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Renal function in gout
Renal Function in Gout V. Factors Influencing the Renal Hemodynamics
TS’AI-FAN
Yij, M.D.
LAWRENCE DOUGLAS HARRY
BERGER,
M.D.
J. DORPH,
M.A.
SMITH,
Ph.D.
New York, New York
From the Department of Medicine and the Department of Biostatistics. Mount Sinai School of Medicine, The City University of New York, New York, New York. This study was supported in part by Grant AM-00162, National Institute of Arthritis, Metabolism and Digestive Diseases, NIH, Grant FR-71, the Division of Research Rcsourccs, General Clinical Research Centers Branch, NIH. Computing was carried out at the City University of New York Computing Center. Requests for reprints should be addressed to Dr. Ts’ai-Fan Yii, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, New York 10029. Manuscript accepted June 27,1979.
766
Renal hemodynamics as measured by inulin clearance (Cin& and para-aminohippurate clearance (CPM) was evaluated in 149 patient! with primary gout over intervals of two to 22 years. In over 30 pel cent of the patients plasma urate was >lO mg/dl and urinary uric acid >800 mg/min. A linear trend in decreasing frequency of hy peruricemia and excessive uricosuria is significantly related to the patient’s age at the onset of gout. Group I consisted of 84 patients with uncomplicated gout in botl clearance studies. C&in and CPAH were somewhat lower in patient9 >50 years of age with longer duration of gout. Further reduction ir clearances was minimal at the second clearance study in intervak of approximately 10 years. Group II included 27 patients who had no associated disease at the time of the first clearance study but ir whom associated disease had developed by the time of the seconc clearance study. A striking reduction in Cinuttn and Cr~n was noted especially in those 50 years old or above. There were 38 patients in group III with associated diseases at the time of both clearance studies. They had lower Cinutin and CPM at the time of the first study particularly the older patients. Further reduction during the second study was less striking than that in group II. Analyses of variance suggest that various coexisting vascular dis eases with associated nephropathy have the most significant impac on the status of renal function in gout, with aging the second mos important and duration of gout, the third. Our previous studies in patients with gout have led us to believe tha renal elimination of uric acid in patients with primary gout is cornpa, rable to that in normal subjects [l-3]. Renal function as measured bj Cinutin for glomerular filtration rate and CPAH for estimated rena plasma flow is usually not adversely affected in uncomplicated gou or hyperuricemia. In only a very few exceptional gouty patients havt we seen nephropathy without associated disease. These include certair patients-usually young with severe recurrent intractable attacks o acute gout, not able to be controlled with routine antigouty measures and with no detectable abnormalities in purine metabolizing enzymes They are designated as having fulminating gout. Another group wit1 nephropathy unassociated with other diseases have hypoxanthine guanine-phosphoribosyltransferase (HPRT) deficiency and uratc urolithiasis [4-61. When renal function does deteriorate in the patien with primary gout, it is correlated with the development of associatec disease such as independently occurring nephropathy, hypertensior with nephrosclerosis, diabetes with nephropathy, renal arteriosclerosi: and arteriolosclerosis [5].
November 1979 The American Journal of Medicine
Volume 67
TABLE I
Clinical Status of 149 Patients with Primary Gout AssociatedDiseases Renal Calculi
Group
No.
s
R
I
84 27 38t
13 6 6
11 3 5
II III
Hypertension 10’ 25 15
NOTE: S = single; R = recurrent: CRD = chronic renal disease; ACCVD = arteriosclerotic * Labile hypertension. 1Intermittent hyperglvcemia. x Includes four with fulminating gout.
In an attempt to better document this concept, we have carried out a computer-assisted analysis of 149 patients with primary gout, in whom measurements of glomerular filtration rate and renal plasma flow were made at least twice over intervals as long as 22 years.
MATERIALS
AND METHODS
At the time of the renal
ClCaMnCC studies, all 149 patients were ambulatory and had not been receiving any drugs sufficiently long enough to assure measurement of their true basal plasma urate level (P,,,.i,tJ. In over 30 per cent of the patients urinary uric acid excretion was above 800 &min. Patients were divided into three groups [Table I). Group I consisted of 84 pa-
ticnts
with
uncomplicated
primary
gout at both clearance
stutlics. Ten did have mild labile hypertension,
and seven had intermittent hyperglycemia without glycosuria. Group II included 27 patients with uncomplicated primary gout at the first clearance study. By the second clearance study at least one associated disease causing renal damage had developed in (!;lch of these patients: persistent hypertension (blood pressure greater than I!%/95 mm/Hg) in 25, arteriosclerotic cardiac or c:~:rr,l)rovascul;Ir disease in eight and renal artery thrombosis with renal infarction in one. Group III. consisting of 38 patients with primary gout, included those in whom associated nel)hropathy existed at the time of both clearance studies. The diseases included in this group were various types of chronic renal disease, persistent hypertension, arteriosclerotic cardiac or cnrebrovascular disease, “fulminant” gout, HPRT deficiency, chronic urinary tract infection with recurrent neI’hrolithiasis and diabetes mcllitus. In all 141)patients, uric acid was analyzed on a Beckman LJV s[)r:ctrophotomctcr using uricasc; Cinulln and CPAIJ were measured by methods previously described [l].
CAD
ACCVD
0 1 10
0 8 8
Diabetes Mellitus 7’ 3 1
cardiac cerebral vascular disease
reduced to 28 per cent. This linear trend in the decreasing frequency of hyperuricemia above 10 mg/dl with increasing age was statistically significant (X’(ldf) = 23.01, P <0.005). The age related decrease in excessive uricosuria, above 800 pg/min, was likewise statistically significant (X2(ldf) = 23.01, P <0.005). Effect of Hyperuricemia on Renal Hemodynamics. The 84 patients with uncomplicated primary gout at both clearance studies were divided into four subgroups, those above 50 years of age, those below 50 years of age, those with hyperuricemia controlled with P,,ri,tc below 7 mg/dl and those with hyperuricemia not controlled (Table III). In all patients whose hyperuricemia was controlled, medication was discontinued before the second clearance study was performed. Forty-nine patients were younger than 50 years at the time of the first clearance study. In 24 of these patients, hyperuricemia was brought under control between the first and second clearance study, the mean Puriltc, at the first clearance study being 10.3 f 0.3 mg/dl, and 9.8 f 0.4 mg/dl at the second clearance study, which was performed after 10.8 f 1.1 years: Cin,llin was 119.5 f 4.1 ml/min at the first clearance study, and 119.3 f 4.4 ml/min at the second clearance study. In 25 of the 49 patients under 50 years of age, hyperuricemia was not brought under control. After an interval of 7.6 f 1.3 years, Cinulin showed no changes, the value at the first clearance study being 122.7 f 3.5 ml/min, and at the second clearance study 119.2 f 4.3 ml/min. The remaining 35 patients in this group had the first clearance study performed at age 50 or above. In 26 patients, hyperuricemia was brought under control, and
RESULTS Prevalence of Plasma Urate (Purate)Above 10 mg/dl and Urinary Urate (UV,,,,) above 800 pg/min. When the 149 patients are grouped by their age at the onset of gout, the older the patient at the onset of disease the less the frequency of marked hyperuricemia and excessive uricosuria (Table II). Thus, P,,,;,,, values were more than 10 mg/dl in 64 per cent of the patients, and the incidence of excessive uricosuria [more ihan 800 pg/?nin) was 50 per cent in 36 patients whose age at onset was 30 years or less. When the age at onset’of gout was 50 years or older, the incidence of hyperuricemia of similar degree was down to 12 per cent and of hyperuricosuria was
November
TABLE II
Age at Onset (vr) ., <39 30-39 40-49 50-72
Plasma and Urinary Urate in Relation to Age at Onset of Gout
No.
