99mTc-DTPA and 131I-hippuran findings in liver transplant recipients treated with cyclosporin A.

The effects of cyclosporin A (CyA), an immunosuppressive agent that is potentially nephrotoxic, on the kidneys of 9 liver transplant recipients were studied with serial 99mTc-DTPA and 131I-hippuran scans. In addition, renal function was determined by measuring serum creatinine levels during the second postoperative week in the 9 unselected CyA-treated patients and, retrospectively, in a control group of 29 liver transplant recipients who had not been treated with CyA and who were selected because they had survived for at least 3 months postoperatively. The early postoperative creatinine level was significantly greater in the CyA group. Eight of the 9 CyA patients showed imaging abnormalities in all preoperative and postoperative studies. Five of the 8 patients showed a pattern similar to that of acute tubular necrosis (relatively preserved perfusion) in at least one study. Lowering the dosage of CyA permitted the continuation of therapy, and all 9 patients are alive after 8 to 14 months

Thoracic duct drainage before and after cadaveric kidney transplantation

Twenty-seven consecutive recipients of cadaveric kidneys, including five with pre-existing warm cytotoxic antibodies, were treated with thoracic duct drainage before and after transplantation. Fourteen patients who had lymph drainage for 26 to 58 days before transplantation had minor cytotoxic antibody responses after grafting, even if the antibodies had been present before therapy. Only one of the 14 recipients had any rejection during the follow-up periods of one to six months. There were two deaths. The 13 patients pretreated for 17 to 23 days exhibited stronger cytotoxic antibody responsiveness, and five of these recipients had significant rejections of which four were reversible. One of the latter 13 patients died. These clinical and immunologic studies have established the value and have defined the appropriate timing of preoperative thoracic duct drainage in kidney transplantation. They have also directed attention to the rationale and the probable value of using other immunosuppressive methods for preparatory host conditioning instead of beginning such therapy at the time of transplantation

The quality of life after liver transplantation

The quality of life after liver transplantation ranges from poor to superior. The social and vocational outcome is dependent on the quality of homograft function and on the steroid doses necessary to maintain function. A good long-term prognosis is usually evident by 1 year postoperatively. The complete rehabilitation of so many patients has encouraged us to continue our efforts in this difficult field

Liver transplantation - 1978

The development of liver transplantation has been made difficult because of the enormous technical difficulties of the procedure and because the postoperative management in early cases was defective in many instances. With surgical and medical improvements, the prospects for success have markedly increased recently. The wider use of thoracic duct fistula as an adjuvant measure during the first 1 or 2 postoperative months is being explored

The use of cyclosporin A and prednisone in cadaver kidney transplantation

Eighteen patients were treated with primary cadaveric renal transplantation using cyclosporin A therapy, and four more patients underwent cadaveric retransplantation. Eleven of the 22 recipients were conditioned with lymphoid depletion before transplantation, using thoracic duct drainage or lymphapheresis for two to eight and one-half weeks. cyclosporin A was begun a few hours before grafting. The other 11 patients were pretreated wtih cyclosporin A for from one day to 18 days. After transplantation, the majority of patients in both subgroups of 11 had rejection develop, but in most, the immunologic process was readily controlled with relatively small dosages of prednisone. After follow-up periods of two to four and one-half months, one patient has died of the complications of a coronary artery reconstruction that was not related to the transplantation. Another graft was lost from rejection, and a third organ was removed because of ureteral necrosis. Nineteen of the original 22 cadaveric kidneys are functioning, including 17 of the 18 kidneys given to patients who were undergoing transplantation for the first time. The only loss in the latter group of 18 patients was in the patient who died after an open heart operation. Results of these studies have shown that cyclosporin A is a superior and safe immunosuppressive drug but that, for optimal use in cadaveric transplantation, it usually should not be given alone. Steroid therapy greatly amplified the value of cyclosporin A. Unless major delayed morbidity develops which is not obvious so far, this drug combination should permit revolutionary advances ion the transplantation of all organs. Other adjunct to the cyclosporin A-steroid combination, including lymphoid depletion techniques, will require further investigation

Thoracic duct fistula and renal transplantation

Thoracic duct drainage (TDD) was established for 21-115 days in 40 kidney recipients with an average removal per patient day of 4.7 1 lymph and 1.88 billion cells. Cellular and humoral immunity were depressed. TDD and immunosuppressive drugs were started at transplantation in 35 recipients of cross-match negative grafts. Although the results were better than in precedent non-TDD controls, eight patients rejected their grafts before a full TDD effect, and three of the eight developed predominantly anti-B lymphocyte cytotoxic antibodies which were probably responsible for positive cross-matches with their next donors. With continuing TDD, all eight patients had good initial function after early retransplantation. In five more 'nontransplantable' patients with performed cytotoxic antibodies, TDD was started 30-56 days before transplantation. In these five pretreated patients, antibodies persisted with positive antidonor cross-matches. Hyperacute rejection occurred repeatedly in two patients with high anti-T (and anti-B) titers, but was surmounted in three patients with lower titers. From the clinical and immunologic data, we have concluded that TDD should be used for pretreatment of all cases with or without prior antibodies, and have suggested an adjustable management plan that takes into account new developments in antibody monitoring

Novel insights into the mechanisms mediating the local antihypertrophic effects of cardiac atrial natriuretic peptide: role of cGMP-dependent protein kinase and RGS2

Cardiac atrial natriuretic peptide (ANP) locally counteracts cardiac hypertrophy via the guanylyl cyclase-A (GC-A) receptor and cGMP production, but the downstream signalling pathways are unknown. Here, we examined the influence of ANP on β-adrenergic versus Angiotensin II (Ang II)-dependent (Gs vs. Gαq mediated) modulation of Ca2+i-handling in cardiomyocytes and of hypertrophy in intact hearts. L-type Ca2+ currents and Ca2+i transients in adult isolated murine ventricular myocytes were studied by voltage-clamp recordings and fluorescence microscopy. ANP suppressed Ang II-stimulated Ca2+ currents and transients, but had no effect on isoproterenol stimulation. Ang II suppression by ANP was abolished in cardiomyocytes of mice deficient in GC-A, in cyclic GMP-dependent protein kinase I (PKG I) or in the regulator of G protein signalling (RGS) 2, a target of PKG I. Cardiac hypertrophy in response to exogenous Ang II was significantly exacerbated in mice with conditional, cardiomyocyte-restricted GC-A deletion (CM GC-A KO). This was concomitant to increased activation of the Ca2+/calmodulin-dependent prohypertrophic signal transducer CaMKII. In contrast, β-adrenoreceptor-induced hypertrophy was not enhanced in CM GC-A KO mice. Lastly, while the stimulatory effects of Ang II on Ca2+-handling were absent in myocytes of mice deficient in TRPC3/TRPC6, the effects of isoproterenol were unchanged. Our data demonstrate a direct myocardial role for ANP/GC-A/cGMP to antagonize the Ca2+i-dependent hypertrophic growth response to Ang II, but not to β-adrenergic stimulation. The selectivity of this interaction is determined by PKG I and RGS2-dependent modulation of Ang II/AT1 signalling. Furthermore, they strengthen published observations in neonatal cardiomyocytes showing that TRPC3/TRPC6 channels are essential for Ang II, but not for β-adrenergic Ca2+i-stimulation in adult myocytes