Renal function in gout

CLINICAL STUDIES

Renal Function in Gout. IV. An Analysis of 524 Gouty Subjects Including Long-Term Follow-Up Studies *

LAWRENCE TS’AI-FAN

BERGER, M.D. VU, M.D.

New York. New York

From Department of Medicine, Mt. Sinai School of Medicine, City University of New York, New York, 10029. This work was supported in part by a grant-in-ad, A-162, from the National Institute of Arthritis. Metabolism and Digestive Diseases, National Institutes of Heatth, Bethesda, Maryland. Requests for reprints shouid be addressed to Dr. Ts’ai-fan Yu. Manuscript accepted April 17, 1975. This paper is dedicated to the late Dr. Alexander B. Gutman, who largely inspired the work presented. l

Renal function studies were performed in 524 gouty subjects, including follow-up studies at intervals up to 12 years in 112 of them. In 49 subjects, the glomerular filtration rate was less than 70 ml/min and C,,t,:glomerular filtration rate ratio tended to rise as the glomerular filtration rate decreased, reflecting a relatively stable urate excretion over varying filtered urate loads. The increment in Ts,,,,t,:glomerular filtration rate was small with spontaneous Puratobetween 7 and 9 mg/lOO ml. It was modest wlth Purat. up to 10 mg/lOO ml. The increment in Ts,,r,:glomerular filtration rate became much higher beyond Purclt.of 10 mg/lOO ml. Urinary urate levels above 800 pg/mln, designated as excess urate excretion, occurred more commonly in subjects wlth Purste above 9 mg/lOO ml, and with better preserved renal function. Tophi were more frequently observed in subjects with low glomerular filtration rate and protelnuria; but lnctdence of urolithiasis seemed to be less affected by a decrease in the glomerular filtration rate. Hyperuricemla alone had no deleterious effect on renal function as evidenced by follow-up studies over periods up to 12 years. Deterioration of renal function was largely associated with aging, renal vascular dlsease, renal calculi with pyelonephrttis or independently occurrlng nephropathy. In only. very few instances was diminished renal function ascribable to gout alone. It is generally agreed that at least a “three-component” system accounts for the renal handling of uric acid [l-4]. After glomerular filtration of uric acid, concomitant processes of tubular reabsorption and secretion affect its tubular fluid content. The uric acid ultimately found in urine probably is a secreted moiety, filtered uric acid being largely reabsorbed [5-lo]. The renal tubular reabsorptive capacity for uric acid is relatively large (in the range of 15 mg/min), and a maximal tubular reabsorptive capacity (reabsorptive T,) for uric acid has not been consistently demonstrated [7-g]. Renal tubular secretion of uric acid in man was implicitly surmised by Gutman and Yu because of the relatively stable urinary uric acid excretion over a large range of plasma levels and filtered loads [ 111, and the paradoxic effect of small doses of uricosuric drugs that decreased urate excretion [ 121. More direct demonstration of urate secretion

November 1975

The American Journal of Medlclne

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RENAL FUNCTION IN GOUT-9EFGEFt.

TABLE I

Yij

An abnormally low excretion of urate in gout, when it occurs, is usualfy associated with nephropathy due to causes other than hyperuricemia alone. Renal disease in gout is most often related to hypertension, vascular disease, independently occurring nephropathy of nongouty nature or urinary tract infection [ 29,301. Our aims in this study are to report (1) the renal function in 524 gouty subjects, (2) the correlation of Pwater U,,t,V, Furate and Tsuate in uncomplicated gout as well as in gout with tophi, urolithiasis, proteinuria and other associated medical conditions, and (3) a long-term re-evaluation of the renal function in 112 gouty subjects.

Relationship Between Glomerular Filtration Rate and C,,,,, in 524 Gouty Patients C urate

Cinulin No.

ml/min

No.

ml/min

6 3 5 6 13 16 38 49 53 71

3.7-20.0 20.1-30.0 30.1-40.0 40.1-50.0 50.1-60.0 60.1-70.0 70.1-80.0 80.1-90.0 90.1-100.0

5 3 3 3 11 15 36 44 47

2.5 3.1 3.9 6.1 6.0 5.8 7.0 7.0 7.2

101.0-110.0 111.0-120.0 121.0-130.0 131.0-140.0 141.0-150.0 151.0-160.0 161.0-170.0 171.0-190.0 ---_ _..-..

67 73 58 44 32 18 10 7

8.0 8.4 8.4 8.9 8.7 8.0 11.1 11.0

C urate’Cinulin

--

80 65 45 35 20 11 8 may

? 1.4 t 0.6 t 2.5 2 2.6 + 2.7 ? 1.8 2 2.9 + 2.3 ? 2.4 t t i t f r t f

2.4 2.5 2.1 2.5 2.1 2.2 2.2 2.9

0.259 0.208 0.163 0.156 0.138 0.122 0.092 0.086 0.075 0.078 0.073 0.067 0.065 0.059 0.053 0.059 0.060 .__^_

f 0.142 t 0.136 * 0.114 t 0.105 t 0.090 + 0.079 I 0.038 i 0.032 + 0.024 2 t t + 2 + i +

