kidney cap

functions of the kidneys

1. Regulate the volume and composition of the extracellular fluid (ECF)

2. Eliminate potentially toxic metabolic wastes and foreign compounds

3. Maintain water balance in body

4. Maintaining proper plasma volume (BP)

5. Maintain osmolarity (solute concentration) of body fluids

6. Regulating quantity and concentration of extracellular fluid ions

7. Maintaining acid-base balance

8. convert vitamin D to active form

9. Producing erythropoietin

renal control body fluid composition

A decrease in water content, by increasing the NaCl concentration, increases osmolarity

An increase in water content, by lowering the NaCl concentration, lowers osmolarity

The osmolarity of plasma and ECF is normally maintained constant at 283 ± 11 mosmol/l.

Basic processes performed by the nephron

1) Filtration of blood

2) Tubular reabsorption

3) Tubular secretion

Renal blood flow (RBF)

• First process in nephron is ultrafiltration of the plasma in the glomerulus. This step is dependent on generation of strong hydrostatic pressure in nephron

• Kidney requires abundant blood supply

• Blood supply to the two kidneys is via the renal arteries

• Blood flow to the kidneys is ~1.2 L/min.

• 1/5 of cardiac output*

blood supply to nephron

Renal artery subdivides to form many afferent arterioles which each supply a nephron

Glomerular capillaries recombine to leave Bowmans Capsule as efferent arterioles.

Efferent arterioles give rise to peritubular capillaries which invest the tubular system of each nephron.

These then recombine to form venules and the renal vein

Function of Peritubular Capillaries

1. Nutritive

2. Reabsorptive

3. Secretive

What passes through the filtration barrier to form the tubular filtrate?

All components of plasma, except cells and proteins, pass

• (a small amount of protein does pass but is immediately reabsorbed – a normal sample of urine should have no protein).

So, useful substances as well as waste pass through

substances reabsorbed during active tubular resorbption

glucose

amino acids

Na+

substances reabsorbed during passive tubular resorbption

water

chloride ion

Volume of tubular filtrate formed

Approx. 180 litres of filtrate forms per day - entire ECF “treated” ~10 times per day

Approx. 1.5 litres of urine are excreted

Therefore, approx. 178.5 litres of filtrate must be reabsorbed (returned to the blood) per day

Distribution of Renal Blood Flow (RBF)

Blood flow to the cortex: 90%

Blood flow to medulla: 10%

Regulation of blood flow to glomerulus

vasoconstriction → decreased blood flow (because of increased resistance)

Glomerular blood flow is major determinant of filtration rate in glomerulus

By maintaining renal blood flow constant, GFR is maintained constant

VIA AFFERENT ARTERIOLES VASOCONSTRICTION

Two mechanisms are responsible for the autoregulation of RBF and GFR

1. Myogenic Mechanism: Responds to arterial pressure changes

• as pressure ↑ so resistance ↑ and therefore flow remains constant.

2.Tubuloglomerular Feedback Mechanism: Responds to [Na Cl]

• when GFR increase→ NaCl concentration rise in LoH→ macula densa release adenosine→ increased resistance

RBF and GFR maintained if MAP between 80-180mmhg

Benefits of autoregulating RBF

Stabilises the amount of filtered solutes that reach the tubules over a wide range of arterial pressures

Protects fragile glomerular capillaries against increases in perfusion pressure

allows consistency vs light exercise, changes in posture etc…

under what conditions do RBF and GFR change

• sympathetic nervous system activity→ vasoconstriction

• adrenaline and angiotension 2→ vasoconstriction

• bradykinin→ vasodilation

The role of extrinsic nervous and hormonal influences in regulation of RBF & GFR;

A person at rest with normal circulating blood volume

Activity in SNS fibres supplying renal vessels is zero.

RBF and GFR maintained constant by auto-regulation

The role of extrinsic nervous and hormonal influences in regulation of RBF & GFR;

Effect of severe exercise, pain, severe emotional stimuli on RBF & GFR

Sympathetic NS activity in renal vessels may be detected and adrenaline is released from adrenal medulla

effects: RBF and GFR decreased.

