Kidney Anatomy, Function, PKD, and Renal Syndromes

Anatomy and Main Functions of the Kidney

Gross and Microscopic Anatomy
- Kidneys are paired, retroperitoneal, bean-shaped organs between T12 and L3.
- Dimensions: ~11 cm length, 6 cm width, 3 cm thickness.
- Weight: ~150 g (males), ~135 g (females).
External Structure
- Superior and inferior poles.
- Anterior and posterior surfaces.
- Medial border: Contains hilum (renal artery, renal vein, lymphatics, ureter entry/exit).
Internal Structure
- Cortex (outer layer): Renal corpuscles, convoluted tubules, blood vessels.
- Medulla (inner layer): Renal pyramids, loops of Henle, collecting ducts.
- Renal pelvis: Funnel-shaped cavity collecting urine before ureter passage.
Blood Supply and Innervation
- Renal arteries (from abdominal aorta) → segmental arteries → interlobar arteries → arcuate arteries → interlobular arteries → afferent arterioles.
- Efferent arterioles form:
  - Peritubular capillaries (cortical nephrons).
  - Vasa recta (juxtamedullary nephrons, countercurrent exchange).
- Innervation: Sympathetic fibers (T10–L1) regulate vasoconstriction and renin release.

Nephron: Functional Unit of the Kidney

Each kidney contains ~1.2 million nephrons.
Components:
1. Glomerulus:
  - Afferent arteriole supplies blood to capillaries in Bowman’s capsule.
  - Filtration barrier: Fenestrated endothelium, glomerular basement membrane (GBM), podocytes.
  - Permits water, electrolytes, small solutes; prevents cells and large proteins from filtering.
2. Proximal Convoluted Tubule (PCT):
  - Reabsorbs 65–70% of sodium, water, glucose, and amino acids.
  - $Na^+/K^+$ ATPase pump maintains sodium gradient.
3. Loop of Henle:
  - Descending limb: Permeable to water, concentrates urine.
  - Ascending limb: Impermeable to water, actively pumps out sodium, dilutes urine.
4. Distal Convoluted Tubule (DCT):
  - Calcium regulation (PTH-mediated) and aldosterone action (sodium reabsorption, potassium secretion).
5. Collecting Duct:
  - Final site of urine concentration.
  - ADH inserts aquaporin-2 channels, increasing water reabsorption.

Physiological Functions of the Kidney

Excretion of Metabolic Waste
- Urea (protein metabolism), creatinine (muscle metabolism), uric acid (purine metabolism), drug metabolites.
Regulation of Fluid and Electrolyte Balance
- Sodium homeostasis (via aldosterone, RAAS).
- Potassium excretion (distal tubule and collecting duct).
- Calcium-phosphate balance (PTH-mediated calcium reabsorption).
Acid-Base Homeostasis
- Bicarbonate reabsorption in PCT.
- Hydrogen ion secretion (via ammonium buffering).
Endocrine Functions
- Erythropoietin (stimulates RBC production).
- Renin (activates RAAS).
- 1,25-dihydroxyvitamin D (calcitriol) (active vitamin D).

Importance of Glomerular Filtration Rate (GFR) in Renal Function & CKD Staging

Glomerular Filtration
- GFR = 125 mL/min (~180 L/day).
- Starling Forces Regulate Filtration:
  - Glomerular Hydrostatic Pressure (55 mmHg): Drives filtration.
  - Oncotic Pressure (30 mmHg): Opposes filtration.
  - Bowman’s Capsule Pressure (15 mmHg): Opposes filtration.
Regulation of GFR
1. Autoregulation:
  - Myogenic mechanism (afferent arteriole constriction in response to BP changes).
  - Tubuloglomerular feedback (macula densa senses sodium concentration).
2. Hormonal Control:
  - RAAS Activation (low BP → renin → angiotensin II → efferent arteriole constriction → increased GFR).
Clinical Significance of GFR
- Normal GFR: >90 mL/min.
- CKD Staging:
  - Stage 1: GFR >90 (with proteinuria).
  - Stage 2: GFR 60–89.
  - Stage 3: GFR 30–59.
  - Stage 4: GFR 15–29.
  - Stage 5 (ESRD): GFR <15 (requires dialysis).
GFR represents plasma flow from blood into Bowman's capsule and is calculated by clearance of indigenous markers.
GFR is age and gender-related but relatively constant in healthy individuals.
In renal failure, GFR decreases due to nephron damage, loss, and reduced blood flow, leading to increased urea and creatinine.
GFR is determined by:
- Balance of colloid osmotic forces and hydrostatic pressure across the capillary membrane.
- Permeability and surface area for filtering of the capillaries.

