The Natural History of Urate Overproduction in Sickle Cell Anemia
HERBERT S. DIAMOND, M.D.; ALLEN D. MEISEL, M.D.; and DOROTHY HOLDEN, M.D.;
Brooklyn, New York.
Serum uric acid and uric acid excretion were studied in 9 5
patients with sickle cell anemia ranging in age from 17
months to 4 5 years to ascertain the natural history of
urate overproduction. Hyperuricemia was infrequent in
children with sickle cell anemia, but was found in 26 of 6 7
adults ( 3 9 % ) . Thirty-six patients studied in a clinical
research center had a mean urate clearance of 9.1 + 0.8
mL/min. Patients with sickle cell anemia were often
normouricemic despite urate overproduction.
Normouricemia was maintained by increased urate
clearance, which was attributed to increased urate
secretion. The hyperuricemic patients had decreased
urate clearance with decreased pyrazinamidesuppressible urate clearance. Para-aminohippurate
clearance was decreased to 6 3 4 mL/min in the
hyperuricemic patients with sickle cell anemia compared
with 8 5 3 mL/min in normouricemic hyperuricosuric
subjects with sickle cell anemia. Hyperuricemia occurs
only in patients who develop altered renal tubular function
with diminished urate clearance secondary to diminished
urate secretion.
IvIosT SUBJECTS with urate overproduction are not identified until they present in adult life with gout, renal
stone, or hyperuricemia. Urate overproduction in such
patients is thought to have been present for many years
before clinical recognition. However, because these subjects are asymptomatic until well into adult life, there
have been few studies of urate overproduction during its
asymptomatic or preclinical phase.
The increase in erythrocyte turnover associated with
sickle cell anemia is known to result in uric acid overproduction (1-5). Because the increase in erythrocyte turnover in these patients begins in childhood, urate overproduction probably begins at an early age. Yet, gout is an
uncommon complication of sickle cell disease and has
rarely been noted before age 30 (6). Patients with sickle
cell disease can readily be identified early in life. To ascertain the natural history of serum uric acid and uric
acid excretion in sickle cell disease, 95 patients with sickle cell anemia, ranging in age from 17 months to 45 years,
were studied.
Method
For screening purposes, serum samples were obtained from
subjects in the adult and pediatric sickle cell clinics at Kings
County Hospital, Brooklyn, New York, and from sickle cell
patients seen in the adult hematology clinic at Downstate Medical Center, Brooklyn, New York. A medication history was
obtained on all subjects, and subjects who had taken drugs
known to affect serum uric acid were not included.
Thirteen adults with sickle cell anemia and hyperuricemia
• F r o m the Downstate Medical Center, State University of New York; Brooklyn,
New York.
752
defined as a serum uric acid concentration of greater than 6.5
m g / d L were studied. The definition of hyperuricemia is based
on the level at which serum becomes supersaturated with urate,
6.4 to 6.8 m g / d L (7, 8), rather than an epidemiologic value for
a largely white population. The patients were admitted to the
Clinical Research Center, Downstate Medical Center, and
maintained on a normal-protein (60 to 80 g), essentially purinefree (300 to 500 mg) isocaloric diet. All medications affecting
urate excretion were withdrawn at least 4 d before the study,
and 3 d were allowed for dietary adjustments. N o patients were
on allopurinol before admission to the Clinical Research Center. All studies were done after signed informed consent was
obtained in accordance with a protocol approved by the Human
Research Committee. The patients and normal control subjects
ranged in age from 16 to 46 years. None of the patients were
hypertensive (Table 1), and none had clinical extracellular fluid
contraction or congestive heart failure at the time of these studies. A total of 108 clearance studies were done in 36 patients
with sickle cell anemia and 36 clearance studies in 12 normouricemic healthy control subjects. In all subjects, the creatinine
clearance was greater than 75 mL/min 1.73 m2. All 14 of the
patients with sickle cell anemia were black, as were five of the
12 control subjects. Clearance values were not corrected for
surface area. Mean surface area was less in the patients with
sickle cell anemia than in the normal control subjects. If clearance values were corrected for surface area, this would have
accentuated the differences in urate clearance between the two
groups. Pyrazinamide-suppressible urate excretion in black control subjects was similar to that in the overall control group.
