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Endo/Renal Path final
period 4 path final (UofM)
32
Medical
Not Applicable
02/12/2008

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Cards

Term
Acute Renal Failure =
Definition
Sudden decrease in creatinine clearance to 20 ml/min or less
Term
Types of acute renal failure (3)
Definition
Pre-renal – decrease in glomerular filtration (decreased BP or vascular volume); reversible if BP restored

Post-renal – obstruction of urine flow, common in bladder or with enlargement of the prostate

Intra-renal – decreased BP leads to a pre-renal state but renal failure persists after correction of blood flow
Term
Acute Kidney Injury
Definition
Used to be known as acute tubular necrosis but is no longer since significant tubular necrosis may or may not be present event though the clinical presentation is the same.
Term
AKI Causes
Definition
Following prerenal failure - ischemic injury caused by hypotension or hypovolemia

Toxic injury

Trauma – very common, due to loss of blood or rhabdomyolysis

Hemolysis – severe

Hypovolemic shock

Rhabdomyolysis

Reactions to drugs (i.e. NSAIDs) – also can happen with cocaine use and the subsequent vascular effects

Septic abortion – or sepsis due to almost any cause
Term
AKI Clinical Features
Definition
Oliguric – most patients, very little or no urine output; < 400 ml urine/dy

Non-oliguric – urine is inadequate to clear waste products and provide electrolyte balance; patients have the same severity of renal failure as the oliguric patients; greater that 500 ml of urine per day; about 35% of patients with AKI

High urine sodium content (FENa) since the tubule epithelial cells are not functioning properly and are not effective in reabsorbing Na.

Urine not concentrated since the tubules are having a hard time reabsorbing water.

Rapid rise in serum creatinine due to rapid fall in clearance
Term
AKI Renal Tubular Function

Pre-renal
Definition
ubular epithelial cells function normally but have decreased glomerular filtration due to hypotension or hypovolemia (↓GFR → ↑Na reabsorption and ↑H2O reabsorption)

Sodium in urine less than 20 mEq/L (FENa < 1%)

Urine concentrated – tubules work correctly
Term
AKI Renal Tubular Function

Ischemic AKI
Definition
Sodium greater than 40 mEq/L – FENa increased (> 1%)

Urine isotonic with plasma – not concentrated
Term
Tubular function distinguishing between pre-renal failure and AKI – urine [Na] can help differentiate pre-renal from AKI
Definition
If pt. is in pre-renal failure (with decreased blood vol.) the tubular epithelial cells still function, so urinary [Na] is low; if pt has progressed to ischemic AKI, all the Na is coming out in their urine. This is important to differentiate because you need to know if the pt is in pre-renal failure and able to be reversed.
Term
Toxic AKI
Definition
Dose dependent toxic renal injury

Extensive tubular cell necrosis – more extensive than ischemia

Involves all nephrons

May be limited to part of a nephron – some toxins are location specific

Caused by : mercuric chloride, lead, carbon tetrachloride (proximal), lithium, ethylene glycol (distal), radio-contrast agents
Term
AKI Pathology
Definition
Loss of proximal tubular epithelial cell brush border (very early finding); this is reversible.

Focal necrosis at multiple points along nephron

“Skip areas” – portions of the tubules are perfectly normal and other portions are necrosed

Casts in the tubular lumens – because epithelial cells are sloughing

Flat epithelium and dilated tubules – due to regeneration

Interstitial edema with occasional mononuclear inflammatory cell – interstitial changes correlate best with renal function
Term
AKI Slide Findings

Biopsy of kidney with AKI and tubular necrosis (Image 1, 1a)
Definition
Glomeruli are normal

Abnormalities are the dilated tubules and space between tubules – they should be back-to-back

Many lack epithelial cells

Image 1: Kidney with AKI and tubular necrosis. Normal glomeruli, but dilated tubules and lack of epithelial cells.

