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HYPERTENSION IN PATIENTS ON REGULAR HÆMODIALYSIS AND AFTER RENAL ALLOTRANSPLANTATION G. D. CHISHOLM M. PAPADIMITRIOU R. SHACKMAN FROM THE UROLOGICAL UNIT, DEPARTMENT OF SURGERY, HAMMERSMITH HOSPITAL, AND ROYAL POSTGRADUATE MEDICAL SCHOOL, LONDON W.12
blood-pressure in a group of forty patients on a renal replacement programme for at least 5 months (mean period 17 months) has been investigated. Sixteen had been on regular intermittent hæmodialysis and twenty-four had been treated by renal allotransplantation. Transplantation provided better results in respect of the blood-pressure. Bilateral nephrectomy in patients on dialysis and after transplantation is recommended for patients with persistent hypertension. In cases where hypertension persists in patients after transplantation and nephrectomy, chronic rejection or stenosis of the arterial anastomosis are usually responsible. Sum ary
The
Introduction HYPERTENSION is a frequent complication of the predialysis and pretransplant period in patients in chronic renal failure but its control may be anticipated in most cases by efficient haemodialysis (Shaldon 1966). However, some patients are difficult to manage by hasmodialysis alone because of fluctuations between hypertension and hypotension, and in these patients control is made easier by bilateral nephrectomy (de Wardener 1968, Peart 1968), because both the renoprival and renal presumably " renin " components are corrected (Kolff et al. 1964). When hypertension develops or persists after transplantation, it may be due to the presence of the recipient’s own diseased kidneys, to rejection (acute or chronic), to narrowing of the arterial anastomosis, or possibly to the development of disease in the transplanted kidney closely resembling the primary renal disease (Hume 1967). We have investigated the blood-pressure status cf the patients on our renal replacement programme and discuss here the incidence, aetiology, and management of hypertension.
Fig. 2-Blood-pressure in twenty-four successful kidney transplants surviving and functioning at least 5 months after operation (mean survival 17 months).
Patients and Methods Forty patients on a renal replacement programme for more than 5 months (on Jan. 1,1969) were investigated; sixteen were still on regular heemodialysis and twenty-four had received successful kidney transplants. The underlying disease in the sixteen patients on hxmodialysis was chronic glomerulo-
nephritis in six, chronic pyelonephritis in four, polycystic kidney disease in three, two were anephric (bilateral nephrectomy), and one had familial nephritis. The underlying disease in the twenty-four patients who had a kidney transplant was chronic glomerulonephritis in twelve, chronic pyelonephritis in nine and polycystic kidney disease in three. In the twenty-four patients with kidney transplants, cadaveric kidneys were used in fifteen and live donor kidneys in nine. Night ha:modialysis was carried out for 12-14 hours on two occasions every week by
modified Kiil machines and Lucas monitors with a warm single-pass automatic dialysate supply. Predialysis and postdialysis (svstolic and diastolic) blood-pressures were measured in mm. Hg with a ward and mean values calculated from the readings obtained during the latest 4 weeks were used for statistical analysis. Weight loss was observed continuously during dialysis. The transplanted patients were examined regularly in the outpatient clinic and mean values of the systolic and diastolic blood-pressure in each patient, deduced from the five latest observations, were used for statistical analysis. The development of a bruit and a low sodiumcreatinine ratio in the urine were suggestive of stenosis at the arterial anastomosis but the diagnosis was made by renal angiography, using a Seldinger catheter through the contralateral femoral artery. Deterioration of kidney function with moderate or heavy proteinuria and a nephrotic-type serum-protein pattern on electrophoresis were taken to be indices of chronic rejection provided urinary infection was absent and that the radiographic appearances of the main vessels in the kidney were normal. Results The mean age of the patients on haemodialysis was 36 (range 19-59). The mean age of the patients who had kidney transplants relation to weight-loss per 10-hour haemodialysis.
sphygmomanometer,
Fig. 1-Fall in blood-pressure in
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systolic and diastolic blood-pressures from 0 to 40 Hg in different patients (fig. 1). After kidney transplantation seventeen of the twentyfour patients had normal blood-pressures and did not require any special therapy (fig. 2); in the remaining seven sodium restriction was required, and antihypertensive drugs were required in five of these. In ten of the transplanted patients the blood-pressure was normal within 4 weeks of operation but hypertension persisted in five others until their own kidneys were removed. In two others in whom there was angiographic evidence of stenosis of the arterial anastomosis, surgical excision of the stenosis and reconstitution of the anastomosis was required in one (fig. 3) and prolonged (8 months) dietetic and antihypertensive drug therapy in the other (fig. 4) before the blood-pressure returned to normal. Both now maintain normal blood-pressures without antihypertensive therapy 20 and 17 months, respectively, after transplantation. Of the seven patients who still require dietetic and antihypertensive drug therapy (fig. 2) chronic rejection is present in three, two are still awaiting bilateral nephrectomy, and two are the oldest patients in our transplant series (56 and 46 years) and have significant calcification and atheroma of the pelvic vessels which was noted at operation.
of
mm.
