Histo: Renal Disease Flashcards
List the major functions of the kidneys.
- Excretion of metabolic waste products and foreign chemicals
- Regulation of fluid, electrolytes and acid/base balance
- Regulation of blood pressure (renin)
- Regulation of calcium and bone metabolism (1,25-dihydroxy vitamin D)
- Regulation of haematocrit (EPO)
List some key anatomical features of the kidneys.
- Retroperitoneal
- T12-L3
- Right kidney lies lower
- Mean length = 11cm
- Normal weight = 115-170g
What proportion of cardiac output goes to the kidneys?
20%
By what mechanism is blood filtered through the glomerulus?
- High hydrostatic pressure (60 mmHg)
- Podocytes create a charge-dependent (anionic) and size-dependent barrier
- Filtration rate = 125 ml/min
Describe the role of the
proximal convoluted tubule.
-
Proximal convoluted tubule
- Actively absorbs sodium
- Carries out hydrogen exchange to allow carbonate resoprtion
- Co-transport of amino acids, phosphate and glucose
- Reabsorption of potassium
Describe the role of the loop of Henle.
Loop of Henle
- Descending limb and thin ascending limb: permeable to water, impermeable to ions and urea
- Ascending limb: actively resorbs sodium and chloride
- This creates a counter-current multiplier that is aligned with the vasa recta
Describe the role of the distal convoluted tubule.
Distal convoluted tubule
- Impermeable to water
- Regulates pH by active transport of protons and bicarbonate
- Regulates sodium and potassium by active transport (aldosterone)
- Regulates calcium (PTH, 1,25-dihydroxy vit D)
Describe the role of the collecting duct.
Collecting duct
- Reabsorb water (principal cells, ADH)
- Regulates pH (intercalated cells, proton excretion)
Describe how disease of the kidney can be classified according to the part of the nephron it affects
1. Glomerulus
Nephrotic:
- Primary = MCD, FSGS, MGD
- Secondary = diabetes, amyloidosis, SLE
Nephritic:
- Acute post-infectious (post-streptococcal)
- IgA nephropathy (Berger Disease)
- Rapidly progressive glomerulonephritis
- Alport’s syndrome (hereditary nephritis)
- Thin basement membrane disease (Benign familial haematuria)
2. Tubules & interstitium
- Acute tubular necrosis
- Tubulointerstitial nephritis
3. Blood vessels
- Thrombotic microangiopathies (HUS, TTP)
Describe how immune complex deposition can lead to renal disease.
Complex deposition in the glomerulus results in complement and inflammatory cell activation resulting in damage to the kidney
List some genitourinary malformations of the kidney.
- Agenesis
- Renal fusion
- Ectopic kidney
- Renal dysplasia
- PUJ obstruction
- Posterior urethral valve
- Vesicoureteric reflux
- Ureteral duplication
Outline the presentation of polycystic kidney disease.
- Hypertension
- Haematuria
- Flank pain
Adult onset
What is the inheritance pattern of polycystic kidney disease and which genes are implicated?
Autosomal dominant (most of the time)
Genes: PKD1 and PKD2
NOTE: PKD is associated with an increased risk of berry aneurysms (and subarachnoid haemorrhage)
In which group of renal patients do renal cysts often develop?
What do they increase the risk of?
- Patients with end-stage renal disease who are on dialysis
- Cysts are often multiple, bilateral and cortical and medullary
NOTE: cystic disease is associated with increased risk of malignancy (papillary renal cell carcinoma)
What is Alport syndrome?
Genetic condition affecting type IV collagen. Leads to triad of:
- Kidney disease
- Hearing loss
- Eye changes (lenticonus, cataracts)
List some causes of acute renal failure.
- Pre-renal = failure of perfusion (shock, heart failure)
- Renal = ATN, acute glomerulonephritis, thrombotic microangiopathy
- Post-renal = obstruction to urine flow
What is the most common cause of acute renal failure?
Reduced renal perfusion
List some causes of acute tubular injury.
- Ischaemia
- Toxins - contrast, haemoglobin, myoglobin, ethylene glycol, drugs)
Which commonly used class of drugs predisposes to acute tubular injury?
NSAIDs - inhibits vasodilatory prostaglandins which predisposes to ATN
How does acute tubular injury lead to reduced GFR?
- Blockage of tubules by casts
- Leakage from tubules into interstitial space
- Secondary haemodynamic changes
Describe the histological appearance of ATN
Necrosis of short segments of tubules
What is acute tubulo-interstitial nephritis?
Inflammation of the renal interstitium, typically due to immune-mediated hypersensitivity reaction
Can be caused by infection and drugs (NSAIDs, antibiotics, diuretics, allopurinol, PPIs)
What is the most common cause of acute interstitial nephritis?
Drugs
Describe the histological appearance of acute tubulo-interstital nephritis.
Heavy interstitial infiltration with eosinophil and granulomas
What are some key signs of acute glomerulonephritis?
- Oligo/anuria
- Haematuria
- Erythrocyte and leukocyte casts on MCS
What is rapidly progressive (crescentic) GN?
