Antihypertensive pharmacotherapy and long-term outcomes in pediatric kidney transplantation.

Hypertension (HTN) is common in pediatric recipients following kidney transplantation (KT). We retrospectively assessed the impact of HTN on long-term (>10-yr) outcomes in pediatric KT recipients (aged < 18 yr) at our center. Two hundred and ninety-three pediatric KT recipients (83% living donor [LD]) with graft survival (GS) for ≥5 yr were studied. HTN was defined by antihypertensive medication use at five yr post-KT. One hundred and sixty (55%) recipients did not have HTN, and 133 (45%) had HTN at five yr post-KT. There were no differences in actuarial patient survival between cohorts. Actuarial GS at 15 and 20 yr was 68% and 53% for recipients without HTN, and 53% and 33% for recipients with HTN (p = 0.006). Among LD recipients using one antihypertensive, GS at 15 yr was 100% for those using an angiotensin-converting enzyme inhibitor (ACEI) and 44% for those not using an ACEI (p = 0.04). Among these recipients, HTN treated with no ACEI was a significant risk factor for graft failure at >5 yr (hazard ratio [HR] = 2.5, p = 0.02), but HTN treated with an ACEI was not (HR = 0.6, p = 0.7). HTN at five yr post-KT is associated with poorer long-term GS in pediatric recipients, but ACEI therapy may enable better outcomes and should be studied further.

Graft loss due to recurrent disease in pediatric kidney transplant recipients on a rapid prednisone discontinuation protocol.

Recurrent disease is the fourth most common cause of graft loss (GL) in pediatric KTx recipients. We studied the incidence of recurrent disease and GL due to recurrent disease in pediatric KTx recipients on a RDP protocol. Between 2002 and 2010, we performed 74 KTxs in patients aged 5-18 yr using an RDP protocol, 25 (34%) were at risk of recurrence of primary disease. Outcomes were compared to 69 historical controls (18 [26%] at risk of recurrence), KTx between 1996 and 2000. Follow-up period was 39 ± 25 months in RDP and 124 ± 38 months in controls. The incidence of recurrent disease at three yr post-KTx was 16% in RDP and 28% in controls (p = NS). Mean time to recurrent disease was 22 ± 26 months in RDP and 46 ± 48 months in controls (p = 0.54). Nine (12%) grafts were lost in the RDP group (1-recurrence) and 32 (46%) in the control group (4-recurrence). Time to GL was 85 months in the RDP recipient and 46 ± 21 months in controls. An RDP protocol in pediatric KTx recipients may not be associated with increased risk of graft loss due to recurrent disease.

Ten-year outcome after rapid discontinuation of prednisone in adult primary kidney transplantation.

BACKGROUND AND OBJECTIVES: Rapid discontinuation of prednisone after kidney transplantation potentially allows for minimization of steroid-related side effects. Although intermediate-term data with rapid discontinuation of prednisone have been promising, concern still exists regarding long-term outcomes. The 10-year experience is reported herein. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Between October 1, 1999 and December 31, 2010, 1241 adult primary kidney transplants (791 living donor and 450 deceased donor) were performed using a protocol in which prednisone is discontinued after postoperative day 5. The 10-year actuarial recipient and graft survival rates and prednisone-related side effects were studied. RESULTS: Ten-year actuarial patient survival was 71% for living donor transplants and 62% for deceased donor transplants; 10-year graft survival was 61% for living donor transplants and 51% for deceased donor transplants, and was comparable to 10-year Scientific Registry of Transplant Recipients national data. Ten-year death-censored graft survival was 79% for living donor transplants and 80% for deceased donor transplants. Ten-year acute rejection rates were 25% for deceased donor transplants and 31% for living donor transplants; 10-year chronic rejection (interstitial fibrosis/tubular atrophy) rates were 39% for deceased donor transplants and 47% for living donor transplants. For nondiabetic recipients of living donor or deceased donor allografts, the incidence of new-onset diabetes was significantly lower than in historical controls on prednisone (P<0.001). We also found significantly reduced rates of cataracts, avascular necrosis, and cytomegalovirus infection in some subgroups. CONCLUSIONS: Prednisone-related side effects can be minimized in a protocol incorporating rapid discontinuation of prednisone for maintenance immunosuppression. Ten-year patient and graft outcomes remain acceptable.