Prevalenceof Purate UVuraie >800 pg/mint > 10 mg/dl’ -No. % No. %
36
23
46 40 27
20 9 3
64 44 22 12
18 22 11 7
50 49 28 28
P”,& >lO mg/dl and age: X2 (linearity) = 23.01 (P 800 mg/min and age: X2 (linearity) = 23.02 (P
1979
The American
Journal of Medicine
Volume 67
767
RENAL
FUNCTION
TABLE III
IN GOUT-Yij
ET AL.
Effect of Hyperuricemia on Clnulinand CPAH in Patients with Uncomplicated Primary Gout Hyperuricemia Not Controlled
Hyperuricemia Controlled Age (vr) <50 150
<50 250
Clearance Study First Second First Second
First Second First Second
Years Between Two Clearance Studies
Patients (no.) 24 26
7 10
119.5 f 4.1 119.3 f 4.4 100.0 f 3.2 92.1 f 4.4 CPAH (mllmin) 528.4 f 29.9 473.0 f 23.5 452.3 f 50.7 394.8 f 31 .a
10.3 f 0.3 9.8 f 0.4 a.8 f 0.3 a.8 f 0.3
10.4 10.0 9.6 9.3
f 0.6 f 0.4 f 0.6 f 0.5
10.8 f
1.1
25
a.1 f
0.8
9
10.4 f
2.3
13
9.6 f
1.1
3
November
1979
The American Journal of Medicine
Years Between Two Clearance Studies
Ci”“ll” (mllmin) 122.7 119.2 105.5
f 3.5 f 4.9 f 5.9
98.8 f
Cinultn showed very little change, being 100.0 f 3.2 ml/min at the first clearance study, and 92.1 f 4.4 ml/min at the second clearance study, after 8.1 f 0.8 years. In nine of the patients over 50 years of age, no uric acid lowering regimen was instituted. Again, there was no appreciable change in Cinutin, the values at the first and second clearance studies being, respectively, 105.5 f 5.9 ml/min and 98.3 f 9.7 ml/min, with the second clearance study performed after 8.3 f 1.8 years. CPAH was determined in 33 patients. In seven patients who were under 50 years of age and whose hyperuricemia was controlled, CPAH at the first and second clearance studies was, respectively, 528.4 f 29.9 ml/min and 473.0 f 23.5 ml/min. In 13 other patients under 50 years in whom hyperuricemia was not controlled, CPAH at the first and second studies was, respectively, 524.3 f 27.4 ml/min and 481.3 f 28 ml/min. In a group of 10 patients over 50 years of age with hyperuricemia controlled, CPAH at the first clearance study was 452.3 f 50.7 ml/min, and at the second clearance study 394.8 f 31.8 ml/min. In three others over 50 years of age, with hyperuricemia not controlled, there was no change in CPAH, respective values being 483.3 f 17.8 and 483.3 f 17.8 ml/min. Relative Effect of Associated Diseases, Aging, Duration of Gout, on CP.QJand Cinulin. To ascertain the significance of various factors on renal hemodynamics, the 149 patients were subdivided into groups based on several criteria: (1) duration of gout (one to nine years or 210 years]; (2) age at the time of the first clearance study (<49 years or 250 years); (3) associated diseases (present or absent). Group I was composed of patients with no associated diseases at either clearance study: group II was made up of patients who had no associated disease at the first clearance study but in whom associated disease had developed by the time of the second clearance study; group III consisted of patients who had associated disease at both clearance studies as mentioned earlier. Table IV gives the mean Cinutin, mean age at the time of the clearance study and mean age at the onset of gout at each clearance study.
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Patients (no.)
9.7
CPAH (ml/min) 524.3 f 27.4 481.3 f 28.0 483.3 f 17.8 483.3 f 17.8
9.4 a.9 7.9 7.8
f 0.2 f 0.3 f 0.4 f 0.5
7.6 f
1.3
a.3 f
1.8
9.7 9.0 7.7 9.4
f 0.3 f 0.6 f 0.6 f 0.8
7.7 f
1.9
13.3 l 1.2
The analysis of variance with unequal cell sizes and the unweighted means analysis of variance method was used to determine statistically significant results. “F” values for the analysis of variance with unequal cell sizes are reported. The model used was a cross classification model with main effects, first order interactions and a second order interaction with a pooled estimate of the within cell variance as the error term. At the first study, the mean Cinulin for the 84 patients in group I was 112.9 f 2.2 ml/min and that for 27 patients in group II 115.4 f 4.3 ml/min. Group III, the group with associated diseases, had a significantly lower Cinulin at the first clearance study, 76.2 f 3.6 ml/min (F = 53.28, P
TABLE
IV
lnulin Clearances in 149 Patients
Age (yr) No. C, (ml/min) Age at CT (yr) Age at onset (yr)
> 10 years
No. C, (ml/min) Age at CI (yr) Age at onset (yr)
l-9 years
Age (yr) No. Cz (ml/min) Age at CZ (yr) Years between C, and C2 C2-Cl (ml/min)
> 10 years
No. C2 (ml/min) Age at C2 (yr) Years between C, and C2 C2-Cl (mUmin)
TABLE
V
35 121.7 zk 3.3 37.2 f 1.1 32.9 f 1.1 14 119.8 f 4.8 43.9 f 1.2 30.4 f 1.4
1.2 f 2.8
f 8.0
14 115.0 f 5.69 54.4 f 1.78 10.6 f 1.67
24 91.5 f 5.0 67.7 f 1.5 7.5 f 0.9
-3.8
-6.6
7
5 118.8 f 13.0 40.8 f 2.1 25.6 f 0.8
f 5.8
f 3.8
-17.9
111.8f 6.9 59.1 f 2.4 40.3 f 3.5
250 7 70.9 f 5.1 67.6 f 1.5 111.1 f 1.5
f 9.2
-37.9
f
15.0
-25.9
89.1 f 6.3 41.3 f 2.1 37.2 f 2.1
10 83.3 f 6.3 58.6 zk 1.4 53.4 * 1.7
5 57.1 f 12.1 39.6 f 3.3 24.8 f 2.6
14 69.6 f 4.7 59.6 f 1.5 40.1 f 2.0
150 10 80.0 f 7.4 65.8 f 2.1 7.2 f 1.3
549 9
69.6 f 13.2 62.3 f 2.3 11.0 f 1.5 -19.5
f 4.1
f
11.7
-3.5
f 5.2
5 54.3 f 15.0 45.2 f 3.0 5.6 f 2.0
14 63.4 f 7.4 64.4 f 1.7 4.8 f 0.9
-2.8
-6.2
7 85.4 f 5.7 67.9 f 2.1 8.7 f 1.2
5 91.0 f 23.2 52.8 f 3.6 12.0 f 2.9 -27.8
f 7.8
250
149 9
f 4.2
f 6.5
PAH Clearances in 63 Patients with Primary Gout GroupI
Age W No.
