Improvement in Echocardiographic Indexes of Systolic Heart Failure Post-Kidney Transplantation: A Retrospective Analysis.

INTRODUCTION: End-stage renal disease is a major risk factor for cardiovascular morbidity and mortality, which can be partially eliminated by kidney transplantation. Systolic heart failure might be considered contraindication for kidney transplant, although some patients demonstrate myocardial recovery post-transplant. We aimed to identify and characterize the phenomenon of reverse myocardial remodeling in kidney transplanted patients. METHODS: The study is a retrospective cohort of patients undergoing kidney transplants between 2016 and 2019 (n = 604) at Rabin Medical Center. Patients were assessed according to availability of two echocardiographic examinations: pre- and post-kidney transplant. The change in estimated ejection fraction (EF) and possible predictors of myocardial recovery were examined. RESULTS: Data of 293 patients was available for the final analysis. Eighty-one (28%) patients had a LVEF improvement equal to or above 5%, whereas 36 (12%) patients had a LVEF improvement of 10% or more post-transplantation. Twenty-five patients (8.5%) had moderate or severe systolic heart failure with LVEF reduced to 40% or less at baseline. 13 of them (52%) had a LVEF improvement of ≥5%, and 10 patients (40%) had an improvement of ≥10% in their EF. Cox regression analyses identified female gender as the only independent variable associated with LVEF improvement of at least 10%. CONCLUSION: Renal transplantation might lead to improved LV systolic function in some patients.

Exposure to tacrolimus trough levels below 6 ng/ml during the first year is associated with inferior kidney graft survival.

BACKGROUND: Accumulating data indicate that sub-therapeutic levels of tacrolimus are associated with long-term kidney graft loss. However, elevated doses increase the risk of infection and drug toxicity, which also threaten graft and patient longevity. We sought to determine the minimal tacrolimus level required to maintain graft survival. METHODS: We conducted a single-center historical cohort study. The first-year post-transplant exposure time was calculated for each of the five tacrolimus trough level intervals. This measure was adjusted to the exposure time below a given interval level, allowing us to define the threshold for the optimal tacrolimus level as the upper limit of the interval. We then determined the association between the adjusted exposure time at each tacrolimus level interval and our primary outcome, death-censored graft loss. RESULTS: One thousand four hundred and seventeen patients with a median follow-up of 5.3 years were included in the final cohort. The tacrolimus level interval of 5-6 ng/ml was the highest interval, which demonstrated a statistically significant association between adjusted exposure time and increased risk of graft loss (HR 1.58, per log days, p = .002). Cumulative exposure time above 14 days with a tacrolimus level below 6 ng/ml was associated with an increased rate of graft loss in most studied subgroups, except for recipients with pre transplant diabetes. CONCLUSIONS: Maintaining tacrolimus levels above 6 ng/ml during the first-year post-transplant might improve kidney graft survival.

Multi-phasic eGFR trajectory during follow up and long-term graft failure after kidney transplantation.

BACKGROUND: The prevailing assumption is that following kidney transplantation the pattern of kidney function decline is consistent. Nevertheless, numerous factors leading to graft loss may emerge, altering the trajectory of kidney function. In this study, we aim to assess alterations in estimated glomerular filtration rate (eGFR) trajectory over an extended period of follow-up and examine its correlation with graft survival. METHODS: We calculated eGFR using all creatinine values available from 1-year post transplantation to the end of follow-up. For pattern analysis, we used a piecewise linear model. RESULTS: Nine hundred eighty-eight patients were included in the study. After a median follow-up of 5.2 years, 297 (30.1%) patients had a multi-phasic eGFR trajectory. Change in eGFR trajectory was associated with increased risk for graft failure (HR 7.15, 95% CI 5.17-9.89, p < .001), longer follow-up time, younger age, longer cold ischemia time, high prevalence of acute rejection, longer hospitalization and a lower initial eGFR. Of the 988 patients included in the study, 494 (50.0%) had a mono-phasic stable trajectory, 197 (19.9%) had a mono-phasic decreasing trajectory, 184 (18.6%) had bi-phasic decreasing trajectory (initial stability and then decline, 46(4.7%) had a bi-phasic stabilized (initial decline and then stabilization) and 67(6.8%) had a more complex trajectory (tri-phasic). Out of the total 144 patients who experienced graft loss, the predominant pattern was a bi-phasic decline characterized by a bi-linear trajectory (66 events, 45.8%). CONCLUSIONS: Changes in eGFR trajectory during long-term follow-up can serve as a valuable tool for assessing the underlying mechanisms contributing to graft loss.

