Sirolimus is associated with new-onset diabetes in kidney transplant recipients

New-onset diabetes (NOD) is associated with transplant failure. A few single-center studies have suggested that sirolimus is associated with NOD, but this is not well established. With the use of data from the United States Renal Data System, this study evaluated the association between sirolimus use at the time of transplantation and NOD among 20,124 adult recipients of a first kidney transplant without diabetes. Compared with patients treated with cyclosporine and either mycophenolate mofetil orazathioprine, sirolimus-treated patients were at increased risk for NOD, whether it was used in combination with cyclosporine (adjusted hazard ratio [HR] 1.61; 95% confidence interval [CI] 1.36 to 1.90),tacrolimus (adjusted HR 1.66; 95% CI 1.42 to 1.93), or an antimetabolite (mycophenolate mofetil orazathioprine; adjusted HR 1.36; 95% CI 1.09 to 1.69). Similar results were obtained in a subgroup analysis that included the 16,861 patients who did not have their immunosuppressive regimen changed throughout the first posttransplantation year. In conclusion, sirolimus is independently associated with NOD. Given the negative impact of NOD on posttransplantation outcomes, these findings should be confirmed in prospective studies or in meta-analyses of existing trials that involved sirolimus.     

Predictors of cardiovascular events and associated mortality of kidney transplant recipients

BACKGROUND: Cardiovascular disease is the most common cause of death after renal transplantation. Furthermore, acute coronary syndrome (ACS) attributable to coronary artery disease (CAD) accounts for the majority of deaths due to cardiovascular disease posttransplant. Although renal transplantation is the treatment of choice for end-stage renal disease, understanding the causes of graft and patient loss is exceedingly important to improve outcomes. METHODS: This observational study included 1200 patients who underwent a kidney transplant between 1988 and 2003. The outcome was the occurrence of an ACS event within a maximum of 15 years after renal transplantation. RESULTS: Of all 215 deaths, 28.3% were caused by complications of CAD, the most common cause of death at our center. On multivariate analysis, diabetes (P = .005), prior transplant (P = .047), body mass index (BMI) at the time of transplant (P = .01), cholesterol level (P = .012), and low-density lipoprotein (LDL) level (P = .007) during 3 years after transplant were associated with early ACS. In conclusion, diabetes, prior transplant, BMI, cholesterol, and LDL were significantly associated with early ACS highlighting the importance of improved screening and perioperative management.     

Higher mycophenolate dosage is associated with an increased risk of squamous cell carcinoma in kidney transplant recipients

BackgroundKidney transplant recipients are at increased risk of keratinocyte cancers, namely squamous cell and basal cell carcinomas (SCCs and BCCs). This is primarily due to the high levels of immunosuppression that are required to prevent allograft rejection. Different immunosuppressive medications confer different risks, and the effect of mycophenolate mofetil on SCC and BCC risk is unclear. We explored the relationship between mycophenolate dose prescribed over the entire transplant period and the risk of SCC and BCC.MethodsKidney transplant recipients from Queensland, Australia, were recruited between 2012 and 2014 and followed until mid-2016. During this time transplant recipients underwent regular skin examinations to diagnose incident SCCs and BCCs. Immunosuppressive medication regimens were obtained from hospital records, and the average mycophenolate dose/day over the entire transplantation period was calculated for each patient. Doses were divided into three ranked groups, and adjusted relative risks (RR_adj) of developing SCC and BCC tumours were calculated using negative binomial regression with the lowest dosage group as reference. Recipients who had used azathioprine previously were excluded; further sub-group analysis was performed for other immunosuppressant medications.ResultsThere were 134 kidney transplant recipients included in the study. The average age was 55, 31% were female and 69% were male. At the highest median mycophenolate dose of 1818 mg/day the SCC risk doubled (RR_adj 2.22, 95% CI 1.03–4.77) when compared to the reference group of 1038 mg/day. An increased risk persisted after accounting for ever-use of ciclosporin, ever-use of tacrolimus, and when excluding mammalian target of rapamycin users. This increased risk was mainly carried by kidney transplant recipients immunosuppressed for five or more years (RR_adj = 11.05 95% CI 2.50–48.81). In contrast, there was no significant association between BCC incidence and therapy with the highest compared with the lowest mycophenolate dosage (RR_adj = 1.27 95% CI 0.56–2.87).ConclusionHigher mycophenolate dosage is associated with increased SCCs in kidney transplant recipients, particularly those immunosuppressed for more than five years. The increased SCC risk persists after accounting for usage of other immunosuppressant medications.     

