Renal Flashcards
Filtration and ultrafiltrate
Filtration by glomerulus forms ultrafiltrate –> same composition of blood except for protein and cells
Sequential renal blood flow
Aorta –> Renal artery –> Interlobar arteries –> arcuate artery –> interlobular artery –> afferent arteriole –> glomerular capillaries –> efferent arteriole –> post glomerular capillaries –> venules –> interlobular vein –. Arcuate vein –> interlobar vein –> renal vein
Glomerular and postglomerular capillaries
2 capillary beds
Glomerular = filtration
Postglomerular = Absorption
Electrical charge and filtration barriers
Negatively charged substances pass less regularly than positve
Electrostatic restriction
More prominent role? Electrostatic restriction or size restriction
Electrostatic
Hallmark of gomerular injury and why?
Protein in urine
Filtration barrier damaged and more protein being filtered than it can be reabsorbed
Parallel arrangement of filtration barrier capillaries
Minimizes hydrostatic pressure drop between entrance and exit
Large surface area for filtration
Filtration forces
Glomerular capillary hydrostatic pressure - filtration
Bowmans Space hydrostatic pressure - Absorption
Bowmans space oncotic pressure = 0 - Filtration
Glomerular capillary oncotic pressure - Reabsorption
Difference between capillaries in Renal vs non renal
Non renal -
Hydrostatic pressure decreases across length Filtration vs reabsorption changes along length
Filtration = Absorption
Renal - Hydrostatic pressure nearly constant Glomerular oncotic pressure increases along length, never higher than hydrostatic pressure
Bowmans space P is constant and oncotic is 0
NEVER ABSORPTION ALONG GLOMERULAR WALL
Increasing GC plasma flow results in —>
More plasma for filtration which slows buildup of proteins in GC –> Lower GC oncotic pressure –> More filtration –> Higher GFR
Forces in peritubular capillaries
Capillary hydrostatic pressure (efferent arteriole)
High Plasma oncotic pressure
Oncotic pressure > hydrostatic pressure = NET FILTRATION
Vasoconstriction of afferent arteriole = ?
Decreased RBF
Decreased GFR
Increased efferent arteriole resistance = ?
Decreases RBF
Increases GFR
Afferent arteriole dilation = ?
Increased GFR
Increased RBF
Nitric Oxide effect on A and E arteriole
A - Dilate
E - Dilate
Prostaglandin I2 effect on A and E arteriole
A - Dilate
E - Dilate
Prostaglandin E2 effect on A and E arteriole
A - Dilate
E - No effect
Angiotensin II effect on A and E arteriole
A - Constrict
E - Constrict
Vasopressin effect on A and E arteriole
A - Constrict
E - Constrict
NE effect on A and E arteriole
A - Constrict
E - Constrict
Endothelin effect on A and E arteriole
A - Constrict
E - Constrict
Thromboxane effect on A and E arteriole
A - Constrict
E - Constrict
ANP effect on A and E arteriole
A - Dilate
E - Constrict/no effect
Autoregulation mechanisms of RBF and GFR
Myogenic
Tubuloglomerular feedback mechanism
Myogenic
Increased constriction if pressure/flow increased
Tubuloglomerular feedback mechanism
Increased GFR –> increased flow through tubule and macula dense –> Paracrine signal from MD to afferent arteriole –> Constriction –> Increased resistance –> decreased hydrostatic pressure –> Decreased GFR
How much of filtered Na load is reabsorbed
>99%
Proximal tubule Na reabsorption %
67%
Loop of Henle Na reabsorption %
Intermediate capacity 25%
Dista nephron (DCT and CCT) Na reabsorption %
Low capacity ~8%
Proximal tubule Na transporters
Na co-transporters
Na/H exchanger
Thick ascending limb Na transporters
NKCC
DCT Na transporters
Na-Cl co trasporter
Collecting duct Na transporter
ENaC
Basolateral membrane Na tranport
Na/K ATPase
Glucose handling early proximal tubule
Apical SGLT2 - Low affinity, high capacity
Na-glu transport Basolateral - GLUT1
Glucose handling late proximal tubule
Apical SGLT1 - High affinity, low capacity 2Na-Glu Basolateral GLUT2
Glucosuria - DM
Amount of glucose exceeds threshold and Tm = glucose excreted in urine
Glucosuria - Defects in NaGlu tranporters
Familial renal Glucosuria
Glucose-Galactose malabsorption syndrome
Familial renal glucosuria
Mutation in SGLT2 decreases transport capacity –> decrease Tm –> glucose excreted
Can result in decreased plasma glucose concentration
Glucose galactose malabsorption syndrome
Mutation of SGLT1 – decrease transport capacity –> slight lower Tm –> mild glucosuria
Can effect gut absorption
Urea diffusion
Urea remains in renal tubules but concentration increases due to water exit –> travels down concentration gradient to renal venous sytem
PAH and Kidney
PAH is filtered and secreted by renal tubules, not reabsorbed
Good measure of Renal plasma flow
[K]ecf
Very closely regulated
3.9 < Normal < 4.5
[K]ecf depends on…
Total body content of K (input - output)
Distribution between ICF and ECF (Na/K ATPase)
Hormones that cause K uptake into cells
Insulin B agonists
Aldosterone
Cause increased activation of Na/K ATPase
pH changes and K
Lower pH = Decrease K uptake
Higher pH = Increased K uptake into cels
Glomerular filtration of potassium
Freely filtered
Kidney reabsorption of K
>90% reabsorbed by proximal tubule and Thick ascending limb
Kidney secretion of K
Distal tubule and CCT
Regulation of K excretion
Occurs in Distal tubule and CCT
Based on levels of K secretion
Proximal tubule K transport
Passive reabsorption H20 reabsorption –> increased K concentration –> K reabsorption down concentration gradient
Loop of Henle K transport
Thick ascending limb Apical NKCC
Basolateral K channel
Collecting tubule and collecting duct K transport - a Intercalated cells
ICT, CCT, MCD
Apical uptake via H/K ATPase Basolateral K channel
Collecting tubule and collecting duct K transport - principal cells
ICT and CCT - active secretion K uptake from peritubular interstitium via basolateral Na/K ATPase
Passive apical K flux
Increased Na/K ATPase activity and K handling
Increased intracellular K concentration –> K secretion
Increased tubular flow and K handing
Secreted K flushed downstream –> Low K concentration in lumen –> Increase K secretion
Increased negative charge of lumen
K secretion due to electrical gradient
K wasting diuretics
Agents that block Na reabsorption by proximal tubule of loop of henle Increased tubular flow in distal tubule and collecting duct = K secretion
K sparing diuretics
Agents that inhibit Na reabsorption in distal nephron
Tubular flow secretion effect minimized because of tubular electrical status (more positive)
Physiological regulation of K excretion
Increased [K] intake –> Increased [K] plasma –> Aldosterone –> Increased distal nephron K secretion –> Increased K excretion Increased [K] intake –> Increased [K] plasma –> Increased distal nephron K secretion –> Increased K excretion
Water handling in proximal tubule
AQP1 in apical and basolateral membrane
Promotes water leaving tubules and entering interstitium
Water handling in Loop of Henle
Descending limb = water reabsorption
Ascending limb - Water impermeable DCT - Water impermeable
No ADH - collecting duct cells
Cells impermeable to water - no basolateral AQP
ADH effect
AQP-2 channels inserted onto apical membrane, cells are water permeable
Net effect of kidney response to water intake
Formation of dilute urine
Proximal tubule - Isosmotic reabsorption of Na/water
Descending limb - Water reabsorption due to increasing medullary osmolarity (via TAL)
Turn of Loop - Concentrated tubular fluid that is isosmotic to medullary intersititum
Ascending limb - Solute reabsorption and fluid becomes hyposmotic
Slight Na reabsorption in distal nephron
NET EFFECT: Low osmolarity urine excreted
Net effect of kidney to dehydration
Requires ADH Formation of dilute urine that reaches distal tubule
CCT - Water permeable tubule comes under effect of intersitial osmolarity –> water reabsorption
Medullary collecting duct - Also water permeable, water reabsorbed
Highly concentrated urine excreted
Synthesis and release of ADH
Synthesized in supraoptic and paraventricular neurons of hypothalamus
Stored in nerve endings in posterior pituitary
ADH regulation - osmoreceptors
increases in plasma osmolarity = ADH release
Small plasma changes = large ADH release
Most sensitive ADH regulator
ADH regulation - baroreceptors
Decrease in blood volume sensed by baroreceptors –> increase ADH release
Need large decrease in blood volume
Other factors that increase ADH secretion
Vomiting
Nausea
Morphine
Nicotine
Cyclophosphamide
Factors that decrease ADH secretion
Alcohol Clonidine Haloperidol
SIADH
Excessive ADH secretion for given plasma osmolarity
Retain water in excess of solute = decreased plasma osmolarity
Diabietes Insipidus
Patients produce large volume of dilute urine Increased plasma osmolarity
Neurogenic - Deficient ADH secretion
Nephrogenic - Insensitivity of kidney tubules to ADH
Actions of AngII
Retention of Na
Vasoconstriction
Promote acquisition and retention of water
AngII retention of Na
Aldosterone activation –> Na reabsorption in collecting duct
Stimulate Na/H exchange –> proximal tubular Na reabsorption
AngII Vasoconstriction
Direct effect on vascular smooth muscle
Increase TPR to increase systemic arterial pressure
AngII promote acquisition and retention of water
Stimulate thirst –> acquire water
Stimulate ADH release from hypothalamus –> water retention
Decrease medullary blood flow
Aldosterone: Stimuli, action, mechanism
Stimuli: Increased AngII, decreased plasma [Na], increased plasma [K]
Action: Increase Na reabsorption by collecting duct
Mechanism: Promote Na entry through apical ENaC and basolateral Na/K ATPase.
PRINCIPAL CELL OF COLLECTING DUCT
Catecholamine: Stimuli, action, mechanism
Stimuli: Activation of SNS
Action: Increase Na reabsorption by proximal tubule
Mechanism: Activate Na/H exchange
Endogenous digitalis like substance: Stimuli, action, mechanism
Stimuli: Increased ECF volume
Action: Decrease Na reabsorption by all nephron segments
Mechanism: Direct effect to inhibit basolateral Na/K ATPase
Glomerular-tubular balance
Proximal tubule reabsorbs constant fraction, 67%, of filtered Na
Increased GFR –> increased oncotic pressure of peritubular capillaries –> increased reabsorption
Reduces impact of increased filtered load on solute/water delivery to distal nephron
Responses to abrupt increase in Na intake
Increased GFR
Decreased Na reabsorption
Factors that increase GFR in response to Na increase
Increased Na = Increased ECF = decreased plasma oncotic pressure = Increased GFR via Starling
Increased arterial pressure –> increased capillary hydrostatic pressure –> increased GFR
Decreased AngII –> decreased arteriolar resistance –> increased RBF/GFR
Increased arterial pressure –> decreased SNS –> decreased arterioloar resistance –> Increased RBF/GFR
Factors that decrease tubular Na reabsorption in response to abrupt increase in Na intake
Decreased AngII –> decreased proximal tubule Na reabsorption (Na/H)
Decreased aldosterone –> decreased Na reabsorption in collecting duct
Decreased sympathetic tone –> decreased Na reabsorption in proximal tubule
Increased blood volume –> increased ANP –> decreased Na reabsorption in collecting duct
Increased endogenous digitalis like substance –> Decreased Na reabsorption
Pressure Natriuresis
Increase in arterial pressure –> Increased Na excretion
Unknown mechanism
IMPAIRED IN HTN
Increased Na intake –> increased ECF volume –> increased arterial pressure –> increased Na excretion –> decreased ECF
Mechanisms of Renin release
- Low blood volume, JG cells secrete renin into circulation
- Decrease in perfusion across macula dense, message sent to JG to secrete renin
- Increased sympathetic activity (B1) via baroreceptors in carotid sinus
ANP stimuli, action, mechanism
Stimuli: Atrial stretch (High ECF)
Action: Decrease Na reabsorption by collecting duct
Mechanism: ENaC inhibitor
