Nephrotic syndrome

• Nephrotic syndrome is the clinical pattern of a leaky glomerular filter: proteinuria above 3.5 g per day (or a protein to creatinine ratio above 300 to 350 mg per mmol), hypoalbuminaemia, oedema, hyperlipidaemia and lipiduria.
• It is a syndrome, not one disease; a range of glomerular pathologies produce it, and the cause is found with biopsy and serology.
• Each feature can be reasoned from its mechanism.
• The two big dangers are thrombosis and infection; renal vein thrombosis in particular is a classic complication of membranous nephropathy.
• Care has two layers: meticulous supportive care for everyone, and cause-directed immunosuppression for selected patients. Children and adults are managed differently.

By the end of this page you should be able to:

1. State the full definition and distinguish nephrotic syndrome from nephritic syndrome.
2. Explain each of the five classic features from its mechanism.
3. Match each major cause to its clinical clues, histology and treatment.
4. Plan investigations and state the indications for renal biopsy.
5. Use the KDIGO 2021 approach to supportive care, drugs and anticoagulation thresholds.
6. Describe childhood versus adult differences.
7. Recognise complications and red flags.
8. Outline management where tests or drugs are scarce.

Heavy proteinuria is usually recorded on a 24-hour collection or on a spot protein to creatinine ratio. Timed collections are more accurate and less variable when proteinuria is heavy, so KDIGO places weight on them for markedly proteinuric patients.^[1]

The five features cluster because they share one root: a filtration barrier that no longer selects. Protein leaks through in large amounts; water and sodium are retained because oncotic pressure falls and neurohormonal systems activate; the liver overproduces lipoproteins in response to albumin loss while their clearance is impaired.

Nephrotic syndrome must be separated from nephritic syndrome, whose dominant features are haematuria with red cell casts, hypertension, mild to moderate proteinuria and modest oedema. A patient can have both, but the investigations and urgency differ: red cell casts and rapidly falling filtration suggest a crescentic immunological process, whereas heavy proteinuria with low albumin and lipid abnormalities indicates a permeability disorder.

A further classification that helps in membranous nephropathy is risk stratification by likelihood of progression (low, medium, high, very high). Primary (idiopathic) and secondary glomerular causes are also separated clinically, because treating a secondary cause (hepatitis B or C, lupus, a solid tumour, a drug) is the first step of treatment.^[3]

Incidence varies with region and age. Minimal change disease accounts for the large majority of idiopathic childhood cases, while membranous nephropathy is the leading primary cause in older non-diabetic adults.^[2][3]

Primary glomerular diseases (minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy) sit alongside secondary causes (diabetes, lupus, infection, drugs, amyloid). Cardiovascular and thrombotic risk rises steeply once the syndrome is established, even before kidney function falls.^[2]

Causes fall into four groups:

Figure 1Focal segmental glomerulosclerosis - high mag

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Light micrograph of a glomerulus in focal segmental glomerulosclerosis, high magnification.

Podocytes form the final filtration barrier. When their foot processes flatten or detach, protein leaks. Minimal change disease and focal segmental glomerulosclerosis are the classic podocytopathies.

Figure 2Membranous Nephropathy Pathology Diagram

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Schematic of a glomerular capillary wall in membranous nephropathy: immune deposits beneath the podocytes, with spikes of basement membrane growing around them as the disease becomes more severe.

In membranous nephropathy, immune complexes deposit on the outer aspect of the glomerular basement membrane. In about 70 to 80% of primary disease the target is the M-type phospholipase A2 receptor (PLA2R). Secondary membranous nephropathy can follow hepatitis B, hepatitis C, syphilis, systemic lupus erythematosus, a solid organ tumour or drugs.^[1][3]

Figure 3Diabetic glomerulosclerosis (4) PAS

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PAS-stained glomerulus with diabetic nodular glomerulosclerosis.

Renal amyloidosis (AL the commonest, from a plasma cell dyscrasia; AA from chronic inflammation) deposits fibrils in the glomerulus. Diabetic nephropathy deposits matrix and produces nodular sclerosis.

