Renal handling of water and solute

ECF volume is largely regulated by sodium balance, so H2O balance typically \(\approx\) serum osmolality.

ECF osmolality tightly maintained ~280mOsm

H2O balance regulated by ADH, polypeptide hormone

• Synthesized in hypothalamus
• Stored in posterior pituitary until released
• \(T_{\frac{1}{2}}=20\)mins; degraded by vasopressinase in liver + kidney

Sensors

1. Osmoreceptors in vascular organ of lamina terminalis in hypothalamus; exposed to ECF. These cells have copious aquaporins and stretch-activated Na channels \(\to\) depolarize when water moves into cells \(\to\) sense changes in ECF osmolality.
2. Central vein stretch receptors and carotid body/aortic arch baroreceptors \(\to\) hypothalamus when \(\downarrow\)preload or \(\downarrow\)MAP.
3. Decreased renal perfusion \(\to\) renin \(\to\) ATII \(\to\) hypothalamus

(2) and (3) are more potent stimulus \(\to\) water retention \(\to\) \(\uparrow\)ECF volume \(\downarrow\)tonicity in shocked states

Controller

Hypothalamus integrates signals

Signals posterior pituitary to release ADH

Effector; ADH \(\to\)

1. Brain: increased thirst
2. Renal vasculature (V1 receptor): constrict efferent arterioles \(\to\) decreased pressure and flow in peritubular vessels \(\to\) pressure gradient favors water reabsorption; reduced medullary concentration gradient washout
3. Cortical collecting duct (V2 receptor) - aquaporin vesicles translocated to surface \(\to\) increased water permeability; also increases urea permeability in distal collecting duct \(\to\) magnified H2O reabsorption by countercurrent mechanism

Na is main ECF cation and determines ECF volume.

\(140\text{mM} \cdot 0.130\text{L/min} \cdot 60\text{min/hr} \cdot 24\text{hr/day} = 26,000\text{mmol/day}\) but only ~140mmol excreted (so 99.5% reabsorbed).

Regulation mainly by SNS, RAAS and ANP

Freely filtered. Catecholamines or ATII \(\to \ \downarrow GFR \to \downarrow\)Na filtered \(\to\) Na retention.

PCT - 65% reabsorbed

1. Apical symport with AAs and glucose (e.g. via SGLT1). Responsible for tubuloglomerular balance (\(\uparrow GFR \to \uparrow \text{tubular Glucose/AA mass} \to \uparrow Na\text{ reabsoption}\))
2. Apical antiport with \(H^+\). CO2 diffuses into cell \(\xrightarrow{\text{carbonic anhydrase}} HCO_3^-+H^+\), then bicarb symported 3:1 with sodium basolaterally.

Both are secondary active powered by basolateral Na/K ATPase which is upregulated by ATII.

Descending LOH impermeable to Na

Ascending LOH - 10% absorbed (90% cumulative)

1. Apical symport w/ 2Cl + K via NKCC2; K cycled back to tubule. Secondary active powered by basolateral Na/K ATPase; \(\propto\) medullary concentration gradient, \(\therefore\) determined by ADH. More Cl anion reabsorbed then cation, which generates...
2. Positive transtubular voltage \(\to\) paracellular Na reabsorption

DCT - 6% absorbed (96% cumulative)

1. Symport w/ chloride with via NCC channel (thiazide-sensitive channel); secondary active with basolateral Na/K ATPase.

Collecting duct - variable absorption

1. Exchange with potassium. Na apically absorbed by ENAC \(\to\) K excreted by ROMK. Maintained by basolateral Na/K ATPase. Upregulated by aldosterone.

K is main ICF cation. \([K]_{ECF}\) important for resting membrane potential \(\to\) tightly regulated.

Normal \([K]_{ECF} \in [3.5-5]\)

Regulation of excretion is by aldosterone; \(\downarrow [K]_{ECF} \to\)Aldosterone release from adrenal cortex.

Freely filtered.

PCT - 60% reabsorbed

1. Entirely paracellular via solvent drag

Descending LOH is impermiable to K

Ascending LOH - 20% reabsorbed (80% cumulative)

1. Apical symport with Na + 2Cl via NKCC2; secondary active with basolateral Na/K ATPase, which also creates positive transtubular voltage \(\to\) paracellular K reabsorption

DCT / Collecting ducts - secreted or reabsorbed

1. Principle cells: secretion in exchange with sodium. Na apically absorbed by ENAC \(\to\) K excreted by ROMK. Maintained by basolateral Na/K ATPase. Upregulated by aldosterone. Increased by \(\uparrow\) sodium delivery or flow rate to distal nephron. Inhibited by low pH.
2. \(\alpha\)-intercalated cells: Apical active antiport of K (in) and H (out) by K/H ATPase

Glucose, an essential monosaccharide, is freely filtered

$$Glu_{\text{filtered}} = GFR \cdot BGL = 0.135 \cdot 5 \approx 0.7\text{mmol/min}$$ (note BGL analysers actually display the plasma glucose concentration)

Normally kidney reabsorbs 100% of filtered load \(\to\) no glucose in urine

All reabsorption is in PCT, by symport with sodium, secondary active powered by basolateral Na/K ATPase. Glucose then exits basolaterally by GLUT1/2.

• SGLT2 is high-capacity, low affinity (reabsorbs first 90% of glucose)
• SGLT1 is low-capacity, high affinity (mops up remaining 10%)

SGLT has a maximal reabsorption rate. When filtered glucose load >Tmax of 2mmol/minute (typically BGL > 16mM), additional glucose is lost to urine.

• Water loss by osmotic diuresis
• Wasting of glucose \(\xrightarrow{may}\) ketogenesis
• Loss of K due to increased flow rate in distal tubule
• Predisposition to UTI