S eminars
in and Rheumatism
Arthritis
MAY
VOL. IV, NO. 4
1975
Renal Disease in Primary Gout: A Study of 253 Gout Patients With Proteinuria By T&al-Fan
YLI, and Lawrence
Berger
R
has long been incriminated as a common cause ENAL INSUFFICIENCY of death in gout. Reports on nephropathy in gout repeatedly emphasize that the kidney in gout is not only the seat of uric acid deposition but also SCOWS significant degree of nephrosclerosis and changes described as pyelonephritis.1-*2 In addition, hypertension is frequently observed in gouty patients with nephrophropathy.2*3*10*12 In attempting to comprehend the complex role of the kidneys in primary gout, it is important to differentiate whether the renal involvement is primary or secondary to other associated diseases. In order to enable the physician to make such a distinction, it is important to have long term clinical and laboratory observations. In the past 20 yr, 1700 cases of primary gout were observed, and many of them were followed for long periods of time.‘3-18 Two hundred and fifty-three cases of the 1700 with primary gout (male : female, 237:16) presented varying degrees of renal involvement, with proteinuria as the minimum criterion. Many of them had such associated diseases as hypertension or other cardiovascular diseases, diabetes, nephropathy, including such diseases as glomerulonephritis, pyelonephritis and congenital renal disease. The existence of such associated diseases makes it difficult to attribute the renal abnormality to gout per se. CLINICAL
AND
BIOCHEMICAL
OF NEPHROPATHY
IN
FEATURES
PRIMARY
GOUT
Hypertension occurred in 151 (60%) of the 253 patients with nephropathy, cardio- and/or cerebrovascular disease in 87 (34%), and diabetes in 20 (8%) (Fig. From the Department of Medicine, Mount Sinai School of Medicine,The City University of New York New York. N. Y. 10029. Supported in part by a Grant-In-Aid A-162, National Institute of Arthritis and Metabolic Diseases, National Institutes of Health. Ts’ai-fan Yil, M.D.: Research Professor of Medicine, Department of Medicine, Mount Sinai School of Medicine. The City University of New York, New York, N.Y. 10029. Lawrence Berger, M.D.: Associate Clinical Professor of Medicine, Department of Medicine. Mount Sinai School of Medicine. The City University of New York. New York, N. Y. 10029. Requests for reprints should be addressed to: Dr. Ts’ai-fan Yii, Mount Sinai School of Medicine, The City University of New York, New York, N. Y. 10029. This paper is dedicated to the late Dr. Alexander B. Guiman in appreciation of his guidance. 0 1975 by Grune & Stratton,
Inc.
Seminars in Arthritis and Rheumatism, Vol. 4. No 4 (May), 1975
293
Vu AND BERGER
294
600 50.0 :
40.0
:: 0
30.0
NEPHROPATHY GROUP (No.253) NON-NEPHROPATHY GROUP (No =1447)
* 20.0 10.0 0
Fig. 1. Incidence of associated diseases in gout. More hypertension and cardiac or cerebral vascular diseases occur in the group with nephmpathy.
HYPERCARDIACOR DIABETES TENSION CEAEBROVASCULAR DISEASE
1). Urate deposition, as tophi, occurred in 13 1 (52%) (Fig. 2), and as calculi in 7 1 (28%) (Fig. 3). In patients without proteinuria, incidence of hypertension was approximately 431, that of cardiac or cerebrovascular disease 20% and incidence of diabetes remained at 8%. Only one-third of the patients without nephropathy had tophi, which were minimal in most cases; 26% of these patients had renal calculi. Serum urate averaged 10.4 + 1.7 mg/lOO ml in the nephropathy group, approximately 1.4 mg/lOO ml higher than the group without proteinuria, which was 9.0 f 1.4 mg/ 100 ml (Fig. 4). Urine urate excretion was lower in the nephropathy group (Fig. 5), as was inulin clearance and PAH clearance (Figs. 6 and 7). Almost one-third of the patients excreted less than 400 mg of uric acid daily; less than 12% excreted more than 800 mg. Renal hemodynamic studies in 98 cases were measured by clearances of inulin and PAH. The distribution of Cinulinshown in Fig. 6 indicates that 30% of the cases had inulin clearance less than 65 ml/min (Fig. 6). The PAH clearances were correspondingly depressed (Fig. 7), and the filtration fraction ratios were, in most cases, within normal limits. The ratios of urate to inulin clearances were greater than 0.11 in 12% of the 23 patients whose C inulin was less than 65 ml/min (Fig. 8), an observation previously noted.17V1Q*20V21
50.0
NON-NEPHROPATHY GROUP
z v)
(No.=14471
40.0
d \o 30.0 0
Fig. 2. Incidence of tophi in gout, without nephropathy end with nephropathy. Total incidence of tophi is greater in patients with nephropathy. particularly *se with extensive tophi.
0
0
t
DEGREEOFTOPHACEOUS
+t
+tt
DEPOSITS
RENAL
DISEASE
IN PRIMARY
295
GOUT
a :
il
NEPHROPATHY GROUP
t No ~253)
NON-NEPHROPATH GROUP (No : 1447)
15.0
m10.0 Id
cn
a 0
8 5.0
Fig. 3. Incidence of renal calculi in gout without and with nephmpathy. Incidences of recurrent and single attacks are similar in both groups.
300
z
-2Cr -IT
t I
M
RECURRENT
RENAL
SINGLE
CALCULI
+,0- +2p NON-NEPHROPATHY GROUP (No.= 1447)
1 -
20.0 NEPHROPATHY
: 0
15.0
INo=253)
-
,\” IO.0
5.0 ”l-l
12.013.014.015.0 16.017.0 6.0 7.0 8.0 9.0 10.011.0 SERUM URATE (mg %)
Fig. 4. Distribution of serum urato in gout with nephropathy. The mean for the group was 10.4 f 1.7 mg/lOO ml as compared to the mean of 9.0 f 1.4 mg/lDO ml forthe group without nephropathy.
NEPHROPATHY
s 20.0
Fig. 5. Distribution of urinary urate in gout, with and without nephropathy. Almost one-third of the group with nephropathy‘hed urinary urete excretion less than 400 mg per day.
0
NON-NEPHROPATHY INo =I0871
GROUP
GROUP
300 400 500 600 700 800 900 1000 II00 URINARY URATE (mg/day)
296
Yii AND BERGER
25 0
:
15.0
s $
NEPHROPATHY 10.0
5.0 0
5
15 25 3545 5565 75 85 95 105115 125 135145155 165
Ci”,ji”
Fig. 6. Distribution of Cinulin in gouty patients with nephropathy, compared With III~~II Cinulin of 116 zt 25 ml/min for the non-nephropathy gout patients. Thirty per cent of the nephropathy group had Cinulin I~SS than 66 ml/min.
(ml/min)
20.0 tNON-NEPHROPATHY
-2u 1
-If7 I
M I
+IP 1
cn 15.0 : 2
NEPHROPATHY 10.0
Fig. 7. Distribution of CPA, in gouty patients with nephropathy, compared with mean CPA, 490 f 120 ml/min for the non-nephropathy gout patients. Twenty-six per cent of the nephropathy group had CPAH less
.\”
5.0 0
50 100 150200 250 300 350 400450 500 550 600
C PAH (ml/min)
than 250 ml/min.
040
.,
, , , , , , , , , , , , , , ,
01”“““““““1 0 20 40 60
80
%viin
I
-2cr
100
I20
(ml/min)
I
I
140
160
1
,
M +lr +2r Clnulin for non-nephropathy group -IrY
C,-/ Fig. 6. Relationship of Cinuliito Cinulin in gouty patients with nephropathy; 12 of the 23 with C~nul~n < 66 ml/min had Cu,&Cinu~~n > 0.11.
Renal
vascular
tCardiac
tBUN
or cerebral
> 25 mg/lOO
hypertension
lithiasis
NPN
vascular
ml,
nn 12.
sclerosis
hypertension
tophaceous
gout
No.
renal
Total
*Systolic
Infected
Fulminating
gout
Long-standmg
Arterio-artenolar
disease
disease
heart
hypertension
Rheumatic
vascular
secondary
Essential
Cardiorenal
Proteinuria,
proteinuria
pyelonephritis
Benign
glomerulonephrltls
disease
cysts
Chronic
renal
renal
Chronic
Chronic
Solitary
kidneys
disease
diseases
renal
of Nephropafhy
Polycystic
Cystic
Intrinsic
Nature
dtsease.
> 45
253
22
5
28
31
4
73
6
8
15
18
30
10
3
NO.
Total
mg/lOO
8
0
15
0
3
1
of Gout
History
Family
Positive
(42)
(211
(37)
(48)
ml or plasma
23-57
16-26
22-49
27-71
(401
(44)
23-50
(52)
24-70
(52)
36-64
31-59
(391
(41)
(421
(56)
(39)
18-62
20-65
25-60
40-73
37-42
1.
