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 a urine protein-to-creatinine ratio of 600 mg/mmol, albumin 22 g/L, and an active sediment that is otherwise bland.[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 malignancy or a clot behind it? Everything below answers those questions at consultant depth.[1][5]

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

Nephrotic syndrome is the clinical expression of severe filtration-barrier (podocyte) injury. The defining tetrad is heavy proteinuria over 3.5 g/day (over 50 mg/kg/day in children, or a spot PCR over 300 mg/mmol), hypoalbuminaemia under 30 g/L (often under 25 g/L), oedema, and hyperlipidaemia with lipiduria. The protein losses drive the entire syndrome.[1]

The single most testable branch-point in glomerular medicine is nephrotic versus nephritic. Nephrotic is proteinuria-dominant — the tetrad above, with few or no cells in the sediment. 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.[2][9]

Relapse is urine protein 3+ or greater (or PCR over 200 mg/mmol) for 3 consecutive days, having previously been in remission. FRNS and SDNS prompt steroid-sparing agents (calcineurin inhibitor or rituximab) to spare the child cumulative steroid toxicity. SRNS carries the worst prognosis and the highest risk of progression to ESKD.[2]

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]

Congenital nephrotic syndrome (CNS) is a distinct, life-threatening entity presenting at birth or within the first three months. The Finnish type (autosomal recessive, NPHS1 encoding nephrin) is the classic — massive placental oedema (placenta over 25 percent of birth weight), premature delivery, severe oedema, proteinuria from the first days of life. Other genetic causes include diffuse mesangial sclerosis (NPHS2/podocin, WT1, PLCE1) and Pierson syndrome (LAMB2). Exclude congenital infections (syphilis, CMV, toxoplasmosis, malaria) in any neonate with nephrotic-range proteinuria.[8]

Why the barrier leaks — and what the losses cause

The filtration barrier has three layers, and the injury is to the podocyte. The fenestrated endothelium, the glomerular basement membrane (GBM), and the podocyte foot processes joined by the slit diaphragm (nephrin, podocin, CD2AP, synaptopodin). The barrier is both size- and charge-selective — it carries a net negative charge (heparan sulphate proteoglycans) that repels albumin, so normally only trace amounts cross (under 30 mg/day). In nephrotic syndrome, podocyte injury effaces the foot processes and disrupts the slit diaphragm; the barrier loses both charge and size selectivity, and albumin pours through.[1]

[1]

Oedema — the underfill vs overfill hypotheses. Underfill: hypoalbuminaemia lowers plasma oncotic pressure, fluid shifts to the interstitium, plasma-volume contraction activates RAAS, which drives sodium and water retention that perpetuates oedema. Overfill: the proteinuric kidney has a primary defect in sodium excretion — enhanced ENaC activity in the collecting duct, possibly driven by filtered serine proteases (plasminogen activator) that activate ENaC — so patients are often volume-overloaded with a raised JVP. Both mechanisms operate; the overfill dominates in most adults.[1]

Compensatory hepatic synthesis. The liver ramps up protein synthesis — but it cannot selectively make albumin, so it overproduces lipoproteins (hyperlipidaemia and lipiduria) and clotting factors, especially fibrinogen and factor VIII, while albumin still cannot keep up with the urinary loss. This explains two cardinal features at once: the hyperlipidaemia of the tetrad, and the hypercoagulable state (more fibrinogen plus urinary antithrombin-III loss).[1]

The two signature complications follow directly from which proteins are lost:[1]

• Infection — loss of IgG and alternative-pathway complement factors B and D impairs opsonisation of encapsulated organisms (Streptococcus pneumoniae, Haemophilus influenzae, Escherichia coli) → spontaneous bacterial peritonitis, cellulitis, pneumococcal sepsis. Highest when albumin is under 20 g/L; amplified by immunosuppression.
• Thrombosis — loss of antithrombin III, increased fibrinogen and factor VIII, platelet activation, and hemoconcentration from over-diuresis → renal vein thrombosis, DVT, PE. Highest in membranous nephropathy (up to 40 percent lifetime risk); correlates with the degree of hypoalbuminaemia.[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][5]

Causes in children

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

Causes in adults

In adults the sex ratio is roughly equal, and the leading primary causes are membranous nephropathy and FSGS, with diabetic nephropathy the single commonest secondary cause overall.[1]

