8.2 Glomerular Filtration and Tubular Reabsorption

Glomerular Filtration Process

Glomerular filtration is the first step in urine formation. Blood pressure forces fluid from the glomerular capillaries into Bowman's capsule, producing a protein-free filtrate that contains water, electrolytes, glucose, amino acids, and waste products. Everything downstream in the nephron works to refine this filtrate into urine.

The glomerular filtration rate (GFR) is the volume of filtrate produced per unit time. In a healthy adult, GFR averages about 125 mL/min, which adds up to roughly 180 L/day. That's an enormous volume, and it's why tubular reabsorption is so critical (you'd be severely dehydrated within minutes without it).

Factors Influencing GFR

GFR depends on the net filtration pressure (NFP) across the glomerular capillaries. NFP is determined by Starling forces:

• Glomerular capillary hydrostatic pressure pushes fluid out into Bowman's capsule (favors filtration)
• Bowman's capsule hydrostatic pressure pushes back against filtration (opposes filtration)
• Plasma oncotic pressure (from proteins like albumin still in the blood) pulls fluid back into the capillary (opposes filtration)

$\text{NFP} = P_{GC} - P_{BC} - \pi_{GC}$

where $P_{GC}$ is glomerular capillary hydrostatic pressure, $P_{BC}$ is Bowman's capsule hydrostatic pressure, and $\pi_{GC}$ is glomerular capillary oncotic pressure.

Autoregulation keeps GFR relatively constant despite changes in systemic blood pressure (effective across a mean arterial pressure range of roughly 80–180 mmHg). Two mechanisms handle this:

1. Myogenic mechanism: When blood pressure rises, afferent arteriolar smooth muscle stretches and reflexively constricts, limiting the pressure increase reaching the glomerulus.
2. Tubuloglomerular feedback: The macula densa cells in the juxtaglomerular apparatus sense the flow rate and solute concentration in the distal tubule. If GFR is too high (more $NaCl$ delivery), they signal the afferent arteriole to constrict.

Neural and hormonal modulation can override autoregulation when the body needs to prioritize:

• Sympathetic nervous system: Strong sympathetic activation (e.g., hemorrhage, severe stress) constricts afferent arterioles, reducing GFR to conserve fluid
• Renin-angiotensin-aldosterone system (RAAS): Angiotensin II preferentially constricts the efferent arteriole, which helps maintain GFR when renal blood flow drops
• Atrial natriuretic peptide (ANP): Released when atrial walls stretch (volume overload), ANP dilates the afferent arteriole and constricts the efferent arteriole, increasing GFR to promote fluid loss

Glomerular Filtration Membrane

The filtration membrane is what makes the glomerulus a selective filter rather than a leaky sieve. It allows water and small solutes through while keeping blood cells and most proteins in the bloodstream.

Membrane Composition

The membrane has three layers, each contributing to selectivity:

1. Fenestrated endothelium: The capillary endothelial cells have small pores (fenestrations, ~70–100 nm) that are freely permeable to water, electrolytes, glucose, and amino acids. They block blood cells but are too large to stop proteins on their own.
2. Basement membrane: A layer of type IV collagen and negatively charged glycoproteins. This provides both size selectivity (blocks larger molecules) and charge selectivity (repels negatively charged proteins like albumin).
3. Podocyte foot processes: Podocytes wrap around the capillaries with interdigitating foot processes. The narrow gaps between them, called filtration slits, are bridged by slit diaphragms that act as the final size-selective barrier.

Membrane Function and Pathology

Together, these three layers ensure that the filtrate is essentially plasma minus proteins. Albumin (molecular weight ~69 kDa) is almost entirely excluded under normal conditions.

When the filtration membrane is damaged, selectivity breaks down:

• Nephrotic syndrome: Damage to podocytes or the basement membrane (often the charge barrier) leads to massive proteinuria, where large amounts of albumin leak into the urine. Loss of plasma albumin drops oncotic pressure, causing widespread edema.
• Glomerulonephritis: Inflammation of the glomerulus damages the membrane, allowing both protein and red blood cells into the filtrate (hematuria + proteinuria).

Finding protein or blood in a urinalysis is a red flag for glomerular membrane damage.

Tubular Reabsorption Substances

Of the ~180 L filtered per day, about 99% of the water and most useful solutes are reclaimed. Different substances are reabsorbed at specific nephron segments.

Water and Electrolytes

• Water: About 65% is reabsorbed in the proximal convoluted tubule (PCT), another 15% in the descending loop of Henle, and the remainder in the distal nephron and collecting duct (under hormonal control). The PCT reabsorption is obligatory and follows solute reabsorption by osmosis.
• Sodium ($Na^+$): Actively reabsorbed along the entire nephron. The PCT handles ~65%, the thick ascending limb of the loop of Henle ~25%, and the distal convoluted tubule (DCT) and collecting duct fine-tune the rest. Sodium reabsorption is the driving force behind most other reabsorption.
• Chloride ($Cl^-$): Follows sodium passively in the PCT (paracellular route). In the thick ascending limb, it's actively transported via the $Na^+-K^+-2Cl^-$ cotransporter (NKCC2).
• Potassium ($K^+$): Reabsorbed in the PCT (~65%) and thick ascending limb (~25%). In the DCT and collecting duct, potassium can be either secreted or reabsorbed depending on the body's needs. Aldosterone promotes $K^+$ secretion here.
• Calcium ($Ca^{2+}$) and Magnesium ($Mg^{2+}$): Primarily reabsorbed in the thick ascending limb (paracellular, driven by the lumen-positive charge) and the DCT (transcellular, regulated by PTH for calcium).

