Retropubic bulbourethral sling in incontinence post-exstrophy repair: 2-year minimal follow up of a salvage procedure.

AIMS: Post-exstrophy incontinence is a challenge because continence is difficult to achieve and more difficult to maintain. Feasibility and outcomes of a bulbourethral sling to treat post-exstrophy incontinence is shown in this report. METHODS: A retropubic bulbourethral sling was applied to male patients with incontinence post-exstrophy-epispadius repair. The study included children with total (continuous) incontinence who underwent multiple previous anti-incontinence procedures, ranging from bladder neck injection to bladder neck reconstruction. Preoperative assessment includes urinalysis, renal US, VCUG, 1-hr pad test and urodynamics. The bulbourethral sling applied is made of polypropylene and is suspended by 4 pairs of nylon sutures, to support the bulbar urethra within its covering muscles with the sutures tied on the rectus muscles. Continence was evaluated as well as adverse events. RESULTS: Seventeen children, (median age 8.7 years) completed 24-month of follow up. All had CPRE. Five children (29.27%) were dry. Four micturated through the urethra and one by catheterizing his cutaneous stoma every 3-4 hr. In none, PVR exceeded 10% of expected capacity. Four children underwent re-tightening 1-4 weeks after removal of urethral catheter. Perineal wound dehiscence occurred in one, perineal/suprapubic pain in seven and epididymo-orchitis in one child. CONCLUSION: The current technique is promising for difficult cases of incontinence after CPRE. It is safe, as no serious adverse events occurred during follow up period. It is economic and re-tightening is easy to perform. Neurourol. Urodynam. 35:497-502, 2016. © 2015 Wiley Periodicals, Inc.

Current status of stem cell therapy for type 1 diabetes: a critique and a prospective consideration.

Over the past decade, there had been progress in the development of cell therapy for insulin-dependent diabetes. Nevertheless, important hurdles that need to be overcome still remain. Protocols for the differentiation of pluripotent stem cells into pancreatic progenitors or fully differentiated ß-cells have been developed. The resulting insulin-producing cells can control chemically induced diabetes in rodents and were the subject of several clinical trials. However, these cells are immunogenic and possibly teratogenic for their transplantation, and an immunoisolation device and/or immunosuppression is needed. A growing number of studies have utilized genetic manipulations to produce immune evasive cells. Evidence must be provided that in addition to the expected benefit, gene manipulations should not lead to any unforeseen complications. Mesenchymal stem/stromal cells (MSCs) can provide a viable alternative. MSCs are widely available from many tissues. They can form insulin-producing cells by directed differentiation. Experimentally, evidence has shown that the transplantation of allogenic insulin-producing cells derived from MSCs is associated with a muted allogeneic response that does not interfere with their functionality. This can be explained by the immunomodulatory functions of the MSC subpopulation that did not differentiate into insulin-producing cells. Recently, exosomes derived from naive MSCs have been used in the experimental domain to treat diabetes in rodents with varying degrees of success. Several mechanisms for their beneficial functions were proposed including a reduction in insulin resistance, the promotion of autophagy, and an increase in the T regulatory population. However, euglycemia was not achieved in any of these experiments. We suggest that exosomes derived from ß-cells or insulin-producing cells (educated) can provide a better therapeutic effect than those derived from undifferentiated cells.

Modulation of naïve mesenchymal stromal cells by extracellular vesicles derived from insulin-producing cells: an in vitro study.

This study was to determine whether extracellular vesicles (EVs) derived from insulin-producing cells (IPCs) can modulate naïve mesenchymal stromal cells (MSCs) to become insulin-secreting. MSCs were isolated from human adipose tissue. The cells were then differentiated to generate IPCs by achemical-based induction protocol. EVs were retrieved from the conditioned media of undifferentiated (naïve) MSCs (uneducated EVs) and from that of MSC-derived IPCs (educated EVs) by sequential ultracentrifugation. The obtained EVs were co-cultured with naïve MSCs.The cocultured cells were evaluated by immunofluorescence, flow cytometry, C-peptide nanogold silver-enhanced immunostaining, relative gene expression and their response to a glucose challenge.Immunostaining for naïve MSCs cocultured with educated EVs was positive for insulin, C-peptide, and GAD65. By flow cytometry, the median percentages of insulin-andC-peptide-positive cells were 16.1% and 14.2% respectively. C-peptide nanogoldimmunostaining providedevidence for the intrinsic synthesis of C-peptide. These cells released increasing amounts of insulin and C-peptide in response to increasing glucose concentrations. Gene expression of relevant pancreatic endocrine genes, except for insulin, was modest. In contrast, the results of naïve MSCs co-cultured with uneducated exosomes were negative for insulin, C-peptide, and GAD65. These findings suggest that this approach may overcome the limitations of cell therapy.

