Renal alterations in dogs during renal arterial constriction, hemorrhagic hypotension and osmotic diuresis

Renal Alterations in Dogs During Renal Arterial Constriction, Hemorrhagic Hypotension and Osmotic Diuresis G E R A L D P. M U R P H Y , Captain, MC, and J O H N A. G A G N O N , Walter Reed Army Medical Center

The exact nature of the hemodynamic disturbances produced in the kidney by experimental moderate constric~on of the renal arterial vasculature is no~ yet fully understood in terms of the resulting apparent stages of functional alterationsY' ~:~ Current clinical expressions indicate a wide diversity of viewpoints as to pathophysiologic mechanisms of the responsesY, 8 The effects of partial constriction of the renal artery upon glomerular filtration rate (GFR) and solute excretion in different acute experimental procedures have varied. Leaf and others ~° and DelGreco and De Wardene~ found that acute reduction in renal blood flow and G F R generally resulted in the production of a dilute urine: Similar resuits were recorded in man by Levitt and associates. ~2 Utilizing infusions of A D H (antidiuretic hormone) in the dog, Levinsky and co-workers ~ found that acute partial constriction of the renal artery with reduction of G F R by 30 per cent resulted in a urine of increased tonicity. Reductions of G F R more than 30 per cent did not result in urine formation of consistent tonicity. Others ~° have recently found both in acute and in chronic pa~ial renal artery occlusion that the response to the subsequent reduction of G F R could be related to the amount of urine sodium. They further observed that urinary osmolality generally rose when sodium excretion was low (during water diuresis), and fell when sodium excretion was high (during hypotonic

M.S.

saline diuresis). Consistent alterations in urinary tonicity were not obtained, however, in the presence of a chronically reduced G F R . Rapoport and associates TM have also observed in dogs with chronic unilateral renal artery obstructions that diagnostic urinary criteria of renal hypoperfusion were not uniformly reproduced, even during urea-ADH-saline diuresis. The latter test, advocated by Stamey, TM is described as being able to detect a wide range of decreases in renal blood flow which result in phenomena of increased tubular reabsorption of water. This diuretic test is described as producing an increased concentration of P A H and inulin on the afflicted side, and is a diagnostic criterion of renal vascular hypertension. Apparently it has not been possible to relate the alterations in renal morphology from chronic reduction in renal blood flow to alterations in renal function. The elaboration of osmotically concentrated urine in human renal disease states has been described but with inconsistent results.: Newer techniques have also demonstrated that 40 per cent of the normal renal blood flow may persist in acute renal failure. We have performed a series of experiments in dogs to determine the patterns of renal response to acute and chronic partial occlusion of the renal artery and its branches. These responses were examined to determine the presence or absence of a characte6stic renal response to various induced diuretic states. 4' 9

From the Division of Basic Surgical Research, Walter Reed Army Institute of Research, Walter Reed Army Medical Center, Washington, D.C. 20012. Present address of Dr. Murphy: Brady Urological Institute, The Johns Hopkins Hospital, Baltimore, Md. 21205 Submitted for publication June 1 I, 1964. JSR -

Vol. V, No. I -- January 1965

11

12

JSR -

MURPHY AND GAGNON

VoL V, No. 1 -

January 1965

The relationships between functional alterations and the alterations in renal morphology were also examined. A functional pattern of renal response to hemorrhagic hypotension with acute reduction in G F R was also determined and compared with that observed during acute partial renal artery occlusion. TM ~ METHODS Eighteen adult mongrel dogs of both sexes, weighting between 10 and 20 kg., were used. The principles of laboratory animal care as promulgated by the National Society for Medical Research were observed. The animals were anesthetized with veterinary pentobarbital sodium (30 mg./kg.) Operative Procedures. In 10 dogs, for variable periods of 10 to 54 days prior to the acute experiment, the left renal artery and its branches were exposed through a lateral extraperitoneal incision. A stainless steel rod (1.5 mm. in diameter) was tied against the main renal a~erial vessel or one of its branches to the lower pole as described by Rapoport. ~ This resulted in a partial renal arteral constriction. Two dogs were studied immediately prior to and after acute partial constriction of the left renal artery. Two other dogs were studied without manipulation of the renal artery during prolonged hemorrhagic hypotension at a preselected blood pressure, maintained by means of an Einheber-Ciarke bleed-out device attached to a cannula inserted in the left femoral artery. ~ Three dogs were also studied while in a normotensive state, without surgical bleed-out or manipulation of the renal a~ery. In one additional animal renal functions were determined bilaterally during continuous infusions of 20% mannitoI-ADH-saline and 8% urea-ADH-saline directly into the renal arteries via curved no. 22 needles. Renal Functional Measurements. Following the various preparatory procedures the animals were reanesthetized and the left kidney exposed through a midline incision. Following heparinization (2.5-4 mg./kg.) the left renal vein was cannulated for measurement of direct renal blood flow (DRBF) in the manner previously described.~4This D R B F cannula was always inserted beyond the origin of the left ovarian or testicular vein. The preparation utilized in the presence of chronic parial left renal artery constriction

