L2 Renal Physiology 1

Overview

First renal physiology lecture, covering two things: what the kidney does, and how the nephron does it. The four functions (excretion, homeostasis, hormone production, metabolism) are set against a chronic renal failure case in which each function has failed. The nephron half introduces the functional unit and its three processes (filtration, reabsorption, secretion), then goes into glomerular filtration in detail: the barrier, the pressures that drive it, GFR and the derived measures (filtration fraction, filtered load, clearance) used to estimate it.

Functions of the kidney

Four functions, shown as one diagram repeated through the lecture as a recap:

• Excretion of water, salts, metabolic wastes and foreign substances. Blood enters by the renal artery, leaves by the renal vein, and waste leaves via the ureter as urine.
• Homeostasis: acid-base balance (H+ / OH-) and electrolyte balance (Na+ / K+).
• Hormones: erythropoietin and calcitriol are produced by kidney cells.
• Metabolism: amino acids feed gluconeogenesis, producing glucose (to blood) and NH3 (to urine).

Important

“The composition of the blood is determined not by what the mouth takes but what the kidneys keep.” Homer W. Smith, 1953.

Kidney and hormones

Renal hormones listed: erythropoietin, calcitriol, renin, dopamine, kallikrein, prostaglandins.

Erythropoietin:

1. Kidney detects low oxygen levels.
2. Kidney releases erythropoietin.
3. Erythropoietin stimulates bone marrow to produce more red blood cells.

Consequence: chronic renal failure leads to anaemia.

Vitamin D:

• Essential for calcium balance and bone mineralisation.
• Must be converted to its active form, calcitriol.
• The renal enzyme 1-hydroxylase catalyses the final conversion.
• Consequence: chronic renal failure leads to calcium and bone problems (renal osteodystrophy).

Kidney and metabolism

• Gluconeogenesis: synthesis of glucose from amino acid precursors occurs in the kidney (and liver).
• Ammonia (NH3): synthesised and secreted in the kidney; roles in nitrogen balance and in pH balance.

Kidney and homeostasis

Acid-base:

• Synthesis of HCO3.
• Excretion of non-volatile acids.

Fluid balance:

• Urine output adjusted to maintain volume.
• Urine output adjusted to maintain osmolarity.

Electrolyte balance:

• Renal control of Na, K, Ca, PO4 and others.
• Most electrolytes are kept in balance by what is excreted rather than by what is absorbed.

Kidney and excretion

• Water and electrolytes: surplus must be excreted to maintain homeostatic balance, especially ECF volume and composition.
• Metabolic waste products: nitrogenous wastes (urea, uric acid), hormones, bile pigments.
• Foreign substances: toxins, drugs.

Case: chronic renal failure

Presented twice, as the opening stem and again at the end of the functions section, titled chronic renal failure.

• 58 year old, 6 months of lethargy/tiredness, nausea, poor appetite, nocturia, swollen ankles, shortness of breath, 6 kg weight gain.
• O/E: 90 bpm, BP 150/100, elevated JVP, creps, ankle swelling.
• Bloods: Na 138 mmol/L, K 5.6 mmol/L, urea 49 mmol/L, creatinine 0.794 mmol/L (GFR 2.2 ml/min), Hb 90 g/L, PaCO2 32 mmHg, pH 7.32, HCO3 16.

Structure of the nephron

• The nephron is the functional unit of the kidney; about $10^6$ per kidney.
• Components: glomerulus and tubules; afferent and efferent arterioles; peritubular capillaries and vasa recta.
• 80% are cortical nephrons; 20% are juxtamedullary nephrons with long loops.
• The juxtamedullary nephron’s loop of Henle descends deep into the inner medulla, while the cortical nephron’s loop stays shallow; both drain into a shared collecting duct. The two types are distinguished at the corticomedullary junction.
• Tubular segments in order: renal corpuscle (glomerular capsule, glomerulus, juxtaglomerular apparatus), proximal convoluted tubule, loop of Henle (thin descending limb, thin segment, thick ascending limb), distal convoluted tubule, collecting duct, then urine outflow.
• Vasculature accompanying the nephron: interlobular artery and vein, afferent and efferent arterioles, peritubular capillaries, vasa recta, arcuate artery and vein.

Nephron processes

Three basic processes:

• Filtration: creates a plasma-like filtrate of the blood.
• Reabsorption: removes useful solutes from the filtrate and returns them to the blood.
• Secretion: adds additional wastes from the blood to the filtrate, from the tubule, i.e. not filtered.

The balance of these processes determines how a particular substance is handled. Net urinary excretion:

$\text{Amount excreted}=\text{Amount filtered}-\text{Amount reabsorbed}+\text{Amount secreted}$

Division of labour along the nephron:

• Glomerulus: filtration.
• Proximal tubule: bulk reabsorption.
• Distal tubule: fine-tuning of electrolytes and pH.
• Collecting duct: fine-tuning of water reabsorption.