Outcome of living kidney donors left with multiple renal arteries.

Individuals with kidneys having ≥ 2 arteries appear to have an increased incidence of hypertension. Whether kidney donors in whom the remaining kidney has ≥ 2 arteries are at increased risk of hypertension is unknown. Therefore, we studied 3685 kidney donors to determine whether donors left with a kidney having ≥ 2 arteries were at increased risk of hypertension, impaired renal function, or death. Cohorts were assigned based on our practice pattern and the anatomy of the donated kidney. Of the 3685 donors, 1211 were estimated to have a remaining kidney with ≥ 2 arteries. Mean follow-up time for the single-artery group was 14.1 (± 11.0) yr and 15.3 (± 11.2) yr for the ≥ 2 artery group. Six-month hospital readmission rate was 1.4% and 1.2%, hypertension was noted in 22.4% and 21.8% and proteinuria in 9.7% and 9.6%, and estimated glomerular filtration rate at last follow-up was 62 (± 28) and 62 (± 16) for single vs. ≥ 2 renal artery groups, respectively. Our data suggest no adverse clinical sequelae nor any decrease in long-term survival for donors left with a kidney having ≥ 2 renal arteries.

Consideration of donor age and human leukocyte antigen matching in the setting of multiple potential living kidney donors.

BACKGROUND: Defining living donor (LD)-related risk factors affecting kidney transplant outcome will allow better donor selection and more educated informed consent when there is more than one potential donor. We studied risk factors in a large cohort at a single institution. METHODS: We reviewed 1632 recipients who underwent LD kidney transplantation at the University of Minnesota between January 1, 1990, and October 1, 2009. Using Cox regression, we studied the effect of donor and recipient risk factors on patient and graft survival. We specifically examined the effect of donor age and human leukocyte antigen (HLA) matching because these are variables that may help clinical decision making when multiple potential donors exist. RESULTS: Mean donor age was 40.6 years for all transplants; 180 (11%) donors were 55 years or older, and 24 (1.5%) donors were older than 65 years. Mean number of HLA mismatches (per transplant) was 2.9 (29.2% of recipients had one to two HLA mismatches, 39.8% had three to four HLA mismatches, and 25% had five to six HLA mismatches). Donor age more than 65 years, five to six HLA mismatches, delayed graft function, and acute rejection were independent predictors of decreased patient and graft survival. When controlling for recipient age, donor age more than 65 years remained a risk factor for worse outcome. CONCLUSIONS: Our data suggest that advanced donor age (>65 years) and degree of HLA mismatch (≥5) are independent donor-related risk factors associated with worse outcome. When multiple potential LDs exist, it may be ideal to attempt to use a donor younger than 65 years and with less than five HLA mismatches.

Pediatric kidney transplantation using a novel protocol of rapid (6-day) discontinuation of prednisone: 2-year results.

BACKGROUND: There are few prospective studies of prednisone-free immunosuppression (IS) in pediatric kidney transplant (KTx) recipients. We studied the outcomes of a protocol using rapid discontinuation of prednisone (RDP, <1 week) and thymoglobulin induction. METHODS: Twenty-one RDP recipients (mean age 14+/-3 years) received KTx between May 2002 and December 2005 and were matched with controls (n=39) for age, race, and donor source. For the RDP group, IS consisted of prednisone tapered off over 6 days, thymoglobulin, mycophenolate mofetil, and cyclosporine A (CsA). In controls, IS consisted of thymoglobulin, maintenance prednisone, azathioprine, and CsA. RESULTS: For the RDP group, graft survival at 1 and 2 years was 90% and 86%; for the controls, graft survival at 1 and 2 years was 92%, and 90% (P=0.86). For the RDP group, the incidence of acute rejection at 1 and 2 years was 14% and 19%; for controls, the incidence of acute rejection at 1 and 2 years was 23%, and 31% (P=0.17). Of the 18 RDP recipients with functioning grafts, 89% remain prednisone-free at follow-up. There was no significant difference between groups in recipient survival rates, incidence of hypertension, chronic allograft nephropathy, or cytomegalovirus disease. CONCLUSIONS: RDP using thymoglobulin, mycophenolate mofetil, and CsA in selected pediatric KTx recipients is associated with recipient and graft survival rates and acute rejection incidence comparable with quadruple drug therapy.