Glomerular filtration rate was estimated on the basis of endogenous creatinine clearance. Urine and serum creatinine were
measured by an Autoanalyzer method (Technicon Corp., Tarrytown, New York). Uric acid levels were measured by an enzymatic spectrophotometric technique (9). Para-aminohippurate
(PAH) levels were measured in urine and plasma by an automated method (10).
CLEARANCE STUDIES
Studies were done in the morning after an overnight fast.
Urine was collected by voiding. All urine specimens exceeded
100 mL in volume. A urine flow rate of approximately 5 m L /
min was established by oral hydration with water before each
clearance study. Thereafter, hydration was limited to replacement of urinary losses. The control phase of each study involved two or three 20-to-30 min clearance periods. The P A H
clearance studies were done in six hyperuricemic patients with
sickle cell anemia, five normouricemic hyperuricosuric patients
with sickle cell anemia, and six normal subjects.
The P A H was administered as a priming dose (PAH 20%, 10
mL; mannitol 25%, 50 mL) followed by a continuous intravenous infusion of P A H (PAH 20%, 90 mL; mannitol 25%, 50
mL; distilled water, 10 mL) administered at a constant rate of 1
to 2 mL/min. Sixty minutes were allowed for equilibration.
Four clearance intervals were then established, with venous
blood samples taken at the midpoint of each clearance interval.
PYRAZINAMIDE STUDIES
In studies of the effect of pyrazinamide on urate excretion, 3
g of pyrazinamide was administered orally at the end of the last
control clearance interval. Urine was collected for three additional clearance periods of approximately 20-min duration be-
Annals of Internal Medicine 90:752-757, 1979
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© 1979 American College of Physicians
Table 1. Clinical Features, Renal Function, and Urate Excretion in Thirteen Hyperuricemic Patients with Sickle Cell Anemia*
Patient
Age, Sex
Hematocrit
Blood
Pressure
Serum Uric
Acid
24-h Urine
Uric Acid
%
mm Hg
mg/dL
mg/24 h
23
18
24
24
17
18
20
25
27
16
26
23
27
110/70
120/60
130/70
130/80
140/90
140/70
120/80
120/70
140/60
110/70
130/80
140/90
130/80
1A
13.8
9.9
7.4
9.7
7.3
7.4
8.1
6.5
8.5
9.5
7.3
9.0
607
296
350
329
431
400
637
749
441
725
298
457
522
yrs
1
2
3
4
5
6
7
8
9
10
11
12
13
24,
21,
28,
17,
16,
38,
18,
18,
16,
16,
46,
32,
27,
F
M
M
M
M
F
M
M
M
M
M
M
M
Cur
Ccr
mL/min
3.6
2.3
1.6
2.6
5.2
6.1
7.2
6.4
10.9
5.6
3.1
6.5
4.3
80
95
83
155
96
83
120
233
133
111
130
165
126
Cur/Ccr X 100
PAH
Clearance
%
mL/min
4.0
3.7
4.2
2.2
4.3
4.8
5.3
2.2
1.9
4.3
2.3
2.8
2.2
..•
...
269
885
535
...
843
676
598
...
* Cur = urate clearance; Ccr = creatinine clearance; PAH = para-aminohippurate.
ginning 90 min after the administration of pyrazinamide. Venous blood specimens were collected at the midpoint of each
clearance interval. Pyrazinamide-nonsuppressible urate excretion and clearance were denned as urate excretion or clearance
in the clearance period with the minimum value for urate excretion after the administration of pyrazinamide (11). Pyrazinamide-suppressible urate excretion was calculated as mean base
line urate excretion minus pyrazinamide-nonsuppressible excretion.
PROBENECID STUDIES
Maximum response to probenecid was measured as previously described (12). In brief, after two control clearance intervals,
probenecid, 2 g, was administered as a single dose at 0900 h.
Four consecutive 30-min urine collections were then done for
the measurement of uric acid and creatinine clearances. Blood
samples were obtained at the midpoint of each clearance interval. Maximum response to probenecid was denned as urate excretion during the period showing maximum urate excretion
after the administration of probenecid minus mean urate excretion during the control intervals.
