MPP II 2.8 - RENAL PHYS. & PHARM.: CKD II

• AKI should be compared to CKD

• Chronic kidney disease (CKD) definition, pathophysiology and the different stages should be understood

• It is important to recognize the normal kidney-bone-parathyroid axis and how it changes during CKD

• Causes and signs of CKD a patient may present with should be identified

• Classify the stages of CKD by GFR and the basic principles of dialysis

• Mechanisms of action for the treatment of CKD should be described and compared in their usage of treating CKD

Treatments for CKD

• Complications of CKD affect kidney functions in different ways, like sodium balance, potassium excretion, and acid excretion
• Some patients calcium/phosphate balance may be off, as well as erythropoiesis
• This can cause issues with sodium retention and volume overload, leading to hyperkalemia, metabolic acidosis, and anemia
• Treatments include sodium restriction diuretics, avoiding NSAIDs, sodium bicarbonate, phosphate binders, and erythropoiesis-stimulating agents

Phosphate Binders

• Chronic hyperphosphatemia can cause phosphate to complex with circulating calcium
• Decreases in plasma calcium concentration can lead to hyperparathyroidism
• Precipitation of calcium phosphate in skeletal can impair their function
• Dietary phosphate restriction and oral phosphate binders can aid in decreasing hyperphosphatemia

Calcium Containing Pi Binders

• Calcium carbonate and calcium acetate can help control plasma phosphate
• This agent binds to dietary phosphate and inhibits its absorption
• May also cause hypercalcemia and increase the risk of vascular calcification
• This is an inexpensive therapy

Non-Calcium Containing Pi Binders

• Sevelamer is a nonabsorbable cationic ion-exchange resin that binds intestinal phosphate
• It also binds to bile acids
• This may cause interruptions of the enterohepatic circulation and to decreased cholesterol absorption
• High cost is the disadvantage with this therapy

Anemia in CKD: Iron Replacement Therapy

• This can be administered orally or intravenously
• IV administration is standard
• There is a growing concern over upward trends in IV iron use
• Adverse effects include Anaphylaxis, infections, Cardiovascular Disease and Vascular Calcification

Agents that Stimulate Erythrocyte Production

• Kidneys produce the hormone erythropoietin (EPO)
• EPO stimulates the production of RBC in the bone marrow
• As CKD progresses EPO levels fall and patients become anemic

Erythropoiesis-Stimulating Agents (ESAS)

• There are currently three ESAs in clinical use:
• These are Rcombinant human erythropoietin (rhEPO) (epoetin alfa), (PEG)-epoetin beta, and Darbepoetin alfa
• MOA acts by stimulating the erythropoietin receptor and inducing erythropoiesis
• Clinical studies have found that patients with anemia and chronic kidney disease are at higher risk for death, serious cardiovascular events, and stroke when they are treated with erythropoiesis-stimulating agents
• This mechanism is an active area of study

Regulation of Erythropoietin Synthesis

• Since the main role of RBC is to carry O2 and a ‘trigger’ for EPO production is hypoxia
• EPO production is strongly induced by hypoxia-inducing factor 1 alpha (HIF-1a)
• It binds to the enhancer element in the EPO gene and activates transcription

PHD Inhibitors

• Roxadustat is one of the PHD inhibitors
• It is a small molecule PHD inhibitor
• Which increases the endogenous production of erythropoietin
• This reduces the production of hepcidin
• Other PHD inhibitors in late phase clinical trials include Daprodustat, Molidustat, Vadadustat, and Desidustat

Combination Iron Replacement and ESA

• In CKD, chronic inflammation increases hepcidin production by inhibiting the uptake of dietary iron
• Patients with CKD receiving ESAs are prone to iron deficiency due to the increased demand for iron to support erythropoiesis
• Commonly leads to hyporesponsiveness to ESA therapy

Examine chronic kidney disease (CKD), including its definition, pathophysiology, and stages. Learn to recognize the kidney-bone-parathyroid axis and identify CKD causes and signs. Also, explore CKD treatment mechanisms and compare their usage.