Evaluation of Antithymocyte Globulin Efficacy in Reversing Refractory Graft Rejection Using Retrospective Event-Based Sequential Graft Biopsy Analysis in Living Related Donor Renal Transplant.

OBJECTIVES: The main risk factor for poor graft outcomes is refractory acute rejection and its consequences. In this study, we compared the efficacy of antithymocyte globulins versus other antirejection strategies in reversing refractory acute graft rejection after living donor renal transplant. MATERIALS AND METHODS: We retrospectively reviewed the records of 745 patients who received living-donor kidney transplants and experienced acute rejection episodes at Mansoura Urology and Nephrology Center in Egypt over the past 20 years. Based on the type of antirejection medication that they received, we divided patients into 2 groups, with 80 patients in the antithymocyte globulin group and 665 patients who had other antirejection strategies. By using event-based sequential graft biopsy histopathology analysis, we compared the efficacy of antithymocyte globulins in reversing refractory rejection in terms of graft and patient complications and survival. RESULTS: Patient survival was comparable in both groups; however, graft survival was better in the antithymocyte globulin group than in the other group; in addition, event-based sequential graft biopsies revealed a lower incidence of acute and chronic rejection episodes after treatment of severe acute rejection in the antithymocyte globulin group compared with the other group. Incidence of posttreatment complications, particularly infection and malignancy, was comparable in both groups. CONCLUSIONS: Our retrospective analysis of event-based sequential graft biopsy allowed us to track graft rejection resolution or worsening. Antithymocyte globulins are highly effective in reversing acute graft rejection when compared with other approaches, with no increased risk of infection or malignancy.

Toward a standardized system for reporting surgical outcome of pediatric and adolescent live donor renal allotransplantation.

PURPOSE: There is a lack of a standardized reporting methodology for surgical complications of pediatric renal transplantation. We applied Martin criteria and the modified Clavien-Dindo classification in pediatric renal transplantation. MATERIALS AND METHODS: We retrospectively reviewed the charts of 447 patients 20 years or younger who underwent renal transplantation between March 1976 and January 2011. Martin criteria were fulfilled and complications were graded according to the modified Clavien-Dindo classification. For early complications grades I and II were considered low grade and III to V high grade. A similar grading system was adopted for late complications. RESULTS: A total of 84 early complications (18.5%) occurred in 77 transplant recipients (17%). Of grade I complications 37 (8.1%) were asymptomatic lymphoceles. Grade II complications were observed in 2 patients (0.4%). Grade IIIa complications included aspiration of hematoma (1 case), percutaneous nephrostomy fixed for ureteral obstruction (3), percutaneous tube drain for symptomatic lymphoceles (7) and antegrade ureteral stenting for ureteral leakage (6). Grade IIIb complications included exploration for wound dehiscence (1 case), revision of ureterovesical anastomosis (8), marsupialization of lymphoceles (4), hemorrhage (3) and vascular thrombotic accidents (6). Graft nephrectomy (grade IVa) complications occurred in 2 transplant recipients. Among 4 mortalities (grade V) only 1 patient died due to surgical complications. On multivariate analysis delayed graft function was the only predicator of high grade surgical complications (p = 0.005). High grade surgical complications affected recipient but not graft survival. CONCLUSIONS: Using a standardized, high quality reporting methodology is feasible in pediatric renal transplantation. However, consensus should be sought regarding medical complications and a grading system should be developed for reporting of late complications.

Transplantation of insulin-producing cells derived from human mesenchymal stromal/stem cells into diabetic humanized mice.

