Renal Disease

Question 1

What are the major functions of the kidney?

Answer 1

· Excretion of metabolic waste products and foreign chemicals (including drugs)

· Regulation of fluid, electrolyte and acid/base balance

· Regulation of blood pressure

o Renin-angiotensin-aldosterone system

· Regulation of calcium and bone metabolism

o 1,25 Dihydroxycholecalciferol

· Regulation of haematocrit

o Erythropoietin

Question 2

What is renal anatomy?

Answer 2

· Retroperitoneal; T12 to L3 on left (right is slightly lower); Mean length 11cm

· Normal weight: 125-170g (male), 115-155g (female)

· Receive around 20% of cardiac output (highest per g of tissue)

· Basic unit is the nephron:

o Glomerulus

o Afferent and efferent arterioles

o Tubules

· Approximately one million nephrons per kidney; large functional reserve

Question 3

What is the nephron?

Answer 3

Blood is filtered at the glomerulus

o High hydrostatic pressure (60mmHg)

o Podocytes create charge-dependent (anionic) + size-dependent barrier (found at outer layer)

o Filtration rate: 125 mL/min (in total, for both kidneys)

o The filtrate is modified in the tubules

Question 4

What does the PCT do?

Answer 4

Proximal Convoluted Tubule actively resorbs sodium

o H+ exchange to allow carbonate resorption (acid-base control)

o Co-transport of amino acids, phosphate, glucose

o Potassium is also reabsorbed

Question 5

What does the LoH do?

Answer 5

doubles back on itself

o Descending / thin ascending limb permeable to H20 but not ions or urea

o Ascending limb actively resorbs sodium and chloride

o Countercurrent Multiplier (aligned with vasa recta)

Question 6

What is the DCT?

Answer 6

Distal Convoluted Tubule is impermeable to water

o Regulates pH via active transport (proton / bicarbonate)

o Regulates Na+, K+ via active transport (aldosterone)

§ Aldosterone = MR agonist

§ Creates ENaC + K+ excretion through ROMK

o Regulates Ca2+ (PTH, 1,25 dihydroxycholecalciferol)

Question 7

What dies the CD do?

Answer 7

o Resorbs water (principal cells, antidiuretic hormone)

o Regulates pH (intercalated cells, proton excretion)

Question 8

What would you see on light and electron microscopy of the renal cortex?

Answer 8

Nephrons are tightly packed

Question 9

What would you see on light and electron microscopy of the glomerulus?

Answer 9

· High hydrostatic pressure

· Filtrate collected in Bowman’s space

· Podocytes feet create slit-like barrier = filtration

· Inner layer: Endothelial cells (fenestrated / gaps)

· Middle layer: Basement membrane

· Outer layer: Podocyte (foot process)

Question 10

What would you see on light and electron microscopy of immune complexes in the kidney?

Answer 10

· Latticework of antibody and antigen

o May be endogenous or exogenous antigens

· May deposit in the glomerulus leading to…

o Inflammatory response

o Complement activation

o Stimulation of inflammatory cells

· May deposit at different rates at different sites (i.e. under podocytes or under endothelial cells)

Question 11

What are the clinical features of renal disease?

Answer 11

· Haematuria

o Inflammation in the glomerulus (blood leaks into urine)

o Tumour

o Renal stone

· Proteinuria

o Inability to repel high MW substances

· Polyuria

o Often unable to concentrate urine or drinking too much

o Often pathology in the collecting duct

· Hypertension Uraemia Oliguria / Anuria

· Oedema Colic

Question 12

What is the classification of renal disease?

Answer 12

· Syndromes (has many causes; a constellation of symptoms)

o Acute renal failure

o Nephrotic syndrome

o Microscopic haematuria

· Morphological Changes

o Glomerulonephritis

o Thrombotic microangiopathy

· Aetiology

o Congenital

o SLE

o Amyloidosis

o Drugs

o Infections

Question 13

What are the genitourinary malformations in the kidney?

Answer 13

· Agenesis

· Renal Fusion (e.g. horse-shoe) – may be asymptomatic -> no medication attention

· Ectopic Kidney

· Renal Dysplasia

· Pelvo-ureteric Junction (PUJ) Obstruction

o Malformed smooth muscle

· Ureteral Duplication

· Vesicoureteral Reflux

· Posterior urethral Valves

Overall, these issues affect the development and flow of urine

Question 14

What are the cystic diseases of the kidney?

Answer 14

· Adult (Autosomal Dominant) Polycystic Kidney Disease

o Affects 1 in 500

o 10% of end-stage renal failure

o Presents in adulthood with

§ Hypertension

§ Flank pain

§ Haematuria

o Types: PKD1, PKD2

o Are associated with Berry aneurysm

· Cysts commonly develop in patients with end stage renal disease who are on dialysis

o Multiple

o Bilateral

o Cortical and Medullary

o Slowly replace the kidney

· ↑risk of cancer

o 7% risk at 10 years

o Papillary renal cell carcinoma (most common neoplasm)

Question 15

What are the medical renal disease syndromes?