Results are expressed as mean plus or minus standard error
of the mean. Statistical comparisons were made using paired or
unpaired t tests as appropriate. The P values greater than 0.05
were recorded as nonsignificant.
Results
SERUM URIC ACID
Mean serum uric acid was 4.9 ± 0.2 m g / d L before age
10. Hyperuricemia, defined as a serum uric acid greater
than 6.5 m g / d L was present in four of 28 children. Hyperuricemia was frequent in adults with sickle cell disease, being found in 26 of 67 patients studied (39%).
Both the mean serum uric acid and the prevalence of
hyperuricemia increased with age to a peak of 6.5 i t 0.3
m g / d L and a frequency of hyperuricemia of 4 5 % in patients between ages 21 and 30. Hyperuricemia was less
frequent in the smaller group of patients older than age
30.
URINARY URIC ACID
Urate production was approximated on the basis of
urinary uric acid-to-creatinine ratios (13). In children
younger than age 10, urinary uric acid-to-creatinine ratios exceeded the mean expected level for age in nine of
12 patients studied and exceeded the mean plus two standard deviations in three of 12.
Twenty-four-hour urinary uric acid excretion was measured after 3 to 5 d on a purine-free diet in 36 adult
patients with sickle cell anemia, ranging in age from 16 to
48 years. All were studied while inpatients on a clinical
research ward. Mean urinary uric acid was 574 + 38.0
m g / 2 4 h and exceeded 600 m g / 2 4 h in 20 patients. This
probably underestimates the frequency of uric acid overproduction in these patients. Increased intestinal loss of
urate in some hyperuricemic patients may have resulted
in normal 24-h urinary uric acid excretion despite urate
overproduction. Consistent with this, uric acid excretion
greater than 600 m g / 2 4 h was more frequent in younger
patients, occurring in 15 of 22 patients between ages 16
and 25 compared with five of 14 patients older than age
25. Similarly, uric acid excretion per 24 hours exceeded
600 m g / 2 4 h in 14 of 21 patients with a plasma urate
level less than 6.5 m g / d L , but was increased in only six
of 15 hyperuricemic patients. Thus, there was no correlation between serum uric acid and urate excretion per 24
hours or urinary uric acid-to-creatinine ratios.
URATE CLEARANCE
Mean urate clearance was 9.0 ± 0 . 8 m L / m i n in 36 patients with sickle cell disease and normal glomerular filtration rate studied as inpatients on a clinical research
ward. Urate clearance was inversely correlated with serum uric acid levels in both adults and children with
sickle cell disease (r = 0.67, P < 0.001; Figure 1). This
suggested that urate clearance, rather than urate production was the major determinant of serum uric acid in
sickle cell disease. Consistent with this, mean urate clearance was 5.0 ± 0.7 m L / m i n in the hyperuricemic adults
with sickle cell disease compared with 13.6 ± 0.7 m L /
min in the normouricemic patients (P < 0.001).
Fourteen normouricemic adults with sickle cell disease
had 24-h urinary uric acid excretion greater than 600 mg
while on a purine-free diet, suggesting urate overproduction. Renal handling of urate in 12 of these adults was
studied while they were inpatients on a clinical research
ward. Data on seven of these patients has been published
previously (14). Mean urinary uric acid excretion per 24
hours on a purine-free diet was 735 + 58 mg, and exDiamond et al. • Urate Overproduction
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753
Discussion
Figure 1 . Relation between plasma urate and urate clearance in 3 6
patients with sickle cell anemia studied in a clinical research center
while on a purine-free diet
ceeded 600 m g / 2 4 h in 10 of 12 patients (Table 2). Urate
excretion in these patients was increased compared with
both normal subjects (P < 0.001) and hyperuricemic patients with sickle cell disease (P < 0.001). Urate clearance was increased to 13.6 m L / m i n in these hyperuricosuric normouricemic patients with sickle cell disease
compared with 8.3 ± 0.6 m L / m i n (P < 0.001) in normal control subjects.
