ABSTRACT
PURPOSE: Simultaneous pancreas-kidney transplantation (SPKT) remains the best treatment option in patients with type 1 diabetes and chronic kidney failure. There are only a few studies addressing the potential ischemic deterioration of peripheral arterial disease (PAD) due to blood diverting from the iliac artery to the kidney graft. We aimed to evaluate diabetic foot lesions and PAD evolution in SPKT recipients and investigate if they are more frequent in ipsilateral lower limb of kidney graft. METHODS: We developed a retrospective cohort, including patients submitted to SPKT in our tertiary center, between 2000 and 2017. Diabetic foot lesions and PAD frequencies were compared in the period before and after transplantation. RESULTS: Two hundred and eleven patients were included, 50.2% (n = 106) female, with a median age at transplantation of 35 years (IQR 9). After a median follow-up period of 10 years (IQR 7), patient, kidney, and pancreatic graft survival were 90.5% (n = 191), 83.4% (n = 176), and 74.9% (n = 158), respectively. Before transplant, 2.8% (n = 6) had PAD and 5.3% (n = 11) had history of foot lesions. In post-transplant period, 17.1% (n = 36) patients presented PAD and 25.6% (n = 54) developed diabetic foot ulcers, 47.6% (n = 35) of which in the ipsilateral and 53.3% (n = 40) in the contralateral lower limb of the kidney graft (p = 0.48). Nine patients (4.3%) underwent major lower limb amputation, 3 (30%) ipsilateral and 7 (70%) contralateral to the kidney graft (p = 0.29). CONCLUSIONS: Diabetic foot lesions were not more frequent in the ipsilateral lower limb of the kidney graft, therefore downgrading the 'steal syndrome' role in these patients.
Subject(s)
Diabetes Mellitus, Type 1 , Diabetic Foot , Kidney Transplantation , Peripheral Arterial Disease , Humans , Female , Child , Diabetic Foot/etiology , Kidney Transplantation/adverse effects , Retrospective Studies , Peripheral Arterial Disease/etiology , Pancreas , Treatment OutcomeABSTRACT
Nerve growth factor (NGF) can augment transmitter release in sensory neurons by acutely sensitizing sensory neurons and by increasing the expression of calcitonin gene-related peptide (CGRP) over time. The current study examined the intracellular signaling pathways that mediate these two temporally distinct effects of NGF to augment CGRP release from sensory neurons. Growing sensory neurons in 30 or 100 ng/mL of NGF for 7 days increases CGRP content and this increase augments the amount of CGRP that is released by high extracellular potassium. Overexpressing a dominant negative Ras, Ras(17N) or treatment with a farnesyltransferase inhibitor attenuates the NGF-induced increase in CGRP content. Conversely, overexpressing a constitutively active Ras augments the NGF-induced increase in content of CGRP. Inhibiting mitogen activated protein kinase (MEK) activity also blocks the ability of NGF to increase CGRP expression. In contrast to the ability of chronic NGF to increase peptide content, acute exposure of sensory neurons to 100 ng/mL NGF augments capsaicin-evoked release of CGRP without affecting the content of CGRP. This sensitizing action of NGF is not affected by inhibiting Ras, MEK, or PI3 kinases. In contrast, the NGF-induced increase in capsaicin-evoked release of CGRP is blocked by the protein kinase C (PKC) inhibitor, BIM and the Src family kinases inhibitor, PP2. These data demonstrate that different signaling pathways mediate the alterations in expression of CGRP by chronic NGF and the acute actions of the neurotrophin to augment capsaicin-evoked release of CGRP in the absence of a change in the content of the peptide.
