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Renal Path, GBM = glomerular basement membrane
EM = electron microscopy
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Renal Path
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Congenital renal defects
Potter sequence
- Chronic placental insufficiency or reduced renal output → fetus cannot excrete urine → oligohydramnios → not enough amniotic fluid to evenly distribute force over surface of the fetus → compression of developing fetus → various problems:
- limb deformities/dysplasia
- facial anomalies (eg, low-set ears, retrognathia, broad, flat nose)
- compression of chest and lack of amniotic fluid aspiration into fetal lungs → pulmonary hypoplasia (cause of death)
- club foot/feet (can be with tibial torsion)
- examples of reduced fetal renal output:
- ARPKD
- obstructive uropathy (eg, posterior urethral valves)
- bilateral renal agenesis
- renal dysplasia ("small dysplastic renal kidneys with scattered cysts")
- considered an issue of deformation in morphogenesis: extrinsic mechanical distortion (e.g. congenital torticollis) that occurs after embryonic period
Horseshoe kidney
- most common congenital renal anomaly
- Kidneys connected at the lower pole. Become abnormally located in the lower abdomen because they get caught on the inferior mesenteric artery root
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Misc.
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Renovascular disease (renal artery stenosis)
- Unilateral or bilateral renal artery stenosis (RAS) → ischemia → ↓ renal perfusion (↓ GFR) → ↑ renin → ↑ angiotensin 2 → ↑ aldosterone → HTN
- Most common cause of 2° HTN in adults
- Unilateral vs. bilateral RAS:
- Unilateral: affected kidney can atrophy → asymmetric kidney size; renal venous sampling will show ↑ renin in affected kidney, ↓ renin in unaffected kidney
- Bilateral: patient starts an ACE inhibitor, ARB, or renin inhibitor (e.g. aliskiren) → interferes with RAAS-mediated renal perfusion → sudden ↑ creatinine (hence ACE inhibitors are used with caution in bilateral renal artery stenosis due to the ↓ GFR (and these patients already have ↓ GFR, so further ↓ GFR can precipitate renal failure)
- Presentation:
- severe/refractory HTN
- flash pulmonary edema (comes on acutely)
- epigastric/flank bruit
- patients with RAS may also have stenosis in other large vessels
Atherosclerotic plaques
- proximal 1/3 of renal artery
- usually in older males, smokers
Fibromuscular dysplasia
- distal 2/3 of renal artery or segmental branches
- usually young or middle-aged females
Angiomyolipoma
- A hamartoma of the kidney composed of blood vessels, smooth muscle, and fat
- Common finding in patients with tuberous sclerosis (neurocutaneous disorder)
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Kidney stones
Calcium
Calcium oxalate
- most common cause is idiopathic hypercalciuria (must exclude hypercalcemia and related causes, also Crohn's)
- Treatment: Treat with hydrochlorothiazide (calcium sparing diuretic)
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Ammonium magnesium phosphate (struvite)
- caused by Proteus spp. and Klebsiella; both are urease(+) organisms, which alkalinize the urine, causing precipitation of the stone
- Treatment: Surgical removal (stones are usually too large to pass); eradication of underlying infection
Uric acid
- radiolucent
- risk factors:
- Hot, arid climates
- ↓ urine volume
- ↓ (acidic) urine pH
- Hyperuricemia (gout, Lesch-Nyhan, tumor-lysis syndrome)
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Renal cyst disorders
Autosomal dominant polycystic kidney disease (ADPKD)
- in adults "ADults"
- Due to mutations in APKD1 (chromosome 16) and APKD2 (chromosome 4)
- associated with:
- berry aneurysms
- hepatic cysts
- mitral valve prolapse
- e.g. patient with family history of renal disease who died of renal disease or brain hemorrhage; would expect berry aneurysms, hepatic cysts, and MVP
Autosomal recessive polycystic kidney disease (ARPKD)
- in infants
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Glomerular diseases
Nephritic syndrome
(inflammatory)
- protein + blood in urine (hematuria, :!: RBC casts in urine)
- decreased GFR → oliguria (low urine output), azotemia (high BUN, creatinine, often with oliguria)
- increased renin release → HTN
- proteinuria too but less than nephrotic (<3.5g/day); in severe cases can be in nephrotic range
Acute PSGN (postinfectious glomerulonephritis when non-strep)
- neutrophilic inflammation of the glomerular tuft
- dark urine (tea/cola color)
- most often in kids
- GAS pharyngitis or skin infection → 2-4 weeks pass → peripheral + periorbital edema, tea or cola-colored urine, HTN → resolves spontaneously in most kids; in adults → may progress to renal insufficiency