0.027 0.023 0.017 0.019 0.015 0.014 0.016 0.014

METHODS All subjects inciuded in this study were ambuhtory men with gout, aged 21 to 82 years. Standard renal clearance technics were employed [ 111. lnuiin was used to estimate the gtomerular filtration rate. Para-aminohtppurate ckarante (CPA”) was measured as a reflection of renal plasma flow. To vary the P,,,,, level and thus to effect alterations of FlHat0without affecting the gtomerutar fittration rate, allopurinol or ribonucleic acid (RNA) was used. To lower PWat, levels, allopurinol was given in oral doses of 100 to 400 mg/day, for periods varying from seven days to several months. To raise P,t, levels, RNA in oral doses of 2 to 4 g/&y was given for three to 14 days. PZA was used to measure the suppression of urate excretion, and thus to estimate the Ts,,*,. Renal function studies were repeated in 112 subjects after intervals of seven to 12 years. Subjects were divided into seven groups. Group A. Included in this group were 30 gouty men with no associated diseases, such as hypertension, independently occurring nephropathy, diabetes or recognizable renal vascular disease at either study. Normouricemia was achieved and maintained during the interval between the two studies. Group B. The 26 subjects in this group were slmibr to those in group A, but hyperuricemia persisted after the first study. No drugs were used to affect the hyperuricemia between the two studies. Group C. The 13 subjects included in this group had no associated medical diseases, as cited in group A, at the first study; but hypertension, with or without other associated medical conditions, developed by the second study. Group D. Included in this group were 25 subjects who had hypertension at both studies, often with cardiorenal involvement, such as coronary artery disease or proteinuria. Group E. This consisted of an eklerly group of seven subjects with a mean age of 60 years at the first study, and 72 years at the second study. No overt recognizable associated medii cal diseases existed at either study. Normouricemia was maintained between the two studies. Group F. This was another elderly group of seven subjects with a mean age of 67 years at the first study, and 75 years at the second. The P,w level was moderately elevated, and no specific drug therapy was given to affect the P,,t, level between the two studies. Group G. There were only four subjects in

be seen in mongrel and Dalmatian dogs [ 13-

171, rabbits [ 18,191, birds [ 20-221 and certain other

species [23-251. In man, the intrarenal-arterial injection of uric acid has been used to demonstrate tubular secretion [ 26,271, and the admlnistration of pyrazinamide (PZA) to suppress renal uric acid excretion has been used as a measure of its renal tubular secretion [4,5,10,28]. If renal tubular reabsorption of urate occurs simultaneously with secretion, urate secretion cannot be estimated accurately. The amount of uric acid in urine represents the net remaining after the introduction of urate into tubular fluid by glomerular filtration and tubular secretion, and removal of urate from tubuhr fluid by tubular reabsorption. Secretion and reabsorption being coextensive, the net amounts of each estimated in clearance studies do not include components transported across the tubule which have neither been filtered nor excreted in urine. Thus, estimates of tubular reabsorption and secretion are, at best, minimum estimates of these transport functions [5,7]. The only quantities of renal urate that can be measured precisely are the amounts filtered at the glomeruli (Furate) and excreted in the urine (UurateV). Our previous studies in man shcwed that the amount of uric acid excreted remains relatively stable when plasma urate (Purate) is within a range of 6 to 9 mg/ 100 ml [ 51. However, when P,,t, increases beyond 9 mg/lOO ml, U,t,V tends to increase [El.

As Furate increases,

there is a proportional increase in the apparent tubular reabsorption (reabsorptive urate) [7]. Measurements of secretory capacity utilizing PZA. demonstrate an increase TTS wate). in tubular secretion as the filtered load increases [ 51.

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RENAL FUNCTION IN GOUT-BERGER.

Vii

this group. They were relatively young with rapidly progressive gout, characterized by frequent attacks of acute gouty arthritis which were difficult to control. signs of renal insufficiency and extensive tophi at the time of the first study. In all clearance studies, except those performed in group G, the administration of uric acid lowering drugs, whether uricosuric agents or allopurinol, was discontinued sufficiently long before the study to permit a spontaneous endogenous Purat, level to be reached.

RESULTS

Between Cwate and Cl,,,,lln. Of 524 gouty subjects, 119 (23 per cent) had an inulin clearance (Cin,cn) more than 130 ml/min; in 269 (51 per cent) Cinulinranged between 90 and 130 ml/tin. Reduced glomerular filtration rate with Cinulin below 70 ml/min occurred in 49 subjects (9 per cent) (Table I). With Cinulinabove 70 ml/min, C,r,*, varied proportionRelationship

ately with glomerular filtration rate, so that the Curate: Cinulin ratio varied relatively little. At Cinurmbetween 171 and 190 ml/min, the Curaw:Cinulinratio was 0.060 f 0.014, and it slowly increased to 0.092 f 0.038 when the glomerular filtration rate was down to 70 or 80 ml/min. With a glomerular filtration rate below 70 ml/min, the Curate:Cinulinratio increased more markedly, from 0.122 f 0.079 at C&in between 60 and 70 ml/min, to 0.259 f 0.142 at Cinulinbetween 3.7 and 20 ml/min. Figure 1 illustrates the relationship between Curate:Cinulinand Cinulin in these 524 gouty subjects.

