600 SEC TION III Renal   

RENAL—Anatomy

RENAL—ANATOMY
` 

Renal blood flow

Peritubular
Left renal vein receives two additional
Efferent capillaries veins: left suprarenal and left gonadal
arteriole
veins.
Glomerulus
Renal medulla receives significantly less
Afferent blood flow than the renal cortex. This
arteriole
makes medulla very sensitive to hypoxia
Interlobular
artery
and vulnerable to ischemic damage.
Arcuate
artery Left kidney is taken during living donor
Interlobar transplantation because it has a longer
artery Interlobular
vein renal vein.
Segmental Arcuate
artery vein
Renal
artery Interlobar
vein

Renal
vein

Glomerular anatomy

Glomerular
filtration barrier
Bowman capsule
Afferent arteriole Podocytes (visceral layer)
(parietal layer)
Basement membrane
Juxtaglomerular Fenestrated capillary
cells endothelium
Macula densa

Distal convoluted
tubule

Endothelial cells

Efferent arteriole Mesangial

cells

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 Renal   
RENAL—Physiology SEC TION III 601

Course of ureters Course of ureter A : arises from renal pelvis, Water (ureters) flows over the iliacs and under
A travels under gonadal arteries Ž over common the bridge (uterine artery or vas deferens).
iliac artery Ž under uterine artery/vas deferens Median
(retroperitoneal). umbilical Ureter
Gynecologic procedures (eg, ligation of ligament
Vas
uterine or ovarian vessels) may damage ureter Uterine deferens
artery (in male)
Ž ureteral obstruction or leak. (in female)
Bladder contraction compresses the intramural
Detrusor
ureter, preventing urine reflux. muscle
Ureteral orifice
Blood supply to ureter:
ƒ Proximal—renal arteries Trigone
Internal urethral orifice
ƒ Middle—gonadal artery, aorta, common and Prostate
internal iliac arteries
ƒ Distal—internal iliac and superior vesical
arteries
3 common points of ureteral obstruction:
ureteropelvic junction, pelvic inlet,
ureterovesical junction.

RENAL—PHYSIOLOGY
` 

Fluid compartments
Body mass: 70 kg HIKIN’: HIgh K+ INtracellularly.
Total body water (TBW) Non water mass (NWM) 60–40–20 rule (% of body weight for average
60% of body mass = 42 kg ≈ 42 L 40% of body mass = 28 kg
person):
Extracellular fluid (ECF)
~ 14 kg (20% of 70 kg)

ƒ 60% total body water

Interstitial fluid = 75% ECF ≈ 10.5 L ≈ 10.5 kg ƒ 40% ICF, mainly composed of K+, Mg2+,
1/3
organic phosphates (eg, ATP)
Blood volume ≈ 6 L

Plasma = 25% ECF ≈ 3.5 L ≈ 3.5 kg

ƒ 20% ECF, mainly composed of Na+, Cl–,
RBC volume ≈ 2.8 L HCO3–, albumin
Plasma volume can be measured by
Intracellular fluid (ICF)

Normal Hct ≈ 45%

~ 28 kg (40% of 70 kg)

radiolabeling albumin.
Extracellular volume can be measured by inulin
2/3
or mannitol.
Serum osmolality = 275–295 mOsm/kg H2O.
Plasma volume = TBV × (1 – Hct).

Glomerular filtration Responsible for filtration of plasma according to Charger barrier—glomerular filtration barrier
barrier size and charge selectivity. contains ⊝ charged glycoproteins that prevent
A Composed of entry of ⊝ charged molecules (eg, albumin).
Endothelial ƒ Fenestrated capillary endothelium Size barrier—fenestrated capillary endothelium
cell pore ƒ Basement membrane with type IV collagen (prevents entry of > 100 nm molecules/blood
M chains and heparan sulfate cells); podocyte foot processes interpose with
GB ƒ Visceral epithelial layer consisting of glomerular basement membrane (GBM);
FP
FP podocyte foot processes (FPs) A slit diaphragm (prevents entry of molecules
G BM > 40–50 nm).

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 602 SEC TION III Renal   
RENAL—Physiology

Renal clearance Cx = (UxV)/Px = volume of plasma from which Cx = clearance of X (mL/min).

the substance is completely cleared in the Ux = urine concentration of X (eg, mg/mL).
urine per unit time. Px = plasma concentration of X (eg, mg/mL).
If Cx < GFR: net tubular reabsorption and/or V = urine flow rate (mL/min).
not freely filtered.
If Cx > GFR: net tubular secretion of X.
If Cx = GFR: no net secretion or reabsorption.

Glomerular filtration Inulin clearance can be used to calculate GFR 14

rate because it is freely filtered and is neither
reabsorbed nor secreted. 12

Cinulin = GFR = Uinulin × V/Pinulin

10
= K f [(PGC – PBS) – (πGC – πBS)]

Plasma creatinine
(mg/100 mL)
(PGC = glomerular capillary hydrostatic pressure; 8
PBS = Bowman space hydrostatic pressure; πGC =
glomerular capillary oncotic pressure; πBS = 6

Bowman space oncotic pressure; πBS normally

equals zero; K f = filtration coefficient). 4

Normal GFR ≈ 100 mL/min. 2

Creatinine clearance is an approximate measure
of GFR. Slightly overestimates GFR because
creatinine is moderately secreted by renal 25 50 75 100 125 150
tubules. Glomerular filtration rate
(mL/min)

Renal blood flow Autoregulatory mechanisms help maintain a constant RBF and GFR to protect the kidney from
autoregulation rapid increases or decreases in renal perfusion pressure that could cause renal injury or decrease
glomerular filtration. Mechanisms:
Myogenic:  arterial pressure Ž stretch of afferent arterioleŽ mechanical activation of vascular
smooth muscle Ž vasoconstriction of afferent arteriole Ž  RBF.
Tubuloglomerular:  NaCl or tonicity of the filtrate sensed by macula densa cells Ž paracrine-
driven vasoconstriction of afferent arteriole Ž  RBF.

