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Biomedical subjects

D E Sutherland

Publications and source records attributed to D E Sutherland.

At least 271 records · Page 15Linked to original sources
PubMed1992

Donor hyperglycemia as a minor risk factor and immunologic variables as major risk factors for pancreas allograft loss in a multivariate analysis of a single institution's experience.

The impact of multiple donor and recipient variables on functional survival of 307 cadaveric pancreas allografts transplanted in 253 recipients at the authors' institution between July 25, 1978 and September 4, 1990 was determined using the Cox proportional hazards regression model. Relative risk of graft loss was calculated for all cases as well as for technically successful (TS) ones. Factors with an impact in descending order of significance for TS cases were immunosuppression (RR = 3.9 for double-drug versus triple-drug maintenance, p less than 0.0001); recipient category (RR = 2.4 for pancreas alone versus simultaneous pancreas/kidney, p = 0.009); retransplantation (RR = 1.8 for retransplants versus primary grafts, p = 0.007); donor hyperglycemia (RR = 1.7 for blood glucose greater than or equal to 200 versus less than 200 mg/dL, p = 0.02); human leukocyte antigen (HLA) matching (RR = 2.1 for poor versus a good match, p = 0.04). A logistic regression analysis also was performed to determine which factors predisposed to technical failure; none were identified. To make the model as relevant as possible to their current program, the authors analyzed only the bladder-drained cases (n = 221; 1984 to 1990). All patients received triple therapy. Recipient category, retransplantation, donor hyperglycemia, and degree of HLA matching remained as significant risk factors. Construction of estimated survival curves showed that the results of retransplantation were significantly improved, and the penalty incurred by using hyperglycemic donors was partially ameliorated by using well-matched donors. Because preservation times up to 30 hours did not exert an adverse effect on outcome, an argument is made to share pancreata between centers to achieve good matches.

Female↗
PubMed1992

Conversion of exocrine secretions from bladder to enteric drainage in recipients of whole pancreaticoduodenal transplants.

Between September 1984 and August 1991, 265 whole pancreaticoduodenal transplants were done at our institution, with bladder drainage of exocrine secretions through a duodenocystostomy. Seventeen patients subsequently underwent conversion from bladder to enteric drainage at 2 to 64 months after transplant. Eight conversion procedures were done to correct chronic intractable metabolic acidosis due to bicarbonate loss from the allograft: seven to alleviate severe dysuria, presumed secondary to the action of graft enzymes on uroepithelium; one to prevent recurrent allograft pancreatitis, presumed secondary to back pressure from the bladder; and one because of graft duodenectomy for severe cytomegalovirus duodenitis with perforation. None were done to correct technical complications from the initial transplant operation. The conversions were done by dividing the graft duodenocystostomy, then re-establishing drainage through a graft duodenal-recipient jejunal anastomosis. A simple loop of recipient jejunum was used for the duodenojejunostomy in 15 cases, and a Roux limb in two. One of those two cases had a previously created Roux limb that was available for use. The other was in the patient who underwent graft duodenectomy and subsequent mucosa-to-mucosa anastomosis of the pancreatic duct to a newly created Roux limb of jejunum. All patients experienced relief of their symptoms after operation. Two patients had surgical complications (12%), an enterotomy in one case, which was closed operatively, and an enterocutaneous fistula in the other case, which healed spontaneously with bowel rest and parenteral nutrition. The drawback to conversion is loss of urine amylase as a marker for rejection, particularly in recipients of solitary pancreas grafts (n = 5). In recipients of simultaneous pancreas-kidney (SPK) allografts (n = 12), the kidney can still be used to monitor for rejection (two with follow-up < 1 year, 10 with follow-up > 1 year). None of our solitary pancreas recipients, however, have lost graft function (follow-up, 10 to 36 months). The only pancreas allograft loss was in an SPK recipient who also rejected the kidney 6 months after conversion. She received a second SPK transplant with enteric drainage, and is insulin independent and normoglycemic 10 months after retransplantation. Patients converted for metabolic acidosis tended to have impaired renal function (mean creatinine, 2.14 +/- 0.98 mg/dL at time of conversion) due to chronic rejection, progression of native kidney diabetic nephropathy, or cyclosporine toxicity, and possibly could not compensate for bicarbonate loss from the pancreas allograft.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1992

Effect of soybean flour on exocrine function in rat pancreas transplant with bladder drainage.

