Urine regulation

concentration of filtrate leaving the ASCENDING limb

• Filtrate leaving the ascending limb is always ~100 mOsm(dilute)

• 300 mOsm= neutral or normal concentration

• Regardless of hydration status — this is the "diluting segment"

• Whether final urine is dilute or concentrated depends entirely on the collecting duct

  • ADH (antidiuretic hormone / vasopressin) is the controller

    • secreted by pituitary gland

What happens to filtrate without ADH

• filtrate becomes overhydrated

• Collecting duct walls remain impermeable to water

  • due to No aquaporin-2 channels inserted by ADH

• Dilute filtrate passes through the medullary gradient without equilibrating

• Result: large volume of dilute urine (~100 mOsm)

  • Theoretically up to 20 L/day

What happens to filtrate with excess ADH

• ADH binds V2 receptors on principal cells

• SO, aquaporin-2 channels inserted into apical membrane of collecting duct

• Water flows out into hypertonic medullary interstitium by osmosis

• Urine concentrates progressively as it descends through gradient

• Result: small volume of concentrated urine (up to 1200 mOsm) AKA dehydrated state

  • Minimum ~500 mL/day (obligatory solute excretion)

Summary of roles of ADH

3 triggers for ADH release

1. increased Plasma osmolality(above ~280-285 mOsm)

   • Osmoreceptors(located in hypothalamus) detect this change

2. decreased blood volume/ BP(large drop)

   • Baroreceptors (i.e. carotid, aortic, atria) detect this

3. Pain, nausea, stress

   • detected by various sensors in CNS

Urea recycling

• ADH also increases urea permeability in the inner medullary collecting duct

• Urea is a solute that exits into medullary interstitium

  • Contributes ~50% of the medullary osmotic gradient

• Urea Recycling process: interstitium → thin ascending limb → tubule → CD → repeat

• So, Low-protein diets → low urea → impaired gradient

What is a diuretic

• any substance that enhances urinary output

• AKA increases urine volume

3 mechanisms of diuretics

1. ADH inhibitors: block ADH release → collecting duct stays impermeable→ water not reabsorbed

2. Na+ reabsorption inhibitors: block Na+ transporters at various nephron segments→ Na+ stays in tubule→ water follows osmotically

3. Osmotic diuretics — Non-reabsorbed solutes hold water in the tubule

Why do you urinate more when drinking beer?

• an example of ADH inhibitor

• Alcohol inhibits ADH release from the posterior pituitary

• Collecting duct stays impermeable to water

• Result: dilute diuresis — large volume of dilute urine

• The same mechanism explains dehydration with alcohol consumption

4 Na+ reabsorption inhibitors

1. Loop diuretics (drug/compound)

2. Thiazides

3. K+ sparing diuretics

4. Caffeine

Na+ reabsorption drives water reabsorption. Block Na+ transport at any segment, and water follows it out as urine

Loop diuretics

• affects the thick ascending limb

• targets and blocks Na+/K+/2Cl- cotransporter

• Is the most potent diuretic and can disrupt medullary gradient

  • Loop diuretics are the most powerful because the thick ascending limb is where the medullary gradient is built — blocking the Na+-K+-2Cl- transporter collapses the gradient → ADH can no longer concentrate urine effectively

• Example= furosemide(Lasix)

Thiazide

• Affects the DCT

• Targets and blocks NaCl transporter

• Has moderate potency

• Example= hydrochlorothiazide

K+ sparing diuretics

• Affect the Collecting duct

• Targets and blocks aldosterone receptors

• Potency is mild

• Example= spironolactone

Caffeine

• Primarily affects PCT

• Causes mild Na+ reabsorption inhibition

• Potency is mid

• Example= coffee, tea

A patient with uncontrolled diabetes has polyuria (excessive urination).