Answer 15

· Acute Renal Failure (= Acute Kidney Injury)

· Nephrotic Syndrome

· Isolated Urinary Abnormalities (e.g. haematuria only)

· Chronic Kidney Diseas

Question 16

What are the causes of acute renal failure?

Answer 16

· Rapid deterioration in renal function (hours, days)

· Common, often in the setting of pre-existing disease

· Causes include

o Pre-Renal

§ Failure of perfusion (e.g. dehydration, cardiac failure)

o Renal:

§ Acute tubular injury/necrosis (MOST COMMON)

§ Acute glomerulonephritis

§ Thrombotic microangiopathy

o Post-Renal

§ Obstruction

Question 17

What is ATN?

Answer 17

· Commonest cause of acute renal failure

o Common in critical illness

· Tubular epithelial cells damaged by:

o Ischaemia

o Toxins (contrast, Hb, myoglobin, ethylene glycol)

o Drugs (NSAIDs)

§ NSAIDs inhibit vasodilatory prostaglandins to predispose ATN

· Failure of Glomerular Filtration

o Blockage of tubules by casts

o Leakage of tubules to interstitial space

o Secondary haemodynamic changes

Question 18

What is acute tubulo-interstitial nephritis?

Answer 18

· Immune injury to tubules and interstitium

· Can also be due to infection and drugs

o NSAIDs Antibiotics

o Diuretics Allopurinol

o PPIs

· Heavy interstitial inflammatory infiltrate with tubular injury

o Can see eosinophils, granulomas

Question 19

What is acute glomerlonephritis?

Answer 19

· Acute inflammation of glomeruli

· Presents with oliguria with urine casts (containing erythrocytes and leucocytes – i.e. red cell casts)

· When sufficient to cause acute renal failure, there are almost always crescents

o Proliferation of cells within Bowman’s space (glomerulus is pushed to one side)

Question 20

What does this show?

Answer 20

Crescent

Question 21

What are the types of acute crescenteric glomerulonephritis?

Answer 21

o Immune Complex-mediated:

§ SLE (SOAP BRAIN MD)

§ IgA nephropathy (adult version of HSP; few days after URTI)

§ Post-Infectious Glomerulonephritis (must fit with clinical picture; 1-2 weeks after URTI)

o Anti-Glomerular Basement Membrane Disease (anti-GBM) – Goodpasture’s Disease

§ Rare, severe disease

§ Antibodies against the glomerular basement membrane (C-terminal domain of Type IV collagen)

· May cross-react with alveolar basement membrane (-> pulmonary haemorrhage)

§ Investigations:

· Serology – can be detected in the blood

· Linear deposition of IgG demonstrable on glomerular basement membrane

· Silver stain: crescent morphology

o Pauci-immune (anti-neutrophil cytoplasm antibodies)

§ Only scanty glomerular immunoglobulin deposits

§ Usually ANCA-associated (trigger neutrophil activation and glomerular necrosis)

§ Vasculitis elsewhere

· Leads rapidly to irreversible renal failure

· Correct diagnosis (morphological diagnosis) and treatment are urgent

Question 22

What is thrombotic microangiopathy?

Answer 22

· Damage to endothelium in glomeruli, arterioles, arteries -> leads to a thrombosis

o -> Red cells may be damaged by fibrin

o -> Microangiopathic haemolytic anaemia

o -> Haemolytic Uremic Syndrome (if renal failure)

· Diarrhoea-associated

o Bacterial gut infection (E. coli) -> Gastroenteritis

o Toxins released that target renal endothelium

· Non-Diarrhoea-associated (many causes)

o Defects in regulation of complement

o Deficiency in ADAMTS13

o Drugs (calcineurin inhibitors; i.e. tacrolimus)

o Radiation

o Hypertension

o Scleroderma

o Antiphospholipid Antibody Syndrome (+/- SLE)

Question 23

What is nephrotic syndrome?

Answer 23

· Breakdown in selectivity of glomerular filtration barrier leading to protein leak

· Characterised by

o Proteinuria (>3.5g/day)

o Hypoalbuminemia (<25g/L)

o Oedema

o Hyperlipidaemia (due to excess lipids in interstitium)

§ They are intravascularly dry

· Primary Glomerular Disease, Non-Immune Complex Related

o Minimal Change Disease

o Focal Segmental Glomerulosclerosis

· Primary Renal Disease, Immune Complex Mediated

o Membranous Glomerulonephritis

· Systemic Disease

o Diabetes mellitus

o Amyloidosis

o SLE

Question 24

What is minimal change disease?

Answer 24

· Glomeruli look normal by light microscopy -> effacement of foot processes on electron microscopy

· Common cause of nephrotic syndrome in children

· Generally, this responds to immunosuppression

Question 25

What is focal segmental glomerulosclerosis?

Answer 25

· Some glomeruli are partially scarred + thickened glomerular basement membrane

· Less likely to respond to immunosuppression

· Must exclude possible other diseases that can produce a similar appearance

· Tend to be inherited or spontaneous

o These tend not to be nephrotic

Question 26

What is membranous glomerulonephritis?