- type 3 HS rxn
- positive strep titers/serologies
- ↓ complement levels (C3) due to consumption
- Histo
- LM: glomeruli enlarged and hypercellular (A in image)
- IF: (“starry sky”) granular appearance (“lumpy-bumpy”) due to deposition of IgG, IgM, and C3 along GBM and mesangium (B in image)
- EM: subepithelial IC humps
- can advance into RPGN with granular IF (due to immune complex deposition); 25% of adult cases progress to RPGN
Rapidly progressive (crescentic) glomerulonephritis (RPGN)
- Poor prognosis (rapidly deteriorating renal function; days to weeks)
- Crescents made of fibrin and plasma proteins (e.g. C3b) with
glomerular parietal cells, monocytes, macrophages accumulating in Bowman's space
- Histo:
- LM: crescent moon shape (see image below)
Goodpasture syndrome
- Linear IF due to antibodies to GBM (antibodies against type 4 collagen) and alveolar basement membrane
- hematuria/hemoptysis
- type 2 HS rxn
- treatment: plasmapheresis
Granulomatosis with polyangitis (formerly Wegener granulomatosis)
- Negative IF/Pauci-immune (no Ig/C3 deposition)
- PR3-ANCA/c-ANCA
Eosinophilic granulomatosis with polyangitis (formerly Churg-Strauss syndrome)
- MPO-ANCA/p-ANCA
Diffuse proliferative glomerulonephritis (DPGN)/lupus nephritis
- often caused by SLE (glomerular deposition of DNA-anti-DNA immune complexes)
- often presents as nephrotic syndrome and nephritic syndrome concurrently (causing hematuria and/or proteinuria)
- granular IF deposits of IgG and irregular subepithelial electron-dense deposits
- can advance into RPGN with granular IF
- Histo
- LM: “wire looping” of capillaries
- IF: granular
- EM: subendothelial, sometimes subepithelial or intramembranous IgG-based immune complexes often with C3 deposition
("wire lupus")
- Note that lupus nephritis is really a broad spectrum of kidney disease in SLE patients, the most severe (and unfortunately the most common) of which is DPGN
IgA nephropathy (Berger disease)
- most common nephropathy worldwide!
- IgA is secreted by mucosal linings so mucosal infection (GI, respiratory) → IgA antibodies made → IgA antibodies form immune complexes that deposit in the mesangium of the glomeruli → type 3 HS glomerulonephritis
- presents as respiratory or GI tract infections → episodic hematuria, flank pain
- can present as PSGN (verify)
- Renal pathology of IgA vasculitis (HSP)
- Histo:
- LM: mesangial proliferatio
- IF: IgA-based IC deposits in mesangium
- EM: mesangial IC deposition
Alport syndrome
- Mutation in type 4 collagen → irregular thinning, thickening, and splitting of GBM →
- eye problems (eg, retinopathy, anterior lenticonus)
- glomerulonephritis → hematuria
- sensorineural deafness
- Most commonly X-linked dominant
- Histo:
- EM: “basket-weave” appearance due to irregular thickening of GBM
“can’t see, can’t pee, can’t hear a bee"
Membranoproliferative glomerulonephritis (MPGN)
• nephritic syndrome that often co-presents with nephrotic syndrome
• both types 1 + 2 exhibit mesangial growth → GBM splitting → thick glomerular basement membrane, "tram track" on H+E and PAS stains
Type 1
- hepatitis B or C infection or idiopathic → subendothelial IC deposits with granular IF
Type 2 ("dense deposit disease")
- C3 nephritic factor (IgG autoantibody that stabilizes C3 convertase) → persistent activation/overactivation of complement → ↓ C3 levels → dense intramembranous deposits
Focal glomerulonephritis
• on microscopy shows inflammation involving < 1/2 glomeruli with other normal glomeruli present
Nephrotic syndrome
(massive proteinuria; >3.5g/day)
- just protein in urine (little blood if any)
- protein imbalances/blood abnormalities (proteins lost in urine and what that causes):
- Loss of albumin → hypoalbuminemia → pitting edema → soft tissue compromise → ↑ risk of infection
- Loss of immunoglobulins → hypogammaglobulinemia → ↑ risk of infection
- Hyperlipidemia and hypercholesterolemia (may result in fatty casts in urine)
- Loss of antithrombin 3 → hypercoagulable state
Minimal change disease/lipoid nephrosis
- idiopathic (most often) OR recent infection, immunization, immune stimulus (can also rarely be caused by Hodgkin's lymphoma, e.g. cytokines produced by Reed-Sternberg cells damage podocytes) → effacement of podocyte foot processes that is only seen on EM (looks normal on LM) → excessive proteinuria → hypoalbuminemia → decreased intravascular oncotic pressure → edema (e.g. dependent edema in the butt, lower back, legs), foamy or dark urine
- Most common cause of nephrotic syndrome in children
- 1° disease has excellent response to corticosteroids
- Histo:
- LM: Normal glomeruli (lipid may be seen in PCT cells)
- IF: negative (nothing seen?)
