How the Kidney Works

The Kidney's Role in the Body

Every adult has two kidneys, located on either side of the lower back, behind the spine. Although the kidneys account for only about 0.5% of body weight, they receive approximately 20% of cardiac output. The kidney's core mission is to maintain the stability of the body's internal environment — filtering metabolic waste from the blood, regulating water and electrolyte balance, controlling blood pressure, maintaining acid-base balance, and producing multiple hormones.

Specifically, the kidneys filter approximately 180 liters of plasma each day, ultimately producing about 1.5 liters of urine. They also produce erythropoietin (EPO) to stimulate bone marrow red blood cell production, produce renin to regulate blood pressure, and convert vitamin D to its active form to maintain bone health.

The Nephron: The Kidney's Basic Functional Unit

Each kidney contains approximately 1 to 1.5 million nephrons. The nephron is the basic structural unit that carries out kidney function, consisting of two parts:

• Renal corpuscle: Includes the glomerulus (a tuft of capillaries) and the surrounding Bowman's capsule. This is where blood filtration begins.
• Renal tubule: A long, winding tube divided into the proximal tubule, loop of Henle (thin and thick segments), distal tubule, and collecting duct. The tubule performs precise reabsorption and secretion of the filtrate.

After age 40, functional nephrons decrease by approximately 10% every 10 years. Remaining nephrons adapt (e.g., enlarging and increasing filtration load) to maintain overall excretory function, but this compensation comes at a cost — prolonged high workload accelerates the loss of remaining nephrons.

Step One: Glomerular Filtration

Blood enters the glomerulus through the afferent arteriole, generating high hydrostatic pressure within the capillaries. The capillary wall has three layers (fenestrated endothelium, basement membrane, podocyte slit diaphragm), forming a precise filtration barrier. Water and small solutes (sodium, potassium, urea, glucose, etc.) are pushed out into Bowman's space, forming primary urine; blood cells and large proteins are retained in the blood.

Glomerular filtration rate (GFR) is the core measure of kidney function. Normal adult GFR is approximately 90–120 mL/min/1.73m². Clinically, estimated GFR (eGFR) is used to stage chronic kidney disease. The glomerulus has an important autoregulation mechanism: through contraction and relaxation of the afferent and efferent arterioles, it maintains relatively stable filtration pressure despite fluctuations in systemic blood pressure.

Step Two: Tubular Reabsorption and Secretion

As primary urine passes through the renal tubule, the vast majority of useful substances are reabsorbed back into the blood, while metabolic waste and excess substances are secreted into the tubular lumen. Each segment has distinct responsibilities:

Proximal Tubule: The Reabsorption Workhorse

The proximal tubule reabsorbs approximately 65–70% of sodium and water, 100% of glucose and amino acids, and about 90% of bicarbonate from primary urine. Sodium is actively reabsorbed via the sodium-glucose cotransporter (SGLT2), sodium-hydrogen exchanger (NHE3), and others. The proximal tubule also secretes organic anions and cations (including many drugs and toxins), making it an important site for drug excretion.

Relevance to PKD: SGLT2 inhibitors (dapagliflozin, empagliflozin) block sodium-glucose reabsorption in the proximal tubule, increasing distal sodium delivery and potentially reducing tubuloglomerular feedback–mediated glomerular hyperfiltration. However, ADPKD patients were excluded from the major SGLT2 inhibitor clinical trials; the STOP-PKD and EMPA-PKD trials are currently evaluating their safety and efficacy.

Loop of Henle: Countercurrent Multiplication and Urine Concentration

The descending limb of the loop of Henle is permeable to water but not to sodium, so water is reabsorbed and the tubular fluid becomes concentrated. The thick ascending limb actively reabsorbs sodium, potassium, and chloride via the Na-K-2Cl cotransporter (NKCC2) but does not reabsorb water, diluting the tubular fluid and establishing the hypertonic gradient in the medullary interstitium. This gradient is the basis for subsequent urine concentration in the collecting duct.

Loop diuretics (furosemide, torsemide) inhibit NKCC2 to produce powerful diuresis, used for volume overload. But they also disrupt the medullary hypertonic gradient, and long-term use may impair kidney concentrating ability.

