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Hyperuricemia and urate excretion in chronic renal disease
Hyperuricemia and Urate Excretion in Chronic Renal Disease ByJOHN
J. MCPHAUL, Jn.
Standard renal clearances were performed in 92 subjects, comparing uric acid excretion, glomerular filtration and renal plasma flow in normal people and people with proven chronic renal disease with normal and sub-normal glomerular filtration. Despite comparable filtered urate loads, patients with chronic renal disease, and normal GFR demonstrate decreased uric acid clearance and hyperuricemia. So too, do patients with decreased GFR, but the latter also mani-
U
RINARY
URIC
investigated
peruricemia
ACID
EXCRETION
adequately.
is common
However,
in advanced
fest enhancement of fractional uric acid excretion. Comparison of true creatinine excretion and maximum rates of glucose reabsorption in normal and abnormal subjects show similar adaptive alterations. Although uric acid retention occurs early in the course of chronic renal disease, compensatory tubular function of a nonspecific nature tends to minimize it as renal disease progresses. (Metabolism 17: No. 5, May, 436-438,1968)
in chronic
renal disease has not been
it is generally
acknowledged
that hy-
renal disease and that secondary gout may
occur. Despite suggestions that a relative augmentation of uric acid excretion may occur in gouty nephropathy’,” and in other types of renal failure,” little study has been made of such an adaptive phenomenon. These present studies were directed toward measurement of urinary uric acid excretion with discriminating markers of renal function in an effort to discern the relationship between renal disease, hyperuricemia, and urinary uric acid excretion. The results are indicative of urate retention with resultant hyperuricemia early in the course of chronic renal disease, when there is no measurable decrease in glomerular filtration rate. As filtration rates deteriorate urate excretion deteriorates to a lesser extent, so that the fractional excretion of uric acid is increased. Measurements of true creatinine excretion and maximum rates of glucose _ From the Department of Medicine, Wilford Hall USAF Hospital, Aerospace Medical Ditiision (AFSC), Lacklund Air Force Base, Texas. Received for publication August 38, 1967. JOHN J. MCPHAUL, JR., M.D., MAJOR, USAF, MC: Department of Medicine, Wilford Hall USAF Hospital, Aerospace Medical Dicision (AFSC), Lackland Air Force Base, Terus. Presently assigned as Research Fellow to the Department of Erpcrimental Pathology. Scripps Clinic and Research Foundation, La Jolla, California. EDITORIAL COMMENT: This is a rather thorough study with a considerable amount of clinical material on the question of the ability of the renal tubule to adapt to longstanding elevated levels of uric acid in the blood. The observations support the suggestion that by a mechanism as yet unknown, a relative increase in uric acid excretion takes pla~c* in chronic renal disease after hvpernricemia has existetl for a prolonged prriod of time.Harold A. Ilaqwr. Ph.D. 430
I3 I
Il~l’~:H~‘l11~:~;h[l;\
Table L-Tabular Analysis of Study Subjects by Sex and Group (Two-wa) disproportionate analysis of variance employed for each variable except filtration rates) Kidney Disease Normal GFR
lM& Female Overall Group
126.86 102.78 119.90
116.09 113.3” 113.4;
57.72 46.40 52.12
100.66 Y9.65
<.O:i
Male Female Overall Group Significance (P) Compared to Normal Subjects
600.92 481.02 576.88
497.64 5’4.12 51j3.42
339.14 316.06 326.90
48246 4.55.67
N.$.
Sex
Cinulin (ml./min.)
CPAH
(ml. /min.)
Filtration Fract)ion
Kidney Disease Subnormal GFR
Sormal Subjects
Variable
Malt Female Overall Group Significance (P)
c.05 ,236 ,220 .228 X.P.
,218 ,222 ,214
,182 .164
5.95 4.68 5.41
4.65 4.28 1.30
5.34 4.84 5.05 <.05
Filtered Vrate* img. /min.)
Male Female Overall Group Significance (P)
5.819 4.287 5.203
6.145 5.452 5.730 N.K.
<.OOl
C,,/xlOO Gin
C,,,/xlOO c ,PAII
*Corrected tN.S. =Not
,212 ,200
4.8.
5.31 4.53
<.Ol
5.155 4.008
<.Ol
<.OOl
3.447 2.096 2.812
Male Wemale Overall Group Significance (I’)
13.83 10.80 12.88
S.58 9.62 9.05 <.OOl
6.67 X.56 7.37 <.OOl
9.42 10.11
<.05
Male Female Overall Group Significance (P)
10.14 10.30 11.25
7.38 5.49
10.47 13.29
<.U5
8.20 <.05
13.84 19.78 16.19 <.OOl
Male Female Overall Group Significance (P)
2.19 2.20 2.33
1.74 1.86 1.83 N.S.
2.47
3.24 2.78 N.S.
2.14 2.49
X.Y.
t,o 1.73 M2 Significant;
-
(I? to
,175 <.OOl
Male Female Overall Group Significance (P)
Arid *
5gniticance Femalea M&B
<.OOl
Serum I:ric Acid img./lOO ml.)
