Ingemar Dawidson

Intraoperative albumin administration affects the outcome of cadaver renal transplantation

The prognostic significance of early malfunction or delayed function after cadaveric renal transplantation is controversial. This study examines the influence of intraoperative management in 438 cadaveric renal transplant recipients on seven posttransplant outcome measures: (1) time of onset of urine output, (2) urine volume, (3) renal function, (4) incidence of delayed function, (5) never-functioning kidney, (6) graft survival, and (7) patient survival. Delayed function, defined as the need for hemodialysis during the first posttransplant week, decreased from 46% in 1982 to 15% in 1990 and was associated with a 25% lower 1-year graft survival rate and a mortality rate of 10% at 3 months, compared with 3% when immediate function was present. The most important factors influencing the outcome were cold ischemia time (P = 0.007), intraoperative administration of albumin (P = 0.0027), duration of surgery (P = 0.020), and recipient age (P = 0.041). A high albumin dose (1.2-1.6 g/kg bodyweight) induced urine output within 30 min in 75% of patients and induced larger urine volumes (7.3 L/24 hr), as compared with the effects of a low dose (0-0.4 g/kg), which induced urine output within 30 min in 39% and only 3.7 L/24 hr. Serum creatinine at 1 week was 3.4 and 5.8 mg/dl for the high and low albumin doses, respectively (P less than 0.0001). Similarly, mean glomerular filtration rates at 1 and 7 days were 33 and 21 ml/min, compared with 47 and 28 ml/min, for the high and low albumin doses, respectively (P less than 0.01). The incidence of delayed function and of never-functioning kidneys declined from 34% and 9% for the low dose to 12% and 1% for the high dose, respectively. Finally, with increasing albumin dose, the graft survival rate at 1 year improved from 59 to 78% (P less than 0.002), and the patient mortality rate at 3 months dropped from 6% to 2%. For albumin dose intervals between the high (1.2-1.6 g/kg) and low (0-0.4 g/kg), the effect on all seven outcome measures was intermediate, generally describing a linear relationship. Weighted least-squares analysis of the relationship of delayed function with high vs. low doses of albumin, mannitol, furosemide, and volumes of crystalloid solutions showed significance only for the albumin effect. High-dose albumin infusion likely produces intravascular volume expansion and achieves a prompt restoration of blood flow, minimizes hypoxic injury, and helps preserve renal tissue. The possibility of other beneficial effects of albumin unrelated to intravascular volume also exists.(ABSTRACT TRUNCATED AT 400 WORDS)

Improved outcome of cadaveric renal transplantation due to calcium channel blockers

Calcium channel blockers (CCB) administerd to recipients of cadaveric renal transplants have been shown to improve graft function, decrease the incidence of delayed function, prevent acute cyclosporine toxicity, and lessen the number of rejection episodes in the first several weeks posttransplant. In order to determine whether CCB provide a similar long-term benefit, a retrospective analysis of 83 first cadaveric renal transplants performed in 1987 and 1988 was performed. The clinical course of 17 patients who were discharged and maintained on CCB therapy for 1 year was compared with that of 24 patients who never received CCB during the same 1-year period. The remaining 42 patients were excluded for failing to meet these inclusion criteria. The two groups were similar with respect to age, sex, cold ischemia time, degree of sensitization, HLA matching, DR matching, and DR mismatching. The no CCB group did receive a significantly greater number of pretrans-plant transfusions. In the 1 year of follow-up, graft loss in the CCB group was less than in the no CCB group (1/ 17, 5.9% vs. 6/24, 25%). There was a striking decrease in the percentage of first rejection episodes in the CCB group as compared with no CCB therapy (35% vs. 83%, P<0.005). In addition, a similar decrease in second rejection episodes was found in the CCB group (18% vs. 33%, P<0.05). The two groups also were compared with respect to graft function. Despite similar serum creatinine levels at 1 month (CCB 1.8 mg% vs. no CCB 2.2

