4.3 Renal Physiology, Body Fluid Balance & Acid-Base Regulation

Why this area matters

The TOS lists:

• body fluid compartments and the intake and losses that change them;
• the structure and function of the renal cortex and medulla;
• the determinants of renal blood flow and GFR;
• nephron transport;
• erythropoietin production and its targets;
• blood pH regulation.

Every diuretic question in Pharmacology and every acid-base question in Medicine builds on this physiology.

Daily water balance

An adult takes in about 2.3 L of water a day: about 2.1 L from food and drink and about 0.2 L from metabolism. Losses at rest are roughly:

• 1.4 L in urine;
• 0.7 L of insensible loss through skin and lungs;
• 0.1 L in sweat;
• 0.1 L in feces.

Heat and heavy exercise can raise sweat loss to several liters a day, and fever raises insensible loss. Diarrhea, vomiting and burns produce large extracellular losses. The body fluid compartments themselves are described in the homeostasis section.

Kidney structure

The cortex contains glomeruli, proximal and distal convoluted tubules and cortical collecting ducts. The medulla contains the loops of Henle, vasa recta and medullary collecting ducts, arranged in renal pyramids.

• About 85% of nephrons are cortical, with short loops.
• About 15% are juxtamedullary, with long loops that reach deep into the medulla. These build the concentration gradient.

The juxtaglomerular apparatus sits where the distal tubule touches its own afferent arteriole. It has three parts: macula densa cells, renin-secreting granular cells and extraglomerular mesangial cells.

Glomerular Filtration, Clearance & Autoregulation

Glomerular filtration produces approximately $180\text{ L/day}$ ($125\text{ mL/min}$) of ultrafiltrate across the three-layered glomerular filtration barrier (fenestrated capillary endothelium, negatively charged basement membrane rich in heparan sulfate, and podocyte foot processes with nephrin slit diaphragms).

Starling Forces Across the Glomerular Capillary

$\text{GFR} = K_f \cdot \left[ (P_{GC} - P_{BS}) - (\pi_{GC} - \pi_{BS}) \right]$

• $K_f$: Ultrafiltration coefficient (product of surface area and hydraulic permeability).
• $P_{GC}$ (Glomerular Capillary Hydrostatic Pressure $\approx 50\text{--}60\text{ mmHg}$): The primary driving force favoring filtration. Remains elevated and relatively flat along the capillary due to high downstream resistance from efferent arterioles.
• $P_{BS}$ (Bowman's Space Hydrostatic Pressure $\approx 10\text{--}15\text{ mmHg}$): Opposes filtration. Increases in urinary tract obstruction (e.g., ureteral calculi, benign prostatic hyperplasia), which lowers GFR.
• $\pi_{GC}$ (Glomerular Capillary Oncotic Pressure $\approx 25\text{--}32\text{ mmHg}$): Opposes filtration. Rises progressively from the afferent to efferent end as protein-free filtrate leaves the vascular space.
• $\pi_{BS}$ (Bowman's Space Oncotic Pressure): Effectively $0\text{ mmHg}$ in health because albumin cannot cross the filtration barrier.

Arteriolar Resistance & Filtration Fraction

$\text{Filtration Fraction (FF)} = \frac{\text{GFR}}{\text{RPF}} \approx \frac{125\text{ mL/min}}{625\text{ mL/min}} \approx 20\%$

• Afferent Arteriolar Constriction (e.g., NSAIDs inhibiting vasodilatory prostaglandins, high sympathetic tone): Reduces $P_{GC}$, thereby decreasing GFR and RPF in equal proportion; FF remains unchanged.
• Efferent Arteriolar Constriction (e.g., low-to-moderate Angiotensin II): Restricts outflow from the glomerular tuft, increasing $P_{GC}$. GFR increases while RPF decreases; FF increases markedly.
• ACE Inhibitors / ARBs: Inhibit angiotensin II, selectively dilating the efferent arteriole. This lowers $P_{GC}$ and GFR while increasing RPF, reducing FF. This effect relieves intraglomerular hypertension, conferring long-term renoprotection in diabetic kidney disease despite an acute modest rise in serum creatinine.

Renal Clearance Calculations

Clearance ($C_x$) represents the volume of plasma completely cleared of a substance by the kidneys per unit time:

$C_x = \frac{U_x \cdot V}{P_x}$

Where $U_x$ is urine concentration, $V$ is urine flow rate (mL/min), and $P_x$ is plasma concentration.