Curie
OWYdll Sex Effect
P > .05
wabsorption in normal and nephritic people indicate net creatinine secretion and increased glucose reabsorption per nephron in advanced renal disease. Such data suggest that the relative augmentation of uric acid excretion in renal disease is not a specific phenomenon but rather is part of a general. active anal tubular adaptation to progressive renal disease. %TERIALS
AND
ME?.HOI)S
Stantlartl supine renal clearances were performed in 92 subjects, fasting in thra fo~noc~~. {Ising oral water hydration. These subjects were 36 norm;11 adult volunteers (32 men antI 4 women) and 56 adult patients with kidney disease (38 men and 18 women). The lattrl were selectetl because of histoq and abnormal urinarv sediment; all hut one undrrwerlt pcrcutancolls rmal biop,.?; which confirmed the clinics1 cliagnosis. On the basis of their measured glomrrular filtration rates (GFR). the grollp with known kidney disease was clivided arbitrarily into a sub-group with normal glomerular filtration rate (21 men and 9 women). and a sub-group with abnormal filtration rate (
Table 2.-Product-Moment Correlation Coefficients Between Uric Acid Clearance and Fractional Excretion of Uric Acid for Each Group by Sex, Demonstrating Degree of Linear Relationship Between Variables Variables Grit
Group
acid
and C!,, x 100
Kidney
Disease,
Normal
Kidney
Disease,
Subnormal
GFR
tin
Curie acid and C,, x 100
Normal Normal Kidney
Disease,
Eormal
GFR
GFR
CPAH
Kidney *Product-Moment from these studies, prior to study.
Disease,
Subnormal
Correlation and
GFR
No.
Significance (IrOIIl hypothetical zero)
IL*
Men
32
Women Men Women Men Women
1; 9 21 9
0.92 0.91 0.91 0.93 0.56 0.09
Men Women Men
31 4 16
0.88< 0.70 0.94
Women
9
0.85 I
Women Men
9 20
0.67 0.43 >
Normal Normal
Sex
.92
P <.Ol
.46
P <.05
.89
P <.Ol
.50
P <.Ol
Coefficient
medications
had
heen
discontinued
in all patients
at least
72 hours
Clearances performed were inulin (C,,,), para-aminohippurate (C,,,,,) and endogenous uric acid (C,,,), using the techniques of Schreiner, 4 Smith,? and the enzymatic method of Feichtmeir and Wrenn,” respectively. Concomitant clearances of true creatinine (C,.,.) and inulin were performed in five normal people and five kidney disease patients with subnormal glomerular filtration rates. Creatinine was measured by the method of Hare. Maximum rates of ghlcose reabsorption (Tm,) were determined after double veasting in 10 patients with kidney disease (3 with normal and 7 with subnormal glomeruiar filtration rates) and compared to Tm, of 16 normal people. Chlcose was analyzed by the glucose oxidnse method of Washko and Rice.8 Clearances and maximum rates of glucose reabsorption were c’orrected to 1.73 sq. meters body surface area. was e!nploVt~tl for analvsis A two-way disproportionate analysis of variance procedure” of each variable except GFR. The sex by group mean and marginal effects :;re presented.for each variable considered in Table 2 and will be detailed in the results. ?‘roduct-lnoment correlation coefficients were computed to determine the degree of linear association between the absolute clearance of uric acid (C,,,) and the fractional excretion of uric acid related to both inulin (C,,,/Ci, x 100) and para-aminohippurate (C,,JC,, ‘,,, K 100). proximate T-tests were used to test the variance between the means of normal people patients
with
kidney
disease
with
respect
to the ratios
C,‘,./Cin
Apand
and Tm,/C,,,.
The overall clearance data for the groups are displayed in Tablcb 1. Inasmuch as glomerular filtration was one criterion of assignment into the groups under consideration, the group means for GFR were not tested statistically. However, the mean GFR was higher for men than women (P < .05), as expected. Renal Plasma Flow (C,.,,, ): No significant sex by group interaction was observed, indicating essentially the same fluctuation between male and female means for all groups, and the means between men and women did not differ significantly. However, the means of kidney disease patients with normal and subnormal GFR differed from the normal group at the .05 and the .OOl levels, respectively. Filtration Fraction: The only significant differences observed in these data were between the mean of patients with subnormal GFR and means of both other groups ( P < .OOl).
Sertlrn, was
IJrie A&
manifest
Concentration:
No significant
sex
by
group
inter~dol~
in
these subjects, although the overall mean for the men us statistically higher (P < .01) than the overall mean for the women. The meal’ concentration for normal people was significantly lower than the means of p;ltients with kidney disease with either normal or subnormal GFR, with probabihties at the .05 and .OOI levels, respectively. Means between the two groups of patients with kidney disease did not differ significantly. Filter& Load of Uric Acid: The mean filtered urate load was statisticall!. higher in men than in women (P < .Ol ), although no sex by group interaction was observed. Despite a smaller uric acid load in patients with subnormal glomerular filtration rates compared both to normal people and patients with normal CFR (P < .OOl), the means of the latter two groups did not differ statistically. Corrected ~iric Acicl Clearance: Each of the means from the groups with kidney disease was lower than the normal mean (P < .OOl), and did not differ statistically from one another. Fractional Ilric Acid CIearancc (Ct,o/Ci,i :< 100): Inasmuch AS uric acid excretion is not due to filtration and reabsorption only, uric acid clearance expressed as a function of glomerular filtration rate is intended to relate it to a marker of intact functioning nephrons and does not imply any specific modt of excretion. Considered in this manner, the mean fractional excretion of uric, acid was higher in women than in men (P < .05) and no significant intrraction was observed. The mean of patients with normal GFR was less than the mean of normnl people, differing at the .05 level. but patients with subnormal GFH demonstrated a mean greater than either group (P < JO1 to each). The latter indicates a significant augmentation of mate excretion per unit functioning nephron in renal failure. Uric Acid Excretion Related to Ronal Pfuswla Flop (C,,,/C,..,,, ,. IMI ): &ralysis of means between groups, relating uric acid clearance to a secretor\ function of the kidney, indicated ;I significant difference only between the two groups of patients with kidney disease (P < .Ol ). The apparent enhancement of uric acid clearance relative to PAH clcarancc in patients with suhnormal (:FR was not statistically different from normal people. Correhtion Coeficients: To test the relationship between uric acid clearanccb the excretion of uric acid relative to GFR or RPF, product-moment corr&tion coefficients were computed for each group and sex independentlv. AS indicated in Table 2, a high degree of linear association (pooled r = 0.92 ) \t’as demonstratrd between these functions in normal people and patients \vith kidnev disease having normal GFR, between sexes and each other. [~ov%,e\er. this hnear association was significantly different from the linear association demonstrated in patients with subnormal GFR (pooled r = 0.46, P < ,001 1. Similar relationships were demonstrated between uric acid elearancc and rrric acid clearance as a function of PAH clearance. md
Although comparison of these linear relationships clearly separates the group of kidnev disease patients with subnormal glomerular filtrations, the differenccL is pr&rilv a reflection of decreasing fijtratiorr rate and/or renal
JOIlh
,I,
\rc:
l’llhrl..
