Proteomic analysis of urine in medication-overuse headache patients: possible relation with renal damages

Medication-overuse headache (MOH) is a chronic disorder associated with overuse of analgesic drugs, triptans, non-steroidal anti-inflammatory drugs (NSAIDs) or other acute headache compounds. Various epidemiologic investigations proved that different drug types could cause nephrotoxicity, particularly in chronic patients. The aim of the present work was to analyze, by a proteomic approach, the urinary protein profiles of MOH patients focusing on daily use of NSAIDs, mixtures and triptans that could reasonably be related to potential renal damage. We selected 43 MOH patients overusing triptans (n = 18), NSAIDs (n = 11), and mixtures (n = 14), for 2–30 years with a mean daily analgesic intake of 1.5 ± 0.9 doses, and a control group composed of 16 healthy volunteers. Urine proteins were analyzed by mono-dimensional gel electrophoresis and identified by mass spectrometry analysis. Comparing the proteomic profiles of patients and controls, we found a significantly different protein expression, especially in the NSAIDs group, in which seven proteins resulted over-secreted from kidney (OR = 49, 95% CI 2.53–948.67 vs. controls; OR = 11.6, 95% CI 0.92–147.57 vs. triptans and mixtures groups). Six of these proteins (uromodulin, α-1-microglobulin, zinc-α-2-glycoprotein, cystatin C, Ig-kappa-chain, and inter-α-trypsin heavy chain H4) were strongly correlated with various forms of kidney disorders. Otherwise, in mixtures and in triptans abusers, only three proteins were potentially associated to pathological conditions (OR = 4.2, 95% CI 0.33–53.12, vs. controls). In conclusion, this preliminary proteomic study allowed us to define the urinary protein pattern of MOH patients that is related to the abused drug. According with the obtained results, we believe that the risk of nephrotoxicity should be considered particularly in MOH patients who abuse of NSAIDs

Omentum facilitates liver regeneration

AIM: To investigate the mechanism of liver regeneration induced by fusing the omentum to a small traumatic injury created in the liver. We studied three groups of rats. In one group the rats were omentectomized; in another group the omentum was left in situ and was not activated, and in the third group the omentum was activated by polydextran particles. METHODS: We pre-activated the omentum by injecting polydextran particles and then made a small wedge wound in the rat liver to allow the omentum to fuse to the wound. We monitored the regeneration of the liver by determining the ratio of liver weight/body weight, by histological evaluation (including immune staining for cytokeratin-19, an oval cell marker), and by testing for developmental gene activation using reverse transcription polymerase chain reaction (RT-PCR). RESULTS: There was no liver regeneration in the omentectomized rats, nor was there significant regeneration when the omentum was not activated, even though in this instance the omentum had fused with the liver. In contrast, the liver in the rats with the activated omentum expanded to a size 50% greater than the original, and there was histologically an interlying tissue between the wounded liver and the activated omentum in which bile ducts, containing cytokeratin-19 positive oval cells, extended from the wound edge. In this interlying tissue, oval cells were abundant and appeared to proliferate to form new liver tissue. In rats pre-treated with drugs that inhibited hepatocyte growth, liver proliferation was ongoing, indicating that regeneration of the liver was the result of oval cell expansion. CONCLUSION: Activated omentum facilitates liver regeneration following injury by a mechanism that depends largely on oval cell proliferation

Genetic variants and cell-free hemoglobin processing in sickle cell nephropathy

Intravascular hemolysis and hemoglobinuria are associated with sickle cell nephropathy. ApoL1 is involved in cell-free hemoglobin scavenging through association with haptoglobin-related protein. APOL1 G1/G2 variants are the strongest genetic predictors of kidney disease in the general African-American population. A single report associated APOL1 G1/G2 with sickle cell nephropathy. In 221 patients with sickle cell disease at the University of Illinois at Chicago, we replicated the finding of an association of APOL1 G1/G2 with proteinuria, specifically with urine albumin concentration (β=1.1, P=0.003), observed an even stronger association with hemoglobinuria (OR=2.5, P=4.3×10(−6)), and also replicated the finding of an association with hemoglobinuria in 487 patients from the Walk-Treatment of Pulmonary Hypertension and Sickle cell Disease with Sildenafil Therapy study (OR=2.6, P=0.003). In 25 University of Illinois sickle cell disease patients, concentrations of urine kidney injury molecule-1 correlated with urine cell-free hemoglobin concentrations (r=0.59, P=0.002). Exposing human proximal tubular cells to increasing cell-free hemoglobin led to increasing concentrations of supernatant kidney injury molecule-1 (P=0.01), reduced viability (P=0.01) and induction of HMOX1 and SOD2. HMOX1 rs743811 associated with chronic kidney disease stage (OR=3.0, P=0.0001) in the University of Illinois cohort and end-stage renal disease (OR=10.0, P=0.0003) in the Walk-Treatment of Pulmonary Hypertension and Sickle cell Disease with Sildenafil Therapy cohort. Longer HMOX1 GT-tandem repeats (>25) were associated with lower estimated glomerular filtration rate in the University of Illinois cohort (P=0.01). Our findings point to an association of APOL1 G1/G2 with kidney disease in sickle cell disease, possibly through increased risk of hemoglobinuria, and associations of HMOX1 variants with kidney disease, possibly through reduced protection of the kidney from hemoglobin-mediated toxicity