64
6
0
0
14
0
23
0
2
4
5
8
2
0
+ -
> 2.0
28
2
3
0
3
0
14
1
0
0
2
1
2
0
++
and
0
29
0
1
28
0
0
0
0
0
0
0
0
0
ml
No.
1
19 35
3 36
4
0
0
3 6
1
6
3
0
2
1
2
1
1
0
0
11
1
1
1
2
2
0
in 253
Recurrent
Calculi
With
Findings
Renal Sinale
Biochemical
++++
mg/lOO
9
3
1
0
0
1
0
0
0
0
2
1
1
0
+++
With
Status
Tophi
No.
Clinical
creatinine
(yr)
of Onset
of Gout
Age
Table
163%
13
2
17
17*
4
73
0
1
3
6
18
6
3
tension
HYPE+
Cases
3
1
1
87
7
2
18
11
30
20
7
0
3
0
1
3
0
3
0
0
8
0
1
Diabetes
1
C.C.V.D.’
Nephropathy
Disease
No. Associated
With With
of Gout
t
10.6
1.6
1.8
1.9
f 2.0
12.9k1.4
11.1
9.9’
11.01
652?
378+
416t-
475*
643?
563
i
494*
637?
136
304
99
144
190
204
? 276
115
171
199
+ 234 6942201
516?
531
547C
496+138
10.5
1.7
* 1.3
1.2
Urine #no/da”
Acid
11.3t2.9
9.9
10.3*
f
10.0
1.5
t 1.2
10.1
10.3r0.9
8.7tO.4
mg/lOO
ml
Uric Plasma
NO.
With
9
8
3
159
18
5
18
20
3
42
3
5
13
12
+
67
2
0
9
9
1
21
2
3
2
4
14
0
0
++
Proteinuria
27
2
0
1
2
0
10
1
0
0
2
7
2
0
+++
No.
With
1
86
4
2
8
6
22
3
4
0
12
17
5
2
Azoremiat
298
Vii AND
BERGER
Primary Intrinsic Renal Disease in Gout
Eighty-four of the 253 patients with proteinuria had primary intrinsic renal diseases, such as polycystic diseases of the kidneys, chronic renal disease, and proteinuria secondary to other diseases (Tables 1 and 2). Three cases in our study had polycystic kidney disease, radiographically proved. The onset of gout occurred relatively early, at ages ranging between 37 and 42 yr. In all three cases, the gouty arthritis was mild; none had renal calculi or tophi. The plasma urate averaged 8.7 & 0.4 mg/ 100 ml, and 24-hr urinary uric acid 496 f 138 mg/day. All three had proteinuria and severe hypertension; two had azotemia. Two patients died of uremia; the duration of azotemia was 2 yr in one case and 5 yr in the other. The third patient died of a myocardial infarction, and had no azotemia. All three died at a relatively young age, from 47 to 55 yr. Ten cases had solitary renal cysts, with the diagnosis established radiographically. Gout was rather mild, with its age of onset ranging from 40 to 73 years, (with a mean age of 56). Five of the group were tophaceous, and two had renal calculi. The mean serum urate was 10.3 f 0.9 mg/lOO ml; six had more than 10 mg/lOO ml. Urinary urate averaged 547 f 136 mg/day. In five cases, death occurred with azotemia after a period of from 5-15 yr, at ages ranging from 67 to 78 yr. Since solitary renal cysts are not likely to cause proteinuria and azotemia, the nephropathy in these ten patients is best correlated with hypertension, occurring in six, or urate calculi in two others. The five surviving patients had persistent proteinuria, but with fairly stable renal function, and with gout well under control. Sixty-three patients had chronic renal disease. Thirty were classified as having chronic glomerulonephritis. In 28 of these 30, some combination of a prior history of proteinuria or hypertension could be elicited. The mean age of onset of gout was 42, and that of the renal disease was between 10 and 52-12 before the age 20. Hence, the onset of the renal disease sometimes preceded that of gout by many years. Nephropathy in these 30 patients was characterized by moderate to marked proteinuria in 21 and minimal proteinuria in 9. Hypertension occurred in 18 cases (60%) and azotemia in 16 (53%). Recurrent acute gouty arthritis was infrequent and mild. Incidence of renal calculi was relatively low, only 10%. Extensive tophi were present in two cases who also had rapidly progressive deterioration of renal function; minimal tophi existed in eight others. The serum urate was 10.1 f 1.2 mg/lOO ml, and urinary uric acid excretion was 531 f 234 mg/ day. Death occurred in 16 patients, 14 of whom had uremia at the time of death. Duration of renal disease prior to death varied greatly, ranging from 1 to 50 yr, with a mean of 24 yr. Interval from azotemia to death varied from 1 to 14 yr. Three of the 14 patients still alive had azotemia, and one required renal hemodialysis. Thus, the nephropathy was severe, but gout was relatively mild. Eighteen patients had a picture of chronic renal disease due to factors other than apparent glomerulonephritis. Four were females, two of whose nephropathy had its onset in pregnancy. Five had obstructive uropathy; one developed nephropathy secondary to tetracycline; and one had rectovesical fistula with ascending pyelonephritis. In the remaining patients, chronic pyelonephritis was the diagnosis. In 12, proteinuria was only minimal, and in others, moderate. In 8 of these 18 patients, the nephropathy preceded the onset of gout; mean age of onset
*Cardiac
no.
or Cerebral
Vascular
Disease.
60 (46-81)
13 (59)
106 (42)
22
253
Total
Renal calculi 74 (70-81) 22 (21)
O( 0)
0)
0)
O( O(
71 (61-83) 67 (47-80)
72 (61-80)
69 (57-75)
21 (75) O( 0)
28 5
gout
4 (15)
59 (38-74)
Long-standing tophaceous Fulminating gout
18 (64)
50 (48-55)
Renal Failure No. (%)
60 (50-76)
83 31
No Uremia Vr
60 (34-78)
28 (33) 27 (33) 17 (55)
84
disease
With Uremia VT
Hypertension and heart failure Arterio-arteriolar sclerosis
Intrinsic renal
TVpe of Nephropathy
Deaths No. (%)
Total No.
Age of Death
3 (23) 45 (42)
(
16 (15)
8)
3 (14) 1
8 (47) 12 (57)
3 (18)
18 (67)
4 (14)
NO AZOtemia No. (%)
5 (18) 4 (15)
With AZOtemia No. (%)
c.c.v.o.*
Table 2: Causes of Deaths in Patients With Nephropathy
3 (3)
1 (8)
O( 2(
1 (5)
0) 2)
0)
2 (12) O(
0 (0)
0)
0) O(
O( 0 (0)
1 (4)
NO AZOtemia No. (%)
Malignancy With AZOtemia No. (%)
3 (23) 6( 6)
3 (14)
0)
0)
O( O(
0)
O(
(
0) 3)
5 (38) 12fll)
2 (10)
4 (24)
1
O(
No AZOtemia No. (%)
Other Causes With AZOtemia No. (%)
300
Yli
AND
BERGER
of nephropathy was 30 yr; of gout, 41 yr. Plasma urate was rather high; 10.0 f 1.5 mg/ 100 ml and urinary mate was 5 16 f 199 mg/day. Only two (11%) of the 18 patients had renal calculi; but nine (50%) had tophi, with extensive deposits in two. Hypertension was present in six patients (33’S), and azotemia of varying degrees in 12 (67%). In two patients, death occurred with myocardial infarction and uremia; in one, it was due to cerebral hemorrhage. The interval from renal disease to death in these three ranged from 25 to 30 yr. In this group, gouty arthritis was mild, as in the prior group. Mild nephropathy occurred in a group of 15 patients with benign proteinuria of undefined cause. The mean age of discovery of proteinuria in the 15 patients was 24 yr; onset of gout was at a mean age of 39 yr. In all cases, proteinuria preceded gout. Of these 15 patients, three (20%) had hypertension, one of whom developed a myocardial infarction. Plasma urate was relatively high, 10.3 f 1.2 mg/ 100 ml; and urinary uric acid was 694 f 201 mg/day. Renal calculi occurred in three cases, (20%), and tophi were present in four (27%). Renal function was well preserved in all cases. Treatment of gout did not alter the proteinuria or renal function in these 15 patients. Eight patients with gout had proteinuria due to some other recognizable disease, such as multiple myeloma, Gaucher’s disease, carcinoma of the kidneys, lead poisoning, and diabetes. Mean age of onset of gout was relatively late, at 52 yr; and renal disease preceded gout in all cases. Gouty arthritis was mild; renal calculi occurred in two cases (25’S), and tophi in two (25%). Plasma urate averaged 9.9 + 1.3 mg/lOO ml and urinary uric acid 627 f 171 mg/day. Three patients were mildly azotemic. The clinical course in these eight patients was related solely to the primary disease. One patient died in uremia with gram-negative septicemia while receiving chemotherapy for multiple myeloma. Gout Associated With Cardiac, Renovascular, or Di$use Vascular Disease Of the 253 patients studied who had proteinuria, 114 had cardiac, renovascular, or diffuse vascular disease, which could have in itself significantly contributed to the nephropathy observed. Six patients had rheumatic heart disease with heart failure. Mean age of onset of gout was 52, and gouty arthritis was mild. Tophi occurred in one case (17%), and renal calculi in two (33%). All except one had serum urate more than 10 mg/ 100 ml, the mean being 11.3 + 2.0 mg/lOO ml. Urinary urate was not high, 494 + 115 mg/day. Three patients had mild azotemia. One died from cerebral embolism at age 58, and another one from ruptured aortic aneurysm at 60. Seventy-three of a total of 151 patients with hypertension were classified as having essential hypertension, with blood pressure above 150/90. Mean age for onset of gout was 44 yr, and for hypertension, 46 yr. In 24 patients, hypertension preceded gout; in 25, gout preceded hypertension, and, in the remainder, the two diseases were diagnosed at about the same time. The severity of gout was variable in these patients. Renal calculi occurred in 17 (23%) an incidence not much different from that in uncomplicated gout. Tophi occurred in 37 (51%) of the 73 patients, a higher incidence than that observed in gout without proteinuria. Twenty-four of the 73 died: 16 from cardiac or cerebral vascular accident, and
RENAL DISEASE
IN PRIMARY
GOUT
301