,IIl.
. NORMAL @KD N GFR d KD ABN GFR
20
40
60
00 CINULIN
100
Irn
110
Ii0
160
ml PER YIN
Fig. L-This graph shows the trend toward decreased minute excretion of uric acid in subjects with chronic renal disease, comparing male patients with abnormal GFR ( A ) and normal GFR ( 0 ) to normal male volunteers ( l) . plasma
flow. The implied
augmentation
of net urinary
uric acid excretion
is a
only, as shown in Fig. 1. The latter demonstrates a decline in absolute minute excretion of uric acid in progressive renal disease in men but not nearly so marked as the concomitant fall of glomerular filtration rate. Creatinine Cle~~unces: In an effort to determine whether the relative augmentation of uric acid excretion in chronic renal disease is a specific phenomenon, concomitant true creatinine clearances were analyzed from two consecutive periods in five normal people and five patients with subnormal GFR. As indicated in Table 3, the means of ratios of creatinine clearance to inulin clearance were significantly greater in patients with subnormal GFH than in normal subjects (P < .Ol for each collection period). This indicates net secretion of true creatinine in advanced renal disease, whereas ratios of creatinine to inulin clearance in normal people do not differ from unity. Maximum Reabsoqdive Rate for Glucose (Tm,): Comparative me:lsnrerelative
increase
Table 3.-Comparison of Ratios of Clearances of True Creatinine to Inuiin in Sequential Collection Periods from 5 Normal Persons and 5 with Subnormal GFR (Ranging from 71.9 to 27.8 ml. per min.). Both Kidney Disease Means Statistically Larger than 1 (P < .05, P < .Ol for Sequential Periods). Normal Group Means Do Not Differ from Unitv. Period
1 2
GlWlp
Standard Deviation
Number
Signilicance
Sormal Persons Kidney Disease, Subnormal
GFR
5 5
,915 1.334
,116 ,238
P <.Ol
?rTormsl Persons Kidney Disease, Subnormal
GFR
5 5
.999 1.394
,077 .06i
P <.Ol
1I \
435
I’l~:I~ulil~:l~~II.\
Table 4.-Tabular Comparison of Means and Variance Patients with Renal Disease. Significance was estimated Variable _.____~ (‘inulin
l’m,/1.73 hl? Tm,/1.73 M2 100 ml. GFR
Group
____
Normal Iiidncy Dktas(s
Number ____16 10
Between Normal Men and from Approximate T-Tests.
MeWI
127 68.9
Standard Deviation
16 44.3
Sigoifirancc
___-
1’ <.Ol
Normal Kidney Discxsc
16 10
325 240
36 127
I’ >.(I.5
Normal Kidney Discasc
16 10
234 377
21 123
P <.Ol
ments \vcre made of Tm,/Ci, in normal people and 10 patients with kidncsl disease, although there was no statistically significant difference between this Tm, of the two groups (Table 4), Tm, per unit measured GFR was significantly greater than normal in patients with kidney disease ( P < .Ol ). From these data it may be inferred that the relative augmentation of mate excretion occurring in renal disease with subnormal filtration rate is not specific but has its counterpart in net creatinine secretion and supra-normal ghrCOW reabsorption per residual functioning nephron unit.
