Prostate cancer characteristics and outcome in renal transplant recipients: results from a contemporary single center study.

BACKGROUND: Prostate cancer (PCa) incidence is expected to increase in renal transplant recipients (RTR) with no clear nor contemporary data on management and oncological outcome. METHODS: We conducted a retrospective single center study of RTR diagnosed with PCa after transplantation between 2000 and 2013. Demographics, PCa characteristics, and treatment were assessed. For each RTR in radical prostatectomy (RP) subset, we included 4 non-organ transplant patients who underwent RP by the same surgeons, and compared pre-operative and post-operative oncological features, and biochemical recurrence (BCR) rate. RESULTS: Twenty-four RTR were included (PCa incidence 1.5%). Mean follow-up was 47 months. PCa was mostly localized (n=21, 87.5%) with treatments including RP (n=16, 76.2%), brachytherapy (n=3, 14.3%), radiation therapy (n=1, 4.7%), and active surveillance (n=1, 4.7%). No graft loss due to PCa treatment was reported. Nineteen RTR with localized PCa (90.5%) were free from BCR. Considering RP subset, no difference in PCa characteristics at diagnosis and BCR rate was found between RTR (n=16) and control patients (n=64). CONCLUSIONS: Localized PCa following renal transplantation was not associated with adverse features as compared with non-transplant patients. Standard treatments could be proposed to RTR with satisfying results both on oncological outcome and graft function.

Renal safety of high-dose, sucrose-free intravenous immunoglobulin in kidney transplant recipients: an observational study.

High-dose intravenous immunoglobulin (IVIg) is commonly used during kidney transplantation. Its nephrotoxicity has been attributed to sucrose stabilizers. We evaluated the renal safety of newer formulations of sucrose-free IVIg. We retrospectively studied clinical and histological data from 75 kidney recipients receiving high-dose, sucrose-free IVIg courses. This group was compared with 75 matched kidney recipients not treated with IVIg. Sucrose-free IVIg treatment was not associated with any acute kidney injury episode at 3 months, but an increased frequency of tubular macrovacuoles (28% vs. 2.8%, P < 0.001) was observed. Among IVIg-treated patients, the presence of macrovacuoles at 3 months was associated with increased IF/TA scores at 3 months (1.7 ± 1 vs. 1 ± 1, P = 0.005) and was more often observed in kidneys with higher IF/TA scores on day 0 (0.6 ± 0.9 vs. 0.3 ± 0.8, P = 0.03) at 3 months. Finally, patients treated with amino-acid-stabilized formulations developed fewer macrovacuoles at 3 months (12% vs. 60%; P < 0.001) than those treated with carbohydrate-stabilized IVIg. Our study shows that high-dose, sucrose-free IVIg use in early kidney recipients is clinically well tolerated. Among sucrose-free IVIg, amino-acid-stabilized formulations are associated with less tubular toxicity than carbohydrate-stabilized IVIg.

Each additional hour of cold ischemia time significantly increases the risk of graft failure and mortality following renal transplantation.

Although cold ischemia time has been widely studied in renal transplantation area, there is no consensus on its precise relationship with the transplantation outcomes. To study this, we sampled data from 3839 adult recipients of a first heart-beating deceased donor kidney transplanted between 2000 and 2011 within the French observational multicentric prospective DIVAT cohort. A Cox model was used to assess the relationship between cold ischemia time and death-censored graft survival or patient survival by using piecewise log-linear function. There was a significant proportional increase in the risk of graft failure for each additional hour of cold ischemia time (hazard ratio, 1.013). As an example, a patient who received a kidney with a cold ischemia time of 30 h presented a risk of graft failure near 40% higher than a patient with a cold ischemia time of 6 h. Moreover, we found that the risk of death also proportionally increased for each additional hour of cold ischemia time (hazard ratio, 1.018). Thus, every additional hour of cold ischemia time must be taken into account in order to increase graft and patient survival. These findings are of practical clinical interest, as cold ischemia time is among one of the main modifiable pre-transplantation risk factors that can be minimized by improved management of the peri-transplantation period.

Maintaining calcineurin inhibition after the diagnosis of post-transplant lymphoproliferative disorder improves renal graft survival.

