Impact of molecular adsorbent recirculating system therapy on tacrolimus elimination: a case report.

BACKGROUND: We report a unique case which quantifies the effect of molecular adsorbent recirculating system (MARS [Gambro, Sweden]) therapy on blood concentrations of tacrolimus in a patient treated for refractory pruritus associated with recurrent hepatitis C of the liver allograft. Tacrolimus is a low-molecular-weight, highly protein-bound drug with the potential to be removed during MARS therapy. CASE REPORT: Results of therapeutic drug monitoring revealed extracorporeal tacrolimus elimination accounted for only 0.3% of total drug removal during the session. CONCLUSIONS: Although no explanation can be offered as to why MARS contributed so little to overall tacrolimus elimination, the data clearly show minimal impact of MARS on tacrolimus blood level.

Kidney allograft function and histology in recipients dying with a functioning graft.

Death with function (DWF) is a major cause of kidney allograft failure. Allograft dysfunction may contribute to DWF. The aim of this study was to examine the relationship between DWF and allograft function using estimated GFR (eGFR) and histology. We retrospectively analyzed 1842 kidney allografts transplanted at our center from 1996 to 2010. eGFR was estimated using the MDRD equation. Biopsies obtained 12 months posttransplant and within 1 year of DWF were analyzed. Proportional hazards models were used to examine the relationship between eGFR and DWF. During 68 ± 43 months of follow-up, 14% (n = 256) of recipients experienced DWF. Risk factors of DWF included increasing recipient age (hazard ratio [HR] = 2.07, confidence interval [CI] 1.77-2.43, p < 0.0001), diabetes (HR = 2.58, CI 1.81-3.69, p < 0.0001), prior dialysis (HR = 1.47, CI 1.05-2.06, p = 0.03) and eGFR <40 mL/min/1.73 m(2) (HR 2.26 per 10 mL/min/1.73 m(2) decrease in eGFR, CI 1.82-2.81, p < 0.0001). Prior to death, only 15.9% (n = 39) of DWF recipients had stage 4 chronic kidney disease (CKD) and only 4.9% (n = 12) had stage 5 CKD. Most biopsies performed within 1 year of DWF (68%) demonstrated benign histology and were comparable to biopsies from matched controls. In conclusion, allograft dysfunction is independently associated with DWF. However, the majority of DWF recipients have well-preserved allograft function and histology prior to death.

Cardiac troponin T before and after kidney transplantation: determinants and implications for posttransplant survival.

Pretransplant cardiac troponin T(cTnT(pre) ) is a significant predictor of survival postkidney transplantation. We assessed correlates of cTnT levels pre- and posttransplantation and their relationship with recipient survival. A total of 1206 adult recipients of kidney grafts between 2000 and 2010 were included. Pretransplant cTnT was elevated (≥0.01 ng/mL) in 56.4%. Higher cTnT(pre) was associated with increased risk of posttransplant death/cardiac events independent of cardiovascular risk factors. Elevated cTnT(pre) declined rapidly posttransplant and was normal in 75% of recipients at 3 weeks and 88.6% at 1 year. Elevated posttransplant cTnT was associated with reduced patient survival (cTnT(3wks) : HR = 5.575, CI 3.207-9.692, p < 0.0001; cTnT(1year) : 3.664, 2.129-6.305, p < 0.0001) independent of age, diabetes, pretransplant dialysis, heart disease and allograft function. Negative/positive predictive values for high cTnT(3wks) were 91.4%/50% respectively. Normalization of cTnT posttransplant was associated with reduced risk. Variables related to elevated cTnT posttransplant included pretransplant diabetes, older age, time on dialysis, high cTnT(pre) and lower graft function. Patients with delayed graft function and those with GFR < 30 mL/min at 3 weeks were more likely to have an elevated cTnT(3wks) and remained at high risk. When allografts restore sufficient kidney function cTnT normalizes and patient survival improves. Lack of normalization of cTnT posttransplant identifies a group of individuals with high risk of death/cardiac events.

Patient survival after kidney transplantation: relationship to pretransplant cardiac troponin T levels.

