Incidence and magnitude of post-transplant cardiovascular disease after pediatric kidney transplantation: Risk factor analysis of 1058 pediatric kidney transplants at the university of Minnesota.

BACKGROUND: KT recipients have increased the risk of CVD. The incidence of post-transplant CVEs among pediatric recipients has not been well-characterized. PATIENTS AND METHODS: Between 1963 and 2015, 884 pediatric (age: 0-17 years old) recipients received 1058 KTs at our institution. The cumulative incidence of CVEs was analyzed. Statistical models were used to estimate risk factors for developing post-transplant CVEs. RESULTS: Overall median patient survival was 33 years (IQR: 18.7-47). A total of 362 CVEs occurred in 161 (18.3%) patients at a median age of 20.5 years. Arrhythmias (18%) were most common. Cumulative risk of post-transplant CVEs was 9% at 10 years, 17% at 20 years, 25% at 30 years, and 36% at 40 years. Development of post-transplant CVEs was associated with increased mortality (HR 2.25 [95% CI 1.61-3.14]); of those who developed a CVE and died, 22/51 (43.1%) died of CVD. Multivariable risk factors for post-transplant CVEs included a history of pretransplant CVD (aHR 1.92 [1.18-3.13] and graft failure (4.57 [3.13-6.67]). DISCUSSION: A pretransplant history of CVD and a failed graft are significant risk factors for the development of post-transplant CVE. CVD increases the risk of post-transplant death or graft loss.

Improved Outcomes of Kidney Transplantation in Infants (Age < 2 years): A Single-Center Experience.

BACKGROUND: Infants (age, < 2 years) with end-stage renal disease (ESRD) have increased morbidity and mortality. We evaluated our long-term outcomes of kidney transplants (KTx) in infants. METHODS: Between 1984 and 2014, 136 infants underwent KTx. We examined trends in survival rates and complications by era (1984-1993 [era 1], 1994-2003 [era 2], 2004-2014 [era 3]). RESULTS: Patients were 92.6% white and 70.6% males. Posttransplant (Tx) initial length of hospital stay declined 37% over the 30-year period (P <0.01). Ten-year death-censored graft survival improved from 60% (era 1) to 80% (era 2) (P = 0.04). The incidence of acute rejection, graft thrombosis, cytomegalovirus, and urine leaks did not significantly change across eras. Frequency of Epstein-Barr virus diagnosis (era 2 vs era 3, P < 0.01) increased. Post-Tx lymphoproliferative disorder incidence was increased in era 2 compared with eras 1 and 3 (P = 0.03). CONCLUSIONS: Infants deserve earlier consideration for KTx. Length of initial hospital stay and patient and graft survival rates after KTx have improved in infants since 1984.

Post-Transplant Malignancy after Pediatric Kidney Transplantation: Retrospective Analysis of Incidence and Risk Factors in 884 Patients Receiving Transplants Between 1963 and 2015 at the University of Minnesota.

BACKGROUND: Post-transplant malignancy (PTM) remains a concern among pediatric kidney transplant (PKT) recipients. STUDY DESIGN: Between 1963 and 2015, 884 pediatric (age 0 to 17 years old) patients received 1,055 PKTs at our institution. Cox proportional hazards models were constructed to identify risk factors for PTM after PKT with time-to-first-PTM as a primary outcome. Secondly, the hazard of death or graft loss was calculated in patients who developed PTM. RESULTS: Median patient survival was 33 years (interquartile range [IQR] 18.7 to 47 years); 260 patients died during the study period and 47 had been diagnosed with PTM. There were 235 PTMs that occurred in 136 (15.4%) recipients at a median age of 29 years (IQR 17.8 to 37 years). The percentages of patients with PTM were 13% at 20 years post-PKT and 26% at 30 years post-PKT. Of PTM patients who died, 63.8% died of PTM. Among those who developed PTM, there was a higher hazard of death or graft loss (hazard ratio [HR] 1.62; 95% CI 1.11 to 2.38). In multivariable proportional hazards models, factors associated with PTM were increasing age at PKT (adjusted HR [AHR] 3.14; 95% CI 1.80 to 5.48 for 14 to 17 year-olds compared with children less than 3 years), having a living unrelated donor (LURD; AHR 3.25; 95% CI 1.27 to 8.35 compared with a living related donor), or implanting an Epstein-Barr virus (EBV)-positive allograft in an EBV-negative recipient (AHR 5.66; 95% CI 1.11 to 29.0). Compared with the general population, the cancer rate for PKT recipients was 6 times higher (126 vs 21 per 100,000 person-years). CONCLUSIONS: Pediatric kidney transplant recipients are at increased risk of PTM, which adversely affects survival. Children receiving transplants at an older age, from a LURD, or who receive an EBV-positive organ, should be monitored closely for the development of PTM.

