10 · Renal Physiology

Body fluids, filtration, tubular handling, the concentrating mechanism and acid-base — three lectures that between them explain most of internal medicine.

Lecture objectives: compare the extracellular and intracellular fluid compartments; describe nephron structure and renal blood flow; explain glomerular filtration and its regulation; describe tubular reabsorption and secretion segment by segment; explain the countercurrent mechanism and ADH; describe renal regulation of potassium, calcium and phosphate; explain acid-base balance and interpret an arterial blood gas.

What the kidney does

Function	Detail
Excretion of waste	Urea from amino acid metabolism, creatinine from muscle creatine, uric acid from nucleic acids, bilirubin from hemoglobin breakdown, and hormone metabolites
Fluid and electrolyte regulation	Water, electrolytes, osmolarity
Acid-base	Hydrogen ion excretion; bicarbonate reabsorption and generation
Blood pressure	The renin-angiotensin-aldosterone system
Erythropoiesis	Erythropoietin
Vitamin D	Activation to calcitriol → calcium deposition in bone and GI calcium absorption
Gluconeogenesis	From amino acids in prolonged fasting

Daily fluid balance: in — 2100 mL from water and food plus 200 mL of metabolic water. Out — 100 mL in feces, 100 mL in sweat (up to 2 L/hour in extreme conditions), 700 mL insensible, and 1400 mL as urine. The kidney is the only adjustable term.

Body fluid compartments

Compartment	Volume in a 70 kg adult	% body weight
Total body water	42 L	60% in men, 50% in women
Intracellular fluid	28 L	40% — two-thirds of TBW
Extracellular fluid	14 L	20% — one-third of TBW
→ Interstitial	11 L	75% of the ECF
→ Plasma	3 L	25% of the ECF
Transcellular	1–2 L	Synovial, peritoneal, pericardial, intraocular fluid and CSF

The ICF is treated as one compartment because electrolyte concentrations are similar in all cells and the barrier — the cell membrane — is the same everywhere. Plasma and interstitial fluid are identical except for protein, which cannot cross, and that difference is the entire basis of oncotic pressure.

Osmolarity is about 300 mOsm/L in all three compartments — 282 when corrected for osmotic activity — because they are at equilibrium. What differs is the composition: ECF osmolarity is about 80% sodium and chloride; ICF osmolarity is about 50% potassium.

How water moves, and the three rules for any fluid-shift problem

Plasma ↔ interstitium	Across the capillary — hydrostatic and oncotic pressure, the Starling forces
ECF ↔ ICF	Across the cell membrane — osmosis only. Water crosses freely; ions do not

1	ICF and ECF osmolarity always end up equal
2	Solutes stay in the compartment they started in
3	Total osmoles are unchanged unless something was added or lost

Then: new osmolarity = total mOsm ÷ total volume, and each compartment's volume = its mOsm ÷ the new osmolarity.

Tonicity versus osmolarity, one more time: tonicity is about whether a solution changes cell volume, and it counts only impermeant solutes. Osmolarity is total particle concentration regardless of permeability. Urea is hyperosmotic but not hypertonic — it crosses, so it produces no lasting volume change. 5% glucose is iso-osmotic but behaves as free water, because the glucose is taken up and metabolized.

Indicator dilution — volume = quantity injected ÷ concentration after dispersal.

Total body water	Deuterium (heavy water), tritiated water, antipyrine
ECF	Radiolabeled ions that cannot enter cells — sodium, chloride, inulin, sucrose
Plasma	Labeled albumin or Evans blue, which bind plasma protein
ICF	Calculated: total body water − ECF
Interstitial	Calculated: ECF − plasma

Note the logic: you can only measure a compartment directly if you have a marker that stops at its boundary. The two you cannot mark, you subtract.