No. Cl (mUmin) Age at Cl (yr) Age at onset (yr)
Age W) No. Cs (ml/min)
Age at C2 W Years between C, and C2 C& (mUmin) > 10 years
-10.1
GrouoIII
150 7 108.7 f 7.4 56.4 f 1.3 50.9 f 1.4
6. Second Clearance (C,) 150 149 11 8 98.6 f 7.0 104.3 f 6.1 66.9 f 1.5 51.5 f 3.2 9.5 f 1.2 12.6 zt 2.0
35 120.5 f 3.6 45.8 f 1.6 8.6 f 1.0
Age at Cl (yr) Age at onset (yr)
l-9 years
24 98.1 f 3.4 60.2 f 1.4 40.0 f 2.1
149
Cl (ml/min)
> 10 years
GroutII
A. First Clearance (C,) 150 549 11 8 108.7 f 4.2 122.3 f 9.1 57.4 f 2.1 38.9 f 2.3 53.9 f 2.8 34.0 ZlI 2.0
149
Duration
l-9 years
Gout
Grout I
Duration
l-9 years
with Primary
No. C2 (mUmin) Age at C2 (yr) Years between Cl and C2 Cl-C2 (ml/min)
549 16 520.9 f 21.9 39.6 f 13.1 34.9 f 1.5 4 545.0 f 56.1 44.5 f 1.9 30.3 f 3.0
149 16 473.8 f 22.4 48.1 f 2.5 8.4 f 1.8 -47.1
f
GroupII
A. First Clearance (Cl) 250 549 3 4 483.3 f 17.8 483.8 f 36.67 51.7 f 0.9 39.0 f 4.1 48.0 f 2.1 34.0 f 3.3 10 452.3 f 50.7 56.7 f 1.5 39.4 f 2.7
6. Second 250 3 483.3 f 65.0 f 13.3 f
13.1
2 621.0 f 1.0 36.5 f 1.5 26.0 f 2.0
Clearance (C,) 149 4 17.8 383.3 f 53.5 1.2 52.0 f 6.1 1.2 13.0 f 3.9
0
-100.5
f 61.9
GroupIll
250 2 492.0 f 50.0 55.5 f 2.5 49.5 f 2.5
549 150 5 5 461.8 f 35.8 333.2 f 28.2 40.4 f 3.1 59.6 f 1.8 35.8 f 3.1 55.8 f 2.0
6 430.0 f 29.7 59.3 f 2.8 41.7 f 3.7
2 4 226.5 f 72.5 372.5 Jo 94.7 41 .o f 4.0 57.0 f 3.1 25.0 f 2.0 36.5 f 5.3
150 2 353.5 f 52.5 66.0 f 0 10.5 f 2.5
149 250 5 5 419.8 f 53.1 327.0 f 42.2 52.8 h 3.1 66.4 f 3.5 12.4 f 1.2 6.80 f 2.5
-138.5
f 2.5
4 497.0 f 44.8 54.0 f 2.8 9.5 f 1.6
10 394.8 f 31.8 66.3 f 1.8 9.6 f 1.1
2 324.0 f 56.0 47.0 f 5.0 10.5 f 6.5
6 351.7 f 36.5 68.2 f 24.4 6.8 f 2.1
-480f
-57.5
-29.7
-78.2
27.2
f 43.5
November 1979
f 55.0
f 29.9
-42.0
f 30.2
-6.2
f 29.3
2 4 226.5 f 72.5 259.0 f 49.1 50.0 f 0 57.0 f 3.1 9.0 f 4.0 4.0 f 0.9 0
The American Journal of Medicine
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Volume 67
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RENAL FUNCTION
IN GOUT-YIj
ET AL.