The urinary output of trypsin, chymotrypsin, elastase, and amylase by rats with a pancreas transplant and bladder drainage was determined after injection with cholecystokinin (CCK) or by feeding diets containing high (raw soy flour) or low (heated soy flour) trypsin inhibitor activity. The injection of CCK produced a significant increase in the urinary output of all four enzymes. Rats were fed heated or raw soy flour in three consecutive 10-day periods in the following sequence: period 1, heated soy flour; period 2, raw soy flour; period 3, heated soy flour. Replacing heated soy flour in period 1 with raw soy flour in period 2 caused a significant increase in the output of the four enzymes. Subsequent feeding with heated soy flour in period 3 resulted in a reduction in the output of trypsin, chymotrypsin, and elastase to levels that were not significantly different from that observed in period 1. Although amylase output was also reduced in period 3, it did not return to the level noted in period 1. These results are consistent with the roles that CCK and trypsin inhibitors are believed to play in the negative feedback control of pancreatic exocrine function. A similar approach might be employed with humans who have undergone a pancreas transplant with bladder drainage.

Animals↗
PubMed1992

Recurrence of disease in patients retransplanted for focal segmental glomerulosclerosis.

The natural history of focal segmental glomerulosclerosis in patients retransplanted after loss of a primary allograft is not well established. We studied 14 patients with FSGS who were retransplanted between April 1964 and September 1990 to determine if recurrence in a second or subsequent allograft could be predicted. In this group, 8 of the primary allografts were lost to recurrent disease and 6 to rejection. None of the 6 patients who lost their primary allograft to rejection without evidence of recurrent FSGS suffered recurrent disease after retransplantation. In contrast, 3 of the 8 patients who lost their primary allograft rapidly to FSGS suffered recurrent disease and loss of function in all subsequent allografts. The remaining 5 patients had prolonged function of the primary allograft ranging between 4 and 10.5 years, despite recurrence of FSGS. Of these 5 patients, 2 have excellent renal function after retransplantation without recurrence of FSGS in the secondary allograft at 9 and 10.5 years posttransplant; 2 have lost their secondary allograft to recurrent FSGS, but are free of recurrence in the third allograft at 0.5 and 5.8 years postoperatively; 1 maintains a serum creatinine level of 1.9 mg% despite recurrence of FSGS in the secondary allograft at 1 year postoperatively. Our data show that, without recurrence of FSGS in the primary allograft, further renal transplants will be free of recurrent disease. Based on this finding, we advocate use of living-related donors for second transplants in these patients. With rapid recurrence of FSGS and subsequent accelerated loss of the primary allograft, further renal transplants carry a high likelihood of recurrent FSGS and graft loss. A substantial proportion of patients with recurrent FSGS in the primary allograft will have prolonged renal function, and are likely to have excellent results with subsequent allografts.

Adolescent↗
PubMed1992

Differential effects of preexisting uremia and a synchronous kidney graft on pancreas allograft functional survival in rats.

