Prospective randomized trial of maintenance immunosuppression with rapid discontinuation of prednisone in adult kidney transplantation.

Rapid discontinuation of prednisone (RDP) has minimized steroid-related complications following kidney transplant (KT). This trial compares long-term (10-year) outcomes with three different maintenance immunosuppressive protocols following RDP in adult KT. Recipients (n=440; 73% living donor) from March 2001 to April 2006 were randomized into one of three arms: cyclosporine (CSA) and mycophenolate mofetil (MMF) (CSA/MMF, n=151); high-level tacrolimus (TAC, 8-12 µg/L) and low-level sirolimus (SIR, 3-7 µg/L) (TACH/SIRL, n=149) or low-level TAC (3-7 µg/L) and high-level SIR (8-12 µg/L) (TACL/SIR(H) , n=140). Median follow-up was ∼7 years. There were no differences between arms in 10-year actuarial patient, graft and death-censored graft survival or in allograft function. There were no differences in the 10-year actuarial rates of biopsy-proven acute rejection (30%, 26% and 20% in CSA/MMF, TACH/SIRL and TACL/SIRH) and chronic rejection (38%, 35% and 31% in CSA/MMF, TACH/SIRL and TACL/SIRH). Rates of new-onset diabetes mellitus were higher with TACH/SIRL (p=0.04), and rates of anemia were higher with TACH/SIRL and TACL/SIRH (p=0.04). No differences were found in the overall rates of 16 other post-KT complications. These data indicate that RDP-based protocol yield acceptable 10-year outcomes, but side effects differ based on the maintenance regimen used and should be considered when optimizing immunosuppression following RDP.

Selective retransplant after graft loss to nonadherence: success with a second chance.

Nonadherence (NA) is a difficult posttransplant problem that can lead to graft loss. A retransplant is controversial because of a fear of recurrent NA. We reviewed our center's data base and identified 114 kidney recipients who lost their graft to overt NA; of this group, 35 (31%) underwent a retransplant after a thorough reevaluation. We compared this NA retransplant group to a control group of second transplant recipients who did not lose their first graft to overt NA (non-NA) (n = 552). After 8 years of follow-up, we found no significant differences between the groups in actuarial graft or patient survival rates, renal function, or the incidence of biopsy-proven chronic rejection. However, 5 of 35 (14%) NA recipients versus 10 of 552 (2%) non-NA recipients lost their retransplant to NA (p = 0.0001). Twenty of 35 (57%) of the NA group exhibited repeat NA behavior after retransplant. We conclude that prior graft loss to NA is associated with increased graft loss to NA after retransplant. However, the majority of NA retransplant recipients did well-with overall long-term outcomes similar to those of the non-NA group. With careful patient selection and aggressive intervention, prior overt NA should not be an absolute contraindication to retransplantation.

2202 kidney transplant recipients with 10 years of graft function: what happens next?

The ultimate goal of clinical transplantation is for the recipients to achieve long-term survival, with continuing graft function, that is equivalent to that of the age-matched general population. We studied subsequent outcome in kidney transplant recipients with 10 years of graft function. In all, 2202 kidney transplant recipients survived with graft function >10 years. For 10-year survivors, the actuarial 25-year patient survival rate for primary transplant living donor (LD) recipients was 57%; graft survival, 43%. For primary transplant deceased donor (DD) recipients, the actuarial 25-year patient survival rate was 39%; graft survival, 27%. The two major causes of late graft loss were death (with graft function) and chronic allograft nephropathy (tubular atrophy and interstitial fibrosis). The two major causes of death with function were cardiovascular disease (CVD) and malignancy. For nondiabetic recipients, the mean age at death with function from CVD was 54 +/- 13 years; for diabetic recipients, 53 +/- 7 years. By 20 years posttransplant, morbidity was common: >40% recipients had skin cancer (mean age for nondiabetic recipients, 53 +/- 13 years; for diabetics, 49 +/- 8 years), >10% had non-skin cancer (mean age for nondiabetic recipients, 53 +/- 16 years; for diabetics, 46 +/- 9 years), and >30% had CVD (mean age for nondiabetic recipients, 53 +/- 15 years; for diabetics, 47 +/- 9 years). We conclude that long-term transplant recipients have a high rate of morbidity and early mortality. As short-term results have improved, more focus is needed on long-term outcome.

