Purpose: Peritransplant renal dysfunction has been associated with poor long-term patient and graft survival in liver transplant recipients. Belatacept was utilized in the perioperative period in patients with acute kidney injury in an effort to minimize the renal toxicities associated with calcineurin inhibitor (CNI)-based immunosuppression. Methods: A retrospective review of adult liver transplant recipients receiving belatacept was conducted under IRB approval. Belatacept use was approved by our institutional Pharmacy and Therapeutics Committee as a bridge to renal recovery in patients not suitable for alternative therapy. Patients were maintained on mycophenolate and steroids. Hepatitis C positive recipients were weaned off steroids in three days. All patients were required to be EBV IgG seropositive. Results: Between 2011 and 2013, 16 liver transplant recipients received belatacept immunosuppression due to perioperative renal dysfunction. 14 patients (87%) underwent liver transplantation alone. Two patients underwent combined liver-kidney transplant. 9 patients (56%) were on dialysis prior transplant (median 13, range 1-3285 days). 12 patients (75%) were trialed on a CNI-based regimen prior to transition to belatacept. 4 were started on belatacept on postoperative days 10±10 prior to a CNI trial. 12 patients (75%) were on dialysis at the time of belatacept initiation. The remaining 4 patients had an estimated GFR of 25±10 mL/min/1.73m2. 9 of 12 patients who had been dialysis dependent (75%) were dialysis free within 2 weeks of belatacept initiation. Patients who were not on dialysis at the time of belatacept initiation showed improvement in eGFR (59±2 mL/min/1.73m2). Belatacept duration was 48±54 days (range 15-209 days). 3 patients (19%) remain on belatacept at present. Patients received 4±2 doses (range 2-10). Conclusions: Belatacept was safe and effective immunosuppressive therapy in patients with renal failure after liver transplant. Most patients can be transitioned to CNI-based immunosuppression after recovery of renal function. Larger comparative studies are needed to define advantages of belatacept-based therapy over conventional immunosuppression.

Background: In an effort to avoid perioperative renal dysfunction in liver transplant recipients, our center has incorporated transient belatacept therapy in patients intolerant of conventional calcineurin inhibitor (CNI)-based regimens. As early clinical trials suggested an increased risk of graft loss and death, recipient safety monitoring is critical to this initiative. Methods: A retrospective review of adult liver transplant recipients receiving belatacept was conducted under IRB approval. Belatacept use was approved by our institutional Pharmacy and Therapeutics Committee as a bridge to renal recovery in patients not suitable for alternative therapy. All patients were EBV IgG seropositive. Patients were maintained on mycophenolate and steroids. Hepatitis C positive recipients underwent a 3-day steroid taper. The primary endpoint was patient and graft survival, with secondary endpoints including the incidence of acute rejection and occurrence of major adverse effects. Results: Belatacept was administered to 18 liver transplant recipients between 2011 and 2013. 14 patients underwent liver transplantation alone. Four patients underwent combined liver-kidney transplant. The indication for belatacept use was nephrotoxicity in 89% and neurotoxicity in 11%. Belatacept was initiated 15±20 days post-transplant and was used for 51±54 days. 3 patients remain on therapy. The remainder were switched to a CNI (72%) or mTOR inhibitor (5%). Three patients experienced rejection on belatacept therapy at 19, 19, and 55 days after belatacept initiation. Banff scores were 5, 5, and 4, respectively. One patient had experienced previous rejection on CNI therapy. One patient was diagnosed with borderline PTLD 4 months post-transplant that had a complete response to rituximab. This patient received 2 doses of belatacept in the first post-transplant month, and had been maintained on tacrolimus for 3 months prior to diagnosis. One patient died of post-operative fungal sepsis on POD 37 while on belatacept therapy. Conclusions: In our cohort, temporary belatacept-based immunosuppression had an acceptable safety profile. These preliminary findings warrant further study in a randomized clinical trial.

