PHRD 572 GMed Exam #1

Increased BUN >20 mg/dL

- Increased production, e.g. high dietary protein, tissue breakdown
- Decreased output, e.g. renal disease, decreased renal perfusion

increased creatinine >1.1 mg/dL

- increased production, e.g. high dietary meat, high muscle mass
- decreased output, e.g. renal disease

hyperbilirubinemia

- increased production, e.g. hemolysis
- decreased output, e.g. liver disease, heart failure, hyperthyroidism, estradiol
- cholestasis

icterus, jaundice

yellow discoloration of the skin, sclera (white of the eye), and other tissues caused by excessive bilirubin in the blood

Kernicterus

Bilirubin encephalopathy, a form of brain damage resulting from unconjugated bilirubin entering the brain. Characterized by lethargy, poor feeding, vomiting, irregular respiration, perhaps death

increase in alkaline phosphatase (ALP)

- hepatic disease, e.g. intrahepatic cholestasis, infiltrative liver disease
- biliary disease, e.g. extrahepatic cholestasis
- bone turnover
- pregnancy

increase in Gamma-Glutamyl transferase (GGT)

- hepatic disease
- biliary disease
- pancreatic disease

increase in alanine aminotransferase (ALT) and aspartate aminotransferase (AST)

- acute hepatocellular injury , e.g. viral hepatitis, ischemic hepatitis, alcoholic liver disease, acetaminophen, other medications

leukopenia (low WBC)

- infection
- bone marrow disorders
- autoimmune disease
- glucocorticoids, chemotherapy, antibiotics

leukocytosis (high WBC)

- infection
- inflammation, stress
- splenectomy
- neoplastic disorders
- medication hypersensitivity
- glucocorticoids, myeloid growth factors, tretinoin

Forms of granulocytes

neutrophils, eosinophils, and basophils

Lymphocytes

infection, especially viral

monocytes and neutrophils

infection, especially bacterial

eosinophils and basophils

- allergy
- parasitic infections

left shift (bands and segs)

an increase in the number of immature neutrophils or polymorphonuclear leukocytes (PMN's)

Reduced RBCs

- iron deficiency, folate deficiency, cobalamin deficiency
- bone marrow disorders
- renal disease, hypothyroidism, hypogonadism, thalassemia
- blood loss, hemolysis
- hemodilution
- chemotherapy

Thrombocytopenia (low Plt)

- infection
- immune-related disease
- bone marrow disorders
- pregnancy
- Beta-lactam antibiotics, sulfonamide antibiotics, vancomycin, linezolid, carbamazepine, phenytoin, valproic acid, heparin, chemotherapy

thrombocytosis (high Plt)

- anemia, blood loss
- infection
- splenectomy
- malignancy, myeloproliferative disease

Increased uric acid

- hemolysis
- high dietary purine
- renal disease
- acidosis
- hypothyroidism
- genetic disorders
- thiazide diuretics, calcineurin inhibitors

anuria

absence of urine production

oliguria

Decreased urine output

Normal PaO2 levels

80-100 mmHg

Left shift of Hb-O2 affinity

- lower CO2
- higher pH
- lower temp

Right shift of Hb-O2 affinity

- higher CO2
- lower pH
- higher temp

Normal CaO2 levels

18 - 22 mL O2 /dL blood

Hypoxemia (low blood oxygen)

- low PAO2
- hypoventilation
- poor diffusion
- V/Q mismatch
- Shunting (V/Q = 0) (no ventilation) (response to O2 poor)
- may be further characterized by A-a gradient and response to supplemental oxygen

Acid-Base Balance in Blood

pH (7.36 - 7.44)
PaCO2 (36 - 44 mmHg)
HCO3- (22 - 26 mEq/L)

7.25 / 28 / 209 / 14

metabolic acidosis
expected ↓ PaCO2 = 1.3 x ↓ HCO3-

(expected ↓ PaCO2 = baseline - expected)
(↓ HCO3- = baseline - actual)

