A 66-year-old man with hypertension and stage IV chronic kidney disease comes to the office for follow-up. The patient has had worsened fatigue and low energy over the past several months but no chest pain or shortness of breath. He was previously nonadherent with antihypertensive therapy but has been following treatment recommendations since renal dysfunction was diagnosed 2 years ago. Blood pressure is 126/78 mm Hg and pulse is 68/min. Cardiac auscultation reveals an S4 sound. The rest of the physical examination is unremarkable. Laboratory results show normocytic, normochromic anemia with a low reticulocyte count. Serum iron studies are within normal limits. Treatment with a recombinant glycoprotein hormone is begun, and repeat laboratory testing several weeks later shows an improvement in hemoglobin level. The effects of the hormone prescribed for this patient are most likely mediated by which of the following pathways?

Question

A 66-year-old man with hypertension and stage IV chronic kidney disease comes to the office for follow-up.  The patient has had worsened fatigue and low energy over the past several months but no chest pain or shortness of breath.  He was previously nonadherent with antihypertensive therapy but has been following treatment recommendations since renal dysfunction was diagnosed 2 years ago.  Blood pressure is 126/78 mm Hg and pulse is 68/min.  Cardiac auscultation reveals an S4 sound.  The rest of the physical examination is unremarkable.  Laboratory results show normocytic, normochromic anemia with a low reticulocyte count.  Serum iron studies are within normal limits.  Treatment with a recombinant glycoprotein hormone is begun, and repeat laboratory testing several weeks later shows an improvement in hemoglobin level.  The effects of the hormone prescribed for this patient are most likely mediated by which of the following pathways?

Quizplus · Accepted Answer

11ec160b_3cc9_9e12_9249_c5369c88edb7_MD0001_00 Patients with chronic kidney disease (CKD) often develop normocytic anemia as the glomerular filtration rate declines, due to an inability to generate adequate quantities of erythropoietin (EPO). EPO is a glycoprotein produced by peritubular fibroblast cells in the renal cortex in response to tissue hypoxia (as seen with anemia). Healthy individuals increase EPO production up to 10,000-fold in response to anemia, but patients with CKD have chronic renal inflammation that damages EPO-producing cells, thereby preventing an adequate EPO response. Therefore, patients with CKD are often treated with recombinant EPO agents (eg, epoetin, darbepoetin) to supplement EPO production. EPO travels from the kidney through the bloodstream to the bone marrow, where it binds to a surface receptor on erythrocyte colony-forming unit cells (erythrocyte precursors). Binding activates the Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT) signaling pathway, which induces the transcription of proteins that inhibit erythrocyte precursor apoptosis and promote survival. Binding also activates signals that increase the differentiation of erythrocyte precursors into mature erythrocytes. Together, these effects increase the production of erythrocytes and improve circulating red blood cell counts. Activating mutations affecting the JAK2 gene are associated with polycythemia vera, a chronic myeloproliferative disorder marked by the clonal proliferation of erythrocytes (leading to dramatic elevations in hematocrit). (Choice A) Cyclic AMP mediates the effects of a variety of hormones including glucagon, antidiuretic hormone (V2 receptor), and corticotropin. However, this pathway is not a primary intermediate in erythrogenesis. (Choice B) Cleavage of membrane phospholipids by phospholipase A2 leads to the formation of arachidonic acid, which is in turn converted into prostaglandins and leukotrienes that help regulate the inflammatory response. A variety of medications directly or indirectly affect this system, including glucocorticoids, nonsteroidal anti-inflammatory drugs, and leukotriene inhibitors. (Choice D) Widely used therapeutic hormones that activate a nuclear receptor include thyroid hormone, vitamins A & D, and the steroid hormones (eg, glucocorticoids, mineralocorticoids, sex hormones). (Choice E) Therapeutic hormones that activate a phosphatidylinositol second messenger system include antidiuretic hormone (V1 receptor), gonadotropin-releasing hormone, and oxytocin. (Choice F) The Ras/mitogen-activated protein kinase signal transduction system is used by a variety of growth factors (eg, epidermal growth factor, platelet-derived growth factor), which primarily act to stimulate cell proliferation. Uncontrolled activation of this system can lead to malignancy. Educational objective: Chronic kidney disease is commonly associated with normocytic anemia due to reduced production of erythropoietin by the kidneys. Erythropoietin signal transduction is primarily mediated by the Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT) pathway, which promotes erythrocyte precursor survival. __________ References: Urology and nephrology update: anemia of chronic kidney disease. (http://www.ncbi.nlm.nih.gov/pubmed/24432707)

A 66-Year-Old Man with Hypertension and Stage IV Chronic Kidney