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Objectives

  • Anatomy ofthe kidney
  • Basic concepts of renal physiology
  • Functions of the kidney
  • The kidney in health
  • The kidney in disease

Functions of the Kidney

  • Salt and water homeostasis
    • Na+, K+, Cl-, HCO3-, Urea
    • Measure as GFR
  • Osmolality
  • Blood pH (acid-base balance)
  • Calcium/phosphate
    • Vitamin D metabolism
      • 1-hydroxylation of vitD
      • FGF23 might have a role here
    • PTH (parathyroid hormone) action
      • increases [Ca+] in blood
  • Blood Pressure
    • Renin-angiotensin system
    • Mineralocorticoid action (aldosterone)
    • Total body salt and water; and also neuroendocrine
  • Erythropoietin production
    • Made in interstitial tissue of kidney
    • interstitial fibroblasts in the kidney in close association with peritubular capillary and tubular epithelial cells
  • Insulin metabolism
    • In the kidney tubules


  • We usually measure GFR, but that's not everything - there are lots of other functions of the kidney. Note that salt control on its own contributes greatly to blood pressure.
  • EPO and anabolic steroids are the two main performance enhancing drugs
  • Euvolemia = normal volume; venous pressure normal, BP normal, no tachycardia
  • Fixed urinary concentration defect (they secrete 600mosm/L fluid)
    • Serum sodium 120 (Normal: 135-145) Plasma osmolality of 240 and urine osm of 400
      • Fixed urine concentration defect = cannot dilute urine below 600 mosm/L
      • =retain free water
      • causes: anticonvulsants (etogrotol, sodium valproate)
      • euvolemic, hyponatremic, hypoosmolar; don't want serum sodium to go down low (look up why)
        • giving normal saline: 300 mosm in normal saline (150 Na, 150 Cl). Within 20 minutes, it goes throughout the body water to increase their osmolality. But then the water distributes everywhere. Patient has to remain isovolemic
          • giving normal saline: this will cause the serum sodium to go down because they can only get rid of half of the 600mosm/L requirement of the kidney
          • giving normal saline: makes problem worse
          • if someone has a low sodium but high volume, then they're actually in water excess. If they're volume depleted (tachycardia, veins are down, look dry), with a low sodium, then they're salt and water depleted, but they're a little more salt depleted than water depleted
          • giving this guy normal sodium will cause the serum sodium to fall. The patient has to remain isovolemic, so if you give them a litre, they have to remove a litre. They have to excrete 600 mosm/L litre fluid. So if you give them one litre of 300 mosm/L fluid, then they can only get rid of 1L of that. That means the other 500mL will be redistributed through their body, effectively reducing their serum sodium --> water retention, making the problem worse.
    • need to know - serum sodium, urine osmolality, volume state of individual
    • volume depleted person will often have an ADH compensation, so the volume depleted person can have low sodium because they're trying to retain water madly
    • similar effect in inapproriate ADH. In volume depletion it's the same thing. Diuretics and hot weather (cause dehydration) are the main cause of appropriate ADH.
  • hyperphosphatemia is an independent risk factor for CVD. Extra-osseous calcification
  • Alcohol actually suppresses ADH.

Anatomy of the Kidney

  • Cortex = glomeruli, rich in oxygen
    • Cortical rays
  • Medulla = more hypoxic
    • Calyces, urinary pelvis, to ureter
  • Renal vein and artery, and ureter
  • A stone in one ureter may change kidney function minimally dependent on function of the other kidney.
  • Kidney is a very specialised blood vessel with pipes around it
  • Renal artery has arterioles that form glomeruli, pushes stuff into the bowman's capsule
    • STUDY THE COUNTERCURRENT EXCHANGE MECHANISM
  • Loop of Henle descending; gets more concentrated down, less concentration going up - look up the book
  • Collecting duct is sensitive to ADH. Collecting duct goes through to the medulla, drops urine out to ureter
  • Alcohol experiment
    • Alcohol makes you want to urinate
    • Because it suppresses ADH - spirits with low volume = dehydration
      • DVT on aeroplanes (low humidity, high altitude, dehydrated)
Renal corpuscle.svg

A - Renal corpuscle
B - Proximal tubule
C - Distal convoluted tubule
D - Juxtaglomerular apparatus
1. Basement membrane (Basal lamina)
2. Bowman's capsule - parietal layer
3. Bowman's capsule - visceral layer
3a. Pedicels (podocytes)
3b. Podocyte or sometimes called Bowman's cells
4. Bowman's space (urinary space)
5a. Mesangium - Intraglomerular cell
5b. Mesangium - Extraglomerular cell
6. Granular cells (Juxtaglomerular cells)
7. Macula densa
8. Myocytes (smooth muscle)
9. Afferent arteriole
10. Glomerulus Capillaries
11. Efferent arteriole