BACKGROUND: The purpose of this study was to investigate allogenic immune responses following the transplantation of insulin-producing cells (IPCs) differentiated from human adipose tissue-derived stem cells (hAT-MSCs) into humanized mice. METHODS: hAT-MSCs were isolated from liposuction aspirates obtained from HLA-A2-negative healthy donors. These cells were expanded and differentiated into IPCs. HLA-A2-positive humanized mice (NOG-EXL) were divided into 4 groups: diabetic mice transplanted with IPCs, diabetic but nontransplanted mice, nondiabetic mice transplanted with IPCs and normal untreated mice. Three million differentiated cells were transplanted under the renal capsule. Animals were followed-up to determine their weight, glucose levels (2-h postprandial), and human and mouse insulin levels. The mice were euthanized 6-8 weeks posttransplant. The kidneys were explanted for immunohistochemical studies. Blood, spleen and bone marrow samples were obtained to determine the proportion of immune cell subsets (CD4+, CD8+, CD16+, CD19+ and CD69+), and the expression levels of HLA-ABC and HLA-DR. RESULTS: Following STZ induction, blood glucose levels increased sharply and were then normalized within 2 weeks after cell transplantation. In these animals, human insulin levels were measurable while mouse insulin levels were negligible throughout the observation period. Immunostaining of cell-bearing kidneys revealed sparse CD45+ cells. Immunolabeling and flow cytometry of blood, bone marrow and splenic samples obtained from the 3 groups of animals did not reveal a significant difference in the proportions of immune cell subsets or in the expression levels of HLA-ABC and HLA-DR. CONCLUSION: Transplantation of IPCs derived from allogenic hAT-MSCs into humanized mice was followed by a muted allogenic immune response that did not interfere with the functionality of the engrafted cells. Our findings suggest that such allogenic cells could offer an opportunity for cell therapy for insulin-dependent diabetes without immunosuppression, encapsulation or gene manipulations.

Catheterizable serous lined urinary outlet in children and adolescents: a choice when other treatments fail.

PURPOSE: We evaluated the functional outcome of continent catheterizable outlet using the serous lined extramural tunnel technique as a continence mechanism in children and adolescents. MATERIALS AND METHODS: We retrospectively studied all patients who underwent continent catheterizable stoma using the serous lined extramural technique between May 1993 and March 2008. Patient records were reviewed for age, sex, indication for surgery, surgical details and postoperative course. All patients were evaluated for continence with emphasis on frequency of clean intermittent catheterization. Urodynamic evaluation was done for patients with leaking stoma. Stoma related complications were also recorded. RESULTS: A total of 37 boys and 23 girls 3 to 18 years old underwent continent catheterizable stoma using the serous lined extramural technique. Total bladder substitution was performed in 13 patients using continent ileal W-shaped reservoir, and 47 patients underwent augmentation ileocystoplasty mounted with serous lined outlet. The outlet channel was appendix in 39 patients (65%), tapered ileal segment in 13 (21.5%) and Monti ileal tube in 8 (13.5%). After a median followup of 43 months (range 10 to 180) 55 patients (91.6%) achieved continence, with catheterization frequency of 3 to 5 times during the daytime and 1 to 2 times at night. Stoma related complications were leaking stoma in 5 patients (8.4%), stomal stenosis in 6 (10%), parastomal hernia in 2 (3.3%) and reservoir stones in 8 (13.3%). Reoperation rate was 18.3% (11 patients). CONCLUSIONS: The serous lined continent outlet seems to be a durable and efficient technique for treating children with incontinence, with an acceptable complication rate.

Impact of posterior urethral valves on pediatric renal transplantation: a single-center comparative study of 297 cases.

OBJECTIVE: This is a retrospective long-term evaluation of the renal allografts and bladder functions in pediatric recipients who had posterior urethral valves (PUV). PATIENTS AND METHODS: Between March 1976 and February 2009, 2033 live-donor renal transplantations were carried out in our center. Of these, 297 (14.2%) were in the pediatric age (≤18 yr). The pediatric recipients included 20 (6.7%) boys who developed end-stage renal disease as a late complication of PUV and recognized as group I while the remaining 277 pediatric recipients were defined as group II. Demographic characteristics, post-transplant complications and graft function were compared among both groups. Patient and graft survivals of both groups were also estimated. Moreover, the bladder function of the study group was evaluated by urodynamic studies. RESULTS: Patients with PUV (group I) were significantly younger than group II. Although the overall rate of urological complications in both groups was essentially similar, the incidence of urinary fistulae and urinary tract infection were higher in group I. The mean (SD) follow up periods for group I and II were 4.7 (4.1) and 6.4 (4.8) yr, respectively. At last follow up the serum creatinine values were similar among patients of both groups. Moreover, there were no differences in graft or patient survival at five and 10 yr. Detrusor over-activity could be elicited in only one of group I patients. Schafer nomogram showed non-obstructed pattern in all cases. CONCLUSION: Good functional outcome could be achieved for patients with PUV if renal transplantation is necessary. Pre-transplant surgical procedures may be required such as nephroureterectomy, cytoplasty or injection of refluxing ureters. A robust anti-refluxing uretero-vesical anastomosis is important, and can be achieved by a Lich-Gregoir procedure.