Insertion of a urinary catheter on admission lowers acute kidney injury incidence in patients with hip fractures.

PURPOSE: Acute kidney injury (AKI) is a common adverse event in patients undergoing hip fracture repair surgery, increasing morbidity and mortality. Our study hypothesis was that routine insertion of a urinary catheter, on admission to the hospital or immediately before surgery, will reduce AKI incidence in hip fracture patients. METHODS: Determined by alternating days of admission, a urinary catheter was inserted routinely on admission (catheter group) or as needed (non-catheter group) in 250 consecutive patients who presented with a hip fracture to our emergency department. The incidence of AKI according to the KDIGO criteria and morbidity and mortality were compared between the study groups. RESULTS: The overall incidence of AKI was 11.6% (29/250). The catheter group (N = 122) had a significantly lower rate of AKI (6.6% vs. 16% p = 0.018). At 12-month follow-up, the overall mortality was 10.8% (27/250), in-hospital 7.4% (2/27), short-term (within 30 days) 7.4% (2/27), and long-term (30 days to 1 year) 85.8% (23/27). All in-hospital mortality occurred in the AKI group. Patients with no AKI had a better survival rate; however, the difference was not significant (p-value = 0.21). Mortality rate was lower in the catheter group but not significant (8.2% compared with 13.8% in the non-catheter group, p = 0.225). Post-operative respiratory and cardiac complications were more frequent in the AKI group (p = 0.02 and 0.043 accordingly). CONCLUSIONS: Insertion of a urinary catheter upon admission or before surgery lowered AKI incidence significantly. Peri-operative AKI was associated with higher rates of post-operative complications and worse survival.

Second pregnancy following kidney transplantation is not associated with an increased risk of graft loss in a single center retrospective cohort study.

INTRODUCTION: Previous studies on first pregnancy following kidney transplantation (KT) show no association with decreased graft survival. This study examined patients with multiple gestations compared to a single pregnancy following KT and evaluated the risk of graft function deterioration. METHODS: A retrospective cohort study on fertile female kidney transplant recipients (KTRs) from Rabin Medical Center between January 2001 and December 2017 was performed. Data were collected on patients' comorbidities, pregnancy complications, graft loss, mortality, and lab results. Time-varying COX analysis was performed - second pregnancy being the time-related variable. RESULTS: Fifty-two KTRs split into 30 single pregnancy and 22 multiple pregnancy patients following KT. Single pregnancy patients were older during their first pregnancy and had a higher caesarian section rate. During a median follow-up period of 5.6 years, multiple pregnancies, compared to a single pregnancy, were not associated with an increased rate of graft loss. No significant difference was seen between first and second pregnancy in gestational age, birth weight, graft function, and proteinuria rates. CONCLUSIONS: Second pregnancy following KT was not shown to be associated with a decreased graft survival. In addition, obstetrical, maternal, and fetal complication rates are not increased in second compared to first pregnancy following KT.

Absence of hemoglobin increase is associated with reduced graft survival after kidney transplantation.

BACKGROUND: Anemia is prevalent following kidney transplantation and is associated with reduced graft survival. The association between temporal changes in hemoglobin (Hb) level at the early post-transplant period and graft survival is unknown. PATIENTS AND METHODS: The study cohort included consecutive patients included in a single center transplantation registry between January 2002 and December 2016. Temporal changes in Hb values during the first 90 days after the transplantation were evaluated by piecewise linear regression model. Significant Hb increase rate was defined as an increase of .5 gram/deciliter/month. Patients were divided into groups according to the presence of significant Hb increase. The primary outcome was death-censored graft failure. RESULTS: Of 946 patients included in the study cohort, 831 (87.8%) had at least one interval of Hb increase, and 115 (12.2%) had no Hb increase. The absence of Hb increase was associated with an elevated risk of death censored graft failure by univariate (HR 2.9, 95% CI 1.88-4.49, P < .001) and multivariate (HR 2.47, 95% CI 1.48-4.12, P = .001) analyses. The timing and rate of Hb increase had no association with the main outcome. CONCLUSIONS: Lack of Hb increase during the early post-transplant period is associated with an increased risk of graft loss.