Pancreas transplant results have been better in uremic recipients of a simultaneous kidney than in nonuremic recipients of a pancreas alone. We studied the relative effect of uremia versus a double transplant on functional survival by performing bladder-drained pancreas transplants alone (PTA), kidney transplants alone (KTA), and simultaneous pancreas/kidney (SPK) transplants from Buffalo donors to diabetic Lewis rat recipients that were or were not made uremic 2-3 weeks before by 1 4/5 native nephrectomy. Pancreas graft exocrine function was monitored by urinary amylase (UA). In the PTA and SPK recipients made diabetic by streptozotocin, endocrine function was monitored by measuring nonfasting plasma glucose (PG) levels. Kidney graft function was monitored by plasma creatinine (Cr). Rejection of the endocrine pancreas was defined as an increase of PG to greater than 200 mg/dl; of the exocrine pancreas, as a decline in UA to less than 6000 U/L or to less than 100 U/24 hr; and of the kidney, as an elevation of Cr to greater than 3 mg/dl. The mean functional survival times (MST) of both the endocrine (12.0 +/- 2.1 versus 10.1 +/- 1.1 days, P = 0.036) and exocrine (8.0 +/- 2.1 versus 6.3 +/- 1.3 days, P = 0.016) components of the pancreas grafts were significantly longer in SPK than in PTA recipients. The MST of kidney allografts, however, was not significantly longer in nonuremic SPK than nonuremic KTA recipients (6.7 +/- 1.4 versus 5.7 +/- 0.7 days, P = 0.13). In parallel experiments in recipients immunosuppressed with cyclosporine, the graft survival times were longer, but the relative differences between the PTA, SPK, and KTA groups persisted. Histologically, lymphocyte infiltration began in the two organs almost simultaneously, but the severity of the rejection was more vigorous in the kidney than in the pancreas in doubly grafted rats, and destruction of pancreas grafts progressed more slowly in SPK than in PTA recipients. Preexisting uremia delayed pancreas rejection in both SPK (exocrine 10.6 +/- 2.3, P = 0.032, and endocrine 14.8 +/- 3.4 days, P = 0.065, versus nonuremics) and PTA (exocrine 8.5 +/- 1.7, P = 0.007, and endocrine 12.6 +/- 2.5, P = 0.026, versus nonuremics) nonimmunosuppressed recipients. The MST of kidney grafts was not significantly longer in uremic (8.9 +/- 2.8 days) than in nonuremic (6.7 +/- 1.4 days) SPK recipients (P = 0.081). A synchronous kidney transplant and uremia independently down-modulate the rejection response to a pancreas graft, and a simultaneous pancreas graft has no detrimental effect on the survival of a kidney graft.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Sequential therapy--a prospective randomized trial of MALG versus OKT3 for prophylactic immunosuppression in cadaver renal allograft recipients.

We prospectively studied the use of prophylactic Minnesota antilymphocyte globulin vs. OKT3 in kidney transplant recipients. Between 7/1/87 and 9/1/90, 138 adult kidney and 35 kidney-pancreas recipients were randomized after stratification for age (18-49 vs. greater than or equal to 50), diabetes (diabetic vs. nondiabetic), transplant number (1 vs. greater than 1) and, for retransplants, the length of survival of the first graft (less than 1 year vs. greater than or equal to 1 year), and then randomized to receive 7 days of either MALG (20 mg/kg/day) or OKT3 (5 mg/day). Immunosuppression was otherwise identical in both groups; prednisone and azathioprine started on the day of surgery, and cyclosporine started on postoperative day 6. Minimum follow-up was 9 months. There was no difference in one- and two-year actuarial patient or graft survival rates, incidence of rejection, or serum creatinine level. MALG was associated with a higher incidence of cytomegalovirus; it was statistically significant in the subgroup of CMV seronegative recipients of kidneys from seropositive donors (P less than .05). OKT3 was more expensive and was associated with significantly more side effects: fever (P less than .0001), dyspnea (P = .04), and acute respiratory distress syndrome (ARDS) (P = .02).

Adolescent↗
PubMed1992

Pancreas transplantation as therapy for diabetes mellitus.