From Mesenchymal Stromal/Stem Cells to Insulin-Producing Cells: Immunological Considerations.

Mesenchymal stem cell (MSC)-based therapy for type 1 diabetes mellitus (T1DM) has been the subject matter of many studies over the past few decades. The wide availability, negligible teratogenic risks and differentiation potential of MSCs promise a therapeutic alternative to traditional exogenous insulin injections or pancreatic transplantation. However, conflicting arguments have been reported regarding the immunological profile of MSCs. While some studies support their immune-privileged, immunomodulatory status and successful use in the treatment of several immune-mediated diseases, others maintain that allogeneic MSCs trigger immune responses, especially following differentiation or in vivo transplantation. In this review, the intricate mechanisms by which MSCs exert their immunomodulatory functions and the influencing variables are critically addressed. Furthermore, proposed avenues to enhance these effects, including cytokine pretreatment, coadministration of mTOR inhibitors, the use of Tregs and gene manipulation, are presented. As an alternative, the selection of high-benefit, low-risk donors based on HLA matching, PD-L1 expression and the absence of donor-specific antibodies (DSAs) are also discussed. Finally, the necessity for the transplantation of human MSC (hMSC)-derived insulin-producing cells (IPCs) into humanized mice is highlighted since this strategy may provide further insights into future clinical applications.

Association and prognostic impact of persistent left ventricular hypertrophy after live-donor kidney transplantation: a prospective study.

AIM: Persistent or de novo left ventricular hypertrophy (LVH) is a risk factor for cardiovascular diseases and congestive heart failure following renal transplantation (RT). Our aim was to determine the associations and impact of persistent LVH on RT outcome. MATERIALS AND METHODS: We included 72 live-donor renal allograft recipients with mean age of 28.5 years who had evidence of LVH at time of transplantation and had stable functioning grafts 1 year after transplantation. Cardiac status of all recipients was assessed before transplantation and at 1 year after transplantation by echocardiography. Recipients were subdivided into two groups according to persistence or regression of LVH 1 year after transplantation. The first group included 33 patients who had persistent LVH. The second group included 39 patients in whom LVH had regressed (control group). Both groups were closely followed for 10 years. RESULTS: Univariate analysis showed that persistent LVH 1 year after RT was significantly associated with high serum creatinine, higher incidence of medical infection, and acute and chronic rejection. Chronic rejection and infection were the only valid associations on multivariate logistic regression analysis. Patient and graft survival were significantly lower in the persistent LVH group (P = 0.012). CONCLUSION: Persistent LVH may be associated with higher incidence of medical infection and chronic rejection that worsen the prognosis for renal transplant recipients.

Cost-benefit of steroid avoidance in renal transplant patients: a prospective randomized study.

OBJECTIVE: Steroids have played a major role in renal transplantation for more than four decades. However, chronic use of steroids is associated with a lot of comorbidities. This study aimed to assess the cost-benefit of steroid-free immunosuppression regimen in a prospective randomized controlled study of live donor renal transplantation, which was lacking in the literature. MATERIAL AND METHODS: One-hundred patients were randomized to receive tacrolimus (Tac), mycophenolate mofetil (MMF), basiliximab (Simulect) induction and steroids only for 3 days (50 patients, study group) or Tac, MMF, Simulect induction and steroid maintenance (50 patients, control group). Median follow-up was 12 months. RESULTS: Both groups showed comparable graft and patient survival, rejection episodes and graft function. Post-transplant hypertension was detected in 4% of the steroid-free group and 24% of the steroid maintenance group (p = 0.0009), while post-transplant diabetes mellitus was detected in 4% and 16% of these two groups, respectively (p = 0.037). By the end of the first year, the cost of managing post-transplant morbidities was significantly higher in the steroid maintenance group, despite the comparable cost of immunosuppression. CONCLUSIONS: Among low immunological risk recipients of live donor renal transplants, steroid avoidance was feasible, safe and with less morbidity, using Simulect induction, and tacrolimus and MMF as maintenance immunosuppression. Steroid avoidance was associated with a lower total cost despite comparable immunosuppression cost, which was attributed to the lower cost of associated morbidities.

