Evaluation of myocardial metabolism with microdialysis during bypass surgery with cold blood- or Calafiore cardioplegia.

BACKGROUND: For the first time, microdialysis was used to investigate in vivo and online the myocardial metabolism during and after cardiac surgery in patients treated with two different methods of myocardial protection. METHODS: Thirty patients underwent standard CABG with one of two different methods of myocardial protection. The patients were randomised to receive either cold blood (COLD group) or warm modified Calafiore cardioplegia (WARM group). Microdialysis probes were implanted into the myocardium of left ventricular apical region of the heart. Cardioplegia was given antegrade only. Microdialysis measurements were performed at time intervals before, during and 24 h after cardiopulmonary bypass and analysed for glucose, lactate, pyruvate and glycerol. RESULTS: Myocardial lactate concentrations were significantly higher in the WARM group compared with that of the COLD group, while serum lactate was comparable. Glycerol was significantly higher at the end of the clamping time in the WARM group. At the same time the glucose-lactate ratio as a marker of nutritional disorder had significantly lower levels in the WARM group. The cumulative CK-MB release over 24 h was significantly higher in those hearts protected with warm blood. CONCLUSIONS: The oxidative stress measured was significantly higher in patients undergoing CABG using modified Calafiore cardioplegia, whereas the cold cardioplegia minimised the effects of aortic clamping. The results indicate that cold cardioplegia offers superior protection of the heart, in terms of more rapid normalisation of myocardial metabolism. In elective myocardial revascularisation, intermittent antegrade warm blood cardioplegia is a comparable safe method of myocardial protection. However, in patients referring to a long clamping time, advantages of cold cardioplegia for myocardial revascularisation may be magnified.     

Evidence of the immunomodulatory role of dual PI3K/mTOR inhibitors in transplantation: an experimental study in mice

The PI3K/mTOR signaling cascade is fundamental in T‐cell activation and fate decisions. We showed the distinct regulation of PI3K/mTOR in regulatory and effector T‐cells and proposed the potential therapeutic benefit of targeting this pathway to control the balance between effector and regulatory T‐cell activities. Substantial adverse effects in long‐term clinical usage of rapamycin suggest the use of alternative treatments in restraining effector T‐cell function in transplant patients. We hypothesize that dual PI3K/mTOR inhibitors may represent an immunosuppressant alternative. Here we show that dual PI3K/mTOR PI‐103 and PKI‐587 inhibitors interfered IL‐2‐dependent responses in T‐cells. However, in contrast to the inhibitory effects in non‐Treg T‐cell proliferation and effector functions, dual inhibitors increased the differentiation, preferential expansion, and suppressor activity of iTregs. Rapamycin, PI‐103, and PKI‐587 targeted different signaling events and induced different metabolic patterns in primary T‐cells. Similar to rapamycin, in vivo administration of PI‐103 and PKI‐587 controlled effectively the immunological response against allogeneic skin graft. These results characterize specific regulatory mechanisms of dual PI3K/mTOR inhibitors in T‐cells and support their potential as a novel therapeutic option in transplantation.     

Prevalence,Risk Factors,Treatment, and Overall Impact of BK Viremia on Kidney Transplantation

BK viremia (BKV) is a recognized and potentially serious problem in renal transplantation. The risk factors and the impact of BKV on renal allograft and patient survival are controversial. This study reports an 8-year, single-center experience on the prevalence, risk factors, and outcomes of BKV in kidney transplant recipients. This is a retrospective analysis of all patients who received a kidney transplant at the University of Kentucky and had BK viral titers available from 2009 to 2017. BKV was defined by a polymerase chain reaction viral load of ≥ 10,000 copies per mL. Demographic, clinical, and laboratory data generated during routine outpatient follow up and inpatients records were collected. Independent risk factors for BKV were determined using uni- and multivariate analysis. Graft and patient survival was compared using Kaplan-Meier analysis, and the severity of polyomavirus nephropathy on biopsy was scored using the Banff 2017 classification. We identified 122 BK positive (19%) and 527 BK negative (81%) patients. BKV developed after a median of 115 days (range, 80–249 days) following kidney transplantation. The 1-, 5-, and 10-year graft survival was 97%, 75%, and 33% in the BKV group and 96%, 85%, and 71% in the BK negative group, respectively. Likewise, the 1-, 5-, and 10-year patient survival was 98%, 84%, and 52% in the BKV group and 98%, 92%, and 84% in the BK negative group. Male sex, age at transplantation, maintenance steroids, and alemtuzumab induction were associated with developing BKV in the multivariate analysis. We concluded that BKV is not uncommon after renal transplantation. The determinants for BKV are male sex, older transplant recipients, and maintenance steroids. BKV adversely affected graft and patient survival. A unified approach for BKV and polyomavirus nephropathy treatment is needed.     

