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Biomedical subjects

D E Sutherland

Publications and source records attributed to D E Sutherland.

At least 631 records · Page 35Linked to original sources
PubMed1983

Differences in susceptibility to rejection of mouse pancreatic islet allografts disparate for class I or class II major histocompatibility antigens.

Pancreatic islet B cells express class I but not class II antigens, and removal of Ia positive passenger cells from H-2 allogeneic islets by anti-Ia serum and complement leads to permanent allograft survival. A test was made of whether the same result can be achieved by genetically removing the Ia stimulus by performing mouse islet allografts in congenic donor-recipient combinations differing at the H-2 K only, D only, or K + D regions. Mice disparate for class I antigens (H-2 K, D, and K + D) alone reject islet allografts, suggesting that Ia positive passenger cells may be involved in presentation of class I disparities. Established islet allografts appear to be sensitive to rejection induced by injection of donor strain splenocytes when donor and recipient differ for class I (H-2 D alone and D + I) but not class II (H-2 I alone) antigens. These results are consistent with the hypothesis that pancreatic islet allografts do not express class II target antigens, but do express class I antigens that in long-established pancreatic islet allografts are capable of acting as targets but not in initiating an immune response.

Animals↗
PubMed1983

Preservation of canine segmental pancreatic autografts: cold storage versus pulsatile machine perfusion.

The reliability of cold storage and pulsatile machine perfusion for preservation of open-duct segmental pancreatic grafts for 24, 48, and 72 hours was determined in a canine autograft model. The tail (left limb) of the pancreas on a pedicle of splenic artery and vein was transplanted to the pelvis with vascular anastomoses to the iliac vessels and the remainder of the pancreas was excised. Twenty nonpreserved grafts functioned immediately (the recipients became normoglycemic, plasma glucose less than 150 mg/dl), 16 long term (80%). Collins solution (CS, osmolality 300 mosm/kg) and a silica gel filtered plasma solution (SGF-I, osmolality 430 mosm/kg) were compared for cold storage at 4 degrees C. The long-term functional survival rate for grafts stored for 24 hours in SGF-I was 9/12 (75%) and in CS was 8/12 (67%). When graft preservation time was extended to 48 hours, 9/12 (75%) stored in SGF-I and 4/10 (40%) in CS functional long term. The preservation failure rates were 0% in grafts stored in SGF for up to 48 hours, but were 20% and 50% for grafts stored in CS for 24 and 48 hours. Storage at 72 hours was not satisfactory; even when SGF-I was used, the preservation failure rate was 57%. SGF was also used as the perfusate for pancreas preservation on the Mox-100 machine at a pressure of 30 mm Hg (achieved by leaving the port opposite the connected pancreas open). Lower pressures gave insufficient perfusion and higher pressures led to severe edema of grafts. Mean (+/- S.E.) flow (ml/min) through the grafts were 4.5 +/- 0.3 initially, 6.5 +/- 0.7 at 24 hours and 6.3 +/- 0.9 at 48 hours. With SGF-I only 6/12 (50%) of grafts perfused for 24 hours and only 1/8 (12%) for 48 hours functioned long term. With a modified perfusate (SGF-II, osmolality 470-500 mosm/kg) the results were slightly improved; 7/12 (58%) grafts perfused for 24 hours and 5/10 (50%) for 48 hours functioned long term. The mean (+/- S.E.) flow rate (ml/min) was 5.0 +/- 0.6 in grafts that functioned long term and was 8.3 +/- 1.0 in those that failed due to preservation complications. Mean (+/- S.E.) peak serum amylase levels (I.U./L.) were similar in recipients of fresh grafts (3953 +/- 365) and those stored hypothermically in SGF (4226 +/- 327), but were significantly lower in recipients of machine perfused grafts (2988 +/- 228). Although the percentage of successful transplants varied according to the preservation techniques, the mean (+/- S.E.) IVGTT K-values in recipients with functioning grafts were similar between the groups (-1.44 +/- .19 to -1.82 +/- .17%). The pure pancreas preservation failure rates with machine perfusion were between 30% and 40% at 24 to 48 hours, compared to 0% in those simply stored in cold SGF for 24 to 48 hours. We conclude that pancreas preservation by cold storage in high osmolar silica gel filtered plasma is more reliable than pulsatile machine perfusion and provides sufficient time to complete the logistical maneuvers necessary for clinical pancreas transplantation from cadaver donors.

Animals↗
PubMed1983

The value of needle renal allograft biopsy. I. A retrospective study of biopsies performed during putative rejection episodes.