Scale of the task:

• Filtration at the glomerulus is not particularly selective.
• About 180 litres per day are filtered across the glomeruli, but only about 1.5 litres per day of urine is produced, so reabsorption is important.
• Summary phrase: “all out, useful stuff back, waste left behind”.

The glomerulus and juxtaglomerular apparatus

• Afferent arteriole enters and efferent arteriole leaves the glomerular tuft at the vascular pole.
• Capillary tuft is fenestrated.
• The tuft interfaces with podocytes lining Bowman’s capsule, which is the blind end of the tubule into which the glomerulus protrudes.
• Mesangial cells and matrix provide support, possibly to the capillaries [slide marks this with a query and does not elaborate].
• The distal tubule interfaces with the glomerulus at the macula densa, forming the juxtaglomerular apparatus together with the granular cells.

Glomerular filtration

• A specialised form of ultrafiltration, with roughly 100 times the permeability of normal capillaries.
• Creates a plasma-like filtrate of the blood; molecular weight cut-offs given as 100000, and 70000 for negatively charged molecules.
• Filters about 180 L/day, or 125 ml/minute.
• What is filtered: plasma water and small solutes. What is retained: blood cells and proteins.
• Route: from the lumen of the glomerular capillary (1), via the filtration barrier (2), to Bowman’s capsule (3).

The filtration barrier, three layers

1. Fenestrations of the endothelial cells of the glomerular capillary. Size barrier, given on the slide as 70 daltons.
2. Basement membrane, common to capillary and podocytes. Negative charge, excluding proteins.
3. Filtration slits of podocytes, between foot processes. Size selective, via the slit diaphragm (nephrins).

Determinants of filtration

• Forces, i.e. the pressure gradient between the glomerular capillary and Bowman’s space.
• Permeability of the glomerular capillary.
• Surface area of the glomerular capillary.
• $K_f$, the ultrafiltration coefficient, roughly 100 times greater than in systemic capillaries.

Starling forces and net filtration pressure

Hydrostatic and osmotic pressures act both into and out of the capillary; the numbers given are:

$\text{Net filtration pressure (10 mmHg)}=\text{glomerular hydrostatic pressure (60 mmHg)}-\text{Bowman’s capsule pressure (18 mmHg)}-\text{glomerular oncotic pressure (32 mmHg)}$

Pressure profile along the renal vessels: about 95 mmHg in the arteries, falling slightly through the afferent arterioles to about 60 mmHg across the glomerular capillaries (roughly flat there), then steeply through the efferent arterioles to about 10 mmHg in the peritubular capillaries, and to near 0 in the veins.

GFR and derived measures

GFR (glomerular filtration rate) is the amount of fluid filtered across the glomerulus per unit time.

• Typically 180 L/day or 125 ml/minute.
• Tightly regulated, by intrinsic and extrinsic mechanisms.
• Some person-to-person variation.
• 70 ml/min/m2 body surface area (1.73).
• Declines slowly from age 30.
• Single-nephron GFR (SNGFR) 60 nl/min or 90 µL/day.

Derived measures:

• Renal plasma flow: $RPF=RBF\times (1-Hct)$, estimated with PAH.
• Filtration fraction $=GFR/RPF$, about 20%.
• Filtered load, the amount of a solute filtered per minute $=GFR\times$ solute plasma concentration.

Clearance

Clearance indicates how a substance is handled by the kidney and can be calculated for any substance.

$\text{Clearance}=\frac{U\times V}{P}$

where $P$ is plasma concentration, $U$ is urine concentration and $V$ is urine production rate in ml/min.

Using clearance to estimate GFR, if a substance is filtered but neither reabsorbed nor secreted, then:

1. Amount filtered = amount in urine.
2. $GFR\times$ plasma concentration = urine concentration $\times$ urine rate.
3. $GFR\times P=U\times V$.
4. $GFR=U\times V/P=$ clearance.

Creatinine is such a substance, so creatinine clearance is used to estimate GFR. Inulin is better but has to be injected.