over, had significantly lower C~AH (F = 5.45, P
COMMENTS The cliiical picture of gout has changed in the past two decades, due to earlier diagnosis and more adequate treatment [7]. Crippling tophaceous gout and renal insufficiency are less common. Hypertension and arteriosclerosis are still commonly encountered. Proteinuria and impaired renal function are seen but probably do not represent a primary adverse effect. Extreme hyperuricemia and hyperuricosuria are more likely to occur in primary gout with early onset. This, we believe, bespeaks overproduction of uric acid in such patients, with normal renal function. There is a normal capacity to eliminate uric acid by the composite renal process of ultrafiltraion of all urate at the glomerulus, and simultaneous renal tubular processes of reabsorption and secretion, with secretion contributing the urate ultimately found in the urine [l-3]. The “gouty kidney,” with deposition of urate in the interstitium and/or renal tubules as a cause of decreased renal function, is a debatable entity. The studies here described, as well as our previous reports, indicate that de&eased renal function, as characterized by proteinuria, azotemia, decreased glomerular filtratiqn rate and/or renal plasma flow, does not generally occur in patiepts with primary gout except in the c&e of concurrent development of associated disease in the kidney [5]. Admittedly, there are a few exceptions to Fhis generality: (1)the young patient with “fulminant gout,” in whom the resistant, recurrent intractable attakks of gouty arthritis are assoc’iated with marked hyperuricemia, proteinuria, decreased glomerular filtration rate and renal plasma flow, at times azotemia and hypeytension [5]; (2) the patient with HPRT deficiency with extreme hyperuricetiia and hyperuricosuria, in whom bilateral urate nephrolithiasis may develop with obstruction and infection of the urinary tract and aksociated azotemia [8,9]; [s) the aging patient’with primary gout, in whom the decrease in glomerular filtration rate and renal plasma flow may simply reflect an associated vascular degenerative process in the kidney [4]. In secondary gout, ‘as occurs in myelopro!iferative diseases and various blood dyscrasias, the hyperuricemia and hyperuricosuria may be quite excessive [lO,ll]. A Puratc of 15 to 20 mg/dl and a urinary excretion of.uric acid of 1 to 2 g a day are common. The degree of hyperuricemia and hyperuricosuria may be exaggerated further by the use of cytotoxic drugs. Nephrolithiasis and obstructive uropathy with infection may occur. Acute renal insufficiency inay develop due to acute oliguric hyperuricemic nephropathy. With proper treatment, this may be avoided or corrected if it does develop. 770
November 1979
The American Journal of Medicine
In patients with acute uric acid nephropathy, crystals of uric acid are found within the renal tubular lumen, and monosodium urate crystals may be found in renal parenchyma, outside the tubule [12]. Urate deposition in renal parenchyma in biopsy or postmortem specimens in primary gout in fact is not as frequent as in secondary gout [13]. The most specific changes in the kidney are the presence of uric acid or urate crystals, with associated foreign body giant cell reaction. Other changes are usually a combination of the effects of tubular obstruction, chronic infection, vascular changes and ischemic changes brought on by the aging process or hypertension [14,15]. Although Gonick et al. [16] found distinctive glomerular lesions, Pardo et al. [l7], in electron microscopic studies, found no distinctive glomerular lesions. Barlow and Beilin [la], in a similar study, did not find unique glomerular changes apart from diabetic glomerulosclerosis in two of their 27 patients. Measurements of glomerular filtration rate and renal plasma flow in the 149 patients show no diminution in patients with uncomplicated gout, and no recognizable adverse effect of hyperuricemia. The most significant decreases are found in patients in whom a disease associated with nephropathy, other than gout, developed between the first and second clearance studies: in group II patients those in the older age group (50 years or older) and with a longer duration of gout (10 years or longer] showed the most notable declines in glomerular filtration rate and renal plasma flow. The possibility exists that patient’s age and duration of gout may be interrelated variables in that those who have lived longer simply have had their gout over a longer interval. Renal function status did not seem to be associated with the duration of gout alone, independent of aging. Interestingly, in group III patients with associated nephropathic diseases at both clearance studies, although there was a significant diminution in measured function even at the first clearance study, the over-all decrease in function by the time of the second clearance studies was not proportionally as great as in group II, in which associated disease developed in the interval between clearance studies. Apparently,‘deterioration of renal function is dependent upon the nature and progress of the associated diseases. We pointed out previously that the impairment of renal function in gout is related to associated diseases and aging [4,5]. We were not able to delineate the relative significance of such factors. Using the analysis of variance technique, we have been able to determine the relative significance of various factors affecting renal function. When there are no coexisting medical diseases, hyperuricemia does not seem to have any significant deteriorative effect on renal function. In this study, an associated medical condition is the most important risk factor for causing renal damage in gout, with aging the second most important, and duration of gout, the third. Volume 67
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t:utman
AB, Yii TF: Rcn;ll function in gout with a commcntar? on the renal regulation of m-ate excretion anti the role of the kitlncy in the pathogcncsis of gout. Am JMcd 23: GOO,
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I,, (;utm;m AB: Renal function in gout II. Effect of uric acid loading on renal cxcrction of uric acid. Am 1 hlctl 33: 82Y, 1962. (Cutman AU, Yii TF. Bcrger I,: Renal function in gout III. Estimation of tubular secretion antI reabsorption of uric acid I)v USC r~f pyr:czinamide (Pyrazinoic acid]. Am 1 Met1 47:
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Ijc:rgt’r 1.. Yii TF: Renal function in gout IV. An analysis of 524 rtrllt\ srll)jects including long-term follow-ul,strldics. Am j’M&l 5~:‘605. 1~75. ’ Yii TF, Bcrgcr L: Kcnal disease in primary gout; a study of 253 gout patients with proteinuria. Scmin Arthritis Rheum 4: ZY’3 lY75. Yii ‘l?, Halis ME, Krcnitsky ‘TA, et al.: Rarity of X-linked I);rrtial h\~~oxanthinc-~u;tninc-phosphoril,osyltr~~nsf~r~sc bcficioncl’in a Iargc g&y popuiatior;. Ann Intern Med 7G: 255, 1!)72. Yil TF: Milestones in the treatment of gout. Am j Med 56: 676, 1Y74. I,csch hl. Nyhan WL: A familial disorder of uric acid mctabolism ,Ind central nervous system function. Am j Metl
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I?. 13. 14. 15.
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3G: 5G I. lYG4. Alcxandor S. Brentllcr H: Trcatmcnt of uric acicl urolithiasis \vith allopurinol: a xanthine oxidaso inhillitor. J UrnI ~7: 340, 1YG7. Yii TF. Wcinrch N. Wittman R. cl al.: Strctrntlary gout associated with chronic mycloproliferativc: disorders. Semin Arthritis Rherlm G: 247, 1976. Rieselbach RE. Bcntzel CJ, Cotlovc E. trt al.: Ilric: acid cxcrelicm and renal function in acllte hyt)crriricomia of leukcmia. Pathogencsis and therapy of uric acid ncphropatlly. Am j bletl 37: 872, lYG4. Sccgmillcr jE, Frazier PD: Biochemical ccansidorations of the renal damage of grout. Ann Rheum Uis 225: GGH. IYGG Y~I TF: Ilnpublishcd data. Talbott JH, Tcrplnn KL: The kitlncy in gollt. hlctlicinc (Daltimctrcj 3% 405. IYGO. Hcptinstall RH: Gout. Pathology of the Kitlnc!y. 2nd otl. Boston, Littlc Bro\%n (i- Co.. IY74. p YG,3. Gonick HC, Rubini ILIE, Gleason 10. ct al.: ‘I’hc renal lesion in gout. Ann Intern Mcd 133: 37Y. lYG5. Pardtr V. Perez-Stahlc E, Fisher ER: Llltr,tstructurr: studies in hypertension III. gout\; nephropathy. I.,~IJ Invest 18: 143.
1968. 18.