Figure 4Membranoproliferative glomerulonephritis - very high mag

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Very high magnification light micrograph of membranoproliferative glomerulonephritis.

Membranoproliferative (mesangiocapillary) glomerulonephritis and C3 glomerulopathy produce a mixed picture. Lupus nephritis (especially class V) and cryoglobulinaemia, most often from chronic hepatitis C, complete the classic list.

Risk factors include recent infection in children, long-standing diabetes, systemic lupus erythematosus, hepatitis B or C, HIV, malignancy (membranous nephropathy in an older adult always raises the question of a solid tumour), drugs (NSAIDs, gold, penicillamine, lithium, interferon, checkpoint inhibitors), and a family history of renal disease. Children with steroid-resistant disease should be considered for genetic testing, since monogenic podocyte disease explains a substantial proportion of steroid-resistant cases.^[1]

The glomerular filtration barrier has three layers: fenestrated endothelium, glomerular basement membrane, and the slit diaphragm between podocyte foot processes. Injury lifts or thins the electrical and size barrier. Podocyte flattening (foot process effacement) is the shared ultrastructural change in minimal change disease and focal segmental glomerulosclerosis; in membranous nephropathy it is subepithelial immune deposits with reactive basement membrane spikes; in diabetic nephropathy it is a thickened basement membrane with mesangial expansion.

Albumin is small enough to be filtered in large amounts once the barrier is damaged, and tubular reabsorption cannot keep up. Hepatic albumin synthesis rises but does not compensate fully, so serum albumin falls. Creatinine-based equations overestimate true glomerular filtration rate in patients with nephrotic syndrome and hypoalbuminaemia, which matters when timing drugs or judging progression.^[1]

Two processes combine. Falling oncotic pressure lets fluid shift from plasma to interstitium. The kidney senses a reduced effective arterial blood volume and activates the renin-angiotensin-aldosterone system, sympathetic fibres and vasopressin, leading to renal sodium and water retention. Filtered serine proteases may stimulate tubular sodium reabsorption directly. The result is periorbital oedema on waking, ankle swelling later in the day and, when severe, ascites and pleural effusions. Patients can be intravascularly depleted while grossly oedematous, and aggressive diuresis can precipitate acute kidney injury.

The liver increases lipoprotein synthesis in response to hypoalbuminaemia, and clearance falls: lipoprotein lipase activity is reduced, hepatic lipase falls, and proprotein convertase subtilisin/kexin type 9 (PCSK9) rises, lowering LDL receptor expression. Patients develop elevated LDL, VLDL and triglycerides, elevated lipoprotein(a), and abnormal HDL with impaired reverse cholesterol transport. Podocyte-derived angiopoietin-like 4 provides a molecular link between glomerular protein leak and systemic dyslipidaemia. The picture is both atherogenic and thrombogenic.^[2]

Lipids lost in the urine give fatty casts and oval fat bodies on microscopy. Cholesterol and cholesterol esters accumulate in renal tubular epithelial cells. Lipiduria is a consequence of hyperlipidaemia spilling through a damaged barrier, not a separate disease.

Patients describe swelling first: periorbital puffiness on waking, abdominal swelling, breathlessness from pleural effusion, ankle swelling. Urine may look frothy from heavy protein. Fatigue, poor appetite and weight loss are common; children may have relapsing oedema with minor infections. Ask about triggers (recent infection in a child, diabetes, lupus, hepatitis, drugs, malignancy, pregnancy) and about complications (calf or chest pain suggesting thrombosis, breathlessness from pulmonary embolism, dark urine from renal vein thrombosis, fever suggesting infection).

Look for gravity-dependent oedema, periorbital oedema, ascites, pleural effusions, scrotal oedema. Measure blood pressure properly. Look for xanthelasma, and for signs of the underlying cause: diabetic retinopathy or neuropathy, malar rash or arthritis in lupus, purpura in cryoglobulinaemia, lymphadenopathy or hepatosplenomegaly in amyloidosis. Test urine for blood: pure nephrotic syndrome has little or no haematuria; blood in the urine swings the differential toward a nephritic process. Minimal change disease often develops over days; membranous nephropathy or diabetic nephropathy over weeks to months.

