Nephrotic syndrome and its complications

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Nephrotic syndrome is a clinical pattern rather than a histological diagnosis. In adults, nephrotic-range proteinuria is conventionally around 3.5 g per 24 hours or a protein:creatinine ratio near 350 mg/mmol, accompanied by low serum albumin and oedema. Thresholds are approximate because creatinine excretion varies and acute illness changes albumin independently. The task is to confirm glomerular protein loss, assess physiological harm, and establish the underlying disease rather than treating the numerical threshold alone.

Oedema develops through interacting mechanisms: reduced plasma oncotic pressure, renal sodium retention and altered capillary dynamics. Some people are intravascularly depleted while others are genuinely volume-expanded. Examination therefore includes postural symptoms, jugular venous pressure, lung signs, perfusion, blood pressure and weight trend. Rapid diuresis can precipitate AKI and thrombosis; inadequate treatment can leave disabling anasarca, effusions and skin breakdown.

Complication prevention is integral to disease treatment. Thrombotic risk varies markedly and may manifest as deep-vein thrombosis, pulmonary embolism or renal-vein thrombosis. Infection risk is amplified by urinary immune-protein loss and by any subsequent immunosuppression. Dyslipidaemia, vitamin-D-binding-protein loss, altered thyroid tests, malnutrition, medicine protein-binding changes and progressive CKD require longitudinal review rather than a one-off diagnostic encounter.

Key points

Adult nephrotic syndrome combines heavy glomerular protein loss, hypoalbuminaemia and oedema; hyperlipidaemia and lipiduria are supportive consequences rather than essential diagnostic criteria.
Quantify urine protein with a laboratory protein:creatinine ratio because albumin-only measurement can underestimate non-albumin proteins and a dipstick is concentration-dependent.
Primary causes include minimal change disease, focal segmental glomerulosclerosis and membranous nephropathy; diabetes, lupus, amyloid, infection, medicines and malignancy are important secondary causes.
Generalised oedema does not prove intravascular excess: low oncotic pressure, diuretics, diarrhoea and sepsis can leave a visibly oedematous patient hypotensive and kidney under-perfused.
Urinary antithrombin loss, increased hepatic procoagulant synthesis and immobility produce substantial venous thromboembolism risk, especially with profound hypoalbuminaemia and membranous nephropathy.
Fever, abdominal pain or subtle deterioration may represent serious infection because immunoglobulin and complement losses, oedematous tissue and immunosuppression impair defence.
Acute kidney injury may reflect hypovolaemia, sepsis, interstitial oedema, renal-vein thrombosis, drug toxicity or the underlying glomerular lesion; do not label every creatinine rise as disease progression.
Salt restriction and carefully titrated loop diuresis treat symptomatic oedema, but daily weights, blood pressure, creatinine and electrolytes must guide the pace of fluid removal.
ACE inhibition or ARB therapy can reduce proteinuria after haemodynamic stability is established; never combine the two, and review potassium and kidney function after initiation or titration.
Prophylactic anticoagulation is not automatic: nephrology weighs albumin, histology, bleeding risk, mobility, previous thrombosis and anticipated biopsy or procedures.
Kidney biopsy usually defines non-diabetic adult disease, but the indication and timing depend on phenotype, diabetes history, serology, bleeding risk and whether histology will alter treatment.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Primary podocyte and capillary-wall disease

Minimal change disease, primary FSGS and membranous nephropathy directly disrupt the glomerular filtration barrier and are important adult biopsy diagnoses.

Metabolic and autoimmune disease

Diabetes and lupus cause glomerular injury through metabolic, haemodynamic or immune-complex mechanisms and may present with heavy albumin loss.

Depositional and monoclonal disease

Amyloid and other monoclonal immunoglobulin lesions alter glomerular structure, sometimes with a bland sediment despite profound proteinuria.

