Acute Renal Failure & Chronic Kidney Disease

Acute Renal Failure & Chronic Kidney Disease

Acute Kidney Injury (AKI)

• Acute loss of kidney function, leading to the accumulation of waste products like Creatinine (Cr) and Urea Nitrogen (BUN).
• Results in fluid and electrolyte abnormalities.
• Types of AKI:
  • Pre-renal: Reduced blood flow to the kidney.
  • Intrinsic (Intra-renal): Dysfunction within the kidney itself.
  • Post-renal: Obstruction of urinary outflow.

Pre-Renal AKI

• Mechanisms of decreased blood flow:
  • Systemic hypoperfusion:
    • Intravascular volume depletion (hemorrhage, dehydration).
    • Reduced cardiac output.
  • Renal hypoperfusion:
    • Renal artery stenosis.
    • Emboli.
• Compensatory Mechanisms:
  • Dilation of afferent arterioles (supplying blood to the glomerulus).
  • Constriction of efferent arterioles (removing blood from the glomerulus).
  • Redistribution of blood to the oxygen-sensitive medulla.
• Impairment by drugs:
  • NSAIDs: Impair Prostaglandin-mediated dilation of afferent arterioles.
  • ACE Inhibitors/ARBs: Inhibit Angiotensin II-mediated efferent arteriole vasoconstriction.
  • Immunosuppressants (Cyclosporine, Tacrolimus): Cause generalized vasoconstriction within the kidney.

Intrinsic AKI

• Intra-renal Dysfunction Mechanisms:
  • Pathologic processes affecting the tubules, glomerulus, interstitium, or vasculature.
  • Acute Tubular Necrosis (ATN): Most common cause of intrinsic renal failure.
    • Damage from toxins or ischemia (e.g., Aminoglycosides, Amphotericin B, contrast media).
  • Diseases affecting glomerulus, interstitium, & vasculature: Glomerulonephritis, SLE, interstitial nephritis, vasculitis.
• Pre-Renal AKI can lead to intra-renal dysfunction.

Post-Renal AKI

• Mechanisms of Urinary Outflow Obstruction:
  • Prostatic enlargement.
  • Tumors/Masses.
  • Renal Calculi.

Measures of Renal Function

• Urinary Output.
• Creatinine (Cr):
  • Normal product of muscle metabolism.
  • Used for estimation of CrCl (Creatinine Clearance) which is useful for drug dosing in patients with renal dysfunction.
• GFR (Glomerular Filtration Rate):
  • Good measure of overall kidney function.
  • Also used to dose medications in renal impairment.
• Fractional excretion of sodium (FeNa):
  • Helps distinguish pre-renal AKI from nephrotoxic intrinsic renal AKI.
  • FeNa < 1\%%: Pre-Renal.
  • FeNa > 2\%%: Intrinsic ATN. (*0.85 for females)

AKI Treatment/Management

• Pre-Renal: Intravascular volume expansion for hypovolemia, CV support for adequate cardiac output.
• Post-Renal: Removal/reduction of obstruction.
• Pharmacologic Approaches:
  • Diuretics for fluid overload
    • Loop Diuretics: Furosemide (Lasix®)
      • IV loading dose: Furosemide 40-80 mg, then continuous infusions (more effective than bolus doses): Furosemide 10-20 mg/h
      • Ethacrynic acid: Use in patients with sulfa allergies, high ototoxic potential
      • Other loop diuretics: Torsemide, Bumetanide
    • Diuretic Resistance:
      • Add diuretics that work along different sections of the nephron to help overcome resistance
      • Metolazone (thiazide-like diuretic, but produces effective diuresis at GFR < 20 mL/min)
  • Diuretics also help prevent hyperkalemia associated with renal dysfunction

AKI Treatment/Management: Pharmacologic Approaches

• Dopamine:
  • Theoretically has benefits in AKI, but studies have shown a lack of efficacy.
  • Low-dose 0.5-3 mcg/kg/min:
    • Predominate stimulation of DA-1 receptors.
    • Renal vasodilation (↑renal blood flow).
    • AE: tachycardia, arrhythmias, myocardial ischemia, ↓ respiratory drive, GI ischemia.
• Fenoldopam:
  • DA-1 receptor agonist approved for short-term management of severe HTN.
  • Causes vasodilation of renal vasculature with potentially fewer AEs than Dopamine.
  • More studies are needed to determine efficacy in AKI.

Nonpharmacologic Management of AKI

• Dialysis (Renal Replacement Therapy):
  • Indications in AKI:
    • Refractory hypervolemia, hyperkalemia, or acidosis.
    • BUN>100.
  • Types:
    • Intermittent hemodialysis (IHD): Several times weekly.
    • Continuous renal replacement therapy (CRRT):
      • Provides slow fluid/solute removal on a 24-hour basis.
      • Better volume control (beneficial in patients who cannot tolerate rapid fluid removal).
• Supportive Therapy:
  • Adequate nutrition.
  • Correction of acid-base abnormalities.
  • Fluid management.
  • Dosage adjustments based on kidney function.