Following renal transplantation, immunosuppression is usually increased to treat presumed rejection episodes. However, a) many conditions mimic rejection in the post-transplant period, and b) many rejection episodes are irreversible. As increased immunosuppressive therapy is associated with an increased risk of infection, it would be ideal to limit antirejection therapy to only the rejection episodes that are reversible. The role of percutaneous allograft biopsy was studied as an aid to decide which patients to treat for rejection, to limit unnecessary immunosuppression and to predict allograft survival. One hundred thirty-five patients with suspected rejection underwent 206 allograft biopsies without complication. Two hundred four biopsies were available for study. Biopsies were coded on a 1-4 scale (minimal, mild, moderate, severe) for acute and chronic tubulointerstitial infiltrate and vascular rejection, as well as no rejection (e.g., recurrence of original disease). Treatment decisions were made on the basis of the biopsy combined with clinical data. All patients have been followed two years and outcome correlated with biopsy findings (death, nephrectomy, and return to dialysis defined as kidney loss). The results were the following: 1) biopsies represented changes within the kidney. Of 16 kidneys removed within one month of biopsy, no nephrectomy specimen showed less rejection than that seen on biopsy. 2) Eighty-one biopsies (39.7%) led to tapering or not increasing immunosuppression (either no rejection, minimal rejection, or irreversible changes). 3) Kidneys having either severe acute or chronic vascular rejection (less than 30% function at three months) had significantly (p less than 0.05) decreased survival three to 24 months postbiopsy than those with minimal or mild vascular rejection or tubulointerstitial infiltrate (83% function at three months). 4) Kidneys with moderate chronic vascular rejection and those with severe acute tubulointerstitial infiltrate had significantly (p less than 0.05) decreased survival at six to 24 months. 5) Kidneys with moderate chronic vascular rejection (MCV) without an acute infiltrate (ATI) had significantly better survival than those having both MCV and ATI. 6) Similarly, kidneys having severe ATI alone had better survival than those with ATI plus vascular rejection. It was concluded that a) percutaneous allograft biopsy can be done without graft loss or infection; b) biopsy represents changes throughout the kidney; c) biopsy aids in deciding when to treat for rejection and in deciding when to withhold increased immunosuppression, and d) allograft biopsy predicts the outcome of treatment of a rejection episode.

Biopsy, Needle↗
PubMed1983

Long-term success with double pediatric cadaver donor renal transplants.

Many institutions are reluctant to use pediatric cadaver kidneys for transplantation because of a fear of an increased risk of technical complications or because these grafts leave the recipient with a relatively small amount of functioning renal tissue. From 1971 to 1981 the authors performed 21 double pediatric cadaver donor renal transplants. Eleven of these grafts are currently functioning for periods up to 11 years post-transplant. Only one graft was lost due to a technical complication. Using actuarial analysis, the graft survival and patient survival in this group of patients was compared with a control group of 39 computer matched and randomly selected recipients of adult cadaver kidneys and to all nonmatched recipients of cadaver kidneys during the same time period. There were no statistically significant differences among the three groups in graft survival or in patient survival. It is concluded that the long-term results with double pediatric cadaver kidney transplants are the same as those using single adult cadaver kidneys. Pediatric kidneys should be used whenever they are available so that transplantation can be extended to more patients.

Adolescent↗
PubMed1983

The use of a cosyntropin stimulation test to predict adrenal suppression in renal transplant patients being withdrawn from prednisone.

Eighteen renal transplant patients were studied to identify predictors of steroid-induced adrenal suppression. A cosyntropin adrenal stimulation test was administered to each patient and the response was correlated with the past transplant course and their subsequent prognosis. Eight (44%) of the 18 patients studied had a suppressed cosyntropin stimulation test. The suppressed adrenal response could not be predicted accurately by any one factor, although a history of a total prednisone dose greater than 25 g or a duration of steroid therapy of more than 12 months occurred more often among the suppressed patients. Four of the five deaths occurred among the suppressed patients. These deaths occurred despite maintenance of steroid administration. The cosyntropin stimulation test can be easily performed to identify renal transplant patients at risk of steroid-induced adrenal suppression when rapid steroid tapering is desired. An unsuppressed response gives assurance that steroid withdrawal is safe.

Adolescent↗
PubMed1983

The effect of mismatching for HLA-DR in recipients of renal allografts sharing one HLA-ABC haplotype with related donors.

