Session 10 Flashcards
What is meant by the mesangium and mesangial cells?
- In the glomerulus of the kidney, the mesangium is a structure associated with the capillaries. It is continuous with the smooth muscles of the arterioles – it is outside the capillary lumen but surrounded by capillaries (contained by the basement membrane which surrounds both the capillaries and the mesangium).
- Mesangial cells are specialized cells around blood vessels in the kidneys, at the mesangium. They are specialized smooth muscle cells that contact and function to regulate blood flow through the capillaries. There are 2 types – extraglomerular mesangial cells and intraglomerular mesangial cells.
- Intraglomerular mesangial cells have 3 central roles: filtration, structural support and phagocytosis.
- Extraglomerular mesangial cells are part of the Juxtaglomerular apparatus (along with macula densa of DCT and juxtaglomerular cells of the afferent arterioles) which regulates BP through RAAS. Extraglomerular mesangial cells are also known as Lacis cells. Their specific function is not well understood though it has been associated with secretion of erythropoietin.
Describe the basic structural patterns of glomerular injury (consider site of injury)
[*] Pathology of any one part of the nephron can secondarily affect the others i.e. if you damage the glomerulus, the tubules will atrophy and if you damage the tubules, feedback will make the glomerulus shut down => acute renal failure
[*] The site of glomerular injury determines a patient’s clinical presentation.
The injury may be primary (just affecting the glomerulus) or secondary (systemic disease that has in turn damaged the glomerulus).
There are four sites of glomerular injury:
Subepithelial
- Anything that effects podocytes/podocyte side of glomerular basement membrane
- The podocytes have interdigitating foot processes with adjacent cells, forming a complex network of intercellular junctions
Within Glomerular Basement Membrane (made up of Type IV collagen)
Subendothelial
- inside the Basement membrane
Mesangial/paramesangial
- Supporting capillary loop
Describe Proteinuria and Nephrotic Syndrome
[*] Proteinuria: Proteinuria is the presence of excess serum proteins (<3.5g filtered every 24hours) in urine. The presence of protein in urine is due to podocyte damage, the widening fenestration slits causing protein to be ‘leaked’ when it would normally not be filtered. Proteinuria is a ‘less severe’ Nephrotic Syndrome.
[*] Nephrotic Syndrome Over 3.5g of Protein is filtered in 24hrs is known as Nephrotic Syndrome.
- As a lot of protein is being filtered, oncotic pressure is reduced giving generalised oedema. Podocyte/Subepithelial damage is the likely site of injury.
- Proteinuria, peripheral oedema, hyperlipidaemia – normally kidney function is ok, normal GFR, creatinine and urea levels
What are the common causes of Proteinuria / Nephrotic Syndrome?
[*] Common Primary Causes of Proteinuria/Nephrotic Syndrome
- Minimal Change Glomerulonephritis (GN)
- Focal Segmental Glomerulosclerosis (FSGS)
- Membranous Glomerulonephritis
[*] Common Secondary Causes of Proteinuria/Nephrotic Syndrome
- Diabetes Mellitus (microvascular complications affect kidneys)
- Amyloidosis
What is Minimum Change Glomerulonephritis?
- Commonest cause of nephrotic syndrome in childhood/adolescence. Presents in childhood/adolescence with incidence reducing with increasing age. It causes heavy proteinuria or Nephrotic syndrome.
- The disease responds well to steroids, but may reoccur once weaned off treatment. There is usually no progression to renal failure and is normally purely protein loss from the kidney.
- Minimal Change Glomerulonephritis is named as such because when looking at the glomeruli under a light microscope they appear to be completely normal.
- However, under an electron microscope, the damage to podocytes is evident, widening fenestration slits and allowing protein to ‘leak’ through. Podocytes’ foot processes disappear – they retract into the cell bodies in response to cell damage, impairing filter function.
- Pathogenesis is unknown. Unknown circulating factor damaging podocytes.
- No immune complex (of host antibodies and antigens deposition)
What is FGFS?
