Nephrology

Question 1

Differential diagnosis of Haematuria?

Answer 1

Question 2

A genetic susceptibility and an exaggerated immune response to an URTI is the cause of a primary IgA nephropathy, but what are the causes of a secondary IgA nephropathy.

Answer 2

Question 3

Differential diagnosis for micro/macro scopic Haematuria in an otherwise asymptomatic patient who has had Urological malignancy ruled out?

Answer 3

Genetic disorders

Thin membrane disease (relatively benign - painless haematuria)

Alports disease (Rare genetically inherited disorder that causes hearing loss, eye problems and an abnormal Glomerular Basement Membrane) - can cause renal failure - most patients end up on dialysis.

Question 4

How do you diagnose IgA nephropathy?

Answer 4

Kidney biopsy

Only indicated if:

• Haematuria and proteinuria
• Haematuria w/ decling kidney fnc

Question 5

Kidney biopsy goes through 3 phases, what are they?

Answer 5

1. Light Microscopy (first image shows classic crescent shape of IgA nephropathy)
2. Immunofluorescence (IHC)
3. Transmission electron microscopy (TEM)

Question 6

Which scoring system can be used to classify prognosis in IgA nepropathy

Answer 6

Oxford Classification (basically characterizes the the mesangium)

MEST-C

Mesangial hypercellularity

Endothelial Hypercellularity

Segmental Glomeruloscelrosis

Tubular atrophy / Interstitial Fibrosis

Crescent formation

Question 7

The hallmark of treatment in IgA nephropathy is ____.

Answer 7

ACE-i

*Not steroids unless acute decline in renal function*

Question 8

Most common cause of Glomerulonephritis?

Answer 8

IgA nephropathy

• especially prevalent in Caucasians and East Asians
• Men 2:1 Women
• Most common in 2nd and 3rd decade of life

*Remember can present with loin pain and thus may mimic renal calculi*

Question 9

Pathophysiology of IgA nephropathy?

Answer 9

Genetic Susceptibilty - URTI - Exaggerated Immune Response - Antibody Complex form in Mesangium - Endothelial/Tubular damage

(i.e Endothelium/GBM/Podocyte interface is damaged)

Question 10

Prognostic markers for glomerulonephritis other than the Oxford histology score (MEST-C)?

Answer 10

BP

Proteinuria (Remember proteinuria is significant in nephrology if >1g / 24hrs)

Renal function

Question 11

Glomerular Disease:

Nephrotic vs Nephritic Syndrome

Answer 11

The key with nephrotic syndrome is an excess amount of protein in the urine, whereas nephritic syndrome is where there is an excess amount of blood in the urine.

Nephrotic Syndrome:

Injury to Podocytes (Proteinuria)

Changed mesangial architecture

(ex. Minimal change disease/ Diabetic nephropathy/ Amyloid)

Nephritic Syndrome:

Inflammation

Reactive cell proliferation

GBM disruption (slit membrane) - blood leaks into urine

Crescent formation

(Ex. Post-Streptococcal infection/Anti-GBM aka goodpasture’s disease - affects lung BM aswell/ANCA small vessel vasculitis)

As outlines above nephrotic syndrome is characterised by very heavy proteinuria (> 3.5 g/24 hrs), hypoalbuminaemia and oedema.

The Nephritic syndrome is characterised by the presence of haematuria frequently in association with hypertension, oliguria, fluid retention and usually (but not always) reduced / declining renal function. Patients with nephritic syndrome may also exhibit varying degrees of proteinuria, including nephrotic-range proteinuria; the prominence of haematuria on
dipstick should, however, alert the physician to the possibility of a glomerulonephritis.

Indeed, it is important to recognise that the characteristic features of nephritic syndrome and nephrotic syndrome do not always present in isolation, but should be considered to be the extreme phenotypes at either end of a spectrum of presentations.

