Introduction
The kidneys are extraordinary organs that perform multiple essential physiological functions beyond simple waste excretion. They regulate fluid and electrolyte balance, maintain acid-base homeostasis, control blood pressure, produce hormones, and activate vitamin D. Understanding renal physiology is fundamental to clinical nephrology, as disturbances in kidney function affect virtually every organ system in the body.
This chapter provides an in-depth exploration of renal physiology, from the hemodynamics of renal blood flow to the intricate mechanisms of tubular transport, hormonal regulation, and the kidney’s endocrine functions. The kidneys filter approximately 180 liters of plasma daily through 1-1.5 million nephrons in each kidney, yet produce only 1-2 liters of urine, demonstrating the remarkable efficiency of tubular reabsorption. This precision in regulating what is retained and what is excreted enables the kidneys to maintain the stable internal environment necessary for life.
Renal Blood Flow and Hemodynamics
Overview of Renal Blood Flow
The kidneys receive an extraordinarily high proportion of cardiac output relative to their size. Despite comprising less than 0.5% of total body weight, the kidneys receive approximately 20-25% of cardiac output, which translates to roughly 1,200 mL/min or 1.2 liters per minute of blood flow. This high renal blood flow (RBF) is not primarily for the metabolic needs of the kidney tissue itself, but rather to support the kidney’s filtration function and enable precise regulation of blood composition.
Renal Vascular Pathway
Blood flow through the kidney follows a unique vascular pathway that includes two capillary beds in series, a configuration that is unusual in the body. The pathway proceeds as follows:
Renal artery → Segmental arteries → Interlobar arteries → Arcuate arteries → Interlobular (cortical radial) arteries → Afferent arterioles → Glomerular capillaries → Efferent arterioles → Peritubular capillaries (cortex) or Vasa recta (medulla) → Venous system
This arrangement creates two distinct capillary networks. The first, the glomerular capillaries, is a high-pressure system designed for filtration. The second, the peritubular capillaries and vasa recta, is a low-pressure system optimized for reabsorption and secretion. The efferent arteriole serves as a resistance vessel between these two capillary beds, allowing independent regulation of glomerular and peritubular pressures.
Distribution of Renal Blood Flow
Renal blood flow is not uniformly distributed throughout the kidney. The renal cortex receives approximately 90% of total RBF (about 400-500 mL/100g tissue/min), while the medulla receives only about 10% (approximately 20-50 mL/100g tissue/min). This unequal distribution reflects the different functions of these regions: the cortex performs the bulk of filtration and reabsorption, requiring high blood flow, while the medulla’s lower blood flow is essential for maintaining the osmotic gradient necessary for urine concentration.
The relatively low medullary blood flow through the vasa recta is critical for preserving the medullary osmotic gradient. If medullary blood flow were high, the osmotic gradient would be “washed out” by rapid removal of solutes, impairing the kidney’s ability to concentrate urine.
Determinants of Renal Blood Flow
Renal blood flow follows the same hemodynamic principles that govern flow in other organs. RBF is determined by the relationship:
RBF = (Renal Artery Pressure – Renal Vein Pressure) / Renal Vascular Resistance
Or more simply:
RBF = Renal Perfusion Pressure (RPP) / Renal Vascular Resistance (RVR)
Since renal venous pressure is typically low (approximately 5-10 mmHg), it is often neglected in calculations, and renal perfusion pressure is approximated by mean arterial pressure.
The kidney’s vasculature is arranged predominantly in parallel, which decreases total vascular resistance compared to a series arrangement. This parallel configuration accounts for the kidney’s high blood flow despite the presence of multiple vascular segments.
Measurement of Renal Blood Flow
Renal plasma flow (RPF) can be measured using the clearance of para-amino hippuric acid (PAH), a substance that is both filtered at the glomerulus and secreted by the proximal tubule, such that it is almost completely cleared from the blood in a single pass through the kidney.
RPF = UPAH × V / PPAH
Where:
• UPAH = urine concentration of PAH (mg/mL)
• V = urine flow rate (mL/min)
• PPAH = plasma concentration of PAH (mg/mL)
Renal blood flow can then be calculated from RPF using the hematocrit (Hct):
RBF = RPF / (1 − Hematocrit)
Example:
If RPF = 600 mL/min and hematocrit = 0.40, then
RBF = 600 / 0.60 = 1,000 mL/min.
Glomerular Filtration
The Glomerular Filtration Rate (GFR)
The glomerular filtration rate (GFR) is defined as the volume of fluid filtered from the glomerular capillaries into Bowman’s space per unit time. GFR is the single best overall indicator of kidney function and is used clinically to stage chronic kidney disease, adjust medication dosages, and guide management decisions.
Normal GFR values are approximately:
•Men: 120-130 mL/min/1.73m²
•Women: 110-120 mL/min/1.73m²
This means that the kidneys filter approximately 180 liters (180,000 mL) of plasma per day, yet produce only 1-2 liters of urine. This remarkable difference highlights the efficiency of tubular reabsorption, which reclaims more than 99% of the filtered fluid and solutes.
Determinants of GFR: The Starling Equation
GFR is determined by the balance of hydrostatic and oncotic pressures across the glomerular capillary wall, as described by the Starling equation:
GFR = Kf × [(PGC – PBS) – (πGC – πBS)]
Where:
• Kf = Filtration coefficient (product of hydraulic conductivity and surface area)
• PGC = Glomerular capillary hydrostatic pressure (~60 mmHg)
• PBS = Bowman’s space hydrostatic pressure (~18 mmHg)
• πGC = Glomerular capillary oncotic pressure (~32 mmHg)
• πBS = Bowman’s space oncotic pressure (~0 mmHg, normally negligible)
The term (PGC – PBS) – (πGC – πBS) represents the net ultrafiltration pressure (PUF).
Substituting typical values:
PUF = (60 – 18) – (32 – 0) = 42 – 32 = 10 mmHg
This net ultrafiltration pressure of approximately 10 mmHg drives glomerular filtration.
Factors Affecting GFR
Several physiological and pathological factors can alter GFR by changing the variables in the Starling equation:
- Changes in Glomerular Capillary Hydrostatic Pressure (PGC)
Increases in PGC increase GFR:
• Afferent arteriole dilation (e.g., prostaglandins, nitric oxide)
• Efferent arteriole constriction (e.g., angiotensin II)
• Increased systemic blood pressure (within autoregulatory limits)
Decreases in PGC decrease GFR:
• Afferent arteriole constriction (e.g., NSAIDs, sympathetic activation, adenosine)
• Efferent arteriole dilation (e.g., ACE inhibitors, ARBs)
• Decreased systemic blood pressure (below autoregulatory range)
- Changes in Bowman’s Space Hydrostatic Pressure (PBS)
Increases in PBS decrease GFR:
• Ureteral obstruction (e.g., kidney stones, tumors)
• Urethral obstruction (e.g., prostatic hypertrophy)
- Changes in Glomerular Capillary Oncotic Pressure (πGC)
Increases in πGC decrease GFR:
• Dehydration (increased plasma protein concentration)
• Multiple myeloma (increased plasma proteins)
Decreases in πGC increase GFR:
• Nephrotic syndrome (decreased plasma albumin)
• Liver disease (decreased albumin synthesis)
- Changes in Filtration Coefficient (Kf)
Decreases in Kf decrease GFR:
• Glomerular disease (reduced surface area or permeability)
• Mesangial cell contraction (reduces filtration surface area)
Filtration Fraction
The filtration fraction (FF) is the fraction of renal plasma flow that is filtered across the glomerulus:
FF = GFR / RPF
Normal filtration fraction is approximately 20% (or 0.20), meaning that about one-fifth of the plasma flowing through the kidneys is filtered, while the remaining 80% continues through the efferent arteriole into the peritubular capillaries.
Changes in filtration fraction have important implications for tubular reabsorption:
•Increased FF: The protein concentration in the peritubular capillaries increases (because more fluid is filtered out), which increases the oncotic pressure driving reabsorption in the proximal tubule. This enhances sodium and water reabsorption.
•Decreased FF: The protein concentration in the peritubular capillaries decreases, reducing the oncotic pressure and decreasing proximal tubule reabsorption.
Clinical Correlation: Effects of Drugs and Disease on GFR
Understanding the determinants of GFR is essential for predicting the effects of medications and disease states:
| Condition | GFR | RPF | FF | Mechanism |
| Afferent arteriole constriction (NSAIDs) | ↓ | ↓ | → | Decreased PGC; prostaglandins normally dilate afferent arteriole |
| Efferent arteriole constriction (Angiotensin II) | ↑ | ↓ | ↑ | Increased PGC; maintains GFR when RBF is low |
| Efferent arteriole dilation (ACE inhibitors, ARBs) | ↓ | ↑ | ↓ | Decreased PGC; can cause acute GFR decline in renal artery stenosis |
| Increased plasma protein (Multiple myeloma) | ↓ | → | ↓ | Increased πGC opposes filtration |
| Decreased plasma protein (Nephrotic syndrome) | ↑ | → | ↑ | Decreased πGC favors filtration |
| Ureteral obstruction (Nephrolithiasis) | ↓ | → | ↓ | Increased PBS opposes filtration |
| Dehydration (Volume depletion) | ↓ | ↓↓ | ↑ | Decreased RBF > decreased GFR; increased πGC |
Autoregulation of Renal Blood Flow and GFR
The Concept of Autoregulation
Autoregulation refers to the intrinsic ability of the kidneys to maintain relatively constant renal blood flow and GFR despite fluctuations in systemic blood pressure. This mechanism operates over a mean arterial pressure range of approximately 80-180 mmHg. Within this range, RBF and GFR remain relatively stable even as blood pressure changes. Outside this range, autoregulation fails, and RBF and GFR become pressure-dependent.