  • Nephron
    • Forming an ultrafiltrate in the kidney - so you can see how the blood vessels are working
    • Leaky bloodvessels = can see in urine (urine dipstick), or albumin (35-45g/L protein in the urine, the #1 protein in the urine by mass, because other proteins are too big)
    • Parietal epithelial cell = important in diabetes and primary glomerular diseases = loss of normal filtration (leak protein, sclerosis of the glomerulus, renal failure)
    • PCT: 60-70% of the work of the kidney (needs a lot of energy)
      • Resorbs about 1.4kg salt per day in the GFR; reabsorbs about 60-70% of your sodium
        • Average serum sodium = 135-145 mmol/L. GFR = 120mL/min = 172 L/day. 140*172 = ... mmol/day = 1.4kg salt
        • use a lot of energy in filtering out salt
        • But we put out very small amount of salt in urine
    • Cortex=lots of oxygen and ATP
    • But Medulla: most hypoxic because less oxygen and a high demand (partly consumed O2 in the PCT - the same blood vessel supplying the cortical region supplies the medullary region later in its course)
  • Histo
    • See the wikipedia diagram of a Nephron above
    • Mesangial cells provide the sturcture of the glomerulus
    • see capillary loops, tubules tightly packed together
  • EM basement membrane; urinary space, lumen of vessels
    • Fenestrated endothelium
    • Foot processes of the visceral epithelium (podocyte). Primary disorders of podocyte = changes in glomerular basement membrane = proteinuria
    • Proteinuria = podocytes fuse together = main cause is diabetes = heavy proteinuria > 3g/day
      • in 60s-70s it was minimal change glomerulonephritus


Kidney Anatomy
Glomeruli Anatomy
Glomeruli Anatomy

Kidney Function

  • Glomerular filtration
    • Filtration of blood at the glomerulus produces an ultrafiltrate of plasma. You reabsorb the vast majority of this ultrafiltrate. This effectively contains all the small molecules in the plasma and some small proteins. Normally there is very little or no albumin filtered at the glomerulus and no molecules larger than albumin are filtered
  • A normal person filters 120 ml/min (range 90 to 150 ml/min). That equates to 172.8 L of filtrate per day. The renal tubules reabsorb the vast majority of this filtrate.
  • Characteristics of GFR biomarker
    • Present constantly in the plasma
    • Shouldn't change with other conditions
    • Shouldn't be excreted or reabsorbed
  • Creatinine is cheap, but 10% is absorbed, there are things that make it go up and down in the plasma
    • But it doesn't tell you much about tubular injury (need new biomarkers of tubular injury in future)
    • 1/x relationship of creatinine vs GFR
    • Normal: 0.06 - 0.11 in male
    • can have small change in creatinine, and a huge change in GFR --> very important not to ignore early changes
    • also muscle production, Jaffey assay are issues in creatinine disturbance

GFR and creatinine.PNG

  • GFR and age
    • Reduced GFR (as creatinine measurement) because of reduced muscle mass. NB also GFR actually does decrease with age
    • NaCL: 1415g daily
    • K+: 27g daily


  • Tubular Function
    • Salt and water reabsorption
      • This effectively regulates the urinary volume and amount of electrolytes conserved or excreted. It is a highly active process requiring expenditure of metabolic energy.
    • Excretion of various molecules
      • K+, Phosphate, Drugs, Acids
  • Problem: decreased GFR with age = less filtration of drug
    • Adjust drug dose

NB: a litre of saline and 2 of glucose is OK for normal people, but people with cardiac problem - you can't just do that

Renal Disease

  • Pre-renal
    • Volume or perfusion related problem (e.g. clamp on renal artery, septic shock, blood loss, fluid loss via diarrhea etc); it's not a condition, it's a category of conditions.
    • Injury to parenchyma
    • Drop perfusion to kidney = kidney injury due to dropped oxygen. Also kidney reperfusion injury.
    • Can't predict acute kidney injury prognosis with any accuracy (multifactorial e.g. septicemia has LPS as well combined with hypovolemia, how good their vascular system is etc)
  • Renal parenchyma
    • Affecting tubules in filtering apparatus e.g. heavy metals
  • Post renal
    • Affecting renal pelvis or below (obstruction)

Presentations of Renal Disease

  • Incidental finding
    • Work/insurance/immigration urine screening test
  • Hypertension
  • Headache
  • Lethargy
  • Aches and Pains
  • Nocturia
    • inability to concentrate urine
    • one of the first manifestations in chronic renal kidney disease
  • Diabetes
  • Systemic illness (joint symptoms, rash, constitutional symptoms)
  • Loin pain
  • haematuria
    • commonest in kidney stones
  • oedema
    • e.g. in nephrotic syndrome - leaking albumin
    • oedema with normal albumin - not kidney problem (it's CCF)

Note that the symptoms are terribly nonspecific. Can range from minor symptoms to relatively serious.