Sodium disorders and edema

	Hyponatremia	Hypernatremia
ECF tonicity	Hypotonic	Hypertonic
Effect on cells	Swelling — worst in the brain	Shrinkage
Causes	Sodium loss (diarrhea, vomiting, diuretic overuse) or water excess (SIADH, water overload)	Water loss (central or nephrogenic diabetes insipidus, inadequate intake) or sodium excess (excess aldosterone)

The classic case is the marathon runner who drinks too much water and then becomes confused and seizes. That is hyponatremia, and the seizure is cerebral edema. The brain does adapt — water enters, then sodium and potassium are transported out of the cells, then water follows them out — which is why chronic hyponatremia is tolerated far better than acute. It is also why correcting it too quickly is dangerous: the adapted brain cell is now vulnerable to shrinking, and osmotic demyelination follows.

Edema

Type	Mechanism
Intracellular — precedes tissue death	Hyponatremia; depressed tissue metabolism; cellular malnutrition
Extracellular — far more common	Raised capillary pressure; reduced plasma protein; increased capillary permeability; blocked venous or lymphatic return

Clinical cause	Force changed
Heart failure	↑ intravascular hydrostatic pressure
Kidney disease	↑ fluid volume from sodium and water retention
Proteinuria or liver disease	↓ plasma oncotic pressure
Reduced arteriolar resistance (drugs, heat, low sympathetic tone)	↑ capillary pressure

Three safety factors delay edema: the interstitium's low compliance in the negative-pressure range (normal interstitial pressure is about −3 mmHg), a lymph flow that can rise 10- to 50-fold, and protein washdown — increased lymph flow carries protein away, lowering interstitial oncotic pressure. Together they absorb about 17 mmHg before visible swelling appears, which is why edema is a late sign.

An effusion is edema in a potential space — pleural, peritoneal, pericardial, synovial — where there is no tissue resistance to oppose accumulation.

The nephron

800,000 to a million nephrons per kidney, which are retroperitoneal. The path: glomerulus → Bowman's capsule → proximal tubule → loop of Henle (thin descending, thin ascending, thick ascending) → macula densa → distal tubule → collecting duct.

The blood supply is the part to get right: renal artery → interlobar → arcuate → interlobular → afferent arteriole → glomerulus → efferent arteriole → peritubular capillaries (plus the vasa recta in juxtamedullary nephrons) → renal vein. Two arterioles in series is the anatomy that makes the kidney unique: their resistance maintains glomerular pressure, that pressure drives filtration, and the peritubular capillaries downstream do the reabsorbing.

	Cortical nephron	Juxtamedullary nephron
Proportion	85%	15%
Loop	Short, ending in the outer medulla	Long, reaching deep into the medulla
Peritubular vessels	Peritubular capillaries	Vasa recta
Function	Bulk reabsorption	Concentrate the urine; salt-conserving

The filtration barrier — three layers, all negatively charged

Layer	Feature	Barrier role
1. Fenestrated endothelium	Fenestrae plus a negatively charged glycocalyx	Blocks cells; hinders anionic proteins
2. Basement membrane	Collagen and proteoglycan meshwork	The main size barrier, and strongly negative
3. Podocytes	Foot processes with filtration slits	Final size and charge barrier

The barrier filters by size AND by charge, and protein is excluded for both reasons at once — it is large and negative.

Molecule	MW	Filterability
Water, sodium, glucose, inulin	18–5,500	1.0 — freely filtered
Myoglobin	17,000	0.75
Albumin	69,000	0.005

The pore is about 8 nm and albumin about 6 nm — so albumin is small enough to pass and is excluded mainly by charge. The proof is elegant: dextrans of identical size cross in the order polycationic > neutral > polyanionic.

The juxtaglomerular apparatus is where the tubule reports back to its own glomerulus: the macula densa, specialized distal tubular cells touching the arterioles, senses sodium chloride, and the juxtaglomerular granular cells in the arteriolar walls secrete renin.

