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The course of hypertension within the first 2 months after kidney transplantation was correlated with renal function, plasma renin activity (PRA), and the daily maintenance dose of prednisone in 18 homograft recipients. During acute rejection blood pressure (BP) closely correlated with PRA. Patients with normal homograft function showed an increase in BP early after transplantation which in most returned to normal 3–8 weeks later. In the latter group no correlation could be found between the level of BP and PRA, however the BP correlated closely with the dose of prednisone. These observations suggest that during acute rejection the increase in BP may at least partly be mediated by a renal pressor mechanism, whereas with normal renal function the high dose of glucocorticoids may play an important role in the development of hypertension.
High blood pressure is a common phenomenon after kidney transplantation.1–8 In view of its potential detrimental consequences9–11 effective control of posttransplant hyptertension is of utmost importance.10 Numerous factors have been implicated as either causing or contributing to the occurrence of hypertension early after kidney transplantation.5,7,12,13 Renal pressor mechanism may be responsible for high blood pressure in states of impaired homograft perfusion resulting from prolonged ischemia time12,14,15 or renal artery stenosis.16,18 Hypertension which occurs during acute rejection has been reported to resemble renal arterial hypertension11,19 and is frequently associated with a high plasma renin activity.15,20,22 Retained diseased kidneys have been proposed as another factor responsible for high blood pressure.23 Reports on cure of hypertension after removal of the residual organs lend support to this notion, although the mechanism is poorly understood.17,23
In a reported series of hypertensive renal homograft recipients, normotension was noticed to prevail as time elapsed and the dose of corticoids was reduced.24 This observation implied a possible cause and effect relationship between the level of blood pressure and the dose of steroids and warranted a more detailed appraisal of the role of glucocorticoids in posttransplant hypertension. Observations on the early course of hypertension after transplantation, its relation to the variations in renal function, plasma renin activity, and the dose of glucocorticoids, form the basis of the present communication.
Fifteen patients with chronic renal disease of diverse etiology and three patients with chronic rejection of renal homografts undergoing transplantation were studied. Sixteen patients had diastolic blood pressure in excess of 90 mm Hg. The sex, age, and the source of the organs are listed in table 1. Seven patients underwent bilateral nephrectomy 1–6 months prior to, and six during the transplantation; five retained their original kidneys. The surgical procedure and the immunosuppressive regimen were described elsewhere in detail.25,26 Sixteen patients were treated with chronic hemodialysis. All patients were on a low-protein diet (40g/24hr), and the amounts of sodium and potassium were adjusted according to the individual needs of each patient. After transplantation, patients with adequate homograft function were given liberal diets. The calculated amounts of sodium in the diets ranged from 100 to 170 mEq/24hr; these amounts were also reflected in urinary excretion rates as shown in tables 2 and and3.3. Salt and water intake were restricted only during acute rejection. All patients were weighed daily.
Endogenous creatinine clearances were used as estimates of glomerular filtration rate. Urine was collected over 24 hours and blood was obtained at the end of the collection periods. Creatinine concentrations in the serum and in the urine were determined with a Technicon autoanalyzer. Creatinine clearances were measured daily during the first 4–6 weeks after surgery and then at least once every week; during episodes of acute rejection, the clearances were measured daily. Sodium concentrations in the serum and in the urine in all specimens were determined with an Instrumentation Laboratory flame photometer model 143.
Blood pressure was measured in supine position four to eight times daily during the first 4–6 weeks after surgery and thereafter at least once a week. During acute rejection crises, it was recorded as frequently as during the initial period. The values to be given represent averages of daily measurements.
Eighty-five determinations of plasma renin activity (PRA) were made during the study; 18 before and the remainder after surgery. Blood collected directly into EDTA-containing vacutainer tubes was spun in a refrigerated centrifuge and the plasmas were frozen. The patients were in a supine position for at least 1 hour before the blood was withdrawn. The measurements of PRA were performed with a radioimmunoassay.27,28 In most of the patients, PRA was determined on two occasions; first, during the first week, and second, 3–8 weeks after transplantation. The dietary sodium intake on these two occasions was very similar; this fact is also reflected in comparable urinary excretion rates of sodium as shown in tables 2 and and3.3. Additional determinations were made within the course of the study. In several patients, serial values were obtained following bilateral nephrectomy and after surgical removal of the rejected homografts.
Antihypertensive therapy after transplantation was instituted in every patient with a diastolic blood pressure exceeding 90 mm Hg. This approach was adopted as a safeguard against the detrimental renal effect of severe hypertension. The antihypertensive regimen was based on the following agents: hydrochlorothiazide, reserpine, methyldopa (aldomet), hydralazine, and guanethidine. The combined dose (usually several drugs were used at the same time) varied in relation to the severity of hypertension, and was reduced or discontinued as blood pressure returned to normal; thus, during the latter part of the study the combined dose of various antihypertensive agents was considerably lower than that employed initially; however, the dose of diuretics (hydrochlorothiazide) did not change throughout the study.
