The impact of mTOR inhibitors in the regression of left ventricular hypertrophy in elderly kidney transplant recipients.

End-stage kidney disease is frequently associated with left ventricular hypertrophy (LVH), a condition more prevalent in the elderly, that may increase mortality after renal transplantation (RTx). Previous studies suggested that mTOR inhibitors (mTORi) can improve LVH, but this has never been tested in elderly kidney transplant recipients. In this prospective randomized clinical trial, we analyzed the impact of Everolimus (EVL) on the reversal of LVH after RTx in elderly recipients (≥60 years) submitted to different immunosuppressive regimens: EVL/lowTacrolimus (EVL group, n = 53) or mycophenolate sodium/regularTacrolimus (MPS group, n = 47). Patients performed echocardiograms (Echo) up to 3 months after RTx and then annually. At baseline, mean age was 65±3 years in both groups and LVH was observed in 63.6% of patients in EVL group and in 61.8% of MPS group. Last Echo was performed at mean time of 47 and 49 months after RTx in EVL and MPS groups, respectively (P = .34). LVH regression was observed in 23.8% (EVL group) and 19% (MPS group) of patients (P = 1.00). Mean eGFR, blood pressure, and use of RAS blockers were similar between groups throughout follow-up. EVL did not improve LVH in this cohort, and this lack of benefit may be attributed to concomitant use of TAC, senescence, or both.

Does the urinary tract infection caused by carbapenem-resistant Gram-negative bacilli impact the outcome of kidney transplant recipients?

The incidence of urinary tract infection (UTI) after kidney transplantation (KT) caused by multidrug-resistant (MDR) bacteria is growing. The aim of this study was to analyze the impact of UTI caused by carbapenem-resistant Gram-negative bacteria (CR-GNB) in the survival of graft and recipients following KT. This was a retrospective cohort study involving patients who underwent KT between 2013 and 2016. Patients were followed since the day of the KT until loss of graft, death or end of the follow-up period (31th December 2016). The outcomes measured were UTI by MDR following KT and graft and patient survival. Analyses were performed using Cox regression; for the graft and patient survival analysis, we used a propensity score for UTI by CR-GNB to matching a control group. UTI was diagnosed in 178 (23.9%) of 781 patients, who developed 352 UTI episodes. 44.6% of the UTI cases were caused by MDR bacteria. Identified risk factors for UTI by MDR bacteria were DM, urologic disease as the cause of end-stage renal failure, insertion of ureteral stent, carbapenem use, and delayed graft function (DGF). Risk factors for death during the follow-up period were female gender, patients over 60 years old at the time of KT, DM, body mass index over 31.8, UTI caused by CR-GNB. In conclusion, UTIs caused by CR-GNB have great impact on patients' survival after KT.

Severe type 1 upgrading leprosy reaction in a renal transplant recipient: a paradoxical manifestation associated with deficiency of antigen-specific regulatory T-cells?

BACKGROUND: Due to its chronic subclinical course and large spectrum of manifestations, leprosy often represents a diagnostic challenge. Even with proper anti-mycobacteria treatment, leprosy follow up remains challenging: almost half of leprosy patients may develop reaction episodes. Leprosy is an infrequent complication of solid organ transplant recipients. This case report illustrates the challenges in diagnosing and managing leprosy and its reactional states in a transplant recipient. CASE PRESENTATION: A 53-year-old man presented 34 months after a successful renal transplantation a borderline-tuberculoid leprosy with signs of mild type 1 upgrading reaction (T1R). Cutaneous manifestations were atypical, and diagnosis was only made when granulomatous neuritis was found in a cutaneous biopsy. He was successfully treated with the WHO recommended multidrug therapy (MDT: rifampicin, dapsone and clofazimine). However he developed a severe T1R immediately after completion of the MDT but no signs of allograft rejection. T1R results from flare-ups of the host T-helper-1 cell-mediated immune response against Mycobacterium leprae antigens in patients with immunologically unstable, borderline forms of leprosy and has been considered an inflammatory syndrome in many aspects similar to the immune reconstitution inflammatory syndromes (IRS). The T1R was successfully treated by increasing the prednisone dose without modifying the other immunosuppressive drugs used for preventing allograft rejection. Immunological study revealed that the patient had a profound depletion of both in situ and circulating regulatory T-cells and lack of expansion of the Tregs upon M. leprae stimulation compared to T1R leprosy patients without iatrogenic immunosuppression. CONCLUSIONS: Our case report highlights that leprosy, especially in the transplant setting, requires a high degree of clinical suspicion and the contribution of histopathology. It also suggests that the development of upgrading inflammatory syndromes such as T1R can occur despite the sustained immunosuppressors regimen for preventing graft rejection. Our hypothesis is that the well-known deleterious effects of these immunosuppressors on pathogen-induced regulatory T-cells contributed to the immunedysregulation and development T1R.