2,500 living donor kidney transplants: a single-center experience.

OBJECTIVE: To review a single center's experience and outcome with living donor transplants. SUMMARY BACKGROUND DATA: Outcome after living donor transplants is better than after cadaver donor transplants. Since the inception of the authors' program, they have performed 2,540 living donor transplants. For the most recent cohort of recipients, improvements in patient care and immunosuppressive protocols have improved outcome. In this review, the authors analyzed outcome in relation to protocol. METHODS: The authors studied patient and graft survival by decade. For those transplanted in the 1990s, the impact of immunosuppressive protocol, donor source, diabetes, and preemptive transplantation was analyzed. The incidence of rejection, posttransplant steroid-related complications, and return to work was determined. Finally, multivariate analysis was used to study risk factors for worse 1-year graft survival and, for those with graft function at 1 year, to study risk factors for worse long-term survival. RESULTS: For each decade since 1960, outcome has improved after living donor transplants. Compared with patients transplanted in the 1960s, those transplanted in the 1990s have better 8-year actuarial patient and graft survival rates. Death with function and chronic rejection have continued to be a major cause of graft loss, whereas acute rejection has become a rare cause of graft loss. Cardiovascular deaths have become a more predominant cause of patient death; infection has decreased. Donor source (e.g., ideally HLA-identical sibling) continues to be important. For living donor transplants, rejection and graft survival rates are related to donor source. The authors show that patients who had preemptive transplants or less than 1 year of dialysis have better 5-year graft survival and more frequently return to full-time employment. Readmission and complications remain problems; of patients transplanted in the 1990s, only 36% never required readmission. Similarly, steroid-related complications remain common. The authors' multivariate analysis shows that the major risk factor for worse 1-year graft survival was delayed graft function. For recipients with 1-year graft survival, risk factors for worse long-term outcome were pretransplant smoking, pretransplant peripheral vascular disease, pretransplant dialysis for more than 1 year, one or more acute rejection episodes, and donor age older than 55. CONCLUSIONS: These data show that the outcome of living donor transplants has continued to improve. However, for living donors, donor source affects outcome. The authors also identify other major risk factors affecting both short- and long-term outcome.

Peri-operative cardiac morbidity in kidney transplant recipients: incidence and risk factors.

BACKGROUND: Renal transplant recipients are known to be at increased risk for developing cardiac disease. In both general and peripheral vascular surgery, pre-operative risk stratification (and intervention when indicated) has decreased the incidence of peri-operative cardiac complications. In this study, we set out to identify subsets of patients at high risk for peri-operative cardiac complications after a renal transplant. METHODS: We retrospectively reviewed the records of 2694 adult renal transplants performed at the University of Minnesota between January 1, 1985 and December 31, 1998. We determined the incidence of peri-operative (within 30 d post-transplant) cardiac complications, including myocardial infarction (MI). Risk factors for the development of these complications were determined by multivariate analysis. RESULTS: We found 163 peri-operative cardiac complications, for an overall incidence of 6.1%. Specific cardiac complications included MI (n=43, 1.6%), arrhythmia (n=74, 2.7%), angina (n=31, 1.2%), cardiac arrest (n=13, 0.5%), and congestive heart failure (n= 2, 0.1%). By multivariate analysis, significant risk factors for any cardiac complication were age> or =50 yr (relative risk (RR)=3.0, p=0.0001) and pre-transplant cardiac disease (RR=3.3, p=0.0001). Not significant were diabetes mellitus (DM), cadaver donor source, pre-transplant dialysis, a history of smoking, and hypertension. Significant risk factors for peri-operative MI were age> or =50 yr, pre-existing cardiac disease, and DM. Diabetic patients with pre-existing cardiac disease were at especially high risk for peri-operative cardiac events. CONCLUSIONS: Patients>50 yr and those with pre-existing cardiac disease, especially if diabetic, are at significantly increased risk for developing peri-operative cardiac complications after a renal transplant. Such patients require aggressive pre-operative investigations, which may include coronary angiography, to decrease the risk of post-transplant complications.

