Influenza del sistema immunogenetico KIR nell'alloreattività Natural Killer nel trapianto di rene

Kidney transplantation is the best treatment option for the restoration of excretory and endocrine kidney function in patients with end-stage renal disease. The success of the transplant is linked to the genetic compatibility between donor and recipient, and upon progress in surgery and immunosuppressive therapy. Numerous studies have established the importance of innate immunity in transplantation tolerance, in particular natural killer (NK) cells represent a population of cells involved in defense against infectious agents and tumor cells. NK cells express on their surface the Killer-cell Immunoglobulin-like Receptors (KIR) which, by recognizing and binding to MHC class I antigens, prevent the killing of autologous cells. In solid organ transplantation context, and in particular the kidney, recent studies show some correlation between the incompatibility KIR / HLA and outcome of transplantation so as to represent an interesting perspective, especially as regards setting of immunosuppressive therapy. The purpose of this study was therefore to assess whether the incompatibility between recipient KIR receptors and HLA class I ligands of the donor could be a useful predictor in order to improve the survival of the transplanted kidney and also to select patients who might benefit of a reduced regimen. One hundred and thirteen renal transplant patients from 1999 to 2005 were enrolled. Genomic DNA was extracted for each of them and their donors and genotyping of HLA A, B, C and 14 KIR genes was carried out. Data analysis was conducted on two case-control studies: one aimed at assessing the outcome of acute rejection and the other to assess the long term transplant outcome. The results showed that two genes, KIR2DS1 and KIR3DS1, are associated with the development of acute rejection (p = 0.02 and p = 0.05, respectively). The presence of the KIR2DS3 gene is associated with a better performance of serum creatinine and glomerular filtration rate (MDRD) over time (4 and 5 years after transplantation, p <0.05), while in the presence of ligand, the serum creatinine and MDRD trend seems to get worse in the long term. The analysis performed on the population, according to whether there was deterioration of renal function or not in the long term, showed that the absence of the KIR2DL1 gene is strongly associated with an increase of 20% of the creatinine value at 5 years, with a relative risk to having a greater creatinine level than the median 5-year equal to 2.7 95% (95% CI: 1.7788 - 2.6631). Finally, the presence of a kidney resulting negative for HLA-A3 / A11, compared to a positive result, in patients with KIR3DL2, showed a relative risk of having a serum creatinine above the median at 5 years after transplantation of 0.6609 (95% CI: 0.4529 -0.9643), suggesting a protective effect given to the absence of this ligand.

Predictive Ability of NGAL as a Marker of Renal Damage: evaluation of Multiple Clinical Settings

Introduction. Neutrophil Gelatinase-Associated Lipocalin (NGAL) belongs to the family of lipocalins and it is produced by several cell types, including renal tubular epithelium. In the kidney its production increases during acute damage and this is reflected by the increase in serum and urine levels. In animal studies and clinical trials, NGAL was found to be a sensitive and specific indicator of acute kidney injury (AKI). Purpose. The aim of this work was to investigate, in a prospective manner, whether urine NGAL can be used as a marker in preeclampsia, kidney transplantation, VLBI and diabetic nephropathy. Materials and methods. The study involved 44 consecutive patients who received renal transplantation; 18 women affected by preeclampsia (PE); a total of 55 infants weighing ≤1500 g and 80 patients with Type 1 diabetes. Results. A positive correlation was found between urinary NGAL and 24 hours proteinuria within the PE group. The detection of higher uNGAL values in case of severe PE, even in absence of statistical significance, confirms that these women suffer from an initial renal damage. In our population of VLBW infants, we found a positive correlation of uNGAL values at birth with differences in sCreat and eGFR values from birth to day 21, but no correlation was found between uNGAL values at birth and sCreat and eGFR at day 7. systolic an diastolic blood pressure decreased with increasing levels of uNGAL. The patients with uNGAL <25 ng/ml had significantly higher levels of systolic blood pressure compared with the patients with uNGAL >50 ng/ml ( p<0.005). Our results indicate the ability of NGAL to predict the delay in functional recovery of the graft. Conclusions. In acute renal pathology, urinary NGAL confirms to be a valuable predictive marker of the progress and status of acute injury.

