Download Path Chapter 20: The Kidney (pages 956

Path Chapter 20: The Kidney (pages 956-967)
Cystic diseases of the kidney are pretty common
Adult polycycstic kidney disease is a major cause of chronic kidney disease
Autosomal dominant (adult) polycystic kidney disease (ADKPD) – hereditary disorder characterized by
many expanding cysts in both kidneys, that destroy functioning kidney and cause renal failure
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Despite being autosomal dominant, ADPKP needs both alleles of the PDK gene to be mutated
The cysts usually start in just one part of the kidney, so the kidneys work fine until your 40’s-50’s
ADKPD is caused by mutations to PKD1 or PKD2
o PKD1 mutations are most (85%) of cases, and more severe than PDK2, causing end stage
renal disease or death at average age of 50’s, as opposed to PKD2 in your 60’s-70’s
o Chances of renal failure by age for PDK1: 5% in 40’s, 1/3 in 50’s, 2/3 in 60’s, 95% in 70’s
o Chances of renal failure by age for PDK2: 5% in 50’s, 15% in 60’s, 45% in 70’s
o PKD1 codes for polycystin-1, which is an integral membrane protein of epithelial cells in
the nephron
o PKD2 codes for polycystin-2, an integral membrane protein found throughout the renal
tubules and also outside the kidney
 Polycystin-2 is a calcium channel – so problems with it mess up intracellular
calcium levels
It’s thought the problem in polycystic disease is with the cilia and its centrosome, of the tubular
epithelial cells
o Epithelial cells fo the kidney each have a nonmoveable primary cilium projecting into
the lumen from the apical surface of the tubular cells
o The cilium is made up of microtubules
o The cilium arises from, and is attached to a basal body derived from the centriole
o The cilia is used to sense mechanical signals
 It’s thought the kidney tubule cilia act as a mechanosensor to monitor changes
in fluid flow and shear stress, and can regulate calcium flux into and out of the
epithelial cells
o So the hypothesis is that cyst formation is caused by defects in mechanosensing, calcium
flux, and signal transduction
o Polycystin-1 and -2 are found only in the primary cilium, and the other genes involved in
cystic disease are also localized to the cilium and/or basal bodies
o It’s thought polycystin-1 and -2 form a protein complex that regulates intracellular
calcium in response to fluid flow
 So problems with one gene then would disrupt intracellular calcium, and
therefore it’s second messenger effects like for cell proliferation, apoptosis,
interactions with ECM, and the secretory function of the epithelia
 These are all common issues seen in ADPKD
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Things that cause the cysts to get bigger are the increase in the # of cells caused by abnormal
prliferatoin, and the expanding volume of fluid in the lumen thanks to abnormal secretion from
epithelial cells lining the cysts
o The fluid secreted also has mediators to cause more fluid secretion, as well as
inflammation, leading to more cyst enlargement, and the fibrosis often seen in ADPKD
Morphology of ADPKD:
o Both kidneys are enlarged, sometimes to an extreme size, and usually palpable
o The surface will look covered in cysts
 You won’t see any normal kidney in between the cysts, but there should be
some normal working nephron in between them
o The cysts are most often filled with a cloudy bloody brown hemorrhagic fluid
o As the cysts get bigger, they can encroach on the calyces and pelvis, causing pressure
problems
o The cysts arise from the tubules throughout the nephron, so it’s lined by epithelia
Many people with ADPKD won’t show any symptoms until their kidneys fail
o In people who do get symptoms before that, the cysts cause them pain
Things that accelerate progression of ADPKD are being black (more likely to have sickle cell),
male, and hypertension
About 1/3 of ADPKD patients will have asymptomatic cysts in the liver (polycystic liver disease)
o The liver cysts come from biliary epithelium
Cysts in ADPKD can also happen less often in the spleen, pancreas, and lungs
Up to 10% of ADPKD deaths are caused by berry aneurysms in the circle of Willis, causing
subarachnoid hemorrhages
o Due to messed up expression of polycystin in vascular smooth muscle
1/5-1/4 of ADPKD will have asymptomatic mitral valve prolapse or other valve issues
Most deaths from ADPKD are caused by coronary or hypertensive heart disease
Autosomal-recessive (childhood) polycystic kidney disease:
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Perinatal and neonatal forms are the most common, causing symptoms at birth that lead to
death quickly from kidney failure
Most cases of ARPKD are caused by mutation to PKHD1 gene
o PKHD1 codes for fibrocystin, which is found in the kidney, liver, and pancreas
o Fibrocystin is an integral membrane protein that is localized to the primary cilium of
tubular cells
Morphology of ARPKD:
o The kidneys are enlarged and have a smooth appearance
o When you cut open the kidney though, you se lots of small cysts int eh cortex and
medulla, making it look sponge-like
o The cortex and medulla are replaced by dilated channels
o The cysts are lined with cuboidal cells, since they come from the collecting ducts
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Almost all cases of ARPKD will include cysts in the liver, along with portal fibrosis and
proliferation of bile ducts, together called congenital hepatic fibrosis
