QT prolongation and near fatal cardiac arrhythmia after intravenous tacrolimus administration: a case report.

BACKGROUND: The use of immunosuppressant agents is mandatory in the long-term management of transplant recipients. Herein, we report a case of near fatal cardiac arrhythmia related to the use of intravenous tacrolimus in a 35-year-old woman undergoing renal transplantation. METHODS: The patient had no previous history of cardiac disease, but an initial electrocardiogram demonstrated slightly prolonged QT and QTc intervals and normal sinus rhythm. Postsurgical immunosuppression included intravenous tacrolimus and methylprednisolone. During intravenous tacrolimus infusion, marked QT prolongation occurred. The patient suffered recurrent runs of torsade de pointes, refractory to aggressive medical management and requiring numerous defibrillations. Rapid atrial pacing eventually controlled the arrhythmia. RESULTS: We note not only a temporal association, but also a direct linear relationship, between this arrhythmia and blood tacrolimus levels. CONCLUSION: We believe this case presents a little recognized hazard associated with the use of intravenous tacrolimus and points to the need for careful predrug screening for QT prolongation. Tacrolimus has been shown to effect intracellular calcium and to prolong the action potential duration experimentally. This suggests that an increase in the intracellular calcium may underlie torsades de pointes associated with intravenous tacrolimus.

Ten years' experience with continuous ambulatory peritoneal dialysis.

Up to January 1989, 171 patients were trained at our center on continuous ambulatory peritoneal dialysis (CAPD), and 17 on continuous cyclic peritoneal dialysis (CCPD). Over 10 years, we have gained 5,068 patient-months experience. Patient survival was 60% and 31% at 5 and 10 years, respectively. In contrast, diabetics had a survival of 32% at 5 years. Major complications included 499 new episodes of peritonitis, 304 exit-site infections, 22 hernias, five bowel perforations, one hydrothorax, and three episodes of sclerosing encapsulating peritonitis. Our technique survival has been 62% and 40% at 5 and 10 years, respectively. We believe that CAPD is a viable dialysis technique for long-term treatment of chronic renal failure and it should be offered as an option to intermittent hemodialysis.

Calcium channel activity of purified human synexin and structure of the human synexin gene.

Synexin is a calcium-dependent membrane binding protein that not only fuses membranes but also acts as a voltage-dependent calcium channel. We have isolated and sequenced a set of overlapping cDNA clones for human synexin. The derived amino acid sequence of synexin reveals strong homology in the C-terminal domain with a previously identified class of calcium-dependent membrane binding proteins. These include endonexin II, lipocortin I, calpactin I heavy chain (p36), protein II, and calelectrin 67K. The Mr 51,000 synexin molecule can be divided into a unique, highly hydrophobic N-terminal domain of 167 amino acids and a conserved C-terminal region of 299 amino acids. The latter domain is composed of alternating hydrophobic and hydrophilic segments. Analysis of the entire structure reveals possible insights into such diverse properties as voltage-sensitive calcium channel activity, ion selectivity, affinity for phospholipids, and membrane fusion.

Renal scans in pregnant transplant patients.

This study demonstrates the normal technetium-99m diethylenetriaminepentaacetic acid ([99mTc]DTPA) renal scan in pregnant patients with transplanted kidneys. Five pregnant renal transplant patients had seven [99mTc]DTPA renal studies to assess allograft perfusion and function. All scans showed the uteroplacental complex. The bladder was always compressed and distorted. The transplanted kidney was frequently rotated to a more vertical position. In all patients allograft flow and function were maintained. There was calyceal retention on all studies and ureteral retention activity in three of five patients. Using the MIRD formalism, the total radiation absorbed dose to the fetus was calculated to be 271 mrad. This radiation exposure is well within NRCP limits for the fetus of radiation workers and an acceptable low risk in the management of these high risk obstetric patients.

Leukotrienes, thromboxane, and platelet activating factor in organ transplantation.

