Pathology - renal Flashcards
1
Q
Horshoe kidney
A
- most common congenital anomaly
- Conjoined kidneys usually located at the lower pole Kidney gets caught on the inferior mesenteric artery (IMA) root during its ascent from pelvis to abdomen
2
Q
Where (anatomically) are horshoe kidneys found? why?
A
Typically at the lower pole because kidney gets caught on the inferior mesenteric artery (IMA) root during its ascent from pelvis to abdomen
3
Q
Most common congenital anomaly
A
Horshoe kidney
4
Q
Where does the kidney develop in normal embryology?
A
Normally develops in the pelvis and ascends to the abdomen
5
Q
Renal agenesis
A
- Absent kidney formation – may be unilateral or bilateral
- Unilateral agenesis --> hypertrophy of the existing kidney –> hyperfiltration increases risk of renal failure later in life
-
Bilateral agenesis –> oligohydramnios which can cause lung hypoplasia, flat face w/ low set ears and development defects of the extremeties (Potter sequence)
- incompatible with life
6
Q
Pathogenesis of unilateral renal agenesis
A
Unilateral agenesis –> hypertrophy of the existing kidney
- Hypertrophy is not a problem until later in life when hyperfiltration can increase the risk of renal failure
7
Q
Pathogenesis of bilateral renal agenesis
A
Amniotic fluid (AF) is essentially the filtrate coming from the kidney (baby is basically floating in its own urine)
Without kidneys, there will be little AF == oligohydramnios.
Without the cushioning of AF then the baby will be pressed up against the mother’s uterus resulting in a flat face and developmental defects of the extremities Incompatible with life.
8
Q
Potter Sequence
A
aka Oligohydramnios sequence.
- Typically resulting from renal agenesis but can be associated with other disease that ultimately result in lack of kidneys.
- Amniotic fluid (AF) is essentially the filtrate coming from the kidney (baby is basically floating in its own urine)
- Without kidneys, there will be little AF == oligohydramnios.
- Without the cushioning of AF then the baby will be pressed up against the mother’s uterus resulting in a flat face and developmental defects of the extremities
9
Q
Dysplastic kidney
A
noninherited, congenital malformation of the renal parenchyma characterized by cysts and abnormal tissue (ie cartilage)
Usually unilateral, but can be bilateral.
When bilateral, need to distinguish from PKD (polycystic kidney disease)
10
Q
A pregnant mother with diagnosed with dysplastic kidney asks what is the chance that her child will have it? Is there anything she can do to prevent or lower the likelihood?
A
Very little risk. Dysplastic kidney is non-inheritable and carries little risk onto the fetus. The chance that the baby develops it is the same as anyone else
11
Q
Polycystic kidney disease (PKD)
A
Inherited defect leading to bilateral enlarged kidneys with cysts in the renal cortex and medulla
Presents as 2 forms: autosomal recessive and autosomal dominant
- Autosomal recessive
- previously called juvenille PKD because it mainly affects infants
- presents as worsening renal failure and HTN
- newborns may present with Potter sequence
- associated with congenital hepatic fibrosis (results in portal HTN) and hepatic cysts
- Autosomal dominant
- due to mutation in APKD1 or APKD2 gene
- cysts develop over time (and will present later in life)
- associated with berry aneurysms, hepatic cysts and mitral valve prolapse
12
Q
PKD - autosomal recessive form
A
High yield: inheritable, enlarged kidneys, always bilateral, renal cortex and medulla involvement
- previously called juvenille PKD because it mainly affects infants
- presents as worsening renal failure and HTN
- newborns may present with Potter sequence
- associated with congenital hepatic fibrosis (results in portal HTN) and hepatic cysts
13
Q
PKD - autosomal recessive form (major presentation)
A
- Cysts in kidney –> enlarged kidneys
- Cysts in liver –> hepatic fibrosis –> portal HTN
14
Q
PKD - autosomal dominant form (major presentation)
A
- Cysts in kidney –> enlarged kidneys
- Cysts in liver –> hepatic fibrosis –> portal HTN
- Cysts in brain === (not really cysts, but look like it) Berry aneuryms
- mitral valve prolapse
15
Q
PKD - autosomal dominant form (mutation)
A
APKD1 or APKD2
16
Q
PKD - autosomal dominant form (when and how does it normally present?)
A
presents in adults as HTN due to increased renin, hematuria and worsening renal failure
17
Q
Medullary cystic kidney disease
A
- Inherited (autosomal dominant) defect leading to cysts in the medullary collecting ducts
- Parenchymal fibrosis results in shrunken kidneys and worsening renal failure
18
Q
How do you distinguish between medullary cystic kidney disease and PKD?
A
MCKD – shrunken kidneys. Involve medullary collecting ducts
PKD – enlarged kidneys. Involve both medullary and cortical portions of kidney
19
Q
Hallmark of acute renal failure
A
azotemia (increased BUN and creatinine)
- “azot” - nitrogen
- “emia” - in the blood
- often occurs with oliguria
20
Q
Divisions of acute renal failure (3)
A
pre-renal, postrenal and intrarenal
21
Q
Prerenal azotemia - cause?
A
Decreased blood flow to kidneys (almost always due to cardiac failure)
Commonly causes acute renal failure
22
Q
Prerenal azotemia - clinical features
A
- Decreased GFR
- azotemia
- oliguria
- serum BUN:Cr ratio > 15
- FENa < 1% (normal)
- Urine osmolarity > 500mOsm/kg (normal)
23
Q
Prerenal azotemia - pathogenesis
A
decreased RBF = decreased GFR –> more pooling of blood in the renal tubules (slower travel speed) –> more re-absorption of urea in the proximal tubules
Creatinine is not re-absorbed (only secreted).
More uptake of urea than creatinine will result in a ratio >15.
24
Q
Postrenal azotemia - cause
A
obstruction of urinary tract downstream from the kidney (ie ureters)
25
Postrenal azotemia - clinical features
* Decreased GFR
* azotemia
* oliguria
* serum BUN:Cr ratio \> 15
* FENa and urine osmolarity depends on the stage of obstruction (and length of time)
* normal during early stages and malfunctional later on
26
Postrenal azotemia - early stages
* Decreased GFR
* azotemia
* oliguria
* serum BUN:Cr ratio \> 15 (increased pressure pushes urea back into the blood)
* Renal tubular function still intact and will result in a normal FENa (\<1%) and urine osmolarity (\>500mOsm/kg)
27
Postrenal azotemia - late stages
Renal tubular function no longer working. Basically long term increased backup (HTN) of renal tubules will damage the lining of the tubules and cause damage. No longer absorbing urea because of this damage.