Effective renal plasma Effective renal plasma flow (eRPF) can be Afferent Efferent
flow estimated using para-aminohippuric acid arteriole arteriole
(PAH) clearance. Between filtration and
secretion, there is nearly complete excretion of
all PAH that enters the kidney.
eRPF = UPAH × V/PPAH = CPAH.
Renal blood flow (RBF) = RPF/(1 − Hct). Bowman
PAH
Usually 20–25% of cardiac output. space
eRPF underestimates true renal plasma flow 20% filtered
(RPF) slightly. (occurs
throughout PT)
80% secreted

100% excreted

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 Renal   
RENAL—Physiology SEC TION III 603

Filtration Filtration fraction (FF) = GFR/RPF. GFR can be estimated with creatinine
Normal FF = 20%. clearance.
Filtered load (mg/min) = GFR (mL/min) RPF is best estimated with PAH clearance.
× plasma concentration (mg/mL). Prostaglandins Dilate Afferent arteriole (PDA).
Angiotensin II Constricts Efferent arteriole
(ACE).
Prostaglandins preferentially
NSAIDs dilate afferent arteriole Bowman capsule
( RPF, GFR, so no ∆ FF) (parietal layer)

man s pace
A ere

Podocytes
Bow (visceral layer)
nt a
r te r
io

PBS
Juxtaglomerular
le

cells πGC
Filtered Excreted
Macula densa PGC

πBS Reabsorbed Secreted

Distal renal
tubule Peritubular
capillary
Net filtration pressure
Endothelial cells = (PGC + πBS ) – (PBS + πGC )

Mesangial Basement
cells membrane
E erent arteriole

Angiotensin II preferentially
ACE inhibitors constricts efferent arteriole
( RPF, GFR, so FF)

Changes in glomerular dynamics

GFR RPF FF (GFR/RPF)
Afferent arteriole constriction   —
Efferent arteriole constriction   
 plasma protein concentration  — 
 plasma protein concentration  — 
Constriction of ureter  — 
Dehydration   

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 604 SEC TION III Renal   
RENAL—Physiology

Calculation of Filtered load = GFR × Px.

reabsorption and Excretion rate = V × Ux.
secretion rate Reabsorption rate = filtered – excreted.
Secretion rate = excreted – filtered.
FeNa = fractional excretion of sodium.
Na+ excreted V × UNa P × UNa U ×V
FeNa = = = Cr where GFR = Cr
Na+ filtered GFR × PNa UCr × PNa PCr

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  GFR.
With  filtration of all substances, including
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.
600
Filtered
Excreted

Glucose transport (mg/min)

Tm ~ 375mg/min
glucose, the glucose threshold occurs at lower 450
Reabsorbed
plasma glucose concentrations Ž glucosuria at
300
normal plasma glucose levels.
Sodium-glucose cotransporter 2 (SGLT2) 150
“Splay”
Renal
inhibitors (eg, -flozin drugs) result in threshold
glucosuria at plasma concentrations 0
< 200 mg/dL. 0 200 400 600 800
Normal Plasma glucose (mg/dL)

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 Renal   
RENAL—Physiology SEC TION III 605

Nephron transport physiology

Apical membrane - urine Basolateral membrane - blood Apical membrane - urine Basolateral membrane - interstitium
Proximal convoluted tubule Distal convoluted tubule
SGLT-2 inhibitors
Thiazide
Na+ diuretics 3Na+
Glucose 3Na+ Na+ ATP
Angiotensin II ATP
CI– 2K+
Na+ 2K+
R PTH
HCO₃– H+ H+ + HCO₃– Mg2+
Na+
H₂ CO₃ Na+
Acetazolamide H₂ CO₃ Ca2+
Ca2+
CA CA CI– CI– channel
CO₂ + H₂O CO₂ + H₂O diffusion
CI–
Base–
Early DCT—reabsorbs Na+, Cl−. Impermeable to H2O.
Makes urine fully dilute (hypotonic).
PTH— Ca2+/Na+ exchange   Ca2+ reabsorption.
Early PCT—contains brush border. Reabsorbs all glucose 5–10% Na+ reabsorbed.
and amino acids and most HCO3–, Na+, Cl–, PO43–, K+,
Apical membrane - urine Basolateral membrane - blood
H2O, and uric acid. Isotonic absorption. Generates and Collecting tubule
secretes NH3, which enables the kidney to secrete more CI–
H+. Principal cell