1979
The American Journal of Medicine
Volume 67
771
TS’AI-FAN
Yij, M.D.
LAWRENCE DOUGLAS HARRY
BERGER,
M.D.
J. DORPH,
M.A.
SMITH,
Ph.D.
New York, New York
From the Department of Medicine and the Department of Biostatistics. Mount Sinai School of Medicine, The City University of New York, New York, New York. This study was supported in part by Grant AM-00162, National Institute of Arthritis, Metabolism and Digestive Diseases, NIH, Grant FR-71, the Division of Research Rcsourccs, General Clinical Research Centers Branch, NIH. Computing was carried out at the City University of New York Computing Center. Requests for reprints should be addressed to Dr. Ts’ai-Fan Yii, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, New York 10029. Manuscript accepted June 27,1979.
766
Renal hemodynamics as measured by inulin clearance (Cin& and para-aminohippurate clearance (CPM) was evaluated in 149 patient! with primary gout over intervals of two to 22 years. In over 30 pel cent of the patients plasma urate was >lO mg/dl and urinary uric acid >800 mg/min. A linear trend in decreasing frequency of hy peruricemia and excessive uricosuria is significantly related to the patient’s age at the onset of gout. Group I consisted of 84 patients with uncomplicated gout in botl clearance studies. C&in and CPAH were somewhat lower in patient9 >50 years of age with longer duration of gout. Further reduction ir clearances was minimal at the second clearance study in intervak of approximately 10 years. Group II included 27 patients who had no associated disease at the time of the first clearance study but ir whom associated disease had developed by the time of the seconc clearance study. A striking reduction in Cinuttn and Cr~n was noted especially in those 50 years old or above. There were 38 patients in group III with associated diseases at the time of both clearance studies. They had lower Cinutin and CPM at the time of the first study particularly the older patients. Further reduction during the second study was less striking than that in group II. Analyses of variance suggest that various coexisting vascular dis eases with associated nephropathy have the most significant impac on the status of renal function in gout, with aging the second mos important and duration of gout, the third. Our previous studies in patients with gout have led us to believe tha renal elimination of uric acid in patients with primary gout is cornpa, rable to that in normal subjects [l-3]. Renal function as measured bj Cinutin for glomerular filtration rate and CPAH for estimated rena plasma flow is usually not adversely affected in uncomplicated gou or hyperuricemia. In only a very few exceptional gouty patients havt we seen nephropathy without associated disease. These include certair patients-usually young with severe recurrent intractable attacks o acute gout, not able to be controlled with routine antigouty measures and with no detectable abnormalities in purine metabolizing enzymes They are designated as having fulminating gout. Another group wit1 nephropathy unassociated with other diseases have hypoxanthine guanine-phosphoribosyltransferase (HPRT) deficiency and uratc urolithiasis [4-61. When renal function does deteriorate in the patien with primary gout, it is correlated with the development of associatec disease such as independently occurring nephropathy, hypertensior with nephrosclerosis, diabetes with nephropathy, renal arteriosclerosi: and arteriolosclerosis [5].
November 1979 The American Journal of Medicine
Volume 67
TABLE I
Clinical Status of 149 Patients with Primary Gout AssociatedDiseases Renal Calculi
Group
No.
s
R
I
84 27 38t
13 6 6
11 3 5
II III
Hypertension 10’ 25 15
NOTE: S = single; R = recurrent: CRD = chronic renal disease; ACCVD = arteriosclerotic * Labile hypertension. 1Intermittent hyperglvcemia. x Includes four with fulminating gout.
In an attempt to better document this concept, we have carried out a computer-assisted analysis of 149 patients with primary gout, in whom measurements of glomerular filtration rate and renal plasma flow were made at least twice over intervals as long as 22 years.
MATERIALS
AND METHODS
At the time of the renal
ClCaMnCC studies, all 149 patients were ambulatory and had not been receiving any drugs sufficiently long enough to assure measurement of their true basal plasma urate level (P,,,.i,tJ. In over 30 per cent of the patients urinary uric acid excretion was above 800 &min. Patients were divided into three groups [Table I). Group I consisted of 84 pa-
ticnts
with
uncomplicated
primary
gout at both clearance
stutlics. Ten did have mild labile hypertension,
and seven had intermittent hyperglycemia without glycosuria. Group II included 27 patients with uncomplicated primary gout at the first clearance study. By the second clearance study at least one associated disease causing renal damage had developed in (!;lch of these patients: persistent hypertension (blood pressure greater than I!%/95 mm/Hg) in 25, arteriosclerotic cardiac or c:~:rr,l)rovascul;Ir disease in eight and renal artery thrombosis with renal infarction in one. Group III. consisting of 38 patients with primary gout, included those in whom associated nel)hropathy existed at the time of both clearance studies. The diseases included in this group were various types of chronic renal disease, persistent hypertension, arteriosclerotic cardiac or cnrebrovascular disease, “fulminant” gout, HPRT deficiency, chronic urinary tract infection with recurrent neI’hrolithiasis and diabetes mcllitus. In all 141)patients, uric acid was analyzed on a Beckman LJV s[)r:ctrophotomctcr using uricasc; Cinulln and CPAIJ were measured by methods previously described [l].
CAD
ACCVD
0 1 10
0 8 8
Diabetes Mellitus 7’ 3 1
cardiac cerebral vascular disease
reduced to 28 per cent. This linear trend in the decreasing frequency of hyperuricemia above 10 mg/dl with increasing age was statistically significant (X’(ldf) = 23.01, P <0.005). The age related decrease in excessive uricosuria, above 800 pg/min, was likewise statistically significant (X2(ldf) = 23.01, P <0.005). Effect of Hyperuricemia on Renal Hemodynamics. The 84 patients with uncomplicated primary gout at both clearance studies were divided into four subgroups, those above 50 years of age, those below 50 years of age, those with hyperuricemia controlled with P,,ri,tc below 7 mg/dl and those with hyperuricemia not controlled (Table III). In all patients whose hyperuricemia was controlled, medication was discontinued before the second clearance study was performed. Forty-nine patients were younger than 50 years at the time of the first clearance study. In 24 of these patients, hyperuricemia was brought under control between the first and second clearance study, the mean Puriltc, at the first clearance study being 10.3 f 0.3 mg/dl, and 9.8 f 0.4 mg/dl at the second clearance study, which was performed after 10.8 f 1.1 years: Cin,llin was 119.5 f 4.1 ml/min at the first clearance study, and 119.3 f 4.4 ml/min at the second clearance study. In 25 of the 49 patients under 50 years of age, hyperuricemia was not brought under control. After an interval of 7.6 f 1.3 years, Cinulin showed no changes, the value at the first clearance study being 122.7 f 3.5 ml/min, and at the second clearance study 119.2 f 4.3 ml/min. The remaining 35 patients in this group had the first clearance study performed at age 50 or above. In 26 patients, hyperuricemia was brought under control, and
RESULTS Prevalence of Plasma Urate (Purate)Above 10 mg/dl and Urinary Urate (UV,,,,) above 800 pg/min. When the 149 patients are grouped by their age at the onset of gout, the older the patient at the onset of disease the less the frequency of marked hyperuricemia and excessive uricosuria (Table II). Thus, P,,,;,,, values were more than 10 mg/dl in 64 per cent of the patients, and the incidence of excessive uricosuria [more ihan 800 pg/?nin) was 50 per cent in 36 patients whose age at onset was 30 years or less. When the age at onset’of gout was 50 years or older, the incidence of hyperuricemia of similar degree was down to 12 per cent and of hyperuricosuria was
November
TABLE II
Age at Onset (vr) ., <39 30-39 40-49 50-72
Plasma and Urinary Urate in Relation to Age at Onset of Gout
No.
