Renal physiology Flashcards
Kidney embryology
Pronephros—week 4; then degenerates.
Mesonephros—functions as interim kidney for
1st trimester; later contributes to male genital
system.
Metanephros—permanent; first appears in 5th
week of gestation; nephrogenesis continues
through weeks 32–36 of gestation.
Ureteric bud (metanephric diverticulum)—derived from caudal end
of mesonephric duct; gives rise to ureter,
pelvises, calyces, collecting ducts; fully
canalized by 10th week
Metanephric mesenchyme (ie, metanephric
blastema)—ureteric bud interacts with this
tissue; interaction induces differentiation
and formation of glomerulus through to
distal convoluted tubule (DCT)
Aberrant interaction between these 2
tissues may result in several congenital
malformations of the kidney (eg, renal
agenesis, multicystic dysplastic kidney)
Ureteropelvic junction—last to canalize
most common site of obstruction (can be detected
on prenatal ultrasound as hydronephrosis)
Potter sequence (syndrome)
Oligohydramnios–>compression of
developing fetus–>limb deformities, facial anomalies (eg, low-set ears and
retrognathia, flattened nose), compression
of chest and lack of amniotic fluid aspiration
into fetal lungs–>pulmonary hypoplasia (cause of death).
Causes include ARPKD (Autosomal recessive polycystic kidney disease), obstructive uropathy (eg, posterior urethral valves), bilateral renal agenesis, chronic placental insufficiency.
POTTER sequence associated with:
Pulmonary hypoplasia
Oligohydramnios (trigger)
Twisted face
Twisted skin
Extremity defects
Renal failure (in utero)
_Inferior poles of both kidneys fuse
abnormally_. As they ascend from pelvis
during fetal development, horseshoe kidneys
get trapped under inferior mesenteric
artery and remain low in the abdomen.
Kidneys function normally.
Associated
with hydronephrosis (eg, ureteropelvic
junction obstruction), renal stones, infection,
chromosomal aneuploidy syndromes (eg,
Turner syndrome; trisomies 13, 18, 21), and
rarely renal cancer.
Congenital solitary functioning kidney
Condition of being born with only one functioning kidney. Majority asymptomatic with compensatory hypertrophy of contralateral kidney, but anomalies in contralateral kidney are
common. Often diagnosed prenatally via ultrasound.
Unilateral renal agenesis
Ureteric bud fails to develop and induce differentiation of metanephric mesenchyme –> complete absence of kidney and ureter.
Multicystic dysplastic kidney
Ureteric bud fails to induce differentiation of metanephric mesenchyme –> nonfunctional kidney consisting of cysts and connective tissue. Predominantly nonhereditary and usually unilateral; bilateral leads to Potter sequence.
congenital solitary functioning kidney-condition of being born with only one functioning kidney. majority are asymtomatic with compensatory hypertrophy of contralateral kidney, but anomalies in contralateral kidney are common. often diagnosed prenatally via ultrasound
Unilateral renal agenesis
multicystic dysplastic kidney
unilateral renal agenesis- ureteric bud fails to develop and induce differentiation of metanephric mesenchyme–> complete absence of kidney and ureter
Multicystic dysplastic kidney- ureter bud fails to induce differentiation of metanephric mesenchyme–> nonfunctional kidney consisting of cyst and connective tissue. predominantly nonhereditary and usually unilateral; bilateral leads to Potter sequence
Duplex collecting system- ureteral duplication, a kidney has two ureters (tubes that carry urine from the kidney to the bladder)
Bifurcation of ureteric bud before it enters the metanephric blastema creates a Y-shaped bifid ureter. Duplex collecting system can alternatively occur through two ureteric buds reaching and interacting with metanephric blastema.
Strongly associated with vesicoureteral reflux (condition in which urine flows backward from the bladder to one or both ureters and sometimes to the kidneys) and/or ureteral obstruction, increase risk for UTIs.
Posterior urethral valves
Membrane remnant in the posterior urethra in males; its persistence can lead to urethral obstruction (obstructive uropathy). Can be diagnosed prenatally by hydronephrosis and dilated or thick-walled bladder on ultrasound.