 The liver fibrosis is seen in kids that survive infancy, and can cause portal
hypertension with splenomegaly
Cystic diseases of the renal medulla – 3 major ones: medullary sponge kidney, nephronophthisis, and
adult-onset medullary cystic disease
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Medullary sponge kidney – multiple cysts of the collecting ducts in the kidney medulla
o It’s common and usually doesn’t impair kidney function
Nephronophthisis and adult-onset medullary cystic disease both show cysts in the medulla
mainly at the corticomedullary junction (where the cortex meets the medulla)
o They both cause damage to the cortical tubules, leading to kidney failure
o 3 types of nephronophthisis: sporadic nonfamilial, familial juvenile (most common), and
renal-retinal dysplasia (kidney disease + eye lesions)
o Nephronophthisis is autosomal recessive, and is the most common genetic cause of
end-stage renal disease in children
o Affected kids present first with polyuria and polydipsia (because the renal tubules are
having trouble concentrating the urine), along with sodium wasting and tubular acidosis
o Nephronophthisis will progress to terminal renal failure in 5-10 years
o The mutations in nephronophthisis are to NPH1, NPH2, or NPH3
 NPH1 and NPH3 code for nephrocystins, found in the primary cilium or the
centrosome
 NPH2 codes inversin, which mediates left-right patterning during embryogenesis
 If they make it to adulthood (adult onset medullary cystic disease), the mutation
is to MCKD1 or 2
o Morphology:
 The kidneys are small, and show small cysts in the medulla, mainly at the
corticomedullary junction
 The cysts are lined by epithelium, and surrounded by inflammatory cells or
fibrous tissue
 The cortex may have cysts too, and will show widespread atrophy and
thickening of the basement membranes of the tubules, along with interstitial
fibrosis
Acquired (dialysis-associated) cystic disease – dialysis can cause cysts, often containing calcium oxalate
crystals
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Most are asymptomatic, but some bleed, causing hematuria
A minority of the cysts can be a site for cancer to develop
Urinary tract obstruction
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Obstruction increases susceptibility to infection and stone formation
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Unrelieved obstruction almost always leads to permanent renal atrophy – called obstructive
uropathy
Common causes of urinary obstruction:
o Congenital anomalies
o Calculi (stones)
o Benign prostatic hypertrophy (enlarged prostate)
o Tumors
o Inflammation – of any part of the urinary tract
o Blood clots
o Pregnancy
o Uterine prolapse and cystocele
o Functional problems – ex: spinal cord problem, or a diabetic nephropathy
Hydronephrosis- dilation of the renal pelvis and calyces that are associated with progressive
atrophy of the kidney from obstruction to the outflow of urine
o Even with complete obstruction, glomerular filtration persists for a while because the
filtrate diffuses back into the renal interstitium and perirenal spaces, where it gets to
the lymph and venous systems
o This continued filtration causes the affected calyces and pelvis to get very dilated
o The high pressure in the pelvis gets transmitted back through the collecting ducts into
the cortex, causing renal atrophy
 It also compresses the medulla blood vessels, decreasing medullary blood flow
o So the initial change caused by obstruction is problems concentrating, then later, the
GFR will decrease
Obstruction also triggers an interstitial inflammatory rxn, causing interstitial fibrosis
Morphology of urinary obstruction:
o When obstruction is sudden and complete, GFR decreases, causing mild dilation of the
pelvis and calyces, and sometimes atrophy
o When obstruction is temporary are incomplete, GFR isn’t decreased, and so you instead
get progressive dilation
o The dilation starts downstream in the urinary tract, and then progresses up to the
kidney
o Obstruction will cause the kidney to enlarge
o Early obstruction will show dilation of the pelvis and calyces with inflammation in the
interstitium
o Chronic obstruction shows cortical tubule atrophy and diffuse interstitial fibrosis
o Extremely long cases transform the kidney into a cystic thing with lots of atrophy, loss of
the pyramids, and thinned cortex
Acute obstruction may cause pain from distention
o Early symptoms are caused by whatever is causing the hydronephrosis
 Ex: so a stone in the ureters may cause renal colic, and enlarged prostate causes
bladder issues
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Unilateral hydronephrosis may not cause symptoms for a while, since the other kidney can
maintain normal renal function for the both of them
Relief of obstruction in the first few weeks can cause reversal back to normal
Bilateral partial obstruction starts with an inability to concentrate the urine, causing polyuria
and nocturia
o Can also see tubule acidosis, salt wasting, stones, and chronic tubulointerstitial nephritis
with scarring and atrophy of the papilla and medulla
o Hypertension is common
Complete bilateral obstruction causes oliguria or anuria, and will cause death if not fixed
Urolithiasis – urinary tract stones
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Most urolithiasis are in the kidneys
Urolithiasis is common, affecting 5-10% of people
