Contrast-induced nephropathy after peripheral vascular intervention: Long-term renal outcome and risk factors for progressive renal dysfunction.

OBJECTIVE: Contrast-induced nephropathy (CIN) is a frequently used quality outcome marker after peripheral vascular interventions (PVIs). Whereas the factors associated with CIN development have been well documented, the long-term renal effects of CIN after PVI are unknown. This study was undertaken to investigate the long-term (1-year) renal consequences of CIN after PVI and to identify factors associated with renal function deterioration at 1-year follow-up. METHODS: From 2008 to 2015, patients who had PVI at our institution (who were part of a statewide Vascular Interventions Collaborative) were queried for those who developed CIN. CIN was defined by the Collaborative as an increase in serum creatinine concentration of at least 0.5 mg/dL within 30 days after intervention. Preprocedural dialysis patients or patients without postprocedural creatinine values were excluded. Preprocedural, postprocedural, and 1-year serum creatinine values were abstracted and used to estimate glomerular filtration rate (GFR). ΔGFR was defined as preprocedural GFR minus 1-year GFR. Univariate and multivariate analyses for ΔGFR were performed to determine factors associated with renal deterioration at 1 year. RESULTS: From 2008 to 2015, there were 1323 PVIs performed; 881 patients met the inclusion criteria. Of these, 57 (6.5%) developed CIN; 47% were male, and 51% had baseline chronic kidney disease. CIN resolved by discharge in 30 patients (53%). Using multivariate linear regression, male sex (P = .027) and congestive heart failure (P = .048) were associated with 1-year GFR decline. Periprocedural variables related to 1-year GFR decline included percentage increase in 30-day postprocedural creatinine concentration (P = .025), whereas CIN resolution by discharge (mean, 13.1 days) was protective for renal function at 1 year (P = .02). A post hoc analysis was performed with 50 PVI patients (randomly selected) who did not develop CIN, comparing their late renal function with that of the CIN group stratified by the periprocedural 30-day variables. Patients with CIN resolution at discharge had similar 1-year renal outcomes to non-CIN patients, whereas the CIN-persistent (at discharge) patients had greater renal deterioration at 1 year compared with non-CIN patients (P = .016). CONCLUSIONS: Male sex and congestive heart failure are risk factors for further renal function decline in patients developing CIN after PVI. The magnitude and duration of increase in creatinine concentration (CIN persistence at discharge) correlated with late progressive renal dysfunction in CIN patients, suggesting that early-resolving CIN is relatively benign.

ERK activation is required for CCK-mediated pancreatic adaptive growth in mice.

High levels of cholecystokinin (CCK) can stimulate pancreatic adaptive growth in which mature acinar cells divide, leading to enhanced pancreatic mass with parallel increases in protein, DNA, RNA, and digestive enzyme content. Prolonged release of CCK can be induced by feeding trypsin inhibitor (TI) to disrupt normal feedback control. This leads to exocrine growth in a CCK-dependent manner. The extracellular signal-related kinase (ERK) pathway regulates many proliferative processes in various tissues and disease models. The aim of this study was to evaluate the role of ERK signaling in pancreatic adaptive growth using the MEK inhibitors PD-0325901 and trametinib (GSK-1120212). It was determined that PD-0325901 given two times daily by gavage or mixed into powdered chow was an effective and specific inhibitor of ERK signaling in vivo. TI-containing chow led to a robust increase in pancreatic mass, protein, DNA, and RNA content. This pancreatic adaptive growth was blocked in mice fed chow containing the MEK inhibitors. PD-0325901 blocked TI-induced ERK-regulated early response genes, cell-cycle proteins, and mitogenesis by acinar cells. It was determined that ERK signaling is necessary for the initiation of pancreatic adaptive growth but not necessary to maintain it. PD-0325901 blocked adaptive growth when given before cell-cycle initiation but not after mitogenesis had been established. Furthermore, GSK-1120212, a chemically distinct inhibitor of the ERK pathway that is now approved for clinical use, inhibited growth similar to PD-0325901. These data demonstrate that the ERK pathway is required for CCK-stimulated pancreatic adaptive growth.