Evolution of Living Donor Nephrectomy at a Single Center: Long-term Outcomes With 4 Different Techniques in Greater Than 4000 Donors Over 50 Years.

BACKGROUND: The development of minimally invasive surgical approaches to donor nephrectomy (DN) has been driven by the potential advantages for the donor, with questions remaining about long-term outcomes. METHODS: All living DN performed from June 1963 through December 2014 at the University of Minnesota were reviewed. Outcomes were compared among 4 DN techniques. RESULTS: We performed 4286 DNs: 2759 open DN (ODNs), 1190 hand-assisted (HA) laparoscopic DNs (LDNs), 203 pure LDN (P-LDNs), and 97 robot-assisted-LDN. Laparoscopic DN was associated with an older (P < 0.001) and heavier (P < 0.001) donor population. Laparoscopic DN was associated with a higher probability of left kidney procurement (P < 0.001). All 3 LDN modalities required a longer operative time (P < 0.001); robot-assisted-LDN took significantly longer than HA-LDN or P-LDN. Laparoscopic DN decreased the need for intraoperative blood transfusion (P < 0.001) and reduced the incidence of intraoperative complications (P < 0.001) and hospital length of stay (P < 0.001). However, LDN led to a significantly higher rate of readmissions, both short-term (<30 day, P < 0.001) and long-term (>30 day, P < 0.001). Undergoing HA-LDN was associated with a higher rate of an incisional hernia compared with all other modalities (P < 0.001). For recipients, LDN seemed to be associated with lower rates of graft failure at 1 year compared with ODN (P = 0.002). The odds of delayed graft function increased for kidneys with multiple arteries procured via P-LDN compared with HA-LDN (OR 3 [1,10]) and ODN (OR 5 [2, 15]). CONCLUSIONS: In our experience, LDN was associated with decreased donor intraoperative complications and hospital length of stay but higher rates of readmission and long-term complications.

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.

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.

Kidney transplantation in infants and small children.

Transplantation is now the preferred treatment for children with end-stage kidney disease. But not all pediatric age groups have enjoyed the same success. The number of transplants in infants and young children has lagged behind the number in older children. One reason for this is the philosophy of some centers to maintain infants on dialysis until they reach some arbitrarily determined age, at which time they would undergo a transplant. If kidney transplantation is the therapy of choice for older children with renal failure, and equivalent results can be obtained in all age groups, why should it not be offered to these youngest patients? Our center's philosophy for many years has been not to restrict transplant based on size or age. We have performed over 50 kidney transplants in infant recipients, and have shown equivalent results to those obtained in older children. Important factors in obtaining a successful outcome include the use of adult kidneys from a living donor, careful attention to operative and perioperative care, and performing the transplant early or in a preemptive fashion. The latter allows for minimizing the negative impact of uremia on physical and neurologic development in infants.

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.

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.

Living donor kidney transplants: personal reflections.