The physiological importance of autoregulation is twofold:
1.Prevents excessive filtration: If GFR increased proportionally with blood pressure, the tubules would be overwhelmed, unable to reabsorb the increased filtered load, leading to massive sodium and water losses.
2.Prevents inadequate filtration: If GFR decreased excessively with blood pressure, metabolic wastes would accumulate in the blood.
Mechanisms of Autoregulation
Two primary mechanisms mediate renal autoregulation: the myogenic mechanism and tubuloglomerular feedback.
1. Myogenic Mechanism
The myogenic mechanism is an intrinsic property of vascular smooth muscle in which increased stretch (from increased pressure) triggers contraction, and decreased stretch triggers relaxation.
Mechanism:
•Increased renal perfusion pressure → increased stretch of afferent arteriole smooth muscle
•Stretch-activated calcium channels open → increased intracellular Ca²⁺
•Smooth muscle contraction → afferent arteriole constriction
•Decreased glomerular capillary pressure → GFR returns toward baseline
Conversely, when renal perfusion pressure decreases, the afferent arteriole dilates, increasing glomerular capillary pressure and maintaining GFR.
The myogenic mechanism responds rapidly (within seconds) and is most effective at buffering rapid changes in blood pressure.
2. Tubuloglomerular Feedback (TGF)
Tubuloglomerular feedback is a negative feedback mechanism mediated by the juxtaglomerular apparatus (JGA), which links tubular fluid composition to glomerular hemodynamics.
Mechanism:
When GFR increases:
1.Increased GFR → increased flow and NaCl delivery to the thick ascending limb and macula densa
2.Macula densa cells sense increased NaCl concentration (via Na-K-2Cl cotransporter)
3.Macula densa releases ATP, which is converted to adenosine in the extracellular space
4.Adenosine binds to A1 receptors on afferent arteriole smooth muscle
5.Afferent arteriole constriction → decreased glomerular capillary pressure → decreased GFR
6.Adenosine also inhibits renin release from juxtaglomerular cells
When GFR decreases:
1.Decreased GFR → decreased NaCl delivery to macula densa
2.Decreased ATP/adenosine release
3.Afferent arteriole dilation → increased glomerular capillary pressure → increased GFR
4.Increased renin release → angiotensin II production → efferent arteriole constriction (further increases GFR)
Tubuloglomerular feedback operates more slowly than the myogenic mechanism (10-30 seconds) but provides sustained autoregulation.
Integration of Myogenic and Tubuloglomerular Feedback
The myogenic mechanism and tubuloglomerular feedback do not operate independently; they interact and complement each other. The myogenic mechanism provides rapid, immediate buffering of pressure changes, while tubuloglomerular feedback provides slower, sustained regulation based on the adequacy of filtration (as reflected by distal tubule NaCl delivery).
Interestingly, these two mechanisms create oscillations in afferent arteriolar resistance that can synchronize across nephrons, creating a propagating electrical signal. This synchronization may enhance the efficiency of autoregulation across the entire kidney.
Limits of Autoregulation
Autoregulation is effective only within the range of 80-180 mmHg mean arterial pressure. Outside this range:
•Below 80 mmHg: Autoregulation fails. RBF and GFR decline proportionally with blood pressure. This can occur in severe hypotension, shock, or hemorrhage, leading to acute kidney injury.
•Above 180 mmHg: Autoregulation fails. RBF and GFR increase with blood pressure, potentially causing glomerular damage from hyperfiltration. This can occur in malignant hypertension.
Clinical Significance
Understanding autoregulation is critical for managing patients with renal disease:
•ACE inhibitors and ARBs: These medications dilate the efferent arteriole, reducing glomerular capillary pressure. In patients with bilateral renal artery stenosis or stenosis in a solitary kidney, efferent arteriole constriction by angiotensin II is essential for maintaining GFR. ACE inhibitors or ARBs can cause acute GFR decline in these patients.
•NSAIDs: These drugs inhibit prostaglandin synthesis. Prostaglandins normally dilate the afferent arteriole, especially in states of reduced renal perfusion (e.g., heart failure, cirrhosis, volume depletion). NSAIDs can precipitate acute kidney injury in these settings by causing afferent arteriole constriction.
•Chronic hypertension: Chronic hypertension shifts the autoregulatory curve to the right, meaning that higher pressures are required to maintain RBF and GFR. Rapid lowering of blood pressure in these patients can cause renal hypoperfusion and acute kidney injury.
Tubular Function: Reabsorption and Secretion
The glomerular filtrate is similar to plasma but lacks proteins and cells. If this filtrate were excreted unchanged, the body would lose more than 10 times its entire extracellular fluid volume every day. Fortunately, the renal tubules reabsorb more than 99% of the filtered water and solutes, returning essential substances to the bloodstream while secreting waste products and excess substances into the tubular fluid.
Figure 1: Tubular Reabsorption in the Nephron
Proximal Tubule
The proximal tubule is the workhorse of the nephron, responsible for reabsorbing the bulk of filtered solutes and water. It consists of the proximal convoluted tubule (PCT ) in the cortex and the proximal straight tubule descending into the medulla.
Quantitative Reabsorption in the Proximal Tubule
The proximal tubule reabsorbs approximately:
•65-70% of filtered sodium and water
•100% of filtered glucose (under normal conditions)
•100% of filtered amino acids
•80-90% of filtered bicarbonate
•65% of filtered potassium
•60-70% of filtered phosphate
•50% of filtered urea
Mechanisms of Reabsorption
Figure 2: Ion Channels and Transport Mechanisms in Tubular Epithelial Cells
Sodium Reabsorption:
Sodium reabsorption is the primary active transport process in the proximal tubule and drives the reabsorption of many other solutes. The process occurs in two steps:
1.Luminal (apical ) membrane: Sodium enters the proximal tubule cell down its electrochemical gradient via multiple transporters:
•Na⁺-glucose cotransporters (SGLT2 in early PCT, SGLT1 in late PCT)
•Na⁺-amino acid cotransporters
•Na⁺-phosphate cotransporter
•Na⁺-H⁺ exchanger (NHE3) – critical for bicarbonate reabsorption
2.Basolateral membrane: Sodium is actively pumped out of the cell into the blood by Na⁺-K⁺-ATPase, which pumps 3 Na⁺ out and 2 K⁺ in, consuming ATP. This maintains the low intracellular sodium concentration that drives luminal sodium entry.
Glucose Reabsorption:
Under normal conditions, 100% of filtered glucose is reabsorbed in the proximal tubule. Glucose cannot cross cell membranes directly and must be transported via sodium-glucose cotransporters:
•SGLT2 (early PCT): Low-affinity, high-capacity transporter; reabsorbs ~90% of filtered glucose
•SGLT1 (late PCT): High-affinity, low-capacity transporter; reabsorbs remaining ~10%
Glucose exits the cell across the basolateral membrane via GLUT2 (early PCT) and GLUT1 (late PCT) facilitated diffusion transporters.
The renal threshold for glucose is approximately 180-200 mg/dL plasma glucose. Above this concentration, the filtered load exceeds the tubular maximum (T<sub>m</sub>) for glucose reabsorption, and glucose appears in the urine (glycosuria).
Clinical Application: SGLT2 inhibitors (e.g., empagliflozin, dapagliflozin, canagliflozin) are medications that block SGLT2, causing glycosuria and lowering blood glucose in diabetes. These drugs also have cardiovascular and renal protective effects and are increasingly used in heart failure and chronic kidney disease.
Bicarbonate Reabsorption:
Approximately 80-90% of filtered bicarbonate is reabsorbed in the proximal tubule, essential for maintaining acid-base balance. The mechanism involves:
1.H⁺ secretion into the lumen via Na⁺-H⁺ exchanger (NHE3)
2.H⁺ combines with filtered HCO₃⁻ → H₂CO₃ (carbonic acid)
3.Carbonic anhydrase IV (on brush border) catalyzes: H₂CO₃ → H₂O + CO₂
4.CO₂ diffuses into the cell
5.Carbonic anhydrase II (intracellular) catalyzes: CO₂ + H₂O → H₂CO₃ → H⁺ + HCO₃⁻
6.HCO₃⁻ exits the cell across the basolateral membrane via Na⁺-HCO₃⁻ cotransporter (NBCe1)
Water Reabsorption:
Water reabsorption in the proximal tubule is passive and obligatory, following the osmotic gradient created by solute reabsorption. The proximal tubule is highly permeable to water due to constitutive expression of aquaporin-1 (AQP1) in both apical and basolateral membranes. As solutes are reabsorbed, the osmolality of the tubular fluid decreases slightly, creating a small osmotic gradient that drives water reabsorption.
