Scand J Urol Nephrol 13: 291-298, 1979
RENOVASCULAR HYPERTENSION AFTER KIDNEY TRANSPLANTATION
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P. Klarskov, L. Brendstrup. T . Krarup, H . E. Jorgensen, M. Egeblad and J . P a l b ~ l From t h r ) University qf’Copenlrcrgen, Deptirtrnrnt of Neplrrology B trnd Deptrrttnc~ntof’ Uro1og.v H . Herlev Hospitul. tind the Depurtnient of‘ Rudiology. Glostrup Hospitul, Copenhugerr, Denrntirk
(Submitted for publication April 8, 1978)
The development of hypertension after kidney transplantation was examined in a consecutive series of 83 transplantations (79 patients) with a graft survival of more than 30 days. After transplantation, 50% of the normotensive recipients developed mild or severe hypertension, while 74 % of the hypertensive recipients remained hypertensive. Stenosis of the graft artery with a narrowing of the diameter of more than 50% was found in 13 patients and in 3 patients a minor or peripheral stenosis was found. Significantly more stenoses were seen in the presence of two donor arteries, whereas no other etiological factors could be shown. In arterial stenosis, severe hypertension was established within a few months after transplantation. but in spite of satisfactory controlled blood pressure and good graft function, hypertensive crises could arise. It is therefore concluded that arteriography and renin analysis should be considered in all cases of severe hypertension, and surgical correction should be considered when arterial stenosis is present.
Absfrucr.
Patients receiving a renal allograft are susceptible t o
a number of acute and chronic complications. Among these the development of arterial hypertension seems to b e found rather frequently. T h e present study was undertaken t o investigate the frequency of newly developed or increased arterial hypertension in a consecutive series of renal allograft recipients. T h e main interest, however, was focused on the occurrence of graft arterial stenosis in post-transplant hypertension, as these patients usually present a major therapeutic problem, though they can b e offered a cure (Lacombe, 1975; Henriksson, Aurell, Claes, Nilson, Thoren & Gelin, 1976; Osborn, Castro & Shackman, 1976).
MATERIAL During a 5-year period (1970 to 1975) 100 patients received I19 renal allografts. The study includes those 83 trans-
plantations in which the graft survival exceeded 30 days. 81 gratis were cadaver kidneys. The age of the donors varied from 5 to 62 years. The distribution of age and sex of the recipients is shown in Fig. I , and the various types of arterial anastomoses used, in Table I l l . Prednisone treatment was carried out according to a fixed scedule, gradually reducing the initial dose of 200 mg to 20 mg per day during the first 3 months and to 10 mg after one year. In cases of suspected acute rejection, methylprednisolone 30 mg per kg body weight was infused daily for up to 5 days. Azathioprin (Imurelm)was administered 100 mg a day and guided by the white blood cell count.
METHODS Mmsurutnent of’ blood prrwurc’
The pre-transplantation blood pressure (BP) was expressed as the average of several measurements before and after haemodialysis during the last month before transplantation. In a few non-dialysed patients the average of several BP measurements was used. The post-transplantation BP was calculated as the average of several BP measurements before graftectomy, reanastomosis, death or the deadline of the study (December 1975). However, BP during exceptional conditions, e.g. the agony, were not taken into consideration. Clirs.s[fi’cution Using the individual limits of normotension and hypertension of Master, Garfield & Walters (1952) the patients were classified as normotensive. mildly hypertensive and severely hypertensive according to the mean BP and the hypotensive medication (Fig. 2). Severe hypertension was defined as a mean BP beyond the individual hypertension limit despite hypotensive medication apart from diuretics alone. As hypotensive medication, methyldopum, hydralazin, propranololi chloridum and alprenololi chloridum were used, alone or in combination.
292
P . Klurskov et ul.
NUMBER OF TRANS- 25
4
mm Hg
+
30
20
f
15
= 42
+
10
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+ 20 10
5
LIMIT OF HYPERTENSIOI NUMBER OF ARTERIAL STENOSIS 1 0 - 1 9 20-29 30.39 4 0 - 4 9 5 0 - 5 9 M)-69
AGE IN
YEARS
Fig. 1 . Sex and age at transplantation in the total material and in patients with graft arterial stenosis (below). Range 17-60 years.
LIMIT OF NORMOTENSIO
- 10
- 20
Investigations
Renography and clearance determinations were performed routinely after the transplantation. Intravenous urography. graft arteriography, graft biopsy and plasma renin measurements were done individually when indicated. In non-nephrectomized recipients, vein catheterization was used to determine the renin source. All arteriograms were re-evaluated blind by two of the authors ( M E & JP). A diagnosis of severe graft arterial stenosis was made when the diameter of the artery was reduced by at least 50%.
RESULTS The BP measurements before and after the transplantation are recorded in Table 1. It appears that before transplantation 52 (63 %) patients were normotensive, 24 (29%) had a mild hypertension and 7 (8 %) a severe hypertension. After the transplantation these figures had changed into 34 (41%), 33 (40%) and 16 ( 1 9 % respectively. ~ At the 3-month follow-up SO % of the patients were hypertensive. In Fig. 2 the BP level and hypotensive treatment of each patient after the transplantation is shown in relation to the individual limits of normotension and hypertension of Master e t al. (1952). The group of 16 patients classified as severely hypertensive is illustrated clearly in the diagram. The graft function was equally good in normotensive and mildly hypertensive recipients but had a tendency to be reduced in the severely hypertensive patients (Fig. 3).
- 30 - 40 - 50 mm Hg NO HYPO- DIURE1 2 3 TENSlVE TICS NUMBER OF HYPOTENDRUGS SlVE DRUGS
Fig. 2. Mean arterial blood pressure and hypotensive treatment after transplantation in relation to the individual limits of hypertension and normotension. (Calculated for the actual age and sex from Master et a!.. 1952). B, Normotension; 0,Mild hypertension; R , Severe hypertension; 0 , No evidence of stenosis; Minor or peripheral stenosis; Severe graft arterial stenosis.
.,
*,
Fig. 4 shows that the graft survival was equal in normotensive and hypertensive patients. The figure also shows the time at which severe hypertension was established in the 16 patients, in whom arterial stenosis was later shown to have developed. Twelve of these patients were normotensive before the transplantation. It appears that severe hyper-
R c n o\'(I F C I I In r hy p ert t>n,s io ti u ft cr L idti t~y trtr n spltr n ttr t ion
DIALYSIS
.to
SERUM CREATl NI N E MG per L
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50 6o
t
1 I
...... .. .
Table 11. Prirnury Primary renal disease
.
.
Total
t
. ....