Are wound complications after a kidney transplant more common with modern immunosuppression?

BACKGROUND: The most common surgical complication after a kidney transplant is likely related to the wound. The purpose of this analysis was to determine the incidence of, and risk factors for, wound complications (e.g., infections, hernias) in kidney recipients and to assess whether newer immunosuppressive drugs increase the risk for such complications. METHODS: Between January 1, 1984 and September 30, 1998, we performed 2013 adult kidney transplants. Of these 2013 recipients, 97 (4.8%) developed either a superficial or a deep wound infection. Additionally, 73 (3.6%) recipients developed either a fascial dehiscence or a hernia of the wound. We used univariate and multivariate techniques to determine significant risk factors and outcomes. RESULTS: Mean time to development of a superficial infection (defined as located above the fascia) was 11.9 days posttransplant; to development of a deep infection (defined as located below the fascia), 39.2 days; and to development of a hernia or fascial dehiscence, 12.8 months. By multivariate analysis, the most significant risk factor for a superficial or deep wound infection was obesity (defined as body mass index>30 kg/m2) (RR=4.4, P=0.0001). Other significant risk factors were a urine leak posttransplant, any reoperation through the transplant incision, diabetes, and the use of mycophenolate mofetil (MMF) (vs. azathioprine) for maintenance immunosuppression (RR=2.43, P=0.0001). Significant risk factors for a hernia or fascial dehiscence were any reoperation through the transplant incision, increased recipient age, obesity, and the use of MMF (vs. azathioprine) for maintenance immunosuppression (RR=3.54, P=0.0004). Use of antibody induction and treatment for acute rejection were not significant risk factors for either infections or hernias. Death-censored graft survival was lower in recipients who developed a wound infection (vs. those who did not); it was not lower in recipients who developed an incisional hernia or facial dehiscence (vs. those who did not). CONCLUSIONS: Despite immunosuppression including chronic steroids, the incidence of wound infections, incisional hernias, and fascial dehiscence is low in kidney recipients. As with other types of surgery, the main risk factors for postoperative complications are obesity, reoperation, and increased age. However, in kidney recipients, use of MMF (vs. azathioprine) is an additional risk factor -one that potentially could be altered, especially in high-risk recipients.

5,000 kidney transplants--a single-center experience.

Between 6/1963 and 12/1998, 5,069 kidney transplants were done at the University of Minnesota. Of these, about half have been living donor, half cadaver. The majority (83%) have been primary transplants. Recipients were grouped in 6 eras based on changes in our immunosuppressive protocols--6/63-12/67 (n = 98); 1/68-7/79 (n = 1,188); 8/79-6/84 (n = 789); 7/84-9/90 (n = 1,006); 10/90-12/95 (n = 1,050; 1/96-12/98 (n = 718)--and their outcomes were compared. Recent eras contained a higher proportion of recipients aged > 50. Since the inception of the program, there has been a steady improvement in actuarial patient survival, graft survival, and death-censored graft survival. Short-term outcome for primary and retransplant recipients has been similar; however, long-term outcome seems worse for retransplant recipients. Importantly, acute rejection and infectious death have become rare causes of graft loss. Chronic rejection and death with function (most often due to a cardiovascular event) have become the predominant causes of graft loss. Recent changes in immunosuppressive protocols (Era VI) have included more aggressive attempts to maintain CsA levels > 150 ng/ml (by HPLC) in the first 3 months and the substitution of mycophenolate mofetil for azathioprine. As a result, the incidence of acute and chronic rejection has decreased and graft survival has improved.

Features of acute rejection that increase risk for chronic rejection.