Posttransplant diabetes mellitus and acute rejection: impact on kidney transplant outcome.

BACKGROUND: The benefits (e.g., low acute rejection [AR] rate) vs. the long-term risk of each immunosuppressive protocol may determine the protocol's value. METHODS: We studied the long-term impact of new-onset posttransplant diabetes (PTDM) and/or AR in 1,487 adult, primary transplant, nondiabetic recipients. Per Cox regression, donor source, AR, and PTDM were independent risk factors for graft loss (each, p<.0001). Recipients were subdivided by donor source and into these 4 groups: no AR, no PTDM [n=857]; no AR, PTDM [n=134]; > or =1 AR, no PTDM [n=403]; > or =1 AR, PTDM [n=93]. RESULTS: There was a significant difference between groups in 15-yr actuarial graft survival (GS) and death-censored (DC) GS (p<.0001). Importantly, > or =1 AR had more impact on 15-yr GS and DC GS than did PTDM; the worst outcome was for those having both AR and PTDM. In separate analyses, we censored those with >1 AR; and then only compared those developing AR or PTDM in the first year. The results were similar--the AR (no PTDM) group did worse than the PTDM (no AR) group (p<.001). CONCLUSIONS: Determining long-term risks associated with immunosuppressive protocols is important for treating future patients. Our data suggests that 15-year actuarial outcome (GS and DC GS) is worse for those developing AR than for those developing PTDM.

Stable kidney function in the second decade after kidney transplantation while on cyclosporine-based immunosuppression.

BACKGROUND: Calcineurin inhibitors (CNIs) have been the mainstay of immunosuppressive protocols in kidney transplantation over the past 20 years. However, in some recipients, the adverse effects of CNIs contribute to chronic allograft nephropathy and death with function--the two leading causes of late graft loss. Other recipients maintain stable graft function. METHODS: We studied the impact of continuing CNI-based immunosuppression in the second decade after kidney transplantation. From 1984 through 1996, a total of 1,263 patients underwent a primary kidney transplant at the University of Minnesota and received cyclosporine-based immunosuppression. Antibody induction was used only in deceased donor recipients. RESULTS: The actuarial 20-year patient survival rate was 38%; graft survival, 30%; and death-censored graft survival, 60%. The annual mean serum creatinine level for recipients whose grafts survived > or =1 year remained stable, although recipients with a history of > or =1 acute rejection episode had a higher serum creatinine level vs. recipients who were rejection-free. The annual mean calculated creatinine clearance was also stable over time. In addition, for recipients who were acute rejection-free, chronic allograft nephropathy/chronic rejection was only responsible for 9% of graft losses. CONCLUSIONS: Our study suggests that some kidney transplant recipients tolerate long-term CNI-based immunosuppression with stable creatinine levels. Identifying certain recipients' predisposition to CNI toxicity and individualizing immunosuppressive therapy may be important in order to improve long-term kidney function, while simultaneously preserving low short-term acute rejection rates.

Risk factors for rising creatinine in renal allografts with 1 and 3 yr survival.

BACKGROUND: Determining factors associated with negative slope of inverse creatinine vs. time (1/Cr vs. t) may help prevent a decline in renal allograft function. METHODS: A total of 1389 adult recipients of primary renal transplants were divided into quartiles based on the slope of 1/Cr vs. t calculated from 6 and 12 months post transplant. A multivariate analysis of risk factors for being in the worst vs. best quartile employed these variables: donor source, HLA mismatch, recipient age, donor age, panel-reactive antibody (PRA), acute rejection (AR), 3-month cyclosporin A (CsA) level, 1-yr CsA level and acute tubular necrosis. Two separate analyses compared risk factors in patients with 1 and 3 yr survival, respectively. RESULTS: In recipients with > or = 1 yr graft survival, high PRA and AR were associated with negative slopes of 1/Cr vs. t. For those with > or = 3 yr graft survival, both AR and 3-month CsA level > 150 ng/mL were significant risk factors, using both 6- and 12-month slopes. Stratification of AR showed 1 AR episode > or = 6 months and multiple AR episodes carried significant risk for negative slopes. CONCLUSION: Optimization of allograft function invokes a conundrum between the needs to avoid both AR and high early CsA levels. We support a policy of carefully balancing these two risks.

