Cell Biology and Physiology of the Kidney¶
Chapter 320 | Part 9: Disorders of the Kidney and Urinary Tract
KEY CLINICAL POINTS¶
- The kidney is a highly differentiated organ with over 900,000 glomeruli in normal adults, critical for endocrine functions, blood pressure regulation, and solute/water balance.
- Renal physiology hinges on nephron architecture, with cortical and juxtamedullary nephrons differing in loop of Henle length and functional roles in urine concentration.
- Glomerular filtration is regulated by autoregulation mechanisms (myogenic response, tubuloglomerular feedback, angiotensin II) to maintain stable GFR despite hemodynamic changes.
- Tubular transport involves Na+/K+-ATPase-driven active transport, paracellular pathways, and hormone-sensitive channels (e.g., ENaC, aquaporins) for reabsorption/secretion.
- Inherited disorders like Bartter’s syndrome and Dent’s disease highlight the genetic basis of renal tubular transport defects with specific ion channel/transporter mutations.
1. DEFINITION & OVERVIEW¶
The kidney is a complex organ with over 900,000 glomeruli in normal adults, responsible for endocrine functions, blood pressure regulation, and solute/water balance. Its physiology is governed by nephron architecture, with cortical and juxtamedullary nephrons differing in loop of Henle length and functional roles in urine concentration. The renal microcirculation, including glomerular and peritubular capillaries, is critical for filtration and reabsorption processes.
Table 320-1: Inherited Disorders Affecting Renal Tubular Ion and Solute Transport¶
| DISEASE OR SYNDROME | PROTEIN (GENE) | OMIMa |
|---|---|---|
| Proximal renal tubular acidosis | Sodium bicarbonate cotransporter (SLC4A4, 4q21) | 604278 |
| Fanconi-Bickel syndrome | Glucose transporter, GLUT2 (SLC2A2, 3q26.2) | 227810 |
| Isolated renal glycosuria | Sodium glucose cotransporter (SLC5A2, 16p11.2) | 233100 |
| Cystinuria (Type I) | Cystine, dibasic and neutral amino acid transporter (SLC3A1, 2p16.3) | 220100 |
| Non-type I Cystinuria | Amino acid transporter, light subunit (SLC7A9, 19q13.1) | 600918 |
| Lysinuric protein intolerance | Amino acid transporter (SLC7A7, 4q11.2) | 222700 |
| DISEASE OR SYNDROME | PROTEIN (GENE) | OMIMa |
|---|---|---|
| Dicarboxylic aminoaciduria | Glutamate transporter (SLC1A1, 9q24.2) | 222730 |
| Hartnup disorder | Neutral amino acid transporter (SLC6A19, 5p15.33) | 34500 |
| Hypophosphatemic nephrolithiasis/osteoporosis 1 | Sodium phosphate cotransporter (SLC34A1, 5q35.3) | 612286 |
| Hereditary hypophosphatemic rickets with hypercalcemia | Sodium phosphate cotransporter (SLC34A3, 9q34) | 241530 |
| Renal hypouricemia (Type 1) | Urate-anion exchanger (SLC22A12, 11q13) | 220150 |
| Renal hypouricemia (Type 2) | Urate transporter, GLUT9 (SLC2A9, 4p16.1) | 612076 |
| Dent’s disease | Chloride channel, ClC-5 (CLCN5, Xp11.22) | 300009 |
| X-linked recessive nephrolithiasis with renal failure | Chloride channel, ClC-5 (CLCN5, Xp11.22) | 310468 |
| X-linked recessive hypophosphatemic rickets | Chloride channel, ClC-5 (CLCN5, Xp11.22) | 307800 |
| Bartter’s syndrome (Type 1) | Sodium, potassium chloride cotransporter (SLC12A1, 15q21.1) | 241200 |
| Bartter’s syndrome (Type 2) | Potassium channel, ROMK (KCNJ1, 11q24) | 601678 |
| Bartter’s syndrome (Type 3) | Chloride channel, ClC-Kb (CLCNKB, 1p36) | 602023 |
| Bartter’s syndrome (Type 3) with sensorineural deafness | Chloride channel accessory subunit, Barttin (BSND, 1p31) | 602522 |
| Autosomal dominant hypocalcemia with Bartter-like syndrome | Calcium-sensing receptor (CASR, 3q13.33) | 601199 |