Thirteen adult patients with sickle cell disease and serum urate greater than 6.5 m g / d L were studied while
inpatients on a clinical research ward (Table 1). Uric acid
excretion per 24 hours on a purine-free diet was similar in
these patients and normal control subjects, and as already
noted, was significantly less than in the normouricemic
patients with sickle cell disease (Table 2). Urate clearance
was 5.0 m L / m i n in the hyperuricemic patients, significantly less than in both normal control subjects
(P < 0.001) and in normouricemic patients with sickle
cell anemia (P < 0.001). Urate clearance-to-creatinine
clearance ratios were markedly decreased in the hyperuricemic patients with sickle cell anemia.
The decrease in urate clearance in these hyperuricemic
subjects was entirely attributed to a decrease in pyrazinamide-suppressible urate clearance (Table 2). Pyrazinamide-suppressible urate clearance was decreased to
4.9 ± 1.2 m L / m i n in the hyperuricemic patients compared with 11.8 ± 0.6 m L / m i n in the normouricemic patients with sickle cell anemia (P < 0.001) and 7.3 + 0.5
m L / m i n in control subjects (P < 0.001) (Table 2). The
P A H clearance (634 m L / m i n ) was similar to that in control subjects (636 m L / m i n ) , but less than that in hyperuricosuric patients. Clearance of P A H was correlated with
urate clearance in patients with sickle cell disease
(r = 0.53), consistent with decreased secretion of both
urate and P A H in these patients. Peak uricosuric response to probenecid was 18.8 m L / m i n in the hyperuricemic patients with sickle cell disease (Table 3). In contrast, the uricosuric response to probenecid was 45.3 m L /
min in normouricemic patients with sickle cell anemia,
and 37.6 m L / m i n in control subjects (Table 3).
754
Urate excretion per 24 hours, considered to be a measure of uric acid production, is frequently increased in
subjects with sickle cell disease, suggesting uric acid overproduction (1-5). However, serum uric acid concentration in sickle cell disease does not correlate with urate
production, but seems to be inversely related to urate
clearance. Patients with sickle cell anemia increased 24-h
urinary uric acid excretion are, in fact, often normouricemic (14). Normouricemia in young patients with sickle
cell disease is associated with increased urate clearance
and has been attributed to enhanced urate secretion (14).
In contrast, approximately 40% of adults with sickle cell
anemia are hyperuricemic (4, 5).
Although uric acid overproduction in sickle cell anemia begins in childhood, hyperuricemia is infrequent before age 10 and has a peak prevalence in the third decade
of life. Hyperuricemia, at any age, tends to occur in the
patients with the lowest urate clearance, irrespective of
measures of urate production.
Surprisingly, urate overproduction has little influence
on serum uric acid concentration, but appears to correlate with increased urate clearance and hyperuricosuria.
This increase in urate clearance may be a normal renal
response to an increased urate load. That major alterations in exogenous urate load result in relatively small
changes on serum uric acid is well known (15). Healey
and Bayani-Sioson (16) made 10 normal subjects hyperuricemic by feeding them yeast RNA. All 10 of the normal white subjects showed a marked increase in urate
clearance. In unpublished observations, we have noted
that normal subjects fed lesser amounts of yeast R N A
increased both their urate clearance and serum uric acid
levels. However, the increase in urate excretion was sufficient to avoid the development of hyperuricemia. In paTable 2. Renal Function and Uric Acid Excretion in Hyperuricemic
Patients with Sickle Cell Anemia Compared with Normal Subjects
Subjects, no.
Plasma urate, mg/dL
24-h urinary uric acid
excretion, mg/min
Uric acid clearance,
mL/min
Creatinine clearance,
mL/min
Pyrazinamidesuppressible urate
clearance, mL/min
Pyrazinamidenonsuppressible
urate excretion,
ng/min
Para-aminohippurate
clearance, mL/min
Hyperuricemic
Patients with
Sickle Cell
Anemia
Normouricemic,
Hyperuricosuric
Patients with
Sickle Cell
Anemia
Normal
Subjects
13
8.6 ± 0.5*
12
4.9 ± 0.3
12
5.3 ± 0.3
480 ± 45
735 ± 58*
400 ± 48
5.0 ± 0.7*
13.6 ± 0.7*
8.3 ± 0.6
132 ± 9.2
130 ± 9.2
108 ± 4.5
4.9 ± 1.2*
11.8 ± 0.6*
7.3 ± 0.5
41.7 ± 8.5
38 ± 5.9
53 ± 6.6
634 ± 92
853 ± 77*
* P < 0.001 is compared with normal subjects.