The mechanisms responsible for net urinary uric acid excretion in normal people have not been defined precisely, although Gutman and his associatesl0.11 and Paulsen’” h*dve demonstrated the likelihood of participation of glomerular filtration, tubular reabsorption and secretion. The quantitative contribution of each of these is uncertain, and it is possible that the role of separate tubular sites may vary depending upon the specific pathophysiologic stimuli that are operative.‘“-rX Although Nugent and Tyler,‘!‘.“’ Lathem and Hodnan”r and Seegmiller and co-worker+ have shown recently that uric acid excretion in gouty people is subnormal when compared to normal people at comparable plasma mate levels and filtered mate loads, no systematic study has been made into hyperuricemi;r occurring in the course of overt renal disease. Reversible suppression of uric acid excretion is a well-documented phenomenon attendant upon the transient renal functional failure of toxemias of pregnancy and preclampsia. 29-L”iThis specific instance has been attributed bv IIandIcr”’ to the direct inhibitory effect of elevated blood lactic acid concentration,s prcsumablv causing tubular secretorv inhibition. Kasanen.. Kallio and MarkkanenG* attempted to correlate serum uric acid concentration and endogenous uric acid clearances with urea and crvatitlinc~ efearances and the phenol red test. The limited relationship documented IX>tween these parameters gave no insight into the mechanisms responsible, A group of goutv patients with varied renal function was studied bv ~oon-th~ arrcl associatcss’ who noted a rising uric acid chromogen to inulin ratio as renal insufficienev, progressed, suggesting a relative augmentation of urinarv uric ac,id excretion in gouts renal failure. Reccntlv. Rieselbach and Steele:; har~c~
suggested an enhanced excretion of uric acid relative to inulin cjcarance
in ad-
vanced, stable, chronic renal disease, not due to gout. The present studies compare normal people and people with chronic kidney disease, and demonstrate endogenous phenomena similar to those of gouty people. Despite normal glomerular filtration rates, patients with kidney disease are hyperuricemic compared to normal subjects, and the hyperuricemia is more obvious when normals are compared to patients with subnormal filtration. Similarly, uric acid clearance is decreased notably in both groups of people with chronic kidney disease, although normal people and nephritic patients with normal GFR have comparable filtered loads of uric acid. Hence, elevation of serum uric acid occurs as one of the early functional consequences of chronic renal disease and is caused by a decrease in uric acid excretion. Similarly, uric acid clearance related to the fractional excretion of uric acid, either as a function of glomerular filtration rate or renal plasma flow, demonstrates marked relative enhancement of net uric acid excretion in renal disease characterized by subnormal GFR. The deviant linear relationship of the latter group suggests that this augmentation of fractional excretion is disproportionate to adaptations of glomerular filtration and renal plasma flow, and is characteristic of failing renal function whether filtration rates are mildly or markedly abnormal. That such a compensation is not unique to the urinary rxcretion of uric acid is demonstrated by evidence of concomitant endogenous creatinine secretion and augmentation of glucose reabsorption by the renal tubules of patients with subnormal glomerular filtration rates. Although this adaptation is therefore nonspecific, it is possibly of importance that such secretory and reabsorptive functions are considered “active,” requiring cellular work. Despite this evidence of adaptation of diverse tubular functions, involving active secretion and reabsorption, the mechanisms responsible for relative enhancement of urinary uric acid excretion are not defined by our data, One alternative is decreased uric acid reabsorption, due either to some direct inhibition of discrete reabsorptive tubular function or indirectly resulting from osmotic forces on the composition of tubular fluid per nephron. Another alternative is an increase of secretion of uric acid at one or more sites within the nephron .2Q,30Conclusive information defining the role of extracellular fluid volume31*32 and of solute competition for common transport mechanism+34 is not yet available. Nevertheless, as renal injury from a variety of diseases affects the kidney, architectural and functional hypertrophy occur. 35 One aspect of this functional hypertrophy is an increase of uric acid excretion per unit nephron, albeit at a higher than normal serum uric acid concentration, a lower absolute rate of clearance, and a larger urate pool. REFERENCES 1. Coombs, F. S., Pecora, L. J., Thorogood, E., Consolazio, W. V., and Talbott, J. H.: Renal function in patients with gout. J. Clin. Invest. 19:525, 1940.
2. Talbott, J. H.: Gout. Oxford Medical Publications, New York, 1: 103, 1943. 3. Rieselbach, R. E., and Steele, T. H.: Increased capacity for urate excretion by re-
nephrons of the chronically diseased human kidney. J. Clin. Invest. 45:1062, 1966 (Abstract). 4. Schreiner, G. E.: Determination of in-
siclual
ulin by means of resorcinol. Riol. Med. 74: 117, 1950.
Proc.
Sot.
5. Smith, H. W.: Principles of renal ology. New York, Oxford Universitv 1956, pp 212,213.
Exp. physiPress,
R. S.: Endogenous
serm1) and twine. I'roc.SW. 74:148, 1950. 8. Washko,
Xl. E., and
creatinine Exp.
Rice,
Biol.
in hfed.
E. W.:
De-
termination of glucose by an improved enqlnatic procedure. Clin. Chem. 7:542, 1961. 9. Steel, R. (:. D., and Torrie, J. H.: ciples and procedures of statistics. York, blcGraw-Hill, 1960, p. 252. 10. Cutman, I..: Tubular Clin. Invest.
A. B., Yii, T. F., and secretion of urate 3X: 1778, 1959.
PrinNem
gout
and
Invest.
in
C. A., and of uric
Berger.
in man.
J.
l-7. Paulsen, II.: Inhibition of uric acid excretion in rabbits given probenecid or salicylic acid. Acta Pharmacol. (Kobenhavn) I 1277, 1955. 13. Gibson, I I. \‘., and Doisy, E. A.: A note on the effect of some organic acids upon the uric acid excretion of man. J. Biol. C!rrm. 55360.5, 1923. 14. Quick, A. J.: The relationship between chemical structure and physiological response. III. Factors influencing the excretion of Ilric acid. J. Biol. Chem. 98:157, 1932. 15. Yii, T. l:., and Cutman, A. B.: Paratlosical retention of uric acid by uricosuric tirlqs in low closage. I’roc. Sot. Eyp. Biol. Xietl. 90:542, 1955. 16. Dubin, A. K;llshner, D. S., Bronsky, D.. al~tl Pascale. 1.. R.: Hyperuricemia in hypop;ll-,ltllyroitlisnr. Xlctabolism 5:703, 1956. 17. Lecoccl, F. R., and McPhaul, .J J., Jr.: The effects of starvation, high fat diets, ant] ketone inftlsions on uric acid balance. hlrtallol:sm 14: 186. 196r;. 18. Slintz, 1). II., Canary, J. J., Carreon. (:.. and Kyl(*, I,.: H~peruricemia in hyperpara[h!~roitlislrr. \(,u Eng. J. hlctl. 265:111.
Tyler,
acid
non-gouty
38:1890,
F .Ll.: ‘I‘ht
in patients subjects.
with
J.
Clin
1959.
20. Nugent, C. A., MacDiarmid, W. I).. and Tvler, F. H.: Renal excretion of urate in patients with gout. Arch. Intern. Med. rCl>icage) 113: 115, 1964. W.,
and
Rodnan,
(;.
pairment of uric acid excretion Clin. Invest. 41:195S, 1962. 22.
Seegmiller,
J.
