[Current state of the problem of allotransplantation of Langerhans cells (achievements and prospects)]. / Sovremennoe sostoianie problemy allotransplantatsii kletok Langergansa (dostizheniia i perspektivy).

Literature data devoted to transplantation of Langerhans cells have been analyzed. The main stages, indications, dissection of islets, immunosuppressive therapy, complications and data of the latest clinical trials were discussed.

Diagnosis of pancreas rejection: cystoscopic transduodenal versus percutaneous computed tomography scan-guided biopsy.

BACKGROUND: The most common cause of graft failure after technically successful pancreas transplants is rejection. Laboratory parameters for detecting pancreas graft rejection are not consistently reliable and can lead to unnecessary antirejection treatment. Histopathologic evaluation is the gold standard in the differential diagnosis of pancreas graft dysfunction. Four biopsy techniques have been described: cystoscopic transduodenal (CB), percutaneous computed tomography scan-guided (PB), open, and laparoscopic biopsy. METHODS: We studied the two most common techniques, CB and PB, in pancreas transplant recipients with presumed rejection. Group 1 comprised 103 attempts at CB in 82 recipients (53 men, 29 women) with bladder-drained (BD) pancreas transplants, at 1 to 80 (median, 14) months after transplant. Group 2 comprised 93 attempts at PB in 68 recipients (41 men, 27 women), at 0.5 to 64 (median, 14) months after transplant. RESULTS: In group 1, of 103 attempts at CB, adequate tissue was obtained in 90 (87%): pancreas alone in 23 (22%), pancreas + duodenum in 35 (34%), duodenum alone in 32 (31%). Of the 58 pancreas biopsies, 23 (40%) showed acute rejection. Of the 67 duodenal biopsies, 16 (24%) showed acute rejection. Complications of CB included macrohematuria in 4 recipients (4%) and microhematuria in 32 (31%). We noted no biopsy-related pancreatitis. The mean cost of CB was $2561+/-246. In group 2, of 93 attempts at PB, adequate tissue (all pancreas) was obtained in 67 (72%); of these, 29 (43%) showed acute rejection. Of 23 inaccessible pancreases, 9 (39%) underwent CB; pancreatic tissue was obtained in four (45%), and results were consistent with rejection in all four. Complications of PB included biopsy-related pancreatitis (serum amylase > or = 25%) in five (7%) recipients, macrohematuria in one (1%), and abdominal hemorrhage in two (3%). The mean cost of PB was $1038+/-78. (1) CB and PB prevented unnecessary antirejection treatment in 44% of our recipients with successful biopsies; (2) CB had a higher success rate for obtaining tissue (including duodenal specimens) and a lower rate of major complications; (3) PB was easier and cheaper, did not require general anesthesia, and was performed as an outpatient procedure. CONCLUSIONS: We conclude that PB should become the biopsy technique of choice in recipients with presumed pancreas graft rejection. If PB fails, recipients with bladder-drained pancreas transplants should undergo CB. If CB fails, or in recipients with enteric-drained or duct-injected pancreas transplants, a laparoscopic or open biopsy should be considered.

Short and long-term outcomes of systemic drainage to IVC: a new technique for pancreas transplantation.

Ninety-eight percent of the whole pancreas does not serve the purpose of pancreatic transplantation and it is a major cause of surgical complications. Up to 30% of pancreas transplant recipients experience surgical complications and require reoperation. Graft thrombosis and pancreatitis are the most common complications of pancreas transplantation (PT). Thus, different surgical techniques have been described to overcome the surgical hurdles and reduce surgical complications. In this study, for the first time, we report short- and long-term outcomes of PT with inferior vena cava (IVC) venous drainage. Forty-five PTs (22 simultaneous pancreas and kidney [SPK] transplantations and 23 pancreas after kidney [PAK] transplantations) were performed with this technique in our center. Sixty-eight percent of the donors were imported from outside of our area after they were declined by their local transplantation center. Patient and graft survival rates were 100% at 1 year. No graft thrombosis or pancreatitis occurred with this technique. Six patients (13.3%) required reoperation (3 bleeding, 2 anastomotic leak, and 1 small bowel perforation). No patient or graft loss occurred due to surgical complications. We conclude that this technique provides fast and easy dissection of the venous drainage of the PT without the need of complete occlusion of venous outflow. Surgical complication rates were lower with this technique compared with other reported techniques.

