NephrologyTier 1Disease (DEADMAN)

Nephrotic syndrome

Description

The definition - all four

Proteinuria >3.5 g/24h (UPCR >3 g/g, or >350 mg/mmol)
Hypoalbuminaemia <30 g/L
Oedema
Hyperlipidaemia (+/- lipiduria, oval fat bodies, Maltese cross under polarised light)

Nephrotic-range proteinuria occurs ONLY with glomerular disease. Tubular disease can cause non-nephrotic proteinuria but never nephrotic range

Proteinuria thresholds

	Albumin excretion	UACR
Normal	<30 mg/day	<3 mg/mmol
Moderately increased ('microalbuminuria')	30-300 mg/day	3-30 mg/mmol
Severely increased ('macroalbuminuria')	>300 mg/day	>30 mg/mmol
Nephrotic range	>3.5 g/day protein	UPCR >300 mg/mmol

Nephrotic vs nephritic

	Nephrotic	Nephritic
Lesion	Podocyte	Endothelial / inflammatory
Proteinuria	>3.5 g/day	<3.5 g/day
Haematuria	Absent or mild	Dysmorphic RBC, RBC casts
BP	Normal or mildly inc	Hypertensive
eGFR	Usually preserved initially	Falling
Urine	Bland, lipiduria	Active sediment

Adults: diabetic nephropathy is the commonest cause overall
Primary glomerular disease in adults: membranous ~25-30%, FSGS ~35% (and rising), MCD ~15%
Children: minimal change disease ~80-90% - biopsy is not needed before a steroid trial
FSGS predominates in African ancestry; membranous in white adults >50

Podocyte injury -> loss of the slit diaphragm size and charge barrier -> albumin loss
Oedema - two mechanisms, both operate
- Underfill: dec oncotic pressure -> dec plasma volume -> RAAS activation -> Na retention
- Overfill: filtered plasminogen activates the epithelial sodium channel (ENaC) in the collecting duct -> primary Na retention. This explains why many nephrotic patients are not hypovolaemic and respond to amiloride
Hyperlipidaemia: dec oncotic pressure -> inc hepatic lipoprotein synthesis; dec LDL receptor and dec lipoprotein lipase activity; PCSK9 upregulated
Hypercoagulability: urinary loss of antithrombin III, protein S; inc hepatic fibrinogen and factors V/VIII; thrombocytosis and platelet hyperaggregability; haemoconcentration
Infection risk: urinary loss of IgG and complement factor B -> impaired opsonisation of encapsulated organisms

Classify the cause by pattern

Nephrotic	Nephritic	Mixed
Minimal change disease	ANCA vasculitis	IgA nephropathy (commonest GN)
FSGS	Anti-GBM disease	MPGN / C3 glomerulopathy
Membranous nephropathy	Post-infectious GN	Lupus nephritis
Lupus nephritis class V	Lupus nephritis class III/IV	Myeloma-related kidney disease
Diabetic nephropathy (commonest overall)	TMA - TTP, HUS, aHUS, APS, scleroderma renal crisis, malignant HTN	Cryoglobulinaemia
Amyloidosis

Secondary causes to exclude in every adult

Diabetes (retinopathy usually present if diabetic nephropathy - its absence should prompt biopsy)
Amyloid (AL/AA), myeloma, MGRS
SLE, hepatitis B (membranous), hepatitis C (MPGN/cryo), HIV (collapsing FSGS), syphilis, malaria
Malignancy - solid tumours with membranous, Hodgkin with MCD
Drugs - NSAIDs (MCD), gold/penicillamine/anti-TNF (membranous), pamidronate/interferon/anabolic steroids (FSGS)
Obesity, reflux nephropathy, preeclampsia

Work-up

Renal biopsy

Indicated in essentially every adult with new nephrotic syndrome
Exceptions: children (assume MCD, treat first); classic long-standing diabetes with retinopathy and no active sediment; anti-PLA2R-positive membranous with no secondary cause

A. Treat the specific lesion

Immunosuppression is lesion-specific and only after the diagnosis is made - see MCD, FSGS, membranous, lupus nephritis notes
Secondary disease: treat the cause (antivirals, remove the drug, treat the malignancy)

B. Antiproteinuric and cardiorenal therapy - everyone

ACEi or ARB at the maximum tolerated dose - lowers proteinuria 30-40%
SGLT2i for residual proteinuric CKD irrespective of diabetes
Dietary sodium <2 g/day - without this, RAS blockade and diuretics both fail
Protein intake ~0.8-1 g/kg/day (do not high-protein feed - it worsens proteinuria)
BP target <120 systolic (standardised)

C. Oedema

Loop diuretic - often needs high oral doses or IV (hypoalbuminaemia impairs delivery of drug to the tubule)
Add a thiazide for sequential nephron blockade; amiloride targets the ENaC mechanism
Aim for 0.5-1 kg/day weight loss - faster risks AKI and thrombosis
IV albumin + frusemide only for refractory oedema; transient benefit

D. Thromboprophylaxis

VTE risk highest in membranous (up to 30%); rises steeply once albumin <25 g/L
Prophylactic anticoagulation if albumin <20-25 g/L, particularly membranous, weighed against bleeding risk
Renal vein thrombosis: sudden flank pain, macroscopic haematuria, dec eGFR, PE

E. Hyperlipidaemia

F. Infection

Pneumococcal and influenza vaccination (spontaneous bacterial peritonitis with S. pneumoniae is the classic complication in nephrotic children)
*No live vaccines while on immunosuppression*
PJP prophylaxis if on high-dose steroids plus a second agent

G. Other

Vitamin D replacement (urinary loss of vitamin D-binding protein)
Check TSH - thyroxine-binding globulin loss can cause hypothyroidism; a treated hypothyroid patient may need a higher dose

Diabetes mellitus - the commonest cause
Amyloidosis (AL, AA), multiple myeloma, MGRS
SLE, rheumatoid arthritis (AA amyloid, drug-induced membranous), Sjogren
Hepatitis B (membranous), hepatitis C (MPGN, cryoglobulinaemia), HIV (collapsing FSGS), syphilis, malaria, schistosomiasis
Malignancy - solid tumours with membranous, Hodgkin lymphoma with minimal change
Obesity - obesity-related glomerulopathy
Preeclampsia
Drugs - NSAIDs, gold, penicillamine, anti-TNF, pamidronate, interferon, anabolic steroids
VTE and renal vein thrombosis

Outcome is entirely determined by the underlying lesion and by whether proteinuria remits
- MCD: >90% steroid-responsive, ESKD rare
- Membranous: rule of thirds (remit / persist / progress)
- FSGS: ~50% ESKD at 5-10 yrs if nephrotic proteinuria persists
- Diabetic nephropathy and amyloid: progressive
Achieving remission of proteinuria is the strongest modifiable determinant of renal survival in every lesion

Complications

VTE, renal vein thrombosis, PE - highest in membranous
Infection - encapsulated organisms; spontaneous bacterial peritonitis, cellulitis, sepsis
AKI - over-diuresis, sepsis, renal vein thrombosis, interstitial oedema, superimposed AIN (NSAIDs)
Accelerated atherosclerosis, protein malnutrition and muscle wasting
Vitamin D deficiency, hypothyroidism, iron-refractory anaemia (transferrin loss)
Progressive CKD -> ESKD

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