Robbins - Tubular and Interstitial Diseases

Question 1

What are the 2 main mechanisms for acute tubular injury/ATI?

Answer 1

Ischemia

&

Direct toxicity - endogenous and exogenous

• endogenous: hemoglobin, monoclonal light chains, bile/bilirubin
• exogenous: drugs, radiocontrast soln., heavy metals, CCl4/solvents

Question 2

Ischemic ATI is often due to what?

Answer 2

period of inadequate blood flow to organs/hypovolemic shock

Question 3

Nephrotoxic ATI is often due to what? What can lead to both ischemic and toxic ATI?

Answer 3

• endogenous: hemoglobin, monoclonal light chains, bile/bilirubin
• exogenous: drugs, radiocontrast soln., heavy metals, CCl4/solvents

Combinations of toxic and ischemic ATI can occur - transfusion blood type mismatch, hemolytic crisis, skeletal mm injuries –> myoglobinuria

Question 5

What are the critical factors in pathogenesis of ATI?

Answer 5

tubular injury

persistent and severe disturbances in blood flow

Question 6

What is the pathogenesis behind tubule cell injury in ATI?

Answer 6

Tubule cells sensitive to toxins and ischemia - high rate of metabolism, transport many things

Insult causes loss of cell polarity - memb proteins redist.

-results in increased Na+ to DCT, causes vasoconstriction via tubuloglomerular feedback

Injured cell invites leukocytes

Tubule cells slough off BM and occlude tubule

Question 7

Injured tubule cells eventually detach from BM, what are the effects of this?

Answer 7

Luminal obstruction

increased intratubular pressure

decreased GFR

glomerular filtrate can leak back into interstitium and cause edema, increased interstitial pressure, and further damage to the tubule

= decreased GFR

Question 8

What is the pathogenesis behind disturbances in blood flow in ATI?

Answer 8

Ischemic renal injury = hemodynamic alterations that cause reduced GFR

• intrarenal vasoconstriction (reduced glom. blood flow and O2 delivery to TAL and PCT in medulla)
• influenced by RAS and NO production by endothelials
• possible mesangial contraction

Question 9

What systems are implicated behind ischemic injury with ATI?

Answer 9

RAS

• increased NA+ delivery to distal tubule (tubuloglomerular feedback)

Sublethal endothelial injury

• increased endothelin - vasoconstricts
• decreased NO and prostaglandins

Question 10

What gross morphological findings help indicate that ATI is possibly reversible?

Answer 10

Patchiness of tubular necrosis

Maintenance of BM - depends on capacity of injured epithelials to proliferate

Question 11

What are some major morphological findings associated with ATI?

Answer 11

Focal tubular epithelial necrosis

rupture of BM - tubulorrhexis

occlusion of tubular lumens by casts - eosinophilic, with Tamm-Horsfall proteins

Interstitial edema

Regenerating epithelium - dark nuclei

Question 12

What are some morphological findings associated with toxic ATI?

Answer 12

acute tubular injury, esp. in PCTs

tubular necrosis

Specific findings can point to toxicity:

• HgCl - large acidophilic inclusions
• CCl4 - neutral lipid accumulation with fatty change and necrosis
• Ethylene glycol - ballooning with degeneration of PCT, calcium oxalate crystals

Question 13

What are the 3 parts of the clinical phase of ATI?

Answer 13

Initiation

Maintenance

Recovery

Question 14

What are the characteristics of the initiation phase of ATI?

Answer 14

~36 hours, after injury/insult

• slight decrease in urine output –> transient decrease in blood flow and GFR
• slight increase in BUN

Question 15

What are the characteristics of the maintenance phase of ATI?

Answer 15

oliguria - 40-400mL/day

salt and water overload

rising BUN

hyperkalemia

metabolic acidosis

uremic syndrome

Question 16

What are the characteristics of the recovery phase of ATI?

Answer 16

• increased urine –> 3L/day
• large amounts of Na+, K+ and water lost

hypokalemia

vulnerable to infection

tubular fxn, conc. ability restored

Question 17

What is the prognosis of ATI?

Answer 17

95% of people who do not succumb to initial toxic event recover

50% of people with shock or multi-organ failure do not recover

Question 18

How is tubulointerstitial nephritis characterized?

Answer 18

inflammatory injuries to tubules and interstitium

insidious in onset, marked by azotemia

Question 19

Acute tubulointerstitial nephritis is characterized by what?

Answer 19

rapid clinical onset

interstitial edema

leukocytic infiltration of interstitium and tubules

tubular injury

Question 20

Chronic tubulointerstitial nephritis is characterized by what?

Answer 20

Infiltration with mononuclear leukocytes

interstitial fibrosis

tubular atrophy

Question 21

How do you distinguish tubulointerstitial nephritis from glomerular disease?

Answer 21

No nephritic/nephrotic syndrome

Defects in tubular fxn

• metabolic acidosis, polyuria, nocturia, salt wasting, defects in tubular wasting

Question 22

What are some major categories of causes for tubulointerstitial nephritis?

Answer 22

Infections

Toxins

Metabolic Disease

Physical Factors

Neoplasms

Immunological Reations

Vascular Diseases

Question 23

What is the 2nd most common cause of acute kidney injury?