* BUN:Cr \< 15
* FENa \> 2% (inability to reabsorb sodium)
* urine osmolarity \< 500mOsm/kg (inability to concentrate urine)
28
Acute tubular necrosis
Injury and necrosis of tubular epithelial cells
most common cause of acute renal failure (intrarenal azotemia)
29
Most common cause of acute renal failure
Intrarenal azotemia (aka acute tubular necrosis)
30
Acute tubular necrosis - pathogenesis
1. necrotic cells plug tubules: obstruction decreases GFR
2. Increased pressure in the renal tubule (due to obstruction)
3. decreased filtration (essentially b/c the pressure pushes all the solutes back into the blood)
31
Acute tubular necrosis - clinical features
Depends on the stage (early or late) and the mechanism.
Typically associated with
* oliguria with brown, granular casts
* Elevated BUN and creatinine
* Hyperkalemia (due to decreased renal excretion) with metabolic acidosis
32
Differences between the early and late stages of postrenal azotemia
* BUN:Cr ratio \> 15 in early but \< 15 in later stages when the tubules are damaged and can't reabsorb urea any longer
* FENa \> 2% in later stages (dysfunctional tubular epithelium)
* Urine osmolarity normal in early, but lowered in late phase when there is an inability to concentrate urine due to tubular destruction
33
Acute tubular necrosis - etiologies (2)
1. Ischemic -- often preceded by prerenal azotemia (decreased blood flow --\> ischemia)
2. Nephrotoxic -- toxic agents result in necrosis of tubules
34
What segments of renal tubules are affected in ischemic ATN?
proximal tubule and medullary segment of the thick ascending limb are particularly susceptible to ischemic damage
35
What often precedes ischemic ATN (acute tubular necrosis)?
prerenal azotemia
Decreased blood flow that causes prerenal azotemia will ultimately cause ischemia if every supply is deprived (renal system requires a lot since it always has to function; demand is quite high)
36
What are some common causes of nephrotoxic ATN (acute tubular necrosis)?
* aminoglycosides (most common)
* heavy metals (ie lead)
* myoglobinuria (ie from crush injury to muscle)
* ethylene glycol ( associated with oxalate crystals in urine)
* radiocontrast dye
* urate (tumor lysis syndrome)
37
How does tumor lysis syndrome cause increased levels of urate?
Tumor lysis syndrome is what happens when chemotherapy is initially started resulting in the death of a large number of cells (the tumor) causing a large turnover of cells.
The large turnover will activate the purine salvage pathway that ultimately generates uric acid and increase the likelihood of having urate crystals flowing around (that can cause obstruction)
38
What is used to decrease risk of urate-induced ATN?
* Hydration (dilutes the level of uric acid and decreases likelihood of crystallization)
* allopurinol (prevents synthesis by inhibition of xanthine oxidation)
39
Why is there hyperkalemia and metabolic acidosis in ATN (acute tubular necrosis)?
Both cause from decreased function of tubular epithelium to secrete potassium (hyperkalemia) and organic acids (metabolic acidosis)
40
Acute tubular necrosis - prognosis
* Reversible but requires supportive dialysis since electrolyte imbalances can be fatal
* Oliguria can persist for 2-3 weeks before recovery
* tubular cells (stable cells) take time to reenter the cell cycle and regenerate
41
Acute interstitial nephritis
Drug-induced hypersensitivity involving the interstitium and tubules resulting in acute renal failure (via intrarenal azotemia)
42
Acute interstitial nephritis - causes
NSAIDs, penicillin, and diuretics
43
How does NSAIDs affect the renal vasculature?
There are 2 mechanisms by which the kidneys can increase blood flow: vasodilation of the afferent arterioles (via prostaglandins) and vasoconstriction of the efferent arterioles (via angiotensin II) NSAIDs inhibits COX which synthesizes prostaglandins which can decrease blood flow to the kidneys
44
Acute interstitial nephritis - clinical presentation
* Fever and rash (typical of hypersensitivity)
* oliguria (renal failure)
* **Eosinophils** may be seen in urine (hallmark of acute interstitial nephritis)
* Typically starts weeks after starting a drug and resolves with cessation of drug
45
Hallmark of Acute interstitial nephritis
eosinophils in urine
46
Acute interstitial nephritis - treatment
Remove drug. Usually resolves with cessation of drug
47
Acute interstitial nephritis - complication (what can it progress into?)
May progress into renal papillary necrosis
48
Renal papillary necrosis
Necrosis of the renal papillae
Presents with gross hematuria and flank plain
49
Renal papillary necrosis - presentation
gross hematuria and flank plain
50
Renal papillary necrosis - causes
1. Chronic analgesic abuse (long-term phenacetin or aspirin use)
2. Diabetes mellitus
3. Sickle cell trait or disease
4. Severe acute pyelonephritis
51
What are some causes of intrarenal azotemia? (3)
* Acute tubular necrosis (ischemic or nephrotoxic)
* Acute interstitial nephritis
* Renal papillary necrosis (may just be a progression of the previous disease)
52
Nephrotic syndrome
Hallmark: Proteinuria (\>3.5g/day)
Characterized additionally by:
* hypoalbuminemia --\> pitting edema (due to decreased oncotic pressure)
* hypogammaglobulinemia --\> increased risk of infection
* hypercoagulable state -- due to loss of antithrombin III
* hyperlipidemia and hypercholesterolemia --\> may result in fatty casts in urine
53
4 characteristics of nephrotic syndrome
1. hypoalbuminemia --\> pitting edema (due to decreased oncotic pressure)
2. hypogammaglobulinemia --\> increased risk of infection
3. hypercoagulable state -- due to loss of antithrombin III
4. hyperlipidemia and hypercholesterolemia --\> may result in fatty casts in urine
54
nephrotic syndrome - why is there a hypercoagulable state?