May 1979 • Annals of Internal Medicine • Volume 90 • Number 5
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634 ± 42
Table 3. Effect of Probenecid on Uric Acid Excretion and Clearance in Hyperuricemic Patients with Sickle Cell Anemia; Normouricemic, Hyperuricosuric Patients with Sickle Cell Anemia; and Normal Subjects*
Subject
Control
UurV
Cur
iig/min
mL/min
Hyperuricemic subjects with sickle cell anemia
1
324
5.5
2
348
3.2
4
340
5.1
5
409
3.2
8
520
6.4
9
329
6.2
10
341
4.1
13
275
3.8
Mean
4.81
3611
SEM
26
0.4
Normouricemic, hyperuricosuric subjects with sickle cell anemia
1
623
10.0
2
503
9.7
3
646
17.7
4
838
15.2
5
642
15.9
6
596
14.2
7
539
10.6
8
516
9.5
9
640
9.5
10
701
13.9
Mean
624 f
12.6f
SEM
33
1.0
Normal subjects
1
541
9.5
2
336
7.0
3
535
9.2
4
494
9.7
5
360
8.2
6
595
10.7
Mean
477
9.1
SEM
47
0.6
Change in Urate Excretion
after Prooenecia. z g
UurV
Cur
Peak Response to
Probenecid5 *^ g
Cur
UurV
tig/min
mL/min
fxg/min
mL/min
1092
595
1043
1879
831
2419
1674
1439
1372
213
19.9
4.3
16.0
16.3
10.3
42.7
22.6
18.2
18.8f
4.0
768
247
703
1470
311
2150
1333
1164
931
258
14.4
1.1
10.9
13.1
4.1
36.5
17.9
14.4
14.0
3.8
2105
1515
4452
2700
2390
1223
1834
2495
3334
1585
2363
322
39.7
27.0
89.0
51.5
52.0
33.6
42.0
38.6
53.8
26.0
45.3
6.1
1482
1012
3806
1862
1748
627
1296
1979
2694
884
1739
315
29.7
17.3
71.3
36.3
36.1
19.4
31.4
29.1
43.3
11.9
32.6
5.6
3340
1261
2841
1331
1836
1495
2017
389
65.5
29.3
48.4
18.9
39.9
23.7
37.6
7.8
2799
931
2306
837
1476
900
1541
372
56.0
22.3
39.2
9.2
31.7
13.0
28.6
7.8
* UurV = total urine urate, Cur = urate clearance.
t P < 0.05 as compared with normal subjects.
t P < 0.001 as compared with normal subjects.
tients with urate overproduction of moderate degree, hyperuricemia may be limited to those whose urate clearance is diminished or who do not respond to an increased
urate load with an increase in urate clearance.
Serum urate concentration is usually maintained within a narrow range in healthy humans, and urate elimination, which is largely by renal excretion, closely approaches the sum of new purine biosynthesis plus dietary
purine intake (17). Filtered urate is completely or almost
completely reabsorbed in the renal tubules. Additional
urate is secreted into the tubule, and most secreted urate
is also reabsorbed.
To better define tubular transport of urate in sickle cell
patients renal clearance studies were done in these patients after administration of either pyrazinamide or probenecid. Interpretation of these results depends on assumptions about the mechanism of action of pharmacologic inhibitors of urate transport. The dominant effect of
pyrazinamide at blood concentrations attained in man is
inhibition of urate secretion, although concomitant inhibition of urate reabsorption cannot be excluded (18, 19).
Changes in pyrazinamide-suppressible urate clearance
are nonspecific. Decreased pyrazinamide-suppressible
urate clearance as observed in hyperuricemic patients
with sickle cell disease would be expected to occur in
patients with diminished urate clearance, either because
of impaired secretion or diminished reabsorption of secreted urate.