Factors associated with erectile dysfunction in male kidney transplant recipients

A transversal study was carried out in order to evaluate the prevalence of erectile dysfunction (ED) in adult kidney transplant patients of our region (N=243), and to investigate the sociodemographic, analytic, and clinical factors associated with it. To evaluate ED, the Spanish five items version of the International Index of Erectile Function (IIEF-5) was employed. Sociodemographic, analytic, and clinical data, including 12 cardiovascular risk factors, were also collected. A total of 199 patients (82%) were included. The median age was 52 y (43-62 y); 106 patients (54.9%) presented with ED. Variables associated with ED were: higher age; longer time on dialysis prior to transplantation; higher comorbidity; presence of diabetes mellitus; had undergone prostatic surgery or peripheric artheriopathy; lower diastolic pressure; and some anti hypertensive drugs. Logistic Regression Model performed step by step showed (R(2)=0.52) that factors independently associated with ED were: age, time on dialysis previous to transplant, and peripheric artheriopathy.     

Preemptive deceased donor kidney transplant not associated with patient survival benefit in minority kidney transplant recipients

Previous studies have shown an inverse association between pre-transplant dialysis exposure and post-kidney transplant outcomes. Socioeconomic and allocation factors, in contrast to medical factors, play a greater role in dialysis exposure among minorities, and medical causes for delay may impact post-transplant outcomes. This study sought to test whether minorities behaved similarly to Caucasians with regard to the effect of duration of dialysis on post-transplant outcomes. All primary deceased donor kidney transplants between 1997 and 2004 (n = 54,162) were analyzed from the Organ Procurement and Transplant Network database and were categorized as either Caucasian or minority. Adjusted patient and graft survivals were determined in each subgroup based on the duration of pre-transplant dialysis. Caucasians recipients show a clear stepwise increase in risk of graft failure and death with increasing duration of dialysis. The risk of graft failure among minorities increased less without a clear stepwise pattern. The risk of death, however, showed a U-shaped risk profile with the highest risk of death among preemptive transplants and recipients with more than five yr of dialysis. The disparate effect of dialysis on minorities suggests that a selection bias and not a biologic effect may explain the association between dialysis duration and outcomes after kidney transplantation previously reported.     

Cytomegalovirus infection in renal transplant recipients is associated with impaired survival irrespective of expected mortality risk

Cytomegalovirus (CMV) infection and CMV disease are associated with increased mortality post-transplantation. We have thus retrospectively examined whether this association is found both in patients with high and low mortality risk. Between 1994 and 1997, 471 kidney transplant recipients were monitored once weekly for CMV pp65 antigenemia and CMV disease the first 100 d after tx and followed prospectively for median 66.6 months. Patients with nephrosclerosis, diabetic nephropathy and amyloidosis were selected as high mortality risk groups (HRG). Overall and cardiovascular mortality beyond 100 d in the low-risk group (n = 372) was 14% and 3.5%, and in the HRG (n = 99) 31% and 16%, respectively. The effects of CMV infection and disease, recipient age and gender, panel-reactive cytotoxic antibodies, acute rejection, HRG, and graft loss in the whole study period were tested on overall mortality beyond 100 d in multiple analysis. HRG was independently associated with overall mortality, RR = 2.03, and still both CMV infection and disease were significant risk factors for mortality, independent of HRG. The same analysis was repeated for HRG (n = 99). Even in this small group CMV disease was independently associated with overall mortality. These data indicate that CMV increase mortality independently both in patients with otherwise high- or low-risk for long-term mortality.     

Vitamin D deficiency is common in kidney transplant recipients,but is not associated with infections after transplantation

The relevance of vitamin D for infections after kidney transplantation is poorly defined. 25-OH vitamin D (25-OHD) levels of 135 kidney transplant recipients, enrolled in the Swiss Transplant Cohort Study, were determined peri-transplant and 6 months post-transplant. Logistic regression was used to address the associations of 25-OHD and overall infections and bacterial infections, respectively. For the first 6 months post-transplant, 25-OHD peri-transplant, and for the second period (after 6 to 30 months post-transplant), 25-OHD at 6 months post-transplant was considered. Vitamin D deficiency was common peri-transplant and remained highly prevalent 6 months after transplantation despite frequent supplementation. Median 25-OHD levels increased from 12.0 ng/mL (IQR 5.3-19.5) peri-transplant to 16.5 ng/mL (IQR 10.6-22.6) 6 months post-transplant (P = .005). We did not detect a significant association between 25-OHD and overall infections (adjusted odds ratio (aOR) 1.05, 95% confidence interval (95%CI) 0.44-2.51; aOR 0.67, 95%CI 0.31-1.43) or bacterial infections (aOR 0.79, 95%CI 0.32-1.96; aOR 0.79, 95%CI 0.35-1.75) for the first and second period. To conclude, at both time points, vitamin D deficiency was observed in more than 50% of kidney recipients, albeit an increase in 25-OHD in the longitudinal course was observed. No significant association between 25-OHD and infections was detected.     

