B&B Renal: Nephron Physiology Flashcards
Reabsorbed substances
- H2O
- NaCl
- K+
- HCO3-
- Glucose
- Amino acids
Diffusion
Reabsorption
[U] > [P]
* Diffusion from urine to blood through cells via channels
* Paracellular diffusion between cells
Osmotic diffusion
Reabsorption
Urine [mOsm] < Plasma [mOsm]
* Water reabsorption via osmosis either through cells or paracellularly
Segments of nephron
Histology
- Proximal tubule
- Descending limb
- Ascending limb
- Distal tubule
- Collecting duct
Proximal tubule
Reabsorption
- Complete reabsorption (100%):
- Glucose
- Amino acids
- Partial reabsorption (67%):
- Water
- HCO3-
- NaCl
- K+
- PO4-
Na/K-ATPase pump
Proximal Tubule
- Located in BL membrane
- Uses ATP to pump Na+ out of cells into blood
* Creates low [Na] in proximal tubule cells
* Cells use low [Na] as driving force to reabsorb solutes & H2O - K+ is pumped into cells from blood
- Creates high [K] in proximal tubule cells
BL = basolateral
Proximal tubule transporters
Reabsorption
- Glucose transporters
- SGLT2: uses [Na] gradient to cotransport glucose across apical membrane into cells
- GLUT1/2: facilitated diffusion of glucose across BL membrane into blood
- Cl-/K+ symporter: BL membrane
- Uses [K] gradient to cotransport K+ & Cl- into blood
- Cl- anion exchanger: apical membrane
- Links Cl- reabsorption to excretion of anions into urine
- Anions: OH-, formate, oxalate, sulfate
- Na+/H+ exchanger: apical membrane
- Cotransports Na+ into cells & H+ into urine
SGLT: sodium-glucose linked transporter; GLUT = glucose transporter
Glucose
Reabsorption
Completely reabsorbed in proximal tubule
* SGLT2: Na/glucose symporter
* Serum glucose: 160 mg/dL –> glycosuria
* Glucose: 300 mg/dL –> all SGLT2 saturated
* Any further increase in serum glucose will be excreted in the urine
* Diabetes mellitus = “sweet” diabetes
* Diabetics have sweet urine
Amino acids
Reabsorption
Completely reabsorbed in proximal tubule
* Na/AA cotransporters
* Hartnup disease
* No tryptophan transporter in PCT
* Tryptophan deficiency –> niacin deficiency
* Presentation:
* Skin rash resembling pellagra (plaques, desquamation)
* Amino acids in urine
Bicarbonate (HCO3-)
Proximal Tubule
- Na/H+ exchanger: apical membrane; cotransports Na into cells & H+ into urine
- H+ combines with HCO3- to form H2CO3
- Luminal CA: converts H2CO3 to CO2 & H2O
- CO2 & H20 diffuse into cells from urine
- Cytoplasmic CA: converts CO2 & H2O to H2CO3
- H2CO3 breaks down into H+ & HCO3-
- NBC: BL membrnae; cotransports Na & HCO3- from cells into blood
- H+ is recycled & progress repeats
- Result: Na+ & HCO3- reabsorbed; H+ secreted
CA: carbonic anhydrase; NBC: sodium bicarbonate cotransporter
Bicarbonate reabsorption
Clinical Correlations
- Carbonic anhydrase inhibitors
- Inhibit bicarcbonate reabsorption
- Weak diuretics: inhibit Na-linked uptake
- Type II renal tubular acidosis
- Ion defect; inability to absorb bicarbonate
- Metabolic acidosis
Fanconi syndrome
Proximal Tubule
Loss of proximal tubule functions
* Impaired resorption of solutes
* Loss of HCO3-, glucose, amino acids, phosphate, low MW proteins
Loss of proximal tubule functions
* Impaired resorption of solutes
* Loss of HCO3-, glucose, amino acids, phosphate, low MW proteins
Pathophysiology
Fanconi syndrome
- Polyuria, polydipsia
- Non-anion gap acidosis
- Hypokalemia
- Hypophosphatemia
- Amino acids in urine
Presentation
Fanconi syndrome
- Polyuria, polydipsia
- Osmotic diuresis due to glucose
- Normal serum glucose: contrast with DM
- Non-anion gap acidosis
- Acidosis due to loss of HCO3-
- Hypokalemia
- Increased nephron flow & loss of K+
- Hypophosphatemia
- Increased nephron flow & loss of PO4
Fanconi syndrome
Epidemiology
- Inherited or acquired syndrome (rare)
- Inherited form associated with cystinosis
- Lysosomal storage disease
- Results in accumulation of cystine
- Presents in infancy with Fanconi syndrome
- PCT = initial site of cystine buildup
Fanconi syndrome
Acquired Causes
- Lead poisoning
- Multiple myeloma
- Drugs
- Cisplatin (CTX)
- Ifosfamide (alkylating agent)
- Tenofovir (HIV drug)
- Valproate
- Aminoglycoside antibiotics
- Deferasirox (iron chelator)
Thin Descending Limb (TDL)
Loop of Henle
Permeable to H2O; impermeable to NaCl
* Hypertonicity of medulla draws water from urine
* Osmotic diffusion
* Water leaves urine & leaves NaCl behind
* Concentrates urine