Outbreak of IMP-producing carbapenem-resistant Enterobacter gergoviae among kidney transplant recipients.

OBJECTIVES: The objective of this study was to investigate a prolonged outbreak of carbapenem-resistant Enterobacter gergoviae (CREG) involving kidney transplant recipients (KTRs) between 2009 and 2014. METHODS: A case-control study was undertaken. Controls (n = 52) were selected from CREG-negative KTRs. Surveillance cultures for CREG were collected weekly. Colonization was defined as isolation of CREG from surveillance samples or from clinical specimens, with no evidence of infection. We also investigated infection control practices at the facility. RESULTS: Of 26 identified cases, 13 had had no known contact with another CREG-positive patient before the first positive culture. Seven patients (27%) developed infection. The site most often colonized was the urinary tract. During the study period two clusters were identified, one in 2009 and another in 2013-14. DNA sequencing revealed blaIMP-1 in all CREG tested. No environmental or hand cultures tested positive for CREG. An audit of infection control practices detected flaws in the handling and cleaning of urinary tract devices. Multivariate analysis identified advanced age, ureteral stent use, retransplantation and male gender as risk factors for CREG acquisition. CONCLUSIONS: An outbreak among KTRs caused by an unusual species of MDR bacteria may have resulted from a common source of contamination related to urinary tract devices.

Risk factors and outcome of infections with Klebsiella pneumoniae carbapenemase-producing K. pneumoniae in kidney transplant recipients.

INTRODUCTION: Solid organ transplant recipients are especially susceptible to healthcare-associated infections with Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp-HAIs). The aim of the study was to evaluate risk factors and outcome of these infections in kidney transplant recipients. METHODS: This was a retrospective cohort of kidney transplant (KTx) recipients between January 2009 and December 2013. Cases were defined as patients who developed KPC-Kp-HAI, confirmed by PCR for bla( KPC) gene after KTx during the study period. We analysed variables related to recipient; induction immunosuppressant therapy; delayed graft function; use of invasive devices; SOFA score on the first day of infection; type of therapy; time from positive culture to appropriate antimicrobial therapy; bacteraemia; and concomitant infection. Outcome measures were the occurrence of KPC-Kp-HAI and 30-day mortality after KPC-Kp-HAI. RESULTS: A total of 1,101 were submitted to KTx in the period, 21 patients were classified as infected with KPC-Kp. Another ten patients had KPC-Kp-HAI in the period and were transplanted before 2009. Of those 31 patients, 48.4 % showed evidence of prior colonization and 38.7 % had bacteraemia. The most common site of infection was the surgical wound. Risk factors for KPC-Kp-HAI were multi-organ transplantation and the use of a ureteral stent. Eight of the infected patients experienced recurrence of the infection. The 30-day mortality rate was 41.9 %. Survival was significantly lower among the patients with KPC-Kp-HAI (72 vs. 89.1 %; P = 0.002). The only risk factor independently associated with 30-day mortality was an elevated SOFA score on the first day of infection. CONCLUSIONS: In KTx recipients, the occurrence of KPC-Kp-HAI was related to invasive devices and type of transplant; these infections had a high rate of recurrence and reduced survival after KTx.

The role of myocardial scintigraphy in the assessment of cardiovascular risk in patients with end-stage chronic kidney disease on the waiting list for renal transplantation.