. .
r i ~ t i discltrsc. ~l
Arterial stenosis
Total number
Histologically verified
27 IS
1
30 35 6 8 4
16
83
58
Glomerulonephritis Interstitial nephritis Polycystic kidney Nephrosclerosis Other diagnosis
8
2 93
6 5 I 3
4 8 4
tension was usually established within a few months after the transplantation. Graft arteriography was performed in 36 patients. A diagnosis of central graft arterial stenosis with a narrowing of the diameter of more than 50% was made in 13 patients, and minor or peripheral
stenoses were found in another 3 patients. Thus a diagnosis of arterial stenosis could be made in 44 95 of the investigated patients. The stenoses were found mainly in the group of patients classified as severely hypertensive (Fig. 2 ) . The age and sex of the patients with graft artery stenosis did not differ from the group of transplanted patients as a whole (Fig. I ) . N o correlation between the development of post-transplant renovascular hypertension and the age or sex of the donor, the warm or cold ischaemic time, the immunological matching or the occurrence of pretransplant hypertension and arteriosclerosis of the iliac vessels was found. The arterial lesions were found with equal frequency among the patients irrespective of their primary renal disease (Table 11). The type of arterial anastomosis used at the transplantation operation and the subsequent development of graft arterial stenosis is given in Table 111. In 70 transplantations the donor kidney had one artery which in 61 of the cases was anastomosed end-to-end to the internal iliac artery. Seven of these 70 patients (10%) developed a severe stenosis, while 3 had a minor one. Six out of 13
Table I . Normntension und hypertension hcforcl and after transplantation.
Table 111. Typc~c~funustomosis
-
-
o J SEVERE HYPERTENSIVE
NORMOTENS IV E
MILD HYPERTENSIVE Fig. 3. Serum creatinine and hypertension. 0 , No eviMinor or peripheral graft arterial dence of stenosis; stenosis; a,Severe graft arterial stenosis.
e,
The classification principles are given in Fig. 2 After transplantation Hypertensive Before transplantation
Normotensive
Mild
Norrnotensive ( n = S 2 )
26
17
9
7
4
1
13 3
34
33
16
Hypertensive mild ( n =24) severe ( n = 7 ) Total, 83
Severe
3
- _ , End-to-end; -1, End-to-side; >--, Two donor arteries anastomosed to one lumen; =/,Two donor arteries anastomosed separately or with aortapatch
Arterial stenosis
Type of anastomosis
Total number
-_
61 9 7 6
8 2
70 13
10 6
-I >=I --
>-
+ -1
+ =I
4 2
294 GRAFT S U R V I V A L PER CENT
2 2
100
I
90
Scand J Urol Nephrol Downloaded from informahealthcare.com by Chinese University of Hong Kong on 12/27/14 For personal use only.
80 70.
60 2
/I
50
LO 30 1 1
1
1 3
I
I
I
6
12
2.5
36
48
MONTH
60
*
m, Severe graft arterial
Fig. 4 . Graft survival and onset of severe hypertension. A, Normotension; 0 , Hypertension; Minor or
peripheral graft arterial stenosis; stenosis.
(46%) receiving a graft with t w o arteries developed a severe stenosis of o n e o r both arteries. This difference is statistically significant ( P < O . O I ) suggesting that stenosis is more likely t o develop when the graft has t w o arteries, whether the arteries a r e
chronic glomerulonephritis was bilaterally nephrectomized because of hypertension. A transient decrease in BP followed, but later symptoms suspicious of chronic rejection developed, resulting in treatment with methylprednisolone. Hypertension persisted, and 34 years after transplantation a central graft arterial stenosis was shown in an arteriogram, and renin in the peripheral blood was raised to 220 pGU/ml. Reanastomosis was performed, a diaphragm-like stenosis at the site of anastomosis being resected. The graft function improved somewhat, but the effect on the hypertension was insignificant. After another 24 years a sudden hypertensive crisis developed with BP of 190/140, encephalopathy and retinal exsudation. Renin was 234 pGU/ml and arteriography revealed a new graft arterial stenosis (Fig. 5). Again the stenosis was resected and reanastomosis performed. The course was completely uneventful, BP normalized immediately and renin decreased to normal. The patient was still normotensive with an excellent graft function 1 year later.
+,
united into o n e lumen o r anastornosed separately. Different methods in handling the post-transplant hypertension d u e t o graft arterial stenosis were employed. Resection of the stenosis and reanastomosis w a s d o n e successfully in case 44, and in case 4 after the second reoperation (see case reports). Graftectomy w a s d o n e in 7 patients and the remainder received medical treatment. S e v e n patients have died, three have been retransplanted, 2 have returned t o haemodialysis, 3 have a satisfactory BP on hypotensive medication and o n e is normotensive following the second reoperation.
CASE R E P O R T S Case 4 ( H . C . M . ) Seven m o n t h s after an otherwise successful kidney transplantation a 22-year-old normotensive recipient with
Cuscj 15 ( A . R . ) A 45-year-old kidney graft recipient with nephrosclerosis and malignant hypertension had a normal graft function postoperatively. During the following 10 months the creatinin clearance gradually decreased and hypertension persisted. Antirejection treatment with methylprednisolone was given but the BP was unaffected, and 3 months later bilateral nephrectomy was performed. No
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ing hypertension after an otherwise successful kidney transplantation. Vein catheterization showed a high renin gradient over her own kidneys and no gradient over the graft. Bilateral nephrectomy was performed, followed by a transient reduction in the hypertension. Three years later the patient unexpectedly developed a hypertensive crisis with pulmonary oedema. The graft function had deteriorated. Arteriography showed several stenoses of the graft artery. The patient died from an acute myocardial infarction. Autopsy was not performed.
DISCUSSION
Fig. 5 . Arteriography before the second reanastomosis
operation showing end-to-end anastomosis to the hypogastric artery and a short stenosis at the anastomosis site and normal peripheral vessels (Case 4).
