F. C. Goetz

A 10-year experience with 290 pancreas transplants at a single institution

Since our report at the 1984 American Surgical Association meeting of 100 pancreas transplants from 1966 through 1983, another 190 have been performed. The current series, begun in 1978, now numbers 276 cases, and includes 133 nonuremic recipients of pancreas transplants alone (PTA), 46 simultaneous pancreas/kidney transplants (SPK), and 97 pancreas tranplants after a kidney transplant (PAK). Duct management techniques used were free intraperitoneal drainage in 44 cases, duct occlusion in 44, enteric drainage in 89, and bladder drainage in 128. The 1-year patient and graft survival rates in the entire cohort of 276 were 91% and 42%. One-year patient survival rates were 88% in the first 100, 91% in the second 100, and 92% in the last 76 cases; corresponding 1-year graft survival rates were 28%, 47%, and 56% (p less than 0.05). A prospective comparison of bladder drainage (n = 82) versus enteric drainage (n = 46) in PAK/PTA cases since November 1, 1984 favored bladder drainage (1-year graft survival rates of 52% vs. 41%) because of urinary amylase monitoring. The best results were in recipients of primary SPK bladder-drained transplants (n = 39), with a 1-year pancreas graft survival rate of 75%, kidney graft survival rate of 80%, and patient survival rate of 95%. Logistic regression analysis, with 1-year graft function as the independent variable, showed significant (p less than 0.05) predictors of success (odds ratio) to be technique: bladder drainage (5.8) versus enteric drainage (2.5) versus duct injection (1.0); category: SPK (6.0) versus PAK from same donor (3.2) versus PAK from different donor (1.2) versus PTA (1.0); and donor HLA DR mismatch: 0 (5.0) versus 1 (2.5) versus 2 (1.0) antigens. On April 1, 1989, 90 patients had functioning grafts (60 euglycemic and insulin-free for more than 1 year, 10 for 5 to 10 years); these, along with 24 others whose grafts functioned for 1 to 6 years before failing, are part of an expanding cohort in whom the influence of inducing a euglycemic state on pre-existing secondary complications of diabetes is being studied. Only preliminary data is available. In regard to neuropathy, at more than 1 year after transplant in patients with functioning grafts, conduction velocities in some nerves were increased over baseline. In regard to retinopathy, deterioration in grade occurred in approximately 30% of the recipients by 3 years, whether the graft functioned continuously or failed early, but thereafter retinopathy in the patients with functioning grafts remained stable.(ABSTRACT TRUNCATED AT 400 WORDS)

Ten Year Experience With Renal Transplantation in Juvenile Onset Diabetics

Between 1968 and 1978, 305 juvenile onset diabetic patients with uremia and 462 nondiabetic uremic patients of similar age received primary renal allografts at the University of Minnesota. Two hundred eight of the diabetic patients are alive and 190 have functioning renal grafts three months to ten years after transplantation. Cumulative patient survival rates at two years for diabetic recipients of kidneys from HLA identical siblings, other related and cadaver donors are 90, 73 and 68%, respectively; the corresponding graft functional survival rates are 90, 67 and 55%. For nondiabetic patients receiving kidneys from the same donor categories the corresponding patient survival rates are 97, 86 and 75%, while the graft functional survival rates are 94, 77 and 64%. The differences in patient and graft survival between diabetic and nondiabetic recipients are statistically significant only for the patients receiving grafts from HLA-nonidentical related donors. For all recipients under the age of 30, there are no statistically significant differences in patient and graft survival. Regardless of the age of the patient or the source of the kidney, the survival of diabetic patients treated with transplantation at our institution is better than the use of chronic hemodialysis, alone. Technical complications do not occur more frequently in diabetic transplant recipients. Cardiovascular disease is responsible for most of the late deaths in these diabetic patients. Amputations of digits or extremities have been required in 15% of the diabetic patients. On the positive side, the vision of 88% of these recipients remained stable or had improved visual acuity, and 82% of the diabetic patients were actively rehabilitated after transplantation. Kidney transplantation is the treatment of choice for end-stage renal failure in diabetic patients, just as it is for most uremic patients.

