle free amino acids in renal transplant patients. Clin Nephrol 42:237-245, 1994 11. Buggy D, Breathnach A, Keogh B, Cooke T, Feely J: Lipoprotein(a) and treatment of chronic renal disease. J Intern Med 234:453-455, 1993 12. Seagraves A, Moore EE, Moore FA, Weil R III: Net protein catabolic rate after kidney transplantation: Impact of corticosteroid immunosuppression. J Parental Enteral Nutr 10:453-455, 1986 13. Phillips A, Shaper AG, Whincup PH: Association between serum albumin and mortality from cardiovascular disease, cancer, and other causes. Lancet 2: 1434-1436, 1989 14. Klonoff-Cohen H, Barrett-Connor EL, Edelstein SL: Albumin levels as a predictor of mortality in the healthy elderly. J Clin Epidemiol 45:207-212, 1992 15. Kuller LH, Eichner JE, Orchard TJ, Grandits GA, McCallum L, Tracy RP: The relation between serum albumin
SERUM ALBUMIN AFTER RENAL TRANSPLANTATION levels and risk of coronary heart disease in the Multiple Risk Factor Intervention Trial. Am J Epidemiol 134:1266-1277, 1991 16. Feldt-Rasmussen B: Increased transcapillary escape rate of albumin in type 1 (insulin-dependent) diabetic patients with microalbuminuria. Diabetologia 29:282-286, 1986 17. Fleck A: Clinical and nutritional aspects of changes in acute-phase proteins during inflammation. Proc Nutr Sot 48:347-354, 1989 18. Stevens RG, Jones Y, Micozzi MS, Taylor PR: Body
123 iron stores and the risk of cancer. N Engl J Med 319:10471052, 1988 19. Gillum RF, Makuc DM: Serum albumin, coronary heart disease, and death. Am Heart J 123507513, 1992 20. Gosling P, Beevers DG, Goode GE, Hickey NC, Littler WA, Shearman CP, Sheridan JJ, West JNW: Letter. Lancet 1:350-351, 1990 21. Grimble R: Letter. Lancet 1:350, 1990 22. Halliwell B: Albumin-An important extracellular antioxidant? Biochem Pharmacol 37:569-571, 1988