Renal blood flow and filtration

Quantity	Value
Renal blood flow	1100 mL/min — 22% of cardiac output, to an organ that is 0.4% of body weight. Flow grossly exceeds metabolic need because filtration, not perfusion, is the point
Renal plasma flow	About 625 mL/min — RBF × (1 − hematocrit)
GFR	125 mL/min = 180 L/day
Filtration fraction	GFR ÷ RPF ≈ 20%
Reabsorbed	Over 99%
Urine output	1 mL/min ≈ 1.4 L/day
Medullary blood flow	Only 1–2% of renal blood flow — deliberately low, to protect the concentration gradient

Sodium reabsorption consumes about 75% of the kidney's energy, so renal oxygen consumption tracks sodium reabsorption rather than blood flow.

Glomerular filtration — the Starling forces

GFR = K_f × (P_G − P_B − π_G + π_B)

Force	Value	Direction
P_G — glomerular capillary hydrostatic	60 mmHg	Favors filtration
P_B — Bowman's capsule hydrostatic	18 mmHg	Opposes
π_G — glomerular capillary oncotic (average)	32 mmHg	Opposes
π_B — Bowman's capsule oncotic	0 — the filtrate is protein-free	—
Net filtration pressure	60 − 18 − 32 = +10 mmHg
K_f	12.5 mL/min/mmHg — about 400 times that of an ordinary capillary bed

Glomerular oncotic pressure rises along the capillary, from 28 mmHg at the entrance to 36 at the exit, as a fifth of the plasma filters out and concentrates the protein left behind — hence the average of 32.

The filtration-fraction loop is the rule the lecture told you to memorize, and it explains more than it looks like it should. Raising the filtration fraction raises glomerular oncotic pressure, which lowers GFR. Conversely, raising renal plasma flow lowers the filtration fraction, so oncotic pressure rises more slowly along the capillary, and GFR goes up. This is why renal plasma flow matters even when glomerular pressure is unchanged, and it is the mechanism behind several of the arrows in the table below.

What changes GFR

Determinant	Effect	Causes
K_f	↑K_f → ↑GFR	Reduced by renal disease, diabetes, hypertension (thickened basement membrane) and aging. Normally stable — not a day-to-day regulator
P_B	↑P_B → ↓GFR	Urinary obstruction — a kidney stone. Prolonged obstruction becomes hydronephrosis and then permanently lowers K_f
π_G	↑π_G → ↓GFR	Reduced renal blood flow, raised plasma protein, raised filtration fraction
P_G	↑P_G → ↑GFR	Raised arterial pressure — but the effect is small because of autoregulation
Afferent constriction	↓GFR and ↓RPF	Sympathetic stimulation, norepinephrine, endothelin, NSAIDs
Efferent constriction	↑GFR modestly, ↓RPF — but severe constriction lowers GFR, because oncotic pressure then rises too far	Angiotensin II

Sympathetic effect is dose-dependent: mild to moderate output causes no arteriolar constriction but does release renin; strong output constricts the renal arteries and drops both blood flow and GFR — hemorrhage, severe stress, brain ischemia.

Autoregulation holds renal blood flow and GFR constant across a MAP of 80–170 mmHg, by two mechanisms.

Myogenic	Sudden stretch of the arteriole contracts its smooth muscle, protecting the glomerulus from hypertensive injury. The lecture explicitly calls its renal role "uncertain", where the textbook treats it as co-equal
Tubuloglomerular feedback	The macula densa senses sodium chloride in the distal tubule. If it falls — implying GFR has fallen — the response is twofold: afferent resistance drops, raising glomerular pressure, and renin is released, generating angiotensin II to constrict the efferent arteriole. Both restore GFR

A neat consequence: a high-protein meal raises renal blood flow and GFR, because amino acids are reabsorbed proximally with sodium, so less sodium reaches the macula densa, which reads this as "GFR is low" and dilates the afferent arteriole. The same mechanism produces the hyperfiltration of early diabetes.