Post-transplant lymphoproliferative disorder (PTLD) is an uncontrolled proliferation of transformed lymphocytes fostered by immunosuppression. In addition to chemotherapy, treatment of PTLD includes a reduction of maintenance immunosuppression. Patients with PTLD have an increased risk of graft loss, suggesting that reduced immunosuppression strategy needs to be optimized with regard to graft outcome. Here we retrospectively reviewed 101 cases involving PTLD to identify the risks associated with graft loss. During a median follow-up of 70 months, 39 patients died and 21 lost their graft. Multivariate analysis found that an eGFR under 30 ml/min per 1.73 m(2) at PTLD diagnosis, a biopsy-proven acute rejection episode following reduction of immunosuppression, and the absence of calcineurin inhibition in maintenance immunosuppression are independent risk factors for allograft loss. Neither the type of PTLD nor the chemotherapy regimen was predictive of allograft failure. Histological analysis of graft biopsies showed that maintaining calcineurin inhibition after the diagnosis of PTLD reduced the risk of developing de novo anti-HLA antibodies and humoral rejection. Remarkably, calcineurin inhibitor maintenance was neither associated with higher mortality nor with worse progression-free survival. Thus, maintaining calcineurin inhibition at a reduced dose after the diagnosis of PTLD seems safe and may improve renal graft outcome, possibly through better control of the recipient's humoral immune response.

A useful scoring system for the prediction and management of delayed graft function following kidney transplantation from cadaveric donors.

Delayed graft function (DGF) is a common complication in kidney transplantation and is known to be correlated with short- and long-term graft outcomes. Here we explored the possibility of developing a simple tool that could predict with good confidence the occurrence of DGF and could be helpful in current clinical practice. We built a score, tentatively called DGFS, from a French multicenter and prospective cohort of 1844 adult recipients of deceased donor kidneys collected since 2007, and computerized in the Données Informatisées et VAlidées en Transplantation databank. Only five explicative variables (cold ischemia time, donor age, donor serum creatinine, recipient body mass index, and induction therapy) contributed significantly to the DGF prediction. These were associated with a good predictive capacity (area under the ROC curve at 0.73). The DGFS calculation is facilitated by an application available on smartphones, tablets, or computers at www.divat.fr/en/online-calculators/dgfs. The DGFS should allow the simple classification of patients according to their DGF risk at the time of transplantation, and thus allow tailored-specific management or therapeutic strategies.

An alternative approach to estimate age-related mortality of kidney transplant recipients compared to the general population: results in favor of old-to-old transplantations.

Compared to dialysis, kidney transplantation appears to be the best treatment for chronic kidney failure, even for older aged patients. Nevertheless, the individual benefit of transplanting elderly patients has to be balanced against the corresponding increase in the number of patients awaiting grafts. We analyzed the excess mortality related to kidney transplant recipients by taking into account the expected mortality of the general population (additive regression model for relative survival). We applied this method to a cohort of patients who received a first deceased-donor kidney transplant between 1998 and 2009 in France (DIVAT, n = 3641). Overall 10-year mortality was 13%. As expected, recipient age was the main risk factor associated with overall mortality. In contrast, recipient age was no longer significantly associated with the excess of mortality related to kidney transplant status by subtracting the expected mortality of the general population. Delayed graft function (DGF), pretransplantation immunization, and past history of diabetes appeared as the main risk factors of this higher mortality rate. Our results constitute a strong argument in favor of kidney transplantation, regardless of the patient's age. Preventing DGF may be more effective for decreasing the risk of death specifically attributable to the disease.

Vitamin D status and outcomes after renal transplantation.

Kidney transplant recipients usually have low vitamin D levels, especially in the early posttransplantation period, but the association between vitamin D status with renal outcomes is not well described in this population. Here, we studied a prospective cohort of 634 kidney recipients who underwent transplantation at a single institution between January 2005 and June 2010. In this cohort, low 25-hydroxyvitamin D concentrations 3 months after transplantation did not predict early death or graft loss but were independently associated with lower measured GFR at 12 months (P=0.001) and higher risk for interstitial fibrosis and tubular atrophy (P=0.01). In contrast, levels of calcium, phosphorus, calcitriol, parathyroid hormone, or fibroblast growth factor-23 were not consistently associated with any of the studied outcomes. In conclusion, low 25-hydroxyvitamin D concentration measured 3 months after transplantation is an independent risk factor for interstitial fibrosis progression and is associated with a lower GFR 1 year after transplantation.