Interrelationship of Purate, Excessive UurdeV, Proteinuria and Age. UurateV greater than 800 pg/min (excessive UurateV) occurs more frequently in those with a Purate of 9 mg/lOO ml or above (Table II). Thus, in the 258 subjects with P,rat, of 9 mg/lOO ml or less, the proportion of subjects with lJ,,,,V above 800 pg/min ranged from 13 to 19 per cent. In 218 subjects with Purate above 9 mg/lOO ml, the proportion with U “rateV above 800 pg/min ranged from 35 to 69 per cent. At Purate of 9 to 10 mg/lOO ml, 35 per cent of the subjects had U,,,,,V above 800 pg/min. The incidence of high uric acid excretion increased to the range of 52 to 55 per cent for those with a Purate of 10 to 12 mg/lOO ml, and to 69 per cent for those with a Purate above 12 mg/lOO ml. Of the total 476 subjects, UurateV was excessive in 140, or 29 per cent. Proteinuria occurred in 98 (20 per cent) of the 476 subjects (Table Ill). There is a modest correlation between the incidence of proteinuria and age. Proteinuria occurs in 17 per cent of those aged 21 to 35 years, and increases to 22 to 25 per cent in those aged over 56 years. The incidence of excessive U,,t,V was greater in those without proteinuria, particularly in the younger

0

I

I

I

I

I

I

20

40

60

80

100

I20

GFR

I

I

1

140 160 180

(ml/min)

Figure 1. Glomerular filtration rate (GFR) compared to Cwate:GFR in 524 gouty subjects. The vertical lines depict the mean f standard deviation of Curate:GFR,and the horizontal lines depict the mean f standard deviation of glomerular filtration rate. age groups (Table IV). Thus, in the age group 21 to 35 years, 22 who had excessive UurateV were without proteinuria and only three had proteinuria. Of 140 subjects with excess U,,,t,V, 121 (86 per cent) had no proteinuria, and only 19 (14 per cent) had proteinuria. The occurrence of excess U,,,,V was about one in three among those without proteinuria, and about one in five among those with proteinuria.

Relationship was estimated

Between

Ts,,,,,,

and Purate. Tsurate

by the PZA suppression

test in 179

subjects (Figure 2). In 102, endogenous urate secretion was studied: in 45 allopurinol was used to lower P“rate; and in 32 RNA was used to elevate

Purate.

Tsurate in each case was ratioed to the glomerular filtration rate (GFR), to give the quantity Ts:GFR. Values are plotted for spontaneous Purat, levels, decreased levels achieved with allopurinol, and increased levels attained with ribonucleic acid (RNA). At spontaneously occurring Purate levels, between mean P,,,t, 7.6 (range 7.1 to 8.0) and 8.6 (range 8.1 to 9.0) mg/lOO ml, no obvious change in the Tsurate:TABLE II

Incidence of Excessive U,,,,,V Relation to P,,,,,

Purate (mg/lOO ml) 6.6-7.0 7.1-8.0 8.1-9.0 9.1-10.0 10.1-11.0 11.1-12.0 12.1-15.0

Novem&r 1975

Total No.

in

ExcessiveU,,,,,V (SO0 j&mid __.._~.___~

of Cases

No.

%

36 82 140 107 66 29 16

7 11 24 37 34 16 11

19 13 17 35 52 55 69

The American Journalof Medicine

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RENAL FUNCTION IN GOUT-BERGER.

TABLE III

Yij

Incidence of Proteinuria in Relation to Age Proteinuria Total No. of Cases

Age (vr) 21-35 36-45 46-55 56-65 66-82

48 132 126 124 46

No.

%

8 23 26 31 10

17 17 20 25 22

No

684~059(51 ,’

subjects

l

865?2.30 (121

_

7.11* I 24(6, 7.12+,

43(6)

X-X

‘/ /.

670+1.47(18, 604?2

/

.a. 0

20(36)

-

4,93t164(361

495tl46~311

4.44,009

TABLE IV

incidence of Excessive U,,r,,,t,V With or Without Proteinuria in Relation to Age

17) / / ,_/

No Proteinuria

No of Age M 21-35 36-45 46-55 56-65 66-82

With Proteinuria

Lluratev (>800&min)

Cases ’

No.

%

40 109 100 93 36

22 45 26 24 4

55 41 26 26 11

No of Ca;es 8 23 26 31 10

No.

%

3 5 7 4 0

38 22 27 13 0

GFR ratio was observed. The Ts,,,~,:.GFR ratio steadily increased beyond 9 mg/lOO ml, and the increment was notably augmented at a mean Purate level of 12 mg/lOO ml. After allopurinol administration, the Ts: GFR ratio fell to values as low as 1.9 f 0.4 pug/ml glomerular filtration rate. At a mean Purat, level of 3.5 mg/lOO ml, a very modest increase was noticed, with a small further increase from 3.5 to 7.4 mg/lOO ml. When Purate was increased by means of RNA, the Ts:GFR ratio was higher than at corresponding endogenous levels of Purate. Unquestionably, after RNA Tsurate increased. The slope of changing Ts:GFR ratios became quite steep when Purat, went beyond 10 mg/lOO ml; at mean Purat, of 13 mg/lOO ml the mean Ts:GFR was 11.2 pg/ml GFR.