The effects of mismatching for DR antigens on renal allograft survival rates have largely been restricted to analyses of cadaver transplant results. Analyses of HLA matching in recipients of transplants from related donors have focused on the number of haplotypes shared between the recipients without regard to DR, or on the total number of HLA antigens mismatched, or on the degree of MLC responsiveness of the recipient to the donor. Most related donor-recipient pairs sharing only one HLA haplotype will be mismatched for DR at the other haplotype, but because there are a limited number of DR alleles, sharing of DR antigens on the mismatched haplotypes occurs relatively frequently. To determine the influence of mismatching for DR on the fate of renal allografts from related donors, we analyzed the results of 172 kidney transplants from related donors who shared one HLA-ABC haplotype with the recipient. There were 156 primary grafts and 16 retransplants; 147 donor-recipient pairs were satisfactory typed for DR antigens. Because genotyping was not usually done, we performed two analyses under two different assumptions. The first assumption was that individuals expressing less than or equal to 1 DR antigen had null antigens, or were homozygous for DR; the alternative assumption was that blanks were true antigens and individuals with blanks were heterozygous. The first assumption is more likely to be correct, and is the assumption used in most analyses of the effect of DR antigen mismatches on the results of cadaveric transplantation. Under the first assumption, of the 147 related donor-recipient pairs in whom DR typing was satisfactory, 33% were mismatched for 0, 64% for 1, and 3% for 2 DR antigens. The one-year absolute graft survival rates in recipients of kidneys from donors with 0 mismatches for DR was 92% (n = 49); in those with one mismatch for DR it was 82% (n = 94); and from those with two mismatches it was 50% (n = 4). The one-year graft survival rate in 25 donor-recipient pairs in which one or both members could not be satisfactorily DR typed was 76%. Differences in graft survival rates between the 0 and 1 and the 1 and 2 DR-mismatched groups were not statistically significant.(ABSTRACT TRUNCATED AT 400 WORDS)

Graft Rejection↗
PubMed1983

Lack of donor-specific tolerance in mice with established anti-Ia-treated islet allografts.

Pancreatic islet allografts pretreated in vitro with monoclonal Ia antibody and transplanted beneath the renal capsule result in normoglycemia beyond 100 days in streptozotocin-induced diabetic recipient mice that differ only at H-2 K, H-2 K + I, or H-2 K + I + D from the donors. Mice with established islet allografts are not tolerant of donor-specific skin or islet antigens, but rather reject donor skin grafts in an accelerated fashion. Established anti-Ia antibody pretreated islet allografts continue to express target antigens and remain susceptible to rejection after challenge with donor skin grafts.

Animals↗
PubMed1983

Failing or thrombosed Brescia-Cimino arteriovenous dialysis fistulas. Angiographic evaluation and percutaneous transluminal angioplasty.

Surgically created arteriovenous fistulas of the Brescia-Cimino type are commonly used for dialysis. When they fail, it can be a very difficult and time-consuming problem to manage surgically. The authors describe a simple method of evaluating and treating failing Brescia-Cimino fistulas in outpatients, involving a combination of cinefistulography, pressure measurements, and balloon angioplasty.

Adult↗
PubMed1983

Effects of intrasplenic injection of hepatocytes, hepatocyte fragments and hepatocyte culture supernatants on D-galactosamine-induced liver failure in rats.

Intraperitoneal injection of 0.5 g/kg D-galactosamine results in 95% lethal acute acute liver failure in male Fisher 344 rats. Intrasplenic injection of viable syngeneic hepatocytes 20-28 h after poisoning improves survival in a dose-dependent fashion, 10(7) cells being the optimal dose with a survival rate of 47.1%. While nonviable cells and hepatocyte fragments are totally ineffective, 42.9% of rats survive after injection of 28-hour liver cell culture supernatant. It is concluded that soluble factors generated by cultured cells in vitro or intrasplenically transplanted cells improve survival either by a direct hepatotrophic effect, by stimulation of the reticulo-endothelial system or by an unspecific humoral mechanism.

Acute Disease↗
PubMed1983

The development of lesions in the glomerular basement membrane and mesangium after transplantation of normal kidneys to diabetic patients.

Renal allograft biopsies at the time of transplantation (baseline) and 2 yr later were obtained in 6 type I diabetic and 12 nondiabetic patients and studied for glomerular basement membrane (GBM) and mesangial changes. Diabetic patients had significantly greater GBM thickness compared with nondiabetics at 2 yr (P = 0.05, rank sum test), and the increase in GBM thickness comparing baseline and 2-yr biopsies was greater in the diabetic compared with nondiabetic patients (P = 0.005, rank sum test). Similarly, diabetic patients developed significant mesangial thickening by light microscopy while no changes were observed in nondiabetic patients (P = 0.001). Electron microscopic morphometric analysis of the percentage of total mesangium was not different on comparing diabetic and nondiabetic patients at 2 yr. There was an increase in the matrix component of the mesangium in the diabetics at this time, although this did not reach statistical significance (P = 0.06). In addition, the surface density of the peripheral glomerular capillary wall, presumably reflecting mesangial expansion, was decreased in the diabetic and unchanged in the nondiabetic patients (P = 0.005). These studies document, for the first time, the development of GBM and mesangial lesions of diabetic nephropathy in normal living related donor and cadaver kidneys transplanted into diabetic patients and support the hypothesis that these lesions are secondary to the diabetic state.