The uricosuric effects of probenecid have generally
been accepted as representing inhibition of urate reabsorption (20, 21). Probenecid is secreted by the same organic acid secretory carrier responsible for para-aminohippurate transport, and secretion seems to be required
for the uricosuric effect (20-22). This secretory mechanism is independent of the urate transport mechanism
(23, 24). Probenecid seems to be a poor inhibitor of urate
reabsorption occurring in the early proximal tubule
(largely reabsorption of filtered urate) and a better inhibitor of urate reabsorption in more distal segments of the
nephron where reabsorption of secreted urate is likely to
predominate (24). Uricosuric response to probenecid
would be expected to be intact or enhanced in patients
with increased reabsorption of secreted urate and diminished in patients with impaired urate secretion (17, 25).
Diamond eta/.
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• Urate Overproduction
755
Thus, the diminished uricosuric response to probenecid
observed in hyperuricemic sickle cell patients suggests
impaired urate secretion. We have previously reported
that hyperuricosuric normouricemic patients with sickle
cell anemia have increased urate secretion (17). Alternatively, the decrease in probenecid response could be due
to a decrease in probenecid transport resulting in a lesser
concentration of probenecid at the intraluminal reabsorptive site.
Clearance of P A H was positively correlated with urate
clearance in patients with sickle cell disease. Mean P A H
clearance was increased in the patients with hyperuricosuria and normouricemia and normal in the hyperuricemic patients who had diminished urate clearance.
These results are consistent with the observation of Etteldorf and coworkers (26, 27). They noted increased P A H
clearance and increased excretory capacity for P A H in
children and young adults with sickle cell disease. Both
PAH clearance and tubular maximum fell with age, but
more slowly than glomerular nitration rate. In young
adults with sickle cell anemia, increased renal blood flow
might account for both enhanced urate and P A H secretion. Increased tubular secretion might be secondary to
altered intrarenal hemodynamics due to sickle cell disease (27). As the disease progresses with microinfarctions
of the kidney, and perhaps renal damage secondary to
hyperuricosuria, the renal blood flow decreases with resultant decreases in both P A H and urate clearance, ultimately leading to hyperuricemia.
Although urate overproduction in sickle cell disease
begins in childhood, patients with sickle cell anemia often
remain normouricemic into adult life. Normouricemia is
maintained by increased urate secretion and urate clearance. Increased secretion may be secondary to increased
renal blood flow associated with sickle cell disease (27) or
a physiologic response to an increased urate load (28).
Hyperuricemia occurs only in those patients who develop
diminished urate clearance. Diminished urate clearance
in sickle cell disease is probably secondary to altered renal tubular function resulting in diminished urate secretion. T h e delayed onset of hyperuricemia probably accounts for the low frequency of gout in young adults with
urate overproduction secondary to sickle cell disease.
The applicability of these observations to patients with
urate overproduction of other causes is uncertain. Subtle
defects in renal tubular function are found in many patients with gout (29, 30). Emerson and Roe (31) have
suggested a similar scheme for the natural history of hyperuricemia in patients with marked urate overproduction due to hypoxanthine guanine phosphoribosyl
transferase deficiency. In these patients renal damage is
presumably secondary to hyperuricosuria, whereas in patients with sickle cell anemia renal damage may be secondary to sickle cell disease.
Hirschl Career Scientist Award. Dr. Meisel is a Clinical Associate Physician
of the General Clinical Research Center Program of the Division of Research Resources and is supported in part by Grant RR318.
• Requests for reprints should be addressed to Herbert S. Diamond, M.D.;
Downstate Medical Center, Box 42; 450 Clarkson Avenue; Brooklyn, NY
11203.
Received 27 November 1978; revision accepted 17 January 1979.
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ACKNOWLEDGMENTS: The authors thank Ms. Ida Walters and the staff
of the Clinical Research Center for their aid in these studies, and Ruth
Weliky for secretarial support.
Grant support: Grant HL-15170 from the National Heart Institute, National Institutes of Health; Grant RR318 from the General Clinical Research Center Program of the Division of Research Resources; and a grant
from the Kroc Foundation. Dr. Diamond is supported in part by an Irma T.
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