Nephrotic Syndrome

Meet the patient

A 4-year-old boy is brought in because his eyes look puffy every morning, and his urine is frothy. He is otherwise well, afebrile, normotensive, and his urine dipstick shows 4+ protein with no blood. The GP thought it was an allergy.^[2]

At the other end of the ward, a 62-year-old smoker presents with leg swelling and heavy proteinuria with hypoalbuminaemia — the same syndrome, at the other end of the age range.^[1]

Two exam questions span both beds: is this nephrotic or nephritic? (the sediment and complement decide) and what is the cause, and is there a secondary disease or a complication behind it? Everything below answers those questions at consultant depth.^[1]

The tetrad — and the one branch-point that runs the whole page

Nephrotic syndrome is the clinical expression of severe filtration-barrier (podocyte) injury. In children it is defined by nephrotic-range proteinuria — at least 40 mg/m² per hour, or a urine protein-to-creatinine ratio of at least 200 mg/mmol, or 3+ protein on dipstick — with hypoalbuminaemia (under 25 g/L) and oedema. In adults the syndrome consists of peripheral oedema, heavy proteinuria and hypoalbuminaemia, often with hyperlipidaemia, and the diagnosis is based on these typical clinical features with confirmation of heavy proteinuria and hypoalbuminaemia.^[2][1]

The single most testable branch-point in glomerular medicine is nephrotic versus nephritic. Nephrotic is proteinuria-dominant — heavy proteinuria with hypoalbuminaemia and oedema. Nephritic is inflammation-dominant — haematuria with dysmorphic red cells, red-cell casts, hypertension, renal impairment, and frequently a low complement. Urinalysis and the serum complement decide it at the bedside.^[1][5]

The paediatric steroid-response categories

In children — where minimal change disease dominates — the disease is classified by the response to the first steroid course, and that category drives every subsequent decision.^[13][9]

Relapse is a return of nephrotic-range proteinuria — 3+ or greater on dipstick, or a urine protein-to-creatinine ratio of 200 mg/mmol or more — after a remission. Frequently-relapsing and steroid-dependent disease is managed with steroid-sparing therapy — calcineurin inhibitors or alkylating agents, and rituximab — to limit cumulative steroid toxicity.^{[2][13][20][21]}

Causes by age — state the commonest for each bracket

The aetiology is strikingly age-dependent, and naming the commonest cause for each age bracket is a guaranteed exam point.^[1][2]

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Congenital nephrotic syndrome (CNS) is a distinct, life-threatening entity presenting in utero or during the first three months of life with nephrotic-range proteinuria, hypoalbuminaemia and oedema. The main cause is genetic defects in podocytes; CNS may also form part of a more generalised syndrome or be caused by a perinatal (congenital) infection or maternal allo-immune disease.^[8][16]

Why the barrier leaks — and what the losses cause

The slit diaphragm of the podocyte is the decisive filtration barrier. Although the glomerular basement membrane was emphasised for decades as the barrier retaining plasma proteins, current evidence locates that role in the slit diaphragm between the podocyte foot processes. Nephrin — the gene product mutated in Finnish-type congenital nephrotic syndrome — sits at the outer leaflet of the slit-diaphragm plasma membrane; podocin, mutated in autosomal-recessive steroid-resistant nephrotic syndrome, interacts with nephrin. An anti-nephrin antibody alone can induce massive proteinuria, which marks nephrin as a key functional barrier protein. In minimal change disease the light microscopy is normal and the foot processes are effaced on electron microscopy — the structural signature of podocyte injury.^[18][9]

^{[1] [15]}

Oedema — the underfill vs overfill hypotheses. Underfill: proteinuria and hypoalbuminaemia lower plasma oncotic pressure, fluid extravasates into the interstitial space, and the resulting intravascular hypovolaemia activates neurohormonal compensatory mechanisms that increase retention of salt and water. On this view the recommended management was diuretics plus human albumin infusion. Overfill: recent human and animal studies reveal a kidney-limited sodium-reabsorption mechanism — serine proteases in the tubular lumen activating ENaC channels — so sodium is retained independently of the filling state. Both mechanisms operate; this is why hypervolaemia, not just hypovolaemia, is seen.^[15]

Hyperlipidaemia and the hypercoagulable state. Hyperlipidaemia is explicitly part of the adult syndrome — "often with hyperlipidemia" — and ranks with venous thrombosis and infection among the important complications of nephrotic syndrome, which is why dyslipidaemia, thrombosis and infection are the three complications to anticipate and manage in every nephrotic patient.^[1]