Alterazioni del metabolismo osseo e fratture vertebrali dopo trapianto di rene

Introduction:Persistent Hyperparathyroidism after transplantation (HPT),bone disease and vertebral fractures are an important clinical problem in renal transplant patients. Several factors such as renal osteodystrophy, immunosuppressive therapy, deficit/insufficiency Vitamin D may contribute to that.In literature are described different percentages of HPT, vertebral fractures and Osteoporosis/Osteopenia that may be due to the different therapy and to the different employ of steroid. We analyzed 90 patients who received a renal graft between 2005 e 2010. Patients and Methods: 44 male and 46 female. Average age 52,2± 10,1 years, follow-up 31,3±16,6 months, time on dialysis 37±29,6 months. Patients who had creatinine level greater than 2,5 mg/dl were excluded. Immunosuppressive therapy was based on basiliximab, steroids (1.6 to 2 mg/kg/day progressively reduced to 5 mg/day after 45 days from the transplantation) in all patients + calcineurin inhibitor+ mycophenolate mophetil/mycophenolic acid in 88,8% of patients or Everolimus± calcineurin inhibitor in the others. Patients were studied with X-ray of the spine, dual-energy-X-ray, PTH, 25(OH)VitD. Results: 41,1% had HPT; 41,1% had osteopenia at femoral neck and 36,7% at vertebral column; 16,7% had osteoporosis at femoral neck and 15,6% at vertebral column. 10 patients (11%) had vertebral fractures. Patients with normal bone mineral density, compared to those with osteoporosis/osteopenia, are more younger (average age 46,4±11,7 years vs 54.3±8,6); they have spent less time on dialysis (26,5±14,8 months vs 40,7±32,6) and they have values of 25(OH)VitD higher (22,1±7,6 ng/ml vs 17,8±8,5). Patients with vertebral fractures have values of 25(OH)VitD lowest (14,1±6,4 ng/ml vs 19,7±8,5) and they had transplant since more time (29,1±16,2 vs 48,1±8,7 months). There is a significant correlation between HPT and PTH pre transplantation; HPT and levels of VitD (p<0,05) Conclusion: Prevention of Bone disease and vertebral fractures after renal transplant includes: a)treatment before transplantation b)supplementation of vitamin D with cholecalciferol or calcidiol c)shorten the dialysis time.

Endovascular stenting of a renal transplant vein

We describe successful endovascular stenting of a high-grade stenosis of a renal transplant vein in a 53-year old patient. Kidney transplantation had been performed due to IgA nephropathy and the patient had become symptomatic two months after uneventful recovery from operation.

Antegrade endopyelotomy for treatment of ureteropelvic junction obstruction in transplanted kidneys

BACKGROUND AND PURPOSE: Little is known about the incidence and treatment of ureteropelvic junction (UPJ) obstruction of renal grafts. We report on three cases treated by endopyelotomy. PATIENTS AND METHODS: Graft function declined in three patients 98, 135, and 144 days after kidney transplantation. Acute rejection was excluded by renal biopsy. Ultrasonography revealed a dilated collecting system, and a percutaneous nephrostomy tube was placed. An antegrade nephrostogram showed UPJ obstruction. Percutaneous antegrade endopyelotomy was performed with the cold-knife technique, and the area was stented for 6 weeks using a 14F/8.2F Smith endopyelotomy stent. RESULTS: No intraoperative or postoperative complications occurred. The endopyelotomies were successful, and the creatinine clearances returned to normal. CONCLUSION: Antegrade endopyelotomy in patients with UPJ obstruction of a renal graft is feasible and effective. Normal kidney function was restored after correction of the obstruction.

