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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypertension is common after orthotopic liver transplantation and may be due, in part, to cyclosporin A-induced renal dysfunction and/or enhanced proximal tubular sodium reabsorption. To determine whether enhanced proximal tubular sodium reabsorption is central to the development of posttransplant hypertension, measurements of renal hemodynamics and fractional clearances of lithium and sodium were compared 1 month after orthotopic liver transplantation in previously normotensive patients receiving either cyclosporin A (N = 24) or FK506 (N = 18), an immunosuppressive agent that is structurally unlike cyclosporin A and that has a lower reported incidence of hypertension. Median prednisone doses were 20 and 13 mg/day in the cyclosporin A and FK506 groups, respectively (P < 0.05). At 1 month, mean arterial blood pressure was higher in the cyclosporin A versus the FK506 group: 108 +/- 2 versus 95 +/- 3 mm Hg (P < 0.05). GFR, RBF, and renal vascular resistance were not different between the two groups: 59 +/- 4 and 53 +/- 5 mL/min per 1.73 m2, 439 +/- 28 and 440 +/- 41 mL/min per 1.73 m2, and 22,429 +/- 1,822 and 22,977 +/- 3,506 dyne s/cm5 per 1.73 m2, respectively. Fractional lithium excretion was similar in the cyclosporin A and FK506 groups: 19.9 +/- 2.2 and 19.4 +/- 2.0% (P = not significant) although both values were lower than those of normal controls (25.5 +/- 1.1%) (P < 0.05). Fractional sodium excretion was 2.7 +/- 0.3 and 2.3 +/- 0.4% in the cyclosporin A and FK506 groups, respectively (P = not significant).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Renal sodium handling with cyclosporin A and FK506 after orthotopic liver transplantation. 754 91

Hypertension, which develops after organ transplantation during immunosuppression with cyclosporine (CSA), is often associated with a loss of nocturnal decrease in blood pressure. Few data correlate circadian blood pressure patterns before transplant with those observed at fixed time points after transplant, or address the role of alternate immunosuppressive agents such as FK506. FK506 is unrelated structurally to CSA and less often leads to hypertension early after transplant. The present study compared nocturnal blood pressure patterns in patients with end-stage liver disease (ESLD) before transplant to those of transplant recipients receiving either FK506 (0.15 mg/kg/day) plus prednisone or CSA (2 to 3 mg/kg/day) plus prednisone and azathioprine after orthotopic liver transplantation. Overnight ambulatory blood pressure profiles were studied in 13 pretransplant ESLD patients and in 34 patients (FK506: n = 13; CSA: n = 21) treated with different steroid doses (24 +/- 11 mg/day FK506; 34 +/- 3 mg/day CSA), according to protocol, 4 weeks (range, 2 to 7 weeks) after liver transplant. Mean blood pressure and heart rate values from awake and nocturnal 5-h time blocks were compared to 13 normotensive control subjects. Patients with ESLD were normotensive and maintained a normal nocturnal blood pressure fall (125 +/- 3/74 +/- 2 mm Hg awake; 109 +/- 3/60 +/- 2 mm Hg nocturnal). Awake ambulatory blood pressures were higher in CSA patients than in FK506 patients (148 +/- 3/95 +/- 2 v 128 +/- 3/78 +/- 2 mm Hg, respectively; P < .01), despite reduced glomerular filtration rates in both transplant groups. Both immunosuppressive regimens led to a loss of nocturnal blood pressure fall, as compared to ESLD patients or normotensive controls.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Loss of nocturnal blood pressure fall after liver transplantation during immunosuppressive therapy. 754 83

Although cyclosporine (CsA)-based immunosuppressive regimens have been highly successful in renal transplantation in infants and children, their adverse influence on somatic growth, general appearance, and blood pressure are of particular importance in this population. Over the past 4 years, we have utilized tacrolimus (formerly FK-506) as the primary immunosuppressive agent in 43 unselected children and achieved 1-year and 3-year allograft survival rates of 96% and 85%, respectively. We have also used tacrolimus to rescue 14 of 19 (74%) renal allografts from CsA-resistant rejection. Corticosteroids were discontinued in 62% of non-rescue patients without increasing the risk of rejection or renal dysfunction over a mean follow-up time of 25 months. Tacrolimus monotherapy has been associated with improved body growth and less obesity, while tacrolimus alone or in combination with prednisone was virtually free of hirsutism or gingival hypertrophy, and posed a low risk for hypertension. A major disadvantage of this regimen may be an increased risk for viral infections and a benign form of posttransplant lymphoproliferative disease. This article describes the tacrolimus protocol utilized in our center and focuses on practical clinical issues including therapeutic monitoring, benefits, and major toxicity in children with renal allografts.
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PMID:Clinical use of tacrolimus (FK-506) in infants and children with renal transplants. 757 18