Fig. 3-Stenosis patient. was
29
at
the arterial anastomosis in
(range 17-56). The
mean
a
transplanted
duration of the
definitive treatment, by haemodialysis
or after transthe same be about plantation, fortuitously happened 17 months 5-58 in the case of the months -viz., (ranges months in the of and 6-55 case the dialysed patients The mean (± S.E.M.) systolic transplanted patients). blood-pressure of the patients on dialysis was 152 (: 3-9) mm. Hg and the diastolic pressure was 95 (± 1-7) mm. Hg. The mean systolic blood-pressure of the transplanted patients was 140 (± 2-9) mm. Hg and the diastolic pressure The mean systolic bloodwas 92 (± 1-3) mm. Hg. different were (Student’st test on pressures significantly but the diastolic pressures were unpaired data) (P =0-017)
to
not
(r=0°090).
haemodialyses, during which no there was no correlation between transfused, of loss and reduction the blood-pressure-e.g.., weight a weight loss of 2 kg. could be associated with reductions In 164 consecutive
blood
was
Fig. 4-Gradual improvement in X-ray (c) 20 months after transplantation.
Discussion the Although blood-pressure is usually easily controlled in patients with chronic renal failure either by dialysis or
successful difficult
kidney transplantation,
some
patients
are more
to manage.
Efficient and adequate removal of sodium and water are required when haemodialysis is used but antihypertensive drug therapy may sometimes be required for some months (Hampers and Schupak 1967). This has been the case in two of our patients treated by haemodialysis. When methyldopa is used unpleasant hypotensive incidents may develop shortly after a patient is connected to a dialyser even when too rapid removal of fluid by the artificial kidney is avoided. These incidents are likely to be exaggerated in patients with a low plasma-protein and a good case can be made for prescribing a relatively high protein diet, more frequent dialysis, and, if they are excreting only very small volumes of urine, bilateral nephrectomy. We feel that a persistently low packed-cell
appearance of renal-artery stenosis in
a
transplanted kidney: (a)
8
months, (b)
11
months, and
904
(20-25%) in the patients treated by dialysis accounts for our observation that their mean systolic blood-pressure was significantly greater than that of the transplanted patients; chronic anaemia is known to lead to a high cardiac output. Dialysis, weight change, and blood-pressure are closely related (Shaldon 1966). When dialysis is done only twice weekly, the blood-pressure may sometimes be difficult to control but if the dialysis is increased to three times a week control may become much easier, and patients may even volume
relax the restriction on their sodium intake (Scribner 1967). We do all we can to ensure that our patients on haemodialysis do not exceed a sodium intake of more than 25 meq. per day. But whatever happens in be allowed
to
patients treated by dialysis, successful kidney transplantation can be expected to be followed by normal blood-pressure without need for dietetic restriction. This has been so in seventeen out of twenty-four of our patients and the contrast between them and the sixteen dialysed patients who all required dietetic restriction has been striking. It could be argued that we have not dialysed our patients frequently enough, and that the contrast might not have been so striking if we had used haemodialysis three times are
a
week, but the economics of such
treatment
questionable.
The development of a normal blood-pressure after successful kidney transplantation is no doubt influenced by the effective sodium excretion of the transplant (Swales 1967), although it has been suggested that a normal kidney can produce hypotensive substances which act independently of sodium excretion (Kolff and Page 1954, Muirhead et al. 1966, Lancet 1968). When hypertension persists after successful kidney transplantation it may be cured by the removal of the recipients own diseased kidneys, as happened in five of our patients. Hypertension may also develop several weeks after transplantation as a manifestation of acute or chronic rejection (Starzl et al. 1965). Hypertension in acute rejection episodes is now relatively uncommon, possibly because the episodes are less severe as a result of improved tissue matching (Shackman 1969). We believe that a fall in 24-hour urea and osmolar excretion, creatinine clearance, and lymphocyturia are the most reliable indices of an acute rejection (Chisholm et al. 1969). However, chronic rejection, as shown by a gradual fall in renal function and confirmed by renal biopsy, was associated with hypertension in three of our patients. These three patients with chronic rejection were transplanted before tissue typing was available and they now have creatinine clearances of 20, 15, and 14 ml. per minute, respectively. Their blood-pressure is controlled with small doses of methyldopa and frusemide, and we hope that they will have a better second chance with good tissue matching when their transplant fails completely. Hypertension may also result from stenosis at the site of arterial anastomosis (Crosnier et al. 1964) and angiography is required to exclude this diagnosis. We have not found angiography to be of value in the diagnosis of rejection but we believe it to be useful in demonstrating a stenosis or confirming an arterial thrombosis. We thank Prof. R. E. Steiner and his colleagues for the renal arteriograms; Sister J. Jennings, Sister J. Child, and the staff nurses of the ward H5/6 and the artificial kidney unit for their help; and Miss C. Wade for secretarial assistance. M. P. is a NATO scholar. Requests for reprints should be addressed to G. D. C.
