Acute Renal Injury I and II

Question 1

Acute Kidney Injury

Answer 1

• Abrupt loss of kidney function that results in the retention of urea and other nitrogenous waste products with dysregulation of extracellular volume and electrolytes
• In critically ill patients with AKI mortality is between 40-60%. Hospital stay is prolonged.

Question 2

Creatinine

Answer 2

•a breakdown product of creatine phosphate in muscle that is filtered by the kidney used to estimate kidney function/filtration. It is inversely proportional to function – the higher the creatinine, the lower the filtration

Question 3

Blood Urea Nitrogen

Answer 3

•Urea nitrogen formed from protein catabolism by the liver. It is filtered by the kidney and is additionally used as a measure of kidney function. Caveat: BUN can increase independent of kidney function (i.e. taking steroids, tetracycline antibiotics, or reabsorption of blood in the GI tract)

Question 4

Oliguria

Answer 4

<500ml urine output/24h

Question 5

Anuria

Answer 5

<50ml urine output/24h

Question 6

Problem with Staging System

Answer 6

• Based on serum creatinine and urine output (imperfect biomarkers) – Biological markers for organ injury
• By the time serum creatinine rises or urine output decreases – substantial injury may have taken place already
• Diminishes ability to begin treatments aimed at preventing the loss of renal function
• Novel biomarkers are being developed (NGAL, KIM 1, NAG) but are not ready for prime-time yet!

Question 7

3 Categories of Acute Kidney Injury

Answer 7

•Pre-Renal

• volume depletion
• decreased effective arterial blood volume

•Intrinsic Renal

• tubulointerstitial disease
• vascular disease
• glomerular disease

•Post-Renal

-urinary obstruction

Question 8

Pre-Renal = Renal Hypoperfusion

2 major causes of hypoperfusion

Answer 8

1. True volume depletion = loss of Na+ from the extracellular fluid volume (vascular and interstitial space)
   - i.e. GI losses (diarrhea, vomiting), hemorrhagic shock (acute blood loss), renal losses (diuretics), cutaneous losses (burns)
2. Decreased effective arterial blood volume = refers to the extracellular fluid volume that is in the arterial circulation. The total ECF may be increased but the arterial blood volume perceived by arterial baroreceptors in the carotid sinus and glomerular afferent arterioles is low (edematous states).
   - i.e. Heart failure, hepatic cirrhosis, sepsis

Question 9

Pre-Renal Disease Glomerular Filtration Rate (GFR) is under autoregulatory control

Answer 9

• As renal perfusion decreases – homeostatic mechanisms activate to maintain GFR
• Afferent arteriolar vasodilitation
• Efferent arteriolar vasoconstriction
• Increase in filtration fraction leads to increase in oncotic pressure in postglomerular capillaries with resultant increase in salt and water absorption in proximal tubule
• Activation of angiotensin II and antidiuretic hormone lead to increase in salt and water reabsorption

-low urine Na+ and concentrated urine

Question 10

Pre-Renal Disease - Diagnostic Work Up

Answer 10

a. Patient history and chart review
1. Vomiting, diarrhea, gastrointestinal bleeding (true volume depletion)
2. Heart failure, liver disease/cirrhosis, sepsis (decreased effective arterial blood volume)
b. Physical Exam
1. Orthostatic hypotension, skin tenting, dry mucous membranes (true volume depletion)
2. Elevated jugular venous pressure (neck veins) with hypotension (Heart failure – decreased effective arterial blood volume)
c. Laboratory Evaluation
1. Blood urea nitrogen (BUN):Creatinine >20:1
2. Urine osmolality >500 mosm/Kg
3. Urine Na+ <10meq/L, Urine Cl- <10meq/L
4. Fractional Excretion of Na+ (FENa) < 1%
a. Measures the percent of filtered Na+ that is excreted in the urine
b. Used to differentiate between prerenal disease and tubular injury (acute tubular necrosis)
c. FENa can be estimated by simultaneously obtained urine and plasma specimens of Na+ and creatinine FENa % = Urine Na+ x Plasma Creatinine x 100 (you do not need to know Plasma Na+ x Urine Creatinine how to calculate for the test!)*
d. Best to use when patients are oliguric (urine output <30cc/h)
i. Becomes less accurate in nonoliguric patients
5. Urine analysis
a. Typically, high specific gravity, no protein, blood, or whitecells
b. Urine sediment review will be bland – no casts or cells

