Vera Delaney

Advanced Glycosylation End Products in Patients with Diabetic Nephropathy

BACKGROUND Glucose reacts nonenzymatically with proteins in vivo, chemically forming covalently attached glucose-addition products and cross-links between proteins. The excessive accumulation of rearranged late-glucose-addition products, or advanced glycosylation end products (AGEs), is believed to contribute to the chronic complications of diabetes mellitus. METHODS To elucidate the relation of AGEs to diabetic complications, we used a radioreceptor assay to measure serum and tissue AGEs in diabetic (Types I and Type II) and nondiabetic patients with different levels of renal function. Serum AGEs were measured as a low-molecular-weight (less than or equal to 10 kd) peptide fraction and a high-molecular-weight (greater than 10 kd) protein fraction. RESULTS The mean (+/- SD) AGE content of samples of arterial-wall collagen from 9 diabetic patients was significantly higher than that of samples from 18 nondiabetic patients (14.5 +/- 5.2 vs. 3.6 +/- 1.5 AGE units per milligram, P less than 0.001). Moreover, diabetic patients with end-stage renal disease had almost twice as much AGE in tissue as diabetic patients without renal disease (21.3 +/- 2.8 vs. 11.5 +/- 1.9 AGE units per milligram, P less than 0.001). The AGE levels in both serum fractions were elevated in the patients with diabetes, and the levels of AGE peptides correlated directly with serum creatinine (P less than 0.001) and inversely with creatinine clearance (P less than 0.005), suggesting that levels of AGE peptides increased with the severity of diabetic nephropathy. In six patients with diabetes who required hemodialysis, the levels of AGE peptides were five times higher than in eight normal subjects (82.8 +/- 9.4 vs. 15.6 +/- 3.4 AGE units per milliliter, P less than 0.001). In another group of diabetic patients the mean serum creatinine level, which decreased by 75 percent during a session of hemodialysis, whereas the level of AGE peptides decreased by only 24 percent. Serum levels of AGE peptides were normal in two patients with normal serum creatinine levels after renal transplantation. CONCLUSIONS AGEs accumulate at a faster-than-normal rate in arteries and the circulation of patients with diabetes; the increase in circulating AGE peptides parallels the severity of renal functional impairment in diabetic nephropathy.

DIABETES MELLITUS AFTER RENAL TRANSPLANTATION IN THE CYCLOSPORINE ERA-AN ANALYSIS OF RISK FACTORS

Despite mounting experimental evidence that cyclosporine inhibits pancreatic islet cell function, clinical data on posttransplant diabetes mellitus (PTDM) in renal allograft recipients in the cyclosporine era are scarce. Between June 1983 and December 1988, 39 of 337 (11.6%) cyclosporine-treated adult renal transplant recipient whose grafts survived longer than 1 year developed PTDM. Of these, 43.6% and 74.4% were diagnosed by 3 and 12 months posttransplant, respectively, and 51.3% were insulin-dependent. Incidence of PTDM was highest in blacks (19.8%) and Hispanics (21.3%) and in those with HLA-A 30 and Bw 42 antigens. Older recipients and those that received cadaveric kidneys were more likely to develop diabetes than those who received living related allografts (14% vs. 5.3%, P less than 0.05). The rate of PTDM appeared to be independent of the type of induction, immunosuppressant therapy, incidence of rejection, total steroid and cyclosporine dose, percentage of body weight gain in the first posttransplant year, and serum creatinine concentration. Actuarial 5-year, decaying from 100% at 1 year, patient and graft survival rates were 87% and 70%, respectively, in the PTDM group compared with 93% and 90%, respectively, in controls. Causes of graft failure among the diabetics included chronic rejection (6), patient death (3), noncompliance with immunosuppressants (2), and sepsis (1). The incidence of infectious complications was significantly higher in the PTDM group compared with the control group (53% vs. 16%, P less than 0.05), with all 5 deaths among the diabetics being sepsis-related.