40 - expected PaCO2 = 1.3 x (24 - 14)

27 = expected PaCO2
28 = actual PaCO2

Yes = simple acid-base disorder

PaCO2 = expected PaCO2
HCO3- = expected HCO3-

simple acid-base disorder

Actual PaCO2 > expected

concurrent respiratory acidosis

Actual PaCO2 < expected

concurrent respiratory alkalosis

Actual HCO3- > expected

concurrent metabolic alkalosis

Actual HCO3- < expected

concurrent metabolic acidosis

Normal anion gap metabolic acidosis

8 - 12 mEq/L

For high anion gap metabolic acidosis, calculate Δ anion gap / Δ HCO3-

- (anion gap - 12) / (24 - HCO3-)
- Normal Δ anion gap / Δ HCO3 is 1

< 1 represents concurrent non anion gap metabolic acidosis
>1 represents concurrent metabolic alkalosis

respiratory acidosis causes

Primary Cause: Hypoventilation (causes hypercapnia); Contributing Causes: COPD, Pulmonary dz, Drugs, Obesity, Mechanical asphyxia, Sleep Apnea

- consider alkali therapy in severe cases

metabolic acidosis causes

High anion gap - methanol, uremia, diabetic ketoacidosis, propylene glycol, iron/isoniazid, lactate (metformin, nitroprusside, nucleoside reverse, transcriptase inhibitors), ethylene glycol, salicylates

Non-anion gap (hyperchloremic) - diarrhea, normal saline, early renal insufficiency, renal tubular acidosis, carbonic anhydrase inhibitors, mineralocorticoid deficiency

- consider alkali therapy in severe cases

Alkali therapy

Sodium bicarbonate
Sodium acetate
Sodium citrate
Sodium lactate
Tromethamine (THAM)

respiratory alkalosis causes

Primary cause: Hyperventilation (causes hypocapnia); Contributing Causes: anxiety, fever, pain, pregnancy, lung disease, brain tumor, stroke, traumatic brain injury, aspirin, caffeine, theophylline, gram-negative sepsis, hepatic disease, high altitude

- consider rebreathing in symptomatic cases

metabolic alkalosis causes

Vomiting, gastric aspiration, loop or thiazide diuretics, laxative abuse, posthypercapnia
Hyperaldosteronism, Cushing's disease, corticosteroids, licorice
Alkali ingestion, milk-alkali syndrome, exchange resin and antacid administration, penicillin, hypercalcemia, hypomagnesemia, hypokalemia
Bartter's syndrome, Gitelman's syndrome

- replace chloride and potassium
- consider hydrochloric acid in severe cases

Cockcroft-Gault equation

((140-age) x kg) / (72 x SCr)) x 0.85 if female. Results in mL/min

Adjusted Body Weight

0.4(TBW-IBW) + IBW

If TBW

Use TBW

If TBW > 1.3 x IBW

Use ABW

albuminuria, proteinuria

Normal to mildly increased
ACR & AER

Classification of acute kidney injury

Prerenal: decreased perfusion pressure (hypovolemia, medications, elevated renal venous pressure)

Intrinsic: direct pathology
- vascular (small/large vessel disease)
- glomerular (idiopathic, medications, systemic rheumatologic disease, paraneoplastic syndrome)
- tubular-interstitial-tubulointerstitial (Acute tubular necrosis (ATN), Acute interstitial nephritis (AIN), cast or crystalline nephropathy, urate or phosphate nephropathy)

Postrenal: obstruction of urine flow (prostate disease)

Renal replacement therapy

Indications
●Acidemia
●Electrolytes
●Intoxicants
●Overload
●Uremia

Modalities
●Hemodialysis (HD or iHD)
●Peritoneal dialysis (PD)
●Continuous renal replacement therapy (CRRT)

