Calcineurin inhibitor avoidance versus steroid avoidance following kidney transplantation: Postoperative complications.

This study compared early postoperative complications in kidney transplant recipients treated with either a sirolimus-based calcineurin inhibitor (CNI)-free regimen or a tacrolimus-based steroid-free regimen. We used a single-center, prospective, sequential but nonrandomized study design. Consecutive recipients of primary cadaveric or non-HLA identical kidney transplant recipients received either a CNI-free regimen, consisting of sirolimus 5 mg daily beginning postoperative day 3, mycophenolate mofetil 1 gm twice a day, and methylprednisolone 500 mg intraoperatively, then prednisone 30 mg daily tapered to 10 mg daily at 3 months, or a prednisone-free regimen, consisting of methylprednisolone 500 mg, 250 mg, and 125 mg from days 0 to 2, then no further steroids, tacrolimus 0.075 mg/kg twice a day, and mycophenolate mofetil 1 g twice a day. All patients received thymoglobulin induction 6 mg/kg total dose. Outcome measures were patient and graft survival, BPAR, surgical and wound complications, viral infections and posttransplant diabetes mellitus (PTDM). Both groups had excellent early outcomes with no significant difference in patient or graft survival, early renal function, BPAR, surgical or wound complications, or viral infections between the two groups. Patients in the sirolimus-based CNI-free group had a significantly higher incidence of PTDM and a trend toward more discontinuation due to drug toxicity. Whether either regimen improves long-term outcomes awaits longer follow-up.

Short-term results under three different immunosuppressive regimens at one center.

We examined short-term outcomes and posttransplant medical complications under three different immunosuppressive regimens at a single center. The study design was a randomized, prospective, open-label trial comparing a calcineurin inhibitor-free (CNI) protocol to standard triple therapy with tacrolimus, prednisone, and mycophenolate mofetil. They were also compared to a concurrent but nonrandomized third cohort treated with a prednisone-free protocol. All three groups had excellent early outcomes with no significant difference in patient or graft survival or biopsy-proven acute rejection. Serum creatinine was significantly lower in the CNI-free recipients. Lipid panels and posttransplant diabetes mellitus were significantly lower in the prednisone-free patients. Prednisone-free kidney transplant recipients have improved early glucose metabolism and hyperlipidemia compared to CNI-free or standard triple therapy recipients with comparable rejection and graft survival rates.

Biotin transport in the human intestine: inhibition by anticonvulsant drugs.

The effect of the anticonvulsant drugs carbamazepine and primidone on the transport of biotin in the human intestine was examined with purified brush border membrane vesicles (BBMVs) and basolateral membrane vesicles (BLMVs). Both agents inhibited biotin transport in BBMV in a concentration-dependent manner. The inhibition by both carbamazepine and primidone was competitive (inhibition constant [Ki] of 4.70 and 2.25 mmol/L, respectively) and appeared to be specific because the transport of D-glucose was not affected by different concentrations of these pharmacologic agents. The transport of biotin in BLMV was not affected by carbamazepine or primidone. These results demonstrate that carbamazepine and primidone are competitive inhibitors of biotin transport in the human intestine and that the inhibitory effect is directed toward the substrate transport system at the brush border membrane of the enterocyte. These findings may relate to possible impairment of biotin status in patients on long-term therapy with anticonvulsant agents.

Folate transport in ileal brush border-membrane vesicles following extensive resection of proximal and middle small intestine in the rat.

Uptake of folic acid (PteGlu) was examined in remnant ileum of rats after resection of 65% of the small intestine with the brush border-membrane vesicle technique. The results were compared to that of sham-operated rats. In both rat groups transport of PteGlu was linear for approximately 40 s of incubation and was similar in the presence of a Na+ and a K+ gradient (out greater than in). In resected rats transport of PteGlu was inhibited by the structural analogues 5-methyltetrahydrofolate (5-CH3H4PteGlu) and methotrexate (MTX), by sulfasalazine, and by 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) and was saturable as a function of concentration (apparent Kt = 18.3 microM). In the ileum of sham-operated rats, on the other hand, transport of PteGlu was not affected by 5-CH3H4PteGlu, MTX, sulfasalazine, or DIDS and was linear with concentration. These results suggest that the PteGlu transport system is induced in remnant ileum of the rat after extensive intestinal resection.

Central venous dialysis access: experience with a dual-lumen, silicone rubber catheter.

The central venous dialysis catheter has gained wide acceptance for short-term hemodialysis with the realization of the need to spare peripheral extremity vessels for the creation of more durable internal arteriovenous fistulas. The Hemocath (Quinton Instrument Co., Seattle, Wash.), a soft, silicone rubber, double-lumen central venous dialysis catheter, was introduced as a permanent access device in 1984. A prospective evaluation of 53 catheters placed in 51 patients over a 9-month period is presented. Forty-nine catheters were placed for temporary access and four were placed for permanent access. All 53 catheters were discontinued after functioning an average of 63.9 days (range, 5 to 324 days). No major complications occurred during insertion or on dialysis. One catheter fragmented during removal and was retrieved in the operating room. Infection led to the removal of 17 catheters (34.7%). Thrombosis occurred in 11 catheters and was the cause of removal in two (4.1%). Excluding the two catheters that functioned at the time of the patient's deaths and those placed for permanent access, 91.5% of the catheters performed successfully as temporary accesses devices until permanent access sites were available for use. The catheter provided reliable, relatively safe, and easily maintained central venous access for hemodialysis.