Alemtuzumab and minimization immunotherapy in kidney transplantation: long-term results of comparison with rabbit anti-thymocyte globulin and standard triple maintenance therapy.

BACKGROUND: Efforts to improve long-term patient and allograft survival have included use of induction therapies as well as steroid and/or calcineurin inhibitor (CNI) avoidance/minimization. METHODS: This is a retrospective review of kidney transplant recipients between September 2004 and July 2009. Immune minimization (group 1; n = 182) received alemtuzumab induction, low-dose CNI, and mycophenolic acid (MPA). Conventional immunosuppression (group 2; n = 232) received rabbit anti-thymocyte globulin, standard-dose CNI, MPA, and prednisone. RESULTS: Both groups were followed up for same length of time (49.4 ± 21.7 months; P = .12). Patient survival was also similar (90% vs 94%; P = .14). Death-censored graft survival was inferior in group 1 compared with group 2 (86% vs 96%, respectively; P = .003). On multivariate analysis, group 1 was an independent risk factor for graft loss (aHR = 2.63; 95% confidence interval [CI], 1.32-5.26; P = .006). Biopsy-proven acute rejection occurred more in group 1, due to late rejections compared with group 2 (7% vs 2%; P < .01 respectively). Graft function was lower in group 1 compared with group 2 at 3 months (49.5 mL/mt vs 70.7 mL/mt, respectively; P < .001) to 48 months (48.6 mL/mt vs 69.4 mL/mt, respectively; P = .04). CONCLUSION: Minimization of maintenance immunosuppression after alemtuzumab correlated with higher acute rejection and inferior graft survival compared with thymoglobulin and conventional triple immunotherapy.

Long-term outcomes of pancreas after kidney transplantation in small centers: is it justified?

BACKGROUND: Currently, the long-term advantages of having a pancreas transplantation (PT) are debated, particularly in patients receiving pancreas after kidney (PAK) allografts. The United Network for Organ Sharing (UNOS) requires that a transplant center perform a minimum number of PT per year to remain an active PT center. The long-term outcomes and challenges of PAK in small pancreas transplant centers are not well studied. METHODS: In this retrospective analysis, we report short- and long-term outcomes in a small center performing 2-9 PT annually. RESULTS: Forty-eight PT (25 simultaneous pancreas and kidney transplantation [SPK], 23 PAK) were performed in our center. Donor and recipient demographics were similar in both groups. All suitable local donors were used for SPK. All organs for PAK transplantation were imported from other UNOS regions. Mean follow-up was 61 ± 46 and 74 ± 46 months for SPK and PAK, respectively. Patient and graft survival rates were similar in SPK and PAK groups and better than the reported national average. Four patients (11%) died (1 due to trauma, 1 brain lymphoma, 1 ruptured aneurysm; and 1 unknown cause). Two patients (4%; 1 SPK, 1 PAK) lost their grafts because of thrombosis on postoperative days 3 and 5 in 2002. No graft thrombosis occurred since 2002. Seven patients (15%) required reoperation (4 for bleeding, 2 anastomotic leaks, 1 small bowel perforation). Two patients (4%) developed post-transplantation lymphoproliferative disease. Five patients (11%) experienced cytomegalovirus antigenemia which responded well to antiviral therapy. CONCLUSIONS: Compared with outcomes for diabetic patients on dialysis, current SPK and PAK short- and long-term results are favorable even in a small PT center. Therefore, unless there is a contraindication, PT should be offered to all type 1 diabetic patients with end-stage renal disease at the time of kidney transplantation or afterward.

African American renal transplant recipients (RTR) require higher tacrolimus doses to achieve target levels compared to white RTR: does clotrimazole help?