Clearance

Excretion = filtration − reabsorption + secretion
Clearance = (urine concentration × urine flow) ÷ plasma concentration

To measure	Use	Why
GFR	Inulin	Freely filtered, not reabsorbed, not secreted, not made in the body. But it must be infused intravenously, so it is impractical clinically
GFR clinically	Creatinine	Endogenous, no infusion needed. It is slightly secreted, which overestimates GFR — but the assay overestimates plasma creatinine, and the two errors roughly cancel
Renal plasma flow	PAH	About 90% cleared in a single pass, being both filtered and secreted

Plasma creatinine is inversely proportional to GFR — halve the GFR and, at steady state, plasma creatinine doubles. That non-linearity is why a creatinine moving from 0.8 to 1.6 represents losing half of renal function while a move from 4 to 8 represents losing very little more.

A clearance ratio — a substance's clearance divided by inulin's — tells you what the tubule did with it: greater than 1 means net secretion, less than 1 means net reabsorption.

Tubular handling, segment by segment

Segment	Sodium reabsorbed	Key transporters	Water	Diuretic target
Proximal tubule	65% — and 100% of glucose and amino acids	Na⁺/K⁺-ATPase basolaterally; SGLT2 then SGLT1 apically; Na⁺-H⁺ exchanger	Highly permeable → the fluid stays isosmotic	Carbonic anhydrase inhibitors; SGLT2 inhibitors
Thin descending limb	None	No active transport	Water-permeable — about 20% of filtered water is reabsorbed here	—
Thin ascending limb	Passive NaCl	—	Impermeable to water	—
Thick ascending limb	25%	NKCC2 — the sodium-potassium-2-chloride cotransporter. Also the major site of potassium and magnesium reabsorption	Impermeable — so the fluid becomes dilute, about 100 mOsm/L	Loop diuretics — furosemide inhibits NKCC2
Early distal tubule	About 5%	NCC — the sodium-chloride cotransporter. Begins at the macula densa	Impermeable — the "diluting segment"	Thiazides
Principal cells of the collecting duct	Variable — the fine tuning	ENaC for sodium entry; potassium channels that secrete potassium; the aldosterone target; aquaporin-2 under ADH control	ADH-dependent	Potassium-sparing diuretics — spironolactone blocks aldosterone, amiloride blocks ENaC
Intercalated cells	—	Type A secretes H⁺ and reabsorbs K⁺ (in depletion); type B secretes bicarbonate and K⁺ (in excess)	—	—
Medullary collecting duct	Final ~5%	Urea transporters moving urea into the medulla; secretes H⁺	ADH-dependent	ADH antagonists

99.4% of filtered sodium is reabsorbed, and water follows salt.

The glucose transport maximum

Normal filtered load	125 mg/min
Threshold — glucose first appears in the urine	Plasma about 200 mg/dL
Transport maximum	375 mg/min

Why is the threshold lower than the transport maximum? Because nephrons are not identical — some saturate before others do, so glucose starts spilling before the kidney as a whole is maxed out. That gap is called splay, and the same logic applies to every Tm-limited system.

Glomerulotubular balance keeps proximal fractional reabsorption at about 65% whatever the filtered load, which prevents the distal nephron from being overwhelmed when GFR swings.

The countercurrent mechanism

Cortex about 300 mOsm/L; papillary tip 1200–1400 mOsm/L — a four- to fivefold gradient, and the whole reason concentrated urine is possible.

Component	Role
Countercurrent multiplier (loop of Henle)	The single effect: the thick ascending limb pumps sodium chloride out while remaining water-impermeable, creating a 200 mOsm/L gradient at any horizontal level. Countercurrent flow then multiplies that modest gradient vertically to 1200
Descending limb	Water-permeable with no active transport, so water leaves and the fluid equilibrates upward toward 1200 at the bend
Ascending limb	Water-impermeable while solute leaves, so the fluid becomes hypo-osmotic, about 100 mOsm/L
Urea recycling	Urea supplies 40–50% of medullary osmolarity. ADH-stimulated urea transporters move it into the inner medullary interstitium, and it re-enters the thin loop — recycling rather than being excreted
Countercurrent exchanger (vasa recta)	Passive U-shaped capillaries. The descending limb gains solute and loses water; the ascending limb does the reverse — so solute is trapped rather than washed out. This only works because medullary flow is 1–2% of renal blood flow; raising medullary flow washes out the gradient and destroys concentrating ability

