Joon H. Hong

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.

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.

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.

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.

Orthotopic Hepatic Transplantation in the Dog

Orthotopic hepatic transplantation has become a well-established treatment modality for end-stage liver disease, and research in this field is constantly evolving. Of the 34 canine liver transplants performed in this study, 17 (50%) survived more than 3 days (mean survival time 15 days). Causes of perioperative death included hemorrhage (4), anesthetic complications (3), systemic anaphylaxis (3), portal vein thrombosis (3), hepatic venous outflow block (2), and hepatic artery thrombosis (2). Gentle handling with minimal dissection of the donor liver in situ resulted in a decreased incidence of hepatic venous outflow block. The incidence of biliary leak was similar irrespective of the method of biliary reconstruction, although the incidence of acute cholangitis was 56% in the cholecystoduodenostomy group compared with 0% in the choledochocholedochostomy cohort. Using celiac to common hepatic end-to-side arterial anastomosis with preservation of the gastroduodenal artery, thrombosis of the hepatic artery was encountered in four instances, an incidence similar to previously reported studies where end-to-end hepaticohepatic arterial anastomosis or donor aortic conduit was utilized. The incidence of postoperative intestinal intussusception was reduced from 40 to 0% in those who underwent transmesenteric intestinal plication following implantation of the liver. Among short-term survivors, sepsis was the most frequent noted complication (10), followed by intestinal intussusception (6), rejection (6), and gastrointestinal bleeding (1). Among recipient dogs that survived more than 3 days, rejection was the most common cause of graft loss (5), followed by biliary leak (4) and hepatic artery thrombosis (2).

Effect of timing of cyclosporine administration on recovery from renal ischemia in rats

The effect of timing of cyclosporine administration on functional recovery from renal ischemia was studied in Sprague-Dawley rats. Animals were given cyclosporine and subjected to renal ischemia by temporarily occluding both the renal artery and vein. Our data demonstrate no significant difference in serum creatinine among rats subjected to renal ischemia, cyclosporine, or cyclosporine-vehicle cremophor EL administration, or the control group. On the other hand, renal ischemia in combination with cyclosporine resulted in rapid and marked deterioration in renal function with serum creatinine peaking on Day 2. The most significant rise was in rats that received cyclosporine 4 hr prior to induction of renal ischemia (4.7 +/- 0.5 mg/dl), followed by those that received cyclosporine 4 and 24 hr postischemia (2.8 +/- 0.5 and 3.2 +/- 0.7 mg/dl, respectively). Cyclosporine administration 24 hr prior to renal ischemia resulted in the least elevation of the serum creatinine (2.1 +/- 0.5 mg/dl) and the earliest return to the baseline value. Our data suggest that the timing of cyclosporine administration in rats subjected to renal ischemia influences the extent of renal injury and the subsequent recovery of renal function.

The Impact of Ciclosporin in Patients with Adult Polycystic Kidney Disease Following Transplantation

In order to evaluate the impact of ciclosporin in patients with adult onset polycystic kidney disease (ADPKD) following renal transplantation, we performed a single-center study of all (n = 65) patients with this disorder since 1978, 43 of whom received CSA (PC-CSA) with the remaining 22 treated with azathioprine (PC-AZA). An additional group of 45 age- and time-matched group of non-polycystic CSA-treated patients (nonPC-CSA) were used as a separate control group. Patient and graft survivals at 1 and 5 years were similar in PC-CSA when compared to nonPC-CSA. The commonest causes of death in both groups were cardiovascular related. The incidence of posttransplant hypertension and acute rejection were also similar. Urinary tract infections (UTIs) were, however, more frequent among PC-CSA (11 and 33% pre- and posttransplant respectively) when compared to the nonPC-CSA (2 and 17% pre- and posttransplant respectively). The PC-CSA cohort showed improved 1-year patient and graft survivals when compared to PC-AZA (94 and 70% vs. 72 and 34%) with less rejection episodes (42 vs. 88%) during the first year posttransplant but a higher mean serum creatinine at the end of the first year (2.0 vs. 1.6 mg/dl, 176.6 vs. 141.3 mumol/l). Posttransplant hypertension (67 vs. 70%) and UTIs (33 vs. 33%) were, however, similar in both groups. In summary, renal transplantation in ADPKD in the CSA era is associated with equal patient and graft survivals when compared with nonpolycystic patients of comparable age, but superior results when compared with the earlier azathioprine era.

The course of HIV disease in renal allograft recipients

The clinical course of HIV seropositive renal allograft recipients is ill defined. Thus, a retrospective analysis of mortality, morbidity and graft survival was performed in two groups of HIV-positive patients. Group 1 (nine patients), seropositive for an indefinite period of time prior to transplantation (eight i.v. drug abusers, one homosexual), all lost their grafts after a mean period of 23 +/- 11 months from chronic rejection (six), complicated by focal glomerular sclerosis and nephrotic syndrome in three cases, sepsis (two) and death with a functioning graft (one). Four patients died, two from sepsis, one from Kaposis sarcoma and one from fluid overload. Of the remaining five patients, all on hemodialysis, one had AIDS and four were asymptomatic after a mean period of 44 months following graft failure. Prolonged hospitalizations for both infections and acute rejection were common. Group 2 (six patients) seroconverted in the perioperative period, and two had functioning allografts at 78 and 100 months post-transplant. Causes of allograft loss, patient death and infection-related complications were similar to those of group 1, but acute rejection was rare. In conclusion, HIV infection in renal allograft recipients was associated with poor allograft survival due mainly to rejection, mostly chronic, often complicated by glomerular sclerosis and nephrotic syndrome. Infectious complications requiring hospitalization were also increased.

Prolonged Simple Cryothermic Immersion Storage of Rat Heart Isografts: A Preliminary Study

In order to extend preservation time for heart transplant, cryothermic immersion storage was studied in a rat heart isograft model. Rat hearts preserved at -2 to 0 degrees C for up to 96 h were successfully transplanted with no deleterious effects noted on defrosting and reperfusion with long-term survival beyond 60 days of transplant.