Infection, medicine or malignancy association

Chronic infection, selected medicines and malignancy can cause secondary podocyte or immune-complex disease, making exposure and systemic review essential.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Filtration-barrier failure
Podocyte, basement-membrane or immune injury increases glomerular permeability and permits sustained urinary loss of albumin and other plasma proteins.
2
Hypoalbuminaemia and oedema
Falling plasma oncotic pressure shifts fluid into interstitial tissue, while renal sodium retention expands total body water and sustains generalised swelling.
3
Prothrombotic rebalancing
Urinary antithrombin loss, increased hepatic procoagulant synthesis and immobility combine to increase venous thromboembolism risk substantially.
4
Immune and metabolic effects
Immunoglobulin and complement loss impairs defence, while hepatic lipoprotein synthesis produces hyperlipidaemia in response to low oncotic pressure.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Nephrotic phenotype

Dependent oedema progressing to anasarca, frothy urine, weight gain, heavy laboratory proteinuria and a low albumin strongly support the syndrome, although each feature has alternative causes.

Possible pulmonary embolismRed flag

Sudden dyspnoea, pleuritic pain, syncope, tachycardia, hypoxaemia or asymmetric leg swelling is not explained away by nephrotic oedema and requires an urgent VTE pathway.

Renal-vein thrombosisRed flag

Flank pain, macroscopic haematuria, abrupt kidney dysfunction or unexplained worsening proteinuria can signal renal-vein thrombosis, but presentation may be silent and imaging choice depends on kidney function.

Intravascular depletion

Postural dizziness, cool peripheries, tachycardia, low blood pressure, rising creatinine and poor urine output despite impressive oedema suggest underfilling or excessive diuresis.

Serious infectionRed flag

Fever, abdominal tenderness, cellulitis, cough, confusion or an unexplained fall in blood pressure may indicate bacterial infection and warrants cultures and prompt sepsis assessment.

Secondary-disease clues

Diabetes complications, inflammatory symptoms, rash, arthralgia, neuropathy, chronic infection, weight loss, a culprit medicine or monoclonal-protein features redirect the aetiological work-up.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Urine PCR, ACR and urinalysisFirst step
Why
Confirm and characterise glomerular protein loss while looking for haematuria or infection.
Interpretation and limitations
PCR better captures total protein in a nephrotic presentation; active sediment suggests an inflammatory lesion, while bland urine does not distinguish minimal change, membranous disease or FSGS.
02
Creatinine, electrolytes, albumin and liver profile
Why
Grade kidney injury, biochemical consequences and competing causes of hypoalbuminaemia.
Interpretation and limitations
Trend creatinine and potassium around diuresis or renin–angiotensin blockade; liver disease and systemic inflammation can lower albumin without accounting for heavy urinary loss.
03
Full blood count, CRP, glucose and lipid profile
Why
Find infection, diabetes, anaemia and the metabolic response to sustained protein loss.
Interpretation and limitations
Marked cholesterol elevation is typical but does not establish cause; CRP may reveal infection that must be treated before immunosuppression.
04
Cause-directed immune and infection screen
Why
Assess ANA, dsDNA, complement, hepatitis B and C, HIV and other tests selected from the history.
Interpretation and limitations
Testing should be targeted and interpreted with pre-test probability; a positive antibody is not a substitute for compatible clinical and biopsy findings.
05
Serum and urine monoclonal-protein assessment
Why
Detect paraprotein-related glomerular disease or amyloid in an appropriate adult phenotype.
Interpretation and limitations
Use immunofixation and serum free light chains with kidney-adjusted interpretation; a small clone can still cause major renal disease.
06
Renal ultrasound
Why
Review kidney size, chronicity clues, obstruction and anatomy before possible biopsy.
Interpretation and limitations
Normal-sized kidneys do not identify the lesion, while small scarred kidneys may alter biopsy benefit and increase procedural concern.
07
Native kidney biopsy
Why
Establish histological diagnosis and guide disease-specific treatment in selected adults.
Interpretation and limitations
Light microscopy, immunofluorescence and electron microscopy are integrated; correct blood pressure and bleeding risk and plan anticoagulant interruption with specialists.
08
Urgent VTE imaging when indicated
Why
Confirm pulmonary, limb or renal venous thrombosis rather than relying on D-dimer alone.
Interpretation and limitations
Nephrotic inflammation and admission can raise D-dimer; select ultrasound, CTPA or alternative imaging using the clinical pathway and renal function.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Heart failure

Raised jugular venous pressure, cardiac imaging abnormalities and pulmonary congestion support cardiac oedema, whereas heavy proteinuria and hypoalbuminaemia identify a nephrotic contribution.