Most common cause of bladder outlet obstruction in male infants
important pathophysiology
the actual cause is unknown, but it is thought that the disruption at 9-14 weeks
typically, the wolffian duct integrate with the posterior uretera to form pilicae colliculi
so there is a theory that PUV result from abnormal integration of wolffian duct resulting in large pilicae colliculi that fused anteriorally, making it more difficult for urine to flow through
result of PUV= bladder wall hypertrophy and deposition of collagen, vesicoureteral reflux–> hydroneophrosis (swelling of kidney due to urin buld up).
urinary stasis–> urinary tract infection–> chronic kidney disease–> end-stage renal disease
Kidney anatomy and glomerular structure
Left kidney is taken during donor transplantation because it has a longer renal vein. Afferent = Arriving.
Efferent = Exiting.
Renal blood flow: renal artery –> segmental artery –> interlobar artery –> arcuate artery –> interlobular artery –> afferent arteriole –> glomerulus –> efferent arteriole –> vasa recta/ peritubular capillaries –> venous outflow.
The left renal vein recieved from 2 additional veins: left suprarenal and left gonadal veins.
In addition, despite the overall high renal blood flow, renal medulla recieve significantly less blood flow than renal cortex–> very sensitive to hypoxia–> vulnerable to ischemic damage.
Renal medulla is inherently at higher risk for ischemic damage
Course of ureters
Course of ureter: arises from renal pelvis, travels under gonadal arteries –> over common iliac artery –> under uterine artery/vas deferens (retroperitoneal).
Gynecologic procedures (eg, ligation of uterine or ovarian vessels) may damage ureter –> ureteral obstruction or leak.
Muscle fibers within the intramural part of the ureter prevent urine reflux
blood supply to the ureter:
- proximal-renal arteries
- middle-gonadal artery, aorta, common and internal iliac artery
- distal- internal iliac and superior vesical arteries
3 constrictions of ureter:
Ureteropelvic junction (most common site for obstruction)
Pelvic inlet
Ureterovesical junction
NOTE:Water (ureters) flows over the iliacs and under the bridge (uterine artery or vas deferens).
Fluid compartments
60–40–20 rule (% of body weight for average person):
60% total body water
40% ICF, mainly composed of K+, Mg2+, organic phosphates (eg, ATP)
reminder that RBC volume is part of the ICF
20% ECF, mainly composed of Na+, Cl–, HCO3 –, albumin
within the ECF, there is 75% interstitial fluid and 25% plasma
Plasma volume can be measured by radiolabeling albumin.
Extracellular volume can be measured by inulin or mannitol.
Osmolality = 285–295 mOsm/kg H2O.
normal Hct= 45% and HCT %=3 times [Hb] in g/dL
Glomerular filtration barrier
Responsible for filtration of plasma according to size and charge selectivity.
Composed of:
Fenestrated capillary endothelium
Basement membrane with type IV collagen chains and heparan sulfate
Epithelial layer consisting of podocyte foot processes
Charge barrier—all 3 layers contain ⊝ charged glycoproteins that prevent entry of ⊝ charged molecules (eg, albumin).
Size barrier—fenestrated capillary endothelium (prevent entry of > 100 nm molecules/blood cells); podocyte foot processes interpose with basement membrane; slit diaphragm (prevent entry of molecules > 50–60 nm).
Renal clearance
Cx = clearance of X (mL/min).
Ux = urine concentration of X (eg, mg/mL).
Px = plasma concentration of X (eg, mg/mL).
V = urine flow rate (mL/min).
Cx = (UxV)/Px = volume of plasma from which the substance is completely cleared per unit time.
GFR= 90 to 120 mL/min/1.73 m2
If Cx < GFR: net tubular reabsorption of X and/or not freely filtered.
If Cx > GFR: net tubular secretion of X.
If Cx = GFR: no net secretion or reabsorption.
Glomerular filtration rate
Inulin clearance can be used to calculate GFR because it is freely filtered and is neither reabsorbed nor secreted.
GFR = Uinulin × V/Pinulin = Cinulin = Kf [(PGC – PBS) – (πGC – πBS)]
(GC = glomerular capillary; BS = Bowman space; πBS normally equals zero; Kf = filtration coefficient).
Normal GFR ≈ 100 mL/min.
Creatinine clearance is an approximate measure of GFR. Slightly overestimates GFR because creatinine is moderately secreted by renal tubules.
Incremental reductions in GFR define the stages of chronic kidney disease.