Short- and long-term living kidney donor morbidity and mortality are discussed herein. The analysis includes over 3000 living donor kidney transplants from 1963 through 2002 at a single institution. The category of living donors includes living related donors, such as fathers, mothers, siblings, offspring, and other genetically related donors, as well as living unrelated donors, such as spouses, friends, or altruistic strangers. Graft and patient survival rates with living related and unrelated living donors are compared to rates with cadaveric donors. Donor risks are discussed, including short-term surgical risks as well as long-term risks of impaired renal function, possible hypertension, and psychological risks. Finally, early and late donor mortality statistics are presented. In addition, the benefits to potential donors are reviewed. Donors are carefully screened before donation. During this screening process, a significant number of donors have been found to have abnormal renal function--some had undisclosed hypertension and others had unknown cardiovascular disease. In addition, six malignancies were found, eventually resulting in curative resection. A secondary benefit to donors was reported in a study from Norway and Sweden, which showed that donors had improved long-term survival versus the general population. Our own long-term studies involving follow-up of 20 to 30 years after kidney donation have shown no significant difference in donor renal function, blood pressure, and incidence of proteinuria, as compared with their nondonor siblings. We also found donors to be perfectly normal in all other categories; several had even undergone normal pregnancies after donation. Most donors reported a high quality of life, with a boost in self-esteem and an increased sense of well-being: 96% felt it was a positive experience. In conclusion, living kidney donation has a very low mortality rate. Long-term follow-up shows minimal impact after donation. Donor quality of life is reported as excellent.

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.

Transplant options for patients undergoing total pancreatectomy for chronic pancreatitis.

BACKGROUND: Total pancreatectomy to treat chronic pancreatitis is associated with severe diabetic control problems in 15% to 75% of patients, causing up to 50% of deaths late postoperatively. We report our experience with islet autotransplants at the time of, or with pancreas allotransplants after, total pancreatectomy. STUDY DESIGN: Between February 1, 1977, and June 30, 2003, we performed 112 islet autotransplants at the time of total pancreatectomy; we also performed 20 pancreas allotransplants in 13 patients who had already undergone total pancreatectomy months to years earlier. RESULTS: Islet autotransplants at the time of total pancreatectomy in patients who had not had previous operations on the body and tail of the pancreas were associated with a high islet yield (>2,500 islet equivalents/kg body weight), and >70% of the recipients achieved complete insulin independence. In contrast, a previous distal pancreatectomy or a Puestow drainage procedure was associated with a low islet yield in 75% of them and with complete insulin independence in <20%. A pancreas allotransplant after total pancreatectomy was not associated with any transplant-related mortality at 1 and 3 years posttransplant. The pancreas graft survival rate at 1 year posttransplant was 77% with tacrolimus-based immunosuppression (versus 67% with cyclosporine). Enteric (over bladder) drainage was preferred to manage exocrine graft secretions, to cure pancreatectomy-induced endocrine and exocrine insufficiency. CONCLUSIONS: Our series shows that pancreas allotransplants can be performed without transplant-related mortality and, when tacrolimus-based immunosuppression is used, with 1-year pancreas graft survival rates >75%. In contrast to a simultaneous islet autotransplant, a pancreas allotransplant has the disadvantage of requiring lifelong immunosuppression, but the advantage of not only curing endocrine but also exocrine insufficiency. Both transplant options, if successful, improve the recipient's quality of life.

Kidney transplants for children under 1 year of age - a single-center experience.

From September 20, 1970 to October 24, 2001, we performed 46 kidney transplants in infants under 1 yr old at the University of Minnesota. This article reviews the preoperative care, surgical technique, and immunosuppression. Recipients included 16 females and 30 males; the youngest recipient was 6 wk old. The mean pretransplant height was 62.8 cm, which increased to 77 cm at 1 yr post-transplant and to 104 cm at 5 yr. We used 40 living donors (all but 1 were related to the recipient) and 6 cadaver donors. The overall actuarial graft survival was 85% at 1 yr and 70% at 5 yr. In the cyclosporine era, graft survival improved to 91% at 1 yr and 80% at 5 yr. Death with function was the most common cause of graft loss (n = 5), followed by biopsy-proven chronic rejection (n = 4), biopsy-proven recurrent disease (n = 3), and graft thrombosis (n = 2). Patient survival was 91% at 1 yr and 86% at 5 yr. In the cyclosporine era, patient survival was 100% at 5 yr and 85% at 10 yr. We concluded that an early transplant is the best treatment option for infants under 1 yr old with chronic renal failure. Whenever possible, adult living kidney donors should be used.