Distal Tubule: Fine-Tuning

The distal tubule reabsorbs approximately 5–10% of sodium via the Na-Cl cotransporter (NCC). Thiazide diuretics (hydrochlorothiazide, indapamide) inhibit NCC to produce diuresis and lower blood pressure. The distal tubule also reabsorbs calcium via calcium channels and calcium-binding proteins; thiazides increase calcium reabsorption (the opposite of loop diuretics).

Collecting Duct: Final Regulation

The collecting duct is the final regulatory site for urine composition and also the most common site of ADPKD cyst formation:

• Principal cells: Express the vasopressin V2 receptor (V2R). When vasopressin (antidiuretic hormone) binds V2R, it activates adenylyl cyclase 6 (AC6) via the Gs protein, generating cyclic AMP (cAMP). cAMP activates protein kinase A (PKA), which phosphorylates aquaporin-2 (AQP2), causing it to translocate from intracellular vesicles to the apical membrane and increase water reabsorption. At the same time, cAMP abnormally promotes cyst epithelial cell proliferation in PKD.
• Intercalated cells: Type A secrete hydrogen ions (acidifying urine), type B secrete bicarbonate (alkalinizing urine), maintaining acid-base balance.

Key relevance to PKD: Collecting duct principal cells are the primary origin of ADPKD cysts. The V2R-cAMP signaling pathway is the core driver of cyst growth — this is why tolvaptan (a V2R antagonist) can slow cyst growth, and why adequate hydration to suppress endogenous vasopressin secretion is theoretically beneficial for ADPKD.

Tubuloglomerular Feedback: The Glomerulus Protects Itself

The macula densa (a specialized group of cells at the beginning of the distal tubule) senses the sodium chloride concentration reaching the distal tubule. When GFR increases and more sodium reaches the macula densa, it releases adenosine and ATP, causing the afferent arteriole to constrict and lowering GFR — this is tubuloglomerular feedback (TGF). This mechanism protects the glomerulus from excessive filtration injury.

SGLT2 inhibitors increase sodium delivery at the macula densa, enhancing TGF and lowering intraglomerular pressure — this is one of their key renoprotective mechanisms in diabetic kidney disease. Whether this mechanism is equally beneficial in ADPKD is under investigation.

Intraglomerular Pressure: Why the Efferent Arteriole Matters

The driving force for glomerular filtration comes from intraglomerular capillary pressure. Afferent arteriole dilation or efferent arteriole constriction increases intraglomerular pressure; the opposite lowers it. This is key to understanding how different antihypertensives affect the kidney:

• ACEI/ARB (pril/sartan classes): Dilate the efferent arteriole > afferent arteriole, lowering intraglomerular pressure and reducing glomerular hypertension and hyperfiltration injury. This is their core renoprotective mechanism.
• Traditional dihydropyridine CCBs (nifedipine, amlodipine): Preferentially dilate the afferent arteriole, with weak effects on the efferent arteriole, potentially increasing intraglomerular pressure.
• T-type CCBs (manidipine, efonidipine): Dilate both afferent and efferent arterioles, without increasing intraglomerular pressure.

The Kidney's Endocrine Functions

• Renin: Secreted by juxtaglomerular cells, initiates the renin-angiotensin-aldosterone system (RAAS), raising blood pressure. Early RAAS activation in ADPKD is the core mechanism of hypertension.
• Erythropoietin (EPO): Secreted by renal interstitial fibroblasts, stimulates bone marrow red blood cell production. When kidney function declines, insufficient EPO leads to renal anemia.
• Active vitamin D (1,25-dihydroxyvitamin D3): The kidney converts 25-hydroxyvitamin D to its active form, promoting intestinal calcium absorption and bone health. In advanced CKD, lack of active vitamin D leads to renal bone disease.

Why Understanding This Matters for PKD Patients

ADPKD cysts primarily originate from the collecting duct and distal tubule. Understanding the function of each tubular segment is essential to understanding:

• Why cysts destroy kidney function — cysts compress and replace normal tubular tissue.
• Why the V2R-cAMP pathway is a therapeutic target — it is the core driver of cyst growth in collecting duct principal cells.
• Why blood pressure control is so important — RAAS activation and glomerular hypertension accelerate kidney injury.
• Why different antihypertensives have different effects on the kidney — efferent arteriole dilation is key to renoprotection.
• Why SGLT2 inhibitors are still under study in ADPKD — the theoretical benefits of tubuloglomerular feedback and proximal tubule mechanisms require clinical validation.

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