Comparison of the effects of saline and homologous plasma infusion on lung fluid balance during endotoxemia in the unanesthetized sheep.

The effects of saline infusion (20 ml/kg/30 minutes) and homologous plasma infusion (20 ml/kg/30 minutes) on the lung fluid balance during increased pulmonary capillary permeability secondary to Escherichia coli endotoxin infusion (1 microgram/kg/15 minutes) were studied in unanesthetized sheep. Saline and homologous plasma infusion increased lung lymph flow by 10.6% and 10.8%, respectively. The bloodless wet-to-dry ratio was 5.1 +/- 0.2 in the saline group and 5.2 +/- 0.2 in the homologous plasma group. The saline infusion decreased the plasma oncotic pressure while the plasma infusion increased plasma oncotic pressure. However, the increase in plasma oncotic pressure was negated by concomitant changes in the lymph oncotic pressure and greater increases in pulmonary microvascular pressure during the plasma infusion. Changes in pulmonary microvascular pressure predominated over changes in the oncotic pressure gradient. Both saline and homologous plasma infusion increase fluid filtration into the interstitial space by the same magnitude. Therefore neither has a clear advantage in the treatment of pulmonary edema during increased permeability.

Thiopental modification of ischemic spinal cord injury in the dog.

Spinal cord ischemia was produced in male mongrel dogs by permanent occlusion of the infrarenal aorta. All animals were anesthetized with a mixture of nitrous oxide and 1.5% halothane. Group 1 animals were the controls. Group 2 animals were pretreated, 30 minutes prior to aortic occlusion, with sodium thiopental, 20 mg per kilogram of body weight, over 5 minutes, followed by an infusion of 10 mg/kg/hr for 2 1/2 hours. Groups 3 animals received the identical dose of sodium thiopental and, in addition, received mannitol, 1 gm/kg, and methylprednisolone 1 mg/kg. There were no differences in hemodynamic data or arterial blood gases among the groups, except that the thiopental bolus caused a transient reduction in mean arterial pressure. Ninety percent of Group 1 animals were paraplegic, while only 30% of Group 2 and 40% of Group 2 animals were paraplegic. The difference in the incidence of paraplegia in Groups 2 and 3 compared with Group 1 was statistically significant (p less than 0.05). Therefore, thiopental significantly decreased the incidence of paraplegia, while methylprednisolone and mannitol did not enhance its protective effect.

Barbiturate protection in acute experimental spinal cord ischemia.

Ischemia is the pathophysiological mechanism in many types of spinal cord injury. In the present study, the infrarenal segment of the aorta was occluded for 25 minutes to produce spinal cord infarction in rabbits. Paraplegia occurred in 100% of control animals. Thiopental administered before aortic occlusion resulted in paraplegia in only 40% of animals so treated (p less than 0.01). Histological study of the spinal cord demonstrated infarction of the gray matter in all paraplegic animals, whereas the microscopic appearance was normal in animals without neurological deficit. The protective influence of thiopental therapy in spinal cord ischemia was demonstrated.

The acute abdomen in the immunocompromised host.

Immunocompromised hosts are a heterogeneous group, including patients receiving transplants, those receiving chemotherapy for malignant disease, and those receiving steroids for autoimmune disease, as well as patients with AIDS. Each group has specific abdominal conditions, and the clinician must be familiar with the specific causes of the acute abdomen within each subset. The causes of the acute abdomen in immunocompromised patients may be divided into two broad categories: (1) those disorders that are closely associated with the immunocompromised state and (2) those processes that can occur in any patient regardless of the immune status. Physicians at every level of specialization must become familiar with the unusual complications that occur in this population and with the ways in which the underlying disease and its therapy can modify the clinical presentation and management of common abdominal conditions. This article outlines broad principles of common clinical findings and surgical therapy in these patients.

A new model to study acute and chronic renal failure.