BACKGROUND: The usefulness of stress myocardial perfusion scintigraphy for cardiovascular (CV) risk stratification in chronic kidney disease remains controversial. We tested the hypothesis that different clinical risk profiles influence the test. METHODS: We assessed the prognostic value of myocardial scintigraphy in 892 consecutive renal transplant candidates classified into four risk groups: very high (aged≥50 years, diabetes and CV disease), high (two factors), intermediate (one factor) and low (no factor). RESULTS: The incidence of CV events and death was 20 and 18%, respectively (median follow-up=22 months). Altered stress testing was associated with an increased probability of cardiovascular events only in intermediate-risk (one risk factor) patients [30.3 versus 10%, hazard ratio (HR)=2.37, confidence interval (CI) 1.69-3.33, P<0.0001]. Low-risk patients did well regardless of scan results. In patients with two or three risk factors, an altered stress test did not add to the already increased CV risk. Myocardial scintigraphy was related to overall mortality only in intermediate-risk patients (HR=2.8, CI 1.5-5.1, P=0.007). CONCLUSIONS: CV risk stratification based on myocardial stress testing is useful only in patients with just one risk factor. Screening may avoid unnecessary testing in 60% of patients, help stratifying for risk of events and provide an explanation for the inconsistent performance of myocardial scintigraphy.

Which patients are more likely to benefit from renal transplantation?

BACKGROUND: We evaluated whether the advantages conferred by renal transplantation encompass all individuals or whether they favor more specific groups of patients. METHODS: One thousand and fifty-eight patients on the transplant waiting list and 270 receiving renal transplant were studied. End points were the composite incidence of CV events and death. Patients were followed up from date of placement on the list until transplantation, CV event, or death (dialysis patients), or from the date of transplantation, CV event, return to dialysis, or death (transplant patients). RESULTS: Younger patients with no comorbidities had a lower incidence of CV events and death independently of the treatment modality (log-rank=0.0001). Renal transplantation was associated with better prognosis only in high-risk patients (p=0.003). CONCLUSIONS: Age and comorbidities influenced the prevalence of CV complications and death independently of the treatment modality. A positive effect of renal transplantation was documented only in high-risk patients. These findings suggest that age and comorbidities should be considered indication for early transplantation even considering that, as a group, such patients have a shorter survival compared with low-risk individuals.

Unexplained sudden death in patients on the waiting list for renal transplantation.

BACKGROUND: The incidence of unexplained sudden death (SD) and the factors involved in its occurrence in patients with chronic kidney disease are not well known. METHODS: We investigated the incidence and the role of co-morbidities in unexplained SD in 1139 haemodialysis patients on the renal transplant waiting list. RESULTS: Forty-four patients died from SD of undetermined causes (20% of all deaths; 3.9 deaths/1000 patients per year), while 178 died from other causes and 917 survived. SD patients were older and likely to have diabetes, hypertension, past/present cardiovascular disease, higher left ventricular mass index, and lower ejection fraction. Multivariate analysis showed that cardiovascular disease of any type was the only independent predictor of SD (P = 0.0001, HR = 2.13, 95% CI 1.46-3.22). Alterations closely associated with ischaemic heart disease like angina, previous myocardial infarction and altered myocardial scan were not independent predictors of SD. The incidence of unexplained SD in these haemodialysis patients is high and probably a consequence of pre-existing cardiovascular disease. CONCLUSIONS: Factors influencing SD in dialysis patients are not substantially different from factors in the general population. The role played by ischaemic heart disease in this context needs further evaluation.

Institutional protocol adherence in the incidence of recurrent urinary tract infection after kidney transplantation.

OBJECTIVES: Recurrent urinary tract infections (rUTIs) occur frequently after kidney transplantation (KT), however their optimal management remains undefined. This study aimed to identify risk factors for rUTI and to validate a protocol for UTI and rUTI treatment after KT. METHODS: This retrospective cohort study involved patients undergoing KT between January 2013 and July 2016. Patients were followed-up from day of KT until graft loss, death or end of follow-up (31 December 2018). We analysed all episodes of symptomatic UTI. The main outcome measure was rUTI after KT. Analysis was done per episode in a multilevel approach; patient features were considered in the distal level and UTI features in the proximal level. Univariate and multivariate analyses were performed by Cox regression. A propensity score was used to adjust the risk of patients with carbapenem-resistant Enterobacteriaceae. RESULTS: During the study period, 787 patients underwent KT, of whom 152 (19.3%) developed 356 UTI episodes. The most common micro-organisms wereEscherichia coli (165/356; 46.3%) and Klebsiella pneumoniae (101/356; 28.4%). Multidrug-resistant micro-organisms were isolated in 161 UTIs (45.2%). Risk factors for rUTI were diabetic nephropathy as the cause of end-stage renal disease (P = 0.02), UTI in first 180 days after KT (P = 0.04), anatomic alteration of the urinary tract at UTI diagnosis (P = 0.004) and length of time to effective therapy (P = 0.002); UTI treatment duration according to institutional protocol (P = 0.04) was the only protective factor identified. CONCLUSION: Appropriate therapy duration has an impact on rUTI prevention after KT.