Urinary stones affect men more most often from ages 20-30
There is a strong family and hereditary predisposition to urinary stones
Many metabolic issues, like gout and cystinuria, cause excessive making and excretion of stoneforming stuff
There are 4 main types of stones:
o Calcium stones – 70%, made of calcium oxalate, with maybe some calcium phosphate
 Calcium stones are radiopaque
 Seen in some cases of hypercalcemia and hypercalcuria, like in
hyperparathyroidism, bone disease, sarcoidosis, and other hyeprcaclemic states
 More often than not, there’s only hypercalcuria, with normal blood calcium
 This can happen from hyperabsorption of calcium from the intestines
(absorptive hypercalciuria), problems with renal tubule reabsorption of
calcium (renal hypercalciuria), or idiopathic hypercalciuria with normal
parathyroid function
 1/5 of calcium oxalate stones are associated with increased uric acid secretion,
called hyperuricosuric calcium nephrolithiasis
 5% of calcium stones happens with hyperoxaluria
 Either hereditary (primary oxaluria) or more often acquired by intestinal
overabsorption in people with enteric issues (enteric hyperoxaluria)
 Enteric hyperoxaluria also happens in vegetarians, cause they’re diet is
heavy in oxalates
o Triple (struvite) stones – 15%, made of magnesium ammonium phosphate
 Triple stones are formed by infections by bacteria that convert urea to
ammonia, mainly proteus and some staph
 The alkaline urine made causes the precipitation of magnesium ammonium
phosphate salts, forming really big stones
o Uric acid stones – 5-10%
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Uric acid stones are common in hyperuricemia, like in gout, and in diseases with
rapid cell turnover, like leukemias
 But over half of uric acid stones happen without hyperuricemia or increased
excretion of uric acid
 Uric acid stones are radiolucent
o Cystine stones – 1-2%, caused by genetic defects in renal reabsorption of amino acids,
causing cystinuria
Stones form a low urinary pH
All stones have an organic mucoprotein matrix
The most important thing leading to stones is increased urinary concentration of things that
make up stones, above that thing’s solubility (supersaturation)
o Low urine volume can also favor supersaturation
Most cases of overproduction of stuff to form stones, doesn’t lead to stones though, making us
think that a problem with things that prevent stones may be a more important cause
o Stone inhibiotrs include pyrophosphate, diphsophanate, citrate, glycosaminoglycans
Most times a stone shows up unilateral
Stones like to form most in the renal calyces and pelvis, and in the bladder
Stones cause problems when they obstruct urinary flow, or cause ulceration and bleeding
Smaller stones are more dangerous, because they can fit into more areas
o Ex: the ureters – a small stone can fit in there and cause colic (an extremely intense
pain)
Larger stones fit into less places, and therefore are more likely to be silent in the renal pelvis
o They’ll cause hematuria
Stones also predispose to infection, due to obstruction and the trauma they cause
Kidney tumors:
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Benign kidney tumors:
o Renal papillary adenoma – small papillary adenomas in the kidney tubule epithelium
 They look pale yellow-gray and papillary
o Angiomyolipoma – benign kidney tumor consisting of vessels, smooth muscle, and fat
 Angiomyolipomas are found in a lot of patients with tuberous sclerosis, caused
by mutations to TSC1 or 2 tumor suppressor genes
 Characterized by lesions of the cerebral cortex that cause epilepsy and
mental retardation, skin problems, and benign tumors in other parts of
the body
 Angiomyolipomas are likely to hemorrhage
o Oncocytoma – arise from intercalated cells of the collecting ducts
 epithelial kidney tumor made of large eosinophilc cells, with small round nuclei
with large nucleoli
 The eosoniphilc cells have many mitochondria
 The tumors look tan or brown
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Malignant kidney tumors:
o Renal cell carcinoma (kidney adenocarcinoma) – causes most of renal cancers in adults
 Happen most often in your 60’s and 70’s, and more in males
 Tobacco is the most significant risk factor, and double the chances of getting
renal cell carcinoma
 Obesity, hypertension, estrogen therapy, asbestos, petroleum, and heavy
metals, are all other risk factors
 Acquired cystic disease, and tuberous sclerosis, increase your risk for renal cell
carcinoma
 Most renal cell carcinomas are sporadic and not hereditary
 Some hereditary ones tho:
o Von Hippel-Lindaue (VHL) syndrome – most of them develop
renal cysts and renal cell carcinomas
 The VHL tumor suppressor gene is involved in both
familial and sporadic clear cell tumors
 The VHL gene codes a protein that’s part of a ubiquitin
ligase complex that targets proteins for degradation
 An important target of VHL protein for destruciton is
hypoxia-inducible factor-1 (HIF-1)
 VHL mutations allow HIF-1 levels to get really
high, causing hypoxia, causing and proangiogenic proteins, like VEGF, PDGF, TGF-α,
and TGF-β
 VHL protein also targets insulin-like growth factor-1
(IGF-1)
 So when VHL is mutated, both cell growth and
angiogenesis are stimulated
 Classification of renal cell carcinoma:
 Clear cell carcinoma – made of cells with clear or granular cytoplasm
o Most common (70-80% of renal cell cancers)
o Clear cell carcinoma is nonpapillary!