• Membranous nephropathy — commonest in Caucasian adults (30 to 40 percent); subepithelial immune deposits and anti-PLA2R antibody (IgG4) positivity in 70 to 80 percent of primary cases.
• FSGS — 20 to 25 percent and rising; frequently steroid-resistant; collapsing variant strongly associated with HIV.
• Minimal change disease — 10 to 15 percent, often younger adults and in association with NSAIDs or Hodgkin lymphoma.
• Diabetic nephropathy — commonest secondary cause; typical picture (long-standing diabetes plus retinopathy plus gradual onset) needs no biopsy.
• Amyloidosis — AA from chronic inflammation (rheumatoid, IBD, chronic infection, familial Mediterranean fever); AL from plasma-cell dyscrasia; Congo-red positive.
• Lupus nephritis (class V membranous) — low complement, ANA/anti-dsDNA positive.
• HIV-associated nephropathy (HIVAN) — collapsing FSGS, rapid progression, predominantly in patients of African descent.
• Hepatitis B (membranous), hepatitis C (membranoproliferative/cryoglobulinaemic).
• Paraproteinaemic disease — multiple myeloma (AL amyloid or light-chain deposition disease).
• Drugs — NSAIDs (MCD or acute interstitial nephritis), pamidronate (collapsing nephropathy/FSGS), lithium (FSGS), gold, penicillamine, captopril (historical, membranous), heroin.[1][5]

Malignancy associations — memorise

A new nephrotic syndrome in an older adult is a pointer to occult malignancy until excluded. The two classic, high-yield associations:[1]

• Membranous nephropathy and solid-organ carcinoma — lung (commonest), colon, stomach, breast, prostate, kidney. Screen an elderly patient with new membranous with an age-appropriate malignancy workup (chest imaging, colonoscopy, mammography, PSA).
• Minimal change disease and Hodgkin lymphoma (less often non-Hodgkin). The Reed-Sternberg cell produces a cytokine (likely IL-13) that injures podocytes; the nephrotic syndrome may precede the lymphoma and remits with treatment of the tumour.[1]

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 — grade oedema (periorbital, dependent/sacral, ascites, pleural effusion, genital/scrotal); check JVP, blood pressure and weight; auscultate for basal crackles (volume overload) versus signs of volume depletion (over-diuresis). Document the daily weight — the single most reliable index of fluid balance.
• Screen for a secondary cause — fundoscopy (diabetic or hypertensive retinopathy); skin (lupus rash, purpura, xanthomata, striae); joints (synovitis); macroglossia (amyloidosis — a specific, easily-missed clue); abdominal masses and organomegaly; lymphadenopathy (Hodgkin/lymphoma, malignancy).
• Screen for complications at the bedside — calf tenderness, unilateral leg swelling (DVT); raised JVP and basal crackles (volume overload); fever, abdominal tenderness/peritonism (spontaneous bacterial peritonitis); cellulitis; signs of pulmonary embolism (tachypnoea, pleuritic pain, tachycardia, hypoxia).
• Targeted history — drugs (NSAIDs, lithium, pamidronate, gold), infection (HIV, hepatitis B/C), malignancy, family history (genetic SRNS, congenital nephrotic syndrome, consanguinity).[1]

Cause-specific clues to seek: diabetes/hypertension with long-standing disease → diabetic nephropathy; chronic rash, arthritis, alopecia, oral ulcers → lupus; chronic inflammatory disease with macroglossia and periorbital purpura → amyloidosis; weight loss, smoking, change in bowel habit → malignancy-associated membranous; fever, night sweats, painless lymphadenopathy → Hodgkin (MCD).[1]

Complication presentations may be the first sign that brings the patient to hospital: sudden flank or loin pain, haematuria, rising creatinine → renal vein thrombosis; fever, abdominal pain/peritonism or cellulitis → encapsulated-organism infection; dyspnoea, pleuritic chest pain, tachycardia → pulmonary embolism; xanthomata → severe hyperlipidaemia.[1]

Investigations — confirm, classify, biopsy

Confirm the syndrome, classify the cause, biopsy every adult. The workup has three layers.[1][4]

Step 1 — Confirm and quantify the syndrome

[1]