PTH—inhibits Na+/PO43– cotransport   PO43– excretion. H₂O V2 ADH

AT II—stimulates Na+/H+ exchange   Na+, H2O, and UT1 receptor Aquaporins on
Urea vesicle membrane
HCO3− reabsorption (permitting contraction alkalosis).
65–80% Na+ and H2O reabsorbed. K+ 3Na+
Amiloride ATP
Triamterene 2K+
Thin descending loop of Henle—passively reabsorbs H2O Na+ R Aldosterone
via medullary hypertonicity (impermeable to Na+).
Concentrating segment. Makes urine hypertonic. Spironolactone
α-intercalated cell
Eplerenone
Apical membrane - urine Basolateral membrane - blood
Thick ascending limb
ATP R Aldosterone
Loop diuretics H+
Na+ 3Na+
K+ ATP K+ HCO₃–
2CI– ATP CI–
2K+
H+

K+ Diffusion down β-intercalated cell

(+) K+ the electrochemical
potential CI– H+
CI– gradient ATP
HCO₃–

Mg2+, Ca2+
Collecting tubule—reabsorbs Na+ in exchange for
secreting K+ and H+ (regulated by aldosterone).
Thick ascending loop of Henle—reabsorbs Na+, K+, and Aldosterone—acts on mineralocorticoid receptor  mRNA
Cl−. Indirectly induces paracellular reabsorption of Mg2+  protein synthesis. In principal cells:  apical K+
and Ca2+ through ⊕ lumen potential generated by K+ conductance,  Na+/K+ pump,  epithelial Na+ channel
backleak. Impermeable to H2O. Makes urine less (ENaC) activity  lumen negativity  K+ secretion. In
concentrated as it ascends. α-intercalated cells: lumen negativity   H+ ATPase
10–20% Na+ reabsorbed. activity   H+ secretion   HCO3−/Cl− exchanger
activity.
ADH—acts at V2 receptor  insertion of aquaporin H2O
channels on apical side.
3–5% Na+ reabsorbed.

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 606 SEC TION III Renal   
RENAL—Physiology

Renal tubular defects Order: Fanconi’s BaGeLS Fanconi

Gitelman
syndrome
syndrome

Bartter
syndrome
Liddle
syndrome,
SAME

DEFECTS EFFECTS CAUSES NOTES

Fanconi syndrome Generalized Metabolic acidosis Hereditary defects Growth retardation
reabsorption defect in (proximal RTA), (eg, Wilson disease, and rickets/osteopenia
PCT Ž  excretion of hypophosphatemia, tyrosinemia, glycogen common due to
amino acids, glucose, hypokalemia storage disease), hypophosphatemia
HCO3–, and PO43–, ischemia, multiple Volume depletion also
and all substances myeloma, drugs (eg, common
reabsorbed by the ifosfamide, cisplatin,
PCT tenofovir, lead
poisoning
Bartter syndrome Reabsorption defect Metabolic alkalosis, Autosomal recessive Presents similarly to
in thick ascending hypokalemia, chronic loop diuretic
loop of Henle hypercalciuria use
(affects Na+/K+/2Cl–
cotransporter)
Gitelman syndrome Reabsorption defect of Metabolic alkalosis, Autosomal recessive Presents similarly to
NaCl in DCT hypomagnesemia, chronic thiazide
hypokalemia, diuretic use
hypocalciuria Less severe than Bartter
syndrome
Liddle syndrome Gain of function Metabolic alkalosis, Autosomal dominant Presents similarly to
mutation Ž  Na+ hypokalemia, hyperaldosteronism,
channel degradation hypertension, but aldosterone is
Ž  Na+ reabsorption  aldosterone nearly undetectable
in collecting tubules Treatment: amiloride
Syndrome of Cortisol activates Metabolic alkalosis, Autosomal recessive Treatment: K+-sparing
Apparent mineralocorticoid hypokalemia, Can acquire disorder diuretics ( mineralo-
Mineralocorticoid receptors; 11β-HSD hypertension from glycyrrhetinic corticoid effects)
Excess converts cortisol to  serum aldosterone acid (present in or corticosteroids
cortisone (inactive on level; cortisol tries licorice), which (exogenous cortico-
these receptors) to be the SAME as blocks activity of steroid  endogenous
Hereditary 11β-HSD aldosterone 11β-hydroxysteroid cortisol production
deficiency Ž  cortisol dehydrogenase Ž  mineralocorticoid
Ž  mineralocorticoid receptor activation)
receptor activity

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 Renal   
RENAL—Physiology SEC TION III 607

Relative 1.90
concentrations along [TF/P] > 1 PAH
1.85 Creatinine
when solute is
proximal tubule reabsorbed less quickly 1.80
than water or when solute Inulin
clearance = GFR
is secreted 1.75
Urea
[TF/P] = 1 1.50
when solute Cl−
and water are [Tubular 1.25
fluid] K+
reabsorbed at the 1.00
same rate [Plasma] Osmolarity, Na+
0.75 HCO3–
[TF/P] < 1
when solute 0.50
is reabsorbed more Amino acids
0.25
quickly than water Glucose
0.0
0% 25% 50% 75% 100%
% Distance along PT length

Tubular inulin  in concentration (but not amount) along the PT 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  before it plateaus.

