Physiology of the kidney (Renal physiology)

Summary

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 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 on the kidney, see also “Kidneys.”

Urine production

General information

  • Site: nephron
    • The functional unit of the kidney, which consists of
      • Glomerulus: the major structure responsible for filtration of plasma
      • Tubules: the structure where the absorption of substances from and their secretion into the ultrafiltrate takes place
  • Aim
  • Process
    1. Blood flows into the glomerular capillaries via the afferent arterioles
    2. Plasma components are filtered from the glomerular capillaries across the glomerular filtration barrier into the urinary space within the Bowman capsule. The result is the primary ultrafiltrate.
    3. 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 production
      • Urine osmolality: 50–1400 mOsmol/L
      • Urine pH: 5.5 (between 4.5–8.2)
    4. Urine flows into the collecting ducts renal pelvis ureters bladder urethra

Homeostasis [1]

Substance Site of reabsorption Site of secretion Transporters Clinical relevance
H2O
Sodium
Chloride
  • The same sites and percentages as for sodium
Potassium
H+ions
Calcium
Magnesium
  • Paracellular diffusion
  • Competes with calcium
Glucose
Urea
Bicarbonate
  • Symport with Na+
  • Maintains acid-base balance
Phosphate

Physiology of the tubular system

Segments

Location

Function Regulation Clinical relevance
Afferent arteriole
  • Regulation of blood flow
Proximal convoluted tubule
  • Brush border resorption of most of the ultrafiltrate
  • Forms NH3 and secretes it into lumen (facilitates H+ secretion)
Loop of Henle Thin descending limb of the loop of Henle
  • Concentration of the ultrafiltrate: medullary hypertonicity (impermeable to Na+) → passive reabsorption of H2O
Thick ascending limb of the loop of Henle
Distal convoluted tubule (DCT)
  • Resorption of ions: Na+, Cl-, Mg2+and Ca2+
  • Impermeable to H2O
  • Decreases ultrafiltrate osmolality
Connecting tubule and collecting duct
Efferent arteriole
  • Regulation of blood flow
  • Angiotensin II causes vasoconstriction increase in GFR
  • Juxtaglomerular feedback

Countercurrent multiplication

  1. NaCl is actively transported from the tubular fluid in the ascending limb into the interstitial space.
  2. 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
  3. 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 blood flow

Regulation of renal blood flow [1]

The kidney has multiple mechanisms to regulate its own blood flow. This allows for changing the rate of glomerular filtration if fluctuations in systemic blood pressure occur.

Myogenic autoregulation (Bayliss effect)

  • Mechanism
    • Blood pressure in the renal arteries remains constant (between 80–180 mmHg).
    • Afferent arterioles contract if blood pressure increases, to maintain a normal pressure within the glomeruli.
    • If blood pressure drops, afferent arterioles dilate, to increase the pressure within the glomeruli

Prostaglandins

  • Mechanism: renal hypoperfusion (particularly renal medulla) → stimulation of prostaglandin synthesis → vasodilation of renal vessels → increased renal perfusion

Tubuloglomerular feedback

  • Description: feedback system between the tubules and glomeruli that adjusts the GFR according to the resorption capacity of the tubules
  • Mechanism: macula densa (of the juxtaglomerular apparatus) senses alterations in the NaCl concentration in the DCT
    • Hypotonic urine (↓ intraluminal Cl- concentration) → vasodilation of afferent arterioles GFR ↑ Cl- intraluminal concentration
    • Hypertonic urine (↑ intraluminal Cl- concentration) vasoconstriction of afferent arterioles capillary pressure → GFR ↓ intraluminal Cl- concentration

Renin-angiotensin-aldosterone system (RAAS) [2]

ACE inhibitors inhibit the conversion of angiotensin I to angiotensin II. ARBs inhibit the effect of angiotensin II. Both drug classes are used to treat arterial hypertension.

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

Autonomic regulation

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.

Measurement of renal function

This section focuses on fluid compartments, the basics of glomerular filtration, and tubular secretion. For more information on kidney function tests, see “Diagnostic evaluation of the kidney and urinary tract.”

Fluid compartments

The 60–40–20 rule refers to total body water (60% of body mass), ICF (40% of body mass), and ECF (20% of body mass).

Think of HIKIN to help you remember the main intracellular ion: HIgh K+ INtracellularly.