Increased cardiac performance has been documented in patients with early systemic hypertension, but its prevalence and determinants in patients with uncomplicated sustained essential hypertension have not been characterized. Radionuclide cineangiography in 116 patients with uncomplicated essential hypertension showed that 12 of 116 (10%) had supranormal resting left ventricular (LV) ejection fraction (>70%, above the highest value in normal subjects), while 104 patients had a normal resting ejection fraction (45 to 70%). Patients with a high resting ejection fraction had higher systolic and diastolic blood pressure compared with patients with normal resting ejection fraction (182 mm Hg vs 169, p < 0.01, and 110 vs 103, p < 0.05, respectively), markedly greater echocardiographic LV mass (136 vs 94 g/m2, p < 0.01), smaller ventricular dimensions in systole (2.5 vs 3.1, p < 0.01) and diastole (4.4 vs 4.9, p < 0.05), and higher relative wall thickness (0.61 ± 0.20 vs 0.39 ± 0.98, p < 0.001). Patients with supranormal resting ventricular performance had lower end-systolic wall stress than normal volunteers or patients with normal resting LV function (48 vs 64 vs 74 × 103 dynes/cm2, respectively). Patients with an elevated LV ejection fraction also had significantly more abnormal funduscopic examinations and greater proteinuria. Thus, a subset of essential hypertensive patients with moderately to severely elevated blood pressure developed marked concentric LV hypertrophy associated with subnormal end-systolic stress and supranormal LV performance. These patients manifested greater peripheral target organ damage than patients with lower ejection fraction but lesser hypertrophy, suggesting that the severity of their hypertensive cardiovascular disease is more accurately reflected by indexes of cardiac hypertrophy than of LV performance.

Human peripheral blood mononuclear cells were incubated for 1 hr in 4-hydroperoxycyclophosphamide (0.5 to 10.0 micrograms/ml), and the adherent, esterase-positive cells (macrophages) were studied. At 2 hr, a reduction was noted in both latex particle ingestion and Fc gamma receptor binding and phagocytosis. At 24 hr, spreading and pinocytosis were reduced, and cytoplasmic vacuoles developed. This vacuolization represented dilatation of the rough endoplasmic reticulum. These morphological and functional changes occurred with 4-hydroperoxycyclophosphamide concentrations which did not reduce viability or produce detectable DNA alkylation. This effect on macrophages may offer a mechanism whereby low-dosage cyclophosphamide could modify the immune response.

HomeCirculationVol. 68, No. 3Left ventricular hypertrophy in patients with hypertension: importance of blood pressure response to regularly recurring stress. Free AccessAbstractPDF/EPUBAboutView PDFSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessAbstractPDF/EPUBLeft ventricular hypertrophy in patients with hypertension: importance of blood pressure response to regularly recurring stress. R B Devereux, T G Pickering, G A Harshfield, H D Kleinert, L Denby, L Clark, D Pregibon, M Jason, B Kleiner, J S Borer and J H Laragh R B DevereuxR B Devereux Search for more papers by this author , T G PickeringT G Pickering Search for more papers by this author , G A HarshfieldG A Harshfield Search for more papers by this author , H D KleinertH D Kleinert Search for more papers by this author , L DenbyL Denby Search for more papers by this author , L ClarkL Clark Search for more papers by this author , D PregibonD Pregibon Search for more papers by this author , M JasonM Jason Search for more papers by this author , B KleinerB Kleiner Search for more papers by this author , J S BorerJ S Borer Search for more papers by this author and J H LaraghJ H Laragh Search for more papers by this author Originally published1 Sep 1983https://doi.org/10.1161/01.CIR.68.3.470Circulation. 1983;68:470–476 Previous Back to top Next FiguresReferencesRelatedDetailsCited By Otto A, Soriano E, Birmingham W, Vadaparampil S, Heyman R, Ellington L and Reblin M (2021) Impact of Relationship and Communication Variables on Ambulatory Blood Pressure in Advanced Cancer Caregivers, Annals of Behavioral Medicine, 10.1093/abm/kaab057, 56:4, (405-413), Online publication date: 2-Apr-2022. 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Patients with systemic arterial hypertension are classified primarily on the basis of the severity of arterial pressure elevation and often, as well, on the basis of biochemical descriptors such as plasma renin activity. However, while such classification is useful for prognostic and therapeutic purposes, 1 Veterans Administration Cooperative Study Group on Hypertensive Agents Effects of treatment on morbidity in hypertension. III. Influence of age, diastolic pressure, and prior cardiovascular disease, further analysis of side effects. Circulation. 1972; 45: 991-1004 Crossref PubMed Scopus (376) Google Scholar 2 Brunner HR Laragh JH Baer L Newton N Goodwin FF Krakoff LR et al. Essential hypertension: renin and aldosterone, heart attack and stroke. N Engl J Med. 1972; 286: 441-449 Crossref PubMed Scopus (938) Google Scholar accurate, precise prediction of the clinical outcome in the individual hypertensive patient cannot be achieved by this approach. Since the left ventricle can be considered an “end organ,” the function of which reflects the results of hypertension, it is not unreasonable to hypothesize that assessment of left ventricular performance, and particularly of the load-independent alterations in left ventricular function, may be valuable adjuncts in the determination of risk and evaluation of therapy in the hypertensive patient.