• Protein quantification — a 24-hour urine protein over 3.5 g/day (over 50 mg/kg/day in children) confirms nephrotic-range; a spot PCR over 300 mg/mmol (over 2 g/g) correlates well and avoids the collection errors of 24-hour urine.
• Serum chemistry — albumin under 30 g/L, renal function (urea, creatinine, eGFR), lipid profile (raised total cholesterol and triglycerides), FBC (haemoconcentration may mask anaemia).
• Urine microscopy — oval fat bodies / Maltese-cross under polarised light (lipiduria); hyaline casts; few or no red cells and no red-cell casts (distinguishes from nephritic). Bence-Jones protein if myeloma suspected.[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.
• ANA and anti-dsDNA — lupus.
• Complement C3 and C4 — low in lupus, membranoproliferative GN, post-infectious GN, cryoglobulinaemia (normal in MCD, membranous, FSGS).
• HBsAg, anti-HCV, HIV serology — infective secondary causes.
• Serum electrophoresis, serum free light chains and urine for Bence-Jones protein — myeloma and AL amyloid.
• Serum anti-PLA2R antibody — the hallmark of primary membranous nephropathy (about 70 to 80 percent sensitivity); also used to monitor disease activity and relapse.[4]
• Pregnancy test in women of childbearing age (pre-eclampsia).

Step 3 — Renal biopsy, the decisive investigation

Renal biopsy is indicated in all adults with nephrotic syndrome, because the histological pattern drives treatment. In children, biopsy is reserved for atypical presentations — age under 1 or over 10, hypertension, haematuria, low complement, renal impairment, or steroid-resistant disease — because the empiric steroid trial is both diagnostic and therapeutic in the classic paediatric case. The biopsy is read on light microscopy (LM), immunofluorescence (IF), and electron microscopy (EM):[1][5]

• MCD — normal LM, no immune deposits on IF, diffuse foot-process effacement on EM.
• Membranous — thickened GBM with spike-and-dome on silver stain (LM); granular subepithelial IgG4 (IF); subepithelial immune deposits (EM); anti-PLA2R positive.
• FSGS — focal segmental sclerosis with hyalinosis (LM); variable IgM/C3 (IF); foot-process effacement (EM); the collapsing variant (HIVAN) shows collapsing glomerulopathy with podocyte hypertrophy/hyperplasia.
• Amyloid — Congo-red apple-green birefringence under polarised light, with amyloid P component on IF.
• Diabetic — nodular glomerulosclerosis (Kimmelstiel-Wilson nodules) if biopsied, though biopsy is unnecessary if the clinical picture is typical.[1][5]

Baseline workup before immunosuppression — glucose, TB screen (Mantoux/IGRA), hepatitis B/C and HIV, bone-density (DEXA) before long steroids, and vaccination status (pneumococcal, influenza, hepatitis B up to date before immunosuppression).[5]

Imaging — renal ultrasound (kidney size, exclude obstruction or venous thrombosis); renal Doppler or CT venography for suspected renal vein thrombosis; age-appropriate malignancy screen (chest imaging, colonoscopy, mammography, PSA) in an elderly patient with new membranous.[1]

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 bland sediment 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 — heavy proteinuria with few cells is unique to the nephrotic kidney. Membranous carries the highest thrombosis risk and is the one most associated with carcinoma; MCD with Hodgkin; collapsing FSGS with HIV.[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 (infection, thrombosis, over-diuresis, accelerated vascular disease).[1]

• Salt and fluid — salt restriction (under 2 g, i.e. under 85 mmol sodium per day) is the single most effective non-drug oedema measure; fluid restriction is added only if hyponatraemic. Control blood pressure (target under 130/80 mmHg).
• Diuretic therapy for oedema — oral furosemide 40 mg daily, titrating to the daily weight; add a potassium-sparing diuretic — amiloride 5 to 10 mg or spironolactone 25 to 50 mg — for resistant oedema. For refractory oedema with severe hypoalbuminaemia (under 20 g/L), gut oedema limits oral absorption — give intravenous furosemide 40 to 80 mg combined with intravenous 20 to 25 percent albumin (e.g. 25 g) to restore oncotic pressure and deliver the diuretic to the tubule; weigh daily and avoid over-diuresis, which precipitates AKI.
• Treat suspected infection promptly — a nephrotic patient with fever is septic from an encapsulated organism until proven otherwise; give empirical broad-spectrum antibiotics immediately (e.g. IV ceftriaxone 1 to 2 g for suspected pneumococcal peritonitis or sepsis, with cloxacillin or vancomycin for cellulitis, adjusting to local resistance). Do not delay for cultures in the septic patient.
• Hospitalise for severe oedema, AKI, suspected thrombosis or infection, or for biopsy/immunosuppression.[1]

Management — definitive, by histology

Disease-specific therapy follows histology. Two principles hold for every nephrotic patient: reduce proteinuria (ACEi/ARB ± SGLT2i) and prevent complications (anticoagulation, vaccination).[1][3]