* Dilute urine enters descending limb: 300 mOsm/L
* Concentrated urine leaves: 1200 mOsm/L
Osmolarity of nephron
Reabsorption
- Cortex: 300 mOsm/L
- Outer medulla: 600 mOsm/L
- Inner medulla: 1200 mOsm/L
Osmolar gradient
Osmolarity of Nephron
- Solutes that maintain gradient: Na, Cl, Urea
- Urea is generated by liver & protein metabolism
- Reabsorbed by collecting duct
- High permeability to urea
- Essential to maintaining gradients
- Resorbed urea accumulates in medullary interstitium
- Reabsorbed by collecting duct
Thick Ascending Limb (TAL)
Loop of Henle
Permeable to NaCl; impermeable to H2O
* NaCl is resorbed from urine
* NaCl resorption pulls solutes out of urine
* Dilutes urine
* Dilute urine leaves ascending limb: 120 mOsm/L
Thick ascending limb transporters
Loop of Henle
- Na/K-ATPase pump: BL membrane
- Uses ATP to pump Na+ into blood & cotransport K+ into cells
* Creates low [Na] & high [K] in cells
- Uses ATP to pump Na+ into blood & cotransport K+ into cells
- NKCC: apical membrane
- Uses [Na] gradient to cotransport Na+, K+, and 2 Cl- from urine into cells
- K+ channel: apical membrane
- Some K+ diffuses out of cells into urine down its concentration gradient
- Increased [K] in urine creates positive charge, which drives reabsorption of Mg2+, Ca2+ from urine via paracellular diffusion
NKCC: Na-K-Cl cotransporter
Distal tubule transporters
Reabsorption
Na+, Cl- , Ca2+ reabsorption
* Na/K-ATPase pump: BL membrane
* Uses ATP to pump Na+ into blood & cotransport K+ into cells
* Creates low [Na] & high [K] in cells
* NCC: apical membrane
* Uses [Na] gradient to cotransport Na & Cl from urine into cells
* Cl- channel: BL membrane
* Cl- diffuses across channels into blood
* Ca2+ channel: apical membrane
* Diffusion of Ca2+ from urine into cells
* Na+/Ca2+ exchanger: BL membrane
* Uses [Ca] to cotransport Na+ into cells & Ca2+ into blood
NCC: Na/Cl cotransporter
Principal cell transporters
Collecting Duct
Na+ & H2O reabsorption; K+ secretion
* * Na/K-ATPase pump: BL membrane
* Uses ATP to pump Na+ into blood & cotransport K+ into cells
* Creates low [Na] & high [K] in cells
* ENaC: apical membrane
* Facilitated diffusion of Na+ into cells
* Na+ reabsorption
* K+ channels: apical membrane
* Facilitated diffusion of K+ into urine
* K+ secretion
* AQP-2: apical membrane
* Increase membrane permeability to H2O
* H2O diffuses into cells following Na+
ENaC: epithelial Na+ channel; AQP-2: aquaporin-2
Intercalated cell transporters
Collecting Duct
H+ secretion
* H+-ATPase: apical membrane; uses ATP to pump H+ from cells into urine
Collecting Duct (CD)
Functions
- Reabsorption: Na+, H2O, urea
- Na: depends on aldosterone
- H2O: depends on ADH
- Urea: depends on ADH
- Secretion: K+, H+
- Increased Na+ delivery –> increased K+ excretion
- Contributes to hypokalemia with loop & thiazide diuretics
- Depends on aldosterone
- Increased Na+ delivery –> increased K+ excretion
Aldosterone
Collecting Duct Hormones
- Steroid (mineralocorticoid) hormone
- Promotes gene expression
- Upregulates: Na/K-ATPases, ENaC channels
- Promotes Na+ & H2O resorption
* Increases ECV - Promotes K+ secretion principal cells
- Promotes H+ secretion intercalated cells
- Promotes Na+ & H2O resorption
- Aldosterone release is stimulated by:
- Ang II (RAAS)
- Hyperkalemia
- ACTH (minor effect)
Nephron water permeability
H2O Reabsorption
- Permeable: proximal tubule, TDL
- Impermeable: TAL, distal tubule
- Variable: collecting duct
ADH
Collecting Duct Hormones
- Promotes free water retention
- Increases water resorption from urine
- Two ADH receptors:
- V1: vasoconstriction
- V2: antidiuretic response
- Released from posterior pituitary is stimulated by:
- Hyperosmolarity: physiologic stimulus
- Volume loss: non-osmotic release
ADH water resorption
Collecting Duct Hormones
- V2 receptors: located in CD principal cells
- GPCR; cAMP 2nd messenger system
- Activation of receptor induces endosome insertion into cell membrane
- Endosomes contain aquaporin-2
- Result: increased water permeability
- CD can be completely permeable / impermeable to water depending on presence of ADH & AQP-2
ADH & urea
- Urea = key osmole in kidney
- Medullary CD is permeable to urea
- ADH increases urea reabsorption - Urea enters medullary interstitium & forms osmotic gradient
- Urea is recycled in TDL: transporters return urea from interstitium into urine for excretion