| Familial hypocalciuric hypercalcemia | Calcium-sensing receptor (CASR, 3q13.33) | 145980 |
| Familial hypomagnesemia type 3 | Claudin-16 (CLDN16, 3q27) | 248250 |
| Familial hypomagnesemia type 5 | Claudin-19 (CLDN19, 1p34.2) | 603959 |
| Isolated renal magnesium loss | Sodium potassium ATPase, g-subunit (ATP1G1, 11q23) | 154020 |
| Gitelman syndrome | Sodium chloride cotransporter (SLC12A3, 16q13) | 263800 |
| Primary hypomagnesemia with secondary hypocalcemia | Melastatin-related transient receptor potential cation channel 6 (TRPM6, 9q22) | 602014 |
| Pseudoaldosteronism (Liddle’s syndrome) | Epithelial sodium channel b and g subunits (SCNN1B, SCNN1G, 16p12.1) | 177200 |
| Recessive pseudohypoaldosteronism type 1 | Epithelial sodium channel, a, b, and g subunits (SCNN1A, 12p13; SCNN1B, SCNN1G, 16pp12.1) | 264350 |
| Pseudohypoaldosteronism type 2 (Gordon’s syndrome) | Kinases WNK-1, WNK-4 (WNK1, 12p13; WNK4, 17q21.31) | 145260 |
| DISEASE OR SYNDROME | PROTEIN (GENE) | OMIMa |
|---|---|---|
| X-linked nephrogenic diabetes insipidus | Vasopressin V2 receptor (AVPR2, Xq28) | 304800 |
| EAST/SeSAME syndrome | Potassium channel Kir4.1 (KCNJ10, 1q23.2) | 612780 |
| Nephrogenic diabetes insipidus (autosomal) | Water channel, aquaporin-2 (AQP2, 12q13) | 125800 |
| Distal renal tubular acidosis (autosomal dominant) | Anion exchanger-1 (SLC4A1, 17q21.31) | 179800 |
| Distal renal tubular acidosis (autosomal recessive) | Anion exchanger-1 (SLC4A1, 17q21.31) | 602722 |
| Distal renal tubular acidosis with neural deafness | Proton ATPase, b1 subunit (ATP6V1B1, 2p13.3) | 192132 |
| Distal renal tubular acidosis with normal hearing | Proton ATPase, 116-kD subunit (ATP6V0A4, 7q34) | 602722 |
1.1 Renal Microcirculation¶
The renal microcirculation includes glomerular capillaries (filtered into Bowman’s space) and peritubular capillaries (reabsorbing solutes). The afferent arteriole regulates hydrostatic pressure, while the efferent arteriole maintains glomerular filtration. The renin-angiotensin system (RAS) modulates vascular resistance and GFR through angiotensin II-mediated vasoconstriction.
1.2 Autoregulation of GFR¶
Autoregulation of GFR is achieved through three mechanisms: myogenic response (afferent arteriole constriction with increased perfusion), tubuloglomerular feedback (TGF, mediated by macula densa), and angiotensin II-induced efferent arteriole constriction. These mechanisms maintain stable GFR despite changes in renal perfusion.
2. EMBRYOLOGIC DEVELOPMENT¶
Kidneys develop from intermediate mesoderm under the control of genes like Wnt4, Pax2, and Gdnf/Ret. The ureteric bud and metanephric blastema interact to form nephrons, with branching events determining the total number of glomeruli. Mutations in genes like SLC3A1 or SLC7A9 cause cystinuria, while defects in CLCN5 lead to Dent’s disease and Bartter’s syndrome.
2.1 Genetic Regulation of Nephrogenesis¶
Genes such as Wnt4, Pax2, and Gdnf/Ret regulate kidney development. The ureteric bud induces nephrogenesis in the metanephric blastema, with branching morphogenesis determining the number of nephrons. Mutations in these genes can lead to congenital anomalies like cystic kidney disease or renal dysplasia.
2.2 Nephron Differentiation¶
Nephrons develop from the ureteric bud and metanephric blastema, with the loop of Henle forming through sequential branching. Cortical nephrons have short loops, while juxtamedullary nephrons have long loops, enabling urine concentration. Disruption in this process leads to structural abnormalities like renal dysplasia.