The two signature complications follow directly from the proteinuric state:^[1]

• Infection — one of the important complications of nephrotic syndrome, and a principal reason these patients are monitored closely; immunosuppressive therapy amplifies the susceptibility.^[1]
• Thrombosis — venous thrombosis is the other important complication. In primary membranous nephropathy, where thromboembolic risk is recognisably increased, a personalised decision on prophylactic aspirin or warfarin is recommended when serum albumin is under 3.2 g/dL (under 32 g/L).^[1][11]

The causes — primary glomerular and secondary

"Nephrotic syndrome" is a syndrome label, not a disease label. The work that matters is identifying the underlying cause, because management and prognosis depend entirely on it. Causes divide into primary (idiopathic) glomerular diseases and secondary systemic diseases.^[1]

Causes in children

In children the cause is overwhelmingly a primary podocytopathy.^[2][9]

Causes in adults

In adults the leading primary causes are membranous nephropathy and focal segmental glomerulosclerosis — the most common histologic subtypes of primary nephrotic syndrome — and the history with selected diagnostic studies is used to rule out important secondary causes including diabetes mellitus, systemic lupus erythematosus and medication adverse effects.^[1]

• Membranous nephropathy — the most common cause of idiopathic nephrotic syndrome in non-diabetic white adults; about 80 percent of cases are renal-limited (primary) and 20 percent are associated with other systemic diseases or exposures.^[1][14]
• FSGS — the other most common histologic subtype of primary nephrotic syndrome in adults.^[1]
• Minimal change disease — approximately 15 percent of adult idiopathic nephrotic syndrome, rising to a much higher proportion in younger adults.^[9]
• Diabetes mellitus, SLE and drug adverse effects — the important secondary causes named for exclusion at diagnosis.^[1]

Malignancy and secondary associations — memorise

The history and selected diagnostic studies exist to rule out important secondary causes, including diabetes mellitus, systemic lupus erythematosus and medication adverse effects.^[1]

• Drug adverse effects are an explicit secondary cause of adult nephrotic syndrome to exclude on the history.^[1]
• Secondary membranous nephropathy — about 20 percent of membranous nephropathy is associated with other systemic diseases or exposures (including systemic lupus erythematosus, hepatitis B virus infection and malignancies).^[14]

The bedside round — fluid, a cause, and a complication

A focused exam quantifies the oedema, assesses fluid status, hunts for a secondary cause, and screens for complications — all in a few minutes.^[1]

• Oedema and fluid status — patients typically present with oedema and fatigue, without evidence of heart failure or severe liver disease; document the daily weight as the most reliable index of fluid balance.^[1]
• Screen for a secondary cause — the patient history targets diabetes mellitus, systemic lupus erythematosus and medication adverse effects, with selected diagnostic studies used to rule them out.^[1]
• Screen for complications at the bedside — the important complications to anticipate are venous thrombosis, infection and hyperlipidaemia.^[1]

Complication presentations may be the first sign that brings the patient to hospital: venous thrombosis, infection (including peritonitis or cellulitis), or the consequences of severe hyperlipidaemia.^[1]

Investigations — confirm, classify, biopsy

Confirm the syndrome, then classify the cause. The workup has three layers.^[1][4]

Step 1 — Confirm and quantify the syndrome

^{[2] [1]}

• Protein quantification — in children, nephrotic-range proteinuria is 40 mg/m² per hour or more, or a urine protein-to-creatinine ratio of 200 mg/mmol or more, or 3+ protein on dipstick; in adults the diagnosis is based on typical clinical features with confirmation of heavy proteinuria and hypoalbuminaemia.^[2][1]
• Secondary-cause workup — the patient history and selected diagnostic studies rule out important secondary causes, including diabetes mellitus, systemic lupus erythematosus and medication adverse effects.^[1]

Step 2 — Serological workup to classify the cause

The serological battery is targeted at the common secondary causes:^[1][4]

• Glucose and HbA1c — diabetes mellitus, a named secondary cause to exclude.
• ANA and anti-dsDNA, complement C3 and C4 — systemic lupus erythematosus, a named secondary cause to exclude.
• Serum anti-PLA2R antibody — sera from 26 of 37 patients (70 percent) with idiopathic — but not secondary — membranous nephropathy specifically identified the M-type phospholipase A2 receptor; the autoantibodies were predominantly IgG4, the predominant immunoglobulin subclass in the glomerular deposits.^[4]
• Medication review — drug adverse effects are a named secondary cause of nephrotic syndrome in adults.^[1]