one from massive gastrointestinal bleeding. Seven died with uremia. Ages at death varied from 50 to 76 yr, with an average of 60 yr. In a separate group of four patients, hypertension was associated with unilateral renal artery stenosis, angiographically proven. Age of onset of gout in these four ranged from 23 to 50 yr; one had tophi, and three had renal calculi. Plasma urate was high, 11.O i 1.9 mg/ 100 ml, and urinary uric acid was 643 f 204 mg/day. Hypertension was severe in all four patients. One patient died with very extensive tophi and rapidly progressive renal insufficiency at age 50; another died from myocardial infarction at age 38; and a third patient survived a ruptured aortic aneurysm. In contrast to the group with essential hypertension, 31 patients were classified as having arteriosclerosis and arteriolar sclerosis, based on clinical findings. These patients all showed signs either of coronary artery disease, cerebrovascular disease, heart failure, or diabetes. Seventeen (55%) of the 31 patients had a systolic pressure above 150 mm Hg; only five had a diastolic pressure above 90. Mean age of onset of gout was 48 yr. Seventeen (55%) were tophaceous, and ten (32%) had renal calculi, a high incidence for both. This is related to an average delay of 13 yr in seeking treatment. Eleven (35%) of the 31 patients had moderate to profuse proteinuria, and six were mildly azotemic. Eleven died of myocardial infarction, cerebrovascular accident, or heart failure. Three died from carcinoma and three from other causes. The mean age of death was 70 yr. In these 31 patients, the course of gout was variable. Nephropathy in general was mild, but the cardiac and cerebral circulatory diseases determined the clinical course. Long-standing Tophaceous Gout Of the 131 with tophaceous deposits, extremely extensive tophi existed in 28 patients who were first seen during the preuricosuric era. Onset of gout was relatively early, 37 yr. There was a delay of 14-36 yr before they received adequate treatment. All had severe recurrent gouty arthritis early in their course. In addition to the extensive tophaceous deposits, there was chronic joint aching and stiffness. Only two (7%) had renal calculi, and two had iatrogenic urate crystalluria. Plasma urate was high, 11.1 f 1.6 mg/ 100 ml, and urinary uric acid was less than normal in many, mean being 416 =t 144 mg/day. Nineteen of the 28 exhibited satisfactory reduction in the size of tophi following protracted uricosuric therapy, either with probenecid or sulfinpyrazone. Proteinuria was profuse in one, moderate in nine, and minimal in the remaining 18. In 17 (6 1%) patients of the 28, hypertension existd. Azotemia occurred in eight, urinary tract infection in three. Seventeen died from myocardial infarction, cardiac insufficiency, or cerebrovascular disease, three from sepsis, and one had carcinoma of the rectum. Age at death was more than 70 yr in two-thirds of the 21 patients. The high incidence of cardiac and cerebrovascular complications was most likely related to aging in these patients. Infected Renal Calculi Of the 253 cases with nephropathy, 71 (28%) had renal calculi. In 22 patients with recurrent calculi, urinary tract infection dominated the clinical picture. In
302
Vii AND
BERGER
16 of these 22, calculi preceded the onset of gout. The mean age of onset of calculi was 38 yr, and onset of gout, 42. Positive family history of gout occurred in nine of the 22 patients (41%). Plasma urate averaged 10.6 f 2.0 mg/ 100 ml, and urinary uric acid 652 f 304 mg/day, with eight patients excreting more than 800 mg/day. One of the 22 had deficient hypoxanthine guanine phosphoribosyltransferase (HPRT). Eleven (50%) had tophi, which were extensive in three; hypertension occurred in 13 (59%), diabetes in seven (32%). Death occurred in 13, associated with uremia in five. Four died from cardiac or cerebral vascular disease and nine others from nonvascular conditions. Fulminating Gout Five relatively young subjects were classified as having fulminating gout, characterized by early onset, severe gouty arthritis, extensive tophaceous deposits, extremely high serum urate and low urinary uric acid. Four of the five patients had a positive family history of gout. Age of onset was between 16 and 26 yr; all had moderate to extensive tophi. In only one case did renal calculi occur, and this happened only after uricosuric therapy. Hyperuricemia was extreme, 12.9 + 1.4 mg/lOO ml, and urinary uric acid was low, 378 f 99 mg/day. Proteinuria was minimal; azotemia occurred in two. Despite energetic uricosuric therapy, the tophi grew relentlessly. All except one eventually responded to allopurinol, with reduction in the size of the tophi, but renal function did not improve. Two developed hypertension, and two had myocardial infarction. One progressed to uremia, requiring hemodialysis, and ultimately received a renal transplant. The development of cardiovascular complications at a relatively young age in these five patients with very severe gout helps to differentiate them from the hypertension-arteriosclerosis patients who develop renal insufficiency. One of the five was found to be deficient in hypoxanthine guanine phosphoribosyltransferase (HPRT). DISCUSSION
The present study shows that in an overwhelming number of cases of renal dysfunction in gout, independent factors other than gout exist to account for the proteinuria and other signs of nephropathy observed. In gouty patients with nephropathy, a frequent occurrence of vascular disease, or independent intrinsic renal disease exists. Nephropathy without renal infection, intrinsic renal disease, or vascular sclerosis is infrequent. Significant nephropathy exists in 253 (15%) of the 1700 gouty patients, a figure fairly consistent with the reported incidence of nephropathy in gout. 3p5Two hundred and ninety-eight of our 1700 cases were known to have died over the 25 yr of observation. Approximately 9% of the deaths were due directly to renal insufficiency, and, in another 7% azotemia accompanied other immediate causes of death. Our data on nephropathy illustrate that a substantial number of those patients dying with uremia have a nongouty cause of uremia. Gout alone rarely causes nephropathy, and nephropathy in gout is most often associated with renal pathology of nongouty nature. Talbott and Terplan3 found lesions of pyelonephritis and nephrosclerosis, in addition to urate deposition, in the kidneys of 164 patients who died with primary gout. Frequently, it was impossible to differentiate pyelonephritic from vascular
RENAL DISEASE
IN PRIMARY
GOUT
303
changes. Moreover, the severity of the morphologic alterations did not bear a direct correlation with the clinical course of the disease, Clinical evidence of arteriolar nephrosclerosis has not been found to be more common in patients with gout than in those with moderate or severe hypertension, coronary artery disease or cerebra1 arteriosclerosis.10*12 Gonick et al.l” reported a glomerular sclerosing lesion, which they considered possibly characteristic of gout, on renal biopsy in 28 patients. However, they also reported an incidence of hypertension in 62%, and degenerative renal lesions of arteries and arterioles. Barlow and Beilin12 reported nephrosclerosis in 21 of 23 renal biopsies in gouty subjects. These authors found an incidence of hypertension in 42% of 52 gouty patients. They did not, however, observe any difference in incidence of glomerular atrophy and nephrosclerosis between hypertensive and nonhypertensive gouty patients. They raised the question whether the patient with gout is predisposed to nephrosclerosis, even in the absence of hypertension. The development of renal insufficiency was, in their opinion, more related to increasing age than to the gouty process itself. In our series of nephropathy patients, 84 cases showed evidence of independently occurring intrinsic renal disease. Admittedly, in the absence of renal biopsies and urinary bacteria1 culture data, the groups of “glomerulonephritis” and “pyelonephritis” cannot be irrefutably defined. Also it is recognized that the criteria for the diagnosis and classification of “glomerulonephritis” and “pyeloHowever, all in the groups we have defined nephritis” are much in dispute. 11~22~23 had a very mild clinical course of gout, and the onset of nephropathy preceded that of gout in most cases. Many of them died from renal failure. Gout secondary Thus these 84 patients could to chronic renal disease is considered to be rare. 24*25 be considered to have primary gout, with coexistent primary renal disease. On the other hand, the onset of renal disease preceding that of gout for many years, in a good number of these patients, does not exclude the possibility that, in some at least, gout could be secondary to the primary renal disease. In 114 patients, we found associated cardiovascular disease extensive enough to cause nephropathy. In view of the lack of direct correlation between the clinical course of gout and renal pathologic changes, and the frequent occurrence of hypertension and arteriosclerosis in both the gouty and the nongouty populations, it is difficult to define a purely “gouty” nephropathy by a clinical study alone. In 55 patients, gout, with or without urinary tract infection, was more primarily involved in causing nephropathy. Even here, however, the high incidence of hypertension and cardiovascular complications have to be considered important in the causation of nephropathy. In 22 cases of recurrent renal calculi with coexisting infection, it is a fair assumption that renal damage is primarily due to urate deposition within the urinary tract, and that the vascular complications are secondary to the renal damage. Even in the group with fulminating gout, hypertension and cardiovascular complications, factors not specifically gouty, existed in four of the five patients. This study does not preclude that gout predisposes to hypertension, nephrosclerosis, and even to proteinuria. The possibility exists that the individual with gout is also metabolically predisposed to hypertension and vascular sclerosis. The one factor in gout which may be considered a precipitant of renal damage
304
YiJ AND BERGER
