Hemodynamic Changes Following Renal Transplantation

THE JOLRNAL OF l°'ROLOGY

Vol. 09, ::V1:is }'tinted 'in

Copyright.@ 1068 by The Willrams & Wilkins Co,

CHANGES l 1'0LLOWING RENAL ALicN B. RETIK,* NOR)1IA::-;f K HOLLE:;\!BEHG, STANLEY M. ROSE;\J, .J. HARTWELL HARRISON, .JOHX P. MERRILL A>ID JOSEPH E. I\IUlUlAY From the Departrnent of Surgery, Division of Urology and the Departrnent of Medicine, Peter Brnt Hriuhmn Hospital ancl Harrnrcl Jfeclical School, IJoston, Jfassachusells .,

Although increasing clinical successes han, been recorded in renal transplant recipients, 1 - 4 a lark of understanding of the basic mechanisms in graft rejection ~till exists. Hemodynamic studies several investigators have shown renal allograft rejection to be accompanied by a progressi\-e decrease in total renal blood flow. 5 · 6 In this , serial measurements of the intrarenal distribution of blood flow ha\-e shown cortical isr'.hemia to occur early in the rejection process. 7 ·8 Accepted for publication Aug1rnt 15, 1967. Read at annual meeting of American Associa .. tion of Genito-l'rinary Surgeons, Rye, New York, May 24-26, 1967. SL1pported in part from the Avalon Foundation, the John Hartford Foundation, United States Public Health 8ervice Grants 1-F'.{HE-30, 063-01. 1-F3-HE1:3-45-80l, AI 04606, 458Cl, The Atomic Energy Commission, The Win .. throp Laboratories and the Cnited States Army Medical Research and Development Command (DA-49-193-MD-2497). * Present address: Department of Surgery, Division of Urology, New England Medical Center Hospita.Js, Boston, MassachLtsetts, 1 flume, D. l\L, Lee, IL M. Williams, G. M., White, IL ,J, 0., :Ferre, J., J, S., Prout, G, R., Jr., Slapak, M,, O'Brien, , Kilpatrick, S. J., Kauffmann, H. ]\L, Jr and Cleveland, lL .J,: Comparative results of cadaver and related donor renaJ homografts in man, and immunologic implications of the outcome of second and paired transplants, Ann. Surg., 164: 352, Hl66, 2 ,L E,, Merrill, J, P, Harrison, ,J. H,, E. and lh,mmin, J,: Prolonged of human kidney homografts by immunosuppressive drug therapy. New Engl, .L Med., 269: ;i, 1963. 3 Il'Iurray, J, E., Wilson, R. E. and O'Connor, N. E,: Evaluation of long-functioning human kidney transplants, Surg,, Gynec, & Obst,, 124: 509, 1967

Straffon, R, A,, Hewitt, C, R, Kiser, W, S,, B, H,, Nakamotu, S. and Kolff, W, J.: experience with the use of 70 kidneys from for transplantatwn, Surg,, Ciynec, & 123: 48'.1, 1966, "Jackson, B, T, and l\fannick, J, A,: Serial blood flow in first set renal homo transplants under .. going rejection, Surg., Uynec, & Obst,, 119: 1265 1964. 6 Kountz, S. L., Williams, ]\I, A., WilliamR, P. L, Kapros, C, and Dempster, W, .J,: Mechanism of rejection of homutnrnsplanted kidneys, 199: 257, HlG3, S. M,, Retik, A. B, Hollenberg, N, K., Merrill, .J, and Murray, J, Effect of immunosuppres,sivc therapy on the intrnrenal distribution 4

The preseHt study compares total blood flow ancl its intrnrcnal distribution in th(: rejecting alkgraftecl clog kidney. MATERIALS AJ\iD METffODR