L$i9 "~ gllat~l ~ffoli~

F i g u r e 1. The animal preparation employed to measure direct renal blood flow, renal clearances and extractions in the presence of chronic partial constriction of the main left renal artery or its branch.

is illustrated in Figure 1. A similar preparation was utilized in the normotensive and hypotensive animals with two exceptions: (I) only left urine flows and renal clearances were obtained in these animals; (2) prior surgical occlusion of the left renal artery was not performed. Figure 2 illustrates the double-lumen polyethylene catheter introduced into the ureters at a position just distal to the renal pelvis. These catheters permit efficient and accurate recovery of urine (especially very small volumes) following iwigation with water and air. An additional feature of this type of catheter is that it tends to minimize dead space errors in urine flow measurement (V=ml./ minute). Chemical Determinations. Appropriate plasma concentrations of PAH (2 to 3 rag. per 100 ml.), creatinine and inulin were maintained by continuous sustaining infusion of these substances in normal saline at an average

JSR -- Vol. V, No. I -- January 1965

F i g u r e 2. Specially designed double-lumen polyethylene ureteral catheter which permits accurate urine volume measurement, even at extremely low flow rates.

rate of 1 ml./minute. In some experiments inulin was not infused. Urine collection periods of 20 to 30 minutes were used during control periods, and varied thereafter according to the rate of urine flow. The methods for collection and analysis of creatinine, inulin and PAH samples for clearance determinations have been described previously. '4 Accurate and valid A-V renal extractions (E = -) of PAH are obA tained utilizing these procedures. ~4 R B F was calculated in the usual manner:

RENAL ALTERATIONS IN DOGS

13

Uosm and Posm are the osmotic concentrations of the urine and plasma respectively and V is the urine flow in ml./minute. M e t h o d s of Diuresis Production. Cont/'ol observations were performed while using intravenous 5% dextrose at 1.5 to 3.5 ml./minute to induce a water diuresis. Following this, a priming solution of A D H 5mU/kg. was Nven in the standard manner. ~9 Thereafter the subsequent infusates contained that amount of A D H calculated to provide 5 mU/kg./hour. Following the dextrose, an 8% urea-saline infusion was given at rates of 1.5 to 5 ml./minute for 90 minutes or longer. In the midpoint of this infusion cannulation of the left renal vein for D R B F was performed14except in those animals subjected to hemorrhaNc hypotension. Twenty per cent mannitol-saline infusion was later given at 5 ml./minute for 20 to 60 minutes. After the completio~ of the acute renal functional studies both kidneys were removed prior to sacrifice. Following gross inspection, tissues were placed in 10% neutral-buffered formalin, and later sectioned and stained with hematoxylin and eosin. These specimens were then examined using light microscopy. RESULTS

CpAt|

(RBF

1

x .............. ). EpaH t ~Hct

........

A direct method of G F R determination independent of urine flow rate was also employed in some cases: (GFRDI~DRBF

x 1 - H c t x EjN ).

Plasma and urine sodium concentrations were determined with the aid of a Patwin flame photometer with an internal lithium standard. Plasma and urinary osmolality were determined using a Fiske osometer. Urinary solute-free water removed by the tubules (Tell20) and osmolar clearance (Cos.O ml./ minute) were calculated by the accepted formulae:

U Osm V

; TcH~O

Cos m

Posm

----

Costa --V.