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 608 SEC TION III Renal   
RENAL—Physiology

Renin-angiotensin-aldosterone system

Distal convoluted Afferent arteriole

tubule
RAAS Activators
↑
BP (renal baroreceptors)
↑
NaCl delivery
(macula densa cells) Angiotensinogen Angiotensin I
↑ sympathetic tone Renin
( β1-receptors) ACE

Macula densa
Efferent arteriole Angiotensin II
Bradykinin
Juxtaglomerular cells breakdown

Hypothalamus

Thirst

Angiotensin II Constricts efferent ↑ Na+/H+ Aldosterone ADH (posterior

receptor type I arteriole activity secretion pituitary)

Vasoconstriction ↑ FF

PCT α-intercalated Principal Renal

↑ BP Preserves cell cell cell cells
GFR (when
↑
RBF )

Na+ , HCO₃ , and H₂O H+ secretion Na+ reabsorption H₂O reabsorption

reabsorption (permits ( ↑ H+ ATPase K+ secretion (via aquaporins)
contraction alkalosis) activity) ( ↑ K+ conductance,
Na+/K+-ATPase,
and ENaC activity)

Renin Secreted by JG cells in response to  renal perfusion pressure (detected in afferent arteriole),  renal
sympathetic discharge (β1 effect), and  NaCl delivery to macula densa cells.
ACE Catalyzes conversion of angiotensin I to angiotensin II. Located in many tissues but conversion
occurs most extensively in the lung. Produced by vascular endothelial cells in the lung.
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  volume; inhibits renin-angiotensin-
aldosterone system; relaxes vascular smooth muscle via cGMP Ž  GFR,  renin. Dilates afferent
arteriole, promotes natriuresis.
ADH (vasopressin) 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
maximize corticopapillary osmotic gradient.
Aldosterone Primarily regulates ECF volume and Na+ content;  release in hypovolemic states. Responds to
hyperkalemia by  K+ excretion.

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 Renal   
RENAL—Physiology SEC TION III 609

Juxtaglomerular Consists of mesangial cells, JG cells (modified JGA maintains GFR via renin-angiotensin-
apparatus smooth muscle of afferent arteriole), and the aldosterone system.
macula densa (NaCl sensor located at the β-blockers  BP by  CO and inhibiting β1-
DCT). JG cells secrete renin in response to receptors of the JGA Ž  renin release.
 renal blood pressure and  sympathetic tone
(β1). Macula densa cells sense  NaCl delivery
to DCT Ž  renin release Ž efferent arteriole
vasoconstriction Ž  GFR.

Kidney hormone functions

Erythropoietin Released by interstitial cells in peritubular Stimulates RBC proliferation in bone marrow.
capillary bed in response to hypoxia. Administered for anemia secondary to chronic
kidney disease.  risk of HTN.
Calciferol (vitamin D) PCT cells convert 25-OH vitamin D3 to 1,25- 25-OH D3 1,25-(OH)2 D3
(OH)2 vitamin D3 (calcitriol, active form). (calcidiol) 1α-hydroxylase (calcitriol)
Increases calcium absorption in small bowel.

PTH

Prostaglandins Paracrine secretion vasodilates afferent arterioles NSAIDs block renal-protective prostaglandin
to  RBF. synthesis Ž constriction of afferent arteriole
and  GFR; this may result in acute kidney
injury in low renal blood flow states.
Dopamine Secreted by PT cells, promotes natriuresis. At
low doses; dilates interlobular arteries, afferent
arterioles, efferent arterioles Ž  RBF, little
or no change in GFR. At higher doses; acts as
vasoconstrictor.

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 610 SEC TION III Renal   
RENAL—Physiology

Hormones acting on kidney

Atrial natriuretic peptide
Secreted in response to ↑ atrial pressure. Causes
indirect afferent arteriole dilation (through inhibition
of NE). Causes ↑ GFR and ↑ Na+ filtration with no
compensatory Na+ reabsorption in distal nephron. Distal
convoluted
Glomerulus Net effect: Na loss and volume loss.
+
tubule Ca2+
Na+
Proximal CI–
convoluted
tubule

Mg2+
Sugars
Amino acids
K+ Aldosterone
H+
Na+ Secreted in response to
Angiotensin II ↓ blood volume (via AT II) and
Synthesized in response to ↓ BP. Causes efferent arteriole ↑ plasma [K+ ]; causes ↑ Na+
constriction ↑ GFR and ↑ FF but with compensatory Na+ Ca2+
reabsorption, ↑ K+ secretion,
↓

Mg2+ Na +

reabsorption in proximal and distal nephron. Net effect: H ↑ H+ secretion.

Cortex
preservation of renal function (↑ FF) in low-volume state
with simultaneous Na+ reabsorption (both proximal Medulla ADH (vasopressin)
and distal) to maintain circulating volume. Na+
K+ Secreted in response to
2CI– ↑ plasma osmolarity and
Parathyroid hormone ↓ blood volume. Binds to
Secreted in response to Ascending limb,
loop of Henle receptors on principal cells,
↓ plasma [Ca2+], ↑ plasma [PO43–],
(permeable to salts) causing ↑ number of
or ↓ plasma 1,25-(OH)2 D3. aquaporins and ↑ H2O
Causes ↑ [Ca2+] reabsorption (DCT), reabsorption.
↓ [PO43–] reabsorption (PCT), and ↑ reabsorption of urea in
↑ 1,25-(OH)2 D3 production Collecting
collecting ducts to maximize
duct
(↑ Ca2+ and PO43– absorption from gut corticopapillary osmotic
via vitamin D). gradient.
Loop of Henle