Immune Response to Third Dose BNT162b2 COVID-19 Vaccine Among Kidney Transplant Recipients-A Prospective Study.

Immune response to two SARS-CoV-2 mRNA vaccine doses among kidney transplant recipients (KTRs) is limited. We aimed to evaluate humoral and cellular response to a third BNT162b2 dose. In this prospective study, 190 KTRs were evaluated before and ∼3 weeks after the third vaccine dose. The primary outcomes were anti-spike antibody level >4160 AU/ml (neutralization-associated cutoff) and any seropositivity. Univariate and multivariate analyses were conducted to identify variables associated with antibody response. T-cell response was evaluated in a subset of participants. Results were compared to a control group of 56 healthcare workers. Among KTRs, we found a seropositivity rate of 70% (133/190) after the third dose (37%, 70/190, after the second vaccine dose); and 27% (52/190) achieved levels above 4160 AU/ml after the third dose, compared to 93% of controls. Variables associated with antibody response included higher antibody levels after the second dose (odds ratio [OR] 30.8 per log AU/ml, 95% confidence interval [CI]11-86.4, p < 0.001); and discontinuation of antimetabolite prior to vaccination (OR 9.1,95% CI 1.8-46.5, p = 0.008). T-cell response was demonstrated in 13% (7/53). In conclusion, third dose BNT162b2 improved immune response among KTRs, however 30% still remained seronegative. Pre-vaccination temporary immunosuppression reduction improved antibody response.

Post-transplantation erythrocytosis in kidney transplant recipients-A retrospective cohort study.

OBJECTIVES: To characterize risk factors for the development of post-transplant erythrocytosis (PTE), and its long-term effect on mortality, graft failure, and thrombosis. METHODS: Retrospective study including all kidney transplant recipients in Rabin Medical Center (RMC) during the years 2005-2014. The primary outcome was a composite outcome of all-cause mortality or graft failure at the end of follow-up. Secondary outcomes included death censored graft loss, venous thromboembolism, major adverse cardiovascular events, and mortality. A matched control group was also evaluated. Univariate and multivariate time-varying Cox model analyses were conducted for outcome evaluation. RESULTS: A total of 1304 patients were included, 169 of whom were diagnosed with PTE (12.9%). PTE was associated with male gender, higher glomerular filtration rate (GFR), and polycystic kidney disease. PTE was found to be associated with a reduced risk of the primary outcome (HR 0.355, CI 95% 0.151-0.89, P = .027) in a univariate time-varying Cox analysis, but was not associated with the composite outcome in a multivariate analysis. There was no difference in the primary outcome when the PTE group was compared with the matched control. CONCLUSION: PTE was not found to be associated with long-term outcomes of graft failure and poor survival.

Apixaban Level and Its Influence on Immunosuppression and Graft Outcome in Kidney Transplant Recipients With Atrial Fibrillation.

BACKGROUND: Currently, there is limited information on the level of apixaban in kidney transplant (KT) patients with atrial fibrillation and the influence of apixaban therapy on the level of immunosuppression and graft function. METHODS: This was a cross-sectional prospective study of 19 KT patients treated with apixaban. The levels of apixaban were measured using a chromogenic assay calibrated for apixaban and compared with those predicted by the manufacturer. Mean immunosuppression trough levels before and after apixaban treatment initiation were calculated using 3 consecutive measurements. Apixaban levels were compared with a historical control group comprising of 20 nontransplant patients with atrial fibrillation who were treated with the standard 5-mg bid apixaban dosage. RESULTS: All KT patients should have been treated with the standard 5-mg bid apixaban dosage according to the clinical parameters; however, 7 were inappropriately treated with a reduced dosage (2.5-mg bid). There was no significant difference in apixaban level between KT patients treated with the 5-mg bid dosage and nontransplant patients. No KT patient administered the standard dose had out-of-range levels. Peak GM level was significantly lower in KT patients administered an inappropriately reduced dose (P = 0.05). Two patients had below-range peak levels. Apixaban treatment initiation had minimal influence on the level of immunosuppression. Furthermore, it had no adverse impact on graft function. CONCLUSIONS: Similar to nontransplant patients, KT patients administered the standard 5-mg bid dosage had apixaban levels that were well within the recommended manufacturers' expected ranges. In addition, this dosage had minimal influence on immunosuppression and no effect on graft function.

