RENAL FUNCTION IN THE SEPARATE KIDNEYS OF MAN I HEMODYNAMICS AND EXCRETION OF SOLUTE AND WATER IN NORMAL SUBJECTS

RENAL FUNCTION IN THE SEPARATE KIDNEYS

OF MAN. I. HEMODYNAMICS AND EXCRETION

OF SOLUTE AND WATER IN NORMAL

SUBJECTS

William H. Hulet, … , Ervin A. Gombos, Herbert Chasis

J Clin Invest.

1960;

39(2)

:389-394.

https://doi.org/10.1172/JCI104049

.

Research Article

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RENAL FUNCTION IN

THE

SEPARATE

KIDNEYS OF

MAN.

I.

HEMODYNAMICS

AND EXCRETION OF

SOLUTE

AND

WATER IN NORMAL SUBJECTS *

BY WILLIAM H.

HULET,t

DAVID S. BALDWIN, ALBERT W.

BIGGS,j

ERVIN

A.

GOMBOS

t

AND HERBERT CHASIS

(From the Department of Medicine, New York University College of Medicine, and the Third (New York University) MedicalDisision, Bellevue Hospital, New York, N. Y.)

(Submitted for publication July

8, 1959; accepted

October

19,

1959)

We are presenting here an evaluation of the

functional capacity of the separate kidneys in

sub-jects without cardiovascular renal disease, as

back-ground for a similar study of

patients

with essential

hypertension (1).

METHODS

Observations have been made in 17 normotensive sub-jects selected from the wards of the Third (New York University) Medical Division of Bellevue Hospital. In-cluded in this report are observations made on 4 addi-tional subjects reported in aprevious communication (2). The total group comprises 19 female and 2 male sub-jects between the ages of 20 and 68 years. All subjects were maintained on the regular hospital diet. Fluids were withheld for 15 hours and the test was performed in the morning on the fasting patients.

After local anesthesia with 2 per cent metycaine, cystoscopy and ureteral catheterization were performed,

employing

Pederson multi-eyed ureteral catheters in-serted toa distance of 12 to 16 cm. Large diameter ca-theters (no. 8 through no. 6 Fr.) were utilized to mini-mize leakage.1 A soft rubber catheter was placed in the bladder to detect leakage around the ureteral catheters. In none of the observations reported here did meas-urable leakage occur. If leakage does occur, analysis of bladder urine permits partition between the right and left kidneysifthe concentrations ofthe test substances are

*_{Thisinvestigationwas supported in part byfundsfrom}

theAbraham S. Birsh FellowshipFund, the Joseph Laffan Morse Foundation and Grants H-3272 and H-1172 from the National Heart Institute, Bethesda, Md.

t

Research

Fellow,

The American Heart Association.

t

Research

Fellow,

The New York Heart Association. 1In subject J.K. (Table I), it was not possible to pass theright ureteral catheter; therefore,with the left catheter in place, the bladder was used for collection from the right kidney. These conditions are not favorable for reliable collection of urine from the separate kidneys since it is possible that the bladder specimen contains urine that has leaked from thecatheterizedureter. When this manner of urine collection is unavoidable, a small amount of indigo carmine can be injected into the ure-teral catheter in order to detect leakage.

different in the urine from the separate kidneys. The origin of the bladder urine cannot be determined when the concentrations are equal.

All individuals were given 100 mg of sodium pento-barbital intramuscularly 30 minutes prior to cystoscopy. In some instances, the barbiturate was supplemented atthe time of cystoscopybythe administration of 25 to 50 mg of meperidine hydrochloride intravenously or 75 to 100 mg intramuscularly. Surgical sterility was main-tained throughout the procedure.

An

antibiotic,

either streptomycin ortetracycline, was sometimes administered for 24 to 48 hours preceding the test, and an antibiotic was

invariably

administered for 72 hours

following

the test.

Satisfactory

flow

from

both

ureteral catheters

was

usually

attained within 15 to

20 minutes after

catheteri-zation. Timedurine samples were then collected for the determination of basal sodium,

solute

and water excre-tion. After injection of suitable

priming

doses of inulin (IN) and p-aminohippurate (PAH), a sustaining infu-sion of these test substances dissolved in distilled water or in 0.85 per cent sodium chloride was administered at a rateof2 ml per minute.

Urine and

appropriately timed

venous

blood samples

were collected during 1, 2 or 3 periods totaling 30 to 40 minutesforthedetermination of glomerular filtrationrate (CIN), renal plasma flow (CPAHI) and sodium, solute and water excretion. This wasfollowed by determination of the maximal tubular excretory capacity for

p-aminohip-purate (TmPAHR) (3).

