Surgical treatment of diabetes mellitus with pancreas transplantation.

OBJECTIVE: The authors compared results and morbidity in insulin-dependent diabetes mellitus (IDDM) patients undergoing preemptive pancreas transplantation (PTx) either before dialysis or before the need for a kidney transplant with IDDM patients undergoing conventional combined pancreas-kidney transplantation (PKT) after the initiation of dialysis therapy. SUMMARY BACKGROUND DATA: Combined PKT has become accepted generally as the best treatment option in carefully selected IDDM patients who either are dependent on dialysis or for whom dialysis is imminent. With improving results, the timing of PKT relative to the degree of nephropathy is evolving. However, it is not well established that the advantages of preemptive PTx can be achieved without incurring a detrimental effect on graft function or survival. METHODS: Over a 4-year study period, data on the following 3 recipient groups were collected prospectively and analyzed retrospectively: 1) 38 IDDM patients undergoing combined PKT while on dialysis (PKT:D); 2) 44 IDDM patients undergoing preemptive PKT before dialysis (PKT:ND); and 3) 20 IDDM patients undergoing solitary PTx. All patients underwent whole organ PTx with bladder drainage and were treated with quadruple immunosuppression. RESULTS: Actuarial 1-year patient survival is 100%, 98%, and 93%, respectively. One-year actuarial PTx survival (insulin-independence) is 92%, 95%, and 78%, respectively. The incidence of rejection, infection, operative complications, readmissions, and total hospital days was similar in the three groups. Long-term renal and pancreas allograft function and quality of life were similarly comparable. Rehabilitation potential favored the solitary PTx and PKT:ND groups. CONCLUSIONS: Preemptive PKT or solitary PTx performed earlier in the course of diabetes is associated with good results, facilitated rehabilitation, and may prevent further diabetic complications.

HLA-D and T lymphocyte reactivity to specific periodontal pathogens in type 1 diabetic periodontitis.

Bacterial antigen fragments complexed with class II major histocompatibility molecules (HLA-D) on antigen presenting cells (APCs) stimulate CD4+ T lymphocyte proliferation, presumably to protect the host. This study examined these responses to antigens of two periodontal pathogens in four groups (n = 15) of age- (young adult) and sex-matched Caucasian subjects with or without type 1 diabetes and moderate to severe periodontitis: Group DP = diabetics with periodontitis; Group DnP = diabetics without periodontitis; Group nDP = nondiabetics with periodontitis; and Group nDnP = nondiabetics without periodontitis. HLA-D phenotypes for each subject were determined by lymphocytotoxicity assays. T lymphocytes purified from peripheral blood were stimulated in cell culture with APC pulsed with various concentrations of tetanus toxoid, Porphyromonas gingivalis, and Capnocytophaga sputigena antigens. T lymphocyte reactivity (3H thymidine incorporation) was numerically lower in cultures from diabetics stimulated with unpulsed APC (not significant), and antigen-pulsed cultures showed low proliferation and no significant differences among groups. Stimulation indices in cultures from diabetic patients stimulated with P. gingivalis or C. sputigena, however, were significantly elevated at all antigen concentrations compared to nondiabetic cultures. The occurrence of HLA-DR4 was moderately associated with diabetes (P < 0.05) and highly associated with periodontitis (P < 0.001, log-linear model for categorical variables); and HLA-DR53 and HLA-DQ3 were significantly associated with periodontitis (P < or = 0.02). HLA-DR was crucial to lymphocyte stimulation (anti-HLA-DR blocking experiments), but the low peripheral blood T cell reactivity to antigens of periodontal pathogens could not be linked with HLA-D type or periodontitis susceptibility.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparative analysis of results and morbidity in type I diabetics undergoing preemptive versus postdialysis combined pancreas-kidney transplantation.