Healthy mo11grel dogs were usecl for the AJl animals were bilaterally llcphrnctomized ar, the time of renal transplantation, which performed by anastomosing the renal arter31 encl-to.encl to the common iliac artery, the renal vein to the common iliac vein, the ureter implanted into the bladder. During the vascuhir anastomoses, 500 cc 5 per cent dextrose in saline was rapidly infu~cd intravenously iu all Four donor animab recrived similar i11fusionH prior to transplantation. At the time of tranc. plantation, a small polyvinyl catheter 9 was im planted in the common iliac arterv distal to thn aortic bifurcation and secured in place (fig. 1) The catheter was brought to the rxterior a lateral abdominal ~tab wound and tunneled subcutaneously to emerge at the posterior axil lary line, Cathetern were irrigated daily with l rni. heparin sodium t (1,000 FS, P. units per mL), each experiment, anesthe~ia wa, induced and maintained with pc11toharbital sodium ia just sufficient to Sllppress the conjunctiva! refie\ or prevent spontaneous activity, In donor animals, total renal blood flow and mean arkrial blood pressure were measnred on the day of tramiplantation. In recipient,, tota.! RBF and its intrarenal clistrilmtion, nwan arterial blood presrnre and blood urea nitrogen 1yere measured and repeated serially at interval:, of 2 to 3 da~'s until either .severe renal insnfiiciency occurrncl, tlw clog died or experiments we1e; terrni11atccl in auto12rafts, Renal a

of blood flow in dog renal allograft rejection, 8urg, Forum, 17: 23:1, HJGG, 8 Truniger, B., Rosen, S, IvL, ,J, P, and l\!Inrray, J. E,: fotrnrcna.l blood flow in the rejeeting hornotrn.nRplantcd do,, kidney. Surg. Fornm, 16: 254, Hl65, 9 Rudolph, A, Ill.,, H.okaw, S. N. and A, C,,: Chronic cathcterizatio11 of tbe renal Technic for sti1dying direct effects of snbstance on kidney function, Proc, Soc, Exper, BioL l\ilmL 93: 323, HJ5G. t The Upjohn Company, Ka.lam,Moo, Michiga11 491

492

RE'l'IK AND ASSOCIATES

. FI?. 1. ~idney transplant prior to restoration of circulat10n. A, polyvinyl catheter. B, flow probe. C, renal artery. D, renal vein. E, ureter.

time of 7 to 10 seconds, represents blood flow to the renal cortex. The remaining components represent flmv to the juxtamedullary zone (CP II), medulla (CP III) and perirenal fat (CP IV). Further analysis permitted the calculation of the fractional distribution of total REF to each of the compartments. In this laboratory, the intrarenal distribution of blood flow in non-transplanted kidneys is as follows: CP I 85 ± 4 per cent standard error (SE), CP II 10 ± 1 per cent SE, CP III 2.5 ± 0.5 per cent SE and CP IV 2.2 ± 0.4 per cent SE. Values obtained in allografted and autografted kidneys on the day of tra.nsplantation do not differ significantly from these figures. 8 • 11 RESULTS

performed at intervals during the study. Sections were fixed in 10 per cent formalin and stained ,Yith periodic acid-Schiff in addition to hematoxylin and eosin. A gated sine wave electromagnetic flow meter* measured total RDF. Probes were removed at the conclusion of the study each day and were replaced at the next experimental run. Frequent in vitro probe calibrations during the experiments were stable. Arterial blood pressure was measured by means of a polyethylene catheter inserted into the carotid or left femoral artery and coupled to a Statham P23A pressure transducer. A Grass polygraph recorded all pressures and total RBF. The intrarenal distribution of blood flow was determined by the method of Thorburn and associates when total RBF was stable. 10 Approximately 200 microcuries of Xe133 in 0.2 to 0.4 ml. normal saline was injected as a bolus through a double-barreled adapter into the previously implanted polyvinyl catheter and followed immediately by a 0.4 ml. saline flush. A scintillation probe with a 2 by 2 inch thalium-activated sodium iodide crystal connected to a digital rate meter and recorder monitored the washout of the gas from the kidney. Analysis of the washout curve revealed 4 exponential components which have been shown by radioautography to correspond to four distinct anatomic compartments both in the normal10 and rejecting dog kidney.8 The most rapid component (CPI), having a half * Statham Instruments Inc. (Model M-4000) ' Los Angeles, California. 10 Thorburn, G.D., Kopald, H. H., Herd, .J. A., Hollenberg, M., O'Morchoe, C. C. C. and Barger A. C.: Intrarenal distribution of nutrient blood flow determined with krypton 86 in the unanesthetized dog. Circulation Res., 13: 290, 1963.