Obligatory urine volume: about 600 mOsm of solute must be excreted daily, and the maximum urine concentration is 1200 mOsm/L — so the minimum possible urine output is 0.5 L/day. Seawater is 1200 mOsm/L, so drinking a liter requires a liter of urine to excrete it: net water loss, which is why you cannot drink seawater.

Concentrated urine requires two things: high ADH and a hyperosmotic medulla. Lose either one and the urine is dilute.

ADH

Made in	Hypothalamus — supraoptic and paraventricular nuclei
Released from	Posterior pituitary
Stimuli	Rising plasma osmolarity — a 1% change is enough; falling blood volume, but only around 10%; also angiotensin II, nausea and pain
Mechanism	V2 receptor → cAMP → aquaporin-2 inserted into the apical membrane
Site of action	Late distal tubule and the collecting duct
Effect	More water reabsorbed → a small volume of concentrated urine

Osmolarity is the more sensitive stimulus and volume the more powerful one — a 1% osmolar change triggers ADH, but a 10% volume loss overrides osmolarity entirely. That hierarchy is why a hypovolemic patient retains water even while becoming hyponatremic.

Disorder	Defect	Urine	Plasma Na⁺	Response to desmopressin
Central DI	Fails to produce or release ADH	Large volume, dilute	High	Urine concentrates — both diagnostic and the treatment
Nephrogenic DI	ADH is normal or high; the kidney cannot respond	Large volume, dilute	High	No response — this is what distinguishes it. Causes: lithium, hypercalcemia, hypokalemia, chronic kidney disease
SIADH	Inappropriate excess ADH	Concentrated despite dilute plasma	Low	Treated by fluid restriction

The RAAS and the volume hormones

Hormone	Site of action	Stimulus	Effect
Angiotensin II	Efferent arteriole; proximal tubule, thick ascending limb, distal tubule and collecting duct	Renin, in turn released by low blood pressure, low distal sodium chloride, or renal sympathetic activity	Constricts the efferent arteriole to preserve GFR when flow falls; increases sodium and water reabsorption and hydrogen ion secretion; stimulates aldosterone; raises thirst and ADH
Aldosterone	Principal cells of the collecting tubule	High ECF potassium; angiotensin II	Sodium and water reabsorption; potassium and hydrogen ion secretion
ADH	Distal tubule, collecting duct	Low volume, high osmolarity	Water reabsorption
ANP	Distal tubule, collecting duct	Atrial stretch from volume expansion	Reduced sodium reabsorption → natriuresis; also inhibits renin and aldosterone
PTH	Loop, distal and proximal tubule	Low ionized calcium	↑ calcium reabsorption; ↓ phosphate reabsorption

Aldosterone escape is worth understanding: chronic aldosterone excess retains sodium and water for only 1–3 days. ECF volume rises 10–15%, blood pressure rises, and pressure natriuresis restores balance. That is why Conn syndrome produces hypertension and hypokalemia but not massive edema — and it is a clean demonstration that the pressure-natriuresis mechanism outranks any hormone.

Potassium, calcium and phosphate

Potassium — 98% intracellular, 2% extracellular. ECF 3.5–5.5 mEq/L against an ICF of about 140. Extracellular potassium must stay stable because it sets the resting membrane potential; small changes cause cardiac arrest.