Nephrotic-range proteinuria is not always nephrotic syndrome; heart failure or severe hypoalbuminaemia from liver disease can mimic some features. Nephritic syndrome with red cell casts is the important alternative. The table separates the causes by their fingerprints.

Red flags include visible haematuria with clots, red cell casts, rapidly rising creatinine, severe hypertension, haemoptysis and nephrotic-range proteinuria in an older adult, which should prompt a search for malignancy in suspected membranous nephropathy.

• Urinalysis: dipstick protein, microscopy for casts and, if blood is present, dysmorphic red cells. Heavy proteinuria, fatty casts and oval fat bodies point toward nephrotic rather than nephritic disease.
• Quantify protein: protein to creatinine ratio on a spot sample, backed by a timed collection where proteinuria is heavy, because timed collections are more accurate and less variable.^[1]
• Renal function and electrolytes: creatinine, estimated glomerular filtration rate, urea or BUN, sodium, potassium, bicarbonate. Creatinine-based estimates overestimate filtration in nephrotic syndrome.^[1]
• Serum albumin, with the assay method noted, because bromocresol green and bromocresol purple give different values and anticoagulation decisions depend on the method.^[2]
• Full blood count and lipid profile.
• Blood pressure and volume assessment.
• Renal ultrasound to exclude obstruction and to judge size and chronicity.

• Complement C3 and C4 (often low in lupus, normal in minimal change and membranous disease); antinuclear antibodies and anti-double-stranded DNA where lupus suspected.
• Hepatitis B and C serology in everyone with glomerular disease, HIV testing where risk factors exist, syphilis and tuberculosis screening where prevalence or risk demands it.^[1]
• Antiphospholipase A2 receptor antibodies (PLA2R) when membranous nephropathy suspected: sensitivity roughly 0.65 to 0.8 and specificity roughly 0.95 to 0.99, depending on the assay.^[1]
• ANCA, anti-GBM, cryoglobulins and serum and urine electrophoresis with immunofixation where a paraprotein disease is suspected, especially in older adults.

Figure 6Membranous nephropathy - cropped - mpas - very high mag

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Silver-stained (methenamine) glomerulus in membranous nephropathy, very high magnification, showing thickened basement membranes with spikes.

• Renal biopsy is central when the cause is not otherwise clear or when the result changes management. Biopsy can be replaced or preceded by serology or genetic testing in classic cases: anti-PLA2R positivity in membranous nephropathy, genetic testing in steroid-resistant childhood disease, and familial focal segmental glomerulosclerosis.^[1]
• Electron microscopy and immunofluorescence are essential: minimal change disease looks normal on light microscopy, and subepithelial spikes or foot process effacement become meaningful only alongside the other two layers.

There is no single numerical diagnostic criterion beyond the proteinuria threshold. Severity and prognosis are described by proteinuria level and trajectory, serum albumin, blood pressure, filtration and its change over time, extent of crescents, and proteinuria after 3 to 6 months of treatment. In membranous nephropathy proteinuria above 0.75 to 1 g per day persisting after 90 days of good supportive care, or proteinuria rising quickly with falling filtration, moves a patient into a higher risk tier. In diabetic nephropathy proteinuria with falling filtration predicts progression. ^[1]

Every patient needs meticulous supportive care, and selected patients additionally need immunosuppression directed at the cause found on biopsy or serology. Two cautions follow from KDIGO's approach: do not start immunosuppression before obvious infection and secondary causes have been excluded, and tailor supportive therapy to the histology. Statins and renin-angiotensin blockade, for example, are not recommended in steroid-responsive minimal change disease.^[1]