- Focal – Involving less than 50% of glomeruli on light microscopy
- Segmental – Involving part of the glomerular tuft
- Glomerular
- Sclerosis – Scarring
- Presents in adulthood and is less responsive to steroids than minimal change glomerulonephritis. Podocytes undergo damage and subsequent scarring (Glomerulosclerosis), so protein is present in the urine.
- A circulating factor is responsible for the damage, evidenced by the fact that transplanted kidneys undergo the same damage.
- Minimal change FSGS can progress to renal failure, but the pathogenesis is unknown.
What is Membranous Glomerulonephritis?
- The commonest cause of Nephrotic syndrome in adults and rarely occurs in children. Results from immune complex deposits in the sub-epithelial space and probably has an autoimmune basis (autoantibody to podocytes – Phospholipase A2 receptor (PLA2R) autoantibody). The podocytes have been damaged by complement activation.
- However there is also evidence that it [Text Box: o Capillary loop far too thick o Basement membrane looks ‘speckley’ –irregular spiky] may be secondary, as it is associated with other conditions, particularly malignancies e.g. lymphoma.
Follows the rule of thirds:
- 1/3 just get better
- 1/3 ‘Grumble along’, proteinuria but are fine
- 1/3 Progress to renal failure
What is Nephritic Syndrome?
Renal failure due to the leaking of filter. Associated with hypertension, low GFR, oedema due to fluid overloading, haematuria (lets blood through)
What is IgA Nephropathy?
- The commonest Glomerular Nephropathy, which can occur at any age, characterised by the deposition of IgA antibody in the Glomerulus. It is classically present with visible/invisible haematuria and has been shown to have a relationship with mucosal infections (IgA protects mucosal surfaces). It can present at the same time as a respiratory tract infection.
- It has variable histological features and course. Some, but not all, patients have proteinuria, and a significant proportion of patients, but not all, progress to renal failure. It is unknown why this variation occurs.
- Immune complexes in the circulation get trapped in the mesangium – deposition of circulating IgA-containing immune-complexes
- Mesangial proliferation => expansion of mesangium => replaced by collagen and scarring may occur (fibrous repair). There is no effective treatment.
- But it does not seem to come back in a damaging way after transplant – doesn’t seem to cause renal failure.
Describe 2 common heriditary nephropathies
There are two hereditary nephropathies, Thin GBM Nephropathy and Alport Syndrome that are relatively common
- The two are not completely distinct however, with a grey area between them. It has been found that they both have a defective gene responsible for producing Type IV collagen however the 2 mutations are different leading to 2 different abnormalities
Thin GBM Nephropathy
- Benign Familial Nephropathy
- Isolated Haematuria
- Thin GBM
- Benign Course
- ‘Just a little bit of blood in urine – no significant protein loss in urine.
- Doesn’t require treatment
Alport Syndrome
- X linked
- Abnormal collagen IV
- Associated with deafness
- Abnormal appearing GBM
- Progresses to renal failure.
- Early onset, blood in urine.
- Doesn’t occur in transplant patients
Describe microvascular nephropathy in Diabetes Mellitus
- Progressive proteinuria
- Progressive renal failure
- Microvascular (Damages glomerulus directly)
- Mesangial sclerosis => collagen deposits and accumulation in the glomerular loop => nodules (lumps of scar tissue) => eventually leads to renal failure
- Basement membrane thickening to 4-5x normal which causes nephrotic syndrome
Describe Goodpasture Syndrome
- Relatively uncommon, but clinically important as it is very rapidly progressing Glomerular Nephritis (very rapid, acute, sudden onset of kidney failure – of severe nephritic syndrome)
- The disease is brought about by an autoantibody to collagen IV in basement membranes, and classically described association with pulmonary haemorrhage (only in smokers) – attacks lung tissue as well as kidney but lung damage only occurs in smokers.
- It is treatable by immunosuppression and plasmaphoresis (removing autoantibody from basement membrane) if caught early.
- Characterised by IgG deposition but no Extracellular Matrix deposit.
