1/30 Tubulointerstitial Disease - Kapoian Flashcards
kidney compartments
- glomerular
- vascular
- tubular
- interstitial
two types of nephrons and difference
- cortical nephron - shorter
- juxtamedullary nephron - longer
anatomy of tubular membrane
3 components and their functions
-
tight junctions (zona occludens)
- brings adj cells together at luminal surface
- barrier to passive diffusion
- boundary between luminal and basolateral membranes
- helps maintain cell polarity
-
luminal/apical membrane
- contains channels/transporters: allow solutes to pass b/w intracellular space and tubular lumen
-
basolateral membrane
- contains: Na/K ATPase, hormone receptors, solute channels/transporters
tubular segment terminology
what is included in…
- prox tubule
- intermed tubule
- distal tubule
- collecting duct system
proximal tubule: prox convoluted tubule + prox straight tubule
intermed tubule: desc thin limb of Henle + asc thin limb of Henle
distal tubule: thick asc limb of Henle + DCT
collecting duct system: connecting tubule + cortical collecting duct + outer/inner medullary collecting duct
thick asc limb of LoH
- aka “distal straight tubule”
- begin: jx of outer/inner medulla
- end: cortex beyond macula densa
- rich in Ha/K ATPase activity
- active Na-Cl resorption
- production of Tamm-Horsfall mucoprotein
- elemental structure of tubular casts → protein that holds casts together!
distal nephron cell types
- dist convoluted tubule cell
- connecting tubule cell
- principal cell (collecting duct cell)
- intercalated cell (alpha and beta)
distal convoluted tubule
begin/end
fx
“diuretic resistance”
begin: beyond macula densa
end: transitional nephron segment
resorbs 5% of filtered Na-Cl
- resorption proportional to delivery
“diuretic resistance”
- loop diuretics enhance distal Na delivery → enhances distal Na reabs
- if prolonged…distal tubular hypertrophy! even more enhanced Na reabs
connecting tubule
impermeable to water
- active Ca reabs
- responds to PTH and calcitriol
- reabs of Na via Na-Cl cotransporter
- sensitive to thiazides
- secretes K in response to aldosterone
collecting duct
two cell types
- principal cells
- aka “collecting duct cell”
- contributes to net Na reabs via Na channels
- primary site of K secretion
- contains ADH and aldosterone receptors
- intercalated cells
- alpha cell and beta cells (based on polarity)
- high deg of carbonic anhydrase activity
ratio of cell types varies b/w species and segment of collecting duct
diet-induced variations in urinary sodium excretion
hi Na vs lo Na
what cell type affected, what effect?
principal cell
low sodium diet
- enhanced aldosterone release
- incr number of open Na channels
- enhanced Na reabs
high sodium diet = opp of low Na diet
alpha intercalated cells
- Apical membrane
- resp for Acid secretion
- responds to Aldosterone
beta intercalated cells
- proton pump on Basolateral membrane
- responsible for Bicarbonate (Base) secretion
opposite polarity of alpha cells!
mechanisms of tubulointerstitial injury:
glomerular injury
loss of permselectivity (proteins enter capsule) → lysosomal degradation of urinary proteins ensues
- complement activation
- Fe dep tubular injury
- ROS
- cytokine release
mechs of TI injury:
immunologic processes
- mononuclear cell infiltrate correlates with fx decline
- altered antigenicity of kidney
- renal tubule can act as APC
- can involve humoral or cell mediated response
mechs of TI injury:
alterations in tubular metabolism
kidney has high rate of O consumption
disease state cause surviving nephrons to display:
- incr oxygen consumption
- incr ammoniagenesis
- incr production of ROS
mechs of TI injury:
alteration in intrarenal dynamics
- incr wall tension
- incr urinary flow rate
mechs of TI injury:
diabetes
hyperglycemia induces:
- protein glycation and polyol production
- GBM releases cytokines, gammaIFN, TNFalpha
- production of collagen type I and IV
- production of fibronectin and laminin
mechs of TI injury:
crystalline deposition
- high PO4 diet assoc with incr Ca and PO4 deposition
- calcification in tubular lumen, interstitium, epi cells of affected tubules
- oxalate → tubular enlargement
- urate → epithelial cell injury and lysozyme release
mechs of TI injury:
nephron obstruction
- intratubular casts in CKD
- obstruction → chemotactic lipid
- infl infiltrate releases cytokines and ROS
- Tamm-Horsfall protein → neutrophil activiation and degranulation + activates complement
clinical clues re: TI disease
- mild-mod proteinuria
- little-no hematuria
- sterile pyuria (eosinophils)
- amino aciduria (prox tubule)
- renal hyperkalemia
- metabolic acidosis