From Mesenchymal Stromal/Stem Cells to Insulin-Producing Cells: Progress and Challenges.

Mesenchymal stromal cells (MSCs) are an attractive option for cell therapy for type 1 diabetes mellitus (DM). These cells can be obtained from many sources, but bone marrow and adipose tissue are the most studied. MSCs have distinct advantages since they are nonteratogenic, nonimmunogenic and have immunomodulatory functions. Insulin-producing cells (IPCs) can be generated from MSCs by gene transfection, gene editing or directed differentiation. For directed differentiation, MSCs are usually cultured in a glucose-rich medium with various growth and activation factors. The resulting IPCs can control chemically-induced diabetes in immune-deficient mice. These findings are comparable to those obtained from pluripotent cells. PD-L1 and PD-L2 expression by MSCs is upregulated under inflammatory conditions. Immunomodulation occurs due to the interaction between these ligands and PD-1 receptors on T lymphocytes. If this function is maintained after differentiation, life-long immunosuppression or encapsulation could be avoided. In the clinical setting, two sites can be used for transplantation of IPCs: the subcutaneous tissue and the omentum. A 2-stage procedure is required for the former and a laparoscopic procedure for the latter. For either site, cells should be transplanted within a scaffold, preferably one from fibrin. Several questions remain unanswered. Will the transplanted cells be affected by the antibodies involved in the pathogenesis of type 1 DM? What is the functional longevity of these cells following their transplantation? These issues have to be addressed before clinical translation is attempted. Graphical Abstract Bone marrow MSCs are isolated from the long bone of SD rats. Then they are expanded and through directed differentiation insulin-producing cells are formed. The differentiated cells are loaded onto a collagen scaffold. If one-stage transplantation is planned, a drug delivery system must be incorporated to ensure immediate oxygenation, promote vascularization and provide some growth factors. Some mechanisms involved in the immunomodulatory function of MSCs. These are implemented either by cell to cell contact or by the release of soluble factors. Collectively, these pathways results in an increase in T-regulatory cells.

PRDX6 Promotes the Differentiation of Human Mesenchymal Stem (Stromal) Cells to Insulin-Producing Cells.

Mesenchymal stem cells (MSCs) can be differentiated in vitro to form insulin-producing cells (IPCs). However, the proportion of induced cells is modest. Extracts from injured pancreata of rodents promoted this differentiation, and three upregulated proteins were identified in these extracts. The aim of this study was to evaluate the potential benefits of adding these proteins to the differentiation medium alone or in combination. Our results indicate that the proportion of IPCs among the protein(s)-supplemented samples was significantly higher than that in the samples with no added proteins. The yield from samples supplemented with PRDX6 alone was 4-fold higher than that from samples without added protein. These findings were also supported by the results of fluorophotometry. Gene expression profiles revealed higher levels among protein-supplemented samples. Significantly higher levels of GGT, SST, Glut-2, and MafB expression were noted among PRDX6-treated samples. There was a stepwise increase in the release of insulin and c-peptide, as a function of increasing glucose concentrations, indicating that the differentiated cells were glucose sensitive and insulin responsive. PRDX6 exerts its beneficial effects as a result of its biological antioxidant properties. Considering its ease of use as a single protein, PRDX6 is now routinely used in our differentiation protocols.

Subcutaneous transplantation of bone marrow derived stem cells in macroencapsulation device for treating diabetic rats; clinically transplantable site.