• Inulin Clearance: Inulin is freely filtered and neither reabsorbed nor secreted along the nephron. Thus, $C_{inulin} = \text{GFR}$ (the gold standard reference).
• Creatinine Clearance: Endogenous metabolic byproduct of muscle creatine. Freely filtered but undergoes slight active secretion by proximal tubule organic cation transporters ($\sim 10\%\text{ to }15\%$). Consequently, $C_{cr}$ slightly overestimates true GFR. Note that serum creatinine has an inverse exponential relationship with GFR: a rise in serum creatinine from $1.0\text{ mg/dL}$ to $2.0\text{ mg/dL}$ represents a loss of roughly $50\%$ of functioning renal mass.
• Para-aminohippuric Acid (PAH) Clearance: Freely filtered and actively secreted by organic anion transporters in the proximal tubule with nearly 100% extraction efficiency in a single pass. Thus, $C_{PAH} = \text{Effective Renal Plasma Flow (ERPF)} \approx 600\text{ mL/min}$.
• Renal Blood Flow (RBF): $\text{RBF} = \frac{\text{RPF}}{1 - \text{Hematocrit}} \approx \frac{650}{1 - 0.45} \approx 1200\text{ mL/min} \quad (20\%\text{--}25\%\text{ of Cardiac Output})$

Autoregulation of GFR

Renal autoregulation maintains nearly constant GFR and RBF across mean arterial pressures between $80\text{ and }180\text{ mmHg}$ through two mechanisms:

1. Myogenic Mechanism: Elevated arterial pressure stretches the vascular smooth muscle of the afferent arteriole, opening stretch-sensitive calcium channels to cause reflex vasoconstriction.
2. Tubuloglomerular Feedback (TGF): Mediated by the juxtaglomerular apparatus. When elevated GFR increases luminal delivery of $NaCl$ to the macula densa (specialized epithelial cells in the thick ascending limb/early distal tubule), apical NKCC2 cotransporters absorb excess $Na^+$ and $Cl^-$. Intracellular ATP is degraded to adenosine, which binds $A_1$ receptors on adjacent extraglomerular mesangial and vascular smooth muscle cells, triggering afferent arteriolar vasoconstriction and suppressing renin release.

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Segmental Tubular Solute & Water Transport

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Acid-Base Regulation & Anion Gap Analysis

The Henderson-Hasselbalch Relationship

$\text{pH} = 6.1 + \log_{10}\left(\frac{[HCO_3^-]}{0.03 \cdot PaCO_2}\right)$

Normal arterial reference values: $\text{pH } 7.35\text{--}7.45$, $[HCO_3^-] = 22\text{--}26\text{ mEq/L}$, $PaCO_2 = 35\text{--}45\text{ mmHg}$.

Primary Disturbances & Compensatory Formulas

1. Metabolic Acidosis: Primary drop in $[HCO_3^-]$. Compensatory alveolar hyperventilation lowers $PaCO_2$. Expected compensation is calculated using Winter's Formula: $\text{Expected } PaCO_2 = (1.5 \times [HCO_3^-]) + 8 \pm 2$
   • If measured $PaCO_2 > \text{expected}$: Concurrent primary respiratory acidosis (hypoventilation, respiratory failure).
   • If measured $PaCO_2 < \text{expected}$: Concurrent primary respiratory alkalosis (hyperventilation, sepsis, salicylate toxicity).
2. Metabolic Alkalosis: Primary rise in $[HCO_3^-]$. Compensatory hypoventilation raises $PaCO_2$: $\Delta PaCO_2 \approx 0.7 \times \Delta [HCO_3^-] \quad (\text{ceiling } \sim 55\text{--}60\text{ mmHg})$
3. Respiratory Acidosis: Primary elevation in $PaCO_2$:
   • Acute: For each $10\text{ mmHg}$ rise in $PaCO_2$, $[HCO_3^-]$ increases by $1\text{ mEq/L}$ ($\text{pH}$ drops by $0.08$).
   • Chronic: For each $10\text{ mmHg}$ rise in $PaCO_2$, $[HCO_3^-]$ increases by $3.5\text{--}4.0\text{ mEq/L}$ ($\text{pH}$ drops by $0.03$).
4. Respiratory Alkalosis: Primary decrease in $PaCO_2$:
   • Acute: For each $10\text{ mmHg}$ drop in $PaCO_2$, $[HCO_3^-]$ decreases by $2\text{ mEq/L}$ ($\text{pH}$ rises by $0.08$).
   • Chronic: For each $10\text{ mmHg}$ drop in $PaCO_2$, $[HCO_3^-]$ decreases by $4\text{--}5\text{ mEq/L}$ ($\text{pH}$ rises by $0.03$).