Short versus prolonged antibiotic treatment for complicated urinary tract infection after kidney transplantation.

There is no consensus regarding the optimal duration of antibiotic therapy for urinary tract infection (UTI) following kidney transplantation (KT). We performed a retrospective study comparing short (6-10 days) versus prolonged (11-21 days) antibiotic therapy for complicated UTI among KT recipients. Univariate and inverse probability treatment weighted (IPTW) adjusted multivariate analysis for composite primary outcome of all-cause mortality or readmissions within 30 days and relapsed UTI 180 days were performed. Overall, 214 KT recipients with complicated UTI were included; 115 short-course treatment (median 8, interquartile range [IQR] 6-9 days), 99 prolonged course (median 14, IQR 12-21 days). The composite outcome occurred in 33 (28.6%) in the short-course group and 30 (30%) in the prolonged-course group; relapsed UTI occurred in 19 (16.5%) vs. 21 (21%), respectively. Duration of antibiotic treatment was not associated with any of these outcomes. The only risk factor for mortality/readmissions in multivariate analysis was deceased donor. No differences between groups were demonstrated for length of hospital stay, rates of bacteraemia, resistance development, and serum creatinine at 30 and 90 days. In conclusion, we found no difference in clinical outcomes between KT recipients treated for complicated UTI with short-course antibiotic (6-10 days) versus longer course (11-21 days).

Long-term results of desensitization protocol with and without rituximab in sensitized kidney transplant recipients.

BACKGROUND: Desensitization protocols have been developed in order to overcome the immunological barrier of donor-specific anti-HLA antibodies (DSA). METHODS: During 2006-2012, we implemented a program for desensitizing sensitized (positive DSA, negative NIH-CDC crossmatch) living-donor recipients. The long-term outcome of 36 sensitized recipients, treated with IVIG and plasmapheresis (PP), with or without rituximab (added when > 7500 MFI), was compared to 252 non-sensitized living-donor recipients. RESULTS: Median peak DSA level before desensitization was 7223 (range 3567-16 000) MFI. During a mean follow-up of 121.9 months, graft loss occurred in 6/36 (17%) of the sensitized and 15/251 (6%) of the non-sensitized recipients (P = 0.021). Five-year and 10-year death-censored graft survival rates were 85% and 81% compared to 95% and 92%, respectively, for the non-sensitized recipients. There was no difference in recipients' survival. Slightly more episodes of acute rejection occurred in the sensitized group but had not influence on graft survival. At the last follow-up, 28 recipients had functioning graft; seventeen (47%) did not have detectable DSA. Eleven recipients had excellent graft function despite having detectable DSA. CONCLUSION: The long-term outcomes of sensitized recipients who underwent desensitization are encouraging. Adding rituximab to PP + IVIG in candidates with very high titers may result in improved outcome.

Reduction of exposure to tacrolimus trough level variability is associated with better graft survival after kidney transplantation.

PURPOSE: High tacrolimus trough drug level variability was found to be associated with reduced graft survival. The primary goal of this study was to find whether reduction of exposure to high tacrolimus trough level variability in patients in which previously had high variability was associated with better graft survival. METHODS: All tacrolimus drug level values in patients that underwent kidney transplantation at our center between 2006 and 2015 were collected. Exposure to variability was calculated using a time-weighted coefficient of variability (TWCV). Time-dependent univariate and multivariate Cox proportional hazard models were used to analyze the primary outcome of graft survival and to determine a cutoff value for TWCV as a predictor of this outcome. RESULTS: A total of 878 patients were included in the study with a median follow-up of 1263 days. TWCV above 25% was significantly associated with reduced graft survival (HR3.66, 95% CI 2.3-5.8, p < 0.001). Of the 480 patients (54.7%) who had a cumulative TWCV of > 25% at a certain time during the follow-up, 110 (22.9%) later returned to a cumulative TWCV of less than 25%. Reduction of TWCV to values below 25% was associated with a hazard of graft loss that was not different from patients who had cumulative TWCV of less than 25% during the entire follow-up period (HR 1.81, 95% CI 0.71-4.62, p = 0.218 and HR 1.08, 95% CI 0.39-2.99, p = 0.780) in univariate and multivariate analyses, respectively. CONCLUSIONS: Monitoring TWCV can help detect the high-risk patients. Interventions intended to reduce variability on long-term graft survival may have a positive effect on graft survival.

