Nabil Sumrani

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.

Causes of late renal allograft failure in the ciclosporin era

A single center experience of 514 ciclosporin-treated renal allografts which survived longer than 1 year was reviewed in order to analyze the causes of renal allograft loss beyond the 1st year post-transplantation and the contribution of selected parameters to long-term survival. 83 grafts were lost between 1 and 5 years with the most common causes of graft loss being chronic rejection (54%), death (14%), noncompliance (13%) and sepsis (11%). Actuarial 5-year graft survival rates, decaying from 100% at 1 year, of living related and cadaveric grafts were 88.6 and 79.5%, respectively. Parameters with a substantial influence on long-term survival included the quality of early graft function and incidence of acute rejection in the 1st year post-transplantation. A marker for long-term survival (> 5 years) was a significantly lower serum creatinine (177 mumol/l; < or = 2 mg/dl) at 1 year. We conclude that chronic rejection is responsible for the majority of late graft losses in the ciclosporin era as in the earlier azathioprine period.

Parathyroidectomy Does Not Correct Hypertension in Patients on Maintenance Hemodialysis

Both hypertension and secondary hyperparathyroidism (2° HPT) are common features of the uremic syndrome. It has been suggested that 2° HPT causes hypertension in end-stage renal disease (ESRD). We compared predialysis blood pressure (BP), weight and dose of antihypertensive medications (AHM) prescribed in 19 hemodialysis patients 1 month before total parathyroidectomy (PTx), during the first month after PTx, and long-term (mean 16 months) in 12 of 19 patients.At the time of PTx, study patients had a mean age of 47 ± 9 years, mean duration of ESRD was 112 ± 57 months, and mean intact parathyroid hormone (PTH) level of 1,181 ± 552 pg/ml. Mean BP and predialysis weight were equivalent during the month before and the month after PTx.Of 12 patients followed long term, 8 (67%) were receiving AHM before PTx; after PTx; 3 (36%) of 8 discontinued AHM within 1 year, 2 (25%) of 8 required more AHM, while 2 (25%) of 8 continued on their original AHM, and 1 patient who was not on AHM prior to PTx required initiation of AHM after PTx.There was a clinically significant increase in predialysis weight at 1 year after PTx (median 13 lb) and over time (r = 0.7; slope = 0.5; p = 0.07). However, there was neither a clinically nor statistically significant change in either systolic (r = –0.18; slope = –0.01; p = 0.61) or diastolic (r = –0.6; slope = –0.24; p = 0.12) BP over time. We conclude that PTx fails to correct hypertension in hemodialysis patients with 2° HPT.

Determinants of type of initial hemodialysis vascular access.

Vascular access thrombosis is more common with polytetrafluoroethylene (PTFE) grafts than with native arteriovenous fistulae (AVF). Recent studies report an unexplained excess vascular access morbidity in women on hemodialysis. We studied 92 consecutive end-stage renal disease (ESRD) patients receiving their first permanent hemodialysis vascular access at initiation of hemodialysis to identify variables that determine assignment of either a PTFE graft or a native AVF. Independent variables included: age, gender, race, etiology of ESRD, and whether or not access surgery was electively planned before need for dialytic therapy. The 51 women and 41 men included 65 blacks, 13 Hispanics, 11 whites, and 3 Orientals aged 50 +/- (SD) 16 years. Of the 92 subjects, 54 (59%) received an AVF, while 38 (41%) received a PTFE graft. 36 (94%) of 38 PTFE grafts were placed in the upper arm as compared with 9 (17%) of 54 AVF (p = 0.0001). Also, 45 (83%) of 54 AVF were placed in the forearm as compared with only 2 (6%) of 38 PTFE grafts (p = 0.0001). Women were more likely to receive a PTFE graft - 28 (55%) of 51 - than men - 10 (24%) of 41 (p = 0.003). By contrast, men were more likely to get an AVF - 31 (76%) of 41 - than women - 23 (45 %) of 51 (p = 0.003). The log linear analysis confirmed that this finding was significant (p = 0.0018) for the coefficient of interaction between gender and type of vascular access. No other independent variable had a significant relationship with type of vascular access. We conclude that women with ESRD are more likely to receive a PTFE graft for hemodialysis, while men are more likely to get an AVF. These findings may explain, in part, the reported excess vascular access morbidity in women on hemodialysis.