C h r o n i c Left Main Ren al Artery Constriction. A summary of the average renal functional alterations obtained in the various experimental groups during 8% u r e a - A D H saline diuresis is shown ira Table I. Only 2 of these 8 animals produced significantly measurable urine from the afflicted kidney. These same 2 animals had sigmficant extraction ratios and clearance values for creatinine. Similar results in 1 of these 2 animals were observed for inulin. However, 5 of 8 animals had D R B F values over 20 rnl./minute. Of these 8 animals only 3 had extraction values of P A H > . I 0 , in addition to measurable clearances. Two illustrative examples from this group are shown in Figures 3 and 4. It will be noted in Figure 3, despite the apparent absence of a significant urine flow from the left kidney during dextrose infusion (.02 ml./ minute), that this rate rose to .06 ml./minute during urea infusion, and then to .15 ml./ minute during mannitol infusion. Despite these alterations only marginal evidence of G F R is observed as determined by Ecr and Ccr. Figure 4 illustrates one of two animals from this group with less debatable evidence of

0

6

7

.20 15

.39 49

.62 49

1.54 70

15"

16

17

-.07

-

0 -.07 .02 0

0

12

0

0

2

0

0

0

10

l

-

-

158

160

147

163

198

155

158

135

0

0

.53

0

0

.395

.001

.157

99

.62

.22 ,23

14

0 15

1 115

188 .~ •55

.51

"

-

"

.54

3.05

"

2.56

1.45

-

.33/.3,1

-

-

-

.,i7/.46

-

-

.50/.42

-

42

42 .28

.~

215

146

181

190

151

125 .55

.69

.50

(E) Normotension

78

59

.21

.31

.17

.l,t

.30

.32

-

.3l

.27 .26

27

24

18

7

12

9

45

24

-

I1

(I3) Prolonged llemorrhagic tlypotension

128

t30

115

70

68

EpA|I

l*|tct

........ ! .........

Arterial-Renal Venous(Concentration) Arterial

E = Renal Extraction Ratio

l3

10

48

54

13

21

14

31

25

18

8.5/64.5

76.8/65.9

60.6/57.l

* A Dtt not used.

16

14

18.8 57,,t/52.3

15,6 60/65.9

18.5 46.8/44.8

,10/41 15.5 46. 7/51.8

10.2

/3.2 17 53/54.6

13

16.0 32.7/52.5 13,5 14.5/44.5

14.3 43.5/46.4 15.5 22.5/60,0

25.6/53.4 20.6 35. 2,/86.4 13 21.7/42.8

19.0

** Right nephrectomy 3 days beiore.

79%

6,1%

,16%

52%

-

-

-

-

70%

-

-

77%

-

-

Filtra% tion Days Post- lleduc- Body Kidney U Na+ Fraction Renal Artery tion in Wt. Wt. (gin.) L/8 L/II Constriction GFtl ( K g.) L/R

(C) Chronic Segmental Constriction of a Branch of the ?.lain I,eft Renal Artery (>50%) 125 25 130 .71 .82 .34/.26 83 89 .58 ,20 12 160 . 5 5 .70 .45/. 34

II3

-

.55

0

0

.,10 .390

0

.1t6

Filtration Fraction = CCr/CpAII

1.02 24

13

14

-

-

,24 .28

-.03

.t3

,01

.01

RUV=fpA! x

1.18 27

12

-.04

,08

.53

-.03

.45

0

.02

DI1BF = Direct Renal Blood Flow (ml./min.)

.35 99

II

5

18

75

11

40

24

39

31

(B) Acute Left Main Renal Artery Constriction (>50%)

0

0

82

0

0

12

0

15

V = Urine flow ml./mim

• 36 42

1

0

0.4

t0

0

0

5

9

0

0

,33 25

0

.0l

4

3

.12

3

0

1

Mean [!PAIIL/liIUlnJtl L U"~ CCr Cln B.P.

(A) Chronic Left Main Renal Arte~ Constriction (> 50%)

CpAII IIBF DRBF EpAIt ECr Eln

.03

.03

V

2

I

Experiment No.

Table 1. Summaryo/Average Renal Functional Alterations Observed in Various Experimental ConaTtions (During 8% Urea.AOll.Saline Infusions). Values are for Left Side Unless Otherwise Indicated

2-5

2

5

2,5

2

2

2-5

1.5-5

2-5

2

2

2

2.5

2.F~.5

5

I1at e (ml./min.)

infusion

0

O~ t~

,<

!

Z 9

<

g

<

I

Z

X

JSR -- Vol. V, No. I -- January 1965

RENAL

ALTERATIONS

15

IN D O G S

Ren~! F~nctiorl~t o n d H e r { ~ o d y r ~ r n ~ c Cho,r~ges ~n ~he P~esence of ChroniC Left R e n a l Artery Co~'~t~e~io~ ; 4C I-

Left

~-*

R~ght

~ol ~-

",-"-"",--7~

. . . . . . . . . .

.........