Step 3 — Renal biopsy, the decisive investigation

Renal biopsy is often recommended in adults with nephrotic syndrome, because the histological pattern drives treatment; in children a biopsy is usually not performed when the presentation is typical and the patient responds to oral prednisone at conventional doses — in that setting steroid-sensitive nephrotic syndrome can be considered synonymous with minimal change disease. The biopsy is read on light microscopy (LM), immunofluorescence (IF), and electron microscopy (EM):^[1][9]

• MCD — absence of visible alterations by light microscopy and effacement of foot processes by electron microscopy.^[9]
• Membranous — an autoimmune disease with thickening of the glomerular capillary walls due to immune complex deposition; the PLA2R target antigen sits on the podocyte membrane and co-localises with IgG4 in the deposits.^[4][14]
• FSGS — can be separated into primary, genetic or secondary causes; primary disease results in nephrotic syndrome.^[17]

The differential — two branch-points

The diagnosis is a clinical syndrome; the differential is the underlying cause. Two branch-points dominate.^[1][5]

Branch-point 1 — nephrotic vs nephritic: proteinuria-dominant with oedema and hypoalbuminaemia is nephrotic; haematuria/RBC casts/hypertension/renal failure/low complement is nephritic. Urinalysis and complement decide at the bedside.^[1][5]

Branch-point 2 — the glomerular causes, distinguished by histology and serology:^[1]

Oedema of nephrotic syndrome versus cardiac, hepatic, or malnutrition causes is separated by the urinalysis — patients typically present with oedema and fatigue without evidence of heart failure or severe liver disease, and heavy proteinuria with hypoalbuminaemia confirms the renal origin.^[1]

Management — general measures for every nephrotic patient

General measures apply to every nephrotic patient regardless of cause, and their disciplined application prevents most of the preventable morbidity.^[1]

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• Salt and fluid — fluid and sodium restriction is a cornerstone of oedema management in childhood nephrotic syndrome, used in combination with corticosteroids, albumin and diuretics.^[20]
• Diuretic therapy for oedema — the classical management pairing is diuretics with human albumin infusion, reflecting the underfill mechanism; newer understanding of kidney-limited sodium retention explains why volume status must be assessed before escalating diuretics.^[15]
• Treat suspected infection promptly — infection is one of the important complications of nephrotic syndrome and is amplified by immunosuppressive therapy; assess and treat promptly.^[1]

Enlarge

Management — definitive, by histology

Disease-specific therapy follows histology. Two principles hold for every nephrotic patient: reduce proteinuria and prevent complications.^[1][3]

Minimal change disease (MCD)

^{[12] [13] [9]}

For frequently relapsing or steroid-dependent disease, steroid-sparing therapies — alkylating agents and calcineurin inhibitors — are used, since among steroid-sensitive children 70 to 80 percent relapse at least once and up to half relapse frequently or become steroid-dependent. Rituximab, given with immunosuppression withdrawal, reduces disease recurrence in steroid-dependent or frequently-relapsing idiopathic nephrotic syndrome. Steroid-resistant disease suggests FSGS or a genetic podocytopathy such as an NPHS2 (podocin) mutation.^[20][21][18]

Membranous nephropathy

Membranous nephropathy runs a rule-of-thirds course. About one-third of patients may achieve spontaneous complete or partial remission with conservative management, another third follow an intermediate course, and another third face an elevated risk of disease progression, potentially to end-stage renal disease within 10 years — so treatment is risk-stratified rather than automatic. Roughly 80 percent of cases are primary; the remainder are linked to drug use or underlying conditions such as systemic lupus erythematosus, hepatitis B virus infection or malignancy.^[14]

• Rituximab — two intravenous infusions of 1000 mg each, administered 14 days apart, repeated at 6 months in case of partial response. MENTOR (Fervenza, NEJM 2019) enrolled patients with membranous nephropathy and proteinuria of at least 5 g per 24 hours receiving angiotensin-system blockade; rituximab was non-inferior to ciclosporin at 12 months (60 percent versus 52 percent complete or partial remission) and superior at 24 months (60 percent versus 20 percent).^[3]
• Ponticelli regimen (corticosteroid plus alkylating agent) — methylprednisolone 1 g intravenously for 3 consecutive days followed by oral methylprednisolone 0.4 mg/kg per day for 27 days, alternating every other month with chlorambucil 0.2 mg/kg per day or cyclophosphamide 2.5 mg/kg per day for 30 days; the whole treatment lasts 6 months — 3 months with corticosteroids and 3 months with one cytotoxic drug. The 1998 randomised trial found cyclophosphamide as effective as and less toxic than chlorambucil.^[6]
• Calcineurin inhibitors — ciclosporin (starting at 3.5 mg/kg per day for 12 months in MENTOR) remains the established comparator alternative.^[3]