Importantly, the proximal tubule reabsorbs solutes and water in iso-osmotic proportions, meaning that the osmolality of the fluid leaving the proximal tubule is approximately the same as that entering it (~300 mOsm/kg), even though the volume has been reduced by 65-70%.
Loop of Henle
The loop of Henle consists of three functionally distinct segments: the thin descending limb, thin ascending limb (present only in juxtamedullary nephrons), and thick ascending limb. The loop of Henle is responsible for creating and maintaining the medullary osmotic gradient essential for urine concentration.
Thin Descending Limb
The thin descending limb is highly permeable to water (via AQP1) but relatively impermeable to solutes. As the tubular fluid descends into the progressively more hypertonic medullary interstitium, water moves out of the tubule by osmosis, and the tubular fluid becomes progressively more concentrated. By the time the fluid reaches the tip of the loop (at the papilla), it can reach an osmolality of 1200-1400 mOsm/kg in humans (higher in desert animals).
Thin Ascending Limb
The thin ascending limb (present only in juxtamedullary nephrons with long loops) is permeable to solutes (particularly NaCl) but impermeable to water. As the concentrated tubular fluid ascends, NaCl diffuses out down its concentration gradient into the medullary interstitium, while water is retained. This begins the process of diluting the tubular fluid.
Thick Ascending Limb (TAL)
The thick ascending limb is the “diluting segment” of the nephron. It actively reabsorbs approximately 25% of filtered sodium and chloride via the Na⁺-K⁺-2Cl⁻ cotransporter (NKCC2) on the apical membrane, powered by the Na⁺-K⁺-ATPase on the basolateral membrane. Critically, the thick ascending limb is impermeable to water, so solute reabsorption without water reabsorption dilutes the tubular fluid.
Key transporters:
•Apical: Na⁺-K⁺-2Cl⁻ cotransporter (NKCC2) – target of loop diuretics (furosemide, bumetanide, torsemide)
•Apical: Renal outer medullary potassium channel (ROMK) – recycles K⁺ back into lumen
•Basolateral: Na⁺-K⁺-ATPase, Cl⁻ channels
The thick ascending limb also reabsorbs calcium and magnesium via the paracellular pathway, driven by the lumen-positive transepithelial potential created by K⁺ recycling.
By the time the tubular fluid exits the thick ascending limb and enters the distal convoluted tubule, it is hypotonic (~100-150 mOsm/kg), regardless of the final urine osmolality. The final urine concentration is determined by water reabsorption in the collecting duct under the influence of ADH.
Distal Convoluted Tubule (DCT)
The distal convoluted tubule reabsorbs approximately 5% of filtered sodium via the Na⁺-Cl⁻ cotransporter (NCC) on the apical membrane. NCC is the target of thiazide diuretics (hydrochlorothiazide, chlorthalidone, metolazone).
The DCT also plays an important role in calcium homeostasis. Parathyroid hormone (PTH) stimulates calcium reabsorption in the DCT via:
1.Increased expression of TRPV5 (calcium channel) on the apical membrane
2.Increased calbindin-D28K (intracellular calcium-binding protein)
3.Increased Na⁺-Ca²⁺ exchanger (NCX1) and Ca²⁺-ATPase on the basolateral membrane
Collecting Duct
The collecting duct is the final site of urine modification and is responsible for fine-tuning sodium, potassium, and water balance under hormonal control. It consists of principal cells and intercalated cells.
Principal Cells
Principal cells are responsible for sodium reabsorption, potassium secretion, and water reabsorption.
Sodium and Potassium Transport:
•Apical: Epithelial sodium channel (ENaC) – allows passive Na⁺ entry; target of potassium-sparing diuretics (amiloride, triamterene)
•Apical: Renal outer medullary potassium channel (ROMK) – allows passive K⁺ secretion
•Basolateral: Na⁺-K⁺-ATPase – actively pumps Na⁺ into blood, K⁺ into cell
Aldosterone increases the expression and activity of ENaC, ROMK, and Na⁺-K⁺-ATPase, resulting in:
•Increased sodium reabsorption
•Increased potassium secretion
•Increased water reabsorption (if ADH is present)
Water Reabsorption:
•Antidiuretic hormone (ADH, vasopressin) increases water permeability by stimulating insertion of aquaporin-2 (AQP2) channels into the apical membrane
•Aquaporin-3 and aquaporin-4 (AQP3, AQP4) are constitutively expressed on the basolateral membrane
•In the absence of ADH, the collecting duct is impermeable to water, and dilute urine is excreted
•In the presence of ADH, water is reabsorbed down the osmotic gradient into the hypertonic medullary interstitium, producing concentrated urine
Intercalated Cells
Intercalated cells are responsible for acid-base regulation and are discussed in detail in the Acid-Base Regulation section.
Urine Concentration and Dilution
The ability to produce urine that is either more concentrated or more dilute than plasma is essential for maintaining water balance. This remarkable capability depends on the countercurrent multiplication system in the loop of Henle and the countercurrent exchange in the vasa recta, combined with variable water permeability in the collecting duct regulated by ADH.
The Medullary Osmotic Gradient
The key to urine concentration is the establishment of a medullary osmotic gradient, with osmolality increasing progressively from the corticomedullary junction (~300 mOsm/kg) to the papillary tip (~1200-1400 mOsm/kg in humans). This gradient is created and maintained by the countercurrent multiplication system.
Countercurrent Multiplication
Countercurrent multiplication is the process by which the loop of Henle uses energy (ATP) to generate and amplify the medullary osmotic gradient. The term “countercurrent” refers to the fact that fluid flows in opposite directions in the descending and ascending limbs, which are in close proximity. The term “multiplication” refers to the amplification of a small single effect into a large osmotic gradient.
Mechanism:
The countercurrent multiplication process can be conceptualized in two steps that repeat continuously:
Step 1: The Single Effect
•The thick ascending limb actively transports NaCl out of the tubular fluid into the medullary interstitium (via NKCC2)
•The thick ascending limb is impermeable to water, so water cannot follow
•The interstitium becomes hypertonic (~400 mOsm/kg)
•Water moves passively OUT of the adjacent descending limb (which is permeable to water) into the hypertonic interstitium
•The tubular fluid in the descending limb becomes more concentrated
Step 2: Fluid Flow
•New tubular fluid continuously enters the descending limb from the proximal tubule
•This pushes the concentrated fluid deeper into the medulla
•The process repeats at each level of the loop
Through repeated cycles of this process, a large osmotic gradient is established along the length of the loop. The longer the loop of Henle, the greater the osmotic gradient that can be achieved. This is why juxtamedullary nephrons with long loops extending deep into the medulla are essential for producing maximally concentrated urine.
Countercurrent Exchange in the Vasa Recta
The vasa recta are specialized capillaries that descend into the medulla alongside the loops of Henle. They play a critical role in preserving the medullary osmotic gradient while removing reabsorbed water and solutes.
The vasa recta function as a countercurrent exchanger:
•As blood descends into the medulla, it equilibrates with the progressively more hypertonic interstitium, gaining solutes and losing water
•As blood ascends back toward the cortex, it equilibrates with the progressively less hypertonic interstitium, losing solutes and gaining water
•The slow blood flow through the vasa recta (~5% of total RBF) allows time for equilibration
This countercurrent exchange allows the vasa recta to remove reabsorbed water and solutes without “washing out” the medullary osmotic gradient. If medullary blood flow were high, the gradient would be dissipated.
Role of Urea in Urine Concentration
Urea plays an important role in the medullary osmotic gradient, contributing approximately 40-50% of the total medullary osmolality at the papillary tip.
Urea recycling:
1.Urea is filtered at the glomerulus
2.~50% is reabsorbed in the proximal tubule
3.Urea is secreted into the thin descending limb and thin ascending limb
4.Urea is reabsorbed in the inner medullary collecting duct via UT-A1 and UT-A3 urea transporters (stimulated by ADH)
5.Urea accumulates in the medullary interstitium, contributing to the osmotic gradient
6.Some urea diffuses back into the loop of Henle, creating a “urea recycling” loop
This urea recycling amplifies the medullary osmotic gradient and enhances the kidney’s ability to concentrate urine. High-protein diets increase urea production and enhance urine concentrating ability, while low-protein diets impair it.