Question 11

Intrinsic Renal Disease

Answer 11

• subdivided into part of nephron that is injured
• tubulointerstitial
• vascular
• glomerular

Question 12

Tubulointerstitial Disease

Answer 12

• Acute Tubular Necrosis
• Acute Interstitial Nephritis
• Acute Tubular Obstruction

Question 13

Acute Tubular Necrosis

Answer 13

• tubular injury
• most common cause of acute intrinsic kidney injury
• ATN is associated with a 4-6 fold increase in mortality.

1. S3 segment of the proximal tubule and thick ascending limb of Henle because of their metabolic activity and location in the outer medulla function at near maximum energy dependency.
2. Any changes in renal perfusion or toxic insults results in patch necrosis of these segments.
3. Risk factors

– volume depletion, underlying chronic kidney disease, use of NSAIDs, diabetes

4. Pathophysiology

– Multifactorial including endothelial and epithelial cell injury, intratubular obstruction, changes in microvascular blood flow, and immunological factors

5. Activation of tubuloglomerular feedback: Alterations in GFR that are induced by changes tubular flow rate.
   a. Cells in the macula densa located at the end of the cortical thick ascending limb of the loop of Henle sense changes in delivery and reabsorption of Cl
   b. In ATN, tubular cells are damaged and cannot reabsorb Na+ and Cl- causing an increase in Cl- delivery to the macula densa which, in turn, will cause renal afferent arteriolar vasoconstriction to reduce intraglomerular hydraulic pressure and filtration.
   i. Decrease in GFR limits ATP-dependent tubular reabsorption –> protects against intracellular ATP depletion which would further augment renal injury

Question 14

ATN Causes

Answer 14

a. Ischemia: low blood pressure or prolonged volume depletion, sepsis
b. Toxin:
i. Radiocontrast media (iodinated contrast for CT scans and angiography)
- Risk factors: underlying chronic kidney disease, diabetes mellitus, concurrent hypotension
ii. Drugs

– aminoglycosides, amphotericin B, cisplatin (these tend to be nonoliguric = >500 ml urine output/24h)

iii. Heme pigments – rhabdomyolysis (breakdown of skeletal muscle i.e. crush injury)

Question 15

ATN Diagnostic Work Up

Answer 15

1. History and chart review:
   a. Prolonged period of hypotension in the ICU (ischemia), exposure to radiocontrast (CT scan or coronary angiogram), sepsis, aminoglycosides for bacterial infections, amphotericin for fungal infections, crush injuries or found down in same position for prolonged period of time (rhabdomyolysis)
2. Physical Exam: a. No specific physical findings – suspect in ongoing hypotension, muscle tenderness for rhabdomyolysis
3. Laboratory Evaluation:
   a. BUN:Creatinine 10-15:1 (tubules are not working so do not reabsorb as much urea at the proximal tubule)
   b. Urine Na+ and Cl- >20 meq/L
   c. FENa > 2%
   d. Urine analysis i. Isosthenuric (specific gravity ~ 1.01) due to loss of concentrating ability ii. Urine osmolality <450 mosom/Kg
   e. May have low grade proteinuria (usually <500 mg per 24h or 30+ on dipstick). This is due to impaired reabsorption of protein at the proximal tubule
   f. Urine sediment shows pigmented granular casts or free floating tubular epithelial cells

Question 16

ATN Clinical Course

Answer 16

1. Creatinine plateaus in 7-10 days
2. As tubule undergo repair, excess solutes and water are excreted – marks the polyuric phase (>3L of urine output per 24h) of ATN from ~ days 10- 14
3. Recovery usually occurs between days 14-21

Question 17

Acute Interstitial Nephritis

Answer 17

•Inflammatory cell infiltration in kidney interstitium caused by immune response to either a medication, autoimmune disease, or infection