The application of lung transplantation to the pediatric population was a natural extension of the success realized in our adult transplantation program, which began in 1982. Twenty pediatric patients (age range 3 to 18 years) have had heart-lung (n = 11), double lung (n = 8), and single lung (n = 1) transplantation procedures. The causes of end-stage lung disease were primary pulmonary hypertension (n = 7), congenital heart disease (n = 5), cystic fibrosis (n = 4), pulmonary arteriovenous malformation (n = 2), graft-versus-host disease (n = 1), and desquamative interstitial pneumonitis (n = 1). Four (20%) patients had thoracic surgical procedures before the transplantation operation. The survival was 80% at a mean follow-up of 2 years. Immunosuppressive drugs included cyclosporine (n = 9) or FK 506 (n = 11) based therapy with azathioprine and steroids. Children were followed up by means of spirometry, transbronchial biopsy, and primed lymphocyte testing of bronchoalveolar lavage fluid. The mean number of treated episodes of rejection was 1.4 at 30 days, 0.5 at 30 to 90 days, and 1.4 at more than 90 days, and the first treated rejection episode occurred on average 28 days after the operation. Obliterative bronchiolitis developed in four (25%) of 16 patients surviving more than 100 days. Results of pulmonary function tests have remained good in almost all recipients. The greatest infectious risk was that of cytomegalovirus: one death and one case of pneumonia. Posttransplantation lymphoproliferative disease was diagnosed in two (12.5%) patients; both recovered. The most common complications were hypertension (25%) and postoperative bleeding (15%). Early results indicate that lung transplantation is a most promising therapy for children with severe vascular and parenchymal lung disease.
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PMID:Pediatric lung transplantation. The years 1985 to 1992 and the clinical trial of FK 506. 767 72

The new immunosuppressive agent FK506 was used with steroids to treat 22 pediatric patients who received living-related partial liver transplantation. Seventeen recipients survived and 5 died between one and 16 months after transplantation. Three of the 5 patients who died had required intensive care preoperatively. Autopsy findings showed no evidence of rejection. There was no episode of rejection that required retransplantation in any of the patients. Liver allograft dysfunction, which was suspected to be a rejection response, was encountered in 2 recipients with ABO-nonidentical but compatible grafts. However, their clinical and biochemical findings were ameliorated upon steroid pulse therapy or upon augmented FK506 administration without additional potent immunosuppressive agents. Steroid treatment has been discontinued in all surviving patients at 1-9 months after transplantation. Infectious complications encountered in 9 patients included 2 bacterial, 5 viral, and 2 fungal infections. One recipient died of fungal pneumonia. Abnormal increase of serum creatinine level was confined to the complicated patients. Hypertension was a temporary adverse reaction in the early postoperative period, and only one patient needed an antihypertensive drug at 2 months after transplantation. Acute pancreatitis with hyperamylasemia was observed in one patient who was treated successfully with reduction of FK506 administration. Tremor was observed in 8 patients, itching in 4, insomnia in 2, and vomiting in one. Hirsutism, gingival hypertrophy, and lymphoma were not observed. FK506 was highly effective in living-related partial liver transplantation not only in terms of immunosuppressive potential but also because it produced fewer adverse effects.
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PMID:Experience with FK506 in living-related liver transplantation. 767 28