E.,
P.: 1111.
in golIt.
Crayzel,
~4.
1.
I ._
Howell, R. R., and Plato, C.: The renal e\cretion of llric acitl in gotIt. J. Clin. Inv~~\t. 41:1094,
196”.
23. Schaffer,
N. K., Dill,
L. \‘., and
CatI-
den, J. F.: Uric acid clearance in norm.~I pregnancy and pre-eclampsia. J. Clin. Invca\t. ““:“Ol, 1943. 24.
Bonsnes,
.i survey and urea
11. -, and Yii, T. F.: A three component system for regulation of renal excretion of uric acid in Nan. Trans. Ass. Amer. Physicians 74:353, 1961.
I 90 I
excretion
21. Lathem,
6. Feichtmeir, T. V., and Wrenn, H. T.: Direct determination of uric acid using uric.ase. Amer. J. Clin. Path. 25:833, 1955. 7. IIare,
l!J. Nugent, renal
R. W.,
pre-eclampsia.
J. Clin.
25. Hayash;,
(Zvnec.
26. Chesley, evaluation eclampsia J. Ohstet.
11. J..
uric aci,l and seven 25:378,
1946
and endogenoll\
studies in normal pregof pregnancv. ,tiner. 1
71:859,
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I,. C., and
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C.:
‘l‘ht, prts-
of tests to differentiate from hypertensive disease. (iynec. 75:1165, 1958.
27. Llandler. in the redltced emia
Stander,
Invest.
T.: Lrric acid
creatinine clearance nancy and toxemias Ohstet.
and
of the twenty-four-hour clearances in eclampsia
.imer.
J. S.: The role of lactic acitl excretion of uric acid in to\-
of pregnanc!~.
J. Clin.
Invest.
39: 1526.
V., and
Markka-
1960. 28.
Ka~ancn,
A., Kallio,
ncn, T.: On scrm,* uric arid and endogenic. uric acid clearance in renal failure. Act:l. Sled. Scantl, 160:503, 1958. 29. (i.
Da\,&
I’., and
B. Ktdes,
B..
Field,
J,
B.,
Rodnall
L,. If .: Localization
ant1
pyrazinamitle inhibition of distal transtubllInr movement of Ilric acid-2-C’” wit11 :, rnotlific~d stop-flow trchnicluc. J. Clin. Invc.at. 44:7 16. 1965. :30. Yii. T. F., Bc%rger, L., Kupper, S., ,~ntl ( ;utnlan, A. R.: Tubular secretion of uratr ill the dog. Alller. J. Physiol. 199:1199, 1960. 31. Dirks.
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liner. R. U’.: The dfect of saline infllsion OII sodilm~ reabsorption 1)~ the proximal tutxlh. of the dog. J. Clin. Invest. 44:1160, 196.5. jr..
32. Suki. W. N., fIu1l. .4. R., Rector. F. (1.. llnd Srildirl. 1). \I’.: \lrchnnism of thl,
cll’ect ot thiazide diuretics uric acid. Clin. Res. 15:78,
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33. Bonsnes, R. W., and Dana, E. S.: On the increased uric acid clearance following the intravenous infusion of hypertonic glucose solutions. J. Clin. Invest. 25:386, 1946. 34. Skeith, ler,
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J. MCPHAUL, Jn.
Standard renal clearances were performed in 92 subjects, comparing uric acid excretion, glomerular filtration and renal plasma flow in normal people and people with proven chronic renal disease with normal and sub-normal glomerular filtration. Despite comparable filtered urate loads, patients with chronic renal disease, and normal GFR demonstrate decreased uric acid clearance and hyperuricemia. So too, do patients with decreased GFR, but the latter also mani-
U
RINARY
URIC
investigated
peruricemia
ACID
EXCRETION
adequately.
is common
However,
in advanced
fest enhancement of fractional uric acid excretion. Comparison of true creatinine excretion and maximum rates of glucose reabsorption in normal and abnormal subjects show similar adaptive alterations. Although uric acid retention occurs early in the course of chronic renal disease, compensatory tubular function of a nonspecific nature tends to minimize it as renal disease progresses. (Metabolism 17: No. 5, May, 436-438,1968)
in chronic
renal disease has not been
it is generally
acknowledged
that hy-
renal disease and that secondary gout may
occur. Despite suggestions that a relative augmentation of uric acid excretion may occur in gouty nephropathy’,” and in other types of renal failure,” little study has been made of such an adaptive phenomenon. These present studies were directed toward measurement of urinary uric acid excretion with discriminating markers of renal function in an effort to discern the relationship between renal disease, hyperuricemia, and urinary uric acid excretion. The results are indicative of urate retention with resultant hyperuricemia early in the course of chronic renal disease, when there is no measurable decrease in glomerular filtration rate. As filtration rates deteriorate urate excretion deteriorates to a lesser extent, so that the fractional excretion of uric acid is increased. Measurements of true creatinine excretion and maximum rates of glucose _ From the Department of Medicine, Wilford Hall USAF Hospital, Aerospace Medical Ditiision (AFSC), Lacklund Air Force Base, Texas. Received for publication August 38, 1967. JOHN J. MCPHAUL, JR., M.D., MAJOR, USAF, MC: Department of Medicine, Wilford Hall USAF Hospital, Aerospace Medical Dicision (AFSC), Lackland Air Force Base, Terus. Presently assigned as Research Fellow to the Department of Erpcrimental Pathology. Scripps Clinic and Research Foundation, La Jolla, California. EDITORIAL COMMENT: This is a rather thorough study with a considerable amount of clinical material on the question of the ability of the renal tubule to adapt to longstanding elevated levels of uric acid in the blood. The observations support the suggestion that by a mechanism as yet unknown, a relative increase in uric acid excretion takes pla~c* in chronic renal disease after hvpernricemia has existetl for a prolonged prriod of time.Harold A. Ilaqwr. Ph.D. 430
I3 I
Il~l’~:H~‘l11~:~;h[l;\
Table L-Tabular Analysis of Study Subjects by Sex and Group (Two-wa) disproportionate analysis of variance employed for each variable except filtration rates) Kidney Disease Normal GFR
lM& Female Overall Group
126.86 102.78 119.90
116.09 113.3” 113.4;
57.72 46.40 52.12
100.66 Y9.65
<.O:i
Male Female Overall Group Significance (P) Compared to Normal Subjects
600.92 481.02 576.88
497.64 5’4.12 51j3.42
339.14 316.06 326.90
48246 4.55.67
N.$.