3. DETERMINANTS AND REGULATION OF GLOMERULAR FILTRATION¶
Glomerular filtration is driven by hydrostatic pressure in the glomerular capillaries, counterbalanced by oncotic pressure. Autoregulation mechanisms (myogenic response, TGF, angiotensin II) maintain stable GFR despite changes in renal perfusion. The filtration fraction (GFR/renal plasma flow) is ~20%, with the proximal tubule reabsorbing ~65% of filtered NaCl.
3.1 Autoregulation Mechanisms¶
Autoregulation of GFR is achieved through three mechanisms: myogenic response (afferent arteriole constriction with increased perfusion), tubuloglomerular feedback (TGF, mediated by macula densa), and angiotensin II-induced efferent arteriole constriction. These mechanisms maintain stable GFR despite changes in renal perfusion.
3.2 Filtration Fraction¶
The filtration fraction is ~20% (GFR/renal plasma flow). The proximal tubule reabsorbs ~65% of filtered NaCl, with the loop of Henle and distal convoluted tubule reabsorbing the remaining 35%.
4. MECHANISMS OF RENAL TUBULAR TRANSPORT¶
Renal tubular transport involves Na+/K+-ATPase-driven active transport, paracellular pathways, and hormone-sensitive channels (e.g., ENaC, aquaporins). The proximal tubule reabsorbs ~60% of filtered NaCl and bicarbonate, while the thick ascending limb reabsorbs ~25% of NaCl through Na+/K+/2Cl − cotransport.
4.1 Proximal Tubule Transport¶
The proximal tubule reabsorbs ~60% of filtered NaCl and ~90% of bicarbonate via Na+/H+ exchange and carbonic anhydrase. Glucose and amino acids are reabsorbed via Na+-dependent cotransporters. Organic anions and cations are secreted via specific transporters, with P-glycoprotein mediating drug excretion.
4.2 Thick Ascending Limb¶
The thick ascending limb reabsorbs ~25% of NaCl via Na+/K+/2Cl − cotransport (NKCC2). This process is inhibited by loop diuretics like furosemide. Calcium and magnesium reabsorption occurs via paracellular pathways, regulated by CaSR and TRPM6/TRPM7 channels.
4.3 Distal Convoluted Tubule¶
The distal convoluted tubule reabsorbs ~5% of NaCl via thiazide-sensitive Na+/Cl − cotransport. Aldosterone enhances Na+ reabsorption via ENaC channels, while potassium secretion is mediated by apical K+ channels. This segment is critical for potassium balance and acid-base regulation.
5. COLLECTING DUCT FUNCTION¶
The collecting duct modulates urine concentration via vasopressin-regulated aquaporins (AQP2) and aldosterone-mediated Na+ reabsorption. Type A intercalated cells secrete H+ and reabsorb HCO3 − , while Type B cells secrete HCO3 − and reabsorb H+ to maintain acid-base balance.
5.1 Vasopressin Regulation¶
Vasopressin (ADH) binds to V2 receptors on collecting duct cells, promoting AQP2 insertion and water reabsorption. This enables the kidney to concentrate urine, with the medullary interstitium reaching ~1200 mOsm/kg. Vaptans (nonpeptide V2 antagonists) induce water diuresis for hyponatremia.
5.2 Aldosterone Action¶
Aldosterone enhances Na+ reabsorption in principal cells via ENaC channels and K+ secretion via apical K+ channels. It also increases AQP2 expression, enhancing water reabsorption. Aldosterone deficiency leads to hypokalemia, hypertension, and metabolic alkalosis (Liddle’s syndrome).
6. HORMONAL REGULATION OF SODIUM AND WATER BALANCE¶
Sodium and water balance are regulated by the renin-angiotensin-aldosterone system (RAAS), atrial natriuretic peptides (ANP), and vasopressin. The kidneys adjust Na+ excretion to maintain extracellular volume, with aldosterone and ANP counteracting each other in volume regulation.
6.1 RAAS and Sodium Balance¶
Renin release from juxtaglomerular cells increases angiotensin II, which constricts efferent arterioles to raise GFR and stimulate aldosterone release. Aldosterone enhances Na+ reabsorption in the distal tubule and collecting duct, promoting volume expansion.
6.2 ANP and Natriuretic Peptides¶
ANP and urodilatin (urotensin) inhibit Na+ reabsorption by reducing ENaC activity and increasing Na+ excretion. These peptides counteract RAAS effects, with ANP also promoting natriuresis and diuresis in response to volume overload.