Pre- and postnatal therapy of lower urinary tract obstruction - an experience of 18 years

With prenatal detection of hydronephrosis and technological advances in surgical equipment, the management of lower urinary tract obstruction has evolved to include prenatal surgical intervention. Surgical intervention, was based upon the rationale that restoring amniotic fluid to normal levels by shunting fetal urine from the obstructed urinary system to the amniotic space would prevent lung hypoplasia and, thus, improve neonatal survival. Inaddition, relief of the obstruction would also reduce back pressure and reduce injury to the developing nephron, thus improving long-term renal function postnatally. However, this remains investigational, and the vast majority of affected infants are treated soon after birth. We have experience since 1991 with prenatal treatment of megacystis. In 23 cases of 50 detected megacystis with oligohydramnion in male and without other abnormalities a prenatal intervention by bladderpunction and in 12 cases additional vesicoamniotic shunt placement was performed. The prognosis of megacystis with oligohydramnion is stated with a survival rate of 10-30%. In our group 54% (13 children) survived. Also we want present 56 cases of urethral valves with a postnatal transurethral intervention. With a follow up time from 8.6 (3 to 15) years we attend 34 children (60%) with normal renal function, 21% (12) with mild or moderate renal insufficiency and there was a kidney transplantation in 6 cases necessary. With our multidisciplinary presentation we want to discuss the indication, interdisciplinary aspects,risks and the follow up of pre- and postnatal intervention in such cases.

Cytomegalovirus Serology and Replication Remain Associated With Solid Organ Graft Rejection and Graft Loss in the Era of Prophylactic Treatment

BACKGROUND Cytomegalovirus (CMV) replication has been associated with more risk for solid organ graft rejection. We wondered whether this association still holds when patients at risk receive prophylactic treatment for CMV. METHODS We correlated CMV infection, biopsy-proven graft rejection, and graft loss in 1,414 patients receiving heart (n=97), kidney (n=917), liver (n=237), or lung (n=163) allografts reported to the Swiss Transplant Cohort Study. RESULTS Recipients of all organs were at an increased risk for biopsy-proven graft rejection within 4 weeks after detection of CMV replication (hazard ratio [HR] after heart transplantation, 2.60; 95% confidence interval [CI], 1.34-4.94, P<0.001; HR after kidney transplantation, 1.58; 95% CI, 1.16-2.16, P=0.02; HR after liver transplantation, 2.21; 95% CI, 1.53-3.17, P<0.001; HR after lung transplantation, 5.83; 95% CI, 3.12-10.9, P<0.001. Relative hazards were comparable in patients with asymptomatic or symptomatic CMV infection. The CMV donor or recipient serological constellation also predicted the incidence of graft rejection after liver and lung transplantation, with significantly higher rates of rejection in transplants in which donor or recipient were CMV seropositive (non-D-/R-), compared with D- transplant or R- transplant (HR, 3.05; P=0.002 for liver and HR, 2.42; P=0.01 for lung transplants). Finally, graft loss occurred more frequently in non-D- or non-R- compared with D- transplant or R- transplant in all organs analyzed. Valganciclovir prophylactic treatment seemed to delay, but not prevent, graft loss in non-D- or non-R- transplants. CONCLUSION Cytomegalovirus replication and donor or recipient seroconstellation remains associated with graft rejection and graft loss in the era of prophylactic CMV treatment.

End-stage renal disease annual report to Congress.

No more published?

Population pharmacokinetic analysis of mycophenolic acid in renal transplant recipients following oral administration of mycophenolate mofetil

