Nephrons are the functional units of the kidneys. They are composed of a renal corpuscle (the glomerulus and the Bowman capsule) and a renal tubule (the proximal convoluted tubule, the loop of Henle, the distal convoluted tubule, the collecting tubule, and the collecting ducts). The main functions of nephrons are urine production and excretion of waste products; regulation of electrolytes, serum osmolality, and acid-base balance; hormone production and secretion (e.g., erythropoietin, renin, calcitriol, prostaglandins); and maintenance of glucose homeostasis. Urine production involves filtration of the plasma in the renal corpuscle (a passive process), the secretion of substances to be eliminated (e.g., urea, hydrogen, potassium) into the lumen of the renal tubules, and the reabsorption of substances (e.g., glucose, urea, uric acid, potassium) within the renal tubules. These processes are regulated by a number of hormones that affect either renal blood flow or the function of the different transporters across the renal tubule. In addition, there are local mechanisms that regulate renal perfusion (e.g., myogenic regulation of the diameter of afferent arterioles) and urine osmolarity (e.g., tubuloglomerular feedback). The most commonly used measure of renal function is the glomerular filtration rate (GFR), which is the volume of primary ultrafiltrate filtered into the Bowman capsule per unit of time. In clinical settings, the GFR is estimated using equations such as the modification of diet in renal disease (MDRD) study equation and the chronic kidney disease epidemiology collaboration (CKD-EPI) equation. For more information, see also “ .”
- Blood flows into the glomerular capillaries via the afferent arterioles
- Glomerular filtration: Plasma components are filtered from the glomerular capillaries across the into the urinary space within the Bowman capsule. The result is the primary ultrafiltrate.
- After passing the glomerulus, the ultrafiltrate (now referred to as “tubular fluid”) flows through the tubular system.; → reabsorption and secretion of plasma components (approx. 99% of the ultrafiltrate is reabsorbed into the bloodstream) → urine concentration
- Urine flows into the collecting ducts → renal pelvis → ureters → bladder → urethra
Renal homeostasis 
|Substance||Site of reabsorption||Site of secretion||Transporters||Clinical relevance|
|Chloride|| || |
|Calcium|| || |
|Magnesium|| || |
|Bicarbonate|| || || |
|Phosphate|| || || |
- Secreted by peritubular interstitial cells
- Function: stimulates erythropoiesis in the bone marrow
- EPO may be reduced in , potentially causing .
- Treatment consists of EPO substitution.
- An adverse effect of chronic EPO administration is EPO-induced hypertension.
- proximal convoluted tubule convert calcidiol into the active calcitriol : cells of the
vasodilation of afferent arterioles : maintain via
- Paracrine secretion by endothelial cells in the afferent arterioles
- NSAIDs block cyclooxygenase (COX) and thereby decrease prostaglandin synthesis
- proximal convoluted tubules : secreted by cells of the
- : See “” in “Renal blood flow” below.
Physiology of the tubular system
|Physiology of the tubular system|
|Afferent arteriole|| |
|Proximal convoluted tubule|| |
|Loop of Henle||Thin descending limb of the loop of Henle|| || || |
|Thick ascending limb of the loop of Henle|| |
|Distal convoluted tubule (DCT)|
|Connecting tubule and collecting duct|| |
|Efferent arteriole|| || |
- NaCl is actively transported from the tubular fluid in the ascending limb into the interstitial space.
- The interstitium becomes hypertonic. This allows water to follow a gradient and move passively from the tubular fluid with a lesser osmolarity to the interstitium with a higher osmolarity
- Continuous production of urine → continuous movement of water from the tubular fluid into the interstitium → steady increase of the osmotic gradient → significant increase in the amount of water reabsorbed in the descending limb.
Renal blood flow
Renal blood supply
- Renal arteries (from the aorta) → segmental arteries → interlobar renal arteries → arcuate arteries → intralobular renal arteries → afferent arterioles → glomeruli → efferent arterioles → vasa recta (kidneys) and peritubular capillaries → renal veins (merge into the inferior vena cava)
- Renal blood flow (RBF): the blood volume that flows through the kidney per unit of time
Renal plasma flow (RPF): the volume of plasma that flows through the kidney per unit of time
- Para-aminohippuric acid (PAH): nearly 100% of PAH that enters the kidney is also excreted (completely filtrated and secreted), thus clearance rate is used to estimate RPF
- Effective renal plasma flow (eRPF)
Regulation of renal blood flow 
Myogenic autoregulation (Bayliss effect)
- Blood flow in the renal arteries remains constant with varying arterial blood pressure (between 80–180 mmHg).