Prednisone was given initially in the amount of 100–200 mg/24hr. Only in one patient (L.L.) in the initial dose was 40 mg/24hr. The dose was reduced gradually after surgery. A high dose was reinstituted during episodes of acute rejection. In several patients, corticoids were also given for several days before surgery.
Fifteen patients had adequate renal function after transplantation (tables 2 and and3).3). In patient D.P. (not listed in tables 2 and and3)3) the homograft functioned only for 1 week. Three patients (N.J., L.N., and C.B.) underwent accelerated acute rejection shortly after surgery and the homografts were removed within the first postoperative week. Episodes of acute rejection occurred in another five patients (R.C., B.W., CM., MX., and K.R.) during a later part of the study. In M.K., acute rejection led to a total infarction of the homograft with renal vein thrombosis; the remaining four patients recovered and regained normal renal function. The diagnosis of acute rejection was based on clinical and biochemical findings in five and on tissue histology in four patients.
All patients who underwent bilateral nephrectomy prior to transplantation showed a decrease in blood pressure (table 1). Hypertension (diastolic pressure 90 mm Hg) was present in most of the patients early during the first week after transplantation (tables 2 and and3).3). Blood pressure increased during acute rejection in seven patients, did not change in one, and fell in one (B.W.); in the later septicemia could account for the observed hypotension (table 4).
Five of six patients who were treated with prednisone for a short period of time prior to transplantation showed an increase in blood pressure (table 5). The latter was not associated with substantial changes in body weights. Five patients were anephric. These patients were treated with hemodialysis three times (8-hr intervals) a week with a Kiil-type hemodialyzer. The listed weights and blood pressure levels were measured before dialysis. The patients were not on antihypertensive therapy during the observation period.
All patients with adequate kidney function showed a decrease in blood pressure as the dose of glucocorticoids was reduced. Table 2 lists the levels of blood pressure in the first postoperative week when the patients were on the peak dose of steroids and at a later period (3–8 weeks after surgery) when the dose was reduced to its lowest value. The blood pressure levels recorded initially were higher than those measured later. Patients who were still on large amounts of prednisone (B.W. and M.L.) during the latter period showed elevated blood pressure. In figure 1, the doses of prednisone were plotted against diastolic blood pressure values in patients with adequate renal function (the diagram contains measurements of blood pressure at three different doses of prednisone and in one patient at four different doses, episodes of acute rejection were not included). A highly significant direct correlation was found between those two variables. Doses of prednisone divided by body weights were plotted against blood pressures. The relationship between these two variables was similar to that noticed in figure 1 (r= 0.72). Similar plot for blood pressure and body weight showed no significant correlation.
Plasma renin activity values measured in a group of normal subjects under varying conditions of posture and salt intake are shown in table 6. Since most of our patients after transplantation were treated with antihypertensive agents which might have affected PRA,28,29 the interpretation of the results is complicated and great caution has to be exercised in arriving at definite conclusions. Antihypertensive therapy was reduced substantially during period II as compared with that during period I (table 3). However, the dose of hydrochlorothiazide was not altered and thus could not contribute to the observed changes in PRA. Methyldopa decreases whereas hydralazine increases PRA;28,29 both drugs were reduced during the latter period of the study. The effect of this alteration in therapy on PRA is difficult to quantitate, however presumably it was minimal, considering the opposite influences of methyldopa and hydralazine on PRA.
Following bilateral nephrectomy (before transplantation) in six patients, PRA was undetectable in four and below 0.5 ng/ml/hr in two (table 1). Serial determinations of PRA in a patient with lupus nephropathy (L.L.) after bilateral nephrectomy are shown in table 7. During the first week after transplantation, the PRA in the majority of patients with adequately functioning homografts was low or normal (table 2). These values were recorded at the time when most of the patients were hypertensive. PRA values measured 3–8 weeks after transplantation were higher than the initial ones in all but one. These values were obtained when most of the patients were normotensive and the amount of antihypertensive agents was markedly lower than that given initially during the first weeks. Three of five patients with PRA exceeding 10 ng/ml/hr (K.R., V.J., and M.L.) had retained their original damaged kidneys. The changes in body weight and in sodium excretion were relatively small and inconsistent. No significant correlation could be found between diastolic blood pressure and PRA in patients with normally functioning homografts (fig. 2). A marked increase in PRA was noticed during acute rejection (table 4). These changes were noticed before readjustments were made in the dose of antihypertensive drugs and in sodium intake. In two patients (N.J., and B.C.) PRA assumed extremely high levels. An additional increase in PRA was recorded in one patient (C.B.) following a weight loss of 2.5 kg with hemodialysis. In patient M.K., PRA remained low; however, the removed homograft was totally infarcted. This patient gained 5.0 kg during the rejection crisis, and blood pressure was restored to normal after hemodialysis. PRA values during acute rejection crisis correlated directly with blood pressure values (fig. 3). Removal of rejected organs in three patients was followed by a drop in PRA and a decrease in blood pressure. Serial measurements of PRA and blood pressure after the removal of a rejected kidney in patient N.J. are shown in table 8. In this patient, the hypertension which was associated with the acute rejection failed to respond to a marked extracellular fluid volume depletion with hemodialysis but responded promptly to nephrectomy.
