Tubular and Interstitial diseases

Question 1

How people get ATI?

Answer 1

Acute Tubular Injury/Necrosis (ATI):
• characterized clinically by acute renal failure and often morphologic evidence of tubular injury in the form of necrosis of tubular epithelial cells
• most common cause of acute kidney injury

Ischemic ATI:
• due to decreased or interrupted bloodflow – hypotension/shock
• exmalignant HTN, HUS, TTP, DIC, hypovolemic shock, microangiopathies

Nephrotoxic ATI: direct toxic injury to the tubules by endogenous or exogenous agents (ex. bile/bilirubin, drugs, heavy metals, gentamicin, mercury, carbon tetrachloride)

Mixed ATI: mismatched blood transfusions, hemolytic crisis causing hemoglobinuria
o Less common causes of ATI:
• Acute tubulointerstitial nephritis due to hypersensitivity rxn to drugs
• Urinary obstruction

Question 2

Pathogenesis of ATI?

Answer 2

see the diagrams…..

Question 3

morphology of ATI?

Answer 3

• focal tubular epithelial necrosis w/ large skip areas in between
• rupture of BM and occlusion of tubular lumens by casts – especially proximal tubule
• Eosinophilic hyaline casts and pigmented granular casts found in distabl tubules and collecting ducts
• in toxic ATI via ethylene glycol see marked ballooning and hydropic/vacuolar degeneration of proximal convoluted tubules

Question 4

patterns of tubular damage in ATI?

Answer 4

Ischemic (on left):
PCT = patchy
PST= patchy
ALH= patchy

Toxic (on right)
PCT = continuous
PST = continuous
ALH = patchy

• Proximal tubular epithelial cells have very high energy requirements and thus are most susceptible to ischemia

Question 5

clinical course of ATI?

Answer 5

Initiation phase: 36 hours – oliguria due to transient decrease in blood flow and decreasing GFR

Maintenance phase:
o oliguric crisis with evidence of uremia
o hyperkalemia and metabolic acidosis
o salt and water overload and rising BUN concentrations

Recovery phase: 
o	large urine volumes
o	large loss of water, Na+ and K+
o	hypokalemia (worse problem b/c causes mm. cramping, paralytic ileus, arrhythmias)
o	susceptibility to infection

Question 6

Tubulointerstitial Nephritis

Answer 6

distinguished clinically from glomerular diseases:
o absence of nephritic/nephrotic syndromes
o defects in tubular function: inability to concentrate urine, polyuria/nocturia, salt wasting, inability to excrete acids (metabolic acidosis)

= inflammatory injuries of the tubules and interstitium, with onset of azotemia and inability to concentrate urine (polyuria)
• Acute tubulointerstitial nephritis = rapid onset of interstitial edema, leukocytic infiltration (neutrophils and mocrophages) of interstitium and tubular injury
• Chronic interstitial nephritis = mononuclear leukocytes, interstitial fibrosis, widespread tubular atrophy

Causes: • Infections: acute bacterial pyelonephritis, chronic
• Toxins (including acute-hypersensitivity reactions)
• metabolic diseases
• Physical obstruction
• Neoplasms (multiple myeloma – Bence Jones proteins)
• Immunologic reactions
• Vascular diseases

Question 7

Pyelonephritis

Answer 7

= infection and inflammation of renal parenchyma, calyces and pelvis and tubules
- one of the most common diseases of the kidney

Two forms:
• acute pyelonephritis: caused by bacterial infection and assoc. w/ UTI
• chronic pyelonephritis: recurrent/continuous long-term infection of kidney w/ damage to pelvis and parenchyma – resulting in anatomic distortion and scarring

Question 8

Etiology of pyelonephritis

Answer 8

• 85% of UTIs are caused by enteric bacteria (E. Coli, Proteus, Klebsiella, Enterobacter) – more common in females

ascending infection = most common, infections arise from bladder:
o colonization of distal urethra and inriotus
o bacterial movement from urethra to bladder, often through instrumentation
o urinary tract obstruction and stasis of urine
o vesicoutereral reflux: incompetence of valve allows for retrograde flow of urine (in absence of VUR most infections remain in bladder)
o intrarenal reflux: most common at upper and lower poles of kidney

hematogenous infection = is a small contributor – i.e. septicemia from endocarditis
• predisposing medical conditions: Diabetes, pregnancy