• Salt restriction: less than 2 g per day (under 90 mmol sodium) along with loop diuretics for overload. ^[1]
• Volume and diuretics: start with a loop diuretic; add a thiazide or potassium-sparing agent where resistance develops; monitor creatinine and electrolytes.
• Blood pressure: renin-angiotensin-aldosterone blockade with an ACE inhibitor or ARB, plus other agents, with a target systolic value under 120 mmHg where tolerated. In nephrotic syndrome these agents also reduce proteinuria, so stricter proteinuria targets below 0.5 to 1 g per day are commonly pursued.^[1]
• Protein and nutrition: moderate dietary protein intake, around 0.8 g per kg per day (sources allow up to about 1.9), preferably plant based, avoiding very high protein intakes; sodium as above.^[1]
• Lipids: statins in patients with high cardiovascular risk, such as those with diabetes or hypertension; for younger patients with a likely short disease course (steroid-sensitive minimal change disease) and no other risk factors, deferring statins is reasonable.^[1][2]
• Anticoagulation: consider prophylactic anticoagulation based on histological cause, degree of proteinuria and serum albumin. The commonly used serum albumin threshold is below 2.0 to 2.5 g per dL depending on the assay: with bromocresol purple an albumin below 20 g per L, and with bromocresol green an albumin below 25 g per L, is commonly used to decide on anticoagulation. Heparin or heparin derivatives and warfarin are preferred; direct-acting oral anticoagulants have limited data in this setting. Bleeding risk should be assessed with a validated risk score. Where thrombotic risk is moderate and bleeding risk high, aspirin alone is a reasonable alternative.^[1][2]
• Vaccination and infection prevention: pneumococcal and influenza vaccines, screening for tuberculosis, syphilis, hepatitis and HIV, and Pneumocystis prophylaxis in patients on high-dose corticosteroids or other immunosuppressants.^[1]
• Pregnancy: renin-angiotensin inhibitors and mycophenolate must be avoided; multidisciplinary management with a blood pressure target below 140 over 90 mmHg; low-dose aspirin, calcium and vitamin D where indicated; prophylactic heparin considered where thrombotic risk is high.^[1]

Steroids remain first line, at standard induction dose, continued daily until proteinuria clears and then tapered. In adults the updated KDIGO advice is to taper glucocorticoids 2 weeks after complete remission rather than the 4 weeks recommended previously.^[1] Most children respond promptly. Frequently relapsing or steroid-dependent disease calls for a steroid-sparing agent: calcineurin inhibitors (ciclosporin or tacrolimus, with tacrolimus increasingly preferred), mycophenolate mofetil, levamisole, or rituximab as a second-line agent. Cyclophosphamide is used less routinely than formerly.^[1]

First determine whether the disease is primary or secondary: secondary forms (obesity, reduced renal mass, reflux, sickle cell disease, HIV, drugs) are treated by addressing the cause. Primary disease is treated with glucocorticoids; steroid-resistant or relapsing primary disease uses calcineurin inhibitors as the preferred steroid-sparing agent. Genetic testing with a targeted next-generation sequencing panel is available in many settings and may precede biopsy in familial cases. Resistant genetic disease is managed supportively.^[1]

All patients, regardless of planned immunosuppression, receive the full non-immunosuppressive package: blood pressure control, renin-angiotensin blockade, salt restriction, moderated protein intake, SGLT2 inhibition, smoking cessation, weight control and exercise. Spontaneous remission occurs in a meaningful minority, so if proteinuria is stable and filtration preserved, treatment can be delayed for 3 to 6 months except in very high-risk patients. Rituximab is the first immunosuppressive agent of choice except for very high-risk disease, which receives cyclophosphamide with glucocorticoids. Calcineurin inhibitors are an alternative, and immunosuppression is titrated using anti-PLA2R titres where the test is positive.^[1][3]

Supportive care alone for patients with sub-nephrotic proteinuria or severely reduced filtration. A limited course of glucocorticoids or calcineurin inhibitors is indicated for immune-complex mediated disease with nephrotic syndrome and near-normal creatinine. High-dose corticosteroids with cyclophosphamide for rapidly progressive crescentic disease. C3 glomerulopathy with proteinuria above 1 g per day, haematuria or declining function is treated with mycophenolate and glucocorticoids for at least 6 months, with eculizumab or newer complement inhibitors for refractory disease.^[1]

Induction therapy combines glucocorticoids with mycophenolate mofetil or cyclophosphamide, followed by maintenance with mycophenolate or azathioprine, plus hydroxychloroquine for the systemic disease. Belimumab and voclosporin are available in some regions. Class matters: mesangial disease needs little or no immunosuppression; focal or diffuse proliferative disease needs induction; membranous class V is treated according to proteinuria; sclerotic class VI is beyond reversal.