Diffusion

solute passes between two fluid compartments driven by concentration gradient

Convection

water (and accompanying solute) passes between two compartments driven by hydrostatic pressure gradient

peritoneal dialysis

●Dialysate fluid instilled into the peritoneal space, allowed to dwell, and drained
●Continuous ambulatory PD, intermittent PD, continuous cyclic PD

peritoneal dialysis vs hemodialysis

Advantage: less physiologically stressful, does not require vascular access or anticoagulation, ability to stay at home to complete dialysis, greater flexibility

Disadvantage: slower solute removal, cannot adjust diffusion:convection, complicated by peritonitis and abdominal involvement, greater patient involvement

Continuous venovenoushemofiltration (CVVH)

convection; removes mid-size and larger molecules

Continuous venovenoushemodialysis (CVVHD)

diffusion; mostly clears small molecules

Continuous venovenoushemodiafiltration(CVVHDF)

convection + diffusion; removes mid-size and larger molecules

Continuous replacement therapy vs hemodialysis

advantage: less physiologically stressful, greater fluid and solute removal per day, greater clearance of inflammatory mediators, consistent

disadvantage: slower fluid and solute removal, continuous

Pharmacokinetics in kidney dysfunction

● Enteral bioavailability may be increased
●Protein binding may be decreased
●Volume of distribution may be increased
●Clearance may be decreased

Prerenal vs Acute tubular necrosis

Prerenal
-normal urine sediment
-FENa < 1%, urine sodium

Urgent renal replacement therapy

●Severe metabolic acidosis (pH < 7.1) with hypervolemia
●Severe hyperkalemia (K+> 6.5 mEq/L)
●Pulmonary edema
●Uremic encephalopathy, seizures, or pericarditis

afferent vasoconstriction

-NSAIDs
-Cyclosporine, tacrolimus

efferent vasodilation

-ACE inhibitors
-ARBs

Drug-induced Acute Tubular Necrosis (ATN)

●Aminoglycosides
●Vancomycin
●Amphotericin B
●Contrast media
●Cisplatin

Drug-induced Osmotic nephrosis

●Immune globulin
●Mannitol
●Hetastarch
●Dextran

Drug induced acute interstitial nephritis

●Antimicrobials
●Diuretics
●NSAIDs
●Proton pump inhibitors
●Anti-epileptics
●Etcetera

Drug-Induced Tubular Obstruction

Medication or metabolites
●Acyclovir
●Foscarnet
●Ciprofloxacin
●Methotrexate
●Ascorbic acid
●Triamterene
●Sulfadiazine
●Indinavir
Tissue degradation products
●Chemotherapy agents
●HMG-CoA reductase inhibitors

Classification of chronic kidney disease

Prerenal
●Heart failure
●Cirrhosis

Intrinsic vascular
●Nephrosclerosis
●Renal artery stenosis

Intrinsic tubular-interstitial
●Polycystic kidney disease
●Nephrocalcinosis
●Systemic rheumatologic disease

Postrenal
●Prostate disease
●Malignancy
●Retroperitoneal fibrosis

Elevated blood pressure with proteinuria

●Prefer ACE inhibitor or ARB (G1-G4 and A2-A3)
●Avoid combination of ACE inhibitors and ARBs (G1-G4 and A2-A3)
●Expert opinion may suggest non-dihydropyridine CCB or diuretic as second-line agents
●Mineralocorticoid receptor antagonists may also reduce proteinuria

Elevated blood pressure without proteinuria

●No guideline-based recommendations
●Expert opinion may suggest ACE inhibitor, ARB, dihydropyridine CCB, or diuretic as first-line agents

CKD with Hyperglycemia

●Goal HbA1C individualized from

Proteinuria

●Goal PCR 500 to 1000 mg/g
●ACE inhibitor or ARB
●SGLT2 inhibitor
●Protein restriction < 0.8 g/kg/day (G4-G5)

Metabolic acidosis

●Goal bicarbonate normal range
●High fruit and vegetable consumption
●Sodium citrate or sodium bicarbonate