Answer 23

drug and toxin-induced tubulointerstitial nephritis

(first is pyelonephritis)

Question 24

What are 3 ways toxins and drugs trigger kidney injury?

Answer 24

1. interstitial immunological rxn - hypersensitivity nephritis
2. cause acute tubular injury - ie CCl4/ethylene glycol
3. Cumulative subclinical injury to tubules, creating chronic renal insufficiency (!)

Question 25

What drugs can trigger acute drug-induced interstitial nephritis?

Answer 25

Synthetic PCNs - methicillin, ampicillin Other synthetic ABs - rifampin thiazide diuretics NSAIDs allopurinol, cimetidine

Question 26

What is the clinical picture of drug-induced interstitial nephritis?

Answer 26

2-40 days (~15 days) aft drug exposure - fever, eosinophilia, rash (25%), renal abnormalities - hematuria, mild proteinuria, leukocyturia - rising serum creatine or acute kidney injury in 50% older patients

Question 27

What is the pathogenesis of acute drug-induced interstitial nephritis?

Answer 27

late phase Type I hypersensitivty rxn - or - T-cell mediated/Type IV rxn Drugs turn to haptens, bind tubules, become immunogenic --\> IgE binding, or T-cell mediated response

Question 28

Why is it important to recognize acute drug-induced interstitial nephritis?

Answer 28

Remove offending drug to start recovery recovery can take several months, irreversible damage can occur 40% of cases are idiopathic

Question 29

What are some clinical features of acute drug-induced interstitial nephritis?

Answer 29

papillary necrosis - compression or obstruction of small vessels in medulla leading to ischemia - can be excreted, causing gross hematuria or renal colic Clinical features - Gross pee, pain.

Question 30

What conditions do you see papillary necrosis for?

Answer 30

analgesic nephropathy DM urinary tract obstruction sickle cell disease/trait - compression of renal medulla small vessels, or microvascular disease

Question 31

What are the NSAID-related renal syndromes?

Answer 31

**Acute kidney injury - lack of vasodilation via prostaglandins, esp. with other kidney problems or volume depletion** Acute hypersensitivity intersitial nephritis Acute interstiital nephritis and Minimal Change Disease - hypersensitivty rxn to glomeruli and interstitium, podocytes collateral damage Membranous nephropathy - correllated, no clear pathology

Question 32

Hyperuricemic disorders can cause nephropathies. Name 3.

Answer 32

1. Acute Uric Acid Nephropathy 2. Chronic Urate Nephropathy 3. Nephrolithiasis

Question 33

What is the pathogenesis behind acute uric acid nephropathy?

Answer 33

ppt of uric acid crystals in renal tubules -\> nephrons obstructed -\> acute renal failure Likely to occur in ind. with leukemia - lymphomas undergoing chemo - cells lyse, release uric acid, ppt in acidic pH in collecting tubules - definitive proof that life is a bitch - got cancer? How about some kidney stones too?

Question 34

What is the pathogenesis behind chronic urate nephropathy?

Answer 34

THE GOUT!! - gouty nephropathy, with people wiht protracted forms of hyperuricemia Monosodium urate crystals deposit in acidic distal tubules, collecting ducts - bifringent crystals that evoke mononuclear cells, giant cells - complex called tophus Eventual tubular defects, nephropathy

Question 35

What problems can cause hypercalcemia? This is renal, why do we care?

Answer 35

Hypercalcemia - hyper-PTH, mult myeloma, Vit D intoxication, excess Ca++ intake, metastatic cancer Leads to formation of calcium stones in kidneys - nephrocalcinosis

Question 36

What problems does nephrocalcinosis cause?

Answer 36

Extensive nephrocalcinosis can lead to tubulointerstitial disease, renal insufficiency Tubular acidosis salt-losing nephritis slowly progressive renal insufficiency kidney stones, secondary pyelonephritis

Question 37

What is acute phosphate nephropathy from?

Answer 37

CaPO4 crystals in tubules from oral phosphate soln for colonoscopy renal insufficiency for several weeks aft

Question 38

What is myeloma kidney? Why would hematopoietic tumors affect the kidney?

Answer 38

Kidneys get clogged with tiny proteins, assorted tumor-related crap tubulointerstitial problems - hypercalcemia, ureteral obstruction Also: therapy - irradiation, hyperuricemia, chemo infection aft bone marrow transplant

Question 39

What factors (previously called tumor crap) contribute to renal damage with myeloma kidney?

Answer 39

Bence-Jones proteinuria, cast nephropathy Amyloidosis Light chain deposition disease Hypercalcemia, hyperuricemia

Question 40

What is the pathogenesis of Bence-Jones proteinuria?

Answer 40

a type of light chain proteinuria light chain Ig's directly toxic to endothelials Light chain Ig's combine with Tamm Horsfall proteins that obstruct tubular lumens Occurs in 70% of people with mult myeloma - significant light chain proteinuria

Question 41

What is hepatorenal syndrome?

Answer 41

Impairment of renal function in patients with acute or chronic liver disease - high serum bilirubin leads to bile cast formation - casts can start in distal nephron and grow in proximal tubule, directly toxic and destroys nephron Tubular bile casts are yellow-green to pink