Question 9

morphology of acute pyelonephritis

Answer 9

• patchy interstitial suppurative inflammation, intratubular aggregates of neutrophils, tubular necrosis
• papillary necrosis: seen in diabetics, sickle cell, UT obstruction (tips of pyramids have gray and white necrosis)
• pyonephrosis: suppurative exudate is unable to drain and fills renal pelvis, calyces and ureter with pus
• perinephric abscess: extension of suppurative inflammation through the renal capsule and into perinephric tissue
• Pyelonephritic scar: inflammation, fibrosis, deformation of underlying calyx and pelvis

Question 10

clinical features of acute pyelonephritis

Answer 10

causes: Urinary tract obstruction, instrumentation, VUR, pregnancy, diabetes mellitus, immunosuppression
• more likely in females from age 1-40,
• urinary obstruction common in males after 60 y/o due to prostatic hypertrophy

sudden onset of pain in CVA, fever and malaise
• dysuria, frequency, urgency
• pyuria (urine contains leukocytes)
• leukocyte casts: indicates renal involvement b/c casts are formed only in tubules

Question 11

chronic pyelonephritis

Answer 11

more common
• chronic tubulointerstitial inflamm. and scarring involve the calyces and the pelvis
• only chronic pyelonephritis and analgesic nephropathy affect and damage the calyces

predisposing conditions
o chronic obstructive pyelonephritis: obstructive lesions lead to repeated bouts of renal inflamm. and scarring
o reflux nephropathy: more common form of scarring – occurs early in childhood due to UTI and VUR – results in renal damage and scarring/atrophy/renal insufficiency

Morphology:
• coarse, discrete corticomedullary scars overlying dilated, blunted/deformed calyces and flattened papillae
• Xanthogranulomatous pyelonephritis: accumulation of foamy macrophages intermingled w/ other cells
o associated w/ Proteus sp.
o Weil Felix reaction used to ddx
• coarse scars and blunting seen on kidneys

Question 12

Xanthogranulomatous pyelonephritis

Answer 12

chronic pyelonephritis

accumulation of foamy macrophages intermingled w/ other cells
o associated w/ Proteus sp.
o Weil Felix reaction used to ddx

Most patients present with recurrent fevers and urosepsis, anemia, and a painful renal mass. Other common manifestations include kidney stones and loss of function of the affected kidney.

Question 13

clinical features of chronic pyelonephritis?

Answer 13

• silent onset or present w/ back pain, fever, pyuria, bacteriuria
• receive medical attn. late in disease due to gradual onset of renal insufficiency and HTN
• polyuria and nocturia
• some individs w/ scars develop secondary focal segmental glomerulosclerosis w/ significant proteinuria – poor prognostic sign, may progress to ESRD

Question 14

acute drug-induced interstitial nephritis

Answer 14

“analgesic nephropathy”
• ex. sulfonamides, penicillins, Abs, diuretics, NSAIDS

Clinical: see fever, eosinophilia, interstitial renal parenchymal infiltrates, rash (sometimes hematuria, proteinuria, leukocyturia, rising serum creatinine)
o sometimes excrete necrotic papillae
• pt. usually improves w/ cessation of drug

Analgesic nephropathy: (ex. aspirin) see necrotic debris that have sloughed into the papilla tip – results in renal papillary necrosis and chronic interstitial nephritis – from decreased blood flow to kidney, HTN and oxid. damage

Pathogenesis:
• hypersensitivity reaction, w/ increased IgE levels (may be type I or type IV)

Morphology:
• edema and infiltration of lymphocytes and macrophages in interstitium (also Eos, and Neutrophils)
• inflammation prominent in medulla
• tubulitis is common

Question 15

NSAIDS nephropathy

Answer 15

• acute kidney injury: decreased synth of vasodilatory prostaglandins → ischemia
• acute hypersensitivity interstitial nephritis
• acute interstitial nephritis and minimal-change disease
• membranous nephropathy

Question 16

Urate nephropathy

Answer 16

acute uric acid nephropathy = precip. of uric acid crystals in tubules → obstruction of nephrons and development of acute renal failure
o common in leukemias/lymphomas due to chemo

Chronic urate nephropathy: due to gout and hyperuricemia
o urate crystals deposit in DT and CD and form bifringment needles
• Nephrolithiasis: uric acid stones