Shifts K⁺ INTO cells (lowers serum K⁺)	Shifts K⁺ OUT of cells (raises serum K⁺)
Insulin — it stimulates the Na⁺/K⁺ pump	Insulin deficiency — diabetes causes hyperkalemia
Aldosterone	Aldosterone deficiency — Addison disease
β-adrenergic stimulation	β-blockers
Alkalosis	Acidosis
	Cell lysis — rhabdomyolysis, hemolysis, tumor lysis
	Strenuous exercise; rising ECF osmolarity

Renal handling: proximal (65%) and loop (25–30%) reabsorption are essentially constant; all the fine-tuning happens at the distal tubule and collecting duct. Principal cells secrete potassium; type A intercalated cells reabsorb it in depletion.

Three stimuli to potassium secretion: a rising ECF potassium, aldosterone — which high potassium itself releases — and increased tubular flow, which is why diuretics waste potassium.

Calcium — only about 50–60% is ionized and filterable; the rest is protein-bound. 99% of filtered calcium is reabsorbed: 65% proximally, 25–30% in the loop, the rest distally.

Factor	Calcium reabsorption
↑ PTH	↑
↑ ECF calcium, via calcium-sensing receptors	↓
↑ ECF volume or arterial pressure	↓ — less water reabsorbed means less calcium reabsorbed
Alkalosis	↑ reabsorption
Acidosis	↑ excretion

Alkalosis also increases protein binding, lowering ionized calcium — which is the mechanism of the tetany that follows hyperventilation, and it ties directly back to the excitability rule from section 2.

Phosphate has a transport maximum and behaves as an overflow system: intake above the Tm is simply excreted. PTH increases phosphate excretion. Magnesium is reabsorbed mostly in the thick ascending limb, so loop diuretics waste magnesium.

Acid-base

pH = 6.1 + log ( [HCO₃⁻] / 0.03 × PCO₂ )

pH	7.35–7.45 (and remember it is logarithmic)
PCO₂	35–45 mmHg
HCO₃⁻	22–28 mEq/L
Urine pH	4.5–8.0

Carbonic anhydrase runs the whole system: CO₂ + H₂O ⇌ H₂CO₃ ⇌ HCO₃⁻ + H⁺, freely reversible. Carbon dioxide is the major metabolic acid source. Raising CO₂ lowers pH; raising bicarbonate raises it.

Three lines of defense, in order of speed

Line	Speed	Mechanism
1. Chemical buffers	Seconds	Bicarbonate in the ECF, phosphate intracellularly and in urine, and proteins including hemoglobin — the most powerful intracellular buffer
2. Respiratory	Minutes	Chemoreceptors sense PCO₂ and alter ventilation. Only 50–75% effective — a diabetic ketoacidosis pH of 7.0 is pulled only to 7.2–7.3
3. Renal	Hours to days	Hydrogen ion secretion, bicarbonate reabsorption, and generation of new bicarbonate. It is the only route that removes non-volatile acid

The distinction between reabsorbing bicarbonate and generating new bicarbonate is the hardest idea in this lecture and the one most worth getting right. The kidney filters about 4320 mEq of bicarbonate a day and reabsorbs essentially all of it — but that requires secreting 4320 mEq of hydrogen ion just to break even, and it excretes no net acid at all. Actual acid excretion requires a urinary buffer, because free hydrogen ion in urine is negligible even at pH 4.5. Two buffers do it: phosphate, which yields one new bicarbonate per hydrogen ion buffered (this is titratable acid), and ammonia, made from glutamine, which accounts for about 75% of hydrogen ion excretion and is the only buffer that increases in chronic acidosis. That last point is why the kidney can adapt to a chronic acid load and the phosphate system cannot.