BACKGROUND: Acute rejection (AR) has been shown to be a significant risk factor for chronic rejection (CR) in kidney transplant recipients, yet many recipients with AR do not progress to CR. The purpose of this study was to determine if certain AR episodes are associated with a worse prognosis. METHODS: The study group consisted of 279 kidney transplant recipients, all treated for a single episode of biopsy-proven AR. All AR episodes were initially treated with steroids; steroid-resistant rejection was managed with an antibody preparation. RESULTS: First, by univariate techniques, we determined the clinical impact of severity of AR (as estimated by delta creatinine [dCr], defined as the change in baseline serum creatinine level 6 weeks after AR treatment) on two different endpoints--biopsy-proven CR and graft survival. Irrespective of 6-week dCr, all recipients with AR had a significantly increased risk of CR vs. those with no AR (P<0.01). Recipients with dCr between 0.5 and 1.0 mg/dl had a significantly higher incidence of CR vs. those with dCr <0.5 mg/dl (P<0.05), but a significantly lower incidence vs. those with dCr >1.0 mg/dl (P<0.05). We then performed multivariate analysis. We used severity of AR in addition to other variables (e.g., timing of AR, donor age) to determine which factors were most associated with risk for CR and graft loss. Risk for CR increased with AR episodes occurring >6 months after transplant (relative risk [RR] = 3.8, P = 0.005); with moderate or severe (vs. mild) AR episodes (RR = 2.7, P = 0.05); and with dCr >0.5 mg(dl (vs. <0.5 mg/dl) at 6 weeks after AR treatment (RR = 2.3, P = 0.1). Findings were similar when graft survival (death-censored) was the endpoint instead of CR. CONCLUSIONS: All AR episodes are associated with some increase in the risk for CR. But AR episodes occurring >6 months after transplant and those of increased severity (as assessed qualitatively by histologic grading and quantitatively by dCr) confer the greatest risk. Recipients with these risk factors could be targeted with measures to decrease their risk for CR, including trials of novel immunosuppressive regimens.

Decreased acute rejection in kidney transplant recipients is associated with decreased chronic rejection.

OBJECTIVE: To determine whether a recent decrease in the rate of acute rejection after kidney transplantation was associated with a decrease in the rate of chronic rejection. SUMMARY BACKGROUND DATA: Single-institution and multicenter retrospective analyses have identified acute rejection episodes as the major risk factor for chronic rejection after kidney transplantation. However, to date, no study has shown that a decrease in the rate of acute rejection leads to a decrease in the rate of chronic rejection. METHODS: The authors studied patient populations who underwent transplants at a single center during two eras (1984-1987 and 1991-1994) to determine the rate of biopsy-proven acute rejection, the rate of biopsy-proven chronic rejection, and the graft half-life. RESULTS: Recipients who underwent transplantation in era 2 had a decreased rate of biopsy-proven acute rejection compared with era 1 (p < 0.05). This decrease was associated with a decreased rate of biopsy-proven chronic rejection for both cadaver (p = 0.0001) and living donor (p = 0.08) recipients. A trend was observed toward increased graft half-life in era 2 (p = NS). CONCLUSIONS: Development of immunosuppressive protocols that decrease the rate of acute rejection should lower the rate of chronic rejection and improve long-term graft survival.

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).

Effect of early cyclosporine levels on kidney allograft rejection.

