D. E. R. Sutherland

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 < 0.001 in each case). Linear regression analysis demonstrated significant correlations (P < 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.

Potent induction immunotherapy promotes long-term insulin independence after islet transplantation in type 1 diabetes.

The seemingly inexorable decline in insulin independence after islet transplant alone (ITA) has raised concern about its clinical utility. We hypothesized that induction immunosuppression therapy determines durability of insulin independence. We analyzed the proportion of insulin‐independent patients following final islet infusion in four groups of ITA recipients according to induction immunotherapy: University of Minnesota recipients given FcR nonbinding anti‐CD3 antibody alone or T cell depleting antibodies (TCDAb) and TNF‐α inhibition (TNF‐α‐i) (group 1; n = 29); recipients reported to the Collaborative Islet Transplant Registry (CITR) given TCDAb+TNF‐α‐i (group 2; n = 20); CITR recipients given TCDAb without TNF‐α‐i (group 3; n = 43); and CITR recipients given IL‐2 receptor antibodies (IL‐2RAb) alone (group 4; n = 177). Results were compared with outcomes in pancreas transplant alone (PTA) recipients reported to the Scientific Registry of Transplant Recipients (group 5; n = 677). The 5‐year insulin independence rates in group 1 (50%) and group 2 (50%) were comparable to outcomes in PTA (group 5: 52%; p>>0.05) but significantly higher than in group 3 (0%; p = 0.001) and group 4 (20%; p = 0.02). Induction immunosuppression was significantly associated with 5‐year insulin independence (p = 0.03), regardless of maintenance immunosuppression or other factors. These findings support potential for long‐term insulin independence after ITA using potent induction therapy, with anti‐CD3 Ab or TCDAb+TNF‐α‐i.

Surgical complications requiring early relaparotomy after pancreas transplantation: a multivariate risk factor and economic impact analysis of the cyclosporine era.

OBJECTIVES To study significant surgical complications requiring early (< or = 3 months posttransplant) relaparotomy (relap) after pancreas transplants, and to develop clinically relevant surgical and peritransplant decision-making guidelines for preventing and managing such complications. SUMMARY BACKGROUND DATA Pancreas grafts are still associated with the highest surgical complication rate of all routinely transplanted solid organs. However, the impact of surgical complications on morbidity, hospital costs, and graft and patient survival rates has not been analyzed in detail to date. METHODS We retrospectively studied surgical complications requiring relap in 441 consecutive cadaver, bladder-drained pancreas transplants (54% simultaneous pancreas and kidney [SPK]; 22% pancreas after kidney [PAK]; 24% pancreas transplant alone [PTA]; 37% retransplant). Outcome and hospital charges were analyzed separately for recipients with versus without reoperation. RESULTS The overall relap rate was 32% (SPK, 36%; PAK, 25%; PTA, 16%; p = 0.04). The most common causes were intraabdominal infection and graft pancreatitis (38%), pancreas graft thrombosis (27%), and anastomotic leak (15%). Perioperative relap mortality was 9%; transplant pancreatectomy was necessary in 57% of all recipients with one or more relaps. The pancreas graft was lost in 80% of recipients with versus 41% without relap (p < 0.0001). Patient survival rates were significantly lower (p < 0.05) for recipients with versus without relap. By multivariate analysis, significant risk factors for graft loss included older donor age (SPK, PAK), retransplant (PAK), relap for infection (SPK, PAK), and relap for leak or bleeding (PAK). For death, risk factors included older recipient age (SPK, PAK),retransplant (SPK, PAK), relap for thrombosis (PAK), relap for infection or leak (SPK), and relap for bleeding (PTA). CONCLUSIONS Posttransplant surgical complications requiring relap were frequent, resulted in a high rate of pancreas (SPK, PAK, PTA) and kidney (SPK, PAK) graft loss, and had a major economic impact (p = 0.0001). Complications were associated with substantial perioperative mortality and decreased patient survival rates. The focus must therefore shift from graft salvage to preservation of the recipients life once a pancreas graft-related complication requiring relap occurs. Thus, the threshold for pancreatectomy should be low. In this context, acceptance of older donors and recipients must be reconsidered.

Insulin independence in type I diabetes after transplantation of unpurified islets from single donor with 15-deoxyspergualin

Islet transplantation has been slow to develop as a therapy for type I diabetes mellitus. Conventional immunosuppression does not protect islet allografts from early failure and by current techniques the yield of purified islets from a single pancreas is inadequate or only marginally in excess of the number needed to sustain normoglycaemia. We transplanted unpurified islets from a single pancreas concomitantly with a kidney to two uraemic diabetic patients. The novel agent 15-deoxyspergualin, along with antilymphocyte globulin, was used for induction immunosuppression, and azathioprine, prednisone, and cyclosporin for maintenance. Islet function has been sustained in both, and the second patient is insulin-independent and euglycaemic more than 6 months after transplantation.