Inulin was determined by a modification of Harrison's method (4) and PAH by the method of Smith and associ-ates

(5). Osmolality of plasma

and

urine

was

determined

by means of a thermistor

bridge-null-point-detector

unit, usingaJohlinfreezing pointapparatus (6). Flame pho-tometry employing lithium as an internal standard was used for sodiumdeterminations.

Calculation of derived data. Theper cent contribution of sodium and its attendant anions to the total osmolality of the urine was calculated from the osmotic coefficient of sodium chloride, i (7), for each urine sodium con-centration:

Per cent =

-

X 100,

Uosm

(1)

HULET, BALDWIN, BIGGS, GOMBOS AND CHASIS

equivalents per literofurine, and

Uo.m

is the urine solute concentration in milliosmoles per kilogram of water.2

Excretion fraction (EF) of sodium or total solute is the percentage of the filtered load excreted in the urine:

EFNa = UNaV X

100,

(2)

PNaCIN

EFosm

-

UormV

x 1oo,

(3)

PosmCIN

where V is the urine volume in milliliters per minute, PNa is the sodium concentration in milliequivalents per liter of plasma and Posm and Uosm are the respective plasma and urine solute concentrations in milliosmoles perkilogram of water.

The differences between the right andleftkidneys were calculated by dividingthe difference, A,bythe mean value for the two kidneys, yielding a per cent difference rela-tive to this mean:

A ~~~2A

Per centdifference = X100 or X 100.

(4)

2

The per centdifference, rather than the absolute differ-ence, was chosen because it

permits

comparison of vari-ous functions in the two kidneys at different absolute values of these functions without identifying either kid-ney as normal or abnormal.

It isconventional to define "normality" by recourse to probability theory and the use of parametric statistical analysis (mean + standard deviation), but the para-metric method has the disadvantage that it is applicable only when the frequency distribution curve approaches the symmetrical or Gaussian form. Since this curve is markedly skewed when ananalysis is made of increasing variation between two positive terms, such as differences betweenthe twokidneys,

parametric

analysis yields nega-tive (and

physiologically meaningless)

values at mean ± 2 standard deviations. A mathematicallymore appro-priate analysisisavailableinthenonparametric percentile methodwhich permits analysis of increasing variation be-tween any two

positive

terms until one term becomes zero (8). Therefore, we have used the nonparametric

percentile

method in our

analysis

of the functional dif-ferences between the two

kidneys.

In addition, however, the same data were analyzed by the conventional para-metric method (mean ± standard deviation) (8).

By anymethodof statistical analysis, wholly arbitrary limitsmust be setbeyondwhich "normal" variation passes into the "abnormal,"even whencomparingthe differences

2_{Because urine flow was measured in milliliters per}

minute rather than in grams of water per

minute,

these and later calculations must

neglect

the differencebetween osmolal (i,

Po.m

and

U08m)

and osmolar

(UN.)

concen-trations; at

physiological

concentrations theerror

thereby

introduced is

negligible.

The error

is,

however,

larger

in Equation 3, but maybe

neglected

for our present pur-poses,

especially

since we are

comparing

urine

composi-tion between the two

kidneys.

between the two kidneys of normotensive subjects. Ac-cordingly, we have arbitrarily identified differences be-tween the two kidneys below the top ninetieth percentile group in variation as normal (or for clinical purposes, as identical). Differences above the ninetieth percentile group, i.e., that 10 per cent of the group which shows the greatest per cent differences, are arbitrarily desig-nated as not identical, or abnormal. This exclusion at the ninetieth percentile is statistically comparable to exclu-sion beyond the limits: mean ± 1.6 standard deviations. Rather than use the term "abnormal," however, we will refer to theninetieth percentile group in variation by the noncommital term "disparate," which is to be set against the clinically convenient terms "identical" or "equal."

For describing glomerular filtration rate (GFR), re-nal plasma flow (RPF) and

TmPAH

bilaterally (right plus left or R +L), as well as in all derived ratios, we have used the arithmetic means of these values.

RESULTS AND DISCUSSION

Function in

the

two

kidneys in this series of 21

subjects

is identical, by our arbitrary definition, in

16 individuals.

Tables I and II give the specific

functions

studied and the differences expressed

as

percentages. Table III

gives

the data pertinent to

nonparametric

analysis, the last column showing

the maximal per cent difference at the ninetieth

percentile

cutoff level. Table IV

gives

the

data on

all subjects analyzed by the parametric method.

The

advantage of

setting

arbitrary limits for

identical function on the two sides lies in the fact

that it

invites

detailed

examination

of the

most

highly aberrant values.