Most aggressive form of GN – can cause ESRF within weeks.
Presents as a nephritic syndrome, but oliguria and renal failure are more pronounced
What causes crescents to appear in acute rapidly progressive glomerulonephritis?
Occurs in severe glomerulonephritis due to proliferation of macrophages & parietal cells in Bowman’s space which pushes glomerulus to one side
Describe the classification of rapidly progressive glomerulonephritis (aka. acute crescentic glomerulonephritis)
Classification based on immunological findings:
- Type 1. Anti-GBM antibody (Goodpasture’s)
- Type 2. Immune complex mediated (SLE)
- Type 3. Pauci-immune (ANCA-associated - GPA)
NOTE: these can rapidly lead to irreversible renal failure
List some causes of immune complex-associated (type 2) rapidly progressive glomerulonephritis (aka. acute crescentic glomerulonephritis)
- SLE
- IgA nephropathy
- Post-infectious glomerulonephritis
- HSP
What techniques can be used to visualise immune complexes in these diseases?
- Immunohistochemistry (fluorescence microscopy)
- Electron (light) microscopy
How does immune complex-associated rapidly progressive glomerulonephritis (aka. acute crescentic glomerulonephritis) appear on fluorescence microscopy?
Granular (lumpy bumpy) IgG immune complex deposition on GBM/mesangium
What are the antibodies directed against in anti-GBM disease?
How can these antibodies be detected?
- Against the C-terminal domain of type IV collagen (COL4-A3)
- Detected by serology
NOTE: these antibodies can cross-react with the alveolar basement membrane leading to pulmonary haemorrhage and haemoptysis
Describe the immunohistochemistry picture produced in anti-GBM disease
Linear deposition of IgG on the glomerular basement membrane
What are the main features of pauci-immune crescentic glomerulonephritis?
- Lack of / scanty glomerular immunoglobulin depositis
- Usually associated with ANCA
- Triggers neutrophil activation and glomerular necrosis
- Vasculitis (elsewhere) – particularly presenting as skin rashes or pulmonary haemorrhage
What is thrombotic microangiopathy?
- Damage to the endothelium in glomeruli, arteriols and arteries resulting in thrombosis
- Red cells can be damaged by fibrin causing MAHA or HUS
List some types of thrombotic microangiopathy.
HUS: Thrombi confined to kidneys
- Typical HUS - usually associated with diarrhoea caused by E.coli O157:H7 (outbreaks caused by children visiting petting zoos/eating undercooked meat)
- Atypical HUS (non-diarrhoea associated) - due to abnormal proteins in complement pathway/endothelium (can be familial)
- Triad - thrombocytopaenia, MAHA, renal damage
TTP: Thrombi occur throughout circulation, esp. in CNS
- A genetic / acquired deficiency of ADAMTS13
- Pentad - thrombocytopaenia, MAHA, renal damage, CNS abnormalities, fever
Also:
- Drugs, radiation, hypertension, scleroderma, antiphospholipid syndrome
What are the characteristic features of nephrotic syndrome?
- Proteinuria (>3.5 g/day or >300mg/mmol PCR)
- Hypoalbuminaemia
- Oedema
- Hyperlipidaemia
List some causes of nephrotic syndrome.
-
Primary glomerular disease (non-immune complex mediated)
- Minimal change disease
- Focal segmental glomerulosclerosis
-
Primary renal disease (immune complex mediated)
- Membranous glomerulonephritis
-
Systemic disease
- SLE
- Amyloidosis
- Diabetes mellitus
What is minimal change disease?
- Most common cause of nephrotic syndrome in children
- Glomeruli look normal on light microscopy, but electron microscopy shows loss of foot processes
- Generally responds well to steroids and immunosuppression
Describe the histological appearance of focal segmental glomerulosclerosis.
Focal and segmental glomerular consolidation and scarring
Hyalinosis
NOTE: this responds less well to immunosuppression
What is membranous glomerulonephritis?
- Common cause of nephrotic syndrome in adults
- Characterised by immune deposits outside the glomerular basement membrane (subepithelial - ‘spikey’)
- Primary disease is autoimmune
- It can occur secondary to epithelial malignancy, SLE, drugs and infections
Which antibodies are often found in primary membranous glomerulonephritis?
Antibodies against phospholipase A2 type M receptor (PLA2R)
Describe the typical progression of diabetic nephropathy.
- Occurs in 30-40% diabetics
- Typically begins with microalbuminuria
- Progresses to proteinuria and, eventually, nephrotic syndrome
List and describe the stages of diabetic nephropathy.
- Stage 1: thickening of the basement membrane on electron microscopy
- Stage 2: increase in mesangial matrix, without nodules
- Stage 3: nodular lesions/Kimmelstein-Wilson nodules
- Stage 4: advanced glomerulosclerosis
What is amyloidosis?
Deposition of extracellular proteinaceous material exhibiting beta-pleated sheet structure
What are the two types of amyloidosis?