Loss of Antithrombin III
Antithrombin is the inhibitor of thrombin which cleaves fibrinogen to fibrin.
* Loss of this inhibition will result in a pro-coagulation state
55
nephrotic syndrome - why is there hyperlipidemia and hypercholesterolemia?
Think of it as due to the huge losses in protein in the urine which thins out the blood, the liver tries to compensate by dumping lipids and cholesterol into the blood to make up for the losses (since it can't make up that much protein)
56
Nephrotic Syndromes (6)
Think of them in pairs
* Minimal change disease, FSGS (Focal Segmental Glomerulosclerosis)
* both due to the effacement of the podocytes
* Membranous nephropathy, membranoproliferative glomerulonephritis
* both due to immune complex deposition in the membrane (membranous in the epithelial/subepithelial layer, Type 1 in the subendothelial, type 2 within the basement membrane)
* Diabetes mellitus, systemic amyloidosis
57
Minimal change disease
* Most common cause of nephrotic syndrome in children
* Characterized by the effacement of the podocyte foot processes on electron microscopy
* due to cytokines
* Negative IF. No immune complex deposits
* Usually idiopathic but may be associated with Hodgkin lymphoma (where there is an overproduction of cytokines)
* Normal glomeruli on H&E stain -- lipid may be seen in proximal tubule cells
* Selective proteinuria (loss of albumin, but not immunoglobulin)
* Excellent response to steroids (damage mediated by cytokines from T cells)
58
Minimal change disease - treatment and prognosis
Steroids -- excellent response
ONLY nephrotic syndrome w/ an excellent response to treatment
59
Minimal change disease - cause
Effacement of foot processes due to cytokines (which is why it responds well to treatment)
60
Minimal change disease - H&E stain
Will mostly look normal. Normal glomeruli
Podocytes are damage (effaced/flattened), but you can't see that unless on EM
61
Focal Segmental Glomerulosclerosis (FSGS)
* Most common cause of nephrotic syndrome in Hispanics and African Americans
* Usually idiopathic, but may be associated with HIV, heroin use, and sickle cell disease
* Characterized by focal (some glomeruli) and segmental (involving only part of the glomerulus) sclerosis on H&E stain
* Effacement of foot processes on EM
* No immune complex deposits, negative IF
* poor response to steroids -- progresses to chronic renal failure
62
Focal Segmental Glomerulosclerosis (FSGS) - causes?
Usually idiopathic, but commonly associated with:
* HIV
* heroin use
* sickle cell disease
63
Focal Segmental Glomerulosclerosis (FSGS) - pathophysiology
Effacement of foot processes
Focal (some glomeruli) and segmental (involving only part of the glomerulus) sclerosis on H&E.
64
Focal Segmental Glomerulosclerosis (FSGS) - prognosis
Poor response to steroids.
Progresses to chronic renal failure
65
You noticed an effacement of foot processes of podocytes in the kidney. How do you distinguish between FSGS and minimal change disease?
FSGS responds poorly to steroids. Think of FSGS as the next step in the progression from minimal change disease. The effacement of the podocytes eventually causes sclerosis that progresses to chronic renal failure
66
If a patient has HIV and then develops nephrotic syndrome, what is the diagnosis?
Focal Segmental Glomerulosclerosis (FSGS)
67
Membranous nephropathy
* Most common cause of nephrotic syndrome in Caucasian adults
* Usually idiopathic, but may be associated with hepatitis B or C, solid tumors, SLE or drugs (ie NSAIDs and penicillamine)
* Thick glomerular basement membrane on H&E
* Characterized by immune complex deposition (granular IF)
* subepithelial deposits with 'spike and dome' appearance on EM
* Poor response to steroids -- progresses to chronic renal failure
68
Most common cause of death in lupus patients?
Renal failure
* Most commonly due to diffuse proliferative glomerulonephritis (nephritic syndrome)
* If the patient has nephrotic syndrome -- it is membranous nephropathy
69
Membranous nephropathy - associated diseases
* Hepatitis B or C
* solid tumors
* SLE
* drugs (ie NSAIDs and penicillamine)
70
Membranous nephropathy - findings on H&E
thickened glomerular basement brane
* immune complex deposition causes hypertrophy/dysplasia and results in thickened membrane
71
Membranous nephropathy
characterized by thickened glomerular BM
72
Membranous nephropathy - Why is there a thickened glomerular basement membrane?
The deposition of the immune complexes (subepithelial) kind of displaces the foot processes so it lays down new basement membrane right ontop of the deposit which thickens the glomerulus (cells do not like to be onto of immune deposits instead of the BM)
73
Membranous nephropathy - immunofluorescence - what is expected?
Granular IF (hard to see unless zoomed in) - granules are the deposits of immune complexes
Subepithelial deposits with "spike and dome" appearance on EM
74
Membranous nephropathy - prognosis
Poor response to steroids -- progresses to chronic renal failure
75
Membranous nephropathy - where are the immune deposits?
Subepithelial (in the layer between the basement membrane and the podocyte foot processes)
76
Membranoproliferative glomerulonephritis
* Thick glomerular BM on H&E often with 'tram-track' appearance
* Characterized by immune complex deposition (Granular IF)
* Divided into two types based on location of deposit
* Type I -- subendothelial
* associated with HBV and HCV
* More commonly associated w/ tram-track appearance than type II
* Type II -- intramembranous
* associated with C3 nephritic factor (autoantibody that stabilizes C3 convertase, leading to overactivation of complement, inflammation and low levels of circulating C3)
* Poor response to steroids -- progresses to chronic renal failure
77
Membranoproliferative glomerulonephritis - subdivisions (2)
Type I -- subendothelial immune complex depositions
* associated with HBV and HCV
* More commonly associated w/ tram-track appearance than type II
Type II -- intramembranous immune complex depositions
* associated with C3 nephritic factor (autoantibody that stabilizes C3 convertase, leading to overactivation of complement, inflmmation and low levels of circulating C3)
78
Membranoproliferative glomerulonephritis - why is there a tram-track appearance?
The deposition of immune complexes stimulates the "proliferation" of mesangial cells to essentially cut through the immune deposit splitting it into 2 halves and creating the 'tram-track' appearance
79
Membranoproliferative glomerulonephritis - what is different between the subdivisons (type 1 vs 2)?