Adult↗
PubMed1983

Diabetic nephropathy. A perspective.

The earliest manifestations of clinical diabetic nephropathy, including proteinuria, hypertension, and declining GFR, represent very advanced diabetic glomerulopathy with especially prominent mesangial expansion. Mesangial expansion, by restricting glomerular capillary filtration surface and lumenal volume, stimulates compensatory mechanisms analogous to those resulting from a marked reduction in nephron number. These compensatory mechanisms involve alterations in glomerular hemodynamics designed to maintain glomerular filtration but which ultimately injure the kidney. These hemodynamic perturbations are not specific to diabetes but represent a final common pathway toward endstage renal failure that also characterizes the remnant kidney. This thesis concludes that the onset of clinical diabetic nephropathy augurs inevitable decline in kidney function, and that only studies and interventions exercised before clinical nephropathy develops can influence understanding and outcome of diabetic nephropathy.

Basement Membrane↗
PubMed1983

Total lymphoid irradiation.

Total lymphoid irradiation by itself can produce sufficient immunosuppression to prolong the survival of a variety of organ allografts in experimental animals. The degree of prolongation is dose-dependent and is limited by the toxicity that occurs with higher doses. Total lymphoid irradiation is more effective before transplantation than after, but when used after transplantation can be combined with pharmacologic immunosuppression to achieve a positive effect. In some animal models, total lymphoid irradiation induces an environment in which fully allogeneic bone marrow will engraft and induce permanent chimerism in the recipients who are then tolerant to organ allografts from the donor strain. If total lymphoid irradiation is ever to have clinical applicability on a large scale, it would seem that it would have to be under circumstances in which tolerance can be induced. However, in some animal models graft-versus-host disease occurs following bone marrow transplantation, and methods to obviate its occurrence probably will be needed if this approach is to be applied clinically. In recent years, patient and graft survival rates in renal allograft recipients treated with conventional immunosuppression have improved considerably, and thus the impetus to utilize total lymphoid irradiation for its immunosuppressive effect alone is less compelling. For example, in our institution, the current one-year patient and graft survival rates in recipients of kidneys from cadaver donors are 91 and 84 per cent in those treated with cyclosporine and 94 and 80 per cent in those treated with conventional immunosuppression. Similar results might also be achieved by protocols that use total lymphoid irradiation as an immunosuppressant, but it will be difficult to improve over the current results with cyclosporine or conventional immunosuppression, at least for primary transplantation. The future of total lymphoid irradiation probably lies in devising protocols in which maintenance immunosuppression can be eliminated, or nearly eliminated, altogether. Such protocols are effective in rodents. Whether they can be applied to clinical transplantation remains to be seen.

Adolescent↗
PubMed1983

Morphology of cyclosporine nephrotoxicity and acute rejection in patients immunosuppressed with cyclosporine and prednisone.

Cyclosporine nephrotoxicity is a common and usually reversible cause of renal insufficiency in the renal allograft recipient. We examined 132 renal biopsy specimens of 54 patients with elevated serum creatinine concentrations in the posttransplant period in an attempt to characterize histologic features that would identify patients with cyclosporine nephrotoxicity as opposed to those with acute rejection. Nine histologic parameters were examined--vasculitis, interstitial edema, distribution and intensity of mononuclear cell interstitial infiltrate, mononuclear cell exudation within glomerular capillaries ("glomerulitis"), tubular ectasia, tubular necrosis, exudation of mononuclear cells within tubular epithelial cells ("tubulitis"), and the ratio of mononuclear cells in interstitial tissues and in the peritubular capillaries (I/C ratio). A clinical response to an increased dose of steroids or a reduced dose of cyclosporine was correlated with the histologic picture. Tubulo-interstitial nephritis was identified in all but one patient with cyclosporine nephrotoxicity and only the finding of vasculitis allowed the identification of rejection with any certainly. However, the linear logistic regression method identified four histologic parameters--vasculitis, edema, glomerulitis, and I/C ratio, which were useful in differentiating the nephritis of cyclosporine nephrotoxicity from that of acute rejection in 94% of the biopsies. Although it is possible to precisely predict clinical response to antirejection therapy or reduction in cyclosporine dose based on histologic criteria, it is possible that cyclosporine toxicity, alone or in combination with rejection, may lead to chronic interstitial fibrosis responsible for late graft loss.

Animals↗