Amikacin prophylaxis and risk factors for surgical site infection after kidney transplantation.

BACKGROUND: Antibiotic prophylaxis plays a major role in preventing surgical site infections (SSIs). This study aimed to evaluate antibiotic prophylaxis in kidney transplantation and identify risk factors for SSIs. METHODS: We evaluated all kidney transplantation recipients from January 2009 and December 2012. We excluded patients who died within the first 72 hr after transplantation, were undergoing simultaneous transplantation of another organ, or were below 12 years of age. The main outcome measure was SSI during the first 60 days after transplantation. RESULTS: A total of 819 kidney transplants recipients were evaluated, 65% of whom received a deceased-donor kidney. The antibiotics used as prophylaxis included cephalosporin, in 576 (70%) cases, and amikacin, in 233 (28%). We identified SSIs in 106 cases (13%), the causative agent being identified in 72 (68%). Among the isolated bacteria, infections caused by extended-spectrum ß-lactamase-producing Enterobacteriaceae predominated. Multivariate analysis revealed that the risk factors for post-kidney transplantation SSIs were deceased donor, thin ureters at kidney transplantation, antithymocyte globulin induction therapy, blood transfusion at the transplantation procedure, high body mass index, and diabetes mellitus. The only factor associated with a reduction in the incidence of SSIs was amikacin use as antibiotic prophylaxis. Factors associated with reduced graft survival were: intraoperative blood transfusions, reoperation, human leukocyte antigen mismatch, use of nonstandard immunosuppression therapy, deceased donor, post-kidney transplantation SSIs, and delayed graft function. CONCLUSION: Amikacin prophylaxis is a useful strategy for preventing SSIs.

[Vasculopathy in the kidney allograft at time of transplantation delays recovery of graft function after deceased-donor kidney transplantation]. / Alteracoes vasculares em rins de doadores falecidos retardam a recuperacao da funcao do enxerto apos o transplante renal.

OBJECTIVE: The purpose of this study was to evaluate the impact of donor and recipient characteristics on duration of delayed graft function (DGF) and 1-year serum creatinine (SCr), as a surrogate endpoint for allograft survival. METHODS: We reviewed 120 first cadaver kidney transplants carried out consecutively at our center to examine the effect on 1-year SCr of the presence and duration of DGF. RESULTS: DGF rate was 68%, with a median duration of 12 days (range, 1-61). Forty-four (38%) patients presented DGF lasting 12 or more days (prolonged DGF group). Mean donor age was 43 ± 13 years, 37% had hypertension and in 59% the cause of brain death was cardiovascular accident. The mean cold ischemia time was 23 ± 5 hours. Twenty-seven (23%) donors were classified as expanded-criteria donors according to OPTN criteria. The mean recipient age was 51 ± 15 years. The recipients median time in dialysis was 43 months (range, 1-269) and 25% of them had panel reactive antibodies > 0%. Patients with prolonged DGF presented higher 1-year SCr in comparison with patients without DGF (1.7 vs. 1.3 mg/dL, respectively, p = 0.03). In multivariate logistic regression analysis, the only significant factor contributing to the occurrence of prolonged DGF was the presence of vascular lesions in the kidney allograft at time of transplantation (HR 3.6, 95% CI 1.2-10.2; p = 0.02). CONCLUSION: The presence of vasculopathy in the kidney allograft at time of transplantation was identified as an important factor independently associated with prolonged DGF. Prolonged DGF negatively impacts 1-year graft function.

Rejection-triggered haemophagocytic syndrome in renal transplantation successfully treated with intravenous immunoglobulin.