Type 1 - has more to associations with tram-track appearance and are subendothelial deposits
Type 2 - intramembranous deposit (within the basement membrane). Associated with C3 convertase overactivation
80
Membranoproliferative glomerulonephritis - prognosis
Poor response to steroids -- progresses to chronic renal failure
81
What does C3 convertase do? What does it have to do with the renal pathophysiology?
Normally activates C3 to create C3a and C3b.
Normally only activated for a short period of time. However, in Membranoproliferative glomerulonephritis type II, it is stabilized by C3 nephritic factor, an auto antibody that stabilizes C3 convertase leading to the overactiation of complement, inflammation and low levels of circulating C3
82
In membranoproliferative glomerulonephritis, why is there low levels of C3?
C3 converatase is an enzyme that activates C3 to create C3a and C3b.
Normally C3 converatase is only activated for a short period of time. However, in Membranoproliferative glomerulonephritis type II, it is stabilized by C3 nephritic factor, an auto antibody that stabilizes C3 convertase leading to the overactiation of complement, inflammation and low levels of circulating C3
83
associated diseases of type I membranoproliferative glomerulonephritis?
Hep B or C (HBV or HCV)
84
What is the difference between membranous nephropathy and membranoproliferative glomerulonephritis?
Membranous nephropathy -- immune deposits in subepithelial layer (between BM and foot processes)
Membranoproliferative glomerulonephritis
* Type I - subendothelial
* Type II - intramembranous
85
How does diabetes mellitus affect renal pathophysiology?
* High serum glucose leads to nonenzymatic glycosylation (first change to occur in the kidney in the diabetes) of the vascular baement membrane resulting in hyaline arteriolosclerosis
* Preferentially affects the efferent arterioles (results in increased glomerular filtration pressure)
* increased hydrostatic pressure results in microalbuminuria (essentially pushes it out)
* Eventually progresses to nephrotic syndrome
* characterized by sclerosis of the mesangium w/ formation of Kimmelstiel-Wilson nodules
86
First physiological change to happen to the kidney in diabetes
High serum glucose leads to nonenzymatic glycosylation of the vascular baement membrane resulting in hyaline arteriolosclerosis
87
What occurs after nonenzymatic glycosylation of basement membrane of kidney vasculature? and where does it occur?
Hyaline arteriolosclerosis
Preferentially affects the efferent arterioles (results in increased glomerular filtration pressure)
* increased hydrostatic pressure results in microalbuminuria (essentially pushes it out)
88
Treatment for diabetes mellitus associated renal problems? how does it work?
ACE inhibitors slow progression of hyperfiltration-induced damage (helps to vasodilate the efferent arteriole so the it can minimize the narrowing that occurred due to hylaine arteriolosclerosis
89
Nephrotic syndrome due to diabetes mellitus - what is the major characteristic?
Sclerosis of the mesangium w/ formation of Kimmelstiel-Wilson nodules
90
Kimmelstiel-Wilson nodules
Found in nephrotic syndrome due to diabetes mellitus
* characterized by sclerosis of the mesangium and the formation of these bodies
91
What commonly involved organ in systemic amyloidosis?
Kidney
92
Systemic amyloidosis affecting the liver
Amyloid deposits in the mesangium, resulting in nephrotic syndrome
Characterized by apple-green birefringence under polarized light after staining w/ Congo Red
93
Biopsy of kidney finds apple-green birefringence under polarized light after staining w/ Congo Red
What is the diagnosis?
Systemic amyloidosis
94
Nephrotic syndrome most common in kids/children?
minimal change disease
95
Nephrotic syndrome most common in hispanics and african americans?
Focal segmental glomerulosclerosis
96
Nephrotic syndrome most common in Caucasian adults?
Membranous nephropathy
97
Nephritic syndrome
1. Limited proteinuria (\<3.5g/day)
2. oliguria and azotemia
3. salt retention --\> periorbital edema and HTN
* perioribital b/c of the loose CT that is present there so tends to show first
4. RBC casts and dysmorphic RBCs in urine
98
Nephritic syndrome - biopsy findings
Hypercellular, inflamed glomeruli
* Immune-complex deposition activates complement; C5a attracts neutrophils which mediate damage and the inflammatory response
99
Nephritic syndrome - most common types (4)
1. Poststreptococcal glomerulonephritis
2. Rapidly progressive glomerulonephritis
3. IgA nephropathy (Berger Disease)
4. Alport Syndrome
100
Poststreptococcal Glomerulonephritis (PSGN)
* Nephritic syndrome that arises after group A ß-hemolytic streptococcal infection of **the skin** (impetigo) or **pharynx**
* occurs with nephritogenic strains (carry the M protein virulence factor)
* May occur after infection w/ nonstreptococal organisms as well
* Presents 2-3 weeks after infection as hematuria (cola-colored urine), oliguria, HTN and periorbital edema
* Usually seen in children but may occur in adults
* Mediated by subepithelial 'humps' on EM
* Treatment is supportive
101
What makes a bacterial strain nephritogenic?
If they carry the M protein virulence factor usually present in the Group A ß-hemolytic streptococci.
102
Poststreptococcal Glomerulonephritis (PSGN) - presentation
Presents 2-3 weeks after infection with:
* hematuria (cola-colored urine)
* oliguria
* HTN
* periorbital edema
103
Poststreptococcal Glomerulonephritis (PSGN) - pathogenesis
Immune complex deposition as a response to the infection.
Deposits start out as subendothelial deposits that continue to move out and dissipate (disease is self-limiting). They do however congregate/pileup in the subepithelial layer creating the **subepithelial "humps"** that is characteristic of this disease
104
Poststreptococcal Glomerulonephritis (PSGN) - treatment
Supportive. The immune deposits eventually move themselves out of the system.