HLA-associated susceptibility to type 2 (non-insulin-dependent) diabetes mellitus : the Wadena City health study

SummaryEpidemiologic data suggest that a parental history of Type 2 (non-insulin-dependent) diabetes mellitus increases the risk of Type 1 (insulin-dependent) diabetes in siblings of a Type 1 diabetes proband. This increase in risk is consistent with a shared genetic susceptibility between Type 1 and Type 2 diabetes. We have previously reported evidence that HLA-DR4-linked factors may represent a homogeneous subset of diabetes susceptibility. First, HLA-DR4 frequency was higher in Type 1 diabetic study subjects with a Type 2 diabetic parent than in Type 1 diabetic subjects whose parents were not diabetic. Second, a DR4-haplotype was transmitted from the Type 2 diabetic parent to the Type 1 offspring more often than expected. These data are consistent with the hypothesis that families with a Type 2 diabetic parent and Type 1 diabetic child, heavily determined by HLA-DR4 linked factors, may represent a homogeneous subset of diabetes susceptibility. In this report, we further explore the relationship between the high-risk HLA antigen (HLA-DR4) in study subjects with differing glycaemic status (National Diabetes Data Group criteria). In this community-based study, we find evidence that HLA-DR4 is increased in study subjects with Type 2 diabetes and may be a marker for Type 2 diabetes susceptibility.

Shared genetic susceptibility of type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus : contributions of HLA and haptoglobin

SummaryEpidemiologic data suggest that having a parent with Type 2 (non-insulin-dependent) diabetes mellitus increases the risk for Type 1 (insulin-dependent) diabetes in siblings of a Type 1 diabetes proband. This increase in risk is consistent with a shared genetic susceptibility between Type 1 diabetes and Type 2 diabetes. We contrast genetic risk factors in three sets of families, consisting of (1) a single Type 1 diabetic child (proband) and non-diabetic parents, (2) multiple Type 1 diabetic siblings and non-diabetic parents, and (3) at least one Type 1 diabetic child and at least one Type 2 diabetic parent. Previous studies have demonstrated that HLA region genes, which elevate the risk in Type 1 diabetes, have no significant effect with respect to the risk for developing Type 2 diabetes. An earlier report cited a contribution by the haptoglobin locus to genetic susceptibility for Type 2 diabetes. We provide evidence that a high risk HLA antigen (HLA-DR3) is decreased to a greater extent in Type 1 patients with a Type 2 parent than in Type 1 patients in which the parents are not diabetic. The role of HLA-DR4 is maintained in these families, with an unexpectedly significant increased rate of transmission of the HLA-DR4 allele from Type 2 parent to Type 1 offspring. The role of haptoglobin in these families does not appear to be important, either with respect to association with diabetes or with respect to linkage with a secondary susceptibility locus. These results indicate that families with a Type 2 parent and Type 1 child, heavily determined by HLA-DR4 linked factors, may represent a homogeneous subset of diabetes susceptibility.

Glomerulosclerosis in Type 2 (non0insulin-dependent) diabetes mellitus: relationship to glycaemia in the University Group Diabetes Program (UGDP)

SummaryKidney tissue of acceptable quality was available from autopsies of 55 patients who had been followed prospectively for 3 to 15 years as participants in the University Group Diabetes Program, a study of vascular disease in Type 2 (non-insulin-dependent) diabetic patients. Slides were prepared for light microscopic reading by uniform histologic techniques, and then were randomly intermixed and coded with tissues identically prepared from matched nondiabetic subjects (morphologic controls). After independent review by three morphologists, the results were tabulated and assigned to one of four diagnostic groups: 1) typical diabetic nodular glomerulosclerosis; 2) mesangial changes suggestive of diabetes (diffuse lesion); 3) non-diabetic renal disease; 4) normal for age. Of the diabetic cases 31% (17 of 55) were found to show nodular glomerulosclerosis, and another 47% (26 of 55) showed suggestive changes; none of the morphologic control slides was read as showing nodular glomerulosclerosis, but some were judged to show suggestive mesangial (diffuse) changes. Although only 4 of the 17 diabetic patients with nodules had died of uraemia, many had hypertension, which may have contributed to their deaths from vascular disease. The patients with nodular glomerular changes also showed, on the average, the highest blood glucose levels during life. Type 2 diabetes in later life appears to be associated with a high risk for typical tissue changes of diabetic kidney damage, which may contribute significantly to morbidity and mortality and may be present before azotaemia and qualitative proteinuria have been recognized.