Relationship Between Glomerular Filtration Rate, Incidence of Proteinuria, Tophi and Renal Calculi. Data for 524 gouty patients are listed in Table V, arranged by the glomerular filtration rate. Incidence of proteinuria is seen to be greater in patients with a low glomerular filtration rate, being 100 per cent in those with a glomerular filtration rate below 40 ml/ min, varying from 5 to 24 per cent in those with a glomerular filtration rate above 80 ml/min, and in the range of 63 to 68 per cent for those with a glomerular filtration rate from 40 to 80 ml/min. Tophi, similarly, are seen to be more frequent in patients with a low glomerular filtration rate, the incidence varying from 50 to 71 per cent in those with a glomerular filtration rate below 80 ml/min, and falling off to levels between 14 and 28 per cent at glomerular filtration

606

November 1975

I a7to

Ll“ratev (>800M/min)

The American Journal of Medicine

0

2.63f0.49l9) z.z3+071,141 43 (I51

I

I

I

I

I

I

I

2

4

6

8

IO

12

14

Mean Purote (mg/lOO ml) Figure 2. Ts,t,:glomerular filtration rate and its relation to P”KW as determined at endogenous levels, Purat, levels elevated after the administration of RNA, or depressed fob lo wing allopurinol therapy. rates above 100 ml/min. Interestingly, the incidence of renal calculi does not increase as the glomerular filtration rate decreases, the incidence varying from 8 to 26 per cent, and showing no clear correlation with glomerular filtration rate.

Relationship of Curclt., Clnullnand CPAHto Advancing Age. Table VI includes the results in 426 subjects without proteinuria and in 98 with proteinuria. With advancing age, a trend is demonstrated of decreasing Gmlim CpAH and Curate. Of note, tO0, is the observation that with proteinuria, the mean Cinulin. CPA” in each age group is lower than in compaand Lt, rable age groups without proteinuria. Among those without proteinuria, a downward trend in glomerular filtration rate is manifested in the age groups after 61 to 65 years. The glomerular filtration rate decreases from 13 1 f 20 ml/min at ages 2 1 to 35, to 103 f 20 at ages 61 to 65, and to 77 f 23 at ages 71 to 82. Among those with proteinuria, a downward trend with age is also seen, although there is a greater variability in glomerular filtration rate, even in the younger age groups, reflecting the degree of renal damage. Figure 3 depicts the correlation of changes in the glomerular filtration rate with age for those with and without proteinuria. C,++# shows trends comparable to glOI’rb3rUlar filtration rate (Figure 4), with a fall in CPA” becoming evident after ages 61 to 65 years. In those without proteinuria, CpAH levels fall from 578 f 95 at ages 21 to 35 years to 384 f 73 at ages 61 to 65 years, and further down to 349 f 38 at ages 71 to 82 years. At all age levels, CPAH among those with proteinuria is lower than in those without proteinuria,

Volume 59

RENAL FUNCTION IN GOUT---BERGER.

TABLE

V

Incidence of Proteinuria,Tophiand

in 524 Cases of Primary -~- ~~-~ ~ --

_~

Glomerular Filtration Rate (ml/min)

121-140 141-190 Total

---~

TABLE Age

VI

.____~_

No.

%

Calculi %

No.

%

100 68 63 24 15 6 5

10 13 27 20 23 20 17

71 68 50 41 44 28 21

2 3 14 8 11 6 11

14 16 26 16 21 8 14

110 74 524

6 8 103

5 11 20

18 10 158

16 14 30

13 15 83

12 20 16

Filtration Rate,Cp~~

21-35 3b40 41-45 46-50 51-55 5660 61-65 66-70 71-82

131 + 20 127 + 22 125+21 119* 18 117t21 115525 103 + 20 88+ 15 77 i- 23

42 52 71 50 67 64 39 27 14

578 r 95 557 r 101 533 t 105 526 * 92 494*79 446r 75 384k73 331 r 19 349+ 38

11 28 25 21 25 23 12 4 2

21-35 3b40 41-45 650 51-55 56-60 61-65

982 39 105 + 33 72+ 39 112+28 85+ 29 61~21 66i27

8 7 16 9 17 19 12

497 t 44Ok 372 * 421 + 350 k 273 f 3llt

3 7 8 4 14 15 7

66-70 71-82

64228 43i 21

5 5

ml/min

No.

A. Without

118 117 163 99 105 100 122

277 t 35 276 i 73

I

PatientsArranged AccordingtoAge -

ml/min

I

and Curate in Gouty

C“rate

CPAH

No.

120

___

14 13 34 12 8 4 4

Cinulin

o--o

Rate

14 19 54 49 53 71 80

Distribution of Glomerular ___-

14Or

__~__

Filtration

Tophi

No.

_ ml/min

(vr)

to Glomerular

Proteinuria

Total No. of Cases

4-40 41-60 61-80 81-90 91-100 101-l 10 111-120

Renal Calculi in Relation

Gout

Yti

2 3

I

r

No.

Curate:Cinuh

Curate:CPAH

0.072 0.070 0.069 0.068 0.071 0.071 0.076 0.083 0.074

L 0.025 + 0.020 i 0.021 r 0.019 f 0.019 t 0.020 + 0.024 t 0.022 + 0.022

0.016 + 0.004 0.015 ?r0.004 0.016 f 0.005 0.016 r 0.005 0.017 f 0.005 0.016 t 0.004 0.018 f 0.008 0.018 + 0.002 0.017? 0.008

0.19 f 0.01 0.23 r 0.05 0.26 + 0.03 0.27 * 0.03 0.25 A 0.05 0.23 + 0.02 0.25 + 0.04