~,o Rqh~ ~

....

................l

~°°r

Figure 3. Experiment I, Chronic partial occlusion of the main left renal artery for 18 days. N o t e despite the absence o f measurable C v r o r E c r that there is a rise in urine flow to. 15 ml./minute during mannitol with a wash-out" o f PAH.

~''"~

L - - t

[ ................~ .............

2

F~BF ~ - ~

v

tO -

2.0]

{~[/~ir,,)

20

Reno!

Funct~0n(ll C h o ~ g e s

40

60

w i I ~ CE~rOn~C P o ~ i o [

80

COO

i ............~

,.oo V

140

160

180

200

I- . . . . . .

.°°I

'

..... "

240

260

........ L

i'

.,~o

220

0 c ¢ | u s l o n L e f ! Renal A ~ f e r y

"~°r ~ 0

120

"

r .........

z. . . . ~ . . . . . . . . .

-

1

Ri@h~ Left ~ - ~

20 °° E

Left O~rect ~enot BIO0~ F{O~ DRB~ - - E~A#

HcV

80 60 aO 2

. . . . . . . . R~lht K~ney 52 $~m~ Left K~elr~ey3 2 7gm~.

Ep~H

.63

.62

.53

.,56

,53 . S O

.6~

EC~

.28

.:~9

.24

,29

.26

26

g~

.29

~35

,28

26

.29

,3~ .28

-

-

,23

! C~n~lofe

C~AH (mL1~ n.} Rght

Left ~ - - - - ~

Left

Renot Ve;~

80* 6040 L 20

- ....

I ....

-~". . . .

'I . . . . . . . . . . . .

t~o,~-

_._.Jr

....

I- ....

1.--.r

.....

It-------

V

3~o Minufe$

Figure 4. Experiment 6. Renal functional changes observed 13 days following partial occlusion o f the left renal artery. Note the lack o f relative rise in either T~H20 or urinary tonicity on the left side during the various infusions, despite the measured decrease in G F R o f over 70 per cent.

16

MURPHY

AND

GAGNON

J S R -- VoI. V , N o . I -- January 1965

G F R . Despite this feature the urinary concentrations of inulin, P A H and creatinine do reveal increased values compared to the contralateral control side. This was seen in all 3 animals with measurable urine flow (Table 1, experiments I, 3 and 6). A pattern of increased urinary sodium concentration from the occluded left kidney (Table 1, experiments 3, 6) was also seen. A c u t e Left Main Renal Artery Constriction. One o f the two animals subjected to acute partial occlusion of the left renal artery and studied during this procedure did not produce measurable urine flow (Table I, experiment 9). The other (Table 1, experiment I0) showed alterations comparable to those seen in chronic partial occlusion. Increased concentration of sodium was found in the urine specimen from the occluded left kidney. An increase was not seen in the relative left/right urinary concentration o f P A H or creatinine.

C h r o n i c O c c l u s i o n o f a Branch of the Left Renal Artery. T w o animals (Table 1, experiments I1 and 12) in which a branch of the renal artery to the lower pole was partially occluded showed considerable persistence of renal function as compared to those with acute and chronic constriction of the left main renal artery (Fig. 5). T h e reductions in the urine flow, CpA,, DR,F and G FR were of lesser magnitudes. N o increased (left/right) concentration o f urinary P A H or creatinine was observed. Prolonged Hemorrhagic Hyl)otension. Typical alterations in renal function following periods of hemorrhagic hypotension are shown in T~able 1 (experiments 13, 14) and Figure 6. In the animal shown in Figure 6, the venous/ arterial plasma osmolality changed from a normotensive control value of 290/290 to 297/291, This reversal in V/A osmolar ratio persisted even after infusion of the osmotic

t 40 2O LO0

T~H~ o

~0 40

"

,~0 0 -a(

2.

i

L ......

J

3"20 F Z ~0

Right--

-

),

~ 0 r[.

Cc~

2~

R)gh) . . . . . . :

I2

.

.

.

.

.

~----~__._~'-:-::-~

•

0

~0~ Renol

)20~

B)Oo~ g)Ow}

100}~

(Oi~cl

I

)

80Ii C~a H

)

40

~C~n~ulo~e Lef~ ~e~O~Vei~ C~

|mh/min }

v

Le{) 20

0

60

B0

IOO

120

I~O

t60

~80

200

220

2,~O

~,60

280

30O

320

3,~0

2560

380

aO0

M~nu~e~

Figure 5. Experiment 12. Changes in renal function seen 13 days after occlusion of a branch of the left main renal artery. Note the absence of an increased urinary tonicity of the occluded side compared to the other, despite the decrease in GFR of 46 per cent.

