Renal Acute Renal Failure

Front 1

Describe the clinical significance of acute renal failure

Back 1

-Occurs in 5-10% of hospitalized patients
-Occurs in up to 25% of ICU patients
-Mortality rate is high especially for severe ARF (20-40%)
-Contributes to morbidity of critically ill patients
-Correct diagnosis and treatment depend upon knowledge of pathophysiology

Front 2

What are the major causes of hospital acquired acute renal insufficiency?

Back 2

-Decreased renal perfusion
-Medications
-Radiographic Contrast Agents
-Post-operative
-Sepsis

Front 3

How do we measure the severity of acute renal injury?

Back 3

Serum markers BUN and creatinine. These give an indication of GFR. As GFR falls both of these build up in the blood. The higher the serum creatinine the higher the mortality

Front 4

Define acute renal failure

Back 4

-A rapid deterioration of renal function (GFR) associated with the accumulation of normally excreted nitrogenous and other waste products
-All forms of ARF typically have an elevated blood level of creatinine and BUN

Front 5

Describe the 3 major patterns of acute renal failure

Back 5

-Post-renal azotemia (obstruction)
-Pre-renal azotemia (perfusion problem)
-Intrinsic renal failure (acute tubular necrosis, acute interstitial nephritis, acute glomerulonephritis, vascular disease)

Front 6

Describe Post-renal Azotemia

Back 6

-ARF caused by obstruction of the outflow of urine
-Blockage can occur at any level from the urethra to the pelvis of the kidneys
-Common causes are prostatic enlargement due to beining hypertrophy or cancer, gynecologic malignancies, kidney stones
-Anuria (<100cc/day) suggests obstruction

Front 7

What are the 3 rules of post-renal azotemia?

Back 7

-Exclude obstruction in every case of ARF
-Radiologic tests (IVP, CT scan, etc) can show there is no blockage
In most cases use ultrasonogrram
-Unilateral obstruction does not cuase progressive severe ARF

Front 8

Describe pre-renal azotemia

Back 8

-An oliguric condition, associated with decreased GFR and retention of nitrogenous wastes, caused by decreased perfusion of the kidney
-Occurs in states of volume depletion and volume overload
-Potentially rapidly reversible if underlying cause is fixed

Front 9

Describe how pre-renal azotemia can develop into acute tubular necrosis and how to distinguish the two

Back 9

-If you have enough fluid loss, your BP drops, the kidney swings over from pre-renal azotemia and develops acute tubular necrosis.
-Severe decreases in BP can cause ATN.
-Mild and moderate only cause pre-renal azotemia.
-If you treat and it rapidly reverses it was just pre-renal azotemia. You can also look at the findings based on the pathophysiology.

Front 10

Describe the urinary findings in pre-renal azotemia

Back 10

-Low urinary Na+ concentration (<20 mEq/L) and low FeNa+ (<1%)
-Large increase in BUN
High BUN/Pcreatinine ratio (>20:1)
-Increased urine osmolality (>400 mOsm/L) and urinary specific gravity

Front 11

Why is there a high BUN/Pcreatinine ratio in pre-renal azotemia?

Back 11

-Creatinine is filtered and not reabsorbed at all, urea is partially filtered and then some is reabsorbed.
-In pre-renal azotemia with a low flow state there is a fair amount of back reabsorption of urea.
-This BUN/Pcreatinine is high. Both are elevated, but the BUN is much higher.
-In pre-renal azotemia the tubules work fine.

Front 12

Describe reabsorption in pre-renal azotemia

Back 12

-In any decreased renal perfusion state the amount of glomerular filtration per unit renal blood flow increases
-Filtration fraction goes up which causes forces that lead to Na reabsorption in the proximal tubule
-The RAS axis is turned on leading to increased Na reabsorption in the distal tubule
-If you reabsorb your Na proximally and distally then the fractional excretion of Na excretion if low and the concentration in low.

Front 13

Describe acute tubular necrosis

Back 13

-Most common pattern of intrinsic ARF
-Physiologic syndrome not morphologic
-Two etiologies: Ischemic and Nephrotoxins
-Has classic oliguric and diuretic phases
-There is a non-oliguric ATN

Front 14

What is oliguria?