Image 1a: High power: kidney with AKI and tubular necrosis. Normal glomeruli, but dilated tubules and lack of epithelial cells.
Term
AKI Slide Findings

Higher power of same kidney (Image 2)
Definition
Trichrome stain – collagen is green

Again, glomeruli are normal and tubules are dilated and widely spaced

Lesions are patchy

Extensive edema with few, if any, inflammatory cells

If AKI doesn’t heal properly, it progresses to chronic tubular interstitial nephropathy where the interstitium becomes fibrotic

When there is regeneration of tubule epithelial cells, it takes place quickly and the cells form normal epithelium. The regeneration can even extend into Bowman’s capsule. On PAS stain, brush borders of the epithelial cells stain pink
Term
AKI Pathophysiology
Definition
Damage to basal Na/K ATPase pump in tubular epithelial cells.
Impaired Na reabsorption and increased Na delivery to distal tubule.
Loss of cell polarity (pumps move to luminal side) and brush border
Tubuloglomerular feedback
Glomerulus can detect an increased in Na delivery to the post-medulla(distal) tubule and decrease glomerular filtration via afferent arteriolar vasoconstriction
Vasoconstriction
Ischemic glomerular endothelial cells release endothelin which causes vasoconstriction and vascular ischemia
A drop in Nitric Oxide leads to decreased vasodilation
So blood supply to tubular epithelial cells is highly reduced
Necrosis and apoptosis with release of inflammatory mediators (cytokines, PMNs, T cells, and complement) that can react with the microvasculature - this step is not reversible unlike the previous steps.
Term
AKI Tubule Involvement
Definition
Toxic – proximal convoluted tubule
Ischemic – outer medulla – most sensitive to oxygen deprivation due to poor vascular supply; helps explain why microscopy shows normal areas next to damaged ones
Straight segment of the proximal tubule (S3)
Ascending limb of the Loop of Henle
Distal tubule
Tubular epithelial cells are very susceptible to oxygen depletion because they are supplied by a second capillary system – they get their blood after the glomerulus (they get the sloppy seconds) – plus, the tubules are highly metabolic.
Why the high metabolism? They have to reabsorb all that Na. Any damage to these cells and Na is not properly re-absorbed, therefore urinary Na content is high. This is measured as the Fractional Excretion of Na or FENa.
Term
Radiocontrast Nephropathy
Definition
Very important clinical problem
Risk factors: elderly, volume deplete, renal insufficiency, congestive heart failure, diabetes, high dosage
Many patients that get radiocontrast materials fall into one of these risk factors so this is a common occurrence.
Morphology: Tubular epithelial cells are very vacuolated. The cells are no longer functionally normal.
Incidence:
Non-diabetic, non-azotemic - 2%
Diabetic, non-azotemic - 16%
Diabetic, azotemic - 38%
Usually non-oliguric, radiocontrast agents are vasoconstrictors (possible cause of AKI), usually reversible
Term
Tubulointerstitial Disease/Tubulointerstitial Nephritis =
Definition
a.k.a. Interstitial Nephritis: pathologically defined by a large number of inflammatory cells in the interstitium. In reality it is hard to always see inflammatory cells, so then the more general term – Tubulointerstitial Nephropathy - is used.
Term
Acute TI Nephritis:
Definition
sudden onset and rapid decline in function
Term
Chronic TI Nephritis:
Definition
slow decline in function w/ interstitial fibrosis
Term
The Causes of Interstitial Nephritis.:
Definition
infections (reactive or direct), obstruction, immune, metabolic, plasma cell disorders, heavy metals, and… drug reactions (85% - 95%)!!
Term
Tubulointerstitial Disease/Tubulointerstitial Nephritis

Clinical Manifestations
Definition
Eosinophilia – 50% present w/ eosinophils in peripheral blood

Acute renal failure (same manifestations as ATN) – often need dialysis

Low grade proteinuria – up to 1 g/ 24 hrs

Eosinophiluria - eosinophils in the urine

Pyuria – eosinophils and lymphocytes in the urine

Eosinophils play an important role in Acute Interstitial
Nephritis secondary to drugs.
Term
Tubulointerstitial Disease/Tubulointerstitial Nephritis

Urinalysis in T.I. Nephritis:
Definition
(Helpful in differentiating the condition from ATN, etc.)
Pyuria: increased lymphocytes and eosinophils in the urine
Mild hematuria and proteinuria (either of these in higher amounts would indicate glomerular cause, so low grade indicates tubulointerstitial disease)
Signs of tubular dysfunction, such as glycosuria and amino aciduria
Term
Tubulointerstitial Disease/Tubulointerstitial Nephritis

Pathogenesis
Definition
Idiosyncratic – not dose related (in contrast to toxic ATN)

Hypersensitivity - Type I - Eosinophils (probably the main cause)

Humoral immunity - Type II or Type III - Immune complexes in the tubular basement membranes (III) or find antibody to the TBM antigens (II).