is urate deposition, which in turn is related to the degree of hyperuricemia and hyperuricosuria. As the renal damage progresses, hyperuricemia becomes more extreme, but the hyperuricosuria levels off resulting in retention of uric acid. It is very probable that this chemical insult then may lead to renal ischemia, pyelonephritic and vascular sclerotic changes. However, such changes also occur in subjects with intrinsic renal disease, and in subjects with hypertension and arteriosclerosis, particularly in advanced age. In order to be able to answer the question whether there is any specific renal lesion in gout, renal biopsy will have to be done in uncomplicated gout of relatively young age and in proteinuric gouty cases with or without hypertension. Uric acid is a weak acid with a pKa of 5.75; that is, in solution at pH 5.75, uric acid is half ionized and half un-ionized. At pH of the plasma and body fluids, uric acid is almost all dissociated, whereas in acid urine, it is largely undissociated. With extreme hyperuricemia and acid urine, excessive uric acid deposition in the renal tubules occurs and may lead to acute oliguric renal failure. This type of oliguric renal failure is more commonly seen in patients with blood dyscrasia, particularly after cytotoxic therapy and does not often occur in primary gout.26-2e We have observed only one patient with repeated bouts of anuric obstructive uropathy due to urate lithiasis, and this was a patient with partial deficiency in HPRT. With hyperuricemia and very highly supersaturated urate concentrations in urine, renal calculus formation occurs in more than 20% in primary gout,15 and approximately 40% in secondary gout associated with myeloproliferative diseases.30 Urate crystals may also precipitate within the kidney tissue itself, similar in nature to those in tophi. 31 It is of interest to note that at the same degree of hyperuricemia, some patients may develop renal calculi without tophi, and others may develop tophi without forming renal calculi (Table 1). The incidence of renal calculi is rather low in the groups with long standing tophaceous gout and fulminating gout; nor were many tophaceous among those with recurrent renal lithiasis. There must be in addition different local factors to cause the precipitation of urate crystals, either juxta-articularly or in the kidney tissue. Interestingly, hyperuricemia of the degree found in patients with azotemia in primary gout with renal insufficiency rarely, if at all, causes urate deposition in One explanation may be that as glomerular filtration kidney or urinary tract. 2Q*30 rate falls, the filtered urate load is decreased, and so is the amount of urate reabsorbed. Urate deposition within the kidney, a not infrequent occurrence in pathologic specimens of gouty subjects, does not correlate with the state of renal function. Those with renal function impairment commonly show other conditions contributing to the development of renal dysfunction either independently occurring renal disease, associated vascular disease involving the kidney, urinary tract infection, hypertension, or cardiac disease. Since gouty patients with or without nephropathy frequently have hypertension, and. signs of vascular sclerosis, it is possible that gout predisposes to these diseases, or more likely, that patients with vascular sclerosis and gout have a common metabolic or hypertension, pathologic predilection. Hyperuricemia alone is not adequate to account for renal dysfunction in most cases of gout. When nephropathy does occur in gout, it is
RENAL
DISEASE
IN PRIMARY
305
GOUT
usually related with coexisting intrinsic renal disease, hypertension, cardiac disease, renovascular disease or urinary tract infection. Gout contributes to renal damage in those with uncontrolled recurrent renal lithiasis accompanied by persistent infection, in neglected cases with long-standing extensive tophaceous deposits, and in fulminating cases with early onset and extreme hyperuricemia refractory to treatment. REFERENCES 1. Garrod AB: A Treatise in Gout and Rheumatic Gout (ed 3). London, Longmans, Green, 1876 2. Schnitker MA, Richter AB: Nephritis in gout. Am J Med Sci 192:241,1936 3. Talbott JH, Terplan KL: The kidney in gout. Medicine 39:405, 1960 4. Brown J, Mallory GK: Renal changes in gout. N Engl J Med 243:325,1950 5. Modern FWS, Meister L: The kidney of gout, a clinical entity. Med Clin North Am 36:941, 1952 6. Fineberg SK, Altschul A: The nephropathy of gout. Ann Intern Med 44:1182, 1956 7. Greenbaum D, Ross JH, Steinberg VL: Renal biopsy in gout. Br Med J 1:1502, 1961 8. Mayne JG: Pathological study of the renal lesions found in 27 patients with gout. Ann Rheum Dis 15:61, 1956 9. SokoloB L: Pathology of gout. Arth Rheum 8:707,1965 10. Gonick HC, Rubini M, Gleason 10, et al: The renal lesion in gout. Ann Intern Med 62:667, 1965 II. Heptinstall RH: Pathology of the Kidney. Boston, Little Brown, 1966 12. Barlow KA, Beilin LJ: Renal primary gout. Quart J Med 37:79,1968
disease
in
13. Gutman AB, Yii TF: Renal function in gout, with a commentary on the renal regulation of urate excretion, and the role of the kidney in the pathogenesis of gout. Am J Med 23:600,1957 14. Yii TF, Berger L, Gutman AB: Renal function in gout, II. Effect of uric acid loading on renal excretion of uric acid. Am. J. Med. 33:829, 1962 15. Gutman AB, Yii TF: Uric acid nephrolithiasis. Am J Med 45:756, 1968 16. YU TF, Gutman AB: Principles of current management of primary gout. Am J Med Sci 254:893, 1967 17. Gutman AB, YU TF, Berger L: Renal function in gout. III. Estimation of tubular
secretion of uric acid by use of pyrazinamide (pyrazinoic acid). Am J Med 47:575, 1969 18. Berger L, Yli TF, Gutman AB: Long term follow up studies of renal function in primary gout. Am Sot Nephrology Meeting, Washington, D.C., 1973, p IO 19. Steele TH, Rieselbach RE: The contribution of residual nephrons within the chronically diseased kidneys to urate homeostasis in man. Am J Med 43:876, 1967 20. Sarr H, Mertz DP: Sekundlre Gicht bei Niereninsulfizienz. Klin Wschr 43:1134, 1965 21. McPhaul JJ Jr.: Hyperuricemia and urate excretion in chronic renal disease. Metabolism 17:430, 1968 22. Heptinstall RH: The enigma of chronic pyelonephritis. J Infect Dis 120: 104, 1969 23. Cameron JS: The natural history of glomerulonephritis, in Black DAK (ed): Renal Disease. Oxford, Blackwell, 1972, p 295 24. Richet P, Mignon GF, Ardaillon R: Goutte secondaire des nephropathies chroniques. Presse Med 73:633, 1965 25. Ross EJ: Chronic renal failure in Black, DAK (ed): Oxford, Blackwell, 1972, p 476 26. Weissberger AS, Persky L: Renal calculi and uremia as complications of lymphoma. Am J Med Sci 225:669, 1953 27. Greenbaum D, Stone HF: Dangers of uric acid excretion during treatment of leukemia and lymphosarcoma. Lancet 1:73, 1959 28. Rieselbach RE, Bentzel CJ, Cotlove E, et al: Uric acid excretion and renal function in the acute hyperuricemia of leukemia; pathogenesis and therapy of uric acid nephropathy. Am J Med 37~872, 1964 29. Kjellstrand CM: Hyperuricemic acute renal failure. Arch Intern Med 133:349, 1974 30. Yii TF: Secondary gout associated with myeloproliferative diseases. Arth Rheum 8:765, 1965 31, Seegmiller JE, Frazier PD: Biological considerations of the renal damage of gout. Ann Rheum Dis 25: suppl6:668, 1966
in and Rheumatism
Arthritis
MAY
VOL. IV, NO. 4
1975
Renal Disease in Primary Gout: A Study of 253 Gout Patients With Proteinuria By T&al-Fan
YLI, and Lawrence
Berger
R
has long been incriminated as a common cause ENAL INSUFFICIENCY of death in gout. Reports on nephropathy in gout repeatedly emphasize that the kidney in gout is not only the seat of uric acid deposition but also SCOWS significant degree of nephrosclerosis and changes described as pyelonephritis.1-*2 In addition, hypertension is frequently observed in gouty patients with nephrophropathy.2*3*10*12 In attempting to comprehend the complex role of the kidneys in primary gout, it is important to differentiate whether the renal involvement is primary or secondary to other associated diseases. In order to enable the physician to make such a distinction, it is important to have long term clinical and laboratory observations. In the past 20 yr, 1700 cases of primary gout were observed, and many of them were followed for long periods of time.‘3-18 Two hundred and fifty-three cases of the 1700 with primary gout (male : female, 237:16) presented varying degrees of renal involvement, with proteinuria as the minimum criterion. Many of them had such associated diseases as hypertension or other cardiovascular diseases, diabetes, nephropathy, including such diseases as glomerulonephritis, pyelonephritis and congenital renal disease. The existence of such associated diseases makes it difficult to attribute the renal abnormality to gout per se. CLINICAL
AND
BIOCHEMICAL
OF NEPHROPATHY
IN
FEATURES
PRIMARY
GOUT
Hypertension occurred in 151 (60%) of the 253 patients with nephropathy, cardio- and/or cerebrovascular disease in 87 (34%), and diabetes in 20 (8%) (Fig. From the Department of Medicine, Mount Sinai School of Medicine,The City University of New York New York. N. Y. 10029. Supported in part by a Grant-In-Aid A-162, National Institute of Arthritis and Metabolic Diseases, National Institutes of Health. Ts’ai-fan Yil, M.D.: Research Professor of Medicine, Department of Medicine, Mount Sinai School of Medicine. The City University of New York, New York, N.Y. 10029. Lawrence Berger, M.D.: Associate Clinical Professor of Medicine, Department of Medicine. Mount Sinai School of Medicine. The City University of New York. New York, N. Y. 10029. Requests for reprints should be addressed to: Dr. Ts’ai-fan Yii, Mount Sinai School of Medicine, The City University of New York, New York, N. Y. 10029. This paper is dedicated to the late Dr. Alexander B. Guiman in appreciation of his guidance. 0 1975 by Grune & Stratton,
Inc.