Clinical and immunological features of very long-term survivors with a single renal transplant.

The aim of this study was to analyze the clinical and immunological features of the 56 still alive patients at our institution harboring a functional first renal transplant since more than 30 years. The mean post-transplant graft survival in all patients was 35.4 ± 3.1 years, the mean serum creatinine concentration was 128.7 ± 7 µmol/l, and the mean urinary protein concentration was 0.6 ± 0.5 g/l. Fifty-one percent of the patients had experienced cancer involving the skin (46.1%) and/or other tissues (28%). Hepatocarcinoma was diagnosed in 11% of the patients with chronic viral hepatitis B and/or C (48%). The 5-year patient survival rate (considered after the 30th transplantation anniversary) was 27% in patients presenting a tumor versus 87% in those tumor-free (P < 0.0001). The thymic output, the proportions of the memory and naïve T cell subsets, and the frequencies of EBV- and CMV-reactive, IFN-γ-producing T cells did not differ from those observed in more recently transplanted patients. These results suggest that the impact of chronic immunosuppression on some immune functions does not worsen over time and that the observed high prevalence of cancer in these patients may be related to the synergistic effects of decreased immunosurveillance and the time required for carcinogenesis.

Very long-term follow-up of living kidney donors.

Knowledge of the very long-term consequences of kidney donors has not been previously reported extensively. The 398 persons who had donated a kidney between 1952 and 2008 at Necker hospital were contacted. Among the 310 donors who were located, the survival probabilities for this population were similar to those of the general population and end stage renal disease incidence was 581 per million population per year. All located donors still alive were asked to complete a medico-psychosocial questionnaire and give samples for serum creatinine and urinary albumin assays. Among the 204 donors who responded to the questionnaire, mean eGFR was 64.4±14.6ml/min per 1.73m(2) and mean microalbuminuria was 27.0±83mg/g. Most donors never regretted the donation and consider that it has no impact on their professional or social lives. Among the 59 donors who gave a kidney more than 30years ago (mean 40.2years, range 30-48years) had a mean eGFR of 67.5±17.4µmol/l, a mean microalbuminuria level of 44.8±123.2mg/g and none was dialyzed. In conclusion, living kidney donation does not impact survival, kidney function, medical condition or psychological or social status over the very long-term.

Outcomes of renal transplantation in patients with autosomal dominant polycystic kidney disease: a nationwide longitudinal study.

Renal transplantation in patients with autosomal dominant polycystic kidney disease (ADPKD) is a medical and surgical challenge. Detailed longitudinal epidemiological studies on large populations are lacking and it is mandatory to care better for these patients. The success of such a project requires the development of a validated epidemiological database. Herein, we present the results of the largest longitudinal study to date on renal transplant in patients with ADPKD. The 15-year outcomes following renal transplantation of 534 ADPKD patients were compared with 4779 non-ADPKD patients. This comprehensive, longitudinal, multicenter French study was performed using the validated database, DIVAT (Données Informatisées et VAlidées en Transplantaion). We demonstrate that renal transplantation in ADPKD is associated with better graft survival, more thromboembolic complications, more metabolic complications, and increased incidence of hypertension, whereas the prevalence of infections is not increased. This study provides important new insights that could lead to a better care for renal transplant patients with ADPKD.

Single graft loss in dual renal transplant recipients: impact of graft placement on recipient outcomes.

