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What is chronic renal injury?

- long duration
- the "chronic" also carries an important additional connotation – this is abnormal renal function associated with irreversible damage to the kidney


What is Chronic Renal Failure?

- insufficient glomerular filtration to:
-- eliminate metabolic wastes
-- maintain water and solute homeostasis
- GFR <15mL/min/1.73m^2
-- the m^2 is body surface area
- may be an element of proteinuria
- often accompanying hypertension

- sallow pale yellow colour
- distinctive smell
- end up anaemic (erythropoietin)


How common is chronic renal failure?

- australian and new zealand dialysis and transplantation registry
- in 2011 19,751 australians (885/million) were receiving renal replacement therapy
-- 8,753 transplant
-- 10,998 renal dialysis
- 2,453 australians commenced renal replacement therapy. this is relatively stable (over previous 5 years)
- mean age at commencement was 60 years


What is a problem with clinical detection?

- as chronic renal injury (from whatever cause) progresses, we end up with scarred, shrunken kidneys, but
-- we have enormous renal functional reserve: a healthy person can do perfectly well with one functioning kidney
-- the organ is hidden from view so we don't see progressive damage (as we would, for example, on the tip of our nose or the back of our hand)
- so we tend to be unaware of chronic renal injury until late in its course

when people get chronic renal failure they tend to get pale, fibrotic kidney (as oppo sed to red). A lot of fibrous tissue. Lose glomeruli.

- even at 50% of kidney function still enough to prevent detectable levels of creatinine
- don't feel sick
- usually not until about 10%
- if you wait for them to show up symptomatically they have probably already lost up to 90% of their renal function
- can't regrow glomeruli


When it does happen, how do people present with CRF?

- asymptomatic
-- blood or urine test taken for various reasons
- symptomatic chronic renal failure
-- lethargy
-- anorexia/nausea
-- anaemia *important*
-- worsening hypertension
- end stage renal failure
-- coma
-- pericarditis
-- sepsis
-- neuropathy


How do we assess it once it's diagnosed?

- severity
-- glomerular filtration rate
-- creatinine clearance
-- kidney size (ultrasound)
-- haemoglobin
- exclude reversible factors
-- particularly manage hypertension, whatever the cause of the CRF
-- kidney secretes renin which increases blood pressure
- diagnose underlying disease if possible - sometimes too late to tell


What causes CRF in Australia?

- ANZ dialysis and transplantation registry (2012 report)
-- 35% diabetic nephropathy
-- 23% glomerulonephritis
-- 15% hypertension

in 1998:
- glomerulonephritis 32%
- diabetic nephropathy 22%
- hypertension 12%
- polycystic kidney 7%
- analgesic nephropathy 6%


How do we manage CRF?

- transplant vs. dialysis
- death rate/100 patient years
-- 13.7 on dialysis
-- 2.4 with renal transplant

- also renal transplants are hard to come by so they tend to be given to people who are going to do well with them (selection bias)

- not easily fixed


What does an end stage kidney look like?

- nobbly, pitted, shrunken, pale


How does diabetes mellitus affect the kidneys?

- significant cause of CRF
- multiple problems for the kidney:
-- diabetic glomerulosclerosis/arteriolosclerosis (deposition of glycosylated proteins in the glomerulus and arterioles)
-- infection (pyelonephritis) (usually an ascending infection --> gram negative bacteria get up the urinary tract
-- papillary necrosis
-- accelerated atherosclerosis in larger arteries

glomerular disease
- may present with proteinuria/nephrotic syndrome or may not be picked up till later in the disease with renal failure
- deposition of glycosylated proteins in mesangium with diffuse mesangial expansion or discrete nodules (Kimmelstiel-Wilson nodules)
- slow with control of glycaemia and blood pressure


What is the K-W nodule?

- nodule of almost acellular collagen
- named after Kimmelstiel and Wilson
- cardinal lesion in histopathology of people with diabetic nephropathy
- round spheres of pink collagen
- haven't obliterated the lumen
- indicator of diabetic nephropathy


What is glomerulonephritis in relation to CRF?