The role of extrinsic nervous and hormonal influences in regulation of RBF & GFR;

Effect of crisis situation e.g haemorrhage on RBF & GFR

High degree of sympathetic NS activity may be detected in renal vessels. Also, adrenaline is released and circulating levels of angiotensin 2 increase

RBF and GFR decreased.

major force driving glomerular filtration

Glomerular capillary blood pressure

Large diameter of afferent vs efferent arteriole generates pressure pushing out plasma through (leaky) capillaries

what influences the passage of components through the filtration barrier to form the tubular filtrate

• Molecular size

• Charge (negatively charged molecules are restricted by barrier)

• Molecule shape – deformable molecules pass better than rigid ones

average GFR

Defined as: the millilitres (mL) of plasma filtered per minute through all glomeruli (i.e. both kidneys)

In adult males, GFR = 125 ml/min

In adult females, GFR = 115 ml/min

Forces favouring Glomerular Filtration

Glomerular capillary blood pressure

net filtration pressure

Forces working against Glomerular Filtration

Plasma-colloid osmotic pressure

bowman’s capsule hydrostatic pressure

unregulated influences on GFR examples

• Decrease in plasma protein reduces force opposing filtration so this increases GFR (burn patients)

• Urinary tract blockage – increases pressure in Bowman’s capsule – decreases GFR

• Plasma-colloid pressure increases in dehydrating diarrhoea so GFR is decreased

Steps of trans-epithelial transport - tubular resorption

1) Substance leaves tubular fluid

2) Passes through cytosol of tubular cell

3) Crosses basolateral membrane

4) Diffuses through interstitial space

5) Penetrates capillary wall to enter blood plasma

FLUID MOVEMENT ALONG THE NEPHRON OCCURS

via osmosis

• Secretion and absorption of solutes across the tubular epithelium creates osmotic gradients

• epithelium in tubules act as semi permeable membrane

what is tubular reabsorption

process by which solutes and water are removed from the tubular fluid and transported into the blood

• include electrolytes, glucose, proteins, amino acids, urea, etc

Finely tuned process that maintains homeostasis of blood volume, pressure, pH and osmolarity

• can be active or passive

Filtrate osmolarity changes dramatically throughout the nephron

filtrate osmolarity PCT

300 mOsm/L

filtrate osmolarity descending LoH

1200 mOsm/L as water is reabsorbed

what is tubular secretion

transport of solutes from peritubular capillaries/interstitium into the tubular lumen

• differs from reabsorption as it deals with clearing substances from the blood, rather than retaining them

• Secreted substances are typically waste/unwanted products (e.g. K+ , H+ , NH4 + , Creatinine, Urea, & some hormones & drugs)

can be passive or active

epithelium PCT

cuboidal epithelium

• microvilli increase surface area for reabsorption

• mitochondria ensure energy is available for active transport needed for efficient reabsorption.

epithelium thick LoH

cuboidal

epithelium thin LoH

squamous

Two common properties of tubular epithelial cells allow them to carry out their absorptive & secretory functions

• tight junctions

• functional polarity

tight junctions

allow cells to carry out their absorptive & secretory functions

• Point of contact between neighbouring cells

• Consist of transmembrane proteins that form homotypic bonds with neighbouring cells.

• Are permeable to water and ions/small molecules.

  • forms paracellular pathway

  • Structural components = occludins, claudins, and junctional adhesion molecule (JAM)

functional polarity

allow cells to carry out their absorptive & secretory functions

Ability of epithelial cells to express different transport proteins on their apical and basolateral sides - enables vectorial transport of solutes

3 main types of epithelial transport protein renal tubules

i) ATPase pumps

ii) Channels

iii) Carriers: Co-transporters and Exchangers

Water crosses cell membranes by two routes

• through the TJs and paracellular space

• through water channels – Aquaporins

• transport is bidirectional, in accordance with prevailing osmotic gradients established by active solute transport

where is aquaporin 1 found

proximal tubule and descending thin limb

where is aquaporin 3 and 4 found

expressed in the DCT/Collecting Ducts

• Important in regulation of water reabsorption by antidiuretic hormone (ADH).

proximal covoluted tubule

Many filtered solutes are reabsorbed in the early proximal convoluted tubule

• (e.g., NaCl and other ions, glucose, amino acids, phosphate, lactate, citrate, urea, etc).

  • Na reabsorbed early- as most other things

  • Cl reabsorbed late

Much of the uptake occurs through Na+ /Nutrient Cotransporters

• Na+ /glucose cotransporter

• Na+ /amino acid Cotransporter

Water is reabsorbed passively due to osmosis (70% water resorption occurs here)

Glycosuria

Normally, almost 100 percent of glucose is reabsorbed in the PCT.