Production of Dilute Urine
To produce dilute urine (osmolality <100 mOsm/kg), the following conditions must be met:
1.Normal thick ascending limb function: The thick ascending limb dilutes the tubular fluid to ~100-150 mOsm/kg by reabsorbing NaCl without water
2.Absence of ADH: Without ADH, the collecting duct is impermeable to water (no AQP2 insertion)
3.Tubular fluid remains dilute: Water is not reabsorbed in the collecting duct despite passing through the hypertonic medulla
4.Dilute urine is excreted: Urine osmolality can be as low as 50-100 mOsm/kg
Maximal free water clearance (excretion of solute-free water) occurs when ADH is completely suppressed, such as after drinking a large volume of water.
Production of Concentrated Urine
To produce maximally concentrated urine (osmolality up to 1200-1400 mOsm/kg in humans), the following conditions must be met:
1.Intact medullary osmotic gradient: Requires normal loop of Henle function and adequate medullary blood flow
2.Presence of ADH: ADH stimulates insertion of AQP2 into the apical membrane of collecting duct principal cells
3.Water reabsorption: Water moves out of the collecting duct down the osmotic gradient into the hypertonic medullary interstitium
4.Urine equilibrates with medullary osmolality: By the time urine reaches the papilla, it has equilibrated with the medullary interstitium (~1200-1400 mOsm/kg)
Maximal urine concentration occurs during states of maximal ADH secretion, such as dehydration, hemorrhage, or syndrome of inappropriate ADH secretion (SIADH).
Clinical Correlation
Diabetes Insipidus:
•Central DI: Deficiency of ADH production (hypothalamus/pituitary damage)
•Nephrogenic DI: Resistance to ADH (collecting duct dysfunction)
•Both result in inability to concentrate urine → polyuria, polydipsia, hypernatremia
Loop Diuretics:
•Block NKCC2 in thick ascending limb
•Impair countercurrent multiplication → dissipate medullary osmotic gradient
•Impair urine concentrating ability → can cause hyponatremia with free water intake
Chronic Kidney Disease:
•Loss of juxtamedullary nephrons → impaired medullary osmotic gradient
•Early manifestation: Isosthenuria (inability to concentrate or dilute urine; urine osmolality fixed ~300 mOsm/kg)
•Patients require higher water intake to excrete solute load
Hormonal Regulation of Renal Function
The kidneys are subject to complex hormonal regulation that allows precise control of sodium, potassium, water, and acid-base balance in response to changing physiological conditions.
Renin-Angiotensin-Aldosterone System (RAAS)
The renin-angiotensin-aldosterone system is the primary hormonal system regulating blood pressure, sodium balance, and potassium balance.
Renin Secretion
Renin is a proteolytic enzyme secreted by juxtaglomerular cells (granular cells) in the walls of the afferent arteriole. Renin secretion is stimulated by three main signals:
1.Decreased renal perfusion pressure (detected by baroreceptors in afferent arteriole)
2.Decreased NaCl delivery to macula densa (detected by macula densa chemoreceptors)
3.Increased sympathetic nervous system activity (via β1-adrenergic receptors on juxtaglomerular cells)
Renin secretion is inhibited by:
•Increased renal perfusion pressure
•Increased NaCl delivery to macula densa (via tubuloglomerular feedback)
•Angiotensin II (negative feedback)
RAAS Cascade
1.Renin cleaves angiotensinogen (produced by liver) → Angiotensin I (inactive decapeptide)
2.Angiotensin-converting enzyme (ACE) (primarily in lungs) cleaves Angiotensin I → Angiotensin II (active octapeptide)
3.Angiotensin II exerts multiple effects via AT1 receptors:
Cardiovascular Effects:
•Potent vasoconstriction (increases systemic vascular resistance and blood pressure)
•Preferentially constricts efferent arteriole (maintains GFR when RBF is low)
•Stimulates cardiac and vascular hypertrophy (chronic effects)
Renal Effects:
•Increases proximal tubule Na⁺ reabsorption (via Na⁺-H⁺ exchanger)
•Constricts efferent arteriole (increases filtration fraction)
•Stimulates aldosterone secretion from adrenal cortex
Central Effects:
•Stimulates ADH secretion from posterior pituitary
•Stimulates thirst (via hypothalamus)
1.Aldosterone (mineralocorticoid from zona glomerulosa of adrenal cortex) acts on principal cells of late distal tubule and collecting duct:
Effects of Aldosterone:
•Increases expression of ENaC (apical Na⁺ channels) → increased Na⁺ reabsorption
•Increases expression of ROMK (apical K⁺ channels) → increased K⁺ secretion
•Increases expression of Na⁺-K⁺-ATPase (basolateral) → maintains Na⁺ gradient
•Net effect: Sodium retention, potassium excretion, water retention (if ADH present)
Aldosterone also acts on intercalated cells (when dephosphorylated by angiotensin II):
•Increases H⁺-ATPase in α-intercalated cells → acid secretion
•Increases Cl⁻-HCO₃⁻ exchanger in β-intercalated cells → bicarbonate secretion
Clinical Significance of RAAS
ACE Inhibitors (e.g., lisinopril, enalapril, ramipril):
•Block conversion of Angiotensin I to Angiotensin II
•Effects: Vasodilation, decreased aldosterone, decreased Na⁺ retention, hyperkalemia
•Side effects: Cough (increased bradykinin), angioedema, acute kidney injury (in bilateral RAS)
•Indications: Hypertension, heart failure, CKD (especially with proteinuria), post-MI
Angiotensin Receptor Blockers (ARBs) (e.g., losartan, valsartan, irbesartan):
•Block AT1 receptors
•Similar effects to ACE inhibitors but without bradykinin-mediated side effects (no cough)
•Indications: Same as ACE inhibitors; alternative for patients intolerant to ACE inhibitors
Aldosterone Antagonists (e.g., spironolactone, eplerenone):
•Block mineralocorticoid receptors
•Effects: Decreased Na⁺ reabsorption, decreased K⁺ secretion → hyperkalemia
•Indications: Heart failure, resistant hypertension, primary hyperaldosteronism
Direct Renin Inhibitors (e.g., aliskiren):
•Block renin activity
•Less commonly used; similar effects to ACE inhibitors/ARBs
Antidiuretic Hormone (ADH, Vasopressin)
Antidiuretic hormone (ADH), also called vasopressin, is a peptide hormone produced by the hypothalamus and secreted by the posterior pituitary. It is the primary regulator of water balance.
Stimuli for ADH Secretion
1.Increased plasma osmolality (>280-285 mOsm/kg) – detected by osmoreceptors in hypothalamus (most sensitive stimulus)
2.Decreased blood volume or blood pressure (>10% decrease) – detected by baroreceptors in carotid sinus, aortic arch, and atria
3.Angiotensin II (stimulates ADH release)
4.Nausea (potent stimulus)
5.Medications: Morphine, nicotine, cyclophosphamide, SSRIs, carbamazepine
Mechanism of ADH Action
ADH binds to V2 receptors on the basolateral membrane of principal cells in the collecting duct:
1.V2 receptor activation → increased cAMP → activation of protein kinase A (PKA)
2.PKA phosphorylates aquaporin-2 (AQP2) vesicles
3.Phosphorylated AQP2 vesicles translocate to and fuse with the apical membrane
4.Water channels inserted into apical membrane → increased water permeability
5.Water moves down osmotic gradient from tubular fluid into hypertonic medullary interstitium
6.Water is reabsorbed into blood via constitutive AQP3 and AQP4 on basolateral membrane
ADH also has additional effects:
•Increases urea reabsorption in inner medullary collecting duct (via UT-A1, UT-A3) → enhances medullary osmotic gradient
•Increases NaCl reabsorption in thick ascending limb → enhances countercurrent multiplication
•Vasoconstriction at high concentrations (via V1 receptors on vascular smooth muscle)
Clinical Disorders of ADH
Diabetes Insipidus (DI):
Central DI:
•Deficiency of ADH production or secretion
•Causes: Pituitary surgery, head trauma, tumors, infiltrative diseases, genetic (autosomal dominant)
•Treatment: Desmopressin (synthetic ADH analog)
Nephrogenic DI:
•Resistance to ADH at the collecting duct
•Causes: Lithium (most common), hypercalcemia, hypokalemia, genetic (X-linked AVPR2 or autosomal recessive AQP2 mutations)
•Treatment: Thiazide diuretics + amiloride (for lithium-induced), NSAIDs, low-sodium diet
Both types: Polyuria (>3 L/day), polydipsia, hypernatremia (if inadequate water intake), urine osmolality <300 mOsm/kg despite dehydration
Syndrome of Inappropriate ADH Secretion (SIADH):
•Excessive ADH secretion despite normal or low plasma osmolality
•Causes: Malignancies (small cell lung cancer), CNS disorders, pulmonary diseases, medications (SSRIs, carbamazepine, cyclophosphamide)
•Features: Hyponatremia, low plasma osmolality, inappropriately concentrated urine (>100 mOsm/kg), euvolemia, normal renal/adrenal/thyroid function
•Treatment: Fluid restriction, salt tablets, vasopressin receptor antagonists (tolvaptan, conivaptan)
Parathyroid Hormone (PTH)
Parathyroid hormone is an 84-amino acid peptide secreted by the parathyroid glands in response to hypocalcemia. PTH has important effects on the kidney:
Renal Effects of PTH:
1.Increases calcium reabsorption in distal convoluted tubule (via TRPV5 channels)
2.Decreases phosphate reabsorption in proximal tubule (inhibits Na⁺-phosphate cotransporter) → phosphaturia
3.Stimulates 1α-hydroxylase in proximal tubule → increased conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D (calcitriol)
Net effect: Increased serum calcium, decreased serum phosphate
Atrial Natriuretic Peptide (ANP) and Brain Natriuretic Peptide (BNP)
Atrial natriuretic peptide (ANP) is secreted by atrial myocytes in response to atrial stretch (volume expansion). Brain natriuretic peptide (BNP) is secreted by ventricular myocytes in response to ventricular stretch.