It

is

noteworthy

in

this

respect that all

disparities

in

function

beyond

the

ninetieth percentile

levels occur in the same five

subjects.3

In two

of

these five

subjects, C.K.

and

A.D., the left kidney showed

proportionately

greater GFR, and sodium and total solute

excre-tion, suggesting that this left kidney

was

larger

than the

right,

an

interpretation

in

conformity

with known differences in kidney

weight (9, 10).

In

D.E., despite

equal

values

of

V, disparately

small

values

of

UNa

and

Uosm

coincided

with small

values

of GFR, RPF and

TmPAH

on

the

right side,

suggesting

either unilateral

or

bilateral

disease

with

unequal impairment

in

function. In

a

fourth

sub-ject,

J.K.,

UNa

and

Uosm

were

disparately

low

on

the

right

side

although

all

other functions

were

identical.

In

the fifth

subject, M.H.,

a

difference

FUNCTION SEPARATE KIDNEYS OF NORMAL MAN a, VU) UoI W~-o NS 00 0)ZOR I*U) U) 00o o CK 4 -U) 00 00-0 00 0) U_0il co0 in

N'40 C-.-4

14"-U)VV10U)

U).-tt'.N)0

u0000000U) U % 1-0r -0 N (1 U) V N* % 0 U)00U) 0%

V.4 ; 11:-41

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U)nU0 d_tU)

)e

Y)N0%0U)U)

u00NV-0

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+N _ oo Ko 000%00V

4N0et>r^~~~e'. Iq CIt- C!

r0__-CN-N_NN_CN4NG-NN

U)NVV0VV\00C-00%-0b0

t-m oo nu -oWi 0++ )oV C-U)0%)V

mO~00-OU*UNt aU))0_V%UsNN)o 0W)aU -Na Na (40O0-00000U)

NU)Y<NNU)1N'.U)^NN

U)0U a)0 N" '.-C W- o ) N U) N U) U) n N N N N N no -oU)N N

Z~OU) 10%U-0 1-%

t-1)OVVC-.NmV0tC4-.U)VNV00 6_;61: W.) 0otin00C00 U)U)NU) 0000

uli 00001 V- U) U) U) NoV0%00' -OVk C-U)ne .... .. . . . ON V.N.*.. i...0% _OO,COO00000000000>NrsWo00. -000C-0000__000U00>00000,. 0 0 10 10 CU CU 0 L.^ 0 co va co r. 0 2 u ax 0 L. 0 m bo 4 -be w C) w1 4) .-N CU . .-0 t-W Ito 00. I 0 -. Ii} 0 0 '0 0 o cd 0 0 0 Cd 0 CU aCZ, 0 _ _ ~ oU X.@

00s M < @ _ -,_C 04) "C 0) AUt 04) 0 3 II& ;0 Q~ le 0) 80

4

x X 0 O 04

x

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x

_

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X

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.-_s0

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'04

z ₁₄ 4 :Z :5

U)n)U)U)00U)U)11- %'-4

14t-0 C41'V~ 0C t -_.; V V 11 . U) * *1-ON. . *.- N* 0

OR UNU C000NOR 0R N N0

e

o0U)>U)o~0_0ooP*%o4.-CM"qfCsa toz0C4Mmte 00 U) o00 0-0U) 0lo

+0 u)ONqU)u) V0 VW __

oV0% -0 -naa%0% tUCC.MO .-0 ocooO

eros0-"%1-0U% -- 00) 0%0%0n%"W'0%U ll

s-_l lqS "!ll lnSnO-bvt

aN --4a 14w C 0.(b>O

t-00c-a" C0 NN" 1-U)IVtoC0

'0.-0)0N00%00V__N0%V9

000-C4co Noooo__

_0 0o 00 Nt0C

NovnUU)0 -U) U)W ) oU)U)VV U

11-N00N 00 Oner0V 00t-t VU)Ore00U)U)U)V11-UN0N

Nnn rin Li n\oC! Wo S

b0000000 0W+ o. trosolnXlno _

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VV,0It U)0 " U)U)in.n-Cl It NNC u nuv

-w00VU-00Vo-0 0000 M, 00e

ro oNo (,0-4C4so 0o DNo e4-4-4 " 4( 4""C

U) 0UNV* -00-o0 0 N0C)o

-~00VU)Nt-V 00)11V)0.U0U) $0U)V~ 00% N U)- 0000 V" t

. 0 -' VC-U)-- ).000U)U)t .0

0-U)0-bt-.VV.0

00U)U00-". . .~. ~. 0.. U.. . . .* .0. 00U). U * 00011.000000u)000000.. NUV)%O%))0N 0U)11-U) U))0*bVV%0*X).-U. rOOOC-OOO0000U)00000_ -'04

