Renal System
The renal system is the body's primary homeostatic regulator of fluid volume, electrolyte balance, and acid-base chemistry. The kidneys filter the entire plasma volume roughly 60 times per day, reclaiming 99% of filtered water and solutes with extraordinary precision while excreting metabolic waste products. Three endocrine outputs — erythropoietin, renin, and calcitriol — extend renal influence to erythropoiesis, blood pressure, and calcium-phosphate metabolism.
Overview
The kidneys receive ~1.2 L of blood per minute — representing 20–25% of resting cardiac output — through the renal arteries, a disproportionate perfusion relative to their ~300 g combined mass. This flow is not for metabolic needs but for filtration: the glomerular capillary bed generates an ultrafiltrate of plasma at ~125 mL/min (glomerular filtration rate, GFR), driven by a net filtration pressure of ~17 mmHg. From that 180 L daily ultrafiltrate, tubular segments selectively reclaim nearly all glucose, amino acids, bicarbonate, and ~67% of filtered sodium in the proximal convoluted tubule (PCT), with further regulated reabsorption in the loop of Henle, distal tubule, and collecting duct governed by aldosterone and ADH. Only ~1–2 L of urine is produced daily.
Beyond filtration, the nephron is a metabolically active segmental machine. Each of the ~1 million nephrons per kidney is specialised: the thick ascending limb (TAL) of Henle's loop drives the countercurrent multiplier that concentrates the medullary interstitium up to ~1200 mOsm/kg, enabling ADH-stimulated water reabsorption in the collecting duct; the distal convoluted tubule (DCT) fine-tunes calcium and sodium reabsorption under PTH and aldosterone control; and intercalated cells of the collecting duct handle acid-base balance through H⁺-ATPase and HCO₃⁻/Cl⁻ exchange. The renin-angiotensin-aldosterone system (RAAS) provides the dominant hormonal feedback loop between renal perfusion pressure, systemic blood pressure, and sodium/potassium homeostasis.
The kidneys also function as endocrine organs: juxtaglomerular (JG) cells release renin when renal perfusion falls; peritubular interstitial fibroblasts in the cortex and outer medulla produce erythropoietin (EPO) in response to hypoxia (HIF-2α-driven), linking renal function directly to red blood cell production; and proximal tubule epithelial cells express 1α-hydroxylase that converts 25-hydroxyvitamin D to active calcitriol (1,25-(OH)₂D₃), the primary regulator of intestinal calcium absorption. These endocrine roles explain why CKD inevitably causes anaemia, hypertension, and renal osteodystrophy — the CRAB complications.
Anatomy & Structure
| Component | Key Features |
|---|---|
| Kidneys | Bean-shaped, ~11 × 6 × 3 cm, ~150 g each; retroperitoneal at T12–L3; right kidney slightly lower (displaced by liver); outer cortex (glomeruli, PCT, DCT) + inner medulla (loop of Henle, collecting ducts) + renal pelvis; cortical blood supply via arcuate arteries; medullary blood by vasa recta |
| Nephron | ~1–1.2 million per kidney; functional unit consisting of glomerulus + Bowman's capsule → PCT → thin descending/ascending limb of Henle → TAL → DCT → connecting tubule → cortical collecting duct → medullary collecting duct; cortical nephrons (85%) have short loops; juxtamedullary nephrons (15%) have long loops deep into medulla — critical for concentration |