Assessing cardiovascular (CV) risk pretransplant is imprecise. We sought to determine whether cardiac troponin T (cTnT) relates to patient survival posttransplant. The study includes 603 adults, recipients of kidney transplants. In addition to cTnT dobutamine stress echography and coronary angiography were done in 45% and 19% of the candidates respectively. During 28.4 +/- 12.9 months 5.6% of patients died or had a major cardiac event. cTnT levels were elevated (>0.01 ng/ml) in 56.2% of patients. Elevated cTnT related to reduced event-free survival (hazard ratio (HR) = 1.81, CI 1.33-2.45, p < 0.0001) whether those events occurred during the first year or beyond. This relationship was statistically independent of all other variables tested, including older age, reduced left ventricular ejection fraction (EF) and delayed graft function. cTnT levels allowed better definition of risk in patients with other CV risk factors. Thus, event-free survival was excellent in older individuals, patients with diabetes, low EF and those with preexisting heart disease if their cTnT levels were normal. However, elevated cTnT together with another CV risk factor(s) identified patient with very poor survival posttransplant. Pretransplant cTnT levels are strong and independent predictors of posttransplant survival. These results suggest that cTnT is quite helpful in CV risk stratification of kidney transplant recipients.

Identifying specific causes of kidney allograft loss.

The causes of kidney allograft loss remain unclear. Herein we investigated these causes in 1317 conventional kidney recipients. The cause of graft loss was determined by reviewing clinical and histologic information the latter available in 98% of cases. During 50.3 +/- 32.6 months of follow-up, 330 grafts were lost (25.0%), 138 (10.4%) due to death with function, 39 (2.9%) due to primary nonfunction and 153 (11.6%) due to graft failure censored for death. The latter group was subdivided by cause into: glomerular diseases (n = 56, 36.6%); fibrosis/atrophy (n = 47, 30.7%); medical/surgical conditions (n = 25, 16.3%); acute rejection (n = 18, 11.8%); and unclassifiable (n = 7, 4.6%). Glomerular pathologies leading to failure included recurrent disease (n = 23), transplant glomerulopathy (n = 23) and presumed nonrecurrent disease (n = 10). In cases with fibrosis/atrophy a specific cause(s) was identified in 81% and it was rarely attributable to calcineurin inhibitor (CNI) toxicity alone (n = 1, 0.7%). Contrary to current concepts, most cases of kidney graft loss have an identifiable cause that is not idiopathic fibrosis/atrophy or CNI toxicity. Glomerular pathologies cause the largest proportion of graft loss and alloinmunity remains the most common mechanism leading to failure. This study identifies targets for investigation and intervention that may result in improved kidney transplantation outcomes.

Survival of patients on the kidney transplant wait list: relationship to cardiac troponin T.

Patients waiting for a kidney transplant have high mortality despite careful preselection. Herein, we assessed whether cardiac troponin T (cTnT) can help stratify risk in patients selected for kidney transplantation. cTnT levels were measured in all kidney transplant candidates but the results were not used for patient selection. Among 644 patients placed on the kidney waiting list from 9/2004 to 12/2006, 61% had elevated cTnT levels (>0.01 ng/mL). Higher levels related to diabetes, longer time on dialysis, history of cardiovascular disease and low serum albumin. High cTnT also related to cardiac anomalies, including left ventricular hypertrophy (LVH), wall motion abnormalities and stress-inducible ischemia by dobutamine echo (DSE). However, 54% of patients without these cardiac findings had elevated cTnT. Increasing cTnT levels were associated with reduced survival (HR = 1.729, CI (1.25-2.39), p = 0.01) independently of low serum albumin (0.449 (0.24-0.83), p = 0.011) and history of stroke (3.368 (1.47-7.73), p = 0.0004). The results of the DSE and/or coronary angiography did not relate significantly to survival. However, high cTnT identified patients with abnormal echo findings and poor survival. Wait listed patients with normal cTnT have excellent survival irrespective of other factors. In contrast, high cTnT levels are strongly predictive of poor survival in the kidney transplant waiting list.