Although combined pancreas-kidney transplantation (PKT) has become a valid treatment option for selected type I diabetics, the timing of PKT relative to the degree of nephropathy remains controversial. We analyzed results and morbidity in 30 type I diabetics undergoing PKT after starting dialysis (PKT:D) versus 31 type I diabetics undergoing PKT prior to dialysis (PKT:ND). The two groups were similar with the respect to age, duration and severity of diabetes, gender, race, preservation time, retransplants, sensitization, HLA-matching, and CMV status. The mean preoperative serum creatinine was higher in the PKT:D group (9.9 +/- 3.4 vs. 3.9 +/- 1.9 mg/dl PKT:ND, P < 0.01). All patients were managed with quadruple immunosuppression with OKT3 induction. Actuarial patient survival is 100% (PKT:D) and 96.8% (PKT:ND). Renal and pancreas allograft survival are 97% and 93%, respectively, in both groups. The incidence of rejection, infection, operative complications, reflux pancreatitis, and total hospital days was similar in both groups. Long-term renal and pancreas allograft function and quality of life were like-wise comparable. No adverse coagulation or immunologic effects were noted in the PKT:ND group. Rehabilitation potential favored the PKT:ND group. PKT can be performed safely and effectively in the absence of uremia. In selected type I diabetics with significant nephropathy, we believe that PKT is the best treatment option and need not be considered as preemptive, especially in view of increasing waiting times and the variable progressive nature of diabetic complications.

Recipient selection and evaluation for vascularized pancreas transplantation.

Vascularized pancreas transplantation (PT) is becoming an accepted therapy for selected type I diabetic patients. However, selection and evaluation criteria remain uncertain. In the last 3.5 years, we have interviewed 205 and evaluated 151 diabetic patients for PT. The degree of renal dysfunction (creatinine clearance below 45 ml/min) was used to select patients for combined pancreas-kidney transplantation (PKT) or solitary pancreas transplantation (PTA) (clearance above 70 ml/min). The cardiovascular evaluation (stress thallium study with liberal use of coronary angiography) was used to determine operative risk and provided the other major selection criterion. A total of 104 patients were selected as candidates for PT; 70 have undergone PKT with 98.6% patient survival (1 cardiovascular death), 97.1% kidney graft survival, and 94.2% pancreas graft survival. Thirty-three evaluated patients (24.1%) were not accepted as candidates for PT; 13 have undergone cadaveric kidney transplantation, 5 were placed on the kidney waiting list, and 9 have died. Criteria for PTA include 2 or more diabetic complications or hyperlabile diabetes. Patient (n = 12) and pancreas graft survival after PTA is 83.3 and 50%, respectively. Our conclusion is that a multidisciplinary approach was used for recipient selection for PT based on degree of nephropathy, cardiovascular risk, and presence of diabetic complications. Nearly 75% of diabetic patients evaluated were acceptable candidates for PT. Only 4 (3.8%) of these selected patients died while awaiting or undergoing PT, thus optimizing the use of scarce allograft resources and providing evidence for appropriate patient selection.

Combined pancreas--kidney transplantation in Nebraska.

UNLABELLED: In the last 2 years, we have performed combined pancreas-kidney transplantation in 38 Type I diabetics with nephropathy. The mean age of the recipient group was 35 years (range 24-51) with a mean duration of diabetes of 22 years (range 13-41). All patients received quadruple immunosuppression with OKT3 induction. All patients are normoglycemic and insulin independent with a mean glycosylated hemoglobin level of 5.2 +/- 1.1% and a mean serum creatinine of 1.9 +/- 0.5 mg/dl. Metabolic effects of pancreas transplantation included fasting hyperinsulinemia and hyperglucagonemia with exaggerated insulin and glucagon responses to glucose and arginine, respectively, that improved slightly with time. Patient and kidney graft survival are 100% and pancreas graft survival is 94.7% after a mean follow-up interval of 15 months. CONCLUSION: Combined pancreas-kidney transplantation is the treatment of choice for selected Type I diabetics with nephropathy and results in euglycemia despite immunosuppression.

Combined pancreas-kidney transplantation: preliminary results and metabolic effects.