ANP actions
- Inhibit vasopressin release in hypothalamus
- Increase GFR a (vasodilation) and decrease Renin
- Inhibit Aldosterone
- Decrease BP via medulla oblongata
- Decrease Na reabsorption via ENaC inhibition
Aldosterone and Potassium
Aldo increases K secretion via compensation for increasing ENaC In collecting duct principal cells
Osmolality definition
Total solute concentration but comprised mainly of Sodium salts
Tonicity
Effective plasma osmolality
Osmolality of solutes that contribute to water distribution
Requirements to excrete excessive free water
Delivery of water/solutes to nephron dilution sites (TAL, DCT)
Proper function of diluting segments (channel function)
No ADH
Requirements for maximal urine concentration (water absorption)
Concentrated medullary interstitium (functioning TAL channels)
Presence of ADH
Normal response to ADH
Osmoregulation of ADH
Serum osmolality sensed by osmoreceptors in hypothalamus
Increase ADH and thirst Increase urine osmolality, water intake
Volume regulation of ADH
Effective tissue perfusion sensed by baroreceptors and macula densa
Activation of RAAS, Aldo, ANP, NE, ADH
Urine sodium and thirst affected
Hypovolemia definition
Decreased fluid volume due to decreased total body Na
Hypervolemia definition
Increased fluid volume due to increased total body sodium
Determinants of Hyponatremia
Plasma tonicity - water distribution
Volume status - Total body Na
Hypertonic hyponatremia osmolar definitions
Posm > 290
PNa < normal
Hypertonic hyponatremia definition/cause
Increased plasma osmolality with decreased Na concentration
Due to other effective osmole causing fluid movement from ICF –> ECF
Hyperglycemia, glycine, mannitol
Hypertonic hyponatremia treatment
Remove underlying cause
Isotonic hyponatremia
Lab artifact
Increased protein/lipid concentration that is sensed as decreased Na concentration
Old lab testing
Brain response to hyponatremia
Immediate effect - water gain (cerebral edema) and altered mental status (low osmolality)
Rapid adaptation - Loss of sodium/K/Cl to reduce edema (low osmolality)
Slow adaptation - Loss of organic osmolytes (low osmolality)
THERAPEUTIC INTERVENTION:
Slow correction = brain returns to normal osmolality
Rapid correction = Osmotic demyelination - no chill
Hypotonic hyponatremia - Definition and types
POsm < 290
PNa < 140
Due to excessive water either because of ADH or impaired water excretion
Hypovolemic Euvolemic Hypervolemic
Hypovolemic hypotonic hyponatremia - Pathogenesis
True volume depletion (ECF loss, Na and water)
ADH stimulation –> water retention –> restored ECF volume but NOT Na
Hypovolemic hypotonic hyponatremia - physical exam
Signs of volume depletion
Flat neck veins
Tachycardia
Hypotension
Orthostatic hypotension
Hypovolemic hypotonic hyponatremia - Causes
Volume losses: GI, blood
Insensible losses - sweating/burns
Renal losses - Loop diuretics, adrenal insufficiency, salt wasting nephropathies
Insensible losses in Hypovolemic hypotonic hyponatremia
Burns and sweating
Low Urine [Na] because RAAS active and Na reabsorption is maximal
Renal losses in Hypovolemic hypotonic hyponatremia
High urine [Na]
Sodium reabsorption not functioning
Euvolemic hypotonic hyponatremia
Euvolemic on exam
SIADH:
High urine Osm
High urine [Na]:
ADH –> water reabsorption –> volume increase –> decrease renin –> decrease RAAS –> decrease Na reabsorption
Primary polydipsia
Cause of euvolemic hypotonic hyponatremia
Excessive water intake that overwhelms excretory capacity of kidney
Urine Osm low due to ADH suppression
Hypervolemic hypotonic hyponatremia
ECF volume excess with decreased intravascular volume
EDEMATOUS STATES
Hypervolemic hypotonic hyponatremia causes - non renal
Heart failure
Liver cirrhosis
Nephrotic syndrome
ADH activated b/c low circulating volume
Urine Osm high b/c ADH
Urine [Na] low b/c RAAS activation
Hypervolemic hypotonic hyponatremia causes - renal
Advanced renal failure
Impaired free water excretion
Effective plasma Osm low b/c water retention
Total Plasma Osm may be high b/c excessive urea
Hypovolemic hypotonic hyponatremia treatment
Correct intravascular volume w/ isotonic fluid
Euvolemic hypotonic hyponatremia treatment
Correct underlying cause
SIADH - Water restrict, increase solute intake, V2 antagonist
Hypervolemic hypotonic hyponatremia treatment
Diuretics
Fluid restriction
Hyponatremia management risks
DO NOT TREAT QUICKLY
Avoid osmotic demyelination syndrome
Hypernatremia definition and general cause
Serum Na >145
Loss of free water
Occurs in patients who cannot express thirst of don’t have access to water
Diabetes insipidus
Decreased ADH action - nephrogenic or neurogenic
Central DI
Neurogenic
Insufficient release of ADH in response to increased Na osmolality
Lesion in hypothalamic osmoreceptors, supraoptic nuclei, or trauma/surgery
Nephrogenic DI
Reduced action of ADH at collecting tubule to due receptor/aquaporin mutation
Lithium
Hypernatremia etiology
Hypotonic fluid loss - Na/water loss but solute concentration is hypotonic to plasma osmolality If free water not replaced –> hypernatremia
Hypertonic sodium gain
4 Mechanisms of K balance
K intake through diet
GI losses (5-10% absorbed K secreted in GI)
Renal losses (90-95% K regulation)
Transcellular K shift (ECF vs ICF distribution)
Renal handling of K - PCT
Freely filtered in glomerulus 65-70% reabsorbed in proximal tubule via passive transport
Renal handling of K - TAL
NKCC channel reabsorption of K
K pumped into lumen in TAL to enhance K recycling and NKCC function
Apical K channel inhibited by ATP - More Na enters cell –> transported out by Na/K ATPase –> low ATP –> apical K activation –> NKCC function and more Na absorbed
Renal handling of K - Principal cell
K transported into cell by Na/K ATPase
Secreted into tubule via ROMK
Principal cell K transport governing factors
- Luminal electrical charge
- Luminal concentration gradient
- K permeability of luminal membrane
4 Main factors that affect K secretion into tubular fluid
- Aldosterone
- Plasma [K]
- Distal flow rate
- Distal Na delivery
Aldosterone and K secretion
Increases # open Na (ENaC) and K (ROMK) channels
Enhances Na/K ATPase activity
Plasma [K] and K secretion
Increased plasma K = enhanced Na/K ATPase activity
Increased # open K & Na channels
Distal flow rate and K secretion
Increased flow = more K washed away = increased K secretion via favorable gradient
Distal Na delivery and K secretion
Na through ENaC = more negative lumen = K secretion More ENaC absorption = more intracellular Na = enhanced Na/K ATPase = more K secreted
a-Intercalated cells and K handling
Reabsorption of K via apical H/K ATPase
Main etiologies of hypokalemia
Transcellular shift
GI losses
Renal losses
Poor intake
Hypokalemia and transcellular shift etiologies
Insulin B2 agonists
Alkalosis
Hypokalemic periodic paralysis
Hypokalemia and insulin
Stimulates Na/K ATPase –> more K secretion
Hypokalemia and B2 agonist
Increase Na/K ATPase activity –> K secretion
Hypokalemia and alkalosis
Alkalosis = high extracellular pH –> H will leave cell –> K enters cell to maintain electroneutrality
Hypokalemic periodic paralysis
Acute attacks precipitated by sudden movement of K into cells
Lowers plasma K significantly
Rest after exercise, stress (catecholamines), high carb meal (insulin)
Familial - autosomal dominant mutation Acquired - Thyrotoxicosis
Hypokalemia - GI losses
Associated with metabolic alkalosis due to HCL loss –> K entry into cells b/c H exit
Concurrent urinary losses: -
Aldosterone activation
Plasma Bicarb increase = too much Bicarb that can be absorbed –> Na pairs with bicarb –> increased distal delivery of Na –> K secretion
Hypokalemia renal losses categories
Metabolic alkalosis
Metabolic Acidosis
Magnesium
Hypokalemia w/ metabolic alkalosis categories
Normo-hypotension
Hypertension
Hypokalemia w/ metabolic alkalosis and normo-hypotension
Diuretics - Loop/Thiazide
Activation of aldosterone by volume depletion Increased distal delivery of Na (blocked absorption more proximally)
Salt wasting nephropathies
Bartters syndrom
THINK LOOP DIURETIC
Defect in solute reabsorption in TAL NKCC2, Luminal K channel, Basolateral Cl channel can be affected
Gitelman’s syndrome
THINK THIAZIDE DIURETIC
Defect in thizide sensitive NaCl cotransporter in DCT
Hypokalemia with metbolic alkalosis - Hypertension
Mineralocorticoid excess:
Primary hyperaldosteronism (adrenal tumor, BAH)
Glucocorticoid remedial aldosteronism
Renal artery stenosis
11BHSD2 deficiency
CAH
Liddle’s syndrome
Gain of function mutation in ENaC
Triad:
Hypertension - Metabolic alkalosis - Hypokalemia
Hypokalemia with metabolic acidosis types
Renal tubular acidosis
Nonreabsorbable anion
Hypokalemia with metabolic acidosis - Renal tubular acidosis
Hyperchloremic, non anion gap metabolic acidosis
- Distal hypokalemic RTA (type I): Impaired distal urine acidification. No protons pumped out = more K secreted
- Proximal (type II): Reduction in bicarb reabsorptive capacity –> all bicarb reabsorbed –> metabolic acidosis that inhibits Na reabsorption –> hypokalemia
Hypokalemia with metabolic acidosis - Nonreabsorbable ion
Non reabsorbable anion paired with Na –> reduced Na –> Increased distal delivery of Na
Diabetic ketoacidosis - Beta hydroxybuterate pairs with Na
Hypokalemia and Magnesium
Hypokalemia occurs in 40-60% of hypoMg diseases
Diseases that waste both K and Mg: Diarrhea, diuretics
Correct Mg to restore K
CV clinical manifestations of Hypokalemia
Cardiac arrhythmias:
Sinus bradycardia, AV block, Vtach/Vfib
Decrease amplitude of T wave, increase U wave amplitude
Muscular clinical manifestations of hypokalemia
Weakness and muscle cramps
Low K = hyperpolarized skeletal muscle cells = impaired contraction
Reduce blood flow by impairing NO release
Severe K depletion = respiratory weakness –> respiratory failure GI muscle weakness = ileus
Hormonal clinical manifestations of hypokalemia
Impaired insulin release and end organ sensitivity to insulin
Worsened glucose control in diabetic patients
Renal clinical manifestations of hypokalemia
Tubulointerstitial and cystic changes in parenchyma
Polyuria: Increased thirst and mild nephrogenic DI, concentrating ability impaired
HTN: Increased renal vascular resistance
Hypokalemia diagnosis: Metabolic acidosis + Low urinary K:creatinine
Stool losses
Hypokalemia diagnosis: Metabolic acidosis + High urinary K:creatinine
RTA
Nonreabsorbable ion
Hypokalemia diagnosis: Metabolic alkalosis + Low urinary K:creatinine
Vomiting
Hypokalemia diagnosis: Metabolic alkalosis + High urinary K:creatinine
Check BP and volume status
Low-normal BP/volume depleted - diuretics, salt wasting nephropathies
High BP/volume overload - Mineralocorticoid excess, Liddle’s
Main etiologies of hyperkalemia
Transcellular shift
Psuedohyperkalemia
Renal - Decreased urinary excretion
Pseudohyperkalemia
Elevation in measured serum K due to K movement out of cells during/after blood draw
Hemolysis Thrombocytosis Leukocytosis
Hyperkalemia transcellular shift - etiologies
Metabolic acidosis
Hyperglycemia and hyperosmolarity
Nonselective B antagonists
Exercise
Tissue breakdown
Digitalis toxicity
Hyperkalemic familial periodic paralysis
Hyperkalemia - metabolic acidosis
H will enter cell in order to buffer extracellular pH –> K will leave and enter ECF/blood vessels
Hyperkalemia - hyperglycemia/hyperosmolarity
Elevation in serum osmolality = H20 movement from ICF –> ECF = More K in cell –> K will move out of cell
Hyperkalemia - non selective B antagonists
Interfere with K uptake by B receptors
Hyperkalemia - Tissue breakdown
Rhabdomyolysis
Lysis of large tumor burden after chemo
Burns
Hyperkalemia and digitalis
Block Na/K ATPase
Hyperkalemia - renal etiology categories
Renal failure
Volume depletion with decreased distal Na delivery