Prednisone-free maintenance immunosuppression-a 5-year experience.

Concern persists that prednisone-free maintenance immunosuppression in kidney transplant recipients will be associated with an increase in late allograft dysfunction and graft loss. We herein report 5-year follow-up of a trial of prednisone-free maintenance immunosuppression. From October 1, 1999, through January 31, 2005, at our center, 589 kidney transplant recipients were treated with a protocol incorporating discontinuation of their prednisone on postoperative day 6. At 5 years, actuarial patient survival was 91%; graft survival, 84%; death-censored graft survival, 92%; acute rejection-free graft survival, 84% and chronic rejection-free graft survival, 87%. The mean serum creatinine level (+/-SD) at 1 year was 1.6 +/- 0.6; at 5 years, 1.7 +/- 0.8. In all, 86% of kidney recipients with functioning grafts remain prednisone-free as of April 30, 2005. As compared with historical controls, recipients on prednisone-free maintenance immunosuppression had a significantly lower rate of a number of complications, including cataracts (p < 0.001), posttransplant diabetes mellitus (p < 0.001), avascular necrosis (p = 0.001), and fractures (p = 0.004). We conclude that prednisone-related side effects can be minimized in a protocol incorporating prednisone-free maintenance immunosuppression. Five-year graft outcome remains good.

A prospective randomized trial of steroid-free maintenance regimens in kidney transplant recipients--an interim analysis.

We compared three maintenance immunosuppressive regimens in a rapid discontinuation of prednisone protocol. From March 1, 2001, through December 31, 2003, 239 first and second kidney transplant recipients (166 LD; 73 DD) were randomized. All recipients were treated with Thymoglobulin; all received steroids intraoperatively and for 5 days postoperatively. Randomization was to cyclosporine-mycophenolate mofetil (n = 85); high-level tacrolimus (TAC) (8-12 ng/mL)-low-level sirolimus (SRL) (3-7 ng/mL) (n = 72); or low-level TAC (3-7 ng/mL)-high-level SRL (8-12 ng/mL) (n = 82). We found no difference at 24 months between groups in patient, graft, death-censored graft, or acute rejection-free graft survival, or in kidney function. Wound complications were more common in SRL-treated recipients (p = 0.02); we found no other differences between groups in complication rates. Our data suggest that excellent patient and graft survival and low rejection rates can be obtained using a variety of maintenance protocols without prednisone.

Thymoglobulin versus ATGAM induction therapy in pediatric kidney transplant recipients: a single-center report.

BACKGROUND: Induction immunosuppressive therapy with the anti-T-cell antibody Thymoglobulin decreases the incidence of acute rejection in adult kidney transplant (KTx) recipients, but limited data are available for pediatric KTx recipients. METHODS: We conducted a historical cohort study to compare rates of survival, rejection, and infection in pediatric (age <19 years) KTx recipients who received induction therapy with polyclonal antibody, ATGAM (n=127) or Thymoglobulin (n=71), from December 1, 1992, to January 31, 2003. Maintenance immunosuppression included cyclosporine, azathioprine or mycophenolate mofetil, and prednisone. Mean follow-up was 90+/-25 months for ATGAM recipients and 32+/-15 months for Thymoglobulin recipients. RESULTS: Overall, the incidence of acute rejection was lower in Thymoglobulin recipients versus ATGAM recipients (33% vs. 50%, P=0.02). Epstein-Barr virus (EBV) infection was higher in Thymoglobulin recipients versus ATGAM recipients (8% vs. 3%, P=0.002). But the two groups did not significantly differ in patient and graft survival rates, incidence of chronic rejection, EBV lymphoma, or other infection. CONCLUSIONS: Thus, Thymoglobulin induction was associated with a decreased incidence of acute rejection and an increased incidence of EBV infection in pediatric KTx recipients. EBV monitoring should be performed in EBV-naive recipients receiving Thymoglobulin.