- Afferent arterioles contract if blood pressure increases; to maintain a normal pressure within the glomeruli: ↑ arterial pressure → stretching of smooth muscle cells in the afferent arteriole wall → contraction of vascular smooth muscles → vasoconstriction → ↓ RBF
- If blood pressure drops, afferent arterioles dilate, to increase the pressure within the glomeruli
- Mechanism: renal hypoperfusion (particularly renal medulla) → stimulation of prostaglandin synthesis → vasodilation of renal vessels → increased renal perfusion
- Description: feedback system between the tubules and glomeruli that adjusts the GFR according to the resorption capacity of the tubules
Mechanism: (of the ) senses alterations in the NaCl concentration in the DCT
- Hypotonic urine (↓ intraluminal Cl- concentration) → vasodilation of afferent arterioles → ↑ GFR → ↑ Cl- intraluminal concentration → ↑ RBF
- Hypertonic urine (↑ intraluminal Cl- concentration) → adenosine secretion; → vasoconstriction of afferent arterioles → ↓ capillary pressure → ↓ GFR → ↓ intraluminal Cl- concentration → ↓ RBF
Renin-angiotensin-aldosterone system (RAAS) 
- Description: hormonal system that regulates arterial blood pressure and sodium concentration
- Baroreceptors in the afferent arteriole detect the following
These changes cause a release of renin by juxtaglomerular cells → conversion of angiotensinogen (produced in the liver) to angiotensin I → conversion of angiotensin I to angiotensin II via angiotensin-converting enzyme (mostly produced in the lungs)
- Angiotensin II
- Aldosterone increases renal reabsorption of sodium and water; and augments the excretion of potassium and protons → ↑ extracellular fluid, ↑ blood pressure, ↓ K+, ↑ pH
- Systemic: ↑ arterial blood pressure and ↑ blood volume
- Renal: maintenance of renal function and volume status in low volume states
- ↑ Vasoconstriction of the efferent arteriole causes ↑ and ↑ which helps maintain GFR (i.e., renal function) during renal hypoperfusion (i.e., decreased renal plasma flow)
- Maintenance of GFR (i.e., renal function) during renal hypoperfusion (i.e., decreased renal plasma flow) which is achieved by ↑ vasoconstriction of the efferent arteriole causing ↑ and ↑
- Compensatory increase in Na+ reabsorption in the proximal convoluted tubule (PCT) and distal convoluted tubule (DCT) prevents net volume loss
Besides their inhibitory effects on the heart (e.g., ↓ heart rate), β-blockers decrease blood pressure by inhibiting β1-receptors of the juxtaglomerular apparatus (JGA), which leads to decreased renin release.
Hormonal effects on the kidney
- Atrial natriuretic peptide (ANP): volume overload → dilation of atria → secretion of ANP by myocytes
- (BNP): volume overload → dilation of ventricles → secretion of BNP by myocytes
- Inhibit epithelial Na+ transporter in the collecting duct → increased Na+ and water secretion → decrease in the central venous pressure
- Dilates renal ↑ cGMP in vascular smooth muscle) → ↑ GFR (without compensatory Na+ reabsorption (via ; ) and ↑ natriuresis
- Inhibits secretion of aldosterone, renin, ADH, and ACTH
- Increases contraction of smooth muscle in blood vessels via V1 receptor → increased blood pressure → increased kidney perfusion
- Increases free water reabsorption in the collecting duct; (stimulation of adenylate cyclase → ↑ cAMP → incorporation of aquaporins in the luminal membrane of collecting ducts)
- Increases urea resorption (↑ incorporation of urea transporters in the collecting duct) → increased corticomedullary osmotic gradient → facilitated concentration of urine
- Angiotensin II and aldosterone: see ““ section above
- Parathyroid hormone (PTH)
Hypovolemic shock with severe hypotension activates the sympathetic nervous system. Subsequently, the hypovolemia and noradrenaline-induced vasoconstriction result in low renal blood flow → low GFR → low urine production → acute renal injury
- 60% of body mass is composed of water.