Potassium and hydrogen ion move together — and the clinical patterns follow

Acidosis	More H⁺ secreted, less K⁺ secreted → hyperkalemia
Alkalosis	The reverse → hypokalemia
Loop and thiazide diuretics	Increase both H⁺ and K⁺ secretion → metabolic alkalosis with hypokalemia
Primary aldosteronism (Conn)	Same combination — metabolic alkalosis with hypokalemia

The four primary disorders

Disorder	pH	Primary change	Compensation
Respiratory acidosis	↓	↑ PCO₂ — hypoventilation	↑ HCO₃⁻, renal, slow
Respiratory alkalosis	↑	↓ PCO₂ — hyperventilation	↓ HCO₃⁻, renal, slow
Metabolic acidosis	↓	↓ HCO₃⁻	↓ PCO₂ — hyperventilation (Kussmaul breathing), fast
Metabolic alkalosis	↑	↑ HCO₃⁻	↑ PCO₂ — hypoventilation

The lecture's three-step algorithm — learn this exact sequence

1	Look at the pH. An abnormal "-emia" describes the blood (acidemia, alkalemia); an "-osis" describes the process
2	Which of PCO₂ or HCO₃⁻ moved in the same direction as the pH? If CO₂ is the abnormal one it is respiratory; if bicarbonate is, it is metabolic
3	Anion gap = Na⁺ − (Cl⁻ + HCO₃⁻), normally 8–12. An elevated gap means an unmeasured anion is the cause

Raised anion gap	Normal anion gap (hyperchloremic)
Diabetic ketoacidosis, lactic acidosis, chronic renal failure, aspirin, methanol, ethylene glycol, starvation	Diarrhea, renal tubular acidosis, carbonic anhydrase inhibitors, Addison disease

Worked blood gases from the lecture

Case	ABG	Interpretation
Post-op patient on a hydromorphone PCA, somnolent, SpO₂ 88%	pH 7.25, PCO₂ 55, HCO₃⁻ 25	Acute respiratory acidosis from opioid hypoventilation — uncompensated, because the kidney has not had time
Pneumonia with a right middle lobe opacity, SpO₂ 90%	pH 7.55, PCO₂ 30, HCO₃⁻ 22	Respiratory alkalosis from hypoxic hyperventilation
Type 1 diabetic, out of insulin for two days	pH 7.25, PCO₂ 28, HCO₃⁻ 15	Raised-anion-gap metabolic acidosis with respiratory compensation
COPD, somnolent with headache and tremor	pH 7.28, PCO₂ 60, HCO₃⁻ 24 → then pH 7.24, PCO₂ 65, HCO₃⁻ 28	Acute-on-chronic respiratory acidosis. Renal compensation takes days, so the bicarbonate lags behind the CO₂

Renal failure

	Acute kidney injury	Chronic kidney disease
Onset	Hours to days	Months to years
Reversibility	Often reversible	Irreversible nephron loss
Kidney size	Normal	Small and shrunken
Anemia and bone disease	Absent early	Present — reduced erythropoietin, and reduced calcitriol causing hypocalcemia and secondary hyperparathyroidism

Category	Mechanism	Examples
Pre-renal	Reduced perfusion, tubules intact	Hypovolemia, hemorrhage, heart failure, sepsis, NSAIDs (afferent constriction), ACE inhibitors (efferent dilation)
Intrinsic	Damage to the nephron itself	Acute tubular necrosis (ischemia, contrast, aminoglycosides, myoglobin); glomerulonephritis; interstitial nephritis
Post-renal	Obstruction downstream	Kidney stone, BPH, tumor — raising Bowman's capsule pressure, lowering GFR, and eventually causing hydronephrosis and permanent loss of K_f

Every consequence traces back to a function listed at the top of this section: uremia (excretion), edema and hypertension (sodium and water handling), hyperkalemia (potassium secretion), raised-anion-gap metabolic acidosis (lost ammonia excretion and new bicarbonate), hyperphosphatemia, anemia (erythropoietin) and renal osteodystrophy (calcitriol).

The renal exam in this course tests three things, and none of them is arithmetic. Site → function — which segment does what, and which diuretic acts there. Direction of change — if this force rises, does GFR go up or down? Cause → consequence — a stone raises Bowman's pressure, which lowers net filtration, which lowers GFR. Practice reciting the nephron in order with each segment's transporter, its water permeability and its diuretic, and you will have answered most of the block before you see the questions.