Fanconi syndrome
prevalence:
- most common in ped pop
- adults, usually assoc with multiple myeloma
generalized proximal tubular dysfx with urinary excretion of:
- glucose → glucouria in presence of normal pl glucose
- a.a.s → aminoaciduria
- PO4
- bicarb → nonAG metabolic adiosis
- other low MW proteins (<50kD)
see: hypokalemia, osteomalacia, malnutrition, volume depletion, failure to thrive
autosomal dom polysystic kidney disease
multisystem disorder (1/400-1000 births)
autodom inheritance
- 85% of affected families: PKD1 gene (chr 16)
- 15% of affected families: PKD2 gene (chr4)
- some have neither
renal manifestations: bilat renal cysts, nephromegaly
- decr concentrating ability
- incr renin production in HTN pts
- preserved epo prod in pts with ESRD
- hematuria/hemorrhage
- acute/chronic pain
- UTI
extrarenal manifestations: hepatic cysts, pancreatic cysts, colonic diverticula, intracranial aneurysms, ovarian/testicular cysts
tx:
- control HTN
- protein restriction (not universally beneficial in slowing progression)
- cyst drainage
- pain mgmt
acute tubular necrosis
either ischemic or nephrotoxic insult → necrotic tubular cells
- recovery after 1-3wk in mild to mod cases (longer in severe)
- ddx: ATN and prerenal azotemia
allergic interstitial nephritis
most often induced by drug tx (but sarcoid, legionella, leptospirosis, streptococcus, viral inf also poss)
- see acute rise in Cr temporally related to drug/
- fever often accomp by rash
- eosinophilia/eosinophiluria in over 75%
- urine sediment with WBC/RBC casts
minimal proteinuria
role of infections
infection can cause kidney disease via:
- reactive change to systemic infection
- direct parenchymal invation (ex. pyelonephritis)
scarlet fever, betahemolytic strep, diphtheria
lesions occur early in course of inf
- can be focal or diffuse (more edema than infiltrate)
- infiltrate forms a circular band around vessels in corticomedullary region
pyelonephritis
most common cause: bacterial infection
- focal lesion usually ltd to single pyramid
- wedge shaped lesion with apex doward medulla
infected areas are well demarcated from adj tissue
infl foci arranged radially
role of drugs
most common cause of acute tubulointerstitial nephritis
best characterized:
- methicillin → rxn to beta lactam ring
- rifampin → cell mediated rxn, also see circ antibodies
- trimethoprim-sulfamethoxasol → produces acute TI nephritis via accumulation of toxic metabolites
- NSAIDs → altered renal hemodynamics due to reduced intrarenal PGE2 and PGI2
- PGE2/PGI2 incr Na excretion and renin release
- PGE2 decr Na reabs in LoH
- also inhibits ADH
results in HSN rxn
- rare, not dose-related
- assoc with fever, skin rash, arthralgia, eosinophilia, eosinophiluria
- recurs with reexposure to drug
medullary sponge kidney
common, benign disorder
malformations of terminal collecting ducts in pericalyceal region of pyramids
assoc with small and large medullary cysts (generally diffuse and bilat, but do not involve cortex)
- most pts asymptomatic, but may have hematuria, UTI, kidney stones
- some incomplete distal TRA, some mild concentrating defect
- good long term prognosis
sickle cell nephropathy
renal sequellae of sickle cell disease due to sickling in vasa recta
concentrating defect, hematuria, paillary rencrosis and renal infarction
hyperkalemia common due to impaired K secretion in collecting tubule
proteinuria → progressive renal dysfx with typical finding of focal glomerulosclerosis
multiple myeloma
almost half of pts will have renal insuff
monoclonal light chain tox produces most of it
cast nephropathy when light chains bind to Tamm-Horsfall mucoprotein
- amyloidosis typically assoc with lambda light chains → stains + for Congo Red
- light chain deposition disease assoc with kapa light chains
plasma cell infiltration into kidney rarely impairs renal fx
GPA
granulomatosis with polyangiitis
(formerly Wegeners)
- presistent rhinorrhea
- purulent/bloody nasal discharge
- oral/nasal ulcers, sinus pain
- polyarthralgias, myalgials
- less common: upper airway symptoms
90% ANCA+
kidneys?
usually presents as acute glomerulonephritis w hematuria, proteinuria, red cell casts seen on urine microscopy
lead poisoning
- abd colic
- extensor muscle weakness
- encephalopathy
- short term memory impairment
- decr libido
- HTN
- gout
- microcytic anemia
- basophilic stippling on periph smear
kidney?
acute lead nephropathy: Fanconi’s syndrome
- prox tubule resorptive defect
- aminoaciduria, glycosuria, phsphaturia
- can reverse with chelation
chronic lead nephropathy: slowly progressive TI nephritis after prolonged lead exp
- chelation not v helpful
*