Students should learn that damage to the podocytes causes (heavy)
proteinuria (see graph above) whilst the glomerular injury caused by Autoantibodies or Immune complex deposition usually causes haematuria +/- mild to moderate proteinuria.

At the other end of the spectrum, inflammation leads to cell damage and proliferation, breaks form in the glomerular basement membrane (GBM) and blood leaks into urine. In its extreme form, with acute sodium retention and hypertension, such disease is labelled nephritic syndrome.

The histology to the right shows a **glomerulus with many extra
nuclei from proliferating intrinsic cells**, and influx of inflammatory cells leading to
crescent formation (arrows) in response to severe post-infectious glomerulonephritis.

Question 12

A blood test can be used to screen for post-infectious (usually streptococcus) glomerulonephritis, which circulating proteins are looked for?

Answer 12

Anti-streptolysin O titre (ASOT)

C3, C4 (complement proteins)

Question 13

Draw out the RAAS system.

Answer 13

Question 14

____ and ___ are the two most common causes of CKD.

Answer 14

Diabetic Nephropathy

Hypertensive Nephropathy

*Both lead to nephrosclerosis*

Question 15

What are the 3 ways in which multiple myeloma causes renal disease?

Answer 15

Light chain cast nephropathy (intralubular collection of light chain-protein complexes) - most common

Light chain deposition disease (deposits in the glomerulus)

AL Amyloidosis

Hypercalcaemia and Hyperuricaemia (Tumour lysis syndrome causes tubular crystallization of uric acid) also possible causes of MM induced nephropathy.

Question 16

Pathophysiology of Diabetic Nephropathy

Answer 16

Glycylated basement membrane and endothelial cells (due to hyperglycaemia) thicken and harden the efferent arteriole of the glomerulus.

This leads to increased pressure within the glomerulus and reduced reabsorption in the collecting tubules. The kidney thinks it needs a great blood supply and the afferent arteriole dilates but this only serves to increase pressure in the glomerulus and this is why the 1st/early stage of diabetic nephropathy actually leads to hyperfiltration.

The increased pressure and size of the glomerulus only serves to disrupt its architecture more and this leads to increased space between podocytes (slit junctions) leading to proteinuria and mesangial expansion. Mesangial expansion leads to increased ECM production - leading to collagenous nodules called Kimmelstiel - Wilson Nodules.

Question 17

4 main events that contribute to diabetic nephropathy

Answer 17

1. Thickened Glomerular Basement membrane
2. Mesangial expansion
3. Kimmelstiel - Wilson nodules
4. Podoctye disruption

Question 18

Remember ANCA vasculitis is a small vessel vasculitis caused by antibodies to the cytoplasmic contents of granulocytes (i.e neutrophils/basophils/eosinophil/monocytes).

This is why it is called granulomatosis with polyangiitis

Remember C-ANCA means _____

whereas pANCA means ____

Answer 18

Cytoplasmic - Anti-Neutrophil Cytoplasmic Autoantibodies

Perinuclear - Anti Neutrophil Cytoplasmic Autoantibodies

*note - Neutrophilic not Nuclear*

Question 19

How do we classify an AKI?

Answer 19

KDIGO Classification (Stage 1, 2, and 3)

Measures from baseline Creatinine and Urine output in 12/24hrs

Question 20

3 drugs to avoid in renal impairment (lecture)

Answer 20

Lithium -100% RC

Gentamicin (aminoglycaside) - 100% RC

LMWH (70% renal clearance)

(unfractionated LMWH can be used in renal dysfunction as it has a greater molecular weight and thus is not filtered by the kidney - essentially this means that it is less dependent on the kidneys for clearance and so we ar eless worried about the drug in patients with renal dysfunction)

Question 21

When taken as an overdose, the metabolism of paracetamol results in a buildup of a toxic substance called _____.

Answer 21

NAPQI (N-acetyl-p-benzoquinone-imine).

NAPQI is inactivated by glutathione. In an overdose, glutathione stores are rapidly depleted, and NAPQI is left un-metabolised. It can cause liver and kidney damage.

