2.1 Nephron Physiology & Endocrine Functions

Nephron Physiology & Endocrine Functions

The kidneys receive approximately 20% to 25% of resting cardiac output (~1.0 to 1.2 L/min of renal blood flow) to present circulating plasma continuously to the functional unit of the kidney: the nephron. Each kidney contains approximately one million nephrons distributed across the outer renal cortex and inner renal medulla. Dialytic therapies replace lost filtration, while clinical protocols must replace missing renal endocrine products.

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Renal Macro- and Micro-Anatomy

A nephron comprises an epithelial tubular system linked to a specialized microvascular network:

• Vascular Components: An afferent arteriole delivers blood to the glomerulus, a high-pressure capillary tuft enclosed within Bowman's capsule. Blood exits via an efferent arteriole, branching into peritubular capillaries (cortical networks surrounding convoluted tubules that reabsorb solutes and fluid) or vasa recta (slender hairpin loops in the medulla of juxtamedullary nephrons that preserve the corticomedullary osmotic gradient as countercurrent exchangers).
• Tubular Components: Bowman's capsule, proximal convoluted tubule (PCT), loop of Henle (descending thin limb, ascending thin limb, thick ascending limb), distal convoluted tubule (DCT), and collecting duct system.

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Glomerular Filtration Barrier & Permselectivity

The filtration barrier consists of fenestrated endothelium with its surface glycocalyx, the glomerular basement membrane, and podocyte foot processes with slit diaphragms. These structures work together to retain cells and most circulating proteins while allowing water and small solutes to enter Bowman’s space. Albumin retention cannot be explained by electrical charge alone. Damage to any component can increase albumin passage; albuminuria is therefore an injury marker, even when the estimated filtration rate remains normal.

Filtration depends on hydraulic pressure and oncotic forces. Glomerular capillary hydrostatic pressure favors filtration; plasma oncotic pressure and pressure in Bowman’s space oppose it. A fall in effective arterial volume may reduce renal perfusion despite edema elsewhere. This is why a patient with heart failure can have both total-body fluid excess and impaired renal filtration. The nurse distinguishes volume distribution from circulating perfusion rather than assuming edema excludes prerenal injury.

• Red cells ordinarily remain within capillaries; hematuria requires investigation.
• Glucose is filtered and normally almost completely reabsorbed below the tubular transport threshold.
• Albuminuria, urine sediment, filtration trends, blood pressure and history provide complementary evidence; no single urine finding identifies every renal lesion.

Segmental Tubular Transport Mechanisms

Ultrafiltrate entering Bowman's space is modified sequentially along tubular segments:

1. Proximal Convoluted Tubule (PCT)

Driven by the basolateral $Na^+/K^+$-ATPase, the PCT executes bulk reabsorption:

• Reabsorbs ~65% of filtered water, sodium, chloride, and potassium.
• The PCT normally reabsorbs almost all filtered glucose and amino acids below transport capacity; glucosuria can occur when transport is saturated or inhibited.
• Reabsorbs 85% to 90% of filtered bicarbonate ($HCO_3^-$): Apical $Na^+/H^+$ exchanger 3 (NHE3) secretes $H^+$, combining with luminal $HCO_3^-$ via carbonic anhydrase IV to yield $CO_2$ and $H_2O$. Intracellular carbonic anhydrase II regenerates $HCO_3^-$, returned to blood via basolateral NBCe1.
• Active secretion of organic anions (urate) and cations (creatinine) via OAT and OCT transporters.

2. Loop of Henle & Countercurrent Multiplication

• The thin descending limb is highly water-permeable in relevant segments; solute permeability varies. The medullary gradient and tubular transport together support urine concentration.
• Thick Ascending Limb (TAL): Water-impermeable. The apical $Na^+$-$K^+$-$2Cl^-$ cotransporter (NKCC2) actively transports solutes into the medullary interstitium. Potassium recycling through ROMK channels generates a lumen-positive potential (+8 to +10 mV), driving paracellular reabsorption of calcium ($Ca^{2+}$) and magnesium ($Mg^{2+}$). NKCC2 is inhibited by loop diuretics (furosemide, bumetanide), dissipating the medullary gradient and impairing concentration.

3. Distal Convoluted Tubule (DCT) & Collecting Duct

• Distal Convoluted Tubule: Reabsorbs 5% to 8% of filtered sodium and chloride via the apical $Na^+$-$Cl^-$ cotransporter (NCC), the target of thiazide diuretics. Calcium reabsorption occurs via apical TRPV5 channels regulated by parathyroid hormone (PTH).
• Collecting Duct Principal Cells: Reabsorb sodium through apical epithelial sodium channels (ENaC), generating a lumen-negative charge that drives potassium excretion via ROMK. Aldosterone upregulates ENaC and basolateral $Na^+/K^+$-ATPase. Antidiuretic hormone (ADH / vasopressin) binds basolateral V2 receptors, stimulating cAMP-mediated insertion of aquaporin-2 (AQP2) water channels to concentrate urine.
• Intercalated Cells: Type A cells secrete $H^+$ via apical $H^+$-ATPase to defend against acidosis; Type B cells express pendrin to excrete base.

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Endocrine Functions & Homeostatic Axes

Beyond filtration, the kidneys operate as vital endocrine organs:

1. Renin-Angiotensin-Aldosterone System (RAAS): The juxtaglomerular apparatus (JGA)—composed of macula densa cells sensing luminal $NaCl$, juxtaglomerular granular cells secreting renin, and lacis cells—regulates systemic pressure. Reduced perfusion pressure or low tubular $NaCl$ triggers renin release. Renin cleaves hepatic angiotensinogen to angiotensin I, converted by ACE to angiotensin II. Angiotensin II induces vasoconstriction, stimulates aldosterone, and preferentially constricts the efferent arteriole, preserving GFR during hypoperfusion.
2. Erythropoietin (EPO): Synthesized by peritubular interstitial fibroblasts in the renal cortex in response to hypoxia sensed by hypoxia-inducible factor 2-alpha (HIF-2-alpha). EPO prevents apoptosis of erythroid precursors (CFU-E) in bone marrow. Renal destruction in CKD causes normocytic, normochromic anemia requiring recombinant ESAs.
3. 1-Alpha-Hydroxylase (Calcitriol): Proximal tubular mitochondria express 1-alpha-hydroxylase (CYP27B1), which converts 25-hydroxyvitamin D into active 1,25-dihydroxyvitamin D [$1,25(OH)_2D$, calcitriol]. Calcitriol promotes intestinal calcium and phosphate absorption and suppresses PTH. Loss of functional tubular mass causes calcitriol deficiency, hypocalcemia, and secondary hyperparathyroidism.
4. Klotho and FGF-23: FGF-23 participates in phosphate regulation and suppresses calcitriol. Reduced renal function alters this axis; early FGF-23 can rise before overt hyperphosphatemia. The relationship is not a simple proof that one hormone causes every vascular lesion.

Sources checked 2026-10-10: NIDDK kidneys