- EM: effacement of podocyte foot processes
PAS-stained biopsy (shows a NORMAL glomerulus):
Focal segmental glomerulosclerosis (FSGS)
- more common in Black people (commonly associated with sickle cell disease); most common cause of nephrotic syndrome in Hispanics too
- also associated with:
- opioid use (e.g. heroin)
- HIV
- sickle cell
- obesity, interferon treatment, congenital malformations
- can also be idiopathic (1°) - 1° disease has inconsistent response to steroids, may progress to CKD
- segmental sclerosis of glomeruli → proteinuria, putting edema
- Histo:
- LM: segmental sclerosis + hyalinosis
- IF: often negative, but can be + for nonspecific focal deposits of IgM, C3, Cl
- EM: effacement of foot processes (similar to minimal change disease)
Membranous nephropathy/membranous glomerulonephritis
- can be 1° (e.g. due to antibodies against phospholipase A2 receptor) → poor response to steroids, may progress to CKD
- can also be 2° to drugs (eg, NSAIDs, penicillamine, gold), infections (eg, HBV, HCV, syphilis), SLE, or solid tumors
- Histo:
- LM: diffuse capillary and GBM wall thickening
- IF: granular due to IgG immune complex (IC) deposition along GBM
- EM: “Spike and dome” appearance of subepithelial deposits
Amyloidosis
- Kidney is the most commonly involved organ (systemic amyloidosis) → nephrotic syndrome
- Associated with chronic conditions that predispose to amyloid deposition (eg, AL amyloid, AA amyloid, prolonged dialysis).
- Histo:
- LM: Congo red stain shows apple-green birefringence under polarized light due to amyloid deposition in the mesangium
See Pathoma Ch. 1-2 notes on Amyloidosis
Diabetic glomerulonephropathy/glomerulosclerosis
- Hyperglycemia → nonenzymatic glycation of tissue proteins (GBM + efferent arterioles; note that there is preferential involvement of the efferent arterioles) → mesangial expansion, GBM thickening and increased permeability (glomerular hyperfiltration injury → glomerular HTN and ↑ GFR) → glomerular hypertrophy and glomerular scarring (glomerulosclerosis) → further progression of nephropathy
- Progression: microalbuminuria (small ↑ in albumin level in urine) → eventually progresses to nephrotic syndrome → macroalbuminuria → ESRD (Most common cause of ESRD in the US)
- Histo:
- LM: Mesangial matrix expansion, GBM thickening, eosinophilic nodular glomerulosclerosis
- Kimmelstiel-Wilson lesions in glomeruli; caused by the glomerular hyperfiltration injury (the nodules are the acellular accumulations seen in the mesangium)
- can cause a ↓ renin state (not sure why?)
- ACE inhibitors can slow progression of hyperfiltration-induced damage
Kimmelstiel-Wilson lesions:
ESRD
- Echinocytes (“burr cells”)
- Treatment: dialysis or kidney transplant
Nephritic-Nephrotic syndrome
• can occur with any nephritic syndrome, but most common with DPGN and MPGM
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Urinary incontinence
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Overflow incontinence
1.