Minimal change disease (MCD)

[9]

For FRNS (two or more relapses within 6 months or four or more within 12 months) or SDNS (two consecutive relapses during taper or within 14 days of stopping), add a steroid-sparing agent: a calcineurin inhibitor (ciclosporin 4 to 5 mg/kg/day or tacrolimus 0.1 mg/kg/day, both monitored by trough levels) or rituximab (375 mg/m² per dose, typically two doses). SRNS — failure to remit after 4 to 6 weeks of daily steroids — mandates biopsy (exclude FSGS) and genetic testing; treat with calcineurin inhibitors, but the long-term ESKD risk is higher.[2][9]

Membranous nephropathy

Membranous nephropathy is risk-stratified at diagnosis. Low-risk patients (albumin over 30 g/L, normal renal function, proteinuria under 4 g/day) are managed conservatively, because about one-third undergo spontaneous remission within five years. High-risk patients (declining renal function, persistent proteinuria over 8 g/day for over 6 months, or severe symptomatic nephrotic syndrome) need immunosuppression:[3][5]

• Rituximab (first-line per KDIGO 2021 and the MENTOR trial) — 1 g IV on day 1 and day 15, repeated at 6 months. MENTOR (Fervenza, NEJM 2019) showed rituximab was non-inferior to ciclosporin at 12 months and superior at 24 months (lower relapse) in primary membranous nephropathy.[3]
• Ponticelli regimen (corticosteroid plus alkylating agent) — alternating monthly cycles: methylprednisolone 1 g IV daily for 3 days at the start of months 1, 3, 5 followed by oral prednisolone 0.5 mg/kg/day for the rest of the month, alternating with oral cyclophosphamide 2 to 2.5 mg/kg/day in months 2, 4, 6 — a 6-month course. The 1998 Ponticelli trial established cyclophosphamide was as effective as and less toxic than chlorambucil.[6]
• Calcineurin inhibitors (ciclosporin or tacrolimus) — an alternative when rituximab is unavailable or contraindicated; effective but relapse-prone on cessation.

Focal segmental glomerulosclerosis (FSGS)

Primary FSGS (an immune-mediated podocytopathy) is treated with high-dose steroids — prednisolone 1 mg/kg/day (maximum 80 mg) for up to 16 weeks before declaring steroid resistance, then a calcineurin inhibitor. Secondary FSGS (obesity, reduced renal mass, reflux nephropathy, sickle cell, heroin, HIV) is not immunosuppression-responsive and is managed by treating the cause plus ACEi/ARB. The DUPLEX trial (Rheault, NEJM 2023) showed sparsentan (a dual endothelin-A and angiotensin-II receptor antagonist) achieved greater proteinuria reduction than irbesartan at 36 weeks in primary FSGS.[10] Prognosis is guarded — up to 50 percent of primary FSGS progresses to ESKD within 5 to 10 years.

Congenital nephrotic syndrome

There is no curative medical therapy for genetic CNS. Management is supportive and staged: ACE inhibitor/ARB ± indomethacin to reduce proteinuria; aggressive nutritional support (high-calorie, high-protein feeds, often via nasogastric tube); daily intravenous albumin infusions (4 to 5 g/kg 20 percent albumin); thyroxine and vitamin D supplementation (loss of thyroxine-binding globulin and cholecalciferol-binding protein); anticoagulation for severe hypoalbuminaemia; and bilateral nephrectomy followed by peritoneal dialysis and renal transplantation once the child reaches adequate size (the only definitive cure, though anti-nephrin antibody-mediated recurrence in the graft is a recognised risk in Finnish-type disease).[8]

Antiproteinuric cornerstone — for all causes

[5] [7]

DAPA-CKD (Heerspink, NEJM 2020) showed dapagliflozin 10 mg/day reduced the composite of sustained eGFR decline, ESKD, or renal/cardiovascular death by 39 percent versus placebo across a broad CKD population including glomerular disease — making SGLT2 inhibition a new cornerstone of antiproteinuric management.[7]

Lipids and anticoagulation

• Lipids — statin (e.g. atorvastatin 20 to 40 mg at night) for persistent hyperlipidaemia; consider in all adults with nephrotic syndrome given the accelerated atherosclerotic risk.
• Anticoagulation — nephrotic patients are hypercoagulable (antithrombin-III loss, high fibrinogen, platelet activation, hemoconcentration). Prophylactic anticoagulation is reasonable when serum albumin is under 25 to 30 g/L, especially in membranous nephropathy (the highest-risk histology). After any thrombotic event, fully anticoagulate (LMWH/warfarin or a DOAC) for as long as nephrotic-range proteinuria persists.[11]