Effective renal plasma flow
Effective renal plasma flow (eRPF) can be estimated using para-aminohippuric acid (PAH) clearance. Between filtration and secretion, there is nearly 100% excretion of all PAH that enters the kidney.
eRPF = UPAH × V/PPAH = CPAH.
Renal blood flow (RBF) = RPF/(1 − Hct). Usually 20–25% of cardiac output.
Plasma volume = TBV × (1 – Hct).
TBV (total blood volume)
eRPF underestimates true renal plasma flow (RPF) slightly
Filtration
Filtration fraction (FF) = GFR/RPF. Normal FF = 20%.
Filtered load (mg/min) = GFR (mL/min) × plasma concentration (mg/mL).
GFR can be estimated with creatinine clearance.
RPF is best estimated with PAH clearance.
Prostaglandins Dilate Afferent arteriole (PDA) Angiotensin II Constricts Efferent arteriole (ACE)
Changes in glomerular dynamics
- what happens when the afferent arteriole constricts?
- what happens when the efferent arteriole constrict?
- what happens when there is an increased in plasma protein concentration?
- what happens when there is a decreased in plasma concentration?
- what happens when there is a constriction of ureter?
- what happens when the patient is dehydrated?
in terms of GFR, RPF, FF (GFR/RPF)
GFR, RPF, FF (GFR/RPF)
- decrease, decrease, unchange
- increased, decreased, increased
- decreased, unchanged, decreased
- increased, unchanged, increased
- decreased, unchanged, decreased
- decreased. double decreased, increased
Calculation of reabsorption and secretion rate
Filtered load = GFR × Px.
Excretion rate = V × Ux.
Reabsorption rate = filtered – excreted.
Secretion rate = excreted – filtered.
FeNa = fractional excretion of sodium.
FeNA= Na excreted/Na filtered = V X UNA/GFR X PNA
where GFR= UCr X V/ PCr = (PCr X UNA)/ (UCr X PNA)
Glucose clearance
Glucose at a normal plasma level (range 60–120 mg/dL) is completely reabsorbed in proximal convoluted tubule (PCT) by Na+/glucose cotransport.
In adults, at plasma glucose of ∼ 200 mg/dL, glucosuria begins (threshold). At rate of ∼ 375 mg/min, all transporters are fully saturated (Tm).
Normal pregnancy is associated with increased GFR. With increased filtration of all substances, including glucose, the glucose threshold occurs at lower plasma glucose concentrations –> glucosuria at normal plasma glucose levels.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors (eg, -flozin drugs) result in glucosuria at plasma concentrations < 200 mg/dL.
Glucosuria is an important clinical clue to diabetes mellitus.
Splay phenomenon—Tm for glucose is reached gradually rather than sharply due to the heterogeneity of nephrons (ie, different Tm points); represented by the portion of the titration curve between threshold and Tm.
Tm (transport maximum)
Nephron physiology
Early PCT—contains brush border. Reabsorbs all glucose and amino acids and most HCO3 –, Na+, Cl–, PO4 3–, K+, H2O, and uric acid. Isotonic absorption. Generates and secretes NH3, which enables the kidney to secrete more H+
PTH—inhibits Na+/PO4 3– cotransport –> PO4 3– excretion.
AT II—stimulates Na+/H+ exchange –> increased Na+, H2O, and HCO3 − reabsorption (permitting contraction alkalosis). 65–80% Na+ reabsorbed.
Thin descending loop of Henle—passively reabsorbs H2O via medullary hypertonicity (impermeable to Na+). Concentrating segment. Makes urine hypertonic.
Thick ascending loop of Henle—reabsorbs Na+, K+, and Cl−. Indirectly induces paracellular reabsorption of Mg2+ and Ca2+ through ⊕ lumen potential generated by K+ backleak. Impermeable to H2O. Makes urine less concentrated as it ascends. 10–20% Na+ reabsorbed.
Early DCT—reabsorbs Na+, Cl−. Impermeable to H2O. Makes urine fully dilute (hypotonic). PTH— increased Ca2+/Na+ exchange increasing Ca2+ reabsorption. 5–10% Na+ reabsorbed.
Collecting tubule—reabsorbs Na+ in exchange for secreting K+ and H+ (regulated by aldosterone).