- AA - derived from serum amyloid associated protein (SAA), an acute phase protein, and associated with chronic inflammatory disease
- AL - derived from immunoglobulin light chains usually as a result of multiple myeloma (80%)
Describe the histological appearance of amyloidosis
Apple green birefringence with Congo red stain
Name two causes of isolated / asymptomatic microscopic haematuria.
- Thin basement membrane disease
- IgA nephropathy
How can the cause of asymptomatic proteinuria be confirmed?
Renal biopsy for histology, IHC, and electron microscopy (could be caused by several abnormalities)
What is thin basement membrane disease and what causes it?
- Basement membrane <250 nm thickness
- Caused by a hereditary defect in type IV collagen synthesis
- Microscopic haematuria is the only consequence in most cases
What is Alport syndrome?
What is its inheritance pattern?
- X-linked dominant condition caused by a mutation in the alpha-5 subunit of type IV collagen (some forms affect alpha-3 and alpha-4)
- Leads to progressive damage resulting in renal failure in middle-age
- Often accompanied by deafness and ocular disease
What is IgA nephropathy?
- Most common cause of glomerulonephritis
- Caused by mesangial IgA immune complex deposition
- 30% will progress to end-stage renal failure
- Presents 1-2 days after an URTI with frank haematuria (earlier than acute post-infectious GN)
- Immunofluorescence shows granular deposition of IgA and C3 in mesangium
NOTE: Henoch-Schonlein purpura is a type of IgA nephropathy
What is acute post-infectious (post-streptococcal) GN?
- Occurs 1-3 weeks after streptococcal throat infection or impetigo (usually Lancefield Group A α-haemolytic strep = Strep. pyogenes)
- Glomerular damage thought to be due to immune complex deposition
What will a biopsy show in post-infectious GN?
- Light microscope: ↑cellularity of glomeruli
- Fluorescence Microscope: granular deposits of IgG and C3 in GBM
- Electron Microscope: Subendothelial humps
List some causes of chronic kidney disease and state which is most common.
- Diabetes mellitus (most common) - 27.5%
- Glomerulonephritis - 14.1%
- Polycystic kidney disease - 7.4%
- Pyelonephritis - 6.5%
- Hypertension - 6.8%
- Renal vascular disease - 5.9%
What are some diseases associated with chronic kidney disease?
- Ischaemic heart disease
- Calcium and phosphate derangement (due to resulting hyperparathyroidism, osteomalacia and osteoporosis)
What is the pathophysiology of hypertensive nephropathy?
- Narrowing of arteries and arterioles leading to scarring and ischaemia of glomeruli
- Hypertension in glomeruli leading to altered haemodynamic environment, stress and segmental scarring
What are consequences of hypertensive nephropathy?
- Shrunken kidneys with granular cortices
- Nephrosclerosis on histology - arterial hyalinosis, arterial intimal thickening, ischaemic glomerular changes, segmental and global glomerulosclerosis
What system is used to classify lupus nephritis?
ISN/RPS classification
Describe the histological appearance of lupus nephritis
- Immune complex deposition in capillaries > ‘wire loop capillaries’ (thickened)
- Deposition of immune complexes & complement in the GBM in a lumpy-bumpy granular fashion.
What are the outcomes of lupus nephritis?
Highly variable
- Acute renal failure
- Nephrotic syndrome
- Isolated urinary abnormality
- CKD
Six stages:
• 1: Minimal mesangial disease, almost normal
• 2: Mesangial disease
• 3: Focal deposits
• 4: Diffuse deposits
• 5: Subepithelial membranous disease
• 6: Advanced sclerosis (>90%)
What condition is the presence of granular (“muddy brown”) casts seen in the urine associated with?
Acute Tubular Necrosis
What condition is the presence of epithelial casts in urine associated with?
Acute Tubular Necrosis
The presence of white cell casts in the urine along with eosinophilia and recent antibiotic use suggests what?
Acute interstitial nephritis
The spike and dome pattern is seen in what condition?
Mebranous glomerulonephritis (a nephrotic syndrome)
Which strain of Escheriscia coli is classically associated with haemolytic uraemic syndrome in children who have spent time around farmyard animals?
0157:H7
What protein is defective in adult polycystic kidney disease?
Polycystin-1
What condition is the presence of fatty casts in urine associated with?
Nephrotic syndrome (due to hyperlipidaemia)
What is the term used to describe small, tube shaped microscopic particles found in urine?
Urinary casts
What is the inheritance pattern of benign familial haematuria?
Autosomal dominant
Immunofluorescence shows the presence of antibody complexes and complement deposits. There are visible areas of scarring of the glomerular basement membrane, however, some areas appear spared. What subtype of nephrotic syndrome does this histological pattern and history suggest?
Focal Segmental Glomerulosclerosis
What condition is the presence of waxy casts in urine associated with?
Chronic Kidney Disease
Which class of lupus nephritis on biopsy may show complete sclerosis of nearly all glomeruli?
Class VI
Class VI lupus nephritis is characterized by advanced sclerosing lesions involving more than 90% of glomeruli on biopsy.
What is another name for benign familial haematuria?
Thin basement disease