Prevalenceof Purate UVuraie >800 pg/mint > 10 mg/dl’ -No. % No. %
36
23
46 40 27
20 9 3
64 44 22 12
18 22 11 7
50 49 28 28
P”,& >lO mg/dl and age: X2 (linearity) = 23.01 (P
1979
The American
Journal of Medicine
Volume 67
767
RENAL
FUNCTION
TABLE III
IN GOUT-Yij
ET AL.
Effect of Hyperuricemia on Clnulinand CPAH in Patients with Uncomplicated Primary Gout Hyperuricemia Not Controlled
Hyperuricemia Controlled Age (vr) <50 150
<50 250
Clearance Study First Second First Second
First Second First Second
Years Between Two Clearance Studies
Patients (no.) 24 26
7 10
119.5 f 4.1 119.3 f 4.4 100.0 f 3.2 92.1 f 4.4 CPAH (mllmin) 528.4 f 29.9 473.0 f 23.5 452.3 f 50.7 394.8 f 31 .a
10.3 f 0.3 9.8 f 0.4 a.8 f 0.3 a.8 f 0.3
10.4 10.0 9.6 9.3
f 0.6 f 0.4 f 0.6 f 0.5
10.8 f
1.1
25
a.1 f
0.8
9
10.4 f
2.3
13
9.6 f
1.1
3
November
1979
The American Journal of Medicine
Years Between Two Clearance Studies
Ci”“ll” (mllmin) 122.7 119.2 105.5
f 3.5 f 4.9 f 5.9
98.8 f
Cinultn showed very little change, being 100.0 f 3.2 ml/min at the first clearance study, and 92.1 f 4.4 ml/min at the second clearance study, after 8.1 f 0.8 years. In nine of the patients over 50 years of age, no uric acid lowering regimen was instituted. Again, there was no appreciable change in Cinutin, the values at the first and second clearance studies being, respectively, 105.5 f 5.9 ml/min and 98.3 f 9.7 ml/min, with the second clearance study performed after 8.3 f 1.8 years. CPAH was determined in 33 patients. In seven patients who were under 50 years of age and whose hyperuricemia was controlled, CPAH at the first and second clearance studies was, respectively, 528.4 f 29.9 ml/min and 473.0 f 23.5 ml/min. In 13 other patients under 50 years in whom hyperuricemia was not controlled, CPAH at the first and second studies was, respectively, 524.3 f 27.4 ml/min and 481.3 f 28 ml/min. In a group of 10 patients over 50 years of age with hyperuricemia controlled, CPAH at the first clearance study was 452.3 f 50.7 ml/min, and at the second clearance study 394.8 f 31.8 ml/min. In three others over 50 years of age, with hyperuricemia not controlled, there was no change in CPAH, respective values being 483.3 f 17.8 and 483.3 f 17.8 ml/min. Relative Effect of Associated Diseases, Aging, Duration of Gout, on CP.QJand Cinulin. To ascertain the significance of various factors on renal hemodynamics, the 149 patients were subdivided into groups based on several criteria: (1) duration of gout (one to nine years or 210 years]; (2) age at the time of the first clearance study (<49 years or 250 years); (3) associated diseases (present or absent). Group I was composed of patients with no associated diseases at either clearance study: group II was made up of patients who had no associated disease at the first clearance study but in whom associated disease had developed by the time of the second clearance study; group III consisted of patients who had associated disease at both clearance studies as mentioned earlier. Table IV gives the mean Cinutin, mean age at the time of the clearance study and mean age at the onset of gout at each clearance study.
766
Patients (no.)
9.7
CPAH (ml/min) 524.3 f 27.4 481.3 f 28.0 483.3 f 17.8 483.3 f 17.8
9.4 a.9 7.9 7.8
f 0.2 f 0.3 f 0.4 f 0.5
7.6 f
1.3
a.3 f
1.8
9.7 9.0 7.7 9.4
f 0.3 f 0.6 f 0.6 f 0.8
7.7 f
1.9
13.3 l 1.2
The analysis of variance with unequal cell sizes and the unweighted means analysis of variance method was used to determine statistically significant results. “F” values for the analysis of variance with unequal cell sizes are reported. The model used was a cross classification model with main effects, first order interactions and a second order interaction with a pooled estimate of the within cell variance as the error term. At the first study, the mean Cinulin for the 84 patients in group I was 112.9 f 2.2 ml/min and that for 27 patients in group II 115.4 f 4.3 ml/min. Group III, the group with associated diseases, had a significantly lower Cinulin at the first clearance study, 76.2 f 3.6 ml/min (F = 53.28, P
TABLE
IV
lnulin Clearances in 149 Patients
Age (yr) No. C, (ml/min) Age at CT (yr) Age at onset (yr)
> 10 years
No. C, (ml/min) Age at CI (yr) Age at onset (yr)
l-9 years
Age (yr) No. Cz (ml/min) Age at CZ (yr) Years between C, and C2 C2-Cl (ml/min)
> 10 years
No. C2 (ml/min) Age at C2 (yr) Years between C, and C2 C2-Cl (mUmin)
TABLE
V
35 121.7 zk 3.3 37.2 f 1.1 32.9 f 1.1 14 119.8 f 4.8 43.9 f 1.2 30.4 f 1.4
1.2 f 2.8
f 8.0
14 115.0 f 5.69 54.4 f 1.78 10.6 f 1.67
24 91.5 f 5.0 67.7 f 1.5 7.5 f 0.9
-3.8
-6.6
7
5 118.8 f 13.0 40.8 f 2.1 25.6 f 0.8
f 5.8
f 3.8
-17.9
111.8f 6.9 59.1 f 2.4 40.3 f 3.5
250 7 70.9 f 5.1 67.6 f 1.5 111.1 f 1.5
f 9.2
-37.9
f
15.0
-25.9
89.1 f 6.3 41.3 f 2.1 37.2 f 2.1
10 83.3 f 6.3 58.6 zk 1.4 53.4 * 1.7
5 57.1 f 12.1 39.6 f 3.3 24.8 f 2.6
14 69.6 f 4.7 59.6 f 1.5 40.1 f 2.0
150 10 80.0 f 7.4 65.8 f 2.1 7.2 f 1.3
549 9
69.6 f 13.2 62.3 f 2.3 11.0 f 1.5 -19.5
f 4.1
f
11.7
-3.5
f 5.2
5 54.3 f 15.0 45.2 f 3.0 5.6 f 2.0
14 63.4 f 7.4 64.4 f 1.7 4.8 f 0.9
-2.8
-6.2
7 85.4 f 5.7 67.9 f 2.1 8.7 f 1.2
5 91.0 f 23.2 52.8 f 3.6 12.0 f 2.9 -27.8
f 7.8
250
149 9
f 4.2
f 6.5
PAH Clearances in 63 Patients with Primary Gout GroupI
Age W No.