The number of African Americans (AAs) on the kidney waiting list is increasing in the United States. Several studies showed that AAs are at higher risk for rejection and graft loss. Because of genetic polymorphisms, AAs may metabolize calcineurin inhibitors faster than Caucasian (C) individuals. The goal of this study is to evaluate the tacrolimus (TAC) dose required to reach therapeutic levels and to assess the impact of clotrimazole on TAC metabolism in AAs compared to C patients. One hundred forty-two AA renal transplant recipients (RTRs) were compared to 309 C RTRs. Demographics were similar in both groups. Induction therapy and maintenance immunosuppression were similar in both groups and included TAC, mycophenolate acid (MPA), and steroids. The goal in all RTRs was to maintain a 12-hour trough level of 10 to 15 ng/mL in the first 3 months, 8 to 10 ng/mL for the first year, and 5 to 8 ng/mL thereafter. To achieve these levels, AA RTRs require a significantly higher dosage of TAC compared to C patients (5.9 ± 2.9 vs 3.6 ± 2 mg/d, respectively, P < .0001). By multivariate analysis, TAC dose requirements were not affected by age, gender, MPA or prednisone dose, diabetes, and renal function. Adding clotrimazole (CTM) to the RTR regimen significantly reduced the TAC dose requirements in all RTRs. When CTM was used, the TAC dose requirement was not statistically significantly different between AA and C patients (2.6 ± 1.2 mg/d vs 1.8 ± 1.5 mg/d, P = .07). We conclude that AAs required a higher TAC dose to reach the desired trough level in RTRs compared to C RTRs. The use of CTM eliminates the need for higher doses of TAC in AA RTRs. Thus, CTM may aid AA RTRs in achieving therapeutic TAC levels while reducing drug costs.

Graft arteriosclerosis and glomerulosclerosis correlate with flow and resistance to machine perfusion in kidney transplantation.

INTRODUCTION: Machine perfusion to preserve kidneys for transplantation has grown over the past decade with demonstrated diagnostic and therapeutic benefits. Flow and resistance patterns are used to predict delayed graft function (DGF) and posttransplant graft survival. Preimplantation biopsies obtained serve a similar role in evaluating kidneys especially if they meet expanded criteria. The reliability of available data is greater if there is a correlation among various forms of assessment. In this study we attempted to study serial pump parameters that might correlate with abnormal findings in preimplantation biopsies and subsequently in outcomes after transplantation. METHODS: Two hundred sixty-eight kidneys were assessed for changes in pump pressures in mm Hg, flow in mL/min, resistance in mm Hg/mL/min, and temperature in °C at 15-minute intervals. Allografts were separated into two groups on the basis of pathology; group 1 showed abnormal (AH) and group 2 normal histology (NH). AH was defined by the presence of glomerulosclerosis in ≥10% of sampled glomeruli or arteriosclerosis affecting at least 10% of the arterial lumens of sampled intrarenal arteries. We assessed discordance between frozen and permanent sections. Measured clinical outcomes included DGF, 1-year graft survival, 1-year serum creatinine and estimated glomerular filtration rate (eGFR). Statistical analysis was performed using a paired Student t test and chi-square analysis. RESULTS: Compared to NH kidneys, those with AH showed uniformly significant lower flow rates and higher resistances during the entire perfusion. Graft pathology did not predict DGF (70% versus 60%, P = .45). However, 1-year graft survival (96.2% versus 80%, P = .07) and eGFR (58 versus 48 mL/min, P = .19) were lower among kidneys with AH, though these matrics did not reach significance. CONCLUSION: Preimplantation biopsy findings correlated with flow and resistance to perfusion. If a discrepancy is evident upon evaluation of a donor kidney, a repeat biopsy is prudent prior to discarding or using the organ.

Effect of increased pressure during pulsatile pump perfusion of deceased donor kidneys in transplantation.

INTRODUCTION: Pulsatile pump perfusion of potential kidneys for transplantation is known to decrease the rate of delayed graft function (DGF) and improve their 1-year survival. Flow and resistance parameters are often used to determine the suitability of kidneys for transplantation. Kidneys with low flow rates are often subjected to higher pressures to improve flow. This study evaluated the effect of higher pump pressures on posttransplant renal function. METHODS: We performed a retrospective analysis of 73 deceased donor kidneys preserved using pump perfusion (LifePort) at our center between May 2006 and September 2009. We calculated the mean pump pressure (MP) for the duration of perfusion of each kidney, using systolic pressure (SP) and diastolic pressure (DP) readings with the following formula: (MP = DP + 1/3 (SP - DP). The kidneys were divided into a low (LP; n = 49) and a high-pressure group (HP; n = 24) based on a MP cutoff value of 23 mm Hg. The two groups were then compared for differences in perfusion dynamics and primary endpoints including DGF and 1-year graft survival. Statistical analysis was performed using paired Student t test and chi-square analysis. RESULTS: The two groups were comparable for donor age, extended criteria, sensitization, and cold ischemic times. They differed significantly in higher initial (0.65 ± 0.4 versus 0.4 ± 0.2, P = .01), average (0.25 ± 0.08 versus 0.18 ± 0.06, P = .0006), and terminal resistance (0.21 ± 0.07 versus 0.17 ± 0.06, P = .008) of HP versus LP kidneys. Flow rates were comparable between the two groups. DGF was higher in HP kidneys (75% versus 40%, P = .006) with similar 1-year graft survival (87.5% versus 89%, P = .7). CONCLUSIONS: Perfusate flow through a kidney can be improved by increasing pressure settings to overcome elevated resistance. This maneuver was not associated with a lower rate of DGF after transplantation. One-year graft survival remained unaffected.