JSR -- Vol. V, No. 1 -- January 1965

RENAL

ALTERATIONS

17

IN D O G S

Reno~ FunctionoI Chcmges Outing Hemo~thogtc HyPotensEon cmd Osmotic O~utesi~,

TCH~O (Cos~--V)

0

.

.

.

.

3.oor 2,50

i"

2.00 I COSM (mb'min. )

,.5oI .oo I

\_ GFR{rnlIm;~,)

60

40 (GF'RoIR,0RBFx EIN~I- HCL| 20 0 ~OO 280

D~rec~ Renol 8100~ FIOw

260 24O 220 EPAH ECR EIN

200

DRBF (mL/m~t~)

IBO

RBF (t~l /m~n,)

160 ~40

EpA~ I-HCL

IO0

"--'~

80 60 40 20

v (ml/traitor)

"E

2,0 i I.O

o~,~

~u

~

=20

i

40

;~

,, ,|

60

'

J

8o

~

eoo

~20

140

i60 i80 Min~e~

2o0

Z20

240

z60

Z80

3OO

3z0

3,~0

Figure 6. Experiment 14. Renal functional alterations following prolonged hemorrhagic hypotension and treatment with osmotic diuretics. N o t e that despite 79 per cent reduction in normotensive G F R the urine remains hypotonic until mannitol infusion,

agents urea and mannitol had been continued for some time. Norrnotensive Osmotic Diuresis. Three animals (Table I, experiments 15, 16, 17) underwent osmotic diuresis while in a normotensive state. Figure 7 depicts a typical response. TCHzO uniformly became negative during mannitol irffusion, reflecting the lack of tubular reabsorption of its molecule. A greater rise in V was always seen during mannitot infusion. Administration of saline or A D H did not alter the renal functional effects of mannitol as previously noted, ~4 Bilateral Infusion of Mannitol and Urea. In a single experiment the comparative effects of 8% u r e a - A D H and 2092b mannitol-ADH solution were compared in terms of urinary tonicity and G F R (Fig. 8). The values shown indicate that, at a wide range of G F R (C~n 12 to 52), urea infusions usually resulted in a

urine of greater tonicity than that following mannitol infusions. Renal Morphologie Alterations. N o significant morphologic alterations were seen in kidneys acutely subjected to normotensive osmotic diuresis or hemorrhagic hypotension. The (right) control kidneys from the 12 animals subjected to p/trtial occlusion of the main left renal artery or a branch were all normal upon microscopic examination except for inconstant, nonsl~ecific interstitial round cell infiltrates. N o consistent alterations were seen in the animals undergoing acute partial occlusion of the main renal artery (Table 1, group B). Of 8 animals with chronic partial occlusion of the left main renal artery only 2 showed areas of normal appearing renal architecture (Table I, experiments 3 and 6, and Fig. 9). Less severe ischemic alterations (Fig. 9, B) characterized by dilated

18

JSR

MURPHY AND GAGNON

Vol. V, No. I -- January 1965

- -

Rerlal Fu~c~'ion O~rin 9 Noemotensive Osmotic O i u r e s i s

,7'0

TCH~O (CO~-- V)

COS~ tmL/~i~3

:

o."'- . . . . . . . . .

÷.so

-

.2 o

.

.

.

_. i

t

.

....

.

I - " ~ ........

.

.

.

.........

"

.

.

.

.

.

;

.

4,01 3,0 2.0 o~

7-'-I

....

i T ......... ...........

Z_

OF R{~LZm~,)

e--.----.Jr ......... ~----'--9

C~N

I

s

300

520

GFR0~R(0RBF'~ EIN~I-HCl} O~'ecl R e n o t

DRB~

~mVmm )

V

(ml/mm,)

20

40

60

80

iOO

120

~40

t60

~80

200

220

240

~60

280

340

Mi~ules

Figure 7. Experiment 17. The renal functional alterations seen during normotensiveosmotic diuresis. Note difference in effect upon T~H~O between urea and mannitol infusions.