Many models have been developed to study renal function following injury. Two types of studies have evolved: acute--to define the acute renal injury and chronic--to determine the pattern of recovery. Current models allow either study alone to be performed, but they lack the flexibility to combine the studies. In this study of renal ischemia, a model was designed which solved this problem. The authors constructed a model for performing a unilateral nephrectomy and episiotomy on female dogs. Catheters were placed in the renal vein, vena cava, and aorta, and a renal artery flow cuff was applied. The catheters and wires were buried in a subcutaneous pocket and were exteriorized after a recovery of several weeks. The episiotomy allowed easy intermittent Foley catheterization. With the animals awake and in a harness, parameters of renal function were measured: renal extraction, filtration fraction, fractional excretion, osmolar clearance, and free water clearance. Glomerular filtration rate and renal plasma flow were calculated by inulin and paramino hippurate clearances. The animals were studied in diuretic and antidiuretic states. In addition, renal artery flow was determined by the Doppler flow cuff. All parameters were determined every half hour in the acute setting, then every day in the chronic setting. The model was easily reproducible and functioned well in the authors' renal ischemia studies. Initial experiments with 1 hour of warm ischemia produced a greater than 50 per cent reduction in GFR acutely. Chronic studies showed a GFR with a return toward normal. All model construction purposes and plans were met.(ABSTRACT TRUNCATED AT 250 WORDS)

Kidney transplantation in a veterans administration medical center: 40 years' experience.

OBJECTIVES: Advances in immunosuppressive therapy have led to substantial improvements in kidney transplant outcomes in the past 20 years. Kidney transplantation activity started in 1963 at the Veterans Administration Medical Center in Nashville, Tennessee, and continues to grow with increasing numbers of transplants from living-related and unrelated donors. In this study, patient and graft survival rates during 2 different periods were evaluated and compared with non-veterans-administration centers. MATERIALS AND METHODS: Six hundred fourteen kidney transplants were performed between March 1963 and December 2002. For analytic purposes, the 40-year experience was divided into 2 eras based on the immunosuppressive agents used. Azathioprine and prednisone were the immunosuppressive agents used in era 1. A calcineurin-inhibitor-based triple immunosuppressive regimen initially including azathioprine and prednisone and later, mycophenolate mofetil and prednisone, was the preferred immunosuppressive regimen in era 2. RESULTS: In era 1, 1-year patient and graft survival rates were 72.5% and 50%, and 89% and 75% for deceased-donor and living-donor transplants respectively. In era 2, patient survival rates increased to 95.1% and 87.8% for 1 and 3 years respectively, while graft survival increased to 87.6% and 74.9%. Forty-three percent of deceased-donor and 21% of living-donor kidneys were lost owing to rejection in era 1. In era 2, the incidence of acute rejection was 14.5% overall. CONCLUSIONS: Overall, our results are comparable with non-veterans-administration centers and the national average and show that kidney transplantation offers veteran patients with end-stage renal disease a safe and effective treatment with increased quality of life.

Biotin transport in the human intestine: site of maximum transport and effect of pH.

Previous studies from our laboratory have characterized the transport process of biotin across the brush border membrane and the basolateral membrane of the human intestine. In this study we further characterized biotin transport in the human intestine by examining the vitamin's transport process in different areas of the small intestine (duodenum, jejunum, and ileum) and the effect of pH on the transport process using a brush border membrane vesicle technique. In all areas examined, the transport of biotin as a function of concentration was saturable in the presence of a Na+ gradient (out greater than in) but was linear and lower in the presence of a choline gradient (out greater than in). Transport of biotin by the Na+-dependent process (i.e., the carrier-mediated process) was found to be higher in the duodenum than the jejunum, which was in turn higher than that in the ileum. This decrease in biotin transport distally was found to be due to a decrease in the Vmax of the transport process of the vitamin with no changes in the apparent Km. This indicates that the number (i.e., the density) of transport carriers for biotin decreases distally. In the presence of a Na+ gradient (out greater than in), decreasing incubation buffer pH from 8.0 to 5.5 (intravesicular pH was 7.4) was found to cause an increase in biotin transport. This increase was found to be due to the acidic buffer pH (i.e., not due to the pH gradient imposed across the membrane) and occurred through an increase in the transport of the vitamin by the nonmediated process. These results demonstrate that the proximal part of the small intestine is the site of maximum transport of biotin in humans. Furthermore, variation in incubation medium pH affects biotin transport through changes in the substrate transport by the nonmediated process.

Biotin transport in basolateral membrane vesicles of human intestine.

The characteristics of the exit process of biotin from the enterocyte, i.e., transport across the basolateral membrane, was determined using an enriched basolateral membrane vesicle preparation of human intestine. Purity and suitability of basolateral membrane vesicles for transport studies was confirmed by enzymatic and functional criteria. Orientation of human basolateral membrane vesicles was determined by [3H]ouabain binding studies and was found to be 64% inside-out vesicles and the rest right-side-out vesicles and membrane sheets. Osmolarity studies indicated that the uptake of biotin by these vesicles represents transport into the intravesicular compartment, with little binding to membrane surfaces. The rate of biotin transport was linear for approximately 40 s but decreased thereafter. Transport of biotin was (a) Na+-independent, (b) saturable as a function of concentration, with an apparent KM of 1.1 microM and Vmax of 0.9 pmol/mg protein.15 s, (c) inhibited by structural analogues (desthiobiotin and biotin methyl ester) and related compounds (thioctic acid and thioctic amide), and (d) stimulated by inducing a positive intravesicular electrical potential. These studies are the first to demonstrate the existence of a carrier-mediated transport system for biotin in the basolateral membrane of human intestine.