Potassium shifts SHIFTS K+ INTO CELL (CAUSING HYPOKALEMIA) SHIFTS K+ OUT OF CELL (CAUSING HYPERKALEMIA)
Digoxin (blocks Na+/K+-ATPase)
Hypo-osmolarity HyperOsmolarity
Lysis of cells (eg, crush injury, rhabdomyolysis,
tumor lysis syndrome)
Alkalosis (low K+) Acidosis
β-adrenergic agonist ( Na /K -ATPase) + +
β-blocker
Insulin ( Na /K -ATPase)
+ +
High blood Sugar (insulin deficiency)
Insulin shifts K+ into cells Succinylcholine ( risk in burns/muscle trauma)
Hyperkalemia? DO LAβSS

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 Renal   
RENAL—Physiology SEC TION III 611

Electrolyte disturbances
ELECTROLYTE LOW SERUM CONCENTRATION HIGH SERUM CONCENTRATION
Sodium Nausea, malaise, stupor, coma, seizures Irritability, stupor, coma
Potassium U waves and flattened T waves on ECG, Wide QRS and peaked T waves on ECG,
arrhythmias, muscle cramps, spasm, weakness arrhythmias, muscle weakness
Calcium Tetany, seizures, QT prolongation, twitching Stones (renal), bones (pain), groans (abdominal
(eg, Chvostek sign), spasm (eg, Trousseau sign) pain), thrones ( urinary frequency), psychiatric
overtones (anxiety, altered mental status)
Magnesium Tetany, torsades de pointes, hypokalemia,  DTRs, lethargy, bradycardia, hypotension,
hypocalcemia (when [Mg2+] < 1.0 mEq/L) cardiac arrest, hypocalcemia
Phosphate Bone loss, osteomalacia (adults), rickets Renal stones, metastatic calcifications,
(children) hypocalcemia

Features of renal disorders

CONDITION BLOOD PRESSURE PLASMA RENIN ALDOSTERONE SERUM Mg2+ URINE Ca2+
SIADH —/   — —
Primary    — —
hyperaldosteronism
Renin-secreting tumor    — —
Bartter syndrome —   — 
Gitelman syndrome —    
Liddle syndrome,    — —
syndrome
of apparent
mineralocorticoid
excess
  = important differentiating feature.

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 612 SEC TION III Renal   
RENAL—Physiology

Acid-base physiology
Metabolic acidosis
Metabolic alkalosis
Respiratory acidosis
Respiratory alkalosis
Key:   = compensatory response.
Metabolic acid-base disorders cause HCO3– alterations. Respiratory acid-base disorders cause PCO2
alterations.
pH Pco2 [HCO3–] COMPENSATORY RESPONSE
   Hyperventilation (immediate)
   Hypoventilation (immediate)
    renal [HCO3–] reabsorption (delayed)
    renal [HCO3–] reabsorption (delayed)

[HCO3−]
Henderson-Hasselbalch equation: pH = 6.1 + log
0.03 Pco2
Predicted respiratory compensation for a simple metabolic acidosis can be calculated using the
Winters formula. If measured Pco2 > predicted Pco2 Ž concomitant respiratory acidosis; if
measured Pco2 < predicted Pco2 Ž concomitant respiratory alkalosis:
Pco2 = 1.5 [HCO3–] + 8 ± 2

Acidosis and alkalosis

Check arterial pH

pH < 7.35 pH > 7.45

Acidemia Alkalemia

Pco2 > 44 mm Hg HCO3– < 20 mEq/L Pco2 < 36 mm Hg HCO3– > 28 mEq/L

Respiratory Respiratory
Metabolic acidosis Metabolic alkalosis
acidosis alkalosis

Check urine Cl–

Hypoventilation Check anion gap Hyperventilation
_
= Na + – (CI– + HCO3 ) > 20 mEq/L < 20 mEq/L
Airway obstruction Anxiety/panic attack
Acute lung disease Hypoxemia (eg, high altitude)
Chronic lung disease Saline-resistant Saline-responsive
Salicylates (early)
Opioids, sedatives Tumor Hyperaldosteronism Vomiting
Weakening of respiratory Pulmonary embolism Bartter syndrome Recent loop/
muscles Pregnancy Gitelman syndrome thiazide diuretics
Current loop/thiazide Antacids
diuretics

> 12 mEq/L 8–12 mEq/L Pco2 =

45 Metabolic
40 mm Hg
alkalosis
40 Respiratory
 Anion gap Normal anion gap acidosis
Plasma [HCO3– ] (mmol/L)

35 Mixed
GOLDMARK: HARDASS 30 alkalosis
Glycols (ethylene glycol, propylene glycol) Hyperchloremia/hyperalimentation
Oxoproline (chronic acetaminophen use) Addison disease 25
Buffer line
L-lactate (lactic acidosis) Renal tubular acidosis 20 Mixed
D-lactate (exogenous lactic acid) Diarrhea acidosis
15
Methanol (and other alcohols) Acetazolamide
Aspirin (late effect) Spironolactone 10 Respiratory
Renal failure Saline infusion Metabolic alkalosis
5 acidosis
Ketones (diabetic, alcoholic, starvation)
6.9 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9
pH

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 Renal   
RENAL—Physiology SEC TION III 613