The decade from 1982 through 1992 witnessed tremendous growth in pediatric cardiac transplantation. At Children's Hospital of Pittsburgh 66 cardiac transplants were performed during this period (age range 7 hours to 18 years). The cause of cardiomyopathy was congenital (n = 30), cardiomyopathy (n = 29), myocarditis (n = 2), doxorubicin toxicity (n = 2), ischemic (n = 1), valvular (n = 1), and cardiac angiosarcoma (n = 1). Nine children (14%) required mechanical circulatory support before transplantation: extracorporeal membrane oxygenation (n = 8) and Novacor left ventricular assist system (n = 1) (Baxter Healthcare Corp., Novacor Div., Oakland, Calif.). The mean follow-up time was 2 years (range 4 months to 8 years). The overall survival in the group was 67%. In children with congenital heart disease (> 6 months of age) the perioperative (30 day) mortality was 66% before mid-1988 (n = 10) and 0% since mid-1988 (n = 11). The late mortality (> 30 days) in children with cardiomyopathy transplanted prior to mid-1988 was 66% (n = 14) and 7% since mid-1988 (n = 15). Since mid-1988 1- and 3-year survival was 82% in children with congenital heart disease and 90% in children with cardiomyopathy. Twenty-six children have had FK 506 as their primary immunosuppressive therapy since November 1989. Survival in this group was 82% at 1 and 3 years. The actuarial freedom from grade 3A rejection in the FK group was 60% at 3 and 6 months after transplantation versus 20% and 12%, respectively, in the 15 children operated on before the advent of FK 506, who were treated with cyclosporine-based triple-drug therapy (p < 0.001, Mantel-Cox and Breslow). Twenty of 24 children (83%) in the FK 506 group are receiving no steroids. The prevalence of posttransplantation hypertension was 4% in the FK 506 group versus 70% in the cyclosporine group (p < 0.001, Fisher). Renal toxicity in children treated with FK 506 has been mild. Additionally, eight children have been switched to FK 506 because of refractory rejection and drug toxicity. FK 506 has not produced hirsutism, gingival hyperplasia, or abnormal facial bone growth. The absence of these debilitating side effects, together with the observed immune advantage and steroid-sparing effects of FK 506, hold tremendous promise for the young patient facing cardiac transplantation and a future wedded to immunosuppression.
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PMID:A decade (1982 to 1992) of pediatric cardiac transplantation and the impact of FK 506 immunosuppression. 768 Mar 96

Immunosuppression after transplantation is complicated by hypertension and nephrotoxicity, reflecting widespread vasoconstriction associated with CsA. FK506 is a novel alternative immunosuppressive agent, structurally unrelated to CsA. These studies compared systemic and renal vascular changes developing in the initial 4 weeks after liver transplantation in patients treated with FK506 (plus PRED) and CsA (plus PRED and AZA). We studied arterial pressure, cardiac index (pulsed doppler ultrasound), and systemic resistance index (SVRI) before and weekly after liver transplant in 32 patients treated with CsA (2 mg/kg initial dose plus PRED; median dose at week 4, 30 mg/day) and 14 patients treated with FK506 (0.15 mg/kg/day initial dose and PRED; mean week 4 dose, 12.5). Renal plasma flow and glomerular filtration rate (GFR) were measured by clearance of para-amino hippurate and 125-iothalamate. Renin activity, aldosterone, and urinary prostanoids were measured by RIA. Pretransplant pressures and hemodynamics reflected low SVRI and increased cardiac index typical of end-stage liver disease. After transplantation, SVRI and pressures rose in both groups, but after week 2, SVRI was lower in patients treated with FK506. This was associated with less prevalent clinical hypertension during the subsequent 4 months (4/14 FK506 (28%) vs. 25/32 (78%) CsA, P < 0.01). By contrast, renal blood flow and GFR fell in both treatment groups similarly, whereas renal vascular resistance rose. Urinary 6-keto-PG-F1-alpha was suppressed in all transplant recipients, but to a greater degree in FK506-treated patients. This value correlated directly to post-transplant GFR (r = 0.48, P < 0.001). These data indicate that FK506-based immunosuppression differs from CsA by inducing less systemic vasoconstriction and hypertension. Renal vasoconstrictive effects were at least as great as those seen with CsA, however, and indicate that nephrotoxicity will remain a common feature to both regimens.
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PMID:Systemic and renal hemodynamic differences between FK506 and cyclosporine in liver transplant recipients. 768 34