Studies of the isolation and viability of human islets of langerhans

Pancreas obtained from 34 adult human cadaver organ donors was divided into proximal and distal segments, and the duct to each segment was cannulated. Collagenase was injected into the proximal duct of 7 glands and into the distal duct of 7 others; the duct of the opposite segment was perfused with collagenase. The pancreas was then dispersed by teasing, trituration, and passage through filters. Perfused proximal and distal segments released 1461 +/- 287 and 2728 +/- 797 islets/g (+/- SEM) versus 710 +/- 149 (P less than 0.05) and 1950 +/- 636 after injection. Twenty other pancreases were perfused with collagenase warmed rapidly to 39 degrees C (n = 4) or warmed slowly to 37 degrees C (n = 6) or 39 degrees C (n = 10): the yield was 1625 +/- 632, 1320 +/- 116, and 2009 +/- 277 islets/g respectively. Total yields from the latter were 76 X 10(3) large (greater than 100 microns) and 85 X 10(3) small (less than 100 microns) islets with recoveries of 61% and 42%, respectively, after Ficoll density gradient purification. Histology showed highly purified islets. Perifusion with glucose elicited a biphasic release of insulin with the mean response (microU/islet/min) rising to a first peak of 0.5 and constant second phase secretion of 0.25, followed by a return to baseline. Reduced response was observed for islets from pancreas stored greater than 6 hr and tissue obtained from multiple centers. Less insulin was produced by freshly isolated islets, islets less than 100 microns, and after Ficoll separation. Secretion was similar for islets derived from proximal or distal segments. Perfusion of collagenase via the ducts of human pancreas improves islet isolation and Ficoll gradient separation yields highly purified islets. Important factors influencing insulin secretion are the source of donor tissue, cold storage of pancreas, Ficoll purification, islet size, and tissue culture.

Prevention of Detrimental Effect of Cyclosporin A on Vascular Ingrowth of Transplanted Pancreatic Islets With Verapamil

The revascularization of pancreatic islet clusters transplanted beneath the renal capsule was studied in a syngeneic mouse model. The degree of vascular ingrowth was visualized by in vivo fluorescence microscopy (fluorescein isothiocyanate-dextran) and judged by a semiquantitative method from coded video recordings. The recipients of isografts were divided into four groups, depending on their daily immunosuppressive treatment: 1) none (controls), 2) 15 mg/kg cyclosporin A (CsA), 3) 0.4 mg/kg verapamil + 15 mg/kg CsA, and 4) 20–30 mg/kg methylprednisolone. In control animals, capillary ingrowth was first demonstrated on day 6, followed by progressive vascularization up to day 34. After 6 mo, the vascular architecture was similar to that seen in normal islets in situ. CsA alone significantly decreased vascular ingrowth on day 14 compared with controls (P < .02). Verapamil prevented the detrimental effect of CsA (P < .01), probably by improving renal subcapsular blood flow. Methylprednisolone did not affect revascularization compared with control animals at day 14. We conclude that CsA inhibits vascular ingrowth into transplanted pancreatic islets, which is likely to have clinical implications. The prevention of CsA vascular ingrowth inhibition by a calcium antagonist indicates a possible approach to the correction of this problem, particularly when the renal capsule is used as the recipients transplant site.

Protection against cyclosporine-induced impairment of renal microcirculation by verapamil in mice.

Fluorescence microscopy was used to examine the effect of cyclosporine (CsA) infusion on renal subcapsular (cortical) blood flow in 53 living mice, using FITC-dextran (MW: 156,000) as a fluorescent marker. CsA (8–19 mg/kg body weight) given i.v. for 1 min induced complete inhibition of blood flow. A complete standstill of flow was also obtained during a continuous infusion with a rate of 0.8–2 mg/kg/min. With lower infusion rates (0.15–0.23 mg/kg/min), blood flow was partially impaired. In all experiments, the decrease in flow occurred after a 15–25 min delay, suggesting a CsA metabolite or exhaustion of a protective mechanism as the causative agent. Pretreatment with an α-blocking agent, phentolamine (1.0 mg/kg), did not prevent the CsA-induced inhibition of blood flow. In contrast, pretreatment with a calcium antagonist, verapamil (0.3–0.4 mg/kg), prevented the impairment of blood flow at low (0.15–0.23 mg/kg/min), and partially at higher (0.8–2.4 mg/kg/min) rates of CsA infusion. Clinical studies are warranted to explore the role of calcium antagonists in the prevention of posttransplant acute cyclosporine-induced nephrotoxicity.

