IPC Kidney Week 1

AKI, Acid-Base Disorders, Drug Induced AKI, Mechanisms of Kidney Disease

Acute Glomerulonephritis (GN)

• Autoimmune

  • Infection

  • Lupus

• Ischemia

• Drugs / toxins

Chronic Glomerulonephritis (GN)

• Systemic Disease

  • Diabetes Mellitus, HTN

  • most common cause of CKD

Glomerulus Microanatomy

• Endothelial fenestrations

  • Initial filter

• Basement membrane

  • prevents passage of large molecules through split pores and negative charge

• Epithelial Podocytes

  • foot processes

  • negative charge

    • repels charged molecules (proteins)

GN Pathophysiology

• Immune Filtration

  • Innate immune system → WBC drive inflammation

• Immune Complex deposition

  • Ag-Ab Complex → blocked by filter, deposit in basement membrane → WBC drive inflammation (cytokine & complement release) → leaky filter

• Foot process malformation

  • Flattened out → leaky filter

• Mesangial Cell Hyperplasia

  • MCell sense inflammation → rapidly multiply → squeeze capillaries, take up filtration space

All lead to leaky filter

Nephrotic vs. Nephritic Syndrome

• Nephrotic

  • Total proteinuria >3.5g/day → hypoproteinemia

  • Edema (loss of oncotic pressure)

    • commonly presents as periorbital edema

  • Hyperlipidemia

    • liver creates VLDL to make up for decrease in oncotic pressure

  • Hypercoagulability → loss of protein C and S, antithrombin

  • Non-inflammation

  • Podocyte injury

• Nephritic

  • Inflammatory

  • some proteinuria

  • granular casts in urine

  • endothelial cell injury

Acute Tubular Necrosis (ATN) Pathophysiology

• Most common in-hospital AKI

• Necrosis = misnomer

  • ATN has majority of tubular injury but not necessarily necrosis

• Tubular obstruction: sloughing of cells → plug and obstruct tubules → blocks ultrafiltrate → decrease in GFR

• Caused by pro-longed ischemia, endogenous toxins (myoglobin), exogenous toxins (drugs)

ATN Pathophysiology → Oxygen Supply

• Proximal tubule and thick ascending limb at highest risk

• high metabolic demand, low oxygen environment

  • medulla has little oxygen

• ischemia quickly depletes ATP stores

Heme Pigment Nephropathy

• ATN

• Rhabdomyolysis → Kidney vasoconstriction and filtering of myoglobin

• Myoglobin precipitates in tubules → obstruction and AKI

ATN Clinical Presentation

• AKI

  • increase SCr, BUN, decrease GFR, urine output

• Urinalysis

  • Muddy brown casts

  • Cellular debris

  • normal/high FeNa → loss of tubular function = lack of Na reabsorption

Tubulointerstitial Nephritis (AIN) Pathophysiology

• Inflammatory cell infiltration of the interstitium

  • hypersensitivity reactions to an Ag (drug or infectious agent)

• Type 4 Hypersensitivity reaction (slow onset)

• Caused by

  • drugs, hypercalcemia, infections, idiopathic

    • dose independent

AIN Clinical Presentation

• Renal biopsy for Dx

  • Triad → Eosinophilia, Fever, Rash

  • Arthralgia

  • Urinalysis → pyuria, WBC casts, hematuria

Vasculitis

• Systemic vasculitis condition → inflammation of the blood vessels within the kidney

Kidney Disease State Timelines

• AKI → decline of kidney function within 7 days

  • may represent injury, risk for damage, or actual damage

• AKD → decline of kidney function within 7-90 days

• CKD → >90 days of kidney function decline

AKI Timeline

• Oliguric Phase

  • decrease in GFR, Urine output (first to drop)

  • increase in BUN, SCr

• Diuretic Phase

  • Improvement → urine output unproportionately increase compared to GFR increase

• Recovery Phase

  • return to normal function over days

AKI Stage Classification

• Stage 1

  • 1.5-1.9 times baseline or

  • >0.3mg/dl increase within 48 hrs of normal baseline

• Stage 2

  • 2.0-2.9 times baseline

• Stage 3

  • SCr >4 or

  • 3 times baseline or

  • initiation of renal replacement therapy

Pre-Kidney AKI

• Decrease kidney perfusion → severe dehydration

• Decrease effective circulating volume → HF

Renin-Angiotensin-Aldosterone System (RAAS)

• Process:

  • Decrease in renal perfusion → renin release from kidneys → conversion of angiotensinogen to angiotensin I → ACE converts to angiotensin II

• Angiotensin II Effects:

  • Increase in sympathetic system

  • Aldosterone secretion → Na & Cl absorption, K excretion

  • Vasoconstriction → increase in BP

  • ADH secretion → water retention

• Goal

  • water & salt retention increase effective circulating volume → increase in kidney perfusion → decrease in renin release

Ischemic ATN Pathophysiology

• Auto-regulation of afferent arterioles vasoconstrict to decrease oxygen demand in medullary nephrons to prevent damage

  • Cost is decrease in GFR

• Ameliorating Effects

  • Decrease in O2 demand → decreased tubular transport & GFR

  • Vasodilators → PG, Adenosine, bradykinin, NO

• Exacerbating Effects

  • Nephrotic medications

  • NSAIDS

  • Angiotensin II (potent vasoconstrictor = decrease O2 supply

  • Calcium

  • Myoglobin

Post-Kidney AKI

• Nephrolithiasis → block renal pelvis or ureter

  • hydronephrosis (expansion of kidney pelvis)

• BPH → block urethra in men

• Malignancy

Complications of AKI

• Edema

• Uremia

• Electrolyte imbalance

• CKD risk

• Acid & Base imbalance

• CVD risk

Risk Factors for Drug-Induced Kidney Disease

• Age >65

• CKD, DM, HTN

• concomitant nephrotoxins

• Renin-dependent state

  • HF, cirrhosis

• Drug allergy

• Duration of therapy

• Prevention

  • Direct prevention strategies

  • Avoid nephrotoxins in high risk patients

  • TDM

  • Maintain hydration

Drug-Induced Pre-Renal AKI

• ACEi/ARBs → efferent arteriole dilation

• NSAID & Calcineurin inhibitor → afferent arteriole constriction

• Loops → decrease circulating volume

• Loss of autoregulation = risk of decrease in GFR due to decrease in hydrostatic glomerular pressure

Drug-Induced Pre-Renal AKI Prevention and Treatment

• Prevention

  • Maintain fluid intake

  • Avoid concomitant nephrotoxins

  • Monitor SCr, BUN, K+, weight

  • start low dose, titrate up

  • Avoid NSAID + ACE/ARB combo in patients with CKD, HF, liver disease

• Treatment

  • Discontinue offending agent (NSAID)

  • Provide fluids (0.9% NS) to maintain effective circulating volume

Acute Tubular Necrosis (ATN) → Causative Agents

• Causative Agents

  • Aminoglycosides (systemic)

    • Tobramycin, Amikacin, Gentamycin

    • Amphotericin B

    • IV iodinated contrast media

ATN & Aminoglycosides

• Nephrotoxicity related to trough concentrations (TDM)

• Goal Trough concentrations:

  • Normal Dosing

    • Gentamycin & Tobramycin → < 2 mg/L

    • Amikacin → <8 mg/L

  • Extended Dosing

    • undetectable (~0.5mg/L)

    • optimizes PKPD compared to traditional dosing

CIN Risk Factors

• CKD

• Diabetes mellitus

• concomitant nephrotoxins

• Contrast Media

  • large iodinated contrast dose

  • high osmolality contrast

  • Ionic contrast

  • short interval between 2 administrations

CIN Prevention

• Saline Hydration

  • 0.9% NS 12 hours prior and after

  • “flush out the kidneys”

• Sodium Bicarb

  • conflicting evidence, may cause harm, usually avoided

• Acetylcysteine

  • maybe beneficial, but not harmful

  • Additional to fluids with patients who are high risk

  • 1200 mg PO BID

Drug-Induced AIN + Treatment

• Beta lactams

  • Oxacillin, methicillin, etc.. (penicillins)

• NSAIDS

• Sulfa-containing drugs

• PPI

• Treatment → aggressive high dose steroids as soon as possible once diagnosed

Vancomycin AKI

• Nanospheric obstructive vancomycin → AIN or ATN

• TDM

  • Trough of 10-20 mg/dL

  • AUC of < 600 mcg*h/mL

• Avoid concomitant nephrotoxins

• avoid in weight >101.4 due to weight based dosing toxicity

• avoid duration > 7 days

Rhabdomyolysis Intra-Tubular Obstruction

• precipitation in tubules from muscle breakdown

  • statins & statin-fibrate combos

• Counsel on muscular symptoms and changes in urine color

• Management → aggressive fluid administration

Lithium induced CKD

• Nephrogenic diabetes insipidus

• Risk factors

  • duration of therapy

  • episodes of acute lithium toxicity

  • cumulative lithium exposure

• Treatment

  • d/c Lithium

  • K+ sparing diuretic

    • triamterene or amiloride

    • Only treats Symptoms (polyuria, polydipsia)