Seminars in Arthritis and Rheumatism, Vol. 4. No 4 (May), 1975
293
Vu AND BERGER
294
600 50.0 :
40.0
:: 0
30.0
NEPHROPATHY GROUP (No.253) NON-NEPHROPATHY GROUP (No =1447)
* 20.0 10.0 0
Fig. 1. Incidence of associated diseases in gout. More hypertension and cardiac or cerebral vascular diseases occur in the group with nephmpathy.
HYPERCARDIACOR DIABETES TENSION CEAEBROVASCULAR DISEASE
1). Urate deposition, as tophi, occurred in 13 1 (52%) (Fig. 2), and as calculi in 7 1 (28%) (Fig. 3). In patients without proteinuria, incidence of hypertension was approximately 431, that of cardiac or cerebrovascular disease 20% and incidence of diabetes remained at 8%. Only one-third of the patients without nephropathy had tophi, which were minimal in most cases; 26% of these patients had renal calculi. Serum urate averaged 10.4 + 1.7 mg/lOO ml in the nephropathy group, approximately 1.4 mg/lOO ml higher than the group without proteinuria, which was 9.0 f 1.4 mg/ 100 ml (Fig. 4). Urine urate excretion was lower in the nephropathy group (Fig. 5), as was inulin clearance and PAH clearance (Figs. 6 and 7). Almost one-third of the patients excreted less than 400 mg of uric acid daily; less than 12% excreted more than 800 mg. Renal hemodynamic studies in 98 cases were measured by clearances of inulin and PAH. The distribution of Cinulinshown in Fig. 6 indicates that 30% of the cases had inulin clearance less than 65 ml/min (Fig. 6). The PAH clearances were correspondingly depressed (Fig. 7), and the filtration fraction ratios were, in most cases, within normal limits. The ratios of urate to inulin clearances were greater than 0.11 in 12% of the 23 patients whose C inulin was less than 65 ml/min (Fig. 8), an observation previously noted.17V1Q*20V21
50.0
NON-NEPHROPATHY GROUP
z v)
(No.=14471
40.0
d \o 30.0 0
Fig. 2. Incidence of tophi in gout, without nephropathy end with nephropathy. Total incidence of tophi is greater in patients with nephropathy. particularly *se with extensive tophi.
0
0
t
DEGREEOFTOPHACEOUS
+t
+tt
DEPOSITS
RENAL
DISEASE
IN PRIMARY
295
GOUT
a :
il
NEPHROPATHY GROUP
t No ~253)
NON-NEPHROPATH GROUP (No : 1447)
15.0
m10.0 Id
cn
a 0
8 5.0
Fig. 3. Incidence of renal calculi in gout without and with nephmpathy. Incidences of recurrent and single attacks are similar in both groups.
300
z
-2Cr -IT
t I
M
RECURRENT
RENAL
SINGLE
CALCULI
+,0- +2p NON-NEPHROPATHY GROUP (No.= 1447)
1 -
20.0 NEPHROPATHY
: 0
15.0
INo=253)
-
,\” IO.0
5.0 ”l-l
12.013.014.015.0 16.017.0 6.0 7.0 8.0 9.0 10.011.0 SERUM URATE (mg %)
Fig. 4. Distribution of serum urato in gout with nephropathy. The mean for the group was 10.4 f 1.7 mg/lOO ml as compared to the mean of 9.0 f 1.4 mg/lDO ml forthe group without nephropathy.
NEPHROPATHY
s 20.0
Fig. 5. Distribution of urinary urate in gout, with and without nephropathy. Almost one-third of the group with nephropathy‘hed urinary urete excretion less than 400 mg per day.
0
NON-NEPHROPATHY INo =I0871
GROUP
GROUP
300 400 500 600 700 800 900 1000 II00 URINARY URATE (mg/day)
296
Yii AND BERGER
25 0
:
15.0
s $
NEPHROPATHY 10.0
5.0 0
5
15 25 3545 5565 75 85 95 105115 125 135145155 165
Ci”,ji”
Fig. 6. Distribution of Cinulin in gouty patients with nephropathy, compared With III~~II Cinulin of 116 zt 25 ml/min for the non-nephropathy gout patients. Thirty per cent of the nephropathy group had Cinulin I~SS than 66 ml/min.
(ml/min)
20.0 tNON-NEPHROPATHY
-2u 1
-If7 I
M I
+IP 1
cn 15.0 : 2
NEPHROPATHY 10.0
Fig. 7. Distribution of CPA, in gouty patients with nephropathy, compared with mean CPA, 490 f 120 ml/min for the non-nephropathy gout patients. Twenty-six per cent of the nephropathy group had CPAH less
.\”
5.0 0
50 100 150200 250 300 350 400450 500 550 600
C PAH (ml/min)
than 250 ml/min.
040
.,
, , , , , , , , , , , , , , ,
01”“““““““1 0 20 40 60
80
%viin
I
-2cr
100
I20
(ml/min)
I
I
140
160
1
,
M +lr +2r Clnulin for non-nephropathy group -IrY
C,-/ Fig. 6. Relationship of Cinuliito Cinulin in gouty patients with nephropathy; 12 of the 23 with C~nul~n < 66 ml/min had Cu,&Cinu~~n > 0.11.
Renal
vascular
tCardiac
tBUN
or cerebral
> 25 mg/lOO
hypertension
lithiasis
NPN
vascular
ml,
nn 12.
sclerosis
hypertension
tophaceous
gout
No.
renal
Total
*Systolic
Infected
Fulminating
gout
Long-standmg
Arterio-artenolar
disease
disease
heart
hypertension
Rheumatic
vascular
secondary
Essential
Cardiorenal
Proteinuria,
proteinuria
pyelonephritis
Benign
glomerulonephrltls
disease
cysts
Chronic
renal
renal
Chronic
Chronic
Solitary
kidneys
disease
diseases
renal
of Nephropafhy
Polycystic
Cystic
Intrinsic
Nature
dtsease.
> 45
253
22
5
28
31
4
73
6
8
15
18
30
10
3
NO.
Total
mg/lOO
8
0
15
0
3
1
of Gout
History
Family
Positive
(42)
(211
(37)
(48)
ml or plasma
23-57
16-26
22-49
27-71
(401
(44)
23-50
(52)
24-70
(52)
36-64
31-59
(391
(41)
(421
(56)
(39)
18-62
20-65
25-60
40-73
37-42
1.