CKD-Mineral and Bone Disorder goals

●Goal 1: lower elevated phosphate towards normal range (G3a-G5D)
●Goal 2: avoid hypercalcemia(G3a-G5D)
●Goal 3: for non-dialysis patients, optimal iPTHis not known (G3a-G5)
●Goal 4: for dialysis patients, maintain iPTHin the range of 2 to 9 times the upper limit of normal (G5D)

CKD-Mineral and Bone disorder interventions

●Phosphate-lowering treatment should be directed towards progressively or persistently elevated phosphate (G3a-G5D)
●Dose of calcium-based phosphate-lowering treatment should be restricted (G3a-G5D)
●Long-term use of aluminum-based phosphate lowering treatment should be avoided (G3a-5D)
●Dietary phosphate intake should be limited (G3a-G5D)
●Reserve PTH-directed pharmacotherapy for severe and progressive secondary hyperparathyroidism (G3a-G5D)
●Calcitriol or vitamin D analogs may be considered for non-dialysis patients with severe and progressive secondary hyperparathyroidism (G4-G5)
●Calcimimetics, calcitriol, or vitamin D analogs (or combination) may be considered for dialysis patients with severe and progressive secondary hyperparathyroidism (G5D)

CKD-Mineral and Bone disorder calcimimetics

●Cinacalcet
- Initiate 30 mg po qday and titrate to max 180 mg po qday
- Administer with or shortly after meal
●Etelcalcitide
- Initiate 5 mg iv push thrice weekly and titrate from min 2.5 to max 15 mg iv push thrice weekly
- Administer post-dialysis
●Monitor closely for hypocalcemia

Anemia

Hgb < 13 g/dL in men
Hgb < 12 g/dL in women

Erythropoiesis

•Production of RBC
•Erythropoietin (EPO)-regulatory hormone produced in kidney
•EPO released when tissue oxygen levels decrease

Microcytic anemia

MCV < 80 fL
- Iron deficiency
- Thalassemia
- Chronic inflammation
- ↓ MCH: microcytosis and hypochromia

Normocytic anemia

MCV 80-100 fL
- acute bleed
- hemolysis
- chronic inflammation
- CKD
- Concomitant micro and macrocytic
- ↑ MCH: macrocytosis

macrocytic anemia

MCV > 100 fL
- Vitamin B12/folate deficiency
- Drugs
- Alcohol
- Liver/thyroid disease

Signs and symptoms of anemia

Tachycardia, Shortness of breath, lightheadedness, weakness/fatigue, decreased exercise tolerance, paleness of the mucous membranes, irritability, decreased mental acuity

Reticulocytes

•1% of RBC removed from circulation everyday-marrow constantly produced new RBC
•Has a lifespan of 1 day before becoming mature RBCs
•Normal range: 0.5-2%
•High reticulocyte-blood loss or hemolysis
•Low reticulocyte-impaired RBC production

Iron deficiency anemia

- Low iron levels
- Low MCV < 80 fL, low MCHC
- low ferritin

causes of IDA (iron deficiency anemia)

•Blood loss
- Acute
- Chronic loss: peptic ulcer disease, hemorrhoids, menstruation
•Malabsorption
- Gastric bypass surgery
- Proton pump inhibitors
- H.Pylori, celiac disease, autoimmune gastritis
- Heme iron vs. plant iron
•Poor nutrition
- Children/vegan/vegetarian diet
•Increased requirement
- Infancy
- Pregnant/lactating women

Signs and symptoms of IDA

•Usually asymptomatic until severe anemia (Hb < 10 g/dL)
•Ferritin levels may be ↓ in asymptomatic patients
•Gross epithelial changes:
- Smooth tongue
- Glossal pain
- Brittle or spoon-shaped nails
- Hair loss
•Pica-craving for non-food items
•Pagophagia-craving for ice

Dietary iron

•Meat, fish, and poultry: ferric (Fe3+) form of iron
•Ferrous (Fe2+)-best absorbed
•Vit C increases absorption
•Milk, tea, and antacids decrease absorption