o 95% of clear cell carcinomas are sporadic
o Almost all clear cell carcinomas involve loss of stuff on the short
arm of chromosome 3 (including the area with the VHL gene)
o Most clear cell carcinomas show mutation to an allele of the
VHL gene
o Clear cell carcinomas arise from proximal tubule epithelium
o Clear cell carcinomas are usually a single lesion
o Clear cell carcinomas are spherical yellow-gray-white masses
 Yellow from lipid accumulation
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Often the clear cell carcinoma includes areas of ischemic
opaque gray-white necrosis, and foci of hemorrhagic
discoloration
o Clear cell carcinoma can grow into something tubular (looks like
tubules) or trabecular (looks like cords)
o Their cytoplasm contain glycogen and lipids
 Papillary carcinoma – characterized by papillary growth pattern
o 10-15% of renal cancers
o No 3p or VHL deletions
o Often the gene lost includes MET, a proto-oncogene that is the
tyrosine kinase receptor for hepatocyte growth factor
 Hepatocyte growth factor mediates growth & mobility
o Unlike clear cell, papillary carcinoma is usually multifocal, and
can be bilateral
o Papillary tumors are thought to arise from distal convoluted
tubules
o Papillary carcinoma are usualy hemorrhagic and cystic
o Papillary carcinoma is made of cuboidal or columnar cells
arranged in papillary formations
o The papillary cores often have interstitial foam cells
 Chromophobe renal carcinoma – cells with prominent cell membranes
and pale eosinophilic cytoplasm, usually with a halo around the nucleus
o About 5% of or renal cell cancers
o Thought to come from intercalated cells of collecting ducts
o Have a much better prognosis than other renal cell carcinomas
 Collecting duct carcinoma – show nests of malignant in the medulla
ducts
o 1% of renal cell cancers
o It’s epithelium is arranged in a “hobnail” pattern
Morphology of renal cell carcinoma:
 Renal cell carcinoma can happen in any part of the kidney, but most
often happen in the poles
 Renal cell carcinoma has a tendency to invade the renal vein and grow
in it
o It can grow right up the inferior vena cava and along the right
heart
The 3 classic diagnostic features of renal cell carcinoma are costovertebral pain,
palpable mass, and hematuria – but this is only seen in 10% of cases
 The most reliable is hematuria
Before symptoms show up, the growing renal cell carcinoma can show fever,
malaise, weakness, and weight loss
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Renal cell carcinomas often cause paraneoplastic syndromes from abnormal
hormone making
 Includes polycythemia, hypercalcemia, hypertension, liver dysfunction,
feminization/masculinization, cushing syndrome, eosinophilia, and
amyloidosis
 A common characteristic of renal cell carcinoma is it tends to metastasize widely
before causing any symptoms or signs
 ¼ of new diagnoses show metastasis
 The most common places it metastasizes to is the lungs (1/2) and bones
(1/3)
 5 year survival rate of renal cell carcinoma is about half, and 2/3 if there is no
sign of metastasis
 If the renal vein is invaded or it goes into kidney fat, it’s 1/5
Urothelial carcinoma of the renal pelvis
 Usually noticed quickly since they’re in the pelvis and easily cause hematuria
 Almost always very small, so they can block urinary flow and cause
hydronephrosis and flank pain
 Urothelial carcinoma is common with analgesic nephropathy and Balkan
nephropathy
 Urothelial carcinomas commonly invade the wall of the pelvis and calyces,
causing a poor prognosis