The antirejection eicosanoids--PGE2, (PGD2), and PGI2--have an attenuating effect on T-cell proliferation by inhibition of IL-1, IL-2, and class II antigen expression on macrophages, and the prorejection eicosanoids--TXA2, LTB4, LTC4, and LTD4--enhance T-cell proliferation. LTB4 stimulates IL-1 and IL-2 formation and expression of IL-2 receptor. The mechanism of enhancement of T-cell proliferation by TXA2 has not been demonstrated. LTC4 and LTD4 promote gamma-interferon release and can replace IL-2 as a stimulator of gamma-interferon. PAF at high concentrations inhibits lymphocyte proliferation. The eicosanoids interfere with the same mechanisms as CsA and corticosteroids on T-cell clonal expansion. In experimental organ transplantation, corticosteroids can be replaced by compounds preventing the formation or expression of the prorejection eicosanoids or analogs of antirejection eicosanoids as well as by PAF antagonists. In addition, these drugs exert synergistic effect with CsA and azathioprine.

Early immunological prediction of renal allograft rejection.

Reliable predictors of impending renal allograft rejection would be valuable for better patient management. To date, no available test has been shown to be consistently predictive and results have often been conflicting. We evaluated an effector of cell-mediated immunity, antibody-dependent cell-mediated cytotoxicity (ADCC) as well as the response of these cells to different biological response modifiers (BRM) in patients following renal allograft transplantation. The in vitro test used assayed monocytes as ADCC effector cells against antibody-sensitized chicken red blood cells. The effects of BRM were studied by preincubating the monocytes with lymphoblastoid IFN, recombinant alpha 2-interferon or gamma-interferon. A follow-up study was performed on 47 patients with end-stage renal disease treated with renal allograft transplantation. ADCC activity and its response to BRM were assayed prior to transplantation, 2, 4, and 9 weeks post transplantation. In the case of rejection, ADCC was then studied prior to initiation of antirejection therapy and for 2 months following treatment of rejection episode. We noted that in patients with stable grafts, the ADCC activity as well as its response to BRM declined gradually during the first 2 weeks post grafting and remained decreased up to 3 months after transplantation. In contrast, in recipients who experienced rejection episodes there was a sustained and significant increase in ADCC response to BRM during the first 3 weeks post grafting. By the time the diagnosis of rejection had been established the baseline ADCC activity had also increased. Following treatment and stabilization of the graft, ADCC activity and its response to BRM was decreased, similar to that in patients with stable grafts.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell-mediated immunity and biological response modifiers in insulin-dependent diabetes mellitus complicated by end-stage renal disease.

Previous studies have shown several immunoregulatory abnormalities in insulin-dependent diabetes mellitus (IDDM). In this report we compared peripheral blood mononuclear cells (PBMC) from patients with IDDM complicated by end-stage renal disease (ESRD) to those from normal subjects and from patients with ESRD of different etiologies for their: natural killer (NK) and antibody-dependent cell-mediated cytotoxic (ADCC) activities; modulation of NK and ADCC activities by biological response modifiers (BRM) including purified human lymphoblastoid interferon, human recombinant alpha-2 interferon, human gamma interferon and human recombinant interleukin 2; proliferative response of T and B lymphocytes to concanavalin A (Con A), phytohemagglutinin and pokeweed mitogen, and ability to produce T-cell growth factor (interleukin 2; IL-2). PBMC of diabetic patients demonstrated significantly lower NK activity than normal and ESRD subjects. Upon treatment with BRM, NK activity was augmented and achieved normal levels. ADCC activity was not different from that of normal controls and exhibited similar increases when stimulated by BRM. The proliferative responses to Con A, phytohemagglutinin and pokeweed mitogen as well as IL-2 production in response to Con A stimulation were significantly lower in the IDDM group. Our results indicated that NK cells from patients with IDDM can respond to IL-2 with enhanced cytotoxicity, and, because activation of resting T cells by mitogenic stimuli depends on the production of IL-2 as well as the appearance of a receptor for IL-2, our finding of low levels of in vitro IL-2 production by PBMC from patients with IDDM may explain the depressed NK activity and the observed poor response to T-cell mitogens.