* Children rarely progress to renal failure (1%)
* Some adults (25%) develop rapidly progressive glomerulonephritis
105
Poststreptococcal Glomerulonephritis (PSGN) - hallmark of the disease
subepithelial 'humps' -- from the progressive outward movement of the immune deposits that start from the subendothelial deposit and move outward piling up in the subendothelial cell layer to create humps
106
Rapidly progressive glomerulonephritis (RPGN)
Nephritic syndrome that progresses to renal failure in **weeks to months**
Characterized by crescents in Bowman space on H&E stain -- comprised of fibrin and macrophages
Clinical picture and IF help resolve etiology
107
Rapidly progressive glomerulonephritis - hallmark
Crescents in Bowman space comprised of fibrin and macrophages
108
What is a complication in poststreptococcal glomerulonephritis in adults?
May progress to rapidly progressive glomerulonephritis (25%) which can result in renal failure in weeks to months
109
Rapidly progressive glomerulonephritis - some causes
* Goodpasture syndrome -- causes a linear IF pattern
* PSGN or diffuse proliferative glomerulonephritis
* Wegener granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis
110
Rapidly progressive glomerulonephritis - IF findings
1. Linear (anti-basement membrane antibody) --\> goodpasture syndrome
2. Granular (immune complex deposition) --\> PSGN (most common) or diffuse proliferative glomerulonephritis
3. Negative IF (pauci-immune) --\> any of the small vessel vasculities
111
If a patient was found to have rapdily progressive glomerulonephritis. The immunofluorescence (IF) comes back with a linear pattern. What does it mean? What is the diagnosis and why?
Linear pattern means it is an anti-basement membrane antibody.
* Ab against collagen in glomerular and alveolar basement membranes
* BOTH lung and renal involvement --\> hematuria and hemoptysis
* Classically seen in young, adult males
Disease/Diagnosis: Goodpasture syndrome
112
If a patient was found to have rapdily progressive glomerulonephritis. The immunofluorescence (IF) comes back with a granular IF pattern. What does it mean? What is the diagnosis and why?
* Granular IF means immune complex deposition.
* This is most commonly due to **poststreptococcal glomerulonephritis** (PSGN) -- which is characterized by immune complex deposits.
* Can also be associated with **diffuse proliferative glomerulonephritis**
* due to diffuse antigen-antibody complex deposition, usually sub-endothelial. Most common type of renal disease in SLE
113
Diffuse Proliferative glomerulonephritis
due to diffuse antigen-antibody complex deposition, usually sub-endothelial. Most common type of renal disease in SLE
114
If a patient was found to have rapdily progressive glomerulonephritis. The immunofluorescence (IF) comes back negative. What does it mean? What is the diagnosis and why?
* Negative IF aka pauci-immune.
* Associated with any of the small vessel vasculitis (Wegeners, microscopic polyangiitis and Churg-Strauss syndrome)
* Wegener granulomatosis is associated with c-ANCA
* Microscopic angiitis associated with p-ANCA
* Churg-Strauss Syndrome associated with p-ANCA. However it can be distinguished from microscopic b/c of granulomatous inflammation, eosinophilia and asthma.
115
Similarities and differences between Churg-Strauss syndrome and microscopic polyangiitis
Similarities: both affect small vessels and associated with p-ANCA
Differences: only Churg-Strauss is associated with granulomatous inflammation, eosinophilia and asthma
116
IgA nephropathy (Berger Disease)
* IgA immune complex deposition in mesangium of glomeruli -- most common nephropathy worldwide
* presents during childhood as episodic gross or microscopic hematuria with RBC casts, usually following mucosal infections (ie gastroenteritis)
* response of a mucosal infection is to produce a lot of IgA
* May slowly progress to renal failure
117
What is the mesangium in terms of renal structure?
In the glomerulus of the kidney, the mesangium is a structure associated with the capillaries. It is continuous with the smooth muscles of the arterioles. It is outside the capillary lumen, but surrounded by capillaries. It is in the middle (meso) between the capillaries (angis). It is contained by the basement membrane, which surrounds both the capillaries and the mesangium.
In the picture, it is (5b) -- the pink stuff inbetween all the capillaries
118
Most common nephropathy worldwide
IgA nephropathy (Berger Disease)
119
IgA Nephropathy - when does it normally present? in what population?
Typically presents in childhood following mucosal infections (such as gastroenteritis)
IgA production is increased during infection (increased chance of deposition)
120
Alport syndrome
Inherited defect in Type IV collagen -- most commonly X-linked
Results in thinning and splitting of the glomerular BM
Presents as isolated hematuria, sensory hearing loss and ocular disturbances
* all due to the splitting of BM in each symptom's respective areas
121
What disease is associated with an inherited defect in type IV collagen?
Alport syndrome -- most commonly X-linked
122
Alport syndrome -- pathogenesis
Defect in type IV collagen (the collagen responsible for basement membranes)
Results in thinning and splitting of basement membranes, particularly in the kidney --\> isolated hematuria
However this occurs everywhere and can frequently cause sensory hearing loss and ocular disturbances.
123
Urinary track infection - possible sites of infection
urethra, bladder or kidney
124
Urinary track infection - most common cause? Who is more at risk and why?
Due to ascending infection. Women are more at risk due to shorter urethra (shorter distance of travel)
125
Why are women more at risk for UTIs?
**Shorter urethra** makes it shorter distance for infection to travel to reach destination
126
Cystitis
infection of the bladder
127
Cystitis - clinical presentation
* Dysuria
* urinary frequency
* urgency
* suprapubic pain
Systemic signs (ie fever) usually absent
128
Cystitis - laboratory findings
* Urinalysis - cloudy urine w/ \>10 WBCs/high power field
* Dipstick
* positive leukocyte esterase (due to pyuria)
* positive nitrites (bacteria convert nitrates to nitrites)
* Culture - greater than 100,000 CFUs (gold standard)
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What is the gold standard for labs for identifying cystitis?
\> 100,000 CFUs
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Cystitis - common causes (etiologies)
1. *E. coli* (80%)
2. *Staphylococcus saprophyticus* - increased incidence in young, sexually active women
3. *Klebsiella pneumoniae*
4. *Proteus mirabilis* - causes alkaline urine with ammonia scent
5. *Enterococcus faecalis*
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Sterile pyuria
Presence of \> 10 WBCs/hpf and leukocyte esterase
w/ negative urine culture (gold standard)
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If a patient is found with sterile pyuria, what bugs come to mind?
*Chlamydia trachomatis* or *Neisseria gonorrhoeae*
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Pyelonephritis
Infection of the kidney
Usually due to ascending infection. Increased risk with vesicoureteral reflux
134
Pyelonephritis - cause?