Renal Effects:
1.Increases GFR (dilates afferent arteriole, constricts efferent arteriole)
2.Inhibits sodium reabsorption in collecting duct (inhibits ENaC)
3.Inhibits renin secretion
4.Inhibits aldosterone secretion
Net effect: Natriuresis, diuresis, decreased blood pressure
Acid-Base Regulation
The kidneys play a critical role in long-term acid-base homeostasis by regulating bicarbonate reabsorption and hydrogen ion excretion. While the lungs provide rapid buffering by adjusting CO₂ excretion (within minutes), the kidneys provide slower but more sustained regulation (over hours to days).
Overview of Renal Acid-Base Regulation
The kidneys contribute to acid-base balance through two main mechanisms:
1.Reabsorption of filtered bicarbonate (prevents loss of base)
2.Excretion of hydrogen ions (eliminates acid)
Normal metabolism produces approximately 50-100 mEq of non-volatile acid per day (from protein metabolism, producing sulfuric acid and phosphoric acid). The kidneys must excrete this acid load while reclaiming all filtered bicarbonate to maintain acid-base balance.
Bicarbonate Reabsorption
Bicarbonate (HCO₃⁻) is freely filtered at the glomerulus. With a normal plasma HCO₃⁻ concentration of 24 mEq/L and GFR of 180 L/day, approximately 4,320 mEq of bicarbonate is filtered daily. Virtually all of this must be reabsorbed to prevent metabolic acidosis.
Distribution of bicarbonate reabsorption:
•Proximal tubule: ~80-90%
•Thick ascending limb: ~10%
•Distal tubule and collecting duct: ~5-10%
Proximal Tubule Bicarbonate Reabsorption
The proximal tubule reabsorbs the majority of filtered bicarbonate via the following mechanism:
1.H⁺ is secreted into the tubular lumen via Na⁺-H⁺ exchanger (NHE3) on the apical membrane
2.H⁺ combines with filtered HCO₃⁻ in the lumen: H⁺ + HCO₃⁻ → H₂CO₃
3.Carbonic anhydrase IV (on the brush border) catalyzes: H₂CO₃ → H₂O + CO₂
4.CO₂ diffuses freely into the proximal tubule cell
5.Carbonic anhydrase II (intracellular) catalyzes: CO₂ + H₂O → H₂CO₃ → H⁺ + HCO₃⁻
6.HCO₃⁻ exits the cell across the basolateral membrane via Na⁺-HCO₃⁻ cotransporter (NBCe1), which transports 1 Na⁺ and 3 HCO₃⁻ into the blood
7.The H⁺ generated intracellularly is recycled back into the lumen via NHE3
Net effect: For each H⁺ secreted, one HCO₃⁻ is reabsorbed into the blood. This process does not result in net acid excretion, but rather prevents the loss of bicarbonate (base).
Factors affecting proximal bicarbonate reabsorption:
•Angiotensin II: Stimulates NHE3 → increased HCO₃⁻ reabsorption
•PTH: Inhibits NHE3 → decreased HCO₃⁻ reabsorption
•Volume depletion: Increased HCO₃⁻ reabsorption (via angiotensin II and increased Na⁺ reabsorption)
•Volume expansion: Decreased HCO₃⁻ reabsorption
Distal Tubule and Collecting Duct Bicarbonate Reabsorption
The remaining 10-20% of filtered bicarbonate is reabsorbed in the thick ascending limb and distal nephron. Additionally, the collecting duct is the primary site of net acid excretion.
Hydrogen Ion Excretion
To maintain acid-base balance, the kidneys must excrete the daily acid load (~50-100 mEq/day) generated by metabolism. Hydrogen ions are excreted in two forms:
1.Titratable acid (~30-40 mEq/day): H⁺ buffered by urinary phosphate and other buffers
2.Ammonium (NH₄⁺) (~30-60 mEq/day): H⁺ combined with ammonia
Intercalated Cells and Acid Secretion
α-Intercalated cells (type A intercalated cells) in the collecting duct are specialized for acid secretion:
Mechanism:
1.CO₂ + H₂O → H₂CO₃ → H⁺ + HCO₃⁻ (via intracellular carbonic anhydrase II)
2.H⁺ is secreted into the lumen via:
•H⁺-ATPase (primary active transport) on apical membrane
•H⁺-K⁺-ATPase (exchanges H⁺ for K⁺) on apical membrane
3.HCO₃⁻ exits the cell into the blood via Cl⁻-HCO₃⁻ exchanger (AE1) on basolateral membrane
Net effect: For each H⁺ secreted, one “new” HCO₃⁻ is added to the blood (this is net acid excretion, not just bicarbonate reabsorption).
Regulation:
•Acidosis: Increases α-intercalated cell H⁺ secretion
•Alkalosis: Decreases α-intercalated cell H⁺ secretion
•Aldosterone: Increases H⁺-ATPase activity (when angiotensin II dephosphorylates mineralocorticoid receptor)
Titratable Acid
Secreted H⁺ must be buffered in the urine to prevent the urine pH from falling too low (minimum urine pH ~4.5). The primary urinary buffer is phosphate (HPO₄²⁻/H₂PO₄⁻).
Mechanism:
1.H⁺ is secreted into the lumen by α-intercalated cells
2.H⁺ combines with filtered HPO₄²⁻: HPO₄²⁻ + H⁺ → H₂PO₄⁻
3.H₂PO₄⁻ is excreted in the urine
Titratable acid is defined as the amount of base (NaOH) required to titrate the urine back to pH 7.4. It represents H⁺ bound to urinary buffers, primarily phosphate.
Ammonium Excretion
Ammonium (NH₄⁺) excretion is the most important mechanism for net acid excretion and can be upregulated in response to chronic acidosis.
Mechanism:
1.Proximal tubule:
•Glutamine is metabolized to α-ketoglutarate and 2 NH₄⁺
•NH₄⁺ is secreted into the lumen via Na⁺-H⁺ exchanger (NHE3) (NH₄⁺ substitutes for H⁺)
•α-Ketoglutarate is metabolized to 2 HCO₃⁻, which enters the blood (new bicarbonate)
2.Thick ascending limb:
•NH₄⁺ is reabsorbed via Na⁺-K⁺-2Cl⁻ cotransporter (NKCC2) (NH₄⁺ substitutes for K⁺)
•NH₄⁺ accumulates in the medullary interstitium
3.Collecting duct:
•NH₃ (ammonia) diffuses from the medullary interstitium into the collecting duct lumen
•NH₃ + H⁺ → NH₄⁺ (traps H⁺ in the lumen)
•NH₄⁺ is excreted in the urine
Net effect: Each NH₄⁺ excreted represents one H⁺ excreted and one new HCO₃⁻ added to the blood.
Regulation:
•Chronic acidosis: Markedly increases ammonium excretion (can increase 5-10 fold over days)
•Hypokalemia: Increases ammonium production (K⁺ depletion stimulates glutamine metabolism)
•Chronic kidney disease: Impaired ammonium excretion contributes to metabolic acidosis
Clinical Correlation: Renal Tubular Acidosis (RTA)
Renal tubular acidosis refers to a group of disorders characterized by impaired renal acid excretion or bicarbonate reabsorption, leading to metabolic acidosis with a normal anion gap (hyperchloremic metabolic acidosis).
Type 1 RTA (Distal RTA):
•Defect: Impaired H⁺ secretion in α-intercalated cells
•Urine pH: >5.5 despite acidosis (cannot acidify urine)
•Serum K⁺: Low (hypokalemia)
•Complications: Nephrocalcinosis, kidney stones (calcium phosphate)
•Causes: Autoimmune diseases, medications (amphotericin B), genetic
Type 2 RTA (Proximal RTA):
•Defect: Impaired HCO₃⁻ reabsorption in proximal tubule
•Urine pH: <5.5 (can acidify urine once serum HCO₃⁻ falls below renal threshold)
•Serum K⁺: Low (hypokalemia)
•Associated: Fanconi syndrome (generalized proximal tubule dysfunction)
•Causes: Multiple myeloma, medications (acetazolamide, topiramate), genetic
Type 4 RTA (Hyperkalemic RTA):
•Defect: Aldosterone deficiency or resistance
•Urine pH: <5.5
•Serum K⁺: High (hyperkalemia) – distinguishing feature
•Causes: Diabetes (hyporeninemic hypoaldosteronism), medications (ACE inhibitors, ARBs, K⁺-sparing diuretics, NSAIDs), adrenal insufficiency
Electrolyte Homeostasis
Sodium Balance
Sodium is the major extracellular cation and the primary determinant of extracellular fluid volume and osmolality. The kidneys regulate sodium balance to maintain blood pressure and volume homeostasis.