CU0

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¢

H 0 _; 40 x ₄ 4: O4O 04 * 13 -k *t rU 'ts

w oo0) m0) 0.t k4 U)~ 03

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IU A' U 0

O0

CU CU .0 0 07 0g CU 0 CU 0 0 _U (._ 4> .CU-0.0 ~CU U.O -C CU .cU CU, OC CUU CUC U 0 CU

'4

HULET, BALDWIN, BIGGS, GOMBOS AND CHASIS

TABLE III

Per centdifferences infunctions ofthe separate

kidneys

innormal

subjects

*

90th

Range Median Percentile

per cent percent percent

Function n difference difference difference

CIN 21 0.37-21.2 6.36 13.0

CPAH

117

0.32-20.2 5.12 12.1

F.F. X 100 17 0.00-10.6 4.36 8.22

TmpAH

9 2.33-16.5 7.85 10.2

CIN

9 0.99- 7.78 3.78 6.75

TmPAH

CPAH

9 0.64-13.5 2.90 11.1

TMPAHs

V 21 0.00-26.3 3.05 10.3

UN.

17 1.48-26.7 3.70 15.5

UNaV

17 0.00-24.2 5.35 14.4

UO^= 17 0.12-27.0 3.22 16.1

UoumV 17 0.00-24.1 5.72 13.3

UNXi

X 100 17 0.00-10.7 3.16 6.43

uosm

EFN,

X 100 17 1.95-15.9 6.15 11.2

EFosm

X 100 17 0.00-10.8 3.46 7.75

* See Methods sectionforabbreviations.

in

GFR accompanied by identical UNaV and

UosmV

resulted in

disparity

in

_EFN.

and

EFosm.

When

disparities

are

found in

apparently

normal

individuals, these

may represent the

extremes

of

normal

variation,

the inclusion

of

subjects

with

re-nal

disease,

or an

effect of

instrumentation,

i.e.,

re-flex responses

or

partial

obstruction

of

urine

flow

by clots or

edema

of ureteral

mucosa.

TABLE IV

Parametric statistical analysis

of

differences

in

functions of

the separatekidneysin normalsubjects*

Range Mean

per cent percent Standard

Function n difference difference deviation

CIN 21 0.37-21.2 7.59 5.04

CPAH

17 0.32-20.2 6.34 4.94

F.F. X 100 17 0.00-10.6 4.21 3.16

TmPAH

9 2.33-16.5 7.85 3.92

CIN _{9 0.99- 7.78 4.05 2.30}

Tmp. CPAH

TmPAH

9 0.64-13.5 5.16 4.42

V 21 0.00-26.3 5.18 6.16

UNa

17 1.48-26.7 6.99 6.53

UN,V

17 0.00-24.2 7.55 6.14

Uogm

17 0.12-27.0 5.81 7.20

Uosmv 17 0.00-24.1 6.83 5.87

UN.X

X 100 17 0.00-10.7 3.85 3.06

EFN,

X 100 17 1.95-15.9 6.52 4.24

EFoem X100 17 0.00-10.8 4.62 2.91

*_{See Methods sectionforabbreviations.}

Anatomical

studies

of kidney

weight

and

size

and

roentgenographic

measurements indicate that the

two kidneys are

approximately equal, although the

mean values are larger for the left kidney (9, 10).

Our

physiologic

observations agree with these

data in that the average values of

GFR,

RPF,

TmPAH, UNaV

and

Uo.mV

are greater for the left

kidney

than for the

right.4

One consequence of a

consistent

difference

in

function in respect to GFR

and

TmPAH

is

that the

derived values of

GFR/

TmPAH

are

the same on

both sides. Although

most

of

the

individuals

in this

study were females,

the

available evidence (9, 10) indicates that the

rela-tive

magnitude of difference in size and function

between

the two kidneys is similar in the two sexes.

Our

bilateral measurements

(calculated

as

R +

L)

for

GFR

agree with

the

reported average for

females determined by bladder catheterization

(R + L, 114; bladder, 109 ml per minute) (3).

Our lower RPF

(R

+

L,

524;

bladder,

592

ml per

minute) and increased filtration fraction (21.7 as

calculated

for

each kidney; bladder, 19.4

per

cent)

may be attributable to reaction from cystoscopy and

ureteral

catheterization, even though the time from

first

manipulation to urine collection was in all

instances over 60 minutes, or to discomfort from

the prolonged recumbent

position.