Usually due to ascending infection. Increased risk with vesicoureteral reflux
135
Pyelonephritis - presentation
* Fever
* flank pain (sensitization of nerves of the capsule due to inflammation)
* WBC casts (reflux of not just the bacteria but also the inflammatory cells)
* Leukocytosis
* Symptoms of cystitis
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Pyelonephritis - why is there flank pain?
Inflammation causes sensitization of the nerves of the renal capsule
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Pyelonephritis - most common pathogens
* *E. coli* (90%)
* *Enterococcus faecalis*
* *Klebsiella* species
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Chronic Pyelonephritis
* Interstitial fibrosis and atrophy of tubules due to multiple bouts of acute pyelonephritis
* Due to vesicoureteral reflux (children) or obstructure (ie BPH or cervical carcinoma in adults)
* Leads to cortical scarring with blunted calyces -- scarring at upper and lower poles is characteristic of vesicoureteral reflux
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Chronic Pyelonephritis - most common cause in children?
Vesicoureteral reflux
140
Chronic Pyelonephritis - most common cause in adults?
obstruction (ie BPH or cervical carcinoma)
141
Chronic Pyelonephritis - what kind of scarring can you expect to see?
Cortical scarring with blunted calyces
Scarring at upper and lower poles is characteristic of vesicoureteral reflux
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Chronic Pyelonephritis - histological findings
Atrophic tubules containing eosinophilic proteinaceous material resembling thyroid follicles ('thyroidization' of the kidney)
Waxy casts may be seen in urine
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What is meant by 'thyroidization' of the kidney?
Atrophic tubules containing eosinophilic proteinaceous material that resemble thyroid follicles
Waxy casts may be seen in urine
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Nephrolithiasis
* Precipitation of a urinary solute as a stone
* Risk factors incude high concentration of solute in urinary filtrate and/or low urine volume
* Presents as colicky pain with hematuria and unilateral flank tenderness
* stone is usually passed within hours, if not, surgical intervention may be required
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Nephrolithiasis - risk factors
High concentration solute in urine
Low urine volume
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Nephrolithiasis - presentation
Colicky pain with hematuria and unilateral flank tenderness
Stone should pass within hours (otherwise surgery may be needed)
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Nephrolithiasis - types (4)
1. Calcium oxalate and/or calcium phosphate
2. Ammonium magnesium phosphate
3. Uric acid
4. Cystine
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Most common cause of calcium oxalate and/or calcium phosphate nephrolithiasis
**Idiopathic hypercalciuria**
Counter-intuitive -- the most common cause is not hypercalcemia but it needs to be excluded
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calcium oxalate and/or calcium phosphate nephrolithiasis - what disease is associated with this? Why?
Crohn's disease -- small bowel destruction causes increased reabsorption of oxalate in the large intestines
This increase in oxalate binds calcium and ends up in the kidney where the increased concentration makes it more likely to precipitate.
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calcium oxalate and/or calcium phosphate nephrolithiasis - treatment and why?
hydrochlorothiazide
Causes calcium reabsorption to reduce the concentration of calcium and chance of precipitation
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Most common type of nephrolithiasis
calcium oxalate and/or calcium phosphate nephrolithiasis
152
Ammonium magnesium phosphate nephrolithiasis - cause?
Most common cause is infection with urease-positive organisms (ie *Proteus vulgaris* or *Klebsiella*) --\> creates an alkaline urine that leads to formation of stone (favors precipitation)
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Ammonium magnesium phosphate nephrolithiasis - complication?
Classically results in staghorn calculi in renal calyces, which act as a nidus for UTIs
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Ammonium magnesium phosphate nephrolithiasis - treatment
Surgical removal of staghorn calculi (due to size) and eradication of the pathogen (to prevent recurrence)
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Uric acid nephrolithiasis
* Third most common stone
* Radiolucent (can't see on xray)
* Risk factors: hot and arid climates low urine volume, acidic pH
* Most common stone seen in patients with gout; hyperuricemia (ie in leukemia or myeloproliferative disorders) increases risk
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Uric acid nephrolithiasis - risk factors
hot and arid climates
low urine volume
acidic pH
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What effect does acidic pH have on nephrolithiasis?
acidic pH favors precipitation and increases the risk of stone formation
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What is common and different between the types of stones found on xray?
Calcium, ammonium magnesium phosphate and cystine nephrolithiasis are radiopaque or radiodense
Uric acid nephrolithasis is radiolucent (hard to identify on xray)
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Uric acid nephrolithasis - treatment
hydration (dilution of urate) and/or alkalinization of urine (w/ potassium bicarbonate)
Allopurinol additionally added in patients with gout
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Cystine nephrolithiasis
Rare cause most commonly seen in children
Associated with cystinuria (a genetic defect of tubules that results in decreased reabsorption of cysteine)
May form staghorn calculi
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Cystine nephrolithiasis - treatment
Hydration and alkalinzation
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What types of nephrolithiasis can result in staghorn calculi?
Most common in **ammonium magnesium phosphate** nephrolithiasis
Can also be seen in **cystine** nephrolithiasis
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Chronic renal failure
aka end-stage kidney failure
May result from glomerular, tubular, inflammatory, or vascular insults
Most common cause: diabetes mellitus, HTN and glomerular disease
164
Chronic renal failure - most common causes
diabetes mellitus
HTN
glomerular disease
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Chronic renal failure - clinical features
1. Uremia -- can result in nausea, anorexia, pericarditis, platelet dysfunction, encephalopathy w/ asterixis and deposition of urea cyrstals in skin
2. salt and water retention with resulting HTN
3. hyperkalemia w/ metabolic acidosis (decreased secretion of K+ and organic acids)
4. Anemia due to decreased EPO production by renal peritubular interstitial cells
5. hyperphosphatemia and hypocalcemia -- due to decreased 1-alpha-hydroxylation of vitamin D (activation step) by proximal renal tubule cells
6. renal osteodystrophy (osteitis fibrosa cystica, osteomalacia, osteoporosis)
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Clinical features/complications of uremia
Increased nitrogenous waste products in blood (azotemia) result in:
* nausea
* anorexia
* pericarditis
* platelet dysfunction
* encephalopathy w/ asterixis
* deposition of urea crystals in skin
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Why is there platelet dysfunction in uremia?