Aldosterone—acts on mineralocorticoid receptor –> mRNA –> protein synthesis. In principal cells: increased apical K+ conductance, increased Na+/K+ pump, epithelial Na+ channel (ENaC) activity –> lumen negativity –> K+ secretion. In α-intercalated cells: lumen negativity –> increased H+ ATPase activity –> increased H+ secretion –> increased HCO3 −/Cl− exchanger activity.
ADH—acts at V2 receptor –> insertion of aquaporin H2O channels on apical side. 3–5% Na+ reabsorbed.
Renal tubular defects
Fanconi syndrome
Bartter syndrome
Gitelman syndrome
Liddle syndrome
Syndrome of Apparent Mineralocorticoid Excess
Fanconi syndrome
Defects: Generalized reabsorption defect in PCT –> increased excretion of amino acids, glucose, HCO3 –, and PO4 3–, and all substances reabsorbed by the PCT
Effects: May lead to metabolic acidosis (proximal RTA), hypophosphatemia, osteopenia
Causes: Hereditary defects (eg, Wilson disease, tyrosinemia, glycogen storage disease), ischemia, multiple myeloma, nephrotoxins/drugs (eg, ifosfamide, cisplatin, expired tetracyclines), lead poisoning
Bartter syndrome
defects: Resorptive defect in thick ascending loop of Henle (affects Na+/K+/2Cl– cotransporter)
effects: Metabolic alkalosis, hypokalemia, hypercalciuria
causes: Autosomal recessive
Notes: Presents similarly to chronic loop diuretic use
Gitelman syndrome
defect: Reabsorption defect of NaCl in DCT
effects: Metabolic alkalosis, hypomagnesemia, hypokalemia, hypocalciuria
causes: Autosomal recessive
Notes: Presents similarly to lifelong thiazide diuretic use
Less severe than Bartter syndrome
Liddle syndrome
defects: Gain of function mutation –> increased activity of Na+ channel –> increase Na+ reabsorption in collecting tubules
effect: Metabolic alkalosis, hypokalemia, hypertension, decreased aldosterone
causes: Autosomal dominant
Notes: Presents similarly to hyperaldosteronism, but aldosterone is nearly undetectable
Treat with amiloride
Syndrome of Apparent Mineralocorticoid Excess
defects: In cells containing mineralocorticoid receptors. cortisol activates mineralocorticoid receptors, 11β-hydroxysteroid dehydrogenase converts cortisol (can activate these receptors) to cortisone (inactive on these receptors)
Hereditary deficiency of 11β-hydroxysteroid dehydrogenase –> excess cortisol –> increased mineralocorticoid receptor activity
effects: Metabolic alkalosis, hypokalemia, hypertension
decrease serum aldosterone level;
cortisol tries to be the SAME as aldosterone
causes: Autosomal recessive
Can acquire disorder from glycyrrhetinic acid (present in licorice), which blocks activity of 11β-hydroxysteroid dehydrogenase
Notes: Treat with K+-sparing diuretics (decreased mineralocorticoid effects) or corticosteroids (exogenous corticosteroid decrease endogenous cortisol production–>decrease mineralocorticoid receptor activation)
Relative concentrations along proximal convoluted tubules
Tubular inulin increase in concentration (but not amount) along the PCT as a result of water reabsorption. Cl− reabsorption occurs at a slower rate than Na+ in early PCT and then matches the rate of Na+ reabsorption more distally. Thus, its relative concentration increase before it plateaus.
Renin-angiotensin-aldosterone system
Renin-Secreted by JG cells in response to decrease renal perfusion pressure (detected by renal baroreceptors in afferent arteriole), increase renal sympathetic discharge (β1 effect), and decrease NaCl delivery to macula densa cells.
AT II-Helps maintain blood volume and blood pressure. Affects baroreceptor function; limits reflex bradycardia, which would normally accompany its pressor effects
ANP, BNP-Released from atria (ANP) and ventricles (BNP) in response to increase volume; may act as a “check” on renin-angiotensin-aldosterone system; relaxes vascular smooth muscle via cGMP –> increase GFR, decrease renin. Dilates afferent arteriole, constricts efferent arteriole, promotes natriuresis.
ADH-Primarily regulates serum osmolality; also responds to low blood volume states. Stimulates reabsorption of water in collecting ducts. Also stimulates reabsorption of urea in collecting ducts to maintain corticopapillary osmotic gradient.
Aldosterone-Primarily regulates ECF volume and Na+ content; responds to low blood volume states. Responds to hyperkalemia by increased K+ excretion.