Predicting long-term kidney graft survival: can new trials be performed?

BACKGROUND: As short-term transplant results improve, it has become difficult to use patient or graft survival or acute rejection as clinical trial endpoints, except in large, multicenter studies. Despite better outcomes, graft failure continues over time. METHODS: We studied 6- and 12-month creatinine (Cr) level and change in creatinine (deltaCr) level (3-12 months, 6-12 months) as predictors of graft survival for 1,389 primary kidney transplants (minimum graft survival 1 year). Determining the prognostic value of Cr level (6 or 12 months), the subgroups were as follows: less than 1, 1 to 1.4, 1.5 to 1.9, 2.0 to 2.4, 2.5 to 2.9, and greater than or equal to 3 mg/dL. For deltaCr level, the subgroups were as follows: less than 0, 0, 0.01 to 0.2, and greater than 0.2. Subgroup actuarial graft survival was determined. Cox regression analyses were performed with forward, stepwise selection. RESULTS: After 12-month Cr level entered the model, no other variable was significant. Repeating this with continuous variables, 12-month Cr level was again the best predictor. Five-year graft survival for 12-month Cr level less than 1 (n=38) was 95%; for 1.0 to 1.4 (n=454), 87%; for 1.5 to 1.9 (n=463), 86%; for 2.0 to 2.4 (n=166), 78%; for 2.5 to 2.9 (n=54), 60%; for greater than or equal to 3 (n=45), 41%. A major breakpoint for outcome is 1-year Cr level=2.0. A power analysis was performed for the combined endpoint of graft loss and 1-year Cr level greater than 2, reached by 30% of patients. To avoid missing a reduction to 20% (actual decrease 33%) (alpha=0.05; power=0.8), 313 patients would be required per group. For a reduction to 15% (actual decrease 50%), 133 patients would be required. CONCLUSIONS: Twelve-month Cr level is an accurate surrogate for long-term outcome. The use of a combined endpoint (graft loss and 12-month Cr level) allows trials to be performed without exorbitant numbers.

Graft and quality of life outcomes in older recipients of a kidney transplant.

BACKGROUND: It is well recognized that kidney transplants significantly improve quality of life for patients with end-stage renal disease (ESRD). This benefit is not as clearly documented for older recipients as it is for younger recipients. We looked at outcomes, both medical and psychosocial, in a group of older (> or =65 years) kidney transplant recipients and compared the results to a group of younger recipients (18 to 64 years). METHODS: From 1990 through 2002, we performed 2,746 kidney transplants at our center: 2,596 (94.5%) in recipients 18 to 64 years old and 150 (5.5%) in recipients 65 years or older. In our retrospective analysis, we determined outcomes such as patient and graft survival rates. To determine whether or not older recipients had an improved health-related quality of life, we used the national SF-36 (short form) questionnaire. We compared those results with a group of younger recipients and with national age-appropriate norms. RESULTS: The mean recipient age was 69.1 years in the older group vs. 42.8 years in the younger group (p < 0.001). Living donors were used in 43.3% of the transplants in the older group vs. 47.5% in the younger group (p < 0.01). At 5 years posttransplant, patient and graft survival rates were 73% and 68% in the older group vs. 86% and 79% in the younger group (p < 0.001). We analyzed the SF-36 responses for all recipients with completed forms: 42 completed forms from the older group vs. 149 from the younger group. The overall benefit to quality of life was similar for both groups. General physical health was rated slightly higher than national norms in both groups. Benefits to mental health were more pronounced in the older group. CONCLUSION: Kidney transplants can be performed in older recipients with acceptable outcomes. Such recipients enjoy significant benefits to their quality of life after a transplant, similar to benefits seen in younger recipients. Older age, by itself, should not be a contraindication to a transplant.