tubules, interstitial scarring, round cell filtration, and thickening of' the renal capsule with gross and microscopic evidence of numerous venous and arterial collaterals were also seen (Fig. 9, C, Fig. 10, C). In 6 of the 8 animals in this group (Table 1, group A) the-majority of the renal parenchyma was occupied by ischemic infarctions (Fig, I0, A) with rims of damaged but morphologically recognizable renal tissue (Fig. 10, B) and numerous capsular collateral vessels (Fig. 10, C). In animals (Table 1, group C) with chronic partial occlusion of a branch of the renal artery to the lower pole, comparable but less severe alterations were observed. In the I0 animals with chronic left renal artery constrictions (Table 1, groups A, C) no correlation was seen between the level of mean aortic blood pressure and the amount of renal atrophy. Eleven of 12 animals with

acute and chronic renal artery consnictions (Table I, groups A, B, C) had mean aortic blood pressure values greater than in the 3 normotensive animals. Gross inspection of kidneys with partial occlusions of the main renal artery demonstrated a large number of renal capsular and pelviureteral vessels. N o relationship was observed between the size and number of collateral vessels and the duration of pa~ial occlusion of the main renal artery. DISCUSSION Acute and chronic severe reductions in G F R have been tested functionally in various diuretic states. These alterations in G F R were induced by a wide variety of means, viz., hemorrhage, major renal arterial partial

JSR -

Vol. V, No. I -

January 1965

RENAL

ALTERATIONS

IN DOGS

19

Changes in Urine Concentration During Urea and M a n n i t o t - A D H Diuresis in Relation to GFR " 2,2Z,O t.8 1.6 0

tA "E 0

0

L2

0

l.O E 0.8 During 8% Ureo--ADH and 2 0 % Bilateral Renal Arterial Infusions

0,6 o

Mannitol ADH

Post Infusion Controls

OA 0,2 J

I

0.2

0.4

................d

0,6

,,

I

0.8

..... 1.0

I 1,2

! ~ .4

~ t .6

Clnulin

f t,8

,

,o| . . . . . . . . . . . . . . . . . . . . . . . 2.0

-

Ureo/Monnilol

F i g u r e 8. Experiment 18. T h e comparative effects on urine tonicity between urea and mannitol infusions are shown. Th es e results were obtained in a single animal during simultaneous bilateral renal arterial infusions at 1.0 mL/minute.

constriction and minor renal arterial partial occlusion, In all instances, in the presence and absence of morphologic damage to the kidney and in the presence of systemic hypertension we failed to observe an increase in urinary tonicity. Only in hemorrhagic hypotension following infusions of 8% urea-saline and 20% mannitol-saline, in the presence of A D H , did the tonicity of the urine increase relative to the normotensive control. The urinary concentrations of PAH, inulin or creatinine also were not increased on the afflicted side in those animals with renal artery constrictions with measurable urine flow during water, urea or mannitol diuresis. However, in the remaining tubules functioning in these severely altered kidneys (Table I, groups A, B, D, Fig. 11), it was found that in terms of the more distal tubular functions little detectable difference between these and normotensive renal tubules can be shown. These values support the intact nephron hypothesis of Bricker and associates~ who find similar data to document the essential integrity of the concentration and

dilution processes in the persisting nephrons of a diseased kidney. The pattern of urinary sodium concentration in those animals with measurable urine flow and severe chronic and acute reductions in G F R is more a diseased nephron pattern, rather than an ischemic oneP It therefore would appear that in the presence of acute and chronic reduction of G F R (>-46%) by renal artery occlusion a diseased rather than an ischemic nephron functional pattern is produced. We have also shown morphologically and by direct measurement in the presence of chronic partial occlusion of the main renal artery that considerable renal blood flow can be derived from capsular-pelvic and ureteral collateral vessels. This blood flow is not preglomerular under these experimental conditions and does not appear to be of any functional benefit to the renal mass, as evidenced by the lack of urine flow, G F R , and significant extraction of PAH, creatinine or inulin in 6 of 8 animals (Table I, group A). Renal morphologic alterations in the pres-

Figure 9. Dog B no. 379. Experiment 3. 31 days after main renal artery constriction. Left kidney 21.7 gin. Right kidney 42.8 gin. C~.r 3 ml./minute. E~.r 13. C~A, 3 mlJminute. EpAH .45. avg. DRBF 24 ml./minute, left V .12 mlJminute, all during urea-ADH-saline infusion. A. Area of normally appearing conical renal tissue. (H&E: x 140.) B. Area of chronic tubular dilatation, interstitial scarring and round cell infiltration. Note thickening of capsule and small collateral arteriole found therein. (H&E; x 140.) C. Area of ischemic infarction with calcifications seen in two glomeruli. (H&E; x I40.)