Functional hypoaldosteronism
Hyperkalemia - renal failure
Able to maintain K with distal flow rate and aldosterone secretion is maintained
Hyperkalemia occurs in patients with decreased flow rate + excess K load/Aldo blocker
Hyperkalemia - decreased distal delivery of Na with volume depletion
Hypovolemia
Effective arterial volume depletion with ECF excess
Heart failure/liver cirrhosis
Hyperkalemia - functional hyoaldosteronisms
Low aldo or resistance to aldo effect
Mineralocorticoid deficiency: primary adrenal insufficiency, hyporeninemic hypoaldosteronism (low renin/aldo)
Tubulointerstitial disease: Sickle cell and urinary tract obstruction -
Distal hyperkalemic RTA - Impaired Na reabsorption reducing K/H secretion
Drug MoA that result in hyperkalemia
Block aldo activity - ACE-I, ARB, Aldo antagonists
Decreased renin release - B blocker, NSAIDs
Bind to ENaC - Amiloride, triamterene Calcineurin inhibitors
Clinical manifestations of hyperkalemia
Severe muscle weakness/paralysis
Cardiac arrhythmias/ECG abnormalities: BBB, AV block, sinus bradycardia, sinus arrest, Vtach/fib
Early - Tall T waves, short QT
Late - prolonged PR/QRS
Hyperkalemia diagnosis - High renin/low aldo
Adrenal insuffieciency
Hyperkalemia diagnosis - Low renin and aldo
Type IV RTA
Diabetic nephropathy
Hyperkalemia diagnosis- normal renin/high aldo
Aldo resistance
Tubuloinsterstitial disease - sickle cell/urinary obstruction
Treatment methods for hyperkalemia
Antagonizing membrane effects of K with Ca
Drive ECF K into cells
Remove excess K from body
Hyperkalemia treatment - Antagonize membrane effects of K with Ca
ONLY for patients with ECG changes or acute rise in serum K
CaCl2
Hyperkalemia induces membrane depolarization and inactivation of Na channels –> Ca antagonizes this effect
Hyperkalemia treatment - Drive K into cells
Insulin + glucose:
Insulin will activate Na/K ATPase, glucose prevents hypoglycemia
B2 agonist: Stimulate Na/K ATPase
Hyperkalemia treatment - K removal - Diuretics
Diuretics: Loop/thizides.
Combine with saline to maintain distal Na delivery and distal flow rate
Hyperkalemia treatment - K removal - Cation exchange resins
Uptake of K in exchange for cation
Hyperkalemia treatment - K removal - dialysis
Warranted when other measures are ineffective
Use when K rises too rapidly
Acute Kidney injury - definition
Abrupt loss of kidney function Retention of urea and other nitrogenous waste products Dysregulation of extracellular volume and electrolytes
AKI general categories
Pre renal
Intrinsic renal
Post renal
Pre renal AKI - major causes
True volume depletion
Decreased effective arterial blood volume
Pre renal AKI - true volume depletion
Loss of Na from ECF
GI losses, hemorrhagic shock, renal losses, cutaneous losses
Pre renal AKI - decreased effective arterial blood volume
Increased ECF but decreased blood volume sensed by baroreceptors –> edematous states: HF, cirrhosis, sepsis
Pre renal AKI GFR
Renal perfusion decreases –> homeostatic mechanisms activated
Afferent arteriolar vasodilation
Efferent arteriolar vasoconstriction
Increased filtration fraction = increased post glomerular oncotic pressure = increased salt/water
Activation of AngII and ADH = Low urine Na and concentrated urine
Pre renal AKI history/chart review
Vomiting Diarrhea GI bleed
HF, liver disease, sepsis
Pre renal AKI physical exam
Orthostatic hypotension, skin tenting, dry mucous membranes
Elevated JVP, edema, hypotension
Pre renal AKI lab workup
BUN:Creatinine >20:1
Urine osmolality > 500
Urine Na <10 Urine Cl <10
Urinalysis: No protein/blood/WBC, no casts no cells
FENa
Measures percent of filtered Na excreted in urine
<1% = patient will be responsive to volume therapy
Intrinsic Renal AKI types
Tubulointerstitial Vascular Glomerular
Acute tubular necrosis - Definition, affected area, risk factors
Most common cause of acute intrinsic kidney injury
Patch necrosis of proximal tubule and TAL: High metabolic activity so very sensitive to changes in renal perfusion
Risk factors: Volume depletion, CKD, NSAIDs, DM
Pathophysiology of acute tubular necrosis
Endothelial/epithelial injury
Intratubular obstruction
Changes in microvascular blood flow
Immunological factors
Tubular cells damaged so cannot absorb salt/water –> increased delivery of salts to macula densa –> afferent vasoconstriction to reduce salt wasting
No TGF = salt wasting and volume depletion = DEATH
Causes of acute tubular necrosis
Ischemia - Low BP, volume depletion, sepsis
Toxin - Radiocontrast media (risk with CKD, DM, hypotension)
Toxins
History/chart review for acute tubular necrosis
Prolonged hypotension in ICU –> ischemia
Radiocontrast exposure
Sepsis (infections)
Drugs - aminoglycosides, amphotericin B
Crush injuries
Acute tubular necrosis lab evaluations
BUN:Creatinine = 10-15:1
Urine Na and Cl >20
FENa >2% (more filtered Na being excreted)
Urine osm <450 May have low grade proteinuria (deficient protein reabsorption in proximal tubule)
Casts and epithelial cells
Acute interstitial nephritis definition and main causes
Inflammatory cell infiltration in kidney interstitium caused by immune response -
Medication -
Autoimmune -
Infection
Acute interstitial nephritis drug causes
NSAIDs Penicillins Cephalosporins Sulfonamides Rifampin Cipro PPI
Acute interstitial nephritis autoimmune and infection causes
Sjogrens Sarcoidosis Legionella, leptospira, CMV
Acute interstitial nephritis clinical presentation
Rash, fever, eosinophilia
Full triad only in ~10% patients
Acute interstitial nephritis lab evaluation
Acute rise in serum creatinine that temporarily correlates with drug administration
Peripheral eosinophilia
Eosinophiluria
Proteinuria
WBC and WBC casts
Acute tubular obstruction
Precipitation of substances in tubules:
Immunoglobulins
Calcium phosphate
Urate
Intratubular crystal precipitations from medications
Volume depletion and acidic urine
Acute tubular obstruction - Cast nephropathy
Occurs in multiple myeloma
Overproduction of immunoglobulin light chains that get filtered into urine, can block tubule
Acute tubular obstruction - Tumor lysis syndrome
Occurs following chemotherapy
Dead tumor cells release chemicals Intracellular release of uric acid, phosphate, potassium –> all levels high in blood
Acute tubular obstruction - phosphorus containing enemas
Bowel preparation for colonoscopy
Acute calcium deposition in tubules with associated interstitial inflammation
Highest risk in patients with underlying CKD
Lab evaluation - tumor lysis syndrome
Elevated serum uric acid, potassium, phosphorus
Lab evaluation - phosphate nephropathy
High phosphorus
Low calcium
Lab evaluation - Cast nephropathy
Elevated free light chains in serum
Vascular intrinsic renal disease causes
Renal atheroembolic disease
Vasculitis
Thrombotic microangiopathies
Renal atheroembolic disease
Occurs in patients with atherosclerotic disease who undergo aorta/large artery manipulation –> plaque breaks off and can occlude multiple small arteries
Low serum complement, eosinophilia, rash
Intrinsic vascular renal disease - vasculitis
Inflammation and necrosis of small arteries
Thrombotic microangiopathies
Endothelial injury –> platelet thrombi occluding small vessels –> ischemia Low platelets, hemolytic anemia -
HUS -
Thrombotic thrombocytopenia purpura -
Malignant HTN
Schistocytes (RBC fragments)
Post renal disease - obstructive uropathy
Obstruction of the flow of urine anywhere from renal pelvis to urethra
Calculi
Anatomic abnormalities (children)
BPH
Urethral stricture
Malignancy
Proteinuria and hematuria = ?
Glomerular disease
Muddy brown casts in sediment review
Acute tubular necrosis
White Blood cell casts in sediment review
Acute interstitial nephritis
Dysmorphic RBC, RBC casts, WBC casts in sediment review
RPGN
AKI complications - uremia
Nausea
Vomiting
Anorexia
Dysguesia
Altered cognition
Pericarditis
AKI electrolyte abnormalities
Hyperkalemia (aminoglycosides and cisplatin = hypokalemia via increased flow)
Metabolic acidosis
ECF volume excess
Renal causes of Secondary HTN
Renovascular HTN
Renal parenchymal HTN
Renovascular HTN
HTN caused by renal artery stenosis
Atherosclerosis (75-90%)
Fibromuscular dysplasia (10-25%)
Renovascular HTN pathophysiology
Reduced renal perfusion –> RAAS activation –> AngII mediated vasoconstriction, ADH, Aldo
Renovascular HTN patient history/physical exam
Onset in 3-5th decade = FMD
>55yo = Atherosclerotic disease
Sudden onset of uncontrolled HTN
Malignant HTN
Physical: Epigastric bruit
Acute unexplained rise in serum creatinine induced
Asymmetric renal size
Renovascular HTN lab evaluation and imaging
Elevated renin and Aldosterone
MRA to asses vessels, contraindicated in high stage CKD
Renovascular HTN treatment - FMD
BP meds Lipid lowering meds
FMD - ACE-I or ARB –> percutaneous transluminal angioplasty if ineffective
Renovascular HTN treatment - atherosclerotic disease
ACE-I or ARB Lipid lowering meds
Anti platelet therapy
Renal Parenchymal HTN
Common feature in acute and CKD
Renal parenchymal HTN - Acute glomerular disease
Volume overload and suppression of RAAS
Renal parenchymal HTN - acute vascular disease
Ischemic activation of RAAS
Renal parenchymal HTN - CKD
Multifactorial pathogenisis
Volume expansion via Na/water retention SNS activation RAAS activation
Secondary hyperPTH Endothelial cell dysfunction
Renal parenchymal HTN - CKD treatment
ACE-I/ARB slow GFR decline
Diuretic for volume removal
CCB if neeed
Primary hyperaldosteronism
Autonomous production of aldosterone
Adrenal adenoma
Bilateral adrenal hyperplasia
Adrenal carcinoma
Triad: HTN, unexplained hypokalemia, metabolic alkalosis
Primary hyperaldosteronism diagnosis
[Plasma aldosterone] : Plasma renin activity Ratio >35-50 and PAC >15 = primary hyperaldosteronism
Discontinue aldo antagonists for accurate results
Primary hyperaldosteronism confirmatory testing
Na loading test: If Aldo still high then primary hyperaldosteronism
Isotonic saline administration: Aldo should fall <5
Primary hyperaldosteronism treatment - unilateral adenoma, BAH
Unilateral adenoma - Laparoscopic surgical removal
BAH - Spironolactone/other aldo antagonists
Cushings syndrome
Excess exogenous or endogenous glucocorticoids
Exogenous administration
Endogenous: Pituitary adenoma, ectopic ACTH production, adrenal adenoma
Cushings syndrome clinical features
Centripetal obesity
Moon facies
Skin atrophy/abdominal striae
Acne and hirsutism
Proximal muscle weakness
HTN
Glucose intolerance
Cushings syndrome diagnosis
24hr urinary cortisol excretion
Late evening salivary cortisol
Low dose dexamethasone suppression test
Cushings syndrome treatment
Cushings disease/pituitary adenoma - Irradiation or resection
Adrenal tumor/ectopic ACTH - Removal
Pheochromocytoma
Catecholamine secreting tumor
Headache, sweating, palpitations
Diagnosis: - Urinary catecholamines - Fractioned plasma metanephrines
Pheochromocytoma treatment
Surgical removal of tumor BP control before surgery -
Phenoxybenzamine/Phenotlamine -
Beta blockers after adequate alpha blockade
Obstructive sleep apnea
Obesity, obstructive sleep apnea and HTN association
SNS abnormalities
Treatment: Weight loss
CPAP
Uvulopalatopharyngoplasty
CKD definition
Presence of EITHER: Kidney damage
Decreased kidney function for > 3 months with decreased GFR
Clinical markers of kidney damage in CKD
Proteinuria - >150mg protein, >30mg albumin
Glomerular hematuria
Imaging - polycystic kidney disease, hydronephrosis, small kidney w/thinned cortices
Creatinine: Definition, use, limitations
Metabolism of creatine in skeletal muscle and dietary meat
Freely filtered, not absorbed
Limitations: Little muscle mass, Secretion by organic pathway in PCT, Does not detect early GFR changes
CKD stages
Stage I: Kidney damage w/normal GFR
Stage II: Kidney damage w/ mild decreased GFR