Hix

(11)

has

demonstrated that

unilateral

trauma

to the

exteriorized

ureters in

dogs

results

in unilateral and

ipsilateral reduction in GFR and

RPF.

We

have noted that within a few minutes

after

catheterization the urine flow was occasionally

reduced and remained so for five to ten minutes.

This usually

occurred at a time when urine flow

was

initially

low and

technical

difficulty

in

ureteral

catheterization

had been encountered.

Differences between the two kidneys in sodium,

solute

and

water

excretion

during hydropenia and

before infusion of test

substances were generally of

the same order as

those

present later in the test

period (Table

V).

In 2

(C.A.,

I.F.) of 13

ob-servations, there were disparities in the basal

ex-cretion of sodium, solute and water which were not

confirmed

during

the

infusion of inulin and PAH

in

saline or water

administered at a rate of

2

ml

per

minute.

It is

possible

that

these

disparities

are

4GFR, R=55.6, L=58.1 ml per minute; RPF, R=

256, L=_{268 ml per minute;}

TmPAH,

_R=_43.0, L=_45.0

mg per minute;

UNav,

R=_{0.12, L}=_{0.13 mEq per} min-ute;

Uo.mV,

R=_0.42, L=_{0.44 mOsm per minute.}

FUNCTION IN SEPARATE KIDNEYS OF NORMAL MAN'

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the result

of

a

temporary reflex disturbance

or an

error in urine collection.

Our data

indicate,

how-ever, that gross

changes

in

hemodynamic

function

do not occur in normal

man

following

ureteral

catheterization.

SUMMARY AND CONCLUSIONS

1.

Observations

were made on

the

functional

ca-pacity of the separate

kidneys

in 21

subjects

free

of cardiovascular

renal

disease.

2. Hemodynamics, maximal tubular excretory

capacity for p-aminohippurate,

and

sodium, solute

and water excretion of the separate kidneys in

nor-mal man are

comparable.

Functional

differences

in

excess

of

15

per cent are abnormal on the basis of

the

present

observations.

Disparities

of function

in apparently normal individuals probably

repre-sent extremes of normal variation

or

unidentified

renal

disease.

3. The

functional data

confirm the

anatomic

ob-servations of the

predominance

of the left kidney.

4.

Ureteral catheterization

does

not

induce

gross

renal

hemodynamic

changes in normal man. The

relative differences

between the two

kidneys in

re-spect to sodium, solute and water excretion are not

altered

by the infusion

of inulin and

p-aminohip-purate administered at 2

ml

per

minute.

REFERENCES

1. Baldwin,D. S., Hulet, W. H., Biggs, A. W., Gombos, E. A., and Chasis, H. Renal function in the sepa-rate kidneys of man. II. Hemodynamics and ex-cretion of solute and water in essential hyperten-sion. J. clin. Invest. 1960, 39, 000.

2. Chasis, H., and Redish, J. Effective renal blood flow in the separate kidneys of subjects with es-sential

hypertension.

J. clin. Invest. 1941, 20, 655. 3.

Smith,

H. W. Principles of Renal Physiology.

New York, Oxford University Press, 1956. 4.

Goldring,

W., and Chasis, H. Hypertension and

Hy-pertensive

Disease. New York, Commonwealth Fund, 1944.

5. Smith, H. W., Finkelstein, N., Aliminosa, L., Craw-ford, B., and Graber, M. The renal clearances of substitutedhippuricacid derivatives and other aro-matic acids in dog and man. J. clin. Invest.

_1945,

24, 388.

6. Johlin, J. M. The freezing point determination of physiologicalsolutions. The usual errors and their elimination. J. biol. Chem. 1931,91, 551.

7. Hall, R. E., and Sherrill, M. S. Freezing-point

HULET, BALDWIN, BIGGS, GOMBOS AND CHASIS

lowerings ofaqueoussolutions in National Research

Council, International Critical Tables, E. W. Wash-burn, Ed. New York, McGraw-Hill, 1928, p. 254. 8. Snedecor, G. W. Statistical Methods Applied to

Experiments in Agriculture and Biology, 5th ed. Ames, The Iowa State College Press, 1956. 9. DeLeon, W., Garcia, A., and Dejesus, P. I. Normal

weights of visceral organs in adult Filipinos.

Philippine J. Sci. 1933, 52, 111.

10. Moell, H. Size of normal kidneys. Acta radiol. (Stockh.) 1956, 46, 640.

11. Hix, E. L. Uretero-renal reflex facilitating renal vasoconstrictor responses to emotional stress. Amer. J. Physiol. 1958, 192, 191.