64
6
0
0
14
0
23
0
2
4
5
8
2
0
+ -
> 2.0
28
2
3
0
3
0
14
1
0
0
2
1
2
0
++
and
0
29
0
1
28
0
0
0
0
0
0
0
0
0
ml
No.
1
19 35
3 36
4
0
0
3 6
1
6
3
0
2
1
2
1
1
0
0
11
1
1
1
2
2
0
in 253
Recurrent
Calculi
With
Findings
Renal Sinale
Biochemical
++++
mg/lOO
9
3
1
0
0
1
0
0
0
0
2
1
1
0
+++
With
Status
Tophi
No.
Clinical
creatinine
(yr)
of Onset
of Gout
Age
Table
163%
13
2
17
17*
4
73
0
1
3
6
18
6
3
tension
HYPE+
Cases
3
1
1
87
7
2
18
11
30
20
7
0
3
0
1
3
0
3
0
0
8
0
1
Diabetes
1
C.C.V.D.’
Nephropathy
Disease
No. Associated
With With
of Gout
t
10.6
1.6
1.8
1.9
f 2.0
12.9k1.4
11.1
9.9’
11.01
652?
378+
416t-
475*
643?
563
i
494*
637?
136
304
99
144
190
204
? 276
115
171
199
+ 234 6942201
516?
531
547C
496+138
10.5
1.7
* 1.3
1.2
Urine #no/da”
Acid
11.3t2.9
9.9
10.3*
f
10.0
1.5
t 1.2
10.1
10.3r0.9
8.7tO.4
mg/lOO
ml
Uric Plasma
NO.
With
9
8
3
159
18
5
18
20
3
42
3
5
13
12
+
67
2
0
9
9
1
21
2
3
2
4
14
0
0
++
Proteinuria
27
2
0
1
2
0
10
1
0
0
2
7
2
0
+++
No.
With
1
86
4
2
8
6
22
3
4
0
12
17
5
2
Azoremiat
298
Vii AND
BERGER
Primary Intrinsic Renal Disease in Gout
Eighty-four of the 253 patients with proteinuria had primary intrinsic renal diseases, such as polycystic diseases of the kidneys, chronic renal disease, and proteinuria secondary to other diseases (Tables 1 and 2). Three cases in our study had polycystic kidney disease, radiographically proved. The onset of gout occurred relatively early, at ages ranging between 37 and 42 yr. In all three cases, the gouty arthritis was mild; none had renal calculi or tophi. The plasma urate averaged 8.7 & 0.4 mg/ 100 ml, and 24-hr urinary uric acid 496 f 138 mg/day. All three had proteinuria and severe hypertension; two had azotemia. Two patients died of uremia; the duration of azotemia was 2 yr in one case and 5 yr in the other. The third patient died of a myocardial infarction, and had no azotemia. All three died at a relatively young age, from 47 to 55 yr. Ten cases had solitary renal cysts, with the diagnosis established radiographically. Gout was rather mild, with its age of onset ranging from 40 to 73 years, (with a mean age of 56). Five of the group were tophaceous, and two had renal calculi. The mean serum urate was 10.3 f 0.9 mg/lOO ml; six had more than 10 mg/lOO ml. Urinary urate averaged 547 f 136 mg/day. In five cases, death occurred with azotemia after a period of from 5-15 yr, at ages ranging from 67 to 78 yr. Since solitary renal cysts are not likely to cause proteinuria and azotemia, the nephropathy in these ten patients is best correlated with hypertension, occurring in six, or urate calculi in two others. The five surviving patients had persistent proteinuria, but with fairly stable renal function, and with gout well under control. Sixty-three patients had chronic renal disease. Thirty were classified as having chronic glomerulonephritis. In 28 of these 30, some combination of a prior history of proteinuria or hypertension could be elicited. The mean age of onset of gout was 42, and that of the renal disease was between 10 and 52-12 before the age 20. Hence, the onset of the renal disease sometimes preceded that of gout by many years. Nephropathy in these 30 patients was characterized by moderate to marked proteinuria in 21 and minimal proteinuria in 9. Hypertension occurred in 18 cases (60%) and azotemia in 16 (53%). Recurrent acute gouty arthritis was infrequent and mild. Incidence of renal calculi was relatively low, only 10%. Extensive tophi were present in two cases who also had rapidly progressive deterioration of renal function; minimal tophi existed in eight others. The serum urate was 10.1 f 1.2 mg/lOO ml, and urinary uric acid excretion was 531 f 234 mg/ day. Death occurred in 16 patients, 14 of whom had uremia at the time of death. Duration of renal disease prior to death varied greatly, ranging from 1 to 50 yr, with a mean of 24 yr. Interval from azotemia to death varied from 1 to 14 yr. Three of the 14 patients still alive had azotemia, and one required renal hemodialysis. Thus, the nephropathy was severe, but gout was relatively mild. Eighteen patients had a picture of chronic renal disease due to factors other than apparent glomerulonephritis. Four were females, two of whose nephropathy had its onset in pregnancy. Five had obstructive uropathy; one developed nephropathy secondary to tetracycline; and one had rectovesical fistula with ascending pyelonephritis. In the remaining patients, chronic pyelonephritis was the diagnosis. In 12, proteinuria was only minimal, and in others, moderate. In 8 of these 18 patients, the nephropathy preceded the onset of gout; mean age of onset
*Cardiac
no.
or Cerebral
Vascular
Disease.
60 (46-81)
13 (59)
106 (42)
22
253
Total
Renal calculi 74 (70-81) 22 (21)
O( 0)
0)
0)
O( O(
71 (61-83) 67 (47-80)
72 (61-80)
69 (57-75)
21 (75) O( 0)
28 5
gout
4 (15)
59 (38-74)
Long-standing tophaceous Fulminating gout
18 (64)
50 (48-55)
Renal Failure No. (%)
60 (50-76)
83 31
No Uremia Vr
60 (34-78)
28 (33) 27 (33) 17 (55)
84
disease
With Uremia VT
Hypertension and heart failure Arterio-arteriolar sclerosis
Intrinsic renal
TVpe of Nephropathy
Deaths No. (%)
Total No.
Age of Death
3 (23) 45 (42)
(
16 (15)
8)
3 (14) 1
8 (47) 12 (57)
3 (18)
18 (67)
4 (14)
NO AZOtemia No. (%)
5 (18) 4 (15)
With AZOtemia No. (%)
c.c.v.o.*
Table 2: Causes of Deaths in Patients With Nephropathy
3 (3)
1 (8)
O( 2(
1 (5)
0) 2)
0)
2 (12) O(
0 (0)
0)
0) O(
O( 0 (0)
1 (4)
NO AZOtemia No. (%)
Malignancy With AZOtemia No. (%)
3 (23) 6( 6)
3 (14)
0)
0)
O( O(
0)
O(
(
0) 3)
5 (38) 12fll)
2 (10)
4 (24)
1
O(
No AZOtemia No. (%)
Other Causes With AZOtemia No. (%)
300
Yli
AND
BERGER
of nephropathy was 30 yr; of gout, 41 yr. Plasma urate was rather high; 10.0 f 1.5 mg/ 100 ml and urinary mate was 5 16 f 199 mg/day. Only two (11%) of the 18 patients had renal calculi; but nine (50%) had tophi, with extensive deposits in two. Hypertension was present in six patients (33’S), and azotemia of varying degrees in 12 (67%). In two patients, death occurred with myocardial infarction and uremia; in one, it was due to cerebral hemorrhage. The interval from renal disease to death in these three ranged from 25 to 30 yr. In this group, gouty arthritis was mild, as in the prior group. Mild nephropathy occurred in a group of 15 patients with benign proteinuria of undefined cause. The mean age of discovery of proteinuria in the 15 patients was 24 yr; onset of gout was at a mean age of 39 yr. In all cases, proteinuria preceded gout. Of these 15 patients, three (20%) had hypertension, one of whom developed a myocardial infarction. Plasma urate was relatively high, 10.3 f 1.2 mg/ 100 ml; and urinary uric acid was 694 f 201 mg/day. Renal calculi occurred in three cases, (20%), and tophi were present in four (27%). Renal function was well preserved in all cases. Treatment of gout did not alter the proteinuria or renal function in these 15 patients. Eight patients with gout had proteinuria due to some other recognizable disease, such as multiple myeloma, Gaucher’s disease, carcinoma of the kidneys, lead poisoning, and diabetes. Mean age of onset of gout was relatively late, at 52 yr; and renal disease preceded gout in all cases. Gouty arthritis was mild; renal calculi occurred in two cases (25’S), and tophi in two (25%). Plasma urate averaged 9.9 + 1.3 mg/lOO ml and urinary uric acid 627 f 171 mg/day. Three patients were mildly azotemic. The clinical course in these eight patients was related solely to the primary disease. One patient died in uremia with gram-negative septicemia while receiving chemotherapy for multiple myeloma. Gout Associated With Cardiac, Renovascular, or Di$use Vascular Disease Of the 253 patients studied who had proteinuria, 114 had cardiac, renovascular, or diffuse vascular disease, which could have in itself significantly contributed to the nephropathy observed. Six patients had rheumatic heart disease with heart failure. Mean age of onset of gout was 52, and gouty arthritis was mild. Tophi occurred in one case (17%), and renal calculi in two (33%). All except one had serum urate more than 10 mg/ 100 ml, the mean being 11.3 + 2.0 mg/lOO ml. Urinary urate was not high, 494 + 115 mg/day. Three patients had mild azotemia. One died from cerebral embolism at age 58, and another one from ruptured aortic aneurysm at 60. Seventy-three of a total of 151 patients with hypertension were classified as having essential hypertension, with blood pressure above 150/90. Mean age for onset of gout was 44 yr, and for hypertension, 46 yr. In 24 patients, hypertension preceded gout; in 25, gout preceded hypertension, and, in the remainder, the two diseases were diagnosed at about the same time. The severity of gout was variable in these patients. Renal calculi occurred in 17 (23%) an incidence not much different from that in uncomplicated gout. Tophi occurred in 37 (51%) of the 73 patients, a higher incidence than that observed in gout without proteinuria. Twenty-four of the 73 died: 16 from cardiac or cerebral vascular accident, and