0.082 0.070 0.116 0.072 0.089 0.102 0.130

t 2 t i k t k

0.013 0.017 0.026 0.019 0.023 0.025 0.027

0.25 0.24

0.129 ? 0.100 0.123 + 0.076

Proteinuria

8.9 2 3.0 37 8.6 f 2.4 45 8.4 + 2.8 61 7.9 + 2.2 39 8.2t2.1 50 8.1 IL 2.5 51 7.9 + 3.0 30 7.0 + 1.6 22 5.6 + 1.5 9 B. With Proteinuria 7.4 Ik 3.1 8 6.8i 1.9 8 6.5 ?- 3.6 13 7.8 ?; 2.1 10 6.9 ?- 2.2 16 6.0 + 3.3 17 6.4 k 2.6 11 6.1 f 1.6 6.5 r 6.4

I

Cinulin:CPAH

5 5

0.21 0.23 0.22 0.23 0.24 0.25 0.26 0.26 0.23

i * A + * -f * + +

0.03 0.04 0.04 0.03 0.03 0.03 0.04 0.04 0.01

* 0.02 * 0.03

0.043 0.025 0.092 0.016 0.029 0.052 0.106

+ 0.006 i 0.005 i 0.002 + 0.004 f 0.009 2 0.014 r 0.013

0.027 f 0.010 0.026 + 0.019 -~-

1

21-3536-40 41-4546-50 51-5556-60 61-6566-70 71-82 Age (years 1 Figure 3. Downward trend of Ci,,,,” with advancing age in the groups with and without protainuria.

November

21-3536-40 41-4546-50 51-5556-60 61.6566-70 71-82 Age (years) Figure 4. Downward trend of CpA,+ with advancing age in the groups with and without proteinuria.

1975

The AmorlcanJoumalcf

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609

RENAL FUNCTION IN GOUT-BERGER.

TABLE VII

Follow-Up

Yij

Studies of Cinulin, CpA”

and CurateClearances

Cinulin

Group -_II--

Study

Age

No. of

(yr)

Cases

___----_

in Primary Gout

cPAH

curate

No. of mllmin

Cases

mlimin

(mllmin) -_--_~~_-._.

c

urate~Cinulin ___~~__. _ ..__~~

A

1 2

42 53

30

116 f 17 115 + 17

17

539 k 105 481 f 84

9.9 t 1.4 9.4 f 1.7

8.5 f 2.0 8.5 i 2.4

0.076 0.073

t 0.019 + 0.023

B

1 2

43 50

26

117 t 19 121 r 21

17

509 k 94 514 i 98

8.7 i_ 1.9 9.1 t 1.6

7.5 t 2.3 7.7 t 1.6

0.066 0.065

f 0.021 I 0.014

C

1 2

48 58

13

126 * 20 94r 12

7

532 i 68 353 + 46

9.8 !: 0.9 10.0 ? 1.5

7.8 t 2.5 7.5 c 1.4

0.064 0.084

+ 0.018 * 0.018

D

1 2

50 58

25

79 i 23 70+ 31

15

333 i 74 330 + 43

9.3 ” 1.5 9.4 c 1.3

6.9 + 2.1 6.7 i 2.5

0.089 0.103

i 0.032 i 0.042

E

1 2

60 72

7

94t 75+

16 11

5

527 * 190 584 i 93

8.5 t 1.6 8.8 4 1.0

6.7 t 1.7 6.6 i 1.7

0.071 0.090

* 0.011 t 0,022

F

1 2

67 75

7

89i 16 74 f 20

5

566 I 199 430 f 180

8.0 I 0.7 7.6 ‘_ 1.0

7.0 + 2.2 5.7 .i 2.4

0.079 0.078

i 0.021 t 0.018

G

1 2

33 40

4

58+ 31 49 t 34

3 1

341 + 169 287

11.7 k 1.9

6.0 i 3.2

0.093

? 0.029

--

_~.

with a comparable downward trend with advancing age, showing the same variability as the Cinulin values. ratios rise slightly with advancing age c urateGiwli* in those without proteinuria. In most groups with proteinuria, Curate:Cinulin ratios are relatively high, especially in those with a low glomeru~r filtration rate: in those in the age group 21 to 35 years c wate:Cinuan with a glomerular filtration rate of 98 f 39 ml/min is 0.082 f 0.043 and rises to more than 0.12 when the glomerular filtration rate decreases in the older age groups. The Cura&p~~ ratio may be regarded as representing that proportion of estimated renal plasma flow completely cleared of &ate. In those without proteinuria, the ratio increases with advancing age, being in the range of 0.015 to 0.0 16 in the younger age groups; and reaching values of 0.017 to 0.018 in the older age groups. Among those with proteinuria, there is a greater variability in C&&~AH, especially in the older age groups. The range of Curate:Cp~~increases from values of 0.013 to 0.017 in the younger age groups, to values as high as 0.026 to 0.027 in the older ones. Since Curateamong those with proteinuria remains fairly stable, increased ratios of Cura&pA~ reflect the relative preservation of urate excretion despite the decrease in estimated renal plasma flow. Follow-up Studies of Clnulln,CPA” and Curate (Table VII). In group A at first study, the mean age was 42 * years, Cinulini 16 f 17 mi/min, CpAH 539 f 105 ml/ 0.076 min, Curate 8.5 f 2.0 mllmin and Curate:Cinulin f 0.019, with a Purateat 9.9 f 1.4 mg/ 100 ml. After a mean interval of 11 years, the respective values were 115 f: 17, 481 f 84, 8.5 If_-2.4, 0.073 f 0.023