Thirty-three serial studies were performed on 13 transplanted kidneys, 8 allografts and 5 autografts. On the day of trarnplantation, no significant differences were observed between allografts and autografts in any of the parameters examined. Renal ischemic times ranged between 33 and 49 minutes, the average being 40 minutes in both groups. Blood flow and subsequent course did not appear to be related to the duration of anoxia. Following restoration of the renal circulation in most animals, total RDF gradually rose and reached a peak within an hour, which was higher than the pre-transplantation mean flow. Flow then gradually declined and stabilized at a level similar to the value prior to transplantation (fig. 2). With donor hydration, total flow stabilized at a post-transplantation level which was similar to the pre-transplantation peak flow observed after the rapid infusion. The results of the serial studies in autografts and allografts are shown in figure 3. The renal autografts showed no tendency to a significant progressive change in any of the measured parameters including total RBF and its distribution. In allografts, total RBF remained stable and did not decrease until late in the rejection process. However, a significant decrease in cortical blood flow (CPI) was observed earlier in rejection when total RBF was still stable. Associated with a decreased cortical blood flow was a transient elevation of mean arterial blood pressure. 11 Rosen, S. M., Truniger, B., Kriek, H. R., Oken, D. E;, ]\.'[urr!iy, J.E. and Merrill, J.P.: Intrarenal d1stnbut10n of blood flow in normal and autotransplanted dog kidneys. Effect of hemorrhagic hypotension and mannitol. J. Clin. Invest.,

44: 1092, 1965.

HEMODYNAMIC CHANGES FOLLOWING RENAL TRANSPLANTATION ALLOGRIJFTS DONORS

RECIPIENTS

IJ

sc~~~:,~ow

fl

O

STABLE

~

200 TOTAL RENAL 160

'ff ~~-:-----'

MEAN ARTERIAL

160 120

P:E~oiiRE SO mm Hg

40

AUTOGRAFTS 240

_L_L I

TOT AL RENAL 200 8L00D FLOW 160 cc I min 120

BO 40

MEAN

A;~~~~L PRESSURE mm Hg

160 120

80 40

Fm. 2. Mean values for total RBF and arterial blood pressure in all donors and recipients on day of transplantation.

a

The data observed in the allograft in expenn1ent 2 clearly demonstrate these findings As BUN was rising, 4 days post-transplantation, cortical blood flow showed a significant decre.a,w although total RBF was relatively stable. A kidney biopsy revealed marked pPrivascular monocellular infiltration without evidence of anatomic disease of blood vessels (fig. 5, On 6 when BUN was 188 and the kidney markedly enlarged and edematous, cortical flow was markedly reduced although total RBF still the same as on clay 0. A significant elevation of mean arterial blood pressure was alw observc·d on this da>'· A decrease in total RB.F wa~ not observed until the last day of the experiment (day 8) when it precipitously dropped to 10 cc a minute. Xenon washout revealed no evidence of cortical flow. Histologic examination of the ex cised kidney revealed thrombi in cortical blood vessels and fibrinoid necrosis of the wall~ of several arteries and arterioles (fig. ,5, and The mean changes in CP I and II juxtamedullary Z(me) in all experiments in allr,grafts and autograHs are shown in figure fi. Thc alterations observed in autogral't.c; were

~ ALLOGRAFTS

ALLOGRAFT #2

~ • AUTOGRAFTS

MEAN ARTERIAL BLOOD PRESSURE

mm Hg

% OF TOTAL RENAL BLOOD FLOW TO CORTEX

MEAN

200 160 120

ARTERIAL BLOOD PRESSURE

80

mm Hg

240 200 160 120

100 100 % OF TOTAL RENAL 80 BLOOD FLOW 60 TO CORTEX 40

80 60 40 20

20

0

TOTAL RENAL BLOOD FLOW cc

I min.

Ll_

200 160 120 80 40

200

TOTAL RENAL 160 BLOOD FLOW 120 cc /min. 80 40 0

200 160

BUN

mg%

~

240

120 80

200

40 0

I

,,I, .~

2

3 4

5

6

7 8

BUN mg%

9

10

DAYS AFTER TRANSPLANTATION

Fw. 3 Serial changes in BUN, total RB:F, cortical flow and arterial blood pressure in all alloand autografts un da.vs following trans-

160 120 80 40 0

--------~ ... . .\ -----·--

/"". 0

2

4

6

8

DAYS AFTER TRANSPLANTATION

F10. 4_ Post-transplantation graft in experiment 2.