effect on the hypertension was noted. Two years later the condition had worsened seriously. BP was 200/120. Renography showed no graft function. arteriography showed no filling of the graft artery and the graft was removed on suspicion of a severe rejection. A few days later the patient died of acute myocardial infarction and acute pancreatitis. Investigation of the removed graft showed a very narrow stenosis at the site of anastomosis and no histological or immunopathological evidence of rejection. CNW 44 ( L . L . )
A normotensive 17-year-old female with chronic reflux nephropathy was treated for acute rejection after the transplantation and obtained a good graft function. During the following 10 months she developed a severe hypertension. Arteriography showed a central stenosis of the graft artery and peripheral renin was 457 pGU/ml. The stenosis was resected and reanastomosis performed leading to a normalization of renin and BP. However, hypertension reappeared, and 4 years after the transplantation the graft function suddenly ceased, accompanied by an instant normalization of the BP. It was believed that a total occlusion of a preexisting arterial stenosis had occurred, resulting in an “autograftectomy”, and the graft was removed. The graft was pale, and the arteries in the hilum had a normal pulse. Microscopy of the graft showed typical rejection. CUSP51 ( J . B . H . )
A 38-year-old woman with medullary sponge kidneys, nephrosclerosis and malignant hypertension had persist-
Arterial hypertension is often recognized in patients with chronic uremia (Coles, Crosby, Jones, Jones & McVeigh, 1973; Maxwell & Weidmann, 1974; Rao, Gupta, Butt, Sharma, Kountz & Friedman, 1976). Usually, in severe refractory hypertension, the pathogenetic factor is production of vasoconstrictors in the diseased kidneys. Renin measurements may be diagnostic in these patients, and nephrectomy prior to kidney allotransplantation is advisable (Weidman. Maxwell, Lupu, Lewin & Massry, 1971; Guyton, Coleman, Cowly, Liard, Manning & Norman, 1974; Maxwell & Weidmann, 1974). In terminal uremia, however, salt and water retention due to dietary breaks o r insufficient dialysis is the dominant cause of hypertension (Weidmann et al., 1971). After the transplantations, in this series, hypertension disappeared o r regressed in one-third of the preoperatively hypertensive patients, while it appeared o r worsened in another third (Table I). Half of the patients were hypertensive 3 months after the transplantation and 5 9 % by the deadline for the study. Accordingly Bachy, Alexandre & van Yppersele de Strihou (1976) found the frequency of post-transplant hypertension to increase to about 60% during the first 3 months. Various factors have been discussed as possibly etiological factors in post-transplant hypertension, i.e. acute or chronic rejection (Bachy et al., 1976), the presence of the patients own diseased kidneys (Cohen, 1973), the possible conversion of immunosuppressive steroids into an aldosterone-like rnineralocorticoid (Sampson, Kirdani, Sandberg & Murphy, 1973) and decreased blood flow through the graft due to arterial stenosis (Bennett, McDonald, Lawson & Porter, 1974; Lacombe, 1975). Both the function and the survival (Fig. 4) of the grafts compared well to the other reports (Lund, Thaysen, Ladefoged & Nerstram, 1976) and were not correlated to the level of the blood pressure. In
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296
P . Klurskov et al.
contrast Bachy et al. (1976) found the prognosis of the graft to be worse in patients with hypertension. Like Coles et al. (1972), Cohen (1973) and Bachy et al. (1976) we could not demonstrate the correlation between the level of hypertension and the dosis of prednisone reported by Sampson et al. (1973). Like other authors (Bachy et al., 1976; Rao et al., 1976) we have arbitrarily defined a group of patients with severe hypertension, among whom the patients with graft arterial stenosis are to be found (Fig. 2 ) . The graft function may remain satisfactory and the hypertension be well controlled for a long period of time, but the course is unpredictable. Deterioration of the graft function and general condition, hypertensive encephalopathy and cardiovascular crisis may suddenly develop (Cases 4 and 51 ; Nerstram, Ladefoged & Lund, 1972; Rice, Levin, Jennings & Ivanovich, 1976). Furthermore the clinical picture of graft arterial stenosis is easily confused with that of rejection (Cases IS and 44; Simmons, Tallent, Kjellstrand & Najarian, 1970; Schrameck, Better, Adler, Tuma, Hashmonai, Barzilai & Chaimowitch, 1975). In those patients, who later proved to have developed arterial stenosis, severe hypertension was present within weeks or few months of the transplantation operation (Fig. 4). The graft arterial stenosis may therefore be diagnosed at an early time before critical complications develop, preferably by an arteriography (Vinik, Smellie, Freed, Hume & Weidner. 1969; Nilson, Henriksson & Thoren, 1976; Osborn et al., 1976). The level of plasma renin may be elevated in arterial stenosis as well as in rejection, but the evaluation is often difficult, as the administration of hypotensive drugs influences the renin measurements (Giese, Jorgensen, Nielsen, Lund & Munck, 1970; Bennett et al., 1974). In some cases renin analyses performed on samples obtained during vein catheterization may be of great help in determining whether the renin source is the graft or the patient’s own diseased kidneys (Case 5 1 ; Coles et al., 1972; Cohen, 1973; Bennett et al., 1974). Graft biopsies may be valuable in the differential diagnosis between rejection and arterial stenosis, as these conditions may be present simultaneously (Case 44). Renography and urography, however, are of minor importance in this context, because of the lack of a coupled organ for comparison (Giese, Mogensen & Munck, 1975). In a prospective study Lacombe (1975) found 23% of kidney graft recipients to develop graft arterial stenosis, but not all Sconrl J iirol Nephrol
/3
were hypertensive. About half of this frequency was noted in another prospective series (Nilson et al., 1976). Our present retrospective material shows an incidence of severe arterial stenosis of 27% among hypertensive recipients and an overall incidence of 1 1 5%. Other retrospective studies report an overall stenosis incidence of l-lO% (Nerstrem et al., 1972; Margules, Beltzer & Kountz, 1973). An incorrect surgical technique usually results in short stenoses at the site of the arterial anastomosis and is apparently the main aetiological factor (Smellie, Vinik & Hume, 1969; Vinik et al., 1969; Morris, Yadav, Kincaid-Smith, Anderton, Hare, Johnson, Johnson & Marshall, 1971; Frodin, Thorarinsson & Willen, 1975; Smith & Ehrlich, 1976). Accordingly we found more stenoses to develop in grafts with two arteries (Table 111) requiring a more elaborate surgical technique. Bewich, Ogg, Parsons, Trafford & Goggin (1976) reported stenoses to develop 10 times more often after end-to-end anastomosis than after all other types of anastomosis, whereas in Morris et al. (1971) the end-to-side anastomoses were dominant. Another main aetiological factor is rejection, usually resulting in long peripheral stenoses (Morris et al. 1971; Kaufman, Ehrlich & Dornfeld, 1976; Nilson et al., 1976). No significance of pre-existing arteriosclerosis, the nature of primary kidney disease, sex, age, immunological matching or the ischaemic time of the graft for the development of graft arterial stenosis has ever been demonstrated. Surgical treatment of renovascular hypertension is improving and the long-term results seem to be best in young patients with an early diagnosis and treatment (Shapiro, Perez-Stable, Scheib, Bron, Moutsos, Berg & Misage, 1969; Hunt & Strong, 1973; Maiz, Safar, Weiss, Ayed & Milliez, 1977). Also in renal transplant recipients with hypertension due to stenosis of the graft artery, the results of reconstructive vascular surgery are encouraging, a cure rate or improvement of more than 50% being reported (Lee, Linehan, Pierce & Hume, 1972; Nerstram et al., 1972; Sterioff, Zachary &Williams, 1974; Lacombe, 1975; Henriksson et al., 1976; Osborn, 1976). In our material the vascular reconstruction was successful after 2 of the 3 operations (Cases 4 and 44). We therefore conclude that in patients with a new, severe hypertension or persisting severe hypertension after kidney allotransplantation, the possibility of a graFt arterial stenosis should always
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Rtviovascular hypertension b e considered. In order t o avoid the danger of hypertensive crises this diagnosis should b e settled as early as possible by graft arteriography and renin analyses. Also, when a renal graft recipient presents with severe symptoms indicative of rejection the possibility of graft arterial stenosis should b e considered and arteriography performed. Once the arterial stenosis is diagnosed the possibility of reanastomosis should b e considered, especially in the younger group of recipients.