Urinary liver-type fatty acid-binding protein is independently associated with graft failure in outpatient kidney transplant recipients

Urinary liver - type fatty acid-binding protein (uL - FABP) is a biomarker of kidney hypoxia and ischemia, and thus offers a novel approach to identify early kidney insults associated with increased risk of graft failure in outpatient kidney transplant recipients (KTR). We investigated whether uL - FABP is associated with graft failure and whether it improves risk prediction. We studied a cohort of 638 outpatient KTR with a functional graft ≥1-year. During a median follow - up of 5.3 years, 80 KTR developed graft failure. uL - FABP (median 2.11, interquartile range 0.93–7.37 µg/24"/>h) was prospectively associated with the risk of graft failure (hazard ratio 1.75; 95% confidence interval 1.27 – 2.41 per 1 - SD increment; P = .001), independent of potential confounders including estimated glomerular filtration rate and proteinuria. uL - FABP showed excellent discrimination ability for graft failure (c-statistic of 0.83) and its addition to a prediction model composed by established clinical predictors of graft failure significantly improved the c-statistic to 0.89 (P for F-test <.001). These results were robust to several sensitivity analyses. Further validation studies are warranted to evaluate the potential use of a risk-prediction model including uL - FABP to improve identification of outpatient KTR at high risk of graft failure in clinical care.     

Delayed kidney graft function in simultaneous pancreas‐kidney transplant recipients is associated with early pancreas allograft failure

Delayed graft function (DGF) is a common complication associated with significant untoward effects in kidney‐alone transplantation. The incidence and outcomes following kidney delayed graft function (K‐DGF) among patients undergoing simultaneous pancreas‐kidney (SPK) transplantation are less certain. We analyzed SPK recipients transplanted at our center between January 1994 and December 2017. A total of 632 recipients fulfilled the selection criteria, including 69 (11%) with K‐DGF and 563 without. The incidence of K‐DGF was significantly higher in recipients of organs from older donors and donation after circulatory death (DCD). The presence of K‐DGF was significantly associated with an increased risk of pancreas graft failure during the first 90 days (n = 9, incidence rate [IR] 2.45/100 person‐months), but not with late pancreas failure (n = 32, IR 0.84/100 person‐months), kidney graft failure, or patient death. Although DCD was associated with K‐DGF, it was not associated with either pancreas (hazard ratio [HR] 0.91, 95% CI 0.58‐1.44, P = .69) or kidney (HR 1.09, 95% CI 0.66‐1.82, P = .74) graft failure after adjustment for potential confounders. We found K‐DGF to be a significant risk factor for pancreas graft failure but not kidney graft failure, with the major risk period being early (<90 days) posttransplant, and the major donor risk factor being older donor age.     

Low-density lipoprotein oxidation is increased in kidney transplant recipients

Abstract  Oxidative modification of low-density lipoproteins (LDL) plays an important role in the pathogenesis of atherosclerosis. In addition, there is evidence that chronic vascular allograft rejection may be mediated by oxidised LDL. Plasma lipoprotein concentrations and parameters of LDL oxidation were determined in 19 kidney transplant recipients and 19 healthy controls. Plasma triglycerides and total cholesterol was significantly higher in patients than in the controls. The mean LDL diameter was smaller in patients than in the controls (23.6 ± 0.71 nm vs 27.78 ± 1.16 nm, P < 0.002). Furthermore, the lag time of copper-induced in vitro LDL oxidation was shorter in patients than in the controls (101 ± 23 min vs 148 ± 81 min, P = 0.02). The titre and concentration of both IgG and IgM autoantibodies against mal-ondialdehyde-modified LDL (MDA-LDL) were higher in the patients. We conclude that there is in vitro and in vivo evidence of increased LDL oxidation in renal transplant recipients. This might facilitate the progression of atherosclerosis and enhance the process of chronic vascular rejection.