Remote conditioning or erythropoietin before surgery primes kidneys to clear ischemia-reperfusion-damaged cells: a renoprotective mechanism?

Acute kidney injury is common, serious with no specific treatment. Ischemia-reperfusion is a common cause of acute kidney injury (AKI). Clinical trials suggest that preoperative erythropoietin (EPO) or remote ischemic preconditioning may have a renoprotective effect. Using a porcine model of warm ischemia-reperfusion-induced AKI (40-min bilateral cross-clamping of renal arteries, 48-h reperfusion), we examined the renoprotective efficacy of EPO (1,000 iu/kg iv.) or remote ischemic preconditioning (3 cycles, 5-min inflation/deflation to 200 mmHg of a hindlimb sphygmomanometer cuff). Ischemia-reperfusion induced significant kidney injury at 24 and 48 h (χ(2), 1 degree of freedom, >10 for 6/7 histopathological features). At 2 h, a panel of biomarkers including plasma creatinine, neutrophil gelatinase-associated lipocalin, and IL-1β, and urinary albumin:creatinine could be used to predict histopathological injury. Ischemia-reperfusion increased cell proliferation and apoptosis in the renal cortex but, for pretreated groups, the apoptotic cells were predominantly intratubular rather than interstitial. At 48-h reperfusion, plasma IL-1β and the number of subcapsular cells in G2-M arrest were reduced after preoperative EPO, but not after remote ischemic preconditioning. These data suggest an intrarenal mechanism acting within cortical cells that may underpin a renoprotective function for preoperative EPO and, to a limited extent, remote ischemic preconditioning. Despite equivocal longer-term outcomes in clinical studies investigating EPO as a renoprotective agent in AKI, optimal clinical dosing and administration have not been established. Our data suggest further clinical studies on the potential renoprotective effect of EPO and remote ischemic preconditioning are justified

Immunoprofile of metaplastic carcinomas of the breast

AimsMetaplastic breast carcinoma (MBC) is a rare type of breast cancer; its diagnosis in routine practice can be challenging, and may require immunohistochemical (IHC) characterization if no conventional invasive or in‐situ carcinoma is present. Previous IHC studies of MBC often had a small sample size and did not investigate the different histological subtypes. This study aimed to assess the immunoprofile of MBC subtypes in a large series.Methods and resultsA total of 172 MBC diagnosed in routine and referral practice in Nottingham during 26 years were reviewed by three breast pathologists. In addition, data on the immunoprofile of 730 MBC in 61 published studies were analysed. The antibodies to a broad spectrum of cytokeratins (AE1/AE3 and MNF116) are most frequently positive in MBC (approximately 80%). Basal cytokeratins (34βE12, CK5/6, CK14 and CK17) are positive in approximately 70%. Luminal cytokeratins (CK8/18, CK7 and CK19) are positive in approximately 30–60%. Myoepithelial markers are also frequently positive, particularly p63. Oestrogen receptor (ER), progestogen receptor (PR) and HER2 are usually all negative. CD34 (a marker often positive in phyllodes tumours) is consistently negative in MBC.ConclusionThis study provides data on the frequency of expression of a wide range of markers in MBC based on a large number of tumours. No consistent immunophenotype was identified and no individual marker was positive in all tumours, most probably reflecting the morphological and molecular heterogeneity of this tumour class and the practical need to use a panel of different antibodies when trying to establish the diagnosis of metaplastic breast carcinoma

Defining a threshold for tacrolimus intra-patient variability associated with late acute cellular rejection in paediatric kidney transplant recipients

Background: Late acute cellular rejection (LACR) is associated with poorer graft outcomes and non-adherence. Non-adherence to tacrolimus can be indirectly assessed by the intra-patient variability (IPV) of tacrolimus trough levels. The threshold of IPV associated with rejection is not known. Methods: We conducted a case-control study comparing 25 patients with biopsy-proven LACR against 25 stable controls matched for age group, primary diagnosis and time post-transplant. IPV was calculated using coefficient of variance (CV) and mean absolute deviation (MAD) using tacrolimus levels in the preceding 12 months. We also assessed the percentage time for tacrolimus levels < 4 μg/L (Tac < 4) and the concentration/weight-adjusted dose (C/D) ratio as a proxy marker of tacrolimus metaboliser status. Results: LACR patients had higher CV (median, IQR 44%, 36–61% v. 24%, 19–35%, p < 0.0001) and higher MAD (33%, 25–48% v. 19%, 15–26%, p < 0.0001). The MAD was less affected by outlying tacrolimus results. Receiver operating curve analysis of the MAD resulted in a sensitivity of 76% and specificity of 76% at a threshold of 26% (AUC 0.85, p < 0.05). LACR patients had more Tac < 4 (50% v. 26%, p < 0.05). There was no difference in C/D suggesting that good IPV can be maintained in fast metabolisers. Patients with LACR had significantly increased creatinine at 12-month follow-up despite treatment (108 v. 5 umol/L increase from baseline) and four patients lost their allograft. Conclusions: Monitoring of tacrolimus IPV using the MAD may be a clinical marker for LACR. A threshold IPV of 26% can potentially be used as a therapeutic target pending further validation studies. © 2019, IPNA

Breast Neoplasms with Dermal Analogue Differentiation (Mammary Cylindroma): Report of 3 Cases and a Proposal for a New Terminology

Salivary gland-like and dermal analogue tumours of the breast are rare lesions that can be diagnostically challenging for pathologists. Data on the clinical behaviour and molecular characterisation of these mammary tumours are limited and their designation is mainly based on similar salivary gland or skin lesions. In this study, we present three cylindromatous breast tumours. These lesions were located within the breast, had ill-defined margins and were composed of nests containing a dual population of cytologically bland cells, surrounded at least partially by basement membrane-like material. The lack of cytological atypia and absence of mitoses led to the diagnosis of benign mammary cylindroma in 1 case. The expression of oestrogen receptor, focal absence of basement membrane material and the focal infiltrative nature together with patchy absence of peripheral basement membrane supported the diagnosis of malignancy in the other 2 cases. We discuss the morphological criteria, immunohistochemical profile and diagnostic pitfalls of these tumours. We also review the literature including previously reported cases of mammary cylindroma and differential diagnoses to be considered before making a diagnosis. We propose the term ‘mammary tumours with cylindromatous differentiation', implying their uncertain malignant nature, and propose management strategies