Prognostic utility of hypothermic machine perfusion in deceased donor renal transplantation.

UNLABELLED: Pulsatile pump perfusion of kidney transplants is known to decrease delayed graft function (DGF) and improve 1 year graft survival when compared to static cold preservation. Kidneys with better flow and resistance parameters on perfusion are likely to have a better post transplant function. These parameters are commonly used to evaluate kidneys being considered for transplantation. This study assesses the time frame for a kidney within which it reaches optimal perfusion parameters. All kidneys pumped between 5/2006 and 9/2009 on a Lifeport© kidney transporter at our local organ procurement agency were studied. 190 kidneys were evaluated and then divided into two groups based on whether terminal flows increased or declined after prolonged perfusion. All kidneys were assessed for changes in flow (F), resistance (R) and temperature at 15 minute intervals. Discards, DGF and one year graft survival were noted. The Student paired t test and Chi-square analysis were used to compare data. A multiple logistic regression analysis was performed to study independent predictors of DGF on pump perfusion. RESULTS: For all kidneys, the mean initial flow was 59 ± 35 mL/min which improved to an average flow of 128 ± 38 mL/min with continued perfusion. The maximal flow and terminal flows were 148 ± 51 and 135 ± 38 mL/min respectively. The flows at 2, 4, and 6 hours was 125 ± 41, 128 ± 42 and 130 ± 39 mL/min respectively. Kidneys that improved on continued perfusion had a significantly lower discard rate (20 vs 34% p < 0.05), but a higher incidence of DGF (64 vs 39%, P < .05). One year graft loss (death censored) was comparable in the two groups. (4/42 vs. 3/33, P = .94). Resistance at 2, 4, and 6 hours was predictive of DGF, as was donor anoxia and cerebrovascular accident (CVA) as the cause of death. CONCLUSIONS: Kidneys on pulsatile pump perfusion tend to show improved flows and decreased resistance over time. The average flow for a kidney is reached by 2 hours. Those kidneys that start with lower flow rates that improve after 2 hours with continued perfusion are less likely to be discarded but are still associated with a greater incidence of delayed graft function. Resistance at 2 hours predicts DGF while initial resistance predicts one year graft survival.

The role of ureteral stents for all ureteroneocystostomies in kidney transplants.

BACKGROUND: Despite significant advancements in renal transplantation, certain basic surgical practices such as the routine use of ureteral stents (US) remain controversial. A recent met-analysis of ureteral stenting concluded that the routine use of US resulted in improved outcomes. In contrast, the indiscriminate use of US can lead to adverse complications. OBJECTIVE: To better define this question, we reviewed our single center experience in which US were placed selectively. METHODS: 301 patients were eligible to be enrolled. 55 living donor and 246 deceased-donor charts were analyzed for donor and recipient clinical characteristics, immunosuppressive therapy and outcomes. RESULTS: 28 US were placed for either small bladder capacity (n=7), unhealthy appearing bladder tissue (n=8) or for an uncertain vascular supply to the ureter (n=13). Patients with US did not develop urinary leaks, 8 (28%) developed complications including obstruction, encrustation, and urinary tract infections. 12 (4.3%) non-stented patients developed a clinically significant urinary leak. Risk factors for urinary leaks included dual and en-bloc pediatric donor kidney transplants, extended criteria donors and the use of single U stitch technique for ureteral anastomoses. CONCLUSION: Our results demonstrate that the majority of patients can be successfully transplanted without the routine use of US. Selective use of US should be reserved for high-risk situations.