Sex
Cinulin (ml./min.)
CPAH
(ml. /min.)
Filtration Fract)ion
Kidney Disease Subnormal GFR
Sormal Subjects
Variable
Malt Female Overall Group Significance (P)
c.05 ,236 ,220 .228 X.P.
,218 ,222 ,214
,182 .164
5.95 4.68 5.41
4.65 4.28 1.30
5.34 4.84 5.05 <.05
Filtered Vrate* img. /min.)
Male Female Overall Group Significance (P)
5.819 4.287 5.203
6.145 5.452 5.730 N.K.
<.OOl
C,,/xlOO Gin
C,,,/xlOO c ,PAII
*Corrected tN.S. =Not
,212 ,200
4.8.
5.31 4.53
<.Ol
5.155 4.008
<.Ol
<.OOl
3.447 2.096 2.812
Male Wemale Overall Group Significance (I’)
13.83 10.80 12.88
S.58 9.62 9.05 <.OOl
6.67 X.56 7.37 <.OOl
9.42 10.11
<.05
Male Female Overall Group Significance (P)
10.14 10.30 11.25
7.38 5.49
10.47 13.29
<.U5
8.20 <.05
13.84 19.78 16.19 <.OOl
Male Female Overall Group Significance (P)
2.19 2.20 2.33
1.74 1.86 1.83 N.S.
2.47
3.24 2.78 N.S.
2.14 2.49
X.Y.
t,o 1.73 M2 Significant;
-
(I? to
,175 <.OOl
Male Female Overall Group Significance (P)
Arid *
5gniticance Femalea M&B
<.OOl
Serum I:ric Acid img./lOO ml.)
Curie
OWYdll Sex Effect
P > .05
wabsorption in normal and nephritic people indicate net creatinine secretion and increased glucose reabsorption per nephron in advanced renal disease. Such data suggest that the relative augmentation of uric acid excretion in renal disease is not a specific phenomenon but rather is part of a general. active anal tubular adaptation to progressive renal disease. %TERIALS
AND
ME?.HOI)S
Stantlartl supine renal clearances were performed in 92 subjects, fasting in thra fo~noc~~. {Ising oral water hydration. These subjects were 36 norm;11 adult volunteers (32 men antI 4 women) and 56 adult patients with kidney disease (38 men and 18 women). The lattrl were selectetl because of histoq and abnormal urinarv sediment; all hut one undrrwerlt pcrcutancolls rmal biop,.?; which confirmed the clinics1 cliagnosis. On the basis of their measured glomrrular filtration rates (GFR). the grollp with known kidney disease was clivided arbitrarily into a sub-group with normal glomerular filtration rate (21 men and 9 women). and a sub-group with abnormal filtration rate (
Table 2.-Product-Moment Correlation Coefficients Between Uric Acid Clearance and Fractional Excretion of Uric Acid for Each Group by Sex, Demonstrating Degree of Linear Relationship Between Variables Variables Grit
Group
acid
and C!,, x 100
Kidney
Disease,
Normal
Kidney
Disease,
Subnormal
GFR
tin
Curie acid and C,, x 100
Normal Normal Kidney
Disease,
Eormal
GFR
GFR
CPAH
Kidney *Product-Moment from these studies, prior to study.
Disease,
Subnormal
Correlation and
GFR
No.
Significance (IrOIIl hypothetical zero)
IL*
Men
32
Women Men Women Men Women
1; 9 21 9
0.92 0.91 0.91 0.93 0.56 0.09
Men Women Men
31 4 16
0.88< 0.70 0.94
Women
9
0.85 I
Women Men
9 20
0.67 0.43 >
Normal Normal
Sex
.92
P <.Ol
.46
P <.05
.89
P <.Ol
.50
P <.Ol
Coefficient
medications
had
heen
discontinued
in all patients
at least
72 hours
Clearances performed were inulin (C,,,), para-aminohippurate (C,,,,,) and endogenous uric acid (C,,,), using the techniques of Schreiner, 4 Smith,? and the enzymatic method of Feichtmeir and Wrenn,” respectively. Concomitant clearances of true creatinine (C,.,.) and inulin were performed in five normal people and five kidney disease patients with subnormal glomerular filtration rates. Creatinine was measured by the method of Hare. Maximum rates of ghlcose reabsorption (Tm,) were determined after double veasting in 10 patients with kidney disease (3 with normal and 7 with subnormal glomeruiar filtration rates) and compared to Tm, of 16 normal people. Chlcose was analyzed by the glucose oxidnse method of Washko and Rice.8 Clearances and maximum rates of glucose reabsorption were c’orrected to 1.73 sq. meters body surface area. was e!nploVt~tl for analvsis A two-way disproportionate analysis of variance procedure” of each variable except GFR. The sex by group mean and marginal effects :;re presented.for each variable considered in Table 2 and will be detailed in the results. ?‘roduct-lnoment correlation coefficients were computed to determine the degree of linear association between the absolute clearance of uric acid (C,,,) and the fractional excretion of uric acid related to both inulin (C,,,/Ci, x 100) and para-aminohippurate (C,,JC,, ‘,,, K 100). proximate T-tests were used to test the variance between the means of normal people patients
with
kidney
disease
with
respect
to the ratios
C,‘,./Cin
Apand
and Tm,/C,,,.
