Renal I

Question 1

What is acute kidney injury?

Answer 1

Clinical term that covers many causes of abrupt renal impairment measured by a fall in GFR occurring over a period of hours or days which results in impaired fluid and electryolyte homeostasis (often reduced urine output) and the accumulation of nitrogenous wastes (urea and creatinine). You may also hear the term acute renal injury that may be used instead of acute renal failure. Acute kidney injury is the most common cause of acute renal failure

Question 2

What are the clinical scenarios of acute kidney injury?

Answer 2

1. Decreased urine output over the past few hours/days (and renal function is checked); or
2. Results on a blood test shows an increase in urea, creatinine and a decrease in GFR (taken because someone is unwell).

Question 3

What is the classification system for the aetiology of acute kidney injury?

Answer 3

Pre-renal: reduced renal perfusion (very common)

1. Hypovolaemia and/or relative hypoension: fluid loss, haemorrhage, decreased cardiac output, renovascular obstruction.
2. Restricted fluid access: elderly, comatosed and sedated patients.
3. Poor cardiac output: signs of heart failure
4. Renovascular obstruction: atherosclerosis, particularly when starting ACE inhibitors and NSAID interactions.

Renal: diseases that directly involve the renal parenchyma. Damage to the kidney filtration (glomerulus) and absorption (tubules) mechanisms secondary to:

1. Nephrotoxins:
   
   • ​​Tubular toxins: abx including gentamycin
   • Radiological contract: those at particular risk are: diabetics, pre-existing renal disease, patients with multiple myeloma.
   • Myoglobinuria-rhabdomyolysis: drug use, crush injury (compartment syndrome)
2. Glomerular disease: glomerulonephritis (look for haematuria/proteinuria), dysmorphic RBCs.
3. Tubulointerstitial nephritis: inflammation of the kidney, primarily the intersftitium, rather than specifically the glomeruli. Can be due to infection, inflammation secondary to drugs, urate, calcium.

Post-renal: diseases associated with urinary tract obstruction. Increases in the tubular pressures reducing how much filtrate can be produced.

1. Prostatic obstruction
2. Urethral stricture
3. Post-surgery
4. Tumours
5. Kidney stones
6. Neurogenic bladder

Question 4

Aetiology of acute tubulointerstitial nephritis

Answer 4

1. Acute and chronic pyelonephritis:** **may arise from bacteria in the blood stream, ascending from lower urinary tract - UTI/reflux nephropathy
2. Acute interstitial nephritis: most often drug induced - common culprits are synthetic penicillins, thiazides, NSAIDs. Characterised by fever, eosinophilia, rash and renal dysfunction.
3. Analgesic nephropathy: excessive use fo analgesic mixtures aspirin, paracetamol.
4. NSAIDs: acute renal failure, interstitial nephritis +/- minimal change, membranous GN.
5. Other: urate nephropathy, hypercalcaemia, multiple myeloma (Bence Jones protein)

Question 5

What is acute tubular necrosis?

Answer 5

The death of tubule cells when they do not get enough oxygen or are damaged by toxins. It is a common cause of ARF in the hospital setting.

Question 6

Aetiology of acute tubular necrosis

Answer 6

1. Ischaemia: this is a common cause. Reduction in perfusion pressures activates the renin-angiotensin, catecholamines, sympathetic nervous systems, and intense intrarenal vasoconstriction occurs. This maximally affects the superficial cortex where most (90%) of the glomeruli are, secondary to the directing of blood flow to juxtamedullary nephrons. This results in an acute fall in urine output, maximal salt and water retention and an acute fall in GFR. Epithelial cell casts and granular casts may be seen in the urinary sediment.
2. **Direct toxic injury to tubules **(common cause): myoglobin (rhabdomyolysis), gentamycin, radiocontrast.
3. Acute tubulointerstitial nephritis: most commonly due to hypersensitivity reactions to drugs
4. Urinary obstruction

Question 7

Pathogenesis of acute tubular necrosis

Answer 7

Characterised pathologically by the destruction of tubular epithelial cells and clinically by acute reduction or less of renal function.