Erythrocytosis after renal transplantation. A prospective analysis.

A prospective analysis of all cyclosporine treated renal transplants performed between 1987 and 1990 was performed to determine the incidence and etiologic factors of post transplant erythrocytosis (PTE) and its effect on shortterm outcome. PTE developed in 25 (8.1%) recipients (mean age, 41 ± 10 years). PTE occurred more frequently in men (12.8%) than women (1.6%) (p<0.001), diabetic patients (22.9%) than nondiabetic patients (6.2%) (p < 0.001), and rejection-free recipients (11%) compared with those with early rejection (4%) (p<0.05) but was independent of recipient race and donor source. Sixteen patients in whom PTE subsequently developed had pretransplant hematocrits above 30%. PTE occurred most frequently in the first year posttransplant (range, 2-29 months). Serum erythropoietin levels were inappropriately elevated in all patients (mean, 24 ± 2.2 mil/ml), but serum iron, folate, and B12 levels were all normal. Mean serum creatinine and creatinine clearance were 1.7 ± 0.5 mg/dl and 58 ± 20 ml/min, respectively. Twenty-three patients underwent phlebotomy (mean, 3.5 ± 0.5 units) and six had PTE-related complications. In 14 patients, PTE persisted with hematocrit of 53 ± 1.5% (range, 51-56) compared with 57 ± 2.6% (range, 54-64) at the time of PTE onset. In conclusion, PTE occurs primarily in the first year posttransplant and is characterized by inappropriate elevation of erythropoietin. Predictors for PTE include male gender, diabetes mellitus, pretransplant hematocrit above 30%, absence of rejection, and excellent renal allograft function

HLA-Identical Renal Transplants: Impact of Cyclosporine on Intermediate-Term Survival and Renal Function

Seventy-two and 34 consecutive HLA-identical sibling renal transplant recipients were treated with azathioprine/prednisone (AZA; follow-up, 5.0 years) and cyclosporine/prednisone (CSA; mean follow-up, 2.9 years), respectively. Both groups were similar in age, sex, race, and number of transplants, but there were more diabetics in the CSA group (34% v 8%). Actual patient survival at 1 year and actuarial patient survival at 5 years were 100% and 96%, respectively in the CSA group compared with an actual patient survival of 91% and 82% at 1 and 5 years, respectively, in the AZA group. Actual graft survival at 1 year improved from 85% in the AZA group to 97% in the CSA-treated recipients (P less than 0.05). Mean serum creatinine at 5 years remained stable in the AZA group at a mean of 123 mumol/L (1.4 mg/dL) compared with a progressive increase in this parameter to a mean of 212 mumol/L (2.4 mg/dL) after the same time interval in the CSA patients. Furthermore, the slopes of the serum creatinine against time were significantly different between the two groups (P less than 0.01). Mean daily CSA dose averaged 4 mg/kg 12 months following transplantation, with a decrease to 2.4 mg/kg by the fifth year. Causes of death in the AZA group were cardiovascular (eight), sepsis (three), cancer (one); and in the CSA group, Kaposis sarcoma (one). Causes of graft failure in the AZA group were immunological (six), sepsis (three), technical (two), recurrence of disease (one), and patient death with a functioning graft (five). Technical (one), noncompliance (two), recurrence of disease (one), and patient death with a functioning kidney (one) caused graft failure in the CSA group. No difference in posttransplantation serum cholesterol or incidence of new onset diabetes was observed between the two groups, but hypertension was significantly more frequent (51% v 21%, P less than 0.01) when CSA was used. In conclusion, intermediate-term results of CSA-treated HLA-identical transplant recipients showed improved patient and graft survival with less complications apart from hypertension. However, the slow, but relentless, increase in serum creatinine in the CSA-treated patients compared with those treated with AZA is of concern.

