Block 4: CKD and glomerulonephritis

Question 1

CKD: monitoring ACEi and ARB’s

Answer 1

• Measure serum potassium concentration and calculate eGFR before starting after 1-2 weeks and with each dose increase. Do not modify the dose if either
• the GFR decrease from pre-treatment baseline is less than 25% or
• the serum creatinine increase from baseline is less than 30%.

Question 2

CKD complications: A WET

Answer 2

• A: Metabolic acidosis, managed with oral bicarbonate or dialysis
• W: water removal, avoid excessive water and sodium intake. Treatment with diuretics and dialysis
• Erythropoiesis: anaemia of chronic kidney disease, can be treated with erythropoietin stimulating agents (erythropoietin) and iron supplements
• Toxin removal: uraemic encephalopathy, treat with dialysis

Question 3

CKD complications: BED

Answer 3

• Blood pressure control: cardiovascular disease due to a combination of water and salt overload, hypertension and atherosclerosis
• Electrolyte balance: Hyperkalaemia, treatment includes restriction of dietary potassium, med review, use oral potassium binders, dialysis
• Vitamin D activation: due to increased secretion of PTH, impaired renal hydroxylation of vitamin D and renal phosphate retention. Management includes giving hydroxylated vitamin D (calcitriol), restrict dietary phosphate and administer phosphate binders (sevelamer)

Question 4

CKD: refer to a nephrologist is

Answer 4

• a urinary albumin:creatinine ratio (ACR) of 70 mg/mmol or more, unless known to be caused by diabetes and already appropriately treated
• a urinary ACR of 30 mg/mmol or more, together with persistent haematuria (two out of three dipstick tests show 1+ or more of blood) after exclusion of a urinary tract infection
• consider referral to a nephrologist for people with an ACR between 3-29 mg/mmol who have persistent haematuria and other risk factors such as a declining eGFR, or cardiovascular disease

Question 5

Creatinine

Answer 5

• Creatine is an energy store for twitch muscles this is then broken down into creatinine.
• It is excreted at a constant rate from the kidneys.
• Blood concentration of creatinine is specific for determining kidney injury, if it goes up suggests kidney damage.
• Creatinine depends on muscle mass. If high creatinine and eGFR then normal but if eGFR is low then damage
• Affects creatinine levels: pregnancy, muscle mass, limb amputation, pregnant, elderly

Question 6

Urea

Answer 6

• Ammonia is converted to urea in the liver, its then transported to the kidneys where it is excreted.
• Not specific for kidney injury
• High levels: dehydration, Gi bleed, increased protein breakdown
• Low levels: malnutrition, liver disease, pregnancy

Question 7

Sodium

Answer 7

• Main component of extra-cellular fluid
• Sodium content is monitored by aortic / carotid bodies and reflects fluid status by cardiac stretch
• Juxtaglomerular apparatus monitors sodium and causes renin release

Question 8

Potassium

Answer 8

• Main intracellular electrolyte component
• Controlled by aldosteron in the DCT acting to increase K+ excretion
• Levels vary with hydrogen ion concentration as they compete for the transporter in the kidney

Question 9

Indications for kidney biopsy

Answer 9

• Unexplained renal impairement
• Unexplained proteinuria
• Unexplained glomerular haematuria
• Renal masses (urology)
• Renal transplant: rejection, dysfunction
• Connective tissue diseases
• Treatment monitoring/Research

Question 10

Kidney biopsy

Answer 10

• Invasive procedure: uses anaesthetics
• Patient lies on stomach: tends to go for left kidney
• Must lie on back for 6 hours after with 15 minute observations
• Sample is hand delivered to lab
• Ultrasound guided- uses biopsy gun
• Need 2 cores of tissue and 10 glomeruli
• Can show: inflammation, scarring, infection and deposition
• Risks: bleeding (visible haematuria), pain

Question 11

Autosomal dominant Polycystic Kidney disease (ADPKD) multisystem disease which can cause

Answer 11

• Berry aneurysms: intracranial haemorrhage
• Valvular heart disease
• Dilatation of aorta
• Diverticulosis
• Pancreas, spleen, liver cysts
• Epididymal cysts