Self-test

1. List the four functions of the kidney given in the lecture, with one example of each.
2. Describe the steps by which the kidney raises red cell production, and state the consequence of losing this function in chronic renal failure.
3. Explain why chronic renal failure causes calcium and bone problems, naming the enzyme involved.
4. Distinguish the two metabolic roles of the kidney described in the lecture.
5. State the equation relating filtration, reabsorption and secretion to urinary excretion.
6. Distinguish reabsorption from secretion, including where the secreted substance comes from.
7. Distinguish cortical from juxtamedullary nephrons, giving their proportions.
8. List the four regions of the nephron with the process each performs.
9. Explain why reabsorption must be extensive, using the daily volumes given.
10. List the three layers of the glomerular filtration barrier and the selectivity each provides.
11. Predict what appears in the urine if the basement membrane’s negative charge is lost.
12. List the determinants of glomerular filtration.
13. Calculate the net filtration pressure from a glomerular hydrostatic pressure of 60 mmHg, a Bowman’s capsule pressure of 18 mmHg and a glomerular oncotic pressure of 32 mmHg.
14. Describe how blood pressure changes from the arteries through to the peritubular capillaries, and identify where the steepest fall occurs.
15. Define GFR and give its typical value in two units.
16. Define filtration fraction and give its approximate value.
17. Define clearance and give the equation with each term defined.
18. Explain why creatinine clearance can be used to estimate GFR, and why inulin is not used routinely.
19. Integrative: for the case patient with GFR 2.2 ml/min, link each abnormal finding (Hb 90, K 5.6, pH 7.32 with HCO3 16, ankle swelling and weight gain) to the specific renal function that has failed.

Answers

Reveal answers

1. Excretion (water, salts, metabolic wastes, foreign substances); homeostasis (acid-base and electrolyte balance); hormones (erythropoietin, calcitriol); metabolism (gluconeogenesis from amino acids, giving glucose to blood and NH3 to urine).
2. The kidney detects low oxygen levels, releases erythropoietin, which stimulates bone marrow to produce more red blood cells. Chronic renal failure therefore causes anaemia.
3. Vitamin D is essential for calcium balance and bone mineralisation but needs conversion to its active form calcitriol; the renal enzyme 1-hydroxylase catalyses the final conversion, so renal failure causes calcium and bone problems (renal osteodystrophy).
4. Gluconeogenesis, synthesis of glucose from amino acid precursors (also in liver); and ammonia synthesis and secretion, with roles in nitrogen balance and pH balance.
5. Amount excreted = amount filtered - amount reabsorbed + amount secreted.
6. Reabsorption removes useful solutes from the filtrate and returns them to the blood; secretion adds additional wastes from the blood to the filtrate, coming from the tubule rather than from filtration.
7. Cortical nephrons are 80% and have short loops staying shallow in the medulla; juxtamedullary nephrons are 20% and have long loops descending into the inner medulla.
8. Glomerulus, filtration; proximal tubule, bulk reabsorption; distal tubule, fine-tuning of electrolytes and pH; collecting duct, fine-tuning of water reabsorption.
9. Filtration is not particularly selective and about 180 litres per day are filtered, yet only about 1.5 litres per day of urine is produced, so almost all of the filtrate must be reabsorbed. “All out, useful stuff back, waste left behind.”
10. Endothelial fenestrations of the glomerular capillary, a size barrier given as 70 daltons; the basement membrane shared by capillary and podocytes, negatively charged and so excluding proteins; podocyte filtration slits between foot processes, size selective via the nephrin diaphragm.
11. Proteins, which are normally retained by that negative charge, would be filtered and appear in the urine.
12. The pressure gradient between glomerular capillary and Bowman’s space, the permeability of the glomerular capillary, its surface area, and Kf, the ultrafiltration coefficient (about 100 times that of systemic capillaries).
13. 60 - 18 - 32 = 10 mmHg net filtration pressure.
14. About 95 mmHg in the arteries, falling slightly through the afferent arterioles to about 60 mmHg across the glomerular capillaries where it stays roughly flat, then falling steeply through the efferent arterioles to about 10 mmHg in the peritubular capillaries and to near 0 in the veins. The steepest fall is across the efferent arterioles.
15. The amount of fluid filtered across the glomerulus per unit time; typically 180 L/day or 125 ml/minute (also given as 70 ml/min/m2 body surface area).
16. Filtration fraction = GFR / RPF, about 20%.
17. Clearance indicates how a substance is handled by the kidney; clearance = UV/P, where P is plasma concentration, U is urine concentration and V is urine production rate in ml/min.
18. Creatinine is filtered but not reabsorbed or secreted, so the amount filtered equals the amount in the urine, giving GFR x P = U x V and hence GFR = UV/P. Inulin is a better marker but has to be injected.
19. Hb 90 g/L reflects loss of erythropoietin production; K 5.6 mmol/L reflects loss of electrolyte balance (renal control of K by excretion); pH 7.32 with HCO3 16 (and compensatory PaCO2 32) reflects loss of acid-base homeostasis, both failure to synthesise HCO3 and failure to excrete non-volatile acids; ankle swelling, raised JVP, creps and 6 kg weight gain reflect loss of fluid balance, with urine output no longer able to maintain ECF volume. Urea 49 mmol/L and creatinine 0.794 mmol/L reflect failed excretion of nitrogenous waste.