Serum Anion Gap Evaluation

$\text{Anion Gap (AG)} = [Na^+] - ([Cl^-] + [HCO_3^-]) \quad (\text{Normal: } 10\text{--}12\text{ mEq/L})$

• Albumin Correction: Serum albumin carries negative charges accounting for the majority of normal unmeasured anions. For every $1\text{ g/dL}$ drop in serum albumin below $4.0\text{ g/dL}$, the expected baseline AG drops by $2.5\text{ mEq/L}$: $\text{Corrected AG} = \text{Observed AG} + 2.5 \times (4.0 - [\text{Albumin}])$
• High Anion Gap Metabolic Acidosis (MUDPILES / GOLDMARK): Methanol, Uremia, Diabetic ketoacidosis, Propylene glycol, Isoniazid/Iron, Lactic acidosis, Ethylene glycol, Salicylates (aspirin: causes early respiratory alkalosis followed by high AG metabolic acidosis).
• Normal Anion Gap (Hyperchloremic) Metabolic Acidosis (HARDUP): Hyperalimentation, Acetazolamide, Renal tubular acidosis (Types 1, 2, 4), Diarrhea (loss of $HCO_3^-$ with proportional retention of $Cl^-$), Ureteral diversion, Pancreatic fistulas.
• Delta-Delta ($\Delta/\Delta$) Ratio: In high AG metabolic acidosis, compares the excess anion gap to the deficit in bicarbonate: $\frac{\Delta \text{AG}}{\Delta [HCO_3^-]} = \frac{\text{AG} - 12}{24 - [HCO_3^-]}$
  • Ratio $< 0.8$: Mixed High AG and Normal AG metabolic acidosis.
  • Ratio $0.8\text{--}2.0$: Pure high anion gap metabolic acidosis.
  • Ratio $> 2.0$: Concurrent metabolic alkalosis or pre-existing compensated chronic respiratory acidosis.

Concentrating and diluting the urine

• The countercurrent multiplier works as follows. The thick ascending limb pumps NaCl into the interstitium without water. The descending limb loses water to the salty interstitium. Repeated along the loop, this builds a medullary gradient from about 300 to 1,200 mOsm/kg.
• Urea recycling in the inner medullary collecting duct, which ADH stimulates through urea transporters, supplies about half of the inner-medullary osmolality.
• The vasa recta act as countercurrent exchangers, so blood flow does not wash out the gradient.
• With high ADH, aquaporin-2 lets collecting-duct water leave, producing urine of up to about 1,200 mOsm/kg. Without ADH, dilute urine as low as about 50 mOsm/kg is excreted.

Potassium handling

About 90% of filtered K+ is reabsorbed before the distal nephron. The amount excreted is set by principal-cell secretion, which increases with:

• aldosterone;
• high distal sodium delivery and flow (loop and thiazide diuretics cause hypokalemia);
• alkalosis;
• a high plasma K+.

Potassium-sparing diuretics and ACE inhibitors reduce secretion and can cause hyperkalemia.

Erythropoietin

Peritubular interstitial (fibroblast-like) cells in the renal cortex sense oxygen through hypoxia-inducible factor. When oxygen delivery falls, they increase erythropoietin, which acts on erythroid progenitors (CFU-E) in the marrow to prevent apoptosis and expand red cell production. Chronic kidney disease causes a normocytic anemia that responds to erythropoiesis-stimulating agents once iron stores are adequate.

Renal acid excretion

Metabolism produces about 1 mEq/kg of fixed (non-volatile) acid a day, about 50 to 100 mEq in an adult. The kidney handles it in two steps:

1. It reclaims filtered bicarbonate, mostly in the proximal tubule through NHE3 and carbonic anhydrase.
2. It excretes H+ as titratable acid (mainly phosphate) and as ammonium. Ammonium comes from glutamine metabolism in proximal cells and can be increased many-fold in chronic acidosis.

Each H+ excreted generates a new HCO3- for the blood. Renal tubular acidosis results when bicarbonate reclamation (type 2, proximal) or H+ secretion (type 1, distal) fails, or when aldosterone action is deficient (type 4, hyperkalemic).