Pancreas transplantation, when successful, is the only reproducibly effective method to normalize glycemia without the use of exogenous insulin treatment in patients with diabetes mellitus. Worldwide success rates for combined pancreas and kidney transplantation are approximately 70%, and patient survival rates are approximately 90% one year postoperatively, although certain institutions have higher rates. Benefits of this procedure include normalization of fasting plasma glucose, hemoglobin A1C, glucose-induced insulin secretion, and intravenous glucose tolerance. Improvements are observed in glucose recovery following insulin-induced insulin hypoglycemia, glucagon secretion during hypoglycemia, kidney structure, and both motor and sensory nerve function. However, no benefits are accrued in pancreatic polypeptide secretion, kidney function, and the retinal pathology of diabetes mellitus. Further progress in these therapeutic results must await improvements in drugs for induction of immunosuppression, methods to induce immune tolerance, or provision of the operative procedure to patients less compromised preoperatively with secondary complications of diabetes.

Blood Glucose↗
PubMed1992

Entrapment of cultured pancreas islets in three-dimensional collagen matrices.

In vitro culture of islets of Langerhans decreases their immunogenicity, presumably by eliminating passenger leukocytes and other Ia+ presenting cells within the islets. Islets cultivated in petri dishes either at 37 degrees C or at 25 degrees C gradually disintegrate during culture in a time-dependent manner which is related to the free-floating condition of the islets. Also, a fraction of the islets disperse as single cells and beta-cell aggregates or adhere to the bottom of the culture dishes. Thus, the retrieval rate of transplantable islets is dampened due to their disintegration and spontaneous dispersion in conventional petri dish cultures. Entrapment of freshly harvested islets of Langerhans in a three-dimensional collagen matrix was studied as an alternative method for islet cultivation. The contraction of collagen fibrils during in vitro culture counteracts the dispersion of islets and helps in maintaining their integrity while in culture. It was observed that the entrapped islets maintain satisfactory morphology, viability, and capability of glucose-dependent insulin secretion for over 2 wk. The oxygen consumption rate and glucose metabolism of these islets was not deranged when entrapped in collagen. Also, the retrieval of islets is easier and more efficient than that observed in conventional culture systems. Our results indicate that culture of islets in three-dimensional collagen gels can potentially develop into an ideal system applicable to clinical transplantation of cultured islets or beta-cell aggregates.

Animals↗
PubMed1992

Characterization of T lymphocytes infiltrating human pancreas allograft affected by isletitis and recurrent diabetes.

We studied a human leukocyte antigen-identical pancreas graft transplanted into an insulin-dependent (type I) diabetic patient shortly after onset of recurrent diabetes to characterize the putative autoreactive T lymphocytes mediating the lesion. The immunohistopathological analysis revealed the presence of isletitis and a selective loss of beta-cells. The isletitis was mostly constituted by CD8+/T-lymphocyte receptor alpha,beta (TCR alpha,beta +) T lymphocytes surrounding and infiltrating the affected islets. CD4-/CD8-/TCR gamma, delta + T lymphocytes were observed within the islets. Incubation of the tissue in 15% interleukin 2 induced the migration and initial expansion of the infiltrating cells (66% CD3+ lymphocytes) for up to 2 wk; most T lymphocytes in this initial isolate were CD4+ (92% CD4+ and 7% CD8+). Long-term anti-CD3 stimulation of this T-lymphocyte population induced the selective growth of CD8+/TCR alpha,beta + (75%) and CD4-/CD8-/TCR gamma,delta + (all V1 delta +) (17%) T lymphocytes. Therefore, this strategy selectively expanded the T lymphocytes, found to be the predominantly islet-infiltrating cells, rather than the lymphocytes predominating in the initial isolate. Anti-CD3 did not stimulate growth of T lymphocytes in cultures of three isletitis-free pancreas graft biopsies. In a control experiment with a CD4(+)-rich T-lymphocyte population, long-term anti-CD3 stimulation and cloning of cytomegalovirus (CMV)-primed peripheral blood mononuclear cells from a CMV+ subject selectively induced the growth of CD4+ T-lymphocyte clones, all CMV specific.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Cell and matrix components of the glomerular mesangium in type I diabetes.

