Hypertension In Transplant Recipients Research Articles

Hypertension in the Kidney Transplant Recipient: Overview of Pathogenesis, Clinical Assessment, and Treatment.

Cardiovascular disease is the leading cause of death in patients with chronic renal disease and the most common cause of death and allograft loss among kidney transplant recipients. Transplant patients often have multiple cardiovascular risk factors antedating transplantation. Among the most prominent is hypertension (HTN), which affects at least 90% of transplant patients. Uncontrolled HTN is an independent risk factor for allograft loss. The etiology of HTN in transplant recipients is complex and multifactorial, including the use of essential immunosuppressive medications. Post-transplant HTN management requires a systematic and individualized approach with nonpharmacologic and pharmacologic therapies. There is no single ideal agent or treatment algorithm. Patients should regularly monitor and record their blood pressure at home. Often, multiple antihypertensive drugs are needed to achieve a goal blood pressure of 120-140/70-90 mm Hg. As transplant recipients commonly must take 8 to 12 different medications daily, adherence must be continually encouraged and monitored. Special attention must be paid to potential drug side effects and drug interactions with immunosuppressive medications.

Vitamin D deficiency is associated with short stature and may influence blood pressure control in paediatric renal transplant recipients

Vitamin D deficiency is common in adult renal transplant recipients, but data in children are scarce. Vitamin D is shown to have multiple effects on the cardiovascular system, renal function, and maintenance of bone health. We hypothesized that 25(OH)D deficiency is common in pediatric renal transplant recipients, and may be associated with hyperparathyroidism, short stature, renal function, and blood pressure control. We recruited 106 children during the winter/spring season who had a functioning renal transplant for at least 3 months. Twenty-five hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)(2)D] were measured and correlated with clinical and biochemical parameters. Of the renal transplant patients, 38% were 25(OH)D deficient, 54% had insufficient levels, and only 8% had adequate 25(OH)D levels. Despite alfacalcidol supplementation in 59 (56%) patients, parathyroid hormone was increased in 58 (55%) and showed an inverse correlation with 25(OH)D (p = 0.0003, r = 0.61) but not with 1,25(OH)(2)D levels. Height standard deviation score (SDS) correlated with 25(OH)D (p = 0.007, r = 0.42) and time post transplantation (p = 0.02, r = 0.23); both were significant and independent predictors of height SDS. 25(OH)D inversely correlated with systolic BP SDS (p = 0.02, r =-0.26); this association was lost on multiple regression analysis, but 25(OH)D was the only modifiable risk factor for hypertension. There was no correlation with estimated GFR or proteinuria. In conclusion, 25(OH)D deficiency is common in pediatric renal transplant recipients and correlates with hyperparathyroidism and short stature. 25(OH)D deficiency may be a modifiable risk factor for hypertension in transplant recipients. Further studies are required to test if routine supplementation with ergo or cholecalciferol is safe and effective in children after renal transplantation.

Association Between CYP3A5 Polymorphisms and Blood Pressure in Kidney Transplant Recipients Receiving Calcineurin Inhibitors

Renal cytochrome P450 3A5 (CYP3A5) has been associated with blood pressure (BP) control in humans. We investigated whether CYP3A5 polymorphisms are associated with post- transplant hypertension in a selected population of kidney recipients receiving calcineurin inhibitors.Ninety-two kidney transplant recipients receiving cyclosporine (CyA) or tacrolimus (Tac) were genotyped for CYP3A5 polymorphisms, and the association between the CYP3A5 alleles (*1,*3) and hypertension on post-operative day (POD) 6 and POD 180 was verified, with multiple regression being used to identify the putative co-variates that may predict the extent and severity of hypertension in transplant recipients at different post-transplant times.The CYP3A5*1 carriers had higher systolic (SBP) and diastolic blood pressure (DBP) in both the immediate and delayed post-transplant period when adjusted for anti-hypertensive medication (POD 6: SBP = 161 ± 23 vs. 140 ± 23 mmHg; DBP = 120 ± 15 vs. 87 ± 14 mmHg, p < 0.05. POD 180: SBP = 136 ± 16 vs. 129 ± 14 mmHg; DBP = 89 ± 15 vs. 80 ± 15 mmHg, p < 0.05). The severity of hypertension between the CYP3A5*1 carriers and noncarriers on POD 6 was documented by the significantly different distribution of hypertension classes, but this was not confirmed on POD 180. The CYP3A5 genotype was the only independent variable affecting mean arterial pressure.The results of this study show that CYP3A5 polymorphisms are associated with the severity and degree of hypertension in kidney transplant recipients receiving calcineurin inhibitors regardless of the time of recording. However, the role of concomitant medications such as steroids with strong CYP3A5 inducing activity, should be taken into account.