Focal segmental glomerulosclerosis (FSGS)

FSGS separates into primary, genetic and secondary causes; primary disease results in nephrotic syndrome. Outcomes are guarded — only about 20 percent of adults with FSGS experience a partial or complete remission of nephrotic syndrome with treatment, and FSGS progresses to kidney failure in about half of the cases — which is why immunosuppressive decisions are individualised and no corticosteroid-versus-placebo randomised trial exists in adults. The DUPLEX trial (Rheault, NEJM 2023) showed sparsentan, a dual endothelin-angiotensin receptor antagonist, achieved a higher rate of partial remission of proteinuria than irbesartan at 36 weeks (42 percent versus 26 percent) in FSGS without known secondary causes.^[17][10]

Congenital nephrotic syndrome

There is no curative medical therapy for genetic CNS. Immunosuppressive medication is not helpful in the genetic forms, and kidney transplantation is the only curative therapy. Pre-transplant management depends on the magnitude of proteinuria: in severe cases daily albumin infusions are required to prevent life-threatening oedema, and the therapy also includes a hypercaloric diet, thyroxine and mineral substitution. The ERKNet-ESPN consensus recommends renin-angiotensin system inhibitors, diuretics, anticoagulation and infection prophylaxis, with management adapted to clinical severity to maintain intravascular euvolaemia, and nephrectomy considered in patients with severe complications despite optimal conservative treatment, and before transplantation in persisting nephrotic syndrome.^[8][16]

Antiproteinuric cornerstone — for all proteinuric kidney disease

^[19]

DAPA-CKD (Heerspink, NEJM 2020) enrolled 4304 participants with chronic kidney disease (eGFR 25 to 75 mL/min/1.73 m², urinary albumin-to-creatinine ratio 200 to 5000 mg/g), with or without type 2 diabetes; dapagliflozin 10 mg once daily reduced the composite of a sustained decline in eGFR, end-stage kidney disease, or death from renal or cardiovascular causes by 39 percent (hazard ratio 0.61) versus placebo over a median of 2.4 years.^[7]

Lipids and anticoagulation

• Lipids — hyperlipidaemia is part of the syndrome and one of its important complications; it should be recognised and managed as part of comprehensive care.^[1]
• Anticoagulation — nephrotic patients are at increased thromboembolic risk. In primary membranous nephropathy, it is helpful for clinicians to make a personalised decision on prophylactic aspirin or warfarin when serum albumin is under 3.2 g/dL (under 32 g/L); the treatment of established thromboembolic complications is largely similar to that in the general population.^[11]

Complications and pitfalls

Most complications arise directly from the proteinuric state, and the important ones are named in every major review:^[1]

• Thromboembolism — venous thrombosis is an important complication of nephrotic syndrome; in primary membranous nephropathy, where the thromboembolic risk is recognisably increased, personalised prophylactic aspirin or warfarin is suggested when serum albumin is under 3.2 g/dL (under 32 g/L).^[1][11]
• Infection — one of the important complications of nephrotic syndrome, amplified by immunosuppressive therapy; assess febrile nephrotic patients promptly.^[1]
• Hyperlipidaemia — "often with hyperlipidemia" is part of the syndrome definition in adults, and dyslipidaemia is an important complication to manage.^[1]

Prognosis and disposition

Prognosis depends almost entirely on the underlying cause.^[1][2]

Disposition — refer to nephrology, where renal biopsy is often recommended in adults and immunosuppressive therapy is individualised by histology and risk; plan for renal replacement therapy in progressive disease.^[1]