AKI Prevention

• Avoid nephrotoxins if possible:
  • Radiocontrast dye:
    • If radiocontrast dye must be used:
      • IV NS: To provide maximum renal perfusion.
      • PO Acetylcysteine.
      • Glycemic control in diabetes.
  • ACEI & ARBs.
  • NSAIDs.
  • Aminoglycosides:
    • Minimize by maintaining trough concentration <2mcg/mL, length of therapy, avoiding repeated courses.
  • Amphotericin B:
    • ↓nephrotoxicity by slowing infusion rate or substituting with liposomal Amphotericin B.

Chronic Kidney Disease

Chronic Kidney Disease

• CKD: Progressive loss of kidney function (months-years); Classified into stages 1-5 based on GFR.
• Renal functions affected by CKD:
  • Production/secretion of Erythropoietin (EPO).
  • Activation of Vitamin D.
  • Regulation of fluid/electrolytes & acid-base balance.
• End Stage Renal Disease (ESRD):
  • GFR < 15 mL/min
  • Requires dialysis or transplant to remove uremic toxins & maintain hemodynamic stability.
• Identify patients who are at-risk & initiate interventions early to slow the progression of CKD to ESRD & to prevent & manage progression of secondary complications.

CKD Stages

• Stage 1: GFR > 90ml/min & albuminuria.
• Stage 2: GFR 60-89ml/min.
• Stage 3: GFR 30-59ml/min.
• Stage 4: GFR 15-29ml/min.
• Stage 5: GFR <15ml/min

CKD Treatment/Management

• Low-protein diet:
  • May help delay progression to ESRD, but malnutrition must be avoided.
  • Consider dietary changes at GFR < 25 mL/min
• Intensive blood glucose control in DM patients:
  • Insulin (preferably insulin pump).
  • Frequent BG checks.
• Adequate blood pressure control:
  • Goal:
  • Medications:
    • ACE Inhibitors & ARBs: ↓ proteinuria & slow progression of CKD to ESKD
      • Discontinue if SCr increases > 30% of baseline
    • Diuretics & Calcium Channel Blockers
    • Beta-Blockers
• Smoking cessation

ACE Inhibitors & ARBs

• Effects:
  • ↓Glomerular pressure & volume due to the effects on angiotensin II
  • The ↓pressure & volume cause a ↓in the amount of protein filtered through the kidneys (↓proteinuria).

SGLT2 Inhibitors

• MoA:
  • SGLT2 transporter is responsible for reabsorbing the majority of filtered glucose in the proximal renal tubule (>90% glucose filtered).
  • Lowers BP via natriuresis & plasma volume contraction, reduction in arterial stiffness, improvement in endothelial function (regardless of HTN status).
  • Increases distal Na+ delivery (by reducing Na+ reabsorption) and inhibits tubuloglomerular feedback → afferent vasoconstriction & reduction in intraglomerular pressure.
  • Intraglomerular pressure reduction reduces albuminuria – largely independent of concomitant changes in metabolic parameters or eGFR.
  • Also lowers pre- and afterload of heart & down regulates sympathetic activity.
  • May also attenuate renal hypoxia which improves hematocrit levels by conserving energy required to reabsorb filtered glucose and Na+ loads.
• Use (some FDA indications require the pt to have DM, others do not):
  • Patients with CKD to slow progression to ESKD.

SGLT2 Inhibitors

• AEs:
  • UTIs, genital mycotic infections, URI, increased urination, polydipsia.
• Dapagliflozin (Farxiga).
• Canagliflozin (Invokana).
• Empagliflozin (Jardiance).

Mineralocorticoid Receptor Antagonist

• MoA:
  • Selective mineralocorticoid receptor antagonist.
  • MR over activation contributes to fibrosis & inflammation in epithelial (kidney) and non-epithelial tissue (i.e., heart, blood vessels).
  • MR activation causes Na+ reabsorption in kidneys.
• Use:
  • CKD to reduce the risk of sustained eGFR decline, ESKD, CV death, nonfatal MI, & hospitalization for HF in adults with CKD associated with T2 DM.
• AE:
  • Hyperkalemia, hypotension, hyponatremia
  • Contraindication: coadministration with strong CYP3A4 inhibitors and/or adrenal insufficiency.
• Finerenone (Kerendia):
  • Highly potent, selective MR.
  • No relevant affinity for androgen, progesterone, estrogen, or glucocorticoid receptors.

CKD Management: Volume Overload/Hypertension

• Diuretics may be required to control edema & blood pressure.
• Loop diuretics are more effective (& provide greater ↓ of K).
• Thiazide diuretics are not as effective when CrCl falls below 30 mL/min but may be beneficial when added to loop diuretics to enhance the excretion of Na/Water & to overcome loop diuretic resistance (often occurs in patients with kidney disease).
• Other options are to use thiazide-like diuretics:
  • Examples: Metolazone (Zaroxolyn®), Indapamide (Lozol®).

CKD Management: Hyperkalemia

• Definitive Tx is Hemodialysis.
• Temporary Measures:
  • Calcium Gluconate.
  • Insulin.
  • Glucose.
  • Albuterol.
  • Sodium Polystyrene Sulfonate (Kayexalate®).
• Metabolic Acidosis:
  • Sodium Bicarbonate may be required in patients with > stage 3 CKD.
  • Dosing is usually determined by approximating the base deficit (using C02).