Increases in filtered load may lead to some glucose being excreted in the urine = Glycosuria

detectable via dipstick test

causes

• DM

• pregnancy

  • ↑ renal blood flow results in ↑ glucose being filtered

• falconi syndrome

Glomerular filtration of protein is dependent primarily on

• Molecular size - Low MW proteins (15 000-40 000 kDa) readily filtered

• ionic charge- Extracellular matrix within the basement membrane of the filtration barrier contains negatively charged proteins and therefore repels negatively charged proteins in the plasma

• Molecular shape -Deformable molecules can pass through more readily than rigid ones

• Plasma Concentrations - Elevated plasma levels of a protein lead to increased filtration

• Normally, small peptide hormones and albumin (~ 200 g) are filtered

steps Protein reabsorption by PCT

1. filtered proteins bind to receptors on luminal membrane - megalin & cubulin

2. bound proteins undergo endocytosis

3. endosomes fuse with lysosomes

4. lysosome proteases degrade proteins

5. resulting amino acids exit via basolateral transporters

proteinuria

defined as increased amounts of protein in urine

Diagnosed as foamy urine and dipstick test

causes

• glomerular damage

• alterations in tubular reabsorption (e.g., Fanconi syndrome)

• Increased plasma concentration of low MW proteins

PCT and organic ions

- Organic ions - typically xenobiotics, such as drugs or environmental/dietary chemicals, and some endogenous metabolites.

• secreted in PCT

Renal elimination of organic ions has great practical significance

• prevent exposure to potentially dangerous xenobiotics

• limit the efficacy of some drugs.

fanconi syndrome

a disease that is associated with dysfunction of the proximal tubule of the kidney.

• characterized by the loss of, amino acids, protein, glucose and bicarbonate in the urine

• Symptoms: thirst, polyuria, vomiting. failure to thrive, frailty, bone pain, rickets, acidosis

causes; hereditary/ exposure to chemicals or drugs

Treatment: Hydration and supplementation of lost substances (e.g. HCO3, phosphate & vitamin D

LoH functional divisions

the thin descending limb

thin ascending limb

thick ascending limb.

LoH function

maintenance of a highly concentrated medullary interstitium

• drives water reabsorption from the tubules

Osmolarity in the fitrate changes dramatically as the LoH dips into the hypertonic medulla

• Osmolarity entering the LoH = 300mOsm/L

• Highest osmolarity in medulla = 1200mOsm/L

• Osmolarity leaving the LoH = 100mOsm/L

thin descending LoH role

has low permeability to ions and solutes, while being highly permeable to water.

• Water is reabsorbed from the filtrate

• Filtrate becomes concentrated

thin ascending LoH role

impermeable to water, but it is passively permeable to ions

moderately permeable to urea**

• NaCl reabsorption

• filtrate less concentrated

thick ascending LoH role

actively reabsorbs Na+ and Cl− ions from the filtrate via the Na/K/2Cl cotransporter - NKCC2).

• dilutes the filtrate and concentrates the medullary interstitium

  • basis of the countercurrent mechanism

DCT

80 percent of filtered water has been recovered by the end of the LoH.

• 36 L of fitrate enters the DCT

• another 10–15% is recovered here

Early distal tubule - impermeable to water

• In the early DCT, Na+ enters via apical Na+ -Cl− cotransporters (NCC) - cotransported

• Cl− leaves passively via basolateral channels.

• Early DCT is also important for active transcellular Ca2+ transport - Regulated by parathyroid hormone

The late distal tubule has water channels and its permeability is regulated by antidiuretic hormone (ADH).

• ADH also regulates urea absorption in the collecting duct

  • Combined effects of aldosterone and ADH on ENaC expression, urea transport and aquaporin expression fine tunes the ability of the kidneys to produce concentrated or dilute urine depending on the body’s needs.

• Low water intake = high water reabsorption

High water intake = low/no water reabsorption

2 types of cells DCT and CD

Principal cells – involved in NaCl transport

• aldosterone dependant

Intercalated cells – participate in acid:base balance

• help to get rid of acid generated by dietary intake (ie., fixed acid) that cannot be eliminated by the lungs

what controls sodium reabsorption in DCT and CD

aldosterone

what controls water reabsorption DCT and CD

ADH

countercurrent multiplier system

in LoH

• nephrons with longer loops have greatest ability to concentrate interstitium

role of LoH; Generate and maintain the hypertonic interstitium

The term countercurrent comes from the fact that fluid is moving in opposite directions in the two limbs of the loop

• 3 characteristics

  1. Countercurrent flow

     • Filtrate flowing down in descending limb and up in ascending limb

  2. Descending limb permeable to water

  3. Ascending limb impermeable to water

countercurrent multiplier; anatomical arrangement of LoH that concentrates solute in medulla