Question 18

AIN Causes

Answer 18

1. Drugs: NSAIDs, Penicillins, Cephalosporins, Sulfonamides (Trimethoprim-Sulfamethoxazole, Furosemide), Rifampin, Ciprofloxacin, proton pump inhibitors
   - Important to identify as removal of the offending agent can result in reversal of the condition
2. Autoimmune disease: Sjogren’s syndrome, sarcoidosis
3. Infection: Legionella, Leptospira, Cytomegalovirus

Question 19

AIN Clinical Presentation

Answer 19

•Drug-induced AIN – onset ranges from 3-5 days after a second exposure to weeks - months after a first exposure (latency)

• Classic triad of rash, fever, and eosinophilia
  i. Full triad observed in only 10% of patients
  ii. Peripheral eosinophilia and fever most common ~ 23% and 27% respectively

Question 20

AIN Diagnostic Work Up

Answer 20

1. History and chart review:
   a. Drug exposure as outlined above (remember – variable latency depending on if first or second exposure)
   b. Known history of Sjogren’s syndrome (autoimmune disease involving exocrine glands – Sicca syndrome), sarcoid (granulomatous disease)
2. Physical Exam: a. Fever, rash (drug-induced AIN)
   b. Dry eyes, dry mouth (Sjogren’s syndrome)
3. Laboratory evaluation:
   a. Acute rise in serum creatinine that temporally correlates with drug administration (drug-induced AIN)
   b. Peripheral eosinophilia on blood smear
   c. Eosinophiluria (urine eosinophils) >1% (not very sensitive or specific)
   d. Proteinuria – variable (ranges from none to >1gram/day
   e. Urine sediment – white blood cells, may have white blood cell casts
4. Renal biopsy is needed for definitive diagnosis (not always done if strong suspicion based on clinical history and lab evaluation)

Question 21

Acute Tubular Obstruction

Answer 21

• Precipitation of a substance in tubules (can be protein from immunoglobulins, calcium phosphate, urate, or intratubular crystal precipitation from medications)
• Typically occurs in the setting of volume depletion and an acidic urine (favors precipitation of medications or substances)

Question 22

Acute Tubular Obstruction - Causes

Answer 22

1. Cast nephropathy – seen in multiple myeloma (plasma cell dyscrasia/malignancy) where an overproduction of immunoglobulin light chains is produced and filtered into the urine
2. Tumor lysis syndrome – occurs following chemotherapy administered in the setting of large tumor burden a. Intracellular release of uric acid and phosphate
3. Phosphorus-containing enemas (Fleet’s enema)– given as a bowel preparation for colonoscopy – acute calcium phosphate deposition in the tubules and associated interstitial inflammation
   - Patients often have underlying kidney disease
4. Medications:
   - Intravenous Acyclovir, methotrexate, sulfonamide antibiotics (trimetthoprim-sulfemathoxazole – remember this can also cause AIN)

Question 23

Acute Tubular Obstruction - Diagnostic Work Up

Answer 23

1. History and chart review:
   a. Known history of multiple myeloma, malignancy (typically lymphoma) with recent chemotherapy administration, history of using a “Fleet’s enema”, medication review (i.e. are they receiving I.V. Acyclovir etc.?)
2. Physical Exam: Nonspecific but patients may be either volume depleted or have a low effective arterial blood volume to favor precipitation of these substances
3. Laboratory evaluation:
   a. High uric acid, phosphorus levels in the serum (tumor lysis syndrome)
   b. High phosphorus, low calcium in serum (phosphate nephropathy)
   c. Elevated free light chains in the serum (cast nephropathy)
   d. Oliguria <500ml urine output/24h e. Urine analysis will often demonstrate crystals of precipitated substance

Question 24

Vascular Disease

Answer 24

1. Renal Atheroembolic Disease
   - cholesterol emboli
2. Vasculitis
   - necrosis of small arteries and arterioles (also causes glomerulonephritis)
3. Thrombotic Miroangiopathies (TMA)
   - endothelial injury with formation of plateley thrombi occluding small vessels –> ischemia