Vaccination

Pneumococcal (conjugate PCV13 then polysaccharide PPSV23), annual influenza, and hepatitis B vaccination — ideally before immunosuppression. Avoid live vaccines (BCG, MMR, varicella, oral polio) while on immunosuppression.[1]

Complications and pitfalls

Most complications arise directly from urinary protein loss — the identity of the lost protein determines the complication:[1]

• Thromboembolism — renal vein thrombosis, DVT, PE from antithrombin-III loss and high fibrinogen; highest in membranous nephropathy (lifetime risk up to 40 percent). Anticoagulate when albumin is under 25 to 30 g/L or after any thrombosis. Presentation is sudden flank pain, haematuria, deteriorating GFR; image with Doppler or CT venography.
• Infection — encapsulated bacteria (pneumococcus, H. influenzae, E. coli); spontaneous bacterial peritonitis (classically pneumococcal, in nephrotic ascites), cellulitis, pneumococcal sepsis. Mechanism: urinary IgG and alternative-complement (factor B/D) loss. Vaccinate; treat empirically and early.
• Hyperlipidaemia — accelerated atherosclerosis and cardiovascular risk; also acute pancreatitis from severe hypertriglyceridaemia. Treat with a statin.
• AKI — from volume depletion, diuretic overuse, bilateral renal vein thrombosis, or progression. Monitor creatinine and weight; avoid over-diuresis.
• Malnutrition and metabolic — protein malnutrition; hypocalcaemia and vitamin D deficiency (loss of cholecalciferol-binding protein); iron-deficiency anaemia (transferrin loss); hypothyroidism (loss of thyroxine-binding globulin, especially in congenital nephrotic syndrome).
• Acute tubular injury — the heavy protein load damages proximal tubular cells, contributing to AKI risk and interstitial fibrosis over time.[1]

Classic pitfalls to avoid: not anticoagulating a severely hypoalbuminaemic patient; missing renal vein thrombosis; not vaccinating; treating oedema with over-diuresis causing AKI; forgetting the ACEi/ARB; failing to biopsy an adult; not screening an elderly patient with membranous nephropathy for malignancy.[1]

Prognosis and disposition

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

Predictors of a poor renal outcome — the four that recur across every glomerular disease: persistent heavy proteinuria, hypertension, reduced renal function at presentation, and interstitial fibrosis with tubular atrophy (IFTA) on biopsy.[1]

Disposition — refer to nephrology for biopsy and immunosuppression as indicated; plan for renal replacement therapy in progressive ESKD, noting that FSGS may recur in the transplant (warranting early aggressive treatment with plasmapheresis and rituximab) whereas genetic FSGS does not recur.[1]

Special populations

• Children — MCD commonest; empiric prednisolone 60 mg/m²/day without biopsy for a classic presentation (age 1 to 10, normotensive, no haematuria, normal complement and renal function); lower threshold to biopsy if atypical or steroid-resistant. Weight-based dosing throughout. Pneumococcal peritonitis is a classic childhood emergency and may be the first presentation of occult nephrotic syndrome.[2]
• Elderly — membranous nephropathy and secondary causes (malignancy, amyloidosis) dominate; actively screen for solid-organ malignancy; higher thrombosis risk and higher drug-toxicity considerations.
• Pregnancy — distinguish nephrotic syndrome from pre-eclampsia (new hypertension after 20 weeks, hyperuricaemia, low complement in some, resolves post-partum); switch ACEi/ARB to labetalol or nifedipine (ACEi/ARB are fetotoxic, especially 2nd/3rd trimester); monitor fetal growth and maternal renal function.
• Diabetic patients — diabetic nephropathy is the commonest secondary cause; do not routinely biopsy if typical (retinopathy, long-standing diabetes, gradual onset); ACEi/ARB and SGLT2 inhibitor are the cornerstone.
• Immunocompromised / HIV — HIVAN presents as collapsing FSGS with rapid progression, predominantly in patients of African descent; screen (HIV test) and start antiretroviral therapy plus ACEi, which has transformed the prognosis.[1]

Evidence, guidelines and regional differences

[7]

• KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases is the international standard — defining biopsy indications, the role of anti-PLA2R antibody (avoiding biopsy in some primary membranous), and risk-stratified immunosuppression (rituximab-based for membranous).[5]
• Anti-PLA2R antibody (Beck LH Jr, NEJM 2009) established the M-type phospholipase A2 receptor as the target antigen in approximately 70 to 80 percent of primary membranous nephropathy; it is now both a diagnostic marker and an activity/relapse-monitoring marker.[4]
• Ponticelli regimen (Ponticelli C, JASN 1998) — the randomised comparison establishing the modern steroid-plus-cyclophosphamide regimen for idiopathic membranous nephropathy.[6]
• IPDN / KDIGO paediatric practice standardises childhood SSNS and SRNS — first-line prednisolone 60 mg/m²/day, definitions of frequent relapse/steroid-dependence/steroid-resistance, and early use of calcineurin inhibitors/rituximab for FRNS/SDNS, with biopsy and genetics for SRNS.[2]

The mantra

Nephrotic = tetrad and bland sediment; biopsy every adult; treat the cause; anticoagulate the hypoalbuminaemic, vaccinate the immunosuppressed. The lost protein names the complication.[1][5]

Ward-round test

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

This is classic minimal change disease. Prednisolone 60 mg/m²/day for 4 to 6 weeks, no biopsy (age 1 to 10, normotensive, no haematuria, normal complement and function). Screen for and prevent the complications — vaccinate, watch for spontaneous pneumococcal peritonitis.[2][9]

A 65-year-old smoker with new nephrotic syndrome and a positive anti-PLA2R — what else must you do?

Screen for occult solid-organ malignancy — membranous nephropathy associates with lung (commonest), colon, stomach, breast, prostate, kidney carcinoma. Chest imaging, colonoscopy, PSA/mammography as appropriate. The anti-PLA2R marks primary membranous, but malignancy screening is still warranted in an older smoker.[1][4]

Sudden flank pain, haematuria and a rising creatinine in a nephrotic patient — diagnosis and action?

Renal vein thrombosis — the signature thrombotic complication (antithrombin-III loss, highest in membranous). Image with Doppler or CT venography and anticoagulate (LMWH/warfarin or a DOAC) for as long as nephrotic-range proteinuria persists.[1][11]

Nephrotic syndrome, albumin 18 g/L — which two interventions are non-negotiable?

Prophylactic anticoagulation (albumin under 25 to 30 g/L, especially membranous — the highest-risk histology) and vaccination (pneumococcal, influenza, hepatitis B) before any immunosuppression. Both prevent the two signature causes of preventable death — thrombosis and encapsulated-organism sepsis.[1][11]

Name the histology triad for membranous nephropathy and the antibody.

LM: thickened GBM with spike-and-dome (silver stain). IF: granular subepithelial IgG4. EM: subepithelial immune deposits. Antibody: anti-PLA2R (positive in 70 to 80 percent of primary disease; also monitors relapse).[4][5]

References

1. [1]Kodner C. Diagnosis and Management of Nephrotic Syndrome in Adults Am Fam Physician, 2016.PMID 26977832
2. [2]Downie ML, Gallibois C, Parekh RS, et al. Nephrotic syndrome in infants and children: pathophysiology and management Paediatr Int Child Health, 2017.PMID 28914167
3. [3]Fervenza FC, Appel GB, Barbour SJ, et al. Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy N Engl J Med, 2019.PMID 31269364
4. [4]Beck LH Jr, Bonegio RG, Lambeau G, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy N Engl J Med, 2009.PMID 19571279
5. [5]Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases Kidney Int, 2021.PMID 34556256
6. [6]Ponticelli C, Altieri P, Scolari F, et al. A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy J Am Soc Nephrol, 1998.PMID 9513907
7. [7]Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in Patients with Chronic Kidney Disease N Engl J Med, 2020.PMID 32970396
8. [8]Jalanko H. Congenital nephrotic syndrome Pediatr Nephrol, 2009.PMID 17968594
9. [9]Vivarelli M, Massella L, Ruggiero B, Emma F. Minimal Change Disease Clin J Am Soc Nephrol, 2017.PMID 27940460
10. [10]Rheault MN, Alpers CE, Barratt J, et al. Sparsentan versus Irbesartan in Focal Segmental Glomerulosclerosis N Engl J Med, 2023.PMID 37921461
11. [11]Zou H, Li Y, Xu G Management of anticoagulation and antiplatelet therapy in patients with primary membranous nephropathy BMC Nephrol, 2019.PMID 31791286