K. J. Gillingham

Risk factors for chronic rejection in renal allograft recipients.

Chronic rejection is a major barrier to long-term renal allograft survival. Cyclosporine, though effective at reducing graft loss to acute rejection, has had little impact on the incidence of chronic rejection. Between June 2, 1986 and January 22, 1991, 587 kidney-alone transplants (566 patients) were performed, and had been entered into our renal transplant database and had at least 1 year of follow-up: 103 with biopsy-proven chronic rejection (37 living-related donor, 66 cadaver) and 484 without chronic rejection (236 LRD 248 CAD). The 5-year patient survival was 84% for recipients with biopsy-proven chronic rejection vs. 89% without (P = .08). The 5-year graft survival was 31% for recipients with biopsy-proven chronic rejection vs. 81% without (P < .0001). Using multivariate analysis, we determined the impact on the incidence of chronic rejection of these variables: transplant number, age at transplant (< 18 years, 18 to 50 years, > 50 years), gender, human leukocyte antigen matching, peak and transplant panel-reactive antibody, acute rejection episodes, infections (including cytomegalovirus, viral, and bacterial), donor age, and CsA dosage at 1 year (< 5 mg/kg vs. > or = 5 mg/kg). Logistic regression models were fit to the data using a forward stepwise selection procedure. In this analysis, risk factors included an acute rejection episode (P < .001), CsA dosage < 5 mg/kg/day at 1 year (P = .007), infection (P = .023), female gender (P = .042), and retransplant (P = .103). Individual analyses were done for CAD and LRD recipients. For both groups, important variables were acute rejection, infection, CsA dosage at 1 year, and age at transplant. In conclusion, acute rejection, CsA dosage < 5 mg/kg/day at 1 year, and infection are the major risk factors for the development of chronic rejection, suggesting that chronic rejection may be the result of inadequate immunosuppression (acute rejection episodes and low CsA dosage) or the production of inflammatory cytokines (infections).

Delayed Graft Function, Acute Rejection, And Outcome After Cadaver Renal Transplantation: A Multivariate Analysis

The impact of delayed graft function on outcome after cadaver renal transplantation has been controversial, but most authors fail to control their analyses for the presence or absence of rejection. We studied 457 adult recipients of primary cadaver allografts at a single institution during the cyclosporine era. All patients received sequential immunosuppression. The incidence of delayed graft function (defined as dialysis being required during the first week after transplant) was 23%. There was a significant association between delayed graft function and cold ischemia time > 24 hr (P = 0.0001) and between delayed graft function and the occurrence of at least one biopsy-proven rejection episode (P = 0.004). Actuarial graft survival was not significantly different when comparing delayed graft function versus no delayed graft function for patients without rejection (P = 0.02). However, it was significantly worse for patients with both delayed graft function and rejection versus those with delayed graft function but no rejection (P = 0.005), as well as for grafts preserved > 24 hr versus < or = 24 hr (P = 0.007). By multivariate analysis, delayed graft function per se was not a significant risk factor for decreased graft survival for patients without rejection (P = 0.42). In contrast, rejection significantly decreased graft survival for grafts with immediate function (relative risk = 2.3, P = 0.0002), particularly in combination with delayed graft function (relative risk = 4.2, P < 0.0001). While cold ischemia time > 24 hr was also a significant risk factor (relative risk = 1.9, P = 0.02), other variables (preservation mode, 0 HLA Ag mismatch, age at transplantation, gender, diabetic status, and panel-reactive antibody at transplantation) had no impact on graft survival. Patient survival was significantly affected by the combination of delayed graft function and rejection (relative risk = 3.1, P < 0.0001), age at transplantation > 50 years (relative risk = 2.6, P < 0.0001), and diabetes (relative risk = 1.8, P = 0.006). Further studies are necessary to elucidate the mechanisms linking delayed graft function and rejection, which, in combination, lead to poor allograft outcome.

Early versus late acute renal allograft rejection : impact on chronic rejection

We studied the effect of acute renal allograft rejection and its timing on the development of chronic rejection and subsequent graft loss. Between January 1, 1987 and April 30, 1991, 424 patients at the University of Minnesota received a primary kidney transplant (minimum follow-up, 1 year). Patients were subdivided by donor source, presence or absence of acute rejection, and the timing of acute rejection onset (early, ≤ 60 days vs. late, > 60 days post-transplant). For living donor (LD) transplant recipients (n=219), the incidence of chronic rejection is 0.8% in those who had no acute rejection (n=130), 20% in those with acute rejection ≤60 days (n=59) (P<0.001 vs. no acute rejection), and 43% in those with acute rejection > 60 days (n=30) (P<0.001 vs. no acute rejection, P=0.04 vs. early acute rejection). For cadaver (CAD) transplant recipients (n=205), the incidence of chronic rejection is 0% in those who had no acute rejection (n=109), 36% in those with acute rejection ≤ 60 days (n=69) (P<0.001 vs. no acute rejection), and 63% in those with acute rejection > 60 days (n=27) (P<0.001 vs. no acute rejection, P=0.03 vs. early acute rejection). For both LD and CAD recipients, no grafts have been lost to chronic rejection among those who did not first have at least 1 acute rejection episode. In contrast, 23 patients with acute rejection have had graft loss to chronic rejection. For both LD and CAD recipients, those with > 1 acute rejection episode had significantly more chronic rejection than those with only 1 rejection (P<0.05). There was no significant difference in the incidence of chronic rejection based on whether the first acute rejection episode was steroid resistant or steroid responsive. We conclude that acute rejection is strongly related to the development of biopsy-proven chronic rejection and subsequent graft loss. Patients undergoing their first acute rejection episode > 60 days (vs. ≤ 60 days) have an increased incidence of chronic rejection.