Renal tubular acidosis

Distal renal tubular acidosis Proximal renal tubular Hyperkalemic tubular
(RTA type 1) acidosis (RTA type 2) acidosis (RTA type 4)
DEFECT Inability of α-intercalated Defect in PCT HCO3– Lumen - urine Hypoaldosteronism orInterstitium - blood
cells to secrete H+ Ž no reabsorption Ž  excretion of aldosterone
α-intercalated resistance;
cell

new HCO3– is generated HCO3 in urine Ž metabolic

–
hyperkalemia
CO +
2 2H O Ž  NH3
K+ CA II
Ž metabolic acidosis acidosis synthesis
ATP
in PCT Ž  NH4+
H2CO3
Urine can be acidified by excretion
H+

α-intercalated cells in –
H+ H+ HCO₃ -
collecting duct, but not ATP RTA 1 CI–
HCO₃

enough to overcome  HCO3–

excretion
URINE pH > 5.5 < 5.5 when plasma HCO3– < 5.5 (or variable)
below reduced resorption Lumen - urine Interstitium - blood
Proximal convoluted tubule
threshold
> 5.5 when filtered HCO3– Na+
RTA 2

exceeds resorptive threshold

HCO₃
-
H+ H+ + HCO₃
– HCO₃
-

SERUM K+   H₂ CO₃
H₂ CO₃
CAUSES Amphotericin B toxicity, Fanconi syndrome, multiple CA  aldosterone production (eg,
CO₂ + H₂O CO₂ + H₂O
analgesic nephropathy, myeloma, carbonic anhydrase diabetic hyporeninism, ACE
congenital anomalies inhibitors inhibitors, ARB, NSAIDs,
(obstruction) of urinary tract, heparin, cyclosporine, adrenal
autoimmune diseases (eg, α-intercalated cell
Lumen - urine Interstitium - blood
insufficiency) or aldosterone
-
SLE) CO2 + H2O
HCO₃ resistance (eg, K+-sparing
α-intercalated cell
K + CA II diuretics, nephropathy due to
ATP ATP
H +
H2CO3
obstruction,
H+ TMP-SMX)
ASSOCIATIONS  risk for calcium phosphate
H+ H+ HCO₃ for hypophosphatemic
 risk –
- K+ HCO₃
–
HCO₃
kidney stones (due to  urine
ATP RTA 1 rickets (in CIFanconi
–
syndrome)
HCO₃
- ATP CI–
H+
pH and  bone turnover
related to buffering)
RTA type 1 RTA type 2 RTA type 4
Lumen - urine Interstitium - blood Lumen - urine Interstitium - blood aldosterone or aldosterone resistance
α-intercalated cell Proximal convoluted tubule
Lumen - urine Interstitium - blood
RTA 2 Proximal convoluted tubule
CO2 + H2O
Na+
K+ CA II
- -
H+ –
ATP HCO₃ H+ + HCO₃ HCO₃
H2CO3 NH₃ NH3 production K+
H+ H₂ CO₃
H₂ CO₃
– CA
H+ H+ HCO₃ -
HCO₃ CO₂ + H₂O CO₂ + H₂O
ATP RTA 1 CI–

α-intercalated cell

ATP R Aldosterone
- H+
HCO₃ NH₄+ RTA 4
α-intercalated cell –
Lumen - urine Interstitium - blood K+ HCO₃
Proximal convoluted tubule
ATP ATP CI–
RTA 2 H+ H+
Na+
K+ –
- – - HCO₃
HCO₃ H+ H+ + HCO₃ HCO₃
- ATP CI–
HCO₃
H+
H₂ CO₃
H₂ CO₃
CA
CO₂ + H₂O CO₂ + H₂O

aldosterone or aldosterone resistance

Lumen - urine Interstitium - blood
Proximal convoluted tubule

- NH3 production K+
HCO₃ NH₃
α-intercalated cell

ATP
H+

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K HCO₃ α-intercalated cell
 614 SEC TION III Renal   
RENAL—Pathology

RENAL—PATHOLOGY
` 

Casts in urine Presence of casts indicates that hematuria/pyuria is of glomerular or renal tubular origin.
Bladder cancer, kidney stones Ž hematuria, no casts.
Acute cystitis Ž pyuria, no casts.
All casts contain a matrix composed primarily of Tamm-Horsfall mucoprotein (uromodulin),
secreted by renal tubular cells to prevent UTIs.
RBC casts A Glomerulonephritis, hypertensive emergency.
WBC casts B Tubulointerstitial inflammation, acute pyelonephritis, transplant rejection.
Granular casts C Acute tubular necrosis (ATN). Can be “muddy brown” in appearance.
Fatty casts (“oval fat Nephrotic syndrome. Associated with “Maltese cross” sign D .
bodies”)
Waxy casts End-stage renal disease/chronic kidney disease.
Hyaline casts E Nonspecific, can be a normal finding with dehydration, exercise, or diuretic therapy.
A B C D E

Nomenclature of glomerular disorders

TYPE CHARACTERISTICS EXAMPLE
Focal < 50% of glomeruli are involved Focal segmental glomerulosclerosis
Diffuse > 50% of glomeruli are involved Diffuse proliferative glomerulonephritis
Proliferative Hypercellular glomeruli Membranoproliferative glomerulonephritis
Membranous Thickening of glomerular basement membrane Membranous nephropathy
(GBM)
Primary glomerular 1° disease of the kidney specifically impacting Minimal change disease
disease the glomeruli
Secondary glomerular Systemic disease or disease of another organ SLE, diabetic nephropathy
disease system that also impacts the glomeruli

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 Renal   
RENAL—Pathology SEC TION III 615