Haemophagocytic syndrome (HPS) is a rare and potentially lethal condition characterized by pancytopoenia, fever, organomegaly and widespread proliferation of macrophages phagocytosing blood elements. Among the triggers of this syndrome, excessive immunosuppression in a context of acute rejection has been rarely reported, although it might be underdiagnosed. Here, we report the case of a kidney transplant recipient with allograft dysfunction due to chronic antibody-mediated rejection treated with antithymocyte globulin and plasmapheresis. The patient developed high fever, pancytopoenia, diarrhoea and respiratory symptoms with no apparent infectious or neoplastic cause, despite an extensive work-up. Haemophagocytosis was found in bone marrow examination, along with hyperferritinaemia and hypertriglyceridaemia. The clinical profile improved after treatment with intravenous immunoglobulin and reduction of the basal immunosuppression.

A new risk score model to predict the presence of significant coronary artery disease in renal transplant candidates.

BACKGROUND: Renal transplant candidates are at high risk of coronary artery disease (CAD). We sought to develop a new risk score model to determine the pre-test probability of the occurrence of significant CAD in renal transplant candidates. METHODS: A total of 1,060 renal transplant candidates underwent a comprehensive cardiovascular risk evaluation. Patients considered at high risk of CAD (age ≥50 years, with either diabetes mellitus (DM) or cardiovascular disease (CVD)), or having noninvasive testing suggestive of CAD were referred for coronary angiography (n = 524). Significant CAD was defined by the presence of luminal stenosis ≥70%. A binary logistic regression model was built, and the resulting logistic regression coefficient B for each variable was multiplied by 10 and rounded to the next whole number. For each patient, a corresponding risk score was calculated and the receiver operating characteristic (ROC) curve was constructed. RESULTS: The final equation for the model was risk score = (age × 0.4) + (DM × 9) + (CVD × 14) and for the probability of CAD (%) = (risk score × 2) - 23. The corresponding ROC for the accuracy of the diagnosis of CAD was 0.75 (P <0.0001) in the developmental model. CONCLUSIONS: We developed a simple clinical risk score to determine the pre-test probability of significant CAD in renal transplant candidates. This model may help those directly involved in the care of patients with end-stage renal disease being considered for transplantation in an attempt to reduce the rate of cardiovascular events that presently hampers the long-term prognosis of such patients.

Validation of a strategy to diagnose coronary artery disease and predict cardiac events in high-risk renal transplant candidates.

BACKGROUND: We validated a strategy for diagnosis of coronary artery disease (CAD) and prediction of cardiac events in high-risk renal transplant candidates (at least one of the following: age > or =50 years, diabetes, cardiovascular disease). METHODS: A diagnosis and risk assessment strategy was used in 228 renal transplant candidates to validate an algorithm. Patients underwent dipyridamole myocardial stress testing and coronary angiography and were followed up until death, renal transplantation, or cardiac events. RESULTS: The prevalence of CAD was 47%. Stress testing did not detect significant CAD in 1/3 of patients. The sensitivity, specificity, and positive and negative predictive values of the stress test for detecting CAD were 70, 74, 69, and 71%, respectively. CAD, defined by angiography, was associated with increased probability of cardiac events [log-rank: 0.001; hazard ratio: 1.90, 95% confidence interval (CI): 1.29-2.92]. Diabetes (P=0.03; hazard ratio: 1.58, 95% CI: 1.06-2.45) and angiographically defined CAD (P=0.03; hazard ratio: 1.69, 95% CI: 1.08-2.78) were the independent predictors of events. CONCLUSION: The results validate our observations in a smaller number of high-risk transplant candidates and indicate that stress testing is not appropriate for the diagnosis of CAD or prediction of cardiac events in this group of patients. Coronary angiography was correlated with events but, because less than 50% of patients had significant disease, it seems premature to recommend the test to all high-risk renal transplant candidates. The results suggest that angiography is necessary in many high-risk renal transplant candidates and that better noninvasive methods are still lacking to identify with precision patients who will benefit from invasive procedures.

Treatment of coronary artery disease in hemodialysis patients evaluated for transplant-a registry study.