Question 12

ADPKD: genetics

Answer 12

• PKD1 (Chr16p) polycystin-1
• PKD2 (Chr4q) polycystin-2
• (subfamily of transient receptor potential (TRP) channels)
• Genes are involved in calcium ion transport and have a role in the primary cilia
• Genetically unresolved cases (7-10%) - GANAB

Question 13

ADPKD: definition and presentation

Answer 13

Definition: most commonly inherited disorder of the kidneys. Characterised by the formation of renal cysts and extrarenal manifestations like hepatic cysts, intracranial aneurysms and aortic root dilation

Presentation: normally between 30 and 60 causes haematuria, loin pain and hypertension. 50% will develop end stage renal disease. Accounts for 10% of patients with renal failure

Question 14

ADPKD types

Answer 14

• Type 1 ADPKD:85% of cases. Caused by a mutation in PKD1 on chromosome 16. Symptoms tend to be more severe in this type
• Type 2 ADPKD:15% of cases. Caused by a mutation in PKD2 on chromosome 4. Symptoms tend to be less severe in this type

Question 15

ADPKD: signs on examination

Answer 15

• Palpable kidneys/abdominal mass
• Hepatomegaly due to hepatic cysts
• Abdominal wall hernias: These are more common in ADPKD, affecting 45% of patients
• Cardiac murmur: This is due to an increased incidence of mitral valve prolapse, mitral regurgitation, aortic regurgitation and dilated aortic root in patients with ADPKD.
• Symptoms: haematuria, chronic loin pain, hypertension, recurrent UTI’s, kidney stone, headaches

Question 16

Management and investigations of ADPKD

Answer 16

Management: control symptoms. Should refer to a nephrologist, control blood pressure and manage renal pain. In end stage renal disease may need transplant or dialysis.

Tolvaptan can slow cyst formation

Investigations: if positive family history ultrasound to look for cysts

Question 17

Alport syndrome

Answer 17

X linked inheritance: females carry the disease and men get the symptoms. Men cant give it to men.

A gene which encodes collagen in the basement membranes of the kidney, inner ear and eye. Defect in type IV collagen

Glomerular disease with haematuria and proteinuria. With early onset sensorineural deafness and blindness

Causes mutations in COL4A3, COL4A4 and COL4A5

Question 18

Glomerulonephritis definition

Answer 18

Refers to several renal diseases which affect both kidneys. Causes inflammation of either the glomeruli or the small blood vessels in the kidneys. Causes proteinuria and haematuria

Question 19

Glomerulus

Answer 19

• A collection of capillaries surrounded by the Bowmans capsule
• Capillaries are supported by cells and connective tissue known as the mesangium
• Fluid and other substances pass from the capillaries to the urinary space which pass into the PCT
• The endothelium, basement membrane and podocytes make up the filtration barrier.
• Damage to the glomerulus causes blood and protein to leak

Question 20

Glomerulonephritis: classification

Answer 20

• Primary: glomerular injury due to primary renal pathology. For example, IgA nephropathy, minimal change disease, focal segmental glomerulosclerosis
• Secondary: glomerular injury occurring as part of a systemic process. For example, Vasculitis (ANCA associated vasculitis), amyloidosis, diabetes mellitus
• Focal versus diffuse: a glomerulopathy can be focal (only some glomeruli are involved) or diffuse (all glomeruli are affected)- 50% cut off
• Global versus segmental: global affects all parts of the glomeruli and segmental only part of the glomeruli is affected- 50% cut off

Question 21

Glomerulonephritis: MoA

Answer 21

• Immune-mediated: deposition or in situ formation of immune complexes (collections of antibodies) that fix complement and activate a pro-inflammatory response. Alternatively, circulating antibodies may directly target key proteins on the basement membrane or endothelial cells precipitating an inflammatory reaction (e.g. ANCA- associated vasculitis).
• Non-immune mediated: the structure and/or function of podocytes may be affected that disrupts the filtration barrier (e.g. minimal change disease). This leads to larger macromolecules leaking through glomeruli. Alternatively, accumulation of non-immune material (e.g. proteins) can disrupt the glomeruli structure causing dysfunction (e.g. diabetes mellitus, amyloid).