Aim To develop a population pharmacokinetic model for mycophenolic acid in adult kidney transplant recipients, quantifying average population pharmacokinetic parameter values, and between- and within-subject variability and to evaluate the influence of covariates on the pharmacokinetic variability. Methods Pharmacokinetic data for mycophenolic acid and covariate information were previously available from 22 patients who underwent kidney transplantation at the Princess Alexandra Hospital. All patients received mycophenolate mofetil 1 g orally twice daily. A total of 557 concentration-time points were available. Data were analysed using the first-order method in NONMEM (version 5 level 1.1) using the G77 FORTRAN compiler. Results The best base model was a two-compartment model with a lag time (apparent oral clearance was 271 h(-1), and apparent volume of the central compartment 981). There was visual evidence of complex absorption and time-dependent clearance processes, but they could not be successfully modelled in this study. Weight was investigated as a covariate, but no significant relationship was determined. Conclusions The complexity in determining the pharmacokinetics of mycophenolic acid is currently underestimated. More complex pharmacokinetic models, though not supported by the limited data collected for this study, may prove useful in the future. The large between-subject and between-occasion variability and the possibility of nonlinear processes associated with the pharmacokinetics of mycophenolic acid raise questions about the value of the use of therapeutic monitoring and limited sampling strategies.

Sampling times for monitoring tacrolimus in stable adult liver transplant recipients

The aim of this study was to determine the most informative sampling time(s) providing a precise prediction of tacrolimus area under the concentration-time curve (AUC). Fifty-four concentration-time profiles of tacrolimus from 31 adult liver transplant recipients were analyzed. Each profile contained 5 tacrolimus whole-blood concentrations (predose and 1, 2, 4, and 6 or 8 hours postdose), measured using liquid chromatography-tandem mass spectrometry. The concentration at 6 hours was interpolated for each profile, and 54 values of AUC(0-6) were calculated using the trapezoidal rule. The best sampling times were then determined using limited sampling strategies and sensitivity analysis. Linear mixed-effects modeling was performed to estimate regression coefficients of equations incorporating each concentration-time point (C0, C1, C2, C4, interpolated C5, and interpolated C6) as a predictor of AUC(0-6). Predictive performance was evaluated by assessment of the mean error (ME) and root mean square error (RMSE). Limited sampling strategy (LSS) equations with C2, C4, and C5 provided similar results for prediction of AUC(0-6) (R-2 = 0.869, 0.844, and 0.832, respectively). These 3 time points were superior to C0 in the prediction of AUC. The ME was similar for all time points; the RMSE was smallest for C2, C4, and C5. The highest sensitivity index was determined to be 4.9 hours postdose at steady state, suggesting that this time point provides the most information about the AUC(0-12). The results from limited sampling strategies and sensitivity analysis supported the use of a single blood sample at 5 hours postdose as a predictor of both AUC(0-6) and AUC(0-12). A jackknife procedure was used to evaluate the predictive performance of the model, and this demonstrated that collecting a sample at 5 hours after dosing could be considered as the optimal sampling time for predicting AUC(0-6).

A systematic review of laparoscopic live-donor nephrectomy

Background. A systematic review was undertaken to assess the safety and efficacy of laparoscopic live-donor nephrectomy (LLDN) compared with open live-donor nephrectomy (OLDN). Methods. Literature databases were searched from inception to March 2003 inclusive. Comparative studies of LLDN versus OLDN (randomized and nonrandomized) were included. Results. There were 44 included studies, and the quality of the available evidence was average. There was only one randomized controlled trial and six nonrandomized comparative studies with concurrent controls identified. In terms of safety, for donors, there did not seem to be any distinct difference between the laparoscopic and open approaches. No donor mortality was reported for either procedure, and the complication rates were similar although the types of complications experienced differed between the two procedures. The conversion rate for LLDN to an open procedure ranged from 0% to 13%. In terms of efficacy, LLDN seemed to be a slower operation with longer warm ischemia. times than OLDN, but this did not seem to have resulted in increased rates of delayed graft function for recipients. Donor postoperative recovery and convalescence seemed to be superior for LLDN, making it a potentially more attractive operation for living donors. Although in the short-term, graft function and survival did not seem to differ between the two techniques, long-term complication rates and allograft function could not be determined and further long-term follow-up is required. Conclusions. LLDN seems to be at least as safe and efficacious as OLDN in the short-term. However, it remains a technique in evolution. Further high-quality studies are required to resolve some of the outstanding issues surrounding its use, in particular, long-term follow-up of donor complications and recipient graft function and survival.