Back 14

Urine output below 400ml/day

Front 15

What is anuria?

Back 15

Urine output below 100 ml/day

Front 16

What is the common cause of non-Oliguric ATN?

Back 16

Nephrotoxins

Front 17

Describe the urinary findings in acute tubular necrosi-High urinary Na+ concentration (>40 mEq/L) and high FeNa+ (>1%)

Back 17

-Unchanged BUN/plasma creatinine ratio in blood (10-15/1)
-Fixed urine osmolality (300mOsm/L) and urinary specific gravity (1.010)

Front 18

Describe Non-Oliguric Acute Tubular Necrosis

Back 18

-Increasing in incidence
-Common with Nephrotoxins
-Difficult to Recognize
-Lower morbidity and mortality

Front 19

Describe the mechanisms of acute tubular necrosis

Back 19

-Ischemic animal models of ATN (renal artery clamping, infuse intraarterial vasoconstrictor)
-Nephrotoxic Animal Models (HgCl2, Uranyl Nitrate, Gentamicin, Cisplatinum, Cyclosporine)
-Not all models have the same pathogenesis
-More than one mechanisms may be involved in each model of ARF

Front 20

Why is the GFR reduced in acute tubular necrosis?

Back 20

-Vasoconstriction
-Back leak of tubular fluid
-Intratubular Obstruction
-Altered glomerular permeability

Front 21

Describe the role of Renin-Angiotensin System in ARF

Back 21

-Early studies - JGA hyperplasia (JGA is where renin is secreted)
-Increased plasma Renin and AII levels in ARF
-Experiments with blockers of Renin-AII system ameliorate acute renal failure
-Tubuloglomerular feedback theory

Front 22

Describe the enzymatic cascade of the renin angiotensin system

Back 22

-Angiotensinogen is made in the liver
-Renin is made in the kidney and converts angiotensinogen to angiotensin I
-ACE is made in various tissues and converts Angiotensin I and Angiotensin II
-AII acts on the AT1 receptors causing:
-Vasoconstriction
-Cell growth
-Sodium and fluid retention
-Sympathetic activation

Front 23

What is the result of increased delivery of Cl- to the macula densa of the distal tubule?

Back 23

-Local vasoconstriction of the afferent arteriole of the same glomerulus by vasoactive local hormones: AII, endothelin, adenosine, NO, prostacyclin
-This shuts down the blood flow to that glomerulus hence the drop in the GFR

Front 24

Describe back leak of tubular fluid

Back 24

Normally you filter inulin, creatinine, and things that are not reabsorbed and they appear in the urine. If you have damage to the tubules (ATN). A lot can back leak through the damaged tubular epithelial cells. They are filtered, but the inulin and creatinine and everything else just go right back into the circulation.

Front 25

Describe intratubular obstruction

Back 25

Normally there is filtration and low pressure in the tubules. If you have blockage due to a cast the pressure rises. When it equals the filtration pressure you turn off glomerular filtration.

Front 26

Summarize the pathogenesis of acute tubular necrosis

Back 26

-There is a generation phase of inschemic or nephrotoxic insult
-There is reduced renal blood flow and release of modifying hormone
-This is followed by a maintainance phase consisting of vasoconstriction, back-leak, tubular obstruction, and decreased glomerular permeability

Front 27

Describe the biochemical markers of cell injury

Back 27

-Basal and max O2 consumption decrease
-Activation of phospholipases
-Increased ROS
-Increased permeability to K and Ca resulting in lower cellular K and increased cellular Ca
-ATP levels decrease, AMP levels increase

Front 28

Describe the possible mechanisms of tubular cell injury and necrosis

Back 28

-Ischemia or nephrotoxic insult leads to reduction of cell ATP and ADP levels
-There is an inability to regulate intracellular ions (Na and Ca)
-There is swelling of cytosol, mitochondrial damage, and activation of enzymes
-This leads to organellar damage and increased membrane permeability

Front 29

Describe the targets of treatment in acute renal failure

Back 29

-Offset vasoconstriction
-Limit inflammation
-Alter cell outcome with growth factors and survival factors
-Change of dialysis prescription
-If there is already established ATN you cannot prevent it, you cant readily reverse it. You can prevent it if you hydrate and give saline before the insult, but after the insult there is no way to prevent it. People recover and they recover at the same pace if you give these things or don’t.