Special populations

• Children — minimal change disease is the commonest cause of nephrotic syndrome in school-aged children; corticosteroids are first-line, initiated at prednisone 60 mg/m² per day (2 mg/kg per day) for 4 to 6 weeks, followed by 40 mg/m² every other day for at least 6 to 8 weeks, and a renal biopsy is usually not performed when the presentation is typical and the child responds to oral prednisone.^[12][9]
• Adults — most cases are primary; membranous nephropathy and FSGS are the most common histologic subtypes, and the workup explicitly excludes diabetes mellitus, SLE and medication adverse effects.^[1]
• Elderly — secondary causes and drug adverse effects deserve particular attention on the history.^[1]
• Congenital — nephrotic-range proteinuria, hypoalbuminaemia and oedema in utero or in the first three months of life; the main cause is genetic podocyte defects, with congenital infection and maternal allo-immune disease in the differential — refer for specialist management.^[8][16]

Evidence, guidelines and regional differences

^{[3] [7] [10]}

• KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases is the international guideline reference for glomerular disease management.^[5]
• Anti-PLA2R antibody (Beck LH Jr, NEJM 2009) established the M-type phospholipase A2 receptor as the target antigen: sera from 26 of 37 patients (70 percent) with idiopathic — but not secondary — membranous nephropathy identified it specifically, and the autoantibodies were predominantly IgG4, the predominant subclass in the glomerular deposits.^[4]
• Ponticelli regimen (Ponticelli C, JASN 1998) — the randomised comparison establishing that methylprednisolone plus cyclophosphamide is as effective as and less toxic than methylprednisolone plus chlorambucil in idiopathic membranous nephropathy.^[6]
• IPNA 2023 clinical practice recommendations for steroid-sensitive nephrotic syndrome in children — approximately 85 to 90 percent attain complete remission of proteinuria within 4 to 6 weeks of glucocorticoids; among the steroid-sensitive, 70 to 80 percent relapse at least once and up to half become frequently-relapsing or steroid-dependent.^[13]

The mantra

Nephrotic = heavy proteinuria with hypoalbuminaemia and oedema, often with hyperlipidaemia; classify the cause; anticipate venous thrombosis, infection and dyslipidaemia.^[1][2]

Ward-round test

A 4-year-old with puffy eyes, frothy urine, 4+ protein, no blood — first move?ShowHide

This is classic minimal change disease — the commonest cause of nephrotic syndrome in school-aged children. Prednisone 60 mg/m² per day (2 mg/kg per day) for 4 to 6 weeks, then 40 mg/m² every other day for at least 6 to 8 weeks; a renal biopsy is usually not performed when the presentation is typical and the child responds to oral prednisone. Watch for and treat the important complications — infection, venous thrombosis and hyperlipidaemia.^[12][9]

A 65-year-old smoker with new nephrotic syndrome and a positive anti-PLA2R — what does the antibody tell you?ShowHide

Anti-PLA2R antibodies are found in idiopathic (primary) — but not secondary — membranous nephropathy (positive in 26 of 37 patients, 70 percent, in the discovery study, predominantly IgG4). A positive result therefore points to primary membranous nephropathy, but the history and selected diagnostic studies still exclude important secondary causes including medication adverse effects, lupus and malignancy-associated disease (about 20 percent of membranous nephropathy is secondary).^[4][14]

Sudden deterioration in a nephrotic patient — what complication must you consider?ShowHide

Venous thrombosis — an important complication of nephrotic syndrome, with a recognisably increased thromboembolic risk in primary membranous nephropathy. Consider it in any unexplained deterioration; in primary membranous nephropathy a personalised decision on prophylactic aspirin or warfarin is suggested when serum albumin is under 3.2 g/dL (under 32 g/L), and established events are treated as in the general population.^[1][11]

Nephrotic syndrome with severe hypoalbuminaemia — which decisions are individualised?ShowHide

Prophylactic anticoagulation and antiplatelet therapy are personalised, not automatic. In primary membranous nephropathy, prophylactic aspirin or warfarin is suggested when serum albumin is under 3.2 g/dL (under 32 g/L); in adults with nephrotic syndrome generally, management focuses on recognising and treating the important complications — venous thrombosis, infection and hyperlipidaemia — rather than blanket prophylaxis.^[11][1]

Name the histology of minimal change disease and the antibody of primary membranous nephropathy.ShowHide

MCD: absence of visible alterations by light microscopy with effacement of foot processes by electron microscopy — and in a child with typical presentation, steroid-sensitive nephrotic syndrome is synonymous with it. Primary membranous nephropathy: predominantly IgG4 anti-PLA2R autoantibodies, positive in about 70 percent of idiopathic cases and absent in secondary disease.^[9][4]

References21ShowHide

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