- can be due to pelvic nerve damage (pelvic nerve plexus) → pelvic sympathetic nerves in the plexus damaged → cannot contract the bladder (muscarinic Ach receptors); sympathetic nerves in the plexus damaged → cannot relax the internal urethral sphincter (alpha-1 adrenergic receptors)
- Findings:
- distended bladder
- absence of micturition reflexes
- bladder fills to capacity, overflow of urine through urethra a few drops at a time
Pyelonephritis
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Chronic pyelonephritis
- Classic pattern of damage:
- Cortical scarring with blunted calyces
- When it is due to vesicoureteral reflux (seen in children): scarring at specifically the upper and lower poles
- can be caused by
- Vesicoureteral reflux
- Obstruction (e.g. BPH or cervical carcinoma (adults); cervical cancer invades bladder to cause obstruction)
- can cause "thyroidization" of the kidney, where eosin-filled atrophic tubules resemble thyroid follicles; waxy urinary casts are often associated with thyroidization
"thyroidization" of the kidney:
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Renal tumors
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Malignant
Renal cell carcinoma
- It arises from the kidney tubules
- Classic triad:
- hematuria (most common symptom)
- palpable mass
- flank pain
- associated w/ von-Hippel-Lindau syndrome or sporadic deletion of the VHL tumor suppressor gene (3p) → causes ↑ IGF-1 (promotes growth) and ↑ HIF transcription factor (increases VEGF and PDGF to promote angiogenesis)
- most common variant: Clear cell type
Clear cell carcinoma
• associated with gene deletion on chromosome 3 (sporadic, or inherited as von Hippel-Lindau syndrome).
Nephroblastoma (Wilms tumor)
- most common malignant renal tumor in children; average age is 3 years
- 90% sporadic
- may be part of various sydromes
- cell composition:
- Blastema (immature kidney mesenchyme)
- primitive glomeruli and tubules
- Stromal cells
WAGR complex
- Wilm's tumor, Aniridia (partial or complete absence of the iris), Genital abnormalities and mental and motor Retardation
- associated with deletion of the WT1 gene
Denys-Drash syndrome
- Wilms tumor, progressive renal disease, male pseudohermaphroditism
- associated with WT1 mutations
- Mnemonic: like "Denny dash," hurry to go to bathroom at Denny's, GU tract involved
Beckwith-Wiedemann syndrome
- Wilms tumor, neonatal hypoglycemia, muscular hemihypertrophy and organomegaly (including tongue)
- Mutations in the WT2 cluster, particularly IGF-2
- Mnemonic: "Wide man" genes are size "2" and not "1"; so wide on one side of hyphen, like imbalanced muscles
Urothelial carcinoma of the bladder (transitional cell carcinoma)
- most common type of lower urinary tract cancer
- risk factors:
- Cigarette smoke (major risk factor)
- Naphthylamine
- Azo dyes
- Long-term cyclophosphamide
- "Field defect" refers to the fact that tumors are multifocal and often recur
Papillary type
Flat type
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Genetic renal defects
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Hartnup disease
- Deficiency of neutral amino acid (eg, tryptophan) transporters in proximal renal tubular cells and on enterocytes → aminoaciduria and ↓ absorption from the gut → ↓ tryptophan for conversion to niacin → pellagra-like symptoms
- Treat with high-protein diet and nicotinic acid
RAAS:
- Renin is secreted by juxtaglomerular cells of kidney
- Renin takes angiotensinogen → angiotensin 1
- ACE takes angiotensin 1 → angiotensin 2
What does angiotensin 2 do?
- acts on angiotensin 2 receptor type 1 → vasoconstriction → ↑ blood pressure
- constricts efferent arteriole → ↑ filtration fraction → preserves GFR when renal blood flow ↓
- ↑ Na+/H+ antiporter activity in PCT → reabsorb more Na+ (and this reabsorb more water), secrete more H+ (and thus reabsorb more HCO3-/bicarb) → allows for contraction alkalosis (increase in blood pH after fluid loss/volume contraction)
- volume loss (vomiting, diuretics, etc.) → RAAS responds to low blood volume states, so RAAS activated (↑ aldosterone) → ↑ bicarb reabsorption, ↑ H+ secretion → worsens the already high bicarb
- acts on adrenal glands to ↑ aldosterone secretion
- acts on posterior pituitary to ↑ ADH/vasopressin/AVP secretion (→ ↑ water reabsorption via aquaporins)
- acts in hypothalamus to ↑ thirst
What does aldosterone do?
- acts on alpha intercalated cells in collecting duct → ↑ H+ATPase activity → ↑ H+ secretion (which ↑ bicarb reabsorption)
- acts on principal cells in collecting duct → ↑ Na+/K+ATPase → ↑ Na+ reabsorbed, ↑ K+ secreted → ↑ blood volume (and thus ↑ blood pressure), etc.