Question 22

Glomerulonephritis: Histopathology

Answer 22

• Proliferative: increase in number of cells in the glomerulus. Associated with marked inflammatory response. Causes glomerular inflammation with haematuria and/or nephritic syndrome
• Non proliferative (structural): may show structural changes and sclerosis, associated with protein loss and nephrotic syndrome
• Crescents: extra capillary lesions in the Bowmans capsule due to accumulation of immune cells, fibroblasts, epithelial cells and fibrin. Due to severe injury in the capillary wall causing glomerular membrane rupture. Means rapidly progressive

Question 23

Features that suggest haematuria is from the glomerular

Answer 23

• Dysmorphic red blood cells: appear normal
• Red blood cell casts: blood cells within urinary casts
• A cast is a cluster of particles coated in uromodulin

Question 24

Causes of Glomerulonephritis

Answer 24

• Isolated haematuria: IgA nephropathy, Alport syndrome, Thin basement membrane disease. Persistent haematuria without proteinuria and with normal renal function
• Isolated proteinuria: glomerular, tubular, overflow (myeloma), post renal. Degree of proteinuria is non-nephrotic (<3.5 g/day)
• Nephrotic syndrome
• Nephritic syndrome
• Rapidly progressive glomerulonephritis

Question 25

Benign causes of proteinuria

Answer 25

• Transient proteinuria: common in young individuals. Absent on repeat testing and exercise is a common precipitant.
• Orthostatic proteinuria: presence of proteinuria only in the upright position

Question 26

Nephritic syndrome

Answer 26

• Prescence of haematuria, variable proteinuria (can be nephrotic range), oliguria (i.e. AKI), renal impairment and hypertension
• Due to an inflammatory process within the glomeruli

Question 27

Classification of nephritic syndrome

Answer 27

• Mild: presentation with minimal haematuria and proteinuria only
• Severe: typically presents with the classical ‘nephritic syndrome’
• Self-limiting: development of an acute
  glomerulonephritis that gets better without treatment
• RPGN: severe glomerulonephritis that has a fulminant course with rapid deterioration in renal function over days to weeks to a few months.
• Chronic: slowly progressive renal disease presenting with features of CKD

Question 28

Proliferative glomerulonephritis

Answer 28

Characterised by increased number of cells in the glomerulus, typically presents with nephritic syndrome

Question 29

Causes of nephritic syndrome

Answer 29

• Immune complex deposition: Poststreptococcal glomerulonephritis, autoimmune (e.g. lupus), IgA nephropathy, SLE. Due to deposition of components of the immune system i.e. immunoglobulins that initiate a local inflammatory response
• Anti-GBM deposition: anti-glomerular basement membrane disease
• Small-vessel vasculitis: eosinophilic granulomatosis with polyangiitis, microscopic polyangiitis, polyangiitis with granulomatosis. Patients normally have circulating autoantibodies known as ANCA which target self antigens leading to vasculitis (inflammation of arterioles, capillaries and venules) that might be limited to the kidneys or multisystem

Question 30

Anti-GBM autoantibodies

Answer 30

A rare small vessel vasculitis that result from GBM antibodies that target type IV collagen in the basement membrane. Causes deposition of IgG in the glomerular capillaries. Different to ANCA associated vasculitis

Question 31

Presentation of nephritic syndrome

Answer 31

• Minimal haematuria and proteinuria
• Acute self-limiting disease
• Acute severe disease: severe renal impairment usually develops without treatment
• Rapidly progressive glomerulonephritis: deterioration in renal function over days to weeks to a few months
• Chronic kidney disease: slowly progressive deterioration in renal function due to inflammation

Question 32

Symptoms of nephritic syndrome

Answer 32

• Lethargy
• Recent infection: fever, sore throat, coryzal symptoms. Typical of post streptococcal glomerulonephritis and IgA nephropathy
• Haematuria
• Oliguria: reduce urine output
• Oedema: peripheral or periorbital
• Shortness of breath: due to fluid overload
• Haemoptysis: due to pulmonary haemorrhage (e.g. Anti-GBM, ANCA-vasculitis)
• Signs: Haematuria, hypertension, oedema (peripheral, periorbital), fluid overload (raised JVP, bibasal crackles on auscultation, peripheral oedema, ascites), reduced urine output