Figure I0. Dog C385. Experiment 4. Fourteen days after left main renal artery occlusion. Left kidney 43.5 gin. Right kidney 46.4 gin. Avg. DRBF 40 m!./ minute, C~.r Zero, C~.a, 0.4 ml./minute, left V .01 mlJ minute all during urea-ADH-saline infusion. A, Widespread ischemic infarction. (H&E; × 100.) B, Small remnant of recognizable glome~alar and tubular tissue. Note hyalinization and interstitial scarring. (H&E; x I00.) C, A collateral capsular vein. (H&E: x t00.)

20

JSR -

RENAL ALTERATIONS

Vol. V, No. I -- January 1965

CONCENTRATING VALUE OF RENAL TUBULES EXPRESSED AS RATIO OF SOLUTE-FREE WATER ABSTRACTED ~ER IOOml OF GLOMER~L&R FilTRATE IO0 90 80

It" ~0 ~0 O

-

~

I

t.

. . . . . . . . . . . . . . . .

fie e~3l Att#~¥

*

~*~ry

(8~ ~0 m m H ~ {N* ~ |

leigure 1 I. A comparison of the similarities in renal concentrating and diluting capacities observed in the various experimental states.

ence of chronically reduced renal blood flow varied greatly in degree. The progression of degenerative changes, howe-~er, indicates a vascular origin rather than an infectious one. a T h e data obtained in the presence of hemorrhagic hypotension support the observations of Selkurt ~7 that there is a wash-out of the osmolar constituents of the kidney with a loss of concentrating power. H o w e v e r , as shown, at the same hypotensive pressure infusion of 8% urea-saline or 20% mannitol-saline will eventually restore this gradient, which apparently exists in the renal papillary zone of h y p e r o s m o l a r i t y ) r Despite the wash-out of this osmolar gradient, at the reduced G F R an increase in urinary tonicity can still be prod u c e d during urea or mannitol diuresis. This ability to raise the urinary mnicity at a controlled low blood pressure and r e d u c e d G F R (64 to 79% of normotensive controls) contrasts sharply with the results obtained during acute and chronic occlusion of the renal artery with similar reductions in G F R (46 to 77%) and similar infusions of urea or mannitol. T h e reasons for this difference are not apparent. T h e animals with renal artery constrictions all had higher blood pressures and were not hypovolemic. It is possible that hormonal alterations or renal vascular or neural reactivity could be determinants. T h e ability of mannitol to produce a greater increase in urine volume c o m p a r e d to urea, in the present experiments and in others, ~4 supports the observations of Rabelo and associates. I'~ T h e ability of urea to produce a greater

IN ~GS

21

increase in uriiaary tonicity than mannitol at a wide range of G F R values (12 to 52 ml./ minute) has been shown (Fig. 8). T h e inability of urea infusion to demonstrate a relative rise in urine tonicity at G F R values (Table 1, group A, experiment 6) in chronic renal artery constriction similar to those seen in other acute experiments (Fig. 8) indicates that lack of sutficient renal urea concentration cannot be evoked as an obvious cause for the failure. W e believe this failure to be related rather to the combination of the chronicity and severity of the renal morphologic changes and the secondary alterations in G F R and renal blood flow. It is doubtful that at such severe limits the diseased nephron can produce such a p h e n o m e n o n of increased urinary tonicity. Such findings could possibly explain the inconsistencies in valid split function tests in some clinical situations of hypertension and severe renal damage due to chronic and severe renal arterial occlusion.

SUMMARY AND CONCLUSIONS Patterns of renal functional alterations have been determined in dogs with acute and chronic pa~ial occlusion of the main renal artery and its branches. Additional experiments conducted in norrnotension and h e m o r r h a ~ c hypotension have c o m p a r e d alterations in renal blood flow, G F R and renal concentrating ability with those o b s e r v e d during pa~ial arterial occlusion of the kidney. T h e s e acute and chronic renal functional alterations w e r e studied both during water diuresis and during osmotic diuresis. Correlations were made between the gross, and microscopic renal morphologic changes and renal function in the various experimental conditions. T h e s e various .results indicate that acute and chronic reductions in G F R ( > 4 6 % ) induced by renal arterial occlusion in "the dog are not associated with p h e n o m e n a of increased water reabsorption and increased urinary concentrations of P A H , creatinine or inulin, even during u r e a - A D H - s a l i n e diuresis. REFERENCES I. Baldwin, D. S., Berman, H. J., Heinemarm, H. O., and Smith, H, W.: T h e elaboration of osmotically c o n c e n t ~ t e d urine in renal disease. J. Clin. Invest., 34:800, 1955.