course

494

RETIIZ AND ASSOCIATES

FIG. 5. A, biopsy from renal allograft in experiment 2, 4 days after transplantation shows infiltration of mononuclear cells around normal artery and arteriole in cortex. H & E X225. B, histologic section of allotransplanted kidney in experiment 2 removed 8 days after transplantation. Fibrinoid necrosis of wall of occluded vessel is seen. Parenchyma is densely infiltrated by mononuclear cells. H & E X288.

nificant and not progressive. Hov,ever, as CP I gradually decreased during rejection in allografts, there was an increase in the relative size of CP II. CP I and II were not demonstrable in 2 animals which were studied in very late rejection, with total flows reduced to approximately 10 cc a minute. DISCUSSION

Post-transplantation amuia, reported in patients12, 13 and in animals, 14 · 15 \Yas not observed 12 Murray, J.E. and Harrison, J. H.: Surgical management of fifty patients with kidney trans-

in allografts or autografts in the present investigation. Total RBF and its intrarenal distribution were similar in both groups. plants, including eighteen pairs of twins. Amer. J. Surg., 105: 205, 1963. 13 Starzl, T. E., Marchioro, T. L., Holmes, J. H. and Waddell, W. R.: The incidence, cause, and significance of immediate and delayed oliguria or anuna after human transplantation. Surg., Gynec. & Obst., 118: 819, 1964. 14 Defalco, A. J., Mund th, E. D., Brettschneider L., Jacobson, Y. G. and McClenathan, J.E.: A possible explanation for transplantation anuria. Surg., Gynec. & Obst., 120: 748, 1965. 15 Dempster, W. J.: The annrias following kidney transplantation. Acta med. scand., 148: 91, 1954.

H}JJ\JODYNAI\IIC CHANGES FOLLOWING RENAL TRANSPLANTATIO:,J

AllOGRAFTS '®, COMPARTMENT I O, COMPARTMENT 1I

100-1

z

0

5~

ao

~3 "'o ,_ ...J :':!1 "0

60

D

...JO


40


20

,_"' ~

0

AUTOGRAFTS 100

is

§~ ~~

,c::o ,_ ...J !!!"-

80-

GO

Co ...J 0


z-'

40-

Cl:: LL


,_a:

20

~

0 0

2

4

6

8

DAYS AFTER TRANSPLANTATION

:Fm. G. Mean changes in size of compartments I (cortex) and TI (juxtameclullary zone) during course of all experiments in allografts and auto-

grafts. Total llBF, measured with the electromagnetic flowmeter, clcarnnce methods and renal venous indicator dilution technique,s, has been previously reported to be reduced rm the of transplantation. 5 • 16 · 18 IVfa1:ipulation of the kidney and its major leading to intrarenal vasospasm, has been impliea.ted a3 the cause for this reduetion, which has been as great as GO per cent of the pre-transplantation blood flow. 17 • 18 ·with adequate hydration of the recipients in the current and, in some instances, the donors prior to nephrecton\l'rn and with continuous L., Louis-Bar., D, and Marson,]:,", G. W.: homotransplanLed kidneys grafted on same dog: A functional comparison. Arch. Internat,. PhysioL, 64: 269, 1956. 17 Cohn, JL and KounLz, L.: Relationship of blood flow in the kidney to homogra.ft reaction. Amer. 8urg., 108: 2,15, 19M. JVL :\L: Hemodvnamic~ of renal trnnsJ. Urol., 86: 493, HlGl. J, S., Uulyassy, P. P., Stoney, R, J., Duffy, Braunstein, P.: Protection of the donor kidney during homotransplantation. Arm. Snrg., 164: 398, 19G6.

monitoring of total RBF for several hour~ aHer restoration of renal circulation, a. post-transplan tation reduction of total RRF was not observed. Although an important vascular component in the pathogenesis of renal allograft ha~ been suggested, there is still disagreement re .. garcling the nature of the early vascular lesions or the mechanism by which ischemia is produced Ischemia has been attributed to vascular spasm,"' progressive dissolution of small blood vcsselc followed by blockage of intratubular spaces hy cellular debris,'' vascular endothelial proliferation resulting in thrombosis 21 and fibrinoid necrosi;; of arterial and arteriolar walls. 22 These vascula1 lesions have been considered to result from mi irnmunulogic reaction and have bem1 associated with a progressive decrease in total RBF, measured by the electromagnetic fiowmeter,5 renai. venous flow and l1 31 hippuran clearance. 5 , 2" Om findings show the earl~, functional following allotrnnsplantation to he reual cortical ischemia with a redistribution of blood flow away from the cortex and maintenance of total RBF Cortical ischemia occmTec! at a time when Uw only evidence ol' a vascular abnormality was perivascular monocellular infiltration which did not iirvolve vessel wall or lumen. A reduction ;n total RBF o<·cunecl relatively late in when the animals were already severely 1ll'emic and histologic evidence· of vas<'ular rlisea:se present. The tramicut but siguifi<'ant hyperten . sion obscrn·d with decreased cortical flow ,':n. courages speculation on the relationship b<,tween renin release and C'.Oltical ischemia in allografl rejection, since the rcnin content per glomerular apparatus is much higher in the outer cortex than in the jnxtameclullary zone. 24 The maintenance of total l-UlF with cortical ischemia may be accounted for by the existence of alternate pathways, as postulated 20 years age 20