Stage III: Moderate GFR decrease (30-59)
Stage IV: Severe GFR decrease (15-29)
Stage V: Kidney failure. <15
CKD causes - tubulointerstitial diseases
PKD
Autoimmune: Sjogrens, Sarcoidosis
Reflux Nephropathy
CKD - PKD
Autosomal dominant polycystic kidney disease
Will progress to kidney failure
CKD autoimmune disease
Sjogrens Sarcoidosis: Inflammatory infiltrates in tubulointerstitium
CKD reflux nephropathy
Vesicouteral reflux
Passage of urine from bladder to upper urinary tract
Inadequate closure of ureterovesical junction
CKD vascular causes
Hypertensive vasculopathy - chronic HTN –> thickening and narrowing of large arteries and glomerular arterioles
Renovascular disease - Renal artery stenosis
Renal atheroembolic disease - Emboli caused by large artery manipulation
CKD glomerular disease
Diabetic nephropathy
Nephritic/nephrotic
CKD post renal causes
Obstructive uropathy
Prolonged obstruction –> parenchymal loss
Loss of nephron mass due to compression from reflux of urine
Pathophysiology of CKD
Initial damage to kidney (tubulointerstitial, vascular, glomerular, obstructive) –> renal function maintained by hyperfiltration –> ongoing hyperfiltration –> glomerular capillary HTN –> cytokine activation and podocyte dysfunction –> proteinuria/glomerular sclerosis/tubulointerstitial fibrosis –> renal scarring
CKD and diabetes mellitus clinical characteristics
Glomerulopathy: mesangial expansion, BM thickening, glomerulosclerosis
Hyperfiltration and golmerular capillary HTN
Microalbuminuria
Overt proteinuria
Pathogenesis of diabetic nephropathy
Glomerular hyperfiltration
Hyperglycemia and AGE’s
Elevated prorenin
Impaired podocyte-specific insulin signaling
CKD consequences - Hypertension
Present in 80-85% CKD
Na retention
SNS activation
RAAS activation
Secondary hyperPTH –> increased Ca –> vasoconstriction Impaired NO synthesis so reduced vasodilation
CKD consequences - mineral bone disorder
Decreased GFR = decreased phosphorus excretion Increased phosphorus = FGF23 increase (to excrete phosphorus) –> FGF23 inhibits 1a-hydroxylase –> decreased calcitrol
Decreased calcitrol –> decreased intestinal Ca absorption –> PTH increase
Vascular calcification
Renal osteodystrophy
Consequences of CKD - anemia
Kidney damage = decreased erythropoetin
Risk factors for CKD –> ESRD
Proteinuria HTN
Underlying disease
AA
Male
Obesity (increased glomerular capillary pressure)
Dyslipidemia
SMoking
Hyperphosphatemia
Metabolic acidosis: Bicarb supplementation = good
High protein diet (increased capillary pressure)
Hyperuricemia
Interventions that slow CKD progression
BP control
Renin-angiotensin-aldosterone antagonism -
Reduce BP - Decrease glomerular capillary pressure
Phosphorus control
Treat metabolic acidosis
Correct anemia
Smoking cessation
Statins
Low protein diet
Treat underlying disease
Arteriovenous fistula
Connection between artery and vein to arterialize vein and increase blood flow for dialysis needle access
Longest lifespan
Low infection rate
Preferred access
Arteriovenous graft
Performed when vasculature not able to permit AVF creation
Higher rate of thrombosis and infection
Tunneled vascular catheter
Least desirable
Highest infection rate
Increased risk of great vessel stenosis
Epithelial cells in glomerulus - Podocytes
Lines outer aspects of capillary loops
Maintains loop shape
Provides size and charge barrier to filtrate
Maintains GBM
Nephrotic syndrome: Definition and components
Clinical condition due to DYSFUNCTION OF PODOCYTE
- Proteinuria >3.5gm/24hr
- Hypoalbuminemia
- Hyperlipidemia with lipiduria
- Generalized edema
H&E stain use
General stain
Good for inflammatory cells
PAS stain use
Mesangium
BM
Silver stain use
BM
Trichrome stain use
Fibrosis, necrosis
Pathogenesis of immune complex mediated renal diseases - proposed mechanisms
Ag/Ab complexes form in blood and deposit in renal tissue
Circulating Ag deposited in kidney, Ab binds Protein intrinsic to kidney acts as auto antigen, Ab recognizes and binds
Pathogenesis of immune complex mediated GN
Activation of complement –> cytokines/chemokines, recruitment of inflammatory cells –> damage to renal tissue
Nephrotic syndrome - glomerular proteinuria
Increased filtration of macromolecules across glomerular capillaries
Podocyte abnormality
Nephrotic syndrome - hypoalbuminemia
Urinary albumin loss = decreased blood albumin
Nephrotic syndrome - edema
Low blood protein = fluid flow to ecf = edema RAAS activation = Na retention, sympathetic stimulation
Nephrotic syndrome - hyperlipidemia/lipiduria
Decreased oncotic pressure stimulates hepatic lipoprotein synthesis –> hypercholestrolemia, hypertrigliceridemia
Lipid in urine trapped in protein material in renal tubules: Maltese crosses under polarized light
Nephrotic syndrome complications - altered coagulation/thromboembolism
Loss of anticoagulation factors through GC
Volume depletion from diuretics –> decreased oncotic pressure –> hemoconcentration and increased platelet aggregation
Thrombus formation - hemoconcentration in post glomerular circulation
Nephrotic syndrome complications - infection
Ig loss in urine
Generalized treatment of Nephrotic syndrome
ACE-I or ARB: Reduce intraglomerular pressure, reduce proteinuria
Loop diuretics, low Na diet
BP control <130/80
Statin for hyperlipidemia
Minimal change disease epidemiology and etiology
Most common cause of nephrotic syndrome in children Etiology: Idiopathic, Drugs (NSAIDs), Neoplasm
Minimal change disease pathogenesis
Exact cause unknown
Key feature: Podocyte injury -
Systemic T cell dysfunction -
Production of glomerular permeability factor –> podocyte injury –> effacement of foot processes = proteinuria
Minimal change disease Biopsy finding: Light microscopy, immunofluorescence, EM
Light microscopy: Normal
Immunofluorescence: Negative
EM: Diffuse effacement of podocyte foot processes
Clinical course of Minimal change disease
Nephrotic syndrome
Untreated MCD associated with mortality due to infection or thromboembolism
Good prognosis, no progression
Minimal change disease treatment
All receive nonspecific Rx: Diuretics, low Na, BP control
High dose steroids (prednisone)
Cyclophosphamide - steroid dependent patients
Cyclosporine - Steroid resistant
FSGS
Focal segmental glomerulosclerosis
Most common cause of nephrotic syndrome in adults
Increased incidence in AA and males
FSGS etiology - primary
Idiopathic
Genetic/Familial: Genetic defect in genes that code slit diaphragm proteins in foot processes of podocytes
FSGS etiology - secondary
Heterogenous - Occurs in many forms of renal injury and systemic disease
Loss of renal mass, obesity, HIV, sickle cell, drugs
Often presents with nephrotic range proteinuria but not full syndrome
Primary FSGS pathogenesis
Immune dysregulation/T cell function
Circulating toxin
Secondary FSGS pathogenesis
Hyperfiltration+increased glomerular capillary pressure: reduced renal mass, obesity, sickle cell
Direct podocyte injury from virus/drugs: HIV, pamidronate/heroin
FSGS biopsy results
Light microscopy: Focal glomeruli with scarring/sclerosis of glomerular capillary tuft
IF: Trapping of C3/IgM in areas of sclerosis
EM: Accumulation of matrix material, cells, plasma protein in sclerotic area
No immune deposits
Primary = diffuse effacement of podocyte foot processes
Secondary = patchy effacement of foot processes
Clinical course primary FSGS
Mat present with acute or insidious onset
Hematuria in 30% patients, HTN, variable degrees of reduced function
No complement abnormalities
Secondary FSGS clinical course
Always presents with insidious onset
Full nephrotic syndrome NOT always present
Untreated primary FSGS and clinical course
Follows progressive course to ESRD
Risk factors for primary FSGS progression
High level proteinuria
Reduced renal function
Presence of tubulointerstitial fibrosis
Primary FSGS treatment
ACE-I, ARB, loop, low Na, BP control, statin
High dose steroids
Cyclophoshamide/cyclosporine
No response to therapies = slit diaphragm mutations
Secondary FSGS treatment
ACE-I, ARB, loop, BP control, low Na, statin
Treat underlying disease - Weight loss - Anti viral -
Discontinue bad drugs
Membranous nephropathy etiology
Primary/idiopathic (70%)
Secondary (30%) - Drugs/Malignancy/SLE/Infections
Membranous nephropathy pathogenesis
Primary - Autoimmune - Circulating IgG antibodies directed against renal tissue (Type M phospholipase A2 receptor on podocyte foot processes)
Secondary - Circulating IgG Ab directed against extrinsic antigens (viral proteins, tumor proteins, drug)
Membranous nephropathy specific pathogenesis
Immune complex formation activates complement cascade
MAC inserts into podocyte membrance
Podocyte foot process effacement
Podocyte death and necrosis
Membranous nephropathy biopsy
Light microscopy: Thick GBM with spikes
IF: Diffuse fine granular deposits on capillary walls, IgG/C3
EM: Subepithelial immune deposits, spikes of GBM, effacement of podocyte foot processes
Membranous nephropathy clinical course and risk for pregression
Nephrotic syndrome 40% progress to ESRD if untreated
Progression risk factors:
- Older age of onset
- Male
- Increased creatinine
- >8gm proteinuria
- Tubulointerstitial fibrosis
Membranous nephropathy treatment
ACE-I, ARB, Na low, B control, statin
Immune targeted therapy
- Cyclophosphamide
- Cyclosporine
- Rituximab
Diabetic Nephropathy
Most common systemic illness to cause nephrotic syndrome
Diabetic nephropathy pathophysiology
Metabolic: - Hyperglycemia + pro inflamm molecules –> biochemical change in glomeruli –> profibrotic growth factors and increased synthesis of collagen/matrix - Non enzymatic glycosylation of proteins
Hemodynamic - Hyperfiltration –> increased glomerular capillary pressure and hypertrophy –> injury
Diabetic nephropathy biopsy findings
LM: Glomerular nodules of matrix material. Thick GBM, thick tubular BM, interstitial fibrosis, vascular sclerosis
IF: No immune deposits. Pseudolinear staining of glomerular/tubular BM with IgG and albumin due to sticky BM
EM: Diffuse thickening of GBM
- Mesangium expansion with increased matrix
- No immune deposits
- Variable foot process effacement
Diabetic nephropathy clinical course
Proteinuria:
Early - microalbuminuria
Late - Overt proteinuria and neprotic syndrome
Progression: Depends on BP and glycemic control
Diabetic nephropathy treatment
ACE-I/ARB (important to reduce capillary pressure),
Low Na, BP control
Strict blood sugar control
Kidney pancreas transplant
Amyloidosis
Cause of proteinuria/nephrotic syndrome in adults
Extracellular deposition of abnormally folded proteins
Poor prognosis
AL type amyloidosis
Multiple myeloma - neoplasm of plasma cells
Amyloid made of monoclonal Ig light chains
AA tyep amyloidosis
Chronic inflammatory disease
Amyloid made of serum amyloid A protein
Amnyloidosis biopsy findings
LM: Congo red stain positive
IF: Variable
EM: Haphazardly arranged fibrils
Amyloidosis clinical course and treatment
Poor prognosis, ESRD common
Treatment: ACE-i, ARB, Low Na, Lop, BP control, statin
Primary - chemo, stem cell transplant
Secondary - Treat underlying disease
Cystitis definition
Inflammation of urinary bladder, usually due to infection
Cystitis triad of symptoms
- Frequency of urination
- Lower abdominal pain
- Dysuria
Most common cystitis organism
E. Coli >> Proteus, Klebsiella, Enterobacter
Predisposing factors for cystitis
Bladder calculi
Urinary obstruction
DM
Instrumentation
Immune deficiency
Cytotoxic drugs
Radiation
Cytotixic drug cystitis risk
Cyclophosphamide
Hemorrhagic cystitis
Gross pathalogical findings of acute cystitis
Hyperemia (redding) of mucosa
Exudate
Large amounts of hemorrhage = hemorrhagic cystitis
Microscopic pathological findings of acute cystitis
Neutrophilic infiltrate
Hemorrhage
Ulceration of mucosa
Large areas of ulceration = ulcerative cystitis