Effect of Angiotensin II Receptor Blocker on Plasma Levels of TGF-β1 and Interstitial Fibrosis in Hypertensive Kidney Transplant Patients

Background/Aim: Transforming growth factor-β1 (TGF-β1) is involved in the pathogenesis of chronic allograft nephropathy after kidney transplantation. The aim of the study was to evaluate the effect of the angiotensin receptor blocker losartan on TGF-β1 plasma levels and proteinuria in hypertensive transplant recipients. Methods: A total of 162 transplant recipients were included in the study. The patients were randomized into 3 groups: group 1 received losartan; group II received an angiotensin-converting enzyme inhibitor (captopril), and group III received a calcium channel blocker (amlodipine). All the parameters were recorded at the time of therapy initiation and at 1, 4 and 12 weeks and 12 months thereafter. Graft biopsy before the start and at the end of the study was done to evaluate histopathological progression. Results: Blood pressure was controlled in the 3 groups; however, the need for other antihypertensive agents was significant in groups I and II. Treatment with losartan significantly decreased the plasma level of TGF-β1, 24-hour urinary protein and serum uric acid (p < 0.05). No significant changes were seen in the hemoglobin or serum potassium levels. The rate of histopathological progression was significantly lower in the losartan group. No patient was discharged from the study due to side effects. Conclusions: After transplantation all drugs were able to control blood pressure with good safety and tolerability. The study demonstrates that ARB significantly decreases the plasma levels of TGF-β1, proteinuria and uric acid. These results could play an important and decisive role in the treatment and prevention of chronic allograft nephropathy.

Effects of carvedilol alone and in the presence of cyclosporine A on the DNA synthesis of cultured vascular smooth muscle cells.

There is still no reliable method of preventing or treating chronic rejection or transplant vascular sclerosis. A recent in vitro cell culture study showed that carvedilol significantly inhibited the proliferation of vascular smooth muscle cells (VSMCs); however, the effect of carvedilol in the presence of cyclosporine (CsA) has not yet been reported. Using in vitro cultured VSMCs, we measured the antiproliferative activity of carvedilol alone and in combination with CsA. Growth-arrested cultured VSMCs from the thoracic aorta of Sprague-Dawley rats were exposed to platelet-derived growth factor (PDGF)-BB, endothelin (ET)-I, and angiotensin (ANG)-II. Carvedilol (1 and 10 microM) and/or CsA (100 nM) were added as test drugs. DNA synthesis was assessed by measuring the incorporated [3H]thymidine activity, and the percentage of inhibition in the presence of the test drugs was determined. Compared with the PDGF-stimulated control, DNA synthesis decreased significantly to 60.3% +/- 10.4% and 18.3% +/- 5.9% in the presence of 1 and 10 microM of carvedilol, respectively (P < 0.05, each). Carvedilol significantly inhibited the activity of VSMCs stimulated by ET-1 and ANG-II. The IC50 of carvedilol was 1-10 microM. CsA only inhibited VSMCs significantly in the PDGF-stimulated subgroup. The addition of CsA in the presence of carvedilol did not affect the inhibitory activity of carvedilol. The pattern of inhibition in the combined group was uniform and similar to that of the carvedilol alone group, regardless of the stimulator used. Carvedilol significantly inhibited the DNA synthesis of VSMCs regardless of the kind of stimulators examined, even in the presence of CsA. These results indicate that carvedilol has the unique potential to inhibit the development of transplant vascular sclerosis in hypertensive transplant recipients under CsA-based immunosuppression.