VERTICAL OSMOTIC GRADIENT

Enables water movement by osmosis down the concentration gradient and the Production of highly concentrated low volume urine

urea general info

• Urea is a small organic molecule comprising two amide groups joined by a carbonyl group

• It is formed in the liver

• Excreted in the urine to get rid of unwanted aa and nitrogen waste

• Normal plasma concentrations of 2.5–6.0 mmol/L.

when urea enters loop of Henle and gets recycled → helps to concentrate the surrounding intersitium of the inner medullary region of kidney

Many segments of the nephron are poorly permeable to urea

*as water is reabsorbed, urea is left behind; concentration in tubule rises

• Some of the urea diffuses into the thin ascending limb of the loop of Henle and recycles

• Urea recycling allows a high [urea] to be built up in the medulla

• Urea can contribute 50% of the osmotic pressure of the medullary fluids in a maximally concentrating human kidney

nephritic syndrome presentation

• proteinuria

• micro heamaturia

• high creatinine serum

due to glomerular inflammation

can also have HPT, low urinary output, oedema…

causes nephritic syndrome

due to glomerular inflammation

IMMUNE

systemic

infectious

diseases that classify as nephritic syndrome

1. rapidly progressing

2. ANCA

3. anti GBM

4. IgA

5. post strep

membranoproliferative glomerulonephritis

rapidly progressing disease

nephritic syndrome

• can lead to renal failure

• causes; ANCA, lupus, anti GBM…

• macrophages bowman’s capsule

ANCA disease

nephritic syndrome

• anti PR3/ MPO

• ocular/ ENT symptoms

• small vessels → lung/ lung hemmorhage

• normal C3/C4

anti GBM

nephritic syndrome

• small vessels→ lung

• fatigue

• antibody type 4 collagen

IgA disease

nephritic syndrome

• most common

• post inf/ strenous exercise

• 3 steps

  1. IgA

  2. C3→ normal levels

  3. mesengial

• henoch schloein; rash, scrotal pain, joints…

post strep disease

nephritic syndrome

• 2-4 weeks post group A beta strep

• strep antigen

what nephritic syndrome can affect small vessels/ lung

ANCA

anti GBM

what nephritic syndrome can arise post infection

post strep

IgA

membranoproliferative glomerulonephritis

not a disease→ pattern of nephritic syndrome

• tramline double membrane

• mesengial proliferation

• low C3/ C4

can also be nephrotic syndrome

• C2/ C3

management nephritic syndrome

BP control

volume status control/ fluid restriction

immunosuppression

nephrotic syndrome presentation

occurs after podocyte damage

1. rise serum albumin

2. heavy proteinuria

3. oedema

jaundice

joint pain

rash

infection++

hypovolemia

causes nephrotic syndrome

primary

• minimal change

• membranous nephropathy

• membranoproliferative nephropathy

• focal segmental sclerosis

secondary

• DM

• lupus

• hepatitis

• amyloidosis

• …

minimal chnage disease

nephrotic syndrome

• erasure of cytokine

• podocytes fusion

membranous nephropathy

nephrotic syndrome

• anti PLA2R antibody vs antigen

  • IgG and C3 deposits

• silver deposits

focal segmental sclerosis

nephrotic syndrome

• IgM

• black segments biopsy

investigations diagnosis nephrotic syndrome

24h proteinuria

protein; creatinine ratio

albumin; creatinine ratio

biopsy/ PLA2R atb

investigating cause nephrotic syndrome

FBC

viral serology

autoantibody panel

complement levels…

managements nephrotic syndrome

low fluids

low proteinuria/ ACEi

immunosupp? depend on cause

common complications nephrotic syndrome

hypercoagulability

infection risk

vit D deficiency

anemia

protein def

CKD

UTI pathogenesis

• Bladder normally sterile

• Anterior urethra colonised with skin or bowel flora

• UTI increases with age & is more common in women than men

• Children with UTI must be followed up, as renal failure & hypertension may ensue

determinants of infection utis

Inoculum size, how many bacteria

Virulence

host defence system

• Complete bladder emptying (no culture medium)

• Increase fluid intake & voiding frequency

• Vesico-ureteral valve

• Length of urethra (male>female)