| Glomerulus | Tuft of fenestrated capillaries (~150 nm pores); surrounded by Bowman's capsule; filtration barrier: fenestrated endothelium + glomerular basement membrane (GBM, type IV collagen, laminin, heparan sulfate) + podocyte foot processes with slit diaphragm (nephrin, podocin); charge and size selectivity; mesangial cells regulate capillary surface area |
| Proximal Convoluted Tubule (PCT) | Brush border (×40 surface area); reabsorbs 65–70% NaCl, 100% glucose (SGLT2 in S1/S2), 100% amino acids, 85% HCO₃⁻, 65% Ca²⁺/Mg²⁺/phosphate; Na⁺/K⁺-ATPase basolateral; NHE3 (Na⁺/H⁺ exchanger) apical — primary acid secretion site |
| Loop of Henle | Thin descending limb: water permeable, NaCl impermeable → water reabsorbed into hyperosmotic medulla; thin ascending limb: NaCl permeable, water impermeable; TAL: NKCC2 (target of loop diuretics: furosemide/bumetanide) reabsorbs 25–30% NaCl; TAL is water impermeable → dilution of tubular fluid; countercurrent multiplication establishes medullary gradient up to 1200 mOsm/kg |
| Distal Convoluted Tubule (DCT) | NCC (Na⁺/Cl⁻ cotransporter, target of thiazides); Ca²⁺ reabsorption via TRPV5 (PTH-stimulated); Mg²⁺ reabsorption via TRPM6; aldosterone increases NCC expression in early DCT; DCT2 and connecting tubule express ENaC (principal cells) for aldosterone-regulated Na⁺ reabsorption |
| Collecting Duct (CD) | Principal cells: ENaC (apical Na⁺ entry, aldosterone-regulated) + ROMK (K⁺ secretion); AQP2 water channels inserted by ADH (V2 receptor → cAMP → vesicle fusion); intercalated cells (A-type): H⁺-ATPase apical → acid excretion; B-type: HCO₃⁻ secretion (alkalosis); final urine concentration up to 1200 mOsm/kg when ADH maximal |
| Ureters, Bladder, Urethra | Ureters (25–30 cm) have 3 physiological narrowings (UPJ, pelvic brim, UVJ) — common sites for stone impaction; ureteric peristalsis 2–6 waves/min; bladder capacity 400–600 mL; detrusor muscle (smooth) + internal urethral sphincter (smooth, sympathetic) + external urethral sphincter (striated, somatic); voiding reflex: parasympathetic S2–S4 (detrusor contraction), sympathetic T10–L2 (sphincter relaxation), somatic pudendal nerve (voluntary external sphincter) |
Function
The kidneys integrate four overlapping functional imperatives: waste excretion, volume regulation, electrolyte homeostasis, and acid-base balance. These are achieved through the nephron's three-step process of filtration (glomerulus), reabsorption (tubules), and secretion (tubules), with the entire process subject to hormonal and neural modulation.
- PCT: 65–70% NaCl; 100% glucose (SGLT2) & amino acids; 85% HCO₃⁻; 65% Ca²⁺, Mg²⁺, phosphate
- TAL (Henle): 25–30% NaCl via NKCC2; Ca²⁺ via paracellular (PTH/calcitriol); Mg²⁺ via paracellular; water impermeable → dilution
- DCT: 5–8% NaCl via NCC; Ca²⁺ via TRPV5 (PTH-stimulated); Mg²⁺ via TRPM6
- CD: Na⁺ via ENaC (aldosterone); H₂O via AQP2 (ADH); K⁺ secretion via ROMK; H⁺ secretion via H⁺-ATPase
- HCO₃⁻ reclamation (PCT): H⁺ secreted by NHE3 combines with filtered HCO₃⁻ → H₂CO₃ → CO₂ + H₂O (carbonic anhydrase IV) → CO₂ enters cell → carbonic anhydrase II → H⁺ + HCO₃⁻ → HCO₃⁻ exits basolateral via NBC1
- New HCO₃⁻ generation (CD): A-type intercalated cells secrete H⁺ via H⁺-ATPase; titratable acids (H₂PO₄⁻) and NH₄⁺ buffer luminal H⁺; each H⁺ excreted generates one new HCO₃⁻ added to blood