The overall clearance data for the groups are displayed in Tablcb 1. Inasmuch as glomerular filtration was one criterion of assignment into the groups under consideration, the group means for GFR were not tested statistically. However, the mean GFR was higher for men than women (P < .05), as expected. Renal Plasma Flow (C,.,,, ): No significant sex by group interaction was observed, indicating essentially the same fluctuation between male and female means for all groups, and the means between men and women did not differ significantly. However, the means of kidney disease patients with normal and subnormal GFR differed from the normal group at the .05 and the .OOl levels, respectively. Filtration Fraction: The only significant differences observed in these data were between the mean of patients with subnormal GFR and means of both other groups ( P < .OOl).
Sertlrn, was
IJrie A&
manifest
Concentration:
No significant
sex
by
group
inter~dol~
in
these subjects, although the overall mean for the men us statistically higher (P < .01) than the overall mean for the women. The meal’ concentration for normal people was significantly lower than the means of p;ltients with kidney disease with either normal or subnormal GFR, with probabihties at the .05 and .OOI levels, respectively. Means between the two groups of patients with kidney disease did not differ significantly. Filter& Load of Uric Acid: The mean filtered urate load was statisticall!. higher in men than in women (P < .Ol ), although no sex by group interaction was observed. Despite a smaller uric acid load in patients with subnormal glomerular filtration rates compared both to normal people and patients with normal CFR (P < .OOl), the means of the latter two groups did not differ statistically. Corrected ~iric Acicl Clearance: Each of the means from the groups with kidney disease was lower than the normal mean (P < .OOl), and did not differ statistically from one another. Fractional Ilric Acid CIearancc (Ct,o/Ci,i :< 100): Inasmuch AS uric acid excretion is not due to filtration and reabsorption only, uric acid clearance expressed as a function of glomerular filtration rate is intended to relate it to a marker of intact functioning nephrons and does not imply any specific modt of excretion. Considered in this manner, the mean fractional excretion of uric, acid was higher in women than in men (P < .05) and no significant intrraction was observed. The mean of patients with normal GFR was less than the mean of normnl people, differing at the .05 level. but patients with subnormal GFH demonstrated a mean greater than either group (P < JO1 to each). The latter indicates a significant augmentation of mate excretion per unit functioning nephron in renal failure. Uric Acid Excretion Related to Ronal Pfuswla Flop (C,,,/C,..,,, ,. IMI ): &ralysis of means between groups, relating uric acid clearance to a secretor\ function of the kidney, indicated ;I significant difference only between the two groups of patients with kidney disease (P < .Ol ). The apparent enhancement of uric acid clearance relative to PAH clcarancc in patients with suhnormal (:FR was not statistically different from normal people. Correhtion Coeficients: To test the relationship between uric acid clearanccb the excretion of uric acid relative to GFR or RPF, product-moment corr&tion coefficients were computed for each group and sex independentlv. AS indicated in Table 2, a high degree of linear association (pooled r = 0.92 ) \t’as demonstratrd between these functions in normal people and patients \vith kidnev disease having normal GFR, between sexes and each other. [~ov%,e\er. this hnear association was significantly different from the linear association demonstrated in patients with subnormal GFR (pooled r = 0.46, P < ,001 1. Similar relationships were demonstrated between uric acid elearancc and rrric acid clearance as a function of PAH clearance. md
Although comparison of these linear relationships clearly separates the group of kidnev disease patients with subnormal glomerular filtrations, the differenccL is pr&rilv a reflection of decreasing fijtratiorr rate and/or renal
JOIlh
,I,
\rc:
l’llhrl..
,IIl.
. NORMAL @KD N GFR d KD ABN GFR
20
40
60
00 CINULIN
100
Irn
110
Ii0
160
ml PER YIN
Fig. L-This graph shows the trend toward decreased minute excretion of uric acid in subjects with chronic renal disease, comparing male patients with abnormal GFR ( A ) and normal GFR ( 0 ) to normal male volunteers ( l) . plasma
flow. The implied
augmentation
of net urinary
uric acid excretion
is a
only, as shown in Fig. 1. The latter demonstrates a decline in absolute minute excretion of uric acid in progressive renal disease in men but not nearly so marked as the concomitant fall of glomerular filtration rate. Creatinine Cle~~unces: In an effort to determine whether the relative augmentation of uric acid excretion in chronic renal disease is a specific phenomenon, concomitant true creatinine clearances were analyzed from two consecutive periods in five normal people and five patients with subnormal GFR. As indicated in Table 3, the means of ratios of creatinine clearance to inulin clearance were significantly greater in patients with subnormal GFH than in normal subjects (P < .Ol for each collection period). This indicates net secretion of true creatinine in advanced renal disease, whereas ratios of creatinine to inulin clearance in normal people do not differ from unity. Maximum Reabsoqdive Rate for Glucose (Tm,): Comparative me:lsnrerelative
increase
Table 3.-Comparison of Ratios of Clearances of True Creatinine to Inuiin in Sequential Collection Periods from 5 Normal Persons and 5 with Subnormal GFR (Ranging from 71.9 to 27.8 ml. per min.). Both Kidney Disease Means Statistically Larger than 1 (P < .05, P < .Ol for Sequential Periods). Normal Group Means Do Not Differ from Unitv. Period
1 2
GlWlp
Standard Deviation
Number
Signilicance
Sormal Persons Kidney Disease, Subnormal
GFR
5 5
,915 1.334
,116 ,238
P <.Ol
?rTormsl Persons Kidney Disease, Subnormal
GFR
5 5
.999 1.394
,077 .06i
P <.Ol
1I \
435
I’l~:I~ulil~:l~~II.\
Table 4.-Tabular Comparison of Means and Variance Patients with Renal Disease. Significance was estimated Variable _.____~ (‘inulin
l’m,/1.73 hl? Tm,/1.73 M2 100 ml. GFR
Group
____
Normal Iiidncy Dktas(s
Number ____16 10
Between Normal Men and from Approximate T-Tests.