Symptoms of a systemic vasculitis

  • Fever, night sweats
  • Rash
  • Haemoptysis, epistaxis, sinusitis
  • Anorexia, weight loss
  • arthralgia
  • alopecia
  • pleurisy
  • Raynaud's phenomenon
  • Mouth ulscres, dry mouth, dry eyes
  • sore throat
  • Cellulitis

Very nonspecific. Mostly you don't get symptoms until loss of 80-90% GFR loss (e.g. change in phosphate, secondary hyperparathyroidism). This is a problem: need to be very astute.

Urine Analysis

  • Dipstick urine test
    • protein
      • marker of vascular function
      • increased risk of vascular disease
      • diabetes - look especially for creatinine:albumin indicating microvascular disease
    • blood
    • pH
    • specific gravity (way to look at protein)
    • glucose (terrible way to look for diabetes)
    • ketones

Cheap, simple, effective, underrated.

  • NB: variant of normal = thin basement membrane = microscopic haematuria, red cells leak across it - but investigate just in case it is disease
  • Normally dip sticks pick up 1-300 mg/L (???) --> risk factors for CVD
  • 20ug/min = normal leak of albumin = 28 mg/day; more than that = something wrong with the filtration barrier = vascular disease
    • Hope study: every quintile in decrease in renal function = CVD risk increase
      • Microvascular structure problem is indicated by microalbuminuria; tells us physical problem with the microvasculature
      • See other risk factors in the CVD assessment lecture
  • To get albumin in the urine is difficult - there is a certain amount of tubular reabsorption; must exceed the Tm for reabsorption of albumin

Urine microscopy

  • Confirm presence/absence of red cells
    • Dysmorphic (indicates they've come from glomeruli rather than bladder) = glomerular bleeding
  • Presence of casts - material precipitated form urinary tubules
    • Hyaline - proteinaceous
    • Granular - cells
      • Casts of red cells = very serious glomerular bleeding, accelerated nephritis = renal emergency
  • Fat droplets - nephrotic state
  • Crystals
    • gout etc.
    • urate, cysteine, phosphate etc

Urinary casts.PNG See dysmorphic red cells

Casts = problem with tubules, need to see the history

The urine sediment

  • Urine sediment showing a fatty cast
  • Fat droplets are variable in size , smaller or larger than a red cell
  • Dark outline
  • Maltese cross under polarized light



Proteinuria

  • One of the most common signs of renal disease
  • Dipstick testing primarily reacts with albumin 150mg/L or more)
  • protein to creatinine ratio of a urine sample - helps you determine if they have a total increase of protein
    • albumin creatinine ratio = diabetic or just diagnosed with hypertension
    • if someone's already got dipstick-positive proteinuria, don't do an albumin creatinine ratio. If they have proteinuria positive this gives you no more information
  • If detected on a dipstick, do a 24 hr urinary collection to quantify protein
  • usually <150mg daily but varies from lab to lab
    • 100-300 is normal
  • Pyrexia, exercise and upright posture may affect urinary protein output
    • e.g. nighttime urine; postural proteinuria, not common, usually young people

Protein dependent ratio in urine sample helps you determine if someone's got a total increase in total protein.

Risk of renal disease.PNG

  • Don’t let things fall between the cracks. Pay attention to the details. Particularly proteinuria, but also the urine sediment, blood pressure and serum creatinine

Clinical presentations of Chronic Renal Disease

  • chronic renal failure is due to loss of nephrons - as compared to acute kidney disease (e.g. tubules became ischaemic - acute dysfunction - can recover)
    • CKD - loss of nephrons - loss of concentration gradient in urine/medulla
    • first symptom = nocturia (sensitive but not specific e.g. alcohol, drunk too much water, prostate problem); because you can't concentrate your urine
  • Therefore loss of ability to maintain a concentration gradient in the medulla
  • This leads to an increased obligate urine volume which most frequently presents as nocturia
  • other features will be more or less prominent depending on the amount of nephrons lost and the rate of loss
    • Other symptoms include lethargy (anaemia), aches and pains (hyperparathyroidism, Vit. D deficiency
      • Much later in disease
  • Lethargy can be treated by EPO
  • Hb targets in CKD should be lower than in general populus
    • e.g. CKD on dialysis: 10-12g% (used to be 8g% before EPO treatment came in)


  • Lethargy
  • Anaemia
  • Aches and pain
  • Hyperparathyroidism and Vitamin D deficiency. Note FGF23 goes up (made by osteoclasts) which deactivates the active form of vitamin D
    • osteomalacia from vitamin D deficiency (can't activate vitamin D)
    • osteoporosis from hyperparathyroidism (due to phosphate retention) --> PTH --> more alk phos from osteoclasts --> bone resorption

Hypertension

Everyone who has kidney disease ends up with hypertension

  • Kidney makes renin in JG cells
    • Renin converts Angiotensinogen (liver) to AT1
    • AT1 to AT2 by ACE in lung
  • Aldosterone acts on kidney to result in salt/water retention
    • In adrenal gland

Renin-ang system.PNG RAS II.PNG

Angiotensin - antiproliferative, antifibrotic, anti-cardiac hypertrophy, vasodilatory.