Risk factors for slow graft function after kidney transplants: a multivariate analysis

Humar A, Ramcharan T, Kandaswamy R, Gillingham K, Payne WD, Matas AJ. Risk factors for slow graft function after kidney transplants: a multivariate analysis. Clin Transplant 2002: 16: 425–429.

Revisiting Traditional Risk Factors for Rejection and Graft Loss after Kidney Transplantation

Single‐antigen bead (SAB) testing permits reassessment of immunologic risk for kidney transplantation. Traditionally, high panel reactive antibody (PRA), retransplant and deceased donor (DD) grafts have been associated with increased risk. We hypothesized that this risk was likely mediated by (unrecognized) donor‐specific antibody (DSA). We grouped 587 kidney transplants using clinical history and single‐antigen bead (SAB) testing of day of transplant serum as (1) unsensitized; PRA = 0 (n = 178), (2) third‐party sensitized; no DSA (n = 363) or (3) donor sensitized; with DSA (n = 46), and studied rejection rates, death‐censored graft survival (DCGS) and risk factors for rejection. Antibody‐mediated rejection (AMR) rates were increased with DSA (p < 0.0001), but not with panel reactive antibody (PRA) in the absence of DSA. Cell‐mediated rejection (CMR) rates were increased with DSA (p < 0.005); with a trend to increased rates when PRA>0 in the absence of DSA (p = 0.08). Multivariate analyses showed risk factors for AMR were DSA, worse HLA matching, and female gender; for CMR: DSA, PRA>0 and worse HLA matching. AMR and CMR were associated with decreased DCGS. The presence of DSA is an important predictor of rejection risk, in contrast to traditional risk factors. Further development of immunosuppressive protocols will be facilitated by stratification of rejection risk by donor sensitization.

Pregnancy Outcomes After Kidney Donation

The outcome of pregnancy in kidney donors has generally been viewed to be favorable. We determined fetal and maternal outcomes in a large cohort of kidney donors. A total of 2102 women have donated a kidney at our institution; 1589 donors responded to our pregnancy surveys; 1085 reported 3213 pregnancies and 504 reported none. Fetal and maternal outcomes in postdonation pregnancies were comparable to published rates in the general population. Postdonation (vs. predonation) pregnancies were associated with a lower likelihood of full‐term deliveries (73.7% vs. 84.6%, p = 0.0004) and a higher likelihood of fetal loss (19.2% vs. 11.3%, p < 0.0001). Postdonation pregnancies were also associated with a higher risk of gestational diabetes (2.7% vs. 0.7%, p = 0.0001), gestational hypertension (5.7% vs. 0.6%, p < 0.0001), proteinuria (4.3% vs. 1.1%, p < 0.0001) and preeclampsia (5.5% vs. 0.8%, p < 0.0001). Women who had both pre‐ and post‐donation pregnancies were also more likely to have these adverse maternal outcomes in their postdonation pregnancies. In this large survey of previous living donors in a single center, fetal and maternal outcomes and pregnancy outcomes after kidney donation were similar to those reported in the general population, but inferior to predonation pregnancy outcomes.

Long-term quality of life after kidney transplantation in childhood.

Transplantation is the treatment of choice for children with end-stage renal disease. However, the long-term quality of life and socioprofessional outcome for those with successful transplants have not previously been reported. We studied these factors in patients transplanted when<18 years old who currently have ≥10 years of graft function. A total of 57 questionnaires were sent out; 57 (100%) responded [24 female and 33 male patients; average (±SD) age at tx = 10±5 years (0.9–17.7); average f/u = 15.6±3 years (10–26); current age = 26±5 years (12–38); 26 had < 1 transplant]. Of the 57 respondents, 9 are<18 (all are in school); 48 are ≥18 (7 in school, 37 employed, 4 unemployed); 12 are married, 1 engaged, and 2 divorced; and 9 have children. While in school, 43 (75%) had participated in sports, 37 (65%) in other extracurricular activities; 7 (12%) were A and 33 (58%) B students; 15 (26%) received awards or scholarships. For those working, the range of occupations is broad (average work week = 41±5 hr). Health-related absence from work has been nonexistent for 93%. Health is rated as good to excellent by 91% and fair by 9%. The future is regarded as hopeful or promising by 80%. Similarly, 89% are satisfied with life in general; 95% said health never or seldom interferes with family life; 95% feel health and drug side effects are of no or minor concern in sexual relationships. Only 3% feel health is a problem in maintaining a sexual relationship (41% are not sexually active). Only 4% stated that health often interferes with social life; 98% meet with friends on a regular basis; 76% are satisfied with personal relationships and 8% dissatisfied; 91% are satisfied with their ability to perform at work or school and 5% dissatisfied. Of note, 32% are dissatisfied with body appearance. Major concerns are short stature and brittle bones. Major suggestions include education/support groups to deal with teasing at school and peer problems. We conclude that transplanted children with long-term graft function have a favorable social and professional outcome. Overall, quality of life seems excellent.