Acute Kidney Injury and Long-Term Risk for Cardiovascular Events in Patients after Kidney Transplantation.

BACKGROUND: Acute kidney injury (AKI) was found to be associated with an increased risk of major adverse cardiovascular events (MACE) in the general population. Patients after kidney transplantation are prone to AKI events and are also at an increased risk of cardiovascular (CV) disease. The association between AKI and MACE in kidney transplant patients is yet to be studied. METHODS: This retrospective single-center cohort study reviewed 416 adult renal allograft recipients transplanted between 2005 and 2010. AKI events were recorded starting 2 weeks after transplantation, or following discharge with a functioning graft. AKI was defined, according to the KDIGO criteria. The primary outcome was the composite of MACE starting 6 months after transplantation and all-cause mortality. For survival analysis, we used univariate and multivariate time varying Cox proportional hazard model. RESULTS: One hundred and twenty-four patients (29.8%) had at least one episode of AKI. During the median follow-up time of 7.2 years (interquartile range 4.3-9.1), 144 outcome events occurred. By time varying Cox regression analysis, AKI was associated with an increased rate of CV outcomes or death (hazard ratio [HR] 1.96, 95% CI 1.36-2.81, p < 0.001), and the association remained significant by multivariate adjusted model (HR 1.76, 95% CI 1.18-2.63, p = 0.005). As for the different components of MACE, all-cause mortality and CV mortality were the only outcomes that were significantly associated with AKI. No interaction between AKI timing and MACE was found. CONCLUSION: AKI in kidney transplant recipient is associated with an increased risk of CV disease.

Post renal transplant anemia: severity, causes and their association with graft and patient survival.

BACKGROUND: Post transplantation anemia (PTA) is common among kidney transplant patients. PTA is associated with increased graft loss and in most studies with increased mortality. However, the effect of the severity of anemia on this associations was not thoroughly evaluated. METHODS: Patients who underwent kidney transplantation in Rabin Medical Center (RMC) were included in the study. Data were collected during the years 2002-2016. Anemia was defined as hemoglobin (Hb) level less than 12 g/dL in women and less than 13 g/dL in men, in accordance with World Health Organization (WHO) criteria. Severe anemia was defined as hemoglobin lower than 11 g/dL. Primary outcome was a composite of patient and graft survival. We used univariate and multivariate models to evaluate association between severity and specific causes of anemia with the outcomes. As the risk associated with anemia changed over time we analyzed the risk separately for the early and the late period (before and after 1251 days). RESULTS: Our cohort included 1139 patients, 412 (36.2%) of which had PTA and 134 (11.7%) had severe anemia. On multivariable analysis, severe anemia was highly associated with the primary outcome at the early period (HR 6.26, 95% CI 3.74-10.5, p < 0.001). Anemia due to either AKI & acute rejection (11.9% of patients) or infection (16.7%), were associated with primary outcome at the early period (HR 9.32, 95% CI 5.3-26.41, p < 0.001 and HR 3.99, 95% CI 2.01-7.95, p < 0.001, respectively). There was non-significant trend for association between anemia due to Nutritional deficiencies (29.1%) and this outcome (HR 3.07, 95% CI 0.93-10.17, p = 0.067). CONCLUSION: PTA is associated with graft loss and mortality especially during the first three years. Anemia severity affects this association. An anemia workup is recommended for PTA.

Structural and Functional Echocardiographic Changes Following Kidney Transplantation: The Role of Allograft Function.