REFERENCES Bachy, C., Alexandre, G. P. J. & van Ypersele de Strihou, C. 1976. Hypertension after renal transplantation. Br Med J i i , 1287. Bennett, W . M., McDonald, W. J., Lawson, R. K. & Porter, G. A. 1974. Posttransplant hypertension: Studies of cortical blood flow and the renal pressor system. Kidney Internat 6 , 99. Bewick, M.. Ogg, C. S . , Parsons, V., Trafford, J. P. & Goggin, M. 1976. The type of arterial anastomosis used in renal transplantation and subsequent complications. In Proc Eur Dial Transplant Assoc (ed. B. H. B. Robinson), vol. 13, p. 192. Pitman Medical, U. K . Cohen, S . L. 1973. Hypertension in renal transplant recipients: Role of bilateral nephrectomy. Br Med J iii, 78. Coles, G. A , , Crosby, D. L., Jones, G. R., Jones, J . H. & McVeigh, S. 1972. Hypertension following cadaveric renal transplantation. Postgrad Med J 48, 399. Frodin, L., Thorarinsson, H. & Willen, R. 1975. Preanastomotic arterial stenosis in renal transplant recipients. Scand J Urol N e p h r o l 9 , 66. Giese, J., Jorgensen, M., Nielsen, M. D., Lund, J. 0. & Munck, 0. Plasma renin concentration measured by use of radioimmunoassay for angiotensin. I . 1970. Scand J Clin L a b Invest 26, 355. Giese, J., Mogensen, P. & Munck, 0. 1975. Diagnostic value of renography for detection of unilateral renal or renovascular disease in hypertensive patients. Scand J Clin L a b Invest 35, 307. Guyton, A. C . , Coleman, T. G . , Cowley, A. W . , Liard, J. F., Manning, R. D. & Norman, R. A. 1974. InProc5th Int Congr Nephrol (ed. H. Villarreal), pp. 74-80. S. Kager, Basle, Switzerland. Henriksson, C., Aurell, M., Claes, G . , Nilson, A. E . , Thoren, 0. & Gelin, L. E. 1976. Surgical correction of artery stenosis in renal transplants. Scand J Urol Nephrol, Suppl. 38, 139. Hunt, J. C. & Strong, C. G. 1973. Renovascular hypertension. Mechanisms, natural history and treatment. A m J Cardiol32, 562. Kaufman, J. J., Ehrlich, R. M. & Dornfeld, L. 1976. Immunologic considerations in renovascular hypertension. J U r o l 1 1 6 , 142. Lacombe, M. 1975. Arterial stenosis complicating renal allotransplantation in man: A study of 38 cases. Ann Surg 181, 283. 20-192923
uftrr kidney transplantation
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Lee, H. M., Linehan, D., Pierce, J. & Hume, D. 1972. Renal artery stenosis and gastrointestinal hemorrhage in human renal transplantation. Transplant Proc 4 , 681. Lund, F., Thaysen, J. H., Ladefoged, J. & Nerstrnm, B. 1976. Long term survival and graft function after cadaveric kidney transplantation. Acta Chir Scand 472, 9. Maiz, H. B., Safar, M., Weiss, Y . , Ayed, H. B. & Milliez, P. 1977. Renovascular hypertension: The role of nonspecific factors in the antihypertensive effect of surgery. Clin Nephrol 7, 26. Margules, R. M., Belzer, F. 0. & Kountz, S . L. 1973. Surgical correction of renovascular hypertension following renal allotransplantation. Arch Surg 106, 13. Master, A. M., Garfield, C. I. & Walters, M. B. 1952. Norma1 Blood Pressure and Hypertension, pp. 1 4 4 . Lea & Febiger, Philadelphia. Maxwell, M. H. & Weidrnann, P. 1974. Hypertension in chronic bilateral renal disease. In Proc 5th Znt Congr Nephrol (ed. H. Villarreal), pp. 6&73. S. Kager, Basle, Switzerland. Morris, P. J . , Yadav, R. V. S., Kincaid-Smith, P., Anderton, J., Hare, W. S. C., Johnson, N., Johnson, W. & Marshall, V. C. 1971. Renal artery stenosis in renal transplantation. Med J Australia I , 1255. Nerstrnm, B., Ladefoged, J. & Lund, F. 1972. Vascular complications in 155 consecutive kidney transplantations. Scand J Urol N e p h r o l 6 , 65. Nilson, A. E., Henriksson, C. & Thoren, 0. 1976. Angiographic diagnosis and follow-up of artery stenosis in renal transplantation. Scand J Urol Nephrol, Suppl. 38, 131. Osborn, D. E., Castro, J . E. & Shackman, R. 1976. Surgical correction of arterial stenosis in renal allografts. Br J U r o l 4 8 , 221. Rao, T. K. S . , Gupta, S . K., Butt, K. M. H., Sharma, H. S. D., Kountz, S. L. & Friedman, E. A. 1976. Relationship of renal transplantation to hypertension in chronic renal failure. Kidney Internat 10, 609. Rice, L. E., Levin, M. L., Jennings, R. B. & Ivanovich, P. 1976. Intractable renovascular hypertension in an adult recipient of a pediatric cadaveric renal transplant. Nephron 17, 279. Sampson, D., Kirdani, R. Y., Sandberg, A. A. & Murphy, G . P. 1973. The aetiology of hypertension after renal transplantation in man. B r J Surg 60, 819. Schramek, A., Better, 0. S . , Adler, 0.. Tuma, S . , Hashmonai, M., Barzilai, A. & Chairnowitz, C. 1975. Hypertensive crisis, erythrocytosis and uraernia due to renal-artery stenosis of kidney transplants. Lancet i, 70. Shapiro, A. P., Perez-Stable, E., Scheib, E. T., Bron, K., Moutsos, S . E., Berg, G. & Misage, J. R. 1969. Renal artery stenosis and hypertension. Observations on current status of therapy from a study of 115 patients. Arner J M e d 4 7 , 175. Simmons, R. L., Tallent, M. B., Kjellstrand, C. M. & Najarian, J. S. 1970. Renal allograft rejection simulated by arterial stenosis. Surgery 68, 800. Srnellie, W. A. B., Vinik, M. & Hume, D. M. 1969. Angiographic investigation of hypertension complicating Scond J Uvol Nrplrrol 13
298
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ril.
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human renal transplantation. Surg Gynec, Ohstel 128. 963. Smith, R. B. & Ehrlich, R. M. 1976. The surgical complications of renal transplantation. U r o l Clin N Amer 3. 621. Sterioff, S . , Zachary, J . B. &Williams, G . M. 1974. Dacron vascular grafts in renal transplant patients. Amer J Surg 127. 525.
Vinik, M., Srnellie, W. A. B., Freed, T. A ,, Hurne, D. M. & Weidner, W. A. 1969. Angiographic evaluation of the human homotransplant kidney. Radiology 92, 873. Weidrnann, P., Maxwell, M . H., Lupu, A . N., Lewin, A . J . & Massry, S . G . 1971. Plasma renin activity and blood pressure in terminal renal failure. Neii, Engl J M e d 285, 757.
