Renal Pharmacology & The Urinary System, Pt. 3

Question 1

What are the most common causes of acute renal failure?

Answer 1

nephrotoxicity and infectious disease

• ethylene glycol
• lilies (cats)
• grapes and raisins (dogs)
• aminoglycosides
• amphotericin B
• cisplatin
• contrast agents
• NSAIDs
• ACE inhibitors

Question 2

What is the most common cause of renal ischemic injury?

Answer 2

reperfusion injury following dehydration, shock, hypotension, cardiac output failure, or thrombosis

Question 3

Renal ischemic reperfusion injury:

Answer 3

Question 4

What is renal ischemia? Reperfusion? How do each cause injury?

Answer 4

ISCHEMIA = interruption of blood supply to the tissue that the cells may adapt to

REPERFUSION = re-establishments of blood flow that tends to cause injury due to the overwhelming oxygen supply

Question 5

Significant changes following reperfusion:

Answer 5

Question 6

What are the 5 key events in acute renal failure resulting in ischemic reperfusion injury? What does this result in?

Answer 6

1. inflammatory cells infiltrate the injured tubular cells resulting in the release of cytokines
2. generation of ROS, like NO, ONOO-, OH, superoxide
3. disruption of cytoskeleton
4. translocation of carriers causing loss of function
5. damaged cells activate apoptotic pathways via caspases and MAP kinase

impaired renal function

Question 7

What are the major ROS and RNS produced by acute renal failure?

Answer 7

ROS: superoxide, peroxynitrite, hydrogen peroxide, hydroxyl radical

RNS: NO from arginine and nitric oxide synthase

Question 8

What ROS causes the most damage?

Answer 8

hydroxyl radical generated from fenton reactions converting hydrogen peroxide, resulting in the oxidation of DNA, proteins, and lipid membranes

Question 9

What are the 2 major generators of ROS?

Answer 9

1. mitochondrial complexes
2. hypoxanthine

Question 10

What is the proposed mechanism for the formation of ROS during ischemic reperfusion injury with hypoxanthine?

Answer 10

• as ischemia prolongs ATP is converted into AMP, adenosine, inosine, then hypoxanthine
• as reperfusion and reoxygenation occurs, released Ca and proteases convert xanthine dehydrogenase into xanthine hydrogenase
• xanthine hydrogenase converts hypoxanthine into superoxide, hydrogen peroxide, and hydroxyl radical

Question 11

What are the 5 main steps to the pharmacological management of acute renal failure?

Answer 11

1. treat or minimize underlying disease
2. manage systemic complications (other organs affected)
3. correct fluid, electrolyte, and acid-base balance
4. initiate diuresis
5. establish a prognosis depending on recovery, chronic disease, and permanent damage

Question 12

How is the fluid deficit measured to properly relace it?

Answer 12

% dehydration x BW = liters required (volume)

Question 13

What fluids are recommended for acute renal failure fluid therapy? In what situation should this be altered?

Answer 13

0.9% NaCl - physiological level will not alter osmolality

HYPERNATREMIA/CARDIAC INSUFFICIENCY - use low sodium fluids, like 0.45% NaCl in 2.5% dextrose or LRS in 2.5% dextrose

Question 14

What should be measured during fluid therapy treatment for acute kidney failure?

Answer 14

• urine output via catheter (1-2 mL/kg/hr)
• BW
• hematocrit
• plasma protein concentration
• sodium concentration

Question 15

What 4 treatments are preferred for urine production enhancement during acute kidney failure?

Answer 15

1. Furosemide*
2. Dopamine
3. 10-20% Mannitol**
4. 10-20% Dextrose

Question 16

What can Furosemide exacerbate during treatment?

Answer 16

gentamicin toxicity

Question 17

How does dopamine act as a urine production enhancer? What are 3 common adverse effects?

Answer 17

it is a positive inotrope and vasodilator that increases cardiac activity to increase renal blood flow and GFR

1. tachycardia
2. hypertension
3. vomiting

Question 18

How do mannitol and dextrose act as urine output enhancers? What additional effects do each have?

Answer 18

osmotic diuretics

• MANNITOL = decreases cellular edema, ROS scavenger
• DEXTROSE = caloric support, increased insulin

Question 19

How is hyperkalemia cause by acute renal failure typically treated? What are 2 possible options if this fails?

Answer 19

normally improves after fluid therapy and diuresis

1. calcium gluconate - cardioprotective
2. (insulin) dextrose - increases intracellular movement of K

Question 20

What is typically used to treat metabolic acidosis caused by acute renal failure?

Answer 20

sodium bicarbonate alkalinizes ECF

Question 21

What 4 drug classes are commonly used to treat nausea/vomiting caused by acute renal failure?

Answer 21

1. H2 antagonists - Famotidine, Ranitidine
2. SR antagonists - Dolasetron
3. dopamine antagonists - Metoclopramide
4. PG analogs - Misoprostol

Question 22

In what species is chronic kidney disease most common? What is it?