UNLABELLED: Vascularized pancreas transplantation (PT) results in a self-regulating endogenous source of insulin. In the last 18 months, we have performed combined pancreas-kidney transplantation in 25 type I diabetics with nephropathy. The mean age of the recipient group was 35 yr (range 24-51) with a mean duration of diabetes of 22 yr (range 13-41). All patients received quadruple immunosuppression with OKT3 induction. All patients remained normoglycemic and insulin independent with a mean glycosylated hemoglobin level of 6.0 +/- 1.1% and a mean serum creatinine of 1.7 +/- 0.5 mg/dl. Metabolic control and hormonal profiles were assessed by intravenous glucose challenge followed by arginine stimulation. Metabolic effects of PT included fasting hyperinsulinemia and hyperglucagonemia with exaggerated insulin and glucagon responses to glucose and arginine, respectively. Patient and graft survival is 100% after a mean follow-up interval of 8 months. CONCLUSION: combined pancreas-kidney transplantation is a valid treatment option for diabetic nephropathy, and results in near-complete normalization of glucose metabolism.

Long-term anticonvulsant therapy and intestinal calcium absorption.

Twelve patients on anticonvulsant therapy were studied to determine whether or not the drugs induced alterations in gastrointestinal absorption of calcium, response to parathyroid hormone (PTH), or serum 25-hydroxy vitamin D (25-OHD) concentrations. Fractional calcium absorption (FCaA) was determined by giving 45Ca intravenously and orally. The short-term response to PTH was assessed by giving 200 U of parathyroid extract (PTE) intravenously over 15 min and measuring hourly urine cyclic adenosine monophosphate (cAMP) and tubular reabsorption of phosphate (TRP). Calcemic response to PTH was followed by giving intramuscular injections of PTE, 200 U every 6 hr. FCaA was 30.8 +/- 3.7% lower than the normal of 42.2 +/- 2.5% (P less than 0.025), and baseline 25-OHD levels were 30.5 +/- 3.4 ng/ml (normal 15 to 50 ng/ml). Anticonvulsant drugs did not alter renal response to PTE. There was a rise in urinary cAMP from 3.7 +/- 0.23 to 6.1 +/- 0.47 mumol/gm creatinine (P less than 0.005) with a fall in TRP from 87.8 +/- 1.2% to 78.8 +/- 1.6% (P less than 0.005). Serum calcium rose from 9.4 +/- 0.1 to 11.1 +/- 0.3 mg/dl (P less than 0.005). We conclude that FCaA is low in patients receiving anticonvulsant drugs, even when serum 25-OHD levels and the response of bone and kidney to PTH remain normal.

Effects of hydrochlorothiazide and dietary sodium restriction on calcium metabolism in corticosteroid treated patients.

The effect of treatment with hydrochlorothiazide (HCT) and dietary sodium restriction on calcium economy in glucocorticoid-treated patients was investigated. Fractional 47Ca intestinal absorption (FCaA) and fractional urinary calcium excretion (FCaEx) were measured in six normal individuals and in ten patients receiving glucocorticoids for chronic obstructive pulmonary disease before and after 60 days of treatment with a 50 mEq sodium diet and HCT 50 mg twice daily. FCaA was significantly decreased on glucocorticoid-treated patients (27.5 +/- 4.3%) when compared to normal individuals (41.8 +/- 2.8%, p less than 0.005). A significant increase in FCaA to 38.9 +/- 4.8%, (P less than .05) was seen in glucocorticoid-treated patients after treatment with HCT and dietary sodium restriction. Baseline FCaEx was higher in glucocorticoid-treated patients than in the normal subjects. A significant decrease in FCaEx after dietary sodium restriction and thiazide administration occurred in both normal (0.99 +/- 0.28% before vs. 0.69 +/- 0.30% after; p less than .025) and glucocorticoid-treated patients (1.46 +/- 0.19% before vs. 0.73 +/- 0.13% after p; less than 0.025). These data suggest that dietary sodium restriction and HCT therapy may improve total body calcium economy in glucocorticoid-treated patients by increasing intestinal calcium absorption and decreasing urinary calcium excretion.