Acute rejection is the greatest risk factor for development of biopsy-proven chronic rejection and late kidney allograft loss. We previously noted that low cyclosporine (CsA) levels were a risk factor for early acute rejection in pediatric recipients (1). In our current study, we used logistic regression to identify risk factors for acute rejection in 726 adult kidney transplant recipients on triple therapy (prednisone, azathioprine, CsA). Variables considered for logistic regression analysis were donor organ source (cadaver vs. living), degree of HLA mismatch (1 to 6 vs. 0 antigen mismatch), transplant number (primary vs. retransplant), CsA levels (< 125 vs. > or = 125 ng/ml, < 150 ng/ml vs. > or = 150 ng/ml, and < 175 vs. > or = 175 ng/ml), and acute rejection episodes (0 vs. > or = 1). Of 726 recipients, 401 (55%) received cadaver kidneys; 325 (45%), living related. Overall, 572 (79%) had a primary transplant; 154 (21%), a retransplant. The vast majority of acute rejection episodes occurred within the first 2 months posttransplant; 68% of recipients had no acute rejection episodes by 2 months and 58% had none by 60 months posttransplant. Logistic regression analysis revealed that a cadaver donor kidney (vs. living) (p = 0.004), a 1 to 6 antigen mismatch (vs. 0 mismatch) (p = 0.001), and CsA levels < 150 ng/ml (vs. > or = 150 ng/ml) correlated with biopsy-proven acute rejection. The correlation for CsA levels < 150 ng/ml (vs. > or = 150 ng/ml) held true for levels at 1 wk (p < 0.05), 1 month (p = 0.0001), 2 months (p = 0.01), and 3 months (p = 0.02) posttransplant. Similar correlation was found for CsA levels < 125 ng/ml (vs. > or = 125 ng/ml) and < 175 ng/ml (vs. > or = 175 ng/ml). Comparative analyses were made (by Chi-square) of acute and chronic rejection rates when recipients were divided into 3 groups by CsA level (< 125 ng/ml, > or = 125 to < 150 ng/ml, and > or 150 ng/ml). At each time point (1 wk, 2 wk, 1 month, 2 months, 3 months), CsA levels < 125 ng/ml (vs. > or = 125 to < 150 ng/ml and > or = 150 ng/ml) were associated with the greatest increased risk of acute rejection--for both cadaver and living related recipients (all p < 0.05). CsA levels < 125 ng/ml at each time point (1 wk, 2 wk, 1 month, 2 months, 3 months) were also associated with a significantly increased risk of chronic rejection (all p < 0.001). The incidence of both acute and chronic rejection was reduced in the group with CsA levels > or = 125 to < 150 ng/ml and further reduced in the > or = 150 ng/ml group. Our data indicate that maintaining CsA levels > or = 150 ng/ml as part of triple therapy reduces the incidence of both acute and chronic rejection. Because chronic rejection is the leading cause of late allograft loss, maintaining adequate CsA levels should improve long-term graft survival. Based on this analysis, we have modified our own immunosuppressive regimens to achieve higher CsA levels earlier posttransplant.

Risk factors for prolonged hospitalization after kidney transplants.

A major variable in the cost of kidney transplants is the length of initial hospitalization. Using multivariate analysis, we studied risk factors for hospital stay > 10 d post-transplant. Between 1 January 1985 and 31 August 1995 a total of 1588 patients underwent first or second kidney transplants at the University of Minnesota. Antibody was used for 1 wk in cadaver donor recipients and for 2 wk in pediatric recipients (resulting in a long stay for all pediatric recipients). Adult living related donor recipients were immunosuppressed with triple therapy. Donor risk factors studied were age (< 15, 15-50, > 50 yr) and,- for cadaver recipients, preservation time (< 12, 12-18, 18-24, 24-30, > 30 h) and cause of death (trauma, cerebrovascular accident, or cardiac). Recipient risk factors studied were age (< 18, 18-55, > 55 yr); sex; transplant number; antigen mismatch; peak PRA; PRA at transplant (< 11, 11-50, > 50); diabetic status; pretransplant dialysis (vs. pre-emptive transplant); pretransplant cardiac, peripheral vascular, or respiratory disease; and delayed graft function (DGF) (dialysis in the first week vs. no dialysis). Risk factors were analyzed separately for living donor and cadaver donor recipients. For cadaver donor recipients, DGF was the major risk factor (p < 0.0001); others were age 55 yr (p = 0.03) and diabetes (p = 0.02). For living donor recipients, DGF was also a risk factor (p = 0.003); others were diabetes (p = 0.01), retransplant (p = 0.006), PRA at transplant > 50 (p < 0.0001), age > 55 yr (p = 0.02), pretransplant respiratory disease (p = 0.005), and pretransplant dialysis (p = 0.005). Because DGF was the major risk factor for a prolonged stay, we then studied risk factors for DGF using multivariate analysis. For cadaver donor recipients, risk factors were recipient weight > 90 kg (p = 0.004), preservation time 24 h (p = 0.03), PRA at transplant > 50 (p = 0.03), and donor age < 15 or > 50 yr (p = 0.002). For living donor recipients, risk factors were recipient age < 18 yr (p = 0.01), donor age > 50 yr (p = 0.03), female sex (p = 0.05), pretransplant respiratory disease (p = 0.1), pretransplant peripheral vascular disease (p = 0.05), and recipient weight > 90 kg (p = 0.1). From our data, a profile emerged of recipients likely to have a longer hospital stay. Important variables, either simultaneous with or related to DGF, include donor and recipient age, diabetes, pretransplant recipient weight, PRA at transplant, preservation time, and pretransplant respiratory or peripheral vascular disease.