- some forms of glomerulonephritis resolve with no long lasting effect, but many can go on to cause chronic glomerular injury and ultimately lead to CRF
- an example is IgA nephropathy and two others are FSGS (focal and segmental glomerulosclerosis) and lupus nephritis (the GN associated with system lupus erythematosus)


What is IgA nephropathy?

- defined (controversially at first) by presence of immune complexes containing predominantly IgA in the mesangium
- can be isolated in kidney or part of a broader vasculitis
- commonest form of GN worldwide
- typically presents with blood in the urine but may present with CRF
- often slowly progressive – up to 50% progress to CRF
- often in children presents in many small vessels of the body
- rash on the skin


What is focal and segmental glomerulosclerosis (FSGS) in relation to CRF?

- presents with heay proteinuria, often with clinical nephrotic syndrome
- responds poorly to steroids
- progresses, with up to 50% CRF in 10 years
- different causes
-- secondary to obesity, infection, hypertension, reduced renal mass
-- so called 'primary', possibly due to a circulating toxin that affects podocytes
- recurs often in transplants


How does systemic lupus erythematosus (SLE) lead to CRF?

- multi-system disease
- kidneys frequently involved
- progression varies greatly, but some progress to CRF
- classified into Classes I to VI (VI is chronic/end stage)
- commonest are Class III/IV which are proliferative GN with immune complexes deposited in mesangium and around capillary walls
- immune complex load is enormous
- laid down in great sheets around the capillary loops
- rapid injury
- IgG


How does hypertension lead to CRF?

- chronically elevated systemic arterial blood pressure
- effects depend on pressure and duration
-- 'benign' used to be used to describe low grade or mild hypertension
-- 'malignant' described rare, generally rapidly developing, extremely high levels of blood pressure
- end result of long-standing mild or moderate HT is described as 'nephrosclerosis'
- INCREASINGLY CLEAR that long-standing low levels of hypertension damage the kidney and that 'benign' is not so benign


What is the so-called 'benign' nephrosclerosis?

- bilaterally shrunken granular kidneys
- larger scars
- histologically
-- atheroma of larger arteries
-- sclerosis of arterioles
-- scarring of glomeruli and interstitium

- reduced renal mass
- massive replacement by fat
- shrunken glomeruli
- fibrotic
- arteriolar wall thickening


What are some genetic conditions that contribute to CRF?

Best example is polycystic kidney disease:
- some rare paediatric types but usually refers to autosomal dominant (adult type) PCKD
- gene on chromosome 16
- associated with cysts in liver, pancreas, and small aneurysms in brain ('berry' aneurysms)
- bilaterally huge (up to 4 or 5 kg) kidneys
- multiple cysts


What is Alport syndrome?

- inherited abnormality in gene for (and hence structure of) Type IV collagen that is the major constituent of the adult glomerular basement membrane
- present with haematuria, progressing deafness and (often) ocular abnormalities
- not fibrinogen/proteinuria
- progresses to end stage renal failure
- most are X linked, fewer autosomal


What is analgesic nephropathy?

- less common now but important for anyone dealing with kidneys or living in Melbourne
- long-standing use of what were called 'compound analgesics' containing phenacetin with caffeine, aspirin or other analgesics
- direct toxic effects of phenacetin metabolites and vascular effects
- damage the medulla with compound analgesics --> the pyramids becoming necrotic, slough off
- no tubules
- glomeruli becoming fibrotic
- calcification

- bilaterally shrunken kidneys
- papillary necrosis:
-- go brownish colour
-- shrink
-- undergo necrosis, slough off/calcify
- renal function deteriorates
- possible obstruction of ureter by sloughed papilla

- less common


What are other causes of CRF?

- chronic or repeated infections
- chronic obstruction ( a good example is the enlarging prostate in many older men, leading to chronic obstruction of the urethra)