RENOVASCULAR HYPERTENSION AFTER KIDNEY TRANSPLANTATION
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P. Klarskov, L. Brendstrup. T . Krarup, H . E. Jorgensen, M. Egeblad and J . P a l b ~ l From t h r ) University qf’Copenlrcrgen, Deptirtrnrnt of Neplrrology B trnd Deptrrttnc~ntof’ Uro1og.v H . Herlev Hospitul. tind the Depurtnient of‘ Rudiology. Glostrup Hospitul, Copenhugerr, Denrntirk
(Submitted for publication April 8, 1978)
The development of hypertension after kidney transplantation was examined in a consecutive series of 83 transplantations (79 patients) with a graft survival of more than 30 days. After transplantation, 50% of the normotensive recipients developed mild or severe hypertension, while 74 % of the hypertensive recipients remained hypertensive. Stenosis of the graft artery with a narrowing of the diameter of more than 50% was found in 13 patients and in 3 patients a minor or peripheral stenosis was found. Significantly more stenoses were seen in the presence of two donor arteries, whereas no other etiological factors could be shown. In arterial stenosis, severe hypertension was established within a few months after transplantation. but in spite of satisfactory controlled blood pressure and good graft function, hypertensive crises could arise. It is therefore concluded that arteriography and renin analysis should be considered in all cases of severe hypertension, and surgical correction should be considered when arterial stenosis is present.
Absfrucr.
Patients receiving a renal allograft are susceptible t o
a number of acute and chronic complications. Among these the development of arterial hypertension seems to b e found rather frequently. T h e present study was undertaken t o investigate the frequency of newly developed or increased arterial hypertension in a consecutive series of renal allograft recipients. T h e main interest, however, was focused on the occurrence of graft arterial stenosis in post-transplant hypertension, as these patients usually present a major therapeutic problem, though they can b e offered a cure (Lacombe, 1975; Henriksson, Aurell, Claes, Nilson, Thoren & Gelin, 1976; Osborn, Castro & Shackman, 1976).
MATERIAL During a 5-year period (1970 to 1975) 100 patients received I19 renal allografts. The study includes those 83 trans-
plantations in which the graft survival exceeded 30 days. 81 gratis were cadaver kidneys. The age of the donors varied from 5 to 62 years. The distribution of age and sex of the recipients is shown in Fig. I , and the various types of arterial anastomoses used, in Table I l l . Prednisone treatment was carried out according to a fixed scedule, gradually reducing the initial dose of 200 mg to 20 mg per day during the first 3 months and to 10 mg after one year. In cases of suspected acute rejection, methylprednisolone 30 mg per kg body weight was infused daily for up to 5 days. Azathioprin (Imurelm)was administered 100 mg a day and guided by the white blood cell count.
METHODS Mmsurutnent of’ blood prrwurc’
The pre-transplantation blood pressure (BP) was expressed as the average of several measurements before and after haemodialysis during the last month before transplantation. In a few non-dialysed patients the average of several BP measurements was used. The post-transplantation BP was calculated as the average of several BP measurements before graftectomy, reanastomosis, death or the deadline of the study (December 1975). However, BP during exceptional conditions, e.g. the agony, were not taken into consideration. Clirs.s[fi’cution Using the individual limits of normotension and hypertension of Master, Garfield & Walters (1952) the patients were classified as normotensive. mildly hypertensive and severely hypertensive according to the mean BP and the hypotensive medication (Fig. 2). Severe hypertension was defined as a mean BP beyond the individual hypertension limit despite hypotensive medication apart from diuretics alone. As hypotensive medication, methyldopum, hydralazin, propranololi chloridum and alprenololi chloridum were used, alone or in combination.
292
P . Klurskov et ul.
NUMBER OF TRANS- 25
4
mm Hg
+
30
20
f
15
= 42
+
10
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+ 20 10
5
LIMIT OF HYPERTENSIOI NUMBER OF ARTERIAL STENOSIS 1 0 - 1 9 20-29 30.39 4 0 - 4 9 5 0 - 5 9 M)-69
AGE IN
YEARS
Fig. 1 . Sex and age at transplantation in the total material and in patients with graft arterial stenosis (below). Range 17-60 years.
LIMIT OF NORMOTENSIO
- 10
- 20
Investigations
Renography and clearance determinations were performed routinely after the transplantation. Intravenous urography. graft arteriography, graft biopsy and plasma renin measurements were done individually when indicated. In non-nephrectomized recipients, vein catheterization was used to determine the renin source. All arteriograms were re-evaluated blind by two of the authors ( M E & JP). A diagnosis of severe graft arterial stenosis was made when the diameter of the artery was reduced by at least 50%.
RESULTS The BP measurements before and after the transplantation are recorded in Table 1. It appears that before transplantation 52 (63 %) patients were normotensive, 24 (29%) had a mild hypertension and 7 (8 %) a severe hypertension. After the transplantation these figures had changed into 34 (41%), 33 (40%) and 16 ( 1 9 % respectively. ~ At the 3-month follow-up SO % of the patients were hypertensive. In Fig. 2 the BP level and hypotensive treatment of each patient after the transplantation is shown in relation to the individual limits of normotension and hypertension of Master e t al. (1952). The group of 16 patients classified as severely hypertensive is illustrated clearly in the diagram. The graft function was equally good in normotensive and mildly hypertensive recipients but had a tendency to be reduced in the severely hypertensive patients (Fig. 3).
- 30 - 40 - 50 mm Hg NO HYPO- DIURE1 2 3 TENSlVE TICS NUMBER OF HYPOTENDRUGS SlVE DRUGS
Fig. 2. Mean arterial blood pressure and hypotensive treatment after transplantation in relation to the individual limits of hypertension and normotension. (Calculated for the actual age and sex from Master et a!.. 1952). B, Normotension; 0,Mild hypertension; R , Severe hypertension; 0 , No evidence of stenosis; Minor or peripheral stenosis; Severe graft arterial stenosis.
.,
*,
Fig. 4 shows that the graft survival was equal in normotensive and hypertensive patients. The figure also shows the time at which severe hypertension was established in the 16 patients, in whom arterial stenosis was later shown to have developed. Twelve of these patients were normotensive before the transplantation. It appears that severe hyper-
R c n o\'(I F C I I In r hy p ert t>n,s io ti u ft cr L idti t~y trtr n spltr n ttr t ion
DIALYSIS
.to
SERUM CREATl NI N E MG per L
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50 6o
t
1 I
...... .. .
Table 11. Prirnury Primary renal disease
.
.
Total
t
. ....