- NH₄⁺ excretion: Glutamine → NH₃ + HCO₃⁻ in PCT; NH₃ diffuses to tubular lumen, binds H⁺ → NH₄⁺ (non-diffusible); medullary recycling concentrates NH₄⁺ for excretion; quantitatively the most important new HCO₃⁻ generating mechanism in acidosis
- Erythropoietin (EPO): Peritubular interstitial fibroblasts (cortex/outer medulla) sense O₂ tension via PHD/HIF-2α axis; hypoxia → HIF-2α stabilised → EPO gene transcription; EPO → bone marrow erythroid progenitors → red cell production; CKD → progressive fibrosis destroys EPO-producing cells → normocytic normochromic anaemia
- Renin: JG cells are modified smooth muscle cells of the afferent arteriole; three stimuli: ↓ stretch (↓ pressure), ↓ NaCl at macula densa, β1-adrenergic activation; renin is rate-limiting step of RAAS
- Calcitriol (1,25-(OH)₂D₃): PCT cells express CYP27B1 (1α-hydroxylase); substrate is 25-OH-D₃ (hepatic product); stimulated by PTH, hypophosphataemia, hypocalcaemia; calcitriol → intestinal Ca²⁺/phosphate absorption, renal Ca²⁺ reabsorption, bone mineralisation; CKD → impaired 1α-hydroxylation → calcitriol deficiency → hyperparathyroidism → renal osteodystrophy
- Urea: Product of hepatic urea cycle (amino acid catabolism); freely filtered; ~50% reabsorbed in PCT; medullary collecting duct reabsorbs urea (UT-A1/UT-A3 — ADH-regulated) → medullary urea recycling contributes to concentrating gradient; BUN (blood urea nitrogen) rises in CKD and pre-renal states (dehydration raises BUN:creatinine ratio >20)
- Creatinine: Non-enzymatic product of creatine phosphate metabolism in muscle; produced at constant rate proportional to muscle mass; freely filtered + small tubular secretion (MATE2-K, OCT2); serum creatinine inversely proportional to GFR; CKD-EPI and MDRD equations estimate GFR from creatinine
- Uric acid: End-product of purine catabolism; filtered, reabsorbed, secreted; net reabsorption ~90%; hyperuricaemia → gout and urate nephropathy; URAT1 (SLC22A12) is target of uricosuric agents (probenecid, lesinurad)
Pathology
Defined as GFR <60 mL/min/1.73 m² and/or markers of kidney damage (proteinuria, haematuria, structural abnormalities) for >3 months. ~850 million affected globally; leading causes are diabetic nephropathy (40%) and hypertensive nephrosclerosis (25%). KDIGO staging G1–G5 by GFR + A1–A3 by albuminuria. CRAB complications: hyperCalcaemia/osteodystrophy (↓ calcitriol), Renal anaemia (↓ EPO), Acidosis (impaired NH₄⁺ excretion + HCO₃⁻ loss), Blood pressure elevation (RAAS activation + Na⁺ retention). First-line renoprotection: RAAS blockade (ACEi or ARB in proteinuric CKD — RENAAL, IDNT trials); SGLT2 inhibitors reduce CKD progression by ~30–40% independent of glycaemia (CREDENCE, DAPA-CKD, EMPA-KIDNEY). G5: renal replacement therapy (haemodialysis, peritoneal dialysis) or transplant.
KDIGO criteria: ↑ serum creatinine ≥0.3 mg/dL within 48h, or ≥1.5× baseline within 7 days, or urine output <0.5 mL/kg/h for >6h. Classified as pre-renal (↓ perfusion — hypovolaemia, cardiac failure, hepatorenal syndrome), intrinsic (ATN, GN, interstitial nephritis, vascular), or post-renal (obstruction). ATN (acute tubular necrosis) is the most common intrinsic cause; PCT cells are most vulnerable to ischaemia and nephrotoxins (aminoglycosides, contrast, cisplatin). Biomarkers: NGAL, KIM-1, cystatin C for early detection. Management: treat underlying cause, optimise haemodynamics, avoid nephrotoxins, renal dose adjustments; RRT if life-threatening electrolyte disturbances, acidosis, or uraemia.