Question 25

Renal Atheroembolic Disease

Answer 25

a. Occurs in patients with atherosclerotic disease following manipulation of the aorta or large arteries (coronary angiography, renal artery angioplasty/stent placement)
b. Cholesterol plaque breaks off after manipulation and embolizes distally resulting in partial or total occlusion of multiple small arteries or glomerular arterioles
c. Serum creatinine rise is subacute occurring between 2-8 weeks following manipulation/procedure (this is in contrast to radiocontrast exposure which causes rise in creatinine within 72h*)
d. Associated with low complement in serum, eosinophilia, and rash

Question 26

Vasulitis

Answer 26

•inflammation and necrosis of small arteries and arterioles (also causes glomerulonephritis)

a. Polyarteritis Nodosa, Wegener’s granulomatosis, and microscopic polyangiitis

Question 27

Thrombotic Microangiopathies

Answer 27

•endothelial injury with formation of platelet thrombi occluding small vessels –> ischemia

a. Hemolytic uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), malignant hypertension
b. Typically associated with low platelets (TTP/HUS)

Question 28

Vascular Diseases - Diagnostic Work Up

Answer 28

1. History and chart review: Aortic manipulation or coronary/renal angiography within the past 2-8 weeks (cholesterol emboli), uncontrolled hypertension (malignant hypertension)
2. Physical Exam: Rash (livedo reticularis in cholesterol emboli), purpura and petechiae (TTP/HUS), hypertension (>180/120 in malignant HTN)
3. Laboratory evaluation:
   a. Low serum complements and peripheral eosinophilia – cholesterol emboli
   b. Thrombocytopenia (low platelets) – TTP/HUS
   c. Schistocytes (red blood cell fragments on peripheral smear) – TTP/HUS
   d. Urine analysis – bland sediment in cholesterol emboli, may have dysmorphic red blood cells in sediment in TTP/HUS

Question 29

Glomerular Diseases

Answer 29

1. Rapidly Progressing Glomerulonephritis (RPGN)

Question 30

Rapidly Progressing Glomerulonephritis (RPGN)

Answer 30

1. Type I: Anti-glomerular basement membrane (GBM) disease
2. Type II: Immune complex diseases (Lupus nephritis, IgA nephropathy, post-infectious glomerulonephritis (PIGN), membranoproliferative glomerulonephritis (MPGN)
3. Type III: Pauci-immune/ANCA-associated vasculitis
   - We are discussing these in the nephritic lecture – just know they are a cause of acute kidney injury!
   - There are many diseases involving the glomeruli; however, only the RPGNs present as acute renal failure or AKI. There are some exceptions when nephrotic syndromes can present with AKI – (ATN in minimal change disease and renal vein thrombosis in membranous nephropathy)

Question 31

Rapidly Progressing Glomerulonephritis (RPGN) - Diagnostic Work Up

Answer 31

1. Laboratory evaluation:
   a. Urine analysis – microscopic hematuria, proteinuria (usually not nephrotic range <3.5g/24h)
   b. Urine sediment evaluation

– dysmorphic red blood cells, red blood cell casts, can have white blood cell casts RBC cast

c. Urine Na+ < 20meq/L 2. Renal biopsy is definitive Dysmorphic RBCs

Question 32

Post Renal Disease (Obstructive Uropathy)

Answer 32

• obstruction of the flow of urine anywhere from the remal pelvis to the urethra
• renal failure can be acute or subacute (occurring over a longer period of time)

Question 33

Post - Renal Disease - Causes

Answer 33

1. Calculi – stone at the ureteropelvic junction in a solitary kidney or bilateral staghorn calculi (can be seen in young and older adults)
2. Anatomic abnormalities – urethral valves, stricture, or stenosis at the ureterovesical or ureteropelvic junction – most common in children
3. Benign prostatic hyperplasia (BPH) – most common in men > 50 years
4. Urethral stricture
5. Malignancies:
   a. Prostate, bladder, or extrarenal pelvic neoplasms (cervical, ovarian, colon cancer) –> compression of bilateral ureters

