Renal Tubular Diseases and Congenital Diseases Flashcards
definition of acute tubular necrosis (ATN)
destruction of tubular epithelial cells with suppression of kidney functions leading to acute renal failure (ARF)
the latter becomes clinically apparent when tubular insufficiency is reduced by 80%
a common cause of ARF
types of ATN
ischemic and toxic
ischemic ATN
usually pre-renal, characterized by pale kidneys, edema, pathcy necrosis of proximal tubule, rupture of TBMs
casts in the distal tubules and collecting ducts
nephrotoxic ATN
antibiotics- or othe rtoxins-induced
characterized by diffuse necrosis of middle segment of the proximal tubule
histologic changes depend on the type of the agent
recovery phase is characterized by regenerating epithelium
What is the primary event in ischemic injury?
marked reduction/cessation of aerobic respiration, impairment of oxidative phsophorylation by mitochondria and loss of ATP
activation of proteases, phospholipases and generation of O2 radicals that cause cell death
What happens in reversible early injury of the tubules in ATN?
the cell polarity and redistribution of Na-K ATPase leads to increased concentration of sodium in the tubular lumen and constriction of afferent arteriole of the glomerulus
note that the proximal tubular cells are very much dependent upon aerobic respiration, while the distal tubular cells are capable of anaerobic glycolysis and thus can maintain cellular integrity and functions for a longer hypoxic period
What happens in irreversible injury in ATN?
there is a loss of mitochondrial functions and cell membrane integrity that leads to cell death (necrosis or apoptosis)
direct hemodynamic effects of ischemia
activation of RAS
increased endothelin expression
decreased NO and PGI2 production
nephrotoxic injury ATN
critical event is the formation of free radicals that injure the cell membranes by lipid peroxidation and followed by cell death
these events are similar to reversible injury that is seen in irreversible injury due to ischemia
phases of acute tubular necrosis
oliguric phase
early diuretic phase
late diuretic phase
oliguric phase of ATN
characterized by loss of tubular functions, uremia, hyperkalemia, metabolic acidosis, and fluid overload
early diuretic phase of ATN
characterized by progressive increase of urine output, howevve,r tubular functions remain impaired
as a result, there are massive losses of fluid and electrolytes, and hypokalemia rather thna hyperkalemia is observed
late diuretic phase of ATN
characterized by progressive increase in the concentrating ability of tubules line with regenerating epithelia, and uremia subsides
renal functions return to level over a period of a couple months
tubulointerstitial nephritis (TIN)
primary structural and functional alterations of tubules and interstitium
may be acute with interstitial edema, PMN infiltration, and focal tubular necrosis
may also be chronis with interstitial fibrosis and tubular atrophy
causes of TIN in man
bacterial infection (pyelonephritis)
toxins
metabolic disorders
urinary stones and strictures
neoplasms
immunologic assault
vascular anomalies
polycystic disease
general characteristics of acute pyelonephritis
characterized by acute suppurative bacterial infection of kidney and renal pelvis
second most common infectious disease in man
usually caused by organisms that include predominantly (85%) gram-negative bacilli, and serological studies point that the organisms are derived from patient’s own fecal flora
there are 2 major routes of infections to the kidneys
What are the two major routes of infection to the kidneys for acute pyelonephritis?
hematogenous and ascending
hematogenous route of infection for acute pyelonephritis
uncommon and caused by circulating Staphylococci or E. coli
normal kidney is highly resistant to blood-born infection, and obstruction dramatically enhances its susceptibility to UTIs
infected kidneys have multiple abcesses on its surface
ascending route of infection for acute pyelonephritis
quite common
bacteria is commonly E. coli
ascends from the urethra and bladder
urinary tract obstruction greatly increases the risk of infection
with obstruction, bacteria multiple and colonization occurs
vesicoureteral reflux is the most important
vesicoureteral reflux
major cause of urinary infections in children, and is due to the anomaly of the vesical segment of the ureter
infection is recurrent
condition is diagnosed by voiding cystourethrogram
surgically correctable
pathology of acute pyelonephritis
characterized by patchy acute suppurative inflammation of interstitium and tubules with pus casts, tubular necrosis, and secondary involvement of glomeruli and blood vessels
the complications include perinephric abcesses, papillary necrosis (particularly in diabetics and urinary tract infections) and pyonephrosis
characteristics of chronic pyelonephritis
characterized by chronic or recurrent infections of the kidney, renal pelvis, and calyces
usually bacterial in origin
usually associated with obstruction or vesicoureteral reflux, and resulting deformities of the pelvcalyceal systems distinguish it from other causes of tubulointerstitial diseases
What are the types of chronic pyelonephritis?
chronic obstructive and reflux type
chronic obstructive pyelonephritis
characterized by recurrent bouts of renal inflammation
usually associated with congenital anomalies
ex. posterior uretheral valve or vessel compressing on the ureter
may be unilateral or bilateral
reflux type chronic pyelonephritis
common in young people
abnormal insertion of ureter into the urinary bladder
recurrent bouts of infection ultimately leading ot chronic polar damage to the kidney
pathology of chronic pyelonephritis
deep surface scars on the kidney along with dilatation and distortion of the pelvicalyceal system
blunting of the papillae
microscopicaly, interstitial chornic inflammation, scarring, tubular atrophy with thyroidization of tubules containing casts are seen
glomeruli are relatively spared, except when focal segmental glomerulosclerosis sets in
What are four factors that may be responsible for the susceptibility of the kidney to drug or toxins?