CKD Treatment/Management

• Hyperlipidemia:
  • Lipid-lowering therapies: Slow the decline of GFR & ↓proteinuria.
  • Statins may have additional benefits in slowing the progression of kidney disease.
• Secondary Hyperparathyroidism:
  • Renal activation of Vit D is impaired, leading to ↓Ca absorption of the GI tract.
  • Low Ca concentration stimulates PTH secretion.
  • Serum Ca balance is maintained at the expense of bone & may lead to bone disease.
  • Cinacalcet (Sensipar®): calcimimetic (↑sensitivity of Ca receptors in the parathyroid & subsequently ↓secretion of PTH).
  • Vitamin D: Calcitriol (Rocaltrol®), Paricalcitol (Zemplar), Doxercalciferol (Hectorol)
    • Acts directly on parathyroid to ↓PTH secretion.
    • Several forms available: most active form is D3.
  • Avoid over-suppression of PTH levels.

CKD Treatment/Management: Hyperphosphatemia

• Dietary phosphorus restriction: 800-1000 mg/day in CKD stage 3 or higher.
• Pharmacologic therapy is usually needed in addition to dialysis to control phosphate.
• Phosphate-Binding Agents: Bind phosphate in the GI tract to form an insoluble complex that is excreted in the feces; given with meals & dosing is approximated based on the expected phosphorous content of the meal.
  • Drugs:
    • Calcium Carbonate, Calcium Acetate.
    • Sevelamer (Renagel®).
    • Lanthanum carbonate (Fosrenol).
    • Sucroferric oxyhydroxide (Velphoro).
    • Ferric citrate (Auryxia).
  • Others (not recommended for chronic use due to Al or Mg accumulation):
    • Aluminum or Magnesium Hydroxide.
    • Aluminum or Magnesium Carbonate.

Phosphate Binders

• MoA: bind to phosphate in the GI tract to reduce hyperphosphatemia.
• Caution: Fe-based products need to be individualized based on Fe and/or Hct need.

NHE3 Inhibitor

• Sodium/Hydrogen Exchanger 3 Inhibitor
• MoA:
  • Inhibits NHE3 to reduce Na+ absorption from the small intestine & colon → increases water secretion into the intestinal lumen → accelerates intestinal transit time → softer stool consistency.
  • Also reduces phosphate absorption by reducing phosphate permeability through the paracellular pathway.
• Use:
  • Indicated to reduce serum phosphate in adults with CKD on dialysis.
  • Add on therapy in patients with inadequate response to phosphate binders or who are intolerant to any dose of phosphate binder therapy.
• AE:
  • Diarrhea
• Tenapanor (Xphozah)

CKD-Anemia

• Begin evaluating for anemia when the $GFR < 60 mL/min$ & goal is Hgb>10-12 g/dL.
• Normochromic, normocytic anemia.
• ↓ functioning nephrons ↓ renal production of EPO Erythropoietin (EPO) deficiency.
• Medications: erythropoietin-stimulating agents.
  • Erythropoietin Alpha (Epogen®): Injections 1-3 times/wk.
  • Darbepoetin (Aranesp®): Injections every 1-2 weeks.
• AE: HTN, thrombosis - Black Box Warning - CV complications include death with Hgb >13g/dL.
• Monitoring Parameters: Hgb.

CKD-Anemia: Iron supplementation

• Necessary to replete iron stores (esp. pts on ESA therapy).
• Parenteral iron:
  • Improves response & ↓ required dosage of EPO.
  • AE: allergic reactions, hypotension, dizziness/syncope, dyspnea, HA, arthralgias/low back pain, z-track injections & staining of the skin.
  • Iron Dextran: requires test dose for allergic reactions.
  • Newer formulations (safer): Iron Sucrose (Venofer®), Sodium ferric gluconate (Ferrlecit®) are both approved for anemia of CKD.
• Monitoring Parameters: Iron indices & Adverse effects.

CKD-OTHER THERAPEUTIC CONSIDERATIONS

• Uremic Bleeding:
  • Uremia can lead to alterations in clotting ability resulting in hemorrhage.
• Pruritus:
  • Cause unknown and tx difficult.
  • Antihistamines (i.e., hydroxyzine), Cholestyramine, oral activated charcoal, Ondansetron, and naltrexone have all been used.
• Vitamin Replacement:
  • Replace water-soluble vitamins.
  • Avoid fat-soluble vitamins A, E, K (can accumulate).

Clinical Application: Renal Dosage Adjustment

• A 60-year-old female with serum Cr of 2.3 requires Diflucan (Fluconazole) for treatment of oropharyngeal candidiasis infection. She weighs 154 pounds. What is the recommended dose for this patient?
• Usual dosage: 200mg on the first day followed by 100mg QD.
• CrCl (mL/min) % of recommended dose
  • >50: 100%
  • $\leq 50$ (no dialysis): 50%
  • Regular dialysis: 100% after each dialysis