Nitrogen inhibits both platelet adhesion and aggregation
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Where and what are responsible for production of erythropoietin (EPO)?
Production by renal peritubular interstitial cells
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Why is there hypocalcemia in chronic renal failure?
1. decreased activation of vitamin D (decreased 1-alpha-hydroxylation by proximal renal tubule cells) --\> decreased Ca2+ absorption
2. hyperphosphatemia --\> phosphate will bind Ca2+ so there will be less free calcium
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Renal osteodystrophy
Associated with chronic renal failure due to secondary hyperparathyroidism. 3 key features:
1. Osteitis fibrosa cystica
1. decreased calcium levels causes increased PTH secretions that causes bone resorption --\> burnout of bone --\> fibrosis and formation of cysts (empty due to increased osteoclast activity)
2. Osteomalacia -- can't mineralize properly due to decreased calcium and vitamin D levels
3. Osteoporosis -- leeching calcium from bones (besides the PTH effect due to low Ca levels) as a means to buffer the metabolic acidosis due to decreased organic acid secretion
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Chronic renal failure - treatment
Dialysis or renal transplant
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Chronic renal failure - do cysts develop? If so, when?
Cysts often develop within shrunken end-stage kidneys during dialysis increasing risk for renal cell carcinoma
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How to distinguish PKD from chronic renal failure? Especially when both diseases have cyst development?
In chronic failure, cysts develop within _shrunken_ end-stage kidneys
PKD has enlarged kidneys.
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Angiomyolipoma
Hamartoma (resembles organ of origin) comprised of blood vessels, smooth muscle and adipose tissue
Increased frequency in tuberous sclerosis
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What disease is angiomyolipoma associated with?
Increased frequency in tuberous sclerosis
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tuberous sclerosis
* Autosomal dominant genetic disease that causes benign tumors to grown in the brain, kidneys, heart, eyes, kidney, skin and lungs
* Associated with the lack of TSC1 or TSC1 which code for hamartin and tuberin (tumor growth suppressors)
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Renal cell carcinoma
* Malignant epithelial tumor arising from kidney tubules
* Presents with a triad of symptoms: hematuria, palpable mass, and flank pain
* all 3 symptoms rarely occur together (\<10%). Hematuria is most common
* Fever, weight loss, or paraneoplastic syndrome (EPO, renin, PTHrP or ACTH) may also be present
* Sometimes include a left sided varicocele (scrotum varicose veins)
* Associated with loss of VHL tumor suppressor gene
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Renal cell carcinoma - classic triad of symptoms
1. hematuria
2. palpable mass
3. flank pain
Rarely occur together (\<10%)
Hematuria is most common presenting symptom
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Renal cell carcinoma - most common presenting symptom
hematuria
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Renal cell carcinoma - Symptoms
* Triad: hematuria, palpable mass, flank pain
* Fever, weight loss
* paraneoplastic syndrome (EPO, renin, PTHrP, or ACTH)
* left sided varicocele (scrotum varicose veins)
* carcinoma blocks drainage of the left spermatic vein
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Paraneoplastic syndromes associated with renal cell carcinoma (4). What results from these syndromes?
1. EPO (job of kidney) --\> reactive polycythemia
2. Renin (job of kidney) --\> HTN
3. PTHrP --\> hypercalcemia
4. ACTH --\> Cushings syndrome
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Cushings syndrome
aka hypercortisolism
Characterized by:
* Increased glucagon activation --\> increased gluconeogenesis
* aberrant gluconeogenesis causes the breakdown of muscle to generate this glucose --\> **muscle weakness**
* Excess glucose in the blood
* glucose is absorbed by all cells
* via insulin dependent maner:
* **fatty deposits** around face and upper back
* fat loss from arms and legs
* weight gain around midsection
* via non-insulin dependent manner: (ie neurons)
* **neuropathy** (glucose in neurons causes metabolic toxicity)
* Cataracts (via cells of the lens)
* blindness (via pericytes of the retina)
* Immune suppression (inhibition of phospholipase A2, IL2 and histamine release)
* Osteoporosis (via inhibition of osteoblasts)
* abdominal striae (via collagen synthesis inhibition)
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How does renal cell carcinoma result in a left-sided varicocele? Why only the left side?
Left spermatic vein drains into the left renal vein which then drains into the IVC. Carcinoma blocks drainage of the left spermatic vein leading to a varicocele (scrotum varicose veins)
Right side drains directly into IVC
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Spermatic vein drainage
Left side --\> renal vein --\> IVC
right side --\> IVC
Left side is more prone to varicocele if there is a block in the renal vein such as in renal cell carcinoma
185
Renal cell carcinoma - gross anatomical presentation
yellow mass
186
Renal cell carcinoma - histology
most common variant exhibits a clear cytoplasm (cear cell type)
187
Renal cell carcinoma - gene involved? pathogenesis?
Involves loss of VHL (3p) tumor suppressor gene
Leads to increased IGF-1 (promotes growth) and increased HIF transcription factor (increases VEGF and PDGF) resulting in excessive growth
188
Renal cell carcinoma - tumor types
* Sporadic or hereditary
* Sporadic
* arise in adult males (average age 60)
* Single tumor in the upper pole of the kidney
* Major risk factor is cigarette smoke
* Hereditary
* arise in young adults
* often bilateral
* associated Von HIppel-Lindau disease (autosomal dominant disorder due to inactivation of VHL gene)
* results in increased risk for hemangioblastoma of the cerebellum and renal cell carcincoma
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Renal cell carcinoma - sporadic form
* arise in adult males (average age 60)
* Single tumor in the upper pole of the kidney
* Major risk factor is cigarette smoke
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renal cell carcinoma hereditary type
* arise in young adults
* often bilateral
* associated Von Hippel-Lindau disease (autosomal dominant disorder due to inactivation of VHL gene)
* results in increased risk for hemangioblastoma of the cerebellum and renal cell carcincoma
191
What disease is renal cell carcinoma associated with?
associated Von Hippel-Lindau disease (autosomal dominant disorder due to inactivation of VHL gene)
The hereditary form is most commonly associated
192
Renal cell carcinoma staging
T - based on size and involvement of the renal vein (occurs commonly and increases risk of hematogenous spread to the lungs and bone)
N - spread to retroperitoneal LN
193
Renal cell carcinoma - major risk factor for sporadic tumors?