Answer 22

cats older than 12 y/o —> most common cause of death in cats older than 5 y/o

complex mixture of disorders that cause irreversible loss of nephrons, decreasing GFR

Question 23

What are the histological hallmarks of chronic kidney disease? What is commonly generated? What systemic change is most commonly seen?

Answer 23

tubulointerstitial nephritis and fibrosis

ROS - NO, ONOO, OH, O2-

angiotensin II is released, resulting in hypertension

Question 24

What is the main cause of nephron destruction in chronic kidney disease? What 3 things most commonly lead to this?

Answer 24

generation and accumulation of ROS

1. glomerular hypertension and hyperfiltration
2. angiotensin II release
3. anemia

Question 25

What role does angiotensin II play in the formation of ROS?

Answer 25

ANGII indices NADPH oxidase, which is responsible for generating superoxide that is able to combine with nitric oxide into ONOO-

Question 26

What are the 3 major steps of pharmacological management of CKD? What else is done?

Answer 26

1. stage 2. renoprotection 3. manage sequelae - hypertension, anemia, metabolic acidosis, ulceration - intervention - monitoring and follow-ups

Question 27

What are the 3 major dietary strategies of managing CKD?

Answer 27

1. low high-quality protein diet that is low in phosphorus to reduce nitrogen waste, acid formation, and mineral deposition 2. moderate sodium restriction, especially in hypertensive patients 3. control lipid intake to reduce hypercholesterolemia, inflammation, and protect renal hemodynamic function

Question 28

What phosphorus binders can be added into the diet to control CKD?

Answer 28

- aluminum hydroxide - calcium acetate - calcium carbonate

Question 29

How is dietary calcitriol used to treat CKD?

Answer 29

increases serum calcium levels and decreases serum PTH levels

Question 30

How can additional alkalinization therapy necessity be calculated in metabolic acidosis caused by CKD?

Answer 30

blood gas analysis - serum total CO2 < 15-17 mmol/L = PO - serum total CO2 < 10-12 mmol/L = parenteral

Question 31

What 2 options are commonly used for alkalinization therapy in CKD? What needs to be checked before they are used?

Answer 31

1. sodium bicarbonate 2. potassium citrate serum Na and K levels

Question 32

What causes the GI effects of CKD? What ones are most common?

Answer 32

uremia - mucosal irritation, impaired GI mucosal barriers, hypergastrinemia ---> vomiting, diarrhea

Question 33

What are the main 3 classes of drugs used for the GI effects of CKD?

Answer 33

1. H2 antagonists - Cimetidine, Famotidine, Ranitidine 2. PPIs - Omeprazole 3. mucosal protectants - Sucralfate (produces a layer that protects ulcers)

Question 34

What 5 drugs are used to treat anorexia-vomiting-hypertension syndrome of CKD?

Answer 34

1. Metoclopramide 2. Maropitant - neurokinin type 1 selective receptor antagonist for motion sickness 3. Misoprostol - synthetic PG analog that inhibits gastric acid and pepsin secretion and protects gastric mucosa 4. Enalapril, Benazepril - ACE inhibitors for hypertension (RAAS and low vasodilator production) 5. Furosemides, Spironolactone - diuretics for hypertension

Question 35

How is calcium homeostasis controlled by PTH?

Answer 35

- in response to low concentrations of plasma calcium, PTH is secreted - PTH mobilizes calcium from bones, reduces loss of calcium by the kidney, and increases calcitriol in the plasma to increase calcium absorption from the intestine - this results in the normalization of plasma calcium levels

Question 36

What hormones are involved in phosphate homeostasis? What regulates its renal reabsorption?

Answer 36

calcitriol and PTH PTH - increases movement of HPO4 from the bones and increases its absorption from the intestines, allowing vitamin D to induce its excretion from the kidney

Question 37

What are 3 causes of secondary hyperparathyroidism? What does this result in? What are the 2 treatments?

Answer 37

1. hypocalcemia 2. hyperphosphatemia 3. impaired vitamin D increased PTH mobilizes calcium and phosphate from bone, causing soft tissue mineralization dietary restruction of phosphorus and calcium supplementation; calcitriol supplementation

Question 38

What hormone is necessary for erythropoiesis? How is it produced?

Answer 38

erythropoietic (EPO) low tissue oxygen tension causes the kidney to produce hypoxia-inducible factor 1, which causes the synthesis of EPO, which induces red blood cells proliferation, maturation, and release due to activation of EPO receptors on the plasma membrane of erythroid precursor cells

Question 39

What anemia results from CKD? What causes this? What are some clinical signs?

Answer 39

progressive, non-regenerative lack of EPO production and GI blood loss apathy, lethargy, poor appetite, poor body condition

Question 40

What treatment is used for anemia caused by EPO? What causes resistance?

Answer 40

recombinant human EPO ---> check hematocrit, may increase too much (doping) antibody production