Urolithiasis after kidney transplantation in pediatric recipients: a single center report.

BACKGROUND: Urolithiasis occurs in approximately 6% of adult kidney transplant (KTx) recipients. Limited data are available on urolithiasis after pediatric KTx. We report the incidence, management of, and risk factors for stone development in children after KTx. METHODS: We reviewed the medical records of 399 children who received KTx at our center between September 1986 and January 2003. Transplant outcomes were compared in stone formers and controls. RESULTS: Twenty (5%) patients, age 9+/-5 (X +/- SD) years, developed stones over the follow-up period (74+/-53 months). Time to stone presentation was 19+/-22 months post-KTx. Presenting features were urinary tract infection (UTI), 8; gross hematuria, 5; microscopic hematuria, 2; dysuria without infection, 6; difficulty voiding, 3; and silent stones, 2. Stones were removed by cystoscopy in 11 (55%) patients. Stone composition was determined in 11 patients: calcium phosphate (55%), calcium oxalate (18%), mixed calcium phosphate and oxalate (9%), and struvite (18%). Factors predisposing to stones in study patients included suture retention (n = 4), elevated urinary calcium excretion (n = 2), recurrent UTI (n = 2), and urinary stasis (n = 2). The incidence of UTI was higher (P = 0.003) and of acute rejection was lower (P = 0.02) in stone patients compared with controls. Patient and graft survival rates and the incidence of chronic rejection did not significantly differ between study patients and controls (P = NS). CONCLUSIONS: Urolithiasis is not uncommon in pediatric KTx patients. Factors associated with post-KTx urolithiasis include retention of suture material, recurrent UTI, hypercalciuria, and urinary stasis. Treatment is associated with excellent outcome and low recurrence rate.

Rapid discontinuation of prednisone in higher-risk kidney transplant recipients.

Prednisone-minimization protocols have been successful in low-risk recipients. We report on the use of a protocol incorporating rapid discontinuation of prednisone in a cohort of kidney transplant recipients (n = 79) at increased immunologic risk. Our data suggests that such recipients should not be excluded from prednisone-minimization protocols.

Long-term immunosuppression, without maintenance prednisone, after kidney transplantation.

BACKGROUND: Concern exists that prednisone-free maintenance immunosuppression in kidney transplant recipients will increase acute and/or chronic rejection. METHODS: From October 1, 1999, through February 29, 2004, at our center, 477 kidney transplant recipients (341 living donor, 136 cadaver) discontinued prednisone on postoperative day 6, per our protocol. Immunosuppression consisted of polyclonal antibody (Thymoglobulin) for 5 days, prednisone intraoperatively and for 5 days, a calcineurin inhibitor, and either sirolimus or mycophenolate mofetil. We compared outcome with that of historical controls who did not discontinue prednisone. RESULTS: The recipients on prednisone-free maintenance immunosuppression had excellent 4-year actuarial patient survival (92%), graft survival (90%), acute rejection-free graft survival (86%), and chronic rejection-free graft survival (95%). The mean serum creatinine level (+/- SD) at 1 year was 1.6 +/- 0.6; at 4 years, 1.6 +/- 0.6. We noted that 8% of recipients had cytomegalovirus (CMV) disease; 4.5%, fractures; 2.8%, cataracts; 1%, posttransplant diabetes; 0.2%, avascular necrosis; 0.2%, posttransplant lymphoproliferative disease; and 0%, polyomavirus. In all, 85% of kidney recipients with functioning grafts remain prednisone-free as of April 1, 2004. As compared with historical controls, the recipients on prednisone-free maintenance immunosuppression had better patient (P = 0.02) and graft survival (P < 0.0001) and lower rates of acute (P = 0.0004) and chronic (P = 0.02) rejection. In addition, they had a significantly lower rate of CMV disease (P < 0.0001), cataracts (P < 0.0001), posttransplant diabetes (P < 0.0001), and avascular necrosis (P = 0.0003). CONCLUSIONS: Prednisone-related side effects can be minimized without maintenance immunosuppression; our prednisone-free recipients do not have increased acute or chronic rejection.

