Nephrotic/nephritic syndrome Hrishi Narayanan

Learning Outcomes Understand the key differences between nephrotic and nephritic syndrome (nephritis) Describe initial investigations and management of nephrotic and nephritic syndrome (nephritis) Describe the possible complications of nephrotic syndrome

Scenario 24 year old man Feeling more tired recently No systemic symptoms on questioning Frothy urine, no urinary symptoms, no blood No past medical history, no medications Non-smoker, social alcohol use Examination is unremarkable Urine dipstick - protein +++

Scenario What are your main differential diagnoses for this gentleman? What are the features of nephrotic syndrome and nephritic syndrome? How would you investigate this gentleman? What would your management plan be for this gentleman? What are the complications of nephrotic syndrome?

Differentials Emotional stress Exercise Fever UTI Orthostatic Seizures Focal segmental glomerulonephritis IgA nephropathy (ie Berger's disease) IgM nephropathy Membranoproliferative glomerulonephritis Membranous nephropathy Minimal change disease Haemoglobinuria Multiple myeloma Myoglobinuria Pre-eclampsia/eclampsia Alport's syndrome Amyloidosis Sarcoidosis Drugs (eg non-steroidal anti- inflammatory drugs (NSAIDs), penicillamine, gold, angiotensin-converting enzyme (ACE) inhibitors) Anderson-Fabry disease Sickle cell disease Malignancies (eg lymphoma, solid tumours) Infections (eg HIV, syphilis, hepatitis, post-streptococcal infection) Aminoaciduria Drugs (eg NSAIDs, antibiotics) Fanconi's syndrome Heavy metal ingestion List of possible differentials

Differentials Transient – exercise, stress, UTI Primary glomerular disease – minimal change, FSGS Secondary glomerular disease – drugs (e.g. NSAIDS), infx (e.g. HIV/hepatitis), sarcoid Tubular – drugs Serum excess – multiple myeloma Other – pre-eclampsia Can be easily broken down into several groups, with just a few examples of each. Important ones to remember include myeloma – with overflow of ? (BJP), and in women of child-bearing age (pre-eclampsia)

Nephrotic syndrome Kidney disease leading to proteinuria, hypoalbuminaemia, oedema & lipiduria Proteinuria - >3g per day Damage to glomerular basement membrane causes increased permeability This causes proteinuria → hypoalbuminaemia →oedema Proteinuria >3g/d or on spot collection >2g per gram of urine creatinine Normal proteinuria = >300mg/d

Nephrotic syndrome Kidney disease leading to proteinuria, hypoalbuminaemia, oedema & hyperlipidaemia Proteinuria - >3g per day Damage to glomerular basement membrane causes increased permeability This causes proteinuria → hypoalbuminaemia →oedema Proteinuria >3g/d or on spot collection >2g per gram of urine creatinine Normal proteinuria = >300mg/d

Causes Minimal change disease Focal glomerulosclerosis Primary Secondary Minimal change disease Focal glomerulosclerosis Membranous nephropathy Diabetes SLE Amyloidosis Usually broken down into primary and secondary causes Diabetes is the most common cause of nephrotic syndrome, primary or secondary Minimal change disease is the main primary cause in children, while FSGS is the main cause in adults Other important differentials – esp. For oedema – heart failure, liver failure, renal failure

Symptoms Oedema Foamy urine Complications Oedema can involve any area – leading to periorbital oedmea, facial swelling, peripheral oedema, or ascites Any pt with oedema should always have a urine dip A patient may present with one of the complications – which you will explain later Any other symptoms & signs are related to the underlying condition – e.g. Long history of diabetes, recent NSAID use,

Nephritic syndrome Collection of findings associated with glomerular inflammation and glomerulonephritis Features: Haematuria & red cell casts Proteinuria Hypertension Uraemia Oliguria HTN, uraemia and oliguria and linked to acute renal failure from the inflammatory process It is linked with acute glomerulonephritis – as it is a glomerular inflammatory process causing the symptoms

Nephritic syndrome Collection of findings associated with glomerular inflammation and glomerulonephritis Features: Haematuria & red cell casts Proteinuria Hypertension Uraemia Oliguria HTN, uraemia and oliguria and linked to acute renal failure from the inflammatory process It is linked with acute glomerulonephritis – as it is a glomerular inflammatory process causing the symptoms

Causes Post-streptococcal Primary: Secondary Membranous glomerulonephritis Rapidly progressive glomerulonephritis IgA nephropathy (Berger’s disease) Secondary HSP Vasculitis Most common presentation is 2-3 weeks after a streptococcal URTI Important differentials include pyelonephritis, AKI, heart/liver failure

Symptoms & signs Classically 2-3 weeks after URTI Oedema Oliguria Haematuria Flank pain General symptoms Classical presentation is in a child, several weeks after an episode of sore throat & fever – they might not even have presented to the doctor There are more symptoms in nephritic syndrome, as there is underlying inflammation to the glomerulus Oedema can be anywhere as in nephrotic syndrome, look for it on examination Oliguria is due to the poor renal function Haematuria and flank pain are direct consequences of the inflammatory process