. .
r i ~ t i discltrsc. ~l
Arterial stenosis
Total number
Histologically verified
27 IS
1
30 35 6 8 4
16
83
58
Glomerulonephritis Interstitial nephritis Polycystic kidney Nephrosclerosis Other diagnosis
8
2 93
6 5 I 3
4 8 4
tension was usually established within a few months after the transplantation. Graft arteriography was performed in 36 patients. A diagnosis of central graft arterial stenosis with a narrowing of the diameter of more than 50% was made in 13 patients, and minor or peripheral
stenoses were found in another 3 patients. Thus a diagnosis of arterial stenosis could be made in 44 95 of the investigated patients. The stenoses were found mainly in the group of patients classified as severely hypertensive (Fig. 2 ) . The age and sex of the patients with graft artery stenosis did not differ from the group of transplanted patients as a whole (Fig. I ) . N o correlation between the development of post-transplant renovascular hypertension and the age or sex of the donor, the warm or cold ischaemic time, the immunological matching or the occurrence of pretransplant hypertension and arteriosclerosis of the iliac vessels was found. The arterial lesions were found with equal frequency among the patients irrespective of their primary renal disease (Table 11). The type of arterial anastomosis used at the transplantation operation and the subsequent development of graft arterial stenosis is given in Table 111. In 70 transplantations the donor kidney had one artery which in 61 of the cases was anastomosed end-to-end to the internal iliac artery. Seven of these 70 patients (10%) developed a severe stenosis, while 3 had a minor one. Six out of 13
Table I . Normntension und hypertension hcforcl and after transplantation.
Table 111. Typc~c~funustomosis
-
-
o J SEVERE HYPERTENSIVE
NORMOTENS IV E
MILD HYPERTENSIVE Fig. 3. Serum creatinine and hypertension. 0 , No eviMinor or peripheral graft arterial dence of stenosis; stenosis; a,Severe graft arterial stenosis.
e,
The classification principles are given in Fig. 2 After transplantation Hypertensive Before transplantation
Normotensive
Mild
Norrnotensive ( n = S 2 )
26
17
9
7
4
1
13 3
34
33
16
Hypertensive mild ( n =24) severe ( n = 7 ) Total, 83
Severe
3
- _ , End-to-end; -1, End-to-side; >--, Two donor arteries anastomosed to one lumen; =/,Two donor arteries anastomosed separately or with aortapatch
Arterial stenosis
Type of anastomosis
Total number
-_
61 9 7 6
8 2
70 13
10 6
-I >=I --
>-
+ -1
+ =I
4 2
294 GRAFT S U R V I V A L PER CENT
2 2
100
I
90
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80 70.
60 2
/I
50
LO 30 1 1
1
1 3
I
I
I
6
12
2.5
36
48
MONTH
60
*
m, Severe graft arterial
Fig. 4 . Graft survival and onset of severe hypertension. A, Normotension; 0 , Hypertension; Minor or
peripheral graft arterial stenosis; stenosis.
(46%) receiving a graft with t w o arteries developed a severe stenosis of o n e o r both arteries. This difference is statistically significant ( P < O . O I ) suggesting that stenosis is more likely t o develop when the graft has t w o arteries, whether the arteries a r e
chronic glomerulonephritis was bilaterally nephrectomized because of hypertension. A transient decrease in BP followed, but later symptoms suspicious of chronic rejection developed, resulting in treatment with methylprednisolone. Hypertension persisted, and 34 years after transplantation a central graft arterial stenosis was shown in an arteriogram, and renin in the peripheral blood was raised to 220 pGU/ml. Reanastomosis was performed, a diaphragm-like stenosis at the site of anastomosis being resected. The graft function improved somewhat, but the effect on the hypertension was insignificant. After another 24 years a sudden hypertensive crisis developed with BP of 190/140, encephalopathy and retinal exsudation. Renin was 234 pGU/ml and arteriography revealed a new graft arterial stenosis (Fig. 5). Again the stenosis was resected and reanastomosis performed. The course was completely uneventful, BP normalized immediately and renin decreased to normal. The patient was still normotensive with an excellent graft function 1 year later.
+,
united into o n e lumen o r anastornosed separately. Different methods in handling the post-transplant hypertension d u e t o graft arterial stenosis were employed. Resection of the stenosis and reanastomosis w a s d o n e successfully in case 44, and in case 4 after the second reoperation (see case reports). Graftectomy w a s d o n e in 7 patients and the remainder received medical treatment. S e v e n patients have died, three have been retransplanted, 2 have returned t o haemodialysis, 3 have a satisfactory BP on hypotensive medication and o n e is normotensive following the second reoperation.
CASE R E P O R T S Case 4 ( H . C . M . ) Seven m o n t h s after an otherwise successful kidney transplantation a 22-year-old normotensive recipient with
Cuscj 15 ( A . R . ) A 45-year-old kidney graft recipient with nephrosclerosis and malignant hypertension had a normal graft function postoperatively. During the following 10 months the creatinin clearance gradually decreased and hypertension persisted. Antirejection treatment with methylprednisolone was given but the BP was unaffected, and 3 months later bilateral nephrectomy was performed. No
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ing hypertension after an otherwise successful kidney transplantation. Vein catheterization showed a high renin gradient over her own kidneys and no gradient over the graft. Bilateral nephrectomy was performed, followed by a transient reduction in the hypertension. Three years later the patient unexpectedly developed a hypertensive crisis with pulmonary oedema. The graft function had deteriorated. Arteriography showed several stenoses of the graft artery. The patient died from an acute myocardial infarction. Autopsy was not performed.
DISCUSSION
Fig. 5 . Arteriography before the second reanastomosis
operation showing end-to-end anastomosis to the hypogastric artery and a short stenosis at the anastomosis site and normal peripheral vessels (Case 4).