Question 34

Post - Renal Disease - Diagnostic Work Up

Answer 34

1. History and chart review: Irritative or obstructive voiding symptoms (hesitancy, dribbling etc. in BPH), flank pain and gross hematuria (stones), known history of malignancy (cancers)
2. Physical exam: Tenderness to percussion at the costovertebral angle (stones), enlarged prostate on digital rectal exam (BPH or prostate cancer), palpation of abdominal/pelvic mass (pelvic neoplasm)
3. Imaging:
   a. *Diagnostic test of choice

– renal ultrasound will show hydronephrosis (enlargement of the kidney due to backflow of urine)

• CT of the abdomen/pelvis without radiocontrast – best for calculi and pelvic masses
  4. Laboratory evaluation:
  a. BUN:creatinine ratio >20:1 (stasis of urine causes increased reabsorption of urea if obstruction is acute)
  b. Urine sediment is bland

Question 35

Answer 35

Post Renal Disease - hydronephrosis

Question 36

Answer 36

Post Renal Disease - Calculi

Question 37

General Approach for a Patient with AKI

Answer 37

1. Take a good history!
2. Look for episodes of prolonged hypotension (i.e. ICU – septic shock)
3. Medication and nephrotoxin exposure
   a. Radiocontrast exposure, Fleet’s enema b. NSAIDs, Aminoglycosides, amphotericin, medications that can cause intratubular crystal precipitation (i.v. acyclovir), medications that can cause AIN (penicillins)
4. Do a good physical exam!
   a. Estimate volume status (low extracellular volume – prerenal, high extracellular volume/edema but low effective arterial blood volume – Heart failure
   b. Look for rash (exanthematous drug rash in AIN, livedo reticularis in cholesterol emboli)
5. Imaging – ultrasound to rule out obstruction (if acute, this can be reversible!)
6. Always look at the urine!
   a. Urine Na+ and FENa to distinguish between prerenal disease and ATN (low in prerenal but remember FENa may not be accurate if patients are nonoliguric)
   b. Proteinuria and hematuria on the urine analysis points to glomerular disease
   c. Crystals can be seen in intratubular crystal obstruction and nephrolithiasis
   d. Sediment review – can demonstrate dysmorphic red blood cells, red blood cell casts, and white blood cell casts concerning for RPGN or “muddy brown” casts suggestive of ATN
   e. Renal biopsy in select cases

Question 38

Complication from AKI

Answer 38

1. Uremia
   - Nausea, vomiting, anorexia, dysgeusia (food tastes different/metallic), altered mental status, pericarditis
2. Electrolyte abnormalities
   - Hyperkalemia (due to decreased distal Na+ delivery and urinary flow)

*Aminoglycosides, cisplatin, can cause hypokalemia due to polyuria/increased urinary flow (remember increased distal flow is a mechanism for hypokalemia!)

• Metabolic acidosis
• Extracellular volume excess or volume overload (edema)
  3. Chronic kidney disease (CKD)
• Unresolved AKI or repeated episodes of AKI can lead to CKD

Question 39

Treatment and Prevention of AKI

Answer 39

1. Volume resuscitate with crystalloid (saline) or colloid (blood) for volume depletion/hemorrhagic shock
2. Ensure renal arterial perfusion during shock keeping mean arterial pressure (MAP) > 65 mmgHg (use of vasopressors or inotropes if needed)
3. Treat underlying infection (sepsis)
4. Avoid further nephrotoxic injuries
   a. Avoid NSAIDs, aminoglycosides
   b. Give adequate hydration with medications that can cause intratubular crystal precipitation (acyclovir)
5. Pre-treat with parenteral (i.v.) sodium bicarbonate and N-acetylcysteine prior to radiocontrast exposure
6. Remove offending agent in AIN, trial of steroids
7. Foley catheter decompression for urinary obstruction, urinary stent placement, nephrostomy
8. Renal replacement therapy is indicated in patients who have refractory acidemia, volume overload (pulmonary edema), hyperkalemia, or uremia