• Vaginal flora

  • decreased by oral contraceptives

• urinary tract abnormalities

  • stones

  • reflux

  • irregular anatomy

UTI; men vs women

age vs uti

• Prostatic enlargement/hypertrophy

• Loss of bactericidal activity of prostatic secretions

• Faecal incontinence

• Pelvic floor muscle weakness, prolapse of the uterus leading to incomplete emptying of the bladder

host defence vs uti

• Regular flow of urine

• Mucosal defense mechanisms

• pH

• Integrity of sphincter

routes of infection UTI

Ascending

• commonest by far

• colonisation of ano-genital region with migration of enteric bacteria (Enterobacterales, enterococci) to bladder +/- renal pelvis

Haematogenous

• Kidneys receive about 33% of cardiac output; bloodstream infection (BSI) may seed in the kidneys

• responsible for <10% of infections, BUT spread from urine to blood far more common

Direct

• fistula, e.g. vesico-colic

acute uti symptoms - localized

• Suprapubic pain (cystitis – inflamed bladder)

• Flank pain (pyelonephritis – inflamed kidney)

• Dysuria = pain when passing urine

• Frequency* = passing urine every 1-2 hours

• Urgency* = The urge to pass urine, must pass urine NOW!

• Nocturia* = passing of urine during night which is out of usual habit

acute uti symptoms - systemic

• Fever

• Rigors

• Acute confusional state/ delerium in elderly

• Nausea, anorexia

• Obstructive uropathy may contribute to acute kidney injury and associated symptoms

UTI CAUSATIVE PATHOGENS

gram neg bacilli

• E. coli

• Klebsiella pneumoniae

• Proteus mirabilis

• Pseudomonas aeruginosa

gram pos cocci

• staph

• group B strep

• Enterococcus faecalis

E coli vs UTI

the most common pathogen causing UTI

gram neg bacilli

staph vs uti

• coagulase-negative staphylococcus – can be part of the normal flora

• Another common cause of UTI in the community

• Tends to affect young women

gram pos cocci

enteroccocci vs uti

• An opportunistic pathogen and not particularly virulent

• Complicated infection in critically ill or immunocompromised patients

gram pos cocci

PSEUDOMONAS AERUGINOSA vs uti

gram neg bacilli

Opportunistic pathogen

• Not a common cause of UTI

• Complicated infection in critically ill or immunocompromised patients or structural urinary tract abnormalities

Characteristic sweet odour

HCA uti

• Pseudomonas aeruginosa

• Enterococcus faecalis/ faecium

Predisposing factors:

• Presence of urinary catheters

• Manipulation of the urinary tract – TRUS-guided prostate biopsy, stone fragmentation, stenting, urinary diversion – nephrostomy, ileal conduit

• Urinary stasis

• Dehydration

• Debility due to underlying disease

how to prevent HCA uti

• Standard precautions including hand hygiene – every patient, every time

• Use antibiotics appropriately and follow the guidelines – reduce the risk of antimicrobial resistance

• Mind the devices:

• only use catheters when necessary

• remove when no longer necessary

• Insert the catheter using an aseptic technique

diagnosing UTI

CONFIRMATION REQUIRES BOTH:

1. PRESENCE OF CLINICAL SYMPTOMS

2. SUPPORTING EVIDENCE FOR UTI

tests

• MSU/ CSU

• dipstick - not a confirmation on its own

• culture/ micro/ susceptibility

• blood - rule out BSI

Asymptomatic bacteriuria

bacteria in urine without symptoms of UTI

• more common with aging/ catheter

not a diagnosis/ should not be treated unless

• Pregnancy

  • If untreated, 20-30% will develop acute pyelonephritis (AP)

• Manipulation of the urinary tract

URINE DIPSTICK/URINALYSIS

look at colour of sample/ cloudy

• Protein

• Blood

• Glucose

• Ketones

• Leucocytes

• Nitrites

DIPSTICK IS A GOOD TEST TO RULE OUT UTI:

• NEGATIVE for nitrites and leucocytes = UTI very unlikely

• POSITIVE for nitrites and leucocytes = Careful interpretation needed

microscopy findings uti

• White blood cells (WBC) or pus cells: normally <10

• Red blood cells (RBC): calculi or glomerulonephritis, tumours or cystitis

• Epithelial cells: presence may indicate specimen contamination

• Bacteria: visible bacteria on microscopy = bacteriuria

• Casts

INTERPRETATION OF THE COLONY COUNT uti

• >10^5 /mL – supports UTI diagnosis, provided patient has symptoms of UTI

• 10^4 /mL – interpret with caution – review microscopy, is the patient symptomatic, was the patient on antimicrobials before the specimen was taken?

• 10^3 /mL - probable contamination

• Mixed growth – likely contamination, send repeat specimen only if clinically indicated