Oral iron supplements

- Ferrous form = 3x better absorption than ferric form
- Give 1 hour before meals
- Take iron 2 hours apart from other drugs
- Separate from food, especially dairy, separate from antacids

Ferrous gluconate
Ferrous sulfate
Ferrous fumarate

Hepcidin

- Hormone that regulates intestinal iron absorption, iron recycling, and iron mobilization from hepatic stores
- Inhibits efflux of iron

Total iron deficit in mg

[total body weight in kg X (target Hb-actual Hb in g/dL) x 2.4] + 500 mg

Blood tranfusions

•Reserve for patients with active bleeding and unstable hemodynamics or Hb < 7 g/dL
•Temporary solution
•associated with adverse effects and anaphylactic reactions

Macrocytic anemia

MCV > 100 fL

Vitamin B12 (

Vitamin B12 and Folate deficiency symptoms

•General anemia symptoms
•Sore tongue
•Glossitis-burning of the mouth
•Beefy smooth, shiny, red tongue
•GI symptoms: diarrhea, gas, nausea
•Neurologic symptoms
•Peripheral neuropathies
•Symmetric paresthesia
•Degeneration of the spinal cord
•Loss of position, ataxia, weakness
•Psychiatric manifestations
•Impaired mentation
•Irritability
•Depression
•Paranoia
•Personality changes

Vitamin B12 deficiency causes

Folate deficiency causes

Vitamin B12 treatment

•Neurologic damage may be irreversible if not treated early on
•Treat underlying cause-(i.eh.pylori)
•Oral: 1000-2000 mcg oral daily
•Neurologic symptoms:
- IM/SubQ: 1000 mcg daily x 1 week, 1000 mcg weekly x 2 weeks, then 1000 mcg monthly
- Pernicious anemia: treat for life
•Gastric bypass surgery: prevention for life

Folate deficiency treatment

Folic Acid
- PO: 1 -5 mg qday
- IV/IM/SubQ: 1-5 mg qday if absorption issues
- Continue for 4 months or until underlying causes are corrected
- Essential during pregnancy to prevent neural tube defects such as anencephaly and spinal bifida

Anemia of CKD

•Primarily caused by a decrease in erythropoietin production
•Morphology: normocytic, normochromic
•Risk factors:
- Shorter life span of red blood cells
- Blood loss during dialysis
- Iron deficiency
•Signs/symptoms similar to anemias of other causes
•Treatment can decrease morbidity and mortality, reduce left ventricular hypertrophy

Treatment of Anemia in CKD with iron

Tsat

Erythropoietin Stimulating Agent (ESA) Therapy

Hgb

ESA Agents

Epoetin α (Epogen, Procrit)
•CKD on HD:
- IV route preferred
- IV/SubQ: 50-100 units/kg 3 x week
•CKD not on HD:
- IV/SubQ: 50-100 units/kg q week

Darbepoetin α (Aranesp)
•Molecular structure modified to increase duration of activity
•CKD on HD
- IV route preferred
- IV/SubQ: 0.45 mcg/kg qweek
0.75 mcg/kg q 2weeks
•CKD not on HD
- IV/SubQ: 0.45 mcg/kg q4weeks

Newer ESA Agents

Epoetin Alfa-epbx (Retacrit)
•Biosimilar to epoetin alfa
•Same indications and doses as epoetin alfa
•Costs less than epoetin alfa

Methoxy polyethylene glycol epoetin beta (Micera)
•Molecular structure modified to increase duration of action
•Slower onset: 7-15 days after initial dose
•Same dose for HD and Non-HD patients
- IV/SubQ: 0.6 mcg/kg q2weeks
- Once Hb stabilizes, can double the dose and give q 1 month

ESA Monitoring

•Maximal increase: 1g/dL q2-4 weeks
•Dosage titration: no more than q4 weeks
•Dosage adjustments: 25 % increments

Adverse Effects
•Hypertension
•BBW: Increased mortality, serious cardiovascular events, thromboembolic events, stroke and increased risk of tumor progression or recurrence