Medicine chapters
Nephrotic syndrome in adults
Heavy proteinuria, low albumin, oedema and high lipids in adults: the primary and secondary causes, the lab findings that point to each, complications such as thrombosis and infection, and general and specific treatment.
- Nephrotic syndrome = proteinuria >3.5 g/day, hypoalbuminaemia, oedema and hyperlipidaemia, caused by a leaky podocyte filter.
- In adults the main primary causes are membranous nephropathy, FSGS and minimal change disease; the main secondary causes are diabetes, amyloidosis, lupus, drugs, infections and cancer.
- Treat with salt restriction, loop diuretic, ACE inhibitor/ARB, statin, consider anticoagulation, and give disease-specific therapy (steroids for minimal change; rituximab or cyclophosphamide for high-risk membranous).
On this page
Overview
Nephrotic syndrome is a clinical picture, not a single disease. Damage to the podocyte layer of the glomerular filter lets large amounts of protein, mainly albumin, into the urine. The result is:
- Proteinuria >3.5 g/24 h (uPCR above about 350 mg/mmol).
- Hypoalbuminaemia.
- Oedema.
- Hyperlipidaemia and lipiduria.
In children it is nearly always minimal change disease. In adults there are many causes, so renal biopsy is usually needed. Complications (thrombosis, infection, AKI) can be life-threatening.
Pathophysiology (why each feature happens)
| Feature | Explanation |
|---|---|
| Proteinuria | Damage to podocyte foot processes and the slit diaphragm (and loss of the negative charge of the barrier) lets albumin and larger proteins through |
| Hypoalbuminaemia | Urinary loss plus increased breakdown of filtered albumin in the proximal tubule; the liver cannot keep up despite making more |
| Oedema | Low plasma oncotic pressure ("underfill") and primary renal sodium retention ("overfill") |
| Hyperlipidaemia | The liver makes more lipoproteins as albumin falls; LDL rises (PCSK9 up), triglyceride clearance falls |
| Hypercoagulability | Urinary loss of antithrombin III (and proteins C and S), increased hepatic fibrinogen, platelet activation, haemoconcentration |
| Infection risk | Loss of IgG and complement factors in urine; oedema fluid and ascites act as culture media |
| Other losses | Thyroid-binding globulin (confusing thyroid tests), vitamin D-binding protein, transferrin |
Aetiology
Primary (idiopathic) glomerular disease
| Disease | Typical patient | Light microscopy | Immunofluorescence / EM | Steroid response |
|---|---|---|---|---|
| Minimal change disease | Children (most cases); 20–25% of adult cases; atopy | Normal | IF negative; EM foot process effacement | Excellent |
| FSGS | All ages; commonest in people of African descent | Some glomeruli, part of each tuft sclerosed | IF negative or IgM/C3 in scars; EM effacement | Often poor |
| Membranous nephropathy | Adults, mainly men; classic primary cause in white adults | Thick GBM; "spikes" on silver stain | Granular IgG4 and C3; EM subepithelial deposits ("spike and dome") | Steroids alone do not work |
| Membranoproliferative GN | Children and young adults | Thick GBM, "tram-track", lobular | Granular C3 ± IgG; subendothelial or dense deposits | Poor |
Secondary causes
| Group | Examples |
|---|---|
| Metabolic | Diabetic nephropathy (commonest secondary cause): Kimmelstiel–Wilson nodular glomerulosclerosis |
| Deposition | Amyloidosis: AL (myeloma, plasma cell dyscrasia) and AA (chronic inflammation: rheumatoid arthritis, TB, bronchiectasis, familial Mediterranean fever); Congo red stain with apple-green birefringence |
| Autoimmune | SLE (class V membranous lupus nephritis) |
| Infections | Hepatitis B (membranous), hepatitis C (MPGN, cryoglobulins), HIV (collapsing FSGS), malaria (P. malariae), schistosomiasis, syphilis |
| Drugs | NSAIDs (minimal change, membranous), penicillamine, gold, captopril, lithium, interferon, heroin (FSGS) |
| Cancer | Solid tumours (lung, colon, breast, stomach) → membranous; Hodgkin lymphoma → minimal change |
| Others | Pre-eclampsia, sickle cell disease, obesity and reduced nephron mass (secondary FSGS) |
A middle-aged or older adult with membranous nephropathy needs screening for cancer (and hepatitis B, lupus and drugs). Hodgkin lymphoma classically causes minimal change disease.
Specific diseases in brief
Minimal change disease
- Glomeruli look normal on light microscopy; only electron microscopy shows fused (effaced) foot processes. No immune deposits.
- Thought to be a T-cell or cytokine disorder affecting podocytes. Triggers: NSAIDs, lithium, antibiotics, atopy and allergy, Hodgkin lymphoma.