Answer 26

· Associated with immune deposits on outside of glomerular basement membrane + thickening of BM

o Subepithelial

· Common cause of nephrotic syndrome in adults

· Primary disease is autoimmune

o Antibody: anti-phospholipase A2 type M receptor (anti-PLA2R) in 75% of cases

· Need to exclude possibility of a secondary disease

o Epithelial malignancy Drugs

o Infections SLE

· Interpret findings in clinical and serological context

Question 27

What is diabetic nephropathy?

Answer 27

· 30-40% of diabetics; high glucose levels thought to be directly injurious

· Typically starts as microalbuminuria before progression to proteinuria and nephrotic syndrome

· Nodular Glomerulosclerosis

o Stage 1 – Thickened BM on EM (basement membrane; electron microscopy)

o Stage 2 – Increase in mesangial matrix, without nodules

o Stage 3 – Nodular lesions / Kimmelstiel-Wilson lesion (KW) - round areas of sclerosis

o Stage 4 – Advanced glomerulosclerosis

Question 28

What is amyloidosis?

Answer 28

· Deposition of extracellular proteinaceous material exhibiting β-sheet structure; Congo red stain

· Light microscopy

o Salmon pink without staining

o Apple-green appearance under polarised light

· Commonest forms in kidney are

o AA Amyloidosis

§ Derived from serum amyloid associated protein (SAA) – acute phase protein

§ Patients tend to have a chronic inflammatory state

o AL Amyloidosis

§ Derived from immunoglobin light chains

§ 80% of patients have multiple myeloma

Question 29

What is isolated urinary abnoramlities?

Answer 29

· Microscopic Haematuria

o Thin basement membranes

o IgA Nephropathy

· Asymptomatic Proteinuria

o May be associated with a broad range of glomerular structural abnormalities or immune complex deposition

o Diagnosis often requires renal biopsy for histology, immunohistochemistry and electron microscopy

Question 30

What is thin basement membranes?

Answer 30

· Hereditary defect in Type IV collagen synthesis

· Basement membrane <250nm thickness

· Haematuria is only consequence in most case

Question 31

What is alport disease?

Answer 31

o X-linked dominant mutations affecting ⍺5 subunit

o Forms exist in which mutation affects ⍺3 or ⍺4 subunit

o Typically, progressive, renal failure in middle age

o Often have deafness, ocular disease

Question 32

What is IgA nephropathy?

Answer 32

· Commonest glomerulonephritis

· IgA predominant mesangial immune complex deposition

· Aetiology not well understood in primary form

o Secondary forms observed in liver, bowel and skin disease

o Can be seen with small-vessel vasculitis (Henoch-Schönlein Purpura)

· 30% develop end stage renal failure

· Oxford Classification (MEST-C)

Question 33

What causes CKD?

Answer 33

· Commonest glomerulonephritis

· IgA predominant mesangial immune complex deposition

· Aetiology not well understood in primary form

o Secondary forms observed in liver, bowel and skin disease

o Can be seen with small-vessel vasculitis (Henoch-Schönlein Purpura)

· 30% develop end stage renal failure

· Oxford Classification (MEST-C)

Question 34

What are the stages of CKD?

Answer 34

Question 35

What is hypertensive nephropathy?

Answer 35

· Pathophysiology is not fully understood

o Narrowing of arteries and arterioles leading to scarring and ischaemia of glomeruli

o Hypertension in glomeruli leading to altered haemodynamic environment, stress and segmental scarring

· Shrunken kidneys with granular cortices

· Histopathology may show “nephrosclerosis” / fibrinoid necrosis:

o Arteriolar hyalinosis Arterial intimal thickening Ischaemic glomerular changes

o Segmental glomerulosclerosis Global glomerulosclerosis

Question 36

What is SLE?

Answer 36

· SLE is a systemic autoimmune disease

· Affects the kidney, skin, joints, heart, serosa surfaces and CNS; 1 in 2500 people; Females > M (9:1)

o SOAP BRAIN MD (Serositis, Oral ulcers, Arthritis, Photosensitivity, Blood [all low], Renal [protein], ANA, Immunological [dsDNA], Neurological [seizures], Malar rash, Discoid rash)

· Deposition of immune complexes in the kidney is common

o Antibodies directed at a broad range of intracellular and extracellular antigens

o Anti-nuclear antibodies and Anti-dsDNA antibodies are typical

· Highly variable disease

· Depending on site, speed and intensity of immune complex deposition, may present as:

o Acute Renal Failure

o Nephrotic Syndrome (membranous glomerulonephritis)

o Isolated Urinary Abnormality

o Chronic Kidney Disease

Question 37

What is the ISN/ RPS classification?

Answer 37

· Wide spectrum of pathology

· Class II: mesangial pattern of injury

· Class III, IV, V: endothelial pattern of injury

Question 38

Answer 38

Yes