Intravascular volumes and colloid dynamics in relation to fluid management in living related kidney donors and recipients

This study examines our current perioperative fluid regimen in relation to body fluid compartments, intravascular volumes, and early kidney function in 17 kidney transplant recipients and their living related donors. Donors were given 0.5 g/kg of 10% dextran-40 during surgery and electrolyte solutions averaging 3032 ml/24 h. Recipients were randomized to receive albumin or dextran-40 infusions and given 0.5 g/kg during surgery. Electrolyte and 5% glucose infusions averaged 5580 ml/ 24 h, to match the urinary output. Total intravascular albumin (TIA) and total intravascular dextran (TID) were calculated from the plasma concentrations and plasma volume (PV).Mean preoperative PV in the donors was 44.5 ml/kg. The TIA loss of 0.37 g/kg was balanced by a TID of 0.27 g/kg, and PV increased to 46 and 49 ml/kg at 3 and 34 h after surgery, respectively. In recipients, the preoperative volume of extracellular water correlated linearly to the total body water and PV, as well as to the urine flow the first 24 h after transplantation. No difference was found in urine volume, serum creatinine, or PV expansion between recipient patients receiving albumin or dextran-40. Twelve patients with immediate urinary onset had blood volume (BV) and PV of more than 70 and 45 ml/kg, respectively, in sharp contrast to five patients with delayed urinary onset, who had lower BV and PV values. A fall in TIA of 0.9 g/kg at 3 h corresponded to a PV loss of 18 ml/kg and was only partially replaced by the 0.5 g/kg of intraoperative colloids.We conclude that BV and PV of more than 70 and 45 ml/kg, respectively, are associated with immediate kidney function in living related transplant recipients. Immediate kidney function may be induced by colloid infusions in a dose of about 1 g/kg, in addition to electrolyte solutions and blood transfusions.

RINGER'S LACTATE WITH OR WITHOUT 3% DEXTRAN-60 AS VOLUME EXPANDERS DURING ABDOMINAL AORTIC SURGERY

ObjectiveTo compare a solution of 3% dextran-60 (D60) in Ringers lactate (RL) with RL alone as maintenance fluids for abdominal aortic surgery. DesignRandomized control trial of 20 consecutive patients undergoing elective aortic reconstructive surgery. SettingA surgical ICU in a university hospital. PatientsConsecutive patients, mean age 64 yr. Five patients had abdominal aneurysm, 12 had aortic obstruction disease, and three had aortic renal bypass surgery. These patients were followed for 1 month. InterventionsPulmonary artery occlusion pressure of at least 10 mm Hg and a urine output >30 mL/h were used to guide the intraoperative fluid infusion rates, which were 36 and 104 mL/kg of D60 and RL, respectively (ratio 1:2.9). Measurements and Main ResultsBody weight at 24 hr had increased more with RL (7.8 kg) than with D60 (3.2 kg) infusion (p < .01), despite intraoperative urine volumes of 151 and 92 mg/kg with RL and D60, respectively. Total intravascular albumin decreased from 0.7 g/kg (1.4 to 0.7 g/kg) in both groups, corresponding to a plasma volume (PV) loss of 13 mg/kg without fluid infusions. A total intravascular dextran of 0.5 g/kg resulted in a PV expansion at 1 hr of 4.4 mL/kg above preoperative level, in sharp contrast to 7.0 mL/kg decrease in PV with RL. Of the intraoperative 3% D60 and RL infused, an estimated 51% D60 and 6% RL remained as PV expansion at 1 hr. ConclusionA diluted colloid solution in Ringers lactate is of significant value in maintaining intravascular volumes and hemodynamics during and after major operative procedures. (Crit Care Med 1991; 19:36)

Syngeneic renal transplantation increases the number of renal dendritic cells in the rat

Dendritic cells participate in the regulation of CD4 and CD8 T cells during transplant rejection. Understanding what causes increased numbers of dendritic cells to appear in the renal transplant is therefore important. We performed syngeneic renal transplants between rats. We used the monoclonal antibody OX62 to detect dendritic cells, and OX6 to detect major histocompatability complex (MHC) Class II in the renal transplant. One week after transplant, dendritic cells appeared. This indicates that the injury of transplantation itself is sufficient to increase the number of dendritic cells in the kidney in a model where there is no alloreactivity.