Risk factors for chronic rejection in pediatric renal transplant recipients--a single-center experience.

Chronic rejection (CR) is the most common cause of graft loss beyond the 1st posttransplant year. The aim of this analysis was to identify the risk factors for the development of CR in pediatric renal transplant recipients. Between June 1984 and March 1994, 217 renal transplants were performed in children at our center. Immunosuppression included prednisone, azathioprine, cyclosporine (CsA), and prophylactic antibody. Using multivariate analysis, we studied the impact of the following variables on the development of biopsy-proven CR: age at transplant (< or = 5 years, > 5 years), gender, race, transplant number (primary, retransplant), donor source (cadaver, living donor), donor age (< 20 years, 20-49 years, > 49 years), number of ABDR mismatches (0, 1-2, 3-4, 5-6), number of DR mismatches (0, 1, 2), percentage peak panel reactive antibody (PRA) (< or = 50%, > 50%), percentage PRA at transplantation (< or = 50%, > 50%), dialysis pretransplant, preservation time > 24 h, acute tubular necrosis requiring dialysis, initial CsA dosage (< or = 5 mg/kg per day, > 5 mg/kg per day), CsA dosage at 1 year posttransplant (< or = 5 mg/kg per day, > 5 mg/kg per day), acute rejection (AR), number of AR episodes (ARE) (1, > 1), timing of AR (< or = 6 months, > 6 months), reversibility of AR (complete, partial), and infection [cytomegalovirus (CMV), non-CMV viral, bacterial]. Risk factors for the development of CR in pediatric renal transplant recipients were: AR (P < 0.0001, odds ratio 19.4), multiple ARE (> 1 vs. 1) (P < 0.0001, odds ratio 30.1), and high percentage peak PRA (> 50%) (P < 0.03, odds ratio 3.6).

Recurrence of haemolytic-uraemic syndrome in renal transplants: a single-centre report.

BACKGROUND: The incidence of recurrence of haemolytic-uraemic syndrome (HUS) in renal allografts appears to vary by centre, with the highest rates reported from the University of Minnesota. It is possible that the high rate of HUS recurrence at this institution reflects a transplant population skewed towards patients with a form of HUS that is more likely to recur in the allograft. METHODS: This study examined whether the initial episode of HUS in the native kidneys was preceded by a diarrhoeal prodrome ('classical HUS') or not ('atypical HUS'), and evaluated transplant outcomes in 24 patients who received 36 transplants at the University of Minnesota between 31 May 1972 and 31 December 1994. RESULTS: Eighteen of the 24 patients had atypical HUS, three had classical HUS, and in three patients the presence or absence of a diarrhoeal prodrome could not be determined. Recurrent HUS, defined as microangiopathic haemolytic anaemia, thrombocytopenia, renal insufficiency, and allograft biopsy findings compatible with HUS, occurred 16 times in 14 grafts in 11 patients. Nine of these patients had atypical HUS, one had classical HUS, and in one the nature of the prodrome could not be determined. Eleven of the 14 initial recurrences took place within 2 months of transplant. Recurrence was not more frequent in patients who received cyclosporin or antilymphocyte preparations. Actuarial analysis using matched controls showed poorer graft survival in patients with a primary diagnosis of HUS (P = 0.007), due to the high frequency of graft loss in HUS patients with recurrence. CONCLUSION: Based upon these data and a review of the literature, it can be concluded that the risk of recurrence of HUS in the allograft is confined almost entirely to patients with atypical forms of HUS.