We aimed to assess the impact of graft placement in dual renal transplantation on the risk for single graft loss and to report recipient outcomes. Between 2004 and 2007, 55 dual renal transplants were performed at our institution. Allografts were placed bilaterally (one in each iliac fossa) in 42 patients and unilaterally (both in the same iliac fossa) in 14 patients. Nine recipients (16.4%) underwent explantation of a single graft as a consequence of vascular thrombosis designated as the SINGLE group, whereas 46 had two functional allografts (DUAL group). There was a higher rate of graft loss in case of unilateral placement (n = 5/14) compared with bilateral placement (n = 4/41) (35.7% vs. 9.8%, P = 0.035). One-year glomerular filtration rate was significantly lower in the SINGLE group (29.4 ml/min/1.73 m(2) vs. 49.4 ml/min/1.73 m(2) in the DUAL group, P < 0.05). Significantly, none of the nine recipients of the SINGLE group returned to dialysis with a mean follow-up of 34.1 months. Graft survival at 1 year was 100% and 97.9% in SINGLE and DUAL groups, respectively. Unilateral placement of both allografts is associated with an increased risk of single graft loss and therefore lower renal function at 1 year. However, this strategy is safe in selected indications.

A clinical scoring system highly predictive of long-term kidney graft survival.

Determining early surrogate markers of long-term graft outcome is important for optimal medical management. In order to identify such markers, we used clinical information from a cross-validated French database (Données Informatisées et VAlidées en Transplantation) of 2169 kidney transplant recipients to construct a composite score 1 year after transplantation. This Kidney Transplant Failure Score took into account a series of eight accepted pre- and post-transplant risk factors of graft loss, and was subsequently evaluated for its ability to predict graft failure at 8 years. This algorithm outperformed the traditional surrogates of serum creatinine and the estimated graft filtration rate, with an area under the receiver-operator characteristic curve of 0.78. Validation on an independent database of 317 graft recipients had the same predictive capacity. Our algorithm was also able to stratify patients into two groups according to their risk: a high-risk group of 81 patients with 25% graft failure and a low-risk group of 236 patients with an 8% failure rate. Thus, although this clinical composite score predicts long-term graft survival, it needs validation in different patient groups throughout the world.

KDIGO clinical practice guideline for the care of kidney transplant recipients: a summary.

The 2009 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline on the monitoring, management, and treatment of kidney transplant recipients is intended to assist the practitioner caring for adults and children after kidney transplantation. The guideline development process followed an evidence-based approach, and management recommendations are based on systematic reviews of relevant treatment trials. Critical appraisal of the quality of the evidence and the strength of recommendations followed the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) approach. The guideline makes recommendations for immunosuppression and graft monitoring, as well as prevention and treatment of infection, cardiovascular disease, malignancy, and other complications that are common in kidney transplant recipients, including hematological and bone disorders. Limitations of the evidence, especially the lack of definitive clinical outcome trials, are discussed and suggestions are provided for future research. This summary includes a brief description of methodology and the complete guideline recommendations but does not include the rationale and references for each recommendation, which are published elsewhere.

Should routine pyeloureterostomy be advocated in adult kidney transplantation? A prospective study of 283 recipients.

PURPOSE: Ureteroneocystostomy surgical techniques have been repeatedly debated in the medical literature, in contrast to pyeloureterostomy, which is merely considered a salvage procedure. We assessed urological complications and their management after routine pyeloureterostomy in adult kidney transplantation cases. MATERIALS AND METHODS: We performed a 2-center, uncontrolled, prospective study from January to December 2007. We compared results in 151 consecutive kidney transplantations with routine pyeloureterostomy (group 1) and in 129 procedures with extravesical anti-reflux ureteroneocystostomy (group 2). Perioperative ureteral stenting was done on demand in each group. Major complications included complex leakage, stenosis and surgical revision. Transient leakage or obstruction less than 15 days in duration were considered minor complications. RESULTS: Recipients in group 1 were more likely to undergo ureteral stenting on demand than those in group 2 (68.9% vs 21.7%). The incidence of overall complications was similar in groups 1 and 2 (9.3% and 13.2%, respectively, p = 0.15), although the major complication rate was higher in group 2. Group 1 recipients had a tendency to require long-term ureteral stenting more often. The only recipient with ureteral necrosis in group 1 was treated with surgical resection and repeat end-to-end ureteroureterostomy. In each group no graft was lost due to urological complications or their management. CONCLUSIONS: Routine pyeloureterostomy is a safe technique that may be a valuable alternative to ureteroneocystostomy for adult renal transplantation. It does not preclude further open re-intervention. Its main advantages include a significant decrease in the risk of surgical re-intervention, the opportunity to perform further endourological procedures on the allograft urinary system and the avoidance of vesicoureteral reflux.