Question 17

Light-Chain cast nephropathy

Answer 17

= “myeloma kidney” = formation of urinary casts from IgG light chains –> plug renal tubules –> renal failure
• renal insuff. occurs in 50% of people with multiple myeloma
• factors contributing to renal damage

Bence-Jones proteinuria and cast nephropathy: some Ig light chains are toxic to epithelial cells
• appear as pink/blue amorphous masses which fill and distend tubular lumens
o Amyloidosis
o Light-chain deposition disease
o Hypercalcemia and hyperuricemia
• form of chronic kidney disease that progresses of month/years

Myeloma cells produce monoclonal proteins of varying types, most commonly immunoglobulins (antibodies) and free light chains, resulting in abnormally high levels of these proteins in the blood. Depending on the size of these proteins, they may be excreted through the kidneys. Kidneys can be damaged by the tubulopathic effects of proteins or light chains

Question 18

Bile cast nephropathy

Answer 18

• hepatorenal syndrome refers to impairment of renal function in patients w/ acute/ chronic liver disease w/ advanced liver failure
• serum bilirubin can be elevated and bile casts form

Question 19

benign nephrosclerosis

Answer 19

: (general process)
• sclerosis of renal arterioles and small aa. – strongly associated with hypertension (which can be both a cause and consequence)
• affected vessels have thickened walls and narrowed lumens → focal parenchymal ischemia
• ischemia → glomerulosclerosis and chronic tubulointerstitial injury → reduction in functional renal mass

Pathogenesis:
• medial and intimal thickening
• hyaline protein deposition in arteriolar walls
• multifocal ischemia of kidney parenchyma supplied by sclerotic vessels

Morphology:
• cortical scarring and shrinking → loss of kidney mass
• hyaline arteriosclerosis: narrowing of lumens and arterioles caused by thickening of hyaline walls
• vascular narrowing → patchy ischemic atrophy: tubular atrophy and interstitial fibrosis and glomerular alterations
• ischemia can lead to wedge shaped infarcts

Clinical features:
• people at risk: African descent, high BP, diabetes, increasing age
• not usually associated w/ renal insufficiency

Question 20

malignant nephrosclerosis

Answer 20

= renal vascular disease associated w/ malignant/accelerated hypertension

Pathogenesis:
• fundamental lesion is vascular injury to kidneys due to HTN, –> injured endothelium → increased permeability of small vessels to fibrinogen → endothelial irrerversible injury → focal death of cells and platelet deposition → fibrinoid necrosis of small arteries → hyperplastic arteriosclerosis
o focal vascular cell death → focal hemorrhage
o platelet deposition → thrombosis
• Kidneys become ischemic
• elevated RAAS, elevated renin
• self-perpetuating cycle of damage and HTN as AngII causes intrarenal vasoconstriction

Morphology:
• “flea-bitten” appearance of petechial renal hemorrhages on gross exam
• fibrinoid necrosis of arterioles (vessel wall takes on smudgy eos. appearance due to fibrin deposition)
• thickening of interlobular aa = “onion skinning” or “hyperplastic artioerolitis” (concentrically arranged smooth mm. cells w/ layers of collagen)
• ischemic atrophy, infarcts

Question 21

clinical features of malignant nephrosclerosis?

Answer 21

• > 200/120 BP
• papilledema (optic disc swelling), retinal hemorrhages, encephalopathy, CV abnormalities, renal failure
• early sx: increased intracranial pressure → h/a, nausea, vomiting, visual impairments

Question 22

renal artery stenosis

Answer 22

“large vessel disease” = HTN secondary to renal artery stenosis, caused by increased production of renin from the ischemic kidney
• elevation in BP is due initially to stimulation of renin secretion by JG apparatus and subsequent production of vasoconstrictor AngII
• Potentially curable form of HTN – clinically pt. presents similar to essential HTN

Morphology:
• 1. narrowing of renal artery by atheromatous plaque (70%)
• 2. fibromuscular dysplasia of renal artery (intimal, medial, adventitial hyperplasia – occurs more frequently in younger women) – smooth mm. takes on “string of beads” appearance
• cause ischemic kidney to reduce in size and show diffuse ischemic atrophy

Clinical course:
• resemble essential HTN
• sometimes bruit can be heard over affected kidney

Question 23

thrombocytopenia?