In a cross-sectional study, glomerular basement membrane (GBM) width, the volume fractions of the mesangium (VvMes), its cell (VvCell) and matrix (VvMatx) components, and surface density of the peripheral capillary surface (SvPGBM) were measured in renal biopsies from 187 nondiabetic living related and cadaveric donors of kidneys for transplantation and from 150 patients with insulin-dependent (type I) diabetes mellitus of 1-41 yr duration. In the diabetic patients, the matrix was the major factor in the expansion of the mesangium. However, both VvCell (0.11 +/- 0.04) and VvMatx (0.20 +/- 10) in diabetic patients exceeded the same measurements in nondiabetic subjects (0.07 +/- 0.02 for each component) (P less than 0.001 in each case). Linear regression analysis demonstrated significant correlations (P less than 0.001 for all) between GBM width, VvMes, VvCell, VvMatx, or SvPGBM and either urinary albumin excretion and creatinine clearance, with the higher correlation coefficients in all cases with albuminuria. Of the structural parameters, VvMatx correlated best with either functional measure by stepwise regression, with GBM as an added factor only with albuminuria. Therefore, although models of diabetic glomerulopathy must consider enlargement of both mesangial cells and matrix, the predominant factor in the progression of structural and functional renal disease is mesangial matrix expansion.

Adult↗
PubMed1992

Kidney transplantation in patients with type I diabetes: 26-year experience at the University of Minnesota.

With current immunosuppressive protocols, 1- and 6-year graft survival is similar in diabetic and nondiabetic kidney transplant recipients. Living-donor transplant recipients have significantly better outcome. Death with function and chronic rejection remain the 2 predominant causes of graft loss for diabetic recipients. Compared with national statistics on diabetic patient survival on dialysis, our data suggest that transplantation is the treatment of choice for diabetic patients with end-stage renal disease.

Adolescent↗
PubMed1992

Analysis of United Network for Organ Sharing (UNOS) United States of America (USA) Pancreas Transplant Registry data according to multiple variables.

As of 1992, more than 4,200 pancreas transplants were reported to the International Pancreas Transplant Registry. Of these, more than 2,600 were performed in the United States, and of these, more than 2,100 have been transplanted since the inception of the UNOS Registry in October 1987. The analyses here are only of the UNOS data. Pancreas transplants performed in conjunction with a liver (either cluster or noncluster) or a heart were excluded from the analysis, and only those performed as a solitary procedure or in conjunction with a kidney were included. Emphasis was placed on those performed with the bladder drainage (BD) technique (96%). In the overall analysis of BD cadaveric pancreas transplants (n = 1,879), 1-year patient survival and pancreas graft function survival rates were 91% and 71%, respectively, 87% and 66% at 2 years, and 81% and 59% at 3 years. There were no differences according to gender, but 1-year graft survival rates were significantly higher in recipients 45 years or younger (72%) (n = 1,679) than in those older than 45 (64%) (n = 200). There were no significant differences according to graft preservation times of less than 12 (n = 749), 12-24 (n = 940), 24-30 (n = 79), and more than 30 (n = 9) hours, function rates at 1 year being 71%, 72%, 72%, and 44%, respectively. When analyzed according to the 3 major recipient categories (simultaneous pancreas/kidney transplants [SPK] [n = 1604]; pancreas after kidney transplants [PAK] [n = 166]; and pancreas transplants alone [PTA] [n = 109]), patient survival rates were no different (91%, 92%, and 92% at 1 year, respectively), but pancreas graft survival rates were significantly higher in the SPK than in the PAK and PTA categories (75%, 48%, and 49%, at 1 year, respectively). In the SPK group, kidney graft survival rates at 1 year were 84%. Outcomes were also compared according to whether induction immunotherapy included ALG, OKT3, or neither. In the SPK category, there was no difference among the protocols, with 1-year graft survival rates being 76% in the ALG (n = 838), 76% in the OKT3 (n = 416), and 72% in the Neither (n = 299) group.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