Recent experience with 89 pancreas transplants at a single institution

SummaryOf 89 pancreas transplants performed in 77 diabetic patients (43 with and 34 without previous kidney transplants), 53 were from cadaver and 36 from related donors. To date, 64 patients (83%) are alive and 27 (35%) have functioning grafts (14 > 1 year), including 0 out of 3 duct-ligated, 3 out of 15 open-duct, 17 out of 32 enteric-drained, and 7 out of 39 duct-injected. Of technically successful allografts, 8 out of 16 (50%) in the azathioprine- and 17 out of 47 (36%) in the cyclosporin-treated recipients are functioning (eight cyclosporin patients also take azathioprine). Seven of the nine (78%) non-kidney-transplant recipients of technically successful pancreas allografts from HLA-identical siblings have functioning grafts. Causes of graft failure include allograft rejection, fibrosis secondary to duct injection, or selective β-cell destruction independent of rejection. Of the 24 recipients who are currently insulin-independent, 14 have normal or near-normal glucose tolerance test results, while 10 have abnormal results, even though they are otherwise euglycaemic. The patient population to whom pancreas transplantation is applied is gradually changing, and non-uraemic, non-kidney-transplant patients currently comprise the majority of our cases (17 out of 24 in 1983; nine of the 17 currently have functioning grafts). We now prefer the enteric drainage technique. Except for recipients of related grafts from a previous kidney donor, in which case it is necessary only to continue the current immunosuppressive regimen, we now administer cyclosporin and prednisone for immunosuppression in recipients of HLA-identical sibling grafts, and cyclosporin, azathioprine and prednisone (triple therapy) for recipients of HLA-mismatched grafts. The most interesting features in this series of cases are the variable patterns of glucose metabolism post-transplant, the finding that processes other than graft rejection, may lead to loss of β-cell function, preliminary observations on changes in morphology of kidneys following restoration of normoglycaemia, and the evolution of an immunosuppressive regimen that appears to prevent allograft rejection in non-uraemic, non-kidney-transplant patients.

Medical Risks and Benefit of Pancreas Transplants from Living Related Donors

The rationale to perform transplants of any organ from living related donors (LRDs) rather than cadaver (Cad) donors is two-fold: there is a shortage of Cad donors for the number in need of a transplant, and the rejection rate will be less with grafts from LRDs. Either reason by itself will justify the use of LRDs, and for kidney transplants both pertain.

A reassessment of fasting plasma glucose concentrations in population screening for diabetes mellitus in a community of northern European ancestry: the Wadena City Health Study

In current clinical and research practice, the determination of diabetic status depends largely on plasma glucose levels 2 h after the ingestion of a standard 75-g glucose load, the oral glucose tolerance test (OGTT). The OGTT, however, remains inconvenient, not highly reproducible, and costly, especially for large-scale studies and population screening tests. Fasting plasma glucose (FPG) determinations are convenient, reliable, and valid measures of glucose intolerance, but the currently prescribed cut-off point of 140 mg/dl (7.8 mM) lacks sensitivity. We evaluated the reliability and validity of fasting plasma glucose (FPG) values compared with other measures of hyperglycemia for a diagnosis of diabetes in a populationbased study of carbohydrate metabolism in Wadena, Minnesota, a community of predominantly northern European ancestry. As a part of this effort, a random sample of Wadena adults, stratified by age and gender, plus all known, previously diagnosed diabetics participated in 2 days of baseline testing and were followed prospectively and retested 5 years later. Cross-sectional analyses of baseline data are presented in this article. Diabetic status was ascertained by administering a standard OGTT according to National Diabetes Data Group (NDDG) specifications. Sensitivity and specificity levels obtained when using a FPG cut-off point of 6.4 mM were 95.2% and 97.4%, respectively. In study subjects with no known diagnosis of diabetes, the FPG cut-off point of 6.4 mM performed reasonably well with a sensitivity and specificity of 67.7% and 97.4%, respectively. A receiver operating characteristic (ROC) curve analysis showed that FPG consistently performed better than glycosylated hemoglobin in distinguishing diabetic from non-diabetic subjects. FPG concentrations accurately and reliably discriminate diabetic from non-diabetic individuals in a population-based study of Caucasians of northern European ancestry.

Anti-islet autoantibodies detected by monoclonal antibody 1A2: further studies suggesting a role in the pathogenesis of IDDM

Summary Insulin-dependent diabetes mellitus (IDDM) is associated with autoantibodies to several pancreatic islet antigens. We have described an assay in which autoantibodies displace a radiolabelled monoclonal anti-islet antibody. Sera from 87 % of 429 children at time of diagnosis of IDDM were positive, while sera from control groups had much lower prevalences (1.3–19 %). Sera from 41.9 % of diabetic subjects remained positive after 20 years duration of IDDM. Sera from 23.6 % of parents and 37.9 % of non-diabetic siblings were positive. Twenty relatives who subsequently developed IDDM had the same prevalence of the antibodies (85 %) as did the patients at time of diagnosis. These findings confirm that the autoantibodies detected by monoclonal antibody (mAb) 1A2 are common at the onset of IDDM and their presence prior to the onset of hyperglycaemia suggests that this method may be useful in screening non-diabetic populations. The high prevalence of antibodies in relatives reduces the efficacy for diabetes prediction, but suggests either that generation of these antibodies is an autosomal dominant trait, or that the antigen detected by these antibodies is cross-reactive with a common environmental antigen. Differentiation between these hypotheses will await the identification of the specific islet-cell antigen detected by mAb 1A2. [Diabetologia (1996) 39: 1365–1371]