Pharmacokinetic considerations relating to tacrolimus dosing in the elderly

Relaxation of the upper age limits for solid organ transplantation coupled with improvements in post-transplant survival have resulted in greater numbers of elderly patients receiving immunosuppressant drugs such as tacrolimus. Tacrolimus is a potent agent with a narrow therapeutic window and large inter- and intraindividual pharmacokinetic variability. Numerous physiological changes occur with aging that could potentially affect the pharmacokinetics of tacrolimus and, hence, patient dosage requirements. Tacrolimus is primarily metabolised by cytochrome P450 (CYP) 3A enzymes in the gut wall and liver. It is also a substrate for P-glycoprotein, which counter-transports diffused tacrolimus out of intestinal cells and back into the gut lumen. Age-associated alterations in CYP3A and P-glycoprotein expression and/or activity, along with liver mass and body composition changes, would be expected to affect the pharmacokinetics of tacrolimus in the elderly. However, interindividual variation in these processes may mask any changes caused by aging. More investigation is needed into the impact aging has on CYP and P-glycoprotein activity and expression. No single-dose, intense blood-sampling study has specifically compared the pharmacokinetics of tacrolimus across different patient age groups. However, five population pharmacokinetic studies, one in kidney, one in bone marrow and three in liver transplant recipients, have investigated age as a co-variate. None found a significant influence for age on tacrolimus bioavailability, volume of distribution or clearance. The number of elderly patients included in each study, however, was not documented and may have been only small. It is likely that inter- and intraindividual pharmacokinetic variability associated with tacrolimus increase in elderly populations. In addition to pharmacokinetic differences, donor organ viability, multiple co-morbidity, polypharmacy and immunological changes need to be considered when using tacrolimus in the elderly. Aging is associated with decreased immunoresponsiveness, a slower body repair process and increased drug adverse effects. Elderly liver and kidney transplant recipients are more likely to develop new-onset diabetes mellitus than younger patients. Elderly transplant recipients exhibit higher mortality from infectious and cardiovascular causes than younger patients but may be less likely to develop acute rejection. Elderly kidney recipients have a higher potential for chronic allograft nephropathy, and a single rejection episode can be more devastating. There is a paucity of information on optimal tacrolimus dosage and target trough concentration in the elderly. The therapeutic window for tacrolimus concentrations may be narrower. Further integrated pharmacokinetic-pharmaco-dynamic studies of tacrolimus are required. It would appear reasonable, based on current knowledge, to commence tacrolimus at similar doses as those used in younger patients. Maintenance dose requirements over the longer term may be lower in the elderly, but the increased variability in kinetics and the variety of factors that impact on dosage suggest that patient care needs to be based around more frequent monitoring in this age group.

Relationships of tacrolimus pharmacokinetic measures and adverse outcomes in stable adult liver transplant recipients

Alternative measures to trough concentrations [non-trough concentrations and limited area under the concentration-time curve (AUC)] have been shown to better predict tacrolimus AUC. The aim of this study was to determine if these are also better predictors of adverse outcomes in long term liver transplant recipients. The associations between tacrolimus trough concentrations (C-0), non-trough concentrations (C-1, C-2, C-4, C-6/8), and AUC(0-12) and the occurrence of hypertension, hyperkalaemia, hyperglycaemia and nephrotoxicity were assessed in 34 clinically stable liver transplant patients. The most common adverse outcome was hypertension, prevalence of 36%. Hyperkalaemia and hyperglycaemia had a prevalence of 21% and 13%, respectively. A sequential population pharmacokinetic/pharmacodynamic approach was implemented. No significant association between predicted C-0, C-1, C-2, C-4, C-6/8 or AUC(0-12) and adverse effects could be found. Tacrolimus concentrations and AUC measures were in the same range in patients with and without adverse effects. Measures reported to provide benefit, preventing graft rejection and minimizing acute adverse effects in the early post-transplant period, were not able to predict adverse effects in stable adult liver recipients whose trough concentrations were maintained in the notional target range.