Cyclosporine A (CsA)-induced hypertension appears to be caused in part by neurogenic vasoconstriction, but the mechanism by which CsA activates the sympathetic nervous system is unknown. In T lymphocytes, the cellular target of CsA and the macrolide immunosuppressant FK506 (as complexes with their endogenous cytoplasmic receptors, or immunophilins) is the Ca(2+)-calmodulin-dependent phosphatase calcineurin. The presence of calcineurin and its colocalization with immunophilin in the brain led us to hypothesize that the phosphatase also mediates CsA-induced sympathetic activation. We now report that sympathetic activity and arterial pressure in rats are increased not only by CsA but also by FK506, which is structurally unrelated to CsA but inhibits the same calcineurin-sensitive T-cell signaling pathway. In contrast, sympathetic activity and blood pressure are not increased by rapamycin, which forms an immunophilin complex that does not bind calcineurin. Furthermore, CsA- and FK506-induced sympathetic activation is attenuated for drug analogues possessing modest changes in molecular structure in a way that closely parallels the ability of each analogue to inhibit calcineurin-mediated T-cell signaling. These results implicate an important role for extralymphoid (ie, neuronal) calcineurin in mediating immunosuppressive drug toxicity.
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PMID:Cyclosporine- and FK506-induced sympathetic activation correlates with calcineurin-mediated inhibition of T-cell signaling. 768 70

Seventy-two long-surviving liver transplant recipients were evaluated prospectively, including a baseline allograft biopsy for weaning off of immunosuppression. Thirteen were removed from candidacy because of chronic rejection (n = 4), hepatitis (n = 2), patient anxiety (n = 5), or lack of cooperation by the local physician (n = 2). The other 59, aged 12-68 years, had stepwise drug weaning with weekly or biweekly monitoring of liver function tests. Their original diagnoses were PBC (n = 9), HCC (n = 1), Wilson's disease (n = 4), hepatitides (n = 15), Laennec's cirrhosis (n = 1), biliary atresia (n = 16), cystic fibrosis (n = 1), hemochromatosis (n = 1), hepatic trauma (n = 1), alpha-1-antitrypsin deficiency (n = 9), and secondary biliary cirrhosis (n = 1). Most of the patients had complications of long-term immunosuppression, of which the most significant were renal dysfunction (n = 8), squamous cell carcinoma (n = 2) or verruca vulgaris of skin (n = 9), osteoporosis and/or arthritis (n = 12), obesity (n = 3), hypertension (n = 11), and opportunistic infections (n = 2). When azathioprine was a third drug, it was stopped first. Otherwise, weaning began with prednisone, using the results of corticotropin stimulation testing as a guide. If adrenal insufficiency was diagnosed, patients reduced to < 5 mg/day prednisone were considered off of steroids. The baseline agents (azathioprine, cyclosporine, or FK506) were then gradually reduced in monthly decrements. Complete weaning was accomplished in 16 patients (27.1%) with 3-19 months drug-free follow-up, is progressing in 28 (47.4%), and failed in 15 (25.4%) without graft losses or demonstrable loss of graft function from the rejections. This and our previous experience with self-weaned and other patients off of immunosuppression indicate that a significant percentage of appropriately selected long-surviving liver recipients can unknowingly achieve drug-free graft acceptance. Such attempts should not be contemplated until 5-10 years posttransplantation and then only with careful case selection, close monitoring, and prompt reinstitution of immunosuppression when necessary.
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PMID:Weaning of immunosuppression in long-term liver transplant recipients. 783 42

This article reviews the current state of knowledge concerning cyclosporine A-induced hypertension after heart transplantation, its pathophysiology and management. The hypothesis is presented that a common molecular mechanism mediates both the immunosuppressive and the hypertensive actions of cyclosporine. The calcium-calmodulin dependent phosphatase, calcineurin, is the common cellular target mediating the salient immunosuppressive effects of both cyclosporine A and FK506. Calcineurin is even more plentiful in nonlymphoid tissues such as the nervous system, muscle, and kidney. Because these are the main target sites for cyclosporine A-induced toxicity, it has been hypothesized recently that inhibition of calcineurin mediates cyclosporine A-induced toxicity. This hypothesis is supported by increasing experimental evidence, at both the whole animal and cellular levels, indicating that the toxicity profile of cyclosporine A is duplicated by FK506 but not by rapamycin, a structural analog of FK506 which is a potent immunosuppressive agent but has no effect on calcineurin. Recent multicenter trials demonstrate that in the clinical setting the hypertensive and other side effects of cyclosporine A are duplicated by FK506. The clinical toxicity of rapamycin is as yet unknown.
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PMID:Hypertension after cardiac transplantation: pathophysiology and management. 856 50


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