Describe Vasculitis
- Group of systemic disorders
- No immune-complex/antibody deposition
- An inflammation of blood vessels that will therefore affect the highly vascularised kidney. => nephritic presentation.
- Blood vessels are attacked directly in the glomerulus by Anti Neutrophil Cytoplasmic Antibody (ANCA) – an autoantibody leading to inappropriate activation of neutrophils which start damaging blood vessels.
- Treatable with immunosuppression therapy if caught early (before patient is on diagnosis). Urgent biopsy service required.
- The crescent pattern of glomeruls nephritis (due to the inflammatory cell infiltrate) – classically caused by Goodpasture’s and Vasculitis.
Describe the basic mechanisms/factors response for the different expression of immune complex mediated disease
[*] Subepithelial Deposits: Antigens lodged in situ in the filter and abnormally recognised on podocytes, circulating IgG (antibodies) binds to it, forming immune complexes in the glomerulus (Not circulating immune complexes causing damage).
- E.g. Membranous Glomerulonephritis
[*] Mesangial Deposits: Immune complexes can be deposited directly in the mesangium, as there is no podocytes or basement membrane to act as a barrier.
- E.g. IgA Nephropathy
Describe the epidemiology of prostate cancer
- Prostate cancer is the most common cancer in men in the UK. It is also the second most common cause of death from cancer in men.
- However, most men who are diagnosed with prostate cancer, have localised disease and are more likely to die with it than of it.
Describe the usual presentation of prostate cancer
[*] Vast majority asymptomatic
[*] Urinary symptoms
- Benign enlargement of prostate
- Bladder over activity
- +/- CaP
[*] Bone pain : in Advanced metastatic disease
[*] Unusual: Haematuria - In advanced prostate cancer
[*] Males with prostate cancer frequently present following a raised serum prostate specific antigen (PSA) test and/or abnormal digital rectal examination.
What are the factors influencing treatment decisions for Prostate Cancer?
- Age (in older patients, treatment might sometimes do more harm than good especially if they have co-morbidities)
- DRE
- Localised (T1/2)
- Locally advanced (T3)
- Advanced (T4)
- PSA Level
- Biopsies
- Gleason Grade (low magnification, based on microscopic appearance)
- Extent
- MRI scan and Bone scan
- Nodal/Visceral Metastases
For patients with urological haematuria of malignant origin, you should understand the principles of investigation
[*] History
- Smoking, Occupation (bladder cancer is linked with some older industries i.e. textiles), painful or painless, other lower urinary tract symptoms and family history need to be asked about.
[*] Examination
- BP
- Abdominal mass
- Varicocele – collection of veins in the scrotum (‘bag of worms’)
- Leg swelling
- Assess prostate by DRE (male) – Size, texture
[*] Investigations
- Urine culture and cytology (abnormal cells), full blood count, ultrasound, flexible cystoscopy
Describe the initial definitive treatment and staging of bladder cancer
Initial Definitive Treatment
- TURBT (Transurethral Resection of Bladder Tumour) is the treatment that many patients will need to have performed after diagnosis of non-muscle invasive bladder cancer and the aim is to remove the cancerous growth and seal the tissue around where the growth was to try and prevent it returning.
- Superficial TURBT
- Separate deep TUR of muscle
- Single intravesical instillation of mitomycin C (chemical treatment aims to reduce recurrence)
Staging
- 75% of Cancers are superficial (Ta/T1)
- 5% are Tis (In situ)
- 20% are muscle invasive (T2, T3, T4)
Describe the treatment of bladder cancer
High risk non-muscle invasive TCC (G3/Tis/T1)
- Check cystoscopies
- Intravesical chemotherapy/immunotherapy
Low risk non-muscle invasive TCC (G1/G2/Ta)
- Check cystoscopies
- +/- intravesical chemotherapy
Muscle Invasive TCC
- Neoadjuvant chemo +
- Potentially curative
Potentially curative
- Radical cystectomy or radiotherapy (+/- chemotherapy)
Not curative
- Palliative chemotherapy/radiotherapy