MeWI
127 68.9
Standard Deviation
16 44.3
Sigoifirancc
___-
1’ <.Ol
Normal Kidney Discxsc
16 10
325 240
36 127
I’ >.(I.5
Normal Kidney Discasc
16 10
234 377
21 123
P <.Ol
ments \vcre made of Tm,/Ci, in normal people and 10 patients with kidncsl disease, although there was no statistically significant difference between this Tm, of the two groups (Table 4), Tm, per unit measured GFR was significantly greater than normal in patients with kidney disease ( P < .Ol ). From these data it may be inferred that the relative augmentation of mate excretion occurring in renal disease with subnormal filtration rate is not specific but has its counterpart in net creatinine secretion and supra-normal ghrCOW reabsorption per residual functioning nephron unit.
The mechanisms responsible for net urinary uric acid excretion in normal people have not been defined precisely, although Gutman and his associatesl0.11 and Paulsen’” h*dve demonstrated the likelihood of participation of glomerular filtration, tubular reabsorption and secretion. The quantitative contribution of each of these is uncertain, and it is possible that the role of separate tubular sites may vary depending upon the specific pathophysiologic stimuli that are operative.‘“-rX Although Nugent and Tyler,‘!‘.“’ Lathem and Hodnan”r and Seegmiller and co-worker+ have shown recently that uric acid excretion in gouty people is subnormal when compared to normal people at comparable plasma mate levels and filtered mate loads, no systematic study has been made into hyperuricemi;r occurring in the course of overt renal disease. Reversible suppression of uric acid excretion is a well-documented phenomenon attendant upon the transient renal functional failure of toxemias of pregnancy and preclampsia. 29-L”iThis specific instance has been attributed bv IIandIcr”’ to the direct inhibitory effect of elevated blood lactic acid concentration,s prcsumablv causing tubular secretorv inhibition. Kasanen.. Kallio and MarkkanenG* attempted to correlate serum uric acid concentration and endogenous uric acid clearances with urea and crvatitlinc~ efearances and the phenol red test. The limited relationship documented IX>tween these parameters gave no insight into the mechanisms responsible, A group of goutv patients with varied renal function was studied bv ~oon-th~ arrcl associatcss’ who noted a rising uric acid chromogen to inulin ratio as renal insufficienev, progressed, suggesting a relative augmentation of urinarv uric ac,id excretion in gouts renal failure. Reccntlv. Rieselbach and Steele:; har~c~
suggested an enhanced excretion of uric acid relative to inulin cjcarance
in ad-
vanced, stable, chronic renal disease, not due to gout. The present studies compare normal people and people with chronic kidney disease, and demonstrate endogenous phenomena similar to those of gouty people. Despite normal glomerular filtration rates, patients with kidney disease are hyperuricemic compared to normal subjects, and the hyperuricemia is more obvious when normals are compared to patients with subnormal filtration. Similarly, uric acid clearance is decreased notably in both groups of people with chronic kidney disease, although normal people and nephritic patients with normal GFR have comparable filtered loads of uric acid. Hence, elevation of serum uric acid occurs as one of the early functional consequences of chronic renal disease and is caused by a decrease in uric acid excretion. Similarly, uric acid clearance related to the fractional excretion of uric acid, either as a function of glomerular filtration rate or renal plasma flow, demonstrates marked relative enhancement of net uric acid excretion in renal disease characterized by subnormal GFR. The deviant linear relationship of the latter group suggests that this augmentation of fractional excretion is disproportionate to adaptations of glomerular filtration and renal plasma flow, and is characteristic of failing renal function whether filtration rates are mildly or markedly abnormal. That such a compensation is not unique to the urinary rxcretion of uric acid is demonstrated by evidence of concomitant endogenous creatinine secretion and augmentation of glucose reabsorption by the renal tubules of patients with subnormal glomerular filtration rates. Although this adaptation is therefore nonspecific, it is possibly of importance that such secretory and reabsorptive functions are considered “active,” requiring cellular work. Despite this evidence of adaptation of diverse tubular functions, involving active secretion and reabsorption, the mechanisms responsible for relative enhancement of urinary uric acid excretion are not defined by our data, One alternative is decreased uric acid reabsorption, due either to some direct inhibition of discrete reabsorptive tubular function or indirectly resulting from osmotic forces on the composition of tubular fluid per nephron. Another alternative is an increase of secretion of uric acid at one or more sites within the nephron .2Q,30Conclusive information defining the role of extracellular fluid volume31*32 and of solute competition for common transport mechanism+34 is not yet available. Nevertheless, as renal injury from a variety of diseases affects the kidney, architectural and functional hypertrophy occur. 35 One aspect of this functional hypertrophy is an increase of uric acid excretion per unit nephron, albeit at a higher than normal serum uric acid concentration, a lower absolute rate of clearance, and a larger urate pool. REFERENCES 1. Coombs, F. S., Pecora, L. J., Thorogood, E., Consolazio, W. V., and Talbott, J. H.: Renal function in patients with gout. J. Clin. Invest. 19:525, 1940.
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5. Smith, H. W.: Principles of renal ology. New York, Oxford Universitv 1956, pp 212,213.
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