effect on the hypertension was noted. Two years later the condition had worsened seriously. BP was 200/120. Renography showed no graft function. arteriography showed no filling of the graft artery and the graft was removed on suspicion of a severe rejection. A few days later the patient died of acute myocardial infarction and acute pancreatitis. Investigation of the removed graft showed a very narrow stenosis at the site of anastomosis and no histological or immunopathological evidence of rejection. CNW 44 ( L . L . )
A normotensive 17-year-old female with chronic reflux nephropathy was treated for acute rejection after the transplantation and obtained a good graft function. During the following 10 months she developed a severe hypertension. Arteriography showed a central stenosis of the graft artery and peripheral renin was 457 pGU/ml. The stenosis was resected and reanastomosis performed leading to a normalization of renin and BP. However, hypertension reappeared, and 4 years after the transplantation the graft function suddenly ceased, accompanied by an instant normalization of the BP. It was believed that a total occlusion of a preexisting arterial stenosis had occurred, resulting in an “autograftectomy”, and the graft was removed. The graft was pale, and the arteries in the hilum had a normal pulse. Microscopy of the graft showed typical rejection. CUSP51 ( J . B . H . )
A 38-year-old woman with medullary sponge kidneys, nephrosclerosis and malignant hypertension had persist-
Arterial hypertension is often recognized in patients with chronic uremia (Coles, Crosby, Jones, Jones & McVeigh, 1973; Maxwell & Weidmann, 1974; Rao, Gupta, Butt, Sharma, Kountz & Friedman, 1976). Usually, in severe refractory hypertension, the pathogenetic factor is production of vasoconstrictors in the diseased kidneys. Renin measurements may be diagnostic in these patients, and nephrectomy prior to kidney allotransplantation is advisable (Weidman. Maxwell, Lupu, Lewin & Massry, 1971; Guyton, Coleman, Cowly, Liard, Manning & Norman, 1974; Maxwell & Weidmann, 1974). In terminal uremia, however, salt and water retention due to dietary breaks o r insufficient dialysis is the dominant cause of hypertension (Weidmann et al., 1971). After the transplantations, in this series, hypertension disappeared o r regressed in one-third of the preoperatively hypertensive patients, while it appeared o r worsened in another third (Table I). Half of the patients were hypertensive 3 months after the transplantation and 5 9 % by the deadline for the study. Accordingly Bachy, Alexandre & van Yppersele de Strihou (1976) found the frequency of post-transplant hypertension to increase to about 60% during the first 3 months. Various factors have been discussed as possibly etiological factors in post-transplant hypertension, i.e. acute or chronic rejection (Bachy et al., 1976), the presence of the patients own diseased kidneys (Cohen, 1973), the possible conversion of immunosuppressive steroids into an aldosterone-like rnineralocorticoid (Sampson, Kirdani, Sandberg & Murphy, 1973) and decreased blood flow through the graft due to arterial stenosis (Bennett, McDonald, Lawson & Porter, 1974; Lacombe, 1975). Both the function and the survival (Fig. 4) of the grafts compared well to the other reports (Lund, Thaysen, Ladefoged & Nerstram, 1976) and were not correlated to the level of the blood pressure. In
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296
P . Klurskov et al.
contrast Bachy et al. (1976) found the prognosis of the graft to be worse in patients with hypertension. Like Coles et al. (1972), Cohen (1973) and Bachy et al. (1976) we could not demonstrate the correlation between the level of hypertension and the dosis of prednisone reported by Sampson et al. (1973). Like other authors (Bachy et al., 1976; Rao et al., 1976) we have arbitrarily defined a group of patients with severe hypertension, among whom the patients with graft arterial stenosis are to be found (Fig. 2 ) . The graft function may remain satisfactory and the hypertension be well controlled for a long period of time, but the course is unpredictable. Deterioration of the graft function and general condition, hypertensive encephalopathy and cardiovascular crisis may suddenly develop (Cases 4 and 51 ; Nerstram, Ladefoged & Lund, 1972; Rice, Levin, Jennings & Ivanovich, 1976). Furthermore the clinical picture of graft arterial stenosis is easily confused with that of rejection (Cases IS and 44; Simmons, Tallent, Kjellstrand & Najarian, 1970; Schrameck, Better, Adler, Tuma, Hashmonai, Barzilai & Chaimowitch, 1975). In those patients, who later proved to have developed arterial stenosis, severe hypertension was present within weeks or few months of the transplantation operation (Fig. 4). The graft arterial stenosis may therefore be diagnosed at an early time before critical complications develop, preferably by an arteriography (Vinik, Smellie, Freed, Hume & Weidner. 1969; Nilson, Henriksson & Thoren, 1976; Osborn et al., 1976). The level of plasma renin may be elevated in arterial stenosis as well as in rejection, but the evaluation is often difficult, as the administration of hypotensive drugs influences the renin measurements (Giese, Jorgensen, Nielsen, Lund & Munck, 1970; Bennett et al., 1974). In some cases renin analyses performed on samples obtained during vein catheterization may be of great help in determining whether the renin source is the graft or the patient’s own diseased kidneys (Case 5 1 ; Coles et al., 1972; Cohen, 1973; Bennett et al., 1974). Graft biopsies may be valuable in the differential diagnosis between rejection and arterial stenosis, as these conditions may be present simultaneously (Case 44). Renography and urography, however, are of minor importance in this context, because of the lack of a coupled organ for comparison (Giese, Mogensen & Munck, 1975). In a prospective study Lacombe (1975) found 23% of kidney graft recipients to develop graft arterial stenosis, but not all Sconrl J iirol Nephrol
/3
were hypertensive. About half of this frequency was noted in another prospective series (Nilson et al., 1976). Our present retrospective material shows an incidence of severe arterial stenosis of 27% among hypertensive recipients and an overall incidence of 1 1 5%. Other retrospective studies report an overall stenosis incidence of l-lO% (Nerstrem et al., 1972; Margules, Beltzer & Kountz, 1973). An incorrect surgical technique usually results in short stenoses at the site of the arterial anastomosis and is apparently the main aetiological factor (Smellie, Vinik & Hume, 1969; Vinik et al., 1969; Morris, Yadav, Kincaid-Smith, Anderton, Hare, Johnson, Johnson & Marshall, 1971; Frodin, Thorarinsson & Willen, 1975; Smith & Ehrlich, 1976). Accordingly we found more stenoses to develop in grafts with two arteries (Table 111) requiring a more elaborate surgical technique. Bewich, Ogg, Parsons, Trafford & Goggin (1976) reported stenoses to develop 10 times more often after end-to-end anastomosis than after all other types of anastomosis, whereas in Morris et al. (1971) the end-to-side anastomoses were dominant. Another main aetiological factor is rejection, usually resulting in long peripheral stenoses (Morris et al. 1971; Kaufman, Ehrlich & Dornfeld, 1976; Nilson et al., 1976). No significance of pre-existing arteriosclerosis, the nature of primary kidney disease, sex, age, immunological matching or the ischaemic time of the graft for the development of graft arterial stenosis has ever been demonstrated. Surgical treatment of renovascular hypertension is improving and the long-term results seem to be best in young patients with an early diagnosis and treatment (Shapiro, Perez-Stable, Scheib, Bron, Moutsos, Berg & Misage, 1969; Hunt & Strong, 1973; Maiz, Safar, Weiss, Ayed & Milliez, 1977). Also in renal transplant recipients with hypertension due to stenosis of the graft artery, the results of reconstructive vascular surgery are encouraging, a cure rate or improvement of more than 50% being reported (Lee, Linehan, Pierce & Hume, 1972; Nerstram et al., 1972; Sterioff, Zachary &Williams, 1974; Lacombe, 1975; Henriksson et al., 1976; Osborn, 1976). In our material the vascular reconstruction was successful after 2 of the 3 operations (Cases 4 and 44). We therefore conclude that in patients with a new, severe hypertension or persisting severe hypertension after kidney allotransplantation, the possibility of a graFt arterial stenosis should always
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Rtviovascular hypertension b e considered. In order t o avoid the danger of hypertensive crises this diagnosis should b e settled as early as possible by graft arteriography and renin analyses. Also, when a renal graft recipient presents with severe symptoms indicative of rejection the possibility of graft arterial stenosis should b e considered and arteriography performed. Once the arterial stenosis is diagnosed the possibility of reanastomosis should b e considered, especially in the younger group of recipients.