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November 1975

The American Journal of Medlclne

and 9.4 f 1.7. In group B at the first study, at the mean age of 43 years, Ci,,li, was ii7 f 19 ml/min, CPAH 509 f 94 mlimin, C,,,,, 7.5 f 2.3 mllmin, Cura&nulin 0.066 f 0.021 and Purate8.7 f 1.9 mg/ 100 ml. After a mean interval of seven years, the respective values were hardly changed. Thus the renal function was well preserved in both groups A and B, whether or not Puratewas controlled. In group C, in which hypertension had developed by the time of the second study, after a mean interval of 10 years, there was a drop in the glomerular filtration rate from a normal value of 126 j, 20 mllmin to 94 f 12 ml/min. There was a proportionately greater decrease in &AH, from 532 i 68 ml/min to 353 f 46 mlfmin, and no great change in Curate. Thus rose from 0.064 f 0.018 to 0.084 f Curat&inulin 0.018, and Cinulin:C PA,-,rose from 0.23 to 0.26. Mean age at the time of the first study was 48 years and at the second study, 58 years. In group D there was a moderate decrease in and C~AH at the first study, with Curatein the Gnulin normal range. After a mean interval of eight years, Cinulinshowed no great change, being 79 f 23 ml/ min and 70 f 31 ml/min at the first and second studies, respectively. Curateremained relatively stable, as did the Cura&nulin. C pAH was unchanged, being slightly depressed on both occasions. There was no significant difference in the followup studies on the two elderly groups without overt circulatory disease, groups E and F. Maintenance of normouricemia (group E) did not result in any important difference in the measured parameters, as compared to group F with persistent hyperuricemia. In both groups, Cinulinwas slightly depressed at the first study, and decreased further with time. C&H fell to a

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RENAL FUNCTION IN GOUT --BERGER,

level slightly below normal at the second study in was comparable in both groups, group F. P,,,t, showing no great change at the time of the second study. Curate levels fell modestly in the second study in group F, and Curate:Cinulinrose slightly at the second study in group E. Group G was comprised of relatively young gouty subjects (mean age of 33 years at the first study), with gout difficult to control. Initial Cinulin and CPAH were decreased, 58 f 31 ml/min and 341 f 169 ml/min, respectively, and Purate was high, 11.7 f 1.9 mg/ 100 ml. By the second study, seven years later, gout was better controlled: Cinulinwas essentially unin these pachanged. Curate was not re-estimated tients. COMMENTS Tswa~e- We further confirm our previous findings that U urateV tends to vary relatively little at Purate levels between 6 and 9 mg/lOO ml, and tends to increase as P,,,,, rises beyond 9 mg/lOO ml, and to decrease as Purate levels fall below 6 mg/lOO ml. PZA inhibits U urateV, supporting the view that l&,V is largely derived from Tsurate [5]. PZA fails to function effectively when the glomerular filtration rate falls to extremely low levels, when C,,,t,:GFR may rise to values well above the normal range of 0.05 to 0.10 [31-341. Failure of PZA to inhibit UurateV in such cases is taken to indicate relatively diminished Tsurate when the glomerular filtration rate falls to very low levels, with decreased reabsorption, possibly related to decreased salt and water reabsorption, accounting for the excretion of a relatively large proportion of filtered urate [31,35,36]. Holmes et al. [37] questioned the validity of interpreting PZA suppression of renal urate excretion as reflecting renal tubular urate secretion, but pharmacologic and physiologic studies indicate that renal tubular urate secretion exists even in species in which the net urinary urate is less than the amount filtered [14,16-19,25,26,38-411 and is inhibited by PZA [14,42,43]. In such species, including man, urinary urate represents the resultant of processes of glomerular filtration, renal tubular reabsorption and renal tubular secretion. All or most of the urinary urate may indeed be contributed by renal tubular secretion, the filtered moiety being largely reabsorbed [ 1,3]. A comparison of the largest net measured reabsorptive capacity in man, approximately 15 mg/min [7-g], and the largest net maximal measurable estimate of renal tubular urate secretion in man, about 3 mg/min [6], supports this possibility, as do studies of the renal tubular sites of reabsorption and secretion by micropuncture intrarenal-arterial injection studies and studies

[ 26,39-441.

Fanelli and Weiner

simultaneous tubular processes

Yti

[ 31 suggested that of urate reabsorption

and secretion, of varying magnitude, may mediate urinary uric acid excretion, with secretion being proximal to reabsorption. Diamond [ 21, largely based on his interpretation of the ability of PZA to blunt a probenecid-induced uricosuria, considers that there may be a postsecretory reabsorptive site for uric acid, beyond the generally recognized proximal sites for reabsorption and secretion, and that urinary urate represents that moiety, presumably largely secreted, which escapes reabsorption at this postsecretory reabsorptive site. These data could however be possibly explained on the basis of simultaneous transtubular processes of secretion and reabsorption variably affected by the pharmacologic agents, or by a pharmacologic inhibition by PZA of the uricosuric agent. Such an effect, of one drug on the pharmacologic disposition and action of another, has been described before [45], and discussed by various investigators [ 3,461. Renal Function and Incidence of Tophi, Urolithiasis and Proteinuria. Our data show that tophi are more frequent as the glomerular filtration rate decreases, and that proteinuria is more common in those with a low glomerular filtration rate, but, interestingly, that the incidence of renal calculi is comparable at varying glomerular filtration rates. Urate precipitation in the tissues as tophi, is related to uric acid concentration in the blood [47,48]. The higher the urate concentration in blood, the greater the likelihood of urate precipitation in tissue as tophi. As the glomerular filtration rate decreases, urate concentration in blood tends to rise and thus the incidence of tophi increases. On the other hand, urolithiasis is better correlated with an increased content and concentration of urate in urine [48-501. These latter parameters do not increase as the glomerular filtration rate falls: more likely, increased urinary urate occurs when the glomerular filtration rate is better preserved. Further, since urine volume [ 5 I] and U,,,,V tend to stay stable even as the glomerular filtration rate falls, the urine concentration of urate also tends to remain relatively unchanged. Thus, factors that might predispose to urolithiasis by virtue of excessive urate concentration in urine may be the same in those with a low glomerular filtration rate, as in those with a normal glomerular filtration rate. Therefore, circumstances predisposing to urinary urate precipitation as calculi need not be affected by variation in the glomerular filtration rate, since variation of the glomerular filtration rate does not in itself affect urine volume or U,,,t,V. Long-term Follow-up Studies Gout. With aging, alterations