Low-dose rabbit antithymocyte globulin versus basiliximab induction therapy in low-risk renal transplant recipients: 8-year follow-up.

Antibody induction is effective in preventing acute rejection, but its effects on long-term renal allograft function and survival remain controversial. Moreover, given the risks of antibody induction, full-dose lymphocyte-depleting therapy for low-risk patients is usually avoided. However, the benefit and risks associated with low-dose (Lo) rabbit antithymocyte globulin (rATG; 3-5 mg/kg total) induction in a low-risk population have not been explored. We now report the long-term outcomes in this patient population. We defined low risk as white, panel-reactive antibody<30%, and non-Donor with Cardiac Death (DCD) recipients. We compared the risk of acute rejection and graft survival for both living donor (LD) and deceased donor (DD) recipients. The average dose of rATG was 3.1±1.2 mg/kg. Forty DD recipients received basiliximab (BSX) and 145 patients were induced with Lo rATG. Twenty LD recipients received BSX and 64 received Lo rATG. The groups did not differ in demographics, donor characteristics, and maintenance immunosuppression. At 8 years, patient survival was higher for LD patients compared to DD recipients (91% vs 45%, P=.004). In recipients of LD kidneys, 8-year patient survivals were not different comparing Lo rATG and BSX groups (92% vs 91%, respectively, P=.55). In LD, 8-year graft survival was excellent irrespective of induction (Lo rATG 100% vs BSX 98%); however, Lo rATG was associated with a lower rate of acute rejection (7.8% vs 35% BSX, P<.01) and better mean serum creatinine at 3 and 5 years (1.2 vs 1.5, P=.02 and 1.18 vs 1.54, P=.04, respectively). For DD, Lo rATG was associated with a better long-term graft survival (86% vs 76% BSX, P=.02). Viral infections and cancer rates were similar for Lo rATG and BSX. Thus, we conclude that Lo rATG induction may add long-term benefit in low-risk patients compared to anti-interleukin-2 receptor therapy without incurring additional risks of infectious or malignant diseases.

Low-dose rabbit antithymocyte globulin induction therapy results in prolonged selective lymphocyte depletion irrespective of maintenance immunosuppression.

Rabbit antithymocyte globulin therapy (rATG) is a potent lymphocyte-depleting agent commonly used following renal transplantation to reduce the risk of acute rejection. Standard doses (7-10 mg/kg) of rATG result in profound lymphopenia and predispose patients to infection and malignancy. The effects of lower doses of rATG (LoD-rATG, 3-5 mg/kg) on peripheral blood lymphocytes (PBL) are as yet unknown. In this prospective clinical trial, PBL subsets were characterized by flow cytometry over 12 months following LoD-rATG therapy. All patients were initially treated with standard doses of tacrolimus, mycophenolic acid, and prednisone. At 3 months, patients were randomized to either lower doses of tacrolimus or sirolimus to examine the effects of maintenance immunosuppression on PBL reemergence. LoD-rATG therapy resulted in prolonged suppression of CD19+ B cells, total CD3+ T cells, as well as naïve and memory CD4+ T cell and CD4/CD25/Foxp3+ T-regulatory subsets irrespective of chronic immunosuppressive therapy. Selective depletion was only noted in the CD4CD45RA+ naïve T-cell subset resulting in an altered memory/naïve CD4+ ratio. LoD-rATG failed to deplete CD8+ T cells, which increased their relative contribution to the total CD3+ pool. All other lymphocyte subsets maintained near normal proportions. Thus, LoD-rATG therapy may lessen the adverse effects of full dose rATG while maintaining overall efficacy.

Low-dose thymoglobulin use in elderly renal transplant recipients is safe and effective induction therapy.