Polycystic Kidney Disease (PKD): Epidemiology & Pathophysiology

Epidemiology
- Autosomal Dominant PKD (ADPKD) affects ~1 in 1,000 people in the UK.
- Accounts for 5–10% of End Stage Renal Disease cases.
- Mutation types:
  - PKD1 (85% cases) – more severe.
  - PKD2 (15% cases) – slower progression.
Pathophysiology
- Defective polycystin-1 and polycystin-2 proteins disrupt calcium signaling.
- Abnormal cAMP accumulation → excessive cell proliferation and fluid secretion → cyst formation.
- Progressive cyst growth → nephron compression → renal ischemia → RAAS activation → hypertension.
Clinical Features
- Hypertension (earliest sign, before renal failure).
- Loss of appetite [chronic production of cytokines (IL-1 + TNF-a) directly acting on glucose-sensitive neurons in ventral-medial and lateral hypothalamic nucleus].
- Abdominal discomfort and flank pain (cyst enlargement, hemorrhage, infection).
- Hematuria (ruptured cysts).
- Recurrent UTIs (urinary retention and nephrolithiasis).
- Symptoms of uremia (gastric bleeding due to platelet dysfunction, nausea/vomiting due to urea acting on the chemoreceptor trigger zone in medulla oblongata).
- Frequent urination (dysfunction of concentration mechanisms).
- Nocturia (diminished DCT response to ADH; decreased ADH secretion in CKD).
- Brain hemorrhage (berry aneurysms).
- Extrarenal complications:
  - Hepatic cysts.
  - Intracranial aneurysms (10–15% of patients).
  - Mitral valve prolapse.

Main Complications of PKD

Hypertension (due to RAAS activation).
End-Stage Renal Disease (ESRD).
Berry Aneurysms (subarachnoid hemorrhage risk).
Recurrent UTIs and pyelonephritis.
Nephrolithiasis (uric acid and calcium oxalate stones).

Renal Complications:
- Hypertension: Activation of RAAS due to renal ischemia.
  - Loss of nephrons and reduced GFR leading to hypervolemia + increased blood pressure
  - Vasoconstriction secondary to RAAS activation leading to increased angiotensin 2 production:
    - Fluid and salt retention.
    - Vasoconstriction.
- Nephrolithiasis (kidney stones): Due to urinary stasis and metabolic abnormalities.
- Hematuria: Cyst rupture into the collecting system.
- Chronic kidney disease (CKD): Progressive nephron loss → ESRD.
Extrarenal Complications:
- Hypertension complications: Brain hemorrhage from intracranial aneurysm, LVH, mitral valve incompetence, mitral valve prolapse.
- Bone disease:
  - Reduced reabsorption of calcium due to vitamin D insufficiency.
  - Hyperparathyroidism related bone mineral density lose
- Intracranial aneurysms: Weak vessel walls, increased rupture risk, weakness in blood vessels caused by polycystin gene mutations.
- Hepatic cysts: More common in women due to estrogen influence (age 30-40, 50-60% of ppl with PKD).
- Cardiac valve abnormalities: Mitral valve prolapse, aortic regurgitation.
- Left Ventricular Hypertrophy: Due to high blood pressure (increased EDV because of hypervolemia, afterload because of vasal constriction leading to increased TPR).