  • Also renin receptors in the heart and other places
  • AT2 can bind to the AT1 receptor causing vasoconstriction and proinflammatory, and increase aldosterone production in adrenal
  • AT2 receptor - cell proliferation, inflammation
  • AT1 receptor is very specific and monogamous
  • ACE lives everywhere - not monogamous. Pleotrophic in terms of potential partners
    • Blocking ACE and blocking AT1 receptor are not the same thing therefore, despite clinical similarities

Second picture = 2013 view

  • Renin to renin receptors
  • ACE is related to bradykinin breakdown and also NO receptors in the heart
    • AT1 receptors don't really have much effect on nitric oxide
  • ACE inhibitors inhibit both pools of the enzyme (may be opportunities to produce more specific ones future)
  • Block AT1 receptor - inhibits metabolic syndrome, promotes uptake of fatty acids/glucose by muscle, is anti-diabetic
    • Reduces the incidence of subsequent development of T2DM
    • Same thing for ACE but mechanism unknown
  • AT2 is converted to AT1-7, acted on by ACE-2 (lets the SARS virus into cells), AT1-7 does the reverse of AT1, binds to MAS receptor and causes vasodilation and good things
  • Overall: ACE acting with other peptidases may allow for production of AT1-7
    • Blocking ACE2 may allow increased production of AT1-7
  • Give drugs that block ACE system --> less CVD (and MI), don't see that with AT1 drugs
    • So there are clearly differences on observation/empirical and metabolic levels

Angiotensin 1-7

*Antiproliferative

  • Anti-fibrotic
  • Anti-cardiac hypertrophy
  • Vasodilatory

RAS in 2013

  • ACE system is a balancing system
  • ACE2 in kidneys, heart, testes, brain

Angiotensin forms AT2 and AT1-7


Angiotensin 2 works on AT1 receptor

  • Vasoconstriction
  • Endothelial dysfunction
  • Proliferation/hypertrophy
  • Atherosclerosis
  • Arrhythmogenesis
  • Thrombosis

Angiotensin 1-7 works on MAS receptors

  • Vasodilation
  • Endothelial function
  • Proliferation/hypertrophy
  • Fibrosis
  • Thrombosis
  • Arrhythmogenesis

Glomerular Syndromes

  • The nephrotic syndrome - not a diagnosis, just a syndrome
    • Proteinuria >3g/24 hours
    • Hypoalbuminaemia
    • Oedema due to low albumin
    • Hyperlipidaemia - hypooncotic pressure causes increase production in lipoproteins in the liver
    • hypercoaguability - unknown mechanism - another thing pointing to CVD (especially in diabetic who gets nephrotic syndrome, and the hyperlipidaemia above)
    • untreated nephrotic syndrome is a risk factor for atherosclerosis/vascular disease
      • hyperlipidaemia very hard to treat
  • causes of nephrotic syndrome (pink glomerular diseases) include diabetic glomerulosclerosis, membranous nephropathy (increased membrane thickness), membrane loss/gain, minimal change disease, glomerulosclerosis and amyloid
  • Face of child with nephrotic syndrome: periorbital puffiness
    • Fluid bubbling under their feet
    • E.g. FSG (focal segmental glomerulonephrosis) due to steroid abuse
  • The nephritic syndrome - more of an inflammatory picture
    • hypertension (may or may not happen in nephrotic syndrome e.g. minimal change syndrome won't get it, diabetes will get it, FSG you probably will)
    • oliguria
    • oedema (due to salt/water retention, not low albumin)
    • haematuria, proteinuria
  • Caused by IgA disease, Berger's disease, SLE, rapidly progressing glomerulonephritis

Diabetes

  • haematuria and proteinuria

Sequence of events:

  1. hyperfiltration - treat with ACEI
  2. intermittent microalbuminuria
  3. Persistent microalbuminura
  4. Proteinuria on a 24hr urine collection
    • At this stage you can slow it down but not stop
    • $80000 per year on dialysis - so you can save the health budget a lot of money. there are about 12k people on dialysis in Australia
  5. renal impairment/glomerulosclerosis
  • electrolyte abnormalities
  • hyperkalemia
  • Hypertension
  • atherosclerotic vascular disease