Hyperlipidemia in pediatric kidney transplant recipients treated with cyclosporine.

Hyperlipidemia is a risk factor for cardiovascular disease in adult kidney transplant (Tx) recipients. We sought to determine the prevalence of, and the risk factors associated with, hyperlipidemia in pediatric kidney Tx recipients on cyclosporine (CsA). We identified 59 patients (mean age 8.2+/-5.7 years) transplanted between 1 January 1991 and 31 December 1993. Pre Tx, 34% had elevated total cholesterol [TC >200 mg/dl (5.17 mmol/l)]; 54% had elevated triglycerides [TG >200 mg/dl (2.26 mmol/L)]. Mean TG was higher pre Tx in dialysis (versus nondialysis) patients: 306 mg/dl (3.46 mmol/l) versus 228 mg/dl (2.58 mmol/l) ( P=0.04). Mean TC was higher in peritoneal dialysis than hemodialysis patients: 222 mg/dl (5.74 mmol/l) versus 169 mg/dl (4.37 mmol/l) ( P=0.03). Pre Tx and 3-year values correlated (TC, r=0.49, P=0.0008; TG, r=0.41, P=0.001); 3- and 5-year TC values correlated ( r=0.57, P=0.003). At 5 years post Tx, 41% of the recipients had elevated TC; 14% had elevated TG. Recipients with elevated TC had higher mean CsA concentrations at 1 year post Tx ( P=0.03). Recipients with elevated TG tended to receive more prednisone ( P=0.06). At 5 years post Tx, recipients had a high prevalence of hyperlipidemia. The identification and treatment of hyperlipidemia should be included in pediatric kidney Tx protocols.

Positive remote crossmatch: impact on short-term and long-term outcome in cadaver renal transplantation.

BACKGROUND: A positive crossmatch with a "current" recipient serum (drawn shortly before the proposed transplant) is a contraindication to renal transplantation because of the risk of hyperacute rejection. Conflicting data have been reported concerning the significance of a positive crossmatch with "remote" sera (obtained months or years earlier) when the current crossmatch is negative. METHODS: Recipients of a first or second cadaver transplant between June 1988 and April 1994 were studied. All transplants were performed with a negative "current" crossmatch. Retrospective crossmatches using "remote" sera were performed for all sensitized recipients. RESULTS: Recipients with a positive remote crossmatch (RXM) demonstrated a higher incidence of delayed graft function and of acute rejection and graft loss occurring in the first year posttransplant than did sensitized recipients with a negative RXM or unsensitized recipients. In multivariate analysis, only recipients with both a positive RXM and delayed graft function were at significantly higher risk for graft loss. Grafts surviving the first year demonstrated similar half-lives whether the RXM was positive or negative. CONCLUSIONS: The positive RXM, possibly in conjunction with other factors leading to very early graft damage, is a significant predictor of unfavorable transplant outcome in first and second renal transplants. This effect is seen early in the transplant course, and there seems to be no impact on outcome after the first year. Newer immunosuppressive modalities may help to reduce the early negative impact.

Five preventable causes of kidney graft loss in the 1990s: a single-center analysis.

BACKGROUND: Despite improvements in immunosuppressive protocols and patient care, kidney allografts continue to fail. We studied causes of graft loss for primary kidney transplants in the 1990s to determine major causes and potential interventions. METHODS: Causes of graft loss were reviewed for 1467 primary kidney transplants done at our institution between January 1, 1990, and December 31, 1999. Graft loss for that entire population was studied and then the causes of loss selectively examined at <1 year, 1 to 5 years, and>5 years post-transplant. Finally, causes of loss in the 1990s versus the 1980s were compared. RESULTS: Five major causes of graft loss were noted in the 1990s: thrombosis, acute rejection (either alone or combined with delayed graft function or infection), chronic rejection, death with function, and noncompliance. In the first year post-transplant, thrombosis (25%) and death with function (41%) were the major causes of graft loss. After the first year, chronic rejection and death with function predominated. For recipients dying with graft function, cardiovascular disease was the major cause of death. CONCLUSIONS: This study identified the five major causes of kidney graft loss in the 1990s. Different interventions are required to decrease loss from each of these causes. Future research needs to be directed at such interventions.