Cirrhosis and portal hypertension

Liver synthetic dysfunction, portal features and ascites with little proteinuria favour hepatic fluid retention, though cirrhosis and renal disease may coexist.

Protein-losing enteropathy

Gastrointestinal protein loss causes hypoalbuminaemic oedema without substantial urinary protein and is supported by bowel disease or specialised stool testing.

Nephritic syndrome

Glomerular haematuria, red-cell casts, severe hypertension and a rapidly falling eGFR indicate inflammatory nephritis, although some diseases produce mixed nephritic–nephrotic features.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01First presentationConfirm, stabilise and find the causeFirst stepHeavy proteinuria with hypoalbuminaemia, oedema or an otherwise convincing nephrotic presentation.

1Assess ABCDE, perfusion and true fluid state; look actively for sepsis, VTE, pulmonary oedema, oliguria and other reasons for immediate admission.
2Quantify total urine protein, establish kidney-function and albumin trends, review systemic disease, infection, malignancy and medicine exposures, and send focused secondary-cause tests.
3Discuss early with nephrology for biopsy planning, complication-risk assessment and disease-specific treatment; avoid empirical glucocorticoids in an undiagnosed adult unless a specialist directs them.

02OedemaRemove sodium and fluid safelyOedema causes breathlessness, impaired mobility, skin compromise or substantial discomfort.

1Set an individual salt and fluid plan, record baseline weight, lying and standing blood pressure, creatinine, sodium and potassium, and identify intravascular depletion.
2Use a loop diuretic regimen chosen by the responsible clinician; severe resistant oedema may need specialist combination diuresis or intravenous treatment with close observation.
3Review weight, urine output, symptoms, perfusion and biochemistry frequently, slowing or withholding therapy if hypotension, cramps, hyponatraemia, hypokalaemia or AKI develops.

03Thrombosis riskSeparate prophylaxis from treatmentProfound hypoalbuminaemia, membranous histology, reduced mobility, previous VTE or symptoms suggest clotting risk.

1Investigate suspected VTE urgently and start therapeutic anticoagulation through the local pathway when clinical probability and bleeding risk justify it.
2For an asymptomatic patient, ask nephrology to balance serum albumin, histology, additional thrombotic factors, bleeding risk and planned kidney biopsy before prophylaxis.
3Reassess the anticoagulation decision as albumin and proteinuria improve, mobility changes or procedures arise; document indication, renal dosing and intended duration.

04InfectionTreat infection before escalationEscalationFever, focal symptoms, haemodynamic change or deterioration occurs in active nephrosis or during immunosuppression.

1Obtain appropriate blood, urine and focal cultures without delaying time-critical antibiotics, and use the local sepsis pathway when high-risk features are present.
2Review immunosuppressive medicines with nephrology rather than stopping them indiscriminately, and adjust antimicrobial doses to current kidney function.
3After recovery, review vaccination, prophylaxis if immunosuppression is planned, skin and dental sources, and education about seeking care early for future infection.

Key medicines and prescribing safety4 treatments · regimens, roles and cautions

Relieves symptomatic oedema by increasing renal sodium excretion when adequate circulating volume is present.

Loop diuretic

Dose and route are individualised to congestion, kidney function and prior exposure; follow the local renal prescription.

Excess treatment causes hypotension, electrolyte loss, ototoxicity at high intravenous exposure and prerenal AKI; daily reassessment is essential.

Reduces intraglomerular pressure, blood pressure and proteinuria and may slow chronic kidney damage.

ACE inhibitor or ARB

Start one agent at a low licensed dose after stabilisation, then titrate with specialist-agreed biochemical checks.

Do not combine classes; pause or review during hypovolaemia, severe AKI or hyperkalaemia, and address pregnancy potential before prescribing.