RENAL DISEASE
IN PRIMARY
GOUT
301
one from massive gastrointestinal bleeding. Seven died with uremia. Ages at death varied from 50 to 76 yr, with an average of 60 yr. In a separate group of four patients, hypertension was associated with unilateral renal artery stenosis, angiographically proven. Age of onset of gout in these four ranged from 23 to 50 yr; one had tophi, and three had renal calculi. Plasma urate was high, 11.O i 1.9 mg/ 100 ml, and urinary uric acid was 643 f 204 mg/day. Hypertension was severe in all four patients. One patient died with very extensive tophi and rapidly progressive renal insufficiency at age 50; another died from myocardial infarction at age 38; and a third patient survived a ruptured aortic aneurysm. In contrast to the group with essential hypertension, 31 patients were classified as having arteriosclerosis and arteriolar sclerosis, based on clinical findings. These patients all showed signs either of coronary artery disease, cerebrovascular disease, heart failure, or diabetes. Seventeen (55%) of the 31 patients had a systolic pressure above 150 mm Hg; only five had a diastolic pressure above 90. Mean age of onset of gout was 48 yr. Seventeen (55%) were tophaceous, and ten (32%) had renal calculi, a high incidence for both. This is related to an average delay of 13 yr in seeking treatment. Eleven (35%) of the 31 patients had moderate to profuse proteinuria, and six were mildly azotemic. Eleven died of myocardial infarction, cerebrovascular accident, or heart failure. Three died from carcinoma and three from other causes. The mean age of death was 70 yr. In these 31 patients, the course of gout was variable. Nephropathy in general was mild, but the cardiac and cerebral circulatory diseases determined the clinical course. Long-standing Tophaceous Gout Of the 131 with tophaceous deposits, extremely extensive tophi existed in 28 patients who were first seen during the preuricosuric era. Onset of gout was relatively early, 37 yr. There was a delay of 14-36 yr before they received adequate treatment. All had severe recurrent gouty arthritis early in their course. In addition to the extensive tophaceous deposits, there was chronic joint aching and stiffness. Only two (7%) had renal calculi, and two had iatrogenic urate crystalluria. Plasma urate was high, 11.1 f 1.6 mg/ 100 ml, and urinary uric acid was less than normal in many, mean being 416 =t 144 mg/day. Nineteen of the 28 exhibited satisfactory reduction in the size of tophi following protracted uricosuric therapy, either with probenecid or sulfinpyrazone. Proteinuria was profuse in one, moderate in nine, and minimal in the remaining 18. In 17 (6 1%) patients of the 28, hypertension existd. Azotemia occurred in eight, urinary tract infection in three. Seventeen died from myocardial infarction, cardiac insufficiency, or cerebrovascular disease, three from sepsis, and one had carcinoma of the rectum. Age at death was more than 70 yr in two-thirds of the 21 patients. The high incidence of cardiac and cerebrovascular complications was most likely related to aging in these patients. Infected Renal Calculi Of the 253 cases with nephropathy, 71 (28%) had renal calculi. In 22 patients with recurrent calculi, urinary tract infection dominated the clinical picture. In
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16 of these 22, calculi preceded the onset of gout. The mean age of onset of calculi was 38 yr, and onset of gout, 42. Positive family history of gout occurred in nine of the 22 patients (41%). Plasma urate averaged 10.6 f 2.0 mg/ 100 ml, and urinary uric acid 652 f 304 mg/day, with eight patients excreting more than 800 mg/day. One of the 22 had deficient hypoxanthine guanine phosphoribosyltransferase (HPRT). Eleven (50%) had tophi, which were extensive in three; hypertension occurred in 13 (59%), diabetes in seven (32%). Death occurred in 13, associated with uremia in five. Four died from cardiac or cerebral vascular disease and nine others from nonvascular conditions. Fulminating Gout Five relatively young subjects were classified as having fulminating gout, characterized by early onset, severe gouty arthritis, extensive tophaceous deposits, extremely high serum urate and low urinary uric acid. Four of the five patients had a positive family history of gout. Age of onset was between 16 and 26 yr; all had moderate to extensive tophi. In only one case did renal calculi occur, and this happened only after uricosuric therapy. Hyperuricemia was extreme, 12.9 + 1.4 mg/lOO ml, and urinary uric acid was low, 378 f 99 mg/day. Proteinuria was minimal; azotemia occurred in two. Despite energetic uricosuric therapy, the tophi grew relentlessly. All except one eventually responded to allopurinol, with reduction in the size of the tophi, but renal function did not improve. Two developed hypertension, and two had myocardial infarction. One progressed to uremia, requiring hemodialysis, and ultimately received a renal transplant. The development of cardiovascular complications at a relatively young age in these five patients with very severe gout helps to differentiate them from the hypertension-arteriosclerosis patients who develop renal insufficiency. One of the five was found to be deficient in hypoxanthine guanine phosphoribosyltransferase (HPRT). DISCUSSION
The present study shows that in an overwhelming number of cases of renal dysfunction in gout, independent factors other than gout exist to account for the proteinuria and other signs of nephropathy observed. In gouty patients with nephropathy, a frequent occurrence of vascular disease, or independent intrinsic renal disease exists. Nephropathy without renal infection, intrinsic renal disease, or vascular sclerosis is infrequent. Significant nephropathy exists in 253 (15%) of the 1700 gouty patients, a figure fairly consistent with the reported incidence of nephropathy in gout. 3p5Two hundred and ninety-eight of our 1700 cases were known to have died over the 25 yr of observation. Approximately 9% of the deaths were due directly to renal insufficiency, and, in another 7% azotemia accompanied other immediate causes of death. Our data on nephropathy illustrate that a substantial number of those patients dying with uremia have a nongouty cause of uremia. Gout alone rarely causes nephropathy, and nephropathy in gout is most often associated with renal pathology of nongouty nature. Talbott and Terplan3 found lesions of pyelonephritis and nephrosclerosis, in addition to urate deposition, in the kidneys of 164 patients who died with primary gout. Frequently, it was impossible to differentiate pyelonephritic from vascular
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changes. Moreover, the severity of the morphologic alterations did not bear a direct correlation with the clinical course of the disease, Clinical evidence of arteriolar nephrosclerosis has not been found to be more common in patients with gout than in those with moderate or severe hypertension, coronary artery disease or cerebra1 arteriosclerosis.10*12 Gonick et al.l” reported a glomerular sclerosing lesion, which they considered possibly characteristic of gout, on renal biopsy in 28 patients. However, they also reported an incidence of hypertension in 62%, and degenerative renal lesions of arteries and arterioles. Barlow and Beilin12 reported nephrosclerosis in 21 of 23 renal biopsies in gouty subjects. These authors found an incidence of hypertension in 42% of 52 gouty patients. They did not, however, observe any difference in incidence of glomerular atrophy and nephrosclerosis between hypertensive and nonhypertensive gouty patients. They raised the question whether the patient with gout is predisposed to nephrosclerosis, even in the absence of hypertension. The development of renal insufficiency was, in their opinion, more related to increasing age than to the gouty process itself. In our series of nephropathy patients, 84 cases showed evidence of independently occurring intrinsic renal disease. Admittedly, in the absence of renal biopsies and urinary bacteria1 culture data, the groups of “glomerulonephritis” and “pyelonephritis” cannot be irrefutably defined. Also it is recognized that the criteria for the diagnosis and classification of “glomerulonephritis” and “pyeloHowever, all in the groups we have defined nephritis” are much in dispute. 