BACKGROUND: Kidney transplantation is associated with early improvement in cardiac function and structure; however, data on cardiac adaptation and its relation to kidney allograft function remain sparse. OBJECTIVES: To investigate the relationship between post-transplant kidney function and echocardiographic measures in patients with normal/preserved pre-transplant cardiac structure and function. METHODS: The study included 113 patients who underwent kidney transplantation at a single tertiary medical center from 2000 to 2012. The patients were evaluated by echocardiography before and after transplantation, and the relation between allograft function and echocardiographic changes was evaluated. Echocardiography was performed at a median of 510 days after transplantation. RESULTS: The post-transplantation estimated glomerular filtration rate (eGFR) was directly correlated with left ventricular (LV) systolic function and inversely correlated with LV dimensions, LV wall thickness, left atrial diameter, and estimated systolic pulmonary arterial pressure. In patients with significant allograft dysfunction (eGFR ≤ 45 ml/min), LV hypertrophy worsened, with no improvement in LV dimensions. In contrast, in patients with preserved kidney function, there was a significant reduction in both LV diameter and arterial pulmonary systolic pressure. CONCLUSIONS: Our results show that in kidney transplant recipients, allograft function significantly affects cardiac structure and function. Periodic echocardiographic follow-up is advisable, especially in patients with kidney graft dysfunction.

The effect of cause, timing, kidney function recovery, and recurrent events on the prognosis of acute kidney injury in kidney transplant recipients.

AIM: To assess the incidence of acute kidney injury (AKI) and its common etiologies in kidney transplant recipients and the effect of AKI's characteristics on graft survival. METHODS: In a retrospective longitudinal cohort study, all serum creatinine (SCr) values of patients that had kidney transplantation between 01/2002-12/2010 were retrieved. AKI was defined as a 50% increase in SCr. Etiologies, recurrence, timing, and kidney function dynamics during the event were evaluated. The primary endpoint was defined as graft loss. Time-varying Cox model was used for the analysis. RESULTS: Of 659 patients, 208 (31.6%) patients had 321 documented AKI events. Of these, 138 (66.4%) patients had one event, and 70 (33.6%) patients had recurrent events. The leading etiologies of the first AKI event were as follows: infection (33.4%), hypovolemia (14.3%), and unknown etiology (16.8%). Both first and recurrent AKI events were associated with an increased risk of graft loss (HR: 2.76, 95% CI: 1.95-3.89) and (HR: 4.54, 95% CI: 2.59-7.93), respectively. This deleterious association was lower within three months after transplantation, compared to later events. Patients in whom kidney function returned to baseline were less prone to graft loss. CONCLUSIONS: Late-onset, incomplete recovery, and recurrent AKI events are associated with increased graft loss.

Association between anemia at three different time points and new-onset diabetes after kidney transplantation--a retrospective cohort study.

PURPOSE: Anemia has been reported to be associated with diabetes, but the association between new-onset diabetes after transplantation (NODAT) and anemia has not been reported. METHODS: Patients who underwent kidney transplantation and did not have diabetes prior to transplantation were included in this study. Hemoglobin levels and the prevalence of anemia (hemoglobin <12 g/dL in females and <13 g/dL in males) were evaluated at three time points (prior to transplantation, 6 months following transplantation or 1 month before the development of NODAT, 2 years following transplantation, or following the development of NODAT) and were compared between those who developed NODAT and those who did not. Variables associated with the development of anemia were compared between the two groups. RESULTS: A total of 266 kidney transplant recipients were included, of which 71 (27%) developed NODAT during the time of the follow-up. Hemoglobin and hematocrit levels and the prevalence of anemia were similar in those with and without NODAT at all three time points evaluated. Ferritin levels, prior to transplantation and mean corpuscular volume (MCV) posttransplantation post-NODAT development, were slightly but significantly lower in those with NODAT, although both were within the normal range. CONCLUSIONS: Pretransplantation ferritin levels and posttransplantation post-NODAT development MCV are inversely associated with the development of NODAT in kidney transplants.

Association of the combination of time-weighted variability of tacrolimus blood level and exposure to low drug levels with graft survival after kidney transplantation.