The importance of early cyclosporine levels in pediatric kidney transplantation.

We studied the impact of early cyclosporine (CSA) levels on the incidence of rejection in pediatric transplant recipients. Between 1 January 1984 and 31 December 1994, a total of 234 pediatric patients underwent kidney transplants and received CSA immunosuppression. We analyzed the impact of CSA levels (at 1 wk, 2 wk, 1 month, 2 months, and 3 months) on the incidence of rejection in the first 3 and the first 6 months post-transplant. We found that CSA levels at all timepoints correlated, i.e. recipients with low levels in the early post-transplant period tended to have low levels throughout the first 12 months. Multivariate analysis for risk factors by biopsy-proven rejection in the first 3 months revealed that the CSA trough level was the critical factor (p < 0.05). Recipients with CSA trough levels < 100 ng/ml had 2.24 times the risk of rejections vs. those with blood levels > 100 ng/ml. Similarly, the CSA trough level at 1 month was the critical risk factor for biopsy-proven rejection within the first 6 months (p < 0.05). The major risk factor for graft loss within the first 12 months was a biopsy-proven rejection episode. We conclude that in pediatric kidney transplant recipients, early CSA trough levels < 100 ng/ml are associated with a significantly increased incidence of rejection in the first 6 months post-transplant.

Delayed graft function in the absence of rejection has no long-term impact. A study of cadaver kidney recipients with good graft function at 1 year after transplantation.

We previously reported that delayed graft function (DGF) in the absence of biopsy-proven acute rejection (Rej) had no effect on outcome of primary cadaver kidney transplantation (TX). By contrast, DGF in combination with Rej strongly predicted poor long-term graft survival. We asked whether this poor long-term outcome was due to early graft loss associated with DGF, or to an ongoing process leading to late graft loss. To answer this question, we studied a subset of 298 cadaver kidney transplant recipients who had not suffered early graft loss and had a serum creatinine level < or = 2.0 mg/dl at 1 year after TX. The incidence of DGF (defined by dialysis during the first week after TX) in this subset was 19%. DGF was associated with cold ischemia time >24 hr (P = 0.0003) and Rej (P = 0.06). For grafts with versus without DGF, the incidence of late acute Rej (>1 year after TX) was similar. Actuarial graft survival was similar for Rej-free recipients with versus without DGF (P = 0.9) and was worse for those with Rej and no DGF (P < 0.02). Importantly, however, in our recipients who all had a serum creatinine level < or = 2.0 mg/dl at 1 year after TX, the worst long-term outcome was noted in the subgroup with both DGF and Rej (P < 0.0001). By multivariate analysis, DGF was also only a risk factor in combination with Rej (P = 0.002, relative risk = 3.7), while a 0-antigen HLA mismatch had no impact. Patient survival decreased for recipients with both DGF and Rej by univariate (P = 0.009) and multivariate (P = 0.02, relative risk = 2.9) analyses. We conclude that DGF without Rej has no impact on long-term survival. However, our data for recipients with both DGF and Rej suggest that a chronic ongoing process leads to late graft failure. Further research is necessary to identify the exact pathophysiology of this process, which appears to be, at least in part, HLA antigen independent.

Chronic renal allograft rejection in the first 6 months posttransplant.