- acts on ENaC in principal cells (in collecting duct) → ↑ Na+ reabsorption
- also ↑ K+ conductance in collecting duct principal cells (not sure what this means but → ↑ K+ secretion)
- released in low volume (hypovolemic) states, as well as in hyperkalemic states
so overall main effects of aldosterone: ↑ blood pressure, loss of K+, ↑ serum Na+, loss of H+
What activates RAAS?
- ↓ blood pressure (renal baroreceptors detect)
- ↓ NaCl delivery (macula densa cells detect)
- ↑ sympathetic tone (beta1 receptors detect)
- ↓ GFR
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GBM = glomerular basement membrane
EM = electron microscopy
LM = light microscopy
IF = immunofluorescence
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- Blood flow autoregulation allows organs to receive the same perfusion/flow across a wide range of pressure; in the kidneys this is done through 2 mechanisms:
1) myogenic response: afferent arterioles constrict when they sense greater stretch forces (high BP)
2) tubuloglomerular feedback: ↑ arterial pressure (BP)→ hyperfiltration (↑ GFR) → ↑ NaCl delivery to macula densa → macula densa secretes vasoactive mediators (e.g. adenosine) to constrict the afferent arterioles
- Thus in chronic HTN, there is a baseline constriction of afferent arterioles → shifts renal autoregulation curve right → kidneys receive less blood flow at any given BP (thus don't lower BP quickly in these patients, as that can precipitate ATN
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Hypoventilation (retain CO2)
- airway obstruction
- acute or chronic lung disease
- opioids, sedatives
- COPD
- weakening of respiratory muscles
(so either low respiratory drive centrally due to something in the brain (e.g. opioid overdose, trauma, neurodegenerative disorders) or caused by a 1° lung problem)
- also sleep (induces mild respiratory acidosis, which activates complement system in PNH BUT confirm this because I haven't seen it outside Duke Pathoma)
GOLDMARK:
- Glycols (ethylene glycol, proplyene glycol)
- Oxoproline (toxic metabolite of acetaminophen)
- Lactate (lactic acidosis)
- D-lactate (exogenous lactic acid)
- Methanol (and other alcohols); also alcoholism!
- Aspirin (late effect)
- Renal failure (uremia)
- Ketones (diabetic, alcohol, starvation) e.g. DKA
- also rhabdomyolysis
orMUDPIIILES:
- Methanol toxicity; e.g. alcoholism!
- Uremia
- Diabetic ketoacidosis (DKA)
- Paraldehyde
- Isoniazid or Iron overdose
- Inborn error of metabolism
- Lactic acidosis
- Ethylene glycol toxicity
- Salicylate toxicity
HARDASS:
- Hyperchloremia/hyperalimentation
- Addison disease
- Renal tubular acidosis (RTA); see below
- Diarrhea (lose a lot of bicarb)
- Acetazolamide
- Spironolactone
- Saline infusion
- note that these conditions will likely have alkaline urine (because losing bicarb in urine)
Hyperventilation (lose CO2)
- Anxiety/panic attack
- Hypoxemia (e.g. high altitude)
- Salicylates (e.g. aspirin); early effect
- Tumor
- Pulmonary embolism (PE)
- Pregnancy (compensated respiratory alkalosis; due to ↑ minute ventilation due to progesterone acting as a respiratory stimulant)
Acid (H+) loss/bicarb excess
- Loop diuretics, also thiazide diuretics
- Vomiting (lose stomach acid)
- Antacid use (neutralize stomach acid)
- Hyperaldosteronism (aldosterone causes you to lose H+)
- Liddle syndrome (lose K+ so more K+/H+ exchange to compensate → lose H+)
- Cystic fibrosis (loss of Na+ in sweat → RAAS activated → ↑ aldosterone → K+/H+ wasting → hypokalemia, metabolic alkalosis)
aka things that cause contraction alkalosis (increase in blood pH after fluid loss/volume contraction):
volume loss (vomiting, diuretics, etc.) → RAAS responds to low blood volume states, so RAAS activated (↑ aldosterone) → ↑ bicarb reabsorption, ↑ H+ secretion → worsens the already high bicarb
FSGS
Membranous nephropathy
- note the thick glomerular basement membranes
Membranous nephropathy subepithelial deposits on EM, 'spike and dome'
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Azotemia = above-normal BUN or serum creatinine concentrations
Uremia = marked azotemia plus clinical signs such as lethargy, depression, reduced appetite, and vomitingSourceSo in my understanding: azotemia is a sign of potential future problems, whereas uremia is a sign that damage has already happened
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