Question 33

Extra-renal manifestations of nephritic syndrome

Answer 33

• Skin: vasculitic rash (palpable purpura)
• ENT: rhinosinusitis, nasal discharge, polychondritis (inflammation of cartilage)
• Eyes: red, painful eyes (e.g. conjunctivitis, scleritis, uveitis)
• Lungs: haemoptysis, pleuritic pain, wheeze
• Heart: chest pain due to pericardial or myocardial involvement
• Nervous system: mononeuropathies
• Seen in patients with systemic causes: vasculitis, SLE, anti-GBM disease

Question 34

Nephritic syndrome: diagnosis and investigations

Answer 34

• Need to identify worsening renal function, haematuria and proteinuria whilst excluding UTI and renal stones. Identify haematuria of glomerular origin:
• Dysmorphic red blood cellsin urine: red cell structure appears abnormal under the microscope
• Red blood cell casts: red bloods cells within urinary casts seen under the microscope.
• Full renal screen
• Renal biopsy to confirm glomerulonephritis

Question 35

Management of nephritic syndrome

Answer 35

• Depends on underlying cause
• Rapidly progressive glomerulonephritis: aggressive immunosuppressants
• Temporary RRT might be needed whilst treatment is initiated

Question 36

Poststreptococcal glomerulonephritis (PSGN)

Answer 36

• Cause of nephritic syndrome: due to prior infection with group A beta haemolytic Streptococcus. Most common cause in children, reduced incidence in developed countries because of antibiotics. Uncommon in adults
• Normally 1-3 weeks after a skin or throat by Group A beta haemolytic Streptococcus
• Due to development of immune complexes containing Streptococcal antigens that are deposited in the renal glomeruli causing cross-reactivity

Question 37

PSGN diagnosis and management

Answer 37

• Highly variable presentation: asymptomatic or acute severe
• Diagnosis: measuring antibody titres against Streptococcus (ASOT). In adults renal biopsy.
• Suspect if nephritis with recent streptococcal infection
• Management: No specific treatment about managing complication i.e. hypertension, oedema. In severe cases renal replacement therapy is needed. In children resolution is rapid. Active infection should be treated with antibiotics

Question 38

Post-infectious glomerulonephritis (PIGN)- cause of nephritic syndrome

Answer 38

• An immunologically mediated glomerular injury triggered by infection, most commonly associated with streptococcus (PSGN)
• Nephritic syndrome presents two weeks after infection
• Investigations: on renal biopsy shows diffuse proliferative and exudative glomerular histology, Dominant C3 staining and subepithelial humps
• Diagnosis: precense of symptoms and signs of glomerulonephritis, history of recent infection (Streptococcal), raised streptococcal titres)
• Management: supportive with monitoring of fluid balance
• Prognosis: self limiting especially in children, long term follow up indicates persistent low grade renal abnormalities

Question 39

Lupus nephritis

Answer 39

• Renal involvement in patients with SLE
• Classified and diagnosed based on renal biopsy
• Deposition of immune complexes within the glomeruli causing injury. Immune complexes form due to anti-double stranded DNA
• Management: depends on classification in class IV need high dose immunosuppression

Question 40

Classification of lupus nephritis

Answer 40

• Class I (minimal mesangial): rarely diagnosed as patients usually asymptomatic
• Class II (mesangial proliferative): typically causes non-visible haematuria and proteinuria
• Class III (focal): variable presentation. May have haematuria, proteinuria, renal
  impairment and/or nephrotic syndrome
• Class IV (diffuse): most common and most severe form. May present with nephrotic or nephritic syndrome.
• Class V (membranous): presents with nephrotic syndrome similar to membranous nephropathy
• Class VI (advance sclerosis): global sclerosis and slowly worsening renal function

Question 41

IgA nephropathy

Answer 41

• Most common primary chronic glomerular disease worldwide. Causes nephritis
• Causes deposition of IgA immunoglobulins in the glomeruli
• Presents with visible or non-visible haematuria and proteinuria, rarely can cause Nephritic or even Nephrotic syndrome
• Treatment is supportive with good blood pressure control
• Also known as Berger’s disease- most common form of glomerulonephritis in adults worldwide- presents 24-48 hours after an upper respiratory tract infection