The influence of nephrectomy of the primary allograft on retransplant graft outcome in the cyclosporine era

The present analysis was undertaken to evaluate the influence of primary allograft nephrectomies on the early function, incidence of rejection, and short-term graft survival of subsequent renal retransplants. Among 95 consecutive cyclosporine treated retransplant recipients, 52 were retransplanted without primary allograft nephrectomy; 35 had removal of their primary grafts prior to retransplantation for fever and graft tenderness (30 patients) and persistent hematuria (5 patients); and 8 patients had an elective primary graft nephrectomy at the time of retransplantation. Demographic characteristics and immunosuppressive regimens were otherwise similar in all three groups. Nephrectomy of the primary allograft prior to retransplantation was associated with a significant subsequent rise in preformed cytotoxic antibody levels (57% having PRA > 30% compared with 33% in those with retention of primary grafts), a significantly higher incidence of delayed graft function among retransplants (63% compared with 30% in those who did not undergo primary allograft nephrectomy) and a trend toward decreased allograft survival in the subgroup who lost their primary allografts in the first year poattranaplant. The incidence of acute rejection and 3-year posttransplant renal function in retransplants were not, however, influenced by nephrectomy of the primary allograft.

Renal transplantation from elderly living donors

A worldwide shortage of cadaveric donors has led to the increased utilization of elderly living donors, with controversial results. In an attempt to assess the effect of donor age on graft survival and subsequent renal function, we analyzed our clinical results in 276 consecutive recipients of living related renal transplants spanning both the cyclosporine and the azathioprine eras, of whom a total of 44 recipients received kidneys from donors over 55 years old. All recipients were otherwise similar in age, race, haplotype mismatch, number of retransplants, and number of pretransplant transfusions, apart from an increased number of diabetics among the CsA-treated recipients of elderly kidneys (38% vs. 14%). The cumulative patient and graft survival rates at 1 and 5 years were independent of donor age whether CsA or AZA was utilized. Nor was the incidence of rejection or infection significantly different in the older donor group when compared with the younger cohort. Short-term and intermediate-term renal function, as assessed by serum creatinine, was however poorer but stable in the older donor group when compared with the younger one. The mean serum creatinine levels at 1 year in the CsA- and AZA-treated recipients of kidneys from older donors were 2.4 and 2.0 mg/dl, respectively, compared with 1.6 and 1.4 mg/dl, respectively, when the donor age was less than 55 years (P less than 0.001). Since renal function at the end of the first posttransplant year is considered a determinant of long-term graft survival, this is a cause for concern, but in view of the universal shortage of organs and the negligible morbidity to donors, renal transplantation from elderly living donors remains an acceptable practice.

Deep vein thrombosis in end-stage renal disease.

Patients who have end-stage renal disease have an acquired platelet dysfunction that leads to prolonged bleeding time and that may put them at risk for bleeding. This platelet dysfunction is manifest in reduced platelet adhesion and impaired platelet aggregation. As a result, a bleeding tendency exists in end-stage renal disease, and understandably deep vein thrombosis is vanishingly rare in patients with this condition. We present three end-stage renal disease patients undergoing maintenance hemodialysis who developed deep vein thrombosis. These cases illustrate that in some patients with end-stage renal disease, the pro thrombotic forces may be so profound that they overwhelm the bleeding tendency.

Retrospective analysis of posttransplantation diabetes mellitus in black renal allograft recipients.

Objective To study the incidence, outcome, and possible etiopathogenic factors involved in posttransplantation diabetes mellitus in cyclosporine-treated black renal allograft recipients. Research Design and Methods One hundred thirty-eight nondiabetic black renal transplant recipients whose grafts survived > 1 yr were studied retrospectively. Results Twenty-eight (20.3%) patients developed posttransplantation diabetes mellitus, 46 and 75% were diagnosed by 6- and 12-mo posttransplantation, respectively, and 46% were insulin dependent. Diabetes was more frequently encountered in older recipients and recipients of cadaveric kidneys but was independent of sex, number of transplants, incidence of acute rejection, percentage of body weight gain, steroid or cyclosporine dose, and use of beta-blockers and/or diuretics. Renal function was similar in the diabetic group compared with the control group. Actuarial 5-yr graft survival was 82% in the diabetic cohort compared with 78% in the control group, with chronic rejection accounting for all graft losses within the diabetic group. Conclusions Twenty percent of black cyclosporine-treated renal allograft recipients developed diabetes mellitus in the posttransplantation period. However, its presence did not appear to influence intermediate-term graft or patient survival.

Malacoplakia of the Prostate in a Renal Transplant Recipient: A Complicated Course

Extrarenal malacoplakia in renal transplant recipients is generally associated with a good prognosis. We report the first case of malacoplakia of the prostate in a renal transplant recipient that was associated with a complicated course despite prophylactic antibiotic therapy and reduction of immunosuppression. Malacoplakia in a renal transplant recipient is not always benign.