Lifetime prevalence 10–15% in developed countries; calcium oxalate 75%, uric acid 10–15%, struvite (Mg·NH₄·PO₄, infection-related) 5–15%, calcium phosphate 5%, cystine (CSNU mutation) <1%. Obstruction at ureteric narrowings → severe colicky flank pain radiating to groin, haematuria, nausea. Diagnosis: CT-KUB (gold standard, non-contrast); ultrasound in pregnancy. Stone passage depends on size: <5 mm ~80%, 5–10 mm ~50%, >10 mm <20%. Medical expulsive therapy: alpha-blockers (tamsulosin) relax ureteric smooth muscle. ESWL for 5–20 mm; ureteroscopy or PCNL for larger stones. Metabolic evaluation for recurrent stones: 24h urine collection for Ca²⁺, oxalate, uric acid, citrate, pH, and volume.
Most common bacterial infection in women; ~50% lifetime prevalence. Uncomplicated UTI: E. coli (80–85%), Staphylococcus saprophyticus, Klebsiella; cystitis symptoms (dysuria, frequency, urgency) without systemic features. Pyelonephritis: ascent to upper tract → fever, flank pain, CVA tenderness, bacteraemia risk; E. coli virulence factors (P-fimbriae binding to GalGal on uroepithelium). Diagnosis: UA (pyuria, bacteriuria, nitrite); urine culture >10⁵ CFU/mL. Uncomplicated: nitrofurantoin or trimethoprim-sulfamethoxazole 5–7 days; pyelonephritis: fluoroquinolone or IV beta-lactam. Complicated/recurrent UTI: evaluate for structural anomalies, stones, incomplete bladder emptying.
Most common inherited kidney disease (1 in 400–1000); bilateral cyst formation progressive from childhood, with median renal replacement at ~58 years. PKD1 (polycystin-1, 85%) and PKD2 (polycystin-2, ~15%) mutations; polycystin-1/2 form mechanosensory ion channels on primary cilia; loss → dysregulated mTOR/MAPK/cAMP → tubular cell proliferation + fluid secretion into cysts. Total kidney volume (TKV) is the primary disease progression biomarker. Cardiovascular manifestations: hypertension (RAAS-driven from renal ischaemia), intracranial aneurysm (5%), mitral valve prolapse. Treatment: tolvaptan (V2 receptor antagonist → ↓ cAMP → slows cyst growth; TEMPO 3:4 trial; monitor for hepatotoxicity); aggressive BP control; limit caffeine; eventual RRT/transplant.
~90% urothelial (transitional cell) carcinoma; remaining 10% squamous (associated with Schistosoma haematobium infection, chronic irritation) or adenocarcinoma. Major risk factors: smoking (4× risk; accounts for ~50% of cases), occupational aromatic amine exposure (dye, rubber, leather industries), cyclophosphamide, radiation. Haematuria (painless, gross) is the cardinal symptom. Non-muscle-invasive (NMIBC, stage Ta/T1/CIS): cystoscopy + TURBT; intravesical BCG immunotherapy for high-risk NMIBC. Muscle-invasive (MIBC, T2+): radical cystectomy ± neoadjuvant cisplatin-based chemotherapy; pembrolizumab second-line for cisplatin-ineligible metastatic disease; FGFR3 mutation present in ~70% of low-grade papillary tumours → erdafitinib (FGFR inhibitor) for FGFR2/3-altered metastatic disease.
Connections
References
- Hall JE. Guyton and Hall Textbook of Medical Physiology. 14th ed. Elsevier; 2021. Ch. 26–32 — Urine Formation by the Kidneys.
- Vanholder R, et al. Reducing the costs of chronic kidney disease while delivering quality health care: a call to action. Nat Rev Nephrol. 2017;13(7):393–409. · PubMed 28479604
- KDIGO CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of CKD. Kidney Int Suppl. 2013;3(1):1–150.
- OpenStax. Anatomy & Physiology 2e, Ch. 25: The Urinary System. OpenStax; 2022.