Post-streptococcal and other infection-related nephritic disease is treated with antibiotics and management of the infection; immunosuppression is unproven even with crescents. Hepatitis C-associated cryoglobulinaemia with nephrotic syndrome is treated with direct-acting antivirals plus immunosuppression with or without plasma exchange for a flare, nephrotic syndrome or rapidly progressive failure, with rituximab for refractory disease. Do not start immunosuppression before screening for hepatitis B, hepatitis C, HIV, tuberculosis or strongyloides where relevant.^[1]

Refer promptly to nephrology when the cause is unclear, biopsy is likely, the patient is a child, proteinuria is rapidly worsening, thrombosis or acute renal failure appears, or a second agent beyond initial steroids is being considered. Refer urgently for membranous nephropathy with rapidly declining renal function and for suspected crescentic or rapidly progressive glomerulonephritis.

• Thrombosis is the hallmark danger: renal vein thrombosis, deep vein thrombosis, pulmonary embolism and arterial thrombosis including stroke and myocardial infarction. Venous thromboembolism risk in nephrotic syndrome can reach 10 to 40% in the first months after diagnosis in high-risk groups; membranous nephropathy carries up to an eight-fold higher rate of arterial thromboembolism than the general population, and cumulative 6-month incidence of around 10% for venous and 5% for arterial events has been reported.^[2]
• Infection, partly from urinary immunoglobulin loss and partly from immunosuppression: peritonitis (especially in children), cellulitis of oedematous skin, pneumococcal sepsis. Pneumococcal and influenza vaccination are sensible.
• Acute kidney injury from hypovolaemia during aggressive diuresis, interstitial nephritis from a drug, or crescentic transformation.
• Hyperlipidaemia itself, which is atherogenic and contributes to the hypercoagulable state.
• Protein malnutrition from urinary protein loss and restricted intake.
• Progressive chronic kidney disease if the underlying disease is uncontrolled.
• Treatment toxicity: infections (Pneumocystis with immunosuppression), steroid-related diabetes and osteoporosis, cyclophosphamide-related infertility and bladder toxicity, calcineurin inhibitor nephrotoxicity, rituximab-related infusion reactions.

Prognosis depends on cause, on speed of remission of proteinuria and on chronic scarring at biopsy.

• Minimal change disease in children has an excellent long-term renal prognosis; relapses are common but usually remain steroid-sensitive and most grow out of them.
• Focal segmental glomerulosclerosis progresses to kidney failure in the majority if untreated, with better outcome when proteinuria remits.
• Membranous nephropathy is variable: roughly one third remit spontaneously, one third remain nephrotic, one third progress toward renal failure over 10 years; long-term renal survival is better in patients who achieve remission.^[3]
• Diabetic nephropathy progresses but can be slowed substantially by good glycaemic control, blood pressure control and renin-angiotensin blockade.
• Amyloidosis prognosis is linked mainly to cardiac involvement and to control of the clone or inflammatory process.
• Lupus nephritis follows the course of the underlying disease.

The most useful intermediate target across all causes is reduction of proteinuria, followed by protection of kidney function and control of blood pressure, lipids and thrombotic risk.

Much of nephrotic syndrome cannot be prevented because it is immunological. Sensible measures include strict glycaemic control in diabetes, early treatment of hepatitis B and C, recognition and treatment of lupus, avoidance of drugs known to produce podocyte injury where safe alternatives exist, and genetic counselling where a monogenic podocytopathy is found.

Minimal change disease is the rule: it makes up the large majority of idiopathic childhood nephrotic syndrome. Steroids are therefore given empirically, and children are usually biopsied only when steroid-resistant, of unusual age, or with haematuria or renal impairment at presentation, or after an adequate steroid course without remission. Genetic causes are materially more common in steroid-resistant childhood disease. Sick-day steroids for upper respiratory infection are no longer recommended except for children already on low-dose alternate-day steroids with infection-associated relapse. Tacrolimus is preferred over ciclosporin in most Australasian centres; rituximab is increasingly used as the second-line steroid-sparing agent.^[1]

Children with infection-associated relapses need prompt recognition. A child with ascites and severe oedema can still be intravascularly depleted, so diuresis must be judicious.