Blood Test Abnormalities in PKD

Increased creatinine & urea (impaired clearance).
Hyponatremia (impaired dilution).
Hyperkalemia (due to tubular dysfunction).
Increased creatinine & urea: Due to declining GFR, failure of renal excretion.
Electrolyte imbalances:
- Hyperkalemia (due to decreased $K^+$ excretion).
- Metabolic acidosis (failure to excrete $H^+$ and retain $HCO_3^-$ .
- Raised potassium
  - Failure of renal excretion.
  - Compensation for acidosis by exchanging $K^+$ for $H^+$ .
- Reduced calcium
  - Excreted with albumin.
  - Binding to phosphate (high phosphate levels in renal disease due to reduced excretion).
  - Low vitamin D synthesis → reduced reabsorption.
  - High phosphate level depresses regulates Vitamin D production
- Reduced albumin
  - Blood loss in urine (RBC loss).
  - Reduced EPO production.
  - Anemia of chronic disease (reduced bone marrow sensitivity to EPO due to chronic cytokine effect).
  - Platelet dysfunction leading to reduced clotting and gastric bleeding.
  - Hamodilution (due to fluid retention)
Anemia: Erythropoietin deficiency.
Hyperphosphatemia & hypocalcemia: Impaired vitamin D activation → secondary hyperparathyroidism.

Genetic Basis of PKD

PKD1 (chromosome 16, polycystin-1): 85% cases, rapid progression.
PKD2 (chromosome 4, polycystin-2): 15% cases, slower progression.
Autosomal Dominant PKD (ADPKD):
- Progressive pattern leading to renal failure (age 40-50), hematuria, hypertension, progressive renal cyst development.
- PKD1 (Chr 16) – polycystin-1 (cell-cell adhesion, mechanosensation).
- PKD2 (Chr 4) – polycystin-2 (calcium-permeable ion channel).
- Mutations lead to dysregulated calcium signaling → cystogenesis.
- Genetic basis: One mutant copy of PKD1 or PKD2 is sufficient.
Autosomal Recessive PKD (ARPKD):
- Cystic dilatation of collecting ducts.
- Presents in infancy with bilateral renal enlargement, pulmonary hypoplasia, hepatic fibrosis.
- PKHD1 mutation – fibrocystin (important for kidney and liver development).
- Genetic basis: Two mutated copies of PKD1 or 2 are required.

Medical Management of PKD

BP Control: ACE inhibitors, ARBs.
Tolvaptan (vasopressin receptor antagonist, slows cyst growth).
Dialysis & Renal Transplant in ESRD.
General Management:
- Blood pressure control (target <130/80 mmHg):
  - ACE inhibitors (e.g., ramipril) – reduce RAAS activation.
- Pain management:
  - NSAIDs cautiously (risk of nephrotoxicity).
  - Opioids for severe pain.
- Management of complications/disease progression:
  - Antibiotics for UTI.
  - Tolvaptan (vasopressin V2 receptor antagonist) – slows cyst growth and reduces cAMP in the principal(water and sodium reabsorption) cells(approved in ADPKD).
  - Long acting somatostatin analogues
- Dialysis & transplantation for ESRD.
  - Heme or peritoneal dialysis
- Anemia management
  - Combatant EPO based medications
- Dietary restrictions
  - Reduce salts
  - Phosphorus restriction
  - Meat limitations (esp red meat)
  - Alcohol

Nephrotic vs Nephritic Syndrome

Feature	Nephrotic Syndrome	Nephritic Syndrome
Proteinuria	>3.5 g/day	<3.5 g/day
Edema	Severe	Mild
Hematuria	Absent	Present (dysmorphic RBCs)
BP	Normal	High
Causes	Minimal change disease, FSGS, DM nephropathy	Post-streptococcal GN, IgA nephropathy

Nephrotic syndrome: Proteinuria (>3.5g/day) with peripheral edema (due to albumin secretion leading to reduced oncotic pressure).
Nephritic syndrome: Hematuria, moderate proteinuria (<3.5g/day), and hypertension. Normal level of albumin is 30g/l