Cigarette smoke
194
Renal cell carcinoma - what vein does it most commonly involve?
Love to go the renal vein --\> hematogenous spread to lungs and bone
195
Renal cell carcinoma - what lymph nodes does it like to spread to?
retroperitoneal LN
196
Wilms tumor
Malignant tumor comprised of:
* blastema (immature kidney mesenchyme)
* primitive glomeruli and tubules
* stromal cells
Most common malignant renal tumor in children -- average age is 3 years
197
Most common malignant renal tumor in children
Wilms Tumor -- average age is 3
198
Wilms Tumor - presentation
Unilateral flank mass with hematuria and HTN (due to renin secretion)
199
Syndromes that include Wilm's tumor (3)
1. **WAGR** -- **W**ilms tumor, **A**niridia, **G**enital abnormalities, and mental & motor **R**etardation
* associated w/ deletion of WT1 tumor suppressor gene
2. **Denys-Drash syndrome** -- Wilms tumor, progressive renal (glomerular) disease and male pseudohermaphroditism
* associated w/ mutations of WT1
3. **Beckwith-Wiedemann syndrome** -- Wilms tumor, neonatal hypoglycemia, muscular hemihypertrophy, and organomegaly (including tongue)
* associated w/ mutations in WT2 gene cluster (imprinted genes at 11p15.5) particularly IGF-2
200
WAGR Syndrome
* **W**ilms tumor
* **A**niridia (absence of iris)
* **G**enital abnormalities
* mental & motor **R**etardation
associated w/ deletion of WT1 tumor suppressor gene
201
Denys-Drash syndrome
* Wilms tumor
* progressive renal (glomerular) disease
* male pseudohermaphroditism
associated w/ mutations of WT1
202
Beckwith-Wiedemann syndrome
* Wilms tumor
* neonatal hypoglycemia
* muscular hemihypertrophy
* organomegaly (including tongue)
associated w/ mutations in WT2 gene cluster (imprinted genes at 11p15.5) particularly IGF-2
203
Lower urinary tract - what structures does it include? (anatomy)
* renal pelvis
* ureter
* bladder
* urethra
204
Lower urinary tract carcinomas (3)
1. Urothelial (transitional cell) carcinoma
2. Squamous cell carcinoma
3. adenocarcinoma
205
Most common type of urinary tract cancer
Urothelial (transitional cell) carcinoma -- usually arises in bladder
206
Urothelial (transitional cell) carcinoma - risk factors?
Major risk factor: **cigarette smoke**
Other risk factors:
* naphthylamine (found in cigarette smoke)
* azo dyes (for coloring such as hair)
* long-term cyclophosphamide use
* phenacetin use (for pain relief)
207
Urothelial (transitional cell) carcinoma - population that it mostly affects
Generally seen in older adults
208
Urothelial (transitional cell) carcinoma - classic presentation
Painless hematuria
209
Urothelial (transitional cell) carcinoma - pathways that it can arise (2)
1. Flat -- develops as a high grade flat tumor and then invades
* associated with early p53 mutations
2. Papillary -- develops as a low-grade papillary tumor that proresses to a high-grade papillary tumor and then invades
* no associations with p53 mutation
210
What is the 'field effect'?
What does it have to do with Urothelial (transitional cell) carcinoma ?
Field effect refers to when you expose carcinogens to the bladder, you expose it to the whole 'field' and hence when you have cancer, it is likely to be multifocal and will like recur (since there can be many different mutations)
211
Urothelial (transitional cell) carcinoma - pathogenesis associated with early p53 mutation
Develops initially as a flat high-grade tumor and then invades
212
Progression of a papillary urothelial carcinoma
Stars out as a papillary growth (fibrovascular core w/ blood vessel runing through it upon which epithelium is placed).
Develops into a low grade papillary tumor --\> progresses to a high grade papillary tumor --\> invasion
213
Squamous cell carcinoma of the lower urinary tract
Usually involves the bladder.
Normal bladder does NOT have squamous cell epithelium --\> requires squamous metaplasia
Risk factors
* chronic cystitis (older women)
* *Schistosoma haematobium* infection (Egyptian male)
* long-standing nephrolithiasis
214
Risk factors for squamous cell carcinoma of the lower urinary tract
* chronic cystitis (older women)
* Schistosoma haematobium infection (Egyptian male)
* inbeds in the bladder wall that causes chronic infection and squamous metaplasia
* long-standing nephrolithiasis
These all cause chronic inflammation --\> which can result in squamous metaplasia (prerequiste to developing this carcinoma)
215
Infection with what bug is associated with squamous cell carcinoma of the lower urinary tract? why?
Schistosoma haematobium infection (classically in an Egyptian male)
The bug inbeds in the bladder wall that causes chronic inflammation resulting in squamous metaplasia
216
Adenocarcinoma of the lower urinary tract
Malignant proliferation of glands, usually involving the bladder
* Normal bladder does NOT have glandular epithelium
Arises from:
* urachal remnant (tumor that develops at the dome of the bladder) -- duct that normally connects the fetal bladder w/ the yolk sac. Normally lined with columnar epithelium, but degenerates after birth
* cystitis glandularis (chronic inflammation that results in columnar metaplasia)
* exstrophy (congenital failure to form the caudal portion of the anterior abdominal and bladder walls --\> exposes the surface of bladder to the outside world --\> increased risk for metaplasia)
217
What can cause adenocarinoma of the lower urinary tract?
Glandular epithelium not present normally. Requires factors that cause metaplasia or its presence.
* urachal remnant (tumor that develops at the dome of the bladder) -- duct that normally connects the fetal bladder w/ the yolk sac. Normally lined with columnar epithelium, but degenerates after birth
* cystitis glandularis (chronic inflammation that results in columnar metaplasia)
* exstrophy (congenital failure to form the caudal portion of the anterior abdominal and bladder walls --\> exposes the surface of bladder to the outside world --\> increased risk for metaplasia)