Sodium handling (for 70 kg adult with GFR 180 L/day and plasma Na⁺ 140 mEq/L):
•Filtered load: 180 L/day × 140 mEq/L = 25,200 mEq/day
•Excreted: ~100-200 mEq/day (varies with intake)
•>99% reabsorbed
Segmental sodium reabsorption:
•Proximal tubule: ~65-70%
•Thick ascending limb: ~25%
•Distal convoluted tubule: ~5%
•Collecting duct: ~3% (regulated by aldosterone)
Regulation of sodium excretion:
Increased sodium excretion (natriuresis):
•Decreased aldosterone
•Increased ANP/BNP
•Decreased angiotensin II
•Volume expansion
•Increased renal perfusion pressure (pressure natriuresis)
Decreased sodium excretion (sodium retention):
•Increased aldosterone
•Increased angiotensin II
•Decreased ANP/BNP
•Volume depletion
•Decreased renal perfusion pressure
•Sympathetic activation
Potassium Balance
Potassium is the major intracellular cation. The kidneys are responsible for excreting ~90% of dietary potassium intake (the remainder is excreted in stool).
Potassium handling:
•Filtered load: ~720 mEq/day
•Proximal tubule reabsorbs: ~65%
•Thick ascending limb reabsorbs: ~25%
•Distal tubule and collecting duct: Site of regulated K⁺ secretion
Potassium secretion in principal cells:
•K⁺ enters the cell via Na⁺-K⁺-ATPase (basolateral)
•K⁺ exits into the lumen via ROMK channels (apical)
•Secretion is enhanced by:
1.Aldosterone (increases ROMK expression)
2.Increased distal tubular flow (washes away secreted K⁺, maintaining gradient)
3.Increased luminal Na⁺ delivery (enhances Na⁺ reabsorption → more negative lumen → increased K⁺ secretion)
Factors affecting potassium excretion:
Increased K⁺ excretion:
•Hyperkalemia (directly stimulates aldosterone secretion)
•Aldosterone excess
•Alkalosis (shifts K⁺ into cells, increasing intracellular K⁺ available for secretion)
•High distal flow (diuretics)
Decreased K⁺ excretion:
•Hypokalemia
•Aldosterone deficiency
•Acidosis (shifts K⁺ out of cells)
•Low distal flow
Clinical correlation:
•Loop and thiazide diuretics: Increase distal flow and Na⁺ delivery → hypokalemia
•K⁺-sparing diuretics (amiloride, triamterene): Block ENaC → decreased Na⁺ reabsorption → less negative lumen → decreased K⁺ secretion → hyperkalemia
•Aldosterone antagonists (spironolactone): Block aldosterone → decreased ROMK → hyperkalemia
Calcium and Phosphate Homeostasis
Calcium and phosphate homeostasis are tightly regulated by PTH, vitamin D, and fibroblast growth factor 23 (FGF23).
Calcium
Calcium handling:
•~60% of plasma calcium is filtered (ionized and complexed forms; protein-bound calcium is not filtered)
•>98% reabsorbed:
•Proximal tubule: ~65% (passive, paracellular)
•Thick ascending limb: ~25% (passive, paracellular, driven by lumen-positive potential)
•Distal convoluted tubule: ~8% (active, transcellular, regulated by PTH)
•Collecting duct: ~2%
PTH increases calcium reabsorption in the distal convoluted tubule via:
•Increased TRPV5 (apical Ca²⁺ channel)
•Increased calbindin-D28K (intracellular Ca²⁺-binding protein)
•Increased Na⁺-Ca²⁺ exchanger and Ca²⁺-ATPase (basolateral)
Clinical correlation:
•Hypercalcemia: Impairs urine concentrating ability (nephrogenic diabetes insipidus), can cause nephrocalcinosis
•Thiazide diuretics: Increase calcium reabsorption (used to treat hypercalciuria and calcium stones)
•Loop diuretics: Decrease calcium reabsorption (used to treat hypercalcemia)
Phosphate
Phosphate handling:
•~90% of plasma phosphate is filtered
•~80-90% reabsorbed, primarily in proximal tubule via Na⁺-phosphate cotransporters (NaPi-IIa, NaPi-IIc)
PTH decreases phosphate reabsorption by:
•Internalization and degradation of NaPi-IIa and NaPi-IIc → phosphaturia
FGF23 decreases phosphate reabsorption by:
•Similar mechanism to PTH (inhibits NaPi-IIa)
•Also inhibits 1α-hydroxylase (decreases calcitriol production)
Clinical correlation:
•Chronic kidney disease: Decreased phosphate excretion → hyperphosphatemia → secondary hyperparathyroidism → CKD-MBD
•X-linked hypophosphatemia: FGF23 excess → phosphate wasting → rickets/osteomalacia
•Tumor-induced osteomalacia: FGF23-secreting tumors → phosphate wasting
Endocrine Functions of the Kidney
In addition to their excretory and regulatory functions, the kidneys serve as important endocrine organs, producing several hormones that have systemic effects.
Erythropoietin (EPO)
Erythropoietin is a glycoprotein hormone that stimulates red blood cell production in the bone marrow.
Production:
•Produced by peritubular interstitial fibroblasts in the renal cortex
•Stimulated by hypoxia (detected by hypoxia-inducible factor, HIF)
Function:
•Stimulates proliferation and differentiation of erythroid progenitor cells in bone marrow
•Increases red blood cell production
Clinical significance:
•Chronic kidney disease: Decreased EPO production → anemia of CKD
•Treatment: Erythropoiesis-stimulating agents (ESAs) – epoetin alfa, darbepoetin alfa
•Polycythemia: Renal cell carcinoma or renal cysts can produce excess EPO → secondary polycythemia
Vitamin D Activation
The kidneys play a critical role in vitamin D metabolism by converting 25-hydroxyvitamin D (calcidiol, produced in the liver) to 1,25-dihydroxyvitamin D (calcitriol, the active form).
Mechanism:
•1α-hydroxylase in the proximal tubule catalyzes: 25(OH)D → 1,25(OH)₂D (calcitriol)
Regulation:
•Stimulated by: PTH, hypophosphatemia, hypocalcemia
•Inhibited by: FGF23, hyperphosphatemia, hypercalcemia, calcitriol (negative feedback)
Functions of calcitriol:
1.Increases intestinal calcium and phosphate absorption
2.Increases bone resorption (with PTH)
3.Increases renal calcium and phosphate reabsorption
4.Suppresses PTH secretion (negative feedback)
Clinical significance:
•Chronic kidney disease: Decreased 1α-hydroxylase → decreased calcitriol → hypocalcemia → secondary hyperparathyroidism → CKD-MBD
•Treatment: Active vitamin D analogs (calcitriol, paricalcitol, doxercalciferol)
Renin
As discussed previously, renin is secreted by juxtaglomerular cells and initiates the RAAS cascade, playing a central role in blood pressure regulation and sodium homeostasis.
Prostaglandins
The kidneys produce several prostaglandins, particularly PGE₂ and PGI₂ (prostacyclin), which have local effects on renal hemodynamics.
Functions:
•Vasodilation of afferent arteriole (maintains RBF and GFR)
•Inhibit sodium reabsorption in collecting duct
•Antagonize ADH (reduce water reabsorption)
Clinical significance:
•NSAIDs: Inhibit cyclooxygenase (COX) → decreased prostaglandin synthesis → afferent arteriole constriction → decreased RBF and GFR
•Risk of acute kidney injury, especially in states of reduced renal perfusion (heart failure, cirrhosis, volume depletion, elderly)
Summary
Renal physiology encompasses the complex mechanisms by which the kidneys regulate fluid, electrolyte, and acid-base balance while eliminating metabolic wastes. The kidneys receive approximately 20-25% of cardiac output (~1,200 mL/min), enabling them to filter approximately 180 liters of plasma daily through 1-1.5 million nephrons per kidney, yet produce only 1-2 liters of urine, demonstrating the remarkable efficiency of tubular reabsorption (>99%).
Glomerular filtration rate (GFR), the volume of fluid filtered per unit time, is determined by the balance of hydrostatic and oncotic pressures across the glomerular capillary wall (Starling equation). Normal GFR is approximately 120 mL/min/1.73m² in men and 110 mL/min/1.73m² in women. GFR is regulated by intrinsic autoregulation (myogenic mechanism and tubuloglomerular feedback) that maintains relatively constant RBF and GFR despite blood pressure fluctuations between 80-180 mmHg. The filtration fraction (GFR/RPF) is normally ~20%.