Question 42

IgA nephropathy: investigations and management

Answer 42

• Investigations: microscopically will see increased number of mesangial cells and an increased matrix. Immunohistochemistry will show IgA deposition in the matrix
• Management: high dose prednisolone (reduces proteinuria and delays renal impairment), other immunosuppressive drugs (used in patients with deteriorating renal function)
• Variable prognosis

Question 43

ANCA associated vasculitis

Answer 43

• Umbrella term for three small vessel vasculitis’s: Microscopic polyangitis (MPA), Granulomatosis with polyangitis (GPA), Eosinophilic granulomatosis with polyangitis (EGPA)
• Causes nephritis
• Affect arterioles, capillaries and venules
• Characterised by positive ANCA
• These autoantibodies specifically target
  myeloperoxidase and proteinase 3 and can affect multiple organs systems.
• Patients may develop rapidly progressive glomerulonephritis and treatment involved high dose immunosuppression

Question 44

Anti-GBM disease

Answer 44

• Rare small vessel vasculitis: causes nephritis
• Formation of anti-GBM antibodies that are directed against type IV collagen in the kidneys and lungs
• Can cause life-threatening glomerulonephritis and/or pulmonary haemorrhage
• Treatment: immunosuppression and plasmapheresis (removing patients plasma and replacing it human albumin to remove the autoantibodies)

Question 45

Nephritic syndrome versus glomerulonephritis

Answer 45

Nephritic syndrome and glomerulonephritis can be used interchangeably. Nephritic syndrome describes a more classic presentation of glomerular disease with haematuria, variable proteinuria (may be nephrotic), renal impairement, hypertension. Glomerulonephritis is a more encompassing term reflecting the variable clinical presentation of glomerular inflammation i.e. minimal haematuria

Question 46

Membranoproliferative glomerulonephritis

Answer 46

• A group of immune mediated disorders caused by glomerular basement membrane (GBM) thickening and proliferative changes
• Associated with hepatitis C and other autoimmune disorders like SLE
• Typical findings on renal biopsy include: Thickened basement membrane, thickened Mesangium, ‘Tram-tracking’ appearance
• Immunofluorescence shows subendothelial deposition of IgG
• Management: children with nephrotic range proteinuria- corticosteroids, Adults- dipyridamole and asprin, kidney transplant in end stage renal disease

Question 47

Rapidly progressive glomerulonephritis- RPGN (crescentic glomerulonephritis)

Answer 47

• An acute nephritic syndrome accompanied by microscopic glomerular crescent formation with progression to renal failure within weeks to months.
• Tends to occur in 20-50
• Can be caused anti-glomerular basement membrane antibody disease and vasculitic disorders

Question 48

Small vessel vasculitis: cause of nephritic syndrome

Answer 48

• Little to none immune deposition
• Due to ANCA which target self antigens causing vasculitis that can be limited to the kidney or multisystem
• Vasculitic disorders which may cause proliferative glomerulonephritis include
  granulomatosis with polyangiitis (GPA) and microscopic polyangiitis.

Question 49

Granulomatosis with polyangitis- cause of nephritic syndrome

Answer 49

• Extremely rare long term systemic disorder that involves granuloma formation and inflammation of blood vessels (vasculitis)
• Affects small and medium sized vessels in many organs (upper respiratory tract, lungs, kidneys)
• Symptoms depend on what vessel is affected, vasculitis is caused by anti-neutrophil cytoplasmic antibodies (c-ANCA)
• A biopsy (e.g. of kidney or cutaneous tissue) will show leukocytoclastic vasculitis with necrotic changes and granulomatous inflammation (clumps of typically arranged white blood cells) on microscopy.
• Management: involves immunosuppression. Remission is induced with rituximab or cyclophosphamide in combination with high dose corticosteroids. Maintenance therapy may include methotrexate and corticosteroids.

Question 50

Microscopic polyangiitis: cause of nephritic syndrome

Answer 50

A systemic small vessel vasculitis without clinical evidence of necrotising granulomatous inflammation. Symptoms: weight loss, fevers, fatigue and renal failure. Ongoing inflammation is driven by anti-neutrophil cytoplasmic antibodies (p-ANCA), which is positive in almost all cases. Management involves long-term prednisolone and cyclophosphamide therapy. Plasmapheresis can remove p-ANCA antibodies.