Acute cystitis

Hemorrhagic cystitis

Acute cystitis

Acute cystitis
Chronic cystitis pathological findings
Longer duration of infection
Chronic infiltrate - lymphocytes/plasma cells
Heaped up and reactive urothelium
Fibrous thickening of muscularis propria

Chronic cystitis
Special histological forms of chronic cystitis
Follicular
Eosinophilic
Interstitial
Malacoplakia
Polypoid
Emphysematous
Cystitis cystica

Chronic follicular cystitis
Germinal center

Eosinophilic cystitis
Interstitial cystitis
Most frequent in women
Inflammation and fibrosis in all layers of bladder wall, often with ulceration
Highliy incapacitating and difficult to treat
Symptoms of interstitial cystitis
Intermittent and severe suprapubic pain
Frequency
Urgency
Hematuria
Dysuria
Malacoplakia
Unique form of chronic cystitis, chronic E coli infection
Immunosuppressed patients
Gross pathology of malacoplakia
Multiple yellowish plaques in mucosa and submucosa

Malacoplakia
Microscopic pathological features of malacoplakia
Large foamy macrophages, multinucleate giant cells, lymphocytes
Michaelis Gutmann bodies: Round intracytoplasmic concretions within macrophages and between cells

Michaelis Gutmann bodies
Polypoid cystits cause and mucosal appearance
Results from mucosal irritation - bladder catheter
Broad polypoid projections due to submucosal edema

Polypoid cystitis

Polypoid cystitis

Emphysematous cystitis

Cystitis cystica
Pyelonephritis major causes
Majority (>95%) are ascending bladder infections
Most are bacterial infections: 85% gram(-) rods from intestinal tract
E. COLI
Pyelonephritis nosocomial infections
Hospital acquired
Due to indwelling bladder catheters, patients on antibiotics
Most are due to E coli
Pyelonephritis hematogenous spread
Associated with virulent organisms
Staph aureus, salmonella
Pyelonephritis predisposing factors to infection
Urinary tract obstruction
Catheters
Vesicouteral reflux
Pregnancy
Pre existing renal disease
DM
Immunosuppression
Pathophysiology of pyelonephritis
Colonization of urethra then bladder
- Usually by intestinal flora
- Bacterial adhesion molecules interact with urothelium receptors –> promote migration to kidney and persistent infection
Multiplication of organisms in bladder: Outflow obstruction/bladder dysfunction –> STASIS –> bacterial growth
Bacteria gain access to upper tract: Catheter. Vesicoureteral reflux (back flow)
Intrarenal reflux
Factors preventing pyelonephritis infection
Active peristalsis of ureters
Ureterovesical valves
Complete voiding of bladder
Turbulent flow of urine exiting urethra
Clinical presentation of acute pyelonephritis
Fever, chills
Flank pain, CVA tenderness
Constitutional symptoms: malaise, anorexia, vomiting, diarrhea, headache
Cystitis symptomsL Urgency, frequency, dysuria
Acute pyelonephritis lab findings
Leukocytosis - Left shift increase WBC
Urinalysis - Pyuria (>5WBC/HPF), WBC casts
Urine culture - colony formation
Positive blood culture - 15-30% cases
Acute pyelonephritis Gross path findings
Focal abscesses, wedge shaped areas of suppuration, hemmorhage
Acute pyelonephritis microscopic path findings
Early: PMN infiltrate in interstitium and within tubule, abscess, tubule destruction
Later: Mixed inflamm infiltrate, PMN/lymphocytes/plasma cells