Tubular function involves reabsorption and secretion along the nephron. The proximal tubule reabsorbs ~65-70% of filtered sodium and water, 100% of glucose and amino acids, and 80-90% of bicarbonate. The thick ascending limb of the loop of Henle reabsorbs ~25% of filtered sodium via the Na-K-2Cl cotransporter (target of loop diuretics) and is impermeable to water, serving as the “diluting segment.” The distal convoluted tubule reabsorbs ~5% of sodium via the Na-Cl cotransporter (target of thiazide diuretics) and is the site of PTH-regulated calcium reabsorption. The collecting duct performs final regulation of sodium (via ENaC, regulated by aldosterone), potassium (secreted via ROMK), and water (via aquaporin-2, regulated by ADH).
Urine concentration and dilution depend on the countercurrent multiplication system in the loop of Henle, which creates a medullary osmotic gradient (300-1200 mOsm/kg from cortex to papilla), and countercurrent exchange in the vasa recta, which preserves this gradient. ADH regulates water reabsorption in the collecting duct by inserting aquaporin-2 channels into the apical membrane. In the presence of ADH, concentrated urine (up to 1200-1400 mOsm/kg) is produced; in its absence, dilute urine (50-100 mOsm/kg) is excreted.
Hormonal regulation of renal function is mediated primarily by the renin-angiotensin-aldosterone system (RAAS), ADH, PTH, and natriuretic peptides. RAAS regulates blood pressure and sodium balance: renin converts angiotensinogen to angiotensin I, which is converted by ACE to angiotensin II. Angiotensin II causes vasoconstriction, stimulates aldosterone secretion (which increases sodium reabsorption and potassium secretion in the collecting duct), and stimulates ADH release and thirst. ADH increases water reabsorption by inserting aquaporin-2 into collecting duct principal cells. PTH increases calcium reabsorption and decreases phosphate reabsorption in the kidney.
Acid-base regulation involves bicarbonate reabsorption (primarily in the proximal tubule via Na-H exchanger and carbonic anhydrase) and hydrogen ion excretion (as titratable acid and ammonium). The proximal tubule reabsorbs ~80-90% of filtered bicarbonate. α-Intercalated cells in the collecting duct secrete H+ via H+-ATPase and generate new bicarbonate. Ammonium excretion is the most important mechanism for net acid excretion and can be upregulated in chronic acidosis.
Electrolyte homeostasis is precisely regulated. Sodium balance determines extracellular fluid volume and blood pressure; >99% of filtered sodium is reabsorbed, with the collecting duct providing fine-tuning under aldosterone control. Potassium secretion occurs primarily in the collecting duct and is enhanced by aldosterone, high distal flow, and alkalosis. Calcium reabsorption is increased by PTH in the distal tubule. Phosphate reabsorption is decreased by PTH and FGF23 in the proximal tubule.
The kidneys also function as endocrine organs, producing erythropoietin (stimulates red blood cell production; deficiency causes anemia of CKD), activating vitamin D (1α-hydroxylase converts 25(OH)D to 1,25(OH)₂D; deficiency in CKD contributes to secondary hyperparathyroidism), secreting renin (initiates RAAS), and producing prostaglandins (vasodilate afferent arteriole; inhibited by NSAIDs, risking acute kidney injury).
Clinical Pearls
1.Autoregulation Range: The kidneys maintain relatively constant RBF and GFR between mean arterial pressures of 80-180 mmHg via myogenic mechanism and tubuloglomerular feedback. Outside this range, RBF and GFR become pressure-dependent, risking acute kidney injury in hypotension or glomerular damage in severe hypertension.
2.Filtration Fraction Effects: Normal filtration fraction (GFR/RPF) is ~20%. Increased FF (e.g., from efferent arteriole constriction by angiotensin II) increases peritubular oncotic pressure, enhancing proximal tubule reabsorption. Decreased FF (e.g., from efferent dilation by ACE inhibitors) decreases proximal reabsorption.
3.ACE Inhibitors in Renal Artery Stenosis: ACE inhibitors and ARBs dilate the efferent arteriole, reducing glomerular capillary pressure. In bilateral renal artery stenosis or stenosis in a solitary kidney, efferent constriction by angiotensin II is essential for maintaining GFR. ACE inhibitors can cause acute GFR decline in these patients.
4.NSAIDs and Renal Perfusion: Prostaglandins dilate the afferent arteriole, especially in states of reduced renal perfusion (heart failure, cirrhosis, volume depletion, elderly). NSAIDs inhibit prostaglandin synthesis, causing afferent constriction and potentially acute kidney injury in vulnerable patients.
5.SGLT2 Inhibitors: SGLT2 (in early proximal tubule) reabsorbs ~90% of filtered glucose. SGLT2 inhibitors (empagliflozin, dapagliflozin, canagliflozin) block this transporter, causing glycosuria and lowering blood glucose. They also have cardiovascular and renal protective effects and are now used in heart failure and CKD regardless of diabetes status.
6.Loop Diuretics and Urine Concentration: Loop diuretics block the Na-K-2Cl cotransporter in the thick ascending limb, impairing countercurrent multiplication and dissipating the medullary osmotic gradient. This impairs urine concentrating ability and can cause hyponatremia if patients continue to drink free water.
7.ADH and Urine Osmolality: In the presence of ADH, urine can be concentrated up to 1200-1400 mOsm/kg. In the absence of ADH (central diabetes insipidus) or resistance to ADH (nephrogenic diabetes insipidus), urine osmolality remains <300 mOsm/kg despite dehydration, causing polyuria and hypernatremia.
8.Aldosterone and Potassium: Aldosterone increases potassium secretion in the collecting duct. Aldosterone excess (primary hyperaldosteronism) causes hypokalemia and metabolic alkalosis. Aldosterone deficiency (type 4 RTA, adrenal insufficiency) or blockade (ACE inhibitors, ARBs, K+-sparing diuretics) causes hyperkalemia.
9.Ammonium Excretion in Acidosis: Ammonium (NH₄⁺) excretion is the most important mechanism for net acid excretion and can increase 5-10 fold in chronic acidosis. In chronic kidney disease, impaired ammonium excretion contributes to metabolic acidosis. Urine anion gap can help assess ammonium excretion: negative gap suggests adequate ammonium excretion (GI losses), positive gap suggests impaired excretion (RTA).
10.CKD and Endocrine Dysfunction: Chronic kidney disease causes multiple endocrine abnormalities: decreased erythropoietin (anemia of CKD), decreased 1α-hydroxylase (decreased calcitriol → hypocalcemia → secondary hyperparathyroidism → CKD-MBD), and impaired urine concentration (loss of medullary gradient → isosthenuria). Early recognition and treatment are essential to prevent complications.
Multiple Choice Questions
Basic Level (Medical Students and Residents)
Question 1: What percentage of cardiac output do the kidneys receive?
A) 5-10%
B) 10-15%
C) 20-25%
D) 30-35%
E) 40-45%
Answer: C) 20-25%
Explanation: The kidneys receive approximately 20-25% of cardiac output, which translates to about 1,200 mL/min or 1.2 liters per minute of blood flow. This extraordinarily high blood flow relative to organ size (kidneys comprise <0.5% of body weight) is not primarily for the metabolic needs of the kidney tissue, but rather to support the kidney’s filtration function. This high flow enables the kidneys to filter approximately 180 liters of plasma daily to produce 1-2 liters of urine. The high renal blood flow also makes the kidneys particularly vulnerable to ischemic injury during hypotension or shock.
Question 2: What is the normal filtration fraction (FF)?
A) 10%
B) 20%
C) 40%
D) 60%
E) 80%
Answer: B) 20%
Explanation: The filtration fraction is defined as GFR divided by renal plasma flow (RPF): FF = GFR / RPF. With normal GFR of approximately 120 mL/min and RPF of approximately 600 mL/min, the filtration fraction is 120/600 = 0.20 or 20%. This means that about one-fifth of the plasma flowing through the kidneys is filtered at the glomerulus, while the remaining 80% continues through the efferent arteriole into the peritubular capillaries. Changes in filtration fraction have important implications for tubular reabsorption: increased FF increases peritubular oncotic pressure (because more fluid is filtered out), which enhances proximal tubule reabsorption of sodium and water.
Question 3: Which segment of the nephron is impermeable to water and is called the “diluting segment”?
A) Proximal convoluted tubule
B) Thin descending limb of loop of Henle
C) Thick ascending limb of loop of Henle
D) Distal convoluted tubule
E) Collecting duct
Answer: C) Thick ascending limb of loop of Henle
Explanation: The thick ascending limb of the loop of Henle is called the “diluting segment” because it actively reabsorbs sodium and chloride (via the Na-K-2Cl cotransporter, NKCC2) while being impermeable to water. This results in dilution of the tubular fluid. By the time the fluid exits the thick ascending limb and enters the distal convoluted tubule, it is hypotonic (~100-150 mOsm/kg), regardless of the final urine osmolality. The thick ascending limb reabsorbs approximately 25% of filtered sodium and is the target of loop diuretics (furosemide, bumetanide, torsemide). The impermeability to water is critical for both diluting the urine and for creating the medullary osmotic gradient via countercurrent multiplication.