THE DIAGNOSIS OF REJECTION OF RENAL ALLOTRANSPLANTS IN MAN G. D. CHISHOLM
M. PAPADIMITRIOU
A. E. KULATILAKE
R. SHACKMAN
UNIT, DEPARTMENT OF SURGERY, HAMMERSMITH HOSPITAL AND ROYAL POSTGRADUATE MEDICAL SCHOOL, LONDON W.12 FROM THE UROLOGICAL
The changes in eight simple laboratory determinations on blood and urine in 20 rejection episodes after renal allotransplantation have been analysed. The most significant changes were a fall in the 24-hour urinary urea and osmolar excretion; these were also the earliest and most reliable evidence of a rejection episode. Changes in 24-hour urine volume and plateletcount were also significant but were harder to evaluate. In all rejection episodes there was a significant decrease in creatinine clearance which returned to previous levels after treatment. The changes in blood-urea, 24-hour urinary protein, and sodium excretion were neither early nor
Summary
significant. Introduction
ANTI-REJECTION measures are likely to be more effective when the diagnosis and treatment of a rejection episode are early. A variety of special tests have been advocated for the early detection of rejection, but these may be either non-specific or not always available, and some still require assessment. Clinical manifestations alone may be misleading and are rarely pathognomonic. In practice, most transplantation units use quite simple standard laboratory determinations on blood and urine for early diagnosis. We have analysed such determinations retrospectively to see which gave the earliest and most reliable indications of rejection. Patients and Methods 20 consecutive patients who had been given renal allografts (10 male and 10 female, mean age 31-5 years, range 17-46), were studied for at least four months after operation (table l). 14 had received cadaveric kidneys, 5 live-donor kidneys, and 1 a free kidney from an unrelated subject. In 6 of the 20 patients (cases 6, 7, 9, 10, 11, and 19) there was neither clinical nor laboratory evidence of rejection during the study. In 2 others (cases 1 and 15) the only evidence of rejection was in the histological findings from open-renal-biopsy specimens, obtained because there was persisting postoperative oliguria which, it was felt, could have been due to rejection. The remaining 12 patients were treated for 23 rejection episodes. In
Chisholm, G. D., Papadimitriou, M., Kulatilake, A. E. K., Shackman, R. (1969) Unpublished. Crosnier, J., Ducrot, H., Jungers, P. (1964) Acquis. Méd. rec., Paris, 1, 195. de Wardener, H. E. (1968) in 4th Symposium on Advanced Medicine (edited by O. Wrong); p. 139. London. Hampers, C. L., Schupak, E. (1967) Long Term Hæmodialysis; p. 77. London.
Hume, D. M. (1967) Ann. Rev. Med. 18, 229. Kolff, W. J., Nakamoto, S., Poutasse, E. F., Straffon, R. A., Figueroa, J. E. (1964) Circulation, 30, suppl. no. 2, p. 23. Page, I. H. (1954) Am. J. Physiol. 178, 75. Lancet (1968) ii, 615. Muirhead, E., Brooks, B., Kosinski, M., Daniels, E., Hinman, J. W. (1966) J. Lab. clin. Med. 67, 778. Peart, W. S. (1968) in 4th Symposium on Advanced Medicine (edited by O. Wrong); p. 118. London. Scribner, B. H. (1967) in Renal Disease (edited by D. A. K. Black); p. 459. -
Oxford.
Shackman, R. (1969) Unpublished. Shaldon, S. (1966) Postgrad. med. J. suppl. p. 18. Starzl, T. E., Marchioro, T. L., Terasaki, P. I., Porter, K. A., Faris, T. D., Herrman, T. J., Vredevoe, D. L., Hutt, M. P., Ogden, D. A., Waddell, W. R. (1965) Ann. Surg. 162, 749. Swales, J. D. (1967) Am. J. Med. Sci., 253, 531.