Dempster, vV. J .. A consideration of the e,wsu

of functional arrest of homotransplanted kid11eyc; Brit. J. UroL, 27: CiG, 1955. 21 Horowitz, R. E., Burrows, L., Paronetto, F and 1Vildstein, W.: Immunocytochernic;d observ,i. tions on canine kidney homogrnfts. :Fed, Proc., 22:: 274, 19G3. 22 Porter, K. A.. , Thomson, \V 1-l., Kenyon, ,J. }L, ]Vlowbray, J. F. aml Peart, Obliterative vascular changes in four humah kidney homotransplants. Brit. Med. J., 2: G:39, l9fi:l. 23 Kountz, fl. L., Laub, D. l:L and Cohn, R." Detecting and treating early renal homotransplant rejection. J.A.M.A., 191: 997, 1965. 24 Peart, vV. 8.: Hen in and hypertension. Ergclrn . Physiol., 50: 409, 1959.

496

RETIK AND ASSOCIATES

by Trueta-Raspall and associates. 25 Thus, the shunting of blood through the juxtamedullary circulation could explain reduced filtration and tubular function despite a normal total flow and absence of glomerular disease on histologic examination. The demonstration, by micro-angiographic techniques, of arteriovenous comrn.unications in renal allograft rejection26 may offer an anatomic explanation for intrarenal shunting. The absence of vascular lesions associated with early cortical ischemia, the rapid reversibility of cortical ischemia with reversal of rejection, as shown in previous studies,7 and the inconstant early structural renal pathology reported in the literature, suggest a functional vasomotor disturbance to be prominent in early rejection. The mechanism producing the increased vasomotor tone is open to conjecture. The prominent perivascular monocellular infiltration with reduced cortical flow suggests the possibility of the elaboration of a humoral substance by some of the cells. The severe renal function alterations observed in the absence of a marked reduction in total RBF resemble the findings in oliguric acute 25 Trueta-Raspall, J., Barclay, A. E., Daniel, P. M., Franklin, K. J. and Prichard, M. M. L.: Studies of the Renal Circulation. Springfield, Illinois: Charles C. Thomas, 1947. 26 Almgard, L. E., Granberg, P-0., Lagergren, C. and Ljungqvist, A.: Arteriovenous anastomoses in the canine renal allografL Nephron, 3: 295,

1966.

renal failure in man27 , 28 in which a primary disturbance of renal vascular tone may be important.29 SUMMARY

Total RBF, measured with an electromagnetic flowmeter, was not reduced on the day of transplantation in canine allografts or autografts under the experimental conditions used, i.e. saline diuresis. Serial measurements of the intrarenal distribution of blood flow, using the xenon washout technique, showed cortical ischemia with redistribution of flow to non-cortical tissue, to· occur early in allograft rejection when total RBF was normal and vascular lesions were not evident on histologic examination. A reduction in total flow resulted from a stepwise elimination of cortical and, later, juxtamedullary tissue and occurred late in rejection when histologic evidence of vascular destruction was apparent. It is suggested that cortical ischemia is an important factor in the pathogenesis of renal allograft rejection. 27 Munck, 0.: Renal Circulation in Acute Renal Failure. Springfield, Illinois: Charles C. Thomas 1958.

'

Reubi, R. C., Gossweiler, N. and Giirtler, R.: Renal circulation in man studied by means of a dye-d~lution method. Circulation, 33: 426, 1966. 29 Fmckh, E. S.: The pathogenesis of uraemia in acute renal failure: Abnormality of intrarenal vascular tone as possible mechanism. Lancet, 2: 28

330, 1962.