- Two-thirds of the total body water (i.e., 40% of body mass) is intracellular fluid (ICF), which is mainly composed of potassium, magnesium, and organic phosphates.
One-third of the total body water (i.e., 20% of body mass) is extracellular fluid (ECF), which is mainly composed of sodium, chloride, bicarbonate, and albumin.
- 75% of ECF is interstitial fluid.
- 25% of ECF is plasma.
- A small amount (∼ 500 mL) of ECF is transcellular fluid (e.g., gastrointestinal secretions, sweat, pleural fluid, pericardial fluid, urine, synovial fluid, intraocular fluid, CSF).
- ECF volume can be measured with crystalloid tracers such as inulin or mannitol, which distribute throughout the ECF but do not enter cells.
- ICF and ECF are separated by capillary walls and cellular membranes.
- H2O can move between fluid compartments by osmosis or in response to pressure differences.
- Total blood volume (TBV) is ∼ 6 L. Blood is composed of:
- Plasma volume can be calculated with VPlasma = TBV x (1 - Hct)
- Serum osmolality (or plasma osmolality): 285–295 mOsm/kg H2O
Think of HIKIN to help you remember the main intracellular ion: HIgh K+ INtracellularly.
- Description: : the volume of plasma that is cleared of a certain substance per unit of time
Cx = Ux x V/Px
- Px = Plasma concentration of substance X (mg/mL)
- V = Urine flow rate (mL/min)
- Ux = Urine concentration of substance X (mg/mL)
- Cx = Clearance of substance X (mL/min)
- If the clearance of substance X is:
- Cx = Ux x V/Px
Glomerular filtration rate 
- Description: : the rate at which fluid is filtered by the kidneys
- Normal GFR
- GFR depends on the effective filtration pressure and is driven by the difference between hydrostatic and osmotic pressure
GFR can be described by the Starling equation for the glomerulus: Jv = Kf × [(PGC - PBS) - σ(πGC - πBS)]
- Jv = net fluid flow
- Kf = filtration constant
- σ = sigma
- In clinical settings, the two most commonly used equations for calculation of estimated GFR are the “Modification of Diet in Renal Disease (MDRD) Study equation” and the “Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation” (see “ “ below.
Relative solute concentrations along proximal convoluted tubules
- Water is absorbed along the PCT along with other solutes (e.g., creatinine, electrolytes, glucose)
- At the beginning of the PCT, the concentration of all solutes within the glomerularly filtered tubular fluid (TF) is equivalent to the plasma concentration (P).
Compared to water, solutes can be reabsorbed along the PCT:
- At the same rate →; no change in tubular fluid concentration compared to plasma concentration (TF/P = 1)
- At a lower rate →; increased tubular fluid concentration compared to plasma concentration (TF/P > 1)
- At a higher rate →; decreased tubular fluid concentration compared to plasma concentration (TF/P < 1)
- Specific solutes
- Sodium (Na+): reabsorbed at the same rate as water throughout the PCT → (TF/P)Sodium = 1
- PAH and creatinine: net tubular secretion along the PCT → (TF/P)PAH/Creat. /Creat. > (TF/P)Inulin > 1
- Chloride (Cl‑): (TF/P)Chloride > 1 throughout the PCT
- Glucose: reabsorbed at a higher rate than water → (TF/P)Glucose < 1
The increase in inulin concentration along the PCT is the result of a constant amount of inulin within the tubular fluid (no reabsorption or secretion) and the reabsorption of water. The increase in inulin concentration along the PCT is the result of water reabsorption and a constant amount of inulin within the tubular fluid (without tubular inulin secretion).
Water is reabsorbed along the PCT while the amount of inulin within the tubular fluid stays the same (no reabsorption or secretion of inulin). This leads to an increasing concentration of inulin along the PCT.
- Description: used to assess the GFR
- Inulin is freely filtered and neither reabsorbed nor secreted in the tubular system, i.e., the amount of inulin in the urine reflects the amount that is filtered by the kidneys.
- Inulin clearance can be used to calculate GFR: GFR = Uinulin x V/Pinulin = Cinulin
- Description: the rate of renal clearance of creatinine
- Used in clinical settings to calculate GFR
- Creatinine clearance = U x V / P
- Direct calculation of creatinine clearance is time-consuming and becomes inaccurate if daily urine is collected inappropriately.