Mean Glomerular Volume and Rate of Development of Diabetic Nephropathy

We studied kidney glomerular structure and function in two groups of type I (insulin-dependent) diabetic subjects with 14–16 yr (group 1, n = 16) and 24–26 yr (group 2, n = 13) duration of diabetes and compared them to a group of 18 nondiabetic subjects with similar age ranges. Within each diabetic group, subjects were selected for normal kidney function (urinary albumin excretion <40 mg/24 h, normal blood pressure, creatinine clearance >90 ml · min−1 · 1.73 m−2) or for nephropathy (urinary albumin excretion >200 mg/24 h). Morphometric analysis of glomeruli revealed a significantly larger mean glomerular volume in subjects with nephropathy (group 2). Mesangial volumes were significantly greater in the nephropathic than the normoalbuminuric diabetic subjects in each group, but filtration surface per glomerulus was constant among all subjects. The percentage of sclerosed glomeruli was also significantly increased in the nephropathic subjects compared with the subjects with normal kidney function, in whom sclerosed glomeruli did not exceed 8%. In addition, there was a significant correlation between percentage of globally sclerosed glomeruli and glomerular volume in group 2 (rs = .79, P < .01) but not group 1 (rs = −.20, NS) subjects. Thus, glomerular size or individual capacity for glomerular expansion may determine the rate of progression of the loss of kidney function in subjects destined to develop diabetic nephropathy.

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 1 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.

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)

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.

Long-term survival following kidney transplantation in 100 type I diabetic patients

Between December 1966 and April 1978, 265 uremic patients with type I diabetes received primary renal allografts at the University of Minnesota. One hundred of the diabetic patients were alive with a functioning graft 10 years after transplantation. The actual 10-year patient and primary graft functional survival rates overall were 40% and 32%, respectively. For recipients of HLA-identical sibling (n = 45), mismatched living-related (n = 121), and cadaver donor grafts (n = 99), the actual 10-year patient survival rates were 64%, 33%, and 36%, respectively, and the actual 10-year graft functional survival rates were 62%, 28%, and 22%, respectively. The differences in patient and graft survival rates between HLA-identical graft recipients and recipients of mismatched related and cadaver grafts were significant (P less than 0.001). Of the 100 patients who survived into a second decade, at 15 years posttransplant 51% were alive, and 41% had functioning grafts. For recipients of HLA-identical sibling, mismatched living-related donor grafts, and cadaver donor grafts who survived 10 years, 47%, 57%, and 43%, respectively, were alive at 15 years, and 31%, 45%, and 43%, respectively, had functioning grafts. For recipients who made it to the second decade, patient and primary graft survival rates thereafter were not statistically different by donor source. Twenty-three patients died in the second decade after transplantation, 10 of cardiovascular disease. Twenty-five patients lost graft function in the second decade, 19 from death with a functioning graft. In regard to diabetic complications, recurrence of diabetic nephropathy was common, but only two patients lost graft function solely for this reason. In 21 patients (42 eyes) followed prospectively for 10 years, visual acuity deteriorated in 26%, was stable in 64%, and improved in 10% of eyes. Neurophysiological test results indicated that correction of uremia does not stop the progression of diabetic neuropathy in recipients of kidney transplants alone. Even without cyclosporine, nearly two-thirds of recipients of HLA-identical kidney grafts, more than one-quarter of recipients of mismatched living-related donor grafts, and more than one-fifth receiving cadaver grafts enjoyed an extension of life for more than 10 years.

Clostridium difficile colitis after kidney and kidney-pancreas transplantation.

Objective – To determine the timing and risk factors involved in the development of Clostridium difficile (CD) colitis in kidney and kidney‐pancreas transplant recipients.Summary background data – The incidence of CD colitis after kidney and kidney‐pancreas transplantation has not been studied in detail. The question of whether the immunosuppressed transplant recipient is more prone to CD colitis and its complications (i.e., megacolon, perforations) and the risk factors involved have not been determined.Methods – We retrospectively reviewed our experience in kidney and kidney‐pancreas recipients who received transplants between January 1, 1985 and December 31, 1994. We divided these recipients into three groups: pediatric kidney recipients, adult kidney recipients, and kidney‐pancreas recipients. For each group, we assessed the timing of infection, primary disease, colitis treatment, and any concurrent complications or risk factors.Results – Of 1932 transplants, 159 recipients developed post‐transplant CD colitis. 132 charts were available for review. Forty‐three pediatric kidney recipients developed CD colitis. Their mean age was 3.2 yr; 74% (n=37) of them developed their colitis during their initial hospital stay, with the mean timing of infection being 33 d. Forty‐one (95%) had undergone intra‐abdominal placement of the graft, with renal artery anastomoses to the aorta.Fifty adult kidney recipients developed CD colitis. Thirteen (26%) developed colitis during their initial hospital stay, with the mean timing of infection (for all adult kidney recipients) being 15 months.Thirty‐nine kidney‐pancreas recipients developed CD colitis. Mean timing of infection was 6 months.The overall incidence of CD colitis was 8%, with 16% in the pediatric kidney group, 15.5% in the kidney‐pancreas group, and 3.5% in the adult kidney group. The difference in mean timing of infection was significant between the three groups (p<0.001 for pediatric versus adult kidney recipients, p=0.002 for pediatric kidney versus kidney‐pancreas recipients, and p=0.2846 for adult kidney versus kidney‐pancreas recipients).Conclusion – The incidence of CD colitis is increased in pediatric kidney and kidney‐pancreas recipients. Young recipient age (<5 yr), female gender, treatment of rejection with monoclonal antibodies, antibiotic use, and intra‐abdominal graft placement have been shown to increase the incidence of this disease. Further studies concerning prevention in the high‐risk groups are needed.