Induction of intrarenal ischaemia triggers production of oxygen free radicals (which can still damage the tissue when blood flow is restored). Tubular cellular damage then ensues, causing back leak of the filtrate and thus also a reduction of the GFR. Dying cells form obstructive cell casts, which also reduce GFR and cause oliguria. The patchiness of tubular necrosis and maintenance of integrity of the BM allow ready repair and recovery of function if the precipitating cause is removed.

Question 8

What are the clinical patterns of glomerular disease?

Answer 8

This presents as one of five clinical syndrome:

1. Asymptomatic haematuria and/or proteinuria
2. Nephritic syndrome
3. Acute renal failure and proteinria
4. Nephrotic syndrome
5. A mix nephritic/nephrotic syndrome

Question 9

Define glomerulonephritis

Answer 9

Characterised anatomically by inflammatory alterations in the glomeruli.

Question 10

What is the clinical presentation of asymptomatic haematuria and/or proteinuria?

Answer 10

Recurrent episodes of macroscopic haematuria after an URTI (less frequently GIT/UTI infection). Periods between infections and haematuria is short - hours to days. Older childrnen and young adults are most commonly affected.

• Association with coeliac disease
• Associated with liver disease (where there is defective clearance of IgA complexes)

Question 11

What is the most common form of glomerulonephritis?

Answer 11

IgA nephropathy

Question 12

What is the aetiology of asymptomatic haematuria and/or proteinuria?

Answer 12

This is largely unknown. Repeated exposure to environmental antigens results in heightened systemic IgA1 subclass. Glomerular damage may result from self-aggregation of abnormally glycosylated IgA1 which interacts with mesangial cells and activates alternative complement pathway.

Question 13

Treatment and prognosis to asymptomatic haematuria and/or proteinuria

Answer 13

Not specific. Maximise renal health - manage HTN. Most have a benign couse, though approximately 25% progress to end stage renal failure (ESRF).

Question 14

Define nephritic syndrome

Answer 14

The definition of nephritic syndrome is:

1. Haematuria (glomerular)*

Secondary features include

1. Variable proteinuria (less than nephrotic)
2. Hypertension (Na and H2O retention + activation of renin-angiotensin system)
3. +/- reduction in GFR (impaired renal function)
4. +/- oedema
5. +/- oliguria

When blood is lost from the glomerulus teh RBC are pleomorphic in size, shapeand volume. RBC casts confirm glomerular origin of blood. Non-gloerular RBC are of uniform appearance. Urine must be examined fresh.

Question 15

What are the classifications of nephritic syndrome?

Answer 15

1. Acute proliferative (poststreptococcal, postinfectious) GN
2. Non-streptococcal (postinfectious) GN

Question 16

What is the clinical manifestatiosn of acute proliferative GN?

Answer 16

This is a disease of children 6-10 years but adolescents and adults (immunocompromised, elderly) can be affected. Over 90% preceded by a specific nephritogenic strain of Group A beta-haemolytic streptococcal infection of the throat or skin. Patients typically present with acute nephritis 7-12 days after a throat or 3 weeks after a skin infection.

Laboratory investigations reveal an increasing ASO titre (less consistent with skin), low C3 (complement being consumed) and microbial culture. Urine sediment may reveal granular or cellular (epithelial, red or white cell) casts.

Question 17

Describe the aetiology of acute proliferative glomerulonephritis

Answer 17

Certain types of group A beta-haemolytic S. pyoegnes. Latent period between infection and nephritis is the time taken for the production of antibodies and formation of immune complexes. Immune complexes are deposited in the mesangium or may be antigen in the GBM. Exact antigen is unclear.

Question 18

Describe the treatment and prognosis of acute proliferative GN.

Answer 18

support renal function until recovery. Antibiotics if persisting infection. Control HTN, wait and monitor. 90% recover, 1% develop acute renal failure, and 5-10% will slowly progress to chronic renal failure (over decades).

Question 19

Describe the aetiology of non-streptococcal GN.