- Selective proteinuria (albumin lost, larger immunoglobulins kept).
- Abrupt onset of oedema; BP and kidney function usually normal.
- Does not usually lead to CKD.
Focal segmental glomerulosclerosis (FSGS)
- Primary: probably a circulating permeability factor; heavy, non-selective proteinuria, often with haematuria, hypertension and impaired function; recurs in transplants.
- Secondary: response to reduced nephron mass and hyperfiltration (obesity, reflux, single kidney, sickle cell), HIV-associated nephropathy (collapsing variant, responds to antiretroviral therapy), heroin, APOL1 gene variants in people of African ancestry.
- Deep juxtamedullary glomeruli are affected first and can be missed on biopsy, leading to a wrong label of minimal change.
- Around half of patients reach ESKD within 10 years.
Membranous nephropathy
- About 75% of primary cases have IgG4 antibodies to the phospholipase A2 receptor (anti-PLA2R) on podocytes; a serum test helps diagnosis and monitoring.
- Thick capillary walls, subepithelial immune deposits with basement membrane spikes between them.
- Rule of thirds: about one-third remit spontaneously, one-third persist, and a significant proportion progress to CKD.
- Highest thrombosis risk of all causes, especially renal vein thrombosis.
Membranous nephropathy is the nephrotic lesion most linked to renal vein thrombosis; suspect it with sudden flank pain, haematuria or a jump in proteinuria.
Diabetic nephropathy: microalbuminuria → overt proteinuria → falling GFR; hypertension and retinopathy usually present; kidneys often normal-sized. Biopsy is not needed if the course is typical.
Amyloidosis: nephrotic syndrome with large kidneys, often with hepatomegaly, heart failure or neuropathy; diagnose with biopsy (kidney, rectal or fat pad) stained with Congo red.
Lab findings
Confirming the syndrome
- Urine dipstick: protein +++ or more; frothy urine.
- uPCR (or 24-hour urine protein) >3.5 g/day equivalent.
- Serum albumin: low.
- Lipids: raised total and LDL cholesterol and triglycerides.
- Urine microscopy: fatty casts, oval fat bodies (Maltese cross); haematuria suggests a nephritic component (FSGS, MPGN, lupus).
- Urea, creatinine, eGFR: often normal at first.
- Total calcium low (less albumin binding); ionised calcium normal.
- ESR often high (raised fibrinogen).
Finding the cause
- Glucose and HbA1c; retinal examination (diabetic nephropathy).
- ANA, anti-dsDNA, C3 and C4 (lupus, MPGN).
- Anti-PLA2R antibody (primary membranous).
- Hepatitis B and C, HIV serology; syphilis serology.
- Serum protein electrophoresis, serum light chain assay, urine Bence Jones protein (myeloma, AL amyloid).
- Age-appropriate cancer screening in membranous disease.
- Ultrasound: kidney size (large in amyloid, diabetes, HIV); renal vein Doppler if thrombosis suspected.
- Renal biopsy in nearly all adults: light microscopy, immunofluorescence and electron microscopy.
In children with typical nephrotic syndrome, steroids are given without biopsy; biopsy is reserved for steroid resistance or atypical features (haematuria, hypertension, low complement, renal failure, age outside the usual range).
Complications
Infection (pneumococcus, peritonitis) and thrombosis are the complications most likely to kill a nephrotic patient.
| Complication | Points to know |
|---|---|
| Venous thromboembolism | DVT, PE, renal vein thrombosis (flank pain, haematuria, sudden rise in proteinuria or creatinine); highest risk in membranous disease and with very low albumin |
| Arterial thrombosis | Less common; MI and stroke risk raised with hyperlipidaemia |
| Infection | Pneumococcal pneumonia, cellulitis, spontaneous bacterial peritonitis (especially children); a major cause of death |
| AKI | Hypovolaemia (over-diuresis), renal vein thrombosis, NSAIDs, interstitial nephritis from diuretics |
| Hyperlipidaemia | Accelerated atherosclerosis |
| Protein malnutrition | Muscle wasting |
| Hypovolaemia | Despite oedema; postural hypotension when diuresed hard |
| Progressive CKD | FSGS, membranous, diabetic, amyloid |
| Drug effects | Steroids, cyclophosphamide, calcineurin inhibitor toxicity |
Management
General measures (all patients)
- Oedema: dietary salt restriction and a loop diuretic (furosemide or bumetanide). Resistant cases need larger doses (furosemide 40–120 mg daily or more) plus amiloride (5 mg daily, watch potassium) or a thiazide. Gut wall oedema can impair absorption, so IV furosemide may be needed at first. Aim for gradual weight loss to avoid hypovolaemia.