11~22~23 had a very mild clinical course of gout, and the onset of nephropathy preceded that of gout in most cases. Many of them died from renal failure. Gout secondary Thus these 84 patients could to chronic renal disease is considered to be rare. 24*25 be considered to have primary gout, with coexistent primary renal disease. On the other hand, the onset of renal disease preceding that of gout for many years, in a good number of these patients, does not exclude the possibility that, in some at least, gout could be secondary to the primary renal disease. In 114 patients, we found associated cardiovascular disease extensive enough to cause nephropathy. In view of the lack of direct correlation between the clinical course of gout and renal pathologic changes, and the frequent occurrence of hypertension and arteriosclerosis in both the gouty and the nongouty populations, it is difficult to define a purely “gouty” nephropathy by a clinical study alone. In 55 patients, gout, with or without urinary tract infection, was more primarily involved in causing nephropathy. Even here, however, the high incidence of hypertension and cardiovascular complications have to be considered important in the causation of nephropathy. In 22 cases of recurrent renal calculi with coexisting infection, it is a fair assumption that renal damage is primarily due to urate deposition within the urinary tract, and that the vascular complications are secondary to the renal damage. Even in the group with fulminating gout, hypertension and cardiovascular complications, factors not specifically gouty, existed in four of the five patients. This study does not preclude that gout predisposes to hypertension, nephrosclerosis, and even to proteinuria. The possibility exists that the individual with gout is also metabolically predisposed to hypertension and vascular sclerosis. The one factor in gout which may be considered a precipitant of renal damage
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is urate deposition, which in turn is related to the degree of hyperuricemia and hyperuricosuria. As the renal damage progresses, hyperuricemia becomes more extreme, but the hyperuricosuria levels off resulting in retention of uric acid. It is very probable that this chemical insult then may lead to renal ischemia, pyelonephritic and vascular sclerotic changes. However, such changes also occur in subjects with intrinsic renal disease, and in subjects with hypertension and arteriosclerosis, particularly in advanced age. In order to be able to answer the question whether there is any specific renal lesion in gout, renal biopsy will have to be done in uncomplicated gout of relatively young age and in proteinuric gouty cases with or without hypertension. Uric acid is a weak acid with a pKa of 5.75; that is, in solution at pH 5.75, uric acid is half ionized and half un-ionized. At pH of the plasma and body fluids, uric acid is almost all dissociated, whereas in acid urine, it is largely undissociated. With extreme hyperuricemia and acid urine, excessive uric acid deposition in the renal tubules occurs and may lead to acute oliguric renal failure. This type of oliguric renal failure is more commonly seen in patients with blood dyscrasia, particularly after cytotoxic therapy and does not often occur in primary gout.26-2e We have observed only one patient with repeated bouts of anuric obstructive uropathy due to urate lithiasis, and this was a patient with partial deficiency in HPRT. With hyperuricemia and very highly supersaturated urate concentrations in urine, renal calculus formation occurs in more than 20% in primary gout,15 and approximately 40% in secondary gout associated with myeloproliferative diseases.30 Urate crystals may also precipitate within the kidney tissue itself, similar in nature to those in tophi. 31 It is of interest to note that at the same degree of hyperuricemia, some patients may develop renal calculi without tophi, and others may develop tophi without forming renal calculi (Table 1). The incidence of renal calculi is rather low in the groups with long standing tophaceous gout and fulminating gout; nor were many tophaceous among those with recurrent renal lithiasis. There must be in addition different local factors to cause the precipitation of urate crystals, either juxta-articularly or in the kidney tissue. Interestingly, hyperuricemia of the degree found in patients with azotemia in primary gout with renal insufficiency rarely, if at all, causes urate deposition in One explanation may be that as glomerular filtration kidney or urinary tract. 2Q*30 rate falls, the filtered urate load is decreased, and so is the amount of urate reabsorbed. Urate deposition within the kidney, a not infrequent occurrence in pathologic specimens of gouty subjects, does not correlate with the state of renal function. Those with renal function impairment commonly show other conditions contributing to the development of renal dysfunction either independently occurring renal disease, associated vascular disease involving the kidney, urinary tract infection, hypertension, or cardiac disease. Since gouty patients with or without nephropathy frequently have hypertension, and. signs of vascular sclerosis, it is possible that gout predisposes to these diseases, or more likely, that patients with vascular sclerosis and gout have a common metabolic or hypertension, pathologic predilection. Hyperuricemia alone is not adequate to account for renal dysfunction in most cases of gout. When nephropathy does occur in gout, it is
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usually related with coexisting intrinsic renal disease, hypertension, cardiac disease, renovascular disease or urinary tract infection. Gout contributes to renal damage in those with uncontrolled recurrent renal lithiasis accompanied by persistent infection, in neglected cases with long-standing extensive tophaceous deposits, and in fulminating cases with early onset and extreme hyperuricemia refractory to treatment. REFERENCES 1. Garrod AB: A Treatise in Gout and Rheumatic Gout (ed 3). London, Longmans, Green, 1876 2. Schnitker MA, Richter AB: Nephritis in gout. Am J Med Sci 192:241,1936 3. Talbott JH, Terplan KL: The kidney in gout. Medicine 39:405, 1960 4. Brown J, Mallory GK: Renal changes in gout. N Engl J Med 243:325,1950 5. Modern FWS, Meister L: The kidney of gout, a clinical entity. Med Clin North Am 36:941, 1952 6. Fineberg SK, Altschul A: The nephropathy of gout. Ann Intern Med 44:1182, 1956 7. Greenbaum D, Ross JH, Steinberg VL: Renal biopsy in gout. Br Med J 1:1502, 1961 8. Mayne JG: Pathological study of the renal lesions found in 27 patients with gout. Ann Rheum Dis 15:61, 1956 9. SokoloB L: Pathology of gout. Arth Rheum 8:707,1965 10. Gonick HC, Rubini M, Gleason 10, et al: The renal lesion in gout. Ann Intern Med 62:667, 1965 II. Heptinstall RH: Pathology of the Kidney. Boston, Little Brown, 1966 12. Barlow KA, Beilin LJ: Renal primary gout. Quart J Med 37:79,1968
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13. Gutman AB, Yii TF: Renal function in gout, with a commentary on the renal regulation of urate excretion, and the role of the kidney in the pathogenesis of gout. Am J Med 23:600,1957 14. Yii TF, Berger L, Gutman AB: Renal function in gout, II. Effect of uric acid loading on renal excretion of uric acid. Am. J. Med. 33:829, 1962 15. Gutman AB, Yii TF: Uric acid nephrolithiasis. Am J Med 45:756, 1968 16. YU TF, Gutman AB: Principles of current management of primary gout. Am J Med Sci 254:893, 1967 17. Gutman AB, YU TF, Berger L: Renal function in gout. III. Estimation of tubular
secretion of uric acid by use of pyrazinamide (pyrazinoic acid). Am J Med 47:575, 1969 18. Berger L, Yli TF, Gutman AB: Long term follow up studies of renal function in primary gout. Am Sot Nephrology Meeting, Washington, D.C., 1973, p IO 19. Steele TH, Rieselbach RE: The contribution of residual nephrons within the chronically diseased kidneys to urate homeostasis in man. Am J Med 43:876, 1967 20. Sarr H, Mertz DP: Sekundlre Gicht bei Niereninsulfizienz. Klin Wschr 43:1134, 1965 21. McPhaul JJ Jr.: Hyperuricemia and urate excretion in chronic renal disease. Metabolism 17:430, 1968 22. Heptinstall RH: The enigma of chronic pyelonephritis. J Infect Dis 120: 104, 1969 23. Cameron JS: The natural history of glomerulonephritis, in Black DAK (ed): Renal Disease. Oxford, Blackwell, 1972, p 295 24. Richet P, Mignon GF, Ardaillon R: Goutte secondaire des nephropathies chroniques. Presse Med 73:633, 1965 25. Ross EJ: Chronic renal failure in Black, DAK (ed): Oxford, Blackwell, 1972, p 476 26. Weissberger AS, Persky L: Renal calculi and uremia as complications of lymphoma. Am J Med Sci 225:669, 1953 27. Greenbaum D, Stone HF: Dangers of uric acid excretion during treatment of leukemia and lymphosarcoma. Lancet 1:73, 1959 28. Rieselbach RE, Bentzel CJ, Cotlove E, et al: Uric acid excretion and renal function in the acute hyperuricemia of leukemia; pathogenesis and therapy of uric acid nephropathy. Am J Med 37~872, 1964 29. Kjellstrand CM: Hyperuricemic acute renal failure. Arch Intern Med 133:349, 1974 30. Yii TF: Secondary gout associated with myeloproliferative diseases. Arth Rheum 8:765, 1965 31, Seegmiller JE, Frazier PD: Biological considerations of the renal damage of gout. Ann Rheum Dis 25: suppl6:668, 1966