Acute pyelonephritis

Acute pyelonephritis

Acute pyelonephritis

Acute pyelonephritis
Natural history of acute pyelonephritis
Most cases follow benign course - antibiotics and supportive care
Adults with normal urinary tract = no rogressive disease
Bacteruria may persist after therapy
Complications of acute pyelonephritis
Bacteremia/sepsis - 15-30%
Papillary necrosis - necrosis of distal medullary tips, diabetics
Pyonephrosis - Exudate filling renal pelvis and ureters. Severe obstruction
Perinephric abscess - Extension of inflmmation through renal capsule into perinephric fat

Severe papillary necrosis
Polyoma virus
Cause of acute ciral pyelonephritis in renal allografts
Immunosuppression –> latent virus activation –> inflammation of tubules and interstitium
Treatment: Reduce immunosuppression

Polyoma virus nephropathy
Chronic pyelonephritis: Definition, cause, progression
Chronic disorder characterized by chronic tubulointerstitial inflammation and progresive scarring
Causes:
- Chronic reflux (reflux nephropathy): Usually in childhood
- Chronic obstruction: Recurrent infection superimposed on obstruction
Abnormal urinary tract –> repeated infections –> progressive injury
Clinical presentation of chronic pyelonephritis
Vague/nonspecific symptoms: Flank pain, low grade fever. History of UTI’s. ESRD w/out prior history
Common cause of HTN in children (via CKD)
Nocturia, polyuria - tubular dysfunction and loss of ability to concentrate urine
Secondary FSGS

Chronic pyelonephritis

Chronic pyelonephritis
Microscopic path findings of chronic pyelonephritis
Chronic interstitial inflammation with fibrosis
Tubular atrophy and dilation with hyaline casts
Glomeruli vary from normal to ischemic to obsolescent

Chronic pyelonephritis
Xanthogranulomatous pyelonephritis
Special form of chronic pyelonephritis
Proteus infections, obstruction
Mixed inflammation with large amouns of foamy macrophages

Xanthomatous pyelonephritis

Xanthogranulomatous pyelonephritis
Staghorn calculi
Associated with chronic infections due to urea splitting bacteria
Proteus
Klebsiella
Ureaplasma
Struvite crystals –> Stones
Difficult to treat

Staghorn calculi

Staghorn calculi
Chronic pyelonephritis natural history
Caught early: Surgical correction of abnormal urinary tract allows normal function, prevents progressive scarring
End stage: No effective therapy
Allergic interstitial nephritis
Inflammatory disorder involving interstitium and tubules - non infectious, hypersensitivity reaction
Penicillins, NSAIDs, antibiotics, thiazdes
Clinical presentation - allergic interstitial nephritis
Fever
Skin rash
Eosinophilia
Microscopic path of allergic interstitial nephritis
Mixed inflammation within interstitium: Eosinophils, lymphocytes, PMN, plasma
Tubular inflammation, tubular injury
Early - interstitial edema
Late - interstitial fibrosis, tubular atrophy

Allergic interstitial nephritis

Allergic interstitial nephritis

Allergic interstitial nephritis
Chronicity with fibrosis
Treatment allergic interstitial nephritis
Discontinue offending drug ASAP
Corticosteroids
Supportive care

Myeloma cast nephropathy
Intratubular cast
Components of nephritic syndrome
Glomerular hematuria: Dysmorphic RBC’s, RBC casts
Proteinuria: Can be nephrotic range
Azotemia: Elevated BUN
Oliguria
HTN: Volume overload via Na retention - RAAS suppression and icnreased Na/K ATPase
Etiology of Membranoproliferative Glomerulonephritis
Idiopathic/autoimmune
Infectious:
- Hep C
- Chronic bacterial infection
Neoplasia
- Mulitple myeloma
- CML
Pathogenesis of MPGN
Immune complex mediated disease
Idiopathic: Antibody directed at unknown antigen
Secondary: Antibody directed at viral/bacterial
Deposition of Ab/Ag complex in glomerulus OR formation of complex in situ
Immune complex formation –> complement activation –> MAC
MPGN blood analysis
Low C3, C4, total complement

MPGN
Global hypercellularity and lobular formation

MPGN
Silver stain
GBM duplication

MPGN
IgM deposits
Smooth BM because deposits are subendothelial

MPGN
Subendothelial deposits
MPGN biopsy findings
LM: Hypercellular, lobulated glomeruli. Duplication of GBM
IF: IgG, IgM, C3 in mesangium or inner aspect of GBM
EM: Immune deposits in mesangium, subendothelium locations. GBM duplication
MPGN clinical course: Idiopathic and secondary
Idiopathic/autoimmune: Prolonged course with slow rate of progression
Secondary: Good prognosis if underlying disease treated
MPGN treatment
Idiopathic/autoimmune: Steroids
Secondary: Treat underlying condition
Dense Deposit Disease
Rare
Excessive activation of alternatic complement pathway
Dense Deposit Disease pathogenesis
Circulating autoantibody: C3 Nephritic Factor
Deficient regulatory protein: Factor H/Factor I
Leads to persistent degradation of C3 and constitutive activation of alternative pathway
LOW C3 ONLY
DDD diagnosis
Low C3, C4, total complement
Assay for C3 nephritic factor, Factor H, Factor I
C3

DDD
DDD biopsy
LM: Similar to MPGN
IF: Mesangial and capillary wall C3
EM: Linear deposition of electron dense material along GBM (ribbon like)

DDD
Dense Deposit Disease clinical course
Poor prognosis
70% –> ESRD at 9 years
DDD treatment
Non specific therapy if nephrotic
Plasmapharesis - Patients with C3 nephritic factor
Plasma infusion - Factor H/I deficiency patients
Eculizumab - antibody to C5 protein, prevents MAC formation, expensive
IgA Nephropathy Etiology
Mucosal infection triggered by environmental antigens –> pathogenic IgA complexes
Antigens: Viral, bacterial, food
Genetic predisposition: Polygenic
IgA Nephropathy pathogenesis
Increased synthesis of abnormal IgA/IgG
Abnormally glycosylated IgA produced –> immune complexes don’t clear –> IgG antibodies directed against abnormal IgA –> Large fucker of a macromolecule –> Deposition in mesangium and complement activation

IgA Nephropathy
Increased size of mesangium

IgA nephropathy
IgA Nephropathy biopsy
LM: Variable, increased mesangium
IF: Mesangial IgA, C3
EM: Immune deposits in mesangium, increased mesangial matrix and cellularity
IgA Nephropathy clinical presentation
40% present with gross hematuria following URI (Synpharyngitic hematuria)
30% present with microscopic hematuria and mild proteinuria
5-10% with acute nephritic syndrome
Associated abnormalities:
- Skin lesions
- GI (celiac, cirrhosis)
- IgA vasculitis
IgA nephropathy treatment
No treatment if normal renal function and low proteinuria
ACE-I/ARB if >1gm proteinuria
Fish oil
Prednisone - Patients with proteinuria even with ACE-I/ARB, progressive disease
Post infectious Glomerulonephritis
Most common cause of acute nephritic syndrome
Children 5-12 and adults >60
Post infectious glomerulonephritis etiology
Develops in response to infection
Acute nephritis 1-6 weeks following infectious illness
Strep pharyngitis/impetigo
Post infectious glomerulonephritis Pathogenesis
Immune complex disease caused by specific nephritogenic strains of bacteria
- Group A beta hemolytic Strep
- Elevated strep titers
Hypotheses:
- Circulating immune complexes comprised of Strep antigen and antibody deposit within glomeruli and activate complement
- Infection causes alterations of intrinsic GBM proteins, Ab bind and activate complement
Post infectious glomerulonephritis clinical presentation
Variable
Range from asymptomatic with microscopic hematuria to full blown nephritic syndrome
Post infectious glomerulonephritis Diagnosis
Active urine sediment: Dysmorphic RBC, RBC casts, WBC, WBC casts
Low C3, CH50, normal C4
Elevated Strep antibody titers - Streptozyme test