- Reduce proteinuria: ACE inhibitor or ARB in all, titrated up; monitor potassium and creatinine. Target BP below 130/80 mmHg.
- Diet: normal protein intake; high-protein diets increase proteinuria and harm the kidney.
- Lipids: statin.
- Thrombosis: avoid prolonged bed rest; prophylactic anticoagulation in high-risk patients (e.g. membranous with very low albumin); full anticoagulation for any thrombosis, long-term after renal vein thrombosis.
- Infection: pneumococcal vaccine (and influenza); treat infections early and aggressively rather than giving long-term antibiotics. Avoid live vaccines while on high-dose steroids.
Patients can be intravascularly depleted despite massive oedema; aggressive diuresis may cause postural hypotension and prerenal AKI.
- IV albumin is reserved for severe hypovolaemia or resistant oedema (combined with a diuretic); its effect is brief.
General care = "DASH": Diuretic + salt restriction, ACE inhibitor/ARB, Statin, Heparin (anticoagulation when high risk).
Specific treatment
| Disease | Treatment |
|---|---|
| Minimal change | Prednisolone at high dose. Children respond within weeks (>95%); adults respond more slowly (up to about 12 weeks of daily treatment, then tapering). Relapsing or steroid-dependent disease: ciclosporin or tacrolimus, cyclophosphamide, rituximab; levamisole in children |
| FSGS (primary) | Prednisolone for up to 6 months before calling it steroid-resistant; calcineurin inhibitors next; ACE inhibitor/ARB for all; treat cause in secondary FSGS (antiretroviral therapy for HIVAN, weight loss) |
| Membranous | Supportive care and watch for 6–12 months if low risk (many remit). High risk (heavy proteinuria, falling function, high anti-PLA2R titre): rituximab, or cyclophosphamide alternating with steroids (modified Ponticelli), or calcineurin inhibitors. Steroids alone do not help |
| Diabetic | Glycaemic control, BP control with ACE inhibitor/ARB, SGLT2 inhibitor; stop smoking |
| Amyloid | AL: chemotherapy directed at the plasma cell clone; AA: control the inflammatory cause |
| Lupus | Immunosuppression according to class |
| Secondary | Stop the drug, treat the infection or cancer |
Steroid response terms: steroid-sensitive (remission on steroids), steroid-dependent (relapses on tapering or soon after stopping), frequent relapser, and steroid-resistant (no remission despite an adequate course; consider FSGS or a genetic podocyte disorder).
Expect: the definition and the 3.5 g/day cut-off; the commonest cause in children (minimal change) and the main adult causes (membranous, FSGS, diabetes); biopsy appearances (normal light microscopy with effaced foot processes; spikes and subepithelial deposits; segmental sclerosis); anti-PLA2R; disease associations (hepatitis B and cancer with membranous, Hodgkin with minimal change, HIV and heroin with FSGS, myeloma or chronic infection with amyloid and Congo red); the mechanisms and treatment of oedema, thrombosis (antithrombin loss, renal vein thrombosis) and infection (pneumococcus); and which disease responds best to steroids.
Quick revision
- Nephrotic: protein >3.5 g/day, low albumin, oedema, high lipids; podocyte injury.
- Minimal change: normal light microscopy, foot process effacement on EM; steroid-sensitive; Hodgkin and NSAIDs.
- FSGS: African descent, HIV (collapsing), heroin, obesity; steroid-resistant; recurs after transplant.
- Membranous: anti-PLA2R, subepithelial deposits, spikes; hepatitis B, SLE, cancer, drugs; renal vein thrombosis.
- Diabetic: Kimmelstiel–Wilson nodules. Amyloid: Congo red, apple-green; big kidneys.
- Thrombosis from antithrombin III loss; infections from IgG loss.
- Treat: salt restriction, loop diuretic ± amiloride, ACE inhibitor/ARB, statin, anticoagulation if high risk, pneumococcal vaccine.
- Specific: steroids (minimal change, FSGS); rituximab or cyclophosphamide + steroids (high-risk membranous).
Written by The House Job from standard references (Kumar and Clark's Clinical Medicine; Fundamentals of Pathology).
FAQ
Why are nephrotic patients at risk of clots?
They lose anticoagulant proteins such as antithrombin III in the urine while the liver makes more fibrinogen and other clotting factors, so the blood becomes hypercoagulable.
Why does minimal change disease have that name?
On ordinary light microscopy the glomeruli look normal; the only change, fusion of podocyte foot processes, is seen on electron microscopy.
Should nephrotic patients eat a high-protein diet?
No. A normal protein intake is advised, because extra protein increases proteinuria and may speed kidney damage.
Which nephrotic disease needs a cancer search?
Membranous nephropathy, especially in older adults, because solid tumours of the lung, bowel, stomach and breast can cause it.