- Cockroft–Gault equation allows to estimate creatinine clearance
- There are several prediction equations used in clinical practice to calculate estimated GFR (eGFR) from serum creatinine concentration and demographic data:
- All of the equations typically overestimate actual GFR slightly because small amounts of creatinine are secreted by the renal tubules; in clinical practice, this overestimation can be neglected.
Para-aminohippuric acid (PAH) 
- Description: used to estimate effective renal plasma flow
- PAH is freely filtered in the glomerulus; and secreted into the tubular lumen, but not reabsorbed. Hence, almost 100% of the PAH that enters the kidney is excreted.
Clearance depends on the plasma concentration of PAH (∼ 650 mL/min)
- If the plasma concentration of PAH is low, it gets completely excreted from the plasma through filtration and secretion.
- Secretion is dependent on an organic anion transporter that is located on the basolateral membrane of the proximal convoluted tubule.
- If concentration of PAH surpasses the transport capacity of the anion transporters (or if there is damage to the PCT ), secretion is impaired, which reduces the total excreted amount of PAH. This leads to slight underestimation of renal plasma flow.
- Description: used to assess for glucosuria
- In normoglycemic states (blood glucose: 60–120 mg/dL), glucose is completely filtered and completely reabsorbed in the proximal convoluted tubule (PCT) through (SGLT2). Glucose is not secreted, therefore, its clearance is normally 0 mL/min.
- Defined as the plasma glucose concentration at which glucose is no longer reabsorbed but instead excreted in urine
- It equals to 180 mg/dL
- When the glucose threshold is met, the tubular in some nephrons are fully saturated, causing glucose to be excreted into the urine.
- At the same time, the maximum glucose reabsorption rate in other nephrons is only reached with higher glucose concentrations (heterogeneity of nephrons).
- Therefore, after exceeding the glucose threshold, the overall glucose reabsorption rate initially increases further with rising glucose concentrations until all glucose transporters in all nephrons are saturated.
- At a tubular glucose transport rate ; of 380 mg/min, all glucose transporters (SGLT2) are saturated and glucose reabsorption cannot increase further.
- Above the glucose filtration rate of 380 mg/min the glucose clearance is proportional to the plasma concentration.
- Pregnancy: ↑ GFR → ↑ filtration of all solutes (including glucose) → glucosuria with normal plasma glucose levels
- SGLT2 inhibitors: inhibition of → decrease of glucose threshold → glucosuria with plasma glucose levels below 180 mg/dL
Filtration fraction (FF)
- Description: the fraction of the renal plasma flow (RPF) that is filtered from the capillaries into the Bowman space
- Description: the amount of a substance X that is filtered by the glomerulus per unit of time
- Mechanism: filtered load (mg/min) = GFR (mL/min) x plasma concentration of substance X (mg/mL)
|Changes in glomerular dynamics|
|Renal plasma flow||Filtration fraction||Possible cause|
|↓ GFR|| || |
| || |
| || |
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|↑ GFR|| || |
| || |
- Description: the amount of substance X that is excreted into the urine per unit of time
- Mechanism: excretion rate (mg/min) = urine flow rate (mL/min) x urine concentration of substance X (mg/mL)
- Description: the proportion of the glomerular filtered substance X that is excreted in the urine
- Fractional excretion = excreted load (urinary flow rate x urinary concentration of X)/filtered load (GFR × plasma concentration of X)
- glomerular filtered sodium that is excreted in the urine (FeNa): percentage of the
- Reabsorption rate = filtered load (GFR × plasma concentration of X) - excreted load (urine flow rate x urine concentration of X)
- Secretion rate = excreted load - filtered load
Catabolism: The kidneys have a high demand for nutrients and oxygen for ATP production. The energy is needed to excrete waste products, reabsorb nutrients, and regulate blood pressure, electrolytes, serum osmolality, and acid-base balance.
- Substrate utilization by individual nephron segments is determined by the following factors:
- Availability of oxygen and pO2: decreases gradually from the renal cortex, which relies on beta-oxidation and oxidative phosphorylation, to the renal medulla, which is more dependent on anaerobic glycolysis to fulfill energy demands
- Density of pumps and channels utilizing ATP (primarily Na+/K+-ATPase):
- Main substrates
- Substrate utilization by individual nephron segments is determined by the following factors:
- Anabolism: Cortical renal cells are capable of gluconeogenesis in fasting states.