Answer 19

This is a similar form of GN occurring sporadically, it is associated with other bacterial infections (Staph endocarditis, pneumococcal pneumonia, meningococcal septicaemia), viral (HBV, HCV, mumps, HIV) and parasitic infections (malaria, toxoplasmosis).

Question 20

Define rapidly progressing (crescentic) GN

Answer 20

Rapidly progressing (crescentic) glomerulonephritis (RPGN) is a syndrome associated with severe glomerular injury and does not denote a specific etiology form of glomerulonephritis.

It is characterized clinically by rapid and progressive loss of renal function associated with severe oliguria and signs of nephritic syndrome.

Question 21

Describe the aetiology of rapidly progressing GN.

Answer 21

RPGN can be caused by a number of different diseases, some restricted to the kidney and others systemic. Although no single mechanism can explain all cases, most cases of glomerular injury are immunologically mediated. A practical classification divides RPGN into three groups on the basis of immunological findings:

Question 22

What is the clasisfication of rapidly progressive GN?

Answer 22

It is divided into thre groups on the basis of immunological findings:

Type I: anti-glomerular BM disease (antigen in type IV collagen)

Type II: immune complex mediated disease (post-infectious GN, SLE, IgA nephropathy)

Type III: Pauci-immune

Question 23

Prognosis and treatment of rapidly progressing GN.

Answer 23

This is a generally aggressive disease, with rapidly declining renal function. HTN is variable. Tretament is specific to disease + rapid intervention with high dose steroids.

Question 24

What are the clinical features of nephrotic syndrome?

Answer 24

Definition fo nephrotic syndrome

• Heavy proteinuria - >3.5g/24 hours (>3g/1.73m^2/24 hours)

Secondary features include:

1. Hypoalbuminaemia (<30g/L)
2. Clinical oedema
3. Hyperlipidaemia and lipiduria
4. +/- hypertension, haematuria, renal impairment

Question 25

What are the different types of nephrotic syndrome?

Answer 25

1. Minimal change disease
2. Membranous GN
3. Focal and segmental GN
4. Membranoproliferative GN (nephrotic or nephritic)

Question 26

Describe minimal change disease

Answer 26

This relatively benign disorder is the most frequent cause of nephrotic syndrome in children, but is less common in adults. It’s peak incidence is 2-6 years of age. The disease sometimes follows a respiratory infection or routine prophylactic immunization. Its most characteristic feature is its usual dramatic response to corticosteroid therapy. It produces a highly selective proteinuria: low molecular weight protein (albumin) > than all proteins (those with higher molecular weight). This implies a less severe membrane damage.

Question 27

What is the aetiology of minimal change disease?

Answer 27

involves some immune dysfunction, eventually resulting in the elaboration of a cytokine that damages visceral epithelial cells and causes proteinuria. It may be associated with atopic disorders, association with HLA haplotypes, Hodgkin disease.

Question 28

What is the treatment of nephrotic syndrome?

Answer 28

Minimal change disease has a dramatic response to corticosteroids, and patients should also be on a low salt diet and at least normal protein diet. The rest do not respond to corticosteroid therapy.

Question 29

Describe membranous GN.

Answer 29

Membranous nephropathy is a common cause of the nephrotic syndrome in adults. It is characterized by diffuse thickening of the glomerular capillary wall due to the accumulation of electron-dense, Ig-containing deposits along the subepithelial side of the basement membrane. It is responsible for 30% of adult nephrotic syndrome,

Question 30

Describe the aetiology of membranous GN

Answer 30

The disease may be idiopathic (85%) or secondary. The most notable causes of secondary membranous GN are:

1. Drugs: penicillamine, captopril, gold, NSAIDs
2. Underlying malignancies
3. SLE
4. Infections: chronic hepatitis B, hepatitis C, syphilis, schistosomiasis, malaria
5. Other autoimmune disorders: thyroiditis can underlie secondary membranous glomerulopathy.

Question 31

Describe the clinical presentation of membranous GN

Answer 31

Peak age of onset is30-50 years. Present with the features of nephrotic syndrome.