Posttransplantation Diabetes Mellitus in FK-506-Treated Renal Transplant Recipients: Analysis of Incidence and Risk Factors. Transplantation 2001; 72: 1655.

Posttransplantation Diabetes Mellitus in FK-506-Treated Renal Transplant Recipients: Analysis of Incidence and Risk Factors. Transplantation 2001; 72: 1655.

Introduction to 'hypertension in transplant recipients'.

Introduction to 'hypertension in transplant recipients'.

Traditional drug therapy of hypertension in transplant recipients.

Hypertension is a very common condition among recipients of transplanted organs, and is often related to immunosuppressive therapy. In many transplant centres, calcium antagonists are often used as first-line antihypertensive drug therapy, not only because of efficacy in lowering blood pressure, but also because certain members of the class have a 'beneficial' drug-drug interaction with cyclosporin, which decreases the cost of administering this very expensive immunosuppressant. Diuretics are often used both for blood pressure and volume control, and some centres have used either alpha-beta-blockers, angiotensin-converting enzyme inhibitors, and even beta-blockers with success in certain patients. The high frequency of perceived adverse effects of antihypertensive drugs in transplant recipients and the diversity of training of the specialist physicians involved in their care makes choice of traditional antihypertensive drug therapy in these patients a major challenge.

Impact of Medical Therapy on Pulmonary Hypertension in Patients With Congestive Heart Failure Awaiting Cardiac Transplantation

Pulmonary artery (PA) hypertension in transplant recipients increases mortality from right heart failure following heart transplantation. We examined the impact of long-term medical therapy on the severity of PA hypertension in patients with end-stage congestive heart failure on a transplant waiting list. The initial and final, quarterly right heart catheterization data on 60 patients (50 men, aged 50 ± 9 years, New York Heart Association class III to IV) awaiting heart transplantation were analyzed and the patients divided into 2 groups: group A, those with persistent elevated systolic PA pressures throughout the 10-month follow-up (n = 31 of 60), and group B, those who had any decrease in systolic PA pressure during that period (n = 29 of 60). Group A had no change in hemodynamics. Group B had a significant decrease (± SD) in right atrial (11 ± 7 to 5 ± 4 mm Hg), PA (57 ± 11 to 37 ± 11 mm Hg), and PA wedge (25 ± 9 to 14 ± 7 mm Hg) pressures, with increases in cardiac output (3.8 ± 0.9 to 4.7 ± 1.1 L/min) and ejection fraction (18 ± 6% to 27 ± 11%) (p <0.05). The combined end point of transplant or death occurred in 28 of 31 patients (90%) in group A versus 14 of 29 (50%) in group B (p = 0.0004). Ischemic etiology was present in 71% of patients in group A versus 68% with idiopathic dilated cardiomyopathy in group B (p = 0.003). The reversibility of PA hypertension rather than its initial severity is predictive of patient clinical outcome. Idiopathic, as opposed to ischemic, cardiomyopathy responds better to medical therapy. (Am J Cardiol 1996;78:440–443)

Cyclosporine-induced stimulation of the renin-angiotensin system after liver and heart transplantation.