Question 4: Which transporter in the proximal tubule is the target of SGLT2 inhibitors?
A) Na-H exchanger
B) Na-glucose cotransporter
C) Na-K-ATPase
D) Na-phosphate cotransporter
E) Na-amino acid cotransporter
Answer: B) Na-glucose cotransporter
Explanation: SGLT2 (sodium-glucose cotransporter 2) is located on the apical membrane of the early proximal convoluted tubule and is responsible for reabsorbing approximately 90% of filtered glucose (the remaining 10% is reabsorbed by SGLT1 in the late proximal tubule). SGLT2 inhibitors (empagliflozin, dapagliflozin, canagliflozin) block this transporter, causing glycosuria (glucose in the urine) and lowering blood glucose levels in diabetes. Importantly, these drugs also have cardiovascular and renal protective effects beyond glucose lowering and are now used in heart failure and chronic kidney disease regardless of diabetes status. Side effects include genital mycotic infections, euglycemic diabetic ketoacidosis (rare), and volume depletion.
Question 5: What is the primary mechanism by which ADH increases water reabsorption in the collecting duct?
A) Increases Na-K-ATPase activity
B) Increases Na-Cl cotransporter expression
C) Inserts aquaporin-2 channels into the apical membrane
D) Increases carbonic anhydrase activity
E) Increases urea transporter expression
Answer: C) Inserts aquaporin-2 channels into the apical membrane
Explanation: Antidiuretic hormone (ADH, also called vasopressin) increases water reabsorption in the collecting duct by binding to V2 receptors on the basolateral membrane of principal cells. This activates a cAMP-mediated signaling cascade that causes phosphorylation and translocation of aquaporin-2 (AQP2) water channels from intracellular vesicles to the apical membrane. Once inserted, AQP2 allows water to move down its osmotic gradient from the tubular fluid into the hypertonic medullary interstitium. Water then exits the cell via constitutively expressed aquaporin-3 and aquaporin-4 on the basolateral membrane. In the absence of ADH, AQP2 is removed from the apical membrane, the collecting duct becomes impermeable to water, and dilute urine is excreted. This is the mechanism underlying diabetes insipidus (central or nephrogenic).
Advanced Level (Nephrology Fellows and Nephrologists)
Question 6: A patient with bilateral renal artery stenosis is started on an ACE inhibitor. What is the most likely effect on GFR?
A) Marked increase in GFR
B) Mild increase in GFR
C) No change in GFR
D) Mild decrease in GFR
E) Marked decrease in GFR
Answer: E) Marked decrease in GFR
Explanation: In bilateral renal artery stenosis (or stenosis in a solitary kidney), renal perfusion pressure is reduced. To maintain GFR despite reduced perfusion, the kidneys rely on angiotensin II-mediated efferent arteriole constriction, which increases glomerular capillary hydrostatic pressure. ACE inhibitors block the production of angiotensin II, causing efferent arteriole dilation, which decreases glomerular capillary pressure and can cause a marked decline in GFR. This is why ACE inhibitors and ARBs are relatively contraindicated in bilateral renal artery stenosis. A rise in serum creatinine >30% after starting an ACE inhibitor or ARB should prompt evaluation for renal artery stenosis. In contrast, in patients without renal artery stenosis, ACE inhibitors typically cause only a mild, transient decrease in GFR (~10-20%) that stabilizes within weeks and provides long-term renoprotection.
Question 7: Which of the following best explains why loop diuretics impair the kidney’s ability to concentrate urine?
A) They block ADH receptors in the collecting duct
B) They inhibit aquaporin-2 insertion
C) They dissipate the medullary osmotic gradient
D) They increase medullary blood flow
E) They inhibit urea reabsorption
Answer: C) They dissipate the medullary osmotic gradient
Explanation: Loop diuretics (furosemide, bumetanide, torsemide) block the Na-K-2Cl cotransporter (NKCC2) in the thick ascending limb of the loop of Henle. The thick ascending limb is responsible for actively reabsorbing NaCl into the medullary interstitium without water reabsorption, which is the key step in countercurrent multiplication that creates and maintains the medullary osmotic gradient (300-1200 mOsm/kg from cortex to papilla). By blocking NKCC2, loop diuretics prevent NaCl reabsorption, thereby dissipating the medullary osmotic gradient. Without this gradient, the collecting duct cannot reabsorb water effectively even in the presence of ADH, impairing urine concentrating ability. This is why patients on chronic loop diuretics may develop hyponatremia if they continue to drink free water, as they cannot excrete maximally dilute urine or concentrate urine appropriately.
Question 8: A patient with chronic metabolic acidosis has a urine pH of 5.0 and a positive urine anion gap. What is the most likely diagnosis?
A) Diarrhea (GI bicarbonate loss)
B) Type 1 (distal) renal tubular acidosis
C) Type 2 (proximal) renal tubular acidosis
D) Type 4 (hyperkalemic) renal tubular acidosis
E) Diabetic ketoacidosis
Answer: D) Type 4 (hyperkalemic) renal tubular acidosis
Explanation: The urine anion gap (UAG = [Na+ + K+] – [Cl-] in urine) is used to assess ammonium (NH₄⁺) excretion in patients with normal anion gap metabolic acidosis. A negative UAG suggests adequate ammonium excretion (appropriate renal response to acidosis), typically seen in GI bicarbonate losses (diarrhea). A positive UAG suggests impaired ammonium excretion (inappropriate renal response), seen in renal tubular acidosis. The patient’s urine pH of 5.0 indicates the ability to acidify urine (pH <5.5), which rules out type 1 (distal) RTA (which has urine pH >5.5 despite acidosis). Type 2 (proximal) RTA can acidify urine once serum bicarbonate falls below the renal threshold. Type 4 RTA is characterized by hyperkalemia (due to aldosterone deficiency or resistance), impaired ammonium excretion (positive UAG), and ability to acidify urine (pH <5.5). Type 4 RTA is the most common form of RTA and is often seen in diabetes (hyporeninemic hypoaldosteronism) or with medications (ACE inhibitors, ARBs, K+-sparing diuretics, NSAIDs).
Question 9: Which of the following conditions would result in an increased filtration fraction?
A) Afferent arteriole constriction (NSAIDs)
B) Efferent arteriole constriction (Angiotensin II)
C) Efferent arteriole dilation (ACE inhibitors)
D) Decreased plasma protein (nephrotic syndrome)
E) Ureteral obstruction
Answer: B) Efferent arteriole constriction (Angiotensin II)
Explanation: Filtration fraction (FF) = GFR / RPF. Efferent arteriole constriction (e.g., by angiotensin II) increases glomerular capillary hydrostatic pressure, which increases GFR, while simultaneously decreasing renal plasma flow (RPF) by increasing resistance. Since GFR increases and RPF decreases, the filtration fraction increases. This is an important compensatory mechanism in states of reduced renal perfusion (e.g., heart failure, volume depletion), where angiotensin II helps maintain GFR despite reduced RBF. In contrast: (A) Afferent arteriole constriction decreases both GFR and RPF proportionally, so FF is unchanged. (C) Efferent arteriole dilation decreases GFR and increases RPF, so FF decreases. (D) Decreased plasma protein increases GFR (decreased oncotic pressure opposes filtration less) with no change in RPF, so FF increases (this is also correct, but B is the best answer given the clinical context). (E) Ureteral obstruction decreases GFR with no change in RPF, so FF decreases.
Question 10: A patient with CKD stage 4 (GFR 25 mL/min) develops anemia (Hgb 9.0 g/dL) despite normal iron studies. What is the most likely mechanism?
A) Decreased vitamin B12 absorption
B) Decreased folate absorption
C) Decreased erythropoietin production
D) Increased red blood cell destruction
E) Bone marrow suppression by uremic toxins
Answer: C) Decreased erythropoietin production
Explanation: Anemia is a common complication of chronic kidney disease, typically developing when GFR falls below 30-40 mL/min (CKD stages 3b-4). The primary mechanism is decreased erythropoietin (EPO) production by peritubular interstitial fibroblasts in the renal cortex. EPO is a glycoprotein hormone that stimulates red blood cell production in the bone marrow in response to hypoxia. As kidney function declines, EPO production decreases, leading to normocytic, normochromic anemia. While uremic toxins may contribute to bone marrow suppression and shortened red blood cell survival, decreased EPO production is the predominant mechanism. Treatment involves erythropoiesis-stimulating agents (ESAs) such as epoetin alfa or darbepoetin alfa, along with ensuring adequate iron stores (oral or IV iron). Target hemoglobin is typically 10-11.5 g/dL, as higher targets have been associated with increased cardiovascular events in clinical trials (TREAT, CHOIR studies). Iron deficiency should always be excluded before attributing anemia solely to CKD, as it is a common coexisting condition.