Impact of surgical procedures and complications on outcomes of third and subsequent kidney transplants.

BACKGROUND: Surgical procedures and complications have rarely been described in patients receiving a third or subsequent renal transplant. METHODS: Data from 61 consecutive third (n=56), fourth (n=4), and fifth (n=1) renal transplants performed during 1974 to 2005 were analyzed retrospectively. RESULTS: Actuarial graft survival was 91%, 74%, and 57% at one, five, and 10 years, respectively. Technical failure accounted for the loss of three grafts (5%). A transperitoneal approach was necessary in 41% of patients. Technical difficulties occurred in half of the procedures, mainly due to atheroma or vascular calcifications. Overall, there were 45 surgical complications in 30 patients, of urological (n=11), vascular (n=6), infectious (n=9), hemorrhagic (n=12), digestive (n=3), or wound origin (n=4). The rate of surgical revision was 16%. Univariate analysis showed that among surgical complications, only vascular complications were associated with a poor graft outcome (P=0.02). Urological complications did not influence long-term graft outcome. Multivariate analysis of all surgical procedures and complications that might have influenced graft survival showed that only vascular complications were associated with a poorer graft outcome (relative risk=6.13, P=0.015). CONCLUSIONS: Despite a high rate of surgical complications and revisions, third and subsequent kidney transplantations may be performed safely by experienced surgeons without surgical complications influencing long-term graft outcome.

Brief communication: sirolimus-associated pneumonitis: 24 cases in renal transplant recipients.

BACKGROUND: Interstitial pneumonitis is an ill-defined side effect of sirolimus, a new immunosuppressant drug recently introduced for patients having organ transplantation. OBJECTIVE: To evaluate clinical and laboratory features of sirolimus-associated pneumonitis. DESIGN: Case series. SETTING: 1 transplantation center in Paris, France. PATIENTS: 24 patients who had renal transplantation and developed sirolimus-associated pneumonitis, including 8 patients previously reported. MEASUREMENTS: Symptoms; laboratory tests, including bronchoalveolar fluid analysis; and computed tomography (CT) of the chest. INTERVENTION: Withdrawal or dose reduction of sirolimus. RESULTS: Clinical symptoms included cough (23 patients), fatigue (20 patients), fever (16 patients), and dyspnea (8 patients). Computed tomography of the chest showed reticular and ground-glass opacities (4 patients), bronchiolitis obliterans-organizing pneumonia (19 patients), and lobar consolidation (1 patient). Bronchoalveolar lavage showed lymphocytic (19 patients) or eosinophilic (3 patients) alveolitis or pulmonary hemorrhage (2 patients). A reduction in the sirolimus dose resulted in transient clinical improvement in 2 patients, but discontinuation of drug therapy was eventually necessary in all patients. All patients recovered completely within 6 months. LIMITATIONS: The sirolimus trough level in patients from this single center was higher than that usually used in patients having renal transplantation. CONCLUSION: Lymphocytic alveolitis and radiologic bronchiolitis obliterans-organizing pneumonia are the key findings in sirolimus-associated pneumonitis. Sirolimus withdrawal was associated with recovery within 6 months.

Lung cancer in renal transplant recipients: A case-control study.

INTRODUCTION: Solid organ transplant patients are at heightened risk of several cancers compared to the general population. Secondary to a higher number of procedures and better survival after transplantation, cancer is a rising health concern in this situation. Limited data exist for lung cancer (LC) after renal transplantation. We report here the most important series of renal transplant recipients with lung cancer. METHODS: Retrospective study of all cases of LC diagnosed in three French Renal Transplant Units from 2003 to 2012. A control group consisted of non-transplant patients with LC matched with the cases for age (<30; 30-50; 50-65; >65 years), gender and diagnosis date. We recruited two controls for each case. RESULTS: Thirty patients (median age 60 years; range 29-85; male/female ratio 80/20%) with LC were analysed. LC incidence was 1.89/1000 person-years over the period 2008-2012. All patients were former or active smokers (median 30 pack-years). Transplanted patients had significantly more comorbidities, mainly cardiovascular disease. The median interval of time from kidney transplantation (KT) to diagnosis of LC was 7 years (range 0.5-47 years). LC was incidentally diagnosed in 40%. Most patients (70%) had advanced LC (stage III or IV) disease. Stage of LC at diagnosis was similar in cases and controls. Surgery and chemotherapy were proposed to the same proportion of patients. In cases, mortality was cancer related in 87% and median survival time after diagnosis was 24 months. Survival was not significantly different between the 2 groups. CONCLUSION: Despite frequent medical and radiological examinations, diagnosis of LC is usually made at an advanced stage and the overall prognosis remains poor.