To analyze the status of the renin-angiotensin system in hypertensive transplant recipients on cyclosporine, we prospectively explored 21 cardiac (CTR: 52 +/- 8.2 yr) and 12 liver (LTR: 45 +/- 10 yr) transplant recipients on a normal salt diet with 19 normotensive controls in the same age range. Systolic and diastolic blood pressure was measured in the supine and standing positions. Renal function was assessed by serum creatinine values, and 24-hr urinary sodium and potassium excretion were recorded. Plasma renin activity (PRA), active renin, total renin, angiotensinogen, aldosterone, and cortisol plasma levels were simultaneously determined. Results were expressed as mean +/- SD, and between-group differences were compared using variance analysis. Supine blood pressure (+/- SD) was 158 +/- 15/103 +/- 8.4 in CTR and 155 +/- 21.4/102 +/- 11.7 mmHg in LTR. Serum creatinine was higher in CTR (159 +/- 52 mumol/L) than in LTR (117 +/- 24.7, P < 0.05) and values in both groups were above controls (83 +/- 14.1, P < 0.05). Urinary sodium excretion tended to be lower in transplant recipients (59 +/- 42 mmol/L) for CTR and 44 +/- 36.7 in LTR than in healthy controls (117 +/- 24.7 mmol/L). Supine and upright PRA values tended to be higher in hypertensive transplant recipients than in healthy volunteers, although not significantly. Supine active renin was significantly higher in CTR (47 +/- 42 pg/ml) and in LTR (44 +/- 29.8 pg/ml) than in normal subjects (17 +/- 4.8 pg/ml, P < 0.05). Total renin levels in CTR (supine: 716 +/- 357 pg/ml) and in LTR (supine: 647 +/- 365 pg/ml) were 3- to 4-fold higher than in controls (supine: 207 +/- 69 pg/ml) (P < 0.05), as were inactive renin levels (P < 0.01). Active renin was effectively correlated with PRA (P < 0.001) and with total renin (P < 0.001) in the supine and in the upright position. Plasma aldosterone was almost within the normal range in CTR and in LTR, and it did not correlate with PRA values. Plasma angiotensinogen levels were normal in LTR (1032 +/- 226 ng/ml) but were significantly lower in CTR (938 +/- 216 ng/ml, P < 0.05). Cortisol plasma levels were lower in both CTR (7 +/- 4.4 micrograms/L) and LTR (6 +/- 1.9 micrograms/L) than in healthy controls (11 +/- 4 micrograms/L, P < 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)

Une nouvelle cause d'hypertension artérielle rénine-dépendante: hypertension artérielle sous cyclosporine

The renin angiotensin system (RAS) was prospectively explored in 21 cardiac (TC), 12 liver (LTR) hypertensive transplant recipients under normal salt diet with 19 age matched controls. Significant increase in plasma active renin and in inactive renin (× 3 to 4) first demonstrated effective stimulation of the RAS in both hypertensive TC and LTR which contributed to the pathophysiology of cyclosporine induced hypertension.

Mechanisms of posttransplant hypertension.

Posttransplant hypertension is an important risk factor for cardiovascular mortality and graft function. We performed metabolic studies in 35 hypertensive patients with well-maintained graft function on maintenance immunosuppressive drugs and in 17 normotensive control transplant recipients. The group of hypertensive recipients were characterized by increased peripheral plasma renin activity, lack of change in blood pressure in response to salt loading and restriction, and by increased peripheral and renal resistance. In contrast, on the same protocol in a group of patients with essential hypertension, blood pressure fell significantly on a low-salt intake. Peripheral resistance in hypertensive transplant recipients fell in response to saline loading, in contrast to the effects in normotensive transplant recipients. Hypertensive patients with retained native kidneys as compared to those who had these removed prior to transplant, but were still hypertensive, differed only with regard to reduced renal plasma flow in the former group. These data are consistent with a predominantly renin-dependent hypertension in these renal transplant recipients. When bilateral nephrectomy or repair of graft renal artery stenosis is being considered, response to captopril may offer a means of selection; acute renal failure on captopril suggests functionally significant renal artery stenosis.

Evaluation of transplant renal artery blood flow by Doppler sound-spectrum analysis.

Doppler ultrasonography sound-spectrum analysis (SSA) was used to evaluate blood flow in the transplanted kidney and its renal artery. Seven patients with posttransplant hypertension and a bruit over the transplanted kidney were screened for renal artery stenosis (RAS). In five patients, RAS was diagnosed by SSA, and in two it was not. These findings were confirmed by subsequent angiography in all patients. Three patients studied after surgical correction of their RAS had improvement in their SSA patterns. Fourteen hypertensive patients with a cause other than RAS were evaluated by SSA. None of them had SSA findings suggestive of RAS. Doppler ultrasonography with SSA is an effective, noninvasive technique of monitoring transplant renal blood flow, especially in the screening of hypertensive transplant recipients for transplant RAS.