Front 30

Describe what occurs with tubular epithelial cell injury and repair

Back 30

-With ischemia or nephrotoxin there is a loss of polarity
-Na-K ATPs is normally along the basolateral and lateral side but it gets shifted to the apical side
-There is necrosis and apoptosis/cell death
-There is sloughing off of cells
-There is a birth of cells along the basement membrane of the tubule, some from viable cells already there and some may be from stem cells
-This proliferation goes on and then you get redistribution, redifferentiation, and reestabilishment of the polarity and you are back to where you were.

Front 31

Describe the outcomes of hospital acquired renal insufficiency

Back 31

-Partial recovery of renal function 23%
-Discharged with increased Pcreat 17%
-Discharged on chronic hemodialysis 3%
-Death 20%

Front 32

What is the biomarker of acute kidney injury?

Back 32

Serum creatinine, although NGAL and KIM-1 are looking promising

Front 33

Back 33

This is a normal ultrasound. The black is the cortex of the kidney. The white inside is the medulla of the kidney.

Back 34

-This is a patient with benign prostatic hypertrophy that had a markedly elevated creatinine and BUN.
-The BPH lead to uretereal blockage and backup of urine.
-His kidney is compressed into a little rim around this giant kidney. The hollow area is the dilated collecting system.
-If this is due to the prostate or a gynecological tumor this will be bilateral because the blockage is low down.

Front 35

Back 35

-This is a patient with benign prostatic hypertrophy that had a markedly elevated creatinine and BUN.
-The BPH lead to uretereal blockage and backup of urine.
-His kidney is compressed into a little rim around this giant kidney. The hollow area is the dilated collecting system.
-If this is due to the prostate or a gynecological tumor this will be bilateral because the blockage is low down.

Front 36

Back 36

US is also good at showing kidney stones. This is a kidney with a kidney stone. There is a sharp cutoff at the stone and a shadow behind it. If you are looking for stones or obstruction, US is great.

Front 37

Back 37

-If you see these muddy brown granular casts in the urine sediment it is very suggestive that the patient has acute tubular necrosis.
-Many times you don’t see these.

Front 38

Back 38

-This is a latex injection of those ARF animals.
-The top left is normal, then 6 hrs, 12 hrs, and 24 hrs.
-At the end it is only the deeper nephrons that are being perfused.

Front 39

Back 39

Here is a kidney glomerulus with the afferent and efferent arteriole.

Front 40

Back 40

-If you look at biopsies from people who have crush injuries, you see casts of proteinacious material and debris blocking the tubule.
-This may be the same tubule going up and down. You only have to block it at one point.

Back 41

-EM of a normal kidney
-If you are sitting in Bowman's space and looking at the capillary loops you can see the visceral epithelial cells sitting on those capillary loops.

Front 42

Back 42

-EM of a normal kidney
-If you are sitting in Bowman's space and looking at the capillary loops you can see the visceral epithelial cells sitting on those capillary loops.

Front 43

Back 43

-EM of a nephrotoxic kidney
-This is what the cpaillary loops look like from Bowman's space.
-You can sort of see a visceral epithelial cell, but there is marked damage.
-The ultrafiltration goes down in these models.

Front 44

Back 44

-Biopsy of ATN
-When you look at a biopsy of ATN sometimes you see simplifications of the tubular cells and loss of brush border. -Sometimes you don’t see anything abnormal when you look at it with light microscopy.

Front 45

Back 45

-EM of ATN
-If you look at an early stage at the tubular cells you see vacuolization and rounding up of the mitochondria.

Front 46

Back 46

-EM of middle stages of ATN
-One cell still has a brush border. The other one has lost the brush border. There are lots of vacuoles, laminated wall type configurations.

Front 47

Back 47

-EM of later stages of ATN
-Even later you find lot of debris and cells in the tubular lumen.