Question 32

Describe focal and segmental glomerulonephritis

Answer 32

This is the commonest cause of nephrotic syndrome in adults. Progressive renal damage (secondary or idiopathic) may result in focal and segmental glomerulosclerosis (sclerosis is the acucmulation of extracellular collegnous matrix). The loss of podocytes/haemodynamic changes/increased glomerular permeability leads to proteinuria.

Question 33

Clinical presentation of focal and segmental

Answer 33

Presents with the signs and symptoms of nephrotic syndrome. But compared with minimal change disease there is more commonly haematuria, reduced GFR and HTN, non-selective proteinuria and generally has a poor response to corticosteroid therapy.

Question 34

Aetiology of focal and segmental GN

Answer 34

1. Idiopathic
2. Secondary: HIV, heroin, sickle cells, severe obesity, glomerular scarring.
3. Adaptive response: compensatory hypertrophy of glomeruli in the presence of renal injury, causing eventually global sclerosis.
4. Inherited forms: changes in podocyte foot processs, affecting glomerular permeability

Question 35

Pathogenesis of focal and segmental GN

Answer 35

Endothelial and epithelial cell injuty (disruption of visceral epithelium - podocytes), increased glomerular permeability to proteins and accumulaiton of proteins in the mesangial matrix with secondary glomerular hypertrophy and haemodynamic changes (glomerular hypertension). Followed by proliferation of mesangial cells, infiltration by macrophages, increased ECM and segmental and global sclerosis of glomeruli.

Question 36

Aetiology of membranoproliferative GN

Answer 36

• Primary: 10-20% of nephrotic syndrome in children and young adults with a nephritic component (ie haematuria)
• Secondary: chronic immune complex disorders - SLE, HBV, HCV, malignancy, alpha1-anti trypsin deficiency.

Question 37

Clinical presentation of diabetic nephropathy

Answer 37

The clinical presentation of diabetic nephropathy includes:

1. Microalbuminuria
2. Macroalbuminuria: overt proteinuria to nephrotic syndrome
3. Chronic kidney disease/end stage renal failure

Question 38

Aetiology of diabetic nephropathy

Answer 38

1. Metabolic defect (hyperglycaemia): causes biochemical alterations in the glomerular BM. Nonenzymatic glycosylation of protein in the GBM, increased amounts of type IV collagen and fibronectin and reduced heparin sulfate moieties, accounting for the thickened GBM and increased mesangial matrix.
2. Haemodynamic changes: characterized at first by an increased GFR, increased glomerular capillary pressure and glomerular hypertrophy that contribute to glomerulosclerosis. Narrowing of vessels supplying the glomeruli can also induce ischaemic changes.

Question 39

What are the types of hypertensive nephropathy?

Answer 39

1. Benign nephrosclerosis
2. Malignant hypertension - necrotising arteriolitis
3. Hyperplastic arteriolosclerosis

Question 40

Discuss benign nephrosclerosis

Answer 40

It is associated with sclerosis of renal arterioles and small arteries. There is luminal narrowing of arterioles and small arteries caused by thickening and hyalinization of the wall; this is termed hyaline arteriolosclerosis.

This result is focal ischaemia leading to glomerular sclerosis and atrophy of renal parenchyma. Some degree of benign nephrosclerosis is seen with increasing age even in the absence of hypertension. The severity and incidence of lesions increases with hypertension and diabetes. Loss of kidney mass is due to mainly cortical scarring and shrinking.

Question 41

Discuss malignant hypertension

Answer 41

This causes necrotizing arteriolitis as the increased pressure leads to increased permeability of the small vessels to fibrinogen and other plasma proteins leading to endothelial injury, focal cell death and platelet deposition leading to the appearance of fibrinoid necrosis of the arterioles and small arteries, swelling of the vascular intima and intravascular thrombosis.

Question 42

Discuss hyperplastic arteriolosclerosis

Answer 42

mitogenic factors from platelets cause hyperplasia of intimal smooth muscle of vessels resulting in ‘onion skin lesions’ that causes further narrowing of the lumens.