PIGN
Hypercellular with numerous PMN

PIGN
Post infectious glomerulonephritis Biopsy
LM: Hypercellular glomerulus with abundant PMN
IF: Large granular deposits of IgG, C3
EM: Large, hump like subepithelial deposits
Post infectious glomerulonephritis Prognosis/Treatment
Good prognosis - most recover
Children - 95% recover without complications
Adults - More insidious, slow progression to chronic GN
Treatment - Supportive Care
- Treat underlying infection
- Manage HTN, edema, proteinuria
Pools of serum calcium in body
50% ionized
10% complexed to phosphate, citrate, carbonate, other ions
40% bound to protein
Sites of Ca reabsorption
PCT - 65%. Mostly passive via gradients
TAL - 20%. Mainly passive, driven by lumen charge
DCT - 10%. Transcellular transport, active
PTH and calcium
Increases serum calcium
- Ca release from bone
- Ca reabsorption from kidney
- Conversion of vit D to calcitrol by stimulating 1-a-hydroxylase –> increase Gi absorption
Calcitrol and Ca
Increase intestinal Ca absorption
Factors that affect renal calcium excretion
- Sodium - saline infusion increases Ca excretion
- Ca - Dietary Ca increases excretion
- Phosphate - Dietary of IV phosphate increases excretion
- Proton - acidosis increases excretion
- PTH and Calcitrol
Renal handling of phosphate
12% filtered phosphate is excreted, remainder reabsorbed
PCT:
Enter apical membrane via Na dependent transporter (type II, I) –> cross basolateral membrane via Na dependent transport (type III)
PTH and Phosphate
Principal regulator of phosphate reabsorption
Inhibits Type II Na dependent phosphate transporter –> reduces reabsorption
Increases phosphate release from bone
Calcitrol and phosphate
Principal phosphate regulator in GI
Increases intestinal reabsorption
Increases renal reabsorption
Phosphatonin and phosphate
FGF 23
Inhibits calcitrol synthesis and NaPi2a synthesis
Calcitrol and high phosphate increase FGF23 –> reduce calcitrol and phosphate
Factors affecting renal phosphate excretion
Sodium - saline infusion = excretion
Calcium - Hypercalcemia = excretion
Proton - Acidosis = excretion
PTH/calcitrol/phosphatonin - major regulators
Decreased GFR = hyperphosphatemia
Secondary hyperPTH and CKD
Decreased kidney f(x) = decreased Vit D = phosphate retention/Ca decline
Decreased Ca = PTH activation
Vascular calcification and CKD
CKD CV risk factors can accelerate vascular calcification - PTH, calcitrol, advanced AGE’s, lipoproteins
Relationship between CKD and abnormal phosphate/Ca, PTH levels, and vascular calcification
Clinical consequences of vascular calcification
Severe organ dysfunction
Heart valve dysfunction
Calciphylaxis - necrotizing skin caused by calcific uremic arteriolopathy
Large vessel stiffening
Renal Osteodystrophy classifications
High turnover bone disease
Osteomalacia
Mixed uremic bone disease
Adynamic bone disease
High turnover bone disease
High PTH
Increased osteoclasts and osteoblasts
Bone structure disruption
Adynamic bone disease
Low PTH
Low turnover
Decrease osteoblasts/clasts
No mineralization defect
Low rate of bone formation
Osteomalacia
Adynamic bone disease with mineralization defect
Mixed uremic bone disease
Histologic features of ostetitis fibrosa and osteomalacia
Clinical manifestations of renal osteodystrophy
Bone pain
Muscle weakness
Skeletal deformities
Growth retardation in children
Management of CKD-MBD
Early prevention
Control hyperphosphatemia: Diet, phosphate binders, dialysis
Control Ca: Supplements for Low Ca, Low Ca dialysate for high Ca
Vit D analogs: Inhibit PTH synthesis and secretion
Calcimimetic agent: Blocks PTH secretion
Phosphate level goals in CKD Stage III, IV, V
Stage III: <70
Stage IV: <110
Stage V: 150-300
4 Disease categories of hematuria
Infection
Kidney stones
Cancer
Glomerular disease
Types of kidney stones
Calcium oxalate stones - increased Ca
Sturvite stones - Urea splitting organisms. High NH4 and high uring pH
Uric acid stones - Low urine pH
Cystine stones - Defect is cystine transporter
Glomerular diseases that can cause isolated hematuria
IgA nephropathy
Familial hematuria/Thin BM disease - GBM collagen defect
Alports syndrome - Hereditary nephritis, collagen defect. Basket weave GBM

Uric acid crystals

Calcium oxalate crystals

Cystine crystals

Cholesterol crystals

RBC cast

RBC cast

ATN

Waxy cast - chronic disease
Lupus Nephritis epidemiology and etiology
Occurs in 50% SLE patients
Genetic
Environmental - Lower SES, viral antigens
Genetic - Loss of tolerance
Lupus Nephritis pathogenesis
Immune complex mediated disease
Antibody target - nucleosome
Cells undergoing apoptosis/necrosis fail to exit circulation –> intracellular contents exposed to immune system
Lupus nephritis: Mechanisms of immune complex formation
Circulating nucleosome Ag/Ab complex deposits in kidney
Anti nucleosome Ab cross reacts with intrinsic renal antigen
Nucleosome antigen deposits first –> Ab binds antigen
Lupus Nephritis Diagnosis: Non biopsy
Serology: Anti ds DNA, ANA
Low complement: C3, C4, total
Active urine sediment
Classification of Lupus Nephritis
Class I: Minimal LN
Class II: Mesangial Prolferative LN
Class III: Focal LN
Class IV: Diffuse LN
Class V: Membranous LN
Class VI: Advanced sclerosing LN
Class IV LN biopsy findings
LM: Hypercellularity involving capillary loops
Necrosis, crescent formation
Immune complexes visible, wire loop capillaries (thickened)

Lupus Nephritis:
Wire loops
Intra capillary immune deposits
Hypercellular areas with capillary loop destruction

Full house IF
Lupus Nephritis

Lupus Nephritis
Global immune deposits
Subepithelial, subendothelial, mesangial
Lupus Nephritis EM findings
Immune complexes in all compartments: Subendothelial, subepithelial, mesangial
Lupus nephritis clinical presentation
Variable, depends on pattern of injury
Relapsing and remitting disease symptoms
Lupus Nephritis treatment
Depends on clinical presentation and biopsy results
Class III-V treated aggressively
Active lesions - Cyclophosphamide, steroids –> induce remission
Maintenence therapy - Cellcept, azathioprine, steroids
Alternative agents: Rituximab
RPGN definition
Rapidly progressive glomerulonephritis
Sever acute nephritic syndrome, progressive loss of renal function over days-weeks –> ESRD if untreated
Categories of RPGN
Type I: Anti GBM
Type II: Immune complex mediated
Type III: Pauci immune
Type I RPGN
Anti GBM - Goodpastures
Formation of autoantibodies against Type IV collagen
Immune deposits in GBM and pulmonary BM
Type II RPGN
Immune complex mediated
IgA nephropathy
PIGN
Lupus Nephritis
Type III RPGN
Pauci Immune type
ANCA
C-ANCA: Proteinase3 target antigen. Renal limited or associated with granulomatosis with polyangitis
P-ANCA: MPO target antigen. Renal limited or associated with microscopic polyangitis
RPGN diagnosis, non biopsy
Serologic tests:
Anti GBM
P/C-ANCA
RPGN biopsy
LM: Necrosis of glomerular capillaries. Crescent formation, proliferation of cells in urinary space
Anti GBM/Pauci: Non involved glomeruli look normal
IF:
Type I - Linear IgG along capillary walls
Type II - Positive, depends on cause
Type III - NEgative
EM: Immune deposits only in Type II
RPGN treatment
High dose steroids
Cyclophosphamide
Rituximab
Azathioprine
Plasmapharesis - Anti GBM

RPGN
Note crescent

RPGN
Note crescent
Fibrinogen stain

RPGN
Fibrinogen crescent
IgG

Type I RPGN
Linear IgG deposits
Chronic Glomerulonephritis Definition and Clinical presentation
End result of many forms of GN
Clinical presentation:
Renal failure with elevated creatinine
Uremia
Proteinuria and/or hematuria
Chronic GN biopsy
LM: Globally sclerosed glomeruli, interstitial fibrosis, arteriolosclerosis, arteriolar hyalinosis
IF: Variable
EM: Variable
Renal Papillary adenoma
Behavior, path features
Common neoplasm
Benign
Papillary/tubular architecture
Bland nuclei, no atypia
No fibrous capsule or desmoplastic response

Renal papillary adenoma
Angiomyolipoma
Behavior, association, path features
Benign, rare
Association with tuberous sclerosis
Microscopic path: Blood vessels, smooth muscle, adipose tissue

Angiomyolipoma - adipose tissue

Angiomyolipoma
Smooth muscle

Angiomyolipoma
Blood vessels

Angiomyolipoma
Oncocytoma
Behavior and path features
Benign neoplasm
Nest arrangement of cells
Eosinophilic granular cytoplasm
Bland, round central nuclei

Oncocytoma

Oncocytoma
Renal cell carcinoma
Behavior
85% of all primary renal malignancies
Behavior related to:
Size
Stage: Involvement of surrounding fat, vascular invasion, lymph node mets
Grade
Renal cell carcinoma clinical features
Adults, male > female
Triad of symptoms:
Costovertebral angle pain
Palpable mass
Hematuria
Polycythemia: Paraneoplastic syndrome, erythropoietin secretion
Renal cell Carcinoma treatment
Partial nephrectomy
Radical nephrectomy: Whole kidney
Adjunct chemotherapy
Renal Cell carcinoma classifications
Clear Cell
Papillary
Chromophobe
Renal cell carcinoma: Clear cell
Chromosomal abnormalities
Deletion of chromosome 3p
Loss of VHL
Promote tumor angiogenesis through VEGF
Renal cell carcinoma: Papillary
Chromosomal abnormalities
Trisomy 7
MET mutation (proto-oncogene)

Renal Cell Carcinoma

Renal Cell carcinoma

Renal Cell carcinoma
Clear Cell Renal cell carcinoma
Path features
Cells arranged in nests/sheets
Delicate fibrovascular network
CLEAR CYTOPLASM

Clear Cell RCC

Clear Cell RCC
Papillary RCC path features
Cuboidal/low columnar epithelial tumor cells
Papillary formation of cells with fibrovascular core
Papillae may contain prominent macrophages

Papillary RCC

Papillary RCC
Chromophobe RCC path features
Eosinophilic cytoplasm with plant like cell borders
Greater nuclear atypia

Chromophobe RCC
RCC pattern of spread
Invasion through renal capsule into perinephric fat
Invasion into renal vein, proximal spread along IVC
Lymph nodes - Renal hilum/para-aortic
Distant mets - Adrenal, liver, brain, lungs, bone
Wilms Tumor
Definition, genetic abnormality, associations
Malignant renal tumor of chilfren
Mutation of WT-1 gene on chromosome 11
WAGR syndroms: Wilms, Aniridia, Genital anomalies, retardation
Denys-Drash syndrome: Wilms, gonadal dysgenesis, early onset nephropathy w/ renal failure
Wilms tumor clinical features
Abdominal mass
Ab pain, hematuria, intestinal obstruciton, HTN

Wilms Tumor
Wilms tumor path features
Triphasic Pattern
- Primitive blastema
- Epithelial component - abortive tubules/glomeruli
- Stroma - Fibrous or myxoid patters

Wilms Tumor

Wilms tumor
Epithelial elements
Consequence of Wilms tumor
Anaplasia of tumor cells
Correlates with more aggressive behavior

Wilms tumor - Anaplasia
Wilms tumor treatment
Combined therapy
Surgical nephrectomy, radiation, chemo
Urothelial carcinoma: Origin, clinical features
Origin in urothelium lining the renal pelvis
Clinical features:
Associated with urothelial carcinoma elswhere in urinary tract
Hematuria, urinary obstruction, hydronephrosis, flank pain

Urothelial cell carcinoma

Urothelial cell carcinoma
Urothelial cell path features
Papillary: Papillae with vascular cores, lined by malignant urothelial cells
Flat: no papillary growth, disordered polarity/maturity of cells

Normal Urothelium

Papillary urothelial cell carcinoma

Low grade papillary urothelial cell carcinoma

High grade urothelial cell carcinoma - papillary

Flat urothelial cell carcinoma
Behavior and prognosis of urothelial cell carcinoma
Presence/absence of invasion
High grade = invasion
Tumor infiltrates adjacent tissue into renal parenchyma