Organic Solutes and Acid-Base Regulation

• Glucose: Normally 100% reabsorbed in the PCT via sodium-glucose cotransporters (SGLTs). SGLT2 handles ~90% in the early PCT; SGLT1 picks up the rest. These transporters have a maximum capacity called the transport maximum ($T_m$). When blood glucose exceeds ~180 mg/dL (the renal threshold), the transporters saturate and glucose spills into the urine. This is why glucosuria is a hallmark of uncontrolled diabetes mellitus.
• Amino acids: Reabsorbed in the PCT through secondary active transport coupled to the $Na^+$ gradient, similar to glucose. Normally 100% reabsorbed.
• Bicarbonate ($HCO_3^-$): About 80–90% is reabsorbed in the PCT, with the remainder handled by the thick ascending limb and collecting duct. This is essential for maintaining blood pH. The process involves $H^+$ secretion into the tubular lumen, where it combines with filtered $HCO_3^-$ to form $CO_2$ and $H_2O$, which then diffuse back into the cell and regenerate $HCO_3^-$.
• Urea: Partially reabsorbed (~50%) in the PCT by solvent drag. In the inner medullary collecting duct, urea is reabsorbed via UT transporters (enhanced by ADH). This recycled urea contributes to the medullary osmotic gradient that concentrates urine.

Tubular Reabsorption Mechanisms

Transport Mechanisms

Understanding how substances cross the tubular epithelium is just as important as knowing where.

1. Primary active transport: Uses ATP directly. The most important example is the $Na^+/K^+$-ATPase on the basolateral membrane of tubular cells. It pumps 3 $Na^+$ out and 2 $K^+$ in, keeping intracellular $Na^+$ low. This gradient powers almost all other reabsorption.
2. Secondary active transport: Uses the $Na^+$ gradient created by the $Na^+/K^+$-ATPase to co-transport other substances. Examples include SGLT ($Na^+$-glucose) and $Na^+$-amino acid cotransporters on the apical membrane. No ATP is used directly, but the process depends on the ATP-driven $Na^+$ gradient.
3. Passive reabsorption (diffusion and osmosis): Substances move down their concentration or electrochemical gradients. Water follows solutes by osmosis through aquaporin channels in the PCT and descending loop of Henle. $Cl^-$ follows $Na^+$ paracellularly in the PCT.
4. Solvent drag: As water moves by osmosis, it carries dissolved solutes along with it through paracellular pathways. This is how some $K^+$, $Ca^{2+}$, and urea get reabsorbed in the PCT without dedicated transporters.

Regulation of Reabsorption

The kidneys don't just reabsorb at a fixed rate. Hormonal, neural, and local signals adjust reabsorption to match the body's current needs.

Hormonal regulation:

• Aldosterone (from the adrenal cortex): Acts on principal cells of the DCT and collecting duct. Increases $Na^+$ reabsorption (by upregulating $Na^+$ channels and $Na^+/K^+$-ATPase) and promotes $K^+$ secretion. Released in response to angiotensin II or elevated plasma $K^+$.
• Antidiuretic hormone (ADH/vasopressin) (from the posterior pituitary): Inserts aquaporin-2 channels into the apical membrane of collecting duct cells, making them permeable to water. Without ADH, the collecting duct is nearly impermeable to water, and you produce dilute urine. With ADH, water is reabsorbed and urine becomes concentrated.
• Parathyroid hormone (PTH): Increases $Ca^{2+}$ reabsorption in the DCT by stimulating apical calcium channels (TRPV5) and basolateral calcium pumps. Also inhibits phosphate reabsorption in the PCT.

Neural regulation:

Sympathetic nerve activity (via norepinephrine on alpha-1 receptors) enhances $Na^+$ and water reabsorption in the PCT. This is part of the body's response to low blood pressure or volume depletion.

Local factors:

• Prostaglandins and nitric oxide act as paracrine signals that can modulate sodium and water reabsorption locally. Prostaglandins generally oppose $Na^+$ reabsorption and promote vasodilation.
• Peritubular capillary Starling forces: After blood leaves the glomerulus through the efferent arteriole, it enters the peritubular capillaries with high oncotic pressure (proteins were concentrated during filtration) and low hydrostatic pressure. This creates a strong driving force to pull reabsorbed fluid from the interstitium back into the blood. If peritubular oncotic pressure drops or hydrostatic pressure rises, reabsorption slows.