Explain the mechanism. (Hint: think back to our Tm discussion in Lecture 3

Blood glucose exceeds the transport maximum (Tm) → glucose spills into urine (glucosuria) → glucose acts as an osmotic diuretic → holds water in the tubule → polyuria

This is why patients with uncontrolled diabetes urinate frequently and feel thirsty

What is renal clearance

• the volume of plasma completely cleared of a substance per unit time (mL/min)

• A measure of how efficiently the kidneys remove a substance

• Not a total amount — it's a rate concept

Renal clearance formula

• RC=U x V/ P

Inulin

• a plant polysaccharide and not naturally synthesized in body

  • is infused

• Freely filtered, NOT reabsorbed, NOT secreted

• Therefore: RC(inulin)is used to estimate GFR

  • it rate is the GFR = 125 mL/min

Interpreting renal clearance: 3 scenarios

when RC<GFR(less than)

• means substance is being reabsorbed after filtration(some is returned to blood)

• EX: urea (~70), glucose(0)

When RC> GFR

• means that substance is being secreted in addition to being filtered

• EX: creatinine(~140), drug metabolites

When RC= GFR

• Substance is freely filtered, with no net reabsorption or secretion

• EX: Inulin

Creatinine: GFR estimate

• Naturally produced from creatine phosphate metabolism in skeletal muscle

• Freely filtered + slightly secreted

• RC ≈ 140 mL/min — slightly overestimates GFR (125 mL/min)

• Advantage: endogenous — no inulin infusion needed

  • Convenient, inexpensive, used to track GFR changes over time

• Declining creatinine clearance = declining kidney function

If a substance has a clearance of 0, what must be true?

It is completely reabsorbed (e.g., glucose, amino acids under normal conditions)

Why does uncontrolled diabetes eventually change creatinine clearance?

• Diabetic nephropathy

• damages glomeruli → GFR drops → creatinine clearance drops

What does renal clearance measure

Renal clearance DOES NOT measure how much of a substance is removed

Think of it as: "How many mL of plasma did the kidney completely clean of this substance each minute?"

Physical characteriistics

• Urinalysis is one of the simplest and most informative diagnostic tests

• Color: Clear to deep yellow(due to urochrome pigment from hemoglobin metabolism)

• Transparency: Clear when fresh; cloudy on standing (precipitates)

• Odor: Slightly aromatic when fresh; ammonia-like on standing (bacterial action on urea)

• pH: 4.5-8.0 (average=6.0; varies with diet)

  • high protein→ acidic

  • vegetarian→ alkaline

• Specific gravity: 1.001-1.035 (reflects solute concentration; pure water=1.000)

• Volume produced: 1.5 L/day (range from 500 mL to 2L+ depending on hydration)

Chemical composition of normal urine

• Normal urine: ~95% water, 5% solutes

• Major solutes found:

  • urea (largest organic component from protein metabolism

  • creatinine

  • uric acid

  • ions: Na+, K+, Cl-, HPO4, SO4

What 8 substances shouldn't be found in urine

• Glucose

• Protein

• RBCs

• WBCs

• ketone bodies

• hemoglobin

• bilirubin

• Casts

Why shouldn’t glucose be found in urine

• Leads to glucosuria

• Found in urine due to Diabetes Mellitus

• indicates that Blood glucose exceeds Tm→ filtered glucose is not being fully reabsorbed

Why shouldn’t proteins be found in urine

• Leads to proteinuria/albuminuria

• Caused by glomerulonephritis and hypertension

• indicates damaged filtration membrane is allowing proteins through

Why shouldn’t RBCs be found in urine

• leads to hematuria

• Caused by infection, kidney stones, tumors, trauma

• indicates that there is bleeding anywhere along urinary tract

Why shouldn’t WBCs be found in urine

• leads to pyuria

• Caused by UTIs

• indicates that immune response activated due to infection

Why shouldn’t ketones be found in urine

• leads to ketonuria

• Caused by starvation, uncontrolled diabetes

• indicates excessive fat metabolism

Why shouldn’t hemoglobin be found in urine

• leads to hemoglobinuria

• Caused by hemolytic anemias, transfusion reactions

• indicated free hemoglobin from lysed RBCs filtered

Why shouldn’t bilirubin be found in urine

• leads to bilirubinuria

• Caused by liver disease, bile duct obstruction

• Indicates conjugated bilirubin excreted by kidneys

Why shouldn’t Casts be found in urine

• Caused by renal tubule disease

• Indicated tube-shaped protein aggregates formed in tubules

Ureters

• Slender retroperitoneal tubes — renal pelvis to bladder

• 3 wall layers: mucosa (transitional epithelium) → muscularis (smooth muscle) → adventitia