Renal transplantation in infants.

The timing of renal transplantation in infants is controversial. Between 1965 and 1989, 79 transplants in 75 infants less than 2 years old were performed: 23 who were 12 months or younger, 52 who were older than 12 months; 63 donors were living related, 1 was living unrelated, and 15 were cadaver donors; 75 were primary transplants and 4 were retransplants. Infants were considered for transplantation when they were on, or about to begin, dialysis. All had intra-abdominal transplants with arterial anastomosis to the distal aorta. Sixty-four per cent are alive with functioning grafts. The most frequent etiologies of renal failure were hypoplasia (32%) and obstructive uropathy (20%); oxalosis was the etiology in 11%. Since 1983 patient survival has been 95% and 91% at 1 and 5 years; graft survival has been 86% and 73% at 1 and 5 years. For cyclosporine immunosuppressed patients, patient survival is 100% at 1 and 5 years; graft survival is 96% and 82% at 1 and 5 years. There was no difference in outcome between infants who were 12 months or younger versus those who were aged 12 to 24 months; similarly there was no difference between infants and older children. Sixteen (21%) patients died: 5 after operation from coagulopathy (1) and infection (4); and 11 late from postsplenectomy sepsis (4), recurrent oxalosis (3), infection (2), and other causes (2). Routine splenectomy is no longer done. There has not been a death from infection in patients transplanted since 1983. Rejection was the most common cause of graft loss (in 15 patients); other causes included death (with function) (7), recurrent oxalosis (3), and technical complications (3). Overall 52% of patients have not had a rejection episode; mean creatinine level in patients with functioning grafts is 0.8 + 0.2 mg/dL. Common postoperative problems include fever, atelectasis, and ileus. At the time of their transplants, the infants were small for age; but with a successful transplant, their growth, head circumference, and development have improved. Transplantation in infants requires an intensive multidisciplinary approach but yields excellent short-and long-term survival rates that are no different from those seen in older children or adults. Living donors should be used whenever possible. Patients with a successful transplantation experience improved growth and development, with excellent rehabilitation.

Venous thromboembolic complications after kidney and kidney-pancreas transplantation : A multivariate analysis

BACKGROUND We reviewed the incidence of and risk factors for venous thromboembolic complications in our population of kidney (KTx) and simultaneous kidney-pancreas transplant (SPK) recipients. METHODS Information was collected retrospectively from a database on 1833 KTx and 276 SPK recipients who underwent transplant surgery between January 1985 and August 1995. RESULTS The incidence of deep venous thrombosis (DVT) was 6.2% (n= 132), with significantly higher rates after SPK (18.1%) vs. KTx (4.5%) (P < 0.001). The number of DVT episodes was highest in the first month; 17.5% occurred during this time. For KTx recipients, early thrombotic events were more common on the side of the graft (P=0.03); however, after 1 month, no correlation existed between the side of the graft and the side of DVT. For SPK recipients, DVT tended to be more common on the side of the pancreas (57%) vs. the kidney (43%) (P=0.10). By multivariate analysis, risk factors for DVT were: age > 40 years (odds ratio [OR]=2.2, P < 0.001), diabetes mellitus (DM) (OR=2.0, P=0.002), previous DVT (OR=4.4, P=0.001), and SPK transplant (OR=2.8, P < 0.001). Pulmonary embolus (PE) was identified in 44 recipients (incidence, 2.1%) and was fatal in 13 (30%). The incidence was significantly higher in SPK (4.71%) vs. KTx recipients (1.69%) (P < 0.01). The risk of death from PE was 0.5% in KTx recipients and 1.37% in SPK recipients (P=0.08). Risk factors for PE included DM (OR=2.6, P=0.005) and recent DVT (OR=8.9, P=0.0001). CONCLUSIONS Based on risk and extrapolating from the general surgical literature, our recommendations for prophylaxis against DVT are use of graduated compression stockings for all recipients and, in addition, low-dose heparin for moderate and high-risk recipients (previous DVT, SPK, age > 40 years, DM).

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.