Current immunosuppressive therapies and protocols have led to significant improvements in early patient and graft survival rates following kidney transplantation. Whether induction therapies such as rabbit anti-thymocyte globulin (rATG) contribute to these improved results remains controversial. Full-dose rATG induction therapy (7-10 mg/kg) has been associated with increased morbidity, which may be especially true in a high-risk population such as the elderly. Therefore, we studied the efficacy and tolerability of a low-dose rATG induction strategy in 45 older recipients (>65 years) compared to 45 concurrently transplanted younger patients (<65 years). Both groups received a similar low-dose of rATG induction therapy (older: 2.96±1.29 vs younger: 3.2±2.11 mg/kg). All patients were maintained on a calcineurin inhibitor, mycophenolic acid, and low-dose prednisone (5 mg/d). To date, none of the older patients experienced acute rejection, whereas one younger patient had an acute rejection episode. Initial hospital stays were equal (older: 7.8±3.2 vs younger: 7.5±4.4 days, P=.35). Within the first 6 months, nine older patients required rehospitalization compared to 15 younger patients (P=.15). Bacterial infections in older and younger recipients were equal including wound (4 vs 0), urine (20 vs 15), lung (1 vs 1), and skin (0 vs 2), respectively. There were two BK viral infections in older patients, whereas there were three viral infections, two cytomegalovirus cases, and one Herpes zoster case in younger patients. Calculated 6-month glomerular filtration rate was equal in both groups (older: 55.7±18.5 vs younger: 52.7±18.5 mL/min). Three-year patient and graft survival rates were equivalent for older and younger patients (86.6% vs 97.6%, respectively). In conclusion, low-dose rATG induction therapy is safe and effective in patients older than 65. When compared to younger patients, low-dose rATG leads to equivalent graft survival and function without incurring excess morbidity in the older population.

Obesity in renal transplantation: the role of induction therapy on long-term outcomes.

Obesity is a burgeoning problem among renal transplant recipients given its association with increased morbidity, graft loss, and mortality. The long-term influence of different induction therapies in obese compared to nonobese patients is uncertain. We examined the long-term effect of low-dose rabbit antithymocyte globulin (rATG; 3-5 mg/kg) induction therapy compared to two doses of 20 mg basiliximab (BSX) in nonobese and obese renal transplant patients. The medical records of all adult (>18 years) recipients of kidney transplants between June 2001 and June 2009 in our center were reviewed. Patients whose body mass index (BMI) was greater than 30 were considered to be obese. The average dose of rATG was 3.2±1.6 mg/kg. A total of 475 patients were included. In the nonobese group with a BMI less than 30, 68 received BSX and 247, rATG. In the obese group, 27 patients were given BSX and 133 were given rATG. Mean follow-up was 1523 days. These four groups were similar in baseline characteristics including: donor and recipient age, percent diabetes, living donors, panel-reactive antibodies>35, HLA mismatch, race, gender, and maintenance immunosuppression. Serum creatinine levels at 3 months and 1, 5, and 7 years were not statistically different between groups. Compared to BSX induction therapy, rATG was associated with better graft survival at 47.4±10 months in obese (63.6% vs 90.3%, P<.05, respectively) as well as nonobese patients (68.2% vs 88.7%, P<.05, respectively). Rejections were numerically lower in rATG-treated obese patients, which reached statistical significance in nonobese patients. Wound and viral infections were not statistically different between rATG and BSX groups. Therefore, low-dose rATG is associated with a better long-term graft survival rate in obese patients without incurring an increased risk of infectious complications. When rATG was used in obese and nonobese patients, there was no difference in graft and patient survival.

Mycophenolic acid dose reductions result in poor long-term renal allograft survival: comparison between mycophenolate sodium and mycophenolate mofetil.

Mycophenolate acid (MPA) therapy is associated with a decrease in acute rejection rates and excellent renal allograft survival. Unfortunately, mycophenolate mofetil (MMF) is associated with significant adverse effects (AE), which, in many cases, preclude full-dose therapy. Previously, lower MMF drug exposure was significantly associated with a greater risk of rejection. Patients who had a ≥50% dose reduction of MMF experienced a lower graft survival compared to those who tolerated full-dose MMF. Mycophenolate sodium (MPS) was designed to lessen MPA-associated AE. In this retrospective study, we studied the tolerability and long-term outcomes in renal transplant recipients (RTR) treated with MPS versus MMF. Four hundred forty-nine RTRs who received MPS or MMF for more than 3 months were classified into three groups: group 1: MMF-treated; group 2: MPS-treated; and group 3; patients who converted from MMF to MPS due to AE. Donor and recipient demographics as well as induction and maintenance immunosuppressive therapies were similar in all groups. Patient survival was not different in all groups. However, long-term graft survival was lower in patients whose dose of either MPS or MMF was reduced by ≥50%. Moreover, a ≥50% MPA dose reduction was associated with a higher rate of rejection compared to full dose (38% vs 21%, respectively, P<.01). Compared to patients treated initially with MMF, fewer MPS-treated recipients required dose reductions (65% vs 42%, respectively, P<.001). Furthermore, 38% of patients in group 3 tolerated full-dose MPS despite previous intolerance to MMF. Finally, the long-term graft survival was best in MPS-treated RTR and worst in those who converted from MMF to MPS due to AE. We conclude that MPS is better tolerated than MMF, which may explain the superior graft outcome in RTR who were treated with MPS from the onset.