Acid / Base Laboratory Values

• pH → 7.4

• pCO2 → 40 mmHg

• pO2 → 80 mmHg

• HCO3- → 24 mEg/L

• SaO2 → 97%

Assessment for Acid/Base Disorders

• pH < 7.35 → Acidemia

  • ↑ pCO2 → respiratory

  • ↓ Bicarb → metabolic

• pH > 7.45 → Alkalemia

  • ↑ Bicarb → metabolic

  • ↓ pCO2 → respiratory

Metabolic Acidosis Overview

• pH < 7.35, Bicarb < 22

• Causes:

  • loss of bicarb (diarrhea, vomiting)

  • increase in organic acids

  • acid accumulation (renal failure)

• Compensation

  • Increased ventilation = ↓ pCO2

    • tachypnea (RR > 22)

Anion Gap Interpretation

• Normal 8-12 mEq/L

• Anion gap = Na - (Cl + Bicarb)

• High Anion Gap acidosis

  • consumption of bicarb = ↓ bicarb, ↑ anion gap due to foreign anions

• Normal Anion Gap acidosis

  • Bicarb loss is replaced by Cl-

High Anion Gap Acidosis - pneumonic

• M → methanol

• U → uremia

• D → DKA

• P → PEG

• I → Isoniazid

• L → lactic acidosis

• E → ethanol

• R → rhabdo

• S → salicylates

Normal Anion Gap Acidosis - pneumonic

• H → hyperalimentation (TPN)

• A → acetazolamide

• R → Renal tubular acidosis

• D → diarrhea

• U → ureterosigmoid fistula

• P → pancreatic fistula

Metabolic Acidosis → Bicarb Deficit

• If bicarb < 10, or pH < 7.2 → emergency

• Bicarb Deficit

  • = 0.5L/Kg * (bicarb_desired - bicarb_measured)

  • Do not administer full deficit in one sitting

  • 50% over 4 hours, 50% over 1-2 days

Sodium Bicarb Formulations + Alternative therapies

• PO

  • 325 mg → 4 mEq bicarb

  • 650 mg → 8 mEq bicarb

• IV

  • 50mL ampule → 50 mEq

  • 150 mEq/1000 mL in D5W

• Sodium Acetate (IV)

  • intact liver and bicarb deficit

• Citrate (PO)

  • 1 mol citrate = 3 mol bicarb, dosed by bicarb mEq’s

  • bicitra, polycitra, urocit

  • oral product, reduced GI side effects

Sodium Bicarb ADR’s + Patient Selection

• ADR

  • GI, belching, flatulence

  • Edema + hypokalemia (IV risk)

  • overcorrection of pH

• Patient Selection

  • Benefit

    • high anion gap

    • RTA

    • Salicylate poisoning

  • Harm

    • volume overload → AKI, CHF, hypervolemia

    • Underlying disease → long injury, DKA, lactic acidosis

Metabolic Alkalosis

• Chloride Responsive

  • Loss of H+ & Cl- → vomiting, NG suction, diuretic use

  • urine chloride <10mEq/L

  • Treatment:

    • correct underlying cause

    • replete with 0.9% NS

      • Fluid restricted → less fluids + carbonic anhydrase inhibitor (block bicarb reabsorption)

• Chloride Resistant

  • excess mineralocorticoid activity

    • ex. hyperaldosteronism, Cushing’s syndrome

  • urine chloride > 20 mEq/L

  • Treatment:

    • correct underlying cause

    • spironolactone

Respiratory Acidosis

• ↑ pCO2 retention caused by restricted ventilation

  • sleep apnea, COPD, asthma, pulmonary embolism/fibrosis/edema

  • CNS depressants → opiates, benzos, anesthetics

• Treatment

  • Restore oxygenation

  • treat underlying cause

  • remove offending drug

Respiratory Alkalosis

• ↓ PCO2 due to ↑ ventilation of CO2 > production of CO2

  • anxiety, panic attacks, high altitude, asthma

• Presentation → lightheaded, confused, syncope, seizure

• Treatment → underlying cause