Robbins - Tubular and Interstitial Diseases Flashcards
What are the 2 main mechanisms for acute tubular injury/ATI?
Ischemia
&
Direct toxicity - endogenous and exogenous
- endogenous: hemoglobin, monoclonal light chains, bile/bilirubin
- exogenous: drugs, radiocontrast soln., heavy metals, CCl4/solvents
Ischemic ATI is often due to what?
period of inadequate blood flow to organs/hypovolemic shock
Nephrotoxic ATI is often due to what? What can lead to both ischemic and toxic ATI?
- 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
What are the critical factors in pathogenesis of ATI?
tubular injury
persistent and severe disturbances in blood flow
What is the pathogenesis behind tubule cell injury in ATI?
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
Injured tubule cells eventually detach from BM, what are the effects of this?
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
What is the pathogenesis behind disturbances in blood flow in ATI?
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
What systems are implicated behind ischemic injury with ATI?
RAS
- increased NA+ delivery to distal tubule (tubuloglomerular feedback)
Sublethal endothelial injury
- increased endothelin - vasoconstricts
- decreased NO and prostaglandins
What gross morphological findings help indicate that ATI is possibly reversible?
Patchiness of tubular necrosis
Maintenance of BM - depends on capacity of injured epithelials to proliferate
What are some major morphological findings associated with ATI?
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
What are some morphological findings associated with toxic ATI?
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
What are the 3 parts of the clinical phase of ATI?
Initiation
Maintenance
Recovery
What are the characteristics of the initiation phase of ATI?
~36 hours, after injury/insult
- slight decrease in urine output –> transient decrease in blood flow and GFR
- slight increase in BUN
What are the characteristics of the maintenance phase of ATI?
oliguria - 40-400mL/day
salt and water overload
rising BUN
hyperkalemia
metabolic acidosis
uremic syndrome
What are the characteristics of the recovery phase of ATI?
- increased urine –> 3L/day
- large amounts of Na+, K+ and water lost
hypokalemia
vulnerable to infection
tubular fxn, conc. ability restored
What is the prognosis of ATI?
95% of people who do not succumb to initial toxic event recover
50% of people with shock or multi-organ failure do not recover
How is tubulointerstitial nephritis characterized?
inflammatory injuries to tubules and interstitium
insidious in onset, marked by azotemia
Acute tubulointerstitial nephritis is characterized by what?
rapid clinical onset
interstitial edema
leukocytic infiltration of interstitium and tubules
tubular injury
Chronic tubulointerstitial nephritis is characterized by what?
Infiltration with mononuclear leukocytes
interstitial fibrosis
tubular atrophy
How do you distinguish tubulointerstitial nephritis from glomerular disease?
No nephritic/nephrotic syndrome
Defects in tubular fxn
- metabolic acidosis, polyuria, nocturia, salt wasting, defects in tubular wasting
What are some major categories of causes for tubulointerstitial nephritis?
Infections
Toxins
Metabolic Disease
Physical Factors
Neoplasms
Immunological Reations
Vascular Diseases
What is the 2nd most common cause of acute kidney injury?
drug and toxin-induced tubulointerstitial nephritis
(first is pyelonephritis)
What are 3 ways toxins and drugs trigger kidney injury?
- interstitial immunological rxn - hypersensitivity nephritis
- cause acute tubular injury - ie CCl4/ethylene glycol
- Cumulative subclinical injury to tubules, creating chronic renal insufficiency (!)
What drugs can trigger acute drug-induced interstitial nephritis?
Synthetic PCNs - methicillin, ampicillin
Other synthetic ABs - rifampin
thiazide diuretics
NSAIDs
allopurinol, cimetidine
What is the clinical picture of drug-induced interstitial nephritis?
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
What is the pathogenesis of acute drug-induced interstitial nephritis?
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
Why is it important to recognize acute drug-induced interstitial nephritis?
Remove offending drug to start recovery
recovery can take several months, irreversible damage can occur
40% of cases are idiopathic
What are some clinical features of acute drug-induced interstitial nephritis?
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.
What conditions do you see papillary necrosis for?
analgesic nephropathy
DM
urinary tract obstruction
sickle cell disease/trait
- compression of renal medulla small vessels, or microvascular disease
What are the NSAID-related renal syndromes?
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
Hyperuricemic disorders can cause nephropathies. Name 3.
- Acute Uric Acid Nephropathy
- Chronic Urate Nephropathy
- Nephrolithiasis
What is the pathogenesis behind acute uric acid nephropathy?
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?
What is the pathogenesis behind chronic urate nephropathy?
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
What problems can cause hypercalcemia? This is renal, why do we care?
Hypercalcemia - hyper-PTH, mult myeloma, Vit D intoxication, excess Ca++ intake, metastatic cancer
Leads to formation of calcium stones in kidneys - nephrocalcinosis
What problems does nephrocalcinosis cause?
Extensive nephrocalcinosis can lead to tubulointerstitial disease, renal insufficiency
Tubular acidosis
salt-losing nephritis
slowly progressive renal insufficiency
kidney stones, secondary pyelonephritis
What is acute phosphate nephropathy from?
CaPO4 crystals in tubules
from oral phosphate soln for colonoscopy
renal insufficiency for several weeks aft
What is myeloma kidney? Why would hematopoietic tumors affect the kidney?
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
What factors (previously called tumor crap) contribute to renal damage with myeloma kidney?
Bence-Jones proteinuria, cast nephropathy
Amyloidosis
Light chain deposition disease
Hypercalcemia, hyperuricemia
What is the pathogenesis of Bence-Jones proteinuria?
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
What is hepatorenal syndrome?
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