REFERENCES Bachy, C., Alexandre, G. P. J. & van Ypersele de Strihou, C. 1976. Hypertension after renal transplantation. Br Med J i i , 1287. Bennett, W . M., McDonald, W. J., Lawson, R. K. & Porter, G. A. 1974. Posttransplant hypertension: Studies of cortical blood flow and the renal pressor system. Kidney Internat 6 , 99. Bewick, M.. Ogg, C. S . , Parsons, V., Trafford, J. P. & Goggin, M. 1976. The type of arterial anastomosis used in renal transplantation and subsequent complications. In Proc Eur Dial Transplant Assoc (ed. B. H. B. Robinson), vol. 13, p. 192. Pitman Medical, U. K . Cohen, S . L. 1973. Hypertension in renal transplant recipients: Role of bilateral nephrectomy. Br Med J iii, 78. Coles, G. A , , Crosby, D. L., Jones, G. R., Jones, J . H. & McVeigh, S. 1972. Hypertension following cadaveric renal transplantation. Postgrad Med J 48, 399. Frodin, L., Thorarinsson, H. & Willen, R. 1975. Preanastomotic arterial stenosis in renal transplant recipients. Scand J Urol N e p h r o l 9 , 66. Giese, J., Jorgensen, M., Nielsen, M. D., Lund, J. 0. & Munck, 0. Plasma renin concentration measured by use of radioimmunoassay for angiotensin. I . 1970. Scand J Clin L a b Invest 26, 355. Giese, J., Mogensen, P. & Munck, 0. 1975. Diagnostic value of renography for detection of unilateral renal or renovascular disease in hypertensive patients. Scand J Clin L a b Invest 35, 307. Guyton, A. C . , Coleman, T. G . , Cowley, A. W . , Liard, J. F., Manning, R. D. & Norman, R. A. 1974. InProc5th Int Congr Nephrol (ed. H. Villarreal), pp. 74-80. S. Kager, Basle, Switzerland. Henriksson, C., Aurell, M., Claes, G . , Nilson, A. E . , Thoren, 0. & Gelin, L. E. 1976. Surgical correction of artery stenosis in renal transplants. Scand J Urol Nephrol, Suppl. 38, 139. Hunt, J. C. & Strong, C. G. 1973. Renovascular hypertension. Mechanisms, natural history and treatment. A m J Cardiol32, 562. Kaufman, J. J., Ehrlich, R. M. & Dornfeld, L. 1976. Immunologic considerations in renovascular hypertension. J U r o l 1 1 6 , 142. Lacombe, M. 1975. Arterial stenosis complicating renal allotransplantation in man: A study of 38 cases. Ann Surg 181, 283. 20-192923
uftrr kidney transplantation
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Lee, H. M., Linehan, D., Pierce, J. & Hume, D. 1972. Renal artery stenosis and gastrointestinal hemorrhage in human renal transplantation. Transplant Proc 4 , 681. Lund, F., Thaysen, J. H., Ladefoged, J. & Nerstrnm, B. 1976. Long term survival and graft function after cadaveric kidney transplantation. Acta Chir Scand 472, 9. Maiz, H. B., Safar, M., Weiss, Y . , Ayed, H. B. & Milliez, P. 1977. Renovascular hypertension: The role of nonspecific factors in the antihypertensive effect of surgery. Clin Nephrol 7, 26. Margules, R. M., Belzer, F. 0. & Kountz, S . L. 1973. Surgical correction of renovascular hypertension following renal allotransplantation. Arch Surg 106, 13. Master, A. M., Garfield, C. I. & Walters, M. B. 1952. Norma1 Blood Pressure and Hypertension, pp. 1 4 4 . Lea & Febiger, Philadelphia. Maxwell, M. H. & Weidrnann, P. 1974. Hypertension in chronic bilateral renal disease. In Proc 5th Znt Congr Nephrol (ed. H. Villarreal), pp. 6&73. S. Kager, Basle, Switzerland. Morris, P. J . , Yadav, R. V. S., Kincaid-Smith, P., Anderton, J., Hare, W. S. C., Johnson, N., Johnson, W. & Marshall, V. C. 1971. Renal artery stenosis in renal transplantation. Med J Australia I , 1255. Nerstrnm, B., Ladefoged, J. & Lund, F. 1972. Vascular complications in 155 consecutive kidney transplantations. Scand J Urol N e p h r o l 6 , 65. Nilson, A. E., Henriksson, C. & Thoren, 0. 1976. Angiographic diagnosis and follow-up of artery stenosis in renal transplantation. Scand J Urol Nephrol, Suppl. 38, 131. Osborn, D. E., Castro, J . E. & Shackman, R. 1976. Surgical correction of arterial stenosis in renal allografts. Br J U r o l 4 8 , 221. Rao, T. K. S . , Gupta, S . K., Butt, K. M. H., Sharma, H. S. D., Kountz, S. L. & Friedman, E. A. 1976. Relationship of renal transplantation to hypertension in chronic renal failure. Kidney Internat 10, 609. Rice, L. E., Levin, M. L., Jennings, R. B. & Ivanovich, P. 1976. Intractable renovascular hypertension in an adult recipient of a pediatric cadaveric renal transplant. Nephron 17, 279. Sampson, D., Kirdani, R. Y., Sandberg, A. A. & Murphy, G . P. 1973. The aetiology of hypertension after renal transplantation in man. B r J Surg 60, 819. Schramek, A., Better, 0. S . , Adler, 0.. Tuma, S . , Hashmonai, M., Barzilai, A. & Chairnowitz, C. 1975. Hypertensive crisis, erythrocytosis and uraernia due to renal-artery stenosis of kidney transplants. Lancet i, 70. Shapiro, A. P., Perez-Stable, E., Scheib, E. T., Bron, K., Moutsos, S . E., Berg, G. & Misage, J. R. 1969. Renal artery stenosis and hypertension. Observations on current status of therapy from a study of 115 patients. Arner J M e d 4 7 , 175. Simmons, R. L., Tallent, M. B., Kjellstrand, C. M. & Najarian, J. S. 1970. Renal allograft rejection simulated by arterial stenosis. Surgery 68, 800. Srnellie, W. A. B., Vinik, M. & Hume, D. M. 1969. Angiographic investigation of hypertension complicating Scond J Uvol Nrplrrol 13
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ril.
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human renal transplantation. Surg Gynec, Ohstel 128. 963. Smith, R. B. & Ehrlich, R. M. 1976. The surgical complications of renal transplantation. U r o l Clin N Amer 3. 621. Sterioff, S . , Zachary, J . B. &Williams, G . M. 1974. Dacron vascular grafts in renal transplant patients. Amer J Surg 127. 525.
Vinik, M., Srnellie, W. A. B., Freed, T. A ,, Hurne, D. M. & Weidner, W. A. 1969. Angiographic evaluation of the human homotransplant kidney. Radiology 92, 873. Weidrnann, P., Maxwell, M . H., Lupu, A . N., Lewin, A . J . & Massry, S . G . 1971. Plasma renin activity and blood pressure in terminal renal failure. Neii, Engl J M e d 285, 757.