Between May 1, 1986 and May 31, 1992 at the University of Minnesota, we interpreted 129 renal allograft biopsy specimens (done in 48 grafts during the first 6 months posttransplant) as showing changes consistent with chronic rejection. For this retrospective analysis, we reexamined these biopsies together with clinical information to determine: (a) whether a diagnosis other than chronic rejection would have been more appropriate, (b) how early posttransplant any chronic rejection changes occurred, and (c) if the diagnosis correlated with outcome. We found that (1) chronic rejection is uncommon in the first 6 months posttransplant; it was documented in only 27 (2.4%) of 1117 renal allografts and was preceded by acute rejection in all but 3 recipients (for these 3, the first biopsy specimen showed both acute and chronic rejection). (2) Chronic vascular rejection was seen in 1 recipient as early as 1 month posttransplant; the incidence increased over time and was associated with an actual graft survival rate of only 35%. (3) The most frequent cause of arterial intimal fibrosis in the first 6 months posttransplant was arteriosclerotic nephrosclerosis (ASNS) of donor origin. Long-term graft function for recipients with ASNS was 67%. (4) Early-onset ischemia or thrombosis was seen in 14 recipients and predicted poor outcome: only 35.7% of these recipients had long-term graft function. (5) Cyclosporine (CsA) toxicity was implicated in only 3 recipients, who had mild diffuse interstitial fibrosis in association with elevated CsA levels. Other variables (including systemic hypertension, urinary tract infection, obstructive uropathy, neurogenic bladder, cobalt therapy, and recurrent disease) were not significantly associated with chronic renal lesions in the first 6 months posttransplant. A significant number of biopsies were originally interpreted as showing chronic rejection, but the diagnosis was changed upon reevaluation in conjunction with clinical data. We conclude that many factors coexist to produce chronic lesions in biopsies during the first 6 months posttransplant, so clinical correlation is needed before establishing a diagnosis of chronic rejection.

Delayed graft function, acute rejection, and outcome after cadaver renal transplantation. The 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.

Characterization and impact of wound infection after pancreas transplantation.

OBJECTIVE: To characterize the incidence, microbial pathogenesis, risk factors, and impact of wound infection after pancreas transplantation. DESIGN: Retrospective analysis. SETTING: A large university hospital. PATIENTS: From January 1, 1990, to September 30, 1993, 197 patients underwent 207 consecutive pancreas transplantation procedures. MAIN OUTCOME MEASURES: Wound infection and patient and allograft survival rates at 1 year. RESULTS: Sixty-nine patients (33%) suffered wound infections: 21 (10%) were superficial; 31 (15%), deep; and 17 (8%), combined. Most (74%) wound infections were monomicrobial. Staphylococcus epidermidis and Candida species were the most common pathogens. Prolonged operating time, older donors, and enteric drainage were associated with higher wound infection rates. Deep and combined wound infections led to allograft loss despite subsequent salvage procedures. Combined wound infection was associated with significantly higher mortality. CONCLUSIONS: A deep wound infection should be an indication for allograft removal. Antifungal prophylaxis, stringent donor criteria, and delayed primary wound closure should lower the incidence of wound infection.

Complications of ureterovesical anastomosis in kidney transplant patients: the Minnesota experience.

We reviewed urologic complications of 1183 consecutive primary or secondary renal transplants performed with bladder anastomoses at the University of Minnesota Hospital between 1985 and 1993. The Politano-Leadbetter (PL) technique of ureteroneocystostomy was used in 410 patients; the multistich (MS) extravesical technique modified from the methods of Witzel, Sampson, and Lich in 295; and the extravesical single-stitch (SS) technique in 478. Urologic complications occurred in 81 patients (6.8%). Of these complications, 68 (5.7%) were early (< 4 months) and 13 (1.1%) late; 32 (7.8%) were after PL, 17 (5.8%) after MS, and 32 (6.7%) after SS. A total of 13 patients had an anastomotic leak, 7 (1.7%) after PL, 4 (1.4%) after MS, and 2 (0.0004%) after SS; 49 patients had a ureterovesical obstruction, 16 (4.0%) after PL, 12 (4.0%) after MS, and 21 (4.2%) after SS; 5 patients had a ureteropelvic obstruction, 2 (0.5%) after PL, 2 (0.7%) after MS, and 1 (0.2%) after SS; and 14 patients had hematuria, 7 (1.7%) after PL, 1 (0.34%) after MS, and 6 (1.3%) after SS. Of the 81 patients with urologic complications, one (1%) resolved spontaneously; 30 (37%) were treated with temporary percutaneous nephrostomy, 17 (21%) with dilatation and stent; the 14 (17.3%) with hematuria were treated via cystoscopy; 19 (23%) required reoperation. Only 2 (2.5%) patients lost their graft. For both cadaver and living donor recipients, there was no difference between techniques for early and late complications of leakage, stricture, and hematuria. Each technique has certain advantages and each should be in every surgeon's repertoire.