Question 22

Stages of Chronic Kidney Disease and active monitoring?

Answer 22

KDIGO (Kidney Disease Improving Global Outcomes)

Question 23

Causes of Hyperkalaemia?

Answer 23

Reduced excretion from kidneys:

AKI

ACE inhibitors

Potassium Sparing Diuretics (ex spironolactone) but also diuretics in general

NSAIDs

Beta Blockers

K+ containing laxatives (movicol/fybogel)

Heparin (which inhibits aldosterone release)

Ciclosporin

Addison’s

Cellular Release:

Rhabdomyolysis

Digoxin Toxicity (NB - Can be precipitated by hypokalemaia) - “Reverse tick sign” on ECG

Tumour Lysis Syndrome

Massive Haemolysis

Acidosis:

DKA or any other metabolic acidosis

Question 24

Hyperkalaemia is a potentially life threatening electrolyte abnormality.

Treat K+ >___ mmol/L or any hyperkalaemia with ECG changes with the following;

Give 10ml of 10% _____ (or chloride) over 10 mins - this is cardioprotective

Intravenous ____ (10u soluble insulin) in 25g ____ (50mL of 50% or 125ml of 20% glucose) - insulin causes intracellular K+ shift and glucose to required to prevent hypoglycaemia

Nebulised salbutamol - also causes intracellular K+ shift

Treatment with sodium bicarbonate is controversial

Other aspects of management:

Check contributing drugs (e.g. ACE inhibitors, spironolactone)

Once initial measures completed, recheck urea and electrolytes and ECG and glucose

Urinary potassium

Answer 24

Hyperkalaemia is a potentially life threatening electrolyte abnormality.

Treat K+ >6.5mmol/L or any with ECG changes with the following;

Give 10ml of 10% calcium gluconate (or chloride) over 10 mins - this is cardioprotective

Intravenous insulin (10u soluble insulin) in 25g glucose (50mL of 50% or 125ml of 20% glucose) - insulin causes intracellular K+ shift and glucose to required to prevent hypoglycaemia

Nebulised salbutamol - also causes intracellular K+ shift

Treatment with sodium bicarbonate is controversial

Other aspects of management:

Check contributing drugs (e.g. ACE inhibitors, spironolactone)

Once initial measures completed, recheck urea and electrolytes and ECG and glucose

Urinary potassium

Question 28

Differential Diagnosis/ causes of SIADH

Answer 28

**Malignancy** - SCLC **Respiratory** (LRTI - particularly *_legionella pneumonia_* / PE) **Neurological** (SOL/CVA/ Trauma/SAH/Meningitis) **Drugs** (Carbamazepine/SSRI's/ PPI's) *MNDR*

Question 29

Causes of Hyponatraemia?

Answer 29

Remember to classify into: **Hypovolaemic** (In the elderly _dehydration is a very common_ cause especially in patients with _dementia_) **Euvolaemic** (SIADH / Hypothyroidism) **Hypervolaemic** and **drugs:** **Thiazide diuretics** \> **Loop Diuretics** \> **K+ sparing diuretics**

Question 30

Hyponatraemia Management

Answer 30

Question 31

Criteria for diagnosing SIADH?

Answer 31

**Low Serum Na** (\<135) **Low Serum Osmolality** (i.e dilute plasma) **High Urine Osmolality** (i.e concentrated urine) **High concentration of urine Na** Normal Renal/Cardiac/Thyroid/Adrenal function No offending drugs Euvolaemic fluid status

Question 32

How do you calculate serum osmolality?

Answer 32

**2 X Na + Glucose + Urea**

Question 33

Complications of Nephrotic Syndrome?