The influence of mode of dialysis pretransplantation on long-term renal allograft outcome

To determine the influence of the need and the mode of dialysis prior to transplantation on long-term renal allograft survival and subsequent renal function, all 662 consecutive cyclosporine-treated renal transplants (484 cadaver and 178 living-related donors), performed between 1983 and 1989 were retrospectively analyzed. Recipients were divided into 3 groups as follows: group I and II recipients underwent hemodialysis and peritoneal dialysis, respectively, prior to transplantation; group III patients were transplanted without dialysis. All groups were similar with respect to demographic and immunologic characteristics, apart from a higher proportion of diabetic and White patients in both cadaver and living-related group III recipients and a fewer number of blood transfusions among living-related group III recipients. A trend toward a decreased incidence of dialysis dependence in the early posttransplant period was noted among cadaver donor recipients in group III (20%) when compared to group I and II patients (36% and 26%, respectively). The incidence of rejection episodes was similar in all groups. No difference in 1- and 5-year patient survival was noted among all recipient groups. Actual 1-year graft survivals in groups I, II, and III were similar (73%, 72%, and 74%, respectively, for cadaver donor; and 86%, 89%, and 91%, respectively for living-related donor recipients). Likewise, actuarial 5-year graft survivals were not significantly different (53%, 51%, and 67%, respectively, for cadaver donor; and 75%, 69%, and 82%, for living-related donor recipients). Renal function, as assessed by serum creatinine concentration, was similar and stable in all recipient groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Beneficial Effect of Thalidomide and Ciclosporin Combination in Heterotopic Cardiac Transplantation in Rats

The effect of thalidomide on the prevention of early rejection was studied in heterotopic cardiac transplants between ACI (donors) and Lewis (recipients) rats, in combination with subtherapeutic doses of ciclosporin. Although allografts treated solely with thalidomide (5 mg/kg/day intraperitoneally) survived longer than controls (9.4 +/- 2.7 and 6.3 +/- 0.6 days, respectively, p less than 0.001), the survival rates of animals treated with low dose ciclosporin (1.25 mg/kg/day intraperitoneally) plus thalidomide (1.25, 2.5 and 5 mg/kg/day) were significantly better at 21 days (70, 88.9 and 88.9%, respectively), compared to 55.6% in those treated with ciclosporin (1.25 mg/kg/day) alone. Graft survival rates at 90 days were not significantly different in the thalidomide-ciclosporin combination groups (60, 77.8 and 55.6%, respectively) compared to the ciclosporin group alone (55.6%). We conclude that thalidomide is effective in preventing early rejection of rat cardiac allograft when combined with subtherapeutic doses of ciclosporin, thus avoiding the dose-dependent side effects of ciclosporin in the early posttransplant period.

Intermediate-term outcome of renal retransplants in the cyclosporine era

To determine the influence of selected parameters on intermediate- term outcome of renal retransplants, univariate and multiple regression analyses were performed on all 100 consecutive cyclosporine treated retransplants performed between 1984 and 1990 (mean follow up, 4.6 ± 2.3 years). Actual 1 year and actuarial 5 year graft survivals were higher in living compared with cadaver donor transplants (84% and 79% vs 69% and 56%, respectively; p<0.05). Among cadaver donor transplant recipients, allografts with immediate early function had better 1 and 5 year graft survivals when compared with those with delayed function (81% and 62% vs 59% and 38%, respectively; p<0.05). Recipients with acute rejection had inferior 1 year and 5 year graft survivals when compared with rejection free patients (65% and 35% vs 80% and 57%, respectively; p<0.05). Graft survival time of primary transplants was also a significant predictor of retransplant outcome with 1 and 5 year graft survivals of 50% and 36%, respectively, in patients in whom primary grafts survived less than 3 months, compared with 75% and 58% in those in whom grafts survived longer than 3 months (p<0.05). Recipient age, race, renal disease, and levels of panel reactive antibodies had no effect on intermediate-term outcome. In a multiple regression analysis, delayed graft function, acute rejection, and primary graft survival time less than 3 months correlated inversely with long-term survival of retransplants (multiple r = 0.65). A total of 39 grafts were lost due to rejection (22), sepsis (6), graft nonfunction (5), death with a functioning graft (4), noncompliance (1), and recurrent renal disease (1). In conclusion, immediate early graft function, absence of acute rejection, and a primary graft survival time of longer than 3 months were predictors of favorable outcome among cyclosporine-treated retransplants

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.