Patients with systemic arterial hypertension are classified primarily on the basis of the severity of arterial pressure elevation and often, as well, on the basis of biochemical descriptors such as plasma renin activity. However, while such classification is useful for prognostic and therapeutic purposes, 1 Veterans Administration Cooperative Study Group on Hypertensive Agents Effects of treatment on morbidity in hypertension. III. Influence of age, diastolic pressure, and prior cardiovascular disease, further analysis of side effects. Circulation. 1972; 45: 991-1004 Crossref PubMed Scopus (376) Google Scholar 2 Brunner HR Laragh JH Baer L Newton N Goodwin FF Krakoff LR et al. Essential hypertension: renin and aldosterone, heart attack and stroke. N Engl J Med. 1972; 286: 441-449 Crossref PubMed Scopus (938) Google Scholar accurate, precise prediction of the clinical outcome in the individual hypertensive patient cannot be achieved by this approach. Since the left ventricle can be considered an “end organ,” the function of which reflects the results of hypertension, it is not unreasonable to hypothesize that assessment of left ventricular performance, and particularly of the load-independent alterations in left ventricular function, may be valuable adjuncts in the determination of risk and evaluation of therapy in the hypertensive patient.

Assessment of left ventricular function may be of value in patients with pressure-loaded, hypertrophied left ventricles for the purpose of characterizing such patients as to prognostic risk. To determine whether left ventricular function is in part independent of loading stresses in such patients, and to assess the effects of removal of loading factors, we have reviewed preliminary data in 60 patients with essential hypertension and in 26 patients with aortic stenosis who were studied with radionuclide cineangiography. Patients with hypertension manifested a poor but statistically significant direct relationship between systolic arterial pressure and left ventricular ejection fraction at rest, and a poor but significant inverse relationship between systolic pressure and the magnitude of change in ejection fraction from rest to exercise. However, a strong correlation existed between echocardiographic systolic fractional shortening and end-systolic wall stress at rest. Nonetheless, many patients with normal fractional shortening-end-systolic wall stress relationships had subnormal ejection fraction responses during exercise; the two patients with subnormal fractional shortening-end-systolic wall stress relationships at rest also had subnormal fractional shortening-end-systolic wall stress relationships during exercise. Arterial pressure alone was not predictive of these functional responses. These data suggest that hypertensive patients can be categorized on the basis of left ventricular function at rest and during exercise, independent of arterial pressure. Among patients with aortic stenosis, ejection fraction at rest averaged 67 percent before valve replacement (normal = 57 percent, p < 0.01), and changed little after operation (71 percent, not significant). However, potential functional benefits of afterload reduction in the patient with the chronically pressure-loaded, hypertrophied left ventricle was suggested by results during exercise: before surgery the ejection fraction during exercise averaged 56 percent (normal = 71 percent, p <0.01), but after valve replacement it rose to 72 percent (not significant versus normal). Thus, our data in patients with aortic stenosis supplement our data in patients with hypertension, indicating that myocardial functional improvement can be achieved by unloading therapy in patients with long-standing left ventricular pressure-loading and hypertrophy.