Answer 33

**Infection** (due to urinary loss of immunoglobulins) - sepsis if NS left untreated **Venous thromboembolism** (due to urinary loss of antithrombin III) **Hyperlipidaemia** (due to increased hepatic production of lipids to restore the serum oncotic pressure)

Question 34

Nephrotic Syndrome is defined as the presence of ____ (\>\_\_\_g/\_\_\_\_), ____ (\<30 g/L), and _____ . \_\_\_\_\_ and ____ disease are also frequently seen.

Answer 34

NS defined as the presence of: **Proteinuria** (**\>3.5 g/24 hours**), **Hypoalbuminaemia** (**\< 30 g/L**) **Peripheral oedema** **Hyperlipidaemia** (liver tries to compensate for loss of albumin) and **thrombotic disease** (loss of clotting factors - antithrombin) are also frequently seen. Patients become hypoalbuminaemic due to the urinary loss of albumin. The liver tries to compensate for this protein loss by increasing the synthesis of albumin, as well as other molecules including LDL and VLDL and lipoprotein(a), contributing to the development of lipid abnormalities including **hypercholesterolaemia** and **hypertriglyceridaemia** (4). Hypercoagulability results from the loss of inhibitors of coagulation in the urine and increased synthesis of procoagulatory factors by the liver (4). Hypercoagulable states predispose to venous thrombosis. Prolonged bed rest should be avoided, as **thromboembolism is very common.**

Question 35

Each kidney has approximately ____ glomeruli, which are the sites of blood filtration. The layers of the glomeruli include the ____ of the capillary, the _____ , and the _____ of the podocytes. The main barrier to filtration is the connection between adjacent _____ . Viral infection, drugs, toxins or the local activation of the renin- angiotensin system can cause direct injury to podocytes. Electron microscopy in MCD (ex. Nephrotic syndrome) demonstrates diffuse effacement of the epithelial cell foot processes and this disruption of the filtration barrier is understood to cause (heavy) glomerular proteinuria. However the Endothelium and GBM is untouched - hence the name MCD.

Answer 35

Each kidney has approximately **1 million glomeruli**, which are the sites of blood filtration. The layers of the glomeruli include the **fenestrated endothelium** of the capillary, the **glomerular basement membrane**, and the **foot processes of the podocytes**. The main barrier to filtration is the **connection between adjacent podocyte foot processes.** **Viral infection, drugs, toxins or the local activation of the renin- angiotensin system** can cause direct injury to podocytes. As outlined above the electron microscopy in MCD demonstrates diffuse effacement of the epithelial cell foot processes and this disruption of the filtration barrier is understood to cause (heavy) glomerular proteinuria.

Question 36

Causes of Nephrotic Syndrome: ## Footnote The probable aetiology differs depending on the patient's age and the presence of specific comorbidities (e.g., diabetes, amyloidosis, or systemic lupus erythematosus). The most common cause in children is _____ . In adults, primary glomerular diseases are more frequent in males (55%), whereas secondary glomerular disease is more frequent in females (72%). The most common cause in younger adults is _____ , followed by minimal change nephropathy. \_\_\_\_\_\_ is the most common cause in older people (8, 9) and diabetic nephropathy in adults with a history of long-standing diabetes. Nephrotic syndrome can also develop in patients with IgA nephropathy, membranoproliferative glomerulonephritis, and post-infectious glomerulonephritis. However, these patients usually have a nephritic pattern with haematuria and red cell casts as the predominant feature.

Answer 36

_Children_ - **Minimal Change Disease** (MCD) _Young adults_ - **Focal Segmental Glomerular Sclerosis** (FSGS) _Older people_ and most common overall - **Membranous Nephropathy**

Question 37

Management of Nephrotic Syndrome?