Treats confirmed thrombosis or prevents it in carefully selected very-high-risk nephrotic patients.

Anticoagulant when indicated

Use the local VTE treatment or specialist prophylaxis regimen adjusted for weight, eGFR, interactions and procedures.

Bleeding, altered pharmacokinetics, severe kidney impairment and an imminent biopsy can change drug choice, dose and timing; obtain specialist advice.

Addresses cardiovascular risk when persistent dyslipidaemia and the person's overall prevention profile justify therapy.

Statin

Use the NICE CKD or cardiovascular-prevention intensity after interaction, liver and pregnancy review.

Nephrosis-driven cholesterol may improve with remission; check interactions with immunosuppressants and investigate unexplained muscle symptoms.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Venous thromboembolism

Deep-vein, pulmonary and renal-vein thrombosis may develop through the procoagulant nephrotic state, particularly with profound hypoalbuminaemia and membranous disease.

Serious infection

Loss of immunoglobulin and complement, oedematous tissue and immunosuppression predispose to bacterial and opportunistic infection with potentially muted signs.

Acute kidney injury

Low effective circulating volume, sepsis, renal-vein thrombosis, interstitial oedema, drug toxicity or the underlying lesion can abruptly reduce filtration.

Severe fluid accumulation

Anasarca, ascites and pleural effusions can impair breathing, skin integrity and mobility, while aggressive diuresis may worsen intravascular underfilling.

Malnutrition and cardiovascular burden

Ongoing protein loss and restrictive intake reduce nutritional reserve, while marked dyslipidaemia and hypertension add longer-term vascular risk.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Track morning weight, oedema distribution, breathlessness, blood pressure and postural symptoms during active fluid removal rather than using appearance alone.
Repeat creatinine, sodium, potassium and bicarbonate after diuretic or renin–angiotensin-system changes and sooner if urine output or perfusion worsens.
Trend urine PCR, serum albumin and eGFR using comparable samples; clinical remission requires more than one improved dipstick.
At every contact screen for VTE symptoms, infection, skin breakdown, functional decline and medicine toxicity, with a low threshold for urgent review.
During immunosuppression follow the chosen regimen's blood-count, liver, infection, vaccination, bone and reproductive-safety plan through the specialist service.
Revisit cardiovascular risk, nutrition and vaccination once the acute oedema settles because chronic nephrosis changes long-term prevention priorities.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Underfill and overfill coexist

The same patient can have extensive interstitial oedema but poor effective arterial volume; jugular venous pressure, perfusion and response trends matter more than ankle size.

Albumin affects medicines

Severe hypoalbuminaemia changes protein binding and distribution, while urinary protein loss may alter exposure; use renal pharmacy support for narrow-therapeutic-index drugs.

Histology changes clot risk

Membranous nephropathy carries particularly high VTE risk, so an identical albumin concentration can lead to a different prophylaxis discussion than another lesion.

Albumin infusion is exceptional

Intravenous albumin does not repair the glomerular leak and its effect may be brief; reserve any diuretic-coupled use for specialist-selected resistant oedema with close monitoring.

Protein replacement is not unlimited

Very high-protein diets can intensify glomerular protein traffic and do not simply correct urinary loss; dietetic advice should preserve nutrition without excessive intake.

Remission changes every risk

As proteinuria falls and albumin rises, diuretic requirements, clot risk, lipid abnormalities and medicine pharmacology can change quickly, requiring active de-escalation.

11Common pitfallsFrequent interpretation and management errors.

01
Calling isolated oedema nephrotic syndrome before quantifying urine protein and checking serum albumin.
02
Giving large diuretic increments to an intravascularly depleted patient without weight, perfusion or biochemical review.
03
Assuming bilateral leg oedema makes pulmonary embolism or deep-vein thrombosis unlikely.
04
Starting prophylactic anticoagulation without considering kidney biopsy, bleeding risk, histology and severe renal impairment.
05
Treating an undiagnosed adult with glucocorticoids before excluding infection and obtaining nephrology advice.
06
Using a negative urine dipstick to exclude non-albumin protein or a single positive dipstick to quantify severity.