• Peristalsis propels urine — not gravity- dependent

Renal Calculi

• AKA kidney stones

• Caused by crystals of calcium, magnesium, or uric acid forming in renal pelvis

• → Can obstruct ureter → severe flank pain (renal colic)

• → Treatment: lithotripsy (shock waves that break stones), surgical removal, or passage with hydration

Urinary bladder

• Retroperitoneal muscular sac on the pelvic floor

• Trigone: smooth triangular area between ureteral + urethral openings

  • Infections tend to persist in the trigone

• Detrusor muscle: three layers of smooth muscle — contracts during micturition

• Capacity: ~500 mL (moderate); can stretch to ~1000 mL

• Lined with transitional epithelium — stretches with filling

Male VS Female urethra

Female:

• Length=3-4 cm

• Has single region

• Function=urine only

• Pathway: Anterior to vagina, direct to exterior

• Has HIGHER UTI risks

  • due to short length and proximity to anus

Male:

• Length=~20 cm

• 3 regions: Has prostatic→ intermediate→ spongy regions

• Pathway: through prostate→ perineum→ penis

• Function= urine AND semen function(shared pathway)

• Has lower UTI risk due to its longer length

2 sphincters of urethra

1. Internal urethral sphincter

   • made ups of smooth muscle

   • has involuntary control (ANS: sympathetic tone)

   • located at neck of bladder

2. External urethral sphincter

   • made up of skeletal muscle

   • Has voluntary control (somatic: pudendal nerve)

   • located at pelvic floor

The voluntary control we develop is over the external sphincter ONLY

Micturition

the act of emptying the bladder (urination / voiding)

3 stimulating effects on micturition

1. Detrusor muscle contracts (parasympathetic — pelvic nerves)

• 2. Internal urethral sphincter opens (PNS relaxes sympathetic tone)

• 3. External urethral sphincter opens (somatic motor neuron inhibition)

Micturition reflex (spinal)steps

1. Bladder fills to ~200 mL urine → stretch receptors in bladder wall activated (bladder wall is expanding)

2. Afferents travel to sacral spinal cord (S2-S4)

3. PNS efferent (pelvic nerves): contract detrusor + relax internal sphincter

4. Simultaneously: Somatic motor neurons inhibited → external sphincter relaxes

5. Urine is expelled

In infants: purely reflexive — no voluntary control

Higher brain control (Pontine) of micturition

We can voluntarily delay voiding(urination), but not indefinitely — eventually the reflex overwhelms voluntary control

Incontinence and urinary retention

Acute Kidney injury (AKI)

• Rapid(hours→ days) decline in kidney function

• Caused by severe dehydration, hemorrhage, drug toxicity (NSAIDs, aminoglycosides, obstruction)

• Is often reversible if cause is treated promptly unlike CKD

Chronic kidney disease (CKD)

occurs because GFR < 60 mL/min for ≥ 3 months

2 main causes of CKD

• usually due to damage to glomerular filtration membrane

  • less filtrate exits

• Diabetes mellitus — 44% of new cases (glomerular damage(scarred, etc) from chronic hyperglycemia)

• Hypertension — 28% (chronic high pressure damages glomerular capillaries)

• Progression: ↓ filtration → nitrogenous wastes accumulate → blood pH drops → electrolyte imbalances

Renal failure

• GFR < 15 mL/min (may reach zero) as kidneys cannot maintain homeostasis

• more extreme progression of CKD

• Symptoms: fatigue, anorexia, nausea, mental changes, edema, cardiac irregularities (hyperkalemia), metabolic acidosis

Uremia

indicator of renal failure because no filtration is occurring

("urine in blood"): wastes that should be in urine accumulate in blood

Symptoms of renal failure

• Fatigue, anorexia, nausea, mental changes

• Edema, cardiac irregularities (hyperkalemia)

• Metabolic acidosis

Anemia

also indicator of renal failure

anemia= loss of EPO production by failing kidneys

rate of blood production decreases

Treatment options of renal failure

Limitations of dialysis

• dialysis replaces filtration/waste removal but CANNOT replace kidney’s endocrine function

  • No EPO production→ anemia persists (treated with exogenous EPO)

  • No vit. D activation→ calcium imbalance

  • No renin production→ BP regulation impaired

  • No gluconeogenesis

Images to study from textbook