Hemodilution and recovery from experimental intestinal shock in rats: A comparison of the efficacy of three colloids and one electrolyte solution

The present experiments were designed to simulate postoperative shock in 145 Wistar rats by exteriori-zation of the intestine in wet gauze and occluding completely the superior mesenteric vessels with a rubber clamp. After 1 h, the clamp was removed, the intestine was returned to the abdominal cavity and the abdomen closed. Two sets of experiments were undertaken. First, in order to study plasma volume loss after untreated shock, animals were sampled for he-matocrit and organ weights. Also, plasma volume loss during this shock after single infusions during 10 min of various fluids was assessed using hematocrit change as a measure of plasma loss. Second, on the basis of the results from the first set of experiments, the relative effectiveness of colloids (albumin, dextran 70, and dextran 40) and one electrolyte solution (Ringers acetate) was evaluated in rats subjected to the intestinal shock using the survival rate as the criterion. The agents were given in volumes needed to maintain similar hemodilution during 4 h. In untreated rats, hematocrit increased from 51.7 ± 3.0 (sd) to 65.7 ± 3.5% at 6 h after return of the intestine, and then gradually decreased to preshock values after 24 h. Concomitantly, the weight of the exteriorized intestine increased from 6.5 ± 0.5 g/100 g of body weight (bwt) to 10.7 ± 1.5 g at 6 h after shock; the survival rate at 24 h was 29%. Large volumes of fluids were required initially in order to maintain hemodilution. Ringers acetate in volumes of 71–118 mg/100 g of bwt were given to obtain hematocrit at the preshock level, but there was no improvement in 24 h survival rate after Ringers acetate. Colloids of 3.5% concentrations hi volumes between 19–24 ml/100 g bwt maintained hematocrit at about > during 4 h and resulted hi 72% survival rate at 24 h. Animals infused with Ringers acetate gained 44–59% in weight versus 9–11% in rats given colloids. It is concluded that shock associated with plasma volume loss and hemoconcentration is best resuscitated with colloid containing fluids at a rate determined by the degree of hemodilution.

Impact of race on renal transplant outcome

The influence of race on the outcome of cadaver renal transplantation (CRT) continues to be controversial even in the cyclosporine era. The present study examines the effect of race in 343 adult CRT performed from 1/1/82 through 10/1/88 with regard to the incidence of delayed function (DF), graft survival (GS), and patient survival (PS). Blacks constituted 38% of the patients. A history of nephrosclerosis secondary to hypertension was more common in blacks, with 51% (67/130) vs. 8% (17/213) in whites, while glomerulonephritis and Type 1 diabetes mellitus were more common in whites. There was no significant difference in the number of HLA (A,B,DR) matches or DR mismatches between whites and blacks. With azathioprine immunosuppression DF was more common in blacks than in whites, 54% (14/26) vs. 20% (11/55) respectively (P less than 0.01). The higher incidence of DF in blacks than in whites on Aza was associated with a significantly lower dose of intraoperative albumin, 0.25 g/kg vs. 0.44 g/kg, respectively (P less than 0.01). Of the Aza treated black recipients who had DF, 79% (11/14) had graft loss within three months, significantly worse than 25% (3/12) with graft loss when immediate function was present (P less than 0.005). Currently, all patients receive at least 0.80 g/kg of albumin intraoperatively and CsA quadruple induction therapy. With the current regimen, black and white recipients of primary CRT recipients have a comparable low incidence of DF of 18% and 22%, respectively. However, DF remains high among repeat black or white recipients: 33% (10/30) and 57% (8/14), respectively. The incidence of rejection within 30 days was similar for black and white recipients during the Aza and CsA eras, 62% vs. 75% and 34% vs. 42% respectively. GS and PS at three months for blacks on Aza were 54% and 89%, respectively, reflecting the corresponding high incidence of DF. This compares with 71% and 97% GS and PS for whites on Aza. Blacks and whites receiving CsA had equivalent 1-year GS and PS: 76% and 92%, respectively. We conclude that, in our center during the Aza era, blacks had a higher incidence of DF and lower GS than whites. With our current intraoperative fluid replacement and CsA immunosuppression, the incidence of DF and GS and PS are equivalent in black and white recipients.