Investigations Urine dip Urine microscopy Bloods – FBC, U&E, ESR, complement, auto- antibodies, myeloma screen, ASOT Renal Ultrasound Renal biopsy Urine dip will help provide the provisional diagnosis i.e. Nephrotic/nephritic. Nephrotic proteinuria will be protein +++ on the dip. As mentioned earlier, any pt with oedema should have a urine dip Microscopy will help show rbc casts in nephritic syndrome, or fat bodies & casts in nephrotic Bloods – FBC for any sign of infx, U&E – check for renal failure, urea levels, ESR – raised in nephritic, complement – low in SLE, membranous & post-streptococcal, ASOT – anti-strptolysin O titre – for strep infx (peak 3-5/52, normal within 6/12) Renal biopsy – look for tissue diagnosis, aids in treatment. Not needed for post-strep GN or nephrotic syndrome with a clear cause – e.g. Long-standing poorly controlled diabetes

Investigations Urine dipstick Urine microscopy Bloods – FBC, U&E, ESR, complement, auto- antibodies, myeloma screen, ASOT Renal Ultrasound Renal biopsy Urine dip will help provide the provisional diagnosis i.e. Nephrotic/nephritic. Nephrotic proteinuria will be protein +++ on the dip. As mentioned earlier, any pt with oedema should have a urine dip Microscopy will help show rbc casts in nephritic syndrome, or fat bodies & casts in nephrotic Bloods – FBC for any sign of infx, U&E – check for renal failure, urea levels, ESR – raised in nephritic, complement – low in SLE, membranous & post-streptococcal, ASOT – anti-strptolysin O titre – for strep infx (peak 3-5/52, normal within 6/12) Renal biopsy – look for tissue diagnosis, aids in treatment. Not needed for post-strep GN or nephrotic syndrome with a clear cause – e.g. Long-standing poorly controlled diabetes

Management Conservative Salt & fluid restriction Medical Diuretics Nephrotic syn. Nephritis Conservative Salt & fluid restriction Medical Diuretics ACE-inhibitors/ARB Steroids/Immunosuppressi on Surgical Conservative Salt & fluid restriction Medical Diuretics Steroids/immunosuppressi on Surgical Dialysis Important to remember fluid balance, for any renal condition. Strict fluid balance should be kept, with electrolytes measured frequently Diuretics – furosemide, spironolactone or metolazone ACE-i/ARB – can reduce proteinuria Can use hypolipidaemic agents Steroids/immunosuppression – type and usefulness dependent on cause. Obviously, renal physicians should be involved. For post-streptococcal, supportiv therapy is all that is required. Abx can be given to local contacts

Management Conservative Salt & fluid restriction Medical Diuretics Nephrotic syn. Nephritis Conservative Salt & fluid restriction Medical Diuretics ACE-inhibitors/ARB Steroids/Immunosuppressi on Surgical Conservative Salt & fluid restriction Medical Diuretics Steroids/immunosuppressi on Surgical Dialysis Diuretics – furosemide, spironolactone or metolazone ACE-i/ARB – can reduce proteinuria Can use hypolipidaemic agents Steroids/immunosuppression – type and usefulness dependent on cause. Obviously, renal physicians should be involved. For post-streptococcal, supportiv therapy is all that is required. Abx can be given to local contacts

Complications Complications of nephrotic syndrome: Infection Hyperlipidaemia Hypocalcaemia Hypercoagulability Hypovolaemia Infx – urinary Ig loss, oedema as culture medium, protein def. immunosuppression Lipids – Low oncotic pressure causes hepatic protein synthesis – inc. lipoproteins. As proteins are lost, this includes lipoprotein lipase (enzyme that usually breaks down lipids) – this means more lipids are found in the blood. These elevated lipoproteins are filtered through the glomerulus – causing fatty casts & bodies Hypocalcaemia – from low albumin and loss of urinary vit D, causing less Ca absorption Hypercoagulability – urinary loss of anticoagulants (e.g. Antithrombin) Hypovolaemia – due to low plasma oncotic pressure and fluid loss into interstitium

Scenario A 12 year old male with dark "cola coloured" urine for 2 days Well until 14 days ago - had a sore throat and fever – resolved without medical input Now facial puffiness and nonspecific abdominal pain. Dark brown urine, voiding less, normal smell Reduced appetite, lethargy, back pain Normally fit & well, no other symptoms Examination reveals only mild periorbital oedema Urine dip: blood +++, protein + Urine microscopy - RBCs are too numerous to count, RBC casts FBC & U&E normal, ASO titre high, complement C3 low

Scenario A 12 year old male with dark "cola coloured" urine for 2 days Well until 14 days ago - had a sore throat and fever – resolved without medical input Now facial puffiness and nonspecific abdominal pain. Dark brown urine, voiding less, normal smell Reduced appetite, lethargy, back pain Normally fit & well, no other symptoms Examination reveals only mild periorbital oedema Urine dip: blood +++, protein + Urine microscopy - RBCs are too numerous to count, RBC casts FBC & U&E normal, ASO titre high, complement C3 low

Scenario What are your main differential diagnoses for this patient? How would you investigate this patient? What would your management plan be for this patient?

Key points Nephrotic syndrome – heavy proteinuria, nephritis (nephritic syndrome) – haematuria Always do a urine dip for patients with oedema Important complications include infection and hypoercoagulability

Questions?