BACKGROUND/AIM: Diabetes mellitus (DM) is a serious, chronic and epidemic disease. Its effective therapy with exogenous insulin places an overwhelming burden on the patient's lifestyle. Moreover, pancreatic islet transplantation is limited by the scarceness of donors and the need for chronic immunosuppression. Cell-based therapy is considered an alternative source of insulin-producing cells (IPCs); encapsulating such cellular grafts in immunoisolating devices would protect the graft from immune attack without the need for immunosuppression. Herein, we investigate the ability of TheraCyte capsule as an immunoisolating device to promote the maturation of differentiated rat bone marrow derived mesenchymal stem cells (BM-MSCs), transplanted subcutaneously to treat diabetic rats in comparison with intratesticular transplantation. MAIN METHODS: Rat BM-MSC were differentiated into IPCs, and either encapsulated in TheraCyte capsules for subcutaneous transplantation or transplanted intratesticular into diabetic rats. Serum insulin, C-peptide & blood glucose levels of transplanted animals were monitored. Retrieved cells were further characterized by immunofluorescence staining and gene expression analysis. KEY FINDINGS: Differentiated rat BM-MSC were able to produce insulin in vitro, ameliorate hyperglycemia in vivo and survive for 6 months post transplantation. Transplanted cells induced higher levels of insulin and C-peptide, lower levels of blood glucose in the cured animals of both experimental groups. Gene expression revealed a further in vivo maturation of the implanted cells. SIGNIFICANCE: These data suggest that TheraCyte encapsulation of allogeneic differentiated stem cells are capable of reversing hyperglycemia, which holds a great promise as a new cell based, clinically applicable therapies for diabetes.

Prediction of survival after radical cystectomy for invasive bladder carcinoma: risk group stratification, nomograms or artificial neural networks?

PURPOSE: We compared 3 predictive models for survival after radical cystectomy, risk group stratification, nomogram and artificial neural networks, in terms of their accuracy, performance and level of complexity. MATERIALS AND METHODS: Between 1996 and 2002, 1,133 patients were treated with single stage radical cystectomy as monotherapy for invasive bladder cancer. A randomly selected 776 cases (70%) were used as a reference series. The remaining 357 cases (test series) were used for external validation. Survival estimates were analyzed using univariate and then multivariate appraisal. The results of multivariate analysis were used for risk group stratification and construction of a nomogram, whereas all studied variables were entered directly into the artificial neural networks. RESULTS: Overall 5-year disease-free survival was 64.5% with no statistical difference between the reference and test series. Comparisons of the 3 predictive models revealed that artificial neural networks outperformed the other 2 models in terms of the value of the area under the receiver operator characteristic curve, sensitivity and specificity, as well as positive and negative predictive values. CONCLUSIONS: In this study artificial neural networks outperformed the risk group stratification model and nomogram construction in predicting patient 5-year survival probability, and in terms of sensitivity and specificity.

Does posttransplant anemia at 6 months affect long-term outcome of live-donor kidney transplantation? A single-center experience.

BACKGROUND/AIMS: Posttransplantation anemia (PTA) frequently occurs. We aimed to assess the prevalence of anemia at 6 months of transplantation in patients under different protocols of immunosuppression, and to determine the impact of anemia on long-term patient and graft survival. METHODS: We included 832 renal transplant recipients who were categorized at 6 months according to hemoglobin (Hb) level into two groups: the first group, with Hb >13 g/dl in males and >12 g/dl in females (group I, 385 cases); and the second group, with Hb <13 g/dl in males and <12 g/dl in females (group II, 447 cases). We compared the two groups regarding posttransplant complications as well as patient and graft survival. RESULTS: Although there was no significant difference between the two groups regarding acute rejection episodes, chronic allograft nephropathy was significantly higher in the anemic group. Other posttransplant medical complications were comparable in both groups. Graft survival was significantly higher in the nonanemic group. However, no difference in patient survival was detected. CONCLUSION: From this study, we can conclude that prevalence of PTA is high, especially in females and those receiving calcineurine inhibitors (CNI) and mycophenolate mofetil (MMF), and that it was associated with poorer graft outcome but with no effect on patient survival.

Safe conversion of mycophenolate mofetil to azathioprine in kidney transplant recipients with sirolimus-based immunosuppression.