Glomerular diseases

Glomerular capillary
Endothelial cell
Protein
Basement membrane

RBC Podocyte
Urinary (Bowman) space

NEPHRITIC SYNDROME NEPHROTIC SYNDROME

NEPHRITIC-NEPHROTIC SYNDROME

TYPE ETIOLOGY CLINICAL PRESENTATION EXAMPLES

Nephritic syndrome Glomerular inflammation Hematuria, RBC casts in urine
Ž GBM damage Ž loss  GFR Ž oliguria, azotemia
of RBCs into urine  renin release, HTN
Ž dysmorphic RBCs, Proteinuria often in the
hematuria subnephrotic range (< 3.5 g/
day) but in severe cases may
be in nephrotic range
Nephrotic syndrome Podocyte damage Ž impaired Massive proteinuria (> 3.5 g/day)
charge barrier Ž proteinuria with edema, hypoalbuminemia
Ž  hepatic lipogenesis Ž
hypercholesterolemia
Frothy urine with fatty casts
Associated with hypercoagulable
state due to antithrombin
III loss in urine and  risk of
infection (loss of IgGs in urine
and soft tissue compromise by
edema)
Nephritic-nephrotic Severe GBM damage Ž loss of Nephrotic-range proteinuria
syndrome RBCs into urine + impaired (> 3.5 g/day) and concomitant
charge barrier Ž hematuria features of nephritic syndrome
+ proteinuria
ƒ Infection-associated
glomerulonephritis
ƒ Goodpasture syndrome
ƒ IgA nephropathy (Berger
disease)
ƒ Alport syndrome
ƒ Membranoproliferative
glomerulonephritis
May be 1° (eg, direct podocyte
damage) or 2° (podocyte
damage from systemic
process):
ƒ Focal segmental
glomerulosclerosis (1° or 2°)
ƒ Minimal change disease (1°
or 2°)
ƒ Membranous nephropathy
(1° or 2°)
ƒ Amyloidosis (2°)
ƒ Diabetic
glomerulonephropathy (2°)
Can occur with any form of
nephritic syndrome, but is
most common with:
ƒ Diffuse proliferative
glomerulonephritis
ƒ Membranoproliferative
glomerulonephritis

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 616 SEC TION III Renal   
RENAL—Pathology

Nephritic syndrome
MECHANISM LIGHT MICROSCOPY IMMUNOFLUORESCENCE ELECTRON MICROSCOPY
Infection-related Type III hypersensitivity Enlarged and Granular (“starry Subepithelial IC humps
glomerulonephritis reaction with hypercellular sky”) appearance
consumptive glomeruli A (“lumpy-bumpy”)
hypocomplimentemia B due to IgG, IgM,
Children: seen ~2–4 and C3 deposition
weeks after group along GBM and
A streptococcal mesangium
pharyngitis or skin
infection
Adults: Staphylococcus
is additional causative
agent
IgA nephropathy Occurs concurrently Mesangial proliferation IgA-based IC deposits Mesangial IC
(Berger disease) with respiratory or in mesangium deposition
GI tract infections
(IgA is secreted by
mucosal linings)
Renal pathology of IgA
vasculitis
Rapidly progressive Poor prognosis Crescent moon Linear IF due to Goodpasture syndrome:
(crescentic) Multiple causes: shape C ; crescents antibodies to breaks in GMB,
glomerulonephritis Type II HSR in consist of fibrin and GBM and alveolar necrosis and crescent
Goodpasture plasma proteins basement membrane: formation with no
syndrome (eg, C3b) with Goodpasture deposits
glomerular parietal syndrome— Pauci-immune: usually
cells, monocytes, hematuria/ no deposits; if IC
macrophages hemoptysis; type deposits, more severe
II hypersensitivity presentation
reaction PSGN: dome-shaped
Negative IF/Pauci- subendothelial and
immune (no subepithelial electron-
IgC3 deposition): dense deposits
granulomatosis with (humps)
polyangiitis—PR3-
ANCA/c-ANCA,
eosinophilic
granulomatosis
with polyangiitis,
or Microscopic
polyangiitis—MPO-
ANCA/p-ANCA
Granular IF—PSGN
or DPGN

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 Renal   
RENAL—Pathology SEC TION III 617

Nephritic syndrome (continued)

Diffuse proliferative Often due to SLE “Wire looping” of Granular Subendothelial,
glomerulonephritis (think “wire lupus”); capillaries D sometimes
DPGN and MPGN subepithelial or
often present as intramembranous
nephritic and IgG-based ICs often
nephrotic syndromes with C3 deposition
concurrently
Alport syndrome Type IV collagen Irregular thinning Initially negative; “Basket-weave”
mutation and thickening Irregular deposits appearance due to
Ž glomerular and splitting of of IgG, IgM, and/or irregular thickening
basement membrane glomerular basement C3 may be observed and longitudinal
alterations; X-linked membrane later. splitting of GBM
dominant. Eye
problems (eg,
retinopathy,
anterior lenticonus),
glomerulonephritis,
SNHL (can’t see,
can’t pee, can’t hear
a bee)
Membrano­ Type I may be 2° Mesangial ingrowth Granular Type I—Subendothelial
proliferative to HBV or HCV Ž GBM splitting IC deposits
glomerulonephritis infection; type II Ž “tram-track” on
associated with C3 H&E and PAS E Type II—
nephritic factor stains Intramembranous
(IgG autoantibody deposits, also called
that stabilizes dense deposit disease
C3 convertase
Ž persistent
complement
activation Ž  C3)
A B C D E