Acne in recipients of renal transplantation treated with sirolimus: clinical, microbiologic, histologic, therapeutic, and pathogenic aspects.

We evaluated the clinical characteristics of sirolimus-induced acne in 80 recipients of renal transplantation. It developed in 36 of 48 (75%) men and 2 of 32 (6%) women. Lesion locations and clinical, bacteriologic, and histologic features differentiated sirolimus-induced acne from acne vulgaris, but therapeutic management was similar. The main limitation for this study was the absence of a control group without sirolimus. Epidermal growth factor inhibition by sirolimus is a plausible explanation for this acne.

Mortality Prediction after the First Year of Kidney Transplantation: An Observational Study on Two European Cohorts.

After the first year post transplantation, prognostic mortality scores in kidney transplant recipients can be useful for personalizing medical management. We developed a new prognostic score based on 5 parameters and computable at 1-year post transplantation. The outcome was the time between the first anniversary of the transplantation and the patient's death with a functioning graft. Afterwards, we appraised the prognostic capacities of this score by estimating time-dependent Receiver Operating Characteristic (ROC) curves from two prospective and multicentric European cohorts: the DIVAT (Données Informatisées et VAlidées en Transplantation) cohort composed of patients transplanted between 2000 and 2012 in 6 French centers; and the STCS (Swiss Transplant Cohort Study) cohort composed of patients transplanted between 2008 and 2012 in 6 Swiss centers. We also compared the results with those of two existing scoring systems: one from Spain (Hernandez et al.) and one from the United States (the Recipient Risk Score, RRS, Baskin-Bey et al.). From the DIVAT validation cohort and for a prognostic time at 10 years, the new prognostic score (AUC = 0.78, 95%CI = [0.69, 0.85]) seemed to present significantly higher prognostic capacities than the scoring system proposed by Hernandez et al. (p = 0.04) and tended to perform better than the initial RRS (p = 0.10). By using the Swiss cohort, the RRS and the the new prognostic score had comparable prognostic capacities at 4 years (AUC = 0.77 and 0.76 respectively, p = 0.31). In addition to the current available scores related to the risk to return in dialysis, we recommend to further study the use of the score we propose or the RRS for a more efficient personalized follow-up of kidney transplant recipients.

Anemia after late introduction of sirolimus may correlate with biochemical evidence of a chronic inflammatory state.

BACKGROUND: The responsibility of sirolimus (SRL) for postrenal transplant anemia has never been proven, because SRL is usually combined with myelotoxic drugs, and because of the high incidence of anemia in the posttransplant period. METHODS: We retrospectively analyzed anemia in 46 renal transplant recipients, who had been switched from calcineurin inhibitors to SRL for biopsy-proven chronic allograft nephropathy. RESULTS: The mean decrease in hemoglobin (Hb) after SRL introduction was 2.8 g/dl. The 24 patients, whose Hb fell by >or=2 g/dl, displayed microcytic aregenerative anemia with low serum iron despite high ferritinemia, consistent with anemia of chronic inflammatory states. Fibrinogen and CRP levels increased in these patients after sirolimus introduction. We subsequently focused our study on eight patients without confounding factors of anemia. Anemia improved in all eight after SRL withdrawal. IL6 and TNFalpha at the nadir of anemia were significantly higher than before SRL introduction and after its withdrawal. Decreases in Hb correlated with increases in proinflammatory cytokine levels in a linear regression model. Unchanged serum IL10 levels measured at the nadir of anemia were discordant with the inflammatory state. CONCLUSIONS: Late introduction of SRL may induce anemia and correlates with biochemical evidence of a chronic inflammatory state possibly due to defective IL10-dependent inflammatory autoregulation.