No. Cl (mUmin) Age at Cl (yr) Age at onset (yr)
Age W) No. Cs (ml/min)
Age at C2 W Years between C, and C2 C& (mUmin) > 10 years
-10.1
GrouoIII
150 7 108.7 f 7.4 56.4 f 1.3 50.9 f 1.4
6. Second Clearance (C,) 150 149 11 8 98.6 f 7.0 104.3 f 6.1 66.9 f 1.5 51.5 f 3.2 9.5 f 1.2 12.6 zt 2.0
35 120.5 f 3.6 45.8 f 1.6 8.6 f 1.0
Age at Cl (yr) Age at onset (yr)
l-9 years
24 98.1 f 3.4 60.2 f 1.4 40.0 f 2.1
149
Cl (ml/min)
> 10 years
GroutII
A. First Clearance (C,) 150 549 11 8 108.7 f 4.2 122.3 f 9.1 57.4 f 2.1 38.9 f 2.3 53.9 f 2.8 34.0 ZlI 2.0
149
Duration
l-9 years
Gout
Grout I
Duration
l-9 years
with Primary
No. C2 (mUmin) Age at C2 (yr) Years between Cl and C2 Cl-C2 (ml/min)
549 16 520.9 f 21.9 39.6 f 13.1 34.9 f 1.5 4 545.0 f 56.1 44.5 f 1.9 30.3 f 3.0
149 16 473.8 f 22.4 48.1 f 2.5 8.4 f 1.8 -47.1
f
GroupII
A. First Clearance (Cl) 250 549 3 4 483.3 f 17.8 483.8 f 36.67 51.7 f 0.9 39.0 f 4.1 48.0 f 2.1 34.0 f 3.3 10 452.3 f 50.7 56.7 f 1.5 39.4 f 2.7
6. Second 250 3 483.3 f 65.0 f 13.3 f
13.1
2 621.0 f 1.0 36.5 f 1.5 26.0 f 2.0
Clearance (C,) 149 4 17.8 383.3 f 53.5 1.2 52.0 f 6.1 1.2 13.0 f 3.9
0
-100.5
f 61.9
GroupIll
250 2 492.0 f 50.0 55.5 f 2.5 49.5 f 2.5
549 150 5 5 461.8 f 35.8 333.2 f 28.2 40.4 f 3.1 59.6 f 1.8 35.8 f 3.1 55.8 f 2.0
6 430.0 f 29.7 59.3 f 2.8 41.7 f 3.7
2 4 226.5 f 72.5 372.5 Jo 94.7 41 .o f 4.0 57.0 f 3.1 25.0 f 2.0 36.5 f 5.3
150 2 353.5 f 52.5 66.0 f 0 10.5 f 2.5
149 250 5 5 419.8 f 53.1 327.0 f 42.2 52.8 h 3.1 66.4 f 3.5 12.4 f 1.2 6.80 f 2.5
-138.5
f 2.5
4 497.0 f 44.8 54.0 f 2.8 9.5 f 1.6
10 394.8 f 31.8 66.3 f 1.8 9.6 f 1.1
2 324.0 f 56.0 47.0 f 5.0 10.5 f 6.5
6 351.7 f 36.5 68.2 f 24.4 6.8 f 2.1
-480f
-57.5
-29.7
-78.2
27.2
f 43.5
November 1979
f 55.0
f 29.9
-42.0
f 30.2
-6.2
f 29.3
2 4 226.5 f 72.5 259.0 f 49.1 50.0 f 0 57.0 f 3.1 9.0 f 4.0 4.0 f 0.9 0
The American Journal of Medicine
-113
Volume 67
f 87.3
769
RENAL FUNCTION
IN GOUT-YIj
ET AL.