Invasive urothelial cell carcinoma

High grade invasive urothelial cell carcinoma
Bladder neoplasm: Pathogenesis
Cigarette smoking - most important
Chemical carcinogens
Infectious agent - Schistosoma haematobium (Bladder SCC)
Radiation, cyclophosphamide
Clinical features of bladder neoplasms
Hematuria
Dysuria
Diagnosis of bladder neoplasms
Urine Cytology - Less invasive, detect high grade. Less specific for low grade
Cytoscopy with biopsy
Benign bladder neoplasms
Leiomyoma
Urothelial papilloma
Common malignant bladder neoplasms
Urothelial cell carcinoma
SCC

Papillary urothelial cell carcinoma

Invasive urothelial cell carcinoma - bladder
Squamous cell carcinoma - bladder
Background, association, appearance, treatment
Background: Often due to chronic irritation/inflammation
Association with schistosomiasis
Appearance: Intercellular bridges, keratinazation of single cells, keratin pearls
Radical cystectomy

Squamous cell carcinoma
Rare bladder cancer - adenocarcinoma
Gland forming tumor, mucin production
May arise from urachal remnant
Treat: Radical cystectomy +/- radiation
Rare bladder carcinoma - Small cell carcinoma
Poorly differentiated appearance
Treatment: Chemo+cystectomy+radiation if localized
Chemo if systemic
Bladder carcinoma T1/2/3
T1 - invasion into lamina proprial
T2 - Invasion into muscularis
T3 - Invasion into soft tissue outside bladder
Bladder urothelial cell carcinoma: Clinical course and prognosis
Clinical course: 60% tumors single, 70% confined to bladder
New tumors after excision ==> higher grade
Prognosis: Depends on grade and stage
Bladder urothelial cell carcinoma trreatment
Transuretheral resection - Low grade, non invasive papillary lesions
Bacillus Calmette Guerin - Attenuated TB. USed for high grade non invasive lesions. Incites granulomatous response against tumor
Radical cystectomy - T2 or higher tumors
Chemotherapy - Advanced disease
Causes of elevated anion gap metabolic acidosis
Diabetic ketoacidosis
Lactic acidosis
Renal failure
Toxins (Aspirin)
Causes of non elevated anion gap metabolic acidosis
Diarrhea
RTA
Carbonic anhydrase inhibitors
Proximal tubule drug: MoA, usage, benefits to treat HTN?
Acetazolamide
Carbonic Anhydrase inhibitor
Not good for HTN because solutes delivered to TAL and can be reabsorbed
Used for epilepsy, glaucoma, altitude sickness
TAL drug: Name, usage, benefit to HTN, consequences
Loop diuretics, Furosemide
NKCC2 inhibitor
Not the best for HTN
Increased excretion of Ca, Mg, K, H
Use for hypervolemic states: HF, cirrhosis
DCT drug: MoA, usage, benefits, consequences
Thiazide drugs (HCTZ, chlorthalidone)
Na/Cl symporter blocker
FIrst line HTN
Not as good as loop for edematous states
Collecting duct/Late DCT drugs: MoA, uses, benefits, consequences
Amilorde/Triamterene
ENaC blockers
Prevents K and H secretion
Use adjunct with Loop/thiazide to prevent hypokalemia
Can cause hyperkalemia
Not great diuretics
Hydrochlorothiazide
DCT Na/Cl symporter blocker
First line HTN drug
Can increase K and H secretion via collecting tubule mechanisms
Chlorthalidone
Na/Cl symporter blocker
First line HTN drug
Furosemide
Loop Diuretic
NKCC2 blocker
Use for treating hypervolemic states (HF, cirrhosis)
Increase excretion of Ca, Mg via electrostatic mechanisms
Not best diuretic for HTN treatment
Mannitol
Osmotic laxative
Helps treat cerebral edema
Spironolactone
Mineralocorticoid receptor blocker
Prevent Aldosterone action - No ENaC uptake
Potassium sparing diuretic b/c no K secretion - Even with increased Na, charge restriction prevents K secretion
Acetazolamide
Carbonic Anhydrase inhibitor
Acts in PCT
Affects acid/base status without disrupting ion balance
Amiloride/Triamterene
ENaC inhibitors
Can result in hyperkalemia (no K secretion)
Use adjunct with thiazides/Loop to prevent hypokalemia
NSAIDs
The devil incarnate for kidneys
Causes arteriolar vasoconstriction and decreased GFR
Cyclophosphamide
Immunosuppressant
Can be used in inflammatory nephrotic syndromes
MCD, FSGS, Membranous nephropathy
Cyclosporine
Immunosupressant
Can be used to treat inflammatory nephrotic syndromes: MCD, MN
Phenoxybenzamine
Non selective irreversible alpha blocker
Use for Pheochromocytoma
Penicillin
Antibiotic
Can cause AIN
Lithium
Bipolar medication
Can cause DI
Calcium Chloride
Use in hyperkalemia ONLY if ECG changes
Short term drug
Kayexalate
Cation exchange resin
Hyperkalemia
Pronephros
Non functional in humans
Mesonephros
Most degenerates, small structure remains
Becomes ducts of reproductive system: Wolffian, mesonephric
Metanephros
Final and definitive kidney and ureter
Urogenital ridge: Origin, development
Derived from intermediate mesoderm
Lateral folding results in dorsolateral ridges that run along length of embryo (urogenital ridge)
Pronephros development
Begins to form and regresses at week 4
Mesenephros development
4th week - mesonephric tubules form in IM, cranial –> caudal
Mesonephric duct forms (solid rod of cells) and fuses with cloaca
Mesonephric tubules fuse with duct, create passage from mesonepchric excretory unit to cloaca
Metanephric kidney: Origin
Arises from ureteric bud and metanephric blastema
Ureteric bud origin and induction
Buds off mesonephric duct
Induces IM to form metanephric blastema
Ureteric bud develops into…
Urine collecting elements
Collecting tubules, major/minor calyces, ureters
Undergoes repeated branching
Metanephric blastema gives rise to…
Portion of kidney between glomerular capillaries and collecting duct
Bowmans capsule, PCT, Loop of Henle, DCT
Regulation of kidney development overall
Reciprocal induction of ureteric bud and metanephric blastema are required for normalbranching and tubulation
Mutations anywhere in pathway cause problems
Ascent of kidney
Metanephric kidney originates deep in pelvic region
Shift towards abdominal region (week 6-8)
90 degree medial rotation, face inward
Urinary bladder formation
Base of allantois and attachment to urogenital sinus expands and forms urinary bladder
Urachus closes and becomes median umbilical ligament
Bladder formation and mesonephric duct/ureteric bud
Growth of bladder incorporates mesonephric duct and ureteric bud into bladder wall
Remaining ureteric bud = ureters
Trigone (smooth part of bladder) formed from entry of mesonephric duct and ureters
Horseshoe kidney
Forms when bilateral metanephric blastema fuse
Get suck under IMA during ascention
Unilateral multicystic dysplasia
Kidney epithelia overexressing PAX2 –> atretic ureter
Bilateral polycystic/multi cystic kidneys
Renal dysplasia characterized by multiple cysts and dysplastic kidney tissue
POTTER
Pulmonary hypoplasia
Oligohydraminos
Twisted face
Twisted skin
Extremity defects
Renal failure in utero
Primary zone of incontinence
External urethral spincter (Rhabdosphincter)
Male urethra and site of incontinence
Bladder neck/prostate –> membranous urethra –> bulbar urethra –> Pendulous urethra
Membranous urethra is site of incontinence
Female urethra and incontinence
Shorter than males, fused to anterior vaginal wall
Incontinence can be caused by:
- Childbirth that damages pudendal nerve –> external sphincter
- Childbirth –> anterior vaginal wall damage
- Menopause –> low estrogen –> atrophy or urethra
Detrusor autonomics
Rich in M3 receptors
M3 activation –> detrusor contraction –> relaxed bladder outlet –> void urine
Bladder body autonomics
Beta adrenergic receptors (B3)
NE release –> detrusor relaxation –> urine storage
Bladder base and proximal urethra autonomics
Alpha receptors
NE –> constriction –. Storage
Pelvic parasympathetics and bladder control
S2-S4
Detrusor contraction, urethral relaxation
Detrusor contracts via Ach relsease
Urethra probably through NO
Lumbar sympathetics and bladder control
NE release
B3 receptors on bladder –> relaxation via cAMP
Constrict urethra (alpha receptors)
Pudendal nerve and bladder control
Somatic cholinergic
Ach release on nicotinic receptors on rhabdosphincter –> contraction –> stop void
Urinary afferent pathways
A delta fibers in detrusor - Sense wall stretch/tension
C fibers in bladder mucosa - Stretch and nociception
Bladder irritation and afferent fibers
Irritation = afferent fibers firing with decreased filling –> frequency/urgency
Guarding Reflex
Storage reflex - based on spinal pathways
Filling –> afferents fire –> reflex firing from hypogastric nerve –> NE release =
Inhibit detrusor contraction
Contract bladder neck/proximal urethra
Block PS transmission
Pudendal nerve also fires = contracted rhabdosphincter
Spino-bulbo-spinal reflex
Filling sends signal to PMC –> PMC only fires when threshold is reached
If threshold reached and PMC disinhibited –>
Stimulate PS transmission - detrusor contraction/urethral relaxation
Inhibit Pudendal nerve mediated rhabdosphincter contraction
Inhibit Guarding reflex via hypogastric nerve - No NE release
Secondary bladder reflex
Urine flow through urethra –> facilitates bladder contraction and more voiding
Detrusor Overactivity: Etiology, presentation
Excessive bladder contraction –> involuntary urine losses
Urge incontinence - Immediate need to urinate that cannot be suppressed
Urgency and frequency
Urethral incompetence
Loss of normal function of bladder outlet
Stress incontinence - Laugh/cough etc
Can result after surgery –> damage to nerves
Overflow incontinence
Primary problem is failure to empty bladder fully
Results in buildup of urine –> overflow trickles out into urethra
Etiology:
Unable to contract bladder
Retention due to blockage (enlarged prostate)
Lesions above brainstem and bladder abnormalities
Detrusor overactivity –> overactive bladder
Impaired PMC inhibition
Spinal cord injury above S2 and bladder abnormalities
Detrusor Sphincter Dyssynergia
No connection with PMC so no relaxed sphincter
Spinal cord injury below S2 and bladder abnormality
Detrusor areflexia, fixed external sphincter
No bladder contraction
Sphincter retains residual tone
Urinary retention and overflow incontinence