22

JSR -

M U R P H Y AND G A G N O N

2. BirchalL R., Batson, H, M., and Brannan, W.: Contribution of differential renal studies to the diagnosis of renal arterial hypertension with emph~is on the value of U sodium/U creatinine. Am. J. Med., 32: 164. 1962. 3. Breslau, A. M., Gonick, H. C., Sommers, S. C.. and Guze. L. B.: Pathogenesis of chronic pyetonephritis. Am. J. Path., 44:679, 1964. 4. Bricker, N. S., Dewey, R. C.. Lubowitz, H., Stokes. J_ and Kirkensgaard, T.: Observations on the concentrating and diluting mechanisms of the diseased kidney. J. Clin, Invest., 38:516, 1959, 5. DelGreco, F . and DeWardener, H- E.: The effect on urine osmolarity of a transient reduction in glomerular'filtration rate and solute output during a water diuresis. J, Physiol., 131:307, 1956. 6, Einheber, A., and Clarke, R. W= Blood pressure stabilizing device and blood reservoir for inducing hemorrhagic hypotension. J. Appl. Physiol., I1: 493, 1957. 7. Goldblatt, H.: Hypertension of renal origin, historical and experimental background. Am. J, Surg.. 107:21 1964. 8. Howard, J. E.: Hypertension as related to renal ischemia. Circulation, 29:657, 1964. 9. Lauler, D, P~ and Harrison, J. H.: Ureteral catheterization measurements in renal hypertension. Am. J, Surg, 107:67, 1964. 10. LeaL A.. Kerr. W. S,, Wrong, O., and Chatillon, J. Y.: Effect of graded compression of the renal artery on water and solute excretion. Am. J. PhysioL, 179:191, 1954. 1I. Levinsky~ N. G.. Davidson, D. G., and Berliner, R. W.: Effects of reduced glomerular filtration on urine concentration in the presence of antidiuretie horome~ J. Clin, Invest.. 38:730, 1959. 12, Levitt, M. F., Levy. M. S., and Polimeros. D.: The effect of a fall in filtration rate on solute and water

13, 14, 15.

16.

17. 18.

19. 20.

21.

VoL V, No. 1 - January 1965

excretion in hydropenic man, J. Clin. Invest,, 38: 463, 1959, Mueller, C, B., Surtshin, A., Carlin, M, R., and White, H. L.: Giomerular and tubular influences on sodium and water excretion, Am. J. PhysioL, 165:411, 195t. Murphy, G. P., Gagnon. J, A., and Teschan. P, E.: Measurement of renal function in hemorrha~c hyl~tension: Effect of mannitoL J. UroL, 90:133, 1963. Rabela, A . Litwin, M. S.~ Brady, M. P., and Moore, F. D.: A comparison of the effects of several osmotic diuretic agents after acute hemorrhage in the dog. Surg.. Gynec. & Obst., 115:657, 1962, RapoporL A., Wilson, D. R , Ranking, G. N.. White, L. W., and Rudd, W. W,: Separate renal function studies on dogs with chronic unilateral renal artery obstruction. Canad. J. Biochem. & Physiol., 41:2273, 1963. Selkurt, E. E.: Osmolar and free water clearance during hemorrhagic shock in the dog. Proc. Soc. Exper. Biol. & Med.. l I t:626, 1962. Shaldon, S.. Higgs, B., Chiandussi~ L,. Walker, G., Garsenstein, M., and Ryder, J.: Measurement of renal blood flow in man with the use of indocyanine green infused into the renal artery. J. Lab. & Clin. Med., 60:954. 1962, Stamey. T, A.: The diagnosis of curable unilateral renal hypertension by ureteral catheterization. Postgrad. Med.. 29:496, 1961. VanGiesen, G.~ Reese, M., Kil, F , Rector, F. C.. and Seldin, D. W.: The characteristics of renal hypoperfusion in dogs with acute and chronic reductions in glomerular filtration rate as disclosed by the paltern of water and solute excretion ~ffter h y p o t o n i c saline infusions. J. Clin. Invest., 43:416, 1964. Walker, J. G., Silva, H , Lawson, T. R., Ryder, J. A., and Shaldon, S.: Renal blood flow in acute renal frdlure measu~d by renal arterial infusion of indocyanine green. Proc. Soc. Exper. Biol. & Med., 112:932. I963,