over, had significantly lower C~AH (F = 5.45, P
COMMENTS The cliiical picture of gout has changed in the past two decades, due to earlier diagnosis and more adequate treatment [7]. Crippling tophaceous gout and renal insufficiency are less common. Hypertension and arteriosclerosis are still commonly encountered. Proteinuria and impaired renal function are seen but probably do not represent a primary adverse effect. Extreme hyperuricemia and hyperuricosuria are more likely to occur in primary gout with early onset. This, we believe, bespeaks overproduction of uric acid in such patients, with normal renal function. There is a normal capacity to eliminate uric acid by the composite renal process of ultrafiltraion of all urate at the glomerulus, and simultaneous renal tubular processes of reabsorption and secretion, with secretion contributing the urate ultimately found in the urine [l-3]. The “gouty kidney,” with deposition of urate in the interstitium and/or renal tubules as a cause of decreased renal function, is a debatable entity. The studies here described, as well as our previous reports, indicate that de&eased renal function, as characterized by proteinuria, azotemia, decreased glomerular filtratiqn rate and/or renal plasma flow, does not generally occur in patiepts with primary gout except in the c&e of concurrent development of associated disease in the kidney [5]. Admittedly, there are a few exceptions to Fhis generality: (1)the young patient with “fulminant gout,” in whom the resistant, recurrent intractable attakks of gouty arthritis are assoc’iated with marked hyperuricemia, proteinuria, decreased glomerular filtration rate and renal plasma flow, at times azotemia and hypeytension [5]; (2) the patient with HPRT deficiency with extreme hyperuricetiia and hyperuricosuria, in whom bilateral urate nephrolithiasis may develop with obstruction and infection of the urinary tract and aksociated azotemia [8,9]; [s) the aging patient’with primary gout, in whom the decrease in glomerular filtration rate and renal plasma flow may simply reflect an associated vascular degenerative process in the kidney [4]. In secondary gout, ‘as occurs in myelopro!iferative diseases and various blood dyscrasias, the hyperuricemia and hyperuricosuria may be quite excessive [lO,ll]. A Puratc of 15 to 20 mg/dl and a urinary excretion of.uric acid of 1 to 2 g a day are common. The degree of hyperuricemia and hyperuricosuria may be exaggerated further by the use of cytotoxic drugs. Nephrolithiasis and obstructive uropathy with infection may occur. Acute renal insufficiency inay develop due to acute oliguric hyperuricemic nephropathy. With proper treatment, this may be avoided or corrected if it does develop. 770
November 1979
The American Journal of Medicine
In patients with acute uric acid nephropathy, crystals of uric acid are found within the renal tubular lumen, and monosodium urate crystals may be found in renal parenchyma, outside the tubule [12]. Urate deposition in renal parenchyma in biopsy or postmortem specimens in primary gout in fact is not as frequent as in secondary gout [13]. The most specific changes in the kidney are the presence of uric acid or urate crystals, with associated foreign body giant cell reaction. Other changes are usually a combination of the effects of tubular obstruction, chronic infection, vascular changes and ischemic changes brought on by the aging process or hypertension [14,15]. Although Gonick et al. [16] found distinctive glomerular lesions, Pardo et al. [l7], in electron microscopic studies, found no distinctive glomerular lesions. Barlow and Beilin [la], in a similar study, did not find unique glomerular changes apart from diabetic glomerulosclerosis in two of their 27 patients. Measurements of glomerular filtration rate and renal plasma flow in the 149 patients show no diminution in patients with uncomplicated gout, and no recognizable adverse effect of hyperuricemia. The most significant decreases are found in patients in whom a disease associated with nephropathy, other than gout, developed between the first and second clearance studies: in group II patients those in the older age group (50 years or older) and with a longer duration of gout (10 years or longer] showed the most notable declines in glomerular filtration rate and renal plasma flow. The possibility exists that patient’s age and duration of gout may be interrelated variables in that those who have lived longer simply have had their gout over a longer interval. Renal function status did not seem to be associated with the duration of gout alone, independent of aging. Interestingly, in group III patients with associated nephropathic diseases at both clearance studies, although there was a significant diminution in measured function even at the first clearance study, the over-all decrease in function by the time of the second clearance studies was not proportionally as great as in group II, in which associated disease developed in the interval between clearance studies. Apparently,‘deterioration of renal function is dependent upon the nature and progress of the associated diseases. We pointed out previously that the impairment of renal function in gout is related to associated diseases and aging [4,5]. We were not able to delineate the relative significance of such factors. Using the analysis of variance technique, we have been able to determine the relative significance of various factors affecting renal function. When there are no coexisting medical diseases, hyperuricemia does not seem to have any significant deteriorative effect on renal function. In this study, an associated medical condition is the most important risk factor for causing renal damage in gout, with aging the second most important, and duration of gout, the third. Volume 67
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t:utman
AB, Yii TF: Rcn;ll function in gout with a commcntar? on the renal regulation of m-ate excretion anti the role of the kitlncy in the pathogcncsis of gout. Am JMcd 23: GOO,
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I,, (;utm;m AB: Renal function in gout II. Effect of uric acid loading on renal cxcrction of uric acid. Am 1 hlctl 33: 82Y, 1962. (Cutman AU, Yii TF. Bcrger I,: Renal function in gout III. Estimation of tubular secretion antI reabsorption of uric acid I)v USC r~f pyr:czinamide (Pyrazinoic acid]. Am 1 Met1 47:
Yii 'I'F, Bcrgcr
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Ijc:rgt’r 1.. Yii TF: Renal function in gout IV. An analysis of 524 rtrllt\ srll)jects including long-term follow-ul,strldics. Am j’M&l 5~:‘605. 1~75. ’ Yii TF, Bcrgcr L: Kcnal disease in primary gout; a study of 253 gout patients with proteinuria. Scmin Arthritis Rheum 4: ZY’3 lY75. Yii ‘l?, Halis ME, Krcnitsky ‘TA, et al.: Rarity of X-linked I);rrtial h\~~oxanthinc-~u;tninc-phosphoril,osyltr~~nsf~r~sc bcficioncl’in a Iargc g&y popuiatior;. Ann Intern Med 7G: 255, 1!)72. Yil TF: Milestones in the treatment of gout. Am j Med 56: 676, 1Y74. I,csch hl. Nyhan WL: A familial disorder of uric acid mctabolism ,Ind central nervous system function. Am j Metl
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I?. 13. 14. 15.
IG. 17.
3G: 5G I. lYG4. Alcxandor S. Brentllcr H: Trcatmcnt of uric acicl urolithiasis \vith allopurinol: a xanthine oxidaso inhillitor. J UrnI ~7: 340, 1YG7. Yii TF. Wcinrch N. Wittman R. cl al.: Strctrntlary gout associated with chronic mycloproliferativc: disorders. Semin Arthritis Rherlm G: 247, 1976. Rieselbach RE. Bcntzel CJ, Cotlovc E. trt al.: Ilric: acid cxcrelicm and renal function in acllte hyt)crriricomia of leukcmia. Pathogencsis and therapy of uric acid ncphropatlly. Am j bletl 37: 872, lYG4. Sccgmillcr jE, Frazier PD: Biochemical ccansidorations of the renal damage of grout. Ann Rheum Uis 225: GGH. IYGG Y~I TF: Ilnpublishcd data. Talbott JH, Tcrplnn KL: The kitlncy in gollt. hlctlicinc (Daltimctrcj 3% 405. IYGO. Hcptinstall RH: Gout. Pathology of the Kitlnc!y. 2nd otl. Boston, Littlc Bro\%n (i- Co.. IY74. p YG,3. Gonick HC, Rubini ILIE, Gleason 10. ct al.: ‘I’hc renal lesion in gout. Ann Intern Mcd 133: 37Y. lYG5. Pardtr V. Perez-Stahlc E, Fisher ER: Llltr,tstructurr: studies in hypertension III. gout\; nephropathy. I.,~IJ Invest 18: 143.
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1979
The American Journal of Medicine
Volume 67
771