Answer 37

Treat underlying pathology is always first step. _Conservative management:_ Symptomatic improvement should usually be achieved with **dietary sodium restriction** **A high-protein diet** (80 - 90 g protein daily) increases proteinuria and can be harmful in the long term. **Prolonged bed rest** should be **avoided**. **VTE stockings (**Thrombo-Embolus Deterrent (TED) Stockings) _Pharmacological:_ **ACE inhibitors** and / or **angiotensin II receptor antagonists** (AII-RAs). These drugs reduce proteinuria by lowering glomerular capillary filtration pressure (a fall in efferent tone decreases the transglomerular capillary pressure, and so protein loss into the urinary space); blood pressure and renal function should be monitored regularly. **Loop diuretic** (e.g. furosemide or bumetanide). Nephrotic patients may malabsorb diuretics (as well as other drugs) owing to gut mucosal oedema, and intravenous administration may be needed initially. Patients are sometimes hypovolaemic, and moderate oedema may have to be accepted to avoid postural hypotension. **LMWH (ex. Dalteparin)** **Pneumococcal vaccine** should be considered due to increased risk of Infection/sepsis. **Statin** (lipid lowering) **Immunosuppressant** (corticosteroid **/**Calcineurininhibitors - Ciclosporin or Tacrolimus/ Cyclophosphamide etc.)

Question 38

Management of AKI?

Answer 38

_1. Find and treat causes (_e.g. sepsis, drugs, obstruction) **Bloods** - FBC, U+Es, CRP, consider antibody screen if autoimmune cause suspected **Urine dip** and **microscopy** **Bladder scan** - if retention suspected **Ultrasound renal tract** - if obstruction suspected **ECG** - looking for _hyperkalaemia_/_pericarditis_ _2. Stop renotoxic drugs_ **ACE-I/ARBs** **Spironolactone** **Diuretics** **Gentamicin** - may need dose adjustment if necessary for treatment **NSAIDs** _3. Give IV fluid_ - aggressiveness depends on severity of AKI and comorbidities Treat complications (e.g. hyperkalaemia, acidosis) _4. Give dialysis if:_ **Refractory hyperkalaemia** **Severe acidosis** (pH\<7.2) **Refractory pulmonary oedema** **Symptomatic uraemia** (pericarditis, encephalopathy) **Drug overdose** (e.g. aspirin)

Question 39

Drugs to avoid in AKI (mnemonic)

Answer 39

**DAMN** **D**iuretics **ACEi/ARB** **M**etformin **N**SAIDs

Question 40

What are the **Pre-Renal**/**Intrinsic**/**Post-Renal** causes of an AKI?

Answer 40

_Pre-Renal:_ Dehydration Hypotension Sepsis NSAIDs ACEi/ARBs Over Diuresis Renal artery stenosis Renal artery thrombosis _Intrinsic:_ Acute Tubular Necrosis Myeloma Glomerulonephritis Vasculitis (SLE) Acute Interstitial Nephritis Nephrotoxic drugs Tumour Lysis Syndrome _Post-Renal:_ Bladder obstruction (Stone/tumour) Prostate (BPH/Cancer) Ureters (stone/stricture) Blocked catheter Retroperitoneal fibrosis

Question 41

\_\_\_\_\_ is the *_most common*_ cause of _*intrinsic_* acute kidney injury (AKI). It involves damage to the tubular epithelial cells within the renal tubules of the kidney due to either ____ or \_\_\_\_.

Answer 41

**Acute Tubular Necrosis (ATN)** **Ischaemia** or **direct toxicity** **Clinical presentation** Acute kidney injury Oliguria Uraemia Electrolyte imbalance **Causes** _Ischaemic:_ Hypotension Shock Haemorrhagic Cardiogenic Septic Direct vascular injury Trauma Surgery **Nephrotoxic** _Drugs:_ Aminoglycocide antibiotics e.g. Gentamicin Antifungal drugs e.g. Amphoteracin Chemotherapy agents e.g. Cisplatin Non-steroidal anti-inflammatory drugs e.g. Ibuprofen Angiotensin converting enzyme inhibitors (ACEi) e.g. Ramipril Angiotensin receptor blocker e.g. Candesartan Statins Contrast **Management** Correction of underlying cause E.g. fluid resuscitation Removal of nephrotoxins May require haemofiltration or haemodialysis