Background: The variability of tacrolimus blood levels has been shown to be associated with inferior graft survival. However, the effect of variability during the early post-transplantation period has not been evaluated. We sought to evaluate the association between time-weighted variability in the early post-transplantation period and graft survival. We also explored the interaction between drug level variability and exposure to inadequate drug levels. Methods: This retrospective cohort study included all patients who underwent kidney transplantation in the Rabin Medical Center and were treated with tacrolimus. Time-weighted coefficient of variability (TWCV) was defined as time-weighted standard deviation divided by the mean drug level. Univariate and multivariate Cox proportional hazard model was used with the primary outcome of patients and graft survival. Results: The study population included 803 patients who underwent kidney transplantation between 1 January 2000 and 29 September 2013. The high tertile of TWCV of tacrolimus blood levels was associated with reduced graft survival by univariate and multivariate analyses [hazard ratio (HR) 1.69, 95% confidence interval (CI) 1.14-2.53, P = 0.01 and HR 1.74, 95% CI 1.14-2.63, P = 0.01, respectively]. The interaction between high TWCV and exposure to inadequately low drug levels was significantly associated with reduced survival (P = 0.004), while the interaction between TWCV and high drug blood levels was not. One hundred and thirty patients (16.2%) had the combination of high TWCV and exposure to low drug values (<5 ng/mL). These patients had reduced graft survival by univariate and multivariate analyses (HR 2.42, 95% CI 1.57-3.74, P < 0.001 and HR 2.6, 95% CI 1.65-4.11, P < 0.001, respectively). Conclusions: The combination of high TWCV and exposure to low drug levels might identify high-risk patients in the early post-transplantation period.

The incidence of post-transplant cancer among kidney transplant recipients is associated with the level of tacrolimus exposure during the first year after transplantation.

PURPOSE: Immunosuppressive therapy plays a major role in the development of post-transplant cancer. In this nested case-control study of kidney transplant recipients (KTRs), we investigated whether the incidence of post-transplant cancer is associated with the level of tacrolimus exposure over time. METHODS: We screened the Rabin Medical Center database for adults who received kidney transplants between 2001 and 2014 and developed post-transplant cancer (excluding basal and squamous cell skin cancers). They were matched against KTRs without cancer. All patients received a maintenance immunosuppressive treatment with tacrolimus, mycophenolate mofetil and corticosteroids. The degree of exposure to tacrolimus was estimated as the time-weighted average (tTWA) value of tacrolimus blood levels. The tTWA was calculated as the area under the curve divided by time at 1, 6, and 12 months after transplantation and at time of cancer diagnosis. RESULTS: Thirty-two cases were matched against 64 controls. tTWA values above 11 ng/mL at 6 and 12 months after transplantation were associated with odds ratio (OR) of 3.1 (95% CI 1.1-9) and 11.7 (95% CI = 1.3-106), respectively, for post-transplant cancer; and with OR of 5.2 (95% CI 1.3-20.5) and 14.1 (95% CI = 1.5-134.3), respectively, for cancer diagnosed more than 3 years after transplantation. CONCLUSION: Exposure to a tacrolimus time-weighted average level above 11 ng/mL at 6 or 12 months after kidney transplantation is associated with an increased risk of developing cancer.

Serum Lactate Dehydrogenase is Elevated in Ischemic Acute Tubular Necrosis but Not in Acute Rejection in Kidney Transplant Patients.

BACKGROUND: Serum lactate dehydrogenase (LDH) levels may help to distinguish ischemic acute tubular necrosis (ATN) from acute rejection after kidney transplantation. METHODS: All kidney biopsies performed in the years 2010 to 2012 were reviewed. Serum LDH, creatinine level, clinical variables, and presence of donor-specific antibodies were recorded before the biopsy. RESULTS: Overall 150 biopsies were included. Ischemic ATN was diagnosed in 45 biopsies and acute cellular-mediated rejection and/or antibody-mediated rejection in 59 biopsies, 38 of which were accompanied by ATN. Serum LDH was elevated in 23 (51%) of 45 cases with ischemic ATN versus 15 (14%) of 105 cases with other diagnoses ( P < .0001). Median serum LDH was 478 U/L (range 277-2018) for ischemic ATN and 372 U/L (range 191-748) for all other diagnoses ( P < .001). When delayed graft function or primary nonfunctioning grafts were caused by ischemic ATN, serum LDH was elevated in 58% of cases, but when caused by acute rejection, LDH was normal in 88% of cases ( P = .02). CONCLUSIONS: There is a strong association between elevated serum LDH 1 to 3 days before performing kidney biopsy and the diagnosis of ischemic ATN after kidney transplantation, especially at the immediate posttransplantation period. Normal serum LDH at this period should raise a suspicion of acute rejection.