BACKGROUND: We assessed the results of a noninvasive therapeutic strategy on the long-term occurrence of cardiac events and death in a registry of patients with chronic kidney disease (CKD) and coronary artery disease (CAD). METHODS: We analyzed 519 patients with CKD (56+/-9 years, 67% men, 67% whites) on maintenance hemodialysis with clinical or scintigraphic evidence of CAD by using coronary angiography. RESULTS: In 230 (44%) patients, coronary angiography revealed significant CAD (lumen reduction > or =70%). Subjects with significant CAD were kept on medical treatment (MT; n=184) or referred for myocardial revascularization (percutaneous transluminal coronary angioplasty/coronary artery bypass graft-intervention; n=30) according to American College of Cardiology/American Heart Association guidelines. In addition, 16 subjects refused intervention and were also followed-up. Event-free survival for patients on MT at 12, 36, and 60 months was 86%, 71%, and 57%, whereas overall survival was 89%, 71%, and 50% in the same period, respectively. Patients who refused intervention had a significantly worse prognosis compared with those who actually underwent intervention (events: hazard ratio=4.50; % confidence interval=1.48-15.10; death: hazard ratio=3.39; % confidence interval 1.41-8.45). CONCLUSIONS: In patients with CKD and significant CAD, MT promotes adequate long-term event-free survival. However, failure to perform a coronary intervention when necessary results in an accentuated increased risk of events and death.

Underuse of American College of Cardiology/American Heart Association Guidelines in hemodialysis patients.

Patients with end-stage renal disease (ESRD) are at high risk for cardiovascular disease (CVD) and therefore should be treated according to ACC/AHA Guidelines. Scant data are available concerning the actual use of cardioprotective drugs in this population. The use of angiotensin-converting enzyme inhibitors (ACE-I), beta-blockers, aspirin, and statins was assessed in 271 (72% males, 66% Caucasians) high-risk ESRD patients on hemodialysis. The study population comprised 27% smokers, 95% with hypertension, 38% with diabetes, and 44% with dyslipidemia; 44% of patients had overt CVD at baseline, including 9% with heart failure, 9% with prior myocardial infarction, and 3% with previous myocardial revascularization. One-third of all patients were not receiving any cardioprotective drugs; among those patients who were, 42% were on one drug, 21% were on two, 3.7% were on three, and 1.5% were on four. The most prescribed agent was ACE-I (35.8%), followed by aspirin (30.6%), and beta-blockers (28.0%). The use of statins was remarkably and significantly low (4.1%) (p < 0.001), even in the higher risk subgroups (patients with diabetes or macrovascular disease). ACE-I plus aspirin was the most prescribed combination (8.5%). Cardioprotective agents recommended for risk-factor modification by the ACC/AHA Guidelines for their well-established efficacy in the general population were underutilized in this cohort of high-risk hypertensive hemodialysis patients, despite an elevated prevalence of clinically evident CVD. Speculatively, this fact may be relevant to better understand the known increased cardiovascular morbidity-mortality associated with chronic renal disease.

Diabetes and coronary artery disease impose similar cardiovascular morbidity and mortality on renal transplant candidates.

BACKGROUND: In renal transplant candidates (RTC), diabetes and coronary artery disease (CAD) are commonly observed. However, whether diabetes imparts a cardiovascular risk equivalent to that of CAD and whether CAD adds to the cardiovascular risk associated with diabetes is unknown. METHODS: To assess the interplay between diabetes and CAD as a determinant of major adverse cardiovascular events (MACE), 288 high-risk RTC (56.4+/-8.1 years old, 72% males) underwent a comprehensive cardiovascular evaluation including coronary angiography. Patients were divided into four groups based on the diagnoses of diabetes and CAD (>70% narrowing), and followed up for 1-60 months (median, 17). The primary endpoint was the composite incidence of fatal/non-fatal MACE. RESULTS: During follow-up, 80 MACE occurred. Patients with diabetes (P=0.03) or CAD (P<0.0001) had a worse long-term prognosis. However, only in patients without diabetes was CAD associated with an increased incidence of MACE (10.6% vs 45.9%, P<0.0001). In patients with diabetes, the endpoints were not different between those with and without CAD. No difference occurred in the long-term prognosis of patients with diabetes (with or without CAD) and patients without diabetes with CAD. CONCLUSIONS: We concluded that in high-risk RTC, diabetes confers a cardiovascular risk comparable to that of CAD in patients without diabetes, independent of coronary obstruction. In patients with diabetes, concomitant CAD does not add to the already very high cardiovascular risk of this population.