The 2018 Banff Working Group classification of definitive polyomavirus nephropathy: A multicenter validation study in the modern era

Polyomavirus nephropathy (PVN) remained inadequately classified until 2018 when the Banff Working Group published a new 3-tier morphologic classification scheme derived from in-depth statistical analysis of a large multinational patient cohort. Here we report a multicenter “modern-era” validation study that included 99 patients with definitive PVN transplanted post January 1, 2009 and followed the original 2018 study design. Results validate the PVN classification, that is, the 3 PVN disease classes predicted clinical presentation, allograft function, and outcome independent of therapeutic intervention. PVN class 1 compared to classes 2 and 3 was diagnosed earlier (16.9 weeks posttransplant [median], P = .004), and showed significantly better function at 24 months postindex biopsy (serum creatinine 1.75 mg/dl, geometric mean, vs class 2: P = .037, vs class 3: P = .013). Class 1 presented during long-term follow-up with a low graft failure rate: 5% class 1, vs 30% class 2, vs 50% class 3 (P = .009). Persistent PVN was associated with an increased risk for graft failure (and functional decline in class 2 at 24 months postdiagnosis; serum creatinine with persistence: 2.48 mg/dL vs 1.65 with clearance, geometric means, P = .018). In conclusion, we validate the 2018 Banff Working Group PVN classification that provides significant clinical information and enhances comparative data analysis.     

Comparative Analysis of Cellular Phenotypes Within the Neointima From Vein Segments Collected Prior to Vascular Access Surgery and Stenotic Arteriovenous Dialysis Accesses

Venous stenosis, secondary to venous neointimal hyperplasia (VNH), at the arteriovenous anastomosis (AV) is a major etiology of vascular access failure in AV fistulas (AVF) and AV grafts (AVG). Recently, our group has reported that severe VNH also occurs prior to vascular access placement. The objective of this study was to perform a comparison of the cellular phenotypes within the neointima from veins collected from subjects at the time of new vascular access creation and stenotic veins from subjects with failed AVGs and AVFs. Vein samples, collected at the time of new access surgery, and stenotic vein segments, collected at access revision, were evaluated for expression of α‐smooth muscle actin (SMA), vimentin, and desmin within the neointima, and quantified using semiquantitative scoring. Within the neointima, the majority of cells from vein samples collected at the time of new access surgery were contractile smooth muscle cells, and veins from stenotic AVF and AVG were predominately myofibroblasts. Our results suggest the possibility of different mechanistic pathways in response to vascular injury that occurs prior to vascular access creation vs. after access creation, and that divergent therapeutic approaches may be needed for treating vascular injury in these two settings.     

Preexisting venous calcification prior to dialysis vascular access surgery

Vascular calcification is present in arterial vessels used for dialysis vascular access creation prior to surgical creation. Calcification in the veins used to create a new vascular access has not previously been documented. The objective of this study was to describe the prevalence of venous calcification in samples collected at the time of vascular access creation. Sixty‐seven vein samples were studied. A von Kossa stain was performed to quantify calcification. A semi‐quantitative scoring system from 0 to 4+ was used to quantify the percentage positive area for calcification as a fraction of total area (0: 0; 1+: 1–10%; 2+: 11–25%; 3+: 26–50%; 4+: >50% positive). Twenty‐two of 67 (33%) samples showed evidence of venous calcification. Histologic examination showed varying degrees of calcification within each cell layer. Among the subset of patients with calcification, 4/22 (18%), 19/22 (86%), 22/22 (100%), and 7/22 (32%) had calcification present within the endothelium, intima, media, and adventitia, respectively. The mean semi‐quantitative scores of the 22 samples with calcification were 0.18 ± 0.08, 1.2 ± 0.14, 1.6 ± 0.13, and 0.36 ± 0.12 for the endothelium, intima, media, and adventitia, respectively. Our results demonstrate that vascular calcification is present within veins used to create new dialysis vascular access, and located predominately within the neointimal and medial layers.     

Disease progression and survival in patients with prostate carcinoma and positive lymph nodes after radical retropubic prostatectomy

OBJECTIVE: To determine disease progression and survival in patients with lymph node-positive prostate carcinoma after ascending radical retropubic prostatectomy (RP) and pelvic lymphadenectomy with different forms of postoperative adjuvant treatment. PATIENTS AND METHODS: We analysed 82 patients with lymph node metastases at the time of surgery and who had a RP between 1993 and 2002. Data from clinical records and follow-up questionnaires were used. Overall survival, time to clinical disease progression and time to biochemical progression were used as endpoints to assess the outcome. Clinical progression was defined as documented local recurrence or distant metastases, and biochemical as an increase in prostate-specific antigen (PSA) of > or = 0.4 ng/mL. Variables analysed included PSA level, Gleason score before and after RP, clinical and pathological stage, number of positive lymph nodes and hormone therapy after RP. The statistical assessment included univariate regression analysis, and to analyse the distribution of clinical findings in different groups, Mantel-Haenszel statistics were used to test for differences in the numbers of patients. Survival and progression-free interval were assessed by Kaplan-Meier estimates and differences between groups calculated by log-rank statistics and Cox regression models. RESULTS: The median (range) follow-up was 55 (10-125) months. Adjuvant hormonal treatment was used in 77 patients, five of whom had immediate adjuvant radiotherapy, and nine delayed radiotherapy because of local progression or symptomatic bone metastases; five had no additional treatment. The rates for 5- and 10-year overall survival, clinical progression-free survival and biochemical progression-free survival were 84% and 79%, 83% and 77%, and 70% and 60%, respectively. Ten patients died (12%), eight (10%) of them from the cancer; bone metastases were detected in nine (11%). Local recurrences developed in three (4%) patients, 10 (12%) had a PSA increase of > or = 0.4 ng/mL alone and 58 (71%) had no signs of progression, but two died from other causes. CONCLUSIONS: Most patients with prostate cancer who had RP and pelvic lymphadenectomy followed by adjuvant hormone therapy, and who had lymph node metastases at the time of surgery, had excellent overall and progression-free survival in the long term.