Cell mediated - Type IV - T cell reactivity to tubular antigens.
Term
Drug classes that lead to Tubulointerstitial Nephritis
Definition
Beta-lactam antibiotics: penicillin and cephalosporin (most common)
Anticonvulsants
Diuretics
Anti-inflammatory drugs
Over 80 types of drugs can cause the condition, so be aware whenever you are prescribing that your patient may end up on dialysis because of your drug (thank you Crosson for that happy, motivational thought :) )
Term
Tubulointerstitial Disease/Tubulointerstitial Nephritis

Pathology
Definition
Interstitial mononuclear cells – T cells and plasma cells in the interstitium
These are required for diagnosis of Acute I.N.

Edema – interstitial

Eosinophils (2-10%) – play a major role in drug reactions and are almost always present

Tubulitis – hallmark of IN
Inflammatory cells in tubular lumen – must have inflammatory cells cross the basement membranes and react with tubular endothelial cells
Role of adhesion molecules – mostly VCAMs that react to integrins; this causes attraction of lymphocytes into the tubular lumen.
Glomeruli normal
Anti-tubular basement membrane (rare)
Immune complexes – TBM (rare)
Term
Tubulointerstitial Disease/Tubulointerstitial Nephritis

Natural History
Definition
Reversible when drug stopped if identified quickly
Improves with steroids – helps speed recovery
Recurrence on re-exposure to drug – usually a worse reaction than with the first exposure
Can progress to chronic interstitial nephritis – fibrotic interstitium
Term
Granulomatous Interstitial Nephritis

Characteristics
Definition
Class IV hypersensitivity reaction
Variant of acute interstitial nephritis
30% of drug induced interstitial nephritis
Granuloma formation in interstitium in relation to tubule
Multinucleated cells rare
Epitheliod macrophages in granuloma
Lymphocytes
Term
Granulomatous Interstitial Nephritis

Differential Diagnosis
Definition
Sarcoidosis
Drug induced – ampicillin and methicillin most common
Tuberculosis – kidneys may be the only involved organ
Fungal
Infectious mono
Term
Light Chain Cast Nephropathy
Definition
Most common cause of renal failure in multiple myeloma
Multiple myeloma: plasma cell malignancy that produces monoclonal immunoglobulin (light chains and heavy chains sometimes not in equal amounts).
Light chains are small and can be cleared into urine easily. When they are made in excess of heavy chains they tend to be cleared by the kidney. But these can be very toxic to the tubular epithelial cells.
Characteristic tubular casts
Primary presentation is renal failure
Term
Nephrocalcinosis
Definition
Hyperparathyroidism
Sarcoidosis
Milk alkali syndrome
Vitamin D excess
Na phosphate (oral) bowel prep for colonoscopy (acute phosphate nephropathy)
Fleet Phospho-soda
Rare complication
Hypertension is risk factor
Term
Nephrocalcinosis and Non-steroidal anti-inflammatory drugs (NSAIDS)
Definition
More of a problem with patients who are elderly, and/or have vascular impairment or other underlying diseases
Vasoconstriction
Cyclooxygenase inhibitor (COX-1 & 2)
Inhibition of vasodilatory prostaglandin synthesis
Na retention and decreased GFR
Angiotensin II unopposed (increased BP)
Acute kidney injury
FENa high
20% with risk factors - renal effects (2.5 million Americans)
Idiosyncratic TI nephropathy – inflammation in the interstitium
Minimal change disease
TI nephropathy often coexist
Consistent with podocyte injury from cytokines released by inflammatory process
Term
Acute Renal Allograft Rejection

Clinical
Definition
Sudden decline in renal function
Fever
Swelling and tenderness of graft
Weeks to years after allograft
May be asymptomatic
Term
Acute Renal Allograft Rejection

Pathology
Definition
Interstitial mononuclear infiltrate
Cortex more than medulla
Interstitial edema
Tubulitis
May have tubular basement membrane disruption
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