Pregnancy in a woman with nephrotic syndrome, or nephrotic-range proteinuria developing in pregnancy, needs multidisciplinary nephrology and obstetric care. Renin-angiotensin inhibitors and mycophenolate must be stopped or not started. Blood pressure targeted below 140 over 90 mmHg. Low-dose aspirin, calcium and vitamin D commonly used. Prophylactic heparin or derivatives considered where thrombotic risk is high, which includes nephrotic syndrome and prior venous thromboembolism. Cyclophosphamide carries a real risk of permanent infertility and should be reserved for threats to organ function. Early pre-eclampsia must be excluded as a cause of new proteinuria in pregnancy.^[1]

Much of nephrotic syndrome can be diagnosed and managed well with modest resources:

• Confirm heavy proteinuria with dipstick and a spot or timed protein to creatinine ratio; microscopy of the sediment distinguishes glomerular from lower-tract disease.
• Measure serum albumin, creatinine and, where available, lipids. Renal ultrasound is highly useful for excluding obstruction and judging chronicity.
• Control oedema with oral loop diuretics and salt restriction, titrating carefully to avoid acute renal failure from over-diuresis.
• Where membranous nephropathy is suspected, PLA2R testing may be unavailable; management then rests on clinical assessment and histology.
• Restrict protein only modestly (around 0.8 g per kg per day, with some sources allowing more, preferably plant-based) and aim for adequate calories and micronutrients; nephrotic patients are at real risk of protein malnutrition.
• Use renin-angiotensin blockade where proteinuria is persistent, monitoring creatinine and potassium; treat hyperkalaemia seriously.
• Choose immunosuppression available locally and affordable: prednisolone is cheap and effective for minimal change disease.
• Screen and treat infection aggressively: peritonitis in a nephrotic child is an emergency; pneumococcal vaccination and Pneumocystis prophylaxis during high-dose steroids are proportionate.
• Where dialysis is scarce, the emphasis is on preventing progression with good blood pressure control and treating dangerous hyperkalaemia, acidosis and pulmonary oedema with whatever exists, including peritoneal dialysis if it is the only option.
• Where biopsy and immunosuppression are not possible, patients with heavy proteinuria, oedema and hypoalbuminaemia still benefit from meticulous supportive care and referral for definitive diagnosis.

• Nephrotic syndrome: proteinuria above 3.5 g per day (or protein to creatinine ratio above 300 to 350 mg per mmol), hypoalbuminaemia, oedema, hyperlipidaemia and lipiduria.
• The filtration barrier, not the tubule, is the problem.
• Each feature can be reasoned from its mechanism.
• Minimal change disease dominates childhood disease and is steroid-sensitive; membranous nephropathy and focal segmental glomerulosclerosis dominate adult primary disease.
• Cause is determined by biopsy (light, IF, EM) and serology; anti-PLA2R identifies most primary membranous nephropathy and its titres guide treatment.
• Supportive care is the backbone: salt restriction below 2 g per day, loop diuretics, ACE inhibitor or ARB for persistent proteinuria, systolic blood pressure under 120 mmHg where tolerated, statin where risk is high, and prophylactic anticoagulation when albumin falls to between 2.0 and 2.5 g per dL with an assay-aware threshold.
• Immunosuppression is cause-directed.
• The two great dangers are thrombosis and infection; renal vein thrombosis is the signature thrombotic complication.
• Children differ from adults in cause, in approach, in steroid sensitivity and in prognosis.
• Lowering proteinuria is the best single intermediate surrogate for good long-term renal outcome.

Nephritic syndrome and glomerulonephritis; Acute kidney injury; Chronic kidney disease; Hypertension; Systemic lupus erythematosus; IgA (Berger) nephropathy; ANCA-associated vasculitis; Alport syndrome; Complement; Diabetic kidney disease; Hyperlipidaemia; Venous thromboembolism. (Plain-text names only; not all yet have MedGrasp topics.)