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 618 SEC TION III Renal   
RENAL—Pathology

Nephrotic syndrome Massive proteinuria (>3.5 g/day)

MECHANISM LIGHT MICROSCOPY IMMUNOFLUORESCENCE ELECTRON MICROSCOPY
Minimal change Also called lipoid nephrosis. Often 1° Normal ⊝ Effacement of
disease (idiopathic), triggered by recent infection, glomeruli podocyte foot
immunization, immune stimulus (4 Is); (lipid may be processes A
rarely 2° to lymphoma (eg, cytokine- seen in PT
mediated damage). Loss of antithrombin cells)
III Ž renal vein thrombosis.
Focal segmental Can be 1° (idiopathic) or 2° (eg, HIV Segmental Often ⊝ but Effacement of
glomerulosclerosis infection, sickle cell disease, heroin use, sclerosis and may be ⊕ for podocyte foot
obesity, INF treatment, or congenital hyalinosis B nonspecific processes
malformations); may progress to CKD. focal deposits
More common in Black people. of IgM, C3, C1
Membranous Also called membranous glomerulo­ Diffuse capillary Granular due “Spike and
nephropathy nephritis. Can be 1° (eg, antibodies and GBM to immune dome”
to phospholipase A2 receptor) or 2° to thickening C complex (IC) appearance of
drugs (eg, NSAIDs, penicillamine, gold), deposition subepithelial
infections (eg, HBV, HCV, syphilis), SLE, deposits
or solid tumors.  risk of thromboembolism
(eg, DVT, renal vein thrombosis).
Amyloidosis Kidney most commonly involved organ. Congo red AL amyloidosis: Mesangial
Associated with chronic conditions that stain shows may be positive expansion by
predispose to amyloid deposition (eg, AL apple-green for lambda and amyloid fibrils
amyloid, AA amyloid, prolonged dialysis). birefringence kappa light
under chains
polarized light
due to amyloid AA amyloidosis:
deposition in positive for AA
the mesangium protein

Diabetic glomerulo­ Most common cause of ESRD in Mesangial Non-specific Prominent

nephropathy United States. Hyperglycemia expansion, staining. thickening of
Ž nonenzymatic glycation of tissue GBM Usually GBM with
proteins Ž mesangial expansion thickening, negative. expanded
Ž GBM thickening and  permeability. eosinophilic mesangium,
Hyperfiltration (glomerular HTN and nodular predominantly
 GFR) Ž glomerular hypertrophy and glomerulo­ due to increased
glomerular scarring (glomerulosclerosis) sclerosis mesangial
Ž further progression of nephropathy. (Kimmelstiel- matrix,
Look for albuminuria with  urine Wilson lesions segmental
albumin-to-creatinine ratio. ACEIs and D) podocyte
ARBs are renoprotective. effacement
A B C D

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 Renal   
RENAL—Pathology SEC TION III 619

Kidney Can lead to severe complications such as hydronephrosis, pyelonephritis, and acute kidney injury. Obstructed
stones stone presents with unilateral flank tenderness, colicky pain radiating to groin, hematuria. Treat and prevent
by encouraging fluid intake. Radiolucent stones: I can’t c (see) u (you) (cystine and uric acid).
CONTENT PRECIPITATES WITH X-RAY FINDINGS CT FINDINGS URINE CRYSTAL NOTES
Calcium Calcium Radiopaque Hyperdense Shaped like Calcium stones most common (80%);
oxalate: envelope A or calcium oxalate more common than
hypocitraturia dumbbell calcium phosphate stones.
Can result from ethylene glycol (antifreeze)
ingestion, vitamin C overuse, hypocitraturia
(usually associated with  urine pH),
malabsorption (eg, Crohn disease).
Treatment: thiazides, citrate, low-sodium diet.
Calcium Radiopaque Hyperdense Wedge-shaped Treatment: low-sodium diet, thiazides.
phosphate: prism
 pH
Ammonium  pH Radiopaque Hyperdense Coffin lid Account for 15% of stones. Caused by
magnesium (“sarcophagus”) infection with urease ⊕ bugs (eg, Proteus
phosphate mirabilis, Staphylococcus saprophyticus,
(struvite) Klebsiella) that hydrolyze urea to ammonia
Ž urine alkalinization. Commonly form
staghorn calculi B .
Treatment: eradication of underlying
infection, surgical removal of stone.
Uric acid  pH Radiolucent Visible Rhomboid C or About 5% of all stones. Risk factors:  urine
rosettes volume, arid climates, acidic pH.
Strong association with hyperuricemia
(eg, gout). Often seen in diseases with  cell
turnover (eg, leukemia).
Treatment: alkalinization of urine, allopurinol.
Cystine  pH Faintly radi- Moderately Hexagonal D Hereditary (autosomal recessive) condition
opaque radiodense in which Cystine-reabsorbing PCT
transporter loses function, causing
cystinuria. Transporter defect also results
in poor reabsorption of Ornithine, Lysine,
Arginine (COLA). Cystine is poorly
soluble, thus stones form in urine. Usually
begins in childhood. Can form staghorn
calculi. Sodium cyanide nitroprusside test ⊕.
“Sixtine” stones have six sides.
Treatment: low sodium diet, alkalinization
of urine, chelating agents (eg, tiopronin,
penicillamine) if refractory.
A B C D

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