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RENAL FUNCTION IN GOUT-BERGER. Vii

rate, CPAH (reflecting effective renal plasma flow) and C “rate, are no different from what would be expected in a similarly aging nongouty population [ 7,11,52,53]. The follow-up studies suggest that even uncontrolled hyperuricemia may not correlate with renal damage over time, and that hypertension, presumably associated with nephrosclerosis, is a common cause of renal damage in gouty patients. Kidney damage in gout usually occurs in a setting that includes either hypertension, diabetes, renal vascular disease, glomerulonephritis, pyelonephritis, renal calculi with uri-

nary tract infection, congenital nephropathy or some other cause of primary nephropathy independent of gout [30,54,55]. Gout, per se, rarely causes severe functional damage to the kidney, except in some cases of rapidly progressive intractable gout, or when urate calculi and urinary tract infection cause secondary renal damage. Impairment of kidney function in gouty patients frequently is due to other factors, such as aging, hypertension, renal vascular disease, nephropathy of various nongouty causes.

1.

Gutman AB and Yu TF: A three component system for regulation of renal excretion of uric acid in man. Trans Assoc Am Physicians 74: 353, 1961. 2. Diamond HS. Paolino JS: Evidence for a post-secretory reabsorptive site for uric acid in man. J Clin Invest 52: 1491, 1973. 3. Fanelli GM Jr, Weiner IM: Pyrazinoate excretion in the chimpanzee. Relation to urate disposition and the actions of uricosuric drugs. J Clin Invest 52: 1946, 1973. 4. Steele TH, Rieselbach RE: The renal mechanism for urate homeostasis in normal man. Am J Med 43: 666, 1967. 5. Gutman AB, Yu TF, Berger L: Renal function in gout. Ill. Estimation of tubular secretion of uric ackl by use of pyrazinamide (pyrazinoic acid). Am J Med 47: 575. 1969. 6. Gutman AB, Yu TF, Berger L: Tubular secretion of urate in man. J Clin Invest 36: 1776, 1959. 7. Yu 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: 629, 1962. 8. Lathem W, Rodnan GP: Impairment of uric acid excretion in gout. J Clin Invest 41: 1955. 1962. 9. Berliner RW, Hilton JG, Yu TF, Kennedy TJ Jr: The renal mechanism for urate excretion in man. J Clin Invest 29: 396, 1950. 10. Rieselbach RE, Steele TH: Influence of the kidney upon urate homeostasis in health and disease. Am J Med 56: 665, 1974. 11. Gutman AB, Yu 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. 12. Yu TF, Gutman AB: Paradoxical retention of uric acid by uricosuric drugs in low dosage. Proc Sot Exp Biol Med 90: 542, 1955. 13. Friedman M, Byers 60: Observations concerning the causes of the excess excretion of uric acid in the Dalmation dog. J Biol Chem 175: 727, 1946. 14. Yu TF. Berger L. Kupfer S, Gutman AB: Tubular secretion of urate in the dog. Am J Physiol 199: 1199, 1960. 15. Kessler RH, Hierholzer K. Gurd RS: Localization of urate transport in the nephron of mongrel and Dalmation dog kidney. Am J Physiol 197: 601, 1959. 16. Lathem W, Davis B. Rodnan GP: Renal tubular secretion of uric acid in the mongrel dog. Am J Physiol 199: 9. 1960. 17. Zins, GR, Weiner IM: Bidirectional urate transport limited to the proximal tubule in dogs. Am J Physiol 215: 411, 1966. 16. Poulsen H. Praetorius E: Tubular excretion of uric acid in rabbits. Acta Pharmacol Toxicol 10: 371, 1954. 19. Beechwood EC, Berndt WO, Mudge GH: Stop flow analysis of tubular transport of uric acid in rabbits. Am J Physiol 207: 1265, 1964.