Dual kidney transplants from very old or very young donors: long-term outcomes and complications.

The disparity between donors and the demand for organ transplants grows steadily. Annually, 4700 patients die on the kidney transplant waiting list in the United States. To increase utilization of deceased donor organs, we expanded our acceptable criteria to include very old (VO) or very young (VY) donors. We transplanted both such kidneys (dual transplant) into a single recipient and evaluated the long-term outcomes and complications. From July 2001 to December 2005, 16 patients (mean age 68, range 60-78) received dual kidneys from VO (mean age 72, range 60-79) donors and 6 patients (mean age 47, range 27-72) were transplanted from VY (mean age 17 months, range 2-36) donors. Seventy-four percent of these kidneys were imported after rejection by their local center due to low glomerular filtration rate (GFR) and extreme age. One- and 5-year patient survival rates were 100% and 88%, respectively. Death-censored 1- and 5-year graft survival rates for recipient of VO kidneys were 95% and 93%, and 66% and 50% for recipients of VY kidneys, respectively. Five-year graft survival rate for recipients of VO donor kidneys was 93% and was equal to the survival of standard deceased donor (SCD) kidney transplants (87%). The 5-year survival of dual transplants from VO donors was higher than expanded criteria deceased donor (ECD; P=.05). Over a mean follow-up of 66±28 months, rejection rates were 10%, not statistically different than other groups. Of 22 dual transplants, four patients experienced urinary tract infections; three developed incisional subcutaneous seromas, and there were more urinary leaks compared to SCD (13.6% vs 2%, P=.002). The average 1- and 5-year estimated GFR (Cockcroft-Gault) was 57.4 and 54.6 mL/min, respectively. When properly placed in a single patient, such marginal organs are a valuable resource that offer comparable outcomes to SCD transplants and superior outcomes to ECD organs.

African-American women and older patients are at risk for a greater decline in renal function following living kidney donation.

Living donor kidney transplantation offers many advantages to the recipients. Longer allograft survival, fewer postoperative complications, and better renal function are some of the benefits of receiving living donor kidneys compared to deceased donor organs. However, the consequences to the donor in terms of renal function are not as well defined. Moreover, it is not clear whether all donors share an equal risk to their renal function following donation regardless to ethnicity, sex, and age. In this retrospective study, we identify and compare the reduction in estimated glomerular filtration rate (eGFR) among ethnic groups, women, and older donors prior to, immediately after, and 1 year postdonation. We compared the percentage decline in renal function among various ages and other demographic groups using individual patients as their own controls. Medical records of 103 consecutive living donors (mean age 40.3±9.6 years) were reviewed. On average, donors experienced a 34.7% fall in eGFR at 273 days posttransplant. A greater decline was noticed in the African-American (AA) group (41% compared to 34% in white patients, P=.03). The majority of the decline in the AA eGFR was among women, in whom the fall was 46% compared to AA men at 31%. White women had a 34% fall in eGFR (P=.02). The percentage decline in eGFR was not different among the different age groups; however, donors older than 50 years had a postdonation eGFR of 55.1 mL/min versus 60.9 mL/min in those less than 50 years old (P=.03), reflecting lower eGFR predonation (older 84.7 mL/min vs younger 95.2 mL/min, P=.02). The percent decline in eGFR did not change with time after donation (0-1 month 37%, 1-12 months 34%, >1 year 30%). eGFR declines abruptly post-kidney donation in all patients but remains stable and improves afterwards. AA women and older donors are more prone to reduction in eGFR post-kidney donations.

Conversion to low-dose tacrolimus or rapamycin 3 months after kidney transplantation: a prospective, protocol biopsy-guided study.

