Contrast-Induced Acute Kidney Injury: Evidence in Support of Its Existence and a Review of Its Pathogenesis and Management.

The role of contrast-induced nephropathy (CIN) remains controversial. Many experts contend that CIN does not exist or is extremely rare. The diagnosis was previously made too frequently and inappropriately in the presence of coexisting and confounding comorbidities and risk factors making it difficult to singularly isolate the etiologic role of intravenous contrast media in acute kidney injury (AKI). It is probable that many patients were denied important diagnostic information from radiocontrast studies for fear of CIN. Recently, a new terminology for CIN was introduced, and the term CIN was replaced by two interrelated new terms: one is contrast-associated acute kidney injury (CA-AKI), and the second one is contrast-induced acute kidney injury (CI-AKI). CA-AKI occurs in association with risk factors or comorbidities, therefore, it is a correlative diagnosis. On the other hand, CI-AKI is a subtype of CA-AKI that results directly from iodinated contrast media. In this review, we present evidence from various studies that argue against CI-AKI and also those that suggest its existence but with much lower frequency. We will also provide the current status of the pathophysiology and management of CA-AKI/CI-AKI.

A case of multiple extrahepatic manifestations in a patient with untreated, chronic hepatitis C virus infection.

Chronic hepatitis C virus (HCV) infection is a complex, multi-organ disorder, not just limited to the liver. Mixed cryoglobulinemia (MC) type 2 is a common extrahepatic complication, in which immunoglobulin complexes deposit in vascular endothelium. This in turn creates a diffuse inflammatory reaction, leading to a variety of disorders involving multiple systems. We report the rare case of a patient with cryoglobulinemia, cutaneous vasculitis, membroproliferative glomerulonephritis, and B cell lymphoma with a variant t(6;10) translocation in the setting of an untreated, chronic HCV infection. This case highlights the challenge associated with diagnosing and managing such a complex presentation.

Activated IGF-1R inhibits hyperglycemia-induced DNA damage and promotes DNA repair by homologous recombination.

The IGF-1R is a genetic determinant of oxidative stress and longevity. Hyperglycemia induces an exponential increase in the production of a key danger signal, reactive oxygen intermediates, which target genomic DNA. Here, we report for the first time that ligand activation of the IGF-1R prevents hyperglycemia-induced genotoxic stress and enhances DNA repair, maintaining genomic integrity and cell viability. We performed single gel electrophoresis (comet assay) to evaluate DNA damage in serum-starved SV40 murine mesangial cells (MMC) and normal human mesangial cells (NHMC), maintained at high ambient glucose concentration. Hyperglycemia inflicted an impressive array of DNA damage in the form of single-strand breaks (SSBs) and double-strand breaks (DSBs). The inclusion of IGF-1 to culture media of MMC and NHMC prevented hyperglycemia-induced DNA damage. To determine whether DNA damage was mediated by reactive oxygen species (ROS), ROS generation was evaluated, in the presence of IGF-1, or the free radical scavenger n-acetyl-cysteine (NAC). IGF-1 and NAC inhibited hyperglycemic-induced ROS production and hyperglycemia-induced DNA damage. We next asked whether IGF-1 promotes the repair of DSB under hyperglycemic conditions, by homologous recombination (HRR) or nonhomologous end joining (NHEJ). Repair of DSB by NHEJ and HRR was operative in MMC maintained under hyperglycemic conditions. IGF-1 increased HRR by nearly twofold, whereas IGF-1 did not affect DNA repair by NHEJ. IGF-1R enhancement of HRR correlated with the translocation of Rad51 to foci of DNA damage. Inhibition of Rad51 expression by short interfering RNA experiments markedly decreased percentage of MMC positive for Rad51 nuclear foci and increased hyperglycemic DNA damage. We conclude that the activated IGF-1R rescues mesangial cells from hyperglycemia-induced danger signals that target genomic DNA by suppressing ROS and enhancing DNA repair by HRR.

IGF-1 inhibits the mitochondrial apoptosis program in mesangial cells exposed to high glucose.

The activated insulin-like growth factor-1 receptor (IGF-1R) protects cells from a wide range of apoptotic stimuli. Hyperglycemia promotes the intracellular generation of superoxide anion and hydrogen peroxide, both of which have been linked to the activation of the mitochondrial apoptosis program. Here, we report for the first time that ligand activation of the IGF-1R protects normal human mesangial cells and SV40 murine mesangial cells from the glycol-oxidant-induced apoptosis program. The IGF-1R antiapoptosis program was dependent on the recruitment of both Akt/PKB and the ERK subfamily of mitogen-activated protein kinases. IGF-1 treatment also protected the redox potential of mesangial cells maintained at high ambient glucose concentration, by inhibiting the generation of reactive oxygen intermediates and preserving mitochondrial transmembrane potential. IGF-1R survival signals targeted the Bcl-2 family of proteins to protect against glucose-induced apoptosis and oxidative stress. IGF-1-treated cells exhibited a decrease in the Bax/Bcl-2 ratio; increased phosphorylation/inactivation of Bad at Ser112 and Ser136; inhibition of cytochrome c release; perturbations directionally opposed to the initiation of the apoptosis program. In addition, we demonstrate IGF-1R-activated ERK signaling modules phosphorylate Ser112 of the mitochondrial Bad protein, establishing a direct link between surface IGF-1R and the survival program in mitochondria. Our findings indicate that in mesangial cells maintained at high ambient glucose concentration, IGF-1 activates a survival program that maintains the integrity of mitochondria and prevents the expression of the genetic program for apoptosis.