Answer 23

low number of platelets

Question 24

MAHA

Answer 24

microangiopathic hemolytic anemia

• endothelial layer of small vessels is damaged w/ fibrin deposition and platelet aggregation –> RBCs become damaged as they travel

Question 25

thrombocytic microangiopathies

Answer 25

= thrombosis in capillaries and arterioles

• HUS and TTP are caused by diverse insults that lead to the excessive activation of platelets which deposit as thrombi in capillaries and arterioles in various tissue beds, including the kidneys
• Widespread “consumption” of platelets → thrombocytopenia → thrombi create flow abnormalities that shear RBCs → microangiopathic hemolytic anemia
• Consequences: vascular obstruction, vasoconstriction, ischemia

Question 26

pathogenesis/morphology of thrombocytic MA?

Answer 26

• Endothelial cell injury and activation, intravascular thrombosis (HUS)
o Shiga-like toxin causes excessive, inappropriate activation of complement and thrombosis w/in microvascular beds
• Platelet activation and aggregation (TTP)
o due to deficiency of ADAMTS13 which induces large multimers of vWF to accumulate
• Endothelial injury triggered:
o bacterial toxins, cytokines, viruses, medications, anti-endothelial Abs

Morphology
• glomerular capillaries occluded by thormbi composed of aggregated platelets and fibrin
• capillary walls are thickened due to endo. cell swelling and subendo. deposits of cell debris and fibrin
• disruption of mesangial matrix → mesangiolysis
• scarring

Question 27

typical hemolytic uremic syndrome

Answer 27

= due to endothelial cell injury
• most frequently associated w/ diarrhea as result of consuming contaminated food with Shiga-like toxin (E. Coli O157:H7)
• mostly children at risk, and older adults
• prodrome of influenza-like diarrheal sx, followed by sudden onset of bleeding, severe oliguria, hematuria, microangiopathic hemolytic anemia, thrombocytopenia (low platelets) and prominent neurological changes
• HTN is present in ½ of patients
• If renal failure is managed properly w/ dialysis, pt. will recover renal fn. in a few weeks

Question 28

atypical HUS

Answer 28

• inherited mutations of complement-regulatory proteins
o multiple acquired causes of endothelial injury (chemo agents, immunosuppressives), mostly adults.
o antiphospholipid syndrome= due to SLE
o postpartum renal failure
o systemic sclerosis and malignant HTN
• many suffer multiple relapses and progress to ESRD

Question 29

thrombocytic thrombocytopenia purpura

Answer 29

= platelet activation and aggregation
• often assoc. w/ inherited/acqd deficiencies of ADAMTS13, a protease that regulates the fn of vWF (via inhibitory autoantibodies)
o onset is often delayed until adolescence and sx are episodic
• neurologic involvement is dominant feature: encephalopathy, obtunded, seizure
• renal failure seen in 50% of patients
• fever, neuro sx, microangiopathic hemolytic anemia, thrombocytopenia and renal failure
• usually adults <40 y/o; more common in females
• responds well to plasmaphoresis due to circulating autoantibodies (as does Good Pasture Sx)

Question 30

Atherosclerotic Ischemic Renal Disease:

Answer 30

• bilateral renal artery disease

* seen in older individuals

Question 31

Atheroembolic Renal Disease:

Answer 31

• embolization of fragments of atheromatous plaques from aorta or renal aa. into intrarenal vessels occurs in adults with severe atherosclerosis
• sx: flank pain/abdominal pain, hematuria, arterial hypertension, arrhythmia, nausea, vomiting, oliguria, anuria

Question 32

Sickle Cell Nephropathy:

Answer 32

• hematuria and diminished concentrating ability (hyposthenuria),
• due to accelerated sickling in the hypoxic areas of renal medulla → dehydrates cells and results in intracellular HbS soncentrations
• Patchy papillary necrosis and 30% exhibit proteinuria

Question 33

Diffuse Cortical Necrosis:

Answer 33

• often seen in abruption placentae, septic shock or extensive surgery
• alterations of massive ischemic necrosis are sharply limited to the cortex
• gives rise to sudden anuria and terminates rapidly in uremic death

Question 34

Renal infarcts:

Answer 34

• major source of emboli is mural thrombosis in left atrium and ventricle as a result of MI, vegetative endocarditis, aortic aneurysms, aortic atherosclerosis
• b/c of lack of collateral blood supply most infarcts are of “white” anemic variety and see ischemic coagulative necrosis