Long-term survival of kidney allografts is primarily limited by a progressive decline in function characterized by the presence of interstitial fibrosis (IF) and tubular atrophy (TA) on biopsy. Since chronic calcineurin-inhibitor (CNI) drug toxicity has been implicated as a significant cause of IF/TA, a major effort in transplantation has been to decrease or eliminate CNI therapy. We now report the clinical and histological consequences of converting renal transplant recipients at 3 months to either very low levels of tacrolimus (TAC; 4-6 ng/mL) or sirolimus (SRL; 6-10 ng/mL) therapy. Fifty-eight enrollees in this prospective randomized trial received low-dose (2.9±0.6 mg/kg) rabbit antithymocyte globulin induction followed by standard doses of TAC (10-15 ng/mL), mycophenolic acid, and low-dose steroids for 3 months. Protocol biopsies were performed at implantation and 3 and 12 months. Six patients had evidence of either borderline changes (n=5) or grade 1A rejection (n=1) on the 3-month protocol biopsy and were not randomized. Only one patient had clinically evident rejection that occurred after randomization to SRL. One patient in each group had borderline changes at 12 months. Renal function (estimated glomerular filtration rate) was equivalent in both groups at 12 months (TAC 74±15 vs SRL 66±18 mL/min, P=.22). Chronic allograft damage index scores at 1 year were similar in both groups (TAC 2.8±2.4 vs SRL 2.0±2.7, P=.71). The percentage of patients with IF/TA scores greater than 2 at 1 year was low in both groups (TAC 12% vs SRL 9%, P=.78). Therefore, in a low-risk population defined as having a normal 3-month protocol biopsy, TAC levels can be successfully decreased to very low concentrations. One-year graft function and histology were equally well maintained with either low-dose TAC or SRL immunosuppression.

The role of antibiotic prophylaxis in the new era of immunosuppression.

Despite significant improvements in renal transplantation (RTX), certain basic issues remain unresolved such as the routine use of perioperative antibiotic prophylaxis (PAP). To address the need for PAP, we retrospectively evaluated the clinical course of 349 consecutive RTX patients who did not receive any PAP except for Bactrim. Of the 349 transplant recipients, 77% received induction therapy with low-dose rabbit antithymocyte globulin (rATG) and the others were treated with basiliximab. All patients received triple immunosuppression with tacrolimus, mycophenolic acid, and prednisone. Seven patients (2%) developed wound infections. Wound infections were more common in obese and older patients. All wound infections were superficial and responded well to wound drainage and outpatient antibiotic therapy. Six patients (1.7%) experienced a urinary tract infection (UTI) within the first postoperative month. UTIs were more common in the patient with ureteral stent compared to nonstented patients (11.4% vs 0.3%, P<.001). No patient or graft was lost due to perioperative bacterial infections (PBI). Our study shows that despite many predisposing factors, PBI are rare following RTX even in the absence of PAP. Therefore, in order to avoid emergence of multiantibiotic-resistant pathogens, excessive costs, and antibiotic-related adverse events, we suggest that PAP should be used only in selected circumstances such as in recipients older than 60 or when the body mass index is greater than 35.

Sirolimus-induced isometric tubular vacuolization: a new sirolimus histopathologic manifestation.

The clinical and pathological experience with sirolimus is limited at this time. In this study, we report severe isometric vacuolization of the proximal tubules after sirolimus therapy in two kidney transplant patients. Patient 1 is a hepatitis C virus-positive, 30-year-old African American man who had end-stage renal disease (ESRD) of unknown etiology. Patient 2 is a 62-year-old white woman with ESRD due to unknown etiology. Both patients were initially placed on tacrolimus, mycophenolic acid, and prednisone immunosuppressive therapy. These patients were switched to sirolimus at 1 and 5 month posttransplant, respectively, due to the development of new-onset hyperglycemia and an elevated serum creatinine. Both patients presented with acute renal failure and high sirolimus levels at 5 years (patient 1) and 10 months posttransplant (patient 2). Biopsies of their kidney transplants showed widespread isometric tubular cytoplasmic vacuolization and severe arterial hyalinosis. Acute renal insufficiency improved after sirolimus dose reduction. In this case report, we introduce a new morphological appearance after sirolimus therapy of isometric cytoplasmic vacuolization of the renal tubules and severe arterial hyalinosis, similar to that seen in calcineurin inhibitor induced tubular toxicity.