Renal clearance

  • Description: : the volume of plasma that is cleared of a certain substance per unit of time
  • Mechanism
    • 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:
      • > GFR: net tubular secretion of substance X
      • < GFR: net tubular reabsorption or substance X is not freely filtered in the glomerulus
      • = GFR: no net tubular secretion of reabsorption

Glomerular filtration rate [3]

GFR is inversely proportional to the renal plasma flow!

The GFR is used to estimate kidney function and to stage chronic kidney disease.

Relative solute concentrations along proximal convoluted tubules

  • Mechanism
    • 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
      • Inulin
        • Not reabsorbed, nor secreted along the PCT → (TF/P)Inulin > 1
        • Inulin is unique in that its amount does not change along the PCT but its tubular concentration is determined solely by water reabsorption.
      • PAH and creatinine: net tubular secretion along the PCT → (TF/P)PAH/Creat. /Creat. > (TF/P)Inulin > 1
      • Chloide (Cl): (TF/P)Chloride > 1 throughout the PCT
        • Initially reabsorbed at a slower rate than water and sodium → (TF/P)Chloride > 1 and rising
        • More distally in the PCT, reabsorbed at the same rate as water and sodium → still (TF/P)Chloride > 1 but no longer increasing (plateaued)
      • 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.

Inulin clearance

  • Description: used to assess the GFR
  • Mechanism
    • 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
      • Uinulin = urine concentration of inulin
      • V = urine flow rate
      • Pinulin = plasma concentration of inulin
      • Cinulin = clearance of inulin

Creatinine clearance

  • Description: the rate of renal clearance of creatinine
  • Mechanism
    • 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:
      • Modification of Diet in Renal Disease (MDRD) Study equation
      • Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation
    • 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) [2]

  • Description: used to estimate effective renal plasma flow
  • Mechanism
    • 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.
    • Effective renal plasma flow (eRPF)
    • 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.

Glucose clearance

  • Description: used to assess for glucosuria
  • Mechanism
    • In normoglycemic states (blood glucose: 60–120 mg/dL), glucose is completely filtered and completely reabsorbed in the proximal convoluted tubule (PCT) through sodium-glucose cotransporters (SGLT2). Glucose is not secreted, therefore, its clearance is normally 0 mL/min.
    • Glucose threshold
      • Defined as the plasma glucose concentration at which glucose is no longer reabsorbed but instead excreted in urine
      • It equals to 180 mg/dL
    • Splay phenomenon
      • When the glucose threshold is met, the tubular sodium-glucose cotransporters 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 sodium-glucose cotransporters → decrease of glucose threshold → glucosuria with plasma glucose levels below 180 mg/dL

Renal filtration

Filtration fraction (FF)

PDA - Prostaglandins Dilate Afferent arterioles

ACE - Angiotensin II Constricts Efferent arterioles

Filtered load

  • 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
  • Unchanged
  • Unchanged
  • Unchanged
  • Unchanged
  • Glomerulonephritis
GFR
  • Efferent arteriole constriction (e.g., due to angiotensin II due to RAAS activation)
  • Unchanged

Renal excretion

Excretion rate

  • Description: the amount of substance X that is excreted into the urine per unit of time
  • Mechanism: excretion rate (mg/mL) = urine flow rate (mL/min) x urine concentration of substance X (mg/mL)

Fractional excretion

  • Description: the proportion of the glomerular filtered substance X that is excreted in the urine
  • Mechanism
    • Fractional excretion = excreted load (urinary concentration of X)/filtered load (GFR × plasma concentration of X)
      • FE < 1: a large proportion of the filtered substance is reabsorbed in the tubules (e.g., water, glucose, amino acids, sodium chloride)
      • FE > 1: a small proportion of the filtered substance is reabsorbed or additional tubular secretion occurs (e.g., PAH, atropine)
    • Fractional excretion of sodium (FeNa): percentage of the glomerular filtered sodium that is excreted in the urine
    • 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
  • 1. Hall JE. Guyton and Hall Textbook of Medical Physiology. Philadelphia, PA: Elsevier; 2016.
  • 2. Corrigan G, Ramaswamy D, Kwon O, et al. PAH extraction and estimation of plasma flow in human postischemic acute renal failure. Am J Physiol Renal Physiol. 1999; 277(2): pp. F312–F318. doi: 10.1152/ajprenal.1999.277.2.f312.
  • 3. Woodcock T. Plasma volume, tissue oedema, and the steady-state Starling principle. BJA Education. 2017; 17(2): pp. 74–78. doi: 10.1093/bjaed/mkw035.
  • Kumar, Clark. Kumar and Clark's Clinical Medicine, 9th edition. Elsevier; 2016.
last updated 08/19/2020
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