The rise in PRA during acute rejection crises as seen in the present study confirms similar observations previously reported by other workers.15,20,21,23 Although an increase in blood pressure during acute rejection was associated with an increasing PRA, no such association could be demonstrated in patients with normally functioning renal homografts. Similarly, other workers failed to show a definite consistency in the relation between the degree of hypertension and PRA after transplantation.3,30,31 The role of a renal pressor mechanism, mediated by the renin-angiotensin system, in the genesis of hypertension during acute rejection requires further evaluation and cannot be established on the basis of presently available information. However, the prompt relief of severe hypertension following the surgical removal of the rejected homografts as observed in three patients, before any appreciable changes in body weight occurred, suggests that a renal mechanism was at least partly responsible for the severe hypertension. Salt and water retention is common during acute rejection and may contribute to the development of hypertension32 as observed in patient M.K.; however, in patient N.J. marked extracellular fluid volume depletion had no appreciable effect on the severe hypertension. Similar observations were also made in our other patients. A rise in PRA following hemodialysis as noticed in patient C.B., suggests that a homograft undergoing acute rejection preserves its physiologic response to extracellular fluid volume depletion; however, additional observations will be necessary before more definite conclusion can be made. The low PRA in patient M.K., during acute rejection, could be explained by the finding of totally infarcted renal homograft with presumably not enough viable tissue left to secrete the hormone. It is possible, therefore, that the measurement of PRA during acute rejection may provide certain information regarding the viability of the transplanted kidney.
The variations in plasma renin activity in patients with adequately functioning renal homografts, showing an increase during the late part of the study 3–8 weeks after transplantation, are not well understood, but several possible explanations are worthy of comment. (1.) Although the denervated transplanted kidney has been shown to be capable of elaborating renin,33 it is quite possible that initially this capability is limited and improves as time passes. (2.) High doses of steroids which were given during the first week could cause suppression of renin production34 whereas lowering of the dose during the latter part of the study might have reversed that effect. (3.) The initial blood samples were obtained while the patients were on a bed rest regimen, whereas during the latter part of the study the patients were ambulatory and assumed a supine position only 1 hour before drawing the blood samples. These differences in posture could influence the results. (4.) The alteration in antihypertensive regimen could exert significant effect on PRA.28, 29
The present observations strongly support the role of glucocorticoids in the development of post-transplant hypertension. An increase in blood pressure presumably not associated with significant changes in sodium balance was observed in anephric patients awaiting transplantation after the administration of a high dose of steroids for several days. A significant relationship between the dose of prednisone and the diastolic blood pressure was demonstrated in patients with well functioning renal homografts. The reported absence of hypertension in patients who are not treated with glucocorticoids after transplantation35 are in agreement with the present findings. The possibility that small changes in renal function played a major role in altering the level of blood pressure seems unlikely, since no significant correlation could be found between creatinine clearances and the levels of blood pressure.
Despite the widespread use of glucocorticoids as therapeutic agents in many disease processes and the well known occurrence of various complications, surprisingly, hypertension has received relatively little attention.36,37 A study undertaken to assess the incidence and the severity of various side effects associated with prolonged administration of glucocorticoids led to a conclusion that hypertension was not a serious complication.38 In contrast to the clinical observations, glucocorticoids have been proved to be highly potent hypertensive agents in experimental animals.39,42 It has also been demonstrated that hypertension which was produced experimentally with glucocorticoids, contrary to that produced with mineralocorticoids, was not salt dependent.39,41 The latter feature rendered the glucocorticoid-induced hypertension unresponsive to salt restriction. The animal studies also demonstrated severe renal damage associated with glucocorticoid-induced hypertension.42
The major difference between the clinical and the experimental conditions is related to the amount of glucocorticoids employed. The dose used in animals to induce hypertension in relation to their body weight was considerably larger than that usually used in humans. However, the doses of steroids which are given to patients to protect their renal homografts may be large enough to account for the hypertension. Our observation that the degree of hypertension was directly related to the dose of prednisone is consistent with that notion. Furthermore patients with renal homografts may differ from subjects with normal kidney by being more sensitive to the hypertensive action of prednisone.
The recognition of glucocorticoid-induced hypertension in renal homograft recipients bears on several important clinical aspects. The appearance of hypertension in patients with adequate renal function who are treated with large amounts of prednisone, early after transplantation, does not necessarily indicate homograft dysfunction and unless other signs of acute rejection are present the dose of immunosuppressive agents should not be increased. The prognosis of that kind of hypertension is usually good and a reduction of the maintenance dose of glucocorticoids, when possible, will eventually result in normotension. However, as long as the hypertension is present, vigorous antihypertensive therapy should be continued. This will likely minimize or prevent the deleterious effect of severe hypertension on the transplanted organ, and on the whole cardiovascular system.
Supported by Grant RR-51 from the General Clinical Research Centers Program of the Division of Research Resources, National Institutes of Health, and U. S. Public Health Service Grants No. AM-06344, AM-07772, FR-00069, AL-04152, AM-12148, and AL-AM08898, and a grant from the Population Council, New York.