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Shannon JA: The excretion of uric acid by the chicken. J Cell Comp Physiol 11: 135, 1936. Nechay BR. Nechay I: Effect of probeneckf. sodium salicylate, 2-4 dinitrophenol and pyrazinamide on renal secretion of uric acid in chickens. J Pharmacol Exp Therap 126: 291, 1959. Berger L, YD TF, Gutman AB: Effect of drugs that alter uric acid excretion in man on uric acid clearance in the chicken. Am J Physiol 196: 575, 1960. Marshall EK Jr: Kidney secretion in reptiles. Proc Sot Exp Biol Med 29: 971, 1932. Dantzler WH: Effect of metabolic alkalosis and acidosis on tubular urate secretion in water snakes. Am J Physiol 215: 747. 1966. Fanelli GM Jr, Bohn DL. Reilly SS: Effects of mercurial diuretics on renal transport of urate in the chimpanzee. Am J Physiol 224: 965. 1973. Porjevin R, Ardaillou R, Paillard F, Fontanelle J, Richet G: Etude chex I’homme de la cinetique d’apparition dans I’urine de I’acide urique 2-l%. Nephron 5: 134. 1968. Podevin R. Paillard, F, Hornych A, Ardaillou R, Fontanelle J, Richet G: Cinetique d’apparition dans I’urine de I’acide para-amtnohippurque (PAH) et de I’acide urique 2-t4C chew I’homme. Effets de la benziodarone, de I’acide a& tyl-salicylique et de la pyrazinamide. Rev Franc Etudes Clin Biol 13: 513, 1968. Yu TF, Berger L, Stone DL, Wolf J, Gutman AB: Effect of pyrazinamide and pyrazinoic acid on urate clearance and other discrete renal functions. Proc Sot Exp Biol Med 96: 264, 1957. Berger L, YD TF, Gutman AB: Long-term follow-up studies of renal function in primary gout (abstract). Am Sot Nephrol 6: 10, 1973. Yu TF, Berger L: Renal disease in primary gout. A study of 253 gout patients with proteinuria. Sem Arthritis Rheum 4: 293, 1975. Steele TH, Rieselbach RE: The contribution of residual nephrons within the chronically diseased kidney to urate homeostasis in man. Am J Med 43: 876, 1967. McPhaul JJ: Hyperuricemia and urate excretion in chronic renal disease. Metabolism 17: 430, 1968. Danovitch GM, Weinberger J, Berlyne GM: Uric acid in advanced renal failure. Clin Sci 43: 331, 1972. Coombs FS, Pecora LJ, Thorogood E, Consolazio WV, Talbott JH: Renal function in patients with gout. J Clin Invest 19: 525, 1940. Suki WN, Hall AR, Rector FC, Seldin DW: Mechanism of the effect of thiazide diuretics on calcium and uric acid (abstract). J Clin Invest 46: 1121, 1987. Weinman E, Eknoyan G. Suki W: Influence of the extracellular fluid volume (ECV) on the tubular reabsorption of uric acid (abstract). Kidney Int 6: 111 A, 1974.

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Holmes, EW. Kelly WN. Wyngaarden JB: The kidney and uric acid excretion in man. Kidney Int 2: 115, 1972. Nolan RP, Foulkes EC: Studies on renal urate secretion in the dog. J Pharmacol Exp Therap 179: 429, 197 1. Lang F, Greger R. Deetjen P: Handling of uric acid by the rat kidney. II. Microperfusion studies on bidirectional transport of uric acid in the proximal tubule. Pflugers Arch 335: 257, 1972. Greger R. Lang, F, Deetjen P: Handling of uric acid by the rat kidney. Pflugers Arch 324: 279, 197 1. Abramson RG. Levitt MF: Micropuncture study of uric acid transport in rat kidney. Am J Physiol 228: 1597, 1975 Davis BB, Field JB, Rodnan GP, Kedes LH: Localization and pyrazinamide inhibition of distal transtubutar movement of uric acid-2-‘% with a modified stop-flow technique. J Clin Invest 44: 716, 1965. Weiner IM, Tinker JP: Pharmacology of pyrazinamide: metabolic and renal function studies related to drug-induced urate retention. J Pharmacol Exp Therap 180:41 I. 1972. Berger L, Yu TF: Urinary excretion of uric acid after instantaneous intra-renalarterial injection in mongrel and Dalmatian dogs. J Mt Sinai Hosp 37: 351, 1970. Yu TF. Dayton PG, Gutman AB: Mutual suppression of the uricosuric effects of sulfinpyrazone and salicylate; a study of interactions between drugs. J Clin Invest 42:

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1330, 1963. Steele TH: Studies in urate handling in man utilizing pyrazinamide. Recent Advances in Renal Physiology and Pharmacology (Wesson LB, Fanelli GM, Jr, eds), Baltimore, University Park Press, 1974, p 36 1. Gutman AB: The biological significance of uric acid. Harvey Lect 60: 35, 1964-1965. Seegmiller JE, Frazier PD: Biochemical considerations of the renal damage of gout. Ann Rheum Dis 25 (suppl): 668, 1966. Gutman AB, Yu TF: Uric acid nephrolithiasis. Am J Med 45: 756, 1968. Yu TF: Gutman AB: Uric acid nephrolithiasis in gout: predisposing factors. Ann Intern Med 67: 1133, 1967. Pitts RF: Physiology of the Kidney and Body Fluids, Chicago, Year Book Medical Publishers, 1974, p 67. Davies DF, Shock NW: Age changes in glomerular filtration rate, effective renal plasma flow, and tubular excretory capacity in adult males. J Clin Invest 29: 496, 1950. Friedman SA, Raizner AE, Rosen H. Solomon NA, Sy W: Functional defects in the aging kidney. Ann Intern Med 76: 41. 1972. Barlow KA, Beilin LJ: Renal disease in primary gout, Q J Med 37: 79, 1968. Talbott JH, Terplan KL: The kidney in gout. Medicine (Baftimore) 39: 405. 1960.

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