1) large blood supply
2) concentration of toxins in tubular fluid
3) secretion of certain toins by nephrons
4) concentration of toxins in medulla by the countercurrent mechanisms
types of TIN
drug-induced TIN
acute hypersensitivity TIN
analgesic abuse TIN
NSAID-induced TIN
analgesic abuse TIN
chronif corm of TIN due to excessive intake of analgesic mixtures (aspirin, phenacetin, caffeine)
papillary/medullary necrosis due to covalent binding, oxidative damage, and decreased prostaglandin synthesis locally
imparied urine concentrating ability and renal tubular acidosis
histological findings of analgesic nephropathy
necorsis of medullary papilla
general characteristics of drug-induced tubulo-interstitial nephritis (DITIN)
antiboitics, diuretics, NSAIDs
fever, rash, proteinuria, increased creatiinine
type-I hypersensitivity, IgE-mediated reaction
eosinophils - body tissue, blood, and urine
histological findings of DITIN
interstitial edema and influx of eosinophils
focus of tubulitis (invasion of tubules)
types of congenital anomalies of the kidney
agenesis - bilateral incompatible, unilateral-associated with adaptive changes
hypoplasia - developmental/acquired, unilateral-associated with adaptive changes
ectopic kidney - abnormal location, susceptible to infection
horseshoe kidney - 1:500 autopsies, 90% lower pole fusion
thrombotic microangiopathies
conditions where the renal vasculature is involved secondarily due to systemic thrombosis
two condition with overlapping features include hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenia purpura (TTP)
pathology - thrombi in the capillaries due to denuddation of endothelium and activation of platelets
cystic kidney disease
ADPKD
ARPKD
medullary sponge kidney
medullary cystic disease complex (recessive/dominant)
simple cysts (mostly incidental finding)
acquired renal cystic disease (hemodialysis)
What are the clinico-pathologic characteristics of the autosomal recessive form of polycystic kidney disease (APRKD)?
large cystic kidneys at birth
radial fusiform cysts
hepatic fibrosis (fibrocystin)
bile duct proliferation
death in early childhood
splenomegaly
cysts appear as longitudinal cysts that are oriented at right angles to the cortical surface
What are defining features of kidneys of patients with ARPKD?
fusiform cysts
large kidneys and hepatic fibrosis
bile duct proliferation
What gene is responsible for ARPKD? What is its function?
fibrocystin
transmembrane protein responsible for cell-cell signaling
immunoglobulin type domain can interact with other proteins on other cells
What are the clinico-pathologic characteristics of medullary sponge disease (MSD)?
bilateral medullary cysts - involves the collecting ducts
hematuria, infections
stones, gravel in urine
sometimes asymptomatic
benign course
What are the clinico-pathologic characteristics of medullary cystic disease complex (MCDC)
cortico-medullary cysts
recessive (juvenile)
dominant (adult)
salt wasting, polyuria
nephronophthisis - wasting of the kidney
(nephrocystin) uremia leads to chronic renal failure
What is the gene responsible for MCDC? What is its function?
nephrocystin
intracytoplasmic protein
important SH3 domain for binding to other adhesion proteins
What are the clinico-pathologic characteristics of autosomal dominant polycystic kidney disease (ADPKD)?
tubular disease, high penetrance, occurs in any segment of the nephron and kidneys, become progressively larger
multiple genes (PKD1, PKD2, and PKD3)
familial, disvered in 2nd or 4th/5th decade of life
prevalence is 1:650
hematuria in teenage yars if received injury to flank regions
complications include rupture of cysts, pain and recurrent UTIs
liver or splenic cysts, colon diverticula, intracranial aneurysm
pathogenesis of ADPKD
abnormal cell-matrix or cell-cell interactions
cellular proliferation and polarity characteristics of the cells with aberrant fluid secretion and accumulation (cAMP)
What do the kidneys look like in ADPKD?
large kidneys with a lot of fluid
normal glomeruli
bilateral cysts
sometimes can see chocolate cysts - large cysts filled with blood clot
What genes are affected in autosomal dominant polycystic kidney disease (ADPKD)?
85% PKD1 - chromosome 16
PKD2 - 15% of cases, chromosome 4
PKD3 - minority of cases
homotypic and heterotypic interactions between C-termini of polycystin-1 and -2 mutations lead to tubular dysmorphogenesis and disease
Polycystin-1
transmembrane protein with extracellular N-terminus and multiple complex domains
extracellular lectin domain and Ig-like folds mediate cell-matrix interactions
complex that it forms lacks focal adhesion kinase (FAK) when mutant
Polycystin-2
Na+ channel transmembrane protein with coiled-coil domain and SH3 domains in the intracellular side that interacts with polycystin-1