AIM: Mycophenolate mofetil (MMF) is a powerful immunosuppressive drug with established efficacy and safety. The long-term use of MMF may bring increased risk of for infection and malignancy and also increased cost of transplantation. The search for minimization of immunosuppressive protocol has led to an open randomized clinical trial of conversion from MMF to azathioprine (AZA). METHODS: A total of 50 kidney allograft recipients treated with prednisone, sirolimus and MMF were randomized into two groups: converted (AZA group) and continuing (MMF group). The average duration of MMF therapy prior to conversion was 43 months in each group. Inclusion criteria included: patients with serum creatinine levels of less than 200 micromol/L; no past history of acute vascular rejection or recent acute rejection 6 months before randomization; and normal liver function tests. RESULTS: Baseline demographics were similar in the two groups. During the 12 month observation period, there were no acute rejection episodes in either group. There were no significant differences in overall patient or graft survival or function. AZA-treated patients had a lower incidence of gastrointestinal complications (P=0.03). Daily cost reduction in the AZA group was more than $US8.79/day per patient. CONCLUSION: In general, replacing MMF with AZA in stable renal transplant recipients is well tolerated and was cost effective with no increased risk of rejection. As the this study was on relatively small samples, larger and longer follow-up studies will be needed to confirm these expected advantages for the long-term outcome and to assess the long-term safety of this minimization of immunosuppressive therapy.

Osteonecrosis in kidney recipients: has hypocalcaemia a role?

In a previous study, the musculoskeletal affections among kidney recipients (KR) were reported, with 63 KR suffering from joint affections. We sought to determine the prevalence of osteonecrosis (ON) among those KR with joint affections, its distribution among the affected joints, and possible risk predictors. KR were subjected to biochemical, haematological, and hepatitis serology estimations. Radiographic and magnetic resonance imaging were performed. Relevant data were retrieved from Patient Information System. Fourteen KR were suffering from ON, with an incidence of 22.2% in KR with joint affections and 12.0% in the target population of KR. The femoral head was affected in 57.1% and the femoral condyles in 28.6%. Hypocalcaemia was observed in KR with ON. Whether hypocalcaemia is a causative or associative of ON yet remains to be decided in forthcoming studies.

Long-term efficacy and safety of a calcineurin inhibitor-free regimen in live-donor renal transplant recipients.

Calcineurin inhibitor (CNI) nephrotoxicity is a major concern after renal transplantation. To investigate the safety and efficacy of a CNI-free immunosuppressive regimen, 132 live-donor renal transplant recipients were included in a prospective, randomized controlled trial. All patients received induction therapy with basiliximab and steroids. The patients were randomized to a maintenance immunosuppression regimen that included steroids, sirolimus, and either low-dose tacrolimus or mycophenolate mofetil (MMF). Over a mean follow-up period of approximately 5 yr, patient and graft survival did not significantly differ between the two maintenance regimens. Patient survival was 93.8% and 98.5% in the tacrolimus/sirolimus and MMF/sirolimus groups, respectively, and graft survival was 83% and 88%, respectively. However, the MMF/sirolimus group had significantly better renal function, calculated by Cockcroft-Gault, from the second year post-transplant until the last follow-up. In addition, this group was less likely to require a change in their primary immunosuppression regimen than the tacrolimus/sirolimus group (20.8% versus 53.8%, P = 0.001). The safety profile was similar between groups. In summary, after long-term follow-up, a CNI-free maintenance regimen consisting of sirolimus, MMF, and steroids was both safe and efficacious among low to moderate immunologic risk renal transplant recipients.

Is matching for human leukocyte antigen-DR beneficial in pediatric kidney transplantation?

This Practice Point commentary discusses the findings and limitations of a report by Gritsch et al., in which the authors concluded that human leukocyte antigen (HLA)-DR-mismatched kidneys from deceased donors aged 35 years or less are suitable for use in pediatric patients. We highlight the issues to be considered before adopting such an allocation policy. Gritsch et al. reported that the 5-year survival rates of grafts with zero HLA-DR mismatches were identical to those of grafts that were completely mismatched for HLA-DR; however, the report did not provide information about the immunosuppressive regimens used or the frequency of rejection episodes and their treatment. Children who receive HLA-DR-mismatched kidneys will ultimately be exposed to more-intensive immunosuppression in order to overcome the potentially increased risks of acute rejection, graft failure and sensitization. In spite of recent improvements in immunosuppressive therapy, we believe that HLA matching remains crucial for the survival of kidney transplants.